Brief Title
Donor Stem Cell Transplant With Treosulfan, Fludarabine, and Total-Body Irradiation for the Treatment of Hematological Malignancies
Official Title
Hematopoietic Stem Cell Transplantation From Haploidentical Donors in Patients With Hematological Malignancies Using a Treosulfan-Based Preparative Regimen
Brief Summary
This phase II trial studies how well a donor stem cell transplant, treosulfan, fludarabine,
and total-body irradiation work in treating patients with blood cancers (hematological
malignancies). Giving chemotherapy and total-body irradiation before a donor stem cell
transplant helps stop the growth of cells in the bone marrow, including normal blood-forming
cells (stem cells) and cancer cells. It may also 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. The donated stem cells may also replace the patient's immune
cells and help destroy any remaining cancer cells.
Detailed Description
OUTLINE: Patients are assigned to 1 of 2 arms.
ARM A (HIGH DOSE TREOSULFAN): Patients receive high dose treosulfan intravenously (IV) over
120 minutes on days -6 to -4 and fludarabine IV over 60 minutes on days -6 to -2. Patients
then undergo total-body irradiation on day -1 and allogeneic hematopoietic stem cell
transplantation on day 0. Patients then receive cyclophosphamide IV over 1-2 hours on days
3-4. Beginning on day 5, patients receive cyclosporine IV twice daily (BID) or three times
daily (TID) over 1-2 hours or orally (PO) (after 3 months, in the absence of GVHD,
cyclosporine tapering will start by 5-10% per week, until drug withdrawal at 6 months
post-transplant). Beginning on day 5, patients also receive mycophenolate sodium PO TID or
mycophenolate mofetil IV or PO TID until day 35 (may be continued if active GVHD is present).
Beginning on day 5, patients also receive filgrastim until the absolute neutrophil count is >
1,000/uL for 3 consecutive days.
ARM B (LOW DOSE TREOSULFAN): Patients receive low dose treosulfan IV over 120 minutes on days
-6 to -4 and fludarabine IV over 60 minutes on days -6 to -2. Patients then undergo
total-body irradiation and allogeneic hematopoietic stem cell transplantation, and receive
cyclophosphamide, cyclosporine, mycophenolate sodium or mycophenolate mofetil, and filgrastim
as in Arm A.
After completion of transplant, patients are followed up at 28, 56, 84, 365, and 730 days.
Study Phase
Phase 2
Study Type
Interventional
Primary Outcome
Graft failure/rejection
Secondary Outcome
Overall survival
Condition
Acute Leukemia
Intervention
Allogeneic Hematopoietic Stem Cell Transplantation
Study Arms / Comparison Groups
Arm A (high dose treosulfan)
Description: Patients receive high dose treosulfan IV over 120 minutes on days -6 to -4 and fludarabine IV over 60 minutes on days -6 to -2. Patients then undergo total-body irradiation on day -1 and allogeneic hematopoietic stem cell transplantation on day 0. Patients then receive cyclophosphamide IV over 1-2 hours on days 3-4. Beginning on day 5, patients receive cyclosporine IV BID or TID over 1-2 hours or PO (after 3 months, in the absence of GVHD, cyclosporine tapering will start by 5-10% per week, until drug withdrawal at 6 months post-transplant). Beginning on day 5, patients also receive mycophenolate sodium PO TID or mycophenolate mofetil IV or PO TID until day 35 (may be continued if active GVHD is present). Beginning on day 5, patients also receive filgrastim until the absolute neutrophil count is > 1,000/uL for 3 consecutive days.
Publications
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Recruitment Information
Recruitment Status
Procedure
Estimated Enrollment
60
Start Date
January 25, 2021
Completion Date
December 31, 2025
Primary Completion Date
December 31, 2023
Eligibility Criteria
Inclusion Criteria:
- Acute leukemia (AL) that includes acute myeloid leukemia (AML) / acute lymphoblastic
leukemia (ALL) / mixed phenotype leukemia (MPAL) in complete morphological remission
(CR) with or without detectable minimal residual disease (MRD); complete morphological
remission is defined by the presence of less than 5% of detectable blasts in bone
marrow specimen, evaluated per standard of care. Patients with documented CR but
without hematologic recovery since last chemotherapy are considered eligible to the
study
- Chronic myelogenous leukemia (CML), except refractory blast crisis. To be eligible in
first chronic phase, patients must have failed or be intolerant to at least one
tyrosine-kinase inhibitor
- Chronic myelomonocytic leukemia (CMML)
- Myelodysplastic syndromes (MDS)
- Lymphoblastic, Burkitt's and other high-grade lymphoma in any complete (CR) or partial
(PR) response
- CR and PR are defined according to Lugano classification: Recommendations for
Initial Evaluation, Staging, and Response Assessment of Hodgkin and Non-Hodgkin
Lymphoma: The Lugano Classification
- Low grade lymphoma (chronic lymphocytic leukemia [CLL]/small lymphocytic lymphoma
[SLL], marginal zone lymphoma, follicular lymphoma) progressed after two treatment
regimens, in CR/PR
- For CLL/SLL, CR and PR are defined according to: International Workshop on CLL
(iwCLL) guidelines for diagnosis, indications for treatment, response assessment,
and supportive management of CLL
- CR and PR are defined according to Lugano classification: Recommendations for
Initial Evaluation, Staging, and Response Assessment of Hodgkin and Non-Hodgkin
Lymphoma: The Lugano Classification
- Large cell lymphoma in > second CR (CR2)/ >= PR2
- CR and PR are defined according to Lugano classification: Recommendations for
Initial Evaluation, Staging, and Response Assessment of Hodgkin and Non-Hodgkin
Lymphoma: The Lugano Classification
- Mantle cell lymphoma, lymphoplasmacytic lymphoma and prolymphocytic leukemia may be
eligible after initial therapy if in CR/PR
- CR and PR are defined according to Lugano classification: Recommendations for
Initial Evaluation, Staging, and Response Assessment of Hodgkin and Non-Hodgkin
Lymphoma: The Lugano Classification
- For prolymphocytic leukemia (PLL), CR is defined as a normalization of
lymphadenopathies (long-axis diameter < 1 cm) and splenomegaly (< 13 cm), absence
of constitutional symptoms, PLL cells < 5% in bone marrow and circulating
lymphocytes count < 4 x 10^9/L. Patients without hematopoietic recovery are
considered eligible to the study. PR is defined as a decrease of >= 30% of the
sum of lymphadenopathies' long-axis diameters, a decrease of >= 50% in spleen
vertical length beyond normal from baseline, peripheral blood (PB) lymphocytes =<
30 x 10^9/L (and a decrease of >= 50% from baseline)
- Hodgkin Lymphoma in > CR2/PR2
- CR and PR are defined according to Lugano classification: Recommendations for
Initial Evaluation, Staging, and Response Assessment of Hodgkin and Non-Hodgkin
Lymphoma: The Lugano Classification
- Subjects must be >= 6 months old
- Karnofsky >= 70 or Eastern Cooperative Oncology Group (ECOG) 0-1 (for adults)
- Lansky score >= 50 (for children)
- Adequate cardiac function defined as absence of decompensated congestive heart failure
or uncontrolled arrhythmia AND left ventricular ejection fraction >= 40% or shortening
fraction > 22%
- Adequate pulmonary function defined as absence of oxygen (O2) requirements and one of
the following:
- Diffusion capacity of the lung for carbon monoxide (DLCO) corrected >= 70% mm Hg
- DLCO corrected between 60% - 69% mm Hg and partial pressure of oxygen (pO2) >= 70
mm Hg
- DLCO corrected between 50% - 59% mm Hg and pO2 >= 80 mm Hg Pediatric patients
unable to perform pulmonary function tests must have O2 saturation >= 92% on room
air. May not be on supplemental oxygen
- Total bilirubin < 2 x upper limit of normal (ULN) unless felt to be related to
Gilbert's disease or hemolysis
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN
- Alkaline phosphatase =< 5 x ULN
- Creatinine < 2.0 mg/dl (adults) or estimated creatinine clearance > 40 ml/min
(pediatrics)
- All adults with a creatinine > 1.2 or a history of renal dysfunction must have
estimated creatinine clearance > 40 ml/min
- If recent mold infection, e.g., aspergillus, must be cleared by infectious disease to
proceed
- Patients who have undergone prior allogeneic hematopoietic cell transplant are
eligible, but the prior transplant must have been performed at least 3 months prior to
enrollment, unless in case of graft failure from the prior transplant
- Written and signed informed consent
- 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
- DONOR: Age >= 12 years
- DONOR: Weight >= 40 Kg
- DONOR: 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: Donor must meet 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
- DONOR: 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
- Red blood cell (RBC) cross match compatible
- Minor ABO incompatibility
- Major ABO incompatibility
Exclusion Criteria:
- Active, uncontrolled, life-threatening viral, bacterial or fungal infection requiring
treatment at time of conditioning regiment administration and transplantation
- Presence of a malignancy other than the one for which the transplant is being
performed, with an expected survival less than 75% at 5 years
- Pregnant or breastfeeding
- Known hypersensitivity to treosulfan, fludarabine or cyclophosphamide
- Dosing with another investigational agent within 30 days prior to entry in the study
- Central nervous system (CNS) leukemic involvement not clearing with intrathecal
chemotherapy and/or cranial radiation prior to initiation of conditioning (day -6)
- DONOR: Since detection of anti-donor-specific-antigen antibodies (anti-DSA) is
associated with higher graft rejection rate, patients will be screened for anti-DSA
pre-transplant. Patients with DSA mean fluorescent intensity (MFI) < 5000 after
desensitization treatment, will be considered eligible to participate in the study.
The first 10 subjects enrolled in the trial will be DSA-negative.
Gender
All
Ages
6 Months - N/A
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Contacts
Filippo Milano, 206.667.5925, [email protected]
Location Countries
United States
Location Countries
United States
Administrative Informations
NCT ID
NCT04195633
Organization ID
RG1005742
Secondary IDs
NCI-2019-07697
Responsible Party
Sponsor
Study Sponsor
Fred Hutchinson Cancer Center
Collaborators
medac GmbH
Study Sponsor
Filippo Milano, Principal Investigator, Fred Hutch/University of Washington Cancer Consortium
Verification Date
October 2022