Mini Review

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: birhiray@msn.com

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.

Received: 21 August, 2017; Accepted: 13 October, 2017; Published: 28 October, 2017

Abstract

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.

Introduction

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 [1]. The estimated overall survival has improved since 2010, and no longer estimable [2]. 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 [3]. 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.

Case Presentation

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 [4].

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 [5] or bortezomib [6] and dexamethasone, or in the refractory setting with pomalidomide and dexamethasone [7], and as a single agent in the double refractory setting [8]. In addition isatuximab (SAR650984; IgG1-κ; chimeric) [9], and MOR202 (IgG1-λ; fully human) [10] 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 [16]. In, addition, CD38 is widely expressed within the hematopoietic system, and its expression is stimulated by proinflammatory cytokines [17]. 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 [25].

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 [26].

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:

  1. A baseline type and screen should be performed.
  2.  
  3. In addition, a baseline RBC phenotype with ABO typing or genotyping is  recommended.

After a patient begins taking anti-CD38:

  1. ABO/RhD typing can be performed normally.
  2.  
  3. For antibody detection (screening) and identification, Dithiothreitol (DTT)-treated cells can be used to eliminate the interference.
  4.  
  5. Because DTT treatment destroys Kell antigens, K-negative units should be provided unless the patient is known to be K-positive.
  6.  
  7. Antibodies against other DTT-sensitive blood group antigens (anti-k, anti-Yta, anti-Doa/Dob, etc.) will not be detectable when the antibody screen with DTT- treated cells is performed; however such antibodies are encountered infrequently.

Crossmatch:

  1. For patients with a negative antibody screen using DTT-treated cells, an electronic or immediate-spin crossmatch with ABO/RhD-compatible, K-matched units may be performed.
  2.  
  3. For patients with known alloantibodies, phenotypically or genotypically matched RBC units may be provided.
  4.  
  5. As some typing antisera require the use of AHG, phenotyping should be performed before the patient receives anti-CD38.
  6.  
  7. Genotyping can be performed either before or after the patient receives anti-CD38.
  8.  
  9. AHG crossmatches with phenotypically or genotypically matched units will still be incompatible.
  10.  
  11. Some clinically significant antibodies may be missed with the use of uncross matched phenotypically or genotypically matched units, although this will occur infrequently.
  12.  
  13. Alternatively, an AHG crossmatch may be performed using DTT-treated donor cells.
  14.  
  15. If an emergency transfusion is required, uncross matched ABO/RhD-compatible RBCs may be given per local blood bank practices.

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 [27]. RBC genotyping is an alternative to phenotyping, but is associated with higher costs, and not commonly used in clinical practice today [27].

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.

 

References

  1. Siegel RL, Miller KD, Jemal A (2017) Cancer Statistics, 2017. CA Cancer J Clin 67: 7-30.
  2. van de Donk NW, Lokhorst HM (2013) New developments in the management and treatment of newly diagnosed and relapsed/refractory multiple myeloma patients. Expert Opin Pharmacother 14: 1569-1573.
  3. Kumar SK, Dimopoulos MA, Kastritis E, Terpos E, Nahi H, et al. (2017) Natural history of relapsed myeloma, refractory to immunomodulatory drugs and proteasome inhibitors: a multicenter IMWG study. Leukemia 31: 2443-2448.
  4. Malavasi F, Deaglio S, Funaro A, Ferrero E, Horenstein AL, et al. (2008) Evolution and function of the ADP ribosyl cyclase/CD38 gene family in physiology and pathology. Physiol Rev 88: 841-886.
  5. Dimopoulos MA, Oriol A, Nahi H, San-Miguel J, Bahlis NJ, et al. (2016) Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med 375: 1319-1331.
  6. Palumbo A, Chanan-Khan A, Weisel K, Nooka AK, Masszi T, et al. (2016) Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med 375: 754-766.
  7. Chari A, Lonial S, Suvannasankha A, Fay JW, Arnulf B, et al. (2015) Open-Label, Multicenter, Phase 1b Study of Daratumumab in Combination with Pomalidomide and Dexamethasone in Patients with at Least 2 Lines of Prior Therapy and Relapsed or Relapsed and Refractory Multiple Myeloma. ASH Blood 126: 508.
  8. Lonial S, Weiss BM, Usmani SZ, Singhal S, Chari A, et al. (2016) Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): an open-label, randomised, phase 2 trial. The Lancet 387: 1551-1560.
  9. Mikhael J, Richardson P, Usmani S, Raje N, Bensinger W, et al. (2017) A Phase IB Study of Isatuximab Plus Pomalidomide (POM) and Dexamethasone (DEX) in Relapsed/Refractory Multiple Myeloma (RRMM) ASCO, EHA Learning Center 2017: 181744.
  10. Raab MS, Chatterjee M, Goldschmidt H, Agis H, Blau I, et al. (2017) A Phase I/IIa Study of the CD38 Antibody MOR202 Alone and in Combination with Pomalidomide or Lenalidomide in Patients with Relapsed or Refractory Multiple Myeloma. ASH Blood 128:1152.
  11. van de Donk NW, Moreau P, Plesner T. Palumbo A, Gay F, et al. (2016) Clinical efficacy and management of monoclonal antibodies targeting CD38 and SLAMF7 in multiple myeloma. Blood 127: 681-695.
  12. Malavasi F (2011) Editorial: CD38 and retinoids: a step toward a cure. J Leukoc Biol 90: 217-219.
  13. Malavasi F, Deaglio S, Funaro A, Ferrero E, Horenstein AL, et al. (2008) Evolution and function of the ADP ribosyl cyclase/CD38 gene family in physiology and pathology. Physiol Rev 88: 841-886.
  14. Vaisitti T, Aydin S, Rossi D, Cottino F, Bergui L, et al. (2010) CD38 increases CXCL12-mediated signals and homing of chronic lymphocytic leukemia cells. Leukemia 24: 958-969.
  15. Malavasi F, Deaglio S, Damle R, Cutrona G, Ferrarini M, et al. (2011) CD38 and chronic lymphocytic leukemia: a decade later. Blood 118: 3470-3478.
  16. Jiang H, Acharya C, An G, Zhong M, Feng X, et al. (2016) SAR650984 directly induces multiple myeloma cell death via lysosomal-associated and apoptotic pathways, which is further enhanced by pomalidomide. Leukemia 30: 399-408.
  17. Albeniz I, Demir O, Turker-Sener L, Yalçintepe L, Nurten R, et al. (2007) Erythrocyte CD38 as a prognostic marker in cancer. Hematology 12: 409-414.
  18. Deaglio S, Canella D, Baj G, Arnulfo A, Waxman S, et al. (2001) Evidence of an immunologic mechanism behind the therapeutical effects of arsenic trioxide (As(2)O(3)) on myeloma cells. Leuk Res 25: 227-235.
  19. Mehta K, Shahid U, Malavasi F (1996) Human CD38, a cell-surface protein with multiple functions. FASEB J 10: 1408-1417.
  20. Zocchi E, Franco L, Guida L, Benatti U, Bargellesi A, et al. (1993) A single protein immunologically identified as CD38 displays NAD1 glycohydrolase, ADP-ribosyl cyclase and cyclic ADP-ribose hydrolase activities at the outer surface of human erythrocytes. Biochem Biophys Res Commun 196: 1459-1465.
  21. Chapuy CI, Nicholson RT, Aguad MD, Chapuy B, Laubach JP, et al. (2015) Resolving the daratumumab interference with blood compatibility testing. Transfusion 55: 1545-1554.
  22. Oostendorp M, Lammerts van Bueren J, Doshi P, Khan I, Ahmadi T, et al. (2015) When blood transfusion medicine becomes complicated due to interference by monoclonal antibody therapy. Transfusion 55: 1555-1562.
  23. Lokhorst HM, Plesner T, Laubach JP, Nahi H, Gimsing P, et al. (2015) Targeting CD38 with daratumumab monotherapy in multiple myeloma. N Engl J Med 373: 1207-1219.
  24. Lonial S, Usmani S, Singha UK, Singhal S, Chari A, et al. (2015) Phase II study of Daratumumab (DARA) monotherapy in patients with ≥3 lines of prior therapy or double refractory Multiple Myeloma (MM): 54767414MMY2002 (Sirius). J Clin Oncol 33: 8512.
  25. Chapuy CI, Aguad MD, Nicholson RT, AuBuchon JP, Cohn CS, et al. (2016) International validation of a Dithiothreitol (DTT)-based method to resolve the daratumumab interference with blood compatibility testing. Transfusion 56: 2964-2972.
  26. Schmidt AE, Kirkley S, Patel N, Masel D, Bowen R, et al. (2015) An alternative method to dithiothreitol treatment for antibody screening in patients receiving daratumumab. Transfusion 55: 2292-2293.
  27. Denomme GA (2011) Molecular basis of blood group expression. Transfusion and Apheresis Science 44: 53-63.