Outcomes After Retreatment With Inotuzumab Ozogamicin for Relapsed/Refractory Philadelphia Chromosome–Negative B-Cell Acute Lymphoblastic Leukemia

Introduction

Approximately 50% of all adults with B-lineage acute lymphoblastic leukemia (ALL) who achieve initial complete remission (CR) will experience relapse, and most will ultimately die of their disease.¹ The prognosis of adults with relapsed or refractory (R/R) disease depends on their response to additional therapies and the completion of an allogeneic stem-cell transplant (allo-SCT).^2,3 Immunotherapies such as the CD19/CD3 bispecific T-cell engager blinatumomab and the CD22 antibody-drug conjugate inotuzumab-ozogamicin (INO) are both approved therapies in the R/R setting with CR rates of 44% and 80.7%, respectively.^4,5 Although these agents have improved overall survival, outcomes are still quite poor in patients with progression of disease after treatment with both INO and blinatumomab, and little is known about the utility of retreatment with these agents.^4-6 In this study, we describe the outcomes of six patients who received INO for B-cell ALL (B-ALL) and were subsequently retreated with INO for later progression of disease.

Patient Selection/Study Design

We retrospectively evaluated the outcomes of patients with Philadelphia chromosome–negative (Ph-) B-ALL at our institution who had previously received INO and went on to receive INO again as salvage therapy during a subsequent progression of disease. Responses to INO retreatment were assessed by criteria used by Kantarjian et al.⁴ Measurable residual disease (MRD) was measured using flow cytometry and next-generation sequencing via Clonoseq with sensitivities of 10⁻⁴ and 10⁻⁶, respectively. Time to last follow-up was measured from INO retreatment to death or last clinical evaluation.

This research was conducted under institutional review board 19-0126 (Clinical Outcome of Adult B-ALL Patients with Blinatumomab/Inotuzumab Ozogamicin). Each patient has provided consent to have clinical information reported via our institutional leukemia registry, cellular therapy registry, or specific to this case series. No photographs (deidentified or otherwise) have been included in this case series.

Results

We identified six patients with Ph- B-ALL who received INO retreatment (INO 2). Baseline characteristics, genetic aberrations, and details of ALL-directed therapies including INO can be found in Tables 1 and 2. The median age at diagnosis of B-ALL was 40 years (range, 18-65 years), and the median age at INO 2 was 48 years (range, 23-68 years). The median number of previous therapeutic regimens was 2 (range, 1-3). Only one patient (3) underwent allo-SCT before initial INO treatment. The indications for first INO included primary refractory disease, first relapse, and second relapse. Two patients (2 and 5) were treated for primary refractory disease. Two patients were in first relapse (1 and 4), and one was in second relapse (3) at time of treatment with INO. One patient (6) received initial INO for MRD-positive disease by flow cytometry. The median number of INO cycles during the initial exposure to INO was two (range, 2-6).

TABLE 1.

Patient Demographics, Disease Characteristics, Acute Lymphoblastic Leukemia-Directed Therapies, and Specifics of INO Treatment

TABLE 2.

Specifics of INO Retreatment, Responses, and Outcomes

Responses to first INO exposure were measured by standard morphological criteria and with flow cytometry for detection of MRD. Five patients achieved an MRD-negative CR and one (2) had a partial response (PR) with 8%-10% blasts still present on bone marrow examination. Patient trajectories can be followed using Figure 1. Three patients (1, 2, and 5) underwent allo-SCT after initial INO though one patient (2) also required blinatumomab salvage after INO for residual disease before transplant. Between initial INO and INO 2, one patient (1) underwent allo-SCT, followed by blinatumomab and chimeric antigen receptor T-cell therapy (CTX110, CRISPR/Cas9) for MRD-positive disease. One patient (3) was observed until relapse and treated with chimeric antigen receptor T-cell therapy (KTE-C19, axicabtagene ciloleucel). Two patients (4 and 6) were treated with POMP maintenance until relapse. Patient 4 developed CNS relapse without systemic relapse and was successfully treated with intrathecal methotrexate and cytarabine while patient 6 developed systemic relapse and was treated with blinatumomab.

FIG 1.

Patient outcomes after initial treatment with INO. allo-SCT, allogeneic stem-cell transplant; CAR-T, chimeric antigen receptor T-cell therapy; INO, inotuzumab ozogamicin; MRD, measurable residual disease; R/R, relapsed or refractory.

Cytogenetic and mutational analysis throughout the clinical course is summarized in Tables 1 and 2. Flow cytometry was used to assess CD22 expression on all patients before the start of INO 2 (Data Supplement). Expression of CD22 on lymphoblasts before INO 2 is detailed in Tables 1 and 2.

After a median of 2.3 years (range, 0.6-6.3) from initial INO, all patients were retreated with INO for either R/R disease (2-5) or MRD-positive disease (1 and 6). During retreatment, the median number of cycles was 1 (range, 1-4). After retreatment, five patients achieved a CR. Three patients (1, 2, and 6) were MRD-negative by flow cytometry and by Clonoseq assay. One patient (4) was MRD-negative by flow cytometry alone (Clonoseq was not performed). One patient's (5) response was assessed by positron emission tomography scan given relapsed disease was confined to left orbit and left anterior cranial fossa. This patient was treated with radiotherapy, dexamethasone pulse therapy, followed by one cycle of INO and intrathecal cytarabine. Patient 5's bone marrow biopsy result was negative for disease at relapse. Therefore, this patient was characterized as achieving a CR. Of note, disease assessment was done after the patient received dexamethasone, radiotherapy, and INO. Finally, one patient (3) had a PR with 10% blasts and weak CD22 expression after retreatment and was subsequently treated with blinatumomab because of uniform CD19-positive expression. After one cycle, patient 3 was MRD-negative by flow cytometry and Clonoseq assay and underwent allo-SCT. In summary, four patients (1, 2, 4, and 6) achieved an MRD-negative CR, one patient (5) achieved a CR on the basis of positron emission tomography scan after INO 2, and one patient (3) achieved a PR.

Of the five patients who achieved a CR, three (2, 5, and 6) were started on maintenance therapy after INO 2 with either blinatumomab, followed by POMP, dexamethasone, vincristine, methotrexate, 6-mercaptopurine, or venetoclax plus dexamethasone. One MRD-negative patient (4) was observed without additional chemotherapy, and one (1) underwent allo-SCT.

Two patients (1 and 4) died while the other four were alive at the time of data lock. Shortly after a second allo-SCT, patient 1 developed multiorgan failure secondary to disseminated adenovirus but was in CR at the time of expiration. Patient 4 expired at another facility and cause of death is unknown; there was no known relapse reported. Patient 5 developed a subdural leukemia mass and meningeal relapse and was treated with intrathecal cytarabine and whole-brain radiation. Bone marrow biopsy at time of relapse was negative for disease. Brain biopsy post-treatment was negative for disease. Median overall survival was not reached at time of data lock with a median follow-up time of 16.5 months (range, 5-26). Kaplan-Meier survival analysis can be seen in Figure 2. We also analyzed the outcomes of 13 patients with Ph- B-ALL who received INO for relapsed disease and were not retreated with INO for subsequent progression. Characteristics and outcomes of these patients are summarized in Table 3. Patients received a median of one regimen after INO (range, 0-3), and six patients received blinatumomab for relapsed disease after INO. Two patients did not receive any leukemia-directed therapy after progression of disease after INO. The median OS was 0.5 years, and one patient went onto receive allo-SCT after INO.

FIG 2.

Kaplan-Meier survival after retreatment with INO. B-ALL, B-cell acute lymphoblastic leukemia; INO, inotuzumab ozogamicin.

TABLE 3.

Characteristics of Patients With Relapsed/Refractory Philadelphia Chromosome–Negative B Cell-Acute Lymphoblastic Leukemia Treated With INO Who Did Not Receive INO Retreatment on Subsequent Progression

There were limited toxicities with INO. During the initial treatment, one patient (4) developed transaminitis (grade 2) and lymphopenia (grade 3) while another (3) developed transaminitis alone (grade 3) although neither progressed to hepatic veno-occlusive disease (VOD). During INO 2, one patient (1) developed hepatic VOD after a second allo-SCT. Of note, four patients (1-3 and 5) received ursodiol prophylaxis with first INO while all six received it with INO 2.

Discussion

No prior studies have demonstrated INO retreatment as a therapeutic approach that can induce responses. Our study shows that retreatment with INO can be considered when R/R or MRD-positive disease has CD22 positivity. All six patients demonstrated comparable CD22 expression in bone marrow samples obtained before retreatment. Two patients (1 and 4) have died, and three patients (2, 5, and 6) have not had systemic relapse of disease after INO retreatment. One patient (3) had detectable disease by flow cytometry and was bridged to allo-SCT after receiving blinatumomab. Median OS has not been reached after INO 2 with a median follow-up time of 16.5 months.

This study serves as an important indicator for the direction of further studies. Patients with relapsed/refractory B-ALL have historically poor outcomes, particularly for those previously treated with blinatumomab and INO.⁶ Given the investigation of INO in frontline regimens, it is important to keep in mind that if CD22-positive relapse of disease occurs, retreatment with INO may allow for a durable CR. Of note, this series may not be applicable to all patients with R/R disease after previous InO treatment. For example, 13 patients at our institution treated with INO for R/R disease did not receive INO retreatment for subsequent progression and had a median OS of 0.50 years and a median time to progression after INO of 0.31 years. Our INO retreatment cohort had a CR rate of 83% to INO 1, and only one patient had a DOR of < 1 year. INO has demonstrated similar efficacy across the spectrum of disease burden and extramedullary disease⁷; however, the role of INO in patients with active CNS disease remains unclear as the INO-VATE trial excluded these patients, and, therefore, intrathecal therapy should be strongly considered.⁴ Ultimately, the decision to retreat with INO for the six patients at our institution was driven by response to initial INO therapy, previous treatment with chemotherapy-based regimens, prior exposure to CD19-directed therapies or lack of CD19 expression, and strong CD22 expression before INO 2.

An adverse event of concern in patients after INO exposure that go onto receive allo-SCT or have previously undergone allo-SCT is hepatic VOD.⁸ In our series, one patient (1) developed VOD. This occurred after the second allo-SCT, and the patient received defibrotide for 10 days with resolution of VOD. This patient carried additional risk factors for development of VOD including prior allo-SCT, transplant less than two months after INO use, and a total of three INO cycles (two on initial use and one on second use). This patient received reduced-intensity conditioning and ursodiol prophylaxis which may have contributed to a decrease in severity of VOD. Overall, repeated use of INO was associated with minimal provider-assessed toxicity.

In summary, patients with relapsed B-ALL have limited treatment options and poor prognosis, particularly if already treated with blinatumomab and INO. Our experience demonstrates that retreatment with INO is possible after a subsequent relapse of CD22-positive disease and may offer durable responses particularly in patients who receive subsequent maintenance therapy.

AUTHOR CONTRIBUTIONS

Conception and design: All authors

Collection and assembly of data: Juan Alban, Sandeep Gurbuxani, Anand Ashwin Patel

Data analysis and interpretation: All authors

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center.

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