Chronic myelogenous leukemia (CML) is usually diagnosed in the chronic phase. Untreated chronic phase CML will eventually progress to advanced phase (accelerated or blast phase) CML. Tyrosine kinase inhibitors (TKIs) have been shown to induce favorable response rates in patients with accelerated and blast phase CML. The addition of TKIs to chemotherapy has also been associated with improved outcomes in patients with blast phase CML. Allogeneic hematopoietic stem cell transplant remains a potentially curative option for patients with advanced phase CML, although treatment with a course of TKIs will be beneficial as a bridge to transplant. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with advanced phase CML.

Abstract

Chronic myelogenous leukemia (CML) is usually diagnosed in the chronic phase. Untreated chronic phase CML will eventually progress to advanced phase (accelerated or blast phase) CML. Tyrosine kinase inhibitors (TKIs) have been shown to induce favorable response rates in patients with accelerated and blast phase CML. The addition of TKIs to chemotherapy has also been associated with improved outcomes in patients with blast phase CML. Allogeneic hematopoietic stem cell transplant remains a potentially curative option for patients with advanced phase CML, although treatment with a course of TKIs will be beneficial as a bridge to transplant. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with advanced phase CML.

NCCN Categories of Evidence and Consensus

Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.

Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.

All recommendations are category 2A unless otherwise noted.

Clinical trials: NCCN believes that the best management for any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

Overview

Chronic myelogenous leukemia (CML) accounts for 15% of adult leukemias. The median age at disease onset is 67 years; however, SEER statistics show that CML occurs in all age groups.1 In 2014, an estimated 5980 people will be diagnosed with CML in the United States, and 810 people will die from the disease.2

CML is characterized by the presence of Philadelphia chromosome (Ph) resulting from a reciprocal translocation between chromosomes 9 and 22 [t(9;22)]. This translocation, t(9;22), results in the head-to-tail fusion of the breakpoint cluster region (BCR) gene on chromosome 22 at band q11 and the Abelson murine leukemia (ABL1) gene located on chromosome 9 at band q34.3 The product of the BCR-ABL1 fusion gene, p210, which is a fusion protein with deregulated tyrosine kinase activity, plays a central role in the pathogenesis of CML. Another fusion protein, p190, is also produced, usually in the setting of Ph+ acute lymphoblastic leukemia (ALL). p190 is detected in only 1% of all patients with CML.4

CML occurs in 3 different phases (chronic, accelerated, and blast phase) and is usually diagnosed in the chronic phase. Untreated chronic phase CML (CP-CML) will eventually progress to advanced phase in 3 to 5 years.5 Gene expression profiling has shown a close correlation of gene expression between accelerated phase CML (AP-CML) and blast phase CML (BP-CML). The bulk of the genetic changes in progression occur in the transition from CP-CML to AP-CML.6 The activation of the β-catenin signaling pathway in CML granulocyte-macrophage progenitors (which enhances the self-renewal activity and leukemic potential of these cells) may also be a key pathobiologic event in the evolution to BP-CML.7

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for CML discuss the clinical management of CML in all 3 phases (chronic, accelerated, and blast phase). This manuscript discusses the management of advanced phase CML.

Advanced Phase CML

Accelerated Phase

Varying definitions have been used for AP-CML (see CML-K, page 1597).813 The most commonly used

F1NCCN Clinical Practice Guidelines in Oncology: Chronic Myelogenous Leukemia, Version 1.2015

Version 1.2015, 08-28-14 ©2014 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 12, 11; 10.6004/jnccn.2014.0159

F2NCCN Clinical Practice Guidelines in Oncology: Chronic Myelogenous Leukemia, Version 1.2015

Version 1.2015, 08-28-14 ©2014 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 12, 11; 10.6004/jnccn.2014.0159

F3NCCN Clinical Practice Guidelines in Oncology: Chronic Myelogenous Leukemia, Version 1.2015

Version 1.2015, 08-28-14 ©2014 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 12, 11; 10.6004/jnccn.2014.0159

definition is the WHO criteria, which defines accelerated phase as the presence of any of the following features: 10% to 19% of blasts in the peripheral blood or bone marrow, 20% or more of basophils in the peripheral blood, persistent thrombocytopenia (<100 × 109/L) unrelated to therapy or persistent thrombocytosis (>1000 × 109/L) unresponsive to therapy, increasing spleen size, and increasing WBC count unresponsive to therapy.13 Cortes et al12 suggested a modification to the WHO criteria (≥10%-29% peripheral blood or bone marrow blasts, ≥30% or more peripheral blood blasts and promyelocytes, ≥20% peripheral blood or bone marrow basophils, platelet count ≤100 × 109/L unrelated to therapy, and clonal evolution). It should be noted that clinical trials of tyrosine kinase inhibitors (TKIs) have largely reported efficacy data using the modified MD Anderson Cancer Center accelerated phase criteria (15% and <30% peripheral blood or bone marrow blasts, ≥30% or more peripheral blood blasts and promyelocytes, ≥20% peripheral blood or bone marrow basophils, platelet count ≤100 × 109/L unrelated to therapy, and clonal evolution).11

Blast Phase

Approximately 50% of all the blast phase cases are of the myeloid subtype, 25% are of the lymphoid subtype, and the remainder are undifferentiated. According to the International Bone Marrow Transplant Registry (IBMTR), blast crisis is defined as 30% or greater blasts in the blood, bone marrow, or both, or as the presence of extramedullary disease (see CML-L, page 1597).14 The WHO criteria defines blast crisis as 20% or greater blast cells in the peripheral blood or bone marrow, the presence of extramedullary blast proliferation, and large foci or clusters of blasts in the bone marrow biopsy (see CML-L, page 1597).13

Workup

Initial evaluation of patients should include a history and physical (H&P), including palpation of the spleen, CBC with differential, chemistry profile, bone marrow aspirate, and biopsy (see CML-1; page 1592).

Bone marrow cytogenetics and measurement of BCR-ABL1 transcript levels using quantitative reverse transcriptase-polymerase chain reaction (qPCR) is recommended before initiation of treatment and for monitoring response to therapy.15 Bone marrow cytogenetics not only provides morphologic review but also detects chromosomal abnormalities other than the Ph chromosome that are not detectable using peripheral blood. BCR-ABL1 transcripts in the peripheral blood at very low levels (1-10 per 108 peripheral blood leukocytes) can also be detected in approximately 30% of normal individuals.16,17 In addition, the incidence of BCR-ABL1 transcripts in healthy individuals has also been shown to increase with advancing age.16 TKI therapy would not be warranted, because most of these individuals would not develop CML.

The guidelines emphasize that conventional bone marrow cytogenetics should be performed to confirm the diagnosis of Ph+ CML at initial workup. If the collection of bone marrow is not feasible, fluorescence in situ hybridization (FISH) on a peripheral blood specimen with dual probes for BCR and ABL1 genes is an acceptable method to confirm the diagnosis of CML.

The guidelines recommend determination of risk score and HLA antigen testing as part of initial workup (see CML-1, page 1592). The 2 prognostic scoring systems by Sokal et al18 and Hasford et al19 can be used to risk stratify patients with CML (see CML-B, page 1596). Both of these scoring systems stratify patients into 3 risk groups (low, intermediate, and high) and have been used in clinical trials evaluating TKIs. The Sokal score is based on the patient’s age, spleen size, platelet count, and percentage of blasts in the peripheral blood.18 The Hasford model includes eosinophils and basophils in the peripheral blood in addition to the same clinical variables used in the Sokal model.19

Patients with BCR-ABL1-positive CML (using bone marrow cytogenetics, FISH, or qPCR) are the focus of the NCCN Guidelines for CML. Patients who are BCR-ABL1-negative do not have CML. Patients who clearly do not have a myeloproliferative neoplasm (MPN; polycythemia vera, essential thrombocythemia, and primary myelofibrosis), have clinical features suggestive of CML, but do not have BCR-ABL1 may have a so-called Ph-negative or atypical CML, and have a significantly worse prognosis than those with BCR-ABL1-positive CML.20

In ambiguous cases of BCR-ABL1-negative MPNs, further mutational analysis may help document clonality and define the entity. For example, mutations involving multiple genes, such as JAK2, MPL, CALR, TET2, ASXL1, CBL, EZH2, IDH, DN-MT3A, LNK, RAS, and IKZF1, have been described in BCR-ABL1-negative MPNs.2127 More recently, activating mutations in the CSF3R and SETBP1 genes have been identified in chronic neutrophilic leukemia and atypical CML (Ph-negative).28,29 Abnormalities in FGFR1, PDGFRA, and PDGFRB genes have been reported in a subset of patients with atypical MPNs that are usually associated with eosinophilia.30

Treatment Options

TKI Therapy: Imatinib has induced favorable hematologic and cytogenetic response rates in patients with AP-CML or BP-CML.11,3138 Dasatinib,3841 nilotinib,38,42,43 bosutinib,44 and ponatinib45,46 have shown clinical activity in patients imatinib-resistant or imatinib-intolerant AP-CML or BP-CML.

The START-A trial evaluated the safety and efficacy of dasatinib (70 mg twice daily) in patients with AP-CML intolerant to imatinib or those with resistant disease.40,47 At 8-month follow-up (for the first 107 patients enrolled in the study), a major hematologic response (MaHR) was achieved in 64% of patients, a major cytogenetic response (MCyR) was achieved in 33%, and 76% of patients remained progression-free.47 Follow-up data from the full patient cohort of 174 patients confirmed the efficacy and safety of dasatinib in patients with AP-CML intolerant to imatinib or those with resistant disease.40 The 12-month progression-free (PFS) and overall survival (OS) rates were 66% and 82%, respectively. The efficacy of dasatinib in patients with CML in myeloid blast crisis (MBC) or lymphoid blast crisis (LBC) intolerant to imatinib or those with resistant disease was evaluated in the START-B and START-L trials, respectively.48 In patients with MBC-CML, 32% had achieved MaHR at 6-month follow-up, which increased to 34% at 8-month follow-up and was maintained at 12-month follow-up.39 MCyR was achieved in 31% of patients. In the LBC-CML group, 31% achieved MaHR at 6-month follow-up, and this rate increased to 35% at 12-month follow-up.39 After a minimum follow-up of 12 months, MCyR was achieved in 33% (MBC-CML) and 52% (LBC-CML) of patients, and complete cytogenetic response (CCyR) was achieved in 26% and 46% of patients, respectively. Median PFS and OS for patients with MBC were 6.7 and 11.8 months, respectively. In patients with LBC, the corresponding survival rates were 3.0 and 5.3 months, respectively.39 Kantarjian et al41 recently reported that once-daily dosing of dasatinib at 140 mg has similar efficacy to 70 mg twice-daily dosing, with an improved safety profile in patients with AP-CML. Recently, 2-year follow-up data from a phase III trial showed that dasatinib, 140 mg once daily demonstrates equivalent efficacy and improved safety compared with 70 mg twice daily in patients with BP-CML.49

A phase II open-label trial evaluated the safety and efficacy of nilotinib (400 mg twice daily) in patients with AP-CML (n=119).50 The efficacy end point for CP-CML was MCyR and the end point for AP-CML was MaHR. In patients with AP-CML, hematologic response was observed in 47% of patients and MCyR was observed in 29%.50 The OS rate among the 119 patients after 12 months of follow-up was 79%. Nonhematologic adverse events were mostly mild to moderate. Grade 3 or higher bilirubin and lipase elevations occurred in 9% and 18% of patients. Long-term follow-up results confirmed that nilotinib induces rapid and durable responses with a favorable risk/benefit profile in patients with AP-CML who were intolerant or resistant to prior imatinib treatment.42 Among patients with at least 24-month follow-up (n=137), a confirmed hematologic response was observed in 55% of patients and 31% had a complete hematologic response (CHR; 30% of patients with AP-CML resistant to imatinib and 37% of those intolerant to imatinib experienced a CHR). MCyR and CCyR were achieved in 32% and 20% of patients, respectively. Cytogenetic and molecular responses were also durable, with 66% of patients maintaining an MCyR at 24 months and 83% maintaining a CCyR at 12 months. The estimated PFS and OS rates at 24 months were 70% and 33%, respectively.42 Nilotinib has also been evaluated in patients with BP-CML. In a phase II study of 136 patients with MBC (n=105) and LBC (n=31), after a minimum follow-up of 24 months, an MaHR was observed in 60% and 59% of patients, respectively.43 An MCyR was achieved in 38% of patients with MBC and 52% of patients with LBC. A CCyR was seen in 30% of patients with MBC and 32% of patients with LBC. The OS rate was 42% at 12 months and 27% at 24 months. However, the responses were not durable. The duration of MCyR was 11 months for patients with MBC and 3 months for those with LBC.

The safety and efficacy of bosutinib (500 mg once daily) in patients with AP-CML or BP-CML was evaluated in a single-arm multicenter phase I-II trial. In the cohort of patients with AP-CML (n=63) and BP-CML (n=48), bosutinib induced CHR and MCyR in patients with and without BCR-ABL1 mutations.44 Among patients with AP-CML evaluable for response, CHR, MCyR, and CCyR were observed in 61% (20 of 33), 48% (13 of 27), and 33% (9 of 27) of patients, respectively. The corresponding response rates in patients with BP-CML evaluable for response were 32% (7 of 22), 52% (11 of 22), and 29% (6 of 22), respectively. Median follow-up for the entire cohort was 8.3 months.

A single-arm, multicenter, phase II trial (PACE trial) evaluated the safety and efficacy of ponatinib (45 mg once daily) in a total of 449 patients with CML intolerant to prior TKI therapy or those with resistant disease (dasatinib or nilotinib) or the T315I mutation (270 patients with CP-CML; 85 patients with AP-CML; 62 patients with BP-CML; 32 patients with Ph+ ALL).45 The primary endpoint was MaHR at any time within 6 months after initiation of treatment for patients with advanced phase CML. The median follow-up was 15 months. Among patients with AP-CML intolerant to dasatinib or nilotinib or those with resistant disease, MaHR by 6 months was observed in 57% of patients. MCyR, CCyR, and major molecular response (MMR) rates were 34%, 22%, and 14%, respectively.45 The corresponding response rates were 50%, 56%, 33%, and 22%, respectively, for patients with T315I mutation. The estimated PFS and OS rates at 12 months were 55% and 84%, respectively. Among patients with BP-CML intolerant to dasatinib or nilotinib or those with resistant disease, MaHR, MCyR, and CCyR were observed in 32%, 18%, and 16%, respectively.45 The corresponding response rates were 29%, 29%, and 21%, respectively, for patients with T315I mutation. The estimated PFS and OS rates at 12 months were 19% and 29%, respectively. Longer-term follow-up data also confirmed the activity of ponatinib in patients with AP-CML and BP-CML; the 2-year OS rates were 72% and 18%, respectively, for patients with AP-CML and BP-CML.46

TKI Therapy and Toxicity: Chronic fatigue (mostly correlated with musculoskeletal pain and muscular cramps) was identified as a major factor limiting health-related quality of life in patients with CML treated with imatinib.51 Hypophosphatemia (with associated changes in bone and mineral metabolism)52 and decrease in bone mineral density have been noted in a small group of patients, suggesting that ongoing management of patients taking imatinib should include monitoring of bone health.53 Congestive heart failure is uncommon among patients receiving imatinib, and its incidence rates are similar to those that occur in the general population. Patients with previous cardiac history should be monitored carefully. Aggressive medical therapy is recommended for symptomatic patients. Electrocardiogram should be considered for patients taking QT interval-prolonging medication.

Pleural effusion can be an adverse effect of dasatinib.54,55 Close monitoring and timely intervention are necessary for patients at risk of developing pleural effusion. Reversible pulmonary arterial hypertension has been reported as a rare but serious side effect associated with dasatinib.5661 Evaluation for signs and symptoms of underlying cardiopulmonary disease before initiating and during treatment with dasatinib is recommended. If pulmonary arterial hypertension is confirmed, dasatinib should be permanently discontinued.

QT interval prolongation is a nonhematologic adverse reaction associated with nilotinib, which could be managed with dose reduction. Nilotinib labeling contains a black box warning regarding the risk of QT interval prolongation, and sudden cardiac death has been reported in patients receiving nilotinib. Electrolyte abnormalities should be corrected before nilotinib is initiated and should be monitored periodically. Drugs that prolong QT interval should be avoided. Electrocardiogram should be obtained to monitor the QT interval at baseline, 7 days after initiation of nilotinib, and periodically thereafter, and after any dose adjustments. Nilotinib may be associated with an increased risk of vascular adverse events, including peripheral arterial occlusive disease (PAOD).6264 Patients should be evaluated for preexisting PAOD and vascular risk factors before initiation of and during nilotinib treatment. If PAOD is confirmed, nilotinib should be permanently discontinued.

Bosutinib was also associated with minimal effects on QTc interval prolongation and a low incidence of pleural effusions, muscle cramps, musculoskeletal events, and cardiac toxicities that may be seen with other TKIs.

Hepatotoxicity, liver failure, and death have been rarely reported in patients treated with ponatinib. Liver function tests should be performed at baseline and at least monthly or as clinically indicated during treatment. Dose interruption and dose reductions or discontinuation of ponatinib should be considered for hepatotoxicity. Serious arterial thrombotic events were observed in 9% of patients (cardiovascular events, 5.1%; cerebrovascular events, 2.4%; and peripheral vascular events, 2.0%) and these events were considered to be treatment-related in 3% of patients (cardiovascular, cerebrovascular, and peripheral vascular events occurred in 2.0%, 0.4%, and 0.4% of patients, respectively).45

Based on the results of the PACE trial, the FDA approved ponatinib for the treatment of patients in all 3 phases of CML who were intolerant to prior TKI therapy or those with resistant disease. However, the recent Drug Safety Communication issued by the FDA on October 31, 2013 revealed an increase in the cumulative incidence of serious arterial thrombotic events.65 Serious arterial and venous thrombosis and occlusions occurred in approximately 27% of patients: cardiovascular occlusion, cerebrovascular occlusion, and peripheral arterial occlusive events occurred in 12%, 6%, and 8% of patients, respectively. Heart failure, including fatalities, occurred in 8% of patients. These adverse events were seen in patients with and without cardiovascular risk factors (eg, history of ischemia, hypertension, diabetes, or hyperlipidemia).66

Ponatinib is now indicated only for the treatment of patients with T315I and those for whom no other TKI therapy is indicated in all 3 phases of CML. Ponatinib labeling also contains a black box warning regarding vascular occlusion, heart failure and hepatotoxicity. Patients should be monitored for evidence of thromboembolism and vascular occlusion. Ponatinib should be interrupted or stopped immediately for vascular occlusion and new or worsening heart failure.

TKI Therapy and Conception

Imatinib has been shown to be teratogenic and embryotoxic in animal studies. Some reports in literature indicate that patients who receive imatinib at the time of conception may have normal pregnancies.6774 Dasatinib and nilotinib are known to cause embryonic or fetal toxicities in animals. Isolated reports can be found in the literature regarding the outcome of pregnancy in patients receiving dasatinib7577 or nilotinib.78

Currently, not enough evidence is available to favor the continuation of TKI therapy during pregnancy. The potential benefit of TKI therapy for the mother or its potential risk to the fetus must be carefully evaluated on an individual basis before administering imatinib, dasatinib, or nilotinib to pregnant women. Men desiring conception should consider sperm cryopreservation before initiation of TKI therapy.

Chemotherapy

High-dose combination chemotherapy has been used in patients with AP-CML or BP-CML, resulting in response rates of 25% to 60%.7983 In a study of 48 patients with AP-CML or BP-CML, intensive chemotherapy induced hematologic and cytogenetic responses in 29% and 23% of patients, respectively; CHR was observed in 25% of patients with AP-CML and 33% of patients with BP-CML.79 Among patients with BP-CML, ALL-type chemotherapy regimens are associated with higher response rates in patients with lymphoid BP-CML (49% vs <20% for other morphologies; P<.001); however, the responses are not durable.80

Recent studies have shown that the addition of TKI to chemotherapy improves outcome in patients with BP-CML or Ph+ ALL.8494 The efficacy of imatinib in combination with chemotherapy in myeloid BP-CML has been demonstrated in several small studies.8789,91 In one study involving 18 patients with AP-CML and 10 patients with myeloid BP-CML, the combination of imatinib and decitabine induced CHR and MCyR in 32% and 18% of patients, respectively.87 Partial hematologic response and minor cytogenetic response was observed in 4% and 11% of patients, respectively. The hematologic response rate was higher in patients without BCR-ABL1 kinase mutations (53% vs 14% for those with mutations). The median duration of hematologic response was 18 weeks. In a pilot study of 19 patients with myeloid BP-CML, the combination of imatinib, low-dose cytarabine, and idarubicin induced CHR in 47% of patients, and 26% returned to CP-CML.88 In a more recent study of 36 patients with myeloid BP-CML, the addition of imatinib to daunorubicin and cytarabine resulted in a hematologic response rate of 78% (CHR rate of 55.5%) with a median follow-up of 6 years.91 Median OS was 16.0 months, and the OS in patients with hematologic response was 35.4 months.

The use of imatinib or dasatinib in combination with hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) has been shown to be effective for the treatment of patients with lymphoid BP-CML.93,94 In a study of 34 patients with lymphoid BP-CML or relapsed Ph+ ALL, the addition of dasatinib to hyper-CVAD resulted in an overall response rate of 91%, with 71% achieving a complete response [CR] and 21% achieving a CR with incomplete platelet recovery); 84% of patients achieved a CCyR after 1 cycle of therapy,93 and the overall CMR rate was 42% (35% achieved MMR). At a median follow-up of 37.5 months among patients with lymphoid BP-CML, the 3-year OS rate was 70%, with 68% remaining in CR at 3 years.93 The efficacy of hyper-CVAD used in combination with imatinib or dasatinib for patients with BP-CML, particularly when followed by allogeneic hematopoietic stem cell transplant (HSCT), was also confirmed in a more recent report.94 Among 42 patients with BP-CML, CHR, CCyR, and CMR were achieved in 90%, 58%, and 25% of patients, respectively. The median remission duration and median OS were 14 and 17 months, respectively. In multivariate analysis, the median remission duration was longer among HSCT recipients (P=.01), and the median OS was longer among HSCT recipients (P<.001) and patients treated with dasatinib (P=.07).94

Omacetaxine (homoharringtonine, a cephalotoxic alkaloid), a protein synthesis inhibitor, has shown activity in patients with disease progression to AP-CML or BP-CML after prior therapy with 2 or more TKIs.95,96 The results of a pooled analysis of 51 patients with AP-CML and 44 patients with BP-CML enrolled in 2 phase II studies (CML-202 and CML-203) demonstrated that omacetaxine is a feasible treatment option for patients with advanced phase CML that had failed treatment with multiple TKIs and those with a T315I mutation.96 The median follow-up was 16.0 months for patients with AP-CML and 3.5 months for patients with BP-CML. Among the 51 patients with AP-CML, MaHR, CHR, and minor cytogenetic response were achieved or maintained in 37%, 29%, and 11% of patients, respectively. The median duration of MaHR was 5.6 months.96 MaHR rates were 55% and 58%, respectively, for patients with a history of T315I mutation and for those with confirmed T315I mutation at baseline. The overall median PFS and OS were 4.8 and 17.6 months, respectively. Among patients with a history of T315I mutation, the median PFS and OS were 5.9 and 18.7 months, respectively. Among the 44 patients with BP-CML, MaHR and CHR were achieved in 9% and 7% of patients, respectively.96 The median duration of overall hematologic response was 1.7 months. The overall median PFS and OS in patients were 2.2 and 3.5 months, respectively. Among the subgroup of patients with a history of T315I mutation (n=21), the median PFS and OS were 1.9 and 3.5 months, respectively.96 The most common grade 3/4 hematologic adverse events were thrombocytopenia (51% and 30%, respectively, for patients with AP-CML and BP-CML), anemia (39% and 21%), neutropenia (20% and 21%), and febrile neutropenia (14% and 18%).

Omacetaxine is approved for the treatment of patients with CP-CML or AP-CML who are intolerant to 2 or more TKIs or those with resistant disease not responding to prior treatment with 2 or more TKIs.

NCCN Recommendations: The guidelines strongly recommend that patients with advanced phase CML be treated in specialized centers. Participation in a clinical trial is recommended for all patients with AP-CML or BP-CML.

Imatinib, dasatinib, nilotinib, and bosutinib are appropriate options for patients with de novo AP-CML (see CML-6, page 1593). Allogeneic HSCT can be considered based on response to TKI therapy. Omacetaxine is a treatment option for patients with resistant disease and/or intolerance to 2 or more TKIs.

TKI therapy alone or in combination with chemotherapy followed by allogeneic HSCT (if feasible) is recommended for patients in myeloid or lymphoid blast phase (see CML-6, page 1593). ALL-type chemotherapy is recommended for patients with lymphoid BP-CML (see NCCN Guidelines for ALL, available online at NCCN.org). Acute myeloid leukemia-type chemotherapy is recommended for those with myeloid BP-CML (see NCCN Guidelines for Acute Myeloid Leukemia, available online at NCCN.org).

A significant portion of patients with AP-CML or BP-CML treated with dasatinib or nilotinib achieve a MCyR but not a concomitant CHR because of persistent cytopenias.97 Fava et al97 reported that failure to achieve a CHR at the time of MCyR was associated with an inferior outcome. The 2-year survival rate was 37% compared with 77% for patients with MCyR and concomitant CHR, suggesting that patients with MCyR without a CHR should be considered for alternate treatment options.

In patients who experienced disease progression to AP-CML or BP-CML during prior TKI therapy, the selection of TKI is based on prior therapy and/or mutational analysis.98100 Dasatinib, nilotinib, and bosutinib are active against many of the imatinib-resistant BCR-ABL1 kinase domain mutations, except T315I. Available clinical evidence indicates that in addition to T315I, mutations F317 and V299 are resistant to dasatinib, and mutations Y253H, E255, and F359 are resistant to nilotinib.101,102 Bosutinib has shown potent activity in patients with BCR-ABL1 mutations resistant to dasatinib (F317L) and nilotinib (Y253H and F359C/I/V).103 Ponatinib has demonstrated activity in patients with E255K/V, F317L, F359V, G250E, M351T, T315I, and Y253H mutations.104,105

See CML-7 (page 1594) for the management of hematologic and cytogenetic resistance to TKI therapy. Mutational analysis is recommended before initiation of treatment for patients with AP-CML and BP-CML who have received prior TKI therapy.

Allogeneic Hematopoietic Stem Cell Transplant

Allogeneic HSCT is a potentially curative treatment for patients with CML, but the excellent results with TKI therapy have challenged the role of allogeneic HSCT as a first-line therapy.106,107 The widespread application of allogeneic HSCT is limited by donor availability and the high toxicity of the procedure in older patients, which limits the age of eligibility at many centers to younger than 65 years. Ongoing advances in alternative donor sources (such as unrelated donors and cord blood), more accurate HLA typing of unrelated donors, and less toxic regimens are broadening the use of allogeneic HSCT. Transplants from unrelated matched donors can now be used for many patients with CML. The advent of molecular DNA assessment of HLA typing has enabled a rigorous and stringent selection of unrelated matched donors, and this improvement in typing has translated into greatly improved transplant outcomes, so that results with unrelated, fully matched donors are comparable to those of related matched donors.108110

Investigational approaches using nonmyeloablative, reduced-intensity conditioning has been pioneered to engender a graft-versus-leukemia effect without exposing the patient to the toxicity associated with the myeloablative preparative regimen.111118 These studies are still investigational but are promising and show that molecular remissions may be achieved with nonmyeloablative, reduced-intensity conditioning in patients with CML.

Indications for Allogeneic HSCT

Allogeneic HSCT is an appropriate first-line treatment option for the rare patients presenting with BP-CML at diagnosis, patients with T315I and other BCR-ABL1 mutations that are resistant to all TKIs, and rare patients who are intolerant to all TKIs.106,119 A recent report from MD Andersen Cancer Center indicated that allogeneic HSCT is an effective strategy for patients with CML with T315I mutation, particularly in earlier stages; patients who underwent transplant in CP-CML had the best outcome.120 In a more recent analysis of patients with CML resistant to imatinib (chronic phase, n=34; accelerated phase, n=9; and blast phase, n=4) who underwent HSCT at MD Anderson Cancer Center, the overall response rate was 89% and 68% of patients had an MMR.121 The 2-year event-free survival rate was 36% for patients with BCR-ABL1 mutations and 58% for those with no mutations. The corresponding 2-year OS rate was 44% and 76%, respectively. Nicolini et al122 reported similar findings in 64 patients with T315I mutations. At a median follow-up of 26 months, survival probabilities at 24 months after allogeneic HSCT were 59%, 67%, and 30% for patients with CP-CML, AP-CML, and BP-CML, respectively. In multivariate analysis, blast phase at the time of transplant and transplants from unrelated donors were identified as adverse prognostic factors for OS.

Monitoring Response After Allogeneic HSCT

BCR-ABL1 transcripts persist after many years in most patients after allogeneic HSCT. Several studies have investigated the clinical significance of monitoring BCR-ABL1 transcript levels with qPCR after HSCT.123128 Radich et al125 reported that PCR positivity 6 or 12 months after HSCT is associated with a higher risk of disease relapse (42%) compared with only 3% in patients who had negative PCR results. This study also showed that early PCR positivity is associated with more aggressive disease and a high risk of relapse. Olavarria et al,127 who performed qPCR at 3 to 5 months after allogeneic HSCT, reported similar findings. At 3 years after allogeneic HSCT, the cumulative relapse rate was 17% for patients with no evidence of BCR-ABL1 transcripts, 43% for those who had less than 100 BCR-ABL1 transcripts, and 86% for those with more than 100 BCR-ABL1 transcripts. PCR positivity at 6 months or less was also highly predictive of relapse in patients who received a T-cell-depleted transplant.126 The prognostic significance of BCR-ABL1 positivity is less evident after a longer period following transplantation. Costello et al129 reported that the relapse rate was only 8% in patients with positive PCR results at more than 36 months after HSCT. Other investigators have reported that BCR-ABL1 transcripts persist even in patients who are in CR for more than 10 years after HSCT.130 More recently, Radich et al128 analyzed 379 consecutive patients with CML alive at 18 months or more after HSCT to assess the relapse risk associated with BCR-ABL1 detection in “late” CML survivors. Of 379 patients, 90 (24%) had at least 1 positive BCR-ABL1 test 18 months after transplantation or later; 13 of 90 BCR-ABL1-positive patients (14%) and 3 of 289 BCR-ABL1-negative patients (1.0%) experienced relapse.

Thus, the prognostic significance of BCR-ABL1 positivity is influenced by the time of testing after allogeneic HSCT. Although qPCR assay positive for BCR-ABL1 at 6 to 12 months after transplant is associated with a high risk of relapse, a positive QPCR assay at a much later time point after transplant is associated with a lower risk of relapse. Early detection of BCR-ABL1 transcripts after transplant may be useful to identify patients who may be in need of alternative therapies before the onset of a complete relapse.

Management of Posttransplant Relapse

Donor lymphocyte infusion (DLI) is effective in inducing durable molecular remissions in most patients with relapsed CML after allogeneic HSCT, although it is more effective in patients with chronic phase relapse than those with advanced phase relapse.131134 The probability of survival at 3 years after DLI was significantly better for patients who achieved molecular remission than for those who did not (95% and 53%, respectively; P=.0001).132 However, DLI is associated with complications such as graft-versus-host disease (GVHD), susceptibility to infections, and immunosuppression.131 Improvements in the methods of detecting BCR-ABL1 transcripts to predict relapse, the development of reduced-intensity conditioning regimens, modified delivery of lymphocytes with the depletion of CD8+ cells, the use of escalating cell dosage regimens, and very-low-dose DLI in combination with interferon-alpha have reduced the incidence of GVHD associated with DLI.135139

Imatinib has also been very effective in inducing durable remissions in most patients experiencing relapse in all phases of CML after allogeneic HSCT.140145 CHR and CCyR rates with posttransplant imatinib are higher in patients with chronicphase relapse than in those with advanced-phase relapse. More recent studies have also reported durable molecular responses with imatinib in patients experiencing relapse of chronic and advanced phase disease.146,147 Imatinib has also been shown to be effective in the prophylactic setting to prevent relapse after HSCT in high-risk patients. In a prospective evaluation of patients with Ph+ ALL (n=15) or CML beyond first chronic phase (n=7) in remission after myeloablative allogeneic HSCT, Carpenter et al148 showed that imatinib can be safely administered during the first 90 days after myeloablative allogeneic HSCT at a dose intensity comparable to that used in primary therapy. Imatinib was administered for 1 year after HSCT. At a median follow-up of 1.4 years, most patients (CML, n=5; ALL, n=12) were in molecular remission. Olavarria et al149 reported similar findings in patients undergoing reduced-intensity allogeneic HSCT in first chronic phase.

In a recent retrospective analysis, disease-free survival was significantly higher in patients receiving DLI than in those treated with imatinib.150 A trend was also seen toward higher rates of complete molecular remissions in the DLI group. Some investigators have suggested that the combination of DLI and imatinib may be more effective at inducing rapid molecular remissions than either modality alone.151 These observations are yet to be confirmed in randomized trials.

NCCN Recommendations: Allogeneic HSCT should be considered for patients with AP-CML or BP-CML. In patients with disease progression to accelerated or blast phase on prior TKI therapy, treatment with a course of alternate TKI (not received before) will be beneficial as a bridge to allogeneic HSCT.

Patients who are in CCyR (qPCR-negative) should undergo regular qPCR monitoring (every 3 months for 2 years, then every 6 months for 3 years). Given the high risk for hematologic relapse in patients with prior AP-CML or BP-CML, posttransplant TKI therapy should be considered for at least 1 year in patients in remission after allogeneic HSCT (see CML-8; page 1595).148

A TKI (Imatinib, dasatinib, nilotinib, or bosutinib), omacetaxine, DLI, or interferon or pegylated interferon can be considered for patients who are not experiencing remission or cytogenetic relapse and those with an increasing level of molecular relapse. Monitored withdrawal of immune suppression is recommended before initiation of therapy for posttransplant relapse.

In patients with CML that has previously failed to respond to imatinib, no data support the use of posttransplant imatinib. Limited data in a small number of patients are available on the use of dasatinib and nilotinib in patients with posttransplant relapse.152156 Dasatinib may also be an effective treatment for extramedullary relapse after allogeneic HSCT.157,158 No data support the use of posttransplant bosutinib, ponatinib, or omacetaxine.

Dasatinib, nilotinib, bosutinib, ponatinib, or omacetaxine may be more appropriate for patients with CML that has previously failed imatinib. Participation in a clinical trial should be considered.

Summary

TKI therapy (alone or in combination with chemotherapy) remains the standard initial treatment for patients with AP-CML. In patients with disease progression, selection of the appropriate TKI is based on previous therapy, the side-effect profile of the agent, and the TKI’s relative effectiveness against BCR-ABL1 mutations. Allogeneic HSCT should be considered for patients with AP-CML or BP-CML. Ongoing clinical trials are evaluating alternate treatment options for patients with BCR-ABL1 mutations resistant to currently approved TKIs. Consistent with NCCN philosophy, participation in clinical trials is encouraged.

Individual Disclosures of the NCCN Chronic Myelogenous Leukemia Panel

T1

References

  • 1.

    HowladerNNooneAM eds. SEER Cancer Statistics Review 1975-2008National Cancer Institute. Bethesda, MDwww.seer.cancer.gov/csr/1975_2008/based on November 2010 SEER data submission posted to the SEER website2011.

    • Search Google Scholar
    • Export Citation
  • 2.

    SiegelRMaJZouZJemalA. Cancer statistics, 2014. CA Cancer J Clin2014;64:929.

  • 3.

    FaderlSTalpazMEstrovZ. The biology of chronic myeloid leukemia. N Engl J Med1999;341:164172.

  • 4.

    VermaDKantarjianHMJonesD. Chronic myeloid leukemia (CML) with P190 BCR-ABL: analysis of characteristics, outcomes, and prognostic significance. Blood2009;114:22322235.

    • Search Google Scholar
    • Export Citation
  • 5.

    SawyersCL. Chronic myeloid leukemia. N Engl J Med1999;340:13301340.

  • 6.

    RadichJPDaiHMaoM. Gene expression changes associated with progression and response in chronic myeloid leukemia. Proc Natl Acad Sci U S A2006;103:27942799.

    • Search Google Scholar
    • Export Citation
  • 7.

    JamiesonCHMAillesLEDyllaSJ. Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML. N Engl J Med2004;351:657667.

    • Search Google Scholar
    • Export Citation
  • 8.

    KantarjianHMDeisserothAKurzrockR. Chronic myelogenous leukemia: a concise update. Blood1993;82:691703.

  • 9.

    SavageDGSzydloRMChaseA. Bone marrow transplantation for chronic myeloid leukaemia: the effects of differing criteria for defining chronic phase on probabilities of survival and relapse. Br J Haematol1997;99:3035.

    • Search Google Scholar
    • Export Citation
  • 10.

    SokalJEBaccaraniMRussoDTuraS. Staging and prognosis in chronic myelogenous leukemia. Semin Hematol1988;25:4961.

  • 11.

    TalpazMSilverRTDrukerBJ. Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: results of a phase 2 study. Blood2002;99:19281937.

    • Search Google Scholar
    • Export Citation
  • 12.

    CortesJETalpazMO’BrienS. Staging of chronic myeloid leukemia in the imatinib era: an evaluation of the World Health Organization proposal. Cancer2006;106:13061315.

    • Search Google Scholar
    • Export Citation
  • 13.

    SwerdlowSHCampoEHarrisNL. WHO classification of tumours of haematopoietic and lymphoid tissues. 4th edition. Lyon, France: IARC; 2008.

  • 14.

    DrukerBJ. Chronic Myelogenous Leukemia. In: DeVitaVTJrLawrenceTSRosenburgSA eds. DeVita Hellman and Rosenberg’s Cancer: Principles and Practice of Oncology. Vol. 2. 8th edition. Philadelphia, PA: Lippincott Williams & Wilkins; 2007:22672304.

    • Search Google Scholar
    • Export Citation
  • 15.

    GuoJQWangJYArlinghausRB. Detection of BCR-ABL proteins in blood cells of benign phase chronic myelogenous leukemia patients. Cancer Res1991;51:30483051.

    • Search Google Scholar
    • Export Citation
  • 16.

    BiernauxCLoosMSelsA. Detection of major bcr-abl gene expression at a very low level in blood cells of some healthy individuals. Blood1995;86:31183122.

    • Search Google Scholar
    • Export Citation
  • 17.

    BoseSDeiningerMGora-TyborJ. The presence of typical and atypical BCR-ABL fusion genes in leukocytes of normal individuals: biologic significance and implications for the assessment of minimal residual disease. Blood1998;92:33623367.

    • Search Google Scholar
    • Export Citation
  • 18.

    SokalJCoxEBaccaraniM. Prognostic discrimination in “good-risk” chronic granulocytic leukemia. Blood1984;63:789799.

  • 19.

    HasfordJPfirrmannMHehlmannR. A new prognostic score for survival of patients with chronic myeloid leukemia treated with interferon alfa. Writing Committee for the Collaborative CML Prognostic Factors Project Group. J Natl Cancer Inst1998;90:850858.

    • Search Google Scholar
    • Export Citation
  • 20.

    CortesJETalpazMBeranM. Philadelphia chromosome-negative chronic myelogenous leukemia with rearrangement of the breakpoint cluster region. Long-term follow-up results. Cancer1995;75:464470.

    • Search Google Scholar
    • Export Citation
  • 21.

    ErnstTChaseAJScoreJ. Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders. Nat Genet2010;42:722726.

    • Search Google Scholar
    • Export Citation
  • 22.

    KohlmannAGrossmannVKleinHU. Next-generation sequencing technology reveals a characteristic pattern of molecular mutations in 72.8% of chronic myelomonocytic leukemia by detecting frequent alterations in TET2, CBL, RAS, and RUNX1. J Clin Oncol2010;28:38583865.

    • Search Google Scholar
    • Export Citation
  • 23.

    OhSTSimondsEFJonesC. Novel mutations in the inhibitory adaptor protein LNK drive JAK-STAT signaling in patients with myeloproliferative neoplasms. Blood2010;116:988992.

    • Search Google Scholar
    • Export Citation
  • 24.

    TefferiA. Novel mutations and their functional and clinical relevance in myeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, CBL, IDH and IKZF1. Leukemia2010;24:11281138.

    • Search Google Scholar
    • Export Citation
  • 25.

    MascarenhasJRoperNChaurasiaPHoffmanR. Epigenetic abnormalities in myeloproliferative neoplasms: a target for novel therapeutic strategies. Clin Epigenetics2011;2:197212.

    • Search Google Scholar
    • Export Citation
  • 26.

    StegelmannFBullingerLSchlenkRF. DNMT3A mutations in myeloproliferative neoplasms. Leukemia2011;25:12171219.

  • 27.

    KlampflTGisslingerHHarutyunyanAS. Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med2013;369:23792390.

  • 28.

    MaxsonJEGotlibJPollyeaDA. Oncogenic CSF3R mutations in chronic neutrophilic leukemia and atypical CML. N Engl J Med2013;368:17811790.

    • Search Google Scholar
    • Export Citation
  • 29.

    MeggendorferMBacherUAlpermannT. SETBP1 mutations occur in 9% of MDS/MPN and in 4% of MPN cases and are strongly associated with atypical CML, monosomy 7, isochromosome i(17)(q10), ASXL1 and CBL mutations. Leukemia2013;27:18521860.

    • Search Google Scholar
    • Export Citation
  • 30.

    CrossNCReiterA. Fibroblast growth factor receptor and platelet-derived growth factor receptor abnormalities in eosinophilic myeloproliferative disorders. Acta Haematol2008;119:199206.

    • Search Google Scholar
    • Export Citation
  • 31.

    KantarjianHMCortesJO’BrienS. Imatinib mesylate (STI571) therapy for Philadelphia chromosome-positive chronic myelogenous leukemia in blast phase. Blood2002;99:35473553.

    • Search Google Scholar
    • Export Citation
  • 32.

    KantarjianHMO’BrienSCortesJE. Treatment of Philadelphia chromosome-positive, accelerated-phase chronic myelogenous leukemia with imatinib mesylate. Clin Cancer Res2002;8:21672176.

    • Search Google Scholar
    • Export Citation
  • 33.

    SawyersCLHochhausAFeldmanE. Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study. Blood2002;99:35303539.

    • Search Google Scholar
    • Export Citation
  • 34.

    PalandriFCastagnettiFTestoniN. Chronic myeloid leukemia in blast crisis treated with imatinib 600 mg: outcome of the patients alive after a 6-year follow-up. Haematologica2008;93:17921796.

    • Search Google Scholar
    • Export Citation
  • 35.

    PalandriFCastagnettiFAlimenaG. The long-term durability of cytogenetic responses in patients with accelerated phase chronic myeloid leukemia treated with imatinib 600 mg: the GIMEMA CML Working Party experience after a 7-year follow-up. Haematologica2009;94:205212.

    • Search Google Scholar
    • Export Citation
  • 36.

    SilverRTCortesJWaltzmanR. Sustained durability of responses and improved progression-free and overall survival with imatinib treatment for accelerated phase and blast crisis chronic myeloid leukemia: long-term follow-up of the STI571 0102 and 0109 trials. Haematologica2009;94:743744.

    • Search Google Scholar
    • Export Citation
  • 37.

    ReaDEtienneGNicoliniF. First-line imatinib mesylate in patients with newly diagnosed accelerated phase-chronic myeloid leukemia. Leukemia2012;26:22542259.

    • Search Google Scholar
    • Export Citation
  • 38.

    OhanianMKantarjianHMQuintas-CardamaA. Tyrosine kinase inhibitors as initial therapy for patients with chronic myeloid leukemia in accelerated phase. Clin Lymphoma Myeloma Leuk2014;14:155-162 e151.

    • Search Google Scholar
    • Export Citation
  • 39.

    CortesJKimDWRaffouxE. Efficacy and safety of dasatinib in imatinib-resistant or -intolerant patients with chronic myeloid leukemia in blast phase. Leukemia2008;22:21762183.

    • Search Google Scholar
    • Export Citation
  • 40.

    ApperleyJFCortesJEKimDW. Dasatinib in the treatment of chronic myeloid leukemia in accelerated phase after imatinib failure: the START A trial. J Clin Oncol2009;27:34723479.

    • Search Google Scholar
    • Export Citation
  • 41.

    KantarjianHCortesJKimDW. Phase 3 study of dasatinib 140 mg once daily versus 70 mg twice daily in patients with chronic myeloid leukemia in accelerated phase resistant or intolerant to imatinib: 15-month median follow-up. Blood2009;113:63226329.

    • Search Google Scholar
    • Export Citation
  • 42.

    le CoutrePDGilesFJHochhausA. Nilotinib in patients with Ph+ chronic myeloid leukemia in accelerated phase following imatinib resistance or intolerance: 24-month follow-up results. Leukemia2012;26:11891194.

    • Search Google Scholar
    • Export Citation
  • 43.

    GilesFJKantarjianHMle CoutrePD. Nilotinib is effective in imatinib-resistant or -intolerant patients with chronic myeloid leukemia in blastic phase. Leukemia2012;26:959962.

    • Search Google Scholar
    • Export Citation
  • 44.

    Gambacorti-PasseriniCCortesJEKhouryHJ. Safety and efficacy of bosutinib in patients with AP and BP CML and ph+ ALL following resistance/intolerance to imatinib and other TKIs: Update from study SKI-200 [abstract]. J Clin Oncol2010;28(Suppl):Abstract 6509.

    • Search Google Scholar
    • Export Citation
  • 45.

    CortesJEKimDWPinilla-IbarzJ. A Phase 2 Trial of ponatinib in Philadelphia chromosome-positive leukemias. N Engl J Med2013;369:17831796.

    • Search Google Scholar
    • Export Citation
  • 46.

    KantarjianHMKimDWPinilla-IbarzJ. Ponatinib (PON) in patients (pts) with Philadelphia chromosome-positive (Ph+) leukemias resistant or intolerant to dasatinib or nilotinib, or with the T315I mutation: longer-term follow up of the PACE trial [abstract]. J Clin Oncol2014;32(Suppl):Abstract 7081.

    • Search Google Scholar
    • Export Citation
  • 47.

    GuilhotFApperleyJKimDW. Dasatinib induces significant hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in accelerated phase. Blood2007;109:41434150.

    • Search Google Scholar
    • Export Citation
  • 48.

    CortesJRousselotPKimDW. Dasatinib induces complete hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in blast crisis. Blood2007;109:32073213.

    • Search Google Scholar
    • Export Citation
  • 49.

    SaglioGHochhausAGohYT. Dasatinib in imatinib-resistant or imatinib-intolerant chronic myeloid leukemia in blast phase after 2 years of follow-up in a phase 3 study: efficacy and tolerability of 140 milligrams once daily and 70 milligrams twice daily. Cancer2010;116:38523861.

    • Search Google Scholar
    • Export Citation
  • 50.

    le CoutrePOttmannOGGilesF. Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is active in patients with imatinib-resistant or -intolerant accelerated-phase chronic myelogenous leukemia. Blood2008;111:18341839.

    • Search Google Scholar
    • Export Citation
  • 51.

    EfficaceFBaccaraniMBrecciaM. Chronic fatigue is the most important factor limiting health-related quality of life of chronic myeloid leukemia patients treated with imatinib. Leukemia2013;27:15111519.

    • Search Google Scholar
    • Export Citation
  • 52.

    BermanENicolaidesMMakiRG. Altered bone and mineral metabolism in patients receiving imatinib mesylate. N Engl J Med2006;354:20062013.

    • Search Google Scholar
    • Export Citation
  • 53.

    BermanEGirotraMChengC. Effect of long term imatinib on bone in adults with chronic myelogenous leukemia and gastrointestinal stromal tumors. Leuk Res2013;37:790794.

    • Search Google Scholar
    • Export Citation
  • 54.

    Quintas-CardamaAKantarjianHO’BrienS. Pleural effusion in patients with chronic myelogenous leukemia treated with dasatinib after imatinib failure. J Clin Oncol2007;25:39083914.

    • Search Google Scholar
    • Export Citation
  • 55.

    PorkkaKKhouryHJPaquetteRL. Dasatinib 100 mg once daily minimizes the occurrence of pleural effusion in patients with chronic myeloid leukemia in chronic phase and efficacy is unaffected in patients who develop pleural effusion. Cancer2010;116:377386.

    • Search Google Scholar
    • Export Citation
  • 56.

    MatteiDFeolaMOrzanF. Reversible dasatinib-induced pulmonary arterial hypertension and right ventricle failure in a previously allografted CML patient. Bone Marrow Transplant2009;43:967968.

    • Search Google Scholar
    • Export Citation
  • 57.

    RasheedWFlaimBSeymourJF. Reversible severe pulmonary hypertension secondary to dasatinib in a patient with chronic myeloid leukemia. Leuk Res2009;33:861864.

    • Search Google Scholar
    • Export Citation
  • 58.

    DumitrescuDSeckCten FreyhausH. Fully reversible pulmonary arterial hypertension associated with dasatinib treatment for chronic myeloid leukaemia. Eur Respir J2011;38:218220.

    • Search Google Scholar
    • Export Citation
  • 59.

    HennigsJKKellerGBaumannHJ. Multi tyrosine kinase inhibitor dasatinib as novel cause of severe pre-capillary pulmonary hypertension?BMC Pulm Med2011;11:30.

    • Search Google Scholar
    • Export Citation
  • 60.

    MontaniDBergotEGuntherS. Pulmonary arterial hypertension in patients treated by dasatinib. Circulation2012;125:21282137.

  • 61.

    OrlandiEMRoccaBPazzanoASGhioS. Reversible pulmonary arterial hypertension likely related to long-term, low-dose dasatinib treatment for chronic myeloid leukaemia. Leuk Res2012;36:e46.

    • Search Google Scholar
    • Export Citation
  • 62.

    AichbergerKJHerndlhoferSSchernthanerGH. Progressive peripheral arterial occlusive disease and other vascular events during nilotinib therapy in CML. Am J Hematol2011;86:533539.

    • Search Google Scholar
    • Export Citation
  • 63.

    TefferiALetendreL. Nilotinib treatment-associated peripheral artery disease and sudden death: yet another reason to stick to imatinib as front-line therapy for chronic myelogenous leukemia. Am J Hematol2011;86:610611.

    • Search Google Scholar
    • Export Citation
  • 64.

    GilesFJMauroMJHongF. Rates of peripheral arterial occlusive disease in patients with chronic myeloid leukemia in the chronic phase treated with imatinib, nilotinib, or non-tyrosine kinase therapy: a retrospective cohort analysis. Leukemia2013;27:13101315.

    • Search Google Scholar
    • Export Citation
  • 65.

    FDA Drug Safety Communication: FDA asks manufacturer of the leukemia drug Iclusig (ponatinib) to suspend marketing and sales. U.S. Food and Drug Administration Web site. Available at: http://www.fda.gov/Drugs/DrugSafety/ucm373040.htm; 2013. Accessed October 21 2014.

    • Search Google Scholar
    • Export Citation
  • 66.

    Ponatinib [package insert]. Cambridge, MA: ARIAD Pharmaceuticals, Inc.; 2014.

  • 67.

    AliROzkalemkasFKimyaY. Imatinib use during pregnancy and breast feeding: a case report and review of the literature. Arch Gynecol Obstet2009;280:169175.

    • Search Google Scholar
    • Export Citation
  • 68.

    AlKindiSDennisonDPathareA. Imatinib in pregnancy. Eur J Haematol2005;74:535537.

  • 69.

    AultPKantarjianHO’BrienS. Pregnancy among patients with chronic myeloid leukemia treated with imatinib. J Clin Oncol2006;24:12041208.

    • Search Google Scholar
    • Export Citation
  • 70.

    ChoudharyDRMishraPKumarR. Pregnancy on imatinib: fatal outcome with meningocele. Ann Oncol2006;17:178179.

  • 71.

    HeartinEWalkinshawSClarkRE. Successful outcome of pregnancy in chronic myeloid leukaemia treated with imatinib. Leuk Lymphoma2004;45:13071308.

    • Search Google Scholar
    • Export Citation
  • 72.

    PrabhashKSastryPSBiswasG. Pregnancy outcome of two patients treated with imatinib. Ann Oncol2005;16:19831984.

  • 73.

    PyeSMCortesJAultP. The effects of imatinib on pregnancy outcome. Blood2008;111:55055508.

  • 74.

    RamasamyKHaydenJLimZ. Successful pregnancies involving men with chronic myeloid leukaemia on imatinib therapy. Br J Haematol2007;137:374375.

    • Search Google Scholar
    • Export Citation
  • 75.

    CortesJO’BrienSAultP. Pregnancy outcomes among patients with chronic myeloid leukemia treated with dasatinib [abstract]. Blood2008;112:Abstract 3230.

    • Search Google Scholar
    • Export Citation
  • 76.

    ConchonMSanabaniSSSerpaM. Successful pregnancy and delivery in a patient with chronic myeloid leukemia while on dasatinib therapy. Adv Hematol2010;2010:136252136252.

    • Search Google Scholar
    • Export Citation
  • 77.

    OweiniHOtrockZKMahfouzRABazarbachiA. Successful pregnancy involving a man with chronic myeloid leukemia on dasatinib. Arch Gynecol Obstet2011;283:133134.

    • Search Google Scholar
    • Export Citation
  • 78.

    ConchonMSanabaniSSBenditI. Two successful pregnancies in a woman with chronic myeloid leukemia exposed to nilotinib during the first trimester of her second pregnancy: case study. J Hematol Oncol2009;2:4242.

    • Search Google Scholar
    • Export Citation
  • 79.

    KantarjianHMTalpazMKontoyiannisD. Treatment of chronic myelogenous leukemia in accelerated and blastic phases with daunorubicin, high-dose cytarabine, and granulocyte-macrophage colony-stimulating factor. J Clin Oncol1992;10:398405.

    • Search Google Scholar
    • Export Citation
  • 80.

    DerderianPMKantarjianHMTalpazM. Chronic myelogenous leukemia in the lymphoid blastic phase: characteristics, treatment response, and prognosis. Am J Med1993;94:6974.

    • Search Google Scholar
    • Export Citation
  • 81.

    DannEJAnastasiJLarsonRA. High-dose cladribine therapy for chronic myelogenous leukemia in the accelerated or blast phase. J Clin Oncol1998;16:14981504.

    • Search Google Scholar
    • Export Citation
  • 82.

    SacchiSKantarjianHMO’BrienS. Chronic myelogenous leukemia in nonlymphoid blastic phase: analysis of the results of first salvage therapy with three different treatment approaches for 162 patients. Cancer1999;86:26322641.

    • Search Google Scholar
    • Export Citation
  • 83.

    AxdorphUStenkeLGrimforsG. Intensive chemotherapy in patients with chronic myelogenous leukaemia (CML) in accelerated or blastic phase--a report from the Swedish CML Group. Br J Haematol2002;118:10481054.

    • Search Google Scholar
    • Export Citation
  • 84.

    ThomasDAFaderlSCortesJ. Treatment of Philadelphia chromosome-positive acute lymphocytic leukemia with hyper-CVAD and imatinib mesylate. Blood2004;103:43964407.

    • Search Google Scholar
    • Export Citation
  • 85.

    YanadaMTakeuchiJSugiuraI. High complete remission rate and promising outcome by combination of imatinib and chemotherapy for newly diagnosed BCR-ABL-positive acute lymphoblastic leukemia: a phase II study by the Japan Adult Leukemia Study Group. J Clin Oncol2006;24:460466.

    • Search Google Scholar
    • Export Citation
  • 86.

    de LabartheARousselotPHuguet-RigalF. Imatinib combined with induction or consolidation chemotherapy in patients with de novo Philadelphia chromosome-positive acute lymphoblastic leukemia: results of the GRAAPH-2003 study. Blood2007;109:14081413.

    • Search Google Scholar
    • Export Citation
  • 87.

    OkiYKantarjianHMGharibyanV. Phase II study of low-dose decitabine in combination with imatinib mesylate in patients with accelerated or myeloid blastic phase of chronic myelogenous leukemia. Cancer2007;109:899906.

    • Search Google Scholar
    • Export Citation
  • 88.

    Quintas-CardamaAKantarjianHGarcia-ManeroG. A pilot study of imatinib, low-dose cytarabine and idarubicin for patients with chronic myeloid leukemia in myeloid blast phase. Leuk Lymphoma2007;48:283289.

    • Search Google Scholar
    • Export Citation
  • 89.

    FruehaufSTopalyJBussEC. Imatinib combined with mitoxantrone/etoposide and cytarabine is an effective induction therapy for patients with chronic myeloid leukemia in myeloid blast crisis. Cancer2007;109:15431549.

    • Search Google Scholar
    • Export Citation
  • 90.

    ThomasDAO’BrienSMFaderlS. Long-term outcome after hyper-CVAD and imatinib (IM) for de novo or minimally treated Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-ALL) [abstract]. J Clin Oncol2010;28(Suppl):Abstract 6506.

    • Search Google Scholar
    • Export Citation
  • 91.

    DeauBNicoliniFEGuilhotJ. The addition of daunorubicin to imatinib mesylate in combination with cytarabine improves the response rate and the survival of patients with myeloid blast crisis chronic myelogenous leukemia (AFR01 study). Leuk Res2011;35:777782.

    • Search Google Scholar
    • Export Citation
  • 92.

    JabbourEKantarjianHMThomasDA. Phase II study of combination of hyperCVAD with ponatinib in frontline therapy of patients (pts) with Philadelphia chromosome (Ph) positive acute lymphoblastic leukemia (ALL) [abstract]. J Clin Oncol2013;31(Suppl):Abstract 7024.

    • Search Google Scholar
    • Export Citation
  • 93.

    BenjaminiODumlaoTLKantarjianH. Phase II trial of hyper CVAD and dasatinib in patients with relapsed Philadelphia chromosome positive acute lymphoblastic leukemia or blast phase chronic myeloid leukemia. Am J Hematol2014;89:282287.

    • Search Google Scholar
    • Export Citation
  • 94.

    StratiPKantarjianHThomasD. HCVAD plus imatinib or dasatinib in lymphoid blastic phase chronic myeloid leukemia. Cancer2014;120:373380.

    • Search Google Scholar
    • Export Citation
  • 95.

    NicoliniFEKhouryHJAkardL. Omacetaxine mepesuccinate for patients with accelerated phase chronic myeloid leukemia with resistance or intolerance to two or more tyrosine kinase inhibitors. Haematologica2013;98:e7879.

    • Search Google Scholar
    • Export Citation
  • 96.

    KhouryHJCortesJBaccaraniM. Omacetaxine mepesuccinate in patients with advanced chronic myeloid leukemia with resistance or intolerance to tyrosine kinase inhibitors [published online ahead of print April 28, 2014]. Leuk Lymphoma.

    • Search Google Scholar
    • Export Citation
  • 97.

    FavaCKantarjianHMJabbourE. Failure to achieve a complete hematologic response at the time of a major cytogenetic response with second-generation tyrosine kinase inhibitors is associated with a poor prognosis among patients with chronic myeloid leukemia in accelerated or blast phase. Blood2009;113:50585063.

    • Search Google Scholar
    • Export Citation
  • 98.

    BranfordSMeloJVHughesTP. Selecting optimal second-line tyrosine kinase inhibitor therapy for chronic myeloid leukemia patients after imatinib failure: does the BCR-ABL mutation status really matter?Blood2009;114:54265435.

    • Search Google Scholar
    • Export Citation
  • 99.

    JabbourEBranfordSSaglioG. Practical advice for determining the role of BCR-ABL mutations in guiding tyrosine kinase inhibitor therapy in patients with chronic myeloid leukemia. Cancer2011;117:18001811.

    • Search Google Scholar
    • Export Citation
  • 100.

    SoveriniSHochhausANicoliniFE. BCR-ABL kinase domain mutation analysis in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors: recommendations from an expert panel on behalf of European LeukemiaNet. Blood2011;118:12081215.

    • Search Google Scholar
    • Export Citation
  • 101.

    MullerMCCortesJEKimDW. Dasatinib treatment of chronic-phase chronic myeloid leukemia: analysis of responses according to preexisting BCR-ABL mutations. Blood2009;114:49444953.

    • Search Google Scholar
    • Export Citation
  • 102.

    HughesTSaglioGBranfordS. Impact of baseline BCR-ABL mutations on response to nilotinib in patients with chronic myeloid leukemia in chronic phase. J Clin Oncol2009;27:42044210.

    • Search Google Scholar
    • Export Citation
  • 103.

    KhouryHJCortesJEKantarjianHM. Bosutinib is active in chronic phase chronic myeloid leukemia after imatinib and dasatinib and/or nilotinib therapy failure. Blood2012;119:34033412.

    • Search Google Scholar
    • Export Citation
  • 104.

    HochhausAKimDWPinilla-IbarzJ. Molecular responses with ponatinib in patients with philadelphia chromosome positive (ph+) leukemia: results from the PACE trial [abstract]. Blood2012;120:Abstract 3763.

    • Search Google Scholar
    • Export Citation
  • 105.

    ShahNPCortesJEKimDW. Impact of baseline (BL) mutations, including low-level and compound mutations, on ponatinib response and end of treatment (EOT) mutation analysis in patients (pts) with chronic phase chronic myeloid leukemia (CP-CML) [abstract]. Blood2013;122:Abstract 652.

    • Search Google Scholar
    • Export Citation
  • 106.

    RadichJ. Stem cell transplant for chronic myeloid leukemia in the imatinib era. Semin Hematol2010;47:354361.

  • 107.

    PavluJSzydloRMGoldmanJMApperleyJF. Three decades of transplantation for chronic myeloid leukemia: what have we learned?Blood2011;117:755763.

    • Search Google Scholar
    • Export Citation
  • 108.

    DaviesSMDeForTEMcGlavePB. Equivalent outcomes in patients with chronic myelogenous leukemia after early transplantation of phenotypically matched bone marrow from related or unrelated donors. Am J Med2001;110:339346.

    • Search Google Scholar
    • Export Citation
  • 109.

    HansenJAGooleyTAMartinPJ. Bone marrow transplants from unrelated donors for patients with chronic myeloid leukemia. N Engl J Med1998;338:962968.

    • Search Google Scholar
    • Export Citation
  • 110.

    HorowitzMMRowlingsPAPasswegJR. Allogeneic bone marrow transplantation for CML: a report from the International Bone Marrow Transplant Registry. Bone Marrow Transplant1996;17(Suppl 3):S56.

    • Search Google Scholar
    • Export Citation
  • 111.

    CrawleyCSzydloRLalancetteM. Outcomes of reduced-intensity transplantation for chronic myeloid leukemia: an analysis of prognostic factors from the Chronic Leukemia Working Party of the EBMT. Blood2005;106:29692976.

    • Search Google Scholar
    • Export Citation
  • 112.

    McSweeneyPANiederwieserDShizuruJA. Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus-tumor effects. Blood2001;97:33903400.

    • Search Google Scholar
    • Export Citation
  • 113.

    OrRShapiraMYResnickI. Nonmyeloablative allogeneic stem cell transplantation for the treatment of chronic myeloid leukemia in first chronic phase. Blood2003;101:441445.

    • Search Google Scholar
    • Export Citation
  • 114.

    FaberEKozaVVitekA. Reduced-intensity conditioning for allogeneic stem cell transplantation in patients with chronic myeloid leukemia is associated with better overall survival but inferior disease-free survival when compared with myeloablative conditioning - a retrospective study of the Czech National Hematopoietic Stem Cell Transplantation Registry. Neoplasma2007;54:443446.

    • Search Google Scholar
    • Export Citation
  • 115.

    KebriaeiPDetryMAGiraltS. Long-term follow-up of allogeneic hematopoietic stem-cell transplantation with reduced-intensity conditioning for patients with chronic myeloid leukemia. Blood2007;110:34563462.

    • Search Google Scholar
    • Export Citation
  • 116.

    PoireXArtzALarsonRA. Allogeneic stem cell transplantation with alemtuzumab-based conditioning for patients with advanced chronic myelogenous leukemia. Leuk Lymphoma2009;50:8591.

    • Search Google Scholar
    • Export Citation
  • 117.

    WarlickEAhnKWPedersenTL. Reduced intensity conditioning is superior to nonmyeloablative conditioning for older chronic myelogenous leukemia patients undergoing hematopoietic cell transplant during the tyrosine kinase inhibitor era. Blood2012;119:40834090.

    • Search Google Scholar
    • Export Citation
  • 118.

    WeisserMSchleuningMHaferlachC. Allogeneic stem-cell transplantation provides excellent results in advanced stage chronic myeloid leukemia with major cytogenetic response to pre-transplant imatinib therapy. Leuk Lymphoma2007;48:295301.

    • Search Google Scholar
    • Export Citation
  • 119.

    BaccaraniMCortesJPaneF. Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet. J Clin Oncol2009;27:60416051.

    • Search Google Scholar
    • Export Citation
  • 120.

    VelevNCortesJChamplinR. Stem cell transplantation for patients with chronic myeloid leukemia resistant to tyrosine kinase inhibitors with BCR-ABL kinase domain mutation T315I. Cancer2010;116:36313637.

    • Search Google Scholar
    • Export Citation
  • 121.

    JabbourECortesJSantosFP. Results of allogeneic hematopoietic stem cell transplantation for chronic myelogenous leukemia patients who failed tyrosine kinase inhibitors after developing BCR-ABL1 kinase domain mutations. Blood2011;117:36413647.

    • Search Google Scholar
    • Export Citation
  • 122.

    NicoliniFEBasakGWSoveriniS. Allogeneic stem cell transplantation for patients harboring T315I BCR-ABL mutated leukemias. Blood2011;118:56975700.

    • Search Google Scholar
    • Export Citation
  • 123.

    RothMAntinJAshR. Prognostic significance of Philadelphia chromosome-positive cells detected by the polymerase chain reaction after allogeneic bone marrow transplant for chronic myelogenous leukemia. Blood1992;79:276282.

    • Search Google Scholar
    • Export Citation
  • 124.

    DelageRSoifferRDearKRitzJ. Clinical significance of bcr-abl gene rearrangement detected by polymerase chain reaction after allogeneic bone marrow transplantation in chronic myelogenous leukemia. Blood1991;78:27592767.

    • Search Google Scholar
    • Export Citation
  • 125.

    RadichJPGehlyGGooleyT. Polymerase chain reaction detection of the BCR-ABL fusion transcript after allogeneic marrow transplantation for chronic myeloid leukemia: results and implications in 346 patients. Blood1995;85:26322638.

    • Search Google Scholar
    • Export Citation
  • 126.

    MackinnonSBarnettLHellerG. Polymerase chain reaction is highly predictive of relapse in patients following T cell-depleted allogeneic bone marrow transplantation for chronic myeloid leukemia. Bone Marrow Transplant1996;17:643647.

    • Search Google Scholar
    • Export Citation
  • 127.

    OlavarriaEKanferESzydloR. Early detection of BCR-ABL transcripts by quantitative reverse transcriptase-polymerase chain reaction predicts outcome after allogeneic stem cell transplantation for chronic myeloid leukemia. Blood2001;97:15601565.

    • Search Google Scholar
    • Export Citation
  • 128.

    RadichJPGooleyTBryantE. The significance of bcr-abl molecular detection in chronic myeloid leukemia patients “late,” 18 months or more after transplantation. Blood2001;98:17011707.

    • Search Google Scholar
    • Export Citation
  • 129.

    CostelloRTKirkJGabertJ. Value of PCR analysis for long term survivors after allogeneic bone marrow transplant for chronic myelogenous leukemia: a comparative study. Leuk Lymphoma1996;20:239243.

    • Search Google Scholar
    • Export Citation
  • 130.

    van RheeFLinFCrossNC. Detection of residual leukaemia more than 10 years after allogeneic bone marrow transplantation for chronic myelogenous leukaemia. Bone Marrow Transplant1994;14:609612.

    • Search Google Scholar
    • Export Citation
  • 131.

    KolbHJSchattenbergAGoldmanJM. Graft-versus-leukemia effect of donor lymphocyte transfusions in marrow grafted patients. Blood1995;86:20412050.

    • Search Google Scholar
    • Export Citation
  • 132.

    DazziFSzydloRMCrossNC. Durability of responses following donor lymphocyte infusions for patients who relapse after allogeneic stem cell transplantation for chronic myeloid leukemia. Blood2000;96:27122716.

    • Search Google Scholar
    • Export Citation
  • 133.

    LuznikLFuchsEJ. Donor lymphocyte infusions to treat hematologic malignancies in relapse after allogeneic blood or marrow transplantation. Cancer Control2002;9:123137.

    • Search Google Scholar
    • Export Citation
  • 134.

    MichalletASNicoliniFFurstS. Outcome and long-term follow-up of alloreactive donor lymphocyte infusions given for relapse after myeloablative allogeneic hematopoietic stem cell transplantations (HSCT). Bone Marrow Transplant2005;35:601608.

    • Search Google Scholar
    • Export Citation
  • 135.

    DazziFSzydloRMCraddockC. Comparison of single-dose and escalating-dose regimens of donor lymphocyte infusion for relapse after allografting for chronic myeloid leukemia. Blood2000;95:6771.

    • Search Google Scholar
    • Export Citation
  • 136.

    ShimoniAGajewskiJADonatoM. Long-Term follow-up of recipients of CD8-depleted donor lymphocyte infusions for the treatment of chronic myelogenous leukemia relapsing after allogeneic progenitor cell transplantation. Biol Blood Marrow Transplant2001;7:568575.

    • Search Google Scholar
    • Export Citation
  • 137.

    GilleeceMHDazziF. Donor lymphocyte infusions for patients who relapse after allogeneic stem cell transplantation for chronic myeloid leukaemia. Leuk Lymphoma2003;44:2328.

    • Search Google Scholar
    • Export Citation
  • 138.

    PosthumaEFMarijtEWBargeRM. Alpha-interferon with very-low-dose donor lymphocyte infusion for hematologic or cytogenetic relapse of chronic myeloid leukemia induces rapid and durable complete remissions and is associated with acceptable graft-versus-host disease. Biol Blood Marrow Transplant2004;10:204212.

    • Search Google Scholar
    • Export Citation
  • 139.

    SimulaMPMarktelSFozzaC. Response to donor lymphocyte infusions for chronic myeloid leukemia is dose-dependent: the importance of escalating the cell dose to maximize therapeutic efficacy. Leukemia2007;21:943948.

    • Search Google Scholar
    • Export Citation
  • 140.

    KantarjianHMO’BrienSCortesJE. Imatinib mesylate therapy for relapse after allogeneic stem cell transplantation for chronic myelogenous leukemia. Blood2002;100:15901595.

    • Search Google Scholar
    • Export Citation
  • 141.

    OlavarriaEOttmannOGDeiningerM. Response to imatinib in patients who relapse after allogeneic stem cell transplantation for chronic myeloid leukemia. Leukemia2003;17:17071712.

    • Search Google Scholar
    • Export Citation
  • 142.

    AnderliniPShethSHicksK. Re: Imatinib mesylate administration in the first 100 days after stem cell transplantation. Biol Blood Marrow Transplant2004;10:883884.

    • Search Google Scholar
    • Export Citation
  • 143.

    DeAngeloDJHochbergEPAlyeaEP. Extended follow-up of patients treated with imatinib mesylate (gleevec) for chronic myelogenous leukemia relapse after allogeneic transplantation: durable cytogenetic remission and conversion to complete donor chimerism without graft-versus-host disease. Clin Cancer Res2004;10:50655071.

    • Search Google Scholar
    • Export Citation
  • 144.

    PalandriFAmabileMRostiG. Imatinib therapy for chronic myeloid leukemia patients who relapse after allogeneic stem cell transplantation: a molecular analysis. Bone Marrow Transplant2007;39:189191.

    • Search Google Scholar
    • Export Citation
  • 145.

    ConchonMSanabaniSSBenditI. The use of imatinib mesylate as a lifesaving treatment of chronic myeloid leukemia relapse after bone marrow transplantation. J Transplant2009;2009:357093.

    • Search Google Scholar
    • Export Citation
  • 146.

    HessGBunjesDSiegertW. Sustained complete molecular remissions after treatment with imatinib-mesylate in patients with failure after allogeneic stem cell transplantation for chronic myelogenous leukemia: results of a prospective phase II open-label multicenter study. J Clin Oncol2005;23:75837593.

    • Search Google Scholar
    • Export Citation
  • 147.

    WrightMPShepherdJDBarnettMJ. Response to tyrosine kinase inhibitor therapy in patients with chronic myelogenous leukemia relapsing in chronic and advanced phase following allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant2010;16:639646.

    • Search Google Scholar
    • Export Citation
  • 148.

    CarpenterPASnyderDSFlowersME. Prophylactic administration of imatinib after hematopoietic cell transplantation for high-risk Philadelphia chromosome-positive leukemia. Blood2007;109:27912793.

    • Search Google Scholar
    • Export Citation
  • 149.

    OlavarriaESiddiqueSGriffithsMJ. Posttransplantation imatinib as a strategy to postpone the requirement for immunotherapy in patients undergoing reduced-intensity allografts for chronic myeloid leukemia. Blood2007;110:46144617.

    • Search Google Scholar
    • Export Citation
  • 150.

    WeisserMTischerJSchnittgerS. A comparison of donor lymphocyte infusions or imatinib mesylate for patients with chronic myelogenous leukemia who have relapsed after allogeneic stem cell transplantation. Haematologica2006;91:663666.

    • Search Google Scholar
    • Export Citation
  • 151.

    SavaniBNMonteroAKurlanderR. Imatinib synergizes with donor lymphocyte infusions to achieve rapid molecular remission of CML relapsing after allogeneic stem cell transplantation. Bone Marrow Transplant2005;36:10091015.

    • Search Google Scholar
    • Export Citation
  • 152.

    AtallahEKantarjianHDe LimaM. The role of dasatinib in patients with philadelphia (Ph) positive acute lymphocytic leukemia (ALL) and chronic myeloid leukemia (CML) relapsing after stem cell transplantation (SCT) [abstract]. Blood2006;108:Abstract 4520.

    • Search Google Scholar
    • Export Citation
  • 153.

    O’ConnorLMLangabeerSMcCannSRConneallyE. Restoration of donor chimerism by nilotinib in a chronic myeloid leukaemia patient post mutation-associated imatinib mesylate resistance and allogeneic stem cell transplant failure. Bone Marrow Transplant2008;42:833835.

    • Search Google Scholar
    • Export Citation
  • 154.

    BrecciaMCannellaLStefanizziC. Efficacy of dasatinib in a chronic myeloid leukemia patient with disease molecular relapse and chronic GVHD after haploidentical BMT: an immunomodulatory effect?Bone Marrow Transplant2009;44:331332.

    • Search Google Scholar
    • Export Citation
  • 155.

    KlyuchnikovESchafhausenPKrogerN. Second-generation tyrosine kinase inhibitors in the post-transplant period in patients with chronic myeloid leukemia or Philadelphia-positive acute lymphoblastic leukemia. Acta Haematol2009;122:610.

    • Search Google Scholar
    • Export Citation
  • 156.

    GarlandPDazziFMarinD. Dasatinib may not suppress the GVL effect of donor lymphocyte infusions for CML. Bone Marrow Transplant2010;45:395396.

    • Search Google Scholar
    • Export Citation
  • 157.

    PorkkaKKoskenvesaPLundanT. Dasatinib crosses the blood-brain barrier and is an efficient therapy for central nervous system Philadelphia chromosome-positive leukemia. Blood2008;112:10051012.

    • Search Google Scholar
    • Export Citation
  • 158.

    OcheniSIwanskiGBSchafhausenP. Characterisation of extramedullary relapse in patients with chronic myeloid leukemia in advanced disease after allogeneic stem cell transplantation. Leuk Lymphoma2009;50:551558.

    • Search Google Scholar
    • Export Citation

If the inline PDF is not rendering correctly, you can download the PDF file here.

Article Sections

Figures

  • View in gallery
    NCCN Clinical Practice Guidelines in Oncology: Chronic Myelogenous Leukemia, Version 1.2015

    Version 1.2015, 08-28-14 ©2014 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

  • View in gallery
    NCCN Clinical Practice Guidelines in Oncology: Chronic Myelogenous Leukemia, Version 1.2015

    Version 1.2015, 08-28-14 ©2014 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

  • View in gallery
    NCCN Clinical Practice Guidelines in Oncology: Chronic Myelogenous Leukemia, Version 1.2015

    Version 1.2015, 08-28-14 ©2014 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

References

  • 1.

    HowladerNNooneAM eds. SEER Cancer Statistics Review 1975-2008National Cancer Institute. Bethesda, MDwww.seer.cancer.gov/csr/1975_2008/based on November 2010 SEER data submission posted to the SEER website2011.

    • Search Google Scholar
    • Export Citation
  • 2.

    SiegelRMaJZouZJemalA. Cancer statistics, 2014. CA Cancer J Clin2014;64:929.

  • 3.

    FaderlSTalpazMEstrovZ. The biology of chronic myeloid leukemia. N Engl J Med1999;341:164172.

  • 4.

    VermaDKantarjianHMJonesD. Chronic myeloid leukemia (CML) with P190 BCR-ABL: analysis of characteristics, outcomes, and prognostic significance. Blood2009;114:22322235.

    • Search Google Scholar
    • Export Citation
  • 5.

    SawyersCL. Chronic myeloid leukemia. N Engl J Med1999;340:13301340.

  • 6.

    RadichJPDaiHMaoM. Gene expression changes associated with progression and response in chronic myeloid leukemia. Proc Natl Acad Sci U S A2006;103:27942799.

    • Search Google Scholar
    • Export Citation
  • 7.

    JamiesonCHMAillesLEDyllaSJ. Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML. N Engl J Med2004;351:657667.

    • Search Google Scholar
    • Export Citation
  • 8.

    KantarjianHMDeisserothAKurzrockR. Chronic myelogenous leukemia: a concise update. Blood1993;82:691703.

  • 9.

    SavageDGSzydloRMChaseA. Bone marrow transplantation for chronic myeloid leukaemia: the effects of differing criteria for defining chronic phase on probabilities of survival and relapse. Br J Haematol1997;99:3035.

    • Search Google Scholar
    • Export Citation
  • 10.

    SokalJEBaccaraniMRussoDTuraS. Staging and prognosis in chronic myelogenous leukemia. Semin Hematol1988;25:4961.

  • 11.

    TalpazMSilverRTDrukerBJ. Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: results of a phase 2 study. Blood2002;99:19281937.

    • Search Google Scholar
    • Export Citation
  • 12.

    CortesJETalpazMO’BrienS. Staging of chronic myeloid leukemia in the imatinib era: an evaluation of the World Health Organization proposal. Cancer2006;106:13061315.

    • Search Google Scholar
    • Export Citation
  • 13.

    SwerdlowSHCampoEHarrisNL. WHO classification of tumours of haematopoietic and lymphoid tissues. 4th edition. Lyon, France: IARC; 2008.

  • 14.

    DrukerBJ. Chronic Myelogenous Leukemia. In: DeVitaVTJrLawrenceTSRosenburgSA eds. DeVita Hellman and Rosenberg’s Cancer: Principles and Practice of Oncology. Vol. 2. 8th edition. Philadelphia, PA: Lippincott Williams & Wilkins; 2007:22672304.

    • Search Google Scholar
    • Export Citation
  • 15.

    GuoJQWangJYArlinghausRB. Detection of BCR-ABL proteins in blood cells of benign phase chronic myelogenous leukemia patients. Cancer Res1991;51:30483051.

    • Search Google Scholar
    • Export Citation
  • 16.

    BiernauxCLoosMSelsA. Detection of major bcr-abl gene expression at a very low level in blood cells of some healthy individuals. Blood1995;86:31183122.

    • Search Google Scholar
    • Export Citation
  • 17.

    BoseSDeiningerMGora-TyborJ. The presence of typical and atypical BCR-ABL fusion genes in leukocytes of normal individuals: biologic significance and implications for the assessment of minimal residual disease. Blood1998;92:33623367.

    • Search Google Scholar
    • Export Citation
  • 18.

    SokalJCoxEBaccaraniM. Prognostic discrimination in “good-risk” chronic granulocytic leukemia. Blood1984;63:789799.

  • 19.

    HasfordJPfirrmannMHehlmannR. A new prognostic score for survival of patients with chronic myeloid leukemia treated with interferon alfa. Writing Committee for the Collaborative CML Prognostic Factors Project Group. J Natl Cancer Inst1998;90:850858.

    • Search Google Scholar
    • Export Citation
  • 20.

    CortesJETalpazMBeranM. Philadelphia chromosome-negative chronic myelogenous leukemia with rearrangement of the breakpoint cluster region. Long-term follow-up results. Cancer1995;75:464470.

    • Search Google Scholar
    • Export Citation
  • 21.

    ErnstTChaseAJScoreJ. Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders. Nat Genet2010;42:722726.

    • Search Google Scholar
    • Export Citation
  • 22.

    KohlmannAGrossmannVKleinHU. Next-generation sequencing technology reveals a characteristic pattern of molecular mutations in 72.8% of chronic myelomonocytic leukemia by detecting frequent alterations in TET2, CBL, RAS, and RUNX1. J Clin Oncol2010;28:38583865.

    • Search Google Scholar
    • Export Citation
  • 23.

    OhSTSimondsEFJonesC. Novel mutations in the inhibitory adaptor protein LNK drive JAK-STAT signaling in patients with myeloproliferative neoplasms. Blood2010;116:988992.

    • Search Google Scholar
    • Export Citation
  • 24.

    TefferiA. Novel mutations and their functional and clinical relevance in myeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, CBL, IDH and IKZF1. Leukemia2010;24:11281138.

    • Search Google Scholar
    • Export Citation
  • 25.

    MascarenhasJRoperNChaurasiaPHoffmanR. Epigenetic abnormalities in myeloproliferative neoplasms: a target for novel therapeutic strategies. Clin Epigenetics2011;2:197212.

    • Search Google Scholar
    • Export Citation
  • 26.

    StegelmannFBullingerLSchlenkRF. DNMT3A mutations in myeloproliferative neoplasms. Leukemia2011;25:12171219.

  • 27.

    KlampflTGisslingerHHarutyunyanAS. Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med2013;369:23792390.

  • 28.

    MaxsonJEGotlibJPollyeaDA. Oncogenic CSF3R mutations in chronic neutrophilic leukemia and atypical CML. N Engl J Med2013;368:17811790.

    • Search Google Scholar
    • Export Citation
  • 29.

    MeggendorferMBacherUAlpermannT. SETBP1 mutations occur in 9% of MDS/MPN and in 4% of MPN cases and are strongly associated with atypical CML, monosomy 7, isochromosome i(17)(q10), ASXL1 and CBL mutations. Leukemia2013;27:18521860.

    • Search Google Scholar
    • Export Citation
  • 30.

    CrossNCReiterA. Fibroblast growth factor receptor and platelet-derived growth factor receptor abnormalities in eosinophilic myeloproliferative disorders. Acta Haematol2008;119:199206.

    • Search Google Scholar
    • Export Citation
  • 31.

    KantarjianHMCortesJO’BrienS. Imatinib mesylate (STI571) therapy for Philadelphia chromosome-positive chronic myelogenous leukemia in blast phase. Blood2002;99:35473553.

    • Search Google Scholar
    • Export Citation
  • 32.

    KantarjianHMO’BrienSCortesJE. Treatment of Philadelphia chromosome-positive, accelerated-phase chronic myelogenous leukemia with imatinib mesylate. Clin Cancer Res2002;8:21672176.

    • Search Google Scholar
    • Export Citation
  • 33.

    SawyersCLHochhausAFeldmanE. Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study. Blood2002;99:35303539.

    • Search Google Scholar
    • Export Citation
  • 34.

    PalandriFCastagnettiFTestoniN. Chronic myeloid leukemia in blast crisis treated with imatinib 600 mg: outcome of the patients alive after a 6-year follow-up. Haematologica2008;93:17921796.

    • Search Google Scholar
    • Export Citation
  • 35.

    PalandriFCastagnettiFAlimenaG. The long-term durability of cytogenetic responses in patients with accelerated phase chronic myeloid leukemia treated with imatinib 600 mg: the GIMEMA CML Working Party experience after a 7-year follow-up. Haematologica2009;94:205212.

    • Search Google Scholar
    • Export Citation
  • 36.

    SilverRTCortesJWaltzmanR. Sustained durability of responses and improved progression-free and overall survival with imatinib treatment for accelerated phase and blast crisis chronic myeloid leukemia: long-term follow-up of the STI571 0102 and 0109 trials. Haematologica2009;94:743744.

    • Search Google Scholar
    • Export Citation
  • 37.

    ReaDEtienneGNicoliniF. First-line imatinib mesylate in patients with newly diagnosed accelerated phase-chronic myeloid leukemia. Leukemia2012;26:22542259.

    • Search Google Scholar
    • Export Citation
  • 38.

    OhanianMKantarjianHMQuintas-CardamaA. Tyrosine kinase inhibitors as initial therapy for patients with chronic myeloid leukemia in accelerated phase. Clin Lymphoma Myeloma Leuk2014;14:155-162 e151.

    • Search Google Scholar
    • Export Citation
  • 39.

    CortesJKimDWRaffouxE. Efficacy and safety of dasatinib in imatinib-resistant or -intolerant patients with chronic myeloid leukemia in blast phase. Leukemia2008;22:21762183.

    • Search Google Scholar
    • Export Citation
  • 40.

    ApperleyJFCortesJEKimDW. Dasatinib in the treatment of chronic myeloid leukemia in accelerated phase after imatinib failure: the START A trial. J Clin Oncol2009;27:34723479.

    • Search Google Scholar
    • Export Citation
  • 41.

    KantarjianHCortesJKimDW. Phase 3 study of dasatinib 140 mg once daily versus 70 mg twice daily in patients with chronic myeloid leukemia in accelerated phase resistant or intolerant to imatinib: 15-month median follow-up. Blood2009;113:63226329.

    • Search Google Scholar
    • Export Citation
  • 42.

    le CoutrePDGilesFJHochhausA. Nilotinib in patients with Ph+ chronic myeloid leukemia in accelerated phase following imatinib resistance or intolerance: 24-month follow-up results. Leukemia2012;26:11891194.

    • Search Google Scholar
    • Export Citation
  • 43.

    GilesFJKantarjianHMle CoutrePD. Nilotinib is effective in imatinib-resistant or -intolerant patients with chronic myeloid leukemia in blastic phase. Leukemia2012;26:959962.

    • Search Google Scholar
    • Export Citation
  • 44.

    Gambacorti-PasseriniCCortesJEKhouryHJ. Safety and efficacy of bosutinib in patients with AP and BP CML and ph+ ALL following resistance/intolerance to imatinib and other TKIs: Update from study SKI-200 [abstract]. J Clin Oncol2010;28(Suppl):Abstract 6509.

    • Search Google Scholar
    • Export Citation
  • 45.

    CortesJEKimDWPinilla-IbarzJ. A Phase 2 Trial of ponatinib in Philadelphia chromosome-positive leukemias. N Engl J Med2013;369:17831796.

    • Search Google Scholar
    • Export Citation
  • 46.

    KantarjianHMKimDWPinilla-IbarzJ. Ponatinib (PON) in patients (pts) with Philadelphia chromosome-positive (Ph+) leukemias resistant or intolerant to dasatinib or nilotinib, or with the T315I mutation: longer-term follow up of the PACE trial [abstract]. J Clin Oncol2014;32(Suppl):Abstract 7081.

    • Search Google Scholar
    • Export Citation
  • 47.

    GuilhotFApperleyJKimDW. Dasatinib induces significant hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in accelerated phase. Blood2007;109:41434150.

    • Search Google Scholar
    • Export Citation
  • 48.

    CortesJRousselotPKimDW. Dasatinib induces complete hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in blast crisis. Blood2007;109:32073213.

    • Search Google Scholar
    • Export Citation
  • 49.

    SaglioGHochhausAGohYT. Dasatinib in imatinib-resistant or imatinib-intolerant chronic myeloid leukemia in blast phase after 2 years of follow-up in a phase 3 study: efficacy and tolerability of 140 milligrams once daily and 70 milligrams twice daily. Cancer2010;116:38523861.

    • Search Google Scholar
    • Export Citation
  • 50.

    le CoutrePOttmannOGGilesF. Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is active in patients with imatinib-resistant or -intolerant accelerated-phase chronic myelogenous leukemia. Blood2008;111:18341839.

    • Search Google Scholar
    • Export Citation
  • 51.

    EfficaceFBaccaraniMBrecciaM. Chronic fatigue is the most important factor limiting health-related quality of life of chronic myeloid leukemia patients treated with imatinib. Leukemia2013;27:15111519.

    • Search Google Scholar
    • Export Citation
  • 52.

    BermanENicolaidesMMakiRG. Altered bone and mineral metabolism in patients receiving imatinib mesylate. N Engl J Med2006;354:20062013.

    • Search Google Scholar
    • Export Citation
  • 53.

    BermanEGirotraMChengC. Effect of long term imatinib on bone in adults with chronic myelogenous leukemia and gastrointestinal stromal tumors. Leuk Res2013;37:790794.

    • Search Google Scholar
    • Export Citation
  • 54.

    Quintas-CardamaAKantarjianHO’BrienS. Pleural effusion in patients with chronic myelogenous leukemia treated with dasatinib after imatinib failure. J Clin Oncol2007;25:39083914.

    • Search Google Scholar
    • Export Citation
  • 55.

    PorkkaKKhouryHJPaquetteRL. Dasatinib 100 mg once daily minimizes the occurrence of pleural effusion in patients with chronic myeloid leukemia in chronic phase and efficacy is unaffected in patients who develop pleural effusion. Cancer2010;116:377386.

    • Search Google Scholar
    • Export Citation
  • 56.

    MatteiDFeolaMOrzanF. Reversible dasatinib-induced pulmonary arterial hypertension and right ventricle failure in a previously allografted CML patient. Bone Marrow Transplant2009;43:967968.

    • Search Google Scholar
    • Export Citation
  • 57.

    RasheedWFlaimBSeymourJF. Reversible severe pulmonary hypertension secondary to dasatinib in a patient with chronic myeloid leukemia. Leuk Res2009;33:861864.

    • Search Google Scholar
    • Export Citation
  • 58.

    DumitrescuDSeckCten FreyhausH. Fully reversible pulmonary arterial hypertension associated with dasatinib treatment for chronic myeloid leukaemia. Eur Respir J2011;38:218220.

    • Search Google Scholar
    • Export Citation
  • 59.

    HennigsJKKellerGBaumannHJ. Multi tyrosine kinase inhibitor dasatinib as novel cause of severe pre-capillary pulmonary hypertension?BMC Pulm Med2011;11:30.

    • Search Google Scholar
    • Export Citation
  • 60.

    MontaniDBergotEGuntherS. Pulmonary arterial hypertension in patients treated by dasatinib. Circulation2012;125:21282137.

  • 61.

    OrlandiEMRoccaBPazzanoASGhioS. Reversible pulmonary arterial hypertension likely related to long-term, low-dose dasatinib treatment for chronic myeloid leukaemia. Leuk Res2012;36:e46.

    • Search Google Scholar
    • Export Citation
  • 62.

    AichbergerKJHerndlhoferSSchernthanerGH. Progressive peripheral arterial occlusive disease and other vascular events during nilotinib therapy in CML. Am J Hematol2011;86:533539.

    • Search Google Scholar
    • Export Citation
  • 63.

    TefferiALetendreL. Nilotinib treatment-associated peripheral artery disease and sudden death: yet another reason to stick to imatinib as front-line therapy for chronic myelogenous leukemia. Am J Hematol2011;86:610611.

    • Search Google Scholar
    • Export Citation
  • 64.

    GilesFJMauroMJHongF. Rates of peripheral arterial occlusive disease in patients with chronic myeloid leukemia in the chronic phase treated with imatinib, nilotinib, or non-tyrosine kinase therapy: a retrospective cohort analysis. Leukemia2013;27:13101315.

    • Search Google Scholar
    • Export Citation
  • 65.

    FDA Drug Safety Communication: FDA asks manufacturer of the leukemia drug Iclusig (ponatinib) to suspend marketing and sales. U.S. Food and Drug Administration Web site. Available at: http://www.fda.gov/Drugs/DrugSafety/ucm373040.htm; 2013. Accessed October 21 2014.

    • Search Google Scholar
    • Export Citation
  • 66.

    Ponatinib [package insert]. Cambridge, MA: ARIAD Pharmaceuticals, Inc.; 2014.

  • 67.

    AliROzkalemkasFKimyaY. Imatinib use during pregnancy and breast feeding: a case report and review of the literature. Arch Gynecol Obstet2009;280:169175.

    • Search Google Scholar
    • Export Citation
  • 68.

    AlKindiSDennisonDPathareA. Imatinib in pregnancy. Eur J Haematol2005;74:535537.

  • 69.

    AultPKantarjianHO’BrienS. Pregnancy among patients with chronic myeloid leukemia treated with imatinib. J Clin Oncol2006;24:12041208.

    • Search Google Scholar
    • Export Citation
  • 70.

    ChoudharyDRMishraPKumarR. Pregnancy on imatinib: fatal outcome with meningocele. Ann Oncol2006;17:178179.

  • 71.

    HeartinEWalkinshawSClarkRE. Successful outcome of pregnancy in chronic myeloid leukaemia treated with imatinib. Leuk Lymphoma2004;45:13071308.

    • Search Google Scholar
    • Export Citation
  • 72.

    PrabhashKSastryPSBiswasG. Pregnancy outcome of two patients treated with imatinib. Ann Oncol2005;16:19831984.

  • 73.

    PyeSMCortesJAultP. The effects of imatinib on pregnancy outcome. Blood2008;111:55055508.

  • 74.

    RamasamyKHaydenJLimZ. Successful pregnancies involving men with chronic myeloid leukaemia on imatinib therapy. Br J Haematol2007;137:374375.

    • Search Google Scholar
    • Export Citation
  • 75.

    CortesJO’BrienSAultP. Pregnancy outcomes among patients with chronic myeloid leukemia treated with dasatinib [abstract]. Blood2008;112:Abstract 3230.

    • Search Google Scholar
    • Export Citation
  • 76.

    ConchonMSanabaniSSSerpaM. Successful pregnancy and delivery in a patient with chronic myeloid leukemia while on dasatinib therapy. Adv Hematol2010;2010:136252136252.

    • Search Google Scholar
    • Export Citation
  • 77.

    OweiniHOtrockZKMahfouzRABazarbachiA. Successful pregnancy involving a man with chronic myeloid leukemia on dasatinib. Arch Gynecol Obstet2011;283:133134.

    • Search Google Scholar
    • Export Citation
  • 78.

    ConchonMSanabaniSSBenditI. Two successful pregnancies in a woman with chronic myeloid leukemia exposed to nilotinib during the first trimester of her second pregnancy: case study. J Hematol Oncol2009;2:4242.

    • Search Google Scholar
    • Export Citation
  • 79.

    KantarjianHMTalpazMKontoyiannisD. Treatment of chronic myelogenous leukemia in accelerated and blastic phases with daunorubicin, high-dose cytarabine, and granulocyte-macrophage colony-stimulating factor. J Clin Oncol1992;10:398405.

    • Search Google Scholar
    • Export Citation
  • 80.

    DerderianPMKantarjianHMTalpazM. Chronic myelogenous leukemia in the lymphoid blastic phase: characteristics, treatment response, and prognosis. Am J Med1993;94:6974.

    • Search Google Scholar
    • Export Citation
  • 81.

    DannEJAnastasiJLarsonRA. High-dose cladribine therapy for chronic myelogenous leukemia in the accelerated or blast phase. J Clin Oncol1998;16:14981504.

    • Search Google Scholar
    • Export Citation
  • 82.

    SacchiSKantarjianHMO’BrienS. Chronic myelogenous leukemia in nonlymphoid blastic phase: analysis of the results of first salvage therapy with three different treatment approaches for 162 patients. Cancer1999;86:26322641.

    • Search Google Scholar
    • Export Citation
  • 83.

    AxdorphUStenkeLGrimforsG. Intensive chemotherapy in patients with chronic myelogenous leukaemia (CML) in accelerated or blastic phase--a report from the Swedish CML Group. Br J Haematol2002;118:10481054.

    • Search Google Scholar
    • Export Citation
  • 84.

    ThomasDAFaderlSCortesJ. Treatment of Philadelphia chromosome-positive acute lymphocytic leukemia with hyper-CVAD and imatinib mesylate. Blood2004;103:43964407.

    • Search Google Scholar
    • Export Citation
  • 85.

    YanadaMTakeuchiJSugiuraI. High complete remission rate and promising outcome by combination of imatinib and chemotherapy for newly diagnosed BCR-ABL-positive acute lymphoblastic leukemia: a phase II study by the Japan Adult Leukemia Study Group. J Clin Oncol2006;24:460466.

    • Search Google Scholar
    • Export Citation
  • 86.

    de LabartheARousselotPHuguet-RigalF. Imatinib combined with induction or consolidation chemotherapy in patients with de novo Philadelphia chromosome-positive acute lymphoblastic leukemia: results of the GRAAPH-2003 study. Blood2007;109:14081413.

    • Search Google Scholar
    • Export Citation
  • 87.

    OkiYKantarjianHMGharibyanV. Phase II study of low-dose decitabine in combination with imatinib mesylate in patients with accelerated or myeloid blastic phase of chronic myelogenous leukemia. Cancer2007;109:899906.

    • Search Google Scholar
    • Export Citation
  • 88.

    Quintas-CardamaAKantarjianHGarcia-ManeroG. A pilot study of imatinib, low-dose cytarabine and idarubicin for patients with chronic myeloid leukemia in myeloid blast phase. Leuk Lymphoma2007;48:283289.

    • Search Google Scholar
    • Export Citation
  • 89.

    FruehaufSTopalyJBussEC. Imatinib combined with mitoxantrone/etoposide and cytarabine is an effective induction therapy for patients with chronic myeloid leukemia in myeloid blast crisis. Cancer2007;109:15431549.

    • Search Google Scholar
    • Export Citation
  • 90.

    ThomasDAO’BrienSMFaderlS. Long-term outcome after hyper-CVAD and imatinib (IM) for de novo or minimally treated Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-ALL) [abstract]. J Clin Oncol2010;28(Suppl):Abstract 6506.

    • Search Google Scholar
    • Export Citation
  • 91.

    DeauBNicoliniFEGuilhotJ. The addition of daunorubicin to imatinib mesylate in combination with cytarabine improves the response rate and the survival of patients with myeloid blast crisis chronic myelogenous leukemia (AFR01 study). Leuk Res2011;35:777782.

    • Search Google Scholar
    • Export Citation
  • 92.

    JabbourEKantarjianHMThomasDA. Phase II study of combination of hyperCVAD with ponatinib in frontline therapy of patients (pts) with Philadelphia chromosome (Ph) positive acute lymphoblastic leukemia (ALL) [abstract]. J Clin Oncol2013;31(Suppl):Abstract 7024.

    • Search Google Scholar
    • Export Citation
  • 93.

    BenjaminiODumlaoTLKantarjianH. Phase II trial of hyper CVAD and dasatinib in patients with relapsed Philadelphia chromosome positive acute lymphoblastic leukemia or blast phase chronic myeloid leukemia. Am J Hematol2014;89:282287.

    • Search Google Scholar
    • Export Citation
  • 94.

    StratiPKantarjianHThomasD. HCVAD plus imatinib or dasatinib in lymphoid blastic phase chronic myeloid leukemia. Cancer2014;120:373380.

    • Search Google Scholar
    • Export Citation
  • 95.

    NicoliniFEKhouryHJAkardL. Omacetaxine mepesuccinate for patients with accelerated phase chronic myeloid leukemia with resistance or intolerance to two or more tyrosine kinase inhibitors. Haematologica2013;98:e7879.

    • Search Google Scholar
    • Export Citation
  • 96.

    KhouryHJCortesJBaccaraniM. Omacetaxine mepesuccinate in patients with advanced chronic myeloid leukemia with resistance or intolerance to tyrosine kinase inhibitors [published online ahead of print April 28, 2014]. Leuk Lymphoma.

    • Search Google Scholar
    • Export Citation
  • 97.

    FavaCKantarjianHMJabbourE. Failure to achieve a complete hematologic response at the time of a major cytogenetic response with second-generation tyrosine kinase inhibitors is associated with a poor prognosis among patients with chronic myeloid leukemia in accelerated or blast phase. Blood2009;113:50585063.

    • Search Google Scholar
    • Export Citation
  • 98.

    BranfordSMeloJVHughesTP. Selecting optimal second-line tyrosine kinase inhibitor therapy for chronic myeloid leukemia patients after imatinib failure: does the BCR-ABL mutation status really matter?Blood2009;114:54265435.

    • Search Google Scholar
    • Export Citation
  • 99.

    JabbourEBranfordSSaglioG. Practical advice for determining the role of BCR-ABL mutations in guiding tyrosine kinase inhibitor therapy in patients with chronic myeloid leukemia. Cancer2011;117:18001811.

    • Search Google Scholar
    • Export Citation
  • 100.

    SoveriniSHochhausANicoliniFE. BCR-ABL kinase domain mutation analysis in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors: recommendations from an expert panel on behalf of European LeukemiaNet. Blood2011;118:12081215.

    • Search Google Scholar
    • Export Citation
  • 101.

    MullerMCCortesJEKimDW. Dasatinib treatment of chronic-phase chronic myeloid leukemia: analysis of responses according to preexisting BCR-ABL mutations. Blood2009;114:49444953.

    • Search Google Scholar
    • Export Citation
  • 102.

    HughesTSaglioGBranfordS. Impact of baseline BCR-ABL mutations on response to nilotinib in patients with chronic myeloid leukemia in chronic phase. J Clin Oncol2009;27:42044210.

    • Search Google Scholar
    • Export Citation
  • 103.

    KhouryHJCortesJEKantarjianHM. Bosutinib is active in chronic phase chronic myeloid leukemia after imatinib and dasatinib and/or nilotinib therapy failure. Blood2012;119:34033412.

    • Search Google Scholar
    • Export Citation
  • 104.

    HochhausAKimDWPinilla-IbarzJ. Molecular responses with ponatinib in patients with philadelphia chromosome positive (ph+) leukemia: results from the PACE trial [abstract]. Blood2012;120:Abstract 3763.

    • Search Google Scholar
    • Export Citation
  • 105.

    ShahNPCortesJEKimDW. Impact of baseline (BL) mutations, including low-level and compound mutations, on ponatinib response and end of treatment (EOT) mutation analysis in patients (pts) with chronic phase chronic myeloid leukemia (CP-CML) [abstract]. Blood2013;122:Abstract 652.

    • Search Google Scholar
    • Export Citation
  • 106.

    RadichJ. Stem cell transplant for chronic myeloid leukemia in the imatinib era. Semin Hematol2010;47:354361.

  • 107.

    PavluJSzydloRMGoldmanJMApperleyJF. Three decades of transplantation for chronic myeloid leukemia: what have we learned?Blood2011;117:755763.

    • Search Google Scholar
    • Export Citation
  • 108.

    DaviesSMDeForTEMcGlavePB. Equivalent outcomes in patients with chronic myelogenous leukemia after early transplantation of phenotypically matched bone marrow from related or unrelated donors. Am J Med2001;110:339346.

    • Search Google Scholar
    • Export Citation
  • 109.

    HansenJAGooleyTAMartinPJ. Bone marrow transplants from unrelated donors for patients with chronic myeloid leukemia. N Engl J Med1998;338:962968.

    • Search Google Scholar
    • Export Citation
  • 110.

    HorowitzMMRowlingsPAPasswegJR. Allogeneic bone marrow transplantation for CML: a report from the International Bone Marrow Transplant Registry. Bone Marrow Transplant1996;17(Suppl 3):S56.

    • Search Google Scholar
    • Export Citation
  • 111.

    CrawleyCSzydloRLalancetteM. Outcomes of reduced-intensity transplantation for chronic myeloid leukemia: an analysis of prognostic factors from the Chronic Leukemia Working Party of the EBMT. Blood2005;106:29692976.

    • Search Google Scholar
    • Export Citation
  • 112.

    McSweeneyPANiederwieserDShizuruJA. Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus-tumor effects. Blood2001;97:33903400.

    • Search Google Scholar
    • Export Citation
  • 113.

    OrRShapiraMYResnickI. Nonmyeloablative allogeneic stem cell transplantation for the treatment of chronic myeloid leukemia in first chronic phase. Blood2003;101:441445.

    • Search Google Scholar
    • Export Citation
  • 114.

    FaberEKozaVVitekA. Reduced-intensity conditioning for allogeneic stem cell transplantation in patients with chronic myeloid leukemia is associated with better overall survival but inferior disease-free survival when compared with myeloablative conditioning - a retrospective study of the Czech National Hematopoietic Stem Cell Transplantation Registry. Neoplasma2007;54:443446.

    • Search Google Scholar
    • Export Citation
  • 115.

    KebriaeiPDetryMAGiraltS. Long-term follow-up of allogeneic hematopoietic stem-cell transplantation with reduced-intensity conditioning for patients with chronic myeloid leukemia. Blood2007;110:34563462.

    • Search Google Scholar
    • Export Citation
  • 116.

    PoireXArtzALarsonRA. Allogeneic stem cell transplantation with alemtuzumab-based conditioning for patients with advanced chronic myelogenous leukemia. Leuk Lymphoma2009;50:8591.

    • Search Google Scholar
    • Export Citation
  • 117.

    WarlickEAhnKWPedersenTL. Reduced intensity conditioning is superior to nonmyeloablative conditioning for older chronic myelogenous leukemia patients undergoing hematopoietic cell transplant during the tyrosine kinase inhibitor era. Blood2012;119:40834090.

    • Search Google Scholar
    • Export Citation
  • 118.

    WeisserMSchleuningMHaferlachC. Allogeneic stem-cell transplantation provides excellent results in advanced stage chronic myeloid leukemia with major cytogenetic response to pre-transplant imatinib therapy. Leuk Lymphoma2007;48:295301.

    • Search Google Scholar
    • Export Citation
  • 119.

    BaccaraniMCortesJPaneF. Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet. J Clin Oncol2009;27:60416051.

    • Search Google Scholar
    • Export Citation
  • 120.

    VelevNCortesJChamplinR. Stem cell transplantation for patients with chronic myeloid leukemia resistant to tyrosine kinase inhibitors with BCR-ABL kinase domain mutation T315I. Cancer2010;116:36313637.

    • Search Google Scholar
    • Export Citation
  • 121.

    JabbourECortesJSantosFP. Results of allogeneic hematopoietic stem cell transplantation for chronic myelogenous leukemia patients who failed tyrosine kinase inhibitors after developing BCR-ABL1 kinase domain mutations. Blood2011;117:36413647.

    • Search Google Scholar
    • Export Citation
  • 122.

    NicoliniFEBasakGWSoveriniS. Allogeneic stem cell transplantation for patients harboring T315I BCR-ABL mutated leukemias. Blood2011;118:56975700.

    • Search Google Scholar
    • Export Citation
  • 123.

    RothMAntinJAshR. Prognostic significance of Philadelphia chromosome-positive cells detected by the polymerase chain reaction after allogeneic bone marrow transplant for chronic myelogenous leukemia. Blood1992;79:276282.

    • Search Google Scholar
    • Export Citation
  • 124.

    DelageRSoifferRDearKRitzJ. Clinical significance of bcr-abl gene rearrangement detected by polymerase chain reaction after allogeneic bone marrow transplantation in chronic myelogenous leukemia. Blood1991;78:27592767.

    • Search Google Scholar
    • Export Citation
  • 125.

    RadichJPGehlyGGooleyT. Polymerase chain reaction detection of the BCR-ABL fusion transcript after allogeneic marrow transplantation for chronic myeloid leukemia: results and implications in 346 patients. Blood1995;85:26322638.

    • Search Google Scholar
    • Export Citation
  • 126.

    MackinnonSBarnettLHellerG. Polymerase chain reaction is highly predictive of relapse in patients following T cell-depleted allogeneic bone marrow transplantation for chronic myeloid leukemia. Bone Marrow Transplant1996;17:643647.

    • Search Google Scholar
    • Export Citation
  • 127.

    OlavarriaEKanferESzydloR. Early detection of BCR-ABL transcripts by quantitative reverse transcriptase-polymerase chain reaction predicts outcome after allogeneic stem cell transplantation for chronic myeloid leukemia. Blood2001;97:15601565.

    • Search Google Scholar
    • Export Citation
  • 128.

    RadichJPGooleyTBryantE. The significance of bcr-abl molecular detection in chronic myeloid leukemia patients “late,” 18 months or more after transplantation. Blood2001;98:17011707.

    • Search Google Scholar
    • Export Citation
  • 129.

    CostelloRTKirkJGabertJ. Value of PCR analysis for long term survivors after allogeneic bone marrow transplant for chronic myelogenous leukemia: a comparative study. Leuk Lymphoma1996;20:239243.

    • Search Google Scholar
    • Export Citation
  • 130.

    van RheeFLinFCrossNC. Detection of residual leukaemia more than 10 years after allogeneic bone marrow transplantation for chronic myelogenous leukaemia. Bone Marrow Transplant1994;14:609612.

    • Search Google Scholar
    • Export Citation
  • 131.

    KolbHJSchattenbergAGoldmanJM. Graft-versus-leukemia effect of donor lymphocyte transfusions in marrow grafted patients. Blood1995;86:20412050.

    • Search Google Scholar
    • Export Citation
  • 132.

    DazziFSzydloRMCrossNC. Durability of responses following donor lymphocyte infusions for patients who relapse after allogeneic stem cell transplantation for chronic myeloid leukemia. Blood2000;96:27122716.

    • Search Google Scholar
    • Export Citation
  • 133.

    LuznikLFuchsEJ. Donor lymphocyte infusions to treat hematologic malignancies in relapse after allogeneic blood or marrow transplantation. Cancer Control2002;9:123137.

    • Search Google Scholar
    • Export Citation
  • 134.

    MichalletASNicoliniFFurstS. Outcome and long-term follow-up of alloreactive donor lymphocyte infusions given for relapse after myeloablative allogeneic hematopoietic stem cell transplantations (HSCT). Bone Marrow Transplant2005;35:601608.

    • Search Google Scholar
    • Export Citation
  • 135.

    DazziFSzydloRMCraddockC. Comparison of single-dose and escalating-dose regimens of donor lymphocyte infusion for relapse after allografting for chronic myeloid leukemia. Blood2000;95:6771.

    • Search Google Scholar
    • Export Citation
  • 136.

    ShimoniAGajewskiJADonatoM. Long-Term follow-up of recipients of CD8-depleted donor lymphocyte infusions for the treatment of chronic myelogenous leukemia relapsing after allogeneic progenitor cell transplantation. Biol Blood Marrow Transplant2001;7:568575.

    • Search Google Scholar
    • Export Citation
  • 137.

    GilleeceMHDazziF. Donor lymphocyte infusions for patients who relapse after allogeneic stem cell transplantation for chronic myeloid leukaemia. Leuk Lymphoma2003;44:2328.

    • Search Google Scholar
    • Export Citation
  • 138.

    PosthumaEFMarijtEWBargeRM. Alpha-interferon with very-low-dose donor lymphocyte infusion for hematologic or cytogenetic relapse of chronic myeloid leukemia induces rapid and durable complete remissions and is associated with acceptable graft-versus-host disease. Biol Blood Marrow Transplant2004;10:204212.

    • Search Google Scholar
    • Export Citation
  • 139.

    SimulaMPMarktelSFozzaC. Response to donor lymphocyte infusions for chronic myeloid leukemia is dose-dependent: the importance of escalating the cell dose to maximize therapeutic efficacy. Leukemia2007;21:943948.

    • Search Google Scholar
    • Export Citation
  • 140.

    KantarjianHMO’BrienSCortesJE. Imatinib mesylate therapy for relapse after allogeneic stem cell transplantation for chronic myelogenous leukemia. Blood2002;100:15901595.

    • Search Google Scholar
    • Export Citation
  • 141.

    OlavarriaEOttmannOGDeiningerM. Response to imatinib in patients who relapse after allogeneic stem cell transplantation for chronic myeloid leukemia. Leukemia2003;17:17071712.

    • Search Google Scholar
    • Export Citation
  • 142.

    AnderliniPShethSHicksK. Re: Imatinib mesylate administration in the first 100 days after stem cell transplantation. Biol Blood Marrow Transplant2004;10:883884.

    • Search Google Scholar
    • Export Citation
  • 143.

    DeAngeloDJHochbergEPAlyeaEP. Extended follow-up of patients treated with imatinib mesylate (gleevec) for chronic myelogenous leukemia relapse after allogeneic transplantation: durable cytogenetic remission and conversion to complete donor chimerism without graft-versus-host disease. Clin Cancer Res2004;10:50655071.

    • Search Google Scholar
    • Export Citation
  • 144.

    PalandriFAmabileMRostiG. Imatinib therapy for chronic myeloid leukemia patients who relapse after allogeneic stem cell transplantation: a molecular analysis. Bone Marrow Transplant2007;39:189191.