Donor Stem Cell Transplant or Donor White Blood Cell Infusions in Treating Patients With Hematologic Cancer

Lymphoma Clinical Trial

Official title:

Transplantation of Unrelated Donor Hematopoietic Stem Cells for the Treatment of Hematological Malignancies

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00281879
• Other study ID #: CDR0000452794
• Secondary ID: P30CA016058OHSU-
• Status: Terminated
• Phase: Phase 2
• First received: January 24, 2006
• Last updated: September 25, 2017
• Start date: February 2006
• Est. completion date: March 2008

Study information

• Verified date: September 2017
• Source: OHSU Knight Cancer Institute
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 200
• Est. completion date: March 2008
• Est. primary completion date: February 2008
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 60 Years

Eligibility

DISEASE CHARACTERISTICS:

• Diagnosis of 1 of the following*:

• Acute lymphoblastic leukemia in any disease phase

• Patients with any of the following high-risk features are encouraged to enroll:

• Philadelphia chromosome positive disease

• L3 morphology, especially in the presence of t(8;14), t(8;22), or t(2;8)

• Patients not in remission at day 28 of first induction

• High LDH (i.e., = 300 IU/mL at presentation)

• Pre-B-cell, mixed lineage, or Burkitt's markers

• Relapsed in the marrow while receiving continuous chemotherapy

• Within 6 months after stopping chemotherapy

• Relapse in one organ or extramedullary relapses in more than one organ while still receiving chemotherapy

• Hodgkin's or non-Hodgkin's lymphoma beyond first complete remission (CR) or in first CR with features of high-risk disease, including, but not limited to:

• Lymphoma not in CR after 3 courses of primary therapy

• Patients with bulky disease at presentation, especially bulky mediastinal disease

• Patients with LDH = 300 IU/mL at presentation

• Patients with extranodal disease

• Patients with first remission within less than 1 year

• Stage IV disease at presentation, especially with marrow involvement

• Patients with high-intermediate or high International Index Scores

• Acute myeloid leukemia (AML) meeting the following criteria:

• Beyond first remission or high-risk disease in first CR

• Required multiple courses of induction therapy to achieve a remission

• Had residual leukemia on day 14-28 bone marrow examination after initial induction

• Patients with any cytogenetic abnormality except inv 16 or t(8;21)

• Chronic myelogenous leukemia in the chronic or early accelerated phase of the disease

• Patients with blast crisis that can be induced back into chronic phase may be transplanted in second chronic phase

• Myelodysplastic syndromes (MDS) meeting the following requirements:

• Transfusion-dependent refractory anemia (RA), RA with excess blasts (RAEB), RAEB in transformation, or chronic myelomonocytic leukemia (CMML)

• Patients with MDS that present with or evolve to AML must be re-induced back to remission prior to initiating a search for an unrelated donor NOTE: *Patients with other hematologic malignancies not listed above, including diseases such as chronic lymphocytic leukemia (CLL), multiple myeloma, or rare pediatric malignancies, or patients who are felt to be at high-risk for relapse but who do not have features listed, may be allowed at the discretion of the investigator.

• Must have failed prior stem cell transplantation

• Must have a suitable unrelated allogeneic hematopoietic stem cell donor

• A 5/6 match degree is acceptable for unrelated bone marrow donors

• A 4/6 match degree is acceptable for unrelated cord blood units

PATIENT CHARACTERISTICS:

• SWOG performance status (PS) 0-2 OR

• Karnofsky PS 50-100% OR

• Lansky PS 50-100%

• Creatinine clearance = 45 mL/min

• Creatinine = 2.5 mg/dL

• Bilirubin = 2 mg/dL (abnormally high liver function tests allowed if the only source for the elevation is due to lymphoma of the liver)

• AST or ALT = 2 times normal (abnormally high liver function tests allowed if the only source for the elevation is due to lymphoma of the liver)

• No patients at high risk of veno-occlusive disease

• Not pregnant or nursing

• Negative serum pregnancy test

• Fertile patients must use an effective contraceptive method

• DLCO = 50% of predicted

• FEV_1/FVC = 65% of predicted

• No current congestive heart failure (CHF) and/or LVEF = 45%

• No myocardial infarction within the past 6 months

• No unstable angina within the past 6 months

• HIV negative

• Life expectancy must not be limited by disease other than malignancy

• No allergy to any chemotherapeutic agent included in the regimen

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics

Related Conditions & MeSH terms

• Chronic Myeloproliferative Disorders
• Leukemia
• Lymphoma
• Multiple Myeloma
• Multiple Myeloma and Plasma Cell Neoplasm
• Myelodysplastic Syndromes
• Myelodysplastic-Myeloproliferative Diseases
• Myelodysplastic/Myeloproliferative Neoplasms
• Myeloproliferative Disorders
• Neoplasms
• Neoplasms, Plasma Cell
• Plasmacytoma
• Preleukemia
• Syndrome
• Unusual Cancers of Childhood

Intervention

Biological:
• anti-thymocyte globulin
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.
• filgrastim
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.

Drug:
• busulfan
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.
• carmustine
300mg/m2 IV dissolved in 500 cc NS infused over 2 hours into right atrial catheter on day -6.
• cyclophosphamide
For transplantation, the drug is diluted in 250 to 500 cc of NS or D5W and administered IV over 2 hours.
• cyclosporine
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.
• cytarabine
400 mg/m2 dissolved in 200cc D5W and infused over 30 minutes into right atrial catheter on days -5, -4, -3, -2.
• etoposide
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.
• fludarabine phosphate
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.
• melphalan
140 mg /m2 in concentration of 0.45 mg/ml of NS infused over 30 minutes into right atrial catheter on day -1.
• methotrexate
Administered on days +1, +3, and +7.
• methylprednisolone
Methyl-prednisolone is administered IV as a rapid infusion.
• mycophenolate mofetil
Mycophenolate may be used as a substitute for Methotrexate
• tacrolimus
A drug used to decrease the risk of graft versus host disease (GvHD).

Procedure:
• peripheral blood stem cell transplantation
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.
• umbilical cord blood transplantation
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

Radiation:
• radiation therapy
Radiation will be given to you 2 times a day for 3 or 4 days.

Locations

Country	Name	City	State
United States	OHSU Knight Cancer Institute	Portland	Oregon

Sponsors (2)

Lead Sponsor	Collaborator
OHSU Knight Cancer Institute	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With Disease Free Survival (DFS).	Determine the effectiveness of unrelated donor allogeneic hematopoietic stem cells for transplantation after conditioning for the treatment of high-risk hematopoietic malignancies.; Disease-free survival: The length of time after treatment ends that a patient survives without any signs or symptoms of that cancer or any other type of cancer.	Duration of the study; Up to 2 years