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Chemotherapy-free and reduced intensity approaches in elderly patients with B-lineage acute lymphoblastic leukemia

      Highlights

      • Treatment of elderly patients with ALL is still extremely challenging.
      • In elderly with Ph- ALL, use of more or less intensive regimens provided poor results.
      • In Ph+ ALL, the use of TKIs has changed the outcome of adults and elderly patients.
      • Immunotherapy, possibly front-line, might be an ideal option for elderly patients.

      Abstract

      Management of older patients - defined by convention above the age of 60 years, but varying widely within study groups - with acute lymphoblastic leukemia (ALL) is still a challenge. The complete remission (CR) rate in these patients is lower than in other age groups and the percentage of deaths in induction or in CR remains high, ranging from 7 to 40%. Overall survival rates do not exceed 30%, depending on the age group included in the different trials group and on the follow-up duration. These unsatisfactory results are sustained by the fact that pre-existing comorbidities often hamper treatment delivery and if treatment intensification improves the CR rates it also increases toxicity and the percentage of deaths.
      Overall, the median life expectancy is rising world-wide, being in the western world around/over 80 years (and increasing); in addition, the proportion of elderly individuals is growing progressively. This means that the management of these frail patients represents a true clinical unmet need.
      While in Ph+ ALL the introduction of tyrosine kinase inhibitors (TKI) has markedly impacted on the outcome of patients of all ages, in Ph− ALL prognosis in the elderly still remains largely unsatisfactory. Novel strategies - mostly based on the use of monoclonal antibodies or of targeted strategies if druggable mutations can be identified - are largely needed.
      In the present review, we will discuss the past and current scenario, and provide an overview on the developing approaches for both Ph− and Ph+ elderly ALL, represented in particular by immunotherapy.
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      References

        • Howlander N.
        • Noone A.M.
        • Krapcho M.
        • et al.
        SEER Cancer statistics review, 1975–2014.
        National Cancer Institute, Bethesda, MDApril 2017 (based on November 2016 SEER data submission, posted to the SEER web site)
        • Chiaretti S.
        • Vitale A.
        • Cazzaniga G.
        • et al.
        Clinico-biologic features of 5202 acute lymphoblastic leukemia patients enrolled in the Italian AIEOP and GIMEMA protocols and stratified in age-cohorts.
        Haematologica. 2013; 98: 1702-1710
        • Gökbuget N.
        Treatment of older patients with acute lymphoblastic leukemia.
        Hematology Am Soc Hematol Educ Program. 2016; : 573-579
        • Altekruse S.F.
        • Kosary C.L.
        • Krapcho M.
        • et al.
        Seer Cancer statistics review 1975–2007.
        National Cancer Institute, Bethesda, MD2007
        • Moorman A.V.
        • Chilton L.
        • Wilkinson J.
        • et al.
        A population-based cytogenetic study of adults with acute lymphoblastic leukemia.
        Blood. 2010; 115: 206-214
        • Juliusson G.
        • Karlsson K.
        • Hallbook H.
        Population-based analyses in adult acute lymphoblastic leukemia.
        Blood. 2010; 116: 1011
        • Dombret H.
        • Gabert J.
        • Boiron J.M.
        • et al.
        Outcome of treatment in adults Philadelphia chromosome-positive acute lymphoblastic leukemia-results of the prospective multicenter LALA-94 trial.
        Blood. 2002; 100: 2357-2366
        • Linker C.A.
        • Levitt L.J.
        • O'Donnell M.
        • et al.
        Treatment of adult acute lymphoblastic leukemia with intensive cyclical chemotherapy: a follow-up report.
        Blood. 1991; 78: 2814-2822
        • Gleissner B.
        • Gökbuget N.
        • Bartram C.R.
        • et al.
        German multicenter trials of adult acute lymphoblastic leukemia study group. Leading prognostic relevance of the BCR-ABL translocation in adult acute B-lineage lymphoblastic leukemia: a prospective study of the German multicenter trial group and confirmed polymerase chain reaction analysis.
        Blood. 2002; 99: 1536-1543
        • Pullarkat V.
        • Slovak M.L.
        • Kopecky K.J.
        • et al.
        Impact of cytogenetics on the outcome of adult acute lymphoblastic leukemia: results of southwest oncology group 9400 study.
        Blood. 2008; 111: 2563-2572
        • Hunault M.
        • Harousseau J.L.
        • Delain M.
        • et al.
        Better outcome of adult acute lymphoblastic leukemia after early genoidentical allogeneic bone marrow transplantation (BMT) than after late high-dose therapy and autologous BMT: a GOELAMS trial.
        Blood. 2004; 104: 3028-3037
        • Sancho J.M.
        • Ribera J.M.
        • Xicoy B.
        • et al.
        PETHEMA group. Results of the PETHEMA ALL-96 trial in elderly patients with Philadelphia chromosome-negative acute lymphoblastic leukemia.
        Eur J Haematol. 2007; 78: 102-110
        • O'Brien S.
        • Thomas D.A.
        • Ravandi F.
        • et al.
        Results of the hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone regimen in elderly patients with acute lymphocytic leukemia.
        Cancer. 2008; 113: 2097-2101
        • Sive J.I.
        • Buck G.
        • Fielding A.
        • et al.
        Outcomes in older adults with acute lymphoblastic leukaemia (ALL): results from the international MRC UKALL XII/ECOG2993 trial.
        Br J Haematol. 2012; 157: 463-471
        • Gökbuget N.
        • Beck J.
        • Bruggemann M.
        • et al.
        Moderate intensive chemotherapy including CNS-prophylaxis with liposomal cytarabine is feasible and effective in older patients with Ph-negative acute lymphoblastic leukemia (ALL): results of a prospective trial from the German multicenter study Group for Adult ALL (GMALL).
        Blood. 2012; 120 ([Abstract]): 1493
        • Schwartz P.
        • Hunault-Berger M.
        • Chevallier P.
        • et al.
        French results with the EWALL chemotherapy backbone in older patients with Philadelphia chromosome-negative acute lymphoblastic leukemia. A GRAALL report.
        Haematologica. 2013; 98 ([Abstract]): 463
        • Ribera J.M.
        • García O.
        • Oriol A.
        • Gil C.
        • PETHEMA group, Spanish Society of Hematology
        • et al.
        Feasibility and results of subtype-oriented protocols in older adults and fit elderly patients with acute lymphoblastic leukemia: results of three prospective parallel trials from the PETHEMA group.
        Leuk Res. 2016; 41: 12-20
        • Huguet F.
        • Leguay T.
        • Thomas X.
        • et al.
        Upper age limit for a pediatric-inspired therapy in younger adults with Ph-negative acute lymphoblastic leukemia (ALL)? analysis of the GRAALL-2005 study.
        Blood. 2016; 128 ([Abstract]): 762
        • Thomas D.A.
        • O'Brien S.
        • Faderl S.
        • et al.
        Chemoimmunotherapy with a modified hyper-CVAD and rituximab regimen improves outcome in de novo Philadelphia chromosome-negative precursor B-lineage acute lymphoblastic leukemia.
        J Clin Oncol. 2010; 28: 3880-3889
        • Maury S.
        • Chevret S.
        • Thomas X.
        • et al.
        Rituximab in B-lineage adult acute lymphoblastic leukemia.
        N Engl J Med. 2016; 375: 1044-1053
        • Topp M.S.
        • Kufer P.
        • Gökbuget N.
        • et al.
        Targeted therapy with the T-cell-engaging antibody blinatumomab of chemotherapy-refractory minimal residual disease in B-lineage acute lymphoblastic leukemia patients results in high response rate and prolonged leukemia-free survival.
        J Clin Oncol. 2011; 29: 2493-2498
        • Topp M.S.
        • Gökbuget N.
        • Zugmaier G.
        • et al.
        Long-term follow up of hematologic relapse-free survival in a phase 2 study of blinatumomab in patients with MRD in B-lineage ALL.
        Blood. 2012; 120: 5185-5187
        • Gökbuget N.
        • Zugmaier G.
        • Klinger M.
        • et al.
        Long-term relapse-free survival in a phase 2 study of blinatumomab for the treatment of patients with minimal residual disease in B-lineage acute lymphoblastic leukemia.
        Haematologica. 2017; 102: e132-e135
        • Topp M.S.
        • Gokbuget N.
        • Zugmaier G.
        • et al.
        Phase II trial of the anti- CD19 bispecific T cell-engager blinatumomab shows hematologic and molecular remissions in patients with relapsed or refractory B-precursor acute lymphoblastic leukemia.
        J Clin Oncol. 2014; 32: 4134-4140
        • Topp M.S.
        • Goekbuget N.
        • Stein A.S.
        • et al.
        Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre,single-arm,phase 2 study.
        Lancet Oncol. 2015; 16: 57-66
        • Kantarjian H.
        • Stein A.
        • Gökbuget N.
        • et al.
        Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia.
        N Engl J Med. 2017; 376: 836-847
        • Kantarjian H.
        • Thomas D.
        • Jorgensen J.
        • et al.
        Inotuzumab ozogamicin, an anti-CD22-calecheamicin conjugate, for refractory and relapsed acute lymphocytic leukaemia: a phase 2 study.
        Lancet Oncol. 2012; 13: 403-411
        • Kantarjian H.
        • Thomas D.
        • Jorgensen J.
        • et al.
        Results of inotuzumab ozogamicin, a CD22 monoclonal antibody, in refractory and relapsed acute lymphocytic leukemia.
        Cancer. 2013; 119: 2728-2736
        • Kantarjian H.M.
        • DeAngelo D.J.
        • Stelljes M.
        • et al.
        Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia.
        N Engl J Med. 2016; 375: 740-753
        • Kantarjian H.
        • Ravandi F.
        • Short N.J.
        • et al.
        Inotuzumab ozogamicin in combination with low-intensity chemotherapy for older patients with Philadelphia chromosome-negative acute lymphoblastic leukaemia: a single-arm, phase 2 study.
        Lancet Oncol. 2018; : S1470-S2045
        • Miller G.D.
        • Bruno B.J.
        • Lim C.S.
        Resistant mutations in CML and Ph(+)ALL - role of ponatinib.
        Biologics. 2014; 8: 243-254
        • Vignetti M.
        • Fazi P.
        • Cimino G.
        • et al.
        Imatinib plus steroids induces complete remissions and prolonged survival in elderly Philadelphia chromosome-positive patients with acute lymphoblastic leukemia without additional chemotherapy: results of the Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) LAL0201-B protocol.
        Blood. 2007; 109: 3676-3678
        • Ottmann O.G.
        • Wassmann B.
        • Pfeifer H.
        • et al.
        GMALL study group. Imatinib compared with chemotherapy as front-line treatment of elderly patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL).
        Cancer. 2007; 109: 2068-2076
        • Foà R.
        • Vitale A.
        • Vignetti M.
        • et al.
        GIMEMA acute leukemia working party. Dasatinib as first-line treatment for adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia.
        Blood. 2011; 118: 6521-6528
        • Martinelli G.
        • Papayannidis C.
        • Piciocchi A.
        • et al.
        Extremely high rate of complete hematological response of elderly Ph+ acute lymphoblastic leukemia (ALL) patients by innovative sequential use of Nilotinib and Imatinib. A GIMEMA Protocol LAL 1408.
        Cancer Res. 2014; 74 ([Abstract]): 5552
        • Martinelli G.
        • Piciocchi A.
        • Papayannidis C.
        • et al.
        First report of the Gimema LAL1811 phase II prospective study of the combination of steroids with Ponatinib as frontline therapy of elderly or unfit patients with Philadelphia chromosome-positive acute lymphoblastic leukemia.
        Blood. 2017; 130 ([Abstract])
        • Delannoy A.
        • Delabesse E.
        • Lhéritier V.
        • et al.
        Imatinib and methylprednisolone alternated with chemotherapy improve the outcome of elderly patients with Philadelphia-positive acute lymphoblastic leukemia: results of the GRAALL AFR09 study.
        Leukemia. 2006; 20: 1526-1532
        • Rousselot P.
        • Coudé M.M.
        • Gokbuget N.
        • et al.
        European working group on adult ALL (EWALL) group. Dasatinib and low-intensity chemotherapy in elderly patients with Philadelphia chromosome-positive ALL.
        Blood. 2016; 128: 774-782
        • Ottmann O.G.
        • Pfeifer H.
        • Cayuela J.-M.
        • et al.
        Nilotinib (Tasigna®) and chemotherapy for first-line treatment in elderly patients with De Novo Philadelphia chromosome/BCR-ABL1 positive acute lymphoblastic leukemia (ALL): a trial of the European working Group for Adult ALL (EWALL-PH-02).
        Blood. 2014; 124 ([Abstract]): 798
        • Chiaretti S.
        • Gianfelici V.
        • Agrippino R.
        • et al.
        Management and outcome of adult Ph+ acute lymphoblastic leukemia (ALL) patients treated at the “Sapienza” university between 1996 and 2016.
        Haematologica. 2017; ([Abstract]): 166
        • Vahdani G.
        • Jeong A.R.
        • Ghaznavi Z.
        • et al.
        Long-term survival outcomes of adult Philadelphia chromosome-positive acute lymphoblastic leukemia patients treated with imatinib or dasatinib.
        Haematologica. 2017; ([PB1644. Abstract])
        • Sasaki K.
        • Jabbour E.J.
        • Ravandi F.
        • et al.
        Hyper-CVAD plus ponatinib versus hyper-CVAD plus dasatinib as frontline therapy for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia: a propensity score analysis.
        Cancer. 2016; 122: 3650-3656
        • Lee S.
        • Kim D.-W.
        • Cho B.-S.
        • et al.
        Impact of minimal residual disease kinetics during imatinib-based treatment on transplantation outcome in Philadelphia chromosome-positive acute lymphoblastic leukemia.
        Leukemia. 2012; 26: 2367-2374
        • Ravandi F.
        • Jorgensen J.L.
        • Thomas D.A.
        • et al.
        Detection of MRD may predict the outcome of patients with Philadelphia chromosome–positive ALL treated with tyrosine kinase inhibitors plus chemotherapy.
        Blood. 2013; 122: 1214-1221
        • Chiaretti S.
        • Vitale A.
        • Vignetti M.
        • et al.
        A sequential approach with imatinib, chemotherapy and transplant for adult Ph+ acute lymphoblastic leukemia. Final results of the GIMEMA LAL 0904 study.
        Haematologica. 2016; 101: 1544-1552
        • Chiaretti S.
        • Vitale A.
        • Elia L.
        • et al.
        Multicenter total therapy this LAL 1509 protocol for De Novo adult Ph+ Acute Lymphoblastic Leukemia (ALL) patients. Updated results and refined genetic-based prognostic stratification.
        Blood. 2015; 126 ([Abstract])
        • Martinelli G.
        • Boissel N.
        • Chevallier P.
        • et al.
        Complete hematologic and molecular response in adult patients with relapsed/refractory Philadelphia chromosome-positive B-precursor acute lymphoblastic leukemia following treatment with Blinatumomab: results from a phase II, single-arm, multicenter study.
        J Clin Oncol. 2017; 35: 1795-1802
        • Roberts K.G.
        • Gu Z.
        • Payne-Turner D.
        • et al.
        High frequency and poor outcome of Philadelphia chromosome-like acute lymphoblastic leukemia in adults.
        J Clin Oncol. 2017; 35: 394-401
      1. Chiaretti S., Messina M., Grammatico S., et al. Rapid identification of BCR/ABL1-like acute lymphoblastic leukemia patients using a predictive statistical model based on quantitative real time-polymerase chain reaction: clinical, prognostic and therapeutic implications. Br J Haematol, [in press].

        • Roberts K.G.
        • Li Y.
        • Payne-Turner D.
        • et al.
        Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia.
        N Engl J Med. 2014; 371: 1005-1115
        • Messina M.
        • Chiaretti S.
        • Wang J.
        • et al.
        Prognostic and therapeutic role of targetable lesions in B-lineage acute lymphoblastic leukemia without recurrent fusion genes.
        Oncotarget. 2016; 7: 13886-13901