Lenalidomide with or without erythropoietin in transfusion-dependent erythropoiesis-stimulating agent-refractory lower-risk MDS without 5q deletion.

After failure of erythropoiesis-stimulating agents (ESAs), lenalidomide (LEN) yields red blood cell (RBC) transfusion independence (TI) in 20-30% of lower-risk non-del5q myelodysplastic syndrome (MDS). Several observations suggest an additive effect of ESA and LEN in this situation. We performed a randomized phase III study in 131 RBC transfusion-dependent (TD, median transfusion requirement six RBC units per 8 weeks) lower-risk ESA-refractory non-del5q MDS. Patients received LEN alone, 10 mg per day, 21 days per 4 weeks (L arm) or LEN (same schedule) + erythropoietin (EPO) beta, 60,000 U per week (LE arm). In an intent-to-treat (ITT) analysis, erythroid response (HI-E, IWG 2006 criteria) after four treatment cycles (primary end point) was 23.1% (95% CI 13.5-35.2) in the L arm and 39.4% (95% CI 27.6-52.2) in the LE arm (P=0.044), while RBC-TI was reached in 13.8 and 24.2% of the patients in the L and LE arms, respectively (P=0.13). Median response duration was 18.1 and 15.1 months in the L and LE arms, respectively (P=0.47). Side effects were moderate and similar in the two arms. Low baseline serum EPO level and a G polymorphism of CRBN gene predicted HI-E. Combining LEN and EPO significantly improves erythroid response over LEN alone in lower-risk non-del5q MDS patients with anemia resistant to ESA.

Cerebro-retinal microangiopathy with calcifications and cysts due to recessive mutations in the CTC1 gene.

Cerebro-retinal microangiopathy with calcifications and cysts (CRMCC) or Coats plus syndrome is a pleiotropic disorder affecting the eyes, brain, bone and gastrointestinal tract. Its primary pathogenesis involves small vessel obliterative microangiopathy. Recently, autosomal recessively inherited mutations in CTC1 have been reported in CRMCC patients. We herein report an adolescent referred to our hospital following new seizures in a context of an undefined multisystem disorder. Cerebral imaging disclosed asymmetrical leukopathy, intracranial calcifications and cysts. In addition, he presented other typical CRMCC features i.e. a history of intrauterine growth retardation, skeletal demineralization and osteopenia, bilateral exudative vitreo-retinopathy reminiscent of Coats disease, recurrent gastrointestinal hemorrhages secondary to watermelon stomach and variceal bleeding of the esophagus due to idiopathic portal hypertension and telangiectatic and angiodysplasic changes in the small intestine and colon, and anemia due to recurrent bleeding and bone marrow abnormalities. The patient was diagnosed with Coats plus syndrome. CTC1 gene screening confirmed the diagnosis with the identification of heterozygous deleterious mutations. CRMCC due to CTC1 mutations has a broad clinical expressivity. Our case report illustrates the main possible associated phenotypes and their complications, demonstrating the need for a careful etiological search in order to initiate appropriate therapeutic and preventive measures.

[Disseminated varicella-zoster virus infection with hemorrhagic gastritis during the course of chronic lymphocytic leukemia: case report and literature review]. / Infection disséminée au virus varicelle-zona avec gastrite hémorragique compliquant une leucémie lymphoïde chronique : une observation et revue de la littérature.

INTRODUCTION: The reactivation of varicella-zoster virus occurs in immunocompromised patients, especially in cases of hematological malignancy. Disseminated reactivation could involve digestive tract with life-threatening condition. CASE REPORT: A 76-year-old woman, with a history of chronic lymphocytic leukemia, presented with left hypochondrium pain, and a vesicular rash with hemorrhagic shock that revealed an hemorrhagic gastritis due to varicella-zoster virus. The literature review identified 28 additional cases of gastrointestinal mucosal damage during reactivation of varicella-zoster virus. Mortality is 40%. We report here the first case in the course of low-grade lymphoid malignancy. CONCLUSION: Acute gastrointestinal symptoms in immunocompromised patients should evoke a varicella-zoster virus reactivation with gastrointestinal involvement. This clinical manifestation, although rare, should not be ignored because of its severity.

Hemolysis and schistocytosis in the emergency department: consider pseudothrombotic microangiopathy related to vitamin B12 deficiency.

BACKGROUND: Hemolytic anemia with thrombocytopenia and schistocytosis is suggestive of thrombotic thrombocytopenic purpura (TTP). However, these features can occur in the context of vitamin B12 deficiency. AIM: To identify simple means of distinguishing between TTP and pseudothrombotic microangiopathies related to vitamin B12 deficiency (pseudo-TMA) at the bedside. DESIGN AND METHODS: Retrospective study of patients with pseudo-TMA compared with patients with TTP. The patients with pseudo-TMA were further compared with other cases of cobalamin deficiency, in order to detect factors associated with microangiopathic hemolysis during vitamin B12 deprivation. RESULTS: Seven patients with pseudo-TMA were compared with six patients with TTP. The pseudo-TMA patients had higher median lactate dehydrogenase (LDH) levels (7310 vs. 1460 IU/l, P = 0.01), a higher platelet count (73 vs.12.5 × 10(9)/l, P = 0.0023), a lower reticulocyte count (13.1 vs. 265.5 × 10(9)/l, P = 0.0012) and a lower neutrophil count (1.3 vs. 5.1 × 10(9)/l, P = 0.0023). When compared with 21 patients with vitamin B12 deficiency and anemia (but no schistocytosis), the pseudo-TMA patients were more likely to present with pernicious anemia [7 out of 21 (33.3%) vs. 5 out of 7 (71.4%), respectively] and had lower vitamin B12 levels (105 vs. 45 µmol/l, respectively). Vitamin supplementation led to hematological improvements in all pseudo-TMA patients. CONCLUSION: In a context of mechanical hemolysis with thrombocytopenia in a patient admitted to the emergency department, very high LDH levels and a low reticulocyte count are strongly suggestive of pseudo-TMA and should prompt the physician to screen for cobalamin deficiency.

Blastic plasmacytoid dendritic cell neoplasm: clinical features in 90 patients.

BACKGROUND: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare disease characterized by malignant proliferation of a contingent blastic plasmacytoid dendritic cell. This rare entity is recognized mostly by cutaneous spreading, or not having a leukaemic component. The prognosis is very poor. OBJECTIVES: To study a large cohort of 90 patients with BPDCN, to define additional symptoms to form a correct diagnosis earlier, and to manage such patients accordingly. METHODS: We retrospectively reviewed BPDCN cases registered in the French Study Group on Cutaneous Lymphoma database between November 1995 and January 2012. Ninety patients were studied. Demographic data, clinical presentation, initial staging and outcome were recorded. RESULTS: The group contained 62 male and 28 female patients (sex ratio 2·2). Their ages ranged from 8 to 103 years at the time of diagnosis (mean 67·2 years). Three major different clinical presentations were identified. Sixty-six patients (73%) presented with nodular lesions only, 11 patients (12%) with 'bruise-like' patches and 13 (14%) with disseminated lesions (patches and nodules). Mucosal lesions were seen in five patients (6%). The median survival in patients with BPDCN was 12 months. CONCLUSIONS: We here distinguish three different clinical presentations of BPDCN. A nodular pattern is a more common feature than the originally reported 'bruise-like' pattern. Despite the fact that BPDCN may initially appear as a localized skin tumour, aggressive management including allogeneic bone marrow transplantation should be considered immediately, as it is currently the only option associated with long-term survival.

Multifocal deficits due to leukemic meningoradiculitis in chronic lymphocytic leukemia.

Symptomatic nervous system leukemic infiltration is rarely observed in CLL. Various clinical manifestations including headache, confusion, cranial nerve palsies, focal central deficits and peripheral neuropathies have been seldom reported, occurring in less than 1% of patients. We report herein 2 CLL patients with unusual clinical presentations of nervous system invasion. They presented multiple progressive peripheral deficits due to meningoradiculitis. In both, CSF immunophenotyping analysis identified a majority of T cells (>90%), and less than 10% of B-CLL cells expressing CD5, CD19 and CD20. Our analyses revealed the transformation of CLL into an aggressive B-cell lymphoma in one case (Richter's syndrome). A post mortem study showed massive infiltration of cranial nerves and spinal roots by large B lymphomatous cells. In the other case, CNS oriented chemotherapy led to remission and total neurological recovery. In practice, the etiological diagnosis of neurological deficits in CLL patients is difficult. CSF analysis may be useful, requiring viral PCR, repeated cytological studies and immunophenotyping analysis. Although rare, leptomeningeal leukemic localization has to be discussed, even in the absence of overt Richter syndrome, and may require an early therapeutic test.

[Management of high risk pregnancy in sickle cell disease by a strategy of prophylactic red cell transfusion or automated red cell exchange]. / Prise en charge des grossesses à risque chez les femmes drépanocytaires : intérêt d'une stratégie préventive par des transfusions de globules rouges ou des échanges érythrocytaires automatisés.

OBJECTIVE: Maternal and fetal risk is often high during pregnancy in sickle cell disease. Our objective was to evaluate the benefits of a transfusion program adapted to each pregnant patient, either by red cell transfusion or by automated red cell exchange, in sickle cell patients with a history of serious obstetrical and/or sickling complications. STUDY DESIGN: We managed 18 pregnancies in 14 patients (12 SS, 1 SC, 1 S/b-thalassemia), seven of whom had a history of one or more pregnancies, with severe maternofetal complications in nine out of 10 cases. The other seven patients were pregnant for the first time and were in care because of a history of severe sickling complications. The aim was to achieve a proportion of abnormal hemoglobin (hemoglobin S or S+C) below 50% and a hemoglobin level between 9 and 11 g/dL. The choice between transfusion and red cell exchange was made in the light of the hemoglobin level. Red cell exchange was done using a Fresenius Com. Tec blood cell separator. Patients had red cell exchange in 10 cases, and transfusions in five cases. In three cases, patients had successive transfusions and red cell exchange. RESULTS: No serious maternal complication was observed. No fetal or perinatal death occurred. In one case, delivery was induced at 36 weeks of gestation because of fetal distress and hypotrophy. CONCLUSIONS: Our study suggests that women with severe sickle cell disease, even if they have a serious obstetrical history, can carry their pregnancy to term, without major obstetric complications, through a combination of early management by a multidisciplinary team and a suitable policy of prophylactic transfusion or automated red cell exchange.

Thallium-201 scintigraphy is not predictive of late cardiac complications in patients with Hodgkin's disease treated with mediastinal radiation.

PURPOSE: To assess whether abnormalities depicted by Thallium-201 scintigraphy can predict the occurrence of late cardiac complications in patients with Hodgkin's disease treated with mantle field radiation therapy. METHODS AND MATERIALS: Thallium scintigraphy was performed in 49 patients at a median of 75 months after initial treatment (range 28-208 months). Initial treatment consisted in chemotherapy, given to two-thirds of the patients and mantle field radiation, delivered to all patients, using a 25-MV linear accelerator. Myocardial perfusion defects were observed in 78% of patients on thallium scintigraphy. These patients had their cardiac status reassessed at a median follow-up of 13.5 years after treatment. RESULTS: Forty-two patients were assessable, as data on the cardiac status were missing in 7 patients. The majority of patients received at least 40 Gy, and 75% of them were treated with one field per day. The median follow-up of patients is 13.5 years (range 9-24.5). Eleven cardiac complications were observed in 9 patients (coronary artery disease [n = 2], conduction-system abnormalities [n = 3], valvular defects [n = 5], and congestive heart disease [n = 1]). The median 15-year actuarial incidence of cardiac complications was 21% (95% confidence interval of 9-40%). The positive and negative predictive value of thallium scintigraphy was 19% and 77%, respectively. The univariate analysis showed that the extent of left ventricle exposure to irradiation was an adverse prognostic factor, and chemotherapy administered before mantle field irradiation was of borderline significance. CONCLUSION: Thallium scintigraphy is not predictive of late cardiac complications. The extent of left ventricle exposure to radiation and possibly chemotherapy given before radiation treatment are adverse prognostic factors.

Human parvovirus B19 infection in organ transplant recipients.

We report a 61-yr-old kidney transplant recipient with human Parvovirus B19 (HPV B19) infection presenting as a severe pancytopenia 1 month after transplantation. Bone marrow aspiration revealed severe erythroid hypoplasia with giant and dystrophic proerythroblasts. Bone marrow cells were positive for HPV B19 DNA detected by polymerase chain reaction (PCR). Pancytopenia resolved shortly after administration of intravenous immunoglobulins. Nineteen cases of HPV B19 infection in organ transplant recipients have been so far reported in the literature. Immunocompromised patients should be considered at risk from developing symptomatic HPV B19 infections. In such patients, specific anti-HPV B19 IgM and IgG antibodies may be absent or transient and therefore their negativity cannot rule out the diagnosis of HPV B19 infestation. Bone marrow smear morphological findings may suggest the diagnosis but testing for viral DNA by PCR is mandatory. Patients may spontaneously recover. However, since specific anti-viral therapy is not currently available, intravenous immunoglobulin administration appears to be the more efficacious treatment.

Doxorubicin-containing regimen with or without interferon alfa-2b for advanced follicular lymphomas: final analysis of survival and toxicity in the Groupe d'Etude des Lymphomes Folliculaires 86 Trial.

PURPOSE: To compare progression-free survival (PFS), overall survival (OS), and toxicity of a doxorubicin-containing regimen administered alone or in combination with interferon alfa-2b (IFNalpha) in patients with low-grade follicular lymphoma (FL) and poor prognostic factors. PATIENTS AND METHODS: Two hundred sixty-eight patients with advanced-stage FL received cyclophosphamide, doxorubicin, teniposide, and prednisone (CHVP) monthly for 6 months, then every 2 months for 12 months. After randomization, 242 patients were evaluated for efficacy: 119 received CHVP alone, and 123 also received IFNalpha at a dose of 5 million units three times weekly for 18 months. RESULTS: After a 6-year median follow-up, the patients treated with CHVP + IFNalpha showed significantly longer median PFS than those who received CHVP alone (2.9 years v 1.5 years, respectively; P = .0002) and significantly longer median OS (not reached v 5.6 years, respectively; P = .008). Although some side effects, which included neutropenia, asthenia, fever, elevated serum transaminase levels, flu-like symptoms, and thrombocytopenia, were more frequently observed in patients who received the combination regimen, these reactions were moderate. IFNalpha was withdrawn because of toxicity in 10% of the patients, and a dosage reduction or temporary suspension was required in 28%. CONCLUSION: With long-term follow-up of 6 years, these results confirm that the addition of IFNalpha to a doxorubicin-containing regimen for patients with advanced-stage and clinically aggressive FL not only increased PFS, as in most other similar trials, but also prolonged OS. Toxicity was moderate. The beneficial effects of this combined chemotherapy and IFNalpha regimen on OS probably reflect the selection of FL patients with poor prognostic factors.

Phase II trial of fludarabine monophosphate in patients with mantle-cell lymphomas.

PURPOSE: The aim of this phase II trial was to assess the efficacy of fludarabine monophosphate in untreated and pretreated mantle-cell lymphomas (MCL). PATIENTS AND METHODS: Fifteen patients with MCL were included in the study. In two cases, fludarabine was the first-line therapy, the second in four cases, the third in five cases, and the fourth in four cases. The diagnosis of MCL was based on the criteria of the European Lymphoma Task Force (ELTF), with morphologic, immunologic, and cytogenetic data. Patients were treated with intravenous fludarabine 25 mg/m2/d for 5 days every 4 weeks. RESULTS: Toxicity of fludarabine was mild: World Health Organization (WHO) grade 3 and 4 granulocytopenia occurred in 15 of 56 assessable cycles (cy) (27%), there was no grade 3 or 4 thrombocytopenia, one grade 3 bacterial lung infection, and no treatment-related death. There were five partial responses (33%) but no complete response. The duration of these responses was short and ranged from 4 to 8 months. CONCLUSION: These results suggest that fludarabine can be moderately effective in the treatment of MCL. Fludarabine appears to be far less effective than in chronic lymphocytic leukemia (CLL) and follicular non-Hodgkin's lymphoma (NHL). Therefore, fludarabine should be evaluated in association with other chemotherapeutic agents in MCL.

Fatal intravascular autoimmune hemolytic anemia after fludarabine treatment for chronic lymphocytic leukemia.

We report the case of a patient with chronic lymphocytic leukemia (CLL) who developed fatal intravascular autoimmune hemolytic anemia (AIHA) after fludarabine treatment. He had previously received several treatments including two courses of fludarabine. The direct antiglobulin test (DAT) was negative at diagnosis but was found to be positive with anti-IgG after the first fludarabine treatment. When the patient was treated again with fludarabine nine months later, the DAT became positive with anti-IgG and anti-C3d antiglobulins after the second course of treatment. Abrupt, fatal intravascular hemolysis occurred after the third course. The occurrence of severe AIHA in CLL patients treated with fludarabine has been reported by several authors. Physicians should be aware of the risk of severe AIHA in CLL patients with a history of AIHA or positivation of the DAT during previous fludarabine administration, or in case of secondary fixation of complement to the red cell membrane occurring during fludarabine treatment.

Additional translocation (9;12)(p13;q24.1) in newly diagnosed chronic myeloid leukemia: complete cytogenetic remission after interferon therapy.

We report the case of a patient with chronic phase CML who exhibited, in the same cells, beside the Philadelphia chromosome, an additional translocation between the other chromosome 9 and one of the chromosomes 12 [t(9;12)(p13;q24.1)]. Complete cytogenetic remission with disappearance of both karyotypic abnormalities was achieved after 18 months treatment with low dose (1.4 x 10(6) U/m2/day) recombinant alpha-interferon and has been sustained with maintenance therapy for 68+ months (actual follow-up). Clonality at diagnosis and recovery of polyclonal hematopoiesis in complete cytogenetic remission were demonstrated using the polymorphism at the human androgen receptor gene (Humara) locus on chromosome X. The role of the additional translocation in the response to low dose alpha-interferon therapy remains hypothetical.

Non Hodgkin's lymphoma presenting as neutropenia related to an IgM monoclonal anti-i antibody.

A sixty-year old female was referred to the Internal Medicine Department for the treatment of a diffuse high-grade non Hodgkin's lymphoma. She presented episodes of fever in context of neutropenia (neutrophils 0.35 x 10(9)/1 from 1.6 x 10(9)/1 white blood cells). Hemoglobin level was 8.2 g/dl and platelets 132 x 10(12)/1. A monoclonal IgM-Kappa protein (48 g/l) was detected in her serum. A direct antiglobulin test on the red cells proved positive with anti-C3d but not with anti-IgG antiglobulin, due to the presence of an IgM cold antibody with a serological anti-i specificity. The IgM antibody was found on the patient's neutrophils as well as in her serum. The antibody recognized all neutrophils tested in conventional serological tests whether the neutrophil phenotypes in systems NA, NB, and 5. It was demonstrated that it recognized the i antigen expressed on the neutrophils. These results suggest that a cold agglutinin anti-i might be responsible for neutropenia in some patients.

Interleukin-13 inhibits interleukin-2-induced proliferation and protects chronic lymphocytic leukemia B cells from in vitro apoptosis.

Human interleukin-13 (IL-13) acts at different stages of the normal B-cell maturation pathway with a spectrum of biologic activities overlapping those of IL-4. B chronic lymphocytic leukemia (B-CLL) is characterized by the accumulation of slow-dividing and long-lived monoclonal B cells, arrested at the intermediate stage of their differentiation. In vitro, B-CLL cells exhibit a spontaneous apoptosis regulated by different cytokines. In this report, we show that IL-13 (10 to 200 ng/mL) acts directly on monoclonal B-CLL cells from 12 patients. (1) IL-13 enhances CD23 expression and induces soluble CD23 secretion by B-CLL cells but does not exhibit a growth factor activity. (2) IL-13 inhibits IL-2 responsiveness of B-CLL cells, activated either with IL-2 alone or through crosslinking of lgs or ligation of CD40 antigen. (3) IL-13 protects B-CLL cells from in vitro spontaneous apoptosis. The effects of IL-13 on neoplasic B cells were slightly less than those of IL-4 and occurred independently of the presence of IL-4. The present observations show that IL-13 may exhibit a negative regulatory effect on neoplasic B cells in contrast with that observed in normal B cells, and suggest that IL-13 could be an important factor in the pathogenesis of CLL by preventing the death of monoclonal B cells. Moreover, B-CLL may be an interesting model to study the regulation of the expression of IL-13 receptor and/or signal transduction pathways.

Abnormal chromatin clumping in granulocytes in a case of Ph1-negative, BCR-ABL rearrangement positive, haematologically atypical chronic myeloid leukaemia (CML).

In the present study, we report the case of a patient displaying an abnormal chromatin clumping (ACC) syndrome, a rare disease which shares features with both myeloproliferative and myelodysplastic disorders. Although various non specific cytogenetic abnormalities have been observed in ACC, the presence of a Ph1 chromosome has not been reported. In our patient, despite a lack of Ph1, PCR analysis of blood and bone marrow samples revealed a BCR-ABL rearrangement. These results indicate that at least some cases of ACC syndrome could represent a form of Ph1-negative chronic myeloid leukaemia.