Mantle Cell Lymphoma:The Inevitable Relapse

Peter Martin, MDAssistant Professor of Medicine

Division of Hematology/OncologyWeill Cornell Medical College

New York, New York

Johnson PWM et al. J Clin Oncol. 1995;13(1):140-147.

Patterns of survival in FL

T = 20 years

Adapted from Johnson PWM et al. J Clin Oncol. 1995;13(1):140-147.

Probable pattern of survival in MCL

T = 5 years

Goy A et al. Ann Oncol 2008;20:520-525

Bortezomib in Relapsed or Refractory MCL (Phase II PINNACLE Study):

Progression-free survival

Haberman TM, et al. Br H Haematol. 2009; Zinzani PL, ASH 2008. Reeder CB, et al. ASH 2008. Wang et al. ICML 2011

STUDY Design Results/Comments

NHL-002

N=15Median of 4 prior rx

Prior ASCTPrior Bort

ORR: 53% (CR-20%)Median DOR: 13.7 mosMedian PFS : 5.6 mon

Dose reductions in 53%

NHL-003N= 39

Median age 66, 3 prior Rx Bort-23%

ORR: 41% (CR or CRu-13%)Median DOR: 13.7 mos

Grade 3-4 : Neutropenia (51%), thrombocytopenia (25%), anemia (13%), fatugue (10%) and Febrile

Neutropenia (10%)

Prior BORT- POOLED NHL-002 and 003

N=14, median prior Rx-4, 50% Bort refractory

ORR-57%, CR or CRu-21%.Similar AEs

Rev+ RituxN=46

Phase IIOORR 57%, CR 33%

RD 19 mo.

Lenalidomide

Mammalian target of rapamycin (mTOR)

Witzig T E et al. JCO 2005;23:5347-5356

Dose N RR TTP Grade 3-4 heme tox.

Witzig 250 mg 35 38% 6.5 mo. 84%

Ansell 25 mg 29 41% 6 mo. 54%

Phase 2 studies of temsirolimus in relapsed MCL

Witzig et al. JCO 2005;23:5347Ansell et al. Cancer 2008;113:508

Hess G et al. JCO 2009;27:3822-3829

Phase 3 trial of temsirolimus compared to investigator’s choice in MCL

Renner et al. Haematol 2012 Epub

Phase 2 trial of everolimus in MCL

RR = 20%Median PFS 5.5 mo.

BCR, NF-κB, and PI3K/AKT/mTOR deregulation in MCL

Pérez-Galán P et al. Blood 2011;117:26-38

Phase 2 trial of fostamatinib (oral Syk inhibitor) in relapsed NHL

Friedberg J W et al. Blood 2010;115:2578-2585

MCL patients N=91 PR4 SD4 PD

CAL-101 (GS-1101) Is an Orally Bioavailable Small Molecule That Inhibits PI3K Delta

Potently and Selectively

CAL-101 (GS-1101) Is an Orally Bioavailable Small Molecule That Inhibits PI3K Delta

Potently and Selectively

Class IPI3K Isoform

Cell-based Activity

PDGF-induced pAKT

LPA-induced pAKT

fMLP-induced CD63+

FcR1-induced CD63+

EC50 (nM) >20,000 1900 3000 8

Alpha Beta Gamma Delta

• Selectivity relative to Class I PI3K isoforms involved in insulin signaling and other physiological functions• No off-target activity against Class II or III PI3K, mTOR, or DNA-PK• No off-target activity seen in screen of >350 protein kinases

Lannutti. Blood. 2011.

CAL-101

Cal-101 in B-cell Lymphoma Best Response

-50*

-75% C

hang

e in

Lym

ph N

ode

Area

-25

-100

+25

+50

+75

+100

0

MCL(n = 21)

iNHL(n = 30)

Best on-treatment change in tumor size(ITT analysis)

Inevaluable (patients without a follow-up tumour assessment; includes two patients with LPL with no adenopathy)

* Criterion for response [Cheson 2007, Hallek 2008]

Kahl B et al. Blood (ASH Annual Meeting Abstracts). 2010;116:1777.

PCI-32765Novel Small-molecule Btk Inhibitor

PCI-32765Novel Small-molecule Btk Inhibitor

• Forms a specific and irreversible bond with cysteine-481 in Btk

• Potent Btk inhibition – IC50 = 0.5 nM

• Orally available

• Once-daily dosing results in 24-hour sustained target inhibition

N

N

NN

N H 2

O

N

O

Best Response Best Response

BTZ-naïve(n = 31)

BTZ-exposed(n = 20)

Total(n = 51)

CR

PR

SD

PD

71%

16%13%

65%69%

20%15% 18%

15%

50%

16%

55%

16%

53%

BTZ= Bortezomib

*Wang et al. ASH 2011; Abstract 442

n/N ORR %All Patients 35/51 69Bulky Disease 4/7 57RefractoryYesNo

14/2121/30

6770

Prior cancer treatments < 3 regimens ≥ 3 regimens

23/3012/21

7757

Prior high intensity therapyYesNo

22/3113/20

7165

MIPI Score: Low RiskIntermediate RiskHigh Risk

6/813/2015/20

756575

Best Response by Patient Characteristics

16

The Cell Cycle

G1

S

G2

M

p21p27p57

Negative

Go

Positive

Cyclin D + CDK4/6

pS-Rb-E2F

Cyclin E + CDK2

pST-Rb E2F release

p16p15p18p19

CDK: Cyclin-Dependent Kinasep18INK4c (CDKN2C)

mid-G1 checkpoint

Slide courtesy of Dr Selina Chen-Kiang

PD0332991-induced changes in Rb phosphorylation and Ki-67 expression in pre- and

on-treatment lymph node biopsies.

Leonard J P et al. Blood 2012;119:4597-4607

Quantification of FDG- and FLT-PET changes on PD0332991 and correlation with each other and

time to progression.

Leonard J P et al. Blood 2012;119:4597-4607

The anti-apoptotic phenotype and alterations in BCL-2 family members in MCL

Pérez-Galán P et al. Blood 2011;117:26-38

Low-dose metronomic oral chemotherapy

• Prednisone 20 mg at breakfast• Etoposide 50 mg at lunch• Cyclophosphamide 50 mg at supper• Procarbazine 50 mg at bedtime• Start daily, then titrate frequency based

on ANC

Regimen Design N RR Outcome

PEPC retrospective 22 82% TTP 17 mo.

RT-PEPC prospective 25 73% PFS 10 mo.

Coleman et al. Leuk Lymphoma 2008;49:447-450Ruan et al. Cancer 2010;116:2655-2664

Conclusion

• All MCL patients eventually acquire resistance to intermittent chemotherapy

• Treatment with novel agents/continuous therapy is required to maintain remissions

Future challenges

• Is there a role for early detection/treatment of subclinical relapse?

• Should novel treatments be used as single agents in relapse or combined with upfront induction/consolidation/maintenance regimens?

• Mechanisms of response/resistance of novel agents need to be clarified to justify rational combinations.