Clinical Trial: Sirolimus to Prevent GVHD after Stem Cell Transplant for Blood Cancers

This study is currently recruiting patients.

Sponsored by: National Cancer Institute (NCI)
Information provided by: Warren G Magnuson Clinical Center (CC)


This study will investigate the safety and effectiveness of a modified stem cell transplant procedure for treating cancers of the blood and immune system. Patients with these cancers can sometimes benefit greatly from, and even be cured by, transplants of stem cells (cells produced by the bone marrow that mature into blood cells). In addition to producing new bone marrow and restoring normal blood production and immunity, the donated cells fight any residual tumor cells that might have remained in the body, in what is called a graft-versus-leukemia effect. However, severe problems, and sometimes death, may follow these transplants as a result of the high-dose chemotherapy and radiation that accompany the procedure. Also, donated immune system cells called T-cells sometimes attack healthy tissues in a reaction called graft-versus-host-disease (GVHD), damaging organs such as the liver, intestines and skin.

This study will use the following strategies to try to improve the outcome of stem cell transplants:

-Patients will receive "non-myeloblative" chemotherapy that is easier for the body to tolerate (I think this last phrase should be deleted, as the period of immune suppression we use is similar to that conventionally utilized)

-Patients will be randomly assigned to one of the following treatments to try to reduce the risk of developing serious GVHD:

1. Cyclosporin A plus Th2 cells (donated immune cells grown in a high concentration of an immune suppression drug called sirolimus); or

2. Cyclosporin A plus sirolimus treatment in tablet form; or

3. Cyclosporin A plus Th2 cells plus sirolimus treatment in tablet form.

Patients between 18 and 75 years of age with non-Hodgkin's lymphoma, Hodgkin's lymphoma, multiple myeloma, chronic lymphocytic leukemia, chronic myelogenous leukemia, acute myelogenous leukemia, acute lymphocytic leukemia, myelodysplastic syndrome, and myeloproliferative disorders may be eligible for this study. Candidates will be screened with physical examinations, diagnostic tests, and consultations with various specialists.

Participants will have a central venous line placed into a major vein. This tube can stay in the body and be used the entire treatment period to deliver the donated stem cells and give medications, including chemotherapy and other drugs, antibiotics, and blood transfusions, and to withdraw blood samples. Treatment will start with chemotherapy, which will include the drugs fludarabine, cyclophosphamide, etoposide, doxorubicin, vincristine, and prednisone. Some patients may also receive an antibody called rituximab. Patients will receive one to three cycles of this treatment, depending on their response to the drugs. (One cycle consists of 4 days on drug therapy followed by a 17-day rest period.) Several days before the transplant procedure, patients will receive additional chemotherapy with cyclophosphamide and fludarabine, and 3 days later, the donor's stem cells will be infused. To help prevent GVHD, all patients will receive cyclosporine therapy for 6 months, beginning the day before the transplant. Depending on their treatment group, patients will also receive either: 1) Th2 cells the day after the transplant, 2) 4 days of sirolimus tablets, or 3) Th2 cells plus 4 days of sirolimus tablets.

The average hospital stay for stem cell transplantation is 3 to 4 weeks. After discharge, patients will return for frequent follow-up visits for the first 3 months. Monthly visits will be scheduled for the next 3 months, then every 3 months for the next 18 months, and less frequently for a total of at least 5 years post-transplant.

Condition Treatment or Intervention Phase
Hematologic Neoplasms
Neural Tube Defects
Myeloproliferative Disorders
 Drug: Th2 Cells in Allogenic HSCT
Phase II

MedlinePlus related topics:  Blood and Blood Disorders;   Bone Marrow Diseases;   Cancer;   Cancer Alternative Therapy;   Neural Tube Defects

Study Type: Interventional
Study Design: Treatment, Safety/Efficacy

Official Title: Randomized Study of Sirolimus (Rapamycin) Generated Donor Th2 Cells and In Vivo Sirolimus for GVHD Prevention after Allogeneic HSCT for Hematologic Malignancy

Further Study Details: 

Expected Total Enrollment:  152

Study start: December 11, 2003

In protocol 99-C-0143, we evaluated a new approach to allogeneic HSCT that involved intensive host T cell ablation prior to transplantation, and graft augmentation with in vitro generated donor Th2 cells. Rapid full donor engraftment occurred with low preparative regimen associated morbidity and mortality. A Th2 cell dose of 2.5 x 10(7) Th2 cells/kg was established that increased donor T cells early post-transplant, and activated Th1 and Th2 cytokine production relative to non-Th2 recipients. Th2-induced immune activation may have been beneficial, as most Th2 recipients entered into a complete remission despite having generally refractory malignancy prior to transplantation. However, grade II to IV acute GVHD was not significantly reduced (non-Th2 recipients, 12/19 cases, 63%; all Th2 recipients, 18/28 cases, 64%; recipients of established Th2 dose of 2.5 x 10(7) cells/kg, 11/19: 58%). In an attempt to reduce GVHD, this protocol will modify the Th2 cell generation method to include the immune suppression drug sirolimus (rapamycin), which results in Th2 cells of increased purity. In murine studies, sirolimus generated Th2 cells reduced GVHD more efficiently than control Th2 or Th1 cells, and preserved a component of the graft-versus-tumor effect. In this protocol, we hypothesize that sirolimus generated Th2 cells (2.5 x 10(7) Th2 cells/kg) will activate a more balanced Th1/Th2 immunity and thereby reduce GVHD. In addition, we hypothesize that this Th2 therapy will be enhanced by sirolimus administration in the peri-transplant period.

This protocol (see schema, page 31) will enroll patients with refractory hematologic malignancy to one of three treatment arms (n=10 subjects/arm). In each arm, subjects will receive outpatient chemotherapy (EPOCH, fludarabine, and when applicable, Rituxan), reduced-intensity preparative chemotherapy (cyclophosphamide, fludarabine), a G-CSF mobilized allograft (T cell replete; 6/6 HLA-matched sibling donor), and cyclosporine A GVHD prophylaxis. In arm I, sirolimus generated Th2 cells will augment the allograft. In arm II, the transplant will include both sirolimus generated Th2 cells and in vivo sirolimus (day -2 to day +1 post-HSCT). In arm III, the transplant will not be augmented by Th2 cells, but will include in vivo sirolimus. If a treatment arm yields grade II-IV GVHD of 50% or less ( 5/10 cases or less), that arm will be considered potentially beneficial relative to single agent cyclosporine A GVHD prophylaxis, and will thus be expanded to a total of n=23 subjects for further evaluation of GVHD rate and clinical anti-tumor responses.


Genders Eligible for Study:  Both


Patients with hematologic malignancies, myelodysplasia, or myeloproliferative disorders, as summarized in the following list:
1. Chronic Lymphocytic Leukemia -Disease Disease Status: a) Relapse post-fludarabine, b) Non-CR after salvage regimen.
2. Hodgkin's and Non-Hodgkin's Lymphoma (all types, including Mantle Cell Lymphoma). Disease Disease Status: a) Primary treatment failure, b) Relapse after autologous SCT, c) Non-CR after salvage regimen.
3. Multiple Myeloma - Disease Disease Status: a) Primary treatment failure, b) Relapse after autologous SCT, c) Non-CR after salvage regimen.
4. Acute Myelogenous Leukemia -Disease Disease Status: a) CR number 1 and "high-risk" [excludes t(8;21), t(15;17), or inv(16)], b) CR number 2 or greater).
5. Acute Lymphocytic Leukemia - Disease Disease Status: a) CR number 1 plus high-risk [t(9;22) or bcr-abl+; t(4;11), 1(1;19), t(8;14)], b) In CR number2 or greater .
6. Myelodysplastic Syndrome - Disease Disease Status: a) RAEB, b) RAEB-T (requires marrow and blood blasts less than 10% after induction chemotherapy).
7. Myeloproliferative disorders (Patients with myeloproliferative disorders must be end-stage, which is primarily defined as disease severity refractory to splenectomy) - Disease Status: a) Idiopathic myelofibrosis, b) Polycythemia vera, c) Essential thrombocytosis, d) Chronic myelomonocytic leukemia.
8. Chronic Myelogenous Leukemia - Disease Disease Status: a) Chronic phase CML, b) Accelerated phase CML(all CML patients must be refractory to imatinib therapy).
Patient age of 18 to 75 years.
Consenting first degree relative matched at 6/6 HLA antigens (A, B, and DR).
Patient or legal guardian must be able to give informed consent.
All previous therapy must be completed at least 2 weeks prior to study entry, with recovery to equalgrade 2 toxicity of previous therapy.
ECOG performance status equal to 0 or 1.
Life expectancy of at least 3 months.
Acute leukemia must be in hematologic remission (less than 5% blood or marrow blasts).
Left ventricular ejection fraction greater than 45%, preferably by 2-D echo, or by MUGA.
Corrected DLCO greater than 50% of expected value.
Creatinine less than 1.5 mg/dl and creatinine clearance greater than 50 ml/min.
Serum total bilirubin less than 2.5 mg/dl; serum ALT and AST equal 2.5 times upper limit of normal. Values above these levels may be accepted, at the discretion of the PI or study chairman, if such elevations are thought to be due to liver involvement by malignancy.
Adequate central venous access potential.
First-degree relative with genotypic identity at 6/6 HLA loci (HLA- A, B, and DR).
Age 18 to 75 years.
Adequate venous access for peripheral apheresis, or consent to use a temporary central venous catheter for apheresis.
Donors must be HIV negative, hepatitis B surface antigen negative, and hepatitis C antibody negative (to prevent disease transmission to recipient).
Lactating donors must substitute formula feeding for her infant during period of filgrastim administration (to prevent any filgrastim effect on infant).
Active infection that is not responding to antimicrobial therapy.
Active CNS involvement by malignancy.
HIV infection (treatment may result in progression of HIV and other viral infections).
Chronic active hepatitis B. Patients may be hepatitis B core antibody positive but must be surface antigen negative and without evidence of active infection.
Hepatitis C infection.
Pregnant or lactating. Patients of childbearing potential must use an effective method of contraception. The effects of the chemotherapy, the subsequent transplant and the medications used after the transplant are highly likely to be harmful to a fetus. The effects upon breast milk are also unknown and may be harmful to the infant.
History of psychiatric disorder which may compromise compliance with transplant protocol, or which does not allow for appropriate informed consent.
History of psychiatric disorder which may compromise compliance with transplant protocol, or which does not allow for appropriate informed consent.
History of hypertension that is not controlled by medication, stroke, autoimmune disease, or severe heart disease (donors with symptomatic angina will be excluded). Donors with a history of coronary artery bypass grafting or angioplasty who are symptom free will receive a cardiology evaluation and be considered on a case-by-case basis.
History of prior malignancy. However, cancer survivors who have undergone potentially curative therapy and have had no evidence of that disease for at least 5 years may be considered for stem cell donation on a case-by-case basis.
Donors must not be pregnant (unknown effect of filgrastim on fetus). Donors of childbearing potential must use an effective method of contraception.
Anemia (Hb less than 11 gm/dl) or thrombocytopenia (platelets less than 100,000 per microliter).

Location and Contact Information

      National Cancer Institute (NCI), 9000 Rockville Pike,  Bethesda,  Maryland,  20892,  United States; Recruiting
Patient Recruitment and Public Liaison Office  1-800-411-1222 
TTY  1-866-411-1010 

More Information

Detailed Web Page


Armitage JO. Bone marrow transplantation. N Engl J Med. 1994 Mar 24;330(12):827-38. Review. No abstract available.

Horowitz MM, Gale RP, Sondel PM, Goldman JM, Kersey J, Kolb HJ, Rimm AA, Ringden O, Rozman C, Speck B, et al. Graft-versus-leukemia reactions after bone marrow transplantation. Blood. 1990 Feb 1;75(3):555-62.

Maraninchi D, Gluckman E, Blaise D, Guyotat D, Rio B, Pico JL, Leblond V, Michallet M, Dreyfus F, Ifrah N, et al. Impact of T-cell depletion on outcome of allogeneic bone-marrow transplantation for standard-risk leukaemias. Lancet. 1987 Jul 25;2(8552):175-8.

Study ID Numbers:  040055; 04-C-0055
Record last reviewed:  March 22, 2005
Last Updated:  March 11, 2005
Record first received:  December 12, 2003 Identifier:  NCT00074490
Health Authority: United States: Federal Government processed this record on 2005-04-08

Cache Date: April 9, 2005