Mantle Cell Lymphoma Current Treatment Strategies

1
Mantle Cell Lymphoma Current Treatment Strategies

• Linda Verkruyse MD

2
Patient

• 59 y/o male
• 11/2000 Initially diagnosed with NHL (mantle
  zone lymphoma ?) from cervical LN - Treated with
  CHOP x 6 with CR
• 9/2002 Disease recurrence with cervical and
  axillary LAD Treated with chemotherapy (?) with
  PR
• 8/2004 Disease recurrence with fatigue, wt.
  loss, B symptoms Re-biopsy of cervical LN
  Mantle Cell Lymphoma Blastoid Variant Treated
  with R-ESHAP x 5 with PR
• 2/2005 Disease recurrence with cervical LAD

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Mantle Cell Lymphoma

• Clinical Features
• 6 of Non-Hodgkins Lymphomas
• 31 male predominance
• Median age 65 years
• Extranodal involvement in 90 (bone marrow, GI)
• Most patients diagnosed with stage III/IV disease
• Peripheral blood involvement common
• Splenomegaly in 30-50
• CNS involvement possible at relapse (5-15)
• Median survival 3 years

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Immunophenotype

• Express
• Cyclin D1
• CD19
• CD20
• CD22
• CD5
• BCL-2
• CD79a
• FMC7
• Surface IgM and/or IgG
• Negative
• CD10
• CD23

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• Initially classified as an indolent lymphoma
• Retrospective analysis of 3 SWOG trials (CHOP) in
  low grade lymphoma separated out cases of mantle
  cell lymphoma
• 36/376 patients identified as having mantle cell
  lymphoma
• 10 year survival in the mantle cell patients was
  8 compared with 35 for most of the remaining
  population
• Mantle cell patients had poor prognosis compared
  with other indolent lymphomas

Fisher, R.I., Dahlberg, S., et al., Blood, 85(4),
1995, pg.1075
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Histology

• Morphologic patterns
• Mantle Zone
• Nodular
• Diffuse
• Blastoid Variant
• Evidence of morphologic progression in some
  patients

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Morphology
Nodular pattern
Diffuse pattern
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Classic Mantle Cell Lymphoma
Blastoid Variant
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Prognosis by Morphology

• Retrospective analysis of 46 patients (1986-1992)
• Patients had various treatments (CHOP, VAD,
  DHAP/CHOP, observation)

Majlis, A., Pugh, W.C., et al., JCO, 15 (4),
1997, pg. 1664
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Genetics

• t(1114)(q13q32) Cyclin D1/IgH chain joining
  region. Results in deregulated expression of
  cyclin D1.
• Loss of p27 (81 in one series of 112 patients),
  increased p27 associated with better survival
• Gene expression profiling combined with clinical
  outcome data has identified a group of mantle
  cell lymphoma patients with a gt 6 year median
  survival

Chiarle, R., Budel, L., et al., Blood, 95(2),
2000, pg. 619 Rosenwald, A., Wright, G., et al.,
Cancer Cell 3, 2003, pg. 185
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Cell Cycle
G1
pRBp E2F
Cyclin D1 CDK 4/6
pRB/E2F
S
INK4 (p15/16, p18/19) KIP/CIP (p21, p27)
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Chemotherapy

• CHOP Rituxan
• 40 patients (new diagnosis)
• CR 48, PR 48
• Molecular CR seen in 36 of patients with PCR
  detectable cyclin D1/IgH translocation
• Median PFS 16.6 months, all patients relapsed by
  36 months
• No significant difference in PFS for patients
  having a clinical or molecular CR

Howard, O., Gribben, J., et al., JCO, 20 (5),
2002, pg. 1288
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Chemotherapy

• Rituxan Hyper-CVAD/HD methotrexateAra-C

Romaguera, J., Khouri, I., et al., Leukemia and
Lymphoma, 39, 2000, pg. 77 Romaguera, J.,
Cabanillas, F., et al., Blood, 98, 2001, Abst.
3030 Romaguera, J., Fayad, L., et al., Blood,
104, 2004, Abst. 128
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Transplant - Autologous

• 26 patients (mixture of untreated and relapsed)
• Chemotherapy Hyper-CVAD / HD MTX Ara-C
• Conditioning regiment HD cyclophosphamide and TBI
• Excluded patient with mantle zone morphology
  pattern
• 3 year EFS 28
• 3 year OS 48

Khouri, I., Romaguera, J., et al., JCO, 16(12),
1998, pg. 3803
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- Included patients treated with allogeneic
transplant as well as chemotherapy only
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Transplant - Autologous

• Second Study
• 33 patients (new diagnosis)
• Chemotherapy Hyper-CVAD / HD MTX Ara-C
• Conditioning regiment HD cyclophosphamide TBI
• 5 year DFS 43
• 5 year OS 77
• Beta2 Microglobulin level correlated with
  survival
• b2M lt 3mg/l OS at 5 years 100
• b2M gt 3mg/l OS at 5 years 22

Khouri, I., Saliba, R., et al., Cancer, 98(12),
2003, pg. 2630
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Transplant - Autologous

• Retrospective Review from the EBMT Registry and
  ABMTR Database
• 195 patients (new diagnosis and relapsed)
• Chemotherapy varied, not given
• Conditioning regiments varied
• All patients 2 year PFS 55 5 year PFS
  33
• 2 year OS 76 5
  year OS 48
• Also indicated survival was better in patients
  transplanted in first remission
• Patients transplanted in CR1
• 2 year PFS 65 5 year PFS 52
• 2 year OS 88 5 year OS 65

Vandenberghe, E., Ruiz, C., et al., British J. of
Hematology, 120, 2003, pg. 793
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Transplant - Autologous

• Nordic Lymphoma Group 2 studies

Geisler, C., Elonen, E., et al., Blood, 104, 2004
abst. 8
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Transplant - Autologous

• Survival may be improved with transplant in first
  remission
• More aggressive chemotherapy regiments and the
  use of rituxan may improve survival
• Plateau in survival curves not seen to date
• Does R-Hyper-CVAD/HD MTX/Ara-C equal
  Hyper-CVAD/HD MTX/Ara-C autologous transplant?

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Transplant - Allogeneic
- Recent studies use non-myeloablative strategies

• European Group for Blood and Bone Marrow
  Transplant
• Retrospective review (188 patients, several
  types)
• 22 mantle cell patients (relapsed, 16
  chemotherapy sensitive)
• Conditioning regiments varied (84 fludaribine
  containing)
• PFS 2 year 0
• OS 1 year 38, 2 year 12.8
• GVHD 60 (all grades), 24 grades 3-4 overall

Robinson, S., Goldstone, A., et al., Blood,
100(13), 2002, pg. 4310
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European Group for Blood and Bone Marrow
Transplant
Overall survival by lymphoma category
Robinson, S., Goldstone, A., et al., Blood,
100(13), 2002, pg. 4310
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Transplant Allogeneic

• MD Anderson Cancer Center
• 2 trials, differed with respect to conditioning
  regiments
• 18 patients total (relapsed disease 16/18
  chemotherapy sensitive disease)
• F/U 26 months
• 3 deaths 1 GVHD, 1 PD, 1 PE
• 3 disease relapse 2 received DLI - 1 with CR, 1
  with PR

Khouri, I., Lee,M., et al., JCO, 21(3), 2003, pg.
4402
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Transplant - Allogeneic

• Fred Hutchinson Cancer Center
• 33 patients (relapsed or refractory)
• Conditioning regiment fludarabine TBI
• 20 patients with measurable disease at transplant
  
• CR 85
• Median time to CR 87 days
• Relapse related mortality 2 years 9
• Non-relapse related mortality 2 years 24
• Median f/u 24.6 months
• 3 patients with PD after transplant
• 1 relapse

Maris, M., Sandmaier, B., et al., Blood, 104(12),
2004, pg. 3535
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Transplant - Allogeneic

• Results are mixed
• Transplant related mortality can be significant
• Evidence for graft vs. tumor effect

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New Therapies

• Velcade
• Mechanism of action not known, possibilities
  include
• Inhibition of p27 degradation through
  ubiquitin-proteasome pathway
• Inhibition of cyclin D1 and cell cycle through
  inactivation of NF-kB

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Velcade

• Phase 2 studies
• Treatment Velcade 1.5mg/m2 days 1,4,8,11 every
  21 days
• Most common adverse effects neutropenia,
  thrombocytopenia, fatigue, nausea

OConnor, O., Wright, J., et al., JCO, 23(4),
2005, pg. 676 Goy, A., Young, A., et al., JCO,
23(4), 2005, pg. 662
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Thalidomide

• Thalidomide Dexamethasone
• 2 cases heavily pre-treated
• Thalidomide doses 100 200 mg/day
• Both with PR with progressive improvement over
  4-5 months
• Response duration 19 months / 10 months
• Thalidomide Rituxan
• 16 patients (relapsed or refractory)
• Rituxan 375mg/m2 weekly x 4, Thalidomide 200
  mg/day x 2 weeks ? 400 mg/day until progression
• CR 31, PR 50, SD 6
• Median PFS 20.4 months
• Thalidomide dose reduction in all patients

Damaj, G., Lefrere, F., et al., Leukemia, 17,
2003, 1914 Kaufmann, H., Raderer, M., er al,
Blood, 104(8), 2004, pg. 2269
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Conclusions

• Prognosis of Mantle Cell Lymphoma is poor
• Survival can be improved with aggressive therapy
• Unclear if this lymphoma is curable
• Velcade and Thalidomide have activity

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Patient

• 59 y/o male
• 11/2000 Initially diagnosed with NHL (mantle
  zone lymphoma ?) from cervical LN
• 9/2002 Disease recurrence with cervical and
  axillary LAD
• 8/2004 Disease recurrence with fatigue, wt.
  loss, B symptoms Re-biopsy of cervical LN
  Mantle Cell Lymphoma Blastoid Variant
• 2/2005 Disease recurrence with cervical LAD
• Treatment
• Initiate Velcade
• Type siblings for allogeneic transplant