Oreofe O. Odejide

A targeted mutational landscape of angioimmunoblastic T-cell lymphoma

The genetics of angioimmunoblastic T-cell lymphoma (AITL) are very poorly understood. We defined the mutational landscape of AITL across 219 genes in 85 cases from the United States and Europe. We identified ≥2 mutations in 34 genes, nearly all of which were not previously implicated in AITL. These included loss-of-function mutations in TP53 (n = 4), ETV6 (n = 3), CCND3 (n = 2), and EP300 (n = 5), as well as gain-of-function mutations in JAK2 (n = 2) and STAT3 (n = 4). TET2 was mutated in 65 (76%) AITLs, including 43 that harbored 2 or 3 TET2 mutations. DNMT3A mutations occurred in 28 (33%) AITLs; 100% of these also harbored TET2 mutations (P < .0001). Seventeen AITLs harbored IDH2 R172 substitutions, including 15 with TET2 mutations. In summary, AITL is characterized by high frequencies of overlapping mutations in epigenetic modifiers and targetable mutations in a subset of cases.

The Public Repository of Xenografts Enables Discovery and Randomized Phase II-like Trials in Mice

More than 90% of drugs with preclinical activity fail in human trials, largely due to insufficient efficacy. We hypothesized that adequately powered trials of patient-derived xenografts (PDX) in mice could efficiently define therapeutic activity across heterogeneous tumors. To address this hypothesis, we established a large, publicly available repository of well-characterized leukemia and lymphoma PDXs that undergo orthotopic engraftment, called the Public Repository of Xenografts (PRoXe). PRoXe includes all de-identified information relevant to the primary specimens and the PDXs derived from them. Using this repository, we demonstrate that large studies of acute leukemia PDXs that mimic human randomized clinical trials can characterize drug efficacy and generate transcriptional, functional, and proteomic biomarkers in both treatment-naive and relapsed/refractory disease.

Low frequency clonal mutations recoverable by deep sequencing in patients with aplastic anemia

Low frequency clonal mutations recoverable by deep sequencing in patients with aplastic anemia

Early lymphoid lesions: conceptual, diagnostic and clinical challenges

There are no “benign lymphomas”, a fact due to the nature of lymphoid cells to circulate and home as part of their normal function. Thus, benign clonal expansions of lymphocytes are only rarely recognized when localized. Recent studies have identified a number of lymphoid proliferations that lie at the interface between benign and malignant. Some of these are clonal proliferations that carry many of the molecular hallmarks of their malignant counterparts, such as BCL2/IGH and CCND1/IGH translocations associated with the in situ forms of follicular lymphoma and mantle cell lymphoma, respectively. There are other clonal B-cell proliferations with low risk of progression; these include the pediatric variants of follicular lymphoma and marginal zone lymphoma. Historically, early or incipient forms of T/NK-cell neoplasia also have been identified, such as lymphomatoid papulosis and refractory celiac disease. More recently an indolent form of T-cell lymphoproliferative disease affecting the gastrointestinal tract has been described. Usually, CD8+, the clonal cells are confined to the mucosa. The clinical course is chronic, but non-progressive. NK-cell enteropathy is a clinically similar condition, composed of cytologically atypical NK-cells that may involve the stomach, small bowel or colon. Breast implant-associated anaplastic large cell lymphoma is a cytologically alarming lesion that is self-limited if confined to the seroma cavity. Atypical lymphoid proliferations that lie at the border of benign and malignant can serve as instructive models of lymphomagenesis. It is also critical that they be correctly diagnosed to avoid unnecessary and potentially harmful therapy.

Limited stage diffuse large B-cell lymphoma: comparative effectiveness of treatment strategies in a large cohort of elderly patients

Abstract Optimal treatment for limited stage diffuse large B-cell lymphoma (DLBCL) in the elderly is controversial. Using the Surveillance, Epidemiology and End Results-Medicare database, we compared overall survival (OS), time to second-line therapy (surrogate for recurrence) and adverse events in elderly patients diagnosed with stage I or II DLBCL in 1999–2009, who received either abbreviated rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (RCHOP) plus radiation or 6–8 cycles of RCHOP alone. Of 874 patients, 359 received abbreviated RCHOP with radiation, and 515 received a full course of RCHOP. In propensity score-adjusted analyses, OS was similar in both groups (hazard ratio [HR] 1.02, 95% confidence interval [CI] 0.76, 1.38). Abbreviated RCHOP with radiation was associated with lower risk of second-line therapy (HR 0.71, 95% CI 0.53, 0.94) and lower odds of febrile neutropenia (odds ratio [OR] 0.27, 95% CI 0.15, 0.50). While the two treatments resulted in similar survival, our data suggest that abbreviated RCHOP with radiation may be better tolerated than a full course of RCHOP.

Hospice Use Among Patients With Lymphoma: Impact of Disease Aggressiveness and Curability

BACKGROUND Little is known about factors that influence hospice use for patients with blood cancers. We aimed to characterize hospice enrollment in a large population of patients with B-cell non-Hodgkin lymphoma (NHL) and assess the impact of disease characteristics such as aggressiveness and curability. METHODS Using the Surveillance, Epidemiology, and End Results-Medicare database, we identified patients age 65 years and older who were diagnosed with indolent NHL, aggressive NHL, or mantle cell lymphoma (MCL, which is aggressive and incurable) and died between 1999 and 2009. We determined the prevalence of hospice use and predictors thereof, using multivariable logistic regression. All statistical tests were two-sided. RESULTS Of 18 777 patients, 9645 had indolent NHL, 8226 had aggressive NHL, and 906 had MCL. Of the total cohort, 41.6% enrolled in hospice, and 34.3% enrolled three or more days before death. Compared with patients with indolent NHL, those with MCL were more likely to enroll (adjusted odds ratio [AOR] = 1.72, 95% confidence interval [CI] = 1.49 to 1.98), followed by patients with aggressive NHL (AOR = 1.41, 95% CI = 1.32 to 1.50). Other factors statistically significantly associated with hospice use included older age, female sex, white race, high socioeconomic status, and later year of death. CONCLUSIONS In this large cohort of patients with lymphoma, hospice use was substantially lower than the national average for all cancers, suggesting either the need for improvement in enrollment or that the current hospice model is not meeting this populations end-of-life needs. Moreover, the fact that patients with MCL were most likely to enroll suggests that the end-of-life phase may be more easily determined in the context of cancers that are both aggressive and incurable.

Erratum: The Public Repository of Xenografts Enables Discovery and Randomized Phase II-like Trials in Mice (Cancer Cell (2016) 29 (574–586))

Elizabeth C. Townsend, Mark A. Murakami, Alexandra Christodoulou, Amanda L. Christie, Johannes Köster, Tiffany A. DeSouza, Elizabeth A. Morgan, Scott P. Kallgren, Huiyun Liu, Shuo-Chieh Wu, Olivia Plana, Joan Montero, Kristen E. Stevenson, Prakash Rao, Raga Vadhi, Michael Andreeff, Philippe Armand, Karen K. Ballen, Patrizia Barzaghi-Rinaudo, Sarah Cahill, Rachael A. Clark, Vesselina G. Cooke, Matthew S. Davids, Daniel J. DeAngelo, David M. Dorfman, Hilary Eaton, Benjamin L. Ebert, Julia Etchin, Brant Firestone, David C. Fisher, Arnold S. Freedman, Ilene A. Galinsky, Hui Gao, Jacqueline S. Garcia, Francine Garnache-Ottou, Timothy A. Graubert, Alejandro Gutierrez, Ensar Halilovic, Marian H. Harris, Zachary T. Herbert, Steven M. Horwitz, Giorgio Inghirami, Andrew M. Intlekofer, Moriko Ito, Shai Izraeli, Eric D. Jacobsen, Caron A. Jacobson, Sébastien Jeay, Irmela Jeremias, Michelle A. Kelliher, Raphael Koch, Marina Konopleva, Nadja Kopp, Steven M. Kornblau, Andrew L. Kung, Thomas S. Kupper, Nicole R. LeBoeuf, Ann S. LaCasce, Emma Lees, Loretta S. Li, A. Thomas Look, Masato Murakami, Markus Muschen, Donna Neuberg, Samuel Y. Ng, Oreofe O. Odejide, Stuart H. Orkin, Rachel R. Paquette, Andrew E. Place, Justine E. Roderick, Jeremy A. Ryan, Stephen E. Sallan, Brent Shoji, Lewis B. Silverman, Robert J. Soiffer, David P. Steensma, Kimberly Stegmaier, Richard M. Stone, Jerome Tamburini, Aaron R. Thorner, Paul van Hummelen, Martha Wadleigh, Marion Wiesmann, Andrew P. Weng, Jens U. Wuerthner, David A. Williams, Bruce M. Wollison, Andrew A. Lane, Anthony Letai, Monica M. Bertagnolli, Jerome Ritz, Myles Brown, Henry Long, Jon C. Aster, Margaret A. Shipp, James D. Griffin, and David M. Weinstock* *Correspondence: dweinstock@partners.org http://dx.doi.org/10.1016/j.ccell.2016.06.008

Safety and Effectiveness of Oxaliplatin-based Chemotherapy Regimens in Adults 75 Years and Older with Colorectal Cancer

UNLABELLED Although the safety and efficacy of oxaliplatin-based chemotherapy regimens for colorectal cancer (CRC) have been demonstrated in adults > 75 years of age enrolled in clinical trials, safety and effectiveness outside the trial setting are less established. In this comparative effectiveness study, we note that older adults with stage III and metastatic CRC treated outside of a clinical trial experienced safety and effectiveness of oxaliplatin-based chemotherapy regimens comparable to that of younger adults. BACKGROUND Although the safety and efficacy of oxaliplatin-based chemotherapy regimens for colorectal cancer (CRC) have been demonstrated in adults ≥ 75 years of age who are enrolled in clinical trials, safety and effectiveness outside the trial setting are less established. METHODS We retrospectively collected cases of patients ≥ 75 years of age who were diagnosed with stage III and metastatic CRC and initiated treatment between January 2000 and January 2007 at 2 academic hospitals in Boston, MA. Cases were matched in a 1:2 ratio to controls who were < 75 years of age by hospital site, stage of disease (stage III vs. metastatic) and line of therapy (first- or second-line or beyond). The primary study endpoints were grade ≥ 3 treatment-associated toxicities and intolerance (number of dose delays/reductions and hospital/facility admissions during treatment). The secondary endpoint was overall survival. RESULTS We identified 84 patients ≥ 75 years of age (25% ≥ 80 years) and 168 controls. In the cohort, 77% had colon cancer, 75% had metastatic disease, and 60% were receiving oxaliplatin as first-line therapy. There was no significant difference in grade ≥ 3 treatment-associated toxicities between the patients and the controls (71.4% vs. 68.5%, respectively; P = .63). Further there was no statistically significant difference between patients and controls for combined endpoints of any grade ≥ 3 toxicity or hospital/facility admission (P = .92). With a median follow-up of 52 months, 2-year overall survival was similar between patients and controls (43% vs. 52%, respectively; P = .87). CONCLUSION Older adults with stage III and metastatic CRC treated outside of a clinical trial experienced safety and effectiveness of oxaliplatin-based chemotherapy regimens that was comparable to that of younger adults.

A Policy Prescription for Hospice Care.

Since the founding of the inaugural hospice in the United States in 1974, there has been substantial growth of the hospice movement, with an estimated 1.6 million patients receiving hospice care in 2014.1 Hospice aims to meet the needs of patients with life-limiting illnesses through expert symptom management, provision of home-based care, and facilitation of caregiver support. An important contributor to the expansion of hospice was the Medicare Hospice Benefit, created by Congress in 1982, which enabled older US adults to receive hospice care. Paradoxically, some of the requirements of the benefit also created barriers to enrollment. To limit Medicare costs during the enactment of the hospice benefit, eligibility was restricted to individuals with an estimated life expectancy of 6 months or less, and individuals had to be willing to forgo all treatment directed at their underlying disease. As science and clinical care have advanced over time, what is appropriate for end-of-life care in 2016 is very different from 1982. These enrollment requirements result in underuse of hospice and instead contribute to excess use of hospital care and intensive care at the end of life. These barriers to hospice enrollment are particularly relevant for patients with hematologic malignancies such as acute myeloid leukemia, the myelodysplastic syndromes, lymphoma, and multiple myeloma. Approximately 57 000 individuals in the United States die as a result of hematologic cancers each year, and an estimated 70% are in the Medicare population ( 65 years old).2 This patient population has been shown to have the lowest rates of hospice use in oncology, and when patients with hematologic malignancies enroll in hospice, they are likely to do so within 3 days of death.3 Admission to hospice within 3 days of death is considered to be an indicator of suboptimal end-of-life care because such a short time frame limits the opportunity for patients and their families to fully benefit from the symptom management and psychosocial support that hospice provides. In addition, patients with hematologic malignancies have high rates of intensive care near the end of life. For example, in one study, 84.5% of 290 adults 60 years or older with acute myeloid leukemia were hospitalized within 30 days of death, and 61% died in the hospital.4 Although attitudinal factors involving patients and physicians, such as equating hospice use to “giving up,” likely contribute to underuse in this population, these factors are inextricably linked to wide-reaching systemlevel factors related to the Medicare Hospice Benefit. As a specific example, the fact that the reimbursement structure of the hospice benefit is insufficient for hospices to provide blood transfusions discourages patients with advanced hematologic cancers from receiving hospice care. The requirement for patients to forgo disease-directed therapy creates an artificial dichotomy between hospice care and disease-directed care that is palliative and does not account for many treatments or procedures whose purpose is simply to help patients feel better (eg, blood transfusions, radiation, or drainage of excessive fluid from the abdomen). For example, consider a 66-year-old patient with a myelodysplastic syndrome who has been receiving routine transfusions of red blood cells and platelets to alleviate the cytopenias characteristic of this disease. The patient experiences improvement in fatigue from the receipt of red cells and reduction of bleeding episodes from the receipt of platelets, but his disease subsequently progresses rapidly and his prognosis is less than 6 months’ survival. How is this patient going to be able to choose hospice when the transfusions that have palliated his symptoms and possibly improved his quality of life will no longer be accessible? Interventions are needed to increase access to hospice services. Previous efforts have focused largely on addressing patient and physician factors thought to be barriers, such as educating patients and physicians about the usefulness of hospice. Although these efforts are necessary for improvement, they are not sufficient. The vast majority of US residents prefer to die at home, and hospice offers the opportunity to actualize this preference. Physician surveys also show that most perceive hospice care to be beneficial. In a national survey of 349 hematologic oncologists conducted by researchers at the Dana-Farber Cancer Institute earlier this year,5 the majority of respondents (93%) agreed that hospice care is helpful. Unfortunately, such strong agreement with the general philosophy of hospice does not readily translate into practice, as demonstrated by the low rates of hospice use among patients with hematologic cancers. To bolster current efforts for improvement, policy prescriptions are clearly needed. Policies that address eligibility barriers have the potential to substantially increase access to hospice services. Some hospice organizations and commercial insurance companies have begun to find innovative ways to address these barriers, and their approaches are instructive. In 2005, Aetna launched a pilot comprehensive case management program and expanded hospice benefits for patients with advanced illness. Specifically, the company extended the definition of terminal illness from 6 months to 12 months and allowed patients to continue to receive some types of antineoplastic treatment while also receiving hospice services. Compared with the 387 patients in the control group, the rates of hospice use among the 387 patients in the expanded hospice benefits group increased from 27.9% to 69.8%, and the average length of stay also increased from 21.4 days to 36.7 days. Although patients had access to disease-directed treatment while receiving hospice care, acute and critical care use decreased.6 Specifically, the proportion of patients with emergency VIEWPOINT

Intensity of end-of-life care for patients with myelodysplastic syndromes: Findings from a large national database.

As the population ages, the prevalence of myelodysplastic syndromes (MDS) will increase, and many patients with MDS will require end‐of‐life (EOL) care. Little is known about the intensity of EOL care received by patients with these malignancies.