bluuebunny/crossref_metadata_2025 huggingface dataset:
Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) following treatment for ovarian cancer
Authors: Gupta B. , Sait S. N. , Block A. W. , Ford L. A. , Moysich K. B. , Baer M. R.
Published: March 2020

17506

Background: Therapy-related AML (t-AML) has been reported in ovarian cancer patients treated with chemotherapy and has been associated with the use of platinum. However, little is known about these patients’ clinical characteristics, cytogenetic changes, clinical course or treatment outcome. Methods: Roswell Park Cancer Institute patients with diagnoses of AML or MDS by French-American- British (FAB) Group or World Health Organization criteria following a diagnosis of ovarian cancer were retrospectively reviewed. Results: Ten patients were identified between 1990 and 2006. All 10 had received platinum chemotherapy, and 8 (80%) had also received taxanes, 4 (40%) cyclophosphamide and 3 (30%) adriamycin. The median age at ovarian cancer diagnosis was 56 (range, 49–78) years, and the median age at AML/MDS diagnosis was 62 (range, 56–81) years. The median interval from diagnosis of ovarian cancer to AML/MDS was 5.5 (range, 3–11) years, while the median survival time of 395 ovarian cancer patients treated at RPCI between 1982 and 1998 was 4.1 years (range, 1 month to 23 years). Eight patients had AML and 2 had MDS. AML FAB types were M2 in 3, M0 and M4 in 2 each, and M6 in 1. Among 9 patients with cytogenetic data available, 6 had complex karyotypes, all of which included monosomy 5 or del(5q), and three had single clonal abnormalities, all involving chromosome 7. Of 7 AML patients who received induction chemotherapy, only 3 achieved complete remissions, and remissions were brief (3, 4.5 and 5 months). Median overall survival for all ten patients after diagnosis of AML or MDS was 4 months (range, 0.5 months to 9.5 months). Conclusions: Patients with t-AML/t-MDS following therapy for ovarian cancer have unfavorable cytogenetic abnormalities, including complex karyotypes and involvement of chromosomes 5 and 7, which are typical findings following alkylating agent therapy, and these patients have a very poor prognosis.

No significant financial relationships to disclose.
Phase I study of nilotinib in patients (pts) from Japan with imatinib-resistant Ph+ chronic myelogenous leukemia (CML) or acute lymphocytic leukemia (ALL)
Authors: Tojyo A. , Miyazaki Y. , Usui N. , Kobyashi Y. , Okamoto S. , Oyashiki K. , Nishimura M. , Okada M. , Natori H. , Tanii H.
Published: March 2020

17511

Background: Nilotinib is a highly selective Bcr-Abl tyrosine kinase inhibitor designed to be more potent than imatinib. Results from a phase I study in Japanese pts with imatinib-resistant/intolerant Ph+CML/ALL are reported. Methods: Japanese pts with imatinib-resistant/intolerant Ph+CML (5 CP; 2 AP; 2 BC) or ALL (2) were enrolled in an open-label, dose-escalation study evaluating safety, efficacy and pharmacokinetics (PK) of oral nilotinib. A standard three-pt-per-cohort design was used; initial cohorts included 200mg QD, 400mg QD, and 400mg BID. Serum samples were collected on days 1 and 15 of cycle 1 in all 11 pts. Results: Peak serum concentration was achieved at 4 hrs in most pts. Systemic exposure increased with dose. Serum level reached steady-state within 1 week and was stable over time. The accumulation ratio (AUC day15/day1) was 2 to 3. Nilotinib 400mg BID maintained serum levels >/= 30 times higher than the IC50 required to inhibit Bcr-Abl phosphorylation. No pt experienced dose-limiting toxicity. 7/11 pts had Grade 3/4 AEs, only 1 pt had an AE (thrombocytopenia) suspected as being related to nilotinib treatment. No pt had EKG abnormalities. 57% of all pts and 75% of CML CP pts achieved MCyR. 3 pts in the 200mg QD cohort discontinued due to disease progression, all other pts completed the study. PK results are summarized in Table 1 . Conclusions: Nilotinib PK profile in Japanese pts is comparable to that reported for pts outside Japan. Based on these data, the recommended starting dose of nilotinib in Japanese pts with imatinib-resistant/intolerant Ph+ CML/ALL is 400mg BID.

[Table: see text]

No significant financial relationships to disclose.
Molecular remission to imatinib-IFN-alpha combination or imatinib monotherapy in chronic myeloid leukemia (CML) patients
Authors: Liberati A. , Schippa M. , Luzi D. , Falchi L. , Emili R. , Capparella V. , Cerroni P. , Gentileschi E. , Gottardi E. , Saglio G.
Published: March 2020

17512

Background: Continously improving results have been obtained in the control of Philadelphia chromosome (Ph’) positive CML. However, the final goal of molecular remission remains difficult to be obtained, even in the imatinib era. Evaluation of the rate of complete molecular remission (undetectable p210 transcript at RQ-PCR confirmed by NESTED/RT-PCR in at least two subsequent tests over a period of 3 mths or more) to imatinib or to imatinib-IFNa combination as first, second or subsequent line of therapy. Imatinib alone or in combination with IFNa was given as first, second or subsequent line of therapy to a total of 47 patients. In particular, 21 patients were treated at the time of diagnosis with imatinib alone (18,G1) or imatinib-pegilated IFN combination (3,G2). Twenty-three additional patients (G3) received imatinib as second line therapy. Finally, 13 patients were treated with the imatinib-IFNa combination as second (7,G4) or third (6,G5) line therapy, but in two cases IFNa was discontinuated after one month because of intolerance to treatment. Methods: Molecular response was evaluated by NESTED/RT-PCR (Guo JQ et al.; Leukemia:2002;15:2447–53) and RQ-PCR (Gabert J et al. Leukemia:2003;17:2318–57) at time intervals of 3–6 months from the beginning of therapy. Results: Complete molecular remission lasting 3 months or more (range 3–34) was obtained in 15 of 44 evaluable patients (therapy duration = 11 mths, range 11–73).The response rate was higher in patients receiving imatinib- IFNa combination given as first or second line therapy (5/13) than in those given imatinib monotherapy (9/37). In 7 of the 15 complete responders, remission duration lasted more than 12 mths (range 12–34) with 6/7 pts still continuous remission. In further 6 cases continuous remission duration ranged from 3–8 mths while in one case fluctuating negative-positive NESTED/RT-PCR tests have been observed over a period of 65 months. Conclusions: It is not possible to draw any firm conclusion regarding the effect of the imatinib-INFa combination on molecular response because of the small sample size of treated patients. However, our findings suggest an additive effect of imatinib and IFNa in Ph’positive clone control.

No significant financial relationships to disclose.
Allogeneic stem cell transplantation (allo-SCT) in adult acute lymphoblastic leukemia (ALL)
Authors: Wu S. J. , Yao M. , Tang J. L. , Chen Y. C. , Cheng A. L. , Tien H. F.
Published: March 2020

17513

Background: Although viewed as a potentially curable disease, the outcome of adult ALL is extremely poor. The role of allo-SCT, a possible curative modality, is of debate. Although the solid evidence is lacking, allo-SCT is viewed as a standard treatment in some institutions and some trials. The objective of the study is to clarify the effect of allo-SCT in the treatment of adult ALL patietns. Methods: From Jan. 1999 to Jun. 2006, we included 103 adult ALL patients whose age were between 15 and 55, the upper limit of age for allo-SCT in this institution. Their data, including clinical characteristics, cytogenetic results, treatment response and outcomes, were collected. To avoid the “immortal-time bias” in assessing the effect of transplant, the results from a time-independent and time-dependent Cox proportional hazards model were compared. We also conducted a population-based study to compare the outcomes of these patients with those diagnosed between Jan. 1986 and Dec.1993 in our institution. Results: There were 46 females and 57 males. The median age was 25.8, with 63 patients (61.2%) younger than 30. The median survival was 21.9 months and the 3-year overall survival was 34.2%. 48 patients(46.6%) received allo-SCT. The transplant conferred to marginally better survival in univariate analysis (p=0.049), but by time-dependent regression method, there was, after adjusting for other risk factors, no survival benefit for patients receiving transplant (HR 1.452, 95% CI 0.766∼2,751, p=0.253). The outcomes of these 103 patients were compared with another group of 69 patients diagnosed in the early period, among whom 13 patients(18.8%) received transplant. Although with higher proportion of patients undergoing allo- SCT, there was no advance in overall survival (p=0.157). Conclusions: In adult ALL, the outcome is still poor. Although there are new treatment protocols and modalities in chemotherapy and transplantation, these advances do not reflect to survival improvement. Transplantation provides limited survival benefit in population-based viewpoint. The candidates of allo-SCT should thus be carefully selected and allo-SCT should not be viewed as a standard in the treatment of adult ALL patients.

No significant financial relationships to disclose.
Prognostic factors in Chinese patients with chronic lymphocytic leukemia
Authors: XU W. , Li J. , Zhang S. , Wu Y. , Zhu Y. , Zhu Y.
Published: March 2020

17518

Background: Recently, some new factors, such as cytogenetic abnormalities, ZAP-70, proliferative antigen Ki-67, and the expression of CD38 in leukaemic cells, were strong indicator of prognosis in B-cell chronic lymphocytic leukaemia (B-CLL). The aim of this study was to explore the characteristics of molecular cytogenetics in Chinese patients with CLL, evaluate the expression of Ki-67, ZAP-70 and CD38 in leukaemic cells, and analyze the influence of factors on the prognosis of CLL. Methods: Interphase fluorescence in situ hybridization (FISH) was used to detect cytogenetic aberrations, and a panel of FISH probes for 13q14 (D13S319), 17p13 (p53 gene), 11q23 (ATM gene), the centromere of chromosome 12 (D12Z3) and 14q32 (IGHC/IGHV) was applied on bone marrow or peripheral blood smears from 52 Chinese B-CLL patients; Four-color flow cytometry was used to determined the expression of ZAP-70 protein and CD38; Immunohistochemistry was applied to measure the expression of Ki-67 antigen and Bcl-2 protein. Kaplan-Meier was used for survival time. Results: Out of the 52 patients, 42 (80.7%) had at least one kind of molecular cytogenetic aberration and 16 (30.8%) with 2 abnormalities. The most frequent abnormalities detected in our patients was deletions of 13q14 in 26 cases (50.0%), followed by trisomy of chromosome 12 in 11 patients (21.2%), deletions of 17p13 in 10 patients (19.2%), deletions of 11q23 in 6 patients (11.5%), and 14q32 translocation in 5 patients (9.6%). Fourteen patients (26.9%) were positive for ZAP-70 (=20%), and 13 patients (25.0%) were positive for CD38. Positive ZAP-70 and CD38 status was associated with advanced disease stage (Binet C). The expression levels of Ki-67 in Binet C stage was higher than that in early stage (Binet A and B). In univariate analysis for survival, 13q14 deletion was a favorable prognostic factor, and the deletions of 17p13 and 11q23 were poor prognostic factors. The survival time was longer in the group with lower expression of Ki-67 than that in the higher expression group. Both ZAP-70 and CD38 expression were shown to predict the clinical course of the disease. Conclusions: Chromosomal aberrations (deletions of 13q14, 17p13 and 11q23), and expression of Ki-67, ZAP-70 and CD38 have been shown highly predictive prognostic value for Chinese patients with B-CLL.

No significant financial relationships to disclose.
Hypereosinophilic syndromes (HESs) variable clinical presentations and responses to treatment
Authors: Mitra S. , Power D. , Thornton P. D. , O Donnell R. , Murphy P. T.
Published: March 2020

17529

Background: Hypereosinophilic syndromes (HESs) refers to a heterogenous group of disorders characterised by marked blood eosinophilia (>1500/cu mm) and tissue eosinophilia (lasting for more than 6 months), in the absence of other eitiologies for eosinophilia, resulting in end organ damage. Eosinophilias may be reactive or due to a chronic myeloproliferative disorder (with evidence of clonal proliferation).Clonal eosinophilias are very often associated with the fusion gene FIP1L1-PDGFR alpha which causes the generation of a constitutively active Tyrosine Kinase. Treatment modalities for HES includes corticosteroids, chemotherapeutic agents, alpha- interferon, tyrosine kinase inhibitors (eg Imatinib mesylate) and the monoclonal anti-interleukin 5. Patients carrying FIP1L1-PDGFRalpha respond very well to Imatinib. Aim:Retrospective review of the variable response of 7 patients with HES (over a period of 6 months), to current treatment modalities. Methods: The 7 patients (6 Male, 1 Female; age range 37–80 yrs; mean age 56 yr) presented with eosinophilia in the range 2600–73,000 /cu mm.They were followed up for >6 months. A response to treatment was defined as Eosinophil count<1500 /cumm or Eosinophil count < 5% of the total leucocyte count .Four of the 7 patients received Imatinib as initial treatment. Two patient initially had steroids followed by Imatinib and 1 patient (aged 80 yr) was treated with Hydroxyurea initially. Results: Four of the 6 patients receiving Imatinib responded to it. Of the 2 patients not responding to Imatinib,1 responded partially to Hydroxyurea and the other did not respond to monotherapy with steroid or alpha-interferon (but eventually responded to a combination of the two). The patient who had initial treatment with Hydroxyurea responded well. Of the 7 patients 1 was positive for the FIP1L1-PDGFRalpha fusion gene,1 result was equivocal, 3 were negative and 2 were not tested (not available at the time). Of the 2 that were negative,1 responded to Imatinib. Conclusions: Response of HES patients to the various treatment modalities, is variable and often unpredictable.The FIP1L1-PDGFR alpha fusion gene is not often present;however other Tyrosine Kinases may be dysregulated and hence a trial of Imatinib is worth considering in most cases.

No significant financial relationships to disclose.
Outcome of patients of CML in AP and BC with imatinib: A retrospective analysis of patients from India
Authors: Menon H. , Hingmire S. S. , Bharath R. , Jain K. , Ghadyalpatil N. , Prasad N. , Biswas G. , Deshmukh C. , Sastry P. , Parikh P. M.
Published: March 2020

17531

Background: Imatinib is a very active agent in advanced phase CML. The present study assesses the impact of Imatinib therapy on the outcome of Indian patients with CML in Accelerated Phase (AP) and Blast Crisis (BC). Methods: Patients of CML in AP or BC who were treated with Imatinib based therapy between 2001 and 2006 were analyzed retrospectively. Results: A total of 65 patients who received Imatinib based treatment for CML in AP or BC were analyzed. Thirty eight (58.46 %) patients diagnosed in chronic phase (CP) were initiated on Imatinib based treatment at time of progression to AP or BC. The remaining 27 (41.53 %) patients had AP or BC of CML at initial diagnosis. At the time of start of Imatinib treatment 36 (55.38 %) patients had AP and 29 (44.61 %) were in BC. Imatinib as a single agent was used in 41 (63.07 %) patients (27 in AP and 14 in BC) and in combination with oral 6-MP and Etoposide was used in 24 (36.92 %) patients (14 in AP and 10 in BC). Hematological response (HR) was seen in 64.61% (42 out of 65) patients, complete HR in 32 (49.23 %) and partial HR in 10 (15.38 %). Cytogenetic response (CR) was noted in 21 (32.31%) patients (Complete -10, Partial -9, and Minor - 2). Twenty eight (43.07%) patients remained progression free (HR+CR in 16 and only HR in 12 patients) till the last date of follow up (median duration of follow-up was 17 months).For the whole group (n=65) the overall survival from the diagnosis of AP or BC after commencing Imatinib treatment was 65.3%, 51.6% and 34.4% at 1, 2 and 3 years respectively. The median survival was 25 months. The median survival and OS at 1 year, as expected, was significantly better for patients in AP (36 months, 77.4 %) as compared to those in BC (11 months, 48.2%)(p=0.004) and both were much longer than previously reported with non-Imatinib therapy. Outcome in patients with AP or BC was not significantly improved by addition of 6-MP and Etoposide. Temporary discontinuation of Imatinb for grade III/IV toxicity was done in 27 (41.53 %) patients for a median duration of 28 days. Conclusions: Imatinib has improved the outcome of patients with advanced phase CML. Our data also documents this in patients from India. However, Imatinib needs to be studied with newer combinations to achieve long term disease control in patients with CML, particularly those in BC.

No significant financial relationships to disclose.
Economic and medical consequences of myelodysplastic syndromes from a medical perspective
Authors: Goldberg S. , Mody-Patel N. , Warnock N.
Published: March 2020

17534

Background: The myelodysplastic syndromes (MDS) are a heterogeneous group of bone marrow failure diseases affecting the elderly. The economic impact on Medicare of MDS is largely unknown. A retrospective analysis of total healthcare resource use and cost of MDS patients (pts) was conducted. Methods: The Medicare Standard Analytic File 5% (SAF5%) claims database was used to identify pts with a new primary MDS diagnosis code in first quarter (Jan-Mar) 2003 then followed through Dec 2005. Pts with myeloid leukemia or anemias of known causes in the previous year were excluded. Newly diagnosed MDS pts were descriptively characterized based on potential cause of MDS, MDS-related complications, and MDS therapies. Total healthcare costs and resource utilization for MDS pts were analyzed. Results: Of the 1,713,502 pts in SAF5%, 705 (4 per 10,000) developed MDS in first quarter 2003, including those with a previous history of unexplained anemia 159, (23%), chemotherapy or radiotherapy exposure 43, (6%), and de novo 503 (71%). Mean age was 76 (range 29- 98); 49% male, 90% Caucasian. 2003 median Medicare payment for MDS pts was $17,556, compared to $1,459 for the total SAF5% Medicare population (mean: $28,023.67 vs. $6,739.48; p< 0.001). Median Medicare payments for therapy induced were $34,271, prior anemia $17,191, and de novo MDS $16,493. 278 (39%) died; including 63% of the therapy-induced, 40% of the prior anemia and 37% of the de novo. 79% were hospitalized and 59% had at least one emergency room visit. Of 46% receiving blood transfusions 6% were coded with transfusional hemachromatosis. 314 (45%) received growth factor treatments and 108 (15%) chemotherapy. Of those at risk for MDS-related complications, 55%, 23%, and 2% experienced new onset cardiac complications, diabetes, and hepatic diseases, post MDS diagnosis. Additionally, 51% had pulmonary problems and 45% infections in the 3 year study. Conclusions: The majority of newly diagnosed MDS pts develop disease-related complications, resulting in significantly higher healthcare resource utilization and costs compared to non-MDS patients.

No significant financial relationships to disclose.
The poor prognostic significance of deletions of derivative chromosome 9 in Chinese patients with chronic myelogenous leukemia
Authors: Li J. , Xu W. , Wu W. , Zhang S. , Zhu Y.
Published: March 2020

17535

Background: Chronic myeloid leukemia (CML) is characterized by formation of the BCR/ABL fusion gene, usually as a consequence of the Philadelphia (Ph) translocation between chromosomes 9 and 22. Deletions of the derivative 9 chromosome [der(9)] in 10- 15% of CML patients with a standard Ph translocation and in >30% of CML patients with a variant Ph translocation. Subsequent studies demonstrated that CML patients who carry a der(9) deletion progress more rapidly to blast crisis and have a shorter survival than those without a deletion. The characteristics of Chinese patients with each hematologic malignancy compared with those in other countries have not yet been clarified. This prompted us to perform molecular and cytogenetic analyses on Chinese patients with CML. Methods: To study the incidence and the prognostic significance of the derivative chromosome 9 [der(9)] deletions in on Chinese patients with CML, a series of 48 BCR/ABL positive Chinese CML blast crisis (CML-BC) patients were investigated using dual colour dual fusion BCR/ABL probe and fluorescence in situ hybridization (FISH). Results: Eight (16.7%) cases showed der(9) deletions, and the deletions were also existed in chromosome preparations made at diagnosis. The estimated median length of chronic phase for patients with der(9) deletions was 18 months (range 4–38 months) compared to 48 months (range 0–204 months) for patients without deletions. Kaplan-Meier analysis revealed a striking difference in length of chronic phase between with and without der(9) deletions, and this difference was highly significant by log-rank analysis. Der(9) deletions are not associated with increased karyotypic instability. There was no difference in the probability of the der(9) deletions between the cases transformed to acute nonlymphocytic leukemia (ANLL) and those to acute lymphoid leukemia (ALL). Conclusions: The results indicate that FISH technique could effectively detect the der(9) deletions. Der(9) deletions occur at the time of Ph translocation. CML patients with der(9) deletions have more rapid process and poorer prognosis. Deletion status is a powerful prognostic factor for patients with CML. Der(9) deletions might not lead to transformation to specific type in CML.

No significant financial relationships to disclose.
Rituximab, gemcitabine, vinorelbine, and methylprednisone (R-GVM), a hematopoietic cell (HC) mobilizing and salvage regimen for malignant lymphoma (ML)
Authors: Rezazadeh A. , Herzig G. , Herzig R.
Published: March 2020

17537

Background: The prognosis of pts with recurrent ML remains poor. High-dose therapy (HDT) with HC rescue can cure a proportion of such pts. HC mobilization can be adversely affected by number and duration of prior treatments, interval from diagnosis to HC collection, prior radiotherapy and marrow involvement. There remains a need for more effective and less toxic salvage regimens, capable of mobilizing HCs. Methods: The mobilizing potential of R-GVM salvage regimen with hematopoietic growth factor (HGF) support (G- and GM-CSF) was evaluated in 6 pts with relapsed (n=5) or primary refractory (n=1) ML. Pts received R-GVM salvage therapy [rituximab (375 mg/m2, day 1), gemcitabine (1 g/m2, day 1, 8), vinorelbine (30 mg/m2, day 1, 8) and methylprednisone (1 g/m2, day 1, 8)] with HGF administration and subsequent HC collection. The HGF support was started on day 9 and was continued through apheresis which started when the CD34+ cell count ≥ 20/μl (median day of R-GVM cycle: 15, range 14–19). Pts had daily apheresis with continued HGF support until at least 5 x 106 CD34+ cells/kg were collected. The hematologic and non-hematologic toxicity were tolerable in all pts; no pt required hospitalization. Results: 6 pts (age range 20–45 years) with Hodgkin (n =3) and non- Hodgkin lymphoma (n =3) were evaluated in this study. Pts had received 1–3 previous treatment regimens. The median number of R-GVM courses given before HC collection was 2.5 (range 1–5). Effective HC mobilization (≥5x106 CD34+ cells/kg) was obtained in all ps. A single apheresis resulted in satisfactory HC collection in 4 pts (range 8.2–17.7 x 106 CD34+ cells/kg); 2 pts required 3 aphereses to collect an adequate number of cells (6.7 and 7.4 x 106 CD34+ cells/kg). One pt was heavily pretreated and had failed two previous attempts of HC mobilization (one with HGF alone and one with cyclophosphamide and HGF); the other pt was HIV+ treated with HAART and had prior marrow involvement. As a salvage regimen, one pt had progressive disease, 1 had stable disease, 1 had a partial response, and 3 had a complete response before proceeding with HDT with HC rescue. Conclusions: R-GVM regimen is feasible, tolerable and effective in mobilizing HPC in patients with relapsed and refractory lymphoma.

No significant financial relationships to disclose.
Relapsed acute megakaryoblastic leukemia in Down syndrome (AMKL-DS) may be cured with chemotherapy alone, without stem cell transplantation (HSCT)
Authors: Jayabose S. , Sandoval C. , Levendoglu-Tugal O. , Ozkaynak M. F.
Published: March 2020

17543

Background: Children with recurrent AMKL -DS have an extremely poor prognosis without HSCT. Methods: We report a case of a relapsed AMKL-DS cured with intensive chemotherapy alone, without HSCT. Results: A 19 month old boy with Down syndrome, who had transient leukemia as a newborn, developed AMKL-DS (GATA1 positive) and was treated with four cycles of CI-TAD: continuous infusion of cytarabine and daunorubicin, and oral thioguanine for four days, and intrathecal cytarabine; followed by two cycles of high dose cytarabine plus L-Asparaginase; and three weekly doses of intrathecal cytarabine. Although he achieved remission at the completion of first cycle of the induction chemotherapy, he relapsed within 6 weeks after the completion of therapy. He then received the following chemotherapy over the next six months: Cycle 1 and 2. High dose Ara-C ( 33. 3 mg/kg q 12 hours x 8 doses) on days 0 to 3 plus mitoxantrone 0. 4 mg/kg/day x 4 on days 3 to 6 Cycle 3. High dose Ara-C 33. 3 mg/kg q 12 hours x 8 doses Cycle 4 and 5 (FLAG): Fludarabine 0. 8 mg/kg/day x 4 plus Ara-C 67 mg/kg/d x 4 and G-CSF 10 mcg/kg/day x 4 all on days 0 to 3. He achieved complete remission after the 1st cycle of chemotherapy, and underwent further cycles of chemotherapy while waiting for HSCT from an unrelated donor. But after the 5th cycle of chemotherapy, he developed a pulmonary lesion of fungal etiology for which he received three months of therapy with liposomal amphotericin. Because of a persistent lung lesion on imaging, he was considered ineligible for HSCT, and no further therapy was given. His bone marrow aspirate after the 3rd cycle of therapy was negative for GATA1. He has been disease-free for 59 months after the completion of his last cycle of chemotherapy, and he is currently in good health without any evidence of pulmonary or cardiac dysfunction. Conclusions: Intensive chemotherapy alone, without HSCT, may be curative for relapsed AMKL- DS.

No significant financial relationships to disclose.
Activity of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in chemotherapy-pretreated non-small cell lung cancer (NSCLC) patients (pts) prospectively selected according to specific molecular predictive factors
Authors: Nuzzo C. , Marchetti A. , Mottolese M. , Cianciulli A. M. , Rinaldi M. , Cecere F. L. , Bria E. , Ceribelli A. , Milella M. , Cognetti F.
Published: March 2020

18006

Background: EGFR TKIs are effective in a small proportion of chemotherapy-pretreated NSCLC pts. A number of molecular alterations along the EGFR pathway have been proposed as predictors of response to EGFR TKIs, but to date none of them has been prospectively validated. Methods: Advanced, chemotherapy-pretreated, NSCLC pts were screened for the following EGFR pathway alterations: EGFR gene mutations (by SSCP and sequencing) and/or increased copy number (by FISH), EGFR protein expression (by IHC), and HER-2, phosphorylated AKT (pAKT), and total AKT protein expression (by IHC). Upon progression, pts were then assigned to treatment with an EGFR TKI (Iressa™ or Tarceva™) according to one of the following groups: A) mutated (regardless of any other parameter); B) non-mutated, amplified (either true gene amplification or high-grade polysomy in > 40% of the tumor cells); C) non-mutated, non-amplified, EGFR positive (IHC score = 1+); D) Adk or BAC histology and no smoking history (non-mutated, non-amplified, EGFR-negative pts or unknown EGFR status). Results: From January 2005, 129 pts were screened for EGFR pathway alterations, while undergoing chemotherapy. Thirteen pts were identified in group A (6 with exon 19 deletions, 6 with exon 21 point mutations, 1 with both); 39 pts in group B (including 7 pts with true gene amplification); 32 pts in group C (including 19 pts with a pAKT IHC score = 1+); 7 pts in group D (including 2 pts with BAC histology). Treatment results in the different subgroups are reported in Table 1 . Conclusions: Based on the data available so far, there seems to be a continuum of response/ disease control rate that progressively declines from group A to group C. Accrual to the study will be continued in all 4 subgroups until computer simulations using a continual reassessment method will allow to confidently exclude a true response rate = 10% in any of the groups.

[Table: see text]

No significant financial relationships to disclose.
Analysis of the prognostic role of plasmatic K-ras mutations in advanced non-small cell lung cancer (NSCLC) patients
Authors: Sirera R. , Camps C. , Berrocal A. , Muñoz-Navarro M. , Garcia-Gomez R. , Viñolas N. , Artal A. , Guillot M. , Taron M. , Rosell R.
Published: March 2020

18009

Background: Qualitative analysis of circulating DNA in blood is a promising non-invasive diagnostic and prognostic tool. Our aim was to study the association between the presence of K-ras mutations at codon 12 and several clinical variables in advanced NSCLC patients. Methods: We examined 451 NSCLC patients in stage IIIB and IV, treated with cisplatin and docetaxel. Blood samples were collected before chemotherapy, and circulating DNA was extracted from the plasma using commercial adsorption columns. K-ras mutational status was determined by a method based in allelic discrimination with RT-PCR. Results: Median age was 61 years [35–82] and 84% were males. 99% had performance status 0–1. 84% were in stage IV and 16% in stage IIIB. The histological subtypes were: 32% squamous cell carcinoma, 50% adenocarcinoma, 14% anaplastic large cell, and 4% undifferentiated. 41% of the patients received second line chemotherapy. 1% achieved complete response (CR), 36% partial response (PR), 35% had stable disease (SD) and 28% progressive disease (PD). Here we present the results of the analysis of K-ras mutations in the plasma of 165 samples. 17 patients presented K-ras mutations (10.3%), being codon 12 TGT in 16 patients and GTT in 1 case. Plasmatic mutations were found either in patients presenting squamous cell carcinoma (n=3) and in patients with adenocarcinoma (14). Patients with K-ras mutations in plasma had a median time to progression (TTP) of 2.3 months (m) [0.5- 4.6] while for wild type K-ras was 4.1 m [3.3–4.8], (p=0.9). Overall Survival (OS) in K-ras mutated patients was 10.1 m [4.1–15.8] and in wild type K-ras was 9.0 m [6.9–11.1], (p=0.6). Conclusions: In advanced NSCLC, there were no significant differences between patients with K-ras mutations and those with wild-type genotype with respect to baseline characteristics, response rates, TTP, or OS. Data from the rest of the cohort will be presented at the meeting.

No significant financial relationships to disclose.
Gene expression levels of ribonucleotide reductase subunit M1 (RRM1), tyrosyl-DNA phosphodiesterase (Tdp1), nuclear factor of activated T-cells (NFAT), and BubR1 mRNA expression in completely resected chemo-naive non-small cell lung cancer (NSCLC) patients
Authors: Chaib I. , Jassem E. , Spkrzypski M. , Rosell R. , Taron M. , Perz-Roca L. , Szymanowska A. , Rzyman W. , Gulida G. , Jassem J.
Published: March 2020

18016

Background: A relationship between gene transcripts and survival in operable NSCLC is now emerging. RRM1 is involved in DNA repair, Tdp1 is implicated in the repair of CPT-induced topoisomerase damage, and NFAT promotes cancer invasion. BubR1 is a key spindle checkpoint gene, and altered BubR1 mRNA levels are associated with lymph node metastasis and chromosome instability. Methods: In order to identify p with a high risk of relapse, we examined the expression of these four genes in frozen resected tumors from 126 resected NSCLC p by real-time quantitative PCR. Gene expression was normalized using β-actin expression as internal reference. Results: Adenocarcinoma (adeno), 33 p; squamous cell carcinoma (SCC), 93 p. Stage: IA, 18 p; IB, 53 p; IIB, 33 p; IIIA, 22 p. Tumor transcript expression: RRM1, 2.10; Tdp1, 1.77; NFAT, 0.56; BubR1, 16.40. Expression of RRM1, Tdp1 and BubR1 was higher in SCC than in adeno (P<0.001). Median time to relapse (TTR) was longer for p with low levels of RRM1 (P=0.11), Tdp1 (P=0.86), NFAT (P=0.29), or BubR1 (P=0.44) (Table). A significant trend towards longer survival was also observed in stage I p with low RRM1 P=0.06). In a multivariate Cox model, tumor size > 4 cm and stage III predicted shorter TTR and survival. Conclusion: Increased mRNA expression of these genes is associated with shorter TTR; this knowledge could be useful for customizing adjuvant chemotherapy.

[Table: see text]

No significant financial relationships to disclose.
Incidence of venous thromboembolic events and effect on survival in patients with lung cancer
Authors: Shah J. , Donegan S. , Wang D. , Robert F.
Published: March 2020

18017

Background: Venous thromboemboli (VTE) is a known complication in patients with cancer, however the true incidence and effect on survival in patients with lung cancer is not clear. Methods: We retrospectively reviewed a cohort of 388 patients with lung cancer from 1997 to 2006 seen at the University of Alabama in Birmingham. Results: Median age was 62 and the male (n=227) to female (n=160) ratio was 1.41:1. Small cell lung cancer (SCLC) was the histology in 50 patients (13%) and non small cell lung cancer (NSCLC) in 331 patients (87%). Among NSCLC, the distribution of various subtypes was: 144 (37%) adenocarcinoma, 93 (24%) squamous cell, 7 (2%) large cells and 93 (24%) non-small cell, not otherwise specified(NOS). Metastatic disease was present in 29% (96/337) of NSCLC and extensive disease in 54% (27/50) of SCLC patients. 73% had a performance status of 0/1 and 29% had weight loss ( > 5% body weight). The overall incidence of VTE was 17 % (n=64); 9 patients prior to the diagnosis and 55 patients (86%) during the course of their disease. The incidence of VTE in SCLC was 10% (n=5) and in NSCLC 19% (n=59). VTE events in patients with non-small cell histologies were: 18% in adenocarcinoma, 25% in NSCLC-NOS, and 8% in squamous cell carcinoma. In patients with SCLC the incidence of VTE in limited stage disease (3/23) was similar to extensive stage disease (2/27). In NSCLC, patients with stage 1–3 disease had an incidence rate of 16% (39/241) compared to 21% (20/96) with metastatic disease. The median survival (MS) in SCLC patients with VTE was 21 months and without DVT was 17 months (P = 0.28). The MS in patients with NSCLC with VTE was 15 months and without VTE was 18 months (P = 0.12). Conclusions: There is a high incidence of VTE in patients with both NSCLC and SCLC with a trend to increased incidence in specific histologic subtypes and increased disease burden. Despite the potential anti-neoplastic benefit of anticoagulants there was a minimal difference in overall survival between cohorts, although this study was not designed to evaluate differences in survival. This data supports trials evaluating the role of prophylactic use of anticoagulants as a means to reduce the morbidity/mortality associated with VTE in this high risk population.

No significant financial relationships to disclose.
Preoperative chemoradiotherapy in non-small cell lung cancer (NSCLC) patients with operable stage IIIB disease. A phase II trial of the Swiss Group for Clinical Cancer Research (SAKK)
Authors: Pless M. , Stupp R. , Kann R. , Zouhair A. , Mayer M. , Thierstein S. , Stahel R. , Betticher D. , Balmer Majno S. , Ris H. B.
Published: March 2020

18021

Background and Methods: Outcome of patients (pts) with locally advanced NSCLC treated with radio- or chemoradiotherapy is poor. This two-stage phase II trial (planned sample size 46) aimed at evaluating feasibility and outcome of a tri-modality concept of neoadjuvant chemotherapy (CT), radiotherapy (RT) followed by definitive surgery in operable, stage IIIB NSCLC pts. Treatment consisted of 3 cycles of cisplatin (100 mg/m2) and docetaxel (85 mg/m2) followed by accelerated, concomitant boost RT (44 Gy/22 fx) and surgery. Primary endpoint is event-free survival at 1 year. Operable pts up to age 75 and a performance status of 0–1 with stage IIIB NSCLC (pleural effusion excluded) were eligible. Results: Forty-five eligible pts (46 accrued) with a median age was 60 years (range 28–70) were treated between September 2001 and May 2006. Tumor location was right-sided in 28 pts and left-sided in 17 pts. Histology was squamous cell 42%, large cell 11%, adeno-13% and undifferentiated carcinoma 33%. N3-disease was present in 29%, T4 stage in 78%. CT (45 pts) and RT (34 pts) were delivered as prescribed in >80% of cycles. The median time from enrollment to surgery was 3.7 months (2.8 - 5.2). The objective response rate after CT was 53% (95% c.i. 38–68%), after additional RT 67% (51–80%). Surgery (pneumonectomy in 17) was performed in 31 pts (69%), with an R0 resection in 24 pts. Median duration of hospitalization was 12 days (8–134). Two pts died in the perioperative phase due to ARDS and a cerebro-vascular event, respectively. Mature results of the primary endpoint and overall survival will be available at the ASCO meeting. Conclusions: Combined multimodality treatment strategy is feasible in a subgroup of patients, with acceptable toxicity. About two thirds of patients responded to the induction therapy, and were able to undergo subsequent surgery.

No significant financial relationships to disclose.
Second-line therapy with irinotecan or gefitinib in docetaxel pretreated patients with non-small cell lung cancer: A new treatment strategy according to clinical predictors for response
Authors: Park S. , Park J. , Cho E. , Shin D.
Published: March 2020

18026

Background: Retrospective analyses of previous trials have shown the clinical advantage of gefitinib in advanced non-small cell lung cancer (NSCLC) patients with certain favorable baseline factors (Asian ethnicity, female, adenocarcinoma, or no smoking history). This prospective phase II study was designed to test the hypothesis that higher response rates might be achieved if patients are selected according to these clinical predictors for response. Methods: Korean NSCLC patients who have failed after docetaxel-based first-line chemotherapy were consecutively accrued. Patients without any of the favorable clinical predictors (i.e., male smoker with non-adenocarcinoma) received irinotecan 100 mg/m2 on days 1, 8 and 15 every 4 weeks (irinotecan arm). Patients who had at least one of the predictors for response received gefitinib 250 mg/d orally from day 1 (gefitinib arm). Primary endpoint was response rate. With a two-stage phase II design, the required number of patients was at least 25 per each arm. Results: Of 68 patients accrued, 25 were treated with irinotecan and 43 with gefitinib. In the gefitinib arm, 22 patients were female, 20 were never-smoker, and 33 had adenocarcinoma. Treatment duration was significantly longer in the gefitinib arm (2.0 months for irinotecan arm v 4.4 months for gefitinib arm; p<0.01). Median number of chemotherapy cycles was 2 (range, 1–4) for irinotecan arm. Fewer drug-related toxicities were observed with gefitinib compared with irinotecan. In the irinotecan and gefitinib arm, 28% and 13% of patients, respectively, discontinued treatment because of toxicity. The objective responses of irinotecan and gefitinib arm were 16% (95% CI, 2–30) and 37% (95% CI, 21–51), respectively (p=0.07). Patients in the gefitinib arm had a longer, although statistically insignificant (p=0.11), progression-free survival (6.5 months; 95% CI, 3.8–9.2) than those in the irinotecan arm (3.2 months; 95% CI, 2.0–4.4). Conclusions: Gefitinib could be a reasonable second-line option in Korean NSCLC patients who had at least one favorable clinical predictor. Updated results, including an exploratory analysis of molecular characterization, will be presented.

No significant financial relationships to disclose.
Clinical significance of pleural lavage cytology in non-small cell lung cancer: A meta-analysis
Authors: Jiao X. , Langenberg P. , Zhan M. , Perencevich E. , Ioffe O. , Yuan Y. , Maruyama R. , Krasna M. J.
Published: March 2020

18031

Background: The clinical significance of pleural lavage cytology (PLC) in non-small-cell lung cancer (NSCLC) remains controversial. This study was performed to estimate the associations of positive PLC with the main clinicopathological characteristics, and its prognostic value. Methods: PLC studies were identified on Medline, supplemented by manual search of bibliographies and proceedings. Authors were contacted for updated information. The quality of the studies was evaluated, and the data were extracted. Pooled odds ratios (ORs) and pooled hazard ratios (HRs) with confidence intervals [95% CIs] were calculated to evaluate the association of positive PLC with clinico-pathological characteristics and survival respectively. Results: Nineteen articles assessing PLC in NSCLC were selected for this study after exclusion of repeated publications or reports with little clinical detail. Positive PLC was diagnosed in 10.2% (516) of a total of 5073 patients. Positive PLC was strongly associated with lymphatic permeation (OR 4.96 [3.29, 7.54]), pleural invasion (OR 4.38 [2.16, 8.89], and vascular involvement (OR 2.94 [1.99, 4.35]). It was also found to be associated with advanced T stage, N stage, and TNM stage. Positive PLC was more frequent in adenocarcinoma than in squamous cell carcinoma (OR 2.32, [1.51, 3.52]). It was relatively more common in moderately- and poorly-differentiated tumors than in well-differentiated tumors (OR 1.89 [0.86, 4.16]). No association was found between positive PLC and fine needle aspiration cytology (OR 1.04 [0.58, 1.81]). Positive PLC was associated with high overall recurrence (OR 2.51 [1.79, 3.53]), as well as high local recurrence (OR 3.85 [1.57, 9.44]) and distant recurrence (2.58 [1.76, 3.76]). In analysis of survival, the overall HR for mortality was 2.43 [1.87, 3.16], suggesting significantly poorer survival for patients with positive PLC. Conclusions: Positive PLC in NSCLC is strongly associated with several existing poor prognosticators including pleural invasion, lymphatic spread, and vascular involvement. It may indicate locally advanced disease with high risk of recurrence and poor survival. We recommend that the PLC test be included in future clinical trials of adjuvant therapy for patients with NSCLC.

No significant financial relationships to disclose.
Safety study of induction chemotherapy and synchronous radiotherapy (RT) and cetuximab in stage III non-small cell lung cancer (NSCLC): SCRATCH (Cohort I)
Authors: Hughes S. R. , Liong J. L. , Miah A. , Ahmad S. , Leslie M. , Ross P. , Harper P. , Prendiville J. , Rankin S. , Landau D.
Published: March 2020

18032

Background: The addition of cetuximab can increase the efficacy of chemotherapy for advanced NSCLC. Concomitant cetuximab and RT is superior to RT alone for locally advanced squamous cell head & neck carcinoma. The SCRATCH study (cohort I) is a phase I study to assess the safety of synchronous cetuximab and radical RT in patients with Stage III NSCLC. Methods: Cohort I will contain 12 patients with inoperable stage III NSCLC. Inclusion criteria are performance status 0–1, adequate organ function, and disease encompassable within a radical RT volume. Exclusion criteria are previous malignancy, thoracic RT or treatment with EGFR targeted therapy. Patients receive platinum-based induction chemotherapy, followed by weekly intravenous cetuximab (initial dose 400mg/m2; maintenance dose 250mg/m2) and concomitant RT (64Gy/32fractions/45days). The primary end-point is toxicity. NCI Common Toxicity Criteria (CTC) V3.0 assessments are performed weekly during radiotherapy, and at regular follow-up visits. Results: Data from the first 9 patients is available. 2 patients stopped receiving cetuximab early due to toxicity. 1 experienced grade 3 fatigue following the initial dose, and the other declined further treatment after developing grade 2 skin toxicity. 2 patients have died, 1 from disease progression and 1 from thromboembolic disease. Both deaths occurred between months 2 and 4 post RT and were not attributed to the cetuximab therapy. Of the 7 living patients, 2 have survived 1 year (measured from the first day of induction chemotherapy). The maximum NCI CTC V3.0 scores are summarised in the table below. Conclusions: The results suggest that the early and late toxicities of synchronous cetuximab and radical RT are acceptable. Data on all 12 patients will be available by June 2007. SCRATCH Study cohorts II-IV follow on and will recruit sequentially. They will assess the safety of adding concomitant cisplatin (±vinorelbine) to cetuximab and radical RT.

[Table: see text]

No significant financial relationships to disclose.
A phase II study of vorinostat (NSC 701852 ) in patients (pts) with relapsed non-small cell lung cancer (NSCLC)
Authors: Traynor A. M. , Dubey S. , Eickhoff J. , Kolesar J. M. , Marcotte S. M. , Hammes L. C. , Hallahan C. M. , Moore C. E. , Zwiebel J. , Schiller J. H.
Published: March 2020

18044

Background: Vorinostat is a small molecule inhibitor of histone deacetylase (HDAC). HDAC inhibitors have shown preclinical activity in lung cancer and are postulated to have an antitumor effect by alteration in acetylation status of histone and non-histone proteins. Methods: Pts with relapsed NSCLC who failed no more than 1 prior cytotoxic therapy were eligible. Treatment: vorinostat, 400 mg po daily in a 21 day cycle. Primary objective: response rate (RR), with goal of at least one responder in first 14 evaluable pts. Secondary objectives: time to progression (TTP), overall survival (OS), safety, and correlative assays. Results: 14 pts enrolled from 12/05- 12/06. Median age 59.5 yrs (range 47–79). 11 females. PS 0:1, 10 pts:4 pts. Thirteen of 14 pts had only 1 prior cytotoxic regimen; 1 pt had only prior erlotinib. Best response to prior treatment: stable disease (SD; 11 pts), progressive disease (PD; 3 pts). Median time since last prior therapy: 2.1 mo (range 0.2–78.5). Vorinostat treatment compliance: 95.8 %. Two pts were not evaluable for response due to not completing Cycle 1 of treatment due to PD. No objective antitumor responses have been seen in the first 12 evaluable pts. Seven pts experienced SD (median 4.2 mo, range 2–10.7). Median TTP: 2.8 mo (range 1–10.7+); median OS 6.5 mo (range 1.4–10.7+); estimated 6 mo OS rate 50% (SE 16%). Grade (Gr) 5 toxicity: CVA (1 pt). Gr 3/4 toxicities: neutropenia (Gr 4–1 pt), lymphopenia (Gr 3–2 pts), fatigue (Gr 3–1 pt), elevated alk phos (Gr 3–1 pt), memory impairment (Gr 3–1 pt), PE/DVT (Gr 3–1 pt; Gr 4–2 pts), dehydration (Gr 3–1 pt). Data from the following correlative studies will be updated: p53 status, gene expression, H3 acetylation, transcription of p21, Nur77, Hsp70, erbB1 and 2, and Akt, cell cycle arrest, and assay of isoprostanes generated by treatment with vorinostat. Conclusions: Vorinostat 400 mg daily is tolerable with more than 80% of patients completing Cycle 1. Vorinostat yields TTP in relapsed NSCLC similar to that of other targeted agents. Although 4 of 14 pts experienced vascular events on treatment, these occurrences are common in this disease setting. At least two additional pts are still to be accrued. Further studies in NSCLC should focus on combining vorinostat with other antitumor agents.

No significant financial relationships to disclose.