The Safety of Repurposing Daratumumab for Relapsed or Refractory Autoimmune-Antibody-Mediated Hemolytic Anemia

Background

Autoimmune Hemolytic Anemia (AIHA) is a disorder in which red blood cells are destroyed by autoantibodies produced by B-cells and plasma cells. The goal of treatment is to maintain a Hemoglobin (Hgb) concentration ≥ 10 g/dL which involves high-dose steroids with a taper; however, steroids are frequently not curative as they do not eliminate the antibody-producing clone.

The use of rituximab, an anti-CD20 monoclonal antibody (mAb), improved outcomes for AIHA, including response rates and cure rates. It is approved in the first-line setting and for relapsed/refractory AIHA. However, for patients who do not respond or relapse after rituximab, options are generally limited.

One putative mechanism of resistance to rituximab is that the B-cell clone matures into a non-CD-20-expressing plasma cell. Using that hypothesis, we designed this study to test the safety and efficacy of daratumumab, an anti-CD38 mAb approved in several combinations for treatment of multiple myeloma as it eliminates CD38 expressing plasma cells.

Study Design

Main inclusion criteria were age ≥ 18, AIHA based on a Hgb < 10 g/dL and a positive direct antiglobulin test, and clinical signs of acute hemolysis including an elevated lactate dehydrogenase (LDH) and reticulocyte count (RC) or low haptoglobin. All patients had to have relapsed after prior treatment with steroids at ≥ 1mg/kg of prednisone (or equivalent) and rituximab ≥100mg. Patients also had to have an Eastern Cooperative Oncology Group function 0-2.

Main exclusion criteria were uncontrolled medical disorders, lymphoid malignancies other than low grade lymphoproliferative disorders not requiring treatment, pregnancy, breastfeeding, COPD with FEV1 < 50%, renal or liver dysfunction, or prior anti-CD38 therapy.

A baseline evaluation included a complete blood count (CBC), complete metabolic panel (CMP), LDH, DAT, haptoglobin, and RC. They received 6 weekly doses of subcutaneous (SC) daratumumab 1800mg and hyaluronidase PH20 2,000 U/ml. A CBC, CMP, LDH, and RC were checked weekly. Follow up with labs occurred every 8 weeks for 1 year.

The primary objective was safety monitoring. Unacceptable toxicity necessitating withdrawal was defined as any grade ≥3 event based on CTCAE version 5.

The secondary objective was treatment efficacy. A complete response (CR) was defined as a normalization in Hgb without evidence of hemolysis. A partial response was defined as an increase in Hgb > 10g/dL while allowing hemolysis with an elevated RC, bilirubin, and/or LDH. PR could include use of prednisone <10mg daily (or equivalent) to maintain Hgb > 10g/dL.

Trough serum concentrations of daratumumab were measured prior to each treatment and post last dose using an ELISA assay.

Results

This study enrolled 2 patients. For our primary endpoint, there were no unexpected toxicities attributed to daratumumab.

Patient 1 was a 57-year-old Caucasian female. Baseline Hgb and absolute RC were 9.3 g/dL and 0.28g/dL on the day of dose 1, respectively. At dose 2, her Hgb was 10.1 g/dL and her RC 0.24g/dL. By week 5, her Hgb and RCnormalized at 12.5 g/dL and 0.11, respectively and have remained in normal range at 9 months. Her bilirubin and LDH remained in normal range throughout the study. She remains in complete remission 10 months from first daratumumab dose.

Patient 2 was a 45-year-old Caucasian female. Baseline Hgb and RC were 9.2 g/dL and 0.23g/dL on day 1, respectively. She displayed normalization of her RC by week 4 measured at 0.08. Her Hgb improved to 10.5 g/dL at week 3 and normalized at 11.8 g/dL at week 8. Total bilirubin and LDH remained in normal limits in this timeframe. At week 14, she displayed evidence of relapsed disease with a Hgb 6.4 g/dL, a RC 0.45, and LDH 785 units/L. At that time, she was diagnosed with a COVID infection and was removed from the study.

Daratumumab trough concentrations increased steadily after the first dose in both patients, peaking after the sixth dose at 268.1 mcg/mL and 366.8 mcg/mL.

Conclusions

Due to the rarity of the disease, we were only able to recruit 2 patients to this single-institution trial, making it difficult to draw definitive conclusions. However, we found it promising that treatment was well-tolerated without unexpected toxicities, and that both patients achieved CRs. We suggest further investigation into daratumumab for relapsed or refractory AIHA where other treatment options are limited.