Code Description CPT
38230 Bone marrow harvesting for transplantation; allogeneic
38232 Bone marrow harvesting for transplantation; autologous
38240 Hematopoietic progenitor cell (HPC); allogeneic transplantation per donor
38241 Hematopoietic progenitor cell (HPC); autologous transplantation
38242 Allogeneic lymphocyte infusions
S2140 Cord blood harvesting for transplantation, allogeneic
S2142 Cord blood derived stem cell transplantation, allogeneic
S2150 Bone marrow or blood-derived stem cells (peripheral or umbilical), allogeneic or autologous, harvesting, transplantation and related complications; including: pheresis and cell preparation/storage; marrow ablative therapy; drugs, supplies, hospitalization with outpatient follow-up; medical/surgical, diagnostic, emergency, and rehabilitative service; and the number of days of pre- and post-transplant care in the global definition
Hematopoietic Cell Transplantation for Chronic Myeloid Leukemia
Chronic myeloid leukemia (CML) is a type of cancer that starts in certain blood-forming cells within the bone marrow. These blood-forming calls are called “hematopoietic” cells. When a person has CML, they make too many white blood cells. Different types of treatment have been used against CML, including chemotherapy and other medications. Another common type of treatment is a hematopoietic cell transplant. In a hematopoietic cell transplant, hematopoietic cells are taken from a donor’s bone marrow and are given to the person with CML, just like in a transfusion. It is hoped that these new cells will then settle into the bone marrow and start producing normal blood cells, and the person will no longer have CML.
When the hematopoietic cells are harvested from another person, it is called an allogeneic transplant. When the cells come from the patient himself, it is called an autologous cell transplant. This policy discusses when an allogeneic hematopoietic cell transplant would be medically necessary to treat CML.
Policy Coverage Criteria
Transplant Medical Necessity
Allogeneic hematopoietic cell transplantation (HCT)
Allogeneic hematopoietic cell transplantation (HCT) using a myeloablative conditioning regimen may be considered medically necessary as a treatment of chronic myeloid leukemia. Allogeneic hematopoietic cell transplantation using a reducedintensity conditioning regimen may be considered medically necessary as a treatment of chronic myeloid leukemia in patients who meet clinical criteria for an allogeneic HCT but who are not considered candidates for a myeloablative conditioning allogeneic HCT.
Autologous HCT Autologous HCT is investigational as a treatment of chronic myeloid leukemia.
* Some patients for whom a conventional myeloablative allotransplant could be curative may be considered candidates for reduced-intensity conditioning allogeneic hematopoietic stem-cell transplantation (HCT). These include those patients whose age (typically >60 years) or comorbidities (eg, liver or kidney dysfunction, generalized debilitation, prior intensive chemotherapy, low Karnofsky Performance Status) preclude use of a standard myeloablative conditioning regimen.
* For patients who qualify for a myeloablative allogeneic HCT on the basis of clinical status, either a myeloablative or reduced-intensity conditioning regimen may be considered medically necessary.
The following considerations may supersede this policy: * State mandates requiring coverage for autologous bone marrow transplantation offered as part of clinical trials of autologous bone marrow transplantation approved by the National Institutes of Health (NIH).
* Some plans may participate in voluntary programs offering coverage for patients participating in NIH-approved clinical trials of cancer chemotherapies, including autologous bone marrow transplantation.
* Some contracts or certificates of coverage may include specific conditions in which autologous bone marrow transplantation would be considered eligible for coverage.
Chronic myeloid leukemia (CML) is a hematopoietic stem cell disorder that is characterized by the presence of a chromosomal abnormality called the Philadelphia chromosome, which results from reciprocal translocation between the long arms of chromosomes 9 and 22. CML most often presents in a chronic phase from which it progresses to an accelerated and then a blast phase. Allogeneic hematopoietic cell transplantation (allo-HCT) is a treatment option for CML.
Background Chronic Myeloid Leukemia
CML is a hematopoietic stem-cell disorder that is characterized by the presence of a chromosomal abnormality called the Philadelphia chromosome, which results from reciprocal translocation between the long arms of chromosomes 9 and 22. This cytogenetic change results in constitutive activation of BCR-ABL, a tyrosine kinase (TK) that stimulates unregulated cell proliferation, inhibition of apoptosis, genetic instability, and perturbation of the interactions between CML cells and the bone marrow stroma only in malignant cells. CML accounts for about 15% of newly diagnosed cases of leukemia in adults and occurs in about 1 to 2 cases per 100,000 adults.
The natural history of the disease consists of an initial (indolent) chronic phase, lasting a median of 3 years, which typically transforms into an accelerated phase, followed by a “blast crisis,” which is usually the terminal event. Most patients present in chronic phase, often with nonspecific symptoms that are secondary to anemia and splenomegaly. CML is diagnosed based on the presence of the Philadelphia chromosome abnormality by routine cytogenetics, or by detection of abnormal BCR-ABL products by fluorescence in situ hybridization or molecular studies, in the setting of persistent unexplained leukocytosis. Conventional-dose chemotherapy regimens used for chronic-phase disease can induce multiple remissions and delay the onset of blast crisis to a median of 4 to 6 years. However, successive remissions are usually shorter and more difficult to achieve than their predecessors.
Historically, the only curative therapy for CML in blast phase has been allogeneic hematopoietic cell transplantation (allo-HCT), which was used more widely earlier in the disease process given the lack of other curative therapies for chronic phase CML as well as improved efficacy when used prior to blast phase. Prior to the current TKI (tyrosine kinase inhibitor) drug era therapies for chronic phase CML were limited to nonspecific agents including busulfan, hydroxyurea, and interferon-a.
Imatinib mesylate (Gleevec®), a selective inhibitor of the abnormal BCR-ABL TK protein, for example, among the initial treatments of choice for newly diagnosed CML. Imatinib and other TKIs can be highly effective in suppressing CML in most patients, and some patients can achieve complete molecular remissions unmaintained after several years of therapy. The overall survival (OS) of patients who present in chronic phase is greater than 95% at 2 years and 80% to 90% at 5 years.
For CML, 2 other tyrosine kinase inhibitors (TKIs; dasatinib, nilotinib) have received marketing approval from the U.S. Food and Drug Administration (FDA) as front-line therapies or following failure or patient intolerance of imatinib. Recently two additional TKIs (bosutinib, ponatinib) have been approved for use in patients resistant or intolerant to prior therapy.
For patients who progress on imatinib, the therapeutic options include increasing the imatinib dose, changing to another TKI, or allo-HCT. Detection of BCR-ABL variants may be important in determining an alternative TKI; the presence of T315I mutation is associated with resistance to all TKIs except ponitinib and may indicate the need for allo-HCT or an experimental therapy. TKIs have been associated with long-term remissions; if progression occurs after exhausting TKI therapy, allo-HCT is generally indicated and offers the potential for cure.
Hematopoietic Cell Transplant
Hematopoietic cell transplantation (HCT) is a procedure in which hematopoietic stem cells are infused to restore bone marrow function in cancer patients who receive bone-marrow-toxic doses of drugs with or without whole body radiotherapy. Hematopoietic stem cells may be obtained from the transplant recipient (autologous HCT) or from a donor (allogeneic HCT). They can be harvested from bone marrow, peripheral blood, or umbilical cord blood shortly after delivery of neonates. Although cord blood is an allogeneic source, the stem cells in it are antigenically “naive” and thus are associated with a lower incidence of rejection or graft-versushost disease (GVHD). Cord blood is discussed in greater detail in another policy. (See Related Policies.)
Immunologic compatibility between infused hematopoietic stem cells and the recipient is not an issue in autologous HCT. However, immunologic compatibility between donor and patient is a critical factor for achieving a good outcome of allogeneic HCT. Compatibility is established by typing of human leukocyte antigens (HLAs) using cellular, serologic, or molecular techniques. HLA refers to the tissue type expressed at the HLA A, B, and DR loci on each arm of chromosome 6. Depending on the disease being treated, an acceptable donor will match the patient at all or most of the HLA loci (with the exception of umbilical cord blood).
Conditioning for HCT
The conventional (“classical”) practice of allogeneic HCT involves administration of cytotoxic agents (eg, cyclophosphamide, busulfan) with or without total body irradiation at doses sufficient to destroy endogenous hematopoietic capability in the recipient. The beneficial treatment effect in this procedure is due to a combination of initial eradication of malignant cells and subsequent graft-versus-malignancy (GVM) effect that develops after engraftment of allogeneic stem cells within the patient’s bone marrow space. While the slower GVM effect is considered to be the potentially curative component, it may be overwhelmed by extant disease without the use of pretransplant conditioning. However, intense conditioning regimens are limited to patients who are sufficiently fit medically to tolerate substantial adverse effects that include pre-engraftment opportunistic infections secondary to loss of endogenous bone marrow function and organ damage and failure caused by the cytotoxic drugs. Furthermore, in any allogeneic HCT, immune suppressant drugs are required to minimize graft rejection and GVHD, which also increases susceptibility of the patient to opportunistic infections. The immune reactivity between donor T cells and malignant cells that is responsible for the GVM effect also leads to acute and chronic GVHD.
The success of autologous HCT is predicated on the ability of cytotoxic chemotherapy with or without radiation to eradicate cancerous cells from the blood and bone marrow. This permits subsequent engraftment and repopulation of bone marrow space with presumably normal hematopoietic stem cells obtained from the patient before undergoing bone marrow ablation. As a consequence, autologous HCT is typically performed as consolidation therapy when the patient’s disease is in complete remission. Patients who undergo autologous HCT are
susceptible to chemotherapy-related toxicities and opportunistic infections before engraftment, but not GVHD.
RIC (Reduced Intensity Conditioning) for Allogeneic HCT
RIC refers to the pretransplant use of lower doses or less intense regimens of cytotoxic drugs or radiation than are used in conventional full-dose myeloablative conditioning treatments. The goal of RIC is to reduce disease burden but also to minimize as much as possible associated treatment-related morbidity and nonrelapse mortality (NRM) in the period during which the beneficial GVM effect of allogeneic transplantation develops. Although the definition of RIC remains arbitrary, with numerous versions employed, all seek to balance the competing effects of NRM and relapse due to residual disease. RIC regimens can be viewed as a continuum in effects, from nearly totally myeloablative, to minimally myeloablative with lymphoablation, with intensity tailored to specific diseases and patient condition. Patients who undergo RIC with allogeneic HCT 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 infusions to eradicate residual malignant cells. For the purposes of this Policy, the term “reduced-intensity conditioning” will refer to all conditioning regimens intended to be nonmyeloablative, as opposed to fully myeloablative (conventional) regimens.
For CML, RIC regimens were initially used to extend the use of allogeneic HCT to the estimated 70% of CML patients who were ineligible for myeloablative conditioning regimens because of advanced age or comorbidities. The use of RIC and allogeneic HCT is of particular interest for treatment of CML given the relatively pronounced susceptibility of this malignancy to the graft versus leukemia (GVL) effect of allogeneic hematopoietic progenitor cells following their engraftment in the host.