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. 2024 Jun 11;8(11):2622-2634.
doi: 10.1182/bloodadvances.2024012585.

Daratumumab monotherapy in refractory warm autoimmune hemolytic anemia and cold agglutinin disease

Marit Jalink  1   2 , Chaja F Jacobs  3   4   5   6 , Jahanzaib Khwaja  7 , Dorothea Evers  8 , Coty Bruggeman  9 , Bruno Fattizzo  10   11 , Marc Michel  12 , Etienne Crickx  12 , Quentin A Hill  13 , Ulrich Jaeger  14 , Arnon P Kater  3   4   5   6 , Anja B U Mäkelburg  15 , Anouk Breedijk  16 , Peter A W Te Boekhorst  17 , Marlijn P A Hoeks  8 , Masja de Haas  2   18 , Shirley D'Sa  7 , Josephine M I Vos  4   5   18
Affiliations

Daratumumab monotherapy in refractory warm autoimmune hemolytic anemia and cold agglutinin disease

Marit Jalink et al. Blood Adv. .

Abstract

Autoimmune hemolytic anemia (AIHA) is a rare autoantibody-mediated disease. For steroid and/or rituximab-refractory AIHA, there is no consensus on optimal treatment. Daratumumab, a monoclonal antibody targeting CD38, could be beneficial by suppression of CD38+ plasma cells and thus autoantibody secretion. In addition, because CD38 is also expressed by activated T cells, daratumumab may also act via immunomodulatory effects. We evaluated the efficacy and safety of daratumumab monotherapy in an international retrospective study including 19 adult patients with heavily pretreated refractory AIHA. In warm AIHA (wAIHA, n = 12), overall response was 50% with a median response duration of 5.5 months (range, 2-12), including ongoing response in 2 patients after 6 and 12 months. Of 6 nonresponders, 4 had Evans syndrome. In cold AIHA (cAIHA, n = 7) overall hemoglobin (Hb) response was 57%, with ongoing response in 3 of 7 patients. One additional patient with nonanemic cAIHA was treated for severe acrocyanosis and reached a clinical acrocyanosis response as well as a Hb increase. Of 6 patients with cAIHA with acrocyanosis, 4 had improved symptoms after daratumumab treatment. In 2 patients with wAIHA treated with daratumumab, in whom we prospectively collected blood samples, we found complete CD38+ T-cell depletion after daratumumab, as well as altered T-cell subset differentiation and a severely diminished capacity for cell activation and proliferation. Reappearance of CD38+ T cells coincided with disease relapse in 1 patient. In conclusion, our data show that daratumumab therapy may be a treatment option for refractory AIHA. The observed immunomodulatory effects that may contribute to the clinical response deserve further exploration.

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Conflict of interest statement

Conflict-of-interest disclosure: B.F. received consultancy honoraria from Alexion, Novartis, Janssen, and Sobi. M.M. received consultancy fees and/or speakers fees received from Novartis, Alexion, Sanofi, Union Chimique Belge, Argenx, and Sobi. E.C. received honoraria (advisory boards, speaker’s fees) from Novartis, Union Chimique Belge, Amgen, and Sanofi. Q.A.H. received speaker honoraria from Grifols and Novartis; consultancy from Amgen, Argenx, Gliknik, Incyte, Immunovant, Janssen, Novartis, Sanofi, and Sobi. U.J. received honoraria from Sanofi, Roche, Novartis, Incyte, Janssen, and Bristol Myers Squibb; advisory role fees from Sanofi, Roche, and Novartis. A.K. received research funding from AbbVie, AstraZeneca, Bristol Myers Squibb, Janssen, and Roche/Genentech; received patent royalties from Janssen and LAVA; and served on the board of directors or advisory committees for AstraZeneca, BMS, Roche/Genentech, Janssen, AbbVie, and LAVA; and received speaker’s fees from AbbVie, AstraZeneca, and Janssen. S.D.S. received research funding from BeiGene and Janssen; advisory board fees from BeiGene, Sanofi, Janssen and Cellectar; speakers bureau fees from Janssen and BeiGene. J.M.I.V. received consultancy and advisory board honoraria from Sanofi and Janssen; research support from BeiGene and AbbVie/Genmab; and participated in the speakers’ bureau for Bristol Myers Squibb, Sanofi, and Amgen. All honoraria received are directed to the institute. The remaining authors declare no competing financial interests.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Hb response after the initiation of daratumumab therapy. (A) Patients with wAIHA. (B) Patients with cAIHA. Gray lines represent individual data of Hb; bold line represents median Hb over time.
Figure 2.
Figure 2.
Daratumumab treatment reduced the abundance of B cells and affected subset distributions of T cells. PBMCs from 2 patients with wAIHA at different time points: baseline (Pre), during treatment (Mid), immediately after treatment cessation (EOT), 6 weeks after the last cycle (6 weeks), and 3 months after end of treatment (Post) were analyzed by flow cytometry, either right after thawing or after a 2- to 5-day culture-cell stimulation by αCD3/αCD28 antibodies. (A) Frequency and subset distribution of B cells over the course of daratumumab treatment. (B) Analysis of CD3+ and Treg frequency, CD4+: CD8+ ratio, CD4+subset distribution and CD38 expression. (C) Hemoglobin (g/dL) levels of patients over course of treatment. CM, central memory; EM, effector memory; EMRA, effector memory RA+.
Figure 3.
Figure 3.
T-cell function and populations altered by daratumumab treatment. (A) Pooled tSNE map, minimal spanning tree, and heat map of the 8 FlowSOM metaclusters based on marker intensity, followed by tSNE maps of metaclusters in individual patients over treatment course: baseline (Pre), during treatment (Mid), immediately after treatment cessation (EOT), 6 weeks after the last cycle (6 weeks) and 3 months after end of treatment (Post). (B) Expression of CD25, CD38 on CD4+ T cells measured after a 48-hour T-cell stimulation. (C) Samples were stained with CTV and proliferation was assessed after 5 days of T-cell stimulation. CM, central memory; CTV, cell trace violet; EM, effector memory; EMRA, effector memory RA+; Treg, T-regulatory.
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