Chronic myelomonocytic leukemia (CMML), predominantly affecting older adults, has a poor prognosis even with hypomethylating agent treatment and long-term survival is rare [1,2]. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative treatment, but relapse and graft-versus-host disease (GVHD) limit its effectiveness [3]. More recently, a CMML-specific Prognostic Scoring System (CPSS) and its subsequent incorporation of molecular mutation status has been developed and validated to guide transplant decision-making [3–5]. Given the rarity of CMML and the lack of prospective trials, most transplant outcomes are derived from retrospective registry studies. A European Group for Blood and Marrow Transplantation (EBMT) study of 513 CMML patients reported 4-year overall survival (OS) of 33% and identified pre-transplant remission status as a key predictor [6]. Similarly, a Center for International Blood and Marrow Transplant Research (CIBMTR) study of 209 patients reported a 5-year OS of 30% and identified CPSS, performance status, and graft source as independent predictors of OS [7]. These studies demonstrate that while allo-HSCT is curative for some CMML patients, relapse and GVHD remain major obstacles.
The GVHD prevention strategy of ex vivo T cell depletion with CD34+ selection, originally developed at our institution, has shown great promise in treating patients with acute leukemias, myelodysplastic syndrome, and lymphomas, and has been validated prospectively in a multi-center study [8–12]. We report here outcomes of 22 consecutive patients with CMML who underwent allo-HSCT on the CD34+ selection platform at our institution between 2003 and 2018. A waiver of patient authorization for this retrospective review was obtained from the Institutional Review and Privacy Board.
Recipients of CD34+ selected grafts received a myeloablative conditioning regimen of either busulfan, melphalan, and fludarabine (n = 17) or hyperfractionated total body irradiation (TBI) 1375 cGy, thiotepa, and fludarabine (n = 5), and all with rabbit anti-thymocyte globulin (ATG). The source of stem cells was peripheral blood of either fully matched or single-antigen mismatched donors. Allografts were depleted of T cells ex vivo by CD34+ selection using the Isolex300i Magnetic Cell Separator (Baxter, Deefield, Illinois) followed by sheep red blood cell rosette depletion (n = 7) or the ClinicMACS CD34 reagent system (Miltenyi Biotech, Gladbach, Germany (n = 15). No post-transplant pharmacologic GVHD prophylaxis was given. The primary endpoint was CRFS, defined as the combined outcome of survival free from extensive chronic GVHD and relapse [13]. Secondary endpoints were OS, relapse-free survival (RFS), cumulative incidences of relapse, non-relapse mortality (NRM), acute GVHD, and chronic GVHD. Standard statistical analyses included Kaplan-Meier analysis and cumulative incidence method.
Patient characteristics are shown in Table 1. The median age was 60.5 years (range 25.7–68.8), and 6 patients (27%) were ≥65 years. Twenty-seven percent of patient had hematopoietic cell transplantation-comorbidity index (HCT-CI) of 3 or more, and 36% patients had KPS<90. Most patients, 73%, received chemotherapy and 55% were in complete remission prior to transplant. Overall, 77% of patients were in low/intermediate-1 CPSS category. Only 9 patients had molecular mutation data available on ASXL1, RUNX1, NRAS, and SETBP2 genes, therefore we were unable to derive the CPSS-Mol risk model [5]. Of note, the general criteria for CD34+ selection platform at our institution usually requires at least some combinations of clinical disease remission, good performance status, and low to intermediate comorbidity burden [8–11].
Table 1.
Baseline Characteristics and Transplant Outcomes
| N (%) | |
|---|---|
| Number of patients | 22 (100) |
| Age, years (median, range) | 60.5 (25.7–68.8) |
| Female | 8 (36) |
| KPS <90 | 8 (36) |
| HCI-CI ≥3 | 6 (27) |
| Mismatched (single antigen) donor | 6 (27) |
| Receipt CMV seronegative | 7 (32) |
| Chemotherapy prior to transplant | 16 (73) |
| Complete remission prior to transplant | 12 (55) |
| CPSS risk category | |
| Low/Intermediate-1 | 17 (77) |
| Intermediate-2/High | 5 (23) |
| Cell Dose | |
| CD34+, 106/kg (median, range) | 6.93 (2.62–15.15) |
| CD3+, 103/kg (median, range) | 1.56 (0.81–7.84) |
| Engraftment | |
| Neutrophil, days (median, range) | 10 (9–15) |
| Platelet, days (median, range) | 16 (13–131) |
| GVHD | |
| Acute GVHD grade 2–4 (95% CI) | 180-day, 27% (11–47) |
| Chronic GVHD, moderate severe (95% CI) | 3-yr, 5% (0.3–22) |
| Survival Outcomes | |
| Non-relapse mortality (95% CI) | 3-yr, 24% (8–44) |
| Relapse/disease progression (95% CI) | 3-yr, 5% (0.3–19) |
| Overall survival (95% CI) | 5-yr, 71% (54–94) |
| Relapse-free survival (95% CI) | 5-yr, 71% (54–94) |
| CRFS (95% CI) | 5-yr, 71% (54–94) |
Abbreviations: N, Number; KPS, Karnofsky Performance Scale; HCI-CI, Hematopoietic cell transplantation-comorbidity index; CMV, Cytomegalovirus; CPSS, CMML-specific Prognostic Scoring System; CD, Cluster of differentiation; GVHD, Graft-versus-host disease; CI, Confidence interval; CRFS, Chronic GVHD-free, relapse-free survival.
The median doses of CD34+ and CD3+ cells were 6.93×106 cells/kilogram of body weight (range, 2.62–15.15) and 1.56×103 cells/kilogram of body weight (range, 0.81–7.84), respectively. All patients engrafted; median neutrophil engraftment was at 10 days (range 9–15) and median platelet engraftment was at 16 days (range 13–131). As shown in Table 1 and Supplemental Figure, with a median follow-up of 5.2 years for survivors (range 0.9–13.1), the 5-year CRFS was 71% (95% CI: 54–94). The 5-year RFS and OS were both 71% (95% CI: 54–94), respectively. Eight patients have died by the latest follow-up. Deaths were attributed to relapse (n = 1) and NRM (n = 7), including 4 from infections, 2 from organ toxicities, and 1 from GVHD. The 3-year cumulative incidence rates of relapse and NRM were 5% (95% CI: 0.3–19) and 24% (95% CI: 8–44), respectively (Table 1). Grade II-IV acute GVHD developed in 6 patients with an overall cumulative incidence rate of 27% (95% CI: 11–47) at 180 days post-transplant. Chronic GVHD developed in 2 patients, 1 mild and 1 moderate in severity. The 3-year cumulative incidence rate for moderate to severe chronic GVHD was 5% (95% CI: 0.3–22) (Table 1). No patient developed cytomegalovirus organ disease and 2 patients developed post-transplant lymphoproliferative disease associated with reactivation of Epstein-Barr virus at 3- and 6-month post-transplant.
In this single-institution study of a relatively older cohort of CMML patients who underwent allo-HSCT on the CD34+ selection platform, we have demonstrated very favorable long-term outcomes with 5-year OS and CRFS rates of 71% and 71%, respectively. We have also demonstrated low relapse and NRM rates of 5% and 24%, respectively, at 3 years post-transplant. Even in a cohort of relatively older patients, our results compare favorably to large registry and single institution studies of allo-HSCT in CMML patients [6,7]. This is likely due to patient selection bias, such as lower disease risk (CPSS), lower comorbidity burden (HCT-CI), or better performance status (KPS), on the CD34+ selection platform at our institution. In addition, the lower relapse rate observed in our series could also reflect the use of myeloablative conditioning on the CD34+ selection platform and the use of pre-transplant chemotherapy in most patients. Not surprisingly, our CD34+ selection platform has achieved excellent long-term GVHD control with 6% cumulative incidence of chronic extensive GVHD at 3 years. Notably, only one previous study in CMML transplantation contained a small number of patients using the CD34+ selection platform [6], which could also explain the observed outcome differences.
Taken together, these results suggested that CD34+ selection maybe a preferred approach for selected patients with CMML who could tolerate myeloablative conditioning and who are in remission. This is consistent with our experience in patients with myelodysplastic syndrome in which CD34+ selection platform appears to limit GVHD without increasing relapse [13]. However, we also note that for many older CMML patients with significant comorbidities, myeloablative conditioning and CD34+ selection platform may not always be possible. We are also exploring novel reduced-intensity conditioning regimen to combine with CD34+ selection for these patients. Alternatively, strategies employing post-transplant cyclophosphamide could be considered in these patients to limit GVHD [14].
Our study has several limitations including its retrospective, single-institution design; small sample size; and potential patient selection bias. Despite these limitations, our results provide additional evidence of the effectiveness of allo-HSCT for CMML patients, and that favorable long-term CRFS and OS rates could be achieved using the CD34+ selection platform in appropriately selected patients. While these findings need to be confirmed in a prospective trial, our results lend additional support for all CMML patients to be evaluated for the potential curative benefit of allo-HSCT.
Supplementary Material
Supplemental Figure. Kaplan-Meier estimates of extensive chronic GVHD-free, relapse-free survival (CRFS) (Red line) with survivor table below.
Acknowledgement:
This research was supported in part by the NIH/NCI Cancer Center Support Grant P30 CA008748, the New York State Empire Clinical Research Investigator Program (ECRIP), the MDS Research Fund, the Phyllis Dunn Fund, and the Satlin Research Fund. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We also acknowledge all patients and their family who allowed us to participate in their care and to present the summary of their clinical disease course over the years at the Memorial Sloan Kettering Cancer Center. Editorial support in the preparation of this paper was provided by Hannah Rice, ELS.
Footnotes
Conflict of Interest:
Dr. Giralt reports research funding from Amgen, Actinium, Celgene, Johnson & Johnson, Miltenyi Biotec, and Takeda and serves as a consultant for Amgen, Actinium, Celgene, Johnson & Johnson, Jazz Pharmaceuticals, Miltenyi Biotec, Takeda, Novartis, Kite Pharma, and Spectrum Pharmaceuticals.
Dr. Perales reports honoraria from Abbvie, Bellicum, Bristol-Myers Squibb, Incyte, Merck, Novartis, Nektar Therapeutics, and Takeda. He serves on DSMBs for Servier and Medigene, and the scientific advisory boards of MolMed and NexImmune. He has also received research support for clinical trials from Incyte and Miltenyi Biotec. All other authors declare no conflict of interest related to the submitted research work.
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Associated Data
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Supplementary Materials
Supplemental Figure. Kaplan-Meier estimates of extensive chronic GVHD-free, relapse-free survival (CRFS) (Red line) with survivor table below.