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

Noam Benyamini; Jacob M Rowe


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

In This Article

Current Status of HSCT in the TKI Era

Despite the excellent data from studies on CML patients in the last decade, there are a number of uncertainties and dilemmas in the management of an unknown proportion of CML patients and the death rate in 'real life' is still significant. According to the SEER data, the CML incidence rate in the USA is about 2.1/100,000 for men and 1.2 for women, while the death rate is 0.4/100,000 for men and 0.2 for women.[101] The pivotal IRIS study,[33] which demonstrated the remarkable superiority of imatinib, was also the first to present a few of the problems we will encounter in the TKI era. At the 8-year follow-up, published >3 years ago, 55% of the patients were still treated at that time with imatinib.[34] Although many patients in the first few years did not have the option of receiving second-generation TKIs, only 3% of patients in this study discontinued imatinib due to HSCT. Indications for those who underwent HSCT and considerations not to 'salvage' more with HSCT have not been published. A large proportion of other patients were probably treated later on with other modalities, mostly second-generation TKIs. Since the beginning of the TKI era, drug treatment has been shown to be superior to HSCT in terms of survival.[35] In a population-based study of CML patients in Northwest England, which can be referred to as 'real life', 49% of newly diagnosed CML patients failed or were intolerant to imatinib in the first 2 years of treatment.[36] Ten out of the 68 chronic phase patients underwent an HSCT or were switched to an alternative TKI. Another study evaluating the survival benefit of imatinib describes 7 out of 279 newly diagnosed CML patients (3%) treated with imatinib, who underwent HSCT.[37] In the PETHEMA study, evaluating early intervention during imatinib therapy with newly diagnosed chronic phase CML, a detailed outcome of all 210 patients was given. Five patients underwent HSCT; only three patients were still in chronic phase at time of transplant.

In studies comparing the second-generation TKIs to imatinib, the DASISION[38] and ENESTnd[39] studies, patients receiving dasatinib and nilotinib, respectively, had progression-free survival and overall survival (OS) similar to patients receiving imatinib, with faster responses. Thus, we can assume that the number of HSCT is probably similar or even lower in these cohorts of patients.

Despite patients failing first-line treatments in studies and 'real life', HSCT in the setting of chronic phase, especially in the newly diagnosed patients not exposed or even failing one TKI treatment, is a rare event in the TKI era. Moreover, in later studies when nilotinib[2] and dasatinib[40,41] were available and evaluated after failure with imatinib, more patients could have gained response, leaving the option of HSCT in chronic phase to an even smaller group of patients.

The fact that a very small proportion of patients who failed TKI are referred to HSCT is of interest and not fully understood. Information from the large studies is lacking. We can assume that some portion of patients in this group were eligible to be enrolled in studies and to be treated off-study, but were not eligible for HSCT because of older age, low performance status and other compatibility issues. There might be other factors influencing the decision to go forward with the HSCT, like economic issues and patient education.

Nonetheless, the German CML study IV reported the subgroup analysis on 56 patients in the chronic phase that underwent HSCT. The 3-year OS was 91% with low transplant-related mortality and the authors suggested HSCT to be the preferred second-line treatment after imatinib failure.[42] In another study, HSCT for imatinib-resistant CML patients resulted in the 2-year event-free survival rates of 36 and 58% in patients with and without BCR–ABL mutations, respectively, and the 2-year OS rates were 44 and 76%, respectively,[43] making HSCT a very reasonable salvage option to imatinib-resistant patients.

Management of patients post HSCT has also changed in the TKIs era. Treatment with TKI post HSCT as prophylaxis or in combination with DLI in the relapse setting, is a reasonable strategy.[44,45]

As time passes and new drugs become available in clinical practice and studies, the pendulum is more in favor of medical treatments rather than HSCT in the chronic phase, despite major improvements in the HSCT techniques and supportive care. Most of the HSCT in CML is now reserved for the advanced phases of the disease.

In a recent EBMT report, CML is no longer one of the main indications for allo-HSCT, as it was in 1990. Allogeneic transplants for CML have stabilized in the past few years at a rate of 400 transplants per year (out of more than 12,000 transplants). The number of CML transplants done after transformation to accelerated phase as compared with chronic phase continues to increase, now at 255 in advanced disease versus 161 in chronic phase.[46]