Still You Hesitate to Use Ino?: Inotuzumab Ozogamicin Optimized Post-Transplant Outcomes in R/R Ph-Negative B-ALL
Authors: Koizumi Ryo , Takagi Shinsuke , Nishida Aya , Kuno Mika , Watanabe Otoya , Yamaguchi Kyosuke , Kageyama Kosei , Kaji Daisuke , Taya Yuki , Ishiwata Kazuya , Yamamoto Hisashi , Asano-Mori Yuki , Yamamoto Go , Wake Atsushi , Taniguchi Shuichi , Uchida Naoyuki 
Published: December 2024

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 &lt; 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&lt;0.01) and the first transplantation (HR 2.43, p&lt;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&lt;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&lt;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.