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Reduced-Intensity Fludarabine, Melphalan, and Total Body Irradiation for the Treatment of Blood Cancer in Patients Undergoing Donor Stem Cell Transplant

Trial Status: Active

This phase II trial studies how well reduced-intensity fludarabine, melphalan, and total body irradiation work in treating patients with blood cancer who are undergoing donor stem cell transplant. Drugs used in chemotherapy, such as fludarabine and melphalan, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high energy x-rays to kill cancer cells and shrink tumors. Giving radiation therapy after chemotherapy may kill the remaining cancer cells.

Inclusion Criteria

  • Age >= 55 years or HCT Co-Morbidity score (HCT-CI) >= 3
  • Lack of a suitable 8/8 HLA-matched sibling donor
  • Adequate performance status is defined as Karnofsky score >= 70% (> 16 years of age) or Lansky score >= 70 (pediatrics)
  • Patients and selected donor must be HLA typed at high resolution using deoxyribonucleic acid (DNA) based typing at the following HLA-loci: HLA-A, -B, -C and DRB1. Donors must be HLA-haploidentical relatives including, but not limited to, children, siblings, or parents, defined as having a shared HLA haplotype between donor and patient at HLA-A, -B, -C, and -DRB1
  • Acute myeloid leukemia (AML): 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 versus (vs). early relapse are acceptable provided there are no associated cytogenetic markers consistent with relapse. * Second or greater complete remission (CR) * First CR (CR1) in patients >= 60 years old * CR1 in < 60 years old that is NOT considered as favorable risk (see exclusion criteria). ** Acute prolymphocytic leukemia (APL) in first molecular remission at the end of consolidation
  • Acute lymphoblastic leukemia (ALL)/lymphoma: second or greater complete remission (CR); first complete remission (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 * Recipient age 30 years and older at diagnosis * White blood cell counts of greater than 30,000/mcL (B-ALL) or greater than 100,000/mcL (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 immonophenotypic or molecular minimal residual disease (MRD) at the end of induction and consolidation therapy
  • Biphenotypic/undifferentiated/prolymphocytic leukemias in first or subsequent CR
  • Myelodysplastic syndrome: any subtype including refractory anemia (RA) if severe pancytopenia or complex cytogenetics. Blasts must be less than 10%. If 10% or more requires chemotherapy for cytoreduction to =< 10% prior to transplantation
  • Chronic myelogenous leukemia in chronic or accelerated phase. Chronic phase patients must failed at least two different tyrosine kinase inhibitor (TKI)s, been intolerant to all available TKIs or have T315I mutation. Accelerated phase requires remission as defined in “AML” section above
  • Myeloproliferative neoplasms/myelofibrosis. Blasts must be less than 5%. If 5% or more requires chemotherapy for cytoreduction to =< 5% prior to transplantation
  • Relapsed large-cell lymphoma, mantle-cell lymphoma and Hodgkin lymphoma that is chemotherapy sensitive and has failed or ineligible for an autologous transplant
  • Burkitt’s lymphoma in second complete remission (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
  • 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 is eligible after initial therapy if chemotherapy sensitive
  • Absence of decompensated congestive heart failure, or uncontrolled arrhythmia and left ventricular ejection fraction >= 40%. For children that are not able to cooperate with multigated acquisition (MUGA) and echocardiography, such should be clearly stated in the physician’s note
  • Carbon monoxide diffusing capability (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 test (PFT)s, a pulse oximetry with exercise should be attempted. If nether test can be obtained it should be clearly stated in the provider’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 or a history of renal dysfunction must have estimated creatinine clearance > 40 ml/min/1.73 m^2
  • Sexually active females of childbearing potential and males with partners of childbearing 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)
  • DONOR: Must be HLA-haploidentical relatives of the patient (biological parents, siblings, halfsiblings, offspring, or other non-first degree relatives), defined as having a shared HLA haplotype between donor and patient at HLA-A, -B, -C, and -DRB1
  • DONOR: 14 to 60 years of age
  • DONOR: Negative for HIV and active hepatitis B
  • DONOR: Not pregnant - females of childbearing potential must have a negative pregnancy test within 7 days of marrow collection

Exclusion Criteria

  • Pregnant or breast feeding. The agents used in this study include Pregnancy Category D: known to cause harm to a fetus. Females of childbearing potential must have a negative pregnancy test prior to starting therapy
  • Untreated active infection
  • Active human immunodeficiency virus (HIV) infection
  • Prior allogeneic HCT at any time point or less than 6 months since prior autologous transplant (if applicable)
  • Evidence of progressive disease by imaging modalities or biopsy - persistent positron emission tomography (PET) activity thought unrelated to lymphoma is not an exclusion criterion in the absence of computed tomography (CT) changes indicating progression
  • Active central nervous system malignancy
  • Favorable risk AML defined as having one of the following: * t(8,21) without cKIT mutation or evidence of immunophenotypic, cytogenetic or molecular minimal residual disease (MRD) * inv(16) or t(16;16) without cKIT mutation or evidence of MRD * Normal karyotype with mutated NPM1 but FLT3-ITD wild type without evidence of MRD * Normal karyotype with double mutated CEBPA without evidence of MRD

Florida

Tampa
Moffitt Cancer Center
Status: ACTIVE
Contact: Hany Elmariah
Phone: 813-745-6008

PRIMARY OBJECTIVE:

I. To estimate probability of the 18 month disease free survival (DFS) after a human leukocyte antigen (HLA)-haploidentical related hematopoietic cell transplant (Haplo-HCT) using a reduced intensity fludarabine/melphalan/total body irradiation (TBI) conditioning in older patients in patients with a myeloid hematologic malignancy.

SECONDARY OBJECTIVES:

I. Incidence of day 90 grade II-IV and grade III-IV acute graft versus host-disease (GVHD).

II. Probability of 6 month and 18 month treatment-related mortality (TRM).

III. Probability of 18 month relapse incidence.

IV. Probability of 18 month overall survival (OS).

TERTIARY/EXPLORATORY OBJECTIVES:

I. Incidence of neutrophil recovery by day +30.

II. Incidence of platelet recovery by day +60.

III. Donor cell engraftment (chimerism) at day +30, +60, +90, +180 and +365.

IV. Incidence of 18 month chronic GVHD.

V. Probability of 18 month year GVHD and relapse-free survival (GRFS).

VI. Incidence of 100 day, 1 year, and 18 month serious fungal and viral infection.

PHARMACOLOGIC OBJECTIVES:

I. Evaluate pharmacokinetics of mycophenolate mofetil (MMF) measured on day 6 after transplant.

II. Evaluate single nucleotide polymorphisms (SNPs) in p450, aldehyde dehydrogenase, and glutathione S-transferase that influence cyclophosphamide metabolism.

OUTLINE:

Patients receive fludarabine intravenously (IV) over 30-60 minutes on days -6 to -2 and melphalan IV over 45 minutes on day -6. Patients undergo total body irradiation (TBI) on day -1 and Haplo-HCT on day 0. Patients receive cyclophosphamide IV over 1 hour on days 3-4. Beginning on day 5, patients receive sirolimus PO once daily (QD) for up to 180 days in the absence of graft versus host disease (GHVD), mycophenolate mofetil PO three time daily (TID) with last dose on day 35, and granulocyte colony-stimulating factor (G-CSF) IV or subcutaneously (SC) in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 1.5 years.

Trial Phase Phase II

Trial Type Treatment

Lead Organization
Moffitt Cancer Center

Principal Investigator
Hany Elmariah

  • Primary ID MCC-20131
  • Secondary IDs NCI-2019-08483
  • Clinicaltrials.gov ID NCT04191187