Abstract
Gemtuzumab ozogamicin (GO) remained available to US clinicians through an open-label expanded-access protocol (NCT02312037) until GO was reapproved. Patients were aged ≥3 months with relapsed/refractory (R/R) acute myeloid leukemia (AML), high-risk myelodysplastic syndrome, or acute promyelocytic leukemia (APL), and had exhausted other treatment options. Three hundred and thirty one patients received GO as monotherapy for R/R AML (n = 139), combination therapy for R/R AML (n = 183), or treatment for R/R APL (n = 9). Corresponding treatment discontinuations occurred in 68, 39, and 33% of patients. All-causality grade 5 AEs occurred in 52, 22, and 22% of patients in the monotherapy, combination, and APL groups, respectively. Corresponding grades 3 and 4 treatment-related AEs were reported in 60, 55 and 78% of patients. Hepatotoxicity occurred in five patients: veno-occlusive disease (n = 4) and drug-induced liver injury (n = 1). GO was generally well tolerated in patients with R/R AML or APL. Most frequent treatment-related grade ≥3 AEs were hematologic AEs.
Clinicaltrials.gov identifier: NCT02312037
Introduction
Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults. Until recently, treatment options for patients with newly diagnosed AML were limited to therapy with cytarabine and anthracycline or hypomethylating agents [Citation1–3]. Selected patients could also benefit from allogeneic hematopoietic stem cell transplant. In the relapsed setting, there is no clear standard of care and many patients do not respond to standard salvage regimens. However, new agents have been recently approved, thus creating a wider range of therapy choices for treating physicians [Citation1–3].
Gemtuzumab ozogamicin (GO) is an antibody–drug conjugate composed of an anti-CD33 monoclonal antibody covalently linked to the potent antibiotic calicheamicin. Previous studies have shown GO is generally well tolerated and can induce durable second remissions when administered as monotherapy or in combination with chemotherapy in patients with relapsed or refractory (R/R) AML [Citation1,Citation2,Citation4–13].
GO was initially approved in the United States in 2000 for use as a single agent in the treatment of AML in first relapse in elderly patients [Citation14]. GO was voluntarily withdrawn from the US market in 2010 after a phase III study evaluating GO in combination with chemotherapy in previously untreated adult AML failed to show clinical benefit versus chemotherapy alone [Citation15]. In that study, a higher rate of early-induction deaths was observed in the GO arm, which was not counterbalanced by a later benefit; although the rate of early mortality was exceptionally low in the control arm compared with historical experience [Citation15]. Despite voluntary withdrawal from the US market, GO remained approved in Japan (9 mg/m2 on Days 1 and 15 in patients with R/R AML) and continued compassionate-use requests reflected an ongoing clinician desire for access to GO. On that basis, an expanded-access protocol (EAP) was opened in December 2014 until September 2017 to make GO available to the US AML community. Results from the ALFA-0701 [Citation16] , AML-19 [Citation17], and MyloFrance-1 [Citation11] studies led to the reapproval of GO by the US Food and Drug Administration (FDA) for the treatment of newly diagnosed AML in adult patients and R/R AML in adults and pediatric patients aged ≥2 years [Citation1,Citation2,Citation4,Citation14]. The objectives of this analysis were to report the safety data from this EAP study that allowed compassionate use of GO in patients with R/R AML or acute promyelocytic leukemia (APL) who did not have access to comparable or alternative therapy.
Methods
Study design and patients
This was an open-label EAP study (ClinicalTrials.gov, NCT02312037) of GO treatment in patients with R/R AML (including myelodysplastic syndrome) or R/R APL (Supplementary Figure S1). The study was conducted between December 27, 2014 and December 4, 2017 at 63 centers across the United States.
Patients 3 months or older (no upper age limit) who had exhausted all standard treatment options, with a confirmed diagnosis of R/R AML, including high-risk myelodysplastic syndrome, with persisting or rising blasts; or R/R APL with persisting or rising leukemic burden (either by morphology, cytogenetic analysis, or molecular techniques) were eligible (see Supplementary Material).
Study materials were reviewed and approved by an institutional review board or independent ethics committee at each study center. The study was conducted in accordance with the protocol, international ethical and clinical practice guidelines, the Declaration of Helsinki, and applicable local regulatory requirements and laws. All patients provided informed consent.
Treatment regimens
The protocol allowed for treatment regimens tested in clinical trial settings and reported in the Mylotarg Investigator’s Brochure or peer-reviewed journals [Citation5–12,Citation14,Citation17–35]. Three types of treatment regimens could be used: GO monotherapy in patients with R/R AML (monotherapy group); GO in combination with tested standard chemotherapy induction and consolidation regimens in patients with R/R AML (combination group); and GO as monotherapy or in combination with all-trans retinoic acid and/or arsenic trioxide in patients with APL (APL group) (Supplementary Material and Supplementary Tables S1 and S2).
The protocol was to remain open to provide compassionate access to GO treatment for patients within the United States until the clinical development of the drug was discontinued, or when GO became commercially available within the United States, whichever occurred first.
Patients could be discontinued from the EAP for the following reasons: adverse events (AEs), including anaphylactic reaction, development of life-threatening veno-occlusive disease (VOD) or elevations of transaminases and bilirubin, intercurrent illness; disease progression; nonadherence; lost to follow-up; pregnancy; sponsor decision, such as drug availability; or withdrawal of informed consent or patient withdrawal from the EAP. Supportive care measures and management of AEs (including transfusions, growth factors, and medications for tumor lysis syndrome, neutropenic fever, and VOD/hepatotoxicity) were not specified and were per institutional standards at each site.
Study assessments and endpoints
The timing and frequency of visits, and assessments performed at visits, were in accordance with each institution’s standard of practice with regard to the treatment regimen used (Supplementary Materials).
Safety data were summarized descriptively for all patients who received at least one dose of GO. AE severity was graded using the Common Terminology Criteria for Adverse Events, version 4.03. Only grades 3–5 AEs were recorded. No formal statistical analyses were performed. A patient was considered to have completed if the treatment regimen and follow-up were completed. Patients were permitted to reenroll in treatment, and their data are summarized according to each enrollment treatment. No efficacy evaluations were required per study protocol.
Results
Patients and treatments
A total of 316 unique patients received GO: n = 132 as monotherapy, n = 175 as combination therapy, and n = 9 as treatment for APL. Fifteen (4.5%) patients reenrolled in the study; therefore, a total of 331 patients received GO and were included in the analysis: n = 139 (age: <18 years, n = 21; ≥18 years, n = 118) as monotherapy for R/R AML; n = 183 (age: <18 years, n = 84; ≥18 years, n = 99) as combination therapy for R/R AML; and n = 9 (all age ≥18 years) as treatment for R/R APL. Respectively, in the monotherapy, combination, and APL groups, discontinuations during the treatment phase occurred in 94 (67.6%), 71 (38.8%), and 3 (33.3%) patients; the most common reasons for discontinuation included death in 39 (28.1%), 23 (12.6%), and 1 (11.1%) patients; resistant disease in 25 (18.0%), 16 (8.7%), and 1 (11.1%) patients; AEs not related to study drug in seven (5.0%), three (1.6%), and one (11.1%) patients; and AEs related to study drug in six (4.3%), four (2.2%), and no patients. Of the 15 patients who reenrolled, 5 and 10 patients were originally assigned to the monotherapy and combination groups, respectively. Twelve patients completed original therapy including all 5 patients receiving monotherapy and 7 patients receiving combination therapy. Three patients did not complete combination therapy: two due to another treatment regimen and one due to bone marrow transplant. After reenrollment, four patients who received upfront monotherapy proceeded onto additional monotherapy; three patients changed from combination to monotherapy; seven patients received combination therapy both upfront and following reenrollment; one patient treated with prior monotherapy received subsequent combination therapy. After reenrollment, 12 patients completed therapy (5 receiving monotherapy and 7 receiving combination therapy). Two patients died before completing therapy, and one patient started another anticancer regimen. Adverse events were generally similar during first and second enrollment, with a few exceptions: one patient had tumor lysis syndrome during second enrollment (GO monotherapy for both enrollments); one patient reported more AEs during second enrollment, including infection and viremia (GO combination regimens for both enrollments); and one patient had sepsis and infection during second enrollment (GO combination regimens for both enrollments). Additionally, for all reenrolled patients, there were no events of VOD in the first or second enrollment.
Overall, most patients were male and white, with a mean age of 42.2 (range 0–94) years (Supplementary Table S3). The most frequently administered doses of GO were 9 and 3 mg/m2 in the monotherapy group, 3 mg/m2 in the combination group, and 6 mg/m2 in the APL group (). For patients younger than 18 years, the most frequently administered dose of GO was 3 mg/m2 in both the monotherapy and combination groups. In patients 18 years or older, the most frequently administered dose of GO was 9 mg/m2 in the monotherapy group, 3 mg/m2 in the combination group, and 6 mg/m2 in the APL group.
Table 1. Summary of treatment exposure to GO.
Overall, in the monotherapy group, the most common treatment regimens were based on the Investigator’s Brochure (n = 119; 85.6%): GO ≤9 mg/m2 on Days 1 and 15 of a 28-day cycle (Supplementary Tables S1 and S2). In the combination group, the most common GO treatment regimens were based on Daver 2012 (n = 41; 22.4%) and 2013 (n = 37; 20.2%): GO 3 mg/m2 in both [Citation20,Citation21]. The most common treatment regimens in the APL group were based on Lo-Coco 2004 (n = 5; 55.6%): two doses of GO 6 mg/m2 at least 15 days apart; patients achieving molecular remission received a third dose [Citation6].
Adverse events
All-causality AEs were reported in 315 (95.2%) patients overall, with 193 (58.3%) patients considered by the investigator to have treatment-related AEs (). Anemia was the most common all-causality AE in the monotherapy (38.8%) and combination (47.0%) groups. In the APL group, febrile neutropenia (77.8%) was the most common all-causality AE.
Table 2. Most common grade ≥3 AEs occurring in ≥15% of all patients in any group.
No patients had dose reductions due to AEs. Overall, 21 (6.3%) patients permanently discontinued treatment due to AEs during the active treatment period: 13 (9.4%), 7 (3.8%), and 1 (11.1%) patients in the monotherapy, combination, and APL groups, respectively. The most common reasons for discontinuation were febrile neutropenia (n = 5; 1.5%), disease progression (n = 4; 1.2%), and sepsis (n = 4; 1.2%) (Supplementary Table S4).
Treatment-related AEs were reported for 193 (58.3%) patients overall: 84 (60.4%), 102 (55.7%), and 7 (77.8%) patients in the monotherapy, combination, and APL groups, respectively. The most common treatment-related AEs were white blood cell (WBC) count decrease (31.7%) in the monotherapy group, anemia (23.0%) in the combination group, and febrile neutropenia (66.7%) in the APL group ().
In patients younger than 18 years, the most common all-causality AE was platelet count decrease in both the monotherapy and combination groups. In patients 18 years or older, the most common all-causality AEs were WBC count decrease in the monotherapy group, anemia in the combination group, and febrile neutropenia in the APL group ().
Table 3. Grade ≥3 all-causality AEs occurring in ≥15% of patients in any group: analysis by age.
Serious AEs and deaths
Serious AEs (SAEs) were reported for 193 (58.3%) patients overall: 101 (72.7%), 86 (47.0%), and 6 (66.7%) patients in the monotherapy, combination, and APL groups, respectively. Treatment-related SAEs were reported in 72 (21.8%) patients overall: 29 (20.9%), 39 (21.3%), and 4 (44.4%) patients in the respective groups.
In the monotherapy group, the most common treatment-related SAEs were febrile neutropenia (n = 14; 10.1%), sepsis (n = 5; 3.6%), and thrombocytopenia (n = 3; 2.2%). In the combination group, the most common treatment-related SAEs were febrile neutropenia (n = 11; 6.0%) and septic shock and sinusitis (each n = 3; 1.6%). In the APL group, the only treatment-related SAE was grade 3 febrile neutropenia (n = 4; 44.4%).
All-causality grade 5 AEs were reported in 114 (34.4%) patients: 72 (51.8%), 40 (21.9%), and 2 (22.2%) in the monotherapy, combination therapy, and APL groups, respectively (). In general, disease progression was the most common grade 5 AE across treatment groups. Fifteen (4.5%) patients were considered by the investigator to have treatment-related grade 5 AEs. In patients younger than 18 years, all-causality grade 5 AEs occurred in 7 (33.3%) and 14 (16.7%) patients in the monotherapy and combination groups, respectively. The corresponding most common grade 5 AEs were disease progression (n = 5; 23.8%) and respiratory failure (n = 3; 3.6%).
Table 4. Summary of grade 5 AEs.
Adverse events of special interest
Hepatotoxicity was reported in five patients: VOD and drug-induced liver injury (n = 1 each; 0.7%) in the monotherapy group and VOD (n = 3; 1.6%; of which one was fatal) in the combination group ().
Table 5. Cases of hepatotoxicity.
Hemorrhage was reported in 18 patients. In the monotherapy group, two (1.4%) patients each had gastrointestinal hemorrhage, oral hemorrhage, and intracranial hemorrhage. In the combination group, three (1.6%) patients reported pulmonary hemorrhage; two (1.1%) patients each reported oral hemorrhage, upper gastrointestinal hemorrhage, and intracranial hemorrhage; and one (0.5%) patient-reported urogenital hemorrhage and pharyngeal hemorrhage. One (11.1%) patient in the APL group reported intracranial hemorrhage.
The most frequently reported myelosuppression AEs were leukopenia (n = 52; 37.4%), febrile neutropenia (n = 69; 37.7%), and febrile neutropenia (n = 7; 77.8%) in the monotherapy, combination, and APL groups, respectively (Supplementary Table S5). Three (2.2%) grade 5 AEs of febrile neutropenia were reported in the monotherapy group.
In the monotherapy group, 42 (30.2%) patients had grade ≥3 infection AEs. The most frequently reported AEs were sepsis (n = 16; 11.5%), pneumonia (n = 10; 7.2%), bacteremia (n = 5; 3.6%), and device-related infection (n = 4; n = 2.9%). In the combination group, 76 (41.5%) patients had grade ≥3 infection AEs. The most frequently reported AEs were sepsis (n = 14; 7.7%) and bacteremia (n = 9; 4.9%), as well as lung infection and device-related infection (n = 8; 4.4% each). In the APL group, three (33.3%) patients had grade ≥3 infection AEs. The AEs were lung infection (n = 2; 22.2%) and neutropenic sepsis and fungal sinusitis (n = 1; 11.1% each); one patient had an event of both lung infection and fungal sinusitis.
Tumor lysis syndrome was reported in three (2.2%) patients in the monotherapy group: one (0.7%) was grade 3 and two (1.4%) were grade 4. Three (1.6%) cases were reported in the combination group, all of which were grade 3. No patients in the APL group reported tumor lysis syndrome.
Infusion-related reactions were reported in five (3.6%) and three (1.6%) patients in the monotherapy and combination groups, respectively, all of which were grade 3. No patients in the APL group reported an infusion-related reaction.
Discussion
Here we report the safety and tolerability of an open-label EAP study of GO conducted across the United States for R/R AML and R/R APL. Of note, this trial provided access to GO before it was reapproved by the FDA. Although the adverse effect of GO has been extensively reported in several other clinical trials [Citation5,Citation8,Citation9,Citation11–13,Citation16–18,Citation20–28,Citation36,Citation37], this is the first study to evaluate drug safety in patients ≥3 months of age with no other treatment options and highlights the unmet need of these patients.
In patients with R/R AML or APL, exposure to GO was variable, with patients receiving one or more doses at dose levels up to 9 mg/m2. In the monotherapy group, the most frequently administered doses of GO were 9 and 3 mg/m2, and the most common treatment regimens were based on the Investigator’s Brochure. In the combination group, the most frequently administered dose of GO was 3 mg/m2, and the most common treatment regimens were based on Daver 2012 (decitabine 20 mg/m2 daily for 5 days and GO 3 mg/m2 on Day 5) and Nand 2013 (hydroxyurea followed by azacitidine 75 mg/m2 for 7 days and GO 3 mg/m2 on Day 8) [Citation20,Citation21]. In the APL group, the most frequently administered dose of GO was 6 mg/m2 and the most common treatment regimens were based on Lo-Coco 2004 [Citation6]. The most frequently administered doses of GO were 3 mg/m2 in both the monotherapy and combination groups in patients younger than 18 years. Compared with patients 18 years or older, a numerically higher proportion of patients younger than 18 years received combination therapy for AML. The approved dose in R/R patients with AML is GO 3 mg/m2 monotherapy on Days 1, 4, and 7, based on Taksin 2007 [Citation11]; a total of three (0.9%) patients received this schedule.
All-causality AEs reported in ≥30% of all patients were anemia, WBC count decrease, platelet count decrease, neutropenia, and febrile neutropenia. Similarly, the most frequent treatment-related grade 3 or higher AEs were cytopenias. There were no formal comparisons between patients younger than 18 years vs. those 18 years or older; however, the percentages of patients who had all-causality AEs were similar between the two age subgroups. Within the monotherapy and combination treatment groups, patients younger than 18 years generally reported a higher proportion of hematologic AEs compared with those 18 years or older. Fewer grade 5 AEs were reported in patients younger than 18 years versus those 18 years or older.
The safety profile was consistent with the known safety profile of GO in clinical trial populations [Citation5,Citation8,Citation9,Citation11–13,Citation16–18,Citation20–28,Citation36,Citation37], with no unexpected major safety findings. GO was generally well tolerated considering the diseases being treated and the treatment regimens used, with no dose reductions due to AEs. Only a small proportion (<5%) of adult and pediatric patients discontinued treatment due to treatment-related AEs. Few patients (<4% in each treatment group) had tumor lysis syndrome and infusion-related reactions. Importantly, the data from this EAP confirmed the low incidence of hepatotoxicity, including VOD ranging from 0.5 to 1.1% across all cohorts. This included heavily pretreated patients on GO >3 mg/m2 and was consistent with prior studies [Citation14,Citation19]. Treatment of VOD and hepatotoxicity with ursodeoxycholic acid and defibrotide was not standardized across sites and was enacted per institutional standard at each treating center.
In summary, although this study does not report on efficacy or provide comparisons between different dosing regimens or age groups, it provided access to GO via an EAP in response to clinical requests during a period where FDA approval had been withdrawn. These results report additional toxicity data for GO in a real-world setting, and support GO as an important and generally well-tolerated treatment option for adult and pediatric patients with R/R AML or APL. Although efficacy was not assessed in this EAP study, GO was successfully used across multiple published regimens in both adult and pediatric patients. GO toxicity was consistent with the reported safety profile of the drug in prior studies. The most frequent treatment-related grade 3 or higher AEs were hematologic in nature, and the incidence of hepatotoxicity, including VOD, was low. Data from this EAP support the use of GO as an important treatment option for appropriately selected adult and pediatric patients with R/R AML or APL.
Author contributions
All authors were involved in the trial conception/design, or the acquisition, analysis or interpretation of data. All authors contributed to the drafting of the manuscript and approved the final version.
GLAL-2019-0943-File002.docx
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The study was sponsored by Pfizer. Medical writing support was provided by Anne Marie McGonigal, PhD, of Engage Scientific Solutions and was funded by Pfizer.
Disclosure statement
Eunice S. Wang: consultancy for Pfizer, AbbVie, Amgen, Agios, AROG, Dava Oncology, ImmunoGen, Jazz Pharmaceuticals, Daiichi Sankyo, Celyad; Speakers Bureaux for Novartis, Astellas and Jazz Pharmaceuticals.
Richard Aplenc: no conflicts to disclose.
Deborah Chirnomas: was an employee of Pfizer at the time of the study.
Michael Dugan: consultancy for AbbVie; Speakers Bureau for Celgene; research funding from Pfizer.
Salman Fazal: Advisory Committee for Incyte, Bristol-Myers Squibb, Jazz Pharmaceuticals, Gilead, Pfizer, Novartis, GlaxoSmith Kline, Amgen; Speakers Bureaux for Incyte, Bristol-Myers Squibb, Jazz Pharmaceuticals, Gilead, Pfizer, Novartis, Stemline Therapeutics, Janssen Pharmaceuticals, Takeda, GlaxoSmith Kline, Karyopharm, Amgen.
Swaminathan Iyer: no conflicts to disclose.
Tara L. Lin: honoraria from Jazz Pharmaceuticals and Advisory Committee for Pfizer.
Sucha Nand: Advisory Committee for Pfizer.
Kristen J. Pierce: employee of Pfizer.
Paul J. Shami: employee of JSK Therapeutics; equity ownership in JSK Therapeutics and Lone Star Thiotherapies; consultancy for Pfizer, Jazz Pharmaceuticals, AbbVie and Agios; research support from Pfizer, Amgen and Aptevo; Board of Directors/Advisory Committee for JSK Therapeutics and Lone Star Thiotherapies.
Jennifer J. Vermette: employee of Pfizer.
Camille N. Abboud: consultancy for Pfizer, Agios, Cardinal Health and Gerson Lehrman Group; honoraria from Jazz Pharmaceuticals, Agios and Cardinal Health; Speakers Bureau for Jazz Pharmaceuticals; Dava Oncology Expert.
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Upon request, and subject to certain criteria, conditions and exceptions (see https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information), Pfizer will provide access to individual de-identified participant data from Pfizer-sponsored global interventional clinical studies conducted for medicines, vaccines and medical devices (1) for indications that have been approved in the US and/or EU or (2) in programs that have been terminated (i.e., development for all indications has been discontinued). Pfizer will also consider requests for the protocol, data dictionary and statistical analysis plan. Data may be requested from Pfizer trials 24 months after study completion. The de-identified participant data will be made available to researchers whose proposals meet the research criteria and other conditions, and for which an exception does not apply, via a secure portal. To gain access, data requestors must enter into a data access agreement with Pfizer.
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