Abstract
Background: Measurable residual disease (MRD) status has recently emerged to evaluate treatment efficacy, predict long-term outcomes, and inform therapeutic strategies in Chronic lymphocytic leukaemia (CLL). By analysing treatment outcomes in terms of CLL MRD and its comparison with the existing iwCLL 2018 response criteria, we aim to highlight MRD's role in response assessment in CLL management.Methodology: Study was a prospective observational study conducted as part of a thesis in the AIIMS Rishikesh, a tertiary centre in Northern India. After institutional ethics committee approval, 29 patients who had an indication of treatment for CLL as per the iwCLL 2018 criteria were included in the study. Response assessment was done at the end of the completion of chemoimmunotherapy (CIT) or CR in peripheral blood in targeted therapy. The primary objective was to assess the responses in the cohort as per iwCLL 2018 criteria and CLL MRD as per ERIC criteria. The secondary objective was to compare these response criteria and responses between the CIT and targeted therapy. Median follow-up was 14 months.
Results: In the cohort, male predominance was seen (ratio 3:1). Median age was 62 years (44-76). Most of the patients had ECOG PS score of 0-2 (86%). Rai staging at diagnosis showed 51.7 % in Stage IV, 13.8 % in Stage III, 27.6 % in Stage II, and 6.9 % in Stage I. Binet staging indicated 65.5 % in Stage C, 20.7 % in Stage B, and 13.8 % in Stage A. B symptoms were present in 31 %. Treatment indications as per 2018 iwCLL guidelines included progressive bone marrow failure (75.9 %), massive splenomegaly (37.9 %), bulky lymphadenopathy (17.2 %), LDT < than 6 months (13.8 %), AIHA not responding to steroids (10.3 %), extra nodal involvement (17.2 %), and B symptoms (17 %).
Cytogenetic analysis were available in 26 patients, showed deletion in 13q (41.4 %), trisomy 12 (31 %), deletion 11q22 (20.7 %), and deletion 17p (13.8 %). TP53 and NOTCH1 mutations were seen in 20.7% and 13.8%, respectively. IgHV mutation analysis were available in 27 patients, revealed 44 % unmutated and 51.7% mutated. Treatments included Acalabrutinib (37.9 %), Bendamustine plus Rituximab (34.5%), Ibrutinib plus Rituximab (17.2%), and single cases of Venetoclax plus Rituximab, R-CHOP, and Mini R-CHOP plus Acalabrutinib. Targeted therapy (62%) averaged 8.11 cycles; CIT (37.9%) had 6 cycles at the time of response assessment.
Response assessment as per 2018 iwCLL guidelines showed 48.3 % complete response (CR), 41.4% partial response (PR), and 10.3% had nodular partial response (NPR). CLL MRD done at the time of response assessment showed undetectable MRD (uMRD) in 27.6%, with CIT showing higher rates (54.5%) than targeted therapy (11.1%) in the cohort. Comparison done between Targeted therapy and CIT revealed that significantly higher CR in the CIT as per iwCLL 2018 (72.7% vs 33.3%, p=0.039) and significantly higher uMRD rates in CIT (63.6% vs 11.1%, p=0.01). The association between iwCLL 2018 response and CLL MRD as per ERIC criteria was assessed using Chi-square and Fisher's exact tests, revealing no significant association (χ²(1) =1.77, p=0.184; Fisher's two-sided p=0.245). Of 15 PR patients, 33.3% had uMRD, and of 14 CR patients, 71.4% had detectable MRD.
Median PFS (mPFS) showed trends towards uMRD (47 months vs 32 months, p=0.14). mPFS was higher in IgHV-mutated (mPFS not reached in mutated IgHV vs 47 months in Unmutated IgHV, p=0.43). Similarly, mPFS in favourable cytogenetics was higher (Not reached vs 47 months).
The most common Adverse events (AEs) included thrombocytopenia (27.5%), fatigue (24.4%), with higher rates in targeted therapy. Other reported AEs are anaemia, febrile neutropenia, diarrhoea, infection, and AKI.
Richter transformation occurred in 2 patients (testicular DLBCL and Hodgkin's lymphoma); extra-nodal disease was seen in 17.2% [with involvement of Skin(n=1), Gut(n=1), Testis(n=2), and Lung(n=1)].
Conclusion: Complete responses were significantly higher in CIT compared to targeted therapy. There was no significant association between the iwCLL 2018 response and CLL MRD assessment as per ERIC criteria. mPFS was higher in uMRD, Mutated IgHV, and favourable cytogenetics. The study is limited by a small sample size for statistical analysis and a shorter follow-up period. Overcoming these limitations would give an answer for the accurate estimation of response to therapy in CLL for future response-guided therapy.
