Relapsed Malignant Blood Cancer After Allogeneic Hematopoietic Stem Cell Transplantation

Background:

Allogeneic hematopoietic stem cell transplantation (or allotransplant; donor blood stem cells) have been used with varying degrees of success as an immune therapy for blood-system cancers (leukemias, myelodysplastic syndrome, lymphomas, multiple myeloma, etc.). Some people's cancer remains active (comes back or continues to spread) after an allotransplant, while other people's cancer disappears and they are hopefully cured . NIH researchers are studying the reasons for these different treatment outcomes, and trying to develop better cancer treatments for people with active cancer after allotransplant. Researchers are collecting data from people who have had allotransplants for a cancer of the blood, whether or not the cancer is in remission, and from their donors. Those with active cancers may be eligible to participate in one of several NIH studies testing treatments for active cancer after allotransplant.

Objectives:

• To develop a systematic, comprehensive evaluation of individuals with relapsed malignant blood cancers after allotransplant (and, if available, their donors) to identify potential treatment study options
• To compare the immune system after allotransplant between people whose cancers are growing with people whose cancers remain in remission.
• To compare the immune system after cancer relapse/progression treatment between people whose cancer responds to treatment with those whose cancers continue to grow.

Eligibility:

• Individuals whose blood system cancer grows or comes back after receiving allotransplant treatment.
• Individuals whose blood system cancer is responding or in remission 100 days or more after receiving allotransplant treatment.
• Related stem-cell donors of eligible allotransplant recipients.

Design:

• Participants will be evaluated with a full physical examination, detailed medical history (for recipients, including a history of allotransplant treatment process, side-effects, etc.), and blood tests. Recipients will also have imaging studies, possible tissue biopsies, quality of life questionnaires/assessments, and other tests to evaluate the current state of their cancer, whether active or in remission. In some cases, it may be possible to substitute results from recent tests and/or biopsies.
• Healthy related donors will have apheresis to provide white blood cells for study and/or for use in potential treatment options. If stem cells would be medically helpful to a recipient, their donors might be asked to take injections of filgrastim before the apheresis procedure to stimulate the production of stem cells for collection.
• As feasible, all recipients will be asked to return to the NIH for detailed follow-up visits in conjunction with 6, 12, and 24 months post-allotransplant evaluations, and may be monitored between visits.
• Recipients whose cancers are active and who are found to be eligible for treatment protocols at the NIH will continue to be monitored on this study while participating on treatment protocols. Return visits and follow-up tests for this study will be coordinated with those required by the treatment protocol.
• Participants may return in the future to be evaluated for new treatment study options (recipients) or additional cell donations for therapy (donors).

Background:

• Cancer relapse is a significant clinical problem following allogeneic hematopoietic stem cell transplantation (allotransplant), affecting up to half of all patients. Effective treatment options are extremely limited and, for most cancers, rarely curative.
• Several CC protocols are evaluating treatment for post-allotransplant relapse. Relapse often progresses quickly; patients require rapid assessment of protocol options in order to expedite initiation of treatment.
• Basic information is needed to improve management of relapse after allotransplant - clinical information regarding risk of relapse and cancer behavior after allotransplant, and information on the biology of relapse after allotransplant - in order to identify risk factors, target prevention strategies, detect early relapse and develop effective treatments.

Objectives:

Primary Objective:

To provide a mechanism for systematic, comprehensive evaluation of individuals with relapsed hematologic malignancy after allotransplant and, if available, their donors, to streamline identification of protocol options, enrollment and initiation of therapy.

Secondary Objectives:

1. To study the clinical features of relapse after allotransplant.
2. To study biologic features of relapse after allotransplant.
3. To facilitate post-allotransplant clinical care for individuals who received allotransplant on CC protocols, as a bridge between treatment protocols.
4. To catalogue regimens used to treat relapse, vis-a-vis safety and efficacy, and develop consensus guidelines for clinical management of relapse after allotransplant.

Eligibility:

1. Individuals who have received allotransplant treatment for hematologic malignancy (Recipient-Subjects). Two comparison cohorts:

   1. Relapse Cohort: Cancer progression, relapse or persistently stable (unremitting) disease
   2. Remission (Control) Cohort: Cancer response or remission at/after Day 100
2. Individuals who are candidates for allotransplant therapy for hematologic malignancies and are being evaluated at the Clinical Center for planned allotransplantation. These subjects will be subsequently assigned to the Relapse or Remission Cohort by Day 100, as appropriate, permitting comparisons of samples collected pre-transplant with samples collected post-allotransplant.
3. Related donors of eligible allotransplant recipients (Donor-Subjects)

Design:

1. Recipient-Subjects with relapse will have clinical and research evaluations at baseline and at six, 12 and 24 months post-allotransplant, then yearly. Evaluation after relapse treatment response and for new protocol options is permitted.
2. Recipient-Subjects in remission will have clinical and research evaluations at baseline and six, 12 and 24 months post-allotransplant. Evaluation for new protocol options, e.g., for relapse, is permitted.
3. Pre-Transplant Subjects will have clinical and research evaluations at baseline and at three months post-allotransplant, thereafter per cohort assignment.
4. Donor-Subjects will undergo a clinical evaluation and cell collection for Recipient-Subject therapy and research. Return evaluation for additional clinical product collection is permitted.
5. Accrual Ceiling: 500 consented subjects (350 Recipient-Subjects and 150 Donor-Subjects) over 5 years, averaging 70 Recipient-Subjects and 30 Donor-Subjects enrolled per year.

• Chronic Myelogenous Leukemia
• Acute Myelogenous Leukemia
• Acute Lymphoblastic Leukemia
• Hodgkins Lymphoma
• Non-Hodgkins Lymphoma

• Pavletic SZ, Kumar S, Mohty M, de Lima M, Foran JM, Pasquini M, Zhang MJ, Giralt S, Bishop MR, Weisdorf D. NCI First International Workshop on the Biology, Prevention, and Treatment of Relapse after Allogeneic Hematopoietic Stem Cell Transplantation: report from the Committee on the Epidemiology and Natural History of Relapse following Allogeneic Cell Transplantation. Biol Blood Marrow Transplant. 2010 Jul;16(7):871-90. Epub 2010 Apr 24. Review.
• Dazzi F, Fozza C. Disease relapse after haematopoietic stem cell transplantation: risk factors and treatment. Best Pract Res Clin Haematol. 2007 Jun;20(2):311-27. Review.
• Porter DL, Alyea EP, Antin JH, DeLima M, Estey E, Falkenburg JH, Hardy N, Kroeger N, Leis J, Levine J, Maloney DG, Peggs K, Rowe JM, Wayne AS, Giralt S, Bishop MR, van Besien K. NCI First International Workshop on the Biology, Prevention, and Treatment of Relapse after Allogeneic Hematopoietic Stem Cell Transplantation: Report from the Committee on Treatment of Relapse after Allogeneic Hematopoietic Stem Cell Transplantation. Biol Blood Marrow Transplant. 2010 Nov;16(11):1467-503. Epub 2010 Aug 10.

• INCLUSION CRITERIA:

RECIPIENT SUBJECTS:

1. Individuals who are candidates for allotransplant therapy for hematologic malignancies and are being evaluated at the Clinical Center for planned allotransplantation.

2. Individuals who have received allotransplant treatment for hematologic malignancy.

   Potential subjects will be evaluated for participation on one of two cohorts. Following hematologic recovery after allotransplant (defined in No. 2, below), individuals have:

   1. Relapse Cohort: Cancer progression, relapse or persistently stable (unremitting) cancer; or
   2. Remission (Control) Cohort: Cancer that is responding or in remission at/after Day 100 post-allotransplant.

   Note: subjects who enroll during screening for allotransplant will be assigned to one of these two cohorts based on the results of their Day 100 (3-month) post-SCT visit or at first progression of cancer, if before Day 100.

3. Hematologic recovery after allotransplant: neutrophil recovery to 500 cells/ml. Secondary cytopenias or cytopenias due to disease progression will be permitted. Note: this requirement will not apply to subjects enrolling pre-SCT.
4. An ongoing relationship with a primary oncologist who will continue to provide continuity of care during and after study participation.
5. Following record review and information exchange between the patient's primary oncologist and the NCI PI/LAI/Designee, the PI/LAI/Designee determines that the individual reasonably could be expected to safely tolerate travel to and from the CC to undergo evaluation as defined in the protocol, in the event that the patient is ineligible or uninterested in participating in open treatment protocols.
6. 0-99 years.
7. Ability of individual or parent/legal guardian to give informed consent.

DONOR SUBJECTS:

1. Individuals who are/will be the donors of allogeneic hematopoietic stem cell transplants received by Recipient-Subjects who are to be enrolled on this protocol.
2. Age 0-99 years. Note: minor subjects (age < 18 years) will be eligible for enrollment only if they will be undergoing a therapeutic cell collection on another protocol. Specifically, allocation of cells collected in excess of clinical requirements for research under this study is permitted, but pediatric donor subjects will not undergo studies and/or sample collections, or re-collection of cells intended exclusively for research under this protocol.
3. Ability of donor or parent/legal guardian to give informed consent.
4. Adequate venous access for peripheral apheresis, or (adults) consent to use a temporary central venous catheter for apheresis.
5. Individuals with evidence of infection with transfusion-transmittable agents (Hepatitis B and C Viruses (HBV, HCV); Human Immunodeficiency Virus (HIV ), Human TLymphotrophic Virus (HTLV I/II), West Nile Virus (WNV) and Trypanosoma cruzi) will not be excluded from study participation. However, Donor-Subjects with evidence of HIV infection will only be able to donate cells for research. Donors with a history of HBV or HCV infection will be able to donate for research, and may be eligible to donate for therapeutic administration. However, determination of permissibility for clinical donation will require a hepatology consultation and the consent of the intended recipient after discussion of the risk/benefit of the donor cell product and the possibility/consequences of transmission. The PI/LAI/Designee will make the final determination of permissibility of donation for recipient cell therapy.
6. Unrelated donor selection will be in accordance with 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 Form) will be submitted as required.

EXCLUSION CRITERIA:

RECIPIENT SUBJECTS:

1. Individuals with rapid disease progression or aggressive cancer histology who, in the opinion of the PI/LAI/Designee, require urgent therapy within 30 days in order to preserve organ function or quality of life. This restriction will not apply if there is no approved therapy with a reasonable chance of disease response, if the patient does not have access to an effective therapy and the patient appears to be eligible for an accruing CC treatment protocol or if the patient is enrolled on an NIH/CC clinical protocol, e.g., allotransplant protocol.
2. Pregnancy or lactating. Additionally, Recipient-Subjects of childbearing potential that will receive cancer treatment under this protocol must be willing to use an effective method of contraception.

DONOR SUBJECTS:

1. Hypertension that is not controlled by medication, stroke, or severe heart disease (donors with symptomatic angina will be excluded). Donor-Subjects with a history of coronary artery bypass grafting or angioplasty who are symptom-free may receive a cardiology evaluation and be considered on a case-by-case basis.
2. Pregnancy. Additionally, Donor-Subjects of childbearing potential must be willing to use an effective method of contraception (Section 4.8) until after completion of apheresis. Potential fetal risks of apheresis, with or without use of exogenous hematopoietic growth factors, are unknown. Lactating donors will be eligible provided they are willing to express and discard milk that is produced while receiving exogenous hematopoietic growth factors. The quantity of excretion into breast milk during receipt of exogenous growth factors is unknown and its safety has not been evaluated in breast-fed infants.
3. History of prior malignancy. Donor-Subjects with a history of prior malignancy will not be able to donate cells for therapeutic administration. Exceptions may be made for individuals who have a history of low-risk cancers that have been fully resected (e.g., nonmelanomatous skin cancers, carcinoma-in-situ, etc.) and/or cancer survivors who have undergone potentially curative therapy and have had no evidence of that disease for at least five years; these individuals may be considered for therapeutic cell donation on a case-by-case basis. Donor-Subjects who are not able to donate cells for therapeutic administration may participate in cell collections intended for research.
4. Anemia (Hb < 11 gm/dl) or thrombocytopenia (platelets < 100,000/microL). However, potential donors with Hb levels < 11 gm/dl 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 will determine the appropriateness of anemic individuals as donors. Anemic donors who are not able to donate cells for therapeutic administration may participate in cell collections intended for research.
5. Adult donors who are not eligible for clinical donation will not be excluded from study participation, but will only be able to donate cells for research.