Intravenous Immunoglobulin May Accelerate Platelet Count Stabilization, Recovery in Obinutuzumab-Related Thrombocytopenia

Intravenous immunoglobulin (IVIG) treatment may accelerate platelet count stabilization and recovery in obinutuzumab- or anti-CD20 monoclonal antibody (mAb)-related thrombocytopenia, according to a case report published in Hemasphere. However, close-meshed monitoring of platelet counts is still recommended for patients undergoing an anti-CD20 mAb treatment.

Targeted anti-CD20 treatment is effectively used in B-cell neoplasia, such as follicular lymphoma (FL). In combination with chemotherapy, the third-generation anti-CD20 mAb obinutuzumab prolonged progression-free survival compared to a rituximab-based therapy in patients with FL.

Obinutuzumab especially benefitted patients with risk factors such as age > 60 years, > 4 nodal sites, elevated lactate dehydrogenase (LDH), hemoglobin <120 g/L, Ann Arbor stage III–IV, leading to an intermediate or high FL International Prognostic Index (FLIPI).

In the case report, a 56-year-old female presented with progressive dyspnea and FL initially diagnosed 1 week prior to the admission. During an inpatient treatment of myocardial infarction 3 weeks preadmission, 2 drug-eluting stents were implanted in the ramus circumflexus within percutaneous coronary intervention.

After, the patient received an oral dual antiplatelet therapy with acetylsalicylic acid (ASA) 100 mg and clopidogrel 75 mg daily. Computer tomography identified ascites and an extensive axillary, clavicular, mediastinal, retroperitoneal lymphadenectomy FL grade 1-2 at initial diagnosis.

Ascites was also possibly associated with FL throughout cytological examination. A bone marrow infiltration up to 20% was detected histologically. FLIPI reached 4 points, indicating a high risk due to the involvements of > 4 nodal sites, a slightly elevated LDH, a hemoglobin <120 g/L, and an Ann Arbor stage IV.

At the time of admission, the patient complained about progressive dyspnea, edema of the lower legs, an increasing abdominal circumference, and a weight gain of about 6 kg over the last week. Night sweats were also reported to occur frequently.

Initial blood count analysis revealed leukocyte count 11.4 × 109/L (4–10 × 109/L), hemoglobin 109.5 g/L (120–160 g/L), and platelet count 245 × 109/L (150–375 × 109/L). A rapid improvement in dyspnea was observed after therapeutic abdominal paracentesis of about 2000 mL ascites and intravenous furosemide therapy.

After a pre-phase treatment with prednisolone, a decision was made to initiate an immunochemotherapy with obinutuzumab and bendamustine. Bendamustine was administered via IV infusion at a dose of 155 mg (90mg/m²) on days 1 and 2.

Due to high tumor burden, obinutuzumab infusion was split to decrease the risk of infusion-related reactions. Physicians administered obinutuzumab as an intravenous infusion at a dose of 100 mg on day 1 (100 mg absolute, 25 mg/h) and 900 mg on day 2 (900 mg absolute, 50 mg/h, increased in increments of 50 mg/h every 30 min up to a maximum of 400 mg/h).

The patient received premedication with paracetamol 1000 mg orally, prednisolone 100 mg, and clemastine 2 mg intravenously about 1 hour before obinutuzumab administration on days 1 and 2. Overall, the treatment was well tolerated; however, the patient experienced mild chills on day 1 during obinutuzumab application.

Within 1 day after immunochemotherapy, the patient developed a marked thrombocytopenia with a platelet count of 19 × 109/L. Thrombocytopenia was confirmed in the control measurements, platelet aggregates, and fragmentocytes were microscopically excluded.

No evidence of type II heparin-induced thrombocytopenia (HIT) or disseminated intravascular coagulation (DIC) was found. Type II HIT was considered less likely because no heparin had been administered since myocardial infarction 3 weeks preadmission. Additionally, no IgG class antibodies against the complex of platelet factor 4 and heparin were detected.

Coagulation parameters were found to remain unaffected over time: prothrombin time (PT) 77% (> 70%), international normalized ratio 1.18 (< 1.15), activated partial thromboplastin time (aPTT) 27.3 seconds (< 34.4 s), thrombin time 14.7 seconds (< 18.5 s), and fibrinogen 3.65 g/L (1.5–4.0 g/L).

DIC was deemed unlikely as no drop of PT or fibrinogen or prolonged aPTT became apparent. Platelet counts reached its lower level with 4 × 109/L 2 days after immunochemotherapy. The dual antiplatelet therapy was indispensable early after coronary stent implantation in the prevention of in-stent thrombosis and reinfarction.

Under a close and constant risk-benefit consideration of antiplatelet therapy and bleeding complications, the risk of in-stent thrombosis and reinfarction was considered as leading. On the recommendation of cardiological colleagues, the physicians decided to continue clopidogrel and discontinue ASA for 1 day.

In addition, 3 platelet concentrates were transfused. The concentration of IgG was found to be slightly reduced with 5 g/L. Due to suspicion of an immune-mediated, obinutuzumab-related thrombocytopenia, IVIG 10 g daily was administered for 3 days. No additional therapy with corticosteroids was performed.

IgG concentration increased to 6.24 g/L. Platelet counts spontaneously increased on day 4, and then completely recovered on day 6 after immunochemotherapy. No signs of bleeding occurred during thrombocytopenia and the patient was discharged without complications.

Though the physicians refrained from further obinutuzumab administration, immunochemotherapy was continued on time using rituximab and bendamustine with platelet counts unaffected. Therapy is still ongoing for this patient.

In the GALLIUM trial, 11.4% of patients administered obinutuzumab experienced thrombocytopenia, opposed to 7.5% of rituximab-treated patients. However, thrombocytopenia is not specifically obinutuzumab-related, but more commonly observed in patients receiving obinutuzumab-based regimens, according to the study authors.

Thrombocytopenia occurring within 24 hours after immunotherapy was considered acute. Thrombocytopenia most frequently occurred during induction therapy. Moreover, infusion-related reactions, such as acute thrombocytopenia, were most common after the first infusion of anti-CD20 mAb.

Obinutuzumab-related acute thrombocytopenia occurring within 24 hours after administration of obinutuzumab is a sudden and severe event.

The authors note that it remains unclear whether complete recovery of platelet counts after obinutuzumab-based therapy in this case was solely due to applying IVIG. However, they suggest that IVIG may accelerate platelet count stabilization and recovery in obinutuzumab- or anti-CD20 mAb-related thrombocytopenia in general.

However, they recommend close-meshed monitoring of platelet counts within patients undergoing an anti-CD20 mAb treatment, especially considering that a marked infusion-related reaction does not necessarily precede acute thrombocytopenia.

Reference

Haage T R, Surov A, Mougiakakos D, Berisha M. Successful use of intravenous immunoglobulins in an obinutuzumab-related acute thrombocytopenia. Hemasphere. 2022;6(8):e751. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9351898/. Published July 15, 2022. Accessed August 17, 2022.