Alemtuzumab, Fludarabine Phosphate, and Total-Body Irradiation Followed by Cyclosporine and Mycophenolate Mofetil in Treating Patients Who Are Undergoing Donor Stem Cell Transplant for Hematologic Cancer

Phase 2

Completed

Conditions: Acute Undifferentiated Leukemia
Angioimmunoblastic T-cell Lymphoma
Childhood Acute Lymphoblastic Leukemia in Remission
Hepatosplenic T-cell Lymphoma
Mast Cell Leukemia
Recurrent Adult Acute Lymphoblastic Leukemia
Recurrent Adult Acute Myeloid Leukemia
Recurrent Adult Burkitt Lymphoma
Adult Acute Lymphoblastic Leukemia in Remission
Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative

Interventions: Biological: alemtuzumab
Radiation: total-body irradiation
Drug: fludarabine phosphate
Drug: cyclosporine
Drug: mycophenolate mofetil
Procedure: allogeneic hematopoietic stem cell transplantation
Procedure: peripheral blood stem cell transplantation
Biological: graft versus host disease prophylaxis/therapy
Other: laboratory biomarker analysis

Registration Number: NCT00118352

Lead Sponsor: Fred Hutchinson Cancer Center

Brief Summary: This phase II trial is studying the side effects and best dose of alemtuzumab when given together with fludarabine phosphate and total-body irradiation followed by cyclosporine and mycophenolate mofetil in treating patients who are undergoing a donor stem cell transplant for hematologic cancer. Giving low doses of chemotherapy, such as fludarabine phosphate, a monoclonal antibody, such as alemtuzumab, and radiation therapy before a donor stem cell transplant helps stop the growth of cancer cells. Giving chemotherapy or radiation therapy before or after transplant also stops the patient's immune system from rejecting the donor's bone marrow stem cells. The donated stem cells may replace the patient's immune cells and help destroy any remaining cancer cells (graft-versus-tumor effect). Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving cyclosporine and mycophenolate mofetil after the transplant may stop this from happening.

Detailed Description: PRIMARY OBJECTIVES:

I. To determine which dose of Campath (alemtuzumab) allows related and unrelated human leukocyte antigen (HLA) class-II mismatched hematopoietic cell transplantation (HCT) with an incidence of grade III-IV acute graft-versus-host disease (GVHD) less than 40%.

SECONDARY OBJECTIVES:

I. Incidence of graft rejection.

II. Number of days of steroids \>= 1mg/kg required before day 100 in each patient.

III. Incidence of non-relapse mortality.

IV. Risk/incidence of infections.

V. Immune reconstitution.

VI. Risk for disease progression and relapse.

OUTLINE: This is a dose-escalation study of alemtuzumab.

NONMYELOABLATIVE CONDITIONING REGIMEN: Patients receive alemtuzumab intravenously (IV) over 6 hours once daily on days -6, -5, and -4 OR days -5 and -4 and fludarabine phosphate IV over 30 minutes on days -4, -3, and -2. Patients also undergo low-dose total-body irradiation (TBI) on day 0.

ALLOGENEIC PERIPHERAL BLOOD STEM CELL TRANSPLANTATION (PBSCT): After completion of TBI, patients undergo allogeneic PBSCT on day 0.

IMMUNOSUPPRESSION: Patients receive cyclosporine orally (PO) or IV every 12 hours on days -3 to 180 followed by a taper until day 365 in the absence of GVHD. Beginning 4-6 hours after completion of allogeneic PBSCT, patients receive mycophenolate mofetil PO every 8 hours on days 0 to 100 followed by a taper until day 156 in the absence of GVHD.

After completion of study treatment, patients are followed up periodically for 12 months, at 18 months, and then annually for 5 years.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 12

Inclusion Criteria

The patient must be not eligible for conventional transplants and must have disease expected to be stable for at least 100 days without chemotherapy
Patients with hematologic malignancies treatable with HCT will be included:
- Aggressive non-Hodgkin lymphomas (NHLs) and other histologies such as diffuse large B-cell NHL: not eligible for autologous HCT, not eligible for conventional myeloablative HCT, or after failed autologous HCT;
- Low grade NHL: with < 6 month duration of complete response (CR) between courses of conventional therapy;
- Mantle cell NHL: may be treated in first CR;
- Chronic lymphocytic leukemia (CLL): must have failed 2 lines of conventional therapy and must be refractory to fludarabine; this includes patients who fail to have a complete or partial response after therapy with a regimen containing fludarabine (or another nucleoside analog] or experience disease relapse within 12 months after completing therapy with a regimen containing fludarabine [or another nucleoside analog);
- Hodgkin's disease (HD): must have received and failed frontline therapy and have failed or were not eligible for autologous transplant;
- Multiple myeloma (MM): must have received prior chemotherapy or failed autografting; following a planned autologous transplant [tandem] is allowed;
- Acute myeloid leukemia (AML): must have < 5% marrow blasts at the time of transplant;
- Acute lymphocytic leukemia (ALL): must have < 5% marrow blasts at the time of transplant;
- Chronic myelogenous leukemia (CML): patients will be accepted beyond first clinical progression (CP1) if they have received previous myelosuppressive chemotherapy or HCT, and have < 5% marrow blasts at time of transplant;
- Myelodysplastic syndrome/myeloproliferative disease (MDS/MPD): must have failed previous myelosuppressive chemotherapy or HCT, and have < 5% marrow blasts at time of transplant;
- Waldenstrom's macroglobulinemia: must have failed 2 courses of therapy
Patient refuses to be treated on a conventional transplant protocol; for this inclusion criteria, transplants must be approved by both the participating institution's patient review committee, such as the Patient Care Conference (PCC) at the Fred Hutchinson Cancer Research Center (FHCRC), and the FHCRC principal investigator
Patient with related or unrelated donors for whom:
- There is a likelihood of disease progression while HLA typing and results of a preliminary search and the donor pool suggest that a 10/10 HLA-A, B, C, DRB1 and DQB1 matched unrelated donor will not be found;
- Patient and donor must be matched for at least one DRB1 allele and one DQB1 allele;
- Best available matches are HLA class I HLA-A, -B, -C allele matched donors allowing for any one or two DRB1 and/or DQB1 antigen/allele mismatch;
- There is no indication for an autologous transplantation as a treatment option
DONOR: For HLA matching inclusion criteria, see patient inclusion criteria
DONOR: Only peripheral blood stem cells (PBSC) will be permitted as a HSC source on this protocol

Exclusion Criteria

Positive crossmatch between donor and recipients
Patient's life expectancy is severely limited by diseases other than malignancy
Patient has central nervous system (CNS) involvement with disease refractory to intrathecal chemotherapy
Presence of circulating leukemic blasts (in the peripheral blood) detected by standard pathology for patients with AML, ALL or CML
Patient is a fertile man or woman unwilling to use contraceptives during and for up to 12 months post treatment
Patient is a female who is pregnant or breastfeeding
Patient is human immunodeficiency virus (HIV) positive
Patients with active non-hematologic malignancies (except non-melanoma skin cancers)
Patients with a history of non-hematologic malignancies (except non-melanoma skin cancers) currently in a complete remission, who are less than 5 years from the time of complete remission, and have a > 20% risk of disease recurrence
Patient has a fungal infection with radiological progression after receipt of amphotericin B or active triazole for greater than 1 month
Patient has the following organ dysfunction:
- Symptomatic coronary artery disease or ejection fraction < 35% or other cardiac failure requiring therapy; ejection fraction is required if age > 50 years or if the patient has a history of anthracyclines or history of cardiac disease;
- Diffusion capacity of the lung for carbon monoxide (DLCO) < 35% total lung capacity (TLC) < 35%, forced expiratory volume of the lung in one second (FEV1) < 35% and/or receiving supplementary continuous oxygen; the FHCRC study principal investigator (PI) must approve enrollment of all patients with pulmonary nodules;
- Liver function abnormalities: patient with clinical or laboratory evidence of liver disease will be evaluated for the cause of liver disease, its clinical severity in terms of liver function, bridging fibrosis, and the degree of portal hypertension; the patient will be excluded if he/she is found to have fulminant liver failure, cirrhosis of the liver with evidence of portal hypertension, alcoholic hepatitis, esophageal varices, a history of bleeding esophageal varices, hepatic encephalopathy, uncorrectable hepatic synthetic dysfunction evinced by prolongation of the prothrombin time, ascites related to portal hypertension, bacterial or fungal liver abscess, biliary obstruction, chronic viral hepatitis with total serum bilirubin > 3mg/dL, or symptomatic biliary disease
Patient has poorly controlled hypertension and on multiple antihypertensives
Karnofsky performance score < 70 for adult patients
Lansky play-performance score < 70 for pediatric patients
Patient received cytotoxic agents for "cytoreduction" within three weeks (or the interval in which a cycle of standard chemotherapy would be administered in a non-transplant setting) prior to initiating the nonmyeloablative transplant conditioning; (exceptions are hydroxyurea and imatinib mesylate)
DONOR: Marrow donors
DONOR: Positive crossmatch between donor and recipient
DONOR: Donor is HIV-positive and/or has a medical condition that would result in increased risk for filgrastim (G-CSF) mobilization and harvest of PBSC
DONOR: Donor age < 12 years

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (chemotherapy, TBI, transplant)	allogeneic hematopoietic stem cell transplantation	NONMYELOABLATIVE CONDITIONING REGIMEN: Patients receive alemtuzumab IV over 6 hours once daily on days -6, -5, and -4 OR days -5 and -4 and fludarabine phosphate IV over 30 minutes on days -4, -3, and -2. Patients also undergo low-dose TBI on day 0. ALLOGENEIC PBSCT: After completion of TBI, patients undergo allogeneic PBSCT on day 0. IMMUNOSUPPRESSION: Patients receive cyclosporine PO or IV every 12 hours on days -3 to 180 followed by a taper until day 365 in the absence of GVHD. Beginning 4-6 hours after completion of allogeneic PBSCT, patients receive mycophenolate mofetil PO every 8 hours on days 0 to 100 followed by a taper until day 156 in the absence of GVHD.
Treatment (chemotherapy, TBI, transplant)	peripheral blood stem cell transplantation	NONMYELOABLATIVE CONDITIONING REGIMEN: Patients receive alemtuzumab IV over 6 hours once daily on days -6, -5, and -4 OR days -5 and -4 and fludarabine phosphate IV over 30 minutes on days -4, -3, and -2. Patients also undergo low-dose TBI on day 0. ALLOGENEIC PBSCT: After completion of TBI, patients undergo allogeneic PBSCT on day 0. IMMUNOSUPPRESSION: Patients receive cyclosporine PO or IV every 12 hours on days -3 to 180 followed by a taper until day 365 in the absence of GVHD. Beginning 4-6 hours after completion of allogeneic PBSCT, patients receive mycophenolate mofetil PO every 8 hours on days 0 to 100 followed by a taper until day 156 in the absence of GVHD.
Treatment (chemotherapy, TBI, transplant)	total-body irradiation	NONMYELOABLATIVE CONDITIONING REGIMEN: Patients receive alemtuzumab IV over 6 hours once daily on days -6, -5, and -4 OR days -5 and -4 and fludarabine phosphate IV over 30 minutes on days -4, -3, and -2. Patients also undergo low-dose TBI on day 0. ALLOGENEIC PBSCT: After completion of TBI, patients undergo allogeneic PBSCT on day 0. IMMUNOSUPPRESSION: Patients receive cyclosporine PO or IV every 12 hours on days -3 to 180 followed by a taper until day 365 in the absence of GVHD. Beginning 4-6 hours after completion of allogeneic PBSCT, patients receive mycophenolate mofetil PO every 8 hours on days 0 to 100 followed by a taper until day 156 in the absence of GVHD.
Treatment (chemotherapy, TBI, transplant)	alemtuzumab	NONMYELOABLATIVE CONDITIONING REGIMEN: Patients receive alemtuzumab IV over 6 hours once daily on days -6, -5, and -4 OR days -5 and -4 and fludarabine phosphate IV over 30 minutes on days -4, -3, and -2. Patients also undergo low-dose TBI on day 0. ALLOGENEIC PBSCT: After completion of TBI, patients undergo allogeneic PBSCT on day 0. IMMUNOSUPPRESSION: Patients receive cyclosporine PO or IV every 12 hours on days -3 to 180 followed by a taper until day 365 in the absence of GVHD. Beginning 4-6 hours after completion of allogeneic PBSCT, patients receive mycophenolate mofetil PO every 8 hours on days 0 to 100 followed by a taper until day 156 in the absence of GVHD.
Treatment (chemotherapy, TBI, transplant)	graft versus host disease prophylaxis/therapy	NONMYELOABLATIVE CONDITIONING REGIMEN: Patients receive alemtuzumab IV over 6 hours once daily on days -6, -5, and -4 OR days -5 and -4 and fludarabine phosphate IV over 30 minutes on days -4, -3, and -2. Patients also undergo low-dose TBI on day 0. ALLOGENEIC PBSCT: After completion of TBI, patients undergo allogeneic PBSCT on day 0. IMMUNOSUPPRESSION: Patients receive cyclosporine PO or IV every 12 hours on days -3 to 180 followed by a taper until day 365 in the absence of GVHD. Beginning 4-6 hours after completion of allogeneic PBSCT, patients receive mycophenolate mofetil PO every 8 hours on days 0 to 100 followed by a taper until day 156 in the absence of GVHD.
Treatment (chemotherapy, TBI, transplant)	laboratory biomarker analysis	NONMYELOABLATIVE CONDITIONING REGIMEN: Patients receive alemtuzumab IV over 6 hours once daily on days -6, -5, and -4 OR days -5 and -4 and fludarabine phosphate IV over 30 minutes on days -4, -3, and -2. Patients also undergo low-dose TBI on day 0. ALLOGENEIC PBSCT: After completion of TBI, patients undergo allogeneic PBSCT on day 0. IMMUNOSUPPRESSION: Patients receive cyclosporine PO or IV every 12 hours on days -3 to 180 followed by a taper until day 365 in the absence of GVHD. Beginning 4-6 hours after completion of allogeneic PBSCT, patients receive mycophenolate mofetil PO every 8 hours on days 0 to 100 followed by a taper until day 156 in the absence of GVHD.
Treatment (chemotherapy, TBI, transplant)	fludarabine phosphate	NONMYELOABLATIVE CONDITIONING REGIMEN: Patients receive alemtuzumab IV over 6 hours once daily on days -6, -5, and -4 OR days -5 and -4 and fludarabine phosphate IV over 30 minutes on days -4, -3, and -2. Patients also undergo low-dose TBI on day 0. ALLOGENEIC PBSCT: After completion of TBI, patients undergo allogeneic PBSCT on day 0. IMMUNOSUPPRESSION: Patients receive cyclosporine PO or IV every 12 hours on days -3 to 180 followed by a taper until day 365 in the absence of GVHD. Beginning 4-6 hours after completion of allogeneic PBSCT, patients receive mycophenolate mofetil PO every 8 hours on days 0 to 100 followed by a taper until day 156 in the absence of GVHD.
Treatment (chemotherapy, TBI, transplant)	cyclosporine	NONMYELOABLATIVE CONDITIONING REGIMEN: Patients receive alemtuzumab IV over 6 hours once daily on days -6, -5, and -4 OR days -5 and -4 and fludarabine phosphate IV over 30 minutes on days -4, -3, and -2. Patients also undergo low-dose TBI on day 0. ALLOGENEIC PBSCT: After completion of TBI, patients undergo allogeneic PBSCT on day 0. IMMUNOSUPPRESSION: Patients receive cyclosporine PO or IV every 12 hours on days -3 to 180 followed by a taper until day 365 in the absence of GVHD. Beginning 4-6 hours after completion of allogeneic PBSCT, patients receive mycophenolate mofetil PO every 8 hours on days 0 to 100 followed by a taper until day 156 in the absence of GVHD.
Treatment (chemotherapy, TBI, transplant)	mycophenolate mofetil	NONMYELOABLATIVE CONDITIONING REGIMEN: Patients receive alemtuzumab IV over 6 hours once daily on days -6, -5, and -4 OR days -5 and -4 and fludarabine phosphate IV over 30 minutes on days -4, -3, and -2. Patients also undergo low-dose TBI on day 0. ALLOGENEIC PBSCT: After completion of TBI, patients undergo allogeneic PBSCT on day 0. IMMUNOSUPPRESSION: Patients receive cyclosporine PO or IV every 12 hours on days -3 to 180 followed by a taper until day 365 in the absence of GVHD. Beginning 4-6 hours after completion of allogeneic PBSCT, patients receive mycophenolate mofetil PO every 8 hours on days 0 to 100 followed by a taper until day 156 in the absence of GVHD.

Primary Outcome Measures

Name	Time	Method
Incidence of Grade III-IV Acute GVHD	100 days after transplant	Severity of Individual Organ Involvement Liver: Stage 2 - bilirubin (3-5.9mg/100ml) Stage 3 - bilirubin (6-14.9mg/100ml) Stage 4 - bilirubin \> 15mg/100ml Gut: Diarrhea is graded stage 1 to stage 4 in severity. Nausea and vomiting and/or anorexia caused by GVHD is assigned as stage 1 in severity. The severity of gut involvement is assigned to the most severe involvement noted. Patients with visible bloody diarrhea are at least stage 2 gut and grade 3 overall Severity of GVHD Grade III - Stage 2 to 4 gastrointestinal involvement and/or Stage 2 to 4 liver involvement with or without a rash Grade IV - Pattern and severity of GVHD similar to grade 3 with extreme constitutional symptoms or death

Secondary Outcome Measures

Name	Time	Method
Incidence of Graft Rejection	84 days after transplant	Percentage patients that experienced graft rejection.
Immune Reconstitution	Up to 1 year post-transplant	The outcome of immune reconstitution was not analyzed by the collaborating laboratory because only a small number of patients were only enrolled in Dose Level 1 (no alemtuzumab). The Dose Level 1 patients were going to be the baseline for which to compare the other patients on Dose Level 2 (and 3) who would have received alemtuzumab. The collaborating investigator determined that the study was not worthwhile performing based on this information.
Disease Progression/Relapse	Up to 5 years	CML New cytogenetic abnormality and/or development of accelerated phase or blast crisis. The criteria for accelerated phase will be defined as unexplained fever greater than 38.3°C, new clonal cytogenetic abnormalities in addition to a single Ph-positive chromosome, marrow blasts and promyelocytes \>20%. AML, ALL \>5% marrow blasts by morphologic or flow cytometric, or appearance of extramedullary disease. CLL ≥1 of: Physical exam/Imaging studies (nodes, liver, and/or spleen) ≥50% increase or new, circulating lymphocytes by morphology and/or flow cytometry ≥50% increase, and lymph node biopsy w/ Richter's transformation. NHL \>25% increase in the sum of the products of the perpendicular diameters of marker lesions, or the appearance of new lesions. MM ≥100% increase of the serum myeloma protein from its lowest level, or reappearance of myeloma peaks that had disappeared w/ treatment; or definite increase in the size or number of plasmacytomas or lytic bone lesions.
Incidence of High-dose Corticosteroid Utilization.	100 days after transplant	Percentage patients requiring steroids greater than 1 mg/kg.
Incidence of Infection	Up to 5 years post-transplant	Percentage patients that experienced infection(s).
Incidence of Non-relapse Mortality	100 days after transplant	Percentage patient deaths due to non-relapse mortality

Trial Locations

Locations (2): University of Torino
🇮🇹
Torino, Italy
Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
🇺🇸
Seattle, Washington, United States