Daniele Armiento

Histopathological and molecular features of persistent polyclonal B-cell lymphocytosis (PPBL) with progressive splenomegaly

Five cases of persistent polyclonal B‐cell lymphocytosis (PPBL) with progressive splenomegaly are reported; three were splenectomized. BCL2/IGH rearrangements were found in three cases; HLA‐DRB1*07 in all. Bone marrow (BM) trephines showed a moderate lymphoid infiltrate with intrasinusoidal distribution resembling a splenic marginal‐zone lymphoma. Splenic white pulp revealed an enlargement of the marginal‐zone area; red pulp was infiltrated by the same lymphocytes engulfing the sinuses. Splenic and BM B‐lymphocytes were CD79a+/CD20+/IgM+/IgD+/bcl‐2+/CD27+/DBA.44−/CD31− and polyclonal by immunophenotype/polymerase chain reaction. PPBL features an expansion of splenic marginal‐zone B‐lymphocytes, which infiltrate BM sinusoids and circulate in the blood with no evidence of clonality, even in cases with progressive splenomegaly.

Bone marrow transplantation for thalassemia from alternative related donors: improved outcomes with a new approach

Bone marrow transplantation (BMT) performance can be limited by a lack of ideal donors, and the role of alternative donor hematopoietic cell transplantation in thalassemia is not well established. Here we used a new treatment protocol (Pc 26.1) in 16 thalassemia patients to perform BMT using phenotypically HLA-identical or 1-antigen-mismatched relatives (related donors [RDs]). We compared these results with HLA-matched sibling (matched sibling donors [MSDs]) BMT in 66 patients. The entire RD group and 88% of MSD group had sustained engraftment. Rejection incidence was 0% in the RD and 12% (95% confidence interval [95% CI], 6%-21%) in MSD groups (P = .15), with respective thalassemia-free survival probabilities of 94% (95% CI, 63%-99%) and 82% (95% CI, 70%-89%) (P = .24). Transplant-related mortality was 6% (95% CI, 1%-26%) in the RD group and 8% (95% CI, 3%-16%) in the MSD group (P = .83). The intensified new protocol was not associated with increased nonhematologic toxicity. The present data show that the Pc 26.1 preparative regimen allows thalassemia patients to safely undergo BMT from RDs who are not HLA-matched siblings, with transplant outcomes similar to patients with MSD grafts.

Identification of monoclonal B-cell lymphocytosis among sibling transplant donors for chronic lymphocytic leukemia patients

To the editor: In patients with chronic lymphocytic leukemia (CLL), a family history of hematologic malignancies is recorded in 12% of cases, half of the latter being CLL.[1][1] First-degree relatives of CLL patients have an 8-fold greater likelihood of harboring a CLL than members of the general

White blood cell count at diagnosis and immunoglobulin variable region gene mutations are independent predictors of treatment-free survival in young patients with stage A chronic lymphocytic leukemia

A comprehensive panel of clinical-biological parameters was prospectively evaluated at presentation in 112 patients with chronic lymphocytic leukemia (<65 years), to predict the risk of progression in early stage disease. Eighty-one percent were in Binet stage A, 19% in stages B/C. Treatment-free survival was evaluated as the time from diagnosis to first treatment, death or last follow up. In univariate analysis, advanced stage, hemoglobin, platelets, white blood cell, leukemic lymphocyte count, raised beta 2-microglobulin and LDH, unmutated immunoglobulin variable region genes, CD38, del(17p), del(11q) and +12, were significantly associated with a short treatment-free survival; the T/leukemic lymphocyte ratio was associated with a better outcome. Multivariate analysis of treatment-free survival in stage A patients selected a high white blood cell count and unmutated immunoglobulin variable region genes as unfavorable prognostic factors and a high T/leukemic lymphocyte ratio as a favorable one. At diagnosis, these parameters independently predict the risk of progression in stage A chronic lymphocytic leukemia patients.

Hematopoietic SCT for the Black African and non-Black African variants of sickle cell anemia.

Sickle cell anemia (SCA) remains associated with high risks of morbidity and early death. Allogeneic hematopoietic SCT (HSCT) is the only curative treatment for SCA. We report our experience with transplantation in a group of patients with the non-Black African variant and the Black African variant of SCA. This study included 40 consecutive SCA patients (13 patients with the non-Black African variant and 27 with the Black African variant) who underwent BM transplantation from HLA-identical sibling donors between June 2004 and May 2013, following a myeloablative-conditioning regimen. All patients obtained sustained engraftment. One patient (non-Black African variant) became a stable mixed chimera with 25% donor cells more than 6 years after transplantation. The probabilities of survival, SCA-free survival and TRM at 5 years after transplant were 91%, 91% and 9%, respectively. All surviving patients remained free of any SCA-related events after transplantation. Our results confirm that it is possible to offer a greater than 90% chance of cure to children with SCA. HSCT should be considered the standard of care for who have an HLA-identical donor, before complications result from the sickling of RBC.

Atypical presentation of anaplastic large T-cell lymphoma mimicking an articular relapse of rheumatoid arthritis in a patient treated with etanercept. A case report and literature review.

Rheumatoid arthritis (RA) is a chronic autoimmune systemic isease with a main but not exclusive interest of joints, that nvolves approximately 0.5–1% of the adult population in westrn countries. The introduction of anti-TNF inhibitors (infliximab, tanercept, adalimumab, efalizumab and alefacept), in association ith synthetic disease-modifying anti-rheumatic drugs (DMARDs), as modified the natural history of this chronic disease. During the ast years concerns about a possible carcinogenetic effect of biologic gents have been posed, with a specific interest in lymphoprolifertive disorders, because of the immunosuppressive effects of these rugs. RA is per se a risk factor for developing a lymphoma: this ncreased risk has been attributed to a persistent inflammatory timulation. Recently, a detailed analysis has shown that large Bell neoplasms predominate among these RA related lymphomas 1]; nevertheless, reports of anaplastic T-cell lymphoma (ALCL) ases are rare. ALCL is an aggressive non-Hodgkin’s lymphoma NHL), accounting for 2–7% of all NHL cases; ALCL are divided into LK positive and ALK negative, on the basis of the expression of everal fusion proteins derived from ALK gene rearrangements. The LK-NPM fusion protein is detectable in 85% of all ALK+ ALCL and is ssociated to the specific translocation t(2;5). The specific NPM-ALK ncogenic protein leads to a constitutive proliferation involving the un N terminal kinase (JNK), Ras-Erk and several other molecular athways [2]. Moreover, molecular studies have demonstrated that lterations of TNF molecular pathways are frequently associated ith ALK+ ALCL, underlying the important role of this cytokine as tumour suppressor [3]. ALK− ALCL is classified as a CD30+ T-cell ymphoma, possessing morphologic characteristics similar to ALK+ LCL. Its epidemiological characteristics and clinical manifestations re highly heterogeneous and, in general, ALK− ALCL has a poorer rognosis than the ALK+ form. In the absence of an exact aetiolgy, specific genetic mutation and characteristic genetic markers, he pathogenesis of ALK− ALCL is poorly understood, even if an poptotic deregulation may be involved. We report a case of a cutaneous anaplastic CD30+ T-cell lymhoma in a patient affected by RA in treatment with the anti-TNF eceptor etanercept. A 47-year old man with a 4-year history f RA came to our attention in August 2011. In the previous years, he was treated as first line therapy with methotrexate nd cyclosporine; due to the occurrence of an acute pancretitis, the patient discontinued synthetic DMARDs after 1 year f treatment and started etanercept 50 mg/week subcutaneously or the subsequent 3 years, from March 2008 to April 2011. In pril 2011, he developed a new, progressive motion limitation ith erythaema and oedema localized only in the left knee; he nderwent a nuclear magnetic resonance (NMR) which showed nly a synovial thickness with articular effusion. The patient

Pulmonary complications and survival after autologous stem cell transplantation: predictive role of pulmonary function and pneumotoxic medications

Autologous stem cell transplantation (ASCT) is the standard of care for multiple myeloma patients eligible for high-dose therapy, lymphoma patients undergoing second-line treatments and for acute myelogenous leukaemia (AML) [1]. Immune system impairment and chemotherapies significantly increase the risk of infections, particularly pneumonia [2]. Overall, pulmonary complications, both infectious and non-infectious, occur in 40–60% of patients after stem cell transplantation [3], and are usually classified as early or late onset, depending on whether they occur within 100 days of the transplant [4]. The underlying disease and baseline pulmonary function, along with conditioning regimens consisting of carmustine, etoposide, aracytin and melphalan for lymphoma, melphalan alone for multiple myeloma or busulpan and cyclophosphamide for acute myeloid leukaemia, all concur to cause pulmonary complications [3, 4]. Pneumotoxic agents prior to ASCT associate with worse event/infection free survival and overall mortality http://ow.ly/1xkL308x3D2

Clinical characteristics and outcome of patients with autoimmune hemolytic anemia uniformly defined as primary by a diagnostic work-up

To the Editor: Primary autoimmune hemolytic anemia (P-AIHA) is a relatively uncommon and hetereogeneous disease characterized by the destruction of red blood cells due to anti-erythrocyte autoantibodies (AeAbs) in the absence of an associated disease [1–3]. Secondary AHIA is frequently associated with lymphoproliferative diseases (LD) in particular, chronic lymphocytic leukemia, aggressive or indolent lymphomas, autoimmune disorders, malignancies other than lymphoid, and infections [1,2,4]. On the hypothetical assumption that in a significant proportion of cases defined as P-AIHA the clinical heterogeneity could be due to an ignored associated disease, we retrospectively analyzed the clinical characteristics and outcome of patients with a diagnosis of P-AIHA based on a diagnostic work-up aimed at excluding or identifying an associated disease. From March 1982 to March 2014, 200 adult patients diagnosed as having a P-AIHA on a clinical basis were managed at our institution. AIHA diagnosis was made in the presence of anemia, signs of hemolysis, the positivity of the direct antiglobulin test, and/ or the detection of an AeAb in the serum of patients (Supporting Information Material and Methods). For the purpose of this study, two main groups of patients were analyzed, the group with a “G” serological profile including cases with an IgG AeAb 6C3d or, in rare cases, combined with an IgA AeAb, and the group characterized by an “M” profile including cases sustained by a cold IgM AeAb and mixed cases with an IgG AeAb associated with a pathogenic IgM AeAb. Patients did not report any previous history of drugs, recent infections, or diseases known to be associated with AIHA. Furthermore, none of them showed on examination any overt signs of a concomitant disease related to AIHA. The diagnostic work-up subsequently performed by each patient was retrospectively reviewed. The minimum panel of tests that we considered as sufficient to exclude, or identify, an associated disease included: (1) bone marrow (BM) biopsy; (2) autoantibody profile incorporating at least the following autoantibodies: anti-nuclear; anti-cardiolipin IgG/IgM; lupus anticoagulant, anti-b2glycoprotein1 IgG/IgM, anti-thyroid peroxidase antibody, and anti-thyroglobulin antibody; (3) B and C hepatitis serology (HBsAg; HBeAg; HBsAb; HBcAb; HBeAb, HCVAb); (4) total body CT scan (or at least, an abdomen ultrasonography combined with a chest X-ray). A front-line treatment with steroids [2] was given to all patients, with the exception of two with mild signs of cold AIHA who received only folic acid support. Patients with severe and symptomatic anemia received also intravenous immunoglobulins and/or RBCs transfusions. In patients who achieved a response, steroids were slowly tapered to reach the lowest effective dose (no more than 5–10 mg of prednisone daily or on alternate days) to maintain the Hb value 10 g/dL. Steroids were discontinued in the presence of a stable Hb value 12 g/dL, no signs of hemolysis and no longer detectable AeAb at two consecutive examinations. In patients who, after the screening, were re-classified as having a secondary AIHA, treatment was addressed to the underlying disease. The response to treatment was defined according to the Hb value, the presence of signs of hemolysis and the detection of the AeAb (Supporting Information Material and Method). We identified 110 patients with an initial diagnosis of P-AHIA who performed the minimum panel of tests that we considered as sufficient to exclude, or identify, an associated disease (Supporting Information Table 1s). The diagnostic work-up did not reveal an associated disease in 72/110 (65.45%) patients whereas in 38 (34.54%) an underlying disease was identified. An ignored malignancy was detected by the CT scan in six patients (5.45%) and an active HCV-RNA positive hepatitis in one patient. In 13 patients (11.81%), the significant positivity of some autoantibodies directed further serological and clinical evaluations allowing the identification of an autoimmune disorder. The proportion of cases with a serological “M” profile was significantly higher in patients with an LD (P< 0.0001). The LD was revealed by the CT scan in two cases (enlarged spleen with nodules, 1; enlarged abdominal lymph-nodes, 1). In 16/18 cases, the LD was detected by the BM biopsy in the absence of other clinical manifestations. As previously described [5], the BM involvement by clonal B lymphocytes was usually limited and these patients, defined as having a primary cold agglutinin disease [5] showed a high response rate, 85.71% with a rituximab-based-chemoimmunotherapy. This observation confirms the benefit of chemoimmunotherapy in these cases [6]. The 72 patients with no evidence of an associated disease after the screening, and uniformly diagnosed with P-AIHA, were relatively younger (P5 0.0056) and more frequently characterized by a “G” than an “M” profile (79.16% vs. 18.05%) (Supporting Information Table 2s). A response to steroids was recorded in 52/68 (76.47%) evaluated patients, with a complete response (CR) in 49 (72.05%). The disappearance of the AeAb was recorded in 12 (17.65%) cases, in 11/56 (19.64%) cases with a “G” profile and in 1/12 (8.33%) with an “M” profile (P5 0.67). Twenty-one patients have died. Refractory hemolysis associated with pneumonia (2 patients), a cerebrovascular event (1 patient), a cardiovascular event (1 patient) were the causes of death in 4 (5.5%) older patients (median age 81 years). In the remaining 17 patients, the most frequent causes of death were cerebrovascular and cardiovascular events. The median overall survival (OS) was 21 years and the median disease-free survival (DFS), 13.21 years (Supporting Information Fig. 1s). Remarkably, the severity of anemia and the serological characteristics of the AeAb did not influence significantly the response to steroids, the DFS and the OS (Supporting Information Fig. 1s) as previously observed by other authors [3]. Even though the small sample size did not allow to recognize statistical differences, patients who achieved a response to front-line steroids showed a better OS (P5 0.28) and DFS (P5 0.17) than those who did not respond (Fig. 1). In particular, the higher survival probability, 81% at 9 years, was displayed by the subset of patients (20%) who obtained a CR with no more detectable AeAbs (Fig. 1). Taken together, our results demonstrate that probably true cases of P-AIHA are less frequent than commonly thought. Furthermore, our study shows that patients with AIHA uniformly defined as primary by a stringent diagnostic work-up aimed at excluding an associated disease show a favorable outcome after a steroid treatment.

Use of PCR for BCL2/IgH + cells in stage I/II follicular lymphoma to identify positive cells in bone marrow and peripheral blood that can be cleared by lymph-node irradiation

8571 Background: Stage I/IIA follicular lymphoma (FL) is considered a localized disease that can be adequately treated with radiotherapy alone. Minimal NHL contamination in peripheral blood (PB) or bone marrow (BM) can be detected by qualitative and quantitative PCR. Aim of this study was to evaluate the role of PCR, the impact of radiotherapy and prognosis in localized FL. Methods: BM and PB involvement in FL was investigated by PCR in a series of 25 consecutive patients with histologically revised diagnosis and treated with involved field radiotherapy alone. Results: Despite a negative BM biopsy, Bcl-2/IgH+ cells were found at diagnosis in the PB and/or BM of 17 patients (68%). After lymph-node involved field radiotherapy, in 10/16 Bcl-2/IgH positive, valuable patients, a disappearance of Bcl-2/IgH+ cells was observed, which persisted after a median follow-up of 42 months (range 5–79) in all but 2 patients.. Quantitative PCR demonstrated the feasibility of clearing PB and BM Bcl-2+ cells after local irr...