Hematologic Malignancies: Top Ten Advances Impacting Clinical Practice

Transcription

1 Hematologic Malignancies: Top Ten Advances Impacting Clinical Practice Adam D. Cohen, MD Abramson Cancer Center University of Pennsylvania June 14, 2018 Please note that some of the studies reported in this presentation were published as abstracts only and/or presented at a conference. These data and conclusions are included because expert faculty found them to be important scientific contributions but should be considered to be preliminary until published in a peer-reviewed journal.

2 Disclosures Consulting/Advisory boards Celgene, Bristol-Meyers Squibb, Janssen, GlaxoSmithKline, Seattle Genetics, Oncopeptides, Kite Pharma Research Funding Bristol-Meyers Squibb, Novartis I am a myeloma doc Thanks to Jakub Svoboda and David Porter for input I won t discuss CAR T cells

3 Acute leukemias Precision medicine for AML FLT3 inhibitors for untreated and rel/ref AML IDH 1/2 inhibitors for rel/ref AML Gemtuzumab ozogamycin for untreated AML Other recent changes in practice Liposomal daunorubicin + ara-c (Vyxeos) for new t-aml or AML with MDS-related changes, ages Inotuzumab ozogamycin (anti-cd22-calicheamicin ADC) approved for rel/ref ALL

4 Midostaurin for FLT3-mutated new AML Similar CR rate: 59% vs 54% Similar grade 3-5 AE rate Med DFS: 26.7 vs 15.5 mos. Improved OS (HR 0.78) FDA approval April 2017 Stone et al, NEJM 2017

5 Other FLT3 inhibitors Gilteritinib (ASP2215) Phase 3 vs salvage chemo ongoing Quizartinib (AC220) Cohort 1: age>60, rel<1yr Phase 3 vs salvage chemo: Met primary endpoint (press release 5/8/18) Perl et al, Lancet Oncol 2017; Cortes et al, Lancet Oncol 2018

6 IDH1/IDH2 inhibitors Mutations in 20% of AML Enasidenib (IDH2) 100mg PO daily ORR 40% in rel/ref AML Tox: Hyperbilirubinemia, Differentiation syndrome Ivosidenib (IDH1) 500mg PO daily ORR 42% in rel/ref AML Tox: Long QTc, Differentiation syndrome Med OS 9.3 mos Med OS 8.8 mos FDA approved 8/1/17 Submitted to FDA 12/2017 Stein et al, Blood 2017; Dinardo et al, NEJM 2018

7 Gemtuzumab ozogamycin (GO) for AML Anti-CD33-calicheamicin antibody-drug conjugate Approved 2000, withdrawn 2010, re-approved 9/2017 Lower doses (3 or 6mg/m2) chemo improved EFS and OS in untreated AML, less hepatotoxicity Favorable Intermediate Unfavorable n=3325, 5 trials Penn: GO for new AML w/ t(8;21) or inv16 or t(16;16) Also approved as single agent for new AML, not candidate for induction (med OS 4.9 vs 3.6 mos for BSC) Hills et al, Lancet Oncol 2014

8 Lymphomas Brentuximab for newly-diagnosed Hodgkin s Acalabrutinib for relapsed mantle cell lymphoma Rituximab/venetoclax for relapsed CLL Other/honorable mention: Ibrutinib/venetoclax for rel/ref MCL (NEJM 2018) Ritux/lenalidomide phase 3 for untreated FL (ASCO 2018) Mogamulizumab (anti-ccr4 mab) phase 3 for rel/ref CTCL (ASH 2017) Ritux/ibrutinib phase 3 for Waldenstrom s (ASCO/NEJM 2018)

9 Brentuximab vedotin (anti-cd30-mmae) n= year OS: 96.6% vs 94.2% (HR 0.73, p=0.2) Connors et al, NEJM 2018

10 Acalabrutinib for rel/ref mantle cell lymphoma phase 2, single arm, acalabrutinib 100mg bid n=124, med 2 priors Tox: HA, diarrhea, fatigue, myalgias no afib, 1 grade 3 GI hemorrhage ORR 81%, CR 40% Med f/up 15.2 mos. FDA approved 10/2017. Activity in CLL (NEJM 2016), Waldenstrom s (ASCO 2018), FL (ASCO 2018) Wang et al, Lancet 2018

11 Ritux + venetoclax for rel/ref CLL (MURANO trial) med 1 prior tx 2% ibrut/idela 26% del17p ORR 92% vs 72% (MRD-: 62% vs 13%) Seymour et al, NEJM 2018

12 Myeloma Venetoclax for t(11;14) patients Daratumomab combo for front-line myeloma Weekly carfilzomib for rel/ref MM Infectious prophylaxis in newly-diagnosed MM Other/honorable mention: Daratumumab SQ for RRMM (ASH 2017/ASCO 2018) Daratumumab for AL amyloidosis (ASH 2017) Phase 3 Pom/Bort/Dex vs Pom/dex for RRMM (ASCO 2018) BCMA CAR T cells for RRMM (ASH 2017/ASCO 2018) BCMA-targeted antibody-drug conjugate for RRMM (ASH 2017)

13 Venetoclax for rel/ref MM with t(11;14) Ph 1/2 ven +/- dex med 5 priors, no MTD (RP2D 1200 mg/d), cytopenias, N/V/D Ph 1/2 bortezomib/ven/dex med 3 priors, RP2D 800 mg/d. Venetoclax +/- dex Bortez/ven/dex med DOR 9 mos. med DOR 9.7 mos. Kumar et al, Blood 2017; Moreau et al, Blood 2017

14 Dara-VMP for untreated, SCT-ineligible MM ORR: 91 vs 74% CR: 43 vs 24% MRD- 22 vs 6% Mateos et al, NEJM 2018

15 Weekly carfilzomib/dex for rel/ref MM (ARROW) 1:1 Randomization N = 478 Relapsed and Refractory MM 2-3 prior lines Prior exposure to IMiD & PI (except carfilzomib or oprozomib) PS 0-1 CrCl of 30 ml/min Stratification: ISS stage Refractory to bortezomib Age (<65 vs. 65) Arm A: Once-weekly carfilzomib + dex (30 min infusion of K) Carfilzomib 20 mg/m 2 IV D1 (Cycle 1) Carfilzomib 70 mg/m 2 IV D8, 15 (Cycle 1), D1, 8, 15 (Cycle 2+) Dexamethasone 40 mg IV/PO D1, 8, 15 (All cycles) Dexamethasone 40 mg IV/PO D22 (Cycles 1-9 only) 28-day cycles Arm B: Twice-weekly carfilzomib + dex (10 min infusion of K) Carfilzomib 20 mg/m 2 IV D1, 2 (Cycle 1) Carfilzomib 27 mg/m 2 IV D8, 9, 15, 16 (Cycle 1), D1, 2, 8, 9, 15, 16 (Cycle 2+) Dexamethasone 40 mg IV/PO D1, 8, 15 (All cycles) Dexamethasone 40 mg IV/PO D22 (Cycles 1-9 only) Primary end point: PFS Mateos et al, ASCO 2018

16 Weekly carfilzomib/dex for rel/ref MM Median 2-3 priors, 45% bort-ref, 75% len-ref ORR 63% vs 42% Similar toxicity rates (gr3 HTN 5-6%, CHF 3-4%) Increased PFS and OS with weekly Mateos et al, ASCO 2018; Moreau et al, Lancet 2018

17 Infectious prophylaxis in new MM (TEAMM study) Ph3, double-blind, placebo-controlled (n=977) in U.K. MM patients starting therapy Levaquin 500mg/d or placebo x 12 weeks med age 67, 54% went for SCT 1 endpoint: febrile episodes requiring antibiotics + death in 1 st 12 weeks Febrile or death Levaquin Placebo 19% 27% Death 1.6% 4.5% Bactrim: additional benefit? No diff in rates of C diff, MRSA, or ESBL GN infections OS at 1 year similar Drayson et al, ASH 2017

18 Conclusions/Take home points 1. Use FLT3 inhibitors for FLT3-mutated AML Midostaurin now; soon gilteritinib or quizartinib 2. Use IDH inhibitors for IDH1 or IDH2-mutated relapsed AML 3. Consider adding gemtuzumab ozogamicin to 7+3 induction for CBF+ AML 4. Substitute brentuximab for bleomycin with AVD for advanced Hodgkin s lymphoma 5. Acalabrutinib new option for RR MCL 6. Ritux-venetoclax new option for RR CLL 7. Consider venetoclax combos for RR MM with t(11;14) after standard PI, IMiD and anti-cd38 mab combos 8. Dara upfront combos are coming D-VRD, D-RD and D-VTD randomized trials ongoing 9. Consider weekly carfilzomib dosing 70 mg/m2 with dex or cytox/dex or dara optimal weekly dose with IMiDs unclear (likely 56 mg/m2) 10. Consider Levaquin prophylaxis for first 12 weeks treating ND MM especially elderly or co-morbidities

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