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Single intravenous infusion with 2x10E6 T-cells/kg

Donor lymphocyte preparation depleted of host functional alloreactive T-cells

Stephan Mielke, MD

Denis-Claude Roy, MD

Andrea Velardi, MD

Katy Rezvani, MD PhD

The purpose of this study is to determine whether the administration of a donor lymphocyte preparation depleted of functional host alloreactive T-cells (ATIR) after a T-cell depleted stem cell transplant from a related, haploidentical donor enhances survival by improving the immune effect against infections while preventing graft-versus-host disease .

Allogeneic stem cell transplantation is the treatment of choice for many patients with leukemia and other hematologic malignancies. However, a major limitation of this therapy is that for a significant number of patients no fully HLA-matched donor can be found. The application of partially HLA-matched (haploidentical) family donors, who are virtually always available, has some complications. If there is no T-cell add-back it increases the risk for life-threatening infections and disease relapse, while in case of T-cell add-back the risk for graft-versus-host disease is raised.

Kiadis Pharma has developed a method to selectively deplete host alloreactive T-cells through photodynamic therapy, using TH9402 ex vivo. The donor lymphocyte preparation depleted of functional host alloreactive T-cells (ATIR) is administered to the patient 28-42 days after the stem cell transplant.

Efficacy and Safety of a Donor Lymphocyte Preparation Depleted of Functional Host Alloreactive T-cells (ATIR) in Patients Undergoing a Peripheral Blood Stem Cell Transplant From a Related, Haploidentical Donor

An Open-label, Uncontrolled, Multicenter, Multinational Study on the Efficacy and Safety of Administration of Donor Lymphocytes Depleted of Alloreactive T-cells (ATIR), Through the Use of TH9402 and Light Treatment in an ex Vivo Process, in Patients Receiving a CD34-selected Peripheral Blood Stem Cell Graft From a Related, Haploidentical Donor

TRM is defined as death due to causes other than disease relapse or progression, or other causes which are unrelated to the transplantation procedure (e.g. accident, suicide)

GVHD was graded according to standard criteria as referred to in the reference module (Filipovich et al. 2005; Przepiorka et al. 1995).

Kiadis Pharma

Donor lymphocyte preparation depleted of host functional alloreactive T-cells: Single intravenous infusion with 2x10E6 T-cells/kg

ATIR

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

Hematologic malignancy

Donor HLA compatibility (HLA-A, -B, -DR)

Andrew Sandler, MD / Chief Medical Officer

TRM at 6 months post HSCT

TRM at 12 months post HSCT

TRM at 24 months post HSCT

Transplant Related Mortality

Grade II acute GVHD (moderate)

Grade III (moderate) or IV (severe) acute GVHD

Severe chronic GVHD

Incidence and Severity Graft-versus-host Disease (GVHD)

Data were not collected, premature termination of study

Progression Free Survival

Data not collected, premature termination of study

Incidence and Severity of Bacterial, Viral or Fungal Infection

Immune Reconstitution

Health Status (Including Quality of Life)

OS 6 months after the HSCT

OS 12 months after the HSCT

OS 24 months after the HSCT

Overall Survival

Overall Study

Leukemia, Myelogenous, Chronic, BCR-ABL Positive

Philadelphia Chromosome

Translocation, Genetic

Chromosome Aberrations

Chronic Disease

Disease Attributes

Chronic Graft Versus Host Disease

Chronic Myeloid Leukemia

All Drugs and Chemicals

Antineoplastic Agents

Antirheumatic Agents

Micronutrients

Anticoagulants

Blood Substitutes

Hematinics

Antibodies

Cyclophosphamide

Fludarabine

Fludarabine phosphate

Iron

Immunoglobulins

Busulfan

Dextrans

Iron-Dextran Complex

Patients with chronic myeloid leukemia suitable for allogeneic stem cell transplantation with a matched related donor.

Patients were conditioned with oral busulfan 12mg/kg (days -6 to -4), cyclophosphamide 120mg/kg (days -3,-2), rabbit antithymocytic globulin, (Fresenius, Bad Hamburg, Germany) 25mg/kg (days -5 to -1) and fludarabine 200 mg/kg (days -7 to-3). CD34 cells were positively selected using anti-CD34 antibody conjugated to iron-dextran microbeads using CliniMACS device (Miltenyi Biotech, Bergisch Gladbach, Germany) with an aim to collect \> 5.0 x 106 CD34 cells/kg. DLI was administered in escalating dose regimen starting from 3 x 106 cells/kg followed as necessary by 1 x 107 cells/kg, 5 x 107 cells/kg and 1 x 108 cells/kg.

Stem cell transplantation

Jacob M Rowe, MD

Allogeneic stem cell transplantation, the only known curative modality for CML, was abandoned in recent years for a very effective and much less toxic targeted therapy with the tyrosine kinase inhibitors (TKIs). However, approximately one third of patients still need another treatment including stem cell transplantation. The study protocol comprised a cohort of consecutive patients with CML who received allogeneic stem cell transplantation using partial T cell depletion, with no post-transplant GvHD prophylaxis. Forty consecutive patients with CML underwent allogeneic stem cell transplantation from a matched sibling using partial T cell depletion (TCD), in a single institution. Escalated dose of donor lymphocyte infusion (DLI) was given in case of either relapse or presence of minimal residual disease (MRD) as detected by cytogenetic or molecular analysis.

The purpose of the study is to decrease transplant-related toxicity.

Patients were conditioned with oral busulfan 12mg/kg (days -6 to -4), cyclophosphamide 120mg/kg (days -3,-2), rabbit antithymocytic globulin, (Fresenius, Bad Hamburg, Germany) 25mg/kg (days -5 to -1) and fludarabine 200 mg/kg (days -7 to-3). Final busulfan dose was individually determined based on measurements of serum busulfan levels with a target dose of 850-1400 microM x minute.

Transplants were performed in reverse isolation rooms equipped with high-efficiency particulate air filtration systems (HEPA). No post-transplant GvHD prophylaxis was given. Post-transplant infection prophylaxis consisted of acyclovir, itraconazole, trimethoprim-sulfamethoxazole and penicillin VK. Cytomegalovirus (CMV) status was determined weekly using PCR for CMV-DNA and pp65 antigenemia in blood leukocytes, followed by preemptive ganciclovir administration when positive.

Donors Donors were human leukocyte antigen (HLA) A,B,C serologically matched and DR and DQ molecularly matched siblings. Donor stem cells were collected following mobilization with 10 µg/kg/day G-CSF, given subcutaneously for 5 consecutive days. CD34 cells were positively selected using anti-CD34 antibody conjugated to iron-dextran microbeads using CliniMACS device (Miltenyi Biotech, Bergisch Gladbach, Germany) with an aim to collect \> 5.0 x 106 CD34 cells/kg.

Disease monitoring Following transplant, all patients were under close surveillance for the presence of minimal residual disease (MRD) using cytogenetic analysis and PCR for the detection of BCR/ABL transcripts. Bone marrow and peripheral blood samples were examined every 3 months in the first year post transplant and every 3-6 months in the subsequent years.

PCR method: RQ-PCR was performed according to the Europe Against Cancer (EAC) protocol.19 The BCR-ABL and ABL copy numbers were calculated by comparing with the standard curve generated using IPSOGEN FusionQuant Standards. The results of quantifying BCR-ABL transcripts were expressed as percentage ratios relative to total ABL transcripts.

A minimum number of 1x104 copies of ABL is the lower limit below which a negative RT-PCR was considered unreliable. In the molecular biology laboratory of the Rambam Health Care Campus the sensitivity for quantitative Q-PCR is (10-5).

Donor leukocyte infusion (DLI). DLI was administered in escalating dose regimen starting from 3 x 106 cells/kg followed as necessary by 1 x 107 cells/kg, 5 x 107 cells/kg and 1 x 108 cells/kg.

DLI was used in case of persistence/reappearance of BCR-ABL transcripts starting from 6 months post transplant onward. In instances where more than 1 DLI was administered the successive escalated dose was given at ≥ 3-month intervals as dictated by MRD follow-up.

Allogeneic Stem Cell Transplantation in CML With Partial T Cell Depletion

Allogeneic Stem Cell Transplantation in CML With Partial T Cell Depletion and Preemptive Donor Lymphocyte Infusion.

Miltenyi Biomedicine GmbH

Rambam Health Care Campus

Tsila Zuckerman, MD

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Efficacy and Safety of a Donor Lymphocyte Preparation Depleted of Functional Host Alloreactive T-cells (ATIR) in Patients Undergoing a Peripheral Blood Stem Cell Transplant From a Related, Haploidentical Donor	NCT00967343	Myeloid Leukemi... Lymphoblastic L... Lymphoma Multiple Myelom... Myelodysplastic... Myeloproliferat...	Donor lymphocyt...	18 Years - 65 Years	Kiadis Pharma
Efficacy and Safety of a Donor Lymphocyte Preparation Depleted of Functional Host Alloreactive T-cells (ATIR) in Patients Undergoing a Peripheral Blood Stem Cell Transplant From a Related, Haploidentical Donor	NCT00967343	Myeloid Leukemi... Lymphoblastic L... Lymphoma Multiple Myelom... Myelodysplastic... Myeloproliferat...	Donor lymphocyt...	18 Years - 65 Years	Kiadis Pharma
Allogeneic Stem Cell Transplantation in CML With Partial T Cell Depletion	NCT00966810	Philadelphia Ch...	Stem cell trans...	18 Years - 65 Years	Rambam Health Care Campus
Allogeneic Stem Cell Transplantation in CML With Partial T Cell Depletion	NCT00966810	Philadelphia Ch...	Stem cell trans...	18 Years - 65 Years	Rambam Health Care Campus

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