bluuebunny/crossref_metadata_2025_split huggingface dataset:
Alternatively spliced truncated BCR-ABL1 protein in CML patients with resistance to kinase inhibitors
Authors: Bruey J. , Kantarjian H. , Ma W. , Yeh C. , Peralta R. , Lee T. , O'Brien S. , Estrov Z. , Cortes J. , Albitar M. 
Published: August 2020

7026 Background: We have reported that some patients with imatinib-resistant chronic myeloid leukemia (CML) express an alternatively spliced BCR-ABL mRNA with a 35-bp insertion (BCR-ABL135INS), resulting in the addition of 10 residues and truncation of 653 residues. Molecular dynamic simulation suggested that this truncation and insertion of new 10 AA results in structural changes similar to those seen in BCR-ABL with T315I mutation. Here we evaluate the prevalence of BCR-ABL135INS in imatinib-resistant CML, examine the effect of this mutation on resistance to compared the efficiency of various kinase inhibitors in vitro, and suggest a model for persistent CML and a possible strategy to eradicate residual disease. Methods: Using a sensitive PCR method, we determined the prevalence of the alternatively spliced BCR-ABL135INS mRNA in 288 patients with chronic-phase CML resistant to imatinib. Expression of truncated protein was confirmed by Western blot. We then tested the effectiveness of various kinase inhibitors on human K562 CML cells expressing different levels of BCR-ABL135INS along with wild-type BCR-ABL1. Results: BCR-ABL135INS mRNA was detected in 210 (73%) of the 288 patients. Only 25% of BCR-ABL135INS positive cases showed coexistance of ABL1 kinase point mutation. Immunoprecipitation studies demonstrated that expression of the predicted 143-kD BCR-ABL135INS protein at levels proportional to those predicted by mRNA. Expression of BCR-ABL135INS in K562 cells was sufficient to conferred resistance to imatinib, dasatinib, and nilotinib in a dose-dependant fashion. However, no resistance was detected using aurora kinase inhibitor (MK 0457) or homoharringtonine (HHT). BCR-ABL135INS suppressed imatinib, nilotinib, and dasatinib-mediated dephosphorylation of CRKL, LYN, SRC, and STAT5, but had no effect on MK 0457-mediated dephosphorylation. The combination of imatinib with nilotinib or HHT showed strong synergy, overcoming BCR-ABL135INS-induced resistance in vitro. Conclusions: These findings emphasize the importance of the overlooked alternatively spliced BCR-ABL135INS protein and may provide a strategy to treat resistant disease and eradicate residual CML. No significant financial relationships to disclose.
Subcutaneous omacetaxine mepesuccinate in chronic myeloid leukemia (CML) patients resistant or intolerant to two or more tyrosine kinase inhibitors (TKIs): Data from an ongoing phase II trial
Authors: Wetzler M. , Hellmann A. , Lipton J. , Roy L. , Jones D. , Schenk T. , Hochhaus A. , Benichou A. , Kantarjian H. , Cortes J. 
Published: August 2020

7027 Background: Omacetaxine (OM), a first-in-class cetaxine, shows clinical activity against Ph+ CML with a mechanism of action independent to tyrosine kinase inhibition. Patients (Pts) who have failed multiple TKIs may benefit from an alternative therapy for CML. Methods: Pts include adult CML following resistance or intolerance to at least 2 TKIs. T315I+ Pts are enrolled in a separate trial. Pts receive OM induction at 1.25 mg/m2 subcutaneous (SC) BID for 14 days every 28 days followed by maintenance at 1.25 mg/m2 SC BID for 7 days every 28 days (maintenance after at least one induction cycle and achievement of hematologic response). Results: 60 pts (30 chronic phase [CP], 14 accelerated phase [AP], and 16 blast phase [BP] have been enrolled with 51% having failed at least 3 prior TKIs. Median age: 58 yrs; 50% male. Median disease duration: 74 months. At baseline, 38.5% of pts had Bcr-Abl mutations including 9.6% with compound mutations. The most frequently observed mutations were F317L (11.5%) and V299L (5.8%). OM is well tolerated with transient myelosuppression as the primary toxicity. Grade 3/4 non-hematologic events are rare with pyrexia occurring in 4.3% of patients. Efficacy data are available for 30 Pts: Conclusions: Omacetaxine in multi-TKI resistant or intolerant CML is well tolerated and has achieved hematologic and cytogenetic responses in these heavily pre-treated Pts. [Table: see text] [Table: see text]
Allogeneic hematopoietic cell transplant for multiple myeloma: Comparative results of planned therapy versus salvage therapy
Authors: Shune L. , Weisdorf D. J. , McClune B. , Ma L. , Burns L. J. , Miller J. , Slungaard A. , Arora M. 
Published: August 2020

7035 Background: Despite advances in therapy for multiple myeloma, the disease remains incurable using chemotherapy or immune-modulating agents alone. Several newer hematopoietic cell transplant (HCT) strategies including tandem HCT, and non- myeloablative (NMA) regimens have reported encouraging results. However, the appropriate timing for utilizing these strategies is not clear. Methods: We report outcomes in 51 patients with multiple myeloma who received an allogeneic HCT; either as salvage therapy (after failing a prior autologous HCT), n= 15 or as planned therapy, n= 36, between the years 1996 and 2008 at University of Minnesota. Results: Patients in salvage therapy group were significantly older than in planned therapy group (median age 58 versus 49 years) and had a longer interval from diagnosis to transplant (median 47 versus 10 months). Forty four patients received a HCT from a HLA-identical sibling. Five received umbilical cord blood (four in salvage therapy, one in planned therapy group) and two received unrelated donor HCT (one in each group). Thirteen patients in planned therapy group underwent a tandem transplant (planned autologous followed by NMA sibling HCT). All patients in salvage therapy group, and 50% in planned therapy group received NMA HCT. Patients in salvage therapy group were more heavily pre-treated, all having failed a prior autologous HCT. Complete response was seen in 34% versus 47% of recipients in the two groups, respectively. After a median follow-up of 24 and 41 months, similar relapse was seen, but transplant related mortality (TRM) was significantly higher in salvage therapy group, leading to significantly lower two year survival and disease free survival (DFS) in salvage group. Conclusions: Good overall survival and low transplant related mortality was seen in patients undergoing a planned allogeneic transplant. In heavily pre-treated patients, receiving allogeneic HCT as salvage therapy, despite lower relapse, the high TRM led to lower survival. [Table: see text] No significant financial relationships to disclose.
Outcomes of autologous bone marrow transplantation in non-Hodgkin's lymphoma patients who failed peripheral blood stem cell mobilization
Authors: Sola C. B. , Silva L. , Saliba R. , De Lima M. , Giralt S. , Qazilbash M. , Champlin R. , Khouri I. , Popat U. , Hosing C. 
Published: August 2020

7040 Background: Patients (pts) with relapsed/refractory non-Hodgkin's lymphoma (NHL) who fail to mobilize adequate peripheral blood stem cells (PBSC) often undergo bone marrow (BM) harvest for autologous transplantation. The outcome of these pts is not known. Methods: In this retrospective study (May 1996-September 2006), we identified 36 out of a total of 750 pts with advanced NHL, who failed to collect adequate PBSC and subsequently underwent BM harvest followed by ABMT. Decision to harvest BM was left to the treating clinician. Median age at transplant was 53 years (range 15–73). Twenty of 36 pts (55%) were male. Histology was intermediate grade in 31 (86%) patients and low grade in 5 (14%). Twelve pts (35%) had history of BM involvement with lymphoma. Median number of chemotherapy cycles received prior to mobilization was 3 (range 1–6). At the time of stem cell mobilization 18 (50%) were in complete remission (CR), 13 (37%) were in partial remission (PR) and 5 (13%) had progressive disease (PD). Twenty four (67%) pts underwent chemo-mobilization and 12 (33%) were mobilized with cytokines alone. Results: The median total nucleated cell dose and CD34+ cell dose harvested/kg were 3.72 x 108 (range 0.25–58.0) and 1.6 x 106 (range 0.03–5.8), respectively. After ABMT, 33 of 35 evaluable (94%) pts engrafted neutrophils with median time to ANC 0.5 x 109/L of 23 days (range 8–47). Median time to platelet count 20 x 109/L was 63 days (range 11–375). Two of 35 (6 %) evaluable pts failed to engraft. After ABMT, 25/36 (70%) pts achieved a CR. The incidence of NRM at 100 days was 15%. Sixteen (45%) pts relapsed at a median of 11 months (range 2–59) from ABMT. After a median follow-up of 34 months (range 0.4–100), the 3-year OS and DFS were 47% and 35%, respectively. Causes of death were: disease progression/relapse in 15 (60%), secondary malignancy in 3 (12%), multiorgan failure in 5 (20%), and unknown in 2 (8%). Conclusions: ABMT is feasible in pts who fail to mobilize adequate PBSC, however, these pts have longer time to engraftment. Although the CR rate after transplant is high, the NRM is higher than expected. Non-myeloablative allogeneic transplantation may provide better outcomes with similar toxicity and needs to be further studied. No significant financial relationships to disclose.
Multiple myeloma: Autologous stem cell transplantation versus conventional chemotherapy—A retrospective age and stage matched analysis
Authors: Gupta A. , Kumar L. , Dabkara D. , Gupta D. , Sharma O. , Sreeniwas V. 
Published: August 2020

7041 Background: We retrospectively analyzed results of MM patients who underwent high-dose chemotherapy and stem cell transplantation (ASCT). In age and stage matched analysis, we compared with those patients who received conventional chemotherapy. Methods: Between January 1995 and June 2007, 95 patients underwent ASCT (Tx Group). 149 age and stage matched patients received conventional chemotherapy (CC Group). High-dose melphalan (200 mg/m2) was used for conditioning in Tx group. Baseline characteristics were comparable in both groups: median age was 50 years (range, 26 to 68 years) in Tx group versus 52 years (range 24 to 68 years) in CC group, p < 0.05; M:F = Tx Group -68:27 versus CC Group 98:51, p = 0.34; stage 3A/3B = 76.8%/23.2% in Tx Group versus 62.4%/37.6%, p = 0.02; mean Hb (Gm/dl) 9.1(range, 3.3–14.3) versus 8.6 (3.3–14.8), p = 0.21; median serum albumin (Gm/dl) 3.5 (range, 1.8–5.2) versus 3.4 (1.6–6.2), p = 0.7, respectively in two groups. Results: Following treatment, the response rates (CR + VGPR + PR = 81%) were significantly higher in Tx group compared to CC group (55%), p = 0.001. CR rate was higher in Tx group, 34.7% versus 12.8%, p < 0.001. The median overall survival was significantly higher in Tx group (75 months, 95%CI [72–106 months]) versus (24 months, 95%CI [19–36months]), p = 0.001. The median progression free survival was 30 months in Tx group (95%CI [21–48 months]) compared to 6 months in CC group (95% CI 3–9 months), p < 0.0001. Estimated overall survival at 5 years in Tx group is 66.6% (95% CI [54.8%-75.9%]) compared to 20.7% (95% CI [13.5%-29%]) in CC group. Conclusions: High-dose chemotherapy followed by autologous stem cell transplantation results in higher overall and complete response rates in multiple myeloma patients. This is associated with improved progression free and overall survival. Low-dose maintenance therapy to sustain the survival benefit of transplant would be possible areas of research in future studies. No significant financial relationships to disclose.
A phase II study of the tolerability and activity of weekly vincristine sulfate liposomes injection (VSLI) in adults with Philadelphia chromosome-negative (Ph-) acute lymphoblastic leukemia (ALL) in second relapse or progressing following two antileukemia treatment lines
Authors: Heffner L. T. , Damon L. E. , Larson M. L. , Schiller G. , Stock W. , Kantarjian H. M. , Lu B. , Imperiale S. M. , O'Brien S. 
Published: August 2020

7046 Background: VSLI (Marqibo) is a nanoparticle formulation of vincristine sulfate (VCR) encapsulated in sphingomyelin/cholesterol liposomes called Optisomes. The optisomal formulation lends itself to an improved pharmacokinetic profile and enhanced tumor penetration and concentration. Preclinical studies of VSLI showed enhanced efficacy versus standard VCR in a variety of solid and hematologic malignancies. VSLI has a maximum tolerated dose of 2.25 mg/m2 with no dose cap, while conventional VCR is dosed at 1.4 mg/m2 with a 2 mg dose cap. A previous study in relapsed ALL showed a complete response rate of 19%, warranting further study. Methods: Eligible adult subjects received single agent intravenous VSLI at a dose of 2.25 mg/m2 weekly with no dose cap. This international, multicenter, single-arm study will enroll approximately 56 subjects. Major endpoints include response rate and overall survival (OS). An interim analysis was planned following enrollment of 29 evaluable subjects. Results: 29 heavily pretreated subjects received ≥ 1 dose of VSLI. To date, at least 9 of 29 subjects had clearing of leukemic blasts and achievement of an M1 bone marrow. Based on preliminary data, the median OS is estimated to be 7.5 months (95% CI: 4.7–10.5) using the Kaplan-Meier method. The most frequent related adverse event (AE) was peripheral neuropathy (PN) (48%), half of which was grade 3. No grade 4 PN was reported. Six subjects had 8 treatment-associated grade 4 AEs of neutropenia (4), thrombocytopenia (2), anemia (1), and inappropriate antidiuretic hormone secretion (1). Conclusions: These results are encouraging, as VSLI was given as a single agent to a heavily pretreated patient population who nearly universally received prior VCR. This population typically has a very low response rate to anti-leukemia therapies. Early OS data compares favorably to an historical median OS of ∼ 2 months (8.7 weeks) in a second salvage population (data on file, M. D. Anderson). VSLI was well tolerated in these patients in the context of universal prior vincristine treatment. [Table: see text]
Effect of the proton pump inhibitor esomeprazole on the oral absorption and pharmacokinetics of nilotinib
Authors: Gallagher N. J. , Fischer D. , Demirhan E. , Zhou W. , Golor G. , Schran H. , Yin O. 
Published: August 2020

7053 Background: Nilotinib, a highly selective and potent BCR-ABL tyrosine kinase inhibitor, is approved for the treatment of CML-CP and CML-AP patients resistant or intolerant to prior therapy including imatinib. The solubility of nilotinib is pH dependent, with lower solubility at higher pH. We evaluated whether esomeprazole, a potent proton pump inhibitor (PPI) that can significantly increase gastric pH, could affect the oral absorption and pharmacokinetics of nilotinib in healthy subjects. Methods: Twenty-two subjects (6 F, 16M, age range 18–64 years) were enrolled to receive nilotinib alone or in the presence of steady-state esomeprazole during two treatment periods. Nilotinib was given as a single oral 400 mg dose on days 1 and 13, and esomeprazole 40 mg once-daily on day 8 through day 13. Serial blood samples were collected up to 72 hours after nilotinib dosing for determination of nilotinib serum concentrations by a validated liquid chromatography-tandem mass spectrometry assay. Gastric pH was monitored in all subjects at baseline (prior to nilotinib and esomeprazole dosing), before and during the first 4 hrs of esomeprazole steady state dosing (fifth dose on Day 12). Results: When coadministered with esomeprazole, nilotinib Cmax was decreased by 27% (397±89 vs 303±157ng/mL) and AUC0-∞ decreased by 34% (11515±6140 vs 7164±3752ng*hr/mL) respectively. The median time to reach nilotinib Cmax was slightly prolonged from 4.0 hrs to 6.0 hrs, but its elimination half-life was not altered (17.3±10.7 vs 15.9±6.6 hrs). Median gastric pH was increased from 0.8 at baseline to 2.0 at pre-dose, and to 3.9, 5.8, 5.5, and 5.7 at 1, 2, 3, and 4 hrs after esomeprazole dosing. Administration of nilotinib alone or in combination with esomeprazole was generally well tolerated in the study subjects. Conclusions: The study results demonstrate a modest reduction in the rate and extent of nilotinib absorption when co-administered with esomeprazole. Such an effect is unlikely to cause a significant clinical consequence for nilotinib therapy, and thus nilotinib can be used with esomeprazole or other PPIs without the risk of substantial decrease in nilotinib systemic exposure. [Table: see text]
Pretransplant comorbidity as an outcome predictor in adult patients younger than 60 years of age receiving standard induction chemotherapy for de novo acute myeloid leukemia
Authors: Kim S. , Lee J. , Lee J. , Kim D. , Lim S. , Lee Y. , Kang Y. , Seol M. , Ryu S. , Lee K. 
Published: August 2020

7055 Background: Comorbidity has been evaluated as an outcome predictor in elderly patients receiving induction chemotherapy for acute myeloid leukemia (AML) as well as in patients undergoing allogeneic hematopoietic cell transplantation (HCT) for various hematologic disorders. In this single-institute retrospective study, we investigated the prognostic significance of comorbidity in younger AML patients. Methods: A total of 276 patients, aged 14 to 59 years, who received standard induction chemotherapy consisting of cytarabine plus daunorubicin or idarubicin for de novo AML excluding M3 subtype between 2000 and 2007 were included. Pre-treatment comorbidity score, assessed by the HCT specific comorbidity index (HCT-CI), was calculated using clinico- pathologic data, which were retrieved from Asan Medical Center Leukemia Registry Database. The HCT-CI score was 0 in 113 patients (40.9%), 1 in 94 (34.1%), and ≥ 2 in 69 (25.0%). Results: In the univariate analyses, the HCT-CI score was not a significant prognostic factor for induction of complete remission (CR), whereas survival outcomes such as overall survival (OS), relapse-free survival (RFS) and event-free survival (EFS) were significantly different according to the HCT-CI scores (Table). The multivariate models showed that the HCT-CI score was an independent prognostic factor for EFS (P=0.044), but not for OS (P=0.301) and RFS (P=0.119). Other independent prognostic factors were age (P=0.001 for OS, P=0.002 for RFS, P=0.006 for EFS), initial leukocyte counts (P=0.006 for CR, P<0.001 for OS, P=0.039 for RFS), initial uric acid levels (P=0.004 for RFS, P=0.001 for EFS), and cytogenetic risk groups (P=0.012 for CR, P<0.001 for OS, P<0.001 for RFS, P=0.005 for EFS). Conclusions: Pre-treatment comorbidity may provide additional prognostic information over established prognostic factors in patients younger than 60 years of age receiving standard induction chemotherapy for de novo AML. [Table: see text] No significant financial relationships to disclose.
Monitoring chronic myeloid leukemia (CML) response to tyrosine kinase inhibitors (TKI) and homoharringtonine (HHT) using peripheral blood (PB) fluorescence in situ hybridization (FISH) and quantitative RT-PCR (Q-PCR): Are bone marrow biopsies still needed?
Authors: Khoury H. J. , Lima L. , Saxe D. , Mann K. P. , Arellano M. , Heffner L. , Bernal-Mizrachi L. , McLemore M. , Langston A. , Winton E. 
Published: August 2020

7064 Background: The purpose of this study is to compare simultaneously obtained PB and bone marrow (BM) BCR-ABL FISH and Q-PCR to monitor response to TKI and HHT in CML. Methods: Between January 2005 and December 2008, 52 patients (pts) with chronic (n = 37, 80%), accelerated (n = 6, 7%), and blast phase (n = 9, 14%) CML had 112 simultaneous PB and BM FISH and Q-PCR before and/or after start of imatinib (IM, n = 27), dasatinib (n = 9), nilotinib (n = 1), bosutinib (n = 13), or HHT (n = 2) for newly diagnosed (n = 27), IM resistant (n = 20), or IM intolerant (n = 5) CML. 13 (26%) had chromosomal abnormalities in addition to the Philadelphia chromosome, and 10 (20%) had a detectable BCR-ABL mutation including the T315I in 2 pts. Results: 24 (46%) had simultaneous PB and BM FISH and/or Q-PCR measurements obtained at 1 time point, 9 (17%) at 2; 9 (17%) at 3; 10 (20%) at > 4 time points before and/or post-initiation of TKI or HHT. Excellent concordance was observed between PB and BM at all time points for both FISH (r = 0.96; p = 0.0003) and Q-PCR (r = 0.88; p= 0.0015). Correlation was not affected by the presence of additional chromosomal abnormalities, phase of the disease, treatment (TKI or HHT), or the number of prior therapies. Conclusions: FISH and Q-PCR are reliable methods to monitor CML response to TKI and HHT in patients with CML and may render the need for BM biopsy monitoring obsolete. No significant financial relationships to disclose.
Patterns of imatinib resistance mutation analysis in chronic myeloid leukemia (CML) patients on imatinib at the time of loss of response to the drug in Asian Indian subjects
Authors: Prabhash K. , Vora T. , Ghadyalpatil N. S. , Rangarajan B. , Hingmire S. S. , Menon H. , Jain P. , Kurkure P. A. , Parikh P. M. 
Published: August 2020

7079 Background: The treatment of (CML) has undergone major changes in the past decade with the introduction of tyrosine kinase inhibitors (TKI). However the initial enthusiasm is waning with increasing recognition of drug resistance. There is an urgent need to identify the types of receptor mutations which lead to drug resistance and their significance in salvage therapy. Methods: We identified 17 males and 8 female patients with median age 40 yrs (range 9–55 years) with CML who were on imatinib at the time of loss of hematologic response (HR), cytogenetic (CyR), or molecular response (MR) and performed imatinib-resistance mutation analysis. The sequencing was done on ABI machine by direct sequencing method. Results: This group included 22 patients with chronic phase (CP) disease, 2 patients with accelerated phase (AP), and 1 patient with extramedullary blast crisis (BC). Fourteen patients received treatment with agents other than imatinib as the first-line therapy due to either nonavailability of the drug at the time of diagnosis in India, but were started on imatinib when drug became available. The other 11 patients received imatinib as first-line therapy. The best response to imatinib included major CyR in 14 patients which included 3 patients with complete CyR and minor CyR in 6 patients. Lack of HR was noted in 2 patients in whom CyR was not evaluated. Imatinib resistance mutation analysis was prompted by no HR (n = 2); loss of HR after achieving CyR (n = 9); failure to achieve CyR milestones (n = 3); loss of CyR (n = 9); development of extramedullary BC (n = 1). The analysis revealed no mutations-11 patients, M351T-4 patients, G250E-3 patients, F317L-2 patients, M244V- 1 patient, T315I-1 patient, F382L-1 patient, results awaited in 4 patients with 2 patients showing 2 mutations. Conclusions: The majority of patients 11/25 had no detectable mutations while T315I which confers resistance to all TKIs was detected only in 1/25 patients who demonstrated loss of response in our population. The correlation of the other mutations to loss of response and the response to second line TKI needs to be studied in further detail. In addition analysis of mutation patterns at baseline may help in stratifying patients for treatment. No significant financial relationships to disclose.