Chimerism monitoring after allogenic Hematopoietic Cell Transplantation (allo-HCT) is critical to determine how well donor cells have engrafted and to detect relapse for early therapeutic ...intervention. The aim of this study was to establish and detect mixed chimerism and minimal residual disease using Next Generation Sequencing (NGS) testing for the evaluation of engraftment and the detection of early relapse after allo-HCT. Our secondary aim was to compare the data with the existing laboratory method based on Short Tandem Repeat (STR) analysis. One hundred and seventy-four DNA specimens from 46 individuals were assessed using a commercially available kit for NGS, AlloSeq HCT NGS (CareDx), and the STR-PCR assay. The sensitivity, precision, and quantitative accuracy of the assay were determined using artificially created chimeric constructs. The accuracy and linearity of the assays were evaluated in 46 post-transplant HCT samples consisting of 28 levels of mixed chimerism, which ranged from 0.3-99.7%. There was a 100% correlation between NGS and STR-PCR chimerism methods. In addition, 100% accuracy was attained for the two external proficiency testing surveys (ASHI EMO). The limit of detection or sensitivity of the NGS assay in artificially made chimerism mixtures was 0.3%. We conducted a review of all NGS chimerism studies published online, including ours, and concluded that NGS-based chimerism analysis using the AlloSeq HCT assay is a sensitive and accurate method for donor-recipient chimerism quantification and minimal residual disease relapse detection in patients after allo-HCT compared to STR-PCR assay.
Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy associated with various combinations of gene mutations, epigenetic abnormalities, and chromosome rearrangement-related gene ...fusions. Despite the significant degree of heterogeneity in its pathogenesis, many gene fusions and point mutations are recurrent in AML and have been employed in risk stratification over the last several decades. Gene fusions have long been recognized for understanding tumorigenesis and their proven roles in clinical diagnosis and targeted therapies. Advances in DNA sequencing technologies and computational biology have contributed significantly to the detection of known fusion genes as well as for the discovery of novel ones. Several recurring gene fusions in AML have been linked to prognosis, treatment response, and disease progression. In this report, we present a case with a long history of essential thrombocythemia and hallmark CALR mutation transforming to AML characterized by a previously unreported AKAP9::PDGFRA fusion gene. We propose mechanisms by which this fusion may contribute to the pathogenesis of AML and its potential as a molecular target for tyrosine kinase inhibitors.
Introduction Induction chemotherapy (IC) in acute myeloid leukemia (AML) in younger and fit patients has historically combined an anthracycline (ie, daunorubicin or idarubicin) with the ...antimetabolite cytarabine, which has been termed the 7 + 3 regimen. Response rates with this current standard approach show complete response rates of 70-80%, however 30-40% still eventually relapse. Recently, the MD-Anderson group published a phase II study in which the drug venetoclax was added to the standard anthracycline/cytarabine induction regimen of FLAG-IDA. Results from this study showed an impressive 96% response rate for newly diagnosed (ND) AML patients. Based on these results we began to adopt this approach for our patients. We have induced 21 patients with this approach at our institution and have had comparable results. No study has compared outcomes between this approach and that of standard 7 +3 in regards to response rates. Based on our improved outcomes we compared outcomes between these two approaches in our patient population by doing a retrospective chart based review on all patients that received cytotoxic induction treatment for ND-AML between 2000-2023. Methods Patients between 2020-2023 that were treated with induction cytotoxic chemotherapy for AML, based on WHO 2016 criteria, were retrospectively reviewed. Patients either received 7+3 or 7+3 plus midostaurin if they were FLT3+ in one arm or FLAG-IDA/Venetoclax. Patients received FLAG-IDA/Venetoclax regardless of FLT3+ status or risk of disease. Patients with extra medullary disease were excluded from this review as well as patients that received an IDH1 or 2 inhibitors in combination with 7 +3. Results Overall 39 patients were included in this study, 20 patients in the FLAG-IDA/Venetoclax arm and 19 patients in the 7/3 arm. In patients which response was able to be evaluated patients in the FLAG-IDA/Venetoclax cohort had a 100% overall response rate with a 95% (N = 19/20) complete response rate. Patients in the 7/3 cohort the complete remission rates were 66% (N = 12/16) with 3 of the patients achieving a complete remission with re-induction. Sixty-day morality rate was 5% (N = 1/20) in patients receiving FLAG-IDA/Venetoclax compared to 16% (N = 3/19). In terms of neutrophil recovery and toxicity results were comparable in both arms, with the average day to cell recovery being the similar in both groups. Conclusions FLAG-IDA/Venetoclax compared to standard 7/3 +/- FLT3 directed therapy in our patient population resulted in improved response rates and decreased 60-day mortality. Our results are similar to previously published reports in patents with ND-AML. Toxicity profiles were similar with the clear benefit of decreased early morality are increased response rates.
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Background: Allogeneic stem cell transplant (allo SCT) is a potentially curative therapy for hematological malignancies but is associated with high treatment related non-relapse mortality ...(NRM). Post-transplant care requires large amount of healthcare and patient resources, imposing higher burden on patients with lower socio-economic status (SES). Adverse health outcomes have been noted in males from lower SES background. We analyzed the effects of social factors on post-transplant survival and NRM in the diverse patient population treated at our institution. Methods: We retrospectively reviewed patients who underwent allo SCT at our program in 2015-2021. We collected baseline patient (demographics, KPS, HCT-CI), disease (diagnosis, risk index) and transplant characteristics (donor type, conditioning intensity). We extracted neighborhood level income data from US Census. Primary outcomes were survival and NRM. We used Fisher’s Exact, Wilcoxon Ranksum tests and logistic regressions. Results: 210 patients (116 males and 94 females) were included in the analysis. Neighborhood level estimated household income range was $26,041-163,074. Both 1 year OS and NRM, but not 100 days OS, significantly correlated with income. Patients who were alive at 1 year follow up (74.8% pts) had median income of $72K, compared to $62K for patients who died before 1 year (25.2% pts) and 60.5K for patients who died before 1 year without disease progression (13.3% pts) (p 0.032). The effect of income on NRM remained significant on multivariable analysis, adjusted for year of transplant, age, race, ethnicity, donor type, KPS, comorbidity index, regimen intensity, and disease risk. Increased conditioning intensity and haplo donor were also associated with increased 1 year NRM, while race and ethnicity did not have significant effect on 1 year NRM on multivariable analysis. The effect of income on NRM was dramatically different in male vs female patients. In men, a $10K increase in neighborhood income reduced the odds of NRM substantially (OR = 0.46, 95% CI 0.28-0.75), while in women there was no effect (OR 1.02, 95% CI 0.71-1.45). 1 year NRM in men was 9% vs 24% for higher vs lower neighborhood income (p 0.036), and in women 8% vs 13% (p 0.52). Conclusions: Our study identifies male patients residing in lower income neighborhoods as a subgroup at increased risk for NRM after allo SCT, after adjustment for the biological variables. The negative effects of lower neighborhood income and male gender become apparent with 1 year but not 100 days follow up, reflecting increasing difficulties with high resourses utilization over prolonged time period. Careful evaluation of controllable risk factors and optimizing social support may reduce the rate of complications. Further research into the factors mediating the relationship of neighborhood income with gender on survival and treatment-related mortality post allo SCT seems necessary.
Teclistamab is a BCMA/ CD3 bispecific T cell engager, FDA approved in relapsed/refractory multiple myeloma (RRMM) after 4 prior lines of therapy, based on the results of MajesTEC-1 study. Early ...toxicities of teclistamab include CRS and ICANS. To mitigate the risk of CRS/ICANS, teclistamab is administered in a step-up dosing approach. 48h inpatient observation after each of the 3 step-up doses is recommended, although not mandated by FDA. Based on our outpatient CAR-T program experience, we implemented an outpatient teclistamab step-up dosing administration program.
To evaluate safety of outpatient teclistamab administration.
Retrospective review of toxicity outcomes of patients treated in outpatient teclistamab program at Fox Chase.
Comprehensive Cancer Center, BMT program.
Eligible patients were required to stay within 1h from Fox Chase with a caregiver during the observation period (days 1-10). Patients and caregivers received education on CRS and ICANS. Teclistamab was administered on days 1, 3, and 8. Safety monitoring protocol included daily evaluation in the outpatient clinic, home monitoring of vital signs, and 8 pm physician phone call on days 1-5 and 8-10, within 48h window after each step-up dose. CBC, CMP, CRP, ferritin were monitored at each visit. Patients with CRS/ ICANS of any grade were admitted for observation and management.
Between 12/2022-5/2023, 18 patients completed outpatient teclistamab step-up dosing. The median age was 66y (46-81). 12(66.7%) patients did not have CRS/ICANS. 5(27.8%) patients had grade 1 CRS, of which 1(5.6%) had concurrent grade 1 ICANS. 1(5.6%) patient had grade 2 CRS. Of the 6 CRS events, 3(50%) occurred after the first dose and 3(50%) after the second dose. 5 of 6 patients with CRS received 1 dose of tocilizumab, and the patient with concurrent ICANS also received dexamethasone, with prompt resolution of symptoms. All patients completed step-up dosing with no recurrent CRS/ICANS.
Outpatient teclistamab step-up dosing administration with close monitoring and prompt hospitalization for toxicity management is safe and feasible in heavily pre-treated RRMM patients. This approach allows a significant reduction of inpatient stay, resulting in significant healthcare resource savings and improvement of patients’ experience.
