Phase 2 study of inotuzumab ozogamicin for measurable residual disease in acute lymphoblastic leukemia in remission

The presence of measurable residual disease (MRD) after treatment of acute lymphoblastic leukemia (ALL) is associated with a higher risk of relapse and worse outcomes.¹ Achieving MRD negativity after induction/consolidation is associated with a low risk of relapse and a better survival.^2-4 Previous reports have demonstrated the efficacy of blinatumomab in inducing a complete MRD response in 75% of patients, which improved the overall survival (OS).^5,6 

Inotuzumab ozogamicin is a humanized anti-CD22 monoclonal antibody conjugated to the cytotoxic agent calicheamicin.⁷ In the phase 3 INO-VATE randomized trial of relapsed/refractory ALL, the median OS with inotuzumab was 7.7 months compared with 6.7 months with standard chemotherapy (P = .04). The MRD negativity rate among responders was 78%.⁸ In a subgroup analysis, MRD negativity after inotuzumab was associated with improved OS.⁹ Herein, we report the results of a phase 2 trial evaluating the role of inotuzumab in eradicating MRD among patients with B-cell ALL in complete remission (CR) with positive MRD ≥ 1 × 10⁻⁴.

Adults aged ≥18 years with B-cell ALL were enrolled in this phase 2 trial. Patients were in morphologic remission with detectable MRD due to failure of MRD response or MRD recurrence. Patients in first CR (CR1) were eligible if they had received ≥3 months of prior therapy. Patients in second CR and beyond (CR2+) were eligible after ≥1 month of prior therapy. Inotuzumab was given at 0.6 mg/m² on day 1 and 0.3 mg/m² on day 8 during cycle 1, and 0.3 mg/m² on days 1 and 8 during cycles 2 to 6 (28-day cycle), for up to 6 cycles. All patients received ursodiol 300 mg 3 times a day for sinusoidal obstruction syndrome (SOS) prophylaxis. Patients with Philadelphia chromosome (Ph)–positive ALL received a concomitant breakpoint cluster region::Abeslon1 (BCR::ABL1) tyrosine kinase inhibitor (TKI).

MRD negativity was evaluated using multicolor flow cytometry (MFC) at a sensitivity of 1 × 10⁻⁴ and polymerase chain reaction (PCR) for BCR::ABL1 at a sensitivity of at least 1 × 10⁻⁴. MRD negativity was defined in Ph-negative ALL as undetectable MRD by MFC and in Ph-positive ALL as undetectable MRD by MFC and the absence of quantifiable BCR::ABL1 transcripts by PCR or BCR::ABL1 transcripts by PCR < 0.01% on the international scale. The primary end point was relapse-free survival (RFS), defined as the time from treatment initiation until death or relapse. Secondary end points included OS, MRD negativity rate, and safety. Patients were considered nonresponders if the criteria for MRD negativity were not achieved after 2 cycles. OS was defined as the time from treatment start until death from any cause. All patients signed an informed consent form in accordance with the Declaration of Helsinki.

Patient characteristics were summarized using the median (range) for continuous variables and the frequencies (percentages) for categorical variables. RFS and OS were estimated with the Kaplan-Meier method and compared between subgroups with the log-rank test. The MRD negativity rate was estimated, along with the exact 95% confidence interval (CI). A P value < .05 (two-tailed) was considered statistically significant.

Between November 2018 and June 2022, 26 consecutive patients were treated; their median age was 46 years (range, 19-70 years) (supplemental Figure 1, available on the Blood website). Sixteen patients (62%) had Ph-positive ALL and received concomitant ponatinib (n = 14) or dasatinib (n = 2) and remained on the same TKI throughout the course of therapy (Table 1). Nineteen patients (73%) were in CR1 and 7 (27%) were in CR2+. Patients received a median of 3 cycles of inotuzumab (range, 1-6). Eighteen (69%) patients achieved MRD negativity overall (Ph-negative ALL, n = 8; Ph-positive ALL, n = 10); 16 (89%) after cycle 1 (supplemental Table 1).

Among the 18 responders, 6 (33%) underwent allogeneic stem cell transplantation (ASCT), and all tested negative for MRD before ASCT. Of them, 3 were alive in MRD-negative remission at the last follow-up, 1 relapsed, and 2 died of ASCT-related complications in MRD-negative remission. Five (28%) of the 18 responders relapsed: 3 relapsed in the bone marrow, 1 in the bone marrow and lymph nodes, and 1 in the central nervous system with positive MRD in the bone marrow. At the time of the last follow-up, 9 patients (35%) had died (5 responders, 4 nonresponders). Of the responders, 2 died of relapsed disease, 2 of ASCT complications, and 1 of septic shock. Of the nonresponders, 2 died of disease progression, 1 of SOS, and in 1 patient, the cause of death was unknown.

After a median follow-up of 24 months (range, 9-43 months), the median RFS was 41 months in the entire cohort, with a 2-year RFS rate of 54% (95% CI, 32-72) (Figure 1A). Among responders, the median RFS was 41 months and the 2-year RFS 58% (95% CI, 31-78) (Figure 1B). The 2-year RFS rates in different subgroups are summarized in supplemental Table 2 and supplemental Figures 2 to 4. The median OS in the entire cohort was not reached, with a 2-year OS rate of 60% (95% CI, 36-77). Among responders, the median OS was not reached, and the 2-year OS was 67% (95% CI, 35-86). The 2-year OS rates were 67% (95% CI, 20-91) and 90% (95% CI, 47-99) in patients who did or did not undergo ASCT, respectively.

The most common nonhematological-related adverse event (AE) was aspartate aminotransferase/alanine aminotransferase elevation in 18 patients (69%) (grades 1-2, 62%; grade 3, 8%) (Table 2; supplemental Table 3). The most common hematological-related AE was thrombocytopenia in 17 patients (65%) (grades 1-2, 31%; grade 3-4, 35%). Overall, 5 patients (19%) had prolonged thrombocytopenia, and 7 (27%) never recovered a normal platelet count. Two patients (8%) developed SOS; both had Ph-positive ALL on concurrent ponatinib: the first developed severe SOS (radiological) 1 month after cycle 5 (cumulative inotuzumab dose 2.7 mg/m² and ponatinib 15 mg/d) and died from SOS; the second developed moderate SOS (histopathological) during cycle 5 (cumulative inotuzumab dose 3.3 mg/m², ponatinib 15 mg/d) and recovered.

Inotuzumab was shown to be effective for patients with B-cell ALL who remain in MRD-positive status after achieving CR. Overall, 69% of the patients converted to a MRD-negative status, with 89% responding after cycle 1. This translated into a 2-year RFS of 54% and a 2-year OS of 60% overall, and 58% and 67% among responders, respectively. Approximately half of the patients had prior blinatumomab and 19% had prior ASCT, suggesting that inotuzumab remains highly active in patients previously exposed to MRD-directed therapies. This regimen was well-tolerated, with most AEs being of low grade. Using a lower and fractionated dose of inotuzumab may have helped to mitigate the risk of SOS, which occurred in 2 patients (8%). This strategy had already been shown to reduce the risk of SOS in a previous study of low-intensity chemotherapy with inotuzumab.¹⁰ The 2 cases of SOS were observed in patients receiving ponatinib 15mg/d; therefore, caution should be exercised when combining inotuzumab and ponatinib because of the liver toxicity associated with ponatinib.

These results compare favorably with those of the GIMEMA ALL2418 trial of inotuzumab for MRD eradication, which reported a MRD negativity rate of 35%.¹¹ The inferior MRD negativity rate compared with that in our study could be explained by several factors. First, 56% of the patients in the GIMEMA trial received a median of 1 cycle (range, 1-2) of inotuzumab, compared with a median of 3 cycles in our study (range, 1-6). Second, responders in our study were maintained on inotuzumab for up to 6 cycles, in contrast to the GIMEMA trial, in which responders were transitioned to short-term maintenance with low-dose chemotherapy or TKI. Third, the difference in sensitivity between the MRD assays used in both trials. In our study, MRD was assessed by MFC and PCR with a sensitivity of 10⁻⁴ and 10⁻⁵, respectively. In the GIMEMA ALL2418 trial, MRD was assessed using highly sensitive molecular methods for BCR::ABL1 or variable diversity joining fusion transcripts, which might detect MRD at a deeper level.

The rates of MRD negativity observed in our study are similar to what has been reported with blinatumomab in the MRD setting, ∼70%.^5,6 In this trial, 50% of the patients were relapsed/refractory to blinatumomab, suggesting that inotuzumab was effective after blinatumomab failure. In a subset analysis of 40 patients with relapsed/refractory ALL, treatment with inotuzumab after blinatumomab resulted in a response rate of 58% and a median OS of 10.5 months.¹² Nonetheless, the administration of inotuzumab is considered by many to be more convenient than blinatumomab. Inotuzumab is given as a 1-hour infusion once a week, compared with a continuous infusion of blinatumomab. Inotuzumab does not require hospital admission compared with blinatumomab, in which hospitalization for several days is needed upon treatment initiation for dose escalation and monitoring of AEs.

Both this study and the GIMEMA ALL2418 study showed that inotuzumab was an effective bridging therapy to ASCT.¹¹ However, similar to the experience with blinatumomab in the MRD setting,^5,6,13 the role of ASCT after inotuzumab was not clearly established. In this study, 6 patients underwent ASCT, and their 2-year survival rates were around 60%. Seven patients treated with inotuzumab remain in MRD-negative remission without ASCT. Future trials assessing the role of CD19-directed chimeric antigen receptor T-cell therapy as consolidation after inotuzumab are warranted.

In conclusion, inotuzumab is safe and effective and is a novel alternative therapy for the eradication of MRD in patients with B-cell ALL with persistent MRD or MRD recurrence. Future confirmatory studies are needed.

The visual abstract was created with BioRender.com.

Free drug supply was provided by Pfizer.

Contribution: E.J. and H.K. designed the study and treated patients; E.J. and F.G.H. wrote the manuscript; F.G.H., N.J.S., J.S., K.S., and R.S.G. collected and analyzed the data; J.J. and S.A.W. analyzed the pathology samples and PCR results; X.W. performed the statistical planning and analysis; N.J., Y.A., C.D., L.M., T.K., and F.R. treated patients; and all authors reviewed and approved the manuscript.

Conflict-of-interest disclosure: E.J. received research grants from AbbVie, Adaptive Biotechnologies, Amgen, Pfizer, and Takeda; and consultancy fees from AbbVie, adaptive biotechnologies, Amgen, Bristol Myers Squibb (BMS), Genentech, Incyte, Novartis, Pfizer, and Takeda. N.J.S. received research grants from Takeda Oncology, Astellas Pharma, Xencor, and Stemline Therapeutics; consultancy fees from Pfizer and Jazz Pharmaceuticals; and honoraria from Novartis, Amgen, Sanofi, and BeiGene. H.K. received research grants from AbbVie, Amgen, Ascentage, BMS, Daiichi-Sankyo, ImmunoGen, Jazz, Novartis, and Pfizer; and honoraria from AbbVie, Amgen, Aptitude Health, Ascentage, Astellas Health, AstraZeneca, Ipsen, Pharmaceuticals, KAHR Medical Ltd, NOVA Research, Novartis, Pfizer, Precision Biosciences, and Taiho Pharmaceutical Canada. The remaining authors declare no competing interests.

Correspondence: Elias Jabbour, Department of Leukemia, The University of Texas, M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 428, Houston, TX 77030; email: ejabbour@mdanderson.org.