Adoptive Transfer of Haplo-identical DLI for AML and MDS

Phase 1

Completed

• Conditions: Acute Myeloid Leukemia; Myelodysplastic Syndrome
• Interventions: Drug: Idarubicin; Drug: Cytarabine; Biological: DLI

• Registration Number: NCT02046122
• Lead Sponsor: Duke University

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2014-01-23
• Study First Submitted QC: 2014-01-23
• Study First Posted: 2014-01-27
• Study Start: 2014-07
• Primary Completion: 2017-06-15
• Results First Submitted: 2018-06-11
• Results First Submitted QC: 2018-07-17
• Results First Posted: 2018-07-18
• Study Completion: 2019-07-31
• Status Verified: 2020-12
• Last Update Submitted: 2020-12-01
• Last Update Posted: 2020-12-03

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 19

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

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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)

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Idarubicin + Cytarabine + DLI	DLI	Chemotherapy combined with adoptive transfer of HLA-haploidentical donor lymphocyte infusion (DLI)
Idarubicin + Cytarabine + DLI	Idarubicin	Chemotherapy combined with adoptive transfer of HLA-haploidentical donor lymphocyte infusion (DLI)
Idarubicin + Cytarabine + DLI	Cytarabine	Chemotherapy combined with adoptive transfer of HLA-haploidentical donor lymphocyte infusion (DLI)

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
Overall Survival	2 years after completing therapy	Number of participants alive 2 years after completing adoptive transfer therapy.
Disease Free Survival	one year following adoptive transfer	1 year disease free survival rate following adoptive transfer
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
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).
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
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

Trial Locations

Locations (1)

Duke University Medical Center; 🇺🇸 Durham, North Carolina, United States