ASH 2024 | The addition of inotuzumab ozogamicin to conditioning for alloSCT in ALL and lymphoid malignancies

My focus has been on lymphoid malignancies and in my presentation I’m going to discuss the addition of novel drug inotuzumab ozogamicin to the conditioning regimen for patients with CD22 lymphoid malignancies who are candidates for allogenic stem cell transplant. Inotuzumab ozogamicin is a humanized antibody drug complex that has made a major improvement in the conventional therapy for patients with CD22 positive malignancies, specifically acute lymphoblastic lymphoma. So because of that we were interested in incorporating this targeted drug in the conditioning regimen for allogeneic transplantation for patients who require a transplant because of high-risk disease. Now studies have shown, or retrospective studies have shown in the past that inotuzumab can be associated or can cause increased risk of veno-occlusive disease when incorporated in the conditioning regimen. The risk can go up to 17 percent and the retrospective studies also have shown that patients who received a double alkylator conditioning in addition to inotuzumab or those of higher risk. And therefore, in our strategy, we tried to use inotuzumab with a single alkylator agent. And we did the initial study with a non-myeloablative conditioning with bendamustine, fludarabine, rituximab. We just published our paper in 20 patients and we saw that no risk of veno-occlusive disease. None of the patients developed veno-occlusive disease. So we are very encouraged, we move to the next step because patients with aggressive malignancies such as acute lymphoblastic leukemia or aggressive lymphoma need a little bit more intense chemotherapy, not necessarily myeloablative but reduced intensity conditioning. And so in this study we added inotuzumab at a dose of 0.3 mg per meter square to the conditioning regimen of melphalan and fludarabine. Melphalan was given at 140 mg per meter square. And the inotuzumab was given a week before the conditioning was started with the idea the primary goal is to look at the risk of veno-occlusive disease and to have some exploring responses and toxicity. And in this trial, we incorporated so far nine patients, and this is what we presented at the American Society of Hematology. And nine patients median age was 54 years of age. Patients were mainly acute lymphoblastic leukemia, and two patients had CLL and Richter’s transformation. And we included patients if they have normal liver function tests. And the other criteria are standard criteria for a transplant procedure. So we saw that those patients went through the procedure, they engrafted their counts, white neutrophil count at day 12. So it’s a standard recovery time, all of them engrafted donor cells. And interestingly, we found no risk so far, no risk of veno-occlusive disease. So we are very, very encouraged. And we obviously expanded this trial to more patients and we’ve taken a referral maybe from outside the institution to continue our exploration and with the hope that with adding this drug which is a targeted therapy drug, we can shy away from myeloablative toxic regimen and we can improve the outcome in patients with aggressive lymphoid maligancies and acute lymphoblastic leukemia and Richter’s in CLL for instance without any adding toxicity. It’s interesting that patients with ALL had risk factors with TP53, three out of seven patients had TP53, MLL mutation was present in two other patients, etc. And one patient was beyond CR3. And so overall survival was very encouraging, 62% at three years. And importantly, treatment-related mortality at two years was only 14%. So this is where we are right now. And we try to include more patients. And we also have moved from using standard tacrolimus methotrexate after the transplant for prophylaxis for graft-versus-host disease to use post-transplant cyclophosphamide in addition to tacrolimus. So hopefully that will also lessen the risk of graft-versus-host disease and further improve survival.

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