Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome, Adult Acute Lymphoblastic Leukemia in Remission, Adult Acute Megakaryoblastic Leukemia (M7), Adult Acute Minimally Differentiated Myeloid Leukemia (M0), Adult Acute Monoblastic Leukemia (M5a), Adult Acute Monocytic Leukemia (M5b), Adult Acute Myeloid Leukemia in Remission, Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities, Adult Acute Myeloid Leukemia With t(16;16)(p13;q22), Adult Erythroleukemia (M6a), Adult Nasal Type Extranodal NK/T-cell Lymphoma, Adult Pure Erythroid Leukemia (M6b), B-cell Adult Acute Lymphoblastic Leukemia, B-cell Childhood Acute Lymphoblastic Leukemia, Blastic Phase Chronic Myelogenous Leukemia, Burkitt Lymphoma, Childhood Acute Erythroleukemia (M6), Childhood Acute Lymphoblastic Leukemia in Remission, Childhood Acute Megakaryocytic Leukemia (M7), Childhood Acute Minimally Differentiated Myeloid Leukemia (M0), Childhood Acute Monoblastic Leukemia (M5a), Childhood Acute Monocytic Leukemia (M5b), Childhood Acute Myeloid Leukemia in Remission, Childhood Chronic Myelogenous Leukemia, Childhood Diffuse Large Cell Lymphoma, Childhood Immunoblastic Large Cell Lymphoma, Childhood Myelodysplastic Syndromes, Childhood Nasal Type Extranodal NK/T-cell Lymphoma, Chronic Myelomonocytic Leukemia, Chronic Phase Chronic Myelogenous Leukemia, Cutaneous B-cell Non-Hodgkin Lymphoma, de Novo Myelodysplastic Syndromes, Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue, Juvenile Myelomonocytic Leukemia, Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable, Nodal Marginal Zone B-cell Lymphoma, Previously Treated Myelodysplastic Syndromes, Prolymphocytic Leukemia, Recurrent Adult Acute Lymphoblastic Leukemia, Recurrent Adult Acute Myeloid Leukemia, Recurrent Adult Burkitt Lymphoma, Recurrent Adult Diffuse Large Cell Lymphoma, Recurrent Adult Diffuse Mixed Cell Lymphoma, Recurrent Adult Diffuse Small Cleaved Cell Lymphoma, Recurrent Adult Grade III Lymphomatoid Granulomatosis, Recurrent Adult Immunoblastic Large Cell Lymphoma, Recurrent Adult Lymphoblastic Lymphoma, Recurrent Childhood Acute Lymphoblastic Leukemia, Recurrent Childhood Acute Myeloid Leukemia, Recurrent Childhood Anaplastic Large Cell Lymphoma, Recurrent Childhood Grade III Lymphomatoid Granulomatosis, Recurrent Childhood Large Cell Lymphoma, Recurrent Childhood Lymphoblastic Lymphoma, Recurrent Childhood Small Noncleaved Cell Lymphoma, Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma, Recurrent Grade 1 Follicular Lymphoma, Recurrent Grade 2 Follicular Lymphoma, Recurrent Grade 3 Follicular Lymphoma, Recurrent Mantle Cell Lymphoma, Recurrent Marginal Zone Lymphoma, Recurrent Mycosis Fungoides/Sezary Syndrome, Recurrent Small Lymphocytic Lymphoma, Refractory Chronic Lymphocytic Leukemia, Relapsing Chronic Myelogenous Leukemia, Secondary Acute Myeloid Leukemia, Secondary Myelodysplastic Syndromes, Secondary Myelofibrosis, Splenic Marginal Zone Lymphoma, Stage I Chronic Lymphocytic Leukemia, Stage II Chronic Lymphocytic Leukemia, Stage III Chronic Lymphocytic Leukemia, Stage IV Chronic Lymphocytic Leukemia, T-cell Adult Acute Lymphoblastic Leukemia, T-cell Childhood Acute Lymphoblastic Leukemia, T-cell Large Granular Lymphocyte Leukemia, Waldenstrom Macroglobulinemia
Conditions
Brief summary
RATIONALE: Giving chemotherapy before a donor umbilical cord blood transplant (UCBT) helps stop the growth of cancer and abnormal cells and helps stop the patient's immune system from rejecting the donor's stem cells. When the stem cells from an unrelated donor, that do not exactly match the patient's blood, 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 antithymocyte globulin before transplant and cyclosporine and mycophenolate mofetil after transplant may stop this from happening. PURPOSE: This phase II trial is studying how well donor umbilical cord blood stem cell transplant works in treating patients with hematologic malignancies.
Detailed description
PRIMARY OBJECTIVES: 1\. To establish the day +180 overall survival after a myeloablative unrelated double unit UCBT in a single institution setting. SECONDARY OBJECTIVES: 1. To determine the rates of hematologic and immune reconstitution in patients with high risk hematologic malignancies, who are undergoing myeloablative chemotherapy followed by infusion of double unit UCBT. 2. To determine the contribution of each umbilical cord unit to immune reconstitution with a focus on both initial (day +21 BM, and +28 PB) and sustained engraftment (day +100 BM; PB at +14, +21, +28, +35, +42, +60, +100, +180, +1 and 2 years). 3. To determine the probability of overall survival and disease free survival at one and two years. 4. To describe the incidence of disease recurrence at one and two years in patients post UCBT. 5. To describe the incidence of acute GVHD and chronic GVHD at 100 days and at one year, respectively. 6. To determine the incidence of day 100 and 180 treatment related mortality. 7. To determine the incidence of serious infectious complications in the first year after transplant. 8. To determine the incidence of donor-derived neutrophil and platelet recovery. 9. To determine the incidence of secondary lymphoproliferative diseases following transplantation with umbilical cord blood. OUTLINE: PREPARATIVE REGIMEN: Patients receive oral busulfan every 6 hours on days -8 to -5, cyclophosphamide IV on days -4 to -3, and anti-thymocyte globulin or methylprednisolone IV on days -3 to -1. TRANSPLANTATION: Patients undergo double-unit umbilical cord blood allogeneic stem cell transplantation on day 0. GRAFT-VS-HOST DISEASE PROPHYLAXIS: Beginning on day -2, patients receive cyclosporine IV and taper beginning on day 100. Patients also receive mycophenolate mofetil IV or orally every 8 hours on days -3 to 45. After completion of study treatment, patients are followed periodically.
Interventions
Given IV
Given IV
Given IV
Given IV
Given orally or IV
Correlative studies
Undergo transplantation
Correlative studies
Given orally
Undergo transplantation
Correlative studies
Correlative studies
Sponsors
Study design
Eligibility
Inclusion criteria
* Patients will be diagnosed with one of the following hematological malignancies: acute myelogenous leukemia (AML), acute lymphoblastic leukemia, non-Hodgkin's lymphoma, myelodysplastic syndrome (MDS), chronic myelogenous leukemia (CML), and myeloproliferative and lymphoproliferative disorders * AML--First remission (CR1) with high risk features including a known prior diagnosis of myelodysplasia (MDS); therapy related AML; white cell count at presentation \> 100,000; presence of extramedullary leukemia at diagnosis; unfavorable AML subtype (M0, M5-M7); poor cytogenetic markers (abnormalities of chromosome 5, 7 or 8, 11q23, Philadelphia chromosome, complex karyotype) * AML--Second remission (CR2) or subsequent remission * AML--Relapse/Persistent Disease with \< 20% bone marrow blasts * ALL--First remission (CR1) at high risk for relapse as defined by: B cell ALL white blood cell count (WBC) at presentation \> 30,000 (T cell ALL WBC \> 100,000); presence of high-risk cytogenetic abnormality such as t(9;22), t(1;19), t(4;11) or other MLL rearrangements (11q23), t(8;14) * ALL--Second remission (CR2) or subsequent remission * ALL--Relapse/Persistent Disease with \< 20% bone marrow blasts * Non-Hodgkin Lymphoma--Induction failure or relapse and sensitive to most recent chemotherapy * MDS--Low or Intermediate-1 International Prognostic Scoring System (IPSS) score with: life-threatening cytopenia(s); and/or red cell or platelet transfusion dependence * MDS--ANC \< 500, recurrent infections, PRBC transfusions \> 2 units/month, poor risk cytogenetics, platelet transfusion dependence * MDS--Intermediate-2 or High IPSS score * CML--Chronic phase I (CP1) and resistant to or intolerant of tyrosine kinase inhibitors (i.e. imatinib, dasatinib, etc.) * CML--CP2 or subsequent chronic phase, including chronic phase achieved after induction therapy for blast crisis * Myeloproliferative and lymphoproliferative disorders--eligibility to be determined by a consensus of the physicians on the Case Comprehensive Cancer Center Leukemia/Lymphoma Multidisciplinary Committee * Myeloproliferative and lymphoproliferative disorders--must have evidence of disease acceleration to be a candidate for umbilical cord blood transplant; myeloproliferative disorders eligible for transplant include chronic myelomonocytic leukemia (CMML) with high IPSS score and myelofibrosis * Myeloproliferative and lymphoproliferative disorders--potential lymphoproliferative disorders eligible for transplant include chronic lymphocytic leukemia, prolymphocytic leukemia, and large granular lymphocytic leukemia * Good performance status: Karnofsky \>= 70 % or ECOG 0-1 * Calculated creatinine clearance \>= 60 mL/min, or measured creatinine clearance \>= 60 mL/min (by 24-hour urine collection) if creatinine \>= 1.5 or history of renal dysfunction * Hepatic Transaminases \< 4 x upper limit normal (ULN); total bilirubin \< 2.5 mg/dL, unless the patient has a history of benign congenital hyperbilirubinemia (Gilbert's syndrome) * Normal cardiac function by echocardiogram or radionuclide scan, (left ventricular ejection fraction \> 45%); if the left ventricular ejection fraction is between 40-50%, clearance by an adult cardiologist is required * Pulmonary function tests demonstrating FEV1 \> 60% of predicted for age * Adults must have a DLCOva \> 60% normal * For patients unable to complete pulmonary function tests clearance by an adult pulmonologist is required * Patients will be eligible for the clinical trial under the following conditions: they do NOT have an HLA-A/B/DR B1 identical RELATED bone marrow donor; they do NOT have a 6/6 HLA-identical matched unrelated adult donor; OR a matched related donor transplant is not in the best interest of the patient (i.e., patient's condition precludes waiting on the donor, too much time to prepare the donor, the donor is ineligible due to medical reasons, or in the case of high risk disease a related donor is not appropriated (syngeneic transplant); the decision must be agreed upon by the consensus of physicians on the Case Comprehensive Cancer Center Leukemia/Lymphoma Multidisciplinary Committee; OR their condition precludes waiting to search and find a donor in the National Marrow Donor Registry
Exclusion criteria
* Female patients who are pregnant or breast-feeding * HIV or HTLV-1 positivity * Any leukemia with a morphologic relapse or persistent disease in the BM with \>= 20% blasts (cytogenetic relapse without morphologic evidence of relapse, or cytogenetic persistent disease is acceptable) * Active extramedullary leukemia, including CNS disease * Prior hematopoietic stem cell transplant (autologous or allogeneic) * Uncontrolled infection * Patient has an identical related bone marrow donor or a 6/6 HLA-identical matched unrelated donor * Any patient who is unable to provide informed consent or comply with the requirements of the protocol
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | On day +180 | Number of participants alive at 180 days post engraftment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | At 1 year | Number of participants that were alive. |
| Disease Free | At 1 year | Number of participants that were disease free |
| Recurrence or Relapse | one year in patients post UCBT | Number of subjects that had disease recurrence |
| Transplant Related Mortality | On day 100 post transplant | Number of subjects that died because of transplant |
| Hematologic Engraftment | On day +42 | Number of participants that were able to complete engraftment by day 42. |
| Immune Reconstitution | Periodically for 2 years | Immunodificency panel to see recovery of immune system. Number of participants that recovered. |
| Toxicity Related to UCB Transplantation and Cytoreduction as Assessed by CTC v3.0 | by day +42 | Number of participants that experienced toxicity related to the transplant |
| Incidence of Acute Graft-versus-host Disease (GVHD) | At 100 days | Number of participants that had acute GVHD |
| Incidence of Chronic GVHD | At 1 year | Number of participants that have chronic GVHD. Chronic GVHD will be diagnosed and graded on clinical and histological criteria from the Center for International Blood and Marrow Transplant Research (CIBMTR) |
| Occurrence of Serious Infections | 1 year | Number of participants that had infections |
Countries
United States
Participant flow
Recruitment details
Participants recruited from medical hospital from 9/2007 thru 2/2013.
Participants by arm
| Arm | Count |
|---|---|
| Arm I PREPARATIVE REGIMEN: Patients receive oral busulfan on days -8 to -5, cyclophosphamide IV on days -4 to -3, and anti-thymocyte globulin or methylprednisolone IV on days -3 to -1. TRANSPLANTATION: Patients undergo a double-unit umbilical cord blood allogeneic stem cell transplantation on day 0. GRAFT-VS-HOST DISEASE PROPHYLAXIS: Beginning on day -2, patients receive cyclosporine IV and taper beginning on day 100. Patients also receive mycophenolate mofetil IV or orally on days -3 to 45. | 14 |
| Total | 14 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Failed to engraft | 3 |
Baseline characteristics
| Characteristic | Arm I |
|---|---|
| Age, Customized 10-19 yrs | 2 Participants |
| Age, Customized 20-29 yrs | 2 Participants |
| Age, Customized 30-39 yrs | 3 Participants |
| Age, Customized 40-49 yrs | 5 Participants |
| Age, Customized 50-59 yrs | 2 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 13 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 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 | 11 Participants |
| Region of Enrollment United States | 14 participants |
| Sex: Female, Male Female | 8 Participants |
| Sex: Female, Male Male | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 11 / 14 |
| other Total, other adverse events | 0 / 0 |
| serious Total, serious adverse events | 9 / 14 |
Outcome results
Overall Survival
Number of participants alive at 180 days post engraftment.
Time frame: On day +180
Population: All participants that went on study, whether completing engraftment or not.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I | Overall Survival | 8 Participants |
Disease Free
Number of participants that were disease free
Time frame: At 1 year
Population: Participants that completed engraftment. 10 participants completed engraftment by day 42 and 1 participant completed engraftment by day 46.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I | Disease Free | 4 Participants |
Disease Free
Number of participants that were disease free
Time frame: At 2 years
Population: Participants that completed engraftment. 10 participants completed engraftment by day 42 and 1 participant completed engraftment by day 46.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I | Disease Free | 4 Participants |
Hematologic Engraftment
Number of participants that were able to complete engraftment by day 42.
Time frame: On day +42
Population: Participants that went on study.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I | Hematologic Engraftment | 10 Participants |
Immune Reconstitution
Immunodificency panel to see recovery of immune system. Number of participants that recovered.
Time frame: Periodically for 2 years
Population: Data not collected, panel not done because of funding.
Incidence of Acute Graft-versus-host Disease (GVHD)
Number of participants that had acute GVHD
Time frame: At 100 days
Population: All participants who went on study
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I | Incidence of Acute Graft-versus-host Disease (GVHD) | 11 Participants |
Incidence of Chronic GVHD
Number of participants that have chronic GVHD. Chronic GVHD will be diagnosed and graded on clinical and histological criteria from the Center for International Blood and Marrow Transplant Research (CIBMTR)
Time frame: At 1 year
Population: All participants that went on study
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I | Incidence of Chronic GVHD | 1 Participants |
Occurrence of Serious Infections
Number of participants that had infections
Time frame: 1 year
Population: All participants that went on study
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I | Occurrence of Serious Infections | 13 Participants |
Overall Survival
Number of participants that were alive.
Time frame: At 1 year
Population: Participants that completed engraftment. 10 participants completed engraftment by day 42 and 1 participant completed engraftment by day 46.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I | Overall Survival | 6 Participants |
Overall Survival
Number of participants that were alive.
Time frame: At 2 years
Population: Participants that completed engraftment. 10 participants completed engraftment by day 42 and 1 participant completed engraftment by day 46.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I | Overall Survival | 4 Participants |
Recurrence or Relapse
Number of subjects that had disease recurrence
Time frame: two years post transplant
Population: Subjects who had completed engraftment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I | Recurrence or Relapse | 2 Participants |
Recurrence or Relapse
Number of subjects that had disease recurrence
Time frame: one year in patients post UCBT
Population: Participants that completed engraftment. 10 participants completed engraftment by day 42 and 1 participant completed engraftment by day 46.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I | Recurrence or Relapse | 2 Participants |
Toxicity Related to UCB Transplantation and Cytoreduction as Assessed by CTC v3.0
Number of participants that experienced toxicity related to the transplant
Time frame: by day +42
Population: Patients that received transplant
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I | Toxicity Related to UCB Transplantation and Cytoreduction as Assessed by CTC v3.0 | 8 Participants |
Transplant Related Mortality
Number of subjects that died because of transplant
Time frame: On day 100 post transplant
Population: Participants that went on study
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I | Transplant Related Mortality | 2 Participants |
Transplant Related Mortality
Number of subjects that died because of transplant
Time frame: On day 180 post transplant
Population: All participants that went on study
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I | Transplant Related Mortality | 6 Participants |