Haploidentical Stem Cell Transplant With Prophylactic Natural Killer DLI for Lymphoma, Multiple Myeloma, and CLL
Haploidentical Stem Cell Transplant With Prophylactic Natural Killer DLI for Lymphoma, Multiple Myeloma, and CLL
This study seeks to examine the investigational use of the conditioning regimen
 (bendamustine, fludarabine, and rituximab) prior to haploidentical peripheral blood
 allogeneic stem cell transplantation with Post-Transplant Cyclophosphamide. The study will
 also test the investigational use of CD56-enriched Donor Lymphocyte Infusion to see if this
 treatment is safe, and whether or not it will help patients achieve better outcomes
 post-transplant, including reduced risk of Graft-Versus-Host Disease (GVHD), and preventing
 disease relapse.
This is a single center Phase I trial of a new haploidentical stem cell transplant regimen
 intended to assess safety. Two groups of patients are planned: patients with lymphoma and
 patients with multiple myeloma. Each subject will receive a haploidentical stem cell
 transplantation using peripheral blood stem cells. Bendamustine-fludarabine-rituximab-TBI
 conditioning will be used, followed by stem cell infusion, with Post-Transplant
 Cyclophosphamide and tacrolimus for GVHD prophylaxis. Patients will receive a CD56-selected
 DLI on day +8. Evaluations will be taken at baseline and at each of the study visits.
 Screening data will be reviewed to determine subject eligibility. Subjects who meet all
 inclusion criteria and none of the exclusion criteria will be entered into the study. Total
 duration of subject participation will be one year. Total duration of the study is expected
 to be three years.
General Inclusion Criteria (For Treatment Groups)

 -  Patient age 18 - 75 years

 -  ECOG 0 - 2

 -  HIV-positive patients are allowed if these criteria are met:

 1. No history of opportunistic infections

 2. CD4+ cell count greater or equal to 250 cells/mm3

 3. No history of non-malignancy AIDS-defining conditions other than historical low
 CD4+ cell counts

 4. Patient is on antiretroviral therapy with undetectable viral load. There must be
 minimal interactions of the antiviral therapy with the experimental treatment
 (antiretroviral such as ritonavir is potent CYP3A4 inhibitor and p-gp inducer may
 interact with tacrolimus resulted in increased serum concentration of
 tacrolimus).

 -  Patients must have a related donor or who is at minimum HLA haploidentical. The donor
 and recipient must be identical at least one allele of each of the following genetic
 loci: HLA-A, HLA-B, HLA-Cw, HLA-DRB1, and HLA-DQB1. A minimum match of 5/10 is
 therefore required, and will be considered sufficient evidence that the donor and
 recipient share one HLA haplotype. An unrelated donor search is not required.
 (Patients with a readily-available, suitable, fully-matched sibling donor less than
 age 55 are not eligible for this trial, these patients should proceed to transplant
 using the matched related donor as standard-of-care).

 Criteria for Donor Eligibility

 -  Age greater than 12 years

 -  Donors must meet the selection criteria as defined by the Foundation for the
 Accreditation of Hematopoietic Cell Therapy (FACT).

 -  In the event that two or more eligible donors are identified, the following order of
 priority will be used to determine the preferred donor:

 -  Medically and psychologically fit and willing to donate

 -  For CMV seronegative recipients, a CMV seronegative donor

 -  Red blood-cell compatibility

 -  RBC cross-match compatible

 -  Minor ABO incompatibility

 -  Major ABO incompatibility

 -  If more than one preferred donor is identified and there is no medical, HLA- or KIR
 ligand reason to prefer one of them, then the following guidelines are recommended:

 If the patient is male, choose a male donor:

 -  Choose the youngest preferred donor

 -  If the patient and family express a strong preference for a particular donor, use that
 one.

 Inclusion Criteria (Lymphoma)

 -  Diagnosis of resistant or relapsed CLL, Non-Hodgkin Lymphoma, Hodgkin Lymphoma, T-cell
 lymphoma, NK or NK/T Lymphoma.

 -  Meets one of the following criteria:

 -  relapsed after auto-transplant, or

 -  failed to mobilize autologous stem cells, or

 -  for whom allogeneic stem cell transplant is deemed appropriate given disease risk
 factors that make cure with autologous transplant seem unlikely, such as history
 of chemotherapy refractoriness, high risk disease
 features/mutations/translocations (e.g., Double Hit / Double Expressor DLBCL),
 short remission after prior chemotherapy, or histologic transformation (see
 below).

 -  For Patients with Aggressive Mantle Cell and Diffuse Large B Cell Lymphoma who have
 not had a prior autologous transplant:

 -  Must have received at least 2 lines of prior therapy, and

 -  Have been exposed to anthracycline, and

 -  High and High-Intermediate aaIPI score (2 or 3 factors), and

 -  Have relapsed within one year of primary therapy

 -  For diagnosis of other aggressive lymphoma (e.g. NK/T Lymphoma, T Cell

 Lymphoma, etc.):

 -  Must have received at least 2 lines of prior therapy, and

 -  Relapsed within 12 months of most recent therapy

 -  For low-grade lymphomas / CLL:

 -  Standard risk patients (absence of del(17p), absence of del(11q), no TP53
 mutation and absence of complex karyotype) must have progressed on BCR inhibitor,
 or undergone histologic transformation, to be eligible.

 -  Patients with high risk disease (del(17p) or TP53 mutations and/or complex
 phenotype) who relapse after frontline therapy, demonstrate refractory disease to
 second line therapy (not BCR inhibitors), but show an objective response to BCR
 inhibitors are eligible to be taken off BCR inhibitors in order to proceed to
 alloHSCT on trial. Patients with high risk disease who relapse after frontline
 therapy, demonstrate refractory disease to second line therapy including BCR
 inhibitors (not BCL-2 inhibitors), but show an objective response to BCL-2
 inhibitors (venetoclax) are eligible to be taken off BCL-2 inhibitors in order to
 proceed to alloHSCT on trial.

 -  For aggressive lymphomas, partial or complete remission (PR or CR) is required
 prior to alloHSCT.

 -  Regarding CD20 expression: Patients with B cell malignancies that were CD20+ at
 any level at the time of relapse diagnosis (including partial / dim staining on
 IHC or partial / low level expression by flow cytometry) will receive rituximab
 as part of allogeneic transplant conditioning, if indicated. Patients with
 primary-refractory disease who were CD20+ at any level at the time of diagnosis
 will likewise receive rituximab, if indicated. Patients with histologies that
 were CD20- will not receive rituximab (T cell lymphoma, NK/T lymphoma, etc.).
 Fresh tissue / repeat biopsy is not required; the most recent biopsy will be
 reviewed to assess CD20 status.

 Inclusion Criteria (Multiple Myeloma)

 - Patient age 18 - 75 years with:

 -  Early relapse (less than 24 months) after primary therapy that included an autologous
 HSCT, or

 -  High risk multiple myeloma defined as t(4;14), del(17p), -13, t(14;16), amp (1q21),
 chromosome 8q24.1/c-MYC abnormality, or LDH > ULN at diagnosis, provided patients
 respond favorably to salvage therapy before enrollment for alloHSCT on trial and
 patient is age < 55, or

 -  Patients failing to mobilize peripheral blood stem cells for autologous
 transplantation, or

 -  Extramedullary disease at diagnosis or relapse, or

 -  Plasma-cell leukemia with chemosensitive disease

 Inclusion Criteria - Control Patients (specimen collection, only)

 -  Age 18-75 years

 -  Undergoing standard-of-care reduced-intensity peripheral blood allogeneic stem cell
 transplantation (any indication, donor source, conditioning regimen) using PTCy GVHD
 prophylaxis.

 -  Willing to provide longitudinal blood samples per Control Specimen Collection Calendar
 for correlative studies (for comparison to specimens from patients treated on the
 trial).

 -  Agrees to let study personnel collect excess bone marrow aspirate whenever a bone
 marrow biopsy is performed for clinical purposes, and use for research.

 Exclusion Criteria

 -  Patient has a readily-available, suitable, fully-matched sibling donor (MRD) less than
 age 55. 'Suitable' means no high-titre donor-specific antibodies present, and negative
 IDM testing with no contraindications.

 -  Patient has a clinically-significant donor-specific antibody for the selected donor
 (DSA clearance is not allowed).

 -  Poor cardiac function: left ventricular ejection fraction <45% as determined by MUGA
 or ECHO.

 -  Symptomatic pulmonary disease. Poor pulmonary function: FEV1, FVC, and DLCO <50%
 predicted (corrected for hemoglobin) for patients who have not received thoracic or
 mantle irradiation. For patients who have received thoracic or mantle irradiation,
 FEV1 and FVC <70% predicted or DLCO < 50 of predicted.

 -  Poor liver function: bilirubin >2 mg/dl (not due to hemolysis, Gilbert's or primary
 malignancy). ALT or AST > 5 x laboratory upper normal limits.

 -  Poor renal function: Creatinine >2.0mg/dl or creatinine clearance (calculated
 creatinine clearance is permitted) < 60 mL/min based on Traditional Cockcroft-Gault
 formula

 -  Women of childbearing potential who currently are pregnant (Β-HCG+) or who are not
 practicing adequate contraception.

 -  Uncontrolled viral, bacterial, or fungal infections. Patients with symptoms consistent
 with RSV, influenza A, B, or parainfluenza at the time of enrollment will be assayed
 for the above viruses and if positive are not eligible for the trial until they are no
 longer symptomatic (patients may have continued assay positivity for a period of time
 post resolution of symptoms secondary to the nature of the assay).

 -  Uncontrolled CNS involvement by malignancy (patients with prior history of CNS disease
 controlled with intrathecal chemotherapy or prior systemic therapy are allowed).

 -  Patients who have any debilitating medical or psychiatric illness which would preclude
 their giving informed consent or their receiving optimal treatment and follow-up.

 Exclusion Criteria - Control Patients (specimen collection, only)

 -  Undergoing myeloablative alloHSCT.

 -  Non-PTCy GVHD prophylaxis.

 -  Non-PBSC transplant (bone marrow stem cell source).

 -  Not willing to give longitudinal blood specimens for research use or not willing to
 allow access to medical records for non-clinical purposes.