Bone Marrow Transplant Studies for Safe and Effective Treatment of Leukemia

Bone marrow transplants (BMT) are one of the accepted therapies used to treat leukemia. However, BMT have risks of complications. One potentially life-threatening complication is known as graft-versus-host disease (GVHD). The GVHD is a reaction caused by an incompatibility between donor cells and recipient cells. Antigens found on the recipient s cells are recognized by the donor s transplanted white blood cell lymphocytes. These lymphocytes begin attacking the recipient s cells and tissues and may lead to death. One of the most effective ways to prevent this reaction is to remove the lymphocytes from the transplanted marrow. Unfortunately, without lymphocytes the recipient s immune system will be lowered and may result in a relapse of leukemia or an infection. Researchers have shown they can perform effective BMT by removing the lymphocytes prior to the transplant and then later adding the lymphocytes back. This technique can reduce the potential for GVHD and preserve the graft-versus-leukemia (GVL) effect of the transplant. In this study researchers plan to use peripheral blood with lymphocytes removed rather than bone marrow. In order to increase the number of progenitor cells, the cells responsible for correcting the leukemia, donors will receive doses of G-CSF prior to the transplant. G-CSF (granulocyte colony stimulating factor) is a growth factor that increases the production of progenitor cells in the donor s blood stream. The study will be broken into two parts. The first part of the study will attempt to determine if peripheral blood with lymphocytes removed can prevent GVHD while preserving the GVL effect of the transplant. In the second part of the study, patients that received the transplant will have the lymphocytes added-back on two separate occasions in order reduce the chances of relapse and infection. The study is designed to treat up to 55 patients ages 10 to 60 years and follow their progress for 5 years.

Sex

All

Minimum age

10 Years

Maximum age

55 Years

* INCLUSION CRITERIA-PATIENT:
* Ages 10 to 55 years.
* Chronic myelogenous leukemia, any of these categories: chronic phase, accelerated phase of blast transformation.
* Acute lymphoblastic leukemia, any of these categories: Adults (greater than 18 years) in first remission with high risk features (presenting leukocyte count greater than 100,000 per cu mm, Karyotypes t9;22, t4, t19, t11, biphenotypic leukemia). All second remissions, primary induction failure, partially responding or untreated relapse.
* Acute myelogenous leukemia (AML): AML in first remission Except AML with good risk karyotypes: AML M3 (t15;17), AML M4Eo (inv 16), AML t(8;21). All AML in second or subsequent remission, primary induction failure and resistant relapse.
* Myelodysplastic syndromes, any of these categories: refractory anemia with excess of blasts, transformation to acute leukemia, chronic myelomonocytic leukemia.
* Multiple myeloma following initial disease control with chemotherapy.
* Chronic lymphocytic leukemia (CLL) and prolymphocytic leukemia, in remission or partial remission following fludarabine treatment. Richter transformation of CLL.
* No major organ dysfunction precluding transplantation.
* DLCO greater than 65 percent predicted.
* Left ventricular ejection fraction: greater than 40 percent predicted.
* ECOG performance status of 0 or 1.
* Informed consent given. Informed consent from both parents for minors.
* Women of childbearing age with a negative pregnancy test may participate.

EXCLUSION CRITERIA:

* Pregnant.
* Age greater than 55 or less than 10.
* ECOG performance status of 2 or more.
* Severe psychiatric illness. Mental deficiency sufficiently severe as to make compliance with the BMT treatment unlikely, and making informed consent impossible.
* Major anticipated illness or organ failure incompatible with survival from BMT.
* DLCO less than 65% predicted.
* Left ventricular ejection fraction: less than 40% predicted.
* Serum creatinine greater than 3 mg/dl.
* Serum bilirubin greater than 4 mg/dl.
* Transaminases greater than 3 x upper limit of normal.
* HIV positive.
* History of other malignancies except basal cell or squamous carcinoma of the skin, positive PAP smear and subsequent negative follow up (patient).

INCLUSION CRITERIA-DONOR:

* HLA 6/6 or 5/6 matched sibling donor.
* Fit to receive G-CSF and give peripheral blood stem cells (normal blood count, normotensive, no history of stroke).
* Informed consent given.

EXCLUSION CRITERIA - DONOR:

* Pregnant.
* Severe psychiatric illness. Mental deficiency sufficiently severe as to make compliance with the BMT treatment unlikely, and making informed consent impossible.
* Donor unfit to receive G-CSF and undergo apheresis. (Uncontrolled hypertension, history of stroke, thrombocytopenia).
* HIV positive.

• BACKGROUNDMavroudis D, Read E, Cottler-Fox M, Couriel D, Molldrem J, Carter C, Yu M, Dunbar C, Barrett J. CD34+ cell dose predicts survival, posttransplant morbidity, and rate of hematologic recovery after allogeneic marrow transplants for hematologic malignancies. Blood. 1996 Oct 15;88(8):3223-9. PMID 8874224
• BACKGROUNDBarrett AJ, Mavroudis D, Tisdale J, Molldrem J, Clave E, Dunbar C, Cottler-Fox M, Phang S, Carter C, Okunnieff P, Young NS, Read EJ. T cell-depleted bone marrow transplantation and delayed T cell add-back to control acute GVHD and conserve a graft-versus-leukemia effect. Bone Marrow Transplant. 1998 Mar;21(6):543-51. doi: 10.1038/sj.bmt.1701131. PMID 9543057
• BACKGROUNDBarrett AJ, Malkovska V. Graft-versus-leukaemia: understanding and using the alloimmune response to treat haematological malignancies. Br J Haematol. 1996 Jun;93(4):754-61. doi: 10.1046/j.1365-2141.1996.d01-1713.x. No abstract available. PMID 8703800
• DERIVEDMcIver ZA, Yin F, Hughes T, Battiwalla M, Ito S, Koklanaris E, Haggerty J, Hensel NF, Barrett AJ. Second hematopoietic SCT for leukemia relapsing after myeloablative T cell-depleted transplants does not prolong survival. Bone Marrow Transplant. 2013 Sep;48(9):1192-7. doi: 10.1038/bmt.2013.39. Epub 2013 Mar 25. PMID 23524640
• DERIVEDMcIver Z, Melenhorst JJ, Wu C, Grim A, Ito S, Cho I, Hensel N, Battiwalla M, Barrett AJ. Donor lymphocyte count and thymic activity predict lymphocyte recovery and outcomes after matched-sibling hematopoietic stem cell transplant. Haematologica. 2013 Mar;98(3):346-52. doi: 10.3324/haematol.2012.072991. Epub 2012 Oct 12. PMID 23065508