Allogeneic Hematopoietic Stem Cell Transplantation After Reduced-intensity Conditioning for Relapsed Follicular Lymphoma

Lymphoma, Follicular Clinical Trial

— RITALLO  

Official title:

Safety and Efficacy of a Strategy of Allogeneic Hematopoietic Stem Cell Transplantation After Reduced-intensity Conditioning for Chemosensitive Relapsed Follicular Lymphoma

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01208896
• Other study ID #: CHUBX 2009/09
• Status: Completed
• Phase: Phase 2
• Start date: February 3, 2011
• Est. completion date: September 28, 2017

Study information

• Verified date: August 2018
• Source: University Hospital, Bordeaux
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 32
• Est. completion date: September 28, 2017
• Est. primary completion date: September 28, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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

Related Conditions & MeSH terms

• Lymphoma
• Lymphoma, Follicular
• Stem Cell Transplantation

Intervention

Drug:
• Reduced_intensity conditioning
The conditioning regimen is composed of Fludarabine (30 mg/m2) and Cyclophosphamide (750 mg/m2), both administered intravenously at Days -5, -4, -3 with Day 0 being the day of transplantation. Rituximab will be administered intravenously at 375 mg/m2 at Day -13 and 1000 mg/m2 at Days -6, +1, +8. Tacrolimus and low-doses of methotrexate will be used for prophylaxis of GVHD.

Locations

Country	Name	City	State
France	University Hospital Angers	Angers Cedex 01	Angers
France	Service Hématologie, Hôpital Minjoz	Besançon
France	Service Hématologie, Hôpital Augustin Morvan	Brest
France	University Hospital, Caen	Caen
France	Service Hématologie et Thérapie cellulaire, Pavillon Villemin Pasteur, CHU Clermont-Ferrand	Clermont-Ferrand
France	CHU Grenoble	Grenoble
France	CHRU Lille	Lille
France	CHU Limoges	Limoges
France	Hôpital Edouard Herriot	Lyon
France	Service Hématologie Oncologie, Hôpital Lapeyronie, CHU de Montpellier	Montpellier
France	CHU Nancy	Nancy
France	Service Hématologie Clinique, CHU -Hôtel Dieu	Nantes
France	Service Hématologie Clinique, Hôpital Archet 1	Nice
France	APHP Hôpital Henri-Mondor	Paris
France	APHP Hôpital Necker-Enfants malades	Paris
France	APHP Hôpital Pitié-Salpêtrière	Paris
France	APHP Hôpital Saint Louis	Paris
France	Service des maladies du sang - Hôpital Haut-Lévêque - avenue de magellan	Pessac
France	CHU Poitiers - La Milétrie	Poitiers
France	Service Hématologie Clinique, Hôpital Pontchaillou	Rennes
France	Centre Henri Becquerel	Rouen
France	Institut de Cancérologie de la Loire	Saint Etienne
France	Département d'Hématologie et d'Oncologie, Hôpital CHRU de Hautepierre	Strasbourg
France	Service Hématologie, Hôpital Purpan	Toulouse
France	CHRU Tours	Tours
France	Institut Gustave Roussy	Villejuif

Sponsors (2)

Lead Sponsor	Collaborator
University Hospital, Bordeaux	Roche Pharma AG

Country where clinical trial is conducted

France, 

References & Publications (5)

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. Epub 2007 Jan 22. — View Citation

Christopeit M, Schütte 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. — View 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. Erratum in: Blood. 2009 Feb 12;113(7):1613. — View 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. — View 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, Socié 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall survival		2 year
Secondary	Toxic mortality		2 year
Secondary	Progression free survival		2 year
Secondary	Incidence of relapse		2 year
Secondary	Grade II-IV acute GVHD incidence		2 year
Secondary	Chronic GVHD incidence		2 year
Secondary	Morbidity and adverse event		2 year
Secondary	Hematologic reconstitution, Immunologic reconstitution, Chimerism		2 years