Helical Tomotherapy, Fludarabine Phosphate, and Melphalan Followed By Allo-HSCT in Hematological Malignancies

Study Overview
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Brief Summary
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RATIONALE: Giving chemotherapy drugs, such as fludarabine phosphate and melphalan, and HT before a donor stem cell transplant helps stop the growth of cancer cells. It also helps stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving HT together with fludarabine phosphate and melphalan before a transplant may stop this from happening. PURPOSE: This clinical trial studies helical tomotherapy (HT), fludarabine phosphate, and melphalan followed by donor stem cell transplant in treating patients with hematologic malignancies.

Detailed Description
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PRIMARY OBJECTIVES: I. To assess the feasibility in terms of toxicity and safety of HT in combination with Fludarabine (fludarabine phosphate) and Melphalan as a preparative regimen for allogeneic stem cell transplantation in patients with Hematological Malignancies: acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and myelodysplastic syndromes (MDS). SECONDARY OBJECTIVES: I. To evaluate within the confines of this pilot study, incidence of neutrophil and platelet engraftment, survival on day +180, the overall survival, and disease free survival in patients with Hematological Malignancies: ALL, AML, and MDS. II. To evaluate incidence of primary and secondary engraftment failure, incidence of relapse, incidence of acute and chronic transplant related complications, including veno-occlusive disease of the liver (VOD), organ toxicity, secondary malignancies, including treatment-related myelodysplastic syndrome, and acute and chronic graft-versus-host disease (GVHD), as well as post-transplant chimerism. OUTLINE: PREPARATIVE REGIMEN*: Patients receive fludarabine phosphate intravenously (IV) on days -7 to -3 and melphalan IV on day -2. Patients also undergo HT twice daily on days -7 to -4. TRANSPLANTATION: Patients undergo allogeneic hematopoietic stem cell transplantation on day 0. NOTE: *Treatment begins 2 days earlier in patients receive tacrolimus and/or sirolimus for GVHD prophylaxis. After completion of study treatment, patients are followed up periodically for 2 years.

Official Title
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Allogeneic Stem Cell Transplant With a Novel Conditioning Therapy Using Helical Tomotherapy, Melphalan, and Fludarabine in Hematological Malignancies

Conditions
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Leukemia, Myelodysplastic Syndromes

Intervention / Treatment
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* Drug: fludarabine phosphate
* Drug: melphalan
* Procedure: allogeneic hematopoietic stem cell transplantation
* Radiation: intensity-modulated radiation therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Recipient, or recipient's parents, or recipient's legal guardians must have signed a voluntary, informed consent in accordance with institutional and federal guidelines Must have histopathologically confirmed diagnosis in one of the followed categories: AML MDS with intermediate or high-risk disease ALL Children and adults at any age with significant morbidity, as determined by the primary bone marrow transplant (BMT) doctor (MD), and approved by the principal investigator (PI) Able to lie supine in a full body cast for approximately 30 minutes, the anticipated duration of each treatment session; for younger patients deep conscious sedation may be required Performance status evaluated by Zubrod or Karnofsky (KPS) Performance Scales in patients > 16 years or Lanksy Performance Scale in children =< 16 years must have a score >= 70% Adequate cardiac function: cardiac ejection fraction > 50% by multi gated acquisition scan (MUGA) scan and/or by echocardiogram Adequate pulmonary function: adults (older than 16 years): diffusing capacity of carbon monoxide (DLCO) > 50%; for young children in whom pulmonary function tests (PFT) are not applicable: assessment by a pediatrician or pulmonary consult Adequate renal function as demonstrated by: creatinine clearance or glomerular filtration rate (GFR) > 60 cc/min (24 hour urine collection) Serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT) =< 5.0 times the institutional upper limits of normal Patients must have less than 15% peripheral blasts Pre-treatment tests must have been preformed within 30 days prior to initiation of high-dose chemotherapy No other medical and/or psychosocial problems, which in the opinion of the primary physician or principle investigator would place the patient at unacceptable risk from this regimen Exclusion Criteria: Patients with Acute Undifferentiated Leukemia (AUL), i.e. no lymphoid or myeloid markers Previous radiation therapy to more than 20% of bone marrow containing areas, or to any area exceeding 2000 cGy Patients with Fanconi Anemia Major medical or psychiatric disorders that would seriously compromise patient tolerance of this regimen Human immunodeficiency virus (HIV) infection Evidence of Hepatitis B or C infection or evidence of cirrhosis Uncontrolled viral, bacterial or fungal infection Patients with recent (within 4 weeks) serious viral, fungal, or bacterial infection are excluded Patients with radiographic changes indicating pulmonary disease, including but not limited to: pulmonary nodules, infiltrates, pleural effusion are excluded unless cleared by pulmonary biopsy showing no evidence for active pulmonary disease

Ages Eligible for Study
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Minimum Age: 7 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 (enzyme inhibitor, radiation therapy, transplant)<br>PREPARATIVE REGIMEN*: Patients receive fludarabine phosphate IV on days -7 to -3 and melphalan IV on day -2. Patients also undergo helical tomotherapy twice daily on days -7 to -4. TRANSPLANTATION: Patients undergo allogeneic hematopoietic stem cell transplantation on day 0. NOTE: *Treatment begins 2 days earlier in patients receive tacrolimus and/or sirolimus for GVHD prophylaxis. | Drug: fludarabine phosphate<br>* 25 mg/m2 day -7 through day -3 prior to transplant<br>Drug: melphalan<br>* 140 mg/m2 day -2 prior to transplant<br>Procedure: allogeneic hematopoietic stem cell transplantation<br>* Cells infused on Day 0 of transplant regimen<br>Radiation: intensity-modulated radiation therapy<br>* Each fraction is 150 cGy, 2 fractions each day on day -7 through day -4 prior to transplant<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Grade 3 and Above Toxicities of Helical Tomotherapy (HT) in Combination With Fludarabine and Melphalan Followed by Allogeneic Stem Cell Transplantation. | Toxicities (adverse events) were evaluated using the modified Bearman Scale and the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. | 100 days post treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival on Day 180 Days Post-transplant | Overall survival (OS) was measured from peripheral stem cell infusion to death from any cause. It was estimated using the Kaplan-Meier method; the 95% confidence interval was calculated using Greenwood's formula. Participants were followed up to 180 days after transplant and Kaplan-Meier survival analysis was used to generate the Overall Survival estimate at 180 days. | Up to 180 days post-transplant | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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acute myeloid leukemia with multilineage dysplasia following myelodysplastic syndrome, 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), untreated adult acute myeloid leukemia, recurrent adult acute myeloid leukemia, childhood acute myeloid leukemia in remission, recurrent childhood acute myeloid leukemia, untreated childhood acute myeloid leukemia and other myeloid malignancies, de novo myelodysplastic syndromes, previously treated myelodysplastic syndromes, secondary myelodysplastic syndromes, secondary acute myeloid leukemia, childhood acute lymphoblastic leukemia in remission, recurrent adult acute lymphoblastic leukemia, recurrent childhood acute lymphoblastic leukemia, untreated adult acute lymphoblastic leukemia, untreated childhood acute lymphoblastic leukemia, childhood myelodysplastic syndromes