Mantle Cell Lymphoma: The Inevitable Relapse

Peter Martin, MD Assistant Professor of Medicine Division of Hematology/Oncology Weill Cornell Medical College New York, New York

Patterns of survival in FL

T = 20 years Johnson PWM et al. J Clin Oncol. 1995;13(1):140-147.

Probable pattern of survival in MCL

T = 5 years Adapted from Johnson PWM et al. J Clin Oncol. 1995;13(1):140-147.

Bortezomib in Relapsed or Refractory MCL (Phase II PINNACLE Study): Progression-free survival Goy A et al. Ann Oncol 2008;20:520-525

STUDY

NHL-002 NHL-003 Prior BORT POOLED NHL 002 and 003 Rev+ Ritux

Lenalidomide

Design Results/Comments

N=15 Median of 4 prior rx Prior ASCT Prior Bort N= 39 Median age 66, 3 prior Rx Bort-23% ORR: 53% (CR-20%) Median DOR: 13.7 mos Median PFS : 5.6 mon Dose reductions in 53% 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%) N=14, median prior Rx-4, 50% Bort refractory N=46 Phase II ORR-57%, CR or CRu-21%.

Similar AEs O ORR 57%, CR 33% RD 19 mo.

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

Mammalian target of rapamycin (mTOR) Witzig T E et al. JCO 2005;23:5347-5356

Phase 2 studies of temsirolimus in relapsed MCL

Witzig Ansell

Dose

250 mg 25 mg

N

35 29

RR

38% 41%

TTP

6.5 mo.

6 mo.

Grade 3-4 heme tox.

84% 54%

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

Phase 3 trial of temsirolimus compared to investigator’s choice in MCL Hess G et al. JCO 2009;27:3822-3829

Phase 2 trial of everolimus in MCL

RR = 20% Median PFS 5.5 mo.

Renner et al. Haematol 2012 Epub

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 MCL patients N=9 1 PR 4 SD 4 PD Friedberg J W et al. Blood 2010;115:2578-2585

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

Class I PI3K Isoform Cell-based Activity

Alpha

PDGF-induced pAKT

Beta

LPA-induced pAKT

Gamma

fMLP-induced CD63+

Fc



Delta R1-induced CD63+ EC 50 (nM)

>20,000 1900 3000

8

• • • 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 in B-cell Lymphoma Best Response

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

+100 +75 +50 +25 0 -25 -50* -75 MCL (n = 21) iNHL (n = 30) -100 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-32765

Novel Small-molecule Btk Inhibitor

O N N H 2 N N N N O • • • •

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

–

IC 50 = 0.5 nM Orally available Once-daily dosing results in 24-hour sustained target inhibition

16%

71%

Best Response

69% 65%

16% 15%

20%

55% BTZ-naïve (n = 31) BTZ= Bortezomib *Wang et al. ASH 2011; Abstract 442

16% 13%

50% BTZ-exposed (n = 20)

15%

53% Total (n = 51)

18% CR PR SD PD

Best Response by Patient Characteristics

All Patients Bulky Disease Refractory

Yes No

Prior cancer treatments

< 3 regimens ≥ 3 regimens

Prior high intensity therapy

Yes No

MIPI Score

: Low Risk Intermediate Risk High Risk

n/N 35/51

4/7 14/21 21/30 23/30 12/21 22/31 13/20 6/8 13/20 15/20

ORR % 69

57 67 70 77 57 71 65 75 65 75 16

The Cell Cycle

Positive Negative Go M G2 S G1 Cyclin D + CDK4/6

pS-Rb-E2F

Cyclin E + CDK2 p16 p15 p18 p19 p21 p27 p57

pST-Rb E2F release

CDK: Cyclin-Dependent Kinase p18 INK4c (

CDKN2C

) Slide courtesy of Dr Selina Chen-Kiang mid-G1 checkpoint

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

PEPC RT-PEPC

Design

retrospective prospective

N

22 25

RR

82% 73%

Outcome

TTP 17 mo.

PFS 10 mo.

Coleman et al. Leuk Lymphoma 2008;49:447-450 Ruan 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.