Catálogo de publicaciones - revistas

<jats:title>Abstract</jats:title> <jats:p>Introduction: Mutations in the chaperone gene calreticulin (CALR) have been recently identified in essential thrombocythemia (ET) and primary myelofibrosis (PMF), and are essentially mutually exclusive with JAK2 or MPL mutations. Normal and mutant CALR proteins may differentially affect the subcellular trafficking of JAK-STAT signaling components. CALR mutations previously reported in ET and PMF have been +1 frameshift (fs) mutations localized to exon (E) 9 that generate a novel C-terminal protein sequence with a shift from acidic to basic residues. CALR E9 in-frame (IF) deletions have been recently rarely reported as polymorphisms such as TMP_ESP_19_13054686_13054688 and TMP_ESP_19_13054650_13054658 (Ensembl database entries). We sought to determine the frequency and associated clinical features of CALR with E9 IF alterations in samples submitted for suspicion of a myeloproliferative neoplasm (sMPN). We also assessed whether CALR IF alterations are differentially associated with +1fs mutations or with JAK2 V617For other somatic mutations in MPN-associated genes.</jats:p> <jats:p>Materials and Methods: CALR mutation analysis of E9 was performed on genomic DNA extracted from blood, bone marrow (BM) aspirate or fixed BM biopsy sections using a Sanger sequencing assay with an analytic sensitivity of at least 15%. E9 IF cases were further assessed and mutations quantified by an Ion torrent sequencing panel assessing CALR, CSF3R, JAK2 and MPL, a second panel containing ASXL1, EZH2, IDH1, IDH2, KRAS, NRAS and TET2 and an Illumina MiSeq extended panel with 20 additional MPN-associated genes. These assays had a sensitivity of approximately 5%. JAK2 V617Fmutations were quantitated using a pyrosequencing assay with an analytic sensitivity of 1%.</jats:p> <jats:p>Results: We assessed CALR E9 mutation status in 733 sMPN samples that were negative for JAK2 V617F mutation. 148 (20.1%) had typical +1fs mutations (95 type 1 and variants, 53 type 2 and variants); 2 (0.3%) had point mutations (E381A and D7373M); 7 (1.0%) had IF deletions including E381_A382&gt;A, D397_D400&gt;D (n =4), D400_K401&gt;D and E405_V409&gt;V. All E9 IF deletions were present at ~50% of reads. Clinical diagnoses were cytopenia/BM fibrosis, ET, thrombocytosis/anemia, and sMPN unspecified. Mutation analysis for 27 additional MPN-associated genes revealed mutations in 5/7 (71.4%) IF deletion cases including in MPL (W515L,40%; D163Y,12%), CSF3R (A470T 46%), ASXL1 (D954fs*26, 45%) and ZRSR2 (S449_R450dup, 27%). No additional mutations were found in the 2 cases with non-synonymous CALR point mutations/SNPs. In a parallel set of 76 MPN samples that had JAK2 V617F at varying levels, we noted 1 E9 IF deletion (D397_D400&gt;D) in a sMPN case with 21.6% JAK2 V617F, and a typical +1fs mutation (K385fs*47) in a case with low (4.2%) JAK2 V617F. All other JAK2 V617F cases had no E9 CALR alterations.</jats:p> <jats:p>Conclusions: CALR E9 in-frame deletions occur in up to 1% of sMPN samples and involve a variety of codons in the acidic domain. Therefore, sizing assays without DNA sequencing are not sufficient to unequivocally distinguish IF deletions from the characteristic +1 frameshift somatic mutations associated with ET and PMF. Given their level, these CALR IF deletions are likely germline sequence variants but are associated with a high frequency of somatic mutations in other MPN-associated genes but not with CALR +1fs mutations. Their co-occurrence with pathogenic somatic mutations in JAK2, MPL and CSF3R affecting the JAK-STAT pathway raises the possibility for a contributory role of altered CALR proteins produced by these E9 deletions in the pathogenesis of MPN.</jats:p> <jats:sec> <jats:title>Disclosures</jats:title> <jats:p>Wang: Quest Diagnostics: Employment. Ho:Quest Diagnostics: Employment. Pan:Quest Diagnostics: Employment. Racke:Quest Diagnostics: Employment. Jones:Quest Diagnostics: Employment.</jats:p> </jats:sec>

<jats:title>Abstract</jats:title> <jats:p /> <jats:p>Introduction: Quantitative 18fluorodeoxyglucose positron emission tomography (PET)/computed tomography assessment using total metabolic tumor volume (TMTV) and tumor lesion glycolysis (TLG) measurements has been found promising as an objective method to predict survival in diffuse large B-cell lymphoma (DLBCL) patients (pts). However, the methodology for PET-derived metrics is still evolving, and their predictive value is yet to be proven in large-scale, prospective, multicenter studies. We investigated the prognostic value of baseline maximum standardized uptake value (SUVmax), TMTV and TLG for progression-free survival (PFS) in a large pt cohort treated with obinutuzumab (GA101; G) or rituximab (R) combined with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in the Phase 3 GOYA study (NCT01287741; Vitolo et al. J Clin Oncol 2017).</jats:p> <jats:p>Methods: Pts aged ≥18 years, with previously untreated, CD20-positive DLBCL and an International Prognostic Index (IPI) score ≥2 and low-risk pts with IPI scores of 1 (not due to age alone) or 0 (with bulky disease) were randomized 1:1 to receive 8 x 21-day cycles of G (1000mg intravenous [IV] on Days [D] 1, 8, and 15 of Cycle [C] 1 and D1, C2-8) or R (375mg/m2 IV on D1, C1-8) plus 6 or 8 cycles of CHOP. All pts had a baseline and end of treatment (EOT) PET. PET images were segmented using an automated workflow program in MIM software, applying thresholds of 1.5 x liver background and a minimum volume of 1mL to the whole body PET images. The data were analyzed for the overall population and according to germinal center B-cell-like (GCB), unclassified, and activated B-cell-like (ABC) subtypes of DLBCL. TMTV, TLG, and SUVmax were split into 4 categories/levels according to the following quartiles: Q1, &amp;lt;25%; Q2, 25-50%; Q3, 50-75%; and Q4, 75-100%, which were obtained based on their distribution in the available population. The reported hazard ratios (HRs) refer to stratified log-rank tests comparing Q2, Q3, and Q4 to Q1, adjusted for stratification factors of the study: IPI score (low [0-2], intermediate [3], and high [4-5]) and number of planned CHOP cycles (6 or 8).</jats:p> <jats:p>Results: Of 1418 enrolled pts, 1346 had a baseline PET scan and 1334 had detectable lesions. There was no statistical difference in PFS between the treatment arms (G vs R), thus the entire cohort was analyzed as a whole. Results of the predictive value of baseline TMTV for PFS are presented in quartiles in Figure 1, and results of the predictive value of TLG for PFS are presented in quartiles in Figure 2, for the overall PET intent-to-treat population. After a median follow-up of 29 months TMTV and TLG were highly predictive of PFS when comparing Q4 vs Q1: HR=2.21, 95% CI 1.48-3.29, p&amp;lt;0.0001, and HR=1.91, 95% CI 1.28-2.85, p=0.0005, respectively. TMTV was also predictive of overall survival (OS): HR=2.63, 95% CI 1.55-4.46; p&amp;lt;0.0001. However, SUVmax-based prediction of PFS was not statistically significant (HR=0.84, 95% CI 0.57-1.23, p=0.3782).</jats:p> <jats:p>Three-year PFS for pts in TMTV Q1, 2, 3 and 4 was 86% (95% CI 81-89%), 84% (95% CI 78-88%), 78% (95% CI 72-83%) and 66% (95% CI 59-71%), respectively. TMTV also showed a trend for a better prediction of PFS (Figure 3) and OS in pts with the unclassified and ABC DLBCL subtypes when compared with those with the GCB subtype.</jats:p> <jats:p>Conclusions: This large prospective study confirms baseline TMTV and TLG as predictors of PFS and OS in DLBCL after first-line immunochemotherapy, while SUVmax may not be a predictor. Furthermore, TMTV and TLG appear to be better predictors of survival for pts with the unclassified and ABC subtypes of DLBCL than for those pts with the GCB subtype. Further analyses are underway comparing these results with the predictive value of percentage change from baseline to EOT PET, Deauville score-based analysis of EOT PET, and the various molecular DLBCL subtypes.</jats:p> <jats:p>Figure 1 Figure 1.</jats:p> <jats:sec> <jats:title>Disclosures</jats:title> <jats:p>Kostakoglu: Roche: Consultancy, Other: GOYA is sponsored by F. Hoffmann-La Roche Ltd. Third-party editorial support, under the direction of Lale Kostakoglu and Denis Sahin, was provided by Helen Cathro of Gardiner-Caldwell Communications, and was funded by F. Hoffmann-La Roche Ltd. Sehn: Celgene: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Roche/Genentech: Consultancy, Honoraria. Chua: Lundbeck: Honoraria; Roche: Honoraria; Seattle Genetics: Honoraria; Gilead Sciences: Honoraria; Merck: Honoraria. Gonzalez-Barca: Gilead: Consultancy; Sandot: Consultancy; Janssen: Speakers Bureau; Roche: Speakers Bureau. Pinto: Millenium Takeda: Research Funding; Gilead: Honoraria; Roche: Honoraria; Bristol Myers Squibb: Honoraria; Merck Sharp Dome: Honoraria; Celgene: Honoraria; Helssin: Honoraria; Mundipharma EDO: Speakers Bureau. Fingerle-Rowson: F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Knapp: Roche: Employment. Mattiello: Roche: Employment. Nielsen: F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Sellam: Roche: Employment. Sahin: Roche: Employment, Equity Ownership. Vitolo: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria; Mundipharma: Honoraria; Takeda: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Trněný: Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding.</jats:p> </jats:sec>

<jats:title>Abstract</jats:title> <jats:p>Background: Management of CML using tyrosine kinase inhibitors (TKIs) is often constrained by treatment failure, which portends a poor prognosis, particularly among patients who fail second-generation TKIs because of resistance. Treatment failure may be due to therapeutic resistance (whether BCR-ABL1 mutation-dependent or independent), intolerance, and/or suboptimal adherence. The BCR-ABL1 T315I ("gatekeeper") genotype is insensitive to first- and second-generation TKIs, and compound mutations complicate management with all members of the class (including third-generation TKI ponatinib). Olverembatinib (HQP1351) is a novel, potent, orally active BCR-ABL1 TKI with promising activity against CML, including antitumor activity regardless of genotype, and a preliminarily favorable safety profile.</jats:p> <jats:p>Methods: This open-label bridging trial is evaluating the PK, efficacy, and safety of olverembatinib administered orally every other day (QOD) in adults who have chronic-phase, accelerated-phase, or blast-phase CML (CP-CML, AP-CML, or BP-CML) and Ph⁺ ALL, with or without the T315I mutation, and have experienced resistance to or intolerance (including NCI CTCAE v5.0 grade ≥ 2 adverse events) of at least 3 TKIs. Eligible patients have no residual grade ≥ 2 adverse events (other than alopecia or skin pigmentation change) due to prior treatments, a maximum ECOG performance status of 2, and a minimum life expectancy of 3 months. Study participants are being randomly allocated in a 1:1:1 ratio to 3 dose cohorts: 30, 40, or 50 mg of oral olverembatinib QOD over a cycle length of 28 days, with 10 patients per cohort and randomization stratified according to CML phase (CP-CML, AP-CML, or BP-CML) or Ph⁺ ALL and T315I mutational status. Study endpoints comprise the PK profile of olverembatinib at Cycle 1 Day 1 and Day 27; efficacy endpoints of major cytogenetic and hematologic responses; and safety. The recommended phase 2 dose of olverembatinib will be determined based on a comprehensive assessment of PK, safety, and efficacy data in US and Chinese patients. As of July 14, 2021, 14 of 30 patients have been enrolled. Internal study identifier HQP1351-CU-101. Clinicaltrial.gov identifier: NCT04260022.</jats:p> <jats:sec> <jats:title>Disclosures</jats:title> <jats:p>Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. Kantarjian: Aptitude Health: Honoraria; Daiichi-Sankyo: Research Funding; Ascentage: Research Funding; Astra Zeneca: Honoraria; Ipsen Pharmaceuticals: Honoraria; Immunogen: Research Funding; Pfizer: Honoraria, Research Funding; KAHR Medical Ltd: Honoraria; BMS: Research Funding; NOVA Research: Honoraria; Astellas Health: Honoraria; Novartis: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Jazz: Research Funding; AbbVie: Honoraria, Research Funding; Precision Biosciences: Honoraria; Taiho Pharmaceutical Canada: Honoraria. Issa: Kura Oncology: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Syndax Pharmaceuticals: Research Funding. Mukherjee: Genentech: Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: Membership on an entity's Board of Directors or advisory committees; Acceleron: Membership on an entity's Board of Directors or advisory committees; Partnership for Health Analytic Research: Honoraria; AbbVie: Membership on an entity's Board of Directors or advisory committees; BioPharm: Consultancy; AAMDS in Joint Partnership with Cleveland Clinic Taussig Cancer Institute: Honoraria; Eusa Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Teaching and Speaking; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research/Independent Contractor, Research Funding; McGraw Hill: Honoraria, Other: Editor of Hematology Oncology Board Review (ongoing); Bristol-Myers Squibb Co.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Research/Independent Contractor, Research Funding; Jazz Pharmaceuticals: Research Funding. Oehler: OncLive: Honoraria; Pfizer: Research Funding; Takeda: Consultancy; BMS: Consultancy. Chen: Ascentage Pharma (Suzhou) Co., Ltd: Current Employment, Current equity holder in publicly-traded company. Lu: Ascentage Pharma Group Inc.: Current Employment, Current equity holder in publicly-traded company. Fu: Ascentage Pharma Group Inc: Current Employment, Current equity holder in publicly-traded company. Zhai: Ascentage Pharma (Suzhou) Co., Ltd.: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests, Patents &amp; Royalties, Research Funding; Ascentage Pharma Group Inc.: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests, Patents &amp; Royalties, Research Funding. Yang: Ascentage Pharma (Suzhou) Co., Ltd: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests, Patents &amp; Royalties, Research Funding.</jats:p> </jats:sec>

<jats:title>Abstract</jats:title> <jats:p>Background: Management of CML with TKIs is constrained by treatment resistance, which portends a poor prognosis particularly in pts failing 2 nd-generation TKIs. Cells with BCR-ABL1 T315I mutations are insensitive to 1 st- and 2 nd -generation TKIs, and compound BCR-ABL1 mutations complicate management with all TKIs (including 3 rd-generation ponatinib). Olverembatinib is a novel, potent, 3 rd-generation, orally active BCR-ABL1 TKI with promising activity against CML , largely irrespective of genotype and has a preliminary favorable safety profile.</jats:p> <jats:p>Methods: HQP1351-CC201 and HQP1351-CC202 are Chinese open, single-arm, multicenter phase 2 trials evaluating the safety and efficacy of olverembatinib in adults with TKI-resistant (BCR-ABL1 T351-mutated) CML-CP and CML-CP, respectively. Olverembatinib was administered at 40 mg orally on alternate days for 28-day cycles. The primary outcome measure is major cytogenetic response (MCyR) and major hematologic response (MaHR) by the end of Cycle 12 in CML-CP and CML-AP, respectively. Secondary study endpoints include : complete CyR (CCyR), complete hematologic response (CHR), major molecular response (MMR), progression-free survival (PFS), overall survival (OS), and safety, including treatment-related adverse events (TRAEs) and serious AEs (SAEs).</jats:p> <jats:p>Results:</jats:p> <jats:p>Baseline characteristics</jats:p> <jats:p>Study CC201 （CML-CP ）</jats:p> <jats:p>On the study cutoff date of August 25,2020, 41 pts were enrolled, of whom 32 (78%) completed ≥ 12 cycles and 21 (51.2%) were male. The median (range) follow-up was 13 (3.1-16.3) months, age was 47 (22-70) years, and interval from CML diagnosis to first olverembatinib dose was 5.31 (0.6-23.2) years. In all, 32 (78.1%) pts had received ≥ 2 prior TKIs and 9 pts withdrew because of progressive disease (PD), intolerance, or consent withdrawal before Cycle 12.</jats:p> <jats:p>Study CC202 （CML-AP ）</jats:p> <jats:p>On the cut-off date of July 27, 2020, 23 pts were enrolled, of whom 14 (61%) had completed ≥ 12 cycles and 18 (78.3%) were male. The median (range) follow-up was 13.5 (1.4-15.2) months, age was 41 (21-74) years, and interval from CML diagnosis to first olverembatinib dose was 4.96 (0.4-10.2) years. In all, 18 (78.3%) pts had received ≥ 2 prior TKIs, and 11 pts withdrew because of PD or intolerance before Cycle 12.</jats:p> <jats:p>Efficacy</jats:p> <jats:p>Study CC201 （CML-CP ）</jats:p> <jats:p>After ≥ 12 treatment cycles in pts without responses at baseline, all 31 (100%) experienced CHR (10 other pts had CHR at baseline); 31/41 (75.6%) MCyR; 28/41 (68.3%) CCyR; and 23/41 (56.1%) MMR (Figure 1). The median time to CHR was 1 (95% CI = 1.0-1.9) month, the median time to MCyR was 2.8 (95% CI = 2.8-5.6) months, and the median time to MMR was 6.5 (95% CI = 2.8 to not reached [NR]) months. At 12 months, the PFS rate was 89.3% (95% CI = 73.9%-95.8%), and the OS was 100% (95% CI = 100%-100%).</jats:p> <jats:p>Study CC202 （CML-AP ）</jats:p> <jats:p>After ≥ 12 treatment cycles in pts without responses at baseline, 17/23 (73.9%) experienced MaHR (65.2% CHR and 8.7% no evidence of leukemia [NEL]); 12/23 (52.2%) MCyR; 11/23 (47.8%) CCyR; and 9/23 (39.1%) MMR (Figure 1). The median time to MaHR was 2.8 (95% CI = 1.0-4.7) months, the median time to MCyR was 5.6 (95% CI = 2.00-NR) months, and the median time to MMR was 13.1 (95% CI = 5.6-NR) months. At 12 months, the PFS rate was 74.1% (95% CI = 48.2%-88.4%), and the OS was 91.3% (95% CI = 69.5%-97.8%).</jats:p> <jats:p>Safety</jats:p> <jats:p>Study CC201 （CML-CP ）</jats:p> <jats:p>Frequent TRAEs (all grades; grade 3-4; SAEs) included thrombocytopenia (70.7%; 48.8%; 7.3%), followed by anemia (61%; 26.8%; 2.4%), leukopenia (43.9%; 17.1%; 0), and neutropenia (36.6%; 19.5%; 0). Common nonhematologic TRAEs (all grades; G3-4) included skin pigmentation (56.1%, 0%) and elevations in creatine kinase (51.2%, 14.6%), ALT (39%, 2.4%) and AST (34.1%, 0) (Table 1). No deaths occurred.</jats:p> <jats:p>Study CC202 （CML-AP ）</jats:p> <jats:p>Common TRAEs (all grades; G3-4; SAEs) included thrombocytopenia (73.9%; 56.5%; 17.4%), anemia (60.9%; 34.8%; 13.0%), leukopenia (56.5%; 30.4%; 0), and neutropenia (26.1%; 21.7%; 0). Common nonhematologic AEs included skin pigmentation (69.6%), hypocalcemia (52.2%), proteinuria (47.8%), hypertriglyceridemia (56.5%), hyperphosphatemia (47.8%), hyperuricemia (21.7%), and arthralgia (34.8%), of which most were grade 1-2 (Table 2).</jats:p> <jats:p>Conclusions: Olverembatinib was efficacious and well tolerated when administered as monotherapy in pts with TKI-resistant CP-CML and AP-CML and the BCR-ABL1 T315Imutation. Internal study identifiers: HQP1351-CC201-CC202. ClinicalTrials.gov identifiers: NCT03883087 and NCT03883100.</jats:p> <jats:p>Figure 1 Figure 1.</jats:p> <jats:p /> <jats:sec> <jats:title>Disclosures</jats:title> <jats:p>Chen: Ascentage Pharma (Suzhou) Co., Ltd: Current Employment, Current equity holder in publicly-traded company. Niu: Ascentage Pharma (Suzhou) Co., Ltd: Current Employment, Current equity holder in publicly-traded company. Men: Ascentage Pharma (Suzhou) Co., Ltd.: Current Employment, Current equity holder in publicly-traded company. Yang: Ascentage Pharma (Suzhou) Co., Ltd: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests, Patents &amp; Royalties, Research Funding. Zhai: Ascentage Pharma Group Inc.: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests, Patents &amp; Royalties, Research Funding; Ascentage Pharma (Suzhou) Co., Ltd.: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests, Patents &amp; Royalties, Research Funding.</jats:p> </jats:sec>