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Survival following allogeneic transplantation in patients with myelofibrosis

Jul 29, 2020

Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by clonal myeloid proliferation, peripheral cytopenias, bone marrow fibrosis, extramedullary hematopoiesis, and heterogeneous symptom burden. The only curative therapy for MF is allogeneic hematopoietic cell transplantation (HCT). While clinical guidelines and emerging prognostic tools are useful to allow appropriate patient selection for HCT, there is no prospective and randomized data comparing HCT with non-HCT therapies to guide clinical decision-making. 1

Krisstina Gowin and colleagues assessed survival outcomes of HCT vsnon-HCT therapies, stratified by the Dynamic International Prognostic Scoring System (DIPSS) risk score, over a median follow-up of 6 years in the largest and most inclusive retrospective analysis performed to date, which was recently published in Blood Advances. 1

Study design 1

For the HCT cohort, data were retrospectively obtained from the Center for International Blood and Marrow Transplant Research (CIBMTR) from 2000 to 2014. For the non-HCT cohort, the Myeloproliferative Neoplasm Research Consortium and its affiliates provided retrospective data from 2000 to 2014.

In the HCT cohort, patients with MF (either primary, post-polycythemia, or post-essential thrombocythemia) who received an HCT were included. Eligible patients, aged ≥ 20 years and < 70 years, had received HCT from an HLA-identical sibling or well-matched/partially matched unrelated donor after an ablative, nonmyeloablative, or reduced intensity conditioning. Patients who received umbilical cord blood HCT, syngeneic HCT, or haploidentical HCT, or patients who had transformed to secondary acute myeloid leukemia prior to HCT were excluded.

In the non-HCT cohort, patients with MF (either primary, post-polycythemia vera, or post-essential thrombocythemia) who were ≥ 20 years and < 70 years were included. The study excluded patients who were never on medical treatment in the non-HCT cohort. The reason for this was that they were not the perfect comparator for the HCT cohort.

A descriptive analysis aimed to compare the HCT and non-HCT cohorts was performed. Ranges, medians, and percentages of overall numbers were assessed for categorical variables. Using the Cox proportional hazards model, the hazard ratio (HR) for overall survival (OS) between the HCT and the non-HCT cohorts was measured. For the non-HCT cohort study, the DIPSS assessment at the time of medical treatment initiation, or time of referral to academic medical center (in case the time of medical treatment initiation was not known), was considered to be the reference time point.

Patient descriptive analysis

A total of 551 transplanted patients with MF and 1,377 non-transplanted patients with MF met the eligibility criteria. Patient characteristics are summarized in Table 1.

Table 1. Characteristic features of patients with MF 1

DIPSS, Dynamic International Prognostic Scoring System; HCT, hematopoietic cell transplantation; HLA, human leukocyte antigen; MF, myelofibrosis

Unless otherwise indicated, the data are shown as percentage of patients.

Variable

HCT (n ⹀ 551)

Non-HCT (n ⹀ 1,377)

Primary MF, %

84

65

Secondary MF, %

16

35

Age at diagnosis, median (range), years

51 (20–69)

59 (20–75)

Median age at HCT/referral, years

55

61

DIPSS at HCT/referral, %

  • Low
  • Int-1
  • Int-2/high
  • Missing

 

15

45

34

6

 

12

39

28

21

Cytogenetics, %

  • Normal/favorable
  • Unfavorable
  • Missing

 

52

14

34

 

73

16

11

Prior therapy, %

  • Ruxolitinib
  • Hydroxyurea
  • Immunomodulatory
  • Splenic irradiation

 

10

26

14

2

 

30

42

26

3

Number of prior therapies, %

  • 0
  • 1
  • 2
  • ≥ 3

 

28

36

17

17

 

16

25

24

34

Donor type

  • HLA identical
  • Well-matched unrelated
  • Partially matched unrelated

 

38

47

15

 

  • Median follow-up time of survivors, months
  • Time of diagnosis to treatment, months
  • Number of centers

72

  19

138

63

  2

14

Results 1

  • OS was higher in the non-transplanted group compared with transplanted patients in the first year; however, this relationship was reversed after 1 year
  • All DIPSS groups benefited from transplantation long-term, except for patients with low DIPSS
  • Prior ruxolitinib improved outcomes in patients with MF, irrespective of whether they received a transplant or not

OS with multivariable regression analysis is summarized in Table 2.

Table 2. OS with multivariable regression analysis 1

DIPSS, Dynamic International Prognostic Scoring System; HCT, hematopoietic cell transplantation; OS, overall survival

OS

HR

95% CI

Overall p value

OS (≤ 12 months)

  • HCT
  • Non-HCT

 

1

0.325

 

 

0.260, 0.406

< .0001

OS (> 12 months)

  • HCT
  • Non-HCT

 

1

2.109

 

 

1.656, 2.685

< .0001

 

DIPSS at HCT/referral

  • Low
  • Int-1
  • Int-2 
  • High 

 

1

2.237

3.327

5.672

 

 

1.683, 2.973

2.496, 4.435

3.810, 8.443

< .0001

 

 

Ruxolitinib

  • No
  • Yes

 

1

0.530

 

 

0.444, 0.633

< .0001

 

Conclusion

This multicenter study evaluating survival of MF patients with HCT vsnon-HCT over a median follow-up of 6 years is one of the largest and most inclusive survival analyses performed in MF. This study highlights the importance of HCT in the setting of DIPSS Int-1–risk MF, supporting the widely held guidance of HCT in DIPSS Int-2/high-risk MF, and underscores the requirement for enhanced supportive care approaches in MF in the early post-HCT period. In addition, this study also suggests a long-term survival advantage with HCT for patients with Int-1 MF, although the increased risk of early mortality during the first year needs to be carefully considered when selecting patients and when choosing therapies aimed at reducing post-HCT complications.

Lack of molecular analysis and the absence of comparative quality of life data (a pivotal factor in transplant consideration) are limitations of this study. Moreover, this study did not assess the impact of splenectomy, splenic radiation, and splenomegaly. Additionally, the DIPSS prognostic score, which was firstly developed in cohorts of patients with primary MF, is not generally accepted in the assessment of patients with secondary MF and requires further elucidation. The retrospective nature of this study is a limitation, however, a randomized study aimed to compare HCT with non-HCT therapies is not likely to be conducted in the US. Therefore, this retrospective survival study is pivotal for practicing clinicians and may be helpful in guiding clinical practice.

  1. Gowin K, Ballen K, Ahn KW, et al. Survival following allogeneic transplant in patients with myelofibrosis. Blood Adv. 2020;4(9):1965-1973. DOI: 10.1182/bloodadvances.2019001084