Commentary (Roy/Rai)-Chronic Myeloid Leukemia: Changing the Treatment Paradigms

June 1, 2006

Molecular discoveries and clinical advances over the past few decades have made the treatment of chronic myeloid leukemia (CML) one of the great success stories of modern medicine. Before the 1980s, the focus was on maintaining normal white blood cell counts with agents such as hydroxyurea and busulfan. With the use of interferon, treatment strategies turned more toward cytogenetic remission. In 1998, targeted therapy was introduced to this setting with the first studies of imatinib mesylate. Since then, treatment objectives have shifted toward the attainment of molecular remission. In this review, we consider the variety of approaches to treating CML, efforts to minimize treatment failures, and possible future directions in therapy.

We have come a long way since the time when chronic myeloid leukemia (CML) was regarded as incurable except in a small minority of patients who were suitable for allogeneic transplant and were fortunate enough to have an HLA-matched donor. The introduction of imatinib mesylate (Gleevec) and other tyrosine kinase inhibitors that specifically block the enzymatic action of the BCR-ABL fusion protein has been a major contribution to the management of CML and has heralded a new era of success with molecularly targeted therapy.

In this issue of ONCOLOGY, Drs. Savona and Talpaz have elegantly summarized current advances in the management of CML. This is a comprehensive and authoritative review that will be helpful to every reader. The authors state that the treatment paradigm is now shifting toward the achievement of molecular remission in an attempt to prolong patient survival and to find a cure through medical management.

 

Before and After Imatinib

Savona and Talpaz have demonstrated that the goals of CML treatment have changed markedly in the past 10 years. Prior to the imatinib era, the treatment options for CML ranged from hydroxyurea and busulfan (Myleran) to achieve a hematologic response to allogeneic stem-cell transplantation (ASCT), which was curative in selected patients. Interferon-alpha, although shown to achieve a long-lasting cytogenetic response in some patients, did not prove to be the answer we sought.

The introduction of imatinib has redefined the management of CML. Imatinib demonstrated superior activity compared to other agents currently used in the treatment of this disease. But, unfortunately, resistance to this "magic bullet" is emerging. As noted by Savona and Talpaz, about 2% of patients annually will have progressive disease while on imatinib. Also, evidence suggests that discontinuation of imatinib leads to recurrence of the disease, revealing that imatinib is not a curative therapy. The quandary that clinicians are facing now is how to identify patients early during imatinib therapy who are at a greater risk of developing resistance or relapse.

 

Prognostic Markers

Some of the new prognostic markers that have been looked into in the International Randomized study of Interferon alpha plus cytarabine vs STI571 (IRIS) trial or its companion studies are worth mentioning here:

(1) Achievement of a complete cytogenetic response after 12 months or of at least a major cytogenetic response after 6 months of imatinib therapy appears to be a significant predictor of improved progression-free survival.[1]

(2) It also appears that attainment of a major molecular response, which is defined as at least a 3-log reduction of BCR-ABL fusion mRNA anytime while on imatinib or the attainment of a 2-log molecular response at the time of complete cytogenetic response is a significant and independent prognostic marker of subsequent progression-free survival.[2]

(3) Sokal score, which is based on age, spleen size, platelet count, and peripheral blast count, correlates well with the likelihood of achieving a complete cytogenetic response.[3] Other areas currently of interest include gene microarray studies and clonal evolution, defined as the acquisition of additional cytogenetic abnormalities.[4] We hope that, in the future, newly recognized prognostic markers will allow physicians to offer individual patients with CML a more precise therapeutic strategy than is currently possible.

 

Newly Diagnosed Patients

The only other areas that Savona and Talpaz might have emphasized would be how to approach a newly diagnosed patient who is in chronic phase CML and how to monitor the disease during imatinib therapy. The standard therapy of a patient with newly diagnosed CML in chronic phase is to start imatinib at 400 mg daily. The use of higher doses of imatinib in the early chronic phase appears promising in small single-arm trials, but that strategy needs to be validated in larger, randomized trials. Current recommendations for disease monitoring in patients who are in complete cytogenetic response include a peripheral blood reverse transcriptase polymerase chain reaction (RT-PCR) assay every 3 months and measurement of bone marrow cytogenetics every 12 to 18 months. Patients, who are not in a cytogenetic remission, should have bone marrow cytogenetics every 3 to 6 months and peripheral blood RT-PCR every 3 months.[5]

Any patient with a suboptimal response or signs of resistance should be considered for a clinical trial. Second-generation tyrosine kinase inhibitors such as AMN107 or dasatinib appear quite promising. However, it should be noted that these agents do not overcome the resistance conferred by BCR-ABL/T315I mutation (seen in a small number of CML patients). Outside of a clinical trial, the most reasonable approach in this setting is dose escalation, which may be effective in 30% to 50% of patients. Lastly, the option of ASCT should be revisited in appropriate patients.

 

Future Investigations

The following questions need to be answered in future trials: What is the best dose of imatinib? Should imatinib be combined with other agents such as interferon-alpha or chemotherapeutic agents? What is the role of allogeneic bone marrow or stem cell transplantation for younger, eligible patients, and when should it be offered? What is the most effective dose and schedule, and what is the long-term efficacy of the newer agents? Given the heterogeneity of imatinib resistance, it is possible that a combination approach will be necessary for maximal antileukemic effect. Whether this will lead to improved progression-free and overall survival remains to be seen.

This is an exciting time for both researchers and clinicians who treat patients with CML or gastrointestinal stromal tumor (GIST), which is also responsive to imatinib. A recent report that GIST cells refractory to imatinib in vitro were responsive to the drug in vivo has led to the observation that there might also be an immune-cell-based mechanism for the total therapeutic effect of imatinib. In mice, a new type of cell has been discovered that may be the basis of the immune effect of imatinib. This new cell, considered a cross between a dendritic cell and a natural killer cell, has been named interferon-producing killer dendritic cell, or IKDC.[6] It would not be too optimistic to believe that it is perhaps only a matter of time before an IKDC equivalent cell is identified in humans. Once that is achieved, the potential of imatinib therapy in CML might be significantly enhanced with appropriate manipulations of the immune system.

The success in understanding and treating CML represents a milestone in the history of medicine. We look forward to the upcoming results of trials investigating newer agents. -Finally, we congratulate Drs. Savona and Talpaz on their extremely
well written and balanced overview of CML.

 

-Rajasree Roy, MD
-Kanti R. Rai, MD

Disclosures:

The author(s) have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

1. Guilhot F: Sustained durability of responses plus high rates of cytogenetic responses result in long-term benefit for newly diagnosed chronic-phase chronic myeloid leukemia (CML-CP) treated with imatinib (IM) therapy: Update from the IRIS study (abstract 21). Blood 104:11, 2004.

2. Press RD, Love Z, Tronnes AA, et al: BCR-ABL mRNA levels at and after the time of a complete cytogenetic response (CCR) predict the duration of CCR in imatinib mesylate-treated patients with CML Blood 107:4250-4256, 2006.

3. Simonsson B, on behalf of the IRIS (International Randomized IFN vs STI571) Study Group: Beneficial effects of cytogenetic and molecular response on long-term outcome in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) treated with imatinib (IM): Update from the IRIS study (abstract 166). Blood 106:52a, 2005.

4. Deininger MWN: Management of early stage disease. Hematology (Am Soc Hematol Educ Program), pp 174-182, 2005.

5. Shah NP: Loss of response to imatinib: Mechanisms and management. Hematology (Am Soc Hematol Educ Program), pp 183-187, 2005.

6. Smyth MJ: Imatinib mesylate-uncovering a fast track to adaptive immunity. N Engl J Med 354:2282-2284, 2006.