| Eligibility |
- INCLUSION CRITERIA:
Inclusion Criteria: Recipient
1. Recipients (patients with B-cell malignancy) must have received an HLA-identical or
9/10 matched sibling allogeneic hematopoietic stem cell transplant, a 1-antigen
mismatched related transplant, or a greater than or equal to 9/10-matched unrelated
donor (URD) alloHSCT for any CD19+ B-cell malignancy. Patients with any CD19+ B-cell
malignancy that is persistent or relapsed after all of the following interventions are
eligible:
1. Donor T cell engraftment after alloHSCT (>50% donor chimerism of the T cell
compartment and a peripheral blood T cell number from the NIH, CC clinical lab of
at least 50 CD3+ cells/uL).
2. A trial of withdrawal of immunosuppressive therapy.
Exception: Prior (DCI) DLI is not an eligibility requirement for patients with ALL,
Burkitt lyphoma, ALL like high-grade lymphomas, or diffuse large B-cell lymphoma.
At least 28 days weeks must have elapsed since the latest trial of withdraw of
immunosuppression or DLI until the patient can be deemed to have persistent disease.
2. CD19 expression must be detected on the majority of the malignant cells by
immunohistochemistry or by flow cytometry in the Laboratory of Pathology, CCR, NCI,
NIH. Definition of which cells are malignant must be determined for each patient by
the Laboratory of Pathology using techniques to demonstrate monoclonality such as
kappa/lambda restriction (other techniques can be used to determine monoclonality at
the discretion of the Laboratory of Pathology). The choice of whether to use flow
cytometry or immuohistochemistry will be determined by what is the most easily
available tissue sample in each patient. Immunohistochemistry will be used for lymph
node biopsies and bone marrow biopsies. Flow cytometry will be used for peripheral
blood, fine needle aspirate, and bone marrow aspirate samples.
3. Patients must be 18-75 years of age.
4. Performance status: ECOG less than or equal to 2
5. Either no evidence of GVHD or minimal clinical evidence of acute GVHD and chronic GVHD
while off of systemic immunosuppressive therapy for at least 28 days. Minimal clinical
evidence of acute GVHD is defined as grade 0 to I acute GVHD. Minimal evidence of
chronic GVHD is defined as chronic GVHD with no organ site with a score exceeding 1,
except for the skin, for which a score of 1 or 2 will be allowable (as defined by the
2005 NIH consensus project) or no chronic GVHD. Subjects with disease that is
controlled to stage I acute GVHD or chronic GVHD meeting the above criteria with local
therapy only, e.g., topical cutaneous steroids, will be eligible for enrollment.
6. Ability to give informed consent.
7. Prior Therapy: Therapy with monoclonal antibodies and/or chemotherapy must be stopped
at least 7 days prior to anti-CD19 CAR-transduced T cell infusion, and recovery of
treatment-associated toxicity to less than or equal to grade 2 is required prior to
infusion of cells. For patients that have received prior DLI, the last dose must be at
least 28 days prior to anti-CD19 CAR-transduced T cell administration. Note that
patients can be enrolled on this study at any time after or during therapy, but at
least 14 days must elapse from the time of prior monoclonal antibody administration or
chemotherapy until anti-CD19 CAR-transduced T cells are infused, and at least 28 days
must elapse from the time of withdraw of immunosuppression, or DLI, or other
immunomodulatory therapies such as lenalidomide until anti-CD19 CAR-transduced T cells
are infused. Systemic immunosuppression given for graft versus host disease must be
stopped at least 28 days prior to protocol entry. There is no time restriction in
regard to prior intrathecal chemotherapy provided there is complete recovery from any
acute toxic effects of such.
8. Recipients of unrelated donor transplants from a National Marrow Donor Program (NMDP)
Center must sign a release of information form to authorize NMDP transfer of
information to the NIH.
9. Previous allogeneic donor must be willing and available to donate again.
10. Patients of childbearing or child-fathering potential must be willing use an effective
method of contraception while being treated on this study and for 4 months after the
last cell infusion.
11. Normal left ventricular function as evaluated by echocardiograph within 4 weeks of
anti- CD19-CAR-transduced T cell infusion
Inclusion Criteria: Donor
1. Donors greater than or equal to 18 years of age must be the same individual whose
cells were used as the source for the patient s original stem cell transplant.
2. Adequate venous access for peripheral leukapheresis, or consent to use a temporary
central venous catheter for leukapheresis.
3. Donors must be HIV negative, hepatitis B surface antigen negative, and hepatitis C
antibody negative.
4. Ability to give informed consent.
5. Donor selection will be in accordance with NIH/CC Department of Transfusion Medicine
(DTM) criteria and, in the case of an unrelated donor from a Transplant Center, the
National Marrow Donor Program (NMDP) standards. When a potentially eligible recipient
of an unrelated donor product from an NMDP Center is identified, the recipient will
complete an NMDP search transfer request to allow NIH NMDP staff to contact the NMDP
Coordinating Center, who will, in turn, contact the donor s prior Donor Center. The
NMDP Policy for Subsequent Donation Requests will be followed and the appropriate
forms (Subsequent Donation Request form) and Therapeutic T Cell Collection
Prescription will be submitted as required.
EXCLUSION CRITERIA:
Exclusion Criteria: Recipients
1. Active infection that is not responding to antimicrobial therapy.
2. Sero positive for HIV antibody. (The experimental treatment being evaluated in this
protocol depends on an intact immune system. Patients who are HIV seropositive can
have decreased immune -competence and thus are less responsive to the experimental
treatment and more susceptible to its toxicities.)
3. Sero positive for hepatitis B antigen, positive hepatitis B tests can be further
evaluated by confirmatory tests (HBV DNA), and if confirmatory tests are negative, the
patient can be enrolled.
4. Sero positive for hepatitis C antibody unless antigen negative. If hepatitis C
antibody test is positive, then patients must be tested for the presence of RNA by
RT-PCR and be HCV RNA negative.
5. Active psychiatric disorder which may compromise compliance with the treatment
protocol, or which does not allow for appropriate informed consent (as determined by
Principal Investigator and/or his designee).
6. Pregnant or lactating. The effects of the immunosuppressive medications that could be
required to treat GHVD are likely to be harmful to a fetus. The effects upon breast
milk are also unknown and may be harmful to an infant.
7. Serum total bilirubin > 2.5 mg/dl, serum ALT and AST values greater than or equal to
2.5 times the upper limit of normal based on age-specific normal values. If the
abnormal liver function is attributable to liver involvement by malignancy, patients
may be eligible with serum total bilirubin up to 5.0 mg/dl, and serum ALT and AST
values up to 5.0 times the upper limit of normal, provided the patient has no evidence
of impending hepatic failure (encephalopathy or prothrombin time >2 times the upper
limit of normal).
8. Serum creatinine greater than 1.6 mg/dL
9. Absolute neutrophil count of less than 1000 cells/microL unless low neutrophil count
is thought to be due to malignancy in the bone marrow and malignancy is documented in
the bone marrow.
10. Active cerebrospinal fluid involvement with malignancy or brain metastasis.
11. Platelet count less than 30,000/microL unless low platelet count is thought to be due
to malignancy in the bone marrow and malignancy is documented in the bone marrow.
12. Hemoglobin less than 8.0 g/dL.
13. Receiving systemic corticosteroids including prednisone, dexamethasone or any other
corticosteroid at doses of higher than 5 mg/day of prednisone within 28 days prior to
anti-CD19-CAR-transduced T cell administration. Corticosteroid creams, ointments, and
eye drops are allowed.
14. Blood blast percentage higher than 5%.
Exclusion Criteria: Donors
1. History of psychiatric disorder which may compromise compliance with this protocol or
which does not allow for appropriate informed consent.
2. History of hypertension that is not controlled by medication, stroke, or severe heart
disease (donors with symptomatic angina will be excluded). Donors with a history of
coronary artery bypass grafting or angioplasty who are symptom free will receive a
cardiology evaluation and be considered on a case-by-case basis.
3. Donors must not be pregnant.
4. Anemia (Hb < 11 gm/dl) or thrombocytopenia (platelets < 100,000 per microL). However,
potential donors with Hb levels < 11 gm/dl that is due to iron deficiency will be
eligible as long as the donor is initiated on iron replacement therapy. The NIH
Clinical Center, Department of Transfusion Medicine/NMDP physicians will determine the
appropriateness of individuals as donors.
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