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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Feasibility Study of Organ-Sparing Marrow-Targeted Irradiation (OSMI) to Condition Patients With High-Risk Hematologic Malignancies Prior to Allogeneic Hematopoietic Stem Cell Transplantation

Conditions
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Adult Acute Lymphoblastic Leukemia in Remission, Adult Acute Myeloid Leukemia in Remission, Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities, Adult Acute Myeloid Leukemia With Del(5q), Adult Acute Myeloid Leukemia With Inv(16)(p13;q22), Adult Acute Myeloid Leukemia With t(15;17)(q22;q12), Adult Acute Myeloid Leukemia With t(16;16)(p13;q22), Adult Acute Myeloid Leukemia With t(8;21)(q22;q22), de Novo Myelodysplastic Syndromes, Previously Treated Myelodysplastic Syndromes, Recurrent Adult Acute Lymphoblastic Leukemia, Recurrent Adult Acute Myeloid Leukemia, Secondary Myelodysplastic Syndromes, Untreated Adult Acute Lymphoblastic Leukemia, Untreated Adult Acute Myeloid Leukemia

Intervention / Treatment
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* Radiation: radiation therapy
* Drug: cyclophosphamide
* Biological: anti-thymocyte globulin
* Drug: tacrolimus
* Drug: methotrexate
* Procedure: allogeneic bone marrow transplantation
* Procedure: allogeneic hematopoietic stem cell transplantation
* Procedure: peripheral blood stem cell transplantation
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (OSMI, allogeneic transplant)<br>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. | Radiation: radiation therapy<br>* Undergo organ-sparing marrow irradiation BID on days -6 to -4<br>* Other names: therapy, radiation;Drug: cyclophosphamide<br>* Given IV over 1-2 hours every 24 hours on days -3 to -2.<br>* Other names: Endoxana;Biological: anti-thymocyte globulin<br> <br> * Other names: Thymoglobulin;Drug: tacrolimus<br>* Given IV or PO<br>* Other names: Prograf;Drug: methotrexate<br>* Given IV<br>* Other names: MTX;Procedure: allogeneic bone marrow transplantation<br>* Undergo allogeneic peripheral blood progenitor cell or bone marrow transplant on day 0<br>* Other names: transplantation, allogenic bone marrow;Procedure: allogeneic hematopoietic stem cell transplantation<br>* Undergo allogeneic peripheral blood progenitor cell or bone marrow transplant<br>Procedure: peripheral blood stem cell transplantation<br>* Undergo allogeneic peripheral blood progenitor cell or bone marrow transplant<br>* Other names: transplantation, peripheral blood stem cell;Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| TRM, defined as death occurring in a patient from causes other than disease relapse | Proportions will be derived for incidence of TRM divided by all evaluable patients along with corresponding 95% binomial confidence intervals. | At day 30 post-transplant | 
| Rate of grade II/III organ toxicity, defined by the Bearman Regimen-Related Toxicities Scale | Toxicities will be tabulated by grade for each cohort, by type of toxicity, as well as the maximum grade overall. Toxicity frequencies will be described for the day +30, day +100, and one year time intervals as well as cumulative over time. Proportions will be derived for incidence of grade II/III organ toxicity divided by all evaluable patients along with corresponding 95% binomial confidence intervals. | Up to 30 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| TRM | Proportions will be derived for incidence of toxicity divided by all evaluable patients along with corresponding 95% binomial confidence intervals. | Day 100 post-transplant | 
| Donor chimerism | Donor chimerism is used to assess failure of engraftment rate. | Day 100 | 
| Incidence of aGVHD, graded according to Ohio State University Bone Marrow Transplant (OSU BMT) Program policy | The first day of aGVHD onset at a certain grade will be used to calculate cumulative incidence curves for that GVHD grade. | Up to day 100 | 
| Incidence of chronic GVHD, scored according to the OSU BMT Program policy | The first day of chronic GVHD onset will be used to calculate cumulative incidence curves. Rates and severity of chronic GHVD will be calculated. | At 1 year | 
| Cumulative incidence of grade II organ toxicity | Toxicity will be tabulated by grade for each cohort, by type of toxicity as well as the maximum grade overall. | Up to day 100 | 
| Incidence of hematopoietic recovery | The rate and kinetics of hematopoietic recovery will be assessed. The kinetics of post-transplant recovery of both neutrophil and platelet engraftment will be assessed. | Up to day 100 | 
| Incidence of graft failure | Primary graft failure (defined by the lack of neutrophil engraftment by 28 days) and secondary graft failure (defined by initial neutrophil engraftment followed by subsequent decline in neutrophil counts < 500/uL unresponsive to growth factor therapy) will be assessed on days 30 and 100 and at 1 year post-transplant. | Up to 1 year post-transplant | 
| Rate of infectious complications | The number of infections and the number of patients experiencing infections will be tabulated by type of infection, severity, and time period after transplant. The cumulative incidence of severe, life-threatening, or fatal infections will be tabulated. | Up to 12 months | 
| Incidence of relapse |  | Time from start of conditioning to relapse, assessed at 1 year | 
| Overall survival |  | Time from start of conditioning to death, loss to follow up, or end of study, whichever comes first, assessed at 1 year | 
| Progression-free survival | Patients are considered a failure of this endpoint if they die or suffer from disease relapse or progression. | Time from start of conditioning to relapse, progression, death, initiation of non-protocol therapy, loss to follow up or end of study, whichever comes first, assessed at 1 year | 
| Immune reconstitution | Quantitative assessments of peripheral blood CD3, CD4, CD8, CD19, and CD56 positive lymphocytes will be done throw flow cytometric analysis at baseline, 100 days, and 12 months post transplantation. | Up to 12 months post transplant |