Low Grade Follicular Lymphomas An Update

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Low Grade Follicular LymphomasAn Update

• Giancarlo Pillot, M.D.
• Grand Rounds 10 Dec 2004

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Background
Derived from data contained in Anonymous, A
Clinical Evaluation of the International Lymphoma
Study Group Classification of Non-Hodgkin's
Lymphoma Blood, Vol. 89 No. 11 (June 1), 1997
pp. 3909-3918
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Pathology
Similar in architecture to normal geminal
centers. Can Resemble Reactive Follicular
Hyperplasia Low proliferation rate in comparison
to RFH Bcl-2 staining absent in RFH Residual
benign mantle zones not seen Dendritic cells are
present and stains can highlight diffuse areas
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Immunophenotyping

• CD19,20,22,79a ()
• CD10 ()
• Express sIg IgM 50-60, IgG 40
• Bcl-2- gt80 express related to t(1418)

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Cytogenetics

• t(1418) is present in 85 of FCL
• Fusion of bcl-2 and IgH loci, leading to
  constitutively expressed protein
• Not sufficient to cause FCL
• Detectable by PCR in some normal subjects
• Insufficient to cause FCL in mouse models
• Also found in 15-20 DLCBCL

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Grading

• Grade 1 0-5 centroblasts/ HPF
• Grade 2 6-15 centroblasts/ HPF
• Grade 3 gt15 centroblasts/ HPF
• 3a centrocytes present
• 3b centroblasts form solid sheets without
  residual centrocytes
• Also cutaneous and Diffuse follicle center
  lymphoma variants

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Compulsory Histology Slides
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Natural History/ Prognosis

• The IPI is limited for FCL- only 10-15 are
  labelled poor- risk in that series
• A series specifically of 4167 FCL patients
  reviewed retrospectively (1985-1992), then tested
  in second cohort of 919 patients.

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Survival
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FLIPI
Philippe Solal-Céligny, et al. Follicular
Lymphoma International Prognostic Index Blood,
Sep 2004 104 1258 - 1265.
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FLIPI
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FLIPI
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Treatment

• Difficult to Assess Value of Various Treatments
• Very Long survival times and multiple treatment
  options for relapsed disease preclude easy
  analysis of OS as an endpoint
• Heterogeneity of outcomes depending on risk
• Most trials demonstrate differences in RR but not
  OS

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No Rx

• With such a long natural history to the disease
  and competing morbidity in older patients, it is
  reasonable to ask if delaying Rx as long as
  possible is a reasonable strategy
• 316 patients with low grade histologies (65
  follicular)
• Stage III/ IV disease
• Absence of B- symptoms
• No organ dysfunction
• Randomized to initial chronic oral chlorambucil
  or observation

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No Rx
Mean time to first treatment was 2.6 years in
observation group
Ardeshna KM et al. Long-term effect of a watch
and wait policy versus immediate systemic
treatment for asymptomatic advanced-stage
non-Hodgkin lymphoma a randomised controlled
trial. Lancet. 2003362516- 522.
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Selected Chemo Regimens

• Peterson BA, Petroni GR, Frizzera G, et al.
  Prolonged single-agent versus combination
  chemotherapy in indolent follicular lymphomas a
  study of the cancer and leukemia group B. J Clin
  Oncol. 2003215-15.
• Kimby E, et al. Chlorambucil/prednisone vs. CHOP
  in symptomatic low-grade non-Hodgkin's lymphomas
  a randomized trial from the Lymphoma Group of
  Central Sweden. Ann Oncol. 19945 Suppl 267-71.
• Klasa RJ et al. Randomized phase III study of
  fludarabine phosphate versus cyclophosphamide,
  vincristine, and prednisone in patients with
  recurrent low-grade non-Hodgkin's lymphoma
  previously treated with an alkylating agent or
  alkylator-containing regimen. J Clin Oncol. 2002
  Dec 1520(24)4649-54.

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Interferon

• Trials exist utilizing interferon- alpha after
  chemotherapy.
• No consistent statistically significant
  improvement in OS or TTP
• However, some trials still use it as maintenance
  Rx

Hagenbeek A, et al Maintenance of remission with
human recombinant interferon alfa-2a in patients
with stages III and IV low-grade malignant
non-Hodgkin's lymphoma. European Organization for
Research and Treatment of Cancer Lymphoma
Cooperative Group. J Clin Oncol. 1998
Jan16(1)41-7. Fisher RI, et al. Interferon
alpha consolidation after intensive chemotherapy
does not prolong the progression-free survival of
patients with low-grade non-Hodgkin's lymphoma
results of the Southwest Oncology Group
randomized phase III study 8809. J Clin Oncol.
2000 May18(10)2010-6.
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Rituximab

• Given enhanced responses and OS in treatment of
  aggressive lymphoma, Rituximan has been tested in
  FL
• Humanized monoclonal antibody to CD20
• Original Trial showed response rate of 46 in the
  relapsed/ refractory setting median TTP was 10.2
  months
• Maloney D, Grillo-López A, White C, et al
  IDEC-C2B8 (RituxanAB) anti-CD20 monoclonal
  antibody therapy in patients with relapsed
  low-grade non-Hodgkin's lymphoma. Blood
  902188-2195, 1997

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More Rituximab Stuff

• Trial looking at Rituximab as upfront therapy
• All 202 patients had FCL
• All patients received rituxuximab upfront-
  overall response rate was 67 in
  chemotherapy-naive patients and 46 in pretreated
  cases
• randomized to no further treatment or prolonged
  rituximab administration (375 mg/m2 every 2
  months for 4 times).
• the median EFS was 12 months in the no rx vs 23
  months in further Rx arm (P .02)

Michele Ghielmini, etal. Prolonged treatment
with rituximab in patients with follicular
lymphoma significantly increases event-free
survival and response duration compared with the
standard weekly x 4 schedule Blood, Jun 2004
103 4416 - 4423.
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EFS of Prolonged Rituxan Infusion
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Rituxan Combinations
1. Robert Marcus, et al. CVP chemotherapy plus
Rituximab compared with CVP as first-line
treatment for advanced follicular lymphoma.
Blood, Oct 2004 10.1182/blood-2004-08-3175.
(epub ahead of print) 2. Glabbeke, et al.
Chimeric anti CD-20 Monoclonal Antibody in
Remission Induction and Maintenance Therapy of
Relapsed/ Resistant Follicular NHL A Phase III
Randomized Intergroup Trial ASH 2004 586 3.
Herold M, et al. Results of a Prospective Open-
Label Phase II R-MCP vs MCP in untreated
advanced indolent lymphoma and MCL. Abstract 584
ASH 2004
X Results for FL subset only in patients with
mixed populations PFS
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RadioImmunotherapy

• yttrium-90 (90Y) ibritumomab tiuxetan (Zevalin)
• relapsed or refractory low-grade, follicular, or
  transformed CD20 transformed NHL (N143).
• ORR was 80 for Zevalin vs 56 for the rituximab
• duration of response was 14.2 mos vs 12.1 mos
• Witzig et al, Randomized controlled trial of
  yttrium-90-labeled ibritumomab tiuxetan
  radioimmunotherapy versus rituximab immunotherapy
  for patients with relapsed or refractory
  low-grade, follicular, or transformed B-cell
  non-Hodgkin's lymphoma. J Clin Oncol. 2002 May
  1520(10)2453-63.
• tositumomab and iodine I 131 tositumomab (Bexxar)
• Response Rate (65), compared with (28) after
  their LQC. MDR was 6.5 months vs 3.4 months after
  the LQC in 60 pts Kaminski M, et al. Pivotal
  Study of Iodine I 131 Tositumomab for
  Chemotherapy-Refractory Low-Grade or Transformed
  Low-Grade B-Cell Non-Hodgkins Lymphomas JCO Oct
  1 2001 39183928.

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High Dose Chemotherapy

• Given Equivalent short- term survivals with
  single and combination chemotherapy regimens,
  high dose strategies have been pursued
• Randomized Trial of Young Patients with Relapsed
  FCL
• All patients received CHOP X 3
• Responders then randomized to additional CHOP X3
  vs. High Dose Chemo with Autologous Stem Cell
  Support (arms with purged and unpurged stem cell
  product)
• Closed Early after 140 patients due to slow
  enrollment

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Schouten HC, et al. High-dose therapy improves
progression-free survival and survival in
relapsed follicular non-Hodgkin's lymphoma
results from the randomized European CUP trial. J
Clin Oncol. 2003 Nov 121(21)3918-27. Epub 2003
Sep 29.
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Note only 89 patients made it to randomization
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Rituxan after Auto

• Rituximab after auto SCT in pts with MRD
• A nodes 1-3cm and marrowlt30 infiltrated
• B CR, with detectable PCR bcl-2
• Rituximab 375mg/m2 X 4 weekly doses 3 months p
  transplant
• Results
• A OR at 71 at 12,24,36 months
• B MR 52 at 5weeks, 46 at 36 months

Morschhauser, F et al. Rituximab given after
High Dose Therapy and Autologous Stem Cell
Transplantation Induces Durable Clearance of
Minimal Residual Disease in about Half of the
Patients with Follicular Non- Hodgkins Lymphoma
36 months of a Multicenter Open Label Phase II
Trial. ASH 2004 Abstract 747
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High- Dose Chemo with SCT 1st line
-307 Previously untreated young (18-59yo) with
FL, MCL, or lymphoplasmacytic lymphoma
randomized -B symptoms, cytopenias, PD, bulky
disease -CHOP or MCP 4 cycles if CR, or addl 2
cycles - Had to have PR or CR
Georg Lenz, et al. Myeloablative
radiochemotherapy followed by autologous stem
cell transplantation in first remission prolongs
progression-free survival in follicular lymphoma
results of a prospective, randomized trial of the
German Low-Grade Lymphoma Study Group Blood, Nov
2004 104 2667 - 2674.
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Progression- Free Survival
Overall Survival
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Allogeneic SCT

• How about allo transplant?

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Auto vs. Allo
Relapses
Treatment related mortality
AutKoen van Besien, et al, Comparison of
autologous and allogeneic hematopoietic stem cell
transplantation for follicular lymphoma Blood,
Nov 2003 102 3521 - 3529.
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Conclusions

• Heterogeneity in clinical course in FCL
• FLIPI can help predict prognosis
• Immediate Treatment never has been shown to
  improve survival
• Multiagent chemo or chemo/Ab therapies
  demonstrate longer TTP and RR but not OS
• Does not imply they do not extend life, simply
  they do not extend life with upfront use!
• High- dose chemo in first relapse in a fit,
  responding subset of patients improves OS in one
  trial
• Allogeneic Transplant leads to prolonged
  remissions, but high upfront mortality

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Up and Coming Strategies

• Anti- Id vaccines

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Accessory cells may dictate outcome

• In data presented at ASH review, two gene
  expression signatures were defined, both from
  non- lymphoma cells
• T cell signature genes with a survival advantage
• Macropage signature genes with inferior survival