Allogeneic Transplantation for Chronic Myelomonocytic Leukemia (CMML) Is Associated with High Disease-Free Survival Even in the Setting of High-Risk Disease
Authors: Sanchez Matias Eugenio , Abbi Kamal Kant Singh , Tamari Roni , Jakubowsky Ann , Papadopoulos Esperanza B , Devlin Sean M. , Shi Weiji , Sauter Craig S. , Barker Juliet N. , Boulad Farid , Giralt Sergio , Meagher Richard , Castro-Malaspina Hugo 
Published: November 2019

Abstract
Background: CMML has a poor prognosis with a median overall survival of about 30 months and a 15-20% risk of transformation to acute myeloid leukemia. For high-risk patients the median survival is 9 months. The only curative therapy is allogeneic hematopoietic stem cell transplantation (allo-HSCT). While several prognostic models have been proposed in CMML, their predictive value in allograft recipients is not well established. We report the outcome of allo-HSCT in 28 patients (pts) with CMML, and the relationship between five CMML prognostic scoring systems and post-transplant disease-free survival (DFS).
Methods: 28 pts with CMML underwent allo-HSCT at MSKCC between 1/2002 and 2/2014. Pt and transplant characteristics are summarized in Table 1. Of the 28 pts, 6 had progressed to CMML-2 and 7 to AML pre-transplant. Except for 3 pts, all received chemotherapy before cytoreduction to decrease disease burden and all patients had <20% blasts prior to conditioning. Five prognostic scoring systems were used to classify the patients into low and high risk: 2 MDS and 3 CMML-specific models. T-cell depleted pts (n = 16, 60%) received myeloablative conditioning (12 busulphan/ melphalan/ fludarabine/ rabbit ATG and 4 TBI-based) whereas 12 pts (40%) received unmodified grafts with varying conditioning intensity. The source of HSC was 23 PB, 2 BM, and 3 cord blood.
Results All pts had sustained donor engraftment. The cumulative incidences of day 100 grade II-IV acute graft-versus-host disease (GVHD) and 1-year chronic GVHD were 18% (95%CI:3-32) and 17% (95%CI:1-33), respectively. The 1-year incidence of transplant-related mortality was 7% (95%CI:0-17) with the most common transplant-related cause of death being infection. Three pts relapsed for a 1-year incidence of 13% (95%CI:0-26). These patients died of their disease. With a median follow-up of survivors of 3.3 years (range 3 months-11.6 years), the 3-year Kaplan-Meier estimate of overall survival is 74% (95%CI: 51-88) and DFS is 71% (95%CI: 47-85). All pts classified as having high-risk disease had similar survival to low risk disease pts (Table 2).
Conclusion: This preliminary data suggests that allo-HSCT can achieve a high DFS in pts with CMML, even in the setting of high-risk disease. Thus, allo-HSCT should potentially be considered in all patients with CMML including pts who have a dismal prognosis based on current prognostic scoring systems.
Table 1. Patient and transplant characteristics Characteristics N=28 Age , years (range) 60 (12-69) Gender Male Female - 18 (64%) 10 (36%) BM Blasts at diagnosis (%) <5 5-9 10-19 - 13 (46%) 7 (25%) 8 (29%) Diagnosis karyotype risk group per Spanish Score Good Intermediate/Poor - 17 (60%) 11 (40%) WHO classification at diagnosis CMML-1 ( <10 % BM blasts) CMML-2 (10-20% BM blasts) - 20 (71%) 8 (29%) FAB classification at diagnosis Myelodysplastic subtype (< 13000 WBC) Myeloproliferative subtype (> 13000 WBC) - 14 (50%) 14 (50%) WHO status at progression (highest disease) CMML -1 CMML -2 AML - 12 (43%) 9 (32%) 7 (25%) Pre-transplant therapy No chemotherapy Hypomethylating agent AML type chemotherapy - 5 (18%) 10 (36%) 13 (46%) BM Blasts pre-transplant (%) <5 5-9 10-19 - 21 (75%) 4 (14%) 3 (11%) Transplant conditioning Myeloablative Reduced intensity - 22 (78%) 6 (22%) Donor 8/8 HLA Matched related donor 8/8 HLA Matched unrelated donors HLA-mismatched unrelated donors Cord blood - 13 (46%) 9 (32%) 3 (11%) 3 (11%) GVHD prophylaxis T cell depletion Calcineurin inhibitor - 16 (60%) 12 (40%)
Table 2: DFS per risk level defined by different prognostic models *CMML- specific scoring systems Prognostic Score N 3 year DFS IPSS-R 0-1 2-3 - 11 17 - 83% 63% MDASC 0-1 2-3 - 21 7 - 71% 69% MDAPS * 0-1 2-3 - 16 12 - 68% 74% Mayo * 0-1 2 - 10 18 - 56% 76% Spanish Score * 0-1 2-3 - 20 8 - 68% 75%

Disclosures
Boulad: Genzyme Sanofi: Trials partially funded by Genzyme Sanofi Other.