Transfusion Practices in the Era of Anti-CD38 Antibodies in the Treatment of Multiple Myeloma: A Mini Review
Ruemu Ejedafeta Birhiray, M.D1,2,3*
1Marian University School of Osteopathic Medicine, Indianapolis, Indiana, USA
2Department of Hematology St. Vincent Hospital, Indianapolis, Indiana, USA
3Hematology Oncology of Indiana, Indianapolis, Indiana, USA
*Corresponding author: Ruemu Ejedafeta Birhiray, M.D, Department of Hematology St. Vincent Hospital, 8301 Harcourt Rd Suite 200 Indianapolis, Indiana, USA, Tel: +1 3174156606; Fax: +1 3174156667; E-mail: firstname.lastname@example.org
Citation: Birhiray RE (2017) Transfusion Practices in the Era of Anti-CD38 Antibodies in the Treatment of Multiple Myeloma: A Mini Review. J Blood Transfus Hematop 2017: 1-3. doi:https://doi.org/10.29199/BTHP.101011
Received: 21 August, 2017; Accepted: 13 October, 2017; Published: 28 October, 2017
The availability of anti CD-38 antibodies in the treatment of multiple myeloma is a welcome addition to our therapeutic arsenal. However, interference of therapeutic antibodies with its target CD38, which is also expressed on erythrocytes results in false positive serological tests used in the phenotyping of red blood cells by blood banks. This could delay the release of blood products for patients requiring transfusions. Neutralization of the therapeutic CD38 antibody or CD38 denaturation on reagent red blood cells mitigates this interference. Thus, the AABB has established guidelines that need to be adopted by all clinicians using these agents in the treatment of multiple myeloma to eliminate this potential problem.
Multiple Myeloma (MM) is the second most common B-cell hematologic malignancy with an estimated incidence of 30,280 cases in the United States annually. Despite significant advances in therapy over the past decade with the introduction of the Proteasome Inhibitors (PIs) and Immunomodulatory Drugs (IMiDs), the annual death rate has remained significant with an estimated death rate of 12,590 . The estimated overall survival has improved since 2010, and no longer estimable . However, patients with double refractory disease to IMids and PIs have a very poor prognosis, with an estimated median Overall Survival (OS) of 13 months . Clearly, new therapeutic modalities are needed in the treatment of this malignancy and thus the recent approval of the immunotherapeutic agents; elotuzumab and daratumumab were a welcome addition to the armamentarium.
A 72 year old male was diagnosed with an IgG kappa, ISS stage 3, MM after presenting with anemia, hypercalcemia and acute renal failure. Following initial response to combination therapy, he relapses 1 year after maintenance therapy, resulting in treatment with a daratumumab based regimen with responsive disease. 3 months into therapy he presents to the local emergency department after a traumatic motor vehicle accident, with serum hemoglobin of 5gm/dl due to hemorrhage.
Anti CD38 Monoclonal Antibodies in the Treatment of Multiple Myeloma
Monoclonal antibodies in the treatment of MM offer a new mechanism of action in the treatment landscape and are uniquely designed to target antigens expressed on the malignant cells. One such antigenic target is CD38, which is expressed universally on myeloma cells .
Daratumumab (DARA) is an IgG1 kappa human anti CD38 antibody, approved by the US FDA for the treatment of multiple myeloma in patients relapsing after initial therapy in combination with lenalidomide  or bortezomib  and dexamethasone, or in the refractory setting with pomalidomide and dexamethasone , and as a single agent in the double refractory setting . In addition isatuximab (SAR650984; IgG1-κ; chimeric) , and MOR202 (IgG1-λ; fully human)  are CD38-targeting antibodies in late clinical development, and Ab79 and Ab19 are antibodies targeting CD38 in early development. Thus expanding arrays of these agents are expected in clinical practice.
Interference with Blood Compatibility Testing
CD38 is a transmembrane glycoprotein with ectoenzymatic activity in the catabolism of extracellular nucleotides [11-15]. Other functions include receptor-mediated adhesion by interacting with CD31 or hyaluronic acid, regulation of migration, and signaling events . In, addition, CD38 is widely expressed within the hematopoietic system, and its expression is stimulated by proinflammatory cytokines . Thus, CD38 is expressed, as expected on erythrocytes, and demonstrated by several investigators [18-20]. Therapeutic CD38-targeting antibodies interfere with routine pretransfusion phenotypic laboratory tests [21,22] and strategies to overcome the interference with blood compatibility testing were studied in detail in the daratumumab trials [23,24]. Daratumumab and other anti-CD38 antibodies, do not interfere with ABO typing of red blood cells but plasma samples of treated patients consistently cause positive agglutination reactions in Indirect Antiglobulin Tests (IATs) such as antibody detection (screening) tests, antibody identification panels, and Antihuman Globulin (AHG) crossmatches. Agglutination due to DARA occurs in all media (normal saline, Low-Ionic-Strength Saline [LISS], and Polyethylene Glycol [PEG]). Positive IATs may persist for up to 6 months after DARA is discontinued. DARA does not affect ABO/RhD typing or immediate-spin crossmatches .
Two strategies for management of blood incompatibility testing in daratumumab treated patients have been described and are now being standardized.
Dithiothreitol (DTT), a common reagent in blood banks, has emerged as an inexpensive and practical way to dissolve pan reactivity caused by DARA. DTT acts by denaturing surface CD38, thus allowing for the identification of underlying clinically relevant alloantibodies against RBCs in the presence of daratumumab. However, DTT is known to destroy the Kell antigen blood group and other, less frequently encountered blood group antigens.
Another strategy aims to neutralize RBC binding of daratumumab through the use of mouse anti-daratumumab antibodies or recombinant soluble CD38.
Potentially, the use of these highly effective therapeutic antibodies could delay transfusions in clinical practice, which could have devastating effects in cases of emergency. The AABB Clinical Transfusion Medicine Committee has developed clinical practice guidelines that should be adopted by all clinicians for the management of MM patients being treated with anti-CD38 antibodies.
AABB Recommendations .
To avoid problems with transfusion, hospitals should set up procedures to inform the transfusion service whenever any patient is scheduled to receive anti-CD38 antibody.
Before a patient begins taking anti-CD38:
After a patient begins taking anti-CD38:
Future Directions and Conclusion
Antibodies or strategies to neutralize anti-CD38 in plasma and eliminate the interference using either recombinant soluble human CD38 or daratumumab idiotype antibody are in development. Both reagents, which are potentially more expensive are widely available at this time, and additional validation studies would be needed. In principle, soluble CD38 could be used to neutralize any anti-CD38, while different idiotype antibodies would be needed to neutralize different CD38 therapeutic antibodies. Finally, antigen-typed cord cells have been used for the antibody screen as an alternative to DTT-treated cells . RBC genotyping is an alternative to phenotyping, but is associated with higher costs, and not commonly used in clinical practice today .
In case of an acute and life-threatening situation, transfusion of ABO/RhD-compatible RBC units that are compatible to as many previously determined other blood group antigens as possible can be considered. During transfusion, the patient should be monitored closely for (hemolytic) transfusion reactions. Blood group O RhD-negative red cells should be issued in emergency situations, where life-saving transfusion is required.