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Keywords: antibody response; COVID; SARS-CoV-2; vaccination; Waldenström EN antibody response COVID SARS-CoV-2 vaccination Waldenström 424 427 4 05/10/22 20220515 NES 220515 Patients with haematological malignancies have shown an increased risk of morbidity and mortality with regard to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.1,2 Immunocompromised patients have been excluded from initial trials evaluating SARS-CoV-2 mRNA vaccines3-5 and there is a crucial need to assess vaccine efficacy among these patients. Underlying disease and B-cell-directed therapies might adversely affect the production of antibodies in response to SARS-CoV-2 vaccination in Waldenström macroglobulinaemia (WM) patients. TN patients had the highest response rate (94.7%, I n i = 36/38) compared to previously treated patients (66.7%, I n i = 64/96; I p i = 0.003), most of whom received chemoimmunotherapy (CIT) (Table 1), and to patients on therapy (38.2%, I n i = 13/34; I p i < 0.001) (Figure 1A). Response rates were markedly different according to the time interval between last therapy and vaccination, as they were respectively 13.8% ( I n i = 4/29) and 89.6% (60/67) ( I p i < 0.001) for WM patients off therapy with a <1-year and >1-year time interval. [Extracted from the article]

n patients with advanced Waldenström macroglobulinemia (WM), overall response rate (ORR) and median progression-free survival (PFS) achieved with bortezomib alone and bortezomib rituximab combination were 27–85% and 7.9 months, and 81% and 16.4 months, respectively. We checked the role of dexamethasone in combination with bortezomib by enrolling in a phase II trial 34 patients with relapsed/refractory WM. Bortezomib (1.3 mg/m2 IV D1, 4, 8, and 11 every 21 days) was used for six cycles. In non-responding patients, dexamethasone (20 mg daily for two days) was added to each infusion after the second cycle. After two cycles, the Bayes estimated ORR was 43.2 (95% Credible Interval: 28.0–59.1%) using the informative prior. Two-year survival rate was 84.0% and the median PFS 15.3 months without difference between patients treated with or without dexamethasone. We conclude that dexamethasone must be associated to bortezomib-based regimen. [ABSTRACT FROM AUTHOR]

Waldenström macroglobulinemia (WM) is a distinct B-cell lymphoproliferative disorder for which clearly defined criteria for the diagnosis, initiation of therapy, and treatment strategy have been proposed as part of the consensus panels of the International Workshop on Waldenström's Macroglobulinemia (IWWM). At IWWM-8, a task force for treatment recommendations was impanelled to review recently published and ongoing clinical trial data as well as the impact of new mutations (MYD88 and CXCR4) on treatment decisions, indications for B-cell receptor and proteasome inhibitors, and future clinical trial initiatives for WM patients. The panel concluded that therapeutic strategies in WM should be based on individual patient and disease characteristics. Chemoimmunotherapy combinations with rituximab and cyclophosphamide-dexamethasone, bendamustine, or bortezomib-dexamethasone provide durable responses and are still indicated in most patients. Approval of the BTK inhibitor ibrutinib in the United States and Europe represents a novel and effective treatment option for both treatment-naive and relapsing patients. Other B-cell receptor inhibitors, second-generation proteasome inhibitors (eg, carfilzomib), and mammalian target of rapamycin inhibitors are promising and may increase future treatment options. Active enrollment in clinical trials whenever possible was endorsed by the panel for most patients with WM. [ABSTRACT FROM AUTHOR]

We retrospectively investigated the feasibility and the toxicity of autologous stem cell transpantation (ASCT) in 21 cases of systemic amyloidosis (AL). The conditioning regimens consisted of high-dose melphalan (HDM) alone (n = 18) or in combination with 12 Gy total body irradiation (n = 3). Toxic death rate was high: 9/21 patients (43%) died within the first month following ASCT, and 10/12 surviving patients achieved a response. With a median follow-up of 14 months, the OS and the EFS rates at 4 years were 57.1% (±10.8) and 29.9% (±14.5) respectively for the whole group. The major prognostic factor for both response and survival was the number of clinical manifestations at the time of ASCT, of the following five criteria, i.e. creatinine clearance <30 ml/min, nephrotic syndrome with urinary protein excretion > 3000 mg/24 h, congestive heart failure, neuropathy, or hepatomegaly associated with alkaline phosphatase level > 200 IU/l. For patients presenting with two or more clinical manifestations the 4-year OS and EFS were both 11.1% compared with 91.7% and 46.3% respectively in patients with fewer than two clinical manifestations at the time of ACST. We conclude that ASCT is feasible in AL in a subset of patients with fewer than two clinical manifestations at the time of ASCT. Given the severe extra-haematological toxicity, ASCT should not be considered in other cases. [ABSTRACT FROM AUTHOR]

Summary: The potential prognostic influence of genetic aberrations on chronic lymphocytic leukaemia (CLL) can vary based on various factors, such as the immunoglobulin heavy variable (IGHV) status. We conducted an integrative analysis on genetic abnormalities identified through cytogenetics and targeted next‐generation sequencing in 536 CLL patients receiving first‐line chemo(immuno)therapies (CIT) as part of two prospective trials. We evaluated the prognostic implications of the main abnormalities, with specific attention to their relative impact according to IGHV status. In the entire cohort, unmutated (UM)‐IGHV, complex karyotype, del(11q) and ATM mutations correlated significantly with shorter progression‐free survival (PFS). Focusing on the subset of mutated IGHV (M‐IGHV) patients, univariate analysis showed that complex karyotype, del(11q), SF3B1 and SAMHD1 mutations were associated with significant lower PFS. The prognostic influence varied based on the patient's IGHV status, as these abnormalities did not affect outcomes in the UM‐IGHV subgroup. TP53 mutations had no significant impact on outcomes in the M‐IGHV subgroup. Our findings highlight the diverse prognostic influence of genetic aberrations depending on the IGHV status in symptomatic CLL patients receiving first‐line CIT. The prognosis of gene mutations and cytogenetic abnormalities needs to be investigated with a compartmentalized methodology, taking into account the IGVH status of patients receiving first‐line BTK and/or BCL2 inhibitors. [ABSTRACT FROM AUTHOR]

Summary: The bendamustine–rituximab (BR) schedule is an efficient first‐line therapy in Waldenström macroglobulinaemia (WM). A previous analysis of 69 patients who received this treatment confirmed a high response rate and good progression‐free (PFS) and overall survival (OS). With a median follow‐up of 76.1 months (95% confidence interval [CI] 69.9–80.6), 5‐year outcome is still excellent at 66.63% (95% CI 56.09–79.17) for PFS and 80.01% (95% CI 70.82–90.41) for OS. The rate of secondary cancers is 17.66% (IQR 7.99–27.64) at 66 months. Relapsed patients who received ibrutinib as second‐line clearly benefited from this schedule. This confirms current recommendations suggesting BR long‐term efficacy as first‐line option in WM. [ABSTRACT FROM AUTHOR]

Summary: Waldenström macroglobulinaemia (WM) is a rare, indolent B‐cell lymphoproliferative disorder characterized by cellular involvement in bone marrow and monoclonal IgM production. Symptoms can be related to cytopenias, tumoural involvement, or IgM‐related disorders. Somatic mutations in the MYD88 gene have been described in the majority of WM cases. The mutation is responsible for a gain‐of‐function and induces activation of nuclear factor‐κB, for DNA transcription and cell survival. It seems that MYD88 mutation is associated with better prognosis and better response to some treatment. Treatments are started when WM is symptomatic, following systematic biological and morphological assessments. Therapeutic choice depends on age, frailty and urgent efficacy need. In first line, the majority of patients are treated with monoclonal anti‐CD20 antibody‐based regimens combined with cytotoxic chemotherapy. Rituximab, cyclophosphamide and dexamethasone remain the most commonly used regimen with good safety. Nevertheless, increasing numbers of new drugs are becoming available or are in development. Proteasome inhibitors, such as bortezomib or carfilzmib, showed good and rapid responses. Bruton tyrosine kinase (BTK) inhibitor demonstrated excellent results and is now available for relapse/refractory disease or as first line for some patients. This review highlights the diagnostic procedures and therapeutic approaches in WM. [ABSTRACT FROM AUTHOR]

Background and Aim: Neurolymphomatosis is defined as an infiltration of the peripheral nervous system (PNS) by malignant lymphoma cells. It is a rare entity and diagnosis is complicated especially when PNS involvement is the initial and leading symptom. To improve knowledge of the disorder and shorten the time to diagnosis, we report a series of nine patients without a history of hematologic malignancy, who were diagnosed with neurolymphomatosis after evaluation and workup of peripheral neuropathy. Methods: The patients were included from the Department of Clinical Neurophysiology at Pitié Salpêtrière and Nancy Hospitals over a period of 15 years. Diagnosis of neurolymphomatosis was confirmed by histopathologic examination for each patient. We characterized their clinical, electrophysiological, biological, imaging, and histopathologic features. Results: The neuropathy was characterized by pain (78%), proximal involvement (44%) or of all four limbs (67%), asymmetrical or with multifocal distribution (78%), abundant fibrillation (78%), a tendency to worsen rapidly, and significant associated weight loss (67%). Neurolymphomatosis was diagnosed principally on nerve biopsy (89%) identifying infiltration of lymphoid cells, atypical cells (78%), a monoclonal population (78%), and supported by fluorodeoxyglucose‐positron emission tomography, spine or plexus MRI, cerebrospinal fluid analysis, and blood lymphocyte immunophenotyping. Six patients had systemic disease and three impairment limited to the PNS. In the latter case, progression could be unpredictable and may be diffuse and explosive, sometimes occurring years after a seemingly indolent course. Interpretation: This study provides better knowledge and understanding of neurolymphomatosis when neuropathy is the initial presentation. [ABSTRACT FROM AUTHOR]

• Cerebral invasive aspergillosis affecting large caliber vessels in immunocompromised patients is discussed. • Diagnosis of invasive aspergillosis may be very challenging. • Cerebral invasive aspergillosis may have atypical clinical presentation. • Antifungal therapy is the mainstay of medical management. • With proper follow-up, the prognosis of these patients would improve. Invasive aspergillosis is a threat for immunocompromised patients. We present a case series of aggressive cerebral vasculitis caused by Aspergillus spp. infection in immunocompromised patients. We present a retrospective case series of three autopsy-proven invasive cerebral aspergillosis with diffuse vasculitis affecting large caliber cerebral vessels. Three patients were immunosuppressed: one on rituximab, one on corticosteroids, and one with a renal transplant. Two of these patients were diagnosed with cerebral aspergillosis on postmortem. Aspergillus cerebral vasculitis is a rare form of invasive aspergillosis that should be considered in an immunocompromised individual with suggestive lesions on imaging. It should be suspected as a possible cause of aseptic neutrophil meningitis. [ABSTRACT FROM AUTHOR]

Summary: Monoclonal immunoglobulin M (IgM) anti‐myelin‐associated glycoprotein (MAG) neuropathy is a rare disabling condition, most commonly treated with rituximab monotherapy (R), which leads to neurological improvement in only 30%–50% of patients. The combination of rituximab plus chemotherapy has been proven to improve the level of responses. We studied the outcomes of anti‐MAG neuropathy patients treated either by R, or by immunochemotherapy (ICT) in our centre, focusing on the incidence of the first neurological response evaluated by the modified Rankin scale (mRS). From 2011 to 2018, 64 patients were studied: 34 were treated with R and 30 with ICT. According to our treatment decision‐making process, the median mRS was higher in the ICT group (mRS 2) than in the R group (mRS 1). At one year, improvements of the mRS rates were 46% and 18% in the ICT and R groups of patients respectively, with median times to response of eight and 13 months (p = 0.023). Adverse effects were higher in the ICT group: 62% vs 15% (p ˂ 0.01), all grades included. One secondary acute leukaemia occurred five years after treatment with ICT. In conclusion, ICT may be used as a valid option for patients with rapidly progressive and/or severe anti‐MAG neuropathy symptoms. [ABSTRACT FROM AUTHOR]

Objectives: Patients with primary systemic (AL) amyloidosis or multiple myeloma are frequently treated with cyclic dexamethasone (DXM) courses and often require oral anticoagulants. We previously reported a strong potentiation of oral anticoagulants with intravenous methylprednisolone and observed a similar potentiation with DXM in 3 patients, which led us to prospectively investigate the interaction between DXM and oral anticoagulants.Methods: Nine patients with multiple myeloma (n=6) or AL amyloidosis (n=3), including 6 prospective patients, taking fluindione (n=8) or warfarin (n=1), were studied for a total of 10 cycles. DXM (40 mg/day for 4 days every 28 days) was administered alone (n=4) or with melphalan (n=5). One patient was studied for 2 consecutive cycles after a moderate increase in the international normalized ratio (INR) during the first course of DXM. International normalized ratio (INR) was measured serially during DXM administration. Plasma oral anticoagulant concentrations were measured for 5 cycles.Results: The mean INR increased from 2.75 (range: 1.80-3.6) at baseline to 5.22 (3.09-7.07) after DXM. Oral anticoagulants were transiently stopped during 8 cycles and 1 mg oral vitamin K was given during 2. No serious bleeding was observed. Plasma oral anticoagulant concentrations increased after DXM administration. In controls receiving DXM without oral anticoagulants, DXM alone did not increase prothrombin time.Conclusion: High dose DXM can potentiate oral anticoagulants and elevate INR substantially. INR should therefore be monitored repeatedly during concomitant administration of these 2 drugs to allow individual adaptation of oral anticoagulant doses. [ABSTRACT FROM AUTHOR]

Candidatus Mycoplasma haemohominis (cMh) is the most human-adapted and lethal hemoplasma. Bats are the common reservoir worldwide. cMh should be suspected in PUO associated with splenomegaly, and hemolytic anaemia or hemophagocytic lymphohistiocytosis, above all in Asia Pacific travellers. Doxycycline can be started preemptively as diagnosis can be retrospectively confirmed. [ABSTRACT FROM AUTHOR]

The diagnostic contribution of 2-D shear-wave elastography (SWE) in management of superficial lymph nodes (LNs) of any origin was evaluated in 222 patients referred for needle core biopsy. Each patient underwent conventional B-mode/Doppler ultrasound examinations (conventional ultrasound) and SWE. Quantitative SWE parameters and qualitative SWE map features were extracted. Carcinomas were found to be significantly stiffer than benign LNs (29.5 ± 32.3 kPa vs. 6.7 ± 12.3 kPa). Lymphomas exhibited intermediate stiffness (11.4 ± 5.2 kPa). Qualitative SWE analysis provided color patterns specific to histopathology (stiff rim, nodular and undetermined patterns related to malignancy and blue pattern to benignity). Adding SWE to conventional ultrasound improved the sensitivity of LN diagnosis (from 81.1% to 92.0%) but decreased its specificity (from 73.2% to 67.6%) because of the high prevalence of lymphomas compared with carcinomas. Inter-observer agreement for quantitative SWE was good (intra-class correlation coefficient = 0.82) as was inter-observer diagnostic agreement for qualitative SWE (κ = 0.65). LN location and histology type were found to influence the reported diagnostic performance of SWE. [ABSTRACT FROM AUTHOR]

Objectives: Progressive multifocal leukoencephalopathy (PML) is a very rare and opportunistic encephalitis caused by JC polyomavirus that is linked to profound immunosuppression and is usually fatal unless immune function can be restored. Immune checkpoint inhibitors (ICI) are monoclonal antibodies (mAbs) that block either CTLA-4 or PD-1 inhibitor receptors, thus enhancing antiviral T-cell activity. Successful treatment of PML by ICI has recently generated some enthusiasm in case reports/small series of patients. However, the initial enthusiasm was mitigated by some individual case reports that did not show any benefit. More data are thus warranted about efficacy of immune checkpoint inhibitors in the specific context of PML. Methods and results: We report here the outcomes of six PML patients treated by ICI between 2017 and 2019. Underlying causes of immunosuppression consisted in hematologic malignancies (n = 4), primary immune deficiency (n = 1) and use of immunosuppressive therapies for myasthenia gravis (n = 1). Three patients were alive with a mean follow-up of 21 months (14–33) after first ICI infusion, including one patient with frank clinical response, one with stabilization, and one with initial worsening and further stabilization of PML. The three other patients rapidly died from PML. Conclusions: Our data suggest that ICI may be effective for PML treatment but were less impressive than the ones previously reported. Larger studies are thus warranted to confirm this efficacy and to identify the predictive factors of response. [ABSTRACT FROM AUTHOR]

Summary: The manageable toxicity profile of obinutuzumab (GA101; G) alone or with chemotherapy in first‐line (1L; fit and non‐fit) and relapsed/refractory (R/R) patients with chronic lymphocytic leukaemia (CLL) was established in the primary analysis of the Phase IIIb GREEN trial (Clinicaltrials.gov: NCT01905943). The final analysis (cut‐off, 31 January 2019) is reported here. Patients received G (1000 mg) alone (G‐mono; fit and non‐fit patients) or with chemotherapy [fludarabine and cyclophosphamide (FC; fit patients); chlorambucil (non‐fit patients); bendamustine (any patient)]. Study endpoints were safety (primary) and efficacy (secondary). Subgroup analyses were performed on prognostic biomarkers in 1L CLL. Overall, 630 patients received 1L and 341 received R/R CLL treatment. At the final analysis, no new safety signals were observed [Grade ≥ 3 adverse events (AEs): 1L 82·7%, R/R 84·5%; serious AEs: 1L 58·1%, R/R 62·5%]. Neutropenia (1L 50·5%, R/R 53·4%) and thrombocytopenia (1L 14·6%, R/R 19·1%) were the most common Grade 3–5 AEs. G‐mono‐, G‐bendamustine and G‐FC‐treated patients with unmutated immunoglobulin heavy chain trended towards shorter progression‐free survival. Achievement of minimal residual disease negativity was greatest in 1L patients treated with G‐FC. In this final analysis of the GREEN trial, the safety profile of G was consistent with current risk management strategies. Biomarker analyses supported efficacy in the specific subgroups. [ABSTRACT FROM AUTHOR]

The article focuses on study that evaluated the efficacy and safety of bendamustine plus rituximab (BR) in symptomatic untreated patients with Waldenstr€om macroglobulinaemia (WM). It mentions the results like a patient developed myelodysplastic syndrome after BR initiation and other developed breast cancer.

Magnetic resonance imaging (MRI) of the brain showed right occipital white-matter lesions that were hyperintense on fluid-attenuated inversion recovery (FLAIR) and hypointense on T1-weighted sequencing, and not enhanced with gadolinium (Fig A). Panel A and B represent MRI FLAIR sequencing (left) and T1-weighted sequencing with gadolinium (right), respectively four weeks before nivolumab therapy (A) and 12 weeks after (B). Thirty months after allo-SCT and 22 months after nivolumab treatment, the patient is still alive, AML is still in complete remission and PML is controlled without any further therapeutic intervention. [Extracted from the article]

We aimed to analyse the response to rituximab in a cohort of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) patients with associated disorders. We conducted a clinical and electrophysiological retrospective monocentric study in 28 CIDP patients. Response to rituximab was defined as (a) a five‐point increase in the Medical Research Council sum score or a one‐point decrease in the Overall Neuropathy Limitations Scale score, compared to the score at the first rituximab infusion, or (b) the discontinuation of, or reduced need for, the last treatments before rituximab initiation. Twenty‐one patients (75%) were responders to rituximab. The median time before response was 6 months (1‐10 months). Only two patients needed to be treated again during a median follow‐up of 2.0 years (0.75‐9 years). Interestingly, the response rate was good in patients with associated autoimmune disease (5/8) and similar to the response rate observed in patients with a haematological disease (16/20) (P = 0.63). A shorter disease duration was associated with a better clinical response to rituximab (odds ratio 0.81, P = 0.025) and the response rate was better (P = 0.05) in common forms (83.3%) than in sensory forms (42.9%). No major adverse events were recorded. Rituximab is efficacious in CIDP patients with haematological or autoimmune disease. It improves clinical response and decreases dependence on first‐line treatments. [ABSTRACT FROM AUTHOR]

Highlights • UCBT is feasible in heavily pretreated patients with HL. • Outcomes are poor for patients not in CR at the time of UCBT. • Cyclophosphamide + fludarabine + 2 Gy total body irradiation conditioning regimen is associated with decreased risk of NRM and better OS. Abstract Allogeneic stem cell transplantation is an alternative for patients with relapsed or refractory Hodgkin lymphoma (HL), but only limited data on unrelated umbilical cord blood transplantation (UCBT) are available. We analyzed 131 adults with HL who underwent UCBT in European Society for Blood and Marrow Transplantation centers from 2003 to 2015. Disease status at UCBT was complete remission (CR) in 59 patients (47%), and almost all patients had received a previous autologous stem cell transplantation. The 4-year progression-free survival (PFS) and overall survival (OS) were 26% (95% confidence interval [CI], 19% to 34%) and 46% (95% CI, 37% to 55%), respectively. Relapse incidence was 44% (95% CI, 36% to 54%), and nonrelapse mortality (NRM) was 31% (95% CI, 23% to 40%) at 4 years. In multivariate analysis refractory/relapsed disease status at UCBT was associated with increased relapse incidence (hazard ratio [HR], 3.14 [95% CI, 1.41 to 7.00], P =.005) and NRM (HR, 3.61 [95% CI, 1.58 to 8.27], P =.002) and lower PFS (HR, 3.45 [95% CI, 1.95 to 6.10], P <.001) and OS (HR, 3.10 [95% CI, 1.60 to 5.99], P =.001). Conditioning regimen with cyclophosphamide + fludarabine + 2 Gy total body irradiation (Cy+Flu+2GyTBI) was associated with decreased risk of NRM (HR,.26 [95% CI,.10 to.64], P =.004). Moreover, Cy+Flu+2GyTBI conditioning regimen was associated with a better OS (HR,.25 [95% CI,.12 to.50], P <.001) and PFS (HR,.51 [95% CI,.27 to.96], P =.04). UCBT is feasible in heavily pretreated patients with HL. The reduced-intensity conditioning regimen with Cy+Flu+2GyTBI is associated with a better OS and NRM. However, outcomes are poor in patients not in CR at UCBT. [ABSTRACT FROM AUTHOR]

Waldenström Macroglobulinemia (WM) is a low-grade B-cell lymphoma characterized by disease progression from IgM MGUS to asymptomatic and then symptomatic disease states. We profiled exosomes from the peripheral blood of patients with WM at different stages (30 smoldering/asymptomatic WM, 44 symptomatic WM samples and 10 healthy controls) to define their role as potential biomarkers of disease progression. In this study, we showed that circulating exosomes and their miRNA content represent unique markers of the tumor and its microenvironment. We observed similar levels of miRNAs in exosomes from patients with asymptomatic (smoldering) and symptomatic WM, suggesting that environmental and clonal changes occur in patients at early stages of disease progression before symptoms occur. Moreover, we identified a small group of miRNAs whose expression correlated directly or inversely with the disease status of patients, notably the known tumor suppressor miRNAs let-7d and the oncogene miR-21 as well as miR-192 and miR-320b. The study of these miRNAs’ specific effect in WM cells could help us gain further insights on the mechanisms underlying WM pathogenesis and reveal their potential as novel therapeutic targets for this disease. [ABSTRACT FROM AUTHOR]

Telomere length in chronic lymphocytic leukemia (CLL) is described as an independent prognostic factor based largely on previously untreated patients from chemotherapy based trials. Here, we studied telomere length associations in high-risk, relapsed/refractory CLL treated with alemtuzumab in the CLL2O study (n = 110) of German and French CLL study groups. Telomere length (median 3.28 kb, range 2.52-7.24 kb) was relatively short, since 84.4% of patients had 17p- which is generally associated with short telomeres. Median telomere length was used for dichotomization into short and long telomere subgroups. Telomere length was associated with s-TK (p = .025) and TP53 mutations (p = .050) in untreated patients, while no association with clinical/biological characteristics was observed in relapsed/refractory CLL. Short telomeres had significant association with shorter PFS (p = .018) only in refractory CLL. Presence of short telomeres, loss of genes maintaining genomic integrity (SMC5) and increased incidence of chromothripsis, indicated the prevalence of genomic instability in this high-risk cohort (clinicaltrials.gov: NCT01392079). [ABSTRACT FROM AUTHOR]

The article presents two case studies of a 59-year-old white male ex-smoker and 76-year-old white male ex-smoker both suffering from shortness of breathe and lung disease. It is mentioned that both were diagnosed with chronic lymphocytic leukemia (CLL). The article further adds that both developed pneumocystis jirovecii pneumonia and immune deficiency due to the lack of the treatment for CLL.

Objectives This study investigates whether achieving complete remission ( CR) with undetectable minimal residual disease ( MRD) after allogeneic stem cell transplantation (allo- SCT) for chronic lymphocytic leukemia ( CLL) affects outcome. Methods We retrospectively studied 46 patients transplanted for CLL and evaluated for post-transplant MRD by flow cytometry. Results At transplant time, 43% of the patients were in CR, including one with undetectable MRD, 46% were in partial response, and 11% had refractory disease. After transplant, 61% of the patients achieved CR with undetectable MRD status. By multivariate analysis, reaching CR with undetectable MRD 12 months after transplant was the only factor associated with better progression-free survival ( P = 0.02) and attaining undetectable MRD, independently of the time of negativity, was the only factor that correlated with better overall survival ( P = 0.04). Conclusion Thus, achieving undetectable MRD status after allo- SCT for CLL is a major goal to improve post-transplant outcome. [ABSTRACT FROM AUTHOR]

Paraproteinaemic neuropathies are a heterogeneous group of disorders most frequently associated with IgM monoclonal gammopathies including Waldenström macroglobulinaemia ( WM). Their consequences are significant for affected patients, and their management challenging for their physicians. The variability in clinical presentation and time course hamper classification and management. The indications for invasive investigations such as cerebrospinal fluid analysis, nerve conduction tests and sensory nerve biopsies are unclear, and the optimum way to measure clinical response to treatment unknown. When to intervene and and how to treat, also present challenges to physicians. As part of its latest deliberations at the International Workshops on WM ( IWWM) in London, UK (August 2014), the IWWM8 panel have proposed a consensus approach to the diagnosis and management of peripheral neuropathies associated with IgM monoclonal gammopathies, including WM. Importantly, a consensus regarding the use of clinical outcome measures and recommended models of care for this group of patients is discussed, as well as appropriate treatment interventions. [ABSTRACT FROM AUTHOR]

Although TP53, NOTCH1, and SF3B1 mutations may impair prognosis of patients with chronic lymphocytic leukemia (CLL) receiving frontline therapy, the impact of these mutations or any other, alone or in combination, remains unclear at relapse. The genome of 114 relapsed/refractory patients included in prospective trials was screened using targeted next-generation sequencing of the TP53, SF3B1, ATM, NOTCH1, XPO1, SAMHD1, MED12, BIRC3, and MYD88 genes. We performed clustering according to both number and combinations of recurrentgene mutations. The number of genes affected by mutation was ≥2, 1, and 0 in 43 (38%), 49 (43%), and 22 (19%) respectively. Recurrent combinations of ≥2 mutations of TP53, SF3B1, and ATM were found in 22 (19%) patients. This multiple-hit profile was associated with a median progression-free survival of 12 months compared with 22.5 months in the remaining patients (P 5 .003). Concurrent gene mutations are frequent in patients with relapsed/refractory CLL and are associated with worse outcome. [ABSTRACT FROM AUTHOR]

Ultra high-risk chronic lymphocytic leukemia (CLL) and Richter's syndrome (RS) usually display a poor prognosis. Platinum and cytarabine-based regimens have not been evaluated in large cohorts of patients with CLL or RS. This retrospective study was aimed to assess the efficacy of these regimens in 75 patients with relapsed/refractory (R/R) CLL or RS. Forty-seven patients had R/R CLL (including 36 ultra high-risk CLL) and 28 had RS. Median age was 62 years (range, 18-79 years). Median number of previous therapies was 3 (range, 1-7), including fludarabine-based regimens (75%) and alemtuzumab (32%), and 61% of patients were refractory to their last treatment. Deletions of chromosomes 17p and 11q were found in 40% and 39% of cases, respectively. The overall response rates were 60% with 24% complete response (CR) in CLL, and 43% with 25% CR in RS. The median progression-free survival and overall survival were 11 and 14.6 months, respectively. Fludarabine refractoriness and 17p deletion were not associated with a poorer outcome. The only factors predicting shorter survival were performance status ≥2 ( P = 0.04) and albumin level <3.5 g/dL ( P = 0.0004). Toxicities were mainly myelosuppression and infectious complications. Platinum and high-dose cytarabine-based regimens provide high response rates in high-risk CLL and in RS. However, these results will be challenged by the new arriving agents at least in non-transformed CLL. [ABSTRACT FROM AUTHOR]

Hairy cell leukaemia (HCL) is a rare haematological malignancy, with approximately 175 new incident cases in France. Diagnosis is based on a careful examination of the blood smear and immunophenotyping of the tumour cells, with a panel of four markers being used specifically to screen for hairy cells (CD11c, CD25, CD103 and CD123). In 2011, the V600E mutation of the BRAF gene in exon 15 was identified in HCL; being present in HCL, it is absent in the variant form of HCL (HCL-v) and in splenic red pulp lymphoma (SRPL), two entities related to HCL. The management of patients with HCL has changed in recent years. A poorer response to purine nucleoside analogues (PNAs) is observed in patients with more marked leukocytosis, bulky splenomegaly, an unmutated immunoglobulin variable heavy chain ( IgVH) gene profile, use of VH4-34 or with TP53 mutations. We present the recommendations of a group of 11 experts belonging to a number of French hospitals. This group met in November 2013 to examine the criteria for managing patients with HCL. The ideas and proposals of the group are based on a critical analysis of the recommendations already published in the literature and on an analysis of the practices of clinical haematology departments with experience in managing these patients. The first-line treatment uses purine analogues: cladribine or pentostatin. The role of BRAF inhibitors, whether or not combined with MEK inhibitors, is discussed. The panel of French experts proposed recommendations to manage patients with HCL, which can be used in a daily practice. [ABSTRACT FROM AUTHOR]

A large, multicentre, retrospective survey of patients with hairy cell leukaemia ( HCL) was conducted in France to determine the frequency of second malignancies and to analyse the long-term effects of the established purine nucleoside analogues ( PNAs), cladribine and pentostatin. The survey retrospectively reviewed the medical history of patients and their immediate family, clinical and biological presentation at the time of HCL diagnosis, treatment choice, response to treatment, time to relapse and cause of death. Data were collected for 487 patients with HCL. Of the patients included in the survey, 18% (88/487) had a familial history of cancers, 8% (41/487) presented with malignancies before HCL diagnosis and 10% (48/487) developed second malignancies after HCL was diagnosed. An excess incidence of second malignancies was observed, with a standardized incidence ratio ( SIR) of 1·86 (95% confidence interval ( CI): 1·34-2·51), with no significant difference between PNAs. For second haematological malignancies alone, the SIR was markedly increased at 5·32 (95% CI: 2·90-8·92). This study highlights the high frequency of cancers in HCL patients and their family members. The frequency of second malignancies is notably increased, particularly for haematological malignancies. The respective role of pentostatin and cladribine in the development of second malignancies is debatable. [ABSTRACT FROM AUTHOR]

Background Norovirus infection is increasingly recognized as an important cause of persistent gastroenteritis in immunocompromised hosts and can be a potential cause of morbidity in these populations. Case presentation Here, we report a case of norovirus-related chronic diarrhea occurring in a 62-year-old immunocompromised patient treated with alemtuzumab for chronic lymphocytic leukemia. Despite different therapeutic strategies including tapering of immunosuppressive therapy and immunoglobulin administration, diarrhea unfortunately did not resolve and lasted for a total of more than twelve weeks with prolonged norovirus fecal excretion. Conclusions Norovirus infection can occur in the setting of alemtuzumab treatment, even as a single agent, and should be included in the differential diagnoses of acute and chronic diarrhea in these immunocompromised patients. Although the administration of oral immunoglobulin has been described as a promising efficient therapy, this was not the case in our patient. Clinical trials are thus clearly warranted to better define risk factors and efficient therapies for norovirus infection in immunocompromised populations. [ABSTRACT FROM AUTHOR]

Objective: Identification of drug-induced liver disease (DILI) is difficult, even among hospitalized patients. The aim of this pilot study was to assess the impact of a specific strategy for DILI screening. Design: We prospectively compared the number of acute DILI cases identified in one week of a proactive strategy based on centralized elevated ALT values to those identified with a standard of care strategy for 24-week period based on referral cases to the hepatology unit. In the centralized strategy, a designated study biochemist identified patients with ALT greater than 3 times the upper limit of normal values (ULN) and notified the designated hepatologists, who then went to the patients' wards, analyzed the charts, and if necessary, interviewed the identified patients. During these two periods, patients with possible DILI were included after signing an informed consent in an ongoing European diagnostic study (SAFE-T consortium). Results: During the 24-week period of the standard strategy, 12 (0.04%) patients out of a total of 28,145 were identified as having possible DILI, and 11 of these accepted to be included in the protocol. During the one-week proactive period, 7 patients out of a total of 1407 inpatients (0.498%) [odds ratio vs. standard = 12.1 (95% CI, 3.9-32.3); P<0.0001] were identified with possible DILI, and 5 were included in the protocol. Conclusion: A simple strategy based on the daily analysis of cases with ALT >3 ULN by designated biochemists and hepatologists identified 12 times more acute cases of drug-induced liver disease than the standard strategy. This pilot cohort is registered on the number AP-HP P110201/1/08-03-2011 and AFSSAPS B110346-70. [ABSTRACT FROM AUTHOR]

A French and Belgian multicenter phase 3 trial was conducted in medically fit patients with untreated chronic lymphocytic leukemia. Of 178 patients enrolled in the study, 165 were randomly assigned to receive 6 courses of oral fludarabine and cyclophosphamide (FC) in combination with rituximab (FCR; 375 mg/m2 in cycle one, 500 mg/m2 in all subsequent cycles) or alemtuzumab (FCCam; 30 mg subcuta-neously injected on cycle days 1-3); each cycle was 28 days. Recruitment was halted prematurely because of excess toxicity; 8 patients died in the FCCam group, 3 from lymphoma and 5 from infection. Overall response rates were 91% with FCR and 90% with FCCam (P = .79). Complete remission rates were 33.75% with FCR and 19.2% with FCCam (P = .04). Three-year progression-free survival was 82.6% with FCR and 72.5% with FCCam (P=.21). Three-year overall survival was similar between the 2 arms at 90.1% in the FCR arm and 86.4% in the FCCam arm (P = .27). These results indicate that the FCCam regimen for the treatment of advanced chronic lymphocytic leukemia was not more effective than the FCR regimen and was associated with an unfavorable safety profile, representing a significant limitation of its use. [ABSTRACT FROM AUTHOR]

Neuropathy in Waldenström's macroglobulinemia (WM) is very heterogeneous. We retrospectively studied 40 patients with WM and neuropathy to analyze the different presentations and mechanisms encountered and to propose a diagnostic strategy. Twenty-five patients (62.5%) had axonal neuropathy, related to the following mechanisms: amyloid neuropathy (n = 5), cryoglobulinemic neuropathy (n = 5), neuropathy associated with tumoral infiltration (n = 2), vasculitic neuropathy (n = 2), a clinical motor neuropathy possibly of dysimmune origin (n = 6), or an unclassified mechanism (n = 5). A demyelinating pattern was observed in 15 patients, 10 having anti-myelin-associated glycoprotein (anti-MAG) antibodies and 5 having neuropathy related to chronic inflammatory demyelinating polyradiculoneuropathy. On the basis of these results, we propose a diagnostic strategy combining: (1) an EMG to distinguish between a demyelinating and an axonal pattern; (2) measurement of anti-MAG and anti-ganglioside antibodies; (3) screening for 'red flag' features to orientate further investigations. This strategy may help clinicians to identify the mechanism of neuropathy in order to adapt the therapeutic strategy. [ABSTRACT FROM AUTHOR]

Follicular lymphomas (FLs) are frequent B-cell derived malignancies, generally demonstrating an indolent evolution. Although circulating FL cells may be detected by high-resolution analysis, bloodstream involvement by FL cells is unusual. We observed in 10 patients a leukemic phase of FL at the onset of the disease. Six of them had concomitant lymph node involvement and all of them required treatment at diagnosis due to a high tumor burden, whereas four patients had pure FL-cell leukemia, which was associated with a more indolent clinical outcome. The detection of a leukemic phase should therefore be studied as a potential prognosis marker in further studies. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Extramedullary chronic lymphocytic leukemia: systematic analysis of cases reported between 1975 and 2012" by M. Ratterman, and colleagues in the 2014 issue.

The occurrence of primary cutaneous anaplastic large cell lymphoma (PCALCL) in immunocompromised patients is rare. Only 11 cases have been reported to date, all of them in organ transplant recipients and none in patient with idiopathic CD4+ T-cell lymphocytopaenia. We describe here the original clinical pattern of deep, fascia and muscle-penetrating PCALCL of the lower limb in two immunocompromised patients, one in a renal transplant recipient, the other in a patient with idio-pathic CD4+ T-cell lymphocytopaenia. Both patients experienced a negative outcome, contrasting with the usually indolent course of PCALCL in immunocompetent patients, since both died of complications related to the lymphoma 30 and 13 months later, respectively. The unusual clinical aggressiveness of these two cases of PCALCL suggests that, in this peculiar subset with a deep structures involvement hallmark, a worse prognosis could be expected, especially in immunocompromised patients. This information should be taken into consideration when making therapeutic choices. [ABSTRACT FROM AUTHOR]

Recovery of human cytomegalovirus (HCMV)-specific T immunity is critical for protection against HCMV disease in the early phase after allogeneic stem cell transplantation (SCT). Using an enzyme-linked immunospot assay with overlapping 15-mer peptides spanning pp65 and immediate-early 1 HCMV proteins, we investigated which HCMV-specific CD8+ gamma interferon-positive (IFN-γ+) T-cell responses against pp65 and IE-1 were associated with control of HCMV replication in 48 recipients of unmanipulated HLA-matched allografts at 3 months (M3) and 6 months (M6) after SCT and in 23 donors. At M3 after SCT, the magnitude of the pp65-specific IFN-γ-producing CD8+ T-cell response was greater in recipients than in donors, regardless of HCMV status. In contrast, expansion of IE-1-specific CD8+ T cells at M3 was associated with protection against HCMV, and no patient with this expansion had HCMV replication at M3. At M6, the number of HCMV-specific CD8+ T cells against both pp65 and IE-1 had expanded in all recipients, regardless of their previous levels of HCMV replication. The recipients' HCMV-specific CD8+ T cells already detectable in related donors were predominantly targeting pp65. In contrast, in 40% of the cases, the HCMV-specific CD8+ T cells in recipients involved new CD8+ T-cell specificities undetectable in their related donors and preferentially targeting IE-1. Taken together, these results showed that the delay in reconstituting IE-1-specific CD8+ T cells is correlated with the lack of protection against HCMV in the first 3 months after SCT. They also show that IE-1 is a major antigenic determinant of the early restoration of protective immunity to HCMV after SCT. [ABSTRACT FROM AUTHOR]

Résumé: Objectifs: Les cures de dexaméthasone sont souvent utilisées pour traiter l''amylose AL et le myélome multiple, deux maladies qui obligent souvent à un traitement antivitamine K en raison de thromboses (parfois liées au thalidomide) ou d''une amylose cardiaque ou rénale. Nous avons observé une potentialisation nette des antivitamines K par la méthylprednisolone puis, chez trois malades, par la dexaméthasone. Nous avons donc réalisé une étude prospective des interactions entre dexaméthasone et antivitamines K. Méthodes: Nous avons étudié neuf malades, dont six de façon prospective, pendant dix cycles de dexaméthasone au total. Parmi eux, six avaient un myélome et trois une amylose AL; huit prenaient de la fluindione et un de la warfarine. Les cures de dexaméthasone (40 mg/j pendant quatre jours tous les 28 jours) ont été données seules (quatre malades) ou en association avec du melphalan (cinq malades). Chez un malade, deux cures consécutives ont été étudiées en raison d''une augmentation modérée du International normalized ratio (INR) pendant la première cure. L''INR a été mesurée de façon répétée pendant les cures. Les concentrations plasmatiques d''antivitamine K ont pu être obtenues pendant cinq cures. Résultats: L''INR moyen a augmenté de 2,75 (extrêmes, 1,80 et 3,6) initialement à 5,22 (3,09 et 7,07) après la cure. Le traitement antivitamine K a été interrompu pendant huit cycles et une prise orale de 1 mg de vitamine K a été administrée pendant deux cycles. Aucune complication hémorragique grave n''a été constatée. Les concentrations plasmatiques d''antivitamine K ont augmenté après l''administration de dexaméthasone. Chez des malades témoins traités par dexaméthasone sans antivitamines K, le temps de prothrombine ne s''est pas allongé pendant les cures. Conclusion: La dexaméthasone à posologie élevée peut potentialiser les antivitamines K, conduisant à une augmentation marquée de l''INR. Une surveillance étroite de l''INR est donc indispensable en cas d''administration concomitante de ces deux médicaments, de façon à permettre l''adaptation de la posologie d''antivitamine K. [Copyright &y& Elsevier]

Abstract: We report a case of myasthenia gravis associated with marked expansion of an unusual CD16+CD56−2B4+ NK subset. These atypical cells were characterized by poor cytotoxicity against CD48+ target cells and high proliferation due to 2B4/CD48 interaction. IL18, IFN-γ and TGF-β levels were profoundly different in this patient than in healthy donors. Immunosuppressive treatment induced disease remission and decreased the CD16+CD56−2B4+NK cells count. Our data suggest that expansion of this NK subset in myasthenia gravis patients may account for the deleterious NK cell functioning that occurs in this autoimmune disease. [Copyright &y& Elsevier]

Abstract: Burkitt-type acute leukemia cells were present in the bone marrow of a patient with B-prolymphocytic leukemia diagnosed from peripheral blood cell morphology. Immunophenotype analysis confirmed morphological patterns. Cytogenetic and fluorescence in situ hybridization (FISH) analysis showed an identical t(8;22)(q24;q21) with MYC locus rearrangement in blood and bone marrow cells, with additional chromosome abnormalities in the bone marrow. In addition, the loss of one copy of the TP53 gene and identical IGH DNA clonal rearrangements were shown with FISH and polymerase chain reaction analysis respectively in the two types of leukemic cells. These data indicated the common origin of the two coexisting leukemias and are the first example of such occurrence in a leukemic patient. [Copyright &y& Elsevier]

Human multidrug resistance protein 2 (MRP2, encoded by ABCC2) is involved in active efflux of anionic drugs such as methotrexate. MRP2 is expressed on the luminal side of hepatocytes and renal proximal tubular cells, indicating an important role in drug elimination. We postulated that loss-of-function mutations in ABCC2, which are involved in the Dubin-Johnson syndrome, may be associated with impaired methotrexate elimination and an increased risk of toxicity. We studied the biological phenotype and ABCC2 coding sequence in a patient receiving a high-dose methotrexate infusion for large B-cell lymphoma and who had an unusual pharmacokinetic profile, mainly characterized by a three-fold reduction in the methotrexate elimination rate. This resulted in severe methotrexate over-dosing and reversible nephrotoxicity. An inversion of the urinary coproporphyrin isomer I/III ratio (a specific biological marker of the Dubin-Johnson syndrome) was observed in this patient. Genetic analysis of ABCC2 identified a heterozygous mutation replacing a highly conserved arginine by glycine in the cytoplasmic part of the second membrane-spanning domain (position 412 of MRP2), a region associated with substrate affinity. This genetic variant was not found in a control population. Functional analysis in transiently transfected Chinese hamster ovary cells revealed a loss of transport activity of the G412 MRP2 mutant protein. An ABCC2 mutation altering MRP2-mediated methotrexate transport and resulting in impaired drug elimination and subsequent renal toxicity was identified. Candidates for methotrexate therapy should be considered for MRP2 functional testing. [ABSTRACT FROM AUTHOR]

Erythroleukemia is, within FAB classification, a proliferation of erythroblasts superior to 50% and of myeloblasts superior to 30%. The new WHO classification abolishes the frontier between RAEB-t with 20% and leukemia with 30% of blasts. AML6 variant is a new entity characterized by the proliferation of immature erythroblasts and the absence of non-erythroid blast cells. We analyzed 16 erythroleukemia, 5 RAEB-t and 2 AML6 variants to clarify their relationship.We suggest on survival, karyotype and cytologic characteristics that secondary erythroleukemia are the same entity as RAEB-t, confirming the WHO classification and that amongst de novo erythroleukemia, there is ‘AML6 variant’ with pure erythroid lineage proliferation. [Copyright &y& Elsevier]

The MTCP1 gene is involved in the t(X;14)(q28;q11) translocation associated with T-cell prolymphocytic leukemia and related conditions. This gene is unusual in that it codes for two distinct proteins: a small mitochondrial protein, p8MTCP1, and a putative oncogenic protein, p13MTCP1. Scarcity of material from t(X;14)-associated proliferations and very low levels of mRNA expression have so far prevented a thorough description of p13MTCP1-encoding transcripts. Here, we characterize two additional t(X;14) bearing leukemias allowing this analysis. In one case, with a breakpoint located 5′ to the MTCP1 gene, the level of transcription of previously described p13MTCP1-encoding transcripts is enhanced. In the second case, with a breakpoint within the MTCP1 intron I, an alternative transcription initiation site is demonstrated in the tumor cells at 229 bp upstream to exon II. The identification of this internal promoter, together with the similarity between TCL1 and MTCP1 genomic structures, allow us to propose a model in which the duplication of an ancestral gene was followed by the insertion of one copy within the intron of a p8-encoding gene, accounting for the unusual feature of the MTCP1 gene. [ABSTRACT FROM AUTHOR]

Th article presents a case study of an 84 year old male patient with Waldenstrom macroglobulinemia and Lewy body dementia who was admitted to a hospital for delirium complicated by a traumatic pelvic fracture. A discussion of diagnostic testing which was conducted on the patient, and resulted in him receiving a diagnosis of late onset Bing-Neel syndrome associated with delirium and Lewy body dementia, is presented.

Fusarium infection is known to cause major morbidity and mortality in immunocompromised hosts. We report the successful treatment of disseminated Fusarium infection with skin manifestations in a severely neutropenic, immunocom-promised host with voriconazole, a new second-generation triazole. Voriconazole might be an alternative therapy for patients with neutropenia who have fusariosis that is refractory or unresponsive to amphotericin B or its liposomal formulation. [ABSTRACT FROM AUTHOR]

Background: Norovirus infection is increasingly recognized as an important cause of persistent gastroenteritis in immunocompromised hosts and can be a potential cause of morbidity in these populations.Case Presentation: Here, we report a case of norovirus-related chronic diarrhea occurring in a 62-year-old immunocompromised patient treated with alemtuzumab for chronic lymphocytic leukemia. Despite different therapeutic strategies including tapering of immunosuppressive therapy and immunoglobulin administration, diarrhea unfortunately did not resolve and lasted for a total of more than twelve weeks with prolonged norovirus fecal excretion.Conclusions: Norovirus infection can occur in the setting of alemtuzumab treatment, even as a single agent, and should be included in the differential diagnoses of acute and chronic diarrhea in these immunocompromised patients. Although the administration of oral immunoglobulin has been described as a promising efficient therapy, this was not the case in our patient. Clinical trials are thus clearly warranted to better define risk factors and efficient therapies for norovirus infection in immunocompromised populations. [ABSTRACT FROM AUTHOR]