Inherited Bleeding Disorders
Evaluation of the patient with a suspected bleeding disorder is both fascinating and frightening for the treating clinician given the broad differential diagnosis coupled with the potential for life-threatening symptoms. Across a diverse spectrum of causes, inherited bleeding disorders present a unique challenge due to the variability in clinical presentation, special requirements for diagnostic testing, and limited access to appropriate therapies for management. For many clinicians, the coagulation cascade is the epitome of a "black box" in their fund of knowledge; a complex set of biochemical reactions made eve...
Source: Hematology/Oncology Clinics of North America - October 4, 2021 Category: Cancer & Oncology Authors: Nathan T. Connell Tags: Preface Source Type: research

Central Nervous System Complications Among Oncology Patients
Cancer treatment related injury to the central nervous system (CNS) is well-recognized in the setting of brain-directed radiation therapies and conventional and novel systemic anticancer therapies. Late-delayed treatment-induced CNS complications frequently result in permanent neurologic disability. Therapeutic options are supportive with limited clinical benefit, whereby alteration or discontinuation of the overall antineoplastic treatment plan is frequently necessary to prevent further neurologic injury. Better identification of patients at high risk for developing late CNS toxicities, neuroprotective strategies with mod...
Source: Hematology/Oncology Clinics of North America - October 2, 2021 Category: Cancer & Oncology Authors: Sebastian F. Winter, Jasmin Jo, David Schiff, Jorg Dietrich Source Type: research

Hemophilia B (Factor IX Deficiency)
The biology of factor IX deficiency leading to hemophilia B has important distinctions from factor VIII deficiency that leads to hemophilia A. In this article, the authors explore the unique biology of factor IX in hemostasis, including the importance of FIX distribution to the extravascular space and the implications on dosing of factor concentrates. The authors review basic treatment principles of hemophilia B, including extended half-life products, and highlight areas of ongoing therapeutic innovation for hemophilia B prophylaxis. (Source: Hematology/Oncology Clinics of North America)
Source: Hematology/Oncology Clinics of North America - October 1, 2021 Category: Cancer & Oncology Authors: Robert F. Sidonio, Lynn Malec Source Type: research

Factor XIII Deficiency
Factor XIII (FXIII) deficiency is a rare autosomal recessive disorder that can result in life-threatening bleeding and early fetal loss. FXIII not only is responsible for cross-linking fibrinogen to stabilize and strengthen clot formation but also facilitates wound healing and angiogenesis and plays an important role in fetal vitality. Modern therapeutics allow for prophylactic treatment that can prevent most major bleeding and increasing fetal viability. Early diagnosis is paramount due to the high risk of intracranial bleeding. (Source: Hematology/Oncology Clinics of North America)
Source: Hematology/Oncology Clinics of North America - October 1, 2021 Category: Cancer & Oncology Authors: Ari Pelcovits, Fred Schiffman, Rabin Niroula Source Type: research

Imaging Advances for Central Nervous System Tumors
This article reviews recent advances in the use of standard and advanced imaging techniques for diagnosis and treatment of central nervous system (CNS) tumors, including glioma and brain metastasis. Following the recent transition from a histology-based approach in classifying CNS tumors to one that integrates histology with the molecular information of tumor, the approaches for imaging CNS tumors have also been adapted to this new framework. Some challenges related to the diagnosis and treatment of CNS tumors, such as differentiating tumor from treatment-related imaging changes, require further progress to implement advan...
Source: Hematology/Oncology Clinics of North America - September 23, 2021 Category: Cancer & Oncology Authors: Raymond Y. Huang, Whitney B. Pope Source Type: research

The Evolving Role of Neurosurgical Intervention for Central Nervous System Tumors
Since its inception, greater than a century ago, neurosurgery has represented the fundamental trait-d ’union between clinical management, scientific investigation, and therapeutic advancements in the field of brain tumors. During the years, oncological neurosurgery has evolved as a self-standing subspecialty, due to technical progress, equipment improvement, evolution of therapeutic paradigms, and the progressively crucial role that it plays in the execution of complex therapeutic strategies and modern clinical trials. (Source: Hematology/Oncology Clinics of North America)
Source: Hematology/Oncology Clinics of North America - September 23, 2021 Category: Cancer & Oncology Authors: Pierpaolo Peruzzi, Pablo Q. Valdes, Manish K. Aghi, Mitchel Berger, Ennio Antonio Chiocca, Alexandra J. Golby Source Type: research

Approach to the Patient with Bleeding
Approach to the patient with bleeding begins with a thorough bleeding, medical, and family history to determine the nature of bleeding and severity of bleeding symptoms. Use of a Bleeding Assessment Tool allows the clinician to obtain a comprehensive bleeding history and ultimately determine the individual bleeding score that reflects bleeding severity and is classifiable as either normal or abnormal. In the absence of significant findings within patient history or presenting symptoms clearly pointing to a specific bleeding pathology, an approach to laboratory investigation is presented that proceeds through first-line, se...
Source: Hematology/Oncology Clinics of North America - September 15, 2021 Category: Cancer & Oncology Authors: Megan Chaigneau, Paula D. James Source Type: research

Acquired Hemophilia A
Acquired hemophilia A is a potentially severe bleeding disorder caused by antibodies against the patient ’s own factor VIII. Acquired hemophilia A is rare. It is most commonly diagnosed in older individuals; about one-half of cases of acquired hemophilia are associated with underlying conditions, including autoimmune disease, cancer, and pregnancy. The diagnosis of acquired hemophilia A can be suspec t with an isolated activated partial thromboplastin time elevation, and confirmed with demonstration of reduced factor VIII activity and the presence of a specific factor VIII inhibitor. Treatment of acquired hemophilia ...
Source: Hematology/Oncology Clinics of North America - September 15, 2021 Category: Cancer & Oncology Authors: Menaka Pai Source Type: research

Factor XI Deficiency
This article summarizes presentation, diagnosis, and management of patients with FXI deficiency in a variety of clinical settings. (Source: Hematology/Oncology Clinics of North America)
Source: Hematology/Oncology Clinics of North America - September 15, 2021 Category: Cancer & Oncology Authors: Magdalena Dorota Lewandowska, Jean Marie Connors Source Type: research

Salivary Gland Cancers
Salivary gland carcinomas are a rare and heterogenous group of cancers with varying underlying biology and clinical behavior. A quickly evolving body of data has advanced the understanding of these tumors, leading to effective therapeutics for several histologic subtypes. Biologically rational clinical trials have developed from an understanding of MYB and NOTCH signaling in adenoid cystic carcinoma. The recognition of androgen receptor signaling and HER2-targeted therapy has offered therapeutic options in non-ACC salivary cancers. The use of TRK inhibitors in salivary secretory carcinoma has led to exceptional responses. ...
Source: Hematology/Oncology Clinics of North America - September 7, 2021 Category: Cancer & Oncology Authors: Vatche Tchekmedyian Source Type: research

Head and Neck Cancer
HEMATOLOGY/ONCOLOGY CLINICS OF NORTH AMERICA (Source: Hematology/Oncology Clinics of North America)
Source: Hematology/Oncology Clinics of North America - September 7, 2021 Category: Cancer & Oncology Authors: Glenn J. Hanna Source Type: research

Copyright
ELSEVIER (Source: Hematology/Oncology Clinics of North America)
Source: Hematology/Oncology Clinics of North America - September 7, 2021 Category: Cancer & Oncology Source Type: research

Contributors
GEORGE P. CANELLOS, MD (Source: Hematology/Oncology Clinics of North America)
Source: Hematology/Oncology Clinics of North America - September 7, 2021 Category: Cancer & Oncology Source Type: research

Contents
Glenn J. Hanna (Source: Hematology/Oncology Clinics of North America)
Source: Hematology/Oncology Clinics of North America - September 7, 2021 Category: Cancer & Oncology Source Type: research

Forthcoming Issues
Inherited Bleeding Disorders (Source: Hematology/Oncology Clinics of North America)
Source: Hematology/Oncology Clinics of North America - September 7, 2021 Category: Cancer & Oncology Source Type: research

Preface
Head and neck cancers comprise a unique set of distinct disease entities, from carcinogen-related and viral-mediated mucosal cancers to the rare salivary gland malignancies, all of which necessitate multidisciplinary expert collaboration to diagnose and treat. In the last few years, there have been important advances made within the head and neck oncology community. This often underrecognized and highly specialized area of cancer medicine has been revolutionized by the established benefits of immunotherapy in the advanced disease setting, and we have made further strides toward treatment deintensification while preserving ...
Source: Hematology/Oncology Clinics of North America - September 7, 2021 Category: Cancer & Oncology Authors: Glenn J. Hanna Source Type: research

Disorders of Fibrinogen and Fibrinolysis
Fibrinogen plays a fundamental role in coagulation through its support for platelet aggregation and its conversion to fibrin. Fibrin stabilizes clots and serves as a scaffold and immune effector before being broken down by the fibrinolytic system. Given its importance, abnormalities in fibrin(ogen) and fibrinolysis result in a variety of disorders with hemorrhagic and thrombotic manifestations. This review summarizes (i) the basic elements of fibrin(ogen) and its role in coagulation and the fibrinolytic system; (ii) the laboratory evaluation for fibrin(ogen) disorders, including the use of global fibrinolysis assays; and (...
Source: Hematology/Oncology Clinics of North America - August 14, 2021 Category: Cancer & Oncology Authors: Jori E. May, Alisa S. Wolberg, Ming Yeong Lim Source Type: research

Von Willebrand Disease
Von Willebrand disease (VWD) is a common bleeding disorder, affecting male and female individuals equally, that often manifests in mucosal bleeding. VWD can be secondary to a quantitative (Type 1 and Type 3) or qualitative (Type 2) defects in Von Willebrand factor (VWF). Initial testing includes VWF antigen, as well as a platelet binding assay to differentiate between qualitative and quantitative defects. Further subtyping requires additional testing and is needed to ensure appropriate treatment. Desmopressin, antifibrinolytics, hormonal treatments for heavy menstrual bleeding, and VWF concentrates are commonly used in the...
Source: Hematology/Oncology Clinics of North America - August 13, 2021 Category: Cancer & Oncology Authors: Angela C. Weyand, Veronica H. Flood Source Type: research

Laboratory Methods in the Assessment of Hereditary Hemostatic Disorders
In patients presenting with a suspect hereditary bleeding disorder a detailed bleeding history is first obtained. Testing proceeds in a tiered manner with platelet count, platelet morphology, platelet histogram, PFA-100, fibrinogen, prothrombin time, and activated partial thromboplastin time. More detailed testing includes von Willebrand factor, individual clotting factor assays, and platelet function testing. Next, testing for a dysfibrinogenemia, FXIII, or a fibrinolytic defect is considered. Hemostatic abnormality is not demonstrated in a fraction of patients. An approach to management in these patients, such as desmopr...
Source: Hematology/Oncology Clinics of North America - August 11, 2021 Category: Cancer & Oncology Authors: Tracey A. Cheves, Sandra DeMarinis, Joseph D. Sweeney Source Type: research

Inherited Platelet Disorders
Bleeding disorders due to platelet dysfunction are a common hematologic complication affecting patients, and typically present with mucocutaneous bleeding or hemorrhage. An inherited platelet disorder should be suspected in individuals with a suggestive family history and no identified secondary causes of bleeding. Genetic defects have been described at all levels of platelet activation, including receptor binding, signaling, granule release, cytoskeletal remodeling, and platelet hematopoiesis. Management of these disorders is typically supportive, with an emphasis on awareness, patient education, and anticipatory guidance...
Source: Hematology/Oncology Clinics of North America - August 11, 2021 Category: Cancer & Oncology Authors: Frederick D. Tsai, Elisabeth M. Battinelli Source Type: research

Acquired von Willebrand Syndrome
Acquired von Willebrand syndrome can occur in the setting of myeloproliferative neoplasms; plasma cell dyscrasias and other lymphoproliferative disorders; autoimmune conditions; and causes of increased shear forces, such as aortic stenosis or other structural heart disease and mechanical circulatory support. The depletion of von Willebrand factor, especially high-molecular-weight multimers, can lead to mucocutaneous bleeding and the formation of arteriovenous malformations, particularly in the gastrointestinal tract. Management focuses on correction of the underlying cause when possible, but may include intravenous immunog...
Source: Hematology/Oncology Clinics of North America - August 11, 2021 Category: Cancer & Oncology Authors: Arielle L. Langer, Nathan T. Connell Source Type: research

Hemophilia A (Factor VIII Deficiency)
Remarkable changes are occurring in the diagnosis and management of individuals with hemophilia A. Genetic testing, including next-generation sequencing, enables family planning, carrier testing, and prenatal diagnosis. Musculoskeletal ultrasound examination facilitates the early detection of acute bleeds and joint disease in clinic, enabling more rapid bleed resolution and treatment planning. Novel therapies offer simpler weekly or monthly administration, some by subcutaneous injection, with better compliance and quality of life, as well as fewer bleeds. Gene therapy provides a 1-time phenotypic “cure” that is...
Source: Hematology/Oncology Clinics of North America - August 10, 2021 Category: Cancer & Oncology Authors: Craig D. Seaman, Frederico Xavier, Margaret V. Ragni Source Type: research

Rare Coagulation Factor Deficiencies (Factors VII, X, V, and II)
Although rare clotting factor deficiencies primarily referred to as rare bleeding disorders (RBD), including factors II, V, VII, and X, make up ∼5% of all inherited bleeding disorders worldwide, each of these clotting factors play a critical role in the coagulation cascade. Incomplete bleeding evaluation or misinterpretation of laboratory studies can result in delayed diagnoses that ultimately affect patient outcomes. Bleeding manifestati ons can range from mild to severe, but the most common are mucocutaneous bleeding. The ideal treatment in RBD is dedicated single-factor concentrates that can be used for acute bleedi...
Source: Hematology/Oncology Clinics of North America - August 10, 2021 Category: Cancer & Oncology Authors: Glaivy Batsuli, Peter Kouides Source Type: research

Cutaneous Malignancies of the Head and Neck
Cutaneous malignancies (CMs), or skin cancers, are the most common cancer worldwide, with a quarter million cases diagnosed annually in the United States alone. The best described risk factor for CM is ultraviolet radiation from sunlight, and therefore most of these cancers develop in sun-exposed skin, including the head and neck. Beginning with melanoma, immunotherapy has increasingly been used over the past decade for treatment of unresectable CM, and immune checkpoint inhibitors are now Food and Drug Administration –approved for first-line treatment of unresectable melanoma, Merkel cell carcinoma, and cutaneous sq...
Source: Hematology/Oncology Clinics of North America - July 16, 2021 Category: Cancer & Oncology Authors: Gino K. In, Jacob S. Thomas, Ann W. Silk Source Type: research

Lip and Oral Cavity Squamous Cell Carcinoma
Lip and oral cavity squamous cell carcinoma (SCC) develop from progressive dysplasia of these mucosal structures. The cancers are often preceded by premalignant lesions, and any nonhealing ulcers of the lip or oral cavity should be biopsied. Some risk factors for these 2 subsites overlap and include tobacco use, alcohol use, and an immunocompromised state. Lip and oral cavity SCC are clinically staged based on physical examination and imaging. The 5-year overall survival for early-stage lip and oral cavity SCC is around 70% to 90% but decreases to about 50% for late-stage disease. (Source: Hematology/Oncology Clinics of North America)
Source: Hematology/Oncology Clinics of North America - July 14, 2021 Category: Cancer & Oncology Authors: Adam Howard, Nishant Agrawal, Zhen Gooi Source Type: research

Cancer of the Larynx and Hypopharynx
The Radiation Therapy Oncology Group 91-11 trial and US Veterans Affairs trial revolutionized the way locally advanced laryngeal cancers are treated. Adjuvant therapies exist aimed toward laryngeal preservation using docetaxel, cisplatin, and fluorouracil. Cetuximab is a cornerstone of treatment due to the large role of epidermal growth factor receptor in laryngeal and hypopharyngeal carcinomas. In addition, the immune system is vital in the prevention of recurrence, and various immunomodulators against programmed cell death receptor 1 are being investigated. Multidisciplinary management of the patient with laryngeal and h...
Source: Hematology/Oncology Clinics of North America - July 13, 2021 Category: Cancer & Oncology Authors: Kristen A. Echanique, Lauran K. Evans, Albert Y. Han, Dinesh K. Chhetri, Maie A. St. John Source Type: research

Cancer of the Oropharynx and the Association with Human Papillomavirus
Squamous cell carcinoma of the oropharynx (OPC) consists of human papillomavirus (HPV)-negative disease caused by tobacco and alcohol use, and HPV-positive disease caused by the sexually transmitted infection HPV. These entities have unique but overlapping risk factors, epidemiologic trends, staging systems, and survival outcomes. HPV-positive tumor status confers a significant survival benefit compared with HPV-negative disease. OPC treatment entails a combination of surgery, radiation, and chemotherapy. Ongoing trials will determine whether treatment of HPV-related disease may be safely deintensified to decrease morbidit...
Source: Hematology/Oncology Clinics of North America - July 6, 2021 Category: Cancer & Oncology Authors: Eleni M. Rettig, Rosh K.V. Sethi Source Type: research

Immunotherapy for Head and Neck Cancer
Head and neck squamous cell carcinomas (HNSCC) remain an important cause of global cancer morbidity and mortality. Historically, outcomes for patients with recurrent or metastatic disease were poor with limited treatment options. In recent decades, the demographic profile of this disease has evolved with an increase in human papilloma virus –associated oropharyngeal carcinoma and a decrease in tobacco-related disease. The treatment paradigm for HNSCC has rapidly evolved with identification of novel, immune-directed, therapeutic strategies that take advantage of immune dysregulation commonly seen in HNSCC. This review...
Source: Hematology/Oncology Clinics of North America - July 6, 2021 Category: Cancer & Oncology Authors: Sumita Trivedi, Lova Sun, Charu Aggarwal Source Type: research

Robotic and Endoscopic Approaches to Head and Neck Surgery
Technological developments have disrupted the practice of medicine throughout history. Endoscopic and robotic techniques in head and neck surgery have emerged over the past half-century and have been incrementally adapted to expanding indications within otolaryngology. Robotic and endoscopic surgery have an established role in treatment of oropharyngeal and laryngeal cancers, reducing surgical morbidity and improving survival relative to traditional open approaches. Surgical treatment of human papillomavirus-mediated oropharyngeal cancer via transoral robotic surgery offers equivalent oncologic and functional outcomes rela...
Source: Hematology/Oncology Clinics of North America - July 2, 2021 Category: Cancer & Oncology Authors: Andrew J. Holcomb, Jeremy D. Richmon Source Type: research

Cancer of the Paranasal Sinuses
Sinonasal malignancies rare and pathologically diverse and make up (Source: Hematology/Oncology Clinics of North America)
Source: Hematology/Oncology Clinics of North America - July 2, 2021 Category: Cancer & Oncology Authors: Melissa A. Taylor, Nabil F. Saba Source Type: research

Managing Recurrent Metastatic Head and Neck Cancer
Head and neck squamous cell carcinoma (HNSCC) treatment is often associated with high morbidity especially in the recurrent and/or metastatic (R/M) setting, limiting effective treatment options. Local disease control is important. Therefore, local therapies including reirradiation and salvage surgery, either alone or in combination with systemic treatment, may be used for selected patients with R/M HNSCC. Although chemotherapy and targeted agents have modest efficacy in HNSCC, the advent of immunotherapy has revolutionized the treatment paradigm of R/M HNSCC. Multiple trials have resulted in the past 5  years advocati...
Source: Hematology/Oncology Clinics of North America - July 2, 2021 Category: Cancer & Oncology Authors: Hira Shaikh, Vidhya Karivedu, Trisha M. Wise-Draper Source Type: research

Nasopharyngeal Carcinoma and Its Association with Epstein-Barr Virus
Nasopharyngeal carcinoma (NPC) is caused by Epstein-Barr virus (EBV) infection, yet incorporating measurement of EBV DNA levels into clinical practice remains a challenge. Here, we summarize the relationship between NPC and EBV infection before describing the use of cell-free DNA as a plasma biomarker in cancer. We then compare conventional polymerase chain reaction methods and emerging next-generation sequencing approaches for EBV viral load detection emphasizing their prognostic and predictive utility. We conclude by considering how assay standardization, novel molecular approaches, and alternative clinical specimens may...
Source: Hematology/Oncology Clinics of North America - June 26, 2021 Category: Cancer & Oncology Authors: Harish N. Vasudevan, Sue S. Yom Source Type: research

Chronic Lymphocytic Leukemia
HEMATOLOGY/ONCOLOGY CLINICS OF NORTH AMERICA (Source: Hematology/Oncology Clinics of North America)
Source: Hematology/Oncology Clinics of North America - June 24, 2021 Category: Cancer & Oncology Authors: Jennifer R. Brown Source Type: research

Copyright
ELSEVIER (Source: Hematology/Oncology Clinics of North America)
Source: Hematology/Oncology Clinics of North America - June 24, 2021 Category: Cancer & Oncology Source Type: research

Contributors
GEORGE P. CANELLOS, MD (Source: Hematology/Oncology Clinics of North America)
Source: Hematology/Oncology Clinics of North America - June 24, 2021 Category: Cancer & Oncology Source Type: research

Contents
Jennifer R. Brown (Source: Hematology/Oncology Clinics of North America)
Source: Hematology/Oncology Clinics of North America - June 24, 2021 Category: Cancer & Oncology Source Type: research

Forthcoming Issues
Head and Neck Cancer (Source: Hematology/Oncology Clinics of North America)
Source: Hematology/Oncology Clinics of North America - June 24, 2021 Category: Cancer & Oncology Source Type: research

Radiologic Evaluation of the Head and Neck Cancer Patient
CT, PET, ultrasound, and MRI examinations all have roles in the staging and surveillance of cancers in the head and neck. Contrast-enhanced CT is generally the primary examination because of availability, cost, reproducibility, and good overall quality regardless of where performed. PET, ultrasound, and MRI have more specific and nuanced applications. Good interdisciplinary interactions with radiologist consultation can streamline the examination process and reduce the examination burden on patients by limiting the number and maximizing the quality of the examinations and image-guided interventions performed. (Source: Hema...
Source: Hematology/Oncology Clinics of North America - June 23, 2021 Category: Cancer & Oncology Authors: Jeffrey P. Guenette Source Type: research

Potential Relevance of B-cell Maturation Pathways in Defining the Cell(s) of Origin for Chronic Lymphocytic Leukemia
This article reviews the literature relating to this issue, focusing on recent findings, in particular made through epigenetic analyses that strongly support the disease developing from a normal Ag-experienced and memory cell –like B lymphocyte. It also reports the known pathways whereby normal B lymphocytes mature after antigenic challenge and proposes that this information is relevant in defining the cells of origin of this disease. (Source: Hematology/Oncology Clinics of North America)
Source: Hematology/Oncology Clinics of North America - June 1, 2021 Category: Cancer & Oncology Authors: Anita Ng, Nicholas Chiorazzi Source Type: research

Bruton Tyrosine Kinase Inhibitors in Chronic Lymphocytic Leukemia
Bruton tyrosine kinase inhibitors have indisputably transformed the treatment landscape of chronic lymphocytic leukemia, but require continuous therapy to maintain response. This places emphasis on their unique toxicity profile and potential loss of efficacy owing to resistance. Data from single-arm clinical studies are suggestive of comparable efficacy and favorable toxicity profiles of next-generation Bruton tyrosine kinase inhibitors. This is supported by the ASPEN study in Waldenstrom ’s macroglobulinemia, which convincingly demonstrated that zanubrutinib has a better toxicity profile than ibrutinib. Novel, rever...
Source: Hematology/Oncology Clinics of North America - May 27, 2021 Category: Cancer & Oncology Authors: Masa Lasica, Constantine S. Tam Source Type: research

Treatment of Chronic Lymphocytic Leukemia After Discontinuation of Bruton ’s Tyrosine Kinase Inhibitors
This article reviews the two most common reasons for ibrutinib and acalabrutinib discontinuation, including adverse events as well as CLL progression. The data for specific CLL-directed therapies following BTKi discontinuation, including venetoclax, phosphatidylinositol 3-kinase inhibitors, cellular therapies, a nd ongoing clinical trials, are reviewed. An evidence-based sequencing algorithm for treatment of CLL following BTKi discontinuation is proposed. (Source: Hematology/Oncology Clinics of North America)
Source: Hematology/Oncology Clinics of North America - May 27, 2021 Category: Cancer & Oncology Authors: Meghan C. Thompson, Anthony R. Mato Source Type: research

The Evolving Use of Phosphatidylinositol 3-Kinase Inhibitors for the Treatment of Chronic Lymphocytic Leukemia
B cells express 4 phosphatidylinositol 3-kinase (PI3K) isoforms and have a dependence on p110 δ for survival. The design of isoform-selective inhibitors is possible, and pharmacologic inhibition of p110δ is toxic to neoplastic chronic lymphocytic leukemia (CLL) cells for both cell-intrinsic and cell-extrinsic reasons. Idelalisib is a first-in-class p110δ inhibitor that exhibits efficacy f or the treatment of relapsed CLL irrespective of adverse prognostic features. Duvelisib is a p110γ/δ inhibitor with a similar efficacy and safety profile to idelalisib. Recent data indicate that umbralisib, a...
Source: Hematology/Oncology Clinics of North America - May 27, 2021 Category: Cancer & Oncology Authors: Benjamin L. Lampson, Jennifer R. Brown Source Type: research

Immune Therapy for Chronic Lymphocytic Leukemia
Despite significant improvement in clinical outcomes of chronic lymphocytic leukemia (CLL), patients who experience failure of Bruton tyrosine kinase inhibitors or venetoclax benefit from immune therapy approaches. Allogeneic transplant is a potentially curative treatment of CLL but is associated with risk of morbidity and mortality. Although still experimental, chimeric antigen receptor T-cell therapy provides durable remissions in patients with deep molecular responses. This review summarizes the relevant literature and discusses an approach to treatment sequencing and timing of referral for immune therapy. Novel immunot...
Source: Hematology/Oncology Clinics of North America - May 27, 2021 Category: Cancer & Oncology Authors: Mazyar Shadman, David G. Maloney Source Type: research

The Ongoing Unmet Needs in Chronic Lymphocytic Leukemia
Despite recent success in regard to targeted therapies in chronic lymphocytic leukemia (CLL), patients with TP53 disruption (including deletion and/or mutation) continue to have poor outcomes compared with other patients with CLL. In this article, a review of common TP53 mutations in CLL, and recent trials using novel targeted agents in CLL patients with TP53 disruption, is provided with the goal of emphasizing the need to continuously focus on this area of research. In addition, limited but available data on double refractory CLL to BTK inhibitor and BCL-2 inhibitor, and on Richter syndrome, are reviewed. (Source: Hematol...
Source: Hematology/Oncology Clinics of North America - May 27, 2021 Category: Cancer & Oncology Authors: Wei Ding Source Type: research

Prognostic and Predictive Implications of Cytogenetics and Genomics
Chronic lymphocytic leukemia (CLL) is characterized by extreme genomic heterogeneity. Numerous recurrent genetic abnormalities are associated with dismal clinical outcome in patients treated with chemo(immuno)therapy, with aberrations of the TP53 gene being the main genomic abnormalities that dictate treatment choice. In the era of novel agents the predictive significance of the genomic aberrations is highly challenged as the results of the clinical trials performed thus far question the previously established unfavorable impact of genomic aberrations, even that of the TP53 gene. The prognostic and predictive value of the ...
Source: Hematology/Oncology Clinics of North America - May 27, 2021 Category: Cancer & Oncology Authors: Viktor Ljungstr öm, Panagiotis Baliakas Source Type: research

The Significance of B-cell Receptor Stereotypy in Chronic Lymphocytic Leukemia
The finding that (quasi)identical, stereotyped B-cell receptor (BcR) immunoglobulins IGs) are expressed in a significant fraction of chronic lymphocytic leukemia (CLL) highlighted the importance of antigen selection in disease pathogenesis. Subsets of patients sharing the same stereotyped BcR IG display consistent biological features and, at least for certain subsets, clinical presentation and outcome, including the response to particular treatment. On these grounds, BcR IG stereotypy emerges as a useful tool for dissecting the pronounced heterogeneity of CLL toward refining risk stratification and therapeutic management a...
Source: Hematology/Oncology Clinics of North America - May 26, 2021 Category: Cancer & Oncology Authors: Elisavet Vlachonikola, Electra Sofou, Anastasia Chatzidimitriou, Kostas Stamatopoulos, Andreas Agathangelidis Source Type: research

Genomics of RESISTANCE to Targeted Therapies
Targeting BCR and BCL-2 signaling is a widely used therapeutic strategy for chronic lymphocytic leukemia. C481S mutation decreases the covalent binding affinity of ibrutinib to BTK, resulting in reversible rather than irreversible inhibition. In addition to BTK, mutations in PLCG2 have been demonstrated to mediate acquired ibrutinib resistance. Venetoclax, a highly selective BCL2 inhibitor, has high affinity to the BH3-binding grove of BCL2. Mutation in BCL2 (Gly101Val) decreases the affinity of BCL2 for venetoclax and confers acquired resistance in cell lines and primary patient cells. This review discusses the common mec...
Source: Hematology/Oncology Clinics of North America - May 26, 2021 Category: Cancer & Oncology Authors: Shanmugapriya Thangavadivel, Jennifer A. Woyach Source Type: research

First-Line Therapy for Chronic Lymphocytic Leukemia
Novel therapies largely have replaced chemoimmunotherapy as optimal first-line treatment of chronic lymphocytic leukemia (CLL). Approved novel therapies for CLL in the first-line setting include Bruton tyrosine kinase inhibitors, ibrutinib and acalabrutinib, and the BCL2 inhibitor venetoclax. Each of these novel agents has its own unique attributes and they have not been compared head to head in randomized trials. This review summarizes the pivotal trials that led to the approval of novel agents and compares the features of each agent to guide treatment decisions in treatment-na ïve CLL. Ongoing studies investigating ...
Source: Hematology/Oncology Clinics of North America - May 26, 2021 Category: Cancer & Oncology Authors: Hua-Jay J. Cherng, Nitin Jain Source Type: research

Can Immunocompetence Be Restored in Chronic Lymphocytic Leukemia?
Reversing or preventing immunodeficiency in patients with chronic lymphocytic leukemia (CLL) is of the highest priority. The past decade of research has met the challenge of treating CLL for most patients. Patients continue to struggle, however, with infections and second primary malignancies related to immunodeficiency. Strategies addressing this need currently are limited to vaccinations, with suboptimal efficacy, and immunoglobulin replacement. Correlative studies have provided insights into immunologic alterations on treatment. Understanding vulnerabilities in the immune system may help identify potential interventions...
Source: Hematology/Oncology Clinics of North America - May 26, 2021 Category: Cancer & Oncology Authors: Clare Sun, Adrian Wiestner Source Type: research

Should Undetectable Minimal Residual Disease Be the Goal of Chronic Lymphocytic Leukemia Therapy?
With the advent of highly effective novel therapies for chronic lymphocytic leukemia, conventional response assessment is not able to sensitively capture depth of response. To achieve a more precise assessment of response, minimal residual disease has been introduced to more accurately classify and quantify treatment outcomes. It is now considered a strong predictor of outcome in chronic lymphocytic leukemia, although its interpretation depends on the therapeutic context. This review discusses available methods of minimal residual disease measurement. It summarizes minimal residual disease data from pivotal clinical trials...
Source: Hematology/Oncology Clinics of North America - May 15, 2021 Category: Cancer & Oncology Authors: Othman Al-Sawaf, John F. Seymour, Arnon P. Kater, Kirsten Fischer Source Type: research