Incidence of Sinusoidal Obstruction Syndrome/Veno-Occlusive Disease in Patients Receiving Inotuzumab Ozogamicin Followed By Total Body Irradiation-Based Conditioning for Stem Cell Transplantation: A Risk Mitigation Strategy

Introduction:

Relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL) in adults remains a therapeutic challenge. While allogeneic hematopoietic stem cell transplantation (allo-HSCT) offers a potential cure, its success largely depends on achieving measurable residual disease (MRD) negativity before transplantation. Inotuzumab ozogamicin (INO) has emerged as an effective salvage therapy, demonstrating higher rates of MRD negativity compared to standard chemotherapy. However, the use of INO before allo-HSCT has raised concerns about the risk of sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD), particularly in relation to certain conditioning regimens. This study aims to investigate the incidence of SOS in adult R/R B-ALL patients who received INO prior to transplant, with a focus on the INO washout period and the conditioning regimen used in HSCT.

Methods:

We conducted a retrospective analysis of all adult patients with R/R B-ALL treated with INO followed by allo-HSCT. Medical records were reviewed to extract clinical and demographic data, including age, gender, diagnosis date, INO treatment details, transplantation information, and post-transplant outcomes. Attention was given to conditioning and the occurrence of VOD/SOS.

VOD/SOS was diagnosed according to the European Society for Blood and Marrow Transplantation (EBMT) criteria.MRD was assessed via MFC (sensitivity of 10^-4).

Results:

Our study included a total of 12 patients (10 male; age range 16-55 years). Eleven had Ph-negative B-ALL, and one had ALL stemming from chronic myeloid leukemia. Eight patients received a single INO cycle (66.6%), while 4 underwent two cycles (33.4%). The median time from INO initiation to transplantation was 52.5 days (range 32-265 days). Ten patients underwent matched donor HSCT with 10/10 HLA matching (99 siblings and one unrelated); the other two underwent Haplo-HSCT; ten patients were conditioned with a TBI-based regimen (8 with VP16/TBI (12 Gray), 2 with Flu/TBI/ATG (10 Gray), and 2 with thiotepa-busulfan3-fludarabine (TBF); all patients received ursodiol as a SOS prophylaxis started prior to conditioning at a dose of 6 mg/kg BID.

Only one patient (8.3%) developed SOS at day +20 post his second HSCT without end organ damage; he was conditioned with TBF and received tacrolimus and PTCY as a GVHD prophylaxis; the last INO dose was 32 days prior to SCT.

At the most recent follow-up (median 5.5 months post-transplant, range 2-9 months), all patients remained alive.

Discussion:

Our study suggests that using INO prior to HSCT for R/R B-ALL patients is relatively safe with low SOS incidence when using TBI-based conditioning and avoiding alkylator-based chemotherapy regimens. The majority of patients received TBI-based conditioning, and the only patient who developed SOS was already at high risk as it was his second HSCT using TBF conditioning, which includes Busulfan, which can cause SOS up to 12% in adults.

Our short-term survival outcomes are promising, with all patients alive at the last follow-up.

Our experience provides preliminary evidence supporting TBI-based conditioning after INO may be preferable over chemo-based conditioning approaches for SOS risk mitigation.

These observations have important implications for clinical practice and future research. Suggesting that carefully selected conditioning regimens may help mitigate SOS risk in INO-treated patients undergoing allo-HSCT. While these findings are promising, larger sample sizes and randomized clinical trials are needed to verify these findings.

Future research should focus on refining conditioning regimens, evaluating the role of SOS prophylaxis, and identifying patients with high-risk factors to guide individualized treatment approaches. Additionally, longer follow-up is needed to assess the durability of responses and long-term survival outcomes with this treatment strategy.

Conclusion:

Our experience suggests that INO followed by allo-HSCT with TBI-based conditioning may offer an effective and potentially safer approach for R/R B-ALL patients compared to chemotherapy-only regimens. While SOS risk remains a concern, our findings indicate it can potentially be mitigated through careful conditioning regimen selection. This study contributes valuable real-world data to inform clinical decision-making and guide future research efforts in refining R/R B-ALL treatment approaches.

Alfayez:Johnson & Johnson: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Astellas: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Biologics: Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria, Research Funding, Speakers Bureau. Saad:Sanofi: Consultancy; Kite: Consultancy.