Abstract
Despite its favorable prognosis, 10-20% of APL patients relapse. Reinduction therapy is often followed by autologous hematopoietic cell transplantation (auto-HCT). Arsenic trioxide (ATO) has become part of standard reinduction and is often followed by auto-HCT. Data on patients in CR2 were collected from two large transplant registries (CIBMTR, EBMT) and two specialty referral centers. The outcome of patients in CR2 who received only ATO-based therapy as reinduction was retrospectively compared with those who got an auto-HCT, with or without ATO. Prognostic factors included age, disease risk, extramedullary disease, and duration of CR1. Of 207 evaluable patients, the median age was 31.5 years, 15.3% had extramedullary disease and median WBC at diagnosis was 4.8×109/L. Sixty-seven patients received ATO alone and 140 underwent auto-HCT. The groups were comparable for age, gender, extramedullary disease, risk group and duration of CR1. At 5 years, OS was 42% and 78% for the ATO-only and auto-HCT groups, respectively (p<0.001). In addition, OS was associated with longer duration of CR1 (p=0.002), but not with disease risk at diagnosis.
These data suggest that auto-HCT for APL patients in CR2 results in better OS than ATO-based therapy alone.
Keywords: acute promyelocytic leukemia, APL, autologous hematopoietic cell transplant, arsenic tri-oxide, ATO, relapse, CR2
Introduction
The standard of care of acute promyelocytic leukemia (APL) patients fundamentally changed in the past 20 years with the introduction of all-trans- retinoic acid (ATRA) and arsenic trioxide (ATO) which have dramatically improved patient outcome. However, approximately 10-20% of APL patients eventually relapse after initial complete remission (CR) 1, 2. The common practice in many countries is to treat relapsed APL patients until molecular CR is achieved and to consolidate with autologous hematopoietic cell transplantation (auto-HCT) 3-7. The long-term leukemia-free survival (LFS) after HCT in CR2 has been reported between 50%7 and 79%8. After the introduction of ATO, it was incorporated into the salvage protocols for relapse9 though generally not altering the paradigm of post-CR auto-HCT consolidation10.
ATO, an active single agent in APL11, 12, has been used for relapsed patients without auto-HCT13, particularly in several countries where auto-HCT is uncommon14,15. It is uncertain whether this approach – post CR2 consolidation with ATO but without auto-HCT, can be effective while avoiding the morbidity and mortality risks of HCT and serving patients who cannot undergo HCT due to age, co-morbidities, financial limitations or their own choice.
Reports of data using ATO alone 14,15, 16 are limited. Thus, we conducted a retrospective multi-center study for APL in CR2, comparing an ATO-based salvage treatment without transplant to any salvage protocol followed by auto-HCT as consolidation.
Patients and Methods
Data on APL patients in CR2 were collected from two large transplant registries; the Center for International Blood and Marrow Transplant Research (CIBMTR) and the European Group for Blood and Marrow Transplant (EBMT) and two specialty referral centers; Hematology Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran and Christian Medical College & Hospital, Vellore, India, who provided data on patients without autografting.
The characteristics and outcome of patients who received ATO and did not undergo transplantation were compared to that of patients who received any reinduction therapy, including ATO, and subsequent auto-HCT. Patient and disease characteristics are presented by median and range for continuous variables, and frequency and percent for categorical variables. Fisher's test and Wilcoxon rank-sum test were used to compare categorical and continuous variables, respectively, between patients who did and did not undergo transplantation. Overall survival (OS) was calculated from two months post relapse to date of death or last followup, with time dependent left truncation from the date of CR2 for patients receiving ATO alone and date of transplant for those receiving auto-HCT to adjust for any time to HCT bias which would censor patients who died or relapsed prior to autografting. Disease free survival (DFS) was calculated from two months post relapse to date of 2nd relapse, death or last followup, with similar left truncation at date of CR2 for patients receiving ATO alone and date of transplant for those receiving auto-HSCT. Cox proportional hazard regression with Huber - White standard errors was used to estimate the univariate and multivariate associations for OS and DFS. Potential prognostic factors included age, disease risk at diagnosis based on WBC ≥ 10×109/L, the presence of extramedullar disease, and duration of CR1. The primary comparison of auto-HCT and ATO-based consolidation was included in all analyses.
Results
Patients
We identified 242 APL patients in CR2 (CIBMTR-76, India- 61, Iran- 54 and EBMT- 51), of whom 35 were excluded due to missing dates of relapse, death or loss to followup (n = 25), death or loss to followup earlier than 2 months after relapse (n = 7), auto-HCT within two months of relapse (n = 2), or had second relapse within two months (n = 1). Of the 207 evaluable patients, the median age was 31.5, 62% were males, 15.3% had extramedullar disease, with most occurring in the CNS (79.3%) and median WBC count at diagnosis was 4.8×109/L Sixty-seven patients received ATO alone and 140 underwent auto-HCT. The groups were comparable for age, gender, extramedullar disease, duration of CR1 and risk group although the WBC was significantly higher in the auto-HCT group (Table 1). Seventy-six percent of the ATO-only group and 17% of the auto-HCT group received ATO during induction and/or consolidation (p<0.001).
Table 1. Characteristics of the ATO-only and auto-HCT groups.
| ATO-only (n=67) | Auto-HCT (n=140) | p-value | |
|---|---|---|---|
| Age | 30 (1 - 56) | 33 (2 - 70) | 0.1101 |
| WBC (1 × 10ˆ9) | 2.5 (0.3 -49.6) | 6.3 (0.6 -169) | 0.002 |
| N missing | 15 | 31 | |
| Platelets (1 × 10ˆ9) | 29 (6 - 317) | 22 (8 - 167) | 0.4921 |
| N missing | 17 | 119 | |
| Gender | |||
| Female | 28 (42) | 50 (36) | 0.4445 |
| Male | 39 (58) | 90 (64) | |
| Induction to achieve CR1 | |||
| ATO | 51 (76) | 22 (16) | < 0.001 |
| Chemotherapy-based | 16 (24) | 59 (42) | |
| Other | 0 | 8 (6) | |
| Missing | 0 | 51 (36) | |
| Consolidation | |||
| ATO | 51 (76) | 23 (16) | < 0.001 |
| Chemo based | 15 (22) | 47 (34) | |
| Other | 0 (0) | 14 (10) | |
| Missing | 1 (1) | 56 (40) | |
| Reinduction+consolidation to achieve CR2 | |||
| ATO | 67 (100) | 79 (56) | < 0.001 |
| ATRA + Chemo | 0 | 4 (3) | |
| Other | 0 | 50 (36) | |
| Missing | 0 | 9 (6) | |
| Year of diagnosis | |||
| Pre 2000 | 7 (10) | 36 (26) | 0.0107 |
| 2001-2011 | 60 (90) | 104 (74) | |
| Duration of CR1 (months) | 19.2 (1.8 -57.1) | 21.1 (1 -111.7) | 0.4593 |
| Missing | 17 | 16 | |
| Time from relapse to transplant (months) | -- | 6.3 (2.5 -23.3) | |
| Risk Group | |||
| Low | 40 (60) | 70 (50) | 0.1468 |
| High (WBC >10×109/L at diagnosis) | 12 (18) | 39 (28) | |
| Missing | 15 (22) | 31 (140) | |
| Center | |||
| CIBMTR | 0 | 61 (44) | < 0.001 |
| EBMT | 0 | 48 (34) | |
| India | 32 (48) | 27 (19) | |
| Iran | 35 (52) | 4 (3) | |
| Extramedullary Disease | |||
| None | 58 (87) | 103 (74) | 0.8489 |
| CNS | 8 (12) | 15 (11) | |
| Other | 0 (0) | 3 (2) | |
| Skin | 1 (1) | 2 (1) | |
| Followup of survivors (months) | 80.1 (0.3 – 183.5) | 62.5 (6.4 – 196.2) | |
Abbreviations: ATO=arsenic trioxide; ATRA = all-trans retinoic acid; CIBMTR =Center for International Blood and Marrow Transplant Research; EBMT =European Group for Blood and Marrow Transplant; HCT = hematopoietic cell transplantation
Among the auto-HCT, 56% of the patients received ATO-based treatment as salvage therapy before transplant and the others received various combinations of chemotherapy plus ATRA. More patients in the auto-HCT group, compared to the ATO-only group, were treated before 2000 (26% vs. 10%, p=0.01). In 24 out of 31 (77.4%) patients with reported explanation for not undergoing transplant, it was a financial reason. The median follow-up was 80.1 (0.3 – 183.5) months in the ATO-only group and 62.5 (6.4 – 196.2) months in the auto-HCT group.
Survival
We found a statistically significant survival advantage for the auto-HCT group (HR = 0.35, 95% CI: (0.27-0.44), p<0.001) compared to the ATO-only group. The median OS was not reached in the auto-HCT compared to 44.1 months in the ATO-only group. At 5 years, OS was 78% (95% CI: 71% - 86%) and 42% (95% CI: 31% - 59%) for the auto-HCT and ATO-only groups, respectively (Figure 1). OS was also significantly associated with longer duration of CR1 (p<0.001) and presence of extramedullary disease (p = 0.046) (Table 2a). In a multivariate model, auto-HCT (p=0.001) and duration of CR1 (p<0.001), but not extramedullary disease (p=0.106) remained statistically significant (Table 2b). Disease risk at diagnosis was not associated with OS.
Figure 1.
OS of the ATO-only and auto-HCT groups.
Table 2a. Overall Survival - Univariate Analysis.
| Variable | N | N died | HR | 95% Lower | 95% Upper | p-value |
|---|---|---|---|---|---|---|
| Auto-HCT (Y vs N) | 207 | 63 | 0.345 | 0.272 | 0.437 | < 0.001 |
| Age (continuous) | 204 | 61 | 1.000 | 0.987 | 1.014 | 0.957 |
| Risk group (high vs low) | 161 | 49 | 1.093 | 0.533 | 2.241 | 0.808 |
| Extramedullary disease (Y vs N) | 190 | 60 | 0.253 | 0.066 | 0.977 | 0.046 |
| CR1 duration (continuous) | 174 | 52 | 0.975 | 0.963 | 0.986 | < 0.001 |
| WBC (continuous) | 161 | 49 | 0.996 | 0.987 | 1.005 | 0.337 |
Abbreviations: CI=confidence interval; HCT =hematopoietic cell transplantation; HR =hazard ratio; N =no; Y= yes.
Table 2b. Overall Survival - Multivariate Analysis.
| Variable | HR | 95% Lower | 95% Upper | p-value |
|---|---|---|---|---|
| Auto-HCT (Y vs N) | 0.325 | 0.165 | 0.638 | 0.001 |
| Extramedullary disease (Y vs N) | 0.144 | 0.014 | 1.504 | 0.106 |
| CR1 duration (continuous) | 0.971 | 0.959 | 0.984 | < 0.001 |
Abbreviations: HCT = hematopoietic cell transplantation; HR =hazard ratio; N= no; Y=yes.
Auto-HCT and longer duration of CR1 were also associated with disease free survival (DFS) in both uni- and multivariate analyses (p<0.001) (Figure 2, Tables 3a and 3b). The median DFS was not reached versus 24.2 months in the auto-HCT and ATO-only groups, respectively.
Figure 2.
DFS of the ATO-only and auto-HCT groups.
Table 3a. Disease Free Survival - Univariate Analysis.
| Variable | N | N died/relapse d | HR | 95% Lower | 95% Upper | p-value |
|---|---|---|---|---|---|---|
| Auto-HCT (Y vs N) | 207 | 76 | 0.435 | 0.306 | 0.619 | < 0.001 |
| Age (continuous) | 204 | 74 | 0.999 | 0.987 | 1.010 | 0.819 |
| Risk group (high vs low) | 161 | 58 | 1.202 | 0.697 | 2.073 | 0.509 |
| Extramedullary disease (Y vs N) | 190 | 72 | 0.626 | 0.269 | 1.455 | 0.276 |
| CR1 duration (continuous) | 174 | 62 | 0.977 | 0.962 | 0.991 | 0.002 |
| WBC (continuous) | 161 | 58 | 0.994 | 0.988 | 1.001 | 0.077 |
Abbreviations: HCT= hematopoietic cell transplantation; HR =hazard ratio; N =no; Y= yes.
Table 3b. Disease Free Survival - Multivariate Analysis.
| Variable | HR | 95% Lower | 95% Upper | p-value |
|---|---|---|---|---|
| Auto-HCT (Y vs N) | 0.495 | 0.345 | 0.710 | < 0.001 |
| CR1 time (continuous) | 0. 978 | 0.965 | 0.991 | < 0.001 |
Abbreviations: HCT= hematopoietic cell transplantation; HR =hazard ratio; N= no; Y=yes.
Prognostic factors in each treatment cohort
Among the auto-HCT group, 79 patients received ATO as part of the salvage therapy before transplant and 54 did not. The OS of the two groups was similar (p=0.274) and each subgroup had better outcome compared to the ATO-only group (p<0.001).
Among the ATO-only group we found that longer DFS and OS were not associated with any other prognostic factor including age, gender, risk group at diagnosis, presence of extramedullary disease, duration of CR1 or receiving ATO at induction.
Among the patients in the ATO-only group, 51 patients received ATO as salvage after relapse and as part of initial induction and/or consolidation and 16 patients only received ATO as salvage. The OS of both groups were similar (p=0.106) and each had worse outcome than the auto-HCT group (both p<0.001). Consolidation with only ATO (n=45) or ATO plus different combinations of chemotherapy and/or ATRA (n=22) did not influence DFS and OS.
Discussion
In APL, auto-HCT is the preferred transplant approach. Autografting has been shown to have similar protection against relapse as allogeneic-HCT4 and prior to the ATRA era it was reported to cure many patients receiving autografts in first CR17. After the inclusion of ATRA in all frontline regimens, auto-HCT was adopted as a frequent approach for 2nd or later remission.
This retrospective analysis clarifies that auto-HCT has an advantage over ATO in 2nd CR yielding a longer DFS and OS compared to ATO-based consolidation alone. These results are consistent with those of the European LeukemiaNet registry13 which reported a 3-year OS of 77% vs. 59%, for the autologous vs. ‘ATO without transplant’ groups, respectively.
The current data also demonstrate that ATO alone can cure some patients who achieve CR2 lasting at least 2 months. Therefore, we sought to determine factors that may identify patients who can receive ATO and have a favorable outcome. Unfortunately, in the ATO-only group, we could not identify factors, including age, gender, risk group at diagnosis, presence of extramedullary disease, duration of CR1 and receiving ATO at induction associated with OS or DFS outcomes which were similar to auto-HCT.
We observed frequent extramedullary leukemia; present in 15.3% of all patients, slightly more than previous reports (between 5% to 12%)18 and most occurred in the CNS (79%)19, 20. In multivariate analysis extramedullary disease was not a significant prognostic factor. These data are consistent with the AIDA0493 data18 and with reports from the European LeukemiaNet,13 but not from European-Pethema21. In addition, It is uncertain whether inclusion of ATO in upfront regimens would induce ATO resistance after relapse. Though examined in only a small number of patients, we found that using ATO before a relapse does not compromise the effectiveness of ATO after relapse.
The preferred treatment for relapsed APL in the ATO-era is unknown. A prospective study may be ideal, but is unlikely to ever be done. In these circumstances, a retrospective analysis can inform recognition of the optimal therapy, though recognizing the inherent shortcomings. To ameliorate the impact of selection bias, we used time censoring and a rigorous attempt to determine why patients did not receive a transplant in the two specialty centers. Molecular data at remission, unfortunately, were incomplete and unsuitable for this retrospective analysis.
Although this multivariate model was adjusted for important clinical factors for the transplant vs. ATO comparisons, there may be additional unknown factors driving the choice or availability of transplant that we could not address, such as the specific details of prior therapy. In addition, other factors such as differences in reinduction therapy and even choices of supportive care may possibly influence the outcome. Taken together, these data tend to support the premise that auto-HCT is the preferred therapy for patients with APL in CR2 and is superior to ATO-based consolidation without auto-HCT.
Footnotes
The authors declare no conflict of interest.
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