Comparison of Triple GVHD Prophylaxis Regimens for Nonmyeloablative or Reduced Intensity Conditioning Unrelated Mobilized Blood Cell Transplantation

  • STATUS
    Recruiting
  • End date
    Oct 11, 2026
  • participants needed
    160
  • sponsor
    Fred Hutchinson Cancer Center
Updated on 5 June 2022
cancer
combinations
remission
sirolimus
chronic myeloid leukemia
stem cell transplantation
graft versus host disease
myeloid leukemia
lymphoid leukemia
fludarabine
hematologic malignancy
mycophenolate mofetil
blood stem cell transplant
cyclophosphamide
chronic lymphocytic leukemia
tyrosine
hla-a
lymphoma
multiple myeloma
hodgkin's disease
cyclosporine
acute leukemia
myelodysplasia
rituximab
chronic myelomonocytic leukemia
filgrastim
waldenstrom's macroglobulinemia
granulocyte colony stimulating factor
cell transplantation
myeloablative conditioning
leukemia
pentostatin
hematologic disorder
lymphocytic leukemia
induction chemotherapy
transplant conditioning
drug combinations
myeloproliferative syndromes
autologous transplant
autologous transplantation
blast cells
cladribine
venetoclax
colony stimulating factor
combination chemotherapy
chemotherapy drug
g-csf
autograft
nucleoside analog
prolymphocytic leukemia
chemotherapy drugs
cytogenetic abnormality
recurrent disease
myelomonocytic leukemia
idelalisib
ibrutinib
chronic myelomonocytic leukaemia
salvage therapy
17p deletion
hematologic disease
2-cda
t cell cll
chromosome abnormality
hla class i antigen
t-cell chronic lymphocytic leukemia

Summary

This randomized phase II trial includes a blood stem cell transplant from an unrelated donor to treat blood cancer. The treatment also includes chemotherapy drugs, but in lower doses than conventional (standard) stem cell transplants. The researchers will compare two different drug combinations used to reduce the risk of a common but serious complication called "graft versus host disease" (GVHD) following the transplant. Two drugs, cyclosporine (CSP) and sirolimus (SIR), will be combined with either mycophenolate mofetil (MMF) or post-transplant cyclophosphamide (PTCy). This part of the transplant procedure is the main research focus of the study.

Description

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients undergo allogeneic hematopoietic stem cell transplant (HCT) at day 0. Patients with an HLA-matched unrelated donor receive mycophenolate mofetil orally (PO) on days 0 to 40, cyclosporine PO every 12 hours twice daily (BID) on days -3 to 96 then tapered to day 150, and sirolimus PO once daily (QD) on days -3 to day 150 then tapered to day 180. Patients with an HLA-mismatched donor receive mycophenolate mofetil PO on days 0-100 then tapered to day 150, cyclosporine PO BID on days -3 to 150 then tapered to day 180, and sirolimus PO QD on days -3 to 180 then tapered to day 365.

ARM II: Patients undergo HCT at day 0. Patients with an HLA-matched unrelated donor receive cyclosporine PO BID on days 5-96 then tapered to day 150, sirolimus PO QD on days 5-150 then tapered to day 180, and cyclophosphamide intravenously (IV) on days 3 and 4. Patients with an HLA-mismatched donor receive cyclosporine PO BID on days 5-150 then tapered to day 180, sirolimus PO QD on days 5-180 then tapered to day 365, and cyclophosphamide IV on days 3 and 4.

After completion of study treatment, patients are followed up at 6 months and every year thereafter.

Details
Condition Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia, Aggressive Non-Hodgkin Lymphoma, Chronic Lymphocytic Leukemia, Diffuse Large B-Cell Lymphoma, Mantle Cell Lymphoma, Myelodysplastic Syndrome, Myelodysplastic/Myeloproliferative Neoplasm, Prolymphocytic Leukemia, Recurrent Chronic Lymphocytic Leukemia, Recurrent Chronic Myelogenous Leukemia, BCR-ABL1 Positive, Recurrent Hodgkin Lymphoma, Recurrent Plasma Cell Myeloma, Recurrent Small Lymphocytic Lymphoma, Recurrent Waldenstrom Macroglobulinemia, Hematologic and Lymphocytic Disorder, Blastic Plasmacytoid Dendritic Cell Neoplasm
Treatment cyclophosphamide, cyclosporine, mycophenolate mofetil, allogeneic hematopoietic stem cell transplantation, Sirolimus
Clinical Study IdentifierNCT03246906
SponsorFred Hutchinson Cancer Center
Last Modified on5 June 2022

Eligibility

Yes No Not Sure

Inclusion Criteria

Ages > 50 years with hematologic malignancies treatable by unrelated hematopoietic cell transplant (HCT)
Ages 18-50 years with hematologic diseases treatable by allogeneic HCT who through pre-existing medical conditions or prior therapy are considered to be at high risk for regimen related toxicity associated with a high dose transplant
Ages 18-50 years with chronic lymphocytic leukemia (CLL)
Ages 18-50 years with hematologic diseases treatable by allogeneic HCT who refuse a high-dose HCT; transplants must be approved for these inclusion criteria by the principal investigator
The following diseases will be permitted although other diagnoses can be considered if approved by PCC and the principal investigator
Aggressive non-Hodgkin lymphomas (NHL) and other histologies such as diffuse large B cell NHL- not eligible for autologous HCT, not eligible for high-dose allogeneic HCT, or after failed autologous HCT
Low grade NHL - with < 6 month duration of CR between courses of conventional therapy
Mantle cell NHL - may be treated in first complete remission (CR); (diagnostic lumbar puncture [LP] required pre-transplant)
CLL - must have either 1) failed to meet National Cancer Institute (NCI) Working Group criteria for complete or partial response after therapy with a regimen containing fludarabine (FLU) (or another nucleoside analog, e.g. cladribine [2-CDA], pentostatin) or experience disease relapse within 12 months after completing therapy with a regimen containing FLU (or another nucleoside analog); 2) failed FLU-cyclophosphamide (CY)-rituximab (FCR) combination chemotherapy at any time point; or 3) have "17p deletion" cytogenetic abnormality; patients should have received induction chemotherapy but could be transplanted in 1st CR; or 4) patients with a diagnosis of CLL (or small lymphocytic lymphoma) or diagnosis of CLL that progresses to prolymphocytic leukemia (PLL), or T-cell CLL or PLL; 5) patients failing to achieve a response to ibrutinib as first-line therapy; 6) patients not responding to ibrutinib, idelalisib, or venetoclax as salvage therapy or intolerant of these agents as salvage therapy due to side effects; all CLL patients must have received prior myelosuppressive chemotherapy
Hodgkin lymphoma - must have received and failed frontline therapy
Multiple myeloma - must have received prior chemotherapy; consolidation of chemotherapy by autografting prior to nonmyeloablative HCT is permitted
Acute myeloid leukemia (AML) - must have < 5% marrow blasts at the time of transplant
Acute lymphocytic leukemia (ALL) - must have < 5% marrow blasts at the time of transplant
Chronic myeloid leukemia (CML) - patients in CP1 must have failed or be intolerant of tyrosine kinase inhibitors (TKIs); patients beyond CP1 will be accepted if they have < 5% marrow blasts at time of transplant
Myelodysplasia (MDS)/myeloproliferative syndrome (MPS)/chronic myelomonocytic leukemia (CMML) - patients must have < 5% marrow blasts at time of transplant
Waldenstrom's macroglobulinemia - must have failed 2 courses of therapy
Mixed Phenotype Acute Leukemia (MPAL) - must have < 5% marrow blasts at the time of transplant
Matched for HLA-A, B, C, DRB1 and DQB1 by high resolution typing
Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) - must be in complete remission at the time of transplant
Only a single allele disparity will be allowed for HLA-A, B, or C as defined by high resolution typing
HLA-MATCHED UNRELATED DONOR: FHCRC matching allowed will be grades 1.0 to 2.1
HLA-MATCHED UNRELATED DONOR: 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
unrelated donors who are prospectively
HLA-MATCHED UNRELATED DONOR: Only granulocyte colony-stimulating factor (G-CSF) mobilized PBSC will be permitted as a HSC source on this protocol
HLA-MISMATCHED UNRELATED DONOR: Unrelated volunteer donors who are mismatched with the recipient within one of the following limitations
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
HLA-MATCHED UNRELATED DONOR: Donors are excluded when preexisting immunoreactivity is
Mismatched for two HLA class I alleles, but matched for HLA-DRB1 and HLA-DQ
identified that would jeopardize donor hematopoietic cell engraftment; this
HLA class I HLA-A, -B, -C allele matched donors allowing for any one or two DRB1 and/or DQB1 antigen/allele mismatch
determination is based on the standard practice of the individual institution
the recommended procedure for patients with 10 of 10 HLA allele level
HLA-MISMATCHED UNRELATED DONOR: 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, A02:01); this mismatch will be considered a one-antigen mismatch for rejection only
(phenotypic) match is to obtain a panel reactive antibody (PRA) screens to
class I and class II antigens for all patients before HCT; if the PRA shows >
% 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
HLA-MISMATCHED UNRELATED DONOR: HLA-matching must be based on results of high
resolution typing at HLA-A, -B, -C, - DRB1, and -DQ

Exclusion Criteria

Patients with rapidly progressive intermediate or high grade NHL
Patients with a diagnosis of chronic myelomonocytic leukemia (CMML) who have not received induction chemotherapy
CNS involvement with disease refractory to intrathecal chemotherapy
Presence of >= 5% circulating leukemic blasts (in the blood) detected by standard pathology for patients with MDS/MPS/CMML
Fertile men or women unwilling to use contraceptive techniques during and for 12 months following treatment
Females who are pregnant or breast-feeding
Patients with active non-hematological malignancies (except non-melanoma skin cancers) or those with non-hematological malignancies (except non-melanoma skin cancers) who have been rendered with no evidence of disease, but have a greater than 20% chance of having disease recurrence within 5 years; this exclusion does not apply to patients with non-hematologic malignancies that do not require therapy
Fungal infections with radiological progression after receipt of amphotericin B or active triazole for greater than 1 month
Organ dysfunction
Cardiac ejection fraction < 35% (or, if unable to obtain ejection fraction, shortening fraction of < 26%); ejection fraction is required if age > 50 years or there is a history of anthracycline exposure or history of cardiac disease; patients with a shortening fraction < 26% may be enrolled if approved by a cardiologist
Pulmonary
Diffusing capacity of the lungs for carbon monoxide (DLCO) < 40%, forced
expiratory volume in the first second of breath (FEV1) < 40% and/or receiving
supplementary continuous oxygen; when pulmonary function tests (PFTs) cannot
be obtained, the 6-minute walk test (6MWT, also known as exercise oximetry)
Patients with MDS-EB or AML who have not received myelosuppressive chemotherapy i.e. induction chemotherapy or at least 4 cycles of a venetoclax-containing regimen will be excluded from Regimen B conditioning (Fludarabine and total body irradiation [TBI])
The FHCRC PI of the study must approve of enrollment of all patients with pulmonary nodules
will be used: Any patient with oxygen saturation on room air of < 89% during a
MWT will be excluded
Presence of circulating blasts determined to be associated with disease (in the blood) for patients with AML, ALL or CML
Karnofsky scores < 60
Patient has poorly controlled hypertension and on multiple antihypertensives
Human immunodeficiency virus (HIV) positive patients
Active bacterial or fungal infections unresponsive to medical therapy
The addition of cytotoxic agents for "cytoreduction" with the exception of tyrosine kinase inhibitors (such as imatinib), cytokine therapy, hydroxyurea, low dose cytarabine, chlorambucil, or Rituxan will not be allowed within three weeks of the initiation of conditioning
Patients on hemodialysis
DONOR: Donor (or centers) who will exclusively donate marrow
DONOR: Donors who are HIV-positive and/or, medical conditions that would result in increased risk for G-CSF mobilization and harvest of peripheral blood stem cell (PBSC)
DONOR: Patients who are homozygous at the mismatched HLA class I or II locus, the donor is excluded if homozygous at the mismatched locus (i.e., patient is homozygous A 01:01 and donor is homozygous A 02:01); this type of mismatch is considered a two-antigen mismatch and is not allowed
Liver function abnormalities: Patients with clinical or laboratory evidence of liver
disease would be evaluated for the cause of liver disease, its clinical
severity in terms of liver function, and the degree of portal hypertension
patients will be excluded if they are found to have fulminant liver failure
cirrhosis of the liver with evidence of portal hypertension, alcoholic
hepatitis, esophageal varices, a history of bleeding esophageal varices
hepatic encephalopathy, uncorrectable hepatic synthetic dysfunction evinced by
prolongation of the prothrombin time, ascites related to portal hypertension
bridging fibrosis, bacterial or fungal liver abscess, biliary obstruction
chronic viral hepatitis with total serum bilirubin > 3 mg/dL, or symptomatic
biliary disease
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