ALL in Older Adults

Abstract

acute lymphoblastic leukemia: acute lymphoblastic leukemiaThe older population, those aged 65 or above, in 2030 is estimated to double the number of their counterparts in 2000, rising from 35 million to 74 million and representing approximately 21 percent of the U.S. population. In parallel to the increase in life expectancy, the overall incidence of leukemia is projected to increase by 68 percent among older adults in 2030 (J Clin Oncol 2009;27(17):2758-2765). Nearly, 12 percent of patients with acute lymphoblastic leukemia (ALL) are diagnosed at age 65 or older. However, the treatment results with intensive chemotherapy in older patients are not as good as in younger patients (Clin Adv Hematol Oncol 2017;15(4):266-274). Increased incidence of other co-morbidities, such as cardiovascular disease, other malignancies, chronic lung diseases, diabetes mellitus, and diminished performance status, makes administration of an intensive regimen difficult (Onkologie 2008;31(Suppl. 4):14(V29). Significant dose reductions and skipping key chemotherapeutic agents to adjust for old age produce mediocre results. Novel treatment strategies are required to address the needs of this rapidly growing older population. In this review, we summarize newly emerging therapeutic modalities that may have a significant role in the treatment of older patients with ALL. Treatment of Older Adults With ALL Due to upper age limits or other exclusions based on underlying comorbidities, older patients have been underrepresented in the clinical trials. Despite selective patient enrollments, major frontline ALL clinical trials published within the past 15 years reported worse outcomes in older patients than in younger patients; 5-year overall survival (OS) ranged between 17 percent and 23 percent (Leukemia 2001;15(2):208-216, Blood 2002;99(3):863-871, J Clin Oncol 2000;18(3):547-561, Br J Haematol 2012;157(4):463-471, Blood 2008;111(5):2563-2572, Eur J Haematol 2007;78(2):102-110). One hundred older adults (aged 55-65 years) with ALL were treated in the UKALL XII/ECOG2993 trial compared with 1,814 younger adults (aged 14-54 years). The complete response (CR) rate in older patients was inferior (73% vs. 93%) as was 5-year OS (21% vs. 41%) (Br J Haematol 2012;157(4):463-471). Induction death was higher in older patients compared with younger patients (18% vs. 4%, respectively). Our experience at MD Anderson showed that administration of intensive regimen (Hyper-CVAD) in ALL resulted in similar CR rates in older (≥ 60 years) and younger patients (<60 years), 84 percent versus 92 percent, respectively (Cancer 2008;113(8):2097-2101). However, it did not translate into improved 5-year OS (20% vs. 48%) due to increased deaths in CR among older patients (34% vs. 7%). Elderly patients with ALL fared even worse when treated with standard of care (Blood 2017;129(13):1878-1881, Blood 2016;128(22):3981-3981). In an analysis of NCI's Surveillance, Epidemiology, and End Results (SEER) database, the 3-year OS rate was only 12 percent in 1,675 older patients (≥60 years old) with ALL diagnosed between 1980 and 2011. In the past decade, the outcome of older ALL patients has improved to a certain extent by the development of tyrosine kinase inhibitors (TKIs) and advances in supportive care. However, there is a considerable amount of room for further improvement. In recent years, a better understanding of ALL biology resulted in the development of targeted therapies aiming CD22 and CD19 cell surface antigens and more potent TKIs. Innovative clinical trial designs using these less intensive but more effective targeted drugs may improve the outcome of older patients with ALL. Philadelphia-Negative ALL Blinatumomab Blinatumomab, a bi-specific T-cell engager (BiTE) antibody, induces T-cell mediated tumor depletion by targeting CD19 antigen expressed on the surface of leukemic blasts and CD3 antigen on T cells (Blood 2000;95(6):2098-2103). Recently, two phase II clinical trials investigated the tolerability and efficacy of blinatumomab in a relapsed/refractory setting. In a dose-finding study of 36 patients (median age 32 years, [range 18-77]) with relapsed/refractory B-ALL, 69 percent achieved CR or CR with incomplete count recovery (CRi) (J Clin Oncol 2014;32(36):4134-4140). In a confirmatory, single-arm study of 189 patients (median age 39 years, [range 18-79]), 43 percent achieved CR/CRi (Lancet Oncol 2015;16(1):57-66). Kantarjian et al., pooled the data from both phase II studies (with an additional 36 patients enrolled later in an extension cohort) and analyzed a total of 261 relapsed/refractory B-ALL patients treated with blinatumomab (Cancer 2016;122(14):2178-2185). Thirty-six (14%) were older patients (aged ≥ 65 years), and 225 (86%) were younger patients (aged < 65 years). Baseline clinical and disease-related characteristics were comparable between older and younger patients including prior relapses. Response rates were similar among older and younger patients, 56 percent (n=20) and 46 percent (n=104) achieved CR/CRi during the first two blinatumomab cycles, respectively. Among responders, 60 percent of older patients (n=12) and 70 percent of younger patients (n=73) achieved minimal residual disease (MRD) negativity. With a median follow-up less than 2 years, relapse-free survival (RFS) was identical, 7.4 months, in older and younger patients. The median OS was also comparable, 5.5 and 7.6 months, respectively. Rates of serious adverse events (AEs) were similar between older and younger patients; any grade ≥3 AE (86% vs. 80%) and febrile neutropenia (22% vs. 23%). Grade ≥3 neurotoxicity was the only distinctive AE that was more common in older patients compared with younger patients (28% vs. 13%). Encephalopathy was the most common type of neurotoxicity, 11 percent and 3 percent in older and younger patients, respectively. All neurologic AEs were resolved with holding blinatumomab in both groups of patients. In a recent phase III clinical trial, 405 patients with relapsed/refractory ALL were randomized in a 2:1 ratio to receive blinatumomab or standard of care chemotherapy (N Engl J Med 2017;376(9):836-847). Patients treated with blinatumomab achieved higher response rates compared with patients who received standard of care chemotherapy; CR/CRi rate was 44 percent versus 25 percent, respectively (p<0.001). The median OS was 7.7 months in the blinatumomab arm and 4.0 months in the chemotherapy arm (p=0.01). In a pre-specified subgroup analysis, the blinatumomab arm was divided by age: remission rates were comparable, 45 percent and 43 percent in older (age ≥ 35 years) and younger (age < 35 years) patients, respectively. In the relapsed/refractory setting, older patients tolerate blinatumomab and achieve responses similar to that of the younger patients. Blinatumomab also induces better survival compared with standard of care chemotherapy in that setting. Incorporation of blinatumomab into frontline ALL treatment is equally important as it may allow de-intensification of conventional chemotherapy and better tolerability in older patients. A phase II study of newly diagnosed patients with B-ALL investigating the sequential use of Hyper-CVAD regimen and blinatumomab is ongoing (NCT02877303). Inotuzumab Ozogamicin Inotuzumab ozogamicin is an antibody-drug conjugate with anti-CD22 antibody attached to a calicheamicin-derived cytotoxic moiety (Ther Adv Hematol 2015;6(5):253-261). Upon internalization by the CD22 positive leukemic blast, calicheamicin gets released and binds to the DNA to exert its toxicity. In a phase II study of 90 patients with relapsed/ refractory ALL, single-agent inotuzumab induced CR/CRi in 58 percent (n=52) of the patients; 72 percent (n=37) of the responders were MRD-negative (Cancer 2013;119(15):2728-2736). The overall response rates were similar in older (age ≥ 60 years) and younger (age < 60 years) patients, 60 percent and 57 percent, respectively. In a phase III study, 326 patients with relapsed/refractory ALL were randomized in a 1:1 ratio to receive inotuzumab or standard of care chemotherapy, and the first 218 patients (109 in each group) were included in the intention-to-treat analysis (N Engl J Med 2016;375(8):740-753). Patients treated with inotuzumab achieved higher response rates compared with patients who received standard of care chemotherapy; CR rate was 81 percent versus 29 percent, respectively (p<0.001). The median OS was 7.7 months in the inotuzumab arm and 6.7 months in the chemotherapy arm (p=0.04). The inotuzumab arm was subdivided by age: remission rates were comparable, 81 percent and 80 percent in older (age ≥ 55 years) and younger (age < 55 years) patients, respectively. Rates of any grade ≥3 AEs were similar between inotuzumab and standard of care arms, 46 percent and 43 percent, respectively. Patients treated with inotuzumab were more likely to develop veno-occlusive disease (VOD), 11 percent (n=15) versus 1 percent (n=1). In the inotuzumab group, five patients developed VOD during or shortly after therapy was administered and 10 developed after stem cell transplantation. In multivariate analysis, use of double alkylator conditioning regimen was the only significant risk factor for VOD. In a recent phase II study, a combination of inotuzumab and mini-hyper-CVD was investigated in newly diagnosed 47 older patients (median 68 years [range 60-81]) with B-cell ALL (ASH 2016, Abstract 588). Mini-hyper-CVD is a lower-intensity regimen with the following dose adjustments in a standard Hyper-CVAD regimen: dexamethasone and cyclophosphamide at 50 percent dose reduction, methotrexate at 75 percent dose reduction, cytarabine at 0.5 g/m2 x 4 doses, and no anthracycline. Despite substantial dose reductions, 98 percent of the patients achieved CR/CRi; 93 percent of responders were MRD-negative by 12 weeks. The 3-year CR duration and OS rates were 76 percent and 52 percent, respectively. In a similar patient population treated with the standard Hyper-CVAD regimen, the 3-year OS was worse, 36 percent (p=0.05). The outstanding results achieved in this study await further confirmation in a randomized clinical trial to establish the new standard of care for older patients with ALL.Table:: Clinical Trials in Older Patients With Philadelphia-Positive ALLPhiladelphia-Positive ALL Development of TKIs targeting BCR-AB1 revolutionized Philadelphia-positive (Ph+) ALL therapy. The addition of TKI to low-intensity chemotherapy improved CR rates and survival in older patients with Ph+ ALL (see Table). In a phase II study of 71 newly diagnosed older patients (median 69 years, [range 59-83]) with Ph+ ALL, 96 percent achieved CR with dasatinib, dexamethasone, and vincristine during induction (Blood 2016;128(6):774-782). The 5-year RFS and OS were 27 percent and 36 percent, respectively. Overall, 36 patients relapsed, 24 were evaluated for mutation by Sanger sequencing, and 75 percent were positive for the T315i mutation. A pan-BCR-ABL1 inhibitor, ponatinib, with known activity against mutated BCR-ABL1 including T315i is a highly active agent in ALL. In a phase II study, 64 patients (median 48-year-old [range, 20-80]) with newly diagnosed Ph+ ALL were treated with Hyper-CVAD and ponatinib combination (J Clin Oncol 2017;35(15_suppl):7013-7013, Lancet Oncol 2015;16(15):1547-1555). Overall, 98 percent of the patients achieved CR; of the responders, 98 percent and 77 percent achieved complete cytogenetic response and complete molecular response, respectively. Three patients developed myocardial infarction while on study attributed to ponatinib. To minimize further thrombotic events, the study was amended to reduce ponatinib dosage: no grade ≥3 vascular AEs were seen after the amendment. In a retrospective study, the outcomes with blinatumomab and a TKI combination therapy have been reported in a small number of patients with Ph+ leukemia (Clinical Lymphoma, Myeloma and Leukemia 2017;17:S265). Nine patients with relapsed refractory ALL (overt relapse, n=5; MRD-only relapse, n=4) and three patients with blast-phase chronic myeloid leukemia (overt relapse, n=1; MRD-only relapse, n=2) received blinatumomab and a TKI (bosutinib, n=1; dasatinib, n=3; ponatinib, n=8). Overall, nine patients (75%) achieved a complete molecular response. The median OS was not reached, and 1-year OS rate was 73 percent. Recently, a phase II study has opened evaluating the safety and efficacy of blinatumomab/ponatinib combination for elderly patients with ALL (NCT03263572). Another monoclonal antibody, inotuzumab ozogamicin, is under investigation as a combination with bosutinib, a TKI with safer cardiovascular side effect profile (NCT02311998). This study accepts newly diagnosed or relapsed refractory patients with Ph+ ALL, and it represents a good option especially for those who have an underlying cardiovascular disorder and are unable to tolerate other TKIs. In a population with increasing life expectancy, it is important to design treatment protocols that can address the needs of older patients. We are in an era where targeted therapies are becoming increasingly more effective and tolerable for older patients. In order to develop the most ideal therapy for ALL, patients should be encouraged to enroll into clinical trials that are designed to accommodate their performance status and common age-related health problems. MUSA YILMAZ, MD, is Assistant Professor, Department of Leukemia, Division of Cancer Medicine; HAGOP KANTARJIAN, MD, is Professor and Chairman, Department of Leukemia, and the Samsung Distinguished University Chair in Cancer Medicine; and ELIAS JABBOUR, MD, is Associate Professor, Department of Leukemia, Division of Cancer Medicine, all at The University of Texas MD Anderson Cancer Center, Houston.Musa Yilmaz, MD: Musa Yilmaz, MDHagop Kantarjian, MD: Hagop Kantarjian, MDElias Jabbour, MD: Elias Jabbour, MD