CCSA’s Howard Higley and Lata Mukundan are co-authors on an article published in JAMA Oncology in May 2017: Association of Minimal Residual Disease with Clinical Outcome in Pediatric and Adult Acute Lymphoblastic Leukemia: A Meta-analysis.
Dr. Howard Higley is Director of Scientific Affairs at CCS Associates. He has extensive knowledge of clinical/regulatory/intellectual property requirements for successful medical product registration. Dr. Higley has been the study director/principal investigator on more than 125 pilot and Good Laboratory Practice in vivo research studies designed and performed in industry.
Dr. Lata Mukundan is a senior scientist at CCS Associates. She is an immunologist with expertise in multiparametric flow cytometry and its application to minimal residual disease measurement in various hematological malignancies.
Minimal residual disease (MRD) refers to the presence of disease in cases deemed to be in complete remission by conventional pathologic analysis. Assessing the association of MRD status following induction therapy in patients with acute lymphoblastic leukemia (ALL) with relapse and mortality may improve the efficiency of clinical trials and accelerate drug development. The objective was to quantify the relationships between event-free survival (EFS) and overall survival (OS) with MRD status in pediatric and adult ALL using publications of clinical trials and other databases. Clinical studies in ALL were identified via searches of PubMed, MEDLINE, and clinicaltrials.gov. The search and study screening process adhered to the PRISMA Guidelines. Studies that addressed EFS or OS by MRD status in patients with ALL were included; reviews, abstracts, and studies with fewer than 30 patients or insufficient MRD description were excluded. Study sample size, patient age, follow-up time, timing of MRD assessment (post-induction or consolidation), MRD detection method, phenotype/genotype (B cell, T cell, Philadelphia chromosome), and EFS and OS parameters were extracted. Searches of PubMed and MEDLINE identified 566 articles. A parallel search on clinicaltrials.gov found 67 closed trials and 62 open trials as of 2014. Merging the results of two independent searches and applying exclusions gave 39 publications in three arms of patient populations (adult, pediatric, and mixed). Separate meta-analyses for each of these three subpopulations were performed. The 39 publications comprised 13,637 patients: 16 adult studies (2076 patients), 20 pediatric (11, 249 patients), and 3 mixed (312 patients). The EFS hazard ratio (HR) for achieving MRD negativity was 0.23 (95% Bayesian credible interval [BCI] 0.18-0.28) for pediatric patients and 0.28 (95% BCI, 0.24-0.33) for adults. The respective HRs in OS were 0.28 (95% BCI, 0.19-0.41) and 0.28 (95% BCI, 0.20-0.39). The effect was similar across all subgroups and covariates. Conclusions and Relevance: The value of having achieved MRD negativity is substantial in both pediatric and adult patients with ALL. These results are consistent across therapies, methods of and times of MRD assessment, cutoff levels, and disease subtypes. MRD status warrants consideration as an early measure of disease response for evaluating new therapies, improving the efficiency of clinical trials, accelerating drug development, and for regulatory approval. A caveat is that an accelerated approval of a particular new drug using an intermediate endpoint, such as MRD, would require confirmation using traditional efficacy end points.
The full paper can be found here.