Immunogenicity of the 13-Valent Pneumococcal Conjugated Vaccine Followed by the 23-Valent Polysaccharide Vaccine in Chronic Lymphocytic Leukemia.

Patients with Chronic Lymphocytic Leukemia (CLL) have a 29- to 36-fold increased risk of invasive pneumococcal disease (IPD) compared to healthy adults. Therefore, most guidelines recommend vaccination with the 13-valent pneumococcal conjugated vaccine (PCV13) followed 2 months later by the 23-valent polysaccharide vaccine (PPSV23). Because both CLL as well as immunosuppressive treatment have been identified as major determinants of immunogenicity, we aimed to assess the vaccination schedule in untreated and treated CLL patients. We quantified pneumococcal IgG concentrations against five serotypes shared across both vaccines, and against four serotypes unique to PPSV23, before and eight weeks after vaccination. In this retrospective cohort study, we included 143 CLL patients, either treated (n = 38) or naive to treatment (n = 105). While antibody concentrations increased significantly after vaccination, the overall serologic response was low (10.5%), defined as a ≥4-fold antibody increase against ≥70% of the measured serotypes, and significantly influenced by treatment status and prior lymphocyte number. The serologic protection rate, defined as an antibody concentration of ≥1.3 µg/mL for ≥70% of serotypes, was 13% in untreated and 3% in treated CLL patients. Future research should focus on vaccine regimens with a higher immunogenic potential, such as multi-dose schedules with higher-valent T cell dependent conjugated vaccines.

Fixed-duration venetoclax plus obinutuzumab improves quality of life and geriatric impairments in FCR-unfit patients with CLL.

Chronic lymphocytic leukemia (CLL)-related symptoms and morbidity related to the advanced age at diagnosis impairs the well-being of older adult patients. Therefore, it is essential to tailor treatment according to geriatric characteristics and aim for an improvement in health-related quality of life (HRQoL) as a primary treatment goal. In the HOVON139/GiVe trial, 12 cycles of fixed-duration venetoclax plus obinutuzumab (Ven-O) were shown to be effective and tolerable in FCR (fludarabine, cyclophosphamide, rituximab)-unfit patients with CLL (n = 67). However, prolonged venetoclax exposure as consolidation treatment led to increased toxicity with limited effect on minimal residual disease. To assess the impact of geriatric assessment on treatment outcomes and the patients' HRQoL, patient-reported outcomes (PROs), including function, depression, cognition, nutrition, physical performance, muscle parameters, comorbidities, and the European Organization for Research and Treatment of Cancer C30 and CLL17 questionnaires were assessed. At baseline, geriatric impairments were present in >90% of patients and ≥2 impairments present in 60% of patients predicted grade ≥3 nonhematological toxicity. During treatment, the number of geriatric impairments diminished significantly and clinically relevant improvements in HRQoL subscales were reached for global health status, physical functioning, role functioning, emotional functioning, fatigue, dyspnea, physical condition or fatigue, and worries or fears related to health and functioning. These improvements were comparable for patients receiving venetoclax consolidation and patients in whom treatment could mostly be discontinued. Collectively, frontline fixed-duration Ven-O improves overall PROs in older, unfit patients with CLL with and without geriatric impairments. This study was registered at EudraCT as 2015-004985-27 and the Netherlands Trial Register as NTR6043.

Diagnosis, treatment and supportive management of chronic lymphocytic leukemia: recommendations of the Dutch HOVON CLL working group.

Management of patients with chronic lymphocytic leukemia (CLL) is changing due to considerable advances in the therapeutic armamentarium, and new therapies will possibly continue to emerge in the near future. Therefore, the CLL working group of the Dutch-Belgium Haemato-Oncology Cooperative Group for Adults in the Netherlands (HOVON) necessitated revising the Dutch CLL guidelines. The current guideline is based on the expert opinion of the HOVON CLL working group members and focusses on well-designed clinical trials taking into account efficacy with special emphasis on toxicity, treatment duration and treatment intensity. This article provides recommendations on diagnosis, treatment strategies in front-line and relapsed setting and provides supportive care measurements during novel-based therapies as well as for infectious CLL-related complications. The recommendations presented here are intended to provide guidance for the management of CLL patients in the Netherlands, and take into account the availability of treatment strategies at the time of this publication.

Venetoclax consolidation after fixed-duration venetoclax plus obinutuzumab for previously untreated chronic lymphocytic leukaemia (HOVON 139/GiVe): primary endpoint analysis of a multicentre, open-label, randomised, parallel-group, phase 2 trial.

BACKGROUND: Fixed-duration 12 cycles of venetoclax plus obinutuzumab is established as first-line treatment for patients with chronic lymphocytic leukaemia. We aimed to determine the activity and safety of 12 cycles of venetoclax consolidation after fixed-duration venetoclax plus obinutuzumab for previously untreated patients with chronic lymphocytic leukaemia who were unfit for fludarabine-based treatment, and whether this could be guided by minimal residual disease status. METHODS: We conducted an open-label, randomised, parallel-group, phase 2 trial (HOVON 139/GiVe) at 25 hospitals in the Netherlands. Eligible patients were aged 18 years or older with previously untreated chronic lymphocytic leukaemia, had an ECOG performance status of 0-2, and were unfit for fludarabine-based treatment. All patients received two debulking cycles of intravenous obinutuzumab (100 mg on day 1, 900 mg on day 2, and 1000 mg on days 8, 15, and day 1 of cycle two), followed by fixed-duration venetoclax plus obinutuzumab for 12 cycles (six cycles of intravenous obinutuzumab 1000 mg on day 1 and 12 during 28-day cycles of oral venetoclax, starting with a 5-week ramp-up and then 400 mg once daily until completion of cycle 12). Patients were then randomly assigned (1:1) by minimal residual disease status in peripheral blood, to receive either 12 cycles of venetoclax consolidation irrespective of minimal residual disease or venetoclax consolidation only if minimal residual disease was detected at randomisation. The primary endpoint was undetectable minimal residual disease in bone marrow and no progressive disease 3 months after end of consolidation treatment (or corresponding timepoint) by intention-to-treat. Safety was assessed in all patients who received at least one dose of any study drug. This is the primary endpoint analysis of this trial, which is ongoing and is registered with EudraCT (2015-004985-27). FINDINGS: Between Oct 28, 2016, and May 31, 2018, 70 patients were enrolled, of whom 67 (47 [70%] men and 20 [30%] women) received fixed-duration treatment and 62 were randomly assigned to receive 12 cycles of venetoclax consolidation (n=32) or minimal residual disease-guided venetoclax consolidation (n=30; one of whom was minimal residual disease positive at randomisation). Median follow-up was 35·2 months (IQR 31·5-41·3). 16 (50% [95% CI 32-68]) of 32 patients in the consolidation group and 16 (53% [34-72]) of 30 in the minimal residual disease-guided consolidation group met the primary endpoint of undetectable minimal residual disease in bone marrow and no progressive disease. 22 (69%) of 32 patients in the venetoclax consolidation group and 11 (37%) of 30 in the minimal residual disease-guided consolidation group had any adverse event (grade 2-4; mainly infections). The most common grade 3 or worse adverse events were infection (two [6%] of 32 patients in the consolidation group and one [3%] of 30 in the minimal residual disease-guided consolidation group) and neutropenia (two [6%] and two [7%]). There were no treatment-related deaths. INTERPRETATION: Consolidation with venetoclax 12-cycle treatment increases the duration of known side-effects and does not prevent the loss of minimal residual disease response and subsequent risk of disease relapse. FUNDING: F Hoffmann-La Roche.

Hb Nouakchott [α114(GH2)Pro→Leu; HBA1: c.344C>T], A Second and Third Case Described in Two Unrelated Dutch Families.

We report two families, members of which are carriers of a hemoglobin (Hb) variant previously described as Hb Nouakchott [α114(GH2)Pro→Leu; HBA1: c.344C>T; p.Pro115Leu]. In the first family of Dutch origin, the proband, a 32-year-old male and his 65-year-old father, were both carriers of Hb Nouakchott. Of the second family we tested, only the proband, a 56-year-old Dutch female was a Hb Nouakchott carrier. Hematological analyses of these cases showed the anomaly behaves as a silent Hb variant without clinical consequences. The Hb variant remained unnoticed using high performance liquid chromatography (HPLC), while an additional peak was detected by capillary electrophoresis (CE). These independent findings of Hb Nouakchott indicate that this Hb variant might not be very rare, but simply remains under diagnosed depending on the Hb separation technique used.

Clinical Practice Guidelines for Diagnosis and Treatment of Chronic Lymphocytic Leukemia (CLL) in The Netherlands.

INTRODUCTION: In recent years, considerable progress has been made in the treatment of patients with chronic lymphocytic leukemia (CLL), and new potent drugs have become available. Therefore, the CLL working party revised the Dutch guidelines. Not only efficacy but also quality of life and socio-economic impact were taken into account in the formulation of treatment recommendations. MATERIALS AND METHODS: The working party discussed a set of questions regarding diagnostic tests and treatment and wrote the draft guideline. This was evidence-based whenever possible, but in cases of low evidence, an expert-based recommendation was formulated with input of the entire working party. The draft guideline was sent to all hematologists in the Netherlands for comment and was subsequently approved. RESULTS: Recommendations were formulated on diagnostic tests and work-up before treatment. Also, recommendations were made for treatment with fludarabine-cyclophosphamide-rituximab, bendamustine-rituximab, chlorambucil with anti-CD20 antibody, ibrutinib, idelalisib-rituximab, venetoclax, and allogeneic stem cell transplantation. CONCLUSION: In the revised Dutch CLL guidelines, chemo-immunotherapy is still the cornerstone of CLL treatment with novel targeted drugs for specific risk groups.

NOD2/CARD15 variants are not a risk factor for clinical outcome after nonmyeloablative allogeneic stem cell transplantation.

Single nucleotide polymorphisms (SNPs) in the innate immunity receptor NOD2/CARD15 have been demonstrated to modulate the outcome of allogeneic hematopoietic stem cell transplantation (SCT). The effect of NOD2/CARD15 polymorphism is reported to be associated with type of donor (sibling or matched unrelated donor) as well as type of conditioning regimen. We reviewed NOD2/CARD15 SNPs in all donor/recipient pairs of 192 consecutive patients who received nonmyeloablative allogeneic SCT at our institution between 2002 and 2006. All patients were treated with fludarabine 30 mg/m(2)/day for 3 days followed by 200 cGy total-body irradiation (TBI) (n = 154) or TBI alone (n = 38) and received grafts from HLA-matched related (n = 132) or unrelated (n = 61) donors. NOD2/CARD15 polymorphisms were observed in 36 of 192 (19%) patients and in 35 of 192 (18%) donors. The incidences of acute and chronic graft-versus-host disease (aGVHD, cGVHD) were 39% and 49%, respectively, in patients with NOD2/CARD15 variants versus 51% and 61% in patients with wild type. The relapse rate at 3 years was 38% in patients with variants and 36% in patients with wild type. The incidence of transplant-related mortality was 22% for patients with variants and 21% for patients with wild type. Overall survival (OS) at 3 years was 56% in patients with variants and 64% in patients with wild-type NOD2/CARD15. There was no significant impact of NOD2/CARD15 mutations on clinical outcome (all P > .05, Kaplan-Meier and Fine and Gray's tests). These data indicate that mutations in the NOD2/CARD15 gene are not a risk factor for clinical outcome in nonmyeloablative allogeneic SCT. Therefore, screening for NOD2/CARD15 polymorphisms in patients or donors does not have additional value in patients undergoing nonmyeloablative SCT.

Allogeneic stem cell transplantation for patients with acute myeloid leukemia or myelodysplastic syndrome who have chromosome 5 and/or 7 abnormalities.

BACKGROUND AND OBJECTIVES: Chromosome 5 and/or 7 abnormalities are cytogenetic findings indicative of a poor prognosis in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). The only potential cure for such patients is allogeneic stem cell transplantation (SCT). As data on allogeneic SCT in this context are limited we did a retrospective study of allogeneic SCT in patients with AML or MDS who had chromosome 5 and/or 7 abnormalities. DESIGN AND METHODS: This was a retrospective study of 65 patients (16 children, 49 adults) with AML (n=33) or MDS (n=32) who had chromosome 5 and/or 7 abnormalities and who underwent allogeneic SCT in six Dutch Centers between 1983 and 2001. Data on all these patients are recorded in the Netherlands Stem Cell Transplant Registry (Typhon). RESULTS: The 3-year overall survival rate among all patients was 25%. Patients below the age of 40 years had significantly fewer relapses (40%) and better survival (38%) than those above the age of 40 (86% and 8%, respectively). Relapses were less frequent in recipients of unrelated grafts than in those whose grafts were from HLA-identical siblings (30% versus 69%). The development of acute graft-versus-host disease (GVHD) grades II-IV was independently associated with significantly higher transplant-related mortality (TRM). Patients with either chromosome 5 or chromosome 7 abnormalities had a significantly better survival than patients with both chromosome 5 and 7 abnormalities. These patients with poor-risk chromosome 5 and/or 7 abnormalities were compared with a group of patients with a secondary AML/MDS and normal cytogenetics and were found to have significantly more relapses and significantly worse survival but a similar TRM. INTERPRETATION AND CONCLUSIONS: We conclude that patients with AML or MDS with chromosome 5 and/or 7 abnormalities do rather poorly after allogeneic SCT, mainly because of the very high relapse rate. Nevertheless, this is the only approach that can cure some of these patients.

Elevated levels of D-dimer and fragment 1+2 upon central venous catheter insertion and factor V Leiden predict subclavian vein thrombosis.

BACKGROUND AND OBJECTIVES: Subclavian vein thrombosis is a well-recognized complication following central venous catheter insertion. We studied whether the determination of D-dimer levels, fragment 1+2 levels and factor V Leiden can identify patients at high risk of developing subclavian vein thrombosis. DESIGN AND METHODS: The presence of central venous catheter associated thrombosis was analyzed in 235 patients undergoing allogeneic bone marrow transplantation, of whom 30 (13%) developed thrombosis. A case-control study was performed with 30 patients matched for age, gender, and type of transplantation who did not develop thrombosis. Blood was sampled 3-5 days after catheter insertion. D-dimer levels were determined using a latex microparticle assay and an enzyme linked immunosorbent assay (ELISA). An ELISA was used to determine fragment 1+2 levels. The factor V genotype was determined by polymerase chain reaction. RESULTS: The levels of D-dimer and fragment 1+2 were significantly elevated in the patients who developed thrombosis. Five patients tested positive for factor V Leiden and all 5 developed subclavian vein thrombosis. Patients with high D-dimer levels (> 1300 microg/L measured by latex agglutination and >350 microg/L measured by ELISA) had a 7.0 and 6.0 times higher risk of developing subclavian vein thrombosis, respectively. A 5.5-fold increased risk of thrombosis was observed in patients with a fragment 1+2 level higher than 1.300 nmol/L. This resulted in positive predictive values of 0.78, 0.80 and 0.83 for the fragment 1+2, D-dimer and D-dimer latex agglutination assays, respectively. The accompanying negative predictive values were 0.39, 0.40 and 0.42, respectively. INTERPRETATION AND CONCLUSIONS: We conclude that the measurement of D-dimer and fragment 1+2 levels after central venous catheter insertion, as well as factor V Leiden determination, can be used to identify patients at high risk of developing symptomatic subclavian vein thrombosis.

The FcgammaRIIa-polymorphic site as a potential target for acute graft-versus-host disease in allogeneic stem cell transplantation.

Graft-versus-host disease (GVHD) is a serious complication of allogeneic stem cell transplantation for hematologic diseases. Antigen mismatches due to polymorphic differences between the patient and donor are central in the mechanisms of GVHD. Polymorphisms are known for FcgammaRIIa, and this molecule is present on endothelial, dendritic, and Langerhans cells. Donor cells reacting against the patient as GVHD can also react against the malignancy of the patient, and this is known as the graft-versus-leukemia (GVL) effect. Because the FcgammaRIIa molecule is also present on acute myeloid leukemia (AML) cells, an FcgammaRIIa mismatch could be a target for both GVHD and GVL. We retrospectively studied 73 AML patients and analyzed the differences in GVHD and relapse incidence between patients with and without a pro-GVHD/GVL FcgammaRIIa allotype mismatch. We observed a difference in FcgammaRIIa receptors with a pro-GVHD/GVL mismatch in 18 patient/donor pairs (25%). Univariate and multivariate analyses demonstrated the pro-GVHD mismatch to be a significant risk factor for the development of acute GVHD. There was no effect on the occurrence of chronic GVHD. The relapse incidence was not significantly different for patients with or without the pro-GVL mismatch, although there was a trend for fewer relapses in standard-risk AML patients with the pro-GVL mismatch. We conclude that the polymorphism of the FcgammaRIIa receptor may be a candidate target for acute GVHD.

Extra-domain-A fibronectin: a new marker of fibrosis in cutaneous graft-versus-host disease.

One of the major complications that limit the success of allogeneic stem cell transplantation is graft-versus-host disease (GVHD). The major target organ in GVHD is the skin. Cutaneous GVHD can eventually lead to fibrosis of the skin. Fibronectin mediates a variety of cellular interactions with the extracellular matrix. The molecular and functional diversity of fibronectin (FN) arises from alternative splicing of pre-mRNA. In normal circumstances endothelial cells and fibroblasts synthesize FN without the ED-A domain. In tissue repair and pathologic circumstances such as fibrosis, the ED-A domain is expressed. We hypothesize that expression of ED-A FN is upregulated in patients with cutaneous GVHD. In frozen skin biopsies the expression of ED-A FN was measured at the protein level by immunohistochemistry and at the mRNA level by quantitative real-time PCR (qPCR). In normal control skin, immunohistochemistry showed slight deposits of ED-A FN just under the basal layer. The expression of ED-A FN significantly increased in acute cutaneous GVHD (p<0.05) and ED-A FN was strongly deposited in chronic cutaneous GVHD (p<0.001). Quantitative PCR also showed increased expression of ED-A FN mRNA in acute and chronic cutaneous GVHD compared with normal control skin (p=0.07 and 0.039, respectively). The expression of ED-A FN is increased in the skin of patients with cutaneous GVHD measured both with immunohistochemistry and qPCR. ED-A FN is a new marker of fibrosis in the skin of patients with cutaneous GVHD.

Anti-CD20 monoclonal antibody treatment in 6 patients with therapy-refractory chronic graft-versus-host disease.

Chronic graft-versus-host disease (cGVHD) is an important determinant of long-term morbidity and mortality in allogeneic stem cell transplantation patients. Because cGVHD has clinical, histologic, and laboratory findings of autoimmune diseases and anti-B-cell therapy has shown efficacy in autoimmune diseases, we hypothesized that monoclonal anti-CD20 antibody therapy might improve patients with cGVHD. We treated 5 men and 1 woman with therapy-refractory extensive cGVHD with anti-CD20 monoclonal antibody. Intravenous infusion was given at a weekly dose of 375 mg/m(2) for 4 weeks. In case of incomplete clinical response, additional courses of 4 weeks were given. Five patients responded to treatment with marked clinical, biochemical, and histologic improvement. One patient failed to respond. Anti-CD20 monoclonal antibody seems to be effective in cGVHD. A controlled trial is mandatory to confirm these results. The outcome of this study suggests a participating role of B cells in the pathogenesis of cGVHD.