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Background: The Cancer and Leukemia Group B evaluated oral topotecan administered at 2 schedules and doses for myelodysplastic syndrome (MDS).Methods: Patients with previously untreated primary or therapy-related MDS were eligible. Patients with refractory anemia (RA), RA with ringed sideroblasts, or refractory cytopenia with multilineage dysplasia (RCMD) were eligible only if they were dependent on erythrocyte transfusion, had a platelet count<50,000/microL, or had an absolute neutrophil count<1000/microL with a recent infection that required antibiotics. Patients were randomized to receive oral topotecan either at a dose of 1.2 mg/m2 twice daily for 5 days (Arm A) or once daily for 10 days (Arm B) repeated every 21 days for at least 2 cycles. Responding patients continued until they developed disease progression or unacceptable toxicity or until they had received 2 cycles beyond a complete response.Results: Ninety patients received treatment, including 46 patients on Arm A and 44 patients on Arm B. Partial responses with improvement in all 3 cell lines occurred in 6 patients (7%), and hematologic improvement (in 1 or 2 cell lines) was observed in 21 patients (23%), for an overall response rate of 30%. Response duration was longer on Arm A (23 months vs 14 months; P=.02). Seven of 14 patients with chronic myelomonocytic leukemia responded. There were 8 treatment-related deaths from infection (6 deaths) and bleeding (2 deaths). Diarrhea was the most frequent nonhematologic toxicity (grade 3, 11%; grade 4, 2%; grading determined according to the National Cancer Institute Comman Toxicity Criteria v.2.0).Conclusions: Oral topotecan in the dose and schedules evaluated in this trial demonstrated only a modest response rate with a troublesome toxicity profile in the treatment of MDS. [ABSTRACT FROM AUTHOR]

In May 2019, the US Food and Drug Administration (FDA) released the Framework for FDA's Real-World Evidence (RWE) Program, a draft guidance to evaluate the potential use of real-world data in facilitating regulatory decisions. As a result, pharmaceutical companies and medical communities see patient registries, which are large, prospective, noninterventional cohort studies, as becoming increasingly important in providing evidence of treatment effectiveness and safety in clinical practice. Patient registries are designed to collect longitudinal clinical data on a broad population to address critical medical questions over time. With their large sample sizes and broad inclusion criteria, patient registries are often used to generate RWE in the general and underrepresented patient populations that are less likely to be studied in controlled clinical trials. Here, we describe the value of industry-sponsored patient registries in oncology/hematology settings to healthcare stakeholders, in drug development, and in fostering scientific collaboration., (© The Author(s) 2023. Published by Oxford University Press.)

Genomic data variability from laboratory reports can impact clinical decisions and population-level analyses; however, the extent of this variability and the impact on the data's value are not well characterized. This pilot study used anonymized genetic and genomic test reports from the Connect Myeloid Disease Registry (NCT01688011), a multicenter, prospective, observational cohort study of patients with newly diagnosed myelodysplastic syndromes, acute myeloid leukemia, or idiopathic cytopenia of undetermined significance, to analyze laboratory test variabilities and limitations. Results for 56 randomly selected patients enrolled in the Registry were independently extracted and evaluated (data cutoff, January 2020). Ninety-five reports describing 113 assay results from these 56 patients were analyzed for discrepancies. Almost all assay results [101 (89%)] identified the sequencing technology applied, and 94 (83%) described the test limitations; 95 (84%) described the limits of detection, but none described the limit of blank for detecting false positives. RNA transcript identifiers were not provided for 20 (43%) variants analyzed by next-generation sequencing and reported by the same laboratory. Of 42 variants with variant allele frequencies ≥30%, 16 (38%) of the variants did not have report text indicating that the variants might be germline. Variabilities and lack of standardization present challenges for incorporating this information into clinical care and render data collation ineffective and unreliable for large-scale use in centralized databases for therapeutic discovery., (Copyright © 2023 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Hematopoietic stem cell transplantation (HCT) is indicated for patients with higher-risk (HR) myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Age, performance status, patient frailty, comorbidities, and nonclinical factors (eg, cost, distance to site) are all recognized as important clinical factors that can influence HCT referral patterns and patient outcomes; however, the proportion of eligible patients referred for HCT in routine clinical practice is largely unknown. This study aimed to assess patterns of consideration for HCT among patients with HR-MDS and AML enrolled in the Connect® Myeloid Disease Registry at community/government (CO/GOV)- or academic (AC)-based sites, as well as to identify factors associated with rates of transplantation referral. We assessed patterns of consideration for and completion of HCT in patients with HR-MDS and AML enrolled between December 12, 2013, and March 6, 2020, in the Connect Myeloid Disease Registry at 164 CO/GOV and AC sites. Registry sites recorded whether patients were considered for transplantation at baseline and at each follow-up visit. The following answers were possible: "considered potentially eligible," "not considered potentially eligible," or "not assessed." Sites also recorded whether patients subsequently underwent HCT at each follow-up visit. Rates of consideration for HCT between CO/GOV and AC sites were compared using multivariable logistic regression analysis with covariates for age and comorbidity. Among the 778 patients with HR-MDS or AML enrolled in the Connect Myeloid Disease Registry, patients at CO/GOV sites were less likely to be considered potentially eligible for HCT than patients at AC sites (27.9% versus 43.9%; P < .0001). Multivariable logistic regression analysis with factors for age (<65 versus ≥65 years) and ACE-27 comorbidity grade (<2 versus ≥2) showed that patients at CO/GOV sites were significantly less likely than those at AC sites to be considered potentially eligible for HCT (odds ratio, 1.6, 95% confidence interval, 1.1 to 2.4; P = .0155). Among patients considered eligible for HCT, 45.1% (65 of 144) of those at CO/GOV sites and 35.7% (41 of 115) of those at AC sites underwent transplantation (P = .12). Approximately one-half of all patients at CO/GOV (50.1%) and AC (45.4%) sites were not considered potentially eligible for HCT; the most common reasons were age at CO/GOV sites (71.5%) and comorbidities at AC sites (52.1%). Across all sites, 17.4% of patients were reported as not assessed (and thus not considered) for HCT by their treating physician (20.7% at CO/GOV sites and 10.7% at AC sites; P = .0005). These findings suggest that many patients with HR-MDS and AML who may be candidates for HCT are not receiving assessment or consideration for transplantation in clinical practice. In addition, treatment at CO/GOV sites and age remain significant barriers to ensuring that all potentially eligible patients are assessed for HCT., (Copyright © 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Importance: Treatment of newly diagnosed multiple myeloma (NDMM) with a quadruplet regimen consisting of a monoclonal antibody, proteasome inhibitor, immunomodulatory imide, and corticosteroid has been associated with improved progression-free survival (PFS) compared with triplet regimens. The optimal quadruplet combination, and whether this obviates the need for frontline autologous stem cell transplant (ASCT), remains unknown. We evaluated elotuzumab and weekly carfilzomib, lenalidomide, and dexamethasone (Elo-KRd) without ASCT in NDMM., Objective: To investigate the efficacy of Elo-KRd using a measurable residual disease (MRD)-adapted design in NDMM regardless of ASCT eligibility., Design, Setting, and Participants: This multicenter, single-arm, phase 2 study enrolled patients between July 2017 and February 2021. Median follow-up was 29 months., Interventions: Twelve to 24 cycles of Elo-KRd; consecutive MRD-negative results at 10-6 by next-generation sequencing (NGS) after cycles 8 (C8) and 12 determined the duration of Elo-KRd. This was followed by Elo-Rd (no carfilzomib) maintenance therapy until disease progression., Main Outcomes and Measures: The primary end point was the rate of stringent complete response (sCR) and/or MRD-negativity (10-5) after C8 Elo-KRd. Secondary end points included safety, rate of response, MRD status, PFS, and overall survival (OS). As an exploratory analysis, MRD was assessed using liquid chromatography mass spectrometry (MS) on peripheral blood samples., Results: Forty-six patients were enrolled (median age 62 years, 11 [24%] aged >70 years). Overall, 32 (70%) were White, 6 (13%) were Black, 3 (6%) were more than 1 race, and 5 (11%) were of unknown race. Thirty-three (72%) were men and 13 (28%) were women. High-risk cytogenetic abnormalities were present in 22 (48%) patients. The rate of sCR and/or MRD-negativity after C8 was 26 of 45 (58%), meeting the predefined statistical threshold for efficacy. Responses deepened over time, with the MRD-negativity (10-5) rate increasing to 70% and MS-negativity rate increasing to 65%; concordance between MRD by NGS and MS increased over time. The most common (>10%) grade 3 or 4 adverse events were lung and nonpulmonary infections (13% and 11%, respectively). There was 1 grade 5 myocardial infarction. The estimated 3-year PFS was 72% overall and 92% for patients with MRD-negativity (10-5) at C8., Conclusions and Relevance: An MRD-adapted design using elotuzumab and weekly KRd without ASCT showed a high rate of sCR and/or MRD-negativity and durable responses. This approach provides support for further evaluation of MRD-guided deescalation of therapy to decrease treatment exposure while sustaining deep responses., Trial Registration: ClinicalTrials.gov Identifier: NCT02969837.

Introduction: The presence of ring sideroblasts (RS) and mutation of the SF3B1 gene are diagnostic of lower-risk (LR) myelodysplastic syndromes (MDS) and are correlated with favorable outcomes. However, information on testing and reporting in community-based clinical settings is scarce. This study from the Connect ® MDS/AML Disease Registry aimed to compare the frequency of RS and SF3B1 reporting for patients with LR-MDS, before and after publication of the 2016 World Health Organization (WHO) MDS classification criteria., Methods: Ring sideroblasts assessment and molecular testing data were collected from patients with LR-MDS at enrollment in the Registry. Patients enrolled between December 2013 and the data cutoff of March 2020 were included in this analysis., Results: Among 489 patients with LR-MDS, 434 (88.8%) underwent RS assessment; 190 were assessed prior to the 2016 WHO guidelines (Cohort A), and 244 after (Cohort B). In Cohort A, 87 (45.8%) patients had RS identified; 29 (33.3%) patients had RS < 15%, none of whom underwent molecular testing for SF3B1. In Cohort B, 96 (39.3%) patients had RS identified; 31 (32.3%) patients had < 15% RS, with 13 undergoing molecular testing of which 10 were assessed for SF3B1., Conclusions: In the Connect ® MDS/AML Registry, only 32% of patients with <15% RS underwent SF3B1 testing after the publication of the WHO 2016 classification criteria. There was no change in RS assessment frequency before and after publication, despite the potential impact on diagnostic subtyping and therapy selection, suggesting an unmet need for education to increase testing rates for SF3B1 mutations., (© 2020 The Authors. International Journal of Laboratory Hematology published by John Wiley & Sons Ltd.)

Health-related quality of life (HRQoL) in patients with chronic lymphocytic leukemia (CLL) is important in guiding treatment decisions. However, the impact of CLL treatment initiation on HRQoL is unclear. We assessed HRQoL using the FACT-Leu and EQ-5D-3L questionnaires in the Connect ® CLL Registry, a large, US-based, multicenter, prospective observational study of CLL patients enrolled between 2010 and 2014, prior to the introduction of novel therapies. Among 889 patients initiating first-line therapy with chemoimmunotherapy or rituximab monotherapy, questionnaire completion rates were 95.7% and 95.8% at enrollment, and 70.8% and 69.4% at 12 months, for FACT-Leu Total and EQ-5D-3L, respectively. For 849 patients completing all five FACT-Leu components, average total scores were 135.7 at enrollment and 141.6 at 12 months. Among 526 patients with FACT-Leu Total scores at enrollment and 12 months, clinically meaningful (≥11-point) improvements or reductions were observed in 179 (34.0%) and 88 (16.7%) patients, respectively. Mean EQ-5D-3L index scores were 0.87 at enrollment and 12 months. Among 513 patients completing EQ-5D-3L at enrollment and 12 months, clinically meaningful (≥0.06-point) improvements or reductions were observed in 125 (24.4%) and 116 (22.6%) patients, respectively. In the Connect ® CLL Registry, HRQoL remained stable or slightly improved after 12 months of follow-up., Competing Interests: J.P.S. has received honoraria/research funding from Abbvie, Acerta, Celgene Corporation, Genentech, Gilead, Janssen, Pharmacyclics and TG Therapeutics. K.C. is employed by Adelphi Values; has received consulting fees from Bristol Myers Squibb, formerly Celgene Corporation, for this work; and has received statistical consulting fees from Amgen and Endomag Ltd. C.N. is employed by Cardinal Health Specialty Solutions; has received research funding from Astellas, Celgene Corporation, Genentech and Seattle Genetics; and has been on advisory boards for AbbVie, Celgene Corporation, Cardinal Health, Genentech and Infinity. N.L. has received research funding from AbbVie, AstraZeneca, Beigene, Genentech, Gilead, Infinity, Juno, Ming, Oncternal, Pronai and TG Therapeutics; has been a consultant for AbbVie, AstraZeneca, Beigene, Genentech, Gilead, Jannsen, Pharmacyclics and Pronai; and has been on an advisory committee for Celgene Corporation. N.E.K. has received research funding from Celgene Corporation, Genentech, Gilead, Hospira and Pharmacyclics; and has been on advisory committees for Celgene Corporation and Gilead. D.L.G. has been a consultant and member of a speakers’ bureau for Celgene Corporation. C.R.F. has received research funding from AbbVie, Acerta, Gilead, Infinity, Janssen, Millennium, Pharmacyclics, Spectrum and TG Therapeutics; has been a consultant for Celgene Corporation, Genentech/Roche, Gilead, Millennium, Optum Rx and Seattle Genetics; and has received honoraria from Celgene Corporation. M.S.D. has served as a consultant for AbbVie, Acerta Pharma, Adaptive Biotechnologies, Ascentage Pharma, AstraZeneca, Beigene, Genentech, Janssen, MEI Pharma, Pharmacyclics, Research to Practice, Sunesis, Syros Pharmaceuticals, TG Therapeutics and Verastem; and received research funding from Acerta Pharma, Ascentage Pharma, Genentech, MEI Pharma, Pharmacyclics, Surface Oncology, TG Therapeutics and Verastem. P.K., A.S.S., K.S., M.M.G. and E.D.F. are employees of Bristol Myers Squibb and have equity. A.T. is employed by Adelphi Values, an agency that consults with various pharmaceutical companies. A.M. has received research funding from AbbVie, Celgene Corporation, Gilead, Pronai and TG Therapeutics; has been a consultant for AbbVie; and has been a member of a speakers’ bureau for Celgene Corporation., (© 2020 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

Diagnostic and molecular genetic testing are key in advancing the treatment of acute myeloid leukemia (AML), yet little is known about testing patterns outside of clinical trials, especially in older patients. We analyzed diagnostic and molecular testing patterns over time in 565 patients aged ≥ 55 years with newly diagnosed AML enrolled in the Connect ® MDS/AML Disease Registry (NCT01688011) in the United States. Diagnostic data were recorded at enrolment and compared with published guidelines. The percentage of bone marrow blasts was reported for 82.1% of patients, and cellularity was the most commonly reported bone marrow morphological feature. Flow cytometry, karyotyping, molecular testing, and fluorescence in situ hybridization were performed in 98.8%, 95.4%, 75.9%, and 75.7% of patients, respectively. Molecular testing was done more frequently at academic than community/government sites (84.3% vs 70.2%; P  < .001). Enrolment to the Registry after 2016 was significantly associated with molecular testing at academic sites (odds ratio [OR] 2.59; P  = .023) and at community/government sites (OR 4.85; P  < .001) in logistic regression analyses. Better understanding of practice patterns may identify unmet needs and inform institutional protocols regarding the diagnosis of patients with AML., Competing Interests: DAP: AbbVie, Bristol‐Myers Squibb, Daiichi Sankyo – advisory board member and consultancy; Agios, Forty Seven, Pfizer – advisory board member; Takeda – consultancy; Glycomimetics – data safety and monitoring committee. TIG: Bristol‐Myers Squibb – consultancy; MA: Bristol‐Myers Squibb – advisory board, AbbVie, Bristol‐Myers Squibb, Gilead, Seattle Genetrix, Takeda – speaker panel; CRC, JPM, GGM: no conflicts to disclose; RB: AbbVie, Astex Daiichi Sankyo, Forty Seven, NeoGenomics – consultancy; Bristol‐Myers Squibb – consultancy, honoraria, research funding; Xian‐Janssen – honoraria; KF: Bristol‐Myers Squibb – advisory board member. DLG: AbbVie – consultancy; Alexion – speakers bureau; Astellas, Bristol‐Myers Squibb – advisory board member. RSK: Alexion, Jazz Pharmaceuticals, Novartis – speakers bureau; Agios, Bristol‐Myers Squibb, Daiichi Sankyo, Inc., Incyte, Janssen, Pfizer – consultancy. DAR: Allergan, Amgen, Bristol‐Myers Squibb, Takeda – research funding and consultancy. GJR: AbbVie, Actinum, Agios, Amphivena, Argenx, Astex, Astellas, Bayer, Bristol‐Myers Squibb, Celltrion, Daiichi Sankyo, Eisai, Janssen, Jazz Pharmaceuticals, Novartis, MEI Pharma, Orsenix, Otsuka, Pfizer, Roche/Genentech, Sandoz, Takeda, Trovgene – consultancy, advisory board or data and safety monitoring committee; Cellectis – research funding. MRS: AbbVie – advisory board member, consulting; Boehringer Ingelheim – patents and royalties; Bristol‐Myers Squibb, Selvita – advisory board member; Incyte – advisory board member, research funding; Karyopharm – advisory board member, consultancy, equity ownership; Sunesis – research funding; Takeda, TG Therapeutics – advisory board member, research funding. BLS: Agios – speakers bureau; Alexion, Bristol‐Myers Squibb – advisory board member, consultancy, speakers bureau; Incyte – advisory board member, speakers bureau; Novartis – research funding. MAS: Bristol‐Myers Squibb, Pfizer, Takeda/Millenium – consulting. MAT: Adaptive, Bristol‐Myers Squibb, Doximity, GlaxoSmithKline, Strata Oncology, Syapse Precision Medicine Council, VIA Oncology, UpToDate – consultancy; Doximity – equity; AbbVie, Bristol Myers‐Squibb, CRAB CTC, Denovo, Hoosier Research Network, Lilly, LynxBio, Stata Oncology, Takeda, TG Therapeutics – institutional research funding; SEK: Agios and Bristol‐Myers Squibb – consultancy. CUL, MN, ASS, PK: Bristol‐Myers Squibb ‐ equity and employment. EDF: Bristol‐Myers Squibb – employment. DPS: Astex, Bristol‐Myers Squibb, Onconova, Pfizer, StemLine, Summer Road, Takeda – consultancy. HPE: Agios, Bristol‐Myers Squibb, Jazz Pharmaceuticals, Incyte, Novartis – speakers bureau; AbbVie, Agios, Amgen, Astellas, Bristol‐Myers Squibb, Daiichi Sankyo, Glycomimetics, ImmunoGen, Incyte, Jazz, MacroGenics, Novartis, Pfizer, Seattle Genetics – consultancy; AbbVie, Daiichi Sankyo, ImmunoGen, Macrogenics – research funding; Glycomimetics – data safety and monitoring committee; Covance – independent review committee., (© 2020 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

Optimal treatment of chronic lymphocytic leukemia (CLL) remains unclear. The Connect CLL Registry, a United States-based multicenter prospective observational cohort study, enrolled 1494 patients between 2010 and 2014 from predominantly community-based settings. Patients were grouped by line of therapy (LOT) at enrollment. With a median follow-up of 46.6 months (range, 0-63.0 months), median overall survival (OS) was not reached in LOT1, 63.0 months (95% confidence interval [CI], 46.0-63.0 months) in LOT2, and 38.0 months (95% CI, 33.0-47.0 months) in LOT≥3. Bendamustine and rituximab (BR; 33.5%); fludarabine, cyclophosphamide, and rituximab (FCR; 21.4%); and rituximab monotherapy (18.5%) were the most common regimens across LOTs. Median event-free survival (EFS) was similar in patients treated with BR (59.0 months) and FCR (55.0 months) in LOT1; median OS was not reached. In multivariable analysis, BR or FCR vs other treatments in LOT1 was associated with improved EFS (hazard ratio [HR], 0.60; P < .0001) and OS (0.67; P = .0162). Using the Kaplan-Meier product limit, ibrutinib vs other treatments improved OS in LOT2 (HR, 0.279; P = .009), LOT3 (0.441; P = .011), and LOT≥4 (0.578; P = .043). Prognostic modeling of death at 2 years postenrollment identified 3 risk groups: low (mortality rate, 6.2%), medium (14.5%), and high (27.4%). The most frequent adverse events across LOTs were pneumonia (11.6%) and febrile neutropenia (6.2%). These data suggest that advantages of LOT1 FCR over BR seen in clinical trials may not translate to community practice, whereas receiving novel LOT2 agents improved outcomes. This trial was registered at www.clinicaltrials.gov as NCT01081015., (© 2020 by The American Society of Hematology.)

Idiosyncratic hepatotoxicity is a leading reason for the discontinuation or dose modification of Food and Drug Administration (FDA)-approved medications in the United States. We report the case of a 53-year-old woman with chronic myeloid leukemia who developed acute cholestatic hepatitis in response to the tyrosine kinase inhibitor nilotinib. Nilotinib was discontinued, and the patient's liver function tests normalized over the next 3 months. We conclude that nilotinib may cause life-threatening hepatotoxicity and recommend that patients on the medication undergo regular monitoring of their liver tests., (© 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Introduction: Prognostic genetic testing is recommended for patients with chronic lymphocytic leukemia (CLL) to guide clinical management. Specific abnormalities, such as del(17p), del(11q), and unmutated IgHV, can predict the depth and durability of the response to CLL therapy., Patients and Methods: In the present analysis of the Connect CLL Registry (ClinicalTrials.gov identifier, NCT01081015), a prospective observational cohort study of patients treated across 199 centers, the patterns of prognostic testing and outcomes of patients with unfavorable-risk genetics were analyzed. From 2010 to 2014, 1494 treated patients were enrolled in the registry by line of therapy (LOT), and stratified by the results of cytogenetic/fluorescence in situ hybridization (FISH) testing into 3 risk levels: unfavorable (presence of del[17p] or del[11q]), favorable (absence of del[17p] and del[11q]), and unknown., Results: Cytogenetic/FISH testing was performed in 861 patients (58%) at enrollment; only 40% of these patients were retested before starting a subsequent LOT. Of those enrolled at the first LOT, unfavorable-risk patients had inferior event-free survival compared with favorable-risk patients (hazard ratio, 1.60; P = .001). Event-free survival was inferior with bendamustine-containing regimens (P < .0001). Event-free survival did not differ significantly between risk groups for patients treated with ibrutinib or idelalisib in the relapse/refractory setting. The predictors of reduced event-free survival included unfavorable-risk genetics, age ≥ 75 years, race, and treatment choice at enrollment., Conclusion: The present study has shown that prognostic cytogenetic/FISH testing is infrequently performed and that patients with unfavorable-risk genetics treated with immunochemotherapy combinations have worse outcomes. This underscores the importance of performing prognostic genetic testing for all CLL patients to guide treatment., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Chemoimmunotherapy for chronic lymphocytic leukemia (CLL) promotes clonal evolution of aggressive clones, which in some patients may lead to early progression of disease (POD). We studied the prognostic value of early POD in a cohort of patients with CLL enrolled between 2010 and 2014 in the Connect CLL Registry. Overall, 829 eligible patients receiving first-line therapy were categorized into 3 groups: early POD (progression <2 years after treatment initiation), late POD (progression ≥2 years after treatment initiation), and no POD as of 1 May 2017. Baseline demographics, treatment characteristics, and overall survival (OS) were analyzed. Logistic regression models identified independent predictors of early POD; Cox regression models were used to evaluate the risk of early POD. With a median follow-up of 48.8 months, 209 (25.2%), 162 (19.5%), and 458 (55.3%) patients had early, late, and no POD, respectively. Patients with early POD were older and had inferior response to similar first-line treatment regimens vs late and no POD groups (overall response rate: 53% vs 80% vs 84%). Patients with early POD were more likely to have unfavorable-risk cytogenetics (del[11q]/del[17p]) than patients with no POD (34% vs 20%; P = .04). Early POD was associated with an inferior OS across all patients (hazard ratio, 3.6; 95% confidence interval, 2.6-5.1; P < .01) and in patients treated with fludarabine, cyclophosphamide plus rituximab, and bendamustine plus rituximab ( P < .05). Early POD within 2 years of first-line therapy is a robust clinical prognostic factor for inferior OS in patients with CLL. The Connect CLL Registry was registered at www.clinicaltrials.gov as #NCT01081015., Competing Interests: Conflict-of interest disclosure: C.M.F. received research funding from Genentech and Gilead; received consulting and lecturing fees from Celgene Corporation, Genentech, Gilead, Janssen, Pharmacyclics, and Seattle Genetics; served on the advisory committee for Celgene Corporation; and received honoraria from Janssen. M.S.D. received research funding and served at the scientific advisory board for Genentech, Infinity, Pharmacyclics, and TG Therapeutics, and received consulting fees from AbbVie, Celgene Corporation, Gilead, Infinity, Janssen, Merck, and AstraZeneca. D.L.G. received consulting and lecturing fees from Celgene Corporation. N.E.K. received research funding from Gilead, Morphosys, Celgene Corporation, and Pharmacyclics. N.L. received research funding from AbbVie, Genentech, Gilead, Infinity, and Pronai; received consulting fees from AbbVie, Genentech, Gilead, Pharmacyclics, and Pronai; and served on the advisory committee for Celgene Corporation. A.M. received research funding from AbbVie, Gilead, Pronai, and TG Therapeutics; received consulting fees from AbbVie; and received lecturing fees from Celgene Corporation. C.N. is an employee of Cardinal Health. P.K., A.S.S., E.D.F., and K.S. are employees of Celgene Corporation and have equity ownership in Celgene Corporation. J.P.S. received consulting fees from Celgene Corporation, Genentech, Gilead, Pharmacyclics, and TG Therapeutics, and received lecturing fees from Gilead. C.R.F. received research funding from AbbVie, Acerta, Gilead, Millennium, Infinity, Janssen, Pharmacyclics, Spectrum, and TG Therapeutics, and received consulting fees from Bayer, Celgene Corporation, Genentech/Roche, Gilead, Millennium, Optum Rx, and Seattle Genetics. I.E.A. declares no competing financial interests.

Background: Median age at diagnosis of patients with chronic lymphocytic leukemia (CLL) is > 70 years. However, the majority of clinical trials do not reflect the demographics of CLL patients treated in the community. We examined treatment patterns, outcomes, and disease-related mortality in patients ≥ 75 years with CLL (E-CLL) in a real-world setting., Methods: The Connect® CLL registry is a multicenter, prospective observational cohort study, which enrolled 1494 adult patients between 2010-2014, at 199 US sites. Patients with CLL were enrolled within 2 months of initiating first line of therapy (LOT1) or a subsequent LOT (LOT ≥ 2). Kaplan-Meier methods were used to evaluate overall survival. CLL- and infection-related mortality were assessed using cumulative incidence functions (CIF) and cause-specific hazards. Logistic regression was used to develop a classification model., Results: A total of 455 E-CLL patients were enrolled; 259 were enrolled in LOT1 and 196 in LOT ≥ 2. E-CLL patients were more likely to receive rituximab monotherapy (19.3 vs. 8.6%; p < 0.0001) and chemotherapy-alone regimens (p < 0.0001) than younger patients. Overall and complete responses were lower in E-CLL patients than younger patients when given similar regimens. With a median follow-up of 3 years, CLL-related deaths were higher in E-CLL patients than younger patients in LOT1 (12.6 vs. 5.1% p = 0.0005) and LOT ≥ 2 (31.3 vs. 21.5%; p = 0.0277). Infection-related deaths were also higher in E-CLL patients than younger patients in LOT1 (7.4 vs. 2.7%; p = 0.0033) and in LOT ≥ 2 (16.2 vs. 11.2%; p = 0.0786). A prognostic score for E-CLL patients was developed: time from diagnosis to treatment < 3 months, enrollment therapy other than bendamustine/rituximab, and anemia, identified patients at higher risk of inferior survival. Furthermore, higher-risk patients experienced an increased risk of CLL- or infection-related death (30.6 vs 10.3%; p = 0.0006)., Conclusion: CLL- and infection-related mortality are higher in CLL patients aged ≥ 75 years than younger patients, underscoring the urgent need for alternative treatment strategies for these understudied patients., Trial Registration: The Connect CLL registry was registered at clinicaltrials.gov: NCT01081015 on March 4, 2010.

The clinical course of chronic lymphocytic leukaemia (CLL) is heterogeneous, and treatment options vary considerably. The Connect ® CLL registry is a multicentre, prospective observational cohort study that provides a real-world perspective on the management of, and outcomes for, patients with CLL. Between 2010 and 2014, 1494 patients with CLL and that initiated therapy, were enrolled from 199 centres throughout the USA (179 community-, 17 academic-, and 3 government-based centres). Patients were grouped by line of therapy at enrolment (LOT). We describe the clinical and demographic characteristics of, and practice patterns for, patients with CLL enrolled in this treatment registry, providing patient-level observational data that represent real-world experiences in the USA. Fluorescence in situ hybridization (FISH) analyses were performed on 49·3% of patients at enrolment. The most common genetic abnormalities detected by FISH were del(13q) and trisomy 12 (45·7% and 20·8%, respectively). Differences in disease characteristics and comorbidities were observed between patients enrolled in LOT1 and combined LOT2/≥3 cohorts. Important trends observed include the infrequent use of genetic prognostic testing, and differences in patient characteristics for patients receiving chemoimmunotherapy combinations. These data represent experiences of patients with CLL in the USA, which may inform treatment decisions in everyday practice., (© 2016 The Authors. British Journal of Haematology published by John Wiley & Sons Ltd.)

The AVIDA registry evaluated azacitidine usage and effectiveness in unselected patients with myelodysplastic syndromes (MDS) in community practice. Treating physicians made all treatment decisions. Hematologic improvement (HI) and transfusion independence (TI) assessments used International Working Group (IWG) 2000 criteria. Enrolled were 421 patients with MDS (n = 228 International Prognostic Scoring System [IPSS] lower-risk, n = 106 higher-risk, 86 patients unclassified) from 105 US sites. Median follow-up was 7.6 months (range: 0.1-27.6). HI and red blood cell TI rates were similar regardless of administration route or dosing schedule. Safety and tolerability were consistent with previous reports. The AVIDA registry data support azacitidine effectiveness and safety in patients with lower- or higher-risk MDS treated in community practice.

Objective: To evaluate medication adherence, pharmacokinetics and exposure versus response relationships in patients with myelodysplastic syndromes (MDS)., Methods: Ninety adult patients with MDS received oral topotecan (1.2 mg/m2) either once a day for 10 days or twice a day for 5 days every 21 days for up to six cycles. Dosing histories were collected using electronic monitoring devices fitted to medication vials. Topotecan plasma concentrations were measured, and exposure was determined by a sparse sampling approach and Bayesian estimation methods. Relationships between exposure and clinical response and toxicity were evaluated using logistic regression., Results: Overall adherence was excellent with 90% of patients taking the prescribed number of doses in cycle 1. Adherence did not differ between the two regimens. Topotecan pharmacokinetics were described using a one compartment open model with first order absorption and elimination. Pharmacokinetic parameter estimates did not differ between the once a day and twice a day dosing groups. While topotecan exposure was greater in the twice a day arm compared to the once a day arm due to drug accumulation, exposure did not correlate with clinical response. However, the probability of needing a platelet transfusion in the twice a day arm was significantly increased (by 35%) as a result of greater steady-state plasma topotecan concentrations., Conclusions: Adherence is high in patients with MDS receiving oral topotecan, whether the drug is prescribed once or twice daily. The optimal schedule cannot be determined from this study, as there was no evident relationship between any pharmacokinetic parameter and clinical response.

Guillain-Barré syndrome, or acute inflammatory demyelinating polyradiculoneuropathy, and immune thrombocytopenic purpura are both autoimmune disorders thought to result from molecular mimicry in response to an antecedent introduction of foreign antigen. Guillain-Barré syndrome is an ascending motor paralysis that can lead to respiratory compromise. Immune thrombocytopenic purpura is an isolated disorder of platelet destruction leading to mucocutaneous bleeding. Guillain-Barré does not typically occur with other autoimmune disorders, and concurrent Guillain-Barré and immune thrombocytopenic purpura has only rarely been reported. We present a patient with both conditions who experienced prompt resolution of neurologic and hematologic sequelae after intravenous immunoglobulin therapy was initiated within 12 hours of presentation. The case provides further evidence that Guillain-Barré syndrome and immune thrombocytopenic purpura can occur simultaneously, possibly caused by a similar pathogenic mechanism, as well as suggesting that the prompt initiation of intravenous immunoglobulin is an effective monotherapy leading to prompt resolution of both conditions and prevention of further sequelae.

Background: DS60 is a novel buoyant density solution, whose density has been adjusted to enrich PBSC from subjects who have been mobilized with cytokines alone, or cytokines plus chemotherapy. This report describes the use of BDS60 to enrich autologous PBSC that were used for hematological reconstitution after myeloablative chemotherapy in women with breast cancer., Methods: Fifty-one consecutive patients with high-risk Stage II or III breast cancer or chemotherapy-sensitive Stage IV breast cancer were enrolled. Forty-seven completed treatment and were evaluable. After mobilization with cyclophosphamide (4.0 g/m(2) i.v. once) and filgrastim (10 microg/kg/day), the patients underwent leukapheresis and the products were enriched with BDS60 using the DACS300 Kit. Myeloablative chemotherapy, given on Day -5 through Day -2, consisted of cyclophosphamide (1.5 g/m(2)/day), thiotepa (150 mg/m(2)/day) and carboplatin (200 mg/m(2)/day)., Results: Forty-one patients underwent a single leukapheresis procedure to achieve the target number of BDS60-enriched CD34+ cells for transplantation (> or = 2 x 10(6)/kg). Five of the other six patients had less than the target number of cells in the leukapheresis product and thus required 2-4 leukapheresis procedures. Median cell recovery was 76.8% for CD34+ cells, 39.1% for nucleated cells, and 17.7% for platelets. Erythrocyte contamination of the final product was negligible. The median time to sustained neutrophil count > 500/mm(3) was 9 days (range: 8-12) and the median time to platelet count > 20 000/mm(3), without transfusion support, was also 9 days (range: 6-15). There were no late graft failures. Infusion-related adverse events were mild and no adverse events were attributed to the use of BDS60 to enrich CD34+ cells., Discussion: BDS60 is an effective, rapid method for enrichment of CD34+ cells by buoyant density centrifugation and the resulting cell product is safe and effective for engraftment after myeloablative therapy.

A subgroup of patients with refractory Hodgkin's (HD) or non-Hodgkin's (NHL) lymphoma may be cured with high-dose chemotherapy and peripheral blood progenitor cell rescue. To investigate the relationship of adequate leukapheresis yield and time course of platelet recovery after mobilization chemotherapy, we retrospectively analyzed the leukapheresis yields in seven patients with Hodgkin's disease and fifteen patients with non-Hodgkin's lymphoma undergoing high-dose chemotherapy. Our goal was to develop a rule to determine when to initiate leukapheresis and then to prospectively validate this rule. All patients were mobilized with cyclophosphamide and G-CSF (granulocyte-colony stimulating factor). A total of 144 leukaphereses were completed and analyzed. Based on the CD34 content in the initial harvest product, fifteen patients were defined as poor mobilizers (CD34 < 0.15 x 10(6)/kg) and seven were good mobilizers. The platelet count on the first day of harvesting was significantly associated with the poor mobilizers (P = .03). Age, sex, marrow involvement, disease (HD vs. NHL), prior radiation, time since last chemotherapy, and total number of cycles of prior chemotherapy were not predictive of poor mobilizers. By using a platelet count cut off of 35 x 10(9)/L, we retrospectively analyzed 144 individual leukapheresis products, to test whether CD34 yield was predicted by the peripheral blood platelet count on the day of leukapheresis. This rule had an excellent sensitivity, 91%, and a specificity of 67%. Subsequently, we validated this rule with the next twenty-four patients undergoing leukapheresis of which there were 143 leukaphereses. The prediction rule exhibited a sensitivity of 72% and a specificity of 68% in the validation set. There does appear to be utility in using the platelet count to guide the initiation of leukapheresis after chemotherapy and G-CSF mobilization.

Background: Paclitaxel, an effective chemotherapeutic agent in the management of breast carcinoma, may have activity in women whose disease has recurred after high dose chemotherapy. With this is mind the authors explored the addition of a 120-hour continuous infusion of paclitaxel to a previously reported regimen comprised of high dose cyclophosphamide and thiotepa., Methods: Thirty-one women with advanced breast carcinoma (30 patients with Stage IV disease and 1 patient with Stage IIIB disease) underwent harvest and cryopreservation of bone marrow and/or peripheral blood progenitor cells. High dose cyclophosphamide (2.5 g/m2) and thiotepa (225 mg/m2) were administered intravenously on Days -7, -5, and -3. Paclitaxel was administered as a 120-hour continuous infusion starting on Day -7., Results: Three patients were treated at the initial cohort dose of 50 mg/m2 (over 120 hours), 6 patients at 100 mg/m2, 6 patients at 125 mg/m2, 6 patients at 150 mg/m2, 6 patients at 180 mg/m2, and 4 patients at 210 mg/m2. All patients completed the treatment protocol as planned with no associated transplant-related deaths. Mucositis as evidenced by either stomatitis or noninfectious diarrhea was experienced by all patients and was determined to be the dose-limiting toxicity at the 210 mg/m2 dose level. One patient with dose-limiting mucositis required intubation for airway protection and also experienced Grade 3 (according to the Cancer and Leukemia Group B common toxicity grading scale) pulmonary and neurologic toxicity. Only one Grade 3 toxicity was encountered below the maximum tolerated dose in a patient who developed diffuse alveolar hemorrhage at a dose of 125 mg/m2. No allergic reactions or clinical evidence of peripheral neuropathies were encountered. Cardiac, hepatic, and renal toxicities were minimal. Response rates in this previously treated patient population were difficult to assess in light of the high incidence of bone metastases; an overall response rate of 24% was obtained., Conclusions: Paclitaxel at a dose of 180 mg/m2 as a 120-hour continuous infusion may be added safely to high dose cyclophosphamide and thiotepa with autologous stem cell rescue. Further studies are ongoing to evaluate the efficacy and further define the toxicity of this recommended Phase II dose.