NGS Analysis of Clonality and Minimal Residual Disease in a Patient with Concurrent Richter’s Transformation and CLL/SLL

B-cell lymphomas are neoplastic proliferations of clonal B lymphocytes. Clonality is generally determined by PCR amplification of VDJ rearrangements in the IgH heavy chain or VJ rearrangements in Igκ/Igλ light chain genes followed by capillary electrophoresis. More recently, next-generation sequencing (NGS) has been used to detect clonality in B-cell lymphomas because of the exponential amount of information that is obtained beyond just detecting a clonal population. The additional information obtained is useful for diagnostic confirmation, prognosis assessment, and response to therapy. In this study, we utilized NGS analysis to characterize two histologically distinct lymphomas (DLBCL and CLL/SLL) that were detected contemporaneously in an asymptomatic patient. NGS analysis showed that the same VDJ rearrangement was present in nodal (DLBCL) and marrow (CLL/SLL) biopsies confirming that the DLBCL resulted from Richter’s transformation of a subclinical CLL/SLL. The V region of the rearrangement remained unmutated without somatic hypermutation. In silico analysis showed that the HCDR3 sequence was heterogeneous and not stereotypic. Minimal residual disease analysis by NGS showed that the tumor clone decreased by 2.84 logs in the bone marrow after R-CHOP therapy. However, a small number of tumor cells were still detected in the peripheral blood after R-CHOP therapy. Subsequent allogeneic transplantation was successful in eradicating the tumor clone and achieving deep molecular remission. We show that NGS analysis facilitated clinical management in our patient by helping to characterize the VDJ rearrangement in detail and by tracking minimal residual disease with high sensitivity and specificity.

Outcomes of R-Mini-CHOP Therapy for Elderly Patients with Diffused Large B Cell Lymphoma (DLBCL) and High-Grade Follicular Lymphoma (FL)

Introduction: DLBCL represents the most common lymphoma of the elderly, with R-CHOP remaining the standard of care. For elderly patients survival and outcomes data remains limited. Reduced dose R-mini-CHOP was demonstrated to be safe and effective treatment for elderly patients with overall survival of 58%. Defining predictor factors of response and identifying patients that benefit from R-CHOP remains essential. Methods: Retrospective analysis of elderly patients (pts) with frontline DLBCL and high-grade FL treated with R-mini-CHOP and R-CHOP between April 2014 and June 2021. Adult pts 75 years and older were included in the analysis. We performed a chart review to obtain treatment responses and analyze correlations between clinical, molecular characteristics and outcomes. A comparative study with outcomes of standard R-CHOP treatment was conducted. Primary objective was to determine safety and efficacy of R-mini-CHOP in elderly pts. Secondary objectives include overall response rates (ORR), overall survival (OS), and progression-free survival (PFS) after R-mini-CHOP compared with standard R-CHOP. Results: A total of 22 frontline elderly pts 75 years and older were included. Twenty pts (91%) were >80 years, with a median age of 83 years. Most patients had a diagnosis of DLBCL (86%), with stage III-IV in 61%. LDH was increased in 54% of pts. Fifteen pts had a high-risk IPI score (68%). Baseline characteristics are listed in Table 1. Sixteen pts (73%) completed at least 3 cycles of therapy, with a median of 4 cycles (range 1-6). Nineteen pts were evaluable for response. With a median follow-up of 16 months, the overall response rate (ORR) was 79%, including 53% complete response and 26% partial response. Figure 1. The overall survival (OS) was 36 months with a progression-free survival of 22 months and event-free survival of 16 months. With a 2-year OS and PFS of 63% and 44%, respectably, with a median duration of response of 44 months. A total of 7 pts died (32%), 3 pts from disease progression (14%), 3 pts from infection (14%), and 1 pt from bleeding (4%); and the 4-week mortality rate was 18%. Response rates were compared with a contemporary group treated with standard R-CHOP therapy. Significant differences were observed between both subgroups with an increased performance status (PS>2) (P=<0.001), LDH (P=0.015), and high-risk IPI score (P=0.002) among R-mini-CHOP pts compared to R-CHOP pts. With a significantly younger median age of 78 years for R-CHOP vs 83 years for R-mini-CHOP pts (P=<0.001). Table 1. Univariate analysis for predictors of response revealed a PS equal to 2 or higher to be significantly associated with decreased response rates. (Odds ratio 0.1, P=0.007) Among R-CHOP treated pts, the ORR was 96% with 76% complete responses, while the OS, PFS, and EFS were not reached. Figure 2. Conclusions: Dose-reduced R-mini-CHOP is an effective and safe therapy for elderly patients with a diagnosis of DLBCL and high-grade FL. Response rates compared favorably with previously reported 2-year OS 58% and PFS 47% by the GELA study. Compared with contemporary subgroup treated with R-CHOP therapy showed higher response rates with significantly improved OS and PFS. However, pts in this group were younger with a significantly lower IPI and PS. Further comparison analysis with historical R-CHOP and R-CVP therapy is undergoing Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Mechanistic physiology-based pharmacokinetic modeling to elucidate vincristine-induced peripheral neuropathy following treatment with novel kinase inhibitors

Purpose Limited information is available regarding the drug–drug interaction (DDI) potential of molecular targeted agents and rituximab plus cyclophosphamide, doxorubicin (hydroxydaunorubicin), vincristine (Oncovin), and prednisone (R-CHOP) therapy. The addition of the Bruton tyrosine kinase (BTK) inhibitor ibrutinib to R-CHOP therapy results in increased toxicity versus R-CHOP alone, including higher incidence of peripheral neuropathy. Vincristine is a substrate of P-glycoprotein (P-gp, ABCB1); drugs that inhibit P-gp could potentially cause increased toxicity when co-administered with vincristine through DDI. While the combination of the BTK inhibitor acalabrutinib and R-CHOP is being explored clinically, the DDI potential between these therapies is unknown. Methods A human mechanistic physiology-based pharmacokinetic (PBPK) model of vincristine following intravenous dosing was developed to predict potential DDI interactions with combination therapy. In vitro absorption, distribution, metabolism, and excretion and in vivo clinical PK parameters informed PBPK model development, which was verified by comparing simulated vincristine concentrations with observed clinical data. Results While simulations suggested no DDI between vincristine and ibrutinib or acalabrutinib in plasma, simulated vincristine exposure in muscle tissue was increased in the presence of ibrutinib but not acalabrutinib. Extrapolation of the vincristine mechanistic PBPK model to other P-gp substrates further suggested DDI risk when ibrutinib (area under the concentration–time curve [AUC] ratio: 1.8), but not acalabrutinib (AUC ratio: 0.92), was given orally with venetoclax or digoxin. Conclusion Overall, these data suggest low DDI risk between acalabrutinib and P-gp substrates with negligible increase in the potential risk of vincristine-induced peripheral neuropathy when acalabrutinib is added to R-CHOP therapy.

Prognostic Impact of Muscle Quantity and Quality and Fat Distribution in Diffuse Large B-Cell Lymphoma Patients

Baseline CT scans of 116 patients (48% female, median 64 years) with diffuse large B-cell lymphoma (DLBCL) were retrospectively reviewed to investigate the prognostic role of sarcopenia and fat compartment distributions on overall survival (OS), progression-free survival (PFS), and early therapy termination. Skeletal muscle index (SMI), skeletal muscle density (SMD), and intermuscular adipose tissue (IMAT) were quantified at the level of the third lumbar vertebra (L3) and proximal thigh (PT). Low L3-SMD, but not low L3-SMI, was associated with early therapy termination (p = 0.028), shorter OS (HR = 6.29; 95% CI = 2.17–18.26; p < 0.001), and shorter PFS (HR = 2.42; 95% CI = 1.26–4.65; p = 0.008). After correction for sex, International Prognostic Index (IPI), BMI, and R-CHOP therapy (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), low L3-SMD remained associated with poor OS (HR = 3.54; 95% CI = 1.10–11.40; p = 0.034) but not with PFS. Increased PT-IMAT was prognostic for poor OS and PFS after correction for sex, IPI, BMI, and R-CHOP therapy (HR = 1.35; CI = 1.03–1.7; p = 0.03, and HR = 1.30; CI = 1.04–1.64; p = 0.024, respectively). Reduced muscle quality (SMD) and increased intermuscular fat (IMAT), rather than low muscle quantity (SMI), are associated with poor prognosis in DLBCL, when measured at the L3 level, and particularly at the level of the proximal thigh. The proximal thigh represents a novel radiological landmark to study body composition.

Optimal timing and criteria of interim PET in DLBCL: a comparative study of 1692 patients

Interim 18F-fluorodeoxyglucose positron emission tomography (Interim-18F-FDG-PET, hereafter I-PET) has the potential to guide treatment of patients with diffuse large B-cell lymphoma (DLBCL) if the prognostic value is known. The aim of this study was to determine the optimal timing and response criteria for evaluating prognosis with I-PET in DLBCL. Individual patient data from 1692 patients with de novo DLBCL were combined and scans were harmonized. I-PET was performed at various time points during treatment with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy. Scans were interpreted using the Deauville score (DS) and change in maximum standardized uptake value (ΔSUVmax). Multilevel Cox proportional hazards models corrected for International Prognostic Index (IPI) score were used to study the effects of timing and response criteria on 2-year progression-free survival (PFS). I-PET after 2 cycles (I-PET2) and I-PET4 significantly discriminated good responders from poor responders, with the highest hazard ratios (HRs) for I-PET4. Multivariable HRs for a PET-positive result at I-PET2 and I-PET4 were 1.71 and 2.95 using DS4-5, 4.91 and 6.20 using DS5, and 2.93 and 4.65 using ΔSUVmax, respectively. ΔSUVmax identified a larger proportion of poor responders than DS5 did. For all criteria, the negative predictive value was >80%, and positive predictive values ranged from 30% to 70% at I-PET2 and I-PET4. Unlike I-PET1, I-PET3 discriminated good responders from poor responders using DS4-5 and DS5 thresholds (HRs, 2.94 and 4.67, respectively). I-PET2 and I-PET4 predict good response equally during R-CHOP therapy in DLBCL. Optimal timing and response criteria depend on the clinical context. Good response at I-PET2 is suggested for de-escalation trials, and poor response using ΔSUVmax at I-PET4 is suggested for randomized trials that are evaluating new therapies.

Novel model predicts prognosis for patients with diffuse large B-cell lymphoma in first relapse after initial R-CHOP therapy: a single-institution study in China

Objective To develop a prognostic model for Chinese patients with relapsed diffuse large B-cell lymphoma (DLBCL) after initial R-CHOP therapy. Methods We retrospectively analyzed the characteristics and survival outcomes of 79 patients with relapsed DLBCL initially treated with R-CHOP at Peking Union Medical College Hospital from February 2012 to September 2016. We used the data to develop a novel prognostic model. Results The median age at the start of salvage therapy was 59 (17–85) years and median time from diagnosis to relapse was 319 (49–1018) days. Multivariate analysis identified short time to relapse (TTR) and B symptoms as independent prognostic factors for reduced progression-free survival (PFS) and overall survival (OS). We created a new prognostic scoring system including TTR, lactate dehydrogenase, absolute lymphocyte count at relapse, and B symptoms, referred to as the TLLB model, which could separate patients into three risk groups with 2-year PFS and OS rates of 70.7%, 40.0%, and 11.1%, and 87.5%, 53.7%, and 29.4%, respectively. Conclusion TTR and B symptoms can be used as important predictors of survival in patients with DLBCL. The TLLB system provides a useful prognostic model compared with the previous TTL system.

Evaluation for pharmacokinetic exposure of cytotoxic anticancer drugs in elderly patients receiving (R-)CHOP therapy

Abstract(R-)miniCHOP therapy, which delivers approximately half-doses of the (R-)CHOP regimen, has shown efficacy and safety in patients who are more than 80 years old. This study aimed to compare the area under the plasma concentration–time curves (AUCs) of vincristine (VCR), doxorubicin (DXR), and cyclophosphamide (CPA) between (R-)CHOP and (R-)miniCHOP regimens. The AUCs were compared between patients aged 65–79 years receiving (R-)CHOP therapy and those aged 80 years and older receiving (R-)miniCHOP therapy. Age was not an independent variable for predicting the dose-adjusted AUCs (AUC/Ds) of cytotoxic anticancer drugs. The median AUCs of DXR and CPA were significantly smaller in the (R-)miniCHOP group than in the (R-)CHOP group (168.7 vs. 257.9 ng h/mL, P = 0.003, and 219.9 vs. 301.7 µg h/mL, P = 0.020, respectively). The median AUCs of VCR showed the same trend but the difference was not significant (24.83 vs. 34.85 ng h/mL, P = 0.135). It is possible that the AUCs of VCR, DXR, and CPA in patients aged 80 years and older receiving (R-)miniCHOP therapy may be lower than those in patients 65–79 years old receiving (R-)CHOP therapy.