East Midlands Cancer Network Guidelines for the Management of Follicular NHL

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1 East Midlands Cancer Network Guidelines for the Management of Follicular NHL Written by: Dr Matthew Lyttelton, Professor Martin Dyer, Dr Andrew Haynes Consultation Group: EMCN Haematology NSSG Summary Whilst the diagnosis of follicular lymphoma usually poses few problems, selection of optimal treatments remains fraught, with little evidence base to aid decisions for many patients both for first-line and relapse therapies. Choice of therapy is complicated by the very variable natural history of the disease and the lack of objective prognostic factors. Although there have been significant improvements in outcomes, chemoimmunotherapy remains palliative rather than curative for most patients. Two important documents are published in a) The PRIMA study shows that the addition of maintenance rituximab after first-line therapy improves outcomes (PFS Hazard Ratio 0.55 CI Salles G et al, Lancet 2010 Lancet Jan 1; 377(9759):42-51), and therefore the recommendation of the EM NSSG is that this is implemented forthwith. b) The BCSH guidelines for follicular lymphoma should be published in the BJH Q and will be available on the BCSH website ( These guidelines should be used to supplement the treatment guidelines here where necessary. Diagnostic Criteria Histology Usually follicular architecture with BCL2+ follicles, but cases may be follicular and diffuse, or entirely diffuse. Sclerosis within the involved lymph node has been associated with a poor prognosis. Like other haematological malignancies, P53 mutations define a small but poor risk group in follicular lymphoma and therefore should be sought at diagnosis as this group may benefit from alternative therapeutic approaches. Written By: M Lyttelton, M Dyer, A Haynes Authorised by: EMCDAG Page Number: 1/15

2 Unlike most other haematological diseases, follicular lymphoma lacks any objective laboratory prognostic markers that indicate when to start treatment or indicate likely responses. Histological transformation to diffuse large B-cell lymphoma (DLBCL) may occur at any stage of the disease; this may occur via a variety of different genetic mechanisms. The annual incidence of transformation is approx 3% - this rate appears to remain static for several years and may plateau with time. There is currently no means of predicting when this may occur. Immunophenotype Germinal centre phenotype is usual: CD10+, CD20+, CD22+, CD23 neg, BCL2+ BCL6+. MIB1 (Ki67) is usually low and is not of prognostic significance. CD10 expression may be lost on cells with the blood or the bone marrow, which may complicate diagnosis in patients with only haematological disease. Follicular structure should be confirmed by using CD21 to show the follicular dendritic cell (FDC) network. 85% of cases express high levels of BCL2 protein, due to the presence of t (14; 18) (q32; q21). Other cases may express high-level BCL2 due to genomic amplification of the locus. If BCL2- or other atypical features (e.g. loss of germinal centre markers, or diffuse morphology), molecular evidence for cryptic BCL2/IGH translocation along with molecular evidence for clonality should be sought. BCL2 expression may be lost as a consequence of BCL2 mutations. Haematological Malignancy Diagnostic Service (HMDS) Review All cases of FCC NHL should be reviewed by the relevant service (Nottingham HMDS or Leicester HMDL). This is especially important for variants such as diffuse FCC NHL, FCC NHL with sclerosis, and grade 3a and 3b. Variants and subtypes Grade 1 & 2 should be treated identically. There is no evidence for a difference in outcome. FCC NHL Grade 3a: management of is controversial. It should probably be treated in the same way as FCC NHL grade 1 & 2, but there may sometimes be concerns about distinguishing from grade 3b. FCC NHL Grade 3b should be treated as DLBCL. After anthracycline containing chemotherapy combinations, long term PFS is better than for FCC NHL grade 1-2, although some series still detect continuing relapse especially in those with advanced stage disease. Cutaneous follicular NHL: o BCL2 negative: is considered a separate disease entity and is not included in this guidance. All such case should be referred to the appropriate Cutaneous lymphoma MDT. Written By: M Lyttelton, M Dyer, A Haynes Authorised by: EMCDAG Page Number: 2/15

3 o BCL2+ is likely to be associated with systemic follicular lymphoma and should be investigated and treated according to this guideline Diagnostic and Staging Investigations Biopsy is always required both at diagnosis and at relapse. Preferably excision biopsy of site of bulkiest disease especially if bulky / raised LDH CT guided trucut needle biopsy if adequate peripheral node not available. Repeat biopsy may be indicated if there is a clinical suspicion of transformation to DLBCL. Full clinical examination including Waldeyer s ring FBC, film review and immunophenotyping if lymphocytosis U&E, LFT, Ca, LDH, β2m Immunoglobulin levels and paraprotein screen HBV; HCV BM aspirate and biopsy including immunophenotyping. Trephine biopsy >2cm is required for exclusion of bone marrow involvement in early stage disease CT body with oral and IV contrast unless contraindicated Head & Neck imaging if clinical suspicion for H&N involvement: CT or MRI according to local practice If clinical suspicion of CNS involvement (almost always in presence of high grade transformation) MRI Head and spine with contrast LP with cytological and flow cytometric examination Stage I & II patients who will be considered for potentially curative IFRT FDG PET/CT BM (at least 2 cm trephine) PB t (14; 18) and IGHV PCR may be helpful in assessing possible lowlevel disease at these sites. The role for 18 FDG-PET/CT in follicular lymphoma in other clinical situations is less well defined. It may be helpful in selecting the most 18 FDG avid area for biopsy (although high avidity is seen in low grade disease). It may be indicated for assessing quality of response after completion of treatment. It should be routinely performed in patients prior to allogeneic BMT to assist in monitoring post transplantation. Written By: M Lyttelton, M Dyer, A Haynes Authorised by: EMCDAG Page Number: 3/15

4 Prognostic Factors FLIPI or FLIPI 2 Score should be collected in all cases, although evidence for modifying treatment on basis of FLIPI is limited at present FLIPI INDICES Age >60 Stage III-IV Hb <12 LDH > ULN Number of nodal sites >=5 Individual sites =right cervical; left cervical; mediastinal; right axillary; left axillary; right epitrochlear; left epitrochlear; mesenteric; paraaortic; right inguinal; left inguinal Buske Blood : FLIPI 2 INDICES Age >60 Hb <12 Bone marrow involved Β2 microglobulin elevated Longest diameter largest involved node >6cm Federico JCO 2009 Sep 20;27(27): FLIPI 2 SCORE 3 YEAR PFS (%) LOW (0) 91 INTERMEDIATE (1-2) 69 HIGH (>=3) 51 Minimum Data Set FCC Grade Clinical Stage Bone marrow involved Diameter largest node PS FLIPI 1 or 2 score Written By: M Lyttelton, M Dyer, A Haynes Authorised by: EMCDAG Page Number: 4/15

5 First Line Treatment Whenever possible patients should be offered entry into any relevant clinical trials (c.f. appendix 2) Early Stage Involved Field Radiotherapy (FDG-PET/CT Negative Limited Stage Disease) 24 Gy 12# No current evidence to support combined modality Excision alone if non-bulky, low FLIPI / FLIPI2, and / or patient preference due to local toxicity Asymptomatic Advanced Stage Watch and Wait Monitoring; initial review at 6 weeks, then 3 monthly till repeat scan, with option to decrease frequency of review thereafter. Frequency of review and imaging may be increased depending on symptoms, LDH, bulk, but at minimum rescan at 6-12 months. Repeat involved bone marrow only if deterioration in FBC. Consider early referral for oocyte collection where appropriate Criteria for Withholding Treatment lack of major symptoms (n.b. fatigue is a common associated symptom and it will be a matter of clinical judgement and patient preference whether to initiate treatment) no cytopenias due to lymphoma (neuts >1.0; plts >100 Hb >10) no bulky disease (>7cm diameter; or >3x >3cm ) no compromised organ function due to lymphoma no raised LDH FLIPI is not a proven criterion for initiating treatment, but closer monitoring may be required patient agreement Written By: M Lyttelton, M Dyer, A Haynes Authorised by: EMCDAG Page Number: 5/15

6 Symptomatic Advanced Stage Induction Consider early referral for oocyte collection where appropriate, if delay is clinically acceptable Good Performance Status / Low Comorbidity There is no compelling evidence to support one particular chemotherapy combination over another for first line therapy. In particular, there is no evidence that the addition of anthracyclines to first-line combination chemotherapy improves outcome. However, this may change with further analysis of the PRIMA data as mentioned below. Use of anthracyclines first-line may limit options at subsequent relapse or at transformation to DLBCL, but also potentially improves the depth of remissions and may permit more effective maintenance therapy with single agent rituximab as described below. R CVP or RCHOP (mainly indicated in presence of bulky disease, raised LDH or other clinical suspicion high grade transformation) are recommended in accordance with NICE guidance (Marcus Blood : ; Hiddeman Blood : ; NICE TAG ). o 6-8 cycles depending on response 3-4 and 6 cycles R FMD may be considered providing future PBSCH is not anticipated, and concern about specific RCVP or RCHOP toxicities (e.g. neuropathy or cardiac.) It is not preferred as first line therapy because repeat treatment with fludarabine containing regimen is problematic owing to stem cell toxicity. Preliminary data on R-Bendamustine (Rummel Blood :168), suggesting superiority to R CHOP are promising but need validation before this can be recommended as first line therapy. Poor Performance Status / High Comorbidity Single agent chlorambucil Clinical trials of novel targeted therapeutic antibodies/small molecules DXT to bulky disease, including low dose 4Gy Cons olidation / Maintenance NICE pronouncement on maintenance rituximab following first-line therapy for follicular lymphoma is anticipated April However, the view of the EM NSSG, based on evidence from the PRIMA study, is that maintenance rituximab should now be offered to our patients who fulfill the following criteria:- Written By: M Lyttelton, M Dyer, A Haynes Authorised by: EMCDAG Page Number: 6/15

7 At least PR following induction therapy HBV negative IgG > 3.0g/l and/or lack of opportunistic infections Patients fulfilling these criteria will be offered maintenance rituximab. First remission maintenance rituximab schedule 375mg / m 2 2 monthly for 2 years. Baseline and 6 monthly Ig s Full restaging including CT (and bm if involved before start of mainteneance) after 12 months and 24 months maintenance. These patients will require close monitoring of efficacy and toxicities. An EM-wide audit will be performed on these patients following the first year of introduction of this therapy. There are no proscribed guidelines for monitoring responses following maintenance therapy in first remission and these will have to be part of the audit. (see appendix 4 for audit proforma) Radioimmunotherapy (RIT): there are insufficient data on RIT consolidation following rituximab-containing regimens to support its routine use in first-line or in any other setting outside of clinical trials. Response Assessment CT / MRI of involved sites 4 weeks after last cycle treatment. Documentation of symptoms and clinical examination. Bone marrow biopsy if involved at presentation There is no evidence to support the use of MRD techniques (t 14; 18 PCR or FCM) to determine further treatment outside a clinical trial. Treatment at First Relapse All patients at relapse should have repeat lymph node biopsy performed. Watch & Wait remains a valid option in patients meeting the standard criteria for this approach at presentation. Involved field radiotherapy may also be an option in certain clinical instances. Induction If rituximab naive, treat according to first line recommendations, and ensure patient is offered maintenance rituximab if at least PR is achieved If long remission (minimum 2 years) following R-Chemo, use alternative R Chemo combination, if toxicity permits (e.g. cardiac toxicity and anthracyclines), and depending on patient age (e.g. consideration of transplantation procedures if relatively short remission) Written By: M Lyttelton, M Dyer, A Haynes Authorised by: EMCDAG Page Number: 7/15

8 If refractory to first line therapy or early relapse post first line therapy, offer the following options o FMD or other fludarabine containing regimen and consider autologous or allogeneic transplantation in suitable patients o dose intensified treatment as for High grade transformation and consider autologous or allogeneic transplantation in suitable patients o radio-immunotherapy if not suitable for intensive chemotherapy, or failure of stem cell harvest o referral to clinical trial if available Maintenance Maintenance rituximab should be offered to all patients achieving 2 nd remission, who were rituximab naive prior to reinduction (van Oers Blood : ; NICE TA ). This should also be offered to patients in second remission after autologous stem cell transplantation. Regimen: 3 monthly for 2 years (notice difference from first-line protocol) o check baseline and 3 monthly Ig s and withhold if IgG < 3g/l or if opportunistic infections o restage at 12 months. If evidence for progression discontinue maintenance. o restaging after completion of maintenance is not indicated unless progression suspected Treatment at Second Relapse consider bendamustine if patient previously treated with both anthracycline containing regimen (RCHOP) and fludarabine containing regimen (FMD) following reinduction, consider autologous or allogeneic transplantation in suitable patients Allogeneic Transplantation C.f. BSBMT guidelines for use of allogeneic BMT in follicular lymphoma ( BSBMT Indications Table June 2010 Autograft Sibling Transplant MUD Transplant CR1 / PR1 GNR GNR GNR CR / PR >1 S CO CO Chemorefractory GNR D D Relapse post GNR CO CO autograft Abbreviations:S = standard of care CO = clinical option, can be considered after assessment of risks and benefits D = developmental, further trials are needed GNR = generally not recommended Written By: M Lyttelton, M Dyer, A Haynes Authorised by: EMCDAG Page Number: 8/15

9 PET-CT scan before allogeneic transplantation is recommended to guide post transplant remission monitoring. Treatment of High grade transformation Transformation to DLBCL must be suspected whenever there is rapidly enlarging lymphadenopathy, high or rising LDH, hypercalcaemia, or sudden increase in symptoms. As at any other relapse, biopsy and preferably excision biopsy is mandatory to confirm. Transformation is an event that has historically been associated with poor prognosis (median survival approx 12 months before the introduction of rituximab), although this has improved with the introduction of rituximab. Transformation at presentation of the lymphoma may be associated with a better outcome. Limited stage DLBCL at transformation is also associated with a better outcome. Evidence for abnormalities of MYC should be sought, as these are associated with very poor outcome in the presence of BCL2/IGH translocations and may influence treatment decisions. Rarely, cases transform to Burkitt lymphoma-like B-cell ALL but differ in the expression of BCL2. The outcome for such patients is dismal. Treatment should follow the same principles as those for treatment of DLBCL (including indications for intrathecal prophylaxis), but with the proviso that treatment will not be curative e.g.: A. Anthracycline naive, and no rituximab exposure within 2 years o RCHOP 6-8 cycles. Consider autologous/allogeneic SCT. B. Other Patients o IVE or ESHAP with a view to very high dose chemotherapy with stem cell rescue or allogeneic transplantation in suitable patients o in patients not eligible for high dose therapy, consider FMD or PMITCEBO or palliative support Monitoring and follow up for patients with follicular lymphoma 3 to 12 monthly follow up generally recommended, according to disease state and patient wishes. Regular review to include FBC UE LFT LDH Specific recommendations regarding follow up scans post therapy are not possible. The need for and frequency of repeat scanning post therapy should be determined by the rate of progression of the disease prior to treatment, the risk of clinically undetectable complications such as hydronephrosis, and likely future treatment options. Owing to the cumulative radiation dose, repeat scanning in the Written By: M Lyttelton, M Dyer, A Haynes Authorised by: EMCDAG Page Number: 9/15

10 asymptomatic patient without clinical evidence of progression should be avoided when possible. Repeat CT scanning is indicated in the event of: recurrent or progressive symptoms recurrent or progressive lymphadenopathy suboptimal response to first line therapy Written By: M Lyttelton, M Dyer, A Haynes Authorised by: EMCDAG Page Number: 10/15

11 Appendix 1 Recommended Network Audits 1. RCVP or RCHOP as first line treatment for advanced stage disease in all patients with good PS with maintenance rituximab. 2. Administration of maintenance rituximab in 2 nd CR patients (rituximab naive at relapse) a. Are Ig levels checked before and during? 3. PET usage a. What proportion early stage patients are staged with PET? b. What proportion patients have PET before biopsy? c. What proportion patients have PET-CT performed to assess response 4. What proportion patients have central histological review, by grade and subtype? Written By: M Lyttelton, M Dyer, A Haynes Authorised by: EMCDAG Page Number: 11/15

12 Appendix 2 Clinical Trials PACIFICO Eligibility: Phase age > 60 (or <60 with anthracycline contraindication) Stage II-IV requiring systemic treatment III Randomisation: (R CVP x8) vs (RFC x4 + ritux x4) All responders to receive maintenance rituximab x12 over 2 years NCRN Yes GAUDI Eligibility: Phase Randomisation: NCRN first line advanced follicular lymphoma 1b no randomization in Leicester all patients receive GA101 CHOP all responders receive GA101 maintenance over 2 years. NO company (Roche) sponsored. BO21223 GA101 Phase 3 trial Eligibility first line advanced follicular lymphoma Phase 3 Randomisation R-chemo (CHOP/CVP/bendamustine) + R maintenance vs GA101-chemo + GA101 maintenance NCRN? Written By: M Lyttelton, M Dyer, A Haynes Authorised by: EMCDAG Page Number: 12/15

13 Appendix 3 PRIMA Study Results from PRIMA were reported June 2010 at ASCO. Please see June%202010/Tracks/Hematologic%20Malignancies/Capsules/8004.aspx for more details The Lancet Vol 377, Jan p42-51 In this Phase 3 international study, patients were able to receive several forms of induction chemotherapy along with rituximab (76% received RCHOP, 21% received RCVP and 3% RFCM), and responding patients were thereafter randomized to maintenance rituximab (375/mg/m 2 ) every two months for two years or to observation alone patients were entered mainly from France and Germany. The study was not powered to detect differences between the different chemotherapy regimens used. Overall, 40% of patients attained a CR, 31% CRu and 28% PR. Planned analysis was undertaken at 2 years. Maintenance rituximab improved PFS by 50% (82% versus 66% for observation alone) as shown in the figures below. Also shown for comparison are comparable data for the use of RCVP in first-line FL. Figure 1A/B preliminary data from the PRIMA study Written By: M Lyttelton, M Dyer, A Haynes Authorised by: EMCDAG Page Number: 13/15

14 Figure 2 initial PFS data from the RCVP study. The benefits of maintenance rituximab in the PRIMA study were obtained without excess toxicities and were seen in all ages of patients and in all FLIPI subgroups. Interestingly, the benefits appeared to be most pronounced in patients receiving RCHOP as opposed to other forms of induction chemotherapy as shown in the figure below. Written By: M Lyttelton, M Dyer, A Haynes Authorised by: EMCDAG Page Number: 14/15

15 Appendix 4 Audit of First Remission Rituximab Maintenance in FCC NHL INITIALS DOB HOSPITAL NUMBER / / Date Stage Grade FLIPI2 Performance Status IgG Level HBV status AT DIAGNOSIS / / INDUCTION DETAILS Start of induction from diagnosis (months) Induction Regimen CR / CRu / PR / Response at completion induction Progression Grade 3-4 toxicity (except haematological) Total cycles PET performed Y/N MONTHS SINCE START REMISSION STATUS PET PEFORMED MAINTENANCE 12 months CR / CRu / PR / Progression Y/N 24 months CR / CRu / PR / Progression Y/N 36 months CR / CRu / PR / Progression Y/N 48 months CR / CRu / PR / Progression Y/N 50 months CR / CRu / PR / Progression Y/N Date of progression / transformation / /20 Remission status to be based on clinical assessment, and imaging according to guidelines MAINTENANCE TOXICITY During maintenance Maintenance stopped early due to toxicity Y/N Number cycles given Within 24 months completion CURRENT REMISSION STATUS CR / CRu / PR / Progression / Transformation Date / /20 Written By: M Lyttelton, M Dyer, A Haynes Authorised by: EMCDAG Page Number: 15/15