bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clearance of leukemic blasts by flow cytometry versus minimal residual disease as predictors of clinical outcome in elderly patients with acute myeloid leukemia.
Authors: Rossi Giovanni , Giambra Vincenzo , Minervini Maria Marta , de Waure Chiara , Giacchetta Irene , la Torre Antonella , Ciavarella Michele , Melillo Lorella M , Scalzulli Potito Rosario , Carella Angelo Michele , Cascavilla Nicola 
Published: May 2020

e19514 Background: Lower-intensity regimens, such as hypomethylating agents (HMAs) are better tolerated and more effective than standard chemotherapy in elderly patients( > 65 years old) with acute myeloid leukemia (AML). Scoring systems to predict clinical outcome in these patients are mainly based on cytogenetic assays and morphological response to therapy. Minimal residual disease (MRD) represents a powerful risk- stratification in younger AML patients but it remains poorly investigated in older patients, particularly in those undergone HMAs. In this subset, the survival benefit is not limited to patients achieving morphologic complete remission (CR). The clearance of leukemic blasts was never be valued as a predictive parameter of outcome in older patients. Thus, in this study we evaluated the most effective and predictive factor of outcome at the optimal time-point among leukemic blasts clearance by flow cytometry (FC), MRD and morphological response in older patients treated with HMAs. Methods: From april 2015 to may 2019, 76 older patients ( > 60 years old) with newly diagnosed AML were treated con azacitidine and decitabine. Among them, 56 completed at least six cycles but 31were properly monitored by FC. Log Clearance was defined as logarithmic ratio between the percentage of blast cells at specific time point and that at the diagnosis. Results: A total of 31 elderly patients with a median age 72 (60-85) were evaluated after 4(T4) and 6(T6) cycles of HMAs. A Median of 10 cycles were administered, equally distributed between azacitidine and decitabine. A higher frequency of CR (73.3%vs 20%) and MRD negativity (16.6% vs 0) was found at T6 compared to T4, thus T6 was chosen for the analysis. Performance status (PS > 2),Hgb < 10 g/dl, MRD positivity and a Log-reduction lower than 2 log predicted a significantly shorter DFS at univariate analysis. However, Log-reduction and PS only confirmed to predict a short DFS also at multivariate analysis, together with CRi (CR with incomplete recovery) and partial remission (PR). When the OS was investigated, only PS represented a strong indicator of prognosis at both univariate and multivariate analysis. Conclusions: Our results suggest that patients achieving 2 Log at least of blasts-reduction by FC had a longer DFS. Dynamic monitoring of blast –reduction stratified better and more widely than the absolute value of MRD in older AML patients. Having a high PS and achieving a CRi instead of a CR showed an unfavorable outcome in terms of both DFS and OS
Pharmacokinetics/pharmacodynamics of liposomal cytarabine (VYXEOS) in AML patients: Influence of cytidine deaminase genetic polymorphisms.
Authors: Donnette Mélanie , Venton Geoffroy , Farnault Laure , Pourroy Bertrand , Costello Regis , Lacarelle Bruno , Ouafik L'Houcine , Ciccolini Joseph , Fanciullino Raphaëlle 
Published: May 2020

e19517 Background: Vyxeos is a liposomal formulation of daunorubicin and cytarabine recently approved for treating adults with newly-diagnosed sAML subtypes therapy-related (t-AML) or AML with myelodysplasia-related changes (AML-MRC). The objective of this pilot study was to evaluate the influence of cytidine deaminase, the enzyme responsible for cytarabine detoxification step in the liver, on drug exposition and clinical outcome. Methods: In this proof-of-concept study, 9 adult patients were treated with Vyxeos. CDA status (i.e., determination of Poor Metabolizer or Extensive Metabolizer phenotypes) was evaluated before treatment by measuring residual CDA activity in serum. Pharmacokinetic sampling was performed 90min before infusion stops, then from T4H to T168H after the end of the infusion. Total cytarabine, encapsulated cytarabine and released cytarabine were discriminated and assayed using a validated LC-MS/MS method. Results: Nine Vyxeos patients (3M, 6F, 66 ±13 years) were included in this pilot study. Aplasia duration was significantly longer in AML-MRC patients than in AML-t (38 ±5.5 days VS. 28 ±3 days, respectively (p < 0.05)). All AML-t had complete response after induction phase (VS. 60% in AML-MRC, p > 0.05). Similar cytarabine exposure was measured in both population. Surprisingly, 8 out of 9 patients (i.e., 88%) were identified as CDA PM (CDA < 2UI/mg). Marked differences in pharmacokinetics were observed between PM and EM patients. Total, encapsulated and released cytarabine AUC’s were 2.77, 1.42, and1.46 mg/ml*h in PM patients. In EM patient, total, encapsulated and released cytarabine AUC’s were 0.97, 0.76 and 0.17 mg/ml*h. When available, microscopy analysis confirmed the presence of liposomes in patients bone marrow. Conclusions: Differences in clinical outcome between AML-t and AML-MRC patient are not supported by differences in exposure levels upon Vyxeos administration. Surprisingly, we found that CDA status has a strong impact on cytarabine pharmacokinetics since PM patients treated with Vyxeos present a +185% increase in cytarabine levels as compared with EM patient. This suggests that upfront CDA testing could help to predict clinical outcome.
Allogeneic stem cell transplantation in elderly lymphoma patients: Single-center experience.
Authors: Gulbas Zafer 
Published: May 2020

e19519 Background: Autologous stem cell transplantation is used as consolidation therapy in relapsed lymphoma patients. However, outcome of lymphoma patients relapsing after autologous stem cell transplantation is poor and allogeneic stem cell transplantation which can be curative is used in the transplant eligible patients in this setting. Besides, allogeneic stem cell transplantation can be an option before autologous stem cell transplantation in some high risk patients. In this study, we aimed to analyze the results of lymphoma patients older than 60 years of age who had undergone allogeneic transplantation in our center. Methods: We collected the data of lymphoma patients older than 60 years of age who had undergone allogeneic transplantation in our center and analyzed the results. Results: There were 20 patients over the age of 60 who had undergone allogeneic stem cell trasplantation with the diagnosis of lmphoma between 2011 and 2019. 18 patients had Non-Hodgkin lymphoma and 2 patients had Hodgkin lymphoma. 12 patients (60%) had been transplanted from HLA-matched sibling, while 6 patients (30%) had been transplanted from unrelted donors and 2 patients (10%) had been transplanted from haploidentical donors. The median age of the patients was 62 (61-66) and 30% of the patients were female. During the follow-up time only 1 patient had relapsed. The 2 year progression free survival (PFS) rate was 32% and the 2 year overall survival (OS) rate was 32%. The OS curve is shown in Figure 1. 100 day mortality was 30% and 1 year non-relapse mortalty (NRM) was 50%. The characteristics and results of the patients are summarized in Table 1. Conclusions: In the present study, although the number of patients is low, we showed that lymphoma patients over 60 years of age have a 2 year overall survival rate of 32% and a relapse rate of 5% suggesting that allogeneic stem cell transplantation which has a curative potential may be employed in transplant eligible elderly lymphoma patients.
A population-based study of chronic neutrophilic leukemia in the United States: 2004 to 2015.
Authors: Ruan Gordon , Smith Caleb , Day Courtney N. , Harmsen William S. , Zblewski Darci , Alkhateeb Hassan , Al-Kali Aref , Litzow Mark Robert , Hogan William J. , Szuber Natasha , Gangat Naseema , Patnaik Mrinal , Pardanani Animesh Dev , Elliott Michelle A. , Tefferi Ayalew , Go Ronald S. , Shah Mithun Vinod 
Published: May 2020

e19538 Background: Chronic neutrophilic leukemia (CNL) is a rare and aggressive myeloproliferative neoplasm with poor survival. No standard of care exists. Case reports describe allogeneic stem cell transplantation (ASCT) as the only curative therapy. Using the National Cancer Database (NCDB), we studied prognostic factors and survival outcomes of CNL. Methods: Patients diagnosed in 2004-2015 were included. 9963/3 was the ICD-O-3 code. Overall survival (OS) was analyzed using the Kaplan-Meier method. Hazard ratios (HR) with confidence intervals (CI) were calculated using Cox proportional hazards model. Variables significant in univariate analysis were included in a multivariate analysis. Data on incidence was obtained from the Surveillance, Epidemiology, and End Results Program (SEER) 21 Registries (2004-2015). The analysis was done with SEER*Stat software. Incidence was age-adjusted to the U.S. 2000 standard population. Results: A total of 121 CNL patients were in NCDB. The median age at diagnosis was 70 years (range 21-90); 74 (61%) were males and 107 (88%) were ≥ 50 years. The median follow up time was 5.8 years (interquartile range [IQR] 2.9-7.4). 32 (26%) had a Charlson Deyo score (CDS) > 1. 80 (70%) had government insurance, while 34 (30%) had private insurance. Median OS was 2.2 years (IQR 0.8-6.7). OS was 70% at 1 year, 29% at 5 years, and 11% at 10 years. The year of diagnosis was not associated with improved OS (HR: 0.95 (95% CI: 0.88-1.02), p =0.14). 71 (59%) patients received chemotherapy. The median time to chemotherapy from the day of diagnosis was 15 days (IQR 7-35). The OS of those who received chemotherapy was 71% at 1 year and 27% at 5 years versus 69% and 32% at 1- and 5- years for those who did not ( p= 0.38). 2 patients received ASCT (age 52 and 61 years) as initial therapy and both were alive at 5 years. Factors predicting inferior OS on univariate analysis were age ≥ 50 years at diagnosis ( p= 0.005), male ( p< 0.001), CDS > 1 ( p= 0.038), and government insurance ( p= 0.004). The table shows the multivariate (MV) analysis. The overall incidence of CNL was 0.1 cases/1,000,000 individuals and did not change significantly from 2004-2015. The incidences by male, female, White, Black, and American Indian/Alaska Native were also 0.1 cases/1,000,000 individuals. Conclusions: OS and incidence of CNL have not changed over the years. Age ≥ 50 years, male gender, and use of government insurance predicted inferior OS. [Table: see text]
A comparison of CD34+ mobilization effects of standard dose pegfilgrastim (Peg) versus low-dose peg combined with plinabulin (Plin).
Authors: Blayney Douglas W. , Huang Lan , Mohanlal Ramon W. 
Published: May 2020

e20000 Background: Plin is a novel, small molecule immune-enhancing agent with in vitro anticancer activity currently in Phase (Ph) 3 clinical trials for NSCLC treatment and Chemotherapy (Chemo)-Induced Neutropenia (CIN). Single agent (SA) Plin is equally effective as Peg for the prevention of CIN, however does not cause bone pain and is given on the same day of Chemo by 30 min IV infusion, 30 min after Chemo (Blayney ASH 2018). SA Plin also mobilizes CD34+ cells to clinically relevant levels (Blayney ASH 2019). Plin has been administered to > 600 patients (pts) and has a favorable safety/tolerability profile. In clinical practice, Peg dose is often reduced to 3 mg in patients (pts) experiencing side effects with standard dose (6 mg) Peg, such as bone pain, myalgia and leucocytosis (Kim ASCO 2010; Goodman Oncology Times 2008; Lacovelli JHOP 2012; Lower Cancer Chemother Pharmacol 2018). We evaluated CD34+ cell counts and adverse events (AE) with low dose Peg combined with Plin vs full dose Peg. Methods: In a subset of Breast Cancer pts in the CIN Ph 2 trial BPI-2358-106 (NCT0329457) receiving TAC (taxotere (75), doxorubicin (50 ) and cyclophosphamide (500) mg/m2, pts also received either Peg 6mg (n = 7) or low dose peg ( n = 9, of which 7pts received 3mg and 2 pts 1.5 mg Peg) combined with Plin (20 mg/m2). CD34+ counts were obtained by central laboratory FACS analysis (Covance) at screening (SC), Day (D) 6,8 and 21 cycle 1 (see table below) and AE frequency was collected. Results: Clinical trial information: NCT0329457 . Frequency of bone pain, myalgia and leukocytosis was numerically lower with low dose Peg/Plin vs 6mg Peg. Conclusions: Under highly myelosuppressive TAC Chemo conditions, CD34+ counts increased significantly (p < 0.03) vs predose SC in cycle 1 in the low dose Peg/Plin goup. CD34+ counts were not different for full dose Peg vs low dose Peg/Plin in cycle 1. Adverse Events were fewer with the low dose Peg/Plin. The Peg/Plin combination is worthy of test in hematopoietic stem cell mobilization regimens. [Table: see text]
Clonal lineage analysis of CLL research samples by IGH chain sequencing to reveal novel CLL subgroups defined by ongoing class-switch recombination and somatic hypermutation.
Authors: Looney Timothy , Quest Graeme , Feilotter Harriet , Davis Zadie 
Published: May 2020

e20001 Background: B cell somatic hypermutation (SHM) and class switch recombination (CSR) are mechanistically related but distinct processes requiring precisely targeted generation and repair of single and double strand DNA breaks. Within the context of chronic lymphocytic leukemia (CLL), the presence of ongoing SHM or CSR may reveal the functionality of DNA damage repair pathways, with potential relevance to therapeutic strategies involving the generation of DNA breaks or inhibition of DNA repair machinery. Here we apply clonal lineage analysis of IGH chain sequencing data to evaluate CSR and SHM in a cohort of CLL and splenic marginal zone lymphoma (SMZL) research samples. We present evidence of ongoing CSR and SHM in a significant subset of samples. Methods: Multiplex primers targeting the IGH framework 1 region and isotype region (Oncomine IGH-LR assay; detection of all nine isotypes) were used for IGH repertoire sequencing via the Ion Gene Studio S5 from 25ng peripheral blood total RNA derived from 63 individuals with CLL and 4 individuals with SMZL. Clonotyping and clonal lineage analysis was performed by Ion Reporter, whereby clonal lineages are defined as sets of unique rearrangements having a shared variable and joining gene, the same CDR3 length, and a minimum CDR3 nucleotide similarity of 85%. Ongoing CSR was defined as the presence of IgM/IgD and at least one switched isotype (IgG, IgA, or IgE), or a combination of switched isotypes, within the same lineage. Ongoing SHM was defined as the presence of subclones that differ within the VDJ region sequence compared to other clonal lineage members. Results: 11/68 cases showed evidence of ongoing CSR or SHM. Of the 57 cases showing no evidence of ongoing CSR or SHM, variable gene mutation analysis revealed the presence of three distinct subgroups having either no SHM, intermediate SHM (average 98% sequence identity) or high SHM < 94% identity). 3 of 4 SMZL cases showed evidence of ongoing CSR or SHM. Conclusions: These results reveal previously underappreciated heterogeneity within CLL and suggest the subdivision of CLL based on a combination of IGHV mutation level and presence of ongoing SHM or CSR. The described heterogeneity may serve as a valuable criterion for stratifying CLL patients in the future.
Retrospective cohort study of real-world treatment patterns and overall survival in patients with chronic lymphocytic leukemia (CLL) diagnosed between 2010 to 2017 in Ontario, Canada.
Authors: Hassan Shazia , Hurry Manjusha , Seung Soo Jin , Walton Ryan , Elnoursi Ashlie , Scheider Krystin , Edwin Jonathan , Wagner Dennis , Aw Andrew Ta Wei 
Published: May 2020

e20003 Background: With recent advances in treatment of CLL, it is important to understand emerging treatment patterns and associated outcomes. A population-based study was undertaken to describe the management and survival of CLL patients in Ontario, Canada. Methods: Patients diagnosed with CLL between January 1, 2010 and December 31, 2017 were identified in the Ontario Cancer Registry and linked to provincial administrative databases. Treatment patterns by line of therapy were characterized, including analyses of time to initiation and between therapies. Overall survival was calculated. Results: 2,887 CLL patients were identified (median age 68yr; 67% male). The mean time from diagnosis to first line (1L) treatment was 651 days with 35% of patients receiving fludarabine-cyclophosphamide-rituximab (FCR) based treatment. During the study period, 71% of patients did not yet receive second line (2L) therapy and did not have subsequent follow up, while 19% received 2L ibrutinib. Median time to 2L initiation from 1L treatment discontinuation was 636 days. The table summarizes 1L and 2L therapies. Of the 827 patients on 2L therapy, 65% received ibrutinib. After the introduction of publicly funded novel agents in 2015, a shift in treatment patterns away from FCR and chlorambucil based regimens was observed. Overall mean survival for the cohort from diagnosis was 6.8yrs, and mean 5 year probability of survival was 72.4%. Conclusions: A shift in treatment patterns for CLL can be seen with the introduction of newer therapies, such as ibrutinib. The results can support healthcare decision-makers by characterizing the size of this patient population, real world treatment patterns and survival outcomes for patients with CLL. [Table: see text]
Neutropenia analysis of venetoclax monotherapy in patients with relapsed or refractory chronic lymphocytic leukemia: Pooled data from VENICE-I and -II Phase IIIb trials.
Authors: Anderson Mary Ann , Davids Matthew Steven , Kater Arnon P. , Cochrane Tara , Demirkan Fatih , Herishanu Yair , Leber Brian , Nikitin Eugene , Masud Abdullah A. , Rosenberg Tanya S. , Sharmokh Simon , Fort Stan , Forconi Francesco 
Published: May 2020

e20011 Background: Neutropenia is a common hematologic Grade (Gr) 3+ adverse event (AE) recorded in patients with chronic lymphocytic leukemia (CLL) receiving venetoclax (VEN). In this analysis, we evaluated fixed duration VEN monotherapy given to patients with relapsed or refractory (R/R) CLL with and without pre-existing Gr3+ neutropenia. Methods: This post-hoc analysis pooled data from patients in the ongoing Phase 3b trials VENICE-I and VENICE-II with R/R CLL who had received ≥1 dose of VEN monotherapy (ramp-up to 400 mg QD). Gr4 hematologic AEs and Gr3+ neutropenia ( < 1000 cells/mm3) with infection or fever were managed using dose interruption/reduction. Granulocyte colony stimulating factor (G-CSF) was used in Gr3+ neutropenia. Results: At data cutoff (June 30, 2019), 44/468 (9%) patients had Gr3+ neutropenia at baseline (BL; Gr3+ neutropenia group), 80% of whom received G-CSF during the study vs 38% of those with < Gr3 neutropenia at BL ( < Gr3 neutropenia group). Median on-study duration for VEN was 20.2 months (range: 0.1–36.1). Median number of prior CLL therapies was 2 for both groups (range: 1–10). Serious infections were experienced by 10/44 (23%) and 69/424 (16%) of patients in the Gr3+ and < Gr3 neutropenia groups, respectively. The most common AEs leading to discontinuation overall were second primary malignancies (13/468; 3%). 5/468 (1%) patients in the total population discontinued due to neutropenia/febrile neutropenia. One case of Gr5 infection with concomitant Gr3 neutropenia was reported in the < Gr3 neutropenia group post-VEN discontinuation. See Table. Conclusions: In this large post-hoc analysis, discontinuation due to neutropenia was rare (1%) in the overall population and accounted for 3/11 AE discontinuations in the Gr3+ neutropenia group; 10 patients had a serious infection. Patients with pre-existing neutropenia can be managed on VEN, though concurrent use of G-CSF is likely to be required. Additional data to follow. Clinical trial information: NCT02756611; NCT02980731 . [Table: see text]
Survival analysis of CLL/SLL patients with Richter’s transformation to DLBCL: An analysis of the SEER database.
Authors: Elnair Radowan , Ellithi Moataz , Kallam Avyakta , Bleeker Jonathan , Bociek Gregory 
Published: May 2020

e20024 Background: Richter's transformation (RT) from Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) to a Diffuse Large B-Cell Lymphoma (DLBCL) is a rare complication with an estimated incidence of less than 5% and a poor prognosis based on small retrospective studies. Large studies investigating the natural history and patient outcomes with this entity of DLBCL are lacking, and prospective data on the best treatment option are scarce and limited by rarity of this condition. Methods: We queried the US Surveillance, Epidemiology, and End Results (SEER) 18 database for patients sequentially diagnosed with CLL/SLL followed by DLBCL from January 2000 to December 2016 with a cutoff latency of 2 months. Data obtained included patient demographics, history of treatment for CLL/SLL, overall survival (OS) after DLBCL diagnosis and latency period between CLL/SLL and DLBCL diagnoses. For comparison, SEER data was obtained for patients with de novo DLBCL and for CLL/SLL patients without RT in the same date range. Survival was estimated by Kaplan Meier method and log rank test was used to compare outcomes. Results: 471 patients who developed RT to DLBCL and 98425 patients with de novo DLBCL were identified. The median time for developing RT to DLBCL was 54 months. Median OS was worse for DLBCL arising from RT compared to de novo DLBCL (64 months versus 10 months, p < 0.0001). In patients with RT to DLBCL, no statistically significant difference in median OS was seen in patients who received treatment for CLL/SLL versus those assigned as No/Unknown treatment status (p = 0.51). In patients with CLL/SLL in the specified time period; median OS was significantly lower for those who developed RT to DLBCL compared to those who did not (91 months versus 100 months, p = 0.0012). Conclusions: DLBCL arising from RT in CLL/SLL patients is not necessarily a late complication. Prognosis is dismal with a trend towards a poor OS in the subset of patients with pretreated CLL/SLL. This large population study correlates with prior reports and highlights the need for prospective data to inform prognosis and treatment decisions.