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.
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.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
33
Undergo organ-sparing marrow irradiation BID on days -6 to -4
Given IV over 1-2 hours every 24 hours on days -3 to -2.
Given IV or PO
Given IV
Undergo allogeneic peripheral blood progenitor cell or bone marrow transplant on day 0
Undergo allogeneic peripheral blood progenitor cell or bone marrow transplant
Undergo allogeneic peripheral blood progenitor cell or bone marrow transplant
Correlative studies
Arthur G. James Cancer Hospital and Solove Research Institute at Ohio State University Medical Center
Columbus, Ohio, United States
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.
Time frame: 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.
Time frame: Up to 30 days
TRM
Proportions will be derived for incidence of toxicity divided by all evaluable patients along with corresponding 95% binomial confidence intervals.
Time frame: Day 100 post-transplant
Donor chimerism
Donor chimerism is used to assess failure of engraftment rate.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: Up to 12 months
Incidence of relapse
Time frame: Time from start of conditioning to relapse, assessed at 1 year
Overall survival
Time frame: 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 frame: 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.
Time frame: Up to 12 months post transplant
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