Abstract
Patients who develop therapy-related myeloid neoplasm, either myelodysplastic syndrome (t-MDS) or acute myeloid leukemia (t-AML) have a poor prognosis. An earlier CIBMTR analysis of allogeneic hematopoietic cell therapy (allo-HCT) (n=868, 1990–2004) showed 5-year overall survival (OS) and disease-free survival (DFS) of 22% and 21%.
Modern supportive care, graft versus host disease (GVHD) prophylaxis and reduced intensity conditioning (RIC) regimens have improved outcomes. Therefore, the Center for International Blood and Marrow Transplant Research (CIBMTR) analyzed 1531 allo-HCT for adults with t-MDS (n = 759) or t-AML (n = 772) performed from 2000 to 2014. Median age was 59 years (18–74) for t-MDS and 52 years (18–77) for t-AML. 24% of patient with t-MDS and 11% of patients with t-AML and had a prior autologous transplant. A myeloablative regimen was used in 49% of patients with t-MDS and 61% of patients with t-AML.
Non-relapse mortality (NRM) at five years was 34% (95% confidence interval (CI) 30–37) and 34% (30–37) for t-MDS and t-AML, respectively. Relapse rates at five years were 46% (43–50) and 43% (40–47), respectively. 5-year OS and DFS was 27% (23–31) and 19% (16–23) for patients with t-MDS and 25% (22–28) and 23% (20–26) for patients with t-AML.
In multivariate analysis, OS and DFS were significantly better in young patients with low risk t-MDS and those receiving MAC HCT during first complete remission (CR1) t-AML, but worse for those with prior autologous HCT, higher risk cytogenetics or IPSS-R score and partially matched unrelated donors (URD). Relapse remains the major cause of treatment failure with little improvement over the past two decades. These data indicate caution in recommending allo-HCT in these conditions and more effective anti-neoplastic approaches before and after allo-HCT.
Keywords: Allogeneic Transplant, Acute Myeloid Leukemia, Myelodysplasia
Introduction
Survival has improved for a wide variety of cancer patients with a subsequent increase in the worldwide prevalence of chemotherapy survivors1. This success has created more individuals at risk for therapy related myeloid neoplasms, including treatment related myelodysplasia (t-MDS), which accounts for 7–12% of MDS, and treatment related acute myeloid leukemia (t-AML) which accounts for 5–10% of AML2–4. There are two well-recognized unfavorable karyotypic patterns of t-MDS/t-AML: 5q and 7q deletions following alkylating agents and those with rearrangements of the MLL/KMT2A gene following topoisomerase inhibitors5–7. Still, even the small population of patients with therapy related myeloid neoplasms harboring favorable cytogenetics t(8;21), t(15;17), and inv(16) experience far worse survival than those with favorable cytogenetics without prior chemotherapy8–10.
One group at particularly high risk for the development of t-MDS/t-AML is recipients of myeloablative conditioning and autologous hematopoietic cell transplantation (auto-HCT) for myeloma, lymphoma, or solid tumors11–13. In a meta-analysis of secondary cancers following auto-HCT compared to other therapies, there was a higher incidence of t-MDS/t-AML in patients who underwent auto-HCT14.
Median survival for patients with t-MDS/t-AML who undergo standard chemotherapy is 7–12 months15,16. Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative treatment option, but retrospective analyses have shown that, in general, outcomes are quite poor with limited factors identifying patients who have a better chance of longer-term survival17–21. Litzow et al analyzed the outcomes of allo-HCT in 868 patients with t-MDS/t-AML reported to the the Center for International Blood and Marrow Transplant Research (CIBMTR) and transplanted between 1990 and 2004. The 5-year overall survival (OS) and disease-free survival (DFS) were 22% and 21%, respectively. Poorer OS and DFS were associated with older age, graft source other than a HLA-matched sibling or HLA well matched unrelated donor (URD), t-AML not in remission, advanced t-MDS, or poor risk cytogenetics18.
Here we analyze more contemporary data from the CIBMTR, evaluating the risks of allogeneic transplantation for t-MDS/t-AML, including a subgroup with prior autologous transplantation.
Methods
Data Source
The CIBMTR collects data from more than 450 transplantation centers worldwide. The CIBMTR transplant registry collects transplant essential data as well as comprehensive patient, disease, and other clinical information pre- and post- stem transplantation using CIBMTR data collection forms. Data are collected pre-HCT, 100 days post-HCT, 6 months post-HCT, and annually thereafter.
Inclusion Criteria
The study included all adult (age ≥ 18 years) patients who received their first allo-HCT for t-MDS or t-AML between January 1, 2000, and December 31, 2014. Patients received prior cytotoxic chemotherapy and/or radiation and were reported with a diagnosis of t-MDS or t-AML. Patients without consent or incomplete research forms were excluded (n=48). Recipients of syngeneic transplants, those transplanted for AML in CR2 or beyond, or who had previous myeloid malignancies were also excluded. Patients with primary induction failure (PIF) and AML in relapse were included. PIF was defined as never achieving remission at any time. Relapse was defined as recurrence of disease after CR. Patient who underwent haplo-identical or haplo-cord transplants were excluded due to low numbers. Consent procedures for data collection and analysis were approved by the Institutional Review Board at the National Marrow Donor Program and the Medical College of Wisconsin for the CIBMTR.
AML risk was assigned according to the cytogenetic classification of the 2017 European Leukemia Net (ELN) recommendations22. Molecular data was not available for the majority of t-AML subjects. MDS risk was classified based upon the Revised International Prognostic Scoring System (IPSS-R)23. Comorbidity index (HCT-CI) data was not collected prior to 2007.
Endpoints
Overall Survival (OS):
Time to death from any cause. Surviving patients were censored at last contact alive. Disease free survival (DFS): Time to disease relapse or death from any cause. Surviving patients in continuous complete remission were censored at last contact. Relapse: Development of relapse from any evidence (including clinical, flow cytometry, cytogenetic and molecular). Death in remission is a competing risk. Non-relapse mortality (NRM): death in remission with relapse as a competing risk. Acute graft versus host disease (GVHD): Occurrence of grade II-IV skin, gastrointestinal or liver abnormalities fulfilling the Consensus criteria for acute GVHD24. Death without acute GVHD is a competing risk. Chronic GVHD: Occurrence of symptoms in any organ system fulfilling the diagnostic criteria of chronic GVHD. Death without chronic GVHD is a competing risk.
Statistical Analysis
Cumulative incidence function was used to estimate relapse, NRM, acute and chronic GVHD. Kaplan-Meier estimate was used to calculate probabilities of OS and DFS.
Cox proportional hazards regression model was used to estimate hazard ratio (HR) of patient / disease / transplant related factors for outcomes of interest. The covariates considered in the Cox models included recipient age at HCT, KPS at HCT, disease status, previous auto-HCT, type of previous therapy, graft type, donor type, conditioning intensity and cytogenetic risk group. The assumption of proportional hazards for each covariate in the Cox model was tested. When the test indicated differential effects over time (non-proportional hazards), models were constructed breaking the post-HCT time course into two periods, using the maximized partial likelihood method to find the most appropriate breakpoint. A backward stepwise model selection approach was used to identify all significant risk factors. Factors which were significant at a 5% level were kept in the final model. All analyses were performed separately for t-MDS and t-AML.
Results
Patients
A total of 1531 patients from 159 reporting centers with t-MDS/t-AML who were treated with allo-HCT between 2000 and 2014 met the inclusion criteria. There was a 20% overlap in this population with the previous analysis by Litzow et al18. Patient characteristics are described in Table 1. The median age for patients with t-MDS and t-AML were 59 (range, 18–74) and 52 (range, 18–77), respectively. Previous malignancies included Hodgkin lymphoma (t-MDS, 8%; t-AML, 10%) Non-Hodgkin lymphoma (t-MDS, 35%; t-AML, 20%), breast cancer (t-MDS, 17%; t-AML, 33%), other solid tumors (t-MDS, 14%; t-AML, 20%), and myeloma (t-MDS, 4%; t-AML, 3%). The median time from previous disease to diagnosis of t-MDS or t-AML was 75 and 48 months, respectively. Twenty-four percent of t-MDS patients had a prior auto-HCT, while 11% of t-AML patients had a prior auto-HCT. Fifty-seven percent of patients with t-MDS and 56% of patients with t-AML had KPS ≥ 90. There was a substantial percentage of patients missing HCT-CI scores (43.6%). Of those with available data, 95% had a HCT-CI ≥ 3.
Table 1:
Patient characteristics who underwent first allogeneic HCT for therapy related MDS or AML registered with CIBMTR between years 2000 and 2014.
| Characteristic | t-AML | t-MDS | Total |
|---|---|---|---|
| No. of patients | 772 | 759 | 1531 |
| No. of centers | 159 | 137 | 185 |
| Patient age at HCT - no. (%) | |||
| Median (min-max) | 52.4 (18.2–76.9) | 58.6 (18–74.2) | 56 (18–76.9) |
| 18–39 | 155 (20.1) | 89 (11.7) | 244 (15.9) |
| 40–49 | 190 (24.6) | 80 (10.5) | 270 (17.6) |
| 50–59 | 236 (30.6) | 266 (35) | 502 (32.8) |
| 60–69 | 169 (21.9) | 289 (38.1) | 458 (29.9) |
| ≥70 | 22 (2.8) | 35 (4.6) | 57 (3.7) |
| Gender - no. (%) | |||
| Male | 282 (36.5) | 398 (52.4) | 680 (44.4) |
| Female | 490 (63.5) | 361 (47.6) | 851 (55.6) |
| Race - no. (%) | |||
| Caucasian | 680 (88.1) | 696 (91.7) | 1376 (89.9) |
| African-American | 31 (4) | 32 (4.2) | 63 (4.1) |
| Asian | 36 (4.7) | 19 (2.5) | 55 (3.6) |
| Pacific islander | 2 (0.3) | 0 | 2 (0.1) |
| Native American | 3 (0.4) | 0 | 3 (0.2) |
| Other / Missing | 20 (2.6) | 12 (1.5) | 32 (2.1) |
| Ethnicity - no. (%) | |||
| Hispanic or Latino | 50 (6.5) | 39 (5.1) | 89 (5.8) |
| Non Hispanic or non-Latino | 596 (77.2) | 643 (84.7) | 1239 (80.9) |
| Non-resident of the U.S. | 47 (6.1) | 25 (3.3) | 72 (4.7) |
| Missing | 79 (10.2) | 52 (6.9) | 131 (8.6) |
| Karnofsky score - no. (%) | |||
| <90 | 303 (39.2) | 295 (38.9) | 598 (39.1) |
| ≥90 | 429 (55.6) | 430 (56.7) | 859 (56.1) |
| Missing | 40 (5.2) | 34 (4.5) | 74 (4.8) |
| HCT-CI - no. (%) | |||
| 0 | 4 (0.5) | 14 (1.8) | 18 (1.2) |
| 1–2 | 9 (1.2) | 12 (1.6) | 21 (1.4) |
| 3+ | 321 (41.6) | 503 (66.3) | 824 (53.8) |
| NA (data not collected prior to 2007) | 438 (56.7) | 230 (30.3) | 668 (43.6) |
| Disease status prior to HCT, for AML - no. (%) | |||
| CR1 | 519 (67.2) | ||
| PIF | 167 (21.6) | ||
| Relapse | 86 (11.1) | ||
| Cytogenetic score ELN for AML - no. (%) | |||
| Favorable | 45 (5.8) | ||
| Intermediate | 328 (42.5) | ||
| Poor | 300 (38.9) | ||
| APL | 7 (0.9) | ||
| Missing | 92 (11.9) | ||
| IPSS-R prior to HCT - no. (%) | |||
| Very low | 34 (4.5) | ||
| Low | 104 (13.7) | ||
| Intermediate | 176 (23.2) | ||
| High | 166 (21.9) | ||
| Very high | 125 (16.5) | ||
| Missing | 154 (20.3) | ||
| Previous therapy related disease - no. (%) | |||
| Lymphoid (Hodgkin and Non-Hodgkin) | 234 (30.3) | 320 (42.1) | 702 (45.8) |
| Breast cancer | 252 (32.6) | 130 (17.1) | 382 (25) |
| Aplastic anemia | 8 (1) | 41 (5.4) | 49 (3.2) |
| Multiple Myeloma | 23 (3) | 28 (3.7) | 51 (3.3) |
| Solid tumor (excluding breast cancer) | 153 (19.8) | 104 (13.7) | 257 (16.8) |
| Autoimmune Disease / Other | 51 (6.7) | 39 (5.2) | 90 (5.9) |
| Therapy for previous disease - no. (%) | |||
| Chemotherapy | 293 (38) | 295 (38.9) | 588 (38.4) |
| Chemotherapy + radiation | 307 (39.8) | 204 (26.9) | 511 (33.4) |
| Radiation alone | 25 (3.2) | 17 (2.2) | 42 (2.7) |
| Auto HCT | 85 (11) | 181 (23.8) | 266 (17.4) |
| Other | 62 (8) | 62 (8.2) | 124 (8.1) |
| Donor Type - no. (%) | |||
| HLA-identical sibling | 210 (27.2) | 214 (28.2) | 424 (27.7) |
| Well-matched unrelated (8/8) | 318 (41.2) | 383 (50.5) | 701 (45.8) |
| Partially-matched unrelated (7/8) | 122 (15.8) | 90 (11.9) | 212 (13.8) |
| Mis-matched unrelated (≤6/8) | 26 (3.4) | 12 (1.6) | 38 (2.5) |
| Unrelated (matching unknown) | 6 (0.8) | 8 (1.1) | 14 (0.9) |
| Cord blood | 90 (11.7) | 52 (6.9) | 142 (9.3) |
| Graft type - no. (%) | |||
| Bone marrow | 139 (18) | 122 (16.1) | 261 (17) |
| Peripheral blood | 543 (70.3) | 585 (77.1) | 1128 (73.7) |
| Cord blood | 90 (11.7) | 52 (6.9) | 142 (9.3) |
| Conditioning regimen - no. (%) | |||
| MAC | |||
| Busulfan-based | 294 (38.1) | 271 (35.7) | 565 (36.9) |
| Melphalan-based | 14 (1.8) | 16 (2.1) | 30 (2) |
| Other + TBI | 151 (19.6) | 82 (10.8) | 233 (15.2) |
| Missing | 8 (1) | 3 (0.4) | 11 (0.7) |
| RIC/NMA | |||
| Busulfan-based | 92 (11.9) | 158 (20.8) | 250 (16.3) |
| Melphalan-based | 99 (12.8) | 117 (15.4) | 216 (14.1) |
| Other + TBI | 103 (13.3) | 107 (14.1) | 210 (13.7) |
| Missing | 1 (0.1) | 5 (0.7) | 6 (0.4) |
| Missing | |||
| Missing | 10 (1.3) | 0 | 10 (0.7) |
| GVHD prophylaxis - no. (%) | |||
| Ex vivo TCD / CD34 selection | 41 (5.3) | 26 (3.4) | 67 (4.4) |
| CNI + MTX + - other | 223 (28.9) | 231 (30.4) | 454 (29.7) |
| CNI + MMF + - other | 390 (50.5) | 383 (50.5) | 773 (50.5) |
| CNI + - other | 45 (5.8) | 52 (6.9) | 97 (6.3) |
| CNI alone | 47 (6.1) | 31 (4.1) | 78 (5.1) |
| Other GVHD prophylaxis | 15 (1.9) | 30 (4) | 45 (2.9) |
| Missing | 11 (1.4) | 6 (0.8) | 17 (1.1) |
| (ATG/Alemtuzumab) for conditioning regimen or GVHD prophylaxis - no. (%) | |||
| Yes(ATG/Alemtuzumab) | 258 (33.4) | 276 (36.4) | 534 (34.9) |
| No | 507 (65.7) | 482 (63.5) | 989 (64.6) |
| Missing | 7 (0.9) | 1 (0.1) | 8 (0.5) |
| Year of transplant - no. (%) | |||
| 2000–2002 | 105 (13.6) | 66 (8.7) | 171 (11.2) |
| 2003–2005 | 187 (24.2) | 87 (11.5) | 274 (17.9) |
| 2006–2008 | 216 (28) | 106 (14) | 322 (21) |
| 2009–2011 | 149 (19.3) | 195 (25.7) | 344 (22.5) |
| 2012–2014 | 115 (14.9) | 305 (40.2) | 420 (27.4) |
| Follow-up - median (min-max) | 73.82 (3.19–192.5) | 52.86 (3.13–170.2) | 69.28 (3.13–192.5) |
HCT, hematopoietic stem cell transplantation; MDS, myelodysplastic syndrome; AML, acute myeloid leukemia; CIBMTR, Center for International Bone Marrow Transplantation Research; t-AML, treatment associated acute myeloid leukemia; t-MDS, treatment related myelodysplasia; HCT-CI, hematopoietic stem cell transplantation comorbidity index, IPSS-R, Revised International Prognostic Scoring System; CLL, chronic lymphocytic leukemia; ALL, acute lymphocytic leukemia; HLA, human leukocyte antigen; MAC, myeloablative conditioning; RIC, reduced intensity conditioning; NMA, non-myeloablative conditioning; GVHD, graft versus host disease; TCD, T-cell depletion; ATG, anti-thymocyte globulin; MTX, methotrexate; CNI, calcineurin inhibitors; MMF, mycophenolate mofeti; PIF, primary induction failure; CR, complete remission; ELN, European Leukemia Network; TBI, total body irradiation.
For patients with t-MDS, 18% had either very low or low risk IPSS-R scores. Nineteen percent of patients with t-MDS previously received azacitidine or decitabine; 32% had induction chemotherapy and 37% had no therapy between t-MDS diagnosis and allo-HCT. For patients with t-AML 6% had favorable risk, 44% had intermediate risk, and 37% had poor risk cytogenetics. Sixty percent of patients with t-AML received induction chemotherapy and 29% received consolidation before allo-HCT. At the time of transplant, 67% of t-AML patients were in CR1.
Preparative regimen intensity (per Bacigalupo et al20) were either myeloablative (MAC) (t-MDS, 49%; t-AML, 61%) or reduced intensity / non-myeloablative (RIC/NMA) (t-MDS, 50%; t-AML, 39%). Amongst those with prior autologous HCT, most received RIC/NMA conditioning (t-MDS, 65%; t-AML, 57%). The majority of patients received an HLA-matched (8/8) sibling or unrelated donor (URD) graft. Peripheral blood grafts were used for 77% of patients with t-MDS and in 70% with t-AML.
The median follow up for t-MDS and t-AML survivors was 53 (range, 3–170) and 74 months (range, 3–193), respectively.
Non-Relapse Mortality
The univariate analysis in Table 2 shows the key study outcomes. For patients with t-MDS, the NRM was 24% and 34% at 1 and 5 years post-transplant (Table 2). In univariate analysis, patients who underwent RIC/NMA had lower NRM at 1 year than those who underwent MAC, however at 5 years there was no difference in NRM between RIC/NMA and MAC cohorts (Table 3). Multivariate analysis identified mis-matched URD grafts (HR 2.80 (1.21–6.49), p = 0.02) to be associated with higher NRM for patients with t-MDS (Table 5a).
Table 2:
Univariate analysis of outcomes.
| t-AML (N = 772) | t-MDS (N = 759) | |||
|---|---|---|---|---|
| Outcomes | N | Prob (95% CI) | N | Prob (95% CI) |
| Non-relapse mortality | 755 | 742 | ||
| 1-year | 283 | 24.5 (21.5–27.7)% | 274 | 24.3 (21.3–27.5)% |
| 5-year | 128 | 33.6 (30.2–37.1)% | 81 | 33.7 (30.2–37.3)% |
| Relapse | 755 | 742 | ||
| 1-year | 283 | 37.1 (33.6–40.6)% | 274 | 38.6 (35.2–42.2)% |
| 5-year | 128 | 43.2 (39.6–46.8)% | 81 | 46.2 (42.5–49.9)% |
| Disease free survival | 755 | 742 | ||
| 1-year | 281 | 38.4 (35–41.9)% | 272 | 36.9 (33.5–40.4)% |
| 5-year | 127 | 22.8 (19.8–26)% | 81 | 19.4 (16.4–22.6)% |
| Overall survival | 772 | 759 | ||
| 1-year | 342 | 46 (42.5–49.5)% | 375 | 50.1 (46.5–53.6)% |
| 5-year | 137 | 25 (21.9–28.3)% | 92 | 26.9 (23.4–30.5)% |
t-AML, treatment associated acute myeloid leukemia; t-MDS, treatment related myelodysplasia; GVHD, graft versus host disease; CI, confidence interval; Prob, probability; N, number.
Table 3:
Univariate analysis of outcomes for t-MDS based on conditioning intensity.
| MAC (N = 372) | RIC/NMA (N = 387) | ||||
|---|---|---|---|---|---|
| Outcomes | N | Prob (95% CI) | N | Prob (95% CI) | P Value |
| Non-relapse mortality | 359 | 383 | 0.290 | ||
| 1-year | 132 | 28.1 (23.6–32.9)% | 142 | 20.7 (16.8–24.9)% | 0.019 |
| 5-year | 48 | 35 (30–40.2)% | 34 | 32.7 (27.8–37.9)% | 0.534 |
| Relapse | 359 | 383 | 0.054 | ||
| 1-year | 132 | 35.1 (30.2–40.1)% | 142 | 41.9 (37–46.9)% | 0.056 |
| 5-year | 48 | 42.5 (37.3–47.8)% | 34 | 49.7 (44.5–55)% | 0.055 |
| Disease free survival | 359 | 383 | 0.632 | ||
| 1-year | 131 | 36.5 (31.6–41.5)% | 141 | 37.4 (32.6–42.3)% | 0.807 |
| 5-year | 48 | 21.6 (17.3–26.2)% | 34 | 17.1 (13–21.5)% | 0.152 |
t-MDS, treatment related myelodysplasia; CI, confidence interval; Prob, probability; N, number; MAC, myeloablative conditioning; RIC, reduced intensity conditioning; NMA, non-myeloablative conditioning.
Table 5a.
Multivariate analysis of outcomes for t-MDS.
| Outcomes | N | HR (95% CI) | p-value |
|---|---|---|---|
| Non-Relapse Mortality | |||
| Type of donor | 0.03 | ||
| HLA-identical sibling | 212 | Reference | |
| Well-matched unrelated (8/8) | 373 | 1.06 (0.78–1.44) | 0.73 |
| Partially-matched unrelated (7/8) | 88 | 1.28 (0.84–1.96) | 0.25 |
| Mis-matched unrelated (<=6/8) | 11 | 2.80 (1.21–6.49) | 0.02 |
| Unrelated (matching unknown) | 8 | 3.12 (1.13–8.59) | 0.03 |
| Cord blood | 50 | 1.51 (0.91–2.50) | 0.11 |
| Relapse | |||
| Age | < 0.001 | ||
| 18–60 | 424 | Reference | |
| 60+ | 318 | 1.56 (1.25–1.94) | < 0.001 |
| Prior auto-HCT | < 0.001 | ||
| No | 564 | Reference | |
| Yes | 178 | 1.58 (1.25–2.01) | < 0.001 |
| IPSS-R | < 0.001 | ||
| Low/very low | 136 | Reference | |
| Intermediate | 171 | 1.04 (0.73–1.49) | 0.83 |
| High | 165 | 1.20 (0.85–1.70) | 0.30 |
| Very high | 122 | 1.98 (1.39–2.81) | < 0.001 |
| Missing | 148 | 1.08 (0.75–1.56) | 0.67 |
| Disease-Free Survival | |||
| Age | < 0.001 | ||
| 18–60 | 424 | Reference | |
| 60+ | 318 | 1.41 (1.20–1.67) | < 0.001 |
| Prior auto-HCT | 0.010 | ||
| No | 564 | Reference | |
| Yes | 178 | 1.28 (1.06–1.54) | 0.010 |
| IPSS-R | 0.003 | ||
| Low/very low | 136 | Reference | |
| Intermediate | 171 | 1.24 (0.96–1.60) | 0.10 |
| High | 165 | 1.12 (0.86–1.46) | 0.39 |
| Very high | 122 | 1.66 (1.26–2.19) | < 0.001 |
| Missing | 148 | 1.12 (0.85–1.47) | 0.41 |
| Overall Survival | |||
| Age | 0.001 | ||
| 18–60 | 435 | Reference | |
| 60+ | 324 | 1.33 (1.12–1.59) | 0.001 |
| Type of donor | 0.002 | ||
| HLA-identical sibling | 214 | Reference | |
| Well-matched unrelated (8/8) | 383 | 0.98 (0.80–1.21) | 0.88 |
| Partially-matched unrelated (7/8) | 90 | 1.13 (0.84–1.52) | 0.44 |
| Mis-matched unrelated (<=6/8) | 12 | 2.78 (1.53–5.07) | < 0.001 |
| Unrelated (matching unknown) | 8 | 2.41 (1.12–5.20) | 0.02 |
| Cord blood | 52 | 1.24 (0.86–1.78) | 0.25 |
| IPSS-R | < 0.001 | ||
| Low/very low | 138 | Reference | |
| Intermediate | 176 | 1.32 (1.00–1.74) | 0.05 |
| High | 166 | 1.17 (0.88–1.56) | 0.27 |
| Very high | 125 | 1.81 (1.35–2.41) | < 0.001 |
| Missing | 154 | 1.17 (0.88–1.56) | 0.28 |
t-MDS, treatment related myelodysplasia; CI, confidence interval; Prob, probability; N, number; MAC, myeloablative conditioning; RIC, reduced intensity conditioning; NMA, non-myeloablative conditioning.
For patients with t-AML, the TRM was 25% and 34% at 1 and 5 years post-transplant (Table 2). In univariate analysis, there was no difference in NRM between patients receiving MAC or RIC/NMA (Table 4b). For patients with t-AML, multivariate analysis identified higher NRM in those with KPS < 90 with (HR 1.53 (1.19–1.98), p<0.001), prior autologous HCT, use of cord blood or partially matched URD (Table 5b). Patients transplanted in PIF has a 5-year TRM of 31%.
Table 4b.
Univariate analysis of outcomes for t-AML based on conditioning intensity.
| MAC (N = 467) | RIC/NMA (N = 295) | ||||
|---|---|---|---|---|---|
| Outcomes | N | Prob (95% CI) | N | Prob (95% CI) | P Value |
| Non-relapse mortality | 460 | 285 | 0.737 | ||
| 1-year | 180 | 25.4 (21.5–29.5)% | 99 | 23.5 (18.8–28.6)% | 0.552 |
| 5-year | 89 | 33.6 (29.2–38.1)% | 38 | 34.1 (28.5–39.8)% | 0.898 |
| Relapse | 460 | 285 | 0.023 | ||
| 1-year | 180 | 33.9 (29.6–38.3)% | 99 | 41.8 (36.1–47.5)% | 0.032 |
| 5-year | 89 | 39.9 (35.4–44.5)% | 38 | 47.8 (42–53.7)% | 0.037 |
| Disease free survival | 460 | 285 | 0.044 | ||
| 1-year | 179 | 40.7 (36.2–45.3)% | 98 | 34.7 (29.3–40.4)% | 0.101 |
| 5-year | 88 | 26.1 (22–30.3)% | 37 | 17.7 (13.3–22.6)% | 0.008 |
t-AML, treatment associated acute myeloid leukemia; HCT, hematopoietic cell transplantation; MAC, myeloablative conditioning; RIC, reduced intensity conditioning; NMA, non-myeloablative conditioning; CI, confidence interval; Prob, probability; N, number.
Table 5b.
Multivariate analysis of outcomes for t-AML.
| Outcomes | N | HR (95% CI) | p-value |
|---|---|---|---|
| Non-Relapse Mortality | |||
| KPS | 0.005 | ||
| >=90 | 419 | Reference | |
| <90 | 296 | 1.53 (1.19–1.98) | 0.001 |
| Missing | 40 | 1.28 (0.75–2.19) | 0.37 |
| Prior auto-HCT | 0.001 | ||
| No | 676 | Reference | |
| Yes | 79 | 1.86 (1.28–2.71) | 0.001 |
| Type of donor | < 0.001 | ||
| HLA-identical sibling | 203 | Reference | |
| Well-matched unrelated (8/8) | 314 | 1.18 (0.85–1.65) | 0.32 |
| Partially-matched unrelated (7/8) | 120 | 1.90 (1.31–2.75) | < 0.001 |
| Mis-matched unrelated (<=6/8) | 25 | 1.87 (0.92–3.81) | 0.09 |
| Unrelated (matching unknown) | 6 | 0.74 (0.10–5.35) | 0.76 |
| Cord blood | 87 | 2.52 (1.68–3.76) | < 0.001 |
| Relapse | |||
| Conditioning intensity | 0.008 | ||
| MAC | 460 | Reference | |
| RIC/NMA | 285 | 1.39 (1.11–1.74) | 0.004 |
| Disease status / cytogenetics | < 0.001 | ||
| CR1, favorable | 31 | Reference | |
| CR1, intermediate | 229 | 2.26 (0.91–5.60) | 0.08 |
| CR1, adverse | 200 | 3.78 (1.53–9.33) | 0.004 |
| PIF | 248 | 8.40 (3.44–20.5) | < 0.001 |
| CR1, missing cytogenetics | 47 | 2.11 (0.75–5.92) | 0.16 |
| Disease-Free Survival | |||
| KPS | < 0.001 | ||
| >=90 | 419 | Reference | |
| <90 | 296 | 1.39 (1.17–1.65) | < 0.001 |
| Missing | 40 | 1.05 (0.72–1.54) | 0.79 |
| Prior auto-HCT | 0.008 | ||
| No | 676 | Reference | |
| Yes | 79 | 1.40 (1.09–1.81) | 0.008 |
| Conditioning intensity | 0.02 | ||
| MAC | 460 | Reference | |
| RIC/NMA | 285 | 1.26 (1.07–1.49) | 0.006 |
| Disease status / cytogenetics | < 0.001 | ||
| CR1, favorable | 31 | Reference | |
| CR1, intermediate | 229 | 2.22 (1.23–4.01) | 0.008 |
| CR1, adverse | 200 | 3.23 (1.79–5.81) | < 0.001 |
| PIF | 248 | 5.47 (3.05–9.81) | < 0.001 |
| CR1, missing cytogenetics | 47 | 2.93 (1.54–5.60) | 0.001 |
| Overall Survival | |||
| KPS | < 0.001 | ||
| >=90 | 429 | Reference | |
| <90 | 303 | 1.44 (1.21–1.72) | < 0.001 |
| Missing | 40 | 1.17 (0.79–1.71) | 0.43 |
| Graft type | 0.02 | ||
| Bone marrow | 139 | Reference | |
| Peripheral blood | 543 | 0.82 (0.66–1.02) | 0.08 |
| Cord blood | 90 | 1.13 (0.84–1.53) | 0.42 |
| Disease status / cytogenetics | < 0.001 | ||
| CR1, favorable | 31 | Reference | |
| CR1, intermediate | 237 | 2.27 (1.23–4.20) | 0.009 |
| CR1, adverse | 204 | 3.20 (1.73–5.91) | < 0.001 |
| PIF | 253 | 5.41 (2.95–9.92) | < 0.001 |
| CR1, missing cytogenetics | 47 | 3.24 (1.65–6.37) | < 0.001 |
t-AML, treatment associated acute myeloid leukemia; CR1, first complete remission; PIF, primary induction failure; HCT, hematopoietic cell transplantation; MAC, myeloablative conditioning; RIC, reduced intensity conditioning; NMA, non-myeloablative conditioning; CI, confidence interval; Prob, probability; N, number.
The most common causes of death beyond relapse of the primary disease were infection (15%), organ failure (11%), and GVHD (10%) (suppl. Table 1).
Graft Versus Host Disease
Rates of aGVHD or cGVHD were similar in patients with t-MDS and t-AML. For t-AML the rates of grades 2–4 and 3–4 aGVHD were 37% and 17%, respectively and the 5 year incidence of cGVHD was 41%.
For patients with t-MDS, multivariate analysis identified partially matched URD associated with higher aGVHD (HR 2.03 (1.22–3.38), p=0.07) while mobilized PBSC grafts were associated with higher cGVHD risk (HR 1.95 (1.34–2.83), p<0.001). RIC and NMA conditioning regimens were associated with a lower cGVHD risk (HR 0.71 (0.56–0.89), p=0.003). For patients with t-AML, multivariate analysis identified previous autologous transplant (HR 1.69 (1.21–2.37), p=0.002), matched (HR 1.62 (1.20–2.18), p = 0.001) and partially matched URD (HR 1.88 (1.32–2.68), p<0.001), cord blood grafts (HR 1.58 (1.03–2.41), p=0.04) were associated with more frequent aGVHD. RIC and NMA was associated with less aGVHD risk (HR 0.64 (0.50–0.83), p<0.001).
Relapse
At 1 and 5 years post-transplant, the relapse rates in patients with t-MDS were 39% and 46% (Table 2).The median time to relapse was 4.6 months with the majority of relapses occurring within the first year after transplant. There was no difference in relapse rate patients with t-MDS receiving either MAC or RIC/NMA (Table 3). Increased relapse risk was associated with age > 60, prior autologous transplant, and very high IPSS-R score (Table 5a).
At 1 and 5 years post-transplant, the relapse rates in patients with t-AML were 37% and 43%; the median time to relapse was 3.9 months, most in the first year after transplant. For patients with t-AML transplanted in CR1, the 1 and 5 year relapse rate (28% and 34%, respectively) was significantly lower than patients transplanted in relapse or PIF (56% and 61%) (Table 4a and Figure 3). t-AML patients receiving MAC had less relapse at 5 years (40% vs. RIC/NMA 48%, p=0.04) (Table 4b). In multivariate analysis increased relapse risk was associated with patients transplanted in relapse or PIF, RIC/NMA, and adverse cytogenetics (Table 5b). Cytogenetics was an important risk factor even for patients in CR1.
Table 4a.
Univariate analysis of outcomes for t-AML based on remission status.
| CR1 (N = 519) | PIF/relapse (N = 253) | ||||
|---|---|---|---|---|---|
| Outcomes | N | Prob (95% CI) | N | Prob (95% CI) | P Value |
| Relapse | 507 | 248 | <0.001 | ||
| 1-year | 235 | 28 (24.2–32.1)% | 48 | 55.5 (49.2–61.7)% | <0.001 |
| 5-year | 112 | 34.4 (30.2–38.7)% | 17 | 61.1 (54.9–67.2)% | <0.001 |
| Disease free survival | 507 | 248 | <0.001 | ||
| 1-year | 234 | 47.7 (43.4–52.1)% | 47 | 19.4 (14.7–24.6)% | <0.001 |
| 5-year | 111 | 30.1 (26–34.3)% | 16 | 8.1 (4.9–11.9)% | <0.001 |
t-AML, treatment associated acute myeloid leukemia; CR1, first complete remission; PIF, primary induction failure; HCT, hematopoietic cell transplantation; CI, confidence interval; Prob, probability; N, number.
Figure 3. Disease Free Survival and Relapse for Favorable Features vs. Others in t-AML and t-MDS.
Favorable Features in t-AML: CR1, age<60, fully matched RTD/URD, intermediate / favorable cytogenetics. Favorable Features in t-MDS: age<60, fully matched RTD/URD, low / intermediate IPSS-R. t-MDS, treatment related myelodysplasia; t-AML, treatment associated acute myeloid leukemia; CR1, first complete remission; RTD, related donor; URD, unrelated donor; IPSS-R, Revised International Prognostic Scoring System.
Disease-Free Survival
DFS was 37% and 19% at 1 and 5 years post-transplant for t-MDS patients (Table 2 and Figure 1). DFS was similar for t-MDS receiving MAC or RIC/NMA (Table 3b). Inferior DFS was associated with age > 60, prior autologous transplant, and very high IPSS-R score (Table 5a).
Figure 1: Outcomes for t-MDS and t-AML.
t-MDS, treatment related myelodysplasia; t-AML, treatment associated acute myeloid leukemia; HCT, hematopoietic cell transplantation.
In t-AML patients, DFS was 39% and 23% at 1 and 5 years. In CR1, the 5-year DFS was 30% vs. those in relapse or PIF with DFS of only 8% (Table 4a and Figure 3). t-AML patients who underwent MAC had superior 5 year DFS (26% vs. 18%, p = 0.008) (Table 4b). In multivariate analysis, lower DFS was associated with transplant in relapse or PIF, prior autologous transplant, RIC/NMA and intermediate/adverse risk cytogenetics or KPS ≤ 90 (Table 5b). Adverse cytogenetics led to worse DFS even in CR1.
Overall Survival
At 1 and 5 years post-transplant OS was 50% and 27% for t-MDS patients (Table 2). Age > 60, partially matched URD, and intermediate or very high IPSS-R were associated with worse OS (Table 5a).
At 1 and 5 years post-transplant OS was 46% and 25% for t-AML patients (Table 2). Transplant in relapse or PIF, and intermediate or adverse risk cytogenetics and KPS ≤ 90 were associated with worse OS (Table 5b). Patients transplanted in PIF had a 5 year OS of 9%.
Superior Outcome with Favorable Features pre-HCT
The most successful t-MDS group included 131 (18%) patients < 60, with matched related or URD, and low or intermediate IPSS-R, with a 5-year DFS of 31% (p = 0.003, Figure 3). These superior outcomes are attributable to less relapse (p<0.001), as they did not impact NRM (p = 0.34).
The best outcome for t-AML was seen in 147 (20%) patients in CR1, age < 60, with matched related or URD, and favorable cytogenetics, who had 5-year DFS was 46%, (p< 0.001, Figure 3). These superior outcomes are attributable to less relapse (p<0.001), as they did not impact NRM (p=0.23).
Discussion
While OS has improved for most allo-HCT patients over the past 20 years, disappointingly OS for patients with t-MDS/t-AML has not improved25. However, the underlying reasons for poor survival reveal some important differences from the prior CIBMTR report18. NRM at 1 year had been 41% and nearly 50% at 5 years while the current analysis indicates an improved NRM of 24% at 1 year and 34% at 5 years. This is encouraging, especially when considering that the median age in this analysis is more than 15 years older than in the previous analysis (56 compared to 40 years old). However, high rates of relapse persist. Relapse had been 27% at 1 year and 31% at 5 years, while currently relapse rates are 37–39% at 1 year and 43–46% at 5 years. This may be attributable to a smaller percentage of patients undergoing MAC (roughly 55% compared to 77%)18. The unmet need in patients with t-MDS/t-AML is thus in relapse reduction, which may be achieved through transplanting in CR and intensified conditioning in patients with t-AML, appropriate patient selection, and potentially using post-HCT maintenance therapy.
Intensified conditioning should be considered if tolerated based upon age, KPS and comorbidities. As shown in BMT CTN 0901, MAC results in superior relapse free survival when compared to RIC, especially for patients with AML in CR who have measurable residual disease before transplant26,27. This observation is consistent with data from the EBMT comparing MAC and RIC for patients with t-AML. While TRM was similar in those who underwent MAC or RIC, OS and DFS were superior with MAC HCT28. For patients with t-MDS, conditioning intensity did not significantly affect OS or DFS in this analysis. RIC/NMA conditioning may be preferred in this setting as there was a reduced 1 year TRM for those who underwent RIC/NMA compared to MAC.
For patients who undergo RIC/NMA conditioning post-HCT maintenance may be of value. The introduction of targeted agents29,30, therapies with low side effect profiles such as hypomethylating agents31, and natural killer cell or donor lymphocyte infusions32,33 may be beneficial for high-risk patients, preferably within the context of clinical research. Because most relapses are early for both t-MDS and t-AML patients, relapse prevention approaches must begin promptly post HCT.
One striking finding of our study is the proportion of patients with a previous history of breast cancer. The previous CIBMTR analysis identified 16% (n=139) of allogeneic transplant recipients as breast cancer survivors18. In the current study, this number has increased to 25% (n=382) of the total population, possibly reflecting the growing use of adjuvant chemo- and radiation therapy for the treatment of early stage breast cancer, which has been associated with an increased risk of secondary malignancies34–37. Further studies will be needed to fully assess the risk of developing t-MDS or t-AML following adjuvant therapy for breast cancer.
This analysis has several limitations beyond its retrospective nature. It was not informed by data on measurable residual disease or TP53 and other mutations and HCT-CI and IPSS-R data was incomplete.
While the 2017 WHO classification combines t-MDS and t-AML into the entity of therapy related myeloid neoplasms, when the decisions about these HCTs were made, the diseases were recognized as distinct38, pre-HCT therapies differed between t-MDS and t-AML, and their outcomes differed. Decision-making about the timing of HCT for these 2 myeloid entities should perhaps recognize these distinctions.
Though rates of relapse and TRM are high after allo-HCT, OS for select patients with t-MDS and t-AML who undergo allo-HCT are promising. Through better patient optimization, more effective conditioning and studies of post-HCT interventions, outcomes for patients with t-MDS and t-AML may improve.
Supplementary Material
Figure 2: Disease Free Survival and Relapse for t-MDS and t-AML based on MAC vs. RIC/NMA conditioning.
t-MDS, treatment related myelodysplasia; t-AML, treatment associated acute myeloid leukemia; CR1, first complete remission; HCT, hematopoietic cell transplantation; MAC, myeloablative conditioning; RIC, reduced intensity conditioning; NMA, non-myeloablative.
Highlights.
5-year DFS for t-MDS and t-AML patients was 19% and 23%, respectively.
Relapse was the main cause of treatment failure.
Young patients with low risk disease have better OS and DFS.
Myeloablative conditioning for t-AML patients was associated with less relapse.
Acknowledgements
The CIBMTR is supported primarily by Public Health Service grant/cooperative agreement U24CA076518 with the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI) and the National Institute of Allergy and Infectious Diseases (NIAID); grant/cooperative agreement U24HL138660 with NHLBI and NCI; grant U24CA233032 from the NCI; grants OT3HL147741, R21HL140314 and U01HL128568 from the NHLBI; contract HHSH250201700006C with Health Resources and Services Administration (HRSA); grants N00014-18-1-2888 and N00014-17-1-2850 from the Office of Naval Research; subaward from prime contract award SC1MC31881-01-00 with HRSA; subawards from prime grant awards R01HL131731 and R01HL126589 from NHLBI; subawards from prime grant awards 5P01CA111412, 5R01HL129472, R01CA152108, 1R01HL131731, 1U01AI126612 and 1R01CA231141 from the NIH; and commercial funds from Actinium Pharmaceuticals, Inc.; Adaptive Biotechnologies; Allovir, Inc.; Amgen, Inc.; Anonymous donation to the Medical College of Wisconsin; Anthem, Inc.; Astellas Pharma US; Atara Biotherapeutics, Inc.; BARDA; Be the Match Foundation; bluebird bio, Inc.; Boston Children’s Hospital; Bristol Myers Squibb Co.; Celgene Corp.; Children’s Hospital of Los Angeles; Chimerix, Inc.; City of Hope Medical Center; CSL Behring; CytoSen Therapeutics, Inc.; Daiichi Sankyo Co., Ltd.; Dana Farber Cancer Institute; Enterprise Science and Computing, Inc.; Fred Hutchinson Cancer Research Center; Gamida-Cell, Ltd.; Genzyme; Gilead Sciences, Inc.; GlaxoSmithKline (GSK); HistoGenetics, Inc.; Immucor; Incyte Corporation; Janssen Biotech, Inc.; Janssen Pharmaceuticals, Inc.; Janssen Research & Development, LLC; Janssen Scientific Affairs, LLC; Japan Hematopoietic Cell Transplantation Data Center; Jazz Pharmaceuticals, Inc.; Karius, Inc.; Karyopharm Therapeutics, Inc.; Kite, a Gilead Company; Kyowa Kirin; Magenta Therapeutics; Mayo Clinic and Foundation Rochester; Medac GmbH; Mediware; Memorial Sloan Kettering Cancer Center; Merck & Company, Inc.; Mesoblast; MesoScale Diagnostics, Inc.; Millennium, the Takeda Oncology Co.; Miltenyi Biotec, Inc.; Mundipharma EDO; National Marrow Donor Program; Novartis Oncology; Novartis Pharmaceuticals Corporation; Omeros Corporation; Oncoimmune, Inc.; OptumHealth; Orca Biosystems, Inc.; PCORI; Pfizer, Inc.; Phamacyclics, LLC; PIRCHE AG; Regeneron Pharmaceuticals, Inc.; REGiMMUNE Corp.; Sanofi Genzyme; Seattle Genetics; Shire; Sobi, Inc.; Spectrum Pharmaceuticals, Inc.; St. Baldrick’s Foundation; Swedish Orphan Biovitrum, Inc.; Takeda Oncology; The Medical College of Wisconsin; University of Minnesota; University of Pittsburgh; University of Texas-MD Anderson; University of Wisconsin - Madison; Viracor Eurofins and Xenikos BV. The views expressed in this article do not reflect the official policy or position of the National Institute of Health, the Department of the Navy, the Department of Defense, Health Resources and Services Administration (HRSA) or any other agency of the U.S. Government.
Footnotes
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