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Advances in the Treatment of Hematologic Malignancies a Review of Newly Approved Drugs

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Advances in the Treatment of Hematologic Malignancies a Review of Newly Approved Drugs Advances in the Treatment of Hematologic Malignancies A Review of Newly Approved Drugs Katherine Shah, PharmD, BCOP Clinical Pharmacy Specialist, Hematology/Oncology Emory University Hospital / Winship Cancer Institute Disclosures • I do not (nor does any immediate family member have) a vested interest in or affiliation with any corporate organization offering financial support or grant monies for this continuing education activity or any affiliation with an organization whose philosophy could potentially bias my presentation • There was no financial support obtained for this CPE activity 1 Objectives • Discuss the pharmacologic principles of several new agents approved for use in hematologic malignancies – Drug class – Mechanism of action – Clinical trial highlights • Review approved dosing and recommend appropriate clinical monitoring and management of toxicities of new agents covered – Dosing recommendations for new agents – Side effect profile – Clinical management Approvals 1980‐2014 http://innovation.org/images/dmImage/SourceImage/lg_FDA_Approval.jpg 2 2014 Novel Drug Approvals Nature Reviews Drug Discovery 14, 77–81(2015) doi:10.1038/nrd4545 Select 2014 Novel Oncology Drugs Drug Indication Approval Date Siltuximab (Sylvant) Multicentric Castleman’s April 2014 Disease Belinostat (Beleodaq) Peripheral T‐cell Lymphoma July 2014 Idelalisib (Zydelig) CLL, Follicular NHL, SLL July 2014 Netupitant and Nausea/vomiting October 2014 palonosetron (Akynzeo) Blinatumomab Acute Lymphoblastic December 2014 (Blincyto) Leukemia, Ph‐ Ph-= Philadelphia Chromosome-negative http://www.fda.gov/downloads/drugs/developmentapprovalprocess/druginnovation/ucm430299.pdf 3 Siltuximab (Sylvant™) •FDA Approval: April 23, 2014 •First in class, accelerated approval for treatment of Multicentric Castleman’s Disease •Chimeric monoclonal antibody against IL‐6 Castleman’s Disease • 1954: First case report by Dr. Benjamin Castleman • Rare, non-clonal lymphoproliferative disorder • Enlarged hyperplastic lymphadenopathy involving either: • Single lymph node = Unicentric (UCD) • Multiple lymph nodes = Multicentric (MCD) •MCD • Risk Factors: HIV and Human Herpes Virus 8 (HHV-8) • Pathogenesis: HIV, HHV-8, Interleukin-6 (IL-6) 4 Classifications Castleman’s Disease Unicentric Multicentric (UCD) (MCD) HHV8 + HHV8 _ HIV + HIV _ Clinical Presentation: MCD • Clinical spectrum range – Waxing and waning lymphadenopathy with mild symptoms to a more aggressive systemic disease • Systemic inflammatory manifestations – Fevers, night sweats, weight loss, fatigue • Physical examination – Generalized lymphadenopathy, hepatosplenomegaly, edema • Common lab abnormalities – Anemia, thrombocytopenia, thrombocytosis, hypergammaglobulinemia, hypoalbuminemia, elevated inflammatory markers Cancer Control. 2014 Oct;21(4):266-78, Expert Rev. Hematol. 7(5), 545–557 (2014). 5 Role of IL‐6 Trends Immunol. 2012 Nov;33(11):571-7 Siltuximab Mechanism Chimeric IL-6 monoclonal antibody 6 Siltuximab in MCD Study design • Randomized, double-blind, placebo-controlled study in HIV- and HHV8- patients with symptomatic MCD • Newly diagnosed or previously treated (except those who had received IL-6 targeted treatment) • Primary endpoint: durable tumor and symptomatic response Treatment groups 2:1 Siltuximab + BSC Placebo + BSC 11 mg/kg IV q3 weeks q3 weeks n=26 n=53 BSC= Best Supportive Care Lancet Oncol. 2014 Aug;15(9):966-74 Results Days to Treatment Failure Disease Related Overall Symptom Score HR 2.774 37% difference (1.068 to 7.206) p= 0.0018 Siltuximab Placebo p value Durable tumor and 34% 0 0.0012 symptomatic response CR 2% 0 ‐‐‐ PR 32% 0 ‐‐‐ Lancet Oncol. 2014 Aug;15(9):966-74 7 Toxicity Adverse Effect (all grades) Siltuximab Placebo Pruritis 42% 12% Upper respiratory tract infection 36% 15% Fatigue 34% 38% Maculopapular rash 34% 12% Peripheral edema 32% 23% Peripheral neuropathy 25% 19% Diarrhea 23% 19% Weight gain 21% 0 • Discontinued due to adverse events in only 1 patient due to anaphylactic reaction Lancet Oncol. 2014 Aug;15(9):966-74 Dosing and Administration First drug approved in MCD (HHV8‐ & HIV‐) Dose: – 11 mg/kg IV infusion over 1 hour every 3 weeks until treatment failure – No renal or hepatic dose adjustments – Treatment should be delayed if: • First dose: ANC <1000; Plt <75,000; Hgb >17 g/dL • Subsequent: ANC <1000; Plt < 50,000; Hgb>17g/dL Sylvant® [package insert] Horsham, PA: Janssen Biotech; 2014 8 Dosing and Administration • Do not administer with severe infections • Infusion reaction rate in 249 patients treated: <5% • T1/2: 20.6 days • Cost: ~ $5,000 for 70 kg patient every 3 weeks Sylvant® [package insert] Horsham, PA: Janssen Biotech; 2014 Belinostat (Beleodaq®) •FDA Approval: July 3, 2014 •Accelerated approval for treatment of relapsed or refractory peripheral T‐cell lymphoma (PTCL) •Histone deacetylase (HDAC) inhibitor 9 Belinostat Mechanism Marks P et al. Nature Reviews Cancer 2001;1:194-202. Belinostat Mechanism • Small molecule 10 Inhibition of HDAC http://medind.nic.in/jat/t14/i3/JCanResTher_2014_10_3_469_137937_f2.jpg 11 Results Response Rate n= 120 ORR 26% Complete Response (CR) 11% Partial Response (PR) 15% Stable disease 15% Progressive disease 40% Not evaluable* 19% *Prior to first radiologic assessment due to death (n=7); clinical progression (n=10); patient withdrawal (n=5); lost to follow-up (n=1) O’Connor OA et al. Proc ASCO 2013; Abstract 8507. Select Grade ≥ 3 Adverse Events O’Connor OA et al. Proc ASCO 2013; Abstract 8507. 12 Dosing and Administration • Indication: Relapsed or refractory PTCL • Dosing: 1000 mg/m2 IV daily on Days 1‐5 of a 21‐day cycle – Continue until disease progression or unacceptable toxicity Idelasilib (Zydelig™) •FDA Approval: July 23, 2014 •First in class, accelerated approval for treatment of relapsed CLL, follicular B‐ cell NHL and SLL. •PI3K inhibitor 13 Idelalisib Mechanism • Inhibits PI3K delta kinase – Expressed on normal & malignant B‐cells • Induces apoptosis, inhibits proliferation & cell signaling pathways – Involved in trafficking and homing of B‐cells to lymph nodes and bone marrow • Inhibits chemotaxis and Fruman DA, Cantly LC. N Engl J Med 2014; 370:1061-1062 adhesion Idelalisib Indications Relapsed CLL in combination 1 with rituximab Relapsed Follicular B‐cell 2 Non‐Hodgkin Lymphoma after at least 2 systemic therapies Relapsed SLL after at least 2 3 systemic therapies 14 Idelasilib in CLL 15 Outcomes Coutre et al ASCO 2014 Toxicities Coutre et al ASCO 2014 16 Toxicities Warnings and Precautions Grade 5 Hepatotoxicity 1/1192 = 0.1% Diarrhea 1/1192 = <0.1% Pneumonitis 3/760 = 0.5% Perforation 2/1192 = 0.2% Zydelig [package insert]. Foster City, CA; Gilead Sciences Inc.; 2014. 17 Warnings and Precautions • Severe cutaneous reactions • Neutropenia – 30% ≥ Grade 3 – CBC at least every 2 weeks for first 3 months • Anaphylaxis Zydelig [package insert]. Foster City, CA; Gilead Sciences Inc.; 2014. Adverse Reactions • Diarrhea • Chills • Pyrexia • Rash • Fatigue • Neutropenia • Nausea • Hypertriglyceremia • Cough • Hyperglycemia • Pneumonia • AST/ALT increases • Abdominal pain 18 Dosing and Administration • Starting dose: 150 mg PO BID • Take without regard to food, swallow whole • Continue until progression or http://images2.ddccdn.com/images/pills/fio/GIL17010.JPG unacceptable toxicity 100 mg, 150 mg tablets Renal Dose No dose adjustment if CrCL ≥ 15 ml/min Adjustment Patients with AST/ALT > 2.5 x ULN and Hepatic Dose T.Bili > 1.5 x ULN excluded from studies. Adjustment If hepatic impairment at baseline, monitor for toxicity. Blinatumomab (Blincyto™) •FDA Approval: July 23, 2014 •First in class, accelerated approval for treatment of relapsed/refractory Ph‐ ALL •Bispecific CD19‐directed CD3 T‐cell engager 19 Blinatumomab Mechanism Bispecific CD19‐directed CD3 T‐cell engager Kapoor A, et al. Clinical Cancer Investigation Journal. 2014: 3 (6) 577-578 Blinatumomab in Relapsed/Refractory B‐Precursor ALL Study Design •Multicenter, single‐arm, open label phase 2 study •Patients ≥ 18 y.o. with Philadelphia chromosome negative, primary refractory or relapsed ALL •Primary endpoint: CR or CRh within the first two cycles Treatment • Blinatumomab (9 mcg/day for the first 7 days and 28 mcg/day thereafter) by continuous intravenous infusion over 4 weeks every 6 weeks CR = complete remission CRh = CR with partial haematological recovery of peripheral blood counts Topp MS et al Lancet Oncol 2015; 16: 57–66. 20 Results Patients (%) CR or CRh during the first two cycles 81/189 (43) Best response during the first two cycles CR 63/189 (33) CRh 18/189 (10) No response to therapy 90/189 (48) Not evaluable 18/189 (10) Allogeneic HSCT after CR or CRh 32/81 (40) Allogeneic HSCT after CR 28/63 (44) Allogeneic HSCT after CRh 4/18 (22) Topp MS et al Lancet Oncol 2015; 16: 57–66 Safety Adverse Event Any Grade (%) Patients with adverse events 188 (99%) Febrile neutropenia 53 (28%) Neutropenia 33 (17%) Anemia 38 (20%) Hyperglycemia 24 (13%) ALT increased 24 (13%) Hypokalemia 45 (24%) Pyrexia 113 (60%) Tremor 33 (17%) Dizziness 26 (14%) Cytokine release syndrome 20 (11%) Topp MS et al Lancet Oncol 2015; 16: 57–66 21 Dosing One cycle = 4 weeks of continuous intravenous infusion followed by a 2 week treatment free interval 2 induction cycles + 3 consolidation cycles Cycle 1 (patients ≥ 45 kg) 9 mcg/day on Days 1‐7 28 mcg/day on Days 9‐28 Hospitalized: first 9 days Cycle 1 first 2 days Cycle 2 Subsequent cycles 28 mcg/day on Days 1‐28 Blincyto [package insert]. Thousand Oaks, CA; Amgen Inc.; 2014. Blinatumomab No dose adjustment; no information in
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