bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I study of midostaurin and azacitidine in relapsed and elderly AML.
Authors: Cooper Brenda W. , Kindwall-Keller Tamila L. , Lazarus Hillard M. , Hamadani Mehdi , Tse William W. , Basu Soumit K. , Craig Michael 
Published: March 2020

7058 Background: The Fms-like tyrosine kinase 3 (FLT3) receptor is expressed in 80% of AML and activating mutations are associated with an adverse prognosis. Midostaurin (mdn), an orally available agent, has been shown to inhibit FLT3 receptor signaling and induces cell cycle arrest and apoptosis of leukemic cells expressing both mutant and wild type FLT3 receptors. Preliminary data has shown modest single agent activity as well as safety and tolerablility of mdn in combination with standard induction chemotherapy. Methods: We conducted a phase I study of azacitidine (75 mg/m2 iv X 7days) with escalating doses of oral mdn (25 mg bid, 50 mg bid, and 75 mg bid) days 8-21 of a 28 day cycle in untreated elderly and relapsed AML. The protocol was IRB approved at participating institutions and all patients gave written informed consent. Dose limiting toxicities (DLTs) were defined as > grade 3 non-heme toxicity during cycle 1 excluding grade 3 hepatotoxicity < 7 days, grade 3/4 stomatitis or diarrhea that resolved by day 28, infections, and electrolyte abnormalities of any grade. Pharmacokinetics (pK) were obtained on day 8,15, and 21 before mdn dosing. Results: 17 pts (11 females and 6 males) ages 57-83 ( median 73) were enrolled of whom 5 patients had prior intensive treatment for AML. All pts were FLT3 negative; 5 had normal cytogenetics and 12 had high risk cytogenetics. ECOG PS: 0 (4pts), 1 (11pts), 2 (2pts). No DLT were observed during escalation or in the expansion cohort of 75 mg bid. Responses were evaluable in 14/17 pts and included 2 CR, 1 PR, and 2 HI (clearing of peripheral blasts, platelet tx independence). Median survival from enrollment was 3.5 months (range 1-12 months). 4 pts remain on treatment (2- 9+ cycles). 3 pts died within 60 days (2 PD, 1 treatment-related). Non-infectious, non hematologic SAE’s are listed on the table below. Plasma concentrations of mdn accumulated in the first week of treatment and declined thereafter despite continued dosing. Conclusions: The combination of azacitidine and midostaurin in safe and tolerable in elderly AML and should be further studied in FLT3 positive leukemia. Clinical trial information: NCT01093573. [Table: see text]
Safety and durability of ponatinib in patients with Philadelphia chromosome-positive (Ph+) leukemia: Long-term follow-up of an ongoing phase I study.
Authors: Mauro Michael J. , Cortes Jorge E. , Kantarjian Hagop M. , Shah Neil P. , Bixby Dale , Flinn Ian , O'Hare Thomas , Hu Simin , Rivera Victor M. , Clackson Tim , Turner Christopher D. , Haluska Frank G. , Druker Brian J. , Deininger Michael W. N. , Talpaz Moshe 
Published: March 2020

7063 Background: Ponatinib is a potent oral pan–BCR-ABL tyrosine kinase inhibitor (TKI) that is active against native and mutated forms of BCR-ABL. The safety and anti-leukemic activity of ponatinib in patients (pts) with chronic myeloid leukemia (CML) or Ph+ acute lymphoblastic leukemia (ALL) were evaluated in a phase I clinical trial. Methods: Pts (N=81) with resistant/refractory hematologic malignancies were enrolled in this ongoing, open-label, dose escalation, phase I study. Ponatinib was dosed once daily (2–60 mg). 65 pts had Ph+ leukemia and are included in the present analysis (data as of 9 Nov 2012). Median follow-up was 25 (0.5–44) mos. Results: The median age of pts was 55 yrs; median time since diagnosis was 6.5 yrs. Pts were heavily pretreated (94% had received ≥2 prior TKIs, 62% ≥3). 65% had baseline BCR-ABL mutations. 46% (67% chronic phase [CP] CML) of pts remained on study. Progression and adverse events (AEs) were the most common reasons for discontinuation (17% each). The most common treatment-related AEs were rash (42%), thrombocytopenia (34%), arthralgia (20%), and increased lipase (20%). Significant anti-leukemic activity was observed (Table). Responses (major cytogenetic response [MCyR] for CP-CML or major hematologic response [MaHR] for accelerated phase [AP] CML, blast phase [BP] CML, or Ph+ ALL) were observed against the following mutations detected in >1 pt at baseline: 14/19 T315I, 4/7 F317L, 2/4 G250E, 2/2 M244V, 2/2 M35IT, and 1/2 F359V. Among CP-CML pts, 73% with complete cytogenetic response (CCyR) and 63% with major molecular response (MMR) are estimated to maintain response at 2 yrs (Kaplan-Meier). Of 28 CP-CML pts with CCyR, 25 remained on study (19 with continuous CCyR); of 22 pts with MMR, 21 remained on study (15 with continuous MMR). Updated data will be presented. Conclusions: Significant and durable responses were observed in heavily pretreated CP-CML pts, regardless of mutation status, and ponatinib was generally well tolerated. Clinical trial information: NCT00660920. [Table: see text]
Results of omacetaxine plus low-dose cytarabine (LD-araC) in older patients with acute myeloid leukemia (AML).
Authors: Kadia Tapan M. , Daver Naval Guastad , Ravandi Farhad , Jabbour Elias , Pemmaraju Naveen , Pierce Sherry , Cortes Jorge E. , Kantarjian Hagop M. 
Published: March 2020

7068 Background: Older patients with AML have poor tolerance to intensive chemotherapy and poor prognosis. Omacetaxine is active in AML and is part of standard combination chemotherapy in China under the name of homoharringtonine. Methods: The aim of the study was to evaluate the efficacy of low intensity therapy with omacetaxine and LD-ara C in newly diagnosed older patients (>/= 60 years) with AML or myelodysplastic syndrome (MDS). Older patients with AML not fit or who refuse intensive chemotherapy were eligible. Normal organ functions and performance status </= 2 were required. Other eligibility criteria were standard. Induction therapy consisted of omacetaxine 1.25 mg/m2 subcutaneously twice daily for 3 days and ara-C 20 mg subcutaneously twice daily for 7 days. Maintenance therapy was with the same induction schedule, repeated every 4-6 weeks for up to 2 years. Dose adjustments for prolonged myelosupression or severe non-hematologic toxicities were made by reducing the number of days of omacetaxine (-1 day by level) and cytarabine (-1 to 2 days by level). Results: 30 patients have been treated, with a median age of 71 years (range 64-81); 60% were age 70 years or older. AML post MDS in 20%; chromosome 5 and 7 abnormalities were present in 23%. Overall, 9 patients achieved CR (30%), 5 had CRp (17%) and 1 had PR (3%), for an overall response rate of 50%. Induction mortality was noted in 4 (Day 5, 27, 27, and 70 from start of therapy; 13%); resistant disease in 8 (27%); too early in 4 (13%). With the median follow-up time of 10 months the median survival is 9.3 months and the estimated 1-year survival rate 42%. No serious drug related adverse effects were observed with the combination. Conclusions: Low-intensity therapy with omacetaxine + LD-ara C shows promising activity and is safe in older patients with AML not fit for intensive chemotherapy. Clinical trial information: NCT01272245.
Comparison of two major intergroup induction intensive regimens in Hispanic adolescent and young adults (AYA) with acute lymphocytic leukemia (ALL): The importance of a complete molecular response.
Authors: Vigil Carlos Enrique , Escalante Lorena , Lopez Lourdes , Villena Marco , Quintana Shirley , Samanez Cesar Augusto , Casanova Luis Augusto 
Published: March 2020

7072 Background: Novel intensive chemotherapy regimens impacted in the prognosis of adolescent and young adult pts with ALL. The application of pediatric inspired therapies demonstrated complete response reported to be > 80%, and long-term survival rates range from 30% to 45%. In the past, ALL treatments had been designed on the presence of risk factors as elevated WBC, time to complete remission or immunophenotype. Recently, MRD monitoring had risen as a risk predictor. Hypothesis: Complete response(CR) associated with a CMR has impact in disease-free survival. Methods: Between March> 2010 and November 2012, 101 adolescent and young adult pts were diagnosed and treated for (Ph)–negative ALL with the C10403 intergroup protocol (N=47) and the 2008 Spanish PETHEMA regimen (N=54). The residual disease status was assessed after induction by multiparametric flow cytometry (MRD <0.1%). Results: The median age of the pts was 17.56 years (range, 14-24); with 69 pts (68%) ≤ 18 year-old. 27 (26.7%) pts were WBC ≥ 50x109/L, 63 pts (62%) B immunophenotype, cytogenetics was unknown in 69 pts. After the induction, the CR was achieved in 81% vs 79.6% pts ( Int C10403 vs Pethema, respectively ). The induction mortality rate was 0% vs 7%. Slow responders to induction chemotherapy were 23.81% and 28.8% respectively (p=0.591). A CMR (CR+MRD ≤0.1%) was seen on 70.21% vs 63.27%. The kaplan-meier 2-year disease free-survival rate calculated for CMR patients on C10403 was 35% vs 17% for the Pethema, which was statistically significant (p< 0.04). A multivariate analysis of pts characteristics in CMR could not identified risk factors for disease prognosis. Conclusions: Two different regimens C10403 vs Pethema, could not demonstrate a statistic difference in morphological CR. Lately,the addition of minimal residual disease ≤0.1% (MRD) in the analysis, demonstrated a plausible monitoring variable of response. We suggest that a CMR (CR +MRD at induction) could be a new standard variable to assess responses regardless of previous risk categories. Further validation may be mandatory.
Use of flow cytometry in acute promyelocytic leukemia.
Authors: Hadid Tarik H. , Sahovic Entezam A. , Lister John 
Published: March 2020

7075 Background: Acute promyelocytic leukemia (APL) is a highly curable disease, with the majority of failures related to hemorrhagic complications. Hence, rapid diagnosis and early initiation of therapy can drastically prevent these complications and reduce mortality. The current diagnostic strategy utilizing fluorescent in situ hybridization (FISH) is often time-consuming and not readily available in some institutions. This is a review of our institutional experience with the use flow cytometry for diagnosis of APL. Methods: All cases with t(15;17) by FISH and karyotype between 2006 and 2012 were identified. A second group of consecutive cases of non-M3 acute myeloid leukemia (AML) and negative FISH and karyotype for t(15;17) was used for comparison. A total of 21 APL and 42 non-M3 AML cases were analyzed. Results: Both groups were comparable in regard to age, gender, white blood cell count, hemoglobin, blast count and lactate dehydrogenase level. The APL group had significantly higher prevalence of thrombocytopenia, disseminated intravascular coagulation and clinical bleeding at time of admission. Expression of CD11c was lacking in 92.3% (12/13) of APL and 14.6% (6/41) of non-M3 AML cases (p<0.0001). CD34 expression was lacking in 68.4% (13/19) of APL and 42.9% (18/42) of non-M3 AML cases (p=0.06). HLA-DR expression was lacking in 88.9% (16/18) of APL and 9.5% (4/42) of non-M3 AML cases (p<0.0001). Given that APL prevalence is 5% among all AML cases, lack of expression of CD11c, CD34 and HLA-DR have negative predictive values (NPVs) of 99.5%, 97.1% and 9933%, respectively. Among various immunophenotypic profiles, lack of expression of CD11c had the highest NPV (99.5%, p<0.0001) and simultaneous lack of expression of CD11c and HLA-DR had the highest specificity (95.1%, p<0.0001). Conclusions: Expression of CD11c reliably excludes the diagnosis of APL in the majority of AML cases. Flow cytometry has the potential of replacing FISH as the initial test to prompt initiating therapy in APL patients.
Plasma trough imatinib levels and molecular response in patients of chronic myeloid leukemia (CML): A single institution study from India.
Authors: Malhotra Hemant , Sharma Pratibha , Bhargava Shipra , Rathode Om Singh , Malhotra Bharti , Gota Vikram 
Published: March 2020

7079 Background: One of the reasons proposed for suboptimal responses in Chronic Myeloid Leukemia (CML) patients receiving standard-dose Imatinib has been low blood levels of the drug. Our study aimed to determine the correlation between mean trough Imatinib plasma levels and molecular response in CML chronic phase patients at our centre. We also attempted to compare imatinib plasma levels in patients receiving Gleevec (Novartis) versus patients who were on the generic version of the drug. Methods: One hundred and thirty one (131) CML Chronic phase patients were included in this study. All patients had received 400 mg of imatinib for more than 2 year. Plasma Imatinib trough levels were estimated by high-performance liquid chromatography (HPLC). In order to estimate a threshold for plasma imatinib level that correlates with a favorable response, a receiver operating characteristic (ROC) curve was constructed. Patients were divided into two groups: those with Major Molecular Response (MMR) [bcr/abl : abl ratio <1% as assessed by RQ-PCR] or better (Responders) and those without MMR (bcr/abl : abl ratio =/> 1% as assessed by RQ-PCR) [Non Responders]. Imatinib plasma levels were also compared in patients who were on Gleevec versus those who were on the generic version of the drug. Results: The mean trough imatinib plasma level in the responders was significantly higher (2.10±1.18µg/ml) than in the non responders (1.31±0.72µg/ml) with p value of 0.001. The area under ROC curve was 0.733, with best sensitivity (51.85%) and specificity (89.42%) at a plasma threshold of 0.988 µg/ml. There was no significant difference between the mean trough plasma imatinib levels of the patients who were on Gleevec as compared to those who were on generic Imatinib (p value > 0.05). Conclusions: Plasma Imatinib trough levels were statistically similar in the Gleevec and generic Imatinib groups. These levels showed a statistically significant correlation with molecular response. Trough plasma imatinib levels may be a marker for suboptimal response to Imatinib and may identify patients in whom increase of drug dose or change to second generation tyrosine kinase inhibitors may be indicated.
Clinical features and outcome of B-cell acute lymphoblastic leukemia in patients older than 9 years: A single center experience of 241 cases from AIIMS, New Delhi, India.
Authors: Sharma Atul , Cyriac Sunu Lazar , Sahai Siddharth Kumar , Bakhshi Sameer , Gupta Ritu , Kumar Lalit , Kumar Rajive , Iqbal Sobuhi , Raina Vinod 
Published: March 2020

7082 Background: Data on B cell Acute Lymphoblastic leukemia (ALL) in the poor prognostic age group of > 9 years from India is minimal. Methods: This is an analysis of patients of above 9 years that were diagnosed and treated from January 2000 to December 2010 at a single institute . All patients who completed at least 4 weeks of induction therapy were analysed for various outcomes. Results: Of the 241 newly registered patients, the median age was 19 years (Range 10-78 years) with an M:F ratio of 1.9:1. Out of this 47%, 25% & 28% patients belonged to 10-18, 19-30 & > 31 years age group respectively. Twenty seven (11.6%) and 5(2%) had CSF and testicular involvement respectively. Thirty nine per cent had a total leucocyte count (TLC) of above 30x109/L. Philadelphia chromosome (Ph) positivity was seen in 27% and was equally distributed among the different age groups. Patients available for outcome analysis were 213(88.4%). Complete remission rate (CRR) was 66.6% and induction mortality was 26.3%.At a median follow up of 65.8 months 5 year leukemia free survival was 30.5%. Seventy eight (55%) patients relapsed (median relapse time of 13.5 months, range 1.7 to 53.4 months) , 55% during maintenance phase. The 5 year overall survival (OS) was 30.3% with a median OS of 15.8 months. The OS was similar in 10-18 and 19-30 age groups (5 year OS 35% vs. 27.5%, p=0.641) but it was significantly lower in >31 years (5year OS 21%, p=0.008). Apart from this, extramedullary disease, not attaining a CR in 1st induction, albumin at presentation below 3.5gm% and TLC of >100x109/L were significant poor prognostic markers for survival. Conclusions: This is a large study of B-ALL outcomes in patients above 9 years from a single center in India. Patients above 30 years had a worse prognosis while the prognosis of 10-18 and 19-30 years age group were similar. Induction mortality was higher mainly because of advanced disease and poor performance status at presentation.
mTOR inhibition in MDR acute myeloid leukemia.
Authors: Karmakar Aditi , Gangopadhyay Sudeshna , Bhattacharyya Gouri Shankar , Mukhopadhyay Ashis 
Published: March 2020

7085 Background: Signaling through the PI3K/PTEN/AKT/mTOR pathway is aberrantly activated in several human cancers, including Acute Myeloid Leukemia (AML) patients where it contributes to leukemic cell proliferation, survival and drug resistance. In leukemia patients treated with drugs such as anthracyclines, vinca alkaloids, chemo-resistance one of the major problems contributing to therapeutic failure, where all this drugs are modulated in their intracellular retention by a 170 kDa Phospho-glycoprotein, an mdr-1 gene product. The role of mTOR in various processes such as proliferation, growth, has been comprehensively described in many reviews, following its inhibition by rapamycin. Thus inhibition of mtor signaling in AML blasts could account for enhancing their sensitivity to cytotoxic agents. This study is to embrace the effect of Rapamycin, an allosteric mTOR inhibitor on MDR AML patients. Methods: We selected samples of 25 MDR AML patients isolated from bone marrow or peripheral blood and cultured in vitro. The effects of Rapamycin on fresh AML samples were analyzed by treating the cells with intermediate drug concentrations (100 nM) for 24 h, 48 h, 72 h, 96 h respectively followed by cytotoxicity assay (MTT assay). The effects of the drug on proliferation of cells were analyzed also by cell counting. Results: A marked reduction in cell viability at 96 h was detected in 25 samples treated with rapamycin. Out of the 25 analyzed samples, 16 were sensitive to the drug where it was observed that the leukemic cell count came down to almost 2% whereas 9 samples displayed various degree of resistance to the drug. Overall, these findings demonstrated that rapamycin has a cytotoxic activity against primary cells from AML patients with up-regulated mTOR signaling. Conclusions: We have evaluated the in vitro effects of Rapamycin on AML patient samples where reduced cell viability primary cells from AML patients were observed. However, further studies of the additional effects of rapamycin will be of the supreme importance, as they could help in designing more efficient curative protocols, for the treatment of acute leukemia patients.
Evolution of bosutinib (BOS) toxicity in patients (pts) with Ph+ leukemia after resistance/intolerance to prior therapy.
Authors: Gambacorti-Passerini Carlo , Brummendorf Tim H. , Cortes Jorge E. , Lipton Jeffrey H. , Kim Dong-Wook , Leip Eric , Turnbull Kathleen Wyant , Kantarjian Hagop M. , Khoury Hanna Jean 
Published: March 2020

7099 Background: BOS is an oral dual Src/Abl tyrosine kinase inhibitor (TKI) approved for treatment of Ph+ CML following resistance/intolerance to prior therapy. Prior reports from this phase I/II trial indicated the BOS safety profile was primarily characterized by myelosuppression, gastrointestinal events, and rash. The current analysis compares the incidence of toxicity in Year 1 (Y1) for pts on treatment ≤1 y and within Y1 and Year 2 (Y2) for pts on treatment for >1 y. Methods: BOS 500 mg/d was evaluated in 3 cohorts: chronic phase (CP) CML after imatinib only (CP 2L cohort; n = 286); CP CML after imatinib + dasatinib and/or nilotinib (CP 3L cohort; n = 119); and accelerated/blast phase CML or ALL after prior TKI therapy (ADV cohort; n = 164). Results: The most common treatment-emergent adverse events (TEAEs) in each cohort occurred more frequently within Y1 than Y2 (Table). The incidence for grade 3/4 events followed a similar pattern. AEs were the most common reason for BOS discontinuation in Y1 (CP 2L, 53%; CP 3L, 32%; ADV, 41%). Of the pts whose primary reason for discontinuing BOS was an AE during the first 2 y, most did so during Y1 (CP 2L, n = 51/60 [85%]; CP 3L, n = 22/24 [92%]; ADV, n = 24/25 [96%]); the most common reasons during Y1 were thrombocytopenia (12%; 9%; 4%), increased ALT (6%; 4%; 2%), neutropenia (3%; 6%; 0%), diarrhea (4%; 3%; 0%), and vomiting (3%; 4%; 1%). Serious AEs were more common among pts who discontinued BOS ≤1 y versus on treatment >1 y in the CP 3L and ADV cohorts, but similar in the CP 2L cohort (Table). Conclusions: Discontinuation due to AEs was observed primarily in Y1. For pts on BOS for >1 y, the incidence of common TEAEs decreased substantially after Y1, suggesting BOS tolerability improves after long-term exposure. Clinical trial information: NCT00261846. [Table: see text]
Outcomes of first-line treatment for chronic lymphocytic leukemia (CLL) with 17p deletion (del17p).
Authors: Strati Paolo , Keating Michael J. , O'Brien Susan Mary , Ferrajoli Alessandra , Burger Jan Andreas , Faderl Stefan , Jain Nitin , Wierda William G. 
Published: March 2020

7102 Background: Patients (pts) with relapsed CLL bearing del17p are very high-risk for poor clinical outcomes. We summarize outcomes for first-line treatment of del17p CLL. Methods: We identified pts with CLL and del17p by FISH who received first-line treatment at MDACC between 1/04 and 12/12. Log-rank test and Cox regression were used for univariable and multivariable analyses. Results: Baseline characteristics are shown (Table). Median time from diagnosis to first treatment (TTFT) was 15 (11-19) mos; no association between % del17p positive cells at diagnosis and TTFT was noted (p=.45). With first-line therapy (Table), 19 pts (30%) achieved complete remission (CR), 2 (3%) nodular partial remission (nPR), 18 (30%) PR, and 24 (37%) were non-responders. Fourteen CR pts (78%) were minimal residual disease negative by flow cytometry. The median time-to-treatment failure (TTF) was 14 (10-18) mos (43 events); the median follow-up was 33 (1-89) mos. Univariable analyses showed age >65 yrs (p=.04), complex karyotype (p=.02), lack of response to therapy (p<.001) and >50% cells positive for del17p by FISH (p=0.009) associated with shorter TTF. The multivariable model showed karyotype (p=.005) and quality of response (p<.001) independently associated with TTF. Median Overall Survival (OS) was 63 (43-83) mos (48 deaths). Fifteen pts (23%) developed Richter Syndrome (RS) after a median of 12 (1-27) mos; 8 deaths (29%) were related to RS. Univariable analysis showed that only lack of response was associated with a shorter OS (p=.001). Conclusions: Del17p CLL is high-risk for first-line therapy; better response to therapy was observed in young patients with low % del17p positive cells by FISH who received FCR. New strategies and agents must aim at both improving response and maintaining remission, particularly in pts with complex karyotype. [Table: see text]