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Chronic Lymphocytic Leukemia: State of the Art and Beyond

John C. Byrd

In the treatment of chronic lymphocytic leukemia (CLL), select genomic studies can assist in risk stratification of newly diagnosed patients. Chemoimmunotherapy targeting CD20 offers a survival advantage in symptomatic patients both with and without these high-risk genetic features, though patients with del(17p13.1) have poor outcomes and require specific intervention. Obinutuzumab plus chlorambucil is a treatment standard for untreated elderly patients and is superior to rituximab plus chlorambucil. In the setting of relapsed CLL, the new kinase inhibitors have the potential to completely change the treatment paradigm of CLL.

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Molecular Complete Remission Following Ivosidenib in a Patient With an Acute Undifferentiated Leukemia

Sandipkumar H. Patel, Sumithira Vasu, Ling Guo, Olivia Lemaster, John C. Byrd, and Alison Walker

Acute undifferentiated leukemia (AUL) is a subtype of acute leukemias of ambiguous lineage. There is no standard treatment approach for AUL, although acute lymphoblastic leukemia–like regimens for induction therapy have been used. Additional data suggest that AUL may be better treated as acute myeloid leukemia (AML), given their similarities in genetic, cytogenetic, and gene expression patterns. Somatic mutations of IDH1 are found in 7% to 14% of patients with AML; however, the patient in this study was the first patient with IDH1-mutated AUL treated with ivosidenib. In this case, a woman aged 39 years was found to have anemia and thrombocytopenia after presenting to her primary care physician with fatigue, weight loss, and persistent infections. During further workup of the cytopenia, she was diagnosed with AUL and received 7+3 (daunorubicin, 60 mg/m2/d intravenously on days 1–3, and cytarabine, 100 mg/m2 24-hour continuous intravenous infusion on days 1–7) due to the presence of the IDH1 mutation. Bone marrow biopsy performed on day 14 of 7+3 showed persistent disease, and ivosidenib was initiated due to severe HLA alloimmunization (panel-reactive antibody, 100%) and significant bleeding complications. The patient achieved a complete morphologic and molecular remission on ivosidenib monotherapy despite critical bleeding complications during induction. Targeted therapy using ivosidenib may represent an encouraging therapeutic option in patients with AUL and IDH1 mutations. Additional evaluation of ivosidenib in this subgroup of patients with AUL is needed.

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Aging Phenotypes and Restoring Functional Deficits in Older Adults With Hematologic Malignancy

Ashley E. Rosko, Sarah Wall, Robert Baiocchi, Don M. Benson, Jonathan E. Brammer, John C. Byrd, Yvonne A. Efebera, Kami Maddocks, Kerry A. Rogers, Desiree Jones, Lara Sucheston-Campbell, Hancong Tang, Hatice Gulcin Ozer, Ying Huang, Christin E. Burd, and Michelle J. Naughton

Background: Gauging fitness remains a challenge among older adults with hematologic malignancies, and interventions to restore function are lacking. We pilot a structured exercise intervention and novel biologic correlates of aging using epigenetic clocks and markers of immunosenescence to evaluate changes in function and clinical outcomes. Methods: Older adults (n=30) with hematologic malignancy actively receiving treatment were screened and enrolled in a 6-month exercise intervention, the Otago Exercise Programme (OEP). The impact of the OEP on geriatric assessment metrics and health-related quality of life were captured. Clinical outcomes of overall survival and hospital utilization (inpatient length of stay and emergency department use) in relationship to geriatric deficits were analyzed. Results: Older adults (median age, 75.5 years [range, 62–83 years]) actively receiving treatment were enrolled in the OEP. Instrumental activities of daily living and physical health scores (PHS) increased significantly with the OEP intervention (median PHS: visit 1, 55 [range, 0–100]; visit 2, 70 [range, 30–100]; P<.01). Patient-reported Karnofsky performance status increased significantly, and the improvement was sustained (median [range]: visit 1, 80 [40–100]; visit 3, 90 [50–100]; P=.05). Quality of life (Patient-Reported Outcome Measurement Information System [PROMIS]) improved significantly by the end of the 6-month period (median [range]: visit 1, 32.4 [19.9–47.7]; visit 3, 36.2 [19.9–47.7]; P=.01]. Enhanced measures of gait speed and balance, using the Short Physical Performance Battery scores, were associated with a 20% decrease in risk of death (hazard ratio, 0.80; 95% CI, 0.65–0.97; P=.03) and a shorter hospital length of stay (decrease of 1.29 days; 95% CI, −2.46 to −0.13; P=.03). Peripheral blood immunosenescent markers were analyzed in relationship to clinical frailty and reports of mPhenoAge epigenetic analysis are preliminarily reported. Chronologic age had no relationship to overall survival, length of stay, or emergency department utilization. Conclusions: The OEP was effective in improving quality of life, and geriatric tools predicted survival and hospital utilization among older adults with hematologic malignancies.

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Thyroid Carcinoma

R. Michael Tuttle, Douglas W. Ball, David Byrd, Raza A. Dilawari, Gerard M. Doherty, Quan-Yang Duh, Hormoz Ehya, William B. Farrar, Robert I. Haddad, Fouad Kandeel, Richard T. Kloos, Peter Kopp, Dominick M. Lamonica, Thom R. Loree, William M. Lydiatt, Judith C. McCaffrey, John A. Olson Jr., Lee Parks, John A. Ridge, Jatin P. Shah, Steven I. Sherman, Cord Sturgeon, Steven G. Waguespack, Thomas N. Wang, and Lori J. Wirth

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Anaplastic Thyroid Carcinoma, Version 2.2015

Robert I. Haddad, William M. Lydiatt, Douglas W. Ball, Naifa Lamki Busaidy, David Byrd, Glenda Callender, Paxton Dickson, Quan-Yang Duh, Hormoz Ehya, Megan Haymart, Carl Hoh, Jason P. Hunt, Andrei Iagaru, Fouad Kandeel, Peter Kopp, Dominick M. Lamonica, Judith C. McCaffrey, Jeffrey F. Moley, Lee Parks, Christopher D. Raeburn, John A. Ridge, Matthew D. Ringel, Randall P. Scheri, Jatin P. Shah, Robert C. Smallridge, Cord Sturgeon, Thomas N. Wang, Lori J. Wirth, Karin G. Hoffmann, and Miranda Hughes

This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Thyroid Carcinoma focuses on anaplastic carcinoma because substantial changes were made to the systemic therapy recommendations for the 2015 update. Dosages and frequency of administration are now provided, docetaxel/doxorubicin regimens were added, and single-agent cisplatin was deleted because it is not recommended for patients with advanced or metastatic anaplastic thyroid cancer.

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Non-Hodgkin’s Lymphomas

Andrew D. Zelenetz, Jeremy S. Abramson, Ranjana H. Advani, C. Babis Andreadis, John C. Byrd, Myron S. Czuczman, Luis Fayad, Andres Forero, Martha J. Glenn, Jon P. Gockerman, Leo I. Gordon, Nancy Lee Harris, Richard T. Hoppe, Steven M. Horwitz, Mark S. Kaminski, Youn H. Kim, Ann S. LaCasce, Tariq I. Mughal, Auyporn Nademanee, Pierluigi Porcu, Oliver Press, Leonard Prosnitz, Nashitha Reddy, Mitchell R. Smith, Lubomir Sokol, Lode Swinnen, Julie M. Vose, William G. Wierda, Joachim Yahalom, and Furhan Yunus

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NCCN Guidelines Insights: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Version 2.2019

William G. Wierda, John C. Byrd, Jeremy S. Abramson, Syed F. Bilgrami, Greg Bociek, Danielle Brander, Jennifer Brown, Asher A. Chanan-Khan, Julio C. Chavez, Steve E. Coutre, Randall S. Davis, Christopher D. Fletcher, Brian Hill, Brad S. Kahl, Manali Kamdar, Lawrence D. Kaplan, Nadia Khan, Thomas J. Kipps, Shuo Ma, Sami Malek, Anthony Mato, Claudio Mosse, Vishala T. Neppalli, Mazyar Shadman, Tanya Siddiqi, Deborah Stephens, Nina Wagner, Mary A. Dwyer, and Hema Sundar

Chronic lymphocytic leukemia (CLL) is generally characterized by an indolent disease course. Histologic transformation (also known as Richter's transformation) to more aggressive lymphomas, such as diffuse large B-cell lymphoma or Hodgkin lymphoma, occurs in approximately 2% to 10% of patients and is associated with a poor prognosis. These NCCN Guidelines Insights discuss the recommendations for the diagnosis and management of patients with histologic transformation.

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Non-Hodgkin's Lymphomas

Andrew D. Zelenetz, Jeremy S. Abramson, Ranjana H. Advani, C. Babis Andreadis, Nancy Bartlett, Naresh Bellam, John C. Byrd, Myron S. Czuczman, Luis E. Fayad, Martha J. Glenn, Jon P. Gockerman, Leo I. Gordon, Nancy Lee Harris, Richard T. Hoppe, Steven M. Horwitz, Christopher R. Kelsey, Youn H. Kim, Ann S. LaCasce, Auayporn Nademanee, Pierluigi Porcu, Oliver Press, Barbara Pro, Nashitha Reddy, Lubomir Sokol, Lode J. Swinnen, Christina Tsien, Julie M. Vose, William G. Wierda, Joachim Yahalom, and Nadeem Zafar

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Hairy Cell Leukemia, Version 2.2018, NCCN Clinical Practice Guidelines in Oncology

William G. Wierda, John C. Byrd, Jeremy S. Abramson, Seema Bhat, Greg Bociek, Danielle Brander, Jennifer Brown, Asher Chanan-Khan, Steve E. Coutre, Randall S. Davis, Christopher D. Fletcher, Brian Hill, Brad S. Kahl, Manali Kamdar, Lawrence D. Kaplan, Nadia Khan, Thomas J. Kipps, Jeffrey Lancet, Shuo Ma, Sami Malek, Claudio Mosse, Mazyar Shadman, Tanya Siddiqi, Deborah Stephens, Nina Wagner, Andrew D. Zelenetz, Mary A. Dwyer, and Hema Sundar

Hairy cell leukemia (HCL) is a rare type of indolent B-cell leukemia, characterized by symptoms of fatigue and weakness, organomegaly, pancytopenia, and recurrent opportunistic infections. Classic HCL should be considered a distinct clinical entity separate from HCLvariant (HCLv), which is associated with a more aggressive disease course and may not respond to standard HCL therapies. Somatic hypermutation in the IGHV gene is present in most patients with HCL. The BRAF V600E mutation has been reported in most patients with classic HCL but not in those with other B-cell leukemias or lymphomas. Therefore, it is necessary to distinguish HCLv from classic HCL. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of classic HCL.

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Non-Hodgkin’s Lymphomas, Version 4.2014

Andrew D. Zelenetz, Leo I. Gordon, William G. Wierda, Jeremy S. Abramson, Ranjana H. Advani, C. Babis Andreadis, Nancy Bartlett, John C. Byrd, Myron S. Czuczman, Luis E. Fayad, Richard I. Fisher, Martha J. Glenn, Nancy Lee Harris, Richard T. Hoppe, Steven M. Horwitz, Christopher R. Kelsey, Youn H. Kim, Susan Krivacic, Ann S. LaCasce, Auayporn Nademanee, Pierluigi Porcu, Oliver Press, Rachel Rabinovitch, Nishitha Reddy, Erin Reid, Ayman A. Saad, Lubomir Sokol, Lode J. Swinnen, Christina Tsien, Julie M. Vose, Joachim Yahalom, Nadeem Zafar, Mary Dwyer, and Hema Sundar

Non-Hodgkin’s lymphomas (NHL) are a heterogeneous group of lymphoproliferative disorders originating in B lymphocytes, T lymphocytes, or natural killer cells. Mantle cell lymphoma (MCL) accounts for approximately 6% of all newly diagnosed NHL cases. Radiation therapy with or without systemic therapy is a reasonable approach for the few patients who present with early-stage disease. Rituximab-based chemoimmunotherapy followed by high-dose therapy and autologous stem cell rescue (HDT/ASCR) is recommended for patients presenting with advanced-stage disease. Induction therapy followed by rituximab maintenance may provide extended disease control for those who are not candidates for HDT/ASCR. Ibrutinib, a Bruton tyrosine kinase inhibitor, was recently approved for the treatment of relapsed or refractory disease. This manuscript discusses the recommendations outlined in the NCCN Guidelines for NHL regarding the diagnosis and management of patients with MCL.