bluuebunny/crossref_metadata_2025_split huggingface dataset:
Five-year follow-up results of imatinib 400 mg in late chronic phase chronic myeloid leukemia (CML) patients
Authors: Iacobucci I. , Palandri F. , Amabile M. , Poerio A. , Soverini S. , Castagnetti F. , Testoni N. , Rosti G. , Baccarani M. , Martinelli G. , Palandri F. 
Published: March 2020

7041 Background: Imatinib (IM) is the drug of choice for the treatment of Ph+ CML, where a complete cytogenetic response (CCgR) is achieved in more than 80% of early chronic phase (ECP) patients, with a 6-year survival of 89%. Methods: We monitored the hematologic, cytogenetic and molecular response to imatinib in a cohort of 295 patients with Ph+ CML in late chronic phase (LCP) who were enrolled in a national prospective study of the GIMEMA CML Working Party, with focus on the rate of major molecular response and on progression-free survival and overall survival of complete cytogenetic responders. Patients were monitored for cytogenetic and molecular response every 6 months. Cytogenetics was performed on bone marrow cells with conventional methods. Molecular response was assessed on peripheral blood samples by quantitative PCR (RQ-PCR) using TaqMan methodology and expressing the results as a ratio of BCR-ABL to ABL x100. The duration of chronic phase prior to IM treatment ranged from 1 to 202 months (median 38). Treatment was IM 400 mg daily through all the study period, with a few dose increase to 600 or 800 mg. Results: 158 patients (54%) achieved a CCgR in 3 to 62 months (median 6) after the first IM dose and 124 of them (78%) are still in continuous CCgR after 5 years whereas 34 patients lost the CCgR, 23 of them within 24 months after the CCgR achievement. For the 158 patients the 5-year survival free from progression to accelerated or blastic phase is 95% and overall survival is 91%. 114 patients were evaluable for molecular response and 68% of them were in major molecular response with a BCR-ABL/ABL ratio lower than 0.05. Conclusions: We showed that for the complete cytogenetic responders progression-free and overall survival are likely to be as good as for ECP patients, suggesting that the quality of the cytogenetic response is prognostically more important than the chronic phase duration before IM start. Supported by European LeukemiaNet, COFIN 2003, AIL, AIRC. No significant financial relationships to disclose.
A phase I study of INNO-406, a dual inhibitor of Abl and Lyn kinases, in adult patients with Philadelphia chromosome positive (Ph+) chronic myelogenous leukemia (CML) or acute lymphocytic leukemia (ALL) relapsed, refractory, or intolerant of imatinib
Authors: Craig A. R. , Kantarjian H. M. , Cortes J. E. , Jones D. , Hochhaus A. , O'Brien S. , Rios M. , Zander C. , Gleich L. , Carroll E. P. , Ottmann O. G. 
Published: March 2020

7046 Background: INNO-406 is an orally available, dual Abl/Lyn kinase inhibitor that is up to 55-times more potent than imatinib in Bcr-Abl cell lines. Numerous Bcr-Abl mutant proteins (not T315I) are sensitive to INNO-406 in vitro. INNO-406 demonstrates specific Src kinase activity against Lyn kinase. Methods: In this phase I study, patients with imatinib-resistant or intolerant Philadelphia (Ph+) chromosome- positive leukemias were eligible for treatment with INNO-406 once a day, orally. Results: 14 pts [median age: 58 yrs (range 18–74); 7 male, 7 female; median CML duration: 53 mo. (range 14–266); and median time on imatinib 45 months (range 12–129); chronic phase CML (8 pts), accelerated phase CML (2 pts), blast phase CML (1 pt), Ph+ ALL (3 pts); previous treatment with nilotinib (5 pts), dasatinib (6 pts)] have been enrolled in the following dose cohorts (mg/day): 30 (3 pts), 60 (3), 120 (6) and 240 mg (2), and have been on treatment between 7 and 123 days. 3 pts remain on study; 10 pts discontinued with disease progression [data unmonitored]. 6 patients who have completed >1 month of treatment, 3 have evidence of clinical response. Patient 5, a chronic phase CML treated with imatinib for 69 mo. before developing resistant disease with an Y253H mutation, had a minimal cytogenetic response after 1 month of INNO-406 therapy. Patient 4, an accelerated phase CML treated with imatinib and nilotinib for 16 and 6 mo., respectively, before becoming intolerant to nilotinib due to thrombocytopenia, has maintained a complete hematologic response following 4.5 months of INNO-406 therapy at a dose of 120 mg/day. Patient 1, a chronic phase CML treated with imatinib for 51 mo. before developing resistant disease without a mutation, has maintained stable white cell counts after 4 months of therapy at a dose of 30–60 mg/day, with a 55-fold reduction in Bcr-Abl transcript levels after 1 month of INNO-406 therapy. Conclusions: INNO-406 is well tolerated in patients at a dose of 240 mg/day, with encouraging evidence of clinical activity in imatinib-resistant and nilotinib-intolerant patients. In the absence of dose limiting toxicity, dose escalation continues. No significant financial relationships to disclose.
Acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) following a diagnosis of breast cancer
Authors: Padmanabhan A. , Block A. , Sait S. , Ford L. A. , O'Connor T. L. , Moysich K. B. , Baer M. R. 
Published: March 2020

7051 Background: Increasing use of chemotherapy and radiation therapy in breast cancer patients in the adjuvant setting heightens concern about therapy-related AML and MDS. Little is known about the characteristics of these disorders following breast cancer. Methods: Roswell Park Cancer Institute (RPCI) patients with diagnoses of MDS or AML by French-American-British Group or World Health Organization criteria following breast cancer were retrospectively reviewed. Results: 34 women were identified between 1983 and 2006. 10 (29%) were also diagnosed with additional malignancies, including non-Hodgkin lymphoma (NHL), bladder, colon, lung, uterine and thyroid cancers, Ewing sarcoma and angiosarcoma. 23 of 31 patients (74%) with family histories documented had first-degree relatives with cancers, including breast, lung, colon, stomach, pancreas, prostate, renal, melanoma, esophagus, thyroid, Hodgkin lymphoma and leukemia, compared to a 45% prevalence of first-degree relatives with cancer among 1982 control RPCI breast cancer patients (p= 0.001). Median age at breast cancer diagnosis was 58 (range, 37–85) years. Among the 29 patients with known treatment, 25 (86%) had received radiation therapy, 13 (45%) had received chemotherapy, including alkylating agents in all 13 (45%) and topoisomerase II inhibitors in 8(28%), while 4 (14%) had received no adjuvant therapy. Median age at AML/MDS diagnosis was 70 (range, 46–90) years. 26 patients had AML and 8 MDS, of whom 4 progressed to AML. Karyotypes were complex in 10 (29%), involved 11q23 rearrangements in 6 (18%), were favorable, normal and unknown in 5 each (45%), and had miscellaneous single structural abnormalities in 3 (9%); they did not strictly correlate with treatment received. Median survival (months) was 1 for complex karyotype, 6 for 11q23 translocation and 40 for favorable karyotype patients. Conclusions: The incidence of other cancers and of cancers in family members was unexpectedly high in breast cancer patients with AML and MDS, in the absence of known genetic syndromes, suggesting genetic polymorphisms predisposing to multiple cancers. Cytogenetic abnormalities included complex, 11q23 and favorable karyotypes, and survival reflected karyotypes. No significant financial relationships to disclose.
Glutathione S-transferase T1, M1 genetic polymorphisms in cases of acute leukemia
Authors: Moawia S. , Elbordiny M. , Saad A. 
Published: March 2020

7053 Background: Glutathione S-transferases (GSTs) are enzymes that detoxify potentially mutagenic and carcinogenic xenobiotics. The genes encoding isoenzymes M1 and T1 are polymorphic in humans and the phenotypic absence of enzyme activity is caused by a homozygous inherited deletion of the gene. The null genotype has been associated with incidence of several types of solid tumors. In addition, GSTM1 and GSTT1 polymorphisms have been considered as risk factors for developing acute leukemia in a number of studies; however the overall results of these previous reports are inconsistent and even controversial. Methods: The present study was undertaken to determine the frequencies of allelic variants in the GST genes in Egyptians and to explore the possibleinfluence of GSTT1, M1 genetic polymorphisms on the risk of acuteleukemia (myeloid and lymphoid). Results: The prevalence of the GSTM1 and GSTT1 homozygous deletions in 53 Egyptian patients with leukemia (21 ALL and 32 AML) and 87 racially,geographically, age and sex matched healthy control individuals was determined using a multiplex polymerase chain reaction (PCR)-based method. Thegenotype frequencies in the leukemia patients and normal controls were compared using Fisher's exact test. A significantly increased incidence of the GSTT1 null genotype was found in the group of patients compared to the controls (34% versus 15% P = 0.03, OR = 2.98, 95% CI 1.6–7.6). GSTM1 null genotype frequencies in cases were slightly but non-significantly higher than controls (68 % versus 49 %, respectively, P=0.07). Conclusions: In conclusion, this study has shown an increased risk of acute leukemia in adult Egyptian patients associated with the GSTT1 null genotype, as well as the combined GSTM1/T1 null genotype, particularly in AML cases. Study will be further extended to examine the relation between the GSTT1 and GSTM1 null genotypes and the patient's response to chemotherapy. No significant financial relationships to disclose.
Amonafide and ara-C treatment for secondary acute myeloid leukemia (sAML)
Authors: Erba H. P. , Rizzieri D. A. , O'Donnell M. R. , Lundberg A. S. , Ajami A. M. , Rampersad A. D. , Capizzi R. L. 
Published: March 2020

7065 Background: sAML portends a poor prognosis due to disease (unfavorable cytogenetics and multidrug resistance (MDR) phenotype) and patient (pt) characteristics (elderly w/comorbid illnesses). Amonafide, a topoisomerase II inhibitor, is not a substrate for the MDR efflux pump, P-glycoprotein (see Chau et al, ASCO 2007). Phase 1 trials of amonafide alone or together with ara-C reported a 50% CR rate (10/20) in pts with sAML (Allen et al, ASCO 2006). The dose-limiting toxicities of amonafide were manageable. Methods: In a Phase II trial pts with sAML (prior MDS or leukemogenic therapy, i.e., tAML) received amonafide 600 mg/m2/day on days 1–5 and CIV ara- C 200 mg/m2/day on days 1–7. A 2nd course could be given if day 14 marrow showed persistent leukemia. CR pts received either stem cell transplant or intermediate/high dose ara-C depending on age. An independent Data Safety Monitoring Board and central morphology review participated in the study. Primary endpoint was CR rate. Results: Enrollment has been completed. 44 % of 80 pts achieved CR. Details are available for the 1st 40 pts: median age 63 yrs (range 26 –87); prior MDS, 57%; tAML, 43%; unfavorable cytogenetics, 40%. 16/40 (40%) achieved CR (15 CR+1CRp). Subgroup CR analysis: MDS→AML without and with prior therapy for MDS (mostly azacytidine), 64% & 33%; tAML, 29%; intermediate and unfavorable cytogenetics, 58% and 18%; <60yrs, 42%; ≥60yrs, 39%. With a median follow up of 39 weeks, the median duration of CR is 28 weeks (range 20+ to 40+ weeks), with 8 of 16 patients in continuous CR. Median overall survival for CR patients has not been reached (range 1–47+ weeks). Death in first 28 days from consequences of hypoplasia was 17.5%. Grade 3, 4 non-heme adverse events occurring in > 10% pts were hypotension 23%, pneumonia 18%, dyspnea 13%, and diarrhea 13%. Data on all patients will be updated. Conclusions: Amonafide and ara-C is well tolerated in patients with poor prognosis sAML. A 64% CR was achieved in pts with untreated MDS→AML. Lower CR occurred with prior therapy for MDS, tAML and unfavorable cytogenetics. Age ≥60 yrs did not affect CR. Amonafide and ara-C may be a promising alternative for patients with sAML, especially those with over-expression of P-glycoprotein. No significant financial relationships to disclose.
Phase II dosing study of cytarabine chemotherapy in combination with cenersen (EL625) and idarubicin in refractory and relapsed acute myelogenous leukemia (AML)
Authors: Alvarado Y. , Kantarjian H. , Freireich E. J. , Garcia-Manero G. , Ferrajoli A. , Koller C. , Estrov Z. , Kornblau S. , Laddie N. , Smith L. , Cortes J. 
Published: March 2020

7070 Background: Cenersen is an antisense oligonucleotide that blocks production of p53. It sensitizes acute myeloid leukemia (AML) stem cells in vitro to DNA damage. Methods: Thirty-seven patients (13 refractory, 24 relapsed) with AML have been enrolled in the ongoing trial. All patients received cenersen (0.1 mg/kg/hr continuous intravenous infusion over 4 days [d]) plus Idarubicin (12mg/m2/dx3). Cytarabine was administered as follows: group (1) no cytarabine; (2) 100mg/m2/dx7; (3) 1g/m2/dx4 (3d > 60y). Chemotherapy started day 2. Results: Eighteen patients were treated per protocol and 19 were inevaluable to include 16 who received prohibited substances that block the action of cenersen (acetaminophen and/or high dose antioxidants). Six (33%) of those treated per protocol achieved CR compared to none of the 16 who received prohibited substances (p=0.02). This rate compares favorably to a literature report of a similar patient population (14%; Estey 1996). There were 2 patients who achieved a CRp, one of whom received acetaminophen on day 7. No significant differences in response occurred between the three treatment arms. The remission duration for 7 of the 8 responding patients was longer than the prior remission duration for the same patients. Several adverse events (AEs) (infection, bleeding, mucositis and hair loss) were significantly (p<0.001) less common for patients in this trial compared to the AE frequency described in the package insert for Idarubicin for its use in combination with standard dose Cytarabine. No adverse events attributable to cenersen were identified. Conclusions: We conclude that cenersen in combination with chemotherapy may improve the response rate compared to that expected with chemotherapy alone. No significant financial relationships to disclose.
Phase I study of frequent low-dose administration of decitabine, alone or in combination with hyperCVAD, in relapsed or refractory acute lymphocytic leukemia (ALL)
Authors: Yang H. , Thomas D. A. , Rytting M. E. , Zweidler-McKay P. A. , Brown D. L. , Kantarjian H. , Garcia-Manero G. 
Published: March 2020

7072 Background: Aberrant DNA methylation is frequent in ALL. Decitabine, a hypomethylating agent, is a potent inducer of apoptosis in lymphoid leukemia cell lines. In vivo, treatment with decitabine results in transient induction of global hypomethylation. Therefore, a more frequent schedule of administration (i.e. every other week (QOW)) may have significant clinical activity. Methods: We have developed a phase I study of low decitabine administered QOW. Patients that do not respond or progress after decitabine can receive the combination of decitabine with hyperCVAD in a sequential phase of the study. Starting doses of decitabine are 10 mg/m2 IV daily×5 every other week, and 5 mg/m2 IV daily×5 concomitant with hyperCVAD. The studies follow a classic “3+3” design. Patients with relapsed/refractory ALL of any age are elegible. Molecular studies include the analysis of global and gene specific DNA methylation and gene expression reactivation. Results: Seven patients have been treated (median age 25, range 8–44). All had refractory disease and had previously completed at least 8 courses of hyperCVAD therapy and 2 years of maintenance therapy or similar. Four patients have been treated at dose level 1 of single agent decitabine, and 3 at dose level 2 (20 mg/m2). Three of these patients have also been treated at dose level 1 of the combination of hyperCVAD and decitabine. No severe drug related toxicites have been observed. Four patients had achieved a response: 1 CR after decitabine and hyperCVAD, and 3 PR (normalization of peripheral blood with bone marrow blasts reduction of more than 50% but above 5%). One PR was achieved after decitabine and hyperCVAD, but two with only decitabine. Two of these patients did not qualify for CR because bone marrow blasts were 6%. Of these four responding patients, 1 in CR received successful alloSCT, 1 progressed after 2 courses of single agent decitabine, and 2 pediatric patients continue on therapy. The study continues. Molecular studies are ongoing. Conclusions: In summary, frequent administration of low dose decitabine, alone or in combination with hyperCVAD, may be clinically safe and active in advanced relapsed/refractory ALL. No significant financial relationships to disclose.
Hyperglycemia and obesity in patients (pts) with acute lymphoblastic leukemia (ALL): Association with prevalence, response, and survival
Authors: Vu K. D. , Lavis V. R. , Strom S. , Faderl S. H. , Konopleva M. , Thomas D. A. , Gruschkus S. , Andreeff M. , Kantarjian H. 
Published: March 2020

7074 Increasing evidence suggests associations between obesity, diabetes and/or hyperglycemia (DM/HG) and solid tumors. Less is known about the relationship of these metabolic factors to the hematologic malignancies. To determine the prevalence of DM/HG and obesity in pts with ALL and whether these are predictors of response and survival, we conducted a retrospective chart review of 299 pts with newly diagnosed ALL, who were evaluated at our institution between November 1999 and May 2005 and received hyper-CVAD therapy: fractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone alternating with methotrexate and high-dose cytarabine. Median age was 43 yrs (range 15–83). Sixty-one percent of pts were male, and 39% female. Seventy-four percent had a diagnosis (dx) of precursor B cell ALL (22% Ph+), 18% Burkitt's ALL, 6% lymphoblastic lymphoma, 2% other. Prior to therapy, the overall prevalence of DM/HG (diabetes based on reported dx prior to ALL-dx, and hyperglycemia based on baseline serum glucose ≥200 mg/dL) was 16%. Pts with DM/HG were significantly older than those without DM/HG (median age 57 yrs vs. 40 yrs, p<0.001). Complete remission (CR) rate and the CR duration (CRD) were similar in the DM/HG vs. non-DM/HG group. However, the mean CRD was 80 wks in the HG separately group and 121 wks in the non-HG group (p=0.04). The mean CRD was 102 wks in the obese pts and 124 wks in the non-obese pts (p=.04). In univariate analysis, DM/HG, obesity, and older age were associated with shorter overall survival (OS). Mean OS of pts with DM/HG was 134 vs. 194 wks for pts without DM/HG, (p=0.2). Mean OS of obese pts was 136 vs. 199 wks for non-obese pts, (p=0.01). In a multivariable Cox regression model, the only factors that remained significant for survival were age, obesity, and white blood cell count (WBC). There was no significant difference in OS by leukemia diagnosis. In conclusion, the prevalence data suggests that DM/HG may be involved in the development of ALL. However, DM/HG has no impact on survival, probably because of its strong correlation with age. The association of obesity with shorter OS warrants further investigation. No significant financial relationships to disclose.
The effect of alemtuzumab maintenance therapy on B and T lymphocytes in chronic lymphocytic leukemia
Authors: Kaufman M. S. , Driscoll N. , Johnson C. , Caramanica A. , Janson D. , Lebowicz Y. , Wasil T. , Rai K. 
Published: March 2020

7092 Background: We are conducting a pilot, exploratory study of the potential value of alemtuzumab(alem) in maintenance therapy of previously treated chronic lymphocytic leukemia (CLL) patients(pts) after they have achieved stable disease or partial remission with chemo or chemo-immunotherapy. We present the results of serially monitored CD19+ (B)lymphocytes and CD4+ (T) lymphocytes on eight evaluable patients. Methods: 30mg doses of alem were administered SC to all patients at the following schedule: wkly for 8 doses (8 wks), followed by q2 wks for 8 doses(16 wks), followed by q3 wks for 8 doses (24 wks). This schedule provides a total of 48 wks of maintenance treatment with alem. Patients received standard prophylaxis with sulfamethoxizole and acyclovir with regular CMV monitoring by quantitative PCR. Results: In the table we present data on the pattern of decrease in blood CD19+(B) cells and CD4+ (T) cells on eight evaluable pts at different time points after starting alem maintenance. Because flow cytometry was not done on all pts at each time point, the number of pts contributing to the calculation of mean counts at each given time point is variable. CD19+(B) cells were markedly reduced to 37% of baseline consistently, from 8 wks onward. CD4+(T) cells, on the other hand, were consistently higher than 50% of the baseline after 8 wks. No opportunistic infections were seen in any pt and treatment was well tolerated. Conclusion: These results from a single institution based pilot study demonstrate that alem used in maintenance schedule is effective in keeping the blood levels of CD19+(B) cells extremely low without concordant suppression of CD4+(T) lymphocytes. No significant financial relationships to disclose. [Table: see text]
A pilot study CD34 selected haploidentical transplant using a chemotherapy-only preparative regimen and intensive antibiotic prophylaxis for treatment of advanced leukemia
Authors: Gajewski J. L. , McMannis J. , Shpall E. , de Lima M. , Giralt S. , Jones R. , Khouri I. , Hosing C. , Korbling M. , Champlin R. E. , Donato M. 
Published: March 2020

7097 Background: We present preliminary data of haploidentical transplant for 13 patients (pts) with acute leukemia. Methods: Phase II Study Results: We present preliminary data of haploidentical transplant for 13 patients (pts) with acute leukemia using a chemotherapy-only preparative regimen of Melphalan 140 mg/m2 on day −8; Thiotepa 10 mg/kg on day −7; Fludarabine 40 mg/m2 on days −6, −5, −4, −3; 1.5 mg/kg of rabbit ATG/day days −6, −5, −4, −3. The transplant was administered on day 0 using positive selection of CD34 positive cells by the CliniMACS device as a means of T-cell depletion. All products had <1 × 104 CD3+ T-cells/kg recipient body weight and needed a minimum of 5 × 106 CD34+ cells/kg but preferably >1 × 107 CD34+ cells/kg recipient body weight. Age ranged 23–50 years/median 37 years, four patients were in advanced remission and nine were in refractory relapse. Patients received intensive PCP prophylaxis with sulfamethoxazole-trimethoprim and pentamidine prior to transplant and during pancytopenia; CMV prophylaxis with valganciclovir during the BMT prep and foscarnet while pancytopenic; and with liposomal amphotericin or cancidas for fungal prophylaxis. Two patients had primary graft failure-one survived disease free and one relapsed. One patient died of multiple organ failure prior to engraftment. Median time to engraftment was 15 days (range, 9–26) to 500 neutrophils and 14 days to platelets 20,000 (range, 13–25). Seven patients died of relapse at a median of 10 months (range 2–13 months), and one patient died of a viral infection. Two of 10 patients who engrafted developed grade one acute graft-versus-host (GVHD) and four patients had chronic GVHD (3 limited, 1 extensive). Four patients survive beyond 2 years, without recurrent disease. Conclusions: This report for haploidentical transplant demonstrates that a chemotherapy only preparative regimen can achieve a high rate of engraftment. Infectious complications were minimal with aggressive prophylaxis. Long-term remission are achievable with little risk of severe GVHD with t-cell depletion with use of CliniMACS in haploidentical stem cell transplant. No significant financial relationships to disclose.