Sequencing of anti-CD19 therapies in the management of diffuse large B-cell lymphoma.

Several second- and third-line immunotherapeutic options for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) ineligible for autologous stem cell transplant are directed against the B-cell antigen CD19. The anti-CD19 monoclonal antibody tafasitamab, paired with the immunomodulator lenalidomide, mediates antibody-dependent cellular toxicity and cellular phagocytosis; the antibody-drug conjugate loncastuximab tesirine delivers the DNA-cross-linking agent tesirine via CD19 binding and internalization; and CD19-directed chimeric antigen receptor T-cell therapy (CAR-T) products are engineered from autologous T cells. While CD19 expression is assessed at diagnosis, clinically relevant thresholds of CD19 expression-which may not be detectable with current routine methodologies-have not been defined and may vary between CD19-directed treatment modalities. Determining optimal treatment sequencing strategies with CD19-directed therapy has been hampered by the exclusion of patients with prior CD19-directed therapies from major clinical trials. Antigen escape, attributed to mechanisms including epitope loss and defective cell-surface trafficking of CD19, is an important cause of CAR-T failure. Limited data suggest that CD19 expression may be maintained after non-CAR-T CD19-directed therapy and retrospective analyses indicate that some patients with disease that relapses after CAR-T may benefit from subsequent CD19-directed therapy. To date, clinical evidence on the effect of anti-CD19 therapy prior to CAR-T is restricted to small case series. Prospective studies and detailed analyses to understand how pre- and post-treatment CD19 expression correlates with clinical responses to subsequent CD19-directed therapy are needed to fully maximize treatment strategies.

A Case of Epstein-Barr Virus-Negative Post-transplant Lymphoproliferative Disorder in a Solid Organ Transplant Recipient With Untreated Chronic Hepatitis C.

Post-transplant lymphoproliferative disorder (PTLD) is one of the most common malignancies affecting solid organ transplant recipients. The disease is frequently associated with Epstein-Barr virus (EBV) infection (70% of cases) and cases are often delineated by EBV positivity status. The oncogenesis of EBV-positive PTLD is well-described in the literature; however, the etiology of the EBV-negative subtype is poorly understood. This report describes a case of EBV-negative PTLD developing in a combined kidney-pancreas transplant recipient with an incidental finding of untreated chronic hepatitis C virus (HCV). Our experience suggests an association between HCV and EBV-negative PTLD. Additional well-designed studies are needed to further investigate this association.

CD19/CD20 Bispecific Chimeric Antigen Receptor (CAR) in Naive/Memory T Cells for the Treatment of Relapsed or Refractory Non-Hodgkin Lymphoma.

To address antigen escape and loss of T-cell functionality, we report a phase I clinical trial (NCT04007029) evaluating autologous naive and memory T (TN/MEM) cells engineered to express a bispecific anti-CD19/CD20 chimeric antigen receptor (CAR; CART19/20) for patients with relapsed/refractory non-Hodgkin lymphoma (NHL), with safety as the primary endpoint. Ten patients were treated with 36 × 106 to 165 × 106 CART19/20 cells. No patient experienced neurotoxicity of any grade or over grade 1 cytokine release syndrome. One case of dose-limiting toxicity (persistent cytopenia) was observed. Nine of 10 patients achieved objective response [90% overall response rate (ORR)], with seven achieving complete remission [70% complete responses (CR) rate]. One patient relapsed after 18 months in CR but returned to CR after receiving a second dose of CART19/20 cells. Median progression-free survival was 18 months and median overall survival was not reached with a 17-month median follow-up. In conclusion, CART19/20 TN/MEM cells are safe and effective in patients with relapsed/refractory NHL, with durable responses achieved at low dosage levels. SIGNIFICANCE: Autologous CD19/CD20 bispecific CAR-T cell therapy generated from TN/MEM cells for patients with NHL is safe (no neurotoxicity, maximum grade 1 cytokine release syndrome) and demonstrates strong efficacy (90% ORR, 70% CR rate) in a first-in-human, phase I dose-escalation trial. This article is highlighted in the In This Issue feature, p. 517.

Impact of comorbidity in older patients with peripheral T-cell lymphoma: an international retrospective analysis of 891 patients.

Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of aggressive neoplasms with poor outcomes, commonly affecting older patients with comorbidities. This study aims to describe outcomes of older patients with PTCL in a large international cohort. Patients aged ≥70 years with PTCL diagnosed from 1 January 2010 to 31 December 2015 in the Swedish Lymphoma Registry (SLR) and California Cancer Registry (CCR) were identified. Data on comorbidity were retrospectively collected according to the Charlson Comorbidity Index (CCI), and clinical outcomes were extracted. A total of 891 patients were included (SLR, n = 173; CCR, n = 718). Median age was 77 (SLR) and 78 (CCR) years. Included subtypes were as follows: angioimmunoblastic T-cell lymphoma, n = 226; anaplastic large-cell lymphoma, n = 122; enteropathy-associated T-cell lymphoma (EATL), n = 31; hepatosplenic TCL, n = 7; natural killer-/T-cell lymphoma, n = 62; PTCL not otherwise specified, n = 443. CCI data were available in 775 patients (87%), and CCI scores were divided into the groups CCI = 0 (39%), CCI = 1 (22%), and CCI > 1 (39%). Median age did not differ among the CCI groups (P = .72). Patients with a CCI > 1 had a worse median overall survival (4.4 months) compared with patients with CCI = 0 (11.9 months) and CCI = 1 (8.4 months; P < .001). Comorbidity and advancing age in as little as 5-year increments are important adverse factors in this group. Most patients died of lymphoma within a year from diagnosis, underscoring the importance of developing new treatments.

The role of transplantation in Hodgkin lymphoma.

Despite the success of frontline anthracycline-based chemotherapy for classical Hodgkin Lymphoma (cHL), approximately 15% of patients do not achieve an adequate response and require further therapy. For transplant-eligible patients, additional treatment followed by high-dose chemotherapy and autologous hematopoietic stem cell transplantation (autoHCT) provides a durable response in 50% of patients. The most refractory patients, including those requiring multiple lines of therapy to achieve a response or those relapsing after an autoHCT, may achieve long-term survival with allogeneic hematopoietic stem cell transplant (alloHCT). Contemporary salvage regimens used as a bridge to transplant have expanded to include not only non-cross resistant chemotherapy, but also brentuximab vedotin (BV) and checkpoint inhibitors (CPI). As the management of relapsed/refractory (R/R) cHL evolves with the introduction of novel agents, so too does the role of transplantation. The paradigm of chemosensitivity as a predictor for autoHCT efficacy is being challenged by favorable post- autoHCT outcomes in heavily pre-treated CPI-exposed patients. Contemporary supportive care measures, validated comorbidity assessments, and an increased donor pool with haploidentical donors have broadened the application of transplantation to an increasingly older and diverse patient population. Despite the introduction of increasingly effective treatment options for R/R cHL, transplantation continues to play an important role in the management of these patients. In this review, we explore the impact of salvage therapy on autoHCT, conditioning regimens, maintenance therapy and the diminishing role of alloHCT for patients with cHL.

Real-World Experience of Axicabtagene Ciloleucel and Tisagenlecleucel for Relapsed or Refractory Aggressive B-cell Lymphomas: A Single-Institution Experience.

BACKGROUND: CD19-directed chimeric antigen T-cell receptor (CAR-T) therapies have revolutionized the treatment of patients with relapsed/refractory (R/R) aggressive B-cell lymphomas (aBCL). The results of the landmark ZUMA-1 and JULIET trials have been reproducible in real-world settings across multiple institutions, and patients with double (DHL) or triple (THL) hit lymphomas have demonstrated non-inferior outcomes compared to non-DHL/THL counterparts. MATERIALS AND METHODS: This retrospective cohort study included 53 patients with R/R aBCL who received CAR-T from October 2017 to June 2020 at the University of California, Los Angeles. Patient characteristics, lymphoma-related variables and outcomes of interest were summarized using descriptive statistics and compared between groups by Fisher's exact test. Kaplan-Meier methods were used for analysis of OS, progression free survival (PFS), and duration of response (DOR). Univariate and multivariate cox regression analysis were performed to evaluate for significant prognostic variables. RESULTS: With a median follow-up of 15.2 months, this cohort demonstrated overall response rate and complete response rate of 72% and 64% (n = 34), respectively. The median DOR, PFS and OS were not reached, 7.9 and 17.7 months, respectively. By univariate analysis, DHL/THL status was the only clinical feature significantly associated with relapse post-CAR-T (OR 5.9, P = .015). CONCLUSIONS: Our single-institution, real-world cohort of R/R aBCL patients demonstrated similar efficacy outcomes to those of the ZUMA-1 and JULIET trials and published real-world studies. Our findings suggest DHL/THL patients may benefit from novel CAR-T constructs, maintenance strategies with immunomodulatory agents or allogeneic-HCT.

Measurable residual disease in hematopoietic stem cell transplantation-eligible patients with acute myeloid leukemia: clinical significance and promising therapeutic strategies.

Allogeneic hematopoietic stem cell transplantation (alloHCT) results in improved outcomes for acute myeloid leukemia (AML) patients compared to consolidation chemotherapy in transplant-eligible patients with adverse-risk disease. Despite achieving a complete remission (CR) to initial therapy, defined as <5% bone marrow blasts with recovery of peripheral blood elements, a large number of patients suffer disease relapse following alloHCT. There is a growing focus on minimal or measurable residual disease (MRD) in patients with AML, variably defined using multiparametric flow cytometry and nucleic acid sequencing techniques, to detect levels of disease not included in current CR terminology. MRD has emerged as an important prognostic tool in AML and may improve risk stratification, further refine selection of post-remission treatment, and provide an opportunity for therapeutic intervention. Herein, we review MRD detection methods, timing of measurement, prognostic implications, and MRD-directed therapy in AML patients undergoing alloHCT.

Chronic Myeloid Leukemia, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology.

Chronic myeloid leukemia (CML) is defined by the presence of Philadelphia chromosome (Ph) which results from a reciprocal translocation between chromosomes 9 and 22 [t(9;22] that gives rise to a BCR-ABL1 fusion gene. CML occurs in 3 different phases (chronic, accelerated, and blast phase) and is usually diagnosed in the chronic phase. Tyrosine kinase inhibitor therapy is a highly effective first-line treatment option for all patients with newly diagnosed chronic phase CML. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with chronic phase CML.

Cardiac Complications in the Adult Bone Marrow Transplant Patient.

PURPOSE OF REVIEW: Due to advancements in oncologic treatment strategies and techniques, the number of survivors who have undergone hematopoetic stem cell transplant (HCT) continues to increase in the United States; this number is projected to reach 502,000 by the year 2030. There is significant interest within the field of cardio-oncology to identify cardiotoxicity and cardiovascular disease in the HCT population. Epidemiologic studies analyzing both short- and long-term cardiovascular effects, risk stratification modeling, cardioprotective strategies, and expert consensus documents for cardiotoxicity surveillance recommendations are reviewed. RECENT FINDINGS: Patients who have undergone HCT are at increased risk of cardiovascular events and mortality compared to matched controls. The type of cardiotoxicity and the incidence rates vary based on specific therapeutic regimens and pre-existing cardiovascular risk factors. Life-threatening cardiotoxicity can present during HCT as acute heart failure, arrhythmias, pericardial tamponade, or cardiac arrest; or it can present late after treatment as cardiomyopathy, ischemic heart disease, vascular disease, stroke, or comorbid conditions, such as hypertension and diabetes mellitus that are associated with cardiac events. HCT is associated with excess cardiovascular risk partially due to exposure to cardiotoxic chemotherapy and radiation, as well as indirect and direct detrimental effects on cardiovascular reserve. This review discusses the epidemiology and the known cardiotoxic effects of historical chemoradiation agents in addition to newer targeted therapies. Recent expert consensus statements from cardiology and hematology/oncology societies are reviewed in regard to risk stratification of the cancer patient based on the type of treatments. Finally, gaps in knowledge are identified with proposed avenues of research that will allow for more accurate risk assessment, prediction, and potential treatment of the HCT patient in attenuating the risk of developing both short- and long-term cardiovascular comorbidities.

Triple-negative breast cancer: advancements in characterization and treatment approach.

PURPOSE OF REVIEW: Triple-negative breast cancer (TNBC) comprises 15-20% of all breast cancer and is defined by the lack of estrogen and progesterone receptor expression and absence of human epidermal growth factor receptor 2 amplification. Compared with patients with hormone receptor positive or Her-2 positive breast cancer, patients with TNBC are more commonly young (age <50 years), African-American and have a higher incidence of BRCA1/2 mutations. The clinical course is frequently characterized by early relapse and poor overall survival. The TNBC phenotype is impervious to therapies commonly used in other breast cancer subtypes, including hormonal therapy and Her-2 receptor antagonism. Cytotoxic chemotherapy remains the only approved treatment. With its aggressive clinical course and paucity of effective treatment options, TNBC represents an unmet clinical need. This review will focus on updates of the biologic underpinnings of TNBC and the associated treatment advances. RECENT FINDINGS: Numerous advancements have been made toward understanding the biologic framework of TNBC. Gene expression profiling has revealed six clinically relevant subsets of TNBC. Further study has demonstrated a portion of TNBC exhibits a strong immune gene signature. Lastly, it is now appreciated that a subgroup of sporadic TNBC shares biologic characteristics with BRCA1/2-mutated breast cancer, notably homologous repair deficiency. Recent studies focus on incorporation of platinum salts and new combinations of conventional chemotherapeutic agents. Targeted agents, including poly-ADP ribose polymerase inhibitors, antiangiogenic agents, phosphoinositide 3-kinase (PI3K) pathway inhibitors, and androgen antagonist are also being evaluated. Most recently, checkpoint inhibitors have demonstrated a modest degree of activity in a subset of TNBC. SUMMARY: These discoveries are informing novel treatment paradigms and identification of correlative biomarkers in TNBC. Improved understanding of the biologic heterogeneity of TNBC is allowing for a more effective and individualized approach to treatment.

Leukemia: an overview for primary care.

Leukemia is a clonal proliferation of hematopoietic stem cells in the bone marrow. The four broad subtypes most likely to be encountered by primary care physicians are acute lymphoblastic, acute myelogenous, chronic lymphocytic, and chronic myelogenous. Acute lymphoblastic leukemia occurs more often in children, whereas the other subtypes are more common in adults. Risk factors include a genetic predisposition as well as environmental factors, such as exposure to ionizing radiation. Symptoms are nonspecific and include fever, fatigue, weight loss, bone pain, bruising, or bleeding. A complete blood count usually reveals leukocytosis and other abnormally elevated or depressed cell lines. Patients with suspected leukemia should be referred promptly to a hematologist-oncologist. The diagnosis is confirmed by further examination of the bone marrow or peripheral blood. Treatment may include chemotherapy, radiation, monoclonal antibodies, or hematopoietic stem cell transplantation. Complications of treatment include tumor lysis syndrome and serious infections from immunosuppression. Leukemia survivors should be monitored closely for secondary malignancies, cardiac complications, and endocrine disturbances such as metabolic syndrome, hypothyroidism, and hypogonadism. Five-year survival rates are highest in younger patients and in patients with chronic myelogenous leukemia or chronic lymphocytic leukemia.