Graft Versus Host Disease-Reduction Strategies for Donor Blood Stem Cell Transplant Patients with Acute Leukemia
- Patients who are considered appropriate candidates for myeloablative, TBI-containing allogeneic hematopoietic stem cell transplantation and have one of the following diagnoses: * Acute lymphocytic leukemia (ALL) in first or subsequent morphological remission (< 5% marrow blasts by morphology). * Acute myeloid leukemia (AML) in first or subsequent morphological remission (< 5% marrow blasts by morphology). * Other acute leukemia or related neoplasm (including but not limited to ‘mixed phenotype’ ‘biphenotypic’, ‘acute undifferentiated’ or ‘ambiguous lineage’ acute leukemia, blastic plasmacytoid dendritic cell neoplasm or lymphoblastic lymphoma) in first or subsequent morphological remission (< 5% marrow blasts by morphology).
- Patient with an HLA-matched (HLA-A, B, C, DRB1, and DQB1 matched) related or unrelated donor capable of donating PBSC.
- Recipient informed consent/assent and/or legal guardian permission must be obtained.
- DONOR: HLA-matched related and unrelated donors (HLA-A, B, C, DRB1 and DQB1 matched based on high-resolution typing).
- DONOR: >= 18 years old.
- DONOR: Willing to donate PBSC.
- DONOR: Matched related donors: * Must give informed consent using the related donor informed consent form. * Must meet institutional donor eligibility criteria or be ineligible with statement that the donor is a first or second degree relative (exception 21 CRF 1271.65(b)(i)).
- DONOR: Matched unrelated donors: * Must consent according to the applicable National Marrow Donor Program (NMDP) donor regulatory requirements. * Must meet eligibility criteria as defined by the NMDP or be ineligible with statement of urgent medical need (exception 21 CRF 1271.65(b)(iii)).
- Patients with central nervous system (CNS) involvement refractory to intrathecal chemotherapy and/or standard cranial-spinal radiation. A patient may have a history of CNS disease. However, any CNS disease must be cleared by the end of the pre-conditioning evaluation time frame. If CNS disease is identified on cerebrospinal fluid (CSF) evaluation within 30 days of the start of the preparative regimen a repeat CSF evaluation must be performed and show no evidence of disease in order for the patient to be eligible for the protocol.
- Patients on other experimental protocols for prevention of GVHD.
- Patient weight: * Patients with HLA-matched related donors will be excluded if they weigh >= 100 kg. * Patients with HLA-matched unrelated donors will be excluded if they weigh >= 100 kg and must be discussed with the Fred Hutch protocol principal investigator (PI) if they weigh >= 80 kg.
- Patients who are positive for human immunodeficiency virus (HIV)-1, HIV-2, human T-cell lymphotropic virus (HTLV)1 or HTLV2.
- Patients with uncontrolled infections for whom myeloablative HCT is considered contraindicated by the consulting infectious disease physician; i.e. patients with active infections require infectious disease consultation and documentation by the infectious disease team that myeloablative HCT is not considered to be contraindicated. Upper respiratory tract infection is not considered to represent an uncontrolled infection in this context.
- Patients with organ dysfunction, including: * Renal insufficiency (creatinine > 1.5 mg/dl) at the time of evaluation for the protocol. Patients with a known history of creatinine > 1.5 mg/dl or a current serum creatinine above the normal range for age must have a current creatinine clearance of > 60 ml/min/1.73 m^2 (measured by 24-hr urine specimen or nuclear glomerular filtration rate [GFR]). * Left ventricular ejection fraction < 45%. * Carbon monoxide diffusing capability (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 test (LFT)s (specifically, total bilirubin, aspartate aminotransferase [AST] or 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, MTX, trimethoprim-sulfamethoxazole, or another drug). If the GI physician considers that HCT on the protocol is contraindicated, that patient will be excluded from the protocol. Patients with Gilbert’s syndrome and no other known liver function abnormality or with reversible drug-related transaminitis do not necessarily require GI consultation and may be included on the protocol.
- Patients who have received previous myeloablative allogeneic or autologous transplantation.
- Patients with a life expectancy < 12 months from co-existing disease other than the leukemia.
- Patients who are pregnant or breast-feeding.
- Patients of childbearing age who are presumed to be fertile and are unwilling to use an effective birth control method or refrain from sexual intercourse during and for 12 months post-HCT.
- Patients with any other significant medical conditions that would make them unsuitable for transplantation, as determined by the PI.
- Patients with a known hypersensitivity to tacrolimus or MTX.
- DONOR: Donors who are HIV-1, HIV-2, HTLV-1, HTLV-2 seropositive or with active hepatitis B or hepatitis C virus infection. Test must be performed using Food and Drug Administration (FDA) licensed, cleared, and approved test kits (serological and/or nucleic acid amplification test [NAT] and/or other approved testing) in a Clinical Laboratory Improvement Act (CLIA)-certified laboratory.
- DONOR: Unrelated donors donating outside of the United States of America (USA).
I. To estimate the rate of clinically significant graft versus host disease (GVHD)-free relapse-free survival (GRFS) at 2 years in patients treated with peripheral blood stem cell transplantation (PBSCT) and Tn cell depletion (TND), tacrolimus, and methotrexate (MTX) (Arm A); CD34+ selection and anti-thymocyte globulin (ATG) (Arm B); post-PBSCT cyclophosphamide (PTCy) and tacrolimus (Arm C); or tacrolimus and MTX (Arm D).
II. To determine whether GRFS may be higher in patients who receive treatment on Arms A, B, or C compared to Arm D.
I. To estimate the rate of overall survival (OS).
II. To estimate the rate of relapse.
III. To estimate the proportion of patients alive and off prednisone (or equivalent systemic corticosteroid) for treatment of GVHD at 3, 6, 9, 12, 15, 18, 21, 24 months post hematopoietic cell transplantation (HCT).
IV. To estimate the rate of chronic (c)GVHD (meeting National Institutes of Health [NIH]-criteria, requiring systemic immunosuppressive drugs [IS]) and the rate of cGVHD requiring IS of specific grades (a. mild; b. moderate; c. severe).
I. To estimate the frequency of graft rejection or irreversible graft failure after PBSCT in the four study arms.
TERTIARY AND EXPLORATORY OBJECTIVES:
I. To estimate chronic GVHD-free, relapse-free survival (CRFS) (cGVHD free relapse-free survival at 2 years) (NIH-criteria, moderate and severe, requiring IS).
II. To estimate current GVHD relapse-free survival at 1 year (success = survival at 1 year, with no graft failure/rejection, relapse, or current GVHD of any sort requiring prednisone/other corticosteroid).
III. To estimate grade II-IV acute (a)GVHD.
IV. To estimate grade III-IV aGVHD.
V. To estimate relapse-free survival (RFS).
VI. To estimate non-relapse mortality (NRM).
VII. To estimate the proportion of patients alive and off prednisone or on > 0 to < 0.5 mg/kg prednisone (or equivalent systemic corticosteroid) for treatment of GVHD at 3, 6, 9, 12, 15, 18, 21, 24 months post HCT.
VIII. To estimate dose of prednisone at day 90.
IX. To estimate days alive out of hospital in first year.
X. To estimate infections.
XI. To estimate lymphocyte reconstitution.
XII. To estimate T cell receptor (TCR) sequence analysis (including productive clonality CD8+, CD4+ at day [d]80-100, 180, 270, 365, 2 years).
XIII. To estimate peripheral blood chimerism (CD3 >= 90%, 50-89%, < 50% and CD33 >= 90%, < 90% at d28, 56, 80-100, 180, 270, 365, 2 years).
XIV. To estimate GVHD biomarkers as predictors of severe GVHD, including but not limited to REG3a (acute gastrointestinal), ST2 (acute and chronic).
XV. To estimate clinical manifestations consistent with immune dysregulation other than GVHD (type 1 diabetes mellitus, Grave’s disease, immune-mediated cytopenias, other).
XVI. To estimate transplant-associated thrombotic microangiopathy (TA-TMA).
XVII. To estimate new symptomatic chronic lung disease requiring oxygen.
XVIII. To estimate patient-reported outcomes (PRO).
OUTLINE: Patients are randomized to 1 of 4 arms.
ARM A: Patients undergo total-body irradiation (TBI) twice daily (BID) on days -10 to -7, and receive thiotepa intravenously (IV) over 4 hours on days -6 and -5, fludarabine IV over 30 minutes on days -6 to -2, tacrolimus (or cyclosporine or sirolimus if toxicities occur) IV continuously starting on day -1, CD34+ enriched CD45RA-depleted donor T-lymphocytes IV on day 0, and methotrexate IV on days 1, 3, 6, and 11. If there is no evidence of grade II-IV acute GVHD on or prior to day 50, tacrolimus (or cyclosporine or sirolimus) is tapered per month for capsules (or per week for liquid).
ARM B: Patients undergo TBI BID on days -9 to -6, and receive thiotepa IV over 4 hours on days -5 and -4, anti-thymocyte globulin IV over 6-8 hours on days -4 and -3, cyclophosphamide IV over 1 hour on days -3 and -2, and CD34+ enriched PBSC IV on day 0.
ARM C: Patients undergo TBI BID on days -4 to -2 or -3 to -1, and receive PBSC IV on day 0. Patients also receive cyclophosphamide IV over 1 hour on days 3 and 4, and tacrolimus (or cyclosporine or sirolimus if toxicities occur) IV continuously starting on day 5. If there is no evidence of grade II-IV acute GVHD on or prior to day 50, tacrolimus (or cyclosporine or sirolimus) is tapered per month for capsules (or per week for liquid).
ARM D: Patients undergo TBI BID on days -6 to -4, and receive cyclophosphamide IV over 1 hour on days -3 to -2, tacrolimus (or cyclosporine or sirolimus if toxicities occur) IV continuously starting on day -1, PBSC IV on day 0, and methotrexate IV on days 1, 3, 6, and 11. If there is no evidence of grade II-IV acute GVHD on or prior to day 50, tacrolimus (or cyclosporine or sirolimus) is tapered per month for capsules (or per week for liquid).
After completion of study treatment, patients are followed up at days 7, 14, 21, 28, 56, 80, 180, and 270 and at 1, 1.5, and 2 years.
Trial Phase Phase II
Trial Type Treatment
Fred Hutch / University of Washington Cancer Consortium
- Primary ID RG1005364
- Secondary IDs NCI-2019-03188, 9749
- Clinicaltrials.gov ID NCT03970096