Use of IV immunoglobulin to treat steroid resistant, immune checkpoint inhibitor‐induced pure red cell aplasia: A case report

Abstract Pure red cell aplasia (PRCA) is characterised by normocytic normochromic anaemia, reticulocytopenia and reduced erythroid precursors in bone marrow. PRCA as an immune‐related adverse event secondary to immune checkpoint inhibitor (ICI) therapy is rare. Steroids are usually used first line to treat ICI‐induced PRCA. Here, we report a case of ICI‐induced PRCA with no response to steroids but where intravenous (IV) immunoglobulin was successfully used second line. ICI therapy was reinitiated following PRCA resolution. PRCA recurrence did not occur.


INTRODUCTION
Pure red cell aplasia (PRCA) is a rare condition characterised by normocytic normochromic anaemia, reticulocytopenia and reduced erythroid precursors on bone marrow biopsy [1].PRCA can be congenital but is usually acquired.Acquired PRCA is most commonly idiopathic, but it can be associated with infection, lymphoproliferative disorders or medications such as immune checkpoint inhibitors (ICIs) [1].Nivolumab and ipilimumab are ICIs inhibiting programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), respectively.PD-1 binds to its ligand PD-L1 and promotes T-cell apoptosis.PD-L1 is expressed by many cancer cells to inhibit T-cell activation [2].CTLA-4 outcompetes CD28-mediated activation of CD80 and CD86, receptors responsible for T-cell stimulation [3].
Nivolumab and ipilimumab promote T-cell-mediated killing of tumour cells and are licensed for the treatment of many malignancies, including uveal and cutaneous melanoma [4].ICIs are efficacious immunotherapies and do not have the classical side effect profile of cytotoxic agents [5,6].Unfortunately, overactivation of the immune system can lead to immune-related adverse effects against non-cancerous cells such as in the skin, digestive tract, blood and bone marrow [7].Abbreviations: AlkP, alkaline phosphatase; ALT, alanine transaminase; Bili, bilirubin; Hb, haemoglobin; IVIG, intravenous immunoglobulin; MCV, mean cell volume; WBC, white blood count.

CASE REPORT
A 38-year-old, white British female with a history of Addison's disease had localised BRAF V600-mutated melanoma diagnosed 6 years previously.This had been treated with wide local excision.She presented

DISCUSSION
Here, we describe a patient with immune-mediated PRCA, neutropenia and thrombocytopenia secondary to nivolumab and ipilimumab.
The neutropenia and thrombocytopenia were steroid responsive but the PRCA required treatment with IVIG.The PRCA responded rapidly, enabling ICI therapy to restart.
Seventeen cases of ICI-induced PRCA have been reported, with 15 of these included in a case series from Guo et al. [6,11,12].
PRCA was triggered by several different ICIs including nivolumab, pembrolizumab, atezolizumab, durvalumab and ipilimumab, which were paused in all cases.
Of the 17 identified patients, four patients did not receive steroids [8,12].Of the 13 patients who were treated with steroids; seven responded but six did not.Of the seven who responded, two suffered from a PRCA relapse upon steroid tapering and needed further treatment with IVIG.Of the six patients who did not respond; three responded to cyclosporin, two were treated successfully with IVIG monotherapy and one had a partial response to IVIG and required further treatment with cyclosporin and steroids to achieve a complete F I G U R E 1 Bone marrow trephine showing marked erythroid hypoplasia with absent erythroid islands when stained with haematoxylin and eosin (A) and markedly reduced erythroid activity when stained with anti-CD71 (transferrin receptor 1) antibody (B).
Like our case, the patient treated with combination therapy was successfully rechallenged with ICI and suffered no PRCA relapse [12].
Unlike our patient however, concurrent treatment with prednisolone, ciclosporin and IVIG was used rather than IVIG monotherapy, making the contribution of IVIG to PRCA remission and prevention of relapse less clear.In both patients there was a need to reinitiate ICI therapy due to likelihood of cancer progression, but this had to be balanced with risk of PRCA relapse.We restarted ICI 3 weeks following IVIG, whereas a delay of 4 months was used by Rueda-Prada et al. [12].Of note, while neither patient suffered PRCA relapse, both had melanoma progression after restarting ICI and required a change of anti-cancer treatment.
Interestingly, a recent cohort study showed increased overall survival in patients with non-small-cell lung cancer who experienced immune-related adverse events [13].It was felt that this was probably due to immune-related adverse events being correlated with increased immune attack on cancer cells [13].The cumulative evidence of case reports for ICI-induced PRCA would agree with this; of the 17 patients reported, eight had favourable cancer outcomes documented, with four unfavourable and five not reported (Supporting Information Table 1).
With worldwide shortages of IVIG, it is important to note that a single dose of 1 g/kg, as used for our patient, can be effective [14].
The mechanism of action of IVIG in treating autoimmune conditions is uncertain.Although multiple mechanisms have been proposed, the most plausible is swamping of Fc receptors on immune cells, leaving them unable to clear the autoantibody-coated erythroid precursors [15].Only two of the described patients failed to fully respond to second-line IVIG, following which further steroids ± ciclosporin was successful in achieving PRCA remission [10][11][12].Whilst the response rates to second-line ciclosporin are also favourable, the attractiveness of IVIG is the rapid response and the lack of on-going treatment.We propose that corticosteroids should remain first-line therapy for ICIinduced PRCA in most cases, with IVIG used as a treatment of choice for steroid-refractory disease and that ciclosporin is only started as a third-line agent.We also provide evidence that it is possible to rechallenge patients with ICI within 4 weeks of IVIG.This is critical in reducing anti-cancer treatment delays and may thus improve cancer relapse and survival.