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Incidence and Time Course of Neutropenia in Patients Treated with Rituximab-Based Therapy for Non-Malignant Immune-Mediated Hematologic Diseases

Background : Rituximab (RTX) is approved for various malignant hematologic and rheumatologic disorders. A noteworthy side effect, late-onset neutropenia, has been reported in patients (pts) treated for hematologic malignancies, often in combination therapies of RTX and chemotherapy with an incidence of 3% to 27%. Conversely, the lack of prospective data and the off-label use of RTX in non-malignant immune-mediated hematologic diseases (NMIHD) limits the availability of evidence on the rate, severity and time course of neutropenia on this patient population, particularly in RTX monotherapy. The present study was performed to determine the frequency, severity, and time course of development and resolution of neutropenia in NMIHD pts treated with RTX, with the goal of providing evidence for clinicians on the safety and potential implications of RTX use in this patient population.
 Methods : We retrospectively analyzed patients diagnosed with autoimmune hemolytic anemia (AIHA), acquired coagulation factor deficiency (ACFD), thrombotic thrombocytopenic purpura (TTP), immune thrombocytopenic purpura (ITP), and antiphospholipid syndrome (APS) between January 2013 and October 2017. Patients with a minimum of 1 laboratory visit every 8 weeks with 1-year of follow-up were included. Date of initial and last RTX infusion, RTX dosing and number of doses, and pre-treatment absolute neutrophil count (ANC) were obtained. ANCs were reviewed from first RTX infusion to at least 12 months from last infusion. For those pts who developed neutropenia, ANC nadir and date when ANC was 1 to 1.5 (mild), 0.5 to <1 (moderate), and <0.5 ˣ 103 cells/µL (severe neutropenia) was recorded. The time to recovery from neutropenia was determined from the time of first neutropenia occurrence to an ANC>1.5. Episodes of febrile neutropenia (FN), hospitalization, infection, and use of granulocyte-colony stimulating factor (GCSF) were also obtained. Kaplan-Meier estimators, and Log-rank Tests were applied to compare between groups.
 Results : 197 patients (ITP=94, TTP=34, AIHA=34, ACFD=22, APS=13) treated with RTX monotherapy (73%), or in combination with other immunosuppressant were included. Clinical features, treatment characteristics and outcomes are summarized in the table. The median age at diagnosis was 51 years (58% female) with a median ANC prior to RTX initiation of 5.6 ˣ 103 cells/µL. Most pts received RTX at 375 mg/m2 in 4 doses (83%). The 1-year estimated probability of developing neutropenia (ANC<1.5) was 18% (Figure 1). Of those who developed neutropenia, the median ANC nadir and time to neutropenia from initial RTX infusion was 1.2 ˣ 103 cells/µL and 4.4 months, respectively. Development of neutropenia was not statistically different by gender, age, hematologic disease type, or RTX dosing. However, RTX given for ≥ 4 doses (p=0.04), or in combination with other immunosuppressant different than steroids (p<0.01) were significantly associated. Severe neutropenia was frequent in pts receiving RTX in combination with other immunosuppressant (36% versus 2%) with longer time to recovery from first neutropenia occurrence to an ANC>1.5 (2.5 versus 1.1 months) (Figure 2) compared to pts receiving RTX alone or with steroids. No episodes of FN were reported, 3 pts were hospitalized for neutropenia workup, and 2 pts had documented infections (pneumonia and cellulitis) with uncomplicated clinical course. One pt, treated with 6-mercaptopurine, received GCSF.
 Conclusions : To the best of our knowledge, this is the first study reporting on the incidence, degree and time-course of development of neutropenia in patients treated with RTX for different NMIHD. Our analysis demonstrates an 18% rate of neutropenia at 1 year, mostly mild neutropenia. Conversely, RTX in combination with other immunosuppressant, as opposed to RTX alone or with steroids, represented a significant risk factor for the development of neutropenia, especially severe neutropenia with longer time to ANC recovery. The rate of hospitalizations, infections and the use of GCSF was low, even in severe neutropenia cases. In conclusion, development of neutropenia in pts treated with RTX for NMIHD is an expected but relatively benign side effect. Neutropenia is more frequent if RTX is given with other immunosuppressant other than steroids, and when the number of doses of RTX given are higher.
 
 
 
 No relevant conflicts of interest to declare.
