Commentary (O’Brien): The Biology and Treatment of Chronic Myelogenous Leukemia

Drs. Brunstein and McGlave’s "The Biology and Treatment of Chronic Myelogenous Leukemia," is an excellent and concise overview of a complex disease. This analysis is very thorough, providing both a historical perspective and data on new approaches to therapy.

When Should Stem Cell Transplant Be Used?

Clearly, one of the most difficult areas in the treatment of chronic myelogenous leukemia is deciding when to use a stem cell transplant approach to therapy. Although this modality will cure some patients, peritransplant morbidity and mortality can be quite significant, particularly in older patients and those receiving transplants from unrelated donors.

While some groups have suggested interferon-based therapy as initial treatment for all patients over the age of 30 years, other groups have stated that transplant therapy should be offered as initial treatment to all patients up to age 65 with a human leukocyte antigen (HLA)-identical sibling donor.[1] Such disparate recommendations are clearly based on the experience of specific groups, as well as varying outcomes at different centers with both interferon and transplant therapy.

Recently, the Italian Cooperative Study Group on Chronic Myeloid Leukemia and the Italian Group for Bone Marrow Transplantation evaluated 840 patients who were less than 56 years old.[2] These patients, registered in trials between 1984 and 1991, received conventional chemotherapy, interferon, or an HLA-identical sibling transplant without T-cell depletion. The only significant pretreatment difference between patients receiving and not receiving a transplant was age (median: 32 vs 42 years). Otherwise, the groups were similar in terms of Sokal’s relative risk.

In this study, the 10-year survival rate for patients receiving interferon was 32%. At 10 years after bone marrow transplant, the overall survival rate was 55% and the leukemia-free survival rate was 50%. The authors noted that pretreatment with interferon did not significantly affect the outcome of the bone marrow transplant.

There was a significant difference in benefit for patients allocated to interferon or bone marrow transplant, depending on risk group. The 10-year survival rate for patients in the low-risk group receiving bone marrow transplant was 57%, compared with 49% in the interferon group (P = .76). Among patients at a higher risk, the rates were 54% for those receiving bone marrow transplant vs 17% for those receiving interferon (P = .01). The authors also noted that in high-risk, younger patients (< 32 years old), the 10-year survival rate was 65% for bone marrow transplant vs 35% for interferon (P = .05). For patients older than 32, the 10-year survival rates were 46% for bone marrow transplant vs 31% for interferon (P = .62).

The authors concluded that among low-risk patients, the 10-year survival rate, irrespective of age, was not significantly different between patients receiving bone marrow transplant and those given interferon. In the case of higher-risk patients, the results of bone marrow transplant were significantly better-but only for younger patients. The authors point out that younger patients are at a lower risk of dying from bone marrow transplant, and low-risk patients are more likely to respond to interferon therapy. This important paper offers useful guidelines for physicians taking care of patients with chronic myelogenous leukemia.

Impressive Data on STI-571

That said, the striking results that have been reported for the tyrosine kinase inhibitor STI-571 may throw such analysis into question. Kantarjian et al recently presented the results of a phase II study of this agent in patients with resistant or refractory chronic myelogenous leukemia.[3] Patients with documented grade 3 interferon intolerance were also included. A total of 532 patients were enrolled globally from 28 American and European centers. STI-571 was administered orally at a dose of 400 mg daily. Side effects were minor and consisted of nausea, diarrhea, muscle cramps, or headache; in general, the agent was extremely well tolerated. The cytogenetic results that were available at 3 months for 388 patients showed an overall 37% rate of major cytogenetic responses (< 35% Philadelphia chromosome-positive [Ph+] cells), with 13% complete remissions (0% Ph+).

After 6 months of therapy, the data available for 290 patients showed a major cytogenetic response rate of 56%. It is reasonable to expect that if this agent were used as initial therapy, the major cytogenetic response rate would be significantly higher, particularly with a longer treatment duration. In this setting, one might extrapolate cytogenetic responses in over three-quarters of patients. However, the durability of these remissions and potential long-term side effects are still unknown.

Nevertheless, given an oral agent with minimal toxicity and a striking cytogenetic response rate in patients pretreated with interferon, it will be difficult to allocate patients to bone marrow transplant rather than STI-571, once this drug becomes available. This brings into question whether any patient should be offered bone marrow transplant as initial therapy for chronic myelogenous leukemia.

References:

1. Applebaum F: ABMT in CML: The Seattle experience. Contemp Oncol 4:46-51, 1994.

2. The Italian Cooperative Study Group on Chronic Myeloid Leukemia and Italian Group for Bone Marrow Transplantation: Monitoring treatment and survival in chronic myeloid leukemia. J Clin Oncol 17(6):1858-1868, 1999.

3. Kantarjian H, Sawyers C, Hochhaus A, et al: Phase II study of STI571, a tyrosine kinase inhibitor in patients (pts) with resistant or refractory Philadelphia chromosome-positive chronic myeloid leukemia (Ph + CML) (abstract). Blood 96(11):470a, 2000.