Clinical trial NCT01208896: Allogeneic Hematopoietic Stem Cell Transplantation After Reduced-intensity Conditioning for Relapsed Follicular Lymphoma
Official title: Safety and Efficacy of a Strategy of Allogeneic Hematopoietic Stem Cell Transplantation After Reduced-intensity Conditioning for Chemosensitive Relapsed Follicular Lymphoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Lymphoma, Follicular
Stem Cell Transplantation
Keywords: Allogeneic hematopoietic stem cell transplantation
Reduced-intensity conditioning
Chemosensitive relapsed follicular lymphoma
Lead sponsor: University Hospital, Bordeaux
Sponsor class: OTHER
Collaborators: name: Roche Pharma AG
First posted: 2010-09-24
Enrollment: 32
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This trial will evaluate the efficacy and the safety of a strategy of allogeneic stem cell transplantation including Rituximab in the conditioning regimen for the treatment of relapsed follicular lymphoma. The rationale for using Rituximab relies on a better control of the disease and a better prophylaxis of the graft versus host disease.

Detailed description: Follicular lymphomas are chemosensitive neoplasms characterized by a relentless succession of remissions and relapses when treated with conventional chemotherapy. The successive periods of remission are of shorter duration and patients invariably die of their disease. At first line, patients are treated with conventional chemotherapy. At first relapse, intensive chemotherapy with autologous stem cell transplantation (SCT) is often proposed.

Allogeneic hematopoietic stem cell transplantation after reduced-intensity conditioning (RIC-allo) is an option for patients relapsing after autologous SCT, allowing long-term progression free survival of 50 to 60%. The toxic mortality related to severe acute graft versus host disease (GVHD) remains a critical issue. The goal of our study is to test in a multicentric approach a strategy of RIC-allo including rituximab in order to reduce the incidence of acute GVHD.

Around half of patients with relapsed or refractory follicular lymphomas treated with allogeneic SCT achieve long-term progression free survival whatever the conditioning regimen. Because the median age of patients with follicular lymphoma is 55 years, a reduced intensity conditioning is the most appropriate option in this setting. The outcome of patients with a chemoresistant disease is usually poor because of a high toxic mortality. As a consequence, only patients with a chemosensitive disease will be included in this study. To further reduce the toxic mortality, it is critical to reduce the incidence of severe acute GVHD. A low incidence of acute GVHD could be obtained by the use of Rituximab before and after the transplantation as reported by the MD Anderson's experience in several hematological malignancies including follicular lymphoma. Their results are impressive in patients with follicular lymphoma with long-term survival of 85%. The favored hypothesis is a depletion of patient and donor B cells reducing the presentation of minor histocompatibility alloantigens. The benefit of Rituximab could also be explained by its anti-lymphoma effects that could compensate the putative reduction of a graft versus lymphoma effect due to a better control of GVHD.

The primary objective is to estimate 2-year overall survival in this setting.

Eligibility criteria: Inclusion Criteria:

* Age ≥ 18 and ≤ 65 years
* Follicular lymphoma confirmed by a biopsy at the last relapse.
* 2nd, 3rd or 4th complete or partial response according to Cheson's criteria 1 (Annexe 1)
* Relapse after autologous-SCT except if the absence of autologous SCT is due to a failure of collecting peripheral stem cells or investigator decision to not proceed to the autologous graft because of serious criteria
* Relapse after at least one line of treatment with rituximab
* Karnofsky index \> 70%
* HLA Matched related or unrelated donor (10/10 matching; HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-DQB1)
* Signed informed consent

Exclusion Criteria:

* Stable or progressive disease according to Cheson's criteria1 (Annexe 1)
* Absence of treatment with rituximab before the last relapse
* Cardiac insufficiency (ejection fraction \< 50% by echocardiography)
* Pulmonary disease characterized by DLCO \< 60%
* Renal insufficiency (clearance of creatinin \< 60 ml/min)
* Hepatic disease characterized by ASAT and/or ALAT and/or total bilirubin \> 2 times the upper normal value except in case of Gilbert's disease or hepatic lymphoma
* HIV positive test
* Bacterial, Viral or Fungal uncontrolled infections
* Pregnant or breast feeding woman
* Cancer in the last 5 years except in case of cutaneous baso-cellular cancer or epithelioma "in situ" of the uterine cervix

Primary outcomes:
measure: Overall survival
timeFrame: 2 year
Secondary outcomes:
measure: Toxic mortality
timeFrame: 2 year
measure: Progression free survival
timeFrame: 2 year
measure: Incidence of relapse
timeFrame: 2 year
measure: Grade II-IV acute GVHD incidence
timeFrame: 2 year
measure: Chronic GVHD incidence
timeFrame: 2 year
measure: Morbidity and adverse event
timeFrame: 2 year
measure: Hematologic reconstitution, Immunologic reconstitution, Chimerism
timeFrame: 2 years
Other outcomes:
Locations:
city: Angers Cedex 01
country: France
facility: University Hospital Angers
state: Angers
city: Besançon
country: France
facility: Service Hématologie, Hôpital Minjoz
city: Brest
country: France
facility: Service Hématologie, Hôpital Augustin Morvan
city: Caen
country: France
facility: University Hospital, Caen
city: Clermont-Ferrand
country: France
facility: Service Hématologie et Thérapie cellulaire, Pavillon Villemin Pasteur, CHU Clermont-Ferrand
city: Grenoble
country: France
facility: CHU Grenoble
city: Lille
country: France
facility: CHRU Lille
city: Limoges
country: France
facility: CHU Limoges
city: Lyon
country: France
facility: Hôpital Edouard Herriot
city: Montpellier
country: France
facility: Service Hématologie Oncologie, Hôpital Lapeyronie, CHU de Montpellier
city: Nancy
country: France
facility: CHU Nancy
city: Nantes
country: France
facility: Service Hématologie Clinique, CHU -Hôtel Dieu
city: Nice
country: France
facility: Service Hématologie Clinique, Hôpital Archet 1
city: Paris
country: France
facility: APHP Hôpital Necker-Enfants malades
city: Paris
country: France
facility: APHP Hôpital Saint Louis
city: Paris
country: France
facility: APHP Hôpital Pitié-Salpêtrière
city: Paris
country: France
facility: APHP Hôpital Henri-Mondor
city: Pessac
country: France
facility: Service des maladies du sang - Hôpital Haut-Lévêque - avenue de magellan
city: Poitiers
country: France
facility: CHU Poitiers - La Milétrie
city: Rennes
country: France
facility: Service Hématologie Clinique, Hôpital Pontchaillou
city: Rouen
country: France
facility: Centre Henri Becquerel
city: Saint Etienne
country: France
facility: Institut de Cancérologie de la Loire
city: Strasbourg
country: France
facility: Département d'Hématologie et d'Oncologie, Hôpital CHRU de Hautepierre
city: Toulouse
country: France
facility: Service Hématologie, Hôpital Purpan
city: Tours
country: France
facility: CHRU Tours
city: Villejuif
country: France
facility: Institut Gustave Roussy
Study officials:
affiliation: University Hospital, Bordeaux
name: Stéphane VIGOUROUX, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, Coiffier B, Fisher RI, Hagenbeek A, Zucca E, Rosen ST, Stroobants S, Lister TA, Hoppe RT, Dreyling M, Tobinai K, Vose JM, Connors JM, Federico M, Diehl V; International Harmonization Project on Lymphoma. Revised response criteria for malignant lymphoma. J Clin Oncol. 2007 Feb 10;25(5):579-86. doi: 10.1200/JCO.2006.09.2403. Epub 2007 Jan 22.
citation: Khouri IF, Saliba RM, Giralt SA, Lee MS, Okoroji GJ, Hagemeister FB, Korbling M, Younes A, Ippoliti C, Gajewski JL, McLaughlin P, Anderlini P, Donato ML, Cabanillas FF, Champlin RE. 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 Dec 15;98(13):3595-9. doi: 10.1182/blood.v98.13.3595.
citation: Khouri IF, McLaughlin P, Saliba RM, Hosing C, Korbling M, Lee MS, Medeiros LJ, Fayad L, Samaniego F, Alousi A, Anderlini P, Couriel D, de Lima M, Giralt S, Neelapu SS, Ueno NT, Samuels BI, Hagemeister F, Kwak LW, Champlin RE. Eight-year experience with allogeneic stem cell transplantation for relapsed follicular lymphoma after nonmyeloablative conditioning with fludarabine, cyclophosphamide, and rituximab. Blood. 2008 Jun 15;111(12):5530-6. doi: 10.1182/blood-2008-01-136242. Epub 2008 Apr 14.
citation: Vigouroux S, Michallet M, Porcher R, Attal M, Ades L, Bernard M, Blaise D, Tabrizi R, Garban F, Cassuto JP, Chevalier P, Facon T, Ifrah N, Renaud M, Tilly H, Vernant JP, Kuentz M, Bourhis JH, Bordigoni P, Deconinck E, Lioure B, Socie G, Milpied N; French Society of Bone Marrow Graft Transplantation and Cellular Therapy (SFGM-TC). Long-term outcomes after reduced-intensity conditioning allogeneic stem cell transplantation for low-grade lymphoma: a survey by the French Society of Bone Marrow Graft Transplantation and Cellular Therapy (SFGM-TC). Haematologica. 2007 May;92(5):627-34. doi: 10.3324/haematol.10924.
citation: Christopeit M, Schutte V, Theurich S, Weber T, Grothe W, Behre G. Rituximab reduces the incidence of acute graft-versus-host disease. Blood. 2009 Mar 26;113(13):3130-1. doi: 10.1182/blood-2009-01-200527. No abstract available.