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Allogeneic Hematopoietic Stem Cell Transplantation for Chronic Myelomonocytic Leukemia: Clinical and Molecular Genetic Prognostic Factors in a Nordic Population

E. Wedge, JW. Hansen, I. Dybedal, M. Creignou, E. Ejerblad, F. Lorenz, O. Werlenius, J. Ungerstedt, MS. Holm, L. Nilsson, AO. Kittang, P. Antunovic, P. Rohon, MK. Andersen, E. Papaemmanuil, E. Bernard, M. Jädersten, E. Hellström-Lindberg, K....

. 2021 ; 27 (12) : 991.e1-991.e9. [pub] 20210906

Jazyk angličtina Země Spojené státy americké

Typ dokumentu časopisecké články, práce podpořená grantem

Perzistentní odkaz   https://www.medvik.cz/link/bmc22011870

Chronic myelomonocytic leukemia (CMML) is an aggressive disease in which survival after allogeneic hematopoietic stem cell transplantation (HCT) remains relatively poor. An assessment of prognostic factors is an important part of treatment decision making and has the potential to be greatly improved by the inclusion of molecular genetics. However, there is a significant knowledge gap in the interpretation of mutational patterns. This study aimed to describe outcomes of allogeneic HCT in patients with CMML in relation to clinical and molecular genetic risk factors. This retrospective study included 64 patients with CMML who underwent allogeneic HCT between 2008 and 2018, with a median follow-up of 5.4 years. Next-generation sequencing using targeted myeloid panels was carried out on saved material from 51 patients from the time of transplantation. Kaplan-Meier and Cox regression were used for analysis of overall survival (OS), and cumulative incidence with competing risks and Fine and Gray models were used for analysis of relapse and nonrelapse mortality (NRM). Mutations were detected in 48 patients (94%), indicating high levels of minimal residual disease (MRD) positivity at transplantation, even among those in complete remission (CR) (n = 14), 86% of whom had detectable mutations. The most frequently mutated genes were ASXL1 (37%), TET2 (37%), RUNX1 (33%), SRSF2 (26%), and NRAS (20%). Risk stratification using the CMML-specific Prognostic Scoring System molecular score (CPSS-Mol) resulted in 45% of patients moving to a higher risk-group compared with risk stratification using the CPSS. High leucocyte count (≥13 × 109/L), transfusion requirement, and previous intensive chemotherapy were associated with higher incidence of relapse. Being in CR was not linked to better outcomes. Neither ASXL1 nor RUNX1 mutation was associated with a difference in OS, relapse, or NRM, despite being high risk in the nontransplantation setting. TET2 mutations were associated with a significantly higher 3-year OS (73% versus 40%; P = .039). Achieving MRD-negative CR was rare in this CMML cohort, which may explain why we did not observe better outcomes for those in CR. This merits further investigation. Our analyses suggest that the negative impact of ASXL1 and RUNX1 mutations can be overcome by allogeneic HCT; however, risk stratification is complex in CMML and requires larger cohorts and multivariate models, presenting an ongoing challenge in this rare disease.

Citace poskytuje Crossref.org

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$a Chronic myelomonocytic leukemia (CMML) is an aggressive disease in which survival after allogeneic hematopoietic stem cell transplantation (HCT) remains relatively poor. An assessment of prognostic factors is an important part of treatment decision making and has the potential to be greatly improved by the inclusion of molecular genetics. However, there is a significant knowledge gap in the interpretation of mutational patterns. This study aimed to describe outcomes of allogeneic HCT in patients with CMML in relation to clinical and molecular genetic risk factors. This retrospective study included 64 patients with CMML who underwent allogeneic HCT between 2008 and 2018, with a median follow-up of 5.4 years. Next-generation sequencing using targeted myeloid panels was carried out on saved material from 51 patients from the time of transplantation. Kaplan-Meier and Cox regression were used for analysis of overall survival (OS), and cumulative incidence with competing risks and Fine and Gray models were used for analysis of relapse and nonrelapse mortality (NRM). Mutations were detected in 48 patients (94%), indicating high levels of minimal residual disease (MRD) positivity at transplantation, even among those in complete remission (CR) (n = 14), 86% of whom had detectable mutations. The most frequently mutated genes were ASXL1 (37%), TET2 (37%), RUNX1 (33%), SRSF2 (26%), and NRAS (20%). Risk stratification using the CMML-specific Prognostic Scoring System molecular score (CPSS-Mol) resulted in 45% of patients moving to a higher risk-group compared with risk stratification using the CPSS. High leucocyte count (≥13 × 109/L), transfusion requirement, and previous intensive chemotherapy were associated with higher incidence of relapse. Being in CR was not linked to better outcomes. Neither ASXL1 nor RUNX1 mutation was associated with a difference in OS, relapse, or NRM, despite being high risk in the nontransplantation setting. TET2 mutations were associated with a significantly higher 3-year OS (73% versus 40%; P = .039). Achieving MRD-negative CR was rare in this CMML cohort, which may explain why we did not observe better outcomes for those in CR. This merits further investigation. Our analyses suggest that the negative impact of ASXL1 and RUNX1 mutations can be overcome by allogeneic HCT; however, risk stratification is complex in CMML and requires larger cohorts and multivariate models, presenting an ongoing challenge in this rare disease.
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$a Hansen, Jakob Werner $u Department of Hematology, Copenhagen University Hospital, Copenhagen, Denmark; Biotech Research and Innovation Center, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; The Danish Stem Cell Center (Danstem), University of Copenhagen, Copenhagen, Denmark
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$a Dybedal, Ingunn $u Department of Hematology, Oslo University Hospital, Oslo, Norway
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$a Lorenz, Fryderyk $u Department of Medicine, University Hospital of Umeå, Umeå, Sweden
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$a Werlenius, Olle $u Section of Hematology and Coagulation, Sahlgrenska University Hospital, Gothenburg, Sweden
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$a Ungerstedt, Johanna $u Center for Hematology and Regenerative Medicine, Karolinska Institute, Stockholm, Sweden; Department of Hematology, Karolinska University Hospital, Stockholm, Sweden
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$a Holm, Mette Skov $u Department of Hematology, Aarhus University Hospital, Aarhus, Denmark
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$a Nilsson, Lars $u Department of Medicine, Skåne University Hospital, Lund, Sweden
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$a Kittang, Astrid Olsnes $u Section for Hematology, Department of Medicine, Haukeland University Hospital, Bergen, Norway
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$a Antunovic, Peter $u Department of Hematology, Linköping University Hospital, Linköping, Sweden
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$a Rohon, Peter $u Department of Hemato-Oncology, University Hospital Olomouc, Olomouc, Czech Republic
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$a Andersen, Mette Klarskov $u Department of Clinical Genetics, Copenhagen University Hospital, Copenhagen, Denmark
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$a Papaemmanuil, Elli $u Computational Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York; Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, New York
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$a Bernard, Elsa $u Computational Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York; Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, New York
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