Sylvain Pilorge

Complex karyotype in mantle cell lymphoma is a strong prognostic factor for the time to treatment and overall survival, independent of the MCL international prognostic index

Mantle cell lymphoma (MCL) is usually an aggressive disease. However, a few patients do have an “indolent” evolution (iMCL) defined by a long survival time without intensive therapy. Many studies highlight the prognostic role of additional genetic abnormalities, but these abnormalities are not routinely tested for and do not yet influence the treatment decision. We aimed to evaluate the prognostic impact of these additional abnormalities detected by conventional cytogenetic testing, as well as their relationships with the clinical characteristics and their value in identifying iMCL. All consecutive MCL cases diagnosed between 1995 and 2011 at four institutions were retrospectively selected on the basis of an informative karyotype with a t(11;14) translocation at the time of diagnosis. A total of 125 patients were included and followed for an actual median time of 35 months. The median overall survival (OS) and survival without treatment (TFS) were 73.7 and 1.3 months, respectively. In multivariable Cox models, a high mantle cell lymphoma international prognostic index score, a complex karyotype, and blastoid morphology were independently associated with a shortened OS. Spleen enlargement, nodal presentation, extra‐hematological involvement, and complex karyotypes were associated with shorter TFS. A score based on these factors allowed for the identification of “indolent” patients (median TFS 107 months) from other patients (median TFS: 1 month). In conclusion, in this multicentric cohort of MCL patients, a complex karyotype was associated with a shorter survival time and allowed for the identification of iMCL at the time of diagnosis.

Pim kinases modulate resistance to FLT3 tyrosine kinase inhibitors in FLT3-ITD acute myeloid leukemia.

Synergy between FLT3 and Pim kinase inhibition in acute myeloid leukemia with FLT3-ITD mutation. ABSTRACT Fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) is frequently detected in acute myeloid leukemia (AML) patients and is associated with a dismal long-term prognosis. FLT3 tyrosine kinase inhibitors provide short-term disease control, but relapse invariably occurs within months. Pim protein kinases are oncogenic FLT3-ITD targets expressed in AML cells. We show that increased Pim kinase expression is found in relapse samples from AML patients treated with FLT3 inhibitors. Ectopic Pim-2 expression induces resistance to FLT3 inhibition in both FLT3-ITD–induced myeloproliferative neoplasm and AML models in mice. Strikingly, we found that Pim kinases govern FLT3-ITD signaling and that their pharmacological or genetic inhibition restores cell sensitivity to FLT3 inhibitors. Finally, dual inhibition of FLT3 and Pim kinases eradicates FLT3-ITD+ cells including primary AML cells. Concomitant Pim and FLT3 inhibition represents a promising new avenue for AML therapy.

Primary bone diffuse large B-cell lymphoma: a retrospective evaluation on 76 cases from French institutional and LYSA studies

Abstract Primary bone diffuse large B-cell lymphoma (PB-DLBCL) is a rare DLBCL location variant. We treated 76 PB-DLBCL patients by immuno-chemotherapy, resulting in an 84% sustained complete remission rate and a 78.9% survival over a 4.7-year median follow-up period. Ann Arbor stage IV and high age-adjusted international prognostic index were predictive of adverse outcome in univariate analysis. In multivariate analysis using a Cox model, only aa-IPI predicted long-term survival. While based on a limited number of cases, we suggested that radiotherapy may be useful as a consolidation modality in PB-DLBCL. We also suggested that positron emission tomography/CT scan should be interpreted with caution due to a persistent [18F]fluorodeoxyglucose [18FDG] uptake of bone lesions even after remission in some in PB-DLBCL patients. Our study based on a homogeneous cohort of PB-DLBCL patients confirmed the favorable outcome of this DLBCL variant and support the implementation of prospective clinical trials in this disease.

Better outcome with haploidentical over HLA-matched related donors in patients with Hodgkin’s lymphoma undergoing allogeneic haematopoietic cell transplantation—a study by the Francophone Society of Bone Marrow Transplantation and Cellular Therapy

The question of the best donor type between haploidentical (HAPLO) and matched-related donors (MRD) for patients with advanced HL receiving an allogeneic hematopoietic cell transplantation (allo-HCT) is still debated. Given the lack of data comparing these two types of donor in the setting of non-myeloablative (NMA) or reduced-intensity (RIC) allo-HCT, we performed a multicentre retrospective study using graft-vs.-host disease-free relapse-free survival (GRFS) as our primary endpoint. We analysed the data of 151 consecutive HL patients who underwent NMA or RIC allo-HCT from a HAPLO (N  =  61) or MRD (N  =  90) between January 2011 and January 2016. GRFS was defined as the probability of being alive without evidence of relapse, grade 3–4 acute GVHD or chronic GVHD. In multivariable analysis, MRD donors were independently associated with lower GRFS compared to HAPLO donors (HR  =  2.95, P   < 0.001). Disease status at transplant other than CR was also associated with lower GRFS in multivariable analysis (HR  =  1.74, P  =  0.01). In addition, the administration of ATG was independently linked to higher GRFS (HR  =  0.52, P  =  0.009). In summary, we observed significantly higher GRFS in HL patients receiving an allo-HCT using the HAPLO PT-Cy platform compared to MRD.

A retrospective, matched paired analysis comparing bendamustine containing BeEAM versus BEAM conditioning regimen: results from a single center experience

Abstract The combination of carmustine, etoposide, aracytin, and melphalan(BEAM) conditioning regimen in autologous stem-cell transplantation (ASCT) is widely used in patients with relapsed/refractory non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma. It is also an option in patients with very-high risk aggressive NHL in first complete remission (CR). Recently, a phase Ib–II feasibility study using bendamustine replacing carmustine (BCNU) was reported. We report herein a safety and efficacy analysis of bendamustine-EAM (BeEAM) with a control BEAM counterpart paired cohort (1/2). One hundred and two patients were analyzed. Overall survival (OS) and progression-free survival (PFS) were not reached and seemed to be comparable between both groups. However, grade III or greater diarrhea was significantly higher in BeEAM patients (44 vs. 15%, p = .002). The median number of days with fever >38 °C was significantly higher in BeEAM group (5.5 vs. 2, p < .001). This case-control study suggests that BeEAM followed by ASCT using bendamustine at 100 mg/m2/d is effective but has a different toxicity profile than the BEAM regimen.

Hemophagocytic Lymphohistiocytosis Due to Acute Myeloid LeukemiaRelapse: A Very Unusual Association

Hemophagocytic lymphohistiocytosis (HLH) diagnosed in the course of acute myeloid leukemia (AML) is generally triggered by treatment-induced infections. AML-induced HLH is a very rare situation for which no diagnostic or therapeutic guidelines are available. We report the occurrence of HLH in an AML5 post-transplant relapse. In our case, the absence of detectable pathogen and the parallel evolution between HLH and leukemia burden suggested a direct link between AML and HLH. We suggest that the diagnostic of AML-related HLH should be promptly considered in front of unexplained fever, cytopenia, liver dysfunction or neurological symptoms as therapeutic intervention is urgent in this life-threatening situation.

Methotrexate- and/or cytarabine-based chemotherapy may be effective and safe in solid-organ transplant recipients with primary central nervous system lymphomas

Primary central nervous system lymphoma (PCNSL) accounts for 10% of all post-transplant lymphoproliferative disorders (PTLDs) [1]. Systemic PTLD with central nervous system localization and PCNSL have been encountered with the same frequency [2]. In most cases, PCNSL involves B-cell proliferation and Epstein–Barr virus (EBV) reactivation and/or replication [3]. Very few cases of PCNSL have been reported in large series of PTLD, and treatment has not been extensively described except in case reports. Because of its rarity, very few homogeneously treated adult cases have been reported in the literature. Various therapeutic options have been explored in PTLD including CNS disease: reduction of immune suppression (RI), combination chemotherapy, and radiotherapy. However, due to the cerebral location of PCNSL, conventional therapies used for the treatment of B-cell lymphoma, including rituximab delivered even by intraventricular infusion [3] or cyclophosphamide, have failed to cure PCNSL because of poor diffusion of the various molecules through the blood–brain barrier. In patients without transplant, chemotherapy used with PCNSL is based on high-dose methotrexate [4]. Cytarabine, a drug capable of crossing the CNS–blood barrier when given at high doses, is widely used in nontransplant patients with PCNSL and may improve the outcome [5]. High-dose methotrexate (HDMTX) must be carefully monitored in adult patients, especially in renal or liver transplant recipients because of its direct renal or hepatic toxicity. By analogy with therapy currently administered to non-transplant patients presenting with PCNSL, we explored whether HDMTX chemotherapy would be feasible and associated with a durable complete remission in solid-organ transplant recipients with PCNSL. From February 2000, 18 patients with PTLD were referred to our institution. Of these 18 patients, nine had PCNSL following renal (n1⁄4 6), hepatic (n1⁄4 1), or both renal and pancreatic (n1⁄4 2) transplants. Patient characteristics are listed in Table I. The median delay between the transplant and PCNSL was 6 years after a solid-organ transplant (1–26 years), and most cases occurred after the first year post-transplant (7/9 patients). The two patients who developed PCNSL within 12 months after their organ transplant received a three-drug immunosuppressive regimen (a combination of mycophenolate mofetil, tacrolimus, and steroids), which was different from the regimens administered to the other seven patients who developed PCNSL later. The median age was 55 (range 33–70). The Eastern Cooperative Oncology Group (ECOG) performance status was53 in 8/9 cases and 3 in one case. There was no clinical or radiological evidence of lymphoma outside the CNS when PCNSL was diagnosed. Only eight out of nine had a histological examination with EBV screening and immunophenotyping. All these lymphomas were diffuse large B-cell lymphomas (DLBCLs). The

Prognostic value of early 18F-FDG PET scanning evaluation in immunocompetent primary CNS lymphoma patients

Primary central nervous system lymphoma (PCNSL) is a rare topographic variant of diffuse large B-cell lymphoma (DLBCL). While prognostic scales are useful in clinical trials, no dynamic prognostic marker is available in this disease. We report here the prognostic value of early metabolic response by 18F-FDG PET scanner (PET) in 25 newly diagnosed immunocompetent PCNSL patients. Induction treatment consisted of four cycles of Rituximab, Methotrexate and Temozolamide (RMT). Based on patients general condition, consolidation by high-dose Etoposide and Aracytine was given to responding patients. Brain MRI and PET were performed at diagnosis, after two and four cycles of RMT, and after treatment completion. Two-year progression-free (PFS) and overall survival (OS) were 62% and 74%, respectively for the whole cohort. Best responses after RMT induction were 18 (72%) complete response (CR)/CR undetermined (CRu), 4 (16%) partial response, 1 (4%) progressive disease and 2 (8%) stable disease. Response evaluation was concordant between MRI and PET at the end of induction therapy. Nineteen patients (76%) had a negative PET2. Predictive positive and negative values of PET2 on end-of-treatment (ETR) CR were 66.67% and 94.74%, respectively. We observed a significant association between PET2 negativity and ETR (p = 0.001) and longer PFS (p = 0.02), while having no impact on OS (p = 0.32). Two years PFS was 72% and 33% for PET2– and PET2+ patients, respectively (p < 0.02). PET2 evaluation may help to early define a subgroup of CR PCNSL patients with a favorable outcome.

Monitoring antibiotic-resistant enterobacteria faecal levels is helpful in predicting antibiotic susceptibility of bacteraemia isolates in patients with haematological malignancies.

Delay of active antimicrobial therapy in haematological patients with Gram-negative bacilli bacteraemia during profound neutropenia exposes them to increased morbidity and mortality. The digestive tract is the main source of enterobacteria causing bacteraemia in these patients. We thus evaluated the usefulness of broad-spectrum beta-lactam resistant enterobacteria (BSBL-RE) faecal shedding assessment in forecasting the susceptibility to BSBLs of the strains isolated from blood cultures. From 2002 to 2011, neutropenic haematological patients with bacteraemia caused by enterobacteria who had a stool culture during the previous 7 days were retrospectively included. BSBL-RE intestinal carriers were compared with non-carriers in terms of clinical and microbiological criteria. One hundred and four patients were included and 16 of them (15.4 %) were BSBL-RE carriers. Multivariate analysis showed that BSBL-RE carriage was independently associated with BSBL-RE identified in blood cultures (P < 0.001) and the use of carbapenems as empirical treatment of the bacteraemia (P = 0.008). Sensitivity, specificity, and the positive and negative predictive values of the test were 80 %, 91 %, 50 % and 98 %, respectively. Among the carriers, those with the highest level of BSBL-RE carriage were also those with the highest risk of bacteraemia due to BSBL-RE (P < 0.001). Close monitoring of BSBL-RE intestinal carriage may help to choose the most appropriate initial antimicrobial treatment for neutropenic haematological patients with bacteraemia.

Rituximab-induced life-threatening coagulopathy occurring in a patient with Waldenström macroglobulinemia treated with fludarabine, cyclophosphamide, and rituximab combination.

Rituximab is a chimeric anti-CD20 monoclonal antibody which has become the standard of care, in combination with chemotherapeutic agents, in virtually all B-lymphoid malignancies including Waldenström macroglobulinemia (WM) [1]. Its broad use has led to the detection of rare side-effects that were not predicted by phase II/III trials, such as the development of late-onset neutropenia, progressive multifocal leukoencephalopathy, reactivation of hepatitis, and interstitial pneumonitis [2]. We report here the case of a 50-year-old male patient diagnosed with WM. The M-component was 22 g/L at diagnosis. The complete blood count was: hemoglobin 86 g/L, platelets 826 10/L, and white blood cell count (WBC) 1.56 10/L (neutrophils 1.346 10/L, lymphocytes 0.146 10/L). The lactate dehydrogenase (LDH) level was 347 IU/L (200–400) and serum albumin was 35.9 g/L (40.2–47.6). The prothrombin rate (PR) was 92%; activated partial prothrombin time (APTT) was 32/32; and fibrinogen was 3.8 g/L. The patient did not take any antithrombotic therapy. Enhanced computed tomography scanning showed enlargement of the deep lymph nodes of both the thoracic and abdominal compartments, which contrasted with the absence of peripheral lymphadenopathy. No splenomegaly was detected, whereas moderate hepatomegaly was found to be due to a benign angiolipoma confirmed by magnetic resonance imaging. Treatment with rituximab 375 mg/m (day 1), cyclophosphamide 250 mg/m (days 1–3), and fludarabine 40 mg/m (days 1–3) (R-FC) was started. The first cycle of R-FC was complicated by a neutropeniarelated fever, with a favorable outcome using broad-spectrum antibiotics. There was no evidence for tumor lysis syndrome after the first cycle, or for immunoglobulin M (IgM) flare phenomenon, as the M-protein was 11 g/L just before the second cycle. Early during the second course of rituximab, the patient developed hypotension, symptoms of tissue hypoperfusion, and tachycardia. His temperature remained normal and he did not show any symptom of allergy. The arterial oxygen saturation was normal. Then he developed acute gastrointestinal bleeding, characterized by nausea, hematemesis, and profuse diarrhea with rectorrhagia. After the discontinuation of rituximab, aggressive fluid resuscitation and red blood cell transfusion improved the hemodynamic parameters. Blood tests at the onset of symptoms showed: hemoglobin 118 g/L, WBC 3.86 10/L, and platelets 1446 10/L. Two hours later, hemoglobin was 114 g/L despite two red blood cell unit transfusions, and the platelet count dropped to 486 10/L. PR was 50%, APTT was 63 s, and fibrinogen was 0.9 g/L. After 4 h, the platelet count was 466 10/L, PR was 39%, APTT was 58 s, fibrinogen was 0.5 g/L, and D-dimers were 110 400 ng/L, which confirmed the diagnosis of disseminated intravascular coagulopathy (DIC). An infectious process was ruled out by the negativity of blood and urine cultures and by the normality of a chest X-ray. Moreover, the C-reactive protein (CRP) level