Management of Advanced-Phase Chronic Myelogenous Leukemia

Chronic myelogenous leukemia represents the poster child of successful precision medicine in cancer, with amazing survival results achieved with targeted tyrosine kinase inhibitors (TKIs) in many patients with chronic-phase disease. Unfortunately, however, this good news has not extended to patients in blast crisis, for whom survival has not clearly been improved with TKIs. During his presentation at the NCCN 21st Annual Conference, Jerald P. Radich, MD, briefly explored the biology behind advanced-stage disease and several of the molecular findings in disease progression. He also reviewed some of the therapeutic options in advanced disease, emphasizing that transplantation, although fraught with some difficulties, offers the best long-term prognosis for patients in blast crisis.

In the absence of stem cell transplantation, treatment of blast crisis in chronic myelogenous leukemia (CML) continues to be mostly unsuccessful and is essentially the same now as it was in 1975, declared Jerald P. Radich, MD, Director of the Molecular Oncology Laboratory, Fred Hutchinson Cancer Research Center; Professor of Medicine, University of Washington School of Medicine; and Chair of the NCCN Guidelines Panel for CML. Although the incidence of blast crisis certainly has decreased with the use of tyrosine kinase inhibitors (TKIs), survival in blast crisis has not clearly improved with these targeted agents.

Progression to blast crisis in CML is a phenomenon that is still not completely understood. Although definitions of both accelerated phase and blast crisis vary, the prime factor is blast count, according to Dr. Radich. In most clinical trials, accelerated phase is between 15% and 29% blasts in blood or marrow, with blast crisis being more than 30% blasts in blood and marrow. This differs from the WHO classification system, which marks the transition from accelerated to blast phase at the 20% blast count.

Up to 80% of patients in blast crisis have additional cytogenetic aberrations. The most common “major route” aberrations include +8, +der(22)t(9;22), and i(17)(q10); the less common “minor route” aberrations consist of gains of chromosomes 17 and 21; losses of chromosomes Y, 7, and 17; and t(3;21)(q26;q22), Dr. Radich said. In most patients in blast crisis, mutations besides the Philadelphia chromosome are detected. In gene expression profiles, blast crisis appears as a distinct disease from CML.

Glimpse at Biology of Blast Crisis

Essentially, the continuum of CML progression/resistance represents a ticking biologic clock, Dr. Radich said. Many possible mutations affect a small number of critical pathways. The timing of TKI therapy is also key.

“If you treat people early on, you can probably block this progression pathway,” he continued. However, “if you wait too long to start TKI therapy,” cells with critical changes may already be present, “and you may push patients past the point of no return.”

“What has been shown in almost every trial looked at is that if patients progress, they usually progress pretty early in this disease,” declared Dr. Radich.

The blast crisis progression rate tends to decline over time, as seen in the IRIS trial, he added. Lead-time bias, in which some patients may have had disease for a long time and others for a short time, may explain some of these findings. Thus, some of these patients may be thought to have chronic-phase CML, but may be closer to having accelerated phase or blast crisis. “You can't tell how long patients have actually had CML when they walk through the door,” he said.

Early molecular response has predicted a higher probability of achieving a future major molecular response. Data from both the IRIS1,2 and DASISION3 trials have shown that early molecular response is associated with a longer duration of complete cytogenetic response and improved progression-free and overall survivals. Similar results have been reported with first- and second-generation drugs.

Dr. Radich briefly mentioned some of the molecular findings in disease progression. Of patients with myeloid blast crisis, approximately one quarter will have p53 deletions. As for those with lymphoid blast crisis, approximately half will have p16 mutations. In a small study by Grossman et al4 of 39 patients in blast crisis, mutations were found by deep sequencing in 77%.

Dr. Radich shared 2 lessons from gene-expression arrays: (1) accelerated phase is similar to blast crisis, which suggests that disease progression is more like a 2-step process; and (2) blast crisis is similar to normal CD34-positive cells. “That makes some sense biologically,” he noted, “because we know that normal stem cells are amazingly resistant to chemotherapy.”

In addition, there seems to be an association between the accumulation of mutations over time and imatinib resistance within 3 years. According to Dr. Radich, “As phase goes up, the probability of acquiring point mutations dramatically increases.” Thus, imatinib-resistant cases are similar to cases of advanced-phase disease, he noted, suggesting an overlapping biology.

Dr. Radich briefly discussed a preclinical model of CML reported recently by Giotopoulos et al.5 The investigators evaluated mice induced into blast crisis, “which looks phenotypically like human disease,” and compared them with the gene expression data from pathways in human blast crisis. The authors reported “a heterogeneous and unique pattern of insertions identifying known and novel candidate genes” and showed that “these pathways drive disease progression” (Figure 1).

“Finally, there is a model that we can use to apply new therapies to get some idea of what drugs and pathways we can target,” Dr. Radich said.

Targeted Therapy

Many effective targeted treatments are available for patients with chronic-phase CML, but the same cannot be said for those with advanced disease. Although no specific drug treatment has been recommended for these patients, Dr. Radich briefly reviewed some of the data on the use of TKIs for those in accelerated phase and blast crisis.

“We assumed early on that all patients in accelerated phase did lousy [on TKI therapy],” noted Dr. Radich. However, it now seems that maybe some of these patients may “do pretty well.” Two fairly recent studies looked at the use of TKIs in patients with newly diagnosed CML in accelerated phase.6,7 Both studies showed that some of these patients did “surprisingly” well on these targeted agents, both first- and second-generation options. However, Dr. Radich emphasized that these results do not apply to patients on TKIs whose disease has evolved from chronic to accelerated phase, where outcomes are quite poor.

As for treatment of patients in blast crisis, in the 1980s and 1990s, various combinations of acute myeloid leukemia (AML) therapies were tried, including 5-azacitidine, etoposide, mitoxantrone, carboplatin, cytarabine, fludarabine, and decitabine. “Nothing seemed to work,” admitted Dr. Radich.

Figure 1.
Figure 1.

A simple model of chronic myelogenous leukemia progression/resistance.

Abbreviations: Ph, Philadelphia chromosome; TKI, tyrosine kinase inhibitor.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 14, 5S; 10.6004/jnccn.2016.0188

Only approximately 9% of patients returned to chronic phase. Median survival rates remained approximately 6 to 10 months regardless of whether chemotherapy agents, TKIs, or a combination was used.

In summary, treatment of patients in blast crisis with TKIs produced complete response rates in the range of 15% to 20%, stated Dr. Radich, with higher rates with the second-generation drugs. However, the median survival remains approximately 6 to 11 months.

Transplantation: Best Chance of Cure

Transplantation has been relegated to a back burner in CML in the era of TKI therapy, Dr. Radich noted. “Most patients taken to transplant now are patients with resistance, who may be intolerant to all of these drugs,” acknowledged Dr. Radich. However, the role of allogeneic stem cell transplantation is being revisited, as it remains the best chance of cure for patients in blast crisis.

“There are huge differences in toxicity [between TKIs and transplant], but [transplant] is a pretty effective therapy,” he added, with a 5-year survival rate of approximately 85%. However, 10-year survival rates for patients in blast crisis reach only approximately 20%.8

The end of transplantation in CML is a bit premature, according to Dr. Radich. In fact, the success of TKI therapy in the United States may ultimately increase the use of transplantation. With increasingly more patients receiving TKI therapy in the years to come, a small percentage of them will progress to accelerated phase or blast crisis and ultimately require another treatment alternative, predicted Dr. Radich.

The 2016 NCCN Clinical Practice Guidelines in Oncology for CML and the European LeukemiaNet recommend allogeneic hematopoietic cell transplantation for patients in blast crisis. In the second-line setting, transplant is “always” recommended in blast phase regardless of a patient's response to TKI therapy. Transplant also is “always” indicated for patients in accelerated phase if the response to TKI trial therapy is less than optimal. The value and meaning of “always” depend on transplant risks such as age, comorbidities, performance status, and donor.

Dr. Radich repeated that most data suggest that a cytogenetic response to TKIs should be seen by 3 months. “That is a handy number because it takes about 3 months to find an unrelated donor nowadays,” he concluded.

Dr. Radich has disclosed that he has served as a scientific advisor for ARIAD Pharmaceuticals, Inc., Incyte Corporation, BMS, and Novartis Pharmaceuticals Corporation, and has received consulting fees, honoraria, and grant/research support from Novartis Pharmaceuticals Corporation.

References

  • 1.

    Druker BJ, Guilhot F, O'Brien SG. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 2006;355:24082417.

    • Search Google Scholar
    • Export Citation
  • 2.

    Hughes TP, Hochhaus A, Branford S. Long-term prognostic significance of early molecular response to imatinib in newly diagnosed chronic myeloid leukemia: an analysis from the International Randomized Study of Interferon and STI571 (IRIS). Blood 2010;116:37583765.

    • Search Google Scholar
    • Export Citation
  • 3.

    Jabbour E, Kantarjian HM, Saglio S. Early response with dasatinib or imatinib in chronic myeloid leukemia: 3-year follow-up from a randomized phase 3 trial (DASISION). Blood 2014;123:494500.

    • Search Google Scholar
    • Export Citation
  • 4.

    Grossman V, Kohlmann A, Zenger M. A deep-sequencing study of chronic myeloid leukemia patients in blast crisis detects mutations in 76.9% of cases. Leukemia 2011;25:557560.

    • Search Google Scholar
    • Export Citation
  • 5.

    Giotopoulos G, van der Weyden L, Osaki H. A novel mouse model identified cooperating mutations and therapeutic targets critical for chronic myeloid leukemia progression. J Exp Med 2015;212:15511569.

    • Search Google Scholar
    • Export Citation
  • 6.

    Rea D, Etienne G, Nicolini F. First-line imatinib mesylate in patients with newly diagnosed accelerated phase-chronic myeloid leukemia. Leukemia 2012;26:22542259.

    • Search Google Scholar
    • Export Citation
  • 7.

    Ohanian M, Kantarjian HM, Quintas-Cardama A. Tyrosine kinase inhibitors as initial therapy for patients with chronic myeloid leukemia in accelerated phase. Clin Lymphoma Myeloma Leuk 2014;14:155162.

    • Search Google Scholar
    • Export Citation
  • 8.

    Saussele S, Leuseker M, Gratwohl A. Allogeneic hematopoietic stem cell transplantation for chronic myeloid leukemia in the imatinib era: evaluation of its impact within subgroup of the randomized German CML Study IV. Blood 2010;115:18801885.

    • Search Google Scholar
    • Export Citation

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Correspondence: Jerald P. Radich, MD, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N, PO Box 19024, D4-100, Seattle, WA 98109-1024. E-mail: jradich@fhcrc.org
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    A simple model of chronic myelogenous leukemia progression/resistance.

    Abbreviations: Ph, Philadelphia chromosome; TKI, tyrosine kinase inhibitor.

  • 1.

    Druker BJ, Guilhot F, O'Brien SG. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 2006;355:24082417.

    • Search Google Scholar
    • Export Citation
  • 2.

    Hughes TP, Hochhaus A, Branford S. Long-term prognostic significance of early molecular response to imatinib in newly diagnosed chronic myeloid leukemia: an analysis from the International Randomized Study of Interferon and STI571 (IRIS). Blood 2010;116:37583765.

    • Search Google Scholar
    • Export Citation
  • 3.

    Jabbour E, Kantarjian HM, Saglio S. Early response with dasatinib or imatinib in chronic myeloid leukemia: 3-year follow-up from a randomized phase 3 trial (DASISION). Blood 2014;123:494500.

    • Search Google Scholar
    • Export Citation
  • 4.

    Grossman V, Kohlmann A, Zenger M. A deep-sequencing study of chronic myeloid leukemia patients in blast crisis detects mutations in 76.9% of cases. Leukemia 2011;25:557560.

    • Search Google Scholar
    • Export Citation
  • 5.

    Giotopoulos G, van der Weyden L, Osaki H. A novel mouse model identified cooperating mutations and therapeutic targets critical for chronic myeloid leukemia progression. J Exp Med 2015;212:15511569.

    • Search Google Scholar
    • Export Citation
  • 6.

    Rea D, Etienne G, Nicolini F. First-line imatinib mesylate in patients with newly diagnosed accelerated phase-chronic myeloid leukemia. Leukemia 2012;26:22542259.

    • Search Google Scholar
    • Export Citation
  • 7.

    Ohanian M, Kantarjian HM, Quintas-Cardama A. Tyrosine kinase inhibitors as initial therapy for patients with chronic myeloid leukemia in accelerated phase. Clin Lymphoma Myeloma Leuk 2014;14:155162.

    • Search Google Scholar
    • Export Citation
  • 8.

    Saussele S, Leuseker M, Gratwohl A. Allogeneic hematopoietic stem cell transplantation for chronic myeloid leukemia in the imatinib era: evaluation of its impact within subgroup of the randomized German CML Study IV. Blood 2010;115:18801885.

    • Search Google Scholar
    • Export Citation
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