bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase I study of INNO-406, a dual inhibitor of Abl and Lyn kinases, in adult patients with Philadelphia chromosome positive (Ph+) chronic myelogenous leukemia (CML) or acute lymphocytic leukemia (ALL) relapsed, refractory, or intolerant of imatinib
Authors: Craig A. R. , Kantarjian H. M. , Cortes J. E. , Jones D. , Hochhaus A. , O'Brien S. , Rios M. , Zander C. , Gleich L. , Carroll E. P. , Ottmann O. G.
Published: March 2020

7046

Background: INNO-406 is an orally available, dual Abl/Lyn kinase inhibitor that is up to 55-times more potent than imatinib in Bcr-Abl cell lines. Numerous Bcr-Abl mutant proteins (not T315I) are sensitive to INNO-406 in vitro. INNO-406 demonstrates specific Src kinase activity against Lyn kinase. Methods: In this phase I study, patients with imatinib-resistant or intolerant Philadelphia (Ph+) chromosome- positive leukemias were eligible for treatment with INNO-406 once a day, orally. Results: 14 pts [median age: 58 yrs (range 18–74); 7 male, 7 female; median CML duration: 53 mo. (range 14–266); and median time on imatinib 45 months (range 12–129); chronic phase CML (8 pts), accelerated phase CML (2 pts), blast phase CML (1 pt), Ph+ ALL (3 pts); previous treatment with nilotinib (5 pts), dasatinib (6 pts)] have been enrolled in the following dose cohorts (mg/day): 30 (3 pts), 60 (3), 120 (6) and 240 mg (2), and have been on treatment between 7 and 123 days. 3 pts remain on study; 10 pts discontinued with disease progression [data unmonitored]. 6 patients who have completed >1 month of treatment, 3 have evidence of clinical response. Patient 5, a chronic phase CML treated with imatinib for 69 mo. before developing resistant disease with an Y253H mutation, had a minimal cytogenetic response after 1 month of INNO-406 therapy. Patient 4, an accelerated phase CML treated with imatinib and nilotinib for 16 and 6 mo., respectively, before becoming intolerant to nilotinib due to thrombocytopenia, has maintained a complete hematologic response following 4.5 months of INNO-406 therapy at a dose of 120 mg/day. Patient 1, a chronic phase CML treated with imatinib for 51 mo. before developing resistant disease without a mutation, has maintained stable white cell counts after 4 months of therapy at a dose of 30–60 mg/day, with a 55-fold reduction in Bcr-Abl transcript levels after 1 month of INNO-406 therapy. Conclusions: INNO-406 is well tolerated in patients at a dose of 240 mg/day, with encouraging evidence of clinical activity in imatinib-resistant and nilotinib-intolerant patients. In the absence of dose limiting toxicity, dose escalation continues.

No significant financial relationships to disclose.
Acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) following a diagnosis of breast cancer
Authors: Padmanabhan A. , Block A. , Sait S. , Ford L. A. , O'Connor T. L. , Moysich K. B. , Baer M. R.
Published: March 2020

7051

Background: Increasing use of chemotherapy and radiation therapy in breast cancer patients in the adjuvant setting heightens concern about therapy-related AML and MDS. Little is known about the characteristics of these disorders following breast cancer. Methods: Roswell Park Cancer Institute (RPCI) patients with diagnoses of MDS or AML by French-American-British Group or World Health Organization criteria following breast cancer were retrospectively reviewed. Results: 34 women were identified between 1983 and 2006. 10 (29%) were also diagnosed with additional malignancies, including non-Hodgkin lymphoma (NHL), bladder, colon, lung, uterine and thyroid cancers, Ewing sarcoma and angiosarcoma. 23 of 31 patients (74%) with family histories documented had first-degree relatives with cancers, including breast, lung, colon, stomach, pancreas, prostate, renal, melanoma, esophagus, thyroid, Hodgkin lymphoma and leukemia, compared to a 45% prevalence of first-degree relatives with cancer among 1982 control RPCI breast cancer patients (p= 0.001). Median age at breast cancer diagnosis was 58 (range, 37–85) years. Among the 29 patients with known treatment, 25 (86%) had received radiation therapy, 13 (45%) had received chemotherapy, including alkylating agents in all 13 (45%) and topoisomerase II inhibitors in 8(28%), while 4 (14%) had received no adjuvant therapy. Median age at AML/MDS diagnosis was 70 (range, 46–90) years. 26 patients had AML and 8 MDS, of whom 4 progressed to AML. Karyotypes were complex in 10 (29%), involved 11q23 rearrangements in 6 (18%), were favorable, normal and unknown in 5 each (45%), and had miscellaneous single structural abnormalities in 3 (9%); they did not strictly correlate with treatment received. Median survival (months) was 1 for complex karyotype, 6 for 11q23 translocation and 40 for favorable karyotype patients. Conclusions: The incidence of other cancers and of cancers in family members was unexpectedly high in breast cancer patients with AML and MDS, in the absence of known genetic syndromes, suggesting genetic polymorphisms predisposing to multiple cancers. Cytogenetic abnormalities included complex, 11q23 and favorable karyotypes, and survival reflected karyotypes.

No significant financial relationships to disclose.
Glutathione S-transferase T1, M1 genetic polymorphisms in cases of acute leukemia
Authors: Moawia S. , Elbordiny M. , Saad A.
Published: March 2020

7053

Background: Glutathione S-transferases (GSTs) are enzymes that detoxify potentially mutagenic and carcinogenic xenobiotics. The genes encoding isoenzymes M1 and T1 are polymorphic in humans and the phenotypic absence of enzyme activity is caused by a homozygous inherited deletion of the gene. The null genotype has been associated with incidence of several types of solid tumors. In addition, GSTM1 and GSTT1 polymorphisms have been considered as risk factors for developing acute leukemia in a number of studies; however the overall results of these previous reports are inconsistent and even controversial. Methods: The present study was undertaken to determine the frequencies of allelic variants in the GST genes in Egyptians and to explore the possibleinfluence of GSTT1, M1 genetic polymorphisms on the risk of acuteleukemia (myeloid and lymphoid). Results: The prevalence of the GSTM1 and GSTT1 homozygous deletions in 53 Egyptian patients with leukemia (21 ALL and 32 AML) and 87 racially,geographically, age and sex matched healthy control individuals was determined using a multiplex polymerase chain reaction (PCR)-based method. Thegenotype frequencies in the leukemia patients and normal controls were compared using Fisher's exact test. A significantly increased incidence of the GSTT1 null genotype was found in the group of patients compared to the controls (34% versus 15% P = 0.03, OR = 2.98, 95% CI 1.6–7.6). GSTM1 null genotype frequencies in cases were slightly but non-significantly higher than controls (68 % versus 49 %, respectively, P=0.07). Conclusions: In conclusion, this study has shown an increased risk of acute leukemia in adult Egyptian patients associated with the GSTT1 null genotype, as well as the combined GSTM1/T1 null genotype, particularly in AML cases. Study will be further extended to examine the relation between the GSTT1 and GSTM1 null genotypes and the patient's response to chemotherapy.

No significant financial relationships to disclose.
Amonafide and ara-C treatment for secondary acute myeloid leukemia (sAML)
Authors: Erba H. P. , Rizzieri D. A. , O'Donnell M. R. , Lundberg A. S. , Ajami A. M. , Rampersad A. D. , Capizzi R. L.
Published: March 2020

7065

Background: sAML portends a poor prognosis due to disease (unfavorable cytogenetics and multidrug resistance (MDR) phenotype) and patient (pt) characteristics (elderly w/comorbid illnesses). Amonafide, a topoisomerase II inhibitor, is not a substrate for the MDR efflux pump, P-glycoprotein (see Chau et al, ASCO 2007). Phase 1 trials of amonafide alone or together with ara-C reported a 50% CR rate (10/20) in pts with sAML (Allen et al, ASCO 2006). The dose-limiting toxicities of amonafide were manageable. Methods: In a Phase II trial pts with sAML (prior MDS or leukemogenic therapy, i.e., tAML) received amonafide 600 mg/m2/day on days 1–5 and CIV ara- C 200 mg/m2/day on days 1–7. A 2nd course could be given if day 14 marrow showed persistent leukemia. CR pts received either stem cell transplant or intermediate/high dose ara-C depending on age. An independent Data Safety Monitoring Board and central morphology review participated in the study. Primary endpoint was CR rate. Results: Enrollment has been completed. 44 % of 80 pts achieved CR. Details are available for the 1st 40 pts: median age 63 yrs (range 26 –87); prior MDS, 57%; tAML, 43%; unfavorable cytogenetics, 40%. 16/40 (40%) achieved CR (15 CR+1CRp). Subgroup CR analysis: MDS→AML without and with prior therapy for MDS (mostly azacytidine), 64% & 33%; tAML, 29%; intermediate and unfavorable cytogenetics, 58% and 18%; <60yrs, 42%; ≥60yrs, 39%. With a median follow up of 39 weeks, the median duration of CR is 28 weeks (range 20+ to 40+ weeks), with 8 of 16 patients in continuous CR. Median overall survival for CR patients has not been reached (range 1–47+ weeks). Death in first 28 days from consequences of hypoplasia was 17.5%. Grade 3, 4 non-heme adverse events occurring in > 10% pts were hypotension 23%, pneumonia 18%, dyspnea 13%, and diarrhea 13%. Data on all patients will be updated. Conclusions: Amonafide and ara-C is well tolerated in patients with poor prognosis sAML. A 64% CR was achieved in pts with untreated MDS→AML. Lower CR occurred with prior therapy for MDS, tAML and unfavorable cytogenetics. Age ≥60 yrs did not affect CR. Amonafide and ara-C may be a promising alternative for patients with sAML, especially those with over-expression of P-glycoprotein.

No significant financial relationships to disclose.
Phase II dosing study of cytarabine chemotherapy in combination with cenersen (EL625) and idarubicin in refractory and relapsed acute myelogenous leukemia (AML)
Authors: Alvarado Y. , Kantarjian H. , Freireich E. J. , Garcia-Manero G. , Ferrajoli A. , Koller C. , Estrov Z. , Kornblau S. , Laddie N. , Smith L. , Cortes J.
Published: March 2020

7070

Background: Cenersen is an antisense oligonucleotide that blocks production of p53. It sensitizes acute myeloid leukemia (AML) stem cells in vitro to DNA damage. Methods: Thirty-seven patients (13 refractory, 24 relapsed) with AML have been enrolled in the ongoing trial. All patients received cenersen (0.1 mg/kg/hr continuous intravenous infusion over 4 days [d]) plus Idarubicin (12mg/m2/dx3). Cytarabine was administered as follows: group (1) no cytarabine; (2) 100mg/m2/dx7; (3) 1g/m2/dx4 (3d > 60y). Chemotherapy started day 2. Results: Eighteen patients were treated per protocol and 19 were inevaluable to include 16 who received prohibited substances that block the action of cenersen (acetaminophen and/or high dose antioxidants). Six (33%) of those treated per protocol achieved CR compared to none of the 16 who received prohibited substances (p=0.02). This rate compares favorably to a literature report of a similar patient population (14%; Estey 1996). There were 2 patients who achieved a CRp, one of whom received acetaminophen on day 7. No significant differences in response occurred between the three treatment arms. The remission duration for 7 of the 8 responding patients was longer than the prior remission duration for the same patients. Several adverse events (AEs) (infection, bleeding, mucositis and hair loss) were significantly (p<0.001) less common for patients in this trial compared to the AE frequency described in the package insert for Idarubicin for its use in combination with standard dose Cytarabine. No adverse events attributable to cenersen were identified. Conclusions: We conclude that cenersen in combination with chemotherapy may improve the response rate compared to that expected with chemotherapy alone.

No significant financial relationships to disclose.
Phase I study of frequent low-dose administration of decitabine, alone or in combination with hyperCVAD, in relapsed or refractory acute lymphocytic leukemia (ALL)
Authors: Yang H. , Thomas D. A. , Rytting M. E. , Zweidler-McKay P. A. , Brown D. L. , Kantarjian H. , Garcia-Manero G.
Published: March 2020

7072

Background: Aberrant DNA methylation is frequent in ALL. Decitabine, a hypomethylating agent, is a potent inducer of apoptosis in lymphoid leukemia cell lines. In vivo, treatment with decitabine results in transient induction of global hypomethylation. Therefore, a more frequent schedule of administration (i.e. every other week (QOW)) may have significant clinical activity. Methods: We have developed a phase I study of low decitabine administered QOW. Patients that do not respond or progress after decitabine can receive the combination of decitabine with hyperCVAD in a sequential phase of the study. Starting doses of decitabine are 10 mg/m2 IV daily×5 every other week, and 5 mg/m2 IV daily×5 concomitant with hyperCVAD. The studies follow a classic “3+3” design. Patients with relapsed/refractory ALL of any age are elegible. Molecular studies include the analysis of global and gene specific DNA methylation and gene expression reactivation. Results: Seven patients have been treated (median age 25, range 8–44). All had refractory disease and had previously completed at least 8 courses of hyperCVAD therapy and 2 years of maintenance therapy or similar. Four patients have been treated at dose level 1 of single agent decitabine, and 3 at dose level 2 (20 mg/m2). Three of these patients have also been treated at dose level 1 of the combination of hyperCVAD and decitabine. No severe drug related toxicites have been observed. Four patients had achieved a response: 1 CR after decitabine and hyperCVAD, and 3 PR (normalization of peripheral blood with bone marrow blasts reduction of more than 50% but above 5%). One PR was achieved after decitabine and hyperCVAD, but two with only decitabine. Two of these patients did not qualify for CR because bone marrow blasts were 6%. Of these four responding patients, 1 in CR received successful alloSCT, 1 progressed after 2 courses of single agent decitabine, and 2 pediatric patients continue on therapy. The study continues. Molecular studies are ongoing. Conclusions: In summary, frequent administration of low dose decitabine, alone or in combination with hyperCVAD, may be clinically safe and active in advanced relapsed/refractory ALL.

No significant financial relationships to disclose.
Hyperglycemia and obesity in patients (pts) with acute lymphoblastic leukemia (ALL): Association with prevalence, response, and survival
Authors: Vu K. D. , Lavis V. R. , Strom S. , Faderl S. H. , Konopleva M. , Thomas D. A. , Gruschkus S. , Andreeff M. , Kantarjian H.
Published: March 2020

7074

Increasing evidence suggests associations between obesity, diabetes and/or hyperglycemia (DM/HG) and solid tumors. Less is known about the relationship of these metabolic factors to the hematologic malignancies. To determine the prevalence of DM/HG and obesity in pts with ALL and whether these are predictors of response and survival, we conducted a retrospective chart review of 299 pts with newly diagnosed ALL, who were evaluated at our institution between November 1999 and May 2005 and received hyper-CVAD therapy: fractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone alternating with methotrexate and high-dose cytarabine. Median age was 43 yrs (range 15–83). Sixty-one percent of pts were male, and 39% female. Seventy-four percent had a diagnosis (dx) of precursor B cell ALL (22% Ph+), 18% Burkitt's ALL, 6% lymphoblastic lymphoma, 2% other. Prior to therapy, the overall prevalence of DM/HG (diabetes based on reported dx prior to ALL-dx, and hyperglycemia based on baseline serum glucose ≥200 mg/dL) was 16%. Pts with DM/HG were significantly older than those without DM/HG (median age 57 yrs vs. 40 yrs, p<0.001). Complete remission (CR) rate and the CR duration (CRD) were similar in the DM/HG vs. non-DM/HG group. However, the mean CRD was 80 wks in the HG separately group and 121 wks in the non-HG group (p=0.04). The mean CRD was 102 wks in the obese pts and 124 wks in the non-obese pts (p=.04). In univariate analysis, DM/HG, obesity, and older age were associated with shorter overall survival (OS). Mean OS of pts with DM/HG was 134 vs. 194 wks for pts without DM/HG, (p=0.2). Mean OS of obese pts was 136 vs. 199 wks for non-obese pts, (p=0.01). In a multivariable Cox regression model, the only factors that remained significant for survival were age, obesity, and white blood cell count (WBC). There was no significant difference in OS by leukemia diagnosis. In conclusion, the prevalence data suggests that DM/HG may be involved in the development of ALL. However, DM/HG has no impact on survival, probably because of its strong correlation with age. The association of obesity with shorter OS warrants further investigation.

No significant financial relationships to disclose.
The effect of alemtuzumab maintenance therapy on B and T lymphocytes in chronic lymphocytic leukemia
Authors: Kaufman M. S. , Driscoll N. , Johnson C. , Caramanica A. , Janson D. , Lebowicz Y. , Wasil T. , Rai K.
Published: March 2020

7092

Background: We are conducting a pilot, exploratory study of the potential value of alemtuzumab(alem) in maintenance therapy of previously treated chronic lymphocytic leukemia (CLL) patients(pts) after they have achieved stable disease or partial remission with chemo or chemo-immunotherapy. We present the results of serially monitored CD19+ (B)lymphocytes and CD4+ (T) lymphocytes on eight evaluable patients. Methods: 30mg doses of alem were administered SC to all patients at the following schedule: wkly for 8 doses (8 wks), followed by q2 wks for 8 doses(16 wks), followed by q3 wks for 8 doses (24 wks). This schedule provides a total of 48 wks of maintenance treatment with alem. Patients received standard prophylaxis with sulfamethoxizole and acyclovir with regular CMV monitoring by quantitative PCR. Results: In the table we present data on the pattern of decrease in blood CD19+(B) cells and CD4+ (T) cells on eight evaluable pts at different time points after starting alem maintenance. Because flow cytometry was not done on all pts at each time point, the number of pts contributing to the calculation of mean counts at each given time point is variable. CD19+(B) cells were markedly reduced to 37% of baseline consistently, from 8 wks onward. CD4+(T) cells, on the other hand, were consistently higher than 50% of the baseline after 8 wks. No opportunistic infections were seen in any pt and treatment was well tolerated. Conclusion: These results from a single institution based pilot study demonstrate that alem used in maintenance schedule is effective in keeping the blood levels of CD19+(B) cells extremely low without concordant suppression of CD4+(T) lymphocytes.

No significant financial relationships to disclose.

[Table: see text]
A pilot study CD34 selected haploidentical transplant using a chemotherapy-only preparative regimen and intensive antibiotic prophylaxis for treatment of advanced leukemia
Authors: Gajewski J. L. , McMannis J. , Shpall E. , de Lima M. , Giralt S. , Jones R. , Khouri I. , Hosing C. , Korbling M. , Champlin R. E. , Donato M.
Published: March 2020

7097

Background: We present preliminary data of haploidentical transplant for 13 patients (pts) with acute leukemia. Methods: Phase II Study Results: We present preliminary data of haploidentical transplant for 13 patients (pts) with acute leukemia using a chemotherapy-only preparative regimen of Melphalan 140 mg/m2 on day −8; Thiotepa 10 mg/kg on day −7; Fludarabine 40 mg/m2 on days −6, −5, −4, −3; 1.5 mg/kg of rabbit ATG/day days −6, −5, −4, −3. The transplant was administered on day 0 using positive selection of CD34 positive cells by the CliniMACS device as a means of T-cell depletion. All products had <1 × 104 CD3+ T-cells/kg recipient body weight and needed a minimum of 5 × 106 CD34+ cells/kg but preferably >1 × 107 CD34+ cells/kg recipient body weight. Age ranged 23–50 years/median 37 years, four patients were in advanced remission and nine were in refractory relapse. Patients received intensive PCP prophylaxis with sulfamethoxazole-trimethoprim and pentamidine prior to transplant and during pancytopenia; CMV prophylaxis with valganciclovir during the BMT prep and foscarnet while pancytopenic; and with liposomal amphotericin or cancidas for fungal prophylaxis. Two patients had primary graft failure-one survived disease free and one relapsed. One patient died of multiple organ failure prior to engraftment. Median time to engraftment was 15 days (range, 9–26) to 500 neutrophils and 14 days to platelets 20,000 (range, 13–25). Seven patients died of relapse at a median of 10 months (range 2–13 months), and one patient died of a viral infection. Two of 10 patients who engrafted developed grade one acute graft-versus-host (GVHD) and four patients had chronic GVHD (3 limited, 1 extensive). Four patients survive beyond 2 years, without recurrent disease. Conclusions: This report for haploidentical transplant demonstrates that a chemotherapy only preparative regimen can achieve a high rate of engraftment. Infectious complications were minimal with aggressive prophylaxis. Long-term remission are achievable with little risk of severe GVHD with t-cell depletion with use of CliniMACS in haploidentical stem cell transplant.

No significant financial relationships to disclose.
Outcome of allogenic SCT in patients with low left ventricular ejection fraction
Authors: Qureshi S. , Bukhari F. , Saliba R. M. , Hosing C. , Champlin R. E. , Giralt S. A. , De Lima M. J. , Yusuf S. W. , Qazilbash M. H.
Published: March 2020

7099

Background: High-dose therapy and allogeneic stem cell transplantation (allo SCT) is a potentially curative treatment for patients with hematologic malignancies. Due to a high risk of regimen-related toxicity, only patients with excellent organ-system function are considered eligible for this treatment. A low left ventricular ejection fraction (LVEF) of ≤ 45% is considered to be a major risk factor for post-transplant cardiac toxicity and nonrelapse mortality. However, several patients with advanced hematologic malignancies and low LVEF can potentially benefit from this therapy. To address this issue, we studied the incidence of cardiac toxicity and non-relapse mortality (NRM) in 56 patients with low LVEF undergoing allo SCT. Methods: We performed a retrospective analysis on 56 patients with impaired cardiac function, who underwent an allo SCT between January 2000 and February 2006 at our institution. Pre-transplant evaluation included bidimensional echocardiogram and an electrocardiogram. Cardiac toxicity was defined as congestive heart failure (CHF), atrial / ventricular arrhythmia or acute myocardial ischemia. Twenty-two patients received a myeloablative (16 busulfan-based, 6 TBI-based), while 34 patients received a fludarabine-based reduced-intensity preparative regimen. Results: Twenty-three patients (41%) received allo SCT from an unrelated donor. Acute leukemia was the reason for allo SCT in 32 (57%) patients. Baseline LVEF, within 30 days prior to allo SCT, ranged from 20 to 45%. After a minimum of 6-month follow up, cardiac toxicity was seen in 7 (12%) patients. That included CHF in 4 (7%) and atrial fibrillation (AF) in 4 (7%). One patient had both CHF and AF. There were no documented episodes of acute myocardial ischemia. Cumulative incidence of NRM at 100 days was 12%, none of the deaths being attributable to a cardiac cause. These were comparable to allo SCT performed in patients with normal LVEF. Age, degree of left vetricular dysfunction, type of transplant or the underlying disease did not emerge as significant predictors of post-transplant cardiac toxicity or NRM. Conclusions: Allogeneic SCT is feasible in patients with hematologic malignancies and low LVEF. A prospective study with stratification for cardiac risk factors is warranted in patients with low LVEF.

No significant financial relationships to disclose.
A rapid immunoassay to determine concentrations of busulfan in plasma
Authors: Salamone S. J. , Courtney J. , Harney R. , He S. , Lundell G.
Published: March 2020

7111

Background: High-dose busulfan is an important component of many bone marrow transplantation preparative regimens. High busulfan plasma levels have been shown to increase the chance of veno-occlusive disease and low levels are associated with recurrence of disease or graph rejection. Currently, busulfan levels are monitored by physical methods which are expensive and time- consuming, resulting in relatively low overall use of busulfan testing for dose adjustment. Methods: Novel, highly selective antibodies for busulfan have been generated and micro-titer plate immunoassays that are capable of quantifying busulfan levels in plasma have been developed. The assay was configured using a busulfan-horseradish peroxidase conjugate as the reporter group and busulfan monoclonal antibodies. The assay requires only 5 μL of plasma per determination with no sample preparation. Results: The immunoassay has a standard curve based on busulfan with a range of 75 to 2,000 ng/mL. The time to first result is 30 minutes with up to 240 tests generated per hour. The coefficient of variation (CV) on signal is < 5% for an entire plate and the 95% confidence interval for negative samples (n=78) is below the lowest calibrator of 75 ng/mL. Cross-reactivity with the major inactive metabolites (tetrahydrothiophene,tetramethyl sulfone and tetrahydrothiophene-3-ol-1,1-dioxide), are <0.1%. Clinical samples (n=70) correlate well to LC-MSMS or GC-MS (R > 0.97) with a slope of < 1.05. Conclusions: This immunoassay method may be suitable for determining levels of busulfan in human plasma. It offers the advantages of using a smaller sample size, does not require sample preparation and is less labor intensive than other methods. The ability to make 240 determinations per hour enables effective routine monitoring of busulfan levels in clinical practice.

No significant financial relationships to disclose.
iTARGET: A phase II trial to assess the response to gefitinib in epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) tumors
Authors: Sequist L. V. , Martins R. G. , Spigel D. , Grunberg S. M. , Jänne P. A. , McCollum D. , Spira A. , Evans T. , Johnson B. E. , Lynch T. J.
Published: March 2020

7504

Background: Somatic EGFR mutations correlate with increased response and survival in NSCLC patients (pts) treated with gefitinib. We conducted the 1st prospective US trial of 1st-line gefitinib in pts with advanced NSCLC harboring EGFR mutations. Methods: Chemotherapy-naïve pts with stage IIIB with effusion or IV NSCLC, measurable disease, and = 1 characteristic associated with mutations (female (F), adenocarcinoma (AC), never-smoking (NS), East Asian (EA)) underwent direct DNA sequencing of tumor tissue EGFR exons 18–24. Mutation-positive pts received gefitinib (250 mg/d) until progression or unacceptable toxicity. The primary outcome was response rate (RR) by RECIST criteria. Results: We sequenced 98 pts and detected EGFR mutations in 34 (35%); 3 were not assessable. Observed mutations were 18 (53%) exon 19 deletions (del), 9 (26%) L858R, 3 (9%) exon 20 insertions (ins), 2 T790M/L858R, 1 G719A, and 1 L861Q. Characteristics of the 98 screened pts were 69 F, 89 AC, 37 NS, and 5 EA; those of the 34 mutation pts were 20 (59%) F, 31 (91%) AC, 19 (56%) NS and 2 (6%) EA. The best predictor of EGFR mutation was NS. Of the 34 mutation pts, 31 (91%) received gefinitib. Reasons for non-treatment were pt preference (1 exon 19 del) and mutation associated with gefitinib-resistance (1 T790M/L858R, 1 exon 20 ins). Adverse events were mainly grade 1–2 rash and diarrhea; 1 case of grade 4 interstitial lung disease occurred after 2 weeks of therapy. The RR was 58% (95% confidence interval 39–75) and was 78% in L858R pts and 65% in del 19 pts. There were no responses among the G719A, L861Q, T790M/L858R and exon 20 ins pts treated. 12 pts have progressed, 18 remain on therapy. The median progression-free survival (PFS) is currently 11.8 mo and does not differ by mutation type, though follow-up is short (median 6.8 mo, range 1–24). 27 pts are still alive. Of the 31 pts treated, 22 (71%) had high EGFR gene copy number (amplification (3) or high polysomy (19)); RR and PFS did not vary by copy number. Conclusions: 1st-line gefitinib therapy in EGFR mutation-positive NSCLC pts is feasible in a multi-institutional study, well tolerated, and yields a substantial RR and PFS. This strategy should be compared to standard chemotherapy in a genotype-directed randomized trial.

No significant financial relationships to disclose.
Validation of proteomic classifier for clinical benefit from erlotinib as first line treatment for advanced non-small cell lung cancer (ECOG 3503)
Authors: Solomon B. J. , Roder H. , Robert R. , Taguchi F. , Brahmer J. , Joan S. H. , Duncan M. W. , Hirsch F. R. , Bunn P. A. , Carbone D. P.
Published: March 2020

7508

Background: In this study we tested the ability of our serum mass spectrometry classifier of clinical benefit from gefitinib to classify pre-treatment sera and plasma samples from non-small cell lung cancer (NSCLC) patients treated first line with erlotinib in ECOG E3503. Methods: Pretreatment serum and plasma samples were available from 73 of the 96 previously untreated advanced NSCLC patients treated with single agent erlotinib on ECOG protocol 3503, 13 subjects had only serum samples, and 10 had only plasma samples. All of these samples analyzed in replicate by MALDI mass spectrometry (MS). A prediction algorithm we established based on a training cohort of 139 patients treated second or third line with gefitinib was used to classify these patients for survival and time to progression, and results obtained from serum and plasma were compared when both were available Results: We found that the signals for the 8 distinct mass-to-charge (m/z) features used in our classifier were highly concordant between serum and plasma samples from the same patient, and that there was no difference in the classification of the patients between serum and plasma when both were available. Therefore we classified all 96 patients using serum if available, and plasma if not. The classification algorithm very successfully classified patients into groups with good and poor survival (median survival of 306 days vs 107 days, p = 0.0007). With the available follow-up, the time to progression was also statistically significant in this group (p = 0.007, data not shown). In a Cox multivariate analysis including the most significant univariate parameters PS (0 vs. 1 vs 2), number of involved sites (=3 vs >3) and prior weight loss (<5% vs = 5%), the MALDI MS classification algorithm retained independent significance at p = 0.03, with a hazard ratio of 0.53. Conclusions: This multi-institutional ECOG study demonstrates that MALDI MS can assist in the pre-treatment selection of a subgroup of NSCLC patients who are likely to show improved survival after treatment with first line erlotinib.

No significant financial relationships to disclose.
Phase III trial of cisplatin (P) plus etoposide (E) plus concurrent chest radiation (XRT) with or without consolidation docetaxel (D) in patients (pts) with inoperable stage III non-small cell lung cancer (NSCLC): HOG LUN 01–24/USO-023
Authors: Hanna N. H. , Neubauer M. , Ansari R. , Govindan R. , Bruetman D. , Fisher W. , Chowhan N. , Nattam S. , Yiannoutsos C. , Einhorn L.
Published: March 2020

7512

Background: Concurrent chemoradiation is standard treatment for pts with inoperable stage III NSCLC. A previously reported single-arm, phase II study by SWOG (Gandara et al JCO 2003) suggested D following EP/XRT further improved survival. We report results from a randomized, prospective phase III trial comparing EP/XRT with or without consolidation D. Methods: Eligible pts had inoperable, stage IIIA/B NSCLC, PS 0–1, FEV-1 ≥ 1 L, and < 5% wt loss. Pts (n=243) received P 50 mg/m2 iv d 1,8,29,36 and E 50 mg/m2 iv d1–5, 29–33 concurrently with chest XRT to 5940 cGy. Non-progressing pts were randomized to D 75 mg/m2 iv every 21 d for 3 cycles vs observation (O). The primary endpoint was to compare OS (Kaplan-Meier analysis). Accrual of 259 pts to randomize180 was planned to demonstrate a difference in MST of 25 vs 15 mos (5% 2-sided alpha, 80% power). Based upon evidence of futility (predefined as p>0.7271), a DSMB recommended early termination after an analysis of the initial 203 pts. Results: Median f/u 25.6 mos. Pt characteristics (n=203): 34%/66% F:M; median age 63; 39.4%/60.6% IIIA/B. G3/4 toxicities during EP/XRT included 9.8% febrile neutropenia (FN), 17.2% esophagitis. 147 of 203 pts (72.4%) were randomized to D (n=73) or O (n=74). G3/4 toxicities during D included: 10.9% FN, 8.2% pneumonitis. 28.8% of pts were hospitalized during D (vs 8.1% in O arm) and 5.5% died due to D. PFS for D was 12.3 vs 12.9 mos for O (p=0.9412). The MST for all pts was 21.15 mos; MST for D was 21.6 mos (95% C.I. 17.7–35) vs 24.2 mos for O (95% C.I. 18.1–34.4) (p=0.9402). Conclusions: The MST with EP/XRT was higher than historical controls; however, consolidation D does not further improve survival, is associated with significant toxicity including an increased rate of hospitalization and premature death, and should no longer be used for pts with unresectable stage III NSCLC.

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Updated analysis of SWOG 0023: A randomized phase III trial of gefitinib versus placebo maintenance after definitive chemoradiation followed by docetaxel in patients with locally advanced stage III non-small cell lung cancer
Authors: Kelly K. , Chansky K. , Gaspar L. E. , Jett J. R. , Ung Y. , Albain K. S. , Crowley J. J. , Gandara D. R.
Published: March 2020

7513

Background: Early clinical studies with gefitinib (G) showed promising efficacy and mild toxicity in patients (pts) with advanced NSCLC. Thus, G was an ideal agent to evaluate in a maintenance setting in stage III disease following definitive treatment. Methods: Untreated pts with stage III NSCLC, a PS of 0–1 and adequate organ function were eligible. Patients received the SWOG 9504 core regimen (cisplatin 50 mg/m2, d1 & 8 plus etoposide 50 mg/m2 day 1–5, every 28 days for 2 cycles with concurrent thoracic radiation, 1.8–2 Gy fractions/day, total dose 61 Gy, followed by 3 cycles of docetaxel 75 mg/m2). Non- progressing pts were randomized to G 250 mg per day or placebo (P) until disease progression, intolerable toxicity or 5 years. The planned sample size was 672, to confer power of 0.89 to detect a 33% increase over the expected median survival of 21 months (one-sided 0.025 level logrank test). Randomization was stratified by stage and histology. Results: Enrollment began in July 2001. An unplanned interim analysis prompted by outside data was conducted in April 2005 and the alternative hypothesis of improved survival was rejected at the 0.0015 level for 243 randomized patients. The study closed and preliminary results were reported (ASCO 2005). Now with a median follow up of 27 months, median survival for the G arm (n=118) was 23 months and was 35 months for the P arm (n=125) (two sided p=0.013). Overall survival for the 571eligible patients was 19 months. ≥ Grade 3 toxicities in the G arm were rash (7%), diarrhea (7%) and pneumonitis (3%). Conclusion: In this unselected population G did not improve survival. Decreased survival was due to cancer not G toxicity. Three year survival estimates will be presented. Molecular studies of the EGFR pathway are underway and will be correlated with outcomes.

No significant financial relationships to disclose.
Pre-operative chemotherapy in patients with resectable non-small cell lung cancer (NSCLC): First results of the MRC LU22/NVALT/EORTC 08012 multi-centre randomised trial
Authors: Nicolson M. , Gilligan D. , Smith I. , Groen H. , Manegold C. , van Meerbeeck J. , Hopwood P. , Nankivell M. , Pugh C. , Stephens R. J.
Published: March 2020

7518

Aims: Although surgery offers the best chance of cure for patients with NSCLC, the overall 5-year survival rate is modest, and improvements are urgently required. This intergroup trial was designed to investigate whether, in patients with operable NSCLC of any stage, neo-adjuvant platinum-based chemotherapy prior to surgery would improve outcomes. Methods: Patients were randomised to receive either surgery alone (S), or 3 cycles of platinum-based chemotherapy prior to surgery (CT-S). Results: 519 patients were randomised (261 S, 258 CT-S) from 70 centres in the UK, the Netherlands, Germany and Belgium. The median age of the patients was 63 years, 72% were male, 59% were PS 0, and 50% had squamous cell histology. The majority were clinical stage I (17% Ia, 45% Ib, 3% IIa, 29% IIb, 7% IIIa), and 12% received mitomycin/vinblastine/cisplatin (MVP), 7% mitomycin/ifosfamide/cisplatin (MIC), 45% vinorelbine/cisplatin, 12% carboplatin/docetaxel, and 25% cisplatin/gemcitabine. The trial showed that neo-adjuvant chemotherapy was feasible (76% of patients received all 3 cycles of chemotherapy), resulted in a good response rate (4% CR, 45% PR, and only 2% PD), appeared to cause down-staging in about 20% of patients, and did not affect the type of surgery performed, the post-operative complication rate, or quality of life. However, there was no evidence of a benefit in terms of progression-free survival (282 events, HR 0.98, 95% CI 0.77,1.23) or overall survival (232 deaths, HR 1.04, 95% CI 0.81, 1.35), and more patients were reported as having brain metastases in the CT-S group (30 CT-S vs 11 S patients). Exploratory analyses showed no evidence that any subgroup of patients benefited from the addition of neo-adjuvant chemotherapy. Conclusions: This intergroup trial, which is the largest trial of neo-adjuvant chemotherapy in patients with resectable NSCLC, indicated that the addition of neo-adjuvant platinum-based chemotherapy did not lead to a benefit in overall survival. However, a 19% survival benefit or a 35% detriment cannot be excluded and this result needs to be considered in the context of all other relevant randomised trials of neo-adjuvant chemotherapy for NSCLC.

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S9900: Surgery alone or surgery plus induction (ind) paclitaxel/carboplatin (PC) chemotherapy in early stage non-small cell lung cancer (NSCLC): Follow-up on a phase III trial
Authors: Pisters K. , Vallieres E. , Bunn P. A. , Crowley J. , Chansky K. , Ginsberg R. , Gandara D. R.
Published: March 2020

7520

Background: Small randomized and non-randomized studies suggest induction chemotherapy may improve survival in early stage NSCLC. The primary objective of this study was to determine if induction PC could improve survival over surgery alone. Preliminary results of this trial were reported at ASCO 2005 (J Clin Oncol, ASCO Proc 23(16S) 2005:7012). Median time for patients alive at last contact is now 46 months (mos). Methods: Consenting patients with clinical stage T2N0, T1–2N1 and T3N0–1 NSCLC (excluding superior sulcus tumors) were stratified by clinical stage (IB/IIA vs. IIB/IIIA) and randomized to induction PC (P:225 mg/m2 over 3 hours, C:AUC=6) on day 1, every 3 weeks × 3 or surgery alone. Eligible patients had a performance status 0–1, age =18 years (yrs), predicted post- resection FEV1 =1.0L. Surgery was at least a lobectomy and mediastinal nodal sampling. The primary endpoint was a 33% increase in overall survival over expected 2.7 yrs median for surgery. Planned sample size was 600 patients, 81% power, 1-sided test, 0.025 significance. Results: S9900 closed 07/04 when adjuvant chemotherapy became standard. 354 patients had accrued; 174-surgery alone, 180- induction PC; 19 were ineligible. Median age 65 yrs, 66% male, 70% IB/IIA, 30% IIB/IIIA. Major radiographic response to induction PC was 41%. Treatment-related deaths: 3 during induction PC, 11 within 30 days of surgery (7-induction PC arm, 4-control). Progression-free survival (PFS), overall (OS) survival rates and hazard ratios (HR) are shown. Conclusions: PFS and OS continue to trend in favor of induction PC with HR similar to those observed in adjuvant trials, supporting the role of chemotherapy in operable NSCLC. Randomized trials comparing induction to adjuvant chemotherapy are warranted. Supported by SWOG CA30102.

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A randomized phase III trial of irinotecan plus carboplatin versus etoposide plus carboplatin in patients with small cell lung cancer, extensive disease (SCLC-ED): IRIS-Study
Authors: Hermes A. , Bergman B. , Bremnes R. , Ek L. , Fluge S. , Sederholm C. , Sundstrøm S. , Thaning L. , Vilsvik J. , Aasebø U. , Sörenson S.
Published: March 2020

7523

Background: A Japanese randomized trial has shown superior survival for SCLC-ED patients receiving irinotecan+cisplatin as compared to etoposide+cisplatin. Our trial was performed to evaluate the effect of irinotecan+carboplatin compared to oral etoposide+carboplatin. Patients and Methods: In a phase III trial, patients with SCLC-ED were randomly assigned to receive carboplatin, AUC=4 (Chatelut formula) and irinotecan, 175 mg/m2, both on day 1 (IC) or carboplatin (Chatelut AUC=4) on day 1 and etoposide 120 mg/m2/day, orally, on days 1–5 (EC). In both arms, courses were repeated on day 21 with 4 cycles planned. Primary endpoint was overall survival (OS), secondary endpoints were quality of life, evaluated by EORTC-QLQ-C30 and QLQ-LC 13, and complete response rate. There were neither upper limits for age or performance status. Results: Between November, 2001 and July, 2005, 220 patients were randomized. 210 patients were eligible for analysis (other type of cancer, 8 pts., limited disease, 1 pt., elevated liver function tests, 1 pt.). Performance status (PS) 0: 20 patients, PS 1: 91, PS 2: 62, PS 3: 29, PS 4: 8. Median age IC was 67 years (46–81), EC 67 years (39–82). OS was 255 days (IC) versus 214 days (EC) (P=0.04, log rank test). HR for overall survival was 1.34, 95% CI: 1.01–1.79. 1-year survival was 35% vs 28%. CR was observed in 18 patients in the IC arm and 7 patients in the EC arm (P=0.02, chi-square test). There were no statistically significant differences with respect to haematological grade III-IV toxicity. No severe diarrhea was observed in the IC group. There were no significant differences regarding quality of life. Conclusion: Irinotecan + carboplatin is superior to oral etoposide + carboplatin with respect to overall survival in SCLC-ED.

No significant financial relationships to disclose.
Randomized trial of amifostine in locally advanced non-small cell lung cancer (NSCLC) patients receiving chemotherapy and hyperfractionated radiation (HRT): Long-term survival results of Radiation Therapy Oncology Group (RTOG) 9801
Authors: Movsas B. , Moughan J. , Langer C. , Werner-Wasik M. , Nicolaou N. , Komaki R. , Machtay M. , Smith C. , Axelrod R. , Byhardt R.
Published: March 2020

7529

Purpose: This analysis was conducted to address the potential antitumor effect of amifostine (AM) in NSCLC patients enrolled on RTOG-9801. The long-term survival results of RTOG-9801 are presented here. Methods: 243 patients (pts) with stage II/IIIAB NSCLC received induction paclitaxel (P) 225 mg/m2IV days 1, 22 and carboplatin (C) AUC 6 days 1, 22 and then concurrent weekly P (50 mg/m2) and C (AUC 2) and HRT (69.6 Gy at 1.2 Gy BID). Pts were randomly assigned to AM 500 mg IV 4x/week or no-AM during chemoradiation. Treatment differences for overall and disease-free survival (OS & DFS) were analyzed with the log-rank test; Gray's test was used for time to progression (TTP). Results: 118 pts were randomly assigned to receive AM and 121 to no-AM (4 pts were ineligible). The median follow-up for pts still alive is 52.3 months (mo) for the AM-arm and 58.3 mo for the no-AM arm (16.6 vs 17.9 for all pts). There are no significant differences in OS, DFS or TTP between arms. The median survival, 3-yr, and 5-yr OS are 17.1 mo, 27% and 17% (AM-arm) vs 18.4 mo, 28% and 16% (no-AM arm) (p=0.97). Grade 3/4/5 late-RT toxicities are similar (11%/3%/2% AM-arm vs 14%/4%/2% no-AM arm). Conclusion: While an earlier publication reported that amifostine did not reduce objective measures of severe esophagitis in RTOG-9801, patient-reported outcome analyses suggested a possible advantage to AM with decreased pain and swallowing symptoms (J Clin Oncol 23:2145–2154, 2005). This long-term follow-up analysis on survival shows no evidence of tumor radioprotection due to amifostine. The promising 5-yr OS suggests that induction paclitaxel/carboplatin (P/C) followed by concurrent RT and weekly low-dose P/C is comparable to other regimens using cisplatin doublets at higher dosages every 3–4 weeks. Research supported by NCI and Medimmune Oncology.

No significant financial relationships to disclose.
Tumor response to chemotherapy as a surrogate endpoint of survival in advanced non-small cell lung cancer (NSCLC): Results of an individual patients data meta-analysis
Authors: Bruzzi P. , Sormani M. , Tiseo M. , Boni L. , Rosell R. , Ardizzoni A.
Published: March 2020

7548

Background: In order to assess the validity of objective response to chemotherapy (CT) as a surrogate endpoint of survival in advanced non-small cell lung cancer (NSCLC), we applied the four Prentice criteria to the data collected in the CISCA meta-analysis, comparing the efficacy of carboplatin and cisplatin in the first-line treatment of advanced NSCLC. Methods: Nine trials including 2,968 patients (pts) were analyzed in the CISCA meta-analysis. The prognostic effect of tumor response on survival was analyzed setting a landmark at two months after randomization (time of response recording), in order to eliminate early death from the analysis. After this landmark correction, pts included in the validation analysis were 2,525 with complete data on tumor response and survival. Results: Cisplatin-based CT was associated with a significantly higher tumor response rate compared with carboplatin-based CT (OR = 1.39; 95% CI: 1.18–1.64; p < 0.001). Carboplatin regimens also led to a numerically higher risk of death as compared to cisplatin (HR = 1.06; 95% CI: 0.98–1.16; p = 0.15). Tumor response was a highly significant predictor of survival (HR = 0.50; 95% CI: 0.46–0.55; p < 0.001). When tumor response was introduced in the Cox model (as a four level variable), the hazard ratio in favour of cisplatin treatment changed from 1.06 to 1.004 (95% CI: 0.922–1.093; p = 0.94), indicating that no residual effect of the cisplatin treatment on survival was present once tumor response was adjusted for. This suggests that the overall survival benefit of cisplatin CT was a result of the increase in response rate. The median survival time of patients with complete and partial response was 19.5 months (95% CI: 11.5–27.5 months) and 14.0 months (95% CI: 13.1–14.9 months), respectively; whereas, the median survival time of patients with no response was 7.8 months (95% CI: 7.5–8.1 months). Conclusions: These results support the hypothesis that the achievement of an objective response to CT in advanced NSCLC is associated with a survival benefit. The potential role of objective response as a surrogate endpoint for survival in CT trials of advanced NSCLC warrants further investigation.

No significant financial relationships to disclose.