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

Sumithira Vasu

Status and phase

Completed

Phase 1

Conditions

Adult Acute Myeloid Leukemia With t(15;17)(q22;q12)

Untreated Adult Acute Myeloid Leukemia

Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities

de Novo Myelodysplastic Syndromes

Adult Acute Myeloid Leukemia With Inv(16)(p13;q22)

Adult Acute Myeloid Leukemia With t(8;21)(q22;q22)

Untreated Adult Acute Lymphoblastic Leukemia

Adult Acute Myeloid Leukemia in Remission

Previously Treated Myelodysplastic Syndromes

Adult Acute Lymphoblastic Leukemia in Remission

Secondary Myelodysplastic Syndromes

Adult Acute Myeloid Leukemia With t(16;16)(p13;q22)

Recurrent Adult Acute Lymphoblastic Leukemia

Recurrent Adult Acute Myeloid Leukemia

Adult Acute Myeloid Leukemia With Del(5q)

Treatments

Other: laboratory biomarker analysis

Procedure: allogeneic bone marrow transplantation

Biological: anti-thymocyte globulin

Procedure: allogeneic hematopoietic stem cell transplantation

Drug: tacrolimus

Procedure: peripheral blood stem cell transplantation

Drug: cyclophosphamide

Radiation: radiation therapy

Drug: methotrexate

Study type

Interventional

Funder types

Other

Identifiers

NCT02122081

NCI-2014-00763 (Registry Identifier)

OSU-13219

Details and patient eligibility

About

This pilot clinical trial aims to assess feasibility and tolerability of using an LINAC based "organ-sparing marrow-targeted irradiation" to condition patients with high-risk hematological malignancies who are otherwise ineligible to undergo myeloablative Total body irradiation (TBI)-based conditioning prior to allogeneic stem cell transplant. The target patient populations are those with ALL, AML, MDS who are either elderly (>50 years of age) but healthy, or younger patients with worse medical comorbidities (HCT-Specific Comorbidity Index Score (HCT-CI) > 4). The goal is to have the patients benefit from potentially more efficacious myeloablative radiation based conditioning approach without the side effects associated with TBI.

Full description

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.

Enrollment

33 patients

Sex

All

Ages

18 to 75 years old

Volunteers

No Healthy Volunteers

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

Trial design

Primary purpose

Treatment

Allocation

N/A

Interventional model

Single Group Assignment

Masking

None (Open label)

33 participants in 1 patient group

Treatment (OSMI, allogeneic transplant)

Experimental group

Description:

CONDITIONING REGIMEN: Patients undergo organ-sparing marrow irradiation BID on days -6 to -4 and receive cyclophosphamide 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 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.

Treatment: