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Letters to the Editor
platelet count >100x109/L and response as a platelet count between 30 and 100x109/L with at least a 2-fold increase from baseline.13 For warm AHAI, complete response was defined as a hemoglobin level ≥12 g/dL in the absence of recent transfusion and response as a hemoglobin level ≥10 g/dL with an increase of at least 2 g/dL from the pre-treat- ment level in the absence of recent transfusion (<1 month).14 Patients who required any other treatment for autoimmune cytopenia including rescue therapy >6 weeks after the first daratumumab infusion were consid- ered non-responders regardless of platelet or hemoglobin levels. The first daratumumab infusion was considered day 0 for subsequent time points. Clinical and biological data were collected with a standardized form. The study received institutional review board approval (00011558, UPEC University, AP-HP).
Eight patients (5 females [62.5%]; median age 45 years [range, 34–70]) from six participating centers received daratumumab for refractory ITP (n=5), acquired Glanzmann syndrome with former ITP and normal platelet count (n=1) or warm AIHA (n=2). Six had second- ary ITP or warm AIHA, five had Evans syndrome with no underlying immunodeficiency (including one patient with primary antiphospholipid syndrome) and one patient had a history of Hodgkin lymphoma that was cured (#5) 9 years before the onset of ITP/Glanzmann syndrome (Table 1). At the time of starting daratumumab treatment, the median disease duration was 84.5 months (range, 18– 174). The median number of previous therapies was 6 [range, 6-11]. No patients had shown a response to their last course of rituximab (except one patient who relapsed at 3 months) and five had undergone splenectomy (Table 1).
For the five patients with ITP, the median platelet count was 11x109/L (range, 0–21x109/L), and all patients had skin and/or mucosal bleeding within the month before daratumumab. Two patients (#1, #2) achieved complete responses at 4 weeks (Figure 1). Patient #1 had a history of arterial and venous antiphospholipid syndrome, with strong positivity of lupus anticoagulant and IgM anti- b2GP1 antibodies without IgG or anticardiolipin antibod- ies. Nine months after daratumumab, the patient had no remaining IgM anti-b2GP1 antibodies, and lupus antico- agulant was barely detectable. He had no recurrence of thrombosis during follow-up with ongoing vitamin K antagonist treatment.
Patient #3 was dependent on corticosteroids and had no response at 4 weeks, which resulted in a transient increase in corticosteroid doses. However, he achieved long-lasting complete response even after corticosteroid discontinuation 24 weeks after starting daratumumab, suggesting a delayed effect of anti-CD38 treatment. The two remaining patients (#4, #6) showed no response after daratumumab.
One 35-year-old patient (#5) had chronic ITP and, after splenectomy, developed acquired Glanzmann thrombas- thenia with bleeding despite normal platelet counts. She had anti-GPIIbIIIa antibodies, and platelet aggregation studies showed no aggregation with adenosine diphos- phate, epinephrine, or arachidonic acid, with reverse ris- tocetin agglutination. She showed no response to intra- venous immunoglobulins, corticosteroids or mycopheno- late mofetil and was given daratumumab, with no response for hemorrhagic symptoms. She eventually had an ITP relapse 24 weeks after starting daratumumab.
For the two patients with warm AIHA, the median baseline hemoglobin level was 9.4 g/dL (range, 8.2–10.7), median reticulocyte count 174x109/L (range, 124–225 x109/L), and median bilirubin level 27 mmol/L (range, 24–
30). For both patients, the haptoglobin level was <0.1 mg/L, and the median lactate dehydrogenase level was 2.8 times the normal range (range, 1.34–4.2). Both had a history of ITP but normal platelet counts at the time of the first daratumumab infusion. One patient achieved a com- plete response after four cycles of daratumumab but relapsed after 9 months, and one had no response after 11 cycles, despite a progressive decrease in transfusion requirement after 3 months.
After a median follow-up of 24 weeks (range, 24–36) from the first infusion of daratumumab, five patients experienced at least one moderate adverse event. Three (#3, #7 and #8) had a minor reaction at the first daratu- mumab infusion. No further infusion-related reactions occurred afterwards. Two patients had infectious events: patient #5 had bacterial pneumonia requiring hospitaliza- tion at 4 weeks and patient #8 had COVID-19 pneumonia requiring hospitalization and convalescent plasma thera- py because of persistent symptoms at 20 weeks (chronic viremia without seroconversion). The median gamma- globulin level decreased from 7.1 g/L (range, 4.8–16.2) before treatment to 4.2 g/L (range, 3.5–7.6) at week 12 and 6.1 g/L (range, 6–15.5) at week 36 (Figure 2). Hypogammaglobulinemia (i.e., gammaglobulin level <6 g/L) was observed in five out of six patients at 12 weeks (after exclusion of 2 patients who had received intra- venous immunoglobulins in the 3 weeks before dosage).
Although this study has some limitations, including its uncontrolled design and the heterogeneity of the patients, our results suggest that daratumumab may be effective for some patients with refractory ITP and/or warm AIHA, two conditions associated with a high mortality rate.2,3 Three of eight patients achieved a complete response and one patient a delayed response despite previous failure to respond to several treatment lines including rituximab, splenectomy and at least one immunosuppressant. One patient showed complete disappearance of antiphospho- lipid antibodies. Whether depletion of CD38-positive cells correlates with response and/or relapses remains an open question that should be addressed in future studies.
We observed rapid response (within 1 month) among responders, suggesting that four daratumumab infusions are sufficient to induce remission in responders. However, the optimal number of infusions remains to be deter- mined. Importantly, two patients with an initial complete response eventually relapsed at 3 and 9 months, suggest- ing that plasma cell reconstitution had occurred. In these patients, the ongoing autoimmune B-cell response may not have been affected by daratumumab, which targets plasma cells and spares CD38-negative B cells. Thus, combining B-cell depletion with an anti-CD20 antibody and daratumumab may impair the generation of newly formed autoreactive plasma cells and prevent relapse.15
In this particular group of immunocompromised patients, the risk of severe infection was a main concern. All but one experienced profound although transient hypogammaglobulinemia, and two had a symptomatic infection. Therefore, the risk/benefit balance of such ther- apy should be carefully discussed according to the patient's clinical history.
In conclusion, daratumumab may provide clinical ben- efit in a subset of patients with ITP or warm AIHA refrac- tory to standard therapy. However, the efficacy seems rel- atively modest and hypogammaglobulinemia exposes patients to a risk of infection. Future prospective trials will evaluate the use of CD38-directed monoclonal antibodies for the management of patients with immune cytopenias, such as daratumumab in ITP (NCT04703621) or isatux- imab in warm AIHA (NCT04661033).
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haematologica | 2021; 106(12)