Vit Campr

Occurrence of B-cell lymphomas in patients with activated phosphoinositide 3-kinase δ syndrome.

To the Editor Activated Phosphoinositide 3-Kinase δ syndrome (APDS) is a novel autosomal dominant (AD) primary immunodeficiency (PID), caused by a heterozygous gain-of-function mutation in the PIK3CD gene encoding the p110δ protein, the catalytic subunit of phosphoinositide 3-kinase δ (PI3Kδ)(1). The c.3061G>A mutation results in a substitution of a glutamic acid by a lysine at position 1021 (E1021K). This new PID is characterized by recurrent respiratory infections, leading to bronchiectasis, progressive lymphopenia, and defective antibody production. Both T and B cell compartments are affected as shown by the propensity of CD4+ and CD8+ T cells to die after in vitro stimulation and their poor capacity for cytokine production, as well as an immunoglobulin (Ig) class switch recombination defect (CSR-D). Most of the cases have an increase of serum IgM levels and a decrease of IgG2 isotype, while total IgG and IgA levels can be either normal or strongly decreased. The clinical presentation is variable, ranging from combined immunodeficiency requiring hematopoietic stem cell transplantation to an isolated primary antibody deficiency which can be well controlled by IgG substitution. In order to identify new APDS patients, we genotyped the PIK3CD gene at position c.3061G as described previously (1) in a cohort of 139 patients with immunological phenotype of Ig CSR-D. We found 8 new APDS patients with the E1021K heterozygous mutation in the PIK3CD gene (“see Tables E1 and E2”) in addition to the 17 described previously (1), bringing the total number of known patients carrying this PIK3CD mutation to 25. We noticed that among these eight new APDS patients two developed B-cell lymphomas, suggesting that a constitutively active PI3Kδ predisposes to malignancies. These two cases are herein reported (Table1A, ​,1B1B). Table 1A Table 1B Lymphocyte populations Patient 1 has no familial history of PID, but his mother died at 35 years of age of sub-arachnoid haemorrhage. He was referred to our hospital at the age of 2 years with recurrent bronchopulmonary infections, lymphadenopathy, hepato-splenomegaly, liver disease (elevated transaminases and portal septal fibrosis at liver biopsy). He had increased serum IgM levels (4.25g/L), normal IgG (5.7 g/L) and decreased IgA (0.65g/L) levels, compatible with the diagnosis of CSR-D. The CD40L and CD40 defects were excluded and intravenous IgG substitution was initiated. At 8 years of age, he developed a high grade diffuse large B-cell lymphoma (DLBCL, WHO classification) of biliary tract (Figure 1 a-c). In situ hybridization for Epstein Barr virus (EBV) was negative and Bcl-6 was expressed as shown by immunohistochemistry. The patient recovered after nine courses of chemotherapy (UKCCSG 9002 protocol; “see E3”). At 19 years of age, under IgG substitution, he again developed a high grade EBV(-) DLBCL of the colon, which was found to be Bcl-6 negative (Figure 1 d-f). He received CHOP (Cyclophophamide, vincristine, steroids) plus rituximab. He died from large bowel perforation and bleeding 12 days after the third course of chemotherapy. Figure 1 B-cell lymphomas. Patient 2 belongs to a family in which two siblings were reported as suffering from a CSR-D (data from the affected sister P7 “see Tables E1 and E2”). From the age of 5 months, he suffered recurrent upper (recurrent acute otitis media) and lower respiratory tract infections complicated by bronchiectasis, chronic non-infectious diarrhea with malabsorption syndrom and failure to thrive. Other infections were also noticed, including pericarditis caused by Echo virus infection and recurrent synovitis. The diagnosis of CSR-D was made, according to his familial history and IgG substitution was started. At 6 and 8 years of age, he displayed episodes of massive enlargement of lymph nodes (cervical and mesenteric) with no malignant feature at biopsy. Serum Ig levels revealed an increase of IgM (4.5g/L at 5 years and 13g/L at 11 years) and a decrease of IgG (<1.9g/L) and IgA (0.41 g/L). At 11 years of age, he had a new episode of cervical lymph nodes enlargement which led to the diagnosis of Hodgkin disease, histological type nodular sclerosis, stage III with localization to cervical, mediastinum, retroperitoneum and spleen (EBV status was unknown and could not be studied retrospectively) (Figure 1 g-i). Patient received chemotherapy and radiotherapy with irradiation of regions above and below diaphragma, which induced complete remission. He is now well on IgG substitution and prophylactic antibiotherapy with a follow-up of more than 10 years. These observations extend our previous data reporting one case of marginal zone B-cell lymphoma in an adult APDS patient (1). Moreover, a recent study reports one further APDS patient who developed an EBV+ diffuse B cell lymphoma. Interestingly, authors describe a similar PID phenotype with two other gain of function mutations (E525K and N334K) in PIK3CD gene, including one case of EBV+ nodular sclerosis form of classical Hodgkin lymphoma (E525K) (2). Altogether these observations pinpoint to the fact that PI3Kδ hyperactivation predisposes to multiple types of B-cell lymphomas. Activation of the PI3K pathway is associated with malignant transformations and it has been shown that overexpression of p110δ can transform cells (3). Constitutive PI3K activation has been found in B-cell malignancies, e.g. Burkitt lymphomas (4, 5). Recently, somatic E1021K mutations of p110δ have been detected in diffuse large B-cell lymphomas from two patients (6) similar to our patient #1, which further supports our observation that activation of PI3Kδ signalling contributes to B cell neoplasia. We propose that a combination of defective T cell mediated immune surveillance and uncontrolled lymphoproliferation of B cells predisposes this PID to B cell lymphomagenesis. So far, only the minority of patients carrying PIK3CD mutation (5 out of 39, 13%) had been diagnosed with lymphomas. However, the risk of malignancies is likely to increase with age, modified by additional acquired somatic mutations. Most APDS patients currently receive treatment with antibiotics and IgG replacement. Such treatment reduces infections, but is unlikely to prevent lymphomas. We have found that selective p110δ inhibitors IC87114 and GS-1101 (CAL-101 or Idelalisib) reduce activity of the mutant p110δ in vitro and in cells of APDS patients ex vivo (1). GS-1101 has been in clinical trials for treatment of chronic lymphocytic leukemia (CLL) and early data suggest that the drug is well tolerated for extended periods of exposure (7). Therefore, GS-1101 and other selective p110δ inhibitors may provide a novel specific therapy for APDS patients that prevent lymphoma development. Susceptibility to lymphomas is observed in other well defined PID, such as the AD hyper-IgE syndrome due to heterozygous mutations in STAT3 and in autosomal recessive IL10RA or IL10RB-deficiencies, suggesting a role for the IL-10R/STAT3 pathway in controlling lymphomagenesis (8). Patients with common variable immunodeficiency are also prone to develop lymphomas (9). Physicians should be aware of this complication that strongly worsens the prognosis for PID patients.

Morphological differentiation of severe aplastic anaemia from hypocellular refractory cytopenia of childhood: reproducibility of histopathological diagnostic criteria

Baumann I, Führer M, Behrendt S, Campr V, Csomor J, Furlan I, de Haas V, Kerndrup G, Leguit R J, De Paepe P, Noellke P, Niemeyer C & Schwarz S 
(2012) Histopathology 61, 10–17

Comparison of horse and rabbit antithymocyte globulin in immunosuppressive therapy for refractory cytopenia of childhood

Refractory cytopenia of childhood is the most common subtype of myelodysplastic syndrome in children. In this study, we compared the outcome of immunosuppressive therapy using horse antithymocyte globulin (n=46) with that using rabbit antithymocyte globulin (n=49) in 95 patients with refractory cytopenia of childhood and hypocellular bone marrow. The response rate at 6 months was 74% for horse antithymocyte globulin and 53% for rabbit antithymocyte globulin (P=0.04). The inferior response in the rabbit antithymocyte globulin group resulted in lower 4-year transplantation-free (69% versus 46%; P=0.003) and failure-free (58% versus 48%; P=0.04) survival rates in this group compared with those in the horse antithymocyte globulin group. However, because of successful second-line hematopoietic stem cell transplantation, overall survival was comparable between groups (91% versus 85%; P=ns). The cumulative incidence of relapse (15% versus 9%; P=ns) and clonal evolution (12% versus 4%; P=ns) at 4 years was comparable between groups. Our results suggest that the outcome of immunosuppressive therapy with rabbit antithymocyte globulin is inferior to that of horse antithymocyte globulin. Although immunosuppressive therapy is an effective therapy in selected patients with refractory cytopenia of childhood, the long-term risk of relapse or clonal evolution remains. (ClinicalTrial.gov identifiers: NCT00662090)

Thrombosis in thrombocythemic Ph-myeloproliferations is associated with higher platelet count prior to the event: results of analyses of prothrombotic risk factors from a registry of patients treated with anagrelide

Controversies still exist regarding definition of the thrombotic risks in Ph‐ (BCR/ABL1‐) myeloproliferative disorders with thrombocythemia (MPD‐T). Platelet counts at diagnosis are currently not taken as a risk factor of thrombosis. In our cohort of 1179 patients with MPD‐T, prospectively registered for anagrelide treatment, we found that the median platelet count prior to the thrombotic event was significantly higher than at time points without any ensuing thrombosis (453 vs. 400 × 109/L, P < 0.001), albeit higher platelet counts at diagnosis tended to be connected with fewer thrombotic events (in contrast to WBC counts at diagnosis). The JAK2V617F mutation predicted both arterial and venous events, while age >65 yr, hypertension, diabetes mellitus, smoking, elevated triglyceride and homocysteine levels predicted arterial events only. For venous events, the specific thrombophilic risk factors (factor V ‘Leiden’ and others), antiphospholipid antibodies, and elevated factor VIII levels played a major role. During anagrelide treatment (± aspirin), we documented a decrease in both venous (6.7‐fold) and arterial events (1.8‐fold), while bleeding (mostly minor events) increased twofold compared to history. Our results suggest that keeping platelet counts at low levels may be a meaningful therapeutic measure to prevent thrombosis, although their counts at diagnosis lack any prognostic value.

Loss of B cells and their precursors is the most constant feature of GATA-2 deficiency in childhood myelodysplastic syndrome

GATA-2 deficiency was recently described as common cause of overlapping syndromes of immunodeficiency, lymphedema, familiar myelodysplastic syndrome or acute myeloid leukemia. The aim of our study was to analyze bone marrow and peripheral blood samples of children with myelodysplastic syndrome or aplastic anemia to define prevalence of the GATA2 mutation and to assess whether mutations in GATA-2 transcription factor exhibit specific immunophenotypic features. The prevalence of a GATA2 mutation in a consecutively diagnosed cohort of children was 14% in advanced forms of myelodysplastic syndrome (refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and myelodysplasia-related acute myeloid leukemia), 17% in refractory cytopenia of childhood, and 0% in aplastic anemia. In GATA-2-deficient cases, we found the most profound B-cell lymphopenia, including its progenitors in blood and bone marrow, which correlated with significantly diminished intronRSS-Kde recombination excision circles in comparison to other myelodysplastic syndrome/aplastic anemia cases. The other typical features of GATA-2 deficiency (monocytopenia and natural killer cell lymphopenia) were less discriminative. In conclusion, we suggest screening for GATA2 mutations in pediatric myelodysplastic syndrome, preferentially in patients with impaired B-cell homeostasis in bone marrow and peripheral blood (low number of progenitors, intronRSS-Kde recombination excision circles and naïve cells).

Radiotherapy with rituximab may be better than radiotherapy alone in first-line treatment of early-stage follicular lymphoma: is it time to change the standard strategy?

Early-stage follicular lymphoma (FL) has traditionally been treated with involved-field radiotherapy (RT). Rituximab (R) is a low-toxic, efficient systemic therapy for FL, but there are no data about its clinical impact in early FL. We retrospectively analyzed 93 patients with stage I–II indolent FL treated with RT (n = 65) or RT + R (n = 14) or R alone (n = 14). Median follow-up was 5.0 years for patients with RT, 2.8 years for the RT + R subgroup and 2.5 years for patients treated with R. The complete response rate was 92%, 100% and 86% (not significant) and the median PFS was 3.3 years, not reached and 4.9 years (p = 0.035) for the RT, RT + R and R arms, with no impact on overall survival. R combined with RT seems to give better results in terms of global FL control, but longer follow-up and prospective comparison are needed to verify these results.

A New Prognostic Score for Elderly Patients with Diffuse Large B-Cell Lymphoma Treated with R-CHOP: The Prognostic Role of Blood Monocyte and Lymphocyte Counts Is Absent

Background Absolute lymphocyte count (ALC) and absolute monocyte count (AMC) have been documented as independent predictors of survival in patients with newly diagnosed Diffuse Large B-cell Lymphoma (DLBCL). Analysis of the prognostic impact of ALC and AMC in the context of International Prognostic Index (IPI) and other significant variables in elderly population treated in the R-CHOP regime has not been carried out yet. Methodology/Principal Findings In this retrospective study, a cohort of 443 newly diagnosed DLBCL patients with age ≥60 was analyzed. All patients were treated with the R-CHOP therapy. An extensive statistical analysis was performed to identify risk factors of 3-year overall survival (OS). In multivariate analysis, only three predictors proved significant: Eastern Cooperative Oncology Group performance status (ECOG), age and bulky disease presence. These predictors were dichotomized (ECOG ≥1, age ≥70, bulk ≥7.5) to create a novel four-level score. This score predicted 3-year OS of 94.0%, 77.4%, 62.7% and 35.4% in the low-, low-intermediate, high-intermediate and high-risk groups, respectively (P<0.001). Further, a three-level score was tested which stratifies the population better (3-year OS: 91.9%, 67.2%, 36.2% in the low, intermediate and high-risk groups, respectively) but is more difficult to interpret. Both the 3- and 4-level scores were compared to standard scoring systems and, in our population, were shown to be superior in terms of patients risk stratification with respect to 3-year OS prediction. The results were successfully validated on an independent cohort of 162 patients of similar group characteristics. Conclusions The prognostic role of baseline ALC, AMC or their ratio (LMR) was not confirmed in the multivariate context in elderly population with DLBCL treated with R-CHOP. The newly proposed age-specific index stratifies the elderly population into risk groups more precisely than the conventional IPI and its existing variants.

G-CSF stimulated islands of haematopoiesis mimicking disseminated malignancy on PET-CT and MRI scans in a patient with hypoplastic marrow disorder

A 25-year-old man was admitted for abdominal pain and bicytopenia (anaemia + thrombocytopenia) in November 2003. Trephine biopsy revealed an aplastic marrow with cellularity less than 5% (panel 5). A diagnostic plan included positron emission tomography-computed tomography (PET-CT) to exclude malignancy before starting immunosuppression. In the week preceding the PET-CT, the patient developed neutropenic sepsis with severe gastro-intestinal bleeding. He was treated with antibiotics and granulocyte colony-stimulating factor (G-CSF). Both PET-CT (panels 3 and 4) andmagnetic resonance imaging (MRI) scans (panels 1 and 2) later showed multiple focal lesions highly suspicious of a neoplasm disseminated to the bone marrow. PET-CT-directed surgical biopsy from the S1 vertebral body was performed. No malignant cells were found. Blood clots with small fragments of hypercellular marrow showing trilinear haematopoiesis were obtained (panel 6), probably a consequence of G-CSF administration. Hypercellular islands mimicked malignancy on the scans. The patient later met the criteria of severe aplastic anaemia and in the absence of a human leucocyte antigen-matched related donor underwent immunosuppressive treatment. Paroxysmal nocturnal haemoglobinuria clones appeared in the granulocyte and thrombocyte lines in the course of the disease. The patient has a reasonable quality of life and only occasionally needs a platelet transfusion; his leucocyte numbers are above 2 · 10/l. This case highlights the importance of avoiding the administration of G-CSF prior to PET imaging and illustrates the irregular pattern of distribution of haematopoetic bone marrow in the initial phases of aplastic anaemia.

Role of rituximab in treatment of patients with primary central nervous system lymphoma: a retrospective analysis of the Czech lymphoma study group registry

Abstract We have investigated whether the addition of rituximab to methotrexate, procarbazine, vincristine, radiotherapy and cytarabine was associated with improved outcome of primary central nervous system lymphomas (PCNSL). Of 164 patients, 49 received rituximab. Median age was 63 years, median Karnofsky performance score (KPS) was 60 and median follow-up of living patients was 59.5 months. 1- and 2-year PFS were 49.7 and 37.9%, 1- and 2-year OS were 57.0 and 45.3%. Median progression-free survival (PFS), but not overall survival (OS) was significantly better for patients treated with rituximab (22.9 vs. 10.9 months, p = 0.037). In multivariate analysis, age ≤70 years and KPS ≥90 were predictive for PFS and OS, rituximab was an independent prognostic factor for PFS only. In landmark analyses, rituximab was not found beneficial for long-term survivors and no group particularly benefited from rituximab. In conclusion, addition of rituximab was associated with improved PFS, but not OS in this unselected cohort of PCNSL patients.

Impact of rituximab maintenance and maintenance schedule on prognosis in first-line treatment of follicular lymphoma. Retrospective analysis from Czech Lymphoma Study Group (CLSG) database.

Abstract Rituximab maintenance (RM) improves time to progression (PFS) in advanced follicular lymphoma (FL), but the impact of various RM schedules remains unknown. This study performed a retrospective evaluation of RM given for up to 2 years vs observation in 319 untreated FL patients (stage II–IV; grade 1–3A) responding to RCHOP induction and a comparison of two different RM schedules (RM8 = eight doses given every 3 months and RM12 = 12 doses given every 2 months). A total of 183 patients received RM and 136 patients were observed; 5-year PFS was better in the RM arm, 74.1% vs 52.3% (p < 0.001), which was projected in 5-year OS 93.8% vs 87.5% (p = 0.005). However, 5-year PFS was similar in both the RM8 (n = 54) and RM12 (n = 56) arms. In the first line, RM significantly prolongs PFS and OS in FL, but different RM schedules bring a similar benefit.