20 research outputs found
Comprehensive Genomic Profiling Reveals Diverse but Actionable Molecular Portfolios across Hematologic Malignancies: Implications for Next Generation Clinical Trials
Background: The translation of genomic discoveries to the clinic is the cornerstone of precision medicine. However, incorporating next generation sequencing (NGS) of hematologic malignancies into clinical management remains limited. Methods: We describe 235 patients who underwent integrated NGS profiling (406 genes) and analyze the alterations and their potential actionability. Results: Overall, 227 patients (96.5%) had adequate tissue. Most common diagnoses included myelodysplastic syndrome (22.9%), chronic lymphocytic leukemia (17.2%), non-Hodgkin lymphoma (13.2%), acute myeloid leukemia (11%), myeloproliferative neoplasm (9.2%), acute lymphoblastic leukemia (8.8%), and multiple myeloma (7.5%). Most patients (N = 197/227 (87%)) harbored ≥1 genomic alteration(s); 170/227 (75%), ≥1 potentially actionable alteration(s) targetable by an FDA-approved (mostly off-label) or an investigational agent. Altogether, 546 distinct alterations were seen, most commonly involving TP53 (10.8%), TET2 (4.6%), and DNMT3A (4.2%). The median tumor mutational burden (TMB) was low (1.7 alterations/megabase); 12% of patients had intermediate or high TMB (higher TMB correlates with favorable response to anti-PD1/PDL1 inhibition in solid tumors). In conclusion, 96.5% of patients with hematologic malignancies have adequate tissue for comprehensive genomic profiling. Most patients had unique molecular signatures, and 75% had alterations that may be pharmacologically tractable with gene- or immune-targeted agents
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Comprehensive Genomic Profiling Reveals Diverse but Actionable Molecular Portfolios across Hematologic Malignancies: Implications for Next Generation Clinical Trials.
Background: The translation of genomic discoveries to the clinic is the cornerstone of precision medicine. However, incorporating next generation sequencing (NGS) of hematologic malignancies into clinical management remains limited. Methods: We describe 235 patients who underwent integrated NGS profiling (406 genes) and analyze the alterations and their potential actionability. Results: Overall, 227 patients (96.5%) had adequate tissue. Most common diagnoses included myelodysplastic syndrome (22.9%), chronic lymphocytic leukemia (17.2%), non-Hodgkin lymphoma (13.2%), acute myeloid leukemia (11%), myeloproliferative neoplasm (9.2%), acute lymphoblastic leukemia (8.8%), and multiple myeloma (7.5%). Most patients (N = 197/227 (87%)) harbored ≥1 genomic alteration(s); 170/227 (75%), ≥1 potentially actionable alteration(s) targetable by an FDA-approved (mostly off-label) or an investigational agent. Altogether, 546 distinct alterations were seen, most commonly involving TP53 (10.8%), TET2 (4.6%), and DNMT3A (4.2%). The median tumor mutational burden (TMB) was low (1.7 alterations/megabase); 12% of patients had intermediate or high TMB (higher TMB correlates with favorable response to anti-PD1/PDL1 inhibition in solid tumors). In conclusion, 96.5% of patients with hematologic malignancies have adequate tissue for comprehensive genomic profiling. Most patients had unique molecular signatures, and 75% had alterations that may be pharmacologically tractable with gene- or immune-targeted agents
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Incidence and Impact of Non-CMV Herpes Viral Infection in Haploidentical and Matched Sibling Donors Receiving Post-Transplant Cyclophosphamide (PTCy): A CIBMTR Analysis
Single-center studies have reported increased risk of CMV infection in patients undergoing allogeneic transplant using haploidentical graft with post-transplant cyclophosphamide (HaploCy), however limited data exists regarding the impact of this transplant platform on the incidence of non-CMV herpes viruses (NCHV) infection (viremia/disease). Furthermore, it is unclear if the donor type or altered immune reconstitution resulting from the use of PTCy contributes to this infection risk. To study this, patients reported to the CIBMTR with AML/ALL/MDS transplanted between 2012 and 2017 receiving HaploCy (n = 757), matched-sibling donors receiving PTCy (SibCy, n=403), or matched sibling with calcineurin inhibitor and methotrexate/mycophenolate mofetil (SibCNI, n=1605) with either marrow or peripheral blood grafts were examined (Table 1). Too few matched unrelated donors (MUD) receiving PTCY reported to CIBMTR resulted in exclusion of MUD transplants.
The cumulative incidence of NCHV in the HaploCy, SibCy and SibCNI were 6.9% (99% CI, 4.7-9.4), 3.2% (1.3-5.9), and 1.7% (1-2.6) respectively by day 30 [p<0.001] and increased to 13.9% (10.8 – 17.3), 10.7 % (7.1 – 15), and 5.7% (4.3 – 7.3) by 6 months after transplant [p<0.001] [Figure 1]. Notably, this is driven by a higher frequency of HHV-6 viremia [HaploCy = 9.3%; SibCy = 5.7%; SibCNI = 1.9%]. Figure 2 shows the multivariable models of survival, relapse, transplant related mortality, and chronic GVHD with a reference group of SibCNI without NCHV infection for the main effect variable of donor and infection. The model examines through the first 2 years after transplant and there was a center effect.
Our results suggest that HaploCY is associated with an increased incidence of NCHV infection and HHV-6 viremia predominates. The SibCy cohort experienced an increased incidence of NCHV infections as well. However, only in the HaploCy group is this independently associated with increased TRM and decreased survival. Improved surveillance and preemptive treatment may mitigate the mortality associated with NCHV infections in HaploCy recipients