Addition of Inotuzumab Ozogamicin to Melphalan Plus Fludarabine Reduced-Intensity Conditioning Regimen of Allogeneic Transplantation in Patients with Acute Lymphoblastic Leukemia and Aggressive Lymphoid Malignancies: A Phase II Prospective Trial

Background: Inotuzumab ozogamicin (INO) is a humanized antibody-drug conjugate that targets CD22+ B-cells. We recently demonstrated that INO can be added safely to a non-myeloablative conditioning of bendamustine, fludarabine, and rituximab in patients with indolent lymphoid malignancies who required an allogeneic hematopoietic transplantation (HCT) (Am J Hematol 2024). No increased risk of veno-occlusive disease was observed. Patients with acute lymphoblastic leukemia (ALL) are frequently exposed to targeted therapy with INO prior to their HCT. In addition, patients with ALL and aggressive lymphoma require more intense conditioning than bendamustine, fludarabine, and rituximab should HCT be required. The safety of INO in these circumstances is unknown.

Patients and Methods: The eligibility criteria were age 18-70 years with CD22(+) disease requiring HCT. The other inclusion criteria were an ECOG performance status score of 0-2 and adequate liver function (serum bilirubin <2 mg/dL and liver enzyme <2 times the upper limit of normal), renal function (creatinine ≤1.6 mg/dL), cardiac function (ejection fraction ≥45%), and pulmonary function (≥50% of predictive value). In addition, patients were required to have a 6/6 HLA-compatible sibling donor or an HLA-A, HLA-B, HLA-C, and DRB1-matched unrelated donor (MUD) if no sibling donors were available. INO was infused intravenously (IV) on day -13 outpatient, at a dose of 0.3 mg/m². Fludarabine 30 mg/m² IV daily on days -5 to -2 and melphalan 140 mg/m² IV on day -2 were given prior to HCT. Tacrolimus and mini-methotrexate were used for graft versus host disease (GVHD) prophylaxis. Patients who received transplants from MUDs received an additional dose of methotrexate 5 mg/m² on day +11 and 1 mg/kg of rabbit anti-thymocyte globulin IV on days -1 and -2 before HCT.

Results: The study included 9 patients with a median age of 54 (range, 27-64) years. Disease types included B-ALL (n=7 [6 in first complete remission (CR1) and 1 in CR2]) and lymphoma (n=2; 1 with Richter’s transformation and 17p deletion), and they all expressed CD22. Risk factors for patients with ALL included the presence of TP53 mutation with complex cytogenetics in 3 patients; 1 also had KMT2A mutation, and another had primary induction failure sensitive to salvage. One additional patient had KMT2A mutation, 1 had IKZF1 mutation with persistent minimal residual disease detected by clonoSEQ, and 1 had Philadelphia-like (Ph) disease. The patient who was in CR2 at transplant had Ph+ ALL and was maintained on ponatinib after HCT. Key prior therapies in ALL patients included blinatumomab (n=5) and INO (n=5). The maximum doses of INO received prior to HCT were 1.2, 1.5, 2.7, and 2.7 mg/m²; 1 patient received an unknown dose at an outside facility. Six (67%) received their transplants from matched sibling donors and 3 (33%) from MUDs. All patients experienced engraftment after receiving unmanipulated donor grafts. Neutrophil counts recovered to more than 0.5 x 10⁹/L a median of 12 days after HCT (range, 9-19 days). Platelet counts recovered to more than 20 x 10⁹/L after a median of 13 days (range, 0-27 days). All patients experienced donor cell engraftment, and no secondary graft failure occurred. None of the treated patients developed veno-occlusive disease. Treatment-related mortality at 2 years was 14%. With a median follow-up of 13 months (range, 1-36 months), the 2-year overall survival and progression-free survival rates were 62% and 60%, respectively. Two patients experienced a relapse: 1 with initial primary induction failure with TP53 mutation and 1 with KMT2A mutation who had extramedullary sarcoma at relapse after HCT. The 2 other patients with TP53 mutation and complex cytogenetics remained alive at 18 and 36 months. The 2 relapsed patients died, together with the Ph-like ALL patient who died in CR due to GVHD. The incidence of grade II-IV GVHD was 48%. One patient had chronic extensive GVHD.

Conclusions: Our conclusions are limited by the small number of patients due to slow accrual. However, our data suggest that INO is safe when combined with a melphalan plus fludarabine HCT conditioning regimen. The survival outcomes are encouraging and need to be validated in a larger number of patients. Currently, post-transplant cyclophosphamide has been implemented to lessen the risk of GVHD.