Total Marrow and Lymphoid Irradiation Before Donor Transplant and Cyclophosphamide in Treating Patients With Acute Myeloid Leukemia

Study Overview
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Brief Summary
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This pilot phase I trial studies the side effects of total bone marrow and lymphoid irradiation and how well it works with cyclophosphamide in treating patients with acute myeloid leukemia. Total marrow and lymphoid irradiation targets cancer in bone marrow and blood, instead of applying radiation to the whole body. Giving total bone marrow and lymphoid irradiation before a donor transplant helps stop the growth of cells in the bone marrow, including normal blood-forming cells (stem cells) and cancer cells. Drugs used in chemotherapy, such as cyclophosphamide, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving total bone marrow and lymphoid irradiation before donor transplant and cyclophosphamide after transplant may work better at treating acute myeloid leukemia.

Detailed Description
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PRIMARY OBJECTIVE: I. To evaluate the safety/feasibility of combining a total marrow and lymphoid irradiation (TMLI) transplant conditioning regimen with a post-transplant high dose cyclophosphamide (PTCy)-based graft versus host disease (GvHD) prophylaxis strategy, through the assessment of: adverse events: type, frequency, severity, attribution, time course, duration and complications: including acute GvHD, infection and delayed neutrophil/platelet engraftment. SECONDARY OBJECTIVES: I. To estimate the cumulative incidence (CI) of acute GvHD at 100 days post allogeneic hematopoietic cell transplantation (alloHCT). II. To estimate the CI of chronic GvHD at 6 months, 1- and 2-years post alloHCT. III. To estimate GVHD-free relapse-free survival (GRFS) at 1- and 2-years post alloHCT. IV. To describe the kinetics of immune reconstitution and T cell repertoire in the first year post alloHCT. V. To estimate overall survival (OS), relapse-free survival (RFS) and CI of relapse, and non-relapse mortality (NRM) at 100 days, 1- and 2-years post alloHCT. VI. To characterize quality of life using 36-Item Short Form Health Survey (SF-36), Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT), and M. D. Anderson Symptom Inventory (MDASI) or Pediatric Quality of Life Inventory (PedsQL) at 100 days, 6 months, 1- and 2-years post alloHCT. VII. To assess bone marrow cellularity from bone marrow samples. VIII. To assess the clonogenic potential of cells from bone marrow samples. IX. To assess stromal damage from bone marrow samples. X. To evaluate cytokines and oxidative stress markers. OUTLINE: This is a dose-escalation study of TMLI. Patients undergo TMLI twice daily (BID) on days -4 to 0, then undergo bone marrow or peripheral blood stem cell transplant on day 0. Patients receive cyclophosphamide intravenously (IV) over 2 hours on days 3 and 4, tacrolimus given by continuous intravenous infusion (CIV) on days 5-90, and filgrastim beginning on day 5 until absolute neutrophil count (ANC) is at least 1,500/mm^3 for 3 consecutive days. After completion of study treatment, patients are followed for up to 24 months.

Official Title
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Pilot Study of Total Marrow/Lymphoid Irradiation (TMLI) Conditioning Prior to Allogeneic Hematopoietic Stem Cell Transplant (HCT) Followed by Post Transplant Cyclophosphamide-Based Graft Versus Host Disease Prophylaxis for Acute Myelogenous Leukemia in Complete Remission

Conditions
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Acute Myeloid Leukemia

Intervention / Treatment
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* Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
* Drug: Cyclophosphamide
* Biological: Filgrastim
* Other: Laboratory Biomarker Analysis
* Other: Quality-of-Life Assessment
* Other: Questionnaire Administration
* Drug: Tacrolimus
* Radiation: Total Marrow Irradiation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: This study is open to patients with acute myeloid leukemia (AML) evaluated within 30 days of the start of conditioning regimen and in first or second complete remission (CR) Karnofsky performance status (KPS) >= 70% The effects of radiation on the developing fetus are known to be teratogenic; for this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control or abstinence) prior to study entry and for six months following duration of study participation; should a woman become pregnant or suspect that she is pregnant while participating on the trial, she should inform her treating physician immediately Patients with acute myelogenous leukemia (AML) who are in first or second complete remission All candidates for this study must have a human leukocyte antigen (HLA) (A, B, C, DR) identical sibling who is willing to donate primed blood stem cells (preferred) or bone marrow, or have a 10/10 allele matched unrelated donor; all ABO blood group combinations of the donor/recipient are acceptable since even major ABO compatibilities can be dealt with by various techniques; (red cell exchange or plasma exchange) A cardiac evaluation with an electrocardiogram showing no ischemic changes or abnormal rhythm and an ejection fraction of >= 50% established by multi-gated acquisition scan (MUGA) or echocardiogram Patients must have a serum creatinine of less than or equal to 1.3 mg/dL or creatinine clearance > 70 ml/min as calculated by the Cockcroft-Gault formula A bilirubin of less than or equal to 1.5 mg/dL, excluding patients with Gilbert's disease Patients should also have a serum glutamic-oxaloacetic transaminase (SGOT) and serum glutamate pyruvate transaminase (SGPT) less than 5 times the upper limit of normal Pulmonary function tests including diffusing capacity of the lung for carbon monoxide (DLCO) will be performed; forced expiratory volume in 1 second (FEV 1) and DLCO should be greater than 50% of predicted normal value All subjects must have the ability to understand and the willingness to sign a written informed consent; signed informed consent form approved by the Institutional Review Board (IRB) is required; the patient, family member, and transplant staff physician (physician, nurse, and social worker) meet at least once prior to starting the transplant procedure; during this meeting, all pertinent information with respect to risks and benefits to the donor and recipient will be presented; alternative treatment modalities will be discussed The time from the end of last induction, re-induction, or consolidation regimen should be greater than or equal to 14 days Prior therapy with etoposide and cyclophosphamide is allowed DONOR: donor evaluation and eligibility will be assessed as per current City of Hope standard operating procedure (SOP) Exclusion Criteria: Patients should not have any uncontrolled illness including ongoing or active or poorly controlled infection Patients may not be receiving any other investigational agents, or concurrent biological, chemotherapy, or radiation therapy; maintenance therapy with Food and Drug Administration (FDA)-approved targeted therapies (e.g. tyrosine kinase inhibitors for Philadelphia chromosome [Ph] positive [+] acute lymphoblastic leukemia [ALL], and FLT inhibitors for FLT3+ patients) will be allowed after day 60 disease assessment Prior radiation therapy that would exclude the use of TMLI Relapsed patients who have undergone autologous or allogeneic hematopoietic stem cell transplantation previously Patients with psychological or medical condition that patient's physician deems unacceptable to proceed to allogeneic hematopoietic stem cell transplantation Electrocardiogram (EKG) showing ischemic changes or abnormal rhythm and/or an echocardiogram or MUGA scan showing abnormal wall motion or ejection fraction < 50% Patients who have been treated with chemotherapy or radiation for the purpose of induction, re-induction or consolidation, within two weeks of planned study enrollment Patients with other active malignancies are ineligible for this study, other than localized malignancies Patients that are pregnant or breastfeeding Any other condition that would, in the investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns or compliance with clinical study procedures, including but not limited to, infection/inflammation, intestinal obstruction, unable to swallow medication, social/ psychological issues, etc. Subjects, who in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 60 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 (TMLI, cyclophosphamide)<br>Patients undergo TMLI BID on days -4 to 0, then undergo bone marrow or peripheral blood stem cell transplant on day 0. Patients receive cyclophosphamide IV over 2 hours on days 3 and 4, tacrolimus given by CIV on days 5-90, and filgrastim beginning on day 5 until ANC is at least 1,500/mm^3 for 3 consecutive days. | Procedure: Allogeneic Hematopoietic Stem Cell Transplantation<br>* Undergo alloHCT<br>* Other names: Stem Cell Transplantation, Allogeneic;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;Biological: Filgrastim<br>* Administer according to City of Hope standard operating procedures<br>* Other names: Tevagrastim;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>Drug: Tacrolimus<br>* Given CIV<br>* Other names: Protopic;Radiation: Total Marrow Irradiation<br>* Undergo TMLI<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 1a. Incidence of adverse events | Assessed using Bearman Scale Regimen-Related Toxicity scale. Scale range: Grade 0-4 (increasing grade reflects increasing severity), where Grade 0-none/did not experience and Grade 4=death. | Up to 24 months | 
| 1b. Incidence of adverse events | Assessed using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 scale. Scale range: Grade 1-5 (increasing grade reflects increasing severity), where Grade 1 reflects a more milder form of the adverse event and Grade 5=death. | Up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to neutrophil and platelet recovery/engraftment |  | From day 0 to recovery or declaration of engraftment failure, assessed up to 24 months | 
| Acute graft versus host disease (GvHD) | Graded according to the Consensus Grading. The first day of acute GvHD onset at a certain grade will be used to calculate cumulative incidence curves for that GvHD grade; relapse/death prior to onset will be considered competing events. Will be calculated using the competing risk method as described by Gooley et al. (1999). | Day 0 to 100 (120) days post-transplant | 
| Chronic GVHD | The first day of chronic GvHD onset will be used to calculate cumulative incidence curves, with relapse/death prior to onset considered competing events. Will be calculated using the competing risk method as described by Gooley et al. (1999). | From day (80) 100 to the onset of chronic GvHD, death or last contact, whichever comes first, assessed up to 24 months | 
| GvHD-free/relapse-free survival (GRFS) | Will be calculated using the Kaplan-Meier method. | From start of treatment (hematopoietic stem cell transplant [HCT]) to grade 3-4 acute GvHD, chronic GvHD requiring systemic treatment, relapse, or death (from any cause), whichever occurs first, assessed p to 24 months | 
| Levels of immune cells | Will be measured by flow cytometry for cell subsets: a. T-cells. | Up to 24 months | 
| Levels of immune cells | Will be measured by flow cytometry for cell subsets: b. B-cells. | Up to 24 months | 
| Levels of immune cells | Will be measured by flow cytometry for cell subsets: c. natural killer (NK) cells. | Up to 24 months | 
| Levels of immune cells | Will be measured by flow cytometry for cell subsets: d. regulatory T cells (T-regs). | Up to 24 months | 
| Overall survival | Will be calculated using the Kaplan-Meier method. | From start of treatment until death, or last follow-up, whichever comes first, assessed up to 24 months | 
| Relapse-free survival | Will be calculated using the Kaplan-Meier method. | From the start of treatment to the date of death, disease relapse, or last follow-up whichever occurs first, assessed up to 24 months | 
| Relapse | Will be calculated using the competing risk method as described by Gooley et al. (1999). | From start of therapy, assessed up to 24 months | 
| Non-relapse mortality (NRM) | The cumulative incidence of NRM will be calculated reflecting relapse as a competing risk. Will be calculated using the Kaplan-Meier method and the competing risk method as described by Gooley et al. (1999). | From start of treatment until non-disease related death, or last follow-up, whichever comes first, assessed up to 24 months | 
| Quality of life -Questionnaire | Assessed using a. 36-Item Short Form Health Survey (SF-36). The SF-36 consists of eight scaled scores, which are the weighted sums of the questions in their section. Each scale is directly transformed into a 0-100 scale on the assumption that each question carries equal weight. The lower the score the more disability. The higher the score the less disability i.e., a score of zero is equivalent to maximum disability and a score of 100 is equivalent to no disability. The eight sections are: a1. vitality a2. physical functioning a3. bodily pain a4. general health perceptions a5. physical role functioning a6. emotional role functioning a7. social role functioning a8. mental health | Up to 24 months | 
| Quality of life-Function Assessment | Assessed using b. Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT). (FACT-BMT) is a 47-item, valid and reliable measure of five dimensions of quality of life in bone marrow transplant patients. The dimensions collected and assessed are: b1.physical well being b2. Social and family well being b3. Emotional well being b4. Functional well being b5. Additional concerns. | Up to 24 months | 
| Quality of life -Symptom Inventory | Assessed using c. M. D. Anderson Symptom Inventory (MDASI). MDASI is a multi-symptom patient-reported outcome (PRO) measure for clinical and research use. Use the MDASI to assess the severity of symptoms experienced by patients with cancer and the interference with daily living caused by these symptoms. The following parameters will be reported: c1a. Pain c1b. Fatigue c1c. Nausea c1d. Disturbed sleep c1e. Distress/feeling upset c1f. Shortness of breath c1g. Difficulty remembering c1h. Lack of appetite c1i. Drowsiness c1j. Dry mouth c1k. Sadness c1l. Vomiting c1m. Numbness/tingling c1n. Walking c1o. Activity c1p. Working (including housework) c1q. Relations with other people c1r. Enjoyment of life c1s. Mood A total of eight quality of life parameters will be reported on each pediatric transplant patient. c2a.Pain and Hurt c2b. Fatigue and Sleep c2c. Nausea c2d. Worry c2e. Nutrition c2f. Thinking c2g. Communication | Up to 24 months | 
| Bone marrow residual damage assessment |  | Up to 24 months | 
| Cytokines |  | Up to 24 months | 
| Oxidative stress Markers |  | Up to 24 months |