The main objective of this randomized trial is to compare disease-free survival (DFS) in high risk leukemia patients who underwent haploidentical HCT followed by an add back strategy of HSV-Tk donor lymphocytes or standard haploidentical HCT
Delayed immune-reconstitution remains one of the main limitation of haploidentical stem cell transplantation. The risk of severe infections remains high for several months and CD3+ reconstitution could take more than 10 months. The low number of lymphocytes infused with the graft, the degree of HLA (Human Leukocyte Antigen) disparity, and a reduced thymic function in adults and differences in host/donor antigen presenting cells are contributing causes. The infusions of HSV-TK engineered lymphocytes may represent a significant therapeutic improvement in haploidentical HCT (hematopoietic cell transplantation), because it remarkably may enhance both GvL (Graft versus Leukemia) activity, thus reducing the occurrence of disease relapse, and post-transplant immune reconstitution in the absence of chronic immune suppression, thus decreasing the rate of both post-transplant opportunistic infections and transplant-related mortality. Furthermore, the efficient control of GvHD achieved via the suicide mechanism allows also the multiple infusion of HSV-TK-treated donor lymphocytes, when needed, that might further improve post-transplant host immune reconstitution, and survival in patients receiving haplo-HCT. Finally, this therapeutic approach can become a valuable option for all candidates, including patients with advanced disease and older age. The proposed clinical trial represents an innovative therapeutic treatment for patients affected by high risk acute leukemia, who have undergone haploidentical stem cell transplantation.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
92
Infusion of approximately 1±0.2 x 10\^7 HSV-Tk genetically modified CD3+ cells/Kg between day +21 and day +49 after haploidentical HCT; in absence of immune reconstitution and GvHD further infusions up to 4 will be administered on monthly basis.
Haploidentical HCT with the infusion of CD34+ cells plus a fixed dose of T cells (1 x 10\^4/Kg) or unmanipulated haploidentical stem cell transplantation followed by high-dose cyclophosphamide as part of GvHD prophylaxis
Disease-free Survival (DFS)
Defined as the measure from the date of randomization until the date of relapse (or progression), or death from any cause, whichever occurs first. Disease relapse or progression was determined by the Investigator based on the following disease examination: * Morphology (bone marrow or peripheral blood) * Confirmation of mixed or full chimerism (evaluation of the degree of chimerism between donor/host, according to institutional clinical practice, on bone marrow or peripheral blood) * Cytogenetic and/or molecular and/or other tests, according to institutional clinical practice (bone marrow or peripheral blood).
Time frame: From the date of randomization, assessed up to 12 months
Overall Survival (OS)
any death without previous occurrence of a documented relapse (or progression).Patients alive or without any follow up will be censored.
Time frame: From the date of randomization to the date of death, assessed up to 12 months
Immune Reconstitution (IR)
Assess how many patients experience IR. For the assessment, competing risk analysis was performed considering death, relapse, and disease progression as competing events. Patients who were still alive and had no recovery (IR) nor relapse (or progression) were censored.IR is defined as achieving a level of circulating CD3+ ≥ 100/μL for two consecutive observations. The following laboratory examinations are performed: * Hematology: WBC (full and differential), RBC, platelets, Hb, Htc, MCV, MPV, serology CMV (PCR and antigenemia). * Blood chemistry: AST, ALT, γGT, total bilirubin, LDH.
Time frame: Weekly up to IR after engraftment of HCT, monthly for 6 months from date of IR and then at month 9 and 12
Engraftment Rate
Defined as the persistent blood cells count above predefined level.
Time frame: At day 15 after HCT, monthly for 6 months after HCT and then at month 9 and 12
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Northwestern University Feinberg School of Medicine
Chicago, Illinois, United States
Washington University Medical School
St Louis, Missouri, United States
John Theurer Cancer Center at Hackensack University Medical Center
Hackensack, New Jersey, United States
Universitair Ziekenhuis
Ghent, Belgium
University Hospitals Leuven
Leuven, Belgium
Centre Hospitalier Universitaire de Liège - Domaine Universitaire du Sart Tilman
Liège, Belgium
Hôpital Jean Minjoz
Besançon, France
Centre Hospitalier Universitaire de Clermont-Ferrand
Clermont-Ferrand, France
Centre Hospitalier Régional Universitaire de Lille
Lille, France
Institut Paoli-Calmettes
Marseille, France
...and 26 more locations
Cumulative Incidence of Grade 2, 3, or 4 Acute GvHD (aGvHD)
Diagnosed and graded according to standard criteria. Grade 1: Skin: Stage 1-2: Rash on \< 25% of skin or Rash on 25-50% of skin Liver: Stage 1-2: Bilirubin 2-3 mg/dl or Bilirubin 3-6 mg/dl Gastrointestinal: Stage 1-2: Diarrhoea \> 500 ml/day or persistent nausea or Diarrhoea \> 1000ml/day
Time frame: from the date of HCT until the date of the first occurrence of aGvHD, assessed up to 6 months
Cumulative Incidence of Chronic GvHD (cGvHD)
Diagnosed and graded according to standard NIH consensus criteria
Time frame: From the date of HCT until the date of the first occurrence of cGvHD, assessed up to 12 months
Duration of GvHD Episodes
Diagnosed and graded according to standard NIH consensus criteria
Time frame: From the date of start until the date of resolution and duration of immunosuppressive treatments administered for controlling GvHD assessed up to 12 months
Cumulative Incidence of Relapse (CIR)
Defined on the basis of morphologic evidence of leukaemia in bone marrow or other sites. Gray's test was used to compare the sub-distribution functions of relapse (or progression) events in the two treatment groups. Patients alive without relapse (or regression) will be censored
Time frame: from the date of randomization to the date of the first occurrence of relapse, assessed up to 12 months
Incidence and Duration of Infectious Episodes and Infectious Disease Mortality
Diagnosis, monitoring and treatment of infectious relevant events
Time frame: From randomization to the date of resolution, assessed up to 12 months
Evaluate the Acute and Long-term Toxicity Related to the HSV-Tk Infusions
Toxicity profile of HSV-Tk infusions
Time frame: From HSV-Tk infusions to the date of resolution, assessed up to 12 months
Quality of Life (QoL) and Medical Care Utilization (MCU) in Both Arms
Medical resource use data collected will be used in health economic analyses where it may be combined with other data from other sources such as cost data or other clinical parameters.
Time frame: from randomization up to 12 months
Non-relapse Mortality (NRM)
Defined for all patients as any death without previous occurrence of a documented relapse (or progression). Absence of relapse was determined by the Investigator based on the following disease examination: * Morphology (bone marrow or peripheral blood) * Confirmation of mixed or full chimerism (evaluation of the degree of chimerism between donor/host, according to institutional clinical practice, on bone marrow or peripheral blood) * Cytogenetic and/or molecular and/or other tests, according to institutional clinical practice (bone marrow or peripheral blood). Gray's test was used to compare the sub-distribution functions of the death without previous relapse (or progression) and relapse (or progression) events in the two treatment groups.
Time frame: From the date of randomization to the date of death, assessed up to 12 months.