Pending Policies - Surgery


Hematopoietic Stem-Cell (HSC) Transplantation (HSCT) or Additional Infusion Following Preparative Regimens (General Donor and Recipient Information)

Number:SUR703.002

Effective Date:04-15-2018

Coverage:

*CAREFULLY CHECK STATE REGULATIONS AND/OR THE MEMBER CONTRACT*

CAREFULLY REVIEW the member’s benefit plan, summary plan description or contract for transplant coverage provisions. If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, then the benefit plan, summary plan description or contract will govern.

NOTE 1: Refer to SUR703.001, Organ and Tissue Transplantation for general donor and recipient information.

NOTE 2: For policy coverage information on hematopoietic stem-cell transplantation (HSCT) for specific malignant or nonmalignant conditions, please refer to the specific Medical Policy.

Hematopoietic Stem-Cells (HSCs) Collection and Storage

Stem-cells, using bone marrow or peripheral blood, for autologous reinfusion or allogeneic infusion or transplantation following a chemotherapy/preparative regimen (high-dose, myeloablative or nonmyeloablative) may be considered medically necessary if the recipient patient has a condition or disorder for which the planned transplant is considered medically necessary and has met the transplant selection criteria; refer to the appropriate individual transplant policy for description and coverage information.

Umbilical cord blood (UCB) hematopoietic stem-cell transplantation (HSCT), following a chemotherapy/preparative regimen (high-dose, myeloablative or nonmyeloablative), may be considered medically necessary in patients who have met the transplant selection criteria, and who have an appropriate indication for allogeneic HSCT, but who do not have a hematopoietic stem-cell donor; refer to the appropriate individual transplant policy for description and coverage information.

Collection and storage of UCB stem-cells from a newborn may be considered medically necessary when an allogeneic HSCT is imminent (less than one year) in an identified recipient, such as a sibling, with a diagnosis that is consistent with the possible need for allogeneic HSCT.

Prophylactic collection and storage of UCB stem-cells from a newborn AND/OR speculative collection and storage of stem-cells from donor-recipient (autologous) or from related or unrelated donor (allogeneic) is considered not medically necessary when proposed for potential and unspecified future use, such as but not limited to a potential and unspecified future use as an:

Autologous HSCT in the original donor; OR

Allogeneic HSCT in a related or unrelated recipient.

Stem-Cell Purging

Stem-cell purging is an integral part of the autologous stem-cell preparation after harvesting and is not eligible for additional reimbursement beyond the standard stem-cell donation preparation prior to recipient infusion.

Stem-cell purging as part of the allogeneic stem-cell preparation after harvesting is considered not medically necessary as an allogeneic stem-cell donation should be cancer free prior to recipient infusion.

Donor Lymphocyte Infusion (DLI) or Hematopoietic Progenitor-Cell (HPC) Stem-Cell Boost

DLI or stem-cell boost may be considered medically necessary following allogeneic HSCT that was originally considered medically necessary for the treatment of hematologic malignancy that has relapsed or is refractory, to prevent relapse in the setting of a high risk of relapse (includes T-cell depleted grafts or nonmyeloablative/reduced intensity conditioning), or to convert a patient from mixed to full donor chimerism.

DLI or stem-cell boost are considered experimental, investigational and/or unproven following allogeneic HSCT that was originally considered experimental, investigational and/or unproven for the treatment of a hematologic malignancy.

DLI or stem-cell boost are considered experimental, investigational and/or proven as a treatment of nonhematologic malignancies following a prior allogeneic HSCT.

DLI or stem-cell boost are considered experimental, investigational and/or unproven as a treatment of hematologic or nonhematologic malignancies following a prior autologous HSCT.

Genetic modification of donor lymphocytes for infusion at any point following any HSCT treatment is considered experimental, investigational and/or unproven.

Short Tandem Repeat (STR) Markers

Short tandem repeat (STR) markers may be considered medically necessary when used in pre- or post- HSCT testing of the donor and recipient DNA profiles as a way to assess the status of donor cell engraftment for some hematological disorders.

Description:

Human blood contains a remarkable variety of cells, each precisely tailored to its own vital function. Erythrocytes, or red blood cells, transport life-sustaining oxygen throughout the body. Tiny platelets stop bleeding by promoting clotting. White blood cells (e.g., lymphocytes, monocytes, and neutrophils) form the immune system that guards against attack by foreign tissue, viruses, and various other microorganisms.

All of these cells develop from master cells or blood cell progenitors, which are known as hematopoietic blood-forming or blood-parent stem-cells (HSC) and reside primarily in bone marrow. Injury to the stem-cells, from chemotherapy, radiation, or disease, can cripple the immune and blood production systems.

Background

HSCs are the main ingredient in bone marrow stem-cell transplantation (also known as hematopoietic stem-cell transplant, transplantation, rescue or support; HSCT). The HSCs in the transplanted marrow can reestablish the patient's blood-producing and immune systems, which have been devastated by leukemia, cancer, chemotherapy, radiation therapy, or unknown causes. The objective of all types of HSCT is to provide the healthy stem-cell population that will differentiate into blood cells to replace the deficient or pathologic cells of the host. Therefore, the purpose of HSCT is to restore the stem-cells after injury to normal function. (1-6)

The most appropriate stem-cell source for a particular patient depends upon his or her disease, treatment history, and the availability of a compatible donor. The most appropriate source of stem-cells for each patient must be balanced by the risks of graft failure, the reinfusion of defective or diseased cells in the autologous procedure, the risks of graft rejections and graft-versus-host disease (GVHD) in allogeneic procedures. This becomes especially critical with the use of a mismatched or unrelated donor. (1-6)

Improvement of stem-cell grafting and long-term, disease-free survival (DFS) is accomplished by:

Intensive preparative regimens, and

Effective graft-versus-host disease treatment, and

Improvements in supportive care.

Steps Involved for a HSCT:

1. Donor matching to the recipient,

2. Preparative conditioning or regimens for the recipient,

3. Harvesting stem-cells from the donor,

4. Infusion or transplantation of stem-cells to the recipient,

5. Engraftment and recovery by the recipient, and

6. Additional infusions to the recipient as needed.

Preparative Conditioning or Regimens for the Recipient

Conventional Preparative Conditioning (High-Dose Chemotherapy [HDC]):

The conventional “classical” practice of allogeneic HSCT involves administration of myelotoxic agents (e.g., cyclophosphamide, busulfan; also known as HDC with or without total body or localized irradiation (known as chemoradiotherapy) at doses sufficient to cause bone marrow failure. HDC may be given as one type of myelotoxic agent only, known as monotherapy, or several types of agents sequentially, known as sequential HDC. The rationale for this type of therapy is that many cytotoxic agents act according to a steep dose-response curve. The beneficial treatment effect in this procedure results from chemotherapeutic eradication of malignant cells with an associated immune-mediated graft-versus-malignancy effect. While such treatment may eliminate the malignant cells, patients are as likely to die from opportunistic infections, GVHD, hemorrhage, or organ failure as from the underlying malignancy. Since the life-threatening toxicity is so high, patients are usually hospitalized for the HDC regimen and may require further hospitalization to treat the drug toxicity effects. Autologous HSCT necessitates myeloablative chemotherapy to eradicate cancerous cells from the blood and bone marrow, thus permitting subsequent engraftment and repopulation of bone marrow space with presumably normal hematopoietic progenitor cells (HPCs). Consequently, autologous HSCT is typically performed as consolidation therapy when the patient’s disease is in complete remission (CR). Patients who undergo autologous HSCT are susceptible to chemotherapy-related toxicities and opportunistic infections prior to engraftment, but not GVHD. (1, 3, 5)

Reduced-Intensity Conditioning (RIC):

RIC (previously known as nonmyeloablative or non-marrow-ablative chemotherapy or mini-transplant) refers to chemotherapy regimens that seek to reduce adverse effects secondary to toxicity while retaining the beneficial graft-versus-malignancy effect of allogeneic HSCT. These regimens do not eradicate the patient’s hematopoietic ability, thereby allowing for relatively prompt hematopoietic recovery (e.g., 28 days or less) even without transplantation. Patients who undergo RIC with allogeneic HSCT initially demonstrate donor cell engraftment and bone marrow mixed chimerism. Most will subsequently convert to full-donor chimerism, which may be supplemented with donor lymphocyte infusion (DLI) or HPC boost (stem-cell boost) to eradicate residual malignant cells. A number of different cytotoxic regimens, with or without radiotherapy, may be used for RIC allogeneic HSCT. They represent a continuum in their effects, from nearly totally myeloablative, to minimally myeloablative with lymphoablation. (1, 3, 5)

Harvesting Stem-Cells from the Donor

Stem-cells can be harvested from the donor’s bone marrow prior to the recipient’s marrow ablative therapy or from a donor’s marrow after verifying the donor and recipient are well-matched with respect to human leukocyte antigens (HLAs). Those types of stem-cells harvesting followed by infusion are:

Autologous – Stem-cells are harvested from an individual prior to any ablative therapy and infused back (reinfusion) into the same individual.

Allogeneic – Stem-cells from a healthy antigen compatible (histocompatible) donor are harvested and then infused into a different recipient.

Syngeneic – Stem-cells refer to genetically identical bone marrow or peripheral stem-cells harvested from an identical twin. Syngeneic bone marrow transplants are obviously limited by the rarity of identical twins. (1, 3, 5)

Infusion of Stem-Cells to the Recipient

Once the recipient has completed the preparative conditioning or regimen, the infusion of stem-cells is accomplished through an intravenous line, similar to a blood transfusion, taking about 1 to 5 hours. (1, 3, 5)

Infusions of stem-cells to the recipient procedures, dependent on the type of stem-cells harvested, are also known as:

Hematopoietic stem-cell transplantation (HSCT),

Peripheral blood HSCT,

Allogeneic HSCT, autologous HSCT, syngeneic HSCT, and

Umbilical cord blood (UCB) HSCT.

Hematopoietic Stem-Cell Transplantation (HSCT) Procedure

The procedure itself is simple. If the patient is not self-donating his/her bone marrow, it is obtained from a donor individual and is known as allogeneic HSCT. The bone marrow is aspirated, under local or general anesthesia, over several sessions from the iliac crests of the pelvis of:

A related or unrelated donor who is HLA compatible (known as allogeneic);

A related donor who is HLA-identical (known as syngeneic). (1, 3, 5)

If the patient is self-donating his/her bone marrow, known as autologous HSCT, the bone marrow is removed from the iliac crests of the pelvis when a complete remission has been induced. The patient is then given HDC with the hope of destroying any residual tumor. (1, 3, 5)

Bone marrow infusions present numerous medical hurdles. The patient must receive a steady supply of fresh red cells, platelets, and antibiotics for several weeks until the transplanted stem-cells begin producing large quantities of mature blood elements. (1, 3, 5)

In an allogeneic HSCT, the patient's immune system must be sufficiently suppressed so that it will not reject the transplanted stem-cells. At the same time, the immune system produced by the donor stem-cells may recognize their new host as foreign, a reaction known as GVHD, in which case they may cause organ damage and/or death. Allogeneic HSCT is an established treatment for certain marrow dysplasias and aplasias and genetic diseases (such as immunodeficiencies and inborn errors of metabolism). (1, 3, 5)

Immunologic compatibility between the donor and patient is a critical factor for achieving a good outcome of allogeneic HSCT. In general, the more compatible the donor and recipient tissue types are, the greater the chances for a successful outcome. Compatibility is established by the typing (testing) of six HLA and the outcome of mixed leukocyte (white blood cell types) cultures. An acceptable donor will match the patient's six HLA. A mismatch of one or more antigens may not be considered an acceptable donor. In all cases, the donor and recipient tissue/cells must be non-reactive (no reaction) in the mixed leukocyte culture. (1, 3, 5)

Autologous HCST eliminates the need to find a compatible marrow donor and bypasses the risk of GVHD. The limitation to this approach is the possibility of reinfusing contaminated marrow. Even if the marrow is truly uninvolved, a significant amount of blood is also collected at the time of the harvest. Thus, circulating disease cells could also be a source of contamination. (1, 3, 5)

Peripheral Blood HCST:

Patients treated with HDC regimens that ablate their own bone marrow function are increasingly being reinfused with autologous stem-cells rather than with bone marrow cells. Small numbers of stem-cells circulate in the peripheral blood and can be harvested via a pheresis procedure. After several cycles of conventional doses of chemotherapy and stimulation with colony stimulating factors, the number of hematopoietic stem-cells in the peripheral circulation rises. The patient may be subjected to a leukapheresis process several times where peripheral blood is removed and undergoes repeated selective separation and removal of leukocytes (white blood cells), progenitor cells, and platelets. The red blood cells and plasma are returned to the donor. After the patient receives HDC, the patient's bone marrow is reconstituted by the reinfusion of the stem-cell population. Peripheral blood stem-cells are now used for nearly all autologous HSCT procedures and nearly half of allogeneic HSCT procedures. (1, 3, 5)

Colony stimulating factor are hematopoietic growth factors that stimulate the growth and maturation of bone marrow stem-cells. Two of these colony stimulating factors are currently available:

Granulocyte colony stimulating factor; or

Granulocyte macrophage colony stimulating factor.

Umbilical Cord Blood (UCB) HCST:

A variety of malignant diseases and nonmalignant bone marrow disorders are treated with chemotherapy/myeloablative therapy followed by infusion of allogeneic stem- and progenitor- cells (HSCs) collected from immunologically compatible donors, either from family members or from an unrelated donor identified through a bone marrow donor bank. In some cases, a suitable donor is not found.

Blood harvested from the umbilical cord and placenta shortly after delivery of neonates contains HSCs capable of restoring hematopoietic function after chemotherapy/myeloablation. This cord blood has been used as an alternative source of allogeneic stem cells. Cord blood is readily available and is thought to be antigenically “naive,” thus hopefully, minimizing the incidence of GVHD and permitting the broader use of unrelated cord blood transplants. Unrelated donors are typically typed at low resolution for HLA -A and -B and at high resolution only for HLA-DR; HLA matching at 4 of 6 loci is considered acceptable. Under this matching protocol, an acceptable donor can be identified for almost any patient. (7)

Several cord blood banks have now been developed in Europe and in the U.S. In addition to obtaining cord blood for specific related or unrelated patients, some cord blood banks are offering the opportunity to collect and store a neonate’s cord blood for some unspecified future use in the unlikely event that the child develops a condition that would require autologous transplantation. In addition, some cord blood is collected and stored from a neonate for use by a sibling in whom an allogeneic transplant is anticipated due to a history of leukemia or other condition requiring allogeneic transplant.

Standards and accreditation for cord blood banks are important for assisting transplant programs in knowing whether individual banks have quality control measures in place to address such issues as monitoring cell loss, change in potency, and prevention of product mix-up. (8) Two major organizations are working toward these accreditation standards; NetCord/FACT and the American Association of Blood Banks (AABB). NetCord, Foundation for the Accreditation of Cellular Therapy (FACT) has developed and implemented a program of voluntary inspection and accreditation for cord blood banking. In September 2012, NetCord and FACT released the fifth edition of their international standards for cord blood banks. (9) The voluntary program includes standards for collection, testing, processing, storage, and release of cord blood products.

According to the U.S. Food and Drug Administration (FDA), cord blood stored for potential use by a patient unrelated to the donor meets the definitions of “drug” and “biological products.” As such, products must be licensed under a biologics license application or an investigational new drug application before use. Facilities that prepare cord blood units only for autologous and/or first- or second-degree relatives are required to register and list their products, adhere to Good Tissue Practices issued by the FDA, and use applicable processes for donor suitability determination. (10)

Additional Infusions or Boosts

Donor Lymphocyte Infusions (DLI):

DLI, also called donor lymphocyte or buffy-coat infusion/transfusion, is a type of therapy in which T-lymphocytes from the blood of a donor are given to a patient who has already received a HSCT from the same donor. The DLI therapeutic effect results from a graft-versus-leukemic or graft-versus-tumor effect due to recognition of certain antigens on the cancer cells by the donor lymphocytes and the resultant elimination of the tumor cells.

Approximately 40% to 60% of patients who receive a DLI develop graft versus-host disease (GVHD), and the development of GVHD predicts a response to the DLI. (11) A Blue Cross and Blue Shield Association (BCBSA) Technology Evaluation Center (TEC) Assessment on this subject was published in 1997. (12) Treatment-related mortality after DLI is 5% to 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. (11, 12) The risk of development of GVHD is related, in part, to DLI dose and therapy before DLI.

Timing of the use of DLI depends upon the disease indication and may be used in the setting of relapse after an allogeneic HSCT, as a planned strategy to prevent disease relapse in the setting of T cell depleted grafts or nonmyeloablative 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 patients, is the most common indication for DLI. (13)

The source of the DLI donor cells can be from a previously collected and cryopreserved reserve or can be freshly harvested, provided from the original stem-cell donor. Collection of donor lymphocytes requires that the original donor undergo a leukapheresis procedure. This additional DLI, which is a form of adoptive immunotherapy, induces a graft-versus-tumor response, without the need for additional peripheral blood stem-cell harvest from the donor, or further chemotherapy for the recipient. These patients do not receive immunosuppressive medication.

The literature is heterogeneous for reporting methods of cell collection, timing of infusion (e.g., after chemotherapy, in early relapse), cell dose infused and cell subtype used. (2) 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 HSCT is performed, including chronic myeloid leukemia, acute myeloid and lymphoblastic leukemias, myelodysplastic syndromes, multiple myeloma and Hodgkin and non-Hodgkin lymphoma.

There is also research interest in the genetic modification of donor lymphocytes. For example, donor lymphocytes can be modified by insertion of a thymidine kinase gene, rendering the cells susceptible to ganciclovir therapy. If the infusion of donor lymphocytes results in severe GVHD, the patients can be treated with ganciclovir to selectively destroy the donor lymphocytes.

Hematopoietic Progenitor Cell (HPC) or Stem-Cell Boost:

Much like DLI, HPC boosts or stem-cell boosts/boost infusions are given as a post-allogeneic HCST for engraftment failure. This may be a result of inadequate stem-cell numbers (such as a single UCB unit), infections, GVHD, graft failure including late rejection, and immunological mediated processes, such as poorly matched donor/recipient, HSCT with depleted T-cells, refractory pure red cell aplasia caused by remaining recipient cells producing anti-erythrocyte antibodies or DLI induced pancytopenia. This post transplantation condition is life-threatening and uncommon, but can be overcome by an additional infusion of HSCs, if available. Additional chemotherapy or total body irradiation is not given prior to the stem-cell boost of donor cells; and this is not considered a second or tandem transplantation. (14)

Tandem Transplantation (Including Triple Transplantation)

Tandem chemotherapy with autologous HCST or allogeneic HCST is a planned process of bone marrow ablation performed alone or with total body irradiation followed by stem-cells by using the patient's or donor’s harvested stem-cells. This process is repeated without regard to response and following recovery of the earlier infusion or transplant. The patient can expect two planned cycles of bone marrow ablation, sequential HDC, followed by HCST. The second (or subsequent) cycle(s) is intended to further tumor cell reduction and eliminate any possibility of tumor progression or relapse. Tandem HDC with HCST are generally administered at intervals of 2- to 6-months, contingent on the recovery from the early HCST. A third (or subsequent) cycle(s) is considered a “triple transplantation”. Tandem HDC with HCST has also been described as the patient is being given the “second” or “final” dose of stem-cells following the first HSCT at an interval of approximately 2-months.

Functional Status of Cancer Patients

Oncologists have identified that the functional status of the patient can be correlated with the outcome of the underlying disease. The following Karnofsky Performance Status Index (Scale), Table 1, has been the most widely used measure of the functional status of cancer patients.

Table 1. Karnofsky Performance Status Index (Scale)

GENERAL CATEGORY

INDEX

SPECIFIC CRITERIA

Able to carry on normal activity, no special care needed

100

Normal, no complaints, no evidence of disease

(same as above)

90

Able to carry on normal activity, minor signs or symptoms of disease

(same as above)

80

Normal activity with effort, some signs or symptoms of disease

Unable to work, able to live at home and care for most personal needs, varying amount of assistance needed

70

Cares for self, unable to carry on normal activity or to do work

(same as above)

60

Requires occasional assistance from others, but able to care for most needs

(same as above)

50

Requires considerable assistance from others and frequent medical care

Unable to care for self, requires institutional or hospital care or equivalent, disease may be rapidly progressing

40

Disabled, requires special care and assistance

(same as above)

30

Severely disabled, hospitalization indicated, death not imminent

(same as above)

20

Very sick, hospitalization necessary, active supportive treatment necessary

(same as above)

10

Moribund (a dying state)

N/A

0

Death

Additional Definitions

Listed below are several definitions, not included in the above Description:

Chemosensitive disease is defined as a tumor, showing at least a 50% reduction in tumor burden in response to chemotherapy, typically measured by serial computed tomography scans.

Complete remission or response (CR) is the disappearance or absence of the signs and symptoms of the disease.

Malignancy refers to a harmful uncontrolled growth that can spread throughout the body and eventually lead to death.

Minimal response is defined as AT LEAST a 25% reduction in tumor burden, such as multiple myeloma being typically measured in terms of serum levels of beta-2 microglobulin or monoclonal immunoglobulins.

Monotherapy refers to a therapy that uses only one drug.

“No change” represents cases that do meet the response classifications of partial or minimal response.

Non-Malignancy refers to a benign growth or condition, such as dysplasias.

Partial response or remission (PR) is defined as AT LEAST a 50% reduction in tumor burden, such as multiple myeloma being typically measured in terms of serum levels of beta-2 microglobulin or monoclonal immunoglobulins.

Plateau indicates stable values or response for at least three months.

Primary progressive disease is progression that occurs during or immediately after the first conventional-dose induction regimen given to a newly diagnosed myeloma patient, such as before any HCST, even before the first transplant cycle in a planned tandem transplant. Patients with primary progressive disease can be categorized as high risk or standard risk. One approach to identifying high-risk patients (other patients are standard risk) is the detection of t(4:14), t(14:16), or 17p deletion by FISH assay, chromosome 13 deletion or hypodiploidy by karyotyping, or plasma cell labeling index greater than 3%; finding one abnormality identifies a patient at high risk. Patients with beta-2-microglobulin levels greater than 5.5 mg per liter are also often considered high risk.

Primary refractory is defined as a tumor that fails to achieve a CR after initial standard dose chemotherapy.

The term refractory is defined as a LESS THAN 50% reduction in tumor burden. Therefore, even those tumors that exhibited a 30% reduction, for example, would be considered refractory. The terms refractory and resistant are synonymous. Tumor response can be measured using serial computed tomography scans, or levels of circulating tumor markers, such as alpha fetoprotein in the case of germ cell tumors.

Relapsed is defined as tumor recurrence after a prior CR.

Responsive is defined as a tumor showing a CR, PR, or minimal response/remission.

The term "salvage therapy" describes chemotherapy given to patients who have:

1. Failed to achieve CR after initial treatment for newly diagnosed malignancy; or

2. Relapsed after an initial CR.

Short tandem repeat (STR) markers may be performed prior to stem-cell reinfusion or transplantation to determine the difference between donor and recipient DNA patterns. This information will be used post stem-cell reinfusion or transplantation to assess the status of donor cell engraftment. Additionally, STR may be used in genetic genealogy or ancestry research, paternity testing, forensic or criminal DNA mapping or profiling and preimplantation genetic testing.

Staging refers to the extent of the disease, based on the Ann Arbor system of stages I through IV, indicating the number and site of involved lymph nodes and the involvement of extralymphatic organs.

Stem-cell purging is a technique to attempt removing any remaining tumor or cancer cells in the patient’s autologous harvested stem-cell donation from bone marrow or peripheral blood to minimize the chance that the malignancy will return. Purging can be done by using protein antigens (i.e., CD34, CD20, CD90, or CD133), monoclonal antibodies (i.e., Rituxan), magnetic attraction, photodynamic techniques, oncolytic viruses (i.e., DNA or RNA), or electroporation (pulsed electric field application). Purging is part of the stem-cell process in preparation for infusion to the autologous donor-recipient minimizing tumor contamination.

Tumor response (TR) can be measured by using serial computed tomography scans or by levels of circulating tumor markers.

Regulatory Status

The U.S. Food and Drug Administration (FDA) regulates human cells and tissues intended for implantation, transplantation, or infusion through the Center for Biologics Evaluation and Research (CBER), under Code of Federal Regulation (CFR) title 21, parts 1270 and 1271. (15) Hematopoietic stem-cells are included in these regulations.

Rationale:

This policy was created in 1990 based on a Blue Cross Blue Shield Association (BCBSA) Technology Evaluation Center (TEC) Assessment in 1987. Since then the policy has been updated with general information and published literature regarding new advances in hematopoietic stem-cell (HSC) research and utilization for a variety of conditions. In 1996, umbilical cord blood use was added as a type of HSC source used for transplantation, based upon a 1996 BCBSA TEC Assessment. (16) BCBSA TEC has updated their Assessment in 2002. (17) Following a 1997 BCBSA TEC Assessment (12), donor lymphocyte infusion (DLI) was addressed separately and moved to each individual stem-cell transplantation policy. The recent MedLine search was completed in April 2017. The following is a summary of the key literature.

Hematopoietic Stem-Cells (HSCs) Collection and Storage

Hematopoietic stem-cell transplantation (HSCT) has been used for treatment for approximately 50 years. The earliest use was for congenital immunodeficiency disorders and end-stage leukemias. Subsequent research focused on designing the preparatory conditioning regimens, decreasing transplant related morbidity and mortality, improving survival and the understanding of the immune responses of the transplanted graft. The list of diseases for which hematopoietic HSCTs have been used to treat patients has rapidly increased. More than 30,000 autologous HSCT and 15,000 allogeneic HSCT procedures are performed every year worldwide. (1-6)

Stem-cells have been damaged by disease or treatment of a disease. HSCT may benefit patients with a variety of both cancerous (malignant) and noncancerous (nonmalignant) diseases by:

Replacing dysfunctional bone marrow. For instance, in aplastic anemia, a noncancerous condition, the bone marrow doesn't make enough new blood cells. A HSCT procedure destroys the dysfunctional marrow, and healthy stem-cells are infused. If all goes well, the new stem-cells migrate to the marrow and begin working normally.

Destroy unhealthy bone marrow that may contain cancer cells. In the case of cancer, such as leukemia, a SCS procedure may help rid the bone marrow of cancer cells. When healthy stem-cells are transplanted, normal cell production can resume. In addition, immune factors in the transplanted cells may help destroy any cancer cells that remain in the bone marrow. (1-6)

For years, the traditional source for hematopoietic stem-cells (HSCs) for use in autologous HSCT and allogeneic HSCT was bone marrow. Use of peripheral blood as a source of stem-cells later replaced bone marrow for nearly all autologous HSCT procedures and most allogeneic HSCT procedures. Utilization of umbilical cord blood (UCB) has started to surpass the use of peripheral blood. (1-6)

Umbilical Cord Blood (UCB) Transplantation HSCT:

Related Allogeneic Cord Blood Transplant

The first cord blood transplant was a related cord blood transplant for a child with Fanconi anemia; results were reported in 1989. (18) At least 60 other cord transplants have subsequently been performed in matched-siblings. The results of these transplants demonstrated that cord blood contains sufficient numbers of hematopoietic stem and progenitor cells to reconstitute pediatric patients. A lower incidence of acute and chronic graft-versus-host disease (GVHD) when cord blood, as compared with bone marrow, was used as the source of donor cells was also observed. (19) This led to the idea that cord blood could be banked and used as a source of unrelated donor cells, possibly without full human leukocyte antigen (HLA) matching. (20)

Unrelated Allogeneic Cord Blood Transplant

In 1996, outcome data from the first 25 unrelated cord blood transplants completed at Duke University were reported. (21) The authors concluded that cord blood contained sufficient numbers of stem cells and progenitor cells to reconstitute the marrow of children who underwent myeloablative treatments, without full HLA matching between donor and recipient.

Since this time, research has been conducted to study the effectiveness of placental/UCB for the treatment of various conditions. The first prospective study of unrelated cord blood transplant was the Cord Blood Transplantation study (COBLT) from 1997 to 2004. COBLT was designed to examine the safety of unrelated cord blood transplantation in infants, children, and adults. In children with malignant and nonmalignant conditions, 2-year event-free survival was 55% in children with high-risk malignancies (22) and 78% in children with nonmalignant conditions. (23) Across all groups, the cumulative incidence of engraftment by day 42 was 80%. Engraftment and survival were adversely affected by lower cell doses, pretransplant cytomegalovirus (CMV) seropositivity in the recipient, non-European ancestry, and higher HLA mismatching. This slower engraftment leads to longer hospitalizations and greater utilization of medical resources. (24) In a retrospective multicenter study of 541 children with acute leukemia, rates of neutrophil recovery at day 60 were statistically different: 96% versus 80% for those receiving unrelated bone marrow and unrelated cord blood, respectively. (25) In the COBLT study, outcomes in adults were inferior to the outcomes achieved in children.

In 2012, Zhang et al. published a meta-analysis of studies comparing unrelated donor cord blood transplantation to unrelated donor bone marrow transplantation in patients with acute leukemia. (26) The authors identified 7 studies with a total of 3389 patients. Pooled rates of engraftment failure (n=5 studies) were 127 events in 694 patients (18%) in the cord blood transplantation group and 57 events in 951 patients (6%) in bone marrow transplantation patients. The rate of engraftment graft failure was significantly higher in cord blood transplantation recipients (p<0.001). However, rates of acute GVHD were significantly lower in the group receiving cord blood transplantation. Pooled rates of GVHD (n=7 studies) were 397 of 1179 (34%) in the cord blood group and 953 of 2189 (44%) in the bone marrow group (p<0.001). Relapse rates, reported in all studies, did not differ significantly between groups. Several survival outcomes including overall survival, leukemia-free survival, and non-relapse mortality favored the bone marrow transplantation group.

In addition, numerous retrospective and registry studies have generally found that unrelated cord blood transplantation is effective in both children and adults with hematologic malignancies and in children with a variety of nonmalignant conditions. (26-28) A 2014 study by Liu et al. compared outcomes after unrelated donor cord blood transplantation versus matched-sibling donor peripheral blood transplantation. (28) The study included patients age 16 years or older who had hematologic malignancies. A total of 70 patients received unrelated cord blood and 115 patients received HLA-identical peripheral blood stem cells, alone or in combination with bone marrow. Primary engraftment rates were similar in the 2 groups, 97% in the cord blood group and 100% in the peripheral blood stem-cell group. Rates of most outcomes, including grades III to IV acute GVHD and 3-year disease-free survival were also similar between groups. However, the rate of chronic GVHD was lower in the unrelated-donor cord blood group. Specifically, limited or extensive chronic GVHD occurred in 12 of 58 (21%) evaluable patients in the cord blood group and 46 of 109 (42%) evaluable patients in the peripheral blood stem cell group (p=0.005). In 2016, Mo et al. reported on outcomes after UCB and haploidentical hematopoietic stem-cell transplantation (haplo-HSCT) in 129 children younger than 14 years old. (29) The 2-year probability of OS was 82% (95% confidence interval [CI], 72.2% to 91.8%) in the haplo-HSCT group and 69.9% (95% CI, 58.0% to 81.2%) in the cord blood group. The difference in OS between groups was not statistically significant (p=0.07). The 2-year incidence of relapse was also similar in the 2 groups: 16% (95% CI, 6.1% to 26.1%) in the haplo-HSCT group and 24.1% (95% CI, 12.5% to 37.5%) in the cord blood group (p=0.17).

In addition, transplantation of 2 UCB (or double-unit transplants) has been evaluated as a strategy to overcome cell dose limitations with 1 cord blood unit in older and heavier patients. Initial experience at a university showed that using 2 units of cord blood for a single transplant in adults improved rates of engraftment and OS. (30) Although cell doses are higher with double-unit transplants, studies published to date have found that survival rates are similar to transplants using single-cord blood units, and there is some suggestion of higher rates of GVHD. In 2014, Wagner et al. published a randomized controlled trial (RCT) comparing outcomes after double-unit (n=111) or single-unit (n=113) cord blood transplants. (31) The trial included patients (age range, 1-21 years) who had high-risk acute leukemia, chronic myeloid leukemia, or myelodysplastic syndrome (MDS) for whom there were 2 cord blood units available with adequate cell doses and HLA matches on at least 4 of 6 loci. One-year OS rate, the primary outcome, was 65% (95% CI, 56% to 74%) after double-unit transplant and 73% (95% CI, 63% to 80%) after single-unit transplant. The difference between groups was not statistically significant (p=0.17). Similarly, 1-year disease-free survival was 64% (95% CI, 54% to 72%) in the double-unit transplant group and 70% (95% CI, 60% to 77%) in the single-unit transplant group (p=0.11). However, rates of acute GHVD (grade II-IV) were significantly higher in the double-unit transplant group (23%; 95% CI, 15% to 31%) than in the single-unit transplant group (13%; 95% CI, 7% to 20%; p=0.02). Incidences of chronic GVHD after 1 year were similar in the 2 groups (32% [95% CI, 23% to 40%] after double-unit transplant versus 30% [95% CI, 22% to 29%] after single-unit transplant; p=0.51).

Results of an observational study were similar to those of the Wagner RCT. In 2013, Scaradavou et al. did not find significant differences in survival after single- or double-cord blood transplant. (32) In patients treated during the first several years of observation (2002-2004), there was a significantly higher risk of acute GVHD (grade II-IV) in recipients of double-cord blood units (hazard ratio [HR], 6.14; 95% CI, 2.54 to 14.87; p<0.001). In the later period (2004-2009), rates of acute GVHD (grade II-IV) did not differ significantly between groups (HR=1.69; 95% CI, 0.68 to 4.18; p=0.30).

A number of observational studies and a meta-analysis of observational studies have compared outcomes after UCB transplantation with stem-cells from a different source. The meta-analysis found similar survival outcomes and lower GVHD after UCB transplantation than bone marrow transplantation. In addition, an RCT has compared single- and double-unit UCB transplantation and found similar outcomes.

Prophylactic Collection and Storage of UCB

No studies have compared outcomes after prophylactic collection and storage of UCB from a neonate for individuals who have an unspecified future need for transplant to standard care without UCB collection and storage.

In addition, although blood banks are collecting and storing neonate UCB for potential future use, data on the use of UCB for autologous HSCT are limited. A 2007 position paper from the American Academy of Pediatrics noted that there is no evidence of the safety or effectiveness of autologous cord blood transplantation for treatment of malignant neoplasms. (33) In addition, a 2009 survey of pediatric hematologists noted few transplants have been performed using cord blood stored in the absences of a known indication. (34)

There is a lack of published evidence comparing outcomes after prophylactic collection and storage of UCB from a neonate for individuals who have an unspecified future need for transplant to standard care without UCB collection and storage.

Ongoing and Unpublished Clinical Trials

Some currently unpublished trials that might influence this review are listed in Table 2.

Table 1. Summary of Key Trials

NCT Number

Trial Name

Planned Enrollment

Completion Date

Ongoing

NCT01728545

The Collection and Storage of Umbilical Cord Blood for Transplantation

250,000

Jun 2099

NCT00012545

Collection and Storage of Umbilical Cord Stem Cells for Treatment of Sickle Cell Disease

99,999,999

Not Provided

Table Key:

NCT: National Clinical Trial.

Practice Guidelines and Position Statements

U.K. Consensus Recommendations on Umbilical Cord Blood Transplantation

In 2015, a consensus conference in the U.K. issued the following recommendation on UCB transplantation (35):

“We recommend that UCB [umbilical cord blood] should be considered as an alternative source of HSC [hematopoietic stem-cells] for transplantation for those patients without a suitably matched sibling or unrelated donor, defined as ‘standard’ or ‘clinical option’ transplants within the BSBMT [British Society of Blood and Marrow Transplantation] transplant indications tables.”

American College of Obstetricians and Gynecologists (ACOG)

In 2015, the ACOG published an opinion on umbilical cord blood banking. (36) The statement discussed counseling patients on options for UCB banking, as well as benefits and limitations of this practice. Relevant recommendations include the following:

• “Umbilical cord blood collection should not compromise obstetric or neonatal care or alter routine practice for the timing of umbilical cord clamping.”

“The current indications for cord blood transplant are limited to select genetic, hematologic, and malignant disorders.”

“The routine storage of umbilical cord blood as ‘biologic insurance’ against future disease is not recommended.”

American Society for Blood and Marrow Transplantation (ASBMT)

On behalf of the ASBMT, in 2008 Ballen et al. published recommendations related to the banking of UCB (37):

• Public banking of cord blood is encouraged when possible.

Storage of cord blood for autologous (i.e., personal) use is not recommended.

Family member banking (collecting and storing cord blood for a family member) is recommended when there is a sibling with a disease that may be successfully treated with an allogeneic HSCT.

Family member banking on behalf of a parent with a disease that may be successfully treated with an allogeneic HSCT is only recommended when there are shared HLA antigens between the parents.

Section Summary: Hematopoietic Stem-Cells (HSCs) Collection and Storage

For individuals who have an appropriate indication for allogeneic HSCT who receive cord blood as a source of stem-cells, the evidence includes a number of observational studies, a meta-analysis of observational studies, and a RCT comparing outcomes after single- or double-cord blood units. Relevant outcomes are overall survival, disease-specific survival, resource utilization, and treatment-related mortality. The meta-analysis of observational studies found similar survival outcomes and lower GVHD after UCB transplantation than bone marrow transplantation. In the RCT, survival rates were similar after single- and double-unit UCB transplantation. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have an unspecified potential future need for stem-cell transplant who receive prophylactic collection and storage of UCB, the evidence includes no published studies. Relevant outcomes are overall survival, disease-specific survival, resource utilization, and treatment-related mortality. No evidence was identified on the safety or effectiveness of autologous UCB transplantation from prophylactically stored UCB for the treatment of malignant neoplasms. The evidence is insufficient to determine the effects of the technology on health outcomes.

Stem-Cell Purging

The value of stem-cell purging, particularly for autologous HSCT, is to improve the hematopoietic elements that are enriched to establish engraftment (positive selection) of progenitor cells or to remove contaminated cancerous cells prior to stem-cell infusion (negative selection) back to the donor. (38) To purge contaminated cells for autologous donation, anti-cancer drugs may be given directly to the stem-cells collected. (5) This process is an integral part of the stem-cell preparation; however, the risk cancer cells return is not known. The most current method is not to purge prior to the transplantation, but administering a monoclonal antibody treatment following the transplantation, particularly for some leukemias and lymphomas, known as in vivo purging. Studies for drug preparations are still being performed to determine the best match of drug to cancer for in vivo purging. (5)

Numerous pre-clinical discussions have been published and clinical trials have been performed from the 1990’s through the early 2000’s in autologous HSCT treatments. (38-49) The conditions studied are ALL, AML, CLL, CML, MDS, MM, and NHL (including follicular and mantle cell lymphoma). The conclusions reached by each study team have been patients undergoing autologous HSCT. These self-donations of progenitor cells are likely to be contaminated with the tumor cells, placing the patients at a higher risk of relapse. Elimination of those tumor cells will decrease the risk of relapse in those with advanced disease. However, this preparative purging step is included in overall HSCT protocol/process to treat a specific condition. (48)

Studies to purge allogeneic donations are scant as this process is considered not medically necessary. The unrelated or related donor should be cancer-free prior to harvesting of progenitor cells. However, some cancer center protocols may include this step in their process to promote engraftment by cleaning the stem-cells of any diseases that may promote relapse or appearance of an unexpected condition (e.g., human immunodeficiency virus [HIV]). (48)

Ongoing and Unpublished Clinical Trials

A search of ClinicalTrials.gov in April 2017 did not identify any ongoing or unpublished trials that would likely influence this review.

Practice Guidelines and Policy Statements

American Society for Blood and Marrow Transplantation (ASBMT)

As of April 27, 2017, the ASBMT does not address with a guideline or position statement for the stem-cell purge process.

Section Summary: Stem-Cell Purging

For individuals who have an appropriate indication for autologous HSCT who receive non-malignant stem-cells, the main challenge is purging malignant cells to prevent relapse. The evidence includes several clinical trials to assess overall survival, disease-specific survival, resource utilization, and treatment-related mortality. There are complex graft manipulations during the process following autologous harvesting in preparation of the autologous donation, achieving less risk of receiving malignant cells back to the individual. During the graft manipulation period, the evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have an appropriate indication for allogeneic HSCT who receive non-malignant stem-cells, the main challenge is reducing the incidence of GVHD and accelerating immune reconstitution or promote engraftment. The evidence includes numerous clinical trials to assess the best cancer-free unrelated or related donor prior to harvesting. Further stem-cell purging is unnecessary. Therefore, the evidence is insufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Donor Lymphocyte Infusion (DLI) and Stem-Cell Boost

DLI

Several review articles summarize studies that have reported the use of DLI as therapy for the treatment of hematologic malignancies after an allogeneic HSCT. (11-12, 50) The role of DLI is based on the presence of a beneficial graft-versus leukemia effect. There have been studies suggesting that a graft-versus-leukemia effect is present in a broader group of hematologic malignancies, including, but not limited to non-Hodgkin’s lymphoma, multiple myeloma, and Hodgkin’s disease.

Chronic Myelogenous Leukemia (CML)

DLI has been found to be most effective in CML, inducing a molecular complete remission (CR) in up to 80% of patients who relapse in chronic phase. Only a 12.5% to 33% response rate has been reported in patients in accelerated or blast phase. Response duration to DLI in patients with relapsed CML after HSCT is long-standing in most patients.

Several large series have reported outcomes of patients with relapsed CML after receiving DLI. (11-13, 30, 32-34, 37, 55-54) These studies comprise more than 500 patients, approximately half of whom had only molecular or cytogenetic relapse at the time of DLI. (11) The cell doses varied among patients, with some patients receiving multiple DLI infusions and others planned dose escalations. Despite these variations, a molecular CR was achieved in 77% of patients (405/527). Overall survival (OS) at 3 or more years ranging from 53% to 95%, (13) was 64% at 5 years, and was 59% at 10 years after DLI in another series. (55)

The role of DLI in CML has recently changed as the use of tyrosine-kinase inhibitors has revolutionized the treatment of CML by keeping the disease under control instead of proceeding to HSCT. However, for patients who develop resistance to the tyrosine-kinase inhibitors or are unable to tolerate the adverse effects, HSCT and DLI may be an option to manage the disease.

Acute Leukemias, Myelodysplasia, and Other Myeloproliferative Diseases

In a 2013 systematic review, El-Jurdi et al. evaluated 39 prospective and retrospective studies on DLI for relapse after HSCT for lymphoid malignancies including acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), multiple myeloma, non-Hodgkin lymphoma (NHL), and Hodgkin lymphoma (HL). (56) No randomized controlled studies were identified. The studies were heterogeneous thus limiting interpretation of the review. Reported pooled proportions of CR (95% confidence interval [CI]) were 27% (16% to 40%) for ALL, 55% (15% to 92%) for CLL, 26% (19% to 33%) for multiple myeloma, 52% (33% to 71%) for NHL, and 37% (20% to 56%) for HL.

An observational study compared different treatments for 147 consecutive patients who relapsed after allogeneic HSCT for myelodysplastic syndrome. (57) Sixty-two patients received HSCT or DLI, 39 received cytoreductive treatment, and 46 were managed with palliative or supportive care. Two-year OS rates were 32%, 6%, and 2%, respectively (p<.001). In multivariate analysis, 4 factors adversely influenced 2-year OS rates: history of acute GVHD (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 an independent factor that favorably impacted OS (HR=0.40; 95% CI, 0.26 to 0.63; p<0.001).

Acute Myelogenous Leukemia (AML)

Use of DLI for patients with relapsed AML after allogeneic HSCT has resulted in overall remission rates ranging from 15% to 42%, with an OS of approximately 15% to 20%. (For comparison, a second HSCT in this group of patients results in 10% to 35% long-term survival with a treatment-related mortality of approximately 50%.) Patients with lower initial disease burden, reduction in the tumor burden with chemotherapy before DLI, and favorable cytogenetics appear to have more benefit with DLI with relapsed AML after HSCT.

A large retrospective analysis from the European Blood and Marrow Transplant Group compared OS in 399 patients with AML with post-transplant relapse who either were treated with DLI (n=171) or were not (n=228). (58) Patients who received DLI had an improved 2-year OS compared with those who did not, (21%±3% versus 9%±2%, respectively (p<0.001).

A 2015 large retrospective series from the Center for International Blood and Marrow Transplant Research (CIBMTR) reported outcomes for 1788 AML patients who experienced a first or second relapsed after allogeneic HSCT, among whom 1231 (69%) received subsequent intensive therapy that included DLI. (59) Among the 1231 patients who received treatment, 660 (54%) received chemotherapy alone; 202 (16%) received DLI with or without chemotherapy; and 369 (30%) received a second allogeneic HSCT with or without additional chemotherapy or DLI. Among all patients who received DLI, 87 (33%) survived more than 1 year after relapse; median survival was 7 months (range, 1-177 months). Cell-based therapy (DLI or second HSCT) resulted in significantly better post-relapse OS than chemotherapy alone. These results are consistent with other reports of DLI in patients who had AML relapse after allogeneic HSCT.

Myelodysplasia Syndrome (MDS) and Other Myeloproliferative Neoplasm (MPN) Diseases

The literature for MDS and other MPN diseases treated with DLI either after relapse or for mixed chimerism consists of small sample sizes, inconsistent pre-DLI therapy, and varied DLI cell doses, making it difficult to draw definite conclusions on outcomes. (50) However, it appears some patients attain durable remissions with DLI after post-transplant relapse.

Warlick et al. reported CR after DLI in 49% of 35 patients with relapsed nonchronic myelogenous leukemia, including AML and MDS, after allogeneic HSCT. (60) OS at 1 year was 30% and 19% at 2 years. The authors reported a lower-dose regimen of DLI was more tolerable and reduced GVHD occurrence to 25% compared with 66% with higher-dose DLI.

An analysis from the German Cooperative Transplant Study Group reported outcomes among a cohort of patients (N=154) who relapsed after undergoing allogeneic HSCT to treat AML (n=124), MDS (n=28), or myeloproliferative syndrome (n=2). (61) All patients received a median of 4 courses of azacitidine, and DLI was administered to 105 (68%). OS among all patients was 29% at 2-year follow-up, which compares favorably with other reports. The overall incidence of acute GVHD based on the total cohort (N=154) was 23%, and 31% in those given DLI (n=105).

Acute Lymphoblastic Leukemia (ALL)

The graft-versus-tumor effect is thought to be less robust in patients with ALL than in the myeloid leukemias. Small studies have reported response rates to DLI ranging from 0% to 20% and OS rates of less than 15%. (36) By comparison, a second allogeneic HSCT provides a 5-year OS of approximately 15% to 20%, with a treatment-related mortality rate of approximately 50%. (50)

The clinically evident graft-versus-leukemia effect of DLI requires weeks to months to become apparent, and, as 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 OS is with a combination of salvage chemotherapy and DLI. Although it is not clear whether DLI adds benefit to salvage chemotherapy, there are reports of long-term survivors with relapsed ALL who received both chemotherapy and DLI. (13)

Lymphomas (Hodgkin and Non-Hodgkin)

Studies in which patients received DLI for lymphomas consist of small numbers of patients and 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 the indolent lymphomas. For NHL, there are too few patients reported with any single histologic subtype of lymphoma to give adequate information of the benefit of DLI for a specific lymphoma subtype. (13)

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. (62)

A series of 14 patients with multiply relapsed HL who received RIC allogeneic HSCT and DLI showed a CR of 57% and survival at 2 years of 35%. (63)

Multiple myeloma (MM)

Observational data suggest a graft-versus-tumor effect in MM, as the development of GVHD has correlated with response in several analyses. (50)

Allogeneic HSCT is currently considered experimental, investigational and/or unproven for this indication. Most patients with MM who undergo HSCT receive an autologous HSCT. In addition, the overall role of HSCT for MM is currently changing with the advent of new, highly active drugs like lenalidomide and bortezomib.

Five studies reporting the role of DLI in relapsed MM consist of patients ranging in number from 5 to 63 (64-68) with the highest response to DLI being reported as 62%, with approximately half of the responders attaining a CR. (50) One confounding factor for high response rates for multiple myeloma treated with DLI is that corticosteroids used for treating GVHD have a known antimyeloma effect, which could potentially enhance response rates in these patients. (11)

There are a few nonrandomized comparative studies and numerous case series of DLI treatment for various hematologic malignancies and other myeloproliferative disorders. The nonrandomized studies, in patients with acute leukemia and MDS, have reported higher response rates for patients treated with DLI than with alternatives. The case series report higher response rates than expected for relapsed disease compared with historical controls. Although there are no high-quality RCTs for DLI treatment, this evidence permits the conclusion that response rates improve with DLI treatment for patients with previous HSCT treatment and relapsed disease.

Modified DLI

In an effort to control GVHD, a group in Italy explored using genetically modified lymphocytes engineered to express the suicide gene thymidine kinase of herpes simplex virus. (69) These lymphocytes were infused into 23 patients with various hematologic malignancies who relapsed after an allogeneic HSCT. Six patients died of progressive disease within 4 weeks of infusion. Eleven patients experienced disease response (CR in 6 and partial remission in 5). Three patients remained alive in CR at a median of 471 days. Twelve patients were evaluable for GVHD, 3 of whom developed acute or chronic GVHD, which was successfully treated with ganciclovir.

In a phase 2 trial, donor lymphocytes were treated with rapamycin ex vivo to produce rapamycin-resistant DLIs. (70) Forty patients undergoing low-intensity HSCT for hematologic malignancy were treated preemptively with chemotherapy and DLI. There were no infusional toxicities or serious events attributable to DLI. Classical acute GVHD occurred in 4 of 40 patients. By the end of the study (follow-up range, 42-84 months), 18 of 40 patients remained in sustained remission.

A phase 1 study evaluated patient response to DLI expressing the herpes simplex virus thymidine kinase suicide gene. (71) Three patients were enrolled in the trial and received a single DLI. No local or systemic toxicity related to the gene-transfer procedure was observed. Two patients achieved stable disease. No patient had severe GVHD requiring systemic steroid and/or ganciclovir administration. Tyrosine kinase cells were detected in the peripheral blood of all 3 patients by polymerase chain reaction, but did not persist more than 28 days.

These early-phase studies are insufficient to determine the efficacy of modified DLI in the treatment of hematologic malignancies. Randomized studies comparing modified DLI to standard treatment would be necessary to determine efficacy.

Ongoing and Unpublished Clinical Trials

A search of ClinicalTrials.gov in April 2017 did not identify any ongoing or unpublished trials that would likely influence this review.

Practice Guidelines and Policy Statements

National Comprehensive Cancer Network (NCCN)

The NCCN has the following guidelines and recommendations when utilizing DLI option when treating hematological malignancies:

ALL (v.2.2016) state that DLI can be considered an option for patients in relapse after allogeneic HSCT (category 2A). (72)

CML (v.2.2017) – DLI can be considered an option for patients who do not achieve remission, are in cytogenetic relapse, or have an increasing level of molecular relapse (category 2A). (73)

MDS (v.2.2017) – DLI can be considered an option for patients who do not respond or are in relapse after allogeneic HCT (category 2A). (74)

MM (v.3.2017) – DLI can be considered an option for patients who do not respond or are in relapse after allogeneic HCT (category 2A). (75)

The NCCN guidelines do not address with a recommendation in the use of DLI in the treatment of the following hematological malignancies

AML (v.1.2017) (76),

HL (v.1.2017) (77),

MPN (v.2.2017) (78) or

Any of the NHLs, including CLL/SLL (v.2.2017) (79), B-cell lymphomas (v.3.2017) (80), hairy-cell leukemia (v.2.2017) (81), primary cutaneous B-cell lymphomas (v.2.2017) (82), and T-cell lymphomas (v.2.2017). (83)

American Society for Blood and Marrow Transplantation (ASBMT)

As of April 27, 2017, the ASBMT does not address with a guideline or position statement for the DLI treatment.

Hematopoietic Progenitor Cell (HPC) Stem-Cell Boost

As with DLI, hematopoietic progenitor-cell (HPC) boost has a positive response rate for relapse following allogeneic HSCT. (14) The boost of stem-cells, a second dose, may be helpful to reduce the graft failure process, avoiding the risk of serious bleeding and/or infection. Slatter et al. (84) assessed the outcome of 20 boost infusions in 19 of 139 patients who received hematopoietic stem cell transplants for primary immunodeficiencies. The authors demonstrated that patients with primary immunodeficiencies may benefit from a boost infusion, resulting in an increase in donor chimerism, clearance of persistent viral infection and improvement in T- and B-cell function.

Larocca et al. compared patients with poor graft function (PGF) and full donor chimerism following allogeneic HSCT who did or did not receive a boost of donor stem-cells. (85) They studied 54 patients with PGF: 20 patients received no further boost infusions (group A), 14 received a boost of unmanipulated stem-cells from the original donor, without further chemotherapy conditioning (group B), and 20 received donor cells after CD34 selection without conditioning (group C). Trilineage recovery was seen in 40%, 36%, and 75% of the patients, respectively. The conclusion was patients with PGF, a boost of CD34-selected stem-cells is associated with a high chance of trilineage recovery and a low risk of acute GVHD.

In 2009, the National Institutes of Health (NIH), released the Mattsson et al. article discussion of graft failure after allogeneic HSCT. (86) They reported, “In patients with continued poor graft function in the absence of graft rejection, a boost of donor stem-cells without additional preparative chemotherapy may improve graft function. Nine of 15 (60%) evaluable patients became transfusion-independent within one month after the boost marrow was given. Because boost marrow may induce GVHD, T-cell depletion of stem-cells can prevent GVHD and improve survival in some patients.” Their review included the Larocca and colleague study discussed in the paragraph above.

Ongoing and Unpublished Clinical Trials

A search of ClinicalTrials.gov in April 2017 did not identify any ongoing or unpublished trials that would likely influence this review.

Practice Guidelines and Policy Statements

American Society for Blood and Marrow Transplantation (ASBMT)

As of April 27, 2017, the ASBMT does not address with a guideline or position statement for the stem-cell purge process.

Section Summary: Donor Lymphocyte Infusion (DLI) and Stem-Cell Boost

For individuals who have had an allogeneic HSCT who receive DLI or stem-cell boost, the evidence includes nonrandomized 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, patients have shown evidence of responding to DLI. Response rates to DLI for relapsed hematologic malignancies following an allogeneic HSCT are best in CML, followed by the lymphomas, MM, and acute leukemias, respectively. Other than CML, clinical responses are most effective when chemotherapy induction is used to reduce the tumor burden before DLI. The evidence is sufficient to determine qualitatively that the technology results in a meaningful improvement in the net health outcome.

For individuals who have had an allogeneic HSCT who receive a modified (genetic or other ex vivo modification) DLI, the evidence includes case series. Relevant outcomes are overall survival and change in disease status. The case series have demonstrated 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.

Short Tandem Repeat (STR) Markers

Following HSCT therapy, it is important to determine whether the new blood forming system is of recipient or donor origin; this phenotypic characterization is called chimerism analysis. The characteristics of the engraftment are analyzed, which is called chimerism analysis. Using STR marker assay to characterize the hematological course and to evaluate the usefulness of the blood forming system (particularly for hematological malignancies, MDS or MPN processes, or certain genetic or metabolic disorders) has been tested initially after the HSCT, when the patient is declared as disease-free, and at the point of the confirmed stable engraftment of only the donor pattern of the blood forming system. (5, 87-88) In the case of treatment of miscellaneous solid tumors of adults, which is not considered a hematologic disorder, the data is insufficient to determine the outcomes without further randomized trials of using STR markers prior to or post HSCT therapy. (5, 14, 38-39, 87-90)

Ongoing and Unpublished Clinical Trials

A search of ClinicalTrials.gov in April 2017 did not identify any ongoing or unpublished trials that would likely influence this review.

Practice Guidelines and Policy Statements

American Society for Blood and Marrow Transplantation (ASBMT)

As of April 27, 2017, the ASBMT does not address with a guideline or position statement for the stem-cell purge process.

Section Summary: Short Tandem Repeat (STR) Markers

For individuals who have an appropriate indication for allogeneic HSCT who receive donor stem-cells, the main challenge is engraftment and chimerism. The evidence includes several clinical trials to assess overall survival, disease-specific survival, resource utilization, and treatment-related mortality. Using STR markers assesses the usefulness of the blood forming system, the evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have a solid organ transplant, confirmation of stable engraftment is assessed by other methods. As solid organ transplants are not a hematological malignancy, STR marker utilization is unnecessary. Therefore, the evidence is insufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Contract:

Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions. Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply. If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.

Coding:

Charges for the acquisition of cord blood (CB) through a CB bank will be submitted as part of the hospital bill or claim. Cryopreservation process and storage may be billed separately from other vendors.

CODING:

Disclaimer for coding information on Medical Policies

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps.

CPT/HCPCS/ICD-9/ICD-10 Codes

The following codes may be applicable to this Medical policy and may not be all inclusive.

CPT Codes

36511, 38204, 38205, 38206, 38207, 38208, 38209, 38210, 38211, 38212, 38213, 38214, 38215, 38220, 38221, 38222, 38230, 38232, 38240, 38241, 38242, 38243, 81265, 81266, 81267, 81268, 81370, 81371, 81372, 81373, 81374, 81375, 81376, 81377, 81378, 81379, 81380, 81381, 81382, 81383, 86805, 86806, 86807, 86808, 86812, 86813, 86816, 86817, 86821, 86822, 86825, 86826, 86828, 86829, 86830, 86831, 86832, 86833, 86834, 86835, 86849, 86950, 86985, 88240, 88241

HCPCS Codes

S2140, S2142, S2150

ICD-9 Diagnosis Codes

Refer to the ICD-9-CM manual

ICD-9 Procedure Codes

Refer to the ICD-9-CM manual

ICD-10 Diagnosis Codes

Refer to the ICD-10-CM manual

ICD-10 Procedure Codes

Refer to the ICD-10-CM manual


Medicare Coverage:

The information contained in this section is for informational purposes only. HCSC makes no representation as to the accuracy of this information. It is not to be used for claims adjudication for HCSC Plans.

The Centers for Medicare and Medicaid Services (CMS) does not have a national Medicare coverage position. Coverage may be subject to local carrier discretion.

A national coverage position for Medicare may have been developed since this medical policy document was written. See Medicare's National Coverage at <http://www.cms.hhs.gov>.

References:

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44. Meehan KR, Wu A, Hassan R, et al. Ex vivo cytokine activation of peripheral blood stem cells: a potential role for adoptive cellular immunotherapy. J Hematother Stem Cell Res Apr 2001; 10(2):283-90.

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46. Wierenga PK, Setroikromo R, Kamps G, et al. Differences in heat sensitivity between normal and acute myeloid leukemic stem cells: feasibility of hyperthermic purging of leukemic cells from autologous stem cell grafts. Exp Hematol. May 2003; 31(5):421-7. PMID 12763141

47. Berkahan L, Simpson D, Raptis A, et al. In vivo purging with rituximab prior to collection of stem cells for autologous transplantation in chronic lymphocytic leukemia. J Hematother Stem Cell Res. Apr 2002; 11(2):315-20. PMID 11983102

48. Rutella S, Pierelli L, Sica S, et al. Transplantation of autologous peripheral blood progenitor cells: impact of CD34-cell selection on immunological reconstitution. Leuk Lymphoma. Nov-Dec 2001; 42(6):1207-20. PMID 11911401

49. Gisselbrecht C, Mounier N. Rituximab: enhancing outcome of autologous stem cell transplantation in non-Hodgkin’s lymphoma. Semin Oncol. Feb 2003; 30(1 Suppl 2):28-33 PMID 12652462

50. Tomblyn M, Lazarus HM. Donor lymphocyte infusions: the long and winding road: how should it be traveled? Bone Marrow Transplant. Nov 2008; 42(9):569-79. PMID 18711351

51. Simula MP, Marktel S, Fozza C, et al. Response to donor lymphocyte infusions for chronic myeloid leukemia is dose-dependent: the importance of escalating the cell dose to maximize therapeutic efficacy. Leukemia. May 2007; 21(5):943-8. PMID17361226

52. 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. Oct 15 2000; 96(8):2712-6. PMID11023502

53. 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. PMID12091328

54. Fozza C, Szydlo RM, Abdel-Rehim MM, et al. Factors for graft-versus-host disease after donor lymphocyte infusions with an escalating dose regimen: lack of association with cell dose. Br J Haematol. 2007; 136(6):833-6. PMID17341269

55. 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. Jul 2015; 21(7):1230-6. PMID 25797175

56. 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):457-66. PMID23638742

57. 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. PMID 26256942

58. 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):4938-45. PMID17909197

59. 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):454-9. PMID 25460355

60. 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. Mar 2012; 18(3):480-6. PMID22155141

61. 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):653-60. PMID 25540937

62. Morris E, Thomson K, Craddock C, et al. Outcomes after alemtuzumab-containing reduced-intensity allogeneic transplantation regimen for relapsed and refractory non-Hodgkin lymphoma. Blood. Dec 15 2004; 104(13):3865-71. PMID15304395

63. Peggs KS, Sureda A, Qian W, et al. Reduced-intensity conditioning for allogeneic hematopoietic 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. PMID17854309

64. Lokhorst HM, Schattenberg A, Cornelissen JJ, et al. Donor leukocyte infusions are effective in relapsed multiple myeloma after allogeneic bone marrow transplantation. Blood. Nov 15 1997; 90(10):4206-11. PMID9354693

65. Salama M, Nevill T, Marcellus D, et al. Donor leukocyte infusions for multiple myeloma. Bone Marrow Transplant. Dec 2000; 26(11):1179-84. PMID11149728

66. 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. Feb 1997; 15(2):433-44. PMID9053463

67. Bensinger WI, Buckner CD, Anasetti C, et al. Allogeneic marrow transplantation for multiple myeloma: an analysis of risk factors on outcome. Blood. Oct 1 1996; 88(7):2787-93. PMID8839877

68. 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):3031-7. PMID10944138

69. Ciceri F, Bonini C, Marktel S, et al. Antitumor effects of HSV-TK-engineered donor lymphocytes after allogeneic stem-cell transplantation. Blood. Aug 2007; 109(11):4698-707. PMID10944138

70. 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):2864-74. PMID 23426943

71. 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):101-10. PMID 25948083

72. NCCN – Clinical Practice Guidelines in Oncology, Acute Lymphoblastic Leukemia (v.2.2016). Prepared by the National Comprehensive Cancer Network. Available at: <http://www.nccn.org> (accessed April 27, 2017).

73. NCCN – Clinical Practice Guidelines in Oncology. Chronic Myelogenous Leukemia (v.2.2017). Prepared by the National Comprehensive Cancer Network. Clinical. Available at <http://www.nccn.org> (accessed April 27, 2017).

74. NCCN – Clinical Practice Guidelines in Oncology. Myelodysplasia Syndrome (v.2.2017). Prepared by the National Comprehensive Cancer Network. Clinical. Available at <http://www.nccn.org> (accessed April 27, 2017).

75. NCCN – Clinical Practice Guidelines in Oncology, Multiple Myeloma (v.3.2017). Prepared by the National Comprehensive Cancer Network. Available at <http://www.nccn.org> (accessed April 27, 2017).

76. NCCN – Clinical Practice Guidelines in Oncology. Acute Myelogenous Leukemia (v.1.2017). Prepared by the National Comprehensive Cancer Network. Clinical. Available at <http://www.nccn.org> (accessed April 27, 2017).

77. NCCN – Clinical Practice Guidelines in Oncology. Hodgkin Lymphoma (v.1.2017). Prepared by the National Comprehensive Cancer Network. Clinical. Available at <http://www.nccn.org> (accessed April 27, 2017).

78. NCCN – Clinical Practice Guidelines in Oncology. Myeloproliferative Neoplasm (v.1.2017). Prepared by the National Comprehensive Cancer Network. Clinical. Available at <http://www.nccn.org> (accessed April 27, 2017).

79. NCCN – Clinical Practice Guidelines in Oncology. Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (v.2.2017). Prepared by the National Comprehensive Cancer Network. Clinical. Available at <http://www.nccn.org> (accessed April 27, 2017).

80. NCCN – Clinical Practice Guidelines in Oncology. B-Cell Lymphomas (v.3.2017). Prepared by the National Comprehensive Cancer Network. Clinical. Available at <http://www.nccn.org> (accessed April 27, 2017).

81. NCCN – Clinical Practice Guidelines in Oncology. Hairy-Cell Lymphoma (v.2.2017). Prepared by the National Comprehensive Cancer Network. Clinical. Available at <http://www.nccn.org> (accessed April 27, 2017).

82. NCCN – Clinical Practice Guidelines in Oncology. Primary Cutaneous B-Cell Lymphomas (v.2.2017). Prepared by the National Comprehensive Cancer Network. Clinical. Available at <http://www.nccn.org> (accessed April 27, 2017).

83. NCCN – Clinical Practice Guidelines in Oncology. T-Cell Lymphomas (v.2.2017). Prepared by the National Comprehensive Cancer Network. Clinical. Available at <http://www.nccn.org> (accessed April 27, 2017).

84. Slatter MA, Bhattacharya A, Abunin M, et al. Outcome of boost hematopoietic stem cell transplant for decreased donor chimerism or graft dysfunction in primary immunodeficiency. Bone Marrow Transplant. Apr 2005; 35:683-9. PMID 15723084

85. Larocca A, Piaggio G, Podesta M, et al. A boost of CD35+-selected peripheral blood cells without further conditioning in patients with poor graft function following allogeneic stem cell transplantation. Hematologica. Jul 2006; 91(7):935-40. PMID 16818281

86. NIH – Mattsson J, Ringden O, et al. Graft failure after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transpl. Jan 2008; 14(Supplement 1):165-70. National Institutes of Health Public Access. Available at <http://www.nih.gov> (accessed April 15, 2013).

87. Borrill V, Schlaphoff T, du Toit E, et al. The use of short tandem repeat polymorphisms for monitoring chimerism following bone marrow transplantation: a short report. Hematology. Aug 2008; 13(4):210-4. PMID 18796246

88. Crow J, Youens K, Michalowski S, et al. Donor cell leukemia in umbilical cord blood transplant patients: a case study and literature review highlighting the importance of molecular engraftment analysis. J Molecul Diagnost. Jul 2010; 12(4):530-7. PMID 20431036

89. Park M, Koh KN, Seo JJ, et al. Clinical implications of chimerism after allogeneic hematopoietic stem-cell transplantation in children with non-malignant diseases. Kor J Hematol. Dec 2010; 46(4):258-64. PMID 22259632

90. Odriozola A, Riancho JA, Colorado M, et al. Evaluation of the sensitivity of two recently developed STR multiplexes for the analysis of chimerism after hematopoietic stem-cell transplantation. Int J Immunogenet. Apr 2013; 40(2):88-92. PMID 22594517

91. Hematopoietic Stem-Cell Transplantation for Plasma Cell Dyscrasias, Including Multiple Myeloma and POEMS Syndrome. Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (2017 January) Therapy 8.01.17.

92. Placental and Umbilical Cord Blood as a Source of Stem-Cells. Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (2017 January) Surgery 7.01.50.

93. Donor Lymphocyte Infusion for Malignancies Treated with Allogeneic Stem-Cell Transplant (Archived). Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (2016 January) Medicine 2.03.03.

Policy History:

Date Reason
4/15/2018 Reviewed. No changes.
6/15/2017 Document updated with literature review. Coverage unchanged. The following NOTE was added, Refer to SUR703.001, Organ and Tissue Transplantation for general donor and recipient information.
5/15/2016 Reviewed. No changes.
7/15/2015 Document updated with literature review. Donor lymphocyte infusion and hematopoietic stem-cell boost coverage statements removed from each individual hematopoietic stem-cell transplantation medical policy back to this general donor and recipient informational medical policy; coverage for each procedure remains unchanged. Title changed from Stem-Cell Reinfusion or Transplantation Following Chemotherapy (General Donor and Recipient Information).
6/1/2014 Document updated with literature review. The following was added: 1) Genetic modification of donor leukocytes for infusion at any point following any SCS treatment is considered experimental, investigational and/or unproven; 2) Short tandem repeat (STR) markers may be considered medically necessary when used in pre- or post-SCS testing of the donor and recipient DNA profiles as a way to assess the status of donor cell engraftment; and, 3) All other uses of STR markers, including use for a condition that was originally considered experimental, investigational and/or unproven, are considered experimental, investigational and/or unproven.
4/1/2010 Revised/updated entire document. Policy contains criteria for umbilical cord blood donation and storage, prophylactic stem-cell storage, and purging of stem-cells, along with general information regarding stem-cell harvesting, typing, and usage. Medical policy combined with SUR703.022, SUR703.023, and SUR703.024. This policy is no longer scheduled for routine literature review and update.
4/7/2005 CPT/HCPCS code(s) updated (SUR713.022)
11/15/2004 Revised/updated entire document (SUR703.022)
4/1/2003 CPT/HCPCS code(s) updated (SUR703.022)
6/1/2001 CPT/HCPCS code(s) updated (SUR703.022)
5/1/2000 Revised/updated entire document (SUR703.022)
1/1/2000 Revised/updated entire document (SUR703.002)
6/1/1999 Revised/updated entire document (SUR703.022)
5/1/1999 Revised/updated entire document (SUR703.002)
12/1/1998 Revised/updated entire document (SUR703.002)
9/1/1996 New medical document (SUR703.022)
9/1/1996 Revised/updated entire document (SUR703.002)
5/1/1996 Medical policy number changed (SUR713.002)
10/1/1994 Revised/updated entire document (SUR703.002)
10/1/1993 Revised/updated entire document (SUR703.002)
7/1/1993 Revised/updated entire document (SUR703.002)
4/1/1993 Revised/updated entire document (SUR703.002)
1/1/1993 Revised/updated entire document (SUR703.002)
7/1/1992 Revised/updated entire document (SUR703.002)
1/1/1992 Revised/updated entire document (SUR703.002)
9/1/1991 Revised/updated entire document (SUR703.002)
5/1/1990 New medical document (SUR703.002)

Archived Document(s):

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