Clonal T cell proliferation in patients with pure red cell aplasia.

Among the patients with idiopathic pure red cell aplasia (PRCA) who do not meet the diagnostic criteria of chronic lymphocytic leukemia, there are some cases which suggest an association with clonal T lymphocytic proliferation. The morphological characteristics and responses to treatment revealed two distinct groups among the present 13 patients. The lymphocytes in one group were typical granular lymphocytes of T cell phenotype which were treated effectively with cyclophosphamide rather than cyclosporine. The response to therapy in this group occurred after a perceptible reduction in lymphocyte mass, which took at least 8 weeks. The lymphocytes in the second group consisted mainly of non-granulated lymphocytes or some granulated lymphocytes with fine and indistinct granules and responded well to cyclosporine therapy. A reduction in lymphocytes mass was not a prerequisite for the development of the remission of red cell aplasia in this group, and responses occurred within 4 weeks. Clonal T cell proliferation was detected in some patients, which raised the possibility of idiopathic PRCA being associated with a clonal proliferation of T cells. Distinguishing lymphocytes in patients with PRCA could potentially be used to plan treatment strategy and assess prognosis.     

Alemtuzumab induced complete remission of therapy-resistant pure red cell aplasia

Two patients with pure red cell aplasia (PRCA) refractory to anti-thymocyte globulin, prednisolone, cyclophosphamide, fludarabine, mitoxantrone, dexamethasone and cyclosporine, were treated with alemtuzumab (anti-CD52 antibody). Case 1, a 35-year-old man with idiopathic PRCA, remitted completely with 130 mg of alemtuzumab. Case 2, a 42-year-old man with PRCA due to T-cell large granular lymphocyte (T-LGL) leukaemia, achieved complete remission of the PRCA with 490 mg of alemtuzumab, although the T-LGL leukaemia responded only transiently. There were no significant side effects, and normalization of erythropoiesis was durable. Alemtuzumab is active in PRCA that is idiopathic or secondary to T-cell lymphoproliferative diseases.     

Pure red cell aplasia in B-cell lymphoproliferative disorder treated with rituximab: report of two cases and review of the literature

Pure red cell aplasia (PRCA) is an unusual cause of anemia in patients with chronic lymphoproliferative disorders. Here, we present two cases of PRCA, one associated with chronic lymphocytic leukemia (CLL) and the other with splenic marginal zone lymphoma, in which the PRCA responded dramatically to treatment with rituximab. We then review the literature on PRCA in lymphoma and response to rituximab. PRCA associated with CLL or lymphoma may be another indication for rituximab therapy.     

侵袭型非霍奇金淋巴瘤合并纯红细胞再生障碍性贫血

目的:研究侵袭性非霍奇金淋巴瘤并发纯红细胞再生障碍性贫血(PRCA)的临床特点和治疗结果。方法:报告两例分别并发于非特指型外周T细胞淋巴瘤(PTCL-NOS)和弥漫大B细胞淋巴瘤(DLBCL)的PRCA,并复习相关文献。结果:在联合化疗治疗后,DLBCL及其相关的PRCA均获完全缓解,而PTCL-NOS虽获缓解,但其相关的PRCA未好转,加用泼尼松治疗后PRCA缓解。结论:NHL相关的PRCA在联合化疗或免疫抑制治疗后可获完全缓解,且可不需维持治疗。     

Cyclosporin A for the treatment of pure red cell aplasia associated with myelodysplasia

Recent reports have highlighted an associated of pure red cell aplasia (PRCA) with myelodysplasia (MDS). There are minimal data on the response of PRCA in this context to immunosuppression; in particular the role of cyclosporin A (CSA) has not been evaluated. We describe a patient with PRCA/MDS in whom CSA and low dose prednisolone led to restoration of marrow erythropoietic activity. Tests indicated the PRCA was likely to be mediated by cytotoxic lymphocytes rather than an inhibitory effect of cytokines. These observations suggest that CSA, due to its suppressive effect on cytotoxic T cell activity, is a rational therapy in this context.     

Autoimmune Hemolytic Anemia in Chronic Lymphocytic Leukemia Patients Treated with Fludarabine

Autoimmune hemolytic anemia (AHA) is a frequent complication of chronic lymphocytic leukemia (CLL). Although the pathogenesis of AHA is still unknown, an imbalance of normal residual T cells is believed to play a central role. Since fludarabine is reported to affect primarily T lymphocytes, we conducted a retrospective study to evaluate the incidence and outcome of AHA in 112 CLL patients treated with fludarabine alone. Eight patients had AHA before therapy; only one achieved remission of both CLL and AHA after fludarabine alone. In the other seven patients, we observed no effect or even a worsening of AHA, although the CLL was responding to fludarabine. Five patients developed AHA from 1 to 19 months after fludarabine therapy while the CLL was responding. One additional patient developed pure red cell aplasia (PRCA) 3 months after starting therapy. Most patients in both groups responded to steroids or other immunosuppressive therapy. The study showed that in these patients, AHA evolved independently of CLL and was not affected by fludarabine.     

侵袭型非霍奇金淋巴瘤合并纯红细胞再生障碍性贫血

目的：研究侵袭性非霍奇金淋巴瘤并发纯红细胞再生障碍性贫血（PRCA）的临床特点和治疗结果。方法：报告两例分别并发于非特指型外周T细胞淋巴瘤（PTCL-NOS）和弥漫大B细胞淋巴瘤（DLBCL）的PRCA,并复习相关文献。结果：在联合化疗治疗后,DLBCL及其相关的PRCA均获完全缓解,而PTCL-NOS虽获缓解,但其相关的PRCA未好转,加用泼尼松治疗后PRCA缓解。结论：NHL相关的PRCA在联合化疗或免疫抑制治疗后可获完全缓解,且可不需维持治疗。     

T-cell large granular lymphocytic (T-LGL) leukemia: experience in a single institution over 8 years

T-cell large granular lymphocytic (T-LGL) leukemia is characterized by cytopenia and clonal proliferation of large granular lymphocytes. We identified 26 patients with T-LGL leukemia seen at our institution over a period of 8 years. The majority of the patients were asymptomatic at diagnosis. Nine patients were treated with cyclosporine; one achieved a complete remission, and four had a hematological response. Other treatment modalities included single agent alemtuzumab, alemtuzumab combined with pentostatin, fludarabine, and combination of fludarabine and cyclophosphamide. Significant responses were not seen with any of these treatment regimens. We conclude that cyclosporine therapy may be beneficial for T-LGL leukemia patients. New treatment modalities are needed for these patients.     

Successful Treatment of Pure Red Cell Aplasia with Rituximab in Patients after ABO-Compatible Allogeneic Hematopoietic Stem Cell Transplantation

Pure red cell aplasia (PRCA) following allogeneic hematopoietic stem cell transplantation (HSCT) has been mostly reported in situations involving major ABO incompatibility between donor and recipient. Conventional treatments such as plasma exchange, erythropoietin, and steroid are often unsatisfactory. Rituximab has been reported to be highly effective for PRCA following major ABO-incompatible allogeneic HSCT. A 49-year-old woman with PRCA following ABO-matched allogeneic HSCT for acute lymphoblastic leukemia, refractory to erythropoietin treatment, received 4 doses of rituximab 375 mg/m² weekly. After the 3rd dose of rituximab, she exhibited a striking rise in her reticulocyte count with an increase in her hemoglobin level. To our knowledge, this is the first case of PRCA following major ABO-compatible allogeneic HSCT resolving completely after rituximab treatment.Key words: Pure red cell aplasia, Allogeneic stem cell transplantation, Rituximab, ABO compatibility     

Epstein-Barr virus associated diffuse large B-cell lymphoma complicated by autoimmune hemolytic anemia and pure red cell aplasia.

A 53-year old man with systemic lymphadenopathy and hepatosplenomegaly was diagnosed with diffuse large B cell-lymphoma after inguinal lymph node biopsy. Anemia was noted, direct and indirect Coombs tests were positive, and the haptoglobin level was low. However, the bone marrow aspirate revealed erythroid aplasia. Co-existing autoimmune haemolytic anemia (AIHA) and pure red cell aplasia (PRCA) were diagnosed. In situ hybridization with Epstein-Barr virus (EBV) encoded small RNA (EBER) showed positive findings in lymphoma cells. Southern blot hybridization revealed immunoglobulin heavy chain gene rearrangement and a clonal EBV terminal repeat, indicating monoclonal proliferation of EBV in infected B cells. The patient was treated with CHOP, resulting in a complete remission (CR). AIHA and PRCA subsided after 3 courses of chemotherapy. In conclusion, this case demonstrates not only the association of B-cell lymphoma with autoimmune disorders but also the involvement of EBV in these conditions.     

Lymphocytes and antibody in retrovirus-induced feline pure red cell aplasia

The possible role of antibody and T-lymphocytes was investigated in the pure red cell aplasia (PRCA) associated with feline leukemia virus, subgroup C (FeLV-C), infection. In previous studies, erythroid colony-forming cells were undetectable in marrow culture of cats with PRCA. Yet erythroid burst-forming cells (BFU-E) remained, suggesting that BFU-E were able to differentiate in vitro but not in vivo. It was inferred that immunologic suppression may contribute to the pathogenesis of feline PRCA, and the interactions of antibody and T-lymphocytes with erythroid and granulocyte-macrophage progenitors were studied. Incubation of normal or PRCA marrow cells with PRCA serum or IgG concentrated from this serum and then complement (C') failed to decrease hematopoietic colony growth when compared to the results obtained with cultures of marrow cells incubated with C' alone. In crossover coculture studies, T-cells from Safari cats with PRCA had no inhibitory effect on colony growth from normal or autologous PRCA marrow cells. For the determination of whether feline PRCAs were associated with a clonal T-cell process, lymphocytes were obtained periodically from glucose-6-phosphate dehydrogenase (Glc-6-PD) heterozygous cats following FeLV-C infection and were expanded with a crude preparation of interleukin-2. The ratios of Glc-6-PD enzyme types in these samples did not change as cats developed anemia, suggesting that the inhibition of erythropoiesis was not associated with the clonal expansion of T-cells. These studies, therefore, do not support the premise that feline PRCA results from the interaction of antibody or T-cells with erythroid progenitors.     

激素治疗ABO血型不合异基因造血干细胞移植后纯红细胞再生障碍性贫血--1例报告及文献复习

目的 探讨异基因造血干细胞移植后纯红细胞再生障碍性贫血(PRCA)的发生机制。方法 报道1例病例并进行文献复习。结果 1例诊断为骨髓增生异常综合征(MDS—RAEBT)组织配型相合、ABO血型不合的患者进行造血干细胞移植获得成功，但移植后出现PRCA，经红细胞生成素治疗失败，改用激素治疗后血红蛋白恢复正常。结论 免疫因素及a抗体是ABO血型不合造血干细胞移植后致PRCA的最可能原因；糖皮质激素(泼尼松)是治疗ABO血型不合造血干细胞移植后PRCA的有效、经济、安全的药物。     

Pure red cell aplasia associated with non-Hodgkin's lymphoma and hemolytic anemia.

Pure red cell aplasia (PRCA) rarely occurs in non-thymic lymphoproliferative disorders. The present article describes a patient with non-Hodgkin's lymphoma (follicular, mixed type), who concurrently developed PRCA and warm type autoimmune hemolytic anemia during the clinical course. The PRCA and hemolytic anemia were successfully treated with prednisolone (60 mg/day). The patient died two years later, however, from advanced lymphoma without any recurrence of the PRCA or hemolytic anemia. To our knowledge, only 20 cases of PRCA associated with malignant lymphoma have been reported. The pathogeneses of the PRCA and hemolytic anemia in our patient are discussed.     

T-cell large granular lymphocytic (T-LGL) leukemia: a single institution experience

Background T-cell large granular lymphocytic (T-LGL) leukemia is a rare lymphoproliferative disease which usually affects elderly people. The clinical course of T-LGL leukemia is generally indolent, with lymphocytosis and splenomegaly in 20–50% patients, hepatomegaly in 5–20% of patients, and less commonly, lymphadenopathy. T-LGL leukemia is associated with immunological abnormalities: rheumatoid factor with or without rheumatoid arthritis (RA), Coombs positive hemolytic anemia, idiopathic thrombocytopenic purpura (ITP), pure red cell aplasia (PRCA), positive anti-nuclear antibodies (ANA), anti-neutrophil cytoplasmic antibodies (ANCA), hypogammaglobulinemia, and polyclonal hypergammaglobulinemia. Aim To compare clinical and laboratory features of T-LGL leukemia patients and their responses to different chemotherapy regimens. Methods Six patients (3 males and 3 females) with T-LGL leukemia were analyzed. The diagnosis was based on accepted morphologic criteria, immunophenotype, and polymerase chain reaction (PCR) detection of T-cell receptor (TCR) gene rearrangements. Results All patients exhibited lymphocytosis, mainly with unusual morphologies, splenomegaly, and elevated serum lactate dehydrogenase (LDH). Three patients were treated with a Fludarabine–Cyclophosphamide (FC) combination as initial therapy while three patients received CHOP. Two patients received more than one treatment regimen. One patient died due to T-LGL leukemia in first year after diagnosis, one patient died 4 years after diagnosis, two patients interrupted their treatment, and two patients are still alive. Conclusions Further prospective studies are needed for establishing a gold standard therapy for T-LGL leukemia.     

Clonality of acquired primary pure red cell aplasia: effectiveness of antithymocyte globulin

Primary pure red cell aplasia (PRCA) was diagnosed in two male patients, 65 and 69 years old respectively. In both, surface markers of peripheral blood nuclear cells revealed the presence of TCR alphabeta+ phenotype. Clonality of T cells was confirmed by the polymerase chain reaction in both patients, in whom, prednisone at a dose of 1 mg/kg/day improved the anemia and lower doses caused its renewal, resulting in the reappearance of the patient's transfusion requirement. On the other hand, the anemia seems to have been treated permanently (second case) with horse antithymocyte globulin (ATG) (20 mg/kg/day 1 to 8 +) since his hemoglobin was about 15 g/dl at the time of writing. In the first patient, the hemoglobin level was 10.5 g/dl one month after the administration of ATG (15 mg/kg/d 1 to 5 +), but unfortunately, the patient died because of a massive gastrointestinal bleeding on the fortieth day following this treatment. We, therefore, suggest that, patients with acquired primary PRCA should be screened to detect the presence of a T-cell clone and recommend that, treatment should start earlier with ATG, if the PRCA is due to a T-cell clonal disorder.     

Allogeneic Hemopietic Stem Cell Transplants for the Treatment of B Cell Acute Lymphocytic Leukemia

Objective: Explore the feasibility of allo- hemopietic stem cell transplants in treating patients with B cell acute lymphocytic leukemia. Methods: Between september 2006 and February 2011, fifteen patients with B cell acute lymphocytic leukemia (ALL) were treated by allo-hemopietic stem cell transplants (HSCT). Stem cell sources were peripheral blood. Six patients were conditioned by busulfan (BU) and cyclophosphamide (CY) and nine patients were conditioned with TBI and cyclophosphamide (CY). Graft versus host disease (GVHD) prophylaxis regimen consisted of cyclosporine A (CSA), methotrex ate (MTX) and mycophenolatemofetil (MMF). Results: Patients received a median of 7.98×108·kg-1 (5.36-12.30×108·kg-1) mononuclear cells (MNC). The median time ofANC> 0.5×109/L was day 12 (10-15), and PLT> 20. 0×109/L was day 13 (11-16). Extensive acute GVHD occurred in 6 (40.0%) patients, and extensive chronic GVHD was recorded in 6 (40.0%) patients. Nine patients were alive after 2.5-65 months follow-up. Conclusion: Allogeneic stem cell transplant could be effective in treating patients with B cell acute lymphocytic leukemia.     

Autoimmune hemolytic anemias, Evans' syndromes, and pure red cell aplasia in non-Hodgkin lymphomas

We analyzed 108 cases of non-CLL non-Hodgkin lymphoma (NHL) associated with autoimmune hemolytic anemia (AIHA) (+/- pure red cell aplasia (PRCA)) or Evans' syndrome. The analysis was based on cases reported in the literature, which were retrieved by means of Pubmed and Medline searches and of an original series of 121 patients with NHL as well as reference lists of papers in the field. The number of cases in various NHL subtypes was small (n = 6 - 25). Nevertheless, interesting and sometimes unexpected differences in sex prevalence, temporal relationship between onset of lymphoma and AIHA, stage of lymphoma, relative frequency of warm antibody-AIHA (WA-AIHA) and cold antibody (CA-AIHA), association with PRCA and response of AIHA to treatments were noted for various lymphoma entities. WA-AIHA was more frequent in B-cell lymphomas, while CA-AIHA and PRCA predominantly occurred in T-cell lymphomas. Anti-lymphoma treatment seemed to be more effective against AIHA than conventional therapy with steroids or immunoglobulin. Although generated by a literature survey, this compilation of data indicates a complex relation of lymphoma and AIHA and warrants more attention and specific studies.     

Metastatic basal cell carcinoma: complete response to chemotherapy and associated pure red cell aplasia

Basal cell carcinoma (BCC) is usually a benign and indolent cancer cured in greater than 95 percent of cases. Nevertheless, it can be locally destructive or occasionally metastasize to distant organs. We report a case of BCC metastatic to the lungs, occurring 17 years after the primary BCC was noticed, that responded to carboplatin and paclitaxel on 3 occasions. The patient also developed pure red cell aplasia (PRCA). Work-up did not reveal underlying thymoma or infectious, rheumatologic, or lymphoproliferative disorders. Parvovirus serologies were negative, and antibodies against erythropoetin were not detected. There was no history of exposure to drugs associated with PRCA. Bone marrow biopsy on 2 different occasions did not show evidence of myelodysplasia. PRCA may represent an unusual paraneoplastic syndrome associated with BCC as reported with other carcinomas. This is the first report of PRCA associated with metastatic BCC or the drugs carboplatin and paclitaxel, which were used to treat it. The literature on chemotherapy for metastatic BCC is reviewed.