Neoplasms

Blood and Lymph Conditions

Immune System Diseases

All Conditions

Behaviors and Mental Disorders

Rare Diseases

Lymphoma, Large B-Cell, Diffuse

Lymphoma

Lymphoma, Mantle-Cell

Lymphoma, B-Cell

Aggression

Neoplasms by Histologic Type

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

B-cell Lymphoma

Diffuse Large B-Cell Lymphoma

Lymphosarcoma

Mantle Cell Lymphoma

CD34+ cell selection applying CliniMACS device (Miltenyi Biotec, Bergisch Gladbach, Germany)

CD34+ cell selection applying a CliniMACS device (Miltenyi Biotec, Bergisch Gladbach, Germany). This method for CD34+ cell selection will be used in this study and is considered as the standard treatment.

CD34+ cell selection

Thomas Pabst, Prof

Gabriela Baerlocher, Prof

Primary objective:

To assess the differences in the overall survival at 3 years of a CD34+ cell selection versus no selection of hematopoietic progenitor cells harvested during peripheral blood stem cell collection before high-dose chemotherapy with autologous stem cell transplantation (ASCT) in advanced stage mantle cell lymphoma (MCL) or diffuse large B-cell lymphoma (DLBCL) patients.

Secondary objectives:

To assess differences in disease-free survival between CD34+ cell selection versus no selection of hematopoietic progenitor cells harvested during peripheral blood stem cell collection before high-dose chemotherapy with autologous stem cell transplantation (ASCT) in advanced stage mantle cell (MCL) or in diffuse large B-cell lymphoma (DLBCL) patients.

To compare hematologic engraftment and the time needed until hematologic recovery after ASCT using CD34+ selected or unselected autologous stem cell grafts.

To compare infectious complications, particularly CMV infections, observed until 100 days after ASCT comparing CD34+ selected or unselected autologous stem cell grafts.

To assess the response rate at day 100 after ASCT in advanced stage mantle cell lymphoma (MCL) or diffuse large B-cell lymphoma (DLBCL) patients after ASCT comparing patients with CD34+ cell selection versus no selection.

To assess the total time needed for the apheresis procedure and the number of apheresis days needed to ensure the collection of a sufficient number of autologous stem cells comparing patients with CD34+ cell selection versus no selection.

To assess the need for the additional use of G-CSF (Neupogen) and of the stem cell releasing compound Plerixafor (Mozobil) to ensure the collection of a sufficient number of autologous stem cells comparing patients with CD34+ cell selection versus no selection.

Outcome(s):

The aim of the study is to show ≥ 15% better 3-year overall survival of lymphoma patients having received CD34+ cell selection during autologous stem cell collection before autologous stem cell transplantation compared to no CD34+ cell selection.

Background and rationale: Autologous stem cell transplantation (ASCT): High-dose chemotherapy (HDCT) followed by ASCT is considered the treatment of choice for relapsed/refractory lymphomas. On the basis of the results of the PARMA study group trial, high-dose chemotherapy followed by ASCT has become the standard of care for patients with relapsed, chemo-sensitive aggressive lymphoma , and it is the treatment of choice in patients relapsing with diffuse large B-cell lymphomas (DLBCL), mantle cell lymphomas (MCL), follicular lymphoma (FL) or Hodgkin's disease (HD). Worldwide, about 11'000 patients are treated with ASCT per year because of relapsing lymphoma. The BEAM chemotherapy regimen is the most frequently used conditioning regimen before ASCT since more than thirty years.

Although HDCT with ASCT is a curative strategy for some patients with aggressive non-Hodgkin lymphoma (NHL), relapse or progression after ASCT is the major limitation of this procedure. Together with previously described factors that affect outcome after ASCT - such as prognostic score index, clinical response to induction or salvage chemotherapy, and the number of chemotherapy regimens received before ASCT - graft contamination with residual lymphoma cells is a major factor for disease relapse.

Graft contamination: Contamination of autologous graft by residual lymphoma cells has been demonstrated using several techniques including flow cytometry, immunohistochemistry or molecular methods. Subsequent studies have suggested that contamination with lymphoma cells contributes to relapse after ASCT using mobilized stem cells. A better outcome in syngenic transplantation in NHL compared with ASCT suggested the potential clinical benefit of purging the stem cell graft used for SCT.

Graft purging: The strategies implemented to remove lymphoma cells from harvested peripheral stem cells include complement-mediated use of lymphoma-directed antibodies, immunomagnetic beads, immunotoxins, or chemotherapeutic agents, as well as oncolytic viruses. Among them, CD34+ cell selection is an alternative and theoretically attractive strategy for tumor cell removal in lymphomas that do not express the CD34+ antigen. Various technologies have been used for positive selection of CD34+ cells, including immunomagnetic bead separation, avidin-biotin immunoaffinity systems, fluorescence-activated cell sorting, and magnetic-activated cell sorting (MACS). The feasibility and safety of CD34+ purified progenitor cell reinfusion after high-dose chemotherapy have also been demonstrated.

Clinical use of purged autologous grafts: Despite the theoretical advantage of using a purged graft in the ASCT setting, the standard procedure for ASCT involves the use of non-selected grafts. Whether the use of ex vivo purged grafts with CD34+ cell selection translates into improved long-term treatment outcome remains controversial. Noteworthy, not a single randomized study has been reported so far directly comparing in a prospective manner purged and unpurged grafts in ASCT. Thus, a randomized prospective direct comparison between these two procedures is long awaited and an unmet clinical need with presumably immediate impact on daily practice of ASCT.

Own experience with purged grafts: the investigator's institution has a long-standing experience with CD34+ cell selection applying the CliniMACS device (Miltenyi Biotec, Bergisch Gladbach, Germany). The investigator recently summarized the data in a retrospective analysis of advanced stage lymphoma patients comparing 31 patients with CD34+ cell selection versus 31 patients without selection (including 32 MCL and 30 DLBCL patients). Remarkably, the investigator found that the 5-year OS for selected versus not selected ASCT patients was 87% and 53% (p=0.004), and the 5-year PFS was 62% and 38% (p=0.031), respectively. These retrospective data suggest that using selected autografts for ASCT in advanced stage MCL and DLBCL is associated with significantly longer OS and PFS without increased toxicity, infectious complications or impaired engraftment. Finally, the investigator propose that these data provide the rationale for initiating a prospective randomized study on the use of CD34+ cell selection of grafts used for ASCT in patients with advanced-stage aggressive lymphomas.

CD34+ Selected ASCT for Aggressive Lymphomas

CD34+ Selected Versus Unselected Autologous Stem Cell Transplantation in Advanced Stage Mantle Cell and Diffuse Large B-cell Lymphoma Patients, a Randomized Phase II Study

Overall survival of lymphoma patients having received CD34+ cell selection during autologous stem cell collection before autologous stem cell transplantation compared to no CD34+ cell selection

Hematologic engraftment after ASCT is defined as the first day of neutrophils rising above 0.5 G/l, and of platelets rising above 20 G/L in the absence of platelet transfusions in the previous 3 days

Infectious complications, particularly CMV infections

Insel Gruppe AG, University Hospital Bern

Leukemia

Leukemia, Myeloid

Leukemia, Myeloid, Acute

Hematologic Diseases

Myeloid Leukemia

Acute Myeloid Leukemia

Acute Non Lymphoblastic Leukemia

Acute Graft Versus Host Disease

Anti-Infective Agents

Antineoplastic Agents

All Drugs and Chemicals

Cytarabine

Ara-C, autologous transplantation, Allogeneic HLA-identical sibling transplantation depending on risk factors (cytogenetics, courses to CR)and availability of an HLA-identical sibling, CD34+ selection.

* Intermediate dose during induction phase to remission.
* High-dose during consolidation phase in patients with favorable cytogenetics.

Ara-C

* In patients with normal karyotype and one cycle of chemotherapy to achieve complete remission.
* In patients with other cytogenetics without HLA-Identical sibling.

Autologous transplantation

* Patients without favorable or normal karyotype(and one course to CR).
* Patients with normal karyotype who need two cycles of chemotherapy to achieve CR, and other cytogenetics.

Allogeneic HLA-identical sibling transplantation

In allotransplants, it is performed a CD34+ cell selection of peripheral blood stem cell transplantation.

CD34+ selection

Jorge Sierra, MD

Salut Brunet, MD

In a protocol of treatment of AML used in 1994 for adults with AML up to the age of 50 years, the Spanish CETLAM group showed a complete remission rate 75 % using the combination of daunorubicin (60 mg/m2, 3 days) plus conventional dose cytarabine (100mg/m2/day in continuous infusion during 7 days) and etoposide (100mg/m2 IV/day 3 days). If idarubicin (10 mg/m2, 3 days) was administered instead of daunorubicin, the complete remission (CR) rate in adults up to 60 years was 75%. To improve the proportion of CRs and to decrease relapse rate appearing in 50% of patients, the phase II AML-99 trial includes intermediate dose-cytarabine during induction and risk-adapted post remission treatment based on the improvement in prognostic characterization of AML and the implementation of novel transplantation techniques.

Induction chemotherapy: idarubicin (12mg/m2/day intravenous), intermediate-dose cytarabine (500mg/m2/12h, intravenous) and etoposide (100mg/m2/day, intravenous) in 3+7+3 schedule. This induction therapy is repeated if complete remission (CR) is not achieved after the first course of treatment.

Consolidation therapy: mitoxantrone (12mg/m2/day, intravenous, days 4, 5 and 6) and intermediate-dose cytarabine (500mg/m2/12h from day 1 to 6).

Risk-stratification according to cytogenetics, courses to CR and availability of an HLA-identical sibling:

* Patients in the favorable cytogenetics group \[t(8;21), inv(16) or t(16;16)\] are treated with high-dose cytarabine (3g/m2/12h, intravenous, days 1, 3 and 5).
* Patients in intermediate cytogenetics group (normal karyotype and a single course to achieve the CR) receive an autologous peripheral blood stem cell (PBSC) transplant, regardless of having an HLA-identical sibling.
* The remaining patients are considered in the high-risk group and are treated with autologous or allogeneic PBSC transplantation depending on the availability of a sibling donor. In allotransplants, CD34+ cell selection of hematopoietic cells is performed.

Risk-adapted Therapy for Adult Acute Myeloid Leukemia.

Risk Adapted Treatment for Primary AML in Adults up to the Age of 60 Years.

Analyze the efficacy and toxicity of IDICE (idarubicin, intermediate doses of ara-C and etoposide) to achieve complete remission.

Analyze the disease free survival (DFS)of patients in remission, with a therapeutic strategy adjusted to the prognostic factors.

Study of the immunophenotypic characteristics of the leukemic population at diagnosis and evaluation of MRD during different treatment phases and follow-up.

CD34+ cell selection from PBSC of HLA-identical siblings. Conditioning regimen. Infusion and post-transplant follow-up.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
CD34+ Selected ASCT for Aggressive Lymphomas	NCT02646098	Malignant Non-H...	CD34+ cell sele...	18 Years - 75 Years	Insel Gruppe AG, University Hospital Bern
CD34+ Selected ASCT for Aggressive Lymphomas	NCT02646098	Malignant Non-H...	CD34+ cell sele...	18 Years - 75 Years	Insel Gruppe AG, University Hospital Bern
Risk-adapted Therapy for Adult Acute Myeloid Leukemia.	NCT01716793	Leukemia, Myelo...	Ara-C Autologous tran... Allogeneic HLA-... CD34+ selection	18 Years - 60 Years	Grupo Cooperativo de Estudio y Tratamiento de las Leucemias Agudas y Mielodisplasias

Spots Global Cancer Trial Database for cd34+ cell selection