# Outcomes of CMML patients undergoing allo-HCT are significantly worse compared to MDS-a study of the CMWP of the EBMT.

Alicia Rovó, Luuk Gras, Brian Piepenbroek, Nicolaus Kröger, H. Christian Reinhardt, Aleksandar Radujkovic, Didier Blaise, Guido Kobbe, Riitta Niityvuopio, Uwe Platzbecker, et al.

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## ► To cite this version:

Alicia Rovó, Luuk Gras, Brian Piepenbroek, Nicolaus Kröger, H. Christian Reinhardt, et al. Outcomes of CMML patients undergoing allo-HCT are significantly worse compared to MDS-a study of the CMWP of the EBMT. American Journal of Hematology, 2023, American Journal of Hematology, 10.1002/ajh.27150. hal-04510879

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# Outcomes of CMML patients undergoing allo-HCT are significantly worse compared to MDS—a study of the CMWP of the EBMT

Alicia Rovó¹ ID

Luuk Gras²

Brian Piepenbroek³

Nicolaus Kröger⁴

H. Christian Reinhardt⁵

Aleksandar Radujkovic⁶ ID

Didier Blaise⁷

Guido Kobbe⁸

Riitta Niityvuopio⁹

Uwe Platzbecker¹⁰

Mathilde Hunault-Berger¹²

J. J. Cornelissen¹³

Edouard Forcade¹⁴

Jean Henri Bourhis¹⁵

Yves Chalandon¹⁶ ID

Francesca Kinsella¹⁷

Stéphanie Nguyen-Quoc¹⁸

Johan Maertens¹⁹

Ahmet Elmaagacli²⁰

Nicola Mordini²¹

Patrick Hayden²²

Kavita Raj²³

Joanna Drozd-Sokolowska²⁴

Liesbeth C. de Wreede²⁵

Donal P. McLornan²³

Marie Robin²⁶ ID

Ibrahim Yakoub-Agha²⁷

Francesco Onida²⁸

## Correspondence

Alicia Rovó, Department of Hematology and Central Hematology Laboratory, INSELSPITAL, Bern University Hospital, Freiburgstrasse, BHH A156, CH- 3010 Bern, Switzerland.

Email: alicia.rovo@insel.ch

## Abstract

Although CMML since long has been separated from MDS, many studies continue to evaluate the outcomes of both diseases after hematopoietic cell transplantation (allo-HCT) together. Data evaluating outcomes of a large CMML cohort after allo-HCT compared to MDS are limited. We aim to compare outcomes of CMML to MDS patients who underwent allo-HCT between 2010 and 2018. Patients ≥18 years with CMML and MDS undergoing allo-HCT reported to the EBMT registry were analyzed. Progression to AML before allo-HCT was an exclusion criterion. Overall survival (OS), progression/relapse-free survival (PFS), relapse incidence (including progression) (REL), and non-relapse mortality (NRM) were evaluated in univariable and multivariable (MVA) Cox proportional hazard models including interaction terms between disease and founders. In total, 10832 patients who underwent allo-HCT were included in the study, there were a total of 1466 CMML, and 9366 MDS. The median age at time of allo-HCT in CMML (median 60.5, IQR 54.3-65.2 years) was significantly higher than in the MDS cohort (median 58.8, IQR 50.2-64.5 years; *p* < .001). A significantly higher percentage of CMML patients were male (69.4%) compared to MDS (61.2%; *p* < .001). There were no clinically meaningful differences in the distribution of Karnofsky score, Sorror HCT-CI score at allo-HCT, and donor type, between the CMML and MDS patients. RIC platforms were utilized in 63.9% of CMML allo-HCT, and in 61.4% of

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MDS patients ($p = .08$). In univariable analyses, we found that OS, PFS, and REL were significantly worse in CMML when compared with MDS (all $p < .0001$), whereas no significant difference was observed in NRM ($p = .77$). In multivariable analyses, the HR comparing MDS versus CMML for OS was 0.81 (95% CI, 0.74-0.88, $p < .001$), PFS 0.76 (95% CI 0.70-0.82, $p < .001$), relapse 0.66 (95% CI 0.59-0.74, $p < .001$), and NRM 0.87 (95% CI 0.78-0.98, $p = .02$), respectively. The association between baseline variables and outcome was found to be similar in MDS and CMML (all interaction $p > .05$) except for a decreasing trend over time of the risk of relapse in CMML (HR allo-HCT per year later 0.94, 95% CI 0.90-0.98), whereas no such trend was observed in MDS (HR 1.00, 95% CI 0.98-1.02). The poor outcome observed for CMML could be related to variables not measured in this study or to factors inherent to the disease itself. This study demonstrates that outcomes of CMML patients after allo-HCT are significantly worse compared to MDS. The results of this study may contribute to future recommendations for allo-HCT in CMML patients.

# 1 | INTRODUCTION

Chronic myelomonocytic leukemia (CMML) is a clonal heterogenic hematopoietic stem cell disorder characterized by peripheral blood monocytosis and features of both myeloproliferative neoplasms (MPN) and myelodysplastic syndromes (MDS).¹⁻³ The French American British (FAB) Group originally classified CMML as a form of MDS.⁴,⁵ In 2001, the World Health Organization (WHO) reclassified the disease as part of a newly created MDS/MPN overlap entity⁶ and the same classification concept has been maintained in subsequent revisions.⁷,⁸ Although CMML and MDS have common features such as the presence of dysplasia, cytopenia, and that both frequently affects older patients, CMML differs by its proliferative behavior, always present at least in the mono-cyte lineage, and by its molecular signature.¹,⁹⁻¹⁵ Making decisions on CMML patients based on data obtained from clinical studies including only MDS patients, therefore, nowadays is no longer appropriate. Despite relatively high mortality and relapse rates, allogeneic hematopoietic cell transplantation (allo-HCT) remains the only curative treatment for both CMML and MDS.¹⁶⁻²⁵

CMML is a disease that classically occurs in older patients, with a reported median age at presentation between 70 and 75 years. Current transplant recommendations in patients with malignant diseases no longer consider chronological age as an insurmountable restriction for intensive treatments, including allo-HCT.¹⁷,²⁶⁻²⁸ Due to increased life expectancy and a greater number of fit adult-aged patients considered for therapeutic interventions, the additional consideration of “biological age” has arisen. Biological age is defined by a set of parameters that include the state of physical and mental health alongside comorbidities as well as chronological age. Indeed, the implementation of a geriatric assessment seems to contribute to a refined selection of older patients becoming candidates for allo-HCT.²⁹ Consequently, during the last few decades, a clear increase in the proportion of patients over 65 years undergoing allo-HCT has been reported within the *European Society for Blood and Marrow Transplantation* (EBMT) registry. In a retrospective

study of the EBMT-CMWP that included a large cohort of more than 1200 MDS patients who underwent allo-HCT between 2003 and 2014, 23.4% were between the ages of 65 and 79 at the time of transplantation.³⁰ In another retrospective EBMT study, data of 6434 MDS and secondary acute myeloid leukemia (AML) adult patients from 21 countries who received a first allo-HCT between 2000 and 2012 showed that the percentage of patients older than 65 years at the time of allo-HCT increased from 5% to 17%).³¹ Utilization of reduced intensity conditioning (RIC) regimens has progressively increased over time, constituting approximately 38% of all the conditioning regimens reported to the EBMT in the year 2018.³² Prognostic assessment of patients with CMML is based on hematological and clinical features, including phenotypic disease sub-classification into proliferative and dysplastic and the proportion of marrow and blood blasts.³³⁻³⁵ More recently, gene mutation profiling has been shown to impact both the progression and prognosis to a certain extent.³⁶⁻³⁸

Likewise, the role of allo-HCT in CMML, especially in elderly patients, remains unclear. Over the years, a number of clinical research efforts have attempted to establish optimal prognostic scores for CMML patients undergoing allo-HCT³⁹,⁴⁰; however, the limited number of patients analyzed in the different and heterogeneous series has represented a major limitation.⁴¹ Therefore, in this retrospective EBMT registry-based study, we aimed to identify factors associated with allo-HCT outcomes in CMML patients, particularly focusing on age, and to compare them with a population of MDS patients undergoing allo-HCT in the same period.

# 2 | MATERIALS/SUBJECTS AND METHODS

## 2.1 | Data source

The study was performed on behalf of the EBMT, a non-profit scientific society comprising more than 600 transplant centers from Europe and
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beyond. Accreditation as a member center requires submission of mini-
mal essential data on patient and donor characteristics, treatment, and
follow-up on clinical outcomes from all patients undergoing blood and
bone marrow transplantation to a central database. EBMT centers com-
mit to obtain informed consent according to the local regulations appli-
cable at the time in order to report pseudonymized data to the EBMT.

## 2.2 | Collection of data and patient selection

Data were extracted from the EBMT registry. We selected CMML and MDS patients who underwent first allo-HCT between January 1, 2010 and December 31, 2018 and were 18 years of age or older at time of allo-HCT and had follow-up available beyond day of transplantation. CMML and MDS patients who progressed to AML before transplantation were excluded from this study.42

## 2.3 | Outcome and definitions

The main objective of the study was to assess the outcomes of CMML patients undergoing allo-HCT and compare them with a population of MDS patients undergoing allo-HCT during the same period. Second, we aimed to identify factors associated with allo-HCT outcomes in both cohorts, particularly focusing on the importance of recipient age. Outcomes studied were overall survival (OS), progression/relapse-free survival (PFS), relapse incidence (REL), non-relapse mortality (NRM), primary graft failure, and acute and chronic graft-versus-host disease (aGvHD and cGvHD). OS was defined as the time from allo-HCT to death from any cause and PFS was defined as the time from allo-HCT to relapse or progressive disease or death from any cause, whichever came first. Event time in patients with continuous progression (without a recorded date of the event) relapse was assumed 3 weeks after allo-HCT. aGvHD was defined as grade II-IV and cGvHD as either limited or extensive.

Patients with CMML were categorized according to the WHO 2008 staging approach (CMML 1 or 2) and the FAB [proliferative (MP-CMML), with WBC count ≥13 × 10⁹/L and dysplastic (MD-CMML), with WBC count <13 × 10⁹/L], sub-classification systems.36,43 Cytogenetic data obtained at time of allo-HCT was used when it was available; otherwise, data collected at diagnosis were used.

## 2.4 | Statistical analysis

Clinical, demographical, and transplantation-related characteristics at baseline were tabulated for MDS and CMML patients as median and interquartile range (IQR) for continuous variables and frequencies and proportions for categorical variables. Differences in characteristics between CMML and MDS patients were assessed using p-values obtained with the χ² test for categorical variables and the Wilcoxon rank sum test for continuous data. Median follow-up after baseline and 95% confidence intervals were calculated using the reverse Kaplan-Meier (KM) method.

The probability of primary graft failure was compared in CMML and MDS patients using the χ² test. OS and PFS probabilities were analyzed using the Kaplan-Meier method and groups were compared using the log-rank test. Competing risks NRM together with REL, aGvHD together with death before aGvHD and cGvHD together with death before cGvHD were analyzed using the crude cumulative incidence estimator in a competing risks framework and groups were compared with Gray's test. Multivariable (MVA) Cox proportional hazard models were used to obtain (cause specific) hazard ratios (HR). Variables included in the MVA, apart from disease (CMML, MDS) were as follows: age at allo-HCT (as a binary variable < and ≥ 65 years, as a continuous linear variable, and in a more flexible manner using restricted cubic splines), sex (male, female), karyotype (normal, abnormal), stage of disease at allo-HCT (CR, untreated, other), type of donor (HLA-identical siblings; unrelated donors; both matched (MUD) and mismatched (MMUD); mismatched-related donors (MMRD), including haploidentical); Karnofsky-score (KPS) (90 or 100, ≤80), HCT- comorbidity index (HCT-CI) risk score44 (0, 1-2, ≥3), year of allo-HCT (as a continuous linear variable) and intensity of the conditioning (RIC, MAC). To evaluate whether the association between these variables and outcome after allo-HCT was different in patients with CMML or MDS we tested for interaction disease x confounder using p-values obtained with the Wald test, where a low p-value provides evidence that the association of MDS/CMML and the outcome is different between different values of the confounder variable. Finally, we analyzed the same outcomes separately in just the CMML patients. All MVA included complete cases only.

All statistical tests were two-sided, and significance was determined when *p* ≤ .05. All analyses were performed in R version 4.2.2⁴⁵; using “survival,” “cmprsk,” “prodlim”, and “rms” packages. No adjustment for multiple comparisons were made.

## 3 | RESULTS

Patient-, disease-, and transplant characteristics of 10 832 patients are summarized in Table 1. There were a total of 1466 CMML, and 9366 MDS patients who underwent allo-HCT. The median age at time of allo-HCT in CMML (median 60.5, IQR 54.3–65.2 years) was significantly higher than in the MDS cohort (median 58.8, IQR 50.2–64.5 years; *p* < .001). The median age at allo-HCT increased over time from 57.6 year (IQR 51.4–61.7) in 2010, to 61.9 year (IQR 57.0–66.8) in 2018 for CMML and 56.2 year (IQR 47.4–62.0) to 60.4 year (IQR 52.7–66.1) for MDS.

A total of 324 (22.1%) CMML patients were aged between 65 and 70 years and 64 (4.4%) aged 70 years or more. A significantly higher percentage of CMML patients were male (69.4%) compared to MDS (61.2%; *p* < .001), while the percentage of patients with low KPS (≤80) was not significantly different between CMML (28.7%) and MDS patients (27.8%; *p* = .49). The distribution of the HCT-CI score did not significantly differ between CMML and MDS patients; 22.6% and 24.2% of the CMML and MDS cohort, respectively, had a HCT-CI ≥3, (*p* = .35). Regarding disease status at time of allo-HCT, 28.6% of
<table><caption>TABLE 1 Patient, disease, and transplant characteristics at baseline for CMML and MDS patients.</caption><thead><tr><th rowspan="2"></th><th>CMML</th><th>MDS</th><th rowspan="2">p</th></tr><tr><th>N (%)</th><th>N (%)</th></tr></thead><tbody><tr><td>Total number of patients</td><td>1466 (100)</td><td>9366 (100)</td><td></td></tr><tr><td>Age at allo-HCT (years), median (IQR)</td><td>60.5 (54.3-65.2)</td><td>58.8 (50.2-64.5)</td><td>&lt;.001</td></tr><tr><td>&lt;65 years</td><td>1078 (73.5)</td><td>7234 (77.2)</td><td>&lt;.001</td></tr><tr><td>65-70 years</td><td>324 (22.1)</td><td>1667 (17.8)</td><td></td></tr><tr><td>≥70 years</td><td>64 (4.4)</td><td>465 (5.0)</td><td></td></tr><tr><td>Sex</td><td></td><td></td><td></td></tr><tr><td>Male</td><td>1018 (69.4)</td><td>5736 (61.2)</td><td>&lt;.001</td></tr><tr><td>Female</td><td>448 (30.6)</td><td>3630 (38.8)</td><td></td></tr><tr><td>Cytogenetics at allo/diagnosis (missing in 33 and 38%, respectively)</td><td></td><td></td><td></td></tr><tr><td>Normal</td><td>663 (67.4)</td><td>2709 (46.7)</td><td>&lt;.001</td></tr><tr><td>Abnormal</td><td>320 (32.6)</td><td>3094 (53.3)</td><td></td></tr><tr><td>Molecular biology at diagnosis (missing in 61 and 73%, respectively)</td><td></td><td></td><td>&lt;.001</td></tr><tr><td>No mutations</td><td>236 (41.5)</td><td>1275 (50.9)</td><td></td></tr><tr><td>At least one</td><td>333 (58.5)</td><td>1231 (49.1)</td><td></td></tr><tr><td>Pretreatment, (missing in 69 and 75%, respectively)*</td><td></td><td></td><td></td></tr><tr><td>Hypomethylating agents</td><td>389 (28.7)</td><td>967 (41.0)</td><td>&lt;.001</td></tr><tr><td>Hydroxyurea</td><td>136 (29.6)</td><td>33 (1.4)</td><td>&lt;.001</td></tr><tr><td>Disease stage at allo-HCT, (missing in 4 and 5%, respectively)</td><td></td><td></td><td></td></tr><tr><td>Complete remission</td><td>402 (28.6)</td><td>2322 (26.0)</td><td>&lt;.001</td></tr><tr><td>Stable disease/minor response</td><td>393 (28.0)</td><td>1766 (19.8)</td><td></td></tr><tr><td>Relapse/progression/refractory</td><td>331 (23.5)</td><td>1952 (21.9)</td><td></td></tr><tr><td>Untreated</td><td>235 (16.7)</td><td>2654 (29.7)</td><td></td></tr><tr><td>Other</td><td>45 (3.2)</td><td>229 (2.6)</td><td></td></tr><tr><td>KPS at allo-HCT, (missing in 7 and 7%, respectively)</td><td></td><td></td><td></td></tr><tr><td>80 or lower</td><td>389 (28.7)</td><td>2417 (27.8)</td><td>.49</td></tr><tr><td>90 or 100</td><td>966 (71.3)</td><td>6291 (72.2)</td><td></td></tr><tr><td>Sorrow HCT-CI risk group, (missing in 26 and 29%, respectively)</td><td></td><td></td><td></td></tr><tr><td>Low risk (0)</td><td>548 (50.3)</td><td>3357 (50.4)</td><td>.35</td></tr><tr><td>Intermediate risk (1-2)</td><td>295 (27.1)</td><td>1688 (25.4)</td><td></td></tr><tr><td>High risk (≥3)</td><td>246 (22.6)</td><td>1610 (24.2)</td><td></td></tr><tr><td>Type of Donor, (missing in 0.2 and 0.1%, respectively)</td><td></td><td></td><td></td></tr><tr><td>MRD</td><td>417 (28.5)</td><td>2783 (29.8)</td><td>.55</td></tr><tr><td>Unrelated (MUD or MMUD)</td><td>926 (63.3)</td><td>5848 (62.5)</td><td></td></tr><tr><td>Mismatched-related donor (Haplo)</td><td>120 (8.2)</td><td>721 (7.7)</td><td></td></tr><tr><td>Source of stem cell, (missing in 0.1 and 0.1%, respectively)</td><td></td><td></td><td>.23</td></tr><tr><td>BM</td><td>129 (8.8)</td><td>936 (10.0)</td><td></td></tr><tr><td>PB stem cell</td><td>1306 (89.1)</td><td>8165 (87.3)</td><td></td></tr><tr><td>CB</td><td>26 (1.8)</td><td>179 (1.9)</td><td></td></tr><tr><td>BM + PBSC</td><td>3 (0.2)</td><td>40 (0.4)</td><td></td></tr><tr><td>BM + CB</td><td>0 (0.0)</td><td>1 (0.0)</td><td></td></tr><tr><td>PBSC+CB</td><td>1 (0.1)</td><td>23 (0.2)</td><td></td></tr><tr><td>BM + PBSC+CB</td><td>0 (0.0)</td><td>13 (0.1)</td><td></td></tr><tr><td>Year of allo-HCT, median (IQR)</td><td>2015 (2013-2017)</td><td>2015 (2012-2017)</td><td>&lt;.001</td></tr><tr><td>2010-2014</td><td>610 (41.6)</td><td>4488 (47.9)</td><td>&lt;.001</td></tr></tbody></table>
<table><caption>TABLE 1 (Continued)</caption><thead><tr><th></th><th>CMML</th><th>MDS</th><th></th></tr><tr><th></th><th>N (%)</th><th>N (%)</th><th>p</th></tr></thead><tbody><tr><td>2015-2018</td><td>856 (58.4)</td><td>4878 (52.1)</td><td></td></tr><tr><td>Conditioning regimen, (missing in 2 and 2%, respectively)</td><td></td><td></td><td></td></tr><tr><td>RIC</td><td>914 (63.9)</td><td>5623 (61.4)</td><td>.08</td></tr><tr><td>MAC</td><td>516 (36.1)</td><td>3540 (38.6)</td><td></td></tr></tbody></table>

Note: *p*-values were obtained using the χ² test for categorical variables and Wilcoxon test for continuous variables. Percentages are calculated over patients with data available.

Abbreviations: BM, bone marrow; CB, cord blood; IQR, interquartile range; KPS, Karnofsky Performance Score; MAC, myeloablative conditioning; MRD, matched related donor; MUD, matched unrelated donor; PBSC, peripheral blood stem cell; RIC, reduced intensity conditioning.

*Pretreatment drugs are not mutually exclusive.

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<figure><img src="image_8.png" /><figcaption>FIGURE 1 Outcome after allo-HCT in CMML and MDS patients: (A) Overall survival (OS), (B) progression-free survival (PFS), (C) cumulative incidence of relapse, and (D) cumulative incidence of non-relapse mortality (NRM). Numbers below the graph indicate the number of patients at risk. The shaded areas show the 95% confidence intervals. In three CMML and 58 MDS patients, relapse status was unknown. [Color figure can be viewed at wileyonlinelibrary.com]</figcaption></figure>
the CMML and 26.0% of MDS patients were in CR at allo-HCT (p < .001). A total of 32.6% of CMML and 53.3% of MDS patients with data available had an abnormal cytogenetic result (p < .001). Cytogenetic data were missing in 37.4% of all patients. Donors were unrelated (matched or mismatched) in 63.3% of CMML patients, while 8.2% had a MMRD, including haploidentical. The distribution of donor types was similar in MDS patients (p = .55). RIC platforms were utilized in the vast majority (63.9%) of CMML allo-HCT, and to a somewhat smaller extent (61.4%) in MDS patients (p = .08).

CMML FAB subtype and disease stage at allo-HCT were missing in 68.0% and 50.5% of CMML patients, respectively. In the remaining CMML patients with available data at allo-HCT, FAB subtype was CMML-MD in 42.0% and CMML-MP in 58.0%, while stage was CMML-1 in 52.5% and CMML-2 in 47.5% of patients. In 64.2% of all MDS patients, ≥5% blasts at allo-HCT were observed.

## 3.1 | Primary graft failure and GvHD

The probability of primary graft failure was similar for CMML and MDS patients, at 3.8% and 3.5%, respectively (p = .55). No significant differences in the cumulative incidence of grade 2-4 aGvHD were observed between both disease entities (100-day cumulative incidence 28% in both diseases, Gray's test p = .91). A higher cumulative incidence of cGvHD was observed in MDS transplant recipients (2-year cumulative incidence 40%, 95% CI 39%-41%) as compared to those transplanted for CMML (36%, 95% CI 33%-38%), Gray's test p < .001. In contrast, cumulative incidence of death before cGvHD was higher in CMML compared to MDS patients (38%, 95% CI 36%-41% vs. 31%, 95% CI 30%-32%, Gray's test p < .0001).

<figure><img src="image_9.png" /></figure>

## 3.2 | Outcomes in CMML versus MDS cohort

For CMML, the median follow-up was 29.2 months (IQR 13.8 to 57.3) and for MDS this was 32.9 (IQR 13.1-60.0) months. In CMML patients, 5 year OS, PFS, and cumulative incidence of relapse and NRM was 37% (95% CI 33%-40%), 31% (95% CI 28%-34%), 38% (95% CI 35%-41%), and 31% (95% CI 28%-34%), respectively. In MDS patients, these 5-year estimates were 47% (95% 46%-48%), 42% (95% CI 41%-43%), 27% (95% CI 26%-28%), and 31% (95% CI 30%-32%), respectively. In univariable analysis, OS, PFS, and REL were significantly worse for CMML than MDS (p < .001, Figure 1), regardless of the blast percentage in MDS patients at allo-HCT (data not shown). No difference was apparent for NRM (Gray's test p = .77, Figure 1). When OS was analyzed by age categories, as expected, a significant inverse association was observed for both CMML and MDS (Figure 2); albeit OS for CMML patients was lower compared to MDS patients in each category. Male CMML patients had a (borderline) significantly poorer OS (log-rank p = .06), PFS (log-rank p = .02), and NRM (p = .02) than female CMML patients yet with no significant difference (Gray's test p = .89) in the cumulative incidence of relapse (Figure 1). Regarding CMML-MD and CMML-MP, despite the high percentage of missing data (68%), the available data were analyzed. No significant differences between CMML-MD and CMML-MP were observed in OS (log-rank p = .90), PFS (log-rank p = .25), cumulative incidence of relapse (Gray's test p = .06), and NRM (p = .49). Nor did we observe significant differences between CMML type I and type II in OS log-rank (p = .43), PFS (p = .44), cumulative incidence of relapse (Gray's test p = .54) and NRM (p = .84). (Figure 2). CPSS information was only available in 416 (28%) CMML patients. Indeed, when allo-HCT outcomes were analyzed according to the CPSS classification, we only observed small differences among groups, with no

<figure><img src="image_10.png" /><figcaption>**FIGURE 2** Overall survival after allo-HCT in (A) CMML and (B) MDS patients. Numbers below the graph indicate the number of patients at risk. The shaded areas show the 95% confidence intervals. [Color figure can be viewed at wileyonlinelibrary.com]</figcaption></figure>
<table><caption>TABLE 2 (Cause specific) hazard ratio's and 95% confidence intervals (CI) of overall survival (OS), progression/relapse-free survival (PFS), relapse, and non-relapse mortality (NRM) obtained with multivariable Cox proportional hazard models in CMML and MDS patients.</caption><thead><tr><th rowspan="2"></th><th colspan="3">OS</th><th colspan="3">PFS</th><th colspan="3">Relapse</th><th colspan="3">NRM</th></tr><tr><th>HR (95% CI)</th><th>(Overall) p*</th><th>Interaction p**</th><th>HR (95% CI)</th><th>(Overall) p*</th><th>Interaction p**</th><th>HR (95% CI)</th><th>(Overall) p*</th><th>Interaction p**</th><th>HR (95% CI)</th><th>(Overall) p*</th><th>Interaction p**</th></tr></thead><tbody><tr><td>Disease</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>CMML</td><td>1.00</td><td></td><td></td><td>1.00</td><td></td><td></td><td>1.00</td><td></td><td></td><td>1.00</td><td></td><td></td></tr><tr><td>MDS</td><td>0.81 (0.74-0.88)</td><td>&lt;.0001</td><td></td><td>0.76 (0.70-0.82)</td><td>&lt;.0001</td><td></td><td>0.66 (0.59-0.74)</td><td>&lt;.0001</td><td></td><td>0.87 (0.78-0.98)</td><td>.02</td><td></td></tr><tr><td>Age</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>per 10 year increase</td><td>1.17 (1.13-1.20)</td><td>&lt;.0001</td><td>.60</td><td>1.15 (1.11-1.18)</td><td>&lt;.0001</td><td>.25</td><td>1.09 (1.04-1.14)</td><td>&lt;.0001</td><td>.17</td><td>1.20 (1.15-1.25)</td><td>&lt;.0001</td><td>.89</td></tr><tr><td>Sex</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Male</td><td>1.00</td><td></td><td>.46</td><td>1.00</td><td></td><td>.33</td><td>1.00</td><td></td><td>.55</td><td>1.00</td><td></td><td>.33</td></tr><tr><td>Female</td><td>0.92 (0.86-0.98)</td><td>.008</td><td></td><td>0.92 (0.86-0.98)</td><td>.006</td><td></td><td>0.99 (0.90-1.08)</td><td>.75</td><td></td><td>0.86 (0.79-0.94)</td><td>.0005</td><td></td></tr><tr><td>Type of donor</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>MRD</td><td>1.00</td><td>(&lt;.0001)</td><td>.40</td><td>1.00</td><td>(&lt;.0001)</td><td>.45</td><td>1.00</td><td>(.007)</td><td>.55</td><td>1.00</td><td>(&lt;.0001)</td><td>.32</td></tr><tr><td>MMRD</td><td>1.50 (1.33-1.70)</td><td>&lt;.0001</td><td></td><td>1.36 (1.21-1.52)</td><td>&lt;.0001</td><td></td><td>0.89 (0.74-1.06)</td><td>.21</td><td></td><td>1.96 (1.68-2.28)</td><td>&lt;.0001</td><td></td></tr><tr><td>MUD</td><td>1.08 (1.00-1.17)</td><td>.04</td><td></td><td>1.02 (0.95-1.10)</td><td>.51</td><td></td><td>0.84 (0.76-0.93)</td><td>.0006</td><td></td><td>1.26 (1.13-1.40)</td><td>&lt;.0001</td><td></td></tr><tr><td>MMUD</td><td>1.39 (1.26-1.53)</td><td>&lt;.0001</td><td></td><td>1.25 (1.14-1.37)</td><td>&lt;.0001</td><td></td><td>0.82 (0.73-0.95)</td><td>.008</td><td></td><td>1.80 (1.59-2.04)</td><td>&lt;.0001</td><td></td></tr><tr><td>Unrelated, MM unknown</td><td>1.20 (1.07-1.33)</td><td>.001</td><td></td><td>1.12 (1.02-1.24)</td><td>.04</td><td></td><td>0.85 (0.73-0.99)</td><td>.03</td><td></td><td>1.47 (1.28-1.69)</td><td>&lt;.0001</td><td></td></tr><tr><td>Year of allo HCT</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Karnofsky score</td><td>80 or lower</td><td>1.00</td><td>.80</td><td>1.00</td><td></td><td>.48</td><td>1.00</td><td></td><td>.62</td><td>1.00</td><td></td><td>.83</td></tr><tr><td>100 or 90</td><td>0.72 (0.67-0.77)</td><td>&lt;.0001</td><td></td><td>0.75 (0.71-0.80)</td><td>&lt;.0001</td><td></td><td>0.86 (0.78-0.94)</td><td>.002</td><td></td><td>0.68 (0.62-0.73)</td><td>&lt;.0001</td><td></td></tr><tr><td>Conditioning</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>RIC</td><td>1.00</td><td></td><td>.67</td><td>1.00</td><td></td><td>.35</td><td>1.00</td><td></td><td>.23</td><td>1.00</td><td></td><td>.73</td></tr><tr><td>MAC</td><td>1.10 (1.02-1.17)</td><td>.000</td><td></td><td>1.07 (1.00-1.14)</td><td>.04</td><td></td><td>0.92 (0.84-1.02)</td><td>.11</td><td></td><td>1.21 (1.10-1.32)</td><td>&lt;.0001</td><td></td></tr><tr><td>Stage of disease at allo HCT</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>CR</td><td>1.00</td><td>(&lt;.0001)</td><td>.65</td><td>1.00</td><td>(&lt;.0001)</td><td>.29</td><td>1.00</td><td>(&lt;.0001)</td><td>.05</td><td>1.00</td><td>(&lt;.0001)</td><td>.82</td></tr><tr><td>Untreated</td><td>0.95 (0.88-1.02)</td><td>.30</td><td></td><td>0.92 (0.84-0.99)</td><td>.04</td><td></td><td>0.64 (0.56-0.72)</td><td>&lt;.0001</td><td></td><td>1.23 (1.10-1.37)</td><td>.0003</td><td></td></tr><tr><td>Other</td><td>1.17 (1.08-1.26)</td><td>&lt;.0001</td><td></td><td>1.16 (1.08-1.24)</td><td>&lt;.0001</td><td></td><td>1.10 (0.99-1.21)</td><td>.06</td><td></td><td>1.23 (1.11-1.36)</td><td>&lt;.0001</td><td></td></tr></tbody></table>

Abbreviations: CI, confidence interval; CR, complete remission; HR, hazard ratio; MAC, myeloablative conditioning; MMRD, mismatched related donor; MRD, matched related donor; MUD, mismatched unrelated donor; MMUD, mismatched unrelated donor; MRD, matched related donor; RIC, reduced intensity conditioning.

*Test whether the risk/hazard of the outcome is different between categories of the variable. For donor type and stage of disease at allo-HCT, the overall p-value obtained with the Wald test is given between brackets.

**Test for interaction tests whether the association between the risk/hazard of the outcome and the variable is different in MDS and CMML patients.
<figure><img src="image_11.png" /><figcaption>**FIGURE 3** Legend on next page.</figcaption></figure>
<figure><img src="image_12.png" /></figure>

statistical significance (Table S2). IPSS and IPSS-R information was
limited in our cohort with less than 25% available data. Outcome
based on calculation of the available data is summarized in the supple-
mentary data (Tables S3 and S4). As expected, the probability of sur-
vival according to IPSS and IPSS-R risk groups was consistently higher
in MDS patients compared to CMML patients.

Results of MVA of OS, PFS, relapse, and NRM in both CMML and MDS are summarized in Table 2 (for CMML analyzed separately also in Table S1) and show significantly better outcomes after allo-HCT for MDS patients than CMML patients. The HR comparing MDS versus CMML for OS was 0.81 (95% CI, 0.74-0.88, *p* < .001), PFS 0.76 (95% CI 0.70-0.82, *p* < .001), relapse 0.66 (95% CI 0.59-0.74, *p* < .001), and NRM 0.87 (95% CI 0.78-0.98, *p* = .02), respectively. Older age at allo-HCT, male gender, earlier year of allo-HCT, low KPS, MAC conditioning, and being in a state of disease at time of allo-HCT other than CR or untreated were all associated with a worse OS, PFS, and NRM. The use of a donor other than a MRD also associated with worse survival and NRM outcomes, even though PFS in MUD was similar to MRD. Older age at allo-HCT and low KPS, were significantly associated with a higher risk of relapse, whereas being transplanted with a MUD or MMUD (as compared to MRD) and patients who were untreated prior to allo-HCT (as compared to patients in CR) were associated with a lower risk of relapse.

We then evaluated whether the association of each prognostic
factor and the outcome was different between CMML and MDS
cohorts by including interaction terms between each variable and dis-
ease (CMML/MDS). With the exception of a significant interaction
between year of allo-HCT and disease on risk of relapse (p = .006),
we found no significant interaction between disease and any variables
included in the model on any outcome. There was no change in the
risk of relapse in MDS patients according to the calendar year of allo-
HCT (for each year later HR 1.00, 95% CI 0.98-1.02), whereas in
CMML the risk decreased over time (HR 0.94, 95% CI 0.90-0.98).

Finally, we modeled age as a continuous linear variable and in a
more flexible manner using restricted cubic splines for each disease
separately, and including the variables listed in Table 2. In CMML
patients, the hazard of death increased strongly in patients ≥65 years
but as there are only few patients in this age range the confidence
intervals were wide and there was no evidence that this model was
significantly different from the linear model (p = .47), (Figure 3A). Also
for PFS, relapse, and NRM, there was no evidence that the restricted
cubic spline model was better than the linear age model (p = .49,
p = .39, and p = .86, respectively). In MDS patients, the confidence
intervals were narrower due to the larger number of patients. Also,
when using the flexible age modeling the HR increased in a linear
manner with older age for each outcome.

4 | DISCUSSION

This study evaluated relevant transplant-specific outcomes of a large CMML cohort who underwent allo-HCT and compared results to a MDS cohort transplanted over the same period. In MVA, adjusted for age and stage at allo-HCT, sex, year of allo-HCT, donor type, KPS, and conditioning intensity, there was still an increased risk of death, relapse, and NRM in CMML compared to MDS patients. Comparison of post-transplant outcomes for CMML patients to other myeloid diseases has been previously analyzed in a study that assessed the impact of the primary disease on allo-HCT outcomes for transformed secondary acute leukemia.⁴² That study evaluated populations at different risk than the one evaluated here, since transformation to AML was an exclusion criterion in our study. Although there are a number of studies investigating the outcomes of CMML⁴⁰,⁴⁶⁻⁴⁹ and MDS³⁰,⁵⁰⁻⁵³ patients after allo-HCT, comparative studies of both diseases including such a large number of patients, as in our study, have not been performed to date.

In this study, we observed that rates of allo-HCT for CMML increased over time, as 59% of the evaluated patients underwent allo-HCT between 2014 and 2018, that is, the second half of the evaluated period, with a predominant use of RIC regimens (63.7%). Moreover, our data also confirm the ongoing trend of allo-HCT use in older patients³⁰,³² as 21.8% of the CMML analyzed population were aged between 65 and 70 years of age and 4.3% were older than 70 years. We want to emphasize that the focus of this study was to evaluate outcomes of CMML patients after allo-HCT, excluding those who transformed into AML before transplantation. It was important to analyze CMML outcomes separately from MDS patients since little information in this regard is available in the literature (CMML data are summarized in Table S1), and subsequently compare these results with MDS.

Comparing CMML versus MDS allo-HCT populations, we found that the CMML cohort comprised of older individuals, contained more males, and had a lower number of patients in CR at time of allo-HCT. KPS and Sorror HCT-CI score, as well as the type of donor did not differ in the MDS cohort. Conditioning intensity, as expected due to disease type, was predominantly RIC in both cohorts, but quantitatively there was a significantly higher percentage of patients transplanted with this modality in patients with CMML. For the MDS population, there was, as expected given the incidence of the disease, a greater number of patients. In summary, apart from the differences concerning the disease per se and their epidemiological aspects, patients' clinical characteristics, as well as the type of donors and conditioning regimens used, both populations were comparable.

**FIGURE 3** Adjusted hazard ratios (HR) by age at allo-HCT (with 60 year of as reference, i.e., HR = 1) for (A) Overall-Survival (OS), (B) progression/relapse free-survival (PFS), (C) Relapse and (D) Non-Relapse Mortality (NRM) in CMML patients and (E) OS, (F) PFS, (G) relapse and (H) NRM in MDS patients. In every graph, the gray dashed lines show the HR and 95% confidence intervals (CI) obtained using a linear age model (HR and 95% CI). The blue line and shading show the HR and 95% CI obtained when age was modeled using restricted cubic splines. The gray shading at the bottom shows the age distribution among CMML and MDS patients. [Color figure can be viewed at wileyonlinelibrary.com]
In univariable analysis, OS, PFS, and REL were significantly worse in the CMML cohort when compared with MDS, whereas NRM was similar in CMML and MDS. Age at allo-HCT ≥65 years in the adjusted model conferred a negative impact on OS, PFS, and NRM in both diseases, indeed, one of the primary objectives of this study was to assess the role of age on the outcomes of patients with CMML and compared to the MDS group. There was no evidence that age “acted differently” in CMML or MDS: older age, as expected, was associated with worse outcomes in both diseases.

Other groups have previously reported a high cumulative incidence of disease recurrence post-allo-HCT for CMML patients. By way of example, in a nationwide retrospective analysis of 159 CMML patients who underwent allo-HCT in Japan, the 3-year total cumulative incidence of death after relapse was 39%.⁴⁷ Another study showed that the 3-year-CI of relapse was 33.3% in 83 CMML patients analyzed retrospectively, including 36 with CMML progressed to AML, who received an allo-HCT between April 1991 and December 2013 at MD Anderson Cancer Center.⁴⁶ In the current study, we demonstrate a significantly higher cumulative incidence of relapse in CMML patients compared to MDS. This difference remained in the MVA and can therefore not be explained by differences in the distribution of risk factors in CMML and MDS patients. There was also no evidence for interaction between disease and any clinical confounder included in the model on any outcome, meaning that the association between risk factors and outcomes is similar for both diseases. The postulated immunological protective effect of cGVHD against relapse,⁵⁴ it was not particularly observed in this cohort, even though in our study we did not specifically investigated on the association between cGVHD and relapse. This could be explained due to the lower rate of cGVHD observed in CMML patients, which could be possibly explained by the observed higher cumulative incidence of death before cGVHD in comparison to MDS patients.

The explanation for the worse outcome in CMML as compared to MDS might therefore be explained by the disease biology or unmeasured confounders. Interestingly, there was only one favorable exception for CMML, as we observed that there was a reduction over time in the probability of relapse in CMML patients, whereas no reduction was seen in MDS patients. This trend could be reflective of greater experience across transplant centers undertaking allo-HCT for CMML patients or indeed differing pre- or post-allo-HCT interventions; however, additional data confirming this trend are required before firm conclusions can be drawn. In CMML patients, there is a clear need to introduce strategies that allow better post-transplant control of the disease. In that sense, disease control models used in other myeloid diseases after allo-HCT, as, for example, MDS and AML,⁵⁵⁻⁵⁷ could be used as a reference to define maintenance strategies specifically designed for CMML.

This retrospective study has both strengths and limitations. Given the nature of a registry-based study, one major strength is the sheer volume of collected data from both cohorts, analyzed in two quite rare diseases, which allowed us to show that the post-allo-HCT outcome in CMML compared to MDS differs, being worse in CMML. There were also several limitations, mainly related to the retrospective

nature of studies based on patient registry data, commonly characterized by limited availability and underreporting of data, in particular the lack of cytogenetic and molecular annotations, a number of missing clinical relevant information (e.g., splenomegaly) and its variable quality.⁵⁸,⁵⁹

## 5 | CONCLUSIONS

The comparison of OS, PFS, and REL shows significantly worse post-allo-HCT outcomes in CMML compared to MDS, regardless of the percentage of blasts in MDS patients at allo-HCT, with no difference in NRM in univariate analysis. After adjustment for evaluated variables, an increased risk for all outcomes in CMML compared to MDS was still observed. There was no evidence that the association between age at allo-HCT and outcome after allo-HCT was different in CMML or MDS patients, and, as expected, advanced age was associated with more adverse outcomes in both diseases, suggesting that the underlying disease biology may be the pivotal factor. The worse survival outcomes in CMML in comparison to MDS appear to be the consequence of the significantly higher rate of post-transplant relapse. These results may contribute to future recommendations for allo-HCT indications in CMML patients. Future research should focus on both pre- and post-transplant strategies to improve disease control.

## AUTHOR CONTRIBUTIONS

Alicia Rovó had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: Alicia Rovó, Francisco Onida, Marie Robin, Ibrahim Yakoub-Agha. Acquisition, analysis, or interpretation of data: Alicia Rovó, Luuk Gras, Brian Piepenbroek, Francisco Onida, and Donal P. McLoran. Statistical analysis: Luuk Gras, Liesbeth C. de Wreede. Administrative, technical, or material support: Alicia Rovó, Luuk Gras, Brian Piepenbroek, Francisco Onida, and Donal P. McLoran. Supervision: Alicia Rovó, Luuk Gras, Francisco Onida, Marie Robin and Donal P. McLoran. Drafting of the manuscript: Alicia Rovó, Luuk Gras, Francisco Onida. Critical revision of the manuscript for important intellectual content: Liesbeth C. de Wreede, Donal P. McLoran, Marie Robin, Brian Piepenbroek, Nicolaus Kröger, H. Christian Reinhardt, Aleksandar Radujkovic, Didier Blaise, Guido Kobbe, Riitta Niityvuopio, Uwe Platzbecker, Katja Sockel, Mathilde Hunault-Berger, J.J. Cornelissen, Edouard Forcade, Jean Henri Bourhis, Yves Chalandon, Francesca Kinsella, Stéphanie Nguyen-Quoc, Johan Maertens, Ahmet Elmaagacli, Nicola Mordini, Patrick Hayden, Kavita Raj, Joanna Drozd-Sokolowska, Ibrahim Yakoub-Agha.

## AFFILIATIONS

<footnote n="1">¹Department of Hematology and Central Hematology Laboratory, University Hospital of Bern, Bern, Switzerland</footnote>

<footnote n="2">²EBMT Statistical Unit, Leiden, Netherlands</footnote>

<footnote n="3">³EBMT Leiden Study Unit, Leiden, Netherlands</footnote>

<footnote n="4">⁴University Hospital Eppendorf, Hamburg, Germany</footnote>
⁵Department of Hematology and Stem Cell Transplantation, University Hospital Essen, Essen, Germany

⁶University of Heidelberg, Heidelberg, Germany

⁷Programme de Transplantation&Therapie Cellulaire, Marseille, France

⁸Heinrich Heine Universitaet, Duesseldorf, Germany

⁹HUCH Comprehensive Cancer Center, Helsinki, Finland

¹⁰Medical Clinic and Policlinic 1, Leipzig, Germany

¹¹Medical Clinic and Policlinic I, University Hospital Dresden, Dresden, Germany

¹²CHRU, Angers, France

¹³Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, Netherlands

¹⁴CHU Bordeaux, Pessac, France

¹⁵Gustave Roussy Cancer Campus, Villejuif, France

¹⁶Département d'Oncologie, Service d'Hématologie, Hôpitaux Universitaire de Genève and Faculty of Medicine of Geneva, University of Geneva, Geneva, Switzerland

¹⁷University Hospital Birmingham NHSTrust, Birmingham, UK

¹⁸AP-HP Sorbonne Université, Hopital Pitié-Salpêtrière, Paris, France

¹⁹University Hospital Gasthuisberg, Leuven, Belgium

²⁰Asklepios Klinik St. Georg, Hamburg, Germany

²¹Az. Ospedaliera S. Croce e Carle, Cuneo, Italy

²²St. James's Hospital, Trinity College Dublin, Dublin, Ireland

²³Department of Stem Cell Transplantation, University College Hospital London, London, UK

²⁴University Clinical Centre, Medical University of Warsaw, Warsaw, Poland

²⁵Leiden University Medical Center, Leiden, Netherlands

²⁶Hopital St. Louis, Paris, France

²⁷CHU de Lille, Univ Lille, INSERM U1286, Lille, France

²⁸ASST Fatebenefratelli-Sacco—University of Milan, Milano, Italy

## ACKNOWLEDGMENTS

We thank all the centers that report data to the EBMT contributing to this study, all those who have worked on the data registry, the health team that cared for the patients and all the patients.

## CONFLICT OF INTEREST STATEMENT

Alicia Rovó received research grants (to institution, not investigator) from Novartis, CSL Behring and AG Alexion, consulting fees from Novartis and honoraria for advisory Board from Novartis, Orpha Swiss GMBH, SOBI, and BMS. H. Christian Reinhardt received consulting and lecture fees from Roche, Novartis, BMS, Abbvie, Astra Zeneca, Vertex, and Merck; he received research funding from Gilead Sciences and Astra Zeneca and he is a co-founder of CDL Therapeutics GmbH. Yves Chalandon has received consulting fees from MSD, Novartis, Incyte, BMS, Pfizer, Abbvie, Roche, Jazz, Gilead, Amgen, AstraZeneca, Servier; Travel support from MSD, Roche, Gilead, Amgen, Incyte, Abbvie, Janssen, Astra-Zeneca, Jazz. Francesca Kinsella has received honoraria from Therakos, DSMB, and TCBiopharm and fees for Advisory board from Sanofi. Ahmet Elmaagaci have received consulting fees and honoraria for advisory Board from Novartis, BMS,

Sanofi, Amgen, JAZZ, Roche, AstraZeneca, and Celgene. Luuk Gras: Nothing to declare. Brian Piepenbroek: Nothing to declare. Nicolaus Kröger: Nothing to declare. Aleksandar Radujkovic: Nothing to declare. Didier Blaise: Nothing to declare. Guido Kobbe: Nothing to declare. Riitta Niityvuopio: Nothing to declare. Uwe Platzbecker: Nothing to declare. Katja Sockel: Nothing to declare. Mathilde Hunault-Berger: Nothing to declare. J.J. Cornelissen: Nothing to declare. Edouard Forcade: Nothing to declare. Jean Henri Bourhis: Nothing to declare. Stéphanie Nguyen-Quoc: Nothing to declare. Johan Maertens: Nothing to declare. Nicola Mordini: Nothing to declare. Patrick Hayden: Nothing to declare. Kavita Raj: Nothing to declare. Joanna Drozd-Sokolowska: Nothing to declare. Liesbeth C. de Wreede: Nothing to declare. Donal P. McLornan: Nothing to declare. Marie Robin: Nothing to declare. Ibrahim Yakoub-Agha: Nothing to declare. Francesco Onida: Nothing to declare.

## DATA AVAILABILITY STATEMENT

EBMT Policy: Data cannot be shared.

## ORCID

Alicia Rovó https://orcid.org/0000-0002-7757-4753

Aleksandar Radujkovic https://orcid.org/0000-0002-8543-5016

Yves Chalandon https://orcid.org/0000-0001-9341-8104

Marie Robin https://orcid.org/0000-0003-1388-9876

## REFERENCES

1. Patnaik MM, Tefferi A. Chronic myelomonocytic leukemia: 2022 update on diagnosis, risk stratification, and management. *Am J Hematol.* 2022;97(3):352-372.

2. Morsia E, Gangat N. Myeloproliferative neoplasms with Monocytosis. *Curr Hematol Malig Rep.* 2022;17(1):46-51.

3. Chan O, Renneville A, Padron E. Chronic myelomonocytic leukemia diagnosis and management. *Leukemia.* 2021;35(6):1552-1562.

4. Bennett JM, Catovsky D, Daniel MT, et al. Proposals for the classification of the acute leukaemias. French-American-British (FAB) cooperative group. *Br J Haematol.* 1976;33(4):451-458.

5. Bennett JM, Catovsky D, Daniel MT, et al. Proposals for the classification of the myelodysplastic syndromes. *Br J Haematol.* 1982;51(2): 189-199.

6. Harris NL, Jaffe ES, Diebold J, et al. The World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues. Report of the clinical advisory committee meeting, Airlie house, Virginia, November, 1997. *Ann Oncol.* 1999;10(12): 1419-1432.

7. Arber DA, Orazi A, Hasserjian RP, et al. International consensus classification of myeloid neoplasms and acute leukemias: integrating morphologic, clinical, and genomic data. *Blood.* 2022;140(11):1200-1228.

8. Khoury JD, Solary E, Abla O, et al. The 5th edition of the World Health Organization classification of Haematolymphoid Tumours: myeloid and histiocytic/dendritic neoplasms. *Leukemia.* 2022;36(7): 1703-1719.

9. Patnaik MM. How I diagnose and treat chronic myelomonocytic leukemia. *Haematologica.* 2022;107(7):1503-1517.

10. Greenberg PL, Stone RM, Al-Kali A, et al. NCCN guidelines(R) insights: myelodysplastic syndromes, version 3.2022. *J Natl Compr Canc Netw.* 2022;20(2):106-117.

11. Itzykson R, Kosmider O, Renneville A, et al. Clonal architecture of chronic myelomonocytic leukemias. *Blood.* 2013;121(12):2186-2198.
12. Patnaik MM, Lasho T. Myelodysplastic syndrome/myeloproliferative neoplasm overlap syndromes: a focused review. *Hematology Am Soc Hematol Educ Program*. 2020;2020(1):460-464.

13. Palomo L, Meggendorfer M, Hutter S, et al. Molecular landscape and clonal architecture of adult myelodysplastic/myeloproliferative neoplasms. *Blood*. 2020;136(16):1851-1862.

14. Xie Z, Campestri G, Lasho T, et al. Clonal compositions involving epigenetic regulator and splicing mutations in CHIP, CCUS, MDS, and CMML. *Leuk Res*. 2022;116:106818.

15. Elmariah H, DeZern AE. Chronic myelomonocytic leukemia: 2018 update to prognosis and treatment. *Curr Hematol Malig Rep*. 2019; 14(3):154-163.

16. Harel S, Cherait A, Berthon C, et al. Outcome of patients with high risk myelodysplastic syndrome (MDS) and advanced chronic myelomonocytic leukemia (CMML) treated with decitabine after azacitidine failure. *Leuk Res*. 2015;39(5):501-504.

17. de Witte T, Bowen D, Robin M, et al. Allogeneic hematopoietic stem cell transplantation for MDS and CMML: recommendations from an international expert panel. *Blood*. 2017;129(13):1753-1762.

18. Bell JA, Galaznik A, Huelin R, et al. Systematic literature review of treatment options and clinical outcomes for patients with higher-risk myelodysplastic syndromes and chronic myelomonocytic leukemia. *Clin Lymphoma Myeloma Leuk*. 2018;18(4):e157-e166.

19. Bewersdorf JP, Zeidan AM. Risk-adapted, individualized treatment strategies of myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML). *Cancers (Basel)*. 2021;13(7):1610.

20. Hunter AM, Zhang L, Padron E. Current management and recent advances in the treatment of chronic myelomonocytic leukemia. *Curr Treat Options Oncol*. 2018;19(12):67.

21. Sharma P, Shinde SS, Damlaj M, et al. Allogeneic hematopoietic stem cell transplant in adult patients with myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) overlap syndromes. *Leuk Lymphoma*. 2017;58(4):872-881.

22. Cao YG, He Y, Zhang SD, et al. Conditioning regimen of 5-day decitabine Administration for Allogeneic Stem Cell Transplantation in patients with myelodysplastic syndrome and myeloproliferative neoplasms. *Biol Blood Marrow Transplant*. 2020;26(2):285-291.

23. Zhao XL, Jiang EL, Zhai WH, et al. Decitabine-based conditioning regimen is feasible and effective in the treatment of myelodysplastic syndrome and chronic myelomonocytic leukemia. *Zhonghua Xue Ye Xue Za Zhi*. 2019;40(6):467-471.

24. Renneville A, Patnaik MM, Chan O, Padron E, Solary E. Increasing recognition and emerging therapies argue for dedicated clinical trials in chronic myelomonocytic leukemia. *Leukemia*. 2021;35(10):2739-2751.

25. Itzykson R, Fenaux P, Bowen D, et al. Diagnosis and treatment of chronic myelomonocytic leukemias in adults: recommendations from the European Hematology Association and the European Leukemia-Net. *Hemisphere*. 2018;2(6):e150.

26. Kroger N. Allogeneic stem cell transplantation for elderly patients with myelodysplastic syndrome. *Blood*. 2012;119(24):5632-5639.

27. Jiang S, Yan H, Lu X, et al. How to improve the outcomes of elderly acute myeloid leukemia patients through allogeneic hematopoietic stem cell transplantation. *Front Immunol*. 2023;14:1102966.

28. Symeonidis A, Chondropoulos S, Verigou E, Lazaris V, Kourakli A, Tsirigotis P. Allogeneic hematopoietic stem cell transplantation for mixed or overlap myelodysplastic/myeloproliferative disorders. *Front Oncol*. 2022;12:884723.

29. Muffly LS, Kocherginsky M, Stock W, et al. Geriatric assessment to predict survival in older allogeneic hematopoietic cell transplantation recipients. *Haematologica*. 2014;99(8):1373-1379.

30. Carre M, Porcher R, Finke J, et al. Role of age and hematopoietic cell transplantation-specific comorbidity index in myelodysplastic patients undergoing an allotransplant: a retrospective study from the chronic malignancies working Party of the European Group for blood and marrow transplantation. *Biol Blood Marrow Transplant*. 2020;26(3):451-457.

31. Schetelig J, de Wreede LC, van Gelder M, et al. Late treatment-related mortality versus competing causes of death after allogeneic transplantation for myelodysplastic syndromes and secondary acute myeloid leukemia. *Leukemia*. 2019;33(3):686-695.

32. Passweg JR, Baldomero H, Chabannon C, et al. The EBMT activity survey on hematopoietic-cell transplantation and cellular therapy 2018: CAR-T's come into focus. *Bone Marrow Transplant*. 2020;55(8):1604-1613.

33. Cervera N, Itzykson R, Coppin E, et al. Gene mutations differently impact the prognosis of the myelodysplastic and myeloproliferative classes of chronic myelomonocytic leukemia. *Am J Hematol*. 2014; 89(6):604-609.

34. Schuler E, Schroeder M, Neukirchen J, et al. Refined medullary blast and white blood cell count based classification of chronic myelomonocytic leukemias. *Leuk Res*. 2014;38(12):1413-1419.

35. Selimoglu-Buet D, Badaoui B, Benayoun E, et al. Accumulation of classical monocytes defines a subgroup of MDS that frequently evolves into CMML. *Blood*. 2017;130(6):832-835.

36. Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. *Blood*. 2016;127(20):2391-2405.

37. Wedge E, Hansen JW, Dybedal I, et al. Allogeneic hematopoietic stem cell transplantation for chronic myelomonocytic leukemia: clinical and molecular genetic prognostic factors in a Nordic population. *Transplant Cell Ther*. 2021;27(12):991 e1-e9.

38. Woo J, Choi DR, Storer BE, et al. Impact of clinical, cytogenetic, and molecular profiles on long-term survival after transplantation in patients with chronic myelomonocytic leukemia. *Haematologica*. 2020;105(3):652-660.

39. Onida F, Sbianchi G, Radujkovic A, et al. Prognostic value of a new clinically-based classification system in patients with CMML undergoing allogeneic HCT: a retrospective analysis of the EBMT-CMWP. *Bone Marrow Transplant*. 2022;57(6):896-902.

40. Koenecke C, Eikema DJ, Hazelaar S, et al. 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. *Bone Marrow Transplant*. 2022;57(10):1607-1611.

41. Padron E, Garcia-Manero G, Patnaik MM, et al. An international data set for CMML validates prognostic scoring systems and demonstrates a need for novel prognostication strategies. *Blood Cancer J*. 2015;5: e333.

42. Kroger N, Eikema DJ, Koster L, et al. Impact of primary disease on outcome after allogeneic stem cell transplantation for transformed secondary acute leukaemia. *Br J Haematol*. 2019;185(4):725-732.

43. Germing U, Gattermann N, Minning H, Heyll A, Aul C. Problems in the classification of CMML-dysplastic versus proliferative type. *Leuk Res*. 1998;22(10):871-878.

44. Sroror ML, Maris MB, Storb R, et al. Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT. *Blood*. 2005;106(8):2912-2919.

45. R CoreTeam. A Language and Environment for Statistical Computing. R: Foundation for Statistical Computing, https://wwwR-project.org/; 2022.

46. Kongtim P, Popat U, Jimenez A, et al. Treatment with hypomethylating agents before allogeneic stem cell transplant improves progression-free survival for patients with chronic myelomonocytic leukemia. *Biol Blood Marrow Transplant*. 2016;22(1):47-53.

47. Itonaga H, Aoki K, Aoki J, et al. Prognostic impact of donor source on allogeneic hematopoietic stem cell transplantation outcomes in adults with chronic myelomonocytic leukemia: a Nationwide retrospective analysis in Japan. *Biol Blood Marrow Transplant*. 2018;24(4):840-848.

48. Robin M, de Wreede LC, Padron E, et al. Role of allogeneic transplantation in chronic myelomonocytic leukemia: an international collaborative analysis. *Blood*. 2022;140(12):1408-1418.
49. Symeonidis A, van Biezen A, de Wreede L, et al. Achievement of complete remission predicts outcome of allogeneic haematopoietic stem cell transplantation in patients with chronic myelomonocytic leukaemia. A study of the chronic malignancies working Party of the European Group for blood and marrow transplantation. *Br J Haematol.* 2015;171(2):239-246.

50. Getta BM, Kishtagari A, Hilden P, et al. Allogeneic hematopoietic stem cell transplantation is underutilized in older patients with myelodysplastic syndromes. *Biol Blood Marrow Transplant.* 2017;23(7):1078-1086.

51. Heidenreich S, Ziagkos D, de Wreede LC, et al. Allogeneic stem cell transplantation for patients age >/= 70 years with myelodysplastic syndrome: a retrospective study of the MDS Subcommittee of the chronic malignancies working party of the EBMT. *Biol Blood Marrow Transplant.* 2017;23(1):44-52.

52. Kroger N, Sockel K, Wolschke C, et al. Comparison between 5-azacytidine treatment and allogeneic stem-cell transplantation in elderly patients with advanced MDS according to donor availability (VidazaAllo study). *J Clin Oncol.* 2021;39(30):3318-3327.

53. Zuanelli Brambilla C, Lobaugh SM, Ruiz JD, et al. Relapse after allogeneic stem cell transplantation of acute myelogenous leukemia and myelodysplastic syndrome and the importance of second cellular therapy. *Transplant Cell Ther.* 2021;27(9):771-e1-e10.

54. Boyiadzis M, Arora M, Klein JP, et al. Impact of chronic graft-versus-host disease on late relapse and survival on 7489 patients after myeloablative allogeneic hematopoietic cell transplantation for leukemia. *Clin Cancer Res.* 2015;21(9):2020-2028.

55. de Lima M, Oran B, Champlin RE, et al. CC-486 maintenance after stem cell transplantation in patients with acute myeloid leukemia or

myelodysplastic syndromes. *Biol Blood Marrow Transplant.* 2018;14(10):2017-2024.

56. Depil S, Deconinck E, Milpied N, et al. Donor lymphocyte infusion to treat relapse after allogeneic bone marrow transplantation for myelodysplastic syndrome. *Bone Marrow Transplant.* 2004;33(5):531-534.

57. Platzbecker U, Middeke JM, Sockel K, et al. Measurable residual disease-guided treatment with azacitidine to prevent haematological relapse in patients with myelodysplastic syndrome and acute myeloid leukaemia (RELAZA2): an open-label, multicentre, phase 2 trial. *Lancet Oncol.* 2018;19(12):1668-1679.

58. Rubinger L, Ekhtiari S, Gazendam A, Bhandari M. Registries: big data, bigger problems? *Injury.* 2023;54(Suppl 3):S39-S42.

59. Gliklich RE, Leavy MB, Dreyer NA, eds. *Registries for Evaluating Patient Outcomes: A User's Guide.* 4th ed. AHRQ Methods for Effective Health Care; 2020.

## SUPPORTING INFORMATION

Additional supporting information can be found online in the Supporting Information section at the end of this article.

**How to cite this article:** Rovó A, Gras L, Piepenbroek B, et al. Outcomes of CMML patients undergoing allo-HCT are significantly worse compared to MDS—a study of the CMWP of the EBMT. *Am J Hematol.* 2024;99(2):203-215. doi:10.1002/ajh.27150