[en] Tremendous progress in treatment and outcomes has been achieved across the whole range of haematological malignancies in the past two decades. Although cure rates for aggressive malignancies have increased, nowhere has progress been more impactful than in the management of typically incurable forms of haematological cancer. Population-based data have shown that 5-year survival for patients with chronic myelogenous and chronic lymphocytic leukaemia, indolent B-cell lymphomas, and multiple myeloma has improved markedly. This improvement is a result of substantial changes in disease management strategies in these malignancies. Several haematological malignancies are now chronic diseases that are treated with continuously administered therapies that have unique side-effects over time. In this Commission, an international panel of clinicians, clinical investigators, methodologists, regulators, and patient advocates representing a broad range of academic and clinical cancer expertise examine adverse events in haematological malignancies. The issues pertaining to assessment of adverse events examined here are relevant to a range of malignancies and have been, to date, underexplored in the context of haematology. The aim of this Commission is to improve toxicity assessment in clinical trials in haematological malignancies by critically examining the current process of adverse event assessment, highlighting the need to incorporate patient-reported outcomes, addressing issues unique to stem-cell transplantation and survivorship, appraising challenges in regulatory approval, and evaluating toxicity in real-world patients. We have identified a range of priority issues in these areas and defined potential solutions to challenges associated with adverse event assessment in the current treatment landscape of haematological malignancies.
Byrd, JC, Brown, JR, O'Brien, S, et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med 371 (2014), 213–223.
Burger, JA, Tedeschi, A, Barr, PM, et al. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med 373 (2015), 2425–2437.
Furman, RR, Sharman, JP, Coutre, SE, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med 370 (2014), 997–1007.
Stilgenbauer, S, Eichhorst, B, Schetelig, J, et al. Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study. Lancet Oncol 17 (2016), 768–778.
Marcus, R, Davies, A, Ando, K, et al. Obinutuzumab for the first-line treatment of follicular lymphoma. N Engl J Med 377 (2017), 1331–1344.
Salles, GA, Seymour, JF, Feugier, P, et al. Long term follow-up of the PRIMA Study: half of patients receiving rituximab maintenance remain progression free at 10 years. Blood, 130(suppl 1), 2017, 486.
Gopal, AK, Kahl, BS, de Vos, S, et al. PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med 370 (2014), 1008–1018.
Dimopoulos, MA, Trotman, J, Tedeschi, A, et al. Ibrutinib for patients with rituximab-refractory Waldenström's macroglobulinaemia (iNNOVATE): an open-label substudy of an international, multicentre, phase 3 trial. Lancet Oncol 18 (2017), 241–250.
Kaplan, HS, The radical radiotherapy of regionally localized Hodgkin's disease. Radiology 78 (1962), 553–561.
Howlader, N, Noone, AM, Krapcho, M, et al. SEER cancer statistics review. https://seer.cancer.gov/csr/1975_2014/, 1975–2014. (Accessed 27 March 2018)
Engert, A, Plütschow, A, Eich, HT, et al. Reduced treatment intensity in patients with early-stage Hodgkin's lymphoma. N Engl J Med 363 (2010), 640–652.
Radford, J, Illidge, T, Counsell, N, et al. Results of a trial of PET-directed therapy for early-stage Hodgkin's lymphoma. N Engl J Med 372 (2015), 1598–1607.
Coiffier, B, Lepage, E, Briere, J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 346 (2002), 235–242.
Pfreundschuh, M, Trümper, L, Osterborg, A, et al., the MabThera International Trial Group. CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol 7 (2006), 379–391.
Habermann, TM, Weller, EA, Morrison, VA, et al. Rituximab-CHOP versus CHOP alone or with maintenance rituximab in older patients with diffuse large B-cell lymphoma. J Clin Oncol 24 (2006), 3121–3127.
Carson, KR, Evens, AM, Richey, EA, et al. Progressive multifocal leukoencephalopathy after rituximab therapy in HIV-negative patients: a report of 57 cases from the research on adverse drug events and reports project. Blood 113 (2009), 4834–4840.
Kumar, SK, Rajkumar, SV, Dispenzieri, A, et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood 111 (2008), 2516–2520.
Palumbo, A, Chanan-Khan, A, Weisel, K, et al., the CASTOR Investigators. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med 375 (2016), 754–766.
Dimopoulos, MA, Oriol, A, Nahi, H, et al., the POLLUX Investigators. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med 375 (2016), 1319–1331.
Rajkumar, SV, Kyle, RA, Progress in myeloma—a monoclonal breakthrough. N Engl J Med 375 (2016), 1390–1392.
Kumar, S, Kaufman, JL, Gasparetto, C, et al. Efficacy of venetoclax as targeted therapy for relapsed/refractory t(11;14) multiple myeloma. Blood 130 (2017), 2401–2409.
Bower, H, Björkholm, M, Dickman, PW, Höglund, M, Lambert, PC, Andersson, TM, Life expectancy of patients with chronic myeloid leukemia approaches the life expectancy of the general population. J Clin Oncol 34 (2016), 2851–2857.
Marin, D, Bazeos, A, Mahon, F-X, et al. Adherence is the critical factor for achieving molecular responses in patients with chronic myeloid leukemia who achieve complete cytogenetic responses on imatinib. J Clin Oncol 28 (2010), 2381–2388.
Efficace, F, Bombaci, F, de Jong, J, et al. Factors predicting intentional non-adherence in chronic myeloid leukemia: a multivariate analysis on 2546 patients by the CML Advocates Network. Blood, 122, 2013, 4023.
Geissler, J, Sharf, G, Bombaci, F, et al. Factors influencing adherence in CML and ways to improvement: results of a patient-driven survey of 2546 patients in 63 countries. J Cancer Res Clin Oncol 143 (2017), 1167–1176.
List, A, Dewald, G, Bennett, J, et al. Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N Engl J Med 355 (2006), 1456–1465.
Fenaux, P, Mufti, GJ, Hellstrom-Lindberg, E, et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase 3 study. Lancet Oncol 10 (2009), 223–232.
Stone, RM, Mandrekar, SJ, Sanford, BL, et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med 377 (2017), 454–464.
Stein, EM, DiNardo, CD, Pollyea, DA, et al. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood 130 (2017), 722–731.
Kantarjian, H, Stein, A, Gökbuget, N, et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med 376 (2017), 836–847.
Ansell, SM, Lesokhin, AM, Borrello, I, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. N Engl J Med 372 (2015), 311–319.
Chen, R, Zinzani, PL, Fanale, MA, et al. Phase II study of the efficacy and safety of pembrolizumab for relapsed/refractory classic Hodgkin lymphoma. J Clin Oncol 35 (2017), 2125–2132.
Neelapu, SS, Locke, FL, Bartlett, NL, et al. A phase 2 multicenter trial of KTE-C19 (anti-CD19 CAR T cells) in patients with chemorefractory primary mediastinal b-cell lymphoma (PMBCL) and transformed follicular lymphoma (TFL): interim results from ZUMA-1. Blood, 128, 2016, 998.
National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE) version 5. https://evs.nci.nih.gov/ftp1/CTCAE/About.html. (Accessed 27 March 2018)
Thanarajasingam, G, Hubbard, JM, Sloan, JA, Grothey, A, The imperative for a new approach to toxicity analysis in oncology clinical trials. J Natl Cancer Inst, 107, 2015, djv216.
Thanarajasingam, G, Atherton, PJ, Novotny, PJ, Loprinzi, CL, Sloan, JA, Grothey, A, Longitudinal adverse event assessment in oncology clinical trials: the Toxicity over Time (ToxT) analysis of Alliance trials NCCTG N9741 and 979254. Lancet Oncol 17 (2016), 663–670.
Postel-Vinay, S, Collette, L, Paoletti, X, et al. Towards new methods for the determination of dose limiting toxicities and the assessment of the recommended dose for further studies of molecularly targeted agents–dose-limiting toxicity and toxicity assessment recommendation group for early trials of targeted therapies, an european organisation for research and treatment of cancer-led study. Eur J Cancer 50 (2014), 2040–2049.
Lee, SM, Backenroth, D, Cheung, YK, et al. Case example of dose optimization using data from bortezomib dose-finding clinical trials. J Clin Oncol 34 (2016), 1395–1401.
Lee, SM, Zhang, Y, Minasian, LM, Unger, JM, Hershman, DL, Using delayed toxicities to re-evaluate tolerability in phase 2 trials: a case example using bortezomib. Cancer Invest 35 (2017), 484–489.
Ji, Y, Wang, SJ, Modified toxicity probability interval design: a safer and more reliable method than the 3 + 3 design for practical phase I trials. J Clin Oncol 31 (2013), 1785–1791.
Weber, JS, Hodi, FS, Wolchok, JD, et al. Safety profile of nivolumab monotherapy: A Pooled Analysis of Patients With Advanced Melanoma. J Clin Oncol 35 (2017), 785–792.
Haverkos, BM, Abbott, D, Hamadani, M, et al. PD-1 blockade for relapsed lymphoma post-allogeneic hematopoietic cell transplant: high response rate but frequent GVHD. Blood 130 (2017), 221–228.
Dunleavy, K, Hakim, F, Kim, HK, et al. B-cell recovery following rituximab-based therapy is associated with perturbations in stromal derived factor-1 and granulocyte homeostasis. Blood 106 (2005), 795–802.
Lionakis, MS, Dunleavy, K, Roschewski, M, et al. Inhibition of B cell receptor signaling by ibrutinib in primary CNS lymphoma. Cancer Cell 31 (2017), 833–843.
Lampson, BL, Yu, L, Glynn, RJ, et al. Ventricular arrhythmias and sudden death in patients taking ibrutinib. Blood 129 (2017), 2581–2584.
Mughal, TI, Schrieber, A, Principal long-term adverse effects of imatinib in patients with chronic myeloid leukemia in chronic phase. Biologics 4 (2010), 315–323.
Meyer, RM, Gospodarowicz, MK, Connors, JM, et al. ABVD alone versus radiation-based therapy in limited-stage Hodgkin's lymphoma. N Engl J Med 366 (2012), 399–408.
Menon, SP, Rajkumar, SV, Lacy, M, Falco, P, Palumbo, A, Thromboembolic events with lenalidomide-based therapy for multiple myeloma. Cancer 112 (2008), 1522–1528.
Rajkumar, SV, Jacobus, S, Callander, NS, et al. Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial. Lancet Oncol 11 (2010), 29–37.
Byrd, JC, Furman, RR, Coutre, SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med 369 (2013), 32–42.
Bossi, P, Botta, L, Bironzo, P, et al. Systematic review of adverse events reporting in clinical trials leading to approval of targeted therapy and immunotherapy. Ann Oncol 27:suppl 6 (2016), 100–102.
Lee, DW, Gardner, R, Porter, DL, et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood 124 (2014), 188–195.
Porter, D, Frey, N, Wood, PA, Weng, Y, Grupp, SA, Grading of cytokine release syndrome associated with the CAR T cell therapy tisagenlecleucel. J Hematol Oncol, 11, 2018, 35.
US Department of Health and Human Services National Institutes of Health Recombinant DNA Advisory Committee Meeting (RAC). https://osp.od.nih.gov/wp-content/uploads/2017/02/Minutes_RAC_Mar2016_508.pdf, March 8–9, 2016. (Accessed 10 May 2018)
Park, JH, Geyer, MB, Brentjens, RJ, CD19-targeted CAR T-cell therapeutics for hematologic malignancies: interpreting clinical outcomes to date. Blood 127 (2016), 3312–3320.
Basch, E, Patient-reported outcomes—harnessing patients' voices to improve clinical care. N Engl J Med 376 (2017), 105–108.
FDA. Guidance for industry. Patient-reported outcome measures: use in medical product development to support labeling claims. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM193282.pdf, December, 2009. (Accessed 27 March 2018)
Wilson, IB, Cleary, PD, Linking clinical variables with health-related quality of life. A conceptual model of patient outcomes. JAMA 273 (1995), 59–65.
Secord, AA, Coleman, RL, Havrilesky, LJ, Abernethy, AP, Samsa, GP, Cella, D, Patient-reported outcomes as end points and outcome indicators in solid tumours. Nat Rev Clin Oncol 12 (2015), 358–370.
EORTC. Quality of life. http://groups.eortc.be/qol. (Accessed 27 March 2018)
FACIT. FACIT measurement system. http://www.facit.org/FACITOrg/Overview. (Accessed 27 March 2018)
Balestroni, G, Bertolotti, G, EuroQol-5D (EQ-5D): an instrument for measuring quality of life. Monaldi Arch Chest Dis 78 (2015), 155–159 (in Italian).
Basch, E, Reeve, BB, Mitchell, SA, et al. Development of the National Cancer Institute's patient-reported outcomes version of the common terminology criteria for adverse events (PRO-CTCAE). J Natl Cancer Inst, 106, 2014, dju244.
Dueck, AC, Mendoza, TR, Mitchell, SA, et al. Validity and reliability of the us national cancer institute's patient-reported outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). JAMA Oncol 1 (2015), 1051–1059.
Robinson, D Jr, Esseltine, DL, Regnault, A, Meunier, J, Liu, K, van de Velde, H, The influence of baseline characteristics and disease stage on health-related quality of life in multiple myeloma: findings from six randomized controlled trials. Br J Haematol 174 (2016), 368–381.
Sonneveld, P, Verelst, SG, Lewis, P, et al. Review of health-related quality of life data in multiple myeloma patients treated with novel agents. Leukemia 27 (2013), 1959–1969.
Nielsen, LK, Jarden, M, Andersen, CL, Frederiksen, H, Abildgaard, N, A systematic review of health-related quality of life in longitudinal studies of myeloma patients. Eur J Haematol 99 (2017), 3–17.
Wagner, LI, Zhao, F, Hong, F, et al. Anxiety and health-related quality of life among patients with low-tumor burden non-Hodgkin lymphoma randomly assigned to two different rituximab dosing regimens: results from ECOG trial E4402 (RESORT). J Clin Oncol 33 (2015), 740–748.
Ardeshna, KM, Qian, W, Smith, P, et al. Rituximab versus a watch-and-wait approach in patients with advanced-stage, asymptomatic, non-bulky follicular lymphoma: an open-label randomised phase 3 trial. Lancet Oncol 15 (2014), 424–435.
Kluetz, PG, Kanapuru, B, Lemery, S, et al. Informing the tolerability of cancer treatments using patient-reported outcome measures: summary of an FDA and Critical Path Institute Workshop. Value Health, 2017 published online Dec 5. https://doi.org/10.1016/j.jval.2017.09.009.
Kim, J, Singh, H, Ayalew, K, et al. Use of PRO measures to inform tolerability in oncology trials: Implications for clinical review, IND safety reporting, and clinical site inspections. Clin Cancer Res 24 (2017), 1780–1784.
Lee, HS, Lee, JY, Ah, YM, et al. Low adherence to upfront and extended adjuvant letrozole therapy among early breast cancer patients in a clinical practice setting. Oncology 86 (2014), 340–349.
Creel, PA, Optimizing patient adherence to targeted therapies in renal cell carcinoma. Clin J Oncol Nurs 18 (2014), 694–700.
Verbrugghe, M, Verhaeghe, S, Lauwaert, K, Beeckman, D, Van Hecke, A, Determinants and associated factors influencing medication adherence and persistence to oral anticancer drugs: a systematic review. Cancer Treat Rev 39 (2013), 610–621.
Basch, E, Iasonos, A, McDonough, T, et al. Patient versus clinician symptom reporting using the National Cancer Institute Common Terminology Criteria for Adverse Events: results of a questionnaire-based study. Lancet Oncol 7 (2006), 903–909.
Bruner, DW, Hanisch, LJ, Reeve, BB, et al. Stakeholder perspectives on implementing the National Cancer Institute's patient-reported outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). Transl Behav Med 1 (2011), 110–122.
Montemurro, F, Mittica, G, Cagnazzo, C, et al. Self-evaluation of adjuvant chemotherapy-related adverse effects by patients with breast cancer. JAMA Oncol 2 (2016), 445–452.
Henon, C, Lissa, D, Paoletti, X, et al. Patient-reported tolerability of adverse events in phase 1 trials. ESMO Open, 2, 2017, e000148.
Bottomley, A, Pe, M, Sloan, J, et al. Analysing data from patient-reported outcome and quality of life endpoints for cancer clinical trials: a start in setting international standards. Lancet Oncol 17 (2016), e510–e514.
Gwaltney, C, Paty, J, Kwitkowski, VE, et al. Development of a harmonized patient-reported outcome questionnaire to assess myelofibrosis symptoms in clinical trials. Leuk Res 59 (2017), 26–31.
Kelley, T, International Consortium for Health Outcomes Measurement (ICHOM). Trials, 16(suppl 3), 2015, 04.
Williamson, PR, Altman, DG, Blazeby, JM, et al. Developing core outcome sets for clinical trials: issues to consider. Trials, 13, 2012, 132.
Calvert, M, Kyte, D, Mercieca-Bebber, R, et al. Guidelines for inclusion of patient-reported outcomes in clinical trial protocols: The spirit-pro extension. JAMA 319 (2018), 483–494.
Mercieca-Bebber, R, Palmer, MJ, Brundage, M, Calvert, M, Stockler, MR, King, MT, Design, implementation and reporting strategies to reduce the instance and impact of missing patient-reported outcome (PRO) data: a systematic review. BMJ Open, 6, 2016, e010938.
Calvert, M, Blazeby, J, Altman, DG, Revicki, DA, Moher, D, Brundage, MD, the CONSORT PRO Group. Reporting of patient-reported outcomes in randomized trials: the CONSORT PRO extension. JAMA 309 (2013), 814–822.
Basch, E, Rogak, LJ, Dueck, AC, Methods for implementing and reporting patient-reported outcome (PRO) measures of symptomatic adverse events in cancer clinical trials. Clin Ther 38 (2016), 821–830.
Bliven, BD, Kaufman, SE, Spertus, JA, Electronic collection of health-related quality of life data: validity, time benefits, and patient preference. Qual Life Res 10 (2001), 15–22.
Anderson, M, Perrin, A, Tech adoption climbs among older adults. http://www.pewinternet.org/2017/05/17/tech-adoption-climbs-among-older-adults/, May 17, 2017. (Accessed 27 March 2018)
Velikova, G, Booth, L, Smith, AB, et al. Measuring quality of life in routine oncology practice improves communication and patient well-being: a randomized controlled trial. J Clin Oncol 22 (2004), 714–724.
Berry, DL, Hong, F, Halpenny, B, et al. Electronic self-report assessment for cancer and self-care support: results of a multicenter randomized trial. J Clin Oncol 32 (2014), 199–205.
Basch, E, Deal, AM, Kris, MG, et al. Symptom monitoring with patient-reported outcomes during routine cancer treatment: a randomized controlled trial. J Clin Oncol 34 (2016), 557–565.
Basch, E, Deal, AM, Dueck, AC, et al. Overall survival results of a trial assessing patient-reported outcomes for symptom monitoring during routine cancer treatment. JAMA 318 (2017), 197–198.
Absolom, K, Holch, P, Warrington, L, et al. Electronic patient self-Reporting of Adverse-events: Patient Information and aDvice (eRAPID): a randomised controlled trial in systemic cancer treatment. BMC Cancer, 17, 2017, 318.
Breen, S, Ritchie, D, Schofield, P, et al. The Patient Remote Intervention and Symptom Management System (PRISMS)— a telehealth-mediated intervention enabling real-time monitoring of chemotherapy side-effects in patients with haematological malignancies: study protocol for a randomised controlled trial. Trials, 16, 2015, 472.
Thomas, ED, Storb, R, Clift, RA, et al. Bone-marrow transplantation (second of two parts). N Engl J Med 292 (1975), 895–902.
Rowlings, PA, Przepiorka, D, Klein, JP, et al. IBMTR Severity Index for grading acute graft-versus-host disease: retrospective comparison with Glucksberg grade. Br J Haematol 97 (1997), 855–864.
Miller, TP, Li, Y, Getz, KD, et al. Using electronic medical record data to report laboratory adverse events. Br J Haematol 177 (2017), 283–286.
Cutler, C, Stevenson, K, Kim, HT, et al. Sirolimus is associated with veno-occlusive disease of the liver after myeloablative allogeneic stem cell transplantation. Blood 112 (2008), 4425–4431.
Kamani, NR, Walters, MC, Carter, S, et al. Unrelated donor cord blood transplantation for children with severe sickle cell disease: results of one cohort from the phase II study from the Blood and Marrow Transplant Clinical Trials Network (BMT CTN). Biol Blood Marrow Transplant 18 (2012), 1265–1272.
Battiwalla, M, Hashmi, S, Majhail, N, Pavletic, S, Savani, BN, Shelburne, N, National Institutes of Health hematopoietic cell transplantation late effects initiative: developing recommendations to improve survivorship and long-term outcomes. Biol Blood Marrow Transplant 23 (2017), 6–9.
Wilkinson, GR, Drug metabolism and variability among patients in drug response. N Engl J Med 352 (2005), 2211–2221.
Glotzbecker, B, Duncan, C, Alyea, E 3rd, Campbell, B, Soiffer, R, Important drug interactions in hematopoietic stem cell transplantation: what every physician should know. Biol Blood Marrow Transplant 18 (2012), 989–1006.
Brüggemann, RJM, Alffenaar, J-WC, Blijlevens, NMA, et al. Clinical relevance of the pharmacokinetic interactions of azole antifungal drugs with other coadministered agents. Clin Infect Dis 48 (2009), 1441–1458.
Jones, W, Chastain, CA, Wright, PW, Iatrogenic Cushing Syndrome secondary to a probable interaction between voriconazole and budesonide. Pharmacotherapy 34 (2014), e116–e119.
Shayani, S, Palmer, J, Stiller, T, et al. Thrombotic microangiopathy associated with sirolimus level after allogeneic hematopoietic cell transplantation with tacrolimus/sirolimus-based graft-versus-host disease prophylaxis. Biol Blood Marrow Transplant 19 (2013), 298–304.
Wingard, JR, Hsu, J, Hiemenz, JW, Hematopoietic stem cell transplantation: an overview of infection risks and epidemiology. Infect Dis Clin North Am 24 (2010), 257–272.
Tomblyn, M, Chiller, T, Einsele, H, et al. Guidelines for preventing infectious complications among hematopoietic cell transplant recipients: a global perspective. Preface. Biol Bone Marrow Transplant 44 (2009), 453–455.
Cordonnier, C, Maury, S, Ribaud, P, et al. A grading system based on severity of infection to predict mortality in allogeneic stem cell transplant recipients. Transplantation 82 (2006), 86–92.
Young, JH, Logan, BR, Wu, J, et al. Infections after transplantation of bone marrow or peripheral blood stem cells from unrelated donors. Biol Blood Marrow Transplant 22 (2016), 359–370.
van Burik, JA, Carter, SL, Freifeld, AG, et al. Higher risk of cytomegalovirus and aspergillus infections in recipients of T cell-depleted unrelated bone marrow: analysis of infectious complications in patients treated with T cell depletion versus immunosuppressive therapy to prevent graft-versus-host disease. Biol Blood Marrow Transplant 13 (2007), 1487–1498.
Syrjala, KL, Kurland, BF, Abrams, JR, Sanders, JE, Heiman, JR, Sexual function changes during the 5 years after high-dose treatment and hematopoietic cell transplantation for malignancy, with case-matched controls at 5 years. Blood 111 (2008), 989–996.
Noerskov, KH, Schjødt, I, Syrjala, KL, Jarden, M, Sexual function 1-year after allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 51 (2016), 833–840.
Syrjala, KL, Langer, SL, Abrams, JR, Storer, BE, Martin, PJ, Late effects of hematopoietic cell transplantation among 10-year adult survivors compared with case-matched controls. J Clin Oncol 23 (2005), 6596–6606.
Li, Z, Mewawalla, P, Stratton, P, et al. Sexual health in hematopoietic stem cell transplant recipients. Cancer 121 (2015), 4124–4131.
Humphreys, CT, Tallman, B, Altmaier, EM, Barnette, V, Sexual functioning in patients undergoing bone marrow transplantation: a longitudinal study. Bone Marrow Transplant 39 (2007), 491–496.
Wong, FL, Francisco, L, Togawa, K, et al. Longitudinal trajectory of sexual functioning after hematopoietic cell transplantation: impact of chronic graft-versus-host disease and total body irradiation. Blood 122 (2013), 3973–3981.
Sanders, JE, Buckner, CD, Amos, D, et al. Ovarian function following marrow transplantation for aplastic anemia or leukemia. J Clin Oncol 6 (1988), 813–818.
Rovó A, Tichelli, A, Passweg, JR, et al. Spermatogenesis in long-term survivors after allogeneic hematopoietic stem cell transplantation is associated with age, time interval since transplantation, and apparently absence of chronic GvHD. Blood 108 (2006), 1100–1105.
Dyer, G, Gilroy, N, Bradford, J, et al. A survey of fertility and sexual health following allogeneic haematopoietic stem cell transplantation in New South Wales, Australia. Br J Haematol 172 (2016), 592–601.
Sanders, JE, Hawley, J, Levy, W, et al. Pregnancies following high-dose cyclophosphamide with or without high-dose busulfan or total-body irradiation and bone marrow transplantation. Blood 87 (1996), 3045–3052.
Salooja, N, Szydlo, RM, Socie, G, et al. Pregnancy outcomes after peripheral blood or bone marrow transplantation: a retrospective survey. Lancet 358 (2001), 271–276.
Dalle, JH, Lucchini, G, Balduzzi, A, et al. State-of-the-art fertility preservation in children and adolescents undergoing haematopoietic stem cell transplantation: a report on the expert meeting of the Paediatric Diseases Working Party (PDWP) of the European Society for Blood and Marrow Transplantation (EBMT) in Baden, Austria, 29-30 September 2015. Bone Marrow Transplant 52 (2017), 1029–1035.
Syrjala, KL, Artherholt, SB, Kurland, BF, et al. Prospective neurocognitive function over 5 years after allogeneic hematopoietic cell transplantation for cancer survivors compared with matched controls at 5 years. J Clin Oncol 29 (2011), 2397–2404.
Wingard, JR, Majhail, NS, Brazauskas, R, et al. Long-term survival and late deaths after allogeneic hematopoietic cell transplantation. J Clin Oncol 29 (2011), 2230–2239.
Miller, KD, Siegel, RL, Lin, CC, et al. Cancer treatment and survivorship statistics, 2016. CA Cancer J Clin 66 (2016), 271–289.
Henning, RJ, Harbison, RD, Cardio-oncology: cardiovascular complications of cancer therapy. Future Cardiol 13 (2017), 379–396.
Ng, AK, Travis, LB, Radiation therapy and breast cancer risk. J Natl Compr Canc Netw 7 (2009), 1121–1128.
Onajin, O, Brewer, JD, Skin cancer in patients with chronic lymphocytic leukemia and non-Hodgkin lymphoma. Clin Adv Hematol Oncol 10 (2012), 571–576.
Morton, LM, Swerdlow, AJ, Schaapveld, M, et al. Current knowledge and future research directions in treatment-related second primary malignancies. EJC Suppl 12 (2014), 5–17.
Travis, LB, Demark Wahnefried, W, Allan, JM, Wood, ME, Ng, AK, Aetiology, genetics and prevention of secondary neoplasms in adult cancer survivors. Nat Rev Clin Oncol 10 (2013), 289–301.
Ng, AK, Current survivorship recommendations for patients with Hodgkin lymphoma: focus on late effects. Blood 124 (2014), 3373–3379.
de Gonzalez, AB, Gilbert, E, Curtis, R, et al. Second solid cancers after radiotherapy: a systematic review of the epidemiological studies of the radiation dose-response relationship. Int J Radiat Oncol Biol Phys 86 (2013), 224–233.
Morton, LM, Curtis, RE, Linet, MS, et al. Second malignancy risks after non-Hodgkin's lymphoma and chronic lymphocytic leukemia: differences by lymphoma subtype. J Clin Oncol 28 (2010), 4935–4944.
Sampson, JN, Wheeler, WA, Yeager, M, et al. Analysis of heritability and shared heritability based on genome-wide association studies for thirteen cancer types. J Natl Cancer Inst, 107, 2015, djv279.
van Leeuwen, FE, Ng, AK, Long-term risk of second malignancy and cardiovascular disease after Hodgkin lymphoma treatment. Hematology (Am Soc Hematol Educ Program) 2016 (2016), 323–330.
Mulrooney, DA, Armstrong, GT, Huang, S, et al. Cardiac outcomes in adult survivors of childhood cancer exposed to cardiotoxic therapy: a cross-sectional study. Ann Intern Med 164 (2016), 93–101.
Zebrack, BJ, Zeltzer, LK, Whitton, J, et al. Psychological outcomes in long-term survivors of childhood leukemia, Hodgkin's disease, and non-Hodgkin's lymphoma: a report from the Childhood Cancer Survivor Study. Pediatrics 110 (2002), 42–52.
Guy, GP Jr, Ekwueme, DU, Yabroff, KR, et al. Economic burden of cancer survivorship among adults in the United States. J Clin Oncol 31 (2013), 3749–3757.
Zafar, SY, McNeil, RB, Thomas, CM, Lathan, CS, Ayanian, JZ, Provenzale, D, Population-based assessment of cancer survivors' financial burden and quality of life: a prospective cohort study. J Oncol Pract 11 (2015), 145–150.
Khimani, N, Chen, YH, Mauch, PM, et al. Influence of new late effects on quality of life over time in Hodgkin lymphoma survivors: a longitudinal survey study. Ann Oncol 24 (2013), 226–230.
Armstrong, GT, Chen, Y, Yasui, Y, et al. Reduction in late mortality among 5-year survivors of childhood cancer. N Engl J Med 374 (2016), 833–842.
Birken, SA, Deal, AM, Mayer, DK, Weiner, BJ, Following through: the consistency of survivorship care plan use in United States cancer programs. J Cancer Educ 29 (2014), 689–697.
Brennan, ME, Gormally, JF, Butow, P, Boyle, FM, Spillane, AJ, Survivorship care plans in cancer: a systematic review of care plan outcomes. Br J Cancer 111 (2014), 1899–1908.
Mayer, DK, Taylor, K, Gerstel, A, Coghill, A, Birken, SA, Implementing survivorship care plans within an electronic health record. Oncology 29 (2015), 980–982.
Parker, PA, Banerjee, SC, Matasar, MJ, et al. Protocol for a cluster randomised trial of a communication skills intervention for physicians to facilitate survivorship transition in patients with lymphoma. BMJ Open, 6, 2016, e011581.
US Food and Drug Administration Code of Federal Regulations (CFR Title 21). Updated April 1, 2017. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=312.32. (Accessed 3 May 2018)
US Government Publishing Office. Investigational new drug safety reporting requirements for human drug and biological products and safety reporting requirements for bioavailability and bioequivalence studies in humans. https://www.gpo.gov/fdsys/pkg/FR-2010-09-29/pdf/2010-24296.pdf. (Accessed 7 May 2018)
European Commission. Communication from the Commission. Detailed guidance on the collection, verification and presentation of adverse event/reaction reports arising from clinical trials on medicinal products for human use (‘CT-3’). https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-10/2011_c172_01/2011_c172_01_en.pdf, 2011. (Accessed 27 March 2018)
Jarow, JP, Casak, S, Chuk, M, Ehrlich, LA, Khozin, S, The majority of expedited investigational new drug safety reports are uninformative. Clin Cancer Res 22 (2016), 2111–2113.
Golder, S, Loke, YK, Wright, K, Norman, G, Reporting of adverse events in published and unpublished studies of health care interventions: a systematic review. PLoS Med, 13, 2016, e1002127.
Sivendran, S, Latif, A, McBride, RB, et al. Adverse event reporting in cancer clinical trial publications. J Clin Oncol 32 (2014), 83–89.
Atkinson, TM, Li, Y, Coffey, CW, et al. Reliability of adverse symptom event reporting by clinicians. Qual Life Res 21 (2012), 1159–1164.
Di Maio, M, Basch, E, Bryce, J, Perrone, F, Patient-reported outcomes in the evaluation of toxicity of anticancer treatments. Nat Rev Clin Oncol 13 (2016), 319–325.
Sivendran, S, Galsky, MD, Adverse event reporting in oncology clinical trials—lost in translation?. Expert Opin Drug Saf 15 (2016), 893–896.
Beaver, JA, Ison, G, Pazdur, R, Reevaluating eligibility criteria—balancing patient protection and participation in oncology trials. N Engl J Med 376 (2017), 1504–1505.
Johnson, JR, Ning, YM, Farrell, A, Justice, R, Keegan, P, Pazdur, R, Accelerated approval of oncology products: the food and drug administration experience. J Natl Cancer Inst 103 (2011), 636–644.
Martinalbo, J, Bowen, D, Camarero, J, et al. Early market access of cancer drugs in the EU. Ann Oncol 27 (2016), 96–105.
US Government Publishing Office. Amendments Act of 2007 (FDAAA), Section 901. Federal Food, Drug and Cosmetic (FD&C) Act, Section 505(o)(3). https://www.gpo.gov/fdsys/pkg/PLAW-110publ85/pdf/PLAW-110publ85.pdf. (Accessed 7 May 2018)
Santoro, A, Genov, G, Spooner, A, Raine, J, Arlett, P, Promoting and protecting public health: how the European Union pharmacovigilance system works. Drug Saf 40 (2017), 855–869.
Tsimberidou, AM, Health policy: strategies to optimize expedited investigational new drug safety reports. Nat Rev Clin Oncol 13 (2016), 207–208.
Vose, JM, Levit, LA, Hurley, P, et al. Addressing administrative and regulatory burden in cancer clinical trials: summary of a stakeholder survey and workshop hosted by the American Society of Clinical Oncology and the Association of American Cancer Institutes. J Clin Oncol 34 (2016), 3796–3802.
Levit, LA, Perez, RP, Smith, DC, Schilsky, RL, Hayes, DF, Vose, JM, Streamlining adverse events reporting in oncology: an American Society of Clinical Oncology research statement. J Clin Oncol 36 (2018), 617–623.
Khozin, S, Chuk, M, Kim, T, et al. Regulatory watch: Evaluating the potential for digital submission of expedited premarket safety reports to the FDA. Nat Rev Drug Discov 15 (2016), 670–671.
US Congress. 21st Century Cures Act. https://www.congress.gov/bill/114th-congress/house-bill/34/. (Accessed 7 May 2018)
EMA. EMA Appendix 2 to the guideline on the evaluation of anticancer medicinal products in man. http://www.ema.europa.eu/docs/en_GB/document_library/Other/2016/04/WC500205159.pdf. (Accessed 3 May 2018)
US FDA. Product label for crizotinib. https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/202570s000lbl.pdf, 2017. (Accessed 3 May 2018)
US FDA. Patient liaison program. https://www.fda.gov/ForPatients/About/ucm550035.htm. (Accessed 27 March 2018)
US FDA. US Food and Drug Administration Professional Affairs and Stakeholder Engagement. https://www.fda.gov/aboutfda/centersoffices/officeofmedicalproductsandtobacco/cder/ucm385522.htm). (Accessed 27 March 2018)
Abernathy, A, Perlmutter, J, Melemed, A, Koehler, M, Khozin, S, Case studies: data collection and application of RWE. Friends of Cancer Research Blueprint for Breakthrough Forum. https://www.focr.org/sites/default/files/pdf/Blueprint2016%20-%20Panel1.pdf, June 16, 2016. (Accessed 3 May 2018)
Mitchell, AP, Harrison, MR, George, DJ, Abernethy, AP, Walker, MS, Hirsch, BR, Clinical trial subjects compared to “real world” patients: generalizability of renal cell carcinoma trials. Proc Am Soc Clin Oncol, 32(15 suppl), 2014 abstract 6510.
US FDA. FDA's Sentinel Initiative. https://www.fda.gov/Safety/FDAsSentinelInitiative/ucm2007250.htm. (Accessed 7 May 2018)
US FDA. FDA's Sentinel Initiative. Deliverables from completed contracts. https://www.fda.gov/Safety/FDAsSentinelInitiative/ucm149343.htm. (Accessed 7 May 2018)
EMA. Guideline on good pharmacovigilance practices (GVP): module VI. http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2017/08/WC500232767.pdf. (Accessed 27 March 2018)
EMA. Innovative medicines initiative WEB-RADR workshop report: mobile technologies and social media as new tools in pharmacovigilance. http://www.ema.europa.eu/docs/en_GB/document_library/Report/2017/02/WC500221615.pdf, Feb 9, 2017. (Accessed 3 May 2018)
Shah, A, Stewart, AK, Kolacevski, A, Michels, D, Miller, R, Building a rapid learning health care system for oncology: why CancerLinQ collects identifiable health information to achieve its vision. J Clin Oncol 34 (2016), 756–763.
Khozin, S, Kim, G, Pazdur, R, Regulatory watch. From big data to smart data: FDA's INFORMED initiative. Nat Rev Drug Discov, 16, 2017, 306.
Sutter, S, Pink Sheet. FDA oncology office looks to get better INFORMED through big data. https://www.focr.org/news/pink-sheet-fda-oncology-office-looks-get-better-informed-through-big-data, 2016. (Accessed 27 March 2018)
Khozin, S, Pazdur, R, Shah, A, INFORMED: an incubator at the US FDA for driving innovations in data science and agile technology. Nat Rev Drug Discov, 2018 published online April 6. DOI:10.1038/nrd.2018.34.
Ford, I, Norrie, J, Pragmatic Trials. N Engl J Med 375 (2016), 454–463.
Schwartz, D, Lellouch, J, Explanatory and pragmatic attitudes in therapeutical trials. J Chronic Dis 20 (1967), 637–648.
Zuidgeest, MGP, Goetz, I, Groenwold, RHH, et al. Series: Pragmatic trials and real world evidence: paper 1. Introduction. J Clin Epidemiol 88 (2017), 7–13.
Sherman, RE, Anderson, SA, Dal Pan, GJ, et al. Real-world evidence—what is it and what can it tell us?. N Engl J Med 375 (2016), 2293–2297.
Jarow, JP, LaVange, L, Woodcock, J, Multidimensional evidence generation and fda regulatory decision making: defining and using “real-world” data. JAMA 318 (2017), 703–704.
Hazell, L, Shakir, SA, Under-reporting of adverse drug reactions: a systematic review. Drug Saf 29 (2006), 385–396.
Atkinson, TM, Ryan, SJ, Bennett, AV, et al. The association between clinician-based common terminology criteria for adverse events (CTCAE) and patient-reported outcomes (PRO): a systematic review. Support Care Cancer 24 (2016), 3669–3676.
Link, BK, Maurer, MJ, Nowakowski, GS, et al. Rates and outcomes of follicular lymphoma transformation in the immunochemotherapy era: a report from the University of Iowa/MayoClinic Specialized Program of Research Excellence Molecular Epidemiology Resource. J Clin Oncol 31 (2013), 3272–3278.
Gang, AO, Strøm, C, Pedersen, M, et al. R-CHOEP-14 improves overall survival in young high-risk patients with diffuse large B-cell lymphoma compared with R-CHOP-14. A population-based investigation from the Danish Lymphoma Group. Ann Oncol 23 (2012), 147–153.
Sehn, LH, Donaldson, J, Chhanabhai, M, et al. Introduction of combined CHOP plus rituximab therapy dramatically improved outcome of diffuse large B-cell lymphoma in British Columbia. J Clin Oncol 23 (2005), 5027–5033.
Thompson, CA, Ghesquieres, H, Maurer, MJ, et al. Utility of routine post-therapy surveillance imaging in diffuse large B-cell lymphoma. J Clin Oncol 32 (2014), 3506–3512.
Arboe, B, El-Galaly, TC, Clausen, MR, et al. The Danish national lymphoma registry: coverage and data quality. PLoS One, 11, 2016, e0157999.
Gimsing, P, Holmström, MO, Klausen, TW, et al. The Danish national multiple myeloma registry. Clin Epidemiol 8 (2016), 583–587.
Østgård, LS, Nørgaard, JM, Raaschou-Jensen, KK, et al. The Danish national acute leukemia registry. Clin Epidemiol 8 (2016), 553–560.
Abrahamsson, A, Dahle, N, Jerkeman, M, Marked improvement of overall survival in mantle cell lymphoma: a population based study from the Swedish Lymphoma Registry. Leuk Lymphoma 52 (2011), 1929–1935.
Murbraech, K, Smeland, KB, Holte, H, et al. Heart failure and asymptomatic left ventricular systolic dysfunction in lymphoma survivors treated with autologous stem-cell transplantation: a national cross-sectional study. J Clin Oncol 33 (2015), 2683–2691.
Glimelius, I, Eloranta, S, Ekberg, S, Chang, ET, Neovius, M, Smedby, KE, Increased healthcare use up to 10 years among relapse-free Hodgkin lymphoma survivors in the era of intensified chemotherapy and limited radiotherapy. Am J Hematol 92 (2017), 251–258.
Pachman, DR, Barton, DL, Swetz, KM, Loprinzi, CL, Troublesome symptoms in cancer survivors: fatigue, insomnia, neuropathy, and pain. J Clin Oncol 30 (2012), 3687–3696.
Meropol, NJ, Egleston, BL, Buzaglo, JS, et al. Cancer patient preferences for quality and length of life. Cancer 113 (2008), 3459–3466.
Murthy, VH, Krumholz, HM, Gross, CP, Participation in cancer clinical trials: race-, sex-, and age-based disparities. JAMA 291 (2004), 2720–2726.
Jin, S, Pazdur, R, Sridhara, R, Re-evaluating eligibility criteria for oncology clinical trials: analysis of investigational new drug applications in 2015. J Clin Oncol 35 (2017), 3745–3752.
Østgård, LS, Nørgaard, M, Sengeløv, H, et al. Improved outcome in acute myeloid leukemia patients enrolled in clinical trials: A national population-based cohort study of Danish intensive chemotherapy patients. Oncotarget 7 (2016), 72044–72056.
Unger, JM, Barlow, WE, Martin, DP, et al. Comparison of survival outcomes among cancer patients treated in and out of clinical trials. J Natl Cancer Inst, 106, 2014, dju002.
Templeton, AJ, Vera-Badillo, FE, Wang, L, et al. Translating clinical trials to clinical practice: outcomes of men with metastatic castration resistant prostate cancer treated with docetaxel and prednisone in and out of clinical trials. Ann Oncol 24 (2013), 2972–2977.
Lesokhin, AM, Ansell, SM, Armand, P, et al. Nivolumab in patients with relapsed or refractory hematologic malignancy: preliminary results of a phase 1b study. J Clin Oncol 34 (2016), 2698–2704.
Herbaux, C, Gauthier, J, Brice, P, et al. Efficacy and tolerability of nivolumab after allogeneic transplantation for relapsed Hodgkin lymphoma. Blood 129 (2017), 2471–2478.
Chen, J, Long, JB, Hurria, A, Owusu, C, Steingart, RM, Gross, CP, Incidence of heart failure or cardiomyopathy after adjuvant trastuzumab therapy for breast cancer. J Am Coll Cardiol 60 (2012), 2504–2512.
Schilsky, RL, Finding the evidence in real-world evidence: moving from data to information to knowledge. J Am Coll Surg 224 (2017), 1–7.
Miller, RS, Wong, JL, Using oncology real-world evidence for quality improvement and discovery: the case for ASCO's CancerLinQ. Future Oncol 14 (2018), 5–8.
Wong, YN, Egleston, BL, Sachdeva, K, et al. Cancer patients' trade-offs among efficacy, toxicity, and out-of-pocket cost in the curative and noncurative setting. Med Care 51 (2013), 838–845.
Weeks, JC, Catalano, PJ, Cronin, A, et al. Patients' expectations about effects of chemotherapy for advanced cancer. N Engl J Med 367 (2012), 1616–1625.
Rotenstein, LS, Huckman, RS, Wagle, NW, Making patients and doctors happier—the potential of patient-reported outcomes. N Engl J Med 377 (2017), 1309–1312.