bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of Ile655Val HER2 polymorphism associated with cardiac toxicity following the administration of trastuzumab in women with breast cancer.
Authors: Diorio Caroline , Lemieux Julie , Cote Marc-Andre , Provencher Louise , Nadeau-Larochelle Corinne , Jacob Simon , Demers Eric , Tremblay-Lemay Rosemarie , Saint-Pierre Christine , Beauchemin Michel , Barabe Frederic , Laflamme Christian
Published: March 2020

634

Background: Trastuzumab is well tolerated without major side effects except for cardiac toxicity. Although a number of clinical parameters have been associated with trastuzumab-associated cardiac toxicity (TACT), there is some indication that genetic variation of the HER2 gene may play a toxic role in a population of metastatic breast cancer patients. However, this finding needs confirmation and we looked at a population of non-metastatic breast cancer. This study aimed to evaluate the association between cardiac toxicity and HER2 [Ile655Val] polymorphism in non-metastatic breast cancer patients treated with trastuzumab. Methods: The Ile655Val HER2 polymorphism was assessed in 73 women using TaqMan technology. For this study, the genotyping was performed using DNA extracted from normal breast tissue located at more than 1 cm of any other lesions. Charts review was used to collect information on TACT which was defined as any decline in LVEF > 10 % from the baseline to < 55 % or a decline in LVEF > 5 % to < 50 % (lower limit of normal). The Fisher exact test was used to evaluate the association between cardiac toxicity and HER2 polymorphism. Results: No deviation from the Hardy-Weinberg equilibrium has been observed for the allele and genotype frequencies. The distribution of HER2 polymorphism was 3 Val/Val (4%), 18 Ile/Val (25%) and 52 Ile/Ile (71%). In this population, 19% (14/73) developed a cardiac toxicity. We found that 29% (6/21) of Ile/Val or Val/Val carriers compared to 15% (8/52) of Ile/Ile carriers showed TACT, but this association did not reach statistical significance (P = 0.21). Conclusions: HER2 Ile655Val polymorphism may be an efficient marker of TACT considering this tendency with this small cohort of patients. Larger sample is needed to strengthen this conclusion, since this result may influence on prescribing decision for adjuvant chemotherapy and anti-HER2 therapy in HER2 positive patients.
A randomized phase II study of sapacitabine in MDS refractory to hypomethylating agents.
Authors: Garcia-Manero Guillermo , Luger Selina M. , Goldberg Stuart , Altman Jessica K. , Arellano Martha Lucia , Wetzler Meir , Seiter Karen , Chiao Judy H. , Kantarjian Hagop
Published: March 2020

6520

Background: Sapacitabine is an orally administered nucleoside analogue which causes single-strand DNA breaks and induces G2 cell cycle arrest. A multi-center, randomized phase 2 study was conducted to evaluate 3 dose regimens in older patients with MDS refractory to hypomethylating agents. The primary endpoint is 1-year survival. Secondary endpoints include the rate of CR, CRp, PR, major hematological improvement (HI) or stable disease and their corresponding durations. The study uses a selection design to identify a dose regimen which produces a better 1-year survival rate in the event that all three dose regimens are active. The planned sample size is 60 patients (20 patients in each arm). Methods: Eligible patients must be ≥ 60 years with intermediate-2 or higher risk MDS previously treated with hypomethylating agents and 6 - < 20% blasts in bone marrow, ECOG 0-2, adequate renal and hepatic functions. Patients were randomized 1:1:1 to receive sapacitabine every 4 weeks at 200 mg b.i.d. x 7 days (Arm G), 300 mg q.d. x 7 days (Arm H), or 100 mg q.d. x 5 days per week x 2 weeks (Arm I). The number of cycles is not limited. Results: As of January 2012, 61 patients were enrolled and 56 had ≥ 30 days of follow-up. Mean follow-up was 173 days. Median age was 71. Two or 3 cytopenias were present in 42 patients and 14 have received both azacitidine and decitabine. Baseline bone marrow had 6-10% blasts in 31 patients and 11-19% blasts in 25 patients. Median number of cycles was 2 and 18 patients received ≥ 4 cycles. To date, 8 patients have responded (2 CRs, 2 CRp, and 4 major HIs): 15% (Arm G), 16% (Arm H) and 12% (Arm I). Time to response is 1-3 cycles. Additionally, 6 patients achieved stable disease lasting longer than 16 weeks. More than 50% of patients have lived 16 weeks or longer. Three deaths occurred within 30 days of randomization and 1 death was considered to be related to sapacitabine. Common adverse events (all grades, regardless of causality) included fatigue, nausea, diarrhea, constipation, edema, dyspnea, pyrexia, pneumonia, febrile neutropenia, anemia, neutropenia and thrombocytopenia, most of which were mild to moderate. Conclusions: Sapacitabine appears to be safe and active across all 3 dose regimens. Updated data will be presented at the meeting.
Use of single polymorphism arrays (SNP-A) to modify prognostic scoring systems for myelodysplastic syndromes.
Authors: Bupathi Manojkumar , Elson Paul , Valeria Visconte , Traina Fabiola , O' Keefe Christine , Tabarroki Ali , Hasrouni Edy , Advani Anjali S. , Sekeres Mikkael A. , Maciejewski Jaroslaw P. , Gondek Lukasz , Tiu Ramon Velasquez
Published: March 2020

6521

Background: MDS are hematologic neoplasms characterized by dysplasia and cytopenias. Two commonly used risk stratifications, IPSS (Greenberg et al Blood 1997) and IPSS-R are based on clinical factors (marrow blasts, number of cytopenias and genetic abnormalities determined by conventional karyotyping), with the IPSS based on 4 cytogenetic risk groups and the IPSS-R based on 5 cytogenetic risk groups defined by Schanz et al JCO 2012. A drawback to metaphase cytogenetics (MC) is its inability to detect small cryptic chromosomal defects and uniparental disomy (UPD). SNP-A can identify these small cytogenetic lesions/UPD and has been shown to be of prognostic value in MDS. The goal of this investigation was to determine if SNP-A detected defects could be used to refine the IPSS and IPSS-R. Methods: SNP-A karyotyping was performed as previously described (Tiu et al, Blood, 2011). We reviewed data from 327 patients idenfitying SNP-A results, MC, and the IPSS/IPSS-R-related clinical factors were identified. Overall survival (OS) measured from the date of sampling for SNP-A karyotyping was the primary endpoint. Data were analyzed using Cox proportional hazards models. Results: SNP-A lesions not detected by MC were grouped as 1) none or only gains/losses; 2) UPD only or gains+losses but no UPD; and 3) UPD+other defects. The frequencies/median os in months (mo) of the groups were: 66%/20.0, 23%/12.7 and 11%/5.8, respectively, p<.0001 for OS. Combining the SNP-A groups with MC resulted in revised definitions of cytogenetic risk that had better discrimination than the underlying models; and when combined with the relevant clinical factors resulted in refined IPSS (IPSSSNP-A) and IPSS-R (IPSS-RSNP-A) risk stratifications (Table). Conclusions: Detection of chromosomal gains, losses, and UPD by SNP-A has prognostic value in MDS and can be used to refine current risk stratifications. [Table: see text]
Allogeneic stem cell transplantation for patients over age 65 with acute myelogenous leukemia and myelodysplastic syndrome.
Authors: Conter Henry Jacob , Rondon Gabriela , Nguyen Nhu-Nhu , Chen Julianne , Shpall Elizabeth J. , Khouri Issa F. , Giralt Sergio , Champlin Richard E. , De Lima Marcos J.G.
Published: March 2020

6529

Background: ASCT represents a potentially curative approach for AML and MDS, diseases that primarily affects patients in 7th and 8th decade of life. Here, we report outcomes of patients older than 64 treated at the MD Anderson Cancer Center from 1996 until December 2011. Methods: 182 patients older than 64 received an ASCT for AML (n=143) or MDS (n=39). Outcomes of interest were transplant-related mortality (TRM), incidence of acute and chronic graft-versus-host disease (GVHD), incidence of relapse, and overall survival (OS) - which were estimated from the date of transplant. Results: The median age of patients was 67 (range 65-79). Most patients were transplanted with active disease (table). Median follow-up for alive patients was 12.6 months (n=63; range 0-118). The cumulative incidence of 100-day, 1 year, and 3 year TRM was 14%, 18%, and 21%, respectively. 26% of patients developed grade II-IV acute GVHD and 35% suffered from chronic GVHD. The actuarial incidence of relapse was 46% at 1 year and 53% at 3 and 5 years. Actuarial OS was estimated to be 45% at 1 year, 28% at 3 years, and 21% at 5 years. 3 year OS for patients transplanted in CR and with active disease was 40% versus 23% (p=0.02). OS of patients age 65-69 or >69 was 30% vs. 20% (p=0.06) at 3 years for all patients; compared to 38% versus 27% (p=0.23) for patients in those age groups transplanted in CR. Conclusions: Although a significant minority of patients older than 64 years may achieve long-term disease control, new approaches are needed to reduce TRM and relapse in this cohort of patients. [Table: see text]
The outcomes of allogeneic stem cell transplantation in AML patients with monosomal karyotypes.
Authors: Sohn Sang Kyun , Lee Soo Jung , Kim Jong Gwang , Chae Yee Soo , Kang Byung Woog , Moon Joon Ho , Baek Jin Ho
Published: March 2020

6538

Background: The prognosis of acute myeloid leukemia (AML) with monosomal karyotype (MK) was reported extremely poor. We investigated the role of allogeneic stem cell transplantation (allo-SCT) for those with MK. Methods: A total of 114 patients who received allo-SCT for treatment of AML were retrospectively analyzed. All patients were treated with standard induction chemotherapy with anthracycline and cytarabine. Cytogenetic abnormalties were grouped according to recently published MRC criteria and MK was defined as at least two autosomal monosomies or one monosomy plus one or more structural abnormality. Results: Thirteen patients had favorable cytogenetic risk, 78 intermediate, 11 adverse without MK, and 12 adverse with MK at the time of diagnosis. Among 12 patients with MK, 5 (41.7%) achieved CR after induction therapy, 1 (8.3%) relapsed and 6 (50.0%) refractory at the time of allo-SCT. The 2-year overall survival (OS) was significantly lower for patients with MK (17.5%) compared to favorable (76.9%), intermediate (61.0%), and adverse without MK (36.4%, p=0.017). In the multivariate analysis, those with MK was related with extremely poor outcomes (HR 6.02, p=0.008), which was independent risk factor for OS. Survival benefit was observed in MK group with chronic GVHD compared to those without chronic GVHD. The median survival was 272 days with chronic GVHD (95% CI 204-339 days) compared to 159 days (95% CI 76-172 days) without chronic GVHD (p=0.010). Conclusions: The prognosis remained poor in patients with MK despite of allo-SCT. Innovative approaches to induce GLV effects are needed to improve SCT outcomes in patients with MK.
Effect of radioimmunotherapy-based conditioning for autologous stem cell transplantation on poor-risk molecular profiling in diffuse large B-cell lymphoma.
Authors: Siddiqi Tanya , Tsai Ni-Chun , Palmer Joycelynne , Forman Stephen J. , Krishnan Amrita Y.
Published: March 2020

6547

Background: Gene expression profiling has improved risk stratification of diffuse large B-cell lymphoma (DLBCL) in the first line setting as shown by DNA microarray analysis and immunohistochemistry (IHC). 5-year overall survival (OS) for germinal center B-cell-like (GCB) DLBCL is significantly better than that for non-GCB DLBCL in newly diagnosed patients. However, in the relapsed/refractory setting, autologous stem cell transplant (ASCT) appeared to overcome the poor prognosis of cell of origin as defined by IHC using CD10, Bcl6 and MUM1 and there was no difference in survival between GCB and non-GCB groups. Ibritumomab tiuxetan (Z)-BEAM conditioning regimen for ASCT in DLBCL has produced promising response rates and progression free survival (PFS). The role of poor risk molecular markers in predicting outcome with the novel conditioning regimen Z-BEAM is unknown. Methods: We evaluated cell of origin (GCB, non-GCB) using IHC in 36 patients undergoing ASCT with Z-BEAM conditioning from 2002 to 2010. Median age of the patients was 54.5 years. There were 12 females and 24 males. 6 patients were in 1st CR/PR ( 17%), 12 had induction failure disease (33%), 9 were in 1st relapse (25%), 1 in 2nd relapse (3%) and 8 were in ≥2nd CR (22%). 27 patients had chemosensitive disease (75%) and all had prior rituximab exposure. Median number of prior treatments was 2. IPI at transplant was mainly low risk (78%). 22 patients had GCB (61%) and 14 (39%) had non-GCB DLBCL. Results: Median follow up is 25.6 months. 12 patients relapsed (33%) and 9 died (25%). The major cause of death is relapse/disease progression. At 2 years, median OS is 79% and median PFS is 64%. No significant difference in 2 year OS and PFS is noted between the GCB and non-GCB groups (p=0.07 and 0.06 respectively). Conclusions: Z-BEAM conditioning for ASCT may overcome the poor prognostic effect of non-GCB DLBCL in relapsed/refractory disease. Further evaluation of cell of origin using new markers like GCET1, LMO2 and FOXP1 could confirm these results as there seems to be better concordance of these markers with DNA microarray analysis.
Cost-effectiveness analysis of bendamustine plus rituximab versus CHOP-R in treatment-naive patients with mantle cell (MCL) and indolent lymphomas (IL).
Authors: Su Wayne , Quon Peter , Whalen John , Ranganathan Gayatri , Wronski Samantha , Mwamburi Mkaya , Knopf Kevin B. , Sterchele James A. , Salvador Christopher G. , Ozer Stillman Ipek , Kadambi Ananth
Published: March 2020

6553

Background: To assess the cost-effectiveness of bendamustine plus rituximab (B-R) vs cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab (CHOP‑R) for treatment-naive patients with MCL or IL from a US healthcare payer perspective. Methods: A discrete event simulation was developed for a mixed population of patients with MCL or IL. Two arms were simulated, each containing 1000 identical MCL or IL patients treated with B-R or CHOP-R. Input data for baseline characteristics, overall response, and risks for treatment-related adverse events (AEs) and infections were obtained from the NHL 1-2003 trial (n=549, primarily stage IV MCL and IL); gaps were filled by consultation with experts. Direct medical costs and utilities were estimated based on US databases and published literature. Costs and benefits were discounted at 3% per annum. Base case model predictions were performed by selecting regression models that had a best fit to progression free survival (PFS). Robustness of these models was evaluated by testing other models with reasonably good fit. Results: In the base case, model predicts longer PFS for B-R than for CHOP-R in MCL (average of 49.8 vs 28.6 months) and IL (67.9 vs 51.0). Quality-adjusted life-years (QALYs) per patient were higher for B-R than CHOP-R for MCL (3.51 vs 2.68) and IL (4.42 vs 3.58). For MCL, total per-patient costs were $115,191 for B-R and $100,261 for CHOP-R; for IL, respective costs were $134,814 and $110,065, resulting in incremental cost-effectiveness ratios (ICERs) for B-R vs CHOP-R of $18,161 per QALY for MCL and $29,549 for IL (ICER<$50,000 to be cost-effective). Higher complete and partial response rates for B-R than for CHOP-R impacted subsequent treatment costs, which were lower for B-R by $21,632 for MCL and $24,961 for IL, as well as AE costs, lower by $10,113 and $10,570, respectively. The model results were robust with respect to the use of alternative regression models for PFS estimation. Conclusions: In patients with MCL or IL, the model demonstrates that B-R is a cost-effective alternative to CHOP-R. Alternative regression models confirmed robustness of results. Support: Teva Pharmaceutical Industries Ltd.
An anthropometric study in children with chronic myeloid leukemia on imatinib.
Authors: Reddy Goteke Vamshi Krishna , Maddi Rahul Narayan , Thota Narender Kumar , Coca Pragnya , Nagalla Balakrishna , Linga Vijay Gandhi , Gundeti Sadashivudu , Digumarti Raghunadharao
Published: March 2020

6554

Background: The long-term adverse effects, especially in children with chronic myeloid leukemia (CML) on imatinib are unknown. There is very little literature addressing the adverse effects on growth in children on imatinib. We analysed the effect of imatinib on anthropometry in children with CML. Methods: The records of children ≤ 18 years with CML diagnosed at our institute between 2003 and 2011 were retrospectively analysed. Children who received imatinib for at least one year and on regular follow up were eligible for growth assessment. The data was analysed using WHO AnthroPlus v1.0.4 and SPSS.v19 software and the Height for age and BMI for age/sex “z” scores were computed. Results: A total of 61 children were started on imatinib. But, only 37 children were eligible for assessment of growth. Of them 3 were further excluded as the WHO AnthroPlus software supported data only till 19 completed years. Median age was 12 years (range: 5 – 17). 17 children were in the prepubertal age (5-11years) at commencement of imatinib. The mean duration of imatinib therapy was 41.24 months (range: 12–91). The overall z- scores for height for age (HAZ) on follow up were significantly (p =0.029) lower, compared to baseline. However when analysed according to age groups, the HAZ was found significantly (p=0.005) lower among 5-11 year age group compared to age group of ≥12 years. No significant differences were observed in BMI for age/sex z scores by age groups, over the period. Conclusions: Imatinib appears to cause growth retardation in prepubertal children. Further follow up may shed more light on the degree of stunting and the deficit in the final adult height.
Treatment outcomes in patients older than age 60 with acute myeloid leukemia (AML) in the nonclinical trial setting.
Authors: Duffy Steven , Bains Puneet , Pavlovitz Brian , Vajpayee Neerja , Newman Nancy , Gajra Ajeet
Published: March 2020

6572

Background: Optimal treatment of older adults with AML remains challenging. While AML tends to be a disease of older adults, this population experiences greater treatment-related toxicity and worse overall survival than younger patients. Only fit older adults enter clinical trials and thus the results may not apply to the entire population. Methods: We conducted a retrospective analysis of patients > 60 years with AML (APL excluded) diagnosed prior to 2008 with IRB approval. The association of clinical factors (age, sex, comorbidities, prior chemotherapy), leukemia (prior myelodysplastic syndrome or myeloproliferative neoplasm, cytogenetics, WBC count), and therapy (induction chemotherapy, palliative chemotherapy, and best supportive care) as they relate to overall survival was evaluated using bivariate and multivariate regression analyses. Results: Of 87 patients (median age 73), 45% were male, 58% had high risk cytogenetics, 38% had prior MDS/MPD, 92% were chemotherapy naive, and 21% were in the high/very high Charlson risk class. The majority (67%) received standard dose induction chemotherapy (IC), 9% received (palliative intent) low-dose chemotherapy (LDC), and 24% received best supportive care (BSC). The median overall survival (OS) of the entire cohort was 2.5 months. On bivariate analysis high WBC (>50,000 at presentation) was negatively associated (1.0 vs 2.7 months p <0.01) with survival. OS for IC, LDC, and BSC were 3.1, 2.8, and 0.7 months, respectively (p=0.001). On multivariable analysis, IC conferred longer survival when compared to LDC and BSC combined (OR 0.33 CI 0.2-0.6, p<0.001). High WBC was associated with a decreased survival time (OR 2.96 CI 1.6-5.5, p=0.02). Mortality during induction or consolidation chemotherapy was 38%. At 5-year follow-up, only 4 patients were alive. Conclusions: In a non-clinical trial setting, OS of older adults with AML remains dismal. While IC offers a chance of longer survival, mortality with IC is unacceptably high. Further studies are required to identify and validate tools for risk stratification in older adults with AML as well as to utilize therapies with an improved toxicity profile.
Outcome of acute myeloid leukemia in patients with a history of autoimmune disease.
Authors: Dinardo Courtney Denton , Ogdie Alexis R , Hexner Elizabeth O. , Frey Noelle V. , Loren Alison W. , Luger Selina M.
Published: March 2020

6579

Background: Increased risks of solid and lymphoid malignancies are described in patients with autoimmune (AI) disease. The association between AI disease, AI treatment (particularly anti-TNF therapy), and AML is less established. Moreover, the pathologic characteristics of AML in this population have not been evaluated. Here we describe our AML experience in patients with prior AI disease. Methods: Patients with AML from 1992 to 2011 were identified from our database, and AI disorder was verified through chart review. Patients were included if they had an AI disorder that required systemic treatment, and diagnosed > 1 year prior to AML. Patients were excluded if details including the year of AI diagnosis or treatment(s) received were not documented. A total of 22 patients were included for analysis. Results: Median age at AML diagnosis was 59 years (range 32 – 78), 4 (18%) were men. 10 (48%) had received an anti-TNF agent, for a median duration of 30 months (range 2 – 120). Median latency from AI diagnosis to AML was 9.4 yrs. All FAB subtypes were represented except M0 and M6, 9 (41%) had M4 or M5 disease. 10/21 patients (45%) had normal cytogenetics, and 5 had favorable cytogenetics (2 with acute promyelocytic leukemia (APML)). Standard induction was given to 19 patients, and APML-directed therapy for those with APML. One patient received an autologous transplant in CR1, and 5 an allogeneic transplant (1 in CR1, 4 in CR2). 9 patients are alive in CR1. 13 relapsed, and 4 (31%) are alive in CR2 or CR3 (3 following allogeneic transplant in later CR). Median OS was 68.1 months. In univariate analysis, factors associated with OS were cytogenetics, FAB subtype, and gender. Anti-TNF therapy may be associated with poorer prognosis; this was not statistically significant. Median OS was 14.1 months for poor, 68.1 months for intermediate, and not reached for favorable risk cytogenetics. Conclusions: Median OS was higher (> 5 years) than expected. Younger age and an increased incidence of favorable risk AML may account for this finding: whether this is a meaningful biologic association or stochastic event can only be verified with larger studies. Our observations do not support a label of “secondary leukemia” or therapy-related neoplasm in this population.
A phase I/II trial of combination of PKC412 and 5-azacytidine (AZA) for the treatment of patients with refractory or relapsed (R/R) acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS).
Authors: Nazha Aziz , Kantarjian Hagop , Borthakur Gautam , Kadia Tapan M. , Faderl Stefan , Ravandi Farhad , Estrov Zeev , Jabbour Elias , Quintas-Cardama Alfonso , Cortes Jorge E.
Published: March 2020

6589

Background: Midostaurin (PKC412) is a FLT3 kinase inhibitor with activity in acute myeloid leukemia (AML). Hypomethylating agents play an important role in the treatment of AML and MDS. We investigated the safety (phase I) and clinical activity (phase II) of combination of 5-azacytidine (AZA) and PKC412 in pts with R/R AML and MDS. Method: Pts ≥18 years with MDS, CMML or AML, who failed prior therapies with performance status <2, adequate liver (bilirubin < 2x ULN, ALT ≤ 2.5x ULN) and renal (creatinine < 2x ULN) functions were eligible. Pts received AZA 75 mg/m2 subcutaneously or intravenously for 7 days of each cycle (Days 1-7) and PKC412 at 25 mg (cohort 1) and 50 mg (cohort 2; target dose) orally twice daily for 14 days (Days 8-21). Pts were to receive up to 12 cycles if benefit from treatment. Supportive care was standard. Results: 14 pts were included in phase I. 1 pt was inevaluable for DLT (withdrawal before completing cycle#1). 6 pts treated in cohort 1 and 7 in cohort 2. 1 pt in cohort 2 received PKC412 dose as per cohort 1 dose by pt error. Pt characteristics and responses are summarized in the Table. The overall response rate (ORR) was 3/13(21%) (2 with CRi, 1 pt dropped BM blasts form 27% to 7% after 2 cycles and went to transplant. 1/4 with FLT3-ITD achieved CRi, 2 of the non-responders received prior FLT3 inhibitors (1 had developed FLT3 D835). All toxicities were grade 1 (nausea 1 pt, vomiting 1 pt, dry skin 1 pt, and rash 1 pt) with no difference between the 2 groups. No DLT was identified. Conclusions: PKC412+AZA is safe and well tolerated at the intended doses with good ORR in high risk pts with R/R AML. Phase II study is enrolling pts with FLT3-ITD. Updated result will be presented. [Table: see text]
The large granular lymphocytic leukemia registry: A detailed analysis of 79 patients with LGL leukemia and rheumatoid arthritis.
Authors: Boughan Kirsten Marie , Loughran Thomas P.
Published: March 2020

6590

Background: The purpose of this study is to analyze patients enrolled in the LGL leukemia registry to distinguish the similarities between LGL leukemia and rheumatoid arthritis in order to access overlapping immune mechanisms that may be responsible for neutrophil mediated destruction. Methods: A retrospective chart review was performed on 79 patients enrolled in the LGL registry at Penn State Cancer Institute. All patients enrolled in the study had a diagnosis of both rheumatoid arthritis and potentially LGL leukemia. Data was collected for age, sex, RF factor positivity, family history, autoimmune disease, T-cell receptor gene rearrangement, and bone marrow invasion. Results: Of 79 patients the mean age of onset for LGL leukemia was 60 years old with no discrepancy noted between sexes, 37 M, 42 F. 49 patients were positive for rheumatoid factor. 27 patients had rheumatoid arthritis in a first degree relative with no discrimination between maternal or paternal inheritance. 22 patients were positive for any other autoimmune process. 60 patients were positive for T-cell receptor gene rearrangement. Of the remaining 19 patients that were negative for T-cell receptor rearrangement, 12 had evidence of bone marrow invasion (CD3/CD8+ infiltrate in >20% bone marrow) and two showed bone marrow invasion of NK cell LGL (CD3/CD8-, CD57+) (Table). Conclusions: Patients with T cell LGL leukemia and rheumatoid arthritis appear to be clinically similar with regard to age, duration of disease, and other autoimmune disorders as patients with rheumatoid arthritis alone. Our patient population showed those with TLGL and RA also tends to have a positive family history of RA in up to 20% as opposed to 5-10% in RA patients. Given that RA and TLGL have a significantly higher expression of the HLA-DR4 haplotype than healthy patients, it is conceivable that with shared genetic alterations, and gene environment interactions that may promote posttranslational modification, there may be a loss of tolerance resulting in T cell activation, and eventual transformation into a T cell clone. [Table: see text]
Analysis of imatinib (IM)-related, low-grade (LG), non-hematologic (heme) adverse events (AEs) in patients (pts) with chronic myeloid leukemia (CML) switched to nilotinib (NIL): ENRICH study update.
Authors: Mauro Michael J. , Lipton Jeffrey Howard , Miller Carole Brennan , Ailawadhi Sikander , Busque Lambert , Akard Luke Paul , Pinilla-Ibarz Javier , Ericson Solveig , Lin Felice , Cortes Jorge E.
Published: March 2020

6605

Background: This study update assesses change in chronic LG non-heme AEs in adult Ph+ CML-CP pts switched from IM to NIL. Methods: Pts were eligible if treated with IM 400 mg/d for ≥3 mo, and had IM-related grade (G) 1/2 non-heme AEs persisting ≥2 mo or recurring ≥3 times and persisting despite best supportive care. Pts received NIL 300 mg BID. Primary endpoint is change in IM-related LG non-heme AEs at 3 mo. Disease response was monitored by RQ-PCR and pt-reported outcomes measured by 2 quality-of-life (QoL) questions and MD Anderson Symptom Inventory (MDASI)-CML. Results: 47 pts were enrolled as of data cut-off (11/14/2011). There were 168 baseline IM-related non-heme AEs: 121 G1, 47 G2. 37 pts completed 3 mo NIL, by 3 mo 103 of 154 IM-related AEs (67%) improved (92 resolved, 11 improved from G2 to G1), 47 unchanged, 4 increased in severity. 13 pts were dose reduced for NIL-related AEs; 8 pts re-escalated after AEs recovered to G1 or resolved. 34 G3 AEs occurred in 15 pts; investigators reported 19 AEs as suspected NIL-related (increased bilirubin, lipase, or blood glucose; hypokalemia; hypophosphatemia; pruritus; bronchitis; dehydration; rash; arthralgia; pleural effusion). 8 pts discontinued NIL: 6 for AEs, 2 withdrew consent. No G4 AEs were reported. 32 pts had MMR (3-log reduction of Bcr-Abl; ≤0.1% IS) at entry; 16 additional pts achieved MMR on NIL. At entry, 18 pts had 4-log reduction and 10 pts 4.5-log reduction in Bcr-Abl. 16 and 13 additional pts achieved 4- and 4.5-log reduction, respectively, on NIL. At 3 mo (n=34) 62% and 53% pts reported QoL improvement from baseline in the previous 24 h and 7 d, respectively. Reduction in MDASI-CML severity/interference scores indicates symptom improvement. Mean reductions in MDASI-CML from baseline at 3 mo: severity, 1.21 (n=34); interference, 1.55 (n=33). Conclusions: 3 mo after switching to NIL, ~70% baseline chronic LG non-heme IM-related AEs improved and ≥53% of pts reported improvement in QoL. Molecular responses were maintained or improved in all patients. Switch from IM to NIL in majority of pts reduces IM-related toxicities and preserves/induces molecular response in CML-CP.
Correlation of TCR diversity with immune reconstitution after cord blood transplant.
Authors: Emerson Ryan , Milano Filippo , Guthrie Katherine , Sherwood Anna , Delaney Colleen , Robins Harlan
Published: March 2020

6631

Background: Umbilical cord blood is an important source of hematopoietic stem cells for allogeneic transplants used to treat hematologic disorders and malignancies. Stem cells from cord blood has several advantages over other sources (peripheral blood or marrow) including reduced incidence of graft-versus-host disease (GvHD) which allows less strict donor-patient HLA-type matching requirements. However, hematopoietic recovery (both myeloid and platelet engraftment) and immune reconstitution is significantly delayed in CBT patients resulting in patients remaining at high risk of infection for an extended period of time. Though the high risk of infections to patients is well-documented and recognized, physicians lack an objective means to monitor each patient’s progress toward functional reconstitution of the adaptive immune system. Our project aims to test if our measure of TCR diversity is a better proxy of immune reconstitution in CBT patients. Methods: To do this, we compare our proposed measure of immune reconstitution, TCRB CDR3 sequence diversity and richness over time, against the observed clinical course of severe infection in patients who have received CBT. Previously, peripheral blood mononuclear cells (PBMC) were collected and cyropreserved from 35 CBT recipients at six time points, pre-transplant, and 28, 56, 100, 180, and 365 days post-transplant. Concordantly, clinical outcomes for these patients were collected for up to four years post-transplant. We use a t-test to test if size of TCR repertoire differs between CBT patients with non-relapse related mortality and all other CBT patients. Results: Our TCR sequencing method was successful at measuring immune reconstitution, and TCR diversity is predictive of subsequent mortality from severe infection by 56 days post-transplant. Conclusions: TCR repertoire sequencing is a viable method to monitor immune reconstitution.
Higher incidence of EGFR exon 19 deletion in younger (age 40 or younger) patients with adenocarcinoma of the lung.
Authors: Sugiyama Eri , Goto Koichi , Ishii Genichiro , Umemura Shigeki , Yoh Kiyotaka , Niho Seiji , Ohmatsu Hironobu , Nagai Kanji , Ohe Yuichiro
Published: March 2020

7044

Background: The proportion of younger patients (≤ 40 years) with lung cancer is reported to be 2-5%. The most frequent histologic type of them is adenocarcinoma, however little is known about the pathological and molecular characteristics of younger patients with lung adenocarcinoma. Methods: Between July 1992 and April 2011, a total of 7443 patients were diagnosed as lung cancer in National Cancer Center Hospital East and 165 patients of whom (2.2%) who were 40 years or younger were identified. Among them, 44 patients with adenocarcinoma who underwent surgical resection were selected for this study. In addition, 185 elderly patients with > 40 years who underwent surgical resection matching gender and smoking status were selected as a control group. Histological predominant growth pattern and any coexisting variant pattern, the status of EGFR mutations were compared between these two groups. Results: The median age in ≤ 40 years patients was 37 years (range, 21 to 40 years) and that in elderly patients was 68 years (range, 42 to 83 years). Between these two groups, there were no significant differences in the distribution of histological predominant growth patterns (lepidic; 31.8% vs. 26.5%, papillary; 34.1% vs. 37.3%, acinar; 9.1% vs. 16.2%, and solid; 25.0% vs. 20.0%, p=0.78) and the incidence of EGFR mutations (40.9% vs. 45.9%; p=0.55). However, signet-ring cell component were significantly found in the younger patients than elderly (11.4% vs. 0%; p<0.01). The incidence of EGFR exon 19 deletion was significantly higher in younger patients than elderly, in contrast, that of EGFR exon 21 L858R was significantly higher in elderly patients (exon 19 del; 31.7% vs. 18.9%, L858R; 4.6% vs. 25.4%, p=0.0091). Three of 17 adenocarcinomas (17.7%) with EGFR-wild type in younger patients showed positive for ALK translocation. Conclusions: Younger patients with lung adenocarcinoma showed significantly higher proportion of EGFR exon 19 deletion genotype and containing histologically signet-ring cell component comparing with elderly patients. EGFR exon 19 deletion genotype may be related to pathogenesis of lung adenocarcinoma in younger patients.
Molecular profiling of patients with non-small cell lung cancer (NSCLC) using bronchoscopic ultra-micro sampling.
Authors: Sakairi Yuichi , Itoga Sakae , Sato Kenichi , Matsushita Kazuyuki , Yoshida Shigetoshi , Takiguchi Yuichi , Nomura Fumio , Yoshino Ichiro
Published: March 2020

7046

Background: Genetic information is essential for molecular targeted therapy for personalized medicine, although tissue sampling for genetic analysis remains challenging. In this study, we investigated the utility of bronchoscopic ultra-micro samples compared with conventional histological materials for multiple gene analyses for NSCLC. Methods: Patients with NSCLC proven by on-site cytological examinations during bronchoscopic survey were eligible. Following conventional needle aspiration biopsy by flexible bronchofiberscope (from primary lesion) or convex probe endobronchial ultrasound (from lymph nodes), the used needle was rinsed with 20 ml of saline and this ultra-micro sample (MS) was used for both cytological diagnosis and genetic analysis. DNA and RNA were extracted from each sample. Gene mutations [EGFR (epidermal growth factor receptor), K-ras, BRAF] and anaplastic lymphoma kinase (ALK) fusion genes were examined by high resolution melting analysis and direct sequencing. The results of cytological diagnoses and gene profiles using MS were compared to conventional histological diagnoses. Results: A total of 79 lesions (30 primary and 49 metastatic nodes) from 76 patients were eligible. Adenocarcinoma (N = 46), squamous cell carcinoma (N = 25), and NSCLC (N = 8) were pathologically confirmed in histological lesion cores; however, only 29 malignancies (37%) were detected with MS. DNA and RNA could be extracted from all histological samples and MS. In 35 cases, genetic disorders were identified, including EGFR mutations (N = 12), K-ras mutations (N = 5), BRAF mutation (N = 1), ALK fusion genes (N = 3), and silent mutations (N = 13); these results were identical for both histological samples and MS. Conclusions: Bronchoscopic ultra-micro samples (biopsy needle rinse fluids) are useful for multiple genetic examinations.
Relationship between tumor size and survival in non-small cell lung cancer (NSCLC): An analysis of the Surveillance, Epidemiology, and End Results (SEER) registry.
Authors: Zhang Jianjun , Gold Kathryn A. , Lin Heather , Swisher Stephen , Lippman Scott Michael , Lee J. Jack , Kim Edward S. , William William
Published: March 2020

7047

Background: Tumor size is a known prognostic factor for early stage (I and II) NSCLC, but its significance in node positive or locally advanced NSCLC has not been determined. We sought to evaluate its prognostic value in early and locally advanced NSCLC and create a nomogram incorporating tumor size and other prognostic variables to predict survival. Methods: The SEER registry was queried for patients (pts) with NSCLC, aged 20-103 and diagnosed between 1998 and 2003. Pts with extra-pulmonary metastases or distant lymph node metastases were excluded. Tumor size was analyzed as a continuous variable. Other demographic variables included age, gender, race, histology, primary tumor extension, node status and primary treatment modality (surgery vs radiation). Log-rank test was performed to evaluate the relationship between these variables and overall survival (OS). Cox proportional hazard model was used to evaluate whether tumor size was an independent prognostic factor. Results: 52,287 eligible pts were divided into 16 subgroups based on primary tumor extension and node status. For example, in group 1, tumor was confined to one lung with no nodes involved; pts in group 12 had tumor invading the mediastinum (T4 by extent) and positive ipsilateral mediastinal nodes. Tumor size had a significant effect on OS in almost all groups after adjustment for age, sex, race, histology, node status, primary tumor extension and primary treatment modality. Our model incorporating tumor size had significantly better predictive accuracy (larger C index) than our alternative model not including this information (p<0.0001). We then developed a nomogram incorporating tumor size, age, gender, race, histology, nodule stage, and tumor extension with the intent to predict OS. In subsequent bootstrap verification, the predicted 2-year OS from the nomogram was almost identical to the actual observed 2-year OS with a very slim biases of estimates. Conclusions: Tumor size is an independent prognostic factor, including pts with node positive or locally advanced NSCLC. We successfully created a nomogram incorporating tumor size and other clinical variables to predict survival.
Breath analysis for early detection of lung cancer.
Authors: Vallabhaneni Geetha D. , Gabram Sheryl G. A. , Lee Kichun Sky , Owonikoko Taofeek Kunle , Brandes Johann Christoph , Kono Scott Arthur , Saba Nabil F. , Khuri Fadlo Raja , Ramalingam Suresh S. , Bayer Charlene W.
Published: March 2020

7048

Background: Lung cancer (LC) is the leading cause of cancer death worldwide. Early detection is critical to reduce LC related mortality. Breath analysis can be used as a non invasive diagnostic tool in conjunction with CT screening. We assessed the diagnostic value of breath volatile organic compounds (BVOCs) in the alveolar breath of female non-small cell lung cancer (NSCLC) patients. Methods: This is a prospective case-control study that enrolled newly diagnosed NSCLC and cancer-free female controls. The study aims: 1) To compare the BVOC signature in female NSCLC patients to a control group without LC 2) To compare the BVOC signature between NSCLC and breast cancer (BC) patients. The study was restricted to women because the pilot data was generated from female subjects with BC. Consenting eligible patients provided a total of five deep breath samples into a proprietary breath sampler developed at the Georgia Tech Research Institute (GTRI) for collecting alveolar breath. Breath samples were collected five minutes apart from each subject. The collected samples were analyzed for BVOCs using thermal desorption/gas chromatographic/mass spectrometric (TD/GC/MS) technique. Statistical differences in BVOCs in breath samples from cases and controls were assessed using this technique. Support vector machine classification method was employed to compare the BVOCs pattern between LC and BC patients. Results: We enrolled 25 NSCLC and 25 cancer-free subjects. TD/GC/MS analysis identified a total of 422 BVOCs among the controls and NSCLC subjects. 75 unique BVOCs that were significantly different between cases and controls were employed for statistical modeling. This 75 BVOCs signature has a sensitivity of 0.75, a specificity of 0.75 and a classification accuracy of 75% for NSCLC and controls. Statistical analysis on the full BVOCs data set from NSCLC and previously collected BVOCs data from BC patients achieved a classification accuracy of 88%. Conclusions: Unique BVOCs pattern can identify patients with established NSCLC. Future studies in at-risk patients will assess the utility of this approach as a less invasive and minimal risk screening tool for early detection of NSCLC. Supported by the Kennedy Seed Grant awarded by the Winship Cancer Institute of Emory University.
Case-control study of prophylactic cranial irradiation in nonmetastatic non-small cell lung cancer.
Authors: Cheng Simon , Corradetti Michael Nino , Horowitz David Paul , Xanthopoulos Eric , Lusa Amanda , Chao K. S. Clifford , Rengan Ramesh
Published: March 2020

7050

Background: Prophylactic cranial irradiation (PCI) reduces the incidence of brain metastases in NSCLC patients after primary therapy, but its impact on survival is uncertain. We report on the largest study of survival in patients treated with and without PCI for non-small cell lung cancer (NSCLC). Methods: We reviewed 17 Surveillance, Epidemiology and End Results (SEER) registries for a retrospective study on patients who had PCI as part of their primary treatment for NSCLC from 1988 - 97. Cases were limited to those with non-metastatic (Stage I-III) NSCLC. To balance the cohorts, we matched each PCI patient with four non-PCI patients on stage, histology, race and sex. Associations between treatment type, clinical factors, and demographics were assessed using the Chi-squared test. Survival time was calculated as the number of months from diagnosis to the date of death. Survival was censored as of the last month when patients were known to be alive. Overall (OS) and cancer cause-specific survival (CSS) were investigated using the Kaplan-Meier, competing risks, Cox proportional hazards, and log-rank tests. Results: We found 472 PCI matched to 1,888 non-PCI patients. Characteristics were balanced across groups: race (p = 1.00), sex (p = 0.95), histology (p = 1.00), stage (p = 1.00), and surgery (p = 0.81). PCI group was younger, median age 64 vs 68 (p < 0.01). PCI vs no PCI median OS was 8 vs 10 months (p < 0.01). OS was 14% vs 28% at 2 years and 5% vs 12% at 5 years, PCI vs no PCI respectively (p < 0.01). Stage III OS was also different; 10% vs 21% at 2 years, PCI vs no PCI respectively (p < 0.01). Median CSS was the same at 9 months in both groups. Median follow-up was 14 years. Conclusions: PCI was not associated with improved OS or CSS in these NSCLC patients, and PCI may have a detrimental effect on OS. In limited-stage small cell lung cancer, a retrospective SEER analysis during the 1988 – 97 period showed a survival benefit in treated patients with PCI, which has been confirmed with prospective studies. To date, 4 prospective trials examining PCI for NSCLC have shown a reduced incidence of brain metastases, but the effect on survival is unclear. Further investigation is needed to determine whether PCI for NSCLC increases the risk of other causes of death.
Anatomic segmentectomy versus lobectomy for clinical stage I non-small cell lung cancer: A propensity-matched analysis.
Authors: Schuchert Matthew J. , Normolle Daniel Paul , McCormick Kristen N. , Wilson David O , Siegfried Jill , Landreneau Joshua P , Reamer Margaret , Luketich James D. , Landreneau Rodney Jerome
Published: March 2020

7071

Background: Although anatomic segmentectomy is considered a “compromised” procedure by many surgeons, new information from several retrospective, single-institution series has countered negative premises regarding tumor recurrence and patient survival. The primary objective of this study was to utilize propensity score matching to compare outcomes following these anatomic resection approaches for stage I NSCLC. Methods: Patients undergoing lobectomy (n=392) vs. segmentectomy (n=793) for clinical stage I NSCLC were matched 1:1 using a propensity score that accounted for the potential confounding effects of pre-operative patient variables. Matching based on propensity scores produced 312 patients in each group. Primary outcome variables included recurrence-free and overall survival. Factors affecting survival were assessed by proportional hazards (Cox) regression and Kaplan-Meier survival function estimates. Results: Peri-operative mortality was 1.2% in the segmentectomy group and 2.5% in the lobectomy group (p=0.38). Ninety-day mortality was 2.6% and 4.8% (p=0.20), respectively. At a mean follow-up of 5.4 years, no differences were noted in locoregional (5.5% vs. 5.1%, p=1.00), distant (14.8% vs. 11.6%, p=0.29) or overall recurrence rates (20.2% vs. 16.7%, p=0.30) when comparing segmentectomy with lobectomy. Furthermore, no significant differences were noted in time to recurrence (p=0.415) or overall survival (p=0.258) when comparing the matched groups. Five year freedom from recurrence (95% CI) was: Segment 0.70 [95% CI: (0.63, 0.78) vs. Lobe 0.71 [95% CI: 0.64, 0.78]. Overall survival (95% CI) was: Segment 0.54 [95% CI: (0.47, 0.51) vs. Lobe 0.60 [95% CI: 0.54, 0.67]. Segmentectomy was not found to be an independent predictor of recurrence (HR: 1.11, 95% CI: 0.87, 1.40) or overall survival (HR = 1.17, 95% CI: 0.89.1.52). Conclusions: In this large propensity-matched comparison, anatomic segmentectomy is associated with similar time to recurrence and overall survival rates when compared to lobectomy for clinical stage I NSCLC. These results will need further validation by prospective, randomized trials (CALGB 140503).