By C.D. Buckner, MD- November 2005

Summary

Gleevec (imatinib) is an Abl-specific tyrosine kinase inhibitor that has marked activity in the treatment of chronic myeloid leukemia (CML) with minimal toxicity. Gleevec induces complete hematologic remission in almost all patients and is associated with a very high rate of cytogenetic response. Information concerning molecular remissions and whether or not it will prolong life in comparison with alfa interferon (IFNa) are not known. Gleevec was first administered to patients with CML in the summer of 1998 and was approved in 2001 by the U.S. Food and Drug Administration for treatment of patients with CML who have failed a trial of IFNa. The introduction of Gleevec has resulted in rethinking of the timing of allogeneic transplants for newly diagnosed patients with CML who have suitable allogeneic related or unrelated donors. Prior to Gleevec, less than ideal transplant candidates were usually advised to undergo a trial of INFa before proceeding to transplant. Now, almost all patients with newly diagnosed CML will receive a trial of Gleevec before proceeding to an allogeneic stem cell transplant.

Introduction

Despite improvement of treatment with Gleevec, allogeneic stem cell transplantation remains the only curative treatment for patients with CML.[1]  This form of treatment is only available for a small minority of patients due to the advanced age of most patients at the time of diagnosis and the lack of a suitable related or unrelated allogeneic stem cell donor. Despite significant progress, allogeneic transplants are associated with significant early mortality and morbidity. Until the advent of Gleevec, “young” patients with an HLA-matched related or unrelated donor were advised to undergo a transplant without a trial of IFNa.  Older patients and patients with high-risk factors for failure of transplantation were advised to have an allogeneic transplant only after failure of IFNa. The definition of who is “young” and who is at “high” risk of transplant failure varies from center to center and is evolving over time. Advising selected patients to have an immediate transplant was based on the observation that the results of transplant were worse for patients transplanted after one or two years than for patients transplanted within one year of diagnosis. Until recently, a major criterion for delay of transplant was a good initial response to IFNa treatment. Now all patients with newly diagnosed CML are receiving initial treatment with Gleevec alone or in combination with other agents before a transplant is considered. However, clinicians should identify a donor early for younger patients without significant co-morbidities since, sooner or later, the disease will progress despite Gleevec and other therapies.

Treatment with Gleevec of Newly Diagnosed Patients with CML

Gleevec has become the initial treatment of choice for newly diagnosed patients with CML since the publication of the IRIS study comparing Gleevec to interferon and cytarabine.[2],[3],[4]   Current data suggests that:

• 97% of newly diagnosed patients with CML will achieve a complete hematological remission.
• 87% will have a major cytogenetic reduction.
• 76% will have a complete cytogenetic remission.

Of the 553 patients entered in this trial, 79% are still receiving first-line therapy with Gleevec. Progression-free survival (PFS) following Gleevec treatment depends on the log reduction of BCR-ABL. Those with a 3 log reduction have a 100% PFS at 30 months compared to 93% for a 2 log reduction and 81% for a 1 log reduction. Despite these results it is still unknown whether or not Gleevec improves long-term survival. It is also the consensus of opinion that it is unlikely that patients will be cured with Gleevec since only 5% have become PCR-negative despite continued Gleevec.

Allogeneic Stem Cell Transplantation

Allogeneic stem cell transplantation can cure up to 80-85% of patients with newly diagnosed CML but can be associated with significant morbidity and mortality.[5]  There have been attempts to define risk factors associated with failure to assist in decision making concerning the appropriate timing of allogeneic stem cell transplantation for an individual patient with CML.[6]  However, these risk factor analyses may be dated and may not be relevant to patients being treated in the Gleevec era and an era of improving results of allogeneic stem cell transplantation.

Age has consistently been an important factor for outcome of allogeneic stem cell transplantation, but the exact upper age limit for performing an allogeneic transplant in early chronic phase is controversial, with ranges from 40-65 years, depending on the institution performing the procedure. In general, treatment-related deaths increase with age in most centers. In one clinical study, no patients under age 20 died. Patients 30-40, 40-50 and 50-60 years were 1.24, 2.30 and 2.54 times more likely to die of the procedure, respectively.[7]   Patients over age 40 had a significant increase in the risk of dying of the transplant compared to younger individuals. Thus, patients under the age of 40 had a 5-year survival of 85%, compared to 65-70% for patients over 40 years of age.

Delay of transplant can also affect outcomes of patients transplanted in chronic phase. In one study, patients transplanted from HLA-matched unrelated donors while in chronic phase within one year of diagnosis had a 5-year survival of 85% while those transplanted between 1 and 2 years from diagnosis had a survival of 78%.[8]  Patients transplanted in chronic phase more than 2 years from diagnosis had a survival 50%, with the excess deaths all being related to complications of the transplant. However, these data were generated in the era of INF alfa treatment and the impact of Gleevec on survival from a subsequent transplant is unknown. This will be very important since patients will be coming to transplant after years of Gleevec treatment.

Researchers from the Fred Hutchinson Cancer Research Center (FHCRC) have reported the best survivals yet for patients with CML in chronic phase receiving allogeneic transplants from HLA matched relatives.[9]They attribute much of the improvement to adjusting the doses of busulfan (Bu) in the busulfan/cyclophosphamide (Bu/Cy) treatment regimen. This study involved 131 consecutive patients treated with targeted Bu in the Bu/Cy preparative regimen. The oral dose of Bu was increased or decreased in order to achieve a Bu steady state serum concentration of 900 ng/ml. This is achievable because the first dose of Bu predicts how the patient will handle the drug on subsequent doses. Although there are marked inter-patient variations, there is little variation in a given patient between doses. The median age of these patients was 43 years with the oldest being 66 years of age. Results showed treatment-related mortality rate of 14% and a relapse rate of 8% with 11% of patients having persistent PCR positivity of “low level.” The 3-year probability of survival was 86% with a 78% probability of disease-free survival. The incidence of chronic graft-versus host disease was 60%, but the median final Karnofsky score was 95%. There was an increased treatment-related mortality in patients transplanted more than one year from diagnosis, but this was not statistically significant in multivariate analysis with only 17 patients in this group. The 3-year survival for the 17 patients transplanted beyond one year from diagnosis was 81%. In multivariate analyses, there was no impact of age on outcome, but virtually all patients were under the age of 65 years. These data represent the best survivals reported for allogeneic transplants for patients with CML in chronic phase. Whether or not other institutions can duplicate these results remains to be determined. With these results, allogeneic transplants for younger individuals remain a viable treatment option early in the disease course. It will be of major interest to determine the outcome of transplantation using the FHRC methodology following failure of Gleevec. However, at the present time it is unlikely that many patients will be transplanted within one year of diagnosis.

Decision Making in the Gleevec Era

Over the past 5-6 years, most transplant centers have seen a 50-75% reduction in the number of transplants for chronic phase CML because patients have opted for initial Gleevec treatment rather than a stem cell transplant. However, the timing of transplantation for patients with a stem cell donor continues to be debated. The most common suggestion is to perform an allogeneic stem cell transplant from a related or unrelated donor in Gleevec failures. This is defined as patients who do not achieve a complete hematologic response within 3 months or who are predominantly PH-positive at 6 months, or those who have >35% PH-positive metaphases at 12 months. Patients could also be transplanted after loss of a previous hematologic or cytogenetic response or if they achieved a complete cytogenetic response and had a 1 log increase in BCR-ABL transcripts.

Some researchers have suggested that the results of allogeneic stem cell transplants are so good that they could be performed as initial therapy for patients under the age of 45 years who have a suitable related donor and for patients under the age of 35 years who have a suitable unrelated donor.[10]This option could certainly be presented to young newly diagnosed patients who might be willing to accept this choice of upfront therapy, with a 10-15% chance of treatment-related mortality, rather than face years of drug therapy.

Predictive models may also help in making a decision about an early allogeneic stem cell transplant. Dr. Goldman, from Hammersmith hospital has presented data showing that the Sokal score, developed in the busulfan era, also predicted for response to Gleevec. (See Goldman news item) Patients at low-risk on the Sokal score had a 94% PFS at 30 months, intermediate-risk had 88% PFS and high-risk patients had an 80% PFS following Gleevec treatment. There are also predictive factors for success or failure of allogeneic transplants. In registry data (EBMT and IBMTR) transplant-related mortality for patients 45 years of age or under is 15% but can be higher with the presence of one or more adverse risk factors, such as increasing time from diagnosis to transplant, a female donor, increasing age, and CMV positivity. Patients without any of these risk factors have decreased treatment-related mortality. Thus, if a patient is high risk on the Sokal score and low risk on the transplant score an up-front transplant could be considered.

Reduced Intensity-Allogeneic Stem Cell Transplants

Over the past several years there has been increased research into the effectiveness of reduced-intensity allogeneic stem cell transplants in patients with a variety of hematologic malignancies including CML. The primary goal of these studies is to increase the age at which transplants can be performed since CML is primarily a disease of older individuals. The European Bone Marrow Transplant (EBMT) has reported the outcomes of 186 patients with CML who received reduced-intensity allogeneic stem cell transplants.[11]  The median age was 50 years and 64% of these patients were in chronic phase. The 100 day treatment-related mortality was 6% and increased to 23% at 2 years. Graft-versus host disease was a major problem in these patients. As expected, patients in first or second chronic phase had better outcomes than patients transplanted in accelerated or blastic phase of CML. For patients transplanted in chronic phase overall survival at 3 years was 70%. The details of prior treatment were not included in this study so it is impossible to determine if Gleevec affected outcomes. A small study of reduced-intensity allogeneic stem cell transplants in patients with CML in chronic phase was also reported from Latin America.[12]  These researchers transplanted 24 patients early in chronic phase of CML with a median age of 41 years with the oldest being 71 years old. Overall survival at 830 days was 92% with 2 patients dying of transplant-related causes. These data are promising for early transplantation but need to be confirmed. Whether or not reduced-intensity regimens will replace conventional regimens remains controversial, but this approach should increase the number of older patients who fail Gleevec who are then treated with stem cell transplantation.

Researchers from the M.D. Anderson Cancer Center have incorporated Gleevec into the pre and post-transplant treatment regimen in recipients of reduced-intensity allogeneneic stem cell transplants.[13]  The transplant regimen consisted of Gleevec, busulfan, ATG and fludarabine. The protocol also included donor lymphocyte infusions in those without GVHD. The researchers treated 18 patients: 7 were in chronic phase with clonal evolution, 8 were in second chronic phase and the rest were in AP. One patient died of chronic GVHD. The researchers observed a cytogenetic CR in 13 patients and a molecular CR in 6 patients. These results suggest that this technique could be applied earlier in the disease course and may represent an alternative to donor lymphocyte infusions, as no patient in this study had it performed.

Effect of Gleevec on Transplant Results

There is emerging evidence that Gleevec may affect transplant-related mortality. It is recommended to allow at least 30 days between discontinuing Gleevec and transplant. Preliminary data suggests deaths from hepatotoxicity and a possible interaction between Tylenol and Gleevec. In one study, treatment related mortality was 74% among 23 patients who had received Gleevec before transplant with an even higher rate for those receiving Gleevec within 15 days of transplant.[14]However, a more recent study did not confirm these findings.[15]  These researchers evaluated transplanted complications in 30 patients previously treated with Gleevec and 48 not treated with Gleevec and could find no evidence that preceding Gleevec increased transplant-related toxicities. However, despite these findings it would still be prudent to discontinue Gleevec 30 days or more prior to transplant.

In Summary

Patients with newly diagnosed CML will probably be treated initially with Gleevec, and allogeneic stem cell transplantation will be reserved for failures. At the present time virtually all patients will have a donor when one includes siblings, unrelated donors and umbilical cord blood. For patients with CML who have a stem cell donor, the most important consideration will ultimately be the preference of the patient. Many patients will be reasonably comfortable with palliative therapy for as long as is feasible followed by a transplant. Other patients, however, will choose the curative approach of allogeneic stem cell transplantation as soon as possible, despite the inherent risks of this approach. One can also expect transplants to become less toxic in the future with the possibility that Gleevec will be incorporated into reduced-intensity regimens.

References