Emerging TREATMENTS FOR BLOOD CANCERS AND DISEASES

RUEMU E. BIRHIRAY, MD

PROGRAM CHAIR

CEO, INDY HEMATOLOGY EDUCATION, INC.,

PARTNER, HEMATOLOGY ONCOLOGY OF INDIANA, AMERICAN ONCOLOGY NETWORK, PA, INDIANAPOLIS, IN

CLINICAL PROFESSOR OF MEDICINE,

MARIAN UNIVERSITY COLLEGE OF MEDICINE, INDIANAPOLIS, IN

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INDY HEMATOLOGY EDUCATION, INC

• Board of Directors:
• President/CEO: Ruemu E. Birhiray, MD
• Vice-President: Michael C. Weimann, MD
• Treasurer/COO: Donna M. Birhiray, OT, MBA
• Secretary: Jennifer Terry, JD
• Director of Conventions: Thalia Hammond

ACHIEVING TOMMORROW’S OUTCOMES TODAY THROUGH EDUCATION™

ACUTE LEUKEMIA

• What is Acute Leukemia ?
• Diseases caused by the maturation arrest of bone marrow stem cells at a very early stage thus resulting in an inability to produce normal cells, with resulting low red blood cells (anemia), low platelets (thrombocytopenia) and white blood cells (neutropenia).
• Untreated Acute Leukemia results in infections, bleeding and other complications of bone marrow failure.
• Subtyptes: Acute Lymphoblastic Leukemia (ALL) and Acute Myeloid Leukemia (AML)

ACUTE MYELOGENOUS LEUKEMIA

• QUAZAR AML-001: Phase III, N=472: CC-486, Maintenance in AML After CR/Cri vs Placebo
• PREVENTING RECURRENCE WITH EARLY ORAL THERAPY
• Ad-Hoc analysis: Escalated CC-486 dosing in early first relapse with 5-15% blasts, reduces blasts to < 5% in 1 in 4 pts (10/43 vs 4/35).
• MRD positivity associated with significantly reduced OS and RFS in either arms.
• MRD-negative response in BL MRD-positive patients: 37% with oral AZA vs 19% with PBO 
• Gilteritinib Plus Induction/Consolidation in Newly Diagnosed FLT3 mutant AML: Phase I,
• STANDARD OF CARE CHEMOTHERAPY AND TARGETED THERAPY:
• N=79
• 82% CRc @120 mg (MTD) mutational clearance (FLT3-ITD:total FLT3 signal ratio ≤ 10-4)
• Magrolimab + Azacitidine in Untreated AML: Phase I, N=64
• First-in-class macrophage immune checkpoint inhibitor targeting CD47 (“DON’T EAT ME”)
• CR/Cri 55.4%, 68% transfusion independence, ORR, CR rates similar in TP53 mutation/WT 
• Flotetuzumab in Primary Induction Failure/Early Relapse AML: Phase I/II, N=44
• Immune Engager of T cells (CD3 and Interleukin Protein CD123
• BiTE targeting CD3 x CD123: CR/Cri: 26%, Grade 3: CRS 1/44

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Acute Lymphoblastic Leukemia

• Hyper-CVAD + Blinatumomab in B-Cell ALL, N=38, Phase II, Ph chromosome negative B-cell ALL:
• HYEPERCVAD chemotherapy with immune cells engager (BiSpecific Antibody) BITE Blinatumumab
• Initial therapy for newly diagnosed ALL
• CR: 100%; MRD negativity: 97%, 2-yr OS: 80%

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• DETECTING RESIDUAL DISEASE AFTER TREAMENT: Next Generation PCR
• Monitoring Measurable Residual Disease Using Peripheral Blood in Acute Lymphoblastic Leukemia: Results of a Prospective, Observational Study
• CLONOSEQ PB MRD was highly correlated with BM MRD (r=0.87; p<0.000)
• Non-invasive monitoring of PB-based MRD in ALL patients undergoing curative intent cellular therapies represents a viable alternative to serial BM examinations

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CHRONIC LEUKEMIA

• What is Chronic Leukemia ?
• Disease of blood and bone marrow associated with abnormal mature white blood cells.
• 2 major subtypes:
• Chronic Myeloid Leukemia (CML)
• Chronic Lymphocytic Leukemia (CLL)

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• Chronic Leukemia can transform into acute leukemia or aggressive lymphoma

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CHRONIC MYELOID LEUKEMIA

• ASCEMBL: Asciminib vs Bosutinib for CML-CP Previously Treated With ≥ 2 TKIs, Phase III
• Asciminib: first-in-class STAMP inhibitor, which targets the myristoyl pocket of ABL1, significantly improved Major Molecular Response rate at 24 weeks: 25.5% vs 13.2%
• 5 arterial occlusive events with asciminib vs 1 in bosutinib, but numerically lower rates of side effects leading to discontinuation, dose adjustment, or requirement for additional therapy with asciminib
• Ponatinib After Second-Generation TKI in Chronic-Phase Chronic Myeloid Leukemia, Phase II, Combined Analysis (n=35) of OPTIC  (n=93)and PACE, (= 257)
• Deep, durable responses and robust survival outcomes, regardless of baseline BCR-ABL1 mutation status (including T315I), preferably starting at higher doses and reducing dose for responding patients.

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CHRONIC LYMPHOCYTIC LEUKEMIA

• RELAPSED/REFRACTORY CLL
• PIRTOBRUTINIB (LOXO-305), next-generation, Wild-type and C481S mutant BTKi, Phase I/II, N=323ORR 63% ( N=139), increased over time to 86% with ≥ 10 months F/U, (N = 29), independent of prior therapy
• TRANSCEND CLL 004: Lisocabtagene Maraleucel + Ibrutinib, Phase I, N=19ORR: 95%, uMRD: PB: 89%, BM: 79%.
• UNITY-CLL: Umbralisib + Ublituximab vs Obinutuzumab + Chlorambucil, Phase III, N=421, TN and R/R CLL/SLL: ORR: 83.3%  vs. 68.7% (TN: R/R: Prior BTKi: 84, 82, 57 vs 78, 57, 25%), U2 DCR: 93%
• ACE-CL-003: Acalabrutinib plus Venetoclax and Obinutuzumab or Rituximab in TN/RR CLL/SLL,N=, ORR: 92% in R/R and 100 in TN; CR/CRi rate: 50%; uMRD: 71% (67% in R/R patients and 75% in TN patients)
• BTKi versus BTKi in Relapsed/Refractory Chronic Lymphocytic Leukemia
• ELEVATE-RR: OPEN LABEL, Phase III, Acalabrutinib vs Ibrutinib in R/R CLL/SLL, N=533
• Efficacy: Equivalent.
• Adverse Events: Afib/flutter (9.4% vs 16.0% similar grade 3/4), HTN (9.4% vs 23.2%;), diarrhea (34.6% vs 46.0%, arthralgia (15.8% vs 22.8%;), bleeding (38.0% vs 51.3%;)
• ALPINE STUDY: ZANUBRUTINIB VS IBRUTINIB in R/R CLL/SLL: 
• Interim analysis, N=415/652 planned Phase III, ORR; Zanubrutinib vs ibrutinib (78.3% vs 62.5%) 2-sided P=0.0006,  neutropenia (28.4% vs 21.7%)

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CHONIC LYMPHOCYTIC LEUKEMIA�FRONTLINE THERAPY

• CAPTIVATE , Phase II, RCT, FD, Ibrutinib + Venetoclax in TN CLL/SLL, N= 164, 
• 1-yr DFS rate 95.3% in patients with uMRD randomized to placebo after 12 cycles of I+V and  30-mo PFS rates  > 95% across all treatment arms
• 24 mos PFS: 96%, unmutated IGHV: 93% vs 97% mutated IGHV, del(17p)/TP53 84% (ASCO 2021)
• GLOW: Fixed-Duration Ibrutinib + Venetoclax vs Chlorambucil + Obinutuzumab in TN CLL
• Median PFS: NR vs 21.0 mo (HR: 0.216; 95% CI: 0.131-0.357; P <.0001, ORR/CR+CRi: 86.8/38.7 vs 84.8/11.4%
• UMRD rates at EOT +3 by NGS (ITT): BM 51.9 vs 17.1 (p = <0.0001), PB 54.7 vs 39 (P = .0259)
• Substained PB uMRD: 84.5% vs 29.3% 

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GLOW PFS – EHA 2021, Kater AP, et al.

LYMPHOMA

• What is Lymphoma?
• Disease of lymphocytes and lymph nodes
• 2 major subtypes:
• HODGKIN LYMPHOMA
• NON-HODGKIN LYMPHOMA

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Lymphoma

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• BISPECIC ANTIBODY
• Mosunetuzumab in R/R FL, Phase I, N=42, humanized anti-CD20 x CD3 bispecific antibody
• ORR: 67.7%; CR: 51.6%, mDoR: 20.4 mos Only Grade @ Cytokine Release Syndrone (CRS) : G2 and no grade ≥3 CRS.
• Odronextamab, Human. Bispecific anti CD3 and CD20 antibody, Phase I, N=136, R/R NHL
• OP Regimen, R/R FL: Durable, CR rate, 70%, R/R DLBCL: CR (no prior CAR-T), 55% (prior CAR-T)21%
• CAR-T THERAPY
• TRANSCEND NHL 001, Lisocabtagene Maraleucel (R/R Mantle Cell Lymphoma Cohort):
• N=44: Phase 1: ORR: 84%; CR : 66%, CRS 50%, PGr3 ≥ 3 cytopenias, 34%; Gr3 ≥ 3 infs, 16%
• ANTI-CD19 ANTIBODY:
• L-MIND: ASCT-ineligible R/R DLBCL, N=81, Tafasitamab + Len: RR; 55%, mDOR 43.9mo
• LOTIS-2: R/R DLCBCL, ≥2 Prior Regimens: ADC, Loncastuximab tesirine, RR: 48.3% mDoR 13.4 mo 

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LYMPHOMA

• NHL TKI THERAPY
• UNITY-NHL: Umbralisib, PI3Kδ inhibitor, in Patients With R/R Indolent NHL , Phase II, N=208
• 47.1% ORR, 16% CR rate in MZL, acceptable safety profile and low rate of discontinuations for AEs.
• CITADEL-204, Parsaclisib, PI3Kδ Inhibitor, in R/R Marginal Zone Lymphoma, Phase II, N=100
• ORR in daily group: 57%; median time to first response: 8.1 wks, DI: 57%, DC: 35% due to TEAEs
• BRUIN: Pirtobrutinib, Waldenström macroglobulinemia, Phase1/2: N = 19, the ORR  68% ,  47%, PR, 21% MRD, 16 SD. 13 patients BTK pretreated, the ORR was 69% 
• CHRONOS-3, Phase III, N=458: Copanlisib plus rituximab vs rituximab in R/R iNHL: mPFS: 21·5 mos vs 13·8 mos (HR 0·52; p<0·0001), PFS improvement in all histology subtypes (HR): FL 0.580, MZL 0.475, SLL 0.243 LPL/Waldenström macroglobulinemia: N= 38, mPFS 33.4 vs 16.6mo, HR 0.443
• HODGKINS LYMPHOMA
• SGN35-015: Brentuximab Vedotin ± Second Agent for Older Patients With cHL Ineligible for CT, Phase II, Frontline therapy, N=87,ORR: 92% (95% CI: 74% to 99%), mOS: 82 mos (95% CI: 40.1-NR)BV + Nivolumab or DTIC: ORRs: 95% and 100%; Severe TEAEs 45% with Bendamustine

MYELODYSPLASTIC SYNDROME (MDS)

• What is Myelodysplastic Syndrome?
• Disease of blood and bone marrow associated with abnormal immature blood cells that could transform to acute leukemia.
• Patients typically present with low blood cells
• 7 major subtypes:
• Refractory anemia (RA).
• Refractory anemia with ringed sideroblasts (RARS).
• Refractory cytopenia with multilineage dysplasia (RCMD).
• Refractory cytopenia with multilineage dysplasia and ringed sideroblasts (RCMD-RS).
• Refractory anemia with excess blasts (RAEB)
• Myelodysplastic syndrome, unclassified (MDS-U) MDS
• MDS associated with isolated del(5q).
• CMML and JMML

MYELODYSPLASTIC SYNDROME

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• Enasidenib in High-Risk IDH2-Mutated MDS:
• ORR of 84% plus AZA (HMA-naive), RR 43% single agent (R/R after HMA), differentiation syndrome 17%.
• Ivosidenib + Venetoclax ± Azacitidine in IDH1-Mutated Myeloid Malignancies, Phase Ib/II, N=29, ND or R/R AML or advanced MDS or MPN (≥10% blasts) with IDH1R132 mutation, mFU 27.6mo
• CRc/mOS: I+V400 = 67%, 9mos, I+v800 = 100%, NR, I+V400+A = 85%, NR, uMRD OS:100% vs 33%
• Roxadustat in Low-Risk MDS: Phase III:, N= 24, effective regardless of RS and baseline EPO levels
• Oral hypoxia-inducible factor prolyl hydroxylase inhibitor that increases RBC production
• TI at 8 weeks: Overall 38%, 78% (7/9) received roxadustat 2.5 mg/kg
• DACOTA Phase III Study of Decitabine vs Hydroxyurea for Advanced Proliferative CMML
• ORR: decitabine 63% vs hydroxyurea 34% ; P = .0002, No differences in OS, EFS, TTF to AML
• GTB-3550 TriKE, Tri-specific killer engager that targets CD16, IL-15, and CD33 stimulates robust natural killer cell activity, with clinical activity. 1 pt @ 50mcg/kg, with R/R MDS responding with transfusion independence.

MYELOPROLIFERATIVE NEOPLASMS (MPNs)

• What are Myeloproliferative Neoplasms?
• Disease of blood and bone marrow associated with abnormal production of blood cells or the spongy bone marrow cells that could transform to acute leukemia, cause low blood cells and enlargement of the spleen.
• 5 major subtypes:
• Primary myelofibrosis
• Polycythemia vera (PV).
• Essential Thrombocythemia (ET).
• Chronic eosinophilic leukemia/hypereosinophilic syndrome (HES)
• Systemic mastocytosis (SM)

MYELOPROLIFERATIVE NEOPLASMS

• MANIFEST: Novel BET Inhibitor, CPI-0610, Plus Ruxolitinib in JAK Inhibitor–Naive Myelofibrosis, N=
• 42 of 63 (67%) JAK inhibitor–naive MF patients treated with CPI-0610 + ruxolitinib achieved SVR35 at Wk 24
• Compares favorably with 29% to 42% SVR35 at Wk 24 with ruxolitinib alone in JAKi – naive patients
• Symptom improvement: 57% TSS50 at Wk 24
• IMBARK, Imetelstat: Telomerase inhibitor, Phase II, in R/R intermediate-2/high-risk MF, N=107
• Comparing 2 doses of imetelstat: 9.4 mg/kg vs 4.7 mg/kg IV Q3W
• Dose-related OS improvement: mOS 19.9 vs 28.1mo;
• Luspatercept in RBC Transfusion-Dependent Patients With Myelofibrosis-Associated Anemia, Phase II, N=100, Transfusion Dependent Groups: Cohort 1: (No RUX) vs Cohort 3b (+ RUX):
• RBC-TI responses lasting ≥ 12 wk10% and 27%
• 25% of patients achieved more than one RBC-TI responses lasting ≥ 12 wks

MULTIPLE MYELOMA

• What is Multiple Myeloma
• Cancer of the antibody producing cells of the bone marrow called plasma cells
• Results in accumulation of plasma cell or the produced abnormal antibody causing:
• Increased blood calcium
• Kidney failure
• Low blood counts, particularly red blood cells
• Destruction of the bone marrow

Multiple Myeloma: Targeting BCMA

• BCMA-Directed CAR T-Cell Therapy in R/R MM
• Ciltacabtagene Autoleucel: Phase Ib/II, N = 97: ORR: 96.9%,  ≥ 67% sCR, 12-mo PFS: 76.6%; OS: 88.5%
• CRB-402: bb21217: Phase I, N=69, mDoR; 17.0 mos across all doses.
• PRIME: P-BCMA-10: Phase I/II, Manufactured with transposons to preferentially transpose T_SCM cells, N=55, ORR: 67%, 1 CRS.
• BCMA-Directed BiSpecific Antibody in R/R MM
• Teclistamab (JNJ-64007957): Phase I, N=149, ORR: 73% (≥ CR rate: 23% and ≥ VGPR rate: 55%)
• AMG 701: Phase I, N= 85, Phase I, Extended half-life for weekly dosing: Responses: 5 sCR, 3 CR, 6 VGPR, 7 PR
• REGN5458: Phase I, N=49, 19 responders, 95% with ≥VGPR, 37% with response ≥ 8 mos, mDoR: 6.0 mos 
• BCMA-Directed ADC in R/R MM
• MEDI2228: Humanized anti-BCMA ADC conjugated to tesirine, Phase I, N=82, ORR: 66% at 0.14 mg/kg, mDoR: 5.9 mos, DLT: Thrombocytopenia, Early onset photophobia with discontinuations
• Belantamab Mafodotin (DREAMM-6:  + Bortezomib/Dexamethasone): Phase II/Preliminary: N=18, ORR: 78%; ≥ VGPR: 67%, 100% keratopathy [61% (11/18) grade 3] (ALGONQUIN: +Pomalidomide/Dexamethasone): Phase II, N=24, ORR: 88% ≥ VGPR: 68% with dose dependent keratopathy (Grade 3/4: 25-70%)

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Multiple Myeloma: Non-BCMA Targeted Therapy

• NON-BCMA-Directed BiSpecific Antibody in R/R MM
• Talquetamab: GPCR5D (G protein-coupled receptor class C group 5 member D) x CD3 Antibody, Phase I, N=157, 66% ORR with active doses.
• Cevostamab: FcRH5 (Fc Receptor Homolog 5) x CD3 Antibody, Phase I, N=53, ORR: 53% with active doses.
• Novel Cereblon E3 ligase modulator CelMOD in R/R MM
• Iberdomide Plus Daratumumab/Dex or Bortezomib/Dex: Phase I/II, N=27/23, ORR 42.3%(IDd) and 60.9% (IVd)
• Exportin 1 (XPO1) Inhibitor in R/R MM 
• STOMP Selinexor/Pomalidomide/Dex: Phase I/II, N=64, ORR: 60% (≥ VGPR 30%), CBR: 75%, mPFS: NR
• CD 38 Targeted Therapy in R/R MM
• APOLLO: Daratumumab SC + Pom/Dex vs Pom/Dex: Phase III, N=304, 37% improved PFS with DPd vs Pd (mPFS: 12.4 vs 6.9 mos; P = .0018, HR 0.63)
• IKEMA: Isatuximab Plus Carfilzomib/Dex vs Carfilzomib/Dex: Phase III, subgroup analysis: N=302, improved PFS in older  ≥ 70 (HR: 0.364), refractoriness status, high risk cytogenetics

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Multiple Myeloma: Newly Diagnosed (NDMM)

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• MAIA in Non-eligible ND MM: (N=737): Phase III,  Daratumumab-Rd (n=368) or Rd (n=369) 5 year Follow-up. 
• Improved OS: 66% vs. 53% [HR: 0.68; p=0.0013], PFS: 53% vs. 29% [HR: 0.53; p<0.0001]
• GRIFFIN in ASCT-eligible ND MM: Daratumumab + VRd followed by D-R maintenance vs VRd followed by R maintenance; Phase II: N=207, 
• D-VRd + D-R maintenance; 24-mo PFS: 94.5%; 24-mo OS: 94.7%, sCR at 12 mos of maintenance cutoff: 63.6% vs 47.4% (P = .0253)
• FORTE: KRd with or without ASCT followed by KR or R maintenance in NDMM; Phase II, N=474
• KRd-ASCT significantly prolonged 4-yr PFS vs KRd12 across cytogenetic risk groups: standard-risk MM (82% vs 67%), high-risk MM (62% vs 45%), double-hit MM (55% vs 33%)
• Maintenance therapy with KR significantly prolonged 3-yr PFS vs R alone: Standard-risk MM (90% vs 73%), high-risk MM (69% vs 59%), double-hit MM (67% vs 42%), except for amp(1q)

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MAIA in Non-eligible ND MM: Facon T et al.  EHA, 2021; LB190 

Hematology: Benign and Not So Benign Disorders

• BTK Inhibitor Rilzabrutinib in R/R ITP: Phase I/II, N=53, ORR 42% (400 mg BID)
• FLIGHT: First-line Mycophenolate + Steroids vs Standard Steroid Treatment ND ITP: Phase III, N=120,
• Similar RR @ 2 wks, fewer TFR with MMF + steroids (22% vs 44%; HR: 0.41; P = .0064), SF36 and FACIT-F worse with MMF.
• Mitapivat (AG-348)Antisickling, oral, small-molecule inhibitor of pyruvate kinase R, in Sickle Cell Disease: Phase I, N=12, Hb increase by ≥ 1 g/dL in 6 of 11 (55%) and lowered markers of hemolysis.
• HOPE-B: Etranacogene Dezaparvovec Gene Therapy in Adults with Severe/Moderately Severe Hemophilia B: Phase III, N=54, total bleeds decreased by 83% and treated bleeds decreased by 91% at 6 mos; 98% d/c of FIX prophylaxis.
• PATHFINDER: AVAPRITINIB IN ADVANCED SYSTEMIC MASTOCYTOSIS: Phase II, N=62: (55% with prior midostaurin). ORR: 75% CR: 9%, 12-month OS: 87%
• PEGASUS: Pegcetacoplan versus Eculizumab in Paroxysmal Nocturnal Hemoglobinuria; N=80, Phase III, Pegcetacoplan  superior; improved hgb from baseline to wk 16,transfusion independence: 85% versus 15%.
• PAZOPANIB FOR SEVERE BLEEDING AND TRANSFUSION-DEPENDENT ANEMIA IN HEREDITARY HEMORRHAGIC TELANGIECTASIA: N= 13 (62% prior Bevacizumab), Phase I/II, @ mean dose 100mg, 100% RBC transfusion independence, increased hgb, decreased epistaxis, @12 mo: freedom from anemia 92%, median ferritin increased 91 ng/mL and  hemostatic procedures decreased 90% 

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Hematopoeitic Stem Cell Cell/Cellular Therapy

• BMT CTN 1102: RIC Allogeneic HSCT vs Non-HSCT Therapy in Patients 50-75 Yrs With Higher-risk MDS: Phase II, N= 384; 3yr OS: Subgroup analysis of the overall population revealed no difference in OS benefit for donor vs no donor arm based on age
• UNIVERSAL, Phase I, trial of allogeneic anti-BCMA CAR T-cell therapy in R/R MM, N=35; ~ 90% received CAR T-cells within 5 days of enrollment, No GVHD or ICANS; 43% grade 1/2 CRS, 5/6 patients assessed with ≥ VGPR had negative MRD status
• CLIMB THAL-111/SCD-121: CTX001(CRISPR/Cas9 modified CD34+ ASCs for TDT β-Thalassemia/Sickle Cell Disease, Phase I/II, first 10 patients with ≥ 3 mos of f/u, achieved TI and no VOC events for SCD
• GRAFT VERSUS HOST DISEASE:
• Gravitas-119: Phase I: N65= Itactinib (JAK-1 inhibitor) plus calcineurin-based regimens as prophylaxis for aGVHD, 98.3% engraftment, lower rates of aGVHD compared to historical controls.
• Baricitinib JAK1/2 inhibitor in R/R cGVHD, Phase II, n=20: ORR at 6 mos (primary endpoint; ITT): 65%
• ROCKstar: Belumosudil (KD025) oral selective inhibitor of ROCK2 in R/R cGHVD, Phase II, N=132, ORR: > 70%; QD, 73%; BID, 77% , 44% mean steroid use decline.

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SAVE THIS DATE !

Evening with Experts 2022

(http://www.indyhematologyreview.com)

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March 25^th, 2022

Westin Indianapolis,

Indianapolis,

Indiana, 46204

Announcements and Acknowledgments