Still You Hesitate to Use Ino?: Inotuzumab Ozogamicin Optimized Post-Transplant Outcomes in R/R Ph-Negative B-ALL

Background

Inotuzumab ozogamicin (InO), an antibody-drug conjugate targeting CD22, has shown efficacy in relapsed or refractory B-cell acute lymphoblastic leukemia (R/R B-ALL). However, there are few real-world data comparing transplant outcomes after InO treatment to those after conventional standard chemotherapy.

Method

To evaluate the safety and efficacy of InO use for R/R B-ALL undergoing transplantation, we retrospectively investigated allogeneic hematopoietic cell transplant (HCT) recipients with R/R B-ALL in Toranomon Hospital from Jan. 2011 to Jun. 2024. The primary endpoint was the 2-year overall survival (OS). The secondary endpoints included cumulative incidence of relapse (CIR), non-relapse mortality (NRM) and cumulative incidence of sinusoidal obstruction syndrome (SOS). Kaplan-Meier method was used to estimate OS. Gray's test was used for CIR, NRM, and cumulative incidence of SOS. For multivariate analysis, Cox proportional hazards models were used with the forced entry method. All tests were two-sided, with p < 0.05 considered statistically significant. The standard chemotherapy (SC) group was defined to include patients who received neither InO nor blinatumomab (Blina).

Results

A total of 75 patients with R/R B-ALL were extracted (median age, 50 years; range, 22-70; 39 females). Philadelphia chromosome (Ph) were negative in 45 (60%) and positive in 30 patients (40%). Of 75 patients, 58 patients (77%) received SC and 20 (34%) achieved CR/CRi, whereas 17 (23%) received InO and 15 (71%) achieved CR/CRi. In 17 InO-treated patients, 13 used Blina sequentially (9 InO to Blina; 4 Blina to InO). Ultimately, 32 patients (43%) were in CR/CRi at the time of transplantation. Donor cell source was umbilical cord blood in 68 patients (91%), bone marrow in 4 (5%) and peripheral blood stem cell in 3 (4%). Of 75 transplants, 44 (59%) were the first-time transplant and 31 (41%) were second or subsequent transplant. Seven patients who underwent transplantation twice or three times were counted as separate cases. At 2 years post-transplant, the OS, CIR, and NRM were 29.4% (95% confidence interval [CI], 19.1-40.3), 28.6% (95% CI, 18.5-39.6), and 43.0% (95% CI, 31.2-54.2), respectively. The median follow-up time for survivors was 1346 days (range: 37-4470 days). Multivariate analysis identified myeloablative conditioning regimen (hazard ratio [HR] 2.40, p<0.01) and the first transplantation (HR 2.43, p<0.01) as significant favorable factors. InO use was identified as a factor tending to have a differential effect (HR 2.26, p = 0.06). Next, we compared outcomes of 2 pre-transplant salvage chemotherapy groups (InO vs. SC). Results showed that the InO group was significantly higher 2-year OS compared to the SC group (51.7% vs. 24.7%, p=0.04), whereas CIR (14.1% vs. 31.0%, p=0.3) and NRM (32.8% vs. 46.6%, p=0.2) were not significantly different. Additionally, we performed subgroup analysis according to Ph status. In Ph-negative patients, multivariate analysis identified myeloablative conditioning regimen (hazard ratio [HR] 5.37, p<0.0001) and InO use (HR 3.44, p =0.02) as significant favorable factors. In univariate analysis on Ph-negative patients, the InO group was significantly higher 2-year OS compared to the SC group (58.3% vs.12.5%, p<0.01), whereas CIR (8.3% vs. 40.6%, p=0.1) and NRM (31.7% vs. 46.9%, p=0.2) were not significantly different. On the other hand, there were no significant difference in Ph-positive patients. Lastly, we studied SOS post-transplant. Of the 75 patients, 19 developed SOS with a cumulative incidence of 25.5% (95% CI, 16.2-35.8) at day 100 post-transplant (6 patients [35%] in the InO group vs. 11 [19%] in the SC group, not significant). All patients received SOS-specific treatment including defibrotide or recombinant human thrombomodulin. SOS cured in 4 patients (67%) in the InO group and 6 (55%) in the SC group.

Conclusion

Our results encourage the salvage chemotherapy with InO before allogeneic HCT especially in Ph-negative R/R B-ALL patients. Compared to SC, InO had a higher remission induction rate, better post-transplant prognosis, and controllable post-transplant SOS.

Takagi:Otsuka Pharmaceutical Co.: Honoraria; Novartis Pharma Co.: Honoraria; Nippon Shinyaku Co.: Honoraria; MSD KK (Merck & Co. Inc.): Honoraria; Kyowa Kirin Co.: Honoraria; Janssen Pharmaceutical KK.: Honoraria; GlaxoSmithKline KK.: Honoraria; Daiichi Sankyo Co.: Honoraria; Chugai Pharmaceutical Co.: Honoraria; Astellas Pharma Inc.: Honoraria; Asahi Kasei Pharma Co.: Honoraria; Amgen KK.: Honoraria; AbbVie GK.: Honoraria; The Japanese Society of Hematology: Research Funding; Okinaka Memorial Institute for Medical Research: Research Funding; Pfizer Japan Inc.: Honoraria; Sumitomo Pharma Co.: Honoraria; Takeda Pharmaceutical Co.: Honoraria. Yamaguchi:AbbVie GK.: Honoraria; Nippon Shinyaku Co.: Honoraria. Kaji:Chugai Pharmaceutical Co.: Honoraria; Genmab: Honoraria; Eisai Co.: Honoraria; Pfizer Japan Inc.: Honoraria; Asahi Kasei Pharma Co.: Honoraria; Bristol Myers Squibb K.K.: Honoraria; Meiji Seika Pharma Co.: Honoraria; AbbVie GK.: Honoraria; Janssen Pharmaceutical KK.: Honoraria; AstraZeneca: Honoraria; Ono Pharmaceutical Co.: Honoraria; SymBio Pharmaceuticals: Honoraria; Sanofi K.K.: Honoraria; Takeda Pharmaceutical Co.: Honoraria. Yamamoto:JCR Pharmaceuticals Co.,Ltd.: Honoraria; AstraZeneca: Honoraria; Novartis Pharma Co.: Honoraria; Chugai Pharmaceutical Co.: Honoraria; Takeda Pharmaceutical Co.: Honoraria; MSD KK (Merck & Co.) Inc.: Honoraria; Janssen Pharmaceutical KK: Honoraria; Otsuka Pharmaceutical Co.: Honoraria; CSL Behring K.K: Honoraria; Astellas Pharma Inc.: Honoraria; Asahi Kasei Pharma Co.: Honoraria; Sumitomo Pharma CO.,Ltd.: Honoraria. Yamamoto:Sanofi K.K.: Honoraria; AstraZeneca: Honoraria; Bristol Myers Squibb K.K.: Honoraria; Chugai Pharmaceutical Co.: Honoraria; Daiichi Sankyo Co.: Honoraria; Eisai Co.: Honoraria; Genmab: Honoraria; Janssen Pharmaceutical KK.: Honoraria; Meiji Seika Pharma Co.: Honoraria; Pfizer Japan Inc.: Honoraria; Ono Pharmaceutical Co.: Honoraria; Novartis Pharma Co.: Honoraria; Nihonkayaku Co.: Honoraria; Mundi Pharma Co.: Honoraria; Takeda Pharmaceutical Co.: Honoraria. Uchida:Astellas Pharma Inc.: Consultancy; Chugai Pharmaceutical Co.: Research Funding; Fuji Pharma Co.: Research Funding; Sumitomo Pharma Co.: Research Funding; Nippon Boehringer Ingelheim Co.: Research Funding; JCR Pharmaceuticals Co.: Research Funding; CSL Behring: Honoraria; MSD (Merck & Co. Inc.): Honoraria; Asahi Kasei Pharma Co.: Honoraria; Astellas Pharma Inc.: Honoraria; AstraZeneca: Honoraria; AbbVie GK: Honoraria; Otsuka Pharmaceutical Co.: Honoraria; Kyowa Kirin Co.: Honoraria; SymBio Pharmaceuticals: Honoraria; Daiichi Sankyo Co.: Honoraria; Takeda Pharmaceutical Co.: Honoraria; Chugai Pharmaceutical Co.: Honoraria; Takeda Pharmaceutical Co.: Consultancy; Nippon Shinyaku Co.: Honoraria; Novartis Pharma Co.: Honoraria.