CHIMERISM & DLI

Dr. Serdar ŞIVGIN

Kayseri Feb,2011

CHIMERISM

‘Chimera’ refers to Greek mythology where Homer described a fire-spitting monster;

with the head of a lion the body of a goat and the tail of a serpent terrorizing Lycia, a

region in Asia Minor, and which was finally sacrificed by the ancient hero Bellerophon.

CHIMERISM

The term chimerism was first introduced into medicine by Anderson et al. in 1951, when they wrote that ‘a chimera is an organism whose cells derive from two or more distinct zygote lineages’,

and it was first used in the field of transplantation by Ford in 1956.

CHIMERISM If all hematopoietic cells post transplant

are of donor origin, the patient is called a ‘complete chimera’ and shows a ‘complete chimerism’.

Patients with complete chimerism at a certain time point post transplant can later develop a state of ‘mixed chimerism’ and vice versa.

CHIMERISM

These patients are then referred to have an ‘increasing’ or an ‘decreasing mixed chimerism’.

Peripheral blood or bone marrow is most often used for chimerism analysis with or without further manipulation of different cell subpopulations

CHIMERISM

Patients could show complete chimerism in one compartment, for example, NK cells, whereas others could be totally or in part recipient derived.

This is called ‘split chimerism’

CHIMERISM

In hematopoietic cell transplantation (HCT), chimerism refers to the presence of lympho-hematopoietic cells of donor origin after an allogeneic HCT.

For practical reasons, the term ‘complete or full (donor) chimerism’ has been defined as 95% of cells of donor origin, while the term ‘mixed chimerism’ is used to describe patients with 5–95% cells of donor origin in hematopoietic tissues

CHIMERISM

Term Definition

Graft rejection <5% of T-cells of donor . origin

Mixed T-cell chimerism 5–95% of T-cells of donor . . origin

Full (complete) donor T-cell

Chimerism >95% of T-cells of donor . origin

Increasing T-cell chimerism Increasing percentage of T- . cells of donor origin

CHIMERISM

Assessment of donor chimerism levels might help identify patients at higher risk of relapse after nonmyeloablative/reduced-intensity conditioning.

First, high donor chimerism levels among immune cells (T-cells and NK cells) might be a surrogate for high graft-versus-tumor effects. Secondly, chimerism analyses might be useful to detect and quantitate minimal residual disease after HCT.

Chimerism as a marker for minimal residual disease

In patients receiving truly non-myeloablative conditioning, chimerism among total blood cells or among myeloid cells in patients with myeloid malignancies has been a poor marker for minimal residual disease, and has not been shown to predict HCT outcomes.

CHIMERISM

Monitoring mixed chimerism among peripheral blood subpopulations early after transplantation identifies patients at risk for graft rejection and for grade II–IV acute GVHD

CHIMERISM

Achievement of full donor T-cell chimerism is associated with decreased risk of relapse.

Chimerism levels among granulocytes have been poor predictors for HCT outcomes, but studies are needed to evaluate the efficacy of chimerism monitoring among cell subtypes enriched for the phenotype of the malignant cells.

DLI

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DONOR LYMPHOCYTE INFUSION (DLI)

DLI

Marrow transplantation was initially developed as a procedure to rescue atomic bomb survivors from marrow aplasia induced by high-dose total body irradiation (TBI).

DLI

. Donor leukocyte infusion (DLI) is a form of adoptive immunotherapy in which a patient with a hematologic malignancy who has previously received an allogeneic bone marrow transplant has relapsed.

The leukocytes are obtained from the original bone marrow donor through a leukapheresis procedure

DLI

. The principle use of donor leukocyte infusion (also know as donor lymphocyte or buffy coat transfusion) is to induce a graft-versus -tumor response by introducing white blood cells from the donor to the patient

DLI

. The objective is for the donor leukocyte cells to recognize the cancer cells and destroy them.

This differs from a repeat bone marrow transplant in that no chemotherapy is given prior to the infusion and the T-cells (which are part of the body’s immune system and fights infection) are not depleted.

DLI

. DLI is considered a salvage

therapy at the time of relapse. DLI has been proposed for a

variety of hematologic malignancies including;

CML, AML, ALL, multiple myeloma, CLL, MDS, Hodgkin’s disease, and NHL.

DLI

. Graft-vs-host disease (GVHD) was a major cause of transplant-related mortality, but circumstantial evidence suggested that donor T cells, the mediators of GVHD, could also induce a therapeutic“graft-vs-leukemia” (GVL) effect

DLI

. Important characteristics of DLI that remain true today are:

First, there is a relationship between the infused cell dose and the likelihood of a clinically significant antitumor response.

Second, the antitumor response mediated by donor immunocompetent cells goes hand in hand with GVHD.

DLI

. DLI is an established therapy of hematologic malignancies in relapse after allogeneic SCT.

DLI induces sustained complete remissions in more than 60% of patients with CML in early stage relapse but in fewer than 20% of patients with acute leukemia, multiple myeloma, and lymphoma.

Complications of DLI

. Graft-vs-Host Disease

Aplasia

Infection

DLI

. The majority of patients experiencing myelosuppression after DLI recover a normal blood cell count spontaneously.

But, myelosuppression may be fatal approximately 10% of patients, with death being caused by infection or bleeding.

DLI

. Grade II-IV acute GvHD develops in almost half of patients (50 %) given DLI.

The highest incidence being observed when the donor is an unrelated volunteer.

DLI

. In fact, only 20- 30% of patients with AML achieve a hematologic remission after DLI and the value for patients with ALL is even lower.

DLI can provide a direct GVL effect and offer an effective therapy for relapsed hematologic malignancies after hematopoietic stem cell transplantation.

DLI

. One of the most important, still unsolved problem of DLI is that concerning the much lower efficacy of GVL in patients with acute leukemia than in those with CML.

The more encouraging results obtained when DLI is used as consolidation therapy for patients who have obtained a complete remission after chemotherapy.

CHIMERISM & DLI

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thank you..