Outcomes of Hematopoietic Stem Cell Transplantation after Inotuzumab Ozogamicin Treatment for B-Cell Acute Lymphoblastic Leukemia without VOD/SOS
Authors: Jiang Erlie , Lv Mengnan , Zhai Weihua 
Published: December 2024

Introduction: AlloHSCT is still curative therapy to R/R B-ALL. Inotuzumab ozogamicin (INO) has demonstrated remarkable efficacy while several articles reported its high risk of veno-occlusive disease (VOD) , especially after bridging to HSCT. In this study, we summarized the outcome of HSCT in patients treated with InO without VOD.

Methods: Forty-four adult patients with B-ALL were treated with INO in our center between June 2022 and March 2024. INO was administered intravenously ≥ 1 doses (0.6 mg/m² per dose), either alone or combined with other chemotherapy. Frontline induction therapy was a standard induction regimen of VIC(L)P plus InO. TKI was administered upon the detection of BCR-ABL fusion gene. We analyzed 25 patients who underwent HSCT.

Results: Median age was 31 yr (range: 15-59 yr). There were 13 Ph+ and 12 Ph- patients. Three patients were with extramedullary disease. INO was used in induction (n=3), consolidation (n=3), MRD clearance (n=12) and R/R B-ALL treatment (n=7). The median number of INO doses administered was2 (range: 1-6). All patients achieved CR before HSCT, with 19 MRD negative. Four patients underwent 2nd alloHSCT following autoHSCT, while the remaining patients received HSCT for the first time. No patient discontinued INO due to adverse events. Grade 3-4 hematological toxicity was observed in 14/25 patients (56%).Grade 3 ALT elevation was observed in 1 patient.

Patients were given total body irradiation (TBI)-based (n=17) and non-TBI conditioning regimens(n=8). TBI regimen included TBI/CY, often supplemented with fludarabine (Flu), cladribine (Clad), cytarabine (Ara-C), melphalan (Mel), or thiotepa. Dosages were as follows: TBI (10Gy), CY (80mg/kg), Mel (100-150mg/m²), Flu (90mg/m²), Clad (15mg/m²), Ara-C (6g/m²), thiotepa (10mg/kg), and VP-16 (50mg/kg). For non-TBI conditioning regimens, primarily comprising intravenous busulfan (BU)/Mel (n=1), thiotepa/Clad (n=1), Mel/CY (n=5), or VP-16/CY (n=1), with BU 9.6mg/kg.

The median follow-up duration was 322 days (range: 162-577 days) after INO treatment and 211 days (range: 58-518 days) post-HSCT. For R/R B-ALL, the 1-yr overall survival (OS) and leukemia-free survival (LFS) rates post-transplantation were 53.6% (95% confidence interval [CI], 25.7-100.0%) and 28.6% (95% CI, 6.2-100.0%). For the remaining 18 patients, the 1-yr OS and LFS rates were 100% and 88.9% (95% CI, 75.5-100.0%),. The cumulative incidence of relapse at 1 year was 71.4% (95% CI, 1.8-97.2%) for R/R patients, and 11.1% (95% CI, 1.7-30.4%) for the remaining patients.

All patients achieved neutrophil and platelet recovery. The median time to neutrophil and platelet engraftment was 13 days (range: 10-20 days) and 20 days (range: 13-84 days). The incidence of grade I-IV aGVHD within 3 months of alloHSCT was 22.2±10.1%, and the incidence of cGVHD within 12 months was 38.1±38.1%.

It should be noted that none of the patients developed VOD/SOS. Several factors potentially contributed to this favorable outcome:

1) INO dosage: The median total INO dose was 2 (1-6) doses, or 1.2 mg/m2, which is lower than the 1.8 mg/m2 each cycle reported in the literature;

2) Timing: The median interval from last INO dose to HSCT was 76 days (range: 25-236 days).

3) Conditioning regimen: Despite the use of myeloablative conditioning regimens involving TBI, dialkylation agents, and trialkylation agents, drug dosages were reduced to mitigate toxicity (BU 9.6mg/kg, TBI 10Gy, Cy 60-80mg/kg, Mel 100-140mg/m²).

4) Prophylactic measures: All patients received ursodeoxycholic acid, heparin, compound salvia dripping pills, or alprostadil, to prevent VOD during transplantation and for one month thereafter.

5) Antifungal prophylaxis: Caspofungin was administered during pretreatment for fungal prophylaxis, followed by triazoles post-stem cell infusion.

6) Hepatitis status: No patient had active hepatitis before HSCT, and all patients had negative hepatitis virus quantification prior to HSCT.

7) Monitoring: Patients' biochemical indexes were closely monitored, with weekly abdominal ultrasound examinations to detect any early signs of complications.

Conclusion: INO is an effective treatment option for ND, MRD positive and R/R B-ALL particularly when followed by HSCT. VOD associated INO bridging to HSCT can be avoided through low cumulative dosages, reasonable conditioning regimen choose and combination therapy.