Nursing Symposium. Lymphoma and Myeloma. Indianapolis, IN

Transcription

1 Nursing Symposium Lymphoma and Myeloma Indianapolis, IN March 7, 2015 Myron S. Czuczman, MD Chief, Lymphoma/Myeloma Service Head, Lymphoma Translational Research Lab Professor of Medicine and Oncology Roswell Park Cancer Institute Buffalo, NY

2 Disclosure Information Myron S. Czuczman, MD I have the following financial relationships to disclose: Membership on advisory committees or consultant / review panels for: Algeta, Boehringer Ingleheim, Celgene, Gilead, Millennium, MorphoSys, Mundipharma, Teva, and TG Therapeutics Honorarium from: MundiPharma I WILL include discussion of investigational or off-label use of product(s) in my presentation

3 NHL: Risk Factors Cause of NHL unknown for most people Inherited Familial: accounts for a small percentage of cancers Environmental Certain chemicals suspected (e.g. certain pesticides / herbicides) High-dose radiation exposure suspected Immunosuppression Immune deficiency (AIDS, post organ transplant, some medications, maturing to a ripe age ) Viral and Bacterial Infections (HTLV-1 virus, EBV, H. pylori bacteria)

4 NHL Subtypes T and NK cell (12%) Burkitt (2.5%) Other subtypes (9%) Diffuse large B cell (DLBCL) (30%) Mantle cell (6%) Follicular (25%) Small lymphocytic (7%) MALT-type marginal-zone B cell (7.5%) Nodal-type marginal-zone B cell (<2%) Lymphoplasmacytic (<2%) Percentages of all NHLs MALT=mucosa-associated lymphoid tissue; NK=natural killer Lichtman. Williams Hematology. 7th ed. New York, NY: McGraw Hill. 2006;1408

5 NHL: A Comparison of General Clinical Subtypes Indolent Aggressive Highly Aggressive Survival if Untreated Years Months Weeks Current Standard of Care Curability With Conventional Therapy Examples Rituximab Chemo SCT No FL, SLL, MZL Rituximab/Chemo SCT Some subtypes curable DLBCL, MCL Rituximab/Chemo Some subtypes curable Burkitt FL=follicular lymphoma; MCL=mantle-cell lymphoma; MZL=marginal-zone lymphoma; SCT=stem cell transplantation; SLL=small lymphocytic lymphoma. DeVita. Cancer: Principles & Practice of Oncology. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins. 2005; ; Lichtman. Williams Hematology. 7 th ed. New York, NY: McGraw-Hill. 2006; ; Jemal. CA Cancer J Clin. 2008;58:71

6 Current Lymphoma Field: Rapidly Changing Landscape Heterogeneity/complexity of NHL will not change We are developing scientific tools to better understand it: Biologic, genetic, and clinical features Results from targeted therapies (e.g. mabs, SMI, etc) and novel Rx approaches are exciting Historical approaches need to be critically reviewed and retested and will require data from well-designed clinical trials: Optimal combination(s) of old and new agents? Optimal timing and sequencing of specific therapies?

7 CD80 CD20 CD40 CD22 NHL: emerging agents Microenvironment Surface markers Bevacizumab 1 Lenalidomide 2* Anti-CD20; anti-cd22 mab/(rit) 2* Anti-CD19 mab 4 /immunoconjugates Chemotherapy Bendamustine 3* Anti-CD79b/Anti-CD22 immunoconjugates/ RIT 1,2* Bcl-2 family inhibitors: ABT-263, 5 ABT-199 Pathways Proteasome PKC inhibitors: inhibitors: mtor Enzastaurin 6,7 Bortezomib; 2,5,6 inhibitors: 2 nd generation 6 Everolimus 6,7 BCR-signaling 7 Temsirolimus 6,7 *Denotes agent is licensed for a B-cell NHL indication Idelalisib; Ibrutinib HDAC inhibitors: Vorinostat (SAHA) 6 Panobinostat (LBH589) 6 Immune check-point inhibitors! 1. Kahl B. SeminHematol 2008;45: Gregory SA, et al. Oncology 2010;24:5. 3. Cheson BD, et al. Clin Lymphoma Myeloma Leuk 2010;10: Gerber H-P, et al. Blood 2009;113: Tageja N, et al. J Hematol Oncol 2009;2: Delmonte A, et al. Oncologist 2009;14: Witzig TE & Gupta M. Hematology Am Soc Hematol Educ Program 2010; Adapted slide courtesy of DeVos, UCLA

8 Potential Future Strategies to Combine in Induction or to Replace Maintenance Rituximab Novel anti-cd20 constructs Enhancing Effector cell # s and function Targeting different surface Ags Immunotoxins/Immunoconjugates/RIT B-cell receptor pathway inhibitors Restoring Pro-Apoptotic Potential (ABT-199) Restoring/Augmenting T-cell function (anti-pd1) Immunomodulatory drugs (IMiDs) Replace R Maintenance with short course of novel consolidation!!!

9 B-Cells: Express Many Surface Antigens That May Serve as Targets for mabs B-Cell Marker B-cell receptor (BCR) CD19 CD20 CD21 CD22 CD23 CD38 CD40 CD52 Antigen expression variable 1,2 Most involved in B-cell growth, differentiation, proliferation, and activation; other functions 1,2 Many are targets of therapeutic mabs for current or potential use in B-cell malignancies 1,2 CD46, CD55, CD59 CD74 CD80 1 Bello C, Sotomayor EM. Hematology Am Soc Hematol Educ Program. 2007;2007: Hotta T. Acta Histochem Cytochem. 2002;35(4):

10 BiTE Technology: Blinatumomab Apoptosis of tumor cells Membrane blebbing Activation of caspases Cleavage of PARP Fragmentation of DNA Morphological changes An bispecific single-chain antibody construct with dual specificity for the CD19 and CD3 antigens on B cells Nagorsen and Baeuerle. Exp Cell Res 2011

11 Proteasome inhibition: affects multiple signaling pathways 2012 by AlphaMed Press Mato A R et al. The Oncologist 2012;17:

12 Effects of Lenalidomide on Tumor Cells and their Microenvironment Chanan-Khan and Cheson. J Clin Oncol 26:1544; 2008

13 FL-001: Phase 3 Study Design Primary end-point: PFS 1st line FL n = 1000 S R R 2 CR, CRu, PR R 2 maintenance R-Chemo Rituximab maintenance R 2 = Rituximab + Lenalidomide R-Chemo (investigator choice of R-CHOP, R-CVP, R-B) Lenalidomide 20 mg x 6 cycles, if CR then 10 mg Co-primary endpoints surrogate endpoint (for initial approval): a) CR/CRu rate at 1.5 years; b) PFS

14 Targeting the B Cell Receptor Pathway utilized by normal cells Differentiation, proliferation Appears some B cell malignancies have tonic signaling through pathway Unclear what is source of signaling One of the most exciting areas of novel therapeutics in B cell malignancies

15 PI3K delta and BTK Inhibition Impacts Multiple Critical Pathways Offering a Novel Targeted Therapeutic Approach in B-Cell Neoplasms Diagram courtesy: Gilead Sciences

16 B-cell Receptor Pathway Inhibitors: Peripheral Lymphocytosis Significant anti-tumor activity of kinase inhibitors that target BCR pathway signaling have been demonstrated (e.g. spleen tyrosine kinase [fostamatinib], PI 3 kᵟ [idelalisib], and Bruton s tyrosine [ibrutinib]) Several MOA s are induced (esp. CLL) Rapid lymph node shrinkage CLL cell redistribution peripheral lymphocytosis Antiproliferation Inactivation of CLL homing mechanisms Mobilization of CLL cells from tissues/ln microenvironment to peripheral blood resensitizes them to chemotherapy/other active agents* *Blood 28: , 2013

17 Targeting Leukemia with Chimeric Antigen Receptor Modified T cells CARs combine an Ag recognition domain of antibody with intracellular signaling domain into single chimeric protein Gene transfer (lentivirus vector) to stably express CAR on T cells confers novel Ag specificity Native TCR T cell CTL019 cell CD19 Dead tumor cell Tumor cell Anti-CD19 CAR construct Courtesy: John Gribben

18 Antibody-Drug Conjugates (ADCs) Composed of a mab, a stable linker, and the microtubule-disrupting agent, monomethyl auristatin E (MMAE) High target specificity restricted to CD22-, CD79b- or CD30-expressing cells e-molecules/anti-cd79b Hence, has the potential to deliver a more potent dose of cytotoxic drug, while minimizing toxic effects on non-expressing cells Polson et al. Blood 2007; Dornan et al. Blood 2009

19 ABT-199: Bcl-2 inhibitor Dose Escalation Schematic of Cohort 1 >95% reduction in lymphocytosis within 24h in two patients Rapid reduction in palpable lymphadenopathy 3 out of 3 patients enrolled in Cohort 1 experienced dose-limiting laboratory tumor lysis syndrome (TLS): No clinical sequelae, no organ dysfunction Dose Escalation Schematic of Cohorts of 53 patients experienced an event of tumor lysis with modified schedule a 3 patients (1 each in cohort 2 and 3, and 1 in cohort 5) received ABT mg as the initial dose. b Week 2 dose in cohorts 2-5 = 100 mg.

20 Where are we going? / Conclusions Use of risk analysis to individualize Rx in future Ongoing translational research will identify additional novel therapeutic targets; Biomarkers associated with response to a given agent are needed Targeted combo therapies increase direct anti-tumor activity while decreasing toxicities Achieveable Goal: Prolongation of life and quality-oflife(and hopefully cure rates) in lymphoma patients with novel non-cross-resistant targeted agents!

21 What is Myeloma? Myeloma is a type of bone marrow cancer involving plasma cells Plasma cells are normally found in the bone marrow Marrow is the spongy tissue found in the center of the bone this is where all blood cells are made Plasma cells are part of the immune system and are a type of white blood cell Plasma cells normally make antibodies, which help fight infection In patients with myeloma, plasma cells are often present in abnormally large numbers Bone marrow Cells in the marrow of a patient with myeloma

22 Myeloma Anemia Immune suppression High calcium M protein Malignant plasma cells Myeloma kidney disease Myeloma bone disease

23 Myeloma Second most common hematological malignancy Median age at diagnosis is 69 and median age at death is 75 Annual incidence of 4-5 per 100,000 11,000 deaths/yr in the US NCI SEER Stat Fact Sheets

24 Myeloma Symptoms Some patients have no symptoms at diagnosis Routine blood work may show: Anemia Elevated creatinine Elevated total protein These results may lead to more specific tests being ordered for myeloma Common symptoms Bone pain Unexpected fractures Frequent infections Fatigue Kidney damage and/or failure Unexplained weight loss

25 Diagnosis of myeloma Blood and urine samples Identify and quantify abnormal protein produced by the cancer cells (SPEP/UPEP, SIFE/UIFE, free light chains) Bone marrow biopsy Identify and quantify the malignant plasma cells Specialized testing of the cancer cells to determine high vs. low risk features (cytogenetics, FISH) Radiology X-rays: look for lytic lesions in the bones MRI: more detailed look at bone involvement PET/CT: look for myeloma outside of the bone marrow (extramedullary)

26 Historical perspective of myeloma therapies

27 Myeloma therapies Corticosteroids: dexamethasone, prednisone Immunomodulatory drugs: thalidomide, lenalidomide, pomalidomide Proteasome inhibitors: bortezomib, carfilzomib Traditional chemotherapy: melphalan, cyclophosphamide, doxorubicin Corticosteroids: dexamethasone, prednisone Single agent or in combination with other myeloma therapies Hyperglycemia, edema, weight gain

28 Myeloma therapy Side-Effects Immunomodulatory drugs: thalidomide, lenalidomide, pomalidomide Risk for DVT all patients need to be on aspirin or anticoagulation Teratogenic Cytopenias (lenalidomide, pomalidomide) Neuropathy (thalidomide) Proteasome inhibitors: bortezomib, carfilzomib Increased risk of shingles all patients need to be on prophylactic anti-viral therapy Peripheral neuropathy (numbness, tingling, pain): bortezomib >>> carfilzomib Cardiopulmonary toxicity: carfilzomib >> bortezomib

29 Autologous stem cell transplant Standard of care for patients <75 years of age Typically done as consolidation following induction with multi-agent therapy High dose melphalan followed by infusion of stem cells Maintenance with lenalidomide after transplant improves progression-free and overall survival

30 On the horizon Monoclonal antibodies (daratumumab, elotuzumab) Histone deacetylase inhibitors (panobinostat) Oral proteasome inhibitors Aurora kinase inhibitors Vaccine-based strategies

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