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High-dose chemotherapy followed by autologous and allogeneic hematopoietic stem cell transplantation in patients with follicular non-Hodgkin’s lymphoma in the rituximab era

Abstract

High-dose chemotherapy in lymphomas, and mainly non-Hodgkin’s lymphomas, has been advancing since the 1970s. This therapeutic strategy is based on the supposed existence of a dose-response curve for cytotoxic agents. However, the available data are contradictory, so high-dose chemotherapy cannot be guaranteed as consolidation treatment for first-remission follicular lymphoma or diffuse large cell lymphoma. The objective of this paper is to review the current knowledge about high-dose chemotherapy followed by hematopoietic stem cell transplantation in follicular non-Hodgkin’s lymphoma. The published studies on follicular lymphoma after first remission, recurrent follicular lymphoma, and transformed follicular ­lymphoma were assessed together with the data available on diffuse large cell lymphoma. During analysis of the studies, difficulties were encountered in comparing studies due to the heterogeneous nature of the data. High-dose chemotherapy as consolidation treatment after first remission or in recurrent or refractory disease was also analyzed.

Tumori 2015; 101(1): 2 - 7

Article Type: ORIGINAL RESEARCH ARTICLE

DOI:10.5301/tj.5000203

Authors

Ignacio García Escobar, Blanca Cantos Sánchez de Ibarg?en, Virginia Calvo de Juan, C. Maximiano Alonso, Miriam Méndez García, Antonio Carlos Sánchez Ruíz, Mariano Provencio Pulla

Article History

Disclosures

Financial support: None.
Conflict of interest: None.

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Introduction

High-dose chemotherapy in lymphomas has been advancing since the 1970s, mainly in non-Hodgkin’s lymphomas (NHL) and especially follicular lymphoma (FL) and diffuse large B cell lymphoma (DLBCL). The basic principle underlying high-dose chemotherapy is the supposed existence of a dose-response curve for cytotoxic agents with a short half-life and fundamentally medullar toxicity that permit subsequent hematological salvage.

Considering the 2 forms of hematopoietic stem cell transplant (HSCT), autologous HSCT (auto-HSCT) is not usually ­curative but may result in prolonged remissions, while allogeneic HSCT (allo-HSCT) may cure but is associated with high treatment-related mortality (TRM).

FL is the second most common type of NHL and accounts for between 15% and 30% of all lymphomas. Individual prognoses are difficult to make, although there have been some advances, especially after publication of the Follicular Lymphoma International Prognostic Index (FLIPI) (1).

The initial treatment of FL depends on the stage of the disease at presentation. Patients with early-stage disease may be cured with radiation therapy while patients with advanced stages are initially managed with an immunotherapy-based regimen (2). Defining the role of HSCT in the therapeutic algorithm is one of the major challenges in the management of this disease – especially in the rituximab era – and is the subject of ongoing clinical trials.

However, when we analyzed and compared the studies carried out to date, we encountered various difficulties due to differing selection criteria and conditioning or follow-up regimens.

Considering that the ideal timing of HSCT in FL is unknown, this review focuses on the current situation regarding the ­indications for autologous and allogeneic HSCT.

Role of high doses of chemotherapy to consolidate the first remission

Several phase II trials have been published, with most data deriving from pre-rituximab studies in which high-dose chemotherapy followed by hematopoietic stem cell transplantation improved relapse free survival compared with historic controls (3-4-5-6-7-8).

On the basis of these data, 4 multicenter randomized trials were initiated, 3 in the pre-rituximab era and 1 in the rituximab era. The German Low-Grade Lymphoma Study Group (GLSG), reported on by Lenz et al (9), studied the value of high-dose versus maintenance interferon in patients under 60 years of age who were in partial or complete first remission after 2 cycles of cyclophosphamide-doxorubicin-vincristine-prednisone (CHOP) or mitoxantrone-chlorambucil-­prednisone (MCF). A total of 240 patients were included. With a mean follow-up of 4.2 years, 31 relapses (27.2%) were observed in the high-dose arm versus 76 (60.3%) in the maintenance interferon arm, with 5-year progression-free survival (PFS) rates of 64.7% and 33.3%, respectively (p<0.0001), but without sufficient follow-up to detect differences in overall survival (OS).

Similar results were published by Gyan et al (10) from the French Groupe Ouest-Est des Leucémies et Autres Maladies du Sang (GOELAMS). Out of 172 patients randomized to receive high-dose chemotherapy followed by autologous purged stem cell transplantation or immunochemotherapy with cyclophosphamide, doxorubicin, teniposide, prednisone and interferon, higher response rates (69% vs 81%, p = 0.045) and longer 9-year progression-free survival (64% vs 39%; p = 0.004) were reported for patients receiving high-dose therapy than those receiving conventional treatment; the patients with worse FLIPI benefited most from high doses. A PFS plateau was observed in the high-dose-therapy group after 7 years, suggesting that in a subgroup of patients FL may be cured by auto-HSCT. However, no differences were observed in OS, due in part to excess mortality owing to the development of second tumors in patients given high doses.

This aspect was also indicated in the monitoring of GLSG patients, especially secondary to myelodysplastic syndromes (sMDS) and acute myeloid leukemia (AML), with an estimated risk at 5 years of 3.8% versus 0% in the interferon arm (11).

Moreover, the Groupe D’Etude des Lymphomes de l’Adulte (GELA) trial (12), which included 401 patients, did not find any advantage for those undergoing intensive treatment. ­Patients received 12 cycles of cyclophosphamide, doxorubicin, teniposide, and prednisone (CHVP) plus interferon alpha for 18 months, or 4 courses of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), followed by high-dose therapy with total-body irradiation and autologous stem cell transplantation. An intent-to-treat analysis after a median ­follow-up of 7.5 years showed that there were no differences in event-free survival (EFS) (p = 0.11) or OS (p = 0.53). This study showed that there was no statistically significant benefit in favor of first-line high-dose therapy in patients with FL.

To address the role of auto-HSCT in upfront consolidation of FL in the rituximab era, Ladetto et al of the Italian Gruppo Italiano Trapianto di Midollo Osseo (GITMO/IIL) published a phase III trial comparing a rituximab-supplement version of high-dose sequential chemotherapy (R-HDT) with 6 cycles of CHOP supplemented by an identical number of rituximab courses (CHOP-R) in 136 high-risk patients with FL (13). Intention to treat was analyzed with EFS as the primary endpoint. At a median follow-up of 51 months, the 4-year EFS rates were 28% and 61%, respectively (p<0.001), with no statistically significant difference in OS between the 2 arms (p = 0.96). Molecular remission was achieved in 44% of the patients treated with CHOP-R and 80% in those treated with R-HDT (p<0.001), and was the strongest independent predictor of outcome.

Finally, 2 meta-analyses have recently been published confirming the benefits of auto-HSCT in PFS but without any benefit in OS (14, 15).

In conclusion, a significant increase in PFS was demon­strated in favor of auto-HSCT, but to date no benefit in OS has been reported for autografting FL patients in first remission, with similar PFS results in patients receiving first-line rituximab chemoimmunotherapy versus those in the auto-HSCT arm. Therefore, taking into consideration strategies such as consolidation with radio-immunotherapy (16), rituximab maintenance (17), and/or rituximab retreatment (18), and in accordance with international guidelines (19, 20), routine use of auto-HSCT in first remission for FL patients should not be considered the first option. However, this is a field for clinical research seeking to reduce relapses, define better conditioning, select patients who can benefit from high doses, and reduce the risk of secondary neoplasms.

Role of allogeneic HSCT in first remission

Allo-HSCT is a potentially curative treatment modality for FL patients who would be considered incurable with conventional chemoimmunotherapy or auto-HSCT treatments in light of the lymphoma-free constitution of the graft and the graft-versus-lymphoma (GVL) immunological effect. Unfortunately, there are no randomized controlled trials to support its use for chemosensitive FL patients in first remission, and its indication is only supported by data from single institutions in small groups of high-risk FL patients with primary refractory disease despite multiple lines of treatment (21, 22). Due to its high toxicity, TRM is one of the major limitations of this procedure. However, with the introduction of reduced-intensity conditioning (RIC) regimens, this procedure will be considered more as a future treatment option. So that, according to existing evidence, currently allo-HSCT should only be offered in the context of clinical trials for this group of refractory FL patients in first remission.

Role of high doses in recurrent FL

Auto-HSCT has a better established role in patients with relapsed chemosensitive FL. The 5-year PFS ranges from 40% to 50% in most prospective and retrospectives studies (8, 23-24-25-26-27-28-28). As a result, several prognostic factors are being studied to determine their impact on the outcome in these patients. In this context, the number of chemotherapy regimens (especially in patients treated with more than 3 regimens), chemosensitivity, FLIPI at the time of transplant, and histological grade have to be considered (8, 23-24-25-26-27-28-29-30).

In the pre-rituximab era, Montoto et al (8) reported on a retrospective series from the European Group for Blood and Marrow Transplantation (EBMT) including 693 FL patients who underwent auto-HSCT. The 10-year PFS and OS were 31% and 52%, respectively, with a non-relapse mortality rate of 9%. In the multivariate analysis, advanced age, chemoresistant disease and conditioning regimens with total-body irradiation were correlated with inferior survival. Similarly, in a series of 241 FL patients, Kornacker et al (27) reported 10-year OS and PFS rates of 75% and 49%, respectively. Finally, Schouten et al (25) published the results of the CUP trial, the only randomized prospective study that compared auto-HSCT with standard therapy in relapsed FL patients. One hundred and forty patients were randomized to receive conventional chemotherapy, auto-HSCT with a purged graft, or auto-HSCT with an unpurged graft. The 4-year OS rates were 46%, 71% and 77%, respectively, with the limitation that the sample size was too small to extract definitive conclusions. The trial was closed prematurely due to low recruitment.

In the rituximab era, the GELA/GOELMANS group compared the impact of auto-HSCT with conventional treatment in 175 FL patients at first relapse (28), of whom 40% had received rituximab. The 3-year OS rate was significantly higher for the HSCT group (92% vs 63%, p = 0.0003). The study was limited by its retrospective nature and the fact that it was probably affected by a selection bias because only ­patients who were chemosensitive to salvage therapy underwent HSCT. In addition, Sebban et al (12) reported an analysis of the results obtained in groups of FL patients treated with various salvage therapies (GELF) including auto-HSCT. In patients treated with rituximab, no statistical differences were observed in PFS or OS when comparing groups with and without auto-HSCT. Similar to these authors, Rohatiner et al (24) published the results of a retrospective analysis which included 121 patients who received myeloablative therapy supported by autologous HSCT as consolidation of second or subsequent remissions. The survival of patients treated in second remission was significantly longer than the survival of patients treated later in the course of the lymphoma.

Therefore, in conclusion, it is difficult to assess which patients are better candidates for auto-HSCT. It seems clear that in chemoresistant patients, those treated with several lines of chemotherapy, patients with a poor performance status or those older than 70 years, auto-HSCT should be considered with caution. On the other hand, taking the consensus of international experts into consideration (31), it is probably a good alternative in first relapse with chemosensitive disease in patients with a short response duration to conventional immunochemotherapy (less than 3 years), patients with high FLIPI at relapse, or in order to maintain chemosensitivity in further relapses.

Graft purging

Several studies have explored the role of ex vivo purging (monoclonal antibodies, CD34+ cell selection, etc.) (32, 33) and in vivo purging (e.g., by rituximab) (34, 35) of autologous stem cell products with interesting results. But the absence of randomized trials to prove the curative potential of this strategy (25), and the possibility of infectious complications with ex vivo purging (36, 37) mean that this option is considered differently between different transplant institutions. Clinical research in this field is ongoing and, considering that rituximab can render autographs in PCR and that patients with bone marrow showing negative PCR for Bcl2/immunoglobulin-H rearrangement after purging have longer survival than those with persisting positive PCR (26, 38, 39), in vivo graft purging with rituximab should be taken into consideration.

Rituximab maintenance after auto-HSCT

There is evidence that relapsed FL patients could benefit from rituximab maintenance after autologous transplant. Phase II trials demonstrated the effectiveness and safety of maintenance therapy, and showed that it could eradicate minimal residual disease that persists after auto-HSCT (37, 40). Furthermore, a large randomized study from the EBMT showed significantly higher PFS rates in patients treated with maintenance rituximab (41). Therefore, there are data supporting this strategy, although it is not clear whether OS is improved and this continues to be an area of active investigation. Rituximab maintenance cannot yet be considered a standard option.

Role of myeloablative allo-HSCT in relapsed FL

Allo-HSCT is a curative modality for patients with FL. Indolent lymphomas are among the histological types most sensitive to the effect of GVL (42). This aspect can be of special relevance in disease regression after relapse, for decreasing doses of immunosuppression treatment, or after leukocyte infusions (43-44-45). When comparing auto and allo procedures, relapse rates are clearly favorable for allo- HSCT (25% vs 55% at 5 years), and the available data show a relapse-risk plateau 2-3 years after allo-HSCT, therefore suggesting the probability of cure in a proportion of LF patients (46, 47). Along these lines, 3 retrospective studies reported durable remissions with 5-year EFS rates ranging from 45% to 75% (48-49-50). However, no differences in OS were found, probably due to the high rate of TRM (35%-40%). In 2008 Kuruvilla et al (49) reported a 15% reduction in TRM, which was probably due to the chemosensitivity of the series and the use of syngeneic HSCT in 10% of the treated patients.

In conclusion, based on this evidence and the international lymphoma guidelines (19, 20), allo-HSCT should be considered the treatment option in selected patients with relapsed FL.

Role of RIC allo-HSCT for relapsed FL

While the effect of conventional allo-HSCT is based to a large extent on cytoreduction of high-dose chemotherapy, RIC-HSCT uses a donor-mediated GVL effect. The objective is to reduce TRM and extend the transplant age to more than 70 years.

Several clinical trials have been conducted to assess the feasibility of this procedure, which obtained PFS rates ranging from 43% to 75% with a median follow-up of 3-10 years (51-52-53-54-55).

Khouri et al (51) published the prospective trial with the longest follow-up of 107 months. The 47 patients with relapsed FL received fludarabine, cyclophosphamide and rituximab (FCR); high-dose rituximab was added at a maximum dose of 1000 mg/m2 in 75% of cycles to prolong serum concentrations. The 11-year EFS and OS rates were 72% and 78%, respectively. The effects of this high rituximab dose should be considered for its probable regulation of GVL or acute graft-versus-host disease (GVHD) (56).

The Blood and Marrow Transplant Clinical Network (BMT CTN) (Protocol 0701) is currently conducting a multicenter phase II trial of RIC for patients with relapsed FL after first complete response, with PFS at 2 years from time of transplant as the primary endpoint. Final data collection and primary outcome measurement are programmed for November 2014.

With regard to the origin of donors, some authors have proposed strategies to improve the high rates of GVHD associated with unrelated donors. Thomson et al (53) employed in vivo T cell depletion with alemtuzumab. The 4-year PFS, OS and TRM were 76%, 76% and 15%, respectively, with higher relapse rates that made frequent donor lymphocyte infusions necessary.

Taking these findings into consideration, the customary and appropriate question is now, Which is the correct transplant to offer relapsed FL patients? Unfortunately, there are no prospective trials comparing these options. The BMT CTN 0202 trial was closed early due to poor accrual. The 3-year PFS and OS were 63% vs 86% and 73% vs 100% for auto-HCST vs allo-HSCT, respectively. Cohen et al (57) recently reported a 96% 3-year PFS and OS with auto-HSCT followed by tandem RIC allo-HSCT. The superiority or not of this strategy is currently unknown and is included as part of an investigational strategy. Nevertheless, current evidence shows a low rate of TRM, a low risk of relapse, and no risk of sMDS/AML for RIC allo-HSCT (53, 54, 58) compared to auto-HSCT, so it could be considered a good curative-intent treatment option for clinically fit FL patients with a suitable donor and chemosensitive disease after several lines of treatment. Nonetheless, auto-HSCT could be reserved for patients unfit for allograft or without a suitable donor, with the disease in these cases being considered incurable.

Role of high doses in transformed FL

Over time a certain proportion of FL patients suffer a transformation to more aggressive histological forms. It is difficult to measure the exact percentage of patients in whom this occurs, but the most important studies calculate that around 26%-60% of patients will develop histological transformation (2). These patients have a very poor short-term prognosis, with a mean survival of 11 to 28 months. Transformed FL is usually treated as if it was an aggressive de novo lymphoma. Studies evaluating the effect of high-dose chemotherapy on relapses are few and had low numbers of patients (59). According to data from the European Bone Marrow Transplant Registry (60), disease-free survival at 5 years in 50 patients was 30%. When only patients with chemosensitive disease were considered, the figure was 69%, with no long-term survivors among those with chemoresistant disease. Similarly, no benefit was found for patients over 60 years of age (61). In any case, the poor prognosis of these patients suggests that high-dose chemotherapy could be a reasonable option for a selected subgroup of patients.

Conclusions

The optimal timing of auto-HSCT in patients with FL remains controversial. The results of 3 large randomized studies show no benefit of auto-HSCT as consolidation therapy in first complete remission. The same conclusion can be drawn when considering allo-HSCT outside clinical trials.

For patients with relapsed disease, it is difficult to define a group of better candidates for auto-HSCT. It is probably a good alternative in first relapse for patients with chemosensitive disease and with a short response duration to conventional immunochemotherapy (less than 3 years), especially those with high FLIPI at relapse. In that sense, strategies such as ex vivo or in vivo graft purging and maintenance treatment with rituximab after auto-HSCT should be taken into consideration for the future. Moreover, allo-HSCT should be considered an option in selected fit patients with a suitable donor and chemosensitive disease after several lines of treatment. Finally, in the group of patients with transformed FL, auto-HSCT can be considered an option in the poor-risk and chemosensitive group.

Disclosures

Financial support: None.
Conflict of interest: None.
References
  • 1. Solal-Céligny P.,Roy P.,Colombat P. Follicular lymphoma international prognostic index. Blood 2004; 104: 1258-1265 Google Scholar
  • 2. Horning SJ.,Rosenberg SA. The natural history of initially untreated low-grade non-Hodgkin’s lymphomas. N Engl J Med 1984; 311: 1471-1475 Google Scholar
  • 3. Apostolidis J.,Foran JM.,Johnson PW. Patterns of outcome following recurrence after myeloablative therapy with autologous bone marrow transplantation for follicular lymphoma. J Clin Oncol 1999; 17: 216-221 Google Scholar
  • 4. González-Barca E.,Fernández de Sevilla A.,Domingo-Claros A. Autologous stem cell transplantation (ASCT) with immunologically purged progenitor cells in patients with advanced stage follicular lymphoma after early partial or complete remission: toxicity, follow-up of minimal residual disease and survival. Bone Marrow Transplant 2000; 26: 1051-1056 Google Scholar
  • 5. Voso MT.,Martin S.,Hohaus S. Prognostic factors for the clinical outcome of patients with follicular lymphoma following high-dose therapy and peripheral blood stem cell transplantation (PBSCT). Bone Marrow Transplant 2000; 25: 957-964 Google Scholar
  • 6. Horning SJ.,Negrin RS.,Hoppe RT. 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 Google Scholar
  • 7. Colombat P.,Cornillet P.,Deconinck E. Value of autologous stem cell transplantation with purged bone marrow as first-line therapy for follicular lymphoma with high tumor burden: a GOELAMS phase II study. Bone Marrow Transplant 2000; 26: 971-977 Google Scholar
  • 8. Montoto S.,Canals C.,Rohatiner AZ. EBMT Lymphoma Working Party. Leukemia 2007; 21: 2324-2331 Google Scholar
  • 9. Lenz G.,Dreyling M.,Schiegnitz E. 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 Google Scholar
  • 10. Gyan E.,Foussard C.,Bertrand P. Groupe Ouest-Est des Leucémies et des Autres Maladies du Sang (GOELAMS). Blood 2009; 113: 995-1001 Google Scholar
  • 11. Lenz G.,Dreyling M.,Schiegnitz E. Moderate increase of secondary hematologic malignancies after myeloablative radiochemotherapy and autologous stem-cell transplantation in patients with indolent lymphoma: results of a prospective randomized trial of the German Low Grade Lymphoma Study Group. J Clin Oncol 2004; 22: 4926-4933 Google Scholar
  • 12. Sebban C.,Mounier N.,Brousse N. 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 Google Scholar
  • 13. Ladetto M.,De Marco F.,Benedetti F. Prospective, multicenter randomized GITMO/IIL trial comparing intensive (R-HDS) versus conventional (CHOP-R) chemoimmunotherapy in high-risk follicular lymphoma at ­diagnosis: the superior disease control of R-HDS does not translate into an overall survival advantage. Blood 2008; 111: 4004-4013 Google Scholar
  • 14. Al Khabori M.,de Almeida JR.,Guyatt GH.,Kuruvilla J.,Crump M. Autologous stem cell transplantation in follicular lymphoma: a systematic review and meta-analysis. J Natl Cancer Inst 2012; 104: 18-28 Google Scholar
  • 15. Schaaf M.,Reiser M.,Borchmann P.,Engert A.,Skoetz N. High-dose therapy with autologous stem cell transplantation versus chemotherapy or immuno-chemotherapy for follicular lymphoma in adults. Cochrane Database Syst Rev 2012; 1: - Google Scholar
  • 16. Morschhauser F.,Radford J.,Van Hoof A. Phase III trial of consolidation therapy with yttrium-90-ibritumomab tiuxetan compared with no additional therapy after first remission in advanced follicular lymphoma. J Clin Oncol 2008; 26: 5156-5164 Google Scholar
  • 17. Salles G.,Seymour JF.,Offner F. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet 2011; 377: 42-51 Google Scholar
  • 18. Khal BS.,Hong F.,Williams ME. Results of Eastern Cooperative Oncology Group protocol E4402 (RESORT): a randomized phase III study comparing two different rituximab dosing strategies for low tumor burden follicular lymphoma. Blood (ASH Annual Meeting Abstracts) 2011; 118: LBA6- Google Scholar
  • 19. NCCN Guidelines 2014. ; : - Google Scholar
  • 20. Dreyling M.,Ghielmini M.,Marcus R.,Salles G.,Vitolo U. Newly diagnosed and relapsed follicular lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2011; 22: vi59-vi63 Google Scholar
  • 21. Gopal AK.,Guthrie KA.,Rajendran J. ?°Y-Ibritumomab tiuxetan, fludarabine, and TBI-based nonmyeloablative allogeneic transplantation conditioning for patients with persistent high-risk B-cell lymphoma. Blood 2011; 118: 1132-1139 Google Scholar
  • 22. Hamadani M.,Benson DM.,Hofmeister CC. Allogeneic stem cell transplantation for patients with relapsed chemorefractory aggressive non-Hodgkin lymphomas. Biol Blood Marrow Transplant 2009; 15: 547-553 Google Scholar
  • 23. Vose JM.,Bierman PJ.,Loberiza FR. 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 Google Scholar
  • 24. Rohatiner AZ.,Nadler L.,Davies AJ. Myeloablative therapy with autologous bone marrow transplantation for follicular lymphoma at the time of second or subsequent remission: long-term follow-up. J Clin Oncol 2007; 25: 2554-2559 Google Scholar
  • 25. Schouten HC.,Qian W.,Kvaloy S. 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 Google Scholar
  • 26. Brown JR.,Feng Y.,Gribben JG. Long-term survival after autologous bone marrow transplantation for follicular lymphoma in first remission. Biol Blood Marrow Transplant 2007; 13: 1057-1065 Google Scholar
  • 27. Kornacker M.,Stumm J.,Pott C. Characteristics of relapse after autologous stem-cell transplantation for follicular lymphoma: a long-term follow-up. Ann Oncol 2009; 20: 722-728 Google Scholar
  • 28. Le Gouill S.,De Guibert S.,Planche L. Impact of the use of autologous stem cell transplantation at first relapse both in naive and previously rituximab exposed follicular lymphoma patients treated in the GELA/GOELAMS FL2000 study. Haematologica 2011; 96: 1128-1135 Google Scholar
  • 29. Keeney GE.,Gooley TA.,Pham RN. The pretransplant Follicular Lymphoma International Prognostic Index is associated with survival of follicular lymphoma patients undergoing autologous hematopoietic stem cell transplantation. Leuk Lymphoma 2007; 48: 1961-1967 Google Scholar
  • 30. Pham RN.,Gooley TA.,Keeney GE. The impact of histologic grade on the outcome of high-dose therapy and autologous stem cell transplantation for follicular lymphoma. Bone Marrow Transplant 2007; 40: 1039-1044 Google Scholar
  • 31. Montoto S.,Corradini P.,Dreyling M. Indications for hematopoietic stem cell transplantation in patients with follicular lymphoma: a consensus project of the EBMT-Lymphoma Working Party. Haematologica 2013; 98: 1014-1021 Google Scholar
  • 32. Freedman AS.,Neuberg D.,Mauch P. Long-term follow-up of autologous bone marrow transplantation in patients with relapsed follicular lymphoma. Blood 1999; 94: 3325-3333 Google Scholar
  • 33. Tarella C.,Corradini P.,Astolfi M. Negative immunomagnetic ex vivo purging combined with high-dose chemotherapy with peripheral blood progenitor cell autograft in follicular lymphoma patients: evidence for long-term clinical and molecular remissions. Leukemia 1999; 13: 1456-1462 Google Scholar
  • 34. Tarella C.,Zanni M.,Magni M. Rituximab improves the efficacy of high-dose chemotherapy with autograft for high-risk follicular and diffuse large B-cell lymphoma: a multicenter Gruppo Italiano Terapie Innnovative nei linfomi survey. J Clin Oncol 2008; 26: 3166-3175 Google Scholar
  • 35. Arcaini L.,Montanari F.,Alessandrino EP. Immunochemotherapy with in vivo purging and autotransplant induces long clinical and molecular remission in advanced relapsed and refractory follicular lymphoma. Ann Oncol 2008; 19: 1331-1335 Google Scholar
  • 36. Crippa F.,Holmberg L.,Carter RA. Infectious complications after autologous CD34-selected peripheral blood stem cell transplantation. Biol Blood Marrow Transplant 2002; 8: 281-289 Google Scholar
  • 37. Hicks LK.,Woods A.,Buckstein R. Rituximab purging and maintenance combined with auto-SCT: long-term molecular remissions and prolonged hypogammaglobulinemia in relapsed follicular lymphoma. Bone Marrow Transplant 2009; 43: 701-708 Google Scholar
  • 38. Mahé B.,Milpied N.,Mellerin MP. PCR detection of residual Bcl-2/IgH-positive cells after high-dose therapy with autologous stem cell transplantation is a prognostic factor for event-free survival in patients with low-grade follicular non-Hodgkin’s lymphoma. Bone Marrow Transplant 2003; 31: 467-473 Google Scholar
  • 39. Finke J. The role of stem cell transplantation in the treatment of follicular lymphoma. Semin Cancer Biol 2003; 13: 233-239 Google Scholar
  • 40. Brugger W.,Hirsch J.,Grünebach F. Rituximab consolidation after high-dose chemotherapy and autologous blood stem cell transplantation in follicular and mantle cell lymphoma: a prospective, multicenter phase II study. Ann Oncol 2004; 15: 1691-1698 Google Scholar
  • 41. Pettengell R.,Schmitz N.,Gisselbrecht C. European Group for Blood and Marrow Transplantation. Randomized study of rituximab in patients with relapsed or resistant follicular lymphoma prior to high-dose therapy as in vivo purging and to maintain remission following high-dose therapy [abstract]. J Clin Oncol 2010; 28: - Google Scholar
  • 42. Armand P.,Kim HT.,Ho VT. Allogeneic transplantation with reduced-intensity conditioning for Hodgkin and non-Hodgkin lymphoma: importance of histology for outcome. Biol Blood Marrow Transplant 2008; 14: 418-425 Google Scholar
  • 43. Mandigers CM.,Verdonck LF.,Meijerink JP.,Dekker AW.,Schattenberg AV.,Raemaekers JM. Graft-versus-lymphoma effect of donor lymphocyte infusion in indolent lymphomas relapsed after allogeneic stem cell transplantation. Bone Marrow Transplant 2003; 32: 1159-1163 Google Scholar
  • 44. van Besien KW.,de Lima M.,Giralt SA. Management of lymphoma recurrence after allogeneic transplantation: the relevance of graft-versus-lymphoma effect. Bone Marrow Transplant 1997; 19: 977-982 Google Scholar
  • 45. Bloor AJ.,Thomson K.,Chowdhry N. High response rate to donor lymphocyte infusion after allogeneic stem cell transplantation for indolent non-Hodgkin lymphoma. Biol Blood Marrow Transplant 2008; 14: 50-58 Google Scholar
  • 46. van Besien K.,Loberiza FR.,Bajorunaite R. Comparison of autologous and allogeneic hematopoietic stem cell ­transplantation for follicular lymphoma. Blood 2003; 102: 3521-3529 Google Scholar
  • 47. Peniket AJ.,Ruiz de Elvira MC.,Taghipour G. European Bone Marrow Transplantation (EBMT) Lymphoma Registry. An EBMT registry matched study of allogeneic stem cell transplants for lymphoma: allogeneic transplantation is associated with a lower relapse rate but a higher procedure-related mortality rate than autologous transplantation. Bone Marrow Transplant 2003; 31: 667-678 Google Scholar
  • 48. Toze CL.,Barnett MJ.,Connors JM. Long-term disease-free survival of patients with advanced follicular lymphoma after allogeneic bone marrow transplantation. Br J Haematol 2004; 127: 311-321 Google Scholar
  • 49. Kuruvilla J.,Pond G.,Tsang R.,Gupta V.,Lipton JH.,Messner HA. Favorable overall survival with fully myeloablative allogeneic stem cell transplantation for follicular lymphoma. Biol Blood Marrow Transplant 2008; 14: 775-782 Google Scholar
  • 50. Hosing C.,Saliba RM.,McLaughlin P. Long-term results favor allogeneic over autologous hematopoietic stem cell transplantation in patients with refractory or recurrent indolent non-Hodgkin’s lymphoma. Ann Oncol 2003; 14: 737-744 Google Scholar
  • 51. Khouri IF.,Saliba RM.,Erwin WD. Nonmyeloablative allogeneic transplantation with or without 90yttrium ibritumomab tiuxetan is potentially curative for relapsed follicular lymphoma: 12-year results. Blood 2012; 119: 6373-6378 Google Scholar
  • 52. Shea T.,Johnson J.,Westervelt P. Cancer and Leukemia Group B. Reduced-intensity allogeneic transplantation provides high event-free and overall survival in patients with advanced indolent B cell malignancies: CALGB 109901. Biol Blood Marrow Transplant 2011; 17: 1395-1403 Google Scholar
  • 53. Thomson KJ.,Morris EC.,Milligan D. T-cell-depleted reduced-intensity transplantation followed by donor leukocyte infusions to promote graft-versus-lymphoma activity results in excellent long-term survival in patients with multiply ­relapsed follicular lymphoma. J Clin Oncol 2010; 28: 3695-3700 Google Scholar
  • 54. Piñana JL.,Martino R.,Gayoso J. GELTAMO Group. Reduced intensity conditioning HLA identical sibling donor allogeneic stem cell transplantation for patients with follicular lymphoma: long-term follow-up from two prospective multicenter trials. Haematologica 2010; 95: 1176-1182 Google Scholar
  • 55. Rezvani AR.,Storer B.,Maris M. Nonmyeloablative allogeneic hematopoietic cell transplantation in relapsed, refractory, and transformed indolent non-Hodgkin’s lymphoma. J Clin Oncol 2008; 26: 211-217 Google Scholar
  • 56. Kharfan-Dabaja MA.,Cutler CS. Rituximab for prevention and treatment of graft-versus-host disease. Int J Hematol 2011; 93: 578-585 Google Scholar
  • 57. Cohen S.,Kiss T.,Lachance S. Tandem autologous-allogeneic nonmyeloablative sibling transplantation in relapsed follicular lymphoma leads to impressive progression-free survival with minimal toxicity. Biol Blood Marrow Transplant 2012; 18: 951-957 Google Scholar
  • 58. Khouri IF.,McLaughlin P.,Saliba RM. Eight-year experience with allogeneic stem cell transplantation for relapsed follicular lymphoma after nonmyeloablative conditioning with fludarabine, cyclophosphamide, and rituximab. Blood 2008; 111: 5530-5536 Google Scholar
  • 59. Friedberg JW.,Neuberg D.,Gribben JG. Autologous bone marrow transplantation after histologic transformation of indolent B cell malignancies. Biol Blood Marrow Transplant 1999; 5: 262-268 Google Scholar
  • 60. Williams CD.,Harrison CN.,Lister TA. European Bone Marrow Transplant Lymphoma Working Party. 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 Google Scholar
  • 61. Chen CI.,Crump M.,Tsang R.,Stewart AK.,Keating A. Autotransplants for histologically transformed follicular non-Hodgkin’s lymphoma. Br J Haematol 2001; 113: 202-208 Google Scholar

Authors

Affiliations

  • Medical Oncology Department, Puerta de Hierro-Majadahonda Universitary Hospital, Madrid - Spain

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