Medical Policy: 07.03.13
Original Effective Date: November 2020
Reviewed: November 2020
Revised:
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This Medical Policy document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy will be reviewed regularly and be updated as scientific and medical literature becomes available.
Donor lymphocyte infusion (DLI), also called donor leukocyte infusion, or buffy coat infusion, is a type of therapy in which lymphocytes from the blood of the donor are given to a patient who has already received allogeneic hematopoietic stem cell transplantation (HSCT) from the same donor. This therapy is based on the premise that the donor lymphocytes will recognize and kill the recipient’s cancer cells in a process known as the graft-versus-leukemia (GVL) or graft-versus-tumor (GVT) effect. It is now accepted that DLI, at a time remote from the transplant conditioning regimen, can treat infections and relapse successfully after allogeneic HSCT in selected patients with hematologic malignancies; however significant complications may result including acute and chronic graft-versus-host disease (GVHD), anemia, and infection. DLI is not used to promote engraftment or enhancement of chimerism. The intent is not to restore hematopoiesis. The recipient does not receive a preparative regimen but may require concomitant therapy for the underlying problem.
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 lymphoblastic leukemia (ALL), multiple myeloma (MM), myelodysplastic syndromes (MDS), chronic lymphocytic leukemia (CLL), Hodgkin lymphoma (HL), and non-Hodgkin lymphoma (NHL). Studies are limited due to small numbers, but they have provided evidence that DLI can establish a graft-versus-leukemia/lymphoma effect.
Donor lymphocyte infusion (DLI) has been most effective in chronic myelogenous leukemia (CML), inducing a molecular complete remission (CR) in up to 80% of patients who relapse in chronic phase. Only a 12% to 33% response rate has been reported in patents in accelerated or blast phase. 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) Guideline Version 2.2021 Chronic Myelogenous Leukemia (CML) states “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 rather 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 acute myelogenous leukemia (AML), since there is evidence of a graft-versus-leukemia effect in individuals with AML treated with allogeneic transplants.
Donor lymphocyte infusion (DLI) therapy has also been found 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 (DLI) in individuals with relapsed disease from other hematologic malignancies including, but not limited to, acute lymphoblastic leukemia (ALL), multiple myeloma (MM), Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) and myelodysplastic syndromes (MDS), consists mostly of multiple small case series. However, there is a preponderance of these smaller studies in combination, demonstrate that DLI may induce an anti-tumor response in individuals who have relapsed disease following an allogeneic hematopoietic stem cell transplant (HSCT).
Published case reports have suggested that the use of donor lymphocyte infusion (DLI) for residual disease or molecular relapse (as noted by levels of BCR-ABL fusion mRNA measured with PCR) after allogeneic HCT may eliminate residual leukemic clones and thereby prevent overt hematologic relapse. Additional case reports have described using newer TKIs such as dasatinib and nilotinib along with DLI to manage relapse after allogeneic HCT.
The clinically evident graft-versus-leukemia effect of DLI requires weeks to months to become apparent, and, because ALL is a rapidly proliferating disease, DLI only is unable to control the disease without a significant reduction in leukemia burden before DLI. Management of patients with relapsed ALL leading to the best overall survival (OS) is with a combination of salvage chemotherapy and DLI. Although it is not clear whether DLI adds benefit to salvage chemotherapy, long-term survivors have been reported with relapsed ALL who received both chemotherapy and DLI.
NCCN Clinical Practice Guideline for Acute Lymphoblastic Leukemia (ALL) (adult and AYA version 2.2020) includes the use of a second allogeneic HCT and/or donor lymphocyte infusion (DLI) for individuals with relapsed disease after allogeneic HCT. This recommendation is based on 2A category of evidence and uniform consensus.
Studies in which patients received donor lymphocyte infusion (DLI) for lymphomas consist of small numbers of patients with various histologies (both Hodgkin lymphoma [HL] and high- and- low grade non-Hodgkin lymphoma [NHL]). In general, the highest response rates have been seen in indolent lymphomas. For NHL too few patients have been reported with any single histologic subtype of lymphoma to give adequate information of the benefit for DLI for a specific lymphoma subtype.
The largest series reported for NHL (N=21) using DLI showed response rates in 3 of 9 patients with high grade NHL, 1 of 2 patients with mantle cell lymphoma, and 6 of 10 patients with low-grade disease.
A series of 14 patients with multiply relapsed HL who received reduced-intensity conditioning allogeneic HSCT and DLI showed a complete remission (CR) of 57% and 2- year survival of 35%.
Observational data suggest a graft-versus-tumor (GVT) effect in multiple myeloma because the development of GVHD has correlated with response in several analyses.
Five studies have reported on the role of donor lymphocyte infusion (DLI) in relapsed multiple myeloma consisting of patients ranging in number of 5 to 63 with the highest response to DLI being reported as 62% with approximately half of the responders attaining complete remission (CR). One confounding factor for high response rates for multiple myeloma treated with DLI following allogeneic HSCT is that corticosteroids used for treating GVHD have known antimyeloma effect which could potentially enhance response rates in these patients.
NCCN Clinical Practice Guideline for Multiple Myeloma (version 3.2021) includes the use of donor lymphocyte infusion in individuals post allogeneic stem cell transplant with unresponsive (refractory) or relapsed disease in- order to stimulate a beneficial graft-versus-myeloma effect. This recommendation is based on 2A category of evidence and uniform consensus.
An observational study comparing different treatments for relapse reported on 147 consecutive patients who relapsed after allogeneic HSCT for myelodysplastic syndrome. Sixty-two patients received HSCT or donor lymphocyte infusion (DLI), 39 received cytoreductive treatment, and 46 were managed with palliative or supportive care. Two-year rates of overall (OS) were 32%, 6%, and 2%, respectively (p<.001). In multivariate analysis, 4 factors adversely influenced 2-year rates of OS: history of acute graft-versus-host disease (hazard ratio [HR], 1.83; 95% CI, 1.26 to 2.67; p=0.002), relapse within 6 months (HR=2.69; 95% CI, 0.82 to 3.98; p<0.001), progression to acute myelogenous leukemia (HR=2.59; 95% CI, 1.75 to 3.83; p<0.001), and platelet count less than 50 g/L at relapse (HR=1.68; 95% CI, 1.15 to 2.44; p=0.007). HSCT or DLI was found to be an independent factor that favorably impacts OS (HR=0.40; 95% CI, 0.26 to 0.63; p<0.001).
NCCN Clinical Practice Guideline for Myelodysplastic Syndromes (version 1.2021) includes the use of a second allogeneic HCT and/or donor lymphocyte infusion in individuals post allogeneic HCT with unresponsive (refractory) or relapsed disease. This recommendation is based on 2A category of evidence and uniform consensus.
NCCN Clinical Practice Guideline for Multiple Myeloma (version 3.2021) includes the use of donor lymphocyte infusion in individuals post allogeneic stem cell transplant with unresponsive (refractory) or relapsed disease in- order to stimulate a beneficial graft-versus-myeloma effect. NCCN Clinical Practice Guideline for Acute Lymphoblastic Leukemia (ALL) (adult and AYA version 2.2020) includes the use of a second allogeneic HCT and/or donor lymphocyte infusion (DLI) for individuals with relapsed disease after allogeneic HCT. NCCN Clinical Practice Guideline for Myelodysplastic Syndromes (version 1.2021) includes the use of a second allogeneic HCT and/or donor lymphocyte infusion in individuals post allogeneic HCT with unresponsive (refractory) or relapsed disease. These recommendations were based on 2A category of evidence and uniform consensus.
The National Cancer Institute (NCI) regarding the treatment with donor lymphocytes includes the following:
Based on the review of the peer reviewed medical literature the evidence for donor lymphocyte infusion (DLI) for hematologic malignancies in individuals who have been treated with an allogeneic hematopoietic stem cell transplant (HSCT) includes few nonrandomized comparative studies and numerous case series. 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, patients have shown evidence of response to DLI. The response rates to DLI for relapsed hematologic malignancies following allogeneic HSCT are best in chronic myelogenous leukemia (CML), followed by lymphomas (Hodgkin and non-Hodgkin), multiple myeloma (MM), and acute leukemias, respectively. The evidence is sufficient to determine the effects of the technology on net health outcomes.
There is also a research interest in the genetic modification of donor lymphocytes in an effort to control graft versus host disease (GVHD). 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 versus. host disease (GVHD), 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. The evidence is insufficient to determine the effects of the technology on net health outcomes.
Donor lymphocyte infusion (DLI) is used in hematologic malignancies as a means of increasing graft versus tumor effect, however, experience with DLI to improve engraftment in nonmalignant disease is extremely limited. The evidence is insufficient to determine the effects of the technology on net health outcomes.
A boost of hematopoietic progenitor cell (HPC) (also known as stem cells) from the original HCST donor is intended to restore hematopoiesis or augment poor graft function after hematopoietic stem cell transplantation (HSCT). Poor graft function is a severe complication of HSCT which is defined as persistent cytopenias and/or transfusion dependence. The cell product used for a HPC boost may be a previously cryopreserved cell product, or alternatively, the donor may need to undergo additional evaluation, stem cell mobilization, and cell harvest. A boost is not preceded by a preparative regimen. A potential source of confusion is that a boost is often required when additional conventional chemotherapy is given to treat relapse and reestablish remission after transplantation. Prolonged cytopenias and immunosuppression may result, requiring additional HPC boost, which is typically given days to weeks after reinduction chemotherapy.
Although data are not robust, several prospective and retrospective clinical trials demonstrate beneficial effects of HPC boost after HSCT.
In 2017, Ghobadi et. al. performed single institution study at the Washington University School of Medicine. A pilot trial was conducted to study three different sources of CD34+ cells for treatment of poor graft function (PGF): (1) fresh mobilized product using G-CSF only, (2) fresh mobilized products using G-CSF and plerixafor, and (3) cryopreserved cells mobilized with G-CSF. Seventeen donor-recipient pairs were enrolled onto this prospective study. A retrospective review of similar patients treated off protocol with the same regimen was conducted. From June 2010 through June 2015, 17 donor-recipient pairs were enrolled in the prospective study and 9 donor-recipient pairs were treated off protocol. Together 26 donor-patient pair were analyzed and reported in this manuscript. The primary objective was the hematologic response rate. Secondary objectives included: (1) CD34+ yields; (2) incidence and severity of acute and chronic GVHD; (3) Overall survival (OS) and relapse free survival (RFS). The Washington University Institutional Review Board (IRB) approved the study. The prospective trial was registered at ClinicalTrials.gov as NCT01026987. PGF was defined as having cytopenia (ANC < 0.5k/μL, platelets < 30k/μL or platelet transfusion dependence, or red blood cell transfusion dependence) for two consecutive weeks in the absence of relapse/persistent hematologic disorder, incomplete (< 90%) donor chimerism, active infectious diseases, or drug related myelosuppression. Primary PGF was defined as PGF in the absence of full engraftment. Secondary PGF was defined as PGF after full engraftment. Complete response was defined as improvement of all involved cells lineages; partial response was defined as improvement of platelets and/or neutrophils with continuing RBC transfusion dependence. Neutrophil improvement was defined as an absolute neutrophil count > 500/μl without growth factor support for >7 days; platelet improvement was defined as platelet count ≥ 50,000/μl without platelet transfusion support for > 7 days; and RBC improvement was defined as hemoglobin > 9 g/dL and transfusion independence. CD34+ yield was defined as the number of CD34+ cells after selection/CD34+ cells in the mobilized product prior to CD34+ selection. Overall survival (OS) was defined as time from SCB to death. Relapse-free survival (RFS) was defined as time from stem cell boost (SCB) to relapse or death. Eligible patients were those who were at least 18 years old, had an ECOG performance status of 2 or below, and had poor graft function (PGF) following allo-HSCT (more than 60 days post allo-HSCT). Patients with poor graft function secondary to relapse/persistent disease, incomplete (< 90%) donor chimerism, or active infectious diseases were excluded, as were patients with significant medical, psychiatric, or social conditions that contraindicated the procedure. Previous allo-HSCT may have been performed using a related or unrelated donor; however, the original donor was required to undergo additional PBSC collection or authorize that cryopreserved cells from a previous PBSC collection be used. Blood counts were performed at least weekly through Day +14 then at least every other week through Day +100, monthly thereafter for patients on the prospective trial; patients reviewed retrospectively were followed per institutional guidelines. Incidence and severity of acute GVHD was defined according to Glucksberg criteria, chronic GVHD as limited or extensive. Patients were monitored for acute GVHD through Day +100 and for chronic GVHD through Day +365 following SCB. The median age at SCB was 52.5 years (range 25–68) and 16 of 26 were male. Twelve patients underwent allo-HSCT for acute myelogenous leukemia, 6 for myelodysplastic syndrome, 4 for acute lymphoblastic leukemia, 2 for aplastic anemia, and 1 for Hodgkin’s lymphoma, and 1 for Diamond-Blackfan Anemia. Sixteen patients had related donors (11 HLA-matched siblings, 5 haplo-identical donors). Ten had unrelated donors (9 HLA-matched and 1 HLA-mismatch). All received peripheral blood stem cell products. Sixteen patients had primary PGF, 10 secondary. The median time from allo-HSCT to SCB was 4.6 months (range 2.1–23.6). At time of SCB 6 had PGF involving neutrophils, 25 platelets, and 23 red blood cells. Twenty-six recipients of SCB for the treatment of PGF following allo-HSCT. The complete response rate was 62% and overall response rate was 81%. Six of the 10 patients who failed to achieve a complete response suffered from disease relapse while only one of 17 patients with complete hematologic response suffered from disease relapse within 3 months of SCB; Treatment was well tolerated; there was no TRM and no grade III–IV acute GVHD. The authors concluded our data suggests that cryopreserved products can be an effective and viable source of cells for SCB (stem cell boost).
In 2018, Mainardi et. al. reported retrospective study results involving 50 children with acute lymphatic leukemia, acute myeloid leukemia and severe aplastic anemia who received 61 boosts with CD34+ selected peripheral blood stem cells after transplantation from matched unrelated (n = 25) or mismatched related (n = 25) donors. No conditioning was performed prior and no immunosuppressive therapy was administered post the allogeneic HSCT. Within 8 weeks, a significant increase in median neutrophil counts (p < 0.05) and a decrease in red blood cell and platelet transfusion requirement (p < 0. 0001 and <0.001) respectively, were observed. 78.8% of patients resolved one or two of their cytopenias and 36.5% had a complete hematological response. The rate of de novo acute graft-versus-host disease (GVHD) grade I–III was only 6% and resolved completely. No GVHD grade IV or chronic GVHD occurred. Patients who responded to hematopoietic progenitor cell (HPC) displayed a trend toward better overall survival (OS) (P = 0.07). Data suggest improved graft function with HPC boost in this cohort of patients.
A boost of hematopoietic progenitor cell (HPC) (also known as stem cells) from the original HCST donor is intended to restore hematopoiesis or augment poor graft function after hematopoietic stem cell transplantation (HSCT). Poor graft function is a severe complication of HSCT which is defined as persistent cytopenias and/or transfusion dependence. The cell product used for a HPC boost may be a previously cryopreserved cell product, or alternatively, the donor may need to undergo additional evaluation, stem cell mobilization, and cell harvest. A boost is not preceded by a preparative regimen. A potential source of confusion is that a boost is often required when additional conventional chemotherapy is given to treat relapse and reestablish remission after transplantation. Prolonged cytopenias and immunosuppression may result, requiring additional HPC boost, which is typically given days to weeks after reinduction chemotherapy. Based on review of the peer reviewed medical literature, although the evidence is not robust, several prospective and retrospective clinical trials demonstrate beneficial effects of HPC boost after HSCT. The evidence is sufficient to determine the effects of the technology on net health outcomes.
For patients with relapsed disease after allogeneic HCT, a second allogeneic HCT and/or donor lymphocyte infusion (DLI) can be considered.
Management of Post-Transplant Relapse: Donor lymphocyte infusion (DLI) is effective in inducing durable molecular remissions in the majority patients with relapsed CML following allogeneic HCT, though it is more effective in patients with chronic phase relapse then advanced phase relapse.
Management of Post-Allogeneic Hematopoietic Stem Cell Transplant: Includes the use of donor lymphocyte infusion in individuals post allogeneic stem cell transplant with unresponsive (refractory) or relapsed disease.
Consider second transplant or donor lymphocyte infusion immune-based therapy for appropriate patients who had a prolonged remission after first transplant.
Donor lymphocyte infusion (DLI) has been shown to induce long-term remissions in a few patients with PD (progressive disease) or disease relapse after allogeneic HCT. An analysis showed that induction of GVL effect via DLI may provide long-lasting remission in selected patients with relapsed ATLL.
The U.S. Food and Drug Administration regulates certain human cells, tissues, and cellular and tissue-based products under the legal authority of section 361 of the Public Health Service Act (42 USC 264). This section authorizes the Surgeon General, with the approval of the Secretary of the U.S. Department of Health and Human Services, to make and enforce such regulations as judged necessary to prevent the introduction, transmission, or spread of communicable diseases from foreign countries into the United States or from state to state. According to Addendum 7342.007—Imported Human Cells, Tissues, and Cellular and Tissue-based Products (HCT/Ps), umbilical cord blood stem cells, peripheral blood stem cells, lymphocytes (donor lymphocytes for infusion, T cells) are identified by product code 57M.P.
Not applicable.
Donor lymphocyte infusion (DLI) is considered medically necessary following an allogeneic (myeloablative or non-myeloablative) hematopoietic stem cell transplant that was originally considered medically necessary for the treatment of hematologic malignancy that has relapsed or is refractory (disease that does not respond), or to prevent relapse in the setting of a high risk of relapse (T-cell depleted grafts or non-myeloablative [reduced intensity conditioning] allogeneic transplant) or to convert an individual from a mixed to full donor chimerism.
Note: The donor for the lymphocytes is the same individual whose stem cells (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 (myeloablative or non-myeloablative) hematopoietic stem cell transplant.
Donor lymphocyte infusion (DLI) is considered investigational including but not limited to the following as there is insufficient scientific evidence to permit conclusions concerning the health outcomes or benefits associated with this procedure:
Hematopoietic progenitor cell (HPC) boost is considered medically necessary following autologous or an allogeneic (myeloablative or non-myeloablative) hematopoietic stem cell transplant that was originally considered medically necessary for the treatment of hematologic malignancy for either of the following indications:
Hematopoietic progenitor cell (HPC) boost is considered investigational for all other indications as there is insufficient scientific evidence to permit conclusions concerning the health outcomes or benefits associated with this procedure.
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