Current Strategies for Relapsed/Refractory ALL in AYAs and Adults: Where We Are Now

Current Strategies for Relapsed/Refractory ALL in AYAs and Adults: Where We Are Now Eunice S. Wang, MD Roswell Park Cancer Institute Buffalo, New York, United States

Relapsed ALL Carries a Poor Prognosis CR after ALL induction = 85%-90% 1,2 5-year OS = 30%-50% 3,4 Up to two-thirds of patients will relapse 3,4 Salvage chemotherapy CR after 1 st salvage = 31%-45% 2,4,5 CR after 2 nd salvage = 18%-33% 6,7 Median OS = 4.5 to 6 months 2,4,5 1-year OS = 17%-24% 4,5 5-year OS = 3%-11% 2,5 Overall survival from first relapse for 248 treated AYA/adult patients aged 15 to 70 years old 5 ALL, acute lymphoblastic leukemia; AYA, adolescent and young adult; CR, complete response; OS, overall survival 1. DeAngelo DJ, et al. Leukemia. 2015;29(3):526-534. 2. Tavernier E, et al. Leukemia. 2007;21(9):1907-1914. 3. Jaime-Pérez JC, et al. Clin Lymphoma Myeloma Leuk. 2017;17(1):60-68. 4. Kantarjian H, et al. Cancer. 2010;116(24):5568-5574. 5. Oriol A, et al. Haematologica. 2010;95(4):589-596. 6. O Brien S, et al. Cancer. 2008;113(11):3186-3191. 7. Gökbuget N, et al. Blood. 2012;120(10):2032-2041.

NCCN Guidelines: Relapsed/Refractory ALL Relapsed/ refractory Ph+ ALL AYA/Adult ABL gene mutation testing Clinical trial or TKI ± chemotherapy ± HCT or TKI ± corticosteroids ± HCT or blinatumomab (failure of 2 TKIs) or inotuzumab ozogamicin (TKI intolerant or refractory) or tisagenlecleucel (patients 25 years, refractory dz, 2 relapses, failure of 2 TKIs) Ph- ALL AYA/Adult Clinical trial or chemotherapy ± HCT or blinatumomab or inotuzumab ozogamicin or tisagenlecleucel (patients 25 years, refractory dz, or 2 relapses) dz, disease; HCT, hematopoietic stem cell transplantation; NCCN, National Comprehensive Cancer Network; TKI, tyrosine kinase inhibitor NCCN Clinical Practice Guidelines in Oncology : Acute Lymphoblastic Leukemia. V5.2017. https://www.nccn.org/professionals/physician_gls/pdf/all.pdf. Accessed November 2017.

Chemotherapy for Relapsed/Refractory ALL Ideal regimen is not known and depends upon timing of relapse: If relapse >2 years in CR: induction regimen similar to newly diagnosed treatments Primary resistant disease/relapse during chemo: reinduction with novel treatments After 2 nd CR, allogeneic transplant should be performed ASAP Single-agent therapy Liposomal vincristine (Ph-neg ALL that has failed 2 prior treatments) Clofarabine (ages 1-21 years that has failed 2 prior treatments) Nelarabine (relapsed T-ALL that has failed 2 prior treatments) Multiple-agent chemotherapy regimens: MOpAD, Hyper-CVAD, BFM, etc BFM, Berlin-Frankfurt-Münster; chemo, chemotherapy; CVAD, cyclophosphamide, vincristine, doxorubicin, dexamethasone; MOpAD, methotrexate, vincristine, pegylated L-asparaginase dexamethasone NCCN Clinical Practice Guidelines in Oncology : Acute Lymphoblastic Leukemia. V5.2017. https://www.nccn.org/professionals/physician_gls/pdf/all.pdf. Accessed November 2017.

Liposomal Vincristine for Relapsed Ph-neg ALL Indicated for adults with Ph-negative ALL in 2 nd relapse or progressed after 2 prior treatments Phase II trial of 65 patients (median age = 31, range = 19-83 years) - Prior VCR in 100% patients - Prior allosct in 48% patients Adverse events: neurotoxicity, constipation CR/CRi ORR All patients 13 (20%) [CR in 7]* 23 (35%) 3 rd line 6/32 (19%) 4 th line 5/24 (21%) 5 th line 2/9 (22%) Relapsed 9/25 (25%) Refractory 4/29 (14%) * 8/12 - (MRD negative) allosct, allogeneic hematopoietic stem cell transplantation; CI, confidence interval; CRi, complete response with incomplete hematologic recovery; MRD, minimal residual disease; ORR, objective response rate; VCR, vincristine O'Brien S, et al. J Clin Oncol. 2013;31(6):676-683.

Clofarabine for Relapsed Pediatric ALL Purine nucleoside metabolic inhibitor Pediatric patients (1-21 years) with relapsed/refractory ALL after at least 2 prior regimens Dose: 52 mg/m 2 IV over 2 hours for 5 consecutive days Open-label, single-arm trial of 61 pediatric patients (62% >2 prior treatments, 30% prior allosct) 1 - Overall response rate 20.7% (CR 11.5%, CRp 8.2%) - Median duration of CR/CRp = 10.7 weeks - No survival data Toxicities: 2 Febrile neutropenia (55%), infection (83%), nausea/vomiting (73%-78%), diarrhea (56%), rash (38%), elevated LFTs (36%-43%) CRp, complete response without platelet recovery; IV, intravenous; LFTs, liver function tests; mg/m 2, milligrams per square meter 1. Jeha S, et al. J Clin Oncol. 2006;24(12):1917-1923. 2. Clofarabine [package insert]. Cambridge, MA: Genzyme Corporation; September 2014.

Nelarabine for Relapsed T-ALL Purine nucleoside antimetabolite similar to cytarabine T-cell ALL & lymphoblastic lymphoma not responded/relapsed after 2 prior treatments Single-arm phase II trial of 126 adult patients with relapsed/refractory T-ALL/T-LBL Complete response = 36% 80% of patients achieving CR underwent subsequent allosct Overall survival: 24% at 1 year, 11% at 6 years, high relapse rates after allosct Toxicities: Neurotoxicity, myelosuppression, infection, asthenia LBL, lymphoblastic lymphoma Gökbuget N, et al. Blood. 2011;118(13):3504-3511.

Harnessing the Immune System for ALL Therapy Antibodies - Blinatumomab - Inotuzumab Macrophage - Vaccine Leukemia cell Helper T cell - Vaccine Natural killer cell Genetically modified CAR T cells CAR, chimeric antigen receptor

Blinatumomab vs Chemotherapy for RR ALL Blinatumomab Chemo CR/CRi/CRp 43.9% 24.6% CR 33.6% 15.7% CRi/CRp 10.4% 9.0% mo, month; RR, relapsed/refractory Kantarjian H, et al. N Engl J Med. 2017;376(9):836-847.

Blinatumomab Beneficial Across Subgroups no., number; yr, year Kantarjian H, et al. N Engl J Med. 2017;376(9):836-847.

Inotuzumab Ozogamicin (IO) Results in High Response Rates Inotuzumab Chemo CR/CRi/CRp 80.7% 29.4% CR 35.8% 17.4% CRi/CRp 45% 11.9% IO, inotuzumab ozogamicin Kantarjian H, et al. N Engl J Med. 2016;375(8):740-753.

Adverse Events Associated With IO Grade 3 or higher Thrombocytopenia Grade 3 or higher Febrile Neutropenia Veno-occlusive Disease (any) Inotuzumab Ozogamicin Salvage Chemotherapy 37% 59% 24% 49% 11% (n = 15) (2 deaths) 1% (n = 1) pts, patients; VOD, veno-occlusive disease Kantarjian H, et al. N Engl J Med. 2016;375(8):740-753.

Salvage IO + Mini-Hyper-CVD for Ph-neg B-ALL Overall and Relapse-Free Survival Overall Survival by Relapse Status N = 59 patients ORR = 78% VOD = 15% pts Median OS = 11 mos CVD, cyclophosphamide, dexamethasone, methotrexate, cytarabine Jabbour E, et al. JAMA Oncology. 2017 Aug 31. [Epub ahead of print].

Advent of CAR T-Cell Therapy for ALL On Friday May 28, 2010 just a few weeks after my 5 th birthday, I was diagnosed with standardrisk pre-b ALL In April 2012 I was enrolled into a phase I clinical trial at Children s Hospital of Philadelphia (CHOP). I was the first pediatric patient to receive genetically modified T cells to help fight my leukemia. I was very sick after and was in the pediatric intensive care for several weeks on a ventilator In May 2012 I found out that the new cells worked and that I was in remission!! I came home from the hospital June 1, 2012 and have been doing very well! Love, Emily Emily Whitehead Foundation. http://emilywhiteheadfoundation.org/emily-whitehead-story/. Accessed November 28, 2017.

Single-Center Trial of CTL019 (Tisagenlecleucel) in RR B-ALL 30 patients with RR B-ALL (follow-up 2 years) Characteristics - Ages 5-60 yrs old - 18 (60%) had prior allosct - 3 (10%) had refractory ALL - 22 (73%) had 2 relapses Responses - 27 pts (90%) achieved CR in 1 month - 2 of 3 pts with prior blinatumomab treatment responded Maude SL, et al. N Eng J Med. 2014;371(16):1507-1517.

Phase II Trial of Tisagenlecleucel in Pediatric Patients With RR ALL First pediatric global CAR T-cell therapy registration trial Single-arm, open-label, multicenter phase II study 25 centers in US, Canada, EU, Australia, and Japan Patients aged 3-23 years old CD19+ B-ALL primary refractory or relapsed or ineligible for allosct 5% marrow blasts by morphology Single dose of 2-5 x 10 6 transduced autologous CTL019 cells/kg (max 2.5 x 10 8 ) IV manufactured at a centralized facility Endpoint: CR + CRp at 3 months Buechner J, et al. Haematologica. 2017;102(Suppl 2): Abstract S476.

Clinical Efficacy of Tisagenlecleucel Median age 12 years (range 3-23 yrs) Median of 3 prior therapies (59% prior allosct) Among 63 evaluable patients: CR/CRi (MRD neg) 83% Single dose of 2-5 x 10 6 per kg transduced autologous T cells CD19 CD19 Survival Survival 79% 89% CTL019 Autologous T-cell Buechner J, et al. Haematologica. 2017;102(Suppl 2): Abstract S476.

Adverse Events With Tisagenlecleucel Effects Percentage Pts Comments Cytokine Release Syndrome 78% Gr 3 (21%), Gr 4 (27%) No grade 5 38% Rx tocilizumab (anti-il-6r antibody) Neutropenic fever 60% -- Hypotension 22% --- Hypoxia 16% --- Neuropsychiatric 15% No grade 4 No cerebral edema Gr, grade Buechner J, et al. Haematologica. 2017;102(Suppl 2): Abstract S476.

AlloSCT vs Chemotherapy for ALL Relapse Auto, autograft; MUD, matched unrelated donor; O/E, observed/expected; sib, sibling Fielding AK, et al. Blood. 2007;109(3):944-950.

Comparison of T-Cell Directed Therapy for ALL Blinatumomab (Antibody) CAR T Cells AlloSCT T-cell source Patient (normal cells) Donor Cells manipulation In-vivo Ex-vivo Target CD 19 on leukemia B cells Multiple Status pretreatment Low tumor burden Low tumor burden CR Administration 24 hr infusion x 28 d 1-3 infusions 1 infusion Activity duration Short Long Permanent CR 40% 1 90% 2 N/A Potential for cure No? Yes Main toxicity CRS (minimal-modest) CRS (modest severe) GVHD CRS, cytokine release syndrome; GVHD, graft-versus-host disease 1. Kantarjian H, et al. N Engl J Med. 2017;376(9):836-847. 2. Maude SL, et al. N Eng J Med. 2014;371(16):1507-1517.

Relapsed Ph+ ALL: Selection of TKI Therapy BCR-ABL1 Resistance Mutations Adverse Event Spectrum Mutation Y253H, E255KV, F359VCI F317LVIC, T315A, V299L E255KV, F317LVIC, F359VCL,T315A, Y253H T315I CNS penetration Imatinib < dasatinib levels in CSF CNS, central nervous system; CSF, cerebrospinal fluid Best TKI Dasatinib Nilotinib Bosutinib Ponatinib Column 2 Ponatinib Elevated Pancreatic Enzymes Hypertension Skin toxicity Thrombotic events Nilotinib Elevated Pancreatic Enzymes Indirect hyperbilirubinemia QT prolongation Cardiovascular events Common Effects Myelosuppression Transaminitis Electrolyte Δ Imatinib Edema/fluid retention Myalgias Hypophosphatemia GI (diarrhea, N/V) Dasatinib Pleural/pericardial effusions Bleeding risk Pulmonary arterial Hypertension Bosutinib GI (diarrhea, N/V) Headache Rash Imatinib [package insert]. East Hanover, NJ: Novartis Pharmaceuticals; August 2016. Dasatinib [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; October 2015. Nilotinib [package insert]. East Hanover, NJ: Novartis; October 2015. Bosutinib [package insert]. New York, NY: Pfizer Labs; September 2015. Ponatinib hydrochloride [package insert]. Cambridge, MA: ARIAD Pharm Inc.; August 2016.

Relapsed Ph+ ALL: TKI Plus Chemotherapy Dasatinib + Hyper-CVAD therapy Overall Survival ORR = 91% Cytogenetic response = 84% Molecular response = 42% Major molecular response = 35% 3-year OS for Ph+ ALL = 26% CML-BC, chronic myeloid leukemia in blast crisis Benjamin O, et al. Am J Hematol. 2014;89(3):282-287.

Blinatumomab for Relapsed Ph+ ALL Open-label phase II study of adults relapsed/refractory to second-generation TKI and/or intolerant of TKI 45 patients Rx blinatumomab monotherapy 36% CR/CRi after 2 cycles 88% of responders achieved MRD response Median RFS = 6.7 mos Median OS = 7.1 mos 44% to allosct RFS, relapse-free survival Martinelli G, et al. J Clin Oncol. 2017;35(16):1795-1802.

Blinatumomab + TKI for Relapsed Ph+ ALL Overall survival 9 Ph+ ALL and 3 CML blast crisis Failed 1 chemotherapy and 1 TKI Treatment: blinatumomab plus ponatinib (n = 8), dasatinib (n = 3), bosutinib (n = 1) - Complete hematologic response = 50% - Cytogenetic response = 71% - Molecular response = 75% - 2 cases of cytokine release syndrome - Median FU = 8 mo - Median OS = not reached - 1-year OS = 73% m, median; NR, not reported Assi R, et al. Clin Lymph Myeloma Lek. 2017;17(12):897-901.

Inotuzumab for Relapsed Ph+ ALL Kantarjian H, et al. N Engl J Med. 2016;375(8):740-753.

Summary: Relapsed/Refractory ALL Ph-positive and negative ALL Blinatumomab (B-ALL) (after failure of two TKIs) Inotuzumab ozogamicin (B-ALL) (TKI intolerant/refractory) Tisagenlecleucel ( 25 years, refractory, 2 relapses, failure of 2 TKIs) Chemotherapy (liposomal vincristine, clofarabine, nelarabine) Multiple-agent chemotherapy regimens Ph-positive ALL TKIs (dasatinib, imatinib, ponatinib, nilotinib, bosutinib) (first priority) TKIs plus chemotherapy Other options as listed for Ph-negative ALL NCCN Clinical Practice Guidelines in Oncology : Acute Lymphoblastic Leukemia. V5.2017. https://www.nccn.org/professionals/physician_gls/pdf/all.pdf. Accessed November 2017.

Images from: Morgan AS, et al. Blood. 2013;121:3546.