Resource-adapted immunotherapy bridging to achieve measurable residual disease negativity before allogeneic hematopoietic stem cell transplantation in high-risk acute lymphoblastic leukemia: A single-center real-world experience

INTRODUCTION

High-risk acute lymphoblastic leukemia (ALL) remains a major therapeutic challenge when relapse biology, persistent measurable residual disease (MRD), prior cellular therapy, or donor limitations complicate the path to allo-HSCT. Achieving the deepest possible remission before transplantation is clinically relevant because lower disease burden at allogeneic hematopoietic stem cell transplantation (allo-HSCT) is associated with improved post-transplant disease control and survival. Blinatumomab and inotuzumab ozogamicin (InO) have therefore become important remission-deepening tools in B-lineage ALL, particularly when the aim is to bridge patients to transplant in better biologic condition.^[1-4]

However, the adoption of these agents in resource-constrained settings is limited not only by acquisition cost but also by delivery complexity. Blinatumomab requires continuous infusion, infusion pumps, trained nursing support, and early toxicity monitoring. InO is operationally easier to administer but may be constrained by fixed vial size, financial burden, and concern regarding sinusoidal obstruction syndrome/venoocclusive disease (SOS/VOD) before transplantation.^[3-6]

In this context, the practical question is not simply whether immunotherapy works, but whether it can be delivered safely, affordably, and with acceptable waste. Published pharmacoeconomic studies suggest that the cost profile of blinatumomab and InO is strongly shaped by hospitalization, administration design, and downstream transplant effects, rather than by drug price alone.^[7-10]

We therefore implemented a structured resource-adapted bridging program using blinatumomab and/or InO with operational modifications intended to reduce avoidable waste while preserving transplant safety. This manuscript expands our conference abstract into an IJMIO-style original article and places the findings within the published literature on cost-conscious immunotherapy use in ALL.

MATERIAL AND METHODS

RESULTS

Nine patients underwent allo-HSCT after MRD-negative bridging. The donor source was haploidentical related in 7 patients and a matched sibling in 2. All transplanted patients achieved MRD-negative status before allo-HSCT.

Blinatumomab was used in 6 of 9 patients. Five patients received 1 cycle, and 1 patient received 2 cycles. InO was used in 4 of 9 patients, with 3 doses per patient using the dose-capped strategy. One Philadelphia chromosome-positive multiply relapsed patient after chimeric antigen receptor T-cell therapy received ponatinib plus asciminib plus InO before transplantation.

Median blinatumomab utilization was 14.5 vials per cycle, corresponding to 38.5 mcg, with a range of 6–16 vials per cycle. All blinatumomab recipients developed grade 1 cytokine release syndrome. One patient developed grade 3 immune effector cell-associated neurotoxicity syndrome with seizure.

At data cutoff, relapse had occurred in 2 of 9 patients, with 1 death after relapse. The estimated 1-year Kaplan–Meier OS was 100%, and the estimated 1-year Kaplan–Meier LFS, defined by relapse or death, was 70%. NRM was 0%. No patient developed SOS/VOD, and no graft failure occurred. TMA occurred in 1 of 9 patients [Table 1].

The principal feasibility signal was that all transplanted patients in this high-risk cohort could be brought to MRD-negative allo-HSCT despite cost and delivery constraints, without an apparent early penalty in transplant safety.

DISCUSSION

This study addresses a question that is particularly relevant in India and other resource-limited settings: Can modern immunotherapy be adapted in a way that preserves efficacy while reducing avoidable cost and waste? In this cohort, the answer appears encouraging. All transplanted patients achieved MRD-negative status before allo-HSCT, and early transplant outcomes were favorable, with 0% NRM, 0% SOS/VOD, and 0% graft failure.

The present findings must be interpreted cautiously because the cohort is small, retrospective, and limited to aggregate abstract-level data. Nonetheless, the study is clinically meaningful because it focuses on implementation – an area often underreported in conventional efficacy manuscripts. In practice, barriers to blinatumomab and InO are frequently operational: Prolonged infusion logistics, wastage from fixed vial sizes, repeated bag changes, hospital bed occupancy, and clinician concern about hepatotoxicity before transplant.

Our blinatumomab strategy rested on a label-supported operational modification. The current prescribing information specifically allows use of 7-day infusion bags prepared with bacteriostatic 0.9% sodium chloride in appropriate patients.^[5]

This matters pharmacoeconomically because more frequent bag changes increase pharmacy workload, nursing contacts, and the risk of avoidable wastage. Consistent with this, a Children’s Oncology Group survey showed that only a minority of centers hospitalize children for the full 28-day infusion, whereas most programs use shorter inpatient monitoring with substantial outpatient or home-based administration.^[11]

A pharmacist-driven home-infusion pathway study from the United States reported actual inpatient drug acquisition savings of US$178,010 across 14 admissions, with average savings of US$12,715 per cycle and US$29,668 per patient.^[12]

These data do not directly prove cost savings in our setting, but they strongly support the principle that administration design is a major determinant of blinatumomab affordability.

The wider pharmacoeconomic literature also supports the value proposition of blinatumomab, although the economic frame matters. In a US payer analysis comparing blinatumomab with salvage chemotherapy, the incremental cost-effectiveness ratio was estimated at US$110,108 per quality-adjusted life-year (QALY), with a 74% probability of cost-effectiveness at a US$150,000/QALY threshold.^[13]

In another US analysis comparing blinatumomab with InO in adults with relapsed/refractory B-cell precursor ALL, incremental costs for blinatumomab versus InO ranged from US$7,023 to US$36,244 and incremental QALYs ranged from 0.54 to 1.78, producing incremental cost-effectiveness ratios of US$4,006 to US$20,737 per QALY gained.^[7]

Pediatric data show a similar trend toward favorable long-term value: A French analysis estimated an incremental cost-effectiveness ratio (ICER) of EUR 7,308/QALY for blinatumomab versus high-risk consolidation chemotherapy, and a Mexican analysis likewise concluded that blinatumomab was cost-effective in pediatric high-risk first-relapse disease.^[9,14]

The InO component of our program was driven by a different economic logic. InO is easier to administer than blinatumomab because it does not require continuous infusion, but pre-transplant hepatotoxicity remains a major concern. The pivotal INO-VATE trial showed superior remission and MRD-negativity rates with InO compared with standard therapy, but VOD was an important adverse event.^[3,4]

More recent transplant-focused real-world data have shown that SOS/VOD risk after allo-HSCT remains clinically relevant in patients exposed to InO, particularly with high-risk conditioning approaches.^[6]

Our use of dose capping, same-day vial sharing, and a planned washout interval before allo-HSCT was therefore designed to balance access with caution.

From a pharmacoeconomic perspective, published studies suggest that InO can be cost-effective versus standard chemotherapy but may also appear less expensive than blinatumomab in short-term real-world claims data because the hospitalization burden is lower. In a Norway/Sweden analysis, base-case ICERs for InO versus standard of care were EUR 16,219/QALY in Sweden and EUR 44,405/QALY in Norway, with all modeled estimates remaining below approximate willingness-to-pay thresholds.^[8]

In a US real-world analysis, total ALL-related monthly costs were 43% lower for InO than for blinatumomab (US$93,767 vs. US$163,470), driven in part by shorter hospitalization patterns.^[10]

The published literature informing cost-conscious use of blinatumomab and Ino is shown in Table 2.^[7-12,15]

These findings help explain why blinatumomab and InO should not be framed as universal economic winners or losers. Long-term value, short-term budget impact, administration burden, and transplant intent are different economic questions.

Our study also aligns with the broader implementation literature in low- and middle-income countries. Duffy et al. argued that expanding blinatumomab access in low- and medium-income countries requires workflow redesign, training, monitoring systems, and implementation science rather than drug availability alone.^[15]

The present series provides a practical example of that concept. The program was not based on compromising care, but on removing avoidable waste from high-cost care.

Several limitations must be acknowledged. This is a small retrospective single-center series. The manuscript is built from aggregate abstract data and therefore lacks granular patient-level biology, conditioning details, supportive care utilization, exact cost capture, and formal comparative statistical analysis. No within-cohort pharmacoeconomic analysis was performed, so the discussion on cost is contextual rather than primary data-driven. These limitations should restrain causal interpretation.

When the clinical objective is transplant in MRD-negative remission, the most relevant measure of value is not the drug price alone but whether a patient can reach allo-HSCT safely, on time, and in deeper remission. Resource-adapted delivery may therefore serve not as a compromise, but as a clinically meaningful pathway to equity in advanced leukemia care.

CONCLUSION

A structured resource-adapted bridging program using blinatumomab and/or InO enabled MRD-negative status and successful allo-HSCT in all transplanted patients in this small high-risk ALL cohort. The combination of label-supported blinatumomab delivery optimization, InO dose capping, vial sharing, and a planned transplant washout strategy was associated with encouraging early survival and no observed SOS/VOD or NRM. Prospective multicenter studies with formal cost capture are warranted.