Allogeneic Stem Cell Transplantation Versus Medical Therapy in Patients with Advanced Myelofibrosis: Matched Survival Analysis and the Effect of JAK2 Inhibitor Therapy
Authors: Masarova Lucia , Popat Uday R. , Bose Prithviraj , Champlin Richard E. , Cortes Jorge E. , Kantarjian Hagop M. , Verstovsek Srdan 
Published: October 2019

Abstract
Introduction: Allogeneic stem cell transplantation (SCT) is a curative option recommended for patients with Dynamic International Prognostic Scoring System (DIPSS) intermediate-2 (int-2) and high risk myelofibrosis (MF). We aimed to compare outcome of patients with advanced chronic phase MF (i.e. DIPSS int-2 and high risk, and peripheral blasts <10%) seen at our center that have undergone SCT, to those that were treated with available medical therapies.
Methods: Data from 49 patients with advanced MF who underwent SCT at our center between 2006-2014 (to assure uniform SCT preparation regimen) were matched to 147 patients (1:3 matching) who did not received SCT (no-SCT group). Groups were matched for int-2 and high risk DIPSS, and for age +/- 7 years, hemoglobin ≤10 g/dL, white cells ≥25x109/L, and presence of systemic symptoms. Matching considered parameters at the time of SCT, or, for no-SCT group, at the time of referral. We have collected all relevant clinical data by retrospective review of medical charts. Categorical and continuous variables were compared by chi-square and t- test, respectively. Survival analysis was done using Kaplan-Meier analysis with the log-rank test. A landmark survival analysis that considered median time to transplant was also conducted. We used SPSS v.23 and R 3.1.0 for statistics.
Results: Characteristics of patients in the two groups are shown in the Table 1. Except for lower median hemoglobin and higher bone marrow blasts in no-SCT patients (both p<0.05), the groups were similar. In both groups, ≥50% of patients had constitutional symptoms, and significant splenomegaly (median spleen size below costal margin of ≥10 cm). Unfavorable cytogenetic (Caramazza, Leukemia 2011), were identified in 50% (no-SCT) and 24% (SCT) of patients, and JAK2V617F mutation in 53% and 41% of patients, respectively.
No-SCT patients received a median of 1 (range, 0-4) and 2 (range, 1-5) treatments prior and after the referral, respectively, including JAK2 inhibitor (JAK2i) in 41 patients (28%). In SCT group, 8 patients (16%) were not treated prior to SCT, while others received a median of 2 therapies (range, 0-6), including JAK2i in 9 patients. Seven of them failed JAK2i before undergoing SCT. Among SCT patients, 29 (59%) underwent matched unrelated, and 20 (41%) matched related SCT. Response to SCT was complete remission (CR) in 38 patients (78%), 5 patients did not respond or engraft, and 6 patients were not evaluable due to early mortality. Among 38 patients with CR, 13 patients (34%) relapsed and 25 (66%) remained in remission.
To eliminate selection bias, we performed a landmark survival analysis (applied to no-SCT group), considering a median time to SCT (SCT-group) from referral of 6 months. Median overall survival (OS) was similar for SCT and no-SCT patients: 46 (range, 5.5-86) vs 34 (range, 22-46) months (p=0.19, Graph 1A). OS rates at 1-year were 69% and 77%, and at 3-year 63% and 49%, and at 5-year 49% and 34% respectively, for SCT and no-SCT groups. To assess for a long-term effect of SCT, we have conducted a sub-analysis excluding patients with early SCT mortality (<100 days, n=6). Median OS was better in SCT patients than in no-SCT (81 vs 34 months, p=0.03).
We further analyzed the impact of JAK2i therapy on OS in no-SCT patients. Median OS of no-SCT patients who were treated with JAK2i was 42 months, similar to patients with SCT of 46 months (p=0.30); with 1-, 3- and 5- year OS (no-SCT patients with JAK2i) of 80%, 51% and 36%, respectively. This finding was also confirmed in a sub-analysis excluding SCT patients with early mortality (<100 days, n=6), where OS was similar in patients with no-SCT treated with JAK2i vs SCT (42 vs 81 months, p>0.05). When we compared SCT patients with no-SCT patients with and without exposure to JAK2i, the respective median OS were 46 (range, 5.5-86), 42 (range, 21-63) and 28 (range, 15-41) months (p=0.28, Graph 1B).
Conclusions: SCT is a feasible and curative strategy for patients with chronic advanced MF, providing long-term survival benefit, which is however limited by early toxicity of the procedure. Recent introduction of JAK2i as a medical therapy for MF has a potential to significantly improve an outcome of patients not subjected to SCT. The combination of JAK2i therapy followed by SCT is being explored in clinical trials.
Table 1 Table 1. Figure 1 Figure 1.

Disclosures
Cortes: ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding.