bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacologically derived schedule of flavopiridol has significant efficacy in refractory, genetically high risk chronic lymphocytic leukemia (CLL)
Authors: Byrd J. C. , Lin T. S. , Dalton J. T. , Phelps M. , Fischer B. , Moran M. , Blum K. , Rovin B. , Colevas A. D. , Grever M. R. 
Published: March 2020

6516 Background: Promising pre-clinical activity with flavopiridol in CLL was followed by disappointing clinical trial results. Differential protein binding of flavopiridol in pre-clinical studies may have misdirected the target concentration and administration schedule in CLL trials. Methods: We initiated a phase I study based on pharmacokinetic (PK) modeling showing that 1.5–2.0 μM flavopiridol for 4–6 hours was necessary for anti-CLL activity in vitro with 10% human serum. A 30 minute loading dose followed by a 4 hour infusion every 4 of 6 weeks was pursued. Eligibility included refractory/relapsed CLL, intact organ function, and performance status of ≤ 2. Results: Fifty-six pts have been enrolled ( Table ) with a median of 4 prior therapies, and most fludarabine-refractory. Dose-limiting toxicity in cohort 2 was tumor lysis syndrome (TLS). Cohort 1 was expanded with aggressive TLS prophylaxis. Of 20 pts in cohort 1, 8 (40%) had a partial response (PR) with a median response duration exceeding 12 months. The 0.5 and 4.5 hr Cmax were 2.08 μM and 0.96 μM. PK modeling showed that higher dose in the 4-hr infusion would achieve desired 4.5 hr Cmax. This escalation was done in cohorts 3 and 4 ( Table 1 ) with acceptable toxicity. In cohort 3, 19 pts enrolled with 14 pts being dose escalated. Improved cytoreduction was seen in most pts with dose escalation. Ten (53%) of pts attained a PR. The 0.5 and 4.5 hr Cmax was 1.95 μM and 1.54 μM in cohort 3;dose escalation continues in cohort 4. WBC of ≥ 200 × 109/L was associated with TLS (5 of 8 pts) versus those with WBC < 200 × 109/L (1 of 34 pts). As such, cohort 4 excludes pts with WBC ≥ 200 × 109/L for safety. Currently there are 14 pts in cohort 4 with only 1 case of TLS. Response assessment for cohort 4 is underway; activity appears similar to cohort 3. Conclusions: Flavopiridol with this PK directed schedule has significant clinical activity independent of the presence of del(17p13.1) and is one of the most active agents in clinical trials for CLL. [Table: see text] No significant financial relationships to disclose.
Proteomic signatures of acute myeloid leukemia (AML) distinguishes different outcome groups across cytogenetics and identified potential therapy targets
Authors: Tibes R. , Qiu Y. , Coombes K. , Hennessy B. , Kantarjian H. , Giles F. , Estey E. , Mills G. , Kornblau S. 
Published: March 2020

6523 Background: Cytogenetics (CG) guide AML treatment but reliable markers predicting response and relapse within CG groups are missing. We therefore determined whether functional proteomic signatures can classify AML into groups with different outcomes and risk of relapse. Method: Using Reverse Phase Protein Array, total and phospho-site specific expression of 37 proteins in 73 primary AML was measured. Outcomes in the set were comprised equally of primary refractory (PR), relapsed (Rel) and continuous complete remission (CCR) patients. Cell lysates were spotted on nitrocellulose coated slides, probed with validated antibodies, expression intensities were quantified, data was standardized and analyzed for correlations using different clustering approaches. Results: Unsupervised hierarchical clustering based on Pearsons’ correlation distance yielded 4 large clusters. Subsequent perturbation bootstrap re-sampling arranged samples into four classes that correlated with initial response to therapy and risk of relapse (see Table ). Protein profiles in each of he 4 classes differed. Cytogenetic marker distribution were similar across the 4 clusters. Class 1 and 4 demonstrated a similar predictive value of patient outcome as cytogenetics. In classes at highest risk of relapse (2, 3) different proteins were predictive of response. In class 2, the most discriminatory proteins predicting CCR were elevated AMPK, p27, 4-EBP1, BclXL. In class 3, relapsed patients had elevated PTEN, phospho-Stat3, total Stat3, and phospho-PKCα compared to CCR patients. Conclusion: Pretreatment protein expression signatures divide AML into classes that predict for initial achievement of CR and subsequent relapse independent of CG. Poteomic profiling may suggest potential therapy targets as opposed to CG or transcriptional profiling. These preliminary results need to be confirmed in formal training and test sets prior to changing patient management. [Table: see text] No significant financial relationships to disclose.
Dasatinib (D) in patients with accelerated phase chronic myeloid leukemia (AP-CML) who are resistant or intolerant to imatinib: Results of the CA180005 ’START-A’ study
Authors: Talpaz M. , Apperley J. F. , Kim D. W. , Silver R. T. , Bullorsky E. O. , Cheng S. , Iyer M. , Guilhot F. 
Published: March 2020

6526 Background: Dasatinib (D) (BMS-354825) is an oral multi-targeted kinase inhibitor with preliminary evidence of efficacy in a previously reported phase I study. START A is an open-label study of dasatinib in AP-CML pts who were imatinib resistant (IM-R) or imatinib intolerant (IM-I). Methods: A total of 192 pts were enrolled between December 2004 and Jun 2005 in 39 centers worldwide. Dasatinib was given orally at 70 mg twice daily (BID). Dose escalations to 100 mg BID were allowed for poor initial response and reductions to 50 or 40 mg BID for persistent toxicity. Evaluations were weekly blood counts and monthly bone marrow evaluation including cytogenetics. The primary endpoint was major confirmed (maintained at least 4 weeks) hematologic response (MaHR) in IM-R pts. Results: The first 107 pts (99 IM-R, 8 IM-I) with at least 6 months of follow-up are currently reported; there were 55 males/52 females; median age 57 years (range 23–86); median time from diagnosis of CML 90.9 months. Prior therapy included IM>600 mg/day in 63 (59%) pts, interferon in 80 (75%) pts. Major cytogenetic response (MCyR) to prior IM was seen in 34 (32%) pts. 56 pts had Bcr-Abl kinase domain mutations. Median duration of therapy was 5.5 months. MaHR was documented in 63 (59%) pts (95% CI: 49–68) with complete hematologic response in 35 (33%) and no evidence of leukemia in 28 (26%). In IM-R pts, the MaHR rate was 59%. MCyR was documented in 33 (32%) pts (95% CI: 22.9–41.6); complete in 23 (22%), partial in 10 (10%). MaHR were seen in pts with Bcr-Abl mutations and in pts who never responded to IM. Molecular response analysis is ongoing. There were 15 disease progressions including one loss of MaHR. Myelosuppression was significant with grade 3–4 thrombocytopenia and neutropenia in 79% and 69% of pts, respectively. Non-hematologic toxicities were generally mild to moderate. The most frequent were diarrhea (46%), peripheral edema (27%), pleural effusion (16%), rash (8%), and GI hemorrhage (7%). Conclusions: Dasatinib was very effective in IM-R pts with AP-CML with high rates of durable MaHR and MCyR. Data on all 192 pts will be presented at the meeting. [Table: see text]
Dasatanib (D) in patients (pts) with chronic myelogenous leukemia (CML) in lymphoid blast crisis (LB-CML) or Philadelphia-chromosome positive acute lymphoblastic leukemia (Ph+ALL) who are imatinib (IM)-resistant (IM-R) or intolerant (IM-I): The CA180015 ‘START-L’ study
Authors: Coutre S. , Martinelli G. , Dombret H. , Hochhaus A. , Larson R. , Saglio G. , Gollerkeri A. , Apanovitch A. , Ottman O. G. 
Published: March 2020

6528 Background: Dasatinib (D) (BMS-354825) is a multi-targeted kinase inhibitor of BCR-ABL and SRC. Preliminary data from a phase I study suggest high efficacy of D in IM pretreated pts. Methods: START L is an open label phase II study of D in IM-R or IM-I pts with LB-CML and Ph+ALL conducted at 42 centers worldwide. D was given orally, 70 mg twice a day (bid), with escalation to 100 mg bid for poor response or reductions to 50 mg and 40 mg bid for toxicity. Pts had weekly blood counts and monthly bone marrow exams, including cytogenetics. The primary endpoint was confirmed (sustained for at least 4 weeks) major hematologic response (MaHR) rates. Results: From January to June 2005, 101 pts were accrued. Data are available on the first 78 treated pts (42 LB-CML, 36 Ph+ALL). Of the 42 LB-CML pts, 37 were IM-R, 52% were male with median (med) age of 47 years. Prior therapy included IM >600 mg/day in 52% and stem-cell transplant (SCT) in 33% of pts. Med baseline platelet (plt) count was 32.5/nl, med BM blasts were 82%, Bcr-Abl mutations were seen in 48%, and extramedullary disease (EMD) was seen in 29% of pts. The D dose was reduced in 14%, temporarily interrupted in 33%, and escalated in 26% of pts. At 6-months, the MaHR rate was 31% including 26% complete hematologic response (CHR), the MCyR rate was 50%, and 17% of pts remained on study. Of the 36 Ph+ALL pts, 34 were IM-R, 64% were male with med age 46 years. Prior therapy included IM> 600 mg/day in 47% and SCT in 42% of pts. Baseline plt count was 53.5/nl, med BM blasts were 69%, Bcr-Abl mutations were seen in 47% and EMD was seen in 31% of pts. The D dose was reduced in 28%, temporarily interrupted in 39%, and escalated in 47% of the pts. At 6-months, the MaHR rate was 42% including 31% CHR, the MCyR rate was 58%, and 33% pts remained on study. Among all 78 pts, grade 3–4 thrombocytopenia and neutropenia was seen in 82% and 76% of pts, respectively. The most frequent D-related non-hematologic toxicities were diarrhea (30%), nausea (23%), fatigue (19%), rash (17%) and pleural effusion (13%). Conclusions: D is active in IM pretreated LB-CML and Ph+ALL pts. Data on all 101 pts will be presented at the meeting. [Table: see text]
Dasatinib (BMS354825), a dual Src-Abl inhibitor, is active in Philadelphia chromosome-positive chronic myelogenous leukemia (Ph+CML) following treatment failure with imatinib mesylate and AMN107
Authors: Estrov Z. , O’Brien S. , Giles F. , Garcia-Manero G. , Borthakur G. , Ravandi F. , Sams I. , Nicaise C. , Kantarjian H. 
Published: March 2020

6530 Background: Dasatinib is a dual Src-Abl kinase inhibitor which is 300 fold more potent than imatinib and 20-fold more potent than AMN107 (a selective potent Bcr-Abl kinase inhibitor). Dasatinib also inhibits Src which may overcome CML resistance. Methods: Study Aims: To report the experience with dasatinib in patients who develop CML failure post AMN107. Patients and Methods: All patients on the ongoing dasatinib studies at our institution were reviewed for prior therapy/response to AMN107 and outcome on imatinib. Results: 16 patients with Ph+CML following treatment failure with AMN107 received dasatinib. All patients had previously shown hematologic resistance to imatinib. AMN107 failure was due to hematologic resistance in all 16 pts. Median age was 60 years (range 22 to 76 years); median follow-up on dasatinib is 3 months (range <1 to 9 months). CML phase was chronic in 2, accelerated in 6, blastic in 6, and second chronic/accelerated in 2. Abl mutations were found in 7/16 patients before dasatinib therapy: G250E+F359L, G250E, Y253F, Y253H, H396R (1 patient each), T315I (2 patients). All patients received dasatinib 70 mg orally BID (n = 10), 140 mg single daily dose (n = 5), or 120 mg orally BID (n = 1). Responses were observed in 5 of 7 patients with mutations including 4/4 with P loop mutations and 1/2 with other mutations; the 2 patients with T315I had resistant disease. Conclusions: Dasatinib is active in patients with CML resistant to both imatinib and AMN107. [Table: see text] [Table: see text]
The kinetics of reduction of minimal residual disease impacts on duration of response and survival of patients with acute myeloid leukemia
Authors: Buccisano F. , Maurillo L. , Del Poeta G. , Del Principe M. , Mazzone C. , Fraboni D. , Panetta P. , Gattei V. , Lo Coco F. , Amadori S. , Venditti A. 
Published: March 2020

6533 Background: Multiparametric flow-cytometry is frequently used to assess the levels of minimal residual disease (MRD) in acute myeloid leukemia (AML) patients achieving complete remission after intensive chemotherapy. In our previous experience, MRD negativity after consolidation cycle, as defined by a level of bone marrow residual leukemic cells ≤3.5x10−4, was associated with a significantly longer relapse free survival (RFS) and overall survival (OS). The aims of the present study were to confirm, in a larger series of patients, the prognostic relevance of the post consolidation MRD assessment and to validate the threshold of 3.5x10−4. Methods: 100 patients affected with AML were entered into the EORTC/GIMEMA protocols AML10/AML12 (age <61 yrs) or AML13/AML15 (age >61 yrs), consisting in intensive induction and consolidation cycles. Median age was 52 years (range 18–78), all FAB subtypes were represented with the exception of APL cases. A Maximally Selected Rank Statistic analysis was used to select the best threshold. Results: The statistical test confirmed that the level of 3.5×10−4 residual leukemic cells was the most significant in discriminating categories of risk. In fact, levels of MRD measured at the post-consolidation time-point identified 2 distinct subgroups: 36 patients MRD negative and 56 MRD positive. MRD negative patients had a better outcome in terms of relapse rate (P<0.001), OS (P=0.039) and RFS (P=0.008), regardless of MRD status after induction. In fact, patients entering MRD negativity only after consolidation showed the same outcome as those achieving early negativity after induction. The multivariate analysis, including karyotype, age, MDR1 phenotype and post induction and post consolidation MRD levels, indicated that the post-consolidation MRD status was an independent factor affecting relapse rate (P<0.001), OS (P=0.039) and RFS (P=0.008). Conclusions: We conclude that 1) the threshold of 3.5x10−4 is valid in discriminating risk categories in AML; 2) MRD assessment at post-consolidation check-point is critical to predict disease outcome. The incorporation in clinical trials of flow-cytometric MRD determination may allow a more accurate risk stratification of AML patients. No significant financial relationships to disclose.
Apoptotic disseminated tumor cells reflect response to primary chemotherapy in breast cancer
Authors: Fehm T. N. , Becker S. , Wallwiener D. , Gebauer G. , Solomayer E. 
Published: March 2020

654 Background: Primary chemotherapy (pCHT) is an established method to reduce tumor size (downstaging) in breast cancer patients before performing breast conserving therapy. The consequences of pCHT on tumor cell dissemination in these patients are not known. The aim of this study was to investigate (1) the incidence of disseminated tumor cells (DTC) including apoptotic DTC in patients with breast cancer after primary chemotherapy and (2) its correlation with pathological therapy response. Methods: Bone marrow aspiration was performed in 157 patients after primary chemotherapy. Cytokeratin-positive cells were detected by immunocytochemistry using the AB45-B/B3 anti-cytokeratin antibody. For detection of apoptotic tumor cells the antibody M30 (Roche Diagnostics, Germany) was used. M30 reacts with a neo-epitope expressed only after caspase cleavage of CK 18 during early apoptosis. Results: The incidence of disseminated tumor cells in breast cancer patients was 57% (84 of 157 pts) after completion of primary systemic therapy. Tumor dissemination was observed more frequently in patients with no change/progressive disease (NC+PD: 63%) than in those who showed partial (PR) or complete remission (CR) of the primary tumor (PR+CR: 43%) (p<0.05). However, 9 of 23 (40%) patients with complete response were still bone marrow positive. Apoptotic tumor cells were present in 36 of 157 (23%) breast cancer patients. The positivity rate of apoptotic cells was higher in bone marrow positive patients with PR or CR (42%) compared to those with stable disease (SD) (26%). No apoptotic tumor cells were detected in patients with tumor progression (n=5). Conclusions: The pathological therapy response is reflected by the presence of apoptotic tumor cells in the bone marrow of breast cancer patients. However, patients with complete response may still have non apoptotic disseminated tumor cells. Patients with tumor cell dissemination after primary systemic therapy may be benefit from additional secondary adjuvant treatment (e.g. bisphosphonates, antibody based strategies). No significant financial relationships to disclose.
Low power laser in the prevention of induced oral mucositis in bone marrow transplantation patients
Authors: Antunes H. S. , De Azevedo A. M. , Adão C. E. , Pinheiro C. T. , Pinheiro L. H. , Azevedo R. , Mayhe R. , Matos V. D. , Zângaro R. A. , Ferreira C. G. 
Published: March 2020

6541 Background: High-dose chemotherapy followed by bone marrow transplant produces undesirable effects in the oral cavity leading to oral mucositis (OM) that may be a painful and debilitating side-effect. Laser therapy has been used to improve the symptoms and duration of already established OM in this group of patients (pts). Recent data suggest the upfront use of laser therapy may decrease the incidence of OM. Methods: Through the use of upfront LPL as protecting and modulating therapy of the oral mucosa membrane, we evaluated the potential for a reduction in the incidence and/or severity of OM in pts submitted to autologous (AT) or allogeneic (AL) bone marrow transplant (BMT). Sample size was based on estimative of P0 control = 0.6 and a P1 LPL = 0.1, β = 0.1; α= 0.05. From Jan 2004 to May 2005, 38 pts treated at the National Bone Marrow Transplant Center in Rio de Janeiro were randomized into a group of 19 pts that received and a group of 19 that did not receive the application of the preventive LPL from the beginning of the conditioning. The irradiation was used an diode InGaAlP, emiting light at 660 nm wavelenght with output power of 50 mW, giving an energy density of 4 J/cm2. The tip of the laser device touched the oral mucosa. The evaluation of OM was done by different investigators both by WHO and OMAS scale. Results: The male to female ratio was 60.5/39.5%. The median age 37 (19–56). The frequency of AT and AL was 73.7 (15.8% non related) vs 26.3%. In the LPL group 94.8% of pts had OM WHO grade < 2 (including 63.2% with grade 0), whereas in the control group 68.4% of pts had OM grade III and IV (p<0,001). Remarkably the HR for grade II, III and IV OM was 0.41 (CI 95% 0.22–0.75, p = 0,002) and for grade III and IV was 0.07 (CI 95%0.11–0.53, p<0,000). Using OMAS scale by the calculation of ulcerous area, 73.6% of LPL pts presented lesions of 0 to 3 cm2, whereas 73.6% of the control group presented ulcers from 9.1 to 18 cm2 (p=0.003). An agreement was observed among investigators (index of 81.7%) and between WHO and OMAS scale (p<0,001). Conclusion: Our results indicate that the use of upfront LPL in bone marrow transplantation patients is a powerful instrument in reducing the incidence of OM and is now standard in our center. No significant financial relationships to disclose.
Phase I/II clinical trials for relapsed elderly acute leukemia patients: Importance of performance status at re-induction. A single center retrospective experience
Authors: Van Heeckeren W. J. , Fu P. , Barr P. , Laughlin M. , Tse W. , Lazarus H. , Remick S. , Cooper B. 
Published: March 2020

6575 Background: Relapsed/refractory acute leukemia patients (pts) have a poor outcome and should be considered for enrollment on clinical trials. Elderly (≥ 60 yr) acute leukemia patients often are excluded from phase I/II cytotoxic agent re-induction chemotherapy trials due to concerns for treatment-related toxicity. Methods: Pts with relapsed/refractory acute leukemia who were enrolled on three consecutive phase I/II clinical trials at University Hospitals of Cleveland were evaluated for outcome data including complete response (CR), serious adverse events, and overall survival (OS). Outcome data was compared for pts age ≥ 60 yr versus < 60 yr. Pts with ECOG Performance Status (PS) 0 to 3 were eligible and there was no age limitation. Results: Between 1994 and 11/2005, 96 acute leukemia pts median age 60 yr (range 19–78) were enrolled: 29 pts received phase I topotecan-etoposide; 31 pts received phase I fludarabine, carboplatin, and topotecan (FCT); and 37 pts received phase II FCT plus thalidomide. In univariate analysis, PS at therapy initiation, mean # prior treatments, and disease status at time of treatment were not statistically different between older and younger pts ( Table ). Using Kaplan-Meier method, early treatment-related mortality and OS were similar in pts age ≥ 60 yr compared to pts < 60 yr ( Table ). Mean # ≥ grade 3 toxicities and CR also were similar in both groups ( Table ). In univariate (p = 0.001) and multivariate (p = 0.0004) analyses by Cox modeling, pts PS 0–1 had better OS than PS 2–3 (PS 0–1: 30-day survival 98% and 1 yr survival 24% versus PS 2–3: 30-day survival 81% and 1 yr survival 6%). Conclusions: Poor PS is an important negative predictor of outcomes in relapsed/refractory acute leukemia pts. Advanced age should not exclude pts from cytotoxic re-induction chemotherapy trials. [Table: see text] No significant financial relationships to disclose.
Reproducibility of the Penn predictive score of tumor lysis syndrome (PPS-TLS) in acute myelogenous leukemia (AML)
Authors: Mato A. R. , Miltiades A. N. , Guo M. , Heitjan D. F. , Carroll M. P. , Loren A. W. , Porter D. L. , Stadtmauer E. A. , Perl A. E. , Luger S. M. 
Published: March 2020

6577 Background: In a previous retrospective study of 194 patients undergoing AML induction chemotherapy, we described a TLS predictive model entitled the Penn Predictive Score for Tumor Lysis Syndrome (PPS-TLS). TLS incidence was 9.8%. The PPS-TLS is defined as the sum of the scores for pre-induction lactate dehydrogenase (LDH), uric acid (UA), and gender (see table ). The area under the receiver operator characteristic (ROC) curve for this cohort was 89% (SD 4%). Methods: To validate the PPS-TLS, we retrospectively analyzed a second dataset of 166 AML patients undergoing induction chemotherapy from 2003–2006 at our institution. All patients received TLS prophylaxis. TLS was defined as (i) doubling of baseline serum creatinine (Cr) in association with elevated serum phosphate, UA, or potassium or (ii) elevations in 2 of the above electrolytes within 7 days of initiation of therapy. Potential TLS predictive factors were analyzed for statistical significance. Results: In this new dataset, TLS incidence is 9.6%. Significant in univariate analysis are male sex (OR=6.0, CI 1.31–27.15), Cr (OR=13.0, CI 2.88–58.23), UA (OR=48.6, CI 5.78–408.95), and LDH (OR=1.2, CI 1.03–1.48). In multivariate analysis, LDH (OR=1.3, CI 1.04–1.70) and Cr (OR=6.8, CI 1.48–30.89) remain significant. PPS-TLS scores were calculated and tested for their ability to predict TLS in this dataset. The area under the ROC curve for the PPS-TLS in this dataset was 75% (CI 61%-89%), indicating that the probability that a patient with TLS would have a higher PPS-TLS score than one without TLS is 75%. The current result is not statistically significantly different from the area under the ROC curve in the initial dataset (89%). Conclusions: The PPS-TLS is the first TLS predictive model in AML. The reproducibility of this model is supported by this study. A prospective multisite study is being designed to further validate this model. This analysis may lay the groundwork for the first evidence-based guidelines for TLS monitoring and management in AML. [Table: see text] No significant financial relationships to disclose.