Mantle Cell Lymphoma: The Inevitable Relapse

1
Mantle Cell LymphomaThe Inevitable Relapse

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

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Patterns of survival in FL
T 20 years
Johnson PWM et al. J Clin Oncol.
199513(1)140-147.
3
Probable pattern of survival in MCL
T 5 years
Adapted from Johnson PWM et al. J Clin Oncol.
199513(1)140-147.
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Bortezomib in Relapsed or Refractory MCL (Phase
II PINNACLE Study) Progression-free survival
Goy A et al. Ann Oncol 200820520-525
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Lenalidomide
STUDY Design Results/Comments
NHL-002 N15 Median of 4 prior rx Prior ASCT Prior Bort ORR 53 (CR-20) Median DOR 13.7 mos Median PFS 5.6 mon Dose reductions in 53
NHL-003 N 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 N14, median prior Rx-4, 50 Bort refractory ORR-57, CR or CRu-21. Similar AEs
Rev Ritux N46 Phase II OORR 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
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Mammalian target of rapamycin (mTOR)
Witzig T E et al. JCO 2005235347-5356
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Phase 2 studies of temsirolimus in relapsed MCL
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
Witzig et al. JCO 2005235347 Ansell et al.
Cancer 2008113508
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Phase 3 trial of temsirolimus compared to
investigators choice in MCL
Hess G et al. JCO 2009273822-3829
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Phase 2 trial of everolimus in MCL
RR 20 Median PFS 5.5 mo.
Renner et al. Haematol 2012 Epub
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BCR, NF-?B, and PI3K/AKT/mTOR deregulation in MCL
Pérez-Galán P et al. Blood 201111726-38
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Phase 2 trial of fostamatinib (oral Syk
inhibitor) in relapsed NHL
MCL patients N9 1 PR 4 SD 4 PD
Friedberg J W et al. Blood 20101152578-2585
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CAL-101 (GS-1101) Is an Orally Bioavailable Small
Molecule That Inhibits PI3K Delta Potently and
Selectively
CAL-101
Class IPI3K Isoform
Cell-based Activity PDGF-induced pAKT LPA-induced pAKT fMLP-induced CD63 Fc?R1-induced CD63
EC50 (nM) gt20,000 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 gt350
  protein kinases

Lannutti. Blood. 2011.
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Cal-101 in B-cell Lymphoma Best Response
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). 20101161777.
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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

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Best Response
71
69
65
16
16
15
20
18
16
15
13
50
55
53
BTZ-naïve(n 31)
BTZ-exposed (n 20)
Total(n 51)
BTZ Bortezomib Wang et al. ASH 2011 Abstract
442
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Best Response by Patient Characteristics
n/N ORR
All Patients 35/51 69
Bulky Disease 4/7 57
Refractory Yes No 14/21 21/30 67 70
Prior cancer treatments lt 3 regimens 3 regimens 23/30 12/21 77 57
Prior high intensity therapy Yes No 22/31 13/20 71 65
MIPI Score Low Risk Intermediate Risk High Risk 6/8 13/20 15/20 75 65 75
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The Cell Cycle
Negative
Positive
Go
M
pS-Rb-E2F
G1
G2
S
CDK Cyclin-Dependent Kinase p18INK4c (CDKN2C)
Slide courtesy of Dr Selina Chen-Kiang
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PD0332991-induced changes in Rb phosphorylation
and Ki-67 expression in pre- and on-treatment
lymph node biopsies.
Leonard J P et al. Blood 20121194597-4607
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Quantification of FDG- and FLT-PET changes on
PD0332991 and correlation with each other and
time to progression.
Leonard J P et al. Blood 20121194597-4607
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The anti-apoptotic phenotype and alterations in
BCL-2 family members in MCL
Pérez-Galán P et al. Blood 201111726-38
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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 200849447-450 Ruan
et al. Cancer 20101162655-2664
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Conclusion

• All MCL patients eventually acquire resistance to
  intermittent chemotherapy
• Treatment with novel agents/continuous therapy is
  required to maintain remissions

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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.