Medical Policies - Surgery


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

Number:SUR703.043

Effective Date:06-15-2018

Coverage:

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

Childhood Acute Lymphoblastic Leukemia (ALL)

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

In the first complete remission but at high-risk (see NOTE 1 below) of relapse; or

In the second or greater remission or refractory ALL.

NOTE 1: Several risk stratification schema exist, but, in general, with any of 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, or

All children with T-cell phenotype, or

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

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

Adult Acute Lymphoblastic Leukemia (ALL)

Autologous HSCT to treat adult ALL may be considered medically necessary in first complete remission but at high-risk of relapse (see NOTE 2 below).

NOTE 2: 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.

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

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

In the first complete remission for any risk factor/level (see NOTE 3 below); or

In the second or greater remissions, or in patients with relapsed or refractory ALL.

NOTE 3: 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), or

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

Time to attain complete remission longer than 4 weeks.

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

NOTE 4: See Medical Policy SUR703.002 Hematopoietic Stem-Cell Transplantation (HSCT) or Additional Infusion Following Preparative Regimens (General Donor and Recipient Information) for detailed, descriptive information on HSCT related services.

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 is a heterogeneous disease with different genetic variations resulting in distinct biologic subtypes. Patients are stratified to risk-adapted therapy according to certain clinical and genetic risk factors that predict outcome. Therapy may include HSCT.

Childhood ALL

ALL is the most common cancer diagnosed in children; it 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 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 to only 10% to 15% for those who relapse less than 3 years after treatment. Thus, HSCT may be a strong consideration in those with short remissions. At present, the comparative outcomes with autologous or allogeneic HSCT are unknown. 

ALL is a heterogeneous disease with different genetic variations resulting in distinct biologic subtypes. Patients are stratified by 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 at diagnosis. (3) Certain genetic characteristics of leukemic cells strongly influence prognosis. Clinical and biologic factors predicting clinical outcomes and relapse risk are summarized as follows (2):

FACTOR

FAVORABLE

UNFAVORABLE

Age at Diagnosis

1-9 years

<1 or >9 years

Sex

Female

Male

White Blood Cell 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 20% of acute leukemias in adults. Between 60% and 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, explain differences in outcomes between the 2 groups. For example, the “good prognosis” genetic abnormalities, such as hyperdiploidy and translocation of chromosomes 12 and 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 (translocation of chromosomes 9 and 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).

Regulatory Status

The U.S. Food and Drug Administration (FDA) regulates human cells and tissues intended for implantation, transplantation, or infusion through the Center for Biologics Evaluation and Research (CBER), under Code of Federal Regulation (CFR) title 21, parts 1270 and 1271. (29) Hematopoietic stem-cells are included in these regulations.

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 April 17, 2017. 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 for those with unfavorable risk factors predictive of relapse (explained in the Description section of this policy).

Three randomized controlled trials (RCTs) comparing 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 these RCTs were being treated for high-risk ALL in CR1 or for relapsed ALL. These trials 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 2007 randomized trial (PETHEMA ALL-93; N=106) demonstrated no significant differences in disease-free survival or overall survival (OS) rates at a median follow-up of 78 months in children with very high-risk ALL in CR1 who received allogeneic (allo-) or autologous HSCT or standard chemotherapy with maintenance treatment. (10) Similar results were observed using intention-to-treat (ITT) or per-protocol analyses. However, several limitations could have affected outcomes: the relatively small numbers of patients, variations across centers in the preparative regimen used before HSCT and time elapsed between CR and undertaking of assigned treatment, and use of genetic randomization based on donor availability rather than true randomization for patients in the allo-HSCT arm.

A 2012 systematic evidence-based review of the literature and position statement by the American Society for Blood and Marrow Transplantation (ASBMT) evaluated the role of cytotoxic therapy with HSCT for pediatric ALL. (11) The systematic review identified 10 studies comparing HSCT with chemotherapy for patients in CR1, including the PETHEMA trial. Reviewers identified a subset of patients at high-risk for whom allo-HSCT would be indicated. Reviewers also identified 12 studies comparing HSCT with chemotherapy for patients in CR2 or beyond, or relapsed disease.

Section Summary: Childhood Acute Lymphoblastic Leukemia (ALL)

While the risks of treatment-related mortality do not outweigh the OS benefit in all patients, as demonstrated by RCT evidence, in some patients (e.g., those at very high-risk of relapse or following relapse HSCT), HSCT remains a therapeutic option to manage childhood ALL.

Adult ALL

The policy on adult ALL was initially based in part on a 1997 BCBSA TEC Assessment of autologous (not allogeneic) HSCT. (12) 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, the evidence was inadequate to determine the relative effectiveness of autologous HSCT compared with conventional chemotherapy.

Systematic Reviews

A 2006 meta-analysis pooled evidence from 7 studies of allo-HSCT published between 1994 and 2005 that included a total of 1274 patients with ALL in CR1. (13) Results showed that, regardless of risk category, allo-HSCT was associated with a significantly longer OS (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 allo-HSCT compared to those without a donor (HR=1.42; 95% CI, 1.06 to 1.90; p=0.019). 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.

In 2012, ASBMT updated its 2005 guidelines for treatment of ALL in adults, covering literature to mid-October 2010. (11) The evidence available at that time supported a grade A treatment recommendation (at least 1 meta-analysis, systematic review, or RCT) that myeloablative allo-HSCT would be an appropriate treatment for adult ALL in CR1 for all risk groups. Further, ASBMT indicated a grade A treatment recommendation for autologous HSCT in patients who did not have a suitable allogeneic stem cell donor; ASBMT suggested that although survival outcomes appeared similar between autologous HSCT and postremission chemotherapy, the shorter treatment duration with the former is an advantage. Finally, ASBMT concluded that allo-HSCT was recommended over chemotherapy for adults with ALL in CR2 or beyond.

In an earlier review (2006), ASBMT had reviewed evidence through January 2005 on HSCT in adults with ALL and recommended HSCT as consolidation therapy for adults with high-risk disease in CR1 but not for standard-risk patients and for patients in CR2. (14) Based on results from 3 RCTs, (15-17) ASBMT further concluded that myeloablative allo-HSCT is superior to autologous HSCT in adult patients in CR1, although available evidence did not permit separate comparisons of high-risk versus low-risk patients.

A 2013 individual patient data meta-analysis included 13 studies (total N=2962 patients), several of which are evaluated herein. (18) Results suggested that matched sibling donor myeloablative HSCT improved 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 suggested a trend toward inferior OS among autologous HSCT recipients compared to 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 in the autograft patients than in chemotherapy recipients. The results did not change the conclusions of the policy, but indicate further study is needed to determine the optimal therapy for adult ALL patients.

Randomized Controlled Trials (RCTs)

In 2005, Ribera et al. reported results from the multicenter (35 Spanish hospitals), randomized PETHEMA ALL-93 trial (N=222 patients), which was published after the ASBMT literature search. (19) Among 183 high-risk patients in CR1, those with a human leukocyte antigen (HLA)-identical family donor were assigned to allo-HSCT (n=84); the remaining cases were randomly assigned to autologous HCT (n=50) or to delayed intensification followed by maintenance chemotherapy up to 2 years in CR (n=48). At a 70-month median follow-up, the trial did not detect a statistically significant difference in outcomes among all 3 arms by per-protocol or ITT analyses. PETHEMA ALL-93 trial investigators pointed out several factors that could have affected outcomes: relatively small numbers of patients; variations among centers in the preparative regimen used before HSCT; differences in risk group assignment; and use of genetic randomization based on donor availability rather than true randomization for patients included in the allo-HSCT arm.

While the utility of allo-HSCT for post-remission therapy in patients with high-risk ALL has been established, its role in standard-risk patients 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 2993). (20) The ECOG 2993 trial was a phase 3 randomized study designed to prospectively define the role of myeloablative allo-HSCT, autologous HSCT, and conventional consolidation and maintenance chemotherapy for adults up to age 60 years with ALL in CR1. This 2008 trial is the largest RCT in which all patients (N=1913) received essentially identical therapy, regardless 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 allo-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 randomized to a single autologous HSCT or consolidation and maintenance chemotherapy.

In ECOG 2993, 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). (20) Analysis of Ph-negative patient outcomes by 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 allo-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 allo-HSCT versus 63% without a transplant (p<0.001), demonstrating the potent graft-versus-leukemia (GVL) effect in an allogeneic transplantation. This evidence clearly showed a significant long-term survival benefit associated with postremission allo-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 non-relapse 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 rates at 2 years were 20% in patients who underwent allo-HSCT and 7% in those who received autologous HSCT or continued chemotherapy.

In a separate 2009 report on the Ph-positive patients in the ECOG 2993 trial, ITT analysis (N=158) showed 5-year OS rates of 34% (95% CI, 25% to 46%) for those who had a matched sibling donor and 25% (95% CI, 12% to 34%) for those with no donor who received consolidation and maintenance chemotherapy. (21) Although the difference in OS rates was not statistically significant, this analysis demonstrated a moderate superiority of post-remission-matched sibling allo-HCT over chemotherapy in patients with high-risk ALL in CR1, in concordance with this policy.

The Dutch-Belgian HOVON Cooperative Group (2009) reported results combined from 2 successive randomized trials in previously untreated adults with ALL ages 60 years or younger, in whom myeloablative allo-HSCT was consistently used for all who achieved CR1 and who had an HLA-matched sibling donor, irrespective of risk category. (22) The 433 eligible patients included 288 who were younger than 55 years, in CR1, and eligible to receive consolidation treatment using autologous HSCT or allo-HSCT. Allo-HSCT was performed in 91 (95%) of 96 with a compatible sibling donor. OS rates at 5-year follow-up were 61% among all patients with a donor and 47% among those without a donor (p=0.08). The cumulative incidences of relapse at 5-year follow-up among all patients were 24% in those with a donor and 55% 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 rate of 69% and a relapse rate at 5 years of 14% compared with 49% and 52%, respectively, among those (n=88) without a donor (p=0.05). High-risk patients with a donor (n=46) had a 5-year OS rate of 53% and relapse rate at 5 years of 34% versus 41% and 61%, respectively, among those with no donor (n=3; p=0.50). NRM rates among standard-risk patients were 16% among those with a donor and 2% among those without a donor; in high-risk patients, NRM rates were 15% and 4%, respectively, among those with and without a donor.

The HOVON data were analyzed from remission evaluation before consolidation whereas the ECOG 2993 data were analyzed from diagnosis, which complicates direct comparison of their outcomes. To facilitate a meaningful comparison, the HOVON data were reanalyzed by donor availability from diagnosis. This reanalysis showed a 5-year OS rate of 60% in standard-risk patients with a donor in the HOVON trial, which is very similar to the 62% OS rate observed in standard-risk patients with a donor in the ECOG 2993 trial. Collectively, these results suggest that patients with standard-risk ALL can expect to benefit from allo-HCT in CR1, provided the NRM risk is less than 20% to 25%. (22)

Observational Studies

Several studies published in 2016 have evaluated changes in survival rates over time. A 2017 multicenter clinical trial from Europe reported on 4859 adults with ALL in first remission treated with allo-HSCT from either a matched sibling donor (n=2681) or an unrelated donor (n=2178). (23) Survival rates generally improved over time (i.e., from 1993-2002 to 2008-2012). For the time period 2008 to 2012, 2-year OS rates after matched sibling donor HSCT were 76% for 18- to 25-year-olds, 69% for 26- to 35-year-olds and 36- to 45-year-olds, and 60% for 46- to 55-year-olds. During that time period, 2-year OS rates after unrelated donor HSCT were 66% for 18- to 25-year-olds, 70% for 26- to 35-year-olds, 61% for 36- to 45-year-olds, and 62% for 46- to 55-year-olds. Also, in 2016, Dinmohamed et al. reviewed survival trends among adults with ALL who underwent HSCT between 1989 and 2012.24 Data were available on 1833 patients. Survival rates increased significantly over time in all age groups (18-24, 25-39, 40-59, 60-69, and ≥70 years old). For the most recent time period (2007-2012), 5-year relative survival rates by age group were 75%, 57%, 37%, 22%, and 5%, respectively.

Section Summary: Adult ALL

The evidence indicates post-remission myeloablative autologous or allo-HSCT is an effective therapeutic option for a large proportion of adults with ALL in CR1. However, the increased mortality and morbidity from GVHD limit use of allo-HSCT, particularly for older patients. For adults who survive HSCT, there is a significant relapse rate. The current evidence support the use of autologous HSCT for adults with high-risk ALL in CR1, or myeloablative allo-HSCT for adults with any risk level ALL, whose health status is sufficient to tolerate the procedure.

Donor Source

A 2011 Cochrane review evaluated the evidence for the efficacy of matched sibling stem-cell donor versus no donor status for adults with ALL in CR1. (25) Fourteen trials with treatment assignment based on genetic randomization (total N=3157 patients) were included. 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 (relative risk [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 allo-HSCT (matched sibling donor) is an effective post-remission therapy in adults.

Allogeneic Transplant after Prior Failed Autologous Transplant

A 2000 BCBSA TEC Assessment focused on allo-HSCT, after a failed autologous HSCT, in the treatment of a variety of malignancies, including ALL. (26) The BCBSA TEC Assessment found the evidence inadequate to permit conclusions about outcomes of this treatment strategy. Published evidence was limited to small, uncontrolled clinical series with short follow-up. Subsequent literature searches have not identified strong evidence to permit conclusions on this use of HSCT.

Section Summary: Allogeneic Transplant After Failed Autologous Transplant

Small uncontrolled case series with short-term follow-up are inadequate to draw conclusions on the effect of all-HSCT after a failed HSCT on health outcomes in patients with ALL.

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 allo-HSCT is considered investigational to treat relapsing ALL after a prior autologous HSCT in either children or adults.

Ongoing and Unpublished Clinical Trials: Childhood and Adult ALL

Some currently unpublished trials that might influence this review are listed in Table 1.

Table 1. Summary of Key Trials

NCT Number

Trial Name

Planned Enrollment

Completion Date

Ongoing

NCT02042690

Haplo-identical HSCT Versus Chemotherapy for Adult Acute Lymphoblastic Leukemia Patients

300

Dec 2018

NCT01700946

Therapy for Pediatric Relapsed or Refractory Precursor B-Cell Acute Lymphoblastic Leukemia and Lymphoma

40

Oct 2021

Table Key:

NCT: National Clinical Trial.

Practice Guidelines and Position Statements: Childhood and Adult ALL

National Comprehensive Cancer Network (NCCN) Guidelines

Current NCCN guidelines (v.2.2016) for ALL indicate allo-HSCT is appropriate for consolidation treatment of most poor risk (e.g., the Ph chromosome-positive, relapsed or refractory) patients with ALL. (27) The guidelines do not include specific recommendations on the use of autologous HSCT. In addition, the guidelines note that chronologic age is not a good surrogate for fitness for therapy and that the patient should be evaluated on an individual basis.

American Society for Blood and Marrow Transplantation (ASBMT)

In 2015, guidelines from the ASBMT were published for autologous and allogeneic HSCT. Recommendations were intended to describe the current consensus on use of HSCT within and outside of the clinical trial setting. (28) Recommendations on ALL are listed in Table 2.

Table 2. ASBMT Guidelines for Autologous and Allogeneic HSCT

Indication

Allogeneic HSCT

Autologous HSCT

First complete response, standard-risk

Not Generally Recommended

Not Generally Recommended

First complete response, high-risk

Standard of Care

Not Generally Recommended

Second complete response

Standard of Care

Not Generally Recommended

At least third complete response

Clinical Evidence Available

Not Generally Recommended

Not in remission

Clinical Evidence Available

Not Generally Recommended

Table Key:

ASBMT: American Society for Blood and Marrow Transplantation;

HSCT: hematopoietic stem-cell transplantation.

Summary of Evidence

For individuals who have childhood acute lymphoblastic leukemia (ALL) in first complete remission (CR1) at high-risk of relapse, subsequent remission, or refractory ALL who receive autologous or allogeneic hematopoietic stem-cell transplantation (HSCT), the evidence includes randomized controlled trials (RCTs) and systematic reviews. Relevant outcomes are overall survival, disease-specific survival, and treatment-related mortality and morbidity. For children with high-risk ALL in CR1 or with relapsed ALL, studies have suggested that HSCT is associated with fewer relapses but higher death rates due to treatment-related toxicity. However, for a subset of high-risk patients in second complete remission or beyond or with relapsed disease, HSCT is a treatment option. This conclusion is further supported by an evidence-based systematic review and position statement from the American Society for Blood and Marrow Transplantation. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have adult ALL in first complete remission or subsequent remission, or refractory ALL who receive autologous or allogeneic HSCT, the evidence includes RCTs and systematic reviews. Relevant outcomes are overall survival, disease-specific survival, and treatment-related mortality and morbidity. Current evidence supports the use of autologous HSCT for adults with high-risk ALL in first complete remission, or myeloablative allogeneic HCT (allo-HSCT) for adults with any risk level ALL, whose health status is sufficient to tolerate the procedure. Reduced-intensity conditioning (RIC) allo-HSCT may be considered for patients who demonstrate complete marrow and extramedullary first or second remission and who could be expected to benefit from a myeloablative allo-HSCT, but for medical reasons would not tolerate a myeloablative conditioning regimen. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have relapse after a prior autologous HSCT for ALL who receive allo-HSCT, the evidence includes case series and systematic reviews. Relevant outcomes are overall survival, disease-specific survival, and treatment-related mortality and morbidity. Evidence Street Assessments have identified only small case series with short-term follow-up, which were considered inadequate evidence of benefit. The evidence is insufficient to determine the effects of the technology on health outcome.

Contract:

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

Coding:

CODING:

Disclaimer for coding information on Medical Policies

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

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

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

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

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

CPT Codes

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

HCPCS Codes

S2140, S2142, S2150

ICD-9 Diagnosis Codes

Refer to the ICD-9-CM manual

ICD-9 Procedure Codes

Refer to the ICD-9-CM manual

ICD-10 Diagnosis Codes

Refer to the ICD-10-CM manual

ICD-10 Procedure Codes

Refer to the ICD-10-CM manual


Medicare Coverage:

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

The Centers for Medicare and Medicaid Services (CMS) does 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 April 14, 2017). National Cancer Institute. Available at <http://www.cancer.gov> (accessed April 17, 2017).

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 July 28, 2016). National Cancer Institute. Available at <http://www.cancer.gov> (accessed April 17, 2017).

5. Autologous Bone Marrow Transplantation in Acute Lymphocytic and Non-Lymphocytic Leukemia Chicago, Illinois: Blue Cross Blue Shield Association Technology Evaluation Center (TEC) Assessment Program. November 1987; 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 (TEC) Assessment Program. November 1990:264-73.

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. Aug 2000; 11(8):999-1006. PMID 11038037

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. Mar 2000; 108(3):531-43. PMID 10759711

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. Oct 1 2000; 96(7):2412-8. PMID 11001892

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. Jan 1 2007; 25(1):16-24. PMID 17194902

11. 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

12. 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 (TEC) Assessment Program. January 1998; 12(25):1-25.

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14. 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. Jan 2006; 12(1):1-30. PMID 16399566

15. 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. Aug 15 1995; 86(4):1619-28. PMID 7632972

16. Dombret H, Gabert J, Boison JM, 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

17. 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. Nov 15 2004; 104(10):3028-37. PMID 15256423

18. 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

19. Ribera JM, Oriol A, Bethencourt C, 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

20. 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

21. 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

22. 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

23. Giebel S, Labopin M, Socie G, et al. Improving results of allogeneic hematopoietic cell transplantation for adults with acute lymphoblastic leukemia in first complete remission: an analysis from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation. Haematologica. Jan 2017; 102(1):139-49. PMID 27686376

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Policy History:

Date Reason
6/15/2018 Reviewed. No changes.
6/1/2017 Document updated with literature review. Coverage unchanged.
7/1/2016 Reviewed. No changes.
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.

Archived Document(s):

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