Genetic factors are more important than disease activity for transplantation outcomes in patients with MPN-BP

Myeloproliferative neoplasms (MPN) in the blast phase (BP) are defined as ≥ 20% myeloblasts in the peripheral blood (PB) or bone marrow (BM)—this is seen in around 5–20% of patients with Philadelphia chromosome-negative MPN. The outcomes after allogeneic hematopoietic cell transplantation (HCT) in these patients are still not fully understood.

In this retrospective study, Vikas Gupta and colleagues investigated molecular, cytogenetic, and clinical factors in patients with MPN-BP and their association with outcome post allogeneic HCT.¹ Their results have been recently published in Blood Advances and are summarized here.

Study design

177 patients with MPN-BP were identified from the Center for International Blood and Marrow Transplant Research database. Next-generation sequencing was possible in only 95 patients (54%), using a panel of 49 genes clinically relevant in hematologic malignancies.

The patients were also analyzed for the following endpoints:

• Overall survival (OS): time from HCT to death from any cause
• Relapse
• Non-relapse mortality (NRM)
• Progression-free survival (PFS)

Patient characteristics

DNA, deoxyribonucleic acid; ET, essential thrombocythemia; HCT, hematopoietic cell transplantation; MPN, myeloproliferative neoplasms; PMF, primary myelofibrosis; PV, primary myelofibrosis.
	Sample DNA obtained (n = 95)	No sample DNA obtained (n = 82)	Total   (n = 177)
Median age at HCT, years (range)	59.9 (41.05–81.55)	58.48 (40.29–74.04)	58.75 (40.29–81.55)
Female sex, %	32.6	36.6	34.5
Karnofsky index < 90%, %	49.5	45.1	47.5
Type of MPN at diagnosis, %      ET      PV      PMF      MPN, unclassifiable	26.3 27.4 33.7 12.6	31.7 24.4 34.1 9.8	28.8 26 33.9 11.3
Cytogenetics, %      Favorable      Intermediate      Poor risk      Not tested      Missing	1.1 52.6 41.1 2.1 3.2	0 56.1 34.1 3.7 6.1	0.6 54.2 37.9 2.8 4.5
Graft source, %      Bone marrow      Peripheral blood	14.7 85.3	9.8 90.2	12.4 87.6
Donor type, %      Matched sibling donor      Other related donor      Matched unrelated donor      Mismatched unrelated donor	7.4 3.2 69.5 20	57.3 12.2 20.7 9.8	30.5 7.3 46.9 15.3

Results

• 43% of patients in both cohorts had active leukemia at the time of HCT.
• The median follow-up of survivors was 71 months (range, 14-169).

Poor-risk cytogenetics and stem cell source impact on transplant outcome

• In the entire cohort, the 5-year OS rate was 18%, with a cumulative incidence of relapse of 61% and NRM of 25%.
• Across the study, 38% of patients had poor-risk cytogenetics, compared with 41% in the cohort of patients with molecular samples.
• Multivariate analysis confirmed that poor-risk cytogenetics was correlated with inferior OS (HR, 1.71; 95% CI, 1.21–2.41), inferior PFS (HR, 1.78; 95% CI, 1.27–2.50), and a higher relapse rate (HR, 1.93; 95% CI, 1.32–2.82).
• When patients underwent HCT using PB progenitor cells, they had improved OS due to lower NRM (HR, 0.28; 95% CI, 012–0.62).
• No difference in OS or relapse was noted between MPN-BP patients with PB/BM blasts < 5% at the time of HCT and those with active leukemia.

Analyzing molecular data in patients with MPN-BP

• In total, 91 patients (96%) had mutations in one or more genes (one mutation in 21%, 2–3 mutations in 43%, and ≥ 4 mutations in 32%).
• The most frequently mutated genes in the study cohort were: JAK2 (55%), TP53 (23%), ASXL1 (22%), TET2 (19%), SRSF2 (16%), DNMT3A (14%), RUNX1 (14%), CALR (13%), and SF3B1 (11%).
• In these patients, the OS after 5 years was 16% while PFS 11%, with an incidence of relapse of 66% and NRM of 23%.

TP53 mutations impact strongly on outcome

• Mutations in the TP53 gene were the most frequent after JAK2 mutation and the only mutation that independently impacted on transplant outcomes.
• There were 27 different TP53 mutations identified in the 22 affected patients; most of them (89%) were missense alterations in the TP53 DNA-binding domain. TP53 variant allele frequency was 18.6 (range, 2.1–91.7) and 67% of these patients had poor risk cytogenetics.
• The 3-year OS and cumulative incidence of relapse of patients with mutated vs unmutated TP53 were 4% vs 33% (p < 0.001) and 91% vs 58% (p < 0.001), respectively.

Key findings

• Genetic factors, namely poor risk cytogenetics and TP53 mutation status, predict inferior outcomes of HCT in patients with MPN-BP. The authors conclude that no meaningful benefit of HCT was observed in patients with MPN-BP when mutated TP53 was detected.
• There was no difference in transplant outcomes for patients undergoing transplantation with PB/BM blasts < 5% compared those with active leukemia.
• Relapse after HCT is frequent in patients with MPN-BP. Half of the patients in this study relapsed within 1 year of HCT, and this proportion was even higher in individuals with poor-risk cytogenetics or mutated TP53.