Topics. Aggressive T-Cell Lymphoma Overview. Lymphoma Research Foundation. Caring for Patients with Rare Lymphomas Focus: Aggressive T-Cell Lymphomas

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1 Lymphoma Research Foundation Caring for Patients with Rare Lymphomas Focus: Aggressive T-Cell Lymphomas Steven Horwitz, MD Attending Physician Memorial Sloan-Kettering Cancer Center Christine Liebertz, NP, RN Memorial Sloan-Kettering Cancer Center Owen A. O Connor Connor, MD, PhD New York University Cancer Institute Topics Overview of T-cell s Emerging approaches in the treatment of aggressive T-cell s Nursing care implications Aggressive T-Cell Lymphoma Overview Steven Horwitz, MD Attending Physician Memorial Sloan-Kettering Cancer Center 1

2 WHO Classification of Lymphoid Neoplasms (2008) Precursor Indolent B Aggressive B Mature T/NK HL and PTLD B lymphoblastic T-cell prolymphocytic leukaemia leukaemia/ Chronic lymphocytic Mantle cell T-cell large granular lymphocytic HODGKIN LYMPHOMA B lymphoblastic leukaemia/ small lymphocytic Diffuse large B cell leukaemia Nodular lymphocyte leukaemia/, NOS (DLBCL), NOS Chronic lymphoproliferative disorder of predominant Hodgkin B lymphoblastic B cell prolymphocytic T cell/histiocyte rich large B cell NK-cells leukaemia/ leukaemia Aggressive NK cell leukaemia Classical Hodgkin with recurrent genetic Splenic marginal zone Primary DLBCL of the CNS Systemic EBV positive T-cell abnormalities Primary cutaneous DLBCL, leg lymphoproliferative Nodular sclerosis classical B lymphoblastic Hairy cell leukaemia type disease of childhood Hodgkin leukaemia/ Splenic /leukaemia, EBV positive DLBCL of the Hydroa vaccineforme-like Lymphocyte-rich classical with t(9;22)(q34;q11.2); BCR- unclassifiable* elderly Hodgkin ABL1 Adult T-cell leukaemia/ Splenic diffuse red pulp small B DLBCL associated with chronic Mixed cellularity classical B lymphoblastic cell inflammation Extranodal NK/T cell, nasal Hodgkin leukaemia/ type Hairy cell leukaemia variant Lymphomatoid granulomatosis Lymphocyte depleted with t(v;11q23); MLL rearranged Enteropathy-associated T-cell Lymphoplasmacytic Primary mediastinal (thymic) classical Hodgkin B lymphoblastic Waldenström s large B cell leukaemia/ mphoma Hepatosplenic T-cell macroglobulinemia Intravascular large B cell POST-TRANSPLANT TRANSPLANT with t(12;21)(p13;q22); TEL- Heavy chain diseases Subcutaneous panniculitis-like T-cell LYMPHOPROLIFERATIVE AML1 Alpha heavy chain disease ALK positive large B cell DISORDERS (PTLD) (ETV6-RUNX1) Gamma heavy chain disease Mycosis fungoides Early lesions B lymphoblastic Mu heavy chain disease Plasmablastic Sézary syndrome Plasmacytic hyperplasia leukaemia/ Plasma cell myeloma Large B cell arising in Primary cutaneous CD30 positive T- Infectious mononucleosislike PTLD with hyperdiploidy HHV8 associated multicentric cell lymphoproliferative disorders Solitary plasmacytoma of bone B lymphoblastic Castleman disease Lymphomatoid papulosis Polymorphic PTLD leukaemia/ Extraosseous plasmacytoma Primary effusion Primary cutaneous anaplastic large Monomorphic PTLD (B- and with hypodiploidy (hypodiploid Extranodal marginal zone Burkitt cell T/NK-cell types) # ALL) of mucosaassociated lymphoid tissue B cell, unclassifiable, Primary cutaneous gamma-delta T-cell Classical Hodgkin B lymphoblastic (MALT ) with features intermediate type PTLD # leukaemia/ between diffuse large B cell Primary cutaneous CD8 positive Nodal marginal zone with t(5;14)(q31;q32); IL3-IGH and Burkitt aggressive epidermotropic cytotoxic T- Paediatric nodal marginal zone B lymphoblastic cell leukaemia/ with B cell, unclassifiable, Primary cutaneous CD4 positive Follicular t(1;19)(q23;p13.3); E2A-PBX1; with features intermediate small/medium T-cell Paediatric follicular between diffuse large B cell Peripheral T-cell, NOS (TCF3-PBX1) Primary cutaneous follicle and classical Angioimmunoblastic T-cell T lymphoblastic centre Hodgkin leukaemia/ Anaplastic large cell, ALK positive Anaplastic large cell, ALK negative WHO 2008 CLASSIFICATION OF MATURE T/NK-CELL NEOPLASMS Leukemic or disseminated T-cell prolymphocytic leukemia T-cell large granular lymphocytic leukemia Chronic lymphoproliferative NK cells Aggressive NK-cell leukemia Adult T-cell /leukemia Systemic EBV-positive T-cell Extranodal Extranodal NK/T-cell, nasal type Enteropathy-type intestinal T-cell Hepatosplenic T-cell Nodal Angioimmunoblastic T-cell (AITL) Anaplastic large cell, ALK-positive Anaplastic large cell, ALK-negative Peripheral T-cell, NOS Extranodal cutaneous Mycosis fungoides Sezary syndrome Primary cutaneous CD30+ lymphoproliferative Primary cutaneous anaplastic large cell Lymphomatoid papulosis Borderline lesions Subcutaneous panniculitis-like like T-cell Primary cutaneous gamma-delta T-cell Hydroa vacciniforme Primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell Primary cutaneous small/medium CD4+ T-cell (provisional) International PTCL Study Major NHL Types by Region Percent NA EU FE PTCL, unspecified Angioimmunoblastic Anaplastic, ALK Anaplastic, ALK NK/T-cell ATLL J.M. Vose submitted 2

3 Expert Agreement:Consensus Diagnosis ALCL, ALK+ 91% PTCL, unspecified 74% ATLL 93% Panniculitis-like 75% Nasal NK/T-cell 84% ALCL, ALK- 74% Angioimmunoblastic 81% Hepatosplenic 72% Enteropathy-type 79% Cutaneous ALCL 66% Vose, Weisenburger, et al, International T-cell Classification Project Other Ways of Classifying T-cell Lymphomas Survival of Cutaneous PTCL by Phenotype Alpha/beta versus Gamma/delta All cases Clinical Tumors Toro et al. Blood 101:3407, Prognosis: Overall and Failure-free Survival PTCL-NOS Cases Proportion Time CENSOR FAIL TOTAL MEDIAN FFS OAS Vose, Weisenburger, et al, International T-cell Classification Project 3

4 Peripheral T-cell Lymphoma Overall Survival by the IPI Lopez-Guillermo et al, Ann Oncol 1998 Prognostic Index for PTCL-U: Incorporation of Markers Prognostic Factors Age > 60 PS >2 LDH elevated Ki-67 >80% Group I (0-1) Group 2 (2) Group 3 (3-4) Went, P. et al. J Clin Oncol; 24: Copyright American Society of Clinical Oncology Mature T and NK Lymphomas: FFS of Different Histologies Proportion ALCL ALK AITL PTCL ALCL ALK- NK/T-nasal type 0.0 ATLL EATCL Time Survival FFS OAS CENSOR FAIL TOTAL MEDIAN Vose, Weisenburger, et al, International T-cell Classification Project 4

5 Cutaneous and Systemic CD30+ Features LyP Primary Cutaneous ALCL ALK + systemic ALK systemi c M: F 1.5:1 3:1 3: 1 0.9:1 B symptoms % 60 % Relapse 94% skin only 2% outside skin 41% Skin only 9% outside skin 82 % 28 % Adapted from Bekkenk et al, Blood 2000, Falini et al Blood 1999 Primary Cutaneous CD30+ Lymphomas: Dutch Cutaneous Lymphoma Group LYP Cut ALCL + Local LN Primary Cut ALCL Secondary Cut ALCL N=219 Bekkenk et al, Blood, Vol. 95 No. 12, 2000: pp Baseline with CHOP/CHOP-Like: PTCL-U BCCA OS by IPI Savage et al. Annals of Oncology 2004; 15:

6 CHOP based therapy for Peripheral (Mature) T/NK Lymphomas Sometimes Peripheral T-cell NOS Angioimmunoblastic T-cell Anaplastic Large Cell-ALK-1 negative Enteropathy-type intestinal Subcutaneous panniculitis-like T-cell Always Anaplastic Large Cell-ALK-1 positive Never Mycosis Fungoides Sezary syndrome Primary cutaneous CD30+ disorders Anaplastic large cell Lymphomatoid papulosis T-cell large granular lymphocytic Extranodal NK/T-cell -nasal Hepatosplenic T-cell NK/T-cell leukemia/ Adult T-cell leukemia/ T-cell prolymphocytic leukemia EMERGING APPROHES IN THE TREATMENT OF AGGRESSIVE T-CELL LYMPHOMA Owen A. O Connor, MD, PhD Director, Lymphoid Development and Malignancy Program Herbert Irving Comprehensive Cancer Center Chief, Lymphoma Service College of Physicians and Surgeons The New York Presbyterian Hospital Columbia University Medical Center New York, N.Y. EMERGING APPROHES IN THE TREATMENT OF AGGRESSIVE T-CELL LYMPHOMA Emerging role of pralatrexate in T-cell The emergence of histone deacteylase inhibitiors in T-cell NHL Promising new experience with the imids in T-cell Lenalidomide 6

7 TUMOR CELL RFC-1 PDX (& Natural Folates) TMTX PDX Plasma membrane FPGS ATP + MgCl 2 PDX(G) n ATP Lysosome G n PDX(G) n ADP PDX FPGH + SH cysteine cysteine cysteine? cmoat/ MRP ATPase PDX cysteine Classical Folate Analogs are Internalized by RFC-1 in Tumor Cells and Fetal Cells but not in Normal Proliferative Tissues EARLY EVIDENCE OF MARKED AND DURABLE TIVITY WITH PRALATREXATE IN LYMPHOMA Disease CR/CRu PR ORR POD All Patients (n=48/57) B-Cell (n=20/24) T-Cell (n=22/30) % % (4 PET (-)) 54% 10 O Connor, O. A. et al. JCO 2009 Disease DURABILITY OF SELECT RESPONSES Response Rate Response to Prior Rx Duration T-Cell ALL (n=1) 1 CR 7 months 12 months HTLV-1 ATLL (n= 3) 1 CR Refractory 21+ months SQ-Paniculitis like TCL (γ,δ) (n = 2) 2 CR Refractory Refractory 9 months AlloTx 7+ months Blastic NK/T (n=1) 1 CRu 6 Weeks 8 months ALK (+) ALCL (n=1) PET(-) PR 4 Years 10+ months PTCL NOS (n=2) Angioimmunoblastic (n = 5) CRu PR 1 (for 5) 4 months Refractory Refractory 3 months - 6+ months PET(-) PR 3 Months Mycosis Fungoides PR Refractory 2 months+ O Connor, O. A. et al. JCO

8 PROPEL Patient Characteristics PRALATREXATE TREATED (N=111) CATEGORY PARAMETER n Percent GENDER M/F 76 / 35 68% / 32% RE White 80 72% Black 14 13% Asian 6 5% Hispanic 9 8% Middle Eastern 1 <1% Unknown 1 <1% AGE (years) < % % Mean (range) yrs ECOG PS % % % O Connor, O. A. et al. ASCO 2008 PROPEL Prior Therapy Number of prior systemic regimens Number of prior regimens (including radiation and topical) N = 111 Number of Regimens n Percent % % % % % Median (range) 3.0 (1-12) % % % % % Median (range) 3.0 (1-13) 53% of patients were refractory to the most recent line of prior therapy 25% of patients never had a response to any prior therapy PROPEL Summary of Response by Central Review: IWC Best Response 69% of responders did so after Cycle 1 Pralatrexate (N=109) n Percent 95% CI CR+CRu+PR 29 28% CR 10 9% CRu 1 <1% PR 18 17% SD 23 21% PD 40 37% UE 3 3% ND: off-treatment in C % C1: Cycle 1 O Connor, O. A. et al. ASCO

9 PROPEL Summary of Response by Central Review in Refractory Patients: IWC Evaluable patients (N=109) CR+CRu+PR n % n % Relapsed / refractory patients % 29 27% Refractory to previous line of therapy Refractory to all previous lines of therapy 68 62% 14 21% 26 24% 5 19% Pralatrexate activity observed in highly refractory PTCL patients PROPEL Waterfall Plot O Connor, O. A. et al. ASCO 2009 PROPEL Response Analyses by Key Subsets Pralatrexate (N = 109) n Percent Response Rate IWC Percent 95% CI Region North America 85 78% 28% Europe 24 22% 21% 7-42 Age < % 24% % 31% Prior systemic therapy 1 regimen 23 21% 26% regimens 29 27% 21% 8-40 > 2 regimens 57 52% 30% Prior Yes 18 17% 33% transplant No 91 83% 25% Histology PTCL NOS 59 54% 31% Angioimmunoblastic 13 12% 8% 0-36 Anaplastic LC 17 16% 29% Transformed MF 12 11% 25% 5-57 Other 8 7% 25% 3-65 O Connor, O. A. et al. ASCO

10 EMERGING APPROHES IN THE TREATMENT OF AGGRESSIVE T-CELL LYMPHOMA Emerging role of pralatrexate in T-cell The emergence of histone deacteylase inhibitiors in T-cell NHL Promising new experience with the imids in T-cell Lenalidomide. Acetylation of Histones Allows Transcription Histone Acetylation (HAT) = Open Conformation Coactivator Complex Protein Expression HAT Deacetylation of Histones Blocks Transcription Histone Deacetylation (HD) = Closed Conformation Corepressor Complex Protein Repression HD 10

11 Inhibition of HDs Blocks Deacetylation of Histones HD Inhibition = Open Conformation Corepressor Complex Protein Expression HD Inhibitor HD CLASSES OF HD INHIBITORS Class / Potency Select Examples Pharmacologic Profile Aliphatic Acids Valproic Acid Phenylbutyric Acid Longest studied HDI. While well tolerated, these drugs exhibit a short-half life due to rapid metabolism, are relative less potent, and are nonspecific Hydroxamic Acids Vorinostat LBH598 Belinostat LAQ-824 Trichostatin A Pan-HDI with Class 1 & 2 activity. Vorinostat first in class approved for CTCL. PO and IV Benzamides MS-275 CI-994 MGCD-0103 Includes both pan- and isotype selective HDI (MGCD-0103). um to nm potency Cyclic peptides Depsipeptide Apicidin A CHAP Structurally complex pan- HDI active in nm range. Depsipeptide metabolicall cnverted to active metabolite Phase II of Vorinostat in Refractory CTCL Treatment Group Schedule 1 st Dose Reduction 2 nd Dose Reduction mg QD 350 QD 300 mg QD 242% (2) and 19% (3) Grade 3 or 4 Thrombocytopenia, 300 mg bid x 3 days/wk x 4 wk 5 days 250 mg x 3d/wk 200 mg QD x 3 d/wk plus dehydration, 3 DVT, pyrexia, 300 mg bid x 14 d hypotension Q 21 days. Population Group 1 (n= 13) Group 2 (n = mg bid 200 mg bid x5 d/wk Patients Attaining a Partial Response (No CR) as a Function of Schedule Group 3 (n=12) All Patients All Patients 4/13 (31%) 1/11 (9%) 3/9 (33%) 8/33 (24%) Stage <IIB 0/2 (0) 0/1 ()) 1/2 (50%) 1/5 (20%) Stage at least 4/11 (36%) 1/10 (10%) 2/7 (29%) 7/28 (25%) IIB Sezary 1/3 (33%) 1/4 (25%) 2/4 (50%) 4/11 (36%) Duvic et al., Blood, 2007, 109:31 11

12 Clinical Activity of SAHA in CTCL Objective Response Time to Response (days) Duration of Response (days) Time to Progressive Disease (days) Population N n (%) Median (Range) Median* (Range) Median* (Range) All patients (29.7) 55 (28, 171) NR* (34+, 441+) NR (78+, 470+) Stage IB or IIA 13 4 (30.8) 42.5 (30, 57) 80.5 (48+, 418+) (78+, 448+) Stage IIB and higher (29.5) 56 (28, 171) NR* (34+, 441+) NR (85, 470+) Sezary syndrome Patients with tumor disease (33.3) 56 (28, 171) NR* (34+, 244+) NR (85, 365+) 22 5 (22.7) 31 (29, 87) 187 (55, 441+) NR (148, 470+) *Estimated KM for DOR 165, 185, and 165 days, respectively. Estimated KM for TTP 256, 299, 209, and 448 days, respectively. Olsen, JCO, 2007, 25:3109 Romidepsin Trials in T-cell Lymphoma NCI 1312: Phase II, single agent CTCL and PTCL Cohorts based on number of prior chemotherapies GPI : Pivotal Phase II trial, single agent CTCL > 1 prior systemic therapy Accrual complete GPI : Pivotal Phase II trial, single agent PTCL > 1 prior therapy Accrual ongoing 35 Phase 2 Romidepsin in PTCL Response Rates Overall Response Rates All Pts N=48 Pts 2 cycles** N=34 ORR (CR+PR), n (%) 15 (31%) 15 (44%) CR*, n (%) 4 (8%) 4 (12%) PR, n (%) 11 (23%) 11 (32%) SD, n(%) 7 (15%) 7 (21%) s Piekarz et al., Abstract 14157; ASH

13 Phase 2 Romidepsin in PTCL Response Data Duration of Response (DOR) &Time to Disease Progression (TTP) Median time to first response was 1.8 (1-6) months Population N* Median (range) DOR in months Median (range) TTP in months ORR (CR & PR) 15 9(2 61+) 12 (4 63+) CR 4 34 (3 61+) NR (14 63+) PR 11 8 (2 41+) 10 (4 42+) SD 7 9 (3 26+) PD (.2 4) *7 patients were not evaluable; NR, median not yet reached; + denotes continuing response Piekarz et al., Abstract 14157; ASH 2008 Phase 2 Study of Romidepsin in CTCL Patient Characteristics (N=96) Age (yrs), median (range) 57 (21 89) Sex (n, %) Men 59 (61.5%) Women 37 (38.5%) IB 15 (15.6%) IIA 13 (13.5%) Clinical Stage (n, %) IIB 21 (21.9%) ECOG Status Prior Systemic CTCL Therapies, median (range) Pruritus at Study Entry, n (%) III 23 (24.0%) IVA 24 (25.0%) 0 49 (51.0%) 1 47 (49.0%) 3 (1-11) Moderate 23/52 (44.2%) Severe 29/52 (55.8%) 71% with advanced stage ( IIB) Kim et al., Abstract 263; ASH 2008 Phase 2 Study of Romidepsin in CTCL Response Results Study Population Evaluable (N=72) As-Treated (N=96) n (%) n (%) ORR 30 (42%) 33 (34%) CR/CCR 6(8%) 6(6%) PR 24 (33%) 27 (28%) SD (36%) 28 (29%) Overall disease control (CR/CCR+PR+SD 90 ) 56 (78%) 61 (64%) ORR in the supportive study (NCI 1312) was 40% in evaluable patients including 4 (6%) CR Kim et al., Abstract 263; ASH

14 Response by CTCL Clinical Stage Evaluable Population (N=72) Clinical Stage N=72 ORR CR/CCR PR IB-IIA 24 7 (29%) 1 ( 4%) 6 (25%) IIB 16 9 (56%) 2 (13%) 7 (44%) III 18 8 (44%) 1 ( 6%) 7 (39%) IVA 14 6 (43%) 2 (14%) 4 (29%) Responses in advanced disease (stages IIB-IVA) 48% ORR for IIB 8 patients with Sézary syndrome, 4 (50%) had a PR Kim et al., Abstract 263; ASH 2008 Depsipeptide Response in CTCL: 1/22/04 2/18/04 Piekarz R, et al. Oral Presentation ASH 2005 Annual Meeting; Blood : Abstract 231 Pruritus Relief 52 Patients with Moderate to Severe Pruritus at Baseline Pruritus assessed using a visual analogue scale (VAS) from 0 to 100 mm Evaluable patients had baseline VAS 30 mm n VAS Change in CR PR SD PD Pruritus relief in 33 of 52 (63%) patients: 17 who achieved CR/CCR or PR 16 who did not achieve objective response Pruritus relief defined as a decrease in VAS of 30 mm Kim et al., Abstract 263; ASH

15 EMERGING APPROHES IN THE TREATMENT OF AGGRESSIVE T-CELL LYMPHOMA Emerging role of pralatrexate in T-cell The emergence of histone deacteylase inhibitiors in T-cell NHL Promising new experience with the imids in T-cell Lenalidomide. Lenalidomide (CC-5013, Revlimid ): New Generation Analogs O N O H N O O N O H N O O Thalidomide NH 2 Lenalidomide 4-amino-glutamyl analogue times more potent Safety profile: non-neurotoxic, non-teratogenic, non-sedating Bartlett JB et al. Nat Rev Cancer. 2004;4:314 Stirling D. Semin Oncol. 2001;28:602 Phase 2 of Lenalidomide in PTCL Baseline Characteristics Characteristic Lenalidomide (n = 24) Median age, years (range) 65 (42 76) Male sex, n 9 Median no. of prior regimens (range) 1 (0 3) Refractory to prior regimen, n 2 Prior therapy, n Relapsed 8 Untreated 2 Histology, n PTCL NOS 10 Angioimmunoblastic T-cell 7 Anaplastic large-cell 5 Hepatosplenic T-cell 1 Dueck et al. Abstract 8524, ASCO

16 Phase 2 of Lenalidomide in PTCL Response Best response, n (%) Lenalidomide (n = 24)* CR 0 PR 7 (30) SD 2 (8) PD 15 (63) ORR 30% Dueck et al. Abstract 8524, ASCO 2009 EMERGING APPROHES IN THE TREATMENT OF AGGRESSIVE T-CELL LYMPHOMA Many promising new drugs in T-cell These agents offer promise for a potentially new non-chop based treatment platform Combination studies already underway and suggest synergistic interactions in lab and clinic Enrollment in a clinical trial is the recommended treatment for all patients Nursing Interventions for Patients with Aggressive T-Cell Lymphomas Christine Liebertz, NP, RN Memorial Sloan-Kettering Cancer Center 16

17 Nursing Management 1. Information about disease and treatment options: clinical trials, palliative care 2. Assessment: a. Comorbidities b. Medications c. Symptoms d. Previous treatment and history 3. Symptom management 4. Education about side effects, monitoring, early intervention. 5. Psychological support and referral: a. Depression b. Social isolation Novel/New Therapeutic Agents Overview Drug Notable Side Effects Nursing Implications PDX: Antifolate Thrombocytopenia Mucositis Neutropenia Anemia Give with folic acid and Vit B12 Romidepsin/ Vorinostat: HD inhibitors Thrombocytopenia GI disturbances and dehydration Pulmonary Embolism and DVT Asthenic Events QTc prolongation, Monitoring electrolytes Ontak: Denileukin diftitox is a Hypersensitivity y reaction, Capillary Leak Syndrome fusion protein (a combination of amino acid sequences from lymphopenia, fever, chills Nausea Premedication diphtheria toxin and interleukin-2) Fatigue Increase in ALT/AST Lenalidomide: Angiogenesis Inhibitor Campath: Monoclonal Antibody Fatigue, myelosuppression, GI toxicities: Diarrhea, Constipation Pancytopenia, Acute allergic reaction Rev assist registration and adherence Potential for fatal infections (CMV) need prophylaxis, Premedicate to prevent allergic reaction Proteasome Inhibitor: Bortezomib Peripheral Neuropathy Weakness Diarrhea, Constipation Anorexia Potential for drug interactions Vitamins may counteract effect of bortezomib 17

18 Mucositis Assessment 1. Inspect all surfaces of the oral cavity and grade using the NCI Common Toxicity Criteria for Adverse Events (CTCAE) v Assessing functional status (e.g., ability to swallow solids, soft foods and liquidsid 3. Presence and severity of mouth or throat pain using a numerical (0-10) or categorical scale (nonesevere) 4. Nutritional status (wt., oral intake, energy) Patient Education/Mucositis 1. Dental consult before starting treatment 2. Consistent regimen to clean their mouth -soft bristle tooth brush/ change frequently -floss daily to avoid plaque build up (d/c if plts < 20, 000, ANC < 1) - rinse mouth every 4-6 hours (up to q 2 if needed) for comfort: sodium bicarb or salt water :quart to teaspoon, change solution daily 3. Apply moisturizer to lips: aquaphor/ A and D ointment 4. Avoid: Tobacco, alcohol, spices, citrus, tomatoes, ill fitting dentures, coarse or hard foods and very hot liquids Mucositis Interventions 1. Topical anesthetic such as viscous lidocaine 2. Coating agent for generalized mouth and throat discomfort such as Gelclair l or Carrington oral wound rinse. 3. Modify diet as needed: blending, soft foods, fortifying food intake with protein powders 4. Pain consult if needed for systemic pain medications 18

19 HD and QTc Intervals - QT interval is the time between the start of the QRS complex and the end of the T wave. - There is an association with prolonged QTc interval and the development of ventricular arrhythmias and sudden cardiac arrest - Dependent on heart rate, age and gender HD and QTc Intervals - QTc interval is 430 milliseconds for men and 450 milliseconds for women - QTc prolongation can be caused by Drugs most common: direct effect or inhibition of hepatic metabolism Congenital syndrome Electrolytes (hypokalemia, hypomagnesemia) Thyroid imbalances Renal, hepatic or cardiac failure Drugs that may cause prolongation of QTc intervals Antifungals: Fluconazole, ketoconazole Antiarrhythmics: amiodarone, Sotalol, quinidine, procainamide Antidepressants: amitriptyline, imipramine, doxepin, clomipramine Antipsychotics: risperidone, haloperidol, clozapine, thioridazine, droperidol, pimozide, ziprasidone Antihistamines: terfenadine, astemizole Anti emetics: dolasetron, ondansetron, tropisetron Antibiotics: Erythromycin, clarithromycin Miscellaneous: Cimetidine, aprepitant, cisapride, Arsenic trioxide, methadone, tacrolimus 19

20 Capillary Leak Syndrome (33%) Potential life threatening capillary leak syndrome has been reported (11%) Capillary leak syndrome is characterized by the presence of 2 or more of the following symptoms (usually seen in the 1 st two weeks after infusion): -Hypotension, edema, hypoalbuminemia (symptoms may be delayed up to 2 weeks post infusion) - Monitor weight, edema, blood pressure and serum albumin levels - Pre medicate with antihistamine and acetaminophen - hold for albumin < 3g/dl - Use in caution > age 65 Peripheral Neuropathy Many drugs cause peripheral neuropathy (vinca alkaloids, taxanes, platinum analogs, bortezomib) Both the incidence and severity appear to be higher in patients with preexisting baseline neuropathy and in heavily pretreated patients The predominant feature is a painful sensory neuropathy with burning dysesthesias of the fingers and toes that typically occurs during the first courses of treatment, reaches a plateau at cycle 5, and thereafter does not appear to increase Motor neuropathy, consisting of mild to severe distal weakness in the lower extremities, develops in up to 10 percent of patients. Dose modifications or treatment discontinuation may lead to improvement or complete resolution in the majority of patients Treatment Options for Peripheral Neuropathy 1. Pregabalin: mg three times daily, adjust for renal insufficiency 2. Duloxetine: 60 mg daily 3. Neurontin: starting dose mg daily, titrate weekly, max dose 3600 mg/day, watch renal function and drug interactions. 4. Antidepressants: t Amitriptyline i t usual starting ti dose mg, effective dose mg at bedtime, monitor anticholinergic effects 5. Topical analgesics: Lidoderm patches, capsaicin ointment 6. Opioid analgesics 7. Vitamins: Alpha lipoic acid, L-carnithine, glutamine, vitamin B12 and folic acid 20

21 Cancer and its Treatment: Domains of Concern Physical/medical Psychological Social/functional Spiritual Informational 61 Causes Biological of fatigue Factors - Anemia - Immune changes Comorbid Medical Conditions - Cardiovascular disease -Thyroid dysfunction Fatigue Demographic Factors -Age - Income - Marital status Comorbid Symptoms -Pain - Sleep disturbance Psychosocial Factors - Coping style - Depression -Anxiety Summary Improvements in our supportive care of patients receiving treatment can lead to improved tolerability and outcomes Nurses are key to: Assisting patients in their decision making Improving overall quality of life Managing symptoms Optimizing treatment outcomes 21

22 Thank you This presentation will be available as a CEU webcast by October Visit.org for access. T-Cell Lymphomas are a Diverse and Heterogeneous Set of Diseases Precursor T/NK Neoplasms Precursor T lymphoblastic leukemia/ Blastic NK Peripheral T/NK Neoplasms Predominantly leukemic/disseminated T-cell prolymphocytic leukemia T-cell large granular lymphocytic NK/T-cell leukemia/ Adult T-cell leukemia/ Predominantly nodal Angioimmunoblastic T-cell Anaplastic large cell Peripheral T-cell (Unspecified) Predominantly Extranodal Mycosis Fungoides (CTCL) Sezary syndrome Primary cutaneous CD30+ disorders Anaplastic large cell Lymphomatoid papulosis Subcutaneous panniculitis T-cell NK/T-cell -nasal Enteropathy-type intestinal Hepatosplenic T-cell (γ,δ) Extranodal peripheral T/NK-cell (Unspecified) H 2 N N 1 N 8 N 4 5 N NH 2 H 3 C -OH = Folic Acid H H H 9 CH 2 10 N METHOTREXATE (10-Methyl Aminopterin) O = COO - C -N-C-CH 2 -CH 2 -COO - H H H 2 N N N 1 N 4 5 N NH 2 H 3 C 8 H H H 9 CH 10 HC H C C 10-Propargyl-10- Deazaaminopterin (PDX) O COO - C -N-C-CH 2 -CH 2 -COO - H H = 22

23 Design PROPEL Study Phase 2 single arm, open label, multi-center, non-randomized, international Target Population Adult patients with relapsed or refractory PTCL Number of Patients Minimum of 100 evaluable patients Treatment Primary Endpoint Secondary Endpoints Pralatrexate 30 mg/m 2 IV x 6 weeks followed by 1 week rest (7 week cycle) in combination with vitamin supplementation Response rate by IWC (CR + CRu + PR) Duration of response Progression-free survival Overall survival IWC: International Workshop Criteria O Connor, O. A. et al. ASCO 2008 Phase 2 Romidepsin in PTCL Response Rates Response by Primary Diagnosis Primary Diagnosis Responses PTCL unspecified or not classified 9/28 (32%) Angioimmunoblastic 1/8 (13%) Primary cutaneous anaplatic large T-cell 1/3 (33%) Gamma-delta T-cell 1/2 (50%) Anaplastic large T-cell, ALK neg 2/2 (100%) Enteropathy associated T-cell 1/1 (100%) Piekarz et al., Abstract 14157; ASH 2008 PROPEL Summary of Response by Investigator Assessment Pralatrexate (N=109) Best Response n Percent 95% CI CR+CRu+PR 42 39% CR 14 13% CRu 4 4% PR 24 22% SD 21 19% PD 40 37% UE 1 < 1% ND: off-treatment in C1 5 5% O Connor, O. A. et al. ASCO

24 PROPEL Summary and Conclusions PROPEL is the largest prospective study ever conducted in patients with relapsed or refractory PTCL Patients in the study received a median of 3 prior systemic regimens (range 1-12) PROPEL established that pralatrexate has impressive clinical activity in patients with relapsed or refractory PTCL Central independent review of all relevant clinical data revealed durable CRs and PRs Responses were seen irrespective of the amount of prior therapy Mucosal inflammation and thrombocytopenia were the most common Grade 3-4 AEs Pralatrexate-based combinations may provide a novel platform for future upfront T-cell treatment programs O Connor, O. A. et al. ASCO 2009 Phase II Trial in Cutaneous and Peripheral T-cell Lymphomas Depsipeptide Day days Schedule: 4-hour infusion 14 mg/m 2 on days 1, 8, & 15 every 28d Piekarz R, et al. Oral Presentation ASH 2005 Annual Meeting; Blood : Abstract 231 Romidepsin Ongoing Studies in PTCL NCI Trial (NCI 1312) Romidepsin 14 mg/m 2 days 1,8,15 of a 28 day cycle O B J E C T I V E Response Rate Response Duration Safety Patient Criteria: PTCL Relapsed or progressive >1 prior chemotherapy GPI Registration Trial Romidepsin 14 mg/m 2 days 1,8,15 of a 28 day cycle O B J E C T I V E Response Rate Response Duration Safety Patient Criteria: PTCL Relapsed or progressive >1 prior systemic therapy 24