bluuebunny/crossref_metadata_2025 huggingface dataset:
Outcomes of second allogeneic hematopoietic stem cell transplantation (SCT) for patients with acute lymphoblastic leukemia (ALL).
Authors: Poon LM , Bassett Roland , Rondon Gabriela , Worth Laura L , Cooper Laurence , Popat Uday R. , Nieto Yago , De Lima Marcos J.G. , Champlin Richard E. , Kebriaei Partow
Published: March 2020

6540

Background: Disease relapse is the major cause of failure after allogeneic hematopoietic stem cell transplantation (SCT) for acute lymphoblastic leukemia (ALL). Treatment options for these patients (pts) are limited and only a second SCT provides a realistic chance for long term disease remission. Methods: We retrospectively analyzed the outcomes of 31 pts with ALL who relapsed following their first allogeneic SCT, and went on to receive a second allogeneic SCT. Univariate analysis was used to assess for risk factors which influenced treatment-related mortality (TRM), and progression free survival (PFS) following second SCT. Results: 31 pts were evaluable for response with 2 early deaths within 30 days of SCT. The median age of the pts was 26 years (range 7- 49), and the median duration between their first SCT (SCT1) to relapse was 9.5 months (range 2.2-32.6 months). 39% of pts were transplanted in active disease (n=12). The complete remission (CR) rate post SCT was 89%; 83% of pts transplanted with active disease attained CR. With a median follow-up of 3 years among survivors, PFS, and OS rates at 1 year were estimated at 23%. The TRM rate was 41% at 12 months. We did not identify any factors that impacted TRM through univariate analysis. We found a significant relationship between the time to progression following SCT 1 and PFS following SCT 2 (p=0.02, HR=0.93/month). Conclusions: In summary, a second transplant remains an effective method for achieving response in a highly refractory patient population. Pts with longer PFS following SCT1 have a better PFS following SCT2. While long-term survival is limited, a significant proportion of pts remain disease-free for up to one year following SCT2, providing a window of time to administer preventive interventions. Notably, our 4 long-term survivors, received novel therapies in the form of a single umbilical cord blood unit in addition to the PBSC to augment the immune response (n=2), a change in the stem cell source for the SCT from cord to mismatched adult unrelated (n=1), and post SCT maintenance therapy with 5-azacytidine (n=1), underscoring the need for a fundamental change with the methods for the second transplant to improve outcome.
Effect of lenalidomide induction therapy on peripheral blood stem cell collection in patients undergoing autologous stem cell transplant for multiple myeloma.
Authors: Bhutani Divaya , Zonder Jeffrey A. , Abrams Judith , Ratanatharathorn Voravit , Uberti Joseph P. , Abidi Muneer Hyder
Published: March 2020

6549

Background: Autologous stem cell transplant (ASCT) remains part of standard therapy for Multiple Myeloma (MM). Lenalidomide (LEN) is a newer, effective therapy for MM. It has been suggested that prior LEN therapy is associated with an increased risk of stem cell collection failure, particularly when only G-CSF is used for mobilization. Methods: We conducted a retrospective chart review of 310 consecutive MM pts who underwent pheresis to collect stem cells for first ASCT between July 1, 2007 and June 30, 2011 at the Karmanos Cancer Institute. We compared differences in quantity of CD34 cells collected, days needed to collect the target number of cells (> 2.5 x 10*6 CD34+ cells/kg), days to platelet and neutrophil engraftment. We also evaluated the association between CD34+ cells collected and the number of cycles of LEN therapy. Results: Of 310 patients, 90% were mobilized with only G-CSF initially. Patients were analyzed as two groups: LEN exposed (LEN(+); n = 128) and LEN naive(LEN(-); n = 182). Median age in both groups was 58 years. No differences in race, sex and MM stage distribution were observed between the two groups. The median number of stem cells collected in the LEN(+) group was significantly less than the LEN(-) group (6.46 vs. 7.56 x 10*6 CD34 cells/kg; p= 0.0004). In addition, the median number of pheresis sessions required for adequate stem cell collection were significantly more in the LEN(+)group as compared to LEN(-) group (2 vs.1 sessions; p=0.002). In the LEN(+) group, there was a negative correlation between CD34+ cells collected and the prior number of cycles of LEN (p=0.0001). There was no statistically significant excess in the number of stem cell collection failures with G-CSF in the LEN(+) group (7% vs. 4% p=0.31). All pts who failed collection after G-CSF were successfully collected with Cytoxan or Plerixafor priming. LEN exposure had no effect on post-ASCT neutrophil or platelet recovery. Conclusions: Although Lenalidomide exposure is associated with a slightly lower CD34+ stem cell yield and on average an extra session of pheresis when G-CSF is used for mobilization, collection failure is uncommon and post-ASCT engraftment is normal.
Secondary neutropenia (SN) after autologous hematopoietic stem cell transplantation (AHSCT) in patients (pts) with lymphoma.
Authors: Nathan Sunita , Maciejewski John Joseph , Rich Elizabeth Shima , Venugopal Parameswaran , Christopherson Kent W. , Gregory Stephanie A. , Fung Henry C.
Published: March 2020

6552

Background: Plerixafor for mobilization of autologous stem cells (ASC) has increased the yield of transplanted ASC and is evolving as an important option for mobilization. A prior study reported a 10% incidence of SN after AHSCT (BMT 2009 Aug; 44(3): 175-83). Incidence and outcome of SN in the setting of Plerixafor/G-CSF (P/G), is unknown. We report the incidence and possible etiology for the development of SN in pts undergoing AHSCT for lymphoma at our institution. Methods: Data from 80 consecutive AHSCT pts over a 2 year period were reviewed. All pts were mobilized using P/G. Demographics, AHSCT indication, prior therapies (Rx), conditioning regimen (CR), engraftment and post-transplant complications were identified and collected. SN was defined as ANC <1000 after initial engraftment. Results: 80 pts underwent an AHSCT for lymphoma from 2009-11. 70 pts had evaluable data. 37 (52.86%) pts (average age 55.4 yrs) were male and 33 (47.14%) pts (average age 48.3 yrs) female. 25 (35.7%) pts had ≥2 comorbidities. Indications included relapsed/ refractory B-NHL, T-NHL and HL. 47 (67%) pts had Stage IV ds, 48.9% with BM involvement. 17 (24.3%) pts had >2 Rx, 18 (25.7%) with loco-regional XRT and 3 (4.3%) with RIT. CR included BEAM, BEC and Benda-EAM +/- Rituxan. # of CD34+ cells given ranged; 1.77-19.99 x 10^6/kg. Neutrophil engraftment occurred at a median of 11 days. 26 (37.14%) pts developed SN possibly from PCP prophylactic antibiotics and infections. Prior BM involvement, Rx or XRT had no role. 5 (45.4%) pts with Benda-EAM CR had SN. Associated morbidity/mortality were not noted. Conclusions: We conclude that secondary neutropenia is common after autologous stem cell transplant using the Plerixafor/GCSF combination for mobilization and is higher than reported in the literature (37% vs 10%). Patients who received this combination for mobilization should be followed up closely in the post-transplant period for secondary neutropenia. About half the patients who received the Benda-EAM conditioning regimen developed secondary neutropenia warranting its use with caution outside of a clinical trial.
Post hoc analysis of relationship between baseline white blood cell count and survival outcome in a randomized phase III trial of decitabine in older patients with newly diagnosed acute myeloid leukemia.
Authors: Arthur Chris , Cermak Jaroslav , Delaunay Jacques , Mayer Jiri , Mazur Grzegorz , Thomas Xavier G. , Wierzbowska Agnieszka , Jones Mark M. , Tarassoff Peter G. , Kantarjian Hagop
Published: March 2020

6559

Background: In a large phase III trial (N=485), patients (pts) ≥65y with newly diagnosed acute myeloid leukemia (AML) received 1-h IV infusion of decitabine (DAC) 20 mg/m2 for 5 consecutive days every 4 wk or treatment choice (TC) with supportive care or cytarabine 20 mg/m2 subcutaneous injection for 10 consecutive days every 4 wk (NCT00260832; Kantarjian et al. JCO, in press). Enrolled pts had white blood cell (WBC) count <40 x109/L; baseline WBC counts were relatively low (median [range] DAC: 3.1 x109/L [0.3-127.0]; TC: 3.7 x109/L [0.5-80.9]). This post hoc analysis assessed baseline WBC count and survival outcome. Methods: Overall survival (OS) and progression-free survival (PFS) were summarized by baseline WBC subgroups (<1, 1-5, >5 x109/L). Results: Mature survival data (2010) were based on intent-to-treat (ITT) population (446 deaths: TC, n=227; DAC, n=219). OS was 5.0 mo for TC vs 7.7 mo for DAC (nominal P=.037). For each WBC subgroup, differences in OS for TC vs DAC were not significant (NS), but hazard ratios (HR) favored DAC for all subgroups (Table). There was a significant difference in PFS in favor of DAC for patients with baseline WBC 1–5 x109/L (P=.005; HR=0.67) and >5 x109/L (P=.027; HR=0.71). Conclusions: These data are consistent with overall results, with a trend toward improved outcome with DAC regardless of baseline WBC count in older pts with newly diagnosed AML. Further analyses are warranted. [Table: see text]
Increased risk of MDS/AML post radiation treatment for breast cancer: Analysis of SEER data 2001-2008.
Authors: Kaplan Henry G. , Malmgren Judith April , DeRoos Anneclaire
Published: March 2020

6560

Background: Ionizing radiation is a known cause of myeloid leukemia, but it is not known whether therapeutic doses for breast cancer (BC) pose risk. We hypothesized that BC radiation treatment is associated with increased risk of myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML)) as seen in a previously conducted institutional cohort study. Methods: We used 2001-2008 Surveillance, Epidemiology and End Results (SEER) database records to identify a cohort of first primary BC patients treated with radiation who were unlikely to be treated with chemotherapy (stage 0 and estrogen receptor positive (ER+) stage I). We identified subsequent MDS/AML diagnoses in the BC cohort, using SEER to query appropriate ICD-O-3 codes. We compared observed MDS/AML rates in the BC cohort to expected rates, estimated for first primary MDS/AML in the entire population, and calculated observed/expected rate ratios with 95% confidence intervals (CI). Results: We estimated an increased overall risk of MDS/AML in the breast cancer cases treated with radiation compared to the general population (RR=4.23, 95% CI 3.41, 5.18). The relative risk was higher for stage I ER+ breast cancer cases <65 years of age (RR=7.75, 95% CI 5.18, 11.05) than for stage 0 cases <65 years of age (RR=3.65, 95% CI 1.57, 7.05). Among women 65 years and older, there was a more modest increased risk, only seen for stage 1 ER+ breast cancer cases (RR=1.52) (table). Conclusions: Our results suggest that radiation treatment for breast cancer is associated with increased risk of MDS/AML. The effect appears to be age-dependent. [Table: see text]
Mevalonate pathway inhibitors in the treatment of B-cell chronic lymphocytic leukemia.
Authors: Bobba Ravi Kiran , Benakanakere Indira , Bearelly Smitha , Arya Monica , Sleigtholm Richard , Freter Carl
Published: March 2020

6561

Background: B-cell chronic lymphocytic leukemia (CLL) cells are arrested in G0/G1 phase of the cell cycle and are resistant to programmed cell death, hypothesized to contribute to the resistance of CLL cells to standard chemotherapy with curative intent. Methods: Mec-2 cells and Wac-3 cells are CLL cells that have been shown to be resistant to fludarabine and rituximab. We tested a novel enzyme inhibitor’s ability to render CLL cells sensitive to fludarabine and rituximab. Results: BIBB515, a lanosterol synthase inhibitor, at a concentration of 10μM, was able to reduce the cell viability from 82% in controls to 65% after 72 hours. Fludarabine 10μM alone did not reduce the cell viability, 82 % in controls compared to 80%. BIBB515+ fludarabine treatment for 72 hours, at the dose of 10μM each decreased the cell viability to 37%. Cell proliferation by MTT assay was 0.66±0.010 in control compared to 0.37±0.01 in BIBB515+fludarbine and 0.21±0.01 in BIBB515+ fludarabine+ rituximab. There is a 68% down-regulation of cell proliferation using this treatment. There was a two fold induction of CD 20 with combination treatment, and BIBB515 treatment. The mechanism of cell death in the combination treatment of BIBB515 and fludarabine may be due to the up regulation of cell surface marker CD-20. WAC-3 is another CLL cell line that is sensitive to fludarabine, and resistant to rituximab. BIBB515 sensitizes WAC-3 cells to CD 20 antibody rituximab. There is a 68.7% decrease in cell proliferation with combination treatment of BIBB515 and rituximab. Proliferation of Mec-2 cells were inhibited by 60µM and 30µM terbinafine. Ro-48-8071, showed dose-dependent activity, alone or in combination to fludarabine was seen to induce cell death in Mec-2 cells. Fludarabine alone did not have any effect on these cells. Conclusions: Inhibitors of the mevalonate pathway make resistant CLL cells sensitive to current chemotherapeutic agents. Exploiting this mechanism could alter the current treatment regimens, leading to control of the disease in advanced stages by either inducing the leukemic cells to be static or to regress. This strategy may also limit the toxicities involved with chemotherapy.
Overall and cancer-specific survival of breast, colon, and lung cancer in patients with and without chronic lymphocytic leukemia: A SEER population-based study of over 1 million patients.
Authors: Solomon Benjamin Maurice , Rabe Kari G. , Slager Susan L , Brewer Jerry D , Cerhan James R. , Shanafelt Tait D.
Published: March 2020

6571

Background: Chronic lymphocytic leukemia (CLL) is associated with an increased risk of developing second cancers. However, it is unknown whether CLL alters the natural history of these cancers once they occur. Methods: All patients with breast (n=583,838), colon (n=412,932), prostate (n=632,922), lung (n=489,290), kidney (n=95,902), pancreas (n=82,121) and ovarian (n=61,958) cancer reported to the Surveillance, Epidemiology, and End Results (SEER) Program from 1990 to 2007 were identified. Overall survival (OS; death due to any cause) and cancer-specific survival (death due to cancer site of interest) were examined, comparing patients with or without pre-existing CLL. Age- and sex-adjusted hazard ratios (HRs) were calculated. Results: OS for patients with pre-existing CLL was inferior for patients with breast (HR=1.61; p<0.001), colon (HR=1.65; p<0.001), kidney (HR=1.41; p<0.001), prostate (HR=1.75; p<0.001), and lung (HR=1.22; p<0.001) cancer after adjusting for age and sex. After excluding CLL-related deaths, OS remained shorter among patients with breast (p<0.001), colon (p<0.001), kidney (p=0.03), prostate (p<0.001), and lung (p<0.001) cancer. Cancer-specific survival was inferior for patients with breast (HR=1.29; p=0.03), colon (HR=1.75; p<0.001), and lung cancer (HR=1.17; p<0.001) who had pre-existing CLL after adjusting for age and sex. Conclusions: Several common cancers, including breast, colon, and lung, have inferior overall and cancer-specific survival when there is coexistent CLL. [Table: see text]
L-arginine depletion by PEG-arginase I, a new potential therapy for acute lymphoblastic leukemia.
Authors: Crombet Ramos Ofelia , Hernandez Claudia , Morrow Kevin , Cole John T. , Rodriguez Paulo
Published: March 2020

6580

Background: Advances in therapies have resulted in an overall complete remission rate of approximately 85% for childhood acute lymphoblastic leukemia (ALL). In contrast, the overall remission rate of adults with leukemia continues to be poor, only about 40% in cases of T cell-ALL (T-ALL). Therefore, it is imperative to generate new therapies that alone or in combination with other treatments could potentially increase the percentages of complete responders or be used to treat the refractory ALL population. Our published results show that a pegylated form of human arginase I (peg-Arg I) prevented T-ALL cell proliferation in vitro and in vivo through the induction of tumor cell apoptosis. Interestingly, the anti-leukemic effects induced by peg-Arg I did not affect the anti-tumor activity of normal T cells, suggesting an anti-tumor specific effect. Our hypothesis states that peg-Arg I has an anti-tumoral effect on B-ALL and T-ALL cells in vitro and that the sensitivity of ALL cells to peg-Arg I depends on their expression of argininosuccinate synthase (ASS) and their ability to produce L-arginine de novo from citrulline. Methods: Malignant T cell proliferation was tested using nonradioactive cell proliferation yellow tretrazolium salt kit. Apoptosis studies were based on the expression of annexin V. Western blot assays were conducted to determine enzymatic expression in different cell lines. Results: The results of our in vitro experiments showed that peg-Arg I had a pro-apoptotic and anti-proliferattive effect on B-ALL cells similar to the one previously seen on T-ALL cells. These effects can be overcome in cell lines able that express ASS and therefore to produce L-arginine de novo. Conclusions: Our results suggest the role of ASS in the ALL-apoptosis induced by peg-Arg-I. Our next steps include: _Understand why ASS-expressing ALL cells do not undergo apoptosis when cultured with peg-Arg-I_Determine the role of ASS in the anti-leukemic effect induced by peg-Arg-I in vivo. Completion of this research is expected to lead to a better understanding of how peg-Arg-I kills ALL cells and could provide the foundation for a novel therapy for ALL patients.
Prognostic and predictive significance of smudge cell percentage on routine blood smear in chronic lymphocytic leukemia patients: A single center study from northern India.
Authors: Gogia Ajay , Raina Vinod , Sharma Atul , Kumar Lalit , Gupta Ritu , Vishnubhatla Sreeniwas , Gajendra Smeeta
Published: March 2020

6593

Background: Smudge cells are ruptured lymphocytes seen on routine blood smears of chronic lymphocytic leukemia (CLL) patients. We evaluated prognostic and predictive significance of smudge cells percentage on a blood smear in CLL patients. Methods: We calculated smudge cell percentages (ratio of smudged to intact cells plus smudged lymphocyte) on archived blood smears of 185 untreated CLL patients registered at I.R.C.H, AIIMS, New Delhi over a period of 11 years. Results: There were 135 males and 50 females. The median age was 60 years (28-89). Median absolute lymphocyte count was 42 X109/L. Clinical Rai stage distribution was: stage 0 - 10%, stage I - 15%, stage II - 40%, stage III -15 % and stage IV - 20%. The median smudge cells percentage was 27% (4% to 76%). There was no correlation of proportion of smudge cells with age, sex, lymphocyte count, organomegaly, ZAP 70 + or CD 38 + CLL patients, but there was significant correlation with stage of disease. Median smudge cell percentage in stage 0 & I -33% (12-76), stage II- 31% (12-61) and stage III&IV-21% (4-51) [ p=<0.001]. One third of early stage (0, I &II) patients required treatment during follow up, at the end of 5 years of follow up 55% required treatment with smudge cell < 30%, against 24% patients requiring treatment with smudge cells > 30% [p=0.01]. The percentage of smudge cells as a continuous variable correlated with OS [HR 0.96, p< 0.001]. The 5-year survival rate was 51% for patients with 30% or less smudge cells compared with 81% for patients with more than 30% of smudge cells. Thirty percent of patients died during follow up. Median OS was 5 years with median follow up period of 3.9 years. Smudge cells percentage (<30% vs. >30%) had significant association with OS [HR 0.47, 95%CI (0.32-0.71), p=0.001)]. Conclusions: Simple and inexpensive detection of smudge cells on blood smears on routine diagnostic test useful in predicting progression free and OS in CLL patients and may be beneficial in countries with limited recourses.
Omacetaxine mepesuccinate in chronic-phase chronic myeloid leukemia (CML) in patients resistant, intolerant, or both to two or more tyrosine-kinase inhibitors (TKIs).
Authors: Akard Luke Paul , Kantarjian Hagop , Nicolini Franck E. , Wetzler Meir , Lipton Jeffrey Howard , Baccarani Michele , Craig Adam , Nanda Nisha , Brown Peter D. , Cortes Jorge E.
Published: March 2020

6596

Background: Omacetaxine mepesuccinate (“omacetaxine”) is a first-in-class, reversible, transient inhibitor of protein elongation that facilitates tumor cell death without depending on BCR-ABL signaling. Clinical activity was shown in two phase 2, open-label, multicenter studies of patients with treatment-resistant CML who had failed at least prior imatinib, many of whom were also resistant to or intolerant of dasatinib and/or nilotinib. Methods: A subset of data from the phase 2 studies included patients in chronic phase who were resistant/intolerant to ≥2 approved TKIs. Omacetaxine 1.25 mg/m2 was given subcutaneously twice daily: ≤14 consecutive days/28-day cycle for induction, ≤7 days/cycle as maintenance. Patients had never achieved or lost response to ≥2 TKIs (R group), were intolerant of ≥2 TKIs (I), or resistant to 1 and intolerant of another (R/I) were evaluated. Results: Of 81 patients (median age, 58 years), 69 were R, 7 I, and 5 R/I. Major cytogenetic response occurred in 13 (19%) in the R group (median duration not reached), 2 (29%) I (median duration 7.4 months), and 1 (20%) R/I (duration 17.7 months). For all patients, cycles of exposure and study duration were 7 cycles and 9.1 months (R); 4 cycles, 7.3 months (I); and 2 cycles, 2.3 months (R/I). Median overall survival in months were 33.9 (R), not reached (I), and 25.0 (R/I). Of 66 (81%) patients with treatment-related grade 3/4 adverse events (AEs), the most common were thrombocytopenia in 44 R, 6 I, and 4 R/I patients and neutropenia in 32 R, 4 I, and 1 R/I. Fifteen patients had an AE leading to discontinuation (10 R, 2 I, 3 R/I), primarily disease progression. There were 9 deaths (the most common were disease progression, sepsis), 8 I, 1 R/I; 2 were considered related to treatment (both sepsis). Conclusions: This subset analysis of patients with chronic-phase CML and prior therapy with ≥2 TKIs shows that omacetaxine provides efficacy and tolerability across TKI-R, I, and R/I groups. Interpretation of the I and the R/I group data was limited by small sample sizes. Support: Teva Pharmaceutical Industries Ltd.
Prospective evaluation of serial 2-hydroxyglutarate in acute myeloid leukemia (AML) to determine response to therapy and predict relapse.
Authors: Fathi Amir Tahmasb , Abdel-Wahab Omar Ibrahim , Sadrzadeh Hossein , Foster Julia , Burke Meghan , Borger Darrell R. , Iafrate A. John , Adamia Sophia , Liu Suiyang , Ballen Karen K. , Amrein Philip C. , Attar Eyal C. , Straley Kimberly , Yen Katharine , Schenkein David P. , Neuberg Donna S. , Levine Ross L. , Chen Yi-Bin Albert , Stone Richard M.
Published: March 2020

6606

Background: Mutations in isocitrate dehydrogenase (IDH1 and IDH2) occur in 10-20% of AML patients and result in production of 2-hydroxyglutarate (2-HG). We hypothesize that serial 2-HG quantification may be used to monitor response and predict relapse in patients with AML. Methods: We are conducting a prospective study at MGH and DFCI to (1) assess changes in serum and urine 2-HG levels during treatment in patients with newly diagnosed AML, (2) compare 2-HG levels in serum, urine, and bone marrow and, (3) serially compare 2-HG levels with IDH1/2mutant allele burden. In those with elevated serum 2-HG (≥1000ng/ml), 2-HG is monitored serially or at relapse. Results: To date, 20 patients have been enrolled, 5 (25%) of whom had elevated baseline serum 2-HG. All 5 were found to have IDH1/2 mutations. The serum 2-HG for these patients was significantly higher than for those who were IDH-wt (median 1933 vs 87ng/mL; p<0.001). Urine 2-HG was also higher in IDH-mutant patients (median 30500 vs 4230ng/mL; p<0.021), as was bone marrow 2-HG (median 9870 vs 309ng/mL; p<0.005). Serum 2-HG levels strongly correlated with that in urine (R2 0.987). Serum 2-HG decreased in all IDH mutant patients on therapy, but more rapidly in those receiving induction chemotherapy (Table), all of whom achieved remission, than those receiving hypomethylatingagents. Conclusions: Patients with IDH-mutant AML have markedly elevated serum and urine 2-HG. 2-HG levels decreased with therapy and there is a strong correlation between serum and urine 2-HG. Data on the sensitivity of serial 2-HG monitoring as well as comparison with mutant IDH1/2allele burden will be presented. This data suggests that serial 2-HG quantification may be a valuable non-invasive biomarker in this genetically defined subset of AML. [Table: see text]
Disease response and survival outcomes in acute myeloid leukemia (AML) patients unfit for chemotherapy treated with 10-day decitabine as initial therapy.
Authors: Gourdin Theodore Stewart , Bhatnagar Bhavana , Duffy Alison P , Tidwell Michael , Ning Yi , Sausville Edward A. , Baer Maria R.
Published: March 2020

6611

Background: AML is primarily a disease of older adults, with a median age of 67 years at diagnosis. Many patients are considered unfit for chemotherapy due to poor performance status and/or comorbidities, prompting investigation of less intensive approaches. A clinical trial in which 10-day courses of decitabine 20mg/m2 were given every 28 days as initial therapy demonstrated a promising complete remission (CR) rate and disease-free survival (DFS). We used this regimen to treat AML patients unfit for chemotherapy outside of a clinical trial. Methods: Charts of 32 newly diagnosed AML patients treated with 10-day courses of decitabine 20mg/m2 as initial therapy at the University of Maryland Greenebaum Cancer Center between September 2010 and November 2011 were retrospectively reviewed. If patients attained bone marrow blasts <5%, 5-day courses were administered subsequently and were continued until disease progression. Results: Median age at diagnosis was 74 years (range, 52-86). 18 patients were male and 14 female. 23 were Caucasian, 7 African-American and 1 Hispanic. 10 patients (31%) had performance status ≥ 2. All had significant cardiac, pulmonary and/or renal disease. Karyotype risk group was unfavorable in 17 patients, intermediate in 14 and unknown in one. There were 9 CRs and 1 partial remission, for an overall response rate of 31%, following a median of 2 (range, 1 to 4) courses. 21 patients did not respond to treatment following 1 to 6 courses, and one died within 29 days of treatment initiation. 21 patients (65%) were hospitalized at least once for fever or infection during treatment. Of the 9 patients who achieved CR, 5 had normal, 3 complex and 1 unknown karyotypes. Median DFS was 390 days (range, 87+-468+) and median OS 180 days (range, 15-623+). Six-month OS was 37.5% and 1-year OS 16.5%. Conclusions: AML patients unfit for chemotherapy treated with 10-day decitabine 20mg/m2 outside of a clinical trial had a higher response rate than reported for 5-day decitabine, but a lower response rate than in the reported clinical trial of the 10-day regimen. Additional novel treatment approaches are needed for these patients.
Time to ATRA in suspected newly diagnosed acute promyelocytic leukemia and association with early death rate at a non-cancer center institution: Are we meeting the target?
Authors: Manji Gulam Abbas , Khan Manji Samira , Karne Sheetal , Chao Jeff
Published: March 2020

6615

Background: ATRA administration in suspected APL patients (sAPL) is thought to impact early death rate (EDR) (Tallman and Manji, Blood Cells Mol Dis. 2011). Delay in ATRA therapy at specialized centers was associated with EDR (Altman et al Blood 2011). EDR within this study was significantly lower compared to the SEER database (12% vs 17.3%) and hence may not reflect overall delay in ATRA therapy. We determined time to ATRA therapy in sAPL, and fraction of sAPL that did not have disease. Methods: Retrospective analysis of patients that received ATRA for newly diagnosed s APL between 01/01/98-12/31/11 at Albany Medical Center. Time to hematologist evaluation, ATRA ordered and administered, and mortality data was collected from cancer registry, medical record, and chemo-pharmacy database. Results: A total of 39 patients with newly diagnosed sAPL were administered ATRA (46% male, mean age 50y). APL diagnosis: 29/39 (75%) true APL (APL); 9/10 ATRA-treated non-APL (A-nAPL); and one patient for whom cytogenetic data unavailable. EDR amongst APL was 5/29 (17%) compared to 2/9 (22%) within A-nAPL. Time variables were compared between APL patients that died early (<30d) to those that survived 30 days, and included: time to hematologist response (0.9d vs. 0.4d); time to ATRA ordered (2.9d vs. 2.0d); time to ATRA administered (3.4d v. 2.2d); and time elapsed between hematologist response to ATRA administered (2.5d v. 1.9d), respectively. Cryoprecipitate was administered to 1/5 (20%) patients who expired within 30d compared to 10/23 (43%) who survived. Overall mortality for APL was 9/29 (31%) compared to 4/9 (44%) for A-nAPL group. Compared to recent reports, time to ATRA administration in our institution was later (2.0d vs. 2.4d). Conclusions: Our data indicate that APL patients who survived 30d received ATRA early. EDR at our institution is comparable to that reported by SEER database and may be attributed to delay in ATRA administration. Higher fraction of patients that survived 30d received cryoprecipitate. Hence aggressive blood product support may contribute to improved survival. Timing at which these products were administered is currently being evaluated.
The prognostic role of serum albumin in patients receiving induction chemotherapy for acute myeloid leukemia (AML).
Authors: Sadrzadeh Hossein , Brunner Andrew Mark , Drapkin Benjamin Jacob , Babirak Loren , Werner Lillian , Ballen Karen K. , Amrein Philip C. , Attar Eyal C. , Chen Yi-Bin Albert , Spitzer Thomas R. , McAfee Steven L , Neuberg Donna S. , Fathi Amir Tahmasb
Published: March 2020

6618

Background: Serum albumin has been investigated as a prognostic tool in the care of patients with hematologic malignancies, including multiple myeloma and myelodysplastic syndromes. However, its prognostic utility in patients with AML is unknown. We hypothesized that a lower serum albumin is associated with worse outcomes following induction chemotherapy for AML. Methods: We conducted a retrospective medical record review of 166 adult, non-promyelocytic AML patients who had received induction chemotherapy at Massachusetts General Hospital from 1992 to 2007. Patient characteristics were summarized as numbers and percentages for categorical variables. The Kaplan Meier method was used to estimate median disease-free survival (DFS) and overall survival (OS). We dichotomized our patients by serum albumin ≥3 and <3, and determined the association of albumin with 60-day survival and complete remission (CR) rate using Fisher’s exact test. Association of albumin with DFS and OS was summarized using Cox regression in both univariate and multivariable analyses. Results: Of 166 patients, 125 (75%) achieved CR and 143 (86%) were alive at 60 days following diagnosis. After risk-adjusting for age and LDH, we found that a serum albumin level <3 mg/dL was associated with decreased 60-day survival (OR 0.30, p=0.015) and CR rate (OR 0.41, p=0.02) compared to patients with serum albumin ≥3. There was no association between serum albumin and DFS (p=0.88) or OS (p=0.31). As expected, younger age was associated with better induction outcomes. Conclusions: Serum albumin was negatively associated with short-term outcomes in patients receiving induction chemotherapy. A serum albumin level less than 3, clinically relevant to oncologic patients, was associated with a significantly decreased CR rate and lower 60-day survival after induction chemotherapy. This data suggests that serum albumin, a surrogate commonly used for nutritional status and suppressed in inflammatory comorbid states, has prognostic utility for AML patients undergoing induction chemotherapy.
Initial characterization of the toxicity and efficacy of elacytarabine (CP-4055), a novel antileukemic agent, using a multidimensional exposure-response relationship model.
Authors: Ducharme Murray P , Hagen Steinar , Hals Petter-Arnt , Jacobsen Tove Flem , Giles Francis J. , O'Brien Susan Mary , Dirven Hubert , Phillipe Colucci , Seng Yue Corinne
Published: March 2020

6619^

Background: Elacytarabine (CP-4055), an elaidic acid ester of ara-C, is a novel antineoplastic agent developed to treat hematologic malignancies (HM). It is metabolized to active ara-CTP and inactive ara-U. In 3 studies, diverse elacytarabine monotherapy doses and regimens were given to patients with advanced HM and solid tumours. This analysis aimed to 1) describe the pharmacokinetics (PK) of elacytarabine in these patients and 2) investigate the relationship between PK and toxicity and efficacy in HM. Methods: Population PK analyses were run with ADAPT 5 (ITS) and included 146 patients given a 2h, 4h or 120h continuous infusion (CIV) of elacytarabine. Elacytarabine, ara-C and ara-U plasma concentrations (Cp) were simultaneously modeled and explained. Standard model discrimination criteria were used to select the best model. With the model, different dosing regimens were simulated to find average exposure and % of patients with efficacious or toxic exposure. A multi-dimensional exposure-response relationship (MDERR) was developed with pre-clinical and clinical data. Results: The best model was a 2-compartment (CPT) model with linear elimination and formation rates for the metabolism of elacytarabine to ara-C. Mean PK parameters were Vc = 4.12 L/m2, CL= 5.27 L/h/m2 and T1/2 = 7.57 h. Elacytarabine PK included a peripheral CPT with a non-linear distribution process to reflect saturable binding to red blood cells, otherwise its PK was linear. Ara-C and ara-U PK were described by 2- and 1-CPT linear models, respectively. The MDERR model related efficacy and toxicity thresholds to elacytarabine dosing regimens, and indicated that a 120 h CIV dosing regimen is preferable, allowing elacytarabine to exceed efficacious Cp for longer than the other investigated regimens. A minimum dose of 1000 mg/m2/day is needed for most patients to receive efficacious exposure. Conclusions: Elacytarabine is a promising anti-leukemic agent for patients with advanced HM. Its PK, toxicity and efficacy were characterized in patients given diverse dosing regimens. An MDERR model, which will be further refined or confirmed in upcoming clinical trials, was proposed.
Use of granulocytes concentrates from a single high yield apheresis to support more than one patient.
Authors: Aung Fleur M , Lichtiger Benjamin , Reddy Virgil , Hosing Chitra
Published: March 2020

6622

Background: Allogeneic granulocyte transfusion therapy is sometimes the only therapeutic option in immunocompromised neutropenic leukemic/HSCT patients with life threatening bacterial and fungal infections. Collection of larger cell doses of granulocyte concentrates (GC) by automated apheresis following G-CSF/steroids administration has renewed interest and its use has grown steadily. Methods: Donors were recruited from family/friends of the patients and informed consent was obtained. GCs were collected via donor stimulation with a single subcutaneous dose of G-CSF (600 mcg). First time donors received an oral dose of dexamethasone (8 mg). GCs were harvested by Hetastarch-assisted leukapheresis 12 hours later via peripheral venous access with the continuous flow cell separator Spectra (COBE Caridian BCT, Lakewood, CO). Results: GCs were collected from 93 donors (67M: 26F; age median 40 (19-73 years) and 1 ½ x blood volume processed median 7048 (3212-8085 mL). The pre/post wbc were median 8.1 (4.1-22.8)/ 42.7 (22.4-77.5). The volume collected was based on the post G-CSF wbc count (> 35 K/UL - 800 mL; <35 K/UL between 600-700 mL). The original yield (10 x10e) was median 9.7 (5.1-17.2 units), volume median 718 (538-860 mL) and WBC median 132.7 (84.2 -241.6 K/UL per bag). The Split GCs were median 4.48 (2.70-7.72 units), with neutrophils median 87% (54-97% per bag). GCs were transfused to 51 patients (31M: 20F; age median 58 [19-83 years]) who received median 3.5 (1-18 split units), containing wbcs median 10734.69 [5778-42 -162698.09 (x10^3/uL)/unit) and achieved a WBC increment median 0.2 (0.0-8.3K/UL). Conclusions: The GCs were split due to the primary care team's reluctance to transfuse the entire volume of the product due to volume restrictions or for some other medical reason. The same rationale to split platelets from high yield single apheresis was used to split our GC products. We found that GCs from each donor was utilized maximally and also brought partial relief to other patients who lacked donors. We would like to make the case that when adequate numbers of GCs are collected it may be feasible to split the unit. This may offer a glimmer of hope to other patients in need of GCs who lack a donor network support.
Is consolidation chemotherapy after concurrent chemoradiotherapy beneficial for locally advanced non-small cell lung cancer? A pooled analysis of the literature.
Authors: Yamamoto Satomi , Tsujino Kazuyuki , Ando Masahiko , Kawaguchi Tomoya , Kubo Akihito , Isa Shunichi , Hasegawa Yoshikazu , Ou Sai-Hong Ignatius , Takada Minoru , Kurata Takayasu
Published: March 2020

7000

Background: There is a growing interest on the efficacy of maintenance chemotherapy to metastatic non-small cell lung cancer (NSCLC) and adjuvant chemotherapy to early stage NSCLC. However, the role of consolidation chemotherapy (CCT) after concurrent chemo-radiotherapy in locally advanced NSCLC is undetermined. Methods: We systematically searched PubMed for phase II/III trials examining survival of locally-advanced NSCLC treated with concurrent chemo-radiotherapy between January 1, 1995 and October 31, 2011. Median overall survival (mOS) and corresponding 95% confidence interval (CI) were collected from each study and pooled. We extracted log-transformated hazards and its standard errors under the assumption that survival follows an exponential distribution, and computed a pooled mOS and its 95% CI using random-effect model. Collected trial arms were divided into two groups by the presence of CCT: Arm with CCT (CCT+) and without CCT (CCT-). Results: Forty-five studies were identified including 9 phase III studies and 36 phase II studies with 51 arms (CCT+: 29, CCT-: 22). Clinical data were comparable in clinical stage, performance status, cancer histology, gender, and median age between the two groups. I2 values for assessing heterogeneity were 15.3, 9.1 and 24.2% in overall, CCT+ and CCT- studies, respectively. There was no statistical difference in pooled mOS between CCT+ (18.5 month, 95%CI: 16.7-20.5) vs CCT- (18.1 month, 95%CI: 16.5-20.2). In regard to the ≥ grade 3 toxicities in pneumonitis, esophagitis, and neutropenia, there was no difference between the two groups throughout the whole treatment courses. In random effect models, predicted hazard ratio of CCT+ to CCT- was 0.98 (95%CI: 0.8-1.13, p=0.7574). These models estimated that addition of CCT could not yield more than 3 months of survival prolongation for patients with locally advanced NCSLC. Conclusions: The pooled analysis on publication basis failed to provide evidence that consolidation chemotherapy yields significant survival benefit for locally advanced NSCLC.
SWOG 0802: A randomized phase II trial of weekly topotecan with and without AVE0005 (aflibercept) in patients with platinum-treated extensive-stage small cell lung cancer (E-SCLC).
Authors: Allen Jeffrey Warren , Moon James , Gadgeel Shirish M. , Kelly Karen , Mack Philip C , Saba Hanna M. , Mohamed Mohamed K. , Gandara David R.
Published: March 2020

7005

Background: Topotecan (T) (oral and IV) is the only FDA-approved second-line chemotherapy for patients with SCLC. Weekly T is associated with less toxicity than the daily x 5 regimen. AVE0005 (aflibercept) (A) is a novel recombinant human fusion protein which binds to circulating VEGF, thereby inhibiting its interaction with cell surface receptors. We sought to evaluate the efficacy and toxicity of weekly IV T (4 mg/m2) with or without A (6 mg/kg Q21D) in patients with relapsed SCLC following one line of platinum-based chemotherapy for E or limited-stage (L) SCLC. Methods: Patients were randomized 1:1 to T or A+T. Eligible patients had adequate organ function, ECOG PS 0-1, and no recent bleeding or cardiac events. Patients with brain metastases stable for ≥ 3 months prior to study entry were allowed. Primary endpoint was 3-month PFS. Patients were stratified as platinum-sensitive (PS) or platinum-refractory (PR). PR patients had progressed within 90 days of last chemotherapy for E and 6 months for L. This report is limited to the PR stratum. Results: 98 patients were registered. 1 was ineligible and 1 withdrew consent, leaving 96 evaluable for the primary endpoint (91 for toxicity (see Table for characteristics)). 3-month PFS was 26% for A+T versus 9% for T (P=0.01). Overall survival was similar in each arm (4.6 mos (A+T) versus 3.9 mos (T) (P=0.25)). There was 1 partial response with A+T. Disease control rate (DCR) was 28% with A+T and 12% with T. Toxicity was mainly hematologic with 14% and 19% of patients experiencing a Grade 4 event with T and A+T, respectively. There was one treatment-related death with T (renal failure). Conclusions: This study met its primary endpoint of improved 3-month PFS with A+T (p=0.01), warranting further study in the PR setting. Clinical benefit with A+T was achieved primarily through improved DCR. Toxicity was manageable and less than is seen with standard dose T. Accrual to the PS cohort is ongoing. [Table: see text]
Comprehensive genomic characterization of squamous cell carcinoma of the lung.
Authors: Govindan Ramaswamy , Hammerman Peter S. , Hayes David N. , Wilkerson Matthew D , Baylin Stephen , Meyerson Matthew ,   on behalf of the Cancer Genome Atlas (TCGA) Group
Published: March 2020

7006

Background: A third of patients with non-small cell lung cancer are diagnosed with squamous cell carcinoma (SCC) histology. This report describes findings from the comprehensive genomic analyses of 178 SCC samples. Methods: The Cancer Genome Atlas (TCGA) is conducting DNA, RNA, and miRNA sequencing along with DNA copy number profiling, quantification of mRNA expression and promoter methylation on surgically resected samples from previously untreated patients with stage I-III SCC of the lung. Results: The demographics of 178 patients enrolled in the study: median age 68 years (range: 40-85); female 47 (26%) and history of tobacco smoking 171 (96%). Over 30 sites of significant somatic copy number alteration (SCNA) were identified. Exome sequencing of 178 lung SCC and matched normal samples revealed 13 significantly mutated genes with a False Discovery Rate (FDR) of <0.01 and high expression levels, including TP53, CDKN2A, PTEN, KEAP1, and NFE2L2. Apart from the near universal loss of TP53 and CDKN2A, alterations in the NFE2L2/KEAP1 and PI3K/AKT pathways were found in 35% and 43% of tumors analyzed. mRNA expression profiling revealed four distinct expression subtypes, each one enriched with distinct mutations and SCNAs - classical (37%): NFE2L2 and KEAP1 mutations, FGFR kinase alterations, increased global methylation and the highest rate of tobacco use; basal (24%): alterations in FGFR kinases; secretory (24%): PDGFRA alterations; primitive (15%): RB1 mutations. Rearrangements involving several known tumor suppressors were detected by whole genome shotgun sequencing of 20 tumor/normal pairs and confirmed by RNA sequencing including PTEN, RB1, NOTCH1, NF1 and CDKN2A. CDKN2A loss by one of several mechanisms (deletion, mutation, rearrangement with loss of function and methylation) was observed in 72% of specimens. Potential therapeutic targets for clinical trials with currently available drugs were identified in 127 patients (75%). Conclusions: SCC of the lung is a distinct molecular subtype of lung cancer potentially amenable to distinct molecularly targeted therapies.
Feasibility trial of adjuvant chemotherapy with docetaxel (DOC) plus cisplatin (CDDP) followed by maintenance chemotherapy of S-1 in completely resected non-small cell lung cancer (NSCLC): Thoracic Oncology Research Group (TORG) 0809.
Authors: Niho Seiji , Suzuki Kenji , Sakai Hiroshi , Kaburagi Takayuki , Koike Teruaki , Minato Koichi , Kato Terufumi , Okamoto Hiroaki , Seto Takashi , Hosomi Yukio , Shimizu Kimihiro , Oshita Fumihiro , Tsuchida Masanori , Yamashita Motohiro , Kawashima Osamu , Kishi Kazuma , Kunitoh Hideo , Takeuchi Masahiro , Watanabe Koshiro , Ikeda Norihiko
Published: March 2020

7012

Background: Maintenance chemotherapy could prolong overall and/or progression-free survival in advanced NSCLC. S-1 is an oral anticancer agent comprised of tegafur, 5-chloro-2, 4-dihydroxypyridine, and potassium oxonate. The TORG 0809 study was conducted to evaluate the feasibility and efficacy of maintenance chemotherapy of S-1 following DOC+CDDP in patients (pts) with curatively resected stage II and IIIA NSCLC. Methods: Pts received 3 cycles of DOC (60mg/m2 d1) plus CDDP (80mg/m2 d1), q3-4w, and subsequently S-1 at 40mg/m2 twice a day for 14 consecutive days, q3w, for more than 6 months (max 1 year). The primary endpoint was determination of feasibility, which was defined as the proportion of pts who had completed maintenance for 8 cycles of S-1 or more. If the lower confidence interval (CI) of this proportion was 50% or more, the feasibility of the treatment was considered confirmed. The sample size was set to be 125. Results: Between Jun 2009 and Nov 2010, 131 pts were enrolled, of whom 129 pts were eligible and assessable. The median age was 63 (23-74 years); PS 0: 107, 1: 22; p-stage IIA: 19, IIB: 30, IIIA: 80; adenocarcinoma: 99, non-adenocarcinoma: 30. Of 129 pts, 109 pts (84.5%) completed 3 cycles of DOC+CDDP. 106 pts initiated the maintenance S-1 and 66 pts (51.2%, 95% CI: 42.5-59.8) completed 8 cycles or more S-1 treatment; this percentage was less than our previously defined criterion for treatment feasibility, since 32 pts terminated maintenance S-1 at 3 cycles or less. Grade 3/4 toxicities during the maintenance S-1 included anemia (7.3%), neutropenia (3.7%), anorexia (3.7%), dyspnea (1.8%), infection with neutropenia of grade 0 to 2 (1.8%). Febrile neutropenia was not observed. One pt developed interstitial pneumonia and sepsis, resulting in treatment-related death. Recurrence-free survival data will be presented. Conclusions: The toxicity level was acceptable, although the results did not meet our criterion for feasibility. Modification of the treatment schedule of maintenance S-1, such as a 2-week rest period rather than 1-week, might improve treatment compliance.