NK Cells in Cord Blood Transplantation

PRIMARY OBJECTIVES:

I. To evaluate the feasibility and safety of ex-vivo expanded cord blood (CB) natural killer (NK) cells with double CB transplantation in patients with hematological malignancies.

SECONDARY OBJECTIVES:

I. To monitor engraftment, chimerism, graft versus host disease, and immune reconstitution in patients receiving expanded CB NK cell therapy.

II. To estimate the time to platelet recovery and the time to absolute neutrophil count (ANC) recovery.

III. To estimate overall survival and disease free survival at one year. IV. To study the in-vivo persistence of cord blood NK cells.

OUTLINE:

PREPARATIVE REGIMEN: Patients are assigned to 1 of 2 treatment plans:

TREATMENT PLAN 1: Patients receive high-dose lenalidomide orally (PO) once daily (QD) on days -8 to -2, fludarabine phosphate IV over 1 hour on days -7 to -4, and melphalan IV over 30 minutes on day -4. CD20 positive patients also receive rituximab intravenously (IV) over 6 hours on days -8 to -4.

TREATMENT PLAN 2: Patients receive high-dose lenalidomide PO QD on days -7 to -2, cyclophosphamide IV over 3 hours on day -7, and undergo total body irradiation (TBI) on day -3. Patients also receive rituximab and fludarabine phosphate as in Treatment Plan 1.

NK CELL INFUSION: All patients receive ex-vivo expanded cord blood NK cells IV over 30 minutes on day -2.

TRANSPLANT: All patients undergo allogeneic umbilical cord blood transplant on day 0.

GRAFT-VERSUS-HOST DISEASE (GVHD) PROPHYLAXIS: All patients receive tacrolimus IV or PO on days -2 to 180 followed by taper and mycophenolate mofetil IV over 2 hours or PO thrice daily (TID) on days -3 to 100.

After completion of study treatment, patients are followed up at 3, 6, and 12 months.

• Allogeneic Hematopoietic Stem Cell Transplantation (Procedure), also known as Allogeneic Hematopoietic Cell Transplantation, Allogeneic Stem Cell Transplantation, HSC, HSCT: Undergo allogeneic umbilical cord blood transplant
• Cyclophosphamide (Drug), also known as (-)-Cyclophosphamide, 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate, Carloxan, Ciclofosfamida, Ciclofosfamide, Cicloxal, Clafen, Claphene, CP monohydrate, CTX, CYCLO-cell, Cycloblastin, Cycloblastine, Cyclophospham, Cyclophosphamid monohydrate, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclophosphanum, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Genoxal, Genuxal, Ledoxina, Mitoxan, Neosar, Revimmune, Syklofosfamid, WR- 138719: Given IV
• Fludarabine Phosphate (Drug), also known as 2-F-ara-AMP, 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, Beneflur, Fludara, SH T 586: Given IV
• Laboratory Biomarker Analysis (Other): Correlative studies
• Lenalidomide (Drug), also known as CC-5013, CC5013, CDC 501, Revlimid: Given PO
• Melphalan (Drug), also known as Alanine Nitrogen Mustard, CB-3025, L-PAM, L-Phenylalanine Mustard, L-sarcolysin, L-Sarcolysin Phenylalanine mustard, L-Sarcolysine, Melphalanum, Phenylalanine Mustard, Phenylalanine nitrogen mustard, Sarcoclorin, Sarkolysin, WR-19813: Given IV
• Mycophenolate Mofetil (Drug), also known as Cellcept, MMF: Given IV or PO
• Natural Killer Cell Therapy (Biological): Given IV
• Rituximab (Biological), also known as ABP 798, BI 695500, C2B8 Monoclonal Antibody, Chimeric Anti-CD20 Antibody, CT-P10, IDEC-102, IDEC-C2B8, IDEC-C2B8 Monoclonal Antibody, MabThera, Monoclonal Antibody IDEC-C2B8, PF-05280586, Rituxan, Rituximab Biosimilar ABP 798, Rituximab Biosimilar BI 695500, Rituximab Biosimilar CT-P10, Rituximab Biosimilar GB241, Rituximab Biosimilar IBI301, Rituximab Biosimilar PF-05280586, Rituximab Biosimilar RTXM83, Rituximab Biosimilar SAIT101, RTXM83: Given IV
• Tacrolimus (Drug), also known as FK 506, Fujimycin, Hecoria, Prograf, Protopic: Given IV or PO
• Total-Body Irradiation (Radiation), also known as Total Body Irradiation, Whole-Body Irradiation: Undergo TBI
• Umbilical Cord Blood Transplantation (Procedure), also known as Cord Blood Transplantation, UCB transplantation: Undergo allogeneic umbilical cord blood transplant

Primary outcomes

• Generation of a minimum of 5 x 10^6 natural killer/kg cells in at least 60% of patients (success rate) [Up to 1 year]: Will be estimated with 90% credible interval.
• Treatment-related mortality [100 days]: The method described by Thall, et al will be used. Will be estimated with 90% credible interval. The product-limit estimator of Kaplan and Meier will be used with 95% confidence intervals.
• Incidence of adverse events graded using National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 [Up to 1 year]: Changes from baseline in vital signs and laboratory values will be summarized. Tabulate adverse events by severity and relationship to therapy.

Secondary outcomes

• Proportion of patients with acute graft-versus-host-disease [Up to 1 year]
• Proportion of patients with chronic graft-versus-host-disease [Up to 1 year]
• Overall survival [1 year]: The product-limit estimator of Kaplan and Meier will be used with 95% confidence intervals.
• Disease-free survival [1 year]: The product-limit estimator of Kaplan and Meier will be used with 95% confidence intervals.
• Time to initial platelet recovery [From the infusion of peripheral blood stem cells to the first of 3 consecutive platelet count measurements tested on different days with a count greater than or equal to 20 x 10e9/L, assessed up to 1 year]: Cumulative incidence of platelet recovery will be estimated with the methods of Gooley, et al.
• Time to initial absolute neutrophil count recovery [From the infusion of peripheral blood stem cells to the first of 3 consecutive days of an absolute neutrophil count greater than or equal to 0.5 x 10e9/L, assessed up to 1 year]: Cumulative incidence of platelet recovery will be estimated with the methods of Gooley, et al.

Sex: All, ages: any to 75 Years

Inclusion Criteria:

* Patients must have one of the following hematologic malignancies: acute myelogenous leukemia (AML), induction failure, high-risk for relapse first remission (with intermediate-risk or high-risk cytogenetics, fms-related tyrosine kinase 3 \[FLT3\] mutation positive and/or evidence of minimal residual disease by flow cytometry), secondary leukemia from prior chemotherapy and/or arising from myelodysplastic syndrome, any disease beyond first remission
* Myelodysplastic syndrome (MDS): primary or therapy related
* Acute lymphoblastic leukemia (ALL): induction failure, primary refractory to treatment (do not achieve complete remission after first course of therapy) or are beyond first remission including second or greater remission or active disease; patients in first remission are eligible if they are considered high risk, defined as any of the following detected at any time: with t(9;22) or t(4;11), hypodiploidy, complex karyotype, secondary leukemia developing after cytotoxic drug exposure, and/or evidence of minimal residual disease, or acute biphenotypic leukemia, or double hit non-Hodgkin's lymphoma
* Non-Hodgkin's lymphoma (NHL) in second or third complete remission, refractory NHL, or relapsed NHL (including relapse post autologous hematopoietic stem cell transplant); double hit lymphomas in first remission or more advanced disease
* Small lymphocytic lymphoma (SLL), or chronic lymphocytic leukemia (CLL) with progressive disease following standard therapy; patients with progressive CLL following standard therapy who meet European Bone Marrow Transplant (EBMT) consensus guidelines of indications for allogeneic stem cell transplantation; this includes patients with (1) lack of response or early relapse within 1 year of receiving a purine analog-containing treatment regimen, (2) disease relapse within 2 years of receiving a purine analog combination therapy or after other therapies such as autologous stem cell transplantation, and (3) CLL associated with tumor protein (p)53 mutations or deletions and/or deletion (del) (17p) requiring therapy; patients must have chemosensitive disease with at least a partial response (PR) or stable disease (SD) with last treatment regimen
* Chronic myeloid leukemia (CML) second chronic phase or accelerated phase
* Hodgkin's disease (HD): induction failures, second or third complete remission, or relapse (including relapse post autologous hematopoietic stem cell transplant)
* Multiple myeloma: stage II or III, symptomatic, secretory multiple myeloma requiring treatment
* Performance score of at least 80% by Karnofsky or 0 to 2 Eastern Cooperative Oncology Group (ECOG)
* Left ventricular ejection fraction greater than 45%
* Pulmonary function test (PFT) demonstrating a diffusion capacity of least 45% predicted
* Creatinine < 1.6 mg/dL
* Serum glutamate pyruvate transaminase (SGPT) =< to 2.0 x normal
* Bilirubin =< to 2.0 x normal
* All study participants must be registered into the mandatory Revlimid Risk Evaluation and Mitigation Strategy (REMS) program, and be willing and able to comply with the requirements of the Revlimid REMS program
* Females of reproductive potential must adhere to the scheduled pregnancy testing as required in the Revlimid REMS program
* Negative beta human chorionic gonadotropin (HCG) test in a woman with child bearing potential defined as not post-menopausal for 24 months or no previous surgical sterilization and willing to ongoing pregnancy testing while on treatment with lenalidomide
* Woman with child bearing potential must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 4 weeks before she starts taking lenalidomide
* Men must agree to use a latex condom during sexual contact with females of child bearing potential even if they have had a successful vasectomy
* Patients must have two CB units available which are matched with the patient at 4, 5, or 6/6 human leukocyte antigen (HLA) class I (serological) and II (molecular) antigens; each cord must contain at least 1.5 x 10\^7 total nucleated cells/Kg recipient body weight (pre-thaw); cord blood units will be procured through the National Marrow Donor Program (NMDP)
* Have identified a backup cells source in case of engraftment failure; the source can be autologous, related or unrelated
* Patients who have had a prior autologous transplant are eligible

Exclusion Criteria:

* Patients with known history of human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS)
* Active central nervous system (CNS) disease in patient with history of CNS malignancy
* Patients with chronic active hepatitis or cirrhosis; if positive hepatitis serology, the study chair may deem the patient eligible based on the results of liver biopsy
* Patients with known hypersensitivity to lenalidomide and/or rituximab
* Patients who have a matched related donor who is eligible and willing to donate stem cells

• Chitra Hosing, Principal investigator, M.D. Anderson Cancer Center

NIH grants: P30CA016672