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.     

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.     

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.     

Acquired pure red cell aplasia: updated review of treatment

Pure red cell aplasia (PRCA) is a syndrome characterized by a severe normocytic anaemia, reticulocytopenia, and absence of erythroblasts from an otherwise normal bone marrow. Primary PRCA, or secondary PRCA which has not responded to treatment of the underlying disease, is treated as an immunologically-mediated disease. Although vigorous immunosuppressive treatments induce and maintain remissions in a majority of patients, they carry an increased risk of serious complications. Corticosteroids were used in the treatment of PRCA and this has been considered the treatment of first choice although relapse is not uncommon. Cyclosporine A (CsA) has become established as one of the leading drugs for treatment of PRCA. However, common concerns have been the number of patients treated with CsA who achieve sustained remissions and the number that relapse. This article reviews the current status of CsA therapy and compares it to other treatments for diverse PRCAs.     

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.     

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.     

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.     

The clinical characteristics and therapy response of patients with acquired pure red cell aplasia

ABSTRACT

Objective: To summarize the clinical characteristics of acquired pure red cell aplasia (PRCA) patients diagnosed in our hospital in the last 10 years.

Method: The clinical features, immune state and treatment response of acquired PRCA patients diagnosed in our hospital from January 2007 to January 2017 were retrospectively analyzed.

Results: The results showed that thymoma (13.21%) and parvovirus B19 (11.32%) were the most common causes for secondary PRCA. Ferritin (Fer) levels and erythropoietin (EPO) levels were increased in PRCA patients. The total CR and PR rate of immunosuppressive therapy in our studies was 68.29% and 12.20%, respectively. Patients with EPO level >400 U/L and Fer level >200?ng/ml had significantly lower CR rate than others. The patients with EPO level >400 U/L also had longer hemoglobin recovery time than patients with EPO level ≤400 U/L. Patients treated with corticosteroids (CS)?+?cyclosporine A (CsA) had lower relapse rate compared to the CS group (29.17% vs. 80.00%, P?<?.05).

Conclusion: Our data showed that patients with PRCA had high EPO and Fer levels. Thymoma and viral infections are the most common causes for secondary PRCA. The CS+ CsA group had lower relapse rate than CS group although response rate was similar. Increased EPO and Fer levels might be the negative factors for prognosis of acquired PRCA.     

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.     

Long‐term outcome of patients with acquired chronic pure red cell aplasia (PRCA) following immunosuppressive therapy: a final report of the nationwide cohort study in 2004/2006 by the Japan PRCA collaborative study group

Immunosuppressive therapy has been employed as the initial treatment for acquired chronic pure red cell aplasia (PRCA), such as idiopathic, thymoma‐associated, or large granular lymphocyte (LGL) leukaemia‐associated PRCA, which is thought to be immune‐mediated. To explore the overall long‐term outcome following immunosuppression and to identify the risk factors for death in these disorders, we conducted nationwide surveys in Japan 2004 and 2006, and identified a total of 185 patients with acquired chronic PRCA, including 72 idiopathic, 41 thymoma‐associated and 14 LGL leukaemia‐associated cases of PRCA for whom data was available. The present study evaluated 127 patients with these three subsets of PRCA. The median overall survival has not yet been reached in idiopathic PRCA. The estimated median overall survival times in patients with thymoma‐associated and LGL leukaemia‐associated PRCA were 142·1 and 147·8 months, respectively. Twenty‐two deaths were reported, and the response to induction therapy and relapse of anaemia were found to be associated with death. The major causes of death were infection in seven patients and organ failure in another seven patients. The results suggest that maintenance therapy and the management of infectious complications are crucial for improving the prognosis of chronic PRCA.     

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.     

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.     

Durable remission of pure red cell aplasia after treatment with high-dose intravenous gammaglobulin and prednisone

Pure red cell aplasia (PRCA) is a rare disorder of erythrocyte production believed to have an autoimmune basis in most cases. Responses to a variety of immunosuppressive regimens are regularly observed, but toxicity is considerable. Brief responses to high-dose intravenous immunoglobulin (IVIg) have been previously reported. This case demonstrates a durable clinical remission of PRCA treated with IVIg and glucocorticoids.     

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.     

Chronic idiopathic pure red cell aplasia: successful treatment during pregnancy and durable response to intravenous immunoglobulin

Abstract. A patient with chronic idiopathic pure red cell hypoplasia responded to intravenous immunoglobulin therapy. No other treatment was administered. During treatment, the patient was taken through two pregnancies without haematological problems. After 22 months of therapy, the intravenous immunoglobulin was discontinued; a durable remission was subsequently maintained. Intravenous immunoglobulin may be the treatment of choice for females of child-bearing potential.     

Recommendations on haematological criteria for the diagnosis of epoetin-induced pure red cell aplasia

Pure red cell aplasia (PRCA) is a rare condition characterised by an arrest in red blood cell production, which may be congenital or acquired. Recombinant human erythropoietin (epoetin) was introduced in 1989 for the treatment of anaemia of chronic kidney disease patients and has maintained an excellent therapeutic and safety record while treating hundreds of thousands of patients. A very rare, but serious adverse event associated with epoetin administration is a condition in which patients develop neutralising anti-erythropoietin antibodies and, consequently, PRCA. This condition is referred to as epoetin-induced PRCA (epo-PRCA). Since it is a rare condition, many haematologists and nephrologists around the world see the condition infrequently and may be uncertain about the diagnosis. For this reason, an ad hoc international working group of expert haematologists and nephrologists met together to derive new recommendations for the haematological diagnosis of epo-PRCA. These recommendations, which represent the consensus opinions of the working group, address haematological approaches to monitor and investigate suspected epo-PRCA and should help physicians differentiate between PRCA and other bone marrow diseases, as well as, between PRCA and epo-PRCA.     

Pure red cell aplasia. Stable complete remission following antilymphocyte globulin administration

A 25-yr-old woman with idiopathic pure red cell aplasia achieved complete remission following a single 5-day course of antilymphocyte globulin at a dose of 50 mg/kg daily by intravenous injection as initial and sole therapy. Apart from transient arthralgia and asymptomatic thrombocytopenia there were no side effects. At 2 yr, the patient has normal peripheral blood, bone marrow and in vitro culture studies. This approach offers an alternative to conventional immunosuppressive therapy where there is evidence of an underlying immune disorder.