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Allogeneic Hematopoietic Stem Cell Transplantation for Post-essential Thrombocythemia and Post-polycythemia Vera Myelofibrosis

Objective Little information is available about the outcome of allogeneic hematopoietic stem cell transplantation (HSCT) for patients with secondary myelofibrosis from essential thrombocythemia (ET) and polycythemia vera (PV). A nationwide retrospective study of the outcome of HSCT for post-ET and post-PV myelofibrosis was conducted in Japan. Patients and Methods Clinical data for patients with post-ET (n=29) and post-PV (n=9) myelofibrosis who had received first allogeneic HSCT were extracted from the Transplant Registry Unified Management Program, which is a registry of the outcomes of HSCT in Japan. Results Five patients died without neutrophil recovery within 60 days after transplantation. The incidence of neutrophil recovery was significantly lower in umbilical cord blood (UCB) transplantation than in related donor transplantation (40% vs. 92%, p=0.010). The 1-year non-relapse mortality for post-ET and post-PV myelofibrosis was 35% and 27%, respectively (p=0.972). No patient or transplantation characteristics were associated with non-relapse mortality. The 4-year overall survival for post-ET and post-PV myelofibrosis was 46% and 65%, respectively (p=0.362). A univariate analysis identified UCB transplantation (vs. related donor, p=0.017) and ≥10 times red blood cell transfusions before transplantation (vs. <10 times, p=0.037) as predictive of a lower overall survival. Conclusion Allogeneic HSCT provides a long-term survival for at least some patients with post-ET and post-PV myelofibrosis. Further studies with more patients are required to determine the best alternative donor.


Introduction
Essential thrombocythemia (ET) is a chronic myeloproliferative neoplasm characterized by sustained thrombocytosis in the peripheral blood and increased numbers of megakaryocytes in the bone marrow (1). ET has a long symptom-free period with the absence of life-threatening thromboembolic or hemorrhagic events. However, myelofibrosis occurs in about 10% of patients with a diagnosis of ET (2). Polycythemia vera (PV) is another chronic myeloproliferative neoplasm characterized by increased red blood cell production independent of the mechanisms that normally regulate erythropoiesis (3). The major symptoms of PV are related to hypertension or vascular abnormalities caused by the increased red blood cell mass. The incidence of myelofibrosis in patients with a diagnosis of PV is reported to be about 10-20% (2).
Despite the remarkable benefits of Janus kinase (JAK) inhibitors in terms of reducing splenomegaly and diseaserelated symptoms (4,5), current drug therapy for post-ET and post-PV myelofibrosis is not curative and unlikely to prolong the survival (6). The only potentially curative therapy for secondary myelofibrosis is allogeneic hematopoietic stem cell transplantation (HSCT) (7). Nonetheless, there are few reports focusing on the outcomes of HSCT for patients with post-ET and post-PV myelofibrosis (8)(9)(10).
We herein report the results of a nationwide retrospective study to analyze the clinical outcomes of HSCT for post-ET and post-PV myelofibrosis in Japan.

Patients
Clinical data for patients with post-ET and post-PV myelofibrosis who had received first allogeneic HSCT were extracted from the Transplant Registry Unified Management Program (TRUMP), which is a registry of the outcomes of HSCT in Japan (11,12). This program is sponsored by the Japan Society for Hematopoietic Cell Transplantation and the Japanese Data Center for Hematopoietic Cell Transplantation. More specifically, the clinical data for patients with "1" in the "no" column, "myelofibrosis" in the "mpd_subtype" column, and "secondary" in the "denovo_secondary" column were extracted from the TRUMP data. We then divided those patients into post-ET or post-PV myelofibrosis according to "ET" or "PV" in the "sec_malig_dx" column. Patients with other diseases, such as "AML", "MDS, " or "macroglobulinemia, " in the "sec_malig_dx" column were excluded. Thus, neither primary myelofibrosis nor secondary myelofibrosis from diseases other than ET and PV was included in this study.
This study was approved by the Data Management Committee of the Japan Society for Hematopoietic Cell Transplantation and by the Ethics Committee of the Nagoya Uni-versity School of Medicine.

Definitions
The conditioning regimen intensity was classified as myeloablative conditioning or reduced-intensity conditioning based on the report by the Center for International Blood and Marrow Transplant Research (13). Neutrophil recovery was defined as an absolute neutrophil count of at least 0.5× 10 9 /L for 3 consecutive days. Engraftment failure was defined as no neutrophil recovery by day 60. Acute graftversus-host disease (GVHD) and chronic GVHD were diagnosed and graded based on traditional criteria (14,15).

Endpoints
The primary endpoint of this study was the overall survival (OS) after allogeneic HSCT in patients with post-ET and post-PV myelofibrosis. Other endpoints included neutrophil recovery, acute and chronic GVHD, relapse rate, nonrelapse mortality (NRM), causes of death, and the impacts of patient and transplant characteristics on the transplant outcome.

Statistical analyses
The probabilities of neutrophil recovery, the acute and chronic GVHD rate, the relapse rate, and NRM stratified by primary disease and donor sources were estimated based on cumulative incidence curves (16). A competing risk regression analysis was used to identify factors associated with NRM. The probabilities of the OS stratified by primary disease and donor sources were estimated according to the Kaplan-Meier method (17). The groups were compared using the log-rank test. Cox's proportional hazards model was used to identify factors associated with the OS (18). All tests were two-sided, and p<0.05 was considered significant. The data were analyzed by the STATA version 12 statistical software program (StataCorp, College Station, USA).

Engraftment
Five patients (13%) died without engraftment within 60 days after transplantation, due to bleeding (n=2) on days 7 and 48, bacterial infection (n=1) on day 15, acute respiratory distress syndrome (n=1) on day 15, and multiple organ failure (n=1) on day 12. The incidences of neutrophil recovery on day 60 in patients with post-ET and post-PV myelofibrosis were 83% [95% confidence interval (CI), 63-92%] and 89% (43-98%), respectively (Fig. 1a). There was no significant difference in the incidence of neutrophil recovery between post-ET and post-PV myelofibrosis (p= 0.591). The median days to neutrophil recovery in patients with post-ET and post-PV myelofibrosis were 21 and 20, respectively.
A patient receiving HLA-haplo donor transplantation achieved neutrophil recovery on day 20. Use of JAK inhibitor before transplantation was not associated with the incidence of neutrophil recovery.

Discussion
The present study demonstrated no significant differences in the incidence of neutrophil recovery, incidences of acute and chronic GVHD, relapse rate, NRM, and the OS between post-ET and post-PV myelofibrosis. Little information has been available comparing transplant outcomes between post-ET and post-PV myelofibrosis. Lussana et al. reported no marked differences in the 3-year NRM and OS rates between post-ET and post-PV myelofibrosis (10). In contrast, Ballen et al. reported a significantly higher 5-year NRM for post-ET myelofibrosis than for post-PV myelofibrosis (9). Thus, whether or not the transplant outcomes for post-ET and post-PV myelofibrosis are equivalent remains controversial.
The OS was significantly lower in UCB transplantation than in related donor transplantation. NRM was not significantly different between UCB and related donor transplantation. However, the incidence of neutrophil recovery was significantly lower in UCB transplantation than in related donor transplantation. These results suggest that efforts to increase the incidence of neutrophil recovery may help improve the OS in UCB transplantation for secondary myelofibrosis. Nonetheless, the present cohort included only five patients undergoing UCB transplantation. Robin et al. evaluated 35 UCB transplantation cases for myelofibrosis, includ-   (20). The recent nationwide retrospective study of HSCT for Japanese patients with primary myelofibrosis reported that the 1-and 4-year OS rates in UCB transplantation (n=29) were 48% and 27%, respectively, and that NRM was significantly higher in UCB transplantation than in HLA-matched related donor BM transplantation (21). Further analyses with more patients are required to evaluate the differences in the transplant outcomes for secondary myelofibrosis between UCB transplantation and related or unrelated donor transplantation. Frequent (!10 times) RBC transfusion before transplantation was identified as a risk factor for the OS. This is compatible with previous analyses of HSCT for primary myelofibrosis (21)(22)(23). The Japanese national registry includes the Dynamic International Prognostic Scoring System (DIPSS) score, but not the DIPSS Plus score, which takes into account the information on RBC transfusion dependency and thrombocytopenia (24). Therefore, if the DIPSS Plus score had been available, it might have been identified as a predictor of the transplant outcome.
The median ages at transplantation for post-ET and post-PV myelofibrosis were 53 and 57 years old, respectively. These ages are younger than the median ages of the general patient cohorts of ET (approximately 55 years old), PV (approximately 64 years old), and primary myelofibrosis (approximately 65 years old) (2,25). A younger patient age is reported to be associated with a higher OS in HSCT for *Two patients with BM transplantation from HLA-matched related donor are included. **95% confidence interval is in parentheses. ***One patient with PB transplantation from unrelated donor is included. PMF: primary myelofibrosis, SMF: secondary myelofibrosis, PB: peripheral blood stem cell, GVHD: graft-versus-host disease, NRM: non-relapse mortality, OS: overall survival, BM: bone marrow, UCB: umbilical cord blood myelofibrosis (21,26,27). Thus, it should be noted that the efficacy of HSCT for secondary myelofibrosis might have been accentuated in this study. A comparison of transplant outcomes of Japanese patients with primary (21) and secondary (present study) myelofibrosis is summarized in Table 4. HLA-matched related donor PB transplantation for secondary myelofibrosis showed a lower NRM and higher OS than that for primary myelofibrosis; however, this was not replicated in unrelated donor BM and UCB transplantation. Some studies have reported no significant differences in the NRM or OS between primary and secondary myelofibrosis (28)(29)(30)(31). However, a recent study reported a significantly higher OS in patients with secondary myelofibrosis than with primary myelofibro-sis (26). A more recent study reported the opposite results, finding that the OS was significantly lower in patients with secondary myelofibrosis than in those with primary myelofibrosis (27). Taken together, these findings underscore the importance of analyzing the transplant outcome of secondary myelofibrosis in distinction from primary myelofibrosis.
In conclusion, it was confirmed that allogeneic HSCT provides a long-term survival for at least some patients with post-ET and post-PV myelofibrosis. Future studies with a large number of patients are needed to determine the best alternative donor, including UCB and HLA-haplo donor, the best preconditioning regimen for successful engraftment, and the best timing for allogeneic HSCT.