Consensus recommendations on the management of toxicity associated with CD3×CD20 bispecific antibody therapy.

ABSTRACT: Bispecific antibodies (BsAb) that target CD3 and CD20 represent a new milestone in the treatment of patients with B-cell non-Hodgkin lymphoma. These drugs have demonstrated remarkable single-agent activity in patients with heavily pretreated disease, and 3 drugs have so far received regulatory approvals in various countries. However, BsAbs can potentially lead to severe toxicity associated with T-cell activation, particularly cytokine release syndrome (CRS). The anticipated widespread use of these off-the-shelf products poses challenges for implementation and highlights the need for guidance in anticipating, mitigating, and managing adverse events. In clinical trials, guidance for the evaluation and treatment of CRS and neurotoxicity associated with BsAb therapy has been modeled after algorithms originally created for chimeric antigen receptor (CAR) T-cell therapies and other immune effector therapies, yet notable differences in timing, quality, and severity exist between the toxicities of BsAbs and CAR T-cell therapies. We therefore convened an international panel of academic and community practice physicians, advanced practitioners, registered nurses, and pharmacists with experience using CD3×CD20 BsAbs in clinical trial and off-trial settings to provide comprehensive, consensus-based recommendations specific to the assessment and management of CD3×CD20 BsAb-related toxicities.

NCCN Guidelines® Insights: B-Cell Lymphomas, Version 6.2023.

Novel targeted therapies (small molecule inhibitors, antibody-drug conjugates, and CD19-directed therapies) have changed the treatment landscape of relapsed/refractory B-cell lymphomas. Bruton's tyrosine kinase (BTK) inhibitors continue to evolve in the management of mantle cell lymphoma (MCL), in both the relapsed/refractory and the frontline setting. Anti-CD19 CAR T-cell therapies are now effective and approved treatment options for relapsed/refractory follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and MCL. Bispecific T-cell engagers represent a novel immunotherapeutic approach for relapsed FL and DLBCL after multiple lines of therapies, including prior CAR T-cell therapy. These NCCN Guideline Insights highlight the significant updates to the NCCN Guidelines for B-Cell Lymphomas for the treatment of FL, DLBCL, and MCL.

Exploring Adolescent and Young Adult Cancer Survivors' Experience with Cancer Treatment-Related Symptoms: A Qualitative Analysis of Semi-Structured Interviews.

Purpose: Few studies have specifically targeted symptom management interventions for adolescent and young adult (AYA) cancer survivors. A greater understanding of AYA cancer survivors' experiences with cancer treatment-related symptoms would help develop age-appropriate oncology symptom management interventions. The purpose of this qualitative analysis was to explore AYA cancer survivors' experience with cancer treatment-related symptoms. Methods: Nineteen post-treatment AYA cancer survivors (18-39 years old) who self-reported moderate-severe cancer treatment-related symptom severity participated in video conferencing or telephone interviews. The questions in the interview guide queried participants to share their experience with cancer treatment-related symptoms. Inductive content analysis was used to identify themes from the interviews. Results: The themes that emerged from the interviews included (1) cancer treatment-related symptoms negatively affected AYA cancer survivors' quality of life (e.g., symptoms served as a reminder of cancer recurrence possibility); (2) AYA cancer survivors' attitudes and feelings about communicating cancer treatment-related symptom concerns to clinicians (e.g., patient-clinician communication was bolstered when AYAs perceived that symptoms were being taken seriously); (3) AYA cancer survivors are interested in oncology symptom management clinical trials, but logistical challenges are barriers to participation; and (4) AYA cancer survivors are interested in nonpharmacological treatments for symptom management. Conclusion: Results highlight the burden of cancer treatment-related symptoms on day-to-day life among post-treatment AYA cancer survivors. Future work is needed to identify nonpharmacological symptom management interventions, strategies to improve patient-clinician communication about symptoms, and strategies to increase the visibility and accessibility of symptom management clinical trials for AYA cancer survivors.

Adding venetoclax to lenalidomide and rituximab is safe and effective in patients with untreated mantle cell lymphoma.

Mantle cell lymphoma (MCL) is a rare, incurable hematological malignancy with a heterogeneous presentation and clinical course. A wide variety of chemotherapy-based regimens are currently used in patients who are untreated. Over the last several years, several targeted or small-molecule therapies have shown efficacy in the relapsed/refractory setting and have since been explored in the frontline setting. Lenalidomide plus rituximab was explored in a phase 2 study of 38 patients with MCL who were untreated and ineligible to receive transplantation, in which the combination produced durable remissions. We looked to build upon this regimen by adding venetoclax to the combination. We conducted a multicenter, open-label, nonrandomized, single-arm study to evaluate this combination. We enrolled 28 unselected patients with untreated disease irrespective of age, fitness, or risk factors. Lenalidomide was dosed at 20 mg daily from days 1 to 21 of each 28-day cycle. The dose of venetoclax was determined using the time-to-event continual reassessment method. Rituximab was dosed at 375 mg/m2 weekly, starting on cycle 1, day 1 until cycle 2, day 1. No dose-limiting toxicities were noted. All patients were treated with venetoclax at the maximum tolerated dose of 400 mg daily. The most common adverse events were neutropenia and thrombocytopenia. The overall and complete response rates were 96% and 86%, respectively. In total, 86% of patients achieved minimal residual disease undetectability via next-generation sequencing. The median overall and progression-free survivals were not reached. The combination of lenalidomide, rituximab, and venetoclax is a safe and effective regimen in patients with untreated MCL. This trial was registered at www.clinicaltrials.gov as #NCT03523975.

High-grade B-cell lymphoma, not otherwise specified: a multi-institutional retrospective study.

In this multi-institutional retrospective study, we examined the characteristics and outcomes of 160 patients with high-grade B-cell lymphoma, not otherwise specified (HGBL-NOS)-a rare category defined by high-grade morphologic features and lack of MYC rearrangements with BCL2 and/or BCL6 rearrangements ("double hit"). Our results show that HGBL-NOS tumors are heterogeneous: 83% of patients had a germinal center B-cell immunophenotype, 37% a dual-expressor immunophenotype (MYC and BCL2 expression), 28% MYC rearrangement, 13% BCL2 rearrangement, and 11% BCL6 rearrangement. Most patients presented with stage IV disease, a high serum lactate dehydrogenase, and other high-risk clinical factors. Most frequent first-line regimens included dose-adjusted cyclophosphamide, doxorubicin, vincristine, and etoposide, with rituximab and prednisone (DA-EPOCH-R; 43%); rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP; 33%); or other intensive chemotherapy programs. We found no significant differences in the rates of complete response (CR), progression-free survival (PFS), or overall survival (OS) between these chemotherapy regimens. CR was attained by 69% of patients. PFS at 2 years was 55.2% and OS was 68.1%. In a multivariable model, the main prognostic factors for PFS and OS were poor performance status, lactate dehydrogenase >3 × upper limit of normal, and a dual-expressor immunophenotype. Age >60 years or presence of MYC rearrangement were not prognostic, but patients with TP53 alterations had a dismal PFS. Presence of MYC rearrangement was not predictive of better PFS in patients treated with DA-EPOCH-R vs R-CHOP. Improvements in the diagnostic criteria and therapeutic approaches beyond dose-intense chemotherapy are needed to overcome the unfavorable prognosis of patients with HGBL-NOS.

Novel Salvage Therapy Options for Initial Treatment of Relapsed/Refractory Classical Hodgkin's Lymphoma: So Many Options, How to Choose?

The treatment landscape for relapsed/refractory classical Hodgkin's lymphoma (cHL) has evolved with the introduction of several novel agents. Historically, the standard of care for relapsed cHL was salvage chemotherapy followed by autologous stem cell transplant (ASCT). However, many patients are ineligible for ASCT or will have poor responses to salvage chemotherapy and ASCT. Brentuximab vedotin (BV) and checkpoint inhibitors (nivolumab/pembrolizumab) were initially approved in the post-ASCT setting. However, as a result of excellent responses and durable outcomes in this setting, they are now being studied and explored in earlier lines of therapy. Additionally, these agents are also being studied for post-transplant consolidation and maintenance with promising results in improving progression-free survival. We will review current salvage therapy options involving these novel agents and provide comparisons between regimens to aid the clinician in selecting the appropriate salvage regimen for patients who progress after first-line therapy.

Divergent paths: management of early relapsed follicular lymphoma.

Follicular lymphoma (FL) is the second most common non-Hodgkin lymphoma in the United States and Western Europe. Overall outcomes for patients with FL have continued to improve over the last several decades-most notably, with the addition of the CD20 monoclonal antibody rituximab to the treatment armamentarium. More recently, we have seen advances in the management of patients with relapsed/refractory FL with the approval of several new treatments including lenalidomide, axicabtagene ciloleucel, copanlisib, umbralisib, and tazemetostat. Unfortunately, there remains a group of patients for which treatment outcomes, especially overall survival (OS), are suboptimal. This group has been identified as patients who relapse within 24 months (POD24) of completion of chemoimmunotherapy (CIT). Data indicate that patients who relapse within this window have a 5-year OS of around 50%, compared to 80% for those who remain in remission beyond 24 months. POD24 patients have been included and evaluated in the studies of the novel agents mentioned. While not specifically designed to treat this high-risk group, early data suggest that outcomes are not significantly impacted by this designation, unlike CIT. While to date the optimal management of POD24 patients has not been elucidated, the future appears bright with the continued use of the approved agents and several others in clinical development.

Targeted Therapies for Follicular Lymphoma.

Follicular lymphoma (FL) is the 2nd most common lymphoma in the USA/Western Europe. While incurable, the majority of patients are able to survive at least a decade with this disease. Response duration though varies, and subset of patients will relapse within 24 months of initial therapy (POD24). These patients have shortened survival compared to those who achieve more durable responses. Treatment interventions for patients are varied and include observation, radiation, or systemic therapies. Treatment outcomes have improved considerably over the last several decades with the introduction of new agents such as the CD 20 antibody rituximab and more recently with the advent of more targeted therapy. Most of the newer agents work differently from cytotoxic chemotherapy and either inhibit tumor-specific mutations, survival pathways, or harness the immune systems. While outcomes with traditional cytotoxic agents have been historically poor in certain subtypes such as POD24 and rituximab refractory disease, the reported outcomes with the newer agents have been encouraging as evident by several new drug approvals in FL. The biggest impact has been in the relapsed/refractory setting where we have approval of the immunomodulatory agent lenalidomide given in combination with rituximab. Based on the AUGMENT study, this agent has been approved for patients with R/R FL after one previous line of therapy. The EZH2 inhibitor, tazemetostat, was approved recently for patients with a known EZH2 mutation after one prior line of therapy or for FL patients who are deemed intolerant to other agents given the impressive safety profile in all patients. Finally, there is a plethora of agents that are designed to harness the immune system to combat this lymphoma. The data for these agents is still very early but nonetheless very impressive. In summary, FL is an incurable lymphoma without any standard of care options but has numerous treatments that have demonstrated some degree of efficacy. Recently we have made enormous strides in the understanding of some of the biological drivers of this disease which has allowed for refinement of treatment options. Moving forward, I would anticipate that we will continue to explore the use of agents that target specific mutations or utilize the immune system to hopefully one day achieve a cure.

Development and Use of Natural Language Processing for Identification of Distant Cancer Recurrence and Sites of Distant Recurrence Using Unstructured Electronic Health Record Data.

PURPOSE: Large-scale analysis of real-world evidence is often limited to structured data fields that do not contain reliable information on recurrence status and disease sites. In this report, we describe a natural language processing (NLP) framework that uses data from free-text, unstructured reports to classify recurrence status and sites of recurrence for patients with breast and hepatocellular carcinomas (HCC). METHODS: Using two cohorts of breast cancer and HCC cases, we validated the ability of a previously developed NLP model to distinguish between no recurrence, local recurrence, and distant recurrence, based on clinician notes, radiology reports, and pathology reports compared with manual curation. A second NLP model was trained and validated to identify sites of recurrence. We compared the ability of each NLP model to identify the presence, timing, and site of recurrence, when compared against manual chart review and International Classification of Diseases coding. RESULTS: A total of 1,273 patients were included in the development and validation of the two models. The NLP model for recurrence detects distant recurrence with an area under the curve of 0.98 (95% CI, 0.96 to 0.99) and 0.95 (95% CI, 0.88 to 0.98) in breast and HCC cohorts, respectively. The mean accuracy of the NLP model for detecting any site of distant recurrence was 0.9 for breast cancer and 0.83 for HCC. The NLP model for recurrence identified a larger proportion of patients with distant recurrence in a breast cancer database (11.1%) compared with International Classification of Diseases coding (2.31%). CONCLUSION: We developed two NLP models to identify distant cancer recurrence, timing of recurrence, and sites of recurrence based on unstructured electronic health record data. These models can be used to perform large-scale retrospective studies in oncology.

A phase 1 study of azacitidine with high-dose cytarabine and mitoxantrone in high-risk acute myeloid leukemia.

In this phase 1 study, azacitidine (AZA) was given before high-dose cytarabine (HiDAC) and mitoxantrone (mito) based on the hypothesis that epigenetic priming with a hypomethylating agent before cytotoxic chemotherapy would improve response rates in patients with high-risk acute myeloid leukemia (AML), including relapsed/refractory disease. The primary objective was to establish the recommended phase 2 dose of AZA given before standard HiDAC/mito. In a dose escalation scheme, 46 patients (median age, 66 years) received AZA at 37.5, 50, or 75 mg/m2 subcutaneously or IV once daily on days 1 to 5 followed by HiDAC (3000 mg/m2) and mitoxantrone (30 mg/m2) once each on days 6 and 10 (the HiDAC/mito dose was reduced 33% in elderly subjects). Two dose-limiting toxicities occurred (both in the same patient): acute liver failure and kidney injury at the 50 mg/m2 dose. The 30-day induction death rate was 2.2% (1 of 46). The overall response rate, including complete remission and complete remission with incomplete count recovery, was 61% (28 of 46). Previously untreated patients aged ≥60 years with therapy-related AML and de novo AML were more likely to respond than untreated patients with AML progressing from an antecedent hematologic disorder (myelodysplastic syndrome and chronic myelomonocytic leukemia). Patients with favorable European Leukemia Network risk (P = .008), NPM1 mutations (P = .007), or IDH2 mutations (P = .03) were more likely to respond, and those with TP53 mutations (P = .03) were less likely to respond. The recommended phase 2 dose of AZA is 75 mg/m2 per day on days 1 to 5 followed by HiDAC (3000 mg/m2) and mitoxantrone (30 mg/m2) once each on days 6 and 10. This trial was registered at www.clinicaltrials.gov as #NCT01839240.