Radiation Oncology/NHL/Follicular

Overview

• Accounts for ~22% of NHLs (2nd most common after DLBCL)
• Incidence increasing at ~4% per year
• Mean age at diagnosis 60
• Less common in Asians and Blacks; more common with "Western" lifestyle
• Presenting symptoms: painless peripheral adenopathy, which can wax and wane in size
• Malignancy grades defined by proportion of centroblasts (large cells)
  • Grade 1-3a: various proportion of centroblasts - indolent
  • Grade 3b: all centroblasts - aggressive (behaves like DLBCL, and should be treated as such)
• Extent of disease at diagnosis
  • Stage I: 10-15%
  • Stage II: 85-90%
  • Frequently have extranodal involvement: bone marrow, spleen, liver in about 1/3 to 1/2.
  • B symptoms: ~20%
• Clinical course is variable
  • Some with indolent clinical course and late relapses over many years
  • Others with rapid disease progression, often with transformation to aggressive lymphoma and early death
• Median survival 10 years. Considered incurable.
• Histologic transformation to aggressive (DLBCL) in ~25%

Pathology

• Arise from germinal center B-cells
• Mixture of centrocytes (small cleaved cells) and centroblasts (large cells)
  • Grade 1: 0-5 large cells per hpf (used to be classified as follicular small-cleaved cell)
  • Grade 2: 6-15 large cells per hpf (used to be classified as follicular mixed small-cleaved and large cell)
  • Grade 3a: >15 large cells per hpf, but centrocytes present
  • Grade 3b: >15 large cells per hpf, no centrocytes (used to be classified as follicular large cell)
• Two variants, relationship to typical follicular lymphoma controversial
  • Cutaneous follicle center lymphoma
  • Diffuse follicle center lymphoma.

Rappaport classification: nodular poorly differentiated lymphocytic, nodular mixed
Working Formulation: follicular small cleaved, follicular mixed

• One model of disease development (based on PMID 17301308 and PMID 17043145 below)
  • t(14;18) translocation occurs in healthy persons after activation (after undergoing Ig class-switch recombination during germinal-center response to antigenic stimulation)
  • t(14;18) translocation results in bcl-2, a re-arranged gene whose product blocks apoptosis
  • These cells are not naive (as previously thought) but capable of responding to an exogenous stimulus (such as virus or auto-antigen)
  • A clone of t(14;18) can be detected in >50% of healthy persons, and persists >3 years. These may be memory B cells, circulating after initial stimulation
  • In rare cases, can see pronounced peripheral blood B lymphocytosis (often secondary to infection), with clonal expansion of t(14;18)
  • Further events may lead to transformation. These may be oncogenic events ("hits") or may be related to stimulation via IgM receptors by T-cells. Predictive gene-array data at time of diagnosis suggest that random acquisition of oncogenic events does not play a large role in determining survival. Rather, it seems to be driven by B-cell interactions with non-malignant environment
  • Can see in-situ follicular lymphoma, with histologically abnormal follicles, on LN biopsy. This may progress to overt follicular lymphoma, but may remain benign
  • Further, there appear 2 separate disease processes (PMID 15548776): indolent (~75% of cases, with median survival of >10 years) and aggressive (~25% of cases, with median survival ~4 years). This gene-array modelling agrees with Stanford watchful waiting outcome (PMID 15024027)
  • This two-disease model, may be driven by mutually exclusive pathways:
    • 1) -6q/+1q
    • 2) duplication(18), +7/+8
  • Depending on the environmental interplay, lymphoma may regress spontaneously
  • t(14;18) in normal persons can therefore be seen as an early marker of lymphoma risk

• St. Bartholomew, 2007 (UK) PMID 17278262 -- "Transformation of follicular lymphoma to diffuse large B-cell lymphoma proceeds by distinct oncogenic mechanisms." (Davies AJ, Br J Haematol. 2007 Jan;136(2):286-93.)
  • Gene expression profiles of 20 patients who transformed (pre- and post- biopsies)
  • Conclusion: Two separate mechanisms; one via high proliferation characterised by presence of known oncogenic abnormalities, and second with similar behavior to the existing FL

• Netherlands, 2007 PMID 17200149 -- "Gene-expression and immunohistochemical study of specific T-cell subsets and accessory cell types in the transformation and prognosis of follicular lymphoma." (Glas AM, J Clin Oncol. 2007 Feb 1;25(4):390-8.)
  • Gene level: highly uniform by gene arrays. Cell level: high discrimination by IHC for transformation phenotype
  • By ICH, 2 cell populations: "cold" and "activated". Activated much more likely to transform to aggressive (DLBCL) lymphoma
  • Conclusion: FL is an immunologically functional disease, highly uniform at time of diagnosis, but where interaction between the tumor cells and the environment determines clinical aggressiveness

• Marseille, 2006 (France) PMID 17043145 -- "Follicular lymphoma-like B cells in healthy individuals: a novel intermediate step in early lymphomagenesis." (Roulland S, J Exp Med. 2006 Oct 30;203(11):2425-31.)
  • A new model for development of follicular lymphoma proposed

• NCI, 2004 PMID 15548776 -- "Prediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells." (Dave SS, N Engl J Med. 2004 Nov 18;351(21):2159-69.)
  • Gene expression profiles. 191 biopsy specimens, 95 used for supervised expression patterns, 96 validating set
  • Two signatures constructed for survival prediction: quartilies median survival 13.6, 11.1, 10.8, and 3.9 years
  • Discriminant gene expression: non-malignant tumor-infiltrating cells
  • Conclusion: 75% of cases indolent disease with >10 year survival, 25% cases aggressive disease with 4 year survival

Natural history

• Stanford, 2005 - PMID 15024027 — "Stage I and II Follicular Non-Hodgkin’s Lymphoma: Long-Term Follow-Up of No Initial Therapy." Advani R et al. J Clin Oncol. 2004 Apr 15;22(8):1454-9.
  • Retrospective. Follicular small cleaved and follicular mixed. 43 pts with therapy deferred at least 3 months after diagnosis and minimum follow-up of 1 year.
  • Median follow-up 86 months. 63% had not been treated. Median time to treatment was 22 months. 4 of 16 transformed to higher grade. Survival at 5, 10, and 20 years was 97%, 85%, and 22%.
  • Conclusion: Delayed therapy is appropriate in selected pts.

Prognostic Factors

• FLIPI: Follicular Lymphoma International Prognostic Index - basically an adaptation of the IPI (which is used for aggressive lymphomas) for low grade lymphomas.
  • Abstract — "Follicular lymphoma international prognostic index." Solal-Celigny P et al. Blood. 2004 Sep 1;104(5):1258-65.

FLIPI

Risk Factors: Five factors calculate FLIPI risk
1. Age > 60 years	low risk
2. Ann Arbor stage III-IV	0-1 factors
3. Hemoglobin < 12 g/dL	intermediate risk
4. Number of nodal areas - 5 or more	2 factors
5. LDH > normal limits	high risk
	3+ factors

• MD Anderson, 1984 Follicular large cell lymphoma - PMID 6376721 Full text, 1984 (1973-81) — "Follicular large cell lymphoma: analysis and prognostic factors in 62 patients." Kantarjian HM et al. J Clin Oncol. 1984 Jul;2(7):811-9.

• GELA, 1999 (France) (1986-95) - PMID 10561315 — "Low-grade stage III-IV follicular lymphoma: multivariate analysis of prognostic factors in 484 patients--a study of the groupe d'Etude des lymphomes de l'Adulte." Decaudin D et al. J Clin Oncol. 1999 Aug;17(8):2499-505.
  • 284 pts treated on two Phase III trials. Stage III-IV.
  • 3 factors significant on multivariate analysis: B symptoms, age > 60, at least 3 nodal sites > 3 cm. IPI score was prognostic, but very few pts had high IPI scores.

Ongoing trials:

• SWOG S0016 - phase III. CHOP vs CHOP + Rituxan (R-CHOP) vs CHOP + I131-tositumomab (Bexxar) for newly diagnosed follicular NHL. CHOP alone arm closed to accrual early (Dec 2002).

Management Overview

• For Stage I-II, radiotherapy is standard. However, long-term data from Stanford suggest that in select patients, active surveillance may be a reasonable approach
• For advanced disease, treatment is deferred until the patient becomes symptomatic. Randomized trials of chemotherapy showed no survival advantage to early treatment thus far

Stage I-II

Watchful Waiting

• Stanford, 2005 - PMID 15024027 — "Stage I and II Follicular Non-Hodgkin’s Lymphoma: Long-Term Follow-Up of No Initial Therapy." (Advani R et al. J Clin Oncol. 2004 Apr 15;22(8):1454-9.)
  • Retrospective. Indolent follicular (follicular small cleaved and follicular mixed). 43 patients with therapy deferred at least 3 months after diagnosis and minimum follow-up of 1 year. Median follow-up 7.2 years.
  • Outcome: 63% not treated. 10-year OS: 85%, 15-year OS: 58%. Estimated median OS 19 years
  • Progression: 16 patients (8 progression, 4 transformation to aggressive). If progression, median time to treatment 22 months. Median time to transformation 7.8 years
  • Conclusion: Delayed therapy is appropriate in selected patients

RT alone

• Stanford, 1996 (1961-94) - PMID 8648385 — "Is radiotherapy curative for stage I and II low-grade follicular lymphoma? Results of a long-term follow-up study of patients treated at Stanford University." Mac Manus MP et al. J Clin Oncol. 1996 Apr;14(4):1282-90.
  • Retrospective. Stage I-II. RT was involved field, extended field, TLI, or STLI.
  • Median f/u 7.7 yrs. 10-yr OS 64%. MS 13.8 yrs. 10-yr RFS 44%. Pts are unlikely to relapse after 10 years.

Chemo-RT

• MD Anderson, 2003 (1984-1992) PMID 12775737 -- "Long-term follow-up of a prospective study of combined modality therapy for stage I-II indolent non-Hodgkin's lymphoma." (Seymour JF, J Clin Oncol. 2003 Jun 1;21(11):2115-22.)
  • Prospective. 102 patients, Stage I-II low grade (follicular 83%, bulky >5cm 24%, Stage II 52%). Treated with risk-adapted COP-Bleo/CHOP-Bleo and RT 30-40 Gy IF. Median F/U 10 years
  • 10-year outcome: OS 82% (follicular 80%); DFS 76% (follicular 72%). After relapse, 10-year survival 46%
  • Toxicity: acute 10% hospitalization, long term 12 malignancies (4 in RT fields)
  • Conclusion: CMT better DFS and OS than previously reported RT alone

Rituxan-based

• PMID 15483015 — "Prolonged clinical and molecular remission in patients with low-grade or follicular non-Hodgkin's lymphoma treated with rituximab plus CHOP chemotherapy: 9-year follow-up." Czuczman MS et al. J Clin Oncol. 2004 Dec 1;22(23):4711-6.
  • CHOP + Rituxan

Stage III-IV

Radiation

• Heidelberg; 2010 PMID 20331739 -- "Clinical outcome of patients with follicular lymphoma and bulky disease after Rituximab-CHOP immunochemotherapy with and without consolidating radiotherapy." (Fabienne M, Eur J Haematol. 2010 Mar 16. [Epub ahead of print])
  • Retrospective. Subset analysis of RCT evaluating number of Rituximab cycles with CHOP x6. 42 patients with bulky disease, protocol specified IRFT but some did not receive it (62% IFRT, 38% no RT). Median F/U 5 years
  • Outcome: Relapse RT+ 46% (50% within original bulk) vs RT- 56% (NS). 6-year PFS 52% vs 48% (NS), 6-year OS 80% vs 73% (NS)
  • Conclusion: In patients treated with CHOP-R, no difference in control regardless if IFRT was used

Rituxan

• Multi-national -- CVP vs R-CVP
  • Randomized. 321 patients, CD20+ Stage III-IV folicullar lymphoma requiring therapy. Arm 1) cyclophosphamide, vincristine, prednisone (CVP) vs. Arm 2) CVP, rituximab (R-CVP)
  • 2008 PMID 18662969 -- "Phase III study of R-CVP compared with cyclophosphamide, vincristine, and prednisone alone in patients with previously untreated advanced follicular lymphoma." (Marcus R, J Clin Oncol. 2008 Oct 1;26(28):4579-86. Epub 2008 Jul 28.) Median F/U 4.4 years
    • Outcome: 4-year OS CVP 77% vs. R-CVP 83% (SS); median TTF (SS) CVP 7 months vs. R-CVP 27 months (SS). Improvement regardless of FLIPI, IPI, B-symptoms, or bulky disease
    • Conclusion: Adding Rituximab to CVP improves all outcome measures, including OS

• Multi-national -- Zevalin consolidation
  • Randomized trial of 414 pts with stage III/IV follicular lymphoma with a CR or PR after first line induction therapy. Allowed a variety of first line therapies, CVP, CHOP, CHOP-like, fludarabine, rituximab.
  • 2008 PMID 18854568 -- "Phase III trial of consolidation therapy with yttrium-90-ibritumomab tiuxetan compared with no additional therapy after first remission in advanced follicular lymphoma." (Morschhauser F, J Clin Oncol. 2008 Nov 10;26(32):5156-64.) Median f/u 3.5 yrs.
    • Patients randomized to zevalin vs no further treatment.
    • A significant increase in PFS was seen with zevalin (36.5 vs 13 months). Benefit for treatment was zevalin was seen regardless of initial CR or PR.

Ongoing trials:

• SWOG S0016
  • Bulky stage II, Stage III-IV, previously untreated.
  • Randomized to: 1) CHOP, 2) CHOP + Rituxan, 3) CHOP + I-131 Tositumomab (Bexxar).

Palliation

• Standard treatment: Limited fields to 20 Gy in 10 fractions
• Low dose treatment: Limited fields to 4 Gy in 2 fractions (2x2)
  • Initially evaluated because:
    • There is no clear dose-response relationship in localized low-grade NHL
    • Low-dose (1.5-2.0 Gy) fractionated TBI resulted in long-term survival in advanced disease patients
    • Good long-term control in patients who stopped treatment for convenience after 5-7 Gy
  • Response rate is ~80-90%, with CR rate ~50-60%, and good local long-term control
  • Response is rapid, typically within a week. Median time-to-progression is >1 year in recurrent/chemo refractory patients
  • Gene-expression profiling showes strong p53-mediated induction of apoptotic pathways
• For spinal cord compression, consider one of the standard (8/1 or 20/5 or 30/10) regimens

Low dose RT:

• Review: France, 2010 PMID 20970029 -- "Localized low-dose radiotherapy for follicular lymphoma: history, clinical results, mechanisms of action, and future outlooks." (Ganem G, Int J Radiat Oncol Biol Phys. 2010 Nov 15;78(4):975-82.)

• Amsterdam
  • 2007 PMID 17483295 -- "In vivo p53 response and immune reaction underlie highly effective low-dose radiotherapy in follicular lymphoma." (Knoops L, Blood. 2007 Aug 15;110(4):1116-22.)
    • Microarray gene-expression profiling of biopsies pre- and post- low-dose RT
    • Outcome: Major induction of p53 target genes involved in cell-cycle arrest and apoptosis, as well as macrophage activation and TH1 immune response
    • Conclusion: Radiation-induced p53 apoptotic response, not immunologically silent
  • 2005 PMID 16039113 -- "Effective palliation by low dose local radiotherapy for recurrent and/or chemotherapy refractory non-follicular lymphoma patients." (Haas RL, Eur J Cancer. 2005 Aug;41(12):1724-30.)
    • Retrospective. 71 non-follicular lymphoma patients (SLL/CLL 23, marginal zone 18, mantle cell 17, DLBCL 13), 177 symptomatic sites. Bulky disease 73%. Low dose IFRT 4 Gy in 2 fractions.
    • Outcome: Response rate 87% (48% CR). Median time-to-local progression 1.8 years. At time of death, 70% without in-field progression
    • Prognostic factors: none identified
    • Conclusion: Low dose RT valuable in relapsed/chemo refractory disease, both indolent and aggresive lymphoma
  • 2003 PMID 12829665 -- "High response rates and lasting remissions after low-dose involved field radiotherapy in indolent lymphomas." (Haas RL, J Clin Oncol. 2003 Jul 1;21(13):2474-80.)
    • Phase II. 109 patients and 304 symptomatic sites (98 follicular, 9 MALT, 2 lymphoplasmocytoid). Bulky disease (>5cm) 52%. Median 2 prior chemo regimens. Treated with 4 Gy in 2 fractions involved field
    • Outcome: Response rate 92% (CR 61%). Median time-to-progression 1.2 years, to local progression 2 years. If CR time to local progression 3.5 years
    • Conclusion: Low dose IFRT valuable in recurrent low-dose lymphoma

• Denmark; 2002 (1997-99) - PMID 12459371 — "Phase II study of palliative low-dose local radiotherapy in disseminated indolent non-Hodgkin's lymphoma and chronic lymphocytic leukemia." Johannsson J et al. Int J Radiat Oncol Biol Phys. 2002 Dec 1;54(5):1466-70.
  • Phase II. Low dose RT. 22 pts with "indolent" lymphoma or CLL (13 with follicular, 7 with CLL, 1 SLL, 1 other). Treat 2 Gy x 2 = 4 Gy.
  • Outcome: Response rate 87% (CR in 65%, PR in 22%). For pts with CLL, response rate 71%. Median duration of response 22 months.
  • Conclusion: Low dose RT is effective for palliation.

• Gustave Roussy; 2001 (1987-1998) PMID 11516864 -- "A high and sustained response rate in refractory or relapsing low-grade lymphoma masses after low-dose radiation: analysis of predictive parameters of response to treatment." (Girinsky T, Int J Radiat Oncol Biol Phys. 2001 Sep 1;51(1):148-55.)
  • Retrospective. 48 patients with low-grade lymphoma, most advanced disease previously treated with chemo. 135 tumor sites (80% nodal, 20% extranodal) treated with 4 Gy in 2 fractions.
  • Outcome: Response rate 81% (CR 57%). 2-year FFLP 56%
  • Predictors: tumor <=5cm (51% vs. 27%), less pretreatment chemo (96% vs. 48%), age <=65
  • Conclusion: Low-dose RT efficient, particularly prior to chemotherapy

• Le Mans; 1994 (France) PMID 8194839 -- "Potential role for low dose limited-field radiation therapy (2 x 2 grays) in advanced low-grade non-Hodgkin's lymphomas." (Ganem G, Hematol Oncol. 1994 Jan-Feb;12(1):1-8.)
  • Prospective. 27/37 patients, 22 with Stage III/IV disease. 19 patients one course of LD RT only, 8 patients subsequent boost LD RT. Limited field RT 4 Gy in 2 fractions
  • Outcome: Response 89% (CR 37%); if 2+ LD RT courses, CR was 75%
  • Toxicity: minimal
  • Conclusion: Low dose limited field RT shows high proportion of responses

Reviews

• JCO 2005 - PMID 16155025 — "Treatment Strategies in Follicular Lymphomas: Current Status and Future Perspectives." Hiddemann W et al. Journal of Clinical Oncology, Vol 23, No 26 (September 10), 2005: pp. 6394-6399.