T Cell Depletion for Recipients of HLA Haploidentical Related Donor Stem Cell Grafts (MOHEL)

• ClinicalTrials.gov Identifier: NCT00368355
• Recruitment Status: Completed
• First Posted: August 24, 2006
• Results First Posted: January 21, 2020
• Last Update Posted: January 21, 2020
• Sponsor: Baylor College of Medicine
• Collaborators: Center for Cell and Gene Therapy, Baylor College of Medicine; The Methodist Hospital System
• Information provided by (Responsible Party): Robert Krance, Baylor College of Medicine

Study Description

Brief Summary:

Subjects are being asked to participate in this study because treatment of their disease requires them to receive a stem cell transplant. Stem cells or "mother" cells are the source of normal blood cells and lead to recovery of blood counts after bone marrow transplantation (BMT). Unfortunately, there is not a perfectly matched stem cell donor (like a sister or brother) and the subject's disease is considered rapidly progressive and does not permit enough time to identify another donor (like someone from a registry list that is not their relative). We have, however, identified a close relative of the subject's whose stem cells are not a perfect match, but can be used. However, with this type of donor, there is typically an increased risk of developing graft-versus-host disease (GVHD), a high rate of transplant failure, and a longer delay in the recovery of the immune system.

GVHD is a serious and sometimes fatal side effect of stem cell transplant. GVHD occurs when the new donor cells (graft) recognizes that the body tissues of the patient (host) are different from those of the donor. When this happens, cells in the graft may attack the host organs, primarily the skin, liver, and intestines. The number of occurrences and harshness of severe GVHD depends on several factors, including the degree of genetic differences between the donor and recipient, the intensity of the pre-treatment conditioning regimen, the quantity of transplanted cells, and the recipient's age. In recipients of mismatched family member or matched unrelated donor stem cell transplants, there is a greater risk of GVHD so that 70-90% of recipients of unchanged marrow will develop severe GVHD which could include symptoms such as marked diarrhea, liver failure, or even death.

In an effort to lower the occurrences and severity of graft-versus-host disease in patients and to lower the rate of transplant failure, we would like to specially treat the donor's blood cells to remove cells that are most likely to attack the patient's tissues. This will occur in combination with intense conditioning treatment that the patient will receive before the transplant.

Condition or disease	Intervention/treatment	Phase
Acute Lymphoblastic Leukemia; Non Hodgkins Lymphoma; Myelodysplastic Syndrome; Acute Myeloid Leukemia; Chronic Myelogenous Leukemia; Hemophagocytic Lymphohistiocytosis (HLH); Familial Hemophagocytic Lymphohistiocytosis (FLH); Viral-associated Hemophagocytic Syndrome (VAHS); X-linked Lymphoproliferative Disease (XLP)	Drug: Ara-C; Drug: Cyclophosphamide; Biological: Campath-1H; Radiation: Total Body Irradiation; Procedure: Stem Cell Infusion	Phase 2

Detailed Description:

To participate in this study, the subject will need to have a central line (a thin plastic catheter or tube that is placed during surgery into one of the large veins in the neck or chest).

Also before treatment can begin, we will test the subject's blood for viruses which can cause problems after the transplant.

Before treatment can begin, stem cells will be collected from the donor that has been selected as the best match for the subject. White blood cells will be collected from the donor. The cells will then be mixed with a special protein called a CD34 antibody that binds to the stem cells which will then be separated out from the white blood cells by a special machine called a CLINIMACs CD34 Reagent System in the laboratory. This is an investigational and experimental device which is not approved by the FDA. Although this device is not approved for use in this country, it has been in use for years and is approved in other countries. The stem cells will be collected and frozen before we start to give chemotherapy.

TREATMENT PLAN

To prepare the subject's body for transplantation, the subject will be given high dose chemotherapy (also called a conditioning treatment) for 8 days prior to the transplant as follows:

The subject will be given a drug called Ara-C in high doses through the central line every 12 hours starting 8 days before transplant (called day - 8) until 5 days before transplant (called day - 5). Starting one day after receiving the first Ara-C dose (day - 7), we will add a drug called cyclophosphamide once a day to the treatment for the next two days. This will be given in high doses (also through the central line). Also on day - 7, we will add a drug called MESNA. MESNA is used to decrease the side effects caused by cyclophosphamide. After the medication treatment is finished (day - 4), radiation treatment will be given to the entire body twice a day for 4 days. The chemotherapy and radiation treatment will last 8 days. If the subject has abnormal cells in the spinal fluid, 6 extra daily doses of radiation treatment may be given to the head. This would be done before any of the drugs are given and before the subject is admitted for transplant.

NOTE: Depending on the subjects health status, the doctor may decide the subject should not receive Ara-C. If this is a possibility, the doctor will discuss this with the subject.

On the second day of radiation (day -3), the subject will receive CAMPATH-1H as a daily 4-hour IV (intravenous, by vein). The subject will receive this infusion once a day for a total of three days. CAMPATH 1H is a special type of protein called an antibody, that works against certain types of blood cells. CAMPATH 1H is important because it stays active in the body for a long time after infusion, which means it may work longer at preventing GVHD symptoms.

The day after the radiation treatment is completed (day 0), the subject will receive the specially selected donor stem cells. Once in the bloodstream, the cells will go to the bone marrow and should begin to grow. If the subject is at risk for developing GVHD or if the subject begins to develop GVHD, the doctor will prescribe medicines to help prevent or treat this side effect. The doctor will describe these medicines at that time.

To learn more about the way the new cells are growing blood will be taken for research purposes at approximately 3 months, 6 months, 9 months, and a year after the transplant. On day 100, the subject will have the same tests/evaluations the subject has been experiencing since the transplant, however, the subject will also have a bone marrow aspirate (we take a sample of bone marrow to evaluate the disease and GVHD status). For patients who do not develop GVHD, they may have an additional bone marrow aspirate on day 180 (about 2 months after the previous one).

After day 365, the subject will be asked to return to the clinic once a year for evaluations. These evaluations will be similar to the ones the subject had on day 100.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 46 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: CD-34 Selection for Ex-vivo T-Cell Depletion of Mobilized Peripheral Blood Stem Cells for Recipients of HLA Haploidentical Related Donor Stem Cell Grafts Receiving Intensive Conditioning
• Study Start Date: April 2000
• Actual Primary Completion Date: November 2015
• Actual Study Completion Date: November 2016

Arms and Interventions

Arm	Intervention/treatment
Experimental: CLINIMACS Device; Subjects will receive transplant conditioning with Ara-C, Cyclophosphamide, Campath-1H, Total Body Irradiation and will then receive T cell depleted stem cell infusion processed by the CLINIMACS Device	Drug: Ara-C; day-8 through day-5 3 g/m2 q 12 hours; Other Name: cytarabine; Drug: Cyclophosphamide; day-7 and day-6 45 mg/kg; Other Name: Cytoxan; Biological: Campath-1H; day-3 through day-1 Dosing for children: 5 - 15kg : 3mg IV in 30ml NS 15.1 - 30kg : 5mg IV in 50ml NS >30 kg : 10mg IV in 100ml NS Adults will receive 10mg IV in 100ml NS; Other Name: Alemtuzumab; Radiation: Total Body Irradiation; day-4 through day-1 175 cGy x 2 at 24 cGy/min; Procedure: Stem Cell Infusion; Stem cells are infused on day 0
Experimental: ISOLEX Device; Subjects will receive transplant conditioning with Ara-C, Cyclophosphamide, Campath-1H, Total Body Irradiation and will then receive T cell depleted stem cell infusion processed by the ISOLEX Device	Drug: Ara-C; day-8 through day-5 3 g/m2 q 12 hours; Other Name: cytarabine; Drug: Cyclophosphamide; day-7 and day-6 45 mg/kg; Other Name: Cytoxan; Biological: Campath-1H; day-3 through day-1 Dosing for children: 5 - 15kg : 3mg IV in 30ml NS 15.1 - 30kg : 5mg IV in 50ml NS >30 kg : 10mg IV in 100ml NS Adults will receive 10mg IV in 100ml NS; Other Name: Alemtuzumab; Radiation: Total Body Irradiation; day-4 through day-1 175 cGy x 2 at 24 cGy/min; Procedure: Stem Cell Infusion; Stem cells are infused on day 0

Outcome Measures

Primary Outcome Measures :

1. Engraftment Rate After Transplant [ Time Frame: 28 days ]
   Percentage of participants with hematopoietic engraftment post-transplant. Engraftment is defined as the first day absolute neutrophil counts exceeded 0.5 X 10^9/ml.

Secondary Outcome Measures :

1. Early Post BMT Toxicities [ Time Frame: 100 Days ]
   Number of participants who experience organ failure or severe infections (defined as Grade III/IV by NCI CTC for Adverse Events (CTCAE), version 2.0)
2. Severe GVHD Rate [ Time Frame: 100 Days ]
   Percentage of participants with Grade III/IV acute GVHD. Severe GVHD is defined as Grade III/IV acute GVHD.
3. Patients With Acute GVHD [ Time Frame: First 100 Days ]
   Number of participants with acute GVHD graded by the method of Przepiorka et al, which evaluates skin involvement, lower and upper GI, and liver function (bilirubin), each being graded in stages from 0 to 4, where 0 means no acute GVHD, and 4 is the highest stage of acute GVHD
4. Patients With Chronic GVHD [ Time Frame: Up to 1 Year ]
   Number of participants with chronic GVHD graded by the method of Przepiorka et al, which evaluates skin, joints, oral, ocular, hepatic, esophagus, GI, respiratory, platelet, and musculoskeletal involvement, in stages from 0 to 3.

Other Outcome Measures:

1. Immune Reconstitution [ Time Frame: 1 Year ]
   To evaluate the effect of T-cell depletion by positive selection for CD34 on immune reconstitution, which will be determined from total lymphocyte count, from T and B cell numbers and from T cell subset analyses.
2. Length of Remission in Patients [ Time Frame: 1 Year ]
   Median length of remission in patients with high risk leukemia treated with myeloablative chemotherapy, radiotherapy and CD34 selected peripheral blood stem cells from haploidentical related donors using Kaplan-Meier method

Eligibility Criteria

• Ages Eligible for Study: up to 55 Years (Child, Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

INCLUSION CRITERIA:

• Lack of suitable conventional donor (i.e. 5/6 or 6/6 related or 5/6 or 6/6 unrelated donor) or presence of a rapidly progressive disease not permitting time to identify an unrelated donor
• Age less than or equal to 55 years of age
• Patients with high risk ALL in CR1 or ALL or high grade (stage III or IV) NHL after first relapse or with primary refractory disease or minimal residual diseases.
• Myelodysplastic syndrome
• Patients with high risk AML in CR1 or after first relapse or with primary refractory disease or minimal residual disease.
• CML
• Hemophagocytic lymphohistiocytosis (HLH), familial hemophagocytic lymphohistiocytosis (FLH), viral-associated hemophagocytic syndrome (VAHS), X-linked lymphoproliferative disease (XLP), Severe chronic active Epstein Barr virus infection (SCAEBV) with predilection for T- or NK-cell malignancy
• Donor cells should be collected and frozen before conditioning starts

EXCLUSION CRITERIA:

• Patients with a life expectancy (< / = 6 weeks) limited by diseases other than leukemia
• Patients with symptomatic cardiac disease, or evidence of significant cardiac disease by echocardiogram (i.e., shortening fraction < 25%)
• Patients with severe renal disease (i.e., creatinine clearance less than 40 cc/1.73 m^2)
• Patients with pre-existing severe restrictive pulmonary disease (FVC less than 40% of predicted)
• Patients with severe hepatic disease (direct bilirubin greater than 3 ug/dl or SGPT (serum glutamic-pyruvic transaminase) greater than 500 ug/dl)
• Patients with severe personality disorder or mental illness
• Patients with a severe infection that on evaluation by the Principal Investigator precludes ablative chemotherapy or successful transplantation
• Patients with documented HIV positivity

'High risk' ALL or AML refers to those acute leukemias identified by the presence of specific biologic features, which predict high likelihood of failure to conventional chemotherapy. As biologic features of high risk disease evolve with improvement of conventional chemotherapy, it is not practical to define this indication with any further specificity. Therefore, high risk AML/ALL will be determined by the primary physician.

Contacts and Locations

Locations

United States, Texas

Houston Methodist Hospital

Houston, Texas, United States, 77030

Texas Children's Hosptial

Houston, Texas, United States, 77030

Sponsors and Collaborators

Baylor College of Medicine

Center for Cell and Gene Therapy, Baylor College of Medicine

The Methodist Hospital System

Investigators

• Principal Investigator: Robert A. Krance, MD; Baylor College of Medicine

More Information

• Responsible Party: Robert Krance, Professor, Baylor College of Medicine
• ClinicalTrials.gov Identifier: NCT00368355
• Other Study ID Numbers: H-8701-MOHEL
• First Posted: August 24, 2006
• Results First Posted: January 21, 2020
• Last Update Posted: January 21, 2020
• Last Verified: January 2020

Keywords provided by Robert Krance, Baylor College of Medicine:

haploidenticalstem cell transplant; acute lymphoblastic leukemia; Non Hodgkins Lymphoma; Myelodysplastic Syndrome; Acute myeloid leukemia; Chronic myelogenous leukemia; Hemophagocytic lymphohistiocytosis (HLH); Familial hemophagocytic lymphohistiocytosis (FLH); Viral-associated hemophagocytic syndrome (VAHS); X-linked lymphoproliferative disease (XLP)

Additional relevant MeSH terms:

Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia; Lymphoma, Non-Hodgkin; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Myelodysplastic Syndromes; Lymphohistiocytosis, Hemophagocytic; Lymphoproliferative Disorders; Syndrome; Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Disease; Pathologic Processes; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Myeloproliferative Disorders; Histiocytosis, Non-Langerhans-Cell; Histiocytosis; Cytarabine; Cyclophosphamide; Alemtuzumab; Immunosuppressive Agents