Updates on Hematologic Malignancies in the Older Adult: Focus on Acute Myeloid Leukemia, Chronic Lymphocytic Leukemia, and Multiple Myeloma
Purpose of Review
Hematologic malignancies are common and difficult to treat in older adults. In this review, we focus on recent updates in diseases with several novel agents relevant to older adults—acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), and multiple myeloma (MM).
In AML, CPX-351 offers a new induction chemotherapy for secondary AML that prolongs survival, and venetoclax and IDH inhibitors are efficacious and well tolerated. In CLL, chemoimmunotherapy is being replaced by monoclonal antibodies and small molecule inhibitors that are more effective and better tolerated. In MM, new immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies have expanded treatment options for older patients.
The introduction of novel agents has dramatically shifted the landscape of therapeutic options for older adults with hematologic malignancies. Clinical trials in older adults are needed to expand treatment options for these patients.
KeywordsOlder adults Geriatric oncology Acute myeloid leukemia Chronic lymphocytic leukemia Multiple myeloma Novel agents
Compliance with Ethical Standards
Conflict of Interest
Sandy W. Wong has received research funding from Janssen, Celgene, and Roche.
Charalambos Andreadis has received research funding from Celgene, GlaxoSmithKline, Novartis, Amgen, and Pharmacyclics; has received compensation from Amgen for service as a consultant and from Celgene, Gilead, Pharmacyclics, and Genentech for service on advisory boards. His spouse is also an employee of Genentech.
Rebecca L. Olin has received research funding (salary support, principal investigator) from Astellas, Daiichi Sankyo, Pfizer, and Genentech, and has received compensation from Jazz Pharmaceuticals and Genentech for service as a consultant.
Li-Wen Huang declares that she has no conflict of interest. She is supported by the National Institute on Aging (T32AG000212).
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 1.Fowler NH, Morschhauser F, Feugier P, Bouabdallah R, Tilly H, Palomba ML, et al. RELEVANCE: Phase III randomized study of lenalidomide plus rituximab (R2) versus chemotherapy plus rituximab, followed by rituximab maintenance, in patients with previously untreated follicular lymphoma. J Clin Oncol. 2018;36(15_suppl):7500. https://doi.org/10.1200/JCO.2018.36.15_suppl.7500.CrossRefGoogle Scholar
- 2.Thieblemont C, Tilly H, Gomes da Silva M, Casasnovas RO, Fruchart C, Morschhauser F, et al. Lenalidomide maintenance compared with placebo in responding elderly patients with diffuse large B-cell lymphoma treated with first-line rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. J Clin Oncol : official journal of the American Society of Clinical Oncology. 2017;35(22):2473–81. https://doi.org/10.1200/jco.2017.72.6984.CrossRefGoogle Scholar
- 3.Platzbecker U, Germing U, Gotze KS, Kiewe P, Mayer K, Chromik J, et al. Luspatercept for the treatment of anaemia in patients with lower-risk myelodysplastic syndromes (PACE-MDS): a multicentre, open-label phase 2 dose-finding study with long-term extension study. Lancet Oncol. 2017;18(10):1338–47. https://doi.org/10.1016/s1470-2045(17)30615-0.CrossRefPubMedGoogle Scholar
- 5.Wildiers H, Heeren P, Puts M, Topinkova E, Janssen-Heijnen ML, Extermann M, et al. International Society of Geriatric Oncology consensus on geriatric assessment in older patients with cancer. J Clin Oncol : official journal of the American Society of Clinical Oncology. 2014;32(24):2595–603. https://doi.org/10.1200/jco.2013.54.8347.CrossRefGoogle Scholar
- 6.Hurria A, Togawa K, Mohile SG, Owusu C, Klepin HD, Gross CP, et al. Predicting chemotherapy toxicity in older adults with cancer: a prospective multicenter study. J Clini Oncol : official journal of the American Society of Clinical Oncology. 2011;29(25):3457–65. https://doi.org/10.1200/jco.2011.34.7625.CrossRefGoogle Scholar
- 7.Extermann M, Boler I, Reich RR, Lyman GH, Brown RH, De Felice J, et al. Predicting the risk of chemotherapy toxicity in older patients: the Chemotherapy Risk Assessment Scale for High-Age Patients (CRASH) score. Cancer. 2012;118(13):3377–86. https://doi.org/10.1002/cncr.26646.CrossRefPubMedGoogle Scholar
- 9.Cohen HJ, Smith D, Sun CL, Tew W, Mohile SG, Owusu C, et al. Frailty as determined by a comprehensive geriatric assessment-derived deficit-accumulation index in older patients with cancer who receive chemotherapy. Cancer. 2016;122(24):3865–72. https://doi.org/10.1002/cncr.30269. CrossRefPubMedPubMedCentralGoogle Scholar
- 10.Noone AM, Howlader N, Krapcho M, Miller D, Brest A, Yu M et al. SEER Cancer Statistics Review, 1975–2015, National Cancer Institute. Bethesda, MD. https://seer.cancer.gov/csr/1975_2015/. Accessed 3 Oct 2018.
- 12.Medeiros BC, Satram-Hoang S, Hurst D, Hoang KQ, Momin F, Reyes C. Big data analysis of treatment patterns and outcomes among elderly acute myeloid leukemia patients in the United States. Ann Hematol. 2015;94(7):1127–38. https://doi.org/10.1007/s00277-015-2351-x.CrossRefPubMedPubMedCentralGoogle Scholar
- 13.Krug U, Rollig C, Koschmieder A, Heinecke A, Sauerland MC, Schaich M, et al. Complete remission and early death after intensive chemotherapy in patients aged 60 years or older with acute myeloid leukaemia: a web-based application for prediction of outcomes. Lancet (London, England). 2010;376(9757):2000–8. https://doi.org/10.1016/s0140-6736(10)62105-8.CrossRefGoogle Scholar
- 14.Walter RB, Othus M, Borthakur G, Ravandi F, Cortes JE, Pierce SA, et al. Prediction of early death after induction therapy for newly diagnosed acute myeloid leukemia with pretreatment risk scores: a novel paradigm for treatment assignment. J Clin Oncol : official journal of the American Society of Clinical Oncology. 2011;29(33):4417–23. https://doi.org/10.1200/jco.2011.35.7525.CrossRefGoogle Scholar
- 15.Klepin HD, Geiger AM, Tooze JA, Kritchevsky SB, Williamson JD, Ellis LR, et al. The feasibility of inpatient geriatric assessment for older adults receiving induction chemotherapy for acute myelogenous leukemia. J Am Geriatr Soc. 2011;59(10):1837–46. https://doi.org/10.1111/j.1532-5415.2011.03614.x.CrossRefPubMedPubMedCentralGoogle Scholar
- 16.Klepin HD, Geiger AM, Tooze JA, Kritchevsky SB, Williamson JD, Pardee TS, et al. Geriatric assessment predicts survival for older adults receiving induction chemotherapy for acute myelogenous leukemia. Blood. 2013;121(21):4287–94. https://doi.org/10.1182/blood-2012-12-471680.CrossRefPubMedPubMedCentralGoogle Scholar
- 17.Lowenberg B, Zittoun R, Kerkhofs H, Jehn U, Abels J, Debusscher L, et al. On the value of intensive remission-induction chemotherapy in elderly patients of 65+ years with acute myeloid leukemia: a randomized phase III study of the European Organization for Research and Treatment of Cancer Leukemia Group. J Clin Oncol : official journal of the American Society of Clinical Oncology. 1989;7(9):1268–74. https://doi.org/10.1200/jco.19126.96.36.1998.CrossRefGoogle Scholar
- 18.Tilly H, Castaigne S, Bordessoule D, Casassus P, Le Prise PY, Tertian G, et al. Low-dose cytarabine versus intensive chemotherapy in the treatment of acute nonlymphocytic leukemia in the elderly. J Clin Oncol : official journal of the American Society of Clinical Oncology. 1990;8(2):272–9. https://doi.org/10.1200/jco.19188.8.131.522.CrossRefGoogle Scholar
- 19.Foran JM, Sun Z, Claxton DF, Lazarus HM, Thomas ML, Melnick A, et al. North American Leukemia, Intergroup phase III randomized trial of single agent clofarabine as induction and post-remission therapy, and decitabine as maintenance therapy in newly-diagnosed acute myeloid leukemia in older adults (age ≥60 years): a trial of the ECOG-ACRIN Cancer Research Group (E2906). Blood. 2015;126(23):217.Google Scholar
- 20.Dombret H, Seymour JF, Butrym A, Wierzbowska A, Selleslag D, Jang JH, et al. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood. 2015;126(3):291–9. https://doi.org/10.1182/blood-2015-01-621664.CrossRefPubMedPubMedCentralGoogle Scholar
- 21.Juliusson G, Antunovic P, Derolf A, Lehmann S, Mollgard L, Stockelberg D, et al. Age and acute myeloid leukemia: real world data on decision to treat and outcomes from the Swedish Acute Leukemia Registry. Blood. 2009;113(18):4179–87. https://doi.org/10.1182/blood-2008-07-172007.CrossRefPubMedGoogle Scholar
- 22.Lancet JE, Cortes JE, Hogge DE, Tallman MS, Kovacsovics TJ, Damon LE, et al. Phase 2 trial of CPX-351, a fixed 5:1 molar ratio of cytarabine/daunorubicin, vs cytarabine/daunorubicin in older adults with untreated AML. Blood. 2014;123(21):3239–46. https://doi.org/10.1182/blood-2013-12-540971.CrossRefPubMedPubMedCentralGoogle Scholar
- 23.•• Lancet JE, Uy GL, Cortes JE, Newell LF, Lin TL, Ritchie EK, et al. CPX-351 (cytarabine and daunorubicin) liposome for injection versus conventional cytarabine plus daunorubicin in older patients with newly diagnosed secondary acute myeloid leukemia. J Clin Oncol : official journal of the American Society of Clinical Oncology. 2018;36(26):2684–92. https://doi.org/10.1200/jco.2017.77.6112. This study is one of the few in the past four decades to show a survival benefit vs. 7+3. The trial is particularly relevant to geriatric oncology given the target population of patients with secondary AML, which is more prevalent in older adults and associated with poor outcomes. In a randomized phase 3 trial of 309 patients with secondary AML aged 60–75 years, CPX-351 (Vyxeos) compared to 7+3 improved ORR and OS with similar safety profiles. CrossRefGoogle Scholar
- 24.McClune BL, Weisdorf DJ, Pedersen TL. Tunes da Silva G, Tallman MS, Sierra J et al. Effect of age on outcome of reduced-intensity hematopoietic cell transplantation for older patients with acute myeloid leukemia in first complete remission or with myelodysplastic syndrome. J Clin Oncol : official journal of the American Society of Clinical Oncology. 2010;28(11):1878–87. https://doi.org/10.1200/jco.2009.25.4821.CrossRefGoogle Scholar
- 25.Devine SM, Owzar K, Blum W, Mulkey F, Stone RM, Hsu JW, et al. Phase II study of allogeneic transplantation for older patients with acute myeloid leukemia in first complete remission using a reduced-intensity conditioning regimen: results from Cancer and Leukemia Group B 100103 (Alliance for Clinical Trials in Oncology)/Blood and Marrow Transplant Clinical Trial Network 0502. J Clin Oncol : official journal of the American Society of Clinical Oncology. 2015;33(35):4167–75. https://doi.org/10.1200/jco.2015.62.7273.CrossRefGoogle Scholar
- 26.Niederwieser D, Al-Ali HK, Krahl R, Kahl C, Wolf H-H, Kreibich U, et al. Higher leukemia free survival after post-induction hematopoietic cell transplantation compared to consolidation therapy in patients >60 years with acute myelogenous leukemia (aml): report from the AML 2004 East German Study Group (OSHO). Blood. 2014;124(21):280.Google Scholar
- 27.Fenaux P, Mufti GJ, Hellstrom-Lindberg E, Santini V, Gattermann N, Germing U, et al. Azacitidine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloid leukemia. J Clin Oncol : official journal of the American Society of Clinical Oncology. 2010;28(4):562–9. https://doi.org/10.1200/jco.2009.23.8329.CrossRefGoogle Scholar
- 28.Kantarjian HM, Thomas XG, Dmoszynska A, Wierzbowska A, Mazur G, Mayer J, et al. Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia. J Clin Oncol : official journal of the American Society of Clinical Oncology. 2012;30(21):2670–7. https://doi.org/10.1200/jco.2011.38.9429.CrossRefGoogle Scholar
- 29.•• Pollyea DA, Pratz KW, Jonas BA, Letai A, Pullarkat VA, Wei A, et al. Venetoclax in Combination with Hypomethylating Agents Induces Rapid, Deep, and Durable Responses in Patients with AML Ineligible for Intensive Therapy. Blood. 2018;132(Suppl 1):285. In this phase 1b dose expansion cohort (venetoclax 400 mg daily) of older patients with untreated AML ineligible for intensive therapy, 84 patients were treated with venetoclax+azacitidine (median age 75, range 61–90) and 31 with venetoclax+decitabine (median age 72, range 65–86). For ven+aza and ven+dec, CR/CRi was 70 and 74%, median time to response was 1.2 and 1.9 months, and median OS was 14.9 and 16.2 months, respectively. These results are impressive compared to historical results for HMA monotherapy with ORR ranging 17.8–28% and OS ranging 7.7–10.4 months (Dombret et al. Blood 2015; Kantarjian et al. J Clin Oncol 2012). In addition, venetoclax+HMA produced deep responses, with 45% of patients with CR/CRi achieving MRD negativity. In certain subsets of patients, the response seems comparable to historical response to intensive therapy, raising the question of whether certain fit patients may also benefit more from lower intensity therapy. Google Scholar
- 30.DiNardo CD, Pratz KW, Letai A, Jonas BA, Wei AH, Thirman M, et al. Safety and preliminary efficacy of venetoclax with decitabine or azacitidine in elderly patients with previously untreated acute myeloid leukaemia: a non-randomised, open-label, phase 1b study. Lancet Oncol. 2018;19(2):216–28. https://doi.org/10.1016/s1470-2045(18)30010-x.CrossRefPubMedGoogle Scholar
- 31.Dinardo CD, Pratz KW, Potluri J, Pullarkat VA, Jonas BA, Wei AH, et al. Durable response with venetoclax in combination with decitabine or azacitadine in elderly patients with acute myeloid leukemia (AML). J Clin Oncol. 2018;36(15_suppl):7010. https://doi.org/10.1200/JCO.2018.36.15_suppl.7010.CrossRefGoogle Scholar
- 32.• Wei A, Strickland SA, Hou J-Z, Fiedler W, Lin TL, Walter RB, et al. Venetoclax with Low-Dose Cytarabine Induces Rapid, Deep, and Durable Responses in Previously Untreated Older Adults with AML Ineligible for Intensive Chemotherapy. Blood. 2018;132(Suppl 1):284. In this phase 1b/2 study of 82 elderly patients aged ≥ 65 with untreated AML, venetoclax + low-dose cytarabine achieved CR/CRi in 54% and CR/CRh in 46% of patients, median time to response of 1.4 months, and median OS of 10 months. These results show that venetoclax combined with low-dose cytarabine is also an effective treatment option for AML patients who are unsuitable for intensive induction therapy. Google Scholar
- 33.Wei A, Strickland SA, Roboz GJ, Hou J-Z, Fiedler W, Lin TL, et al. Phase 1/2 study of venetoclax with low-dose cytarabine in treatment-naive, elderly patients with acute myeloid leukemia unfit for intensive chemotherapy: 1-year outcomes. Blood. 2017;130(Suppl 1):890.Google Scholar
- 34.Cortes JE, Heidel FH, Hellmann A, Fiedler W, Smith BD, Robak T et al. Randomized comparison of low dose cytarabine with or without glasdegib in patients with newly diagnosed acute myeloid leukemia or high-risk myelodysplastic syndrome. Leukemia. 2018. https://doi.org/10.1038/s41375-018-0312-9.
- 35.Roboz GJ, Rosenblat T, Arellano M, Gobbi M, Altman JK, Montesinos P, et al. International randomized phase III study of elacytarabine versus investigator choice in patients with relapsed/refractory acute myeloid leukemia. J Clin Oncol : official journal of the American Society of Clinical Oncology. 2014;32(18):1919–26. https://doi.org/10.1200/jco.2013.52.8562.CrossRefGoogle Scholar
- 37.•• Stein EM, Di Nardo CD, Pollyea DA, Fathi AT, Roboz GJ, Altman JK, et al. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood. 2017;130(6):722–31. https://doi.org/10.1182/blood-2017-04-779405. This first-in-human phase 1/2 study of enasidenib in a primarily older population (median age 70) of patients with relapsed/refractory IDH2-mutated AML showed a promising median OS of 9.3 months (including median OS of 19.7 months in patients who achieved CR), compared to median OS of only 3.3 months with conventional salvage regimens (Roboz et al. J Clin Oncol 2014). The results were promising enough for enasidenib to be FDA-approved, and the phase 3 trial IDHENTIFY of enasidenib versus conventional care regimens for relapsed/refractory IDH2-mutated AML is ongoing (NCT02577406). CrossRefPubMedPubMedCentralGoogle Scholar
- 38.•• Di Nardo CD, Stein EM, de Botton S, Roboz GJ, Altman JK, Mims AS, et al. Durable remissions with ivosidenib in IDH1-mutated relapsed or refractory AML. N Engl J Med. 2018;378(25):2386–98. https://doi.org/10.1056/NEJMoa1716984. This phase 1 study of ivosidenib in a primarily older population (median age 68) of patients with relapsed/refractory IDH1-mutated AML showed a promising median OS of 8.8 months. In addition, 21% of patients with CR/CRi had molecular remission, which was associated with longer OS (14.5 months). Ivosidenib is FDA-approved, and the phase 3 trial AGILE of ivosidenib+azacitidine versus azacitidine alone for untreated IDH1-mutated AML is ongoing (NCT03173248). CrossRefGoogle Scholar
- 39.Stein EM, Shoben A, Borate U, Baer MR, Stock W, Patel PA, et al. Enasidenib is highly active in previously untreated IDH2 mutant AML: early results from the beat AML master trial. Blood. 2018;132(Suppl 1):287.Google Scholar
- 40.Roboz GJ, DiNardo CD, Stein EM, de Botton S, Mims AS, Prince GT, et al. Ivosidenib (AG-120) induced durable remissions and transfusion independence in patients with IDH1-mutant untreated AML: results from a phase 1 dose escalation and expansion study. Blood. 2018;132(Suppl 1):561.Google Scholar
- 41.Beat AML Master Trial. https://www.lls.org/beat-aml/beat-aml-for-healthcare-professionals. Accessed October 1, 2018.
- 43.Goede V, Bahlo J, Chataline V, Eichhorst B, Durig J, Stilgenbauer S, et al. Evaluation of geriatric assessment in patients with chronic lymphocytic leukemia: results of the CLL9 trial of the German CLL study group. Leuk Lymphoma. 2016;57(4):789–96. https://doi.org/10.3109/10428194.2015.1091933.CrossRefPubMedGoogle Scholar
- 44.Stauder R, Eichhorst B, Hamaker ME, Kaplanov K, Morrison VA, Osterborg A, et al. Management of chronic lymphocytic leukemia (CLL) in the elderly: a position paper from an international Society of Geriatric Oncology (SIOG) Task Force. Ann Oncol : official journal of the European Society for Medical Oncology. 2017;28(2):218–27. https://doi.org/10.1093/annonc/mdw547.CrossRefGoogle Scholar
- 45.Tam CS, O'Brien S, Wierda W, Kantarjian H, Wen S, Do KA, et al. Long-term results of the fludarabine, cyclophosphamide, and rituximab regimen as initial therapy of chronic lymphocytic leukemia. Blood. 2008;112(4):975–80. https://doi.org/10.1182/blood-2008-02-140582.CrossRefPubMedPubMedCentralGoogle Scholar
- 46.Hallek M, Fischer K, Fingerle-Rowson G, Fink AM, Busch R, Mayer J, et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet (London, England). 2010;376(9747):1164–74. https://doi.org/10.1016/s0140-6736(10)61381-5.CrossRefGoogle Scholar
- 47.Thompson PA, Tam CS, O'Brien SM, Wierda WG, Stingo F, Plunkett W, et al. Fludarabine, cyclophosphamide, and rituximab treatment achieves long-term disease-free survival in IGHV-mutated chronic lymphocytic leukemia. Blood. 2016;127(3):303–9. https://doi.org/10.1182/blood-2015-09-667675.CrossRefPubMedPubMedCentralGoogle Scholar
- 48.Eichhorst BF, Busch R, Stilgenbauer S, Stauch M, Bergmann MA, Ritgen M, et al. First-line therapy with fludarabine compared with chlorambucil does not result in a major benefit for elderly patients with advanced chronic lymphocytic leukemia. Blood. 2009;114(16):3382–91. https://doi.org/10.1182/blood-2009-02-206185.CrossRefPubMedGoogle Scholar
- 49.• Eichhorst B, Fink AM, Bahlo J, Busch R, Kovacs G, Maurer C, et al. First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): an international, open-label, randomised, phase 3, non-inferiority trial. Lancet Oncol. 2016;17(7):928–42. https://doi.org/10.1016/s1470-2045(16)30051-1. This phase 3 trial in treatment-naïve CLL patients showed FCR was not better than BR in older adults aged > 65 years in terms of PFS or OS, and more adverse events occurred in the FCR group. Thus, FCR is not recommended for older adults or those with significant comorbidities. CrossRefPubMedPubMedCentralGoogle Scholar
- 51.Leblond V, Aktan M, Ferra Coll CM, Dartigeas C, Kisro J, Montillo M, et al. Safety of obinutuzumab alone or combined with chemotherapy for previously untreated or relapsed/refractory chronic lymphocytic leukemia in the Phase 3b GREEN study. Haematologica. 2018;103(11):1889–98. https://doi.org/10.3324/haematol.2017.186387.CrossRefPubMedPubMedCentralGoogle Scholar
- 52.Hillmen P, Robak T, Janssens A, Babu KG, Kloczko J, Grosicki S, et al. Chlorambucil plus ofatumumab versus chlorambucil alone in previously untreated patients with chronic lymphocytic leukaemia (COMPLEMENT 1): a randomised, multicentre, open-label phase 3 trial. Lancet (London, England). 2015;385(9980):1873–83. https://doi.org/10.1016/s0140-6736(15)60027-7.CrossRefGoogle Scholar
- 53.O'Brien S, Furman RR, Coutre SE, Sharman JP, Burger JA, Blum KA, et al. Ibrutinib as initial therapy for elderly patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: an open-label, multicentre, phase 1b/2 trial. Lancet Oncol. 2014;15(1):48–58. https://doi.org/10.1016/s1470-2045(13)70513-8.CrossRefPubMedGoogle Scholar
- 54.•• O’Brien SM, Furman RR, Coutre SE, Flinn IW, Burger J, Blum K, et al. Five-year experience with single-agent ibrutinib in patients with previously untreated and relapsed/refractory chronic lymphocytic leukemia/small lymphocytic leukemia. Blood. 2016;128(22):233. This phase 1b/2 trial showed that single-agent ibrutinib is safe and active (ORR 84%, CR 29%) in elderly patients aged ≥ 65 with previously untreated CLL, with durable responses continuing to be observed at 5 years (5-year PFS 92%). This orally administered, well-tolerated regimen is a particularly attractive treatment option for older patients who may be poor candidates for chemoimmunotherapy. One potential downside is the need for indefinite therapy. Google Scholar
- 56.•• Woyach JA, Ruppert AS, Heerema NA, Zhao W, Booth AM, Ding W, et al. Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL. N Engl J Med. 2018;379:2517–28. https://doi.org/10.1056/NEJMoa1812836. In this phase 3 trial for untreated CLL patients aged ≥65, ibrutinib alone or in combination with rituximab was compared to bendamustine-rituximab and with each other. Two-year PFS was higher with ibrutinib alone (87%, HR = 0.39, p < 0.001) and ibrutinib-rituximab (88%, HR = 0.38, p < 0.001) compared to bendamustine-rituximab (74%); there was no additional benefit of adding rituximab to ibrutinib. The ibrutinib-containing regimens were associated with fewer grade ≥ 3 hematologic adverse events compared to bendamustine-rituximab (40% vs. 61%) but more grade ≥ 3 nonhematologic adverse events (74% vs. 63%), with hypertension and infection being most common. The results of this study suggest there is no longer a role for cytotoxic chemotherapy for older patients with CLL.
- 58.O’Brien SM, Lamanna N, Kipps TJ, Flinn I, Zelenetz AD, Burger JA, et al. A phase 2 study of idelalisib plus rituximab in treatment-naive older patients with chronic lymphocytic leukemia. Blood. 2015;126(25):2686–94. https://doi.org/10.1182/blood-2015-03-630947.CrossRefPubMedPubMedCentralGoogle Scholar
- 60.O’Brien S, Patel M, Kahl BS, Horwitz SM, Foss FM, Porcu P et al. Duvelisib, an oral dual PI3K-delta,gamma inhibitor, shows clinical and pharmacodynamic activity in chronic lymphocytic leukemia and small lymphocytic lymphoma in a Phase 1 study. Am J Hematol 2018. https://doi.org/10.1002/ajh.25243.
- 61.Broderick JM. FDA Approves duvelisib for CLL and follicular lymphoma. https://www.onclivecom/web-exclusives/fda-approves-duvelisib-for-cll-and-follicular-lymphoma. Accessed 3 Oct 2018.
- 62.• Roberts AW, Davids MS, Pagel JM, Kahl BS, Puvvada SD, Gerecitano JF, et al. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374(4):311–22. https://doi.org/10.1056/NEJMoa1513257. This first-in-human trial showed for the first time that venetoclax induces substantial responses with a manageable safety profile for patients with relapsed/refractory CLL, including those with poor prognostic features. CrossRefPubMedGoogle Scholar
- 63.Stilgenbauer S, Eichhorst B, Schetelig J, Coutre S, Seymour JF, Munir T, et al. Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study. The Lancet Oncology. 2016;17(6):768–78. https://doi.org/10.1016/s1470-2045(16)30019-5.CrossRefPubMedGoogle Scholar
- 64.•• Seymour JF, Kipps TJ, Eichhorst B, Hillmen P, D’Rozario J, Assouline S, et al. Venetoclax-Rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2018;378(12):1107–20. https://doi.org/10.1056/NEJMoa1713976. This phase 3 trial showed that venetoclax-rituximab compared to bendamustine-rituximab significantly improved 2-year PFS (84.9% vs. 36.3%, HR = 0.17) and 2-year OS (91.9% vs. 86.6%, HR = 0.48) for patients with relapsed/refractory CLL (median age 65). Substantial MRD negativity rates were achieved (62.4%) with a fixed duration of treatment, raising the possibility of a treatment-free interval for patients with CLL, but further studies with longer follow-up are needed. CrossRefPubMedGoogle Scholar
- 66.• Jain N, Thompson PA, Ferrajoli A, Burger JA, Borthakur G, Takahashi K, et al. Combined Venetoclax and Ibrutinib for Patients with Previously Untreated High-Risk CLL, and Relapsed/Refractory CLL: A Phase II Trial. Blood. 2017;130(Suppl 1):429. This phase 2 trial showed that the combination of ibrutinib+venetoclax is safe and active in patients with untreated CLL (mean age 65) and relapsed/refractory CLL (mean age 59). Several patients achieved MRD negativity as early as 3 months from the start of combination therapy, raising the possibility of a treatment-free interval or even cure for patients with CLL, but further studies with longer follow-up are needed. Google Scholar
- 67.Wierda WG, Siddiqi T, Flinn I, Badoux XC, Kipps TJ, Allan JN, et al. Phase 2 CAPTIVATE results of ibrutinib (ibr) plus venetoclax (ven) in first-line chronic lymphocytic leukemia (CLL). J Clin Oncol : official journal of the American Society of Clinical Oncology. 2018;36(suppl; abstr):7502.CrossRefGoogle Scholar
- 68.Hillmen P, Munir T, Rawstron A, Brock K, Munoz Vicente S, Yates F, et al. Initial results of ibrutinib plus venetoclax in relapsed, refractory CLL (Bloodwise TAP CLARITY Study): high rates of overall response, complete remission and MRD eradication after 6 months of combination therapy. Blood. 2017;130(Suppl 1):428.Google Scholar
- 71.Palumbo A, Avet-Loiseau H, Oliva S, Lokhorst HM, Goldschmidt H, Rosinol L, et al. Revised international staging system for multiple myeloma: a report from International Myeloma Working Group. J Clin Oncol : official journal of the American Society of Clinical Oncology. 2015;33(26):2863–9. https://doi.org/10.1200/jco.2015.61.2267.CrossRefGoogle Scholar
- 72.Palumbo A, Bringhen S, Mateos MV, Larocca A, Facon T, Kumar SK, et al. Geriatric assessment predicts survival and toxicities in elderly myeloma patients: an International Myeloma Working Group report. Blood. 2015;125(13):2068–74. https://doi.org/10.1182/blood-2014-12-615187.CrossRefPubMedPubMedCentralGoogle Scholar
- 73.Engelhardt M, Dold SM, Ihorst G, Zober A, Moller M, Reinhardt H, et al. Geriatric assessment in multiple myeloma patients: validation of the International Myeloma Working Group (IMWG) score and comparison with other common comorbidity scores. Haematologica. 2016;101(9):1110–9. https://doi.org/10.3324/haematol.2016.148189.CrossRefPubMedPubMedCentralGoogle Scholar
- 74.• Larocca A, Dold SM, Zweegman S, Terpos E, Wasch R, D’Agostino M, et al. Patient-centered practice in elderly myeloma patients: an overview and consensus from the European Myeloma Network (EMN). Leukemia. 2018;32(8):1697–712. https://doi.org/10.1038/s41375-018-0142-9. These consensus recommendations from the European Myeloma Network provide advice on how to assess elderly patients for fitness level to determine treatment goals as well as frailty-adjusted dose reductions. CrossRefPubMedGoogle Scholar
- 75.Larocca A, Salvini M, De Paoli L, Cascavilla N, Benevolo G, Galli M, et al. Efficacy and feasibility of dose/schedule-adjusted Rd-R Vs. continuous Rd in elderly and intermediate-fit newly diagnosed multiple myeloma (NDMM) patients: RV-MM-PI-0752 Phase III randomized study. Blood. 2018;132(Suppl 1):305.Google Scholar
- 77.Facon T, Mary JY, Hulin C, Benboubker L, Attal M, Pegourie B, et al. Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99-06): a randomised trial. Lancet (London, England). 2007;370(9594):1209–18. https://doi.org/10.1016/s0140-6736(07)61537-2.CrossRefGoogle Scholar
- 79.Sharma M, Zhang M-J, Zhong X, Abidi MH, Akpek G, Bacher U, et al. Older Patients with myeloma derive similar benefit from autologous transplantation. Biol Blood Marrow Transplant : journal of the American Society for Blood and Marrow Transplantation. 2014;20(11):1796–803. https://doi.org/10.1016/j.bbmt.2014.07.013.CrossRefGoogle Scholar
- 81.Garderet L, Beohou E, Caillot D, Stoppa AM, Touzeau C, Chretien ML, et al. Upfront autologous stem cell transplantation for newly diagnosed elderly multiple myeloma patients: a prospective multicenter study. Haematologica. 2016;101(11):1390–7. https://doi.org/10.3324/haematol.2016.150334.CrossRefPubMedPubMedCentralGoogle Scholar
- 82.Nadiminti K, Dozeman L, Tricot A, Schultz A, Ouverson S, Zhan F, et al. A Single autologous stem cell transplant (ASCT) followed by two years of post-transplant therapy is safe in older recently diagnosed multiple myeloma (MM) patients. Preliminary results from the prospective phase II trial (NCT01849783). Blood. 2017;130(Suppl 1):4543.Google Scholar
- 83.Palumbo A, Bringhen S, Caravita T, Merla E, Capparella V, Callea V, et al. Oral melphalan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly patients with multiple myeloma: randomised controlled trial. Lancet (London, England). 2006;367(9513):825–31. https://doi.org/10.1016/s0140-6736(06)68338-4.CrossRefGoogle Scholar
- 84.Hulin C, Facon T, Rodon P, Pegourie B, Benboubker L, Doyen C, et al. Efficacy of melphalan and prednisone plus thalidomide in patients older than 75 years with newly diagnosed multiple myeloma: IFM 01/01 trial. J Clin Oncol : official journal of the American Society of Clinical Oncology. 2009;27(22):3664–70. https://doi.org/10.1200/jco.2008.21.0948.CrossRefGoogle Scholar
- 86.Mateos MV, Hernandez JM, Hernandez MT, Gutierrez NC, Palomera L, Fuertes M, et al. Bortezomib plus melphalan and prednisone in elderly untreated patients with multiple myeloma: updated time-to-events results and prognostic factors for time to progression. Haematologica. 2008;93(4):560–5. https://doi.org/10.3324/haematol.12106.CrossRefPubMedGoogle Scholar
- 89.• Magarotto V, Bringhen S, Offidani M, Benevolo G, Patriarca F, Mina R, et al. Triplet vs doublet lenalidomide-containing regimens for the treatment of elderly patients with newly diagnosed multiple myeloma. Blood. 2016;127(9):1102–8. https://doi.org/10.1182/blood-2015-08-662627. Previous standard of care regimens for elderly, transplant-ineligible patients with MM contained alkylators. This phase 2 trial is the first to compare a lenalidomide and alkylator-containing triplet regimen (MPR vs. CPR) with an alkylator-free doublet regimen including lenalidomide (Rd). This study found that lenalidomide-based triplet regimens were not better than doublet regimens. However, post hoc analysis stratified on frailty showed a PFS advantage for MPR over Rd in fit patients (HR, 0.671; p = 0.037), suggesting that patients who are more fit may benefit from triplet therapy, supporting the utility of basing treatment decisions on fitness. CrossRefPubMedGoogle Scholar
- 90.• Durie BG, Hoering A, Abidi MH, Rajkumar SV, Epstein J, Kahanic SP, et al. Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): a randomised, open-label, phase 3 trial. Lancet (London, England). 2017;389(10068):519–27. https://doi.org/10.1016/s0140-6736(16)31594-x. This phase 3 trial in patients aged ≥ 18 with newly diagnosed MM not planned for immediate ASCT (median age 63) showed that VRd produced superior PFS (43 vs. 30 months, HR = 0.712, p = 0.0018) and OS (75 vs. 64 months, HR = 0.709, p = 0.025) compared to Rd. Although the Rd group had more patients aged ≥ 65, age-adjusted multivariate analysis showed the effect of treatment group remained significant for both PFS and OS. The VRd group had more adverse effects, treatment discontinuations, and deaths. In addition, this study excluded patients with compromised renal function and bone marrow function, so conclusions cannot be drawn for these groups. CrossRefGoogle Scholar
- 91.Niesvizky R, Flinn IW, Rifkin R, Gabrail N, Charu V, Clowney B, et al. Community-BASED Phase IIIB trial of three UPFRONT bortezomib-based myeloma regimens. J Clin Oncol : official journal of the American Society of Clinical Oncology. 2015;33(33):3921–9. https://doi.org/10.1200/jco.2014.58.7618.CrossRefGoogle Scholar
- 92.•• Mateos MV, Dimopoulos MA, Cavo M, Suzuki K, Jakubowiak A, Knop S, et al. Daratumumab plus Bortezomib, Melphalan, and Prednisone for Untreated Myeloma. N Engl J Med. 2018;378(6):518–28. https://doi.org/10.1056/NEJMoa1714678. This phase 3 trial designed for elderly transplant-ineligible MM patients showed that daratumumab + VMP significantly improved PFS compared to VMP. This confirmed for older treatment-naïve patients the efficacy of daratumumab that was shown previously in younger relapsed/refractory patients in the CASTOR and POLLUX trials. In addition, this study showed that quadruplet therapy can be used in older patients with coexisting conditions, supporting the idea that combinations with more drugs is more effective, though with higher toxicity, so the individual drugs used and the patients need to be selected carefully. CrossRefPubMedGoogle Scholar
- 93.•• Facon T, Kumar SK, Plesner T, Orlowski RZ, Moreau P, Bahlis N, et al. Phase 3 randomized study of daratumumab plus lenalidomide and dexamethasone (D-Rd) versus lenalidomide and dexamethasone (Rd) in Patients with newly diagnosed multiple myeloma (NDMM) ineligible for transplant (MAIA). Blood. 2018;132(Suppl 1):LBA-2. The phase 3 MAIA study evaluated the addition of daratumumab to Rd (DRd) in newly diagnosed, transplant-ineligible MM patients, with median age 73 years and 44% aged ≥ 75. Compared to Rd, DRd was found to improve median PFS (not reached vs. 31.9 months, HR = 0.55, p < 0.0001) and rates of very good partial response or better (47.6% vs. 24.7%, p < 0.0001). The DRd group had higher rates (≥ 5% difference) of grade 3/4 pneumonia, neutropenia, and leukopenia. This data support the addition of daratumumab to standard of care combinations in patients with newly diagnosed MM ineligible for transplant. Google Scholar
- 94.• Hulin C, Belch A, Shustik C, Petrucci MT, Duhrsen U, Lu J, et al. Updated outcomes and impact of age with lenalidomide and low-dose dexamethasone or melphalan, prednisone, and thalidomide in the randomized, Phase III first trial. J Clin Oncol : official journal of the American Society of Clinical Oncology. 2016;34(30):3609–17. https://doi.org/10.1200/jco.2016.66.7295. These updated outcomes of the FIRST trial and stratification by age > 75 reinforces the findings of the FIRST trial that using continuous lenalidomide-dexamethasone therapy improved outcomes compared to fixed duration therapy, even in patients aged > 75. CrossRefGoogle Scholar
- 95.Palumbo A, Gay F, Cavallo F, Di Raimondo F, Larocca A, Hardan I, et al. Continuous therapy versus fixed duration of therapy in patients with newly diagnosed multiple myeloma. J Clin Oncol : official journal of the American Society of Clinical Oncology. 2015;33(30):3459–66. https://doi.org/10.1200/jco.2014.60.2466.CrossRefGoogle Scholar
- 96.San-Miguel JF, Hungria VT, Yoon SS, Beksac M, Dimopoulos MA, Elghandour A, et al. Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase 3 trial. Lancet Oncol. 2014;15(11):1195–206. https://doi.org/10.1016/s1470-2045(14)70440-1.CrossRefPubMedGoogle Scholar