Updates In Management of Hematological - PowerPoint Presentation

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Updates In Management of Hematological Malignancies

Abhinav Deol, MD

Professor of Oncology

Wayne State University /

Karmanos

Cancer Institute

June 8

th

, 2022

Slide2

Advisory Board/ Consultant Kite/GileadJanssen/Johnson& JohnsonAdicet Therapeutics

Disclosures

Slide3

Hallmarks of Cancer

Hanahan

D, Weinberg RA; Hallmarks of cancer: the next generation

Cell

2011 Mar 4; 144(5): 646-74

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Immune TherapiesChimeric Antigen Receptor T cellsAntibodiesBi-specific T Cell Engaging AntibodiesAntibody-Drug ConjugatesPathway inhibitorsDrugs Classes

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Immune Therapieshttps://doi.org/10.1016/j.exphem.2017.07.003

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Pathway InhibitorsLavanya V et al; Small Molecule as emerging cancer therapeutics. ICST; Volume 1(3): 39-46

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Since Jan 2020, There have been 33 new approvals for single agent/ combinations for Hematological malignancies for Adult patientsThese include approvals for Myelodysplastic Syndrome, Multiple Myeloma, Lymphomas and Leukemia FDA approved Drugs

https://

www.fda.gov

/drugs/resources-information-approved-drugs/oncology-cancer-hematologic-malignancies-approval-notifications

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FDA Approvals: Cellular Therapies

04/2010

08/2017

10/2017

05/2018

07/2020

02/2021

03/2021

Sipucel

-T

Axi-cel

Brex-Cel

Tisagen

Liso-Cel

Prostate

ALL

DLBCL

DLBCL

MCL

DLBCL

Follicular

MM

Ide-

Cel

03/2021

ALL

10/2021

2

nd

DLBCL

03/2022

05/2022

Follicular

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Manufacturing CAR T Cells

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Anti CD 19 CAR T Cells- ALL

Company/

Institution

Co-Stimulatory Molecule

N

ORR

CR

≥ Grade 3

CRS; NT

Tisagenleucel

*

1

4-1BB

75

81%

60%

46 % ; 13%

Kite*

2

CD28

54

83%

69%

31%

; 38%

MSKCC

3

CD28

53

--

83%

26%; 42%

China

4

CD28

4-1BB

28

62

92%

92%

16%;12%

* FDA approved, ORR: Overall response rate, CR: Complete remission, CRS: Cytokine release syndrome, NT: Neurotoxicity

N Engl J Med 2018; 378:439-44

Blood (2021) 138 (1): 11–22.

N

Engl

J Med 2018;378:449-59

Abstract # 280: ASH 60th Annual Meeting and Exposition, 2018, San Diego, CA

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Anti CD 19 CAR T Cells- 3rd

line DLBCL

Company

Co-Stimulatory Molecule

N

ORR

CR

≥ Grade 3 CRS; NT

Axi-Cel

*

1

CD28

111

82%

42%

13 % ; 28%

Tisagenleucel

*

2

4-1BB

160

53%

40%

23%

; 18%

Liso-Cel

*

3

4-1BB

256

73 %

53%

2% ; 10%

* FDA approved, ORR: Overall response rate, CR: Complete remission, CRS: Cytokine release syndrome, NT: Neurotoxicity

Lancet 2019;20:31-42

N

Engl

J Med 2019;380:45-56

Lancet 2020; 396:839-52

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Anti CD19 CAR T cells- 2nd Line DLBCL( Primary refractory/ relapse <12 months)

Study

Name

(Product)

N

Bridging Chemotherapy

Primary end point

Median

EFS

(CAR T vs SOC)

≥ Grade

3 CRS / NT

ZUMA -7

1

(

Axi-Cel

)

359

No

EFS

8.3 vs. 2 months

6% / 22%

BELINDA

2

(Tisa-

Cel

)

322

Yes

(83%)EFS

3 vs. 3 months

5% / 2%

TRANSFORM 3(Liso-Cel

)184Yes(63%)EFS

10.1 vs. 2.3 months1% / 4 %

N

Engl

J Med 2021, Dec11

N

Engl

J Med 2021, Dec14

ASH Annual Meeting Dec 2021, Abstract #91

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Brexucabtagene

Autoleucel

: MCL

N

Engl

J Med 2020; 382:1331-1342

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Anti CD 19 CAR T Cells: Indolent NHL ASH Annual Meeting 2021, Abstract # 93

≥ Grade 3 CRS/NT = 7/19%

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Anti BCMA CAR T Cells- MM

Product

Co-Stimulatory Molecule

N

ORR

CR

≥ Grade 3 CRS; NT

Ide-

cel

*

1

4-1

BB

128 (54)

73 %(81%)

33% (39%)

5% (3%), 3% (6%)

Cilta-Cel

*

2

4-1BB

97

97%

67%

5%, 2%

FDA approved, ORR: Overall response rate, CR: Complete remission, CRS: Cytokine release syndrome, NT: Neurotoxicity

Numbers in brackets indicate dose of 450 x 10

6

CAR T cell dose

NEJM 2021 Feb 25;384(8):705-716

Lancet. 2021 Jul 24;398(10297):314-324

Despite achieving MRD negative

sCR

, disease will relapse

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Bi-specific T cell Engaging AntibodiesCancers 11(12):2022

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BITE FDA ApprovalBlinatumomab: Directed at CD19 is approved for B cell ALLMosunetuzumab: Directed at CD 20 is approved for use in R/R follicular lymphoma

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Antibodies

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STEM CELL TRANSPLANT : ACUTE GVHDN

Engl

J Med 2017; 377:2167-2179

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AbataceptSevere acute GVHD was 6.8 % in pts

who received

abatacept vs. 14.8% among pts

who received CNI+MTX alone

GVHD free survival was about 10% higher

Journal of Clinical Oncology

 39, no. 17 (June 10, 2021) 1865-1877

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Antibody Drug Conjugates (ADC)Antibodies directed at antigens expressed on the surface of malignant cells are conjugated with chemotherapyThe ADC is internalized and drug is released in the cell leading to toxicity to the malignant cells

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ADC in Hematological MalignanciesGemtuzumab Ozogamicin directed at CD 33 and used for AMLBrentuximab

Vedotin

directed at CD30 and used for HD, NHLPoltuzumab

Ozogamicin

directed at CD79 and used for NHL

Belantamab

Mafodotin

directed at BCMA and used for MM

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Belantamab MafodotinResponse rate is around 30%

Ocular toxicity was seen in about 75% of the

ptsNeeds ocular exam prior to each dose

LANCET ONCOLOGY. VOLUME 21, ISSUE 2, P207-221, FEBRUARY 01, 2020

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Luspartacept: MDSBlood Advances, Volume 5, Issue 5, 9 March 2021, 1565-1575

N

Engl J Med 2020; 382:140-151

Recombinant Fusion Protein

In

pts

with Low risk MDS, 38% in the

luspartacept

arm vs. 13% in the placebo arm achieved transfusion independence

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NHL: BTK #, Selinexor, Tazmetostat, VenetoclaxMM: Selinexor, Venetoclax (11;14 translocation)AML:

Ivosidenib

, Endasidenib, FLT 3 #CML: Asciminib

GVHD:

Ruxolitinib

,

bromosodil

,

Ibrutinib

Small Molecule Pathway Inhibitors

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BTK Pathway

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Drug Name

Indications

Common Side

effects

Ibrutinib

CLL/SLL,

Mantle Cell Lymphoma,

Waldenstorm’s

Macroglobulinemia

, Marginal Zone Lymphoma, Chronic GVHD

Bleeding, Infection, Cardiac

Arrhythmias,

Cytopenias

Acalibrutinib

CLL/SLL,

Mantle Cell Lymphoma

Infections, Lower risk of cardiac arrhythmias,

cytopenias

Zanibrutinib

Waldenstorm’s

Macroglobulinemia

, Mantle Cell Lymphoma, Marginal Zone lymphoma

Infection,

Low risk for cardiac arrhythmias,

cytopeniasBTK INHIBITORS

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Selinexor

Selinexor

reversibly inhibits nuclear export of tumor suppressor proteins by blocking

exportin

1

DLBCL: ORR 39%

MM: Single Agent ORR 21%, Combo SVD vs. VD, ORR 76 vs. 63%

Main toxicities are GI and

cytopenias

NEJM 2019; 381:727-738

LANCET 2020, VOLUME 7, ISSUE 7, E511-E522

LANCET 2020, VOLUME 396, ISSUE 10262, P1563-1573

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Bcl2 Inhibitor: Venetoclax

EXP HEM, VOLUME 61, P10-25, MAY 01, 2018

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CLL/SLL: 70% Response rate in R/R setting. Upfront treatment compared to chlorambucil was effective in over 90% of pts for initial treatmentAML: Approved for use in pts in combination with hypomethalating agents showed CR rate of 37% vs. 18% on placebo arm

Venetoclax

: FDA Approval

N. Engl. J. Med. 378(12), 1107–1120

N

Engl

J Med 2020; 383:617-629

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EZH2 Inhibitor used in R/R follicular lymphomaResponse rate was 69% in pt with EZH2 mutation and 54% in wild type EZH2Tazemetostat

FUTURE ONCOLOGY, VOL. 17, NO 17, 12 March2021

LANCET 2020, VOLUME 21, ISSUE 11, P1433-1442,

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STEM CELL TRANSPLANT: CHRONIC GVHDN

Engl

J Med 2017; 377:2565-2579

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Ruxolitinib: JAK 2 #Ibrutinib: BTK #Belumosudil: ROCK #Chronic GVHD

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Drug

Response (Drug Vs. Placebo)

Side effects: Major

Ibrutinib

Response rate 67%

Bleeding, Infection, Fatigue

Ruxolitinib

49.7 % vs. 25.6%

Cytopenias

Belumosudil

Response rate as 74% and 77% for 2 doses used in the study

Infections,

HTN, hyperglycemia

Chronic GVHD

Blood 2017 Nov 23; 130(21): 2243-2250

N

Engl

J Med 2021; 385:228-238

Blood (2021) 138 (22): 2278–2289

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AsciminibN Engl

J Med 2019; 381:2315-2326

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MMR rate in pts with T315I mutation was 49% at 96 weeksMMR rate vs. Bosutinib at 24 weeks was 24% vs. 13 in pts previously treated with 2 or more TKIsMajor side effects were cytopenias, pancreatitis, HTN

Asciminib

Blood (2021) 138 (21): 2031–2041

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CAR T cells for AML, T cell NHL are being developedNewer indications for BTK #, Jak2 # are being investigated in clinical trialsBITE Abs for MM may get approval in the next few monthsFuture Directions

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Over 30 new drugs have been approved for hematological malignancies by the FDA in the last 2 yearsThere are multiple drugs under investigation for hematological malignancies to help improve outcomes. Summary