A 35-year-old male with a FLT3+ AML underwent allogeneic peripheral blood stem cell transplant using a myeloablative non-total body irradiation (TBI) conditioning regimen from his HLA-matched sibling donor. Following transplantation, he developed grade II acute graft-versus-host disease (GVHD) that resolved with increasing immunosuppression. The medications were subsequently discontinued, and he did not develop any evidence of chronic GVHD. Eighteen months after transplant, while off all immunosuppression, he developed fatigue and a blood count showed circulating blasts consistent with relapse of his disease. Among the various therapeutic questions is whether there is a role for a second allogeneic transplant to treat his disease and if so, at what time, with what conditioning, and with which type of donor.
Options to treat relapse after allogeneic transplantation include the choice of no further therapy, withdrawal of immunosuppression to elicit a therapeutic graft-versus-tumor (GVT) response, reinduction chemotherapy with the same or different agents, donor lymphocyte infusions with or without preceding chemotherapy, and second transplants with or without preceding chemotherapy. Clinical nuances, including the presence of antecedent GVHD, organ function, willingness of the donor (sibling or unrelated), time between transplant and relapse, and the specific characteristics of the leukemia contribute to the difficulty of the decision. As allogeneic transplant is performed with curative intent, the question is whether patients who relapse and then undergo second allogeneic transplant can be cured of their disease.
To examine the current evidence-based literature evaluating the efficacy of second allogeneic transplant after relapse, we performed a comprehensive literature review using Ovid Medicine from 1996 to the present time. The MESH terms “hematopoietic cell transplantation” (10,254 hits) and “relapse” (12,744 hits) were combined and yielded 498 hits. When combining “second hematopoietic cell transplantation” (854 hits) and “relapse” we had a more reasonable result of 34 articles. After narrowing these articles to those relevant to the question and excluding single case reports, in addition to adding relevant studies gleaned from the reference lists of these articles, 16 studies were chosen as the basis for this mini-review. These articles described a variety of malignant hematopoietic disorders, disease status at the time of second transplant, conditioning regimens, and donor sources. These items and selected outcomes of specific interest are listed in Table 1 of this review.
Despite the apparent heterogeneity of these studies, several principles have emerged that are relevant to the question. As a practical matter, most centers tended to use the same donor for both the first and second transplant. Most patients underwent reinduction treatment with chemotherapy in order to reduce the disease burden, knowing that the outcome for any transplant is improved if the patient is in remission. However, there are exceptions to this rule, as described by one study in this review where some patients transplanted with active disease remained alive and disease free after transplant.2 In addition, although numerous different conditioning regimens were employed, typically patients who underwent a TBI-based regimen for initial transplant would undergo a non-TBI myeloablative regimen for their second transplant. Recently, with increased appreciation of the role of the graft-versus-leukemia effect in facilitating cure of leukemia, several studies reported patients who underwent transplant using a reduced-intensity transplant regimen with some favorable outcomes, almost exclusively in those patients who underwent transplant in remission. In this review, overall survival ranged anywhere between 0 and 67% for the studies described herein, although, admittedly, for some studies the follow-up is short.
In general, patients with chemo-sensitive disease in remission who had a long initial remission (> 6 to 12 months) after first transplant and who never developed any GVHD are those who benefited with long-term control of their disease after a second transplant. Conversely, those patients who had a short remission and who did not achieve a beneficial response with reinduction chemotherapy were unlikely to benefit and probably should not be considered for second allogeneic transplant. In those patients who undergo second transplant and had no significant chronic GVHD, an attempt is generally made to taper the immunosuppression more quickly in order to harness a therapeutic GVT effect in the post-transplant setting. Additionally, patients who had acute and chronic GVHD without a GVT effect during the first transplant are less likely to benefit from a second transplant from the same donor.
Based on this mini-review, we conclude a second allogeneic hematopoietic cell transplant does have an important potential role in treating relapse after failing allogeneic transplant in selected patients. Those patients who have an early relapse, high tumor burden, or chemo-resistant disease are not patients who should undergo second transplant, as the literature does not support the clinical benefit for these selected patients. Thus the decision to undergo a second transplant should be weighed against the associated co-morbidities that can contribute to transplant-related mortality, for which a reduced-intensity approach can certainly be considered, with earlier tapering of immunosuppression. With regard to the donor, under most circumstances the same donor is used, but if there is a different HLA-matched sibling or unrelated donor, this also could be considered, especially if there was no antecedent GVHD. As randomized-controlled trials are non-existent to answer the question of the role of second allogeneic transplant to treat relapse, multi-institutional observational studies were used in this mini-review to make these recommendations. Given that relapse after transplant can be a lethal situation and that select patients can remain alive and disease-free after second allogeneic transplant, we are giving our recommendations a score of 1B.17
Disclosures Conflict-of-interest disclosures: SJF is employed by City of Hope; MST declares no competing financial interests. Off-label drug use: None disclosed.
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA
Department of Hematology/HCT, City of Hope National Medical Center, Duarte, CA