It was believed that a second transplantation was almost the only salvage for GF. We previously reported encouraging results of second haplo-SCT as salvage [19]. In the current study, we updated our experience, and further confirmed the excellent engraftment and improved survival of the novel regimen compared to historical group. It suggests that this novel regimen might be a feasible option of salvage for GF after allogeneic stem cell transplantation in patients with hematological malignancies.
Currently there is no standard second transplantation regimen. Previous studies were almost retrospective summaries of outcomes from a group of patients with great heterogenicity, and rarely explore the transplant protocol. We performed the first prospective study using a homogeneous protocol in 2021 [19], and our current updated data further confirmed the encouraging results. To our knowledge, this is the first study to report a uniform salvage regimen for GF after transplantation, especially in haplo-SCT.
When performing a second transplantation for GF, there is usually no or limited chance to find a matched sibling donor or unrelated donor (URD), especially after the first haplo-SCT. Cord blood (CB) or haploidentical donor was usually adopted since choosing a donor with fast access is critical. It has been reported that CB has inferior outcome compared to haplo-SCT as salvage transplantation [20, 21], and there are increasing reports of salvage transplantation using haploidentical donors for GF. However, haploidentical donor is usually used as salvage after transplantation from other type of donor (CB or URD). There are few reports of using haploidentical donors as salvage after first haplo-SCT. The Italian group reported 19 cases in 2022, with the engraftment rate of 74% and 1-year OS of 66% [16]. The French group reported 24 haploidentical salvage transplantations for GF, within which 5 were after first haplo-SCT, and 3 were successfully engrafted [18]. The Japanese group reported 33 salvage haplo-SCT and 6 were after first haplo-SCT, and 4 of the 6 were successfully engrafted [17]. In our previous study, we reported 13 GF (11 were haplo-SCT, and 2 were URD SCT) salvaged by second haplo-SCT. The engraftment rate of neutrophil was 100%. Altogether, all the above studies suggest that a second haploidentical transplantation could be a feasible option for salvage of GF after first haplo-SCT.
Historically, the TRM of early second transplantation was as high as 50–75% [5, 7, 10]. To reduce the early treatment-related toxicity, non-myeloablative but immunosuppressive conditioning regimen was preferred to balance the regimen-related toxicity and engraftment. The conditioning regimens used for salvage transplantation were very heterogenous. The most frequently used conditioning regimens includes total nodal irradiation-based conditioning [22] and combination of fludarabine, cyclophosphamide and low-dose total body irradiation (TBI) [16, 23]. Gimamarco et al. used a combination of fludarabine 150mg/m2 plus Cy 29mg/kg and TBI 2Gy, and the engraftment rate was 74% and 1-year TRM was 26% [16]. In the current study, we used a combination of fludarabine 150mg/m2 and cyclophosphamide 2g/m2, and the engraftment rate was 100% and the TRM was around 30%, suggesting this regimen is safe and efficacious.
In the current study, we chose a different donor to avoid a second rejection based on the hypothesis that there might be unknown rejection mechanisms between the initial donor and the patient. However, the benefit of changing donors in second transplantation is still conflicting [7]. Giammaco et al. reported that failure to recover after a second transplant was recorded in 4/13 (30%) patients receiving a graft from the same donor and in 1/6 (16%) patients grafted from a different haploidentical donor [16]. Interestingly, there seems to be a trend of using a different donor in recent studies compared to early studies. In a recent study published in 2023, 51% cases received the second transplantation with a different donor [7] while the number was only 32% in a study from Guardiola et al. in late 1990s [24]. In another study from Germany, 13 of the 16 patients initially underwent haploidentical transplantation received stem cells from a second haploidentical donor for retransplant, and 3 patients received grafts from the same haploidentical donor because a second donor was not available [25]. However, it should be noted that most of the previous studies were with small sample size and were retrospective, and it is not feasible to perform a randomized controlled study. Therefore, further study is still needed.
Interestingly, our result suggests that this novel protocol has similar engraftment rate for either graft rejection or poor graft function, and for either primary or secondary GF. It has been suggested that poor graft function and graft rejection has different mechanisms and management strategies [26, 27], and the current data suggest that our salvage method was effective for both types of GF.
Although we have further confirmed the encouraging outcomes, there are still several aspects awaiting to be improved. First, multicenter study should be performed to further validate this novel regimen. Second, the underlying mechanisms was not clear, and further clarification of the underlying pathogenesis might help optimizing the transplantation protocol. Third, whether our method could be used in other situations, such as in non-malignant diseases, or in other transplant modalities is still unknown. Therefore, further investigation should be performed to answer these questions.
In conclusion, our novel method using a low-toxic regimen followed by haploidentical transplantation from a different donor represents a promising option to rescue patients with GF after first haploidentical stem cell transplantation.