Acute Myeloid Leukemia, Myelodysplastic Syndrome
Conditions
Brief summary
The primary hypothesis is that chemotherapy followed by donor lymphocyte infusion (DLI) from HLA-haploidentical donors is a safe procedure that will not cause Graft versus Host Disease (GVHD) or increased treatment-related mortality. The Investigator further believes that this will improve outcomes of elderly patients with high-risk AML or MDS compared to chemotherapy alone, and that that this benefit will be even greater in donor-recipient pairs that share maternal-fetal microchimerism or non-inherited maternal antigen (NIMA) mismatch. A large part of this trial will include immune function assays as well as assessments of efficacy, toxicity, and GVHD. Because this therapy may be a tolerable alternative to allogeneic hematopoietic stem cell transplantation (alloHSCT) for elderly patients, the Investigator will validate functional measurements (e.g. Comprehensive Geriatric Assessment (CGA)) with biologic correlates (cytokine and genomic profiles) and clinical outcomes.
Interventions
DRUGIdarubicin
Eligible subjects will receive induction chemotherapy with idarubicin (12 mg/m2 intravenously for 3 days) and cytarabine (100 mg/m2 intravenously for 7 days) starting Day 1 and ending Day 7. Patients 80 years or older will only receive 2 and 5 days of idarubicin and cytarabine respectively starting Day 1 and ending Day 5. Subjects who experience no remission or partial remission will receive a second course of the identical induction chemotherapy.
DRUGCytarabine
Cytarabine (100 mg/m2 intravenously for 7 days) starting Day 1 and ending Day 7. Patients 80 years or older will only receive 2 and 5 days of idarubicin and cytarabine respectively starting Day 1 and ending Day 5. Subjects who achieve a complete remission (CR) will receive 2 further courses of cytarabine postremission chemotherapy (consolidation) at 1.0 g/m2 for 6 dosages followed by HLA-mismatched DLI after the second consolidation.
BIOLOGICALDLI
HLA-mismatched DLI will be administered Day 9, approximately 24-48 hours following completion of chemotherapy at a dose of 1x10\^8 cluster of differentiation 3 (CD3+) cells; however, due to logistics of planning infusions with staffing, donor availability, weekends/holidays, etc., it may be necessary to postpone cell infusion up to 96 hours. Given the time constraints presented by the need to start induction chemotherapy as soon as possible, in some cases, it may not be logistically possible to administer cells with induction. In these cases, patients would just receive standard induction chemotherapy and cells would be administered after consolidation 1 in addition to consolidation 2 Subjects who achieve a CR will receive 2 further courses of cytarabine postremission chemotherapy (consolidation) at 1.0 g/m2 for 6 dosages followed by HLA-mismatched DLI after the second consolidation.
Sponsors
Duke University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
55 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Subjects must have their diagnosis of high-risk AML or high-risk MDS confirmed by pathologic review of bone marrow biopsy according to WHO guidelines 2. Patients will be defined as high risk AML and thus eligible if they meet one or more of the following criteria: 1. Secondary AML (from underlying MDS or therapy related) 2. Presence of complex cytogenetic abnormalities (3 or more cytogenetic abnormalities), all monosomies, del 5q, del 7q, inv3, t(3;3), t(6;9), t(9;22), abn 11q23 (excluding t(9;11)) 3. Fms-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD) mutation positive 4. Age ≥ 65 years given poor outcomes even with favorable cytogenetics 3. Patients will be defined as high risk MDS and thus eligible if they have a MD Anderson Comprehensive Cancer MDS Risk Score ≥9 4. Subjects must have Eastern Cooperative Oncology Group (ECOG) Performance status of 0,1,or 2; if ECOG 2, they must also have a Charlson comorbidity index of ≤5. 5. Subjects must be 55 years of age or older 6. Subjects should have a 3-5/6 HLA-matched related haploidentical donor who is evaluated and deemed able to provide DLI. 7. Patient should be able to provide informed consent 8. Subjects must have a multigated acquisition (MUGA) and /or ECHO or cardiac magnetic resonance imaging (MRI). The required minimum standards include MUGA or ECHO or cardiac MR showing an ejection fraction( EF) of 40%. Those with an EF 40-49% must also have a cardiologist consult and assist with management. 9. Pulmonary function tests (PFTs) with diffusing capacity of lung for carbon monoxide (DLCO) are conditional for subjects at the discretion of the physician. The required minimum standards for those who have PFTs include DLCO of 40%. Those with DLCO of 40-49% must have a pulmonologist consult and assist with management. 10. Subjects of all genders and races are eligible
Exclusion criteria
1. Pregnant or lactating women. 2. Patients with other major medical or psychiatric illnesses which the treating physician feels could seriously compromise tolerance to this protocol 3. Patients with known active central nervous system (CNS) disease 4. Patients with acute promyelocytic leukemia (FAB M3)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects With Unacceptable Toxicity | up to 8 weeks after last cell infusion | Unacceptable toxicity is defined as: i. Grade III or IV acute GVHD (aGVHD) of the gut or liver or Grade IV aGVHD of the skin lasting \> 7 days; ii. Grade IV Common Terminology Criteria for Adverse Events (CTCAE) toxicity attributable to DLI (e.g. infusion reaction, as opposed to Grade IV CTCAE toxicity from chemotherapy) and lasting \>7 days iii. Treatment-related mortality (TRM) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | 2 years after completing therapy | Number of participants alive 2 years after completing adoptive transfer therapy. |
| Percentage of Subjects With Acute GVHD | 8 weeks after last cell infusion | Grade III or IV aGVHD of the gut or liver or Grade IV aGVHD of the skin lasting \> 7 days |
| Percentage of Subjects With Unacceptable Toxicity | 8 weeks after the last cell infusion | Grade IV CTCAE toxicity attributable to DLI (e.g. infusion reaction, as opposed to Grade IV CTCAE toxicity from chemotherapy) and lasting \>7 days, Grade III or IV aGVHD of the gut or liver or Grade IV aGVHD of the skin lasting \> 7 days, or death |
| Disease Free Survival | one year following adoptive transfer | 1 year disease free survival rate following adoptive transfer |
| Number of Participants With Immune Recovery | up to 2 years after completing therapy | Immune recovery determined by measurements of cytokine profiles, lymphocyte and natural killer (NK) enumeration and flow-based assays, measured prior to induction, prior to each round of consolidation, 8 weeks after the last cycle of consolidation, and every 3 months after treatment for up to 2 years |
| Number of Days to Hematopoietic Recovery | 2 years after completion of therapy | Hematopoietic recovery as measured by the date of the first of three consecutive laboratory values where the absolute neutrophil count (ANC) ≥ 500/μl , the date of the first of three consecutive laboratory values obtained on different days where the platelet count was \> 20,000/μl without transfusion. |
| Rate of Efficacy | 2 years after completing therapy | Efficacy as measured by the number of subjects with a complete remission. Responses were evaluated according to standard criteria defined by the National Comprehensive Cancer Network Guidelines for AML (www.nccn.org). |
Countries
United States
Participant flow
Pre-assignment details
1 subject was a screen failure and 1 subject withdrew prior to starting study.
Participants by arm
| Arm | Count |
|---|---|
| Idarubicin + Cytarabine + DLI Chemotherapy combined with adoptive transfer of HLA-haploidentical donor lymphocyte infusion (DLI)
Idarubicin: Eligible subjects will receive induction chemotherapy with idarubicin (12 mg/m2 intravenously for 3 days) and cytarabine (100 mg/m2 intravenously for 7 days) starting Day 1 and ending Day 7. Patients 80 years or older will only receive 2 and 5 days of idarubicin and cytarabine respectively starting Day 1 and ending Day 5.
Subjects who experience no remission or partial remission will receive a second course of the identical induction chemotherapy.
Cytarabine: Cytarabine (100 mg/m2 intravenously for 7 days) starting Day 1 and ending Day 7. Patients 80 years or older will only receive 2 and 5 days of idarubicin and cytarabine respectively starting Day 1 and ending Day 5.
Subjects who achieve a complete remission (CR) will receive 2 further courses of cytarabine postremission chemotherapy (consolidation) at 1.0 g/m2 for 6 dosages followed by HLA-mismatched DLI after | 19 |
| Total | 19 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Physician Decision | 8 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Idarubicin + Cytarabine + DLI |
|---|---|
| Age, Continuous | 71 years STANDARD_DEVIATION 5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 19 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 | 3 Participants |
| Race (NIH/OMB) More than one race | 1 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 | 15 Participants |
| Region of Enrollment United States | 19 Participants |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 12 / 17 |
| other Total, other adverse events | 17 / 17 |
| serious Total, serious adverse events | 8 / 17 |
Outcome results
Primary
Number of Subjects With Unacceptable Toxicity
Unacceptable toxicity is defined as: i. Grade III or IV acute GVHD (aGVHD) of the gut or liver or Grade IV aGVHD of the skin lasting \> 7 days; ii. Grade IV Common Terminology Criteria for Adverse Events (CTCAE) toxicity attributable to DLI (e.g. infusion reaction, as opposed to Grade IV CTCAE toxicity from chemotherapy) and lasting \>7 days iii. Treatment-related mortality (TRM)
Time frame: up to 8 weeks after last cell infusion
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Idarubicin + Cytarabine + DLI | Number of Subjects With Unacceptable Toxicity | 1 Participants |
Secondary
Disease Free Survival
1 year disease free survival rate following adoptive transfer
Time frame: one year following adoptive transfer
Population: Data not collected on one subject.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Idarubicin + Cytarabine + DLI | Disease Free Survival | 3 Participants |
Secondary
Number of Days to Hematopoietic Recovery
Hematopoietic recovery as measured by the date of the first of three consecutive laboratory values where the absolute neutrophil count (ANC) ≥ 500/μl , the date of the first of three consecutive laboratory values obtained on different days where the platelet count was \> 20,000/μl without transfusion.
Time frame: 2 years after completion of therapy
Population: Data not collected on one subject.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Idarubicin + Cytarabine + DLI | Number of Days to Hematopoietic Recovery | Neutrophil recovery | 29 days |
| Idarubicin + Cytarabine + DLI | Number of Days to Hematopoietic Recovery | Platelet recovery | 32 days |
Secondary
Number of Participants With Immune Recovery
Immune recovery determined by measurements of cytokine profiles, lymphocyte and natural killer (NK) enumeration and flow-based assays, measured prior to induction, prior to each round of consolidation, 8 weeks after the last cycle of consolidation, and every 3 months after treatment for up to 2 years
Time frame: up to 2 years after completing therapy
Population: Data not collected on one subject.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Idarubicin + Cytarabine + DLI | Number of Participants With Immune Recovery | 3 Participants |
Secondary
Overall Survival
Number of participants alive 2 years after completing adoptive transfer therapy.
Time frame: 2 years after completing therapy
Population: Seventeen patients were enrolled between 2014 and 2017 with a median follow-up time of 299 days among all patients. One enrolled patient who developed sepsis during induction chemotherapy did not receive MST, and was excluded from final analysis of safety and efficacy.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Idarubicin + Cytarabine + DLI | Overall Survival | 16 participants |
Secondary
Percentage of Subjects With Acute GVHD
Grade III or IV aGVHD of the gut or liver or Grade IV aGVHD of the skin lasting \> 7 days
Time frame: 8 weeks after last cell infusion
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Idarubicin + Cytarabine + DLI | Percentage of Subjects With Acute GVHD | 0 percentage of participants |
Secondary
Percentage of Subjects With Unacceptable Toxicity
Grade IV CTCAE toxicity attributable to DLI (e.g. infusion reaction, as opposed to Grade IV CTCAE toxicity from chemotherapy) and lasting \>7 days, Grade III or IV aGVHD of the gut or liver or Grade IV aGVHD of the skin lasting \> 7 days, or death
Time frame: 8 weeks after the last cell infusion
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Idarubicin + Cytarabine + DLI | Percentage of Subjects With Unacceptable Toxicity | 5.88 percentage of participants |
Secondary
Rate of Efficacy
Efficacy as measured by the number of subjects with a complete remission. Responses were evaluated according to standard criteria defined by the National Comprehensive Cancer Network Guidelines for AML (www.nccn.org).
Time frame: 2 years after completing therapy
Population: Data not collected on one subject.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Idarubicin + Cytarabine + DLI | Rate of Efficacy | 10 Participants |