Hyper CVAD-Based Regimens Are Best Frontline


CNS prophylaxis with IT chemo Rx(no XRT)1. • Hyper CVAD+rituximab in Burkitt and pre-B ALL2. • Hyper CVAD+imatinib/dasatinib/ponatinib in Ph- positive ...

Hyper CVAD-Based Regimens Are Best Frontline Therapy in AYA and Adult ALL

Hagop Kantarjian M.D. MD Anderson Cancer Center Emory Meeting-July 2016; Sea Island

Developmental Therapeutics in ALL

• Hyper CVAD regimen1 • CNS prophylaxis with IT chemo Rx(no XRT)1 • Hyper CVAD+rituximab in Burkitt and pre-B ALL2 • Hyper CVAD+imatinib/dasatinib/ponatinib in Ph• •

positive ALL3,4 Liposomal vincristine (FDA approval 2012)5 Activity of monoclonal antibodies (blinatumomab; inotuzumab) in adult ALL6,7

1. Kantarjian HM. J Clin Oncol. 2000;18(3):547-561. 2. Thomas DA, et al. Cancer. 2006;106(7):1569-1580. 3.Thomas DA, et al. Blood. 2004;103(12):4396-4407. 4. Ravandi R, et al. Blood. 116(12):2070-2077. 5. O’Brien S, et al. J Clin Oncol. 2012;31(6):676-683. 6. Kantarjian H, et al. J Clin Oncol. 2012;30(27):3876-3382. 9. Kantarjian H, et al. Lancet Oncol. 2012;13(4):403-411.

The Present… ALL Therapy or “Personalized Therapy” Entity

Management

Burkitt

HCVAD-R x 8; ITx16; 80-90 R/O-EPOCH HCVAD + TKI; TKI 50+ maintenance; allo SCT in CR1 Lots of HD CTX, HD 50-60 ara-C, Asp; nelarabine?

Ph-positive ALL

T-ALL CD20 – positive ALL AYA MRD by FCM

ALL chemo Rx+ rituximab/ofatumomab Augmented BFM; HCVAD-R/O Prognosis; need for allo SCT in CR1

% Cure

40-50

60+ --

Survival in Ph-ALL by Regimen (Excluding Primary Refractory) 1.0

No. No. Fail 21 Hyper-CVAD + imatinib 48 p 21 years Median follow-up (mos)

Kantarjian H, et al. Am J Hematol. 2016. [In press.]

Augmented BFM N=106

HCVAD N=102

99 (93) 1 (1) 6 (6) 82 (77)

100 (98) 1 (1) 1 (1) 77 (75)

0.75

58 (62) 68 (83)

48 (61) 57 (90)

0.83 0.19

53 60 65 57 66 [17-107]

55 60 68 58 88 [1-152]

0.98 0.99 0.67 0.75

P-value

0.17

ABFM vs Hyper-CVAD. Survival 1 .0

F r a c t io n s u r v iv a l

0 .8

0 .6

0 .4

0 .2 AugBFM HCVAD p=ns

0 .0 0

1

2

3

4

5

6

7

8

Y e a rs

Rytting. Cancer 120: 3660-8; 2014 Kantarjian. AJH 2016; In press

9

10

11

12

ABFM vs Hyper CVAD. CRD C o m p le te R e m is s io n D u r a tio n b y P r o to c o l 1 .0

F r a c tio n s u r v iv a l

0 .8

0 .6

0 .4

0 .2

AugBFM HCVAD p=ns

0 .0 0

12

24

36

48

60

72

84

96

108

120

M o n th s

Rytting ME, et al. Cancer. 2014;120(23):3660-3668. Kantarjian H, et al. Am J Hematol. 2016. [In press.]

132

HyperCVAD vs Augmented BFM. G3/4 Non-Hematologic Adverse Events Percentage Parameter Infections

Augmented BFM 73

HCVAD 83

 Bilirubin Allergic reaction Aspa

37 19

18 NA

Pancreatitis Neuropathy

11 5

3 7

Thrombotic events

21

6

Osteonecrosis

10

10

Kantarjian H, et al. Am J Hematol. 2016. [In press.]

ABFM vs HCVAD in AYA ALL. CNS Events Parameter Intensive Chemotherapy IT chemotherapy CNS relapses, % Isolated Plus systemic

Kantarjian H, et al. Am J Hematol. 2016. [In press.]

Augmented BFM HCVAD No Yes 15-22 14 9 6

8 11 7 4

Why R/O-Hyper-CVAD Better Than Pediatric Regimens?



Pediatric regimens with asparaginase not compatible with novel/future regimens: 1. ASP+ponatinib=bad liver toxicities and pancreatitis 2. ASP+inotuzumab=bad LFTs and VOD • Future regimens with hyper-CVAD x 3-4, followed by inotuzumab/blinatumomab x 3-4 = 8 to 9 mos total Rx, minimal chemotoxicity, and ↑ cure rates • ASP effective but highly toxic, particularly with age>40yrs • Inotuzumab/blinatumomab superior to intensive chemoRx, therefore can replace asparaginase and increase cure rate while reducing toxicity

Hyper-CVAD Difficult to Deliver?





Hyper-CVAD + dasatinib in SWOG—94 pts; no induction mortality Hyper-CVAD + imatinib in French Study– 268 pts; CR 91%

Chalandon Y, et al. Blood. 2015;125(24):3711-3719.

MiniHCVD-INO in ALL. Design Intensive phase 1 D3

2 D3

3 D3

4

5

6

7

8

D3

Maintenance phase 36 months

MiniHCVD

Mini-MTX-cytarabine

POMP Maintenance

Inotuzumab

Inotuzumab

First 6 pts

7 to 34

35 and beyond

First cycle (mg/m2)

1.3

1.8

1.3

C2-4 (mg/m2)

0.8

1.3

1.0

Inotuzumab + Hyper-CVD in Elderly ALL Parameter

N (%) / Median [Range]

No. of pts

33

Age (yrs)

69 [60-79]

CD22

98 [72-100]

CD20 (≥20%)

23/33 (70%) *

CR

24 (80)

CRp

5 (17)

Death in CR

2

2-year PFS %

85

2-year OS %

70

Jabbour E, et al. Haematologica. 2015;100(Suppl 1): Abstract S114.

Monoclonal Antibodies in ALL

Bi-specific MoAb (CD19 & CD3)

Jabbour E, et al. Blood. 2015;125(26):4010-4016.

INO-VATE: InO vs SOC in R/R ALL

Study Design

● Open-label, phase 3 study; 326 pts randomized at 117 sites in 19 countries InO • Starting dose 1.8 mg/m2/cyclea

•R/R CD22+ ALL •Salvage 1 or 2 •Ph– or Ph+

1:1 Randomization (N=326) Stratifications:

Standard of Care (SOC)

• Duration of 1st CR ≥12 vs
Recommend Documents
8:30pm. 9PM. 9:30pm. 10PM. 10:30pm. 1. MON. 2. TUE. 3. WED. 4. THU. 5. FRI. 6 .... Queen and Country: Celebrates Queen Elizabeth II's Diamond Jubilee.

Ghosts of Machu Picchu: Why did the Incas abandon their city in the clouds? ... Nine Long Days: TR's Journey to The White House: WMHT explores the future ...

Apr 15, 2010 - Army Special Forces soldiers as part of a two-week sniper training course in Mosul, Iraq. See story Page ...... The Post-9/11 GI Bill, Chapter 33, is a non-contrib- utory benefit ... The Peterson's Online Academic Skills Course is.

American Masters: Woody Guthie, Ain't ... Woody Guthrie - Ain't Got No Home: Hear the story of Guthrie's creative energy, personal imperfections and tragedies.

Oct 10, 2009 - enterprises in the district do not even have a bank account in a ... difficult to repay the high-interest loans they have taken from private banks.

American Masters: The Doors - When ... American Masters: Billie Jean King ... Guilt: Explores the conceivable effects of neuroscience on criminal law and ...

Great Performances from Vienna: The New Year's Celebration ... Meet the Coywolf: Unravel the mysteries that define the coywolf, a mixture of western coyote ...

Nov 18, 2010 - explore the Georgia Virtual Technical College Web site at www.gvtc.org. ...... 629 Dromedary, Kissimmee, FL 34759-4205. Military personnel ...

“We at Insitu could not have gotten close to understanding the cryogenic hydrogen realm without Washington State… The skill set and knowledge base,.

Wolf Hall on Masterpiece. Call the Midwife. Masterpiece Classic: Mr. Selfridge .... 5PM Daniel O'Donnell Music & Memories. 1PM. 1PM America's Test Kitchen.