Clinical trial NCT01866839: Preventing Stem Cell Transplant Complications With a Blood Separator Machine
Official title: Peripheral Blood Stem Cell Allotransplantation For Hematological Malignancies Using Ex Vivo CD34 Selection - a Platform For Adoptive Cellular Therapies
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: MDS (Myelodysplastic Syndrome)
Myeloproliferative Disorder
Lymphoma, Non-Hodgkin
ALL (Acute B-Lymphoblastic Leukemia)
AML (Acute Myelogenous Leukemia
Keywords: Acute Lymphoblastic Leukemia (ALL)
Acute Myelogenous Leukemia (AML)
Chronic Lymphocytic Leukemia (CLL)
Chronic Myelogenous Leukemia (CML)
Myelodysplastic Syndrome (MDS)
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
Collaborators: name: Children's National Research Institute
First posted: 2013-06-03
Enrollment: 41
Sex: ALL
Minimum age (years): 2
Maximum age (years): 80
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: * 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.

Primary outcomes:
measure: Overall Survival
timeFrame: 200 days
Secondary outcomes:
measure: Disease Free Survival at 2 Years
timeFrame: 2 years
measure: Disease Progression
timeFrame: 3 years
measure: Incidence of Acute GVHD
timeFrame: 100 days
measure: Incidence of Chronic GVHD
timeFrame: 3 years
measure: Median Time to ANC>500/mm3
timeFrame: 3 years
measure: Median Time to Platelets>20K/mm3
timeFrame: 3 years
measure: Severity of Acute GVHD
timeFrame: 100 days
measure: Severity of Acute GVHD
timeFrame: 100 days
measure: Severity of Acute GVHD
timeFrame: 100 days
measure: Severity of Acute GVHD
timeFrame: 100 days
measure: Severity of Chronic GVHD
timeFrame: 3 years
measure: Severity of Chronic GVHD
timeFrame: 3 years
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center, 9000 Rockville Pike
state: Maryland
Study officials:
affiliation: National Heart, Lung, and Blood Institute (NHLBI)
name: Sawa Ito, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Armitage JO. Bone marrow transplantation. N Engl J Med. 1994 Mar 24;330(12):827-38. doi: 10.1056/NEJM199403243301206. No abstract available.
citation: 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.
citation: Appelbaum FR. Haematopoietic cell transplantation as immunotherapy. Nature. 2001 May 17;411(6835):385-9. doi: 10.1038/35077251.