Tuesday, 10 July 2012

The Use of Donor Lymphocyte Infusion’s (DLI’s) and Early Treatment for Relapse

Presented on Friday, 29 June 2012

Introduction to Bone Marrow Transplant Nursing

Aim & Objectives

Aim: to gain a basic understanding of what DLI’s are and their use in BMT.
• Define DLI’s
• Discuss where they fit in the treatment algorithm of BMT

Definition of DLI

• Donor Lymphocytes Infusions
• Also known as Leukocyte infusions or Buffy coat infusions
• Cytotoxic T Lymphocytes
• DLI may have modified cells à T helper, Cytokines (IL-2, GM-CSF, Interferon)


• B Cell
• T Cell à
- Helper (CD4+), to promote other cells function
# T Helper 0 à
# T Reg
# T helper 17
- Cytotoxic (CD8+) à Effector cell
- Natural Killer Cell à Innate immunity
- Gamma delta
- Memory T cell à Helper & Cytotoxic

Minimising Toxicity

• Minimise toxicity à reduce Transplant Related Mortality (TRM) à Relapse
• Relapse rates are higher in patient who don’t develop GVHD

Maximising Toxicity

• Maximise anti tumour effect à High morbidity and mortality or High Transplant Related Mortality (TRM)
• Relapse rates are lower in patient who develop GVHD versus who don’t
• Same cell that cause GVHD give some tumour effect therefore protection à Disease not return


• Allogeneic HSCT
• Combination of high dose chemotherapy & Allogeneic transplant à Remission
• Disease relapse is a major cause of treatment failure and salvage treatment options for these patients are limited

Relapse After Allogeneic HSCT

• No further therapy
• Withdrawal of immunosuppression to elicit a therapeutic graft-versus-tumor (GVT) response
• Reinduction chemotherapy with the same or different agents
• Or second transplants with or without preceding chemotherapy à Risk of serious, life-threatening complications
• Donor lymphocyte infusions with or without preceding chemotherapy à eliminate the need for second transplant.


• Patient who received syngeneic stem cell transplants relapsed more frequently than those who received allogeneic transplant.
• A rapid decrease or elimination of post grafting prophylaxis or treatment immunosuppression would often lead into remissions.
• Higher numbers of relapses were seen in patient who received T Cell depleted grafts compared to patients who received unmanipulated grafts.

Withdrawal of Immunosuppression

• Cyclosporine à blocks interleukin-2 (IL-2) transcription on the T cell
• Tacrolimus à inhibit IL-2 synthesis
• Graft versus Leukemia effect
• HSCT was used to allow for higher doses of chemotherapy and radiation therapy during treatment
• Graft-versus-leukemia/lymphoma (GVL) effect àin which the new immune cells produced by a matched donor (allogeneic) transplant can recognize cancer cells as a threat to the body and destroy them, reducing the rate of disease relapse.

Collection of DLI

• Collected from original stem cell transplant donor
• Obtained by using automated Apheresis equipment
• Collected cells may be infused unmanipulated or may be manipulated

The Goal of Therapy

• The goal of this therapy is to induce a remission of the patient's cancer by a process called the graft versus tumour effect (GVT). The donor T-cells can attack and control the growth of residual cancer cells providing the GVT effect.
• It is hoped that the donor leukocyte infusion will cause GVT and lead to a remission of the patients cancer.
• Patients might require standard chemotherapy, to reduce the amount of cancer cells they have prior to their donor lymphocyte infusion.

Cell Dose

• Ranged from 0.1 to 8.8 x 108 T Cell per Kg.
• @ RPAH we collect T Cell (CD4 positive T cell) ranged from 1 x 107 to 5 x 107 per Kg.
• Divided according to request
• How many T cells should be infused in the dose of DLI for prophylaxis or treatment?
• How many doses should be given?
• How frequently they should be given to maintain a GVL effect?
• When should infusion be stopped?

Un-manipulated Lymphocytes

• Harvested and infused fresh
• Harvested & cryopreserved
• Harvested, selected & infused fresh
• Harvested, selected & cryopreserved
• To prevent or treat relapse of the disease
• To treat mixed or decreasing chimerism
• To treat infections
• Prophylaxis or pre emptive therapy for relapse, chimerism or infections

Manipulated Lymphocytes

• Primed with expanded with cytokines
• Cultured with antigens, viruses, etc
• Gene modified with suicide genes
• Depleted of unwanted lymphocytes
• To enhance immune reconstitution
• To improve engraftment
• To prevent or modulate GvHD
• In combination with other cells such as mesenchimal stem cells, dendritic cells, etc

Response to DLI post Allo Tx.

• CML > 70%
• MM : 40%
• NHL : 20%
• Acute Leukemias : 15%
à MDS 36%, AML 22% & ALL 8%

Assessing efficacy of DLI:

- Morphologic response
- Molecular response
such as BCR-ABL for CML


• DLI is best suited for treating slowly relapsing Leukemia
• The use of DLI to boost anti leukemia/anti lymphoma effects in patient who fail develop GvHD
• The use of DLI for patients with only cytogenetic/molecular relapse continues to give excellent remissions rates


• DLI for relapse AML following HSCT is not very effective in getting patient into remission.
• Lower initial disease burden, reductions in the tumour burden with chemotherapy prior to DLI and favourable cytogenetic appear to be beneficial for patient with relapse leukemia after SCT


• Responds even more poorly than AML
• The poor response of relapse to DLI is thought to be mediated by diverse immune escape mechanisms of leukaemia cells


• Highest response rates were seen in the indolent lymphoma
• More aggressive lymphomas had a lower response rates
• Lower tumour burdens and slower growing malignancies are essential conditions for DLI to be effective

Multiple Myeloma

• The role of DLI is unclear, but can be considered


• Complications of DLI include acute and chronic graft versus host disease and bone marrow aplasia
• Resulting in immunosuppressant and susceptibility to opportunistic infections.
• Progessive disease is the major cause of death after DLI followed by GvHD, infections and pancytopaenia

RPA Experience

• 17 à Donor Lymphocyte collected from 2001 to 2011
• 17 à Patients had Donor Lymphocyte Infusions from 2001 to 2011

Summary & Future Direction

• Donor lymphocyte infusion (DLI) attempts to stimulate a donor versus leukemic reaction and thus eradicate the malignant clone of cells. in hopes of triggering additional GVL activity.
• But this option is effective only in a minority of patients, mostly those with chronic myelogenous leukemia.
• Searching for ways to increase the effectiveness of donor leukocyte infusions and minimize its side effects.


• Campregher, PV, Gooley, T, Scott, BL, Moravec, C, Sandmaier, B, Martin, PJ, Deeg, HJ, Warren, EH & Flowers, MED 2007, Result of donor lymphocyte infusions for relapsed myelodysplastic syndrome after hematopoietic cell transplantation, Bone Marrow Transplantation, 40, pp. 965-971
• Deol, A & Lum, LG 2010, Role of donor lymphocyte infusions in relapsed hematological malignancies after stem cell transplantation revisited, Cancer Treatment Reviews, 36, pp. 528-538.
• Luznik, L & Fuchs, E 2002, Donor lymphocyte infusions to treat hematologic malignancies in relapse after allegeneic Blood or marrow transplantation, Cancer Control, 9 (2), pp. 123-137.
• Roush, KS & Hillyer, CD 2002, Donor lymphocyte infusion therapy, Transfusion Medicine Reviews, 16 (2), pp. 161-176.


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