No Benefit to Upfront Autologous Transplant for Follicular Lymphoma
No Benefit to Upfront Autologous Transplant for Follicular Lymphoma
Abstract & Commentary
By Andrew S. Artz, MD, MS, Section of Hematology/Oncology, University of Chicago. Dr. Artz reports no financial relationship to this field of study.
Synopsis: The role of autologous stem cell transplant (ASCT) in newly diagnosed follicular lymphoma (FL) patients is controversial. Patients were randomized to standard chemotherapy (CHVP) and interferon-alpha or chemotherapy (CHOP) followed by ASCT. Among 401 patients younger than 61 years of age with newly diagnosed advanced stage FL, event-free and overall survival did not statistically differ between the two cohorts. A trend existed for an event-free survival benefit in the ASCT arm for patients having a high FLIPI score. Based upon this study in the pre-monoclonal antibody era, upfront ASCT for FL should be reserved for clinical trials.
Source: Sebban 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.
Among the indolent lymphomas, follicular lymphoma (FL) is the most common subtype. The marked heterogeneity in outcome has lead to the development of scores to facilitate prognostication such as The Follicular Lymphoma International Prognostic Index (FLIPI).1 The disease is not usually considered curable although patient may have prolonged survival. Treatment is often initiated for advanced- and/or high-risk disease. The optimal treatment and the precise role of autologous stem cell transplant (ASCT) remains poorly defined. Generally, ASCT has been reserved for relapsed, transformed FL although some studies have suggested a benefit for ASCT for newly diagnosed FL after induction chemotherapy.2
Eligibility criteria included age younger than 61 years, recently diagnosed FL, and the need for treatment based upon advanced disease and/or symptoms. Pathology was centrally reviewed. Patients were randomized to either CHVP-I (cyclophosphamide, doxorubicin, teniposide or etoposide, and prednisone with interferon-alpha) or to CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) followed by ASCT. In the standard arm, 6 monthly courses of CHVP-I were given. For those achieving a PR or CR, they were then given CHVP-I every 2 months for 1 year for a total of 6 courses. In the ASCT group, patients received CHOP every 3 weeks for 4 cycles. Responding patients were mobilized with cyclophosphamide and G-CSF. The transplant preparative regimen consisted of cyclophosphamide 60 mg/kg/d, mesna 60 mg/kg/d and etoposide 150 followed by total body irradiation (TBI) of 10 Gy in 5 fractions.
The final analysis included 401 patients: 209 in the CHVP-I arm and 192 in the ASCT arm. After central review, 339 of the 401 had FL. Analysis was by intention to treat.
Seven-year event-free survival (EFS) estimates were 28% (95% CI, 21%-34%) for the CHVP-I arm and 38% (95% CI, 31%-45%) for ASCT arm (P = .11). Estimated 7-year overall survival was 71% (95% CI, 65%-71%) for the CHVP-I arm compared to 76% (95% CI, 69%-82%) for the ASCT arm. There was a trend for longer EFS for ASCT compared to CHVP-I in the intermediate and high FLIPI groups (P = 0.057).
Commentary
In this relatively large well-designed randomized study of standard chemotherapy and interferon maintenance compared to ASCT for untreated and newly diagnosed FL, no benefit either in progression-free or overall survival was seen with prolonged follow-up. Two prior randomized studies showed a considerable PFS benefit for upfront ASCT for FL compared to standard chemotherapy.3,4 How do we reconcile these results?
In one study by Deconinck and colleagues using purged autografts, there was no overall survival benefit, in part from secondary malignancies in the autologous arm.3 In a second study by Lenz and colleagues who studied FCL patients who achieved complete or partial remission after induction chemotherapy, they were then randomized to ASCT or further chemotherapy.4 Among the 245 randomized patients, the 5-year PFS rate was 64.7% for ASCT compared to the control arm of Q33.3% (P < .0001). Analysis of ASCT was restricted to patients who responded and eventually underwent ASCT (rather than intention to treat), thus introducing a source of potential bias. Because of the immature data, survival by study arm was not reported.
A closer inspection indicates the studies do not truly differ. Both of these studies had shorter follow-up then the present analysis. All three studies suggested an enhanced benefit in PFS in the high-risk subset identified by FLIPI. No study demonstrated a survival benefit. One may argue the long natural history of FL mandates even longer follow-up before a survival benefit will be detected. The potential for response to second-line agents (including rituximab) and the increased risk of therapy-related leukemia (if not other malignancies) after ASCT will likely preclude demonstrating a survival benefit. In short, none of these studies confirm a meaningful clinical benefit employing ASCT for patients with untreated FL.
The authors deserve credit for these randomized trials. However, in the era of monoclonal antibodies such as rituximab, which affords increased response rates and probably improved survival, the landscape has changed both for initial therapy and relapsed disease. We must be very cautious about inferences of benefit of ASCT in subset analysis of high-risk disease defined by FLIPI. Again, the high-response rate to rituximab and possibility of ameliorating the adverse prognosis of high-risk disease features may lessen the importance of this finding. Further, these are subset analysis and no survival benefit has been confirmed. It would be difficult to infer from these studies of ASCT prior to rituximab that even the high-risk subset defined by FLIPI should undergo an autograft. Even reserving ASCT for those FL patients who have an incomplete response to initial chemotherapy is problematic since the best outcomes with ASCT are achieved following a complete response to pre-transplant systemic therapy. Whether allogeneic hematopoietic transplant, which permits the infusion of a non-contaminated graft and the possibility of a graft-versus-lymphoma reaction, has any benefit requires study.
In summary, ASCT can not be recommended as front-line therapy for FL and should be reserved for clinical trials.
References
1. Solal-Celigny P, et al. Follicular lymphoma international prognostic index. Blood. 2004;104:1258-1265.
2. Williams CD, 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.
3. Deconinck E, 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.
4. Lenz G, 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.
The role of autologous stem cell transplant (ASCT) in newly diagnosed follicular lymphoma (FL) patients is controversial.Subscribe Now for Access
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