Prognostic value of CPSS cytogenetic risk classification in patients with CMML after allogeneic hematopoietic cell transplantation: a retrospective multicenter study of the Chronic Malignancies Working Party of the EBMT


 Introduction: The only curative treatment approach for patients with Chronic Myelomonocytic Leukemia (CMML) is allogeneic hematopoietic stem cell transplantation (HSCT), but disease relapse after transplantation is a major concern. Predictors for disease outcome after HSCT are limited. However, unfavorable cytogenetic abnormalities have been shown to serve as predictors for relapse after transplantation. The aim of this large multicentric, international study was to retrospectively determine the impact of cytogenetic information according to the CMML-specific prognostic scoring system (CPSS) on outcome after allogeneic HSCT.
 Patients and Methods: Patients were selected from the EBMT database who had received a first allogeneic HSCT for the treatment of CMML between 2000 and 2015. 268 centers participated into this study. In total, 1503 patients were included. Impact of CPSS-cytogenetic classification was analyzed regarding overall survival (OS) and cumulative incidence of relapse and non-relapse mortality after HSCT (gray test).
 Results: 488 female (32.5%) and 1013 male (67.5%) patients were included to the study. Median age at HSCT was 57.6 years (range 0.3-75.4). At time of HSCT, only 422 (28.1%) patients were in complete remission, whereas 1004 (66.8%) had active disease (77 missing). Matched related donor HSCT was performed in 35.7% of the patients, matched unrelated donor HSCT in 57.6%, mismatched related in 3.3% and mismatched unrelated in 3.4%. Bone marrow (12.6%), peripheral blood (84.3%), or both (0.3%) served as the stem cell graft. Cord blood was used as a graft in 2.8%. Myeloablative preparative regimens wereused in 223 patients (15.0%), and less intensive regimens were given to 1268 patients (85.0%). Median survival of patients included into this study was 52.2 months. 637 patients had sufficient cytogenetic information according to CPSS (866 missing), complete relapse information was available in 1385 patients. 143 patients could be categorized into CPSS-high, 85 in intermediate and 375 in low risk cytogenetics, respectively. In univariate analysis high risk CPSS cytogenetic information was found to be strongly associated with OS (low 38% (32-44%), intermediate 41% (30-53%), high 26% (18-34%)), and higher cumulative incidence of relapse (low 40% (35-46%), intermediate 42% (30-54%), high 48% (39-56%)), but not with non relapse mortality (low 28% (23-33%), intermediate 25% (16-35%), high 30% (22-38%)) at 60 months (Figure 1).
 Conclusion: In this international, multicentric analysis we show that CMML patients with high-risk cytogenetics had significantly worse OS after HSCT than patients with intermediate or low risk cytogenetics according to CPSS. New therapeutic strategies to prevent relapse after HSCT in CMML patients with high-risk cytogenetics are needed.
 
 
 
 Koenecke: Amgen: Consultancy; abbvie: Consultancy; BMS: Consultancy; Roche: Consultancy. Beelen:Medac: Consultancy, Other: Travel Support. Finke:Novartis: Consultancy, Honoraria, Other: travel grants, Research Funding; Riemser: Consultancy, Honoraria, Research Funding; Medac: Consultancy, Honoraria, Other: travel grants, Research Funding; Neovii: Consultancy, Honoraria, Other: travel grants, Research Funding. Niederwieser:Novartis: Research Funding; Miltenyi: Speakers Bureau. Chalandon:Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel costs. Ganser:Novartis: Membership on an entity's Board of Directors or advisory committees. Kobbe:Amgen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Celgene: Honoraria, Other: Travel Support, Research Funding.



TO THE EDITOR:
The only curative treatment approach for patients with chronic myelomonocytic leukemia (CMML) is allogeneic hematopoietic cell transplantation (allo-HCT), but disease relapse after transplantation is a major concern [1]. Predictors for disease outcome after transplant are limited. However, beside other risk factors (ASXL1 mutations, monocytosis, cytopenias and circulating immature myeloid cells), cytogenetic abnormalities have been shown to serve as predictors for outcome in CMML patients [2][3][4][5]. Cytogenetic abnormalities are frequently seen in 20-30% of patients [6,7]. According to the CMML-specific prognostic scoring system (CPSS) patients can be categorized into three risk groups (high risk: trisomy 8, chromosome 7 abnormalities, or complex karyotype; low risk: normal karyotype and -Y; intermediate risk: all other chromosomal abnormalities) [8]. There is evidence, that adverse cytogenetics are also a risk factor for worse outcome after allo-HCT [9]. However, cytogenetic information according to CPSS was not evaluated in the setting of allo-HCT to date. Therefore, the aim of this large multicentric, international study was to retrospectively determine the impact of CPSS-cytogenetic on outcome after allo-HSCT.
Adult patients (age > = 18years) who had received a first allo-HCT for the treatment of CMML between 2000 and 2015 were selected from the European Society of Bone and Marrow Transplantation (EBMT) database. 233 centers participated into this study. In total, 1347 patients were included. Impact of CPSScytogenetic classification was analysed regarding overall survival (OS), progression free survival (PFS) and cumulative incidence of relapse and non-relapse mortality (NRM) after transplant. OS and PFS were estimated using the Kaplan-Meier product limit estimation method, and differences in subgroups were assessed by the Log-Rank test. Median follow-up was determined using the reverse Kaplan-Meier method. The cumulative incidence of relapse (RI) and NRM were analysed together in a competing risks framework. Subgroup differences in cumulative incidences were assessed using Gray's test. Multivariable Cox regression was applied to investigate the simultaneous impact of multiple covariates on OS and PFS. Included covariates were: CPSS (intermediate, high versus low), stage at transplant (no CR, untreated versus CR), disease (transformed to AML versus other), age at transplant (in decades) and year of allo-HCT. Continuous variables are presented in the text as median and interquartile range (IQR) or range and categorical variables as percentages. All survival estimates and hazard ratios are reported with corresponding 95% confidence intervals in parentheses. All p-values are two-sided and p < 0.05 is considered significant. Statistical analyses were performed in R version 3.6.0 (R Development Core Team, Vienna, Austria), using packages 'survival', 'prodlim' and 'cmprsk'.
In multivariable analysis (MVA), including only patients with available data on included covariates, CPSS-high risk cytogenetics was associated with shorter overall survival after allogeneic transplantation compared to intermediate and low risk cytogenetics (hazard ratio (HR), 1.57 (1.17-2.1)). This finding was also present in MVA for PFS (HR 1.44 (1.09-1.91)) and RI (HR 1.6 (1.12-2.27)). Patients' age, year of transplant, and status of the disease at transplant were not associated with a reduced OS, PFS and RI (Table 1). In another study by this working group, status of the disease before transplantation was associated with survival [10].
Our results show that CPSS cytogenetics is a strong predictor of relapse and overall survival after allo-HCT. Adverse cytogenetic alterations lead to a disease biology which is more likely to be resistant to an allograft. This observation has been made in a variety of myeloid malignant diseases, such as MDS and AML [11]. Currently, molecular diagnostics are becoming more and more standard in patients with CMML. We were not able to include such information into this retrospective study. It might be that even more distinct risk-groups can be identified using that diagnostic tool [5].
In this international, multicentric analysis we show that CMML patients with high-risk cytogenetics had significantly worse overall and progression-free survival after allo-HCT than patients with intermediate or low risk cytogenetics according to CPSS. New therapeutic strategies to prevent relapse after allo-HCT in CMML patients with high-risk cytogenetics are needed.