updates from the american society of hematology annual ......ptcl pd - - deceased ptcl cr no...
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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
Hill et al. ASH 2019;session 704. Abstr 199. 7
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
Hill et al. ASH 2019;session 704. Abstr 199. 8
d:Day, Flu: Fludarabine, Cy: cyclophosphamide, CR: complete response
Baseline Characteristics
Hill et al. ASH 2019;session 704. Abstr 199. 10
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
Hill et al. ASH 2019;session 704. Abstr 199. 11
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
Hill et al. ASH 2019;session 704. Abstr 199. 12
AE: adverse effect, CMV: cytomegalovirus, CLABSI: central line-associated bloodstream infection, CONS: coag negative staph
Outcomes
Hill et al. ASH 2019;session 704. Abstr 199. 13
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
Hill et al. ASH 2019;session 704. Abstr 199. 15
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
Topp MS, et al. ASH 2019;session 626. Abstr 243. 18
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
Topp MS, et al. ASH 2019;session 626. Abstr 243. 19
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
Topp MS, et al. ASH 2019;session 626. Abstr 243. 21
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
Topp MS, et al. ASH 2019;session 626. Abstr 243. 22
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)
Topp MS, et al. ASH 2019;session 626. Abstr 243. 23
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
Topp MS, et al. ASH 2019;session 626. Abstr 243. 24
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
Topp MS, et al. ASH 2019;session 626. Abstr 243. 26
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
Jain MD, et al. ASH 2019;session 626. Abstr 245. 29
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
Jain MD, et al. ASH 2019;session 626. Abstr 245. 30
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
Jain MD, et al. ASH 2019;session 626. Abstr 245. 31
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.
Jain MD, et al. ASH 2019;session 626. Abstr 245. 32
Bridging Therapy in SOC Axi-Cel
Jain MD, et al. ASH 2019;session 626. Abstr 245. 33
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
Jain MD, et al. ASH 2019;session 626. Abstr 245. 35
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)
Jain MD, et al. ASH 2019;session 626. Abstr 245. 36
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
Jain MD, et al. ASH 2019;session 626. Abstr 245. 38
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
Kittai AS, et al. ASH 2019;session 704. Abstr 780.41
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
Kittai AS, et al. ASH 2019;session 704. Abstr 780.42
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#
Kittai AS, et al. ASH 2019;session 704. Abstr 780.43
*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
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
Cowan AJ, et al. ASH 2019;session 704. Abstr 204.47
IMID: immunomodulatory therapy, PI: proteasome inhibitors, IHC: immuno-histocompatibility complex
Baseline Characteristics (n=10)
Cowan AJ, et al. ASH 2019;session 704. Abstr 204.48
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
Cowan AJ, et al. ASH 2019;session 704. Abstr 204.49
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
Cowan AJ, et al. ASH 2019;session 704. Abstr 204.50
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
Merryman RW, et al. ASH 2019;session 704. Abstr 775.55
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
Merryman RW, et al. ASH 2019;session 704. Abstr 775.
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
Merryman RW, et al. ASH 2019;session 704. Abstr 775.57
• 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
Merryman RW, et al. ASH 2019;session 704. Abstr 775.
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
• 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
Merryman RW, et al. ASH 2019;session 704. Abstr 775.60
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
• 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%
Merryman RW, et al. ASH 2019;session 704. Abstr 775.
61CIR: cumulative incidence of relapse
Factor 2-yr OS
PTCy
Yes 84%
No 80%
Secondary Objectives: GFRS*
Merryman RW, et al. ASH 2019;session 704. Abstr 775.62
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
Merryman RW, et al. ASH 2019;session 704. Abstr 775.63
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:
Webster J, et al. ASH 2019;session 704. Abstr 778.
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
Patient Characteristics
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
Webster J, et al. ASH 2019;session 704. Abstr 778.67
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
Webster J, et al. ASH 2019;session 704. Abstr 778.68
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
Webster J, et al. ASH 2019;session 704. Abstr 778.
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
Ali H, et al. ASH 2019;session 634. Abstr 669.71
MF: myelofibrosis, TRM: treatment-related mortality, JAK: Janus kinase
Study Design: NCT02917096
Ali H, et al. ASH 2019;session 634. Abstr 669.72
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
Patient Characteristics
Ali H, et al. ASH 2019;session 634. Abstr 669.73
, 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
Ali H, et al. ASH 2019;session 634. Abstr 669.74
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
Ali H, et al. ASH 2019;session 634. Abstr 669.75
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
Ali H, et al. ASH 2019;session 634. Abstr 669.76
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
Patient Characteristics
Ghosh N, et al. ASH 2019;session 732. Abstr 319.80
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
Ghosh N, et al. ASH 2019;session 732. Abstr 319.82
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
Ghosh N, et al. ASH 2019;session 732. Abstr 319.83
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
Ghosh N, et al. ASH 2019;session 732. Abstr 319.84
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
Ghosh N, et al. ASH 2019;session 732. Abstr 319.85
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
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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
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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