The development of novel therapeutics in acute myeloid leukemia (AML) is driven by the need to improve efficacy and reduce toxicity. Clearly, elderly patients with AML represent a highly heterogeneous group, based on a wide array of disease- and patient-specific characteristics. Therefore, novel treatment strategies aimed at overcoming specific biologic modifiers of disease resistance will be paramount to successful therapy for some, whereas in others, the ability to administer a low-toxicity regimen on a chronic basis to achieve disease control may prove beneficial, perhaps even in the absence of complete responses. In addition, identifying genomic and proteomic expression patterns using an individual's unique neoplastic clone will likely optimize the ability to predict responders to novel therapies and identify new and relevant therapeutic targets. The development of reduced-intensity preparative regimens for allogeneic transplants has allowed physicians and patients to explore the option of long-term disease control. The risk–benefit ratio for this procedure will depend on the disease state, patient performance status, and comorbidities. However, current results underscore that age alone should no longer be a contraindication for allogeneic transplant with curative intent in these patients, and long-term disease control with good quality of life is possible and can be expected. Future trials combining the novel therapies described in this article and novel transplant technologies should allow more elderly patients with AML or myelodysplastic syndromes to experience long and productive lives.
Jeffrey E. Lancet and Sergio Giralt
Stefanie S. Jeffrey, Per Eystein Lønning, and Bruce E. Hillner
Breast cancer is a heterogeneous disease. DNA microarray technology is being applied to breast cancer to identify new prognostic biomarkers, to predict response to therapy, and to discover targets for the development of novel therapies. New diagnostic assays based on global gene expression are being introduced into clinical practice or tested in large-scale clinical trials. This review focuses on translational studies using microarray analyses and discusses best practice features and pitfalls. We note that factors that predict metastatic disease are not necessarily the same factors that predict therapeutic response. We believe that the characterization and discernment of different systems among breast cancers is crucial for understanding drug sensitivity and resistance mechanisms and for guiding therapy.
Jorge Casas-Ganem and John H. Healey
Primary bone tumors are rare, accounting for less than 0.2% of all cancers diagnosed yearly in the United States. Study of the molecular mechanisms of these diseases has given insight into their pathobiology. It has also identified molecular alterations that, if present, may be used in conjunction with histologic evaluation to further refine diagnosis, allowing cases to be stratified into prognostic groups more or less likely to show response to current cytotoxic protocols. Recent findings have lead to the identification of molecular pathways that may serve as targets of novel therapies, especially in the case of Ewing sarcoma. Telomere maintenance mechanisms are also emerging as potential targets for anticancer therapy. As the molecular mechanisms underlying malignant bone tumors are better understood, new anticancer agents targeting specific pathways are likely to emerge. This may make it possible to tailor treatment for each individual patient, using a combination of cytotoxic and targeted therapies based on the histologic and molecular profile of the patient's tumor.
Scott M. Schuetze
Sarcomas of bone are rare malignancies diagnosed in fewer than 3000 individuals yearly in the United States. Ewing's sarcoma and most osteosarcoma are high-grade neoplasms and account for approximately one half of bone sarcoma cases. Fewer than 20% of patients presenting with localized Ewing's sarcoma or osteosarcoma are cured with surgery alone. Current management typically involves collaboration among orthopedic oncologists, medical oncologists, musculoskeletal radiologists, sarcoma pathologists, and radiation oncologists. Modern multidisciplinary management of Ewing's sarcoma and osteosarcoma has improved the cure rate of patients with localized disease to more than 50%. Primary chemotherapy for high-grade bone sarcomas often involves intensive, multiagent regimens, and few secondary chemotherapy options are available to treat refractory or relapsed disease. Patient participation in clinical trials of novel therapies for Ewing's sarcoma and osteosarcoma should be strongly encouraged.
Andy I. Chen and Ranjana H. Advani
Edited by Kerrin G. Robinson
Peripheral T-cell lymphomas (PTCLs) are a rare and diverse group of neoplasms with a poor prognosis. Management of these disorders has been largely extrapolated from the treatment of aggressive B-cell lymphomas; however, therapeutic responses to this approach are neither adequate nor durable for most patients with PTCL. Given the rarity of PTCL, much of the literature consists of studies with small sample size and anecdotal case reports. Therefore, no consensus exists on the best therapeutic strategy for either newly diagnosed or relapsed/refractory PTCL. This article reviews promising novel approaches in the treatment of PTCL and its subtypes. Investigation into the pathogenesis of PTCL has also identified new targets for treatment. These emerging therapies include new uses of existing agents and the development of novel agents specifically targeted against T-cell lymphoma. Results using antimetabolites, immunotherapies, and histone deacetylase inhibitors have been particularly encouraging. These novel therapies are being tested as single agents and in combination with conventional lymphoma regimens in the frontline and salvage settings. Because of the rarity and heterogeneity of PTCL, national and international cooperation is needed to conduct the clinical studies required for the development of more effective treatment paradigms. These efforts are ongoing and will hopefully guide new strategies to improve the historically poor outcome of PTCL.
Vijaya Raj Bhatt, R. Gregory Bociek, Ji Yuan, Kai Fu, Timothy C. Greiner, Bhavana J. Dave, Sandeep K. Rajan, and James O. Armitage
Essential thrombocythemia is well-known to transform to other myeloid disorders, such as leukemia; however, the risk for development of lymphoma is not as well studied. This case report discusses a 76-year-old man with a history of prefibrotic post-essential thrombocythemia myelofibrosis on ruxolitinib, who developed anemia, thrombocytopenia, and leukocytosis with peripheral blasts. Results of a bone marrow biopsy and PET and CT scans revealed stage IV leukemic diffuse large B-cell lymphoma. Several days after cessation of ruxolitinib, the patient developed fevers, hypotension, and low-grade disseminated intravascular coagulation, and subsequently developed spontaneous tumor lysis syndrome, which resulted in death. This case is unique in several aspects: it highlights the rare possibility of lymphomatous transformation of myeloproliferative disorders, an unusual presentation of lymphoma masquerading as leukemia, and the possibility of ruxolitinib withdrawal syndrome. Additionally, this case serves as a reminder that the use of novel therapies should be adopted after a thorough assessment of long-term risks, including those associated with abrupt withdrawal.
Cynthia L. Gong and Joel W. Hay
Of patients diagnosed with prostate cancer, 0% to 20% experience disease progression to metastatic castration-resistant prostate cancer (mCRPC). Recently, 4 novel therapies have been introduced for the treatment of mCRPC; of these, abiraterone and sipuleucel-T have been studied in the asymptomatic, pre-docetaxel population. Both have shown clinical benefits compared with placebo. This study evaluated the cost-effectiveness of abiraterone acetate and sipuleucel-T compared with prednisone in asymptomatic, pre-docetaxel mCRPC from a US societal perspective. A Markov model was constructed to simulate stable disease, progressed disease, and death. Survival and event rates were derived from published clinical trial data. Costs were derived from the literature and government reimbursement schedules. Outcomes were measured as average cost-effectiveness ratios (ACERs), incremental cost-effectiveness ratios (ICERs), and net monetary benefits (NMBs). One-way and probabilistic sensitivity analyses were conducted to test the robustness of the model. The base-case ACER was $114K/quality-adjusted life-years (QALY) for abiraterone, $85K/QALY for sipuleucel-T, and $31K/QALY for prednisone. The base-case ICER was $389K/QALY for abiraterone and $547K/QALY for sipuleucel-T. Prednisone dominates both abiraterone and sipuleucel-T in terms of NMB at willingness-to-pay (WTP) thresholds of $400K or less. One-way sensitivity analyses revealed that the model was most sensitive to overall survival and utility inputs. Probabilistic sensitivity analyses showed abiraterone to be cost-effective 50% or more of the time at a WTP of greater than $400K, whereas sipuleucel-T was cost-effective 50% or more of the time at a WTP of greater than $270K. Neither abiraterone nor sipuleucel-T was found to be cost-effective compared with prednisone in the treatment of asymptomatic, pre-docetaxel mCRPC.
Alyssa A. Schatz, Katy Winckworth Prejsnar, James McCanney, Meghan Gutierrez, Stefanie Joho, Joseph Alvarnas, and Robert W. Carlson
Scott Gottlieb, recently introduced policies intended to accelerate approval of novel therapies, which has been particularly impactful in oncology. Commissioner Gottlieb joined NCCN at the June 2018 NCCN Policy Summit to discuss actions the FDA is taking
Gene A. Wetzstein, Dima Decker, and James Mond
. Management strategies vary substantially with no clear consensus and an unmet need exists. Novel therapies are warranted to help combat RVIs in this highly susceptible patient population.
Candice Yong, Brian Seal, M. Janelle Cambron-Mellott, Oliver Will, Martine C. Maculaitis, Kelly Clapp, Emily Mulvihill, Ion Cotarla, and Ranee Mehra
of currently available therapies and how they value the different efficacy and toxicity profiles of novel therapies. This study quantified CG preferences for attributes associated with chemotherapy and immunotherapy, alone or in combination, for