Dr Shankara Paneesha. ASH Highlights Department of Haematology & Stem cell Transplantation

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1 ASH Highlights 2015

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6 Themes of ASH 2015 Novel therapies - Myeloma AML Lymphoma Pd-L1 & PD-l inhibitors Emerging concepts in biology HIF-1a pathway Cautionary tales ASH Choosing Wisely list

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8 IFM/DFCI 2009: Phase III Study Design Pts 65 yrs of age or younger with symptomatic, measurable NDMM (N = 700) RVd* 3 cycles RVd* 8 cycles MEL200 ASCT RVd* 2 cycles consolidation Lenalidomide maintenance 12 mos Primary objective: PFS Secondary objectives: ORR, MRD, TTP, OS, Safety *RVD: bortezomib 1.3 mg/m 2 IV on Days 1, 4, 8, 11 + lenalidomide 25 mg on Days dexamethasone 20 mg on Days 1, 2, 4, 5, 8, 9, 11, 12. Included PBSC collection with cyclophosphamide 3 g/m 2 + G-CSF after cycle 3. Slide credit: clinicaloptions.com Attal M, et al. ASH Abstract 391.

9 IFM/DFCI 2009 : Responses Response, % RVd (n = 350) Transplantation (n = 350) P Value CR VGPR PR < PR 2 1 VGPR Negative MRD by FCM Treatment Phase VGPR Rate, % RVd (n = 350) Transplantation (n = 350).02 P value After induction NS After transplant or cycle 4 of consolidation <.0001 After consolidation completed <.006 At end of maintenance phase <.001 Slide credit: clinicaloptions.com Attal M, et al. ASH Abstract 391.

10 IFM/DFCI 2009 : PFS (Primary Endpoint) Parameter RVd (n = 350) Transplantation (n = 350) Median follow-up, mos Progression or death, n Median PFS, mos yr PFS, % P Value HR (95% CI) ( ) <.001 At second interim analysis in June 2015 with median follow-up of 39 mos, the data and safety monitoring board for this trial recommended that the trial be stopped Slide credit: clinicaloptions.com Attal M, et al. ASH Abstract 391.

11 IFM 2009: Overall Conclusions ASCT vs RVD in pts with NDMM is associated with: 31% reduced risk of progression or death (P <.001) Improved TTP and rate of MRD negativity Similar, low rate of mortality Longer follow-up required to make any conclusions about OS Authors concluded that ASCT should remain a standard of care for eligible pts with myeloma Similar, confirmatory trial ongoing in US Slide credit: clinicaloptions.com Attal M, et al. ASH Abstract 391.

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13 Blinatumomab in MRD-Positive BCP ALL: Study Design International, multicenter, open-label phase II study from centers 11 countries Primary endpoint: achieving MRD < 10-4 in cycle 1 Secondary endpoints: OS, RFS, DoR, MRD < 10-4, safety CD19+ BCP ALL pts 18 yrs of age or older with < 5% BM blasts, MRD 10-3 after 3 chemotherapies, and no prior allo-sct, CNS/extramedullary involvement, or Ph+ ALL eligible for TKIs (N = 116) Cycle 1* Blinatumomab 15 µg/m 2 QD IVCI *28 days on tx, 14 days off. Pts with MRD response received 3 additional cycles and/or allo-sct (eligible pts); tx discontinuation upon hematologic relapse Gökbuget N, et al. ASH Abstract 680. Slide credit: clinicaloptions.com Followed for 2-yr efficacy, survival

14 Blinatumomab in MRD-Positive BCP ALL: Efficacy Outcome, Mos Median OS MRD complete responder MRD incomplete responder Median RFS CR1 CR2/CR3 MRD complete responder MRD incomplete responder Median DoR MRD complete responder MRD incomplete responder Median follow-up: 30 mos Complete MRD response: 80% Transplant realization rate: 72% Blinatumomab (n = 110) NR NR 17.2 MRD Complete vs Incomplete, P Value Gökbuget N, et al. ASH Abstract 680. Slide credit: clinicaloptions.com

15 Blinatumomab in MRD-Positive BCP ALL: Conclusions 80% of MRD-positive BCP ALL pts achieved complete MRD response on blinatumomab therapy Achieving complete (vs incomplete) MRD response was associated with improved outcomes OS: 38.9 vs 12.5 mos; P =.002 RFS: 23.6 vs 5.7 mos; P =.003 DOR: NR vs 17.2 mos; P = % of pts in CR following blinatumomab were able to receive allo- SCT Most neurologic AEs were grade 2 10% of pts required therapy interruption or discontinuation Gökbuget N, et al. ASH Abstract 680. Slide credit: clinicaloptions.com

16 RATIFY: Midostaurin in FLT3-Positive AML: Study Design yrs of age with FLT3- mutated (non-apl) AML (N = 717) Stratified by ITD/TKD; randomized Induction* Daunorubicin (1-2 cycles) 60 mg/m 2 IVP D1-3 + Cytarabine 200 mg/m 2 /d IVCI D1-7 + Midostaurin 50 mg PO BID D8-21 (n= 360) Daunorubicin 60 mg/m 2 IVP D1-3 + Cytarabine 200 mg/m 2 /d IVCI D1-7 + Placebo D8-21 (n = 357) Double-blind, placebo-controlled, randomized phase III study of midostaurin, an FLT3 inhibitor Primary endpoint: OS (not censored for SCT) Secondary endpoint: EFS CR CR Consolidation (up Cytarabine to 4 cycles) 3 g/m 2 over 3h q12h D1,3,5 + Midostaurin 50 mg PO BID D8-21 (n = 231) Cytarabine 3 g/m 2 over 3h q12h D1,3,5 + Placebo D8-21 (n = 210) Stone RM, et al. ASH Abstract 6. Maintenance (12 cycles) Midostaurin 50 mg PO BID D1-28 (n = 120) Placebo D1-28 (n = 85) *Hydroxyurea allowed for 5 days prior to induction therapy. Slide credit: clinicaloptions.com

17 RATIFY: Efficacy Characteristic Midostaurin + Chemo (n = 360) Placebo + Chemo (n = 357) Median OS, mos (range) 74.7 (31.7-NE) 25.6 ( ) 4-yr OS, % (95% CI) Uncensored* Censored for SCT 51.4 ( ) 63.8 ( ) SCT, n (%) Any time CR1 only CR, n (%) By Day 60 In induction/consolidation Median EFS, mos (range) By day 60 In induction/consolidation 212 (59) 100 (28) 212 (59) 239 (66) 8.0 ( ) 11.3 ( ) 44.2 ( ) 55.7 ( ) 196 (55) 79 (22) 191 (53) 211 (59) 3.0 ( ) 6.1 ( ) P Value *HR: HR: Longer OS shown in midostaurin arm in all FLT3 cohorts. 4-yr EFS rate was 28% with midostaurin vs 20% in placebo, regardless of FLT3 status. Stone RM, et al. ASH Abstract 6. Slide credit: clinicaloptions.com DFS, mos (range) 25.9 (19.4-NE) 14.4 ( ).002

18 RATIFY: Conclusions Midostaurin added to standard chemo in pts with newly diagnosed FLT3-mutated AML Improved OS and EFS, regardless of ITD/TKD stratification group and despite high SCT rate (57%), vs placebo Reduced risk of death by 23% vs placebo Safety/tolerability similar in midostaurin and placebo arms Study investigators suggest midostaurin addition to current standard chemo with 1-yr subsequent maintenance as a new standard of care for these pts Stone RM, et al. ASH Abstract 6. Slide credit: clinicaloptions.com

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20 Ibrutinib vs Chlorambucil in Tx-Naive Elderly Pts With CLL (RESONATE-2) Open-label, randomized phase III trial Treatment-naive CLL pts 65 yrs of age or older; for pts yrs, comorbidity that precludes FCR; no warfarin use; no del(17p) (N = 269) Stratified by ECOG PS 0-1 vs 2 Rai stage III-IV vs II Ibrutinib 420 mg QD until PD or unacceptable toxicity (n = 136) Chlorambucil 0.5 mg/kg* Days 1 and 15 of 28-d cycle up to 12 cycles (n = 133) *Up to 0.8 mg/kg maximum. Primary endpoint: IRC-evaluated PFS Secondary endpoints: OS, ORR, hematologic improvement, safety PCYC-1116 extension study after IRCconfirmed progression Crossover upon PD (n = 43) Tedeschi A, et al. ASH Abstract 495. Burger JA, et al. N Engl J Med. 2015:373; Slide credit: clinicaloptions.com

21 PFS (%) PFS (%) Dr Shankara Paneesha RESONATE-2: PFS (Primary Endpoint) IRC Assessment Investigator Assessment 100 Ibrutinib 100 Ibrutinib Chlorambucil Chlorambucil Mos Pts at Risk, n Ibrutinib Chlorambucil Chlorambucil Ibrutinib 18.9 Median, mos NR HR: 0.16 (95% CI: ; P <.001) PFS results not dependent on age, Rai stage, ECOG PS, or bulky disease 1 Richter s transformation in chlorambucil arm; none on ibrutinib arm 0 0 Pts at Risk, n Ibrutinib Chlorambucil Chlorambucil Ibrutinib 15.0 Median, mos NR HR: 0.09 (95% CI: ; P <.001) Mos Tedeschi A, et al. ASH Abstract 495. Burger JA, et al. N Engl J Med. 2015:373; Slide credit: clinicaloptions.com

22 OS (%) Dr Shankara Paneesha RESONATE-2: OS 84% reduction in risk of death with ibrutinib Ibrutinib Chlorambucil Pts at Risk, n Ibrutinib Chlorambucil 20 HR: 0.16 (95% CI: ; P =.001 by log-rank test) Mos Tedeschi A, et al. ASH Abstract 495. Burger JA, et al. N Engl J Med. 2015:373; Slide credit: clinicaloptions.com

23 Ibrutinib vs Temsirolimus in Previously Treated MCL: MCL3001 (RAY) Randomized, open-label phase III trial Stratified by smipi and prior lines of therapy Previously treated pts with MCL (N = 280) Ibrutinib 560 mg QD PO (n = 139) Temsirolimus IV Crossover to ibrutinib arm if Cycle 1: 175 mg Days 1, 8, 15 progressive Subsequent cycles: 75 mg Days 1, 8, 15 disease (n = 141) (n = 32) Median drug exposure: 14 mos of ibrutinib vs 3 mos of temsirolimus. Primary endpoint: PFS Secondary endpoints: ORR, OS, DoR, time to next treatment, and safety Rule S, et al. ASH Abstract 469. Dreyling M, et al. Lancet. 2015;[Epub ahead of print]. Slide credit: clinicaloptions.com

24 MCL3001 (RAY): Response Outcome, % Ibrutinib (n = 139) Temsirolimus (n = 141) P Value ORR by IRC CR PR SD <.0001 ORR by previous lines of therapy Median DoR: Not reached (95% CI: 16.2-NE) with ibrutinib vs 7.0 mos (95% CI: ) for temsirolimus Rule S, et al. ASH Abstract 469. Dreyling M, et al. Lancet. 2015;[Epub ahead of print]. Slide credit: clinicaloptions.com

25 PFS (%) OS (%) Dr Shankara Paneesha MCL3001 (RAY): Survival Outcomes Pts at Risk, n 3 6 Ibrutinib Temsirolimus Ibrutinib Temsirolimu s 69 PFS Median, 14.6 mos 6.2 HR (95% CI) 0.43 ( ) P < Mos Ibrutinib Consistent PFS improvement across pt subgroups 23% of pts treated with temsirolimus crossed over to ibrutinib at progression Rule S, et al. ASH Abstract 469. Dreyling M, et al. Lancet. 2015;[Epub ahead of print]. 8 3 Temsirolimus OS Mos Ibrutinib Temsirolimus Median, NR mos 21.3 HR (95% CI) 0.76 ( ) P < Slide credit: clinicaloptions.com

26 Nivolumab in R/R chl: Phase I Dose Expansion Cohort chl pts with ECOG PS 0/1, previous treatment with 1 chemotherapy, no autoimmune or previous organ allograft or allogeneic BMT Nivolumab 3 mg/kg IV Wk 1, Wk 4, then Q2W for up to 2 yrs (N = 23) Primary endpoints: safety and tolerability Secondary endpoints included: ORR, DoR, PFS Ansell S, et al. N Engl J Med. 2015;372: Ansell S, et al. ASH Abstract 583. Slide credit: clinicaloptions.com

27 Idelalisib Given Front-Line for the Treatment of Chronic Lymphocytic Leukemia Results in Frequent and Severe Immune-Mediated Toxicities Benjamin L Lampson, et al.

28 PI3Kdelta Inhibitors Increase Genomic Instability By Upregulating Aid Expression Mara Compagno et al.

29 Phase I Study of Rituximab, Lenalidomide, and Ibrutinib in Previously Untreated Follicular Lymphoma (Alliance ) Chaitra S. Ujjani, et al.

30 ASH Choosing Wisely list Do not transfuse more than the minimum number of red blood cell (RBC) units necessary to relieve symptoms of anemia or to return a patient to a safe hemoglobin range (7 to 8 g/dl in stable, non-cardiac, in-patients). Don't test for thrombophilia in adult patients with venous thromboembolism (VTE) occurring in the setting of major transient risk factors (surgery, trauma or prolonged immobility). Don't use inferior vena cava (IVC) filters routinely in patients with acute venous thromboembolism (VTE). Don't administer plasma or prothrombin complex concentrates for non-emergent reversal of vitamin K antagonists (i.e. outside of the setting of major bleeding, intracranial hemorrhage or anticipated emergent surgery). Limit surveillance computed tomography (CT) scans in asymptomatic patients following curative-intent treatment for aggressive lymphoma.

31 ASH Choosing Wisely list Don't treat with an anticoagulant for more than three months in a patient with a first venous thromboembolism occurring in the setting of a major transient risk factor. Don't routinely transfuse patients with sickle cell disease for chronic anemia or uncomplicated pain crisis without an appropriate clinical indication. Don't perform baseline or routine surveillance computed tomography (CT) scans in patients with asymptomatic, early stage chronic lymphocytic leukemia. Don't test or treat for suspected heparin-induced thrombocytopenia (HIT) in patients with a low pre-test probability of HIT. Don't treat patients with immune thrombocytopenic purpura in the absence of bleeding or a very low platelet count.

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