Oncology

Donor lymphocyte infusion

Donor lymphocyte infusion

What every physician needs to know:

Donor leukocyte infusion (DLI) has several indications after both myeloablative and non-myeloablative allogeneic stem cell transplantation (SCT). It is predominately used to treat and prevent relapse after SCT by exploiting the graft-versus-tumor effect (GVT) of donor derived T cells. It is also used to maximize donor chimerism and treat graft rejection. Less commonly, it is used to enhance immune reconstitution, to treat severe infectious illness and to treat post-transplant lymphoproliferative disorder (PTLD).

The major side effect of DLI is graft versus host disease (GVHD), which is treated similarly to GVHD that occurs after SCT. In general, DLI is reserved for patients without active GVHD and in most cases is administered without concurrent immune suppression. It can be used after related, unrelated and haploidentical transplants but is not available after unrelated umbilical cord transplants. Depending on the clinical situation, DLI may be administered in conjunction with chemotherapy.

DLI for disease relapse - general

The success of allogeneic SCT relies in part on the T cell mediated GVT effect. Through enhancement of this GVT activity, DLI can be curative for some patients who relapse after SCT. The success of this approach depends on several factors including underlying disease and its sensitivity to GVT induction, disease burden, timing of relapse in relation to SCT, presence of comorbid disease, donor availability and whether DLI is preceded by chemotherapy.

DLI is dramatically effective in inducing sustained remissions and cure in patients with chronic phase chronic myelogenous leukemia (CML) but is less effective in the treatment of other hematologic malignancies including advanced phase CML, acute myelogenous leukemia (AML), acute lymphocytic leukemia (ALL), non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL) and multiple myeloma.

In general, DLI should be given to patients off immune suppression who do not have GVHD. The optimization of DLI dosing and administration with or without chemotherapy in these disorders is the subject of ongoing disease specific investigations. Most studies use 1 x 10^7 to 1 x 10^8 CD3+ cells/kg of patient weight with little evidence to support a "dose:response" effect. In addition, studies to manipulate DLI through selection or engineering of antigen specific T cells are underway.

Alternative treatment options for relapse after SCT are very limited and poorly studied but include second SCT from the same or different donor, disease specific chemotherapy agents alone, or the testing of novel agents.

DLI for disease relapse - CML

Currently, SCT for patients with chronic phase CML is reserved for those who are intolerant or resistant to tyrosine kinase inhibitors. Relapsed chronic phase CML after SCT is very responsive to DLI with sustained complete remission (CR) rates of 70 to 90% even with low doses of DLI. CML in accelerated phase or blast crisis is less responsive to DLI alone and pretreatment with chemotherapy and/or tyrosine kinase inhibitors is recommended.

The use of tyrosine kinase inhibitors after DLI is a subject of debate since it is not clear whether their use enhances or weakens the GVT effect. In addition, tyrosine kinase inhibitors may not be appropriate for patients resistant to their activity before transplant.

DLI for disease relapse - AML

DLI is less successful in inducing sustained remissions for patients with relapsed AML after SCT. It is most successful when used for patients in a minimal disease state, when relapses occur more than 6 months after SCT and when administered after cytoreductive chemotherapy. These observations are highlighted in a large study by the European Group for Blood and Marrow Transplant, which reported outcomes of 399 patients with relapsed AML after SCT who received (n=171) and did not receive (n=228) DLI. Improved survival was noted for recipients of DLI. Factors associated with improved survival included the use of DLI once already in CR and good risk cytogenetics.

Other options for disease relapse after SCT are limited but include a second SCT and cytoreductive chemotherapy alone. Azacitidine either alone or with DLI is being explored to treat relapsed AML after SCT. This agent offers improved tolerability compared to conventional chemotherapy, and may increase the immunogenicity of malignant cells.

DLI for disease relapse - ALL

Despite a clear donor mediated GVT effect, relapsed ALL after allogeneic SCT has a poor prognosis with poor response to any salvage therapy including DLI. Remission rates of 0 to 20% have been reported with DLI but durations of these remissions are usually short and few survive long-term. The best outcomes for DLI are associated with prior use of cytoreductive chemotherapy and a minimal disease state at time of DLI. For patients with relapsed Philadelphia chromosome-positive ALL not resistant to tyrosine kinase inhibitors, sustained responses (either with or without DLI) have been reported with these agents. Due to poor response rates to DLI, alternative options should be explored, preferably as part of a clinical trial.

Exciting areas of investigation involve the manipulation of donor cells to be more tumor-specific (for example engineering donor T cells and natural killer (NK) cells with B-lymphocyte antigen CD19 (CD19) directed chimeric antigen receptors). Young patients with good performance status should be evaluated for a second SCT.

DLI for disease relapse - NHL, HL and multiple myeloma

Patients with recurrent NHL and HL after SCT may be candidates for DLI either alone or in conjunction with disease specific chemotherapy, monoclonal antibody therapy or radiation therapy. For example, patients with relapsed indolent NHL after SCT may have an effect from DLI alone, while patients with other more aggressive lymphomas may require chemotherapy or radiation therapy before DLI. Long term responses to DLI for patients with relapsed multiple myeloma (MM) have been clearly linked to an increased incidence of GVHD.

Due to their effects on immunologically active cells, current anti-myeloma therapies offer unique potential ways to enhance the effectiveness of DLI, without necessarily increasing the risk of GVHD. For example, immunoregulatory agents such as lenalidomide or thalidomide, which activate T cells and NK cells, can be used with or without DLI to treat relapsed MM after SCT. The proteasome inhibitors such as bortezomib inhibit T cell proliferation and GVHD and are effective in treating relapsed MM after SCT. The optimal uses of these agents after SCT (and in conjunction with DLI) have yet to be elucidated.

Prophylactic DLI

DLI can be used prophylactically for patients with high risk of disease relapse after SCT. It is often used after T cell depleted transplants to separate infusion of T cells from tissue injury to minimize risk of GVHD, or with T cell replete transplants with high risk of relapse based on underlying disease or disease stage.

DLI to enhance chimerism

After reduced intensity or non-myeloablative SCT, patients can have mixed chimerism (presence of both recipient and donor cells) for several months. It is hypothesized (though surprisingly not well established) that achieving full donor chimerism is essential for long-term disease free survival. DLI, even at low doses, can improve donor chimerism but administration needs to be balanced against the risks of developing DLI associated GVHD. The optimal use of DLI in this setting is controversial and needs to be investigated further.

It is not at all clear when (in relation to SCT) a patient with persistent mixed chimerism should be treated with DLI. It is also not clear what degree of mixed chimerism should be treated. It is unknown when the benefits of DLI to establish full donor chimerism outweigh DLI associated risks. To further complicate potential investigations to answer these questions, the risk/benefit ratio is likely to be dependent on several factors including type and intensity of conditioning regimen used for SCT, GVHD prophylaxis used for SCT, underlying disease, sensitivity of chimerism analysis, and cell fraction analyzed.

A more clear indication for use of DLI is when there is loss of donor chimerism over time. It is important to differentiate whether this is representative of disease relapse or loss of donor chimerism as treatment approaches (choice of chemotherapy prior to DLI and cell dose of DLI) may be different. When the clinician has made a decision to administer DLI for persistent mixed chimerism or falling donor chimerism, a lower cell dose than used to treat relapsed disease can be used with plans for a sequential dose escalation of DLI if needed.

An example of the application of DLI for mixed chimerism highlights many of these features. Peggs et al treated 76 patients with relapsed or refractory Hodgkin lymphoma with reduced intensity SCT and in vivo T cell depletion with alemtuzumab. Nineteen of 22 patients with mixed chimerism received DLI and converted to full donor chimerism and had a subsequent relapse rate of 5%, significantly less than patients who had full donor chimerism and hence did not get DLI. DLI was given to 24 patients for relapse and 79% responded. CD3 cell doses between 1 x 10^6 -1 x 10^7/kg were used for mixed chimerism and 1 x 10^7-1 x 10^8/kg for relapse.

This study highlights the potent GVT activity of DLI, and that outcomes may vary depending on the use of prior T cell depletions, chimerism status and timing of DLI.

DLI and chemotherapy

DLI is often administered in conjunction with chemotherapy in order to improve outcomes. Cytoreductive chemotherapy for relapsed AML, ALL or aggressive lymphomas is often administered prior to DLI, in order to control the disease in the short term, to allow time for the GVT effect of DLI to exert its effect. The optimal timing of DLI in relation to chemotherapy (both in terms of efficacy and toxicity) is unknown and likely to be dependent on the chemotherapy regimen used and the underlying disease.

The advantages of early administration of DLI in relation to chemotherapy needs to be balanced by potential risks of increased inflammation and resulting potential increased incidence of acute GVHD. A large study evaluated outcomes of 65 patients with relapsed myeloid malignancies after SCT who were treated with standard induction regimens followed by DLI at nadir. In this study response rates were 47% and the incidence of Grade II-IV GVHD was 45%, similar to GVHD rates after DLI alone.

Some studies have shown an increased incidence of GVHD in association with very early administration (2-4 days) of DLI after cytotoxic chemotherapy and with certain chemotherapeutic regimens (such as fludarabine based regimens which may allow for a more rapid expansion of donor T cells). As a general recommendation, DLI can be administered at nadir or beyond after standard cytotoxic chemotherapy. The European Group of Blood and Marrow Transplantation (EBMT) retrospective review of DLI for AML suggested DLI is most effective when given to patients already in remission after other relapse therapy.

It may be that DLI is most effective in the setting of minimal disease state, or it may be that inducing remission selects those patients most likely to benefit from DLI. The increasing availability of non-cytotoxic chemotherapy agents raises interesting questions about timing of these agents with DLI to affect both efficacy and separate from GVHD effects.

The optimal use of DLI with targeted therapies such as tyrosine kinase inhibitors is also a subject of debate.

GVHD after DLI

GVHD is the major treatment related toxicity of DLI and there is a strong correlation between DLI's GVT effects and the incidence of GVHD. When administered for relapsed disease after myeloablative SCT, the incidence of acute GVHD ranges from 40-60% with Grade III-IV GVHD affecting 20-35% of patients. Chronic GVHD occurs in 33-61% of patients. The median time to onset of acute GVHD after conventional DLI is 28-32 days but the range is quite broad. History of acute GVHD after SCT does not appear to increase the incidence of acute GVHD after DLI.

The incidence of GVHD after unrelated DLI does not appear to be increased over recipients of related DLI, although many clinicians use different doses of DLI from unrelated versus related donors. The incidence of severe GVHD after haploidentical DLI is high and it is recommended in this setting that GVHD prophylaxis be used. The clinical signs and symptoms of GVHD after DLI are similar to GVHD that occurs after SCT and treatment approaches are the same.

DLI is often administered in conjunction with preceding cytoreductive chemotherapy and the timing and choice of chemotherapeutic regimens can impact the incidence and severity of GVHD (discussed in more detail in section "DLI and chemotherapy").

Interestingly, there is no clear association between DLI cell dose and the incidence of GVHD. However, it has been hypothesized that there may be a minimal effective dose of DLI, which can induce remissions without causing GVHD. Low dose DLI followed by sequential dose escalation strategies to treat relapsed chronic phase CML have shown lower incidences of GVHD when a lower starting dose of DLI is used without a corresponding loss in response rates.

DLI after alternative donor transplants

DLI is not an option after unrelated donor cord transplants. DLI has been studied as a method to treat relapsed disease after haploidentical SCT. Conventional doses of DLI for prophylaxis or relapse have invariably been associated with high rates of severe GVHD and GVHD related deaths. For this reason DLI has been administered with GVHD prophylaxis in the haploidentical SCT setting, with improved rates of severe GVHD without an obvious compromise in response rates. For this reason, GVHD prophylaxis should be administered with haploidentical DLI.

DLI to treat PTLD and infectious complications after allogeneic SCT

The administration of DLI not only can induce a potent GVT response but may also be useful in restoring cell-mediated immunity, which is critical to treat non-relapse complications after transplant. Epstein-Barr virus (EBV) associated post-transplantation lymphoproliferative disorder (PTLD) occurs in the setting of unrestrained EBV driven proliferation of B cells in the absence of effective T cell regulation; they are more common after T cell depleted grafts and are usually of donor origin. PTLD previously carried a dismal prognosis after SCT but DLI and rituximab have now been shown to induce durable responses in the majority of patients. With the goal of minimizing toxicity from GVHD, lower doses of DLI (1.0 x 10^6 CD3+ cells/kg) have been effectively used. DLI has also been used in the post SCT setting to successfully treat serious viral infections.

What features of the presentation will guide me toward possible causes and next treatment steps:

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What laboratory studies should you order to help make the diagnosis and how should you interpret the results?

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What conditions can underlie donor lymphocyte infusions:

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What imaging studies (if any) will be helpful?

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What therapies should you initiate immediately and under what circumstances – even if root cause is unidentified?

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What other therapies are helpful for reducing complications?

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What should you tell the patient and the family about prognosis?

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Pathophysiology

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What other clinical manifestations may help me to diagnose donor lymphocyte infusions?

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What’s the evidence?

Porter, DL, Alyea, EP, Antin, JH. "NCI First International Workshop on the Biology, Prevention, and Treatment of Relapse after Allogeneic Hematopoietic Stem Cell Transplantation: Report from the Committee on Treatment of Relapse after Allogeneic Hematopoietic Stem Cell Transplantation". Biol Blood Marrow Transplant. vol. 16. 2010. pp. 1467-1503.

[This is a thorough review of options for management of disease relapse after SCT by disease subtype. Puts DLI in context of other management options and reports the available evidence extensively.]

Noelle, V. "Frey and David L. Porter. GVHD after DLI: Presentation and Management. Best Practice and Research". Clinical Hematology. vol. 21. 2008. pp. 205-222.

[This is a thorough review of the most significant toxicity of DLI.]

Rager, A, Porter, D. "Cellular therapy following allogeneic stem cell transplantation". Therapeutic Advances in Hematology. 2011.

[A thorough review of the indications for DLI including treatment of PTLD or infectious complications post SCT.]

Schmid, C, Labopin, M, Nagler, A. "Donor lymphocyte infusion in the treatment of first hematologic relapse after allogeneic stem-cell transplantation in adults with acute myeloid leukemia: a retrospective risk factors analysis and comparison with other strategies by the EBMT Acute Leukemia Working Party". J Clin Oncol. vol. 25. 2007. pp. 4938-4945.

[One of the largest experiences evaluating benefit of DLI and chemotherapy for relapse after SCT. A rigorous study despite retrospective nature.]

Collins, RH, Goldstein, S, Giralt, S. "Donor leukocyte infusions in acute lymphocytic leukemia". Bone Marrow Transplant. vol. 26. 2000. pp. 511-516.

[Long term follow for patients who received DLI for ALL.]

Dazzi, F, Szydlo, RM, Craddock, C. "Comparison of single dose and escalating dose regimens of donor lymphocyte infusion for relapse after allografting for chronic myeloid leukemia". Blood. vol. 95. 2000. pp. 67-71.

[Addresses possible dose relationship of DLI with efficacy and toxicity.]

Levine, JE, Braun, T, Penza, SL. "Prospective trial of chemotherapy and donor leukocyte infusions for relapse of advanced myeloid malignancies after allogeneic stem-cell transplantation". American Journal of Clinical Oncology. vol. 20. 2002. pp. 405-412.

[Large prospective study using DLI for AML.]

Peggs, KS, Kayani, I, Edwards, N. "Donor lymphocyte infusions modulate relapse risk in mixed chimeras and induce durable salvage in relapsed patients after T-cell-depleted allogeneic transplantation for Hodgkin's lymphoma". J Clin Oncol. vol. 29. 2011. pp. 971-978.

[Best available evidence for the potential impact of DLI to impact outcomes when administered for low donor chimerism.]
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