P375: inotuzumb ozogamicin prior to allogeneic hematopoietic stem cell transplantation in relapsed or refractory acute b-lymphoblastic leukemia

Background: Inotuzumab ozogamicin (INO) is a humanized anti-CD22 monoclonal antibody conjugated to calicheamicin, developed as a targeted therapy for B-cell malignancies and favorable efficacy in patients (pts) with relapsed or refractory (r/r) acute lymphoblastic leukemia (ALL). At present, allogeneic hematopoietic stem cell transplantation (allo-HCT) is considered a curative option for pts with r/r B-ALL with best outcomes achieved after effective salvage therapy and allo-HCT in complete remission (CR). Veno-occlusive disease, also known as sinusoidal obstruction syndrome (VOD/SOS), is a potentially life-threatening complication of allo-HCT. Furthermore, rates of VOD/SOS may be further increased after pre-treatment with INO. Aims: To characterize a series of r/r B-ALL pts and evaluate outcome after treatment with INO prior to allo-HCT, particularly with respect to risk of VOD/SOS. Methods: We studied 61 r/r pts (median age, 42 years; range, 16-69 years), who were treated with INO between 2016 and 2022 within a compassionate use program (n=7) or in-label after EMA approval (n=54). Fifty (82%) of the 61 pts were heavily pretreated receiving intensive chemotherapy +/- TKI, as well as blinatumomab in 24 (39%), respectively. In addition, allo-HCT at first-line therapy was performed in 11 (18%) pts. All 61 pts were CD22 positive at relapse/progressive disease. Up to 6 INO cycles (1 cycle, n=24; 2 cycles, n=31; 3-4 cycles, n=4; ≥5-6 cycles, n=2) were administered according to the approved regimen. Results: At the time of r/r B-ALL median white blood cell and platelet counts were 5.7/nl (range, 0.2-127/nl) and 104.5/nl (range, 6-400/nl), respectively. Median blast cell count in bone marrow was 36% (range, 0-98%). Twenty-two (36%) pts were female; ECOG was 0 in 60% and 1 or 2 in 40%. Cytogenetic analysis at the time of r/r ALL was available in 27 pts (44%). Eight pts displayed a t(9;22), 10 had a normal karyotype, 4 were complex and 5 had other abnormalities. Fourty-two (75%) of 56 evaluated pts achieved CR after the first INO cycle. Prior to allo-HCT, 52 (85%) of 61 pts achieved CR, 4 (7%) a partial remission, 4 (7%) were refractory and one (1%) with CR after INO relapsed directly before allo-HCT. Median follow-up was 30.5 months (95%-CI, 25.7-41.6) and median overall survival (OS) measured from start of INO was 12.2 months (95%-CI, 7.59-37.1 months). One- and two-years OS rates were 50% (95%-CI, 39-65%) and 37.5% (95%-CI, 26-53%), respectively. VOD/SOS after allo-HCT occurred in 17 (28%) pts. Of those, 9 (53%) pts died due to VOD and multi-organ failure. One had received 5 INO cycles, all others ≤2 INO cycles prior to allo-HCT. In univariable analyses risk factors for VOD/SOS were allo-HCT during first-line therapy (P=0.06) as well as time between last INO and allo-HCT below 60 days (P=0.06). In addition, multivariable models revealed a negative impact of pretreatment with blinatumomab (P=0.05) and allo-HCT during first-line therapy (P=0.03). Relapse/progressive disease occurred in 14 (23%) pts. Of those, only two pts are still alive, all others succumbed of their disease. Cumulative incidences of relapse/progression and death after 20 months were 33% (standard error, (SE) 4.2%) and 38% (SE, 4.3%), respectively. Sixteen (26%) pts died in remission and 22 (36%) pts are in ongoing CR. Summary/Conclusion: This outcome analysis demonstrates that treatment with INO is an effective approach with successful bridge-to-transplant. However, risk of VOD/SOS is high, necessitating continuous monitoring and recognition of VOD/SOS risk factors. Keywords: Allogeneic hematopoietic stem cell transplant, Acute lymphoblastic leukemia, Monoclonal antibody, Clinical outcome