Efficacy Study on the Strategy of HSV-Tk Engineering Donor Lymphocytes to Treat Patients With High Risk Acute Leukemia

TK008: Randomized Phase III Trial of Haploidentical HCT With or Without an Add Back Strategy of HSV-Tk Donor Lymphocytes in Patients With High Risk Acute Leukemia

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.

Inclusion Criteria:

• Age ≥ 18 years

• Any of the following conditions:

  1. AML and ALL in 1st complete remission (CR1)
  2. AML and ALL in 2nd or subsequent CR
  3. secondary AML in CR
  4. AML and ALL in 1st or 2nd relapse or primary refractory

• Family donor with patient-donor number of HLA mismatches ≥ 2 (full haploidentical), or family donors sharing one HLA-haplotype with the patient

• Stable clinical conditions and life expectancy > 3 months

• PS ECOG < 2

• Serum creatinine < 1.5 x ULN

• Bilirubin < 1.5 x ULN; transaminases < 3 x ULN

• Left ventricular ejection fraction > 45%

• QTc interval < 450 ms

• DLCO > 50%

• Patients, or legal guardians, and donors must sign an informed consent indicating that they are aware this is a research study and have been told of its possible benefits and toxic side effects

Exclusion Criteria:

• Patients with life-threatening condition or complication other than their basic condition
• Contraindication to haploidentical HCT as defined by the Investigator
• Patients with active CNS disease
• Pregnant or lactation.

Exclusion criteria for HSV-Tk infusion:

• Infections requiring administration of ganciclovir or valganciclovir at the time of infusion
• GvHD requiring systemic immunosuppressive therapy
• Ongoing systemic immunosuppressive therapy after haploidentical HCT
• Administration of G-CSF after haploidentical HCT

HSV-Tk cells can be administered after an adequate patient wash-out period (24 hours)