bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of delaying therapy in newly diagnosed AML
Authors: estey e. , Thall P. , Wang X. , Borthakur G. , Ravandi-Kashani F. 
Published: March 2020

7020 Background: Given CR rates < 50% in pts with chromosome 5 and/or 7 abnnormalities given standard therapies, such pts might be offered investigational treatments at diagnosis. However the delay entailed in waiting for cytogenetic results might be problematic. Here we examine the effect on survival time and CR rate of the interval (TDT) from M.D. Anderson (MDA) diagnosis to start of treatment. Methods: At physicians’ discretion, therapy was delayed (TDT > 0) in 97% of the 1,378 pts with WBC < 50,000 treated at MDA 1996-2005. We used regression models to evaluate TDT's effect on survival and CR, after accounting for other covariates measured on day 1 of treatment. Covariates strongly associated with TDT were represented as binary variables (Z) and evaluated using interactive terms of the type Z*TDT. Results: TDT was = 2 days in 24% of pts, = 1 week in 68%, and = 10 days in 80%. TDT was longer in older pts, those with performance status (PS) 0–2, no fever or infection, a higher albumin, and lower WBC count and % marrow blasts (p < .02 for each). Considered alone, TDT had no effect on survival time (p= .33). However, longer TDT was independently associated with shorter survival in pts age > 62, with fever or infection, PS 3–4, (p < .001 for each), WBC > 5.0 and marrow blasts > 43% (p NS for each). A longer TDT was independently beneficial only for patients with an albumin > 3.4 (p= 0.007) with the values for the numerical covariates being the medians for the 1,368 patients. The albumin at MDA diagnosis remained unchanged relative to the median at time of treatment in 60% of the 103 pts in whom TDT = 7 days; corresponding value for WBC was 88%, with the presence (absence) of fever or infection unchanged in 85%. Adding the effect of the above noted covariates, delaying treatment within the range of TDTs seen here did not decrease survival in 86% of our 703 pts < age 63; exceptions were pts with PS > 2 or with fever/ infection. However longer TDT shortened survival in 57% of the 675 pts age > 62; exceptions were pts with PS < 3, albumin > 3.4, and no fever/infection. The effect of TDT on CR rate mirrored its effect on survival. Conclusions: Recalling the passage of time between outside diagnosis and referral to MDA, our results suggest that delaying start of treatment to ascertain cytogenetic (and in the future molecular) results is feasible in most younger, but probably not in most older, pts. No significant financial relationships to disclose.
Drug treatment or stem cell transplantation as primary treatment for patients with CML
Authors: Hehlmann R. , Lahaye T. , Pfirrmann M. , Hochhaus A. , Müller M. C. , Hasford J. , Kolb H. J. , Heimpel H. , Hossfeld D. K. , Gratwohl A. 
Published: March 2020

7028 Background: Early allogeneic stem cell transplantation (SCT) has been proposed as primary treatment modality for patients (pts) with chronic myeloid leukemia (CML). This concept has been challenged by persisting transplantation mortality and improved drug therapy. Methods: A randomized controlled trial was designed to compare primary SCT and best available drug treatment in 621 newly diagnosed CML pts in chronic phase (CP). Assignment to treatment strategy was by eligibility for SCT and genetic randomization according to availability of a matched related donor (MRD). 354 pts (62% male; median age 40 (11–59) years) were eligible and randomized. 135 pts (38%) had a MRD of which 123 (91%) received a transplant within a median of 10 (2–106) months from diagnosis. 4 pts died before scheduled SCT, 8 pts withdrew consent. 219 pts (62%) had no MRD and received drug therapy. Of these, 97 pts (44%) received a matched unrelated donor (MUD) transplant in 1st CP and were censored at the time of SCT. As 1st line drug treatment pts received interferon alpha based therapy. During the study 197 pts were switched to imatinib. Results: With an observation time up to 11.2 (median 8.9) years median survival of all 621 pts was 8.1 years. During the first 8 years after diagnosis survival curves of drug treated patients were superior to those of transplanted patients reflecting transplant-related mortality. Beyond 8 years survival curves were no longer distinct. 5 (10) year survival was 62% (53%) for transplanted and 73% (52%) for drug treated pts. Survival was superior for drug treated pts up to the cutpoint of survival curves at year 8 (p<0.041) and during the study period up to 11 years from diagnosis (p<0.049). Significantly higher proportions of complete cytogenetic remissions (91% vs 48%, p=0.002) and of major molecular responses (ratio BCR-ABL/ABL <0.1%; 81% vs 45%, p=0.001) were found in the transplant group. These results will be compared to those of a more recent randomized trial of the group (CML-study IIIA). Conclusions: The general recommendation of SCT as 1st line treatment option in CP CML can no longer be maintained. It should be replaced by a trial with modern drug treatment first. Exceptions may be patients’ preference, very low transplantation risk and economic reasons. No significant financial relationships to disclose.
Evaluating safety and efficacy of AMG 531 for the treatment of thrombocytopenic patients with myelodysplastic syndrome (MDS): Preliminary results of a phase 1/2 study
Authors: Kantarjian H. M. , Giles F. J. , Fenaux P. , Becker P. S. , Boruchov A. M. , Bowen D. T. , Hellström-Lindberg E. , Larson R. A. , Lyons R. M. , Muus P. 
Published: March 2020

7032 Background: The prevalence of thrombocytopenia in MDS ranges from 40% to 65%, hemorrhagic complications range from 3% to 53%, and hemorrhagic deaths range from 14% to 24% (Kantarjian 2006). Platelet transfusion can lead to reactions, infection, and alloimmunization. AMG 531 is a thrombopoiesis-stimulating peptibody that increases platelet production. This phase 1/2 study evaluated the safety and efficacy of AMG 531 in thrombocytopenic MDS patients. Methods: A minimum of 5 subjects with low risk MDS (IPSS low or intermediate-1) and a platelet count of = 50×109/L were enrolled to receive 3 QW SC injections of AMG 531 in each of 4 sequential dose cohorts. After evaluation at week 4, subjects could continue AMG 531 in an optional treatment extension at their assigned dose or escalated to a responding dose. Erythroid growth factors were allowed, but no other active treatment. Results: 28 subjects (9 transfusion-dependent) have been enrolled to date. All subjects were evaluable for response and entered the extension; 17 continue treatment. Dose-limiting toxicity (DLT) was defined as a drug-related grade 3 or 4 adverse event (AE) or a platelet count ≥ 600×109/L. Two DLTs occurred, both due to elevated platelet counts. No treatment-related severe AEs occurred. There was 1 treatment-unrelated death. Overall, 17 subjects (61%) achieved a platelet response. Median baseline platelet count for responders was 25×109/L with a median peak platelet count of 130×109/L during the 4 week treatment period. Of the 18 subjects to date completing at least 12 weeks of treatment, 11 (48%) achieved a durable response of at least 8 consecutive weeks (revised IWG criteria, Cheson 2006). A total of 90 clinically significant thrombocytopenic events (39 bleeding, 51 transfusions) were observed over both treatment phases. There were 16 such events (12 bleeding, 4 transfusions) in 6 subjects with a durable response, 6 events (6 minor bleeds, 0 transfusions) during the durable response period. There were 74 events (27 bleeding, 47 transfusions) in 11 subjects without a durable response. Conclusions: These preliminary data suggest that bleeding and transfusion events can be reduced in thrombocytopenic low risk MDS patients who respond to AMG 531. [Table: see text]
A phase II study of nilotinib administered to patients with imatinib resistant or intolerant chronic myelogenous leukemia (CML) in chronic phase (CP), accelerated phase (AP) or blast crisis (BC) who also failed dasatinib
Authors: Giles F. J. , le Coutre P. , Bhalla K. , Rosti G. , Ossenkoppele G. , Alimena G. , Weitzman A. , Zheng M. , Kantarjian H. 
Published: March 2020

7038 Background: Nilotinib and dasatinib are two new second generation tyrosine kinase inhibitors used in the treatment of imatinib-resistant/intolerant CML. There is limited data regarding the efficacy and safety of these therapies when given sequentially. Methods: This phase II open-label study was designed to evaluate the safety and efficacy of nilotinib at a dose of 400mg BID in CML-CP, -AP, and -BC pts who previously received and either failed or were intolerant to imatinib and dasatinib. Results: A total of 42 pts are reported - CP (16), AP (9), and BC (17 total; 13 myeloid, 4 lymphoid). Overall 10 (24%) pts had extramedullary disease at baseline. For all pts, median time from first diagnosis was 16.8 (0.6–265) months. The median duration of nilotinib exposure was 81 days with median dose intensity of 800mg/day. A total of 13 (31%) pts with dasatinib failure remain on treatment, 29 (69%) discontinued (6 for AEs, 16 for disease progression). CP: Of the 16 pts, 5 (31%) had a MCyR (3 complete, 2 partial). Complete hematologic response (CHR) was reported in 5/13 (39%) pts without CHR at baseline. Disease progression only occurred in 2 pts. AP: 2/9 (22%) pts had a return to chronic phase (RTC), 6 pts were not evaluable and there was 1 death. Disease progression occurred in 5 pts. BC: 3/17 (18%) achieved CHR, 1 (6%) had RTC, and 4 (24%) pts had disease progression. For all pts, the most common Grade 3/4 AEs reported were thrombocytopenia (26%), neutropenia (24%), and anemia (7%) pts. Conclusions: Nilotinib has significant clinical activity in CML-CP, AP, and BC patients who have failed imatinib and dasatinib. Nilotinib is safe and well tolerated, consistent with its kinase selectivity profile. No significant financial relationships to disclose.
Nilotinib is associated with minimal cross intolerance to imatinib in patients with imatinib-intolerant chronic myelogenous leukemia (CML) in chronic phase (CP)
Authors: Jabbour E. , le Coutre P. , Baccarani M. , Bhalla K. , Ossenkoppele G. J. , Hochhaus A. , Gattermann N. , Haque A. , Weitzman A. , Kantarjian H. 
Published: March 2020

7039 Background: Nilotinib is a highly selective Bcr-Abl tyrosine kinase inhibitor that is 30-fold more potent than imatinib and is an important therapeutic option for patients (pts) who have either imatinib-resistant or -intolerant CML disease. Results of a subset of pts with Ph+ CML-CP who received nilotinib for imatinib-intolerance are reported Methods: Pts were part of a phase II open-label study evaluating the safety and efficacy of nilotinib in imatinib-resistant or -intolerant CML-CP. Imatinib intolerance was defined as no MCyR and discontinuation of imatinib due to Grade 3/4 AEs or persistent (> 1 mo) or recurrent Grade 2 AE (recurred > 3 times) despite optimal supportive care. The proportion of pts achieving MCyR was the primary endpoint, and safety and toxicity were secondary endpoints. Planned starting dose was nilotinib 400mg BID. Results: Of the 316 pts with CML-CP enrolled, 95 (30%) pts had imatinib-intolerance for either non-hematologic and/or hematolgic AEs. Some pts had more then one AE satisfying the criteria for intolerance. The frequency of intolerant symptoms for imatinib and nilotinib is shown in the table below. Only 2/80 (3%) pts with non-hematologic imatinib-intolerance experienced a recurrence of similar symptoms during nilotinib therapy. 33 patients entered the study due to hematologic intolerance (neutropenia, thrombocytopenia) and only 7/33 (21%) developed similar problems. In 86 pts with intolerance and at least 6 mos of follow up, 55% of these patients achieved MCyR, similar to that previously reported for imatinib-resistant patients. Conclusions: These are the first reported results evaluating cross intolerance symptoms to TKIs. The results demonstrate that nilotinib is effective in imatinib-intolerant CML-CP and has a very low rate of cross- intolerance, further supporting the excellent tolerability of nilotinib No significant financial relationships to disclose. [Table: see text]
A phase II study of nilotinib administered to imatinib resistant or intolerant patients with chronic myelogenous leukemia (CML) in blast crisis (BC) or relapsed/refractory Ph+ acute lymphoblastic leukemia (ALL)
Authors: Larson R. , Ottman O. , Kantarjian H. , le Coutre P. , Baccarani M. , Weitzman A. , Giles F. 
Published: March 2020

7040 Background: Nilotinib is a highly selective Bcr-Abl tyrosine kinase inhibitor that is 30-fold more potent than imatinib. In a phase I trial, nilotinib demonstrated efficacy and favorable tolerability in these pts. These results expand upon the phase I experience Methods: This phase II open-label study was designed to evaluate the safety and efficacy of nilotinib in adult imatinib-resistant or - intolerant BC pts or pts with relapsed/refractory Ph+ALL. Primary endpoint was investigator assessment of best hematologic response for BC and complete response for Ph+ALL pts. Nilotinib was started at 400mg BID with escalation to 600mg BID if no adequate response. Results: Safety and efficacy data are reported for 120 BC (27 lymphoid, 87 myeloid, 6 unknown) and 41 Ph+ALL pts (37 active disease, 4 residual disease, 38 relapsed, 3 refractory). 60% of pts had >35% Ph+ metaphases for BC and 31% for Ph+ALL. Median ages was 54 yrs for BC and 46 yrs for Ph+ALL pts. Chromosomal abnormalities other than Ph+ were noted in 64 (53%) BC and 12 (29%) Ph+ALL pts. Extramedullary involvement was present in 44 (37%) BC and 3 (7%) Ph+ALL pts. Treatment is ongoing for 21 (18%) BC and 4 (10%) Ph+ALL pts. Majority of discontinuations were due to disease progression [61 (51%) in BC; 26 (63%) in Ph+ALL). Median treatment duration was 53 (1–441) and 72 (3–363) days for BC and Ph+ALL, respectively. Median dose intensity was 800mg/day for both pt groups. CHR was reported in 25 (21%) pts, marrow responses in 7 (6%) pts, and return to chronic phase in 10 (8%) pts. Complete response was reported in 10 (24%) Ph+ALL; of which, 1 patient had minimal residual disease. The most common Grade 3/4 AEs were thrombocytopenia (41%), neutropenia (28%), pneumonia (11%), and anemia (27%) in BC and thrombocytopenia (24%) in Ph+ALL pts. During study period death occurred in 9 (8%) BC and 3 (7%) Ph+ALL pts. No Ph+ALL pt developed CNS disease while on therapy. Conclusions: Nilotinib has significant clinical activity and is well tolerated in imatinib-resistant or -intolerant BC and relapsed/refractory Ph+ALL pts. Nilotinib represents an important new treatment option for these pts in which there remains a high unmet medical need. No significant financial relationships to disclose.
Central nervous system (CNS) leukemia after imatinib mesylate therapy for chronic myelogenous leukemia (CML)
Authors: Solh M. M. , Kantarjian H. , O'Brien S. , Giles F. , Faderl S. , Garcia-Manero G. , Rios M. , Shan J. , Cortes J. , Ravandi-Kashani F. 
Published: March 2020

7042 Background: Imatinib is the standard first line treatment for CML. Imatinib penetrates the CSF poorly. We examined the incidence and outcome of CNS disease in pts with CML treated with imatinib at our institution. Methods: The clinical data for pts with early or late chronic phase and accelerated phase CML treated with imatinib between 1999 and 2006 were reviewed. Pts who were started on imatinib elsewhere and progressed to blast phase were also included. CNS disease was defined as a pathologically proven enhancing lesion (leptomeningeal or parenchymal) or presence of CSF leukemic cells. Results: Nine hundred and ten pts with chronic or accelerated phase CML were treated with imatinib. Fifty five developed blast crisis while on imatinib; another 28 pts had blast transformation while receiving imatinib elsewhere, making up a total of 83 pts. At diagnosis, their median age was 51 yrs, median Hgb, WBC and PLT counts were 10.6 g/dl, 59.7×109/L and 307×109/L, respectively. Median time from diagnosis to starting imatinib was 45.4 mts and the median duration of imatinib therapy was 17.9 mts. Fifteen pts had achieved a complete cytogenetic response and 47 had a complete hematologic response before progressing to blast phase. Their median overall survival from diagnosis was 73.2 mts. Thirty pts developed extramedullary disease; they had similar baseline characteristics as the rest with a median survival of 68.3 mts. Fifteen pts developed CNS disease (5 leptomenigeal, 5 CSF, 3 parenchymal, and 2 spinal cord); 14 had concomitant medullary blast crisis. They had a statistically significant younger age at diagnosis (41.9 vs 52.4 yrs), lower platelet counts (186 vs 334×109/L), and shorter overall survival (66.7 vs 73.2 mts) compared to the other pts with blast phase. Conclusions: CNS disease occurs infrequently in pts receiving imatinib for CML but should be suspected in pts with relevant symptoms. Pts developing CNS leukemia had a worse prognosis; this may be secondary to an inherently worse disease, poor CSF penetration of imatinib, and subsequent difficulty in eradicating CNS disease using available therapies. More potent tyrosine kinase inhibitors, such as nilotinib and dasatinib, and new agents with the ability to cross the blood-brain barrier should be evaluated in this setting. No significant financial relationships to disclose.
Imatinib (I) plus etoposide (Vp16) compared to I + cytarabine (Ara-C) for the frontline treatment of accelerated phase (AP) chronic myeloid leukemia (CML)
Authors: Cervera E. , Vargas P. , Cruz J. , Enriquez V. , Martinez A. , Lozano V. , Candelaria M. , Labardini J. , Hurtado R. 
Published: March 2020

7047 Background: Higher doses than 600 mg/day of I is the most recommended initial treatment of advanced CML disease. Nevertheless clinical and molecular results are lower than on early chronic phase, challenging for new treatment developments in face to better results. Main objective of present trial was to increase the hematological (HR) and major cytogenetical responses (MCR) with the addition of Ara- C or Vp16 to I at doses higher than 600 mg/day as a frontline therapy of AP CML. Methods: on march, 2004 we began this multicentric, phase III randomized, clinical trial, comparing I (600 mg/day) plus Vp16 (50 mg PO/day for 7 days/ 21 days cycles) vs I (600 mg/day) plus subcutaneous Ara-C (10 mg/m2/day, for 7 days/21 days cycles), doses could be adjusted due to tolerance and toxicity and in case of failure to respond at 3 months, I doses could be escalated to 800 mg/day. Inclusion criteria: newly diagnosed AP (hematological or clonal evolution permitted) CML, not elective to allogeneic transplant. Primary endpoint was the acquisition and time to acquisition of HR, MCR by conventional criteria. Secondary endpoints were main toxicities, dead to progression and overall survival. Results: 35 patients were randomized with median follow-up pf 487 days (range 21–858) for entire group. Table 1 shows results for both treatment arms. Table 1 Important toxicities (more than grade II) were thrombocytopenia (20%), neutropenia (28%) and gastrointestinal disturbances (32%) for entire group. Statistical analysis for response and toxicity (chi-square, paired T-student, Log-rank survival analysis) did not show significant differences among treatment arms. . Conclusions: We can not observe significant differences among both treatment arms, but important to note is the rates of HR and MCR, suggesting than the addition of chemotherapy could decrease the leukemic burden improving the function of I. Further research is required to confirm this data. No significant financial relationships to disclose. [Table: see text]
Contributions of the kinase cross-reactivity profile of MK-0457 to clinical activity
Authors: Buser C. A. , Furey B. , Hoover R. , Harding M. , Pollard J. 
Published: March 2020

7050 Background: MK-0457 was designed as a small-molecule inhibitor of the Aurora kinases, AUR A, B, and C (Ki,app = 0.66–18 nM). Kinase screens indicate high selectivity of MK-0457 over other Ser/Thr kinases, but nM potency against a small set of wild type and mutant Tyr kinases, including BCR-ABL, JAK-2, and FLT-3. Consistent with this biochemical profile, MK-0457 has clinical activity in patients with chronic myeloid leukemia (CML) and acute lymphocytic leukemia (ALL) with the T315I BCR-ABL mutation and in patients with JAK-2 positive myeloproliferative diseases (MPD). This study compared the enzyme inhibitory profile of MK0457 with kinase inhibition profiles in cell models to further associate biological and clinical activity. Methods: MK-0457 was tested against a panel of ∼200 kinases (at Km for ATP). Viability of BaF3 cells transfected with wild type or mutant BCR-ABL or FLT3 (D845Y and FLT3-ITD mutants) was measured in MTS assays (72 hrs). Cell cycle profiles were determined by FACS analyses. Cellular inhibition of kinase activities was measured by Western Blots using phospho-substrate specific antibodies. Results: In enzyme profiling, MK-0457 (200 nM) shows = 50% inhibition of ABL, T315I ABL, ABL2, FLT-3, FLT-3 D835Y, BMX, JAK2, YES, LYN, and LCK kinases. Western blot analyses indicate nM IC50s for inhibition of phosphorylation of AUR B, Histone H3 (AUR B substrate), FLT-3, BCR-ABL, and STAT5 (substrate of BCR-ABL and FLT-3 mutants). In addition to AUR kinase inhibition, the Tyr kinases are expected to be inhibited at clinical doses of 24–32 mg/m2/hr (achieving plasma exposures of >1 μM in patients). Depsite its multi-kinase profile, MK-0457 induces similar cytotoxicity (IC50 ∼300 nM) and shows an AUR B-like inhibitory phenotype of G2/M arrest, endoreduplication and apoptosis in BaF3 cells transfected with ABL or FLT-3 (mutant and wild type) kinases. Conclusions: MK-0457 is a potent Aurora kinase inhibitor with cross-reactivity against a small set of Tyr kinases. Although MK-0457 displays an AUR inhibition phenotype in cells, inhibition of these Tyr kinases may contribute to its observed clinical activity in T315I mutant CML and ALL and in JAK-2 positive MPD. No significant financial relationships to disclose.