Page 17 - Haematologica March 2020

Editorials
Table 1. Predictive factors for overall survival after allogeneic hematopoietic cell transplantation in relevant series of patients with chronic myelomonocytic leukemia.
Study period
N. of patients
Median age, years (range)
EBMT {Symeonidis:201513}
1988-2009
513
53 (18-75)
MDACC {Kongtim:201614}
1991-2013
83
57 (18-78)
CIBMTR {Liu:201715}
2001-2012
209
57 (23-74)
FHCRC {Woo:201917}
1986-2017
129 55 (7-74)
DiseaseatHCT(CMML/AML,%) 56/44 57/43 100/0 71/29
Factors predicting OS
Complete remission at HCT
Higher-risk categories by CPSS/MDAPS Performance Status (KPS≥90)
HCT-CI ≥4
High-risk CMML-specific cytogenetics Graft source (peripheral blood) Transplant from matched related donors Prior HMA treatment
Molecular profile
Conditioning intensity Development of chronic GvHD Age
Year of transplant
Favorable NA NA NA No effect No effect No effect No effect NA
No effect No effect No effect No effect
Favorable NA No effect NA No effect NA Favorable Favorable NA
No effect Favorable No effect No effect
NA Unfavorable/NA Favorable NA
NA Favorable NA
No effect NA
NA NA NA NA
No effect Unfavorable/Unfavorable NA Unfavorable Unfavorable
No effect
No effect
No effect
Increased relapse: -Mutations in NRAS, ATRX, WT1
- ≥10 gene mutations
- ≥4 mutations in epigenetic regulators
No
NA No effect No effect
EBMT: European Society for Blood and Marrow Transplantation; MDACC: MD Anderson Cancer Center; CIBMTR: Center for International Blood and Marrow Transplantation Research; FHCRC: Fred Hutchinson Cancer Research Center; HCT:: hematopoietic cell transplant; CMML; chronic myelomonocytic leukemia; AML: acute myeloid leukemia; OS: overall survival; CPSS: CMML-specific prognostic scoring system; MDAPS: MD Anderson prognostic scores; KPS: Karnofsky Performance Score; HCT-CI: Hematopoietic Cell Transplant-Comorbidity Index; PB: peripheral blood; HMA: hypomethylating agents, GvHD: graft-versus-host disease; NA: information not available.;
CMML. The most commonly mutated genes were ASXL1 (52%), TET2 (42%), and SRSF2 (25%). Other frequently encountered mutations were evident for WT1 (27%), RUNX1 (17%), DNMT3A (17%), SMC1A (17%), EZH2 (12%), and ATRX (12%), highly likely because most patients had intermediate-2 or high-risk disease according to the CPSS.17
In the study by Woo et al., mutations in NRAS were associated with an increased relapse risk whereas muta- tions in ATRX and WT1, conferred both a higher relapse risk and inferior OS. Moreover, this study showed that a high overall mutation burden (≥10 mutations) as well as the presence of four or more mutated epigenetic regulato- ry genes were linked to a higher risk of relapse. Unsupervised clustering revealed two higher-risk groups with specific associations between mutations and clinical features. The presence of a higher mutation burden was closely related to a longer period between diagnosis and transplantation but not with complex chromosomal abnormalities or an excess of blasts. The currently pub- lished recommendation of an international expert panel is to use the CPSS for considering a patient as a candidate for allogeneic HCT and to transplant those CMML patients belonging to the intermediate-2/high CPSS risk groups.18 Whether the better outcomes observed with lower CPSS scores and the lower mutational burden observed in less advanced disease could argue in favor of
transplanting patients with CMML earlier in the course of their disease (e.g., extending transplantation to patients with intermediate-1 CPSS risk score) is debatable and can only be properly answered by a carefully designed study.
As previously reported in other HCT series on CMML, in the study by Woo et al., relapse risk was also signifi- cantly associated with adverse cytogenetics, higher-risk CPSS and MDAPS scores, and measurable residual dis- ease by cytogenetics at transplantation. A higher mortali- ty was seen in patients with high-risk cytogenetics and a high HCT Comorbidity Index. Of interest, neither dis- ease status at transplantation (complete remission vs. non-complete remission) nor pre-transplant therapy (intensive chemotherapy or hypomethylating agents) nor conditioning intensity had a clear and independent impact on transplant outcomes. Additionally, the year of transplant did not affect the risk of relapse or OS, clearly indicating that newer transplant strategies are needed to improve those outcomes.17
In summary, this study has identified both clinical and novel molecular risk factors for outcomes after allogeneic HCT that add relevant information which could be taken into account when planning transplantation for CMML patients. Table 2 illustrates the clinical and molecular risk factors for allogeneic HCT outcome in CMML patients, among whom different groups of higher-risk patients amenable to transplantation can be detected at different
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