Latest Review Date: March 2024

Category: Surgical                                                                 

POLICY:

Donor lymphocyte infusion (DLI) may be considered medically necessary when it is performed following allogeneic-hematopoietic cell transplantation (HCT) that was originally considered medically necessary and was for the treatment of a hematologic malignancy that has relapsed or is refractory AND:

• The DLI is to prevent a relapse for those at high risk for relapse. This would include T cell depleted grafts or non-myeloablative (reduced-intensity conditioning) allogeneic HCT. OR
• To convert an individual from mixed to full donor chimerism.

Donor lymphocyte infusion (DLI) is considered investigational following allogeneic-hematopoietic cell transplantation (HCT) that was originally considered investigational for the treatment of a hematologic malignancy.

Donor lymphocyte infusion is considered investigational as a treatment of non-hematologic malignancies following a prior allogeneic HCT.

Genetic or other modification of donor lymphocytes is considered investigational.

DESCRIPTION OF PROCEDURE OR SERVICE:

Donor lymphocyte infusion (DLI), also called donor leukocyte or buffy-coat infusion is a type of therapy in which T lymphocytes from the blood of a donor are given to an individual who has already received a hematopoietic stem cell transplant (HCT) from the same donor. The DLI therapeutic effect results from a graft-versus-leukemic or graft-versus-tumor effect due to the recognition of certain antigens on the cancer cells by the donor lymphocytes and the resultant elimination of the tumor cells.

Approximately 40-60% of individuals who receive a DLI develop graft-versus-host disease (GVHD), and the development of GVHD predicts a response to the DLI. Treatment-related mortality after DLI is 5-20%. There does not seem to be a correlation between the type of hematologic malignancy for which the DLI was given and the development of GVHD. The risk of development of GVHD is related, in part, to DLI dose and therapy before DLI.

DLI may be used for various indications such as relapse after an allogeneic HCT, as a planned strategy to prevent disease relapse in the setting of T cell depleted grafts or non-myeloablative conditioning regimens, or as a method to convert mixed to full donor chimerism. Management of relapse, which occurs in approximately 40% of all hematologic malignancy individuals, is the most common indication for DLI.

The literature is heterogeneous for reporting methods of cell collection, indication (e.g., after chemotherapy, in early relapse); cell dose infused and cell subtype used. In addition, many studies include multiple diseases with little information regarding disease-specific outcomes; however, DLI is used in nearly all hematologic malignancies for which allogeneic HCT is performed, including chronic myeloid leukemia (CML), acute myeloid and lymphoblastic leukemias, myelodysplastic syndromes, multiple myeloma and Hodgkin’s (HL) and non-Hodgkin’s lymphoma (NHL).

KEY POINTS:

The most recent literature review was performed through March 8, 2024.

Summary of Evidence

For individuals who have been treated with an allogeneic HCT who receive DLI, the evidence includes non randomized comparative studies and case series. Relevant outcomes are overall survival and change in disease status. In various hematologic malignancies and for various indications such as planned or preemptive DLI, treatment of relapse, or conversion of mixed to full donor chimerism, individuals have shown evidence of response to DLI. The response rates to DLI for relapsed hematologic malignancies following an allogeneic HCT are best in CML, followed by lymphomas, multiple myeloma and acute leukemias, respectively. Other than CML, clinical responses are most effective when chemotherapy induction is used to reduce the tumor burden before DLI. Based on comparison to the natural history of relapsed hematologic malignancy, the evidence is sufficient to determine qualitatively that the technology results in a meaningful improvement in the net health outcome.

For individuals who have been treated with an allogeneic HCT who receive modified (genetic or other ex vivo modification) donor lymphocytes infusion, the evidence includes case series. Relevant outcomes are overall survival and change in disease status. The case series demonstrate the feasibility of the technique and no serious adverse effects. Without a comparison to standard treatment, the efficacy of administering modified donor lymphocytes is unknown. The evidence is insufficient to determine the effects of the technology on health outcomes.

Practice Guidelines and Position Statements

National Comprehensive Cancer Network

National Comprehensive Cancer Network (NCCN) recommendations for treating CML (v2.2024) state that DLI is effective in inducing durable molecular remissions in the majority of individuals with relapsed CML following allogeneic HCT, though it is more effective in individuals with chronic phase relapse than advanced phase relapse.

NCCN guidelines references a study that suggests that azacitidine followed by donor lymphocyte infusions (DLIs) may be a treatment option for therapy in individuals who have AML that relapses after allogeneic HCT (v1.2024).

NCCN recommendations for treating acute lymphoblastic leukemia (v4.2023) state that DLI can be considered an option for patients in relapse after allogeneic HCT (category 2A).

NCCN guidelines do not include the use of DLI in the treatment of non-Hodgkin lymphoma or Hodgkin lymphoma (v2.2024).

NCCN recommendations for treating multiple myeloma (v2.2024) state that DLI can be considered an option for individuals who do not respond or are in relapse after allogeneic HCT (category 2A).

U.S. Preventive Services Task Force Recommendations

Not Applicable.

KEY WORDS:

DLI, Donor lymphocyte infusion, HSCT, HCT, Hematopoietic cell transplantation, allogeneic stem cell transplantation

APPROVED GOVERNING BODIES:

The U.S. Food and Drug Administration regulates human cells and tissues intended for implantation, transplantation or infusion through the Center for Biologics Evaluation and Research, under Code of Federal Regulation (CFR) title 21, parts 1270 and 1271. Hematopoietic stem cells are included in these regulations.

BENEFIT APPLICATION:

Coverage is subject to member’s specific benefits.  Group specific policy will supersede this policy when applicable.

ITS: Home Policy provisions apply.

FEP:  Special benefit consideration may apply.  Refer to member’s benefit plan. 

CURRENT CODING: 

CPT Codes:

REFERENCES:

1. Bejanyan N, Weisdorf DJ, Logan BR, et al. Survival of patients with acute myeloid leukemia relapsing after allogeneic hematopoietic cell transplantation: a center for international blood and marrow transplant research study. Biol Blood Marrow Transplant. Mar 2015; 21(3):454-459.
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. Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). Donor Leukocyte Infusion for Hematologic Malignancies that Relapse after Allo-BMT. TEC Assessments 1997; Volume 12, Tab 22.
5. 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.
6. Collins RH, Goldstein S, Giralt S, et al. Donor leukocyte infusions in acute lymphocytic leukemia. Bone Marrow Transplant. 2000; 26(5):511-516.
7. Dazzi F, Szydlo RM, Cross NC et al. Durability of responses following donor lymphocytic infusions for patients who relapse after allogeneic stem cell transplantation for chronic myeloid leukemia. Blood. Oct 15 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. El-Jurdi N, Reljic T, Kumar A et al. Efficacy of adoptive immunotherapy with donor lymphocyte infusion in relapsed lymphoid malignancies. Immunotherapy. May 2013; 5(5):457-466.
10. Flowers ME, Leisenring W, Beach K, et al. Granulocyte colony-stimulating factor given to donors before apheresis 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. Fowler DH, Mossoba ME, Steinberg SM, et al. Phase 2 clinical trial of rapamycin-resistant donor CD4+ Th2/Th1 (T-Rapa) cells after low-intensity allogeneic hematopoietic cell transplantation. Blood. Apr 11 2013; 121(15):2864-2874.
12. Guglielmi C, Arcese W, Dazzi F et al. Donor lymphocyte infusion for relapsed chronic myelogenous leukemia: prognostic relevance of the initial cell dose. Blood. Jul 15 2002; 100(2):397-405.
13. Guieze R, Damaj G, Pereira B, et al. Management of myelodysplastic syndrome relapsing after allogeneic hematopoietic stem cell transplantation: a study by the French Society of Bone Marrow Transplantation and Cell Therapies. Biol Blood Marrow Transplant. Aug 6 2015.
14. Hashimoto H, Kitano S, Ueda R, et al. Infusion of donor lymphocytes expressing the herpes simplex virus thymidine kinase suicide gene for recurrent hematologic malignancies after allogeneic hematopoietic stem cell transplantation. Int J Hematol. Jul 2015; 102(1):101-110.
15. IOM (Institute of Medicine). 2011. Clinical Practice Guidelines We Can Trust. Washington, DC: The National Academies Press.
16. 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.
17. Lokhorst HM, Schattenberg A, Cornelissen JJ et al. Donor lymphocyte infusions for relapsed multiple myeloma after allogeneic stem-cell transplantation: predictive factors for response and long term outcome. J Clin Oncol. Aug 2000; 18(16):3031–3037.
18. Lokhorst HM, Schattenberg A, Cornelissen JJ, et al. Donor leukocyte infusions are effective in relapsed multiple myeloma after allogeneic bone marrow transplantation. Blood. Nov 1997; 90(10):4206–4211.
19. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Acute Lymphoblastic Leukemia (v4.2023). www.nccn.org/professionals/physician_gls/pdf/all.pdf.
20. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Acute Myeloid Leukemia (v1.2024). www.nccn.org/professionals/physician_gls/pdf/aml.pdf.
21. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Multiple Myeloma (v2.2024). www.nccn.org/professionals/physician_gls/pdf/myeloma.pdf.
22. National Comprehensive Cancer Network. Chronic Myelogenous Leukemia. Clinical Practice Guidelines in Oncology (v1.2023).  www.nccn.org/professionals/physician_gls/pdf/cml.pdf.
23. National Comprehensive Cancer Network. Hodgkins Lymphoma. Clinical Practice Guidelines in Oncology (v2.2024).  www.nccn.org/professionals/physician_gls/pdf/hodgkins.pdf. 
24. National Comprehensive Cancer Network. B-cell Lymphoma. Clinical Practice Guidelines in Oncology (v1.2024). www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf
25. Negrin S, Robert. (2024). Immunotherapy for the prevention and treatment of relapse following allogeneic hematopoietic cell transplantation. In:Rosmarin G, Alan (Ed.), UpToDate. www.uptodate.com/contents/immunotherapy-for-the-prevention-and-treatment-of-relapse-following-allogeneic-hematopoietic-cell-transplantation? 
26. Peggs KS, Sureda A, Qian W, et al. 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. Oct 2007;139(1):70-80.
27. Qian W, et al. 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. Oct 2007; 139(1):70-80.
28. Radujkovic A, Guglielmi C, Bergantini S, et al. Donor lymphocyte infusions for chronic myeloid leukemia relapsing after allogeneic stem cell transplantation: may we predict graft-versus-leukemia without graft-versus-host disease? Biol Blood Marrow Transplant. Mar 19 2015.
29. Salama M, Nevill T, Marcellus D, et al. Donor leukocyte infusions for multiple myeloma. Bone Marrow Transplant. Dec 2000; 26(11):1179–1184.
30. 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. Nov 1 2007; 25(31):4938-4945.
31. Schroeder T, Rachlis E, Bug G, et al. Treatment of acute myeloid leukemia or myelodysplastic syndrome relapse after allogeneic stem cell transplantation with azacitidine and donor lymphocyte infusions-a retrospective multicenter analysis from the german cooperative transplant study group. Biol Blood Marrow Transplant. Apr 2015; 21(4):653-660.
32. 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.
33. Simula MP, Marktel S, Fozza C, et al. Response to donor lymphocyte infusions for chronic myelogenous leukemia is dose-dependent: the importance of escalating the cell dose to maximize therapeutic efficacy. Leukemia. May 2007; 21(5):943-948.
34. Tomblyn M, Lazarus HM. Donor lymphocyte infusions: the long and winding road: how should it be traveled? Bone Marrow Transplant 2008; 42(9):569-579.
35. van den Brink MR, Porter DL, Giralt S et al. Relapse after allogeneic hematopoietic cell therapy. Biol Blood Marrow Transplant. Jan 2010; 16(1 Suppl):S138-145.
36. Warlick ED, DeFor T, Blazar BR et al. Successful remission rates and survival after lymphodepleting chemotherapy and donor lymphocyte infusion for relapsed hematologic malignancies post allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. Mar 2012; 18(3):480-486.

POLICY HISTORY:

Medical Policy Group, May 2012 (4)

Medical Policy Administration Committee, May 2012

Available for comment May 22 through July 5, 2012

Medical Policy Panel, May 2013

Medical Policy Group, May 2013 (3):  2013 Updates to Key Points and References; no change in policy statement

Medical Policy Panel, May 2014

Medical Policy Group, June 2014 (3):  2014 Updates to Key Points & References; no change in policy statement

Medical Policy Group, May 2015

Medical Policy Panel, June 2015 (2): 2015 Updates to Key Points and References; no change to policy statement.

Medical Policy Panel, January 2016

Medical Policy Group, February 2016 (2): Updates to Description, Key Points, Approved Governing Bodies, and References; policy section updated- added “or other” to investigational statement on genetic modification of donor lymphocytes – intent of policy statement is unchanged.

Medical Policy Panel, September 2016

Medical Policy Group, September 2016 (7): No new literature to add. No changes to policy. Retiring policy effective September 12, 2016.

Medical Policy Group, August 2019 (3): 2019 Updates to Key Points, References and Key Words: added: Hematopoietic cell transplantation and allogeneic stem cell transplantation. A peer reviewed literature analysis was completed and no new information was identified that would alter the coverage statement of this policy.

Medical Policy Group, March 2021 (3): 2021 Updates to Key Points, Practice Guidelines and Position Statements, and References. A peer reviewed literature analysis was completed and no new information was identified that would alter the coverage statement of this policy.

Medical Policy Group, March 2022 (3): 2022 Updates to Key Points, Practice Guidelines and Position Statements, and References. Reviewed by consensus. No new published peer-reviewed literature available that would alter the coverage statement in this policy.

Medical Policy Group, March 2023 (3): 2023 Updates to Key Points, Approved by Governing Bodies, and References. Reviewed by consensus. No new published peer-reviewed literature available that would alter the coverage statement in this policy.

Medical Policy Group, March 2024 (3): 2024 Updates to Key Points, Practice Guidelines and Position Statements, and References. Policy statement updated for clarity- removed the phrase not medically necessary. No change to the policy intent. A peer-reviewed analysis was completed and no new literature was available that would alter the coverage statement in this policy.

This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.

This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and pre-procedure review) in Blue Cross and Blue Shield’s administration of plan contracts.

The plan does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. The plan administers benefits based on the member’s contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination.

As a general rule, benefits are payable under health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage.

The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage:

1. The technology must have final approval from the appropriate government regulatory bodies;

2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes;

3. The technology must improve the net health outcome;

4. The technology must be as beneficial as any established alternatives;

5. The improvement must be attainable outside the investigational setting.

Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are:

1. In accordance with generally accepted standards of medical practice; and

2. Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient’s illness, injury or disease; and

3. Not primarily for the convenience of the patient, physician or other health care provider; and

4. Not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that patient’s illness, injury or disease.