Thursday, June 8, 2023
| ICD cohort (n = 730) | EBMT cohort (n = 384) | |
|---|---|---|
| Year of diagnosis | 2008 (2004-2010) | 2011 (2008-2013) |
| Age at diagnosis, years | 64.0 (58.8-67.8) | 57.3 (51.0-61.9) |
| Sex | ||
| Male | 508 (69.6) | 266 (69.3) |
| Female | 222 (30.4) | 118 (30.7) |
| FAB subsets | ||
| CMML-MD | 348 (47.7) | 173 (45) |
| CMML-MP | 382 (52.3) | 211 (55) |
| WHO category* | ||
| CMML-1 | 582 (79.7) | 238 (62) |
| CMML-2 | 148 (20.3) | 146 (38) |
| Hemoglobin level | ||
| ≥10 gr/dl | 472 (64.7) | 235 (61.2) |
| <10 gr/dl | 258 (35.3) | 149 (38.8) |
| Cytogenetic risk† | ||
| Low | 498 (68.2) | 264 (68.7) |
| Intermediate | 113 (15.5) | 46 (12.0) |
| High | 119 (16.3) | 74 (19.3) |
| CPSS risk‡ | ||
| Low | 159 (21.8) | 61 (15.9) |
| Intermediate-1 | 227 (31.1) | 116 (30.2) |
| Intermediate-2 | 286 (39.2) | 162 (42.2) |
| High | 58 (7.9) | 45 (11.7) |
| Follow-up duration from diagnosis, months (median, 95% CI) | 51.06 (47.34-56.77) | 78.03 (67.61-84.07) |
| Underwent allo-HCT | 98 (13.4) | 384 (100) |
| Transformation to AML before allo-HCT | 33 (33.7)§ | 78 (20.3) |
Table 1. Patient characteristics and main events
Data are presented as median with interquartile range unless otherwise specified, or numbers and percentages.
CMML-MP, CMML-myeloproliferative; FAB, French-American-British.
* According to Vardiman et al.[21]
† According to Such et al.[23]
‡ According to Such et al.[22]
§ Percentage of transplanted patients.
| Covariates | Transition | Lower-risk CMML | Higher-risk CMML | ||
|---|---|---|---|---|---|
| HR (95% CI) | P | HR (95% CI) | P | ||
| AML vs diagnosis state | To death | 4.99 (3.23-7.72) | <.001 | 3.60 (2.51-5.16) | <.001 |
| Allo-HCT from AML vs from diagnosis | To death | 1.49 (0.86-2.59) | .159 | 1.19 (0.68-2.07) | .547 |
| AML vs diagnosis state | To allo- HCT | 8.34 (3.97-17.50) | <.001 | 5.48 (2.60-11.52) | <.001 |
| Female vs male | Diagnosis to AML | 0.78 (0.46-1.33) | .367 | 0.72 (0.47-1.11) | .135 |
| Age at diagnosis* | Diagnosis to AML | 1.07 (0.77-1.49) | .683 | 0.79 (0.66-0.94) | .008 |
| Female vs male | Diagnosis to allo-HCT | 1.11 (0.55-2.24) | .766 | 1.40 (0.68-2.89) | .359 |
| Age at diagnosis* | Diagnosis to allo-HCT | 0.47 (0.35-0.64) | <.001 | 0.60 (0.45-0.78) | <.001 |
| Female vs male | Diagnosis to death | 0.69 (0.45-1.05) | .082 | 0.73 (0.51-1.06) | .099 |
| Age at diagnosis* | Diagnosis to death | 1.14 (0.87-1.48) | .347 | 1.29 (1.01-1.64) | .045 |
| Female vs male | AML to allo-HCT | 0.44 (0.10-1.97) | .280 | 0.90 (0.32-2.53) | .844 |
| Age at diagnosis* | AML to allo-HCT | 0.64 (0.40-1.02) | .058 | 0.72 (0.51-1.01) | .056 |
| Female vs male | AML to death | 0.74 (0.37-1.46) | .383 | 0.87 (0.52-1.44) | .583 |
| Age at diagnosis* | AML to death | 1.15 (0.77-1.70) | .494 | 1.16 (0.88-1.52) | .289 |
| Female vs male | Allo-HCT (prior to AML) to death | 0.55 (0.33-0.93) | .025 | 1.24 (0.85-1.87) | .317 |
| Age at diagnosis* | Allo-HCT (prior to AML) to death | 1.17 (0.87-1.58) | .304 | 1.05 (0.87-1.26) | .625 |
| Female vs male | Allo-HCT (post-AML) to death | 0.54 (0.17-1.64) | .274 | 0.83 (0.31-2.22) | .708 |
| Age at diagnosis* | Allo-HCT (post-AML) to death | 1.83 (0.74-4.52) | .192 | 1.09 (0.67-1.79) | .729 |
Table 2. Transition-specific covariate effect estimates in the multistate model according to CMML risk at diagnosis
Because some pairs of transitions were assumed to be proportional, they share the same baseline hazard function. The relative difference of the hazards, within a pair, is expressed in terms of hazard ratio. For example, the hazard of death (without/before transplantation) after transformation to AML for lower-risk patients is estimated to be 5 times as high as the hazard of death without transformation to AML. Similarly, an effect of transformation to AML was estimated on the hazard of transplantation and the hazard of death after transplantation. Additionally, transition-specific age and sex effects were modeled. The same multistate model was estimated separately in lower- and higher-risk CMML patients as CPSS risk violated the proportional hazards assumption.
* Age by unit of 10 years.
| Hazard ratio | (95% CI) | P | |
|---|---|---|---|
| Patient sex: female vs male | .80 | (0.67-0.96) | .017 |
| Age at diagnosis* | .12 | (1.02-1.24) | .023 |
| Lower-risk patients | |||
| Td AML | .14 | (3.63-7.28) | <.001 |
| Td allo-HCT (without AML): 0-2 y | .19 | (2.30-4.42) | <.001 |
| Td allo-HCT (without AML): >2 y | .98 | (0.58-1.64) | .924 |
| Td allo-HCT (after AML): 0-2 y | .89 | (0.53-1.50) | .675 |
| Td allo-HCT (after AML): 2+ y | .20 | (0.0.07-0.56) | .002 |
| Higher-risk patients | |||
| Td AML | .68 | (2.74-4.92) | <.001 |
| Td allo-HCT (without AML): 0-2 y | .46 | (1.09-1.96) | .012 |
| Td allo-HCT (without AML): 2+ y | .60 | (0.34-1.08) | .089 |
| Td allo-HCT (after AML): 0-2 y | .45 | (0.28-0.73) | .001 |
| Td allo-HCT (after AML): 2+ y | .08 | (0.0.02-0.33) | .001 |
Table 3. Multivariable analysis of OS
Effect estimates from multivariable Cox proportional hazards model allowing different baseline hazards for lower and higher CPSS risk groups. The model was adjusted for age and sex. Transformation to AML and transplantation were included as time-dependent (Td) covariates. To overcome violations of the proportional hazards assumption, the effect of allo-HCT was split into an average short-/midterm effect covering the first 2 years after transplantation and an average long-term effect covering the period beyond 2 years after allo-HCT. The latter is estimated in patients who are alive at 2 years since allo-HCT
* Unit 10 years
Physicians - maximum of 1.00 AMA PRA Category 1 Credit(s)™
ABIM Diplomates - maximum of 1.00 ABIM MOC points
This activity is intended for hematologists, oncologists, internists, and other clinicians caring for patients with chronic myelomonocytic leukemia (CMML).
The goal of this activity is for learners to be better able to describe the survival benefit of allogeneic hematopoietic cell transplantation (allo-HCT) in CMML, according to a retrospective cohort study of patients with CMML aged 18 to 70 years diagnosed between 2000 and 2014.
Upon completion of this activity, participants will:
Medscape, LLC requires every individual in a position to control educational content to disclose all financial relationships with ineligible companies that have occurred within the past 24 months. Ineligible companies are organizations whose primary business is producing, marketing, selling, re-selling, or distributing healthcare products used by or on patients.
All relevant financial relationships for anyone with the ability to control the content of this educational activity are listed below and have been mitigated. Others involved in the planning of this activity have no relevant financial relationships.
Medscape, LLC designates this Journal-based CME activity for a maximum of 1.0
AMA PRA Category 1 Credit(s)™
. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to 1.0 MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program. Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting ABIM MOC credit.
For questions regarding the content of this activity, contact the accredited provider for this CME/CE activity noted above. For technical assistance, contact [email protected]
There are no fees for participating in or receiving credit for this online educational activity. For information on applicability
and acceptance of continuing education credit for this activity, please consult your professional licensing board.
This activity is designed to be completed within the time designated on the title page; physicians should claim only those
credits that reflect the time actually spent in the activity. To successfully earn credit, participants must complete the
activity online during the valid credit period that is noted on the title page. To receive AMA PRA Category 1 Credit™, you must receive a minimum score of 70% on the post-test.
Follow these steps to earn CME/CE credit*:
You may now view or print the certificate from your CME/CE Tracker. You may print the certificate, but you cannot alter it.
Credits will be tallied in your CME/CE Tracker and archived for 6 years; at any point within this time period, you can print
out the tally as well as the certificates from the CME/CE Tracker.
*The credit that you receive is based on your user profile.
CME / ABIM MOC Released: 9/22/2022
Valid for credit through: 9/22/2023
processing....
To determine the survival benefit of allogeneic hematopoietic cell transplantation (allo-HCT) in chronic myelomonocytic leukemias (CMML), we assembled a retrospective cohort of CMML patients 18-70 years old diagnosed between 2000 and 2014 from an international CMML dataset (n = 730) and the EBMT registry (n = 384). The prognostic impact of allo-HCT was analyzed through univariable and multivariable time-dependent models and with a multistate model, accounting for age, sex, CMML prognostic scoring system (low or intermediate-1 grouped as lower-risk, intermediate-2 or high as higher-risk) at diagnosis, and AML transformation. In univariable analysis, lower-risk CMMLs had a 5-year overall survival (OS) of 20% with allo-HCT vs 42% without allo-HCT (P < .001). In higher-risk patients, 5-year OS was 27% with allo-HCT vs 15% without allo-HCT (P = .13). With multistate models, performing allo-HCT before AML transformation reduced OS in patients with lower-risk CMML, and a survival benefit was predicted for men with higher-risk CMML. In a multivariable analysis of lower-risk patients, performing allo-HCT before transformation to AML significantly increased the risk of death within 2 years of transplantation (hazard ratio [HR], 3.19; P < .001), with no significant change in long-term survival beyond this time point (HR, 0.98; P = .92). In higher-risk patients, allo-HCT significantly increased the risk of death in the first 2 years after transplant (HR 1.46; P = .01) but not beyond (HR, 0.60; P = .09). Performing allo-HCT before AML transformation decreases life expectancy in lower-risk patients but may be considered in higher-risk patients.
Chronic myelomonocytic leukemia (CMML) is a rare disease predominantly affecting men, with a median age of 75 years at diagnosis. The prognosis remains unsatisfactory, with median overall survival (OS) of 30 to 36 months.[1-5] Allogeneic hematopoietic cell transplantation (allo-HCT) is the only treatment recognized as potentially curative in CMML.[6-12] However, allo-HCT in CMML patients is associated with a 20% to 50% 3-year nonrelapse mortality and a 25% to 60% cumulative incidence of relapse.[6-12] The benefit of upfront allo-HCT over a nontransplant treatment thus remains questionable. Because CMML is a rare disease, transplantation indications and procedures are largely extrapolated from myelodysplastic syndromes (MDSs) or classical myeloproliferative neoplasms. In MDS, a first study reported that higher-risk patients had a survival benefit when transplanted upfront.[13] More recent studies including prospective comparisons between allo-HCT and hypomethylating agents confirmed this finding.[14-17] In CMML where the benefit of hypomethylating agents is less established,[18,19] the question of transplantation is only relevant in the minority of patients young and fit enough for transplantation. Among patients younger than 65 years, Patnaik et al reported that 20% of them underwent transplantation, but the benefit of allo-HCT could not be analyzed in this series.[20]
The current study leverages the international CMML dataset (ICD)[5] and the EBMT registry,[9] applying statistical models taking into account timing of allo-HCT to study the role of allo-HCT in survival of CMML patients. This study, based on 2 large international cohorts, represents the first multicentric transplantation decision analysis in CMML.
