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Hematopoetic Stem Cell Transplantation in CML

Few examples in clinical medicine demonstrate such a fascinating interaction as chronic myeloid leukemia (CML) and hematopoietic stem cell transplantation (HSCT). CML did provide first proof of principle that an incurable disease was amenable to successful treatment, that immune mediated mechanism could control a malignancy and that the risk of HSCT could be quantified by a few key factors. HSCT was nearly abandoned at the introduction of targeted therapy with imatinib. Today, it has a clear position and exemplifies the modern risk adapted approach.

The disappearance of Philadelphia chromosome in patients given intensive chemo-radio therapy and bone marrow from their syngeneic twin donors more than 30 years ago marked the beginning of a new area in the treatment of CML: it became possible to cure patients from their disease. The concept was rapidly adopted. Allogeneic HSCT became the treatment of choice for young patients with CML and a compatible donor. At the end of the century, CML was the most frequent indication for an allogeneic transplant with more than 2’000 HSCT worldwide. Imatinib changed this trend and numbers of HSCT for CML began to decline even years before the results of the first clinical trials with imatinib were published. Numbers of HSCT declined primarily for first chronic phase but remained relatively stable for advanced stages.
The large number of early transplants gives clear information on the long term expectations More than 40% of the patients transplanted in first chronic phase are alive without the disease beyond 20 years after the transplant, about 20% of those transplanted in accelerated phase and about 10% of those transplanted in blast crisis. No other form of treatment has yet achieved these results and transplant results have substantially improved since. In addition, outcome is not erratic. Five key pre transplant risk factors, stage of the disease, age at the time of the transplant, time from diagnosis to transplant, donor type and donor recipient sex combination provide for a score from 0 to 7, with decreasing survival with increasing score due to increasing transplant related mortality. The predictive value of this risk score has been confirmed in several independent series, with different transplant technologies and holds for all allogeneic HSCT for a hematological malignancy. Risk assessment can further be fine tuned by integrating additional elements, such as CMV serostatus, cytokine polymorphisms or co morbidity score. Hence, risk assessment of the transplant has become a reality. Indeed, in a recent series of the German CML study group, survival of 56 patients transplanted in first chronic phase with high risk disease and low risk donors showed a survival probability at 3 years of 90% with less than 10% transplant related mortality.

Based on these data, the new updated European Leukemia Net recommendations for the treatment of CML include this risk adapted approach and give guidance on when to search for a donor and when to proceed to a transplant. Early recognition of a failed response to imatinib is essential in order to initiate donor search and to proceed to HSCT in time. This has become even more important, since most failures occur within the first two years of treatment. HSCT is recommended for all patients in accelerated phase, blastic transformation or with T315I mutation; it is recommended for all patients who failed second line TKI therapy and for those who failed first line therapy with a low EBMT risk score. Last, HSCT might be the most cost efficient approach in some countries with limited resources.

Physicians treating patients with CML have been intensively trained in the use of imatinib and other tyrosine kinase inhibitors. It is now time to inform more in-depth patients and physicians about the modern risk adapted strategy for HSCT. Patients with failed response and optimal donor should proceed to the transplant whenever possible before transformation has occurred. Such a strategy will save lives and costs and improve overall outcome.

Alois Gratwohl,
Stem Cell Transplant Team, University Hospital, University of Basel,
Basel, Switzerland