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Cyclophosphamide, Fludarabine Phosphate, and Total-Body Irradiation with or without Anti-Thymocyte Globulin before Donor Umbilical Cord Blood Transplant in Treating Patients with Hematologic Cancer

Trial Status: Active

This phase II trial studies the side effects of cyclophosphamide, fludarabine phosphate, and total-body irradiation with or without anti-thymocyte globulin before donor umbilical cord blood transplant and to see how well they work in treating patients with hematologic cancer. Giving chemotherapy and total-body irradiation before donor umbilical cord blood transplant helps stop the growth of cells in the bone marrow, including normal blood-forming cells (stem cells) and cancer cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells (called graft-versus-host disease). Giving sirolimus and mycophenolate mofetil before and after the transplant may stop this from happening.

Inclusion Criteria

  • < 70 years of age with no matched 5/6 or 6/6 sibling donor - patients >= 70 and =< 75 years of age may be eligible if they have a co-morbidity score =< 2
  • Karnofsky score >= 70% (>= 16 years) or Lansky score >= 50 (< 16 years)
  • UCB graft selected according to current University of Minnesota umbilical cord blood graft selection algorithm
  • Acute leukemias: Must be in remission by morphology (< 5% blasts); Note cytogenetic relapse or persistent disease without morphologic relapse is acceptable; also a small percentage of blasts that is equivocal between marrow regeneration vs. early relapse are acceptable provided there are no associated cytogenetic markers consistent with relapse
  • Acute myeloid leukemia (AML) and related precursor neoplasms: 2nd or greater complete remission (CR); first complete remission (CR1) in patients > 60 years old; CR1 in =< 60 years old that is NOT considered as favorable-risk; favorable risk AML is defined as having one of the following: * t(8,21) without cKIT mutation * inv(16) or t(16;16) without cKIT mutation * Normal karyotype with mutated NPM1 and wild type FLT-ITD * Normal karyotype with double mutated CEBPA * Acute prolymphocytic leukemia (APL) in first molecular remission at the end of consolidation
  • Acute lymphoblastic leukemia (ALL)/lymphoma: second or greater CR; CR1 unable to tolerate consolidation chemotherapy due to chemotherapy-related toxicities; CR1 high-risk ALL; high risk ALL is defined as having one of the following: * Evidence of high risk cytogenetics, e.g. t(9;22), t(1;19), t(4;11), other MLL rearrangements, IKZF1 * 30 years of age or older at diagnosis * White blood cell counts of greater than 30,000/mcL (B cell [B]-ALL) or greater than 100,000/mcL (T cell [T]-ALL) at diagnosis * Central nervous system (CNS) leukemia involvement during the course of disease * Slow cytologic response (> 10% lymphoblasts in bone marrow on day 14 of induction therapy) * Evidence of persistent immunophenotypic or molecular minimal residual disease (MRD) at the end of induction and consolidation therapy
  • Biphenotypic/undifferentiated/prolymphocytic leukemias in first or subsequent CR
  • Chronic myelogenous leukemia in chronic or accelerated phase, or chronic myelogenous leukemia (CML) blast crisis in morphological remission (< 5% blasts): chronic phase patients must have failed at least two tyrosine kinase inhibitors been intolerant to all available tyrosine kinase inhibitors (TKIs) or have T315I mutation
  • Myelodysplastic syndrome: International Prognostic Scoring System (IPSS) interleukin-2 (INT-2) or high risk; revised (R)-IPSS high or very high; World Health Organization (WHO) classification: refractory anemia with excess blasts (RAEB)-1, RAEB-2; severe cytopenias: absolute neutrophil count (ANC) < 0.8, anemia or thrombocytopenia requiring transfusion; poor or very poor risk cytogenetics based on IPSS or R-IPSS definitions; therapy-related MDS; blasts must be < 5% by bone marrow aspirate morphology; if >= 5% blasts, patient requires chemotherapy for cytoreduction to < 5% blasts prior to transplantation
  • Minimal residual disease (MRD) positive leukemia (AML, ALL or accelerated/blast phase CML); selected patients in morphologic CR, but with positive immunophenotypic (flow cytometry) or molecular evidence of MRD may be eligible if recent chemotherapy has not resulted in MRD negative status
  • Leukemia or MDS in aplasia; these patients may be taken to transplant if after induction therapy they remain with aplastic bone marrow and no morphological or flow-cytometry evidence of disease >= 28 days post-therapy; these high risk patients will be analyzed separately
  • Burkitt’s lymphoma in CR2 or subsequent CR
  • Relapsed T-cell lymphoma that is chemotherapy sensitive in CR/partial remission (PR) that has failed or ineligible for an autologous transplant
  • Natural killer cell malignancies
  • Large-cell lymphoma, Hodgkin lymphoma and multiple myeloma with chemotherapy sensitive disease who are ineligible for an autologous transplant
  • Relapsed chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), marginal zone B-cell lymphoma, follicular lymphoma which have progressed within 12 months of achieving a partial or complete remission; patients who had remissions lasting > 12 months, are eligible after at least two prior therapies; patients with bulky disease should be considered for debulking chemotherapy before transplant; patients with refractory disease are eligible, unless bulky disease and an estimated tumor doubling time of less than one month
  • Lymphoplasmacytic lymphoma, mantle-cell lymphoma, prolymphocytic leukemia are eligible after initial therapy if chemotherapy sensitive
  • Relapsed multiple myeloma that is chemotherapy sensitive and has failed or ineligible for an autologous transplant
  • Plasma Cell Leukemia after initial therapy if achieved at least in partial remission; or relapsed and achieved subsequent remission (CR/PR)
  • Acquired bone marrow failure syndromes, except for Fanconi anemia
  • Myeloproliferative neoplasms/myelofibrosis
  • Additional criteria for bulky disease (lymphomas): *If stable disease is best response, the largest residual nodal mass must < 5 cm (approximately) *If response to previous therapy, the largest residual mass must represent a 50% reduction and be < 7.5 cm (approximately)
  • Absence of decompensated congestive heart failure, or uncontrolled arrhythmia and left ventricular ejection fraction >= 40%; for children that are not able to cooperate with multi-gated acquisition scan (MUGA) and echocardiography, such should be clearly stated in the physician’s note
  • Diffusing capacity of the lungs for carbon monoxide (DLCO), forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC) >= 40% predicted, and absence of oxygen (O2) requirements; for children that are not able to cooperate with pulmonary function tests (PFTs), a pulse oximetry with exercise should be attempted; if neither test can be obtained it should be clearly stated in the physician’s note
  • Transaminases =< 5 x upper limit of normal (ULN) and total bilirubin =< 2.5 mg/dL except for patients with Gilbert’s syndrome or hemolysis
  • Creatinine =< 2.0 mg/dl (adults) and creatinine clearance >= 40 mL/min (pediatrics); adults with a creatinine > 1.2 mg/dl or a history of renal dysfunction must have estimated creatinine clearance >= 40 ml/min/1.73m^2
  • Adequate performance status is defined as Karnofsky score >= 70% (>= 16 years of age) or Lansky score >= 50 (pediatrics)
  • Sexually active females of childbearing potential and males with partners of child-bearing potential must agree to use adequate birth control during study treatment
  • Voluntary written consent (adult or parent/guardian with presentation of the minor information sheet, if appropriate)

Exclusion Criteria

  • Pregnant or breast feeding; females of childbearing potential must have a negative pregnancy test prior to starting therapy
  • Untreated active infection
  • Active human immunodeficiency virus (HIV) infection or known HIV positive serology
  • Less than 3 months since prior myeloablative transplant
  • Evidence of progressive disease by imaging modalities or biopsy - persistent positron emission tomography (PET) activity, though possibly related to lymphoma, is not an exclusion criterion in the absence of computed tomography (CT) changes indicating progression
  • CML in blast crisis
  • Large cell lymphoma, mantle cell lymphoma and Hodgkin disease that is progressing on salvage therapy
  • Active central nervous system malignancy

Minnesota

Minneapolis
University of Minnesota / Masonic Cancer Center
Status: ACTIVE
Contact: Claudio G. Brunstein
Phone: 612-625-3918

PRIMARY OBJECTIVES:

I. To estimate the probability of grade II-IV acute graft-versus-host disease (GVHD) at day 100 after unrelated donor umbilical cord blood transplantation using a non-myeloablative preparative regimen along with sirolimus/ mycophenolate mofetil (MMF) for GVHD prophylaxis in persons with hematologic malignancies.

SECONDARY OBJECTIVES:

I. Incidence of grade III-IV acute GVHD at 100 days.

II. Transplant related mortality (TRM) at 6 months.

III. Chimerism at day 21, 100,180 and 365.

IV. Incidence of neutrophil engraftment by day 42.

TERTIAR OBJECTIVES:

I. Incidence of platelet engraftment by six months.

II. Incidence of one year chronic GVHD.

III. Probability of one and two year overall survival (OS).

IV. Probability of one and two year progression free survival (PFS).

V. Incidence of one and two year relapse or disease progression.

OUTLINE: Patients are assigned to 1 of 2 arms.

PREPARATIVE REGIMEN:

ARM I: Patients who have received a previous autologous transplant or >= 2 courses of chemotherapy within 3 months, receive fludarabine phosphate intravenously (IV) over 1 hour on days -6 to -2 and cyclophosphamide IV over 2 hours on day -6. Patients also undergo total body irradiation (TBI) on day -1.

ARM II: Patients who have not received a previous autologous transplant or =< 1 course of chemotherapy within 3 months, receive fludarabine phosphate, cyclophosphamide, and undergo TBI as in Arm I. Patients also receive anti-thymocyte globulin IV every 12 hours on days -6 to -4 for a total of 6 doses.

UMBILICAL CORD BLOOD (UCB) INFUSION: In both arms, patients undergo unrelated donor umbilical cord blood transplant on day 0.

GVHD PROPHYLAXIS: In both arms beginning on day -3, patients receive sirolimus orally (PO) with a taper starting on day 100 and completed by day 180. Beginning day -3, patients also receive mycophenolate mofetil IV or PO for up to day 30.

After completion of study treatment, patients are followed up for 2 years after transplantation.

Trial Phase Phase II

Trial Type Treatment

Lead Organization
University of Minnesota / Masonic Cancer Center

Principal Investigator
Claudio Brunstein

  • Primary ID 2015LS149
  • Secondary IDs NCI-2016-00768
  • Clinicaltrials.gov ID NCT02722668