EBMT 2020 | Graft failure after unmanipulated haplo-HSCT with PT-Cy in AML

Graft failure is one of the most critical complications, which could occur after haploidentical stem cell transplantation, mainly due to the HLA disparities, which in the case of haplo is 50% of the HLA matching. Historically the incidence of graph failure with the haploidentical transplant to using the T cell-depleted platform was around 15%, as reported by authors in the [inaudible]. But the incidence and the risk factor of graft failure after haploidentical transplant, using post-transplant cyclophosphamide are not clearly known. Taking the advantage of the EBMT acute leukemia working party registry. We were able to analyze more than 1,200 patients, affected by acute myeloid leukemia, which were transplanted in first or second complete remission and who underwent an HLA haploidentical transplant using post-transplant cyclophosphamide. Those transplants were performed between 2010 and 2012. The majority of these patients were transplanted the using a myeloablative conditioning regimen and in 40% of the case bone marrow was the stem cell source.

All patients had post-transplant cyclophosphamide in combination with the other calcineurin inhibitor and no patients received a T-cell depletion with a ATG. There were a proportion of patients which were transplanted for secondary AML, mainly AML secondary to myelodysplastic syndrome or myeloproliferative disease. Median age of the patients were of 54 years. We were willing to understand that the incidence, the risk factor and the cumulative incidence of the non-engraftment day 45, excluding non-engraftment due to early relapse of the original disease, was approximately 6%. This is an important point because it’s lower than what is reported after the conventional T-cell depleted haploidentical transplant. Also we were able to analyze the main risk factor associated with the transplant, which could be modified modifiable factor, in order to prevent these complications.

Importantly we had almost 43% of patients experiencing a primary graft failure. 9 patients had late engraftment, meaning that the neutrophil engraftment from donor origin occur after the 45, which is quite long and unusual after transplant. Among those patients who were having the primary graft failure, which is a really a life threatening complication, 29 were able to undergo a second allogenic transplant. I have to say that the topic of the second allogenic transplant to rescue a primary graft failure, is really a dramatic event for different reasons. Firstly, because the donor should be found very quickly, in order to avoid the severe infectious complication to the recipient. Not all the patients who are experiencing primary graft failure could undergo a second transplant, and this decision should be carefully discussed among the transplant physician.

In our large cohort of patients, we found three main risk factor associated with the graft failure. Mainly, the diagnosis of secondary leukemia in some way could be explained by the different biological diseases, considering MDS and MPN different from the De Novo-AML. Patients with MDS & MPN are usually subjected to blood transfusion, and this could be a factor for increasing alloimmunization in those cases. Another important factor, which was associated with increasing the risk of graft failure was the use of bone marrow as stem cell source. And this a is important because those cases who had less than 3×10^8 nucleated cells/kg of a donor cell had a higher incidence of graft failure.

This is really important because bone marrow, in some cases, is associated with reducing the risk of GvH. Which is a critical point in the setting of haploidentical transplant, on manipulated or whoever, for some at risk patients, do increase the risk of graft failure, should be taken in consideration. And another factor, which could be modulated in case to avoid the risk of graft failure, is the use of reduced intensity conditioning regimens. Because, in some patients those who are all there or with co-morbidity the use of reduced intensity regimen is preferred over the myeloablative.

In that case, there is an increase of the risk of delayed Donor cell engraftment. This study is also very important because it highlights the critical role of the timing to perform second transplant. In our analysis of the 43 patients having a graft failure, 29 were able to undergo a second transplant. And this is a high proportion because, as I already mentioned, it’s important to consider that sometimes a severe infection could prevent the recipient to undergo the second transplant and also their donor availability. In majority of cases, in our cities, the donor was another haploidentical donor using a peripheral blood stem cell in order to decrease the time of engraftment, which in our study was around 19 days. And some patients were rescued with unrelated cord blood transplantation. It’s important to know that while we’re serious, the overall survival of a patient receiving a second allogenic transplant was around 35%, which is comparable with what is reported in literature among other kind of transplant from an unrelated donor or even an identical donor.

There are some single-center reports reporting a higher probability of survival when the second transplant is performed very heavily after graft failure. So, what I can consider a really important take home message is, if a patient after a haploidentical transplant, who had received bone marrow, had secondary leukemia, with a background of myelodysplastic or myeloproliferative disease is still in aplasia at 20, 25 days after haploidentical transplant. Think of starting on performing some further analysis to investigate the chimerism analysis and try to planify in case if that patient’s condition would allow a rescue strategy with a second transplant, if the clinical condition and the donor availability are possible.