Background:
- Bone marrow stem cells, which are found in the bone marrow and blood stream, can be
collected and transplanted to treat a variety of types of cancer in a process known as
hematopoietic stem cell transplantation (HSCT). When stem cells are taken from one
person, most commonly a sibling or a family member, and then given to another person,
this is referred to as allogeneic HSCT. Allogeneic HSCT has proven to be an especially
effective treatment for patients with some types of cancers of the blood (leukemia) and
certain solid tumors. The transplanted stem cells travel to the patient's bone marrow
and begin producing normal blood cells, and also attack patients cancer cells.
- Because allogenic HSCT does not always prevent the cancer from returning, researchers
are interested in determining whether another type of immune cell taken from the stem
cell donors white blood cells, called a "natural killer" (NK) cell, can be given in
addition to the HSCT to help fight the tumor. In the laboratory, NK cells have been
shown to kill tumor cells, but it is not yet know if this will occur when given to
patients after HSCT.
Objectives:
- To determine the safety, effectiveness, and immune system response of giving NK white
blood cells to individuals who have received allogeneic HSCT.
- To identify possible side effects from the treatment.
Eligibility:
- Donors: Stem cell donors whose blood matches one of the recipients on six out of six
human leukocyte antigen (HLA) (blood immune marker) types. The donor may not be the
identical twin of a recipient.
- Recipients: Individuals between 4 and 35 years of age who have been diagnosed with
pediatric solid tumors that have not responded to standard treatment, or individuals
between 4 and 18 years of age who have been diagnosed with leukemia that has not
responded to standard treatment.
- Other eligibility requirements which include a physical exam and blood laboratory
evaluation are included to make sure it is safe for both the donor to donate and the
recipient to undergo the transplant procedure.
Design:
- Donors and recipients will be screened with a full medical history and physical
examination, and will provide blood and urine samples; recipients will have tumor
imaging studies and other tests as required by the researchers.
- Donors:
- Participants will receive filgrastim injections (to stimulate the bone marrow) for 1
week to make stem cells travel from bone marrow to blood.
- Participants will provide stem cells and NK cells through apheresis.
- Recipients:
- Participants will have three cycles of chemotherapy to treat the underlying cancer and
weaken the immune system so that it will accept the donor cells.
- Participants will then receive preparative chemotherapy for the transplant and two days
after the last dose of chemotherapy, participants will have allogenic HSCT using the
donated stem cells.
- Participants will receive an infusion of NK cells on days 7 and 35 after the HSCT. -
Participants will remain in the hospital for monitoring after the HSCT and NK cell
treatments, and will be followed closely as outpatients for the first 6 months after the
transplant and then less frequently for at least 5 years.
Background
- Despite progress in pediatric oncology, some patient subsets with hematologic
malignancies and pediatric solid tumors continue to experience extremely poor overall
survival. Allogeneic Hematopoietic Stem Cell Transplant (HSCT) is effective in some
high-risk hematologic malignancies.
- Allogeneic HSCT can be performed safely in these patient populations, but disease
recurrence is common and new approaches to enhance the antitumor effect of this therapy
are needed. Natural killer (NK) mediated killing appears to confer improved outcomes
after HSCT for patients with acute myelogenous leukemia (AML) and acute lymphoblastic
leukemia (ALL), and NK cell infusions have induced complete remissions in patients with
AML.
- Preclinical data demonstrates that activated NK cells readily kill pediatric solid
tumors and leukemias, that large numbers of activated NK cells can be generated ex vivo
using artificial antigen-presenting cells (APCs) and that the post-transplant period may
be favorable for expansion and survival of adoptively transferred NK cells.
Objectives
- To assess the feasibility and toxicity of infusing escalating doses of donor-derived
activated NK cell donor lymphocyte infusions (NK-DLI) on Days 7 plus or minus 2 days and
49 plus or minus 7 days following human leukocyte antigen (HLA)-matched T cell depleted
(TCD) peripheral blood stem cell transplant (PBSCT) in patients with metastatic or
recurrent pediatric solid tumors and high risk leukemias who have unrelated donors or
related donors;
- To determine if patients treated in this manner experience rapid, sustained donor
engraftment and acceptable rates of acute graft versus host disease (aGVHD) (less than
25% incidence of grade III or grade IV).
Eligibility
-Patients 4-35 years with hematologic malignancies (e.g., ALL, AML, Chronic Myelogenous
Leukemia (CML), Hodgkins Lymphoma (HD), Non-Hodgkins Lymphoma (NHL), with a 5/6 or 6/6
HLA-matched related or 9/10 or 10/10 HLA matched unrelated donor.
Design
- Pre-transplant disease specific immune depleting chemotherapy and the preparative
regimen will be the same as that used previously on 02-C-0259 and 01-C-0125, for those
patients undergoing reduced intensity transplant.
- For patients with ALL or AML, a myeloablative regimen based on current Children's
Oncology Group (COG) standard-of- care preparative regimen will also be included.
- Donors will undergo 1-3 apheresis sessions for filgrastim mobilized peripheral blood
stem cells (PBSC). This product will be T cell and NK cell depleted prior to
cryopreservation. NK cells selected from the product will be used for ex vivo activation
and expansion using KT64.4-BBL artificial antigen presenting cells.
- A phase 1 cell dose escalation of donor derived NK-DLI will be performed using 3 dose
levels (1 x 10(5), 1 x 10(6) and 1 x 10(7) NK cells/kg) infused on days 21 more or less
3 post-PBSCT and a second infusion on day 49 more or less 7 post-PBSCT.
- Three patients will be enrolled at each dose level, with the cohort expanded to 6 if
dose-limiting toxicity occurs. An expanded group of 12 patients will be treated at the
highest dose level tolerated.
- INCLUSION CRITERIA: PATIENTS (RECIPIENT)
- Hematologic Malignancies Diagnoses:
1. Acute lymphoblastic leukemia (ALL) with a history of bone marrow relapse in
clinical remission (CR) #2 or greater, or in CR#1 if prior induction failure; or
with an M1 marrow if unable to achieve CR.
2. Philadelphia chromosome positive ALL patients who;
1. Have progressed through or relapsed following tyrosine kinase inhibitor
(TKI) therapy or conventional myeloablative therapy
OR
2. Are ineligible to receive tyrosine kinase inhibitor (TKI) therapy AND
myeloablative hematopoietic stem cell transplant (HSCT)
3. Acute Myelogenous Leukemia (AML) with a history of bone marrow relapse in
remission CR #2 or greater; or with an M1 marrow if unable to achieve CR; or in
CR#1 if prior induction failure; or any of the following High-Risk categories:
1. Fms-related tyrosine kinase 3 (FLT3)/internal tandem duplication (ITD)+ with
high allelic ratio > 0.4 (high allelic ration (HR) FLT3/ITD+) regardless of
low risk features.
2. Presence of monosomy 7, monosomy 5, or del5q, without inv(16)/t(16;16) or
t(8;21) cytogenetics or NPM or CEBP(alpha) mutations.
3. Acute myelogenous leukemia (AML) without inv(16)/t(16;16), t(8;21),
nucleophosmin (NPM), CCAAT/enhancer binding protein (CEPB)(alpha) mutations,
monosomy 7, monosomy 5, del5q, or HR FLT3/ITD+, but with evidence of
residual AML (greater than or equal to 0.1%) at end of Induction I.
4. Hodgkin's and Non-Hodgkin's Lymphoma with refractory disease or relapse after at
least one salvage regimen, or after autologous stem cell transplant
5. Juvenile Myelocytic Leukemia (JMML) with less than 10% blasts in marrow and
blood, who are not eligible for effective standard therapies.
- Age: 4 to less than or equal to 35 years old at the time of enrollment for solid tumor
patients and 4 to less than or equal to 35 years old for hematologic malignancies.
- All previous cytotoxic chemotherapy must be completed at least 3 weeks prior to study
entry. Any prior non-hematologic vital organ toxicity (cardiac, pulmonary, hepatic,
renal) of any previous therapy must have resolved to grade 1 or less, unless specified
elsewhere in Inclusion Criteria for Patient (Recipient).
EXCEPTIONS:
There is no time restriction in regard to prior intrathecal chemotherapy provided there is
complete recovery from any acute toxic effects; or
Subjects receiving standard acute lymphoblastic leukemia (ALL) maintenance chemotherapy
will not require washout.
- All previous immunologic or molecularly targeted therapy must be completed at least 1
week prior to study entry. Any prior non-hematologic toxicity of any previous therapy
must have resolved to grade 1 or less, unless specified elsewhere in Inclusion
Criteria for Patient (Recipient).
- Prior investigational therapy must be completed at least 30 days prior to study entry
- Patients with prior autologous or allogeneic transplant are eligible. Patients must be
greater than 100 days post transplant and have no evidence of active graft versus host
disease (GVHD).
- Performance status: Eastern Cooperative Oncology Group (ECOG) 0, 1 or 2, or for
children less than or equal to 10 years of age, Lansky greater than or equal to 60.
Life expectancy greater than 3 months.
- Availability of human leukocyte antigen (HLA)-matched (5-6/6 antigen or 8/8 allele)
related or unrelated donor.
- Cardiac function: Left ventricular ejection fraction greater than or equal to 45% by
multi-gated acquisition scan (MUGA) or echocardiogram (ECHO), fractional shortening
greater than or equal to 28% by ECHO.
- Pulmonary function: Diffusing capacity of the lungs for carbon monoxide (DLCO) >= 40%
of the expected value corrected for alveolar volume and hgb for reduced intensity
transplant and DLCO >=55% for myeloablative regimen. For children who are unable to
cooperate for pulmonary function tests (PFTs), the criterion is: No evidence of
dyspnea at rest, no exercise intolerance, and no requirement for supplemental oxygen
therapy.
- Liver function: Serum total bilirubin less than 2 mg/dl, serum aspartate
aminotransferase (AST) and alanine aminotransferase (ALT) less than or equal to 2.5
times upper limit of normal. Patients with Gilbert syndrome are excluded from the
requirement of a normal bilirubin. (Gilbert syndrome is found in 3-10% of the general
population, and is characterized by mild, chronic unconjugated hyperbilirubinemia in
the absence of liver disease or overt hemolysis).
- Renal function: Age-adjusted normal serum creatinine according to the following, or a
creatinine clearance greater than or equal to 60 ml/min/1.73 m(2):
- For age (years) of less than or equal to 5, a Maximum serum creatinine (mg/dl) of
0.8
- For age (years) of greater than 5 but less than or equal to 10, a Maximum serum
creatinine (mg/dl) of 1.0
- For age (years) of greater than 10 but less than or equal to 15, a Maximum serum
creatinine (mg/dl) of 1.2
- For age (years) of greater than 15, a Maximum serum creatinine (mg/dl) of 1.5
- Marrow function: Absolute neutrophil count (ANC) must be greater than 750/mm(3)
(unless due to underlying disease in which case there is no grade restriction),
platelet count must be greater than or equal to 75,000/mm(3) (not achieved by
transfusion) unless due to underlying disease in which case there is no grade
restriction). Lymphopenia, cluster of differentiation 4 (CD4) lymphopenia, leukopenia,
and anemia will not render patients ineligible.
- Ability to give informed consent. For patients less than 18 years of age their legal
guardian must give informed consent. Pediatric patients will be included in
age-appropriate discussion in order to obtain verbal assent.
- Durable power of attorney form completed (patients greater than or equal to 18
years of age only).
- Female patients (and when relevant their male partners) must be willing to
practice birth control (including abstinence) during and for two months after
treatment, if of childbearing potential.
EXCLUSION CRITERIA: PATIENT (RECIPIENT)
- Uncontrolled infection.
- Active central nervous system (CNS) malignancy as defined by:
1. Solid Tumors: History of untreated CNS tumor involvement. Extradural masses which
have not invaded the brain parenchyma or parameningeal tumors without evidence
for leptomeningeal spread will not render the patient ineligible. Patients with
previous CNS tumor involvement are eligible IF the CNS tumor(s) has been treated
and has been stable or resolving for at least 6 months; and if the patient does
not currently require steroids.
2. Lymphoma: tumor mass on computed tomography (CT) scan or leptomeningeal disease
3. Leukemia: CNS 2 or CNS 3 classification.
- Lactating or pregnant females (due to risk to fetus or newborn).
- Human immunodeficiency virus (HIV) positive (due to unacceptable risk associated with
severe immune suppression).
- Hepatitis B surface antigen (HBsAg) positive or hepatitis C antibody positive with
elevated liver transaminases. All patients with chronic active hepatitis (including
those on treatment) are ineligible.
- Patients who require systemic corticosteroid or other immunosuppressive therapy.
Immunosuppressive therapy must be stopped at least 28 days prior to protocol cycle 1,
day 1 (C1D1). Topical agents and/or inhaled corticosteroids are permitted.
- High risk of inability to comply with transplant protocol, or inability to give
appropriate informed consent in the estimation of the principal investigator (PI),
social work, psychiatry, or the stem cell transplant team.
- Fanconi Anemia
- Clinically significant systemic illness (e.g. serious active infections or significant
cardiac, pulmonary, hepatic or other organ dysfunction), that in the judgment of the
PI would likely compromise the patients ability to tolerate protocol therapy or
significantly increase the risk of complications.
INCLUSION CRITERIA: DONOR
- Weight greater than or equal to 15 kilograms and for unrelated donors, greater than or
equal to 18 years.
- HLA-matched related or unrelated allogeneic donors. Genotypically identical twins may
serve as stem cell donors. Related donors must be 5 or 6/6 antigen matched. Unrelated
donors must be 8/8 allele matched.
- For donors less than 18 years of age, he/she must be the oldest suitable donor, their
legal guardian must give informed consent, the donor must give verbal assent, and
he/she must be cleared by social work and a mental health specialist to participate.
- For donors greater than or equal to 18 years of age, ability to give informed consent.
- Adequate peripheral venous access for apheresis or consent to use a temporary central
venous catheter for apheresis.
- Donor selection will be in accordance with National Institutes of Health
(NIH)/Clinical Center (CC) Department of Transfusion Medicine (DTM) criteria and, in
the case of an unrelated donor, the National Marrow Donor Program (NMDP) standards and
Food and Drug Administration (FDA) 21 Code of Federal Regulations (CFR) 1271.
EXCLUSION CRITERIA: DONOR
- History of medical illness that in the estimation of the PI or DTM/NMDP physician
poses prohibitive risk to donation including, but not limited to, stroke, hypertension
that is not controlled with medication, or heart disease. Individuals with symptomatic
angina or a history of coronary bypass grafting or angioplasty will not be eligible.
- Anemia (Hemoglobin (Hb) less than 11 gm/dl) or thrombocytopenia (less
than100,000/microliters).
- Identical twins will be excluded; the lack of Major histocompatibility complex Major
histocompatibility complex (MHC) incompatibility will alter the toxicity profile in
such a way as to make the results uninterpretable.
- Breast feeding or pregnant females. Donors of childbearing potential must use an
effective method of contraception during the time they are receiving filgrastim. The
effects of cytokine administration on a fetus are unknown and may be potentially
harmful. The effects upon breast milk are also unknown and may potentially be harmful
to the infant.
- High risk of inability to comply with protocol requirements as determined by the
principal investigator and donor center team.
- Positive screening test for transfusion-transmissible infection in accordance with DTM
or NMDP donation standards, including HIV-positive, hepatitis B surface antigen
(HBsAg) positive or hepatitis C antibody positive.
