updates from the american society of hematology annual ......ptcl pd - - deceased ptcl cr no...

Updates from the American Society of Hematology Annual

Meeting 2019: Part II

Rebecca Gonzalez PharmD, BCOP

Clinical Pharmacy Specialist, Blood and Marrow Transplantation/Cellular Immunotherapy

Moffitt Cancer Center

Disclosures

Disclosure of conflicts of interest

I have none

Discussion of off-label/investigational uses of commercial products

During this presentation, I will discuss off-label and/or investigational use drugs

2

Learning Objectives

1. Discuss impact of hematologic advances on role with hematopoietic cell transplantation (HCT) presented at 2019 ASH Meeting

2. Describe updates to current chimeric antigen receptor cell therapy (CAR-T)/Cellular immunotherapy (CI) within hematologic malignancies

3. Recognize emerging data regarding management of hematology patients to apply evidence-based medicine for treatment

3

CAR-T: Updates in Hematologic Malignancies

4

Abstract 199: Treatment of Relapsed/Refractory CD5 T-cell

Malignancies with Autologous CD5 CAR-T Cells: A Phase I Study

(MAGENTA)

Hill et al. ASH 2019;session 704. Abstr 199. 5

Background: CD5 Targeting for T-cell Malignancies

• Challenges for T-cell CAR selection

—Fratricide “self-killing”

• Impairs expansion

—Targetable antigen on malignant/ normal T-cells

• Immune deficiencies

—Inadvertent generation of cells with malignant blasts

• Tumor escape by gene editing

• CD5 cell surface marker on ~85%

• CD5 CARs escape fratricide ↓ expression of CD5 (intrinsic resistance)

—↑ in ex-vivo expansion

• CD5 CARs have shown ↓ toxicity against non-malignant CD5+ T-cells

Mamonkin M, Rouce RH, Tashiro H, Brenner MK. Blood. 2015 Aug 20; 126(8):983-92.

Scherer LD, Brenner MK, Mamonkin M. Front Oncol. 2019;9:126.

Hill et al. ASH 2019;session704. Abstr 199. 6

Phase I Study Review: NCT03081910

• Autologous CD5.28z 2nd generation CAR

—1º objective: safety/feasibility as bridge to alloHCT

—2º objectives: anti-tumor response, in-vivo expansion, persistence and impact on normal T-cell #’s/function

• Inclusion Criteria

—>50% CD5 expression by flow or IHC

—<75 yrs.

—Eligible for alloHCT (potential donor identified)

• Exclusion Criteria

—Active infection and/or uncontrolled viral reactivation

—Advanced CNS disease


AlloHCT: allogeneic HCT, IHC: immunohistocompatibiity complex,

CNS: central nervous system, CD3ζ: CD3-zeta, SCFV: single chain variable fragment

CD3ζ

CD28

Co-stimulatory

Domain

VH VL

CD5 scFv

Study Design

• Lymphodepleting chemotherapy

—Flu 30mg/m2/d + Cy 500mg/m2/d days -4 thru -2

• Dose escalation study: 3 dose levels

—1 x 107, 5 x 107, 1 x 108 CAR-T cells/m2 given on day 0

• Disease re-evaluation @ 4-8 weeks post-CAR

• AlloHCT if in CR


d:Day, Flu: Fludarabine, Cy: cyclophosphamide, CR: complete response

Baseline Characteristics


TCL: T-cell lymphoma, T-ALL: T-cell acute lymphoblastic lymphoma, auto-HCT: autologous HCT

Characteristic Total (n=11) TCL (n=6) T-ALL (n=5)

Age, median 62 (21-71) 64 (48-71) 39 (16-50)

Male, % 63 66 60

Median # of prior lines of therapy 5 (3-18) 5 (3-18) 5 (4-7)

Relapse

Post allo-HCT 2 1 1

Post auto-HCT 3 3 0

Primary Refractory 5 2 3

CD5 CAR-T Toxicities


ALT: alanine aminotransferase, AST: aspartate aminotransferase, Alk Phos:Alkalinephosphatase, NT: neurotoxicity, ICANS: immune effector cell-associated neurotoxicity

syndrome, CRS: cytokine release syndrome, NF: neutropenic fever

0 2 4 6 8 10 12

Anemia

Neutropenia

Thrombocytopenia

NF

CRS

NT/ICANS

Hypoalbuminemia

Hyponatremia

Elevated AST

Elevated ALT

Elevated Alk Phos

Grade 1 Grade 2 Grade 3 Grade 4

*Note not all toxicities included

Safety

• No severe CRS/ICANS—Max grade 2: CRS (n=2) /ICANS (n=1)

• No severe infections—CLABSI

• CONS n=1

—CMV and BK reactivation n=1

• Prolonged cytopenia > 6 weeks

—No fungal infections

• No hematologic AE’s (grade 4)—Prolonged cytopenias n=2


AE: adverse effect, CMV: cytomegalovirus, CLABSI: central line-associated bloodstream infection, CONS: coag negative staph

Outcomes


DL: Dose level, CTCL: cutaneous t-cell lymphoma, AITL: angioimmunoblastic t-cell lymphoma, PTCL: peripheral t-cell lymphoma, DOR: duration of response, f/u: follow-up, PD: progressive disease, MR: mixed response, CR: complete response, NR: no response

Disease

Type

Dose

level/m2

Disease

Subtype

Best Clinical

Response

Bridge to

alloHCTDOR

Outcome @ last

f/u

Lymphoma

(n=6)

DL1: 1 x 107CTCL/Sezary PD - - Deceased

AITL CR No 7-months Alive in CR

DL2: 5 x 107

AITL *MRCR Yes 9-months Alive in CR

PTCL PD - - Deceased

PTCL CR No 7-months Alive in CR

PTCL PD - - Deceased

Leukemia

(n=5)

DL1: 1 x 107 NR - - Deceased

DL2: 5 x 107

NR - - Deceased

CR No 6-weeks Alive in CR

PD - - Deceased

PD - - Deceased

ORR=50%

ORR=20%

*Had 2nd infusion

Conclusions

• Use of CD5 CAR is feasible and safe in CD5+ T-cell malignancies

—No prolonged T-cell aplasia or severe infections

—Similar cytopenias to CAR-T cells for B-cell malignancies

• Potential opportunities

—Curative potential

—Bridge to alloHCT

• Manufacturing time did impact potency

—↓ production time limit terminal differentiation/T-cell exhaustion during expansion

• Dose level 3 ongoing


Abstract 243: Earlier Steroid Use with Axicabtagene Ciloleucel (Axi-Cel) in

Patients with Relapsed/Refractory Large B-cell Lymphoma

Topp MS, et al. ASH 2019;session 626. Abstr 243. 16

Background and Objectives

• ZUMA-1: pivotal, multicenter, single-arm, phase I/II study evaluating Axi-Cel(anti-CD19 CAR-T)

—Adult with R/R LBCL after > 2 lines of systemic therapy

• BBW for CRS and NT

• Cohort 3 = use of prophylactic tocilizumab on day +2

—↓ rates of grade > 3 CRS but not grade > 3 NT

• Cohort 4 = safety expansion cohort

—Use of earlier corticosteroids on AE’s

17

R/R: relapsed or refractory, LBCL: large B-cell lymphoma, ORR: overall response rate, BBW: black box warning

Locke FL, et al. Lancet Oncol. 2019; 20:31-42.

Yescarta® [package insert]. Santa Monica, California: Kite Pharma, Inc; 2017

Topp MS, et al. ASH 2019;session 626. Abstr 243.

Axicabtagene Ciloleucel

CAR Type CD19/CD28/CD3z

Costimulatory Domain CD28

scFv FMC63

Vector Retrovirus

Defined Cells No

ZUMA-1 Study Design

Original AE Management

Phase 2 (n=101)

Cohort 1

Refractory DLBCL

(n=77)

Cohort 2

Refractory PMBCL/TFL

(n=24)

Revised AE Management

• Optional bridging allowed for cohort 4

—Dexamethasone, HD-MP + rituximab, or bendamustine + rituximab

• Cohort 4: 1º incidence and severity of CRS/NT


Phase 2 (n=41)

Cohort 4

R/R LBCL

• Key eligibility

—Cohorts 1/2: No response or relapse <12months post auto-HCT

—Cohort 4: R/R LBCL after > 2 lines of therapy

PMBCL: primary mediastinal B-cell lymphoma, TFL: transformed follicular lymphoma, HD-MP: high-dose methylprednisolone

Descriptive comparison of cohorts 1/2 (1º ) and cohort 4 8.7 months median f/u

Adverse Events Management

Tocilizumab CorticosteroidsToxicity Grade

Tocilizumab Corticosteroids

NT CRS NT CRS NT CRS NT CRS

Grade 1 ⦿ ⦿

✪ △ △ Grade 2

✤ Grade 3

Grade 4


Original AE Management Revised AE Management

△ Only if comorbidities or older age✪ Tocilizumab only given for grade 2 NT if concurrent CRS✤Only if no improvement after tocilizumab⦿ If no improvement after 3 days of supportive care

Baseline Characteristics


Tx: therapy, SPD: sum of the product diameters

Cohort 1 +2 Cohort 4

Disease stage (IV), n (%) 58 (57) 19 (46)

# prior lines of therapy, % 1/2/3/4/>5 2/29/30/28/12 0/37/37/20/7

Prior HCT, n (%) 25 (25) 14 (34)

PD from last chemo, n (%) 66 (65) 15 (37)

Median tumor burden by SPD (range), mm3 3723 (171-23297) 2100 (204-24758)

Median LDH, U/L (range) 356 (116-7802) 262 (145-4735)

Median ferritin, ng/ml (range) 786 (1-10,576) 393 (23-3457)

Refractory Subgroup, n (%)

Primary refractory 2 (2) 0 (0)

Refractory > 2nd line Tx/ Relapsed > 2nd line Tx 78 (77)/ 0 (0) 28 (68)/ 5 (12)

Relapsed post autoHCT 21 (21) 8 (20)

Primary Endpoint: Incidence and Severity of CRS and NT


Cohort 1 +2 (n=101) Cohort 4 (n=41)

CRS, n (%) 94 (93) 38 (93)

Grade 1 36 (36) 13 (32)

Grade 2 44 (44) 24 (59)

Grade 3 13 (13) 1 (2)

Median time to onset, days (range) 2 (1-35) 2 (1-8)

Median duration, days 8 7

NT, n (%) 65 (64) 25 (61)

Grade 1 22 (22) 14 (34)

Grade 2 14 (14) 4 (10)

Grade 3 28 (28) 7 (17)

Median time to onset, days (range) 5 (1-17) 6 (1-93)

Median duration, days 12 9

No Grade 4 or higher CRS/NT in Cohort 4

Steroid Cumulative Dose and Frequency

Cohort 1 + 2 (n=26) Cohort 4 (n=30)

Patients receiving # doses of steroids, n (%)

1 3 (12) 7 (23)

2 1 (4) 7 (23)

3 0 (0) 3 (10)

> 5 22 (85) 13 (43)

Cumulative steroid dose (mg)

Mean (SD) 13,156 5,235 (7,679)

Median (min-max) 5451 (6.3-109,876) 939 (313-33,463)


76% (31/41) of patients (Cohort 4) received tocilizumab vs. 43% (43/101) in Cohort 1+2

Additional Comparisons

• Biomarker Effects

—Lower peak levels of INFγ, IL-2, GM-CSF, ferritin and CRP seen in cohort 4 vs. 1+2

• ↓ association of inflammatory markers noted for worse NT

• Expansion

—Similar peak and AUC CAR-T cells between groups

—No differences in responses comparing tumor burden

• Ongoing 6-month responses similar in above or below median tumor burden

• Early use of steroids may impact inflammatory cytokines production but not CAR proliferation


INFγ: interferon gamma, IL-2: interleukin-2, CRP: C-reactive protein, GM-CSF: granulocyte monocyte colony stimulating factor, AUC: Area under the curve

Conclusions

• Early steroid use reduced toxicity profile without compromising efficacy

—↓ rates of severe CRS and NT seen in cohort 4 vs. cohorts 1 +2

—↓ cumulative steroids doses in cohort 4

—↓ biomarkers of inflammation noted to increase side effect profile

—No clinically meaningful effects on CAR expansion or responses regardless of tumor burden

• Median f/u 8.7-months


Abstract 245: Characteristics and Outcomes of Patients Receiving Bridging Therapy While Awaiting Manufacture of

Standard of Care Axicabtagene Ciloleucel CD19 Chimeric Antigen Receptor (CAR) T-

cell Therapy for Relapsed/Refractory Large B-cell Lymphoma: Results from the

US Lymphoma CAR-T Consortium

Jain MD, et al. ASH 2019;session 626. Abstr 245. 27

The US Lymphoma CAR T-cell Consortium

Jain MD, et al. ASH 2019;session 626. Abstr 245. 28SOC: standard of care , mITT: modified intention to treat

Leukapheresis for SOC Axi-Cel (n=298)• As of 9/30/2018

Unable to proceed to CAR-T infusion (n=23)

• Disease progression/death (n=20)

• Infection (n=1)

• Attained CR with bridging therapy (n=1)

• Renal failure (n=1)

Axi-Cel CAR-T infusion (n=275)• Axi-Cel SOC (n=268)

• Expanded access program Zuma-9 (n=7)

Leukapheresed

patients

Infused patients

“mITT”

Bridging

therapy

opportunities

All Patient Characteristics: n=298


ECOG: Eastern Cooperative Oncology Group, IPI: International Prognostic Index, DLBCL: Diffuse large B-cell lymphoma, PMBCL: Primary mediastinal B-cell lymphoma, TFL: transformed follicular lymphoma, GCB: germinal center B-cell, ULN: Upper limit of normal

Baseline Characteristics N %

Age >60 yrs. 154 52

Male 192 64

ECOG Performance Status 2-4 58 20

Disease stage advanced (III or IV) 244 82

IPI score 3-5 162 54

DLBCL/PMBCL/TFL 203/19/76 68/6/26

Non-GCB 106 40

Double/Triple hit 64 23

LDH > ULN @ lymphodepleting tx 155 59

Bulky Disease (>10cm) 68 23

> 3 prior lines of therapy 222 75

Patients not meeting Zuma-1 inclusion criteria 129 43

SOC Axi-Cel Outcomes: n=298

• Median follow-up from leukapheresis=13.8 months

• Median PFS 7.18 months (95%CI 5.65-12.4 months)

• Median OS not reached


PFS: progression free survival, OS: overall survival

Covariates Associated with Worse OS

• Male: HR 1.7, p=0.04

—65% of cohort

• ECOG 2-4: HR 1.8, p=0.02

—16% of cohort

• Disease status

—Primary refractory: HR 1.9, p=0.04

• 32% of cohort

—Refractory: HR 1.7, P=0.04

• 43% of cohort

• Total bilirubin >1.5g/dl: HR 5.1, p=0.002

—2% of cohort

• LDH > ULN prior to lymphodepletion: HR 3.0, p=0.0001

—59% of cohort

• Bridging therapy: HR 1.8, p=0.03

—51% of cohort


Bridging Therapy in Pivotal CAR-T Lymphoma Trials

Zuma-1 JULIET TRANSCEND

CD19 CAR-T Axi-Cel Tisa-Cel Liso-Cel

Leukapheresed N=111 N=165 N=342

Infused CAR-T n=101 (91%) n=111 (67%) n=268 (78%)

Bridging therapy 0% 92% 59%

Median time from apheresis to CAR-T (days)

17(to CAR-T delivery)

54(to CAR-T infusion)

24(“optimized

subset”)

Neelapu SS, Locke FL, et al. N Engl J Med 2017; 377:2531- 2544.

Schuster S, Bishop MR, et al. N Engl J Med 2019; 380:45-56

Abramson JS, Palomba ML, et al. ASH 2019 session 262. Abstr 241.


Bridging Therapy in SOC Axi-Cel


XRT: radiation therapy

All leukapheresed (n=298)

Bridging Therapy (n=158, 53%)

• Axi-Cel infused (n=141, 89%)

No Bridging Therapy (n=140, 47%)

• Axi-Cel infused (n=131, 96%)

55%

23%

12%

10%

Chemotherapy

Steroids only

XRT

Targeted

Baseline Covariates Bridging vs. Non-Bridging

34

Covariate Level No Bridging n=140 Bridging n=158 P-value

Age (yrs.) > 65 32% 32% 1.0

Sex Female 36% 35% 0.81

ECOG 2-4 8% 30% <0.001

Stage III/IV yes 75% 89% <0.001

IPI 3-5 38% 69% <0.001

Prior # of lines > 3 72% 77% 0.43

Refractory disease yes 74% 78% 0.42

Bulky disease yes 14% 31% <0.001

Prior autoHCT yes 36% 30% 0.27

Met ZUMA-1 eligibility no 34% 52% 0.002

Cell of origin Non-GCB 37% 33% 0.74

LDH @ lymphodepletion <200 26% 12% 0.03

200-300 21% 21%

300-500 21% 24%

> 500 20% 30%

Jain MD, et al. ASH 2019;session 626. Abstr 245.

Axi-Cel Toxicity and Cause of Death


Received cells (n=275) No Bridging Bridging Total

Grade 3 or higher CRS 5% 9% 7%

Grade 3 or higher NT 28% 34% 31%

NRM 1.5% 7.1% 4.4%

Death from relapse after

12-months post-infusion

17% 37% 28%

Bridging Associated with Worse PFS and OS

• No difference in efficacy of Axi-Cel with different bridging strategies (n=298)

—PFS (p=0.918), OS (p=0.598)


00.10.20.30.40.50.60.70.80.9

1

0 3 6 9 12 16

Months post-leukapheresis

OS

Bridging

No Bridging

Pro

babili

ty o

f surv

ival

00.10.20.30.40.50.60.70.80.9

1

0 3 6 9 12 16

Months post-leukapheresis

PFS

Bridging

No Bridging

Pro

babili

ty o

f surv

ival

HR 1.61, p=0.002

HR 2.45, p<0.001

Conclusions

• Bridging therapy associated with—Worse OS and PFS (univariate analysis)

—Worse OS (multivariate analysis)

—Worse OS (propensity matched analysis)

• No bridging method impacted effectiveness of Axi-Cel

• Limitations—Without bridging died/unable to receive therapy

—Bridging therapy group worse prognostic baseline characteristics

• Universal bridging should not be given while awaiting manufacturing of cells


Abstract 780 Comorbidities Predict Inferior Survival in Patients Receiving

CAR T-Cell therapy for Relapsed/Refractory DLBCL: A Multicenter

Retrospective Analysis

Kittai AS, et al. ASH 2019;session 704. Abstr 780.39

Background and Hypothesis

• Registration trial comorbidities: were patients enrolled representative?

• Modified Cumulative Illness Rating Scale (CIRS)

—Comprehensive tool for indication of health status

—Assess organ system (14 total) on scale 0 to 4

—Used in geriatric oncology

—Highest score = total CIRS >7, 1 organ system >3: CIRS 3+

• HCT-CI

—HCT-specific comorbidity assessment

—Assess organ system (15 total) with points 1-3 given for each impairment or illness

—Highest score > 3

• Authors hypothesized that CIRS and HCT-CI comorbidity assessments predict inferior outcomes in R/R DLBCL patients receiving CAR-T

Kittai AS, et al. ASH 2019;session 704. Abstr 780.,

Neelapu SS, Locke FL, et al. N Engl J Med 2017; 377:2531- 2544.

Extermann M, Hurria. J Clin Oncol. 2007;25(14):1824-31.

Schuster S, Bishop MR, et al. N Engl J Med 2019; 380:45-56

Sorror ML, Maris MB, Storb R, et al. Blood. 2005;106(8):2912–2919. 40

Tisa-Cel: tisagenlecleucel, HCT-CI: hematopoietic cell transplantation-specific comorbidity index

Axi-Cel Tisa-Cel

Median age 58 56

Age > 65 (%) 24 23

ECOG PS 1 (%) 58 45

> 3 Prior lines (%) 69 52

Any grade > AE (%) 95 89

Methods and Patient Characteristics

• Multicenter retrospective analysis

• Inclusion

—Either Axi-Cel or Tisa-Cel not enrolled in clinical trial & have cells manufactured

—R/R DLBCL

• Comorbidity scores calculated @ time of cell collection

• High comorbidity scores defined as: —CIRS > 7

—CIRS 3+ in any organ

—HCT-CI > 3


BCL-2: B-cell lymphoma 2, GCB: geminal center b-cel

Baseline N=130

Age, median (range) 63 (23-82)

> 65, n (%) 55 (42)

Treatment, n (%)

Axi-Cel 94 (72)

Tisa-Cel 36 (28)

PS, n (%)

0 29 (22)

1 80 (61)

> 2 21 (17)

Prior therapy, n (%)

1-2 41 (31)

3 51 (39)

4 15 (12)

> 5 23 (18)

Double Hit (MYC, BCL2), n (%) 22 (20)

Cell of Origin, n (%)

GCB 67 (52)

Outcomes


Results

Total CIRS, median (range) 10 (1-20)

CIRS > 7, n (%) 74 (57%)

CIRS 3+ 81 (62%)

CIRS > 7 or CIRS 3+, n (%) 92 (71%)

HCT-CI, median (range) 2 (0-13)

HCT-CI > 3, n (%) 35 (27%)

PFS months, median (range) 5.8 (4.6-11.1)

OS months, median (range) NR (10.9-NR)

Conclusions

• Univariate analysis

—Worse PFS (HR 1.43)* and OS (HR 1.9)* with ↑ ECOG score

—Worse OS (HR 2.39)* if presence of either CIRS > 7 or CIRS 3+

• Presence of CIRS > 7 (HR 2.6)* or CIRS 3+ (HR 1.35) or either (HR 2.43)*

—Inferior OS in multivariate analysis

• HCT-CI score above 3 was not predictive of worse OS or PFS#

• No association noted for comorbidities and CRS or NT#


*Statistically significant difference

# Small numbers noted

Abstract 204: Fully Human BCMA CAR-T Cells in Combination with a Gamma

Secretase Inhibitor to Increase BCMA Expression in R/R Multiple Myeloma (MM)

Cowan AJ, et al. ASH 2019;session 704. Abstr 204.44

BCMA: B-cell maturation antigen

Background: Fred Hutch BCMA CAR-T (FCARH143)

• BCMA is a validated target for CAR therapy in MM

—Despite initial responses most relapse

• Loss of BCMA expression on tumor cells immune escape method

• Limiting cleavage of BCMA is one targetable action

• Selected CD4:CD8 construct

—CD4+ and CD8+ cells kept independently until mixed @ the end in CD4/CD8 ratio of 1:1

• Lentiviral vector transduction

• EGFRt = surface marker for CAR identification for persistence

Cowan AJ, et al. ASH 2019;session 704. Abstr 204.

Green DJ, Pont M, Sather BD, Cowan AJ, Turtle CJ, Till BG, et al. Blood. 2018;132:1011.45

EGFRt :truncated epidermal growth factor receptor

Anti-BCMA scFv CD3z4-1BB

Tumor binding

domainSignaling

Domains

Hinge EGFRt

Armor

γ-Secretase Inhibitors (GSI)

• GSI ↑ BCMA surface density, ↓ soluble BCMA levels and augment anti-tumor effect of BCMA CAR

• Phase I first-in-human combination of BCMA CAR with oral GSI (JSMD194)

—Initial therapy 25mg x 3 doses Q48hours 5 days prior to bone marrow aspirate (day +5)

• Goal impact of GSI on BCMA expression @ baseline

—Post-FluCy lymphodepletion

• BCMA CAR-T cells infused in combo with GSI @ 25mg three times weekly x 3 weeks

• Start day of cell infusion

Cowan AJ, et al. ASH 2019;session 704. Abstr 204.

Pont MJ, et al. Blood. 2019;34 (19): 1585-1597.

Adapted from Marvin C. A failed Alzheimer’s drug stops cancer cells from shedding their coats and hiding from the immune system

https://massivesci.com/articles/alzheimers-blood-cancer-myeloma-drug-development-immunotherapy/. Accessed January 1, 202046

GSI

Gamma

secretase

https://massivesci.com/articles/alzheimers-blood-cancer-myeloma-drug-development-immunotherapy/

Trial Overview: NCT03502577

• Primary Objective—Safety and dose finding

• Secondary Objective—Anti-tumor effect—Peak concentration, persistence and phenotype of transferred CAR following GSI therapy

• Inclusion—Dual refractory (IMID/PI)—No threshold for BCMA expression—Measurable disease—Prior autoHCT or ineligible —> 10% CD138+ plasma cells by IHC—Prior BCMA therapy allowed


IMID: immunomodulatory therapy, PI: proteasome inhibitors, IHC: immuno-histocompatibility complex

Baseline Characteristics (n=10)


Dose LevelAge/Gender

(median=66)

Prior Tx.

(median=10)High-risk Features

50 x 106 cells

66M 6 Refractory Disease

60F 23 (AutoHCT x2) 17p del

69M 18 (AutoHCT) Complete karyotype

66F 4 (AutoHCT) 1p del

70M 9 (AutoHCT) t(4;14)

150 x 106 cells

58F 11 (AutoHCT) t(4;14)

50M 13 (Auto + AlloHCT) 1q+

70F 7 (AutoHCT) 17p del, t(14;16)

300 x 106 cells 74F 12 (AutoHCT) 1q+, new 17p del

44M 6 (AutoHCT) IGL-MYC translocation

Toxicity Profile


SAE: severe adverse event, DLT: dose limiting toxicity

Dose Level Age/Gender CRS Grade TLS SAE* DLT NT Tocilizumab Steroids

50 x 106 cells

66M 1 No Yes No No No No

60F 4 No Yes Yes Yes Yes x 2 Yes

69M 3 No Yes No Yes Yes x 1 Yes

66F 2 No No No Yes Yes x 2 Yes

70M 1 No Yes No Yes No Yes

150 x 106 cells

58F 3 No Yes No Yes Yes x 2 Yes

50M 2 No Yes No Yes Yes x 1 Yes

70F 2 No Yes No No No No

300 x 106 cells74F 3 No Yes No No Yes x 2 No

44M 2 No No No No No No

*Grade >3 SAE: 70% NF and 100% CRS

Conclusion

• Dose-dependent upregulation in BCMA expression—Median BCMA expression 99%

• 20-fold ↑ in median BCMA surface expression

• 100% overall response rate regardless of dose level

• Best responses overall: 5 VGPR, 1 CR, 2 sCR and 2 PR—No relapse or late progression to date

—9/10 patients are alive without disease

• 1 death (day +33) due to CRS/concurrent fungal infection

• Future evaluation of durability is key


VGPR: very good partial response, sCR: stringent complete response

Advances in Management of Hematologic HCT Patients

51

Abstract 775: Safety and Efficacy of Allo-HCT after Programmed Cell Death 1 (PD-1)/Programmed Cell Death Ligand 1 (PD-

L1) Blockade for Classical Hodgkin Lymphoma: Analysis of a Large

International Cohort

Merryman RW, et al. ASH 2019;session 704. Abstr 77552

Background and Objectives: PD-1 and Impact with AlloHCT

• ↑ iREs, non-infectious febrile syndrome and CRS PD-1 exposure pre-HCT

—Severe aGVHD and VOD complications

• FDA package insert warning for ICIs

• Majority of HL patients relapse post PD-1 therapy

—Allo-HCT is a potential curative method

• Goal: long-term outcomes/complications, RF and impact of HCT specific strategies

—Large international cohort of cHL who had alloHCT after PD-1 or PDL-1 blockade

Herbaux C, Gauthier J, Brice P, et al. Blood 2017;129:2471-8.

Ijaz A, Khan AY, Malik SU, et al. Blood and Marrow Transplantation 2019;25:94-9.

Schoch LK, Cooke KR, Wagner-Johnston ND, et al. Blood Adv 2018;2:2226-9.

Merryman RW, Armand P, Wright KT, Rodig SJ. Blood Adv. 2017;1(26):2643-2654.

Merryman RW, et al. ASH 2019;session 704. Abstr 775.53

iREs : immune-related events, aGVHD: acute graft versus host disease, VOD: venous occlusive disease, ICI: immune checkpoint inhibitors, RF: risk-factors, cHL/HL: (classical) Hodgkin lymphoma

Patient Characteristics

Merryman RW, et al. ASH 2019;session 704. Abstr 775.

*Merryman RW, Armand P, Wright KT, Rodig SJ. Blood Adv. 2017;1(26):2643-2654.54

mAb: monoclonal antibody

Baseline PD-1/PDL-1 Factors N=197

Median follow-up , months (range) 24.3 (0.8-72)

Age, median (range) 63 (23-82)

Male, n (%) 117 (59)

Median # lines of Tx. (exclude PD-1), n (range) 4 (2-11)

Prior autoHCT, n (%) 143 (73)

PD-1/PDL-1 therapy

PD-1 mAb monotherapy, n (%) 174 (88)

PD-1 based combination, n (%) 22 (11%)

PDL-1 mAb monotherapy, n (%) 1 (1%)

Median # of doses, n (range) 9.5 (1-74)

Best Response to PD-1/PDL-1 therapy

CR, n (%) 77 (39%)

PR, n (%) 74 (38%)

SD, n (%) 23 (12%)

PD, n (%) 22 (11%)

Unknown, n (%) 1 (1%)

Median days from Tx. to alloHCT, n (range) 82 (17-1029)

*15% patients included in prior publication

• Data from 26 European and US HCT centers

• Data from 2014-2019

• Included cHL patients received—Nivolumab>>Pembrolizumab>>>Avelumab

AlloHCT Characteristics


PTCy: post-transplant cyclophosphamide, ATG: anti-thymocyte globulin

AlloHCT Factors N=197

Donor Type

Haploidentical (Haplo) 87 (44%)

Matched unrelated (MUD) 50 (25%)

Matched related (MRD) 48 (24%)

Mismatched unrelated (MMUD) 9 (5%)

Cord blood 3 (2%)

GVHD Prophylaxis

PTCy 113 (57%)

ATG 34 (17%)

Neither PTCy nor ATG 50 (25%)

GVHD groups

Haplo + PTCy 87 (44%)

No Haplo + PTCy 26 (13%)

No Haplo + no PTCy 84 (43%)

Baseline AlloHCT Factors N=197

Disease status @ alloHCT

CR, n (%) 116 (59%)

PR, n (%) 61 (31%)

SD, n (%) 5 (3%)

PD, n (%) 15 (8%)

Conditioning Chemotherapy

Reduced intensity (RIC) 109 (55%)

Non-myeloablative (NMA) 72 (37%)

Myeloablative (MAC) 16 (8%)

Donor Source

Peripheral blood (PBSC) 148 (75%)

Bone Marrow (BM) 47 (24%)

Cord blood 3 (2%)

Early Toxicity


Lee DW, et al. Biol Blood Marrow Transplant. 2018 Dec 25. pii: S1083-8791(18)31691-4.56

AlloHCT Factors 180-day cumulative incidence

aGVHD

Any grade 56%

Grade 2-4 38%

Grade 3-4 16%

Hyperacute GVHD (<14 days post-HCT) 3%

Non-infectious febrile syndrome/CRS

Grade 1 16%

Grade 2 6%

Grade 3-4 3%

Median day of onset, n (range) 3 (0-20)

Predictors of Severe aGVHD


• Intervention therapy required in 11% versus 22%

• Univariate analysis (p=0.04)

• Multivariate analysis (p=0.59)

24%

9%

</= 82 > 82

Days From PD-1 Therapy to alloHCT

180 Incidence of Severe aGVHD

P=0.01 univariate analysis

P=0.07 multivariate analysis27%

17%

10%

<45 45-90 >90

Days From PD-1 Therapy to alloHCT

180 Incidence of Severe aGVHD

P=0.034

Predictors of cGVHD

Factor 2-yr CI cGVHD Multivariate HR P-value

# no-PD-1 Tx. lines

< 4 31%1.99 (1.16-3.40) 0.012

>4 47%

Donor Sex

Female 47%1.77 (1.05-3.00) 0.028

Male 33%

PTCy

Yes 27%0.55 (0.33-0.94) 0.033

No 51%

Days from PD-1 to HCT

> 82 days 31%0.5 (0.29-0.85) 0.011

< 82 days 45%

Doses of PD-1 Tx.

> 10 28%0.45 (0.26-0.78) 0.005

< 10 48%

Merryman RW, et al. #ASH 2019;session 704. Abstr 775.58

cGHVD: chronic graft versus host disease, CI: cumulative incidence

2-yr cGVHD incidence = 38%

• 25% required systemic

therapy

Secondary Outcomes: CIR

• At a median follow-up of 24.3 months (range 0.8-70.2 months)

—2-yr NRM 14%

—2-yr CIR 18%

—2-yr PFS

—2-yr OS


59CIR: cumulative incidence of relapse, CT: computed tomography

Factor 2-yr CIR Multivariate HR P-value

Disease status @ HCT

CR 11%0.36 (0.17-0.77) 0.01

Other 19%

Intervening CT

Yes 24%2.76 (1.28-5.98) 0.01

No 12%

Donor Type

Other 24%1.89 (1.35-6.33) 0.004

Haplo 8%

PTCy

Yes 11%0.37 (0.17-0.8) 0.01

No 25%

Secondary Outcomes: PFS


—2-yr NRM 14%

—2-yr CIR 18%

—2-yr PFS 68%

—2-yr OS


Factor 2-yr PFS Multivariate HR P-value

Disease status @ HCT

CR 77%0.5 (0.29-0.84) 0.009

Other 57%

PTCy

Yes 76%0.56 (0.33-0.95) 0.03

No 60%

GVHD Prophylaxis

Haplo + PTCy 77% -- --

No Haplo + PTCy 70% -- --

No Haplo/ No PTCy 60% -- --

Secondary Outcomes: OS


—2-yr NRM 14%

—2-yr CIR 18%

—2-yr PFS 68%

—2-yr OS 82%


61CIR: cumulative incidence of relapse

Factor 2-yr OS

PTCy

Yes 84%

No 80%

Secondary Objectives: GFRS*


GFRS: GVHD-free relapse-free survival

• At a median follow-up of 24.3 months (range 0.8-70.2 months)—2-yr NRM 14%

—2-yr CIR 18%

—2-yr PFS 68%

—2-yr OS 82%

—2-yr GFRS 46%

Factor 2-yr GFRS Multivariate HR P-value

PTCy

Yes 58%0.58 (0.39-0.87) 0.008

No 30%

Doses of PD-1 Tx.

> 10 55%0.62 (0.41-0.94) 0.023

< 10 35%

GVHD Prophylaxis

Haplo + PTCy 57% -- --

No Haplo + PTCy 58% -- --

No Haplo/ No PTCy 30% -- --

*GFRS event defined as grade 3-4 aGVHD, cGVHD requiring therapy, relapse, or death

Conclusions

• Use of PD-1/PDL-1 therapy pre-HCT is feasible

—Exposure to PD-1 blockade therapy

• ↑ rates of acute and chronic GVHD

• < 82 days did result in significant severe aGVHD

• GVHD strategies with PTCy may be optimal prophylactic strategy

—↓ incidence of relapse

—Improved 2-yr GRFS and PFS

—Similar rates of severe aGVHD, NRM and OS

• AlloHCT should not be delayed due to PD-1 therapy risk of missed HCT window

—Use of PTCy may mitigate toxicities with improved outcomes


Abstract 778: Phase IB Study of Blinatumomab in Patients with B-cell Acute Lymphoblastic (ALL) and B-cell

Non-Hodgkin Lymphoma (NHL) as Post-allogeneic Blood and Marrow Transplant

Remission Maintenance

Webster J, et al. ASH 2019;session 704. Abstr 778.64

Background

• AlloHCT curative for high-risk B-ALL/ NHL

—CIBMTR data (2001-2012)

• 3-yr NRM of 25%

• 3-yr CIR 47%

• 3-yr OS of 38%

• 49% died from relapse post-HCT

• PTCy-based prophylaxis —Improves cellular

reconstitution/minimal toxicities

—Augment anti-tumor activity

• Use of blinatumomab, a CD19/CD3 BiTE in the treatment of CD19 + ALL and NHL

—Enhances T-cell activation and tumor-specific T-cell responses

Webster J, et al. ASH 2019;session 704. Abstr 778.

Rosko A, et al. Am J Hematol. 2017 Jan;92(1):42-4965

Blina: blinatumomab, CIBMTR: Center for International Blood and Marrow Transplant Research, BiTE: bispecific T-cell engager antibody

Combining a PTCy-based platform with blina post-HCT may lead to improved graft-

versus-tumor effect

Study Design:


66MMF: mycophenolate mofetil, IST: immunosuppressive therapy, MRD: minimal residual disease

Eligibility

Pre-B ALL: High-risk in CR1 or CR2

Low or high-grade NHL s/p NMA

No active GVHD requiring steroids within 4

weeks

PTCy-based GVHD prophylaxis required

Off all IS therapy x 4 weeks

ANC > 1 x 109/L and platelets > 30 x 109/L,

donor engraftment

>60 and < 180 days post-HCT

Day 0

HCT/Recovery

PTCy Day +3 and +4

MMF 15mg/kg TID until Day +35

Tacrolimus or Sirolimus Day +5 to Day +60

Day 60

Blina C1

• Day 1-7: 9mcg/d

• Day 8-28: 28mcg/d

Day 180

Blina C2

• ONLY if DETECTABLE DISEASE pre-HCT or post-HCT

• Day 1-28: 28mcg/d

Off IST

• Endpoints Phase Ib (n=12)

• Primary: safety/tolerability

• Secondary: NRM, PFS, OS and MRD monitoring

• Endpoints Phase II (n=52 additional)

• 2 cohorts: NHL and ALL

• Primary: DFS @ 1-yr

• Secondary: safety/tolerability, NRM, PFS, OS, MRD

• Exploratory: T-cell kinetics, cytokines, checkpoint

expression and MRD


Diagnosis Age/Gender HCT-Type Graft Source Prior # Tx. Disease Status @ HCT

B-ALL 46F Haplo BM 3✰ CR3

B-ALL 50M Haplo BM 1 CR1

B-ALL 30M Haplo PBSC 5✰ CR3

B-ALL 42M MUD PBSC 1✰ CR1

DLBCL (from FL) 70M Haplo BM 6 PR

DLBCL (from FL) 65M Haplo BM 2 CR2

DLBCL (from FL) 60M Haplo BM 2 CR2

MCL 51M Haplo BM 2 CR2

PCNSL 73M MUD PBSC 3 CR2

DLBCL 50M MUD BM 2 CR2

DLBCL (from CLL) 59F Haplo PBSC 4 CR3

DLBCL (from CLL) 55M MRD PBSC 1 CR1


MCL: mantle cell lymphoma, PCNSL: primary central nervous system lymphoma, FL: follicular lymphoma, CLL: chronic lymphocytic lymphoma, PBSC: peripheral blood stem cells. BM: bone marrow

• All patients received NMA conditioning (FluCyTBI)

• Off all IST @ median 63 days (range, 50-141 days)

• Grade 1/2 cutaneous GVHD (n=7), 3 requiring systemic steroids

✰Prior Blina therapy

Toxicities/Outcomes

• Blina initiated a median of 144 days post-HCT (range, 90-180 days)

—Median # of cycles 1

• No GVHD or graft rejection

• Toxicities—1 stopped due to tremors (grade 2)

—1 dosage reduction due to neutropenia @ day 25

• Median follow-up of 17.7 months—83% still in remission (range, 8-27 months)

—N=1 had CNS relapse (3rd relapse) @ 20.6 months

—N=1 relapse of transformed lymphoma shortly after completion of blina

—N=3 non-enrolled due to relapse, elevated LFTs and death


0 2 4 6

Anemia

Neutropenia

Thrombocytopenia

Dysmetria

Tremor

Headache

Fogginess/Difficulty with words

Fever/Chills

Night sweats/Flush

GI symptoms

Grade 1 Grade 2 Grade 3 Grade 4

Conclusions

• Toxicities associated with blina post-HCT were mild with no exacerbations of GVHD

• High rate of responders 83% of included patients in CR

• Phase II of trial is currently ongoing but will enroll an additional 52 patients

—Correlative studies regarding T-cell kinetics, cytokines and checkpoint expression will be additionally reported


69

Abstract 669: Peri-HCT Administration of Ruxolitinib in Myelofibrosis is Safe and

Feasible During Reduced Intensity Conditioning Transplant: Primary Results

of a Pilot Open-Label Study

Ali H, et al. ASH 2019;session 634. Abstr 669.70

Background

• AlloHCT is a curative therapy option for MF

—↑ TRM, ↓ OS due to GVHD, infection, graft-failure and chemo-related toxicities

• Optimal conditioning chemotherapy/prophylactic methods are unknown

• Ruxolitinib, a JAK 1/2 inhibitor, is typically discontinued pre-HCT

—Offers immunologic, anti-inflammatory and therapeutic properties

—Concern for “ruxolitinib withdrawal syndrome”

• Expanding use of ruxolinitib peri-HCT may improve outcomes of MF patients undergoing alloHCT


MF: myelofibrosis, TRM: treatment-related mortality, JAK: Janus kinase

Study Design: NCT02917096


DIPSS: Dynamic International Prognostic Scoring System Flu/Mel: fludarabine/melphalan, MTD: maximum tolerated dosage, PO: orally, BID: twice

daily, KPS: Karnofsky performance status, PK: pharmacokinetics

• Endpoints—Primary: safety, ruxolitinib MTD recommended phase II dose (RP2D)

—Secondary: hematologic recovery, day +100 NRM and aGVHD, 1 and 2-year cGVHD, PFS and OS

• aGVHD changes via biomarkers and cytokines

• PK of ruxolitinib during peri-HCT setting

Eligibility

Age 18-75

KPS >70

Primary or secondary MF

Intermediate II/High-risk by DIPPS

RIC HCT

8/8 MRD or MUD

Prior ruxolitinib use allowed

Dose Level 1

5mg PO BID (n=6)

Dose Level 2

10mg PO BID (n=12)

2-year follow-up

FluMel140mg/m2

Days -9 thru -4

Tacrolimus+

Sirolimus

(goal 5-10ng/mL)

Day -3 Day +30Tapered Off by Day +33



, CALR: calreticulin

Dose Level 1

(n=6)

Dose Level 2

(n=9)

Median Age @ HCT (range) 53 (25-67) 70 (56-72)

Gender

Male, n (%) 5 (83) 7 (78)

Fibrosis, n (%)

MF-1 1 (17) 0

MF-2 4 (33) 2 (22)

MF-3 1 (17) 7 (78)

DIPSS Score HCT, n (%)

High 1 (17) 3 (33)

Intermediate II 5 (83) 6 (67)

HCT-CI, n (range) 1 (0-3) 3 (1-5)

Driver Mutations, n

JAK2 8

CALR 3

MPL 0

Triple negative 4

HCT-Outcomes

• Median follow-up 341 days

—Range, 42-1005 days

• Engraftment (n=15)

—Neutrophil median 17 days (range, 12-23 days), platelets median 28 days (range, 13-19)

• Infectious complications (n=15)

—Sepsis, Cdiff and CMV reactivation

—Most common infectious grade was 0 (45%) and 20% had a grade 3 complication

• Cause of Death (n=3)

—n=1 GI GVHD, n=1 respiratory failure, n=1 cardiac arrest/liver GVHD


Cdiff: clostridium difficile, CMV: cytomegalovirus

Outcome N=15

Time to aGVHD, n (range) 30.5 (18-93)

Max aGVHD

Yes, n (%) 8 (53)

Grade 1 6 (40)

Grade 2 1 (7)

Grade 3-4 1 (7)

No, n (%) 7 (47)

Time to cGVHD, n (range) 291.5 (195-370)

Max cGVHD

Yes, n (%) 6 (40)

Limited 2 (13)

Extensive 4 (27)

No, n (%) 9 (60)

NRM @ 100 days, n (%) 2 (13)

Relapse/ProgressionYes, n (%) 1 (7)

No, n (%) 14 (93)

Vital StatusDeceased, n (%) 3 (20)

Alive, n (%) 12 (80)

Characteristics of Ruxolitinib PK and GVHD Biomarkers

• Trough concentration, Cmax, and AUC were ↑ x2 with higher dosage of ruxolitinib

—Ruxolitinib drug clearance and t½ were not affected by dose levels

• Cytokines associated with aGVHD were suppressed with ruxolitinib

—↓ REG3A, IL-2, IL-6 and INFγ

• Dose-dependent effect


REG3A: regenerating Family Member 3 Alpha, IL-2/6: interleukin 2 and 6, Cmax: maximum concentration, AUC: area under the curve, T1/2: half-life

Conclusions

• Use of peri-HCT ruxolitinib at dosage 5-10mg twice daily was safe and feasible—100% engraftment rate

—Low hematologic toxicities

—Minimal infectious complications

• Low rates of grade 2-4 aGVHD and no withdrawal symptoms noted

• Direct correlation between Cmax and AUC and higher oral clearance compared to prior studies

—Indicative of reduced GI absorption in HCT patients

• Longer follow-up is needed to evaluate impact on cGVHD rates


Abstract 319: Comparison of Reduced Intensity Conditioning (RIC) Regimens for

Allo-HCT in NHL: A Center for International Blood and Marrow Transplant

Research (CIBMTR) Analysis

Ghosh N, et al. ASH 2019;session 732. Abstr 319.77

Background: Choice of RIC Regimens

• Limitations in literature—Small n

—Excluded FluCy-based therapy

—Combined HL with NHL

Ghosh N, et al. ASH 2019;session 732. Abstr 319.

♦Kekre N, et al. Biol Blood Marrow Transplant. 2016 Oct;22(10):1808-1815.

ΔYerushalmi R, et al. Bone Marrow Transplant. 2015 Dec;50(12):1526-3578

Conditioning Regimen Outcome

FluBu (n=61) vs. FluMel (n=75) ♦ ↓ NRM, ↓ aGVHD and ↑ OS with FluBu

FluBu (n=38) vs. FluMel (n=56) vs.

Flu/Treosulfan (n=50) Δ↑ NRM and ↓ OS with FluMel

• RIC/NMA regimens frequently used for alloHCT in NHL patients

—↓ NRM versus MAC regimens

• Optimal conditioning regimen is unknown

Study Overview (n=1823)

• Hypothesis: Choice of RIC/NMA conditioning therapy for NHL may impact OS

• Objectives: OS, NRM, progression/relapse, acute/cGVHD, and PFS

• Eligibility

—Adult alloHCT patients undergoing first HCT for NHL (2008-2016)

—RIC/NMA Regimens

• FluBu (Bu dose ~6.4mg/m2 IV)

• FluMel 140mg/m2 (FluMel140)

• FluCy

• FluCyTBI (2Gy)

—CNI-based GHVD prophylaxis

Ghosh N, et al. ASH 2019;session 732. Abstr 319.

79Flu: Fludarabine, Cy: Cyclophosphamide, Mel: melphalan, TBI: total body irradiation, CNI: calcineurin inhibitor



Baseline FluBu FluCyTBI FluMel FluCy P-value

# of patients, n (%) 458 (25) 89 (5) 885 (49) 391 (21) --

Age, median (range) 58 (23-75) 57 (29-74) 56 (20-76) 56 (19-76) <0.001

> 60, n (%) 187 (41) 34 (38) 282 (32) 123 (32) --

KPS > 90, n (%) 260 (57) 58 (65) 549 (62) 265 (68) <0.001

HCT-CI, n (%)

0 107 (23) 46 (52) 323 (36) 143 (37)

<0.0011-2 142 (31) 20 (22) 246 (28) 112 (29)

> 3 207 (45) 19 (21) 293 (33) 98 (25)

Donor Type, n (%)

MRD 219 (48) 45 (51) 456 (52) 236 (60)0.003

MUD 239 (52) 44 (49) 429 (48) 155 (40)

ATG/alemtuzumab used in conditioning, n (%) 159 (35) 47 (53) 269 (30) 81 (21) 0.001

Rituximab used in conditioning, n (%) 7 (2) 35 (39) 80 (9) 199 (51) 0.001

CMV Status-donor (-)/Recipient (+), n (%) 113 (25) 15 (17) 222 (25) 88 (23) 0.04

Median follow-up of survivors, months 48 71 47 60 --

Outcomes: Hematopoietic Cell Recovery/GVHD


OutcomesFluBu

(n=458)

FluCyTBI

(n=89)

FluMel

N=885)

FluCy

(n=391)P-value

Neutrophil recovery (30 days) 99% (98-100%) 99% (96-100%) 96% (94-97%) 98% (97-99%) <0.001

Platelet recovery (30 days) 97% (95-98%) 97% (92-99%) 90% (88-92%) 99% (97-100%) <0.001

aGVHD, II-IV @ 6 months 40% (35-45%) 29% (20-40%) 38% (35-42%) 34% (29-39%) 0.12

cGVHD @ 1-year 41 (36-46%) 32 (23-43%) 43 (39-46%) 42 (37-48%) 0.29

FluMel had ↑ cGVHD vs. FluCy (HR 1.38, p<0.001)

Outcomes: Progression/Relapse and PFS


0%

10%

20%

30%

40%

50%

60%

70%

80%90%

100%

0 1 2 3 4 5

Years

Progression/Relapse

FluMel

FluCyTBI

FluBu

FluCy

Ad

jus

ted

Cu

mu

lati

ve

In

cid

en

ce

P<0.001

0%10%20%30%40%50%60%70%80%90%

100%

0 1 2 3 4 5

Years

PFS

FluMel

FluCyTBI

FluBu

FluCy

Ad

jus

ted

Pro

bab

ilit

y P=0.07

Multivariate Analysis: NRM and OS


NRM Overall Survival

HR 95% CI P-value HR 95% CI P-value

FluBu 1 <0.001 1 <0.001

FluMel 140 1.78 1.37-2.31 <0.001 1.34 1.13-1.59 0.001

NRM adjusted for covariates: Age, KPS,

prior-HCT, use of ATG/alemtuzumab

OS adjusted for covariates: Age, KPS, HCT-CI, NHL

subtype, remission status, use of ATG/alemtuzumab

FluMel had inferior NRM/OS versus BuFlu, no significant differences in NRM between FluCy +/- TBI and FluBu

0%

20%

40%

60%

80%

100%

0 1 2 3 4 5Years

NRM

FluMelFluCyTBIFluBuFluCy

Ad

jus

ted

Cu

mu

lati

ve

In

cid

en

ce

P<0.001

0%

20%

40%

60%

80%

100%

0 1 2 3 4 5

Years

OS

FluMel

FluCyTBI

FluBu

FluCy

Ad

jus

ted

Pro

ba

bil

ity

P<0.001

Conclusions

• FluMel associated with ↑ rate of NRM —↓ risk of relapse with FluMel compared to FluBu

• No improvement in PFS—↓ OS vs. FluBu

• No difference in other RIC/NMA regimens regarding aGVHD incidence

—FluMel associated with ↑ cGVHD rate

• FluMel showed inferior outcomes compared to all other RIC/NMA regimens

—Delayed hematologic recovery


ARS Question #1

Post-transplant blinatumomab was associated with which of the following:

a) Increased risk of hyperacute GVHD requiring systemic therapy initiation

b) Risk of immune-related adverse effects were more common in patients who received blinatumomab pre-transplant

c) Blinatumuab is safe to administer post-transplant to patients with low immunosuppression levels

d) Resulted in no graft failures and can be given for an additional cycle in patients with detectable disease

86

ARS Question #2

Use of gamma-secretase inhibitor (GSI) concurrently with BCMA CAR therapy provided successful improvement in BCMA expression resulting in almost 100% expression?

a) True

b) False

87

ARS Question #3

Administration of corticosteroids early for CRS and NT in patients receiving axicabtagene ciloleucel resulted in all the following outcomes:

a) Improvements in CRS and neurotoxicity severity

b) Beneficial reduction in cumulative steroid exposure

c) No significant effect on expansion of CAR in response to tumor burden

d) All the following are true

e) A and C

88

Recommended Additional Abstracts• Session: 653. Abstract 927- Updated Results From an Ongoing Phase I Clinical Study of bb21217

Anti-BCMA CAR T-cell Therapy

• Session: 653. Abstract 929-Kydar Multicenter Trial of Quadruple Regimen for Induction Resistant Myeloma Combined with Translational Single-Cell Analysis Identifies Potential Drivers of Advanced Resistance, Including Novel Immune Checkpoints

• Session: 732. Abstract 259-Tandem Autologous-Autologous Vs. Autologous-Allogeneic Transplantation for Newly Diagnosed Multiple Myeloma: Pooled Analysis of 1,338 Patients from Four Trials with Long-Term Follow up

• LBA-1-A Randomized Phase 3 Trial of Blinatumomab Vs. Chemotherapy As Post-Reinduction Therapy in High and Intermediate Risk (HR/IR) First Relapse of B-Acute Lymphoblastic Leukemia (B-ALL) in Children and Adolescents/Young Adults (AYAs) Demonstrates Superior Efficacy and Tolerability of Blinatumomab: A Report from Children’s Oncology Group Study AALL1331

• Session: 722. Abstract 371-Time-Restricted Versus Standard Duration Immunosuppression after Allogeneic Hematopoietic Stem Cell Transplantation: Results from the Prospective Randomized Phase III HOVON-96 Trial

89

Acknowledgments

• Dr. LaQuisa Hill

• Dr. Max Topp

• Dr. Michael Jain

• Dr. Adam Kittai

• Dr. Andrew Cowan

• Dr. Reid Merryman

• Dr. Jonathan Webster

• Dr. Haris Ali

• Dr. Nilanjan Ghosh

90

Updates from the American Society of Hematology Annual

Meeting 2019: Part II

Rebecca Gonzalez PharmD, BCOP

Clinical Pharmacy Specialist, Blood and Marrow Transplantation/Cellular Immunotherapy

Moffitt Cancer Center

updates from the american society of hematology annual ......ptcl pd - - deceased ptcl cr no...

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