Co-infusion of haematopoietic stem cells from a haplo-identical donor and single unit unrelated cord blood in patients with a high risk of relapse:
A Phase l/ll study to assess safety and to investigate the biological mechanism of the anti-tumor response.

Although haematopoietic stem cells transplantation (HSCT) has become much safer over the last decade the major limitation remain “transplantation related mortality (TRM; e.g. due to viral reactivations/disease)” and relapse (in malignancies). Within the group of malignancies there is a subgroup of patients with a ”very high risk (of relapse) profile” (e.g. relapse AML, refractory lymphoma, relapse after first allo-HSCT). Although this “very high risk group” may potentially benefit from allo-HSCT with the currently available “standard” transplant protocols the expected survival rates are very low <20%. Cord blood (CB) is emerging as stem cell source for HSCT because it has many advantages above the conventional bone marrow grafts. Disadvantages are however low stem cell count/kg for adults associated with prolonged neutropenia and a slower T cell recovery. T cell depleted haplo-grafts have the advantage of early neutrophil engraftment but are associated with higher rates of secondary graft-failure and poor T-cell reconstitution associated with viral infections. KIR-mismatching in Haplo-grafting is suggested to have anti-leukemic potential.



RATIONALE:

Combining cord blood and readily available haplo-identical family donor-HSCT combines beneficial effects of both allogeneic transplantations strategies, such as the in the long term excellent T-cell recovery after CB HSCT, and the NK-cell mediated anti-tumor activity of CB with the early haplo-mediated neutrophil recovery and the targeted anti-leukemia effect of NK (KIR mismatch) and T-cells after selected haplo-HSCT. We propose therefore that this multimodal treatment protocol may be a treatment option in the selected group of patients with a “very high risk (on relapse) profile”. These patients with the very high risk profile may profit for from this double grafting because of:

Multi-modal cellular therapy: Strong early (first 2-4 weeks) NK + T-cells mediated anti-tumor activity from the haplo-graft and NK + T-cellular anti-tumor activity (> 4 weeks) from the CB-graft, without increasing the risk of aGVHD.



OBJECTIVE:

To study the safety of co-infusion of a T-/CD19 B-cell depleted haematopoietic stem cells from haplo-identical donor and a single unit cord blood unit and to investigate the anti-tumor responses from both grafts.



STUDY DESIGN:

Prospective study, Phase l/ll trial with an optimal 2-stage design.

To study the safety of co-infusion of a T-/CD19 B-cell depleted haematopoietic stem cells from haplo-identical donor and a single unit cord blood unit and to investigate the anti-tumor responses from both grafts.

T= 0 is inclusion till 12 months after allogeneic stem cell transplantation.

For a group of patients with a very high risk malignancy: Instead of using a single donor, or no transplantation at all, a combination of a cord blood unit and selected cells from a haplo-identical family-donor are infused at the day of transplant. The selection procedure of the haplodonor allows mismatch NK-cells and T-cells in the graft for extra anti-tumor effect.