Delayed neutrophil engraftment in patients receiving Daratumumab as part of their first induction regimen for multiple myeloma
Authors: Abdullah S. Al Saleh, M. Hasib Sidiqi, Morie A. Gertz, Eli Muchtar, Martha Q. Lacy, Rahma M. Warsame, Wilson I. Gonsalves, Taxiarchis V. Kourelis, William J. Hogan, Suzanne R. Hayman, Prashant Kapoor, Francis K. Buadi, Angela Dispenzieri, David Dingli, Shaji K. Kumar
Journal: American Journal of Hematology (2019)

Daratumumab is a humanized immunoglobulin (IgG-κ) that targets CD38 expressed on plasma cells. It is effective for the treatment of multiple myeloma (MM) in the relapsed/refractory setting and data is emerging to show its efficacy as part of induction therapy for newly diagnosed MM patients. Hematopoietic stem cells (HSCs) have been shown to express CD38 on the cell surface. Therefore during mobilization there is a theoretical risk of circulating daratumumab binding to and having downstream effects on these cells. There is limited data in the literature on the potential impact of daratumumab on stem cell mobilization and post transplant outcomes, in patients receiving the drug prior to autologous stem cell transplant (ASCT). In the Cassiopeia trial,1 patients who received daratumumab in combination with bortezomib, thalidomide, and dexamethasone required more plerixafor and had a lower median number of collected and infused stem cells, compared to patients who did not receive daratumumab. However, data on engraftment is not available. Also, it is not clear if daratumumab used in combination with lenalidomide, a drug shown to impact stem cell mobilization, would affect the overall outcomes. We conducted a retrospective review of myeloma patients treated with daratumumab, prior to stem cell collection and ASCT, to identify any effects daratumumab therapy may have on the efficacy of the stem cells in bone marrow recovery. The study was conducted at Mayo Clinic Rochester from February 2018 to May 2019, and it was approved by the Mayo Clinic Institutional Review Board. Categorization of high risk cytogenetic abnormalities was according to the International Myeloma Working Group (IMWG) definition and included deletion (17p), t(4;14) and t(14;16).2 Risk stratification was according to the International Staging System (ISS) and the Revised International Staging System (R-ISS).2, 3 Granulocyte colony-stimulating factor was the preferred agent used for stem cell mobilization, and plerixafor was added in a risk adapted fashion. Only few patients received cyclophosphamide for mobilization (one in the daratumumab group and three in the other group). All patients received melphalan infused at day minus one before their ASCT, and the decision about dosing (200 mg/m2 vs 140 mg/m2) was at the physicians' discretion. Neutrophil engraftment was defined as the first date of three consecutive neutrophil counts >0.5 × 10^9/L, and platelet engraftment was defined as the first date of three consecutive platelet counts >50 × 10^9/L, in the absence of platelet transfusion in the preceding 7 days. The time to engraftment in days was calculated from the stem cell infusion day to the neutrophil and platelet engraftment days, respectively. Statistical analysis was performed on JMP software (SAS, Cary, NC). We identified 12 patients who received daratumumab as part of their first induction regimen (daratumumab cohort) and compared them to 129 patients who did not receive daratumumab, prior to stem cell mobilization and transplant during the study period (no daratumumab cohort). Of the daratumumab cohort, 11 patients received daratumumab, ixazomib, lenalidomide, and dexamethasone, and one received daratumumab, cyclophosphamide, bortezomib and dexamethasone. Patients receiving daratumumab were younger and had a lower ISS stage. No differences were noted in terms of melphalan dose, number of CD34+ stem cell infused, or the use of cyclophosphamide priming between the two cohorts (Table S1). The median time from the last dose of daratumumab to stem cell collection was 3.9 weeks. In patients receiving daratumumab, the median time for neutrophil engraftment was 3 days later than patients who did not receive daratumumab (median of 19 days vs 16 days, P = .017) (Figure 1). Median platelet engraftment was delayed by 1 day, although this was not statistically significant (median of 18 days vs 17 days, P = .12) (Figure 1). A total of 6 patients (50%) from the daratumumab cohort and 52 (40%) from the no daratumumab cohort required hospital admission. Of these admissions, there was no difference between the two groups in rates of admission for fever (50% in the daratumumab group vs 42% in the no daratumumab group, P = .7). Rates of bacteremia did not differ significantly between the two groups (25% in the daratumumab group vs 16% in the no daratumumab group, P = .4). Note, CD38 is a glycoprotein that is expressed not only on plasma cells, but also on lymphoid and myeloid cells.4 Precursor cells in the bone marrow can also express CD38.5 In our cohort, patients receiving daratumumab had a longer time to neutrophil engraftment. The reasons for this are not clear, however daratumumab may have an effect on maturation of neutrophil precursors, or it may delay homing of stem cells after their infusion. In our cohort, the delay in platelet engraftment was not statistically significant, and this may reflect a difference in the potential effect of daratumumab on the myeloid precursors. However, it should be noted that our sample size was small and underpowered to detect a significant difference. In a pharmacokinetic model, the mean half-life of daratumumab was 23.3 days, with a SD of 11.8 days.6 This suggests that circulating daratumumab is likely present during stem cell mobilization and collection and is able to bind to CD38 expressed on HSC's. The negative effects of daratumumab on engraftment may lead to complications, such as increased rates of febrile neutropenia and more prolonged hospitalization. A better characterization of this phenomenon is important, given the increasing use of daratumumab as front line therapy prior to ASCT in patients with myeloma. Our study is limited by its retrospective nature, the small sample size for patients who received daratumumab, and a lack of uniformity in selecting patients to receive daratumumab during induction. Despite this, our case series provides the first report of daratumumab leading to delayed engraftment post transplant in myeloma patients, receiving it prior to stem cell collection. Clinical trials studying daratumumab prior to stem cell transplant should report transplant related outcomes, including feasibility of stem cell mobilization and engraftment times. Preclinical studies are required to identify whether there is a direct role in suppression of stem cell lines by daratumumab. None. The authors have no conflicts of interest to report related to this manuscript. 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.