bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Effect of Interleukin-11 (Oprelvekin, Neumega®) on Thrombocytopenia Associated with Tyrosine Kinase Inhibitors (TKI) in Patients with Chronic Myeloid Leukemia (CML).
Authors: Aribi Ahmed M. , Kantarjian Hagop , Ault Patricia , Koller Charles Asa , Thomas Deborah , Faderl Stefan , Garcia-Manero Guillermo , Cortes Jorge 
Published: October 2019

Abstract
During therapy with Imatinib and other TKI, 20–50% of patients with CML develop grade ≥3 thrombocytopenia. This frequently leads to treatment interruptions and dose reductions that may decrease the probability of achieving a cytogenic response. IL-11 is a megakaryopoietic cytokine that reduces the incidence and the severity of thrombocytopenia associated with chemotherapy. We investigated the efficacy and the safety of low dose IL-11 in improving thrombocytopenia associated with imatinib and other TKI therapy in 13 patients (pts) with CML. Pts were included if they
had CML in chronic or accelerated phase receiving therapy with imatinib, nilotinib, or dasatinib; developed grade ≥3 thrombocytopenia (platelets <50x109/L) after the first 4 weeks of therapy with TKI, and had thrombocytopenia that was either recurrent or requiring TKI dose reductions.
The starting dose of IL-11 was 10mcg/kg 3 times weekly and the dose escalated by 1 dose level every 2 weeks if the patients had no sustained platelet increase ≥10x109 /L above the baseline on at least 2 consecutive measures 1 weeks apart.
The median age is 52 yrs (range, 34–77 yrs). Median platelet count at diagnosis was 164 x109/L (range, 911–72 x109/L); median platelet count at the time IL-11 was started was 37 x109/L (range, 3–74 x109/L). Eleven pts were in chronic, and 2 in accelerated phase. Eight pts were treated with imatinib with a dose range from 300 to 800 mg/day; 3 pts with dasatinab 70–75 mg twice daily; and 2 pts with nilotinib 400mg twice daily. All pts had dose reduction of the TKI prior to initiation of IL-11. After initiation of IL-11, eight of 13 pts had an increase in platelet count with median peak platelet count of 102 x109/L (range, 51–160 x109/L), including 1 pt that normalized platelet counts. Only one of the 8 responders had further TKI dose reduction after IL-11 was started; one of the 8 responders was taken off study secondary to noncompliance, and 1 had IL-11 therapy discontinued secondary to fatigue. One pt that did not show a platelet increase had however his imatinib dose increased from 300 to 500 mg daily. Seven patients had decrease in the number of days of TKI therapy interruption secondary to thrombocytopenia after initiation of IL-11 (12 % of the total treatment time as compared to 30% before the start of interleukin-11). There was no significant toxicity observed with IL-11 therapy except for grade 4 fatigue in one patient which led to discontinuation of therapy and grade 2 peripheral edema in one patient which led to dose reduction.
We conclude that the IL-11therapy in CML pts with ≥ grade 3 thrombocytopenia may lead to improvement in platelet count and minimize treatment interruptions of TKI. At the doses used in this study, IL-11 can be administered with minimal toxicity in most pts.
The FcR γ Chain Potentiates Outside-In Integrin Signaling.
Authors: Boylan Brian , Newman Debra K. , Newman Peter J. 
Published: October 2019

Abstract
The FcRγ chain is a 12 kDa homodimer that exists in the platelet plasma membrane non-covalently associated with platelet membrane glycoprotein (GP)VI. Interaction of laminin or collagen fibers in the vessel wall with GPVI results in rapid transmission of activation signals into the cell - a process that is dependent on Src family kinase-mediated phosphorylation of Immunoreceptor tyrosine-based activation motifs (ITAMs) within the cytoplasmic domain of FcRγ. Tyrosine phosphorylated FcRγ, in turn, recruits the tyrosine kinase Syk, which then initiates a signal amplification pathway involving assembly of a series of adaptor proteins, activation of phospholipase Cγ2, and generation of second messengers that facilitate granule secretion, activation of the platelet integrins, and platelet aggregation. We and others have recently shown that loss of the GPVI/FcRγ chain complex from the surface of either human or murine platelets renders them unresponsive to collagen and laminin. Unexpectedly, GPVI/FcRγ-chain-depleted platelets also exhibited moderately reduced reactivity to adenosine diphosphate (ADP) and thrombin, which activate platelets by binding to the G protein coupled receptors (GPCRs) P2Y1, P2Y12, PAR1, and PAR4, respectively. Because GPCR-mediated platelet activation has not previously been thought to involve signals emanating from the GPVI/FcRγ-chain complex, we sought to determine whether the FcRγ chain might function to amplify platelet activation responses following GPCR-mediated signaling. Human platelets were exposed to ADP, thrombin or the TXA2-mimetic, U46619, allowed to aggregate, and detergent lysed. Phosphotyrosine immunoblot analysis revealed that the FcRγ chain became rapidly phosphorylated on its ITAMs during platelet aggregation induced by either thrombin or U46619. Interestingly, FcRγ chain phosphorylation was completely inhibited when platelets were activated in the presence of RGD peptides, which allow platelet activation and granule release, but prevent fibrinogen binding to the major platelet integrin, GPIIb-IIIa. The observation that the FcRγ chain becomes tyrosine phosphorylated following GPCR signaling in an RGD-inhibitable manner suggests that integrin-associated kinases might be capable of phosphorylating FcRγ, either directly or indirectly, downstream of ligand binding, though evidence for this remains to be determined. Taken together, these dataprovide support for the notion that the FcRγ chain functions as a general amplifier of platelet activation,helps to explain why GPVI-depleted platelets exhibit blunted responses to agonists specific for GPCRs, andmay lead to important new insights into the mechanism of action of contemplated GPVI-based therapeutics.
Correlations between BCR-ABL Ratio and Cytogenetic Response at Months 12 of the Randomized French SPIRIT Study on Behalf the Fi-LMC Group.
Authors: Preudhomme Claude , Roche-Lestienne Catherine , Crinquette Antoine , Roumier Christophe , Eclache Virginie , Guilhot Joëlle , Guilhot Francois , Mahon François-Xavier 
Published: October 2019

Abstract
In September 2003, the French CML study group (Fi-LMC) activated the four armed randomized SPIRIT trial comparing imatinib 400mg with imatinib 600mg, imatinib 400mg + ara-C and imatinib 400mg + pegylated interferon in newly diagnosed CML in chronic phase. The molecular monitoring was centralized and performed, according to the EAC protocol, in duplicate on the same BCR-ABL cDNA among two French laboratories (Bordeaux and Lille). Data were expressed as BCR-ABL/ABLx100 on the new internationally agreed scale (IS) using a conversion factor of 1.33 and 0.80 for Bordeaux and Lille respectively. A good correlation between the two laboratories was observed. During the first year of follow-up the quantification was performed each three months (M0 to M12). In May 2006, 297 of the 492 enrolled pts had a follow up of more than 12 months, and 263 pts were analysed at M12. Using the IS, the median values of the BCR-ABL/ABL normalized ratios were 90%, 6,4%, 0.68%, 0.32% and 0.16% at M0, M3, M6, M9, and M12 respectively. At M12, 15%, 29%, 27%, 17% and 12% of the pts presented a BCR-ABL/ABL ratio lower than 0.01%, 0.1% ,1%, 10%, and 100% respectively. Overall, 71% of the pts presented a ratio lower than 1%. Conventional cytogenetic data were available for 193 pts at M12: 156 pts (80%) were in complete cytogenetic response (CCR), 25 pts (13%) were in major cytogenetic response (MCR) and 12 pts (6.2%) were in minor or a lack of cytogenetic response. Among pts with a BCR-ABL transcript ratio lower than 1%, all except four were in CCR. The last 4 cases were in MCR associated with BCR-ABL ratios of: 0.96% for one pt, 0.08% and 0.12% for 2 pts (who further reached CCR at 6 and 18 months) and 0.128% for the last one. Percentages of Philadelphia positive metaphase (Ph+) were 4%, 6%, 5 % and 15% respectively. Among the 30 pts with a BCR-ABL ratio > 5%, none were in CCR and only 18 pts were in MCR. Among the 27 pts presenting a BCR-ABL ratio in the 1%–5% intervals, 20 pts were in CCR and 7 pts were in MCR (5 pts with Ph+ lower than 10% and two pts with 16% and 20% Ph+).
In conclusion, our findings suggest that a ROC statistical test will be able to determine critical BCR-ABL/ABL ratios associated to CCR in our study. Nevertheless, at M12 the percentage of available data was superior using molecular than cytogenetic monitoring, suggesting that molecular monitoring expressed with the new international scale is probably sufficient fore more than 85 % of the pts treated by IM solely or in association.
A Half-Log Increase in Quantitative RT-PCR for BCR-ABL (RQ-PCR) as a Trigger for Kinase Domain Mutation Analysis.
Authors: Press Richard D. , Willis Stephanie , Rempfer Carole , Mauro Michael J. , Druker Brian J. , Deininger Michael W.N. 
Published: October 2019

Abstract
RQ-PCR for BCR-ABL is standard of care for monitoring patients with chronic myeloid leukemia on Abl kinase inhibitor therapy, and mutations in the kinase domain (KD) of BCR-ABL are the most frequent mechanism of acquired drug resistance. From a practical point of view, it is important to establish an RQ-PCR trigger for mutation analysis that is sufficiently sensitive, while avoiding a high rate of false positive results. In one study, a single 2-fold (0.3 log) rise in BCR-ABL transcript levels predicted mutations in 61% (1). However, the results were not confirmed in a similar study(2). We therefore analyzed the correlation between a slightly more conservative 0.5 log rise in RQ-PCR levels and mutation detection in an unselected cohort of imatinib-treated CML patients. A database search identified 273 samples (from 150 patients) with a half-log or greater RQ-PCR rise. Mutation analysis (by direct DNA sequencing) has been completed on 54 samples. BCR-ABL levels were higher in 44 samples with successful amplification and sequencing compared to 10 without sufficiently good sequencing quality [median log-drop 0.31 (range −1.2 − 2.4) vs. 2.2 (range 0.17 – 3.2), p<0.0001]. KD mutations were detected in 11 samples (25%) and included L248V, G250E, Y253H, E282G, E292V, T315I (n=2), F359V+H396R, V379I, F382L, F482S). A similar mutation rate was detected by using a trigger of a 1.0-log increase of RQ-PCR levels [4 mutations out of 19 eligible samples (21%)], but with this higher trigger level, 7 patients with mutations would be excluded from detection. We then analyzed the risk of relapse according to mutation detection. The 44 samples with a >0.5 log RQ-PCR increase were from 34 different patients. Eleven of these 34 patients had cytogenetic or hematologic progression at the time of the mutation analysis and 7 never achieved even a partial cytogenetic response (<65%). Of 16 remaining eligible patients, 9 subsequently relapsed at a median of 5.8 (range 2.6–17) months after mutation detection. Freedom from progression was shorter in patients with a half-log RQ-PCR increase compared to patients without (34 months from imatinib start vs. median survival not reached, p = 0.019).
Conclusion: In our hands, a half-log increase of BCR-ABL levels is associated with mutation detection in 25% of samples, yields a significantly increased risk of subsequent relapse, and may be used as a practical trigger for kinase domain sequencing. Analysis of additional samples is ongoing to determine the ideal trigger level that optimizes specificity and sensitivity.
Imatinib Mesylate Discontinuation in Patients with Chronic Myelogenous Leukemia in Complete Molecular Remission: An Update Follow Up.
Authors: Mahon Francois-Xavier , Huguet Francoise , Etienne Gabriel , Réa Delphine , Cayuela Jean-Michel , Marit Gerald , Gardembas Martine , Reiffers Josy , Philippe Rousselot 
Published: October 2019

Abstract
The BCR-ABL tyrosine kinase inhibitor imatinib mesylate (Gleevec) induces complete cytogenetic responses (CCR) in more than 85% of patients with chronic myelogenous leukemia (CML). However, patients in CCR relapse after imatinib interruption in case of detectable residual disease. In fact, less than 10% of patients achieve a molecular remission, defined by an undetectable residual disease using real time quantitative polymerase chain reaction (RTQ-PCR). We previously reported the outcome of CML patients in CCR after cessation of interferon-alpha during the pre-imatinib era. Seven (all with a negative PCR) out of 15 patients did not relapse (J Clin. Oncol.,20,2002:214–220). In the present study, we address the issue of the discontinuation of imatinib in CML with undetectable residual disease for more than 2 years in 15 patients. The median duration of RTQ-PCR negativity and imatinib therapy were respectively 32 months (24–46) and 45 months (32–56) before imatinib interruption. Eight patients displayed a molecular relapse with a detectable BCR-ABL transcript appearance between the first 6 months. Imatinib was then re-introduced and led to a novel molecular response in most patients. Seven other patients have still an undetectable level of BCR-ABL transcript after a median follow up of 20 months (9–24). With the assumption that the doubling time of a proliferative CML cell is 8 days, it will take a maximum of 6 months if only one leukemic cell persists and proliferates to reach 107 cells i.e corresponding to a residual disease detectable by RTQ-PCR. Relapses observed within 6 months may reflect the kinetic of undetectable dividing CML cells. Those cells may be eradicated or controlled in long term non relapsing patients described in our study.
Imatinib Mesylate Therapy in Late Ph+ Chronic Myeloid Leukemia Patients in Stable Complete Cytogenetic Response after Interferon-Alpha Results in a Very High Complete Molecular Response Rate.
Authors: Alimena Giuliana , Breccia Massimo , Luciano Luigia , Quarantelli Fabrizio , Diverio Daniela , Izzo Barbara , De Angelis Biagio , Mancini Marco , Latagliata Roberto , Carmosino Ida , Nanni Mauro , Rotoli Bruno , Mandelli Franco , Pane Fabrizio 
Published: October 2019

Abstract
Imatinib mesylate was given to 26 Philadelphia positive (Ph+) chronic myeloid leukemia (CML) patients who were in late chronic phase (CP) and in stable complete cytogenetic response (CCR) after interferon-alfa (IFN-α), but showed persistent positive residual disease at PCR analysis under this treatment. At diagnosis median age was 40 years (range 21–64) and according to Sokal’s score, 18 patients were low risk and 8 were intermediate risk. Median IFN treatment was 88 mo.s (range 15–202) and median CCR duration was 73 mo.s (range 10–148). Imatinib was administered at the standard dose of 400 mg/die, after stopping IFN for 1 week. Residual disease was measured on bone marrow (BM) cells at baseline, before starting Imatinib, at 3, 6, 12, 18 mo.s and at the last follow-up (median 32 mo.s, range 21–49), by assaying BCR-ABL transcripts using quantitative PCR (RQ-PCR). The copy number (CN) of BCR/ABL and ABL transcript were derived by the interpolation of CT values to the appropriate standard curve, and the result, for each sample, was expressed as ratio of BCR/ABL mRNA copies to ABL mRNA x 100 (normalized copy number - NCN).
Imatinib treatment resulted in a progressive and consistent decline of residual disease in all but one patient, from a median of 0.89 at baseline to 0.01 at the end of follow-up. Major molecular response (BCR/ABL levels <0.1) was reached in 20 patients (77%) and BCR/ABL transcripts were undetectable in 13 (50%). Achievement of molecular response was significantly correlated with post-IFN baseline transcript level (mean 1.194 for patients achieving complete molecular response vs 18,97 for those who did not; p<0.001), but not with other clinical/biological patient characteristics. In all patients, imatinib was well tolerated with no side effects requiring drug dose reduction or dose discontinuation.
Albeit obtained from an unusual subset of selected patients with favourable prognosis, and likely particularly sensitive to imatinib, present results confirm the efficacy of combining Imatinib and IFN-α and further support investigating treatment approaches employing these two drugs.
Dasatinib (SPRYCEL®) in Patients (pts) with Chronic Myelogenous Leukemia in Accelerated Phase (AP-CML) That Is Imatinib-Resistant (im-r) or -Intolerant (im-i): Updated Results of the CA180–005 ’START-A’ Phase II Study.
Authors: Cortes Jorge , Kim D.W. , Guilhot F. , Rosti G. , Silver R.T. , Gollerkeri A. , Agarwal P. , Branford S. , Apperley J.F. 
Published: October 2019

Abstract
Dasatinib (SPRYCEL®, formerly BMS-354825) is a novel, oral, multi-targeted kinase inhibitor that induces complete hematologic and cytogenetic remissions in pts in all phases of im-r or im-i CML. START-A is an open-label study of dasatinib in pts with im-r or im-i AP-CML. Preliminary results with early follow-up suggested significant activity. The present report updates the results of this study with a minimum of 9 months of follow-up. Dasatinib was given orally at 70 mg twice daily (BID). Dose escalation to 100 mg BID was allowed for inadequate initial response and reduction to 50 or 40 mg BID for persistent toxicity.
Evaluation included weekly blood counts and monthly bone marrow including cytogenetics. Molecular evaluation of BCR-ABL transcript levels by real-time qPCR was performed at baseline and upon documentation of complete cytogenetic response. A total of 174 pts (161 im-r and 13 im-i) were enrolled between December 2004 and July 2005 in 39 centers worldwide. There were 96 (55%) males; median age was 57 years (range 22–86); median time from original diagnosis of CML was 82 months.
Prior therapy included im in all pts (>600 mg/day in 91 (52%), im for >3 years in 103 (59%) pts, interferon in 126 (72%) pts, stem cell transplantation in 23 (13%) pts. Major cytogenetic response (MCyR) to prior im had been seen in 57 (33%) pts. The average daily dose (median across all pts) was 130 mg/day (range 44–199). Major hematologic response (MaHR) was documented in 110 (63%) pts with complete hematologic response in 75 (43%) and no evidence of leukemia in 35 (20%). At 9 months, 85% of pts have maintained their MaHR. MCyR was documented in 65 (37%) pts, complete in 49 (28%), partial in 16 (9%). Median progression-free survival (PFS) has not been reached; estimated PFS at 9 months is 70%. In the 94 pts with BCR-ABL mutations at baseline the MaHR rate was 69%. Generally, response rates were similar in the im-i and im-r groups. Cytopenias were significant with grade 3–4 thrombocytopenia and neutropenia in 82% and 76% of pts, respectively. Non-hematologic toxicities were generally mild to moderate. The most frequent (% any grade, % grade 3–4) were diarrhea (51%, 8%), headache (29%, 1%), fatigue (26%, 4%), fever (25%, 3%) and pleural effusion (25%, 3%). Pleural effusions were optimally managed with dose interruption and diuretics and/or pulse steroids. Dasatinib is highly effective in pts with im-r or im-i AP-CML with high rates of durable MaHR and MCyR. An updated analysis with at least 12 months of follow-up, including molecular response data and mutational analysis at time of progression, will be presented.
IRF-4 Functions as a Myeloid Tumor Suppressor.
Authors: Acquaviva Jaime , Schatz Jonathan , Singh Harinder , Ren Ruibao 
Published: October 2019

Abstract
Interferon regulatory factor 4 (IRF-4, also know as pip, LSIRF, ICSAT and MUM1) is a transcription factor with well-characterized functions in B and T cell development and immune response regulation. Though its expression has been demonstrated in macrophages, its function in the myeloid system is not as well characterized. The closely related IRF family member IRF-8 (ICSBP) has more clearly defined functions in the myeloid system. IRF-8 is a critical regulator of myelopoiesis, and its loss has been implicated in the pathogenesis of chronic myelogenous leukemia (CML). IRF-8 deficient mice manifest a CML-like syndrome, and we have shown previously that forced expression of IRF-8 in a BCR/ABL-induced murine model of CML represses the resulting myeloproliferative disease and prolongs survival. In the B-cell system, we have found that IRF-4 and IRF-8 function redundantly at the pre-B-to-B transition point of development. In this study we investigate whether IRF-4 and IRF-8 may also have overlapping function in myeloid cells. Our results show that mice deficient in both IRF-4 and IRF-8 develop from a very early age a more aggressive CML-like disease than mice deficient in IRF-8 alone. Bone marrow progenitors from IRF-4/8 DKO mice have increased proliferation, GM-CSF stimulated granulocytic differentiation, and colony-forming capacity compared to progenitors from WT or single KO mice. These data suggest that IRF-4 plays a role in myeloid lineage development and may act to suppress proliferation and granulocytic differentiation of myeloid progenitor cells. We further examined if, like IRF-8, IRF-4 is able to suppress BCR/ABL mediated transformation. We used a murine stem cell virus vector to co-express BCR/ABL and either IRF-4 or IRF-8 in BM progenitor cells and assessed colony forming capacity of infected cultures as well as the ability of IRF-4 to suppress BCR/ABL induced CML-like disease in a murine model. Our results demonstrate that IRF-4 potently suppresses BCR/ABL induced colony formation and that forced expression of IRF-4 suppresses BCR/ABL-induced CML-like disease in mice even more potently than IRF-8. These results provide direct evidence that IRF-4 is an important myeloid tumor suppressor and may allow elucidation of new molecular pathways significant to the pathogenesis of human CML.
Leukemic Transformation of Primary Human CD34+ Progenitor Cells by MLL-AF9 Recapitulates the Phenotype and Gene Expression Profile of MLL Rearranged AML.
Authors: Mulloy James C. , Wei Junping , Rettig Catherine , Wunderlich Mark , Alvarez Sara , Cigudosa Juan , Jansen Michael , DiMartino Jorge F. 
Published: October 2019

Abstract
The t(9;11)(p22;q23) results in the creation of an MLL-AF9 fusion gene and is observed in 27% of 11q23 leukemias. t(9;11) is commonly associated with an M5 monocytic leukemia and patients harboring this translocation are included in the intermediate or poor cytogenetic risk groups, with an average 42% overall survival at five years. Using primary human hematopoietic progenitor cells, we have developed a system that closely mimics the MLL-AF9 associated disease observed in human acute myeloid leukemia (AML). Injection of MLL-AF9 expressing cells into sublethally-irradiated NOD/SCID mice produced an aggressive FAB-M5-like leukemia that infiltrated the spleen and liver and induced death with an average latency of 8 weeks. Serial transplantation of leukemic cells recapitulated the disease with a similar latency. MLL-AF9 expression conferred the ability to grow indefinitely in culture, promoted an accumulation of cells resembling monoblasts and was associated with an increase in telomerase activity. Mono- or oligoclonal outgrowth arose in vitro as well as in vivo. Numeric karyotypic changes or normal karyotypes, in the absence of structural rearrangements, additions or deletions were detected in cultured cells as well as samples from leukemic mice. Principal Component Analysis of genome-wide gene expression data from MLL-AF9 expressing cultured cells revealed a gene expression signature that closely mirrors that observed in MLL-rearranged leukemic cells from patient samples. Furthermore, training of a (linear) Support Vector Machine with gene expression data from patient samples resulted in the correct classification of all MLL-AF9-expressing cell cultures as MLL-rearranged leukemia. We conclude that expression of MLL-AF9 in a normal human hematopoietic progenitor is sufficient to recapitulate many key aspects of the clinical disease. This model will yield valuable insights into the molecular pathogenesis of MLL fusion driven leukemia and will serve as a powerful in vivo model for testing much needed novel therapeutic targets.