Abstract
Information on the use of hypomethylating agents (HMAs) as a pre-transplant cytoreductive therapy in MDS is limited. We retrospectively evaluated outcomes of 172 adult MDS patients, who underwent allogeneic hematopoietic stem cell transplantation between January 2000 and December 2016. Patients were divided into three groups: group 1 − pre-transplant blasts <5% with HMA (n=42), group 2 − pre-transplant blasts ≥5% with HMA (n=38), 3 − no HMA (n=92). With a median follow up of 4.08 years, 1-year survival and relapse rates for groups 1, 2, and 3 were 75%, 40.2%, and 60.71%, respectively; and 17.6%, 26.6%, and 9.8%, respectively. Multivariate analysis revealed adverse relapse (HR 3.54; p=.03) in group 2 compared to groups 1 and 3, while no difference in overall survival was noticed. Our study shows no survival association with pre-transplant HMA; although, higher relapse rate was observed in the non-responding patients indicating possible chemotherapy resistant disease.
Keywords: Hypomethylating agents (HMAs), azacitidine, decitabine, cytoreduction in MDS, myelodysplastic syndrome (MDS), revised international prognostic scoring system (R-IPSS)
Introduction
Intermediate-2 and high risk international prognostic scoring system (IPSS) myelodysplastic syndrome (MDS) patients are at higher risk of progression to acute myeloid leukemia (AML) and poor survival [1] and early allogeneic hematopoietic stem cell transplantation (AHSCT) has shown to improve survival in this group [2]. Despite transplant being a potentially curative treatment modality, post-transplant relapse remains a daunting challenge. Higher blast percentage at transplant and poor risk cytogenetics are associated with higher relapse rate and poor disease-free survival [3–7]. AML type induction chemotherapy has been used to reduce pre-transplant disease burden. However, it is often associated with significant treatment-related morbidity including organ toxicities and prolonged myelosuppression and mortality, rendering some of the older patients ineligible for curative AHSCT [8]. Estey et al. conducted a prospective study evaluating applicability of reduced intensity conditioning (RIC) AHSCT following induction therapy among 259 older AML and MDS patients. Ninety-nine patients achieved complete remission (CR) with induction, only 53 were of them were evaluated by transplant service and 14 patients eventually received RIC AHSCT [9]. Effect of pre-transplant induction chemotherapy has been assessed and revealed no difference in post-transplant relapse or long-term survival [10–13].
Treatment with hypomethylating agents (HMAs), like azacitidine and decitabine, can induce CR rate of 10–20%, and hematological improvement in 23–49% patients and improved overall survival (OS) in intermediate-2 and high risk MDS patients [14,15]. Given their superior response in poor risk cytogenetics, easy tolerability in borderline performance status patients and manageable toxicity profile compared to induction chemotherapy, HMA has gained popularity as a bridging or debulking therapy in MDS patients while awaiting AHSCT. Previous studies revealed equivalent results with pre-transplant HMA in comparison with induction therapy [3,16–18]. However, these studies were limited by small number of patients and/or compared one type of cytoreduction therapy versus another [19–21]. In our study, we aimed to compare effect of pre-transplant HMA with best supportive care (BSC) prior to AHSCT.
Methods
We conducted a retrospective study of consecutive adult MDS patients who underwent AHSCT between January 2000 and December 2016 at Karmanos Cancer Institute (KCI). We excluded patients >20% blasts at the time of diagnosis. This study was approved by the Wayne State University Institutional Review Board.
The KCI Bone and Marrow Transplant Program database was used. We divided MDS patients who received pre-transplant HMA into <5% blasts (group 1) and ≥5% blasts (group 2) at transplant and compared transplant outcomes of both these groups with untreated patients (group 3). Cytogenetic findings were classified by Schanz et al. [7] and monosomal karyotype (MK) reported by Breems et al. [22]. MDS patients were categorized into five groups (very low, low, intermediate, high, and very high) as per revised IPSS criteria at diagnosis [1,23]. Disease status at transplant was divided further into response, nonresponse and untreated. Response groups included CR, stable disease, and hematological improvement. Nonresponse consisted progressive disease, relapse and treated but no CR patients. Demographic and transplant details for all patients were collected including age at transplant, sex, race, the Karnofsky performance status (KPS) score, donor type (related vs. unrelated), HLA matching, cytomegalovirus (CMV) serotype status of donor/recipient, ABO matching, conditioning regimen, graft versus host disease (GVHD) prophylaxis, G-CSF use, and busulfan pharmacokinetics. Comorbidity index (CI) was calculated using HSCT-CI formula [24]. All patients’ records were reviewed to determine the extent of acute and chronic GVHD (cGVHD). Patients were followed till the last follow up or death.
Outcome measures
The objectives of our study were to compare OS, non-relapse mortality (NRM), relapse rate, relapse-free survival (RFS), and GVHD-free relapse-free survival (GRFS) between patients with pre-transplant HMA and untreated patients.
Preparative regimen
Full intensity regimen included: busulfan 130 mg/m2 (day −6 to −3)/fludarabine 30 mg/m2 (day −6 to −2). Reduced intensity regimen (RIC) included (1) busulfan 130 mg/m2 (day −6 and −5)/fludarabine 30 mg/m2 (day −6 to −2)/total body irradiation (TBI) 200 cGy (day 0), (2) Flu 30 mg/m2 (day −6 to −2)/melphalan 140 mg/m2 (day −2)/TBI 200 cGy (day 0), (3) Cy 60 mg/kg/day (day −5 and −4)/Flu 25 mg/m2 (day −6 to −4)/TBI 220 cGy twice daily (day −3 to −1). Busulfan was based on pharmacokinetic dosing per institutional guidelines.
GVHD prophylaxis
Thymoglobulin at a total dose of 4.5 mg/kg was given in divided doses (day −3: 0.5 mg/kg; day −2: 1.5 mg/kg; and day −1: 2.5 mg/kg). Tacrolimus was administered intravenously (0.03 mg/kg/day) starting on day −3 and tapered starting around day +100 in the absence of active GVHD with a goal of tapering off completely by day +180. Sirolimus was given on day −3 with a 12 mg loading oral dose, followed by 4 mg/daily beginning on day −2 onwards. Oral MMF was initiated at 15 mg/kg twice daily from day −3 and stopped at day +30.
Statistical analysis
The Kruskal–Wallis tests were used to compare three groups for continuous variables and Chi-squared or Fisher’s exact tests for categorical variables. The length of hospital stay was calculated as the time from the date of admission prior to transplantation to the date of discharge post transplantation. OS was defined as the time from the date of transplantation to death from any cause. Patients who were alive were considered censored at the date of last observation. RFS was defined as the time from the date of transplantation to the date of relapse or death from any cause. Patients who were alive without relapse were considered censored at the date of last observation. GRFS was defined as the time from the date of transplantation to the date of grades III and IV acute GVHD (aGVHD), extensive cGVHD, disease relapse, or death from any cause, whichever occurs first. The Kaplan–Meier estimates were used to summarize the distributions of GRFS, RFS, and OS. The cumulative incidences of aGVHD and cGVHD were calculated with relapse or death without GVHD as competing risks. When calculating the cumulative incidence of grades II–IV aGVHD, grades III and IV aGVHD and extensive cGVHD, the events of grade I aGVHD, those of grades I and II aGVHD and those of limited cGVHD were ignored, respectively. The cumulative incidences of relapse and non-relapse mortality (NRM) were calculated with death without relapse for relapse and death with relapse for NRM, respectively, as competing risks. Univariable and multivariable Cox proportional hazards regression models were fit to assess associations between five prior chosen predictors (group, type of transplant, type of conditioning regimen, cytogenetics at diagnosis and revised IPSS score) and survival benefit (RFS and OS). For relapse and NRM, the proportional sub distribution hazards regression model in competing risks was used for univariable and multivariable analyses with the five predetermined covariates. The proportional hazards assumption was assessed, and no violation was found. The follow-up time was calculated using the reverse Kaplan–Meier estimate.
Results
A total of 172 MDS patients received AHSCT. Patient characteristics are shown in Table 1. The median age at transplant was 60 years (range, 24–80). Eighty patients received pre-transplant HMA, and 42 of them had <5% blast (group 1), whereas 38 had ≥5% blasts (group 2) at the time of transplant. Ninety-two patients did not receive HMA (group 3). The duration between diagnosis and transplant was >3 months in more patients with pre-transplant HMA than the untreated group.
Table 1.
MDS characteristics.
| Treated | Untreated | ||||
|---|---|---|---|---|---|
| Group 1 < 5% blast (N = 42) | Group 2 ≥ 5% blast (N = 38) | Group 3 (N = 92) | All (N = 172) | p | |
| Age at transplant - median (range) | 60 (31–72) | 65 (30–79) | 58 (24–80) | 60 (24–80) | <.001 |
| Sex - no. (%) | .391 | ||||
| Male | 29 (69) | 27 (71) | 55 (60) | 111 (65) | |
| Female | 13 (31) | 11 (29) | 37 (40) | 61 (35) | |
| Race - no. (%) | .760 | ||||
| Caucasian | 39 (93) | 34 (89) | 86 (93) | 159 (92) | |
| AA | 2 (5) | 1 (3) | 3 (3) | 6 (3) | |
| Others | 1 (2) | 3 (8) | 3 (3) | 7 (4) | |
| Subtype of MDS - no. (%) | .030 | ||||
| MDS with single lineage dysplasia | 1 (2) | 3 (8) | 4 (4) | 8 (5) | |
| MDS with Multilineage dysplasia | 7 (17) | 1 (3) | 23 (25) | 31 (18) | |
| MDS-RS | 3 (7) | 2 (5) | 4 (4) | 9 (5) | |
| MDS with del (5q) | 1 (2) | 0 (0) | 1 (1) | 2 (1) | |
| MDS-EB-1 | 5 (12) | 13 (34) | 16 (17) | 34 (20) | |
| MDS-EB-2 | 14 (33) | 17 (45) | 22 (24) | 53 (31) | |
| MDS-unclassifiable | 8 (19) | 0 (0) | 16 (17) | 24 (14) | |
| Therapy related MDS | 1 (2) | 1 (3) | 4 (4) | 6 (3) | |
| Hypoplastic MDS | 1 (2) | 0 (0) | 2 (2) | 3 (2) | |
| Cytogenetics at diagnosis - no. (%)d | .652 | ||||
| Others | 21 (50) | 22 (58) | 39 (42) | 82 (48) | |
| Monosomy 5 + 7, del (5q) | 4 (10) | 3 (8) | 14 (15) | 21 (12) | |
| Complex karyotype | 11 (26) | 10 (26) | 25 (27) | 46 (27) | |
| Revised IPSS score at diagnosis - no. (%)b | .136 | ||||
| Very low | 5 (12) | 2 (5) | 6 (7) | 13 (8) | |
| Low | 8 (19) | 1 (3) | 18 (20) | 27 (16) | |
| Intermediate | 7 (17) | 13 (34) | 30 (33) | 50 (29) | |
| High | 8 (19) | 8 (21) | 16 (17) | 32 (19) | |
| Very high | 14 (33) | 13 (34) | 22 (24) | 49 (28) | |
| Days from diagnosis to transplant - no. (%) | .001 | ||||
| ≤3 months | 2 (5) | 3 (8) | 26 (28) | 31 (18) | |
| >3 months | 40 (95) | 35 (92) | 66 (72) | 141 (82) | |
| Prior use of induction chemotherapy and hypomethylating agents - no. (%)b | .010 | ||||
| Yes | 0 (0) | 3 (8) | 0 (0) | 3 (2) | |
| No | 41 (98) | 35 (92) | 92 (100) | 168 (98) | |
| Type of hypomethylating agentsa | |||||
| Azacitidine - no. (%) | 36 (86) | 28 (74) | - | 64 (37) | >.99 |
| Decitabine - no. (%) | 6 (14) | 6 (16) | - | 12 (7) | .263 |
| Number of cycles used - median (range) | 4 (1–39) | 3 (1–18) | - | 4 (1–39) | .550 |
| Days from last dose of hypomethylating agents to transplant - median (range) | 65 (16–688) | 54 (20–330) | - | 58 (16–688) | .209 |
| Prior use of epo agents - no. (%)c | .499 | ||||
| Yes | 10 (24) | 5 (13) | 18 (20) | 33 (19) | |
| No | 32 (76) | 32 (84) | 72 (78) | 136 (79) | |
| Group 1 (N = 42) | Group 2 (N = 38) | Group 3 (N = 92) | All (N = 172) | p | |
| The percentage of blasts prior to transplant - median (range)e | 0 (0–4.9) | 10 (5–19) | 3 (0–20) | 3 (0–20) | <.001 |
| Disease status at transplant - no. (%) | <.001 | ||||
| Response | 25 (60) | 21 (55) | 22 (24) | 68 (40) | |
| Nonresponse | 17 (40) | 17 (45) | 20 (22) | 54 (31) | |
| Untreated | 0 (0) | 0 (0) | 50 (54) | 50 (29) | |
| Transfusion dependent at transplant - no. (%) | .755 | ||||
| PRBC | 13 (31) | 7 (18) | 26 (28) | 46 (27) | |
| Platelets | 1 (2) | 0 (0) | 3 (3) | 4 (2) | |
| Both | 6 (14) | 8 (21) | 13 (14) | 27 (16) | |
| Comorbidity index - median (range) | 2 (0–8) | 3 (0–10) | 2 (0–8) | 2 (0–10) | .004 |
| HLA match - no. (%) | .782 | ||||
| 8/8 | 32 (76) | 31 (82) | 74 (80) | 137 (80) | |
| 7/8 | 8 (19) | 5 (13) | 16 (17) | 29 (17) | |
| <7/8 | 2 (5) | 2 (5) | 2 (2) | 6 (3) | |
| ABO mismatch - no. (%) | .748 | ||||
| Matched | 19 (45) | 23 (61) | 53 (58) | 95 (55) | |
| Major mismatch | 9 (21) | 7 (18) | 14 (15) | 30 (17) | |
| Minor mismatch | 12 (29) | 7 (18) | 19 (21) | 38 (22) | |
| Bidirectional | 2 (5) | 1 (3) | 6 (7) | 9 (5) | |
| CMV serogroup status - no. (%)e | .696 | ||||
| +/+ | 10 (24) | 7 (18) | 17 (18) | 34 (20) | |
| +/− | 7 (17) | 4 (11) | 11 (12) | 22 (13) | |
| −/+ | 10 (24) | 16 (42) | 29 (32) | 55 (32) | |
| −/− | 14 (33) | 11 (29) | 35 (38) | 60 (35) | |
| Sex mismatch - no. (%)f | .146 | ||||
| M–M | 7 (17) | 3 (8) | 11 (12) | 21 (12) | |
| M–F | 0 (0) | 1 (3) | 12 (13) | 13 (8) | |
| F–M | 2 (5) | 5 (13) | 15 (16) | 22 (13) | |
| F–F | 3 (7) | 2 (5) | 8 (9) | 13 (8) | |
| Type of transplant - no. (%) | .023 | ||||
| Matched related | 11 (26) | 11 (29) | 44 (48) | 66 (38) | |
| Matched unrelated | 31 (74) | 27 (71) | 48 (52) | 106 (62) | |
| Stem cell Source - no. (%) | .420 | ||||
| PBSC | 42 (100) | 37 (97) | 88 (96) | 167 (97) | |
| BM | 0 (0) | 1 (3) | 4 (4) | 5 (3) | |
| Infused CD34 - median (range) | 7.38 (1.62–18.57) | 7.055 (0.92–17.68) | 6.395 (1.03–25.58) | 6.875 (0.92–25.58) | .144 |
| Conditioning regimen - no. (%) | .003 | ||||
| Bu-Flu-TBI | 25 (60) | 29 (76) | 37 (40) | 91 (53) | |
| Bu-Flu | 17 (40) | 8 (21) | 47 (51) | 72 (42) | |
| Flu-MEL-TBI | 0 (0) | 0 (0) | 3 (3) | 3(2) | |
| CY-Flu-TBI | 0 (0) | 0 (0) | 1 (1) | 1 (1) | |
| BAC | 0 (0) | 0 (0) | 4 (4) | 4 (2) | |
| Others (Bu-Flu-TBI-ATG, Flu-TBI-ATG) | 0 (0) | 1 (3) | 0(0) | 1 (1) | |
| Type of conditioning regimen - no. (%) | .002 | ||||
| Reduced intensity | 25 (60) | 30 (79) | 42 (46) | 97 (56) | |
| Full intensity | 17 (40) | 8(21) | 50 (54) | 75 (44) | |
| GVHD prophylaxis - no. (%) | .004 | ||||
| Calcineurin inhibitors with thymoglobulin | 26 (62) | 22 (58) | 32 (35) | 80 (47) | |
| Calcineurin inhibitors without thymoglobulin | 16 (38) | 16 (42) | 60 (65) | 92 (53) | |
MDS: Myelodysplastic syndrome; MDS-RS: Myelodysplastic Syndrome with Ring Sideroblasts; MDS-EB-1: Myelodysplastic Syndrome with Excess Blasts-1; MDS-EB-2: Myelodysplastic Syndrome with Excess Blasts-2; PRBC: Packed Red Blood Cells; CMV: Cytomegalovirus; M: Male; F: Female; PBSC: Peripheral Blood Stem cell; BM: Bone Marrow; Bu: Busulfan; Flu: Fludarabine; TBI: Total Body Irradiation; MEL: Melphalan; CY: Cylophoshamide; BAC: Busulfan-Cytarabine-Cyclophosphamide; ATG: Anti-thymocyte globulin; GVHD: Graft Versus Host Disease. Bold and Italic numbers indicate statistically significant result.
Four patients had both hypomethylating agents in group 2.
Data are not available for one patient.
Data are not available for three patients.
Data are not available for 23 patients.
Data are not available for one patient.
Data are not available for 103 patients.
Pre-transplant HMA was used as a bringing treatment to AHSCT in 19 patients and for worsening MDS in 76 patients. The decision of HMA use was determined by the treating physician. Azacitidine was administered in 64 patients, decitabine was used in 12 patients and both azacitidine and decitabine were used in four patients. The median number of cycles was 4 (range, 1–39). Three patients in group 2 received induction chemotherapy and azacitidine. Forty-six out of 80 patients (58%) responded to pre-transplant HMA. The responses to HMA included CR (8%), partial responses (10%), stable disease (42%), and hematological improvement (6%). Progressive disease was noted in 32% of patients. Thirty-eight percent patients received matched related and 62% received matched unrelated donor AHSCT. RIC regimen was used in 56% of patients. GVHD prophylaxis with calcineurin inhibitors with thymoglobulin was more commonly used in treated group compared to untreated group (p=.004).
Engraftment and GVHD
The median time to neutrophil engraftment in groups 1, 2, and 3 was 12 days (range, 9–19), 11 days (range, 7–25), and 11 days (range, 6–23), respectively (p=.135). The median time to platelet engraftment in groups 1, 2, and 3 was 16 days (range, 9–32), 16 days (range, 10–90), and 17 days (range, 0–675), respectively (p=.115). Graft failure occurred in one and two patients in groups 2 and 3, respectively. Two patients received second AHSCT for graft failure.
The cumulative incidence of grades II–IV aGVHD at 6 months was 33.5% (95% CI, 19.7–48%), 52.6% (95% CI, 35.4–67.3%), and 45.7% (95% CI, 35.2–55.5%) in groups 1, 2, and 3, respectively (p=.194). The cumulative incidence of grades III and IV aGVHD was 9.5% (95% CI, 3–20.7%), 28.9% (95% CI, 15.5–43.9%), and 26.1% (95% CI, 17.6–35.4%) at 1 year in groups 1, 2, and 3, respectively (p=.062) (Figure 1(a)). The 1-year cumulative incidence of cGVHD was 54.9% (95% CI, 37.4–69.4%), 28.4% (95% CI, 14.4–44.3%), and 51.1% (95% CI, 40.3–60.9%) in groups 1, 2, and 3, respectively (p=.047) (Figure 1(b)). Chronic extensive GVHD occurred in 46.9% (95% CI, 30.2–61.9%), 25.3% (95% CI, 12.1–40.8%), and 38% (95% CI, 28.1–47.9%) at 1 year for groups 1, 2, and 3, respectively (p=.129).
Figure 1.
(a) Cumulative incidence curves for grades III and IV acute GVHD by group with disease relapse or death as competing risks. (b) Cumulative incidence curves for chronic GVHD by group with disease relapse or death as competing risks.
Post-transplant infections
CMV reactivation was noted in 10 patients (24%), 21 patients (55%), and 27 patients (29%) in groups 1, 2, and 3, respectively (p=.007). GI and lung CMV disease occurred in eight patients (5%) and two patients (2%), respectively. Fifty patients (29%) received ganciclovir and five (3%) required foscarnet. EBV reactivation occurred in two (5%), five (13%) and 10 (11%) patients in groups 1, 2, and 3, respectively (p=.409). Blood stream bacterial infections occurred in 14 (33%), 20 (53%), and 40 (43%) of patients in groups 1, 2, and 3, respectively (p=.224). Aspergillus sp. was observed in two (5%) and two (2%) of patients in groups 2 and 3, respectively. Mucormycosis was noted in one patient in group 3.
Overall survival and non-relapse mortality
The median post-transplant follow-up among survivors was 2.98 years (95% CI, 2.12–4.96), 2.29 years (95% CI, 1.36–NR), and 5.86 years (95% CI, 4.65–6.95) in groups 1, 2, and 3, respectively. The estimated 1-year OS was 75% (95% CI, 62.6–89.76%), 40.2% (95% CI, 26.56–61.03%), and 60.71% (95% CI, 51.48–71.60%) in groups 1, 2, and 3, respectively. The risk of post-transplant death was higher for group 2 compared to group 3 (HR 1.94; 95% CI 1.17–3.23%; p=.01); however, no such difference was noted between group 3 and group 1 (HR 0.81; 95% CI 0.46–1.45; p=.492) (Figure 2(a)). The 1-year cumulative incidence of NRM was 14.8% (95% CI, 5.9–27.6%), 38.2% (95% CI, 22.4–53.9%), and 33.8% (95% CI, 24.3–43.5%) in groups 1, 2, and 3, respectively (p=.117) (Figure 2(b)). The multivariable analysis demonstrated that high-risk R-IPSS was independently associated with adverse survival (HR 1.97; p=.014). Compared to group 3, a trend for poor OS was noted in group 2 (p=.08). No effect of donor type or conditioning regimen was observed (Table 2). To evaluate the impact of pre-transplant blast percentage, we further divided untreated patients into <5% and ≥5% blasts and performed multivariate analysis among all four groups (Tables S1 and S2).
Figure 2.
(a) Kaplan-Meier survival curves for overall survival (OS) by group. (b) Cumulative incidence curves for non-relapse mortality (NRM) by group with death with relapse as a competing risk.
Table 2.
Univariable and multivariable analyses of factors associated with OS and NRM.
| OS | NRM | |||||||
|---|---|---|---|---|---|---|---|---|
| Unadjusteda | Adjustedb | Unadjusteda | Adjustedb | |||||
| HR (95% CI) | Signif | HR (95% CI) | Signif | SHR (95% CI) | Signif | SHR (95% CI) | Signif | |
| Group | ||||||||
| Group 3 | Reference | Reference | Reference | Reference | ||||
| Group 1 | 0.817 (0.460, 1.453) | .492 | 0.703 (0.373, 1.326) | .277 | 0.562 (0.286, 1.106) | .095 | 0.493 (0.229, 1.062) | .071 |
| Group 2 | 1.947 (1.172, 3.233) | .010 | 1.693 (0.934, 3.070) | .083 | 1.217 (0.673,2.201) | .520 | 0.959 (0.460, 2.000) | .910 |
| Type of transplant | ||||||||
| Related | Reference | Reference | Reference | Reference | ||||
| Unrelated | 1.138 (0.732, 1.771) | .565 | 1.018 (0.625, 1.657) | .943 | 0.929 (0.573, 1.508) | .770 | 0.963 (0.544, 1.706) | .900 |
| Type of conditioning | ||||||||
| regimen | ||||||||
| Reduced intensity | Reference | Reference | Reference | Reference | ||||
| Full intensity | 1.057 (0.687, 1.625) | .802 | 1.218 (0.737,2.012) | .441 | 1.158 (0.712, 1.886) | .550 | 1.227 (0.706, 2.135) | .470 |
| Cytogenetics at | ||||||||
| diagnosis | ||||||||
| Others | Reference | Reference | Reference | Reference | ||||
| Monosomy 5 + 7, | 0.831 (0.399, 1.733) | .622 | 0.617 (0.283, 1.343) | .223 | 0.714 (0.325, 1.569) | .400 | 0.529 (0.231, 1.212) | .130 |
| del (5q) | ||||||||
| Complex karyotype | 2.036 (1.254, 3.307) | .004 | 1.484 (0.862, 2.554) | .154 | 0.812 (0.445, 1.481) | .500 | 0.613 (0.303, 1.240) | .170 |
| Revised IPSS score | ||||||||
| Lowc | Reference | Reference | Reference | Reference | ||||
| Highd | 1.951 (1.257, 3.028) | .003 | 1.971 (1.148, 3.383) | .014 | 1.132 (0.697, 1.837) | .620 | 1.698 (0.916, 3.149) | .093 |
OS: overall survival; NRM: non-relapse mortality; HR: hazard ratio; SHR: subdistribution hazard ratio; CI: confidence interval. Bold and Italic numbers indicate statistically significant result.
Univariable Cox (for OS) and subdistribution (for NRM) proportional hazards regression analysis.
Multivariable Cox (for OS) and subdistribution (for NRM) proportional hazards regression.
Very low, low, and intermediate.
High and very high.
Relapse, RFS, and GRFS
At the time of data cut off, 37 patients have relapsed, and 1-year cumulative incidence of relapse was 17.6% (95% CI, 7.6–31%), 26.6% (95% CI, 13.6–41.6%), and 9.8% (95% CI, 4.8–16.9%) in groups 1, 2, and 3, respectively (p=.09) (Figure 3(a)). Relapsed patients received following treatments: re-induction chemotherapy (n=8), 2nd AHSCT (n=5), azacitidine (n=4), hydroxyurea (n=2), lenalidomide (n=1), and donor lymphocyte infusion (n=1). Multivariate analysis demonstrated group 2 (HR 3.54; p=.03) and complex karyotype (HR 7.26; p=.001) as independent factors for higher post-transplant relapse (Table 3).
Figure 3.
(a) Cumulative incidence curves for relapse by group with death without relapse as a competing risk. (b) The Kaplan–Meier survival curves for relapse-free survival (RFS) by group. (c) The Kaplan–Meier survival curves for GVHD-free relapse-free survival (GRFS) by group.
Table 3.
Univariable and multivariable analyses of factors associated with RFS and relapse.
| RFS | Relapse | |||||||
|---|---|---|---|---|---|---|---|---|
| Unadjusteda | Adjustedb | Unadjusteda | Adjustedb | |||||
| HR (95% CI) | Signif | HR (95% CI) | Signif | SHR (95% CI) | Signif | SHR (95% CI) | Signif | |
| Group | ||||||||
| Group 3 | Reference | Reference | Reference | Reference | ||||
| Group 1 | 0.905 (0.538, 1.523) | .707 | 0.925 (0.517, 1.656) | .794 | 1.805 (0.818, 3.981) | .140 | 2.523 (0.933, 6.821) | .068 |
| Group 2 | 1.941 (1.199, 3.142) | .007 | 2.010 (1.110, 3.639) | .021 | 2.153 (0.957,4.842) | .064 | 3.547 (1.111, 11.321) | .032 |
| Type of transplant | ||||||||
| Related | Reference | Reference | Reference | Reference | ||||
| Unrelated | 1.099 (0.729, 1.657) | .653 | 1.016 (0.633, 1.630) | .947 | 1.338 (0.649, 2.760) | .430 | 1.611 (0.581,4.467) | .360 |
| Type of conditioning | ||||||||
| regimen | ||||||||
| Reduced intensity | Reference | Reference | Reference | Reference | ||||
| Full intensity | 1.017 (0.681, 1.52) | .934 | 1.301 (0.794, 2.131) | .296 | 0.859 (0.438, 1.687) | .660 | 0.956 (0.298, 3.066) | .940 |
| Cytogenetics at diagnosis | ||||||||
| Others | Reference | Reference | Reference | Reference | ||||
| Monosomy 5 + 7, | 0.750 (0.363, 1.549) | .437 | 0.605 (0.282, 1.295) | .196 | 1.110 (0.230, 5.365) | .900 | 1.359 (0.273, 6.758) | .710 |
| del (5q) | ||||||||
| Complex karyotype | 2.294(1.459,3.607) | <.001 | 1.780 (1.081, 2.932) | .023 | 6.526 (2.813, 15.14) | <.001 | 7.269 (3.150, 16.773) | <.001 |
| Revised IPSS score | ||||||||
| Lowc | Reference | Reference | Reference | Reference | ||||
| Highd | 2.110 (1.402, 3.175) | <.001 | 1.849 (1.121, 3.050) | .016 | 3.273 (1.609,6.657) | .001 | 1.247 (0.523,2.971) | .620 |
RFS: relapse-free survival; HR: hazard ratio; SHR: subdistribution hazard ratio; CI: confidence interval. Bold and Italic numbers indicate statistically significant result.
Univariable Cox (for RFS) and subdistribution (for relapse) proportional hazards regression analysis.
Multivariable Cox (for RFS) and subdistribution (for relapse) proportional hazards regression.
Very low, low, and intermediate.
High and very high.
The median follow-up for RFS was 3.07 years (95% CI, 2.14–5.10), 2.29 years (95% CI, 1.36–NR), and 6 years (95% CI, 4.65–6.97) in groups 1, 2, and 3, respectively. The 1-year RFS was 67.55% (95% CI, 54.45–83.81%), 34.89% (95% CI, 22.23–54.76%), and 56.46% (95% CI, 47.17–67.57%) in groups 1, 2, and 3, respectively (Figure 3(b)). The RFS was poor in group 2 compared to group 3 (HR 1.94; 95% CI, 1.19–3.14%; p=.007), while no difference was noted between group 3 and group 1 (HR 0.9; 95% CI, 0.53–1.52%; p=.70). The multivariable analysis revealed group 2 (≥5% blasts after treatment) (HR 2.01; p=.02), complex karyotype (HR 1.78; p=.02), and high R-IPSS (HR 1.84; p=.01) to be associated with poor RFS. The GRFS at 1-year was 28.56% (95% CI, 17.24–47.3%), 16.92% (95% CI, 8.08–35.4%), and 22.83% (95% CI, 15.68–33.24%) in groups 1, 2, and 3, respectively (Figure 3(c)).
As of data cutoff, 85 out of 172 patients were deceased. Causes of deaths were: GVHD (25%), relapse (21%), infection (19%), multiorgan failure (18%), graft failure (4%), second malignancy (2%), and unknown (11%).
Discussion
MDS is a disease of elderly. Previously, we and others demonstrated that patients can have improved leukemia-free and OS with AHSCT without adverse NRM [25] and they should be referred to transplant centers early in the course of the disease. Our current study revealed that the duration between diagnosis and transplant was longer than 3 months in approximately 80% of the patients and this interval was even longer in the group who received cytoreductive therapy. The detrimental effects of delay in AHSCT in MDS patients have previously been reported in various studies [2,16,17]. In a prospective study of 163 transplant eligible MDS patients, 117 patients received azacitidine and 40 patients had induction therapy [26]. Of total 129 patients who had donor availability, only 69% of patients with HLA-identical donor and 57% with HLA-mismatched donor were transplanted eventually. This study further supports our argument that some patients may experience rapid disease progression or performance status may decline during cytoreductive therapy, which could prohibit them from receiving this life-saving modality.
Our study showed that despite having similar distribution of R-IPSS and adverse cytogenetics, the untreated patients (group 3) performed as well as treated patients with low disease burden at the time of transplant (group 1). Although 60% of patients had disease response to HMA and 8% of them achieved CR, the transplant outcomes of patients with <5% blasts after treatment (group 1) were not different than the untreated patients (group 3). We did not find any association of reduced post-transplant relapse and improved survival with the pre-transplant cytoreduction therapy with HMA. Like our study, no difference in OS and relapse rate was noted when pre-transplant HMA was compared to BSC prior to AHSCT [17]. Interestingly, the patients who achieved cytoreduction with blasts counts <5% fared better than ≥5% blast, which implies chemo-sensitivity and biology of the disease impacts the post-transplant outcomes rather than impact of the pre-transplant treatment. Previous studies have also reported similar results [3,16].
Older AML-MDS patients have higher incidence of MK and unfavorable-risk cytogenetics, predisposing them to higher risk of relapse and adverse OS [22,27,28]. Approximately, 25% of patients in our study had complex cytogenetics and were associated with higher relapse rate after AHSCT regardless of pre-transplant HMA treatment. We utilized R-IPSS to incorporate cytogenetic features into the prognostic model and show that patients with high R-IPSS had poor RFS and OS. We think that patients with these high-risk features may not derive any clinically meaningful benefit from pre-transplant HMA. Moreover, they may experience adverse effects of therapy, eventually either delaying or precluding them from undergoing AHSCT. Unlike prior studies [29,30], we did not notice any adverse impact of RIC regimens on relapse rate. We think that incorporation of TBI to Bu/Flu based RIC regimen might have influenced the observed outcomes [31].
Our study is retrospective in nature and thus non-randomized. Therefore, the results must be interpreted with caution. Moreover, the outcomes of patients who received pre-transplant HMA but were unable to receive AHSCT could not be evaluated in this study.
In conclusion, the use of HMA in an effort to minimize pre-transplant tumor burden does not appear to have any association with post-transplant survival in MDS; however, higher relapse and lower RFS were observed in non-responding patients, which indicates that treatment resistance is a poor prognostic marker for MDS patients who receive AHSCT. In addition, high R-IPSS is predictive of lower relapse-free and OS post-transplant, regardless of pre-transplant treatment. With these finding, early referral to a transplant center is essential for MDS patients, so that eligible patients can proceed to potentially curative therapy early in the course of their disease.
Supplementary Material
Footnotes
Supplemental data for this article can be accessed here.
Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article online at https://doi.org/10.1080/10428194.2019.1605070.
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