Allogeneic transplantation for myelofibrosis with adverse risk karyotype: Attack on the clones?
Authors: Jason P. Cooper, Bart L. Scott
Journal: American Journal of Hematology (2018)

Prognostic and therapeutic considerations remain a challenging aspect in the appropriate care of patients with myelofibrosis. Critical to these considerations are the use and development of prognostic models. Prognostic models have been defined and refined over the last 50 years—starting with early observations of “short lived” and “long lived” groups with median survivals of 2 years versus 10 years.1 Progressing to scoring models that evolved based on clinical features, the most commonly employed of which are the International Prognostic Scoring System (IPSS) and Dynamic IPSS (DIPSS).2-4 Finally and most recently, the presence of an unfavorable karyotype was incorporated to augment clinical feature-based scoring models (DIPSS-Plus).5 These models provide patient-specific estimates of survival and of the risk of transformation to leukemia; key pieces of information to guide discussions of therapeutic options. Although molecular responses to a pharmacologic inhibitor of Janus kinase 1 and 2 (JAK1 and JAK2)6 have been reported, allogeneic hematopoietic cell transplantation remains the only therapeutic option that provides a chance of cure in myelofibrosis. Even when reduced-intensity conditioning regimens are used, transplantation carries substantial risks—5-year non-relapse mortality of up to 40% and a greater than 50% risk of developing chronic GVHD—and a substantial cost estimated at over $200 000 for the first 100-days post-transplant in allogeneic transplants performed during the years 2007–2009.7, 8 Thus, decisions to proceed to transplant should have solid footing based on data. We previously demonstrated that the evolution of prognostic models continues to predict outcomes of transplantation—most recently in an analysis of DIPSS-Plus classification in 233 myelofibrosis patients who underwent transplantation at our institution.7 We showed that DIPSS-Plus classification was superior to its predecessor DIPSS in discriminating patients with high and low probabilities of transplantation success and long-term survival. We also found that, while transplantation improved survival for some high-risk patients, it still carries with it a considerable risk of treatment-related mortality. A key question remains—how can we further delineate contributors to pre-transplant risk to more accurately predict post-transplant outcomes in high-risk patients? The answer likely lies in understanding the influence of disease biology. Tefferi and coworkers have been steadily working to integrate both clinical and genetic factors into prognostic models for myelofibrosis. Starting with the MIPSS70 prognostic model in transplantation-age patients, which, in addition to clinical features, for the first time incorporates driver-mutation status (absence of CALR type-1 mutation) and the presence of high-molecular risk mutations (ASXL1, EZH2, SRSF2, IDH1/2).9 MIPSS70 was augmented through incorporation of the presence (or absence) of unfavorable karyotype. More recent efforts have focused on refining the contribution of karyotype abnormalities to prognosis; their analysis of 1002 consecutive myelofibrosis patients followed at the Mayo Clinic yielded a three-tiered karyotype risk model—favorable, unfavorable, and very high risk which predicted survival and leukemic transformation.10 In this issue of the American Journal of Hematology, Tefferi et al. present a retrospective analysis of 67 patients with chronic-phase primary or secondary myelofibrosis who underwent allogeneic transplantation at the Mayo Clinic and for which pre-transplant karyotype information was available.11 The majority of patients were in the high and intermediate-2 categories according to DIPSS, and karyotype risk distribution was 11% very high risk, 34% unfavorable, and 55% favorable. After a median follow-up of 5 years, during which time 28 of the 67 patients died, allogeneic transplantation overcame the survival disadvantage of very high risk and unfavorable karyotype. In a multivariable analysis of a combined dataset of the cohort of 67 transplanted patients with 383 non-transplanted (control) patients, the beneficial effect of transplant was again demonstrated for patients with either very high risk and unfavorable karyotypes, as well as for patients classified as DIPSS intermediate-2 and intermediate-1. The authors further selected and analyzed a more stringently matched case–control cohort composed of 56 transplanted and 56 non-transplanted patients, which confirmed the results of the analysis of the larger 450-patient cohort. Tefferi and colleagues conclude that allogeneic transplantation in myelofibrosis improves survival in patients whose pre-transplant karyotype is very high risk or unfavorable, as compared to patients with similar adverse risk karyotype, age, and DIPSS category who are not transplanted. While their cohort size was small and the benefit of transplantation was not confirmed in DIPSS high-risk patients (as has been previously shown by ourselves and others), both limitations the authors readily concede, this new evidence that transplantation benefits myelofibrosis patients with adverse risk karyotypes will help to simplify prognostic and therapeutic conversations with patients. It also raises the question about whether there are particular sole or combinations of high-molecular risk mutations (ASXL1, SRSF2, etc.) that affect transplant outcomes. This naturally extends to the question of whether combinations of karyotype, driver mutations, and high-molecular risk mutations affect transplantation outcomes. We are certain that answers will emerge with time and per the authors, some of these questions are already under investigation. Lastly, as stated by the authors, the results of the current study, “underline the power of immunotherapy, as opposed to drug therapy alone, in eradicating cytogenetically aggressive clones.”11 Future endeavors will further elucidate disease biology and its interaction with currently available and future therapies. For now, Tefferi and colleagues have given us insight into the potential patients who should be considered for transplantation and provide further evidence of the curative potential of allogeneic transplantation even in those patients with high risk features such as an adverse karyotype. Nothing to report.