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1 Updates in Lymphoma Siddhartha Ganguly, MD, FACP Director, Lymphoma/Myeloma and Autologous Transplantation Program; Associate Professor of Medicine; Blood & Marrow Transplant Program, Division of Hematology/Oncology Conflict of Interest Disclosure Research Funding: Novartis, Janssen and Sanofi Aventis Speaker: Seattle Genetics 1

2 45 year old male with axillary and cervical lymphadenopathy Biopsy diagnosis of diffuse large cell lymphoma Case I: Initially treated with combination of Rituximab and CHOP chemotherapy 6 cycles Remained in remission for 6 months Now presents with abdominal pain 2

3 Autologous Transplant for NHL Parma trial , n=215 Prospective, randomized Chemo x 4 Auto BMT 5yr EFS: 12% vs. 46% 5 yr OS: 32% vs. 53% 3

4 AUTOLOGOUS TRANSPLANTATION IS THE STANDARD OF CARE IN RELAPSED CHEMO-SENSITIVE DIFFUSE LARGE B-CELL LYMPHOMA Dose-Response Linearity 100 Tumor Cell Kill ICE CHOP BEAM 0 Increasing Myeloablative Potential 4

5 Dose-Response Linearity 100 Tumor Cell Kill CHOP ICE BEAM 0 Increasing Myeloablative Potential Salvage Regimens: 5

6 CORAL (Collaborative Trial in Relapsed Aggressive Lymphoma Trial) of RICE v DHAP Which salvage regimen is the best? CD20+ DLBCL Relapsed/Refractory R A N D O M I Z E R-ICE x 3 R-DHAP x 3 A B S E C A T M SD/POD Off PR/CR R A N D O M I Z E R x 6 Obs N=400 Place of immunotherapy post transplantation? CORAL Trial Survival according to Salvage Regimen Overall Survival Event Free Survival R-ICE R-DHAP 0.2 P = Mos P = Mos

7 64% 31% N=160 N=228 PROGRESSION-FREE SURVIVAL ACCORDING TO FAILURE FROM DIAGNOSIS (INDUCTION ITT) 62% 30% N=147 N=241 PROGRESSION-FREE SURVIVAL ACCORDING TO PRIOR RITUXIMAB (INDUCTION ITT) 7

8 MYC + Patients do Worse with ASCT than MYC - PFS IPI 2-3 pts OS Cuccini et al, Blood, 2012 DOUBLE HIT (BCL2+C-MYC) TRIPLE HIT (BCL-2+ C-MYC+BCL-6) Worse Prognosis?Auto SCT in CR1 8

9 Are We Really Doing Well with Our Choice of Salvage? 58 year old, C myc positive, Relapsed within 8 months, saapi 2, High LDH, Stage III disease At best response rate is 50%; 20% cure and 40% 3 year PFS Need to do better 1. Better salvage?r Gem Ox; RDHAX; R GDP R GDP(n=310) vs. R DHAP (n=309) [ASH 2012 Crump et al] GDP is not inferior to the standard regimen DHAP prior to ASCT similar rates of transplantation, EFS and OS. significantly less toxicity, superior QoL scores 2. O DHAP vs. R DHAP and Auto SCT HOVON international Trial. Available at KUMC 3. Add BCR signaling inhibitors Ibritinib, PI3Kinase inhibitor 4. Antibody Drug Conjugate Inotuzumab/Calichaemycin Plerixafor 9

10 A Novel Hematopoietic Progenitor Cell (HPC) Mobilization regimen, utilizing Bortezomib (Bor) and Filgrastim (G-CSF), for patients undergoing Autologous HPC Transplant (AHPCT) for Multiple Myeloma (MM) and Non-Hodgkin s Lymphoma (NHL). Sunil Abhyankar MD, Shaun DeJarnette MT, Dean Merkel MT, Jennifer Bunch, Kelly Daniels RN, Omar Aljitawi MD, Sid Ganguly MD, Joseph McGuirk DO. ASBMT/CIBMTR Tandem meeting, Salt lake City, Utah Feb 2013 What is the Value of Different Conditioning Regimens in Autologous Stem Cell Transplants Is any regimen better than the standard BEAM or BEAC? 10

11 Bu-CY-E vs BEAM No difference in OS or PFS Kim et al, Leukemia Research 2011 How about adding Radiation? (TBI is too toxic) Radio-Immunotherapy 11

12 Bexxar-BEAM vs R-BEAM as Conditioning Regimen Therapy in Relapsed DLBCL BMT CTN 0401 R-BEAM: R=375 mg/m 2 on days -19 and -12 Bexxar-BEAM: 75 cgy dose of 131 I on day -12 Both regimens included standard BEAM conditioning on days -6 to randomized patients B-BEAM R-BEAM # Length of f/u Median age Vose et al, ASH abstr 661, 2011 Bexxar-BEAM vs R-BEAM as Conditioning Regimen Therapy in Relapsed DLBCL BMT CTN 0401 B-BEAM R-BEAM # yr PFS (%) yr OS (%) Relapse at 2 yrs (%) Maximum mucositis (OMAS) (p<.0001) No difference in TRM, time to engraftment of platelets or WBC, rates of AML or MDS, or immunologic recovery out to two years Vose et al, ASH abstr 661,

13 OUTSIDE A CLINICAL TRIAL BEAM OR BEAC REMAINS THE STANDARD PREPARATIVE REGIMEN FOR RELAPSED AGGRESSIVE NHL OTHER LYMPHOMAS 13

14 PHASE II TRIAL OF HIGH-DOSE RITUXIMAB WITH THIOTEPA / BUSULFAN / CYCLOPHOSPHAMIDE (TBC) AUTOLOGOUS STEM CELL TRANSPLANTATION FOR PATIENTS WITH CNS INVOLVEMENT BY NON- HODGKIN LYMPHOMA Yi-Bin Chen, Tracy Batchelor, Ephraim Hochberg, Mark Brezina, Erin Coughlin, Sooae Jones, Candice Del Rio, Karen K. Ballen, Jeffrey Barnes, Andrew Chi, Jessica Driscoll, Fred Hochberg, Ann S. LaCasce, Steven McAfee, Laskhmi Nayak, Philippe Armand February 13 th, 2013 ASBMT Study Schema - Mobilization Stem cell pheresis when WBC appropriate Day: GCSF begins Optional LP hours after Day 1 Rituximab dose 14

15 Study Schema High Dose Therapy Autologous stem cell transplant Day: Objectives Primary Objective To assess the proportion of patients who are alive and progression free at one year after R HiDAC R mobilization and R TBC ASCT Secondary Objectives To examine the safety and toxicities of this treatment program To assess 1 year event free survival (EFS), overall survival (OS), and overall response rate (complete and partial response) in this patient population 30 15

16 Patients 23 out of 30 planned patients enrolled at the time of abstract submission 12 patients with primary CNS NHL 7 patients in CR1, 5 patients with relapsed disease in PR/CR All were DLBCL by histology including 1 case of EBV PTLD 11 patients with secondary CNS NHL Histology: 2 cases of CLL 2 cases of transformed follicular NHL 7 cases of DLBCL with spread to CNS 5 patients were in CR1, 6 patients with relapsed disease in PR/CR 31 Transplant Characteristics Outcomes Engraftment All patients engrafted neutrophils (median 9 days, range 8 12) All patients engrafted platelets (median 12 days, range 8 40) Toxicities No issues with high dose Rituximab Most common were diarrhea and mucositis Neurotoxicity (n=2) 1 patient who had previously had WBRT, eventually died 5 months after ASCT from this 1 patient with TMA from high grade candidemia 32 16

17 Transplant Characteristics Survival Transplant related mortality No cases by day +100 after ASCT Only one case thus far from neurological complications Median follow up of 399 days (3 mo. 2 yr.) Only one patient has died (TRM as above) Only one patient has relapsed 73 yo F with multiply relapsed cutaneous DLBCL with CNS disease since the 1990s relapsed 9 months after ASCT in the skin. Remains alive in remission after salvage chemotherapy 33 Next Steps 30 patients enrolled Accrual finished Should have at least 9 individual samples of CSF to confirm levels of rituximab observed Longer follow up needed Will such high doses translate into less relapses? Heterogeneity of this study makes any comment on efficacy difficult Does having such high systemic levels slow CSF elimination of Rituximab? Does it make sense to combine high dose IV with intrathecal administration? 34 17

18 Diffuse Large Cell Lymphoma Auto-HSCT in First Remission? Randomized phase III US / Canadian Intergroup trial (SWOG S9704) comparing CHOP±R x 8 vs CHOP±R x 6 followed by high dose therapy and auto transplant for patients with diffuse aggressive non-hodgkin s lymphoma (NHL) in highintermediate (H-Int) or high IPI risk groups. P.J. Stiff, J.M. Unger J.R. Cook, L.S. Constine, S. Couban, T.C. Shea, J.N. Winter, T.P. Miller, R.R. Tubbs, D.C. Marcellus, J. Friedberg, K. Barton, G. Mills, M. LeBlanc, L. Rimsza, S.J. Forman, R.I. Fisher 1Loyola University Medical Center, Maywood, IL; 2SWOG Statistical Center, Seattle, WA; 3Cleveland Clinic Foundation, Cleveland, OH; 4University of Rochester, Rochester, NY; 5Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia, CAN; 6University of North Carolina at Chapel Hill, Chapel Hill, NC; 7Northwestern University, Chicago, IL; 8University of Arizona, Tucson, AZ; 9Margaret and Charles Juravinski Cancer Centre, Hamilton, Ontario, CAN; 10Louisiana State University Medical Center, Shreveport, LA; 11City of Hope Medical Center, Duarte, CA Stiff, et al: JCO 8001a,

19 Overall Outcome : PFS Stiff, et al: JCO 8001a, 2011 Overall Outcome: Survival Stiff, et al: JCO 8001a,

20 Outcome of All Randomized Patients Based on IPI: PFS/OS RELAPSE IS THE MOST COMMON CAUSE OF FAILURE OF AUTO TRANSPLANTATION IN NHL 20

21 Maintenance Therapy Following ASCT for DLBCL EFS PFS RTX Female p=.74 Obs p=.04 Male Female pts benefited from RTX maintenance 21

22 Monoclonal Antibodies of Lymphoma Killers Enhancers/Modulators CD20 CD19 CD22 CD23 CD30 CD40 CD52 CD79 TRAIL-R1 and R2 4-1BB OX40 CTLA4 PD-1 CD40 VEGF Clinical application of PD-1 agonists and antagonists (rejection) (Tolerance) Okazaki T, Honjo T Int. Immunol. 2007;19: The Japanese Society for Immunology All rights reserved. For permissions, please journals.permissions@oxfordjournals.org 22

23 Anti-PD-1 CT-011 to Augment Post Transplant Immunity: CT ASCR CT-011 Follow up 1-3 m 6wk 6wk 18 months Hypothesis: Anti-PD-1 antibody (CT-011) can elicit tumor-immune control leading to favorable clinical outcome in DLBCL patients following HDT/ASCR Gordon et al, Lugano 2011 Adverse Event Severity Grade All Neutropenia 19 (4.2) 3 (0.4) 8 (1.2) 9 (1.6) 5 (0.8) 0 Fatigue 19 (3.5) 17 (3.2) 2(0.3) Thrombocytopenia 10 (3.5) 6(1.1) 4(0.9) 4 (0.8) 2 (0.6) 0 Diarrhea 12 (3.2) 10 (2.4) 4(0.8) WBC count decreased 9 (2.4) 7 (1.6) 4(0.6) 1 (0.1) 0 0 Upper respiratory tract infection 13 (2.2) 9 (1.6) 4 (0.6) Cough 12 (2.2) 11 (2.1) 1(0.1) Hyperglycaemia 9(2.2) 8 (1.9) 2 (0.3) Haemoglobin decreased Gordon et al, Lugano 2011 Most Frequent Adverse Events ( 2% of events): Number of patients (percent of total events) 8 (2.1) 7 (1.3) 3 (0.8)

24 CT-011 following HDT/ASCR for DLBCL: Preliminary Efficacy Data: PFS and OS 1 18 months 0.70 (95% C.I. [ ]) Probability of PFS Study PFS Historical PFS Historical Control is the median of: Fenske TS; Biol. Blood & Marrow Transpl, (2009), 15(11), Chen, Yin-Bin; Leuk & Lymph, (2010), 51(5), Gisselbrecht C. et al. JCO, (2010), 28 (27), Gordon et al, Lugano Months CT-011 following HDT/ASCR for DLBCL: Preliminary Efficacy Data: PFS and OS 1 18 month 0.84 (95% C.I. [ ]) Probability of OS Months Study OS Historical OS Historical Control is the median of: Fenske TS; Biol. Blood & Marrow Transpl, (2009), 15(11), Chen, Yin-Bin; Leuk & Lymph, (2010), 51(5), Gisselbrecht C. et al. JCO, (2010), 28 (27), Gordon et al, Lugano

25 B Cell Receptor Signaling Inhibitors Bruton s Agammaglobulinemia Bronchiectasis in 14 yo male Ogden Car Bruton 25

26 B-Cell Receptor Signaling Antigen B Cell Receptor C D 7 9 P B SYK P C D 7 9 A P LYN PI3K P BTK P P PLCγ BLNK C D 1 9 DAG PIP3 IP3--Ca++ Cytokine Receptor AKT PKCβ CK JAK1 TLR MYD88 ERK Bcl10 MALT1 CARD11 P IkB NFkB IkB Proteosomal Degradation Transcriptional Activation e SPDBaselinehange from% Ch m Maximum Change in Tumor Burden in CLL * 420 mg/d 840 mg/d *Patient developed progressive disease, but did not have tumor measurements available Limited to patients with measurable disease at baseline (n=55) 26

27 Response in ABC and GCB DLBCL Conclusions Ibrutinib, a selective covalent inhibitor of BTK, induced a high response rate in relapsed/refractory ABC DLBCL in addition to CLL, MCL and FL Ibrutinib had marginal activity in GCB DLBCL, supporting the use of the ABC DLBCL molecular subtype as a biomarker for activity Ibrutinib was associated with a favorable safety profile 27

28 Proposed Study Schema Alliance/BMT-CTN: Andreadis et al Relapsed/Refractory DLBCL-ABC Salvage PR, stem cells collected Randomization Stratify by response, TTR, regimen Arm A Arm B ASCT: CBV or BEAM Ibrutinib Maintenance <60 d ASCT: CBV or BEAM Placebo Maintenance Follow Up Follow Up Summary of Maintenance Regimens after Auto Transplantation in Aggressive NHL Interventions Outcomes Maintenance Regimens Ibrutinib, Inotuzumab Ozogamicin Anti PD1 antibody, CT 011 Rituximab Future Promising Overall ineffective in Phase III trial 28

29 Hodgkin s Disease: Transplant Everybody beyond CR1 Hodgkin Lymphoma Progressive Despite Primary Treatment 4 Cases 34 yo Stage IVB ABVD x 6 => CR 2 months => Prog thorax nodes only GDP X 2 => PR 34 yo Stage IVB ABVD x 6 => CR 8 years => Prog thorax nodes only GDP X 2 => PR 34 yo Stage IVB ABVD x 6 => CR 2 months => Prog thorax nodes only GDP X 2 => 34 yo Stage IVB ABVD x 6 => Prog thorax nodes only GDP X 2 => Prog Progression A. Mantle RT B. MOPP +/- RT C. COPP/ABV +/- RT D. HDC + auto SCT A. Mantle RT B. MOPP +/- RT C. COPP/ABV +/- RT D. HDC + auto SCT A. Mantle RT B. MOPP +/- RT C. COPP/ABV +/- RT D. ICE +/- RT & SCT only if PR E. HDC + auto SCT A. Mantle RT B. MOPP +/- RT C. COPP/ABV +/- RT D. ICE +/- RT & SCT only if PR E. HDC + auto SCT 58 29

30 Hodgkin Lymphoma Progressive Despite Primary Treatment 4 Cases 34 yo Stage IVB ABVD x 6 => CR 2 months => Prog thorax nodes only GDP X 2 => PR 34 yo Stage IVB ABVD x 6 => CR 8 years => Prog thorax nodes only GDP X 2 => PR 34 yo Stage IVB ABVD x 6 => CR 2 months => Prog thorax nodes only GDP X 2 => 34 yo Stage IVB ABVD x 6 => Prog thorax nodes only GDP X 2 => Prog Progression A. Mantle RT B. MOPP +/- RT C. COPP/ABV +/- RT D. HDC + auto SCT A. Mantle RT B. MOPP +/- RT C. COPP/ABV +/- RT D. HDC + auto SCT A. Mantle RT B. MOPP +/- RT C. COPP/ABV +/- RT D. ICE +/- RT & SCT only if PR E. HDC + auto SCT A. Mantle RT B. MOPP +/- RT C. COPP/ABV +/- RT D. ICE +/- RT & SCT only if PR E. HDC + auto SCT 59 German HDSG and EORTC HD-R1 German Hodgkin s Study Group, Schmitz, Lancet 2002;359:2065 Relapsed HD: A Dexa BEAM Dexa BEAM CR or PR Dexa BEAM Dexa BEAM n Radiotherapy to residual disease B Dexa BEAM Dexa BEAM CR or PR HSC/BM harvest BEAM HSCT 30

31 HSCT Chemo German Hodgkin Study Group, Schmitz, Lancet 2002;359:2065 Primary progressive, early and late relapsed HL Outcome after Secondary Tx GHSG ,0 n = 3809; relapses = 513 (13%),8 Probability,6,4 late relapse 169 (33%) early relapse 138 (27%) refractory 206 (40%),2 p < , Overall Survival (Months) 31

32 Late relapse > 12 months (n = 55) HSCT Chemo German Hodgkin Study Group, Schmitz, Lancet 2002;359:2065 Early relapse < 12 months (n = 38) HSCT Chemo German Hodgkin Study Group, Schmitz, Lancet 2002;359:

33 1.0 Hodgkin's Lymphoma: Tx HDC/HSCT By Disease Status at HDC/HSCT.8 REL-1 n = 133 Cum Survival.6.4 REL-2 n = Post SCT Survival (y) REL-3 n=9 20 Prognosis for HL Patients who Relapse after ASCT Note the very poor prognosis for the 72% of patients whose relapse occurs in the first 12 months after ASCT Probability, % TTR, mo > yr mortality 40% N % N = 756 p < Median OS, yr Time from relapse, y TTR = Time to relapse. Horning et al. 10th International Conference on Malignant Lymphoma; Lugano, Switzerland;

34 How Can We Improve our Auto SCT results in HD? Autologous stem cell transplantation for refractory or poorrisk relapsed Hodgkin's lymphoma: effect of the specific high dose chemotherapy regimen on outcome. Nieto Y, Popat U, Anderlini P, Valdez B, Andersson B, Liu P, Hosing C, Shpall EJ, Alousi A, Kebriaei P, Qazilbash M, Parmar S, Bashir Q, Shah N, Khouri I, Rondon G, Champlin R, Jones RB. Biol Blood Marrow Transplant Mar;19(3):410 7 COMPARISON OF GEMCITABINE, BUSULFAN AND MELPHALAN (GEMBUMEL) WITH BEAM AND BUSULFAN/MELPHALAN (BUMEL) IN CONCURRENT COHORTS OF REFRACTORY HODGKIN S LYMPHOMA PATIENTS RECEIVING AN AUTOLOGOUS STEM-CELL TRANSPLANT Y Nieto, R Jones, P Anderlini, U Popat, B Andersson, P Thall, B Valdez, EJ Shpall, A Alousi, P Kebriaei, C Hosing, M Qazilbash, G Rondon, R Champlin Depts of Stem Cell Transplantation and Biostatistics, UT MD Anderson Cancer Center, Houston, TX 34

35 GemBuMel vs BuMel vs BEAM for Refractory HL Contemporaneous Matched Cohorts (N=201) 1. GemBuMel (N=80) HL patients treated with GemBuMel (Jan 07- July 11) All had high-risk disease, defined as: Primary refractory tumor Poor-prognosis relapse: CR1 <6 months >1 relapse/pd PET+ tumor at HDC Median follow-up: 20 (6-60) months 2. BuMel (N=38) All pts meeting high-risk disease criteria enrolled in a phase 2 trial of Busulfan/Melphalan (Jan 05 Dec 09) 78% of all HD pts in this trial Median f/u: 34 (17-74) months 3. BEAM (N=83) All pts with high-risk disease treated with BEAM (Jan 05 July 11) 40% of all HD pts receiving BEAM Median f/u: 17 (6-74) months EFS analysis % EFS Median EFS P Value Log rank Cox (Proportional hazard regression) GemBuMel 61% NR BuMel 35% 14 months BEAM 43% 13 months Probability GemBuMel Probability GemBuMel 0.4 BEAM BuMel 0.2 BEAM / BuMel Months post-hdc Months post-hdc 35

36 OS analysis % OS Median OS P Value Log rank GemBuMel 84% NR Cox (Proportional hazard regression) BuMel 62% NR BEAM 60% 71 mo GemBuMel GemBuMel Probability 0.6 BuMel BEAM Months post-hdc Probability BuMel/BEAM Months post-hdc Refractory HL - Subgroup Analyses Patients in CR at HDC PET Negative PET Positive GemBuMel (74% EFS) Probability Probability GemBuMel (48% EFS) BuMel/BEAM (46% EFS) 0.3 P= P= Months post-hdc BuMel/BEAM (18% EFS) Months post-hdc 36

37 Patients with Active Disease at HDC PR PD/SD Probability GemBuMel (60% EFS) Probability P= GemBuMel (30% EFS) 0.3 BuMel/BEAM (22% EFS) Months post-hdc 0.1 BuMel/BEAM (0% EFS) Months post-hdc Conclusions In this nonrandomized comparison, the cohort of refractory HL pts receiving GemBuMel showed, despite its worse prognostic features, superior outcome compared to two contemporaneous cohorts of refractory HL pts receiving BEAM or BuMel The superiority of GemBuMel was seen across the different prognostic categories This benefit was detected despite most, if not all, GemBuMel patients receiving a dose of Gemcitabine below its MTD These results warrant further study of GemBuMel in HL. A phase 2 trial at dose level 9 is actively accruing patients at MDA 37

38 Mantle Cell International Prognostic Index (MIPI) 4 factors independently associated with OS Age Perf Status LDH WBC Probability of OS Survival After Diagnosis by MIPI Risk Low Int High Survival not reached 51 mos 29 mos Months Hoster E, et al. Blood. 2008;111: Nordic Group: AutoSCT for newly diagnosed MCL Patients (%) Yr Outcomes 15% 20 EFS, P <.0001 EFS Yrs 2012 update 75% OS 63% EFS Median OS: >10 yrs Prognostic Factors: MIPI, Ki 67 Median EFS: 7.4 yrs Follow up: 6.6 yrs MCL-2 MCL-1 Geisler et al. Blood. 2008;112:2687 Geisler et al. Brit J Heme 2012;158:355 38

39 HCT for Mantle Cell Lymphoma Younger pts with good perf status: R-hyperCVAD or RCHOP-like regimen with HD Arac autosct Maintenance therapy after SCT? Auto SCT has minimal benefit in relapsed or refractory pts Allogeneic HCT is only known cure Pts who failed prior autosct Pts with high MIPI score or Ki67 (or novel therapies) Poor Outcome For Most Subtypes with Standard Tx International PTCL Project Vose et al. J Clin Oncol,

40 166 pts enrolled Histologies: PTCL NOS (39%) Alk- ALCL (19%) AITL (19%) EATL (13%) Induction: CHOEP x pts autohct Results: 5 yr PFS and OS = 51% Alk- ALCL has best survival PFS (all pts) PFS by histology JCO Sept 2012 Hematopoietic Stem Cell Transplantation: PTCL Autologous HSCT more efficacious in early disease Myeloablative allogeneic SCT associated with high TRM Reduced intensity conditioning promising Histologies to consider for allosct in CR1/PR1 Hepatosplenic T cell Enteropathy associated T cell Gamma delta T cell 40

41 Personalized Cancer Diagnostics Corless CL Science 334:1217, 2011 Cancer patient Whole-genome sequencing Tumor analysis Whole-exome sequencing Combine information Whole-transcriptome sequencing Chromosomal changes Gene copy number alterations Gene mutations Gene fusions Sequencing tumor board Clinicians, geneticists, pathologists, biologists, bioinformaticians, bioethicists Distill information for clinical use Personalized patient treatment Acknowledgement Our BMT Team Dr. Tom Shea, UNC Chapel Hill, NC Dr. Moskowitz, Sloan Kettering, NYC Dr. Gisselbrecht, France Dr. Gina Laport, Stanford, CA Dr. Yago Nieto, MD Anderson Cancer Center, Houston, TX Dr. Julie Vose, UNMC, Omaha, NE Dr. Y Bin Chen, MGH, Harvard, Boston, MA 41

42 Questions? 83 42