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Sie, sies, gitmo revised guidelines for the management of follicular lymphomaSIE, SIES, GITMO revised guidelines for the management of follicular lymphoma Pier Luigi Zinzani,1 Monia Marchetti,2 Atto Billio,3 Giovanni Barosi,4* Angelo Michele Carella,5 Mario Lazzarino,6 Maurizio Martelli,7 Alessandro Rambaldi,8 Luigi Rigacci,9 Corrado Tarella,10 Umberto Vitolo,11 and Sante Tura12 By using the GRADE system, we updated the guidelines for management of follicular cell lymphoma issuedin 2006 from SIE, SIES, and GITMO group. We confirmed our recommendation to frontline chemoimmuno-therapy in patients with Stage III–IV disease and/or high tumor burden. Maintenance rituximab was alsorecommended in responding patients. In patients relapsing after an interval longer than 12 months fromfrontline therapy, we recommended chemoimmunotherapy with non cross-resistant regimens followed byrituximab maintenance. High dose chemotherapy followed by hematopoietic stem cell transplant wasrecommended for young fit patients who achieve a response after salvage chemoimmunotherapy. Am. J.
Hematol. 88:185–192, 2013.
2012 Wiley Periodicals, Inc.
consecutive consensus conferences, the issues were analyzed and dis- Follicular cell lymphoma (FL) is a frequent disorder for cussed according to the nominal group technique, as previously described .
proposed. In order to promote widespread adoption of appropriate clinical practice, the Italian Society of Hematol- Issue 1: Staging (consensus-based recommendations) ogy (SIE), and the affiliate societies SIES (Societa Italiana FL is a (18)F-FDG avid disease, since more than 90% of di Ematologia Sperimentale) and GITMO (Gruppo Italiano patients with FL show a PET positive disease and sensitiv- Trapianto Midollo Osseo) established regular updating of ity of staging PET is usually higher than 95% [6–9]. Pub- published guidelines. Previous guidelines addressed indo- lished literature includes 10 retrospective analyses [9–18] lent non-Hodgkin's lymphomas (NHL) , but more recently, and 1 prospective one : pooled analysis of 356 patients specific treatment options were devoted to FL; therefore, revealed that 24% were upstaged from Stage I–II to Stage current guidelines are specifically directed to the manage- III–IV. Baseline PET also showed to have a high prognostic ment of FL. In the 2008 WHO classification, grade 3b FL were separated and are universally treated as diffuse large reported the clinical outcomes in patients in which the ther- B-cell lymphoma (DLBCL) . Therefore, the present guide- apy was adjusted according to a PET-staged disease. The lines targeted grade 1-2-3a FL. We used the GRADE assessment of bone marrow involvement by PET is not reli- (grades of recommendation, assessment, development, able due to low sensitivity [8,9,20]. Globally, the analyzed and evaluation) system , which is based on a sequential studies showed a moderate quality.
assessment of the quality of evidence followed by an analy- The predictive role of pretreatment BCL2/IgH levels in sis of the benefit-risk balance and subsequent judgment bone marrow and peripheral blood is still controversial. In a about the strength of recommendations.
seminal study, Rambaldi et al.  showed that the pres- Guidelines development process.
The Advisory Council (AC), com- posed of three members with expertise in clinical epidemiology, hema- 1Istituto di Ematologia ed Oncologia Medica ‘ Seragnoli,' Universita di Bolo- tology, and critical appraisal, oversaw the process. An Expert Panel gna, Bologna, Italy; 2Unita di Ematologia, Ospedale Cardinal Massaia, Asti, (EP) was selected according to the conceptual framework elements of Italy; 3Unita di Ematologia, Ospedale Civile di Bolzano, Bolzano, Italy; 4Lab-oratory of Clinical Epidemiology and Center of the Study of Myelofibrosis, the NIH Consensus Development Program . During a first meeting, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; 5Divisione di Emato- the EP decided which clinical issues needed an update and the AC logia I, IRCCS Azienda Ospedaliera Universitaria San Martino, Genova, checked which clinical queries might be addressed by a critical Italy; 6Divisione di Ematologia, Fondazione IRCCS Policlinico San Matteo, appraisal of evidence .
Pavia, Italy; 7Dipartimento di Biotecnologie Cellulari ed Ematologia, Cattedra Producing and grading evidence-based recommendations.
di Ematologia, Universita La Sapienza, Roma; 8Divisione di Ematologia, selected the clinical questions that needed to be addressed by a critical Spedali Riuniti, Bergamo, Italy; 9Unit of Hematology, AOU Careggi, Univer- appraisal of evidence. The EP chose the critical outcomes for each sity of Florence, Firenze, Italy; 10Divisione di Ematologia, Ospedale Mauri-ziano, Torino, Italy; 11Divisione di Ematologia, Azienda Ospedaliera San Gio- clinical query. Literature search was performed in July 2011 and limited vanni Battista, Torino, Italy; 12Department of Hematology, University of Bolo- to English-language publications edited after 2005. The search included gna, Bologna, Italy proceedings 2009 through 2010 of the American Society of Hematol-ogy, the European Hematology Association, and the 11-ICML (11th Conflict of interest: Nothing to report International Conference on Malignant Lymphoma). According to *Correspondence to: Giovanni Barosi, Laboratorio di Epidemiologia Clinica- GRADE methodology , the AC prepared ‘ evidence tables'' and Centro per lo Studio della Mielofibrosi, Fondazione IRCCS Policlinico S.
‘ quality of evidence tables'' (available by the corresponding author on Matteo, Viale Golgi 19, 27100 Pavia, Italy. E-mail: email@example.com request) for each critical appraisal. The EP received the critical apprais- Contract grant sponsors: SIE, SIES, GITMO Societies, Mundipharma, Jans- als and was asked to draft recommendations based on the benefit to sen Cilag, Celgene, Roche (Italy).
risk profile of each compared intervention. Definite agreement of the Received for publication 8 June 2012; Revised 15 November 2012; Accepted recommendations and of their strength (weak or strong) was made through subsequent face-to-face meetings.
Am. J. Hematol. 88:185–192, 2013.
Published online 10 December 2012 in Wiley Online Library (wileyonlinelibrary.
methodology was applied by the EP for all the issues worth to be updated but not addressable by a critical appraisal. During three DOI: 10.1002/ajh.23372 2012 Wiley Periodicals, Inc.
American Journal of Hematology ence of less than 1/1,000 BCL2/IgH (1) cells in the bone Issue 3: First line therapy (evidence–based recommen- marrow was the best predictor of complete response after first-line treatment and levels less than 1/100 a good pre- In asymptomatic stage II–IV non bulky patients is rit- dictor of five-year event-free survival (EFS). However, this uximab alone better than watchful waiting? With the result has not been validated, and in 238 patients with re- advent of rituximab and its relatively favorable side effect fractory-relapsed FL enrolled into the EORTC 20981 phase profile, a randomized trial compared watchful waiting with III trial, a BCL2 positive bone marrow was associated with rituximab 375 mg/m2 weekly for 4 consecutive weeks fol- a worse progression-free survival (PFS) but the BCL2/IgH lowed by rituximab maintenance every 2 months for 2 years levels were not correlated with the rates of post-induction  in 462 asymptomatic patients. Time for initiation of response . However, recognizing that FLIPI was vali- new therapy was significantly improved in the maintenance dated in the prerituximab era , a FLIPI 2 score including group in comparison with the watchful group: at 3 years 52 age, serum beta2 microglobulin, hemoglobin concentration, versus 9% of patients required treatment (HR, 0.20; 95% bone marrow involvement and tumor burden correlating CI 0.13–0.29; P 5 0.001). PFS was also significantly with the longest diameter of the largest involved lymph improved (81 vs. 33% at 3 years) by rituximab maintenance node was recently proposed . Both indexes have not (HR, 0.21; 95% CI 0.15–0.29; P 5 0.001). No statistically been validated in prospective trials; therefore, they cannot significant difference in OS was detected. Quality of life be used to inform treatment decision in clinical trials.
appeared to be ameliorated in patients receiving rituximab Recommendations Appropriate staging is a fundamental . The panel agreed that improvement in long-term sur- step in the initial approach to patients with FL. Initial work- vival was the critical endpoint to be considered in this set- up should include a CT scan of the neck, thorax, abdomen ting and that more evidence is needed before recommend- and pelvis, and a bone marrow biopsy. FL is a FDG avid ing rituximab in asymptomatic patients.
disease and PET allows the identification of a higher num- Recommendations For asymptomatic Stage II–IV, non ber of nodal and extranodal areas compared with CT scan.
bulky patients watchful waiting remains the standard of PET scan should be included in staging of patients with lim- care and rituximab cannot be recommended (quality of evi- ited-stage disease at CT scan and possibly candidates to dence, low; strength of recommendation, weak).
radiotherapy only. The panel agreed that PET upstaged In patients with stage I–II disease, which dose of patients should receive a therapy according to the new radiotherapy is recommended? Involved field radiother- stage, even though there is no evidence that this choice is apy (IF-RT) remains the recommended treatment for able to improve the outcome of the disease.
patients with limited stage disease, as detailed in our previ- Pretreatment PET is also advisable to allow an optimal ous guidelines . A recent randomized trial compared 40– assessment of response for those patients needing chemother- 45 Gy with 24 Gy radiotherapy in 661 sites in patients with apy in which an early stage disease (i.e., Stage II) and therapy indolent NHL, predominantly follicular, reporting no differ- fitness make the probability of CR high. Staging should be ence in the major outcomes, which is response rate, PFS assigned according to the Ann Arbor system. Bone marrow bi- and OS .
opsy histology should be performed with monolateral upper Recommendations Patients with Stage I–II disease, a low posterior iliac spine biopsy of at least 20 mm length and should tumor burden, and with documented contiguity of involved include appropriate immunohistochemistry for the lymphoma- lymph-nodes treatable in the same radiotherapy field, tous tissue. A complete blood count and routine blood chemis- should receive external involved field radiotherapy, at the try including LDH, beta2microglobulin and uric acid are dose of 24 Gy (quality of evidence, low; strength of recom- required. Like for all patients' candidate to receive cytotoxic mendation, strong).
and/or immunomodulatory drugs, screening for main infectious In patients with stage II–IV deserving treatment, is diseases, including HIV and hepatitis B and C, is recom- chemoimmunotherapy better than chemotherapy? Che- mended. Bone marrow and peripheral blood tests with polymer- moimmunotherapy with rituximab was recommended for ase chain reaction for t(14;18) chromosomal translocation and/ patients candidates to chemotherapy in our previous guide- or for immunoglobulin gene rearrangement (Ig CDR3) is not lines . Four randomized trials [30–33] comparing chemo- recommended for routine assessment and outside clinical trials.
immunotherapy with rituximab to chemotherapy without rit- A follicular lymphoma international prognostic index (FLIPI) (>4 uximab in naı¨ve patients with FL Stage III–IV were nodal sites, elevated LDH, age >60 years, Stage III–IV, hemo- selected. A pooled analysis was performed on the critical globin <12 g/dl) should be determined in all the patients.
endpoints, that is, OS, failure free survival (FFS) andsevere infections (Fig. 1). OS (HR, 0.59; 95% CI 0.44– Issue 2: When to start treatment (consensus-based 0.79) and FFS improved (HR, 0.54; 95% CI 0.44–0.66).
However, no relevant increase of severe infections was Based to the lack of overall survival (OS) improvement shown. Stage I–II patients with a high tumor burden were after treatment of asymptomatic advanced-stage patients not enrolled into the above trials, but in absence of new evi- , and according to the previous SIE guideline edition  dence, the panel maintained the recommendation of the and to GELF data , the panel agreed on the following previous version of the guidelines , and agreed that patients with Stage II disease and high tumor burden, or Recommendations Treatment can be started in patients FLIPI >2 should receive frontline chemoimmunotherapy.
with Stage II–IV disease in case of one of the following fea- Recommendations Patients with Stage III–IV should receive tures occurs: systemic symptoms, high tumor burden (i.e., front-line chemoimmunotherapy. No evidence indicates che- >3 lymph nodes measuring >3 cm or a single lymph node moimmunotherapy in Stage II disease. However, the panel >7 cm), extranodal disease, cytopenia due to marrow agreed that these patients should receive chemoimmuno- involvement, spleen involvement (516 cm by CT), leukemic therapy when there is high tumor burden or high-risk scor- phase, serous effusion, symptomatic or life endangering ing system (quality of evidence, moderate; strength of organ involvement, rapid lymphoma progression, consis- tently increased LDH levels. A policy of watchful waiting is In patients candidates to frontline chemoimmuno- not recommended in patients with Stage I–II disease, with the exception of patients with a short life expectancy due to chosen? Two randomized trials comparing different chemo- severe comorbidity or with contraindications to therapy.
therapy regimens associated with rituximab are available American Journal of Hematology
Result of the pooled analysis on the critical endpoints (overall survival, failure free survival, and severe infections) of the three published trials comparing che- moimmunotherapy with rituximab the chemotherapy without rituximab in patients with follicular lymphoma Stage III–IV. [Color figure can be viewed in the online issue,which is available at wileyonlinelibrary.com.] for analysis; however, both have been reported only in Recommendations There is evidence that many frontline abstract form. Federico et al. in the FOLL05 trial compared chemotherapy regimens, whether antracycline-based poly- R-CVP versus R-CHOP versus R-FM in a homogenous FL chemotherapy (CHOP or CHOP like regimens) or fludara- population of 534 patients . A trend to longer 3 year bine-based polychemotherapy, or CVP regimen or benda- PFS and a significant amelioration of time to treatment fail- mustine can be used in association with rituximab (quality ure was noted in the patients treated with R-CHOP and R- of evidence, low; strength of recommendation, weak).
FM. However, a higher rate of adverse events was shown In patients candidates to frontline chemoimmuno- with R-FM compared to the other two treatment schedules.
therapy, high-dose chemoimmunotherapy with autolo- A preliminary GRADE table could be built based on the data reported by the oral presentation. Rummel et al.
chemoimmunotherapy? The impact of high-dose therapy tested R-bendamustine versus R-CHOP in a heterogene- and autologous hematopoietic stem cell transplantation ous population of 513 patients, half of which had a FL while (HSCT) versuss conventional-dose chemotherapy in the the remaining patients had a diagnosis of either mantle cell management of FL has been faced by a systematic review lymphoma or non-FL indolent lymphoma . In the R- of the randomized clinical trials addressing the question bendamustine group PFS was prolonged from 35 to 55 . Seven trials proved eligible, four of which provided months compared to R-CHOP (HR, 0.57; 95% CI 0.43– data from 941 patients that could be included in a meta- 0.77). Moreover, R-bendamustine had a lower rate of analysis and three of which remain unpublished. The Grade 3–4 adverse events compared to R-CHOP. In elderly results suggest that high-dose therapy and autologous SCT unfit patients several therapeutic options have been tested as part of FL initial treatment does not improve OS.
in phase II or retrospective studies: rituximab monotherapy, In the post-rituximab era, only one trial compared high- chlorambucil and rituximab, abbreviated chemoimmunother- dose therapy and autograft with R-CHOP: 136 patients with apy. However, no randomized study is available to guide untreated advanced FL Grades 1–3 were randomized therapeutic decision. No GRADE table could be built based either to six cycles of R-CHOP or to R-HDS schedule .
on the subset of data reported by the abstract.
The R-HDS consisted of two cycles of APO regimen (dox- American Journal of Hematology orubicin, vincristine, and prednisone totaling 75 mg/sqm of patients. No significant difference in mortality was reported doxorubicin administration); patients not achieving complete in the two groups. Grades 3–4 adverse effects were 24% in remission (CR) received two additional DHAP; the high- the rituximab group and 17% in the observation group (RR, dose phase consisted of 2 g/sqm etoposide followed by 1.46; 95% CI 1.14–1.87). Grades 3–4 neutropenia was 1% two rituximab doses; afterwards 7 g/sqm of cyclophospha- in the observation group and 4% in the maintenance group.
mide were delivered followed again by two rituximab doses; Grades 3–4 infections were 1% in the observation group eventually mitoxantrone 60 mg/sqm and melphalan 180 and 4% in the maintenance group. No statistical difference mg/sqm followed by autologous HSCT were administered.
was documented in quality of life between the two groups.
CRs were 62% following R-CHOP and 85% following R- Recommendations Maintenance therapy with rituximab is HDS (P < 0.001). Four years projected values for EFS recommended in patients who reach at least a partial were 28% for R-CHOP and 61% for R-HDS (P < 0.001).
response at the end of first-line therapy (quality of evi- Four years projected values for PFS were 31% for dence, high; strength of recommendation, strong).
R-CHOP and 68% for R-HDS (P < 0.001). OS was similar In patients who achieved partial response after in the two arms (R-CHOP, 80%; R-HDS, 81%). The cumu- first-line chemoimmunotherapy, is consolidation with lative incidence of sMDS/AML at 4 years was 6.6% for radioimmunoconjugates an option? Four hundred and R-HDS and 1.7% for R-CHOP (P 5 0.111). A total of 26 fourteen patients were enrolled in a multicenter randomized non-fatal grades III to IV extra-hematologic early toxicities trial (FIT trial) testing ibritumomab tiuxetan consolidation occurred in the R-HDS arm compared to a total of seven after response (PR or CR) to first-line chemotherapy in FL registered in the R-CHOP arm (P < 0.001).
Stage III–IV compared to observation . Radioimmuno- Recommendation Upfront high-dose chemoimmunotherapy therapy (RIT) consolidation converted 77% of patients who with autologous stem cell support cannot be recommended were in PR after induction therapy to CR (P < 0.001). After a (quality of evidence, low; strength of recommendation, median follow-up of 3.5 years, median PFS was 36.5 months in the RIT group and 13.3 months in the control group (HR, Issue 4: Assessment of response (consensus-based 0.465; P < 0.0001). At follow-up, there was no difference in OS between the two groups. Grades 3–4 infections were 8% The independent prognostic significance of PET-CT per- in the RIT arm compared to 2.4% in the control group. The formed at the end of induction therapy has been recently trial, however, enrolled only 15% of patients receiving rituxi- confirmed ; irrespective of conventional response , mab as part of the induction regimen. This conclusion is fur- PET positivity was associated with a reduced PFS (33 vs.
ther supported by several phase II studies where ibritumo- 71%) and an increased risk of death (HR, 7.0; P 5 0.001).
mab tiuxetan was given to patients after remission induction However, no study addressed the management of patients with R-CHOP [43,44] or FNR [45,46].
with discordant CT and PET results. Therefore, therapeutic Recommendations Ibritumomab tiuxetan proved to prolong decisions cannot be actually based on PET results. The progression free survival in patients achieving partial prognostic role of molecular response is controversial, even response after first-line chemoimmunotherapy. However, though any residual positivity at the end of a rituximab con- the lack of comparison between ibritumomab tiuxetan and taining program is associated with a remarkably poor out-come . The prognostic role of BCL2/IGH levels after rituximab maintenance does not allow to produce recom- induction treatment still needs to be assessed in patients mendations on radioimmunotherapy in this setting (quality receiving rituximab maintenance.
of evidence, low; strength of recommendation, weak). The Recommendations Clinical response to first-line therapy panel claimed to be important to have a randomized study should be assessed according to revised IWG criteria .
evaluating the role of radioimmunotherapy versus rituximab Even though there is preliminary evidence that the best maintenance in patients who achieved a response after response evaluation includes PET, the panel did not reach a consensus on the extensive use of PET in response assess- Issue 6: Relapsed/refractory patients (evidence-based ment. The panel agreed that PET could be indicated in patients in which the intention of therapy is achieving CR.
In patients relapsing after first line chemoimmuno- There is no evidence to support interim PET for guiding therapy and requiring treatment, is rituximab and treatment decisions. PET is not recommended for routine chemotherapy reinduction superior to chemotherapy use in the follow-up setting. The assessment of molecular alone? A trial randomized 465 FL patients relapsed after response is not recommended for routine assessment.
first-line chemotherapy not including rituximab to eitherR-CHOP or CHOP . R-CHOP induction yielded an Issue 5: Post-induction therapy (evidence-based increased CR rate compared to CHOP therapy (CHOP, 15.6%; R-CHOP, 29.5%; P > 0.001). At a median follow-up In patients with at least partial response after first- of 33 months, patients treated with R-CHOP had signifi- line chemoimmunotherapy, is maintenance with rituxi- cantly longer median PFS (33 vs. 20 months) from first ran- mab better than watchful waiting? The panel agreed that domization (HR, 0.65; P < 0.001). A slight non significant improvement in PFS was the critical endpoint to be consid- increase of Grade 3–4 neutropenia was reported in the ered in this setting. The PRIMA study  randomized R-CHOP arm (55 vs. 48%).
1019 FL patients responsive to R-CHOP or RCVP to obser- Recommendations In fit patients relapsing after first-line vation or rituximab maintenance (12 infusions of 375 mg/ chemoimmunotherapy and requiring treatment, rituximab sqm given intravenously one every 8 weeks) starting 8 should be added to chemotherapy as reinduction, provided weeks after the last induction treatment. Three-year PFS there is no evidence of resistance to rituximab (quality of was 74.9% (95% CI 70.9–78.9) in the rituximab mainte- evidence, low; strength of recommendation, weak).
nance group and 57.6% (95% CI 53.2–62.2) in the obser- In patients relapsing after first-line chemoimmuno- vation group (stratified log rank, P 5 0.0001). The HR for therapy and achieving a response to reinduction rituxi- risk of progression was significantly in favor for the rituxi- mab and chemotherapy, is rituximab maintenance mab maintenance group (HR, 0.55; 95% CI 0.44–0.68).
better than observation? Van Oers et al.  randomly Conversion from PR to CR was documented in 44% of the assigned relapsing/resistant patients after R-CHOP or American Journal of Hematology CHOP to either observation or maintenance with single (3–5) and rituximab (375 mg/m2 on day 13; 1,000 mg/m2 on agent rituximab 375 mg/m2 once every 2 months for a max- days –6, 11 and 18) (FCR ) regimen in 47 chemosensitive imum of 2 years. When CHOP 1 rituximab was used for FL patients treated with sibling donor (n 5 45) or matched induction, the median PFS from second randomization for unrelated donor (n 5 2). With a median follow-up of 60 patients who received rituximab maintenance therapy was months PFS and OS were 83% and 85%, respectively. Non 4.4 years compared with 1.9 years (HR, 0.69; P 5 0.43).
relapse mortality (NRM) accounted for 15% of the patients.
When CHOP only was used for induction, these figures Pinana et al.  described the long term outcome of 37 FL were, respectively, 3.1 years versus 1 year in the observa- patients with median age of 50 years (range 34–62 years) en- tion arm (HR, 0.37; P < 0.001). For patients in CR, median rolled in two prospective protocols between 1999 and 2007.
PFS was 4.4 years in the rituximab maintenance arm ver- Patients with relapsed or refractory FL were treated with a sus 1.2 years in the observation arm (HR, 0.48; P 5 conditioning regimen based on fludarabine (125–150 mg/m2) 0.003). The last median follow-up  of 6 years showed combined with melphalan (80–140 mg/m2). With a median that maintenance rituximab significantly improved median follow-up of 52 months (range, 0.6–113 months), DFS at 4 PFS (3.7 vs. 1.3 years; HR, 0.55), but was associated with years for patients with PD, PR or CR at transplantation were a significantly higher rate of severe (Grades 3–4) infection 29, 48, and 64%, respectively. The 4-year cumulative inci- (9.7 vs. 2.4%; P 5 0.01). There was a non significant trend dence of nonrelapse mortality were 71, 33, and 26%, respec- towards improved OS at 5 years with maintenance (74 vs.
tively. Thomson et al.  reported the results of 82 consecu- 64%; P < 0.07). Seven out of 167 patients withdrew from tive patients with relapsed or refractory FL conditioned for maintenance treatment because of toxicity: four had allogeneic HSCT with alemtuzumab (20 mg on days –8 to –4) recurrent infections, one had severe neutropenia, one had combined with fludarabine (30 mg/m2 on days –7 to –3) and ventricular arrythmia, and one had persistent general com- melphalan (140 mg/m2 on day –2). With a median follow-up plaints. There were no deaths related to maintenance treat- of 43 months the NRM was 15% at 4 years. Risk of relapse ment. Three other randomized trials assessed rituximabmaintenance in relapsed FL patients [48–50]. However, the was 26%. At 4 years, the OS rate was 76%.
studies enrolled patients with refractory FL, mantle cell lym- The EBMT Group reported a retrospective analysis on 44 phoma or other indolent NHL. Moreover, no chemotherapy matched unrelated donor stem cell transplantation (MUD- reinduction was applied in two trials [49,50]. All the above SCT) for relapsed or refractory FL. Compared to myeloabla- studies were reported by a Cochrane systematic review tive conditioning regimens, RIC showed on multivariate anal- . Meta-analysis of the four available randomized trials ysis reduced NRM and significantly longer PFS and OS .
reported that OS was significantly ameliorated (HR, 0.58; Hari et al.  compared retrospectively the outcomes of 95% CI 0.42–0.79) while also infection and severe infec- 208 FL patients (27–70 years) treated either with myeloa- tions were increased (HR, 1.99; 95% CI 1.24–6.76).
blative conditioning (n 5 120) or reduced intensity condi-tioning (n 5 88) before an HLA-identical sibling allogeneic Recommendations In patients relapsing after first-line che- moimmunotherapy and achieving a response to reinduction HSCT. There were no significant difference in 3-year PFS rituximab and chemotherapy, rituximab maintenance is or OS between the two cohorts. On multivariate analysis, recommended (quality of evidence, low; strength of recom- an increased risk of disease progression after RIC was mendation, weak).
observed (RR, 2.97, P 5 0.04).
Recommendations Young (<65-year old) fit patients who relapsed after or were refractory to a previous therapy Which role for autologous HSCT? Two retrospective including autologous SCT are candidates to allogeneic SCT.
The availability of a compatible donor and the patient studies [52,53] analyzed the outcomes of patients treated preference should be considered in making this decision with autologous HSCT or chemotherapy or chemoimmuno- Which role for radioimmunoconjugates? The efficacy therapy in patients progressed or relapsed FL. Other and safety of radiolabelled ibritumomab tiuxetan (single cohorts assessed the role of autologous HSCT in rituximab dose of 14.8 MBq/Kg) and tositumomab in patients with re- pretreated patients [37,54–59]. The efficacy of rituximab fractory/relapsed indolent NHL were compared with rituxi- prior to stem cell collection as in vivo purging has been mab (375 mg/sqm once weekly for 4 weeks) and unlabelled tested by a randomized trial . A retrospective analysis tositumomab, respectively, in two randomized trials [66,67].
conducted by the Gruppo Italiano Terapie Innovative nei Response rates ranged from 55 to 86% and CRs were Linfomi (GITIL) reported the results of addition of rituximab achieved in more than 30% of the patients. Higher response pre-HSCT . Rituximab maintenance after autologous rates, longer TTP and fewer adverse effects were observed HSCT was also assessed . Several design limitations by retrospective analyses of patients receiving ibritumomab restrict the applicability of the trial results to the indication tiuxetan or tositumomab as a second line therapy versus of autologous SCT in patients relapsed or refractory. So the third or further lines [68,69].
panel provided consensus based-recommendations.
Recommendations The panel argued that for relapsed/re- fractory patients, treatment with radioimmunoconjugates is Recommendations Autologous HSCT is recommended in a therapeutic option. This should apply for those patients young (<65-year old) fit patients relapsing within 12 months non eligible to high-dose chemotherapy and HSCT.
from the end of frontline chemoimmunotherapy and achiev-ing a response to chemoimmunotherapy reinduction. Auto- logous HSCT is a therapeutic option in young (<65-year At present, several treatments are available for FL but old) fit patients relapsing after at least 12 months from the the information derived from literature may not fit with end of frontline chemoimmunotherapy and achieving a relevant clinical questions, and the endpoints and/or the response to chemoimmunotherapy reinduction. No suffi- population of patients included in trials are not always those cient evidence support universal rituximab maintenance in relevant in the clinical practice. In this project, aimed at patients achieving a response after autologous HSCT.
revising the guidelines for management of FL issued in Which role for allogeneic HSCT? Khouri  recently 2005, we made specific evidence-based recommendations reported the 8-year experience with the fludarabine (30 mg/ for the most relevant key issues according to the GRADE m2 on days –5 –3), cyclophosphamide (750 mg/m2 on days methodology, which imposes a preliminary judgment of the American Journal of Hematology American Journal of Hematology quality of evidence and a subsequent assessment of the 9. Wo¨hrer S, Jaeger U, Kletter K, et al. 18F-fluoro-deoxy-glucose positron emis- strength of the recommendation based on a qualitative risk- sion tomography (18FFDG-PET) visualizes follicular lymphoma irrespective ofgrading. Ann Oncol 2006;17:780–784.
benefit analysis. Also other institutions recently produced or 10. Janikova A, Bolcak K, Pavlik T, et al. Value of [18F]fluorodeoxyglucose posi- updated evidence-based guidelines for the management of tron emission tomography in the management of follicular lymphoma: The FL (NCCN, BCSH, ESMO) [70–72] (Table I). Systematic end of a dilemma? Clin Lymphoma Myeloma 2008;8:287–293.
reviews and consensus conferences addressed to specific 11. Le Dortz L, De Guibert S, Bayat S, et al. Diagnostic and prognostic impact of 18F-FDG PET/CT in follicular lymphoma. Eur J Nucl Med Mol Imaging therapeutic issues, such as HSCT  and radioimmuno- therapy  have also been published. The majority of pro- 12. Bishu S, Quigley JM, Bishu SR, et al. Predictive value and diagnostic accu- duced recommendations in our project are common to the racy of F-18-fluoro-deoxyglucose positron emission tomography treated grade above guidelines: in particular, several chemotherapy regi- 1 and 2 follicular lymphoma. Leuk Lymphoma 2007;48:1548–1555.
mens are accepted for association with rituximab in front- 13. Jerusalem G, Beguin Y, Naijar F, et al. Positron emission tomography (PET) with 18Ffluorodeoxyglucose (18F-FDG) for the staging of low-grade non- line therapy of symptomatic advanced stage disease. In Hodgkin's lymphoma (NHL). Ann Oncol 2011;12:825–830.
deciding the best frontline therapy, we grounded our deci- 14. Imataki O, Tamai Y, Yokoe K, et al. The utility of FDG-PET for managing sion on the resulting efficacy and safety evidence. However, patients with malignant lymphoma: Analysis of data from a single cancer the economic impact of frontline chemoimmunotherapy was center. Intern Med 2009;48:1509–1513.
15. Wirth A, Foo M, Seymour JF, et al. Impact of [18f] fluorodeoxyglucose posi- also assessed in several studies, and R-CVP resulted cost- tron emission tomography on staging and management of early-stage effective versus CVP [75–77], and R-CHOP versus CHOP follicular non-hodgkin lymphoma. Int J Radiat Oncol Biol Phys 2008;71:213– . Moreover, rituximab maintenance after chemoimmuno- therapy was associated with an incremental cost per QALY 16. Karam M, Novak L, Cyriac J, et al. Role of fluorine-18 fluoro-deoxyglucose positron emission tomography scan in the evaluation and follow-up of patients €12,600 to €18,147 versus R-CHOP followed by with low-grade lymphomas. Cancer 2006;107:175–183.
observation [78,79]. The guidelines issued in the last year, 17. Hofman MS, Hicks RJ. Imaging in follicular NHL. Best Pract Res Clin Haema- however, showed discrepancies about recommendations on radioimmunoconjugates and HSCT. Indeed, the available 18. Blum RH, Seymour JF, Wirth A, et al. Frequent impact of [18F]fluorodeoxyglu- evidence for such therapies is low-level due to indirectness cose positron emission tomography on the staging and management ofpatients with indolent non-Hodgkin's lymphoma. Clin Lymphoma 2003;4:43– in available randomized studies and to lack of randomized studies. The results of ongoing trials investigating new ther- 19. Scott AM, Gunawardana DH, Wong J, et al. Positron emission tomography apeutic modalities and novel agents will probably modify changes management, improves prognostic stratification and is superior to the treatment management of FL in the next years. Thus, gallium scintigraphy in patients with low-grade lymphoma: Results of a multi-center prospective study. Eur J Nucl Med Mol Imaging 2009;36:347–353.
we have planned to update the present guidelines by the 20. Pakos EE, Fotopoulos AD, Ioannidis JP. 18F-FDG PET for evaluation of bone end of 2015.
marrow infiltration in staging of lymphoma: A meta-analysis. J Nucl Med Author Contributions 21. Rambaldi A, Carlotti E, Oldani E, et al. Quantitative PCR of bone marrow GB, ST, MM, and AB designed the research; MM and AB BCL2/IgH1 cells at diagnosis predicts treatment response and long-term out- performed the systematic review of literature, graded the come in follicular non-Hodgkin lymphoma. Blood 2005;105:3428–3433.
evidence, and prepared the summary tables of evidence.
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American Journal of Hematology
HBV treatment and pregnancy Jörg Petersen⇑ Liver Unit, IFI Institute for Interdisciplinary Medicine, Asklepios Klinik St. Georg Hamburg, Germany See Article, pages MS The management of hepatitis B virus (HBV) infection in preg- often results in clinical remission This scenario is in contrast nancy is complex. Because infection with HBV in infancy often to the oral antiviral agents that generally require long-term ther-