![]() It seems that after failure of 2 transplants a new donor is mandatory. The majority of long term survivors in this study had a different donor that was unrelated or mismatched. These patients seemed to have a better LFS. Similarly, in the EBMT study 2/3 of patients had at least 2 different donors in the three transplants and 56% changed a donor between the second and third transplant. In the current study, 83% had a new donor for the third transplant and a donor change was associated with reduced relapse rate after the third transplant. However, in the setting of a second transplant, there is no proven survival advantage for donor or stem cell source change. Therefore, switching to a different donor is logical. In the mismatched setting relapse after a previous transplant is often related to immune escape by the loss of the unshared haplotype. Theoretically, changing the donor in a subsequent transplant may reduce relapse by changing the graft-versus-leukemia (GvL) effect induced by minor histocompatibility antigens or by major HLA mismatches such as when using a mismatched haplo-identical or umbilical cord blood donors. Among other subsets, the chances for cure are minimal. In all, it seems that young patients with a good performance status, long remission after a second transplant and achieving a good response, preferentially with negative measurable residual disease, can be candidates for a third transplants. They may also be used for bridging to a third transplant. While they are not considered curative they can extend survival. In Acute myeloid leukemia new treatment combinations such as azacitidine with venetoclax, new FLT3 inhibitors and IDH inhibitors, can achieve responses. In ALL, new monoclonal antibodies and CAR-T cells are promising compared to the very few survivors of a third transplant in this disease. There are novel therapies that were not available during the two studies period. We have not offered a third transplant and among 47 patients relapsing after a second transplant, 3 patients were alive 5 years after relapse, 2 with no recurrent disease (personal communication). The data on a third transplant is so far retrospective and does not compare the transplant group to patients treated with other modalities. Assuming a cure rate of 10%, this will allow cure of less than 1–2% of all patients relapsing after a second transplant. It was estimated to be 16 and 4.5% of all patients relapsing after a second transplant in the Japanese and EBMT studies, respectively. The group of patients given a third transplant is obviously a very selected group. In particular, the role of a third transplant has not been defined. There is much less data on treatment approaches in this setting and whether there is any hope for long- term survival or cure. Relapse is the major obstacle after a second transplant occurring in more than 50% of recipients. ![]() However, there is no data to support a second transplant over DLI. Achieving a second remission prior to second transplant and a long prior remission (>6–12 months) are considered the most significant factors predicting subsequent survival. A second transplant has an established role in this setting with about 20–25% of recipients achieving long-term disease control. Prior studies have shown that cellular therapy is required to achieve long-term remission or even possible cure. Treatment goals and approaches vary from palliative care alone, to low-dose or intensive chemotherapy, targeted therapies (such as hypomethylating agents, tyrosine kinase inhibitors and various immunotherapies) and up to cellular therapies including donor lymphocyte infusions (DLI) or a second transplant, or any combinations. There is no standard of care for the treatment of relapse after SCT. New treatment modalities led to marked reduction of non-relapse mortality after SCT in more recent years, however, recurrent diseases remains the major cause of treatment failure. Allogeneic stem-cell transplantation (SCT) is a curative therapeutic approach for acute leukemia.
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