Donor Lymphocyte Infusion (DLI)

Harnessing the graft-versus-leukemia effect after allogeneic transplant — indications, dosing, GvHD risk, and outcomes by disease

Key Points

• DLI involves infusing additional donor T lymphocytes after allogeneic HSCT to harness the graft-versus-leukemia effect for relapsed or mixed-chimerism disease.
• DLI is most effective in chronic myeloid leukemia (CML) relapse after HSCT — inducing molecular remission in >70% — and has moderate efficacy in AML and MDS.
• The principal risk is GvHD (acute and chronic), which is dose-dependent; escalating low-dose schedules reduce GvHD while preserving GvL.
• Aplasia (pancytopenia) can occur if the infused lymphocytes attack residual host hematopoiesis; this is more common when the patient has mixed chimerism at the time of DLI.
• Cytoreductive therapy (azacitidine, venetoclax, TKIs) given before DLI to reduce tumor burden substantially improves outcomes.
• DLI from haploidentical donors carries higher GvHD risk than MUD/MSD DLI and is used more cautiously with lower T-cell doses.

What Is Donor Lymphocyte Infusion?

Donor lymphocyte infusion (DLI) is the administration of lymphocytes — predominantly T cells — collected from the original allogeneic stem cell donor to a patient who has undergone prior allogeneic HSCT. Unlike the original transplant, DLI does not require conditioning chemotherapy or hospitalization in most cases; it is given as a simple intravenous infusion in the outpatient setting. The rationale is straightforward: if a patient's leukemia relapses after allogeneic HSCT, or if the graft is losing ground (declining donor chimerism), the immunosuppression can be reduced and additional donor…

Mechanism: The Graft-versus-Leukemia Effect

The therapeutic effect of DLI depends on donor T cells (and to a lesser extent NK cells) recognizing antigens on host leukemia cells that distinguish them from normal donor cells — the same mechanism that underlies post-transplant GvL. **Key antigenic targets:** - **Minor histocompatibility antigens (mHAs):** Even in fully HLA-matched transplants, donor and recipient differ in non-HLA polymorphic proteins. Donor T cells primed against these mHAs can attack both normal host cells (GvHD) and host leukemia cells (GvL). The ideal scenario is mHAs expressed predominantly or exclusively on…

Indications for DLI

DLI is used in three principal clinical scenarios after allogeneic HSCT: **1. Overt hematologic relapse:** When the underlying malignancy returns after transplant — rising blasts in AML, BCR-ABL detection in CML, lymphoma recurrence. DLI is most effective when disease burden is low; cytoreductive therapy to reduce bulk disease before DLI substantially improves outcomes (see below). **2. Declining donor chimerism (mixed chimerism):** Routine chimerism monitoring detects progressive decreases in donor hematopoiesis before frank morphological relapse. Declining donor chimerism is an early…

DLI Collection, Dosing, and Schedules

**Collection:** DLI lymphocytes are collected from the original stem cell donor by peripheral blood apheresis (leukapheresis) without prior G-CSF mobilization — a relatively straightforward outpatient procedure for the donor. The collected mononuclear cells are either used fresh or cryopreserved. In planned escalating-dose protocols, multiple collections may be stored in advance. **Dosing — the critical variable:** T-cell dose (expressed as CD3+ cells/kg recipient body weight) is the primary determinant of both GvL efficacy and GvHD risk. Higher doses deliver more potent GvL but…

Toxicities: GvHD and Aplasia

**Graft-versus-Host Disease:** GvHD is the principal risk of DLI — it is the same T-cell alloreactivity that mediates GvL, directed at normal host tissues. Acute GvHD after DLI occurs in 30–60% of recipients (higher with MUD and haploidentical donors, higher with higher T-cell doses). Chronic GvHD occurs in 30–40% of patients who achieve long-term engraftment. Severe GvHD (Grade III–IV acute or severe cGvHD) occurs in 10–15%. Management follows standard GvHD protocols: topical therapy for skin-limited Grade I, systemic prednisone (1–2 mg/kg/day) for Grade II–IV acute GvHD, ruxolitinib for…

Cytoreduction Before DLI

Disease burden at the time of DLI is the most important modifiable predictor of response. Patients with bulky relapsed AML who receive DLI without prior cytoreduction have very low response rates — the tumor is simply outpacing the immune response. Cytoreductive therapy given before DLI reduces tumor burden, potentially improves tumor immunogenicity, and creates a more favorable immune environment for DLI to work. **Azacitidine:** The most extensively studied cytoreductive agent pre-DLI. Azacitidine has direct cytoreductive effects on myeloid malignancies AND independent immunomodulatory…

Specific DLI Protocols and Emerging Approaches

**Pre-emptive (prophylactic) DLI:** Some centers administer DLI as scheduled prophylaxis to all high-risk patients who complete post-transplant immunosuppression — rather than waiting for relapse. The rationale: delivering GvL while disease burden is at its lowest maximizes efficacy and minimizes toxicity. Data from European and German cooperative group studies support this approach in high-risk AML and MDS, with lower relapse rates without significantly increased GvHD mortality. **Virus-specific T cells (VSTs):** A more targeted application of the DLI principle — isolating or expanding T…