For patients with ALL who relapse following allo-SCT, only a second SCT provides a realistic chance for long-term disease remission. We retrospectively analyzed the outcomes of 31 patients with relapsed ALL after a prior allo-SCT, who received a second SCT (SCT2) at our center. With a median follow-up of 3 years, 1- and 3-year PFS was 23 and 11% and 1- and 3 year OS rates were 23 and 11%. Twelve patients (39%) were transplanted with active disease, of whom 75% attained a CR. We found a significant relationship between the time to treatment failure following first allograft (SCT1) and PFS following SCT2 (P=0.02, hazard ratio=0.93/month). In summary, a second transplant remains a potential treatment option for achieving response in a highly refractory patient population. While long-term survival is limited, a significant proportion of patients remains disease-free for up to 1 year following SCT2, providing a window of time to administer preventive interventions. Notably, our four long-term survivors received novel therapies with their second transplant underscoring the need for a fundamental change in the methods for SCT2 to improve outcome.
One of the major causes of death following allo-SCT for patients with ALL is disease relapse. In patients with ALL who relapse following SCT, the prognosis is very poor with long-term survival of <10%.1, 2 Second allo-SCT may be effective salvage for a minority of patients and provide durable long-term disease remission. However, current data for second transplantation remain limited, and consist mainly of registry analyses of both acute myeloid and lymphoid leukemias.3, 4 In one of the largest series, Eapen et al.3 reported data from the Center for International Blood and Marrow Transplant Research, and reported 3 year leukemia-free survival and OS of 30% after second SCT for patients with relapsed ALL. In the largest report of patients with ALL who relapse following an allogeneic transplant, Spyridonidis et al.1 showed that only 6 of 93 patients who underwent a second SCT were alive at a median follow-up of 46 months. The limitations of registry data, however, preclude a closer look at the individual characteristics of patients reviewed. The objective of our study was to retrospectively analyze outcomes and prognostic factors of patients with ALL receiving a second SCT in our institution.
Materials and methods
Patients and data collection
We reviewed all patients with ALL who underwent a second allograft (SCT2) for relapsed ALL following a first allograft (SCT1) between 1 January 1993 and 31 December 2009 at MD Anderson Cancer Center. Data regarding patient characteristics, disease characteristics at diagnosis, as well as disease status at the time of SCT1 and SCT2, source of stem cells (BM vs peripheral blood vs cord blood), type of transplant donor, conditioning regimens, GVHD prophylaxis, acute and chronic GVHD data for both the first and second allogeneic transplants were collected. This retrospective analysis received institutional review board approval.
Definitions and clinical outcome variables
Cytogenetic abnormalities were classified as good, intermediate or poor-risk based on previously published reports5 Myeloablative and reduced intensity conditioning regimens were defined according to the Center for International Blood and Marrow Transplant Research criteria.6 Criteria for complete response included normal cytogenetics, the absence of circulating blasts, <5% marrow blasts and a platelet count of 100 × 109/L or higher. Standard morphologic criteria were used to diagnose recurrent disease. The disease stage at transplantation was defined using established criteria. Response was documented as best response occurring after day 30 following SCT. Molecular response measured by quantitative PCR analysis for BCR-ABL rearrangement was obtained when possible.
Our study examined the cumulative incidence of acute and chronic GVHD, treatment-related mortality (TRM), PFS and OS after SCT2 for recurrent leukemia. The outcome data were compiled from the date of SCT2 to the date of last contact or death. The cumulative incidence of grades 2–4 acute GVHD was evaluated in all patients and chronic GVHD was evaluated in patients surviving 90 days or longer after second transplant. The diagnosis of GVHD was confirmed by biopsy when feasible but was ultimately determined by clinical presentation. Acute GVHD was clinically graded as 0 to IV based on standard criteria,7 and chronic GVHD was classified as none, limited or extensive.8
TRM was defined as death while in continuous remission; patients who died of other causes and patients who survived were censored at last follow-up. The method of Kaplan and Meier was used to estimate the distribution of survival parameters.9 Cox proportional hazards regression analysis was used to assess the association between survival parameters and covariates of interest. The method of Fine and Gray was used to model the association between acute/chronic GVHD and covariates of interest in a competing risks framework.10
Patients and transplant characteristics
Between 1993 and 2011, a total of 544 first transplants were performed in our center for patients with ALL, of whom 33.8% subsequently relapsed (n=184). Among these patients, 31 received a second transplant. Treatment details of the remaining 153 patients were not available, but 148 of them have died of either disease or salvage therapy-related complications. The five remaining patients have relapsed <1 year ago, and are currently undergoing salvage chemotherapy/radiotherapy and remain disease-free at the time of this analysis. Patient, disease and transplant characteristics at time of SCT1 and SCT2 are presented in Table 1. The 31 patients receiving SCT2 had a median age of 26 years at time of SCT2 (range 7–49 years). At the time of SCT2, 61% of these patients were transplanted in CR (n=19), while 39% (n=12) were transplanted with persistent disease. The salvage therapy the patients received before SCT2 could be broadly divided into ‘intensive chemotherapy’ if either a standard induction or salvage protocol for ALL was used or ‘mild’ if combinations of steroids and vincristine, ± asparaginase, a single cytotoxic drug (for example, clofarabine, nelarabine or liposomal vincristine), tyrosine kinase inhibitors, hypomethylating agents or MoAb therapies were used. Among the 19 patients who received SCT2 in CR, 12 received intensive salvage chemotherapy before SCT, of which the most frequent regimen used was HyperCVAD11 (n=9). Seven patients achieved remission following ‘mild’ chemotherapy (vincristine/steroids±asparaginase (n=3), clofarabine (n=2), nelarabine (n=1)), and anti-CD22 antibody therapy (n=1). Of the 12 patients who were transplanted with refractory disease, three were transplanted without any salvage therapy given, while the six failed up to two lines of intensive therapy, and three failed 1–2 lines of milder chemotherapy, with no intensive regimen attempted.
Hematopoietic stem cell sources for SCT2 were matched-related donors (n=19), matched-unrelated donors (n=10) and mismatched cord-blood donors (n=2). Donors for SCT2 were changed in 48% of cases (n=15). As discussed earlier, at the time of SCT2, 61% of patients were transplanted in CR (n=19), while 39% (n=12) were transplanted with persistent disease.
Conditioning regimens and GVHD prophylaxis were determined by departmental protocols at the time of transplant, as well as physician preference. In SCT1, the majority of the transplant preparative regimens were classified as myeloablative (n=24, 80% of all transplants), of which 14 were TBI based and 10 were not, while for SCT2, 65% (n=20) of the transplants were done utilizing reduced intensity conditioning. The median time to treatment failure from the time of first transplant was 9.5 months (range 2.2–32.6 months), and median time between transplants was 12.8 months (range 2.7–36.8 months).
In view of the high risk of relapse in these patients, a number of them were offered additional unconventional measures in addition to a second transplant, in an attempt to consolidate their responses and reduce the risks of disease relapse. These novel measures were offered either on study protocol or at the discretion of the treating physician, and included the addition of a single-umbilical cord blood unit in an attempt to augment the GVL response (n=6), post-transplant maintenance with azacitidine (n=3) and consolidation with DLI following transplant (n=1). One patient received both azacitidine and umbilical cord blood augmentation.
Remission rates, PFS and OS
Out of the twelve patients who were transplanted with active disease, nine achieved a second remission (75% CR rates) following SCT2. All except one of these patients (who died of transplant-related complications) subsequently had disease relapse and died of their disease. For the nineteen patients who were in remission at the time of SCT2, eleven patients died of treatment-related complications while in remission, while four had disease progression and four remain alive and disease free with characteristics as shown in Table 2. The median time of progression from the second transplant for the patients in the study was 4.3 months. With a median follow-up of 3 years among survivors (range 1.0–8.5 years), PFS at 1 year and 3 years was 23 and 11% respectively, and OS at 1 year and 3 years was 23 and 11%, respectively.
On univariate analysis, only the time to progression from the first transplant had an impact of PFS, with longer progression times from SCT1 associated with longer time to progression from SCT2. We were not able to identify any risk factors that had an impact on TRM or OS, possibly because of the relatively small numbers of patients. The univariate analyses of factors that may affect PFS, OS and TRM are summarized in Table 3.
Outcomes of patients who received additional therapy
Among the nine patients who received additional therapies in an attempt to consolidate the responses post SCT2, three remain alive and disease-free (see Table 2). Four of six patients receiving the umbilical cord unit for augmentation of the GVL effect have died of disease progression, while one died of transplant-related complications and one remains alive and disease-free. Two of three patients who received post-transplant azacitidine have died of disease progression while one remains alive and disease-free. The sole patient who received donor lymphocyte infusion consolidative treatment remains alive and disease free.
The most important factors which affected early survival were therapy-related toxicities, including regimen-related toxicity, infections and acute GVHD. Twelve patients died of treatment-related complications within the first year after SCT2 (1 year TRM: 41%), half of them in the first 3 months. Causes of death included infectious complications (n=9, three of which had associated acute GVHD and went on high doses of immunosuppressive therapy), pulmonary regimen-related toxicity (n=2), and one death of unknown cause.
Following SCT2, the incidence of grade 2–4 acute GVHD was 26% (n=8), cumulative incidence of grade 3–4 GVHD was 16% (n=5) and for the patients who survived 100 days, the incidence of chronic limited GVHD was 17% (n=4) and that of extensive chronic GVHD was 22% (n=5).
Relapse of acute leukemia following an allogeneic transplant is associated with a generally dismal outcome. We analyzed long-term follow-up data on patients who underwent SCT2 for ALL at our institution. The primary objective of our study, apart from looking at factors affecting TRM, relapse and OS in a consecutive series of patients treated at a single institution, was also to look in greater depth at the characteristics and disease status of this patient population, and possibly clarify some of the issues, which the nature of a registry or population-based survey would not allow.
Results from registry and multi-institutional retrospective reviews (as summarized in Table 4) have previously suggested that some of the main factors that appear to affect relapse/leukemia-free survival following SCT2 for acute leukemias include longer duration of remission of the first transplant, as well as disease in remission at the time of second transplant, and possibly the SCT conditioning regimen.3, 4, 12 On univariate analysis in our study, we found that longer time to treatment failure from the first transplant was associated with a longer PFS from the second transplant, a finding that is consistent with that seen with registry data (Table 4). Although persistence of disease at the time of transplant showed a trend towards a poorer PFS (hazard ratio 1.69, 95% confidence interval 0.78–3.69), we were not able to demonstrate statistical significance for this factor, which might be attributed to our small patient numbers.
Nevertheless, it is interesting to note that of the 12 patients in our study who were transplanted with active disease (of whom 9 were refractory to salvage chemotherapy, while 3 were brought directly to transplant without further salvage therapy), 9 were able to be brought to a second remission (75%) following the transplant. Among patients who relapse following a first transplant for ALL, only a small percentage may eventually be brought to a second transplant. While reasons such as physician or patient preference may contribute to this, one of the key reasons remains the significant potential TRM or morbidity associated with salvage chemotherapy, that may prohibit patients from a second transplant. Our data suggest that proceeding to allogeneic transplant without salvage chemotherapy remains a feasible way of getting patients back into another CR, and may increase the number of patients who may be brought to SCT2. However, it is clear that despite the initial attainment of CR, the duration of remission following SCT2 (time to progression (TTP) of 4.2 months) remains short.
Of our four long-term survivors, all had received some form of additional therapy with their second transplant, which was significantly different from SCT1, in the form of a single-umbilical cord blood unit in addition to the PBSC to augment the immune response (n=1), consolidation of remission with DLI (n=1), a change in the stem cell source for the SCT from cord to mismatched adult unrelated (n=1), and post SCT maintenance therapy with 5-azacytidine (n=1). The small number of patients receiving each of these interventions, however, makes it difficult for us to draw any definitive conclusions regarding the efficacy of these novel measures in preventing disease relapse. What is clear from our findings however is that by merely repeating the routine transplant procedure of SCT1 in SCT2, especially in patients with disease relapse within 6 months of SCT1, and in patients with active disease, the chances of attaining any form of long-term control is extremely slim. This raises the question of whether the risks of a second transplant (39% TRM in our population), as well as the issue of stem cell donations in this setting (especially from a sibling who has donated previously or from a matched-unrelated donor) can be justified.
However, given that a significant proportion of patients remains disease-free for up to 1 year following SCT2, the role of a second transplant may be in cytoreduction and allowing disease control, thereby providing a window of time for administration of consolidation/maintenance therapy. The advent of novel therapeutic agents such as the bispecific T-cell engaging antibody blinatumomab,13, 14, 15 as well as CD22-directed antibody therapy (inotuzumab ozagamicin) have shown significant responses with minimal toxicity in the salvage setting.16, 17 Incorporation of these agents as consolidation in the second transplant setting may provide options for further disease control post transplantation without added cytotoxicity. In addition, novel adoptive cellular therapies post transplantation such as with CD19-directed chimeric antigen receptor T-cell therapies,18, 19 or genetically modified NK-cell therapies may provide other important options for disease control in the future.20
In conclusion, our findings suggest that a second transplant for ALL does not result in durable disease remission control for majority of patients. The use of novel therapeutic agents and adoptive cellular therapy may improve the poor prognosis in this setting and further research in this area should be considered.
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The authors declare no conflict of interest.
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Poon, L., Bassett Jr, R., Rondon, G. et al. Outcomes of second allogeneic hematopoietic stem cell transplantation for patients with acute lymphoblastic leukemia. Bone Marrow Transplant 48, 666–670 (2013). https://doi.org/10.1038/bmt.2012.195
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