Clinical Trials

The James Cancer Center Columbus, OH

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Organ-Sparing Marrow-Targeted Irradiation Before Stem Cell Transplant in Treating Patients With High-Risk Hematologic Malignancies

Protocol: OSU-13219

Full Title

A Feasibility Study of Organ-Sparing Marrow-Targeted Irradiation (OSMI) to Condition Patientswith High-risk Hematologic Malignancies Prior to Allogeneic Hematopoietic Stem Cell Transplantation

Purpose

This pilot clinical trial studies the side effects of organ-sparing marrow-targeted irradiation before stem cell transplant in treating patients with high-risk hematological malignancies. Total-body irradiation (TBI) is used to treat patients before an allogeneic stem cell transplant (where patients receive stem cells from another person) to eliminate leukemia cells. Newer radiation therapy can shape the radiation beam so that normal organs can be shielded, but the radiation will still reach other sites where leukemic cells exist. This type of radiation, called organ-sparing marrow-targeted irradiation (OSMI), may help more people benefit from the same dose of radiation as TBI without as many side effects.

Study Objective

PRIMARY OBJECTIVES:

I. To assess feasibility and tolerability of OSMI based hematopoietic stem cell transplant (HSCT) as defined by transplant-related mortality (TRM) at day 30 as well as rate of grade II/III organ toxicity (defined by Bearman Regimen-Related Toxicities Scale) attributable to conditioning occurring within 30 days.

SECONDARY OBJECTIVES:

I. Day 100 transplant-related mortality (TRM).

II. Donor chimerism assessment at day 100 (to assess failure of engraftment rate).

III. Incidence of acute graft-versus-host disease (aGVHD) by day 100.

IV. Incidence of chronic GVHD at one year.

V. Cumulative incidence of grade II organ toxicity through day 100.

VI. Rate and kinetics of hematopoietic recovery.

VII. Incidence of graft failure (primary and secondary).

VIII. Rate of infectious complications.

IX. Cumulative incidence of relapse, overall survival, and progression-free survival at 1 year.

OUTLINE:

CONDITIONING REGIMEN: Patients undergo organ-sparing marrow irradiation twice daily (BID) on days -6 to -4 and receive cyclophosphamide intravenously (IV) over 1-2 hours every 24 hours on days -3 to -2. Patients with an unrelated donor also receive anti-thymocyte globulin every 24 hours on days -4 to -2.

GVHD PROPHYLAXIS: Patients receive tacrolimus IV or orally (PO) beginning on day -1 and continuing for at least 6 months and methotrexate IV on days 1, 3, 6, and 11.

TRANSPLANT: Patients undergo allogeneic peripheral blood progenitor cell or bone marrow transplant on day 0.

After completion of study treatment, patients are followed up weekly for 12 weeks, at day 100, and then at 6 and 12 months.

Are you eligible?

Inclusion Criteria:

Patients with a diagnosis of acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or myelodysplastic syndromes (MDS) with fewer than 10% myeloblasts or lymphoblasts in the bone marrow and no blasts in the peripheral blood on morphologic analysis performed within 30 days of start of the conditioning regimen; if remission bone marrow is available beyond 30 days a new bone marrow evaluation is required to assess remission status

The diagnosis of AML, ALL, or MDS will be based on World Health Organization (WHO) criteria

Pre-transplant bone marrow sample must be evaluable for assessment of remission status (i.e. aspirate smear containing particles and/or evaluable bone marrow core biopsy)

Patients with leukemia infiltration in the central nervous system (CNS) are eligible if cerebrospinal fluid (CSF) cytospin is negative for myeloblasts or lymphoblasts at time of enrollment

If the patient has an intra-abdominal chloroma on presentation, and has a partial response or complete response to treatment (size reduction of chloroma and marrow blast < 10%), the patient is eligible; however the chloroma must be included as part of the treatment target

For patients receiving treatment of their AML, MDS or ALL prior to transplantation:

Interval between the start of a cycle of conventional cytotoxic chemotherapy and the start of conditioning regimen must be at least 30 days

Interval between completing treatment with a hypomethylating agent or other non-cytotoxic chemotherapy and the start of conditioning regimen must be at least 10 days

Hematopoietic Cell Transplantation-Specific Comorbidity Index score (HCT-CI) =< 4 for patients in Cohort 1 and > 4 for Cohort 2

Patient must be able to lie still in full body cast for 45 minutes

Must have a suitable donor defined as a sibling matched at 5/6 or 6/6 antigens (human leukocyte antigen [HLA]-A, B, and DRB1) or an unrelated volunteer matched at 7/8 or 8/8 HLA alleles (HLA-A, B, C, and DRB1)

Signed informed consent

DONOR: “High resolution” typing at HLA-A, B, C and DRB1 alleles

Single antigen mismatch for siblings and single allele mismatch for volunteer unrelated donors is acceptable

Donors must be >= 17 years of age

Exclusion Criteria:

Circulating peripheral blood myeloblasts or lymphoblasts on morphologic analysis from time of last treatment to time of enrollment

Prior allograft or prior autograft

Active CNS disease as identified by positive CSF cytospin at time of enrollment

Karnofsky performance score < 70

Symptomatic uncontrolled coronary artery disease or ejection fraction < 40%

Total bilirubin >= 2 x the upper limit of normal

Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) >= 3 x the upper limit of normal

Diffusion capacity of the lung for carbon monoxide (DLCO) < 40%

Forced expiratory volume in one second (FEV1) < 50% (corrected for hemoglobin)

Receiving supplementary continuous oxygen

Creatinine clearance < 50 mL/min/1.73m^2

Patients with active uncontrolled bacterial, viral or fungal infections (undergoing appropriate treatment and with progression of clinical symptoms)

Patients seropositive for the human immunodeficiency virus (HIV)

Females who are pregnant or breastfeeding

Fertile men and women unwilling to use contraceptive techniques during and for 12 months following treatment

Patients who had prior radiation to more than 20% bone marrow containing areas or to any areas exceeding 2000 cGy

DONOR:

Donors will be excluded if they are an identical twin of the recipient

Females who are pregnant (positive serum beta human chorionic gonadotropin beta [β HCG]) or uninterruptible breastfeeding

HIV seropositive

Donors receiving experimental therapy or investigational agents unless approved by the protocol chair

Acute Lymphoblastic Leukemia Leukemia Acute Myeloid Leukemia