Long-term follow-up of autologous stem-cell transplantation for follicular and transformed follicular lymphoma

Despite the fact that follicular lymphomas are both chemo- and radiosensitive, the disease is generally non-curable. These lymphomas often undergo transformation to a more malignant state. In order to improve the prognosis, high-dose treatment with stem cell support has been tested, but its role in the treatment of this disease is still unclear. Fourteen men and eight women with a median age of 45 yr (34-59) were treated with high-dose therapy with autologous stem cell transplantation between 1987 and 1996. The patients were selected to undergo intensive therapy because of an estimated short survival (median < 3 yr), even though they had chemosensitive disease and adequate performance status. Eleven patients' lymphomas had transformed, and the other eleven patients had one or more unfavourable prognostic signs such as advanced stage, bulky disease, multiple relapses, or short remission duration. The conditioning regimen has varied over the period, but BEAC (Becenum, etoposide, cytarabine, cyclophosphamide) or etoposide/cyclophosphamide with or without total body irradiation (TBI) was used in most patients. Nine patients had their stem cells purged. After a median follow-up time of 74 months overall survival was 81% and disease-free survival 72%. One toxic procedure-related death occured. There was no difference in outcome between patients with a transformed lymphoma compared to those without transformation. The patients treated with TBI had a significantly worse outcome. Toxicity was also much higher in TBI-treated patients, including four cases of secondary malignancy (three myelodysplastic syndrome (MDS) cases and one patient with breast carcinoma). This retrospective study, with the longest follow-up time so far reported, shows a promising 6-yr DFS of 72% in a group of follicular lymphoma patients with a bad prognosis. The outcome of patients with transformed lymphoma compared to historical controls is especially encouraging. The high incidence of MDS is worrying. The role of TBI should be questioned because this and other studies have not shown any advantage of using TBI. In the absence of randomised trials the role of high-dose treatment for patients with follicular lymphoma is still not defined.     

Long-term follow-up demonstrates curative potential of autologous stem cell transplantation for relapsed follicular lymphoma

Although autologous stem cell transplantation (ASCT) can achieve durable responses in eligible patients with follicular lymphoma (FL), long-term follow-up is needed to determine if it has curative potential. This retrospective, multicenter study included 162 patients who received ASCT for relapsed FL in Alberta, Canada. With a median (range) follow-up time of 12.5 years (0.1–27.9), the 12-year time-to-progression (TTP) was 57% (95% confidence interval [CI] 49%–65%), time-to-next-treatment was 61% (95% CI 52%–69%), progression-free survival was 51% (95% CI 42%–59%) and overall survival was 69% (95% CI 60%–76%). A plateau emerged on the TTP curve at 57% starting 9 years after ASCT with no relapses occurring beyond this timepoint. Ten patients remained in remission 20 years or more after ASCT. Patients undergoing ASCT at first or second relapse had superior outcomes compared to third or later relapse (12-year TTP 61% vs. 34%), as did patients without progression of disease within 24 months (POD24) of frontline treatment versus those with POD24 (12-year TTP 67% vs. 50%). ASCT achieves high rates of durable remission in relapsed FL, with long-term follow-up revealing that more than 50% of transplanted patients may be functionally cured of their lymphoma. The optimal timing to consider ASCT is at first or second relapse, regardless of POD24 status.     

Conservative management of follicular non-Hodgkin's lymphoma in childhood

Among 447 children with non-Hodgkin's lymphoma (NHL) on the childhood U.K. registry, seven children with follicular (NHL) were identified. Four were male and their age ranged from 4.25 to 13.5 years (median 7.5); all had localized disease, Murphy's stage I ( n  = 4) and II ( n  = 3). Sites involved at presentation were cervical lymph nodes and tonsils ( n  = 5), ileum ( n  = 1) and parotid gland ( n  = 1). Three had complete surgical excision only and four had complete ( n  = 1) or incomplete excision ( n  = 3) followed by a short multi-agent chemotherapy regimen (UKCCSG 9001 protocol). With a median follow-up of 1.5 years (range 0.25–5 years) from diagnosis, six are alive in complete remission (CR) including three who had no chemotherapy.
These results confirm previous reports that follicular lymphomas in children are rare (1.5%) and tend to be localized at presentation. Their rarity makes it difficult to produce guidelines about treatment, but in localized cases a period of non-intervention may be justified.     

The differential effect of lenalidomide monotherapy in patients with relapsed or refractory transformed non-Hodgkin lymphoma of distinct histological origin

Transformed lymphoma (TL) represents a heterogeneous group of lymphomas with an aggressive course and poor prognosis. We assessed the clinical benefit of single‐agent lenalidomide based on histological origin, including transformed follicular lymphoma (tFL) and transformed chronic lymphocytic leukaemia/small lymphocytic lymphoma (tCLL/SLL). Our analysis included 33 patients with TL. Patients received lenalidomide at a median dose of 25 mg/d. The overall response rate (ORR) was 46%, with a median response duration of 12·8 months after a median follow‐up of 5·6 months. Median progression‐free survival was 5·4 months. Among patients with tFL, ORR was 57%, with a median response duration of 12·8 months. None of the patients with tCLL/SLL responded to lenalidomide monotherapy. The most common grade 3/4 adverse events were reversible myelosuppression. Our results suggest that the original lymphoma histology (i.e. FL) in TL patients may potentially be associated with response to salvage lenalidomide monotherapy.     

High-dose therapy and autologous stem cell transplantation for follicular lymphoma undergoing transformation to diffuse large B-cell lymphoma

The transformation of follicular lymphoma (FL) to high-grade histology occurs in up to 70% of patients. The role of hematopoietic stem cell transplantation (HSCT) in transformed FL is poorly defined. Twenty-four FL patients with histologically confirmed transformation to diffuse large B-cell lymphoma underwent unpurged autologous HSCT at our institution. Their median age was 56 yr. The median number of prior chemotherapies was 2 (range 1-6). Thirteen patients had residual nodal disease measuring more than 2 cm and four patients had bulky disease at the time of HSCT. Six patients had refractory disease at transplantation. At a median follow-up of 38 months, 3-yr progression-free survival following autologous HSCT was 40%. The 3-yr overall survival was 52%. The cumulative incidence of relapse and non-relapse mortality rate was 41% and 25%, respectively.     

How I manage patients with follicular lymphoma

Recent advances in the treatment of follicular lymphoma (FL) have provided insight into molecular and biological influences on pathogenesis and prognosis. Additionally, numerous available treatment strategies for both newly diagnosed and relapsed disease require thoughtful consideration of patient selection to avoid the burden of overtreatment and toxicities. This review provides a broad overview on our approach to managing patients with low grade FL.     

Diagnosis and management of follicular lymphoma: A comprehensive review

Follicular Lymphoma (FL) is an indolent lymphoma and may have various clinical courses. Worldwide, FL is the second most common non‐Hodgkin lymphoma (NHL) type after diffuse large B‐cell lymphoma. In this review article, the author is discussing relevant diagnostic tools, prognostic factors, and updated study results on the management of patients with newly diagnosed and relapsed/refractory FL. Controversies in the treatment, maintenance therapy, stem cell transplantation, and novel treatment approaches will be comprehensively discussed.     

Surveillance investigations after high-dose therapy with stem cell rescue for recurrent follicular lymphoma have no impact on management

Background

The impact of active surveillance, comprising annual computed tomography scanning and bone marrow biopsies, in the follow-up of patients after high-dose therapy with autologous stem cell rescue for recurrent follicular lymphoma was analyzed.

Design and Methods

Seventy-one of 99 patients who received high-dose therapy commenced the surveillance program. Response duration, time to next treatment and overall survival were compared according to whether disease progression had been diagnosed on the basis of surveillance investigations or on clinical grounds.

Results

After a median follow-up of 16 years, progression was documented by surveillance in 16 patients and clinically in 18, the median response duration being 2.4 and 2.3 years, respectively (P=NS). Ten patients with a relapse detected clinically started treatment immediately, contrasting with one patient whose relapse was detected by surveillance investigations. Five patients with relapses detected by surveillance investigations have not required treatment after a median follow-up of 18 years, whereas all but two patients with a relapse detected clinically have been treated. The median time to next treatment was 7 years for patients with a relapse identified by surveillance investigations and 4 years for those whose relapse was manifested clinically (P=0.03). Overall survival was not significantly different between the two groups.

Conclusions

Surveillance investigations, consisting of annual computed tomography scanning and bone marrow biopsies, have no impact on the management of patients with recurrent follicular lymphoma and do not improve the outcome of these patients.     

Extranodal diffuse follicular center lymphoma mimicking mantle cell lymphoma of the intestine

We report a case of diffuse follicular center lymphoma (FCL), which is a morphological variant of follicular lymphoma, resembling multiple lymphomatous polyposis (mantle cell lymphoma of the intestine). The patient was a 48-year-old Japanese man who was found, by colonoscopy, to have numerous small polypoid lesions along the entire large intestine. Abdominal computed tomography revealed hepatosplenomegaly and enlargement of multiple mesenteric lymph nodes. Histologically, the lesion was characterized by diffuse proliferation of small- to medium-sized lymphocytes with cleaved nuclei in the mucosa and submucosa. Immunohistochemical studies showed that the tumor cells were CD20+, CD10+, BCL-2+, CD5-, surface IgM-, and cyclin D1-. Moreover, a cytogenetic study showed a translocation at (14;18)(q32;q21). Finally, this case was diagnosed as diffuse FCL, although the tumor was mimicking mantle cell lymphoma.     

Secondary follicular lymphoma of the bone, transformed into large cell lymphoma, in a patient with chronic lymphocytic leukaemia: an uncommon manifestation of Richter's syndrome

Patients with chronic lymphocytic leukemia (CLL) are at a significantly increased risk of developing a second malignant neoplasm in the course of their disease. The occurrence of large cell lymphoma [Richter's syndrome (RS)] has been described in approximately 3-5% of CLL patients. Other types of secondary lymphoid malignancies are extremely rare. Here we describe a patient, heavily pretreated, with long history of CLL who developed a secondary follicular lymphoma, transformed into a diffuse large cell lymphoma (LCL), with isolated manifestation in the bone, a very rare manifestation of RS. CLL and LCL cells were of distinct clonal origin, as documented by DNA sequencing of the CDR3 regions. Twelve months after the completion of chemo- and local radiotherapy, the patient is still in remission.     

Maintenance rituximab or observation after frontline treatment with bendamustine-rituximab for follicular lymphoma

Bendamustine (B) with rituximab (R) is a standard frontline treatment for medically fit follicular lymphoma (FL) patients. The safety and efficacy of maintenance rituximab (MR) after BR induction has not been formally compared to observation for FL, resulting in disparate practice patterns. Prospective trials have shown benefit of MR after R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) or R-CVP (rituximab, cyclophosphamide, vincristine, prednisone), yet recent data from the GALLIUM study comparing outcomes of patients treated with chemotherapy with R or obinutuzumab (G) showed higher than anticipated fatal adverse events with BR/BG. In order to assess the efficacy and tolerability of MR after BR, we retrospectively collected data on 640 newly diagnosed patients treated with FL. We found that patients who achieved partial remission (PR) after ≥4 cycles of BR had improved duration of response (DOR) with MR vs. no maintenance, whereas those in complete remission did not. These findings were confirmed in a validation cohort. In the entire study population, the known fatal adverse event rate after BR was 2·5% and did not significantly differ in those receiving MR versus no maintenance. [Correction added on 14 January 2019, after online publication: The preceding sentence has been corrected in this current version.] Within the limitations inherent to retrospective analysis, these data suggest that FL patients with a PR to BR experience prolongation of remission with MR with an acceptable safety profile.     

Vascularization predicts overall survival and risk of transformation in follicular lymphoma

Follicular lymphoma patients display heterogeneous overall survival and variable risk of transformation. Recent studies have highlighted the role of the microenvironment. The contribution of microvessel density to follicular lymphoma survival remains controversial. We used a quantitative tumor mapping approach to determine whether the degree of vascularization correlated with outcome in a uniformly treated cohort. Whole-tissue sections of diagnostic biopsies from 84 cases were stained for CD34 and tumor-to-vessel-distance that encompassed 90% of the tumor (TVD₉₀) was determined using image analysis. Twenty-one cases with lower TVD₉₀ showed inferior overall survival (P=0.0001) and high risk of transformation (P=0.01). These cases significantly correlated with increased Lymphoma-Associated Macrophages (χ²=0.025). In multivariate analysis macrophages content, IPI and TVD₉₀ were independent predictors of overall survival (P=0.05, P=0.001 and P=0.01, respectively) and IPI and TVD₉₀ predicted risk of transformation (P=0.008 and P=0.08, respectively). Increased angiogenesis is an independent marker of inferior survival and may promote transformation.     

Transformation of follicular lymphoma to diffuse large B-cell lymphoma proceeds by distinct oncogenic mechanisms

This study was undertaken to further elucidate the biological mechanisms underlying the frequent event of transformation of follicular lymphoma (FL) to diffuse large B-cell lymphoma (t-FL). The gene expression profiles of 20 paired lymph node biopsies, derived from the same patient pre- and post-transformation, were analysed using the Lymphochip cDNA microarray. TP53 mutation analysis was performed and copy number alterations at the c-REL and CDNK2A examined. Immunohistochemistry was performed on an independent panel of paired transformation paraffin-embedded samples. Transformed follicular lymphoma was predominantly of the germinal centre B-like phenotype both at the mRNA and protein level. Despite this homogeneity, transformation proceeded by at least two pathways. One mechanism was characterised by high proliferation, as assessed by the co-ordinately expressed genes of the proliferation signature. This group was associated with the presence of recurrent oncogenic abnormalities. In the remaining cases, proliferation was not increased and transformation proceeded by alternative routes as yet undetermined. Genes involved in cellular proliferation prevailed amongst those that were significantly increased upon transformation and T cell and follicular dendritic-associated genes predominated amongst those that decreased. t-FL is a germinal centre B (GCB)-like malignancy that evolves by two pathways, one that is similar in proliferation rate to the antecedent FL and the other that has a higher proliferation rate and is characterised by the presence of recognised oncogenic abnormalities.