MEDICAL POLICY

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APPENDIX
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Hematopoietic Stem-Cell Transplantation for Acute Lymphoblastic Leukemia

Number 8.01.520

Effective Date July 24, 2013

Revision Date(s) 07/08/13; 03/13/12; 09/13/11; 11/09/10; 05/12/09; 05/13/08; 10/09/07; 01/10/06; 12/14/04; 08/12/03; 06/17/03; 12/21/00; 06/27/00

Replaces 8.01.32

Policy

Children

Autologous or Allogeneic hematopoietic stem-cell transplantation (HSCT) may be considered medically necessary to treat childhood acute lymphoblastic leukemia (ALL) for ANY of the following:

  • First complete remission but at high risk of relapse (see Policy Guidelines for high-risk factors) or
  • Second or greater remission or
  • Refractory ALL.

Allogeneic HSCT may be considered medically necessary to treat relapsing ALL after a prior autologous HSCT.

Adults

Autologous HSCT may be considered medically necessary to treat adult acute lymphoblastic leukemia (ALL) in:

  • First complete remission for any relapse risk level (see Policy Guidelines for risk factors).

Allogeneic HSCT may be considered medically necessary to treat adult ALL for ANY of the following:

  • First complete remission for any relapse risk level or
  • Second or greater remission or
  • Relapsed or refractory ALL or
  • Relapsing ALL after a prior autologous HSCT.

Reduced-intensity conditioning (RIC) allogeneic hematopoietic SCT may be considered medically necessary as a treatment of ALL in patients who are in complete marrow and extramedullary first or second remission, and who for medical reasons (see Policy Guidelines), would be unable to tolerate a standard myeloablative conditioning regimen.

Autologous HSCT is considered investigational to treat adult ALL for the following:

  • Second or greater remission, OR
  • Those with refractory disease.

Note: The use of donor leukocyte infusions to treat relapse after high-dose chemotherapy (HDC) with allogeneic HSCT for either children or adults is addressed in a separate medical policy. (See Related Policies)

Related Policies

7.01.50

Placental and Umbilical Cord Blood as a Source of Stem Cells

8.01.01

Adoptive Immunotherapy

8.01.17

Hematopoietic Stem-Cell Transplantation for Plasma Cell Dyscrasias, Including Multiple Myeloma and POEMS Syndrome

8.01.20

Hematopoietic Stem-Cell Transplantation for Non-Hodgkin Lymphomas

8.01.21

Allogeneic Stem-Cell Transplantation for Myelodysplastic Syndromes and Myeloproliferative Neoplasms

8.01.22

Allogeneic Hematopoietic Stem-Cell Transplantation for Genetic Diseases and Acquired Anemias

8.01.23

Hematopoietic Stem-Cell Transplantation for Epithelial Ovarian Cancer

8.01.24

Hematopoietic Stem-Cell Transplantation for Miscellaneous Solid Tumors in Adults

8.01.25

Hematopoietic Stem-Cell Transplantation for Autoimmune Diseases

8.01.26

Hematopoietic Stem-Cell Transplantation for Acute Myeloid Leukemia

8.01.27

Hematopoietic Stem-Cell Transplantation for Breast Cancer

8.01.28

Hematopoietic Stem-Cell Transplantation for CNS Embryonal Tumors and Ependymoma

8.01.29

Hematopoietic Stem-Cell Transplantation for Hodgkin Lymphoma

8.01.30

Hematopoietic Stem-Cell Transplantation for Chronic Myelogenous Leukemia

8.01.31

Autologous Hematopoietic Stem-Cell Transplantation for Malignant Astrocytomas and Gliomas

8.01.35

Hematopoietic Stem-Cell Transplantation in the Treatment of Germ Cell Tumors

8.01.42

Hematopoietic Stem-Cell Transplantation for Primary Amyloidosis

8.01.511

Hematopoietic Stem-Cell Transplantation for Solid Tumors of Childhood

8.01.514

Hematopoietic Stem-Cell Support for Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma

Policy Guidelines

Relapse Risk Prognostic Factors

Childhood ALL

Adverse prognostic factors include the following: age less than one year or more than nine years, male gender, white blood cell count at presentation above 50,000/μL, hypodiploidy (<45 chromosomes), t(9:22) or BCR/ABL fusion, t(4;11) or MLL/AF4 fusion, and ProB or T-lineage immunophenotype. Several risk stratification schema exist, but, in general, the following findings help define children at high risk of relapse: 1) poor response to initial therapy including poor response to prednisone prophase defined as an absolute blast count of 1000/μL or greater, or poor treatment response to induction therapy at six weeks with high risk having ≥1% minimal residual disease measured by flow cytometry), 2) all children with T-cell phenotype and 3) patients with either the t(9;22) or t(4;11) are considered high risk regardless of early response measures.

Adult ALL

Risk factors for relapse are less well defined, but an adult patient with any of the following may be considered at high risk for relapse: age greater than 35 years, leukocytosis at presentation of >30,000/μL (B-cell lineage) and >100,000/μL (T-cell lineage),“poor prognosis” genetic abnormalities like the Philadelphia chromosome (t(9;22)), extramedullary disease and time to attain complete remission longer than 4 weeks.

Reduced Intensity Conditioning

Some patients for whom a conventional myeloablative allogeneic HSCT could be curative may be considered candidates for RIC allogeneic HSCT. These include those whose age (typically older than 60 years) or co morbidities (e.g., liver or kidney dysfunction, generalized debilitation, prior intensive chemotherapy, low Karnofsky Performance Status) preclude use of a standard myeloablative conditioning regimen.

Note: Unless otherwise specified in the text of this Policy, it is assumed that the term “allogeneic SCT” refers to the use of a myeloablative pretransplant conditioning regimen.

The ideal allogeneic donors are HLA-identical siblings, matched at the LHA-A, B and DR loci (six of six). Related donors mismatched at one locus are also considered suitable donors. A matched, unrelated donor identified through the National Marrow Donor Registry is typically the next option considered. Recently, there has been interest in haploidentical donors, typically a parent or a child of the patient, where usually there is sharing of only three of the six major histocompatibility antigens. The majority of patients will have such a donor; however, the risk of GVHD and overall morbidity of the procedure may be severe, and experience with these donors is not as extensive as that with matched donors.

Description

Hematopoietic Stem-Cell Transplantation

Hematopoietic stem-cell transplantation (HSCT) refers to a procedure in which hematopoietic stem cells are infused to restore bone marrow function in cancer patients who receive bone-marrow-toxic doses of cytotoxic drugs, with or without whole-body radiation therapy. Bone-marrow stem cells may be obtained from the transplant recipient (i.e., autologous HSCT) or from a donor (i.e., allogeneic HSCT). They can be harvested from bone marrow, peripheral blood, or umbilical cord blood and placenta shortly after delivery of neonates. Although cord blood is an allogeneic source, the stem cells in it are antigenically “naïve” and thus are associated with a lower incidence of rejection or graft-versus-host disease (GVHD). Cord blood is discussed in greater detail in a separate policy (See Related Policies).

Background

Immunologic compatibility between infused stem cells and the recipient is not an issue in autologous HSCT. However, immunologic compatibility between donor and patient is a critical factor for achieving a good outcome of allogeneic HSCT. Compatibility is established by typing of human leukocyte antigens (HLA) using cellular, serologic, or molecular techniques. HLA refers to the tissue type expressed at the HLA A, B, and DR loci on each leg of chromosome 6. Depending on the disease being treated, an acceptable donor will match the patient at all or most of the HLA loci.

Conventional Preparative Conditioning for HSCT

The success of autologous HSCT 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 prior to undergoing bone marrow ablation. As a consequence, autologous HSCT is typically performed as consolidation therapy when the patient’s disease is in complete remission. Patients who undergo autologous HSCT are susceptible to chemotherapy-related toxicities and opportunistic infections prior to engraftment, but not GVHD.

The conventional (“classical”) practice of allogeneic HSCT involves administration of cytotoxic agents (e.g., 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 HSCT, immune suppressant drugs are required to minimize graft rejection and GVHD, which also increases susceptibility of the patient to opportunistic infections.

Reduced-Intensity Conditioning for Allogeneic HSCT

Reduced-intensity conditioning (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 non-relapse mortality (NRM) in the period during which the beneficial GVM effect of allogeneic transplantation develops. Although the definition of RIC remains arbitrary, with numberous 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 disease and patient condition. 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 infusions to eradicate residual malignant cells. For the purposes of the Policy, the term “reduced-intensity conditioning” will refer to all conditioning regimens intended to be non-myeloablative, as opposed to fully myeloablative (conventional) regimens.

Acute Lymphoblastic Leukemia (ALL)

Childhood ALL

ALL is the most common cancer diagnosed in children and represents almost 25% of cancers in children younger than 15 years. (1) Approximately 95% of children with ALL achieve remission with up to 85% long-term survival rates. Survival rates have improved with the identification of effective drugs and combination chemotherapy through large, randomized trials, integration of presymptomatic central nervous system prophylaxis, and intensification and risk-based stratification of treatment. (2)

ALL is a heterogeneous disease with different genetic alterations resulting in distinct biologic subtypes. Patients are stratified according to certain clinical and genetic risk factors that predict outcome, with risk-adapted therapy tailoring treatment based on the predicted risk of relapse. (3) Two of the most important factors predictive of risk are patient age and white blood cell count (WBC) at diagnosis. (3) Certain genetic characteristics of the leukemic cells strongly influence prognosis. Clinical and biologic factors predicting clinical outcome can be summarized as follows: (2)

PROGNOSTIC FACTOR

FAVORABLE

UNFAVORABLE

Age at diagnosis

1-9 years

<1 or >9 years

Sex

Female

Male

WBC count

<50,000/μL

≥50,000/μL

Genotype

Hyperdiploidy (>50 chromosomes)

t(12;21) or TEL/AML1 fusion

Hypodiploidy (<45 chromosomes)

t(9:22) or BCR/ABL fusion

t(4;11) or MLL/AF4 fusion

Immunophenotype

Common, preB

ProB, T

lineage

Adult ALL

ALL accounts for approximately 20% of acute leukemias in adults. Approximately 60-80% of adults with ALL can be expected to achieve complete remission after induction chemotherapy; however, only 35-40% can be expected to survive two years. (4) Differences in the frequency of genetic abnormalities that characterize adult ALL versus childhood ALL help, in part, to explain the outcome differences between the two groups. For example, the “good prognosis” genetic abnormalities like hyperdiploidy and t(12;21) are seen much less commonly in adult ALL, whereas they are some of the most common in childhood ALL. Conversely, “poor prognosis” genetic abnormalities like the Philadelphia chromosome (t(9;22)) are seen in 25-30% of adult ALL but infrequently in childhood ALL. Other adverse prognostic factors in adult ALL include age greater than 35 years, poor performance status, male sex, and leukocytosis at presentation of >30,000/μL (B-cell lineage) and >100,000/μL (T-cell lineage).

Note: The use of killer (LAK) cells in the treatment of malignancies is addressed in a separate policy (See Related Policies).

Scope

Medical policies are systematically developed guidelines that serve as a resource for Company staff when determining coverage for specific medical procedures, drugs or devices. Coverage for medical services is subject to the limits and conditions of the member benefit plan. Members and their providers should consult the member benefit booklet or contact a customer service representative to determine whether there are any benefit limitations applicable to this service or supply.

Benefit Application

N/A

Rationale

Childhood ALL

The policy on childhood acute lymphoblastic leukemia (ALL) was initially based on TEC Assessments completed in 1987 and 1990. (5, 6) In childhood ALL, conventional chemotherapy is associated with complete remission rates of about 95%, with long-term durable remissions of 60%. Therefore, for patients in a first complete remission (CR1), stem-cell transplantation (HSCT) therapy is considered necessary only in those with risk factors predictive of relapse (see the Description section).

The prognosis after first relapse is related to the length of the original remission. For example, leukemia-free survival is 40%–50% for children whose first remission was longer than three years, compared to only 10%–15% for those with early relapse. Thus, HSCT may be a strong consideration in those with short remissions. At present, the comparative outcomes with either autologous or allogeneic HSCT are unknown.

Three reports describing the results of randomized-controlled trials (RCTs) that compared outcomes of HDC with HSCT in children with ALL were identified subsequent to the TEC Assessment. (7-9) The children enrolled in the RCTs were being treated for high-risk ALL in first complete remission (1st CR) or for relapsed ALL. These studies reported that overall outcomes after HSCT were generally equivalent to overall outcomes after conventional-dose chemotherapy. While HSCT administered in 1st CR was associated with fewer relapses than conventional-dose chemotherapy, it was also associated with more frequent deaths in remission (i.e., from treatment-related toxicity). A more recently published randomized trial (PETHEMA ALL-93, n = 106) demonstrated no significant differences in disease-free survival or overall survival rates at median follow-up of 78 months in children with very high-risk ALL in CR1 who received allogeneic or autologous HSCT versus standard chemotherapy with maintenance treatment. (10) Similar results were observed using either intention-to-treat (ITT) or per-protocol (PP) analyses. However, the authors point out several study limitations that could have affected outcomes, including the relatively small numbers of patients; variations among centers in the preparative regimen used prior to HSCT and time elapsed between CR and undertaking of assigned treatment; and the use of genetic randomization based on donor availability rather than true randomization for patients included in the allogeneic HSCT arm.

These results, and reviews of other studies, (11,12) suggest that while overall and event-free survival are not different after HSCT compared to conventional-dose chemotherapy, HSCT remains an important therapeutic option in the management of childhood ALL, especially for patients considered at high risk of relapse. This conclusion is further supported by an evidence/based systematic review of the literature sponsored by the American Society for Blood and Marrow Transplantation (ASBMT). Other investigators recommend that patients should be selected for this treatment using risk-directed strategies. (14,15)

Adult ALL

The policy on adult ALL was initially based on a 1997 TEC Assessment of HDC and autologous (not allogeneic) stem cell support. (16) This Assessment offered the following conclusions:

  • For patients in CR1, the data suggest survival is equivalent after high-dose therapy plus autologous HSCT or conventional chemotherapy. For these patients the decision between HDC and conventional chemotherapy may reflect a choice between an intensive therapy of short duration and longer but less-intensive treatment.
  • In other settings such as in second (CR2) or subsequent remission, data were inadequate to determine the relative effectiveness of high-dose therapy plus autologous stem-cell support compared to conventional chemotherapy.

A subsequent evidence-based systematic review sponsored by the American Society for Blood and Marrow Transplantation (ASBMT) addressed the issue of HSCT in adults with ALL. (17) Based on its review of evidence available through January 2005, the ASBMT panel recommended HSCT as consolidation therapy for adults with high-risk disease in CR1, but not for standard-risk patients. It also recommended HSCT for patients in CR2, although data are not available to directly compare outcomes with alternatives. Based on results from three RCTs (18-20), the ASBMT panel further concluded that myeloablative allogeneic HSCT is superior to autologous HSCT in adult patients in CR1, although available data did not permit separate analyses in high-risk versus low-risk patients.

Results that partially conflicted with the ASBMT conclusions were obtained in a multicenter (35 Spanish hospitals) randomized trial (PETHEMA ALL-93; n=222) published after the ASBMT literature search. (21) Among 183 high-risk patients in CR1, those with an HLA-identical family donor were assigned to allogeneic HSCT (n=84); the remaining cases were randomized to autologous HSCT (n=50) or to delayed intensification followed by maintenance chemotherapy up to two years in CR (n=48). At median follow-up of 70 months, the study did not detect a statistically significant difference in outcomes among all three arms by both per-protocol and ITT analyses. The PETHEMA ALL-93 trial investigators pointed out several study limitations that could have affected outcomes, including the relatively small numbers of patients; variations among centers in the preparative regimen used prior to HSCT; differences in risk group assignment; and the use of genetic randomization based on donor availability rather than true randomization for patients included in the allogeneic HSCT arm.

In 2012, the ASBMT published an update to the 2006 guidelines for treatment of ALL in adults. (22) An electronic search of the literature through PubMed and Medline extended to mid-October 2010. The evidence available at that time supported a grade A treatment recommendation (at least 1 meta-analysis, systematic review, or RCT) that myeloablative allogeneic HSCT is an appropriate treatment for adult ALL in CR1 for all risk groups. Further, the ASBMT panel indicated a grade A treatment recommendation for autologous HSCT in patients who do not have a suitable allogeneic stem-cell donor; they suggested that although survival outcomes appear similar between autologous HSCT and post-remission chemotherapy, the shorter treatment duration with the former is an advantage. Finally, the ASBMT panel concluded that allogeneic HSCT is recommended over chemotherapy for adults with ALL in CR2 or beyond.

A recent meta-analysis pooled data from seven studies of allogeneic HSCT published between 1994 and 2005 that included a total of 1,274 patients with ALL in CR1. (23) The results showed that regardless of risk category, allogeneic HSCT was associated with a significant overall survival advantage (hazard ratio [HR]: 1.29, 95% confidence interval [CI]: 1.02–1.63; p=0.037) for all patients who had a suitable donor versus patients without a donor who received chemotherapy or autologous HSCT. Pooled data from patients with high-risk disease showed an increased survival advantage for allogeneic HSCT compared to those without a donor (HR: 1.42, 95% CI: 1.06–1.90; p=0.019). None of the studies in this meta-analysis showed significant benefit of allogeneic HSCT for patients who did not have high-risk disease, nor did the meta-analysis. However, the individual studies were relatively small, the treatment results were not always comparable, and the definitions of high-risk disease features varied across all studies.

A subsequent meta-analysis from the Cochrane group evaluated the evidence for the efficacy of matched sibling stem cell donor versus no donor status for adults with ALL in CR1.(24) A total of 14 trials with treatment assignment based on genetic randomization including a total 3,157 patients were included in this analysis. Matched sibling donor HSCT was associated with a statistically significant overall survival advantage compared to the no donor group (HR 0.82; 95% CI: 0.77, 0.97, p=0.01). Patients in the donor group had a significantly lower rate of primary disease relapse than those without a donor (RR 0.53; 95%CI: 0.7, 0.76, p=0.0004) and significantly increased non-relapse mortality (RR 2.8; 95% CI:1.66, 4.73, p=0.001). These results support the conclusion of this policy, that allogeneic HSCT (matched sibling donor) is an effective post-remission therapy in adult patients.

While the utility of allogeneic HSCT for post remission therapy in patients with high-risk ALL has been established, its role in those who do not have high-risk features has been less clear. This question has been addressed by the International ALL trial, a collaborative effort conducted by the MRC in the United Kingdom and the Eastern Cooperative Oncology Group (ECOG) in the United States (MRC UKALL XII/ECOG E2993). (25) The ECOG 2993 trial was a Phase III randomized study designed to prospectively define the role of myeloablative allogeneic HSCT, autologous HSCT, and conventional consolidation and maintenance chemotherapy for adult patients up to age 60 years with ALL in CR1. This study is the largest randomized controlled trial in which all patients (total n=1,913) received essentially identical therapy, irrespective of their disease risk assignment. After induction treatment that included imatinib mesylate for Philadelphia (Ph) chromosome-positive patients, all patients who had an HLA-matched sibling donor (n=443) were assigned to receive an allogeneic HSCT. Patients with the Ph chromosome (n=267) who did not have a matched sibling donor could receive an unrelated donor HSCT. Patients who did not have a matched sibling donor or were older than 55 years (n=588) were randomly allocated to receive a single autologous HSCT or consolidation and maintenance chemotherapy.

In ECOG2993, the overall survival (OS) at 5-years follow-up of all 1,913 patients was 39%; it reached 53% for Ph-negative patients with a donor (n=443) compared to 45% without a donor (n=588) (p=0.01). (25) Analysis of Ph-negative patient outcomes according to disease risk showed a five-year OS of 41% among patients with high-risk ALL and a sibling donor versus 35% of high-risk patients with no donor (p=0.2). In contrast, OS at 5-years follow-up was 62% among standard-risk Ph-negative patients with a donor and 52% among those with no donor, a statistically significant difference (p=0.02). Among Ph-negative patients with standard-risk disease who underwent allogeneic HSCT, the relapse rate was 24% at 10 years’ follow-up, compared to 49% among those who did not undergo HSCT (p<0.00005). Among Ph-negative patients with high-risk ALL, the rate of relapse at the10-year follow-up was 37% following allogeneic HSCT versus 63% without a transplant (p<0.00005), demonstrating the potent graft-versus-leukemia (GVL) effect in an allogeneic transplantation. These data clearly show a significant long-term survival benefit associated with post remission allogeneic HSCT in standard-risk Ph-negative patients, an effect previously not demonstrated in numerous smaller studies. Failure to demonstrate a significant OS benefit in high-risk Ph-negative cases can be attributed to a high nonrelapse mortality (NRM) rate at one and two years, mostly due to graft-versus-host disease (GVHD) and infections. At two years, NRM was 36% among high-risk patients with a donor compared to 14% among those who did not have a donor. Among standard-risk cases, the NRM rate at two years was 20% in patients who underwent allogeneic HSCT versus 7% in those who received autologous HSCT or continued chemotherapy.

In a separate report on the Ph-positive patients in ECOG2993, an ITT analysis (n=158) showed a five-year OS of 34% (95% CI: 25–46%) for those who had a matched sibling donor versus 25% (95% CI: 12–34%) with no donor who received consolidation and maintenance chemotherapy. (26) Although the difference in survival rates was not statistically significant, this analysis demonstrated a moderate superiority of post remission matched sibling allogeneic HSCT over chemotherapy in patients with high-risk ALL in CR1, in concordance with this policy.

The Dutch HOVON cooperative group reported results combined from two successive randomized trials in previously untreated adult patients with ALL aged 60 years or younger, in which myeloablative allogeneic HSCT was consistently used for all patients who achieved CR1 and who had an HLA-matched sibling donor, irrespective of risk category. (27) A total 433 eligible patients included 288 younger than 55 years, in CR1, and eligible to receive consolidation treatment by an autologous HSCT or an allogeneic HSCT. Allogeneic HSCT was performed in 91 of 96 (95%) with a compatible sibling donor. The OS at 5-year follow-up was 61% + 5% among all patients with a donor and 47% + 5% among those without a donor (p = 0.08). The cumulative incidence of relapse at five years follow-up among all patients was 24% + 4% (SE) in those with a donor versus 55% + 4% (SE) in those (n=161) without a donor (p<0.001). Among patients stratified by disease risk, those in the standard risk category with a donor (n=50) had a 5-year OS of 69% + 7% and relapse rate at five years of 14% + 5% compared to 49% + 6% and 52% + 5%, respectively, among those (n = 88) without a donor (p=0.05). High-risk patients with a donor (n=46) had a five-year OS of 53% + 8% and relapse at five years of 34% + 7%, versus 41% + 8% and 61% + 7%, respectively, among those with no donor (n=73) (p=0.50). NRM rates among standard-risk patients were 16% + 5% among those with a donor and 2% + 2% among those without a donor; in high-risk patients, NRM rates were 15% + 7% and 4% + 3%, respectively, among those with and without a donor.

The HOVON studies were analyzed as from remission evaluation prior to consolidation, whereas the ECOG2993 data were analyzed and presented as from diagnosis, which complicates direct comparison of their outcomes. To facilitate a meaningful comparison, the HOVON data were reanalyzed according to donor availability from diagnosis. This showed a five-year OS rate of 60% in standard-risk patients with a donor in the HOVON study, which is very similar to the 62% OS observed in standard-risk patients with a donor in the ECOG2993 trial. Collectively, these results suggest that patients with standard-risk ALL can expect to benefit from allogeneic HSCT in CR1, provided the NRM risk is less than approximately 20% to 25%. (27)

Most data indicate post remission myeloablative allogeneic HSCT is an effective therapeutic option for a large proportion of adults with ALL. However, the increased morbidity and mortality from GVHD limit its use, particularly for older patients. For adults who survive the procedure, there is a significant relapse rate. Furthermore, a recent individual patient meta-analysis that included a number of the studies compiled in this Policy suggests that a matched sibling donor myeloablative HSCT improves survival only for younger adults (< 35 years old) in CR1 compared to chemotherapy.(28) Notwithstanding those caveats, taken together, current evidence and clinical guidelines supports the use of myeloablative allogeneic HSCT for patients with ALL in CR1 whose health status is sufficient to tolerate the procedure (see Policy Guidelines).

Reduced-Intensity Conditioning Allogeneic HSCT

The use of RIC regimens has been investigated as a means to extend the substantial GVL effect of post remission allogeneic HSCT to older adult patients who otherwise could expect to benefit from this procedure. In a multicenter single-arm study of patients (n=43, median age 19 years; range: one to 55) in second complete remission (CR2), a three-year OS rate of 30% was achieved, with 100-day and NRM rates of 15% and 21%, respectively. Despite achievement of complete donor chimerism in 100% of the patients, 28 (65%) had leukemic relapse, with 67% ultimately succumbing to their disease. (29)

A registry-based study included 97 adult patients (median age 38 years, range 17–65) who underwent RIC and allogeneic HSCT to treat ALL in CR1 (n=28), beyond CR1 (CR2/CR3, n=26/5), and advanced or refractory disease (n=39). (28) With median follow-up of about three years, in the overall population two-year OS was 31%, with non-relapse mortality of 28% and relapse rate of 51%. In patients transplanted in CR1, OS was 52%; in CR2/CR3, it was 27%; in patients with advanced or refractory ALL, OS was 20%. These data suggest RIC and allogeneic HSCT have some efficacy as salvage therapy in high-risk ALL.

RIC for allogeneic HSCT was investigated in a prospective Phase II study that included 37 consecutive adults (median age 45 years; range 15–63 years) with high-risk ALL (43% Ph-positive, 43% high WBC) in CR1 (81%) or CR2 (19%) who were ineligible to receive a myeloablative allogeneic HSCT because of age, organ dysfunction, low Karnofsky performance status (<50%), or the presence of infection. (29) Patients received stem cells from a matched sibling (n=27) or matched unrelated donor (n=10). Post remission RIC conditioning consisted of fludarabine and melphalan, with GVHD prophylaxis (cyclosporine or tacrolimus, plus methotrexate). All Ph-positive patients also received imatinib prior to HSCT. The three-year cumulative incidence of relapse was 19.7% + 6.9%, that of NRM was 17.7% + 6.9%. The three-year cumulative OS rate was 64.1% + 8.6%, with DFS rate of 62.6% + 8.5% at the same point. After a median follow-up of 36 months (range: 121–96 months), 25 (67.6%) of patients remained alive, among whom 24 (96%) remained in continuous CR.

A multicenter prospective study published in 2010 involved 47 pediatric patients (median age 11 years, range: 2-20 years) with hematologic cancers, including ALL (n=17), who underwent allogeneic HSCT with a fludarabine-based RIC regimen. (30) It represents the first large cooperative group study to be published in this setting. Among the 17 cases, 4 were in CR2, 12 in CR3, and 1 had secondary ALL. All patients were heavily pretreated, including previous myelobablative allogeneic or autologous HSCT, but these were not individually reported. While most data were presented in aggregate, some survival findings were specified, showing EFS of 35% and OS of 37% at 20year follow-up for the ALL patients. Although most patients lived only a few months after relapse or rejection, some were long-term survivors after further salvage treatment. Among those, 1 ALL patient received chemotherapy and donor lymphocyte infusion (DLI) for low chimerism and relapse and was reported alive 1 year following DLI and 3 years from HSCT. A second ALL case, who rejected an initial mismatched0related donor graft, underwent a second RIC regimen using the same donor and was alive with moderate chronic GVHD more than 3 years after HSCT. Treatment-related mortality was not reported by disease, nor was HSCT-related morbidities. However these data do suggest allogeneic HSCT with RIC can be used in children with high-risk ALL and achieve some long-term survival in patients with no therapeutic recourse.

Thus, based on currently available data and clinical input as noted in the following section, RIC allogeneic HSCT may be considered medically necessary in patients who demonstrate complete marrow and extramedullary first or second remission; could be expected to benefit from a myeloablative allogeneic HSCT; and, who for medical reasons, could not tolerate a myeloablative conditioning regimen. Additional data are necessary to determine whether some patients with ALL and residual disease may benefit from RIC allogeneic HSCT.

The European Group for Blood and Marrow Transplantation published a retrospective study that assessed the outcome of 576 adult ALL patients aged >/=45, and who received a reduced-intensity (RIC; n=127) or a myeloablative conditioning (MAC; n=449) allogeneic stem cell transplantation (allo-SCT) from an HLA-identical sibling while in complete remission. With a median follow-up of 16 months, at two years, the cumulative incidences of non-relapse mortality (NRM) and relapse (RI) were 29+/-2% (MAC) versus 21+/-5% (RIC; P=0.03), and 31+/-2% (MAC) versus 47+/-5% (RIC; P<0.001) respectively. In a multivariate analysis, NRM was decreased in RIC recipients (P=0.0001, HR=1.98) whereas it was associated with higher relapse rate (P=0.03, HR=0.59). At 2 years, LFS was 38+/-3% (MAC) versus 32+/-6% (RIC; P=0.07). In multivariate analysis, the type of conditioning regimen (RIC versus MAC) was not significantly associated with LFS (P=0.23, HR=0.84). Despite the need for randomized trials, the conclusion is that RIC allogeneic SCT from an HLA-identical donor is a potential therapeutic option for ALL patients aged >/=45 in CR and not eligible for MAC allogeneic SCT.

Allogeneic Transplant after Prior Failed Autologous Transplant

A 2000 TEC Assessment focused on allogeneic SCT after a prior failed autologous SCT in the treatment of a variety of malignancies, including ALL. (33) The TEC Assessment found that data were inadequate to permit conclusions about outcomes of this treatment strategy. Published evidence was limited to small, uncontrolled clinical series with short follow-up. Updated literature searches have not identified any additional evidence to permit conclusions on this use of SCT.

Summary

Clinical study results summarized above suggest that while OS and EFS are not different after HSCT compared to conventional-dose chemotherapy in most children with standard risk ALL, HSCT remains an important therapeutic option for patients considered at high risk of relapse. This conclusion is further supported by an evidence-based systematic review of the literature sponsored by the ASBMT. It has been recommended that patients should be selected for this treatment using risk-directed strategies.

Data indicated post remission myeloablative allogeneic HSCT is an effective therapeutic option for a large proportion of adults with ALL. However, the increased morbidity and mortality form GVHD limit its use, particularly for older patients. Further, for adults who survive the procedure, there is a significant relapse rate. Notwithstanding those caveats, taken together, current evidence supports the use of myeloablative allogeneic HSCT for patients with ALL in CR1 whose health status is sufficient to tolerate the procedure.

RIC allogeneic HSCT may be considered medically necessary in patients who demonstrate complete marrow and extramedullary first or second remission, could be expected to benefit from a myeloablative allogeneic HSCT, and who, for medical reasons, would be unable to tolerate a myeolablative conditioning regimen. Additional data are necessary to determine whether some patients with ALL and residual disease may benefit from RIC allogeneic HSCT.

Strong evidence is unavailable to permit conclusions on the use of allogeneic HSCT following failure of an autologous HSCT and clinical trials are unlikely. However, allogeneic HSCT after failed autologous HSCT has been shown to be of clinical benefit in other hematologic malignancies and is potentially curative. In addition, clinical input supports this use, particularly with RIC regimens, in adults or children. Therefore, an allogeneic HSCT after a prior failed autologous HSCT may be considered medically necessary.

Clinical Input Received through Physician Specialty Society and Academic Medical Center Input

In response to requests, input was received from one physician specialty society (two reviewers) and two academic medical centers while this policy was under review in December 2008. While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted. There was strong consensus among reviewers that RIC allogeneic HSCT was of value in patients who were in complete remission. With this exception, there was general support for the policy statements.

National Comprehensive Cancer Network Guidelines

The 2013 National Comprehensive Cancer Network clinical practice guidelines for acute lymphoblastic leukemia indicate allogeneic HSCT is appropriate for consolidation treatment of most poor-risk (e.g., Ph1+, relapsed or refractory) patients with ALL. (34) These guidelines are generally consistent with this policy. However, the NCCN guidelines now stratify treatment according to the categories adolescent and young adult (age 15-39 years) and adult (age 40 or more years), rather than in more traditional children (18 years or younger) and adult categories (18 or more years).

National Cancer Institute Clinical Trials Database (PDQ®)

A search of the NCI PDQ database in April 2013 identified 18 active Phase II/III trials that involve stem-cell support for adult patients with ALL (Available online at: http://www.cancer.gov/clinicaltrials/search/results?protocolsearchid=7147167).

Fifteen trials were identified for pediatric ALL (Available online at: http://www.cancer.gov/clinicaltrials/search/results?protocolsearchid=9873567).

References

  1. Physician Data Query (PDQ®). Childhood acute lymphoblastic leukemia. Last modified July 15, 2011, last accessed June 3, 2013.
  2. Pieters R, Carroll WL. Biology and treatment of acute lymphoblastic leukemia. Pediatr Clin N Am 2008; 55(1):1-20.
  3. Carroll WL, Bhojwani D, Min DJ et al. Pediatric acute lymphoblastic leukemia. Hematology Am Soc Hematol Educ Program 2003:102-31.
  4. Physician Data Query (PDQ®). Adult acute lymphoblastic leukemia treatment. Last modified July 14, 2011, last accessed June 3, 2013.
  5. Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). TEC Assessments. 1990; p. 254.
  6. Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). TEC Assessments. 1987; p. 243.
  7. Harrison G, Richards S, Lawson S et al. Comparison of allogeneic transplant versus chemotherapy for relapsed childhood acute lymphoblastic leukaemia in the MRC UKALL R1 trial. Ann Oncol 2000; 11(8):999-1006.
  8. Lawson SE, Harrison G, Richards S et al. The UK experience in treating relapsed childhood acute lymphoblastic leukaeima: a report on the Medical Research Council UK ALLR1 study. Br J Haematol 2000; 108(3):531-43.
  9. Wheeler KA, Richards SM, Bailey CC et al. Bone marrow transplantation versus chemotherapy in the treatment of very high-risk childhood acute lymphoblastic leukemia in first remission: results from Medical Research Council UKALL X and XI. Blood 2000; 96(7):2412-8.
  10. Ribera JM, Ortega JJ, Oriol A et al. Comparison of intensive chemotherapy, allogeneic, or autologous stem-cell transplantation as postremission treatment for children with very high risk acute lymphoblastic leukemia: PETHEMA ALL-93 trial. J Clin Oncol 2007; 25(1);16-24.
  11. Uderzo C. Indications and role of allogeneic bone marrow transplantation in childhood very high risk acute lymphoblastic leukemia in first complete remission. Haematologica 2000; 85(11 suppl):9-11.
  12. Uderzo C, Dini G, Locatelli F et al. Treatment of childhood acute lymphoblastic leukemia after the first relapse: curative strategies. Haematologica 2000; 85(11 suppl):47-53.
  13. Oliansky DM, Camitta B, Gaynon P et al. Role of cytotoxic therapy with hematopoietic stem cell transplantation in the treatment of pediatric acute lymphoblastic leukemia: update of the 2005 evidence-based review. Biol Blood Marrow Transplant 2012; 18(4):505-22.
  14. Gaynon PS, Trigg ME, Heerema NA et al. Children’s Cancer Group trials in childhood acute lymphoblastic leukemia: 1983-1995. Leukemia 2000; 14(12):2223-33.
  15. Oyekunie A, Haferlach T, Kroger N er al. Molecular Diagnostics, Targeted therapy, and the Indication for Allogeneic Stem Cll Transplantation in Acute Lymphoblastic Leukemia. Adv Hematol 2011; 2011:154745.
  16. Blue Cross and Blue Shield Association Technology Evaluation Association (TEC). TEC Assessments. 1997; Tab 25.
  17. Hahn T, Wall D, Camitta B et al. The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of acute lymphoblastic leukemia in adults: an evidence-based review. Biol Blood Marrow Transplant 2006; 12(1):1-30.
  18. Attal M, Blaise D, Marit G et al. Consolidation treatment of adult acute lymphoblastic leukemia: a prospective, randomized trial comparing allogeneic versus autologous bone marrow transplantation and testing the impact of recombinant interleukin- 2 after autologous bone marrow transplantation. BGMT Group. Blood 1995; 86(4):1619-28.
  19. Dombret H, Gabert J, Boiron JM et al. Outcome of treatment in adults with Philadelphia chromosome-positive acute lymphoblastic leukemia-results of the prospective multicenter LALA-94 trial. Blood 2002; 100(7):2357-66.
  20. Hunault M, Harousseau JL, Delain M et al. Better outcome of adult acute lymphoblastic leukemia after early genoidentical allogeneic bone marrow transplantation (BMT) than after late high-dose therapy and autologous BMT: a GOELAMS trial. Blood 2004; 104(10):3028-37.
  21. Ribera JM, Oriol A, Bethencourt C et al. Comparison of intensive chemotherapy, allogeneic or autologous stem cell transplantation as postremission treatment for adult patients with high-risk acute lymphoblastic leukemia. Results of the PETHEMA ALL-93 trial. Haematologica 2005; 90(10):1346-56.
  22. Oliansky DM, Larson RA, Weisdorf D et al. The Role of Cytotoxic Therapy with Hematopoietic Stem Cell Transplantation in the Treatment of Adult Acute Lymphoblastic Leukemia: Update of the 2006 Evidence-Based Review. Biol Blood Marrow Transplant 2012; 18(1):18-36.e6.
  23. Yanada M, Matsuo K, Suzuki T et al. Allogeneic hematopoietic stem cell transplantation as part of postremission therapy improves survival for adult patients with high-risk acute lymphoblastic leukemia. Cancer 2006; 106(12):2657-63.
  24. Pidala J, Djulbegovic B, Anasetti C et al. Allogeneic hematopoietic cell transplantation for adult acute lymphoblastic leukemia (ALL) in first complete remission. Cochrane Database Syst Rev 2011; (10): CD008818.
  25. Goldstone AH, Lazarus HJ, Richards SM et al. The outcome of 551 1st CR transplants in adult ALL from the UKALL XII/ECOG 2993 study [abstract]. Blood 2004; 104:178a.
  26. Fielding AK, Rowe JM, Richards SM et al. Prospective outcome data on 267 unselected adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia confirms superiority of allogeneic transplantation over chemotherapy in the pre-imatinib era: results from the International ALL Trial MRC UKALLXII/ECOG2993. Blood 2009; 113(19):4489-96.
  27. Cornelissen JJ, van der Holt B, Verhoef GE et al. Myeloablative allogeneic versus autologous stem cell transplantation in adult patients with acute lymphoblastic leukemia in first remission: a prospective sibling donor versus no-donor comparison. Blood 2009; 113(6):1375-82.
  28. Gupta V, Richards S, Rowe J et al. Allogeneic, but not autologous, hematopoietic cell transplantation improves survival only among younger adults with acute lymphoblastic leukemia in first remission: an individual patient data meta-analysis. Blood 2013; 121(2):339-50.
  29. Gutierrez-Aguirre CH, Gomez-Almaguer D, Cantu-Rodriguez OG et al. Non-myeloablative stem cell transplantation in patients with relapsed acute lymphoblastic leukemia: results of a multicenter study. Bone Marrow Transplant 2007; 40(6):535-9.
  30. Mohty M, Labopin M, Tabrizzi R et al. Reduced intensity conditioning allogeneic stem cell transplantation for adult patients with acute lymphoblastic leukemia: a retrospective study from the European Group for Blood and Marrow Transplantation. Haematologica 2008; 93(2):303-6.
  31. Cho BS, Lee S, Kim YJ et al. Reduced-intensity conditioning allogeneic stem cell transplantation is a potential therapeutic approach for adults with high-risk acute lymphoblastic leukemia in remission: results of a prospective phase 2 study. Leukemia 2009; 23(10):1763-70.
  32. Pulsipher MA, Boucher KM, Wall D et al. Reduced-intensity allogeneic transplantation in pediatric patients ineligible for myeloablative therapy; results of the Pediatric Blood and Marrow Transplant coinsortium Study ONC0313. Blood 2009; 114(7): 1429-36.
  33. Blue Cross and Blue Shield Association Technology Evaluation Association (TEC). Salvage high-dose chenmotherapy with allogeneic stem-cell support for relapse or incomplete remission following high-dose chemotherapy with autologous stem-cell transplantation for hematologic malignancies. TEC Assessments. 2000; Volume 15, Tab 9.
  34. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. Non-Hodgkin’s Lymphoma (V.4.2011). Last accessed June 3, 2013.
  35. BlueCross BlueShield Association Medical Policy Reference Manual, Hematopoietic Stem-Cell Transplantation for Acute Lymphoblastic Leukemia. Medical Policy Reference Manual, Policy No. 8.01.32, 2013.
  36. Reviewed and recommended by the Oncology Advisory Panel on February 19, 2009; August 19, 2010; February 16, 2012.

Coding

Codes

Number

Description

CPT

38205

Blood-derived hematopoietic progenitor cell harvesting for transplantation, per collection; allogeneic

 

38206

Blood-derived hematopoietic progenitor cell harvesting for transplantation, per collection; autologous

 

38210

Transplant preparation of hematopoietic progenitor cells; specific cell depletion within harvest, T-cell depletion

 

38211

Transplant preparation of hematopoietic progenitor cells; tumor cell depletion

 

38212

Transplant preparation of hematopoietic progenitor cells; red blood cell removal

 

38213

Transplant preparation of hematopoietic progenitor cells; platelet depletion

 

38230

Bone marrow harvesting for transplantation

 

38240

Bone marrow or blood-derived peripheral stem cell transplantation; allogeneic

 

38241

autologous

 

86812

HLA typing; A, B, or C (e.g., A10, B7, B27, single antigen

 

86813

A, B, or C, multiple antigens

 

86816

DR/DQ, single antigen

 

86817

HLA typing; DR/DQ, multiple antigens

 

86821

lymphocyte culture, mixed (MLC)

 

86822

lymphocyte culture, primed (PLC)

 

86825

Human leukocyte antigen (HLA) crossmatch, non-cytotoxic (e.g., using flow cytometry); first serum sample or dilution

 

86826

Human leukocyte antigen (HLA) crossmatch, non-cytotoxic (e.g., using flow cytometry); each additional serum sample or sample dilution (List separately in addition to primary procedure)

ICD-9 Procedure

41.01

Autologous bone marrow transplant without purging

 

41.02

Allogeneic bone marrow transplant with purging

 

41.03

Allogeneic bone marrow transplant without purging

 

41.04

Autologous hematopoietic stem cell transplant without purging

 

41.05

Allogeneic hematopoietic stem cell transplant without purging

 

41.91

Aspiration of bone marrow from donor for transplant

 

99.79

Other therapeutic apheresis (includes harvest of stem cells)

ICD-9 Diagnosis

204.00

Acute lymphoblastic leukemia without mention of remission

 

204.01

in remission

HCPCS

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

ICD-10-CM
(effective 10/01/14)

C91.00 - C91.02

Acute lymphoblastic leukemia [ALL] code range

ICD-10-PCS
(effective 10/01/14)

30250G0, 30250X0,
30250Y0

Administration, circulatory, transfusion, peripheral artery, open, autologous, code by substance (bone marrow, cord blood or stem cells, hematopoietic)

 

30250G1, 30250X1,
30250Y1

Administration, circulatory, transfusion, peripheral artery, open, nonautologous, code by substance (bone marrow, cord blood or stem cells, hematopoietic)

 

30253G0, 30253X0,
30253Y0

Administration, circulatory, transfusion, peripheral artery, percutaneous, autologous, code by substance (bone marrow, cord blood or stem cells, hematopoietic)

 

30253G1, 30253X1,
30253Y1

Administration, circulatory, transfusion, peripheral artery, percutaneous, nonautologous, code by substance (bone marrow, cord blood or stem cells, hematopoietic)

 

6A550ZT, 6A550ZV

Extracorporeal Therapies, pheresis, circulatory, single, code by substance (cord blood, or stem cells, hematopoietic)

 

6A551ZT, 6A551ZV

Extracorporeal Therapies, pheresis, circulatory, multiple, code by substance (cord blood, or stem cells, hematopoietic)

Type of Service

Therapy

 

Place of Service

Inpatient
Outpatient

 

Appendix

N/A

History

Date

Reason

06/27/00

Add to Therapy Section - New Policy — replaces 8.01.15, original master policy on HDC for miscellaneous malignancies. However, policy statement is unchanged.

12/21/00

Replace Policy - Policy statement revised to state that allogeneic transplant after a prior failed autotransplant is considered investigational, based on 2000 Tec Assessment.

06/17/03

Replace Policy - Policy updated w/expanded rationale and new references; policy statement unchanged.

08/12/03

Replace Policy - Reviewed and recommended for adoption without any changes by Company Oncology Advisory Panel July 22, 2003.

12/14/04

Replace Policy - Policy reviewed w/literature search; update added on clinical trials and NCCN guidelines; policy statement unchanged.

01/10/06

Replace Policy - Policy reviewed with literature search; no change to policy statement.

06/02/06

Disclaimer and Scope update - No other changes

10/9/07

Replace Policy - Policy reviewed with BCBSA literature update through March 2007. NCI clinical trials updated; NCCN guidelines information unchanged. New references added; Policy statement unchanged.

11/12/07

Code updated - CPT code 86817 deleted as directed by RPIW.

05/13/08

New PR status - Policy statement regarding HDC and allogeneic SCT to treat relapsing ALL after a prior course of HDC and autologous SCT changed from investigational to medically necessary for children and adults. Reviewed and recommended by the OAP on February 21, 2008. Replaces BC.8.01.32, status changed from BC to PR.

05/12/09

Replace Policy - Policy revised with literature search. Clinical input received. New policy statement added that RIC allogeneic SCT may be considered medically necessary in select patients in complete remission. Policy titles changed to: “Hematopoietic Stem Cell Transplantation for Acute Lymphocytic Leukemia”. Reviewed and recommended by the OAP on February 19, 2009.

12/08/09

Code Update - 86817 added back to the policy.

02/09/10

Code Update - New 2010 codes added.

11/09/10

Replace Policy - Policy statement updated. Allogeneic HSCT considered medically necessary for any risk level in first complete remission. Updated with literature review and references. References added. Reviewed by the OAP on August 19, 2010.

09/15/11

Replace Policy – Policy updated with literature review; no change in policy statement.

03/23/12

Replace policy. Policy updated with literature review; no change in policy statement. References added, removed and reordered. Reviewed and recommended by OAP on February 16, 2012.

08/01/12

Update Related Policies Titles: 8.01.21, 8.01.22, 8.01.29, 8.01.30, 8.01.31, 8.01.35, 8.01.514. Policy 8.01.507 was changed to 8.01.17.

02/01/13

Update Related Policies, change title of policy 8.01.21.

03/20/13

The following codes were removed from the policy, as they were not suspending and just informational: HCPCS J9000-J9999 and Q0083 – Q0085.

07/24/13

Replace policy. Policy statements formatted for readability. References 13,22,34,28 added; others renumbered/removed. Policy statement unchanged.

09/30/13

Update Related Policies. Change title to policy 8.01.31.

10/18/13

Update Related Policies. Change title to policy 8.01.17.

12/03/13

Coding Update. Add ICD-10 codes.

02/27/14

Update Related Policies. Change title to 8.01.30.


Disclaimer: This medical policy is a guide in evaluating the medical necessity of a particular service or treatment. The Company adopts policies after careful review of published peer-reviewed scientific literature, national guidelines and local standards of practice. Since medical technology is constantly changing, the Company reserves the right to review and update policies as appropriate. Member contracts differ in their benefits. Always consult the member benefit booklet or contact a member service representative to determine coverage for a specific medical service or supply. CPT codes, descriptions and materials are copyrighted by the American Medical Association (AMA).
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