Archived Policies - Surgery


Stem-Cell Transplant for Acute Lymphoblastic Leukemia (ALL)

Number:SUR703.043

Effective Date:06-01-2014

End Date:09-14-2015

Coverage:

Coverage of evaluation for and subsequent single treatment by stem-cell transplant (SCT) (using bone marrow, peripheral blood, or umbilical cord blood as a stem-cell source), derived from a specific donor category, and following a chemotherapy regimen for treatment of acute lymphoblastic leukemia (ALL) are identified in the grids below.

NOTE: SCT may be known by different terminology and used interchangeably. Hereinafter, SCT will be known as stem-cell support (SCS) throughout the balance of this medical policy.

Children Acute Lymphoblastic Leukemia (ALL):

Allogeneic

May be considered medically necessary to treat childhood acute lymphoblastic leukemia (ALL) in first complete remission but at high-risk of relapse (see * NOTE below), or in second, or greater remission or refractory ALL.

*NOTE:  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 6 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) regardless of early response measures.

Is considered experimental, investigational and/or unproven to treat relapsing ALL after prior autologous stem-cell support (AutoSCS).

Autologous

 

May be considered medically necessary to treat childhood ALL in first complete remission but at high-risk of relapse (see NOTE below), or in second, or greater remission or refractory ALL.

Tandem or Triple Stem-Cell Support

Is considered experimental, investigational and/or unproven for ALL.

Donor Leukocyte Infusion

May be considered medically necessary to treat childhood ALL that has relapsed following an allogeneic stem-cell support (AlloSCS) regimen, to prevent relapse in the setting of a high-risk relapse (see *** NOTE below), or to convert a patient from mixed to full donor chimerism.

***NOTE: High-risk for relapse includes T-cell depleted grafts or non-myeloablative (RIC) allogeneic stem-cell support (AlloSCS).

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.

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

May be considered medically necessary to treat childhood ALL that has relapsed or is refractory, to prevent relapse in the setting of a high-risk relapse (see ***NOTE below), or to convert a patient from mixed to full donor chimerism.

***NOTE: High-risk for relapse includes T-cell depleted grafts or non-myeloablative (RIC) AlloSCS.

Is considered experimental, investigational and/or unproven following an allogeneic stem-cell support (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.

Adults Acute Lymphoblastic Leukemia (ALL):

Allogeneic

May be considered medically necessary to treat adult ALL in first complete remission for any risk factor/level (see **NOTE below), or in second, or greater remissions, or in patients with relapsed or refractory ALL.

**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:

  1. Age greater than 35 years, leukocytosis at presentation of >30,000/µL (B cell lineage) and >100,000/µL (T cell lineage),
  2. “Poor prognosis” genetic abnormalities like the Philadelphia chromosome (t(9;22)), extramedullary disease, and
  3. Time to attain complete remission longer than 4 weeks.

Is considered experimental, investigational and/or unproven to treat relapsing ALL after prior AutoSCS.

Autologous

 

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

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

Tandem or Triple Stem-Cell Support

Is considered experimental, investigational and/or unproven for ALL.

Donor Leukocyte Infusion

May be considered medically necessary to treat adult ALL that has relapsed following an AlloSCS regimen, to prevent relapse (see *** NOTE below), in the setting of a high-risk relapse, or to convert a patient from mixed to full donor chimerism.

***NOTE: High-risk for relapse includes T-cell depleted grafts or non-myeloablative (RIC) allogeneic stem-cell support (AlloSCS).

Is 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 childhood ALL OR as a treatment prior to AlloSCS.

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

May be considered medically necessary to treat adult ALL that has relapsed or is refractory, to prevent relapse in the setting of a high-risk relapse (see ***NOTE below), or to convert a patient from mixed to full donor chimerism.

***NOTE: High-risk for relapse includes T-cell depleted grafts or non-myeloablative (RIC) AlloSCS.

Is considered experimental, investigational and/or unproven following an allogeneic stem-cell support (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.

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.

All other uses of STR markers for any form of ALL not listed above are considered experimental, investigational and/or unproven.

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).”

NOTE:  For detailed information on Tandem or Triple Stem-Cell Transplant and Donor Leukocyte Infusion, see Medical Policy SUR703.002, “Stem Cells Reinfusion or Transplantation Following Chemotherapy (General Donor and Recipient Information)”

Description:

Acute lymphoblastic leukemia (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 Acute Lymphoblastic Leukemia (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 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)

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):

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 Acute Lymphoblastic Leukemia (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 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 2 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 25–30% 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) and 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:

High-dose chemotherapy (HDC) followed by hematopoietic stem-cell transplant (HSCT) or stem-cell support (SCS) (i.e., blood or marrow) is an effective treatment modality for many patients with certain malignancies and non-malignancies. The rationale of this treatment approach is to provide a very dose-intensive treatment in order to eradicate malignant cells followed by rescue with peripheral blood, bone marrow, or umbilical cord blood stem-cells.

Childhood Acute Lymphoblastic Leukemia (ALL):

The policy on childhood ALL is 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 rates of about 95%, with long-term durable remissions of 60%. Therefore, for patients in a first complete remission (CR1), SCT therapy is considered necessary only in those with risk factors predictive of relapse (explained in the Description section of this policy).

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 3 years, compared to only 10–15% for those with early relapse. Thus, stem-cell support (SCS) may be a strong consideration in those with short remissions. At present, the comparative outcomes with either autologous SCS (AutoSCS) or allogeneic SCS (AlloSCS) are unknown.

Three reports describing the results of randomized controlled trials (RCTs) that compared outcomes of SCS to outcomes with conventional-dose chemotherapy in children with ALL were identified subsequent to the BCBSA TEC Assessment. (7, 8, 9) The children enrolled in the RCTs were being treated for high-risk ALL in CR1 (first remission) or for relapsed ALL. These studies reported that overall outcomes after SCS were generally equivalent to overall outcomes after conventional-dose chemotherapy. While SCS 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 (OS) rates at median follow-up of 78 months in children with very high-risk ALL in CR1 who received AlloSCS or AutoSCS 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 SCS, time elapsed between complete remission and undertaking of assigned treatment and the use of genetic randomization based on donor availability rather than true randomization for patients included in the AlloSCs arm.

These results, and reviews of other studies, (11, 12) suggest that while OS and event-free survival (EFS) are not different after SCS compared to conventional-dose chemotherapy, SCS 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). (13) Other investigators recommend that patients should be selected for this treatment using risk-directed strategies. (14, 15)

Adult Acute Lymphoblastic Leukemia (ALL):

The policy on adult ALL was initially based in part on a 1998 BCBSA TEC Assessment of autologous (not allogeneic) SCS. (16) This Assessment offered the following conclusions:

  • For patients in CR1, the data suggest survival is equivalent after AutoSCS or conventional-dose chemotherapy. For these patients, the decision between AutoSCS 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 (CR2) or subsequent remissions, data were inadequate to determine the relative effectiveness of AutoSCS compared to conventional chemotherapy.

A subsequent evidence-based systematic review sponsored by the ASBMT addressed the issue of SCS in adults with ALL. (17) Based on its review of evidence available through January 2005, the ASBMT panel recommended SCS as consolidation therapy for adults with high-risk disease in CR1, but not for standard-risk patients. It also recommended SCS for patients in CR2, although data are not available to directly compare outcomes with alternatives. Based on results from 3 RCTs (18, 19, 20) the ASBMT panel concluded that AlloSCS is superior to AutoSCS 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 human leukocyte antigen- (HLA-) identical family donor were assigned to AlloSCS (n=84); the remaining cases were randomized to AutoSCS (n=50) or to delayed intensification followed by maintenance chemotherapy up to two years in complete remission (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 prior to SCS; differences in risk group assignment; and the use of genetic randomization based on donor availability rather than true randomization for patients included in the AlloSCS arm.

A meta-analysis published in 2006 pooled data from 7 studies of AlloSCS published between 1994 and 2005 that included a total of 1,274 patients with ALL in CR1. (22) The results showed that regardless of risk category, AlloSCS was associated with a significant OS 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 AutoSCS. Pooled data from patients with high-risk disease showed an increased survival advantage for AlloSCS 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 AlloSCS 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. (23) A total of 14 trials with treatment assignment based on genetic randomization including a total of 3,157 patients were included in this analysis. Matched sibling donor SCS was associated with a statistically significant OS 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 (risk ratio [RR]: 0.53; 95% CI: 0.37, 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 conclusions of this policy, that AlloSCS (matched sibling donor) is an effective postremission therapy in adult patients.

While the utility of AlloSCS 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). (24) The ECOG 2993 trial was a Phase III randomized study designed to prospectively define the role of myeloablative AlloSCS, AutoSCS, 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=1,913) received essentially identical therapy, irrespective of their disease risk assignment. After induction treatment that included imatinib mesylate for Philadelphia chromosome-positive patients, all patients who had an HLA-matched sibling donor (n=443) were assigned to receive AlloSCS. Patients with the Philadelphia (Ph) chromosome (n=267) who did not have a matched sibling donor could receive an unrelated donor SCS. Patients who did not have a matched sibling donor or were older than 55 years (n=588) were randomly allocated to receive a single AutoSCS or consolidation and maintenance chemotherapy.

In ECOG2993, OS at 5-year 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). (24) 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-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 AlloSCS, the relapse rate was 24% at 10-years, compared to 49% among those who did not undergo SCS (p<0.00005). Among Ph-negative patients with high-risk ALL, the rate of relapse at 10-year follow-up was 37% following AlloSCS 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 postremission AlloSCS 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 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 to 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 AlloSCS versus 7% in those who received AlloSCS 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: 25-46%) for those who had a matched sibling donor versus 25% (95% CI: 12-34%) with no donor who received consolidation and maintenance chemotherapy. (25) Although the difference in survival rates was not statistically significant, this analysis demonstrated a moderate superiority of postremission-matched sibling AlloSCS 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 AlloSCS was consistently used for all patients who achieved CR1 and who had an HLA-matched sibling donor, irrespective of risk category. (26) A total 433 eligible patients included 288 younger than 55 years, in CR1, and eligible to receive consolidation treatment by an AutoSCS or AlloSCS. AlloSCS 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% +/- 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 5-year OS of 69% +/- 7% and relapse rate at 5 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 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 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 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 AlloSCS in CR1, provided the NRM risk is less than approximately 20% to 25%. (26)

Current data indicate postremission 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. Even for adults who survive the procedure, there is a significant relapse rate. Notwithstanding those caveats, taken together, current evidence supports the use of myeloablative AlloSCS for patients with ALL in CR1 whose health status is sufficient to tolerate the procedure.

Allogeneic Transplant after Prior Failed Autologous Transplant

A 2000 BCBSA TEC Assessment focused on AlloSCS after prior failed AutoSCS, in the treatment of a variety of malignancies, including ALL. (27) 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 SCS.

Clinical Guidelines and Trials for Childhood and Adult ALL:

National Comprehensive Cancer Network (NCCN) Practice Guidelines:

The 2012 National Comprehensive Cancer Network clinical practice guidelines for ALL indicate AutoSCS and AlloSCS is appropriate for treatment of poor-risk patients with lymphoblastic lymphoma (i.e., when disease is considered to be systemic). (28) These guidelines are generally consistent with this policy.

National Cancer Institute (NCI) Clinical Trials Database (PDQ®):

A search of the NCI PDQ database in December 2011 identified 20 trials were identified for pediatric ALL. Seventeen active Phase II/III trials that involve stem-cell support for adult patients with ALL.

Additional Infusion Treatments for ALL

Tandem or triple SCS for ALL is considered experimental, investigational and/or unproven due to lack of adequate evidence of safety and effectiveness documented in published, peer-reviewed medical literature.

Donor Leukocyte Infusion (DLI)

The graft-versus-tumor effect is thought to be less robust in patients with ALL than in the myeloid leukemias. Small studies have reported response rates to DLI ranging from 0% to 20% and OS rates of less than 15%. (29) By comparison, a second AlloSCS provides a 5-year OS of approximately 15-20%, with a treatment-related mortality (TRM) rate of approximately 50%. (29)

The clinically evident graft-versus-leukemia effect of DLI requires weeks to months to become apparent, and, as ALL is a rapidly proliferating disease, DLI only is unable to control the disease without a significant reduction in leukemia burden prior to DLI. Management of patients with relapsed ALL leading to the best OS is with a combination of salvage chemotherapy and DLI. Although it is not clear whether DLI adds benefit to salvage chemotherapy, there are reports of long-term survivors with relapsed ALL who received both chemotherapy and DLI. (30)

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

As with DLI, HPC Boost has a positive response rate for relapse following AlloSCS. (31) The boost of stem-cells, a second dose, may be helpful to reduce the graft failure process, avoiding the risk of serious bleeding and/or infection. Slatter et al. assessed the outcome of 20 boost infusions in 19 of 139 patients who received SCS for primary immunodeficiencies (PID). (32) The authors demonstrated that patients with PIDs may benefit from a boost infusion, resulting in an increase in donor chimerism, clearance of persistent viral infection and improvement in T- and B-cell function. 

Larocca and colleagues compared patients with poor graft function (PGF) and full donor chimerism following AlloSCS who did or did not receive a boost of donor stem-cells. (33) They studied 54 patients with PGF: 20 patients received no further boost infusions (group A), 14 received a boost of unmanipulated stem-cells from the original donor, without further chemotherapy conditioning (group B), and 20 received donor cells after CD34 selection without conditioning (group C). Trilineage recovery was seen in 40%, 36%, and 75% of the patients, respectively. The conclusion was patients with PGF, a boost of CD34-selected stem-cells is associated with a high chance of trilineage recovery and a low risk of acute GVHD.

In 2009, the National Institutes of Health (NIH), released the Mattsson et al. article discussion of graft failure after AlloSCS. (34) They reported, “In patients with continued poor graft function in the absence of graft rejection, a boost of donor stem-cells without additional preparative chemotherapy may improve graft function. Nine of 15 (60%) evaluable patients became transfusion-independent within one month after the boost marrow was given. Because boost marrow may induce GVHD, T-cell depletion of stem-cells can prevent GVHD and improve survival in some patients.” Their review included the Larocca and colleague study discussed in the paragraph above.

Short Tandem Repeat (STR) Markers

Following SCS therapy, it is important to determine whether the new blood forming system is of recipient or donor origin; this phenotypic characterization is called chimerism analysis. The characteristics of the engraftment are analyzed, which is called chimerism analysis. Using STR marker assay to characterize the hematological course and to evaluate the usefulness of the blood forming system (particularly for hematological malignancies, myelodysplastic/myeloproliferative processes, or certain genetic or metabolic disorders) has been tested initially after the SCS, when the patient is declared as disease-free, and at the point of the confirmed stable engraftment of only the donor pattern of the blood forming system. (35, 36)

Multiple small size case studies have been done testing assays of varied combinations of STR polymerase chain reactions for periods of 3 to 60 months following SCS (35-41) In 2011, Park et al. (37) retrospectively evaluated the association between chimerism and transplant outcomes in children with nonmalignant diseases. Chimerism was evaluated using short-tandem repeat polymerase chain reaction (STR-PCR) in 48 patients, with mixed chimerism (MC) defined as greater than 1% recipient cells. MC was detected in 23 transplants (9 showing transient MC; 10 with sustained low levels [≤30%] of autologous cells; and 4 with high-level MC [>30%]). The degree of STR-PCR at 28 days after SCS was significantly higher in patients with high-level MC than those with transient or low-level MC. (37) All patients with transient or low-level MC successfully maintained engraftment and showed a clinical response to SCS, whereas 2 of the 4 patients with high-level MC experienced graft failure. The incidences of grades II-IV acute and chronic GVHD were significantly higher in patients with complete donor chimerism (CC) than MC. We observed no significant survival differences between CC and MC groups. However, the survival rate was lower in patients with high MC than those with low-level or transient MC (P=0.03). The authors concluded that in non-malignant diseases, MC may indicate a tolerant state with a decreased incidence of GVHD. However, high-level MC may signify an increased risk of graft failure and a lower survival rate.

There was no scientific evidence in the peer-reviewed scientific literature demonstrating the use of forensic-oriented STR marker kits developed to analyze genetic parentage, kinship, or other DNA mapping that would be useful in monitoring hematopoietic chimerism following SCS therapies.

Summary

Clinical study results summarized above suggest that while OS and EFS are not different after SCS compared to conventional-dose chemotherapy in most children with standard risk ALL, SCS 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.

Current data indicate postremission myeloablative AlloSCS 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 AlloSCS for patients with ALL in CR1 whose health status is sufficient to tolerate the procedure.

Evidence is insufficient to permit conclusions on the use of AlloSCS following failure of AutoSCS.

DLI is used in nearly all hematologic malignancies that relapse after a prior AlloSCS, as a planned strategy to prevent disease in a setting of high-risk of disease (such as reduced intensity conditioning with AlloSCS), and to convert mixed to full donor chimerism.

HPC Boost is one option available to treat potential graft failures that may occur after a prior AlloSCS for the treatment of ALL. Prevention of graft failures, increasing donor chimerism, reconstituting the immune system, and consolidating cell lineages, avoids complication outcomes, such as serious bleeding and/or infection.

STR has shown a clinical utility in studies to analyze the process of engraftment following SCS treatments of certain hematological malignancies, myelodysplastic/myeloproliferative processes, or certain genetic or metabolic disorders. Therefore STR following AlloSCS for ALL may be considered medically necessary.

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:

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

204.00, 204.01, 204.02

ICD-9 Procedure Codes

41.00, 41.01, 41.02, 41.03, 41.04, 41.05, 41.06, 41.07, 41.08, 41.09, 41.91, 99.25, 99.74, 99.79

ICD-10 Diagnosis Codes

C91.00-C91.02 

ICD-10 Procedure Codes

30243G0, 30243X0, 30243Y0, 30243G1, 30243X1, 30243Y1, 07DQ0ZZ, 07DQ3ZZ, 07DR0ZZ, 07DR3ZZ, 07DS0ZZ, 07DS3ZZ 


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. National Cancer Institute. Available online at <http://www.cancer.gov> (accessed 2012 December).
  2. Pieters R, Carroll WL. Biology and treatment of acute lymphoblastic leukemia. Pediatr Clin North Am 2008; 55(1):1-20, ix.
  3. Carroll WL, Bhojwani D, Min DJ et al. Pediatric acute lymphoblastic leukemia. Hematology Am Soc Hematol Educ Program 2003:102-31.
  4. PDQ – Physician Data Query (PDQ®). Adult acute lymphoblastic leukemia. 2012. National Cancer Institute. Available online at <http://www.cancer.gov> (accessed 2012 December).
  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. Annals of Oncology (2000) 11(8):999-1006.
  8. Lawson, S.E., Harrison, G., et al. The UK experience in treating relapsed childhood acute lymphoblastic leukaeima: a report on the Medical Research Council UK ALLR1 study. British Journal of Haematology (2000) 108(3):531-43.
  9. Wheeler, K.A., Richards, S.M., 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, J.M., Ortega, J.J., 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. Journal of Clinical Oncology (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., et al. Treatment of childhood acute lymphoblastic leukemia after the first relapse: curative strategies. Haematologica (2000) 85(11 suppl):47-53.
  13. Hahn, T., Wall, D., et al. The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of acute lymphoblastic leukemia in children: an evidence-based review. Biology of Blood and Marrow Transplant (2005) 11(11):823-61.
  14. Gaynon, P.S., Trigg, M.E., et al. Children’s Cancer Group trials in childhood acute lymphoblastic leukemia: 1983-1995. Leukemia (2000) 14(12):2223-33.
  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.
  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. 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. Biology of Blood and Marrow Transplant (2006) 12(1):1-30.
  18. 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 (1995) 86(4):1619-28.
  19. 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 (2002) 100(7):2357-66.
  20. Hunault, M., Harousseau, J.L., 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, J.M., 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 (2005) 90(10):1346-56.\
  22. 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 2006; 106(12):2657-63.
  23. 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.
  24. 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 2008; 111(4):1827-33.
  25. 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.
  26. 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.
  27. 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.
  28. NCCN –Acute Lymphoblastic Leukemia. NCCN Clinical Practice Guidelines in Oncology. National Comprehensive Cancer Network. Version.1.2012. Available at <http://www.nccn.org> (accessed on 2012 December 20).
  29. Deol A, Lum LG. Role of donor lymphocyte infusions in relapsed hematological malignancies after stem cell transplantation revisited. Cancer Treat Rev 2010; 36(7):528-38.
  30. Tomblyn M, Lazarus HM. Donor lymphocyte infusions: the long and winding road: how should it be traveled? Bone Marrow Transplant 2008; 42(9):569-79.
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  32. Slatter, M.A., Bhattacharya, A., et al. Outcome of boost hematopoietic stem cell transplant for decreased donor chimerism or graft dysfunction in primary immunodeficiency. Bone Marrow Transplantation (2005) 35:683-9.
  33. Larocca, A., Piaggio, G., et al. A boost of CD35+-selected peripheral blood cells without further conditioning in patients with poor graft function following allogeneic stem cell transplantation. The Hematology Journal (2006) 91(7):935-40.
  34. NIH – Mattsson, J., Ringden, O., et al. Graft failure after allogeneic hematopoietic cell transplantation. Biology and Blood Marrow Transplant (2008 January) 14(Supplement 1):165-70. National Institutes of Health Public Access. Available at <http://www.nih.gov> (accessed – 2013 April 15).
  35. Borrill, V., Schlaphoff, T., et al. The use of short tandem repeat polymorphisms for monitoring chimerism follow bone marrow transplantation: a short report. Hematology (2008 August) 13(4):210-4.
  36. Crow, J., Youens, K., et al. Donor cell leukemia in umbilical cord blood transplant patients: a case study and literature review highlighting the importance of molecular engraftment analysis. Journal of Molecular Diagnostics (2010 July) 12(4):530-7.
  37. Park, M., Koh, K.N., et al. Clinical implications of chimerism after allogeneic hematopoietic stem-cell transplantation in children with non-malignant diseases. Korean Journal of Hematology (2011 December) 46(4):258-64.
  38. Odriozola, A., Riancho, J.A., et al. Evaluation of the sensitivity of two recently developed STR multiplexes for the analysis of chimerism after hematopoietic stem-cell transplantation. International Journal of Immunogenetics (2013 April) 40(2):88-92.
  39. Lawler, M., Crampe, M., et al. The EuroChimerism concept for standardized approach to chimerism analysis after allogeneic stem-cell transplantation. Leukemia (2012 August) 26(8):1821-8.
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  42. Donor Leukocyte Infusion for Malignancies A Treated with an Allogeneic Stem-Cell Transplant. BCBSA Medical Policy Reference Manual (2012 May) Medicine: 2.03.03.

Policy History:

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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