Gilteritinib combined with venetoclax and azacitidine for relapsed acute myeloid leukemia cocurrent with pure red cell aplasia after allogeneic hematopoietic stem cell transplantation: a case report.

Pure red cell aplasia (PRCA) is a rare bone marrow (BM) disorder characterized by ineffective erythropoiesis, reduced reticulocyte count, normocytic anemia, and the absence of erythroid precursors. Here, we present a rare instance of PRCA occurring after ABO-matched allo-HSCT in a refractory/relapsed acute myeloid leukemia (R/R AML) patient. In this case, the patient received a combination treatment of Gilteritinib, Venetoclax, and Azacitidine. Remarkably, this treatment not only reduced myeloblasts but also facilitated the restoration of erythroid hematopoiesis.

Immune-mediated hemolytic anemia and pure red cell aplasia in a Jack Russell Terrier during treatment for hypoadrenocorticism.

An 11-year-old neutered male Jack Russell Terrier was presented to Yuki Animal Hospital for regenerative anemia during the treatment of hypoadrenocorticism. A blood smear examination showed spherocytes, polychromatic erythrocytes, and erythrocyte ghosts. The direct agglutination test was positive at 37°C. The dog was then diagnosed with immune-mediated hemolytic anemia (IMHA). Although prednisolone and mycophenolate mofetil were administered, the hematocrit and reticulocyte count decreased, and nonregenerative anemia developed. A bone marrow examination was performed to diagnose the cause of the nonregenerative anemia. Histologic and cytologic bone marrow examination revealed a normocellular to hypercellular medulla with severe erythroid hypoplasia. No proliferation of lymphocytes or lymphoblast-appearing cells was observed. This dog was diagnosed with pure red cell aplasia (PRCA). Despite treatment with immunosuppressive agents, the patient died of thrombosis. Although these associations were unclear, this is the first report of PRCA diagnosis following IMHA and while treating hypoadrenocorticism.

Successful treatment pure red cell aplasia after ABO major mismatched allogeneic hematopoietic stem cell transplantation with avatrombopag and low dose rituximab.

BACKGROUND: Pure red cell aplasia (PRCA) following allogeneic hematopoietic stem cell transplantation (allo-HSCT) with ABO major incompatibility is characterized by transfusion dependent anemia. No standard treatment existed for PRCA following allo-HSCT yet. STUDY DESIGN AND METHODS: We conducted a retrospective study, and reported our experience with the use of avatrombopag and lower dose rituximab to treat five patients with PRCA subsequent to major ABO-incompatible allo-HSCT. RESULTS: Five cases of PRCA were identified from 72 patients who underwent allo-HSCT with major or bidirectional ABO mismatch. Cumulative incidence at Day +60 was 6.9% (5/72) at our center. All donor and recipient blood groups were A+  and O+ , respectively. In the first three cases we reported, patients received erythropoietin, plasma exchange, and donor lymphocyte infusion, but none of them had any effect. After 4 weeks of treatment with low dose rituximab (100 mg/week) combined with avatrombopag (40 mg/day), favorable outcomes were obtained. According to the aforementioned experience, Cases 4 and 5 were administered low-dose rituximab and avatrombopag in 3 months after transplantation, and erythroid response was observed on 3 weeks after treatment. Our patients tolerated low-dose rituximab and avatrombopag well and experienced rapid efficacy, with a median duration of 3 weeks. Furthermore, no severe infection or thrombocytosis necessitated a dose adjustment. CONCLUSION: Low-dose rituximab and avatrombopag may be an effective treatment for patients with PRCA after major ABO-incompatible allo-HSCT. The patients should be treated at least 90 days post transplantation if conventional erythropoietin therapy fails.

Niraparib-induced pure red cell aplasia.

INTRODUCTION: Niraparib, a strong poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor, contributed significantly to progression-free survival as a maintenance therapy in the platinum-sensitive period in both first-line and recurrent ovarian cancer, regardless of the BRCA mutation. Grade 3-4 anemia, which has a manageable side effect profile, especially hematological, is seen in almost 1 out of every 4 patients. To the best of our knowledge, there has been no reported case of pure red cell aplasia (PRCA) induced by niraparib treatment. CASE REPORT: A 65-year-old woman diagnosed with stage 3 serous carcinoma of the tuba received niraparib front-line maintenance treatment had grade 4 anemia after 3 months of niraparib treatment. She underwent bone marrow aspiration and biopsy because of refractory anemia, which needs red blood cell (RBC) transfusions despite interruption of treatment. MANAGEMENT AND OUTCOME: The patient was treated with 1 mg/kg methyl prednisolone, after histopathological assessment was consistent with PRCA. The hemoglobin count returned to the normal range with steroid treatment. DISCUSSION: In daily practice, it should be kept in mind that in the case of refractory anemia induced by niraparib, the underlying cause might be PRCA and can be improved with steroid administration.

HLA-B*46:01:01:01 and HLA-DRB1*09:01:02:01 are associated with anti-rHuEPO-induced pure red cell aplasia.

Treatment of anemia in patients with chronic kidney disease (CKD) with recombinant human erythropoietin (rHuEPO) can be disrupted by a severe complication, anti-rHuEPO-induced pure red cell aplasia (PRCA). Specific HLA genotypes may have played a role in the high incidence of PRCA in Thai patients (1.7/1,000 patient years vs. 0.03/10,000 patient years in Caucasians). We conducted a case-control study in 157 CKD patients with anti-rHuEPO-induced PRCA and 56 controls. The HLA typing was determined by sequencing using a highly accurate multiplex single-molecule, real-time, long-read sequencing platform. Four analytical models were deployed: Model 1 (additive: accounts for the number of alleles), Model 2 (dominant: accounts for only the presence or absence of alleles), Model 3 (adjusted additive with rHuEPO types) and Model 4 (adjusted dominant with rHuEPO types). HLA-B*46:01:01:01 and DRB1*09:01:02:01 were found to be independent risk markers for anti-rHuEPO-induced PRCA in all models [OR (95%CI), p-values for B*46:01:01:01: 4.58 (1.55-13.51), 0.006; 4.63 (1.56-13.75), 0.006; 5.72 (1.67-19.67), 0.006; and 5.81 (1.68-20.09), 0.005; for DRB1*09:01:02:01: 3.99 (1.28-12.49), 0.017, 4.50 (1.32-15.40), 0.016, 3.42 (1.09-10.74), 0.035, and 3.75 (1.08-13.07), 0.038, in Models 1-4, respectively. HLA-B*46:01:01:01 and DRB1*09:01:02:01 are susceptible alleles for anti-rHuEPO-induced PRCA. These findings support the role of HLA genotyping in helping to monitor patients receiving rHuEPO treatment.

Immune Checkpoint Inhibitor-Induced Pure Red Cell Aplasia: A Review of 2 Cases in Metastatic Melanoma.

BACKGROUND Immunotherapy is a novel treatment offering an alternative to traditional chemotherapeutic agents for different malignancies. Hematologic adverse reactions (HARs) related to immune checkpoint inhibitors (ICIs) are uncommon. Pure red cell aplasia (PRCA) is a rare hematologic complication of ICI therapy in metastatic melanoma with significant mortality risk despite treatment with steroids or immunosuppressive therapy. For unexplained acute anemia after exclusion of other causes, performing bone marrow biopsy is imperative to diagnose PRCA and rule out involvement of bone marrow by primary tumor. HARs can occur during ICI therapy or even after ICI therapy is stopped. ICI rechallenge, even after the development of HARs, is considered in some patients with good response to treatment of HARs from ICIs. Recurrence of HARs with the same or different type of reaction is seen in some patients. CASE REPORT Two cases of ICI-induced PRCA were confirmed on bone marrow biopsy after dual ICI treatment with nivolumab and ipilimumab in metastatic melanoma. In case 2, PRCA was successfully treated with steroids and later rechallenged with single-agent nivolumab, causing mild ICI-induced immune thrombocytopenia, which did not require treatment with steroids. CONCLUSIONS It is crucial to increase clinician awareness of the possibility of PRCA development not only during treatment with ICI but also after finishing treatment with ICI; there is high mortality associated with missing an opportunity to diagnose and treat PRCA on time with favorable results. ICI rechallenge can be considered in patients who showed response to immunotherapy, especially those with limited alternative therapeutic options.

Secondary Pure Red Cell Aplasia During Daratumumab/ Hyaluronidase Therapy for Multiple Myeloma.

Predominantly autoimmune in origin, severe normochromic, normocytic anemia with reticulocytopenia in the setting of the normal production of leukocytes and megakaryocytic lineages is known as pure red cell aplasia (PRCA), which is unlike aplastic anemia in which all lineages are affected due to a stem cell defect. PRCA can be primary (such as autoimmune) or acquired, which can be an acute self-limited illness or a chronic disease that may be induced by medications, including immunotherapy such as monoclonal antibodies (mAbs). Daratumumab is a mAb directed against CD38 used for the treatment of multiple myeloma and systemic amyloid light-chain amyloidosis. The intravenous formulation of daratumumab received initial FDA approval, and later approval was received for the subcutaneous formulation daratumumab and hyaluronidase-fihj. The subcutaneous version increases patient convenience and has become the preferred route of administration since its approval. We herein present the case of a patient with multiple myeloma who developed acquired DNMT3A-positive PRCA while transitioning to daratumumab/hyaluronidase after initial treatment with daratumumab.

En mann i 40-årene med transfusjonskrevende anemi.

BACKGROUND: While standard blood tests are often sufficient for an anaemia workup, sometimes more invasive diagnostic testing is required to exclude rare conditions. CASE PRESENTATION: A man in his forties contacted his general practitioner because of increasing functional dyspnoea. He had completed a course of dicloxacillin a few months previously for a skin abscess on his abdomen. Bloodwork revealed severe anaemia (haemoglobin 5.4 g/dL), which required transfusion. Subsequent testing excluded iron and vitamin deficiency anaemia, haemolysis and malignancy. Initial bone marrow biopsy was of suboptimal quality. However, repeat tissue sample supported a diagnosis of pure red cell aplasia. The patient improved with ciclosporin treatment, which was gradually tapered. INTERPRETATION: Pure red cell aplasia should be considered in patients with new onset isolated anaemia with severe reticulocytopenia. Diagnosis depends on obtaining representative tissue from bone marrow biopsy. It is difficult to conclude for this patient whether the aetiology of his pure red cell aplasia was idiopathic or secondary to recent dicloxacillin use.

A late relapse thymoma and pure red cell aplasia case with an over 5 years of clinical response under everolimus.

Although several agents showed some clinical activity in patients with recurrent thymoma, there is no standard treatment option. Here, we report a late relapse thymoma and pure red cell aplasia case, responsive to everolimus with over 5 years of clinical benefit following multiple lines of treatment. Everolimus controlled the rapidly progressive disease in our patient without significant toxicity.

Treatment strategy for acquired pure red cell aplasia: a systematic review and meta-analysis.

The treatment of autoimmune acquired pure red cell aplasia (aPRCA) is challenging. Guidelines are based on expert recommendations in the absence of controlled trials. We assessed the efficacy of the main treatment strategy through a systematic review and meta-analysis using MEDLINE, EMBASE, and the Cochrane Library up to September 2022. The overall response rate (ORR) was pooled using random-effects models. In total, 24 observational studies (19 retrospective, median follow-up of 48 months) encompassing 753 patients (49% male) were included. Primary aPRCA represented 57% of the cases. The risk of bias was moderate to high using the ROBINS-I tool. Substantial heterogeneity (I2 > 50%) was retrieved. Corticosteroids as monotherapy as first-line treatment (186 patients, 13 studies) provided an ORR of 47% (95% confidence interval [CI], 34-60). Cyclosporine A was the most frequently used immunosuppressant agent (384 patients, 18 studies), providing an ORR of 74% (95% CI, 66-82) with a similar ORR in first- (73%) and second-line (76%) treatment and when cyclosporin was used as monotherapy (83%) or with corticosteroids (77%). A total of 112 patients (10 studies) received cyclophosphamide, with an ORR of 49% (95% CI, 35-64), which was higher when cyclophosphamide was combined with corticosteroids (48%) and used in second-line treatment (58%) than in monotherapy (31%), and in first-line treatment (44%). Sirolimus use was reported only after cyclosporine A failure and provided an ORR of 87% (95% CI, 68-100; 64 patients, 3 studies). Substantial uncertainty remains regarding the best treatment strategy in the absence of high-quality evidence. This study was registered on the PROPERO database as #CRD42022360452.

[Comparison of Cyclosporine A and Cyclosporine A Combined with Corticosteroid in the Treatment of Acquired Pure Red Cell Aplasia].

OBJECTIVE: To evaluate the efficacy, safety and relapse of cyclosporine A (CsA) and CsA combined with corticosteroid (CS) as the frontline therapy for patients with newly diagnosed acquired pure red cell aplasia (aPRCA). METHODS: The clinical features, treatment responses, relapses and clinical outcomes of patients with newly diagnosed aPRCA in Peking Union Medical College Hospital (PUMCH) from January 2015 to May 2020 were analyzed retrospectively. All the enrolled patients had been treated with either CsA or CsA+CS for at least 6 months and had been followed up for at least 12 months, with complete clinical data and consent forms. RESULTS: 96 patients including 72 treated with CsA and 24 treated with CsA+CS were enrolled. With comparable baseline characteristics and follow-up periods, patients treated with CsA or with CsA+CS had similar overall response rates (ORRs) and complete response rates (CRRs) at the 3rd, 6th and 12th month and at the end of follow-up (P>0.05). Meanwhile, no significant difference was found between the two groups in the optimal ORR, optimal CRR, time to response or time to complete response. CsA+CS and CsA groups had similar adverse event (AE) rates, but CsA+CS group had higher CS-related infection rate (P <0.05). One patient in CsA+CS group died of multiple infections. As for the relapse, the two groups had compatible relapse rates at different time points, time to relapse, overall relapse rate and relapse-free survival (P>0.05). CsA exposure time, rather than different therapy regimens, was the only influence factor for either ORR or relapse rate (P <0.05). CONCLUSION: CsA monotherapy has similar efficacy, AE rate and relapse rate as compared with CsA+CS for patients with newly diagnosed aPRCA, and shows less CS-related AEs such as infection.

Case report: Successful treatment with daratumumab for pure red cell aplasia in a patient with mixed lymphoid chimerism after ABO-mismatched stem cell transplant for sickle cell disease.

Pure red cell aplasia (PRCA) is a serious complication after ABO-mismatched allogeneic hematopoietic stem cell transplantation (HSCT). Following HSCT, persistent anti-donor isohemagglutinins against donor ABO antigens are considered the immunological cause of PRCA. Patients with post-transplant PRCA are at risk for graft rejection and prolonged red blood cell transfusion dependency. No standard treatment exists. Recently however, the anti-CD38 monoclonal antibody daratumumab has been reported to be an effective treatment for post-transplant PRCA in patients with complete donor chimerism. Here, we describe the first case of PRCA in a patient with mixed lymphoid patient/donor chimerism that was successfully treated with daratumumab. This is also the first report of a transplant recipient with sickle cell disease who was treated with this relatively new approach. Fourteen months post-transplantation and twelve months after treatment with daratumumab, our patient has a normal complete blood count and the anti-donor isohemagglutinins remain undetectable despite mixed lymphoid chimerism. Mixed chimerism is a common manifestation in adult patients with sickle cell disease transplanted with non-myeloablative conditioning and a matched sibling donor. The application of non-myeloablative HSCT for patients with sickle cell disease is steadily increasing. Therefore, the incidence of PRCA in this setting might also increase. As the risk of graft rejection due to PRCA can be especially high in patients with mixed chimerism, clinicians should be aware that daratumumab can be an effective treatment in the setting of mixed chimerism.

Pure red cell aplasia occurring during ibrutinib therapy for chronic lymphocytic leukemia.

INTRODUCTION: Chronic lymphocytic leukemia (CLL) has long been known for its complications related to immune deregulation, of which autoimmune cytopenias (AIC) were frequently reported. Ibrutinib has dramatically changed the overall prognosis of patients with CLL. However, whether ibrutinib can induce or aggravate AIC in CLL patients is still disputable. Here we report a CLL patient with pure red cell aplasia (PRCA) occurring during ibrutinib treatment and review available data to discuss the possible role of ibrutinib in developing AIC. CASE REPORT: A 70-year-old female was diagnosed with CLL with indications to initiate ibrutinib treatment given progressive bulky disease. She was admitted for advanced fatigue on the 14th day of ibrutinib monotherapy. A complete blood count revealed severe anemia of hemoglobin (Hb) 37 g/L and a meager reticulocyte count. After excluding other conditions that could cause anemia, PRCA was diagnosed as a complication of CLL. MANAGEMENT AND OUTCOME: Ibrutinib was discontinued on the day of admission. At the same time, the patient received prednisone and intravenous immunoglobulin (IVIg). Five days later, the Hb did not improve. Cyclosporine A (CsA) was added; IVIg was discontinued, and prednisone was tapered. Ten days later, the Hb had risen to 92 g/L with a high reticulocyte count of 0.279 × 1012/L. The CLL treatment restarted with Zanbrutinib in combination with a low dose of prednisone and CsA. Her CLL was in partial remission by the latest follow-up with an average Hb count. DISCUSSION: Our case demonstrates a need to evaluate the risk of developing AIC before initiating ibrutinib. For patients with high-risk factors for AIC episodes, the transient addition of other immunosuppressive therapies should be taken into consideration.

Pure red cell aplasia: The second hundred years.

Pure red cell aplasia (PRCA) is a rare hematologic syndrome, characterized by an isolated normocytic anemia with severe reticulocytopenia, and defined by absence or near absence of erythroid precursors in the bone marrow. First described in 1922, PRCA may be a primary autoimmune or clonal myeloid or lymphoid disorder, but may also be secondary to other disorders of immune dysregulation/autoimmunity, to infections, to neoplasms, or to drugs. Insights from the study of PRCA have helped illuminate the understanding of the regulation of erythropoiesis. This review summarizes the classification, diagnostic, and therapeutic approach to PRCA as it begins its second century, with a particular focus on opportunities and challenges provided by new developments in the role of T-cells and T-cell regulatory mutations; the role of clonal hematopoiesis; and new developments in therapy for refractory PRCA and PRCA associated with ABO incompatible stem cell transplantation.

Hematologic Manifestations of Parvovirus B19 Infection.

Parvovirus B19 virus infection is widespread among humans because of its highly infectious and obstinate nature, with up to 80% of the population testing positive for IgG antibodies against the virus. Pronormoblasts observed in biopsy are the hallmarks of PVB19 infection. In addition, PVB19 affects the skin, heart, brain, joints, and liver and can be diagnosed through antibody detection or DNA detection via PCR. Due to its capsid proteins' high affinity for bone marrow receptors, its main presentation is the suppression of bone marrow functions. It has been shown to affect patients with hemolytic anemia and patients with hematological malignancies, presenting with pure red cell aplasia. The main available effective treatment option is IV immunoglobulins; however, the risk of recurrence remains high after treatment.

Distinct mutational pattern of T-cell large granular lymphocyte leukemia combined with pure red cell aplasia: low mutational burden of STAT3.

T-cell large granular lymphocyte leukemia (T-LGL) is often accompanied by pure red cell aplasia (PRCA). A high depth of next generation sequencing (NGS) was used for detection of the mutational profiles in T-LGL alone (n = 25) and T-LGL combined with PRCA (n = 16). Beside STAT3 mutation (41.5%), the frequently mutated genes included KMT2D (17.1%), TERT (12.2%), SUZ12 (9.8%), BCOR (7.3%), DNMT3A (7.3%), and RUNX1 (7.3%). Mutations of the TERT promoter showed a good response to treatment. 3 of 41 (7.3%) T-LGL patients with diverse gene mutations were revealed as T-LGL combined with myelodysplastic syndrome (MDS) after review of bone marrow slide. T-LGL combined with PRCA showed unique features (low VAF level of STAT3 mutation, low lymphocyte count, old age). Low ANC was detected in a STAT3 mutant with a low level of VAF, suggesting that even the low mutational burden of STAT3 is sufficient for reduction of ANC. In retrospective analysis of 591 patients without T-LGL, one MDS patient with STAT3 mutation was revealed to have subclinical T-LGL. T-LGL combined with PRCA may be classified as unique subtype of T-LGL. High depth NGS can enable sensitive detection of concomitant MDS in T-LGL. Mutation of the TERT promoter may indicate good response to treatment of T-LGL, thus, its addition to an NGS panel may be recommended.

Waldenström macroglobulinemia with secondary pure red cell aplasia in a patient with metastatic castrate resistant prostate cancer receiving an immune checkpoint inhibitor: a case report.

BACKGROUND: Hypoproliferative anemia is a frequently encountered adverse event in cancer patients receiving immune checkpoint inhibitors (ICI). Secondary pure red cell aplasia (PRCA) is a rare but recognized immune related adverse event. With the burgeoning use of ICIs, the association of secondary PRCA with an underlying lymphoproliferative disorder is often overlooked. CASE PRESENTATION: We report a case of a 67-year-old non-Hispanic Caucasian male with metastatic castrate resistant prostate cancer, who developed severe transfusion dependent anemia with reticulocytopenia while receiving treatment with olaparib and pembrolizumab. His bone marrow findings demonstrated erythroid hypoplasia, in addition to a CD5-negative, CD10-negative monotypic B-cell population and a somatic MYD88L265P mutation. With a presence of an IgM-paraprotein, he was diagnosed with Waldenström macroglobulinemia (WM) with secondary PRCA and treated with 6 cycles of bendamustine and rituximab. He achieved a complete response with this regimen and was transfusion independent. CONCLUSION: In this case, underlying WM was uncovered through systematic investigation of anemia caused by ICI therapy. This report highlights the possibility of a lymphoproliferative disorder in patients with concerns for PRCA with prior ICI exposure. If identified, treating the underlying lymphoproliferative disorder is highly efficacious in the management of the secondary PRCA.