Abstract
Allogeneic hematopoietic cell transplant (HCT) remains the primary curative option for patients (pts) with poor-risk hematologic malignancies, but graft-versus-host disease (GVHD) and relapse remain major obstacles. Of note, GVHD therapy with systemic steroid and more potent immunosuppression abrogates graft-versus-tumor effect and further increases relapse. The NF-κB signaling pathway has a pivotal role in maintaining malignant cell survival and in mediating inflammatory and immune response by promoting activated T and dendritic cell function and survival. Inhibition of proteasome function results in down-regulation of the NF-κB signaling pathway, thus selective apoptosis of malignant cells, in which this pathway is up-regulated, and of allo-reactive T and dendritic cells. The reversible proteasome inhibitor bortezomib may abrogate GVHD and relapse based on pre-clinical studies and a phase 1/2 clinical trial when added to high-risk mismatched unrelated donor HCTs for pts with hematologic malignancies. (Koreth J, et al. J Clin Oncol 2012;30(26):3202-8.) Carfilzomib is a second-generation irreversible immunoproteasome inhibitor, with potentially increased efficacy and specificity to the immune and hematologic malignancy cells. It has a less off-target toxicity profile, especially myelosuppression, neuropathy and diarrhea. We are exploring the addition of carfilzomib to fludarabine-based conditioning regimens and GVHD prophylaxis with tacrolimus and methotrexate.
Primary Objective: To identify the maximal tolerated dose (MTD) of carfilzomib when administered on day +1, +2, +6, +7.
Methods: The phase 1 design is standard 3+3. Eligible conditioning regimens include fludarabine/busulfan and fludarabine/melphalan. Tacrolimus is started on day -3 and tapered off by day +180 if ≥grade II acute GVHD do not occur. Methotrexate 5 mg/m2 is given IV on day +1, +3, +6, +11. Carfilzomib is administered IV on days +1, +2 at 20 mg/m2/day fixed dose and on day +6, +7 at 4 dose levels: 20, 27, 36, 45 mg/m2/day. Premedication with 4 mg dexamethasone IV is administered prior to each dose of carfilzomib 20 and 27 mg/m2 and with 8 mg prior to each dose of 36 and 45 mg/m2, respectively. Carfilzomib is given after IV methotrexate on day +1 and +6. Subcutaneous filgrastim 5 μg/kg/day is started on day +1 until engraftment. Dose-limiting toxicities (DLTs) are defined as any ≥grade 3 non-hematologic National Cancer Institute Common Terminology Criteria for Adverse Events version 4 toxicities which occur within 28 days of carfilzomib treatment (day +35) and are directly attributed to carfilzomib.
Results: Since October 2014, 10 pts (Male: Female, 5:5) have been enrolled. Nine pts received all planned 4 doses and 1 female received 3 doses only before being removed due to unrelated infectious adverse events. Among 9 evaluable pts, the median age was 55 (range, 29-61) years; all donors were 8/8 matched (7 sibling, 2 unrelated). Stem cell sources were peripheral blood in 8 and bone marrow in 1 unrelated donor. Primary diseases included FLT3-ITD+ acute myeloid leukemia in 2, acute bi-phenotypic leukemia in 1, BCR/ABL+ acute lymphoblastic leukemia in 1, myelodysplastic syndrome in 2, lymphoma in 2, and multiple myeloma in 1. All pts received the myeloablative reduced-toxicity fludarabine and busulfan x 4 (FluBu4), with busulfan kinetics targeting the concentration at steady state at 600-900 ng/mL. One pt with diffuse large B cell lymphoma received rituximab-FluBu4. All 9 pts engrafted neutrophil and platelet at a median time of 10 (range, 10-15) and 12 (9-14) days, respectively. A pt of dose level 2 (20/27 mg/m2) who received a bone marrow stem cell dose of 1.3 x 106 CD34+ cells/kg unexpectedly engrafted as early as day +15. Expected common toxicities related to the FluBu4 treatment was oral mucositis. Median CD33+ and CD3+ donor chimerisms were 100% and 88% at day 30, respectively, and were 100% and 91% at day 100, respectively. As of 8/4/15, no DLTs occurred in the 8 pts who had passed day +35, with the median transplant day of day +172 (range, 65-292). The 9th pt of dose level 3 (20/36 mg/m2) is day +14 and has engrafted.
Conclusion: Adding the irreversible immunoproteasome inhibitor carfilzomib to fludarabine-based conditioning HCT appears safe and feasible. Dose escalation to level 4 (20/45 mg/m2) is ongoing and the results will be updated at the meeting.
Disclosures
Pawarode: Onyx Pharmaceuticals: Research Funding. Off Label Use: Carfilzomib is an irreversible proteasome inhibitor and is FDA approved for treament of relapsed refractory multiple myeloma. It is here being investigated for its immunomodulatory and anti-tumor properties in the prevention of graft-versus-host disease (GVHD) and disease relapse when incorporated into fludarabine based conditioning and GVHD prophylaxis regimens for allogeneic hematopoietic cell transplantation in patients with high-risk hematologic malignancy.. Levine:Novartis: Consultancy.
MGTA-456, A CD34 Expanded Cord Blood Product, Permits Selection of Better HLA Matched Units and Results in Rapid Hematopoietic Recovery, Uniform Engraftment and Reduced Graft-Versus-Host Disease in Adults with High-Risk Hematologic Malignancies