INCLUSION CRITERIA - RECIPIENT
Diagnosis of hematologic malignancy and expected survival of approximately 1 year or less with conventional therapy, as judged by the principal investigator and/or study chairperson, in consultation with associate investigators as appropriate. Recipients must have one of the diagnoses:
Acute Myelogenous Leukemia (AML) - Disease Status:
In Complete Remission (CR1)
-Adverse cytogenetics with minimal residual disease
-Following primary induction failure
-Secondary AML
b)In CR2 or greater
2. Acute Lymphocytic Leukemia (ALL)-Disease Status:
a)In CR1
-Adverse cytogenetics with minimal residual disease
-Following primary induction failure
b)In CR2, if CR1 was less than 12 months
c)In CR3 or greater
3.Myelodysplastic Syndrome (MDS)-Disease Status:
a)INT-2 or High risk by International Prognostic Scoring System
4.Chronic Myelogenous Leukemia (CML)-Disease Status:
a)Accelerated phase CML with treatment failure after imatinib
b)Blast phase CML
5.Myeloproliferative Disorders(MPD)-Disease Status:
a)Agnogenic myeloid metaplasia with adverse-risk features
b)Polycythemia vera or essential thrombocythemia in transformation to secondary AML
6.Myelodysplastic/Myeloproliferative Disease (MDS/MPD) - Disease Status:
a)Chronic myelomonocytic leukemia: CMML-2
7.Hodgkin's and Non-Hodgkin's Lymphoma-Disease Status:
a)Refractory lymphoma with progressive disease during combination chemotherapy, and:
b)Relapse after autologous SCT, or ineligible for autologous SCT
8.Chronic Lymphocytic Leukemia (CLL)-Disease Status:
a)Treatment failure after fludarabine, chlorambucil, and at least one other salvage regimen
9.Prolymphocytic Leukemia (PLL)-Disease Status:
a)T-PLL: Treatment failure after Campath-1H and at least one other regimen
b)B-PLL: Treatment failure after fludarabine and at least one other salvage regimen
10.Multiple Myeloma-Disease Status:
a)Relapse after autologous SCT
b)Plasma cell leukemia
c)Adverse cytogenetics: del(13q) or 11q translocation
Age 18-55 years. This is the upper age range that is acceptable for a myeloablative alloHSCT from a matched unrelated donor.
Must have a sibling, parent, or offspring who shares one haplotype (HLA A, B, and DR) and who can provide informed consent or assent to be the stem cell donor. The recipient and donor must have at least a two-antigen disparity in either the host-versus-graft or graft-versus-host direction, except as specified below:
-Recipients with a parent or offspring donor who is mismatched for a single HLA antigen (i.e., 5/6 match) will be accepted, as such donors are truly haploidentical with some alleles in common on the mismatched haplotype. Recipients with a sibling donor who is mismatched for a single HLA antigen (i.e., 5/6 match) will not be eligible.
-A National Marrow Donor Program registry search for an unrelated donor must be performed (or have been performed previously) for all recipients.
1.Recipients will be eligible for enrollment if a preliminary search of the NMDP registry fails to identify a matched unrelated donor .
2.If a matched unrelated donor is identified on a preliminary search of the NMDP Registry, the recipient will be referred for a formal registry search to confirm the availability of an appropriate matched unrelated donor. If such a donor is confirmed, the recipient will be referred for conventional allogeneic HSCT or for transplantation on an alternative clinical trial. A recipient may be considered for enrollment in this study even when a preliminary registry search identifies a matched unrelated donor, in the following specific circumstances:
i.The recipient has previously undergone autologous stem cell transplantation, and no unrelated donor can be identified who is matched for 6/6 HLA antigens, with molecular matching for HLA-DR. Prior autologous HSCT is an exclusion for unrelated donor transplantation if the unrelated donor is not fully HLA-matched, with molecular matching at HLA-DR.
ii.The recipient has not undergone a prior autologous stem cell transplant, and no unrelated donor can be identified who is matched for 5/6 HLA antigens, with molecular matching for HLA-DR. A 5/6 antigen matched unrelated donor with identity at HLA-DR by molecular typing is considered acceptable for recipients who have not previously undergone autologous HSCT.
iii.More than 4 weeks has elapsed from the initiation of a formal registry search to confirm donor availability, without successfully procuring an appropriate unrelated donor and/or obtaining insurance approval for unrelated donor transplantation.
Transplant recipient must give informed consent.
Recipients with primary or secondary acute leukemia, refractory anemia with excess blasts (RAEB), CML, or other eligible diagnosis in transformation to acute leukemia must have less than 10% blasts in bone marrow and no circulating blasts in peripheral blood at study entry. Recipients who do not meet these criteria may be re-evaluated for study eligibility after receiving standard induction therapy for acute leukemia and determined to be in remission.
Recipients with AML in CR1 must have one of the following:
-Adverse cytogenetics with residual disease detectable by flow cytometry, cytogenetic analysis, FISH, or PCR. Adverse cytogenetics in AML are defined as complex karyotype ( 3 abnormalities or more); inv(3) or t(3;3); t(6;9); t(6;11); monosomy 7; trisomy 8, alone or with an abnormality other than t(8;21), t(9;11), inv(16) or t(16;16); or t(11;19)(q23;p13.1)
-Primary induction failure, defined as failure to achieve CR with primary induction chemotherapy
-Secondary AML, defined as AML related to antecedent MDS, MPD, or cytotoxic chemotherapy
Recipients with ALL in CR1 must have one of the following:
-Adverse cytogenetics, with residual disease detectable by flow cytometry, cytogenetic analysis, FISH, or PCR. Adverse cytogenetics in ALL are defined as translocations involving 11q23, t(9;22) or bcr-abl rearrangement.
-Primary induction failure, defined as failure to achieve CR with primary induction chemotherapy
Recipients with agnogenic myeloid metaplasia must have at least 2 of the following features:
-Hemoglobin less than10 g/dl, or greater than 10 g/dl with transfusion dependence
-WBC less than 4,000 or greater than 30,000/mm3 or requires cytoreductive therapy to maintain WBC less than 30,000/mm3
-Abnormal cytogenetics including +8, 12p-
For recipients with CLL or PLL, treatment failure for a specified therapy is defined as relapse within 6 months or failure to achieve remission. Recipients who are ineligible for a specified therapy (e.g., due to refractory cytopenias) may be considered for enrollment in this protocol.
ECOG performance status must be equal to 0, 1, or 2, and Karnofsky performance status of greater than or equal to 60%.
Transplant recipients must have a life expectancy of at least 3 months.
All previous systemic chemotherapy or monoclonal antibody therapy must be completed at least 2 weeks prior to study entry.
Any grade 3 or 4 non-hematologic toxicity of previous therapy must have resolved to grade 2 or less
Cardiac function: Left ventricular ejection fraction (LVEF) greater than or equal to 45%, obtained within 28 days of enrollment. In adult patients with adequate LVEF receiving EPOCH-based chemotherapy, the cumulative dose of doxorubicin received is not a basis for exclusion.
Pulmonary function: DLCO greater than or equal to 50% of expected value (corrected for blood hemoglobin level and alveolar volume), obtained within 28 days of enrollment.
Renal function: Serum creatinine less than or equal to 1.5 mg/dl or 24-hour creatinine clearance greater than or equal to 50 mL/min/1.73 m(2).
Hepatic function: Serum total bilirubin, serum ALT, and AST values less than or equal to 2.5 times the upper limit of normal. Higher values may be accepted, at the discretion of the PI or study chairperson, if such elevations are likely to be due to liver involvement by malignancy. If these values do not normalize during induction chemotherapy, such recipients will not be eligible for the transplant phase of the protocol, and will thus be taken off study. A history of unconjugated hyperbilirubinemia that is consistent with Gilbert's syndrome will not be considered an exclusion to participating in the study.
Minimum absolute neutrophil count of 1,000 cells/µ (Micro)l and minimum platelet count (without transfusion) of 20,000/mm(3). Lower values may be accepted at the discretion of the PI or study chairperson, if deemed to result from bone marrow involvement by malignancy.
EXCLUSION CRITERIA - RECIPIENT:
Availability of a 6/6 HLA-matched sibling as a stem cell donor. Recipients with a fully matched unrelated donor must meet the criteria to be eligible. Recipients with a 5/6 HLA-matched sibling donor are excluded.
Active infection that is not responding to antimicrobial therapy.
MDS with Fanconi Anemia
Active CNS involvement by malignancy. History of CNS involvement with no current evidence of CNS malignancy is not an exclusion. Active CNS malignancy is defined by:
-Lymphoma: tumor mass on CT scan or leptomeningeal disease
-Leukemia: Blasts present on CSF cytospin.
HIV infection. Immune suppression related to allogeneic HSCT may permit progression of HIV or associated opportunistic infections.
Chronic active hepatitis B infection. Recipients may be hepatitis B core antibody positive but must have negative surface antigen (HbsAg) and without evidence of active infection.
Hepatitis C viral infection, defined by seropositivity for anti-hepatitis C antibody and detectable hepatitis C viral RNA by RT-PCR.
Recipients must not be pregnant or lactating. Recipients of childbearing potential must use an effective method of contraception. The effects of chemotherapy, transplantation, and the medications used after the transplant are highly likely to be harmful to a fetus. The effects upon breast milk are also unknown and may be harmful to the infant.
History of psychiatric disorder which may compromise compliance with transplant protocol, or which does not allow for appropriate informed consent or assent (as determined by principal investigator or study chairman).
High risk of inability to comply with transplant protocol as determined by principal investigator, social work, and transplant team.
INCLUSION CRITERIA - DONOR:
A donor must be a sibling, parent, or offspring who shares one full haplotype with the recipient . If multiple potential donors are eligible, a donor will be selected according to the following factors, in order of priority:
1.Donors will be selected for the greatest number of shared HLA alleles with the recipient.
2.If two donors share an equal number of HLA alleles with the recipient, the donor most closely matched in the host-versus-graft direction will be selected.
3.Donors will be selected for KIR ligand disparity in the graft-versus-host direction, based upon preliminary evidence that such donor-versus-recipient KIR ligand incompatibility is associated with decreased risks of GVHD and relapse after haploidentical HSCT
4.Donors who are seronegative for exposure to Cytomegalovirus (CMV) will be selected in preference to seropositive donors, unless the recipient is CMV positive. Seropositive donors are preferred for CMV positive recipients, but other donor risk factors may be given priority over CMV status in the case of a CMV positive recipient.
5.Sibling donors will be selected in preference to parent or offspring donors.
6.Donors will be selected for ABO blood type compatibility.
7.Male donors are preferred to female donors.
8.Donors will be selected for younger age.
Donors must be able to give informed consent.
Donor age must be 18 to 75 years. Because potential cerebrovascular and cardiac complications may increase with age, 75 years has been chosen arbitrarily as the upper age limit.
Donor selection criteria will be in accordance with NIH/CC Department of Transfusion Medicine standards.
Donors must have adequate venous access for peripheral apheresis, or consent to use a temporary central venous catheter for apheresis.
A donor who is lactating must substitute formula feeding for her infant during the period of cytokine administration. Filgrastim may be secreted in human milk, although its bioavailability from this source is not known. Limited clinical data suggest that short-term administration of filgrastim or sargramostim to neonates is not associated with adverse outcomes.
EXCLUSION CRITERIA: DONOR
History of psychiatric disorder which may compromise compliance with transplant protocol, or which does not allow for appropriate informed consent.
History of hypertension that is not controlled by medication, stroke, severe heart disease, or other medical contraindications to stem cell donation (i.e. severe atherosclerosis, autoimmune disease, cerebrovascular accident, prior malignancy) .
-An individual with symptomatic angina will be considered to have severe heart disease and will not be eligible to be a donor.
-Persons with a history of coronary artery bypass grafting or angioplasty will undergo cardiology evaluation and be considered on a case-by-case basis.
-Persons with a history of non-hematologic malignancy must have undergone potentially curative therapy for that malignancy and (1) have had no evidence of that disease for 5 years, and/or (2) be deemed at low risk for recurrence (less than or equal to 20% at 5 years). Such persons will be considered eligible for stem cell donation at the discretion of the PI or study chairperson, who will evaluate the possible benefit to the potential transplant recipient and the risk of disease transmission in consultation with Department of Transfusion Medicine staff. Prospective donors with a history of non-hematologic malignancy who have received potentially curative therapy and are in remission, but whose estimated risk of recurrence is greater than 20% at 5 years, will be considered on an individual basis in consultation with the NCI IRB. Any prospective transplant recipient whose donor has a history of malignancy will be counseled about the theoretical risk of transmission of cancer from the donor to the recipient.
-Persons with a history of congenital hematologic, immunologic, or metabolic disorder that, in the estimation of the PI or study chairperson, poses prohibitive risk to the recipient, will be excluded.
Evidence of prior infection with HIV or hepatitis C, or chronic active infection with hepatitis B (e.g., hepatitis B surface antigen positive).
Donors must not be pregnant. The effects of cytokine administration on a fetus are unknown. Donors of childbearing potential must use an effective method of contraception.
Anemia (hemoglobin less than 11 gm/dl) or thrombocytopenia (platelets less than 100,000 per micro L).
High risk of inability to comply with transplant protocol as determined by principal investigator, social work, and transplant team.
Warren Grant Magnuson Clinical Center (CC)