This phase 1 dose-escalation trial examines whether inotuzumab ozogamicin plus dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (EPOCH) is safe and effective for adults with relapsed or refractory B-cell acute lymphoblastic leukemia or lymphoma (ALL).
Key Points
Question
Does the addition of inotuzumab ozogamicin (InO) to dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (DA-EPOCH) result in a safe and effective treatment for adults with relapsed or refractory B-cell acute lymphoblastic leukemia or lymphoma?
Findings
In this phase 1 dose-escalation trial of 24 adult participants receiving DA-EPOCH-InO, the highest studied dose level of InO (0.6 mg/m2 on days 8 and 15) was the maximum tolerated dose. Significant severe hepatic toxic effects were rare, and there was only 1 case of sinusoidal obstructive syndrome.
Meaning
The findings suggest that DA-EPOCH-InO is a safe, well-tolerated, and clinically active chemoimmunotherapy regimen warranting further clinical investigation.
Abstract
Importance
Options for adults with relapsed or refractory B-cell acute lymphoblastic leukemia or lymphoma (B-ALL) are limited, and new approaches are needed. Inotuzumab ozogamicin (InO) has been combined with low-intensity chemotherapy, with modest improvements over historical controls, and dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (DA-EPOCH) treatment is safe and active for newly diagnosed ALL.
Objective
To assess the safety and clinical activity of DA-EPOCH and InO in adults with relapsed or refractory B-ALL.
Design, Setting, and Participants
This single-center, single-arm, nonrandomized, phase 1 dose-escalation trial included adults with relapsed or refractory CD22+ B-ALL and was conducted between September 2019 and November 2022. At least 5% blood or marrow blasts or measurable extramedullary disease (EMD) was required for enrollment.
Interventions
DA-EPOCH was given on days 1 to 5, while InO was given on day 8 and day 15 of a 28-day cycle. Three dose levels were studied using a bayesian optimal interval design.
Main Outcomes and Measures
The primary outcome was the maximum tolerated dose of InO when combined with DA-EPOCH, defined as the highest dose level that produced a rate of dose-limiting toxicity below 33%. Secondary objectives included response rates, survival estimates, and descriptions of toxic effects.
Results
A total of 24 participants were screened and enrolled (median age, 46 [range, 28-76] years; 15 [62%] male). The median number of lines of prior therapy was 3 (range, 1-12). Three of 11 participants (27%) treated at the highest dose level (InO, 0.6 mg/m2, on day 8 and day 15) experienced dose-limiting toxicity, making this the maximum tolerated dose. No deaths occurred during the study, and only 1 patient (4%; 95% CI, 0.1%-21%) developed sinusoidal obstructive syndrome after poststudy allograft. The morphologic complete response rate was 84% (95% CI, 60%-97%), 88% (95% CI, 62%-98%) of which was measurable residual disease negative by flow cytometry. Five of 6 participants with EMD experienced treatment response. The overall response rate was 83% (95% CI, 63%-95%). Median overall survival, duration of response, and event-free survival were 17.0 (95% CI, 8.4-not reached), 15.0 (95% CI, 6.7-not reached), and 9.6 (95% CI, 4.5-not reached) months, respectively.
Conclusions
In this study, adding InO to DA-EPOCH in adults with relapsed or refractory B-ALL was feasible, with high response rates and sinusoidal obstructive syndrome occurring rarely in a heavily pretreated population. Many patients were able to proceed to poststudy consolidative allogeneic hematopoietic cell transplant and/or chimeric antigen receptor T-cell therapy. Further investigation of this combination is warranted.
Trial Registration
ClinicalTrials.gov Identifier: NCT03991884
Introduction
Outcomes for adults with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL) have historically been poor.1 Chimeric antigen receptor T-cell therapy (CAR-T), blinatumomab, and inotuzumab ozogamicin (InO)2,3,4,5 have expanded treatment options. However, CAR-T and blinatumomab have distinct drawbacks, including unique toxic effects, cost, and logistical complexity, which limit their availability to specialized centers. Conversely, InO can be delivered in most clinical settings and, unlike CAR-T and blinatumomab, has retained activity in high-volume disease states.6 However, InO is associated with the risk of hepatic toxic effects, particularly sinusoidal obstructive syndrome (SOS), often occurring after allogeneic hematopoietic cell transplant (HCT).5,7,8 Additionally, single-agent InO yields short remissions.5 There have been efforts to extend the activity of InO by combining it with low-intensity chemotherapy, such as mini-hyper-CVD (cyclophosphamide and dexamethasone at 50% dose reduction with vincristine but without doxorubicin; alternating with methotrexate at 75% dose reduction and cytarabine 0.5 mg/m2 × 4 doses)7 or cyclophosphamide, vincristine, and prednisone.9 These approaches have translated into modest improvements in survival compared with historic controls,7 with concerns surrounding hepatotoxicity and early mortality.7,9
We sought to address these limitations by developing a novel InO-based chemoimmunotherapy approach. Dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (DA-EPOCH) has a well-established role in aggressive, mature B-cell neoplasms.10 Compared with more intense adult regimens, such as hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone, alternating with methotrexate and cytarabine), DA-EPOCH is less toxic and relatively simpler to administer, while retaining comparable antileukemia activity,11,12 suggesting that DA-EPOCH would be an ideal backbone to which novel agents could be added. Thus, in this nonrandomized, phase 1 dose-escalation trial (NCT03991884), we combined DA-EPOCH with InO. We hypothesized that using a more effective chemotherapy backbone with lower, fractionated doses of InO would yield a less toxic and more effective combination without the logistical constraints associated with CAR-T and blinatumomab.
Methods
The primary objective of this study was to estimate the maximum tolerated dose (MTD) of InO when combined with DA-EPOCH, defined as the dose level of InO associated with a true dose-limiting toxicity (DLT) rate of 33%. The trial protocol is given in Supplement 1. Dose-limiting toxicity was defined as any grade 4 to 5 nonhematologic treatment-related adverse event (TRAE), any occurrence of SOS regardless of timing, inability of a participant to complete 1 cycle due to a TRAE, and treatment delays of greater than 3 weeks. Bone marrow and extramedullary disease (EMD) response rates were assessed by National Comprehensive Cancer Network criteria; additional methods and definitions are given in the eMethods in Supplement 2. All participants provided written informed consent. The protocol was approved by the Fred Hutch/University of Washington/Seattle Children’s Cancer Consortium institutional review board. The Transparent Reporting Evaluations With Nonrandomized Designs (TREND) reporting guideline was followed.
Participants were screened between September 2019 and November 2022. Eligible participants included adults aged 18 years or older with CD22+ relapsed or refractory B-ALL. Participants needed to have at least 5% bone marrow or peripheral blood blasts or 1 site of EMD measuring 1.5 cm or greater to be included. Other key eligibility criteria included adequate organ function and no history of SOS or known chronic liver disease; prior HCT and receipt of InO treatment or CD19-directed immunotherapies were permitted. Full eligibility criteria details can be found in the eMethods in Supplement 2.
DA-EPOCH was given on days 1 to 5 of each 28-day cycle, as previously described.11,13 All participants started at DA-EPOCH level 1 (eTable 1 in Supplement 2). Three dose levels of InO were used, with InO given on days 8 and 15 of a 28-day cycle, as follows (eTable 2 in Supplement 2): 0.3 and 0.3 mg/m2 (dose level 1), 0.6 and 0.3 mg/m2 (dose level 2), and 0.6 and 0.6 mg/m2 (dose level 3). The first 5 participants started at InO dose level 1, initially using a 6 + 6 dose-escalation schema. After the fifth patient, a bayesian optimal interval design was used to govern dose escalation for subsequent participants (eFigure 1 in Supplement 2).14 Analysis was performed using SAS, version 9.4 (SAS Institute Inc).
Results
A total of 24 participants were screened (median age, 46 [range, 28-76] years; 9 [38%] female; 15 [62%] male); all were enrolled and evaluable for DLT and treatment response (Figure 1). Baseline characteristics are detailed in eTable 3 in Supplement 2. The median number of lines of prior therapy was 3 (range, 1-12). Five participants were enrolled at InO dose level 1, 8 at dose level 2, and 11 at dose level 3. There were 4 dose-limiting toxic events: 1 at dose level 1 (grade 4 sepsis), none at dose level 2, and 3 at dose level 3 (grade 4 hyponatremia, treatment delay for protracted pancytopenia, and grade 5 SOS). With an observed DLT rate of 27%, dose level 3 was determined to be the MTD. There were no deaths during the study.
Figure 1. Trial Flow Diagram of Study Participants Screened, Enrolled, and Evaluable for Toxic Effects and Treatment Response.
InO indicates inotuzumab ozogamicin.
Two participants (8%) had grade 3 alanine aminotransferase elevation (3 events total). Transient grade 1 to 2 aspartate aminotransferase and/or alanine aminotransferase elevations occurred in 15 participants (62%), as did transient grade 1 to 2 bilirubin elevations. All abnormal liver test findings resolved. There were no grade 4 abnormal liver test findings observed during the study. The SOS rate was 4% (95% CI, 0.1%-21%; 1 case); this occurred after poststudy HCT and was grade 5. (Despite occurring after study completion, this case of SOS was still counted as a DLT per our definitions.) Details of all grade 3 or higher TRAEs during the study can be found in the Table and eTables 4 and 5 in Supplement 2.
Table. Summary of Grade 3 or 4 Nonhematologic Treatment-Related Adverse Events During the Study per National Cancer Institute CTCAE, Version 5.0a.
| Adverse event | Patients, No. (%) (N = 24) | |
|---|---|---|
| Grade 3 | Grade 4 | |
| Febrile neutropenia | 8 (33) | 0 |
| Sepsis | 3 (12) | 1 (4) |
| Other infections | 4 (17)b | 0 |
| ALT level elevation | 3 (12) | 0 |
| Syncope | 3 (12) | 0 |
| Hypotension | 2 (8) | 0 |
| Abdominal pain | 2 (8) | 0 |
| Typhlitis | 2 (8) | 0 |
| Hyponatremia | 0 | 1 (4) |
| Miscellaneous | 4 (17)c | 0 |
Abbreviations: ALT, alanine aminotransferase; CTCAE, common terminology criteria for adverse events.
There were no grade 5 adverse events.
Pulmonary aspergillosis (n = 2), oropharyngeal candidiasis (n = 1), and Clostridioides difficile enterocolitis (n = 1).
One case each of pancreatitis, atrial fibrillation, diarrhea, and fatigue.
Among the participants with 5% or more blood or marrow blasts at enrollment (n = 19), the rate of morphologic complete remission (CR) or complete remission with incomplete hematologic recovery (CRi) was 84% (95% CI, 60%-97%). Measurable residual disease negativity by multiparameter flow cytometry was achieved in 14 of 20 evaluable participants (70%; 95% CI, 46%-88%), 14 of 16 participants who achieved CR/CRi (88%; 95% CI, 62%-98%), and 5 of 15 participants who were evaluable by high-throughput sequencing (33%; 95% CI, 12%-62%). Of all participants with non–central nervous system–based EMD (n = 6), 5 (83%) experienced treatment response (4 complete responses and 1 partial response). Collectively, the per-protocol and intention-to-treat overall response rates were 83% (95% CI, 63%-95%; 20 of 24). eTable 6 and eResults in Supplement 2 detail morphologic and measurable residual disease assessments. Most participants proceeded to consolidative immunotherapies (HCT, CAR-T, and blinatumomab) (Figure 2). In total, 9 participants (45% of those with treatment response) received poststudy HCT as consolidation (eTable 7 and eResults in Supplement 2).
Figure 2. Responses to Dose-Adjusted Etoposide, Prednisone, Vincristine, Cyclophosphamide, and Doxorubicin Plus Inotuzumab Ozogamicin and Consolidative Immunotherapies.
Consolidative immunotherapies (CIs) included allogeneic hematopoietic cell transplant (HCT), chimeric antigen receptor T-cell therapy (CAR-T), and blinatumomab delivered to participants who achieved remission with study therapy. ID indicates identifier.
With a median follow-up of 17.3 months (range, 4.9-30.8), the median overall survival, duration of remission, and event-free survival were 17.0 (95% CI, 8.4-not reached), 15.0 (95% CI, 6.7-not reached), and 9.6 (95% CI, 4.5-not reached) months, respectively (eFigure 2 in Supplement 2). The 12-month overall survival estimate was 54% (95% CI, 31%-72%), the 12-month estimate of patients with treatment response remaining in an ongoing remission (duration of remission) was 51% (95% CI, 27%-70%), and the 12-month event-free survival was 43% (95% CI, 22%-62%).
Discussion
This study showed that DA-EPOCH-InO was safe and highly active in a heavily pretreated cohort of participants with relapsed or refractory B-ALL. Severe hepatic toxic effects were uncommon; there was only 1 case of SOS (4%), and abnormal grade 3 liver test results occurred in 8% of participants. No unique safety signals were observed. Our use of lower cumulative doses of InO per cycle (0.6-1.2 mg/m2) than those studied previously (1.3-1.8 mg/m2),5,7,9 along with a fractionated dose schedule, may have contributed to a better safety profile than the combination of InO with mini-hyper-CVD.15
The observed responses rates (CR/CRi rate of 84% and overall response rate of 83%) compare favorably to those in prior trials of InO combined with low-intensity chemotherapy (CR/CRi rates of 61%-78%).7,9 Additionally, the pivotal trials for brexucabtagene autoleucel and tisagenlecleucel had response rates in the full intention-to-treat populations of 55% and 66%, respectively; response rates were higher when restricted to per-protocol populations.2,3 Unlike these other important trials (particularly those with CAR-T cells), we had 0% attrition, with study treatment usually commencing within days of patient screening. This suggests that DA-EPOCH-InO is not only highly active but also relatively easy to administer and readily accessible. As a result, this is a regimen that can be offered outside specialized centers provided that staff are comfortable with toxic effects germane to patients with acute leukemia.
Limitations
Study limitations included the relatively small sample size and the relatively long duration of remission observed, which may reflect an impact of novel consolidation strategies, such as blinatumomab and CAR-T cells, which were not as routinely available at the time of previous InO-based trials. Additional details are given in the eDiscussion in Supplement 1.
Conclusions
This phase 1 dose-escalation trial found that adding InO to DA-EPOCH in adults with relapsed or refractory B-ALL was feasible, with high response rates and SOS occurring rarely in a heavily pretreated population. Our findings suggest that DA-EPOCH-InO is a viable treatment option in this patient population, warranting further investigation in larger confirmatory trials. Pending these data, it is a reasonable and accessible option that can be considered in routine practice.
Trial Protocol
eMethods.
eResults.
eDiscussion.
eTable 1. Details of DA-EPOCH Including Agents, Doses, Dose-Schedules, and Dose Escalation Guidelines
eTable 2. Dose Levels of InO
eTable 3. Baseline Patient Characteristics
eTable 4. Hepatic Treatment-Related Adverse Events, by InO Dose Level
eTable 5. Non-Hepatic Treatment-Related Adverse Events, by InO Dose Level
eTable 6. Summary of Bone Marrow Responses and MRD Assessments by Different Testing Modalities
eTable 7. Details on Subsequent HCT for Study Participants
eFigure 1. Dose Escalation De-Escalations Across Consecutive Study Subjects
eFigure 2. Kaplan-Meier Survival Curves
eReferences.
Data Sharing Statement
References
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Trial Protocol
eMethods.
eResults.
eDiscussion.
eTable 1. Details of DA-EPOCH Including Agents, Doses, Dose-Schedules, and Dose Escalation Guidelines
eTable 2. Dose Levels of InO
eTable 3. Baseline Patient Characteristics
eTable 4. Hepatic Treatment-Related Adverse Events, by InO Dose Level
eTable 5. Non-Hepatic Treatment-Related Adverse Events, by InO Dose Level
eTable 6. Summary of Bone Marrow Responses and MRD Assessments by Different Testing Modalities
eTable 7. Details on Subsequent HCT for Study Participants
eFigure 1. Dose Escalation De-Escalations Across Consecutive Study Subjects
eFigure 2. Kaplan-Meier Survival Curves
eReferences.
Data Sharing Statement