CLAG-M or FLAG-Ida Chemotherapy and Reduced-Intensity Conditioning Donor Stem Cell Transplant for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia, Myelodysplastic Syndrome, or Chronic Myelomonocytic Leukemia
This phase I trial studies the best dose of total body irradiation when given with cladribine, cytarabine, filgrastim, and mitoxantrone (CLAG-M) or idarubicin, fludarabine, cytarabine and filgrastim (FLAG-Ida) chemotherapy reduced-intensity conditioning regimen before stem cell transplant in treating patients with acute myeloid leukemia, myelodysplastic syndrome, or chronic myelomonocytic leukemia that has come back (relapsed) or does not respond to treatment (refractory). Giving chemotherapy and total body irradiation before a donor peripheral blood stem cell transplant helps kill cancer cells in the body and helps make room in the patient's bone marrow for new blood-forming cells (stem cells) to grow. When the healthy stem cells from a donor are infused into a patient, they may help the patient's bone marrow make more healthy cells and platelets and may help destroy any remaining cancer cells. Sometimes the transplanted cells from a donor can attack the body's normal cells called graft versus host disease. Giving cyclophosphamide, cyclosporine, and mycophenolate mofetil after the transplant may stop this from happening.
Eligibility criteria
This trial does not accept healthy volunteers
Qualifiers
Age >= 18 years with an Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI) =< 5 for patients over 60 years -(Enrollment of patients >= 75 years of age will require case presentation at the transplant Patient Care Conference (PCC) and approval by consensus)
Acute myeloid leukemia (AML) (2016 World Health Organization [WHO] criteria) that is either primary refractory (as defined by failure of 2 cycles of 7+3-like chemotherapy, 1 cycle of high-dose cytarabine-based chemotherapy, or at least 2 cycles of venetoclax in combination with other therapies), or is in untreated or unsuccessfully treated first or subsequent relapse. Patients in morphological remission (i.e. < 5% blasts in the bone marrow) but evidence of minimal residual disease (MRD) by multiparameter flow cytometry, cytogenetics/fluorescence in situ hybridization (FISH), or molecular means will be eligible for trial participation. Patients with relapsed or refractory acute leukemia of ambiguous lineage (acute undifferentiated leukemia, mixed phenotype acute leukemia) that is either primary refractory or is in untreated or unsuccessfully treated first or subsequent relapse are also eligible
Subjects with previously treated myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML), defined as prior treatment with at least one hypomethylating agent (HMA; azacitidine and/or decitabine) whose disease progressed, relapsed, or was refractory to HMA treatment as follows: 1) patients who have failed at least 4 cycles of monotherapy with azacitidine or decitabine, 2) patients who received at least 2 cycles of HMA in combination with another therapeutic agent. Subjects with MDS and CMML who failed at least 1 cycle of induction chemotherapy will be also eligible
The use of hydroxyurea prior to initiation of study treatment is allowed. Patients with symptoms/signs of hyperleukocytosis, WBC > 100,000/uL or with concern for other complications of high tumor burden (e.g. disseminated intravascular coagulation) can be treated with leukapheresis or may receive up to 2 doses of cytarabine (up to 500 mg/m² per dose) prior to start of study treatment
Disqualifiers
Patients >= 18 years being treated at Seattle Children's Hospital
Active central nervous system (CNS) disease
Concomitant illness associated with a likely survival of < 1 year
Active systemic fungal, bacterial, viral, or other infection, unless disease is under treatment with anti-microbials and/or controlled or stable. Patients with fever thought to be likely secondary to myeloid malignancy are eligible
Trial design
Design model
Parallel
Treatments tested in this trial
Cladribine
Drug
Given IV
Cyclophosphamide
Drug
Given IV
Cyclosporine
Drug
Given IV then PO
Cytarabine
Drug
Given IV
Filgrastim
Biological/Vaccine
Given SC
Hematopoietic Cell Transplantation
Procedure/Surgery
Undergo HCT
Mitoxantrone
Drug
Given IV
Mycophenolate Mofetil
Drug
Given IV or PO
Mycophenolate Sodium
Drug
Given PO
Total-Body Irradiation
Radiation
Undergo TBI
Idarubicin
Drug
Given IV
Fludarabine
Drug
Given IV
Cytarabine
Drug
Given IV
Multigated Acquisition Scan
Procedure/Surgery
Undergo MUGA
Echocardiography Test
Procedure/Surgery
Undergo ECHO
X-Ray Imaging
Procedure/Surgery
Undergo x-ray
Bone Marrow Biopsy
Procedure/Surgery
Undergo bone marrow biopsy and aspirate
Bone Marrow Aspiration
Procedure/Surgery
Undergo bone marrow biopsy and aspirate
Biospecimen Collection
Procedure/Surgery
Undergo blood sample collection
Treatment groups
120 Participants
are divided into 2 treatment groups
Group A: Arm I (CLAG-M, TBI, HCT, GVHD prophylaxis)Experimental treatment 16 interventions
Group B: Arm II (FLAG-Ida, TBI, HCT, GVHD prophylaxis)Experimental treatment 15 interventions
Trial outcomes
Primary outcomes
1
Rate of hematopoietic cell transplantation (HCT) failure
Defined as graft rejection (\< 5% donor T-cell chimerism).
Time frame
Within 200 days post-transplant
2
Rate of disease progression
Defined by European LeukemiaNet (ELN) 2017 criteria and International Working Group (IWG).
Time frame
Within 200 days post-transplant
Secondary outcomes
1
Incidence of adverse events
Time frame
Up to 100 days post-transplant
2
Rates of stem cell engraftment and donor chimerism
Time frame
At 80 days (+/- 7 days)
3
Rates of grades II-IV acute graft versus host disease (GVHD) and chronic GVHD requiring systemic immunosuppressive treatment
Time frame
Up to 2 years
4
Disease response
Time frame
Up to 2 years
Other outcomes
Sponsors and contacts
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