Is There a Role for Allogeneic Transplantation in Chronic Myeloid Leukemia?

Noam Benyamini; Jacob M Rowe

Disclosures

Expert Rev Hematol. 2013;6(6):759-765. 

In This Article

Introduction & evolution in the management of CML

Chronic myeloid leukemia (CML) is a pluripotent stem cell disease, characterized by a reciprocal translocation between chromosomes 9 and 22, resulting in the fusion gene BCR–ABL. Since 1960, the year the Philadelphia chromosome was first described by Peter Nowell and David Hungerford,[1] there has been an enormous development in the understanding of the pathogenesis of CML. At the same time, treatments for CML have also changed dramatically. Nonspecific treatments, such as radiation, busulfan and hydroxyurea that were developed during the 20th century, were used successfully for controlling symptoms and blood counts, but did not change the natural course of the disease. IFN-α and hematopoietic stem cell transplantation (HSCT) were the first treatments to change cytogenetic status and improve survival.

In 2001, the first tyrosine kinase inhibitor (TKI), imatinib mesylate, was approved for the treatment of CML. The introduction of TKIs has completely changed the way most patients with CML were treated and has immensely improved their prognosis. Following imatinib, other TKIs have been developed, including nilotinib,[2] dasatinib,[3] bosutinib[4] and lately pomatinib,[5] which is also effective against the T315I mutation. In the end of 2012, omacetaxine, a protein translation inhibitor, was approved for the treatment of patients resistant and/or intolerant to two or more TKIs, offering another therapeutic option for CML patients.[6] New combinations and strategies continue to develop and new drugs continue to emerge.

Despite the progress that has been made in the understanding of the pathogenesis of CML and the vast improvement in the management and treatment of CML patients, complete cure is still not feasible in most patients. HSCT is still considered the only curative treatment available. A major effort is being made exploring ways to eradicate the leukemic stem cells, deepening the molecular responses and maintaining remission without the use of a long period of treatment with TKIs. Patients who achieve complete cytogenetic remission (CCyR) on IFN-α and cease therapy may remain in CCyR without treatment for a long period of time. In a group of 15 patients who stopped IFN-α, 7 patients (47%) did not lose the CCyR at a median follow-up of 36 months.[7] Another retrospective study reported the outcome of 317 patients treated with IFN-α and achieving CCyR. Thirty-six patients stopped treatment at a 10-year follow-up. Of these 36, 15 patients (41%) who stopped treatment are still in CCyR.[8] Stopping treatment with imatinib in patients with at least 2 years of complete molecular response (CMR) may result in maintaining undetectable BCR–ABL transcripts in about 40% of patients.[9–11] Moreover, there are currently several ongoing studies evaluating discontinuation of nilotinib or dasatinib.

Another approach for cure is targeting the leukemic stem cell; although this is rational, it has not been clinically tested yet[12] or been successful.[13] One approach being tested is to increase the anti-leukemic activity by using combinations of TKIs and IFN-α. Among other mechanisms, IFN-α induces cytotoxic T cells specific for CML progenitors, increasing the potential benefit of combination therapy with TKI.[14] Hedgehog signaling is increased in BCR–ABL1-positive stem cells becoming more active with disease progression. Inhibition of the hedgehog signaling pathway may be another way to target leukemic stem cell.[15,16] Although intriguing, clinical data using these strategies are still lacking.

Thus, HSCT has been a reasonable strategy for >30 years. Since the late 1970s, strategies using HSCT for CML have been developed and studied. Autologous HSCT (auto-HSCT) was used to re-establish chronic phase in blast crisis patients[17] and, later, to prolong survival in the chronic phase.[18] Allogeneic HSCT (allo-HSCT), although suffering from disappointing results in the first reported transplants, has rapidly become a very reasonable option for prolonged survival in CML in all phases.[19] For chronic phase patients under 50 years of age, transplanted from HLA-identical sibling donors, the probability of long-term disease-free survival (DFS) was 60–80%.[20,21]

Very soon, it was understood that the rate of survival from allo-HSCT correlated with the clinical phase, making patients in chronic phase the best candidates for this treatment. Only 15–20% of transplanted patients in the advanced stages become long-term survivors.[20] In a large retrospective study, DFS after allo-HSCT was 35–40% for patients in second chronic phase, 26–27% in accelerated phase and only 8–9% in blast crisis.[22] Moreover, it was acknowledged that HSCT should be performed early in the management of the disease. There was an increase in the treatment failure in patients transplanted more than a year after diagnosis. Notably, most of deaths were nonrelapse and were believed to reflect cumulative toxicity of cytotoxic drugs before the transplant.[23] In the TKI era, it is not clear if time from diagnosis has the same effect on transplant results.

After experience with matched siblings, transplantation using HLA-matched unrelated donors became more feasible and the outcome of HSCT with unrelated donors became almost comparable to that of matched siblings with survival at 5 years of 57%.[24]

Cord blood allografts are another emerging donor option, increasing the pool of matched donors.[25]

The most popular conditioning regimen used in allo-HSCT in CML in the early years was cyclophosphamide and total body irradiation,[20] but soon the use of busulfan and cyclophosphamide were found to be equally efficacious but better tolerated.[26,27]

Another reasonable approach, especially in the older patients, is using reduced intensity conditioning (RIC). In the largest retrospective analysis of 306 CML patients reported to undergo RIC allo-HSCT, the 3-year overall survival was 41–54%, the 3-year relapse incidence was 36–66% and the DFS was 16–35%, all correlated with age and disease phase. Results were comparable to historical outcome in patients undergoing myeloablative conditioning, although DFS was slightly reduced.[28]

It was quickly recognized that graft-versus-leukemia effect was very important in CML and probably has an important role in effecting a cure after HSCT.[29]

T-cell depletion, in vivo or in vitro, in allo-HSCT was shown to reduce graft-versus-host disease in CML but is associated with an increase in relapse rate.[30] However, donor lymphocyte infusions (DLI) have been shown to be very effective in CML, re-inducing remission in a large percentage of patients,[31] especially those who relapse in the chronic phase.

Monitoring minimal residual disease by estimating the level of BCR–ABL transcripts is important for managing patients after HSCT, although the very sensitive RT quantitative PCR may detect low BCR–ABL transcript levels >10 years after HSCT, and is probably not a good predictor for relapse.[32] Never-the-less, this very late possible persistence of CML stem cells may have a role in the rare late relapses. A vast research has made HSCT an excellent strategy in CML, and much has been learned about CML thanks to the field of HSCT. Never-the-less, TKIs have made a major change in the management of most patients with CML. The question of the role of HSCT in the management of CML must be challenged time after time, as newer and safer therapies are being developed. Who should be offered an allo-HSCT in 2013 remains an important and sometimes controversial issue.

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