Reply to a note on the magnitude of hazard ratios Borate, Uma M.; Mineishi, Shin; Costa, Luciano J.
Cancer,
April 15, 2016, 2016-Apr-15, 2016-04-15, 20160415, Volume:
122, Issue:
8
Journal Article
The safety and efficacy of sabatolimab, a novel immunotherapy targeting T‐cell immunoglobulin domain and mucin domain‐3 (TIM‐3), was assessed in combination with hypomethylating agents (HMAs) in ...patients with HMA‐naive revised International Prognostic System Score (IPSS‐R) high‐ or very high‐risk myelodysplastic syndromes (HR/vHR‐MDS) or chronic myelomonocytic leukemia (CMML). Sabatolimab + HMA had a safety profile similar to that reported for HMA alone and demonstrated durable clinical responses in patients with HR/vHR‐MDS. These results support the ongoing evaluation of sabatolimab‐based combination therapy in MDS, CMML, and acute myeloid leukemia.
This multicenter trial was conducted to determine whether the addition of dasatinib to chemotherapy followed by an allogeneic hematopoietic cell transplant (HCT) in patients with Philadelphia ...chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) was feasible. Patients ≥18 and ≤60 years of age with newly diagnosed Ph+ ALL received up to 8 cycles of alternating hyperfractionated cyclophosphamide, vincristine, Adriamycin, and dexamethasone and high-dose cytarabine and methotrexate with dasatinib. Patients with an available matched sibling or unrelated donor underwent an allogeneic HCT in first complete remission (CR1), followed by daily dasatinib starting from day 100. Others received maintenance therapy with vincristine and prednisone for 2 years and dasatinib indefinitely. Ninety-seven patients (94 evaluable) with a median age of 44 years (range, 20-60 years) and median white blood cells at presentation of 10 × 109/L (range, 1-410 × 109/L) were accrued. Eighty-three patients (88%) achieved CR or CR with incomplete count recovery (CRi), and 41 underwent allogeneic stem cell transplant in CR1. Median follow-up is 36 months (range, 9-63). For the overall population, overall survival (OS), event-free survival, and relapse-free survival (RFS) at 3 years were 69%, 55%, and 62%, respectively. The 12-month RFS and OS after transplant were 71% and 87%, respectively. Landmark analysis at 175 days from the time of CR/CRi (longest time to HCT) showed statistically superior advantages for RFS and OS (P = .038 and P = .037, respectively) for the transplanted patients. Addition of dasatinib to chemotherapy and HCT for younger patients with Ph+ ALL is feasible and warrants further testing.
•Addition of dasatinib to chemotherapy followed by allogeneic stem cell transplant is well tolerated in younger patients with Ph+ ALL.•Landmark analysis showed statistically superior advantages for relapse-free and overall survival for the transplanted patients.
In order to establish the workflows required to implement a real-time process involving multi-omic analysis of patient samples to support precision-guided therapeutic intervention, a tissue ...acquisition and analysis trial was implemented. This report describes our findings to date, including the frequency with which mutational testing led to precision-guided therapy and outcome for those patients.
Eligible patients presenting to Oregon Health and Science University Knight Cancer Institute were enrolled on the study. Patients with biopsy proven metastatic or locally advanced unresectable prostate cancer, breast cancer, pancreatic adenocarcinoma, or refractory acute myelogenous leukemia receiving standard of care therapy were eligible. Metastatic site biopsies were collected and analyzed using the Knight Diagnostic Lab GeneTrails comprehensive solid tumor panel (124 genes). CLIA certified genomic information was made available to the treating physician.
Between 1/26/2017 and 5/30/2018, 38 patients were enrolled, with 28 successfully undergoing biopsy. Of these, 25 samples yielded sufficient tumor for analysis. The median biopsy cellularity and number of cores collected were 70% (15-90%) and 5 (2-20), respectively. No procedure-related complications occurred. GeneTrails analysis revealed that 22 of 25 (88%) tumor samples harbored at least one potentially actionable mutation, and 18 (72%) samples harbored 2 or more potentially actionable mutations. The most common genetic alterations identified involved: DNA damage repair genes, cell cycle regulating genes, PIK3CA/Akt/mTOR pathway, and FGF gene family. To date, CLIA certified genomic results were used by treating physicians for precision-guided therapy in 5 (23%) patients.
We report the feasibility of real-time tissue acquisition and analysis to support a successful translational oncology platform. The workflow will provide the foundation to improve access and accrual to biomarker driven precision oncology trials.
Abstract
Background
We evaluated the frequency of genomic testing and treatment patterns by age category in patients with newly diagnosed (ND) acute myeloid leukemia (AML) treated in both academic‐ ...and community‐based health systems within a single Midwestern State.
Methods
Retrospective analysis of data from the Indiana University Health System Enterprise Data Warehouse and two local cancer registries, of 629 patients aged ≥18 years with ND AML during 2011–2018. Primary outcome variables were, proportion of patients with genomic analysis and frequency of mutations. Chemotherapy was categorized as “standard induction” or “other chemotherapy”/targeted therapy, and hypomethylating agents.
Results
Overall, 13% of ND AML patients between 2011 and 2018 had evidence of a genomic sequencing report with a demonstrated increase to 37% since 2016. Genomic testing was more likely performed in patients: aged ≤60 years than >60 years (45% vs. 30%;
p
= 0.03), treated in academic versus community hospitals (44% vs. 26%;
p
= 0.01), and in chemotherapy recipients than non‐therapy recipients (46% vs. 19%;
p
< 0.001). Most common mutations were
ASXL1
,
NPM1
, and
FLT3
. Patients ≥75 years had highest proportion (46%) of multiple (≥3) mutations. Overall, 31.2% of patients with AML did not receive any therapy for their disease. This subgroup was older than chemotherapy recipients (mean age: 71.4 vs. 55.7 years,
p
< 0.001), and was highest (66.2%) in patients ≥75 years.
Conclusions
Our results highlight the unmet medical need to increase access to genomic testing to afford treatment options, particularly to older AML patients in the real‐world setting, in this new era of targeted therapies.
Inspite of medication compliance, some chronic myeloid leukemia (CML) patients will relapse/progress into an accelerated phase or blast crisis. Central nervous system (CNS) involvement is a rare ...manifestation of such a relapse. Here, we report a case of 23-year-old female who was diagnosed with CML in the accelerated phase and subsequently treated with imatinib. She developed early relapse in her CNS, and her treatment was switched to dasatinib and intrathecal chemotherapy with cytarabine and methotrexate. Her CNS disease went into remission, and she underwent matched unrelated donor (MUD) hematopoietic stem cell transplant (HSCT). We discuss various mechanisms of treatment failure, importance of vigilance for symptoms and signs of treatment failure/relapse, indications for use of different tyrosine kinase inhibitors (TKIs), and management of blast crises in CML.
Older patients (≥ 60 years) with acute myeloid leukemia (AML) often have multiple, sequentially acquired, somatic mutations that drive leukemogenesis and are associated with poor outcome. Beat AML is ...a Leukemia and Lymphoma Society-sponsored, multicenter umbrella study that algorithmically segregates AML patients based upon cytogenetic and dominant molecular abnormalities (variant allele frequencies (VAF) ≥ 0.2) into different cohorts to select for targeted therapies. During the conception of the Beat AML design, a historical dataset was needed to help in the design of the genomic algorithm for patient assignment and serve as the basis for the statistical design of individual genomic treatment substudies for the Beat AML study.
We classified 563 newly diagnosed older AML patients treated with standard intensive chemotherapy on trials conducted by Cancer and Leukemia Group B based on the same genomic algorithm and assessed clinical outcomes.
Our classification identified core-binding factor and NPM1-mutated/FLT3-ITD-negative groups as having the best outcomes, with 30-day early death (ED) rates of 0 and 20%, respectively, and median overall survival (OS) of > 1 year and 3-year OS rates of ≥ 20%. All other genomic groups had ED rates of 17-42%, median OS ≤ 1 year and 3-year OS rates of ≤ 15%.
By classifying patients through this genomic algorithm, outcomes were poor and not unexpected from a non-algorithmic, non-dominant VAF approach. The exception is 30-day ED rate typically is not available for intensive induction for individual genomic groups and therefore difficult to compare outcomes with targeted therapeutics. This Alliance data supported the use of this algorithm for patient assignment at the initiation of the Beat AML study. This outcome data was also used for statistical design for Beat AML substudies for individual genomic groups to determine goals for improvement from intensive induction and hopefully lead to more rapid approval of new therapies. Trial registration ClinicalTrials.gov Identifiers: NCT00048958 (CALGB 8461), NCT00900224 (CALGB 20202), NCT00003190 (CALGB 9720), NCT00085124 (CALGB 10201), NCT00742625 (CALGB 10502), NCT01420926 (CALGB 11002), NCT00039377 (CALGB 10801), and NCT01253070 (CALGB 11001).
Therapy related acute lymphoblastic leukemia (t‐ALL) of B cell origin is rare and constitutes approximately 2% of all ALL. Previously compiled data on the complete cytogenetic analysis of 48 t‐B‐ALL ...cases suggested that MLL rearrangement at 11q23 gene locus is the most common abnormality. Philadelphia chromosome (Ph) and a normal karyotype were reported as the second and third most common karyotypes, respectively. We investigated cytogenetic karyotypes of six t‐B‐ALL cases with a pre‐B cell immunophenotype. Ph + t‐B‐ALL was noted in four of six patients previously treated with radiation and/or chemotherapy. In addition, one case demonstrated MLL rearrangement at 11q23 locus while one case demonstrated normal cytogenetic karyotype. Five of the six t‐B‐ALL patients had persistent leukemia following initiation of chemotherapy for secondary leukemia with survival ranging from 10 to 21 months. To our knowledge, only fourteen patients with Ph + t‐B‐ALL have been described in the literature. In the current study, three of four cases with Ph + t‐B‐ALL were associated with treated breast carcinoma while one patient was treated for Hodgkin lymphoma. All four patients had undergone radiation therapy. The results may indicate a plausible association between Ph+t‐B‐ALL and prior radiation exposure.
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