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 2: Follicular Lymphoma International Prognostic Index Update (2012) PMID: 19652063 — "Follicular lymphoma international prognostic index 2: a new prognostic index for follicular lymphoma developed by the international follicular lymphoma prognostic factor project." Federico et al. J Clin Oncol. 2009 Sept 20;27(27).

FLIPI2: The following factors were found to be predictive of outcome in patients with follicular lymphoma:

Age > 60

Largest diameter of largest involved node > 6 cm

bone marrow involvement

β2-microglobulin > upper limit normal

serum hemoglobin level < 12 g/dl

Low risk = 0 risk factors, 5 year PFS 79.5%

int risk = 1-2, 51.2%

High risk = 3-5, 18.8%

• 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.

RT dose

• UK FORT (2006 - 2011) -- 24 Gy vs 4 Gy
  • Randomized, multinstitutional 43 centers in UK. 614 patient, age >18, follicular or marginal zone lymphoma, both radical and palliative intent. Arm 1) 24/12 vs Arm 2) 4/2 (4 Gy in 2 fractions)
    • Long-term update 2021 PMID 33539729 — "4 Gy versus 24 Gy radiotherapy for follicular and marginal zone lymphoma (FoRT): long-term follow-up of a multicentre, randomised, phase 3, non-inferiority trial." Hoskin P, et al. Lancet Oncol. 2021 Mar;22(3):332-340.
      • pending...
    • 2014 PMID 24572077 — "4 Gy versus 24 Gy radiotherapy for patients with indolent lymphoma (FORT): a randomised phase 3 non-inferiority trial." (Hoskin PJ, Lancet Oncol. 2014 Apr;15(4):457-63. doi: 10.1016/S1470-2045(14)70036-1. Epub 2014 Feb 24.). Median F/U 2.2 years
    • Outcome: Local progression 24 Gy 7% vs 4 Gy 22%. Time to local progression in 4 Gy worse than 24 Gy (HR 3.4, SS).
    • Acute grade 3-4 toxicity: 24 Gy 3% vs 4 Gy 1%
    • Conclusion: 24 Gy in 12 fraction is more effective for indolent lymphoma. However, 4 Gy remains a useful alternative for palliative treatment

• UK Multicenter -- 45-45 Gy vs 24 Gy
  • Randomized dose-finding for NHL (primarily follicular and marginal zone). RT involved region. Randomized to 40-45 Gy versus 24 Gy in 12 fractions (indolent) or 30 Gy in 15 fractions (aggressive).
  • 2011 PMID 21664710 — "Reduced dose radiotherapy for local control in non-Hodgkin lymphoma: a randomised phase III trial." (Lowry et al. Radiother Oncol. 2011 Jul;100(1):86-92.)
    • Median f/u 5.6 yrs. Progression-free and overall survival equivalent between low- and high-dose arms. No difference of in-field progression (HR 1.09 in indolent, and HR 0.98 in aggressive)
    • Toxicity: No difference but trend toward reduced toxicities in low dose arms
    • Conclusion: 24 Gy in 12 fractions effective for indolent NHL, and 30 Gy in 15 fractions for aggressive NHL

• Florida, 1999 PMID 10348285 -- "The impact of radiotherapy dose and other treatment-related and clinical factors on in-field control in stage I and II non-Hodgkin's lymphoma." (Kamath SS, Int J Radiat Oncol Biol Phys. 1999 Jun 1;44(3):563-8.)
  • See also page at: Radiation_Oncology/NHL/Treatment_high_grade
  • 285 pts w/ Stage I-II NHL (72 low grade, 92 intermediate to high grade, 21 unclassified). 159 treated w/ RT alone, 126 combined modality. 95 treatment failures with 12 in-field failures. Most failures occurred in contiguous non-irradiated areas.
  • Conclusion: "Our analysis suggests that the overwhelming problem in the treatment of non-Hodgkin's lymphoma is not in-field failure but, rather, failure in contiguous unirradiated sites. A dose of 20-25 Gy may be sufficient for small-volume LGL of the orbit. A dose of 30 Gy is sufficient for LGL in general"

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
    • However, a randomized trial (FoRT) shows that the low dose RT regimen is inferior to 24 Gy in 12 fractions
  • 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

Randomized:

• FoRT - 24/12 vs 4/2
  • Randomized, non-inferiority trial. 548 pts (614 treatment sites) with FL or MZL requiring either palliative or radical RT. Closed early (short of 650 treatment sites). FL in 86%, MZL in 14%. Curative in 40%, palliative in 60%. Stage I-II in 63%, Stage III-IV in 37%. Prior chemo in 33%, prior RT in 24%.
  • 2012 ASTRO #LBA 3 PDF -- "FoRT: A Phase 3 Multi-Center Prospective Randomized Trial of Low Dose Radiation Therapy for Follicular and Marginal Zone Lymphoma" (Hoskin P, Int J Radiat Oncol Biol Phys Vol. 85, Issue 1, Page 22)
  • Median f/u 22.8 mo. Response rate: 24 Gy - 81% overall, 60.3% CR; 4 Gy - 74.1%, 44.3% CR (SS). Local progression free survival rate at 2 yrs: 93.7% (24 Gy) vs 80.4% (4 Gy). No OS difference.
  • Toxicity: limited in both arms -- Acute G3+ in 8 pts vs 5 pts; Late G3+ in 9 pts vs 6 pts. No overall difference in QOL.
  • Conclusion: "While 4 Gy in 2 fractions can be effective in the palliative setting, it is significantly inferior to 24 Gy in 12 fractions which should remain the schedule of choice for curative radiation therapy in follicular or marginal zone lymphoma."

Non-randomized:

• 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.

• CTO 2014 - "Radiotherapy of Follicular Lymphoma: Updated Role and New Rules" Yahalom J. Current Treatment Options in Oncology (2014) 15:262 DOI 10.1007/s11864-014-0286-4