Real-world treatment outcome and toxicity analysis of inotuzumab ozogamicin in adult patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia: multicenter prospective observational study

Abstract

Background:

Adults with relapsed or refractory (R/R) B-cell precursor acute lymphoblastic leukemia (BCP-ALL) have dismal prognoses, underscoring the need for effective salvage therapies. Inotuzumab ozogamicin (INO) and blinatumomab (BLIN) have demonstrated efficacy in achieving complete remission (CR) and measurable residual disease (MRD) response.

Objectives:

We tried to evaluate the clinical outcomes and toxicities of INO in adults with R/R BCP-ALL.

Design:

Prospective observational multicenter study.

Methods:

A total of 100 patients (25 Ph-positive, 75 Ph-negative) received INO (0.8 mg/m² on week 1; 0.5 mg/m² on weeks 2–3) for the initial cycle, followed by 0.5 mg/m² dosing in subsequent cycles. Allogeneic hematopoietic cell transplantation (allo-HCT) was planned after remission.

Results:

Among the cohort, 7 patients were primary refractory (4 post-BLIN), 36 relapsed after chemotherapy (23 post-BLIN), and 57 relapsed after allo-HCT (23 post-BLIN). Extramedullary relapse occurred in 39% of patients. After the first cycle, 60% achieved CR or CR with incomplete hematologic recovery; the overall best response rate after two cycles was 67%, with MRD negativity achieved in 63.1%. Thirty-nine patients (58.2%) underwent allo-HCT. Early mortality occurred in 12%, and hepatic veno-occlusive disease/sinusoidal obstruction syndrome was observed in 10%. With a median follow-up of 31.5 months, the 3-year overall survival was 21.3% in the entire cohort and 37.6% among transplanted patients.

Conclusion:

INO represents a potent salvage option for R/R BCP-ALL. However, substantial toxicities highlight the critical need for careful patient selection and dose optimization strategies to maximize its therapeutic benefit.

Trial registration:

This study was registered in Clinical Research Information Service (CRIS #KCT0010009) which is connected to WHO ICTRP (Operated by Korea Centers for Disease Control and Prevention, Ministry of Health and Welfare, Republic of Korea).

Keywords

acute lymphoblastic leukemia blinatumomab inotuzumab ozogamicin salvage sinusoidal obstruction syndrome

Introduction

Acute lymphoblastic leukemia (ALL) is an aggressive hematologic malignancy caused by the clonal proliferation of lymphoblasts that are arrested at a state of incomplete differentiation in the blood, bone marrow (BM), and other tissues. Although the complete remission (CR) rates exceed 90% in adults with B-cell precursor acute lymphoblastic leukemia (BCP-ALL), many patients continue to relapse, with a long-term overall survival (OS) rate of 20%–40% after intensive chemotherapy or allogeneic hematopoietic cell transplantation (allo-HCT).^1
–4

Recent data indicate that approximately 350 new cases of ALL are diagnosed annually in South Korea.⁵ Among these, 80–100 patients per year are diagnosed as relapsed or refractory (R/R) BCP-ALL and undergo several lines of salvage therapy. For R/R BCP-ALL, allo-HCT after achieving CR remains the best curative option.⁶ However, it has been difficult to achieve a CR with conventional chemotherapy due to treatment-related toxicity and insufficient response.⁷ In addition, allo-HCT is still associated with a high non-relapse mortality (NRM) rate, including various acute and chronic complications.^8
–10 Prior to the development of blinatumomab (BLIN) and inotuzumab ozogamicin (INO), there were no established treatments for R/R BCP-ALL, resulting in significant advancements in treatment approaches and improved outcomes.^11
–14

BLIN obtained reimbursement approval in South Korea earlier than INO and has been widely utilized as first-line salvage therapy at a much higher rate compared to conventional chemotherapy. Two real-world studies published in Korea demonstrated that the efficacy and safety of BLIN exceeded those observed in the TOWER trial.^15,16 However, to date, only a few real-world data of INO have been introduced, and no large data have been published in Asian countries. Consequently, there is a significant unmet need for real-world data reflecting the outcomes of patients treated with INO in actual clinical settings. In this prospective multicenter study, we tried to evaluate the real-world clinical efficacy and toxicity of INO in adult patients with R/R BCP-ALL, with the primary outcome being overall response rate (ORR, CR+ incomplete CR), and key secondary outcomes including OS, measurable residual disease (MRD) response, allo-HCT implementation rate, and incidence of adverse events (AEs).

Methods

Study design and population

This is a prospective, multi-center, real-world observational study that was conducted from October 2019 to December 2023. Inclusion criteria were adults (⩾19 years old) diagnosed with CD22-positive R/R BCP-ALL who were treated with INO salvage after failure to remission induction chemotherapy or relapsed post-chemotherapy or -allo-HCT. Both Philadelphia chromosome (Ph)-positive and Ph-negative BCP-ALL were eligible for enrollment. Exclusion criteria were patients younger than 19 years old. Overall, 100 patients were gathered from Seoul St. Mary’s hospital (n = 79), Asan Medical Center (n = 8), Chungnam National University Hospital (n = 7), and Chonnam National University Hwasun Hospital (n = 6). This study was approved by the Institutional Review Board of each healthcare center and was conducted in accordance with the Declaration of Helsinki. This study was registered in Clinical Research Information Service (CRIS #KCT0010009), which is connected to the WHO ICTRP (Operated by Korea Centers for Disease Control and Prevention, Ministry of Health and Welfare, Republic of Korea). The reporting of this study conforms to the STROBE statement.¹⁷

Treatment protocol

For R/R BCP-ALL patients, both BLIN and INO have been available from first-line salvage since 2019. Thus, there were many patients who failed to previous BLIN. INO was administered as a monotherapy in cycles of up to three doses per cycle and all enrolled patients received a median of two cycles of INO (range: 1–5). Dosage was determined by body surface area (BSA), with adjustments based on tolerability. Initial dosages included 0.8 mg/BSA (week 1) and 0.5 mg/BSA (week 2–3), with subsequent cycles at 0.5 mg/BSA (week 1–3) for patients in CR. If patients failed to INO, BLIN, or traditional intensive chemotherapy were sequentially applied for salvage.^7,16 For patients who achieved CR, allo-HCT was offered as early as possible if a matched sibling donor (MSD) or ⩽1 allele-mismatched unrelated donor (URD) was available. Patients with no available MSD or URD were offered HCT using cord blood or haploidentical related donor grafts as an alternative source. The myeloablative conditioning (MAC) regimen for patients receiving MSD-HCT or URD-HCT consisted of total body irradiation (TBI, 1320 cGy in total) and cyclophosphamide (120 mg/kg in total), while the reduced-toxicity conditioning regimen consisted of fludarabine (150 mg/BSA in total) and busulfan (9.6 mg/kg in total). The detailed transplantation procedures were introduced in our previous publications.^{4,7,16,18
–20}

Endpoints and disease-related parameters

The primary endpoint was the rate of ORR, while the secondary endpoints included the rate of MRD negative conversion rate, allo-HCT proceeding rate, OS, disease-free survival (DFS), and AEs. The International System for Cytogenetic Nomenclature (ISCN) was used to detect clonal abnormalities,²¹ which were classified into risk subgroups according to the National Comprehensive Cancer Network (NCCN) guidelines. Poor-risk cytogenetics were defined as complex karyotype, defined as five or more chromosomal aberrations, hypodiploidy, and KMT2A rearrangements, while other abnormalities were classified into standard-risk cytogenetics. Cytoplasmic CD22 expression was calculated by the proportion of leukemic blasts using flow cytometry (BD Biosciences, San Jose, CA, USA). CR was defined as ⩽5% BM blasts, absolute neutrophil count >1 × 10⁹/L, and platelets >100 × 10⁹/L, and incomplete CR was defined as CR without full recovery of blood counts. Complete molecular response was defined as no detectable level of MRD using a high-throughput sequencing method for clonal rearrangements of immunoglobulin gene (assay sensitivity, <10⁻⁶) which was assessed by the LymphoTrack^® IGH FR1/2/3 assay panel (InVivoScribe Technologies, San Diego, CA, USA) from a BM sample. Amplified and purified amplicons were measured by Agilent 2100 BioAnalyzer (Agilent Technologies, Inc., Santa Clara, CA, USA).²² MRD monitoring for BCR::ABL1 transcripts was centrally evaluated by real-time quantitative PCR with 5.0-log sensitivity.

Statistical analysis

As for sample size by the conditional method, the remission rate in the INO-VATE phase III trial was reported to be 81.5%, while the real-world data on BLIN, analyzed and published by our research team, showed a remission rate of 67.5%. Assuming that a similar remission rate would be observed in this study compared to our previous findings on BLIN, with a non-inferiority margin of 0.15, the appropriate sample size was calculated as 95 patients at a significance level of 0.01 and a power of 0.8. Considering a dropout rate of 5%, the target enrollment was set at 100 patients. Survival curves were plotted using the Kaplan–Meier method and compared by log-rank tests. Relapse and NRM were calculated using cumulative incidence estimates to accommodate the following competing events: death for relapse and relapse for NRM, and groups were compared by the Gray test. The prognostic significance of covariates affecting DFS was determined using a Cox proportional hazards model. Prognostic significances of covariates affecting cumulative incidence of relapse (CIR) and NRM were determined using Fine-Gray proportional hazards regression for competing events. Data analyses were performed using R software (version 4.4.1; R Foundation for Statistical Computing, Vienna, Austria) and EZR software (version 1.68; Jichi Medical University, Saitama, Japan), and a p-value of <0.05 was considered statistically significant.²³

Results

Patient characteristics

A total of 100 patients with a median age of 39 years (range: 19–83) were enrolled in this study and prospectively observed for analyses of treatment outcomes regarding disease-related parameters (Table 1). Seven patients (7.0%) were primary refractory (BLIN failure in 4), while 36 (36.0%) relapsed after chemotherapy (BLIN failure in 23), and 57 (57.0%) relapsed after allo-HCT (BLIN failure in 23). Among the 50 patients with BLIN failure, 30 were BLIN refractory and 20 were relapse after BLIN-induced CR. Early relapses with CR duration (CRD) <12 months were observed in 60 (60.0%) patients, while 33 (33.0%) were late relapses with CRD ⩾12 months. As a marker of tumor burden, high BM blast count > 80% was observed in 40%, and significant cytoplasmic CD22 expression on blast >20% was observed in 63% of patients. Among the 75 patients with Ph-negative ALL, poor-risk karyotype was observed in 49 (65.3%) patients. Among the 39 patients with extramedullary relapses (EMR), 11 of them had isolated EMR and 28 had concomitant bone marrow relapses (BMR).

Table 1.

Baseline characteristics of patients.

Parameters	Value
Age, median (range), years	39 (range 19–83)
<40 years	50 (50.0%)
⩾40 years	50 (50.0%)
Male gender	54 (54.0%)
Disease status
Primary refractory disease	7 (7.0%)
Relapses after chemotherapy	36 (36.0%)
Relapses after previous allo-HCT	57 (57.0%)
CRD^a, median (range), months	8.2 (0.6–142.5)
CRD <12 months	60 (60.0%)
CRD ⩾12 months	33 (33.0%)
BM blasts, median (range), %
<5%	13 (13.0%)
5% to <80%	47 (47.0%)
⩾80%	40 (40.0%)
CD22 expression^b
<20%	29 (29.0%)
⩾20%	63 (63.0%)
Cytogenetic risk before INO salvage, n (%)
Ph-positive ALL	25 (25.0%)
Ph-negative ALL	75 (75.0%)
Standard-risk	26 (34.7%)
Poor-risk	49 (65.3%)
Disease site
BM alone	61 (61.0%)
BM + extramedullary	28 (28.0%)
Extramedullary alone	11 (11.0%)
INO salvage lines
1st line salvage	38 (38.0%)
2nd line salvage	32 (32.0%)
3rd line salvage	19 (19.0%)
4th line salvage	11 (11.0%)
Allo-HCT proceeding	47 (47.0%)
INO-induced CR	39 (83.0%)
Other salvage chemotherapy induced CR	8 (17.0%)
Conditioning intensity
Myeloablative	23 (48.9%)
Reduced toxicity	24 (51.1%)
Donor
Matched sibling donor	6 (12.8%)
Unrelated donor	22 (46.8%)
Haploidentical donor	9 (19.1%)
Cord blood	2 (4.3%)

CRD was calculated in 93 patients, excluding 7 patients with primary refractory disease.

Flow cytometry data were available in 92 patients at relapse.

allo-HCT, allogeneic hematopoietic cell transplantation; BM, bone marrow; CR, complete remission; CRD, CR duration; INO, inotuzumab ozogamicin.

Response to INO treatment

During first cycle with 3 doses of INO, 12 (12.0%) patients showed early deaths without BM evaluation—10 patients died after 1 dose and 1 patient died after 2 doses of INO showing sudden hepatic failure mimicking tumor lysis syndromes (TLS), and 1 died of sepsis and progressive multiorgan failure (MOF) after 3 doses of INO (Supplemental Table 1). Most of early deaths were hepatic failure, needed for differential diagnosis among viral hepatitis, hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS), and TLS, or infectious complications including sepsis, pneumonia, and viral infection leading to MOF. Among the 88 patients evaluated after first cycle of INO, 60 (60.0%) patients showed overall response (CR 35, incomplete CR in 25), while 28 (28.0%) showed failed response to INO—12 patients with partial response went on to the second cycle of INO, and 12 received other salvage therapy and next treatment was delayed in 4 patients due to infection and liver toxicity. We found out that the response to INO was not significantly influenced by any disease-related parameters in terms of early relapse with CRD <12 months, line of salvage, EMR status, and BM blast proportion and CD22 expression. Among the 60 responders after the first INO cycle, 7 underwent allo-HCT, 1 delayed next treatment, and the rest 52 went on to the second INO cycle (Table 2).

Table 2.

Response to INO treatment and allo-HCT realization.

Parameters	Value
At the end of the first cycle (n = 100)
Overall response (CR + incomplete CR)	60 (60.0%)
Relapse duration
Primary refractory	4/7 (57.1%)
CRD <12 months	37/60 (61.7%)
CRD ⩾12 months	19/33 (57.6%)
Line of salvage
1st line	23/38 (60.5%)
2nd line	17/32 (53.1%)
3rd line	12/19 (63.2%)
4th line	8/11 (72.7%)
EMR status
BMR alone	38/61 (62.3%)
BMR+EMR	15/28 (53.6%)
Isolated EMR	7/11 (63.6%)
Allo-HCT in CR after one cycle of INO	7/60 (11.7%)
Treatment delay after one cycle of INO	1/60 (1.7%)
Early death during the first INO cycle	12 (12.0%)
INO failure	28 (28.0%)
INO second cycle	12 (12.0%)
Another salvage	12 (12.0%)
Treatment delay (i.e., VOD, infection)	4 (4.0%)
At the end of the second cycle (n = 64, 52 CR, 12 PR)
Overall response	54 (84.3%)
Persistent CR	47/52 (90.3%)
Relapse	5/52 (9.7%)
New CR	7/12 (58.3%)
Relapse status
Primary refractory	3/4 (75.0%)
CRD <12 months	20/23 (87.0%)
CRD ⩾12 months	31/37 (83.8%)
Line of salvage
1st line	22/27 (81.5%)
2nd line	15/17 (88.2%)
3rd line	11/12 (91.7%)
4th line	6/8 (75.0%)
EMR status
BMR alone	32/36 (88.9%)
BMR+EMR	14/19 (73.7%)
Isolated EMR	8/9 (88.9%)
Allo-HCT after two cycles of INO	32/54 (59.2%)
Deaths during CR	9/54 (16.7%)
Relapses after CR	10/54 (18.5%)
Alive in CR	3/54 (5.6%)
MRD <0.001% in patients with persistent CR	24/38 (63.1%)
Allo-HCT in INO-induced CR, n (%)	39/100 (39.0%)
Cumulative incidence of relapses at 3 years, % (95% CI)	45.8 (28.8–61.2)
Transplant-related mortality at 3 years, % (95% CI)	25.8 (13.2–40.4)
Overall survival rate at 3 years, % (95% CI)	37.6 (21.8–53.5)

Allo-HCT, allogeneic hematopoietic cell transplantation; BMR, bone marrow relapses; CI, confidence interval; CR, complete remission; CRD, CR duration; EMR, extramedullary relapses; INO, inotuzumab ozogamicin; PR, partial remission; VOD, veno-occlusive disease.

Overall, 64 patients were treated with a second cycle of INO—5 relapsed from the 52 responders, while 7 achieved response (CR 3, incomplete CR 4) from the previous 12 partial responders. Among the 54 responders after the second INO cycle, 32 patients underwent allo-HCT, 9 died in remission, and 10 showed subsequent relapse. Our final analysis showed the best response to INO was observed in 67 (67.0%) patients (CR 38, incomplete CR 29) with MRD response of 63.1% (24 out of 38 evaluable cases), and allo-HCT was conducted in 39 (39.0%) patients. Other salvage chemotherapy followed by allo-HCT was successfully done in eight patients, and three are alive in remission after a median follow-up duration of 30.3 months (Table 2).

Survival analysis

With a median follow-up period of 31.5 months (range: 13.5–61.8 months), 3-year OS, DFS, NRM, and CIR rates were 21.3% (95% CI 13.4–30.5), 22.0% (95% CI 12.5–33.2), 34.0% (95% CI 24.8–43.4), and 48.1% (95% CI 35.2–59.9), respectively (Supplemental Figure 1). As was suggested in response rates to INO salvage, those survival outcomes were not specifically affected by several disease-related parameters like age, blast counts in BM or peripheral blood (PB), CD22 expression, and poor karyotype at relapse, but only early relapse with CRD <12 months showed poor 3-year OS (10.1% vs 39.4%, p = 0.020) and DFS (10.5% vs 41.9%, p = 0.006) showing higher relapse rate (55.9% vs 35.5%, p = 0.157) compared to late relapse with CRD ⩾12 months (Figure 1). Multivariate analysis (Table 3) also revealed that only early relapses with CRD <12 months showed poorer 3-year OS (HR 1.824, 95% CI 1.09–1.82, p = 0.022) and DFS (HR 1.832, 95% CI 1.83–1.12, p = 0.015). Among them, 39 patients finally proceeded to allo-HCT during CR after INO salvage, while 61 failed INO, and the 3-year OS of each group was 37.6% and 13.7% (p < 0.001), and 3-year DFS was 26.9% and 15.7% (p = 0.018), respectively (Figure 2).

Figure 1.

Survival outcomes after salvage therapy using INO. (a) OS according to CRD (early relapse: CRD <12 months vs late relapse: CRD ⩾12 months). (b) DFS according to CRD (early relapse: CRD <12 months vs late relapse: CRD ⩾12 months).

Table 3.

Multivariate analysis of affecting factors for response to INO and OS in R/R BCP-ALL.

Variables	Response to INO				Overall survival
	Univariate		Multivariate		Univariate		Multivariate
	ORR (%)	p	OR (95% CI)	p	3-Year OS (%)	p	HR (95% CI)	p
Age		0.671				0.280
<40 years old (n = 50)	47.8		—		24.1		—
⩾40 years old (n = 50)	52.2		—		19.6		—
BM blast at relapse		0.516				0.478
<80% (n = 60)	62.7		—		26.5		—
⩾80% (n = 40)	37.3		—		12.5		—
PB blasts at INO salvage		0.668				0.478
<5% (n = 60)	58.2		—		26.5		—
⩾5% (n = 40)	41.8		—		12.5		—
CD22 expression		0.793				0.369
<20% (n = 29)	26.9		—		20.7		—
⩾20% (n = 63)	64.2		—		23.4		—
EMR		0.389				0.736
No (n = 61)	64.2		—		19.4		—
Yes (n = 39)	35.8		—		23.1		—
Cytogenetic risk		0.166				0.581
Standard-risk (n = 26)	31.3		—		23.2		—
Poor-risk (n = 49)	43.3		—		19.7		—
Ph-positive (n = 25)	25.4		—		20.0		—
INO salvage line		0.817				0.282
1–2 lines (n = 70)	68.7		—		24.8		—
3–4 lines (n = 30)	31.3		—		13.3		—
Disease status		0.822				0.021
CRD ⩾12 months (n = 33)	34.3		—		39.4		1
CRD <12 months (n = 67)	65.7		—		10.1		1.824 (1.1–3.1)	0.022

Boldface suggests statistical significance.

Allo-HCT, allogeneic hematopoietic cell transplantation; BM, bone marrow; CR, complete remission; CRD, complete remission duration; EMR, extramedullary relapses; INO, inotuzumab ozogamicin; ORR, overall response rate; OS, overall survival; R/R BCP-ALL, relapsed or refractory B-cell precursor acute lymphoblastic leukemia.

Figure 2.

Survival outcomes after INO salvage. (a) OS after INO followed by allo-HCT versus INO failure. (b) DFS after INO followed by allo-HCT versus INO failure.

Transplantation outcomes

In the subgroup of patients treated with allo-HCT following INO-induced CR (n = 39), 3-year OS, DFS, NRM, and CIR rates were 37.7% (95% CI 21.4–54.1), 27.3% (95% CI 14.0–42.4), 25.8% (95% CI 13.2–40.4), and 45.8% (95% CI 28.8–61.2), respectively (Supplemental Figure 2). Age, preconditioning intensity, and adverse-risk cytogenetics were not significant for transplantation outcomes, while early relapses with CRD <12 months showed inferior 3-year OS (64.3% vs 15.2%, p = 0.043), 3-year DFS (48.2% vs 14.6%, p = 0.038), showing higher CIR rate (64.2% vs 25.8%, p = 0.013), and alternative donors, including haploidentical donor transplantation (HIDT) and cord blood transplantation (CBT) showed poor 3-year OS (49.6% vs 0.0%, p = 0.002), 3-year DFS (38.9% vs 0.0%, p < 0.001), showing a higher NRM rate (54.5% vs 14.3%, p = 0.013) associated with VOD/SOS, graft-versus-host disease (GVHD), post-transplantation lymphoproliferative disese (PTLD), and infection (Figure 3). Multivariate analysis revealed that CRD <12 months showed inferior 3-year OS (HR 5.667, 95% CI 1.49–21.5, p = 0.011) and DFS (HR 5.608, 95% CI 1.51–20.9, p = 0.010) showing higher CIR rate (HR 4.772, 95% CI 1.21–18.8, p = 0.026), and alternative donors showed poor 3-year OS (HR 7.463, 95% CI 1.70–32.0, p = 0.006) and DFS (HR 8.866, 95% CI 2.14–36.7, p = 0.002) showing higher NRM rate (HR 4.610, 95% CI 1.34–15.8, p = 0.015).

Figure 3.

Transplantation outcomes after INO salvage. (a) OS after allo-HCT according to CRD (early relapse: CRD <12 months vs late relapse: CRD ⩾12 months). (b) DFS after allo-HCT according to CRD (early relapse: CRD <12 months vs late relapse: CRD ⩾12 months). (c) OS after allo-HCT according to donor types (Conventional donors: MSD and URD vs Alternative donors: HIDT and CBT). (d) NRM after allo-HCT according to donor types (Conventional donors: MSD and URD vs Alternative donors: HIDT and CBT).

Adverse events

The most frequently reported AEs were hematological toxicity, including lymphopenia (80.0%), neutropenia (67.0%), thrombocytopenia (62.0%), and anemia (47.0%). Grade 3–4 neutropenia, thrombocytopenia, and anemia were observed in 56.0%, 46.0%, and 31.0%, respectively. Hematological toxicities were followed by hepatotoxicity in 51% and infectious complications in 34%. Grade 3–4 hepatotoxic AEs were observed in 12%, and severe to very severe hepatic VOD/SOS was observed in 8%. Regarding rare complications, several cases of cardiotoxicity, including arrhythmia, cardiomyopathy, heart failure, and coronary artery disease, were observed. Additionally, renal toxicity and neurotoxicity were noted, although a definitive causal relationship remains uncertain (Table 4).

Table 4.

Toxicity during INO treatment.

Adverse events	All grades	Grade 3–4
Skin rash	3 (3.0%)	1 (1.0%)
Arthralgia	5 (5.0%)	2 (2.0%)
Hematological toxicity
Neutropenia	67 (67.0%)	56 (56.0%)
Lymphopenia	80 (80.0%)	12 (12.0%)
Anemia	47 (47.0%)	31 (31.0%)
Thrombocytopenia	62 (62.0%)	46 (46.0%)
Hepatotoxicity	51 (51.0%)	12 (12.0%)
Hepatic VOD/SOS	10 (10.0%)	8 (8.0%)
Infection	34 (34.0%)	24 (24.0%)
Gastrointestinal	16 (16.0%)	3 (3.0%)
Others	2 Edema	1 Heart failure
	2 Arrhythmia	1 coronary artery disease
	2 Cardiomyopathy
	1 Ocular pain
	1 Neurotoxicity
	1 Acute kidney injury

INO, inotuzumab ozogamicin; VOD/SOS, veno-occlusive disease/sinusoidal obstruction syndrome.

Discussion

The findings of this prospective real-world observational study reinforce the efficacy and safety profile of INO as demonstrated in prior pivotal clinical trials.^13,14 INO consistently achieved high rates of CR and MRD negativity, thus providing a valuable therapeutic option for patients with R/R BCP-ALL. In our cohort, 67.0% of patients achieved the best overall response, and 63.1% reached MRD negativity, in line with previous clinical evidence. Notably, our study further demonstrates that INO’s therapeutic efficacy is preserved across a wide range of clinical and disease-related factors. Response to INO was not significantly influenced by older age, baseline tumor burden as measured by BM or PB blast counts, CD22 expression level, prior lines of salvage therapy, EMR status, adverse-risk cytogenetics, or early relapses with short CRD <12 months. This finding is of particular clinical relevance, as it underscores INO’s robustness even in patients with traditionally poor-risk features. Among these variables, only short CRD <12 months emerged as a significant adverse prognostic factor, being associated with inferior OS, DFS, as well as a higher CIR rate even following allo-HCT. This observation echoes previous real-world findings with BLIN, where early relapse similarly predicted poor post-transplant outcomes.^7,16 Taken together, these data support the utility of INO as a bridging therapy to allo-HCT, particularly in patients with otherwise high-risk disease biology.

Importantly, our study underscores the preserved efficacy of INO in patients with EMR, particularly in those presenting with both BMR and EMR. This is clinically meaningful given that BLIN has been associated with limited response rates and inferior survival outcomes in patients with EMR.¹⁶ Although our prior studies suggested a potential role for BLIN in isolated EMR cases,^24,25 the current findings support the preferential use of INO in patients with concurrent BMR and EMR. In our current clinical practice, INO is now generally favored for patients with both BMR and EMR, whereas isolated EMR is managed with either agent depending on CD marker expression (as assessed by immunohistochemistry) and patient preference. Nonetheless, therapeutic decision-making remains more complex in patients with central nervous system (CNS) involvement. Despite emerging evidence supporting the CNS activity of certain tyrosine kinase inhibitors, BLIN, and chimeric antigen receptor (CAR)-T therapy,²⁶ no standardized treatment guidelines currently exist. Further investigation is needed to clarify optimal strategies for CNS-relapsed disease.

While the efficacy of INO is well established due to its potent anti-leukemic activity, its associated toxicities warrant careful clinical attention. Among these, prolonged hematologic toxicities including neutropenia, lymphopenia, and thrombocytopenia are the most significant concern given their contribution to serious infectious complications and the consequent need for treatment delays or dose reductions in subsequent cycles. Unexpectedly, we observed 12 early deaths occurring after the first (0.8 mg/BSA) or second (0.5 mg/BSA) dose of INO during the first treatment cycle. A substantial proportion of these patients experienced rapid multi-organ deterioration, resulting in death within several days. Clinically, most cases presented with acute hepatic failure and/or acute kidney injury, suggestive of TLS or acute viral hepatitis. Importantly, conventional clinical risk factors such as advanced age, high tumor burden, the extent of EMR, or CRD did not reliably predict these early fatalities. However, an intriguing and potentially critical observation was that 10 out of the 12 patients with early deaths harbored adverse-risk cytogenetic abnormalities, including complex karyotypes (n = 6), MLL/AF4 rearrangement (n = 2), and chromosome 7 abnormalities (n = 2). In multivariate analysis (Supplemental Table 2), adverse-risk cytogenetics were significantly associated with a higher incidence of early death (20.4% vs 3.9%, p = 0.014). These early deaths often appeared to be related to aggressive disease progression despite initial INO administration, as evidenced by liver failure or TLS-like features, which may reflect underlying leukemic biology associated with INO resistance. Notably, most of these events occurred during the early phase of our study enrollment. In response, we adopted more conservative approaches for high-risk patients by initiating the first dose of INO during inpatient admission and reducing the initial dose from 0.8 to 0.5 mg/BSA, particularly for elderly patients.

Hepatotoxicity, particularly hepatic VOD/SOS, remains a significant concern, especially among patients undergoing allo-HCT. This issue is particularly relevant in Korea, where the rate of allo-HCT is notably higher than in Western countries, thereby amplifying the clinical importance of VOD/SOS risk management. In our study, overall hepatotoxic events occurred in 51% of patients, and the incidence of hepatic VOD/SOS was 10% (n = 10); notably, eight of these cases were categorized as severe to very severe and resulted in death. More specifically, traditional VOD/SOS after allo-HCT occurred in 6 of 47 transplant recipients (12.8%) who had received prior INO salvage therapy. Meanwhile, four additional VOD/SOS cases (4.0%) developed during INO treatment, aligning with the incidence reported in earlier clinical trials.^13,27 All six post-HCT VOD/SOS cases occurred following a MAC preconditioning regimen, which consisted of cyclophosphamide plus 1320 cGy of TBI, reinforcing the association between intensive preconditioning and hepatic complications. Collectively, these data suggest that INO-associated VOD/SOS can arise via two distinct clinical trajectories: (1) post-HCT VOD/SOS following INO salvage and (2) VOD/SOS occurring during INO treatment, particularly in the setting of post-HCT relapse. The latter scenario is diagnostically challenging due to factors such as unclear symptom onset, pre-existing hepatic GVHD, and atypical presentations.^28,29 To mitigate these risks, strategies such as INO dose reduction, individualized conditioning regimens, and vigilant liver function monitoring should be prioritized.

Despite the historical emphasis on INO-related toxicities, recent studies have explored novel therapeutic frameworks that incorporate reduced-dose INO in combination with other agents. For instance, a landmark trial introduced a regimen combining mini-hyper-CVAD with attenuated INO dosing (0.6 mg/BSA on day 2 and 0.3 mg/BSA on day 8 of cycle 1; 0.3 mg/BSA on day 2 and 8 of cycles 2–4), followed by BLIN consolidation.^30,31 This protocol has since been amended into an even lower-toxicity regimen, which is currently being evaluated as a frontline treatment strategy for elderly patients.³²

The clinical utility of dose-reduced INO has recently expanded beyond R/R BCP-ALL, with emerging applications in MRD-positive settings. In patients who achieved CR but remained MRD-positive after induction therapy, a recent study tested reduced-dose INO (0.6 mg/BSA on day 1 and 0.3 mg/BSA on day 8 of cycle 1; 0.3 mg/BSA on day 1 and 8 of cycles 2–6) for patients with positive MRD >0.01% reporting an MRD negative response rate of 69%.³³ Another study investigated the prophylactic use of low-dose INO after allo-HCT in patients with high-risk features, administering 0.3–0.6 mg/BSA on D1 every 4 weeks for up to four cycles and decided the maximum tolerated dose at 0.6 mg/BSA. This study reported a 1-year NRM of only 5.6% and a 1-year DFS of 89%, establishing 0.6 mg/BSA as the maximum tolerated dose.³⁴

Most recently, dose-reduced INO is being evaluated as a bridging therapy before CD19-directed CAR-T cell therapy (CRIS #KCT0009690). The rationale is to reduce leukemic burden while minimizing treatment-related toxicities, thereby optimizing CAR-T efficacy and tolerability. This strategy may also evolve into a potential pre-conditioning platform that enhances T-cell fitness and engraftment. Taken together, these developments suggest that INO’s therapeutic role is transitioning from a salvage-only agent toward a more strategic, risk-adapted, and integrated component across various treatment phases of BCP-ALL. Future research should prioritize the refinement of INO-based regimens through the identification of predictive biomarkers, rational combination strategies, and the investigation of its immunomodulatory effects, particularly in relation to post-HCT and CAR-T–related toxicities.

Limitations

This study has several limitations. First, despite being prospectively conducted, this was an observational study without a comparator arm or randomized design, which limits the ability to infer causality. Second, potential selection bias may have occurred in the choice of INO over other agents such as BLIN, especially in patients with high tumor burden or EMR; although the decision was not standardized across participating centers, it may still influence the interpretation of outcomes. Third, early deaths were observed in a substantial proportion of patients (12%), but due to limited laboratory and imaging data in some cases, the exact etiology (i.e., INO-induced toxicity vs leukemia-related organ failure) could not be fully delineated. Fourth, although multivariate analyses were performed, some subgroups, such as alternative donor transplants, were small and may have influenced the statistical power for subgroup comparisons. Lastly, this study included only Korean patients, and the generalizability of the findings to other populations or ethnicities remains to be established. Future randomized and biomarker-stratified studies are warranted to optimize the use of INO in various clinical contexts.

Conclusion

This prospective multicenter observational study confirms the real-world efficacy of INO in Korean patients with R/R BCP-ALL but also revealed significant toxicities and early deaths if applied without vigilant monitoring or dose reduction. By demonstrating high CR rate and MRD response, along with toxicity management and various positioning optimization, INO would represent a critical component of the therapeutic armamentarium for BCP-ALL. Ongoing research and trials are essential to further refine its clinical application and improve patient outcomes.

Supplemental Material

sj-docx-1-tah-10.1177_20406207251401046 – Supplemental material for Real-world treatment outcome and toxicity analysis of inotuzumab ozogamicin in adult patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia: multicenter prospective observational study

Supplemental material, sj-docx-1-tah-10.1177_20406207251401046 for Real-world treatment outcome and toxicity analysis of inotuzumab ozogamicin in adult patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia: multicenter prospective observational study by Jae-Ho Yoon, Han-Seung Park, Ik-Chan Song, Sung-Hoon Jung and Seok Lee in Therapeutic Advances in Hematology

Footnotes

Acknowledgements

We appreciate the participating investigators and patients. Special thanks to the clinical research coordinator Mijue Kim, and our charging nurses Ji Yeon Yoon, Suk Heo, and Bomi Kim. We thank the clinical and administrative staff of the participating institutions for their assistance. These contributions did not meet the criteria for authorship.

Declarations

ORCID iDs

Jae-Ho Yoon

Seok Lee

Supplemental material

Supplemental material for this article is available online.

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