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Accelerated Phase Chronic Myelogenous Leukemia, BCR-ABL1 PositivePhase 2NCT02220985

Selective Depletion of CD45RA+ T Cells From Allogeneic Peripheral Blood Stem Cell Grafts From HLA-Matched Related and Unrelated Donors in Preventing GVHD

A Phase 2 study testing Allogeneic Hematopoietic Stem Cell Transplantation, Cyclophosphamide and Fludarabine Phosphate in people with Accelerated Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive and Acute Biphenotypic Leukemia, run by Fred Hutchinson Cancer Center at 2 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial summary

This phase II trial is for patients with acute lymphocytic leukemia, acute myeloid leukemia, myelodysplastic syndrome or chronic myeloid leukemia who have been referred for a peripheral blood stem cell transplantation to treat their cancer. Read more about this study

Who is it for?
Ages Up to 60 yearsHealthy volunteers can take part
What is being tested?
Allogeneic Hematopoietic Stem Cell Transplantation, Cyclophosphamide and Fludarabine Phosphate
Could I receive a placebo?
No, everyone receives an active treatment
How many people
84 participants
Where
2 sitesUnited States
Study dates
23 Mar 2015to 1 May 2025
Phase
Phase 2

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages Up to 60 years
  • All sexes
  • Healthy volunteers accepted
  • Child, Adult

Who may be able to join

  • Patients who are considered appropriate candidates for allogeneic hematopoietic stem cell transplantation and have one of the following diagnoses:
  • Acute lymphocytic leukemia in first or subsequent remission
  • Acute myeloid leukemia in first or subsequent remission
  • Acute lymphocytic leukemia in relapse or primary refractory disease with a circulating blast count of no more than 10,000/mm^3 (Arms A or C only)
  • Acute myeloid leukemia in relapse or primary refractory disease with a circulating blast count of no more than 10,000/mm^3 (Arms A or C only)
  • Refractory anemia with excess blasts (RAEB-1 and RAEB-2) (if the patient has received previous induction chemotherapy within 60 days)
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  • Chronic myelogenous leukemia with a history of accelerated phase or blast crisis (if the patient has received at least one course of induction chemotherapy)
  • Other acute leukemia or related neoplasm (including but not limited to 'biphenotypic', 'undifferentiated' or 'ambiguous lineage' acute leukemia, blastic plasmacytoid dendritic cell neoplasm or lymphoblastic lymphoma)
  • Patients 0-49 years old will be enrolled in Arm A or C (high-intensity)
  • Patients 50-60 years old will be enrolled in Arm B or D (lower intensity); patients eligible for Arms B or D also include those who have received previous allogeneic HCT, or who have co-morbid conditions rendering them unsuitable for high-dose conditioning, determined in consultation with the principal investigator
  • Patient with a HLA-matched (HLA-A, B, C, and DR beta 1 [DRB1] molecularly matched) unrelated donor or related donor capable of donating PBSC
  • DONOR INCLUSION:
  • HLA-matched related donors >= 18 years and capable and willing to donate PBSC (Arms A and B)
  • HLA-matched unrelated donors (HLA-A, B, C, and DRB1 matched based on high-resolution typing) capable and willing to donate PBSC (Arms C and D)

Who cannot join

  • Patients with central nervous system (CNS) involvement refractory to intrathecal chemotherapy and/or standard cranial-spinal radiation
  • Patients on other experimental protocols for prevention of acute GVHD
  • Patient weight >= 100 kg; patients >= 70 kg with MUDs must be discussed with the principal investigator
  • Patients who are human immunodeficiency virus positive (HIV+)
  • Patients with uncontrolled infections for whom myeloablative HCT is considered contraindicated by the consulting infectious disease physician (upper respiratory tract viral infection does not constitute an uncontrolled infection in this context)
  • Patients with organ dysfunction
Show all 26Show fewer
  • ARM A OR C EXCLUSION:
  • Creatinine > 1.5 mg/dl at the present time; patients with a known history of creatinine > 1.5 mg/dl must have a current estimated creatinine clearance of > 40 ml/min
  • Cardiac ejection fraction < 45%
  • Diffusing capacity of the lung for carbon monoxide (DLCO) corrected < 60%; patients who are unable to perform pulmonary function tests (for example, due to young age and/or developmental status) will be excluded if the oxygen (O2) saturation is < 92% on room air
  • Liver function abnormality; patients who have liver function tests (LFTs) (including total bilirubin, aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) >= twice the upper limit of normal should be evaluated by a gastrointestinal (GI) physician; unless there is a clear precipitating factor (such as an azole, methotrexate, Bactrim or another drug); if the GI physician considers that HCT on the high-intensity arms of protocol is contraindicated for that patient the patient may be considered for treatment on the lower intensity arm of the protocol or excluded from the protocol; patients with Gilbert's syndrome and no other known liver function abnormality and patients with reversible drug-related transaminitis do not necessarily require GI consultation and may be included on the high-intensity arms of the protocol
  • ARM B OR D EXCLUSION:
  • Creatinine > 2.0 mg/dl at the present time; patients with a known history of creatinine > 1.5 mg/dl must have a current estimated creatinine clearance > 40 ml/min
  • Cardiac ejection fraction < 35%
  • DLCO corrected < 50%; patients who are unable to perform pulmonary function tests (for example, due to young age and/or developmental status) will be excluded if the O2 saturation is < 92% on room air; patients with a DLCO 50-60% must also have a partial pressure of oxygen (pO2) of > 80 mmHg
  • Liver function abnormality; patients who have LFTs >= twice the upper limit of normal should be evaluated by a GI physician unless there is a clear precipitating factor (such as an azole, methotrexate, Bactrim or another drug); patients with fulminant liver failure, cirrhosis with evidence of portal hypertension or bridging fibrosis, alcoholic hepatitis, esophageal varices, a history of bleeding esophageal varices, hepatic encephalopathy, or correctable hepatic synthetic dysfunction evidenced by prolongation of the prothrombin time, ascites related to portal hypertension, bacterial or fungal abscess, biliary obstruction, chronic viral hepatitis with total serum bilirubin > 3 mg/dL, and symptomatic biliary disease will be excluded
  • Patients will be excluded from Arms A and C if they have received a previous myeloablative transplant; patients who have received a prior HCT at least 6 months prior may be considered for inclusion on Arms B or D after discussion with the principal investigator (PI)
  • Patients with a life expectancy < 3 months from co-existing disease other than the leukemia or RAEB
  • Patients who are pregnant or breast-feeding
  • Fertile patients of child bearing age unwilling to use contraception during and for 12 months post-transplant
  • Patients with a significant other medical conditions that would make them unsuitable for transplant
  • Patients with a known hypersensitivity to tacrolimus, methotrexate (Arm A or C) or MMF (Arm B or D)
  • DONOR EXCLUSION:
  • Donors who are HIV-1, HIV-2, human T-lymphotropic virus (HTLV)-1, HTLV-2 seropositive or with active hepatitis B or hepatitis C virus infection
  • Donors who fail eligibility requirements for donation of cells or tissue for donation of a Human Cell and Tissue Products (HCT/P) will be excluded unless use of the cells complies urgent medical need or allogeneic use in a first-degree or second-degree relative
  • Unrelated donors donating outside of the United States of America (USA)

Trial locations and contacts

2 sites in 1 country.

United States2 sites

  • University of Pittsburgh Cancer Institute (UPCI)

    Pittsburgh, Pennsylvania, 15232

  • Fred Hutch/University of Washington Cancer Consortium

    Seattle, Washington, 98109

Other trials in United States

About this study

Official title: A Phase II Study Evaluating Selective Depletion of CD45RA+ T Cells From Allogeneic Peripheral Blood Stem Cell Grafts From HLA-Matched Related and Unrelated Donors for Prevention of GVHD

This phase II trial is for patients with acute lymphocytic leukemia, acute myeloid leukemia, myelodysplastic syndrome or chronic myeloid leukemia who have been referred for a peripheral blood stem cell transplantation to treat their cancer. In these transplants, chemotherapy and total-body radiotherapy ('conditioning') are used to kill residual leukemia cells and the patient's normal blood cells, especially immune cells that could reject the donor cells. Following the chemo/radiotherapy, blood stem cells from the donor are infused. These stem cells will grow and eventually replace the patient's original blood system, including red cells that carry oxygen to our tissues, platelets that stop bleeding from damaged vessels, and multiple types of immune-system white blood cells that fight infections. Mature donor immune cells, especially a type of immune cell called T lymphocytes (or T cells) are transferred along with these blood-forming stem cells. T cells are a major part of the curative power of transplantation because they can attack leukemia cells that have survived the chemo/radiation therapy and also help to fight infections after transplantation. However, donor T cells can also attack a patient's healthy tissues in an often-dangerous condition known as Graft-Versus-Host-Disease (GVHD). Drugs that suppress immune cells are used to decrease the severity of GVHD; however, they are incompletely effective and prolonged immunosuppression used to prevent and treat GVHD significantly increases the risk of serious infections. Removing all donor T cells from the transplant graft can prevent GVHD, but doing so also profoundly delays infection-fighting immune reconstitution and eliminates the possibility that donor immune cells will kill residual leukemia cells. Work in animal models found that depleting a type of T cell, called naïve T cells or T cells that have never responded to an infection, can diminish GVHD while at least in part preserving some of the benefits of donor T cells including resistance to infection and the ability to kill leukemia cells. This clinical trial studies how well the selective removal of naïve T cells works in preventing GVHD after peripheral blood stem cell transplants. This study will include patients conditioned with high or medium intensity chemo/radiotherapy who can receive donor grafts from related or unrelated donors.

Read the detailed description

OUTLINE: Patients are assigned to 1 of 4 treatment arms.

CONDITIONING:

ARMS A AND C (high-intensity myeloablative conditioning): Patients undergo total body irradiation twice daily (BID) on days -10 to -7. Patients also receive thiotepa intravenously (IV) over 4 hours on days -6 and -5 and fludarabine phosphate IV over 30 minutes on days -6 to -2.

ARMS B AND D (lower-intensity myeloablative conditioning): Patients receive cyclophosphamide IV over 1 hour on day -6, fludarabine phosphate IV over 30 minutes on days -6 to -2, and thiotepa IV over 4 hours on days -5 and -4. Patients also undergo total body irradiation once daily (QD) on days -2 and -1.

TRANSPLANT: In all arms, patients undergo allogeneic HSCT with granulocyte colony-stimulating factor (GCSF)-mobilized CD34-enriched PBSC and CD45RA-depleted cells on day 0.

GVHD PROPHYLAXIS:

ARMS A AND C: Beginning day -1, patients receive tacrolimus IV over 22-24 hours or orally (PO) (BID if given PO) for 50 days with taper in the absence of GVHD. Patients also receive methotrexate IV on days 1, 3, 6, and 11.

ARMS B AND D: Beginning day -1, patients receive tacrolimus IV over 22-24 hours or PO (BID if given PO) for 50 days and mycophenolate mofetil IV and PO every 8 hours on days -3 to approximately day 30, with or without taper at the discretion of the treating physician. Mycophenolate mofetil should be continued or resumed after day 30 if donor chimerism is low, after discussion with the principal investigator.

After completion of study treatment, patients are followed up at 80-100 days, 360 days, and then yearly for up to 5 years.

Being tested
Allogeneic Hematopoietic Stem Cell Transplantation, Cyclophosphamide, Fludarabine Phosphate, Laboratory Biomarker Analysis, Methotrexate
Medical subject headings
Leukemia, Myeloid, Accelerated Phase, Leukemia, Biphenotypic, Acute, Blast Crisis, Blastic Plasmacytoid Dendritic Cell Neoplasm, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Anemia, Refractory, with Excess of Blasts, Leukemia, Myeloid, Acute, Leukemia, Myelogenous, Chronic, BCR-ABL Positive

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Allogeneic Hematopoietic Stem Cell TransplantationProcedure or surgery

    Also called Allogeneic Hematopoietic Cell Transplantation, Allogeneic Stem Cell Transplantation, HSC, HSCT

    Undergo allogeneic HSCT

  • CyclophosphamideDrug

    Also called (-)-Cyclophosphamide, 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate, Carloxan, Ciclofosfamida

    Given IV

  • Fludarabine PhosphateDrug

    Also called 2-F-ara-AMP, 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, Beneflur, Fludara

    Given IV

  • Laboratory Biomarker AnalysisOther

    Correlative studies

  • MethotrexateDrug

    Also called Abitrexate, Alpha-Methopterin, Amethopterin, Brimexate

    Given IV

  • Mycophenolate MofetilDrug

    Also called Cellcept, MMF

    Given IV and PO

  • Peripheral Blood Stem Cell TransplantationProcedure or surgery

    Also called PBPC transplantation, PBSCT, Peripheral Blood Progenitor Cell Transplantation, Peripheral Stem Cell Support

    Undergo PBSCT with GCSF-mobilized CD34-enriched PBSC

  • Peripheral Blood Stem Cell TransplantationProcedure or surgery

    Also called PBPC transplantation, PBSCT, Peripheral Blood Progenitor Cell Transplantation, Peripheral Stem Cell Support

    Undergo PBSCT with CD45RA-depleted cells

  • TacrolimusDrug

    Also called FK 506, Fujimycin, Hecoria, Prograf

    Given IV or PO

  • ThiotepaDrug

    Also called 1,1',1''-Phosphinothioylidynetrisaziridine, Girostan, N,N', N''-Triethylenethiophosphoramide, Oncotiotepa

    Given IV

  • Total-Body IrradiationRadiation

    Also called Total Body Irradiation, Whole-Body Irradiation, TBI, Whole Body Irradiation

    Undergo TBI

Study groups in NCT02220985
Study groupRoleWhat they receive
Arm A (MRD)ExperimentalHIGH-INTENSITY MYELOABLATIVE CONDITIONING: Patients undergo total body irradiation BID on days -10 to -7. Patients also receive thiotepa IV over 4 hours on days -6 and -5 and fludarabine phosphate IV over 30 minutes on days -6 to -2. TRANSPLANT: In all arms, patients undergo allogeneic HSCT with GCSF-mobilized CD34-enriched PBSC and CD45RA-depleted cells on day 0. GVHD PROPHYLAXIS: Beginning day -1, patients receive tacrolimus IV over 22-24 hours or PO (BID if given PO) for 50 days with taper in the absence of GVHD. Patients also receive methotrexate IV on days 1, 3, 6, and 11.
Receives: Procedure: Allogeneic Hematopoietic Stem Cell Transplantation; Drug: Cyclophosphamide; Drug: Fludarabine Phosphate; Other: Laboratory Biomarker Analysis; Drug: Methotrexate; Procedure: Peripheral Blood Stem Cell Transplantation; Drug: Tacrolimus; Drug: Thiotepa; Radiation: Total-Body Irradiation
Arm B (MRD)ExperimentalLOWER-INTENSITY MYELOABLATIVE CONDITIONING: Patients receive cyclophosphamide IV over 1 hour on day -6, fludarabine phosphate IV over 30 minutes on days -6 to -2, and thiotepa IV over 4 hours on days -5 and -4. Patients also undergo total body irradiation QD on days -2 and -1. TRANSPLANT: In all arms, patients undergo allogeneic HSCT with GCSF-mobilized CD34-enriched PBSC and CD45RA-depleted cells on day 0. GVHD PROPHYLAXIS: Beginning day -1, patients receive tacrolimus IV over 22-24 hours or PO (BID if given PO) for 50 days and mycophenolate mofetil IV and PO every 8 hours on day -3 to approximately day 30, with or without taper at the discretion of the treating physician. Mycophenolate mofetil should be continued or resumed after day 30 if donor chimerism is low, after discussion with the Principal Investigator.
Receives: Procedure: Allogeneic Hematopoietic Stem Cell Transplantation; Drug: Cyclophosphamide; Drug: Fludarabine Phosphate; Other: Laboratory Biomarker Analysis; Drug: Mycophenolate Mofetil; Procedure: Peripheral Blood Stem Cell Transplantation; Drug: Tacrolimus; Drug: Thiotepa; Radiation: Total-Body Irradiation
Arm C (MUD)ExperimentalHIGH-INTENSITY MYELOABLATIVE CONDITIONING: Patients undergo total body irradiation BID on days -10 to -7. Patients also receive thiotepa IV over 4 hours on days -6 and -5 and fludarabine phosphate IV over 30 minutes on days -6 to -2. TRANSPLANT: In all arms, patients undergo allogeneic HSCT with G-CSF-mobilized CD34-enriched PBSC and CD45RA-depleted cells on day 0. GVHD PROPHYLAXIS: Beginning day -1, patients receive tacrolimus IV over 22-24 hours or PO (BID if given PO) for 50 days with taper in the absence of GVHD. Patients also receive methotrexate IV on days 1, 3, 6, and 11.
Receives: Procedure: Allogeneic Hematopoietic Stem Cell Transplantation; Drug: Cyclophosphamide; Drug: Fludarabine Phosphate; Other: Laboratory Biomarker Analysis; Drug: Methotrexate; Procedure: Peripheral Blood Stem Cell Transplantation; Drug: Tacrolimus; Drug: Thiotepa; Radiation: Total-Body Irradiation
Arm D (MUD)ExperimentalLOWER-INTENSITY MYELOABLATIVE CONDITIONING: Patients receive cyclophosphamide IV over 1 hour on day -6, fludarabine phosphate IV over 30 minutes on days -6 to -2, and thiotepa IV over 4 hours on days -5 and -4. Patients also undergo total body irradiation QD on days -2 and -1. TRANSPLANT: In all arms, patients undergo allogeneic HSCT with G-CSF-mobilized CD34-enriched PBSC and CD45RA-depleted cells on day 0. GVHD PROPHYLAXIS: Beginning day -1, patients receive tacrolimus IV over 22-24 hours or PO (BID if given PO) for 50 days and mycophenolate mofetil IV and PO every 8 hours on day -3 to approximately day 30, with or without taper at the discretion of the treating physician. Mycophenolate mofetil should be continued or resumed after day 30 if donor chimerism is low, after discussion with the Principal Investigator.
Receives: Procedure: Allogeneic Hematopoietic Stem Cell Transplantation; Drug: Cyclophosphamide; Drug: Fludarabine Phosphate; Other: Laboratory Biomarker Analysis; Drug: Mycophenolate Mofetil; Procedure: Peripheral Blood Stem Cell Transplantation; Drug: Tacrolimus; Drug: Thiotepa

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Chronic GVHD

    Occurrence of chronic graft-versus-host disease (GHVD), defined operationally as the occurrence of compatible symptoms meeting National Institutes of Health criteria and requiring systemic pharmacological immunosuppression.

    Measured: Up to 5 years post-transplant

  2. Time to Completion of Prednisone

    Measure the number of days to discontinuation of prednisone in recipients of CD45RA+ T cell-depleted PBSCT by arm. Possible outcomes range from no systemic immunosuppression (best outcome) to 5 years on immunosuppression (poor outcome)

    Measured: Up to 5 years post-transplant

  3. Time to Completion of All Immunosuppression

    Measure the number of days to discontinuation of all immunosuppression in recipients of CD45RA+ T cell-depleted PBSCT by arm. Possible outcomes range from no systemic immunosuppression (best outcome) to 5 years on immunosuppression (poor outcome)

    Measured: Up to 5 years post-transplant

  4. Requirement of Immunosuppression at 2 Years After Transplant

    Number of patients requiring immunosuppression 2 years after transplant.

    Measured: At 2 years post transplant

  5. Acute GVHD

    Presence of acute graft-versus-host disease (GVHD) grades II-IV, defined operationally as the occurrence of compatible symptoms or signs in the skin, gastrointestinal tract, or liver, in patients who received Naive t cell depleted PBSCT. Staging and grading are found on page 8 of the JCO supplement (Bleakley et al., 2022, original references Glucksberg et all, 1974, Przepiorka et all, 1995 ) with higher grade indicating worse outcomes.

    Measured: Through day 100 post-transplant

  6. Graft Failure

    Defined operationally as failure to reach an absolute neutrophil count (ANC) of > 500/ul for 3 consecutive days by day 28 or irreversible decrease in ANC to < 100 after an established donor graft.

    Measured: Up to 5 years post-transplant

Secondary outcomes (2)

  1. Transplant Related Mortality by Day 100

    Defined as mortality in any patient for whom there has not been a diagnosis of relapse.

    Measured: Through day 100 post-transplant

  2. Relapse

    Defined by the presence of malignant cells in marrow, peripheral blood, or extramedullary sites by histopathology.

    Measured: Up to 5 years post-transplant

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted20 Aug 2014 (estimated)
  2. Study start23 Mar 2015
  3. Primary completion1 Apr 2025
  4. Study completion1 May 2025

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
84 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02220985
Sponsor's protocol ID
2684.00
Other IDs
NCI-2014-01301, 2684.00, R01HL121568, RG9214012, 2P01CA018029
Status last verified
May 2026
First submitted
18 Aug 2014
Last updated
1 Jun 2026
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No

Publications

  • Bleakley M, Sehgal A, Seropian S, Biernacki MA, Krakow EF, Dahlberg A, Persinger H, Hilzinger B, Martin PJ, Carpenter PA, Flowers ME, Voutsinas J, Gooley TA, Loeb K, Wood BL, Heimfeld S, Riddell SR, Shlomchik WD. Naive T-Cell Depletion to Prevent Chronic Graft-Versus-Host Disease. J Clin Oncol. 2022 Apr 10;40(11):1174-1185. doi: 10.1200/JCO.21.01755. Epub 2022 Jan 10.

    PubMed 35007144

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