Evaluation of Measurable Residual Disease Assessment Dynamics in Hairy Cell Leukemia Clinical Trials from 1980 to 2020
Authors: Borja Montes Oscar , Jawadi Altamash , Varatharaj Sushrruti , Herring Hannah E , Escobar Gil Tomas , Epperla Narendranath , Andritsos Leslie A. 
Published: December 2024

Introduction:
Hairy cell leukemia (HCL) is a rare hematological malignancy originating from a mature B lymphocyte. The diagnosis is based on morphological characteristics of hairy cells, immunophenotype by multiparametric flow cytometry (MFC), immunohistochemistry (IHC), and the presence of the somatic mutation BRAF V600E (Grever et al. Blood 2017). One of the challenges in HCL is the difficulty in predicting progression-free survival (PFS) following treatment. Recently, minimal residual disease (MRD) negativity has been shown to be associated with higher rates of durable complete response (Robak et al. Front Oncol, 2022). MRD is defined as the lowest level of neoplastic cells that can be identified using validated techniques. For HCL, IHC of the bone marrow biopsy (BMBx), MFC of the bone marrow aspirate (BMA) and/or peripheral blood (PB), and clone-specific quantitative PCR of mutations like BRAF are being utilized as MRD methods (Ravandi et al. Blood Cancer J, 2022). Herein we explored the heterogeneity of MRD assessment in HCL clinical trials and how methods have evolved over the last four decades.
Methods:
In this retrospective study, we conducted a comprehensive search across multiple databases including PUBMED, EMBASE, Cochrane Central, and ClinicalTrials.gov from January 1980 to January 2024. We identified publications including both full manuscripts and abstracts from clinical trials reporting on HCL treatments. Articles that were unavailable in English were excluded. We reviewed individually each of the articles and determined the proportion of clinical trials that collected MRD data, and the method of MRD assessment. We also characterized how the use of MRD in clinical trial protocols has changed over time. Descriptive statistical analysis was performed obtaining proportions and measures of frequency to summarize these variables and explore trends over time.
Results:
A total of 60 studies were selected, the majority of which included cytotoxic chemotherapy (46.6%, n=28), were phase II (78.3%, n=47), and recruited both newly diagnosed and relapsed/refractory patients (56.6%, n=34) with HCL. MRD assessment was reported as being part of the clinical trial for 52% (n=31) of the studies. Of these, 77% (n=24/31) were phase II clinical trials. 46% of all the studies (n=28/60) evaluated cytotoxic chemotherapy agents only, cladribine being the most common one. Immunotherapy agents such as rituximab, obinutuzumab, and interferon-alpha were tested in 23% of the studies (n=14/60). Targeted therapies that were studied included BRAF inhibitors (BRAFi), and bruton tyrosine kinase inhibitors (BTKi), comprising 15% of the trials that were evaluated (n=9/60). The most common method of MRD assessment was IHC in BMBx specimens which were used in 74% (n=23/31) of the studies, followed by MFC + IHC in 32% (n=10/31) of the trials. 6% of the studies (n=2/31) that reported MRD evaluation did not specify the method used. MRD assessment was also performed in 89% of clinical trials (8/9) testing targeted therapies compared to 32% of clinical trials testing cytotoxic chemotherapy (9/28). Notably, the MRD assessment trend increased significantly over time, being only 7% (n=1) of the clinical trials performed between 1980 to 1989, compared to 92.3% (n=12) of the clinical trials performed between 2010 to 2020. Over the years the MRD assessment method preference has also changed. Between 1990-1999 the most common method was IHC of the BMBx which accounted for 67% (n=6/9) of all the studies performed. Later studies developed between 2010-2020 most commonly used a combination of MFC of the BMA and/or PB + IHC at 50% (n=5/10). Clone-specific PCR was also utilized in more recent years and clinical trials evaluating targeted therapies comprised 10% (3/31) of the studies.
Conclusions:
We found that MRD testing in HCL remains heterogeneous, with a notable increase in MRD assessment in recent clinical trials. While IHC was the predominant method used in the past four decades, MFC has emerged as the preferred technique in recent years. It is important to not only select the most sensitive method for MRD assessment but also use it uniformly across the future HCL trials so the results could be interpreted appropriately. Our study highlighted the evolving characteristics of MRD assessment in HCL clinical trials reflecting the shift towards precision oncology.