bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase I trial of bexarotene, a retinoid X receptor agonist, in non-M3 acute myeloid leukemia
Authors: Tsai D. E. , Luger S. , Kemner A. , Andreadis C. , Loren A. , Porter D. , Stadtmauer E. , Swider C. , Goradia A. , Carroll M. 
Published: March 2020

7061 Background: In vitro, bexarotene inhibits the proliferation of non-M3 AML cell lines and induces differentiation of leukemic blasts. This phase I study was designed to evaluate the safety of escalating doses of bexarotene in patients with non-M3 AML and has completed enrollment. Methods: Bexarotene was administered daily until disease progression occurred. Dose escalation occurred in cohorts of 3–6 patients through 6 dose levels ranging from 100–400mg/m2. Results: 27 patients were enrolled: 19M/8F, median age 69 (range 51–82), 13 prior MDS, 12 primary refractory, median number of induction attempts 2, no prior chemotherapy 3, prior autologous stem cell transplant 5, 26 blood transfusion dependent, 18 platelet transfusion dependent, and 20 neutropenic. Despite prophylactic use of antihyperlipidemic agents, 4 patients developed grade ≥3 hypertriglyceridemia. Two patients developed a syndrome reminiscent of retinoic acid syndrome, consisting of dyspnea, pleural/pericardial effusions, and edema in the setting of a rising neutrophil count. This syndrome resolved with stopping bexarotene and initiating steroids. Evidence of activity was noted with bone marrow blasts decreasing to ≤5% in 4 patients. Seven patients showed evidence of neutrophil response (pretreatment median ANC 364/μL, range 28–1,242/μL, treatment ANC 3,540/μL, range 1,200–26,207/μL). Flow sorted peripheral blood neutrophils were collected from 3 of these patients and examined by FISH. Between 92–100% of neutrophils contained the patient's leukemic cytogenetic abnormality suggesting differentiation of the leukemic blasts. Eleven patients with platelet counts <100,000/μL had increases in their platelet counts >20,000/μL (peak range 40- 292x103/μL). Five of these patients with platelet counts <20,000/μL had improvement to 40–91,000/μL and became transfusion independent. Conclusions: Bexarotene is well tolerated at the dose levels studied. Evidence for clinical activity has been seen as exemplified by improvement in platelet counts, increased neutrophil counts and decreased bone marrow blasts. We postulate that bexarotene may induce leukemic blast differentiation in non-M3 AML and represent a novel non-cytotoxic treatment. No significant financial relationships to disclose.
Risk factors for early mortality, relapse and overall survival in new cases of APL treated by arsenic trioxide
Authors: Alimoghaddam K. , Ghavamzadeh A. , Rostami S. , Ghaffari S. , Hosseini R. , Bahar B. , Baybordi E. , Radsafa P. , Shadpoor M. , Eini E. , Abdolahi S. 
Published: March 2020

7069 Background: There are several known risk factors for APL treatment by ATRA and chemotherapy, but risk factors for new cases of APL treated by Arsenic Trioxide are unknown. Methods: Between May 2000 and September 2006, we treated 141 new cases of APL (Median age 28±12.8 y/o min=11, max=71) by 2 hours iv infusion of 0.15mg/kg ATO until complete remission. Trial approved by IRB and consent form obtained. Diagnosis was by clinical and morphologic characteristics and confirmed by cytogenetic and RT-PCR for detection of t(15,17) and presence of PML-RARa. After complete remission patients received consolidation by 28 days infusion of ATO for one or four courses. Known risk factors for APL treatment outcome (including PML-RARa isoforms, presence of MRD during follow up and WBC count at presentation analyzed for early mortality, relapse rate, DFS and OS. Results: Complete remission observed in 121 cases (85.8%) and early mortality rate was 14.9%. short isoform of detected in 36% of patients and 18% presented by WBC more than 10,000/μl. For early mortality, APL differentiation syndrome during treatment and WBC count more than 10,000/μl were risk factors. (P<0.001 and p=0.011 respectively) For DFS only predicting factor for relapse was detection of MRD (by nested PCR or by real time PCR) during follow up (P=0.05). For prediction of OS, again only risk factor was detection of MRD(P<0.0001). Conclusions: Although WBC count before treatment and APL differentiation syndrome during treatment are risk factor for relapse, short isoform of APL is not a risk factor. After achieving to CR only risk factor is detection of MRD. No significant financial relationships to disclose.
Epoetin-alpha compared to standard of care decreases number of packed red blood cell transfusions in patients receiving hyper-CVAD for acute lymphocytic leukemia, lymphoblastic lymphoma, and Burkitt’s lymphoma
Authors: Cabanillas M. E. , Thomas D. A. , Kantarjian H. , Mattiuzzi G. N. , Bekele B. N. , Foudray M. C. , Cassat J. L. , Cortes J. E. 
Published: March 2020

7075 Background: Anemia is common in patients with acute lymphocytic leukemia (ALL), lymphoblastic lymphoma (LL), and Burkitt’s lymphoma (BL) treated with chemotherapy and is associated with poor cancer control. Studies have shown that mild correction of anemia is associated with a significant improvement in quality of life. The current standard of care (SOC) for treatment of anemia in ALL, LL, BL is packed red blood cell (PRBC) transfusions. Objectives: To evaluate if EPO 1)decreases number/frequency of transfusions, and 2) adversely influences the complete remission (CR) rate. Methods: Patients with newly diagnosed ALL, LL, or BL receiving hyper-CVAD were randomized to EPO vs SOC within 14 days of starting chemotherapy. EPO dose was 40,000 units SQ weekly and escalated to 60,000 units after 4 weeks if indicated. Both arms received PRBC transfusions as per guidelines. Patients were considered evaluable if they had been on the study for at least 5 weeks. Results: 46 of 70 patients were evaluable: 16 ALL, 4 BL, and 3 LL on EPO (total 23) and 20 ALL, 1 BL, 2 LL in the SOC arm (total 23). The 2 groups were comparable in baseline hemoglobin and number of courses of chemotherapy completed. Median baseline erythroepoietin level was 299 (r 12–10,532) in the EPO arm vs. 104 (r 7–491; p=0.02) in the SOC arm. Time to neutrophil and platelet recovery was comparable in both arms. All patients with ALL (both arms) achieved a CR. One patient with LL on the EPO arm had no response to chemotherapy while all patients with BL and LL on the SOC arm achieved a CR. Conclusions: 1) EPO significantly decreased the frequency and number of PRBC transfusions in patients with ALL, LL, and BL on hyper-CVAD. 2) EPO does not affect recovery of other cell lines. 3) Use of EPO does not appear to have an adverse impact on CR rates in patients with ALL. No significant financial relationships to disclose. [Table: see text]
Natural history of patients with myelodysplastic syndromes (MDS) with interstitial deletions of chromosome 5q detected on G-banded karyotyping
Authors: Holtan S. G. , Santana-Davila R. , Dewald G. , Ketterling R. , Tefferi A. , Steensma D. P. 
Published: March 2020

7077 Background: MDS includes a heterogenous group of hematopoietic stem cell malignancies characterized by ineffective hematopoiesis and recurring clonal cytogenetic abnormalities with poorly understood functional consequences. Interstitial deletion of chromosome 5 including band q31 is of special interest currently because of the striking effectiveness of lenalidomide therapy in patients with this lesion. Methods: We reviewed the clinical and pathological features of 175 consecutive patients with 5q31 deletions whose final diagnosis was MDS from 1996 to 2006. Patients not meeting the definition of a clonal chromosomal anomaly (i.e., only 1 abnormal metaphase) and those with >20% marrow blasts (now defined as AML) were excluded. Results: The median age at diagnosis was 73 years old (range 8–91). The 5 most common MDS subtypes (WHO classification) were RAEB2 (38 cases), 5q- syndrome (33 cases), MDS NOS (26 cases), RCMD (22 cases), and RAEB1 (20 cases). Chromosomal breakpoints encountered most frequently were q13q33 (86 cases), q15q33 (38 cases), and q22q33 (14 cases). The 5q deletion was present as a sole cytogenetic anomaly in 31%, was present along with one other anomaly in 10%, and was part of complex karyotype in 59%. Median time to death from confirmation of diagnosis at our institution was only 7.2 months (range 1 month –1.8 years). Survival was greatest in those diagnosed with 5q- syndrome, but the median survival time of 1.8 years (p=0.001) was lower than reported in other series. Survival was also superior in women (7.9 months, versus 6.6 months for men, p=0.05) and those with non-complex cytogenetics (1.44 versus 0.41 years, p<0.001). Poorer survival was noted in those with prior chemotherapy (median 6.6 months versus 7.6 months, p=0.01). Differences in breakpoint (p=0.55) and number of metaphases involved with the 5q abnormality (p=0.08) did not have a statistically significant impact on survival. Conclusion: Classic 5q- syndrome as defined by the WHO represents only a minority of MDS patients with interstitial 5q deletions. Although the short survival in our series compared with previous reports may be due in part to referral bias, it is also possible that deletions of chromosome 5q are less benign than previously suspected. No significant financial relationships to disclose.
Changing the treatment paradigm for patients with MDS: How the development of therapeutics influences population-based care in community oncology, the Georgia Cancer Specialists Outcomes Database experience
Authors: Feinberg B. A. , Gilmore J. , Hawke W. , Gondesen T. 
Published: March 2020

7080 Background: Clinical trials that lead to approval of new cancer therapeutics are based upon rigorous studies of safety & efficacy in a highly-restricted pt population. Community oncology practices are evolving to contribute to our understanding of the population- based effectiveness of these therapeutics by capturing and analyzing outcomes data. Georgia Cancer Specialists, a group practice of 41 hematologists/oncologists has been routinely tracking outcomes data since 1999. We now report outcomes for pts with MDS from our database. MDS was selected since this is a Medicare population, has typically been treated with supportive care only, and 3 new agents, 5-azacytadine (VID), lenalidomide (REV) and decitabine (DAC) have recently been approved allowing assessment of their impact on this cancer population. Methods: The Georgia Cancer Specialists Outcomes Database is an integrated electronic medical records and billing database that captures over 45 parameters on every pt visit at 31 sites. This study is a retrospective, observational study using de-identified pt-level information. Results: We followed 824 MDS pts from Jan-Oct, 2006, with 63% women; mean age 71 yrs; 61% Medicare/Medicaid. Only 7% of pts received at least one MDS-indicated chemotherapeutic. Of these, 44% received VID; 36% REV, and 43% DAC and 18% received at least two. At initial therapy, more REV pts (73%) were transfusion-dependent than VID (20%) and DAC (55%) (p=0.034). Average duration of observed therapy ranged from 2.3–3.25 cycles. A greater proportion of DAC pts (93%) had an improvement in RBC count within the first 4 cycles when compared to VID (44%) and REV (62.5%) (p<0.01). The treatment response profile for platelets was similar for VID and DAC. Conclusions: Practice patterns of elderly pts with MDS are changing as new therapies are adopted in community oncology practice. DAC appears to be very active, with the shortest time to initial response. Rigorous population based outcomes analyses at the practice level is an important component of quality cancer care and must supplement information generated by randomized clinical trials. No significant financial relationships to disclose.
An oral dosage formulation of azacitidine: A pilot pharmacokinetic study
Authors: Ward M. R. , Stoltz M. L. , Etter J. B. , Patton L. M. , Garcia Manero G. , Sharma S. 
Published: March 2020

7084 Background: Azacitidine, a cytidine analog, induces DNA demethylation that leads to tumor suppressor gene expression. Cellular effects of azacitidine treatment include differentiation, cell cycle arrest and/or apoptosis. There is a complex, non-linear relationship between plasma exposure and pharmacodynamic effect of azacitidine that can be fully explored with an oral formulation of azacitidine, enabling alternate dosing strategies ranging from intermittent high dose to continuous, low-dose approaches to DNA demethylation. Methods and Results: A pharmacokinetic study in dogs given oral azacitidine demonstrated rapid absorption with absolute bioavailability of 67% (compared to 71% following SC dosing). When comparing a single parenteral dose of 75 mg/m2 (∼2 mg/kg) given SC to humans vs. a single oral dose of 16 mg/m2 (0.8 mg/kg) given to dogs, plasma concentrations of azacitidine were similar despite the 4- to 5-fold difference in dose as calculated by body surface area (BSA). A 14-day toxicology study in dogs evaluated the oral doses of 0.2, 0.4, and 0.8 mg/kg/day. The high dose is the previously identified MTD of 0.55 mg/kg/day based on an oral bioavailability of 67% (approximately equal to 16 mg/m2/day). Hematologic toxicity, a known and expected effect of azacitidine administered in a repeat-dose regimen was observed at the two highest doses. The oral MTD was determined to be 0.2 mg/kg/day for 14 consecutive days followed by a 21-day recovery period. This provides a cumulative MTD of 2.8 mg/kg for the14 day dosing regimen, which is similar to that seen with IV dosing (2.75 mg/kg over 5 days). Based on the preclinical studies, a multicenter, single-treatment study of oral azacitidine is underway in subjects with MDS, AML, or solid tumors. The trial assesses the safety, tolerability and pharmacokinetics of escalating single doses of orally administered azacitidine. Clinical data from this study will be presented. [Table: see text]
Allogeneic immunotherapy by hematopoietic stem cell transplantation (ASCT) after reduced intensity conditioning (RIC) following high-dose chemotherapy for patients with acute myeloblastic leukemia (AML) in first complete remission (CR1): Reduced toxicity
Authors: Blaise D. , Tabrizi R. , Faucher C. , Mohty M. , Bay J. , Marit G. , Furst S. , Charbonnier A. , Chabannon C. , Vey N. 
Published: March 2020

7098 Background: RIC-based ASCT can be used after intensive chemotherapy in pts with CR1AML(Blaise, Cancer, 2005). Initial disease control was high and was not related to selection bias (Mohty, Leukemia, 2005).Here, we investigated if this control was maintained after a long follow-up. Methods: 37 pts (age: 51 (26–60)) with high risk clinical characteristics (70%) (Age = 50 (N=22, 59%); severe comorbidity (30%)) and/or poor risk leukemic features (65%) (Cytogenetics (35%); 2 induction courses (27%); secondary leukemia (11%), High white blood cell counts(14%) or partial remission (3%)) were treated. After CR1, pts received at least either 1 course of high dose cytarabine (24 g/m2) and anthracycline (HIDAC: N=21) or HIDAC + 1 course of. melphalan (140 mg/m2) (HDMEL) with auto-SCT Pts (HIDAC +HDM N=16). All pts were then scheduled to receive ASCT prepared with RIC (fludarabine (180 mg/m2), busulfan (8 mg/kg), Thymoglobulin (2.5 to 10 mg/kg)) followed with BMT (28%) or PBSC (72%). Results: With a Median follow-up of 3 years (16–70 mths). 15 pts experienced aGVHD (grade 2–4 aGVHD cumulative incidence (CI):22% (9–35). 10 and 14 pts presented a limited and extensive cGVHD respectively (CI cGVHD:65 % (50–80). 3 deaths were attributed to non-relapse causes (NRD) (AGVHD: 1; CGVHD: 2° (NRD CI: 8% (0–17). In all, 9 pts relapsed at 5 mths (2–19) (24% (9–35). Relapse was associated with the absence of cGVHD (cGVHD: 8 (0–19), no cGVHD 44% (12–76), p=.05). 25 pts are still alive in CR1 for overall survival and leukemia-free survival (LFS) probability estimates at 4 years of 65 % (48–79%) and 66% (49–80%) respectively. When restricting the analysis to the 33 pts evaluable for cGVHD, cGVHD remained the only independent risk factor positively influencing LFS (cGVHD: 81% (59–92); no cGVHD (56% (27–81), p=.05) Conclusions: We conclude that RIC Allo-SCT preceded by adequate prior intensive chemotherapy might offers a relatively low NRD while exerting a sustained leukemia control even in high risk pts deserving prospective evaluation against standard strategy of conventional Allo SCT. No significant financial relationships to disclose.
Effects of high-dose chemotherapy (HDCT) and stem cell transplant (SCT) on cardiac function: A prospective study
Authors: Vallabhaneni G. , Momin F. 
Published: March 2020

7106 Background: The effects of HDCT on Cardiac function have not been well defined. In our experience the deleterious effect of HDCT on cardiac function has been overestimated. There is recent evidence that infused peripheral blood progenitor cells have a reparative effect on the myocardium. We prospectively analyzed cardiac function in adult recipients of HDCT and stem cell transplantation before and 100 days after they received HDCT and SCT. Methods: From 1997 to 2004, 109 adult patients received HDCT and SCT. Of these, 34 were male and 51 were female. 55 patients received autologous SCT and 30 patients received allogeneic SCT from HLA matched siblings. Cardiac function was measured by 2D-ECHO two weeks prior to and 100 days post-HDCT and SCT. HDCT was administered according to standard protocols. An ejection fraction [E.F] of greater than 45% was defined as normal. Post-HDCT E.F decrease was defined as reduction of > 10% from baseline. An increase in the EF of greater than 10% from baseline was considered an improvement in cardiac function. Results: 85 patients were evaluable. Median age was 56 years. Auto SCT: Pre-HDCT E.F was normal in 53 auto- SCT and was < 45% in 2 patients. EF declined by 15 and 20% in 2/53 patients (3.7%) who had a normal E.F at baseline. Neither were symptomatic. There was no change in E.F, in patients who had a decreased E.F at baseline. Allogeneic SCT: Pre-HDCT was normal in 29 patients and was < 45% in 1 patient. Post-HDCT E.F remained unchanged in all 29 patients, who had a normal E.F at baseline. The EF improved to normal in the recipient who had a low EF prior to transplant. Conclusions: There was no significant change in cardiac function after HDCT and SCT by 2D-ECHO. The improvement in cardiac function in one of our allogeneic recipients was quite impressive and long lasting and seemed to coincide with engraftment of healthy donor stem cells suggesting that there may be a role for healthy stem cells in improving myocardial dysfunction. No significant financial relationships to disclose.
Association of serum interleukin-7 and interleukin-15 levels with immune reconstitution (IR), graft-versus-host disease (GVHD), and survival after reduced-intensity allogeneic stem cell transplantation (RIST)
Authors: Dean R. M. , Hakim F. T. , Fry T. , Steinberg S. M. , Boyiadzis M. , Fowler D. H. , Odom J. , Mackall C. , Gress R. E. , Bishop M. R. 
Published: March 2020

7107 Background: In laboratory models, interleukin-7 (IL-7) and IL-15 significantly influence IR after allogeneic stem cell transplantation (SCT), thereby affecting immunity, graft-versus-malignancy (GVM) effects, and GVHD. Interleukin-7 (IL-7) is the main homeostatic regulator of naïve CD4+ and CD8+ T cells, and IL-15 is homeostatic for CD8+ memory and effector T cells and NK cells. The contributions of these cytokines to IR after allogeneic SCT are not well characterized in a clinical setting. Methods: We studied serum IL-7 and IL-15 levels in 31 pts with hematologic malignancies undergoing RIST from HLA-matched siblings in a prospective trial. Pts received identical transplant conditioning (fludarabine/cyclophosphamide) and GVHD prophylaxis (CSA/MTX). IL-7 and IL-15 levels and peripheral blood lymphocyte subpopulations (ALC, CD3, CD4, CD8, B, NK, and NKT) were measured before RIST, and post RIST at 1 and 2 weeks; 1, 2, 3, 6, 9, and 12 months. Results: Consistent with their homeostatic effects, IL-7 and IL-15 levels rose from baseline as transplant conditioning induced lymphopenia, and then decreased with lymphocyte recovery. These inverse correlations were strongest within 1 month post RIST. In an exploratory analysis, IL-15 levels at day 0 were correlated with baseline age (r=0.49; p=0.0058) and were higher among patients with CMV reactivation after RIST (p=0.048). At 2 weeks post RIST, higher IL-7 levels were strongly associated with subsequent acute GVHD (p=0.000033), and higher IL-15 levels were associated with inferior survival (p=0.007), mainly from relapse. At 3 months post RIST, superior survival was associated with higher NK cell counts (p=0.0008), and to a lesser extent with higher CD4 counts (p=0.036). Conclusions: These data support preclinical observations that IL-7 promotes GVHD after allogeneic SCT. The association of higher post-RIST IL-15 levels with death from relapse may identify pts with impaired IR leading to inadequate GVM effects. This hypothesis is consistent with the finding that higher NK cell counts after RIST were associated with better survival. Further studies must confirm the hypotheses generated in this setting. No significant financial relationships to disclose.
The occurrence of idiopathic secondary post-transplant thrombocytopenia and the kinetics of platelet recovery predict survival in patients undergoing autologous hematopoietic progenitor cell transplantation
Authors: Waller E. , Ninan M. J. , Roback J. , Arellano M. , Flowers C. 
Published: March 2020

7109 Background: The frequency and clinical significance of secondary thrombocytopenia following initial engraftment in autologous hematopoietic progenitor cell transplantation (HPCT) is unknown. Methods: An IRB-approved retrospective study of thrombopoiesis in 359 patients transplanted with autologous blood (97%) or marrow (3%) who achieved transfusion-independent platelet engraftment to >50,000/mcL. Idiopathic secondary post-transplant thrombocytopenia (ISPT) was defined as >50% decline in blood platelets to <100,000/mcL in the absence of relapse or sepsis. Results: 62 of 359 study subjects (17%) met the criteria for ISPT within the first 100 days post-transplant. Patients with ISPT had more rapid platelet engraftment (17 + 5 days) versus non-ISPT patients (18 + 18 days; p=0.002) and partial recovery of platelet counts (median 96K/mcL) by day 75 post-transplant. The median survival for the entire population was 6.2 years with shorter survival in AML (1.3 years), breast cancer (6.2 years) and myeloma (5.5 years) than lymphoma patients (median not reached). Co- variates associated with post-transplant death (p<0.1) were entered into a multivariable logistic regression analysis stratified by cancer diagnosis at the time of transplant. Three factors were independently associated with worse survival: the number of prior chemotherapy regimens, failure to achieve a normal platelet counts post-transplant, and the occurrence of ISPT. A prognostic score was developed based upon the occurrence of ISPT and post-transplant platelet counts of <150,000/mcL. Survival of patients with both factors (n=25) was poor (15% alive at 5 years); patients with one factor (n=145) had 49% 5-year survival; patients with 0 factors (n=189) had 72% 5-year survival. Patients who failed to achieve a normal post-transplant platelet count received significantly fewer CD34+ cells/kg (P<0.001), while patients with ISPT received fewer CD34+CD38- cells/kg (P=0.001). Conclusion: ISPT reflects poor engraftment with long-term-repopulating CD34+ CD38- stem cells. The quantity and quality of autologous HPC in the graft are important prognostic variables for long-term survival. No significant financial relationships to disclose.