Impact of Molecular Genetics on Outcome in Myelofibrosis Patients after Allogeneic Stem Cell Transplantation

Kröger, Nicolaus; Panagiota, Victoria; Badbaran, Anita; Zabelina, Tatjana; Triviai, Ioanna; Cruz, Michelle; Shahswar, Rabia; Ayuk, Francis; Gehlhaar, Marten; Wolschke, Christine; Bollin, Robin; Walter, Carolin; Dugas, Martin; Wiehlmann, Lutz; Lehmann, Ulrich; Koenecke, Christian; Chaturvedi, Anuhar; Alchalby, Haefaa; Stadler, Michael; Eder, Matthias; Christopeit, Maximilian; Göhring, Gudrun; Koenigsmann, Michael; Schlegelberger, Brigitte; Kreipe, Hans-Heinrich; Ganser, Arnold; Stocking, Carol; Fehse, Boris; Thol, Felicitas; Heuser, Michael

doi:10.1016/j.bbmt.2017.03.034

Cited by 94 publications

(95 citation statements)

References 25 publications

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“…CALR mutations in PMF have also been shown to favorably affect spleen response and survival outcome in the setting of JAK2 inhibitor therapy . Consistent with the observations from the current study, triple‐negative mutational status did not affect post‐alloSCT outcome in a recent study of patients with primary or secondary myelofibrosis, where CALR mutations were associated with decreased non‐relapse mortality and increased overall and progression‐free survival; in the particular study, differences in outcome between type 1 and type 2 CALR mutations were not evident. Additional studies in both the transplant and nontransplant settings are needed to confirm the prognostically favorable impact of type 1/like CALR mutations in PMF, in the presence and absence of HMR mutations, and also in post‐ET MF, where recent studies have suggested a salutary effect for CALR mutations and a detrimental effect for triple‐negative mutational status …”

Section: Discussionsupporting

confidence: 88%

Driver mutations and prognosis in primary myelofibrosis: Mayo‐Careggi MPN alliance study of 1,095 patients

et al. 2017

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The 2013 discovery of calreticulin (CALR) mutations in myeloproliferative neoplasms was attended by their association with longer survival in primary myelofibrosis (PMF). Subsequent studies have suggested prognostic distinction between type 1/like and type 2/like CALR mutations and detrimental effect from triple-negative mutational status. Among 709 Mayo Clinic patients with PMF, 467 (66%) harbored JAK2, 112 (16%) CALR type 1/like, 24 (3.4%) CALR type 2/like, 38 (5.4%) MPL mutations and 68 (10%) were triple-negative. Survival was longer with type 1/like CALR, compared to JAK2 (HR 2.6, 95% CI 1.9-3.5), type 2/like CALR (HR 2.5, 95% CI 1.4-4.5), MPL (HR 1.8, 95% CI 1.1-2.9) and triple-negative mutational status (HR 2.4, 95% CI 1.6-3.6), but otherwise similar between the non-type 1/like CALR mutational states (P = .41). In multivariable analysis, the absence of type 1/like CALR (P < .001; HR 2, 95% CI 1.4-2.7), presence of ASXL1/SRSF2 mutations (P < .001; HR 1.9, 95% CI 1.5-2.4) and DIPSS-plus (P < .001) were each predictive of inferior survival. Furthermore, among 210 patients with ASXL1/SRSF2 mutations, survival was significantly longer in the presence vs. absence of type 1/like CALR mutations (median 5.8 vs. 2.9 years; P < .001). Triple-negative status did not disclose additional prognostic information for overall or leukemia-free survival. The observations regarding the prognostic distinction between CALR mutation variants were validated in an external cohort of 386 patients from the University of Florence Careggi hospital. We conclude that type 1/like CALR mutations in PMF not only predict superior survival, but also partially amend the detrimental effect of high molecular risk mutations.

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Section: Discussionsupporting

confidence: 88%

Driver mutations and prognosis in primary myelofibrosis: Mayo‐Careggi MPN alliance study of 1,095 patients

et al. 2017

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“…The observed mitigating effect of HCT on high risk and unfavorable karyotype was encouraging and underline the power of immunotherapy, as opposed to drug therapy alone, in eradicating cytogenetically aggressive clones in MF. Whether or not the same holds true for adverse mutations, as has been previously suggested for other chronic myeloid neoplasms, is currently under investigation and such information might also further clarify the interaction between DIPSS and transplant outcome. Finally, we recognize several limitations of the current study, including its retrospective design, relatively small sample size and the inclusion of post‐ET and post‐PV cases; the latter point was especially noteworthy considering the fact that our control group consisted entirely of patients with PMF and that both the revised cytogenetic risk stratification and DIPSS are based on PMF patients, although potentially applicable to secondary MF .…”

Section: Discussionmentioning

confidence: 63%

Allogeneic hematopoietic stem cell transplant overcomes the adverse survival effect of very high risk and unfavorable karyotype in myelofibrosis

et al. 2018

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The prognostic importance of genetic information in primary myelofibrosis (PMF) was recently highlighted in a study of over 1000 cytogenetically-annotated patients; 5-year survival rates were 8% for very high risk (VHR), 27% "unfavorable" and 45% "favorable" karyotype. The current study addresses the practice-relevant question of whether or not allogeneic hematopoietic stem cell transplant (HCT) can overcome the detrimental survival effect of VHR or unfavorable karyotype. The study included 67 patients with PMF or secondary MF who received HCT at the Mayo Clinic and in whom pretransplant cytogenetic information was available. Dynamic international prognostic scoring system (DIPSS) risk distribution was 13% high, 66% intermediate-2 and 21% intermediate-1. Cytogenetic risk distribution was 11% VHR, 34% unfavorable and 55% favorable. At median post-HCT follow-up of 60 months for living patients (range 34-170), 28 (42%) deaths were recorded. Five-year survival was 62% and was not affected by VHR or unfavorable karyotype (P = .68). The salutary effect of HCT in patients with VHR or unfavorable karyotype was also apparent during analysis of a combined dataset that included a nontransplant cohort of 383 patients with PMF; multivariable analysis of the combined dataset (n = 450) resulted in HRs (95% CI) of 2.4 (1.6-3.6) for absence of transplant, 3.3 (2.2-4.8) for VHR karyotype, 1.6 (1.2-2.1) for unfavorable karyotype, 2.9 (2.0-4.2) for DIPSS high and 1.7 (1.4-2.2) for DIPSS intermediate-2. These observations were further confirmed by analysis of more stringently matched case-control subset cohorts and provide the evidence for the therapeutic preference of HCT in cytogenetically high risk patients with MF.

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“…[14][15][16][17] A recent study about the outcome of 169 MF patients with different driver mutations reported 5y-OS and 5y-PFS of 56% and 48%, respectively. 18 In the cited study, only 4% of patients were MPL mut , 60% of them were Jak2 mut , 20%…”

Section: Discussionmentioning

confidence: 94%

Allogeneic stem cell transplantation in patients with myelofibrosis harboring the MPL mutation

Mannina

Gagelmann

Badbaran

et al. 2019

European J of Haematology

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Introduction Primary and post‐ET/PV myelofibrosis are myeloproliferative neoplasms harboring in most cases driving mutations in JAK2, CALR or MPL, and a variable number of additional mutations in other genes. Molecular analysis represents a powerful tool to guide prognosis and clinical management. Only about 10% of patients with myelofibrosis harbor alterations in MPL gene. No data are available about the transplantation outcome in the specific MPL‐mutated group. Patients We collected the data of 18 myelofibrosis patients(primary: 14; post‐ET: 4) transplanted in 4 EBMT centers (Hamburg, Paris, Essen, and Hannover) between 2005 and 2016. Results Before the transplant, we explored the molecular profile by NGS and reported the frequency of mutations occurring in a panel of genes including JAK2, MPL, CALR, U2AF1, SRSF2, SF3B1, ASXL1, IDH1, IDH2, CBL, DNMT3A, TET2, EZH2, TP53, IKZF1, NRAS, KRAS, FLT3, SH2B3, and RUNX1. The 1‐year transplant‐related mortality was 16.5%, 5‐years overall survival and 5‐y relapse‐free survival 83.5%. The only relapse occurred in a patient who harbored mutations in both ASXL1 and EZH2 genes. Conclusion These retrospective data suggest that MPL‐mutated myelofibrosis patients have a favorable outcome after allogeneic transplantation with very low rate of disease relapse (5.5%) in comparison with the available historical controls regarding myelofibrosis in all.

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Impact of Molecular Genetics on Outcome in Myelofibrosis Patients after Allogeneic Stem Cell Transplantation

Cited by 94 publications

References 25 publications

Driver mutations and prognosis in primary myelofibrosis: Mayo‐Careggi MPN alliance study of 1,095 patients

Driver mutations and prognosis in primary myelofibrosis: Mayo‐Careggi MPN alliance study of 1,095 patients

Allogeneic hematopoietic stem cell transplant overcomes the adverse survival effect of very high risk and unfavorable karyotype in myelofibrosis

Allogeneic stem cell transplantation in patients with myelofibrosis harboring the MPL mutation

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