Acute Myeloid Leukemia
Conditions
Keywords
Clofarabine, Haploidentical stem cell transplantation, matched and mismatched unrelated donors, Non-remission AML
Brief summary
The Investigators would like to study the incidence of complete remission (CR) at day +30 after Clofarabine followed by haploidentical transplant. The conditioning regimen used is Fludarabine, Busulfan (2 doses) or cyclophosphamide (2 doses) and Total Body Irradiation (TBI) with post transplant cyclophosphamide for patients with Acute Myeloid Leukemia (AML) who are not in remission prior to considering allogeneic transplant with haploidentical donors.
Detailed description
Approximately 30-40% of patients with acute myeloid leukemia (AML) experience induction failures. In these patients who do not achieve remission with two cycles of standard induction therapies, the probability of achieving remission with subsequent inductions is limited. Hematopoietic stem cell transplantation (HSCT) is the only curative option for these patients, but high relapse rate and transplant-related mortality often preclude them to proceed to transplant. Thus, AML not in remission at time of HSCT remains a huge unmet need in current HSCT practice, particularly if the patient does not have a Human Leukocyte Antigen (HLA)-matched donor identified by the time of two induction failures. Salvage chemotherapy with clofarabine appears to be another promising option in relapsed and refractory AML. Clofarabine is a second-generation purine nucleoside analog with substantial single-agent activity in adult patients with AML. It is an effective immunosuppressive agent and several trials have shown the feasibility of conditioning with clofarabine-based regimen. In the past, a conditioning regimen of clofarabine with busulfan (4 doses) has been successfully used prior to allogeneic stem cell transplantation for non-remission AML with day +30 complete remission rates were 90-100%. However, these patients were transplanted with HLA matched donors. This study will examine those patients undergoing transplantation from haploidentical related donor or matched and mismatched unrelated donors. Achieving a long-term remission is clearly the goal of AML treatment. The investigators would like to propose a protocol for non-remission AML and expand the patient population to older than 55 years of age as well as those who relapsed after initial allogeneic transplant to improve enrolling patients in the near future. The investigators have many patients achieving remission but for those without remission, clofarabine preconditioning may be a reliable protocol to bring these patients into the early complete remission.
Interventions
DRUGClofarabine
Clofarabine to be administered pre-stem cell transplant infusion (Day 0) once a day for 5 days total.
DRUGFludarabine
Fludarabine will be administered once a day for 4 days as part of the transplant conditioning regimen.
DRUGBusulfan
Busulfan will be administered once a day for 2 days as part of the transplant conditioning regimen.
PROCEDURETotal Body Irradiation (TBI)
TBI will be administered at a dose of 200cGys on Day -1 prior to transplant
DRUGCyclophosphamide
Cyclophosphamide will be given once a day for 2 days after the transplant infusion.
DRUGGranulocyte Colony-Stimulating Factor
G-CSF will be administered to subjects starting on Day +5 and will continue as clinically indicated
DRUGTacrolimus
Tacrolimus will be administered to subjects starting on Day +5 and will continue as clinically indicated
DRUGCellcept
Mycophenolate Mofetil will be administered to subjects starting on Day +5 and will continue as clinically indicated
Sponsors
Milton S. Hershey Medical Center
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Dose de-escalation: Enrollment will begin at 30 mg/m2 to analyze any grade 4-5 organ toxicities as defined in Section 12.2. If the trial is stopped due to excessive toxicities, then dose de-escalation to 20 mg/m2 will occur for the next cohort of participants. For each participant, the observation period is from start of treatment through post-transplant day +30. Adverse effects will be continuously monitored as patients are enrolled. The trial will be stopped when the toxicity rate exceeds 20% with a posterior probability of 80% and a margin of no more than 5%. This leads to the following stopping rule: the trial will be stopped if 2 of the first 3 subjects experience grade 4-5 organ toxicity, or 3 out of 6, 4 out 9, 5 out of 12, 6 out of 16, or 7 out 19.
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
No
Inclusion criteria
1. Diagnostic criteria of AML, induction failure without having achieved remission after at least 2 attempts at induction chemotherapy, or relapsed after any complete remission (CR). 2. 18 to 75 years of age. 3. Planned or scheduled to receive an allogeneic HSCT from haploidentical related donors, matched and mismatched unrelated donors. 4. All organ function testing should be done within 28 days of study registration. * Performance status: Karnofsky ≥ 70% (Appendix A). * Cardiac: LVEF ≥ 50% by MUGA or echocardiogram. * Pulmonary: FEV1 and FVC ≥ 50% predicted, DLCO (corrected for hemoglobin) ≥ 50% of predicted. * Renal: Creatinine clearance (CrCl) ≥ 60 mL/min/1.73 m2 * Hepatic: Serum bilirubin ≤1.5 x upper limit of normal (ULN); (AST)/(ALT) ≤ 2.5 x ULN; Alkaline phosphatase ≤ 2.5 x ULN. 5. Both men and women need to use an approved method of birth control and/or abstinence due to unknown risks to the fetus.
Exclusion criteria
1. Acute promyelocytic leukemia (APL) 2. Known history of non-compliance with medication regimens, scheduled clinic visits, or self-care. 3. In the opinion of the investigator, no appropriate caregivers identified. 4. HIV1 (Human Immunodeficiency Virus-1) or HIV2 positive 5. Active Hepatitis B and Hepatitis C orepatitis positive serology including HBsAg, hepatitis B core antibody, and hepatitis C antibody. Hepatitis B surface antibody positive due to vaccination or natural immunity are permitted. 6. In the opinion of the physician investigator, uncontrolled medical or psychiatric disorders. 7. Uncontrolled infections requiring treatment within 14 days of registration. 8. Active central nervous system (CNS) leukemia. 9. Cord blood transplant excluded. 10. Prior allogeneic HSCT within last 6 months. 11. Patients with \>= grade 2 acute GVHD. 12. Patients with \>=moderate chronic GVHD. 13. Pregnant or Breastfeeding. Women of child bearing potential (WCBP) are required to have a negative serum or urine pregnancy test prior to initiation of conditioning regimen. 14. Haploidentical related donors who are positive for DSA ≥ 5000 MFI by solid phase microarray method (Luminex). 15. Any patient with steroid dose more than 10 mg/day within a week of registration . 16. Autoimmune disorder requiring any active immunosuppression therapy.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Complete Remission (CR) Rate at Day 30 Post HSCT | 30 days | The CR rate at 30 days (Day +30) post stem cell transplant infusion |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Neutrophil Engraftment | 1 year | Rates of engraftment, defined as the first day of Absolute Neutrophil Count (ANC) greater than 500 for the first of three consecutive days |
| Rate of Acute Graft-versus-host Disease (GVHD) | 100 days | The rate of any grade (1-4) of acute GvHD as measured from day of transplantation to Day +100 using the Glucksberg criteria. |
| Non-relapse Related Mortality | 100 days | Determine the rate of non-relapse related mortality at 100 days post transplant (Day +100) |
| Rate of Chronic GVHD | 1 year | The rate of any grade (1-4) of Chronic GvHD as measured from Day +100 to Year 1 post-transplantation using the Glucksberg criteria. |
| Severity of Chronic GVHD | 1 year | The highest overall grade (1-4) of chronic GvHD experienced by participants as measured from Day +100 to Year 1 post-transplantation using the Glucksberg criteria |
| Severity of Acute Graft-versus-host Disease (GVHD) | 100 days | The highest grade (1-4) of acute GvHD experienced by participants as measured from day of transplantation to Day +100 using the Glucksberg criteria |
Countries
United States
Participant flow
Pre-assignment details
Both subjects were between age 56 and 75 years old, therefore they were assigned treatment of Regimen B.
Participants by arm
| Arm | Count |
|---|---|
| Clofarabine 30 mg/m^2 Day -14 through Day -10 Clofarabine 30 mg/m\^2, Day - 9 Day of rest, Day - 8 Day of rest, Day - 7 Day of rest, Day - 6, Fludarabine 24 mg/m\^2 IV and Cyclophosphamide 14.5 mg/kg IV for Regimen B, Day - 5 Fludarabine 24 mg/m\^2 IV and Cyclophosphamide 14.5 mg/kg IV for Regimen B, Day - 4 Fludarabine 24 mg/m\^2 IV for Regimen B, Day - 3 Fludarabine 24 mg/m\^2 IV for Regimen B, Day - 2 Fludarabine 24 mg/m\^2 IV for Regimen B, Day -1 Total Body Irradiation 200 cGys, Day 0 stem cell transplant infusion, Day +1 Day of rest, Day +2 Day of rest, Day +3 Cyclophosphamide 50 mg/kg IV, Day +4 Cyclophosphamide 50 mg/kg IV, Day +5 Start G-CSF, Tacrolimus, and MMF. | 2 |
| Total | 2 |
Baseline characteristics
| Characteristic | Clofarabine 30 mg/m^2 |
|---|---|
| Age, Continuous | 68 years STANDARD_DEVIATION 0 |
| 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 | 2 Participants |
| Region of Enrollment United States | 2 Participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 2 / 2 |
| other Total, other adverse events | 2 / 2 |
| serious Total, serious adverse events | 1 / 2 |
Outcome results
Primary
Complete Remission (CR) Rate at Day 30 Post HSCT
The CR rate at 30 days (Day +30) post stem cell transplant infusion
Time frame: 30 days
Population: The CR rate at 30 days (Day +30) post stem cell transplant infusion was 2/2.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Clofarabine 30 mg/m^2 | Complete Remission (CR) Rate at Day 30 Post HSCT | 100 percentage of Participants |
Secondary
Neutrophil Engraftment
Rates of engraftment, defined as the first day of Absolute Neutrophil Count (ANC) greater than 500 for the first of three consecutive days
Time frame: 1 year
Population: Rate of engraftment was 0/2.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Clofarabine 30 mg/m^2 | Neutrophil Engraftment | 0 percentage of Participants |
Secondary
Non-relapse Related Mortality
Determine the rate of non-relapse related mortality at 100 days post transplant (Day +100)
Time frame: 100 days
Population: The rate of non-relapse related mortality at 100 days post transplant (Day +100) is 0/2.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Clofarabine 30 mg/m^2 | Non-relapse Related Mortality | 0 percentage of Participants |
Secondary
Rate of Acute Graft-versus-host Disease (GVHD)
The rate of any grade (1-4) of acute GvHD as measured from day of transplantation to Day +100 using the Glucksberg criteria.
Time frame: 100 days
Population: The rate of any grade (1-4) of acute GvHD as measured from day of transplantation to Day +100 was 0/2.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Clofarabine 30 mg/m^2 | Rate of Acute Graft-versus-host Disease (GVHD) | 0 percentage of Participants |
Secondary
Rate of Chronic GVHD
The rate of any grade (1-4) of Chronic GvHD as measured from Day +100 to Year 1 post-transplantation using the Glucksberg criteria.
Time frame: 1 year
Population: The incidence of any grade (1-4) of Chronic GvHD as measured from Day +100 to Year 1 post-transplantation was 0/2.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Clofarabine 30 mg/m^2 | Rate of Chronic GVHD | 0 percentage of Participants |
Secondary
Severity of Acute Graft-versus-host Disease (GVHD)
The highest grade (1-4) of acute GvHD experienced by participants as measured from day of transplantation to Day +100 using the Glucksberg criteria
Time frame: 100 days
Population: The highest grade (1-4) of acute GvHD experienced by participants as measured from day of transplantation to Day +100 was 0/2.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Clofarabine 30 mg/m^2 | Severity of Acute Graft-versus-host Disease (GVHD) | 0 percentage of Participants |
Secondary
Severity of Chronic GVHD
The highest overall grade (1-4) of chronic GvHD experienced by participants as measured from Day +100 to Year 1 post-transplantation using the Glucksberg criteria
Time frame: 1 year
Population: The highest overall grade (1-4) of chronic GvHD experienced by participants as measured from Day +100 to Year 1 post-transplantation was 0/2.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Clofarabine 30 mg/m^2 | Severity of Chronic GVHD | 0 percentage of Participants |