Clinical UM Guideline

This document addresses the use of donor lymphocyte infusions 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). Donor lymphocyte infusion (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 hematopoietic progenitor cell donor. This procedure attempts to induce a beneficial graft-versus-leukemia (GVL) response without the need for additional bone marrow harvest from the donor or further high-dose chemotherapy for the recipient.

Medically Necessary:

Donor* lymphocyte infusion is considered medically necessary for individuals following a medically necessary allogeneic (myeloablative or non-myeloablative) hematopoietic progenitor cell transplant used to treat a hematologic malignancy.

*Note: The donor for the lymphocytes is the same individual whose hematopoietic progenitor cells were used for the transplant procedure.

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

Not Medically Necessary:

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

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

The following codes for treatments and procedures applicable to this guideline are included below for informational purposes. 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.

Donor lymphocyte infusion
When services may be Medically Necessary when criteria are met:

When services are Not Medically Necessary:
For the procedure codes listed above when criteria are not met or for all other diagnoses not listed.

Genetic modification of donor lymphocytes
When services are Not Medically Necessary:
When the code describes a procedure designated in the Clinical Indications section as not medically necessary.

Infusing lymphocytes from the original hematopoietic cell donor can be used to treat transplant recipients with hematologic malignancies in relapse following allogeneic hematopoietic progenitor cell transplantation. DLI, 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. After collection, these cells are infused into the recipient either immediately or after frozen storage.

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 2 to 3 hours to complete. DLI is used as an alternative to a second hematopoietic cell transplant.

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

There is clear clinical evidence that DLI can eradicate and cure relapsed 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 hematopoietic cell transplant (HCT). The National Comprehensive Cancer Network^® (NCCN) Clinical Practice Guidelines (CPG, V.2.2024) for CML state “Donor lymphocyte infusion (DLI) is effective in inducing durable molecular remissions in the majority of patients with relapsed CML following allogeneic HCT, though it is more effective in patients with chronic phase relapse than advanced phase relapse.” These recommendations were based on 2A category of evidence and uniform consensus. The results from CML may be extrapolated to individuals with relapsed AML, since there is evidence of a graft-versus-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 DLI in individuals with relapsed disease from other hematologic malignancies including, but not limited to, 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.

Beitinjaneh and colleagues (2012) reported a higher response rate and longer overall survival when DLI was used preemptively in individuals treated with allogeneic HCT as a treatment for multiple myeloma. Between July 1996 and June 2008, 23 individuals with multiple myeloma received DLI, 8 as preemptive DLI for residual disease (RD) and 15 as DLI for the treatment of recurrent or progressive disease (PD). With a median follow-up of 24 months, 5 of 23 individuals (22%) achieved a complete response (CR) or a very good partial response (2 CR, 3 very good partial response [VGPR]), and stable disease (SD) in 8 individuals (34%) after DLI. A higher response rate (≥ VGPR 50% vs. 7%, p=0.03), a longer overall survival (28.3 vs. 7.6 months, p=0.03) and a trend toward longer progression-free survival (11.9 vs. 5.2 months, p=0.1) were reported in individuals who received DLI for RD. Five individuals (22%) had Grade II-IV acute graft-versus-host disease (GVHD). The authors concluded the preemptive use of DLI after an allogeneic HSCT for multiple myeloma may be associated with improved outcomes. Additional clinical trials are encouraged to identify the optimal timing for DLI.

The NCCN CPGs for multiple myeloma (V.3.2024) include the use of DLI in individuals with unresponsive or relapsed disease after allogeneic hematopoietic cell grafting in order to stimulate a beneficial graft-versus-myeloma effect. Similarly, the NCCN CPGs for Acute Lymphoblastic Leukemia (V4.2023) state that, “For patients with relapsed disease after allogeneic HCT, a second HCT and/or donor lymphocyte infusion (DLI) can be considered.”

Sala and colleagues (2014) reported results from a retrospective series of 18 individuals with relapsed and/or refractory Hodgkin lymphoma after allogeneic HSCT that were treated with a combination of bendamustine followed by DLI. Nine of the participants were eligible for DLI after bendamustine, based on the pre-specified criteria. A median of two DLIs were infused into the individuals. Adverse events from the DLI included 3 individuals with chronic GVHD and 3 cases of Grade IV acute GVHD. Acute hospitalization was required for 3 individuals with acute GVHD. Of those treated with DLI, CR was seen in 3 individuals and PR in 7 individuals, for an overall response rate (ORR) of 55% with a 9-month (range 1-26 months) median duration of response. For the 18 participants, the median overall survival was 11 months (range 1-52 months) and the progression-free survival (PFS) was 6 months (range, 1-28 months). The authors noted the combination of bendamustine followed by DLI demonstrated a response. However, a randomized trial is needed to determine if the treatment effect was due to the bendamustine compared to the DLI or the combination.

Thomson and colleagues (2010) reported multicenter results of 82 individuals with follicular lymphoma 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 25 DLIs with remission in 10 individuals (77%). At a median of 44 months after the last DLI, the ongoing complete response seemed durable. There was no response in 3 individuals treated with DLI. The authors concluded the frequency and duration of response demonstrated was an “encouraging strategy to treat follicular lymphoma.”

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.

However, in a study by Alho and colleagues (2016), the authors observed that the “development and maintenance of immune tolerance after allogeneic hematopoietic stem cell transplantation requires the balanced reconstitution of donor-derived CD4 regulatory T cells (CD4Tregs) as well as effector CD4 (conventional CD4 T cells [CD4Tcons]) and CD8 T cells.” They studied 107 adult participants who received “T-replete stem cell grafts after reduced-intensity conditioning who were monitored” over a 2-year period. The authors found that the imbalances assisted in the “production, expansion, and persistence of effector T cells over CD4Tregs and were associated with the development of chronic GVHD.”

There is interest in the genetic modification of donor or the individual’s own lymphocytes, or chimeric antigen receptor T-cell (CAR-T) therapy. 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. Other editing techniques may involve disrupting the GVHD process by targeting T-cell receptors and cell surface expression or the genetic editing to evade host-mediated rejection (Qasim, 2023). The early studies involving the use of CAR-T therapy in hematologic malignancies have reported promising results when compared to standard DLI (Hua, 2021; Liang, 2023; Tan, 2023). Studies regarding the safety and efficacy of genetic modifications of DLI on GVHD and/or graft-versus-leukemia (GVL) are ongoing. The use of modified DLI therapy following an allogeneic hematopoietic progenitor cell transplant is not considered a standard of care.

Schmid and associates (2021) reviewed the role of both modified and unmodified DLI in the treatment of high-risk hematologic malignancies. The authors summarized that there is still a place for DLI therapy, although there are alternative potential adaptive immunotherapy options under evaluation. The authors note:

Given the increasing availability of innovative, disease modifying drugs, DLI is currently at risk to be superseded by other, more specific treatment options, despite its great biologic potential and low costs.

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 effect (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 attack 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: Another term for white blood cells. There are several types of leukocytes: granulocytes (neutrophils, eosinophils, and basophils), monocytes, and lymphocytes.

Lymphocyte: Cells present in the blood and lymphatic tissue derived from stem cells. Comprised of T cells and B cells.

Non-myeloablative allogeneic hematopoietic stem cell transplant: Also called reduced intensity or mini-allogeneic 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).

Peer Reviewed Publications:

1. Alho AC, Kim HT, Chammas MJ, et.al. Unbalanced recovery of regulatory and effector T cells after allogeneic stem cell transplantation contributes to chronic GVHD. Blood. 2016; 127(5):646-657.
2. Beitinjaneh AM, Saliba R, Bashir Q, et al. Durable responses after donor lymphocyte infusion for patients with residual multiple myeloma following non-myeloablative allogeneic stem cell transplant. Leuk Lymphoma. 2012; 53(8):1525-1529.
3. Berglund S, Gertow J, Uhlin M, Mattsson J. Expanded umbilical cord blood T cells used as donor lymphocyte infusions after umbilical cord blood transplantation. Cytotherapy. 2014; 16(11):1528-1536.
4. Chalandon Y, Passweg JR, Guglielmi C, et al.; Chronic Malignancies Working Party of the European Group for Blood and Marrow Transplantation (EBMT). Early administration of donor lymphocyte infusions upon molecular relapse after allogeneic hematopoietic stem cell transplantation for chronic myeloid leukemia: a study by the Chronic Malignancies Working Party of the EBMT. Haematologica. 2014; 99(9):1492-1498.
5. Collins RH, Goldstein S, Giralt S, et al. Donor leukocyte infusions in acute lymphocytic leukemia. Bone Marrow Transplant. 2000; 26(5):511-516.
6. 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.
7. 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.
8. 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.
9. Dodero A, Spina F, Narni, F, et al. Allogeneic transplantation following a reduced-intensity conditioning regimen in relapsed/refractory peripheral T-cell lymphomas: long-term remissions and response to donor lymphocyte infusions support the role of a graft-versus-lymphoma effect. Leukemia. 2012; 26(3):520-526.
10. 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.
11. 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.
12. Horwitz ME. Stem-cell transplantation for inherited immunodeficiency disorders. Pediatr Clin North Am. 2000; 47(6):1371-1387.
13. Hua J, Zhang J, Zhang X, et al. Donor-derived anti-CD19 CAR T cells compared with donor lymphocyte infusion for recurrent B-ALL after allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant. 2021; 56(5):1056-1064.
14. 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.
15. Kolb HJ. Graft-versus-leukemia effects of transplantation and donor lymphocytes. Blood. 2008; 112(12):4371-4383.
16. Kolb HJ, Schmid C, Barrett AJ, Schendel DJ. Graft-versus-leukemia reactions in allogeneic chimeras. Blood. 2004; 103(3):767-776.
17. Kumar AJ, Hexner EO, Frey NV, et al. Pilot study of prophylactic ex vivo costimulated donor leukocyte infusion after reduced-intensity conditioned allogeneic stem cell transplantation. Biol Blood Marrow Transplant. 2013; 19(7):1094-1101.
18. 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.
19. Liang Z, Xu H, Zhou X, et al. Donor-derived CAR-T therapy improves the survival of relapsed B-ALL after allogeneic transplantation compared with donor lymphocyte infusion. Hum Cell. 2023; 36(5):1716-1728.
20. 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.
21. 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.
22. 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.
23. Peggs KS, Mackinnon S. Cellular therapy: donor lymphocyte infusion. Curr Opin Hematol. 2001; 8(6):349-354.
24. Peggs KS, Sureda A, Qian W, et al.; UK and Spanish Collaborative Groups. Reduced-intensity conditioning for allogeneic haematopoietic stem cell transplantation in relapsed and refractory Hodgkin lymphoma: impact of alemtuzumab and donor lymphocyte infusions on long-term outcomes. Br J Haematol. 2007; 139(1):70-80.
25. 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.
26. 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.
27. Qasim W. Genome-edited allogeneic donor "universal" chimeric antigen receptor T cells. Blood. 2023;141(8):835-845.
28. 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.
29. 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.
30. Sala E, Crocchiolo R, Gandolfi S, et al. Bendamustine combined with donor lymphocytes infusion in Hodgkin's lymphoma relapsing after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2014; 20(9):1444-1447.
31. Salama M, Nevill T, Marcellus D, et al. Donor leukocyte infusions for multiple myeloma. Bone Marrow Transplant. 2000; 26(11):1179-1184.
32. 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.
33. Schmid C, Kuball J, Bug G. Defining the role of donor lymphocyte infusion in high-risk hematologic malignancies. J Clin Oncol. 2021; 39(5):397-418.
34. Schmidt S, Liu Y, Hu ZH, et al. The role of donor lymphocyte infusion (DLI) in post-hematopoietic cell transplant (HCT) relapse for chronic myeloid leukemia (CML) in the tyrosine inhibitor (TKI) era. Biol Blood Marrow Transplant. 2020; 26:1137-1143.
35. Takami A, Yano S, Yokoyama H, et al. Donor lymphocyte infusion for the treatment of relapsed acute myeloid leukemia after allogeneic hematopoietic stem cell transplantation: a retrospective analysis by the Adult Acute Myeloid Leukemia Working Group of the Japan Society for Hematopoietic Cell Transplantation. Biol Blood Marrow Transplant. 2014; 20(11):1785-1790.
36. Tan X, Wang XQ, Zhang C, et al. Donor-derived CD19 CAR-T cells versus chemotherapy plus donor lymphocyte infusion for treatment of recurrent CD19-positive B-ALL after allogeneic hematopoietic stem cell transplantation. Curr Med Sci. 2023; 43(4):733-740.
37. 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.
38. 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.
39. Warlick ED, DeFor T, Blazar BR, et al. Successful remission rates and survival after lymphodepleting chemotherapy and donor lymphocyte infusion for relapsed hematologic malignancies postallogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2012; 18(3):480-486.

Government Agency, Medical Society, and Other Authoritative Publications:

1. NCCN Clinical Practice Guidelines in Oncology™. ^©2024. National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website: http://www.nccn.org/index.asp. Accessed on March 25, 2024.
   • Acute Lymphoblastic Leukemia. (V.4.2023). February 5, 2024.
   • Chronic Myeloid Leukemia (V.2.2024). Revised December 5, 2023.
   • Multiple Myeloma (V.3.2024). Revised March 8, 2024.
   • T-Cell Lymphomas. (V.2.2024). Revised March 14, 2024.

1. American Cancer Society. Types of stem cell transplant and bone marrow transplants. Available at: https://www.cancer.org/treatment/treatments-and-side-effects/treatment-types/stem-cell-transplant/types-of-transplants.html. Accessed on March 25, 2024.
2. American Society for Transplantation and Cellular Therapy (ASTCT). Available at: http://www.asbmt.org. Accessed on March 25, 2024.
3. National Cancer Institute. Available at: https://www.cancer.gov/about-cancer. Accessed on March 25, 2024.
4. National Marrow Donor Program. Available at: http://www.marrow.org. Accessed on March 25, 2024.

Buffy Coat Transfusion
Donor Leukocyte Infusion
Donor Lymphocyte Infusion
Leukapheresis

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