Daratumumab in transfusion-dependent patients with low or intermediate-1 risk myelodysplastic syndromes

Myelodysplastic syndromes (MDS) are heterogeneous malignant hematopoietic stem cell disorders characterized by ineffective hematopoiesis, peripheral-blood cytopenias, and risk of progression to acute myeloid leukemia (AML). Treatment for MDS is guided by risk category (low, intermediate-1, intermediate-2, and high risk) based on the International Prognostic Scoring System. Most patients who relapse or are refractory to erythropoiesis-stimulating agents (ESA) treatment become dependent on red blood cell (RBC) transfusions. Myelodysplastic syndromes are associated with bone marrow inflammation driven by myeloid-derived suppressor cells (MDSCs) and regulatory T (Treg) cells.1, 2 The MDSCs in patients with MDS express increased levels of CD38 (data on file) and CD123. Therapies that target these cells may improve clinical outcomes in MDS. Talacotuzumab is a humanized monoclonal antibody targeting CD123, and induces natural killer cell–mediated antibody-dependent cellular toxicity against CD123+ cells.3 A phase one study established the dose of talacotuzumab (≥3 mg/kg) and suggested talacotuzumab was safe with efficacy warranting further evaluation.3 Daratumumab, a human immunoglobulin Gκ monoclonal antibody targeting CD38 with a direct on-tumor and immunomodulatory mechanism of action, is approved as monotherapy and with standard-of-care treatment for multiple myeloma (MM).4 A preclinical study in AML xenografts suggested therapeutic potential for daratumumab in AML cells.5 Based on these data, a proof-of-concept, phase two, randomized study was planned to separately evaluate the safety and efficacy of talacotuzumab and daratumumab in transfusion-dependent patients with lower-risk MDS who were relapsed or refractory to ESAs. However, recruitment to the talacotuzumab arm was closed as a precaution after the first dose in the first patient resulted in a serious grade four infusion-related reaction (IRR). This report therefore presents outcomes from patients who received daratumumab. This phase two, randomized, multicenter, open-label, study (ClinicalTrials.gov, NCT03011034) enrolled patients who were ≥18 years of age, had International Prognostic Scoring System low or intermediate-1 risk MDS, were RBC transfusion dependent, and were relapsed or refractory to ESA treatment. Complete eligibility criteria are in supplementary material. The study was planned to evaluate separately the safety and efficacy of daratumumab and talacotuzumab by 1:1 randomization. A protocol amendment enacted April 25, 2017 closed the talacotuzumab arm as a precaution (see supplementary material for patient narrative). The screening phase occurred within 28 days before day 1 of cycle one. During the treatment phase, patients received daratumumab (16 mg/kg intravenously) weekly (days 1, 8, 15, and 22) for cycles 1–2, every 2 weeks (days 1 and 15) for cycles 3–6, and every 4 weeks (day 1) for subsequent cycles (all 28-day cycles). All patients received pre-infusion medication (see supporting information). Treatment was allowed to continue without cycle limit given continued patient benefit. An end-of-treatment visit was scheduled within 30 days of the last dose. In the post-treatment follow-up phase, patients were contacted every 16 weeks after end-of-treatment until patient discontinuation or study end. Clinical cut-off was defined as 1 year after the last patient's first dose date. The primary endpoint was eight-week transfusion independence (TI), defined as the absence of RBC transfusions for any eight consecutive weeks after the first dose. Additional procedures, endpoints, and details on statistical analyses are provided in supporting information. Between March 8, 2017 and January 23, 2019, 34 patients were enrolled (Figure S1). Of those, 33 patients received daratumumab and one patient received talacotuzumab before enrollment to talacotuzumab treatment was discontinued. The following results are from only patients in the daratumumab arm. Baseline patient characteristics are presented in Table S1. At the clinical cut-off date (January 23, 2019), the median duration of follow-up was 17.1 months (range 14.3–20.2) and the median number of treatment cycles was seven (range 2–20). The most common AEs, occurring in ≥15% of patients, included pyrexia, thrombocytopenia, diarrhea, and asthenia (Table S2). A total of 21 (63.6%) patients reported grade ≥3 AEs, the most common being thrombocytopenia (six patients [18.2%]) and neutropenia (five patients [15.2%]; four patients reported both of these grade ≥3 AEs). Serious AEs were reported by 15 (45.5%) patients, including pneumonia and pyrexia by three (9.1%) patients each. Daratumumab-related AEs were reported in 18 (54.5%) patients, three of whom experienced four serious AEs (diarrhea, autoimmune disorder, respiratory tract infection, and laryngeal edema). None of the six (18.2%) patient deaths during the study were within 30 days of the last dose of daratumumab and none were considered related to daratumumab. The IRRs were reported in 13 (39.4%) patients who received daratumumab; all occurred on day 1 of cycle one. Two IRRs (hypertension and laryngeal edema) were grade three; the remainder were grade one or two. No patients discontinued treatment due to IRRs, and no new safety signals were identified. Two (6.1%, 95% CI 0.7–20.2%) patients achieved eight-week TI, and time to eight-week TI was approximately 4–5 weeks after the first daratumumab infusion. One (3.0%, 95% CI 0.1–15.8%) patient achieved 24-week TI. The durations of eight-week TI achieved were 16 and 65 weeks, with response in one patient continuing with ongoing daratumumab treatment at the clinical cut-off date (Figure S2). Additional details for these two patients can be found in supplementary information. Additionally, 18 (54.5%) patients met International Working Group criteria for hematologic improvement-erythroid response for transfusion reduction. However, responses were not sustained and most patients required transfusions every 4 weeks. One (3.0%, 95% CI 0.1–15.8%) patient achieved a best response of complete response (CR) + partial response+marrow CR based on a decrease in myeloblast percentage (7% at baseline to 2% at study day 175), but at study day 344, disease progression was reported with a myeloblast percentage increase to 12%. At a median follow-up of 17.1 months, overall survival data remain immature. One (3.0%) patient reported progression to AML after 54.7 weeks. All 33 patients who received daratumumab were included in the pharmacokinetic, immunogenicity, and biomarker analysis. Serum daratumumab concentrations accumulated through weekly doses during the first two cycles (Figure S3). The mean peak (end of infusion) serum daratumumab concentration after the first dose at day 1 of cycle one was 204 (standard deviation, 56.79) μg/mL, and was 2.98-fold higher at the end of the ninth planned infusion (day 1 of cycle three). No relationship was found between serum daratumumab concentrations and safety or efficacy (Figures S4 and S5). No patients were positive for anti-daratumumab antibodies. Immunophenotyping of peripheral blood revealed an immediate and sustained reduction in natural killer cell populations and a decrease in CD38+ Treg cells with daratumumab treatment (Figure 1). The two patients who achieved TI did not have unusually high or low baseline values for either of these cell populations. This study initially aimed to evaluate the safety and efficacy of daratumumab or talacotuzumab separately for the treatment of MDS in lower-risk patients who are relapsed or refractory to ESAs, but the study was amended to enroll patients in only the daratumumab arm. Evidence for clinical activity of daratumumab in MDS was found in two patients who achieved the primary endpoint of eight-week TI. However, this was fewer than the eight patients needed to rule out a TI rate ≤15%. The daratumumab safety profile in the current study was consistent with prior results reported for daratumumab monotherapy in MM.4 Any-grade cytopenias were individually observed in <30% of patients, and the most common grade ≥3 AEs were thrombocytopenia and neutropenia. Note, IRRs occurred in 39% of patients who received daratumumab, all at first infusion. No patient discontinued the study due to hematologic AEs or IRRs. Pharmacokinetic analyses demonstrated that serum daratumumab concentrations did not correlate with TI status or presence of grade ≥3 neutropenia or thrombocytopenia; however, these observations are based on a limited number of TI patients. Biomarker analysis showed an expected reduction in natural killer cells and CD38+ Treg cells, consistent with the mechanism of action of daratumumab.4 These reductions may cause a decrease in bone marrow inflammation, which is driven by the presence of MDSCs and Treg cells.1, 2 The mean daratumumab trough concentration at the end of weekly dosing in the current study was slightly lower than that observed in MM studies4; however, the mean daratumumab concentrations for responders and non-responders were above the previously identified threshold required to achieve 99% CD38 target saturation for MM.6 It is possible that inhibition of the CD38 pathway alone may not be sufficient for the treatment of MDS. In this study, a grade four IRR was reported in the single patient given talacotuzumab, after which this treatment arm was closed. Similar safety concerns occurred in the phase two SAMBA trial (NCT02992860) of talacotuzumab monotherapy (9 mg/kg dose) in elderly patients with high-risk MDS or AML, resulting in the early termination of the trial. In conclusion, the current study shows that daratumumab was safe and provided some clinical activity in patients with low-risk to intermediate-risk MDS who were relapsed or refractory to ESA treatment. Although cytopenias were the most frequently reported grade three or four AE, the safety profile of daratumumab was consistent with published data from daratumumab studies in MM.4 The clinical benefit of daratumumab in MDS was limited, as too few patients achieved eight-week TI to demonstrate positive proof of concept. This study was supported by Janssen Research & Development. The authors thank the patients who participated in this trial and their family members, and staff at the study sites. The authors thank Maria Krevvata, PhD, of Janssen Research & Development, LLC, for contributions to the study. Medical writing support was provided by Grace Wang, PharmD, of MedErgy, and was funded by Janssen Global Services, LLC. Guillermo Garcia-Manero, Matteo Giovanni Della Porta, Helen Varsos, Liang Xiu, Esther Rose, and Koen van Eygen contributed to study design; Guillermo Garcia-Manero, Edo Vellenga, Meagan A. Jacoby, Brayan Merchan, Dimitri Breems, Agostino Cortelezzi, Vadim Doronin, Valle Gomez, Marielle Beckers, Matteo Giovanni Della Porta, Helen Varsos, and Esther Rose acquired the data; Guillermo Garcia-Manero, Maria Diez-Campelo, Dimitri Breems, Marielle Beckers, Matteo Giovanni Della Porta, Nikki DeAngelis, Ivo Nnane, and ER analyzed or interpreted the data; all authors contributed to drafting and revising the manuscript and approved it for submission. Medical writing support was provided by Grace Wang, PharmD, of MedErgy, and was funded by Janssen Global Services, LLC. GG-M has received research support from Johnson & Johnson. MD-C has served on an advisory board for Celgene and Novartis. MAJ has served as an advisor for Novo Nordisk and has served on an advisory board for Jazz Pharmaceuticals. DB has served on an advisory board for Janssen. MB has served on an advisory board for Janssen and Takeda. KvE has served on an advisory board for Janssen. HV, LX, ND, IN, and ES are employed by Janssen Pharmaceuticals. EV, BM, AC, VD, VG, and MGDP declare no potential competing interests. The data sharing policy of Janssen Pharmaceutical Companies of Johnson & Johnson is available at https://www.janssen.com/clinical-trials/transparency. As noted on this site, requests for access to the study data can be submitted through Yale Open Data Access (YODA) Project site at http://yoda.yale.edu. This study was conducted in accordance with the Declaration of Helsinki principles and the International Conference on Harmonization Good Clinical Practices guidelines,and with approval by each local institutional review board; all patients provided written informed consent. Appendix S1. Supporting Information Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.