Brief Title
CLAG-M 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
Brief Summary
This phase I trial studies the best dose of total body irradiation when given with CLAG-M
<br /> chemotherapy reduced-intensity conditioning regimen before stem cell transplant in treating
<br /> patients with acute myeloid leukemia, myelodysplastic syndrome, or chronic myelomonocytic
<br /> leukemia that has come back (relapsed) or does not respond to treatment (refractory). Giving
<br /> chemotherapy and total body irradiation before a donor peripheral blood stem cell transplant
<br /> helps kill cancer cells in the body and helps make room in the patient's bone marrow for new
<br /> blood-forming cells (stem cells) to grow. When the healthy stem cells from a donor are
<br /> infused into a patient, they may help the patient's bone marrow make more healthy cells and
<br /> platelets and may help destroy any remaining cancer cells. Sometimes the transplanted cells
<br /> from a donor can attack the body's normal cells called graft versus host disease. Giving
<br /> cyclophosphamide, cyclosporine, and mycophenolate mofetil after the transplant may stop this
<br /> from happening.
Detailed Description
OUTLINE: This a dose-escalation study of TBI.
Patients receive filgrastim (G-CSF) subcutaneously (SC) daily on days -9 to -4, cladribine
intravenously (IV) over 2 hours daily on days -8 to -4, cytarabine IV over 2-4 hours daily on
days -8 to -4, and mitoxantrone IV daily on days -8 to -6. If white blood cell (WBC) >
20,000/uL, filgrastim on days -9 and -8 may be omitted at physician discretion. Patients
undergo TBI on either day -1 or 0 and HCT on day 0.
GVHD PROPHYLAXIS: Patients receive cyclophosphamide IV over 1-2 hours daily on days 3-4,
cyclosporine IV over 1-2 hours twice daily (BID) on days 5-60, and mycophenolate mofetil IV
or orally (PO) BID on days 5-28 (transplant with related donors) or three times daily (TID)
on days 5-35 (transplant with unrelated donors). After day 60, patients continue to receive
cyclosporine tapered through day 180 at the discretion of the treating physician in the
absence of GVHD.
After completion of study treatment, patients are followed up at 100 days, at 6, 12, and 24
months post-transplant.
Study Criteria
Inclusion Criteria:
- 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 must be
presented and approved at the Presentation Clinical Case [PCC] conference)
- 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/m^2 per dose) prior to start of study treatment
- Karnofsky score >= 70; Eastern Cooperative Oncology Group (ECOG) 0-1
- Adequate cardiac function defined as absence of decompensated congestive heart failure
and/or uncontrolled arrhythmia and left ventricular ejection fraction >= 45%
- Bilirubin =< 2.5 x institutional upper limit of normal unless elevation is thought to
be due to hepatic infiltration by AML, Gilbert's syndrome, or hemolysis
- Adequate pulmonary function defined as absence of oxygen (O2) requirements and either
carbon monoxide diffusing capability test (DLCO) correct >= 70% mmHg or DLCO corrected
60-69% mmHg and partial pressure of oxygen (pO2) >= 70 mmHg
- Serum creatinine =< 1.5 mg/dL
- Prior autologous HCT is permissible if relapse occurred > 3 months but =< 6 months
after HCT
- Prior TBI-containing allogeneic HCT up to 3 Gy is permissible if > 6 months after HCT
- A human leukocyte antigen (HLA)-matched or near-matched related or unrelated donor or
haploidentical donor for collection of stimulated peripheral blood stem cells must be
identified and readily available
- Women of childbearing potential and men must agree to use adequate contraception
beginning at the signing of the consent until at least 12 months post-transplant
- Patients may have previously received chemotherapy with a mitoxantrone- or
cladribine-based regimen for MDS or AML. If the patient has received CLAG-M before and
has been sensitive to this regimen, eligibility will be determined on a case-by-case
basis by the study principal investigator (PI)
- Ability to understand and sign a written informed consent document (or legal
representative)
- DONOR: Patients must have an HLA-matched related donor or an HLA-matched unrelated
donor, or haploidentical donor who meets standard FHCC and/or National Marrow Donor
Program (NMDP) or other donor center criteria for peripheral blood stem cell (PBSC)
donation as follows:
- Related donor: related to the patient and genotypically or phenotypically
identical for HLA-A, B, C, DRB1 and DQB1. Phenotypic identity must be confirmed
by high-resolution typing
- Unrelated donor:
- Matched for HLA-A, B, C, DRB1 and DQB1 by high resolution typing; OR
- Mismatched for a single allele without antigen mismatching at HLA-A, B, or C
as defined by high resolution typing but otherwise matched for HLA-A, B, C,
DRB1 and DQB1 by high resolution typing
- Donors are excluded when preexisting immunoreactivity is identified that
would jeopardize donor hematopoietic cell engraftment. The recommended
procedure for patients with 10 of 10 HLA allele level (phenotypic) match is
to obtain panel reactive antibody (PRA) screens to class I and class II
antigens for all patients before HCT. If the PRA shows > 10% activity, then
flow cytometric or B and T cell cytotoxic cross matches should be obtained.
The donor should be excluded if any of the cytotoxic cross match assays are
positive. For those patients with an HLA class I allele mismatch, flow
cytometric or B and T cell cytotoxic cross matches should be obtained
regardless of the PRA results. A positive anti-donor cytotoxic crossmatch is
an absolute donor exclusion
- Patient and donor pairs homozygous at a mismatched allele in the graft
rejection vector are considered a two-allele mismatch, i.e., the patient is
A*0101 and the donor is A*0102, and this type of mismatch is not allowed
- Haploidentical donor:
- Donors must be haploidentical relatives of the patients. Donor-recipient
compatibility will be tested through HLA typing at high resolution for the HLA
loci (-A, -B, -C, -DRB1, -DQB1). Donor and recipient should share at least 5/10
HLA loci.
- Age ≥ 12 years
- Weight ≥ 40 kg.
- Ability of donors younger than 18 years of age to undergo apheresis without use
of a vascular access device. Vein check must be performed and verified by an
apheresis nurse prior to arrival.
- Donor must meet the selection criteria as defined by the Foundation of the
Accreditation of Cell Therapy (FACT) and will be screened per the American
Association of Blood Banks (AABB) guidelines.
- In case of more available haploidentical donors, selection criteria should
include, in this order:
- For cytomegalovirus (CMV) seronegative recipients, a CMV seronegative donor
- Red Blood Cell compatibility
- i. RBC cross match compatible
- ii. Minor ABO incompatibility
- iii. Major ABO incompatibility
Exclusion Criteria:
- 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
- Known hypersensitivity or contraindication to any study drug used in this trial
- Pregnancy or lactation
- Concurrent treatment with any other approved or investigational anti-leukemia agent
- Haploidentical donor exclusion criteria:
- Since detection of anti-donor-specific antibodies (anti-DSA) is associated with
higher graft rejection rate, patients will be screened for anti-DSA
pre-transplant. Patient with DSA mean fluorescent intensity (MFI) <5000 after
desensitization treatment, will be considered eligible to participate in the
study.
