Acute Leukemia, Acute Myeloid Leukemia, Aplastic Anemia, Chronic Myelogenous Leukemia, Hodgkin's Disease, Lymphocytic Leukemia, Malignant Lymphoma, Multiple Myeloma, Myelofibrosis, Myeloproliferative Disorder, Polycythemia Vera
Conditions
Keywords
Acute myeloid leukemia, First remission, Acute lymphocytic leukemia, Acute leukemia, Second remission, Early relapse, Partial remission, Accelerated phase, Blast-crisis, Chronic myelogenous leukemia, Chronic phase, Recurrent malignant lymphoma, Refractory malignant lymphoma, Hodgkin's disease, Multiple myeloma., Chronic lymphocytic leukemia, Myeloproliferative disorder, Polycythemia vera, Myelofibrosis, Severe aplastic anemia
Brief summary
New conditioning regimens are still needed to maximize efficacy and limit treatment-related deaths of allogeneic transplantation for advanced hematologic malignancies. Over the past several years, the investigators have evaluated several new conditioning regimens that incorporate fludarabine, a novel immunosuppressant that has limited toxicity and that has synergistic activity with alkylating agents. Recent data have suggested that fludarabine may be used in combination with standard doses of oral or IV busulfan, thus reducing the toxicity previously observed with cyclophosphamide/ busulfan regimens.
Detailed description
Treatment-related mortality and recurrence of disease account for the majority of treatment failures in allogeneic transplantation for advanced hematologic malignancies. The most commonly utilized conditioning regimens consist of cyclophosphamide and total-body irradiation or busulfan and cyclophosphamide. Other agents such as etoposide or thiotepa are sometimes added to maximize the antileukemic effect. New conditioning regimens are however still needed to maximize efficacy and limit treatment-related deaths. Over the past several years, the investigators have evaluated several new conditioning regimens that incorporate fludarabine, a novel immunosuppressant that has limited toxicity and that has synergistic activity with alkylating agents. Recent data have suggested that fludarabine may be used in combination with standard doses of oral or IV busulfan, thus reducing the toxicity previously observed with cyclophosphamide/ busulfan regimens.
Interventions
DRUGfludarabine/busulfan
All patients below age 55, should receive fludarabine/busulfan, and ATG in case of unrelated or mismatched donor, unless there is significant pulmonary, hepatic or cardiac damage: (E.g FEV1 \<40%, DLCO\<50%, LVEF\<40, Serum bilirubin \>1.5 mg% or serum transaminases \> 2x nl) and/or specific medical conditions such as preventing a standard myeloablative treatment, as per discussion with the PI.
DRUGfludarabine/ melphalan
All patients above age 55 or below age 65, should receive fludarabine/melphalan, and ATG, unless there is significant pulmonary, hepatic or cardiac damage: (E.g FEV1 \<40%, DLCO\<50%, LVEF\<40, Serum bilirubin \>1.5 mg% or serum transaminases \> 2x nl).
DRUGATG
Patients receiving a transplant from a matched unrelated or mismatched related/unrelated donor would receive ATG in the conditioning regimen.
Sponsors
University of Illinois at Chicago
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
10 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Patients with the following diseases: * Acute myeloid or lymphocytic leukemia in first remission at standard or high-risk for recurrence. * Acute leukemia in greater than or equal to second remission, or with early relapse, or partial remission. * Chronic myelogenous leukemia in accelerated phase or blast-crisis. * Chronic myelogenous leukemia in chronic phase * Recurrent or refractory malignant lymphoma or Hodgkin's disease * Multiple myeloma. * Chronic lymphocytic leukemia, relapsed or with poor prognostic features. * Myeloproliferative disorder (polycythemia vera, myelofibrosis) with poor prognostic features. * Severe aplastic anemia after failure of immunosuppressive therapy. * Age 10-65 years. * Zubrod performance status less than or equal to 2. * Adequate cardiac and pulmonary function. Patients with decreased LVEF \< 40% or DLCO \< 50% of predicted will be evaluated by cardiology or pulmonary prior to enrollment on this protocol. * Patient or guardian able to sign informed consent.
Exclusion criteria
* Life expectancy is severely limited by concomitant illness. * Serum creatinine greater than 1.5 mg/dL or Creatinine Clearance less than 50 ml/min . * Serum bilirubin greater than or equal to 2.0 mg/dl, SGPT greater than 3 x upper limit of normal * Evidence of chronic active hepatitis or cirrhosis * HIV-positive * Patient is pregnant
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Engraftment. | Up to 30 days post-transplant | Median time to ANC engraftment and platelet engraftment in both groups as well as the transfusion requirements measured within 30 days after transplant. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Participants With 100 Day Transplant-related Mortality. | Up to 100 days post-transplant. | Day 100 transplant-related mortality was measured in both groups. |
| Time to ANC and Platelet Engraftment | Up to 30 days post-transplant | Days to ANC or platelet engraftment |
| Number of Participants With Moderate to Severe (Grade 2-4) Acute Graft Versus Host Disease (GVHD). | Up to 100 days post-transplant (acute GVHD). | Acute GVHD grade 2-4 was assessed in patients in the FluBU and FluMel groups up to 100 days after transplant. |
Countries
United States
Participant flow
Recruitment details
We analyzed the clinical outcome of patients with hematological malignancies at standard or high-risk, who were transplanted (allogeneic peripheral blood or BMT HSCT) after receiving FluBU as a conditioning regimen. A total of 30 patients were recruited for this study which was conducted at the UIC Medical Center Inpatient BMT unit.
Pre-assignment details
Criteria for FluBu conditioning: \<60 years old; no diagnosis of myeloma or myelofibrosis (MF) in chronic phase; and not having received an autologous stem cell transplant with the last 2 years. Patients not fulfilling these criteria but still eligible for allogeneic transplantation were prepared with FluMel.
Participants by arm
| Arm | Count |
|---|---|
| Arm 1 All patients below age 55 should receive fludarabine/busulfan and ATG in case of unrelated or mismatched donor.
fludarabine/busulfan: All patients below age 55, should receive fludarabine/busulfan, and ATG in case of unrelated or mismatched donor, unless there is significant pulmonary, hepatic or cardiac damage: (E.g FEV1 \<40%, DLCO\<50%, LVEF\<40, Serum bilirubin \>1.5 mg% or serum transaminases \> 2x nl) and/or specific medical conditions such as preventing a standard myeloablative treatment, as per discussion with the PI. | 18 |
| Arm 2 All patients above age 55 or below age 65 should receive fludarabine/ melphalan and ATG.
fludarabine/ melphalan: All patients above age 55 or below age 65, should receive fludarabine/melphalan, and ATG, unless there is significant pulmonary, hepatic or cardiac damage: (E.g FEV1 \<40%, DLCO\<50%, LVEF\<40, Serum bilirubin \>1.5 mg% or serum transaminases \> 2x nl). | 12 |
| Total | 30 |
Baseline characteristics
| Characteristic | Arm 2 | Arm 1 | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 12 Participants | 18 Participants | 30 Participants |
| Age, Continuous | 49 years | 34 years | 42.5 years |
| Region of Enrollment United States | 12 participants | 18 participants | 30 participants |
| Sex: Female, Male Female | 8 Participants | 8 Participants | 16 Participants |
| Sex: Female, Male Male | 4 Participants | 10 Participants | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 30 | 0 / 18 | 0 / 12 |
| serious Total, serious adverse events | 8 / 30 | 5 / 18 | 3 / 12 |
Outcome results
Primary
Number of Participants With Engraftment.
Median time to ANC engraftment and platelet engraftment in both groups as well as the transfusion requirements measured within 30 days after transplant.
Time frame: Up to 30 days post-transplant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fludarabine/Busulfan + ATG | Number of Participants With Engraftment. | 18 participants |
| Fludarabine/Melphalan + ATG | Number of Participants With Engraftment. | 12 participants |
Secondary
Number of Participants With Moderate to Severe (Grade 2-4) Acute Graft Versus Host Disease (GVHD).
Acute GVHD grade 2-4 was assessed in patients in the FluBU and FluMel groups up to 100 days after transplant.
Time frame: Up to 100 days post-transplant (acute GVHD).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fludarabine/Busulfan + ATG | Number of Participants With Moderate to Severe (Grade 2-4) Acute Graft Versus Host Disease (GVHD). | 2 participants |
| Fludarabine/Melphalan + ATG | Number of Participants With Moderate to Severe (Grade 2-4) Acute Graft Versus Host Disease (GVHD). | 1 participants |
Secondary
Participants With 100 Day Transplant-related Mortality.
Day 100 transplant-related mortality was measured in both groups.
Time frame: Up to 100 days post-transplant.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fludarabine/Busulfan + ATG | Participants With 100 Day Transplant-related Mortality. | 1 participants |
| Fludarabine/Melphalan + ATG | Participants With 100 Day Transplant-related Mortality. | 1 participants |
Secondary
Time to ANC and Platelet Engraftment
Days to ANC or platelet engraftment
Time frame: Up to 30 days post-transplant
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Fludarabine/Busulfan + ATG | Time to ANC and Platelet Engraftment | 15 days to ANC and platelet engraftment |
| Fludarabine/Melphalan + ATG | Time to ANC and Platelet Engraftment | 12 days to ANC and platelet engraftment |