Preventing Stem Cell Transplant Complications With a Blood Separator Machine

Peripheral Blood Stem Cell Allotransplantation For Hematological Malignancies Using Ex Vivo CD34 Selection - a Platform For Adoptive Cellular Therapies

Background:

- Researchers are working to make stem cell transplant procedures safer and more effective. One complication of transplants is graft-versus-host disease (GVHD). This complication happens when certain white blood cells from the donor attack the recipient's own body. Researchers want to test a blood separator machine that may help remove more of the donor's white blood cells before transplant. They will study donors and recipients during stem cell transplant to see how well this process can prevent GVHD and other complications.

Objectives:

- To see if a new blood separator machine can improve outcomes of stem cell transplants.

Eligibility:

• Individuals between 10 and 75 years of age who are having a stem cell transplant for leukemia or other blood-related cancers.
• Donors for the stem cell transplant.

Design:

• Recipients and donors will be screened with a physical exam and medical history.
• Donors will have two blood collection procedures. The first will collect only white blood cells, and return the rest of the blood. After the first collection, participants will have filgrastim injections to help their stem cells enter their blood. Then, they will have a second blood collection for the stem cells.
• Recipients will have radiation and chemotherapy to prepare for the stem cell transplant. They will then have the stem cell transplant with the donor cells that have been treated with the blood separator machine.
• Recipients will be monitored closely after the procedure. They may receive some of their donor's white blood cells if needed to fight serious infections.
• Recipients will have the regular standard of care after their transplant. Blood samples will be taken and any side effects will be monitored and treated.

Study Overview

• Status: Completed
• Conditions: Lymphoma, Non-Hodgkin; MDS (Myelodysplastic Syndrome); Myeloproliferative Disorder; ALL (Acute B-Lymphoblastic Leukemia); AML (Acute Myelogenous Leukemia
• Intervention / Treatment: Device: Graft Manipulation (CD34+ Selection)

Detailed Description

Peripheral blood stem cell transplant research carried out by the NHLBI BMT Unit focus on transplant techniques designed to decrease graft versus host disease (GVHD), increase the graft-versus-leukemia (GVL) effect and reduce the risk of post-transplant graft rejection.

Through incremental transplant clinical trials we have shown that by controlling the stem cell (CD34+ cell) and T lymphocyte (CD3+ cell) dose, severe GVHD can be reduced whilst beneficial GVL effects can be preserved. We found that T cell depleted transplants using the Nexell/Baxter Isolex 300i system and subsequently, the Miltenyi CliniMACS[registered] CD34+ system to obtain high CD34+ doses depleted of lymphocytes were safe to administer and associated with less severe acute GVHD and promising response rates and overall survival. Our previous trials have helped us to create the transplant environment (significant lymphodepletion and minimal post transplant immunosuppression) that make for an ideal platform for adoptive cellular immunotherapy. Adoptive cell transfer is the passive transfer of immune cells, into a new recipient host with the goal of transferring the immunologic functionality and characteristics into the new host.

This protocol is designed to evaluate the safety and efficacy of the Miltenyi CliniMACS[registered] CD 34 selection system in HLA-matched sibling allogeneic peripheral blood stem cell transplant. The manipulation of the graft is the primary research intervention, subject to IDE# 15632, and all other aspects of clinical management on this protocol are standard care. The target CD34+ dose range will be >3 x 10(6)/kg and the target CD3+ dose range will be 5 x 10(4)/kg to 1 x 10(6)/kg. Once we demonstrate adequacy of this platform for engraftment and absence of significant GVHD in ten consecutive recipients, we will seek IRB permission to proceed with planned adoptive cellular therapies.

The protocol will accrue up to 96 transplant recipients aged 10-80 with a hematological malignancy and their HLA-matched sibling donors, in whom allogeneic stem cell transplantation from an HLA-matched sibling would be routinely indicated. Diagnostic categories will include acute and chronic leukemia, myelodysplastic syndromes, lymphomas, multiple myeloma and myeloproliferative syndromes.

Subjects will receive a myeloablative conditioning regimen of cyclophosphamide (120 mg/kg total), fludarabine (125 mg/m(2) total) and total body irradiation (1200 cGy with lung shielding to 600 cGy), followed by an infusion of a stem cell product selected for CD34+ progenitors using the Miltenyi CliniMACS[registered] system. Older subjects will receive a lower dose of irradiation (800 or 600 cGy based on age) to reduce the regimen intensity.

The overall objective is to assess the feasibility of using this system as a platform for cellular immunotherapy initiatives. The primary study endpoint will be overall survival at day +200. Stopping criteria for safety will monitor non-relapse mortality at day +200 and late disease free survival at 2 years. Secondary endpoints will be standard transplant outcome variables such as non-hematologic toxicity, incidence and severity of acute and chronic GVHD and relapse of disease.

• Study Type: Interventional
• Enrollment (Actual): 41
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center, 9000 Rockville Pike

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 80 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

• INCLUSION CRITERIA RECIPIENT

5.1.1 Ages 10-80 years inclusive

5.1.2 Any one of the following hematologic conditions, confirmed by pathology, meeting a standard indication for allogeneic stem cell transplant:

5.1.2.1 Chronic myelogenous leukemia (CML): Subjects under the age of 21 in chronic phase OR Subjects ages 10-80 in chronic phase who have failed or are intolerant to treatment with second generation tyrosine inhibitors OR Subjects ages 10-80 in accelerated phase or blast transformation. OR

5.1.2.2 Acute lymphoblastic leukemia (ALL): any of these categories: Adult ALL including standard risk; Pediatric ALL in first remission with high-risk features (presenting leukocyte count >100,000/cu mm, karyotypes t(9; 22), t4, t19, t11, biphenotypic leukemia). All second or subsequent remissions, primary induction failure, partially responding or untreated relapse. OR

5.1.2.3 Acute myelogenous leukemia (AML): AML in first remission - except AML with good risk karyotypes: AML M3 (t15; 17), AML M4Eo (inv 16), c-kit unmutated AML t (8; 21). All AML in second or subsequent remission, primary induction failure and resistant relapse. OR

5.1.2.4 Myelodysplastic syndromes(MDS): any of these categories - refractory anemia with transfusion dependence, refractory anemia with ANC<500/microL, refractory anemia with excess of blasts, transformation to acute leukemia, chronic myelomonocytic leukemia, atypical MDS/myeloproliferative syndromes. OR

5.1.2.5 Myeloproliferative disorders including atypical (Ph-negative) chronic myeloid and neutrophilic leukemias, progressing myelofibrosis, and polycythemia vera, essential thrombocythemia either in transformation to acute leukemia or with progressive transfusion requirements or pancytopenia. OR

5.1.2.6 Chronic lymphocytic leukemia refractory to fludarabine treatment and with bulky progressive disease or with thrombocytopenia (less than or equal to 100,000 / microl) or anemia (less than or equal to 10g/dl) not due to recent chemotherapy. OR

5.1.2.7 Non-Hodgkin s lymphoma including Mantle cell lymphoma relapsing or refractory to standard of care treatments. OR

5.1.2.8 Multiple myeloma, Waldenstroms macroglobulinemia, unresponsive or relapsed following standard of care treatments. OR

5.1.2.9 Hodgkin's Lymphoma relapsing following an autologous transplant. OR

5.1.2.10 Other rare hematologic malignancies for which hematopoietic stem cell transplantation has been performed and offers a durable remission or as the only option for potential for cure.

• Chemotherapy-resistant multisystem Langerhans cell histiocytosis (MSLCH) especially involving organs like the bone marrow, liver, spleen, and lungs
• Aggressive systemic mastocytosis, and mast cell leukemia (MCL) in first CR (CR1)
• Hypereosinophilic syndrome who have failed imatinib therapy or FIP1L1-PDGFRa-negative patients who develop end-organ dysfunction
• Adult T-cell leukemia/lymphoma at first diagnosis
• Refractory or disseminated nasal-type extranodal NK/T-lymphoma or aggressive Natural killer cell leukemia/lymphoma
• Mycosis fungoides and S(SqrRoot)(Copyright)zary syndrome after failure of two or three initial therapies
• Primary or relapsed refractory Angioimmunoblastic T-cell lymphoma at first diagnosis
• Hepatosplenic T-cell lymphoma (gamma/delta T-cell lymphoma) at first diagnosis
• T-cell prolymphocytic leukemia at first diagnosis
• Subcutaneous panniculitic T-cell lymphoma at first diagnosis
• Hematodermic neoplasm (blastic natural killer cell lymphoma or Blastic plasmacytoid dendritic cell neoplasm) at first diagnosis

5.1.3 HLA identical (6/6) related donor.

5.1.4 For adults: ability to comprehend the investigational nature of the study and provide informed consent. For minors: written informed consent from one parent or guardian. Informed oral assent from minors: the process will be explained to the minor on a level of complexity appropriate for their age and ability to comprehend.

EXCLUSION CRITERIA RECIPIENT (any of the following)

5.2.1 Major anticipated illness or organ failure incompatible with survival from transplant

5.2.2 Severe psychiatric illness or mental deficiency sufficiently severe as to make compliance with the transplant treatment unlikely and making informed consent impossible.

5.2.3 Positive pregnancy test for women of childbearing age

5.2.4 DLCO adjusted for Hb and ventilation< 50% predicted

5.2.5 Left ventricular ejection fraction < 40% (evaluated by ECHO) or < 30% (evaluated by MUGA)

5.2.6 AST/SGOT > 10 times ULN

5.2.7 Total bilirubin > 5 times ULN

5.2.8 Estimated GFR < 15 mL/min

5.2.9 Recipients who have active infections with HIV or active hepatitis C (HCV)

INCLUSION CRITERIA DONOR

5.3.1 Related donor, HLA identical (6/6) with recipient

5.3.2 Weight greater than or equal to 18 kg

5.3.3 Age greater than or equal to 2 or less than or equal to 80 years old

5.3.4 For adults: ability to comprehend the investigational nature of the study and provide informed consent. For minors: written informed consent from one parent or guardian and informed assent: The process will be explained to the minor on a level of complexity appropriate for their age and ability to comprehend.

EXCLUSION CRITERIA DONOR (any of the following)

5.4.1 Pregnant or breast-feeding. Lactating donors are permitted provided breast milk is discarded during the days filgrastim (G-CSF) is given

5.4.2 Unfit to receive G-CSF and undergo apheresis (abnormal blood counts, history of stroke, uncontrolled hypertension)

5.4.3 Sickling hemoglobinopathy including HbSS, HbSC

5.4.4 Donors who are positive for HIV, active hepatitis B (HBV), hepatitis C (HCV) or human Tcell lymphotropic virus (HTLV-I/II)

5.4.5 Severe psychiatric illness or mental deficiency sufficiently severe as to make compliance with the donation process unlikely, and making informed consent impossible.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: CD34+ cell positively selected graft stem cell recipient; Recipients received a myeloablative conditioning regimen of cyclophosphamide (120 mg/kg total), fludarabine (125 mg/m2 total) and total body irradiation (1200 cGy with lung shielding to 600 cGy), followed by an infusion of a stem cell product selected for CD34+ progenitors using the Miltenyi CliniMACS® system. Older subjects will receive a lower dose of irradiation (800 or 600 cGy based on age) to reduce the regimen intensity.

Device: Graft Manipulation (CD34+ Selection)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival	Determine the rate of overall survival at 200 day	200 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Disease Free Survival at 2 Years	Disease Free Survival at 2 years	2 years
Disease Progression	Incidence of relapse / disease progression	3 years
Incidence of Acute GVHD	Participants who develop acute GVHD	100 days
Incidence of Chronic GVHD	Participants who develop chronic GVHD	3 years
Median Time to ANC>500/mm3	Time in days	3 years
Median Time to Platelets>20K/mm3	Time in days	3 years
Severity of Acute GVHD	Grade I	100 days
Severity of Acute GVHD	Grade II	100 days
Severity of Acute GVHD	Grade III	100 days
Severity of Acute GVHD	Grade IV	100 days
Severity of Chronic GVHD	Extensive	3 years
Severity of Chronic GVHD	Limited	3 years

Collaborators and Investigators

• Sponsor: National Heart, Lung, and Blood Institute (NHLBI)
• Collaborators: Children's National Research Institute

Publications and helpful links

General Publications

• Armitage JO. Bone marrow transplantation. N Engl J Med. 1994 Mar 24;330(12):827-38. doi: 10.1056/NEJM199403243301206. No abstract available.
• Barrett AJ. Graft-versus-host disease: basic considerations. Recent Results Cancer Res. 1993;132:185-95. doi: 10.1007/978-3-642-84899-5_19. No abstract available.
• Appelbaum FR. Haematopoietic cell transplantation as immunotherapy. Nature. 2001 May 17;411(6835):385-9. doi: 10.1038/35077251.

Study record dates

Study Major Dates

• Study Start: May 29, 2013
• Primary Completion (Actual): May 23, 2018
• Study Completion (Actual): June 28, 2018

Study Registration Dates

• First Submitted: May 29, 2013
• First Submitted That Met QC Criteria: May 29, 2013
• First Posted (Estimate): June 3, 2013

Study Record Updates

• Last Update Posted (Actual): July 21, 2020
• Last Update Submitted That Met QC Criteria: July 20, 2020
• Last Verified: June 28, 2018

More Information

Terms related to this study

• Keywords: Chronic Lymphocytic Leukemia (CLL); Acute Lymphoblastic Leukemia (ALL); Acute Myelogenous Leukemia (AML); Chronic Myelogenous Leukemia (CML); Myelodysplastic Syndrome (MDS)
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Lymphoma; Myelodysplastic Syndromes; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Lymphoma, Non-Hodgkin; Preleukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Myeloproliferative Disorders
• Other Study ID Numbers: 130144; 13-H-0144

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: No