Ibrutinib as first-line therapy for mantle cell lymphoma: a multicenter, real-world UK study.

ABSTRACT: During the COVID-19 pandemic, ibrutinib with or without rituximab was approved in England for initial treatment of mantle cell lymphoma (MCL) instead of immunochemotherapy. Because limited data are available in this setting, we conducted an observational cohort study evaluating safety and efficacy. Adults receiving ibrutinib with or without rituximab for untreated MCL were evaluated for treatment toxicity, response, and survival, including outcomes in high-risk MCL (TP53 mutation/deletion/p53 overexpression, blastoid/pleomorphic, or Ki67 ≥ 30%). A total of 149 patients from 43 participating centers were enrolled: 74.1% male, median age 75 years, 75.2% Eastern Cooperative Oncology Group status of 0 to 1, 36.2% high-risk, and 8.9% autologous transplant candidates. All patients received ≥1 cycle ibrutinib (median, 8 cycles), 39.0% with rituximab. Grade ≥3 toxicity occurred in 20.3%, and 33.8% required dose reductions/delays. At 15.6-month median follow-up, 41.6% discontinued ibrutinib, 8.1% due to toxicity. Of 104 response-assessed patients, overall (ORR) and complete response (CR) rates were 71.2% and 20.2%, respectively. ORR was 77.3% (low risk) vs 59.0% (high risk) (P = .05) and 78.7% (ibrutinib-rituximab) vs 64.9% (ibrutinib; P = .13). Median progression-free survival (PFS) was 26.0 months (all patients); 13.7 months (high risk) vs not reached (NR) (low risk; hazard ratio [HR], 2.19; P = .004). Median overall survival was NR (all); 14.8 months (high risk) vs NR (low risk; HR, 2.36; P = .005). Median post-ibrutinib survival was 1.4 months, longer in 41.9% patients receiving subsequent treatment (median, 8.6 vs 0.6 months; HR, 0.36; P = .002). Ibrutinib with or without rituximab was effective and well tolerated as first-line treatment of MCL, including older and transplant-ineligible patients. PFS and OS were significantly inferior in one-third of patients with high-risk disease and those unsuitable for post-ibrutinib treatment, highlighting the need for novel approaches in these groups.

Relapsed mantle cell lymphoma presenting with lactic acidosis and hypoglycemia: A case report.

Lactic acidosis and hypoglycemia are rare presentations of malignancy with a poor prognosis. We present the case of a mantle cell lymphoma patient who relapsed with lactic acidosis and hypoglycemia. Although blood glucose, pH, and lactate normalized following chemotherapy and intensive care support, the patient died from ventilator-associated pneumonia.

Managing relapsed refractory lymphoma with palliative oral chemotherapy: A multicentre retrospective study.

PEP-C (prednisolone, etoposide, procarbazine and cyclophosphamide) is an orally administered daily chemotherapy regimen used with palliative intent in relapsed refractory lymphoma. To our knowledge, no data on PEP-C have been reported since the original group described the regimen. Here we present a multicentre retrospective cohort reporting our use of PEP-C in 92 patients over an 8-year period. We find that even heavily pretreated lymphoma can respond to PEP-C, particularly low-grade lymphoma (including mantle cell) and lymphoma that was sensitive to the previous line of systemic therapy (chemosensitive). These characteristics may help in the selection of patients likely to derive benefit. The median overall survival of patients with chemosensitive lymphoma treated with PEP-C is 217 days. Within the limitations of a retrospective cohort, we find that PEP-C is well tolerated: the most common toxicity leading to discontinuation is marrow suppression. We suggest that PEP-C should be considered for patients with relapsed refractory lymphoma in two settings: first, where there is no licensed alternative; and second, where the licensed alternative is an intravenous drug and the patient would prefer to choose an oral chemotherapy option.

Minimising the Toxicities of First Line Hodgkin Lymphoma Treatment in the Modern Era.

Striking advances in the treatment of Hodgkin lymphoma over the last 30 years have culminated in high rates of disease-free survival in younger patients with early and advanced stage disease. In this review we focus on strategies that have evolved over recent years to reduce short and long-term toxicities of treatment. These strategies include the selection of first-line chemotherapy, the stratification of patients based on initial response and subsequent adaptation of treatment, the addition of novel agents (e.g., brentuximab vedotin), the removal of specific drugs (e.g., bleomycin), the use of drug substitution, and the removal of consolidation radiotherapy based on interim and end of treatment PET assessment. While these strategies have successfully reduced toxicity of Hodgkin lymphoma therapy, the cornerstone of treatment continues to be combination chemotherapy and radiotherapy with significant short- and long-term side effects. To further reduce toxicity while maintaining or improving efficacy, we shall need to incorporate novel agents into our first-line treatment algorithms, and several such potentially practice-changing trials are underway.

Incidence and outcomes of post-transplant lymphoproliferative disease after 5365 solid-organ transplants over a 20-year period at two UK transplant centres.

Post-transplant lymphoproliferative disease (PTLD) is a life-threatening complication of solid-organ transplantation (SOT). We present the incidence and outcomes of PTLD in a cohort of 5365 SOT recipients over a 20-year period at two UK transplant centres. With a median follow-up of 7.7 years, 142 of 5365 patients have developed PTLD. Cumulative incidence was 18% at five years after multivisceral transplant and 1%-3% at five years following the other SOT types. Twenty-year cumulative incidence was 2%-3% following liver and heart transplantation and 10% following kidney transplantation. Median overall survival (OS) following SOT was 16 years, which is significantly reduced compared with the age-adjusted UK population. There is relatively high early mortality following diagnosis of PTLD and only patients surviving two years regained a longer-term survival approaching the non-PTLD SOT cohort. Of 90 patients with monomorphic PTLD, diffuse large B-cell lymphoma, 66 were treated with first-line rituximab monotherapy and 24 received first-line rituximab plus chemotherapy. Up-front rituximab monotherapy does not appear to compromise OS, but the number of patients dying from non-lymphoma causes before and after treatment remains high with both treatment approaches. Multivariate analysis of all 90 monomorphic PTLD patients identified an International Prognostic Index (IPI) of 3+ as the strongest pretreatment variable associating with inferior one-year OS.

Timing of high-dose methotrexate CNS prophylaxis in DLBCL: a multicenter international analysis of 1384 patients.

Prophylactic high-dose methotrexate (HD-MTX) is often used for diffuse large B-cell lymphoma (DLBCL) patients at high risk of central nervous system (CNS) relapse, despite limited evidence demonstrating efficacy or the optimal delivery method. We conducted a retrospective, international analysis of 1384 patients receiving HD-MTX CNS prophylaxis either intercalated (i-HD-MTX) (n = 749) or at the end (n = 635) of R-CHOP/R-CHOP-like therapy (EOT). There were 78 CNS relapses (3-year rate 5.7%), with no difference between i-HD-MTX and EOT: 5.7% vs 5.8%, P = .98; 3-year difference: 0.04% (-2.0% to 3.1%). Conclusions were unchanged on adjusting for baseline prognostic factors or on 6-month landmark analysis (n = 1253). In patients with a high CNS international prognostic index (n = 600), the 3-year CNS relapse rate was 9.1%, with no difference between i-HD-MTX and EOT. On multivariable analysis, increasing age and renal/adrenal involvement were the only independent risk factors for CNS relapse. Concurrent intrathecal prophylaxis was not associated with a reduction in CNS relapse. R-CHOP delays of ≥7 days were significantly increased with i-HD-MTX vs EOT, with 308 of 1573 (19.6%) i-HD-MTX treatments resulting in a delay to subsequent R-CHOP (median 8 days). Increased risk of delay occurred in older patients when delivery was later than day 10 in the R-CHOP cycle. In summary, we found no evidence that EOT delivery increases CNS relapse risk vs i-HD-MTX. Findings in high-risk subgroups were unchanged. Rates of CNS relapse in this HD-MTX-treated cohort were similar to comparable cohorts receiving infrequent CNS prophylaxis. If HD-MTX is still considered for certain high-risk patients, delivery could be deferred until R-CHOP completion.

Burkitt Lymphoma International Prognostic Index.

PURPOSE: Burkitt lymphoma (BL) has unique biology and clinical course but lacks a standardized prognostic model. We developed and validated a novel prognostic index specific for BL to aid risk stratification, interpretation of clinical trials, and targeted development of novel treatment approaches. METHODS: We derived the BL International Prognostic Index (BL-IPI) from a real-world data set of adult patients with BL treated with immunochemotherapy in the United States between 2009 and 2018, identifying candidate variables that showed the strongest prognostic association with progression-free survival (PFS). The index was validated in an external data set of patients treated in Europe, Canada, and Australia between 2004 and 2019. RESULTS: In the derivation cohort of 633 patients with BL, age ≥ 40 years, performance status ≥ 2, serum lactate dehydrogenase > 3× upper limit of normal, and CNS involvement were selected as equally weighted factors with an independent prognostic value. The resulting BL-IPI identified groups with low (zero risk factors, 18% of patients), intermediate (one factor, 36% of patients), and high risk (≥ 2 factors, 46% of patients) with 3-year PFS estimates of 92%, 72%, and 53%, respectively, and 3-year overall survival estimates of 96%, 76%, and 59%, respectively. The index discriminated outcomes regardless of HIV status, stage, or first-line chemotherapy regimen. Patient characteristics, relative size of the BL-IPI groupings, and outcome discrimination were consistent in the validation cohort of 457 patients, with 3-year PFS estimates of 96%, 82%, and 63% for low-, intermediate-, and high-risk BL-IPI, respectively. CONCLUSION: The BL-IPI provides robust discrimination of survival in adult BL, suitable for use as prognostication and stratification in trials. The high-risk group has suboptimal outcomes with standard therapy and should be considered for innovative treatment approaches.