Natural history of monoclonal B-cell lymphocytosis among relatives in CLL families.

Chronic lymphocytic lymphoma (CLL) has one of the highest familial risks among cancers. Monoclonal B-cell lymphocytosis (MBL), the precursor to CLL, has a higher prevalence (13%-18%) in families with 2 or more members with CLL compared with the general population (5%-12%). Although, the rate of progression to CLL for high-count MBLs (clonal B-cell count ≥500/µL) is ∼1% to 5%/y, no low-count MBLs have been reported to progress to date. We report the incidence and natural history of MBL in relatives from CLL families. In 310 CLL families, we screened 1045 relatives for MBL using highly sensitive flow cytometry and prospectively followed 449 of them. MBL incidence was directly age- and sex-adjusted to the 2010 US population. CLL cumulative incidence was estimated using Kaplan-Meier survival curves. At baseline, the prevalence of MBL was 22% (235/1045 relatives). After a median follow-up of 8.1 years among 449 relatives, 12 individuals progressed to CLL with a 5-year cumulative incidence of 1.8%. When considering just the 139 relatives with low-count MBL, the 5-year cumulative incidence increased to 5.7%. Finally, 264 had no MBL at baseline, of whom 60 individuals subsequently developed MBL (2 high-count and 58 low-count MBLs) with an age- and sex-adjusted incidence of 3.5% after a median of 6 years of follow-up. In a screening cohort of relatives from CLL families, we reported progression from normal-count to low-count MBL to high-count MBL to CLL, demonstrating that low-count MBL precedes progression to CLL. We estimated a 1.1% annual rate of progression from low-count MBL, which is in excess of that in the general population.

Minimal residual hairy cell leukemia eradication with moxetumomab pasudotox: phase 1 results and long-term follow-up.

Anti-CD22 moxetumomab pasudotox achieved 46% complete remissions (CRs) in previously reported phase 1 testing in relapsed/refractory hairy cell leukemia (HCL; n = 28). The importance of minimal residual disease (MRD) after CR in HCL is unknown. A 21-patient extension cohort received 50 µg/kg every other day for 3 doses in 4-week cycles. These patients plus 12 previously reported at this upper dose level received 143 cycles without dose-limiting toxicity. The combined 33-patient cohort achieved 64% CR and 88% overall response rates, with median CR duration of 42.4 months. Of 32 50-µg/kg patients evaluable for MRD by bone marrow aspirate flow cytometry (most stringent assessment), median CR duration was 13.5 (4.9-42.4) months in 9 MRD-positive CRs vs 42.1 (24.0-69.2) months in 11 MRD-negative CRs (P < .001). Among MRD-negative CRs, 10 patients had ongoing CR, 9 without MRD, at end of study. To our knowledge, moxetumomab pasudotox is the only nonchemotherapy regimen that can eliminate MRD in a significant percentage of HCL patients, to enhance CR duration. Repeated dosing, despite early neutralizing antibodies, increased active drug levels without detectable toxicity from immunogenicity. The activity and safety profiles of moxetumomab pasudotox support ongoing phase 3 testing in HCL. This trial was registered at www.clinicaltrials.gov as #NCT00586924.

CALLA: Efficacy and safety of concurrent and adjuvant durvalumab with chemoradiotherapy versus chemoradiotherapy alone in women with locally advanced cervical cancer: a phase III, randomized, double-blind, multicenter study.

BackgroundConcurrent chemoradiotherapy is the standard of care for locally advanced cervical cancer. Concurrent chemoradiotherapy with programmed blockade of the cell death-1/programmed cell death-ligand 1 pathway may promote a more immunogenic environment through increased phagocytosis, cell death, and antigen presentation, leading to enhanced immune-mediated tumor surveillance. PRIMARY OBJECTIVE: The CALLA trial is designed to determine the efficacy and safety of the programmed cell death-ligand 1 blocking antibody, durvalumab, with and following concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone in women with locally advanced cervical cancer. STUDY HYPOTHESIS: Durvalumab concurrent with and following concurrent chemoradiotherapy will improve progression-free survival in patients with International Federation of Gynecology and Obstetrics (FIGO) 2009 stage IB2 to IVA cervical cancer compared with concurrent chemoradiotherapy alone. TRIAL DESIGN: CALLA is a phase III, randomized, multicenter, international, double-blind, placebo-controlled study. Patients will be randomized 1:1 to receive either durvalumab (1500 mg intravenously (IV)) or placebo every 4 weeks for 24 cycles. All patients will receive external beam radiotherapy with cisplatin (40 mg/m2) IV or carboplatin (area under the curve 2) IV once a week for 5 weeks, followed by image-guided brachytherapy. MAJOR INCLUSION/EXCLUSION CRITERIA: The study will enroll immunotherapy-naïve adult patients with histologically confirmed cervical adenocarcinoma, cervical squamous, or adenosquamous carcinoma FIGO 2009 stages IB2-IIB node positive and stage IIIA-IVA with any node stage. Patients will have had no prior definitive surgical, radiation, or systemic therapy for cervical cancer. PRIMARY ENDPOINT: The primary endpoint is progression-free survival (assessed by the investigator according to Response Evaluation Criteria in Solid Tumors v1.1, histopathological confirmation of local tumor progression or death). SAMPLE SIZE: Approximately 714 patients will be randomized 1:1 to receive either durvalumab + concurrent chemoradiotherapy or placebo + concurrent chemoradiotherapy. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Patient enrollment is continuing globally with an estimated completion date of April 2024. TRIAL REGISTRATION: NCT03830866.

Phase 1 study of the anti-CD22 immunotoxin moxetumomab pasudotox for childhood acute lymphoblastic leukemia.

Novel therapies are needed to overcome chemotherapy resistance for children with relapsed/refractory acute lymphoblastic leukemia (ALL). Moxetumomab pasudotox is a recombinant anti-CD22 immunotoxin. A multicenter phase 1 study was conducted to determine the maximum-tolerated cumulative dose (MTCD) and evaluate safety, activity, pharmacokinetics, and immunogenicity of moxetumomab pasudotox in children, adolescents, and young adults with ALL (N = 55). Moxetumomab pasudotox was administered as a 30-minute IV infusion at doses of 5 to 50 µg/kg every other day for 6 (cohorts A and B) or 10 (cohort C) doses in 21-day cycles. Cohorts B and C received dexamethasone prophylaxis against capillary leak syndrome (CLS). The most common treatment-related adverse events were reversible weight gain, hepatic transaminase elevation, and hypoalbuminemia. Dose-limiting CLS occurred in 2 of 4 patients receiving 30 µg/kg of moxetumomab pasudotox every other day for 6 doses. Incorporation of dexamethasone prevented further dose-limiting CLS. Six of 14 patients receiving 50 µg/kg of moxetumomab pasudotox for 10 doses developed hemolytic uremic syndrome (HUS), thrombotic microangiopathy (TMA), or HUS-like events, exceeding the MTCD. Treatment expansion at 40 µg/kg for 10 doses (n = 11) exceeded the MTCD because of 2 HUS/TMA/HUS-like events. Dose level 6B (ie, 50 µg/kg × 6 doses) was the MTCD, selected as the recommended phase 2 dose. Among 47 evaluable patients, an objective response rate of 32% was observed, including 11 (23%) composite complete responses, 5 of which were minimal residual disease negative by flow cytometry. Moxetumomab pasudotox showed a manageable safety profile and evidence of activity in relapsed or refractory childhood ALL. This trial was registered at www.clinicaltrials.gov as #NCT00659425.

Otlertuzumab (TRU-016), an anti-CD37 monospecific ADAPTIR(™) therapeutic protein, for relapsed or refractory NHL patients.

CD37 is cell surface tetraspanin present on normal and malignant B cells. Otlertuzumab (TRU-016) is a novel humanized anti-CD37 protein therapeutic. Patients with relapsed or refractory follicular non-Hodgkin lymphoma (FL), mantle cell lymphoma (MCL), or Waldenström's macroglobulinaemia (WM) received otlertuzumab at 20 mg/kg administered intravenously once a week for up to 8 weeks followed by 4 monthly doses. Sixteen patients were treated; median age was 62·5 years (range, 41-81), and median number of prior regimens was 4 (range, 1-7). Twelve patients were refractory to prior treatment, 5 were refractory to rituximab. The mean terminal half-life was 9·5 days. Lymph node reduction of ≥50% by computerized tomography scan measurements was seen in 3 of 12 patients, including one FL patient who had a partial response. One WM patient had a minor response. The most frequent adverse events were neutropenia, fatigue, nausea, thrombocytopenia, diarrhoea, and peripheral oedema; most were grade 1/2. Otlertuzumab treatment appears to have been well tolerated by the patients in this study. Clinical activity was observed in this small heterogeneous cohort of highly refractory, heavily pretreated B-cell non-Hodgkin lymphoma patients. These data suggest that further clinical investigation in non-Hodgkin lymphoma is warranted.

Single nucleotide polymorphisms and inherited risk of chronic lymphocytic leukemia among African Americans.

The incidence of chronic lymphocytic leukemia (CLL) is significantly lower in African Americans than whites, but overall survival is inferior. The biologic basis for these observations remains unexplored. We hypothesized that germline genetic predispositions differ between African Americans and whites with CLL and yield inferior clinical outcomes among African Americans. We examined a discovery cohort of 42 African American CLL patients ascertained at Duke University and found that the risk allele frequency of most single nucleotide polymorphisms known to confer risk of development for CLL is significantly lower among African Americans than whites. We then confirmed our results in a distinct cohort of 68 African American patients ascertained by the CLL Research Consortium. These results provide the first evidence supporting differential genetic risk for CLL between African Americans compared with whites. A fuller understanding of differential genetic risk may improve prognostication and therapeutic decision making for all CLL patients.

Common variation at 6p21.31 (BAK1) influences the risk of chronic lymphocytic leukemia.

We performed a meta-analysis of 3 genome-wide association studies to identify additional common variants influencing chronic lymphocytic leukemia (CLL) risk. The discovery phase was composed of genome-wide association study data from 1121 cases and 3745 controls. Replication analysis was performed in 861 cases and 2033 controls. We identified a novel CLL risk locus at 6p21.33 (rs210142; intronic to the BAK1 gene, BCL2 antagonist killer 1; P = 9.47 × 10(-16)). A strong relationship between risk genotype and reduced BAK1 expression was shown in lymphoblastoid cell lines. This finding provides additional support for polygenic inheritance to CLL and provides further insight into the biologic basis of disease development.

Clinical characteristics, response to therapy, and survival of African American patients diagnosed with chronic lymphocytic leukemia: joint experience of the MD Anderson Cancer Center and Duke University Medical Center.

BACKGROUND: Little is known regarding racial disparities in characteristics and outcomes among patients with chronic lymphocytic leukemia (CLL). METHODS: The characteristics and outcomes of untreated African American (AA) patients with CLL (n = 84) were analyzed and compared with a reference nonblack (NB) patient population (n = 1571). RESULTS: At the time of presentation, AA patients had lower median hemoglobin levels (12.9 g/dL vs 13.7 g/dL), higher ß2 microglobulin levels (2.7 mg/dL vs 2.4 mg/dL), greater frequency of constitutional symptoms (27% vs 10%), unmutated immunoglobulin heavy-chain variable region (IGHV) mutation status (65% vs 47%), ζ-chain-associated protein kinase 70 (ZAP70) expression (58% vs 32%), and deletion of chromosome 17p or chromosome 11q (28% vs 17%; P ≤ 02 for each comparison). Fifty-one percent of AA patients and 39% of NB patients required first-line therapy and 91% and 88%, respectively, received chemoimmunotherapy. Overall response rates to treatment were 85% for AA patients and 94% for NB patients (P = .06); and the complete response rates were 56% and 58%, respectively (P = .87). The median survival of AA patients was shorter compared with that of NB patients (event-free survival: 36 months vs 61 months; P = .007; overall survival: 152 months vs not reached; P = .0001). AA race was an independent predictor of shorter event-free and overall survival in multivariable regression models. CONCLUSIONS: The current results indicated that AA patients with CLL have more unfavorable prognostic characteristics and shorter survival compared with their NB counterparts.

Ofatumumab-based chemoimmunotherapy is effective and well tolerated in patients with previously untreated chronic lymphocytic leukemia (CLL).

BACKGROUND: Although rituximab-based chemoimmunotherapy (CIT) has substantially improved clinical outcomes in chronic lymphocytic leukemia (CLL), only 40% to 50% of patients achieve a complete remission (CR). There remains interest in identifying new approaches to improve the effectiveness of CIT. Ofatumumab is a fully human anti-CD20 monoclonal antibody with greater apparent single-agent activity than rituximab in CLL patients. METHODS: Previously untreated CLL patients in need of therapy received 6 cycles of CIT induction with pentostatin, cyclophosphamide, and ofatumumab (PCO) followed by response assessment. RESULTS: Of the 48 patients enrolled, 77% completed PCO induction. Adverse events during induction included grade 3+ hematologic toxicity (27%) and grade 3+ nonhematologic toxicity (23%). Median CD4 count after induction and 6 months later were 186 × 10(6)/L and 272 × 10(6) /L. The overall response rate was 96% (46 of 48 patients), and the CR rate was 46% (22 of 48 patients). Among the 38 patients who underwent minimal residual disease evaluation, 7 (18%) were negative for minimal residual disease. After median follow-up of 24 months, 10 (21%) patients have progressed and 8 (17%) have required retreatment. The efficacy and toxicity of ofatumumab-based CIT compare favorably to our historical trials of rituximab-based CIT using an identical chemotherapy backbone (n = 64). Time to retreatment also appeared longer for ofatumumab-based CIT (free of retreatment at 24 months: 86% [95% confidence interval = 75-99] versus 68% [95% confidence interval = 56-81] for rituximab-based CIT). CONCLUSIONS: Ofatumumab-based CIT is well tolerated in patients with previously untreated CLL. The efficacy of ofatumumab-based CIT compares favorably to historical trials of rituximab-based CIT, suggesting randomized trials comparing ofatumumab-based CIT and rituximab-based CIT should be considered.

SET oncoprotein overexpression in B-cell chronic lymphocytic leukemia and non-Hodgkin lymphoma: a predictor of aggressive disease and a new treatment target.

B-cell chronic lymphocytic leukemia (CLL), an incurable leukemia, is characterized by defective apoptosis. We found that the SET oncoprotein, a potent inhibitor of the protein phosphatase 2A (PP2A) tumor suppressor, is overexpressed in primary CLL cells and B-cell non-Hodgkin lymphoma (NHL) cell line cells. In CLL, increased levels of SET correlated significantly with disease severity (shorter time to treatment and overall survival). We developed SET antagonist peptides that bound SET, increased cellular PP2A activity, decreased Mcl-1 expression, and displayed selective cytotoxicity for CLL and NHL cells in vitro. In addition, shRNA for SET was cytotoxic for NHL cells in vitro. The SET antagonist peptide COG449 inhibited growth of NHL tumor xenografts in mice. These data demonstrate that SET is a new treatment target in B-cell malignancies and that SET antagonists represent novel agents for treatment of CLL and NHL.

Genome-wide association study identifies a novel susceptibility locus at 6p21.3 among familial CLL.

Prior genome-wide association (GWA) studies have identified 10 susceptibility loci for risk of chronic lymphocytic leukemia (CLL). To identify additional loci, we performed a GWA study in 407 CLL cases (of which 102 had a family history of CLL) and 296 controls. Moreover, given the strong familial risk of CLL, we further subset our GWA analysis to the CLL cases with a family history of CLL to identify loci specific to these familial CLL cases. Our top hits from these analyses were evaluated in an additional sample of 252 familial CLL cases and 965 controls. Using all available data, we identified and confirmed an independent association of 4 single-nucleotide polymorphisms (SNPs) that met genome-wide statistical significance within the IRF8 (interferon regulatory factor 8) gene (combined P values ≤ 3.37 × 10(-8)), located in the previously identified 16q24.1 locus. Subsetting to familial CLL cases, we identified and confirmed a new locus on chromosome 6p21.3 (combined P value = 6.92 × 10(-9)). This novel region harbors the HLA-DQA1 and HLA-DRB5 genes. Finally, we evaluated the 10 previously reported SNPs in the overall sample and replicated 8 of them. Our findings support the hypothesis that familial CLL cases have additional genetic variants not seen in sporadic CLL. Additional loci among familial CLL cases may be identified through larger studies.

Durvalumab Plus Olaparib in Previously Untreated, Platinum-Ineligible Patients With Metastatic Urothelial Carcinoma: A Multicenter, Randomized, Phase II Trial (BAYOU).

PURPOSE: Homologous recombination repair gene mutations (HRRm) are common in urothelial carcinoma (UC), rendering tumor cells sensitive to poly (ADP-ribose) polymerase (PARP) inhibition. We assessed efficacy and safety of durvalumab (anti-programmed cell death ligand-1) plus olaparib (PARP inhibitor) in patients with metastatic UC (mUC). METHODS: This randomized, multicenter, double-blind, phase II trial enrolled untreated, platinum-ineligible patients with mUC. Patients (N = 154) were randomly assigned 1:1 to receive durvalumab (1,500 mg intravenously once every 4 weeks) plus olaparib (300 mg orally, twice daily) or durvalumab plus placebo. The primary end point was progression-free survival (PFS) assessed by investigators per RECIST version 1.1. Secondary end points included overall survival in all patients and PFS in patients with HRRm. RESULTS: Overall, median PFS was 4.2 months (95% CI, 3.6 to 5.6) for durvalumab plus olaparib and 3.5 months (95% CI, 1.9 to 5.1) for durvalumab plus placebo (hazard ratio [HR], 0.94; 95% CI, 0.64 to 1.39; log-rank P value, .789). Median overall survival was 10.2 months (95% CI, 7.0 to 13.9) and 10.7 months (95% CI, 7.2 to 17.3), respectively (HR, 1.07; 95% CI, 0.72 to 1.61). In the 20% of patients with HRRm, median PFS was 5.6 months (95% CI, 1.9 to 8.1) and 1.8 months (95% CI, 1.7 to 2.2), respectively (HR, 0.18; 95% CI, 0.06 to 0.47). Treatment-related grade 3 or 4 adverse events occurred in 18% and 9% of patients, respectively. CONCLUSION: Adding olaparib to durvalumab did not improve survival outcomes in an unselected mUC population. Efficacy outcomes with durvalumab were similar to those reported for other anti-programmed cell death-1/programmed cell death ligand-1 agents. However, the results of secondary analyses suggest a potential role for PARP inhibition in patients with UC harboring HRRm.

Common variants within 6p21.31 locus are associated with chronic lymphocytic leukaemia and, potentially, other non-Hodgkin lymphoma subtypes.

A recent meta-analysis of three genome-wide association studies of chronic lymphocytic leukaemia (CLL) identified two common variants at the 6p21.31 locus that are associated with CLL risk. To verify and further explore the association of these variants with other non-Hodgkin lymphoma (NHL) subtypes, we genotyped 1196 CLL cases, 1699 NHL cases, and 2410 controls. We found significant associations between the 6p21.31 variants and CLL risk (rs210134: P = 0·01; rs210142: P = 6·8 × 10(-3)). These variants also showed a trend towards association with some of the other NHL subtypes. Our results validate the prior work and support specific genetic pathways for risk among NHL subtypes.

Clinical aspects of monoclonal B-cell lymphocytosis.

BACKGROUND: Monoclonal B-cell lymphocytosis (MBL) is an asymptomatic precursor condition for chronic lymphocytic leukemia (CLL). It is defined by the presence of small clones of aberrant B cells in the peripheral blood, with a total B-cell count below the threshold for diagnosis of CLL (<5.0x10(9) cells/L). METHODS: The authors review current literature on the prevalence of MBL, and the clinical course of this CLL precursor condition, and recommended management for individuals with MBL. RESULTS: MBL occurs in approximately 4% to 5% of healthy adults. While most cases of CLL are preceded by MBL, progression to leukemia requiring CLL treatment occurs in only 1% to 2% of individuals with MBL per year. The absolute B-cell count is most strongly associated with progression, and patients with low-count MBL identified in population screening studies rarely develop CLL. Studies are ongoing to better define the relationship between MBL and CLL and to identify prognostic indicators that predict which patients will progress to CLL. Given their elevated risk of developing malignancy, individuals with clinical MBL should be monitored at least annually for progressive lymphocytosis and signs or symptoms of CLL. CONCLUSIONS: Many of the epidemiologic and genetic factors associated with MBL development and its progression to CLL have not yet been identified. However, ongoing studies by many research groups are aimed at answering these questions to facilitate management of individuals with this premalignant condition. In addition, active investigation of MBL will likely yield new insights into the biology of CLL, potentially identifying new therapeutic targets for this incurable disease.

Safety and activity of the TGFß receptor I kinase inhibitor galunisertib plus the anti-PD-L1 antibody durvalumab in metastatic pancreatic cancer.

BACKGROUND: We assessed the safety, efficacy, and pharmacokinetics of the transforming growth factor beta (TGFß) receptor inhibitor galunisertib co-administered with the anti-programmed death-ligand 1 (PD-L1) antibody durvalumab in recurrent/refractory metastatic pancreatic cancer previously treated with ≤2 systemic regimens. METHODS: This was a two-part, single-arm, multinational, phase Ib study. In a dose-finding phase, escalating oral doses of galunisertib were co-administered on days 1-14 with fixed-dose intravenous durvalumab 1500 mg on day 1 every 4 weeks (Q4W), followed by an expansion cohort phase. RESULTS: The galunisertib recommended phase II dose (RP2D) when co-administered with durvalumab 1500 mg Q4W was 150 mg two times per day. No dose-limiting toxicities were recorded. Among 32 patients treated with galunisertib RP2D, 1 patient had partial response, 7 had stable disease, 15 had objective progressive disease, and 9 were not evaluable. Disease control rate was 25.0%. Median overall survival and progression-free survival were 5.72 months (95% CI: 4.01 to 8.38) and 1.87 months (95% CI: 1.58 to 3.09), respectively. Pharmacokinetic profiles for combination therapy were comparable to those published for each drug. There was no association between potential biomarkers and treatment outcomes. CONCLUSION: Galunisertib 150 mg two times per day co-administered with durvalumab 1500 mg Q4W was tolerable. Clinical activity was limited. Studying this combination in patients in an earlier line of treatment or selected for predictive biomarkers of TGFß inhibition might be a more suitable approach. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier: NCT02734160.

Common occurrence of monoclonal B-cell lymphocytosis among members of high-risk CLL families.

Monoclonal B-cell lymphocytosis (MBL) is an asymptomatic haematological condition characterized by low absolute levels of B-cell clones with a surface immunophenotype similar to that of chronic lymphocytic leukaemia (CLL). In the general population, MBL increases with age with a prevalence of 5-9% in individuals over age 60 years. It has been reported to be higher among first-degree relatives from CLL families. We report results of multi-parameter flow cytometry among 505 first-degree relatives with no personal history of lymphoproliferative disease from 140 families having at least two cases of CLL. Seventeen percent of relatives had MBL. Age was the most important determinant where the probability for developing MBL by age 90 years was 61%. MBL clustered in certain families but clustering was independent of the number of known CLL cases in a family. As is the case with CLL, males had a significantly higher risk for MBL than did females (P = 0·04). MBL patients had significantly higher mean absolute lymphocyte counts (2·4 × 10(9) /l) and B-cell counts (0·53 × 10(9) /l) than those with a normal B-cell immuno-phenotype. Our findings show that MBL occurs at a very high rate in high risk CLL families. Both the age and gender distribution of MBL are parallel to CLL, implying a shared inherited risk.

Phase I study of samalizumab in chronic lymphocytic leukemia and multiple myeloma: blockade of the immune checkpoint CD200.

PURPOSE: Samalizumab is a novel recombinant humanized monoclonal antibody that targets CD200, an immunoregulatory cell surface member of the immunoglobulin superfamily that dampens excessive immune responses and maintains self-tolerance. This first-in-human study investigated the therapeutic use of samalizumab as a CD200 immune checkpoint inhibitor in chronic lymphocytic leukemia (CLL) and multiple myeloma (MM). EXPERIMENTAL DESIGN: Twenty-three patients with advanced CLL and 3 patients with MM were enrolled in an open-label phase 1 study (NCT00648739). Patients were assigned sequentially to one of 7 dose level cohorts (50 to 600 mg/m2) in a 3 + 3 study design, receiving a single dose of samalizumab intravenously once every 28 days. Primary endpoints were safety, identification of the maximum tolerated dose (MTD), and pharmacokinetics. Secondary endpoints were samalizumab binding to CD200, pharmacodynamic effects on circulating tumor cells and leukocyte subsets, and clinical responses. RESULTS: Twenty-one patients received > 1 treatment cycle. Adverse events (AEs) were generally mild to moderate in severity. Samalizumab produced dose-dependent decreases in CD200 expression on CLL cells and decreased frequencies of circulating CD200 + CD4+ T cells that were sustained at higher doses. The MTD was not reached. Decreased tumor burden was observed in 14 CLL patients. One CLL patient achieved a durable partial response and 16 patients had stable disease. All MM patients had disease progression. CONCLUSIONS: Samalizumab had a good safety profile and treatment was associated with reduced tumor burden in a majority of patients with advanced CLL. These preliminary positive results support further development of samalizumab as an immune checkpoint inhibitor. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00648739 registered April 1, 2008.

Recurrent spontaneous abortion and skewed X-inactivation: is there an association?

OBJECTIVE: The purpose of this study was to determine whether there is an association between skewed X-inactivation and recurrent spontaneous abortion in a large, well-defined sample of women with recurrent loss. STUDY DESIGN: X-chromosome inactivation patterns were compared in 5 groups of women. Group 1 (recurrent spontaneous abortion) consisted of 357 women with 2 or more spontaneous losses. In group 2 (infertility), there were 349 subjects from infertility practices recruited at the time of a positive serum beta-human chorionic gonadotropin. Group 3 (spontaneous abortion) women (n = 81) were recruited at the time of an ultrasound diagnosis of an embryonic demise or an anembryonic gestation. Groups 4 (primiparous) and 5 (multiparous) were healthy pregnant subjects previously enrolled in another study to determine the incidence and cause of pregnancy complications, such as preeclampsia and intrauterine growth restriction. The Primiparous group included 114 women in their first pregnancy, whereas the Multiparous group consisted of 79 women with 2 or more pregnancies but without pregnancy loss. RESULTS: The rate of extreme skewing (90% or greater) in the recurrent spontaneous abortion population was 8.6%, and not statistically different from any of the other groups, except the Primiparous group (1.0%, P < .01). The incidence of X-inactivation skewing of 90% or greater was no different whether there had been at least 1 live birth (9.9%), or no previous live births and at least 3 losses (5.6%, P > .05). When age and skewing of 90% or greater are compared, subjects with extreme skewing have a mean age of 2 years older than those without extreme skewing (P < .05). CONCLUSION: Skewed X-inactivation is not associated with recurrent spontaneous abortion but is associated with increasing maternal age.

Characteristics and treatment patterns among US patients with hairy cell leukemia: a retrospective claims analysis.

AIM: Describe hairy cell leukemia (HCL) treatment patterns using a large, nationally representative US database. PATIENTS & METHODS: Adults newly diagnosed with HCL (1 January 2006 to 30 June 2014) with continuous health plan enrollment ≥180 days pre- and 90 days post-diagnosis were identified from the QuintilesIMS PharMetrics Plus Health Plan Claims Database. Treatment patterns by line of therapy were assessed over the variable follow-up. RESULTS: Among 749 HCL patients (77.4% male; mean age 55.6; mean 32.3 months follow-up), only 37.7% initiated first-line therapy during the available follow-up in a mean of 4.4 months following diagnosis; the majority (75.5%) received cladribine (mean duration 7.3 days). Thirty-eight patients (5.1%) received second-line treatment. CONCLUSION: Over 2.7 years follow-up, more than a third of patients initiated first-line therapy which appeared to provide a long-lasting response.