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

NCT ID: NCT01208896

Last Updated: 2018-08-09

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 32 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-02-03
• Study Completion Date: 2017-09-28

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.

Conditions

Lymphoma, Follicular; Stem Cell Transplantation

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Rituximab

Group Type: EXPERIMENTAL

Reduced_intensity conditioning

Intervention Type: DRUG

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.

Interventions

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.

Intervention Type: DRUG

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Roche Pharma AG

INDUSTRY

Sponsor Role: collaborator

University Hospital, Bordeaux

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Stéphane VIGOUROUX, MD

Role: PRINCIPAL_INVESTIGATOR

University Hospital, Bordeaux

Locations

University Hospital Angers

Angers, 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 Necker-Enfants malades

Paris, , France

APHP Hôpital Saint Louis

Paris, , France

APHP Hôpital Pitié-Salpêtrière

Paris, , France

APHP Hôpital Henri-Mondor

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, , France

Countries

France

References

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.

Reference Type: BACKGROUND

PMID: 17242396 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 11739162 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 18411419 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 17488686 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 19324911 (View on PubMed)

Other Identifiers

CHUBX 2009/09

Identifier Type: -

Identifier Source: org_study_id