bluuebunny/crossref_metadata_2025 huggingface dataset:
Treatment-related deaths (TRD) in investigator-initiated cancer cooperative group trials: From the datasets of 44 studies (4,964 patients) by the Japan Clinical Oncology Group (JCOG)
Authors: Kanato K. , Nakamura K. , Saito I. , Takashima A. , Tomii Y. , Kaba H. , Shibata T. , Fukuda H. , Sato A. , Shimada Y.
Published: August 2020

6632

Background: The proportion of Serious Adverse Events (SAE) including TRDs has a critical impact on choosing a new standard therapy as well as the efficacy of treatment in clinical trials. The proportion of TRD (%TRD) has been reported in a single clinical trial, but an overall % TRD in plural clinical trials has merely been evaluated so far. Methods: The JCOG trials which met both of the following criteria were included in this analysis: i) started after 1995 by 2008, ii) primary analysis was completed. In JCOG, attribution of all reported SAE are classified by Data and Safety Monitoring Committee into 5 categories (definite, probable, possible, unlikely, not related) according to causality to protocol treatment, and the death with causality judged as definite, probable, or possible is defined as TRD. The total number of any deaths and TRD were counted in all included trials and the incidences (%) of TRD were calculated. The association between %TRD and the following trial profiles was evaluated: arm (standard vs. testing), phase, modality and median survival time of each arm. Results: In total, 44 JCOG trials (67 arms) with 4,964 patients were included in the analysis. The number of all deaths and TRD were 2,974 and 60. Thus, the overall %TRD for all enrolled patients was 1.2% (95%CI, 0.9–1.6%), and %TRD among all deaths was 2.0% (95%CI, 1.5–2.6%). Major results of the association between %TRD and trial profiles are shown in the table. The later phase trials showed the lower %TRD, and the trials with shorter MST tended to have higher %TRD. Conclusions: When the trial is in earlier phase and includes more advanced disease, the trial should be planned and performed more carefully about minimization of patient risk.

[Table: see text]

No significant financial relationships to disclose.
Subcutaneous or intravenous administration of romiplostim in thrombocytopenic patients with myelodysplastic syndrome (MDS)
Authors: Sekeres M. , Kantarjian H. , Fenaux P. , Becker P. , Boruchov A. , Guerci-Bresler A. , Hu K. , Franklin J. , Berger D.
Published: August 2020

7009

Background: Thrombocytopenia is common in patients (pts) with MDS, and treatment options are currently limited to platelet (plt) transfusions. Romiplostim is an Fc-peptide fusion protein (peptibody) that stimulates plt production by the same mechanism as thrombopoietin. Methods: This was a phase II, multicenter, single arm, open-label study. Eligibility criteria included IPSS low or intermediate-1 risk MDS and a mean baseline plt count ≤50x109/L. Safety and efficacy of romiplostim were evaluated in pts receiving 750μg romiplostim according to one of 3 schedules: weekly or biweekly subcutaneous injections (QWSC or Q2WSC), or biweekly intravenous injections (Q2WIV). Plt responses were measured per IWG 2006 criteria. Results: Of the 28 pts enrolled, 17 (61%) completed the study; 22 (79%) were male and the mean (±SD) baseline plt count was 29 (±10) x 109/L. The mean age was 71 years and 19 pts (68%) had received plt transfusions in the past year. Mean duration of exposure to romiplostim was 12 (±8) weeks. The most common adverse events (AEs) were fatigue and headache (both 18%). Five pts experienced serious AEs, and there were 2 cases of disease progression to AML: one pt in the QWSC cohort who received romiplostim for 4 weeks and one in the Q2WSC cohort who received romiplostim for 20 weeks. For pts who completed 8 weeks treatment, 15/23 (65%) achieved a plt response, defined by IWG 2006 criteria, and 14/23 (61%) did not require a plt transfusion during this period. The small number of pts limited the ability to compare administration schedules; minor differences were observed in plt responses and plt transfusions, and the incidence of AEs appeared similar among cohorts. Conclusions: IV and SC romiplostim appeared well-tolerated and effective in raising plt counts and avoiding plt transfusions in low and intermediate-1 risk MDS pts. The dose recommendation for future studies is 750μg, given QW or Q2W SC.

[Table: see text]

[Table: see text]
Prognostic value of FLT3 mutations among different cytogenetic subgroups in acute myeloid leukemia (AML)
Authors: Santos F. P. , Qiao W. , Cortes J. E. , Jones D. , Ravandi F. , Verma D. , Kantarjian H. , Borthakur G.
Published: August 2020

7015

Background: Mutations of the FLT3 gene (in special internal tandem duplication -ITD) are common in normal karyotype AML (NK-AML) and are associated with shorter relapse free and overall survival (OS). The frequency of FLT3 mutations is lower in other cytogenetic subgroups and the impact on outcome is unclear. Methods: The records of patients (pts) with newly diagnosed AML (from 2003 to 2007) were reviewed. Pts were divided among three cytogenetic subgroups: Good-risk (t(8;21), Inv(16)/t(16;16)) Intermediate-Risk (Diploid,-Y) and Poor Risk (-5,-7, 11q abnormalities). FLT3 ITD and tyrosine kinase domain (TKD) mutations were determined on baseline DNA samples by a PCR based method with 1% sensitivity. Since the frequencies of FLT3 mutations were lower in good- and poor-risk subgroups, ITD/TKD mutations were considered together in the analysis, while in the intermediate risk group they were analyzed separately. Survival curves stratified by FLT3 mutation were estimated by Kaplan Meier plots and compared by logrank test. A Cox model was fit for OS, and non-significant variables were eliminated in a step-down fashion with a p- value cut-off of p = .10. Results: A total of 481 pts were included (65 pts=good risk, 272 pts=intermediate risk and 144 pts= poor risk). Prevalence of FLT3 mutations is shown in the Table. No difference was found in median OS between FLT3-mutated and FLT3- wild type pts in the good risk group (not reached (NR) vs NR, P = 0.57) nor in the poor risk group (55 vs 24 weeks, P = 0.44). In intermediate risk, OS was worse in FLT3-ITD positive pts (33 vs 89 weeks, P < 0.0001) but not in FLT3-TKD positive pts (77 vs 70 weeks, P = 0.89). In the Cox model, FLT3 mutations were prognostic for OS only in intermediate risk pts with FLT3-ITD (HR 2.63, P < 0.0001). Conclusions: In our cohort of pts, FLT3 mutations did not have a prognostic impact in AML with good and poor risk karyotype.

[Table: see text]

No significant financial relationships to disclose.
Results of a phase I study of clofarabine (CLO) plus cyclophosphamide (CY) in adult patients (pts) with relapsed and/or refractory acute lymphoblastic leukemia (ALL)
Authors: Faderl S. , Thomas D. A. , Gandhi V. , Huang X. , Borthakur G. , O'Brien S. , Ravandi F. , Plunkett W. , Bretz J. L. , Kantarjian H. M.
Published: August 2020

7020

Background: CLO is a second generation nucleoside analog with FDA approval for children with ALL relapse. Single agent CLO in adult ALL was less active so that combinations of CLO with other active agents are pursued. As CLO inhibits DNA repair following exposure to DNA damaging agents, we designed a phase I study of the combination of CLO with CY. Methods: Pts ≥ 21 years (yrs) with primary refractory or relapsed ALL, NYHA class < 3, and a cardiac ejection fraction ≥ 45% were eligible. The continual reassessment method (CRM) was used to determine the maximum tolerated dose (MTD) from 4 pre-defined dose levels. The starting dose level was CLO 40 mg/m2 i.v. daily x 3d and CY 200 mg/m2 i.v. q12h x 3d. For cohort 2, CY was 300 mg/m2 and cohorts 3 and 4 maintained these doses with the treatment duration extended to 4 and 5 days, respectively. Results: Thirty pts have been enrolled. Median age was 28 yrs (range 21–72). Twenty-one pts had pre-B ALL, 5 pts pre-T/T ALL, 1 pt mature B ALL, and 3 pts biphenotypic acute leukemias. Karyotype was diploid in 10 pts and 2 pts had Ph+ ALL. Median number of prior regimens was 2 (1–5). Seven (23%) pts were primary refractory. Among the remainder, preceding median remission duration was 8.6 mos (1–39 mos). Five pts were treated in cohort 1 and 25 in cohort 2. One (20%) pt in cohort 1 and 9 (36%) in cohort 2 experienced DLTs (≥ grade 3) including transaminase elevations, diarrhea, hyperbilirubinemia, and (1 pt each) elevation of creatinine/renal failure, lipase elevation, rash, nausea/vomiting. Evaluable for response were 28 pts: 3 CR (one pt in cohort 1) and 1 marrow CR (OR 14%). All pts had pre-B ALL. One pt had Ph+ ALL, and one was primary refractory to HCVAD. Three early deaths due to infectious complications occurred (all in cohort 2). Conclusions: The MTD for this combination is CLO 40 mg/m2 i.v. daily x 3d and CY 200 mg/m2 i.v. q12h x 3d. DLT are mainly GI-related. A phase II extension is ongoing and will focus on efficacy data.

[Table: see text]
A randomized phase II study of sapacitabine, an oral nucleoside analogue, in elderly patients with AML previously untreated or in first relapse or previously treated MDS
Authors: Garcia-Manero G. , Luger S. , Venugopal P. , Maness L. , Wetzler M. , Coutre S. , Stock W. , Borthakur G. , Chiao J. , Kantarjian H.
Published: August 2020

7021

Background: Sapacitabine is a novel nucleoside analogue with a unique ability to cause irreparable single-strand DNA breaks and induce G2 cell cycle arrest. It is orally administered and has demonstrated promising anti-leukemic activity against relapsed or refractory AML and MDS in a phase 1 trial. We are conducting a multi-center, open-label, randomized phase 2 study to evaluate 3 dosing regimens of this drug. Methods: Eligible patients must be ≥70 years with AML previously untreated or in first relapse or ≥60 years with MDS previously treated with hypomethylating agents. The planned sample size is 60 AML patients and 60 MDS patients. Patients are to be randomized 1:1:1 to receive one of the 3 dosing regimens. The primary efficacy endpoint is 1-year survival. Secondary efficacy endpoints include rate of CR, CRi, or hematological improvement (HI) and response durations. Results: As of December 2008, 60 AML and 13 MDS patients were enrolled and had ≥ 30 days of follow-up. Preliminary efficacy data were available for the AML stratum. Overall response rate is 31% (13% CR/CRp, 5% PR and 13% HI). Median time to CR/CRp is 3–4 cycles (range 1–7). Eight deaths of all causes occurred within 30 days of randomization and all were in the AML stratum (13%). One death was considered to be possibly related to sapacitabine. Common adverse events (all grades, regardless of causality) included fatigue, nausea, vomiting, diarrhea, constipation, anemia, leukopenia, febrile neutropenia, neutropenia, thrombocytopenia, dyspnea and peripheral edema, most of which were mild to moderate in intensity. Conclusions: These interim data suggest that sapacitabine is safe and active across all 3 dosing schedules. Updated data will be presented at the meeting.

[Table: see text]

No significant financial relationships to disclose.
Effect of antithymocyte globulins (ATG) as part of the myeloablative conditioning (MAC) regimen on the risk of severe graft-versus-host disease (GVHD) after allogeneic stem cell transplantation (allo-SCT) from matched-unrelated donors (MUD)
Authors: Mohty M. , Balere M. , Socie G. , Milpied N. , Ifrah N. , Harousseau J. L. , Michallet M. , Blaise D. , Esperou H. , Yakoub-Agha I.
Published: August 2020

7025

Here, we report the results of a multicenter retrospective study analyzing the effect of ATG, incorporated within the MAC regimen for MUD-transplants in leukemic patients. The purpose of the study was to compare the incidence and severity of acute and chronic GVHD as well as overall outcome. 171 adult patients with acute leukemia and MDS, for whom detailed allelic HLA typing (4 digits) was available, were included. 81% of patients were transplanted from 10/10 allelic MUD, and 19% from a MUD with at least one allelic difference. 120 patients (70%) did not receive ATG (no-ATG group), while 51 patients received ATG (ATG group; thymoglobuline* in all cases) as part of the MAC regimen. Except for a significantly higher number of allelic differences between recipient and donor (33% vs. 13%; p = 0.002), the no-ATG and ATG groups were strictly comparable. With a median follow-up of 30.3 (range, 2.6–68.1) months, grade 0–1 and 2–4 acute GVHD occurred in 74 (46%) and 88 patients (54%) respectively, with grade 3–4 acute GVHD being significantly lower in the ATG group (18% vs. 32%; p = 0.04). Extensive chronic GVHD was significantly lower in the ATG group (5% vs. 33%; p = 0.001). Patients from the ATG group had a higher incidence of limited chronic GVHD (33% vs. 18%; p = 0.06). Moreover, infection-related mortality was comparable between both groups (23% vs. 27%, p = NS). Also, NRM was comparable between both groups (30% vs. 29%; p = NS). In multivariate analysis, an HLA allelic mismatch and the non-use of ATG were associated with an increased risk of grade 3–4 acute GVHD (RR = 2.80, 95% CI, 1.5–5.3, p = 0.001; and RR = 2.4, 95% CI, 1.1–5.0, p = 0.02 respectively). Similarly, multivariate analysis showed that the absence of use of ATG was the unique parameter associated with an increased risk of extensive chronic GVHD (RR = 6.9; 95% CI, 1.7–29.0, p = 0.008). Finally, LFS and OS at 2 years were not significantly different between the no-ATG and ATG group (48.8% vs. 41.3%, p = NS; and 53.6% vs. 54.3%, p = NS; respectively). These results suggest a global long-term beneficial effect of ATG when used as part of the MAC regimen prior to allo-SCT from MUD (especially in the HLA mismatch setting).

No significant financial relationships to disclose.
Usefulness of the hematopoietic cell transplantation-specific comorbidity index (HCT-CI) in predicting outcomes for adolescents and young adults (AYAs) with hematologic malignancies (HM) undergoing allogeneic stem cell transplant (alloSCT)
Authors: Wood W. A. , Deal A. M. , Moore D. T. , Whitley J. , Sharf A. , Serody J. S. , Gabriel D. A. , Shea T. C.
Published: August 2020

7034

Background: The HCT-CI was developed to help predict overall survival (OS) and non-relapse mortality (NRM) in pts undergoing alloSCT, a procedure with significant toxicity. AYAs with cancer (ages 16–40) have been identified by the NCI as a high-risk group, but it is not known whether the HCT-CI is a useful predictor of outcomes in this relatively healthy population. Methods: All pts ages 16–39 at the time of alloSCT from 1992–2008 were included. HCT-CI was retrospectively calculated for pts with complete data available. Univariable Cox regression models were used to examine the association between covariates and OS and NRM. Results: 62 evaluable pts included 38 males and 24 females. 50 (81%) were Caucasian, 9 (15%) African American, and 3 (5%) other. Diseases included AML (23), CML (14), ALL (14), and other (11). All comorbidities had a frequency of <5% in this population except for pulmonary dysfunction (69%), hepatic dysfunction (27%), infection (19%), and psychiatric disturbance (10%). When dichotomized into categories of 0–2 (32) and >3 (30), the HCT-CI was significantly associated with OS (p = 0.0006) and marginally with NRM (p = 0.07). Because pulmonary dysfunction appeared to be the most important contributor to the HCT-CI, the diffusing capacity adjusted for hemoglobin and alveolar volume (DLCO/VA adj) was examined independently. When dichotomized into categories of <80% and >80% of normal, the DLCO/VA adj alone was also significantly associated with OS (p = 0.008), but not with NRM (p = 0.2). Conclusions: AYAs with HM undergoing alloSCT have a limited number of comorbidities in the HCT-CI. Pulmonary dysfunction is most prevalent, and the DLCO/VA adj alone appears to be nearly as predictive for OS as the HCT-CI. The discrepancy between the predictiveness for OS and NRM may reflect pre-treatment or disease status of this population at the time of transplant.

No significant financial relationships to disclose.
A phase II study of voreloxin as single agent therapy for elderly patients (pts) with newly diagnosed acute myeloid leukemia (AML)
Authors: Maris M. B. , Ravandi F. , Stuart R. , Stone R. , Cripe L. , Cooper M. , Strickland S. , Turturro F. , Stock W. , Berman C.
Published: August 2020

7048

Background: Voreloxin is a naphthyridine analog that intercalates DNA and inhibits topoisomerase II, inducing apoptosis. Interim results of REVEAL-1, a phase II study of single agent voreloxin in newly diagnosed elderly AML pts, are reported. Methods: Phase II study of 3 voreloxin schedules (approximately 30 pts/schedule): A) 72 mg/m2qw x 3; B) 72 mg/m2qw X 2; or C) 72 mg/m2/dose on D1 and D4. Eligibility: newly diagnosed AML (de novo or secondary AML), pts age ≥ 60 and ≥ 1 additional adverse risk factor (age ≥ 70, secondary AML, intermediate or unfavorable cytogenetics, or PS 2). PK were evaluated in a pt subset in cycle 1. ex vivo sensitivity of pt BMA to voreloxin was evaluated by CellTiter-Glo proliferation assay. Results: Enrollment targets for schedules: A) (29) and B) (31) are met. Demographics (N = 54): 66% male, 35% female; median age 75 years; ECOG PS 0–1 90%, PS 2 10%. 20% AHD and cytogenetics were intermediate in 29%, unfavorable in 34%, and unknown in 36%. Final CR + CRp rate: A) 38%; B) too early to evaluate. Median duration of remission has not been reached. Thirty day all-cause mortality: A) 17%; B) 1 of 22, 4.5%. Infection was the most common cause of early mortality. Tolerability improved markedly in B): G3 or higher pneumonia (A 24%, B 11%) and mucositis (A 21%, B 11%) incidence were reduced. Voreloxin PK were similar to those in an earlier single agent phase I study in relapsed/refractory AML. C) enrollment is pending. Ex-vivo sensitivity did not predict clinical response. Conclusions: In REVEAL-1, voreloxin demonstrates clinical activity with 2 dosing schedules in previously untreated elderly (age ≥ 60) patients with AML who are unlikely to benefit from standard chemotherapy. CR + CRp rate was 38% (11 of 29 pts) for 3 weekly voreloxin doses (A). Early results from 2 weekly voreloxin doses (B) show 6 CR + CRp of 21 evaluable pts, with 2 pts in heme recovery, and improved tolerability. Enrollment to (C), voreloxin dosed D1 and D4, is pending.

[Table: see text]
High-sensitivity detection of M351T, F317L, and F311C BCR-ABL kinase domain mutation in chronic myeloid leukemia patients treated with novel tyrosine kinase inhibitors (TKIs) imatinib and dasatinib
Authors: Mir A. R. , Sazawal Sazawal S. , Saxena A. , Saxena R.
Published: August 2020

7061

Objectives: (1) To study the detection of M351T, F317L, and F311C ABL kinase domain mutation in CML patients treated with TKIs (imatinib and dasatinib). (2) To evaluate the effect of imatinib dose esculation in the CML patients carrying M351T mutations. Methods: One hundred CML patients were treated with imatinib at 400 mg/day from 2 to 4 years .They were diagnosed by RT-PCR for BCR-ABL transcripts. Early screening for the M351T, F317L, and F311C mutations was performed by allele specific-oligonucleotide-PCR (ASO-PCR). Results: We evaluated 100 CML patients for kinase domain mutation by ASO-PCR after three years of imatinib initiation. Patients were categorized into three groups. Group A All 100 CML patients were treated with imatinib at conventional dose of 400 mg/day and were screened for M351T mutation after three years of imatinib initiation. (40%) 40/100 were positive for M351T mutation consequently 20/40 were treated with high dose imatinib at 600 to 800 or 1,000 mg/day. After 11 months of dose escalation, 15/20 lost M351T mutation but remaining five who resist M351T mutation, developed a more fatal mutation called gate keeper mutation T315I. 2/5 died, three progressed to advanced disease. Group B All 100 CML patients were screened for F311C mutation after three years of imatinib initiation and (10%) 10/100 were positive. After 10 months, 4/10 developed a more fatal mutation in 315 and consequently 2/4 died and one progressed to advanced disease. Group C It included 12 imatinib-resistant CML patients treated with dasatinib at 70 to 100 mg/day. At the initiation of dasatinib, no one was positive for F317L and T315I mutation. After 10 months of dasatinib treatment, all were screened for F317L/ T315I mutation by ASO-PCR, 4/12 were positive for F317L mutation and no one was positive for T315I mutation. After 6 months of mutation detection 2/4 progressed to blast crisis, and 1/4 died. Conclusions: ASO-PCR proved to be a very economical, sensitive, and rapid technique for detection of KD mutations M351T, F317L, and F311C ABL mutation and is more sensitive than mutation detection by sequencing. The detection of M351T, F317L, and F311C -ABL mutation at any stage has prognostic significance.

No significant financial relationships to disclose.
Imatinib mesylate experience of young patients with chronic myeloid leukemia in chronic phase—Care to cure
Authors: Biswajit D. , Rejiv R. , Manjunath N. , Prasad G. , Lakshmi S. , Devika P. , Geetha K. , Sagar T. G.
Published: August 2020

7072

Background: Chronic myeloid leukemia (CML) with introduction of imatinib has been transformed into a chronic illness. The options of treatment in a patient less than 35 years include imatinib or allogenic stem cell transplantation. Hence we studied this unique subset to look at the response rates, adverse effects, progression free survival, and overall survival with imatinib mesylate. Methods: 477 patients with Philadelphia positive CML in chronic phase were retrospectively analyzed from January 2002 to December 2007 at Cancer Institute (WIA), Chennai, India. Standard criteria were used for response evaluation and adverse effects. Results: A total of 248 young CML patients with age less than 35 years (51.9%) were diagnosed in chronic phase. The median age of study population was 27 years (4–35). The male to female ratio was 1.9: 1. Risk stratification was done using Sokal index and were classified into low (32.3%), intermediate (50.4%), and high (17.3%). All patients received imatinib 400 mg as the initial dose. Complete hematological remission (CHR) was seen in 96.7%.Cytogenetic (FISH) and molecular (RTPCR) monitoring was possible in 53.2% and 17.3%, respectively. 72% of the patients had major cytogenetic response. Major molecular response was seen in 34.8% while complete molecular response occurred in 23.2% of the patients. Primary and secondary imatinib failure was seen in 3.1% and 16.9%, respectively. 6.7% had grade 3 and grade 4 hematological toxicities. The other common non hematological toxicities included pedal edema (13.7%), hypo or hyper pigmentation (60.0%), hyalgia (14.5%), diarrhea (1.6%), and liver dysfunction (1.6%). None of the patients discontinued imatinib due to toxicities. The 3-year DFS and OS was 86.2% and 89.5%, respectively. Patients with male sex (p = 0.04), spleen > 8 cm (p = 0.02), high sokal index (p = 0.02), and loss of CHR (p < 0.001) were associated with poor outcome. Conclusions: Imatinib in young patients have an excellent tolerance and response. A small subset does not respond to therapy or develop resistance during treatment. Hence it is essential to identify these poor responders and to offer stem cell transplantation at the earliest.

No significant financial relationships to disclose.
A phase II pilot study of valproic acid in relapsed/refractory chronic lymphocytic leukemia
Authors: Ganesan P. , Raina V. , Kumar R.
Published: August 2020

7081

Background: Valproic acid (VA) has demonstrated cell-kill by triggering pro-apoptotic pathways in chronic lymphocytic leukemia (CLL) in preclinical studies. We studied the safety and efficacy of VA in patients with relapsed and refractory CLL. Methods: Adult patients with CLL diagnosed by the NCI-WG criteria who had received at least one previous fludarabine-based therapy and subsequently progressed or relapsed with ECOG performance status (PS) ≤3 and normal organ functions were included. Patients were started on VA 10 mg/kg which was gradually increased to 20 mg/kg. Efficacy (NCI-WG criteria) and safety (NCI common toxicity criteria) were assessed at 3 months. Responding patients were continued on the study medication. Results: Five patients have so far been included, age 48–70 years (mean 62 years); sex: 3 males/ 2 females; disease duration: 2–16 years (mean 5.4 years). Previous therapies included fludarabine/alkylators in all patients; in addition rituximab was given in one and lenalidomide in two. Three patients have completed three months of therapy and are evaluable. One patient had partial response and one had stable disease. In the third patient the total leucocyte count continued to rise but there was response in other parameters like decrease in lymphadenopathy by 50%, stabilization of hemoglobin, increase in absolute neutrophil (ANC) and platelet counts. Two of these patients who were requiring 2–3 blood transfusions per month and frequent admissions for infectious complications have not required further transfusions or hospital admissions since starting VA. Significant improvements were also seen in their ECOG PS from 3 to 0–1, 61% and 230 % rise in ANC and 50% and 83% rise in platelet counts. Grade 3 hypersensitivity skin rashes developed in one patient at one month and the therapy was discontinued. Most patients had mild drowsiness and two patients had significant weight gain of grade 2. Conclusions: VA produces very impressive palliation in advanced/ refractory CLL in terms of improvement of hemoglobin, ANC, platelets, PS, and a reduction in the number of infective episodes –apparently a sequel to significant rise in neutrophils. We are encouraged by these results and are continuing the study.

No significant financial relationships to disclose.
The pharmacokinetics of azacitidine following subcutaneous treatment in patients with myelodysplastic syndromes (MDS) or acute myelogenous leukemia (AML)
Authors: Laille E. , Ward R. , Nasser A. , Stoltz M. , Cogle C. , Gore S. , Skikne B. S. , Garcia-Manero G.
Published: August 2020

7087

Background: 5-azacitidine (AZA), through its effects on DNA metabolism, gene expression, and cell differentiation, has proven beneficial in treatment of MDS and AML and AZA therapy significantly increases survival in higher-risk MDS and AML compared to conventional care. Few studies have evaluated the pharmacokinetics (PK) of AZA and the renal elimination of AZA has not been previously published to our knowledge. Plasma PK of AZA are herein reported in patients receiving SC doses of 75 mg/m2. This study was designed to also assess the contribution of renal elimination to the overall clearance of AZA. Methods: Adult patients with MDS or AML and ECOG status 0–2 were treated with 7 consecutive daily SC doses of 75 mg/m2 AZA during their first treatment cycle. PK parameters of AZA were derived from drug concentrations in plasma and urine collected after the first and last dose (day 7) of AZA. Safety was evaluated by adverse event reporting (NCI-CTC). Results: Currently, 18 patients have been treated with SC AZA. AZA was rapidly absorbed and reached peak plasma concentrations (concs) within 0.5 hr post dosing. The AUCinf after SC doses was 1170 hr*ng/mL. The AZA concs declined in a pseudo bi-phasic manner with an elimination half-life of 1.25 hours. The plasma PK profiles after the first and last dose were superimposable. The apparent total clearance (CL/F) and volume of distribution (Vd/F) were 143 L/hr and 318 L, respectively. AZA recovery in urine was very small relative to dose (<2%). AZA was well tolerated and no unexpected toxicities were observed. Conclusions: The AZA AUCinf after SC doses is similar to the published AUC value (1044 hr*ng/mL) after 75 mg/m2 IV doses indicating approximating 100% systemic bioavailability. After SC dosing, CL/F exceeded hepatic blood flow indicating extra-hepatic metabolism. Vd/F was 4–5 fold greater than total body water suggesting extensive AZA tissue distribution. Renal elimination appears to play a minor role in the overall clearance of AZA.

[Table: see text]
Abrogation of tumor necrosis alpha (TNF-alpha) pathway by anti-TNF therapy in hematological malignancies
Authors: Ramanarayanan J. , Pahuja S. , Elefante A. N. , Hernandez-Ilizaliturri F. J.
Published: August 2020

7093

Background: Tumor necrosis factor-alpha (TNF-alpha) enhances tumor growth and mediates cancer-related inflammatory symptoms by inducing secretion of cytokines. Anti-TNF approaches have been evaluated in pilot studies for cancer treatment and for alleviation of cancer related cachexia, fatigue, and other constitutional symptoms with conflicting results. While the incidence of malignancies with TNF alpha inhibitors (infliximab, adalimumab, etanercept) are not significantly higher than the untreated control population, their role in cancer treatment itself is unclear. We explored the activity and tolerance of TNF-alpha inhibitors in various hematological malignancies. Methods: We reviewed the English literature by conducting systematic MEDLINE using the terms TNF-, infliximab, adalimumab, etanercept, cancer therapy, hematologic malignancies, myelodysplastic syndrome (MDS), multiple myeloma (MM), myeloproliferative disease (MPD), chronic lymphocytic leukemia (CLL), and lymphoma from January 2001 to August 2008. We also performed a complete literature search of American Society of Hematology (ASH) and American Society of Clinical Oncology (ASCO) published abstracts. Studies were analyzed for observed activity of TNF alpha inhibitors and also for reported safety. Results: Overall 11 phase I and II studies (n = 237; CLL n = 44, MM n = 10, MDS n = 109, MPD n = 51, HCL n = 3, TCL 13, FL 7) that involved anti-TNF- therapy in hematological malignancies were identified. As a single agent, etanercept did not yield significant responses. In conjunction with ATG or azacitidine in low-/intermediate-risk MDS, TNF inhibitors resulted in improvement in cytopenia. Improvement in constitutional symptoms were noted in at least 50% of patients with myelofibrosis(MF)/Ph- MPD. No significant clinical benefit was seen among lymphoproliferative disorders, but treatment was well tolerated. Conclusions: Existing data suggests that anti-TNF therapy by itself does not induce a therapeutic response in hematologic malignancies. Combination strategy with TNF inhibitors has to be evaluated further to determine any anti-tumor activity and their role to alleviate constitutional symptoms particularly in MF/MPD.

No significant financial relationships to disclose.
Effect of mobilization chemotherapy with cyclophosphamide and etoposide on stem cell collection by lenalidomide
Authors: Talamo G. , Claxton D. F. , Ehmann W. C. , Mierski J. , Rybka W. , Ibrahin S.
Published: August 2020

7096

Background: The combination of dexamethasone and lenalidomide is currently considered one of the standards of care for induction therapy of patients with multiple myeloma (MM) before autologous stem cell transplantation (ASCT). Increasing evidence suggests that lenalidomide impairs the ability to collect peripheral blood stem cells (PBSC). Methods: We retrospectively analyzed the outcomes of PBSC collections of MM patients who received induction therapy with dexamethasone and lenalidomide, and who were collected with either granulocyte-colony stimulating factor (G-CSF) alone, 10–16 mcg/Kg/day (group A, n= 12), or G-CSF 5 mcg/kg/day + mobilization chemotherapy, consisting of cyclophosphamide 5,000 mg/m2 and etoposide 1,000 mg/m2 (group B, n=27). In all patients, lenalidomide was stopped 2 weeks before the predicted day of PBSC collection. Results: The median number of PBSC collected was 3.2 million CD34+ cells/Kg in group A (range, 0.3–6.3) and 28.1 million CD34+ cells/Kg in group B (range, 4.8–134) (p<0.01). The median number of days to collect PBSC was 1 in group A (range, 1–4) and 2 in group B (range, 1–5) (p=0.015). Three patients in group A failed to collect an adequate number of PBSC, either for a single ASCT (n=1) or tandem ASCT (n=2). No PBSC collection failures were observed in group B. No difference in the rapidity of PBSC engraftment was seen between the two groups. Conclusions: Chemotherapy with cyclophophamide and etoposide can overcome the inhibitory effect of lenalidomide in the collection of PBSC for ASCT in MM patients.

No significant financial relationships to disclose.
Expansion of umbilical cord blood mesenchymal stem cells
Authors: Peters R. E. , Heikenwälder M. , Knuth A.
Published: August 2020

7103

Background: Umbilical cord blood (UCB) is known to harbor 2 major types of stem cells, the hematopoietic stem cells (HSC) & the non-hematopoietic or mesenchymal stem cells (MSC). Under appropriate conditions, MSCs can give rise to cells of bone, fat, hepatic lineages, etc. Based on this potential, MSC hold promise for clinical applications in regenerative medicine. Methods: Stroma-free liquid culture: UCB cryopreserved mononuclear cells (MNC) were cultured in the presence of early growth factors: Flt-3 & SCF (25ng/ml), MGDF (10ng/ml) & human serum (10%). MNC derived adherent MSC were passaged at day 14 during HSC expansion & after enriching in MesenCult medium. Results: We developed a technology to generate & expand HSC & stromal/ MSC from all UCB units (5/5) at the same time using one culture system (stroma-free liquid culture). Following repeated passages, MSC count increased 357- 600-folds & CFU-Fibroblasts colonies (CFU-F) increased too (61–513 & 648–697) after 10 and 20 passages respectively. We used the CFU-F assay to demonstrate MSC activity in stromal cell formation in vitro. Phenotypically, MSC were negative for hematopoietic antigens (CD45, CD34 & CD14) & MHC class-II but >95% + for CD73, CD105, CD29, CD44 & MHC class I. To demonstrate MSC differentiation capacity in vitro, cells were incubated in various induction media to differentiate into adipocytes (fat)), osteoblasts (bone) and hepatocytes (liver) at passage 5. Following induction, positive staining with oil red O for cells of adipocyte and with alkaline phosphatase for cells of osteoblsts lineages was observed. The identity of hepatocytes was verified by the characteristic hexagonal hepatocytic shape as well as albumin, cytokeratin (CK) 18 and CK14 expression, as assessed by flow cytometry. Our data were corroborated by RT-PCR analysis. Conclusions: MSC described herein exhibit in vitro properties of multipotent stem cells. The established, stroma-free culture system facilitates expansion of MSC from all tested UCB units. Our data underline that it will be possible in the future to substitutes properly differentiated hepatocytes which might lead to efficient applications in patients suffering from various end stage liver disease.

No significant financial relationships to disclose.
The role of prophylactic antimicrobials during autologous stem cell transplantation: A single center experience
Authors: Yoon D. , Sohn B. , Kim J. , Yoo C. , Kim S. , Lee D. , Kim S. , Huh J. , Lee J. , Suh C.
Published: August 2020

7105

Background: The aim of this retrospective study was to investigate the efficacy of antibiotic prophylaxis during autologous peripheral stem cell transplantation (ASCT) in patients with multiple myeloma (MM) and non-Hodgkin's lymphoma (NHL). Methods: We searched Asan Medical Center Registry for NHL and MM: Total 114 cases received antimicrobial prophylaxis; while 118 cases did not receive antimicrobial prophylaxis during ASCT. Results: In prophylaxis group, 80 of 114 (70.2%) patients had experienced febrile episodes at median day +6 after transplantation with a statistically significant difference (P<0.001). In no-prophylaxis group, 111 of 118 (94.1%) patients had experienced at median day +5. Documented infection occurred in 14 of 114 (12.3%) patients in prophylaxis group, and 16 of 118 (13.6%) patients in no-prophylaxis group (P=0.846). In these patients, the positive blood culture was seen in 12 (10.5%) of 114 patients in prophylaxis group, and 12 (10.7%) of 118 patients in no-prophylaxis group (P=1.000). Documented viral infection or reactivation was not observed in prophylaxis group, but observed in 4 patients of no-prophylaxis group. Both groups showed no invasive fungal infection or serious adverse event during ASCT. The day of infection resolved was a median day +15 (range, 3–29) in prophylaxis group and day +14 (range, 2–70) in no-prophylaxis group (P=0.945). The duration of antimicrobial treatment was median 10 days both in prophylaxis group and in no-prophylaxis group (P=0.565). Conclusions: In our experience, the antimicrobial prophylaxis seems to decrease the incidence of febrile episodes during ASCT, but seems to have no beneficial effect on reducing infectious complications. The antimicrobial prophylaxis of our study did not show the difference in the detection of causative organism as an infective agent, duration of antimicrobial therapy and hospitalization between two groups.

No significant financial relationships to disclose.
Results of autologous transplants for lymphomas from a tertiary cancer center in India
Authors: Jeevangi N. , Joshi A. , Shah M. , Kannan S. , Gupta S. , Nair R. , Khattry N.
Published: August 2020

7106

Background: Autologous stem cell transplanation is the standard of care for patients of relapsed and refractory non-Hodgkin's lymphoma (NHL) and Hodgkin's lymphoma (HL). We report the results of transplants in lymphomas from our center and role of possible prognostic factors. Methods: All 50 consecutive patients who underwent transplant for HL (70%) and NHL (30%) from August 1994- August 2008 were included in this retrospective study. Fifty eight percent of patients received BEAM (carmustine, etoposide, ara-c and melphalan), 30% LACE (lomustine, ara-c, cyclophosphamide and etoposide), 8% ICE (ifosfamide,carboplatin and etoposide) and 4% high dose melphalan (200mg/m2) conditioning regimens. Seventy eight percent of patients received peripheral blood stem cells (PBSC), 8% bone marrow (BM) and 14% both PBSC and BM. Prognostic factors evaluated for progression free survival (PFS) were serum albumin level and body mass index (BMI) at the time of transplant, stage at diagnosis and source of stem cells, while for over all survival (OS), status of disease at transplant was also included. Results: The median time to transplant was 2.25 years from the time of diagnosis. The median age at transplant was 25 years. Seventy four percent of patients were male. At the time of transplant, thirty two percent were in complete remission (CR), 50% in partial remission (PR) and 18% had refractory disease (RD). The median serum albumin and BMI at the time of transplant were 4 g/dl and 22.5 kg/m2 respectively. The best disease response rate was 86% (CR+PR) in patients evaluable for response. Thirteen patients relapsed at a median interval of 11 months post transplant. The cumulative probability of OS and progression free survival PFS at 5 years were 40% and 34% respectively for the whole group. Multivariate analysis using cox regression identified serum albumin greater than 4 g/dl and those receiving PBSC grafts as independently associated with improved OS and PFS. Conclusions: These data provide the first published report of outcomes of autologous transplants in lymphomas from India. Our data suggests that serum albumin level at the time of transplant and stem cell source are important prognostic factors for PFS and OS.

No significant financial relationships to disclose.
Randomized, phase III study of mitomycin/vindesine/cisplatin (MVP) versus weekly irinotecan/carboplatin (IC) or weekly paclitaxel/carboplatin (PC) with concurrent thoracic radiotherapy (TRT) for unresectable stage III non-small cell lung cancer (NSCLC): WJTOG0105
Authors: Satouchi M. , Yamamoto N. , Chiba Y. , Kudoh S. , Hida T. , Kubo A. , Seto T. , Nishimura Y. , Nakagawa K. , Fukuoka M.
Published: August 2020

7504

Background: Weekly chemotherapy with concurrent TRT displays acceptable toxicities and dependable efficacy. We conducted a randomized phase III trial to assess the efficacy and toxicity of weekly chemotherapy with concurrent TRT against MVP with concurrent TRT via a non-inferiority design. Methods: MVP: mitomycin (8 mg/m2 on days 1, 29), vindesine (3 mg/m2 on days 1, 8, 29, 36), and cisplatin (80 mg/m2 on days 1, 29) with concurrent TRT (60 Gy). Patients (pts) subsequently received 2 courses of consolidation chemotherapy with MVP; IC: weekly irinotecan (20 mg/m2)/carboplatin (AUC 2) for 6 weeks and TRT (60 Gy) followed by 2 courses of irinotecan (50 mg/m2)/carboplatin (AUC 5); PC: weekly paclitaxel (40 mg/m2)/carboplatin (AUC 2) for 6 weeks and TRT (60 Gy) followed by 2 courses of paclitaxel (200 mg/m2)/carboplatin (AUC 5). The primary endpoint was overall survival (OS), with secondary endpoints of progression free survival (PFS), response, and toxicity. Results: From Sep 2001 to Sep 2005, 456 pts were randomized. Pretreatment characteristics were well-balanced among 3 arms. Major toxicity incidences: The incidence of G3–4 neutropenia in the MVP, IC, and PC arms was 95.9, 72.1, and 46.9 % (p<0.001). The G3–4 non-hematologic toxicity incidences in terms of fatigue, febrile neutropenia, and gastrointestinal disorder were 13.0, 6.1, and 4.8 % (p<0.001), 37.0, 8.8, and 10.2 % (p<0.001), and 24.0, 8.2, and 9.5% (p<0.001) in the respective arms. The overall response rates were 66.4, 56.5, and 63.3 %, in the MVP, IC and PC arms, respectively. The median survival times were 20.5, 19.8 and 22.0 months and the median PFS (MPFS), 8.2, 8.0 and 9.5 months in MVP, IC and PC. Non-inferiority of the 2 experimental arms compared with MVP was not achieved, though no significant differences in OS and PFS were apparent among treatments. The PC arm displayed the most favorable MST, MPFS, and hematologic/non-hematologic toxicities. Conclusions: Weekly PC with TRT displays similar efficacy and more favorable toxicity profiles compared to MVP with TRT. Weekly PC with TRT warrants use as the reference regimen in forthcoming studies.

[Table: see text]
A phase III comparison of prophylactic cranial irradiation versus observation in patients with locally advanced non-small cell lung cancer: Initial analysis of Radiation Therapy Oncology Group 0214
Authors: Gore E. M. , Bae K. , Wong S. , Bonner J. , Sun A. , Schild S. , Gaspar L. E. , Bogart J. , Werner-Wasik M. , Choy H.
Published: August 2020

7506

Background: The incidence of central nervous system (CNS) metastases is high in patients with locally advanced non-small cell lung cancer. Brain as an only site of relapse appears increasingly common as loco-regional and extra-cranial systemic treatment improves. There is not standard agreement as to how to address this risk. Methods: Patients with stage III NSCLC without progression of disease after loco-regional treatment with surgery and/or radiation therapy with or without chemotherapy were eligible. Participants were randomized to prophylactic cranial irradiation (PCI) or observation and stratified by stage (IIIA or B), histology (non-squamous or squamous) and therapy (surgery or no surgery). PCI was delivered once daily at 2Gy per fraction to 30Gy. The primary endpoint of the study was overall survival (OS). Secondary endpoints were disease free survival (DFS) and the impact of PCI on incidence of CNS metastases, neuropsychological function, and quality of life (QoL). Kaplan- Meier estimation with the log-rank test was used for OS and DFS and the logistic regression model was used for calculating the incidence of CNS metastasis. Results: Total accrual was 356 patients of the targeted 1058 between 9/19/02 and 8/30/07. The study was closed early due to slow accrual. 340 patients were evaluable. One year OS (p=0.86, 75.6 % and 76.9% for PCI and observation) and one year DFS (p=0.11, 56.4% and 51.2% for PCI and observation) were not statistically significantly different. However, CNS metastatic rate at 1 year was statistically significantly different with CNS relapse 7.7% vs. 18% for PCI vs. observation (p=0.004). Logistic regression showed that the patients in the observation arm are 2.52 times more likely to develop CNS metastases than those in the PCI arm (odds ratio=2.52, 95% CI=(1.32–4.80)). Conclusions: PCI in patients without progressive disease after loco-regional therapy for III NSCLC significantly decreases the rate of CNS metastases. This study did not show a statistically significant difference in OS or DFS. Forthcoming analysis of the impact of PCI on neuropsychological function and QoL will influence the recommendations regarding the standard use of PCI.

No significant financial relationships to disclose.
Randomized, multicenter phase III study of ranpirnase plus doxorubicin (DOX) versus DOX in patients with unresectable malignant mesothelioma (MM)
Authors: Reck M. , Krzakowski M. , Jassem J. , Eschbach C. , Kozielski J. , Costanzi J. J. , Gatzemeier U. , Shogen K. , von Pawel J.
Published: August 2020

7507

Background: Ranpirnase (Onconase), a novel ribonuclease with preclinical activity against various tumors, has led to a median survival of 8.3 ms (one year survival: 42%) in a multicentre phase II trial in chemonaive and pretreated pts whom met the Cancer and Leukemia Group B (CALGB) prognostic criteria for group 1–4 (Mikulski, J Clin Oncol 20, 2001). Methods: This multicenter controlled phase III trial compared efficacy and safety of Dox (one of the most active single agents when the study was planned) with or without ranpirnase. Primary endpoint was overall survival (OS), secondary endpoints included progression-free survival, response rate, safety and disease related symptoms. Eligibility criteria: histologically proven unresectable MM; CALGB group 1–4, ECOG PS 0–1, adequate organ function. Stratification was performed according to CALGB group and histology (epitheloid vs. non-epitheloid). One line of prior therapy was permitted. Between 08/01 and 09/07 413 eligible pts were randomized to DOX 60 mg/m2 every 3 wks with or without ranpirnase 240 μg/m2 weekly (cycle 1) and 480 μg/m2 in subsequent cycles (maximum 6) if no severe toxicity had occurred. The study was designed to detect an increase of 4 ms (9 vs. 13) in median OS (MST) using a two-sided logrank test (α = 5%) with 90% power. Results: Both arms were well balanced (DOX + ranpirnase / DOX: 203/210 pts): Mean age 62.2/61.8 yrs; males 157/156; PS 0 52/60; PS 1 151/150; prior chemo 65/65 pts (pemetrexed 35/35; other chemo 30/30). CALGB groups 14/14 (1), 45/51 (2), 117/115 (3), 27/30 (4). In the intent to treat population (ITT) there was no significant difference in OS (MST: 11.1 vs 10.7 ms; HR 1.02, 95% CI 0.82–1.26) whilst in a preplanned analysis including 130 pretreated patients a significant advantage in survival in favor of DOX + ranpirnase was found (MST: 10.5 vs 9 ms; HR 1.49, 95% CI 1.02–2.17). The safety profile for both treatment arms was similar. Most frequent side effects reported for both treatment groups included nausea, fatigue and alopecia. Conclusions: Combination of ranpirnase and DOX is a safe and feasible treatment in unresectable MM and showed a significant impact on survival of pretreated patients compared to DOX alone.

[Table: see text]