Hypogammaglobulinemia and Anti-CD20 Therapy-Induced Acute Thrombocytopenia: Perhaps More than a Coincidence? Open Access

The development of secondary hypogammaglobulinemia (sHGG) because of tumor treatment and/or the underlying hematologic disorder holds substantial clinical significance. B-cell-derived malignancies such as follicular lymphoma (FL) and B-cell targeting therapies such as anti-CD20 monoclonal antibodies (mAbs) represent important risk factors for the development of sHGG [1]. HGG is defined as an immunoglobulin G (IgG) serum level falling below 6–7 g/L, with varying degrees of severity: mild (IgG = 4–6 g/L), moderate (IgG = 2–4 g/L), and severe (IgG <2 g/L). According to standard guidelines, administration of intravenous immunoglobulins (IVIg) is recommended for cases of sHGG with IgG levels below 4 g/L [1].

Thrombocytopenia within 24 h after anti-CD20 mAb therapy is referred to as acute thrombocytopenia (AT). Various reports of patients with B-cell-derived malignancies addressed the occurrence of AT after rituximab or obinutuzumab [2‒7]. Comparing rituximab and obinutuzumab in combination with chemotherapy within the GALLIUM trial in FL patients, severe thrombocytopenia at <50 × 10⁹/L (National Cancer Institute’s Common Terminology Criteria for Adverse Events [CTCAE] assessed as grade ≥3) was more frequent in the obinutuzumab (6.1%) as compared to the rituximab cohort (2.7%) [8].

A 54-year-old male patient was admitted with relapsed FL for salvage therapy. The classic FL (grade 1–2) was initially diagnosed 1 year prior to admission at advanced stage (IV_B according to Ann Arbor) and at high risk (Follicular Lymphoma Prognostic Index [FLIPI] = 4/5). After frontline immunochemotherapy with obinutuzumab and bendamustine, the patient attained partial remission. However, a few months later, the patient presented with progressive systemic lymphoma. Progression was confirmed through histological examination of an involved lymph node without evidence of transformation in high-grade non-Hodgkin’s lymphoma. Subtotal bone marrow infiltration persisted with disease progression (shown in Fig. 1a).

At admission, blood count analysis was as follows: 29.1 × 10⁹ leukocytes/L (4–10 × 10⁹/L), hemoglobin at 109.6 g/L (120–160 g/L), and 120 × 10⁹ platelets/L (150–375 × 10⁹/L). We initiated pre-phase steroids and continued with salvage therapy according to the R-DHAP protocol (i.e., rituximab, dexamethasone, cytarabine, and cisplatin). Rituximab was administered at a dose of 750 mg (375 mg/m²) after premedication. Due to fever and a small drop in peripheral oxygen saturation, rituximab treatment continued at a slow infusion rate after repeated premedication. Platelet count dropped from 116 × 10⁹/L to 13 × 10⁹/L within 24 h after rituximab (shown in Fig. 1b) and before administering chemotherapy. There was no evidence of type II heparin-induced thrombocytopenia. Blood coagulation showed no abnormal changes. Reduced IgG levels of 3.43 g/L indicated moderate HGG. We immediately started substitution with 10 g of IVIg for three consecutive days, assuming an immune thrombocytopenia (ITP)-like rituximab-induced AT. Transfusion of one platelet concentrate was necessary before placement of a central venous catheter and administration of chemotherapy. Within 5 days after anti-CD20 mAb therapy, platelet count increased and stabilized at >50 × 10⁹/L without any bleeding signs. Through retrospective laboratory testing, we found that HGG (IgG = 4.02 g/L) was present before salvage therapy. After IVIg substitution, IgG concentration increased to 6.13 g/L. AT did not recur after rituximab re-exposure during the second cycle of R-DHAP (shown in Fig. 1b).

The presented case describes the simultaneous occurrence of HGG and anti-CD20 mAb-induced AT in a patient with relapsed FL. The immediate occurrence of AT within 24 h after rituximab therapy supports an immunologically induced genesis. Since thrombocytopenia occurred before administering chemotherapy, myelosuppression caused by chemotherapy was unlikely. A FL-associated acute occurrence of thrombocytopenia was also improbable. However, baseline platelet concentration may not have been reached due to bone marrow infiltration and a depleted bone marrow reserve. In view of the clinical course of thrombocytopenia, the exclusion of other conceivable causes, and the response after IVIg substitution, the ITP-like character of anti-CD20 mAb-induced AT is supported in this context.

The precise pathophysiological background of anti-CD20 therapy-induced AT is to date uncertain. Anti-CD20 mAb-triggered immune-mediated lysis of platelets, complement-related, and cytokine-mediated mechanisms are discussed [2, 3, 5, 9]. Aslam et al. [4] described obinutuzumab-related AT as ITP, diagnosed by exclusion. It seems possible that anti-CD20 mAbs act like or activate similar mechanisms as autoantibodies in ITP, explaining their comparable phenotype (shown in Fig. 2). Due to similar risk factors, an association of HGG and anti-CD20 therapy-induced AT is conceivable. In a cohort of FL patients receiving rituximab with chemotherapy, a high-risk FLIPI denoting a high tumor burden was an independent risk factor for the post-immunochemotherapy development of sHGG [10]. Recently, we reported a case of obinutuzumab-related AT in a patient with high-risk FL [6]. After administering IVIg, platelet count recovered within 6 days. However, mild sHGG (IgG = 5 g/L) was also noted at the onset of AT. In other cases of obinutuzumab-related AT, IVIg were successfully applied, unfortunately without determination of IgG levels [6, 7]. While the occurrence of AT induced by anti-CD20 therapy is a known albeit rare condition, an association with HGG has not yet been demonstrated.

In patients with common variable immunodeficiency (CVID), the most common autoimmune-mediated condition is ITP [11]. Although decreased platelet production is suspected, the pathophysiologic relationship between CVID and ITP is still unclear [12]. However, among a cohort of adult CVID patients, the occurrence of ITP was significantly associated with decreased IgG levels <7 g/L, indicating a key role of HGG in CVID-related ITP [13]. Somasundaram et al. [14] reported a milder clinical course of CVID-related ITP compared with non-CVID-related ITP, possibly due to previously administered IVIg. In addition, relapses of CVID-related ITP appeared more frequently before IVIg administration. Similar to CVID-related ITP, an ITP-like anti-CD20 therapy-induced AT is conceivably triggered or amplified by HGG. IVIg inhibit autoantibody-mediated degradation of platelets in ITP patients, counteracting platelet destruction and, as in drug-induced ITP, can accelerate platelet recovery [15, 16]. Considering an ITP-like phenotype, IVIg are suitable to counteract platelet destruction related to anti-CD20 therapy-induced AT. In particular, the use of IVIg is generously recommended in drug-induced ITP [16].

Assuming that anti-CD20 mAb-related AT is an ITP-like condition, HGG could be considered a potential risk factor for the development of anti-CD20 therapy-induced AT. Screening for sHGG and subsequent treatment should be performed generously before anti-CD20 therapy. In particular, an appropriate HGG therapy could potentially alleviate anti-CD20 therapy-induced AT. Investigation is needed, whether IgG provide physiological protection against platelet degradation. In case of an unclear thrombocytopenia, a drug-induced ITP should be considered in the differential diagnosis and thrombocytic antibodies should be determined. In the future, the presence of HGG in this context may allow the identification of high-risk groups for anti-CD20 therapy-induced AT in already susceptible patients with hematologic disorders.

Ethical approval is not required for this study in accordance with local or national guidelines. Written informed consent was obtained from the patient for publication of this case report and any accompanying images. We thank the patient for giving his consent.

The authors have no conflicts of interest to declare.

This study was not supported by any sponsor or funder.

Tobias R. Haage: conceptualization, validation, writing – original draft, and writing – review and editing; Vanja Zeremski, Mirjeta Berisha, and Dimitrios Mougiakakos: conceptualization and writing – review and editing.

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.