Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Version 4.2020, NCCN Clinical Practice Guidelines in Oncology

Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are characterized by a progressive accumulation of leukemic cells in the peripheral blood, bone marrow, and lymphoid tissues. Treatment of CLL/SLL has evolved significantly in recent years because of the improved understanding of the disease biology and the development of novel targeted therapies. In patients with indications for initiating treatment, the selection of treatment should be based on the disease stage, patient’s age and overall fitness (performance status and comorbid conditions), and cytogenetic abnormalities. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with CLL/SLL.

Abstract

Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are characterized by a progressive accumulation of leukemic cells in the peripheral blood, bone marrow, and lymphoid tissues. Treatment of CLL/SLL has evolved significantly in recent years because of the improved understanding of the disease biology and the development of novel targeted therapies. In patients with indications for initiating treatment, the selection of treatment should be based on the disease stage, patient’s age and overall fitness (performance status and comorbid conditions), and cytogenetic abnormalities. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with CLL/SLL.

Overview

Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are characterized by a progressive accumulation of leukemic cells in the peripheral blood, bone marrow, and lymphoid tissues. Morphologically, these leukemic cells appear as small, mature lymphocytes that may be found admixed with occasional larger or atypical cells, or prolymphocytes. CLL remains the most prevalent adult leukemia in Western countries. In 2019, an estimated 20,720 people will be diagnosed with CLL in the United States, and an estimated 3,930 people will die of the disease.1 CLL and SLL are different manifestations of the same disease and are managed in much the same way.2 The major difference is that in CLL, a significant number of the abnormal lymphocytes are found in the peripheral blood in addition to bone marrow and lymphoid tissue, and in SLL, the bulk of disease is in lymph nodes, bone marrow, and other lymphoid tissues, and there are few (if any) abnormal lymphocytes circulating in the peripheral blood.

Staging

The Rai and Binet systems are the 2 staging systems currently used for the evaluation of patients with CLL, both in the routine practice and clinical trial settings.3,4 Both staging systems rely on physical evidence (ie, presence of lymph node involvement, enlarged spleen and/or liver) and blood parameters (presence of anemia or thrombocytopenia) to assess the degree of tumor burden.

The Lugano Modification of the Ann Arbor Staging System is used for patients with SLL.5

Prognostic Factors

Immunoglobulin heavy chain variable region (IGHV) gene mutation status is an important predictor of survival outcomes. Unmutated IGHV (≥98% homology with germline gene sequence) is associated with poor prognosis and significantly decreased survival compared with mutated IGHV, irrespective of the stage of the disease.6,7 In addition, VH3-21 gene usage is associated with poor outcomes regardless of the IGHV mutation status (as defined by percent homology with germline sequence).8 Unmutated IGHV or the VH3-21 gene usage was shown to be an independent predictor of shorter treatment-free interval and/or survival outcomes, even when high-risk genetic abnormalities were included in the multivariable regression models.912

Cytogenetic abnormalities detected by fluorescence in situ hybridization (FISH) are present in more than 80% of patients with previously untreated CLL. Del(13q) (55%), del(11q) (18%), trisomy 12 (16%), del(17p) (7%), and del(6q) (7%) are the most common abnormalities at the time of diagnosis.13

Del(13q) as a sole abnormality is associated with favorable prognosis and the longest median survival (133 months). Del(11q) is often associated with extensive lymphadenopathy, disease progression, and shorter median survival (79 months).13 The addition of an alkylating agent to fludarabine-based chemoimmunotherapy may help to overcome the adverse prognostic significance of del(11q) in patients with previously untreated CLL.12,14 Del(17p), which reflects the loss of the TP53 gene and is frequently associated with mutations in the remaining TP53 allele, is associated with short treatment-free interval, short median survival (32 months), and poor response to chemotherapy.13 The prognostic significance of del(17p) may be dependent on the proportion of malignant cells with this abnormality, and the prognosis is more favorable when the percentage of cells with del(17p) is low.12,15,16 Del(17p) is more frequently observed in patients with previously treated CLL, suggesting that acquisition and/or expansion of CLL clones with del(17p) may occur during the course of treatment.17 TP53 abnormalities can occur in the absence of del(17p), and TP53 mutations have been identified as predictors of resistance to fludarabine-based or bendamustine-based regimens and poor survival, independent of 17p chromosome status.1821

The prognostic significance of IGHV mutation status and cytogenetic abnormalities has been evaluated in large prospective randomized studies evaluating chemotherapy or chemoimmunotherapy.12,22,23 In the CLL4 trial (chlorambucil vs fludarabine vs fludarabine and cyclophosphamide [FC] as first-line therapy), the loss of TP53 was found to be the strongest predictor of poor outcomes to first-line therapy.12 In addition, del(11q) and treatment allocation were independent predictors for progression-free survival (PFS) and age was an independent predictor for overall survival (OS). In the long-term follow-up from the CALGB 9712 study (concurrent vs sequential fludarabine and rituximab as first-line therapy), unmutated IGHV was a significant independent predictor for shorter PFS and OS, and del(17p) or del(11q) were independent predictors for shorter survival.22 In the CLL8 (FC versus FCR as first-line therapy), the presence of TP53 mutation, del(17p), and unmutated IGHV were the strongest predictors of shorter PFS and OS.23

Among the cell surface markers detected by flow cytometry, immunohistochemistry, or methylation (CD38, CD49d, and ZAP-70), CD49d (≥30%) is the strongest predictor of OS and treatment-free survival.2428 CD38 expression (≥30%)6,10,12,2931 and/or ZAP-70 (≥20%) are associated with shorter PFS and OS outcomes.3237 In addition, it was suggested that ZAP-70 positivity may be a stronger predictor of clinical outcomes than IGHV mutation status or CD38.3537 ZAP-70 methylation analysis (which is closely associated with ZAP-70 expression and IGHV mutation status) was also reported to be a useful prognostic test for patients with CLL but is not routinely performed clinically.3840

Beta-2 microglobulin is readily measured by standard laboratory evaluation of blood samples, and an elevated level of serum beta-2 microglobulin was shown to be a strong independent prognostic indicator for treatment-free interval, response to treatment, and OS in patients treated with first-line chemoimmunotherapy regimens.41,42 However, it is influenced in a CLL disease–independent manner by renal dysfunction.

Recurrent mutations in NOTCH1, SF3B1, and BIRC3 genes with prognostic implications have been identified in approximately 4%–15% of patients with newly diagnosed CLL, and the incidences are much higher (15%–25%) in patients with fludarabine-refractory CLL.4351 Several prognostic models incorporating traditional and newer prognostic markers have been developed for the risk stratification.5258

Collectively, data from the previously cited studies suggest that the prognostic significance of aforementioned prognostic markers may vary depending on the patient population, treatment regimens, and clinical outcomes being evaluated. In addition, the survival estimates for traditional and newer prognostic markers were generated in an era of chemotherapy or chemoimmunotherapy. Newer small-molecule inhibitor-based therapy has significantly improved survival outcomes, including for patients with high-risk disease. The duration of follow-up is short in many of these studies and the prognostic significance of these markers in patients treated with newer targeted therapies is uncertain.

Complex karyotype (CK; ≥3 unrelated chromosomal abnormalities in >1 cell on CpG-stimulated karyotype of CLL cells) may be a stronger predictor of poor clinical outcomes than del(17p) or TP53 mutation in patients with CLL treated with ibrutinib-based regimens.5964 In a multivariate analysis, among patients with relapsed/refractory CLL treated with ibrutinib-based regimens, only CK was significantly associated with inferior event-free survival (P=.006), whereas CK (P=.008) and fludarabine-refractory CLL (P=.005) were independently associated with inferior OS.60 In another analysis of 308 patients treated with ibrutinib on 4 sequential clinical trials, in a multivariate analysis, CK at baseline, presence of del(17p), and age <65 years were all independently associated with a risk for CLL progression.65 In patients ≥65 years without CK or del(17p), the estimated cumulative incidence of CLL progression at 4 years was 2% compared with 44% in patients <65 years with CK and del(17p). A more recent retrospective analysis of >5,000 patients with available cytogenetic data suggests that CK is associated with variable clinical behavior.64 High CK (≥5 unrelated chromosomal abnormalities) emerged as an adverse prognostic factor independent of clinical stage, IGHV mutation status, and TP53 aberrations (del(17p) and/or TP53 mutation) whereas low CK (3 unrelated chromosomal abnormalities) and intermediate CK (4 unrelated chromosomal abnormalities) were clinically relevant only if coexisting with TP53 aberrations.

Acquired resistance to ibrutinib is predominantly mediated by BTK and PLCG2 mutations, which have been detected in patients with relapsed CLL after treatment with ibrutinib at an estimated median of 9 months before relapse.65,66 BTK and/or PLCG2 mutations have also been detected in patients with progressive CLL during ibrutinib therapy up to 15 months before the manifestation of clinical progression.67 Similar mutations have also been described in patients receiving acalabrutinib.68 These findings suggest that testing for these mutations may be helpful to confirm resistance to ibrutinib or acalabrutinib. However, the reported variant allele frequencies are variable, with often low variant allele frequencies associated with disease progression on ibrutinib, leading to speculation that these mutations do not fully explain clinical resistance.65,67 Testing for mutations as screening for resistance is not currently recommended.

Response Criteria

The response criteria developed by the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) are outlined in CSLL-E (page 196). In the clinical practice setting, response assessment involves both physical examination and evaluation of blood parameters. The IWCLL guidelines provide further recommendations for the evaluations and response assessments appropriate for the general clinical practice setting versus for clinical trials.69

Immunomodulating agents such as lenalidomide can result in a tumor flare reaction characterized by painful enlargement of lymph nodes, lymphocytosis, rash, and bone pain. Tumor flare reaction correlated with clinical response in patients with CLL treated with lenalidomide.70

B-cell receptor (BCR) pathway inhibitor (BCRi) therapy with Bruton’s tyrosine kinase inhibitors (BTKi; ibrutinib and acalabrutinib) and phosphatidylinositol 3-kinase inhibitors (PI3Ki; idelalisib and duvelisib) cause early mobilization of lymphocytes into the blood, resulting in a transient lymphocytosis in most patients, which does not signify disease progression.7173 Prolonged lymphocytosis after ibrutinib treatment was reported to represent the persistence of a quiescent clone, and slow or incomplete resolution of lymphocytosis does not appear to impact outcome as measured by PFS.71

Considering these findings, the IWCLL response criteria were revised to more precisely predict the outcome of patients with CLL treated with immunomodulating agents and BCRi.74 The revised IWCLL response criteria allow for a new response category, “PR with lymphocytosis,” for patients receiving BTKi (ibrutinib or acalabrutinib) or PI3Ki (idelalisib or duvelisib) to include clinical response (reduction in lymph nodes and splenomegaly) with persistent lymphocytosis (in the absence of other indicators of progressive disease). Isolated progressive lymphocytosis in the setting of reduced lymph node size or organomegaly or improvement in hemoglobin/platelets will not be considered progressive disease.

Undetectable minimal residual disease (MRD; <10−4 detectable leukemic cells in peripheral blood or bone marrow) after the end of treatment (EOT) is associated with long-term survival.7578 In the combined analysis of 2 randomized phase III studies of the German CLL Study Group (GCLLSG) (CLL8 and CLL10), among patients who experienced complete response (CR) and partial response (PR), PFS was longer for those with MRD-negative CR and MRD-negative PR (61 and 54 months, respectively) than those with MRD-positive CR and MRD-positive PR (35 and 21 months, respectively).75 The persistence of posttreatment splenomegaly as a sole abnormality in MRD-negative patients did not have a negative impact on PFS. In a prospective study of 289 patients with CLL, undetectable MRD at end of first-line chemoimmunotherapy with FCR correlated with longer PFS.76 The median PFS was not reached for patients with undetectable MRD compared with 38 months for those with detectable MRD (P<.001). MRD level (≤1% vs >1%) after 3 courses of FCR predicted greater likelihood of achieving undetectable MRD by the EOT (64% vs 9%; P<.001). PFS was significantly longer for patients with MRD ≤1% versus >1% after 3 courses of FCR (median 73 vs 41 months; P<.001), but similar for <0.01% versus 0.01%–1%. The prognostic significance of MRD after EOT with venetoclax + obinutuzumab was confirmed in the prospective analysis of the CLL14 study.78 In this study, venetoclax + obinutuzumab achieved higher rates of undetectable MRD at EOT than chlorambucil + obinutuzumab both in the peripheral blood (76% vs 35%) and bone marrow (57% vs 17%). The 24-month PFS rate for venetoclax + obinutuzumab was higher for patients with undetectable MRD compared with those with detectable MRD (89% vs 62%) and the undetectable MRD translated into improved PFS regardless of the clinical response status at EOT.

These findings suggest that undetectable MRD in the peripheral blood after EOT is an important predictor of treatment efficacy, supporting the integration of MRD assessment as part of response evaluation. Allele-specific oligonucleotide polymerase chain reaction and 6-color flow cytometry (MRD flow) are the 2 validated methods used for the detection of MRD at the level of 10−4 to 10−5.79,80 Next-generation DNA sequencing–based assays have been reported to be more sensitive, allowing for the detection of MRD at the level of 10−6.8082

Diagnosis

The diagnosis of CLL requires the presence of at least 5×109/L monoclonal B-lymphocytes in the peripheral blood, and the clonality of B cells should be confirmed by flow cytometry.69 The diagnosis of SLL requires the presence of lymphadenopathy and/or splenomegaly with <5×109/L B-lymphocytes in the peripheral blood.69 B-cells with a CLL/SLL phenotype may be found in samples from patients with reactive lymph nodes; however, a diagnosis of SLL should only be made when effacement of the lymph node architecture is seen in biopsy samples.

Flow cytometry of peripheral blood with immunophenotyping using cell surface markers is adequate for the diagnosis of CLL, and bone marrow biopsy is generally not required. A diagnosis of SLL should ideally be confirmed using lymph node biopsy. Evaluation of cyclin D1 (flow cytometry or immunohistochemistry) or FISH analysis for t(11;14), flow cytometry evaluation of CD200, and immunohistochemistry for LEF1 may be helpful in the differential diagnosis of CLL, especially to exclude other CD5+B-cell lymphoproliferative disorders, specifically mantle cell lymphoma.8386

FISH for the detection of del(11q), del(13q), trisomy 12, del(17p), CpG-stimulated metaphase karyotype, TP53 sequencing, and molecular genetic analysis for IGHV mutation status can provide useful prognostic information and may guide selection of therapy.

Interphase FISH is the standard method to detect specific chromosomal abnormalities that may have prognostic significance. Conventional metaphase FISH is difficult in CLL due to the very low in vitro proliferative activity of the leukemic cells. CpG oligonucleotide stimulation can be used to enhance metaphase cytogenetics.87,88

Molecular analysis for IGHV mutation status is preferred over flow cytometry. IGHV mutation testing is recommended based on reproducibility and ready availability. A variety of IGHV percent cut-off levels ranging from 1%–5% have been studied.89 In a retrospective analysis of 203 patients treated with the FCR (fludarabine, cyclophosphamide, and rituximab) regimen, higher IGHV percentage levels were incrementally associated with favorable PFS and OS, suggesting that IGHV percentage is a continuous variable in patients treated with the FCR regimen.90 A cut-off level of ≤2% IGHV mutation is routinely used in clinical practice to differentiate patients with IGHV-mutated CLL from those with IGHV-unmutated CLL.91,92 Patients with IGHV mutated CLL by this definition can have long-term PFS after FCR (54% at 13 years).93 IGHV mutation status is necessary when considering treatment with chemoimmunotherapy.

CD38, CD49d, and ZAP-70 expression correlate with unmutated IGHV, and these have been proposed as surrogate markers for IGHV mutation status.6,25,32,33 However, discordant results between IGHV mutation status and CD38 or ZAP-70 positivity have been reported in about 20%–28% of cases.12,35,94 Furthermore, standardization and reproducibility of these markers across laboratories remains a challenge. Evaluation of CD38, CD49d, and ZAP-70 is not recommended outside the context of clinical trials.

Monoclonal B-Cell Lymphocytosis

Monoclonal B-cell lymphocytosis (MBL) is a condition in which an abnormal B-cell population with immunophenotype of CLL or related low-grade lymphoproliferative disorder does not meet the diagnostic criteria for CLL.95,96 An absolute monoclonal B-lymphocyte count of <5×109/L that is stable over a 3-month period in the absence of palpable lymphadenopathy or other clinical features characteristic of a lymphoproliferative disorder (anemia, thrombocytopenia, constitutional symptoms, organomegaly) is defined as MBL.97

MBL is further categorized into low-count MBL (<0.5×109/L) that rarely progresses to CLL and high-count MBL (>0.5×109/L) that progresses to CLL requiring therapy at a rate of 1%–2% per year.98,99 High-count MBL is distinguished from Rai 0 CLL based on whether the monoclonal B-cell count is above or below 5×109/L.100 A nodal variant characterized by nodal infiltration of CLL-line cells without apparent proliferation centers and absence of lymphadenopathy has also been described in a subset of patients with MBL.101

MBL is associated with favorable molecular characteristics, mutated IGHV and del(13q), lower prevalence of del(11q)/del(17p) and mutated TP53, slower lymphocyte doubling time, longer treatment-free survival, and very low rate of progression to CLL.96 Observation is recommended for all individuals with MBL.

Workup

The workup for CLL/SLL is similar to the workup for other lymphoid neoplasms. Quantitative immunoglobulins may be informative in patients with recurrent infections. Measurement of beta-2 microglobulin may provide useful prognostic information.52 Reticulocyte counts and a direct Coombs test should be performed to evaluate for the possibility of hemolysis and pure red cell aplasia in patients with anemia.

The prognostic significance of bone marrow involvement (diffuse vs nodular) is no longer a factor with the availability of more reliable prognostic markers that can be obtained by analysis of circulating lymphocytes (eg, IGHV mutation status and cytogenetic abnormalities detected by FISH). Thus, bone marrow biopsy with or without aspirate is no longer considered a required part of the diagnostic evaluation of patients with suspected CLL, but it may be informative for the diagnosis of immune-mediated or disease-related cytopenias before start of treatment.

CT scans may be useful for the evaluation of symptoms or bulky disease, to monitor disease progression in patients with new symptoms when peripheral adenopathy is not present or for the assessment of tumor lysis syndrome (TLS) risk category before the initiation of venetoclax. However, serial CT scans are not recommended for asymptomatic patients. PET scan is generally not useful in CLL but can assist in directing nodal biopsy if Richter’s transformation is suspected.102,103

Localized SLL (Lugano Stage I)

Locoregional radiation therapy (24–30 Gy) is an appropriate induction therapy for patients with symptomatic localized disease. In rare patients, radiation therapy may be contraindicated or may be a suboptimal therapy due to the presence of comorbidities or the potential for long-term toxicity. Patients with localized SLL that has progressed after initial radiation therapy should be treated as described for patients with SLL (Lugano stage II–IV).

SLL (Lugano Stage II–IV) or CLL (Rai Stages 0–IV)

Early-stage disease in some patients may have an indolent course and in others may progress rapidly to advanced disease requiring immediate treatment. In the absence of disease symptoms, a “watch and wait” approach is often appropriate for patients with stage II–IV SLL, low-risk CLL (Rai stage 0 or Binet A), or intermediate-risk CLL (Rai stage I–II or Binet B) and treatment will be beneficial if they become symptomatic or show evidence of progressive disease.69 Patients with advanced-stage or high-risk CLL (Rai stage III–IV or Binet C) with progressive cytopenia require treatment. Selected patients with mild, stable cytopenia may continue to be observed.

Indications for initiating treatment include severe fatigue, weight loss, night sweats, and fever without infection; threatened end-organ function; progressive bulky disease (enlarged spleen or lymph nodes); progressive anemia or thrombocytopenia; or steroid-refractory autoimmune cytopenia.69 Absolute lymphocyte count alone is not an indication for treatment, and symptoms related to leukostasis are exceedingly rare in CLL patients.69

In patients with indications for initiating treatment, patient age, performance status or fitness, and the presence or absence of del(17p) or TP53 mutation should then help to direct treatment options, as discussed subsequently. Reevaluation for TP53 mutation status and del(17p) by FISH, and IGHV mutation status if not previously done (important for selection of initial treatment when considering chemoimmunotherapy) are recommended before starting treatment. CpG-stimulated karyotyping is useful to identify high-risk patients, particularly for treatment with targeted agents.

Assessment of Functional Status and Comorbidity

CLL/SLL is diagnosed mainly in older adults, with a median age of 72 years at diagnosis. The age cutoff of 65 years is used in most clinical trials, including the studies conducted by the GCLLSG.104 Comorbidities are frequently present in older patients and the presence of multiple comorbidities (≥2 comorbidities) was an independent predictor of clinical outcome, independent of patients’ age or disease stage.105 In a multivariate analysis, after adjustment for other prognostic factors and treatment, comorbidity maintained independent prognostic value. These findings underscore the need to assess comorbidities, in addition to patient age and performance status, before treatment selection.

Cumulative Illness Rating Scale (CIRS), Charlson Comorbidity Index, and the NCI Comorbidity Index are some of the scoring systems that can be used to assess comorbidities in patients with CLL. CIRS in combination with creatinine clearance (CrCl) was used by the GCLLSG to assess the overall fitness of patients enrolled in clinical trials.105,106 In the CLL14 study, CIRS score >6 or an estimated CrCl <70 mL/min was used as the eligibility criteria for patients with significant comorbidities.107

Patients are stratified into 3 groups based on their functional status and presence or absence of comorbidities: frail patients with significant comorbidities; patients ≥65 years or younger patients with significant comorbidities (CrCl <70 mL/min); and patients <65 years without significant comorbidities.

The NCCN CLL Panel stratified all the regimens into 3 categories (based on the evidence, efficacy, toxicity, preexisting comorbidities, and in some cases access to certain agents): preferred regimens, other recommended regimens, and useful under certain circumstances.

CLL/SLL Without del(17p) or TP53 Mutation

First-Line Therapy: Preferred Regimens

Ibrutinib

The efficacy and safety of ibrutinib monotherapy in patients ≥65 years with untreated CLL or SLL without del(17p) has been established in 2 phase III randomized trials, first demonstrated in the RESONATE-2 study108,109 and more recently in the Alliance North American Intergroup Study (A041202).21

In the RESONATE-2 study, 269 patients (≥65 years of age) were randomized to receive ibrutinib (420 mg continuous treatment) or chlorambucil as first-line therapy.108 After a median follow-up of 5 years, ibrutinib resulted in significantly higher overall response rate (ORR; 92% vs 37%; P<.0001) and significantly longer PFS rate (70% vs 12% at 60 months; P<.0001) compared with chlorambucil.109 With 57% of patients switching to ibrutinib after disease progression on chlorambucil, the estimated 5-year OS rates (without censoring for crossover from chlorambucil to ibrutinib) were 83% and 68% respectively, for patients treated with ibrutinib and chlorambucil. Neutropenia (13%), pneumonia (12%), hypertension (8%), and anemia (7%) were the common grade ≥3 adverse events. Ibrutinib also improved PFS compared with chlorambucil in patients with high-risk CLL, and the estimated 5-year PFS rates were 79% and 67%, respectively, for patients with del(11q) and unmutated IGHV.

In the Alliance North American Intergroup Study (ibrutinib monotherapy [n=182] versus ibrutinib + rituximab [n=182] versus BR [n=183]), ibrutinib monotherapy and ibrutinib + rituximab resulted in superior ORR and PFS compared with BR in patients ≥65 years with untreated CLL.21 The ORRs were 93% and 94%, respectively, for ibrutinib and ibrutinib + rituximab compared with 81% for BR. With a median follow-up of 38 months, the estimated 2-year PFS rates were 87% and 88%, respectively, for ibrutinib monotherapy and ibrutinib + rituximab compared with 74% for BR (P<.001 for both ibrutinib vs BR and ibrutinib + rituximab vs BR). There was no difference in PFS between treatment groups based on IGHV mutation status. The 2-year OS rates, however, were not significantly different among the treatment arms (90%, 94%, and 95%, respectively, for the 3 treatment arms; P=.87). The presence of CK did not have an impact on PFS among patients treated with ibrutinib. The estimated 2-year PFS rates were 91% and 87%, respectively, for ibrutinib and ibrutinib + rituximab among patients with CK. This study also showed primary benefit for ibrutinib and ibrutinib + rituximab in patients with unmutated IGHV (61% of patients had unmutated IGHV) rather than mutated IGHV.

Ibrutinib monotherapy was approved for first-line therapy for all patients based on the results of the RESOANTE-2 study that established the efficacy of ibrutinib monotherapy as first-line therapy in patients ≥65 years without del(17p). The panel consensus was to continue the listing of ibrutinib with a category 1 recommendation for frail patients with significant comorbidities (not able to tolerate purine analogs) and for patients ≥65 years or younger patients with significant comorbidities.

The ECOG-ACRIN cancer research group (E1912) study showed that ibrutinib + rituximab was more effective than FCR for patients ≤70 years without del(17p)/TP53 mutation, especially in patients with unmutated IGHV.110 These results suggest that ibrutinib may be an appropriate option (instead of chemoimmunotherapy) for younger patients with IGHV unmutated CLL who do want to enroll in a clinical trial. Therefore, based on the results of the E1912 study, the panel consensus was to change the recommendation of ibrutinib from a category 2A to category 1 recommendation for patients <65 years without del(17p) or TP53 mutation.

Acalabrutinib ± Obinutuzumab

The ELEVATE-TN phase III study randomized 535 patients (≥65 years or <65 years with coexisting conditions [CIRS score >6; CrCl <70 mL/min) to acalabrutinib + obinutuzumab (n=179), acalabrutinib (n=179), or chlorambucil + obinutuzumab (n=177).111 Acalabrutinib was given continuously until disease progression and obinutuzumab was added to acalabrutinib and chlorambucil for 6 cycles. The ORRs were higher with acalabrutinib + obinutuzumab (94%; 13% CR) and acalabrutinib monotherapy (85% consisting entirely of PRs) than chlorambucil + obinutuzumab (79%; 5% CR). At a median follow-up of 28 months, acalabrutinib ± obinutuzumab significantly improved PFS compared with chlorambucil + obinutuzumab (P<.0001). The estimated 2-year PFS rates were 93%, 87%, and 47% for acalabrutinib + obinutuzumab, acalabrutinib, and chlorambucil + obinutuzumab, respectively. Acalabrutinib + obinutuzumab was associated with a PFS benefit in patients with IGHV unmutated CLL as well as IGHV mutated CLL compared with chlorambucil + obinutuzumab. This study, however, was not powered to compare the PFS benefit between the 2 acalabrutinib arms. The estimated 2-year OS rates were 95%, 95%, and 92%, respectively. There was a trend toward improved OS for acalabrutinib ± obinutuzumab, despite crossover for disease progression in the chlorambucil + obinutuzumab arm, although longer follow-up is needed to confirm any OS benefit. The incidences of grade ≥3 neutropenia were higher with chlorambucil + obinutuzumab (70%) than with acalabrutinib + obinutuzumab (30%) and the addition of obinutuzumab increased neutropenia compared with acalabrutinib (10%).

Acalabrutinib was recently granted broad FDA approval for the treatment of patients with untreated and relapsed/refractory CLL. Based on the results of the ELEVATE-TN trial, the panel consensus was to include acalabrutinib ± obinutuzumab with a category 2A recommendation for all patients with CLL without del(17p) or TP53 mutation.

Venetoclax + Obinutuzumab

The CLL14 study evaluated venetoclax + obinutuzumab versus chlorambucil + obinutuzumab for previously untreated CLL in 432 patients with comorbidities (CIRS score >6 and/or an estimated CrCl <70 mL/min; 216 patients in each treatment group).107 Fixed-duration treatment with 12 cycles of venetoclax 400 mg daily or chlorambucil was given, and both groups received obinutuzumab for first 6 cycles. After a median follow-up of 29 months, the ORR (85% vs 71%; P<.001), CR rate (50% vs 23%), and 24-month PFS rate (88% vs 64%; HR, 0.35; P<.001) were significantly higher for venetoclax + obinutuzumab compared with chlorambucil + obinutuzumab. No difference in PFS was seen between treatment groups for patients with mutated IGHV. The median OS was not reached in either treatment group. The undetectable-MRD rate (<10−4 as assessed by allele-specific oligonucleotide polymerase chain reaction assay) at 3 months after completion of treatment was significantly higher with venetoclax + obinutuzumab compared with chlorambucil + obinutuzumab in both peripheral blood (76% vs 35%; P<.0001) and bone marrow (57% vs 17%; P<.0001). The undetectable-MRD rate at 12 months after completion of treatment was 81% and 27% for venetoclax + obinutuzumab and chlorambucil + obinutuzumab, respectively. Undetectable-MRD status at 3 months after completion of treatment correlated with longer PFS. Venetoclax + obinutuzumab was also associated with low rate of conversion to MRD-positive status 1 year after treatment. Grade 3 or 4 neutropenia occurred in 53% of patients in the venetoclax + obinutuzumab group and in 48% of patients in the chlorambucil + obinutuzumab group. Grade 3 or 4 infections occurred in 18% and 15% of patients, respectively.

Venetoclax in combination with obinutuzumab was recently granted broad FDA approval for the treatment of patients with untreated and relapsed/refractory CLL.

The panel consensus was to include venetoclax + obinutuzumab as a preferred regimen with a category 2A recommendation for frail patients with significant comorbidities (not able to tolerate purine analogs) and patients ≥65 years or younger patients with significant comorbidities based on the results of the CLL14 study.107

The CLL14 study established the efficacy of this combination only in patients with comorbidities (CIRS score >6 or an estimated CrCl <70 mL/min).107 The panel members acknowledged that the efficacy of this combination in patients without significant comorbidities has not been established in a randomized clinical trial. However, with the recent FDA approval, some panel members agreed that venetoclax + obinutuzumab may be an appropriate fixed-duration chemotherapy-free treatment option for younger patients without comorbidities who do want to enroll in a clinical trial. Therefore, initially, the consensus of the panel was to include venetoclax + obinutuzumab as an option under “other recommended regimens” with a category 2B recommendation for patients <65 years of age without significant comorbidities. After rereview of the data from the CLL14 study (following publication of the full paper), the panel consensus was to change the recommendation of venetoclax + obinutuzumab from category 2B (other recommended regimen) to category 2A (preferred regimen) for patients <65 years of age without significant comorbidities.

First-Line Therapy: Other Recommended Regimens

Bendamustine + Anti-CD20 Monoclonal Antibody

Bendamustine + anti CD20 monoclonal antibody (mAb; obinutuzumab, ofatumumab or rituximab) has demonstrated activity in patients with previously untreated CLL, resulting in an ORR of 81% (35% CR) to 95% (43% CR).112114 In the CLL10 study (discussed subsequently), no significant difference was seen in PFS between BR and FCR as first line therapy for CLL without del(17p) in patients >65 years, although the PFS benefit of FCR was significant in physically fit patients <65 years.115 The incidence of severe neutropenia and infections was significantly more frequent in the FCR arm, especially among patients >65 years. The updated results of the CLL10 study also confirmed that BR is associated with a decreased risk of secondary acute myeloid leukemia or myelodysplastic syndrome.115 After a median follow-up of 58 months, the incidences of secondary acute myeloid leukemia and myelodysplastic syndrome were 3% and 1% in FCR and BR arms, respectively.

Bendamustine + anti-CD20 mAb may be a reasonable alternative for older patients otherwise eligible for chemoimmunotherapy and is included as an option for patients ≥65 years or younger patients with significant comorbidities and for patients <65 years without significant comorbidities.

Chlorambucil + Obinutuzumab

The CLL11 study established that chlorambucil + obinutuzumab is superior to chlorambucil + rituximab for elderly patients and for those with comorbidities lacking del(17p) or TP53 mutation.116

The results of the iLLUMINATE study demonstrated ibrutinib + obinutuzumab as a more-effective first-line therapy than chlorambucil + obinutuzumab for patients ≥65 years and for patients <65 years with comorbidities (median age was 71 years; ibrutinib + obinutuzumab, n=113; chlorambucil + obinutuzumab, n=116).117 Ibrutinib was given continuously until disease progression, and both groups received obinutuzumab for the first 6 cycles. At a median follow-up of 31 months, ibrutinib + obinutuzumab resulted in superior (independent review committee [IRC]-assessed) PFS (median not reached vs 19 months; P<.0001) and higher (IRC-assessed) ORR (88% vs 73%) compared with chlorambucil + obinutuzumab. In the high-risk population, the ORRs were 90% (14% CR) and 68% (4% CR), respectively. The estimated PFS rate at 30 months was 79% and 31%, respectively, for ibrutinib + obinutuzumab and chlorambucil + obinutuzumab. The PFS benefit with ibrutinib + obinutuzumab was observed across all subgroups of patients [unmutated IGHV: not reached vs 15 months; del(17p): not reached vs 11 months]. The 30-month OS rate was not significantly different between the treatment arms (86% and 85% for ibrutinib + obinutuzumab and chlorambucil + obinutuzumab, respectively). Pneumonia (5%), atrial fibrillation (4%), febrile neutropenia (4%), and pyrexia (4%) were the most common adverse events in the ibrutinib + obinutuzumab arm. Infusion-related reactions (7%), febrile neutropenia (6%), pneumonia (4%), TLS (4%), and pyrexia (3%) were more common with chlorambucil + obinutuzumab. Infusion-related reactions were less frequent with ibrutinib + obinutuzumab versus chlorambucil + obinutuzumab (any grade, 25% vs 58%; grade ≥3, 3% vs 9%).

Based on the results of the iLLUMINATE study, the panel consensus was to change the recommendation of chlorambucil + obinutuzumab from category 1 (preferred regimen) to category 2A (other recommended regimen) for frail patients with significant comorbidities and patients ≥65 years or younger patients with significant comorbidities. Chlorambucil + rituximab or ofatumumab is no longer recommended as an option for first-line therapy for this group of patients based on the results of the CLL11 study that established the superiority of chlorambucil + obinutuzumab over chlorambucil + rituximab for elderly patients and for those with comorbidities.

Fludarabine, Cyclophosphamide, and Rituximab

The FCR regimen results in high response rates and improved OS in specific subgroups of fit patients with previously untreated CLL, especially in those with mutated IGHV.23,93,115

In the CLL8 study, 817 physically fit patients with previously untreated CLL (median age 61 years) were randomized to receive up to 6 courses of either the FCR (n=408) or FC (n=409) regimen.23 The FCR regimen resulted in higher ORR (90% vs 80%; P<.001) and CR rate (44% vs 22%; P<.001) compared with FC. After a median follow-up of 6 years, the median PFS was 57 months and 33 months, respectively, for FCR and FC (P<.001). The median OS was not reached for FCR and was 86.0 months for FC (P=.001). FCR was associated with a statistically significant survival benefit compared with FC in patients <65 years (5-year OS rates were 81% and 69%, respectively; P=.002). The corresponding 5-year OS rates were 74% and 62%, respectively, in patients ≥65 years (P=.288). The incidence of prolonged neutropenia was significantly higher with the FCR regimen than with FC during the first year after treatment (17% vs 9%; P=.007).

In a phase II study of 300 patients with previously untreated CLL, at a median follow-up of 13 years, the ORR was 95% (72% CR).93 The overall 13-year PFS rate was 31% (54% for patients with mutated IGHV and 9% for patients with unmutated IGHV). MRD negativity was achieved in 51% of patients with mutated IGHV, with a PFS rate of 80% at 13 years. In a multivariable analysis, unmutated IGHV and del(17p) by conventional karyotyping were significantly associated with inferior PFS. Long-term PFS was notable particularly for patients with mutated IGHV, with a plateau on the PFS curve beyond 10 years.

The final analysis of the CLL10 study confirmed the superiority of FCR over BR as first-line therapy for CLL without del(17p) in fit patients (n=567; CIRS score ≤6; CrCl >70 mL/min).115 The median age was 62 years, but a significantly higher proportion of patients were >65 years in the BR arm (39% vs 30%). After a median follow-up of 37 months, the ORR was 95% for FCR and 96% for BR (P=1.0) with no difference in OS (3-year OS rate was 91% for FCR vs 92% for BR; P=.89). FCR resulted in higher CR rate (40% vs 31%), more MRD negativity (59% vs 26% at 12 months; P<.0001; 55% vs 27% at 18 months; P=.002), and longer median PFS (55 months vs 42 months; P=.0003) compared with BR. The PFS benefit of FCR was significant in physically fit patients <65 years and in patients with mutated IGHV. The median PFS was 54 months and 39 months, respectively, for FCR and BR in patients ≤65 years (P=.0004) and there was no significant difference in PFS between the treatment groups for patients >65 years (median not reached for FCR and 49 months for BR; P=.172). Among patients with a mutated IGHV, the median PFS was not reached for FCR compared with 55 months for BR (P=.089). The incidences of severe neutropenia and infections were significantly more frequent in the FCR arm (39% vs 25%), especially in patients >65 years.

The E1912 study showed that ibrutinib + rituximab was more effective than FCR for patients ≤70 years without del(17p)/TP53 mutation (354 patients were randomized to ibrutinib and rituximab [ibrutinib was given continuously until disease progression and rituximab was added for the first 6 cycles] and 175 patients were randomized to 6 cycles of FCR).110 At a median follow-up of 34 months, ibrutinib + rituximab was associated with significantly improved PFS (89% vs 73% at 3 years; hazard ratio [HR], 0.35; P<.0001) and OS (99% vs 92% at 3 years; HR, 0.17; P<.0001) compared with FCR. In a subgroup analysis for PFS, ibrutinib + rituximab was more effective than FCR, especially for patients with unmutated IGHV (91% vs 63% at 3 years; HR, 0.26; P<.0001), but ibrutinib + rituximab was not superior to FCR in patients with mutated IGHV (87.7% vs 88%; HR, 0.44; P=.07). The extended follow-up results also confirmed these findings.118 The incidences of grade ≥3 neutropenia [45% vs 26%], and neutropenic fever (20% vs 11%) were higher with FCR, whereas the incidences of grade ≥3 cardiac toxic effects (7% vs 2%), atrial fibrillation (7% vs 3%), hypertension (19% vs 8%), and hemorrhagic events (grade ≥3; 1% vs 0%) were higher with ibrutinib.

Based on the results of the E1912 study, the panel consensus was to change the recommendation for FCR from category 1 (preferred regimen) to category 2A (other recommended regimen) for patients <65 years without significant comorbidities. The panel emphasizes that FCR is the preferred first-line therapy option for IGHV-mutated CLL in patients <65 years without significant comorbidities.

Fludarabine + Rituximab

Fludarabine with concurrent or sequential administration of rituximab was evaluated in the CALGB 9712 study in patients with untreated CLL.22,119 The concurrent regimen was associated with a higher rate of overall response (ORR; 90% vs 77% for the sequential regimen) and CR (47% vs 28%) at the expense of higher incidence of grade 3 or 4 toxicity (primarily comprising neutropenia and infusion-related events).119 After a median follow-up of 117 months, the median PFS (42 months) and OS (85 months) were similar for the 2 treatment groups and the estimated 5-year PFS rate was 27%.22

Fludarabine + rituximab (FR) is included as an option for patients <65 years without significant comorbidities. Outcomes for CLL with del(11q) are better with chemoimmunotherapy containing an alkylating agent. Therefore, FR is not recommended for CLL with del(11q).

High-Dose Methylprednisolone + Rituximab

High-dose methylprednisolone (HDMP) + rituximab is included with a category 2B recommendation for all patients, regardless of patient’s age and comorbidities.120 HDMP + rituximab was associated with a lower risk of myelosuppression and lower incidences of infectious complications (attributed to treatment in the frontline setting, good performance status of the patients, use of anti-infective prophylaxis during treatment, and the administration of intravenous immunoglobulin to patients with infections and hypogammaglobulinemia).

Ibrutinib + Rituximab or Obinutuzumab

The results of recent randomized phase III trials demonstrated that ibrutinib + rituximab is more effective than chemoimmunotherapy with BR (Alliance North American Intergroup Study)27 and ibrutinib + obinutuzumab is more effective than chlorambucil + obinutuzumab (iLLUMINATE study)21,117 for untreated CLL without del(17p) or TP53 mutation in patients ≥65 years and for patients <65 years with comorbidities. Ibrutinib + obinutuzumab was recently approved by the FDA for first-line therapy based on the results of the iLLUMINATE study.117 The E1912 study also showed that ibrutinib + rituximab was more effective than FCR for patients ≤70 years without del(17p)/TP53 mutation, especially for those with unmutated IGHV.110,118

However, the results of 2 randomized studies did not show a benefit for the addition of rituximab to ibrutinib.21,121 In the Alliance North American Intergroup Study (A041202), the estimated 2-year PFS rates were 88% and 87%, respectively, for ibrutinib + rituximab and ibrutinib monotherapy (P=.49).21 In a single center randomized study of 208 patients with high-risk CLL (27 patients with untreated CLL), at a median follow-up of 36 months, the estimated PFS rates were 86% and 87% respectively, for ibrutinib and ibrutinib + rituximab.121

Most panel members acknowledged that the addition of rituximab to ibrutinib has not yet shown improvement in clinical outcomes compared with ibrutinib monotherapy in a randomized clinical trial and there are no randomized clinical trials that have compared ibrutinib and ibrutinib + obinutuzumab. In all of the previously mentioned randomized clinical trials that have evaluated ibrutinib + rituximab or obinutuzumab, ibrutinib was given continuously until disease progression and obinutuzumab or rituximab was added to the combination arm only for the first 6 cycles. Therefore, the consensus was that the longer PFS was more the result of continuous and indefinite treatment with ibrutinib, rather than due to the contribution of an anti-CD20 mAb (rituximab or obinutuzumab) during the first 6 months of treatment. Improved outcomes with the addition of an anti-CD20 mAb may more likely be seen with fixed-duration treatment with this regimen.

Ibrutinib + obinutuzumab (for frail patients with significant comorbidities and patients aged ≥65 years and younger patients with significant comorbidities) and ibrutinib + rituximab (for patients <65 years without significant comorbidities) are included as a category 2B (other recommended regimens).

Pentostatin, Cyclophosphamide, and Rituximab

Pentostatin, cyclophosphamide, and rituximab (PCR) regimen is included as an option with a category 3 recommendation for patients <65 years without significant comorbidities.122124 In a phase III randomized trial that compared PCR and FCR regimens in 184 patients with previously untreated (80% of patients) or minimally pretreated CLL, although the ORRs were similar for PCR and FCR (49% vs 59%), the CR rate was lower in the PCR group (7% vs 14%; P=.04).124 The incidence of grade 3 or 4 infectious events and neutropenia were similar between treatment arms, with increased incidence of leukopenia and thrombocytopenia in the FCR group.124

Monotherapy With Rituximab, Obinutuzumab, or Chlorambucil

With multiple randomized studies showing a survival advantage for combination regimens containing chlorambucil or rituximab or obinutuzumab compared with monotherapy with either of these agents, most panel members acknowledged that monotherapy with any of these agents is not an effective first-line treatment even for frail patients with comorbid conditions. However, some panel members felt that given the favorable tolerability profile, monotherapy with rituximab or obinutuzumab or chlorambucil might be an appropriate treatment option for a small fraction of very frail patients or patients ≥65 years with substantial comorbidities or decreased performance status for whom more intensive regimens are not appropriate.

Obinutuzumab monotherapy is included with a category 2B recommendation and monotherapy with rituximab or chlorambucil is included with a category 3 recommendation for frail patients with significant comorbidities and for patients ≥65 years or younger patients with significant comorbidities.125127

Post First-Line Maintenance Therapy

In patients receiving BTKi (ibrutinib or acalabrutinib), continuation of ibrutinib or acalabrutinib is recommended (until disease progression) for patients with responding disease. Observation (until indications for retreatment) is recommended for patients experiencing response to first-line chemoimmunotherapy or targeted therapy with fixed-duration treatment (venetoclax + obinutuzumab).

Lenalidomide maintenance after first-line chemoimmunotherapy is included as an option under other recommended regimens for CLL without del(17p)/TP53 mutation in high-risk patients (MRD ≥10−2 or ≥10−4 and <10−2 with unmutated IGHV) based on the results of the CLLM1 study.128

Relapsed or Refractory Therapy: Preferred Regimens

Acalabrutinib, ibrutinib, venetoclax + rituximab (VenR), duvelisib, and idelalisib + rituximab (IdR) are included as options for patients with relapsed or refractory disease, regardless of patient’s age and comorbidities.

Acalabrutinib, ibrutinib, and VenR are included with a category 1 recommendation, based on the results of the phase III randomized studies (ASCEND, RESONATE and MURANO, respectively).129131 Although the panel acknowledged that duvelisib and IdR are preferred treatment options based on the efficacy data (in terms of median PFS) from randomized phase III studies,132,133 the panel consensus was to include duvelisib and IdR with a category 2A recommendation due to their toxicity profile (colitis, diarrhea, and increased risk of infections).

Acalabrutinib

In a phase II study of 134 patients with relapsed or refractory CLL, acalabrutinib resulted in an ORR of 85% (ORR including PR with lymphocytosis was 93%) and the ORRs were consistently high across all high-risk subgroups, including those with del (11q) or unmutated IGHV (86% and 88%, respectively).73,134 After a median follow-up of 20 months, the estimated median PFS was not reached, and the 18-month PFS rate was 88%.134

The ASCEND trial (310 patients were randomized to receive acalabrutinib or the investigator’s choice of IdR or BR) confirmed that acalabrutinib is superior to IdR or BR in terms of prolonging PFS in patients with relapsed/refractory CLL.131 The ORR was 81% and 76% for acalabrutinib and IdR or BR, respectively. After a follow-up of 16 months, the median PFS was not reached, 16 months, and 17 months for acalabrutinib, IdR, or BR respectively (P<.0001). The 1-year PFS rates were 88%, 68%, and 69%, respectively. The median OS was not different between the treatment groups. At the time of this interm analysis, 51% of patients randomized to IdR or BR with documented disease progression had crossed over to acalabrutinib. Headache (22%), neutropenia (19%), diarrhea (18%), anemia (15), cough (15%), pyrexia (12%), fatigue (10%), and nausea (7%) were the most common adverse events of any grade observed in ≥15% of patients treated with acalabrutinib.

Patients with ibrutinib intolerance have also been successfully treated with acalabrutinib without recurrence of symptoms.135 In a cohort of 33 patients with ibrutinib intolerance, after a median follow-up of 19 months, the ORR (including PR with lymphocytosis) was 76% and the median PFS was not reached. The estimated 1-year and 2-year PFS rates were 83% and 75%, respectively. Diarrhea (58%), headache (39%), cough (33%), weight increase (30%), nausea (27%), upper respiratory tract infection (24%), arthralgia (21%), pyrexia (21%), and fatigue (18%) were the most common adverse events of any grade observed in ≥20% of patients. Grade 3 or 4 neutropenia (12%) and thrombocytopenia (9%) were the most common grade 3 or 4 adverse events.

Acalabrutinib is recommended for relapsed/refractory therapy, regardless of patient’s age and comorbidities. Based on the results of the ASCEND trial, the panel consensus was to change the recommendation of acalabrutinib from category 2A (other recommended regimen) to category 1 (preferred regimen). Acalabrutinib is not effective for ibrutinib-refractory CLL with BTK C481S mutations.

Ibrutinib

The safety and efficacy of ibrutinib in relapsed/refractory CLL/SLL was established in a phase III randomized study (RESONATE; 391 patients with previously treated CLL were randomized to monotherapy with ibrutinib [420 mg once daily] or ofatumumab).129 The final analysis of this study (up to 6-year follow-up) also confirmed that ibrutinib significantly improved ORR, PFS, and OS compared with ofatumumab in patients with relapsed/refractory CLL/SLL who had received at least one prior therapy.136 At a median follow-up of 74 months, the median PFS (44 months vs 8 months for ofatumumab; P<.0001) and the estimated 5-year PFS rate (40% vs 3%) were significantly better for ibrutinib. At the time of this analysis, 68% of patients randomized to ofatumumab had crossed over to ibrutinib. The ORR was 91% and the median OS (with censoring or adjustment for patients who have crossed over to ibrutinib) was better for ibrutinib (HR, 0.64). Grade ≥3 atrial fibrillation and hypertension occurred in 9% and 6% of patients, respectively. The incidence of most of the grade ≥3 adverse events (neutropenia, pneumonia, and atrial fibrillation) decreased with follow-up.

Venetoclax + Rituximab

The results of a phase III randomized study (MURANO) demonstrated that fixed duration of treatment with VenR is associated with superior outcomes compared with BR in patients with relapsed/refractory CLL.130 In this study, 389 patients were randomized to receive 6 cycles of VenR (n=194) or BR (n=195). Patients received venetoclax monotherapy for 2 years after completing 6 cycles of VenR. After a median follow-up of 24 months, the ORR (92% vs 72%; P<.0001) and the 2-year PFS rate (85% vs 36%) were significantly higher for VenR than for BR. The 2-year PFS was also higher for VenR than for BR among patients with del(17p) (82% vs 28%) as well as for those without del(17p) (86% vs 41%). The rate of clearance of MRD from peripheral blood samples was higher for VenR than for BR (62% vs13%) and the rate was also higher for VenR than for BR at any time during the trial (84% vs 23%). The incidence of grade 3 or 4 neutropenia (58% vs 39%) and grade ≥3 TLS (3% vs 1%) were higher with VenR. Posttreatment follow-up at 36 months confirmed the superiority of VenR over BR in terms of undetectable MRD, PFS, and OS rates.137 The undetectable MRD after completion of treatment with VenR was a predictor of longer PFS (low-level MRD [10−4 to <10−2] was associated with improved PFS compared with high-level MRD [≥10−2]).

Duvelisib

Duvelisib was recently approved by the FDA for the treatment of relapsed/refractory CLL and SLL based on the results of the phase III randomized DUO study and the DYNAMO study.132,138,139

In the DUO study, 319 patients with relapsed/refractory CLL/SLL were randomized to either duvelisib (n=160) or ofatumumab (n=159).132 Patients who had received prior treatment with BTKi or PI3Ki were excluded. With a median follow-up of 22 months, duvelisib resulted in significantly improved lymph node response (>50% reduction in lymph node burden; 85% vs 16%), higher ORR (74% vs 45%; P<.0001), and longer median PFS (13 vs 10 months; P<.0001) compared with ofatumumab. At follow-up, the median OS was not significantly different between the treatment arms (not reached with an estimated 1-year OS rate of 86% in both treatment arms). Grade ≥3 adverse events including neutropenia, diarrhea, pneumonia, and colitis were reported in 30%, 15%, 14%, and 12% of patients, respectively. The efficacy of duvelisib after disease progression on ofatumumab in patients with relapsed/refractory CLL was established in the DUO crossover extension study (90 patients crossed over to duvelisib after disease progression on ofatumumab).138 The ORR after crossover to duvelisib was 77% compared with 29% on ofatumumab precrossover. In the subset of 47 patients with no response on ofatumumab precrossover, the ORR after crossover to duvelisib was 73%. The median PFS was 15 months for patients who crossed over to duvelisib compared with 9 months on ofatumumab precrossover.

In the phase II study (DYNAMO) evaluating the safety and efficacy of duvelisib in 129 patients with relapsed or refractory indolent non-Hodgkin lymphomas (NHL) (28 patients with relapsed/refractory SLL), duvelisib resulted in an ORR of 47% (68% for patients with SLL).139 With a median follow-up of 12 months, the estimated median PFS was 10 months for the entire study population. Neutropenia (28%), anemia (12%), thrombocytopenia (13%), and diarrhea (15%) were the most common grade ≥3 adverse events.

Idelalisib + Rituximab

In the multicenter phase III randomized study, 220 patients with relapsed CLL were randomized to receive rituximab with either idelalisib (150 mg) or placebo.133 Most of the patients (78%) were ≥65 years, 40% had moderate renal dysfunction (CrCl, <60 mL/min), 35% had poor bone marrow function (grade 3 or higher cytopenias), and 85% had a CIRS score >6. At the first planned interim analysis, the study was stopped early owing to the overwhelming efficacy of IdR. At 24 weeks, the PFS rate was 93% and 46% in the idelalisib group and placebo group, respectively.133 After a median follow-up of 18 months, IdR significantly improved ORR (84% vs 16%; P<.001), median PFS (19 vs 6 months), and median OS (41 vs 35 months), compared with rituximab + placebo in patients with relapsed CLL with coexisting conditions.140 Pyrexia (40%), diarrhea (29%), and rash (25%) were the most common adverse events in the idelalisib group.

IdR is an appropriate treatment option for relapsed/refractory CLL/SLL in patients for whom rituximab monotherapy would be considered appropriate due to the presence of other comorbidities (reduced renal function as measured by CrCl <60 mL/min, or grade ≥3 neutropenia or thrombocytopenia resulting from myelotoxic effects of prior therapy with cytotoxic agents).

Clinicians should be aware of the increased risk for infections in patients with relapsed/refractory CLL. Anti-infective prophylaxis for herpes simplex virus, Pneumocystis jirovecii pneumonia, and cytomegalovirus reactivation are recommended for patients on idelalisib. Due to infection-related toxicity and deaths seen with idelalisib in previously untreated CLL in phase III clinical trials, it should not be used as first-line therapy.

Relapsed/Refractory Therapy: Other Recommended Regimens

Alemtuzumab ± Rituximab

Alemtuzumab (subcutaneous or intravenous) ± rituximab has demonstrated activity in patients with fludarabine-refractory CLL and is included as an option, regardless of patient’s age or comorbidities.141144 Alemtuzumab + rituximab results in a higher ORR than that observed with alemtuzumab monotherapy, and no significant difference in response rates was seen between patients with fludarabine-sensitive and fludarabine-refractory disease.143 Myelosuppression and infections were the most common grade 3–4 toxicities. However, it should be noted that bulky lymphadenopathy does not typically respond well to alemtuzumab monotherapy in patients with refractory CLL.141,144

Bendamustine and Rituximab ± Idelalisib or Ibrutinib

The BR regimen also has shown activity in patients with relapsed/refractory CLL, resulting in an ORR of 46% in the subgroup of patients with fludarabine-refractory disease.145 The results of recent phase III trials have shown that the addition of idelalisib or ibrutinib to BR significantly improves PFS in patients with relapsed or refractory CLL.146,147

BR ± idelalisib or ibrutinib is included as an option for relapsed/refractory therapy, regardless of patient’s age or comorbidities.

Fludarabine, Cyclophosphamide, and Rituximab or Pentostatin, Cyclophosphamide, and Rituximab

In the phase III randomized REACH trial (n=552; patients were excluded if they had received prior FC regimen or prior rituximab and patients were required to have fludarabine-sensitive disease at relapse), FCR was associated with significantly improved median PFS (based on investigator assessment) compared with the FC arm (31 vs 21 months; P<.001), although OS was not significantly different between the treatment regimens.148 The median PFS (27 vs 22 months; P=.022), ORR (61% vs 49%; P<.005), and CR rate (9% vs 3%; P<.005) as assessed by an IRC, were also significantly higher with the FCR regimen.

The final analysis of a phase II study that evaluated FCR in patients with relapsed or refractory CLL (n=284; median 2 prior therapies) confirmed the safety and efficacy of this regimen in patients without high-risk features (refractory to prior therapy or chromosome 17 abnormalities).149 The ORR was 74% with a CR rate of 30% and the median PFS was 21 months. After a median follow-up of 43 months, the estimated median survival was 47 months. The most common adverse events with FCR were hematologic toxicities, including grade 3 or 4 neutropenia associated with 56% of treatment cycles and grade 3 or 4 thrombocytopenia in 20% of cycles. Pneumonia or sepsis was reported in 16% of patients. The subgroup of patients with fludarabine-refractory disease (n=54) had a significantly lower ORR (56% vs 79%; P<.001) and CR rate (7% vs 39%; P<.001) compared with fludarabine-sensitive patients; the median PFS (8 months vs 28 months; P<.001) and OS (38 months vs 52 months; P<.05) were also significantly decreased among patients with fludarabine-refractory CLL.149 In addition, the subgroup of patients (n=20) with chromosome 17 abnormalities (based on standard karyotyping) had worse outcomes with an ORR of 35% (no CR), median PFS of 5 months, and median survival of only 11 months. These findings suggest that FCR is a more appropriate treatment option for patients who have received fewer prior therapies (<4 prior regimens) and have fludarabine-sensitive disease, with no chromosome 17 abnormalities.149

The PCR regimen is also safe and effective in patients with previously treated CLL, resulting in an ORR of 75% among patients with fludarabine-refractory disease.150

FCR and PCR are included as options for relapsed/refractory therapy in patients <65 years without significant comorbidities. Reduced-dose FCR or PCR should be used for frail patients with significant comorbidities and for patients ≥65 years or younger patients with significant comorbidities.

Fludarabine, Cyclophosphamide, and Ofatumumab

In the COMPLEMENT 2 study that evaluated the combination of FC + ofatumumab (n=183) versus FC alone (n=182) in patients with relapsed CLL (median age 61 years; 134 patients [37%] >65 years), FC + ofatumumab was associated with improved PFS with a manageable safety profile. The median PFS (primary endpoint; assessed by the IRC) was 29 months and 19 months, respectively, for the combination of FC + ofatumumab and FC (P=.0032).151 There was no significant difference in OS between the treatment arms. The incidences of grade ≥3 adverse events were 74% and 69%, respectively, for the 2 treatment groups. Neutropenia was the most common adverse event reported in 49% of patients treated with FC + ofatumumab and in 36% of patients treated with FC.

FC + ofatumumab is included as an option for relapsed/refractory therapy, for patients <65 years without significant comorbidities.

HDMP + Rituximab

In small studies, HDMP + rituximab was effective in patients with heavily pretreated CLL (including fludarabine-refractory disease), resulting in an ORR of 93% (CR in 14%–36% of patients) and a median PFS of 7 to 15 months.152,153 The regimen was associated with infectious complications (including opportunistic fungal infections) in about 30% of patients, which may necessitate adequate anti-infective prophylaxis and close monitoring for early signs of infections.152,153

HDMP + rituximab is included as an option for relapsed/refractory therapy, regardless of patient age or comorbidities.

Idelalisib

Idelalisib monotherapy also had clinical activity in relapsed/refractory CLL resulting in an ORR of 72% (39% PR and 33% PR with treatment-induced lymphocytosis).72 The median PFS was 16 months and the median OS was not reached, with 75% of patients surviving at 36 months.

A post hoc analysis of 39 patients with relapsed or refractory SLL enrolled in phase I (n=11) and phase II (n=28) studies (that evaluated the efficacy and safety of idelalisib patients with relapsed/refractory indolent NHL) showed that idelalisib monotherapy resulted in an ORR of 55%–61% in the subset of patients with relapsed or refractory SLL.154 The median PFS was 4 months and 11 months, respectively.

Idelalisib monotherapy is included as an option for relapsed/refractory therapy, regardless of patient age or comorbidities.

Lenalidomide ± Rituximab

Lenalidomide ± rituximab is included as an option for relapsed/refractory therapy, regardless of patient age or comorbidities.155157

In a phase II study of 59 patients with relapsed or refractory CLL, lenalidomide + rituximab resulted in an ORR of 66% with CR in 12%.155 The median OS was not reached, with an estimated 3-year OS rate of 71%. However, the ORR was lower for the subgroup of patients with fludarabine-refractory CLL compared with those with fludarabine-sensitive CLL (33% vs 70%; P=.04). The most common grade 3 or 4 toxicity included neutropenia (74%), thrombocytopenia (34%), and infections or febrile episodes (24%). Tumor flare reactions (grade 1 or 2) occurred in 27% of patients.

In the prospective, multicenter, randomized phase II trial of 103 patients with relapsed/refractory CLL (CLL-009 trial), at a median follow-up of 24 months, lenalidomide monotherapy resulted in an ORR of 40%. The median PFS and OS were 10 months and 33 months, respectively.156 The median PFS and OS were significantly different between patients with CLL responding to lenalidomide and patients with stable disease (median PFS, 27 vs 7 months, P<.001; median OS, not reached vs 20 months, P=.011). Myelosuppression and tumor flare reactions were the most common grade 3 or 4 adverse events.

Lenalidomide can be given as continuous or intermittent dosing for patients with CLL. Growth factors and/or dose adjustment may be needed to address cytopenias, without necessitating holding treatment.

Monotherapy With Obinutuzumab or Ofatumumab

In the GAUGIN study (n=20 patients), obinutuzumab at a fixed dose of 1,000 mg resulted in a best ORR of 30%, in patients with heavily pretreated relapsed or refractory CLL.158 The median PFS and duration of response were 11 and 9 months, respectively.

In the final analysis of the pivotal international clinical trial (n=207; 95 patients with fludarabine- and alemtuzumab-refractory CLL [FA-ref CLL] and 112 patients with fludarabine-refractory CLL with bulky lymphadenopathy [>5 cm; BF-ref CLL]), ofatumumab monotherapy resulted in an ORR of 49% in patients with FA-ref CLL and 43% in those with BF-ref CLL.159 The median PFS was 5 months and 6 months, respectively, for patients with FA-ref CLL and BF-ref CLL. The median OS was 14 months and 17 months for the FA-ref and the BF-ref groups, respectively. The most common grade 3 or higher adverse events were infections (24%) and neutropenia (12%). An ad hoc retrospective analysis of patients with FA-ref CLL (n=96) and BF-ref CLL (n=112) showed that ofatumumab was also effective and well tolerated in patients with FA-ref CLL and previous rituximab exposure.160 The ORRs were 43%, 44%, and 53%, respectively, for CLL with previous rituximab exposure, rituximab-refractory CLL, and rituximab-naive CLL. The median PFS was 5.3, 5.5, and 5.6 months, respectively, and median OS was 15.5, 15.5, and 20 months, respectively.

Monotherapy with obinutuzumab or ofatumumab is included as an option for relapsed/refractory therapy, regardless of patient age or comorbidities.

Venetoclax

Venetoclax monotherapy has also shown promising activity in patients with relapsed or refractory CLL after prior treatment with ibrutinib or idelalisib, resulting in an ORR of 65% and 67%, respectively.161,162 The median PFS has not yet been reached, and the estimated 12-month PFS rate was 79% for patients with relapsed or refractory CLL after prior treatment with idelalisib.162 The most common grade 3 or 4 adverse events were neutropenia, thrombocytopenia, anemia, and decreased lymphocyte count. In a posthoc subgroup analysis of 28 patients enrolled in the aforementioned phase II studies who received >1 BCRi therapy (ibrutinib or idelalisib), venetoclax resulted in higher ORR (75% vs 43%) and longer PFS (not reached vs 16 months) in patients who had received only one BCRi compared with those who had received >1 BCRi. The estimated 12-month OS rates were 93% and 89% for patients previously treated with only one BCRi and >1 BCRi, respectively.163 The results of a retrospective analysis showed that the use of venetoclax was associated with better ORR (79% vs 46% following failure of idelalisib) and a trend toward improved PFS after failure of ibrutinib compared with failure of idelalisib.164

Venetoclax monotherapy is included as an option for relapsed/refractory therapy, regardless of patient age or comorbidities.

Post Second-Line Maintenance Therapy

Ofatumumab maintenance or lenalidomide maintenance (category 2B) is included as an option (“Other Recommended Regimens, page 193) in patients who are in CR or PR after second-line chemoimmunotherapy based on the results of the phase III randomized trials (PROLONG and CONTINUUM trials).165,166

CLL/SLL With del(17p) or TP53 Mutation

First-Line Therapy: Preferred Regimens

Ibrutinib

Enrollment in an appropriate clinical trial is recommended for patients with del(17p) CLL. In the absence of a clinical trial, ibrutinib is the preferred treatment option. In a phase II trial that included 35 treatment-naïve patients with del(17p)/TP53 mutation (median age, 62 years), at a median follow-up of 24 months, ibrutinib resulted in objective responses in 32 of 33 evaluable patients (55% of patients had a PR and 42% of patients had a PR with lymphocytosis) and the estimated OS at 24 months was 84%.167 After a median follow-up of 57 months, the estimated 5-year PFS and OS were 74% and 85%, respectively.168 The cumulative incidence of progression at 24 months was 9%. Grade ≥3 neutropenia, anemia, and thrombocytopenia were reported in 24%, 14%, and 10% of patients, respectively. Grade 3 pneumonia and rash were reported in 6% and 2% of patients, respectively.

Patients with del(17p) CLL were excluded from the RESONATE-2 trial, but 12 patients treated with ibrutinib had TP53 mutation.109 In the final analysis of this study, after 6-year follow-up, the median PFS was not reached and the estimated 5-year PFS rate was 56% for this group of patients. However, comparison between ibrutinib and chlorambucil could not be made since only 3 patients in the chlorambucil group had TP53 mutation.

Acalabrutinib ± Obinutuzumab

In the ELEVATE-TN phase III study (discussed previously) that demonstrated the efficacy of acalabrutinib ± obinutuzumab in 535 patients with previously untreated CLL, del(17p) and TP53 mutations were present in 10% and 12% of patients, respectively in the acalabrutinib + obinutuzumab arm.111 In the acalabrutinib monotherapy arm, del(17p) and TP53 mutations were present in 9% and 11% of patients, respectively. The PFS benefit for acalabrutinib ± obinutuzumab was seen across all patient subgroups, including those with del(17p) or TP53 mutation.

Based on the recent FDA approval and the results of the ELEVATE-TN study, the panel consensus was to include acalabrutinib ± obinutuzumab with a category 2A recommendation.

Venetoclax + Obinutuzumab

In the CLL14 study (discussed previously) that demonstrated the efficacy of this combination in 432 patients with previously untreated CLL, del(17p) and TP53 mutations were present in 9% and 11% of patients, respectively.107 The undetectable-MRD rate in peripheral blood at 3 months after completion of treatment (71% vs 7%) and 24-month PFS rate (74% vs 33%; HR, 0.31) were significantly higher for venetoclax + obinutuzumab compared with chlorambucil + obinutuzumab in patients with del(17p) or TP53 mutation.

The panel consensus was to include venetoclax + obinutuzumab as a preferred regimen with a category 2A recommendation. Observation is recommended for patients with responding disease.

First-Line Therapy: Other Recommended Regimens

The panel emphasizes that the efficacy of BTKi (ibrutinib or acalabrutinib) and venetoclax + obinutuzumab in del(17p) CLL exceeds that of the other recommended regimens and should be considered as the best choice in the absence of a contraindication to give this treatment.

The following regimens are included as options (when BTKi or venetoclax is not deemed appropriate):

  • Alemtuzumab ± rituximab169172
  • HDMP + rituximab120
  • Obinutuzumab125

Relapsed/Refractory Therapy: Preferred Regimens

Acalabrutinib

In the phase II study that evaluated acalabrutinib in relapsed/refractory CLL, acalabrutinib resulted in an ORR of 85% in patients with del(17p).134 The median PFS was not reached and the 18-month PFS rate was 78%. In the ASCEND trial, PFS benefit for acalabrutinib was seen across all patient subgroups including those with del(17p) or TP53 mutation.131

Based on the results of the ASCEND trial, the panel consensus was to change the recommendation of acalabrutinib from category 2A (other recommended regimen) to category 1 (preferred regimen).

Ibrutinib

Ibrutinib is included with a category 1 recommendation. The results of the RESONATE-17 phase II study confirmed the safety and efficacy of ibrutinib in 145 patients with relapsed or refractory del(17p) CLL.173 At a median follow-up of 12 months, the ORR (as assessed by the IRC) was 83%. In an extended analysis with a median follow-up of 28 months, the investigator-assessed ORR and the 24-month PFS and OS rates were 83%, 63%, and 75%, respectively.173 In the RESONATE study, del(17p) (32% and 33%, respectively) and TP53 mutation (51% and 46%, respectively) were present in similar proportions of patients in the ibrutinib and ofatumumab arm. The final analysis of this study also showed that the presence of del(17p)/TP53 mutation or CK was not associated with inferior PFS outcomes.136 In an exploratory analysis that combined data from patients with del(17p) and TP53 mutation, the median PFS was 41 months for patients with del(17p) and/or TP53 mutation vs 57 months for those without del(17p) or TP53 mutation. Similarly, the median PFS was 41 months for patients with CK compared with 45 months for those without CK.

Venetoclax ± Rituximab

In the phase III randomized MURANO study that compared VenR and BR in patients with relapsed/refractory CLL, VenR was superior to BR in prolonging PFS across all subgroups of patients, including those with del(17p) or TP53 mutation.130 Del(17p) and TP53 mutation were present in 27% and 25% of patients, respectively, in patients randomized to VenR and in 27% and 28% of patients, respectively, in patients randomized to BR.

In a phase II study of 158 patients with relapsed or refractory del(17p) CLL, at a median follow-up of 23 months, venetoclax monotherapy resulted in an ORR of 77% (20% CR and 57% PR).174 The estimated 24-month PFS and OS rates were 54% and 73%, respectively. The ORR and the estimated 24-month PFS and OS were 63%, 50%, and 55%, respectively, for patients who had received prior BCRi therapy. The ORR was also high (>70%) in all subgroups of patients with additional risk features [eg, fludarabine-refractory status, bulky disease, del(17p), TP53 mutation]. Neutropenia (40%), infection (20%), anemia (18%), and thrombocytopenia (15%) were the most commonly treatment-related adverse events.

Based on these results, VenR is included with a category 1 recommendation and venetoclax monotherapy is included with a category 2A recommendation.

Duvelisib

In the phase III randomized study (DUO) that evaluated duvelisib for relapsed/refractory CLL (n=319), del(17p), and/or TP53 mutation were present in 31 of 160 patients randomized to receive duvelisib.132 The PFS advantage with duvelisib was maintained across all subgroups of patients, including those with del(17p) or TP53 mutation. In the subgroup of patients with del(17p), the median PFS was significantly extended for duvelisib compared with ofatumumab (17 vs 9 months).175

Idelalisib + Rituximab

In the phase III randomized study, IdR significantly prolonged survival in patients with del(17p) or TP53 mutations compared with those treated with rituximab + placebo.140 The median OS was 29 months for patients treated with IdR compared with 15 months for those treated with rituximab + placebo. IdR is included as an option with a category 2A recommendation.

Relapsed/Refractory Therapy: Other Recommended Regimens

The regimens discussed subsequently are included as options for relapsed/refractory therapy based on the results from retrospective analyses or subgroup analyses from the prospective clinical trials that had included patients with del(17p) or TP53 mutation. However, it should be noted that these were not sufficiently powered to evaluate the efficacy and safety of regimens in patients with del(17p) or TP53 mutation.

  • Alemtuzumab ± rituximab142,143
  • HDMP + rituximab176
  • Idelalisib72
  • Lenalidomide ± rituximab.155,156
  • Ofatumumab177

Special Considerations for the Use of Small-Molecule Inhibitors

Atrial fibrillation (grade ≥3) and major hemorrhage (defined as serious or grade 3 or higher bleeding events or central nervous system hemorrhage of any grade) have been reported in 6% and 4% of patients treated with ibrutinib, respectively.108 Hypertension (grade ≥3) associated with ibrutinib (reported in 20% of patients) has uncommonly been the basis for discontinuation and should be managed with antihypertensives as appropriate.178 Recent reports have indicated the risk for supraventricular arrhythmias and other potentially severe cardiac events in patients exposed to ibrutinib.179,180

In the ELEVATE-TN trial, atrial fibrillation, hypertension, bleeding of any grade, infections and secondary malignancies were reported in 4%, 5%, 39%, 65% and 3% of patients treated with acalabrutinib, respectively.111 Grade ≥3 hypertension, bleeding, and infection were observed in 2%, 2%, and 14% of patients, respectively. In the ASCEND trial, atrial fibrillation, hypertension, and bleeding of any grade were reported in 5%, 3%, and 26% of patients treated with acalabrutinib, respectively.131 Grade ≥3 atrial fibrillation, hypertension, and bleeding were observed in 1%, 3%, and 2% of patients, respectively. Headaches commonly observed with acalabrutinib early in the treatment course typically resolve after 1 to 2 months of treatment and generally can be managed with analgesics (eg, acetaminophen) and caffeine supplements.

The benefit and risk of ibrutinib or acalabrutinib should be evaluated in patients requiring antiplatelet or anticoagulant therapies. Patients requiring warfarin have been excluded from clinical trials evaluating ibrutinib and acalabrutinib. Patients should be monitored for signs of bleeding. Concomitant administration of ibrutinib or acalabrutinib with warfarin should be avoided. Monitoring for atrial fibrillation and hypertension along with appropriate management is recommended for patients receiving ibrutinib or acalabrutinib. Switching to alternate therapy should be considered, especially in patients with atrial fibrillation/hypertension that is not medically controllable. Transition to alternate therapy should be done as soon as possible because progression may accelerate when ibrutinib or acalabrutinib is stopped. Treatment-free interval should be as short as possible.

Hepatitis B virus reactivation and invasive fungal infections have been rarely reported in patients treated with ibrutinib.181,182 There currently are no sufficient data to recommended routine screening and prophylaxis.

Hepatotoxicity (transaminase elevations), severe diarrhea or colitis, infections, pneumonitis, and intestinal perforation have been observed in patients treated with idelalisib or duvelisib. Hepatotoxicity is a major concern in younger patients treated with idelalisib as first-line therapy.183 Close monitoring of transaminase levels is essential and concurrent administration of idelalisib or duvelisib with other hepatotoxic drugs should be avoided.

Idelalisib and duvelisib are also associated with increased risk of opportunistic infections and febrile neutropenia. The addition of anti-CD20 mAb or chemoimmunotherapy to idelalisib increases the risk of febrile neutropenia.147 Anti-infective prophylaxis for herpes simplex virus, Pneumocystis jirovecii pneumonia, and cytomegalovirus reactivation are recommended for patients receiving idelalisib or duvelisib.

TLS was an important side effect of venetoclax therapy in early clinical trials. Initiation at lower dose (20 mg for 1 week) and gradual step-wise ramp-up over 5 weeks to target dose (400 mg daily) along with prophylaxis for TLS is recommended to mitigate the risk and frequency of TLS in patients receiving venetoclax.184 Initiation and accelerated escalation of venetoclax (20–400 mg over 3 weeks) with close inpatient monitoring for TLS can be performed to quickly regain disease control in a selected subgroup of patients with high tumor burden, rapid disease progression, or disease relapse after treatment with BCRi therapy.161,185,186 This accelerated schedule has been explored in a small number of hospitalized patients, who received intensive monitoring and TLS prophylaxis. Additionally, continued treatment with BTKi concurrent with initiation and escalation of venetoclax with discontinuation of BTKi after venetoclax dose escalation to 400 mg daily can be considered.161,185,186 Recommendations for TLS prophylaxis based on tumor burden are outlined in CSLL-G (page 203).

Growth factor support should be considered for patients with neutropenia. Dose reduction may be necessary for patients with persistent neutropenia and limited bone marrow involvement.

Careful monitoring of adverse events after initiation of treatment and supportive care for treatment-related complications should be an integral part of CLL/SLL management.

Allogeneic Hematopoietic Cell Transplant

Long-term results from several prospective studies have shown that allogeneic hematopoietic cell transplant (HCT) can provide long-term disease control and also overcome the poor prognosis associated with del(17p) and TP53 mutations.187194

It is understood that studies involving allogeneic HCT are subject to significant selection biases. Nonetheless, at the present time, given the favorable outcome of patients with del(17p) or TP53 mutation treated with ibrutinib as first-line therapy and the availability of venetoclax as an effective treatment option for relapsed or refractory CLL, allogeneic HCT is not considered a reasonable treatment option for relapse/refractory CLL after initial purine analog-based therapy.195

Indications for Allogeneic HCT

Allogeneic HCT can be considered for CLL/SLL refractory to small-molecule inhibitor therapy in patients without significant comorbidities. HCT-specific comorbidity index could be used for the assessment of comorbidities before HCT and to predict the risks of nonrelapse mortality and the probabilities of survival after HCT.196,197

For patients with CLL/SLL with del(17p) or TP53 mutation, a discussion of allogeneic HCT could be considered for patients in remission with or after ibrutinib therapy, if CK (≥3 abnormalities) is present. However, available data suggest that CK (≥5 abnormalities) is associated with inferior OS and event-free survival after allogeneic HCT with reduced-intensity conditioning in patients with high-risk interphase cytogenetics.198

Summary

The choice of first-line treatment of CLL/SLL should be based on disease stage; presence or absence of del(17p) or TP53 mutation; IGHV mutation status (if considering chemoimmunotherapy); patient age, performance status, and comorbid conditions; and the agent’s toxicity profile. Targeted therapy with BTKi and venetoclax is the preferred first-line treatment of all patients with CLL. FCR is preferred for patients <65 years with untreated IGHV-mutated CLL. Ibrutinib, idelalisib (± rituximab), acalabrutinib, duvelisib, and venetoclax ± rituximab are effective treatment options for relapsed/refractory CLL/SLL. Careful monitoring of adverse events and supportive care for treatment-related complications should be an integral part of management.

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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 of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

PLEASE NOTE

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult the NCCN Guidelines is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network® (NCCN®) makes no representations or warranties of any kind regarding their content, use, or application and disclaims any responsibility for their application or use in any way.

The complete NCCN Guidelines for Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma are not printed in this issue of JNCCN but can be accessed online at NCCN.org.

© National Comprehensive Cancer Network, Inc. 2020. All rights reserved. The NCCN Guidelines and the illustrations herein may not be reproduced in any form without the express written permission of NCCN.

Disclosures for the NCCN Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Panel

At the beginning of each NCCN Guidelines Panel meeting, panel members review all potential conflicts of interest. NCCN, in keeping with its commitment to public transparency, publishes these disclosures for panel members, staff, and NCCN itself.

Individual disclosures for the NCCN Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Panel members can be found on page 217. (The most recent version of these guidelines and accompanying disclosures are available at NCCN.org.)

The complete and most recent version of these guidelines is available free of charge at NCCN.org.

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

Individual Disclosures for the NCCN Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Panel

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