Pentostatin and Lymphocyte Infusion in Preventing Graft Rejection in Patients Who Have Undergone Donor Stem Cell Transplant

Pentostatin and Donor Lymphocyte Infusion for Low Donor T-cell Chimerism After Hematopoietic Cell Transplantation - A Multi-center Trial

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00096161

Enrollment

Registered

2004-11-09

Start date

2003-05-31

Completion date

2015-08-31

Last updated

2020-01-31

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia, Chronic Lymphocytic Leukemia, Chronic Myelogenous Leukemia, BCR-ABL1 Positive, Graft Versus Host Disease, Hodgkin Lymphoma, Myelodysplastic/Myeloproliferative Neoplasm, Non-Hodgkin Lymphoma, Plasma Cell Myeloma, Waldenstrom Macroglobulinemia

Brief summary

This phase II trial studies pentostatin and donor lymphocyte infusion in preventing graft rejection in patients who have undergone donor stem cell transplant. Giving pentostatin and an infusion of the donor's T cells (donor lymphocyte infusion) after a donor stem cell transplant may stop the patient's immune system from rejecting the donor's 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 pentostatin before donor lymphocyte infusion may stop this from happening.

Detailed description

PRIMARY OBJECTIVES: I. To assess the safety and efficacy of the combined use of pentostatin and donor lymphocyte infusion (DLI) in patients with low or falling donor T-cell chimerism to prevent graft rejection after transplantation both from matched related donors (MRDs) or unrelated donors (URDs). SECONDARY OBJECTIVES: I. To determine the incidence of graft-versus-host disease (GvHD) infections and disease response, if persistent disease is present. OUTLINE: This is a dose-escalation study of donor lymphocyte infusion. GROUP I: Patients receive pentostatin intravenously (IV) over 20-30 minutes on day -2 and DLI over 15-30 minutes on day 0. Treatment may repeat once beginning with an escalated or same cluster of differentiation (CD)3-dose at least 4 weeks if persistent donor T-cells are documented, no GvHD has developed, and the chimerism status worsens or, if chimerism status is unchanged after at least 8 weeks with two subsequent tests of chimerism 4 weeks apart. GROUP II (initiated if patients in group I do not achieve sustained engraftment and improved chimerism): Patients receive treatment as in group I. Patients also receive cyclosporine orally (PO) twice daily (BID) on days -3 to 56 and mycophenolate mofetil PO once daily (QD) on days 0 to 27. Treatment continues in the absence of GvHD. After completion of study treatment, patients are followed up every 6 months for 2 years and then annually thereafter.

Interventions

DRUGCyclosporine

Given PO

DRUGMycophenolate Mofetil

Given PO

DRUGPentostatin

Given IV

BIOLOGICALTherapeutic Allogeneic Lymphocytes

Given IV

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Healthy volunteers

Inclusion criteria

* Patients having received a preceding allogeneic transplantation from either a human leukocyte antigen (HLA)-matched related or unrelated donor are eligible for this protocol * Related donor: HLA genotypically identical at least at one haplotype and may be phenotypically or genotypically identical at the allele level at HLA A, B, C, DRB1, and DQB1 * Unrelated donor who are prospectively: * Matched for HLA-A, B, C, DRB1 and DQB1 by high resolution typing; OR * Only a single allele disparity will be allowed for HLA-A, B, or C as defined by high resolution typing * Patients with less than 50% donor CD3 peripheral blood chimerism on two separate, consecutive evaluations; the two evaluations must be at least 14 days apart OR patients with absolute decreases of donor CD3 peripheral blood chimerism of \>= 20% if the second test shows \< 50% donor CD3 cells; the two evaluations must be at least 14 days apart * Patients with evidence of disease are only eligible if the disease is stable (or persistent) in comparison to the status prior to transplantation * Patients must be tapered off systemic steroids to a dosage of less than or equal to 0.25 mg/kg/day * Patients must have persistent donor CD3 cells (\>= 5% donor CD3 cells by a deoxyribonucleic acid \[DNA\]-based assay that compares the profile of amplified fragment length polymorphisms \[ampFLP\] \[or fluorescent in situ hybridization (FISH) studies or variable number of tandem repeats (VNTR)\]) * DONOR: Alternatively to a fresh unmodified leukapheresis product, previously collected cryopreserved peripheral blood stem cells (PBSC) after mobilization with G-CSF or cryopreserved unmodified leukapheresis product from the original donor can be used; if cryopreserved product is not available, the following criteria apply for the DLI product: * DONOR: Original donor of hematopoietic cell transplantation * DONOR: Donor must give consent to leukapheresis * DONOR: Donor must have adequate veins for leukapheresis or agree to placement of central venous catheter (femoral or subclavian) * DONOR: Donor must be medically fit to undergo the apheresis procedure (institutional guidelines for apheresis)

Exclusion criteria

* Current grade II to IV acute GVHD or extensive chronic GVHD * Karnofsky score \< 50% * Pediatric criteria * Lansky play-performance score \< 40 * Evidence of relapse or progression of disease after transplantation * Prior recipient of cord blood * DONOR: Donors who are not suitable for medical reasons to donate peripheral blood mononuclear cells (PBMC) by continuous centrifugation according to the criteria of the American Association of Blood Banks (AABB) * DONOR: Pregnancy * DONOR: Human immunodeficiency virus (HIV) or human T-lymphotrophic virus (HTLV) infection * DONOR: Recent immunization may require a delay

Design outcomes

Primary

Measure	Time frame	Description
Percentage Patients With an Increase of at Least 10 Percentage Points in Donor T-cell Chimerism	From the time of enrollment maintained to day 56 after the last DLI, up to Day 112	A regimen will be considered successful if 20 patients are enrolled, at least 13 demonstrate improved chimerism. If fewer than 5 patients have shown improvement in chimerism then it can be at least 75% confident that the true rate of improvement is less than 0.53. Enrollment to the regimen will stop and the next regimen will be opened. Enrollment to a regimen may also be stopped at any time it becomes impossible to achieve 5 of 10 or 13 of 20 successful improvements. Chimerism in hematopoietic cell transplant derives from this idea of a mixed entity, referring to someone who has received a transplant of genetically different tissue. A test for chimerism after a hematopoietic cell transplant involves identifying the genetic profiles of the recipient and of the donor and then evaluating the extent of mixture in the recipient's blood cells or marrow cells.
Incidence of Grade IV Acute GVHD	Within 100 days after the last DLI	Clinical Stage of acute GVHD according to Organ System Skin: 1. \- Maculopapular rash \<25% of body surface 2. \- Maculopapular rash 25-50% of body surface 3. \- Maculopapular rash \>50% body surface area or generalized erythroderma 4. \- Generalized erythroderma with bullous formation and desquamation Liver: 1. \- Bilirubin 2-3 mg/dl 2. \- Bilirubin 3.1-6 mg/dl 3. \- Bilirubin 6.1-15 mg/dl 4. \- Bilirubin \>15 mg/dl Gut: 1. \- \>500-1000 mL diarrhea per day or (nausea, anorexia or vomiting with biopsy (EGD) confirmation of upper GI GVHD 2. \- \>1000 -1500 mL diarrhea per day 3. \- \>1500 mL diarrhea per day 4. \- \>1500 mL diarrhea per day plus severe abdominal pain with or without ileus Overall Clinical Grading of Severity of acute GVHD Grade IV: 0-4 Skin, 2-4 Liver, and/or 2-4 GI

Secondary

Measure	Time frame	Description
Incidence of GVHD	1 year after DLI	Percentage patients with acute or chronic GVHD. The diagnosis of chronic GVHD requires at least one manifestation that is distinctive for chronic GVHD as opposed to acute GVHD. In all cases, infection and others causes must be ruled out in the differential diagnosis of chronic GVHD.
Incidence of Infections	100 days after DLI	—
Incidence of Relapse/Progression	1 year after DLI	CML Acquisition of a new cytogenetic abnormality and/or development of accelerated phase or blast crisis. Criteria for accelerated phase: unexplained fever \>38.3° C, new clonal cytogenetic abnormalities in addition to a single Ph-positive chromosome, BM blasts and promyelocytes \>20%. AML, ALL, CMML \>30% BM blasts w/ deteriorating performance status, or worsening of anemia, neutropenia, or thrombocytopenia. CLL Progressive disease: ≥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/ tx; or definite increase in the size/number of plasmacytomas or lytic bone lesions.
Survival	1 year after DLI	Percentage patients surviving.

Countries

Italy, United States

Participant flow

Participants by arm

Arm	Count
Group 1A (Pentostatin, DLI Dose Level 1) Patients receive pentostatin IV over 20-30 minutes on day -2 and DLI (1x10\^7 CD3+ cells/kg) over 15-30 minutes on day 0. Treatment may repeat once beginning with an escalated or same CD3-dose at least 4 weeks if persistent donor T-cells are documented, no GvHD has developed, and the chimerism status worsens or, if chimerism status is unchanged after at least 8 weeks with two subsequent tests of chimerism 4 weeks apart. Pentostatin: Given IV Therapeutic Allogeneic Lymphocytes: Given IV	20
Group 1B (Pentostatin, DLI Dose Level 2) Patients receive pentostatin IV over 20-30 minutes on day -2 and DLI (3x10\^7 CD3+ cells/kg) over 15-30 minutes on day 0. Treatment may repeat once beginning with an escalated or same CD3-dose at least 4 weeks if persistent donor T-cells are documented, no GvHD has developed, and the chimerism status worsens or, if chimerism status is unchanged after at least 8 weeks with two subsequent tests of chimerism 4 weeks apart. Pentostatin: Given IV Therapeutic Allogeneic Lymphocytes: Given IV	10
Group 2C (Pentostatin, DLI Dose Level 1, Add'l IS) Patients receive treatment as in group 1A. Patients also receive cyclosporine PO BID on days -3 to 56 and mycophenolate mofetil PO QD on days 0 to 27. Treatment continues in the absence of GvHD. Pentostatin: Given IV Therapeutic Allogeneic Lymphocytes: Given IV	6
Group 2D (Pentostatin, DLI Dose Level 2, Add'l IS) Patients receive treatment as in group 1B. Patients also receive cyclosporine PO BID on days -3 to 56 and mycophenolate mofetil PO QD on days 0 to 27. Treatment continues in the absence of GvHD. Pentostatin: Given IV Therapeutic Allogeneic Lymphocytes: Given IV	0
Total	36

Baseline characteristics

Characteristic	Group 1A (Pentostatin, DLI Dose Level 1)	Group 1B (Pentostatin, DLI Dose Level 2)	Group 2C (Pentostatin, DLI Dose Level 1, Add'l IS)	Group 2D (Pentostatin, DLI Dose Level 2, Add'l IS)	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	3 Participants	3 Participants	2 Participants	0 Participants	8 Participants
Age, Categorical Between 18 and 65 years	17 Participants	7 Participants	4 Participants	0 Participants	28 Participants
Age, Continuous	55 years	59.3 years	60.3 years	—	56.9 years
Region of Enrollment United States	20 participants	10 participants	6 participants	—	36 participants
Sex: Female, Male Female	2 Participants	2 Participants	1 Participants	—	5 Participants
Sex: Female, Male Male	18 Participants	8 Participants	5 Participants	—	31 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —	— / —
other Total, other adverse events	10 / 20	2 / 10	2 / 6	0 / 0
serious Total, serious adverse events	6 / 20	0 / 10	0 / 6	0 / 0

Outcome results

Primary

Incidence of Grade IV Acute GVHD

Clinical Stage of acute GVHD according to Organ System Skin: 1. \- Maculopapular rash \<25% of body surface 2. \- Maculopapular rash 25-50% of body surface 3. \- Maculopapular rash \>50% body surface area or generalized erythroderma 4. \- Generalized erythroderma with bullous formation and desquamation Liver: 1. \- Bilirubin 2-3 mg/dl 2. \- Bilirubin 3.1-6 mg/dl 3. \- Bilirubin 6.1-15 mg/dl 4. \- Bilirubin \>15 mg/dl Gut: 1. \- \>500-1000 mL diarrhea per day or (nausea, anorexia or vomiting with biopsy (EGD) confirmation of upper GI GVHD 2. \- \>1000 -1500 mL diarrhea per day 3. \- \>1500 mL diarrhea per day 4. \- \>1500 mL diarrhea per day plus severe abdominal pain with or without ileus Overall Clinical Grading of Severity of acute GVHD Grade IV: 0-4 Skin, 2-4 Liver, and/or 2-4 GI

Time frame: Within 100 days after the last DLI