Medical College of Wisconsin Biostatistics News

Yu Wang at 2024 JSM, January 12, 2024

Peter Zhang, February 2, 2024

The winner of the Florence Nightingale Award for 2024 award and $1,000.00 USD prize is Ulrich Kemmo Tsafack (“Tri-level Variable Selection Method for Ultra-high Dimensional Multi-omics Data”). Congratulations to Ulrich Kemmo Tsafack!

Aniko Szabo

Authors:
Shah NN, Colina AS, Johnson BD, Szabo A, Furqan F, Kearl T, et al.

PMID:
40163793

Abstract:
PURPOSE: Mantle cell lymphoma (MCL) is an aggressive B-cell malignancy characterized by t(11;14) and bright CD20 expression. To improve outcomes from single targeted CD19 chimeric antigen receptor (CAR) T cells, we used dual targeted lentiviral anti-CD20/anti-CD19 (LV20.19) CAR T cells as part of a phase I/II clinical trial in relapsed, refractory (R/R) MCL (ClinicalTrials.gov identifier: NCT04186520).METHODS: Patients with MCL who had failed two lines of therapy or relapsed post-transplant were eligible. LV20.19 CAR T cells were manufactured on-site via CliniMACS Prodigy using an adaptive 8- to 12-day process to optimize the final CAR product for increased numbers of naïve and stem-cell memory (SCM) like T cells. RESULTS: Seventeen patients with R/R MCL received a single dose of LV20.19 CAR T cells at 2.5 × 10⁶ cells/kg (phase I = three patients; phase II = 14 patients). The best overall response rate (ORR) was 100% (complete response [CR] = 88%; partial response = 12%) and the phase II efficacy threshold for day-90 CR rate was exceeded. Two patients have relapsed as of the data cutoff and neither the median progression-free survival nor overall survival has been reached with a median follow-up of 15.8 months. Ninety-four percent (n = 16) experienced cytokine release syndrome, all grade 1-2. Eighteen percent (n = 3) had immune effector cell-associated neurotoxicity syndrome in the first 28-days, two with reversible grade 3 toxicity. Three patients had nonrelapse mortality events; all occurred in the setting of ongoing B-cell aplasia. The final LV20.19 CAR products were enriched for higher percentages of T-_SCM/T-naïve cells and most patients received CAR T cells within 8 days of apheresis. CONCLUSION: In conclusion, we demonstrate that on-site adaptive manufactured LV20.19 CAR T cells are feasible, safe, and efficacious for R/R MCL with best ORR of 100%, a favorable safety profile, and few relapses to date.

PubMed Date:
3/31/2025

Citation:
2025 Mar 31:JCO2402158

Journal:
Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology

Ruta Brazauskas

Authors:
Eapen M, Malec LM, Armant MA, Johnson BD, Shi Q, Xu H, et al.

PMID:
39842018

PubMed Date:
1/22/2025
 
Citation:
2025 Jan 23;392(4):412-414

Journal:
The New England Journal of Medicine

Paul Auer

Authors:
Jakubek YA, Ma X, Stilp AM, Yu F, Bacon J, Wong JW, Aguet F, et al.

PMID:
39809269

Abstract:
Mosaic loss of Y (mLOY) is the most common somatic chromosomal alteration detected in human blood. The presence of mLOY is associated with altered blood cell counts and increased risk of Alzheimer disease, solid tumors, and other age-related diseases. We sought to gain a better understanding of genetic drivers and associated phenotypes of mLOY through analyses of whole-genome sequencing (WGS) of a large set of genetically diverse males from the Trans-Omics for Precision Medicine (TOPMed) program. We show that haplotype-based calling methods can be used with WGS data to successfully identify mLOY events. This approach enabled us to identify differences in mLOY frequencies across populations defined by genetic similarity, revealing a higher frequency of mLOY in the European (EUR) ancestry group compared to other ancestries. We identify multiple loci associated with mLOY susceptibility and show that subsets of human hematopoietic stem cells are enriched for the activity of mLOY susceptibility variants. Finally, we found that certain alleles on chromosome Y are more likely to be lost than others in detectable mLOY clones.

PubMed Date:
1/15/2025

Citation:
2025 Feb 06;112(2):276-290

Journal:
American Journal of Human Genetics

Brent Logan

Authors:
Levis MJ, Hamadani M, Logan BR, Jones RJ, Singh AK, Litzow MR, Wingard JR, et al.

PMID:
39775763

Abstract:
BMT CTN (Blood and Marrow Transplant Clinical Trials Network) 1506 (""MORPHO"") was a randomized study of gilteritinib compared with placebo as maintenance therapy after hematopoietic cell transplantation (HCT) for patients with FLT3-ITD-mutated acute myeloid leukemia (AML). A key secondary end point was to determine the impact on survival of before and/or after HCT measurable residual disease (MRD), as determined using a highly sensitive assay for FLT3-ITD mutations. Generally, gilteritinib maintenance therapy was associated with improved relapse-free survival (RFS) for participants with detectable peri-HCT MRD, whereas no benefit was evident for those lacking detectable MRD. We conducted a post hoc analysis of the data and found that the level of MRD detected with this approach correlated remarkably with RFS and relapse risk, and that MRD detectable at any level negatively affected RFS. In the placebo arm, 42.2% of participants with detectable FLT3-ITD MRD relapsed compared with 13.4% of those without detectable MRD. We found that 14.8% of participants had multiple FLT3-ITD clones detected as MRD and had worse survival irrespective of treatment arm. Finally, we examined the kinetics of FLT3-ITD clonal relapse or eradication and found that participants on the placebo arm with detectable MRD relapsed rapidly after HCT, often within a few weeks. MRD-positive participants on the gilteritinib arm relapsed either with FLT3 wild-type clones (assessed by capillary electrophoresis), after cessation of gilteritinib with persistent MRD, or on progression of multiclonal disease. These data demonstrate the potential of FLT3-ITD MRD to guide therapy with gilteritinib for this subtype of AML. This trial was registered at www.clinicaltrials.gov as #NCT02997202.
 
PubMed Date:
1/8/2025

Citation:
2025 May 08;145(19):2138-2148

Journal:
Blood

Michael Martens

Authors:
Holtan SG, BolaÃos-Meade J, Al Malki MM, Wu J, Kitko CL, Reshef R, Rezvani AR, Shaffer BC, et al.

PMID:
39752608

Abstract:
The BMT CTN 1703 phase III trial confirmed that graft-versus-host disease (GVHD) prophylaxis with post-transplantation cyclophosphamide (PTCy), tacrolimus (Tac), and mycophenolate mofetil (MMF) results in superior GVHD-free, relapse-free survival (GRFS) compared with Tac/methotrexate (MTX) prophylaxis. This companion study assesses the effect of these regimens on patient-reported outcomes (PROs). Using the Lee Chronic GVHD Symptom Score and PROMIS subscales (physical function, GI symptoms, social role satisfaction) as primary end points and hemorrhagic cystitis symptoms and Lee subscales as secondary end points, responses from English and Spanish speakers were analyzed at baseline and days 100, 180, and 365 after transplant. PRO scores were compared between the arms using inverse probability weighted-independent estimating equation models. The PTCy arm had significantly lower scores on the Lee Chronic GVHD Symptom Scale (<i>P</i> = .01), indicating lower GVHD symptom burden. Lee Scale nutrition and mouth subscores were also better in the PTCy arm compared with the Tac/MTX arm (<i>P</i> &lt; .01 for both). Older participants (age &gt;65 years) reported better Lee Scale psychological subscores than younger participants (<i>P</i> = .003). No significant differences were identified in hemorrhagic cystitis or in the PROMIS subscales between treatment arms. The updated clinical end points at 2 years for the parent trial confirmed that PTCy/Tac/MMF maintained a significant advantage over Tac/MTX in GRFS (42.4% <i>v</i> 28.8%, <i>P</i> = .001). In addition to improved GRFS, patients randomly assigned to the PTCy arm reported lower symptom burden during the first year after transplant.

PubMed Date:
1/3/2025

Citation:
2025 Mar 10;43(8):912-918

Journal:
Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology