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Follicular lymphoma

1. GENARAL INFORMATION

1.1 Definition

Follicular lymphomas are defined as a group of malignancies composed of follicle center cells, usually a mixture of centrocytes (cleaved cells) and centroblasts (large non-cleaved cells). Diffuse areas may be present and, in fact, may even predominate, but fllicles exist. This group of lymphomas includes many cases formerly recognized as centroblastic/centrocytic follicular or follicular centroblastic according to the Kiel classification (Banks 1992; Lennert 1978) and follicular, small cleaved, mixed or large cell according to the Working Formulation classification. The term follicular lymphoma encompass most malignancies classified as nodular lymphomas in Working Formulation, most tumors classified as follicular center cell lymphoma in the Lukes-Collins classification, all cases in the Kiel classification category of centroblastic/centrocytic with any follicular pattern, and follicular centroblastic lymphoma (Harris 1994). The REAL classification (Harris 1994) and more recently the WHO classification (Harris 1999) proposes the term follicle center lymphoma, follicular grad I, grade II, grade III a and b to distinguish predominantly small-cell, mixed small and large cell, and large-cell respectively. Grade I, II and IIIa are treated similarly, while grade IIIb disease is treated the same as diffuse large B-cell lymphoma. These lymphomas have been postulated as arising from a germinal center B cell, both centrocytes (small cleaved follicular center cells) and centroblasts (large non-cleaved follicular center cells) (Jaffe 1974; Ngan 1991; Stein 1987).

1.2 incidence

Follicular lymphomas constitute the 30 – 35% of all NHL. Grade 1 follicular lymphoma is the 20% – 25%, grade 2 the 5 – 10% and grade 3 the 5% of all NHLs in the Western countries. These rates exhibit marked geographical variations.

1.3 Risk factors

The cause and risk factors of follicular lymphomas are unclear. Although environmental and occupational exposures, such as exposure to solvents and chemical, have been implicated in the etiology of the disease.

2. PATHOLOGY AND BIOLOGY

2.1 Morphology

Follicular lymphomas are characterized by at least partially follicular growth pattern, but diffuse areas may be present (Lennert 1978). Sclerosis is common in diffuse areas. Centrocytes typically predominate; centroblasts are usually in the minority, but by definition are always present. Rare lymphomas with a follicular pattern consist almost entirely of centroblasts; because the follicular pattern implies a germinal center origin, these cases have been included in the category of follicular center cells lymphomas. Both the proportion of centroblasts and the size of the centrocytes vary among cases. This group of lymphomas should not be divided into distinct subtypes, but rather shows a continuous gradation in the number of large cells. On the bases of this grading, three groups have been defined: grade I, II and III (Harris 1994). Several studies suggest that the Berard criteria for the diagnosis of grade 3 follicular lymphoma (> 15 centroblasts/high-power field) may best define the group of cases with a potential for early relapses that may be prevented by anthracycline-containing chemotherapy (Mann 1983). There is a consensus that grade 3 follicular lymphomas, namely grade 3b, should be discriminate from lower-grade cases. Although there are minor differences in natural history and response to treatment between grades 1 and 2 follicular lymphoma, there is a consensus that these do not mandate different approaches to treatment and thus are not of great clinical importance. Nonetheless, there was concern that changing the nomenclature would potentially confusing and that a three-grade system should be retained (Harris 1999). The proportions of follicular or diffuse areas vary also from case to case, which seems to be associated with prognosis. The pattern in a given case is reported as follicular or follicular and diffuse. Diffuse areas should be reported and quantified according to the recommendations of the REAL classification, i.e. predominantly follicular (> 75% follicular), follicular and diffuse (25% to 75% follicular) and predominantly diffuse (< 25% follicular). In grade 3 follicular lymphoma, diffuse areas represent areas of diffuse large-cell lymphoma and should be reported as such, that is as follicular lymphoma grade 3/3 (75% with diffuse large cell lymphoma (25%). For the rare cases of purely diffuse lymphoma that seems to be of follicle center origin, that is with predominance of centrocytes, rare centroblasts and bcl-2 rearranged, the term follicle center lymphoma, diffuse, will be retained as a separate category. This diagnosis should only be made if both small and large cells are B cells and preferably with demonstration of some indicator of follicle center derivation, such as bcl-2 rearrangement or CD10 expression (Harris 1999).

2.2 Immunophenotype

The cells of follicular lymphomas express surface immunoglobulin, more frequently IgM +/- IgD > IgG > IgA, B-cell-associated antigens (CD19, CD20, CD22, CD79a and CD79b), CD10+/-. They are CD5-, CD23-/+, CD43-, and CD11c-. CD5 and CD43 negativity is useful in differential diagnosis with chronic lymphocytic leukemia and mantle cell, while CD10 reactivity is useful in distinguishing follicular lymphomas from marginal zone lymphomas. Follicular lymphomas express bcl-2 proteins (Harris 1994), which is useful in distinguishing reactive from neoplastic follicles (Ngan 1988; Pezzella 1990).

2.3 Genetic features

t(14;18) is present in 70% – 95% of follicular lymphomas, involving rearrangement of bcl-2 gene (Yunis 1987; Bakhshi 1985 ; Cleary 1986). This results in the expression of an anti-apoptosis gene, and the expression of the bcl-2 protein permits accumulation of long-lived centrocytes (Hockenbery 1991; McDonnell 1989; Tsujimoto 1985). This translocation occurs at an early stage of B-cell development, during Ig gene rearrangement (Tsujimoto 1985; Kuppers 1999), being occasionally present in normal individuals (Limpens 1991; Summers 2001). Thus, when a resting B cell that carries the bcl-2 translocation undergoes blast transformation in response to antigen, failure to switch off the bcl-2 gene may contribute to development of a lymphoma.

3. DIAGNOSIS

3.1 Clinical presentations

Clinical presentation and behavior of follicular lymphoma differ according to its histologic grade. Follicular lymphoma presents as advanced disease in 80% – 85% of grade 1 cases, in 70 – 75% of grade 2 cases and in 65% – 70% of grade 3 cases. Systemic symptoms are observed in 20% of grade 1-2 cases, and in 30% of grade 3 cases. Bone marrow involvement is observed in 50% of grade 1 cases and in 30% – 35% of grade 2 – 3 cases. Although not uncommon in the third and fourth decades, these lymphomas occur most commonly in middle-aged patients and elderly (Gallagher 1986; Armitage 1998). Every anatomic district may be involved by follicular lymphomas, but the most common presentation is multiple lymphadenopathy, with or without abdominal or mediastinal masses, splenomegaly, hepatomegaly, and marrow involvement. Leukemic phase is less common than for other indolent lymphomas, and extranodal sites are usually involved with e lower frequency respect to diffuse large cell lymphomas.

3.2 Diagnostic criteria

From a morphologic point of view, follicular lymphomas are characterized by at least partially follicular growth pattern, but diffuse areas may be present (Lennert 1978). Sclerosis is common in diffuse areas. Centrocytes typically predominate; centroblasts are usually in the minority, but by definition are always present. Rare lymphomas with a follicular pattern consist almost entirely of centroblasts; because the follicular pattern implies a germinal center origin, these cases have been included in the category of follicular center cells lymphomas. Both the proportion of centroblasts and the size of the centrocytes vary among cases. This group of lymphomas should not be divided into distinct subtypes, but rather shows a continuous gradation in the number of large cells. The proportions of follicular or diffuse areas vary also from case to case, which seems to be associated with prognosis. The pattern in a given case is reported as follicular or follicular and diffuse. When diffuse areas are reported according to the recommendations of the REAL classification, three subgroups can be defined, i.e. predominantly follicular (> 75% follicular), follicular and diffuse (25% too 75% follicular) and predominantly diffuse (IgG > IgA, B-cell-associated antigens (CD19, CD20, CD22, CD79a and CD79b), CD10+/-. They are CD5-, CD23-/+, CD43-, and CD11c-. CD5 and CD43 negativity is useful in differential diagnosis with chronic lymphocytic leukemia and mantle cell, while CD10 reactivity is useful in distinguishing follicular lymphomas from marginal zone lymphomas. Follicular lymphomas express bcl-2 proteins (Harris 1994), which is useful in distinguishing reactive from neoplastic follicles (Ngan 1988; Pezzella 1990). t(14;18) is present in 70% – 95% of follicular lymphomas, involving rearrangement of bcl-2 gene. This results in the expression of an anti-apoptosis gene, and the expression of the bcl-2 protein permits accumulation of long-lived centrocytes (Hockenbery 1991; McDonnell 1989; Tsujimoto 1985). This traslocation occurs at an early stage of B-cell development, during Ig gene rearrangement (Tsujimoto 1985), being occasionally present in normal individuals (Limpens 1991). Thus, when a resting B cell that carries the bcl-2 translocation undergoes blast transformation in response to antigen, failure to switch off the bcl-2 gene may contribute to development of a lymphoma.

3.3 Additional useful tests

Other than standard tests used in clinicopathological staging for all NHL, especial techniques of molecular biology are useful in diagnosis of follicular lymphoma. In effect, rearrangement of bcl-2 studied by PCR technique and PCR amplification and sequencing of IgH genes can be used.

4. STAGING

4.1 Staging procedures

Complete staging work-up for follicular lymphomas is the same that routinely used for other NHL. It includes an accurate physical examination, complete hematological and biochemical exams, total-body computerized tomography, and bone marrow aspirate and biopsy. Bone marrow assessment in follicular lymphoma should follow the general statements for all NHL. Abdominal staging, with evaluation of potential hepatic or splenic involvement in follicular lymphomas should follow the general statements for all NHL. Some particular sites of disease frequently involved by follicular lymphomas require especial diagnostic procedures. If clinically indicated, gastrointestinal tract radiological and endoscopic assessment, ultrasonography of the neck and magnetic resonance imaging of the orbits and soft tissues are useful to investigate the involvement of these anatomical regions.

4.2 Staging system

The standard staging system used for follicular lymphomas is the same as that proposed for Hodgkin’s disease at the Ann Arbor Conference in 1971 (Carbone 1971). This system is currently used for all non-Hodgkin’s lymphomas, even if other staging systems are used in some extranodal lymphomas with particular biological behavior. The Ann Arbor staging system reflects both the number of sites of involvement and the presence of disease above or below the diaphragm. This staging system considers four stage of disease: Stage I: involvement of a single lymph node region (I) or a single extranodal site (IE). Stage II: involvement of two or more lymph node regions on the same side of the diaphragm (II) or localized involvement of an extralymphatic site (IIE). Stage III: involvement of lymph nodes regions on both sides of the diaphragm (III) or localized involvement of an extralymphatic site (IIIE) or spleen (IIIs) or both (IIIEs). Stage IV: diffuse or disseminated involvement of one or more extralymphatic organs with or without associated lymph node involvement. Localized involvement of liver or bone marrow is also considered stage IV. Patients are divided in two subsets according to the presence (A) or not (B) of systemic symptoms. Fever of no evident cause, night sweats and weight loss of more than 10% of body weight are considered systemic symptoms. Even if a frequent accompanying symptom, itch should not be considered as a systemic symptom. The presence of bulky mass, such as a lesion of 10 cm or more in the longest diameter is signaled as “X”, while the extranodal involvement should be identified by a symbol (O: bone, L: lung, D: skin, etc.).

4.3 Molecular analysis of minimal residual disease

Molecular monitoring of minimal residual disease in follicular lymphoma provides an early endpoint to assess the curative potentiality of novel chemotherapy approaches and predicts relapse considering its sensitivity to detect tumor cells contained in the graft in autographing programs. Minimal residual disease in follicular lymphoma is currently detected by polymerase chain reaction (PCR), analyzing the rearrangement of bcl-2. This rearrangement is detectable in 60% – 80% of patients with follicular lymphoma. PCR amplification and sequencing of IgH genes is an alternative strategy in bcl-2-negative cases. The rearrangement of variable, diversity and joining segments of IgH genes generates unique DNA sequences that are clone specific. These sequences are named complementary-determining regions (CDR) and code for the antigen-binding site (Alt 1987). Clone-specific primers and probes can be obtained from CDR sequences and used for the PCR detection of residual lymphoma cells. Comprehensively, the bcl-2/IgH translocation and clonally rearranged IgH genes provided molecular markers for detection and follow-up of minimal residual disease by PCR amplification in several cases. Several prospective studies documented that the achievement of a sustained molecular response after conventional chemotherapy with or without rituximab was a favourable prognostic factor and correlated with prolonged FFS (Lopez-Guillermo 1998; Czuczman 2004). Serial PCR analysis to determine the molecular response correlates well with outcome (Rambaldi 2005; Freedman 1999). The number of bcl2+ circulating cells decreases with autologous SCT (Voso 2000) and patients with a molecular response after autologous SCT have a lower risk of relapse, (Ladetto 2002; Freedman 1999) the chance of relapse being proportional to the quantity of PCR positive cells found in peripheral blood. A negative PCR status post-transplant also reduced the chance of death and was more relevant onto overall survival than the PCR status of the reinfused graft (Apostolidis 2000).

4.4 Restaging procedures

Restaging should include all diagnostic procedures positive at time of diagnosis and initial staging.

5. PROGNOSIS

5.1 Natural history

Clinical behavior of follicular lymphomas is heterogeneous and differs according to the histologic grade and extension of disease at presentation. Moreover, the evaluation of these malignancies is conditioned by therapeutic decision, which is also determined by main prognostic factors. Similarly than for other indolent lymphomas, follicular lymphomas are considered fatal malignancies with conventional treatments. With time, these lymphomas often transform into a more aggressive histologic malignancy. Twenty-eight to 44% of patients with repeat biopsy during the course of the disease may show evidence of high-grade transformation (Bastion 1991; Gallagher 1986; Longo 1991; Horning 1984). Actually, this rate arises up to 70% in cases examined at autopsy (Garvin 1983;Risdall 1979). These transformed lymphomas are usually quite aggressive and poorly responsive to chemotherapy (Gallagher 1986; O’Brien 1991). In the largest reported series, a median survival of 22 months has been reported, while patients with high-grade transformed follicular lymphomas but limited-stage disease showed a median survival of 81 months (Yuen 1995).
The risk of transformation is higher in patients with advanced stage, high-risk FLIPI, and IPI scores at diagnosis. Expectant management (as opposed to treatment being initiated at diagnosis) also predicts for a higher risk of transformation (Montoto 2007). Older age, low hemoglobin level, high LDH, and high-risk FLIPI or IPI score at the time of first recurrence are associated with the diagnosis of transformation in a biopsy performed at that time. The median survival from transformation is about one year (Montoto 2007).

5.2 Prognostic factors

Several groups have described prognostic factors for patients with advanced follicular lymphoma (Johnson 1995; Soubeyran 1991; Leonard 1991). In the Groupe d’Etude des Lymphomes Folliculaires schema, patients with any one of the following features are considered to have a high tumor burden: systemic symptoms, elevated LDH, bulky lesion > 7 cm, effusion, three or more Ann Arbor sites each 3 cm or greater, circulating lymphoma cells, cytopenias, and splenomegaly (Brice 1997; Solal-Celigny 1998). The International Prognostic Index for aggressive lymphomas has been applied to follicular lymphomas and found to identify subgroups with significantly different prognosis (Foussard 1997;Lopez-Guillermo 1994; Decaudin 1999). However, only a small percentage of patients full into the higher risk group, such that this system of stratification may not be optimal for follicular lymphoma. In contrast, the International Prognostic Index showed a significant efficacy to identify risk groups in patients with follicular large cell lymphoma (grade 3) (Rodriguez 1999). In these patients, age, stage, LDH ratio, ß2-microglobulin level, and bone marrow involvement seem to play an independent prognostic role. In a series of 398 patients of the British National Lymphoma Investigation group, the Ann Arbor staging classification fared poorly, minimally separating relapse-free and cause-specific survival probabilities in patients with the largest staging grouping, III and IV. Increasing number of lymph node regions involved, systemic symptoms, splenomegaly and increasing age have been reported to have powerfully independent adverse influence on probability of complete response to treatment and cause-specific survival (Denham 1996). Molecular response, tested as PCR analysis of the rearrangement of bcl-2 in blood and marrow, is significantly related to event-free-survival in patients with follicular lymphoma treated with anthracycline-containing chemotherapy, with or without fludarabine, and with or without Rituximab (Lopez-Guillermo 1998; Rambaldi 2005). Serial PCR analysis to determine the molecular response correlates well with outcome, especially when combined with pretreatment ß2-microglobulin level. The number of bcl2+ circulating cells decreases with autologous SCT (Voso 2000) and patients with a molecular response after autologous SCT have a lower risk of relapse, (Ladetto 2002; Freedman 1999) the chance of relapse being proportional to the quantity of PCR positive cells found in peripheral blood. A negative PCR status post-transplant also reduced the chance of death and was more relevant onto overall survival than the PCR status of the reinfused graft (Apostolidis 2000). Some chromosomal abnormalities with prognostic value in terms of risk or high-grade transformation and survival have been reported (Tilly 1994).
The presence of sclerosis within the lymphoma seems to be a marker of poor overall survival that is independent of the FLIPI (Klapper JCO 2007)
. High serum ß2-microglobulin level (Bastion 1997), chromosomal abnormalities involving 6q23-26 and 17p (Tilly 1994), alterations or mutations of c-myc and p53 (Lo Coco 1993; Sander 1993; Yano 1992), and deletions of p15 and p16 (Dreyling 1998; Elenitoba-Johnson 1998; Pinyol 1998) have been associated with an increased risk of high-grade transformation. Due to the lack of prognostic system specifically devised for follicular lymphomas, in the last few years two specific prognostic scores have been developed based on large series of patients treated in the last 15 years with mainly pre-Rituximab treatments: the Italian Lymphoma Intergroup Index (ILI) (Federico 2000) and more recently, the Follicular Lymphoma International Prognostic Index (FLIPI) (Solal-Celighy 2004). Six variables were used to construct ILI index, three of them also being included in IPI (age, extrandal involvement and LDH level). The other three variables considered were: presence of B-symptoms, male sex and erythrocyte sedimentation rate > 30 mm/h. Patients were classified into low-, intermediate- or high-risk groups each of them with significantly different 5 and 10 years overall survival: 90% and 65% for patients at low risk; 75% and 54% for patients at intermediate risk; and 38% and 11% for those at high risk. Characteristics of diagnosis were collected from 4167 Follicular Lymphoma patients to construct FLIPI index. The variables used to classify patients according to the FLIPI index were age e 60, advanced stage (III-IV), increased serum LDH, hemoglobin level < 12 g/dl and nodal involvement (five or more sites). Three risk groups were considered with different 5 and 10 year survival: score 0-1, low risk (90.6% and 70.7%); score 2 intermediate-risk (77.6% and 50.9%); and score e 3, high-risk (52.2% and 35.5%). It is recommended to use one of this specific index to classify follicular lymphoma patients (Perea 2005).

6. TREATMENT

6.1 ‘Watch and wait’ policy

Treatment can be safely deferred without no disadvantage on survival for patients with Follicular Lymphoma in stage III-IV disease (Horning 1984), provided that none of the following features occurs: systemic symptoms, high tumor burden, extranodal disease, cytopenia due to marrow involvement, spleen involvement, leukemic phase, serous effusion, high LDH levels. This “watch and wait” policy was evaluated by three trials that randomized to either chemotherapy or watchful waiting (WW) strategy patients with de novo, asymptomatic, advanced-stage and a low tumor burden indolent lymphomas. Two old trials compared WW with ProMace-MOPP polychemotherapy,(Young 1988) prednimustine or interferon (Brice 1997) in stage II-IV patients and did not show any significant difference in 4- and 5-year survival, respectively, except for a significant prolongation of failure-free survival (FFS) with polychemotherapy. A more recent randomized trial (Ardeshna 2003) with a 16-year median follow-up, reported that median overall survival (OS) was 5.9 years for oral chlorambucil versus 6.7 years (p=0.84) for observation. Cause-specific survival was also similar in the two arms: 9 vs 9.1 years, respectively. The median time to first systemic treatment was 2.7 years in the WW group. Delay of treatment until significant clinical progression does not seem to hamper the prognosis or subsequent response to treatment. Patients with low-grade and limited disease follicular lymphomas should not be managed with a frontline watchful wait strategy because these patients can obtain a long-term survival when treated with involved-field irradiation (Besa 1995; Pendlebury 1995).

6.2 Treatment of stage I-II low-grade follicular lymphoma

Standard therapeutic option for patients with stage I-II grade 1-2 follicular lymphoma is matter of debate. However, there is sufficient evidence supporting involved-field irradiation is suitable for individual clinical use on a type 3 level of evidence (De Los Santos 1997; Mac Manus 1996;Pendlebury 1995; Wilder 2001). “Involved field” (IF) RT is most commonly used in localized lymphomas and implies treatment to the nodal region or extranodal sites and, if involved, its immediate lymphnode drainage area. A treatment plan including the adjacent, second echelon not involved lymph nodes is usually considered “extended field” RT, even if a true extended field is referred to the classical Hodgkin’s fields. Stage I and II FL patients treated with a radiation dose of 30 to 36 Gy delivered in 15 to 20 fractions over 2-4 weeks experienced local control rates of more than 95%, while there is insufficient information to assess the impact of doses lower than 30 Gy on local control. Moreover, radiation therapy alone achieved an excellent survival and long-term disease control: in a recent update of the Princess Margareth Hospital experience, OS at 5 and 10 years were 79% and 62%, while DFS was 56% and 41%, respectively (Petersen 2004). In a retrospective study, 43 untreated stage I and II follicular lymphoma patients deferred initial therapy for various reasons. Only 16 (37%) patients received a treatment within 7 years from the diagnosis. Estimated 10-year OS was 85% after a median follow-up of 86 months. Patients with limited disease (stage I disease) without residual lymphoma after excisional biopsy, may attain a very good outcome despite no further treatment and adjuvant radiotherapy seems to be unnecessary (Advani 2004; Soubeyran 1996). Some authors reported improved results with the addition of primary chemotherapy to radiation therapy (McLaughlin 1986). A 5-yr overall and failure-free survival of 89% and 74% has been reported in 44 patients treated with cyclophosphamide, vincristine, bleomycin, and prednisone, with or without doxorubicin (McLaughlin 1986). However, six randomised level I-II trials reported that the adjunct of chemotherapy to first-line RT does not prolong patients’ survival in stage-I-II follicular lymphoma patients (Carde 1984; Monfardini 1980). An innovative approach in the treatment of localized stage disease with low tumor burden might be the association of immunotherapy (rituximab) to radiotherapy. So far, no studies have been reported which compare radiotherapy alone to combination radiotherapy and rituximab.

6.3 Treatment of stage I-II with high tumor burden and/or high-risk follicular lymphoma

Within the subset of patients with limited stage I-II disease, high tumour burden and high risk (IPI>1, ILI >2) were considered negative predictors of progression-free survival (PFS) in three phase II studies (Kamath 1999; Wilder 2001; Seymour 2003). Frontline chemotherapy followed by involved-field irradiation is suitable for individual clinical use in stage I-II patients with a high tumor burden. With this strategy, 5-yr failure-free and overall survival are 55% – 65% and 70% – 75%, respectively.

6.4 Treatment of stage III-IV follicular lymphoma

A univocal standard therapeutic option for patients with stage III-IV low-risk follicular lymphoma does not exist. The role of extended field RT alone has been evaluated in stage III FL in three retrospective phase studies (De Los Santos 1997; Jacobs 1993; Murtha 2001). The subset of patients with “limited” stage disease (defined as fewer than 5 disease sites, tumor masses less than 10 cm and no B symptoms), showed a better outcome, i.e. FFS of 88% at over 23 years follow-up. However the risk of secondary cancers with extended radiotherapy/central lymphatic irradiation, as compared with chemotherapy alone, is high and extended RT should not be considered a valuable first-line therapy in patients with advanced disease. The choice of optimal chemotherapy is still a matter of debate. Many randomized trials compared different regimens of chemotherapy in advanced stage indolent lymphomas: alkylating agents, antracycline-based chemotherapies, purine analogs and CVP-like regimens. Single agent chemotherapy with chlorambucil or cyclophosphamide was widely used in advanced stage indolent lymphomas with an overall response rate from 54-72% with a CR rate from 30 to 70% and a median OS ranging from 4.5 to 9 years (Ezdinli 1985). Single agent chemotherapy was compared to polychemotherapy like CVP or antracycline-containing regimens: although some studies reported a higher response rate with polychemotherapy, none were able to show a better outcome compared to single agent chemotherapy (Unterhalt 1996; Brandt 2001; Peterson 2003). Although chlorambucil toxicity is limited, long term exposure to cumulative alkylating dose may induce impairment of peripheral blood stem cell mobilization and a higher risk of secondary myelodysplasia and single agent chemotherapy should be avoided in young patients. CVP combination regimen (cyclophosphamide, vincristine and prednisone) shows equivalent efficacy to monochemotherapy. Several prospective and retrospective studies reported outcomes of first-line therapy with CHOP in overall 1343 patients (Dana 1993). A superior outcomes with CHOP as compared with CHOP-like regimens or with CVP-like regimens has not been confirmed so far (Brandt 2001; Barosi 2005). Fludarabine single-agent therapy was shown to be effective in indolent lymphoma with an overall response rate of 60-70% and CR rate of 30-37% (Coiffier 1999). In an EORTC randomised trial, fludarabine showed significantly better overall response rates than CVP; however, both time to progression and OS did not differ between the two arms (Hagenbeek 2006). Fludarabine-containing regimens with mitoxantrone ± dexamethasone were able to induce a overall response rate from 81% to 94% and a 4-year PFS near of 20% to 38% (McLaughlin 1996; Velasquez 2003). This regimen was recently shown to give a higher complete remission and molecular response rates than CHOP chemotherapy regimen in a randomized trial, although no survival benefit has been reported so far (Zinzani 2004). The addition of interferon-alfa 2b to primary chemotherapy was tested in randomized trials. In a meta-analysis of 8 randomized trials, a significant improvement in 5-year OS and PFS was reported (Allen 2001), but in a subsequent meta-analysis based on individual-patient data from 10 randomized trials (Rohatiner 2005), IFN addition to initial chemotherapy did not significantly improve the response rate, however, IFN significantly improved OS only when associated with a dose higher than 5 million units and a cumulative dose over 36 million units. At least on third of the patients treated with IFN combination therapy dropped out due to severe fatigue or toxicity. Taking into account toxicity and cost-effectiveness analysis, the combination of IFN and chemotherapy dose not balance a possible survival benefit. Chimeric anti-CD20 antibody (Rituximab) is effective in relapsed or refractory follicular lymphomas (Maloney 1997; McLaughlin 1998). Rituximab single-agent was also used in untreated patients with indolent NHL with stage III-IV disease and low tumor burden. With an overall response rates ranged from 72% to 100% and molecular response in peripheral blood was 53%. One-year PFS ranged from 69% to 80% and was from 32% to 49% at 3 years. Ongoing studies are comparing the efficacy of “wait and watch” strategy or radiotherapy with that of rituximab monotherapy in this subset of patients. Combination of rituximab to chemotherapy, either concurrent or sequential, has been proved to be effective in advanced stage follicular lymphoma who required treatment (Rambaldi 2002; Vitolo 2003; Czuczman 2004; Czuczman 2005). Four randomized studies, enrolling more than 1.000 patients, recently provided evidence on the efficacy of rituximab combined with CVP, CHOP, MCP or CHVP+IFN regimens in advanced-stage FL (Marcus 2005; Hiddemann 2005;Herold 2004; Salles 2004). The addition of rituximab to first line chemotherapy (CVP or CHOP) significantly increased overall response rates and prolonged TTF in both studies. A survival benefit was also shown with CHOP and Rituximab compared to CHOP alone (Hiddemann 2005). There is a strong evidence, on a type 1 level of evidence, on the benefit of adding rituximab to chemotherapy and the combination of rituximab to any type of conventional chemotherapy regimens should be considered the standard care as first line treatment in advanced stage follicular lymphoma who required treatment (Barosi 2005). The choice of chemotherapy largely depends on many factors such as: patient’s age and performance status, comorbidity, the pace of disease and the aim of the treatment, i.e. palliation or attempt to cure.

6.5 Treatment of stage III-IV high-risk follicular lymphoma

Standard option in stage III-IV high risk (IPI > 2, ILI > 2, FLIPI >2) follicular lymphoma has not been yet established. Conventional chemotherapy with the addition of Rituximab should be regarded as the standard treatment also in these patients outside clinical trials. The use of high-dose chemotherapy (HDC) supported by autologous stem cell transplantation (ASCT) as consolidation treatment in patients who achieved a remission after primary chemotherapy is an investigational option tested in phase II studies (Morel 1995; Ladetto 2002). With this approach a high overall and complete response rate has been reported with a 3-year PFS ranged from 40-65% and many patients achieved molecular remission, however the inclusion criteria differed between the trials and patients were not always selected as high risk ones. The effectiviness of fontline HDC+ASCT has been recently tested in randomized phase III studies by the GOLEAMS and GLSG study group (Deconink 2005; Lenz 2004). The German Low-grade Study Group (GLSG) trial showed that consolidation with myeloablative radiochemotherapy followed by autologous SCT, after CHOP-like therapy, compared to conventional IFN maintenance, prolonged PFS in 307 patients with FL in first remission (Lenz 2004). The GOLEAMS 064 trial, however, did not report a significant advantage in OS of autologous SCT at 56 months of median follow-up, while 5-year EFS increased from 48% to 60% (Deconink 2005). In a randomized comparison on 401 treatment-naive patients with advanced follicular lymphoma, there was not difference in terms of event-frre or overall survival between standard CHVP chemotherapy regimen (cyclophosphamide, doxorubicin, teniposide, and prednisone) plus interferon and 4 courses of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) followed by high-dose therapy with autologous stem cell transplantation (ASCT) (Sebban, Blood 2006). These observations seem to suggest that high-dose chemotherapy should be reserved for relapsing patients. None of these studies showed a plateau in survival curves after HDC + ASCT and no definite data are available comparing this approach with frontline chemoimmunotherapy. Such studies are ongoing and high risk follicular lymphoma patients less than 60 years should be encouraged to be enrolled into prospective clinical trials testing this approach compared to standard chemoimmunotherapy.

6.6 Maintenance Treatment of stage III-IV follicular lymphoma

The role of IFN maintenance therapy has been tested in many trials with conflicting results. A recent meta-analysis (Rohatiner 2005) analysed 10 randomized trials and concluded that IFN could not improve OS when administered as a maintenance therapy. Moreover, long-term IFN therapy severely impairs patients’ quality of life and such detrimental effect may offset the potential clinical benefit. Preliminary results supported the positive role of maintenance rituximab infusion on response duration in FL patients (Piro 1999). A Swiss trial showed that prolonging rituximab monotherapy for 4 to 8 doses induced a prolongation of median EFS in 185 patients with FL, from 12 to 23 months (Ghielmini 2004). The benefit of maintenance Rituximab after first line chemoimmunotherapy has not yet been demonstrated and the safety of long-term administration of Rituximab has not been fully evaluated. Rituximab maintenance treatment is stil an investigational approach and the real long-term benefit of rituximab in this setting should be tested in more randomized studies with adequate follow-up.

6.7 Treatment of relapsed or refractory follicular lymphoma

Histopathological transformation of low-grade FL to large cells aggressive NHL occurs frequently in the course of FL, especially within the first 6 years from diagnosis (Bastion 1997) and they have a dismal prognosis. Therefore histopathological reassessment is mandatory before any treatment decision in relapsed patients. Standard treatment in relapsed or refractory follicular lymphoma is controversial. It depends on prior treatment, duration of the time-to-relapse, patient’s age, and histological findings at relapse. To use again the same strategy used as first-line treatment is suitable for individual clinical use on a type R basis in aged patients with a long time-to-relapse and without high-grade transformation. Patients who did not respond to or relapsed after alkylator single-agent as first-line therapy might benefit of an antracycline- or fludarabine-based chemotherapy associated with Rituximab. Purine analogs, mainly in association, are suitable for individual clinical use on a type 3 level of evidence in patients relapsed after anthracycline-containing primary chemotherapy. Excellent results have been reported with fludarabine, which produces a response rate of 50% in relapsed cases (Zinzani 1997; McLaughlin 1996), and prospective evidence supports the use of rituximab. In refractory/relapsed patients, rituximab monotherapy achieved overall response rates of 48%, but CR was only 6%. The median duration of response is shorter than one year (McLaughlin 1998). Association of rituximab with chemotherapy is much more effective than single-agent therapy. In phase II studies enrolling patients with relapsed/resistant follicular lymphoma, the association of CHOP-like or fludarabine-based polychemotherapy with rituximab gave an overall response rate ranging from 82% to 97%. Moreover, chemoimmunotherapy with rituximab achieved molecular response in 70-90% of bcl2 positive patients. The elderly did not achieve lower response rates than the younger (Vitolo 2003). A randomized trial in patients with relapsed and refractory FL reported a prolonged PFS with the addition of rituximab to fludarabine, cyclophosphamide and mitoxantrone compared to FCM alone (Forstpointer 2004). High-dose chemotherapy (HDC) supported by autologous stem cell transplantation (ASCT) was shown to be superior to standard chemotherapy in retrospective controlled studies (Rohatiner 1994; Apostolidis 2000; Freedmann 1999; Brice 2000;Sabloff 2007) and in a randomised trial (Schouten 2003). The CUP trial, (Schouten 2003) comparing standard chemotherapy (CHOP) to autologous SCT in relapsed FL showed a nearly 50% reduction of relapse rate and a statistically significant improvement of PFS and OS by SCT. Status of disease at transplant is the best predictor for outcome after ASCT: in 419 FL patients undergoing autologous SCT 12-year OS and DFS was 61% and 37% and transplantation in second CR increased the risk of being disease-free by 2.3 (Conde 2002). Therefore HDC with ASCT is advisable in relapsed patients who achieved a response to re-induction chemotherapy. In a recently reported retrospective study (Vose 2008), histological grade 3, high-risk FLIPI score at the time of transplantation, and 3 or more previous chemotherapy regimens were significant factors for predicting a worse outcome. In addition, the use of a transplantation regimen including a monoclonal antibody decreased the relative risk of progressive lymphoma. These data suggest that transplantation earlier in the course of the disease for patients with follicular lymphoma with use of a monoclonal antibody-based regimen may lead to improved outcomes. The major long-term complications of autologous SCT were sMDS, occurring in 3% to 15% of patients in 5 years after transplantation (Apostolidis 1999; Milligan 1999; Micallef 2000). However in a report of the EBMT Working Party im almost 5000 lymphoma patients, the incidence of sMDS was only 3% (Milligan 1999). TBI conditioning was reported to increase the incidence of sMDS by up to fivefold and should be avoided (Brown 2005). Recently, conditioning strategies for autologous SCT have incorporated radioimmunoconiugate (Tositumobab or Ibritumobab) regimens suggesting a better outcome comapred with retrospective cases (Gopal 2003). However prospective controlled studies are still lacking. Lymphoma cells often contaminate bone marrow and peripheral blood stem cell collections and may contribute to relapse after autologous SCT. More recently, in vivo purging was achieved by administering rituximab prior to autologous SCT. Three-year relapse-free survival and 2-year PFS were 84% and 97%, respectively, in the most recent studies (Benekli 2003). A negative PCR status post-transplant also reduced the chance of death and was more relevant onto OS than the PCR status of the reinfused graft (Apostolidis 2000). Allogeneic bone marrow transplantation is also an investigational option, which has been associated with a 3-yr survival of 49% in high-risk relapsed patients (Mandigers 1998; van Besien 1998). Allogeneic SCT proved to have a high benefit-to-risk ratio, especially in chemosensitive young patients with excellent PS (van Besien 1998). A high number of trials indicate that long-term molecular remission are frequent, and a survival plateau in patients alive at 2 years from transplant was reported. In patients with no response to standard chemotherapy the chance of failure even with HDC and ASCT is high and these young patients, if a sibling donor is available, may benefit from allogeneic SCT. The incidence of post-transplant sMDS/AML is very low, (van Besien 2003) however, allogeneic SCT has an overall transplant related mortality (TRM) of about 20% at the latest reports (van Besien 2003; Bierman 2003) and TRM was higher in chemorefractory patients. An attempt to reduce TRM is the use of reduced intensity conditioning regimns in allogeneic transplantation. No randomised trial supported the superiority of reduced intensity conditioning over conventional conditioning, although TRM data retrospectively collected in mixed NHL cohorts would suggest it (Perez-Simon 2002; Khouri 2001; Robinson 2002). The role and place of allogeneic SCT in follicular lymphoma needs to be better defined, however the low relapse rate after allogeneic transplantation is strongly suggestive for the existence of a graft-versus-low-grade lymphoma effect. Radioimmunotherapy (RIT) is a relative new approach to follicular lymphomas and is another therapeutic option in patients not responding to or relapsing after first-line chemotherapy. RIC are effective in relapsed patients also outside a transplantation procedure. Beta-emitting anti-CD20 antibodies, i.e. tositumomab and ibritumomab, achieved 60%-70% overall response rate and 20%-35% CR (Kaminsky 2000; Witzig 2003; Emmanoulides 2003). Durable reponses were shown at long-term follow-up in large cohorts of patients with relapsed/ refractory follicular NHL treated with ibritumomab, tiuxetan or tositumomab. Complete responders kept the response status for over 24 months and median response duration was longer than for the previous line of therapy. 90Y-Ibritumomab was also more effective than rituximab single-agent in a randomized trial (Gordon 2004). Myelotoxicity is the most common adverse effect of these treatements with grade IV neutropenia occurring in 5% to 35% of the patients and grade IV thrombocytopenia occurring in 3% to 16%. However serious infections were rare occurring in 5% to 7% of the patients (Emmanouilides 2001). The risk of severe complications increased in patients with bone marrow involvement. Long-term complications of RIC included secondary myelodysplastic syndromes, however the actuarial risk is less than 1.5% that is not different from the risk observed after chemotherapy (Witzig 2003;Bennett 2005). This therapeutic modality has substantial promise for the future, either alone or in alternative to total-body irradiation as conditioning regimen for ASCT or as an adjunct to chemotherapy.

6.8 Treatment of high-grade transformed follicular lymphoma

The prognosis for transformed lymphoma is generally poor, being median survival from transformation about 10 months (Bastion 1997) thus accounting for a large proportion of mortality in patients with FL. Standard management for high-grade transformed follicular lymphomas is the same as for diffuse aggressive lymphomas. Outcome in transformed NHL treated with standard chemotherapy was poorer than for de novo diffuse large-cell lymphoma (DLCL). Age, response to salvage therapy, B symptoms, LDH values, bone marrow involvement, stage, no prior chemotherapy, and early transformation were all predictive factors for survival after transformation (Bastion 1997;Williams 2001). HDC and ASCT is advisable in young patients who respond to chemotherapy. Median OS from autologous SCT was reported to be 40-60% at 4-5 years (Williams 2001; Cao 2001) and 5-year DFS was about 30% in over 200 patients included in published series (Foran 1998). Survival after autologous SCT was not dissimilar to that reported for nontransformed indolent NHL and primarily aggressive NHL undergoing autologous SCT. In refractory cases, high-dose chemotherapy supported by allogeneic transplantation is an investigational option, may having something to offer in the setting of selected younger patients with a compatible marrow donor (van Besien 1995;Prezepiorka 1999). High overall response rates, ranging from 50% to 80%, and an acceptable safety were reported in transformed patients with a bone marrow involvement < 25% treated with radioimmunotherapy, ibritumomab and tositumomab (Kaminsky 2001; Witzig 2003). For the subset of patients with both the bcl-2 and the c-myc translocations, the results appeared to be particularly poor and no effective regimen was reported (Macpherson 1999).

6.9 New drugs and combinations in follicular lymphoma

Several investigational approaches are currently under investigation in phase II trials. Some forms of immunotherapy like idiotypic vaccinations against human B-cell lymphoma are being explored (Hawkins 1994; Stevenson 1995b; Stevenson 1995a). Immunization with patient- and tumor-specific vaccines using idiotypic proteins as immunogen has been applied in patients in first or second complete remission, obtaining a specific anti-idiotypic immune response in half of cases (Hsu 1997). Median time to progression in patients who developed an immune response was 7.3 years, in comparison to 1.3 years for those without immune response. This difference seems to be associated with a survival advantageous. An 18-base phosphorothionate-stabilized antisense oligonucleotide that is complementary to the first 6 codons of the bcl-2 mRNA has been administered to 5 patients with follicular lymphoma (Webb 1997). The aim of that trial was to restore apoptosis blocking the expression of bcl-2 gene. One complete remission and one minor response were seen. Expanded phase II trials are currently developed.

INDEX

Advani R, Rosenberg SA, Horning SJ. Stage I and II follicular non-Hodgkin’s lymphoma: long-term follow-up of no initial therapy. J Clin Oncol 2004; 22: 1454-1459 [ Medline]

Alkan S, Karcher DS. Low grade lymphomas in the elderly. Ann Clin Lab Sci 1995; 25: 218-227 [Medline]

Allen IE, Ross SD, Borden SP, Monroe MW, Kupelnick B, Connelly JE, et al. Meta-analysis to assess the efficacy of interferon-alpha in patients with follicular non-Hodgkin’s lymphoma. J Immunother 2001; 24: 58-65 [Medline]

Alt FW, Blackwell TK, Yancopoulos GD. Development of the primary antibody repertoire. Science 1987; 238: 1079-1087 [ Medline ]

Apostolidis J, Foran JM, Johnson PW, Norton A, Amess J, Matthews J, et al. Patterns of outcome following recurrence after myeloablative therapy with autologous bone marrow transplantation for follicular lymphoma. J Clin Oncol 1999; 17: 216-221 [Medline]

Apostolidis J, Gupta RK, Grenzelias D, Johnson PW, Pappa VI, Summers KE, et al. High-dose therapy with autologous bone marrow support as consolidation of remission in follicular lymphoma: long-term clinical and molecular follow-up. J Clin Oncol 2000; 18: 527-536 [Medline ]

Arbuck SG, Sorensen JM, Christian MC, Ho P, Pluda JM, Cheson BD. New drugs in non-Hodgkin’s lymphoma. Ann Oncol 1997; 8 Suppl 1:119-28.: 119-128 [ Medline]

Ardeshna KM, Smith P, Norton A, Hancock BW, Hoskin PJ, MacLennan KA, et al. Long-term effect of a watch and wait policy versus immediate systemic treatment for asymptomatic advanced-stage non-Hodgkin lymphoma: a randomised controlled trial. Lancet 2003; 362: 516-522 [Medline]

Armitage JO, Weisenburger DD. New approach to classifying non-Hodgkin’s lymphomas: clinical features of the major histologic subtypes. Non-Hodgkin’s Lymphoma Classification Project. J Clin Oncol 1998; 16: 2780-2795 [ Medline ]

Arranz R, Garcia-Alfonso P, Sobrino P, Zamora P, Carrion R, Garcia-Larana J, et al. Role of interferon alfa-2b in the induction and maintenance treatment of low-grade non-Hodgkin’s lymphoma: results from a prospective, multicenter trial with double randomization. J Clin Oncol 1998; 16: 1538-1546 [Medline]

Ataulfo GF, Armada B, Villegas A, Llorente L, Perez J, Diaz MJ, et al. [PCR study of bcl-2 rearrangement in autologous transplantation of peripheral stem cells in follicular non-Hodgkin’s lymphoma]. Med Clin (Barc ) 1997; 108: 730-733 [Medline ]

Ataulfo GF, Armada B, Villegas A, Llorente L, Perez J, Diaz MJ, et al. [PCR study of bcl-2 rearrangement in autologous transplantation of peripheral stem cells in follicular non-Hodgkin’s lymphoma]. Med Clin (Barc ) 1997; 108: 730-733 [ Medline]

Bakhshi A, Jensen JP, Goldman P, Wright JJ, McBride OW, Epstein AL, et al. Cloning the chromosomal breakpoint of t(14;18) human lymphomas: clustering around JH on chromosome 14 and near a transcriptional unit on 18. Cell 1985; 41: 899-906 [Medline]

Banks PM. Incorporation of immunostaining data in anatomic pathology reports. Am J Surg Pathol 1992; 16: 808 [ Medline]

Barosi G, Carella A, Lazzarino M, Marchetti M, Martelli M, Rambaldi A, et al. Management of nodal indolent (non marginal-zone) non-Hodgkin’s lymphomas: practice guidelines from the Italian Society of Hematology, Italian Society of Experimental Hematology and Italian Group for Bone Marrow Transplantation. Haematologica 2005; 90: 1236-1257 [ Medline]

Bartlett NL, Rizeq M, Dorfman RF, Halpern J, Horning SJ. Follicular large-cell lymphoma: intermediate or low grade? J Clin Oncol 1994; 12: 1349-1357 [Medline]

Bastion Y, Berger F, Bryon PA, Felman P, Ffrench M, Coiffier B. Follicular lymphomas: assessment of prognostic factors in 127 patients followed for 10 years. Ann Oncol 1991; 2 Suppl 2:123-9.: 123-129 [Medline]

Bastion Y, Sebban C, Berger F, Felman P, Salles G, Dumontet C, et al. Incidence, predictive factors, and outcome of lymphoma transformation in follicular lymphoma patients. J Clin Oncol 1997; 15: 1587-1594 [ Medline]

Ben Haim S, Bar-Shalom R, Israel O, Haim N, Epelbaum R, Ben Shachar M, et al. Utility of gallium-67 scintigraphy in low-grade non-Hodgkin’s lymphoma. J Clin Oncol 1996; 14: 1936-1942 [Medline]

Benekli M, Hahn T, Shafi F, Qureshi A, Alam AR, Czuczman MS, et al. Effect of rituximab on peripheral blood stem cell mobilization and engraftment kinetics in non-Hodgkin’s lymphoma patients. Bone Marrow Transplant 2003; 32: 139-143 [ Medline]

Bennett JM, Kaminski MS, Leonard JP, Vose JM, Zelenetz AD, Knox SJ, et al. Assessment of treatment-related myelodysplastic syndromes and acute myeloid leukemia in patients with non-Hodgkin lymphoma treated with tositumomab and iodine I131 tositumomab. Blood 2005; 105: 4576-4582 [ Medline]

Bentley M, Taylor K. Low-grade non-Hodgkin’s lymphoma–biology and therapeutic approaches. Aust N Z J Med 1997; 27: 150-155 [Medline]

Bentz M, Werner CA, Dohner H, Joos S, Barth TF, Siebert R, et al. High incidence of chromosomal imbalances and gene amplifications in the classical follicular variant of follicle center lymphoma. Blood 1996; 88: 1437-1444 [ Medline]

Berinstein N, White CA, Grillo-Lopez A, Maloney D, Jain V. IDEC-C2B8 (rituximab) levels correlate with response in low-grade or follicular non-Hodgkin’s lymphoma (LG-F NHL) (Meeting abstract). Proc Annu Meet Am Assoc Cancer Res 1997; 38 [ Medline]

Berinstein NL, Grillo-Lopez AJ, White CA, Bence-Bruckler I, Maloney D, Czuczman M, et al. Association of serum Rituximab (IDEC-C2B8) concentration and anti-tumor response in the treatment of recurrent low-grade or follicular non-Hodgkin’s lymphoma. Ann Oncol 1998; 9: 995-1001 [Medline]

Bernell P, Jacobsson B, Liliemark J, Hjalmar V, Arvidsson I, Hast R. Gain of chromosome 7 marks the progression from indolent to aggressive follicle centre lymphoma and is a common finding in patients with diffuse large B-cell lymphoma: a study by FISH. Br J Haematol 1998; 101: 487-491 [ Medline]

Besa PC, McLaughlin PW, Cox JD, Fuller LM. Long term assessment of patterns of treatment failure and survival in patients with stage I or II follicular lymphoma. Cancer 1995; 75: 2361-2367 [Medline]

Betticher DC, Zucca E, von Rohr A, Egger T, Radford JA, Ambrosetti A, et al. 2-chlorodeoxyadenosine (2-CDA) therapy in previously untreated patients with follicular stage III-IV non-Hodgkin’s lymphoma. Ann Oncol 1996; 7: 793-799 [Medline]

Bierman PJ, Sweetenham JW, Loberiza FR, Jr., Taghipour G, Lazarus HM, Rizzo JD, et al. Syngeneic hematopoietic stem-cell transplantation for non-Hodgkin’s lymphoma: a comparison with allogeneic and autologous transplantation–The Lymphoma Working Committee of the International Bone Marrow Transplant Registry and the European Group for Blood and Marrow Transplantation. J Clin Oncol 2003; 21: 3744-3753 [ Medline]

Brandt L, Kimby E, Nygren P, Glimelius B. A systematic overview of chemotherapy effects in indolent non-Hodgkin’s lymphoma. Acta Oncol 2001; 40: 213-223 [Medline]

Bremnes RM, Vik A, Helbekkmo N. Low-grade non-Hodgkin’s lymphoma in northern Norway: treatment, outcome, and prognostic factors. Anticancer Res 1998; 18: 1921-1929 [ Medline]

Brice P, Bastion Y, Lepage E, Brousse N, Haioun C, Moreau P, et al. Comparison in low-tumor-burden follicular lymphomas between an initial no-treatment policy, prednimustine, or interferon alfa: a randomized study from the Groupe d’Etude des Lymphomes Folliculaires. Groupe d’Etude des Lymphomes de l’Adulte. J Clin Oncol 1997; 15: 1110-1117 [ Medline]

Brice P, Simon D, Bouabdallah R, Belanger C, Haioun C, Thieblemont C, et al. High-dose therapy with autologous stem-cell transplantation (ASCT) after first progression prolonged survival of follicular lymphoma patients included in the prospective GELF 86 protocol. Ann Oncol 2000; 11: 1585-1590 [Medline]

Brown JR, Yeckes H, Friedberg JW, Neuberg D, Kim H, Nadler LM, et al. Increasing incidence of late second malignancies after conditioning with cyclophosphamide and total-body irradiation and autologous bone marrow transplantation for non-Hodgkin’s lymphoma. J Clin Oncol 2005; 23: 2208-2214 [Medline ]

Cao TM, Horning S, Negrin RS, Hu WW, Johnston LJ, Taylor TL, et al. High-dose therapy and autologous hematopoietic-cell transplantation for follicular lymphoma beyond first remission: the Stanford University experience. Biol Blood Marrow Transplant 2001; 7: 294-301 [Medline ]

Carbone PP, Kaplan HS, Musshoff K, Smithers DW, Tubiana M. Report of the Committee on Hodgkin’s Disease Staging Classification. Cancer Res 1971; 31: 1860-1861 [Medline]

Carde P, Burgers JM, van Glabbeke M, Hayat M, Cosset JM, Somers R, et al. Combined radiotherapy-chemotherapy for early stages non-Hodgkin’s lymphoma: the 1975-1980 EORTC controlled lymphoma trial. Radiother Oncol 1984; 2: 301-312 [Medline]

Carella AM, Cavaliere M, Lerma E, Ferrara R, Tedeschi L, Romanelli A, et al. Autografting followed by nonmyeloablative immunosuppressive chemotherapy and allogeneic peripheral-blood hematopoietic stem-cell transplantation as treatment of resistant Hodgkin’s disease and non-Hodgkin’s lymphoma. J Clin Oncol 2000; 18: 3918-3924 [Medline]

Cleary ML, Smith SD, Sklar J. Cloning and structural analysis of cDNAs for bcl-2 and a hybrid bcl-2/immunoglobulin transcript resulting from the t(14;18) translocation. Cell 1986; 47: 19-28 [Medline ]

Coiffier B, Neidhardt-Berard EM, Tilly H, Belanger C, Bouabdallah R, Haioun C, et al. Fludarabine alone compared to CHVP plus interferon in elderly patients with follicular lymphoma and adverse prognostic parameters: a GELA study. Groupe d’Etudes des Lymphomes de l’Adulte. Ann Oncol 1999; 10: 1191-1197 [Medline ]

Cole BF, Solal-Celigny P, Gelber RD, Lepage E, Gisselbrecht C, Reyes F, et al. Quality-of-life-adjusted survival analysis of interferon alfa-2b treatment for advanced follicular lymphoma: an aid to clinical decision making. J Clin Oncol 1998; 16: 2339-2344 [Medline]

Conde E, Insunza A, Lahuerta JJ, Sureda A, Caballero D, Arranz R, et al. Autologous Stem Cell Transplantation (ASCT) in 419 Patients with Follicular Lymphoma (FL). Blood 2002; 100 [ Medline]

Connors JM, Klasa R. Treatment of follicular lymphoma. Curr Opin Oncol 1998; 10: 392-395 [Medline]

Cooper K, Haffajee Z. bcl-2 and p53 protein expression in follicular lymphoma. J Pathol 1997; 182: 307-310 [Medline]

Czuczman M, Grillo-Lopez AJ, McLaughlin P, Link BK, Rogers J, Cabanillas F, et al. IDEC-C2B8 clears bcl-2 (t14;18) in patients (pts) with relapsed low grade or follicular lymphoma (LG/F NHL) (Meeting abstract). Proc Annu Meet Am Assoc Cancer Res 1997; 38 [Medline]

Czuczman MS, Koryzna A, Mohr A, Stewart C, Donohue K, Blumenson L, et al. Rituximab in combination with fludarabine chemotherapy in low-grade or follicular lymphoma. J Clin Oncol 2005; 23: 694-704 [ Medline ]

Czuczman MS, Weaver R, Alkuzweny B, Berlfein J, Grillo-Lopez AJ. 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. J Clin Oncol 2004; 22: 4711-4716 [Medline]

Dana BW, Dahlberg S, Nathwani BN, Chase E, Coltman C, Miller TP, et al. Long-term follow-up of patients with low-grade malignant lymphomas treated with doxorubicin-based chemotherapy or chemoimmunotherapy. J Clin Oncol 1993; 11: 644-651 [Medline ]

Davidge-Pitts M, Dansey R, Bezwoda WR. Prolonged survival in follicular non Hodgkins lymphoma is predicted by achievement of complete remission with initial treatment: results of a long-term study with multivariate analysis of prognostic factors. Leuk Lymphoma 1996; 24: 131-140 [ Medline]

Davidge-Pitts M, Dansey R, Bezwoda WR. Salvage treatment after failure or relapse following initial chemotherapy for follicular non-Hodgkin’s lymphoma. Leuk Lymphoma 1997; 24: 341-347 [Medline]

De Los Santos JF, Mendenhall NP, Lynch JW, Jr. Is comprehensive lymphatic irradiation for low-grade non-Hodgkin’s lymphoma curative therapy? Long-term experience at a single institution. Int J Radiat Oncol Biol Phys 1997; 38: 3-8 [Medline]

Decaudin D, Lepage E, Brousse N, Brice P, Harousseau JL, Belhadj K, et al. 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. J Clin Oncol 1999; 17: 2499-2505 [Medline]

Deconinck E, Foussard C, Milpied N, Bertrand P, Michenet P, Cornillet-LeFebvre P, et al. High-dose therapy followed by autologous purged stem-cell transplantation and doxorubicin-based chemotherapy in patients with advanced follicular lymphoma: a randomized multicenter study by GOELAMS. Blood 2005; 105: 3817-3823 [ Medline]

Denham JW, Denham E, Dear KB, Hudson GV. The follicular non-Hodgkin’s lymphomas–II. Prognostic factors: what do they mean? Eur J Cancer 1996; 32A: 480-490 [Medline]

Dolken G, Illerhaus G, Hirt C, Mertelsmann R. BCL-2/JH rearrangements in circulating B cells of healthy blood donors and patients with nonmalignant diseases. J Clin Oncol 1996; 14: 1333-1344 [Medline]

Dreyling MH, Roulston D, Bohlander SK, Vardiman J, Olopade OI. Codeletion of CDKN2 and MTAP genes in a subset of non-Hodgkin’s lymphoma may be associated with histologic transformation from low-grade to diffuse large-cell lymphoma. Genes Chromosomes Cancer 1998; 22: 72-78 [ Medline]

Elenitoba-Johnson KS, Gascoyne RD, Lim MS, Chhanabai M, Jaffe ES, Raffeld M. Homozygous deletions at chromosome 9p21 involving p16 and p15 are associated with histologic progression in follicle center lymphoma. Blood 1998; 91: 4677-4685 [Medline]

Emmanouilides C, Witzig TE, Molina A, Gordon LI, Multani PS, Wiseman GA, et al. Improved safety and efficacy of yttrium-90 ibritumomab tiuxetan radioimmunotherapy when administered as 2nd or 3rd line therapy for relapsed low-grade, follicular, and transformed B-cell non-Hodgkin’s lymphoma (NHL). Proc ASCO 2003; 22: 595 [Medline]

Emmanouilides C, Witzig TE, White CA, Gordon LI, Wiseman GA, Murray JL, et al. Zevalin?Radioimmunotherapy is associated with a low infection risk. Blood 2001; 98: 228b [ Medline]

Ezdinli EZ, Anderson JR, Melvin F, Glick JH, Davis TE, O’Connell MJ. Moderate versus aggressive chemotherapy of nodular lymphocytic poorly differentiated lymphoma. J Clin Oncol 1985;3:769-75 [Medline]

Federico M, Vitolo U, Zinzani PL, Chisesi T, Clo V, Bellesi G, et al. Prognosis of follicular lymphoma: a predictive model based on a retrospective analysis of 987 cases. Intergruppo Italiano Linfomi. Blood 2000; 95: 783-789 [Medline]

Foran JM, Apostolidis J, Papamichael D, Norton AJ, Matthews J, Amess JA, et al. High-dose therapy with autologous haematopoietic support in patients with transformed follicular lymphoma: a study of 27 patients from a single centre. Ann Oncol 1998; 9: 865-869 [ Medline]

Foran JM, Rohatiner AS, Norton AJ, Mathews J, Amess JL, Lister TA. High-dose (HD) therapy with autologous hematopoietic support in patients with transformed follicular lymphoma (FL): a study of 27 patients (pts) from a single centre (Meeting abstract). Proc ASCO 1997; 16: A59 [Medline]

Forstpointner R, Dreyling M, Repp R, Hermann S, Hanel A, Metzner B, et al. The addition of rituximab to a combination of fludarabine, cyclophosphamide, mitoxantrone (FCM) significantly increases the response rate and prolongs survival as compared with FCM alone in patients with relapsed and refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood 2004; 104: 3064-3071 [ Medline ]

Foussard C, Desablens B, Sensebe L, Francois S, Milpied N, Deconinck E, et al. Is the International Prognostic Index for aggressive lymphomas useful for low-grade lymphoma patients? Applicability to stage III-IV patients. The GOELAMS Group, France. Ann Oncol 1997; 8 Suppl 1:49-52.: 49-52 [Medline]

Freedman A, Neuberg D, Mauch P, Gribben J, Soiffer R, Anderson K, et al. Cyclophosphamide, doxorubicin, vincristine, prednisone dose intensification with granulocyte colony-stimulating factor markedly depletes stem cell reserve for autologous bone marrow transplantation. Blood 1997; 90: 4996-5001 [Medline ]

Freedman AS, Gribben JG, Neuberg D, Mauch P, Soiffer RJ, Anderson KC, et al. High-dose therapy and autologous bone marrow transplantation in patients with follicular lymphoma during first remission. Blood 1996; 88: 2780-2786 [ Medline]

Freedman AS, Neuberg D, Mauch P, Soiffer RJ, Anderson KC, Fisher DC, et al. Long-term follow-up of autologous bone marrow transplantation in patients with relapsed follicular lymphoma. Blood 1999; 94: 3325-3333 [Medline]

Friedberg JW, Freedman AS. High-dose therapy and stem cell transplantation in follicular lymphoma. Ann Hematol 1999; 78: 203-211 [Medline ]

Gaidano G, Pastore C, Capello D, Cilli V, Saglio G. Molecular pathways in low grade B-cell lymphoma. Leuk Lymphoma 1997; 26 Suppl 1:107-13.: 107-113 [ Medline]

Gallagher CJ, Gregory WM, Jones AE, Stansfeld AG, Richards MA, Dhaliwal HS, et al. Follicular lymphoma: prognostic factors for response and survival. J Clin Oncol 1986; 4: 1470-1480 [Medline]

Garvin AJ, Simon RM, Osborne CK, Merrill J, Young RC, Berard CW. An autopsy study of histologic progression in non-Hodgkin’s lymphomas. 192 cases from the National Cancer Institute. Cancer 1983; 52: 393-398 [Medline ]

Ghielmini M, Schmitz SF, Cogliatti SB, Pichert G, Hummerjohann J, Waltzer U, et al. Prolonged treatment with rituximab in patients with follicular lymphoma significantly increases event-free survival and response duration compared with the standard weekly x 4 schedule. Blood 2004; 103: 4416-4423 [ Medline]

Gopal AK, Gooley TA, Maloney DG, Petersdorf SH, Eary JF, Rajendran JG, et al. High-dose radioimmunotherapy versus conventional high-dose therapy and autologous hematopoietic stem cell transplantation for relapsed follicular non-Hodgkin lymphoma: a multivariable cohort analysis. Blood 2003; 102: 2351-2357 [Medline ]

Gordon LI, Witzig TE, Murray JL, Czuczman MS, Emmanouilides C, Joyce RM, et al. Yttrium-90 ibritumomab tiuxetan radioimmunotherapy produces high response rates and durable remissions in patients with relapsed or refractory low grade, follicular or transformed B-cell NHL: Final results of a randomized controlled trial. Proc ASCO 2004 [ Medline]

Haas R, Moos M, Mohle R, Dohner H, Witt B, Goldschmidt H, et al. High-dose therapy with peripheral blood progenitor cell transplantation in low-grade non-Hodgkin’s lymphoma. Bone Marrow Transplant 1996; 17: 149-155 [Medline]

Hagenbeek A, Carde P, Somers R, Thomas J, de Bock R, Raemaekers J, et al. Maintenance of remission with human recombinant alpha-2 interferon (Roferon-A) in patients with stage III and IV low grade malignant non-Hodgkin’s lymphoma. Results from a prospective, randomised phase III clinical trial in 331 patients. Blood 1992; 80: 74a. Blood 1992; 80: 74a [ Medline]

Hagenbeek A, Eghbali H, Monfardini S, Vitolo U, Hoskin PJ, Wolf-Peeters C, et al. Phase III intergroup study of fludarabine phosphate compared with cyclophosphamide, vincristine, and prednisone chemotherapy in newly diagnosed patients with stage III and IV low-grade malignant Non-Hodgkin’s lymphoma. J Clin Oncol 2006; 24: 1590-1596 [ Medline]

Hainsworth JD, Litchy S, Barton JH, Houston GA, Hermann RC, Bradof JE, et al. Single-agent rituximab as first-line and maintenance treatment for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma: a phase II trial of the Minnie Pearl Cancer Research Network. J Clin Oncol 2003; 21: 1746-1751 [Medline ]

Harris NL, Jaffe ES, Diebold J, Flandrin G, Muller-Hermelink HK, Vardiman J, et al. World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee meeting-Airlie House, Virginia, November 1997. J Clin Oncol 1999; 17: 3835-3849 [Medline ]

Harris NL, Jaffe ES, Stein H, Banks PM, Chan JK, Cleary ML, et al. A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood 1994; 84: 1361-1392 [Medline]

Hawkins RE, Zhu D, Ovecka M, Winter G, Hamblin TJ, Long A, et al. Idiotypic vaccination against human B-cell lymphoma. Rescue of variable region gene sequences from biopsy material for assembly as single-chain Fv personal vaccines. Blood 1994; 83: 3279-3288 [ Medline]

Herold M, Pasold R, Srock S, Neser S, Niederwieser D, Neubauer A, et al. Results of a Prospective Randomised Open Label Phase III Study Comparing Rituximab Plus Mitoxantrone, Chlorambucile, Prednisolone Chemotherapy (R-MCP) Versus MCP Alone in Untreated Advanced Indolent Non-Hodgkin’s Lymphoma (NHL) and Mantle-Cell-Lymphoma (MCL). ASH 2004 [ Medline]

Hickish T, Serafinowski P, Cunningham D, Oza A, Dorland E, Judson I, et al. 2′-Chlorodeoxyadenosine: evaluation of a novel predominantly lymphocyte selective agent in lymphoid malignancies. Br J Cancer 1993; 67: 139-143 [Medline ]

Hiddemann W, Griesinger F, Unterhalt M. Interferon alfa for the treatment of follicular lymphomas. Cancer J Sci Am 1998; 4 Suppl 2:S13-8 [Medline]

Hiddemann W, Kneba M, Dreyling M, Schmitz N, Lengfelder E, Schmits R, et al. Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood 2005; 106: 3725-3732 [ Medline]

Hiddemann W, Unterhalt M, Buske C, Sack H. Treatment of follicular follicle centre lymphomas: current status and future perspectives. J Intern Med 1997; 740 Suppl: 62 [ Medline]

Hockenbery DM, Zutter M, Hickey W, Nahm M, Korsmeyer SJ. BCL2 protein is topographically restricted in tissues characterized by apoptotic cell death. Proc Natl Acad Sci U S A 1991; 88: 6961-6965 [Medline]

Hollowood K, Goodlad JR. Follicular lymphomas. Histopathology 1996; 29: 195 [Medline]

Horning SJ, Negrin RS, Hoppe RT, Rosenberg SA, Chao NJ, Long GD, et al. High-dose therapy and autologous bone marrow transplantation for follicular lymphoma in first complete or partial remission: results of a phase II clinical trial. Blood 2001; 97: 404-409 [ Medline ]

Hsu FJ, Caspar CB, Czerwinski D, Kwak LW, Liles TM, Syrengelas A, et al. Tumor-specific idiotype vaccines in the treatment of patients with B-cell lymphoma–long-term results of a clinical trial. Blood 1997; 89: 3129-3135 [Medline]

Isaacson PG. Malignant lymphomas with a follicular growth pattern. Histopathology 1996; 28: 487-495 [Medline]

Jacobs JP, Murray KJ, Schultz CJ, Wilson JF, Goswitz MS, Stevens CW, et al. Central lymphatic irradiation for stage III nodular malignant lymphoma: long-term results. J Clin Oncol 1993; 11: 233-238 [ Medline ]

Jaffe ES, Shevach EM, Frank MM, Berard CW, Green I. Nodular lymphoma–evidence for origin from follicular B lymphocytes. N Engl J Med 1974; 290: 813-819 [Medline]

Johnson PW, Rohatiner AZ, Whelan JS, Price CG, Love S, Lim J, et al. Patterns of survival in patients with recurrent follicular lymphoma: a 20-year study from a single center. J Clin Oncol 1995; 13: 140-147 [Medline]

Juneja S, Matthews J, Lukeis R, Laidlaw C, Cooper I, Wolf M, et al. Prognostic value of cytogenetic abnormalities in previously untreated patients with non-Hodgkin’s lymphoma. Leuk Lymphoma 1997; 25: 493-501 [ Medline]

Kamath SS, Marcus RB, Jr., Lynch JW, Mendenhall NP. 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. Int J Radiat Oncol Biol Phys 1999; 44: 563-568 [Medline]

Kaminski MS, Estes J, Zasadny KR, Francis IR, Ross CW, Tuck M, et al. Radioimmunotherapy with iodine (131)I tositumomab for relapsed or refractory B-cell non-Hodgkin lymphoma: updated results and long-term follow-up of the University of Michigan experience. Blood 2000; 96: 1259-1266 [Medline ]

Kaminski MS, Zelenetz AD, Press OW, Saleh M, Leonard J, Fehrenbacher L, et al. Pivotal study of iodine I 131 tositumomab for chemotherapy-refractory low-grade or transformed low-grade B-cell non-Hodgkin’s lymphomas. J Clin Oncol 2001; 19: 3918-3928 [Medline]

Kay AC, Saven A, Carrera CJ, Carson DA, Thurston D, Beutler E, et al. 2-Chlorodeoxyadenosine treatment of low-grade lymphomas. J Clin Oncol 1992; 10: 371-377 [Medline]

Khouri IF, Saliba RM, Giralt SA, Lee MS, Okoroji GJ, Hagemeister FB, et al. Nonablative allogeneic hematopoietic transplantation as adoptive immunotherapy for indolent lymphoma: low incidence of toxicity, acute graft-versus-host disease, and treatment-related mortality. Blood 2001; 98: 3595-3599 [ Medline]

Klapper W, Hoster E, Rolver L, Schrader C, Janssen D, Tiemann M, et al. Tumor sclerosis but not cell proliferation or malignancy grade is a prognostic marker in advanced-stage follicular lymphoma: the German Low Grade Lymphoma Study Group. J Clin Oncol 2007; 25: 3330-3336 [Medline]

Kuppers R, Klein U, Hansmann ML, Rajewsky K. Cellular origin of human B-cell lymphomas. N Engl J Med 1999; 341: 1520-1529 [Medline]

Ladetto M, Corradini P, Vallet S, Benedetti F, Vitolo U, Martelli M, et al. High rate of clinical and molecular remissions in follicular lymphoma patients receiving high-dose sequential chemotherapy and autografting at diagnosis: a multicenter, prospective study by the Gruppo Italiano Trapianto Midollo Osseo (GITMO). Blood 2002; 100: 1559-1565 [ Medline]

Lennert K. Malignant lymphomas: other than Hodgkin’s disease: histology, cytology, ultrastructure, immunology. Berlin: Springer-Verlag. 1978 [Medline]

Lenz G, Dreyling M, Schiegnitz E, Forstpointner R, Wandt H, Freund M, et al. Myeloablative radiochemotherapy followed by autologous stem cell transplantation in first remission prolongs progression-free survival in follicular lymphoma: results of a prospective, randomized trial of the German Low-Grade Lymphoma Study Group. Blood 2004; 104: 2667-2674 [Medline]

Leonard RC, Hayward RL, Prescott RJ, Wang JX. The identification of discrete prognostic groups in low grade non-Hodgkin’s lymphoma. The Scotland and Newcastle Lymphoma Group Therapy Working Party. Ann Oncol 1991; 2: 655-662 [ Medline]

Limpens J, de Jong D, van Krieken JH, Price CG, Young BD, van Ommen GJ, et al. Bcl-2/JH rearrangements in benign lymphoid tissues with follicular hyperplasia. Oncogene 1991; 6: 2271-2276 [Medline]

Linassier C, Fouillard L, Milpied N, Tilly H, Pico J, Abgrall JF, et al. Value of autologous bone marrow transplantation (ABMT) in 42 patients with follicular lymphomas responsive to conventional chemotherapy: a “France Autogreffe” study. Cancer Detect Prev 1996; 20: 11-19 [Medline ]

Lister TA. Follicular lymphoma: grounds for optimism. Ann Oncol 1997; 8 Suppl 1:89-92.: 89-92 [Medline]

Lo Coco F, Gaidano G, Louie DC, Offit K, Chaganti RS, Dalla-Favera R. p53 mutations are associated with histologic transformation of follicular lymphoma. Blood 1993; 82: 2289-2295 [Medline]

Longo DL, DeVita VT, Jr., Duffey PL, Wesley MN, Ihde DC, Hubbard SM, et al. Superiority of ProMACE-CytaBOM over ProMACE-MOPP in the treatment of advanced diffuse aggressive lymphoma: results of a prospective randomized trial. J Clin Oncol 1991; 9: 25-38 [Medline ]

Longo DL. Solving the puzzle of follicular lymphoma. Cancer J Sci Am 1998; 4 Suppl 2:S1-4 [Medline]

Lopez-Guillermo A, Cabanillas F, McDonnell TI, McLaughlin P, Smith T, Pugh W, et al. Correlation of bcl-2 rearrangement with clinical characteristics and outcome in indolent follicular lymphoma. Blood 1999; 93: 3081-3087 [Medline]

Lopez-Guillermo A, Cabanillas F, McLaughlin P, Smith T, Hagemeister F, Rodriguez MA, et al. The clinical significance of molecular response in indolent follicular lymphomas. Blood 1998; 91: 2955-2960 [Medline ]

Lopez-Guillermo A, Montserrat E, Bosch F, Terol MJ, Campo E, Rozman C. Applicability of the International Index for aggressive lymphomas to patients with low-grade lymphoma. J Clin Oncol 1994; 12: 1343-1348 [Medline]

Mac Manus MP, Hoppe RT. 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. J Clin Oncol 1996; 14: 1282-1290 [Medline]

Mac Manus MP, Rainer Bowie CA, Hoppe RT. What is the prognosis for patients who relapse after primary radiation therapy for early-stage low-grade follicular lymphoma? Int J Radiat Oncol Biol Phys 1998; 42: 365-371 [ Medline]

Macpherson N, Lesack D, Klasa R, Horsman D, Connors JM, Barnett M, et al. Small noncleaved, non-Burkitt’s (Burkit-Like) lymphoma: cytogenetics predict outcome and reflect clinical presentation. J Clin Oncol 1999; 17: 1558-1567 [Medline]

Maloney DG, Grillo-Lopez AJ, White CA, Bodkin D, Schilder RJ, Neidhart JA, et al. IDEC-C2B8 (Rituximab) anti-CD20 monoclonal antibody therapy in patients with relapsed low-grade non-Hodgkin’s lymphoma. Blood 1997; 90: 2188-2195 [Medline ]

Maloney DG, Liles TM, Czerwinski DK, Waldichuk C, Rosenberg J, Grillo-Lopez A, et al. Phase I clinical trial using escalating single-dose infusion of chimeric anti-CD20 monoclonal antibody (IDEC-C2B8) in patients with recurrent B-cell lymphoma. Blood 1994; 84: 2457-2466 [ Medline]

Mandigers CM, Raemaekers JM, Schattenberg AV, Roovers EA, Bogman MJ, van der Maazen RW, et al. Allogeneic bone marrow transplantation with T-cell-depleted marrow grafts for patients with poor-risk relapsed low-grade non-Hodgkin’s lymphoma. Br J Haematol 1998; 100: 198-206 [Medline]

Mann RB, Berard CW. Criteria for the cytologic subclassification of follicular lymphomas: a proposed alternative method. Hematol Oncol 1983; 1: 187-192 [ Medline]

Manzke O, Titzer S, Tesch H, Diehl V, Bohlen H. CD3 x CD19 bispecific antibodies and CD28 costimulation for locoregional treatment of low-malignancy non-Hodgkin’s lymphoma. Cancer Immunol Immunother 1997; 45: 198-202 [ Medline]

Marcus R, Imrie K, Belch A, Cunningham D, Flores E, Catalano J, et al. CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma. Blood 2005; 105: 1417-1423 [Medline]

McDonnell TJ, Deane N, Platt FM, Nunez G, Jaeger U, McKearn JP, et al. bcl-2-immunoglobulin transgenic mice demonstrate extended B cell survival and follicular lymphoproliferation. Cell 1989; 57: 79-88 [Medline]

McLaughlin P, Cabanillas F, Hagemeister FB, Swan F, Jr., Romaguera JE, Taylor S, et al. CHOP-Bleo plus interferon for stage IV low-grade lymphoma. Ann Oncol 1993; 4: 205-211 [ Medline]

McLaughlin P, Fuller LM, Velasquez WS, Sullivan-Halley JA, Butler JJ, Cabanillas F. Stage I-II follicular lymphoma. Treatment results for 76 patients. Cancer 1986; 58: 1596-1602 [Medline ]

McLaughlin P, Grillo-Lopez AJ, Link BK, Levy R, Czuczman MS, Williams ME, et al. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol 1998; 16: 2825-2833 [Medline]

McLaughlin P, Hagemeister FB, Romaguera JE, Sarris AH, Pate O, Younes A, et al. Fludarabine, mitoxantrone, and dexamethasone: an effective new regimen for indolent lymphoma. J Clin Oncol 1996; 14: 1262-1268 [ Medline]

McQuaker IG, Haynes AP, Anderson S, Stainer C, Owen RG, Morgan GJ, et al. Engraftment and molecular monitoring of CD34+ peripheral-blood stem-cell transplants for follicular lymphoma: a pilot study. J Clin Oncol 1997; 15: 2288-2295 [ Medline]

Merup M, Spasokoukotskaja T, Einhorn S, Smith CI, Gahrton G, Juliusson G. Bcl-2 rearrangements with breakpoints in both vcr and mbr in non-Hodgkin’s lymphomas and chronic lymphocytic leukaemia. Br J Haematol 1996; 92: 647-652 [Medline]

Micallef IN, Lillington DM, Apostolidis J, Amess JA, Neat M, Matthews J, et al. Therapy-related myelodysplasia and secondary acute myelogenous leukemia after high-dose therapy with autologous hematopoietic progenitor-cell support for lymphoid malignancies. J Clin Oncol 2000; 18: 947-955 [Medline ]

Miettinen M, Lasota J. Polymerase chain reaction based gene rearrangement studies in the diagnosis of follicular lymphoma–performance in formaldehyde-fixed tissue and application in clinical problem cases. Pathol Res Pract 1997; 193: 9-19 [Medline]

Miller TP, LeBlanc M, Grogan TM, Fisher RI. Follicular lymphomas: do histologic subtypes predict outcome? Hematol Oncol Clin North Am 1997; 11: 893-900 [ Medline]

Milligan DW, Ruiz De Elvira MC, Kolb HJ, Goldstone AH, Meloni G, Rohatiner AZ, et al. Secondary leukaemia and myelodysplasia after autografting for lymphoma: results from the EBMT. EBMT Lymphoma and Late Effects Working Parties. European Group for Blood and Marrow Transplantation. Br J Haematol 1999; 106: 1020-1026 [ Medline]

Monfardini S, Banfi A, Bonadonna G, Rilke F, Milani F, Valagussa P, et al. Improved five year survival after combined radiotherapy-chemotherapy for stage I-II non-Hodgkin’s lymphoma. Int J Radiat Oncol Biol Phys 1980; 6: 125-134 [Medline ]

Montoto S, Davies AJ, Matthews J, Calaminici M, Norton AJ, Amess J, et al. Risk and clinical implications of transformation of follicular lymphoma to diffuse large B-cell lymphoma. J Clin Oncol 2007; 25: 2426-2433 [Medline ]

Morel P, Laporte JP, Noel MP, Lopez M, Douay L, Fouillard L, et al. Autologous bone marrow transplantation as consolidation therapy may prolong remission in newly diagnosed high-risk follicular lymphoma: a pilot study of 34 cases. Leukemia 1995; 9: 576-582 [Medline]

Muramatsu M, Akasaka T, Kadowaki N, Ohno H, Yamabe H, Edamura S, et al. Rearrangement of the BCL6 gene in B-cell lymphoid neoplasms: comparison with lymphomas associated with BCL2 rearrangement. Br J Haematol 1996; 93: 911-920 [ Medline]

Murtha AD, Rupnow BA, Hansosn J, Knox SJ, Hoppe R. Long-term follow-up of patients with Stage III follicular lymphoma treated with primary radiotherapy at Stanford University. Int J Radiat Oncol Biol Phys 2001; 49: 3-15 [ Medline]

Ngan BY, Chen-Levy Z, Weiss LM, Warnke RA, Cleary ML. Expression in non-Hodgkin’s lymphoma of the bcl-2 protein associated with the t(14;18) chromosomal translocation. N Engl J Med 1988; 318: 1638-1644 [Medline]

Ngan BY, Warnke RA, Wilson M, Takagi K, Cleary ML, Dorfman RF. Monocytoid B-cell lymphoma: a study of 36 cases. Hum Pathol 1991; 22: 409-421 [ Medline]

Nomdedeu JF, Baiget M, Gaidano G, Estivill C, Lasa A, Rubiol E, et al. p53 mutation in a case of blastic transformation of follicular lymphoma with double bcl-2 rearrangement (MBR and VCR). Leuk Lymphoma 1998; 29: 595-605 [ Medline]

O’Brien ME, Easterbrook P, Powell J, Blackledge GR, Jones L, MacLennan IC, et al. The natural history of low grade non-Hodgkin’s lymphoma and the impact of a no initial treatment policy on survival. Q J Med 1991; 80: 651-660 [Medline]

Ottensmeier C, Mead G. Histological transformation of indolent (follicular) lymphoma. Ann Oncol 1996; 7: 849-853 [ Medline]

Ozer H, Wiernik PH, Giles F, Tendler C. Recombinant interferon-alpha therapy in patients with follicular lymphoma. Cancer 1998; 82: 1821-1830 [ Medline]

Pendlebury S, el Awadi M, Ashley S, Brada M, Horwich A. Radiotherapy results in early stage low grade nodal non-Hodgkin’s lymphoma. Radiother Oncol 1995; 36: 167-171 [Medline]

Perea G, Altes A, Montoto S, Lopez-Guillermo A, Domingo-Domenech E, Fernandez-Sevilla A, et al. Prognostic indexes in follicular lymphoma: a comparison of different prognostic systems. Ann Oncol 2005; 16: 1508-1513 [ Medline]

Perez-Simon JA, Kottaridis PD, Martino R, Craddock C, Caballero D, Chopra R, et al. Nonmyeloablative transplantation with or without alemtuzumab: comparison between 2 prospective studies in patients with lymphoproliferative disorders. Blood 2002; 100: 3121-3127 [ Medline]

Petersen PM, Gospodarowicz M, Tsang R, Pintilie M, Wells W, Hodgson D, et al. Petersen PM, Gospodarowicz M, Tsang R, Pintilie M, Wells W, Hodgson D, et al. Long-term outcome in stage I and II follicular lymphoma following treatment with involved field radiation therapy alone. J Clin Oncol 2004; 22 (14S): 561 [Medline]

Peterson BA, Petroni GR, Frizzera G, Barcos M, Bloomfield CD, Nissen NI, et al. Prolonged single-agent versus combination chemotherapy in indolent follicular lymphomas: a study of the cancer and leukemia group B. J Clin Oncol 2003; 21: 5-15 [ Medline ]

Petroni GR, Johnson JL, Barcos M, Peterson BA. Second malignancies in patients with follicular, low grade lymphomas. An analysis of CALGB 7951 (Meeting abstract). Proc ASCO 1996; 15: A1284 [Medline]

Pezzella F, Tse AG, Cordell JL, Pulford KA, Gatter KC, Mason DY. Expression of the bcl-2 oncogene protein is not specific for the 14;18 chromosomal translocation. Am J Pathol 1990; 137: 225-232 [Medline]

Pinyol M, Cobo F, Bea S, Jares P, Nayach I, Fernandez PL, et al. p16(INK4a) gene inactivation by deletions, mutations, and hypermethylation is associated with transformed and aggressive variants of non-Hodgkin’s lymphomas. Blood 1998; 91: 2977-2984 [ Medline ]

Piro LD, White CA, Grillo-Lopez AJ, Janakiraman N, Saven A, Beck TM, et al. Extended Rituximab (anti-CD20 monoclonal antibody) therapy for relapsed or refractory low-grade or follicular non-Hodgkin’s lymphoma. Ann Oncol 1999; 10: 655-661 [Medline]

Piro LD. Purine nucleoside therapy of low-grade follicular lymphoma. Ann Oncol 1996a; 7 Suppl 6:S41-7.: S41-S47 [Medline]

Poetsch M, Weber-Matthiesen K, Plendl HJ, Grote W, Schlegelberger B. Detection of the t(14;18) chromosomal translocation by interphase cytogenetics with yeast-artificial-chromosome probes in follicular lymphoma and nonneoplastic lymphoproliferation. J Clin Oncol 1996; 14: 963-969 [ Medline]

Przepiorka D, van Besien K, Khouri I, Hagemeister F, Samuels B, Folloder J, et al. Carmustine, etoposide, cytarabine and melphalan as a preparative regimen for allogeneic transplantation for high-risk malignant lymphoma. Ann Oncol 1999; 10: 527-532 [Medline]

Rambaldi A, Carlotti E, Oldani E, Della S, I, Baccarani M, Cortelazzo S, et al. Quantitative PCR of bone marrow BCL2/IgH+ cells at diagnosis predicts treatment response and long-term outcome in follicular non-Hodgkin lymphoma. Blood 2005; 105: 3428-3433 [Medline ]

Rambaldi A, Lazzari M, Manzoni C, Carlotti E, Arcaini L, Baccarani M, et al. Monitoring of minimal residual disease after CHOP and rituximab in previously untreated patients with follicular lymphoma. Blood 2002; 99: 856-862 [Medline]

Risdall R, Hoppe RT, Warnke R. Non-Hodgkin’s lymphoma: a study of the evolution of the disease based upon 92 autopsied cases. Cancer 1979; 44: 529-542 [Medline]

Robinson SP, Goldstone AH, Mackinnon S, Carella A, Russell N, de Elvira CR, et al. Chemoresistant or aggressive lymphoma predicts for a poor outcome following reduced-intensity allogeneic progenitor cell transplantation: an analysis from the Lymphoma Working Party of the European Group for Blood and Bone Marrow Transplantation. Blood 2002; 100: 4310-4316 [ Medline]

Rodriguez J, McLaughlin P, Hagemeister FB, Fayad L, Rodriguez MA, Santiago M, et al. Follicular large cell lymphoma: an aggressive lymphoma that often presents with favorable prognostic features. Blood 1999; 93: 2202-2207 [Medline]

Rodriguez J, Pugh WC, Cabanillas F. T-cell-rich B-cell lymphoma. Blood 1993; 82: 1586-1589 [Medline]

Rohatiner AZ, Gregory WM, Peterson B, Borden E, Solal-Celigny P, Hagenbeek A, et al. Meta-analysis to evaluate the role of interferon in follicular lymphoma. J Clin Oncol 2005; 23: 2215-2223 [ Medline ]

Rohatiner AZ, Johnson PW, Price CG, Arnott SJ, Amess JA, Norton AJ, et al. Myeloablative therapy with autologous bone marrow transplantation as consolidation therapy for recurrent follicular lymphoma. J Clin Oncol 1994; 12: 1177-1184 [Medline]

Sabloff M, Atkins HL, ce-Bruckler I, Bredeson C, Fergusson D, Genest P, et al. A 15-year analysis of early and late autologous hematopoietic stem cell transplant in relapsed, aggressive, transformed, and nontransformed follicular lymphoma. Biol Blood Marrow Transplant 2007; 13: 956-964 [Medline ]

Sack H, Hoederath A, Stuschke M, Bohndorf W, Makoski HB, Muller RP, et al. [Radiotherapy of follicle center lymphoma. Results of a German multicenter and prospective study. Members of the Study Group “NHL-early stages”]. Strahlenther Onkol 1998; 174: 178-185 [ Medline]

Salles G, Foussard C, Nicolas M, Franck M, Chantal D, Thierry L, et al. Rituximab Added to áIFN+CHVP Improves the Outcome of Follicular Lymphoma Patients with a High Tumor Burden: First Analysis of the GELA-GOELAMS FL-2000 Randomized Trial in 359 Patients. ASH 2004 (abstract 160). ASH 2004 [Medline]

Sander CA, Yano T, Clark HM, Harris C, Longo DL, Jaffe ES, et al. p53 mutation is associated with progression in follicular lymphomas. Blood 1993; 82: 1994-2004 [ Medline]

Schouten HC, Qian W, Kvaloy S, Porcellini A, Hagberg H, Johnson HE, et al. High-dose therapy improves progression-free survival and survival in relapsed follicular non-Hodgkin’s lymphoma: results from the randomized European CUP trial. J Clin Oncol 2003; 21: 3918-3927 [ Medline]

Schouten IC, Raemaekers JJ, Kluin-Nelemans HC, van Kamp H, Mellink WA, van’t Veer MB. High-dose therapy followed by bone marrow transplantation for relapsed follicular non-Hodgkin’s lymphoma. Dutch HOVON Group. Ann Hematol 1996; 73: 273-277 [Medline ]

Sebban C, Mounier N, Brousse N, Belanger C, Brice P, Haioun C, et al. Standard chemotherapy with interferon compared with CHOP followed by high-dose therapy with autologous stem cell transplantation in untreated patients with advanced follicular lymphoma: the GELF-94 randomized study from the Groupe d’Etude des Lymphomes de l’Adulte (GELA). Blood 2006; 108: 2540-2544 [Medline ]

Seymour JF, Pro B, Fuller LM, Manning JT, Hagemeister FB, Romaguera J, et al. Long-term follow-up of a prospective study of combined modality therapy for stage I-II indolent non-Hodgkin’s lymphoma. J Clin Oncol 2003; 21: 2115-2122 [Medline ]

Solal-Celigny P, Brice P, Brousse N, Caspard H, Bastion Y, Haioun C, et al. Phase II trial of fludarabine monophosphate as first-line treatment in patients with advanced follicular lymphoma: a multicenter study by the Groupe d’Etude des Lymphomes de l’Adulte. J Clin Oncol 1996; 14: 514-519 [Medline]

Solal-Celigny P, Lepage E, Brousse N, Tendler CL, Brice P, Haioun C, et al. Doxorubicin-containing regimen with or without interferon alfa-2b for advanced follicular lymphomas: final analysis of survival and toxicity in the Groupe d’Etude des Lymphomes Folliculaires 86 Trial. J Clin Oncol 1998; 16: 2332-2338 [ Medline ]

Solal-Celigny P, Roy P, Colombat P, White J, Armitage JO, Arranz-Saez R, et al. Follicular lymphoma international prognostic index. Blood 2004; 104: 1258-1265 [Medline]

Soubeyran P, Eghbali H, Bonichon F, Trojani M, Richaud P, Hoerni B. Low-grade follicular lymphomas: analysis of prognosis in a series of 281 patients. Eur J Cancer 1991; 27: 1606-1613 [Medline]

Soubeyran P, Eghbali H, Trojani M, Bonichon F, Richaud P, Hoerni B. Is there any place for a wait-and-see policy in stage I0 follicular lymphoma? A study of 43 consecutive patients in a single center. Ann Oncol 1996; 7: 713-718 [ Medline ]

Stein RS, Magee MJ, Lenox RK, Cousar JB, Collins RD, Flexner JM, et al. Malignant lymphomas of follicular center cell origin in man. VI. Large cleaved cell lymphoma. Cancer 1987; 60: 2704-2711 [Medline]

Stevenson FK, Zhu D, King CA, Ashworth LJ, Kumar S, Hawkins RE. Idiotypic DNA vaccines against B-cell lymphoma. Immunol Rev 1995b; 145:211-28 [Medline]

Stevenson FK, Zhu D, King CA, Ashworth LJ, Kumar S, Thompsett A, et al. A genetic approach to idiotypic vaccination for B cell lymphoma. Ann N Y Acad Sci 1995a; 772:212-26 [ Medline ]

Stuschke M, Hoederath A, Sack H, Potter R, Muller RP, Schulz U, et al. Extended field and total central lymphatic radiotherapy in the treatment of early stage lymph node centroblastic-centrocytic lymphomas: results of a prospective multicenter study. Study Group NHL-fruhe Stadien. Cancer 1997; 80: 2273-2284 [Medline]

Summers KE, Goff LK, Wilson AG, Gupta RK, Lister TA, Fitzgibbon J. Frequency of the Bcl-2/IgH rearrangement in normal individuals: implications for the monitoring of disease in patients with follicular lymphoma. J Clin Oncol 2001; 19: 420-424 [Medline ]

Takimoto Y, Takafuta T, Imanaka F, Kuramoto A, Sasaki N, Nanba K. Histological progression of follicular lymphoma associated with p53 mutation and rearrangement of the C-MYC gene. Hiroshima J Med Sci 1996; 45: 69-73 [ Medline]

Tatham L, Tolbert P, Kjeldsberg C. Occupational risk factors for subgroups of non-Hodgkin’s lymphoma. Epidemiology 1997; 8: 551-558 [Medline]

Tilly H, Rossi A, Stamatoullas A, Lenormand B, Bigorgne C, Kunlin A, et al. Prognostic value of chromosomal abnormalities in follicular lymphoma. Blood 1994; 84: 1043-1049 [Medline ]

Tsujimoto Y, Cossman J, Jaffe E, Croce CM. Involvement of the bcl-2 gene in human follicular lymphoma. Science 1985; 228: 1440-1443 [ Medline]

Unterhalt M, Herrmann R, Tiemann M, Parwaresch R, Stein H, Trumper L, et al. Prednimustine, mitoxantrone (PmM) vs cyclophosphamide, vincristine, prednisone (COP) for the treatment of advanced low-grade non-Hodgkin’s lymphoma. German Low-Grade Lymphoma Study Group. Leukemia 1996; 10: 836-843 [Medline]

van Besien K, Loberiza FR, Jr., Bajorunaite R, Armitage JO, Bashey A, Burns LJ, et al. Comparison of autologous and allogeneic hematopoietic stem cell transplantation for follicular lymphoma. Blood 2003; 102: 3521-3529 [ Medline ]

van Besien K, Sobocinski KA, Rowlings PA, Murphy SC, Armitage JO, Bishop MR, et al. Allogeneic bone marrow transplantation for low-grade lymphoma. Blood 1998; 92: 1832-1836 [Medline]

van Besien KW, de Lima M, Giralt SA, Moore DF, Jr., Khouri IF, Rondon G, et al. Management of lymphoma recurrence after allogeneic transplantation: the relevance of graft-versus-lymphoma effect. Bone Marrow Transplant 1997; 19: 977-982 [Medline]

van Besien KW, Khouri IF, Giralt SA, McCarthy P, Mehra R, Andersson BS, et al. Allogeneic bone marrow transplantation for refractory and recurrent low-grade lymphoma: the case for aggressive management. J Clin Oncol 1995; 13: 1096-1102 [ Medline]

Velasquez WS, Lew D, Grogan TM, Spiridonidis CH, Balcerzak SP, Dakhil SR, et al. Combination of fludarabine and mitoxantrone in untreated stages III and IV low-grade lymphoma: S9501. J Clin Oncol 2003; 21: 1996-2003 [Medline]

Vitolo U, Boccomini C, Ladetto M, Pogliani E, Rota Scalabrini D, Tarella C, et al. A brief course of chemo-immunotherapy FND + Rituximab is effective to induce a high clinical and molecular response in elderly patients with advanced stage follicular lymphoma (FL) at diagnosis. Blood 2003; 102 [Medline]

Vose JM, Bierman PJ, Loberiza FR, Lynch JC, Bociek GR, Weisenburger DD, et al. Long-term outcomes of autologous stem cell transplantation for follicular non-Hodgkin lymphoma: effect of histological grade and Follicular International Prognostic Index. Biol Blood Marrow Transplant 2008; 14: 36-42 [ Medline]

Voso MT, Pantel G, Weis M, Schmidt P, Martin S, Moos M, et al. In vivo depletion of B cells using a combination of high-dose cytosine arabinoside/mitoxantrone and rituximab for autografting in patients with non-Hodgkin’s lymphoma. Br J Haematol 2000; 109: 729-735 [Medline]

Weaver CH, Schwartzberg L, Rhinehart S, West J, Zhen B, West WH, et al. High-dose chemotherapy with BUCY or BEAC and unpurged peripheral blood stem cell infusion in patients with low-grade non-Hodgkin’s lymphoma. Bone Marrow Transplant 1998; 21: 383-389 [Medline ]

Webb A, Cunningham D, Cotter F, Clarke PA, di Stefano F, Ross P, et al. BCL-2 antisense therapy in patients with non-Hodgkin lymphoma. Lancet 1997; %19;349: 1137-1141 [Medline]

Wendum D, Sebban C, Gaulard P, Coiffier B, Tilly H, Cazals D, et al. Follicular large-cell lymphoma treated with intensive chemotherapy: an analysis of 89 cases included in the LNH87 trial and comparison with the outcome of diffuse large B-cell lymphoma. Groupe d’Etude des Lymphomes de l’Adulte. J Clin Oncol 1997; 15: 1654-1663 [Medline]

Wilder RB, Jones D, Tucker SL, Fuller LM, Ha CS, McLaughlin P, et al. Long-term results with radiotherapy for Stage I-II follicular lymphomas. Int J Radiat Oncol Biol Phys 2001; 51: 1219-1227 [Medline]

Williams CD, Harrison CN, Lister TA, Norton AJ, Blystad AK, Coiffier B, et al. High-dose therapy and autologous stem-cell support for chemosensitive transformed low-grade follicular non-Hodgkin’s lymphoma: a case-matched study from the European Bone Marrow Transplant Registry. J Clin Oncol 2001; 19: 727-735 [Medline]

Witzig TE, White CA, Gordon LI, Wiseman GA, Emmanouilides C, Murray JL, et al. Safety of yttrium-90 ibritumomab tiuxetan radioimmunotherapy for relapsed low-grade, follicular, or transformed non-hodgkin’s lymphoma. J Clin Oncol 2003; 21: 1263-1270 [Medline ]

Yamazaki T, Kura Y, Sato Y, Irie T, Kaneita Y, Mochimaru J, et al. [Clinical outcomes in low grade follicular lymphoma]. Rinsho Ketsueki 1999; 40: 1-8 [Medline]

Yano T, Jaffe ES, Longo DL, Raffeld M. MYC rearrangements in histologically progressed follicular lymphomas. Blood 1992; 80: 758-767 [Medline]

Younes A, Sarris A, Consoli U, Rodriguez A, McLaughlin P, Huh Y, et al. A pilot study of high-dose interleukin-3 treatment of relapsed follicular small cleaved-cell lymphoma: hematologic, immunologic, and clinical results. Blood 1996; 87: 1698-1703 [Medline ]

Young RC, Longo DL, Glatstein E, Ihde DC, Jaffe ES, DeVita VT, Jr. The treatment of indolent lymphomas: watchful waiting v aggressive combined modality treatment. Semin Hematol 1988; 25: 11-16 [Medline]

Yuen AR, Kamel OW, Halpern J, Horning SJ. Long-term survival after histologic transformation of low-grade follicular lymphoma. J Clin Oncol 1995; 13: 1726-1733 [Medline]

Yunis JJ, Frizzera G, Oken MM, McKenna J, Theologides A, Arnesen M. Multiple recurrent genomic defects in follicular lymphoma. A possible model for cancer. N Engl J Med 1987; 316: 79-84 [Medline]

Zhang XY, Safah H, Mudad R, Maher E, Krause J, Miller A, et al. Frequency of BCL-2/J(H) translocations in peripheral blood of follicular lymphoma patients. Am J Hematol 1997; 55: 205-207 [Medline]

Zinzani PL, Bendandi M, Magagnoli M, Gherlinzoni F, Merla E, Tura S. Fludarabine-mitoxantrone combination-containing regimen in recurrent low-grade non-Hodgkin’s lymphoma. Ann Oncol 1997; 8: 379-383 [Medline]

Zinzani PL, Pulsoni A, Perrotti A, Soverini S, Zaja F, De Renzo A, et al. Fludarabine plus mitoxantrone with and without rituximab versus CHOP with and without rituximab as front-line treatment for patients with follicular lymphoma. J Clin Oncol 2004; 22: 2654-2661 [ Medline]

Dr. Andrés Ferreri (Associate Editor)
San Raffaele Scientific Institute – Milan, Italy
mail: ferreri.andres@hsr.it

Dr. Silvia Montoto (Reviewer)
Institute of Cancer and the CR-UK Clinical Centre Barts and The London Queen Mary’s School of Medicine and Dentistry – London, UK
mail: silvia.montoto@cancer.org.uk

Dr. Umberto Vitolo (Author)
Azienda Ospedaliera S.Giovanni Battista (Molinette)
mail: uvitolo@molinette.piemonte.it