Acquired pure red cell aplasia in Japan

Abstract: We reviewed the clinical features of 150 patients with acquired pure red cell aplasia (PRCA) in Japan. There were 35 patients with acute type and 115 with chronic type PRCA. Of the acute PRCA patients, 17 had human parvovirus B19 infection. Drug-induced PRCA was demonstrated in 7 patients. Of the 115 patients with chronic PRCA, 51 patients were classified as primary and 64 cases were associated with miscellaneous diseases such as thymoma, a variety of hematological disorders and collagen diseases. Among the hematological disorders, PRCA was most frequently seen in granular lymphocyte proliferative disorders (GLPD). The erythroid colony growth patterns from bone marrow were variable. The serum erythropoietin level was high in most patients. Various kinds of treatment were tried for the chronic PRCA cases. Cyclosporin A (CyA) was the most effective form of treatment and the response rate was 82% (31/38). Twenty-three of 37 patients (62%) responded to bolus methylprednisolone therapy. The largest number of patients were treated with oral prednisolone, and the therapy was effective in 27 of the 55 (49%). The response rate to cyclophosphamide was only 29% (5/17), but in combination with prednisolone, half of the patients (7/14) responded to the therapy. CyA is recommended as the first-line therapy for acquired chronic PRCA.     

Azathioprine-associated pure red cell aplasia

Abstract. Azathioprine-associated pure red cell aplasia in patients with a renal allograft is a rare complication. Although immunological inhibition of erythroid progenitor cell has been suggested, the cause of this phenomenon remains unclear. The patient we describe showed a decrease in the number of erythroid progenitor cells and no evidence for the presence of a serum inhibitor of these precursor cells. Discontinuation of azathioprine was associated with a complete recovery from anaemia as well, with an increase in the number of erythroid progenitor cells.     

Cytotoxic immunosuppressive drug treatment strategy in pure red cell aplasia

Remissions occurred in 2 of 5 consecutive cases of acquired pure red cell aplasia (PRCA) during an initial course of treatment with either azathioprine and prednisolone, or cyclophosphamide and prednisolone. Crossover to therapy with the alternative cytotoxic immunosuppressive agent in conjunction with continued administration of prednisolone in 3 unresponsive cases resulted in remission induction. Crossover to azathioprine was effective in 2 cases initially unresponsive to cyclophosphamide, and crossover to cyclophosphamide in 1 initially unresponsive to azathioprine. This emphasises that lack of cross-resistance to these drugs can occur in PRCA, and that crossover to treatment with the alternative agent in refractory cases is a useful strategy which has been underutilised in reported approaches to management. Administration of the effective regimen was continued for a mean of 15 months, and this more extended period of treatment was associated with a longer mean duration of remission than reported in previous studies.     

Sirolimus for the treatment of multi-resistant pure red cell aplasia

Patients with relapsed, refractory or advanced stage B non-Hodgkin lymphoma (NHL) continue to have a dismal prognosis. This review summarises current and novel cellular and immunotherapy for these high-risk populations, including haematopoietic stem cell transplant, bispecific antibodies, viral-derived cytotoxic T cells, chimeric antigen receptor (CAR) T cells, and natural killer (NK) cell therapy, as discussed at the 6th International Symposium on Childhood, Adolescent and Young Adult Non-Hodgkin Lymphoma on September 26th–29th 2018 in Rotterdam, the Netherlands, and explores the future of NK/CAR NK therapies.     

Rituximab to treat chronic lymphoproliferative disorder‐associated pure red cell aplasia

We report four patients (mean age 65 yr; range 40–77 yr) affected by acquired pure red cell aplasia (PRCA) complicating chronic lymphoid disorders and treated with anti‐CD20 monoclonal antibody rituximab. Three out of four patients were given packed red cell transfusion. Steroids and recombinant erythropoietin (r‐Epo) were also administered as first‐line therapy without response. After a mean time of 57 d (range 23–62 d) from PRCA diagnosis, all patients received rituximab at a dosage of 375 mg/m²/wk for four consecutive weeks. First injection side effects of rituximab were minimal. All patients showed an increase in hemoglobin levels in response to rituximab, in one patient just after the first dose, in another patient after the second and in two other patients after the third dose. Three patients (75%) were considered in complete remission (CR) and one patient (25%) in partial remission 4 wk after the last rituximab infusion, despite a CR was obtained later (16 wk following the beginning of the therapy). Finally, at the last follow‐up (mean 18.5 months, range 2–60 months), all patients were alive and in continue CR. Despite very limited in number, these results suggest that rituximab is very effective in the treatment of PRCA complicating B‐cell chronic lymphoproliferative disorders.     

Remission of acquired pure red cell aplasia following plasma exchanges:

A 22-year-old woman had an idiopathic pure red cell aplasia that failed to respond to high doses of corticosteroids. After a series of 10 plasma exchange procedures, bone marrow erythropoiesis and reticulocyte blood count returned to normal; the haematological remission has been now persistent for 12 months. The place of plasma exchange in the management of pure red cell aplasia and its mode of action will be discussed.     

Successful treatment of thymoma-associated pure red cell aplasia with intravenous immunoglobulins

Repeated cycles of intravenous immunoglobulins (IVIG) have been reported to be successful in a few patients with idiopathic pure red cell aplasia (PRCA) or associated with another pathology. The efficacy of this treatment for PRCA with thymoma has not been reported previously. We describe here the case of a 75-yr-old man who presented with PRCA associated with a benign thymoma. After failure of thymectomy, corticosteroids and octreotide, a complete durable remission was obtained after a single 5-d cycle of IVIG.     

Successful treatment of refractory pure red cell aplasia associated with lymphoproliferative disorders with the anti-CD52 monoclonal antibody alemtuzumab (Campath-1H)

Acquired pure red cell aplasia (PRCA) is a rare, but significant, complication of lymphoproliferative disorders. It is characterized by anaemia, absence of red cell precursors in the bone marrow and normal granulopoiesis and megakaryopoiesis. We describe two patients with refractory pure red cell aplasia associated with chronic lymphocytic leukaemia (CLL) and a large granular CD8 T-lymphocytic leukaemia (LGL) respectively. Both patients had failed multiple treatment regimens for PRCA and were transfusion dependent. Both patients were subsequently treated with the anti-CD52 humanized monoclonal antibody, alemtuzumab, receiving total doses in excess of 300 mg. Response to treatment, as documented by a rapid increase in the reticulocyte count, occurred as early as the third infusion. At the time of this report, both patients remain in complete remission with normal haemoglobin levels. Alemtuzumab appears to be an effective and well-tolerated therapy for pure red blood cell aplasia associated with lymphoproliferative disorders.     

Cyclophosphamide therapy for pure red cell aplasia associated with granular lymphocyte-proliferative disorders

Granular lymphocytes have been characterized as cells with azurophilic granules in the cytoplasm. Patients with increased numbers of granular lymphocytes are designated as granular lymphocyte-proliferative disorders (GLPDs). A variety of haematological abnormalities are associated with T-cell-lineage GLPD. Among these, pure red cell aplasia is frequent, and adequate therapy is required. Seven patients with pure red cell aplasia, or a related condition complicating T-cell-lineage GLPD, were entered into this study. Cyclophosphamide was initiated at a daily oral dose of 100 mg. After 2 weeks the dose was reduced to 50 mg/d, and maintained at that dose. Cyclophosphamide was administered until the lymphocyte count was <1 ×10⁹ l and T-cell receptor-β gene analysis was used to monitor the response to treatment. All the patients were successfully treated, irrespective of their former treatment. Clinical remission was associated with the disappearance of the abnormal granular lymphocyte clone, as detected by Southern blot hybridization analysis. Therapeutic responses began after 8 weeks, and clinical complete remissions were obtained after 6 months. Oral cyclophosphamide monotherapy can successfully treat the pure red cell aplasia associated with T-cell-lineage GLPD.     

Prolonged course of pure red cell aplasia after erythropoietin therapy

Pure red cell aplasia (PRCA) caused by neutralising anti-erythropoietin antibodies is a very rare disease. Since 1998, an increased incidence of PRCA in patients with kidney failure following treatment with recombinant human erythropoietin (rhEpo) has been reported, mostly in Europe. In most cases, PRCA was cured by immunosuppressive therapy, immunoglobulins, plasmapheresis or renal transplantation. We report an exceptionally prolonged course of PRCA over 68 months despite renal transplantation and different immunosuppressive regimens.     

Severe acute hepatitis A associated with acute pure red cell aplasia

A rare case of severe acute hepatitis A complicated by pure red cell aplasia (PRCA) is reported. A 60-year-old man with jaundice and hepatomegaly was diagnosed as having acute hepatitis A by positive IgM anti-hepatitis A antibody (anti-HAV). Severe anemia rapidly developed 3 weeks after admission, and the patient was diagnosed with PRCA by both bone marrow smears and crythrocyte survival study. The anemia was transient and bone marrow recovered within 1 week. However, concomitant with bone marrow recovery, the hepatitis worsened. He became drowsy and disoriented and severe jaundice, ascites, prolonged prothrombin time, increased transaminase levels, and abnormal electroencephalogram (EEG) were exhibited. Plasma exchange transfusion and glucagon-insulin (GI) therapy improved the consciousness level, but bilirubin, transaminase levels, and IgM anti-HAV titer remained high. Intravenous administration of lipophilized prostaglandin E₁ (lipo-PGE₁) was added to the GI therapy. Bilirubin and transaminase levels were normalized in the 8th week after the initiation of this combination therapy (17 weeks after admission). The combined use of lipo-PGE₁ with plasma exchange and GI therapy appeared to be useful for the prolonged severe hepatitis in this patient.     

Monoclonal gammopathy‐associated pure red cell aplasia

Pure red cell aplasia (PRCA) is a rare disorder characterized by inhibition of erythroid precursors in the bone marrow and normochromic, normocytic anaemia with reticulocytopenia. Among 51 PRCA patients, we identified 12 (24%) patients having monoclonal gammopathy, monoclonal gammopathy of undetermined significance or smouldering multiple myeloma, with presence of monoclonal protein or abnormal serum free light chains and atypical bone marrow features of clonal plasmacytosis, hypercellularity and fibrosis. Thus far, three patients treated with anti‐myeloma based therapeutics have responded with reticulocyte recovery and clinical transfusion independence, suggesting plasma cells play a key role in the pathogenesis of this specific monoclonal gammopathy‐associated PRCA.     

Cyclosporin-A therapy of pure red cell aplasia in a patient with B-cell chronic lymphocytic leukemia

A 65-year-old woman with B-cell chronic lymphocytic leukemia (CLL) and pure red cell aplasia (PRCA) is described. After initial chemotherapy with three different regimens over 3 months (prednisone, chlorambucil/vincristine, cyclophosphamide, bleomycin/cyclophosphamide, etoposide, prednisone), normalization of the blood lymphocyte count was observed, but lymphocyte infiltration of the bone marrow persisted and erythropoiesis remained virtually absent. Monotherapy with cyclosporin-A (CyA) was begun. After 35 days, a marked increase in the reticulocyte count was observed, and with continuing therapy, there was a rapid increase in the hemoglobin level. Follow-up after 13 months of uninterrupted treatment with CyA revealed remission of both CLL and PRCA. CyA should be investigated further as a therapeutic modality for PRCA in patients with CLL, and such trials might provide further clues to the pathogenesis of this peculiar association.     

主要血型不合骨髓移植后纯红细胞再生障碍性贫血的临床观察

目的　探讨主要血型不合骨髓移植（ＭＩｃ－ ＢＭＴ）后的纯红细胞再生障碍性贫血（ＰＲＣＡ） 的临床及实验室特点。方法　对３ 例ＭＩｃ－ ＢＭＴ 后ＰＲＣＡ 的临床及实验室有关资料进行分析,并与９ 例对照组（８ 例血型相合,１ 例次要血型不合） 进行比较。结果　３ 例ＰＲＣＡ发生于ＭＩｃ－ ＢＭＴ后８ 周内,伴有较高的血型凝集素滴度;未治疗的ＰＲＣＡ 骨髓中幼红细胞比例在０．０５ 左右,网织红细胞计数≤０．００１ ;骨髓植活时间、血小板数、骨髓中粒细胞与巨核细胞在ＭＩｃ－ ＢＭＴ 与对照组间无明显差异。ＭＩｃ－ ＢＭＴ 后８ 周内输血量明显增多。结论　ＭＩｃ－ ＢＭＴ 后ＰＲＣＡ有显著的临床与实验室特点,其发生的主要机理可能为受者血型凝集素对供者红系前体细胞的抑制作用。     

Is pure red cell aplasia (PRCA) a clonal disorder?

Summary Pure red cell aplasia (PRCA) is an uncommon disorder, many cases lacking a well defined aetiology. This report describes three cases of PRCA (two idiopathic and one associated with B-CLL) who were investigated to assess the possibility of their PRCA being associated with a clonal proliferation of T-lymphocytes. The results show that one patient had evidence of T-cell receptor (TCR) gamma chain rearrangement, and the other had a TCR delta chain rearrangement. These two cases raise the possibility of PRCA being associated with a clonal proliferation of T-cells and further studies are warranted.     

Pure red cell aplasia: further evidence of T cell clonal disorder

Summary. We report a patient with pure red cell aplasia and type I autoimmune polyglandular syndrome who also had an expansion of suppressor T lymphocytes in the peripheral blood. Southern blotting of DNA from these cells suggested T cell receptor (TCR) γ gene rearrangement. We confirmed true clonality of this by amplification of the gene rearrangement using the polymerase chain reaction and subsequent analysis of the product by gene cloning and DNA sequencing.     

Chronic myeloid leukemia associated with pure red cell aplasia and terminating in promyelocytic transformation

After intermittent treatment with busulphan over a 7-year period for chronic myeloid leukemia (CML) in chronic phase, a 39-year-old female developed leukocytosis in association with pure red cell aplasia (PRCA). Bone marrow examination confirmed erythroid aplasia, and culture revealed a total absence of erythroid progenitor cells. The patient then was treated with azathioprine, corticosteroids, cyclophosphamide, plasma exchange, and cyclosporin A, but she remained erythroblastopenic and transfusion dependent for more than a year, at which time a promyelocytic transformation supervened. The authors propose that this sequence of events, hitherto unreported, is a manifestation of the multistep progression of CML.