Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia, Aggressive Non-Hodgkin Lymphoma, Blastic Plasmacytoid Dendritic Cell Neoplasm, Chronic Lymphocytic Leukemia, Diffuse Large B-Cell Lymphoma, Hematologic and Lymphocytic Disorder, Mantle Cell Lymphoma, Myelodysplastic/Myeloproliferative Neoplasm, Myelodysplastic Syndrome, 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
Conditions
Brief 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.
Detailed 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.
Interventions
PROCEDUREAllogeneic Hematopoietic Stem Cell Transplantation
Undergo HCT
DRUGCyclophosphamide
Given IV
DRUGCyclosporine
Given PO
DRUGMycophenolate Mofetil
Given PO
DRUGSirolimus
Given PO
Sponsors
Fred Hutchinson Cancer Center
National Cancer Institute (NCI)
National Institutes of Health (NIH)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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 * Mantle cell NHL - may be treated in first complete remission (CR); (diagnostic lumbar puncture \[LP\] required pre-transplant) * Low grade NHL - with \< 6 month duration of CR between courses of conventional therapy * 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. * Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) - must be in complete remission at the time of transplant * HLA-MATCHED UNRELATED DONOR: FHCRC matching allowed will be grades 1.0 to 2.1; unrelated donors who are prospectively: * Matched for HLA-A, B, C, DRB1 and DQB1 by high resolution typing; * Only a single allele disparity will be allowed for HLA-A, B, or C as defined by high resolution typing * HLA-MATCHED UNRELATED DONOR: Donors are excluded when preexisting immunoreactivity is identified that would jeopardize donor hematopoietic cell engraftment; this determination is based on the standard practice of the individual institution; the recommended procedure for patients with 10 of 10 HLA allele level (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 \> 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 * 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 * 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 * Mismatched for two HLA class I alleles, but matched for HLA-DRB1 and HLA-DQ * HLA class I HLA-A, -B, -C allele matched donors allowing for any one or two DRB1 and/or DQB1 antigen/allele mismatch * HLA-MISMATCHED UNRELATED DONOR: HLA-matching must be based on results of high resolution typing at HLA-A, -B, -C, - DRB1, and -DQ * 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, A\*02:01); this mismatch will be considered a one-antigen mismatch for rejection only
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 * 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 \[TBI\]) * CNS involvement with disease refractory to intrathecal chemotherapy * Presence of circulating blasts determined to be associated with disease (in the blood) for patients with AML, ALL or CML * 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) will be used: Any patient with oxygen saturation on room air of \< 89% during a 6MWT will be excluded * The FHCRC PI of the study must approve of enrollment of all patients with pulmonary nodules * 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 * 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Chronic Graft Versus Host Disease (GVHD)-Free, Relapse-free Survival (CRFS) | At 1 year post- hematopoietic cell transplantation (HCT) | Composite time-to-event outcome in which events include moderate or severe chronic GVHD based on National Institute of Health consensus criteria, relapse, or death from any cause. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Grades II-IV Acute Graft Versus Host Disease (GVHD) | At day 100 post-HCT | Number of patients with grades II-IV acute GVHD aGVHD Stages Skin: a maculopapular eruption involving \< 25% BSA a maculopapular eruption involving 25 - 50% BSA generalized erythroderma generalized erythroderma w/ bullous formation and often w/ desquamation Liver: bilirubin 2.0 - 3.0 mg/100 mL bilirubin 3 - 5.9 mg/100 mL bilirubin 6 - 14.9 mg/100 mL bilirubin \> 15 mg/100 mL Gut: Diarrhea is graded 1 - 4 in severity. Nausea and vomiting and/or anorexia caused by GVHD is assigned as 1 in severity. The severity of gut involvement is assigned to the most severe involvement noted. Patients w/ visible bloody diarrhea are at least stage 2 gut and grade 3 overall. aGVHD Grades Grade II: Stage 1 - 2 skin w/ no gut/liver involvement Grade III: Stage 2 - 4 gut involvement and/or stage 2 - 4 liver involvement Grade IV: Pattern and severity of GVHD similar to grade 3 w/ extreme constitutional symptoms or death |
| Number of Patients With Grades III-IV Acute Graft Versus Host Disease (GVHD) | At day 100 post-HCT | Number of patients with grades II-IV acute GVHD aGVHD Stages Skin: a maculopapular eruption involving \< 25% BSA a maculopapular eruption involving 25 - 50% BSA generalized erythroderma generalized erythroderma w/ bullous formation and often w/ desquamation Liver: bilirubin 2.0 - 3.0 mg/100 mL bilirubin 3 - 5.9 mg/100 mL bilirubin 6 - 14.9 mg/100 mL bilirubin \> 15 mg/100 mL Gut: Diarrhea is graded 1 - 4 in severity. Nausea and vomiting and/or anorexia caused by GVHD is assigned as 1 in severity. The severity of gut involvement is assigned to the most severe involvement noted. Patients w/ visible bloody diarrhea are at least stage 2 gut and grade 3 overall. aGVHD Grades Grade II: Stage 1 - 2 skin w/ no gut/liver involvement Grade III: Stage 2 - 4 gut involvement and/or stage 2 - 4 liver involvement Grade IV: Pattern and severity of GVHD similar to grade 3 w/ extreme constitutional symptoms or death |
| Number of Patients With Late Graft Versus Host Disease (GVHD) Not Meeting National Institute of Health (NIH) Consensus Criteria for Chronic GVHD | At 1 year post-HCT | GVHD occurring after day 100 and not meeting NIH consensus criteria for chronic GVHD. Estimated by cumulative incidence methods. |
| Number of Patients With Moderate and Severe Chronic Graft Versus Host Disease | At 1 year post-HCT | Estimated by cumulative incidence methods. Based on NIH consensus criteria. |
| Number of Patients With Relapse/Progression | At 1 year post-HCT | Relapse/Progression criteria: CML New cytogenetic abnormality and/or development of accelerated phase or blast crisis. The criteria for accelerated phase will be defined as unexplained fever \>38.3°C, new clonal cytogenetic abnormalities in addition to a single Ph-positive chromosome, marrow blasts and promyelocytes \>20%. AML, ALL, MDS \>5% blasts by morphologic or flow cytometric evaluation of the BMA or appearance of extramedullary disease CLL ≥1 of: Physical exam/imaging studies ≥50% increase or new, circulating lymphocytes by morphology and/or flow cytometry ≥50% increase, and lymph node biopsy w/ Richter's transformation. NHL \>25% increase in the sum of the products of the perpendicular diameters of marker lesions, or the appearance of new lesions. MM ≥100% increase of the serum myeloma protein from its lowest level, or reappearance of myeloma peaks that had disappeared w/ treatment; or definite increase in the size or number of plasmacytomas or lytic bone lesions |
| Number of Non-relapse Mortalities | At 1 year post-HCT | Number of subjects expired without disease progression/relapse. |
| Number of Patients With Progression or Relapse-free Survival | At 1 year post-HCT | Relapse/Progression criteria: CML New cytogenetic abnormality and/or development of accelerated phase or blast crisis. The criteria for accelerated phase will be defined as unexplained fever \>38.3°C, new clonal cytogenetic abnormalities in addition to a single Ph-positive chromosome, marrow blasts and promyelocytes \>20%. AML, ALL, MDS \>5% blasts by morphologic or flow cytometric evaluation of the BMA or appearance of extramedullary disease CLL ≥1 of: Physical exam/imaging studies ≥50% increase or new, circulating lymphocytes by morphology and/or flow cytometry ≥50% increase, and lymph node biopsy w/ Richter's transformation. NHL \>25% increase in the sum of the products of the perpendicular diameters of marker lesions, or the appearance of new lesions. MM ≥100% increase of the serum myeloma protein from its lowest level, or reappearance of myeloma peaks that had disappeared w/ treatment; or definite increase in the size or number of plasmacytomas or lytic bone lesions |
| Number of Patients Surviving Overall | At 1 year post-HCT | Number of subjects surviving overall post-transplant. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORMasumi Ueda Oshima
Fred Hutch/University of Washington Cancer Consortium
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 83 Participants |
| Age, Categorical Between 18 and 65 years | 62 Participants |
| Age, Continuous | 66.3 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 71 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 4 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 4 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 133 Participants |
| Region of Enrollment United States | 72 participants |
| Sex: Female, Male Female | 58 Participants |
| Sex: Female, Male Male | 45 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 11 / 73 | 10 / 72 |
| other Total, other adverse events | 59 / 73 | 63 / 72 |
| serious Total, serious adverse events | 0 / 73 | 1 / 72 |
Outcome results
None listed