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Hematopoietic Cell Transplantation for Chronic Myelogenous Leukemia - Medical Clinic... Page 1 of 21 --> (https://www.aetna.com/) Hematopoietic Cell Transplantation for Chronic Myelogenous Leukemia Policy His tory Last Review 11/16/2017 Effective: 11/21/2003 Next Review: 07/12/2018 Review History Definitions A dditiona l In form at ion Clinical Policy Bulletin Notes Number: 0674 *Please see amendment for Pennsylvania Medicaid at the end of this CPB. Policy Aetna considers allogeneic hematopoietic cell transplantation medically necessary for the treatment of chronic myelogenous leukemia (CML) when the member meets the transplanting institution's written eligibility criteria. In the absence of such criteria, Aetna considers allogeneic hematopoietic cell transplantation medically necessary for the treatment of members with CML who have failed to respond to, who have developed resistance to, or who are intolerant to tyrosine kinase inhibitors (imatinib, dasatinib, nilotinib) for persons without serious organ dysfunction based on the transplanting institution's evaluation. Aetna considers autologous hematopoietic cell transplantation (auto BM/PSCT) experimental and investigational for the treatment of CML under all circumstances because its effectiveness for this indication has not been established. http://aetnet.aetna.com/mpa/cpb/600_699/0674.html 10/29/2018

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  • Hematopoietic Cell Transplantation for Chronic Myelogenous Leukemia - Medical Clinic... Page 1 of 21

    -->

    (https://www.aetna.com/)

    Hematopoietic Cell Transplantation for ChronicMyelogenous Leukemia

    Policy His tory

    Last Review

    11/16/2017

    Effective: 11/21/2003

    Next

    Review: 07/12/2018

    Review History

    Definitions

    A dditiona l In form at ion

    Clinical Policy

    Bulletin Notes

    Number: 0674 *Please see amendment for Pennsylvania Medicaid at the end of this CPB.

    Policy

    Aetna considers allogeneic hematopoietic cell

    transplantation medically necessary for the treatment of

    chronic myelogenous leukemia (CML) when the member

    meets the transplanting institution's written eligibility criteria. In

    the absence of such criteria, Aetna considers allogeneic

    hematopoietic cell transplantation medically necessary for the

    treatment of members with CML who have failed to respond to,

    who have developed resistance to, or who are intolerant to

    tyrosine kinase inhibitors (imatinib, dasatinib, nilotinib) for

    persons without serious organ dysfunction based on the

    transplanting institution's evaluation.

    Aetna considers autologous hematopoietic cell transplantation

    (auto BM/PSCT) experimental and investigational for the

    treatment of CML under all circumstances because its

    effectiveness for this indication has not been established.

    http://aetnet.aetna.com/mpa/cpb/600_699/0674.html 10/29/2018

    http://aetnet.aetna.com/mpa/cpb/600_699/0674.htmlhttps://www.aetna.com/

  • Hematopoietic Cell Transplantation for Chronic Myelogenous Leukemia - Medical Clinic... Page 2 of 21

    See also CPB 0404 - Interferons

    (../400_499/0404.html) CPB 0634 - Non-myeloablative

    Hematopoietic Cell Transplantation (Mini-Allograft /

    Reduced Intensity

    , Conditioning Transplant) (0634.html)

    , CPB 0638 - Donor Lymphocyte Infusion (0638.html),

    CPB 0640 - Hematopoietic Cell Transplantation for Selected

    and Leukemias (0640.html)

    .

    Background

    Chronic Myelogenous Leukemia:

    Chronic myelogenous leukemia (CML) is a hematologic

    malignancy associated with a specific chromosomal

    abnormality in the form of the Philadelphia chromosome (Ph).

    This Ph abnormality represents a reciprocal balanced

    translocation between the long arms of chromosomes 9 and

    22, and produces the BCR–ABL fusion gene, which leads to

    the expression of an abnormal protein. The resulting chimeric

    protein is known as p210BCR–ABL, which is characterized by

    constitutive activation of its tyrosine kinase activity. At

    diagnosis, the Ph can be detected in about 95 % of patients

    with CML. The incidence of CML is 1 to 2 cases per 100,000

    per year. Chronic myelogenous leukemia accounts for

    approximately 15 % of all leukemias and 7 % to 20 % of all

    adult leukemias. Although CML can occur at any age, it most

    often appears in adults with a median age of 45.

    A hallmark of CML is the over-production of granulocytes.

    Clinically, CML is characterized by an initial chronic or stable

    phase lasting a median of 3 years. During this phase there is

    a disordered maturation and excessive proliferation of myeloid

    cells. Clinical manifestations that appear during the chronic

    phase can usually be controlled with cytotoxic drugs or splenic

    irradiation, however true remissions are rare and for the most

    part the marrow remains predominantly populated with

    leukemic cells. The chronic phase typically transforms into an

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    acute phase, known as a blast phase or crisis, which is usually

    terminal. In many patients the blast phase is preceded by an

    accelerated phase characterized by progression of symptoms

    and resistance to treatment. Conventional chemotherapy

    (e.g., busulfan, and other alkylating agents such as

    cyclophosphamide and anti-metabolites) used for chronic

    phase CML can induce multiple remissions and delay the

    onset of blast phase to a median of 4 to 6 years.

    Until recently, treatment options for patients with CML, in

    addition to conventional chemotherapy, include interferon-

    based therapies or allogeneic bone marrow/peripheral stem

    cell transplantation (allo BM/PSCT). Treatment decisions are

    generally based on the age of the patient and the phase of the

    disease. Recently, several new therapies have been

    developed that may change the natural history of CML and

    patient prognosis. One of the new therapies is imatinib

    mesylate (ST1571, Gleevec), an oral, selective BCR-ABL

    kinase inhibitor that has demonstrated activity in all phases of

    CML. It has been reported that imatinib produces both

    hematologic and cytogenetic remission in CML patients. In

    CML patients in the chronic phase, who had previously failed

    interferon, imatinib induced a complete hematologic response

    in 88 % and a complete cytogenetic response in 30 % of

    patients. This agent has been rapidly adopted into treatment

    strategies for CML. However, the response rate generally

    decreases in patients with accelerated or blast phase CML.

    Conventional chemotherapy during the chronic phase may

    improve the patient’s quality of life, however, it does not (i)

    influence the duration of the chronic phase, (ii) prevent

    blastic crisis, or (iii) prolong the overall survival time.

    Currently, allo BM/PSCT is considered the only potentially

    curative therapy for CML. Due to the indolent nature of the

    disease and the morbidity and mortality associated with BMTs,

    allo BMT was initially limited to patients with CML already in

    blast crisis. Although treatment with high-dose chemotherapy

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  • Hematopoietic Cell Transplantation for Chronic Myelogenous Leukemia - Medical Clinic... Page 4 of 21

    (HDC), followed by allo BMT (during blast phase) induced

    transient disappearance of the Ph, relapses were common and

    survivals short. The somewhat disappointing results were

    attributed to the advanced stage of disease and the debilitated

    nature of the recipients. Subsequent attempts to perform

    transplantation during the accelerated phase did result in

    prolonged disease-free survival (DFS) in a small proportion of

    patients. However, the incidence of relapse was high. Thus,

    focus was shifted to initiating HDC and allo BMT during the

    chronic phase of the disease. Results for this therapy during

    the chronic phase were very encouraging. As a result,

    patients are offered the option of treatment with an allo BMT

    as soon as possible following initial diagnosis of chronic phase

    CML, prior to evidence of disease progression.

    Hehlmann and colleagues (2007) noted that early allo-PSCT

    has been proposed as primary treatment modality for patients

    with CML. This concept has been challenged by

    transplantation mortality and improved drug therapy. In a

    randomized study, primary allo-PSCT and best available drug

    treatment (interferon-based) were compared in newly

    diagnosed chronic phase CML patients. Assignment to

    treatment strategy was by genetic randomization according to

    availability of a matched related donor. Evaluation followed

    the intention-to-treat principle. A total of 621 patients with

    chronic phase CML were stratified for eligibility for allo-PSCT.

    Three hundred and fifty four patients (62 % male; median age

    of 40 years; range of 11 to 59 years) were eligible and

    randomized. A total of 135 patients (38 %) had a matched-

    related donor, of whom 123 (91 %) received a transplant within

    a median of 10 months (range of 2 to106 months) from

    diagnosis; 219 patients (62 %) had no related donor and

    received best available drug treatment. With an observation

    time up to 11.2 years (median of 8.9 years), survival was

    superior for patients with drug treatment (p = 0.049),

    superiority being most pronounced in low-risk patients (p =

    0.032). The authors stated that the general recommendation

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  • Hematopoietic Cell Transplantation for Chronic Myelogenous Leukemia - Medical Clinic... Page 5 of 21

    of allo-PSCT as first-line treatment option in chronic phase

    CML can no longer be maintained. It should be replaced by a

    trial with modern drug treatment first.

    Allogeneic BM/PSCT:

    High-dose chemotherapy followed by allo BM/PSCT is

    currently considered the only potentially curative therapy for

    CML. Studies have confirmed that patients who receive allo

    BM/PSCT during the chronic phase have significantly better

    survival rates than those who receive transplants during the

    accelerated or blast phase.

    Fyles et al (1991) reported on long-term results of allo BMT for

    patients with CML (n = 70). Patients were stratified according

    to risk (good risk subgroup was defined as first chronic phase

    CML; poor risk subgroup was defined as other than first

    chronic phase CML), as well as diagnosis. The median follow-

    up was 67 months with a range of 33 to 120 months.

    According to the authors, the most important factor that

    determined the outcome in this patient population was disease

    status at the time of BMT. The effect of risk status was

    evaluated separately for each diagnosis. Good risk patients

    with CML had a 5-year event-free survival (EFS) of 43 %, as

    compared to the poor risk patients who had only a 15 %

    chance of DFS over the same time interval. Patients with CML

    in first chronic phase showed a significantly better long-term

    EFS than patients transplanted with more advanced disease.

    The effect of risk status was also evaluated for each diagnostic

    subgroup. Patients with CML in the good risk category

    relapsed significantly less frequently at 5 years than poor risk

    patients: 13 % versus 58 %. Sixteen patients with CML

    relapsed. A hematologic relapse was noted in 14 of these 16

    recipients. All 14 were in the poor risk category and eleven of

    the 14 poor risk recipients have died from their disease. The

    remaining 2 patients (categorized as good risk) relapsed

    cytogenetically only. Both of these patients were treated with

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  • Hematopoietic Cell Transplantation for Chronic Myelogenous Leukemia - Medical Clinic... Page 6 of 21

    interferon and have subsequently become Ph negative. The

    authors concluded that in order to achieve the best results,

    patients should be transplanted early in their disease.

    Wagner et al (1992) described results of a retrospective study

    evaluating the efficacy of HDC and total body irradiation

    followed by allo BMT in patients with chronic phase CML (n =

    75). Patients were classified into groups according to age and

    graft-versus-host disease (GVHD) prophylaxis. Groups were

    defined as follows: Group 1 -- patients less than 30 years of

    age receiving immunosuppressive therapy and unmanipulated

    bone marrow; Group 2 -- patients 30 years of age or over

    receiving immunosuppressive therapy and unmanipulated

    bone marrow; Group 3 -- patients 30 years of age or over

    receiving lymphocyte-depleted bone marrow plus

    immunosuppressive therapy. Survival rate at 4.5 years was 52

    %. When classified by age and GVHD prophylaxis, the

    actuarial survival was 65 % in Group 1, 33 % in Group 2, and

    38 % in Group 3. In uni-variate analysis, patients age 30

    years and over, and the use of lymphocyte-depleted bone

    marrow negatively influenced EFS. Thirty-seven of the 79

    patients died following BMT. The principal causes of treatment

    failure were acute and chronic GVHD and disease relapse.

    According to the authors, results of the study confirm previous

    reports that allo BMT for CML in chronic phase improves

    survival in over 50 % of the patients. In addition, the authors

    recommended that for patients aged 55 or younger with CML

    in the chronic phase, allo BMT should be considered early

    after disease presentation.

    Gratwohl and co-workers (1993) conducted a retrospective

    analysis on data collected by the European Bone Marrow

    Transplantation Group since 1979. A total of 1,480 BMTs for

    CML were done between 1979 and 1990. Of these, 1,082

    patients were transplanted in first chronic phase, 88 in a

    subsequent chronic phase, 251 in accelerated phase and 59 in

    blast crisis. For these 4 disease stages leukemia-free survival

    at 5 years was 39 %, 22 %, 22 % and 0 %, respectively. A

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  • Hematopoietic Cell Transplantation for Chronic Myelogenous Leukemia - Medical Clinic... Page 7 of 21

    more detailed analysis was done on 947 patients who received

    transplants in the first chronic phase from an human leukocyte

    antigen (HLA)-identical sibling. There were 526 patients alive

    2 to 10 years after transplant, 409 have died and 12 were lost

    to follow-up. The great majority who died, 350 patients, had a

    transplant-related death, while 59 patients died with or due to

    relapsed disease. Of the 526 patients alive, 428 were alive

    without any signs of relapse, 98 were alive with relapse. This

    meant a total of 157 patients relapsed. The probability of

    staying alive without relapse at 8 years was 34 %. Since not

    all patients with relapse have died, actual survival is better and

    the probability of being alive for the whole group was 47 % at 8

    years. This long-term analysis allowed a few conclusions: (i)

    patients with CML in blastic transformation should not be

    considered routine candidates for BMT; (ii) BMT should be

    carried out as soon after diagnosis as possible if an HLA-

    identical sibling is available; and (iii) age, donor/recipient

    sex combination, time span from diagnosis to transplant

    and initial disease status influence outcome.

    The National Comprehensive Cancer Network’s practice

    guidelines on CML (2003) states that 3 effective modalities are

    currently available for the primary management of CML: (i)

    allo-BMT, (ii) interferon alpha with or without cytarabine,

    and (iii) imatinib mesylate. Moreover, in a recent review on

    therapeutic strategies for the treatment of CML, Garcia-

    Manero et al (2003) stated that allo-PSCT is curative in

    selected patients, and is most effective when carried out

    during the chronic phase of disease. For patients with a high-

    predicted risk of disease recurrence (e.g., transplantation in

    accelerated-blastic phase) after allo-PSCT, preventive post-

    allo-PSCT maintenance measures such as interferon alpha or

    imatinib may be beneficial.

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  • Hematopoietic Cell Transplantation for Chronic Myelogenous Leukemia - Medical Clinic... Page 8 of 21

    Guidelines from the British Society of Haematology on

    CML (Goldman, 2007) state that allogeneic stem cell

    transplantation may be considered for patients with suitable

    donors as an alternative to a second generation tyrosine

    kinase inhibitor or if they fail such treatment.

    Guidelines from Cancer Care Ontario (Imrie et al, 2009) state

    that allogeneic stem cell transplantation is an option for

    patients with CML for whom medical therapy has failed, as well

    as those in accelerated phase or blast crisis.

    Chalandon et al (2014) noted that patients with CML relapsing

    after allogeneic stem cell transplantation may be treated by

    tyrosine kinase inhibitors and/or by donor lymphocyte

    infusions. Best strategies and timing of administration of

    lymphocytes are unclear. These investigators analyzed 155

    patients who relapsed after allogeneic stem cell

    transplantation for CML with disease detectable only by

    molecular methods and who subsequently received

    lymphocytes. Transplants were performed in first chronic

    phase (n = 125) or in advanced disease (n = 29) from identical

    siblings (n = 84) or unrelated donors (n = 71) between 1986

    and 2003. They received lymphocytes either during molecular

    relapse (n = 85) or upon progression to more advanced

    disease between 1993 and 2004. The median interval from

    relapse to lymphocytes infusion was 210 (0 to 1,673) days.

    The median follow-up after it was 46 (3 to 135) months.

    Overall survival was 76 ± 4 % at 5 years after lymphocyte

    infusions (89 ± 8 % with sibling donors and 63 ± 13 % with

    unrelated donors (p = 0.003)). Survival was 69 ± 14 % if

    lymphocytes were given within 6 months of the detection of

    molecular relapse and 81 ± 10 % (p = 0.061) if given later; 81

    ± 11 % if given at molecular relapse versus 71 ± 12 % (p =

    0.26) with more advanced disease. In multi-variate analysis

    survival was worse if the donor was unrelated (HR 2.54 (95 %

    confidence interval [CI]: 1.15 to 5.53), p = 0.021) and better

    with lymphocyte infusion beyond 6 months from molecular

    relapse (HR 0.4 (95 % CI: 0.19 to 0.84), p = 0.0.018). These

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  • Hematopoietic Cell Transplantation for Chronic Myelogenous Leukemia - Medical Clinic... Page 9 of 21

    data confirmed the remarkable effectiveness of lymphocyte

    infusion for this disease. The authors concluded that there

    appears to be no advantage of administering it early upon

    detection of molecular relapse in patients who received

    allogeneic stem cell transplantation for CML.

    Kitanaka (2016) noted that the introduction of tyrosine kinase

    inhibitors (TKIs) has dramatically changed the management of

    patients with CML. Despite improved outcomes for most CML

    patients, disease progression from chronic phase (CP) to

    accelerated phase (AP) or blast phase (BP) occurs in 1 to 1.5

    % of cases per year with current TKI therapy. In addition,

    about 10 to 15 % of newly diagnosed patients present in AP or

    BP. Even in the TKI era, the prognosis of patients with CML-

    AP is not satisfactory. Although de-novo AP patients who

    respond optimally to TKI have excellent outcomes, the

    prognosis of the remaining CML –AP patients treated with TKI

    remains poor. For CML-AP patients, allogeneic stem cell

    transplantation (allo-HSCT) is the only curative therapy.

    Patients eligible for allo-HSCT should first be treated with TKI

    with or without chemotherapy, in order to obtain reversion to

    CP, followed promptly by allo-HSCT. The author concluded

    that the survival rates of patients undergoing allo-HSCT for

    CML-AP are still disappointing; prophylactic or pre-emptive

    use of TKIs after allo-HSCT may improve long-term survival.

    They stated that further investigation to improve the treatment

    outcomes of patients with CML-AP is needed.

    Shulman and associates (2016) stated that the management

    of CML in children changed dramatically with the introduction

    of TKIs. Unfortunately, outcomes for patients presenting in an

    advanced stage (AP- or BP-CML) continues to be poor,

    requiring chemotherapy and all-HSCT to attempt cure.

    Integration of TKIs in the therapy of advanced CML is still an

    area of active investigation. There are little published data on

    TKI use in children with advanced stage CML. These

    researchers performed a retrospective review of all children

    treated at their institution between January 1, 2010 and June

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  • Hematopoietic Cell Transplantation for Chronic Myelogenous Leukemia -Medical Cli... Page 10 of 21

    30, 2013, and identified 5 children, aged 12 to 18 years, with

    advanced stage CML. All patients were treated with a TKI

    before allo-HSCT and TKIs were re-started following allo-

    HSCT in 4/5 with a goal of continuing until 2 years post-

    transplant. At time of allo-HSCT, all were in a morphologic

    and cytogenetic remission; 1 patient had also achieved

    molecular remission. All patients were alive and in molecular

    remission at an average of 38 months (range of 14 to 51

    months) following transplant. The authors concluded that their

    experience indicated that TKIs were safe and well-tolerated in

    children both pre-transplant and post-transplant and may

    improve outcomes in this aggressivedisease.

    Londo and colleagues (2017) noted that TKIs are widely used

    to treat patients with CML-CP, and outcomes of TKI treatment

    for patients with CML-CP have been excellent. Since multiple

    TKIs are currently available, 2nd-line or 3rd-line TKI therapy is

    considered for patients who are intolerant of or resistant to the

    previous TKI treatment. Thus, allo-HSCT is considered only

    for patients with disease progression or for patients after

    treatment failure with multiple TKIs. To reflect the current

    clinical situation of patients with CML-CP, these investigators

    examined if prior TKI treatment affects the outcome of allo-

    HSCT. Data from 237 patients for whom the number of pre-

    transplant TKIs varied from 1 to 3 were used for analysis.

    Before allo-HSCT, 153 patients were treated with 1 TKI, 49

    patients were treated with 2 TKIs, and 35 patients were treated

    with 3 TKIs. In addition to conventional risk factors, i.e.,

    disease status at transplantation and patient's age, the use of

    3 TKIs before transplantation was identified as a significant

    adverse factor for prognosis. Non-relapse mortality rate was

    higher in patients treated with 3 TKIs than in patients treated

    with 1 or 2 TKIs. The authors concluded that these findings

    suggested that allo-HSCT could be considered for young

    patients with CML-CP who manifest resistance to 2nd-line TKI

    therapy and who have an appropriate donor.

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    Autologous BM/PSCT:

    Available scientific evidence has not established autologous

    bone marrow/peripheral stem cell transplantation (auto-

    BM/PSCT) as an effective treatment for CML. Patient

    populations varied across these studies. Some focused on

    newly diagnosed patients or those in the first year since

    diagnosis. Others focused on patients who did not respond to

    or relapsed after initial treatment using interferon alpha.

    Finally, some focused on patients transplanted in late chronic

    phase or after transformation to accelerated phase or blast

    crisis. Although some patients achieved complete or partial

    molecular remissions and long-term DFS, these studies do not

    permit conclusions free from the influence of patient selection

    bias. Moreover, all autotransplanted patients included in these

    reports were treated before Gleevec became available. Since

    this drug has been shown to induce major hematologic and,

    less often, cytogenetic remissions even among patients in

    accelerated phase and blast crisis, future studies of

    autotransplants for CML, may focus on patients who fail or

    become resistant to imatinib mesylate. Alternatively, it may be

    incorporated into combination regimens used for high dose

    therapy.

    Bhatia et al (1997) stated that the role of autologous

    transplantation in the early therapy of CML is not yet

    understood. Analysis of a first generation of autologous

    transplants performed largely in previously treated, older

    patients unsuitable for allogeneic transplantation or not

    responding to interferon alpha therapy suggests that this

    approach has anti-leukemia activity associated with

    prolongation of survival and acceptable peri-transplantation

    mortality. However, because these trials were uncontrolled

    and patient selection could have contributed to the longer than

    expected survival, controlled studies are needed to confirm the

    encouraging findings of these early reports and determine if

    autologous transplantation prolongs survival.

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  • Hematopoietic Cell Transplantation for Chronic Myelogenous Leukemia -Medical Cli... Page 12 of 21

    Podesta et al (2000) examined changes that occur in the

    percentage of Ph-negative- and Ph-positive-committed

    progenitor cells and ascertained the relationship between

    changes and clinical outcome in 15 patients with CML who

    were autografted soon after diagnosis with 85 % to 100 % Ph-

    negative peripheral blood progenitor cells (PBPC). The

    authors reported that a prolonged period of complete or almost

    complete Ph-negative hemopoiesis was achieved in patients

    with CML who underwent autografting with Ph-negative

    progenitors. These researchers stated that longer follow-up

    studies are needed to evaluate whether these changes are

    associated with improved survival.

    Michallet et al (2000) reported data on 28 CML patients

    autotransplanted in chronic phase with PBPC mobilized with

    G-CSF (5 ug/kg/day for 5 days) given subcutaneously while

    continuing interferon alpha therapy. The authors concluded

    that the results of this strategy were encouraging in poor

    interferon alpha responders, however, other prospective

    studies that try to maintain the cytogenetic responses obtained

    immediately after transplantation are needed.

    Meloni and associates (2001) stated that the potential role of

    auto-SCT as an alternative therapeutic strategy in CML has

    been widely explored in pilot studies, but the clinical results in

    terms of survival have so far been evaluated only

    retrospectively and in heterogeneous groups of patients.

    These investigators evaluated the feasibility and long-term

    efficacy of unmanipulated auto-SCT followed by low dose

    interferon alpha in a homogeneous group of patients affected

    by CML in a very early phase of disease (n = 26). The authors

    concluded that high dose therapy followed by unmanipulated

    peripheral blood stem cell transplantation and low-dose

    interferon alpha is a feasible approach, which results in long-

    term survival in newly diagnosed CML patients. However,

    these findings need to be confirmed in controlled trials

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    comparing auto-SCT with other therapeutic approaches, such

    as the use of interferon alpha alone or in combination with

    other agents.

    Koziner et al (2002) evaluated the role of auto-SCT in

    prolonging DFS and overall survival (OS) in patients with CML

    who received autografts of Ph-positive or Ph-negative cell

    harvests (n = 53). The authors found that auto-SCT with Ph-

    negative cell harvests after myeloablative chemotherapy

    resulted in prolonged periods of hematologic and cytogenetic

    remission or stable disease after cytogenetic/molecular

    recurrence in some patients with CML. A superior DFS was

    observed without any benefit observed for OS. These

    investigators concluded that auto-SCT with Ph-negative cells

    is a promising procedure because it can improve the DFS

    probability of patients who are unsuitable for allo-SCT from a

    histo-identical sibling.

    The National Comprehensive Cancer Network’s practice

    guidelines on CML (2009) as well as a recent review on

    therapeutic strategies for the treatment of CML did not discuss

    the use of autologous transplantation as a treatment option

    (Garcia-Manero et al, 2003). Schiffer and colleagues (2003)

    stated that auto-SCT following intense chemoradiotherapy

    may prolong survival and reduce complications and mortality

    during peri-transplantation in patients with CML, however, this

    procedure is not curative. The collection of stem cells when

    the patient is in complete cytogenetic response for use in case

    of relapse is considered an investigative procedure.

    A meta-analysis of 6 randomized studies (CML Autograft Trials

    Collaboration, 2007) reported that the results do not suggest a

    role for auto-SCT in initial treatment for CML, but it may still

    merit investigation in patients resistant to tyrosine kinase

    inhibitors.

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    Guidelines from Cancer Care Ontario (Imrie, et al., 2009) state

    that autologous stem cell transplantation is not recommended

    for patients with CML.

    A ppendix

    The Hematopoietic Cell Transplantion-Specific

    Comorbidity Score Calculator is available at the following

    website:

    Calculate by QxMD (http://www.qxmd.com/calculate

    online/hematology/hct-ci)

    .

    CPT Codes / HCPCS Codes / ICD-10 Codes

    Information in the [brackets] below has been added for clarification purposes. Codes requiring a 7th character are represented by "+":

    Code Code Description

    CPT codes covered if selection criteria are met:

    38230 Bone marrow harvesting for transplantation;

    allogenic

    38240 Hematopoietic progenitor cell (HPC); allogeneic

    transplantation per donor

    38242 Allogeneic lymphocyte infusions

    CPT codes not covered for indications listed in the CPB:

    38206 Blood-derived hematopoietic progenitor cell

    harvesting for transplantation, per collection;

    autologous

    38232 autologus

    38241 Hematopoietic progenitor cell (HPC);

    autologous transplantation

    Other CPT codes related to the CPB:

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    http://aetnet.aetna.com/mpa/cpb/600_699/0674.htmlhttp://www.qxmd.com/calculate-http://www.qxmd.com/calculate-online/hematology/hct-cihttp://www.qxmd.com/calculate-online/hematology/hct-ci

  • Hematopoietic Cell Transplantation for Chronic Myelogenous Leukemia -Medical Cli... Page 15 of 21

    Code Code Description

    38204 -

    38215

    Bone Marrow or Stem Cell Services/Procedures

    HCPCS codes covered if selection criteria are met::

    S2150 Bone marrow or blood-derived stem cells

    (peripheral or umbilical), allogeneic or

    autologous, harvesting, transplantation, and

    related complications; including: pheresis and

    cell preparation/storage; marrow ablative

    therapy; drugs, supplies, hospitalization with

    outpatient follow-up; medical/surgical,

    diagnostic, emergency, and rehabilitative

    services; and the number of days of pre- and

    post-trasnplant care in the global definition

    Other HCPCS codes related to the CPB:

    S0088 Imatinib, 100mg

    ICD-10 codes covered if selection criteria are met:

    C92.10 -

    C92.11

    Chronic myeloid leukemia

    The above policy is based on the following references:

    Allogeneic Bone Marrow Transplantation:

    1. Fyles G, Messner HA, Lockwood G, et al. Long-term

    results of bone marrow transplantation for patients

    with AML, ALL, CML prepared with single dose total

    body irradiation of 500cGy delivered with a high dose

    rate. Bone Marrow Transplant. 1991;8(6):453-463.

    2. Wagner J, Zahurak M, Piantadosi S, et al. Bone marrow

    transplantation of chronic myelogenous leukemia in

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  • Hematopoietic Cell Transplantation for Chronic Myelogenous Leukemia -Medical Cli... Page 16 of 21

    chronic phase: Evaluation of risks and benefits. J Clin

    Oncol. 1992;10(5) :779-789.

    3. Gratwohl A, Hermans J, Niederwieser D, et al. Bone

    marrow transplantation for chronic myeloid leukemia:

    Long term results. Chronic Leukemia Working Party of

    the European Group for Bone Marrow

    Transplantation. Bone Marrow Transplant. 1993;12

    (5):509-516.

    4. Silver RT, Woolf SH, Hehlmann R, et al. An evidence-

    based analysis of the effect of busulfan, hydroxyurea,

    interferon and allogeneic bone marrow

    transplantation in treating the chronic phase of

    chronic myeloid leukemia: Developed for the American

    Society of Hematology. Blood. 1999;94(5):1517-1536.

    5. Druker BJ, Talpaz M, Resta DJ, et al. Efficacy and safety

    of a specific inhibitor of the BCR-ABL tyrosine kinase in

    chronic myeloid leukemia. N Eng J Med. 2001;344

    (14):1031-1037.

    6. Goldman JM, Melo JV. Targeting the BCR-ABL tyrosine

    kinase in chronic myeloid leukemia. N Engl J Med.

    2001;344(14):1084-1086.

    7. Weisdorf DJ, Anasetti C, Antin JH, et al. Allogeneic bone

    marrow transplantation for chronic myelogenous

    leukemia: Comparative analysis of unrelated versus

    matched sibling donor transplantation. Blood. 2002;99

    (6):1971-1977.

    8. O'Dwyer ME, Mauro MJ, Druker BJ. Recent

    advancements in the treatment of chronic

    myelogenous leukemia. Ann Rev Med. 2002;53:369

    381.

    9. Garcia-Manero G, Talpaz M, Kantarjian HM. Current

    therapy of chronic myelogenous leukemia. Intern Med.

    2002;41(4):254-264.

    10. Novartis Oncology. Gleevec (imatinib mesylate).

    Prescribing Information. East Hanover, NJ: Novartis;

    January 2002.

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  • Hematopoietic Cell Transplantation for Chronic Myelogenous Leukemia -Medical Cli... Page 17 of 21

    11. Aetna Inc. Protein kinase inhibitors -- Gleevec.

    Pharmacy Clinical Policy Bulletins. Hartford, CT: Aetna;

    January 1, 2005.

    12. Garcia-Manero G, Faderl S, O'Brien S, et al. Chronic

    myelogenous leukemia: A review and update of

    therapeutic strategies. Cancer. 2003;98(3):437-457.

    13. Dalziel K, Round A, Stein K, et al. Effectiveness and

    cost-effectiveness of imatinib for first-line treatment of

    chronic myeloid leukaemia in chronic phase: a

    systematic review and economic analysis. Health

    Technology Assess. 2004;8(28):1-134.

    14. Oehler VG, Radich JP, Storer B, et al. Randomized trial

    of allogeneic related bone marrow transplantation

    versus peripheral blood stem cell transplantation for

    chronic myeloid leukemia. Biol Blood Marrow

    Transplant. 2005;11(2):85-92.

    15. Bornhauser M, Kroger N, Schwerdtfeger R, et al.

    Allogeneic haematopoietic cell transplantation for

    chronic myelogenous leukaemia in the era of imatinib:

    A retrospective multicentre study. Eur J Haematol.

    2006;76(1):9-17.

    16. Greenberg PL, Baer MR, Bennett JM, et al.

    Myelodysplastic syndromes clinical practice guidelines

    in oncology. J Natl Compr Canc Netw. 2006;4(1):58-77.

    17. Hehlmann R, Berger U, Pfirrmann M, et al. Drug

    treatment is superior to allografting as first-line

    therapy in chronic myeloid leukemia. Blood. 2007;109

    (11):4686-4692.

    18. Hehlmann R, Hochhaus A, Baccarani M; European

    LeukemiaNet. Chronic myeloid leukaemia. Lancet.

    2007;370(9584):342-350.

    19. Goldman J. Recommendations for the management of

    BCR-ABL-positive chronic myeloid leukaemia. London,

    UK: British Committee for Standards in Haematology;

    2007.

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  • Hematopoietic Cell Transplantation for Chronic Myelogenous Leukemia -Medical Cli... Page 18 of 21

    20. National Comprehensive Cancer Network (NCCN).

    Chronic myelogenous leukemia. NCCN Clinical Practice

    Guidelines in Oncology. Jenkintown, PA: NCCN; 2009.

    21. Gratwohl A, Heim D. Current role of stem cell

    transplantation in chronic myeloid leukaemia. Best

    Pract Res Clin Haematol. 2009;22(3):431-443.

    22. Champlin R, de Lima M, Kebriaei P, et al.

    Nonmyeloablative allogeneic stem cell transplantation

    for chronic myelogenous leukemia in the imatinib era.

    Clin Lymphoma Myeloma. 2009;9 Suppl 3:S261-S265.

    23. Baccarani M, Cortes J, Pane F, et al; European

    LeukemiaNet. Chronic myeloid leukemia: An update of

    concepts and management recommendations of

    European LeukemiaNet. J Clin Oncol. 2009;27 (35):6041

    6051.

    24. Sun YQ, Xu LP, Liu DH, et al. Allogeneic hematopoietic

    stem cell transplantation for chronic myelomonocytic

    leukemia: A report of 12 patients. Zhonghua Xue Ye

    Xue Za Zhi. 2013;34(2):113-116.

    25. Chalandon Y, Passweg JR, Guglielmi C, et al. Early

    administration of donor lymphocyte infusions upon

    molecular relapse after allogeneic hematopoietic stem

    cell transplantation for chronic myeloid leukemia: A

    study by the Chronic Malignancies Working Party of

    the EBMT. Haematologica. 2014;99(9):1492-1498.

    26. Baccarani M, Castagnetti F, Gugliotta G, Rosti G. A

    review of the European LeukemiaNet

    recommendations for the management of CML. Ann

    Hematol. 2015;94 Suppl 2:S141-S147.

    27. Shimoni A, Volchek Y, Koren-Michowitz M, et al. Phase

    1/2 study of nilotinib prophylaxis after allogeneic stem

    cell transplantation in patients with advanced chronic

    myeloid leukemia or Philadelphia chromosome-

    positive acute lymphoblastic leukemia. Cancer.

    2015;121(6):863-871.

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  • Hematopoietic Cell Transplantation for Chronic Myelogenous Leukemia -Medical Cli... Page 19 of 21

    28. Kitanaka A. Management of advanced-phase chronic

    myeloid leukemia. Rinsho Ketsueki. 2016;57(10):1962

    1971.

    29. Shulman DS, Lee MA, Lehmann LE, Margossian SP.

    Outcomes following bone marrow transplantation in

    children with accelerated phase or blast crisis chronic

    myelogenous leukemia in the era of tyrosine kinase

    inhibitors. J Pediatr Hematol Oncol. 2016;38(8):610

    614.

    30. Ozen M, Ustun C, Oztürk B, et al. Allogeneic

    transplantation in chronic myeloid leukemia and the

    effect of tyrosine kinase inhibitors on survival: A quasi-

    experimental study. Turk J Haematol. 2017;34(1):16-26.

    31. Kondo T, Nagamura-Inoue T, Tojo A, et al. Clinical

    impact of pre-transplant use of multiple tyrosine

    kinase inhibitors on the outcome of allo-HSCT for CML.

    Am J Hematol. 2017 May 20 [Epub ahead of print].

    Autologous Bone Marrow Transplantation:

    1. Bhatia R, Verfaillie CM, Miller JS, McGlave PB.

    Autologous transplantation therapy for chronic

    myelogenous leukemia. Blood. 1997;89(8):2623-2634.

    2. Boiron JM, Cahn JY, Meloni G, et al. Chronic myeloid

    leukemia in first chronic phase not responding to

    alpha-interferon: Outcome and prognostic factors

    after autologous transplantation. EBMT Working Party

    on Chronic Leukemias. Bone Marrow Transplant.

    1999;24(3):259-264.

    3. Pigneux A, Faberes C, Boiron JM, et al. Autologous

    stem cell transplantation in chronic myeloid leukemia:

    A single center experience. Bone Marrow Transplant.

    1999;24(3):265-270.

    4. Podesta M, Piaggio G, Sessarego M, et al. Autografting

    with Ph-negative progenitors in patients at diagnosis

    of chronic myeloid leukemia induces a prolonged

    http://aetnet.aetna.com/mpa/cpb/600_699/0674.html 10/29/2018

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  • Hematopoietic Cell Transplantation for Chronic Myelogenous Leukemia -Medical Cli... Page 20 of 21

    prevalence of Ph-negative hemopoiesis. Exp Hematol.

    2000;28(2):210-215.

    5. McBride NC, Cavenagh JD, Newland AC, et al.

    Autologous transplantation with Philadelphia-negative

    progenitor cells for patients with chronic myeloid

    leukaemia (CML) failing to attain a cytogenetic

    response to alpha interferon. Bone Marrow

    Transplant. 2000;26(11):1165-1172.

    6. Michallet M, Thiebaut A, Philip I, et al. Late autologous

    transplantation in chronic myelogenous leukemia with

    peripheral progenitor cells mobilized by G-CSF and

    interferon-alpha. Leukemia. 2000;14(12):2064-2069.

    7. Meloni G, Capria S, Vignetti M, et al. Ten-year follow-up

    of a single center prospective trial of unmanipulated

    peripheral blood stem cell autograft and interferon-

    alpha in early phase chronic myeloid leukemia.

    Haematologica. 2001;86(6):596-601.

    8. Koziner B, Dengra C, Lucero G, et al. Autologous stem

    cell transplantation for patients with chronic myeloid

    leukemia. The Argentine Group of Bone Marrow

    Transplantation (GATMO) experience. Cancer. 2002;95

    (11):2339-2345.

    9. Schiffer CA, Hehlmann R, Larson R. Perspectives on the

    treatment of chronic phase and advanced phase CML

    and Philadelphia chromosome positive ALL(1).

    Leukemia. 2003;17(4):691-699.

    10. Bhatia R, McGlave PB. Autologous hematopoietic cell

    transplantation for chronic myelogenous leukemia.

    Hematol Oncol Clin North Am. 2004;18(3):715-732, xi.

    11. CML Autograft Trials Collaboration. Autologous stem

    cell transplantation in chronic myeloid leukaemia: A

    meta-analysis of six randomized trials. Cancer Treat

    Rev. 2007;33(1):39-47.

    12. Imrie K, Rumble RB, Crump M; Advisory Panel on Bone

    Marrow and Stem Cell Transplantation; Hematology

    Disease Site Group of Cancer Care Ontario Program in

    Evidence-based Care. Stem cell transplantation in

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  • Hematopoietic Cell Transplantation for Chronic Myelogenous Leukemia -Medical Cli... Page 21 of 21

    adults. Recommendation Report. Toronto, ON: Cancer

    Care Ontario; 2009.

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    Copyright Aetna Inc. All rights reserved. Clinical Policy Bulletins are developed by Aetna to assist in administering plan

    benefits and constitute neither offers of coverage nor medical advice. This Clinical Policy Bulletin contains only a partial,

    general description of plan or program benefits and does not constitute a contract. Aetna does not provide health care

    services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors

    in private practice and are neither employees nor agents of Aetna or its affiliates. Treating providers are solely

    responsible for medical advice and treatment of members. This Clinical Policy Bulletin may be updated and therefore is

    subject to change.

    Copyright © 2001-2018 Aetna Inc.

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  • AETNA BETTER HEALTH® OF PENNSYLVANIA

    Amendment to Aetna Clinical Policy Bulletin Number:

    0674 Hematopoietic Cell Transplantation for Chronic Myelogenous Leukemia

    There are no amendments for Medicaid.

    www.aetnabetterhealth.com/pennsylvania Updated 11/16/2017

    http://www.aetnabetterhealth.com/pennsylvania

    Prior Authorization Review Panel MCO Policy SubmissionHematopoietic Cell Transplantation for Chronic Myelogenous LeukemiaCPT Codes / HCPCS Codes / ICD-10 CodesReferencesAmendment to Aetna Clinical Policy Bulletin Number: 0674 Hematopoietic Cell Transplantation for Chronic Myelogenous Leukemia