This research is being done to investigate the safety and effectiveness of Darzalex Faspro (daratumumab and hyaluronidase-fihj) (a monoclonal antibody that targets plasma cells that make antibodies) and whether it can lower donor specific antibodies (DSA) levels to low enough levels to permit patients to proceed with allogeneic peripheral blood transplant (alloBMT). Those being asked to participate have high DSA levels that puts those being asked to participate at high risk of rejecting the available donor's blood stem cells and making those being asked to participate ineligible to receive a stem cell transplant.
Allogeneic blood or bone marrow transplant (alloBMT) remains the definitive curative treatment for many with relapsed or refractory hematologic malignancies. In recent years, increased use of alternative (non-fully human leukocyte antigen (HLA)-matched) donors has led to increased rates of donor specific antibodies (DSA). DSA are pre-formed HLA-antibodies in the recipient directed against the donor's class I and/or class II HLA antigens. DSA can be formed by exposure to foreign HLA antigens most commonly by pregnancy, blood transfusions, and previous organ or blood transplantation. High levels of circulating anti-HLA antibodies directed towards mismatched donor HLA antigens at the time of alloBMT can dramatically increase the risk of primary graft failure (PGF). The strength of these donor specific antibodies (DSA) can be assessed with several methodologies including cross-matched cellular based assays (cytotoxic or flow cytometric assessment) or the more sensitive solid phase immunoassay (SPI) that estimates antibody level. Methods to "desensitize" patients with elevated DSAs using therapeutic plasma exchange (TPE), intravenous immunoglobulin (IVIG), and immunosuppression (i.e., mycophenolate mofetil and tacrolimus) are successful in patients with moderate levels of DSAs. However, in many patients, the DSA levels are considered too high for desensitization, or, desensitization has failed to lower levels of the DSA, and suitable alternative donors cannot be readily identified. In this single-institution study at the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center (SKCCC), we will identify patients in whom alloBMT is indicated, but where DSA levels are above a pre-defined threshold using a proprietary algorithm that combines information from flow cytometric crossmatch (FCXM) and SPI (the Johns Hopkins (JH)-DSA Semi-Quant Screen Score). Patients who meet eligibility criteria will undergo 4 weekly doses of treatment with Darzalex Faspro, an anti- 38 (cluster of differentiation 38) antibody that kills plasma cells and lowers immunoglobulin levels, followed by standard desensitization with TPE, IVIG, and immunosuppression. Eight subjects will be treated in this pilot study. The primary endpoint will be based on safety of Darzalex Faspro and the number of patients who have DSA levels lowered enough to proceed to conditioning based on a pre-defined algorithm called JH-DSA Semi-Quant Response Score.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
8
Darzalex Faspro will be administered weekly as a subcutaneous injection on Days -42, -35, -28 and -21 (+/- 1 day) for a total of four doses at 1800 mg each.
Serum based semi-quantifiable investigational testing regimen used to screen for high DSA level or assess response to desensitization. It is based on results from cross-matched flow cytometric assessment cellular-based and solid phase immunoassays (SPI) that estimates antibody level.
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Baltimore, Maryland, United States
RECRUITINGEfficacy as assessed by percentage of patients with reduced DSA levels
Efficacy as assessed by the percentage of patients with DSA levels that are reduced to a level permissible for RIC alloHSCT with DSA strength of II or less and at least a 10% decrease in MFI from the baseline as determined by the JH-DSA Response Score.
Time frame: 2 years
Safety as assessed by proportion of patients with grade 3 or higher toxicities
Proportion of patients with Grade 3 or higher toxicities attributable to daratumumab for one cycle of Darzalex Faspro
Time frame: 2 years
Time (days) to neutrophilic recovery
Average amount of time taken to obtain an absolute neutrophil count (ANC) greater than or equal to 500 (10\^6/L) for 3 consecutive days
Time frame: 2 years
Time (days) to platelet recovery
Average amount of time taken to reach platelet count greater than 20 (10\^9/L) for 3 consecutive days
Time frame: 2 years
Number of participants who achieve T-cell chimerism
Number of participants who acheive T cell chimerism by day +60
Time frame: 2 years
Number of participants who have primary graft failure
Number of participants who have primary graft failure defined by failure to achieve a T-cell chimerism of 5% or more or neutrophilic engraftment by day +60.
Time frame: 2 years
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