Page 12 - 2021_12-Haematologica-web

Editorials
References
1. Kayser S, Schlenk R, Lebon D, et al. Characteristics and outcome of patients with low-/intermediate-risk acute promyelocytic leukemia treated with arsenic trioxide - an international collaborative study. Haematologica. 2021;106(12):3100-3106.
2. Lo-Coco F, Avvisati G, Vignetti M, et al. Retinoic acid and arsenic tri- oxide for acute promyelocytic leukemia. N Engl J Med. 2013;369(2):111-121.
3. Zhu HH, Wu DP, Du X, et al. Oral arsenic plus retinoic acid versus intravenous arsenic plus retinoic acid for non-high-risk acute promyelocytic leukaemia: a non-inferiority, randomised phase 3 trial. Lancet Oncol. 2018;19(7):871-879.
4. Estey E, Garcia-Manero G, Ferrajoli A, et al. Use of all-trans retinoic acid plus arsenic trioxide as an alternative to chemotherapy in untreat- ed acute promyelocytic leukemia. Blood. 2006;107(9):3469-3473.
5.Zhou Q, Xi S. A review on arsenic carcinogenesis: epidemiology, metabolism, genotoxicity and epigenetic changes. Regul Toxicol Pharmacol. 2018;99:78-88.
6. Lehmann S, Ravn A, Carlsson L, et al. Continuing high early death rate in acute promyelocytic leukemia: a population-based report from the Swedish Adult Acute Leukemia Registry. Leukemia. 2011;25(7):1128-1134.
7. Sidhom JW, Siddarthan IJ, Lai BS, et al. Deep learning for diagnosis of acute promyelocytic leukemia via recognition of genomically imprinted morphologic features. NPJ Precis Oncol. 2021;5(1):38.
Daratumumab: new indications revolving around "off-targets"
Yishai Ofran
Department of Hematology, Shaare Zedek Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Israel E-mail: YISHAI OFRAN - yofran@szmc.org.il
doi:10.3324/haematol.2021.279487
The IgG1k monoclonal anti-CD38 antibody daratu- mumab, approved only 5 years ago, has become a principal agent in the treatment of patients with multiple myeloma. Evidence from multiple trials and real- world experience proved its safety and effectiveness.1 Daratumumab targets CD38, a membrane glycoprotein with various functions. Binding of CD38 to its ligand (CD31) enables plasma cells to interact with surrounding immune and endothelial cells. Additionally, CD38 serves as a dual active enzyme involved in generating and hydrolyzing ADP-ribosyl cyclase and, therefore, affects intracellular calcium signaling and energy metabolism.2 Normal human plasma cells, as well as myeloma cells, express CD38 highly. The anti-myeloma effect of daratu- mumab is mediated through the elimination of CD38- expressing plasma cells. During anti-myeloma therapy, binding of daratumumab to CD38+ natural killer (NK), T and B cells, and erythrocytes leads to "off-target" effects as well as to some common side effects, such as interference with blood product cross-matching or potential immune- modulation through regulatory T-cell elimination. However, the clinical significance of "off-target" effects of daratumumab on CD38+ non-plasma cells is not yet fully characterized.
In this issue of Haematologica, Crickx and colleagues3 reported the outcome of eight patients treated with dara- tumumab for refractory immune thrombocytopenia (ITP) or warm autoimmune hemolytic anemia (AIHA). Patients were struggling with long-lasting diseases, with a median duration of 84.5 months (range, 18–174), refractory to mul- tiple lines of standard therapies. The protocol of daratu- mumab administration was weekly infusions of 16 mg/kg combined with oral dexamethasone for at least four doses. Three out of five ITP patients and one of two patients with warm AIHA responded. A decrease in gammaglobulin lev- els was reported, but the autoimmune suppressive effect of daratumumab in these patients most probably went beyond its effect on patients’ normal plasma cells. Notably, in addition to plasma and mature B cells, CD38 is also expressed by T and NK cells, and can also be induced by
interferon and other cytokines. These cells are considered "off-targets" and in multiple myeloma patients treated with daratumumab, a reduction in regulatory T-cell count and expansion of CD4+ and CD8+ T cells were reported.4 Therefore, caution is required with co-administration of daratumumab and checkpoint inhibitors or other immune therapies. Studies are ongoing to confirm the safety of such combinations. Given its multiple targets, predicting which patients with autoimmune diseases will benefit from dara- tumumab is a challenge.
The patients treated by Crickx and colleagues had long- lasting ITP or warm AIHA resistant to various lines of ther- apy. ITP and warm AIHA are antibody-mediated diseases and therefore one can speculate that daratumumab target- ed mature B or plasma cells which survived previous lines of therapy. Such a mechanism may apply in other anti- body-mediated refractory diseases. Indeed, reports of suc- cessful treatments in similar situations are accumulating (Table 1), including daratumumab as a therapeutic option in ABO mismatch-derived post-allogeneic stem cell trans- plantation hemolysis/cytopenia or pure red cell aplasia, antibody-mediated rejection of transplanted kidney, and even in a refractory case of antiphospholipid syndrome. An attempt to investigate the immune pathophysiology of ITP was made through a comprehensive pathology evalu- ation of patients’ spleens. CD38 was identified as a promi- nent marker specifically present in clinically severe cases.5 However, despite broad-range staining for multiple mark- ers, the authors could not definitely confirm that the CD38+ cells were of B-cell or plasma-cell phenotype.
The potential activity of daratumumab in targeting T cells or early lymphoid precursors was demonstrated in a preclinical study in mice injected with T-cell acute lym- phoblastic leukemia.6 Next came reports of successful treatment of patients with resistant cases of acute lym- phoblastic leukemia with daratumumab,7-9 with best and lasting responses achieved in patients treated for minimal residual disease eradication. Interestingly, daratumumab was recently reported to be active in diseases in which the pathological immune response was complicated and
3032
haematologica | 2021; 106(12)