Clinical trial NCT00281879
Conditions: Chronic Myeloproliferative Disorders Leukemia Lymphoma Multiple Myeloma and Plasma Cell Neoplasm Myelodysplastic Syndromes Myelodysplastic/Myeloproliferative Neoplasms Unusual Cancers of Childhood
Keywords: adult acute lymphoblastic leukemia in remission L1 adult acute lymphoblastic leukemia L2 adult acute lymphoblastic leukemia L3 adult acute lymphoblastic leukemia recurrent adult acute lymphoblastic leukemia accelerated phase chronic myelogenous leukemia blastic phase chronic myelogenous leukemia chronic phase chronic myelogenous leukemia relapsing chronic myelogenous leukemia childhood acute lymphoblastic leukemia in remission L1 childhood acute lymphoblastic leukemia L2 childhood acute lymphoblastic leukemia L3 childhood acute lymphoblastic leukemia recurrent childhood acute lymphoblastic leukemia recurrent adult Hodgkin lymphoma recurrent/refractory childhood Hodgkin lymphoma stage IV adult Hodgkin lymphoma stage IV childhood Hodgkin lymphoma adult acute myeloid leukemia in remission adult acute myeloid leukemia with 11q23 (MLL) abnormalities adult acute myeloid leukemia with t(15;17)(q22;q12) adult acute myeloid leukemia with t(16;16)(p13;q22) childhood acute myeloid leukemia in remission recurrent adult acute myeloid leukemia recurrent childhood acute myeloid leukemia myelodysplastic/myeloproliferative neoplasm, unclassifiable previously treated myelodysplastic syndromes secondary myelodysplastic syndromes secondary acute myeloid leukemia refractory anemia with excess blasts in transformation refractory anemia with excess blasts refractory anemia chronic myelomonocytic leukemia childhood chronic myelogenous leukemia chronic eosinophilic leukemia primary myelofibrosis chronic neutrophilic leukemia de novo myelodysplastic syndromes atypical chronic myeloid leukemia, BCR-ABL negative extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue juvenile myelomonocytic leukemia nodal marginal zone B-cell lymphoma noncontiguous stage II adult Burkitt lymphoma noncontiguous stage II adult diffuse large cell lymphoma noncontiguous stage II adult diffuse mixed cell lymphoma noncontiguous stage II adult diffuse small cleaved cell lymphoma noncontiguous stage II adult immunoblastic large cell lymphoma noncontiguous stage II adult lymphoblastic lymphoma noncontiguous stage II grade 1 follicular lymphoma noncontiguous stage II grade 2 follicular lymphoma noncontiguous stage II grade 3 follicular lymphoma noncontiguous stage II mantle cell lymphoma noncontiguous stage II marginal zone lymphoma noncontiguous stage II small lymphocytic lymphoma recurrent adult Burkitt lymphoma recurrent adult diffuse large cell lymphoma recurrent adult diffuse mixed cell lymphoma recurrent adult diffuse small cleaved cell lymphoma recurrent adult immunoblastic large cell lymphoma recurrent adult lymphoblastic lymphoma recurrent childhood large cell lymphoma recurrent childhood lymphoblastic lymphoma recurrent childhood small noncleaved cell lymphoma recurrent grade 1 follicular lymphoma recurrent grade 2 follicular lymphoma recurrent grade 3 follicular lymphoma recurrent mantle cell lymphoma recurrent marginal zone lymphoma recurrent small lymphocytic lymphoma refractory chronic lymphocytic leukemia refractory hairy cell leukemia refractory multiple myeloma splenic marginal zone lymphoma stage I multiple myeloma stage II multiple myeloma stage III adult Burkitt lymphoma stage III adult Hodgkin lymphoma stage III adult diffuse large cell lymphoma stage III adult diffuse mixed cell lymphoma stage III adult diffuse small cleaved cell lymphoma stage III adult immunoblastic large cell lymphoma stage III adult lymphoblastic lymphoma stage III chronic lymphocytic leukemia stage III grade 1 follicular lymphoma stage III grade 2 follicular lymphoma stage III grade 3 follicular lymphoma stage III mantle cell lymphoma stage III marginal zone lymphoma stage III multiple myeloma stage III small lymphocytic lymphoma stage IV adult Burkitt lymphoma stage IV adult diffuse large cell lymphoma stage IV adult diffuse mixed cell lymphoma stage IV adult diffuse small cleaved cell lymphoma stage IV adult immunoblastic large cell lymphoma stage IV adult lymphoblastic lymphoma stage IV chronic lymphocytic leukemia stage IV grade 1 follicular lymphoma stage IV grade 2 follicular lymphoma stage IV grade 3 follicular lymphoma stage IV mantle cell lymphoma stage IV marginal zone lymphoma stage IV small lymphocytic lymphoma stage III childhood Hodgkin lymphoma stage III childhood large cell lymphoma stage III childhood lymphoblastic lymphoma stage III childhood small noncleaved cell lymphoma stage IV childhood large cell lymphoma stage IV childhood lymphoblastic lymphoma stage IV childhood small noncleaved cell lymphoma unusual cancers of childhood childhood myelodysplastic syndromes
Sponsor: OHSU Knight Cancer Institute
Start date: 2006-02-01; Completion date: 2008-03-01
Enrollment: 200 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
RATIONALE: A peripheral stem cell transplant or an umbilical cord blood transplant from a donor may be able to replace blood-forming cells that were destroyed by chemotherapy or radiation therapy. Giving an infusion of the donor's white blood cells (donor lymphocyte infusion) after the transplant may help destroy any remaining cancer cells (graft-versus-tumor effect). Sometimes the transplanted cells can make an immune response against the body's normal cells. Methotrexate, cyclosporine, tacrolimus, or methylprednisolone may stop this from happening.

PURPOSE: This clinical trial is studying how well a donor stem cell transplant or donor white blood cell infusions work in treating patients with hematologic cancer.

Detailed description:
OBJECTIVES:

Primary

* Determine the effectiveness of unrelated donor allogeneic hematopoietic stem cells for transplantation after conditioning for the treatment of patients with high-risk hematologic malignancies.
* Compare survival, disease-free survival (DFS), response rate, and toxicity rates in these patients with historical controls.
* Compare the rate and severity of acute and chronic GVHD after allogeneic hematopoietic stem cell transplantation in patients with hematopoietic malignancies with historical controls transplanted with stem cells from related sibling donors
* Assess engraftment, long-term hematopoietic recovery, relapse rate, and disease-free survival when allogeneic hematopoietic stem cells are used as a source of stem cells for transplantation in patients with high-risk hematological malignancies.
* Assess engraftment, long-term hematopoietic recovery, and overall survival when allogeneic hematopoietic stem cells are used as a source of stem cells for transplantation in patients who have graft failure or graft rejection.
* Compare engraftment, long-term hematopoietic recovery, rate of GVHD, rate of relapse, toxicity rates, overall disease-free survival and overall survival when donor leukocyte infusions (DLI) are given for patients who have disease recurrence, progression, or low donor chimerisms after unrelated stem cell transplantation or before DLI with historical controls of other donor leukocyte infusions.

Secondary

* Determine the quality of life of patients undergoing hematopoietic stem cell transplantation or donor leukocyte infusions from unrelated HLA genotypically-identical donors.

OUTLINE: Patients are assigned to 1 of 8 treatment groups.

* Group 1\*: Patients undergo total body irradiation (TBI) twice a day on days -7 to -4. Patients then receive cyclophosphamide IV over 1 hour on days -3 and -2. On day 0 patients undergo stem cell transplantation (SCT). Beginning on day 7, patients receive filgrastim (G-CSF) IV once daily until blood counts recover.
* Group 2 (patients who have previously experienced dose-limiting radiotherapy): Patients receive oral busulfan 4 times daily on days -7 to -4 and cyclophosphamide IV over 1 hour on days -3 and -2. On day 0 patients undergo SCT. Beginning on day 7, patients receive G-CSF IV once daily until blood counts recover.
* Group 3 (pediatric patients only): Patients receive busulfan IV 4 times daily on days -9 to -6 and cyclophosphamide IV over 1 hour and fludarabine IV over 30 minutes on days -5 to -2. On day 0 patients undergo SCT. Beginning on day 7, patients may receive G-CSF IV once daily until blood counts recover.
* Group 4 (second SCT for patients who have experienced graft rejection or failure)\*: Patients receive low-dose fludarabine IV over 30 minutes on days -4 to -2. Patients then undergo low-dose TBI once followed by SCT on day 0. Beginning on day 7, patients may receive G-CSF IV once daily until blood counts recover.
* Group 5 (patients who developed grade 3 cystitis after prior cyclophosphamide-containing therapy): Patients receive carmustine IV over 2 hours on day -6, etoposide IV over 2 hours and cytarabine IV over 30 minutes on days -5 to -2, and melphalan IV over 30 minutes on day -1 (BEAM). On day 0, patients undergo SCT. Beginning on day 7, patients receive G-CSF IV once daily until blood counts recover.
* Group 6 (cord blood transplantation): Patients receive anti-thymocyte globulin IV once daily and methylprednisolone IV twice daily on days -3 to -1. On day 0, patients undergo an umbilical cord blood SCT.
* Group 7 (patients with relapsing or progressive disease after prior transplants or low donor chimerisms)\*: Patients must not have existing graft-versus-host disease (GVHD). Patients receive donor lymphocyte infusions with conditioning chemotherapy and/or radiotherapy at the discretion of the investigator.
* Group 8 (pediatric patients only)\*: Patients undergo TBI twice a day on days -7 to -5. Patients also receive etoposide IV over 24 hours on day -4 and cyclophosphamide IV over 1 hour on days -3 and -2. On day 0, patients undergo SCT. Beginning on day 7, patients may receive G-CSF IV once daily until blood counts recover.

NOTE: \*Patients who have received \> 3000 cGy to the central nervous system or \> 2000 cGy to the lung or liver may not receive any regimen containing total body irradiation (TBI)

All patients receive GVHD prophylaxis comprising methotrexate IV on days 1, 3, 6, and 11; cyclosporine and/or tacrolimus on days -2 to 100; and/or methylprednisolone IV on days 7 to 100.

Patients with an unrelated donor who experience a relapse prior to transplantation, may proceed directly to transplantation. However, if immediate transplantation from the unrelated donor is not possible, the patient must be re-induced into a complete hematological remission. Patients who experience graft failure or graft rejection after allogeneic transplantation are eligible for a second stem cell infusion from the original donor.

Quality of life is assessed at baseline and at 7 days, 3 months, and 1 year after transplantation.

After completion of study treatment, patients are followed periodically for survival.

PROJECTED ACCRUAL: A total of 43 patients will be accrued for this study.

Arms: arm 1: None arm 2: None arm 3: On the day of your admission, you will start to take a drug called allopurinol which helps to protect your kidneys as your body works to discharge cells killed off by your chemotherapy and TBI. Chemotherapy will begin on Day -6 with carmustine (BCNU), followed by etoposide (VP-16), cytosine arabinoside (ARA-C), and melphalan. This conditioning regimen is known as the BEAM regimen. The dose of this therapy is high enough to kill cancer cells but will also kill all of your normal blood forming cells. Subjects undergoing the BEAM regimen will not have total body irradiation (TBI). arm 4: A conditioning regimen of low-dose fludarabine and TBI is used in the event that a second donation of hematopoietic stem cells is necessary. Chemotherapy with Fludarabine will begin 4 days prior to your transplant. This drug will be given through the catheter in your chest daily for 3 days. TBI (radiation) will be given to you on the day of your transplant. After your TBI, your donor's stem cells / bone marrow will be given to you through your catheter. The drugs cyclosporine and mycophenolate mofetil (MMF) will be given orally to help you accept your donor's cells. arm 5: On the day of your admission you will start to take a drug called Dilantin which is used to help prevent seizures while you receive your chemotherapy drugs. You will also start to take a drug called allopurinol which helps to protect your kidneys as your body works to discharge cells killed off by your chemotherapy and TBI. On the next day, you will then begin your conditioning therapy with a drug called busulfan. This medicine will be given to you by an infusion into your bloodstream through a small tube in the vein of your arm four times per day for four days. After the busulfan treatment, you will receive 4 doses each of two drugs, cyclophosphamide (also known as Cytoxan) and fludarabine, over 2 hours into your vein. arm 6: If you are undergoing a pre-transplant conditioning regimen prior to undergoing a cord blood transplant, you will receive a drug called ATG to improve your chances of engraftment and decrease your risk of graft versus host disease. You may receive ATG 3 times during your transplant regimen on days -3 through days -1 in addition to your pre-transplant conditioning therapy. Methylprednisolone will also be given during each dose of ATG to help reduce any reactions during infusion. arm 7: Donor Leukocyte Infusions: You will receive DLI from your original transplant donor. This will be given through a vein , usually in your arm. It will be similar to getting a platelet or blood transfusion. You may require more than one DLI. The decision to give you another infusion will be determined by your condition, relapse status, GVHD and how much DLI you were given before. You may need chemotherapy and/or radiation to improve your disease status prior to additional DLI's. arm 8: On the day after your admission, you will start receiving radiation therapy (TBI). Radiation will be given to you 2 times a day for 3 days. On the next day, you will then begin your chemotherapy with a drug called etoposide. This medicine will be given to you by an infusion into your bloodstream through a small tube in the vein of your arm for one day. After the etoposide treatment, on the next day you will receive cyclophosphamide (also known as Cytoxan) for 2 days. When you are given cyclophosphamide, you will also be given a medication called MESNA to help protect your bladder from damage. After you have completed the cyclophosphamide you will rest one day without any anti-cancer therapy. This allows your body time to remove and inactivate the chemotherapy. After a day of rest, you will be given your donor's cells.
Interventions: intervention 1: anti-thymocyte globulin intervention 2: filgrastim intervention 3: busulfan intervention 4: carmustine intervention 5: cyclophosphamide intervention 6: cyclosporine intervention 7: cytarabine intervention 8: etoposide intervention 9: fludarabine phosphate intervention 10: melphalan intervention 11: methotrexate intervention 12: methylprednisolone intervention 13: mycophenolate mofetil intervention 14: tacrolimus intervention 15: peripheral blood stem cell transplantation intervention 16: umbilical cord blood transplantation intervention 17: radiation therapy
Intervention descriptions: intervention 1: Intravenous, 1.5 mg/kg of body weight daily for 7 to 14 days The first dose should be administered over a minimum of 6 hours and over at least 4 hours on subsequent doses through a high-flow vein. intervention 2: Will be given IV at 5 µg/kg/day. The first injection will be administered on day +7, i.e. 7 days after the hematopoietic stem cells are infused.

Will be administered until the ANC is 1500 / µl for 2 days. Dose and schedule of G-CSF administration is left to each center's discretion. intervention 3: Patients who take the drug PO, busulfan will be administered at 1 mg/kg/ dose given by mouth every 6 hours for 16 consecutive doses. Pediatric patients who receive busulfan IV continuous infusion will receive a dose of 3.0 mg/kg/IBW if under the age of 2.Pediatric patients over the age of 2 will receive busulfan at a dose of 0.8 mg/kg/dose. intervention 4: 300mg/m2 IV dissolved in 500 cc NS infused over 2 hours into right atrial catheter on day -6. intervention 5: For transplantation, the drug is diluted in 250 to 500 cc of NS or D5W and administered IV over 2 hours. intervention 6: Initial doses will be administered IV at a starting dose of 1.5 mg/kg BID. The infusion will vary from 2-24hr depending on the incidence of side-effects. intervention 7: 400 mg/m2 dissolved in 200cc D5W and infused over 30 minutes into right atrial catheter on days -5, -4, -3, -2. intervention 8: Etoposide administration 200 mg /m2 dissolved in 1 liter NS and infused over 2 hours into right atrial catheter. Infusion to begin after cytarabine administration on days -5, -4, -3, -2.

Etoposide administration 50 mg/kg IV over 24 hours, divided into 3 doses. Dilute in normal saline at a concentration of 0.4 mg/ml (Observe for precipitation). Administered IV with continuous infusion over 24 hours. Diuretics may be given for fluid overload. intervention 9: Fludarabine administered at 30 mg/m2 IVPB infused over 30 minutes into right atrial catheter on days -4, -3, -2.

Fludarabine administered at 40 mg/m2 IVPB infused over 30 into the right atrial catheter on days -5, -4, -3, and -2. intervention 10: 140 mg /m2 in concentration of 0.45 mg/ml of NS infused over 30 minutes into right atrial catheter on day -1. intervention 11: Administered on days +1, +3, and +7. intervention 12: Methyl-prednisolone is administered IV as a rapid infusion. intervention 13: Mycophenolate may be used as a substitute for Methotrexate intervention 14: A drug used to decrease the risk of graft versus host disease (GvHD). intervention 15: The stem cells will be given to you by intravenous injection (through your vein) using a catheter that was placed prior to beginning chemotherapy. The stem cell infusion takes 1-6 hours. intervention 16: The patient will receive ATG to improve the changes of engraftment and decrease their risk of graft versus host disease. The patient may receive ATG 3 times during their transplant regimen on days -3 through days -1 intervention 17: Radiation will be given to you 2 times a day for 3 or 4 days.

Protocol documents: