Early Allogeneic Hematopoietic Cell Transplantation in Treating Patients With Relapsed or Refractory High-Grade Myeloid Neoplasms

Study Overview
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Brief Summary
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This clinical trial studies how well early stem cell transplantation works in treating patients with high-grade myeloid neoplasms that has come back after a period of improvement or does not respond to treatment. Drugs used in chemotherapy, such as filgrastim, cladribine, cytarabine and mitoxantrone hydrochloride, 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 chemotherapy before a donor peripheral blood cell transplant helps stop the growth of cells in the bone marrow, including normal blood-forming cells (stem cells) and cancer 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. The donated stem cells may also replace the patient's immune cells and help destroy any remaining cancer cells. Early stem cell transplantation may result in more successful treatment for patients with high-grade myeloid neoplasms.

Detailed Description
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OUTLINE: RE-INDUCTION CHEMOTHERAPY: Patients receive filgrastim subcutaneously (SC) on days 0-5, mitoxantrone hydrochloride intravenously (IV) over 60 minutes on days 1-3, cladribine IV over 2 hours on days 1-5, and cytarabine IV over 2 hours on days 1-5. CONDITIONING REGIMEN: Beginning 14-60 days after re-induction chemotherapy, patients receive fludarabine phosphate IV over 30 minutes on days -6 to -2, melphalan IV on days -3 to -2, cyclosporine orally (PO) twice daily (BID) starting on day -3. Sirolimus PO BID starting on day -3 will be given to patients who have matched unrelated donors or mismatched unrelated donors. Patients >55 years or with significant co-morbidities will only receive melphalan IV on day -2 and will also receive total body irradiation (TBI) on day -1 or day 0. EARLY TRANSPLANT: Patients undergo allogeneic HCT after conditioning regimen on day 0. GVHD PROPHYLAXIS: Patients with matched donors will receive mycophenolate mofetil PO three times daily (TID) on days 0-30, then twice a day (BID) until day 40; and cyclosporine PO BID on days -3 to 96, with a taper until day 150. Patients with matched unrelated donors also receive sirolimus PO BID on days -3 to 150, with a taper until day 180. Patients with mismatched unrelated donors will receive mycophenolate mofetil PO TID on days 0-30, then BID until day 100, with a taper until day 150; cyclosporine PO BID on days -3 to 150, then taper until day 180; and sirolimus BID PO days -3 to 180, then a taper until day 365. After completion of study treatment, patients are followed up periodically.

Official Title
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A Feasibility Study of Early Allogeneic Hematopoietic Cell Transplantation for Relapsed or Refractory High-Grade Myeloid Neoplasms

Conditions
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Blasts 10 Percent or More of Bone Marrow Nucleated Cells, Chronic Myelomonocytic Leukemia-2, High Grade Malignant Neoplasm, Myelodysplastic Syndrome, Myelodysplastic Syndrome With Excess Blasts-2, Myeloid Neoplasm, Previously Treated Myelodysplastic Syndrome, Recurrent Acute Myeloid Leukemia, Refractory Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: Cladribine
* Drug: Cyclosporine
* Drug: Cytarabine
* Biological: Filgrastim
* Drug: Fludarabine Phosphate
* Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
* Other: Laboratory Biomarker Analysis
* Drug: Melphalan
* Drug: Mitoxantrone Hydrochloride
* Drug: Mycophenolate Mofetil
* Other: Questionnaire Administration
* Drug: Sirolimus
* Radiation: Total-Body Irradiation
* Drug: Melphalan Hydrochloride


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: INCLUSION CRITERIA (ENROLLMENT) Relapsed or refractory high-grade myeloid neoplasms, defined as having a blast count of >= 10% blasts at initial diagnosis; examples include excess blasts (EB)-2, with >= 10% blasts at initial diagnosis, acute myeloid leukemia (AML) or chronic myelomonocytic leukemia (CMML-2); standard definitions of relapse will apply (i.e., characterized by >= 5% abnormal blasts or blast equivalents as assessed by multiparameter flow cytometry or morphologic examination; peripheral blood blasts or blast equivalents; or extramedullary granulocytic sarcoma, per European LeukemiaNet [ELN] 2017 guidelines); bone marrow aspirate/biopsy will be accepted if performed outside University of Washington/Fred Hutchinson Cancer Research Center (UW/FHCRC); determination of disease status should occur within 30 days of signing informed consent R/R high-grade myeloid neoplasm following intensive induction chemotherapy; relapsed high-grade myeloid neoplasm: patients will be classified as relapsed if they have >= 5% blasts after being in a complete remission (CR) following treatment for high-grade myeloid neoplasm; refractory high-grade myeloid neoplasm: patients may be classified as refractory if they have received at least one prior cycle of induction chemotherapy, whether with cladribine cytarabine mitoxantrone (GCLAM) or another regimen ** Patients may have received up to two courses of intensive induction chemotherapy during initial treatment prior to enrollment on this protocol; for example, patients who have received two courses of granulocyte colony stimulating factor (G-CSF) GCLAM (or similar) chemotherapy, with most recent high-dose cytarabine-containing chemotherapy > 6 months ago and CR lasting > 6 months, will be eligible for this protocol; regimens similar to GCLAM would include cytarabine at doses of 1g/m^2 for at least 5 doses; examples of regimens similar to GCLAM would be GCLA, fludarabine cytarabine granulocyte (FLAG), and FLAG-idarubicin (ida); however, patients who received more than two courses of GCLAM (or similar) chemotherapy, or patients who received two courses of GCLAM and had CR lasting < 6 months, would not be eligible R/R high-grade myeloid neoplasm following less intensive induction chemotherapy. Patients who have received at least three cycles of treatment with a hypomethylating agent (HMA; such as azacitidine or decitabine) and still have >= 10% blasts will be eligible for the study (they will be considered refractory); similarly, patients who have received three or more cycles of HMA therapy who have had a response (e.g., achieving CR with < 5% blasts), but who then progress using standard definitions of relapse, will also be eligible (they will be considered relapsed) Potentially eligible for reduced intensity conditioning based on known organ function (formal organ function testing may occur after consent) Caregiver capable of providing post-HCT care Written informed consent INCLUSION CRITERIA (TRANSPLANT) Identified donor (see DONOR SELECTION below for further details) Matched related or unrelated (one allele mismatch in HLA-A, B, or C OK) donor according to institutional standards Unrelated volunteer donor who is mismatched with the recipient (i.e. 9/10 match) Caregiver capable of providing post-HCT care, who will be present once induction therapy with filgrastim, cladribine, cytarabine, mitoxantrone hydrochloride (GCLAM) begins Written informed consent for transplant Either bone marrow or peripheral blood is allowed Exclusion Criteria: EXCLUSION CRITERIA (ENROLLMENT) Prior allogeneic HCT More than two prior courses of induction chemotherapy Relapse after minimal residual disease (MRD)-negative CR within 3 months of most recent GCLAM chemotherapy Low likelihood of being eligible for reduced intensity conditioning HCT based on known information Cardiac ejection fraction < 40% or symptomatic coronary artery disease or uncontrolled arrhythmia, as assessed by multigated acquisition (MUGA) or transthoracic echocardiography (TTE) within previous 3 months and since the most recent anthracycline exposure Corrected diffusing capacity of the lungs for carbon monoxide (DLCOc) < 40% or forced expiratory volume in 1 second (FEV1) < 50% Estimated glomerular filtration rate (GFR) < 40 ml/min Need for supplemental oxygen Direct bilirubin or alanine aminotransferase (ALT) > 2 x upper limit of normal, unless these abnormalities are thought to be related to Gilbert's disease or leukemic infiltration of hepatic parenchyma Known human immunodeficiency virus (HIV) positivity Pregnant or nursing (to be confirmed with quantitative human chorionic gonadotropin [HCG] testing) Invasive solid tumor within 5 years; non-melanoma skin cancer or in situ malignancies are allowed Evidence of serious uncontrolled infection Eastern Cooperative Oncology Group (ECOG) of 3 or 4 EXCLUSION CRITERIA (TRANSPLANT) Donor specific antibodies against donor HLA-DQ or -DP Active bacterial, fungal or viral infections unresponsive to medical therapy Active leukemia in the central nervous system (CNS) HIV positive Cardiac ejection fraction < 40% or symptomatic coronary artery disease or uncontrolled arrhythmia DLCOc < 40% or FEV1 < 50% Estimated GFR < 40 ml/min Need for supplemental oxygen Direct bilirubin or ALT > 2 x upper limit of normal, unless these abnormalities are thought to be related to Gilbert's disease or leukemic infiltration of hepatic parenchyma DONOR SELECTION: Identification of an appropriate donor will follow the general guidelines listed below. HLA-matched related or unrelated donor. Donors must be: Matched for HLA-A, B, C, DRB1 and DQB1 by high resolution typing Only a single allele disparity will be allowed for HLA-A, B, or C as defined by high resolution typing HLA-mismatched unrelated donor. Unrelated volunteer donors who are mismatched with the recipient within one of the following limitations will be permitted: Mismatch for one HLA class I antigen with or without an additional mismatch for one HLA-class I allele, but matched for HLA-DRB1 and HLA-DQ, OR Mismatched for two HLA class I alleles, but matched for HLA-DRB1 and HLA-DQ HLA class I HLA-A, -B, -C allele matched donors allowing for any one or two DRB1 and/or DQB1 antigen/allele mismatch HLA-matching must be based on results of high resolution typing at HLA-A, -B, -C, -DRB1, and -DQ. If the patient is homozygous at the mismatch HLA class I locus or II locus, the donor must be heterozygous at that locus and one allele must match the patient (i.e., patient is homozygous A*01:01 and donor is heterozygous A*01:01, A*02:01)

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 (chemotherapy, HCT)<br>See Detailed Description | Drug: Cladribine<br>* Given IV<br>* Other names: RWJ-26251;Drug: Cyclosporine<br>* Given PO<br>* Other names: SangCya;Drug: Cytarabine<br>* Given IV<br>* Other names: WR-28453;Biological: Filgrastim<br>* Given SC<br>* Other names: Tevagrastim;Drug: Fludarabine Phosphate<br> <br> * Other names: SH T 586;Procedure: Allogeneic Hematopoietic Stem Cell Transplantation<br>* Undergo allogeneic hematopoietic stem cell transplantation<br>* Other names: HSC;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Melphalan<br>* Given IV<br>* Other names: WR-19813;Drug: Mitoxantrone Hydrochloride<br>* Given IV<br>* Other names: Pralifan;Drug: Mycophenolate Mofetil<br>* Given PO<br>* Other names: MMF;Other: Questionnaire Administration<br>* Ancillary studies<br>Drug: Sirolimus<br>* Given PO<br>* Other names: WY-090217;Radiation: Total-Body Irradiation<br>* Undergo TBI<br>* Other names: Whole-Body Irradiation;Drug: Melphalan Hydrochloride<br>* Given IV<br>* Other names: Evomela;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Feasibility of Early Allogeneic Hematopoietic Cell Transplant Assessed by Enrollment and Incidence of Early Transplant | Success will be defined as enrollment of at least 30 patients with transplants occurring in 15 of these 30 (50%) within 60 days of enrollment or start of induction chemotherapy with G-CLAM, whichever is earlier. | Up to 60 days after start of chemotherapy | 
| Feasibility of Early Allogeneic Hematopoietic Cell Transplant Assessed by Relapsed-free Survival 6 Months After Transplant | Success will be defined as observing a 40% of higher 6-month relapse-free survival among patients who received early transplant on study. | 6 months after early allogeneic HCT on study | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Assessments After Early Allogeneic Hematopoietic Cell Transplant, Day 28 | Complete Remission (CR), defined as <5% blasts in bone marrow with hematologic recovery (ANC>1000/ul and platelets >100,000/ml). CRi, defined as complete remission with insufficient hematologic recovery (ANC<1000/ul or platelets<100,000/ul). CRp, defined as complete remission but platelets <100,000/ul. Minimal residual disease (MRD), defined as any detectable disease by flow cytometry, cytogenetics, FISH or PCR in a patient otherwise fulfilling remission criteria. Morphologic leukemia-free state (MLFS), defined as <5% blasts in bone marrow with no hematologic recovery. Relapse, defined as >5% blasts in bone marrow, flow cytometry, or manual differential; OR treatment for active relapsed disease. | Approximately 28 days after early allogeneic HCT | 
| Response Assessments After Early Allogeneic Hematopoietic Cell Transplant, Day 84 | Complete Remission (CR), defined as <5% blasts in bone marrow with hematologic recovery (ANC>1000/ul and platelets >100,000/ml). CRi, defined as complete remission with insufficient hematologic recovery (ANC<1000/ul or platelets<100,000/ul). CRp, defined as complete remission but platelets <100,000/ul. Minimal residual disease (MRD), defined as any detectable disease by flow cytometry, cytogenetics, FISH or PCR in a patient otherwise fulfilling remission criteria. Morphologic leukemia-free state (MLFS), defined as <5% blasts in bone marrow with no hematologic recovery. Relapse, defined as >5% blasts in bone marrow, flow cytometry, or manual differential; OR treatment for active relapsed disease. | Approximately 84 days after early allogeneic HCT | 
| Relapse-free Survival (RFS) Among Patients Who Received Early Transplant | Relapse-free survival among patients who received early allogeneic HCT on study as estimated with the Kaplan-Meier method. | Up to 100 days post-transplant | 
| Relapse-free Survival (RFS) Among Patients Who Received Early Transplant | Relapse-free survival among patients who received early allogeneic HCT on study as estimated with the Kaplan-Meier method. | Up to 6 months post-transplant | 
| Event-free Survival (EFS) Among Patients Who Received Early Transplant | Event-free survival among patients who received early allogeneic HCT on study as estimated with the Kaplan-Meier method. Events included death, relapse, and grade 3-4 acute graft vs host disease. | Up to 100 days post-transplant | 
| Event-free Survival (EFS) Among Patients Who Received Early Transplant | Event-free survival among patients who received early allogeneic HCT on study as estimated with the Kaplan-Meier method. Events included death, relapse, and grade 3-4 acute graft vs host disease. | Up to 6 months post-transplant | 
| Overall Survival (OS) Among Patients Who Received Early Transplant. | Overall survival among patients who received early allogeneic HCT on study as estimated with the Kaplan-Meier method. | Up to 100 days post-transplant | 
| Overall Survival (OS) Among Patients Who Received Early Transplant. | Overall survival among patients who received early allogeneic HCT on study as estimated with the Kaplan-Meier method. | Up to 6 months post-transplant | 
| Overall Survival (OS) Among Patients Who Did Not Receive Early Transplant | Overall survival among patients who did not receive early allogeneic HCT on study as estimated with the Kaplan-Meier method. | Up to 100 days after induction day 1 | 
| Overall Survival (OS) Among Patients Who Did Not Receive Early Transplant | Overall survival among patients who did not receive early allogeneic HCT on study as estimated with the Kaplan-Meier method. | Up to 6 months after induction day 1 | 
| Acute Graft Versus Host Disease Among Patients Who Received Early Transplant | Acute graft versus host disease (graded II, III, or IV) among patients who received early allogeneic HCT on study. | At day 100 | 
| Treatment Related Mortality Among Patients Who Received Early Transplant vs Patients Who Did Not Receive Early Transplant | Treatment related mortality calculated among patients who received early allogeneic HCT on study vs patients who did not receive early transplant on study. | At day 100 | 
| Factors That Distinguish Patients Who Received Early Transplant From Those Who Did Not - TREATMENT RELATED MORTALITY | Patients who receive early transplant will be compared to those that don't using the Wilcoxon rank sum test for the quantitative variable of treatment-related mortality (TRM). This outcome measure is intended to report a predicted TRM score assessed at the time of feasibility evaluation. The TRM score is used to measure treatment-related mortality, or likelihood of death within 28 days of initiation of induction chemotherapy for patients with AML. The score is normalized from 0 to 100, so that a score of 0 demonstrates the patient has a very low likelihood of TRM and a score of 100 a very high likelihood of death. A calculation is used to predict TRM using age, performance status, if they have secondary AML, albumin, creatinine, platelet count, white blood cell count, and peripheral blood blast percentage. The higher the TRM score, the higher the risk of TRM. Calculator and table of relationship between TRM score and TRM probability found here: https://trmcalculator.fredhutch.org/. | From time of subject's study enrollment to time of subject's feasibility success assessment (i.e. when subject received transplant within 60 days or when it was determined subject would not proceed with transplant on study) | 
| Factors That Distinguish Patients Who Received Early Transplant From Those Who Did Not - GENDER | Patients who receive early transplant will be compared to those that don't using the Fisher's exact test for the categorical variables of gender. | From time of subject's study enrollment to time of subject's feasibility success assessment (i.e. when subject received transplant within 60 days or when it was determined subject would not proceed with transplant on study) | 
| Factors That Distinguish Patients Who Received Early Transplant From Those Who Did Not - AGE | Patients who receive early transplant will be compared to those that don't using the Wilcoxon rank sum test for the quantitative variable of age. | From time of subject's study enrollment to time of subject's feasibility success assessment (i.e. when subject received transplant within 60 days or when it was determined subject would not proceed with transplant on study) | 
| Demonstrate the Feasibility of Collecting Patient-reported Outcomes for Trial Participants | The amount of returned patient-reported outcome questionnaires will be summarized for each collection timepoint using percent collection from surviving patients for PRO timepoints. | Up to 12 months post-HCT | 
| Demonstrate the Feasibility of Collecting Resource Utilization Data for Trial Participants | The amount of days of hospitalization (the major driver of costs within the first year) will be collected for resource utilization. | Within the first year of induction chemotherapy on study |