This document addresses the use of donor lymphocyte infusions (DLI) after an allogeneic hematopoietic progenitor cell transplant to treat a hematologic malignancy (e.g., cancer of the blood or bone marrow, such as leukemia or lymphoma). DLI is a form of adoptive immunotherapy in which a transplant recipient is infused with lymphocytes obtained in a leukapheresis procedure from the original allogeneic stem cell (hematopoietic progenitor cell) donor. This procedure attempts to induce a beneficial graft versus leukemia response without the need for additional bone marrow harvest from the donor or further high-dose chemotherapy for the recipient. Collection of donor lymphocytes requires that the original hematopoietic progenitor cell donor undergo a leukapheresis procedure. After collection, these cells are infused into the recipient either immediately or after frozen storage.

Medically Necessary:

Donor lymphocyte infusion, when donor lymphocytes are collected from the original hematopoietic progenitor cell donor, is considered medically necessary for individuals following a medically necessary, allogeneic or mini-allogeneic hematopoietic progenitor cell transplant for a hematologic malignancy.

Collection and cryopreservation of donor lymphocytes is considered medically necessary prior to, at the time of, or after a medically necessary allogeneic or mini-allogeneic hematopoietic progenitor cell transplant.

Investigational and Not Medically Necessary:

Donor lymphocyte infusion is considered investigational and not medically necessary in all other cases.

Genetic modification of donor lymphocytes as an adjunct to donor lymphocyte infusion is considered investigational and not medically necessary.

There is clear clinical evidence that donor lymphocyte infusion can eradicate and cure relapsed chronic myelogenous leukemia (CML). In addition, infusions using lymphocytes obtained from the original hematopoietic progenitor cell donor can induce long-term, complete, hematological, cytogenetic, and molecular genetic remissions in individuals treated for relapsing CML after an allogeneic transplant. The National Comprehensive Cancer Network^® (NCCN) Clinical Practice Guideline (2012) for CML states "DLI is effective in inducing remissions in patients with relapsed CML following allogeneic hematopoietic stem cell transplant (HSCT) though it is more effective in chronic phase than advanced phase." These recommendations were based on 2A category of evidence and uniform consensus. The results from CML may be extrapolated to individuals with relapsed acute myelogenous leukemia (AML), since there is evidence of a graft vs. leukemia effect in individuals with AML treated with allogeneic transplants.

Therapy is also effective for relapse of hematologic malignant diseases other than CML, although response rates are lower. The medical evidence currently available for the use of donor lymphocyte infusions in individuals with relapsed disease from other hematologic malignancies including, but not limited to, acute lymphocytic leukemia (ALL), multiple myeloma, Hodgkin disease and non-Hodgkin lymphoma consists mostly of multiple small case series. However, there is a preponderance of these smaller studies that in conjunction, demonstrate that DLI may induce an anti-tumor response in individuals who have relapsed disease following an allogeneic hematopoietic progenitor cell transplant.

The NCCN Clinical Practice Guideline for multiple myeloma (2012) includes the use of donor lymphocyte infusions in individuals with unresponsive or relapsed disease after allogeneic stem cell grafting in order to stimulate a beneficial graft-versus-myeloma effect.

The British Committee for Standards in Haematology (Smith, 2005) recommends "the use of DLI should be considered for patients with persistent or progressive disease following transplantation". Deol and colleagues (2010) concluded "response rates are best in CML, followed by lymphomas, multiple myeloma and acute leukemias."

Thomson and colleagues (2010) reported multicenter results of 82 individuals with follicular lymphoma (FL) that were treated with allogeneic stem cell transplantation. All individuals with mixed chimerism or residual or progressive disease were eligible for DLI. Thirteen participants received twenty-five DLIs with remission in ten individuals (77%). At a median of 44 months after the last DLI, the ongoing complete response seems durable. There was no response in three individuals treated with DLI. The authors concluded the frequency and duration of response demonstrated was an "encouraging strategy to treat FL."

Graft versus host disease (GVHD) is a common occurrence with DLI. As a result, studies continue to investigate various dosing, timing of DLI infusions, and new approaches, including modifications to T-lymphocytes to minimize GVHD complications. The level of evidence is insufficient to permit conclusions in terms of uses of DLI for other than hematologic malignancies that have relapsed following a prior allogeneic hematopoietic progenitor cell transplant or to permit conclusions regarding the use of genetic modification (e.g., modified T-lymphocytes) of donor lymphocytes in the treatment of hematologic malignancies. 

There is also research interest in the genetic modification of donor lymphocytes. For example, it has been proposed that donor lymphocytes can be modified by insertion of a thymidine kinase gene, rendering the cells susceptible to ganciclovir therapy. If the infusion of the genetically modified donor lymphocytes results in severe graft vs. host disease, the transplant recipient can then be treated with ganciclovir to selectively destroy the donor lymphocytes. However, further investigation and data regarding the safety and efficacy of genetic modifications of DLI on GVHD and/or graft versus leukemia (GVL) are needed.

Infusing lymphocytes from the original stem cell donor can be used to treat transplant recipients with hematologic malignancies in relapse following allogeneic hematopoietic progenitor cell transplantation. Donor lymphocyte infusion, which is also referred to as donor leukocyte or buffy coat transfusion, is a form of adoptive immunotherapy and attempts to induce a beneficial GVL or graft versus tumor (GVT) response without the need for an additional bone marrow harvest from the donor or further high-dose chemotherapy for the recipient. Collection of donor leukocytes requires the original donor to undergo a leukapheresis procedure.

Leukapheresis is the removal of white blood cells from blood that is drawn directly from a blood vessel in the arm or through a small tube (catheter) placed in a single vein. The blood goes through a centrifuge where white blood cells, along with some platelets and a small amount of red blood cells, are removed. The remainder of the cells and plasma will pass through the centrifuge and will then be returned to the donor through a needle or catheter that is placed in the opposite arm. The procedure is performed in the outpatient setting and takes two to three hours to complete. After collection, these cells are infused into the recipient either immediately or after frozen storage. DLI is used as an alternative to a second stem cell transplant.

DLI has been researched as a treatment for a variety of hematologic malignancies, including most prominently chronic myeloid leukemia, but also acute myeloid leukemia, acute lymphocytic leukemia, multiple myeloma, myelodysplastic syndromes, chronic lymphocytic leukemia, Hodgkin's disease, and non-Hodgkin's lymphoma. Studies are limited due to small numbers but they have provided evidence that DLI can establish a graft-versus-leukemia/lymphoma effect.

Allogeneic: Genetically dissimilar; involves a donor and recipient.

Bone marrow: A soft, spongy tissue that fills the cavities inside most bones in the human body. Bone marrow is a source of stem cells that manufacture red blood cells, white blood cells, and platelets.

Graft versus host disease (GVHD): A potential complication of transplants associated with the use of blood or tissue from a different person (allogeneic). The transplanted cells recognize the recipient's tissue as foreign and attack the recipient.

Graft versus leukemia/lymphoma affect (GVL): Transplanted white blood cells that recognize residual cancer cells (cells that survived chemotherapy and radiation therapy and continue to grow in the body) and attacks them.

Hematologic malignancy: A cancer of the blood or bone marrow, such as leukemia or lymphoma.

Hematopoietic progenitor cells: Primitive cells capable of replication and formation into mature blood cells in order to repopulate the bone marrow. Cells may be obtained from bone marrow, peripheral blood or umbilical cord blood.

Leukocytes: White blood cells.

Lymphocyte: Cells present in the blood and lymphatic tissue derived from stem cells.

Mini-allogeneic hematopoietic stem cell transplant: Also called non-myeloablative or reduced intensity transplant. The conditioning regimen is less intense and does not completely ablate the stem cells in the individual's bone marrow.

Peripheral blood: Blood derived from the circulatory system (as opposed to blood in the bone marrow where it is made).

The following codes for treatments and procedures applicable to this document are included below for informational purposes.  A draft of future ICD-10 Coding (effective 10/01/2014) related to this document, as it might look today, is included below for your reference.  Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy.  Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services may be Medically Necessary when criteria are met:

When services are Investigational and Not Medically Necessary:
For the procedure and diagnosis codes listed above when criteria are not met or for all other indications, or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

When services are also Investigational and Not Medically Necessary:

Peer Reviewed Publications:

1. Collins RH, Goldstein S, Giralt S, et al. Donor leukocyte infusions in acute lymphocytic leukemia. Bone Marrow Transplant. 2000; 26(5):511-516.
2. Corradini P, Dodero A, Zallio F, et al. Graft-versus-lymphoma effect in relapsed peripheral T-cell non-Hodgkin's lymphomas after reduced-intensity conditioning followed by allogeneic transplantation of hematopoietic cells. J Clin Oncol. 2004; 22(11):2172-2176.
3. Dazzi F, Szydlo RM, Cross NC, et al. Durability of responses following donor lymphocyte infusions for patients who relapse after allogeneic stem cell transplantation for chronic myeloid leukemia. Blood. 2000; 96(8):2712-2716.
4. Deol A, Lum LG. Role of donor lymphocyte infusions in relapsed hematological malignancies after stem cell transplantation revisited. Cancer Treat Rev. 2010; 36(7):528-538.
5. Flowers ME, Leisenring W, Beach K, et al. Granulocyte colony-stimulating factor given to donors before aphoresis does not prevent aplasia in patients treated with donor leukocyte infusion for recurrent chronic myeloid leukemia after bone marrow transplantation. Biol Blood Marrow Transplant. 2000; 6(3A):321-326.
6. Guglielmi C, Arcese W, Dazzi F, et al. Donor lymphocyte infusion for relapsed chronic myelogenous leukemia: prognostic relevance of the initial cell dose. Blood. 2002; 100(2):397-405.
7. Horwitz ME. Stem-cell transplantation for inherited immunodeficiency disorders. Pediatr Clin North Am. 2000; 47(6):1371-1387.
8. Ishikawa J, Maeda T, Kashiwagi H, et al. Successful second allogeneic peripheral blood stem cell transplantation and donor leukocyte infusion in patients with relapsed acute leukemia using the same donor as for the initial allogeneic bone marrow transplantation. Bone Marrow Transplant. 2003; 31(11):1057-1059.
9. Kolb HJ. Graft-versus-leukemia effects of transplantation and donor lymphocytes. Blood. 2008; 112(12):4371-4383.
10. Kolb HJ, Schmid C, Barrett AJ, Schendel DJ. Graft-versus-leukemia reactions in allogeneic chimeras. Blood. 2004; 103(3):767-776.
11. Levine JE, Braun T, Penza SL, et al. Prospective trial of chemotherapy and donor leukocyte infusions for relapse of advanced myeloid malignancies after allogeneic stem cell transplantation. J Clin Oncol. 2002; 20(2):405-412.
12. Lokhorst HM, Schattenberg A, Cornelissen JJ, et al. Donor Leukocyte infusions are effective in relapsed multiple myeloma after allogeneic bone marrow transplantation. Blood. 1997; 90(10):4206-4211.
13. Luznik L, Fuchs EJ. Donor lymphocytes infusions to treat hematologic malignancies in relapse after allogeneic blood or marrow transplantation. Cancer Control. 2002; 9(2):123-134.
14. Orsini E, Alyea EP, Chillemi A, et al. Conversion to full donor chimerism following donor lymphocyte infusion is associated with disease response in patients with multiple myeloma. Biol Blood Marrow Transplant. 2000; 6(4):375-386.
15. Peggs KS, Mackinnon S. Cellular therapy: donor lymphocyte infusion. Curr Opin Hematol. 2001; 8(6):349-354.
16. Porter DL, Collins RH, Hardy C, et al. Treatment of relapsed leukemia after unrelated donor marrow transplantation with unrelated donor leukocyte infusions. Blood. 2000; 95(4):1214-1221.
17. Przepiorka D, Smith TL, Folloder J, et al. Controlled trial of filgastim for acceleration of neutrophil recovery after allogeneic blood stem cell transplantation from human leukocyte antigen-matched related donors. Blood. 2001; 97(11):3405-3410.
18. Raiola AM, Van Lint MT, Valbonesi M, et al. Factors predicting response and graft-versus-host disease after donor leukocyte infusions: a study on 593 infusions. Bone Marrow Transplant. 2003; 31(8):687-693.
19. Russell NH, Byrne JL, Faulkner RD, et al. Donor lymphocyte infusions can result in sustained remissions in patients with residual or relapsed lymphoid malignancy following allogeneic haematopoietic stem cell transplantation. Bone Marrow Transplant. 2005; 36(5):437-441.
20. Salama M, Nevill T, Marcellus D, et al. Donor leukocyte infusions for multiple myeloma. Bone Marrow Transplant. 2000; 26(11):1179-1184.
21. Schmid C, Labopin M, Nagler A, et al. Donor lymphocyte infusion in the treatment of first hematological 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. 2007; 25(31):4938-4945.
22. Thomson KJ, Morris EC, Milligan D, et al. T-cell-depleted reduced-intensity transplantation followed by donor leukocyte infusions to promote graft-versus-lymphoma activity results in excellent long-term survival in patients with multiply relapsed follicular lymphoma. J Clin Oncol. 2010; 28(23): 3695-3700.
23. Vela-Ojeda J, Garcia-Ruiz Esparza MA, Reyes-Maldonado E, et al. Donor lymphocyte infusions for relapse of chronic myeloid leukemia after allogeneic stem cell transplantation: prognostic significance of the dose of CD3+ and CD4+ lymphocytes. Ann Hematol. 2004; 83(5):295-301.

Government Agency, Medical Society, and Other Authoritative Publications: 

1. Smith A, Wisloff F, Samson D; on behalf of the UK Myeloma Forum, Nordic Myeloma Study Group and British Committee for Standards in Haematology. Br J Haematol. 2006; 132(4):410-451.

1. American Society for Blood and Marrow Transplantation (ASBMT). Available at: http://www.asbmt.org. Accessed on August 24, 2012.
2. NCCN Clinical Practice Guidelines in Oncology™. © 2012 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website: http://www.nccn.org/index.asp. Accessed on August 24, 2012.
   • Chronic Myelogenous Leukemia (V.1.2013). Revised July 5, 2012.
   • Multiple Myeloma (V.1.2013). Revised August 16, 2012.
   • non-Hodgkin Lymphoma (V.3.2012). Revised July 9, 2012.
3. National Marrow Donor Program. Available at: http://www.marrow.org. Accessed on August 21, 2012.

Buffy Coat Transfusion
Donor Leukocyte Infusion
Donor Lymphocyte Infusion
Leukapheresis