bluuebunny/crossref_metadata_2025 huggingface dataset:
Binding mode of the tyrosine kinase inhibitor bosutinib (SKI-606) to Abl kinase
Authors: Soverini S. , Tasco G. , Grafone T. , Colarossi S. , Gnani A. , Baccarani M. , Casadio R. , Martinelli G.
Published: March 2020

7049

Background: Bosutinib (SKI-606) is a 4-anilino-3-quinolinecarbonitrile Src/Abl kinase inhibitor. The crystal structure of Abl kinase domain in complex with bosutinib has not yet been determined and the mode of binding of this inhibitor is therefore unknown. Methods: In the present study, we used a molecular docking approach to investigate the following: a) Which Abl conformation(s) bosutinib is more likely to bind? b) Which Abl residues are likely to be involved in bosutinib binding? c) Which imatinib-resistant Abl mutants bosutinib is likely to be active against? A three-dimensional model of bosutinib was generated by Chemsketch ( http://www.acdlabs.com ). Modelling of the human Abl kinase in its inactive (closed) conformation was performed with the software Modeller, v7.7 ( http://salilab.org/modeller ) adopting the highly related Mus musculus Abl homologue as a template structure (PDB entry: 1OPJ , 0.175nm resolution). Active (open) Abl conformation is available as PDB entry 1OPL . Flexible docking of bosutinib to Abl was performed with Autodock v3.0 ( http://www.scripps.edu/mb/olson ). Results: Our binding hypothesis predicts that a) similarly to IM, the interaction between bosutinib and Abl seems to be more stable when the latter is in its inactive (closed) conformation; b) 21 Abl residues (including Y253, T315, F317 and F359 among others) surround bosutinib and engage H-bonds or Van der Waals interactions; c) bosutinib is likely to retain the ability to bind and inhibit the IM-resistant Y253H, M351T, F359V, F317L and E255V Abl mutants. In contrast, bosutinib binding to E255K and T315I mutants is predicted to be less efficient. Detailed models will be presented. Conclusions: Bosutinib is a promising second-line treatment for Ph+ leukemia patients harbouring several IM-resistant Abl mutations. The T315I remains the biggest hurdle for pharmacological therapy of Ph+ leukemias. Supported by European LeukemiaNet, AIRC, AIL, COFIN and FIRB projects, and by Fondazione del Monte di Bologna e Ravenna.

No significant financial relationships to disclose.
Acute myeloid leukemia (AML) after a prior diagnosis of other hematological malignancies (HM), breast cancer (BC), and other cancers (OC) in the Australian female population between 1982 and 2002
Authors: Beadle G. , Baade P. , Fritschi L.
Published: March 2020

7052

Background: AML is a widely reported complication of chemotherapy for HM and BC but few population based studies have investigated the nature and magnitude of AML risk after a diagnosis of cancer. Methods: This retrospective study examined 3 cohorts of female patients 30 years and over reported to state and territory cancer registries in Australia between 1982 and 2002. The cohorts comprised 40,030 women with HM, 162,142 with BC and 379,347 with OC. Results: The AML incidence rate/100,000 (IR) was 4.1 for all Australian females. The rate was much higher in the cohort with HM (IR 36.2; CI 25.3 –51.7), and slightly higher among those with BC (IR 11.7; CI 9.4 –14.9) and OC (IR 7.7; CI 6.4 –9.2). Standardized incidence ratio (SIR) estimates confirmed that women in the 3 cohorts had higher risks of subsequent AML than the general female population. These ranged from 5.5 times higher for those with HM (p <0.001), 2.7 for BC (p <0.001) and 1.7 for OC (p <0.001). Although the IR for AML rose sharply with age, the SIR estimates for HM and BC, but not OC, were highest in the young age group and decreased with increasing age (30–49 years HM 21.6, BC 5.1; 50–69 years HM 10.4, BC 2.9; 70 years and older HM 1.8, BC 1.9; all p values < 0.001). There was no evidence that time to diagnosis curves for AML were different for the 3 cohorts (53% within 5 years for HM, 60% for BC and 59% for OC). Conclusion: AML risk was higher for female cancer survivors than for the non-cancer population and was a continuing risk for long term survivors. Although the absolute risk increased with age, the relative risk was highest in young survivors of HM and BC, and decreased with age. There was no evidence of a disproportionate increase of AML risk for cancer survivors during this era of expansion of the evidence base for more extensive chemotherapy, although there was a significant increase in the risk of AML for the Australian female population.

No significant financial relationships to disclose.
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.
Successful engraftment following reduced-intensity cord blood transplantation with fludarabine and oral busulfan for advanced hematologic diseases
Authors: Azuma T. , Kami M. , Kusumi E. , Sato Y. , Miura Y. , Komatsu T.
Published: March 2020

7110

Background: Feasibility of reduced-intensity cord blood transplantation (RI-CBT) has been demonstrated in adult patients. Most researchers use preparative regimens containing total body irradiation (TBI) 2–4 Gy, while TBI causes considerable toxicities in elderly patients. We investigated the feasibility of RI-CBT using non-TBI regimen for the treatment of adult hematologic diseases. Methods: Nineteen patients (median age, 61, range, 38–74) with advanced hematological diseases were enrolled in this study. Fifteen patients had chemorefractory diseases at RI-CBT. Preparative regimen comprised fludarabine 180 mg/m2 and oral busulfan 8 mg/kg. Graft-versus-host disease (GVHD) prophylaxis was tacrolimus. Engraftment was defined as an absolute neutrophil count > 0.5 × 10E9/l. Primary graft failure was defined as the complete loss of donor-type hematopoiesis occurring without engraftment. Secondary graft failure was defined as the loss of donor-type hematopoiesis occurring after primary engraftment. Endpoint of this study was engraftment. Median follow-up of surviving patients was 24.7 months (range, 21.6–25.8). Results: All the patients tolerated the preparative regimen. Median dose of infused nuclear cells was 2.7x10E7/kg (range, 1.9–4.6). HLA disparity was found in 2/6 antigens (n=16) and 1/6 antigen (n=3). Eleven patients achieved engraftment at a median of day 18 (range, 9–30). Chimerism analysis was conducted in six of these eleven patients, and complete donor-type chimerism was documented within 30 days of transplant in five patients. Primary graft failure was diagnosed in two patients. The other six patients died without engraftment due to diffuse alveolar hemorrhage(n=1) and disease progression(n=5). No patients developed acute GVHD. Five of the 11 patients who achieved primary engraftment developed secondary graft failure. As of December 2006, four patients survived in complete remission with complete donor-type chimerism. Estimated 1-year overall survival rate was 21.1%. Conclusions: This study demonstrated the feasibility of RI-CBT using non-TBI regimen; however, high incidences of disease progression before engraftment and secondary graft failure were significant problems.

No significant financial relationships to disclose.
Pharmacogenomic (PG) analysis of Japan-SWOG common arm study in advanced stage non-small cell lung cancer (NSCLC): A model for testing population-related pharmacogenomics
Authors: Gandara D. R. , Kawaguchi T. , Crowley J. J. , Moon J. , Kawahara M. , Teramukai S. , Williamson S. K. , Furuse K. , McLeod H. L. , Mack P. C.
Published: March 2020

7500

Background: We have previously reported differences in outcomes (increased survival, neutropenia & febrile neutropenia) in Japanese versus US patients (pts) treated with a paclitaxel-carboplatin “common arm” in a prospectively designed fashion in 3 phase III trials (FACS, LC03, S0003) in advanced NSCLC (Gandara, ASCO 05 & Crowley, ASCO 06). We hypothesized that these findings were due in part to PG alterations in paclitaxel disposition. Methods: Genomic DNA was prospectively collected from pts in 2 of these phase III trials (LC03 [N=78, 37 on common arm] & S0003 [N=78]) with identical eligibility, staging, treatment plan (paclitaxel 225 mg/m2 & carboplatin AUC 6), response & toxicity criteria. Analysis for genotypic variants of CYP3A4, CYP3A5, CYP2C8, NR1I2–206, ABCB1, ERCC2 was performed by pyrosequencing, and results assessed by Cox model for survival/PFS & logistics regression for response/toxicity. Results: There was a significant difference between Japan & US pts in genotypes: CYP3A4*1b (p=0.01), CYP3A5*3c (p=0.03), ERCC2 k751q (p <0.001), and CYP2C8 r139k (p=.01). Genotypic correlations were observed between CYP3A4*1b for PFS (HR 2.75, 1.06–7.08, p=0.04) & ERCC2 k751q for response (HR 0.33, 0.13–0.84, p=0.02). There were no other statistically significant associations, although for grade 4 neutropenia, the HR for ABCB1 3425c->T was 1.84 (0.77–4.48), p=0.19. The low number of events for febrile neutropenia within this data set precluded assessment of this parameter. Additional PG testing is ongoing & will be presented. Conclusions: 1) Differences in allelic distribution for genes involved in paclitaxel disposition or DNA repair were observed between Japanese & US pts. 2) Statistically significant genotype-associated correlations were present for PFS (CYP3A4*1b) & response (ERCC2 k751q), but not for neutropenia (p=0.19). 3) The small sample size limits interpretation of these data. Further studies based on this common arm approach are warranted for the prospective study of population-related PGs where ethnic/racial differences in anti-neoplastic drug disposition are anticipated.

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Gene expression patterns of oncogenic signaling pathways provide a novel approach to targeted therapeutics in advanced non-small cell lung cancer (NSCLC)
Authors: Potti A. , Bild A. , Dressman H. , Kelley M. , Harpole D. , Nevins J.
Published: March 2020

7503

Gene expression profiles reflect unique aspects of individual tumors and may characterize tumor heterogeneity in NSCLC. We used gene expression signatures that reflect the deregulation of major oncogenic signaling pathways (Ras, PI3 kinase, Akt, Src, β-catenin, E2F, and Myc) to identify patterns of pathway activation in 118 samples from patients with recurrent (n = 69) and metastatic (n = 49) NSCLC. These individuals, in particular, the patients with metastatic disease are likely to be resistant to standard chemotherapy pointing to the need for alternative therapeutic options. As one approach to this challenge, we used Affymetrix expression data to identify patterns of pathway deregulation in patients with advanced (recurrent/metastatic) disease and compared them to our previously described data on early stage NSCLC (n = 91). Unique to the recurrent and metastatic disease cohorts, a majority of the tumors (greater than 80%) had deregulation of multiple signaling pathways. In particluar, NSCLC tumors with deregulated Src and Myc pathways had a much worse prognosis than those with deregulated Ras and Akt pathways [median survival: 15.5 months vs. 55.3 months, hazard ratio: 2.6, p < 0.01]. Further, using cell proliferation assays, we have shown that the predicted deregulation of Ras, Src and PI3K pathways was directly proportional (p < 0.01, log rank test) to the sensitivity of NSCLC cell lines (n = 17) to agents that specifically target these pathways, suggesting that an ability to profile the status of oncogenic pathways in a tumor sample provides an opportunity to better characterize the oncogenic process in patients with recurrent and advanced NSCLC. More importantly, such a strategy provides a novel approach to targeted therapeutics in NSCLC by guiding the appropriate use of pathway specific inhibitors. Finally, data on gene expression patterns involving other signatures representing unique cancer biology relevant to NSCLC (e.g. hypoxia, chromosomal instability, and angiogenesis) will be also be presented.

No significant financial relationships to disclose.
High correspondence between EGFR mutations in tissue and in circulating DNA form non-small-cell lung cancer (NSCLC) patients (p) with poor performance status (PS)
Authors: Moran T. , Paz-Ares L. , Isla D. , Cobo M. , Massuti B. , Insa A. , Queralt C. , Pradas A. , Taron M. , Rosell R.
Published: March 2020

7505

Background: We evaluated the correspondence between EGFR mutations in NSCLC tissue and matched serum DNA and the value of EGFR mutations as a serological marker. Methods: 121 Spanish stage IV NSCLC p received customized first- or second-line erlotinib monotherapy based on the presence of EGFR mutations in the tumor tissue. Serum genomic DNA was obtained from all p prior to erlotinib administration. EGFR exon 19 deletions were studied by length analysis of fluorescently labeled PCR products and the exon 21 L858R mutation by a PCR Taqman assay. Results: The EGFR mutation status in the serum was consistent with that in the tumor tissue of 82/121 p (68%) and of 15/16 p (93.8%) with PS 2 had mutations. Overall, 64.3% of p had an exon 19 deletion and 35.7% had L858R. 78% of mutations were found in females (P=0.01) and 77.6% in never-smokers (P=0.07). Response rate was 88% in p with mutations only in the tumor and 87% in p with mutations in tumor and serum. Complete responses were observed in 20% of p with mutations in tumor and serum vs 4% of p with mutations only in tumor (P=0.09). With a median follow-up of 6.8 months (m) (range, 1.2–17.6), time to progression (TTP) and median survival have not been reached. A trend to better outcome was seen in p without serum EGFR mutations. TTP was longer for p with EGFR exon 19 deletions (not reached) than for p with L858R (7.7 m) (P=0.02). TTP for p with PS 2 with exon 19 deletions was not reached, while it was 2.7 m for p with L858R (P=0.17). Conclusions: EGFR mutations in serum could be a non-invasive source of information on the genotype of the original tumor cells and could be a useful tool to predict p response to erlotinib, especially in p with poor PS.

No significant financial relationships to disclose.
Efficacy of the anti-insulin like growth factor I receptor (IGF-IR) antibody CP-751871 in combination with paclitaxel and carboplatin as first-line treatment for advanced non-small cell lung cancer (NSCLC)
Authors: Karp D. D. , Paz-Ares L. G. , Blakely L. J. , Kreisman H. , Eisenberg P. D. , Cohen R. B. , Garland L. , Langer C. J. , Melvin C. L. , Gualberto A.
Published: March 2020

7506

Background: CP-751871 is a fully human, IgG2 monoclonal antibody against the IGF-IR active in preclinical models of NSCLC. Methods: We are conducting a phase II, randomized, non-comparative study in ten centers to evaluate the safety and efficacy of combination paclitaxel (T), carboplatin (C) and CP-751871 (I) versus TC alone in stage IIIB, IV or recurrent, treatment-naive NSCLC pts with performance status 0–1. The statistical hypotheses are 28% (null) versus 40% (response of interest). Pts are randomized (2:1) to T (200 mg/m2), C (AUC of 6) and I (10 mg/kg), or TC alone every 3 weeks for up to 6 cycles; pts receiving TCI with response (PR) or stable disease following discontinuation of chemotherapy are eligible to continue I as single agent until disease progression. Pts progressing on TC alone are eligible to receive I as single agent or in combination with TC at the judgment of the investigator. Responses are assessed by investigator using RECIST. Results: An interim analysis for futility has been conducted with 73 pts enrolled: 48 treated with TCI; 25 with TC. TCI was well tolerated. All causality grade 3,4 toxicity included (TCI, TC): hyperglycemia (20%, 10%), fatigue (15%, 8%), neutropenia (13%, 20%) and neuropathy (10%, 4%). 22/48 pts receiving TCI (46%) and 8/32 pts on TC (32%) had objective responses. Furthermore, 14 out of 27 TCI pts (52%) with non-adenocarcinoma responded to treatment. In addition, a PR was observed in 1 out of 4 TC pts who elected to receive single agent I after progression on TC alone. Conclusions: CP-751871 appears safe in combination with TC. Interim TCI activity warranted further investigation. An additional 83 pts will be enrolled to assess further the safety and efficacy of this combination treatment.

[Table: see text]
Phase III study of vinflunine versus docetaxel in patients (pts) with advanced non-small cell lung cancer (NSCLC) previously treated with a platinum-containing regimen
Authors: Krzakowski M. , Douillard J. , Ramlau R. , Jassem J. , Szczesna A. , Zatloukal P. , von Pawel J. , Hansen O. , Sun X.
Published: March 2020

7511

Background: Vinflunine (VFL) is a new microtubule inhibitor of the vinca alkaloid class with clinical activity in NSCLC (J. Bennouna, BJC, 2006). Single-agent efficacy and safety of VFL and docetaxel (DTX) were compared in the 2nd line chemotherapy. Methods: Open-label, multi-center, randomised, phase III study in platinum pre-treated locally advanced/metastatic NSCLC pts. At least 275 pts were to be randomized by arm to receive VFL (320 mg/m2, 20-min IV infusion) or DTX (75 mg/m2, 1-hour IV infusion with dexamethasone over 3 days) every 3 weeks. The primary endpoint was progression free survival (PFS), with a non-inferiority analysis based on a 10% difference (types I and II error rates: 5%, 20%). Results: From 06/03 to 03/05, 551 pts were randomized (VFL: 274; DTX: 277) and 547 treated (411 men, 136 women); median age 61 years [range 22–83]; ECOG PS 0–1: 89%; metastatic: 90%. All pts were platinum pre-treated, in combination with a vinca alkaloid (22%), paclitaxel (21%), or gemcitabine (48%). A total of 950 [1–20] and 1,025 [1–18] cycles were given with VFL and DTX respectively. Grade 3/4 toxicities were low in both arms: neutropenia (33% vs 30%), anemia (8% vs 3%), thrombocytopenia (2% vs <1%), febrile neutropenia (3% vs 5%), fatigue (11% vs 6%), vomiting (2% vs 1%), abdominal pain (4% vs <1%), constipation (7% vs <1%). Overall incidence of alopecia was: 20% vs 35%, nail disorders 1% vs 6%, injection site reaction 25% vs 1%, peripheral neuropathy 11% vs 15%, diarrhea 6% vs 12%. Efficacy: All efficacy endpoints were similar: median PFS (2.3 vs 2.3 months, HR:1.004 [95% CI: 0.841–1.199]), independent review response rate (4.4% vs 5.5%), stable disease (36.0% vs 39.6%), disease control (40.4 vs 45.1), median overall survival (6.7 vs 7.2 months, HR: 0.973 [0.805–1.176]). Conclusion: VFL shows efficacy equivalent to docetaxel in 2nd line NSCLC chemotherapy. Low, manageable but different toxicity profiles were observed in either arm. Vinflunine offers a new and useful alternative for the 2nd line treatment of pts with this disease.

No significant financial relationships to disclose.
A phase III study of Æ-941 with induction chemotherapy (IC) and concomitant chemoradiotherapy (CRT) for stage III non- small cell lung cancer (NSCLC) (NCI T99–0046, RTOG 02–70, MDA 99–303)
Authors: Lu C. , Lee J. J. , Komaki R. , Herbst R. S. , Evans W. K. , Choy H. , Desjardins P. , Esparaz B. T. , Truong M. , Fisch M. J.
Published: March 2020

7527

Background: Æ-941 is a shark cartilage extract with antiangiogenic properties. We conducted a placebo-controlled trial testing Æ-941, with IC and CRT, in unresectable stage III NSCLC. Methods: Eligibility criteria included performance status (PS) < 2, weight loss < 10%. Subjects received one of two treatment regimens depending on site of enrollment: carboplatin (C) (AUC 6) and paclitaxel (P) (200 mg/m2) × 2 cycles followed by CRT (60 Gy/30 fractions) with weekly C (AUC 2) and P (45 mg/m2) × 6 doses or cisplatin (CDDP) (75 mg/m2, d1) and vinorelbine (V) (30 mg/m2, d1 and 8) × 2 cycles followed by CRT (60 Gy/30 fractions) with CDDP (75 mg/m2, day 1) and V (15 mg/m2, d1 and 8) × 2 cycles. Subjects were randomized to receive Æ-941 (Arm A) or placebo (Arm B), 120 mL orally twice daily, at the start of IC and continuing after CRT as maintenance therapy. Randomization was stratified for stage, gender, and type of chemotherapy. The primary endpoint was overall survival (OS), with a planned sample size of 756 subjects providing 80% power to detect a 25% difference in OS, assuming a control arm median survival time (MST) of 13 months, type I error 0.05. Results: Between 6/00 and 2/06, 384 subjects were enrolled onto the trial and randomized. In 2/06 the trial was closed to new patient entry due to insufficient accrual. This final analysis is based on 379 randomized and eligible subjects (188 arm A, 191 arm B). Subject characteristics: 60% male, median age 63 years (range 37–84), 56% stage IIIB, 58% C-based chemotherapy, median follow-up 3.7 years. There was no significant difference in OS between arms A and B, with MSTs of 14.4 (95% CI 12.6–17.9) and 15.6 (95% CI 13.8–18.1) months, respectively (log-rank p=0.73). OS by pre-specified stratification factors: stage IIIB vs IIIA (MST 13.9 vs. 17.4 months, p=0.25), C vs. CDDP chemotherapy (MST 14.4 vs. 16.7 months, p=0.13), and male vs. female (MST 15.7 vs. 15.1 months, p=0.74). The study drug was well tolerated. Fewer subjects in arm A experienced grade 3 or higher adverse events (66% vs. 77%, p=0.018). Conclusions: The addition of Æ−941 to IC and CRT does not improve OS in patients with unresectable stage III NSCLC.

No significant financial relationships to disclose.
Phase II open-label study to investigate efficacy and safety of PTK787/ZK 222584 (PTK/ZK) orally administered once daily or twice daily at 1,250 mg as second-line monotherapy in patients (pts) with stage IIIB/IV non-small cell lung cancer (NSCLC)
Authors: Gauler T. C. , Besse B. , Meric J. B. , Gounant V. , Fischer B. , Overbeck T. , Krissel H. , Laurent D. , Soria J. C. , Eberhardt W. E.
Published: March 2020

7541

Background: Overexpression of vascular endothelial growth factor receptor (VEGF-R) in NSCLC-tumors is linked to poor prognosis and shorter overall survival (OS). PTK/ZK is a novel, oral, anti-angiogenic compound blocking all currently known VEGF receptors (VEGF-R 1–3). Methods: A prospective, single-arm, multi-center, proof-of-principle phase II study to investigate efficacy and safety of PTK/ZK in pretreated pts with stage IIIB/IV NSCLC. Only one platinum-based chemotherapy regimen was allowed as first-line treatment. 55 pts each were planned to receive a fixed dose of 1,250 mg PTK/ZK once daily (qd) or twice daily (500 mg a.m. + 750 mg p.m.) (bid) for continuous treatment until disease progression or unacceptable toxicities. Response evaluation was based on RECIST. A disease stabilization of at least 12 weeks was defined as clinically relevant drug activity. Additional biomarker evaluation included DCE-MRI and serum proteomics. Results: Enrolment is completed with 54 pts starting qd and 58 pts starting bid treatment. Most frequent adverse events in both cohorts were nausea (44%), vomiting (40%), and dizziness (34%). Three possibly related deaths were observed, 2 due to pulmonary hemorrhage and 1 due to pulmonary embolism. Best response by RECIST for the qd cohort (n=54) include 1 pt with a confirmed partial response (cPR) (2%), 32 pts (59%) with stable disease (SD) at week 4, hereof 18 pts (33%) for at least 12 weeks, and 21 pts (39%) with progressive disease (PD); for the bid cohort (n=57) 4 pts with cPR (7%), 18 pts (32%) with SD (=12 weeks), 19 pts (33%) not yet evaluated, and 16 pts (28%) with PD. Progression free survival (PFS)/OS were 2.4/7.0 months (mo) for the qd vs. 3.7/6.8 mo for the bid cohort. Conclusions: These results suggest that both qd and bid second-line treatment with single-agent PTK/ZK is generally safe and well tolerated. In this unfavorable pt population a considerably high rate of disease control could be achieved. Four pts with PR out of 38 evaluated pts in the bid cohort might indicate additional benefit of bid dosing. Final data of the primary endpoint (efficacy) for both cohorts will be presented at the meeting.

[Table: see text]