HLA-Compatible Related or Unrelated Donors With CD34+ Enriched, T-cell Depleted Peripheral Blood Stem Cells Isolated by the CliniMACS System in the Treatment of Patients With Hematologic Malignancies

A Phase II Trial of Transplants From HLA-Compatible Related or Unrelated Donors With CD34+ Enriched, T-cell Depleted Peripheral Blood Stem Cells Isolated by the CliniMACS System in the Treatment of Patients With Hematologic Malignancies and Other Lethal Hematologic Disorders

The purpose of this study is to find out the effects of using a system called CliniMACS to remove Tcells from blood stem cells. Removing T-cells may help stop a side effect called Graft-Versus-Host Disease (GVHD). Some studies have been done with CliniMACS, but the Food and Drug Administration (FDA) has not yet approved it.

Study Overview

• Status: Completed
• Conditions: Multiple Myeloma; Acute Lymphoblastic Leukemia; Myelodysplastic Syndrome; Acute Myelogenous Leukemia
• Intervention / Treatment: Radiation: total body irradiation; Drug: Thiotepa; Drug: Cyclophosphamide; Procedure: (CliniMACS) T-cell depleted PBSC Transplant; Drug: Busulfan; Drug: Melphalan; Drug: Fludarabine; Drug: Clofarabine

• Study Type: Interventional
• Enrollment (Actual): 422
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 69 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Malignant conditions or other life threatening disorders correctable by transplant for which CD34+ selected, T-cell depleted allogeneic hematopoietic stem cell transplantation is indicated such as:
• AML in 1st remission - for patients whose AML does not have 'good risk' cytogenetic features (i.e. t 8;21, t15;17, inv 16).
• Secondary AML in 1st remission
• AML in 1st relapse or > than or = to 2nd remission
• ALL/CLL in 1st remission clinical or molecular features indicating a high risk for relapse; or ALL/CLL > than or = to 2nd remission
• CML failing to respond to or not tolerating Imatinib or dasatinib in first chronic phase of disease; CML in accelerated phase second chronic phase or in CR after accelerated phase or blast crisis.

• Non-Hodgkins lymphoma with chemoresponsive disease in any of the following categories:

  1. intermediate or high grade lymphomas who have failed to achieve a first CR or have relapsed following a 1st remission who are not candidates for autologous transplants.
  2. any NHL in remission which is considered not curable with chemotherapy alone and not eligible/appropriate for autologous transplant.
• Myelodysplastic syndrome (MDS): RA//RARS/RCMD with high risk cytogenetic features or transfusion dependence as well as RAEB-1 and RAEB-2 and Acute myelogenous leukemia (AML) evolved from MDS, who are not eligible for transplantation and/or unable to enroll onto protocol IRB 08-008.
• Chronic myelomonocytic leukemia: CMML-1 and CMML-2.

• Multiple Myeloma with disease in the following categories:

  1. Patients with relapsed multiple myeloma following autologous stem cell transplantation who have achieved at least partial response following additional chemotherapy.
  2. Patients with high risk cytogenetics at diagnosis must have achieved a partial response following autologous stem cell transplantation. Patients must have complex karyotype, del17p, t4;14 and/or t14;16 by FISH and/or del13 by karyotyping.
• Other rare lethal disorders of Hematopoiesis and Lymphopoiesis for which a T-cell depleted transplant is indicated (e.g. hemophagocytic lymphohistiocytosis; refractory aplastic anemia or congenital cytopenias; non-SCID lethal genetic immunodeficiencies such as Wiskott Aldrich Syndrome, CD40 ligand deficiency, or ALPS, as well as refractory autoimmune cytopenias, PNH, metabolic storage diseases or heavily transfused congenital hemoglobinopathies).
• Accrual to each treatment arm will include up to 30 standard risk and 30 poor risk patients (60 patients/treatment arm) except for Regimen D, which will include 30 patients/treatment arm, all of which will be poor risk by virtue of risks of relapse and/or transplant related mortality.
• Standard risk patients will include eligible patients, as defined above, who are receiving transplants as treatment for MDS in RA//RARS/RCMD, AML in 1st or 2nd remission, ALL in 1st CR, NHL in 1st remission, MM in 1st remission, Very Good Partial Response, or 1st Partial Response or CML in the first chronic phase or 1st remission.
• All other patients, including those with treatment related malignancies and/or those who have AML derived from MDS, will have received extensive prior chemo/radiotherapy and, therefore, will be considered to be at poor risk of conditioning and transplant related morbidities, and potentially transplant related mortality. Patients with life threatening non-malignant genetic and acquired disorders will also, by virtue of their history of, optional transfusions and/or infection be considered poor risk. Stopping rules for non-relapse related mortality in these heavily treated patients are, therefore, slightly less stringent than patients in the poor risk transplant groups. Stopping rules for the principal endpoints of graft failure and GvHD are the same for all groups.

The following inclusion criteria are also required:

• Patient's age includes from birth on to < 70 years old.
• Patients may be of either gender or any ethnic background.
• Patients must have a Karnofsky (adult) or Lansky (pediatric) Performance Status > or = to 70%
• Patients must have adequate organ function measured by:

Cardiac: asymptomatic or if symptomatic then LVEF at rest must be > or = to 50% and must improve with exercise.

Hepatic: < 3x ULN AST and ≤ to 1.5 total serum bilirubin, unless there is congenital benign hyperbilirubinemia or if the hyperbilirubinemia is directly caused by the disease in which the patient is receiving a transplant (e.g. AML Chloroma obstructing the biliary tree). Patients with higher bilirubin levels due to causes other than active liver disease are also eligible with PI approval e.g. patients with PNH, Gilbert's disease or other hemolytic disorders.

Renal: serum creatinine < than or = to 1.2 mg/dl or if serum creatinine is outside the normal range, then CrCl > 40 ml/min (measured or calculated/estimated) Pulmonary: asymptomatic or if symptomatic, DLCO > or = to 50% of predicted (corrected for hemoglobin)

• Each patient must be willing to participate as a research subject and must sign an informed consent form.

Exclusion Criteria:

• Female patients who are pregnant or breast-feeding
• Active viral, bacterial or fungal infection
• Patient seropositive for HIV-I/II; HTLV -I/II
• Presence of leukemia in the CNS.

Donor Inclusion Criteria:

• Each donor must meet criteria outlined by institutional guidelines
• Donor should agree to undergo general anesthesia and bone marrow harvest collection if PBSC yield is inadequate or otherwise not transplantable for whatever reason.

Donor Exclusion Criteria

• If donors do not meet institutional guidelines, exclusion will be considered.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Total Body Irradiation, Thiotepa and Cyclophosphamide; Hyperfractionated total body irradiation to a dose of 1375-1500 cGy (depending on age, stage of disease and requirement of general anesthesia) with lung shielding) Thiotepa (5 mg/kg/day x 2 or 10 mg/kg/day x 1) Cyclophosphamide (60 mg/kg/day x 2) (or fludarabine 25mg/m2 x 5 if cyclophosphamide is contraindicated)	Radiation: total body irradiation; dose of 1375-1500 cGy; Drug: Thiotepa; 5 mg/kg/day x 2 or 10 mg/kg/day x 1; Drug: Cyclophosphamide; 60 mg/ kg/day x 2 (or fludarabine 25mg/m2 x 5 if cyclophosphamide is contraindicated).; Procedure: (CliniMACS) T-cell depleted PBSC Transplant
Experimental: Busulfan, Melphalan and Fludarabine; Busulfan (0.8 mg/kg every 6 hours x 10 or 12 doses), (depending on disease) with dose modified according to pharmacokinetics Melphalan (70mg/m2/day x 2 ) Fludarabine (25mg/m2/ day x 5)	Procedure: (CliniMACS) T-cell depleted PBSC Transplant; Drug: Busulfan; 0.8 mg/kg every 6 hours x 10 or 12 doses (depending on disease) with dose modified according to pharmacokinetics; Drug: Melphalan; 70mg/m2/day x 2; Drug: Fludarabine; 25mg/m2/ day x 5
Experimental: Clofarabine, Melphalan and Thiotepa; Clofarabine (20mg/m2/ day x 5) (or, for children <18 years of age, 30mg/m2/day x 5 if deemed suitable and with PI approval), Melphalan (70 mg/m2/day x 2) Thiotepa (5 mg/kg/day x 2 or 10mg/kg/day x1)	Drug: Thiotepa; 5 mg/kg/day x 2 or 10 mg/kg/day x 1; Procedure: (CliniMACS) T-cell depleted PBSC Transplant; Drug: Melphalan; 70mg/m2/day x 2; Drug: Clofarabine; 20mg/m2/ day x 5 (or, for children <18 years of age, 30mg/m2/day x 5 if deemed suitable and with PI approval)
Experimental: Melphalan, Fludarabine and Thiotepa; Melphalan (70 mg/m2/day x 2) Fludarabine (25mg/m2/ day x 5 ) Thiotepa (5 mg/kg/day x 2 or 10mg/kg/day x1)	Drug: Thiotepa; 5 mg/kg/day x 2 or 10 mg/kg/day x 1; Procedure: (CliniMACS) T-cell depleted PBSC Transplant; Drug: Melphalan; 70mg/m2/day x 2

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Incidence of Durable Hematopoietic Engraftment for T-cell Depleted Transplants Fractionated by the CliniMACS System Administered After Each of the Four Disease Targeted Cytoreduction Regimens.		3 years
Number of Participants With Acute and Chronic GVHD Following T-cell Depleted, CD34+ Progenitor Cell Enriched Transplants Fractionated by the CliniMACS System.	Standard BMT-CTN and IBMTR systems clinical criteria as defined by Rowlings, et al will be used to establish and grade acute GvHD. Chronic GvHD will be diagnosed and graded according to the criteria of Sullivan (CIBMTR).	3 years
Incidence of Non-relapse Mortality (Transplant-related Mortality) Following Each Cytoreduction Regimen and a Transplant Fractionated by the CliniMACS System.		3 years
Survival and Disease-free Survival (DFS)		at 6 months post transplant
Survival and Disease-free Survival (DFS)		1 year post transplant
Survival and Disease-free Survival (DFS)		2 years post transplant

Secondary Outcome Measures

Outcome Measure	Time Frame
Proportion of Patients Receiving Optimal CD3+ (<1x10^5/kg) Cell Doses the Proportion of Patients Receiving CD3+ T-cell Doses > 1x10^5/kg.	Up to 3 years
Proportion of Patients Receiving Optimal CD34+ (> 5x10^6/kg) Cell Doses the Proportion Recurring Suboptimal Doses (< 2x10^6/kg) CD34+ Cells	3 years
Correlation of Doses of CD34+ Progenitors and CD3+ T Cells With Engraftment	3 years

Collaborators and Investigators

• Sponsor: Memorial Sloan Kettering Cancer Center

Publications and helpful links

Helpful Links

• Memorial Sloan Kettering Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): May 3, 2010
• Primary Completion (Actual): March 30, 2021
• Study Completion (Actual): March 30, 2021

Study Registration Dates

• First Submitted: May 4, 2010
• First Submitted That Met QC Criteria: May 5, 2010
• First Posted (Estimate): May 7, 2010

Study Record Updates

• Last Update Posted (Actual): August 5, 2022
• Last Update Submitted That Met QC Criteria: July 11, 2022
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Keywords: Multiple Myeloma; Thiotepa; Leukemia; radiation; cyclophosphamide; fludarabine; Clofarabine; CliniMACS device; GCSF; 10-050
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Neoplasms by Site; Bone Marrow Diseases; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Neoplasms, Plasma Cell; Leukemia, Lymphoid; Myelodysplastic Syndromes; Hematologic Neoplasms; Multiple Myeloma; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Cyclophosphamide; Clofarabine; Melphalan; Fludarabine; Thiotepa; Busulfan
• Other Study ID Numbers: 10-050