This is the largest study reported to date on the outcome of children with relapsed or refractory APL. All patients were able to ultimately achieve morphologic remission with various salvage regimens and proceed to consolidative HSCT, though two patients entered HSCT positive for the PML-RARα fusion transcript. Outcomes following any form of HSCT were excellent, with a combined 5-year EFS of 72% and OS of 78%.
In the 11 children with relapsed or refractory APL (6 in molecular remission, 1 with molecular evidence of disease, and 4 unknown molecular status) undergoing autologous HSCT, we found a 5-year EFS of 73%. Reports of autologous HSCT for APL in adults have included from 10 to 50 patients each, and have demonstrated an EFS ranging from 51-90% (10
). Molecular status has not always been known prior to autologous HSCT, though de Botton, et al
, demonstrated that 7-year EFS is superior for those patients in molecular remission at time of HSCT, compared to unknown molecular status (77% vs. 50%; p = 0.07) (10
In the 21 children with relapsed or refractory APL undergoing allogeneic HSCT, we found a 5-year EFS of 71%. Roman, et al
reported a group of 10 patients (including 1 child) undergoing allogeneic HSCT with an EFS of 90% (11
). The only patient that relapsed was not in remission at the time of HSCT(11
). Larger reports of allogeneic HSCT for APL in adults have included from 17 to 137 patients each, and have demonstrated an EFS ranging from 46-59% (10
). The only report of allogeneic HSCT for APL in a solely pediatric population demonstrated a 5-year OS of 73% in a group of 11 patients (8 with cytogenetic confirmation) (16
For most patients with leukemia, the primary reason for transplant failure is relapse. In children with acute myeloblastic leukemia (AML) in second complete remission, the relapse incidence following autologous HSCT ranges from 52-54% (24
), while the relapse incidence following allogeneic HSCT ranges from 33-42% (24
). In our cohort, patients undergoing autologous and allogeneic HSCT demonstrated a relapse incidence of 27% and 10%, respectively. Unfortunately, we were not able to confirm the PML-RARα status of all autograft products in this cohort. Meloni, et al
confirmed the importance of a negative RT-PCR for the t(15
) prior to autologous HSCT in their group of 15 patients (including 2 children) (14
). In that series, all 7 patients with positive RT-PCR in their pre-transplant bone marrow aspirate relapsed following HSCT, while 6 of 8 patients with negative RT-PCR experienced sustained remission (14
). Clearly, the ability to confirm RT-PCR negativity in both the patient and the autograft product prior to infusion may play a significant role in the successful selection of patients most likely to benefit from autologous transplant. Of note, while prior reports suggest that the median time to relapse following autologous HSCT is 5-8 months (13
), 2 of the 3 relapses seen following autologous HSCT in this cohort occurred over one year post-HSCT, suggesting that PCR-based screening of either peripheral blood or bone marrow for relapse should be continued on a regular basis for at least 2 years following autologous HSCT.
In the allogeneic setting, the only patients experiencing a relapse in this cohort underwent fully-matched sibling donor HSCT and did not manifest any evidence of GVHD. We postulate that the low incidence of relapse after allogeneic HSCT may be due to a high susceptibility of APL to a graft-versus-leukemia (GVL) effect. It has been shown in vitro
that the PML-RARα fusion protein contains a novel antigenic site recognizable by CD4+ lymphocytes in an HLA-restricted context on antigen-presenting cells (27
). Lo-Coco, et al
, reported two patients with RT-PCR positive testing for disease post-allogeneic HSCT, both of whom converted to negative following withdrawal of immunosuppression, which provides evidence for an in vivo
GVL effect (15
). In addition, successful treatment of persistent molecular disease following MRD-HSCT with donor lymphocytes infusions has been reported (28
). Other groups have reported low relapse incidences of 4%-17% following allogeneic HSCT for APL (10
), providing further support for a stronger GVL effect against residual APL as compared to non-promyelocytic AML.
In this cohort, the biggest impediment to successful outcome after allogeneic HSCT was a TRM of 19%. Possibly due to low subject numbers, we were not able to identify any predictors of TRM in patients with relapsed or refractory APL. One contributor to TRM after HSCT may be the intensity of the conditioning regimen. In patients with high-risk AML, Mengarelli, et al
, reported no benefit of the addition of agents such as etoposide or cytarabine to the standard regimen of TBI plus cyclophosphamide or busulfan plus cyclophosphamide (15
). In adults with APL undergoing allogeneic HSCT, several groups have shown that TBI-based conditioning is not superior to busulfan-based conditioning (10
). Given the low relapse rate seen in this cohort, and in other reports of HSCT for relapsed or refractory APL, it appears likely that intensified conditioning regimens will not be found to be superior to standard regimens, especially in the setting of mismatched and/or unrelated donor transplants, where the GVL effect is expected to be strongest.
Another variable that might impact TRM is the type of secondary chemotherapy regimen used to achiever remission prior to HSCT. Due to the wide variety of regimens utilized in this cohort, no regimen could be conclusively linked to an impact on HSCT-outcome. However, the importance of the pre-transplant salvage regimen has been highlighted by the case of gemtuzumab ozogamicin (GO), a monoclonal antibody against CD33, which has been shown to be highly effective in relapsed APL (15
). As many as 64% of patients that receive GO within 3.5 months prior to HSCT ultimately develop evidence of sinusoidal obstruction syndrome following transplant (29
). In patients with APL, several groups have shown a high incidence of TRM following intensive cytotoxic chemotherapy regimens prior to allogeneic HSCT (10
). As demonstrated by one patient in this cohort, successful outcomes have been reported following allogeneic HSCT despite lack of molecular remission (10
). Some salvage regimens for APL utilize differentiating agents (such as ATRA or ATO) that lack significant cytotoxicity. Use of these agents in place of conventional chemotherapy may represent a less aggressive method by which to achieve morphologic remission prior to HSCT that could potentially translate into decreased post-HSCT TRM.
In addition to low patient numbers, the other major limitation of this study is the retrospective nature, in which we attempt to analyze the outcomes of transplants done at different centers, utilizing multiple different salvage regimens, donor types, conditioning regimens, and GVHD prophylaxis strategies. Clearly, the optimal method to analyze outcomes for patients with relapsed or refractory APL treated by HSCT would be in the context of a standardized prospective clinical trial in which inter-institutional variances could be minimized.
In summary, this study provides further evidence that for children with relapsed or refractory APL, autologous HSCT can be successfully performed for patients in remission. Other reports suggest that that molecular remission of the patient and an autologous stem cell product that is PCR negative for disease significantly decrease relapse incidence following autologous transplantation (10
). If molecular remission is not able to be achieved, allogeneic HSCT can be curative for many children. Few patients experience relapse of APL following allogeneic HSCT, possibly due to a strong GVL effect against residual disease. However, further improvements in supportive care are needed in order to minimize the impact of TRM in the allogeneic setting and thereby improve the overall survival of children with relapsed or refractory APL.