Reduced Intensity Conditioning and Stem Cell Transplant in Treating Patients with Blood Cancer

Status: Active

Description

This phase II trial studies how well reduced intensity conditioning (a short course of chemotherapy) and stem cell transplant work in treating patients with blood cancer. 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. The donated stem cells may also replace the patient’s immune cells and help destroy any remaining cancer cells. Giving reduced intensity conditioning and total body irradiation before a donor blood stem cell transplant helps to stop the growth of cells in the bone marrow, including normal blood-forming cells (stem cells) and cancer cells with shorter recovery and fewer side effects.

Eligibility Criteria

Inclusion Criteria

  • Must have no 7/8 or 8/8 HLA-matched sibling donor - patients >= 70 and =< 75 years of age may be eligible if they have a co-morbidity score =< 2
  • 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 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 versus (vs.) early relapse are acceptable provided there are no associated cytogenetic markers consistent with relapse
  • Acute myeloid leukemia (AML): 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 * 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 but FLT3-ITD wild type * 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 * 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 immunophenotypic 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 5%. If 5% or more requires chemotherapy for cytoreduction to =< 5% prior to transplantation
  • Chronic myelogenous leukemia in chronic or accelerated phase; chronic phase patients must failed at least two different TKIs, been intolerant to all available TKIs or have T315I mutation
  • MRD positive leukemia (AML, ALL or accelerated/blast phase chronic myelogenous leukemia [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 myelodysplastic syndrome (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
  • Myeloproliferative neoplasms/myelofibrosis
  • 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 CR2 or subsequent CR
  • Relapsed T-cell lymphoma that is chemotherapy sensitive in CR/partial response (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
  • Relapsed multiple myeloma that is chemotherapy sensitive and has failed or ineligible for an autologous transplant
  • Bone marrow failure syndromes, except for Fanconi anemia
  • 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 (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 1 (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 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/1.73m^2
  • 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; legally authorized representative on behalf of cognitively impaired adult; or parent/guardian with presentation of the minor information sheet, if appropriate)

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 or known human immunodeficiency virus (HIV) positive serology
  • Less than 3 months since prior myeloablative transplant (if applicable); 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, 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

Locations & Contacts

Minnesota

Minneapolis
University of Minnesota / Masonic Cancer Center
Status: Active
Contact: Nelli Bejanyan
Phone: 612-624-0123
Email: nbejanyan@umn.edu

Trial Objectives and Outline

PRIMARY OBJECTIVE

I. To estimate probability of the 1 year disease free survival (DFS) after a human leukocyte antigen (HLA)-haploidentical related hematopoietic cells transplant (haplo-hematopoietic cell transplant [HCT]) using a reduced intensity cyclophosphamide/fludarabine/melphalan/total body irradiation (TBI) conditioning with modifications based on factors including age and comorbidities in patients with a hematologic malignancy.

SECONDARY OBJECTIVES:

I. Incidence of day 100 grade II-IV and grade III-IV acute graft versus-host disease (GVHD).

II. Probability of 6 month, 1 and 2 year treatment-related mortality (TRM).

III. Probability of 1 and 2 year relapse incidence.

IV. Incidence of serious fungal and viral infections at day 100 and 1 year post-HCT.

TERTIARY OBJECTIVES:

I. Incidence of neutrophil recovery by day +30.

II. Incidence of platelet recovery by day +60.

III. Donor cell engraftment (chimerism) at day +21, +60, +100, +180 and + 365.

IV. Incidence of 1 and 2 year chronic GVHD.

V. Probability of 1 and 2 year GVHD and relapse-free survival (GRFS).

VI. Probability of 2 year DFS.

VII. Probability of 1 and 2 year overall survival (OS).

OUTLINE:

PREPARATIVE REGIMEN: Patients receive fludarabine intravenously (IV) over 30-60 minutes on days -6 to -2, cyclophosphamide IV over 2 hours on day -6, and melphalan IV over 15-20 minutes on day -5. Patients undergo TBI on days -2 and -1.

TRANSPLANT: Patients undergo HCT IV over 1 hour on day 0.

POST- HCT: Patients receive cyclophosphamide IV over 1-2 hours on days 3-4, tacrolimus on days 5-180, mycophenolate mofetil (MMF) on days 5-35, and granulocyte colony-stimulating factor (G-CSF) IV or subcutaneously (SC) on day 5.

After completion of study treatment, patients are followed up weekly for 3 months and then at 6, 12 and 24 months.

Trial Phase & Type

Trial Phase

Phase II

Trial Type

Treatment

Lead Organization

Lead Organization
University of Minnesota / Masonic Cancer Center

Principal Investigator
Claudio G. Brunstein

Trial IDs

Primary ID 2016LS092
Secondary IDs NCI-2017-01068
Clinicaltrials.gov ID NCT02988466