A phase II study of bortezomib in combination with pegylated liposomal doxorubicin for acute myeloid leukemia
Authors: Benjamin K. Tomlinson, Joseph M. Tuscano, Mehrdad Abedi, Jeanna Welborn, Mili Arora, Robert T. O'Donnell, Ted Wun, Brian A. Jonas
Journal: American Journal of Hematology (2019)

To the Editor: Acute myelogenous leukemia (AML) in patients unfit for standard induction chemotherapy, or in relapsed/refractory cases, remains a difficult challenge. Intensive induction therapy is associated with early mortality rates as high as 30% in older and high-risk patients, and patients with relapsed and refractory disease consistently have poor long-term outcomes. Additional treatment options with greater efficacy and reduced therapy-related mortality are needed for these populations. Bortezomib is a proteasome inhibitor with FDA approval for treatment of multiple myeloma and mantle cell lymphoma. Bortezomib administration results in downregulation of NF-κB, which is constitutively active in AML. Prior clinical trials of single agent bortezomib in AML have suggested modest activity, though without observation of complete or partial remissions (PR).1 However, targeting the proteasome can maintain cellular sensitivity to anthracyclines. This has lead to studies of bortezomib added to standard induction therapy that have reported encouraging complete remission (CR), or CR with incomplete platelet recovery (CRp) rates of 69%.2 Pegylated liposomal doxorubicin (PLD) is an FDA approved liposomal encapsulated anthracycline that has distinct pharmacokinetics, and favorable side effect profile when compared to the free doxorubicin. The improved toxicity of PLD over free doxorubicin suggests it has potential to safely provide anthracycline in elderly and unfit AML patients. Safety and tolerability of the combination of bortezomib with PLD, was confirmed by Orlowski et al. in a phase 1 study for advanced hematologic malignancies. Although the majority of patients had multiple myeloma, five patients were included with relapsed and refractory AML. The regimen was tolerable and modest clinical efficacy was observed even with the small sample size.3 Given the prior clinical observations, we hypothesized that the combination of bortezomib and PLD would have meaningful clinical activity. We also hypothesized a reasonable safety profile for patients with relapsed and refractory AML, and patients with newly diagnosed AML unfit for or refusing standard induction chemotherapy. To test this hypothesis, we conducted a phase II study of the combination of bortezomib and PLD, using doses and schedule previously described as safe. Herein we present our results. The protocol was approved by the UC Davis institutional review board, and all patients provided informed consent. Adult patients up to age 90 with pathologically confirmed de novo or relapsed/refractory AML were eligible. Patients with de novo AML were eligible if felt unfit for or unlikely to respond to standard induction by their treating physician. A leukocyte count <50 × 109 cells/L (± hydroxyurea) was required. Except for hydroxyurea, no anti-leukemic therapy was permitted within 4 weeks, and transplant recipients had to be at least 100 days from stem cell infusion. Bortezomib was administered at 1.5 mg/m2 subcutaneously or IV on days 1, 4, 8, 11 and PLD was given at 40 mg/m2 IV on day 4 of 21 day cycles previously published.3 Dose modifications and delays and were required for grade 2 peripheral neuropathy, hand-foot syndrome, stomatitis, and diarrhea. Treatment was continued until progressive disease, unacceptable toxicity, or withdrawal of consent. Response and progression was evaluated using International Working Group criteria.4 Primary endpoints were overall response rate (ORR) and event free survival (EFS). Secondary endpoints were overall survival (OS) and toxicity. The ORR was defined as combination of CR, CR with incomplete count recovery (CRi) and PR. The objective response was monitored using Simon's optimal two-stage design. An increase in the ORR to 45% from an estimated 20% would have warranted consideration of expansion to a larger trial. With a type I error rate of 5% and a 90% power to conclude a true response rate of 45% or higher, five or fewer objective responses in the first 17 patients would be considered insufficiently active, to warrant additional patients. The EFS and OS were estimated with the Kaplan-Meier method from the day of initiation of treatment. Events (for EFS) were progression of leukemia and death from any cause. Toxicity data included adverse event type and severity according to Common Terminology Criteria for Adverse Events v4.0. A total of 15 patients were enrolled. The median age was 70 (range of 32-83). Eight patients were male, seven were female. Median performance status was 80% (range of 60%-100%). Seven patients were newly diagnosed including four patients with de novo AML, one therapy-related, and two with antecedent hematologic disorders (chronic myelomonocytic leukemia and hypoplastic myelodysplastic syndrome). Eight patients had relapsed/refractory AML including two patients with prior allogeneic stem cell transplantation. Six patients had normal karyotypes, five had single chromosomal abnormalities, and four had complex karyotypes. Additional molecular data identified five patients with FLT3 mutations, including one with an NPM1 mutation, and one patient with a biallelic CEBPα mutation. Based on karyotype and molecular data, one patient was considered favorable risk, 10 intermediate risk, and four adverse risk. For primary endpoint analysis, 10 patients completed one cycle of chemotherapy and had assessable bone marrow biopsies. One patient who completed cycle 1 died prior to bone marrow biopsy. Three additional patients died prior to completion of cycle 1, and a fourth patient withdrew consent prior to completion of cycle 1, after an infusion reaction to PLD. There was one confirmed PR with >50% blast reduction, and appropriate peripheral cell counts resulting in an ORR 6.7%. No patient had a CR. Two additional patients had greater than 50% blast reductions, including one achieving morphologic leukemia free state but without count improvement. There was a trend toward reduction in leukemia burden early during treatment. All 11 patients who completed cycle 1, had a decrease in the percentage of circulating peripheral blasts after therapy initiation (Figure 1A). Improvements were transient; however, as only four of 10 patients evaluable by bone marrow biopsy had a decrease in marrow blasts (Figure 1B). Five patients had progressive disease after cycle 1, with increasing marrow blasts and were removed from study. In the remaining five patients that started cycle 2, no observed blast reductions persisted, and no patients had improvements in marrow blasts with additional cycles. All five patients progressed or were considered treatment failures after cycle 2. The median EFS according to intention to treat analysis was 21 days (95% confidence interval [CI] 17 to not reached [NR]), with a maximum EFS of 58 days. Kaplan-Meier median OS was 50 days (95% CI 41 to NR), and three patients lived over 180 days. As it was not possible to achieve the target response rate with expansion to 30 patients, enrollment was halted after 15 patients. Three of the deaths on therapy were due to respiratory failure. In these cases, pulmonary infection was the suspected cause, but a possible relationship to the study therapy could not be ruled out. As there have been case reports of bortezomib-related pulmonary toxicity in AML patients, future trials of proteasome inhibition in AML should monitor closely for pulmonary toxicity.5 A fourth, grade 3 pulmonary adverse event (upper respiratory infection) was observed in one additional patient. Febrile neutropenia was common, as expected, and was not associated with confirmed infection in a majority of patients. Two patients reported grade 3 peripheral neuropathy likely due to bortezomib. One patient who did not complete cycle 1 experienced an infusion reaction during administration of PLD resulting in syncope. This event was likely a vasovagal response and retreatment on protocol was offered, but the patient withdrew consent. Additional grade 3-4 toxicities included fatigue, tumor lysis syndrome, colitis, esophagitis, abdominal pain, and a fall. The overall adverse event profile largely mirrored expectations for this patient population as well as those observed in previous studies with this combination, including neuropathy and infection. As noted, concerning serious adverse events included three patients with death from respiratory failure. Observed reductions in circulating and marrow blasts with this low-dose intensity regimen suggest that proteasome inhibition with anthracycline does have some clinical activity. Nevertheless, either additional agents or increased dose intensity are clearly required. One potential candidate therapy is decitabine. Blum et al has described an association between high levels of miR-29b, which can be increased by proteasome inhibition, and efficacy of decitabine in AML patients. A phase I study of bortezomib in combination with decitabine showed a tolerable toxicity profile along with an efficacy signal, and is being examined in an ongoing phase II clinical trial.6 In this phase 2 study, the combination of bortezomib and PLD at FDA approved doses demonstrated minimal and nondurable anti-leukemic activity, in a cohort of AML patients selected for non-intensive therapy. That all patients with improving marrow blasts after cycle 1 progressed during cycle 2 of therapy was disappointing, given prior observations of bortezomib in AML.3 Our study suggests that proteasome inhibition alone is insufficient to augment sensitivity to anthracyclines, and additional work would be required to optimize dosing or identify further evidence of synergy. We thank the patients and their families for their willingness to participate in clinical trials. We would like to acknowledge Kelly Jones for her diligent management of patient data. Data from this trial was presented at the 2015 American Society of Clinical Oncology Annual Meeting (Abstract #7081). Tomlinson - Consultant for Foundation Medicine; Travel support from Actinium. Tuscano - Speaker bureau for Amgen, Celgene, Seattle Genetics; Research funding from Celgene, Genentech, Pharmacyclics, Spectrum Pharmaceuticals, Takeda. Abedi - Speaker bureau for BMS, Celgene, Seattle Genetics, Takeda, Gilead; Research funding from Celgene, Takeda, Kite. Welborn - Nothing to disclose. Arora - Nothing to disclose. O'Donnell - Speaker bureau for Novartis. Wun - Research funding and Steering Committee for Janssen and Pfizer. Jonas - Consulting or advisory role for AbbVie, Amgen, Celgene, Glycomimetics, Jazz, Pharmacyclics, Tolero; Travel support from AbbVie, Amgen, Glycomimetics; Research funding to his institution from AbbVie, Accelerated Medical Diagnostics, AROG, Celgene, Daiichi Sankyo, Esanex, Forma, Genentech/Roche, GlycoMimetics, Incyte, KaloBios, LP Therapeutics, Pharmacyclics. J.M.T. and B.A.J. designed the study. B.K.T., J.M.T., and B.A.J. wrote the article. All authors treated patients, collected and analyzed data, and edited the article. All authors read and approved the final version of this article.