*Please see amendment for Pennsylvania Medicaid at the

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1 1 of 13 Number: 0638 Policy *Please see amendment for Pennsylvania Medicaid at the end of this CPB. I. Aetna considers donor lymphocyte infusion (DLI) medically necessary for persons who have a prior, medically necessary allogeneic bone marrow or peripheral stem cell transplantation. Last Review 06/22/2017 Effective: 08/16/2002 Next Review: 06/21/2018 Review History Definitions II. Aetna considers the modification of donor lymphocytes (e.g., donor lymphocyte depletion, ex vivo expansion, expanding antigen specific T cell lines, T cell depletion, genetic modification) experimental and investigational because the clinical value of these approaches in the treatment of malignancies has not been established. III. Aetna considers intrathecal donor lymphocyte infusion experimental and investigational because the effectiveness of this approach has not been established. Clinical Policy Bulletin Notes IV. Aetna considers donor lymphocyte infusion for the treatment of multiple myeloma experimental and investigational because the effectiveness of this approach has not been established. See also CPB 0641 Adoptive Immunotherapy and Cellular Therapy.

2 2 of 13 Background High dose chemotherapy (HDC) in combination with allogeneic bone marrow transplantation results in remission in significant numbers of patients with chronic myelogenous leukemia (CML), acute myeloid leukemia (AML) or acute lymphocytic leukemia (ALL). However, disease relapse is a major cause of treatment failure, and salvage treatment options for these patients are limited. Patients can either be treated with an additional course of conventional chemotherapy or a second round of HDC and repeat allogeneic transplantation. Conventional chemotherapy is unlikely to result in a complete durable remission, and the morbidity and mortality of a second allogeneic transplant is unacceptably high. Furthermore, patients with CML have been treated with interferon. While this treatment can be associated with normalization of peripheral blood counts, interferon fails to eradicate the malignant clone of cells. Donor lymphocyte infusion (DLI), also known as donor leukocyte or buffy coat infusion, has been used in an attempt to stimulate a donor versus leukemia (GVL) reaction and thus eradicate the malignant clone of cells. Donor lymphocyte infusion entails the collection (from the original donor) of peripheral lymphocytes during an apheresis procedure; donors generally undergo 2 to 8 procedures. The lymphocytes are then simply infused into the patient either immediately or after frozen storage. Donor lymphocyte infusion differs from allogeneic bone marrow transplantation in that it is not preceded by chemotherapy and T cells are not depleted. Lymphocyte infusion with a defined T cell dose can cause a profound GVL effect and is an effective form of salvage immunotherapy in allogeneic marrow transplanted recipients. The advantage in using DLI versus second allogeneic transplantation is the lower treatment related morbidity and mortality. The GVL effect is a well described phenomenon, which is associated with the presence of graft versus host disease (GVHD). For example, the likelihood of relapse post allogeneic transplantation is lower in those patients who experience either acute or chronic GVHD. In addition, there is a higher rate of relapse in patients receiving a syngeneic (identical twin)

3 3 of 13 transplant compared to allogeneic transplant. However, the presence of GVL is not dependent on the presence of GVHD. For example, the rate of leukemic relapse is higher in patients receiving T cell depleted allogeneic marrow, even after controlling for the degree of GVHD. This observation suggests that there may be a distinct subset of T cells responsible for GVL. Donor lymphocyte infusion attempts to harness the anti leukemic properties of donor T cells. In a recent review on adoptive allogeneic cellular therapy, Peggs and Mackinnon (2001) stated that DLI is effective in generating anti tumor responses, especially for relapsed chronic phase CML. Response rates and durability appear lower with myeloma, AML and myelodysplasia syndrome, and minimal with ALL. There is relatively little data on indolent lymphoid malignancies. This is in agreement with the observation of Slavin and associates (2001) who reported that pre clinical and clinical studies have indicated that much more effective eradication of the host immunohematopoietic system cells can be attained by adoptive allogeneic cellular therapy with DLI following bone marrow transplantation. Thus, eradication of blood cancer cells, particularly in patients with CML and, less frequently, in patients with other hematological malignancies, can frequently be achieved despite the complete resistance of such tumor cells to maximally tolerated doses of chemo and radio therapy. In a review on DLI for the treatment of hematologic malignancies in relapse following allogeneic blood or marrow transplantation, Luznik and Fuchs (2002) reported that DLI induces complete remissions in the majority of patients with CML in early stage relapse and in less than 30 % of patients with relapsed acute leukemia, myelodysplasia, and multiple myeloma. Remissions of chronic phase CML induced by DLI are durable, but as many as half of patients with other diseases ultimately relapse. Pre planned DLI has also been used as part of transplant protocols in persons with hematologic malignant diseases who have not relapsed. Donor lymphocyte infusion is intended to facilitate establishment of full donor chimerism (complete donor stem cell grafting in the recipient's bone marrow) and

4 4 of 13 potentiation of anti tumor effect (graft versus tumor reaction) (Cheong et al, 2002). There is also ongoing research on the genetic modification of donor lymphocytes. Transplantation of suicide gene modified allogeneic T lymphocytes is an approach to prevent T cell mediated GVHD while preserving the GVL effect of an allograft. However, existing techniques allow insufficient transduction of T lymphocytes. Further investigation is needed to develop more efficient gene transfer protocols and is possible value in the treatment of hematological malignancies. Beitinjaneh et al (2012) stated that the role of DLI in mediating the graft versus myeloma (GVM) effect after allogeneic hematopoietic stem cell transplant (allo HCT) is not clearly defined. These investigators evaluated the safety and utility of DLI in patients with either persistent or recurrent multiple myeloma (MM) after allo HCT. A total of 23 patients with MM received DLI after allo HCT between July 1996 and June 2008 were included in this study. Eight patients received preemptive DLI for residual disease (RD) while 15 patients received DLI for the treatment of recurrent or progressive disease (PD). These researchers evaluated the response to DLI and the factors that may predict a response. Median DLI dose was (7) CD3 + cells (range of 0.5 to (7)). Grade II to IV acute GVHD was seen in 5 patients (22 %). Median follow up in surviving patients was 24 months. Five of 23 patients (22 %) achieved a complete or a very good partial response (2 CR, 3 VGPR), while 8 patients (34 %) had stable disease (SD) after the DLI. Patients who received DLI for RD had a higher response rate (greater than or equal to VGPR 50 % versus 7 %, p = 0.03), a longer overall survival (28.3 versus 7.6 months, p = 0.03) and a trend toward longer progression free survival (11.9 versus 5.2 months, p = 0.1). In this largest single institution study, the authors concluded that the use of preemptive, non manipulated DLI for RD after reducedintensity conditioning allo HCT is encouraging, and it was associated with a higher response rate and a longer overall survival when given preemptively. They stated that the role of DLI needs to be further explored in prospective clinical trials.

5 5 of 13 According to the 2009 edition of Thomas Hematopoietic Cell Transplantation, in patients with poor graft function following allogeneic transplantation, CD34+ selected cell boost following granulocyte colony stimulating factor (G CSF) mobilization was associated with a high likelihood of hematopoietic cell recovery and a low risk of GVHD. Patients did not receive conditioning prior to the CD34+ cell boost. It is unclear how long to wait before requesting a second donation of cells. An UpToDate review on Immunotherapy for the prevention and treatment of relapse following hematopoietic cell transplantation (Negrin, 2014) states that Various techniques have been used to manipulate the donor lymphocyte graft in an effort to increase the lymphocyte specificity to eradicate tumor while minimizing effects on the host. As yet, these techniques are considered experimental and require further study in humans before they can be widely applied. Intrathecal Donor Lymphocyte Infusion: Yanagisawa et al (2016) reported on the case of an 8 year old boy with a bone marrow relapse of T cell acute lymphoblastic leukemia underwent stem cell transplantation from a human leukocyte antigen (HLA) haploidentical mother. Five months later, he relapsed with central nervous system (CNS) involvement. Systemic chemotherapy and repeated intrathecal chemotherapy induced consciousness disturbances and frequent arrhythmia, prompting discontinuation of the chemotherapy. He had already received an 18 Gy prophylactic cranial irradiation, an 8 Gy total body irradiation, and a 15 Gy local irradiation for pituitary gland involvement. Thus, these researchers performed 5 intrathecal DLIs (IDLIs) in escalating doses from 1 10(4) up to 1 10(6) cells/kg. All IDLIs were safe without infusion reactions or GVHD. After the 2nd and later IDLIs, donor mononuclear cells were continuously detected in cerebrospinal fluid; however, he did not achieve donor dominant chimerism. The authors concluded that based on this case and 4 cases reported in the literature, the effectiveness of IDLI therapy is limited for CNS relapse of hematological malignancies. However, they suggested that IDLI remains a feasible and safe option, as no GVHD or other adverse

6 6 of 13 effects occurred, even in the HLA haploidentical setting. These investigators noted that they will make further efforts to increase the efficacy. Multiple Myeloma: Oostvogels and colleagues (2017) stated that DLI can induce durable remissions in MM patients, but this occurs rather infrequently. As the graft versus tumor (GvT) effect of DLI depends on the presence of host dendritic cells (DCs), these researchers tested in a phase I/II clinical trial whether the effectiveness of DLI could be improved by simultaneous vaccination with host DCs. They also analyzed the possibility of further improving the GvT effect by loading the DCs with peptides of mis matched hematopoietic cell specific minor histocompatibility antigens (mhags). A total of 15 MM patients not responding to a 1st DLI were included in this study; 11 patients could be treated with a 2nd equivalent dose DLI combined with DC vaccinations, generated from host monocytes (modc). For 4 patients, the DC products did not meet the quality criteria. In 4 of the treated patients the DCs were loaded with host mhag peptides. To xicity was limited and no acute GVHD occurred. Most patients developed objective anti host T cell responses and in 1 patient a distinct mhag specific T cell response accompanied a temporary clinical response. The authors concluded that these findings confirmed that DLI combined with host DC vaccination, either unloaded or loaded with mhag peptides, is feasible, safe and capable of inducing host specific T cell responses. They stated that the limited clinical effects may be improved by developing more immunogenic DC products or by combining this therapy with immune potentiating modalities like checkpoint inhibitors. National Comprehensive Cancer Network s clinical practice guideline on Multiple myeloma (Version ) states that Patients whose disease either does not respond to or relapse after allogeneic stem cell grafting may receive donor lymphocyte infusions to stimulate a beneficial graft versus myeloma effect or other myeloma therapies on or off a clinical trial. There is no explicit recommendation regarding the use of DLI.

7 7 of 13 Furthermore, an UpToDate review on Treatment of relapsed or refractory multiple myeloma (Rajkumar, 2017) does not mention DLI as a management tool. CPT Codes / HCPCS Codes / ICD 10 Codes Information in the [brackets] below has been added for clarification purposes. Codes requiring a 7th character are represented by "+": ICD 10 codes will become effective as of October 1, 2015: CPT codes covered if selection criteria are met: , Bone marrow or stem cell services/procedures (except autologous) Allogeneic lymphocyte infusions Other CPT codes related to the CPB: Therapeutic apheresis; for white blood cells Compatibility studies code range HCPCS codes covered if selection criteria are met: S2150 Bone marrow or blood derived stem cells (peripheral or umbilical), allogeneic or autologous, harvesting, transplantation, and related complications; including: pheresis and cell preparation/storage; marrow ablative therapy; drugs, supplies, hospitalization with outpatient follow up; medical/surgical, diagnostic, emergency, and rehabilitative services; and the number of days of pre and post transplant care in the global definition ICD 10 codes covered if selection criteria are met: C91.00 C91.02 C92.00 C92.02 C92.10 C92.12 Acute lymphoblastic leukemia [ALL] Acute myeloblastic leukemia Chronic myeloid leukemia, BCR/ABL positive Z94.81 Bone marrow transplant status

8 8 of 13 Z94.84 Stem cells transplant status The above policy is based on the following references: 1. Kolb HJ, Mittermuller J, Clemm C, et al. Donor leukocyte transfusions for treatment of recurrent chronic myelogenous leukemia in marrow transplant patients. Blood. 1990;76: Cullis JO, Jiang YZ, Schwarer AP, et al. Donor leukocyte infusions for chronic myeloid leukemia in relapse after allogeneic bone marrow transplantation. Blood. 1992;79: Kolb HK, Mittermuller J, Hertenstein H, et al. High dose therapy and bone marrow transplantation. Adoptive immunotherapy in human and canine chimeras the role of interferon alfa. Semin Hematol. 1993;30: Drobyski WR, Keever CA, Roth MS, et al. Salvage immunotherapy using donor leukocyte infusions as treatment for relapsed chronic myelogenous leukemia after allogeneic bone marrow transplantation: Efficacy and toxicity of a defined T cell dose. Blood. 1993;82: van Rhee R, Cullis JO, Spencer A, et al. Relapse of chronic myeloid leukemia after allogeneic bone marrow transplant: The case for giving donor leukocyte transfusions before the onset of hematologic relapse. Blood. 1994;83: Porter DL, Roth MS, McGarigle C, et al. Induction of graft vs host disease as immunotherapy for relapsed chronic myeloid leukemia. N Engl J Med. 1994;330: Collins RH Jr, Shpilberg O, Drobyski WR, et al. Donor leukocyte infusions in 140 patients with relapsed malignancy after allogeneic bone marrow transplantation. J Clin Oncol. 1997;15(2): Dazzi F, Goldman J. Donor lymphocyte infusions. Curr Opin Hematol. 1999;6(6): Collins RH Jr, Goldstein S, Giralt S, et al. Donor leukocyte infusions in acute lymphocytic leukemia. Bone Marrow Transplant. 2000;26(5): Salama M, Nevill T, Marcellus D, et al. Donor leukocyte

9 9 of 13 infusions for multiple myeloma. Bone Marrow Transplant. 2000;26(11): Peggs KS, Mackinnon S. Cellular therapy: Donor lymphocyte infusion. Curr Opin Hematol. 2001;8(6): Slavin S, Nagler A, Aker M, et al. Non myeloablative stem cell transplantation and donor lymphocyte infusion for the treatment of cancer and life threatening non malignant disorders. Rev Clin Exp Hematol. 2001;5(2): Luznik L, Fuchs EJ. Donor lymphocyte infusions to treat hematologic malignancies in relapse after allogeneic blood or marrow transplantation. Cancer Control. 2002;9(2): Ishikawa J, Maeda T, Kashiwagi H, et al. Successful second allogeneic peripheral blood stem cell transplantation and donor lymphocyte infusion in patients with relapsed acute leukemia using the same donors as for the initial allogeneic bone marrow transplantation. Bone Marrow Transplant. 2003;31(11): Raiola AM, Van Lint MT, Valbonesi M, et al. Factors predicting response and graft versus host disease after donor lymphocyte infusions: A study on 593 infusions. Bone Marrow Transplant. 2003;31(8): Bethge WA, Hegenbart U, Stuart MJ, et al. Adoptive immunotherapy with donor lymphocyte infusions after allogeneic hematopoietic cell transplantation following nonmyeloablative conditioning. Blood. 2004;103(3): 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): Ballester OF, Fang T, Raptis A, et al. Adoptive immunotherapy with donor lymphocyte infusions and interleukin 2 after high dose therapy and autologous stem cell rescue for multiple myeloma. Bone Marrow Transplant. 2004;34(5): Cheong SK, Eow GI, Leong CF. Non myeloablative conditioning for hemopoietic stem cell transplantation does it work? Malays J Pathol. 2002;24(1):1 8.

10 10 of Loren AW, Porter DL. Donor leukocyte infusions after unrelated donor hematopoietic stem cell transplantation. Curr Opin Oncol. 2006;18(2): Huang XJ, Liu DH, Liu KY, et al. Donor lymphocyte infusion for the treatment of leukemia relapse after HLAmismatched/haploidentical T cell replete hematopoietic stem cell transplantation. Haematologica. 2007;92(3): Porter DL, Antin JH. Donor leukocyte infusions in myeloid malignancies: New strategies. Best Pract Res Clin Haematol. 2006;19(4): Levenga H, Woestenenk R, Schattenberg AV, et al. Dynamics in chimerism of T cells and dendritic cells in relapsed CML patients and the influence on the induction of alloreactivity following donor lymphocyte infusion. Bone Marrow Transplant. 2007;40(6): Heaney NB, Copland M, Stewart K, et al. Complete molecular responses are achieved after reduced intensity stem cell transplantation and donor lymphocyte infusion in chronic myeloid leukemia. Blood. 2008;111(10): Tomblyn M, Lazarus HM. Donor lymphocyte infusions: The long and winding road: How should it be traveled? Bone Marrow Transplant. 2008;42(9): Dvorak CC, Gilman AL, Horn B, et al. Clinical and immunologic outcomes following haplocompatible donor lymphocyte infusions. Bone Marrow Transplant. 2009;44(12): 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): Roddie C, Peggs KS. Donor lymphocyte infusion following allogeneic hematopoietic stem cell transplantation. Expert Opin Biol Ther. 2011;11(4): Kamimura T, Miyamoto T, Kawano N, et al. Successful treatment by donor lymphocyte infusion of adult T cell leukemia/lymphoma relapse following allogeneic hematopoietic stem cell transplantation. J Hematol.

11 11 of ;95(6): Karasu GT, Yesilipek MA, Karauzum SB, et al. The value of donor lymphocyte infusions in thalassemia patients at imminent risk of graft rejection following stem cell transplantation. Pediatr Blood Cancer. 2012;58(3): Beitinjaneh AM, Saliba R, Bashir Q, et a. Durable responses after donor lymphocyte infusion for patients with residual multiple myeloma following non myeloablative allogeneic stem cell transplant. Leuk Lymphoma. 2012;53(8): El Jurdi N, Reljic T, Kumar A, et al. Efficacy of adoptive immunotherapy with donor lymphocyte infusion in relapsed lymphoid malignancies. Immunotherapy. 2013;5(5): Slesarchuk OA, Babenko EV, Semenova EV, et al. Efficacy of donor lymphocyte infusion in patients after different types of allogeneic hematopoietic stem cell transplantation. Ter Arkh. 2013;85(7): Zeidan AM, Forde PM, Symons H, et al. HLA haploidentical donor lymphocyte infusions for patients with relapsed hematologic malignancies after related HLA haploidentical bone marrow transplantation. Biol Blood Marrow Transplant. 2014;20(3): Negrin RS. Immunotherapy for the prevention and treatment of relapse following hematopoietic cell transplantation. UpToDate [serial online]. Waltham, MA: UpToDate; reviewed May Gozdzik J, Rewucka K, Krasowska Kwiecien A, et al. Adoptive therapy with donor lymphocyte infusion after allogenic hematopoietic SCT in pediatric patients. Bone Marrow Transplant. 2015;50(1): Haines HL, Bleesing JJ, Davies SM, et al. Outcomes of donor lymphocyte infusion for treatment of mixed donor chimerism after a reduced intensity preparative regimen for pediatric patients with nonmalignant diseases. Biol Blood Marrow Transplant. 2015;21(2): Kurnaz F, Sahin C, Kaynar L, et al. Factors affecting survival in acute leukemia with donor lymphocyte infusion in the first relapse after allogeneic stem cell transplantation. J BUON. 2016;21(1):

12 12 of Yanagisawa R, Nakazawa Y, Sakashita K, et al. Intrathecal donor lymphocyte infusion for isolated leukemia relapse in the central nervous system following allogeneic stem cell transplantation: A case report and literature review. Int J Hematol. 2016;103(1): Tsirigotis P, Byrne M, Schmid C, et al. Relapse of AML after hematopoietic stem cell transplantation: Methods of monitoring and preventive strategies. A review from the ALWP of the EBMT. Bone Marrow Transplant. 2016;51(11): Oostvogels R, Kneppers E, Minnema MC, et al. Efficacy of host dendritic cell vaccinations with or without minor histocompatibility antigen loading, combined with donor lymphocyte infusion in multiple myeloma patients. Bone Marrow Transplant. 2017;52(2): National Comprehensive Cancer Network. Clinical practice guideline: Multiple myeloma. Version NCCN: Fort Washington, PA. 43. Rajkumar SV. Treatment of relapsed or refractory multiple myeloma. UpToDate Inc., Waltham, MA. Last reviewed April 2017.

13 13 of 13 Copyright Aetna Inc. All rights reserved. Clinical Policy Bulletins are developed by Aetna to assist in administering plan benefits and constitute neither offers of coverage nor medical advice. This Clinical Policy Bulletin contains only a partial, general description of plan or program benefits and does not constitute a contract. Aetna does not provide health care services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in private practice and are neither employees nor agents of Aetna or its affiliates. Treating providers are solely responsible for medical advice and treatment of members. This Clinical Policy Bulletin may be updated and therefore is subject to change. Copyright Aetna Inc.

14 AETNA BETTER HEALTH OF PENNSYLVANIA Amendment to Aetna Clinical Policy Bulletin Number: 0638 Donor Lymphocyte Infusion There are no amendments for Medicaid. revised 08/25/2017