Archived Policies - Surgery


Hematopoietic Stem-Cell Transplantation for Acute Lymphoblastic Leukemia (ALL)

Number:SUR703.043

Effective Date:09-15-2015

End Date:06-30-2016

Coverage:

Childhood Acute Lymphoblastic Leukemia (ALL)

Autologous or allogeneic hematopoietic stem cell transplantation (HSCT) may be considered medically necessary to treat childhood acute lymphoblastic leukemia (ALL) in first complete remission but at high-risk (see *NOTE below) of relapse.

*NOTE: Several risk stratification schema exist, but, in general, the following findings help define children at high-risk of relapse:

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 6 weeks with high risk having ≥1% minimal residual disease measured by flow cytometry),

All children with T-cell phenotype, and

Patients with either the t(9;22) or t(4;11) regardless of early response measures.

Autologous or allogeneic HSCT may be considered medically necessary to treat childhood ALL in second or greater remission or refractory ALL.

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

Adult Acute Lymphoblastic Leukemia (ALL)

Autologous HSCT may be considered medically necessary to treat adult ALL in first complete remission but at high-risk of relapse (see **NOTE below).

**NOTE: Risk factors (or levels) for relapse are less well-defined in adults, but a patient with any of the following may be considered at high-risk for relapse:

Age greater than 35 years; or

Leukocytosis at presentation of >30,000/µL (B cell lineage) and >100,000/µL (T cell lineage); or

Poor prognosis” genetic abnormalities like the Philadelphia (Ph) chromosome (t(9;22)); or

Extramedullary disease; or

Time to attain complete remission > 4 weeks.

Allogeneic HSCT may be considered medically necessary to treat adult ALL in first complete remission for any risk factor/level (see **NOTE below).

**NOTE: Risk factors (or levels) for relapse are less well-defined in adults, but a 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 Ph chromosome (t(9;22)), extramedullary disease, and

Time to attain complete remission longer than 4 weeks.

Allogeneic HSCT may be considered medically necessary to treat adult ALL in second or greater remissions, or in patients with relapsed or refractory ALL.

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

Autologous HSCT is considered experimental, investigational and/or unproven to treat adult ALL in second or greater remission or those with refractory disease.

NOTE: For detailed, descriptive information on stem-cell support sources, harvesting, storage and infusion, preparative regimens, including high-dose chemotherapy and reduced intensity conditioning, tandem or triple stem-cell support, donor leukocyte infusion, hematopoietic progenitor cell boost (stem-cell boost), and short tandem repeat markers see Medical Policy SUR703.002, “Stem Cells Reinfusion or Transplantation Following Chemotherapy (General Donor and Recipient Information).”

Description:

Hematopoietic Stem-Cell Transplantation (HSCT)

HSCT refers to a procedure in which hematopoietic stem cells are infused to restore bone marrow function in patients who receive bone-marrow-toxic doses of cytotoxic drugs with or without whole body radiation therapy. Hematopoietic stem cells may be obtained from the transplant recipient (autologous HSCT) or from a donor (allogeneic HSCT). 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-versus-host disease (GVHD).

Immunologic compatibility between infused hematopoietic 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 class I and class II loci on 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).

Acute lymphoblastic leukemia (ALL)

ALL results from an acquired (not inherited) genetic injury to the DNA (Deoxyribonucleic acid) of a single cell in the bone marrow. The effects are:

The uncontrolled and exaggerated growth and accumulation of cells called "lymphoblasts" or "leukemic blasts," which fail to function as normal blood cells, and

The blockade of the production of normal marrow cells, leading to a deficiency of red cells (anemia), platelets (thrombocytopenia), and normal white cells (especially neutrophils, i.e., neutropenia) in the blood.

ALL occurs in multiple forms that vary with regard to cellular morphology, cytochemistry, immunophenotype, cytogenetic abnormalities, and other prognostic features. Although adult and childhood forms of ALL vary in the distribution of these prognostic features, there is considerable overlap, particularly among late adolescents and young adults.

Childhood ALL

ALL is the most common cancer diagnosed in children and represents nearly 25% of cancers in children younger than 15 years. (1) Complete remission (CR) of disease is now typically achieved with pediatric chemotherapy regimens in approximately 95% of children with ALL, 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) The prognosis after first relapse is related to the length of the original remission. For example, leukemia-free survival is 40% to 50% for children whose first remission was longer than 3 years, compared with only 10% to 15% for those who relapse less than 3 years following treatment. 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.

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 (WBC) count at diagnosis. (3) Certain genetic characteristics of the leukemic cells strongly influence prognosis. Clinical and biologic factors predicting clinical outcomes Clinical and biologic factors predicting clinical outcome can be summarized as follows (2):

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% to 80% of adults with ALL can be expected to achieve CR after induction chemotherapy; however, only 35% to 40% can be expected to survive 2 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 such as 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 such as the Philadelphia chromosome (t[9;22]) are seen in 25% to 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 greater than 30,000/μL (B-cell lineage) or greater than 100,000/μL (T-cell lineage).

NOTE: For additional definitions of evaluations or treatments, and general information other than the specific disease or condition listed in this policy, please see Medical Policy SUR703.002, “Stem Cells Reinfusion or Transplantation Following Chemotherapy (General Donor and Recipient Information).”

Rationale:

This policy was originally created in 1990, moved to this policy in 2010. The policy has been updated with reviews of the MedLine database. The most recent literature review was performed through May 2015. While the coverage of this policy does not address myeloablative (MA) or reduced intensity conditioning (RIC) prior to hematopoietic stem-cell transplantation (HSCT), discussion of HSCT outcomes maybe influenced by the type of preparative conditioning completed prior to the transplantation. The following is a summary of the key literature to date.

Childhood Acute Lymphoblastic Leukemia (ALL)

The policy on childhood ALL was initially based on Blue Cross Blue Shield Association (BCBSA) Technology Evaluation Center (TEC) Assessments completed in 1987 and 1990. (5, 6) In childhood ALL, conventional chemotherapy is associated with complete remission (CR) rates of approximately 95%, with long-term durable remissions up to 85%. Therefore, for patients in a first complete remission (CR1), HSCT is considered only in those with unfavorable risk factors predictive of relapse (explained in the Description section of this policy).

Three reports that describe the results of randomized controlled trials (RCTs) that compared outcomes of HSCT with outcomes with conventional-dose chemotherapy in children with ALL were identified subsequent to the BCBSA TEC Assessment. (7-9) The children enrolled in the RCTs were being treated for high-risk ALL in CR1 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 CR1 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 (DFS) or overall survival rates (OS) 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, several study limitations that could have affected outcomes include the relatively small numbers of patients; variations among centers in the preparative regimen used before 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.

Conclusion

Clinical evidence and reviews of studies (11, 12) suggest that while OS and event-free survival (EFS) are not significantly different after HSCT compared with conventional-dose chemotherapy, HSCT remains a therapeutic option in the management of childhood ALL, especially for patients considered at high-risk of relapse or following relapse. This conclusion is further supported by a 2012 evidence-based systematic review of the literature sponsored by the American Society for Blood and Marrow Transplantation (ASBMT). (13) 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 in part on a 1997 BCBSA TEC Assessment of autologous (not allogeneic) HSCT. (16) This Assessment offered the following conclusions:

For patients in CR1, available evidence suggested survival was equivalent after autologous HSCT or conventional-dose chemotherapy. For these patients, the decision between autologous HSCT and conventional chemotherapy may reflect a choice between intensive therapy of short duration and longer but less-intensive treatment.

In other settings, such as in second complete remission (CR2) or subsequent remissions, evidence was inadequate to determine the relative effectiveness of autologous HSCT compared with conventional chemotherapy.

Systematic Reviews and Meta-Analyses

A meta-analysis published in 2006 pooled evidence from 7 studies of allogeneic HSCT published between 1994 and 2005 that included a total of 1274 patients with ALL in CR1. (17) The results showed that regardless of risk category, allogeneic HSCT was associated with a significant OS advantage (hazard ratio [HR], 1.29; 95% confidence interval [CI], 1.02 to 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 evidence from patients with high-risk disease showed an increased survival advantage for allogeneic HSCT compared with those without a donor (HR=1.42; 95% CI, 1.06 to 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.

An evidence-based systematic review sponsored by ASBMT in 2006 addressed the issue of HSCT in adults with ALL. (18) 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 evidence is not available to directly compare outcomes with alternatives. Based on results from 3 RCTs (19-21) the ASBMT panel further concluded that myeloablative allogeneic HSCT is superior to autologous HSCT in adult patients in CR1, although available evidence did not permit separate analyses in high-risk versus low-risk patients.

A meta-analysis from the Cochrane group in 2011 evaluated the evidence for the efficacy of matched sibling stem cell donor versus no donor status for adults with ALL in CR1. (22) A total of 14 trials with treatment assignment based on genetic randomization including a total of 3157 patients were included in this analysis. Matched sibling donor HSCT was associated with a statistically significant OS advantage compared with the no donor group (HR=0.82; 95% CI, 0.77 to 0.97; p=0.01). Patients in the donor group had a significantly lower rate of primary disease relapse than those without a donor (risk ratio [RR]=0.53; 95% CI, 0.37 to 0.76; p<0.001) and significantly increased NRM (RR=2.8; 95% CI, 1.66 to 4.73; p=0.001). These results support the conclusions of this policy, that allogeneic HSCT (matched sibling donor) is an effective postremission therapy in adult patients.

In 2012, ASBMT published an update to the 2006 guidelines for treatment of ALL in adults. (13) An electronic search of the literature 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 MA 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 postremission 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.

An individual patient data meta-analysis published in 2013 included 13 studies (total N=2962), several of which are compiled in this policy. (23) The results suggest that a matched sibling donor MA HSCT improves survival only for younger adults (<35 years old) in CR1 compared with chemotherapy, with an absolute benefit of 10% at 5 years. The analysis also suggests a trend toward inferior OS among autologous HSCT recipients compared with chemotherapy in CR1 (odds ratio [OR], 1.18; 95% CI, 0.99 to 1.41; p=0.06), primarily due to higher transplant-related mortality (TRM) in the autograft patients compared with chemotherapy recipients. This result does not change the conclusions of this policy but indicates further study is needed to determine the optimal therapy for adult ALL patients.

Clinical Studies

Results that partially conflicted with ASBMT conclusions in 2006 were obtained in a multicenter (35 Spanish hospitals) randomized trial (PETHEMA ALL-93; N=222) published after the ASBMT literature search. (24) Among 183 high-risk patients in CR1, those with a human leukocyte antigen (HLA)?identical family donor were assigned to allogeneic HSCT (n=84); the remaining cases were randomly assigned to autologous HSCT (n=50) or to delayed intensification followed by maintenance chemotherapy up to 2 years in CR (n=48). At median follow-up of 70 months, the study did not detect a statistically significant difference in outcomes between all 3 arms by both PP and ITT analyses. The PETHEMA ALL-93 trial investigators 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 before 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.

While the utility of allogeneic HSCT for postremission 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 Medical Research Council (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 3 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 RCT in which all patients (total N=1913) 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, OS at 5-year follow-up of all 1913 patients was 39%; it reached 53% for Ph-negative patients with a donor (n=443) compared with 45% without a donor (n=588) (p=0.01). (25) Analysis of Ph-negative patient outcomes according to disease risk showed a 5-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-year 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 compared with 49% among those who did not undergo HSCT (p<0.001). Among Ph-negative patients with high-risk ALL, the rate of relapse at 10-year follow-up was 37% following allogeneic HSCT versus 63% without a transplant (p<0.001), demonstrating the potent graft-versus-leukemia (GVL) effect in an allogeneic transplantation. This evidence clearly shows a significant long-term survival benefit associated with postremission 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 1 and 2 years, mostly due to graft-versus-host-disease (GVHD) and infections. At 2 years, NRM was 36% among high-risk patients with a donor compared with 14% among those who did not have a donor. Among standard-risk cases, the NRM rate at 2 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 5-year OS of 34% (95% CI, 25% to 46%) for those who had a matched sibling donor versus 25% (95% CI, 12% to 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 2 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. 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 5-year follow-up among all patients was 24% (SE=4%) in those with a donor versus 55% (SE=4%) 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 5-year OS of 69% ± 7% and relapse rate at 5 years of 14%±5% compared with 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 5-year OS of 53%±8% and relapse at 5 years of 34%±7%, versus 41%±8% and 61%±7%, respectively, among those with no donor (n=3; 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 before 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 5-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)

Conclusion

Current evidence indicates postremission MA autologous or allogeneic HSCT is an effective therapeutic option for a large proportion of adults with ALL in CR1. However, the increased morbidity and mortality from GVHD limit use of allogeneic HSCT, particularly for older patients. For adults who survive the procedure, there is a significant relapse rate. Notwithstanding those caveats, taken together, current evidence and clinical guidelines support the use of autologous HSCT for adult patients with high-risk ALL in CR1, or MA allogeneic HSCT for adult patients with any risk level ALL, whose health status is sufficient to tolerate the procedure.

Allogeneic Transplant after Prior Failed Autologous Transplant

A 2000 BCBSA TEC Assessment focused on allogeneic HSCT, after a prior failed autologous HSCT, in the treatment of a variety of malignancies, including ALL. (28) The TEC Assessment found that evidence was 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 strong evidence to permit conclusions on this use of HSCT.

Ongoing and Unpublished Clinical Trials

A search of ClinicalTrials.gov in April 2015 did not identify any ongoing or unpublished phase 3 RCTs in adults or pediatric patients that would likely influence this policy.

Clinical Input Received Through Physician Specialty Societies and Academic Medical Centers

During the 2013 update by Blue Cross Blue Shield Association (BCBSA), they requested and received clinical input from 2 academic medical centers, 1 medical society, and 3 physicians from Blue Distinction Centers. In general, clinical input supported most existing coverage statements. However, most reviewers disagreed that allogeneic HSCT is considered investigational to treat relapsing ALL after a prior autologous HSCT in either children or adults.

Clinical Guidelines and Trials for Childhood and Adult ALL:

National Comprehensive Cancer Network (NCCN) Guidelines

The latest NCCN clinical practice guidelines for ALL indicate allogeneic HSCT is appropriate for consolidation treatment of most poor-risk (e.g., Ph1+, relapsed or refractory) patients with ALL. (29) These guidelines are silent on the use of autologous HSCT, but are otherwise generally consistent with this policy. However, NCCN guidelines now stratify treatment according to the categories adolescent and young adult (age 15-39 years) and adult (≥age 40 years), rather than in more traditional children (≤18 years) and adult categories (≥18 years).

Summary

Clinical study results previously summarized suggest that while OS and EFS are not significantly different after autologous HSCT compared with conventional-dose chemotherapy in most children with standard-risk ALL, HSCT remains a 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.

Evidence indicates postremission MA 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. 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.

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 received in 2013 by BCBSA supports this use, particularly with RIC regimens, in adults or children.

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:

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, 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 have a national Medicare coverage position.

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

References:

1. PDQ – Physician Data Query (PDQ®). Childhood acute lymphoblastic leukemia. (2012, updated 2015 May 20). National Cancer Institute. Available online at <http://www.cancer.gov> (accessed 2015 June 18).

2. Pieters R, Carroll WL. Biology and treatment of acute lymphoblastic leukemia. Pediatr Clin North Am. Feb 2008; 55(1):1-20, ix. PMID 18242313

3. Carroll WL, Bhojwani D, Min DJ, et al. Pediatric acute lymphoblastic leukemia. Hematology Am Soc Hematol Educ Program. 2003:102-31. PMID 14633779

4. PDQ – Physician Data Query (PDQ®). Adult acute lymphoblastic leukemia. (2012, updated 2015 April 17). National Cancer Institute. Available online at <http://www.cancer.gov> (accessed 2015 June 18).

5. Autologous Bone Marrow Transplantation in Acute Lymphocytic and Non-Lymphocytic Leukemia Chicago, Illinois: Blue Cross Blue Shield Association – Technology Evaluation Center (1987 November):243-57.

6. High-Dose Chemotherapy with Autologous Bone Marrow Transplantation for Acute Lymphocytic and Non-Lymphocytic Leukemia in the First Remission. Chicago, Illinois: Blue Cross Blue Shield Association – Technology Evaluation Center (1990 November):264-73.

7. Harrison G, Richards S, et al. Comparison of allogeneic transplant versus chemotherapy for relapsed childhood acute lymphoblastic leukaemia in the MRC UKALL R1 trial. Ann Oncol. Aug 2000; 11(8):999-1006. PMID 11038037

8. Lawson SE, Harrison G, 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. Mar 2000; 108(3):531-43. PMID 10759711

9. Wheeler KA, Richards SM, 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. Oct 1 2000; 96(7):2412-8. PMID 11001892

10. Ribera JM, Ortega JJ, 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. Jan 1 2007; 25(1):16-24. PMID 17194902

11. Uderzo, C. Indications and role of allogeneic bone marrow transplantation in childhood very high risk acute lymphoblastic leukemia in first complete remission. Haematologica. Nov 2000; 85(11 suppl):9-11. PMID 11268333

12. Uderzo C, Dini G, et al. Treatment of childhood acute lymphoblastic leukemia after the first relapse: curative strategies. Haematologica. Nov 2000; 85(11 suppl):47-53. PMID 11268324

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. Apr 2012; 18(4):505-22. PMID 22209888

14. Gaynon PS, Trigg ME, et al. Children’s Cancer Group trials in childhood acute lymphoblastic leukemia: 1983-1995. Leukemia. Dec 2000; 14(12):2223-33. PMID11187913

15. Oyekunle A, Haferlach T, Kroger N, et al. Molecular Diagnostics, Targeted Therapy, and the Indication for Allogeneic Stem Cell Transplantation in Acute Lymphoblastic Leukemia. Adv Hematol 2011; 2011:154745. PMID22110503

16. High-Dose Chemotherapy with Autologous Stem-Cell Support in the Treatment of Adult Acute Lymphoblastic Leukemia. Chicago, Illinois: Blue Cross Blue Shield Association – Technology Evaluation Center Assessment Program (1998 January) 12(25):1-25.

17. 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: a metaanalysis. Cancer. Jun 15 2006; 106(12):2657-63. PMID 16703597

18. Hahn T, Wall D, 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. Jan 2006; 12(1):1-30. PMID 16399566

19. Attal M, Blaise D, 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. Aug 15 1995; 86(4):1619-28. PMID 7632972

20. Dombret H, Gabert J, et al. Outcome of treatment in adults with Philadelphia chromosome-positive acute lymphoblastic leukemia–results of the prospective multicenter LALA-94 trial. Blood. Oct 1 2002; 100(7):2357-66. PMID 12239143

21. Hunault M, Harousseau JL, 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. Nov 15 2004; 104(10):3028-37. PMID 15256423

22. 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. PMID 21975786

23. 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. Jan 10 2013; 121(2):339-50. PMID 23165481

24. Ribera JM, Oriol A, et al. Comparison of intensive chemotherapy, allogeneic or autologous stem cell transplantation as post-remission treatment for adult patients with high-risk acute lymphoblastic leukemia. Results of the PETHEMA ALL-93 trial. Haematologica. Oct 2005; 90(10):1346-56. PMID 16219571

25. Goldstone AH, Richards SM, Lazarus HM, et al. In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood. Feb 15 2008; 111(4):1827-33. PMID 18048644

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. May 7 2009; 113(19):4489-96. PMID 19244158

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. Feb 5 2009; 113(6):1375-82. PMID 18988865

28. Salvage HDC/AlloSCS for Relapse or Incomplete Remission Following HDC/AuSCS for Hematologic Malignancies. Chicago, Illinois: Blue Cross Blue Shield Association – Technology Evaluation Center. (2000 August) Tab 9.

29. NCCN –Acute Lymphoblastic Leukemia. NCCN Clinical Practice Guidelines in Oncology. National Comprehensive Cancer Network. Version.2.2014. Available at <http://www.nccn.org> (accessed on 2015 June 18).

30. Hematopoietic Stem-Cell Transplantation for Acute Lymphoblastic Leukemia. Chicago Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (2015 January) Therapy 8.01.32.

Policy History:

Date Reason
9/15/2015 Document updated with literature review. The following coverage changed for children and adults was: “Allogeneic HSCT may be considered medically necessary to treat relapsing ALL after a prior autologous HSCT.” Title changed from Stem-Cell Transplant for Acute Lymphoblastic Leukemia (ALL).
6/1/2014 Document updated with literature review. The following was added: 1) expanded coverage to consider a) donor leukocyte infusion (DLI) as medically necessary for childhood acute lymphoblastic leukemia (ALL) that has relapsed following an AlloSCS procedure, to prevent relapse in the setting of a high-risk relapse, or to convert a patient from mixed to full chimerism; b) DLI is considered experimental, investigational and/or unproven following an AlloSCS treatment for childhood ALL that was originally considered experimental, investigational and/or unproven for the treatment of childhood ALL OR as a treatment prior to AlloSCS; 2) Expanded coverage as follows a) donor leukocyte infusion (DLI) and hematopoietic progenitor cell (HPC) boost may be considered medically necessary for adult ALL that has relapsed following an AlloSCS procedure, to prevent relapse in the setting of a high-risk relapse, or to convert a patient from mixed to full chimerism; b) DLI and HPC boost are considered experimental, investigational and/or unproven following an AlloSCS treatment for adult ALL that was originally considered experimental, investigational and/or unproven for the treatment of adult ALL OR as a treatment prior to AlloSCS and 3) Expanded coverage as follows a) short tandem repeat (STR) markers may be considered medically necessary when used in pre- or post-stem-cell support testing of the donor and recipient DNA profiles as a way to assess the status of donor cell engraftment following AlloSCS for ALL; b) all other uses of STR markers are considered experimental, investigational and /or unproven, if not listed in the coverage section . Title changed from Stem-Cell Transplant for Acute Lymphocytic Leukemia (ALL). Description and Rationale substantially revised.
4/1/2010 New medical document originating from: SUR703.017, Peripheral/Bone Marrow Stem Cell Transplantation (PSCT/BMT) for Non-Malignancies; SUR703.018, Peripheral/Bone Marrow Stem Cell Transplantation (PSCT/BMT) for Malignancies; SUR703.022, Cord Blood as a Source of Stem Cells (CBSC); SUR703.023, Donor Leukocyte Infusion (DLI); and SUR703.024, Tandem/Triple High-Dose Chemoradiotherapy with Stem Cell Support for Malignancies. Stem cell transplant continues to be medically necessary when stated criteria are met. [NOTE: A link to the medical policies with the following titles can be found at the end of the medical policy SUR703.002, Stem-Cell Reinfusion or Transplantation Following Chemotherapy (General Donor and Recipient Information): Peripheral/Bone Marrow Stem Cell Transplantation (PSCT/BMT) for Non-Malignancies; Peripheral/Bone Marrow Stem Cell Transplantation (PSCT/BMT) for Malignancies; Cord Blood as a Source of Stem Cells; Donor Leukocyte Infusion (DLI); and Tandem/Triple High-Dose Chemoradiotherapy with Stem Cell Support for Malignancies.

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