The Increasing Use of Targeted Therapies for Leukemia and Lymphoma

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Presentation transcript:

The Increasing Use of Targeted Therapies for Leukemia and Lymphoma Shira Dinner, MD Northwestern University

Educational Objectives Define terminology used regarding leukemia Describe the latest developments in the treatment of acute lymphoblastic leukemia (ALL) Blinatumomab Inotuzumab ozogamicin Chimeric antigen receptor T cells Engage patients and caregivers in clinical trial discussions on emerging therapies in ALL Identify strategies fro optimal patient care What is the best treatment for me?

Common Terminology in Leukemia Acute: Develops from immature cells in the bone marrow that replicate quickly and aggressively The cells do not grow up and perform their normal function (i.e. fight infection) Chronic: Develops from mature cells that do not function normally Typically progresses more slowly Acute lymphoblastic leukemia: An aggressive cancer that develops from a type of white blood cells in the bone marrow called lymphocytes

Common Terminology in Leukemia Complete remission (CR) The absence of any signs or symptoms of the disease < 5% blast cells in the bone marrow (when looking at the cells under a microscope) and no evidence of leukemia anywhere outside of the bone marrow Minimal residual disease (MRD) A very low level of leukemia cells that remain in the bone marrow that cannot be seen by the microscope Detected by looking for certain gene or chromosome mutations that may be present in the leukemia or by looking at antigens (proteins) on the surface of the leukemia cells Refractory disease The leukemia does not respond to treatment or does not achieve a CR Relapsed disease The leukemia was in CR, but has now come back

Common Terminology in Leukemia Overall survival (OS) The length of time from either the date of diagnosis or the start of treatment for a disease that patients diagnosed are still alive. In a clinical trial, measuring the overall survival is one way to see how well a new treatment works. Progression free survival The length of time during and after the treatment of a disease that the disease remains in remission or does not get worse.

Immunotherapies Using the immune system to attack the leukemia Antibody: A Y shaped protein made by the immune system to identify, bind, and neutralize harmful things (antigens) such as infections in the body Immunotherapies: Use antibodies created in the lab to recognize and attack the leukemia cells

Antigens in ALL There are many different proteins or antigens on the surface of ALL cells that we can design antibodies to target as part of immunotherapies

Blinatumomab: bispecific T cell engaging antibody Blinatumomab has been particularly promising in MRD positive patients, with response rates of approximately 80%. Currently under investigation in the ECOG 1910 clinical trial in newly diagnosed diseaes after induction chemotherapy and for newly diagnosed elderly patients in SWOG 1318 in elderly adults who cannot tolerate chemo: blina induction and consolidation followed by chemo maintenance

Phase 2 Blinatumomab in Relapsed/Refractory ALL Pts (%) CR/CRi during first 2 cycles, n (%) 81/189 (43%) CR 63/189 (33%) CRi 18/189 (10%) Allogeneic SCT after CR/CRi 32 of 81 (40%) Median Overall Survival 6.1 months (n=189) ~40% of patients had received 2 or more lines of therapy 80% of patients had received at least 1 prior chemotherapy to treat relapsed or refractory ALL Topp et al. Lancet Oncology 2015;16(1):57-66.

Blinatumomab: Side effects Most Common side effects Fever 113 (60%) Headache 65 (34%) Neutropenic fever 53 (28%) Neurologic side effects occurred in 98 (52%) patients, all reversible This could include confusion or delirium to rarely stroke or seizure symptoms Most were mild and resolved spontaneously 74 (76%) Most occurred during Cycle 1 85 (87%) 29 pts discontinued for neuro side effects Higher rates of neurologic toxicities in elderly patients presented at ASCO 2015 Topp et al. Lancet Oncology 2015;16(1):57-66. Topp et al. Lancet Oncology Jan;16(1):57-66.

Inotuzumab Ozogamicin (IO): antibody-drug conjugate

Baseline characteristic Phase 3 IO vs Standard of Care (SOC) chemotherapy in relapsed/refractory ALL Baseline characteristic INO (n=109) SOC (n=109) CR1 duration ≥ 12 mo 43% 35% Age < 55 yo 61% 63% Salvage 1 67% Safety The most common serious side effects were low blood counts Serious liver or gallbladder side effects occurred in 9% INO vs 3% SOC Veno-occlusive liver disease (VOD) 14% INO vs 1% SOC VOD: blockage in small veins in the liver that can cause fluid Retention and increased liver function tests (esp bilirubin) INO: 5 VOD events during treatment, 10 post SCT (2 fatal) DeAngelo et al. EHA 2015. Abstract 2073

IO Efficacy INO (n=109) SOC (n=109) Median duration of treatment 8.3 weeks (0.1-26.4) 0.9 weeks (0.4-15.1) CR/CRi 80.7 33.3 S1 87.7 31.3 S2 66.7 37.9 Median DOR, mo 4.6 (3.9-5.4) 3.1 (1.4-4.9) MRD negativity 78.4 28.1 Treatment discontinuation: 83% INO mainly due to CR 89% SOC mainly due to resistant disease AlloHSCT 44% INO vs 18% SOC DeAngelo et al. EHA 2015. Abstract 2073

Chimeric Antigen Receptor T Cells

Generation of CAR T Cells 5’ LTR 3’ LTR ψ SD SA VH VL α-tumor scFv CD28 ζ chain ScFv CD28 2. Subclone CAR gene into a vector 1. Construct a CAR CD3ζ 3. Transduce and expand patient T cells ex vivo Retroviral vector encoding CD19 CAR cDNA Genetically modified CD19-targeted T cell T cell CD19 Tumor cell CAR

Common Side Effects Cytokine release syndrome (CRS) Fever Hypotension Respiratory insufficiency Neurological changes or symptoms Delirium/disorientation Global encephalopathy (tremors, seizure-like jerks) Aphasia Seizure Can occur within 1-14 days of T cell infusion Patients must be monitored in the hospital More severe symptoms in patients with higher leukemia disease burden

Results of CAR T cell trials Patients +ALL prior to CAR T infusion CR N(%) MRD negative N (%) HSCT DFS OS CRS % Neuro Side effects UPenn pediatric and adult 30 (25 pediatric, 5 adult) 80% 27 (90) 23 (77) 3 (10%) 63% at 6 months 78% at 6 months 90% 43% MSKCC adult 43 51% 36 (84) 29 (83) 12 (28%) 28% after 12 months Median 8.5 months 77% 52% NCI adult 20 NR 14 (70) 12 (60) 10 (50%) 79% at 4.9 months for MRD negative patients 51.6% at 10 months 75% 30% EFS: time of remission until relapse or death

Remaining questions with CAR T cells How long do CAR T cells last in the body? Do you need an allogeneic stem cell transplant after achieving remission with CAR T cells? Could patients be retreated with CAR T cells?

Possible side effects of CAR T cells Cytokine release syndrome Fever Neurotoxicity T-cell infusion reaction Tumor lysis syndrome Low B-cell levels (increased infection risk) GVHD The virus used to engineer the T cells could replicate in the patient’s body Uncontrolled T-cell proliferation The genetically modified product may insert itself into the patient’s DNA and cause other cancers Key toxicities observed in the Phase 1 studies Potential toxicities of CAR T cell therapy, but not observed in the Phase 1 studies

Summary New therapies for leukemia and lymphoma are taking advantage of copying or utilizing the immune system to attack the cancer Several new immunotherapies are available for ALL No clinical trials have compared blinatumomab vs IO vs CAR T cells We do not yet know which is the “best” treatment or what order we should give the treatments in It is important to consider side effects when selecting a treatment with your doctor Blinatumomab: neurologic side effects, cytokine release syndrome IO: liver side effects CAR T cells: CRS, neurologic side effects Talk to your doctor about a clinical trial