Chronic Myelomonocytic Leukemia, Previously Treated Myelodysplastic Syndrome, Recurrent Adult Acute Lymphoblastic Leukemia, Recurrent Adult Acute Myeloid Leukemia, Refractory Anemia With Excess Blasts, Secondary Acute Myeloid Leukemia
Conditions
Brief summary
This phase I trial studies the side effects and maximum tolerated dose of yttrium Y 90 anti-cluster of differentiation 45 (CD45) monoclonal antibody BC8 (90Y-BC8) followed by donor stem cell transplant in treating patients with acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or myelodysplastic syndrome (MDS) that is likely to come back or spread. Giving chemotherapy drugs, such as fludarabine phosphate (FLU), and total-body irradiation (TBI) before a donor peripheral blood stem cell (PBSC) or bone marrow transplant helps stop the growth of cancer or abnormal cells and helps stop the patient's immune system from rejecting the donor's stem cells. Radiolabeled monoclonal antibodies, such as 90Y-BC8, can find cancer cells and carry cancer-killing substances to them without harming normal 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. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving FLU, 90Y-BC8, and TBI before the transplant together with cyclosporine and mycophenolate mofetil after the transplant may stop this from happening.
Detailed description
PRIMARY OBJECTIVES: I. To estimate the maximum tolerated dose (MTD) of radiation delivered via 90Y-DOTA-BC8 (90Y-BC8) when combined with FLU and 2 Gy TBI as a preparative regimen for patients aged \>= 18 with advanced AML, ALL, and high-risk MDS. SECONDARY OBJECTIVES: I. To determine disease response and duration of remission. II. To determine the rates of engraftment and donor chimerism resulting from this combined preparative regimen, and to correlate level of donor chimerism with estimated radiation doses delivered to hematopoietic tissues via antibody. OUTLINE: PREPARATIVE REGIMEN: Patients receive 90Y-BC8 via central line on approximately day -12 and FLU intravenously (IV) over 30 minutes on days -4 to -2. TRANSPLANTATION: Patients undergo TBI followed by allogeneic PBSC or bone marrow transplant on day 0. GRAFT-VS-HOST DISEASE (GVHD) PROPHYLAXIS: Patients receive mycophenolate mofetil orally (PO) or IV every 12 hours on days 0-27 (for patients with related donors) or every 8 hours on days 0-40 with taper to day 96 (for patients with unrelated donors). Patients also receive cyclosporine PO or IV every 12 hours on days -3 to 56 (for patients with related donors) or 100 (for patients with unrelated donors) with taper to day 180. After completion of study treatment, patients are followed up at 6, 9, 12, 18, and 24 months, and then annually thereafter.
Interventions
PROCEDUREAllogeneic Bone Marrow Transplantation
Undergo allogeneic bone marrow transplant
PROCEDUREAllogeneic Hematopoietic Stem Cell Transplantation
Undergo allogeneic PBSC or bone marrow transplant
DRUGCyclosporine
Given PO or IV
DRUGFludarabine Phosphate
Given IV
Given IV (dosimetric dose)
OTHERLaboratory Biomarker Analysis
Correlative studies
DRUGMycophenolate Mofetil
Given PO or IV
PROCEDUREPeripheral Blood Stem Cell Transplantation
Undergo allogeneic PBSC transplant
OTHERPharmacological Study
Correlative studies
RADIATIONTotal-Body Irradiation
Undergo TBI
Given via central line (therapeutic dose)
Sponsors
National Cancer Institute (NCI)
Fred Hutchinson Cancer Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients must have advanced AML, ALL or high-risk MDS meeting one of the following descriptions: * AML or ALL beyond first remission (i.e., having relapsed at least one time after achieving remission in response to a treatment regimen) * AML or ALL representing primary refractory disease (i.e., having failed to achieve remission at any time following one or more prior treatment regimens) * AML evolved from myelodysplastic or myeloproliferative syndromes; or * MDS expressed as refractory anemia with excess blasts (RAEB) or chronic myelomonocytic leukemia (CMML) by French-American-British (FAB) criteria * Patients not in remission must have CD45-expressing leukemic blasts; patients in remission do not require phenotyping and may have leukemia previously documented to be CD45 negative (because in remission patients, virtually all antibody binding is to non-malignant cells which make up \>= 95% of nucleated cells in the marrow) * Patients should have a circulating blast count of less than 10,000/mm\^3 (control with hydroxyurea or similar agent is allowed) * Patients must have an estimated creatinine clearance greater than 50/ml per minute (serum creatinine value must be within 28 days prior to registration) * Bilirubin \< 2 times the upper limit of normal * Aspartate aminotransferase (AST) and alanine transaminase (ALT) \< 2 times the upper limit of normal * Eastern Cooperative Oncology Group (ECOG) =\< 2 or Karnofsky \>= 70 * Patients must have an expected survival of \> 60 days and must be free of active infection * Patients must have an human leukocyte antigen (HLA)-identical sibling donor or an HLA-matched unrelated donor who meets standard Seattle Cancer Care Alliance (SCCA) and/or National Marrow Donor Program (NMDP) or other donor center criteria for PBSC or bone marrow donation, as follows: * Related donor: related to the patient and genotypically or phenotypically identical for HLA-A, B, C, DRB1 and DQB1; phenotypic identity must be confirmed by high-resolution typing * Unrelated donor: * Matched for HLA-A, B, C, DRB1 and DQB1 by high resolution typing; OR mismatched for a single allele without antigen mismatching at HLA-A, B or C as defined by high resolution typing but otherwise matched for HLA-A, B, C, DRB1 and DQB1 by high resolution typing * Doors 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 panel reactive antibody (PRA) screens to class I and class II antigens for all patients before hematopoietic cell transplant (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 and 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 * 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 * DONOR: Donors must meet HLA matching criteria and standard SCCA and/or National Marrow Donor Program (NMDP) or other donor center criteria for PBSC or bone marrow donation
Exclusion criteria
* Circulating human anti-mouse antibody (HAMA) * Prior radiation to maximally tolerated levels to any critical normal organ, or \> 20 Gy prior radiation to large areas of the bone marrow (e.g., external radiation therapy to whole pelvis) * Patients may not have symptomatic coronary artery disease and may not be on cardiac medications for anti-arrhythmic or inotropic effects * Left ventricular ejection fraction \< 35% * Corrected diffusion lung capacity of carbon monoxide (DLCO) \< 35% or receiving supplemental continuous oxygen * Liver abnormalities: fulminant liver failure, cirrhosis of the liver with evidence of portal hypertension, alcoholic hepatitis, esophageal varices, hepatic encephalopathy, uncorrectable hepatic synthetic dysfunction as evidenced by prolongation of the prothrombin time, ascites related to portal hypertension, bacterial or fungal liver abscess, biliary obstruction, chronic viral hepatitis, or symptomatic biliary disease * Patients who are known to be seropositive for human immunodeficiency virus (HIV) * Perceived inability to tolerate diagnostic or therapeutic procedures * Active central nervous system (CNS) leukemia at time of treatment * Women of childbearing potential who are pregnant (beta-human chorionic gonadotropin positive \[HCG+\]) or breast feeding * Fertile men and women unwilling to use contraceptives during and for 12 months post-transplant * Inability to understand or give an informed consent
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The MTD of Radiation Delivered Via 90Y-DOTA-BC8 When Combined With FLU and 2 Gy TBI as a Preparative Regimen for Patients Aged ≥ 18 With Advanced AML, ALL, and High-risk MDS. | Within the first 30 days following transplant | The MTD will be defined as the dose that is associated with a true DLT rate of 25%. The highest dose achieved was 28 Gy but none of the patients experienced a DLT. Thus, the MTD was not reached. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disease-free Survival | 100 days after transplant | Number of study participants who are alive and remains in complete remission after transplant. |
| Duration of Remission | 1 year | Median time to relapse after achieving complete remission (CR). CR is defined as complete resolution of all signs of myelodysplasia or leukemia for at least 4 weeks with all of the following: 1. Normal bone marrow with blasts \<5% with normal cellularity, normal megakaryopoiesis, \> 15% erythropoiesis and \> 25% granulocytopoiesis 2. Normalization of blood counts (no blasts, platelets \> 100000/mm3, granulocytes \>1500/mm3) 3. No extramedullary disease. Relapse Criteria: 1. After CR: \>5% blasts in the bone marrow and/or peripheral blood 2. After partial remission (PR): increase of blasts cells in the marrow to \>50% of those during PR 3. Extramedullary disease confirmed cytologically or histologically. |
| Estimation of Absorbed Radiation Doses to Normal Organs, Marrow and Tumor | Approximately day -20 to day -12 prior to transplant | The amount of energy absorbed per unit weight of the organ or tissue is called absorbed dose and is expressed in units of gray (Gy). One gray dose is equivalent to one joule radiation energy absorbed per kilogram of organ or tissue weight. |
| Overall Survival | Up to 5 years | Number of participants who are still alive after transplant with or without disease. |
| Achievement of Remission | 4 weeks after transplant | Number of participants who are in complete remission (CR) 4 weeks after transplant. CR is defined as complete resolution of all signs of myelodysplasia or leukemia for at least 4 weeks with all of the following: 1. Normal bone marrow with blasts \<5% with normal cellularity, normal megakaryopoiesis, \> 15% erythropoiesis and \> 25% granulocytopoiesis 2. Normalization of blood counts (no blasts, platelets \> 100000/mm3, granulocytes \>1500/mm3) 3. No extramedullary disease. |
| Rates of Donor Chimerism | Up to 100 days post-transplant | Number of participants who has 100% donor chimerism within 100 days after transplant |
| Rates of Engraftment | Up to 84 days post-transplant | Average number of days to ANC \>= 500 after transplant |
| Rates of Non-relapse Mortality | Within the first 100 days following transplant | Transplant-related deaths within 100 days after transplant |
| Rates of Acute GvHD | Up to 84 days post-transplant | Number of participants who developed acute GVHD post-transplant, aGVHD stages: Skin: a maculopapular eruption involving \< 25% BSA a maculopapular eruption involving 25 - 50% BSA generalized erythroderma generalized erythroderma with bullous formation and often with 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 with visible bloody diarrhea are at least stage 2 gut and grade 3 overall. aGVHD Grades 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 with extreme constitutional symptoms or death |
Countries
United States
Participant flow
Recruitment details
This protocol is open to participants age 18 and above, of either gender and any race/ethnicity. The study is looking at the use of Y-90-DOTA-BC8 in conjunction with a standard reduced-intensity transplant regimen.
Participants by arm
| Arm | Count |
|---|---|
| Treatment (90Y-BC8, Allogeneic PBSC or Bone Marrow Transplant) Study participants will receive an infusion of 0.5 mg/kg of ideal body weight of DOTA-BC8 trace labeled with \
5-10 mCi of Indium-111 to evaluate biodistribution and calculate the radiation absorbed doses to major organs and the whole body. The subsequent therapy infusion of Yttrium-90-DOTA-BC8 will deliver an amount of Yttrium-90 calculated not to exceed the target dose to the critical normal organ receiving the highest radiation dose. The therapy dose will be administered on approximately day -12 of the preparative regimen, which will typically be approximately 1 to 2 weeks after the biodistribution dose. | 16 |
| Total | 16 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | HAMA + post dosimetry | 1 |
Baseline characteristics
| Characteristic | Treatment (90Y-BC8, Allogeneic PBSC or Bone Marrow Transplant) |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 8 Participants |
| Age, Categorical Between 18 and 65 years | 8 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 16 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 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 | 0 Participants |
| Race (NIH/OMB) White | 16 Participants |
| Sex: Female, Male Female | 8 Participants |
| Sex: Female, Male Male | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 5 / 15 |
| other Total, other adverse events | 11 / 15 |
| serious Total, serious adverse events | 9 / 15 |
Outcome results
Primary
The MTD of Radiation Delivered Via 90Y-DOTA-BC8 When Combined With FLU and 2 Gy TBI as a Preparative Regimen for Patients Aged ≥ 18 With Advanced AML, ALL, and High-risk MDS.
The MTD will be defined as the dose that is associated with a true DLT rate of 25%. The highest dose achieved was 28 Gy but none of the patients experienced a DLT. Thus, the MTD was not reached.
Time frame: Within the first 30 days following transplant
Population: Study participants who completed the study regimen.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (90Y-BC8, Allogeneic PBSC or Bone Marrow Transplant) | The MTD of Radiation Delivered Via 90Y-DOTA-BC8 When Combined With FLU and 2 Gy TBI as a Preparative Regimen for Patients Aged ≥ 18 With Advanced AML, ALL, and High-risk MDS. | 28 Gy |
Secondary
Achievement of Remission
Number of participants who are in complete remission (CR) 4 weeks after transplant. CR is defined as complete resolution of all signs of myelodysplasia or leukemia for at least 4 weeks with all of the following: 1. Normal bone marrow with blasts \<5% with normal cellularity, normal megakaryopoiesis, \> 15% erythropoiesis and \> 25% granulocytopoiesis 2. Normalization of blood counts (no blasts, platelets \> 100000/mm3, granulocytes \>1500/mm3) 3. No extramedullary disease.
Time frame: 4 weeks after transplant
Population: Study participants who completed the study regimen
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment (90Y-BC8, Allogeneic PBSC or Bone Marrow Transplant) | Achievement of Remission | 13 Participants |
Secondary
Disease-free Survival
Number of study participants who are alive and remains in complete remission after transplant.
Time frame: 100 days after transplant
Population: Study participants who completed study regimen and in CR after transplant.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (90Y-BC8, Allogeneic PBSC or Bone Marrow Transplant) | Disease-free Survival | 7 participants |
Secondary
Duration of Remission
Median time to relapse after achieving complete remission (CR). CR is defined as complete resolution of all signs of myelodysplasia or leukemia for at least 4 weeks with all of the following: 1. Normal bone marrow with blasts \<5% with normal cellularity, normal megakaryopoiesis, \> 15% erythropoiesis and \> 25% granulocytopoiesis 2. Normalization of blood counts (no blasts, platelets \> 100000/mm3, granulocytes \>1500/mm3) 3. No extramedullary disease. Relapse Criteria: 1. After CR: \>5% blasts in the bone marrow and/or peripheral blood 2. After partial remission (PR): increase of blasts cells in the marrow to \>50% of those during PR 3. Extramedullary disease confirmed cytologically or histologically.
Time frame: 1 year
Population: Study participants who relapsed after achieving complete remission after transplant.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (90Y-BC8, Allogeneic PBSC or Bone Marrow Transplant) | Duration of Remission | 213 days |
Secondary
Estimation of Absorbed Radiation Doses to Normal Organs, Marrow and Tumor
The amount of energy absorbed per unit weight of the organ or tissue is called absorbed dose and is expressed in units of gray (Gy). One gray dose is equivalent to one joule radiation energy absorbed per kilogram of organ or tissue weight.
Time frame: Approximately day -20 to day -12 prior to transplant
Population: All study participants who completed the study regimen.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment (90Y-BC8, Allogeneic PBSC or Bone Marrow Transplant) | Estimation of Absorbed Radiation Doses to Normal Organs, Marrow and Tumor | Average absorbed dose to the marrow | 11.4 Gy | Standard Deviation 9.2 |
| Treatment (90Y-BC8, Allogeneic PBSC or Bone Marrow Transplant) | Estimation of Absorbed Radiation Doses to Normal Organs, Marrow and Tumor | Average absorbed dose to the liver | 17.2 Gy | Standard Deviation 6.8 |
| Treatment (90Y-BC8, Allogeneic PBSC or Bone Marrow Transplant) | Estimation of Absorbed Radiation Doses to Normal Organs, Marrow and Tumor | Average abosorbed dose total body | 3.1 Gy | Standard Deviation 5.7 |
| Treatment (90Y-BC8, Allogeneic PBSC or Bone Marrow Transplant) | Estimation of Absorbed Radiation Doses to Normal Organs, Marrow and Tumor | Average absorbed dose to the spleen | 70 Gy | Standard Deviation 43 |
Secondary
Overall Survival
Number of participants who are still alive after transplant with or without disease.
Time frame: Up to 5 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment (90Y-BC8, Allogeneic PBSC or Bone Marrow Transplant) | Overall Survival | 7 Participants |
Secondary
Rates of Acute GvHD
Number of participants who developed acute GVHD post-transplant, aGVHD stages: Skin: a maculopapular eruption involving \< 25% BSA a maculopapular eruption involving 25 - 50% BSA generalized erythroderma generalized erythroderma with bullous formation and often with 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 with visible bloody diarrhea are at least stage 2 gut and grade 3 overall. aGVHD Grades 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 with extreme constitutional symptoms or death
Time frame: Up to 84 days post-transplant
Population: Overall number of participants analyzed is 14 because one patient died prior to d+84 after transplant.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment (90Y-BC8, Allogeneic PBSC or Bone Marrow Transplant) | Rates of Acute GvHD | Grade 0 acute GVHD | 4 Participants |
| Treatment (90Y-BC8, Allogeneic PBSC or Bone Marrow Transplant) | Rates of Acute GvHD | Grade I acute GVHD | 1 Participants |
| Treatment (90Y-BC8, Allogeneic PBSC or Bone Marrow Transplant) | Rates of Acute GvHD | Grade II acute GVHD | 6 Participants |
| Treatment (90Y-BC8, Allogeneic PBSC or Bone Marrow Transplant) | Rates of Acute GvHD | Grade III acute GVHD | 2 Participants |
| Treatment (90Y-BC8, Allogeneic PBSC or Bone Marrow Transplant) | Rates of Acute GvHD | Grade IV acute GVHD | 1 Participants |
Secondary
Rates of Donor Chimerism
Number of participants who has 100% donor chimerism within 100 days after transplant
Time frame: Up to 100 days post-transplant
Population: Overall number of participants analyzed is 14 because one patient died prior to d+84 after transplant.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment (90Y-BC8, Allogeneic PBSC or Bone Marrow Transplant) | Rates of Donor Chimerism | 14 Participants |
Secondary
Rates of Engraftment
Average number of days to ANC \>= 500 after transplant
Time frame: Up to 84 days post-transplant
Population: Study participants with an ANC \<= to 500 after transplant
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment (90Y-BC8, Allogeneic PBSC or Bone Marrow Transplant) | Rates of Engraftment | 16 days | Standard Deviation 6 |
Secondary
Rates of Non-relapse Mortality
Transplant-related deaths within 100 days after transplant
Time frame: Within the first 100 days following transplant
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment (90Y-BC8, Allogeneic PBSC or Bone Marrow Transplant) | Rates of Non-relapse Mortality | Severe refractory GVHD | 1 Participants |
| Treatment (90Y-BC8, Allogeneic PBSC or Bone Marrow Transplant) | Rates of Non-relapse Mortality | Bacterial infection | 1 Participants |