Chronic Myeloid Leukemia

Published on 04/03/2015 by admin

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Chapter 27 Chronic Myeloid Leukemia

Management of the Newly Diagnosed Chronic Myeloid Leukemia Patient

What should be the initial management for CML patients? After years of clinical research, we know (a) imatinib is remarkably effective for patients treated in chronic phase, because greater than 85% of patients obtain a complete cytogenetic response and approximately 70% of cases remain in CCR at 5 years of follow-up; (b) second-generation tyrosine kinase inhibitors, dasatinib and nilotinib, used as first-line treatment for chronic phase CML may be even more effective, resulting in faster and more profound reduction in BCR-ABL levels; (c) allogeneic transplantation is generally associated with 10-year survival rates of 70% or better for younger patients in early chronic phase; and (d) outcome for patients receiving TKI treatment can be effectively monitored by sensitive RT-PCR assays.

Imatinib has become the initial treatment of choice for patients with CML. For patients diagnosed during chronic phase, imatinib is a reasonable first choice of therapy. However, in view of the association between cytogenetic and molecular responses on imatinib and survival, it is reasonable to suggest that the faster and deeper reduction in disease burden using the second-generation agents may reduce the risk for progression when compared with imatinib. The tolerability of the newer agents appears to be comparable to imatinib, although follow-up is shorter and the long-term effects of treatment are not known. It is notable that differences in overall survival have not been observed as yet. In addition, low-risk chronic-phase patients demonstrate excellent survival with imatinib. In addition, imatinib is considerably less expensive than the newer agents and a generic form will soon be available, reducing costs further. Careful monitoring of imatinib response could potentially identify the subset of patients who will benefit from second-generation tyrosine kinase inhibitor treatment. Longer-term follow-up of patients from the front-line studies and better prognostication measures for response to individual agents will be required to resolve these issues. Until then, the choice of first-line TKI is dependent on individual preference based on risk group, toxicity profile, dosing schedule, and economic factors.

For patients with chronic-phase disease, tyrosine kinase treatment can be initiated with simultaneous workup of family donors and unrelated donors. Criteria for failure or suboptimal response have been developed. Certainly, the failure of imatinib treatment to achieve a complete hematologic response at 3 months of treatment, lack of any cytogenetic response by 6 months, or lack of a major cytogenetic response by 12 months is an indication to switch therapy. By a conservative approach, patients should achieve a complete cytogenetic response by 18 months of therapy. Similarly, BCR-ABL mRNA levels greater than 10% at 6 months and greater than 1% at 12 months (using the international scale) are indicators to switch treatment. Patients who relapse after a CCR, especially those with ABL point mutations, should consider alternative therapy, including transplant. For patients diagnosed in accelerated phase or in blast crisis, initial treatment with dasatinib results in better responses than those seen with imatinib, but in general, these responses tend to be short-lived; thus advanced-phase patients should consider transplantation as soon as possible.

Table 27-2 Response Definition and Monitoring

Hematologic Response Cytogenetic Response Molecular Response
Complete: Platelet count <450 × 109/L; WBC count <10 × 109/L; differential without immature granulocytes and with less than 5% basophils; nonpalpable spleen Complete: Ph+ 0
Major: Ph+ 1%-35%
Minor: Ph+ 36%-65
Minimal: Ph+ 66%-95%
None: Ph+ <95%
Complete: BCR-ABL transcripts nonquantifiable and nondetectable*
Major: ≤0.10%

BCR-ABL to control gene ratio according to the proposed international scale for measuring molecular response, with a standardized “baseline,” as established in the IRIS trial, taken to represent 100% on the international scale, and a 3-log reduction from the standardized baseline (MMR) fixed at 0.10%.

*Qualified by the limit of sensitivity of the PCR assay employed.

Can Tyrosine Kinase Inhibitor Treatment Cure Chronic Myeloid Leukemia?

An increasing proportion of CML patients treated with tyrosine kinase inhibitors may not have detectable levels of the BCR-ABL gene, even with sensitive PCR assays. This raises the question as to whether patients can actually be cured with tyrosine inhibitor treatment. Patients with negative PCR may still have significant numbers of residual malignant cells. The definition of a cure remains controversial. Although cure might theoretically require the total eradication of all leukemia cells, it can be argued that patients may be considered cured if low numbers of leukemia cells still persist but are not expected to be able to reestablish clinical disease. Such a situation may occur in CML after allogeneic transplantation in which a graft-versus-leukemia effect may help maintain remission. In AML associated with the t(8;21), many long-term survivors continue to demonstrate molecular evidence of this translocation. On the other hand, late relapses can be observed in patients with childhood ALL more than 10 years after remission, with molecular evidence that the relapse originated from the same clone that caused the disease originally.

Therefore it is important to consider whether BCR-ABL–expressing cells that escape elimination with imatinib include cells with leukemogenic potential. Mathematical modeling of the effect of imatinib on different hematopoietic cell compartments in CML suggests that leukemia stem cells are resistant to elimination by this drug. This is supported by evidence that BCR-ABL–positive stem and progenitor cells are retained in patients in CCR on imatinib treatment, including patients with sustained undetectable molecular evidence of disease by RT-PCR. In vitro treatment with tyrosine kinase inhibitors inhibits proliferation of CML primitive progenitors but only modestly increases apoptosis. Similarly, tyrosine kinase inhibitor treatment fails to eradicate primitive leukemia cells in a mouse model of CML. These observations suggest that TKI treatment does not eliminate primitive leukemogenic cells. On the other hand, some patients can maintain a BCR-ABL–negative status for more than 1 year following discontinuation of imatinib treatment. Although the long-term durability and frequency of such responses are not clear at present, these observations suggest that additional factors related to the frequency and leukemogenic potential of residual cells, or immune or microenvironmental factors determine the risk for relapse after discontinuation of tyrosine kinase inhibitor treatment.

In the future, a better understanding of these factors will allow for improved prediction of patients in whom treatment can be safely stopped. In addition, better understanding of the mechanisms underlying persistence of leukemogenic cells may allow development of improved strategies to enhance the number of CML patients in whom TKI treatment can be stopped and who are considered effectively “cured.”

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Figure 27-5 EVENT FREE SURVIVAL (EFS) OF NEWLY DIAGNOSED CHRONIC MYELOID LEUKEMIA (CML) PATIENTS TREATED WITH IMATINIB MESYLATE AFTER 7 YEARS’ FOLLOW-UP ON THE INTERNATIONAL RANDOMIZED INTERFERON AND STI571 (IRIS) STUDY BASED ON MOLECULAR RESPONSE AT 6- (A), 12- (B), AND 18-MONTH (C) LANDMARKS.

(Data from Hughes TP, Hochhaus A, Branford S, et al: 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 116:3758, 2010.)