SUMMARY

• DARZALEX for intravenous (IV) use and DARZALEX FASPRO for subcutaneous (SC) use are not approved by the regulatory agencies for the treatment of autoimmune hemolytic anemia (AIHA). Janssen does not recommend the administration of DARZALEX or DARZALEX FASPRO in a manner that is inconsistent with the approved labeling.
• Johnson et al (2024)¹ conducted a study to evaluate the safety and efficacy of DARZLEX FASPRO in patients with relapsed or refractory AIHA. Of the 2 patients enrolled, there were no unexpected toxicities attributed to DARZALEX FASPRO. One patient had to discontinue the study due to coronavirus disease 2019 (COVID-19) infection and the other patient was in complete remission at 10 months from the first dose of DARZALEX FASPRO.  
• Jalink et al (2024)² conducted an observational, retrospective, multinational study to evaluate 19 adult patients who were treated with DARZALEX or DARZALEX FASPRO monotherapy for either warm or cold AIHA. Of the 12 patients with warm AIHA, 50% (6/12) of patients achieved overall response (OR), including ongoing response in 2 patients after 6 and 12 months. Of the remaining 50% (6/12) of patients who did not achieve OR, 4 patients had underlying Evans syndrome. Of the 7 patients with cold AIHA, overall hemoglobin (Hb) response was achieved in 57% (4/7) of patients, with ongoing response in 3 patients. Overall, 7 safety events were reported and included grade 3 adverse events (AEs) requiring hospitalization or surgery (n=3), grade 2 AEs (n=3), and grade 1 AE (n=1).
• McGlothlin et al (2023)³ conducted a single institution, retrospective review to evaluate 8 patients who were treated with DARZALEX and bortezomib for refractory AIHA. OR was reported in 88% of patients; 63% and 25% of patients achieved complete response (CR) and partial response (PR), respectively. The only nonresponder experienced grade 2 nausea + vomiting and died from sepsis + pulmonary embolism that was not attributed to the treatment. Of the remaining 7 patients who were alive, 4 patients tolerated their treatments with no AEs.
• Yoo et al (2023)⁴ conducted a single institution retrospective chart review to evaluate 6 pediatric patients who were treated with DARZALEX for refractory AIHA. No cases of AIHA recurrence were reported. Only 1 patient who remained transfusion dependent died due to mycobacterial pneumonia, which was not attributed to the treatment. The remaining 5 patients were alive.
• Crickx et al (2021)⁵ conducted an observational, retrospective, multicenter study to evaluate 8 patients who were treated with DARZALEX once a week (QW) for either refractory immune thrombocytopenia (ITP) or warm AIHA. Of the 2 patients with warm AIHA, 1 patient achieved a CR after 4 DARZALEX infusions then relapsed after 9 months, and 1 patient had no response after 11 DARZALEX infusions. After the firstDARZALEX infusion, minor infusion-related reactions (IRRs) were experienced in patients with warm AIHA.
• Rieger et al (2021)⁶ conducted a retrospective analysis of 4 patients treated with DARZALEX QW for a maximum of six doses for refractory warm-type AIHA. Two patients sustained disease control. In the other 2 patients, a clinically significant relapse was observed. There were no major side effects reported with DARZALEX.
• Relevant literature regarding this topic have been included as citations for your review.^7-18

PRODUCT LABELING

• DARZALEX (daratumumab) [Prescribing Information]. Horsham, PA: Janssen Biotech, Inc.; https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/DARZALEX-pi.pdf
• DARZALEX FASPRO (daratumumab and hyaluronidase-fihj) [Prescribing Information]. Horsham, PA: Janssen Biotech, Inc.; https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/DARZALEX+Faspro-pi.pdf.  

CLINICAL DATA

Study in Patients with Relapsed or Refractory AIHA

Johnson et al (2024)¹ conducted a study to evaluate the safety and efficacy of DARZLEX FASPRO in patients with relapsed or refractory AIHA.

Study Design/Methods

• Patients received 6 weekly doses of DARZALEX FASPRO 1800mg SC.
• Key inclusion criteria: ≥18 years old, AIHA (defined as Hb <10 g/dL and positive direct antiglobulin test), clinical signs of acute hemolysis (elevated lactate dehydrogenase [LDH] and reticulocyte count [RC] or low haptoglobin), relapsed after prior steroid and rituximab treatment.
• Primary endpoint: safety monitoring.
• Secondary endpoints: CR (defined as an increase in Hb >10 g/dL without evidence of hemolysis), PR (defined as an increase in Hb >10 g/dL while allowing hemolysis with elevated RC, bilirubin and/or LDH).

Results

Efficacy

• Two patients were enrolled in the study. By week 5 of DARZALEX FASPRO treatment, Patient 1’s Hb and RC normalized at 12.5 g/dL and 0.11, respectively. The patient remained in complete remission by month 10.
• Patient 2’s RC and Hb normalized at 0.08 by week 4 and 11.8 g/dL by week 8, respectively. At week 14, Patient 2 experienced decreased Hb (6.4 g/dL) and elevated RC and LDH (0.45 and 785 units/L, respectively). The patient diagnosed with COVID-19, resulting in removal from the study.

Safety

• There were no unexpected toxicities attributed to DARZALEX FASPRO treatment.

Observational, Retrospective, Multinational Study in Patients with Warm or Cold AIHA

Jalink et al (2024)² conducted an observational, retrospective, multinational study to evaluate the use of DARZALEX or DARZALEX FASPRO for warm or cold AIHA.

Study Design/Methods

• Retrospective review of patients who received DARZALEX or DARZALEX FASPRO monotherapy.
• The Hb response was defined as none, PR (Hb 10-12 g/dL or >2 g/dL increase), or CR (Hb >12 g/dL), in the absence of recent red blood cell (RBC) transfusion.
• The initial OR was defined as the percentage of patients with CR and PR of the total number of patients.

Results

Patient Characteristics

• A total of 19 patients with either warm AIHA (n=12) or cold AIHA (n=7) were included in this study.
• Patients with warm AIHA received either 4 or 8 QW DARZALEX or DARZALEX FASPRO doses (n=9) or a median of 11 (range, 11-13) DARZALEX or DARZALEX FASPRO doses (n=3). See Table: Key Characteristics of Patients with Warm AIHA.
• Patients with cold AIHA received 8 QW DARZALEX or DARZALEX FASPRO doses (n=3) or DARZALEX or DARZALEX FASPRO maintenance dose for a median duration of 15.5 months (range, 11-40) (n=4). See Table: Key Characteristics of Patients with Cold AIHA.
• The median baseline Hb level was 8.5 g/dL (range, 4-11.2) and 8.6 g/dL (range, 5-12.5) in patents with warm and cold AIHA, respectively.
• The median duration of therapy was 2 months (range, 1-6) and 11 months (range, 2-40) in patients with warm and cold AIHA, respectively.
• The median duration of follow-up after DARZALEX infusions was 4 months (range, 2-12) and 11 months (range, 2-40) in patients with warm and cold AIHA, respectively.

Efficacy

• Of the 12 patients with warm AIHA, 50% achieved OR with a median time to response of 2 weeks (range, 2-8), including ongoing response in 2 patients after 6 and 12 months. The remaining 6 patients who did not achieve OR had a median of 7 (range, 3-10) previous lines of therapies. Of these 6 nonresponders, 4 had underlying Evans syndrome. See Table: Treatment and Response to DARZALEX or DARZALEX FASPRO in Patients with Warm AIHA.
• Of the 7 patients with cold AIHA, overall Hb response was achieved in 57% of patients, with a median time to response of 3 weeks (range, 2-12) and ongoing response in 4 patients. See Table: Treatment and Response to DARZALEX or DARZALEX FASPRO in Patients with Cold AIHA.
• The overall median time to PR and CR was 2 weeks (range, 2-12) and 2 weeks (range, 2-16), respectively.

Safety

• Overall safety events reported include:
  • Three grade 3 events requiring hospitalization or surgery (chronic COVID-19 infection, n=1; febrile neutropenia and presumed pneumonia, n=1; bacterial sepsis and an anal abscess, n=1).
  • Grade 2 infusion reaction after the first dose of DARZALEX (n=3).
  • Grade 1 varicella zoster virus infection (n=1).
• Among patients with warm AIHA, 2 patients showed alterations in T-cell skewing and a severely diminished capacity for T-cell activation and proliferation. Reappearance of cluster of differentiation (CD)38+ T-cells coincided with disease relapse after DARZALEX discontinuation in 1 patient.
• Among patients with cold AIHA and acrocyanosis, 4 of 6 showed improvement in symptoms with complete resolution in 2 patients.
• Two patients (1 each with warm AIHA and cold AIHA) died 3 months after the start of DARZALEX due to uncontrolled severe hemolytic anemia.

Single Institution, Retrospective Review in Patients with Refractory AIHA

McGlothlin et al (2023)³ conducted a single institution retrospective review to evaluate the use of DARZALEX and bortezomib for refractory AIHA.

Study Design/Methods

• Retrospective review of 8 patients who received DARZALEX and bortezomib for refractory AIHA.
• CR was defined as normal Hb or Hb ≥12 g/dL with normalized laboratory markers of hemolysis, PR was defined as Hb >10 but <12 g/dL or at least an increase by >2 g/dL, with or without biochemical resolution of hemolysis, and no response was considered when neither CR nor PR was reported.

Results

Patient Characteristics

• A total of 8 patients with refractory AIHA were included in this study. See Table: Key Characteristics and Treatment Response of Patients with Refractory AIHA.
• Of the 8 patients, 5 had warm AIHA, 2 had cold agglutinin disease (CAD), and 1 had mixed AIHA subtype. Of these, 2 patients received DARZALEX infusion alone, 4 patients received bortezomib infusion alone, and 2 received DARZALEX + bortezomib infusions.
• Most patients (67% [6/8]) received at least 3 lines of treatment prior to initiating either DARZALEX or bortezomib.

Efficacy

• Overall response rate was 88% with a median duration of response of 24.5 months (range, 15-42).
• A total of 63% of patients and 25% of patients achieved CR and PR, respectively. The median time to treatment was 2.1 months (range, 1-5). See Table: Key Characteristics and Treatment Response of Patients with Refractory AIHA.

Safety

• The only nonresponder experienced grade 2 nausea + vomiting and died from sepsis + pulmonary embolism that was not attributed to the treatment.
• Of the remaining 7 patients who were alive, 4 tolerated their treatments with no AEs. Three patients experienced AEs, including grade 3 atrial fibrillation (n=1), grade 1 injection site reaction (n=1), and grade 1 dizziness (n=1).

Retrospective Chart Review in Pediatric Patients with Refractory AIHA

Yoo et al (2023)⁴ conducted a single institution retrospective chart review to evaluate the use of DARZALEX for pediatric patients with refractory AIHA.

Study Design/Methods

• Retrospective chart review of 6 pediatric patients with allogeneic hematopoietic cell transplant (HCT) who were treated with DARZALEX for refractory AIHA.
• The patients received 16 mg/kg/dose of DARZALEX with a median of 4.5 doses (range, 4-8).

Results

Patient Characteristics

• A total of 6 pediatric patients (83% males; median age, 11 years [range, 2-20]) with refractory AIHA were included in this study.
• The study included 50%, 33%, and 17% of Caucasian, Hispanic, and African American patients, respectively.
• Indications for allogeneic HCT included hematologic malignancies (50%) and primary immunodeficiencies (50%).

Efficacy

• A total of 83.3% of patients achieved transfusion independence within a median of 48 days (range, 0-110) from the first dose of DARZALEX.
• No cases of AIHA recurrence were reported over a median follow-up of 375 days (range, 145-1237).

Safety

• One patient remained transfusion dependent and died due to mycobacterial pneumonia, which was not attributed to the treatment. The remaining 5 patients were alive.

Observational, Retrospective, Multicenter Study in Patients with ITP or Warm AIHA

Crickx et al (2021)⁵ conducted an observational, retrospective, multicenter study to evaluate the use of DARZALEX for refractory ITP or warm AIHA.

Study Design/Methods

• Retrospective review of patients who received at least 4 QW DARZALEX infusions in combination with oral dexamethasone 20 mg before each infusion.
• For warm AIHA, CR was defined as a hemoglobin level ≥12 g/dL in the absence of recent transfusion and a hemoglobin level ≥10 g/dL with an increase of at least 2 g/dL from the pre-treatment level in the absence of recent transfusion (<1 month).
  • Additionally, patients who required additional treatments >6 weeks after the first DARZALEX infusion were considered nonresponders regardless of hemoglobin levels.

Results

Patient Characteristics

• A total of 8 patients with either refractory ITP or warm AIHA were included in this study of which 2 patients had warm AIHA. See Table: Key Characteristics of Patients with Warm Autoimmune Hemolytic Anemia.
  • Patients with warm AIHA (n=2) also had a history of ITP with normal platelet counts at 1^st DARZALEX infusion:
    • Median baseline hemoglobulin level was 9.4 g/dL (range, 8.2-10.7), reticulocyte count was 174 x 10⁹ g/dL (range, 124-225), and bilirubin level was 27 µmol/L (range, 24-30).
    • Haptoglobin level was <0.1 mg/L, and median lactate dehydrogenase (LDH) level was 2.8 times the normal range (range, 1.34-4.2).
• Median follow-up after DARZALEX infusions was 24 weeks (range, 24-36).
• The median disease duration was 84.5 months (range, 18-174).
• The median number of previous therapies was 6 (range, 6-11).
  
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Efficacy

• Of the 2 patients with warm AIHA, 1 patient achieved a CR after 4 DARZALEX infusions then relapsed after 9 months, and 1 patient had no response after 11 DARZALEX infusions. See Table: Treatment and Response to DARZALEX in Patients with Warm Autoimmune Hemolytic Anemia.

Safety

• Of the 2 patients with warm AIHA, minor IRRs were experienced at the 1^st DARZALEX infusion with none during subsequent infusions afterwards.
• Of the 2 patients with warm AIHA, 1 patient (who had no response to DARZALEX) had COVID-19 pneumonia requiring hospitalization and convalescent plasma therapy because of persistent symptoms at 20 weeks (chronic viremia without seroconversion).

Retrospective Analysis of Patients with Refractory Warm-Type AIHA

Rieger et al (2021)⁶ conducted a retrospective analysis of patients with rituximab-refractory warm-type AIHA who were treated with DARZALEX.

Study Design/Methods

• Retrospective analysis of 4 patients who presented with warm-type AIHA after insufficient response to rituximab.
• Warm-type AIHA was defined as progressive anemia with a positive direct antiglobulin test (DAT) and laboratory signs of hemolysis (high serum levels of LDH, bilirubin, reticulocyte count and suppressed haptoglobin).
• Response to treatment was assessed by an increase in hemoglobin level, reduction in laboratory signs of hemolysis (LDH and bilirubin), and transfusions needed, as recommended by the First International Consensus guidelines.
• DARZALEX infusions were administered every week for a maximum of 6 doses.

Results

Patient Characteristics

• All patients had a positive DAT with anti-immunoglobin G (IgG), additionally:
  • Patient 1 also had anti-C3d
  • Patient 4 also had anti-C3d and anti-IgA
  • Patient 3 experienced AIHA along with severe ITP (platelet count <20 g/l)
• Characteristics of 4 patients who experienced refractory warm-type AIHA is presented in Table: Patient Characteristics with AIHA.

Patient Disposition

• After 3 doses, DARZALEX infusions were discontinued in 1 of 4 patients due to a very good response based on recommendations for the treatment of AIHA from the First International Consensus Guidelines.
• In 2 of 4 patients, DARZALEX infusions were interrupted after 2 doses due to very good response. Remainder of the DARZALEX infusions were restarted due to imminent relapse.
• Patient 3 was administered another 6 doses of DARZALEX infusions at an external hospital.
• Due to secondary hypogammaglobinemia after ASCT, patient 1 and 2 received repeated immunoglobulin substitutions before and after DARZALEX infusions.

Efficacy

• Median transfusions from AIHA diagnosis to the 1^st dose of DARZALEX decreased from 40 units (range, 4-71) to 1 unit (range, 0-3).
  • After DARZALEX infusions, decrease in LDH and bilirubin levels were observed in all 4 patients.
  • After DARZALEX infusions, an increase in hemoglobin and platelet levels were observed in all 4 patients.
  • In 3 of 4 patients, a decrease in intensity of DAT was observed without any disease-specific antibody levels after DARZALEX infusions.
• Median follow-up after the last DARZALEX infusion was 360 days (range, 87-492).
  • In patient 2 and 3, sustained disease control was observed.
  • In patient 1 and 4, a clinically significant relapse was observed.
    • After the last DARZALEX dose, alternative treatment was administered for patient 1 and 4 after 58 days and 163 days, respectively.

Safety

• There were no major side-effects reported with DARZALEX.
• There were no infections reported.

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File databases (and/or other resources, including internal/external databases) was conducted on 11 June 2025.