Immunochemotherapy, in Vivo Purging, PBSC Mobilization and Autotransplant in Relapsed or Refractory Follicular Lymphoma

• Sponsor: IRCCS Policlinico S. Matteo (Other)
• Overall Status: Completed
• CT.gov ID: NCT00366275
• Collaborator: (none)
• Enrollment: 64
• Location: 1
• Arm: 1
• Duration (Months): 68
• Patients Per Site Per Month: 0.9

Study Details

Study Description

Brief Summary

The purpose of this study is to determine the rate and duration of complete remission and molecular response in patients with relapsed/refractory follicular lymphoma, using a combined treatment with rituximab plus chemotherapy followed by in vivo purged peripheral blood stem cells (PBSC) mobilization and autotransplant.

Condition or Disease	Intervention/Treatment	Phase
Follicular Lymphoma	Procedure: Immunochemotherapy, in vivo purging and autrotransplant	Phase 2

Detailed Description

Autologous stem cell transplantation has been shown effective in the long-term control of follicular lymphoma. Lymphoma, however, can progress after high-dose treatments. Lymphoma cells have been proved to contaminate bone marrow and peripheral blood stem cells (PBSC) collections and may contribute to relapse after autotransplant. The presence in peripheral blood and marrow of PCR-detectable cells bearing the bcl-2 rearrangement appeared to be a surrogate marker of disease and the achievement of a bcl-2 negative status is associated with a lower risk of recurrence. Several methods have been attempted to abolish graft contamination: in vitro treatment with cytotoxic agents, in vitro treatment with anti-B-cell monoclonal antibodies and complement, immunomagnetic beads, positive selection of CD34+ cells. All these techniques usually produce loss of cells, are time-consuming and expensive, and neoplastic depletion is often partial with residual polymerase chain reaction (PCR)-positive cells in the graft.

In the last years the chimeric anti-CD20 monoclonal antibody Rituximab has been shown to be an effective therapeutic option for low-grade lymphoma. Owing to the different mechanism of action, the synergism with cytotoxic agents, and the non-overlapping toxicity, Rituximab is an ideal drug for combination with chemotherapy. On this basis, Rituximab has been used during mobilisation procedures as a tool to obtain in vivo purging and collection of lymphoma-free progenitor cells. In addition, several studies have demonstrated that the efficiency of peripheral blood stem cells (PBSC) harvested is not adversely affected by Rituximab and that engraftment and all parameters of hematopoietic recovery are not compromised. The incorporation of Rituximab into sequential high-dose therapy programs produced high rates of clinical and molecular remission in patients with indolent lymphoma, indicating that the antibody has an additive effect on chemotherapy.

Study Design

• Study Type: Interventional
• Actual Enrollment: 64 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II of Immunochemotherapy, in Vivo Purging, PBSC Mobilization and Autotransplant in Patients With Relapsed or Refractory Follicular Lymphoma
• Study Start Date: Jan 1, 2002
• Actual Primary Completion Date: Jan 1, 2007
• Actual Study Completion Date: Sep 1, 2007

Arms and Interventions

Arm

Intervention/Treatment

Experimental: In vivo purging autotransplant

Procedure: Immunochemotherapy, in vivo purging and autrotransplant; 2-4 courses every 3 weeks with rituximab 375 mg/m^2 on day 1, vincristine 1.4 mg/m^2 on day 2 and cyclophosphamide 400 mg/m^2 on days 2-6. Courses were started if granulocytes >1.5 · 10^9/l. The phase of peripheral blood stem cells (PBSC) mobilization coupled rituximab 375 mg/m^2 on days 1 and 9 with high-dose cytarabine (AraC) 2 g/m^2 every 12 hours on days 2 and 3. Granulocyte colony-stimulating factor (G-CSF)(5 mcg/kg/day subcutaneously) was administered from day 6. High-dose chemotherapy with autotransplant consisted of BEAM [carmustine (BCNU), etoposide, Cytarabine (AraC), melphalan] followed by the infusion of in vivo purged peripheral blood stem cells (PBSC) + 2 consolidation doses of rituximab 375 mg/m^2 on days +14 and +21 after autotransplant.

Outcome Measures

Primary Outcome Measures

1. Progression-free Survival [every 3 months for the first year after autotransplant and every 6 months after the first year of follow up]

   PFS is calculated according to the Kaplan-Meier estimator. The observation time of each subject is defined as the time from entry into the study until lymphoma progression or death as a result of any cause whichever occurs first. The 5-year PFS is the estimated cumulative probability of surviving at least 5 years without progression.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 60 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients with relapsed or refractory follicular lymphoma after chemotherapy

• Patients with relapsed or refractory follicular lymphoma after rituximab as single agent or with chemotherapy

• Patients with transformed follicular lymphoma

• CD20-positivity

• Age between 18 and 60 years

• Advanced Ann Arbor stage

• Normal cardiac, renal and hepatic functions

• Negativity for human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV)

• Total amount of anthracycline previously received < 300 mg/m^2

Exclusion criteria:

• Creatinine > 2 mg/dl

• Alanine transaminase (ALT) and alkaline phosphatase > 2N

• Cardiac or pulmonary disease

• Severe organic or psychiatric disease

• Positivity for human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV)

• Pregnancy, breastfeeding

• Cancer diagnosis in the 5 years before lymphoma diagnosis, except of non-melanoma skin cancer and Cervical Intraepithelial Neoplasia (CIN)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Division of Hematology, IRCCS Policlinico S. Matteo, University of Pavia	Pavia		Italy	27100

Sponsors and Collaborators

• IRCCS Policlinico S. Matteo

Investigators

• Principal Investigator: Mario Lazzarino, M.D., Division of Hematology, IRCCS Policlinico S. Matteo, University of Pavia

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Web site of Division of Hematology, IRCCS Policlinico S. Matteo, University of Pavia, Italy

Publications

• Arcaini L, Orlandi E, Alessandrino EP, Iacona I, Brusamolino E, Bonfichi M, Bernasconi P, Calatroni S, Tenore A, Montanari F, Troletti D, Pascutto C, Regazzi M, Lazzarino M. A model of in vivo purging with Rituximab and high-dose AraC in follicular and mantle cell lymphoma. Bone Marrow Transplant. 2004 Jul;34(2):175-9.
• Lazzarino M, Arcaini L, Bernasconi P, Alessandrino EP, Gargantini L, Cairoli R, Orlandi E, Astori C, Brusamolino E, Pagnucco G, Colombo AA, Calatroni S, Iacona I, Regazzi MB, Morra E. A sequence of immuno-chemotherapy with Rituximab, mobilization of in vivo purged stem cells, high-dose chemotherapy and autotransplant is an effective and non-toxic treatment for advanced follicular and mantle cell lymphoma. Br J Haematol. 2002 Jan;116(1):229-35.

• Responsible Party: Luca Arcaini, MD, IRCCS Policlinico S. Matteo
• ClinicalTrials.gov Identifier: NCT00366275
• Other Study ID Numbers: ML17165; LNH 1-02
• First Posted: Aug 21, 2006
• Last Update Posted: Oct 31, 2012
• Last Verified: Oct 1, 2012

• Keywords provided by Luca Arcaini, MD, IRCCS Policlinico S. Matteo: follicular lymphoma; rituximab; immunochemotherapy; peripheral blood stem cells (PBSC) mobilization; in vivo purging; autotransplant; bcl-2 rearrangement; molecular response
• Additional relevant MeSH terms: Lymphoma; Lymphoma, Follicular

Study Results

Participant Flow

Recruitment Details	Between January 2002 and September 2007, 64 patients with relapsed or refractory follicular lymphoma were enrolled in the trial

Arm/Group Title	Immunochemotherapy, in Vivo Purging and Autotransplant
Arm/Group Description	2-4 courses every 3 weeks with rituximab 375 mg/m^2 on day 1, vincristine 1.4 mg/m^2 on day 2 and cyclophosphamide 400 mg/m^2 on days 2-6. Courses were started if granulocytes >1.5 · 109/l. The phase of peripheral blood stem cells (PBSC) mobilization coupled rituximab 375 mg/m^2 on days 1 and 9 with high-dose cytarabine (AraC) 2 g/m^2 every 12 hours on days 2 and 3. Granulocyte colony-stimulating factor (G-CSF)(5 mcg/kg/day s.c.) was administered from day 6. High-dose chemotherapy with autotransplant consisted of BEAM [carmustine (BCNU), etoposide, Cytarabine (AraC), melphalan] followed by the infusion of in vivo purged peripheral blood stem cells (PBSC) + 2 consolidation doses of rituximab 375 mg/m^2 on days +14 and +21 after autotransplant.
Period Title: Overall Study
STARTED	64
COMPLETED	58
NOT COMPLETED	6

Baseline Characteristics

Arm/Group Title	Immunochemotherapy, in Vivo Purging and Autotransplant
Arm/Group Description	2-4 courses every 3 weeks with rituximab 375 mg/m^2 on day 1, vincristine 1.4 mg/m^2 on day 2 and cyclophosphamide 400 mg/m^2 on days 2-6. Courses were started if granulocytes >1.5 · 109/l. The phase of peripheral blood stem cells (PBSC) mobilization coupled rituximab 375 mg/m^2 on days 1 and 9 with high-dose cytarabine (AraC) 2 g/m^2 every 12 hours on days 2 and 3. Granulocyte colony-stimulating factor (G-CSF)(5 mcg/kg/day s.c.) was administered from day 6. High-dose chemotherapy with autotransplant consisted of BEAM [carmustine (BCNU), etoposide, Cytarabine (AraC), melphalan] followed by the infusion of in vivo purged peripheral blood stem cells (PBSC) + 2 consolidation doses of rituximab 375 mg/m^2 on days +14 and +21 after autotransplant.
Overall Participants	64
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	64 100%
>=65 years	0 0%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	50
Sex: Female, Male (Count of Participants)
Female	29 45.3%
Male	35 54.7%
Region of Enrollment (participants) [Number]
Italy	64 100%

Outcome Measures

1. Primary Outcome

Title	Progression-free Survival
Description	PFS is calculated according to the Kaplan-Meier estimator. The observation time of each subject is defined as the time from entry into the study until lymphoma progression or death as a result of any cause whichever occurs first. The 5-year PFS is the estimated cumulative probability of surviving at least 5 years without progression.
Time Frame	every 3 months for the first year after autotransplant and every 6 months after the first year of follow up

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Immunochemotherapy, in Vivo Purging and Autotransplant
Arm/Group Description	2-4 courses every 3 weeks with rituximab 375 mg/m^2 on day 1, vincristine 1.4 mg/m^2 on day 2 and cyclophosphamide 400 mg/m^2 on days 2-6. Courses were started if granulocytes >1.5 · 109/l. The phase of peripheral blood stem cells (PBSC) mobilization coupled rituximab 375 mg/m^2 on days 1 and 9 with high-dose cytarabine (AraC) 2 g/m^2 every 12 hours on days 2 and 3. Granulocyte colony-stimulating factor (G-CSF)(5 mcg/kg/day s.c.) was administered from day 6. High-dose chemotherapy with autotransplant consisted of BEAM [carmustine (BCNU), etoposide, Cytarabine (AraC), melphalan] followed by the infusion of in vivo purged peripheral blood stem cells (PBSC) + 2 consolidation doses of rituximab 375 mg/m^2 on days +14 and +21 after autotransplant.
Measure Participants	58
Number (95% Confidence Interval) [percent chance of PFS at 5 years]	59

Adverse Events

Arm/Group Title	Immunochemotherapy, in Vivo Purging and Autotransplant
Arm/Group Description	2-4 courses every 3 weeks with rituximab 375 mg/m^2 on day 1, vincristine 1.4 mg/m^2 on day 2 and cyclophosphamide 400 mg/m^2 on days 2-6. Courses were started if granulocytes >1.5 · 109/l. The phase of peripheral blood stem cells (PBSC) mobilization coupled rituximab 375 mg/m^2 on days 1 and 9 with high-dose cytarabine (AraC) 2 g/m^2 every 12 hours on days 2 and 3. Granulocyte colony-stimulating factor (G-CSF)(5 mcg/kg/day s.c.) was administered from day 6. High-dose chemotherapy with autotransplant consisted of BEAM [carmustine (BCNU), etoposide, Cytarabine (AraC), melphalan] followed by the infusion of in vivo purged peripheral blood stem cells (PBSC) + 2 consolidation doses of rituximab 375 mg/m^2 on days +14 and +21 after autotransplant.
All Cause Mortality
	Immunochemotherapy, in Vivo Purging and Autotransplant
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Immunochemotherapy, in Vivo Purging and Autotransplant
	Affected / at Risk (%)	# Events
Total	2/64 (3.1%)
General disorders
sepsis	1/64 (1.6%)	64
Vascular disorders
Vasculitis	1/64 (1.6%)	64
Other (Not Including Serious) Adverse Events
	Immunochemotherapy, in Vivo Purging and Autotransplant
	Affected / at Risk (%)	# Events
Total	54/64 (84.4%)
Blood and lymphatic system disorders
Hematological toxicity grade 3-4	54/64 (84.4%)	64

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.