A study of patients with primary or post-essential thrombocythemia (PET) and post-polycythemia vera (PPV) myelofibrosis found that those treated with reduced intensity transplantation had improved survival overall, but patients with accelerated-phase (AP) myelofibrosis had an increased rate of relapse. The retrospective study, published in Blood Advances, specifically evaluated survival and relapse outcomes for patients with AP myelofibrosis (i.e., defined as those with circulating or bone marrow blasts 10-19%) who received hematopoietic cell transplantation (HCT).
Patients with AP myelofibrosis historically have a high risk of progression and poor outcomes, but data on the outcome after undergoing HCT as a treatment option is limited. In this study, researchers led by Nico Gagelmann, MD, of the University Medical Center Hamburg-Eppendorf in Germany, examined transplantation as a curative option while also comparing outcomes for patients with AP myelofibrosis to those with chronic-phase (CP) myelofibrosis (defined as <10% blasts).
Patients with a diagnosis of primary, PET, or PPV myelofibrosis who underwent reduced intensity allogeneic hematopoietic cell transplantation (alloHCT) between 2004 and 2018 at one of four centers were included. Patients were considered to have received reduced intensity conditioning (RIC) if they underwent one of three regimens before transplantation:
- 2-Gray total-body irradiation-fludarabine at 150 mg/m2
- fludarabine-melphalan at 150 mg/m2 and 140 mg/m2
- busulfan-fludarabine at 10 mg/kg bodyweight and 150 or 180 mg/m2
Since patients with chronic-phase disease typically do not receive cytoreductive chemotherapy prior to alloHCT, patients were excluded if they had received cytoreductive chemotherapy before alloHCT, to eliminate it as a confounder in the analysis. Lastly, patients whose disease had advanced to blast-phase (blasts ≥20%) were also excluded.
Data from 349 patients were evaluated, including 35 patients with AP myelofibrosis, and the primary endpoint was overall survival (OS).
Researchers found that after a median follow-up of 5.9 years, patients in both the AP and CP groups had similar survival rates, with an estimated OS for the AP group of 65% (95% CI 49-81%) compared to 64% (95% CI 59-69%) for patients in the CP group. During the study period, researchers reported that the median OS was never achieved.
Patients in the CP group had better rates of relapse-free survival of 55% (95% CI 50-61%) at the estimated five-year outcome compared to 49% (95% CI 32-67%) for patients in the AP group (p=0.65). The estimated non-relapse mortality rate was higher at 30% (95% CI 24-35%; p=0.25) in the CP group compared to 20% (95% CI 8-32%) for the AP group.
Researchers also assessed the five-year cumulative incidence of relapse and found that 31% (95% CI 15-47%) of those in the AP group relapsed compared with 15% of those in the CP group (95% CI 11-19%; p=0.02). The median time to relapse was 1.4 years in the AP group compared with 2.4 years in the CP group (p=0.46).
While evaluating the relapse incidence and the role of circulating blasts, investigators discovered an independent association between an increased risk of relapse and increasing blast count and reported a hazard ratio of 1.05 (95% CI 0.99-1.11; p=0.08). This association was strongest when the blast count was ≥10%. Circulating blast counts were not associated with OS.
The study was limited by its retrospective design, which introduced a possible selection bias. Other limitations included the small sample size of patients with AP myelofibrosis, lack of data on patient spleen size, and potential differences in treatment among the treatment centers.
“The presented results may facilitate offering these patients evaluation for curative treatment together with current risk stratification tools, while close screening for relapse will be needed,” the researchers wrote.
Any conflicts of interest declared by the authors can be found in the original article.
Gagelmann N, Wolschke C, Salit RB, et al. Reduced intensity hematopoietic stem cell transplantation for accelerated-phase myelofibrosis. Blood Adv. 2022;6(4):1222-1231.
In this retrospective analysis, Gagelmann et al. report on a cohort of 349 patients from four centers in Europe with primary or secondary myelofibrosis who underwent alloHCT with a reduced intensity conditioning (RIC) regimen. The study aimed to compare outcomes of patients transplanted in CP (n=314) versus AP (n=35).
The patients with AP disease had lower levels of hemoglobin and higher white blood cell counts, and constitutional symptoms were more commonly reported compared to patients with CP disease. Additionally, RAS mutation was detected more frequently in the AP group (though numbers were small).
Survival outcomes were very similar in the two groups. The five-year survival was 65% in the AP group and 64% in the CP group, and the five-year relapse-free survival (RFS) was 49% in the AP group and 55% in the CP group. There was a higher non-relapse mortality (NRM) rate of 30% in the CP group versus 20% in the AP group, and the relapse rate was higher in the AP group at 30% compared to 15% in the CP group.
In a multivariate analysis, researchers found that older age, higher leukocyte count (>25×109/L), low platelet count (<150×109/L), lack of CALR/MPL mutation, presence of ASXL1 mutation, having a mismatched unrelated donor, and a Karnofsky performance status below 90% were associated with worse OS. AP disease was associated with higher risk of relapse in a multivariate analysis but not associated with any other outcome.
The authors also aimed to study the relation between circulating and bone marrow blasts and transplant outcome. Among patients with CP disease, circulating blasts were not associated with differences in OS, RFS, and NRM. Yet, increased risk of relapse was seen with circulating blasts of >7%.
In summary, this study, which is the first to describe transplant outcomes for patients with AP myelofibrosis, the researchers present excellent outcomes for a disease that, without transplant, has a five-year OS of less than 30%. The results of this study should be validated in a larger cohort of patients, and the role of higher intensity conditioning should be explored in patients with high circulating blasts burden with the aim to reduce the risk of relapse.
Roni Tamari, MD
Memorial Sloan Kettering Cancer Center