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Hematopoietic Cell Transplantation for Chronic Myeloid Leukemia

Policy Number: MP-397

Latest Review Date:  February 2019

Category:  Surgery                                                                 

Policy Grade:  A

Description of Procedure or Service:

Chronic myelogenous leukemia (CML) is a hematopoietic stem-cell disorder that is characterized by the presence of a chromosomal abnormality called the Philadelphia chromosome, which results from reciprocal translocation between the long arms of chromosomes 9 and 22. CML most often presents in a chronic phase which it progresses to an accelerated and then a blast phase. Allogeneic hematopoietic stem cell transplant (HSCT) is a treatment option for CML.

Chronic Myelogenous Leukemia

Chronic myelogenous leukemia (CML) is a hematopoietic stem-cell disorder that is characterized by the presence of a chromosomal abnormality called the Philadelphia chromosome, which results from reciprocal translocation between the long arms of chromosomes 9 and 22.  This cytogenetic change results in constitutive activation of BCR-ABL, a tyrosine kinase (TK) that stimulates unregulated cell proliferation, inhibition of apoptosis, genetic instability, and perturbation of the interactions between CML cells and the bone marrow stroma only in malignant cells. CML accounts for about 15% of newly diagnosed cases of leukemia in adults and occurs in about 1 to 2 cases per 100,000 adults.

The natural history of the disease consists of an initial (indolent) chronic phase, lasting a median of three years that typically transforms into an accelerated phase, followed by a "blast crisis," which is usually the terminal event. Most patients present in chronic phase, often with nonspecific symptoms that are secondary to anemia and splenomegaly. CML is diagnosed based on the presence of the Philadelphia chromosome abnormality by routine cytogenetics or by detection of abnormal BCR-ABL products by fluorescence in situ hybridization or molecular studies, in the setting of persistent unexplained leukocytosis.  Conventional-dose chemotherapy regimens used for chronic-phase disease can induce multiple remissions and delay the onset of blast crisis to a median of four to six years.  However, successive remissions are invariably shorter and more difficult to achieve than their predecessors.

Treatment

Historically, the only curative therapy for CML in blast phase was HCT, and was used more widely earlier in the disease process given the lack of other therapies for chronic phase CML. Drug therapies for chronic phase CML were limited to nonspecific agents including busulfan, hydroxyurea, and interferon-alpha.

Imatinib mesylate (Gleevec®), a selective inhibitor of the abnormal BCR-ABL TK protein), is considered the treatment of choice for newly diagnosed CML.  While imatinib can be highly effective in suppressing CML in most patients, it is not curative and is ineffective in 20% to 30%, initially or due to development of BCR-ABL mutations that cause resistance to the drug. Even so, the overall survival (OS) of patients who present in chronic phase is greater than 95% at two years and 80% to 90% at five years.

Two other TK inhibitors (TKIs, dasatinib, nilotinib) have received marketing approval from the U.S. Food and Drug Administration (FDA) to treat CML as front-line therapy or following failure or patient intolerance of imatinib. Two additional TKIs, bosutinib and ponatinib, have been approved for use for patients resistant or intolerant to prior therapy.

For patients who progress on imatinib, the therapeutic options include increasing the imatinib dose, changing to another TKI, or allo-HSCT. Detection of BCR-ABL mutations may be important in determining an alternative TKI; the presence of T315I mutation is associated with resistance to all TKIs and should indicate the need for allo-HSCT or an experimental therapy. TKIs have been associated with long-term remissions; however, if progression occurs on TKI therapy, allo-HCT is generally indicated and offers the potential for cure.

Hematopoietic Cell Transplantation

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

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

Conventional Preparative Conditioning for HCT

The conventional (“classical”) practice of allogeneic HCT involves administration of cytotoxic agents (e.g., cyclophosphamide, busulfan) with or without total body irradiation at doses sufficient to destroy endogenous hematopoietic capability in the recipient. The beneficial treatment effect in this procedure is due to a combination of initial eradication of malignant cells and subsequent graft-versus-malignancy (GVM) effect that develops after engraftment of allogeneic stem cells within the patient’s bone marrow space. While the slower GVM effect is considered to be the potentially curative component, it may be overwhelmed by extant disease without the use of pretransplant conditioning. However, intense conditioning regimens are limited to patients who are sufficiently fit medically to tolerate substantial adverse effects that include pre-engraftment opportunistic infections secondary to loss of endogenous bone marrow function and organ damage and failure caused by the cytotoxic drugs. Furthermore, in any allogeneic HCT, immune suppressant drugs are required to minimize graft rejection and GVHD, which also increases susceptibility of the patient to opportunistic infections. The immune reactivity between donor T cells and malignant cells that is responsible for the GVM effect also leads to acute and chronic GVHD.

The success of autologous HCT is predicated on the ability of cytotoxic chemotherapy with or without radiation to eradicate cancerous cells from the blood and bone marrow. This permits subsequent engraftment and repopulation of bone marrow space with presumably normal hematopoietic stem cells obtained from the patient prior to undergoing bone marrow ablation. As a consequence, autologous HCT is typically performed as consolidation therapy when the patient’s disease is in complete remission. Patients who undergo autologous HCT are susceptible to chemotherapy-related toxicities and opportunistic infections prior to engraftment, but not GVHD.

Reduced-Intensity Conditioning for Allogeneic HCT

Reduced-intensity conditioning (RIC) refers to the pretransplant use of lower doses or less intense regimens of cytotoxic drugs or radiation than are used in conventional full-dose myeloablative conditioning treatments. The goal of RIC is to reduce disease burden, but also to minimize as much as possible associated treatment-related morbidity and non-relapse mortality (NRM) in the period during which the beneficial GVM effect of allogeneic transplantation develops. Although the definition of RIC remains arbitrary, with numerous versions employed, all seek to balance the competing effects of NRM and relapse due to residual disease. RIC regimens can be viewed as a continuum in effects, from nearly totally myeloablative, to minimally myeloablative with lymphoablation, with intensity tailored to specific diseases and patient condition. Patients who undergo RIC with allogeneic HCT initially demonstrate donor cell engraftment and bone marrow mixed chimerism. Most will subsequently convert to full-donor chimerism, which may be supplemented with donor lymphocyte infusions to eradicate residual malignant cells. For the purposes of this evidence review, the term “reduced-intensity conditioning” will refer to all conditioning regimens intended to be nonmyeloablative, as opposed to fully myeloablative (conventional) regimens.

For CML, RIC regimens were initially used to extend the use of allogeneic HCT to the estimated 70% of CML patients who were ineligible for myeloablative conditioning regimens because of advanced age or comorbidities. The use of RIC and allogeneic HCT is of particular interest for treatment of CML given the relatively pronounced susceptibility of this malignancy to the graft versus leukemia (GVL) effect of allogeneic hematopoietic progenitor cells following their engraftment in the host.

Policy:

Allogeneic hematopoietic cell transplantation using a myeloablative conditioning regimen may be medically necessary for the treatment of chronic myeloid leukemia.

Allogeneic hematopoietic cell transplantation using a reduced-intensity conditioning (RIC) regimen may be medically necessary for the treatment of chronic myeloid leukemia in patients who meet clinical criteria for an allogeneic HCT, but who are not considered candidates for a myeloablative conditioning allogeneic HCT.

Autologous hematopoietic cell transplantation is not medically necessary and is considered investigational as a treatment of chronic myeloid leukemia.

Key Points:

The most recent literature update was performed through December 21. 2018.

The clinical evidence to determine whether the use of technology improves the net health outcome is assessed by evidence reviews. Health outcomes are assessed by the length of life, quality of life, and ability to function, including benefits and harms. Every clinical condition has specific outcomes that are important to patients and managing the course of that condition. Outcome measures are validated to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

The net health outcome of technology is assessed by whether the evidence is sufficient enough to draw conclusions, while examining two domains: the relevance, and quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. In various conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence is determined by study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is favored to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Allogeneic Hematopoietic Cell Transplantation

Clinical Context and Test Purpose

The purpose of allo-HCT is to provide a treatment option that is an alternative to or an improvement on existing therapies in individuals with chronic myeloid leukemia (CML).

The question addressed in this evidence review is: In individuals with CML, does the use of allo-HCT improve the net health outcomes?

The following PICOTS were used to select literature to inform this review.

Patients

The patient population of interest are patients with CML.

Interventions

The therapy being considered is allo-HCT.

Comparators

Comparators include cytotoxic chemotherapy and treatment with tyrosine kinase inhibitors (TKIs).

Outcomes

The outcomes of interest are overall survival (OS), disease-specific survival, treatment-related mortality, and treatment-related morbidity.

Timing

Follow-up over months to years is of interest for relevant outcomes.

Setting

Patients are actively managed by hematologists/oncologists in an inpatient and outpatient clinical setting.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

1. To assess efficacy outcomes, comparative controlled prospective trials were sought,   

              with a preference for RCTs;

2. In the absence of such trials, comparative observational studies were sought, with

              a preference for prospective studies.

3. To assess long-term outcomes and adverse events, single-arm studies that capture longer

               periods of follow-up and/or larger populations were sought.

4. Studies with duplicative or overlapping populations were excluded.

In the pre-tyrosine kinase inhibitor (TKI) era, allogeneic HCT was the standard treatment for CML. Evidence in support of allo-HCT includes a randomized controlled trial (RCT) comparing primary HCT from a matched family donor (n=166) with best available drug treatment (n=261) which enrolled patients from 1997 to 2004, there were no differences in overall survival between groups (10-year survival 0.76 for HCT patients vs 0.69 for best available drug treatment patients). Those with low transplant risk treated with HCT had improved survival compared with those treated with medical therapy, but after patients entered blast crisis, survival did not differ between groups.

The advent of tyrosine kinase inhibitor (TKI) therapy has altered the treatment paradigm for CML such that the majority of patients are treated initially with a TKI until disease progresses. While progression may occur within months of starting a TKI, this may be delayed for years, as shown by the results of the IRIS trial and other studies. With the addition of three other TKIs (dasatinib, nilotinib, and bosutinib) plus the possibility of effective dose escalation with imatinib to override resistance, it is possible to maintain a typical CML patient past the upper age limit (usually 50-55 years) at which a myeloablative allogeneic HCT is considered an option.

Nonrandomized Studies

Several nonrandomized comparative studies have compared treatment with TKI therapy and allo-HCT in CML patients. Liu et al evaluated outcomes for chronic-phase CML patients who underwent HCT after imatinib failure. The authors retrospectively evaluated 105 patients with newly-diagnosed chronic-phase CML seen at a single institution from 1999 to 2011. Sixty-six patients received first-line imatinib therapy, 26 (treated before 2003) received interferon followed by imatinib, and 13 received front-line allo-HCT with curative intent. Twenty-two (21.0%) patients received allo-HCT overall, including 13 as front-line therapy and nine following imatinib failure. Compared with those who received front-line allo-HCT, those who underwent HCT following imatinib failure had higher European Group for Blood and Bone Marrow Transplantation (EBMT) risk score (p=0.03). Among patients receiving allo-HCT (n=22), patients with imatinib failure and disease progression had a significantly worse OS (p=0.015) compared with those receiving allo-HCT as front-line therapy (median follow-up, 134 months, range, 6-167 months). One patient died of relapse and one of chronic GVHD among patients receiving front-line allo-HCT, with a three-year survival rate of 91.7% (95% confidence interval [CI], 29 to 38 months).

In 2015, Xu et al retrospectively compared second-generation TKI therapy with allo-HCT in 93 patients with accelerated phase CML. The second-generation TKI therapy group included 33 subjects, most of whom had been previously treated with another TKI (n=31 with imatinib and n=2 with nilotinib). Of 60 patients treated with allo-HCT, 10 were treated with primary HCT and 50 had been previously treated with imatinib. Median OS was significantly shorter with second generation TKI treatment than with allo-HCT (22 months vs 82 months). Median progression-free and event-free survival rates were similarly shorter with second-generation TKI treatment with allo-HCT.

Zhang et al (2016) retrospectively compared imatinib (n=292) and allo-HCT (n-141) in patients with CML. Survival rates were significantly higher in the imatinib group than the allo-HCT group. Five year EFS were 84% and 75%, respectively (p<0.05) and 5-year OS rates were 92% and 79%, respectively. Findings were similar in patients with chronic phase and advanced phase disease.

Several studies have compared outcomes for CML patients treated with allo-HCT the pre- and post-TKI eras. While these studies generally report no worsening in treatment outcomes for allo-HCT following TKI, they are limited by the underlying differences in treatment regimen in different eras. In a retrospective analysis of 106 patients who underwent allo-HCT who either did (n=36) or did not (n=70) received prior treatment with TKIs, Shen et al (2015) reported no difference in 10 year relapse free survival or OS. However, TKI-treated patients had higher 0.5 year transplant-related mortality rate. In another retrospective analysis comparing patients treated with allo- HCT in the pre-TKI era (2002-2013; n=30), Chamseddine et al (2015) reported longer 3 year OS and leukemia-free survival (LFS) in TKI era-treated patients.

Case Series

In addition to the comparative studies, a number of case series, primarily single-center, reported outcomes of patients treated with allo-HCT post TKI treatment of failure. In a 2015 series of 51 patients treated with allo-HCT, 32 of whom were treated for TKI resistance or intolerance, 8 year OS and event-free survival were 68% and 46%. A prospective series of 28 patients who underwent HSCT after failure of at least 2 TKIs reported deep molecular remission in 18 subjects. However, all 6 patients transplanted in blast crisis died. In a smaller series, Zhao et al reported outcomes for 12 patients with CML with disease progression on imatinib who were treated with either dasatinib or nilotinib followed by allo-HCT at a single center. After a median follow-up of 28 months (range, 12-37 months) after allo-HCT, 8 of 12 (66.7%) patients were alive, including 7 with complete molecular remission.

In addition to being used prior to allo-HCT, TKI therapy may be used after HCT to prevent or treat disease relapse. Egan et al conducted a retrospective analysis of patients at a single institution who underwent allogeneic HCT for CML and Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL) at a single institution with detectable BCR-ABL transcripts and RNA available for sequencing of the ABL kinase domain in both the pre- and post-HCT settings to evaluate the impact of pre-HCT mutations in the ABL kinase domain on post-HCT relapse. Among 95 patients with CML with available polymerase chain reaction transcripts, ten (10.5%) were found to have pre-HCT ABL kinase mutations known to confer resistance to TKIs. Of those with CML, 88.4% underwent myeloablative chemotherapy and 11.6% underwent nonmyeloablative chemotherapy. Twenty-nine CML patients received post-HCT TKIs, 19 (65.5%) for prophylaxis and ten (34.5%) for treatment of refractory or relapsed disease. In nine (64.2%) of the 14 patients with pre-HCT mutations (both CML and Philadelphia chromosome –positive ALL), the same mutation conferring TKI resistance was also detectable after allo-HCT. Among the 14 with pre-HCT mutations, eight (57.1%) received a TKI in the post-HCT setting, and seven (50%) demonstrated post-HSCT refractory disease or relapse. Of the seven with relapsed disease, five had been given a predictably ineffective TKI based on mutation status in the first 100 days after allo-HCT, based on mutation analysis conducted by the authors.

HCT with Nonmyeloablative Conditioning

Techniques for allogeneic HCT have continued to develop, with important advancements in the use of nonmyeloablative or reduced-intensity conditioning (RIC) preparative regimens. Overall, among nine studies compiled in a recent review, outcomes achieved with RIC allogeneic transplants have been similar to those with conventional allotransplants, with overall survival (OS) rates ranging from 35% at 2.5 years to 85% at five years among patients in chronic phase I at transplant.   Among the studies included in this review, treatment-related mortality or non-relapse mortality ranged from 0% at one year to 29% at one year.  In the largest experience, a retrospective European Group for Blood and Marrow Transplantation (EMBT) study of 186 patients, overall survival (OS) was 54% at three years using a variety of RIC regimens in patients in chronic phase I (n=118), chronic phase II (n=26), acute phase (n=30), and blast crisis (n=12).  Among patients transplanted in the first chronic phase (CP1), OS was 69% at three years.

RIC regimens have many of the same limitations as standard-intensity conditioning: relapse, GVHD (particularly chronic GVHD), and mortality from treatment-related causes other than myelotoxicity. However, in the absence of prospective, comparative, randomized trials, only indirect comparisons can be made between the relative clinical benefits and harms associated with myeloablative and RIC regimens with allogeneic HCT. Comparison of study results is further compromised by heterogeneity among patients, treatments, and outcome measures.  Nonetheless, clinical evidence suggests outcomes in CML are similar with myeloablative and RIC allogeneic HCT.

Section Summary: Allogeneic Hematopoietic Cell Transplantation

Allogeneic HCT is accepted as a standard treatment in CML, although the use of targeted TKI therapy has allowed many patients who would previously have required allo-HCT to forestall or avoid HCT. Direct comparisons between myeloablative and nonmyeloablative conditioning regimens are not available, but the available evidence suggests that allo-HCT following nonmyeloablative conditioning regimens can lead to short and medium-term survival rates that are on the order of those seen after myeloablative conditioning regimens. Although research into the optimal timing of allo-HCT in the setting of TKI therapy is limited, the available evidence suggests that pre-treatment with TKIs does not worsen outcomes after allo-HCT and may actually improve outcomes.

Autologous Hematopoietic Cell Transplantation

Clinical Context and Test Purpose

The purpose of autologous HCT is to provide a treatment option that is an alternative to or an improvement on existing therapies in individuals with CML.

The question addressed in this evidence review is: In individuals with CML, does the use of autologous HCT improve the net health outcome?

The following PICOTS were used to select literature to inform this review.

Patients

The patient population of interest are patients with CML.

Interventions

The treatment being considered is autologous HCT.

Comparators

Comparators include cytotoxic chemotherapy and treatment with TKIs.

Outcomes

The outcomes of interest are OS, disease-specific survival, treatment-related mortality, and treatment-related morbidity.

Timing

Follow-up over months to years is of interest for relevant outcomes.

Setting

Patients are actively managed by hematologists/oncologists in an inpatient and outpatient clinical setting.

Study Selection Criteria

Methodologically credible studies were selected using principles described above.

A major limitation in the use of autologous HCT in patients with CML is a high probability that leukemic cells will be infused back into the patient. However, it is recognized that many CML patients still have normal marrow stem cells. Techniques used to isolate and expand this normal clone of cells have included ex vivo purging, long-term culture, and immunophenotype selection. Even without such techniques, there have been isolated case reports of partial cytogenetic remissions after autologous HCT, and one study has suggested that patients undergoing such therapy may have improved survival compared with historical controls.

In the pre-TKI era, there was active research into the use of autologous HCT for CML. McGlave et al reported the outcomes of 200 consecutive autologous transplants using purged or unpurged marrow from 8 different transplant centers. Of the 200 patients studied, 125 were alive at a median follow-up of 42 months. Of the 142 transplanted in chronic phase, the median survival had not been reached at the time of publication, while the median survival was 35.9 months for those transplanted during an accelerated phase. Other data consist of small, single institution case series using a variety of techniques to enrich the population of normal stem cells among the harvested cells. 

Additional reports of small, uncontrolled studies with a total of 182 patients (range: 15–41 patients) given autologous transplants for CML included patient populations that varied across the 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 alfa. Finally, some focused on patients transplanted in the late chronic phase or after transformation to accelerated phase or blast crisis. Although some patients achieved complete or partial molecular remissions and long-term disease-free survival, these studies do not permit conclusions free from the influence of patient selection bias. All autotransplanted patients included in these reports were treated before imatinib mesylate, or newer TKIs became available.

Section Summary: Autologous Hematopoietic Cell Transplantation

No controlled studies have evaluated autologous HCT for treatment of CML. The available data consists of case reports and case series. In the largest series of 200 patients, median survival was 36 months for patients transplanted during an accelerated phase and median survival data were not available for patients transplanted in chronic phase. Controlled studies are needed to draw conclusions about the impact of autologous HCT on health outcomes in patients with CML.

Summary of Evidence

For individuals who have CML who receive allo-HCT, the evidence includes systematic reviews, randomized controlled trials (RCTs), and multiple prospective and retrospective series. Relevant outcomes include overall survival, disease-specific survival, and treatment-related morbidity and mortality. The introduction of the tyrosine kinase inhibitors (TKIs) imatinib, dasatinib, nilotinib, bosutinib, and ponatinib, has significantly changed the practice of HCT for CML. TKIs have replaced HCT as initial therapy in patients with chronic phase CML. However a significant proportion of cases fail to respond to TKIs, develop resistance to them, or become unable to tolerate all TKIs and go on to allogeneic HCT. In addition, allogeneic HCT represents the only potentially curative option for those patients in accelerated or blast phase.  The currently-available evidence suggests that TKI-pretreatment does not lead to worse outcomes if HCT is needed. Myeloablative conditioning regimens prior to HCT are used in younger (<60 years) patients without significant comorbidities. However, for patients with more comorbidities and/or more advanced ages in whom myeloablative conditioning regimens would be prohibitively high risk, evidence suggests that reasonable outcomes can be obtained after HCT. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have CML who receive autologous HCT, the evidence includes case series. Relevant outcomes are overall survival, disease-specific survival, and treatment-related morbidity and mortality. In the largest series of 200 patients, median survival was 36 months for patients transplanted during an accelerated phase and median survival data were not available for patients transplanted in chronic phase. Controlled studies are needed to draw conclusions about the impact of autologous HCT on health outcomes in patients with CML. The evidence is insufficient to determine the effects of the technology on health outcomes.

Practice Guidelines and Position Statements

National Comprehensive Cancer Network (NCCN)

Current National Comprehensive Cancer Network guidelines (v.1.2019) recommend allogeneic hematopoietic cell transplantation (allo-HCT) as an alternative treatment only for high-risk settings or in patients with advanced phase chronic myeloid leukemia (CML). Relevant recommendations are:

      “Allogeneic HCT is no longer recommended as a first-line treatment option for CP [chronic   

        phase] CML.”

      “Allogeneic HCT is an appropriate treatment option for the very rare patients presenting        

       with BP [blast phase]-CML at diagnosis, patients with disease that is resistant to TKIs,   

       patients with progression to AP [accelerated phase]-CML or BP-CML while on TKI therapy,

       and for the rare patients intolerant to all TKIs”

      “Evaluation for allogeneic HCT….is recommended for all patients with AP [accelerated

        phase] CML or BP [blast phase] CML”

NCCN guideline states, “Nonmyeloablative allogeneic HCT is a well-tolerated treatment option for patients with a matched donor and the selection of patients is based on their age and presence of comorbidities.

Autologous bone marrow transplant for CML is not addressed in the NCCN guidelines.

American Society for Blood and Marrow Transplantation

In 2015, guidelines by the American Society for Blood and Marrow Transplantation were published on indications for autologous and allogeneic HCT.

Recommendations regarding CML are listed in Table 1.

Table 1. Recommendations on Allogeneic and Autologous HCT for CML

Indications

Allogeneic HCT

Autologous HCT

Pediatric

Chronic phase

C

N

Accelerated phase

C

N

Blast phase

C

N

Adult

Chronic phase, tyrosine kinase inhibitor intolerant

C

N

Chronic phase, tyrosine kinase inhibitor refractory

C

N

Chronic phase 2+

S

N

Accelerated phase

S

N

Blast phase

S

N

C: Standard of care, clinical evidence available; S: standard of care; N: Not generally recommended; HCT: hematopoietic cell transplantation

U.S. Preventive Services Task Force Recommendations

Not applicable.

Key Words:

Chronic Myelogenous Leukemia, High-Dose Chemotherapy, Stem-Cell Transplant, Myeloid, CML, HSCT, HCT, allogeneic, allo-HCT, autologous, chronic myeloid leukemia, hematopoietic cell transplantation

Approved by Governing Bodies:

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

Benefit Application:

Coverage is subject to member’s specific benefits.  Group specific policy will supersede this policy when applicable.

ITS: Home Policy provisions apply

FEP: Special benefit consideration may apply. Refer to member’s benefit plan. FEP does not consider investigational if FDA approved and will be reviewed for medical necessity.

Current Coding: 

CPT Codes:

38204 Management of recipient hematopoietic cell donor search and cell acquisition
38205 Blood-derived hematopoietic progenitor cell harvesting for transplantation, per collection, allogeneic
38206   Blood-derived hematopoietic progenitor cell harvesting for transplantation, per collection, autologous
38208  Transplant preparation of hematopoietic progenitor cells; thawing of previously frozen harvest, without washing; per donor
38209   ;thawing of previously frozen harvest, with washing; per donor  
38210 ;specific cell depletion within harvest, T-cell depletion
38211 ;tumor cell depletion
38212   ;red blood cell removal
38213 ;platelet depletion
38214 ;plasma (volume) depletion
38215   

;cell concentration in plasma, mononuclear, or buffy coat

                                                layer

38220   Diagnostic bone marrow; aspiration(s)
38221  Diagnostic bone marrow; biopsy(ies)
38222 Diagnostic bone marrow; biopsy(ies) and aspiration(s) (Effective 01/01/2018)
38230  Bone marrow harvesting for transplantation; allogeneic
38232 ; autologous
38240   Bone marrow or blood-derived peripheral stem-cell transplantation; allogeneic
38241  Bone marrow or blood-derived peripheral stem-cell transplantation; autologous
38242  Allogeneic donor lymphocyte infusions

             

HCPCS:    

S2140      Cord blood harvesting for transplantation, allogeneic
S2142 Cord blood-derived stem-cell transplantation, allogeneic
S2150

Bone marrow or blood-derived stem cells (peripheral or umbilical),allogeneic or autologous, harvesting, transplantation and related complications including pheresis and cell preparation/storage; marrow ablative therapy; drugs; supplies; hospitalization with outpatient follow-up; medical/surgical, diagnostic, emergency, and rehabilitative services; and the number of days of pre- and post-transplant care in the global definition

     

        

             

             

References:

  1. Apperley JF. Managing the patient with chronic myeloid leukemia through and after allogeneic stem cell transplantation. In: Hematology 2006 (Am Soc Hematol Education Program Book); N Berliner, C Linker, CA Schiffer (eds.). Washington, DC: American Society of Hematology, 2006; pp. 226-232.

  2. Baccarani M, Cortes J, Pane F et al. Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet. J Clin Oncol 2009; 27(35):6041-6051.

  3. Baccarani M, Deininger MW, Rosti G et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood 2013; 122(6):872-884.

  4. Bhatia R, Verfaillie CM, Miller JS, et al. Autologous transplantation therapy for chronic myelogenous leukemia.  Blood 1997; 89(8):2623-2634.

  5. 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.

  6. Cervantes F, Mauro M. Practical management of patients with chronic myeloid leukemia. Cancer 2011; 117(19):4343-4354.

  7. Chakrabarti S and Buyck HC. Reduced-intensity transplantation in the treatment of haematological malignancies: Current status and future prospects. Current Stem Cell Res Ther 2007; 2(2):163-188.

  8. Chamseddine An, Wilekens C, De Botton S, et al. Retrospective study of allogeneic hematopoietic stem cell transplantation in Philadelphia chromosome-positive leukemia: 25 years’ experience at Gustave Roussy Cancer campus. Clin Lymphoma Myeloma Leuk. Jun 2015: 15 Suppl: S129-140.

  9. Crawley C, Szydlo R, Lalancette M, et al.  Outcomes of reduced-intensity transplantation for chronic myeloid leukemia: An analysis of prognostic factors from the Chronic Leukemia Working Party of the EBMT.  Blood 2005; 106(9):2969-2976.

  10. Druker BJ, Guilhot F, O’Brien SG, et al.  Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia.  N Engl J Med 2006; 355(23):2408-2417.

  11. Egan DN, Beppu L, Radich JP. Patients with Philadelphia-positive leukemia with BCR-ABL kinase mutations before allogeneic transplantation predominantly relapse with the same mutation. Biol Blood Marrow Transplant. Jan 2015;21(1):184-189.

  12. Fernandez HF and Kharfan-Dabaja MA.  Tyrosine kinase inhibitors and allogeneic hematopoietic cell transplantation for chronic myeloid leukemia: Targeting both therapeutic modalities.  Cancer Control 2009; 16(2):153-157.

  13. Giralt SA, Arora M, Goldman JM, et al.  Impact of imatinib therapy on the use of allogeneic haematopoietic progenitor cell transplantation for the treatment of chronic myeloid leukaemia.  Br J Haematol 2007; 137(5):461-467.

  14. Gratwohl A, Pfirrmann M, Zander A, et al. Long-term outcome of patients with newly diagnosed chronic myeloid leukemia: a randomized comparison of stem cell transplantation with drug treatment. Leukemia. Mar 2016;30(3):562-569.

  15. Jabbour E, Kantarjian H. Chronic myeloid leukemia: 2014 update on diagnosis, monitoring, and management. Am J Hematol. May 2014; 89(5):547-556.

  16. Jain N, van Besien K. Chronic myelogenous leukemia: role of stem cell transplant in the imatinib era. Hematol Oncol Clin North Am 2011; 25(5):1025-1048.

  17. Kantarjian H, Shah NP, Hochhaus A et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 2010; 362(24):2260-2270.

  18. Lee SE, Choi SY, Kim SH, et al. Prognostic factors for outcomes of allogeneic stem cell transplantation in chronic phase chronic myeloid leukemia in the era of tyrosine kinase inhibitors. Hematology. Mar 2014; 19(2):63-72.

  19. Liu YC, Hsiao HH, Chang CS, et al. Outcome of allotransplants in patients with chronic-phase chronic myeloid leukemia following imatinib failure: prognosis revisited. Anticancer Res. Oct 2013; 33(10):4663-4667.

  20. Majhail NS, Farnia SH, Carpenter PA, et al. Indications for autologous and allogeneic hematopoietic cell transplantation: guidelines from the American Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant. Nov 2015; 21(11):1863-1869.

  21. Mauro MJ and Deininger MW.  Chronic myeloid leukemia in 2006: A perspective. Haematologica 2006; 91(2):152-158.

  22. Maziarz RT. Who with chronic myelogenous leukemia to transplant in the era of tyrosine kinase inhibitors? Curr Opin Hematol 2008; 15(2):127-133.

  23. 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.

  24. McGlave PB, De Fabritiis P, Deisseroth A, et al. Autologous transplants for chronic myelogenous leukemia: results from eight transplant groups. Lancet 1994; 343(8911):1486-1488.

  25. McGlave PB, Shu XO, Wen W, et al. Unrelated donor marrow transplantation for chronic myelogenous leukemia: 9 years' experience of the national marrow donor program. Blood 2000; 95(7):2219-2225.

  26. 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.

  27. Michallet M, Thiebaut A, Philip I, et al.  Late autologous transplantation in chronic myelogenous leukemia with peripheral blood progenitor cells mobilized by G-CSF and interferon-alpha.  Leukemia 2000; 14(12):2064-2069.

  28. Nair AP, Barnett MJ, Broady RC, et al. Allogeneic hematopoietic stem cell transplantation is an effective salvage therapy for patients with chronic myeloid leukemia presenting with advanced disease or failing treatment with tyrosine kinase inhibitors. Biol Blood Marrow Transplant. Aug 2015; 21(8):1437-1444.

  29. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Chronic Myeloid Leukemia. Version 1.2019. https://www.nccn.org/professionals/physician_gls/pdf/cml.pdf. Accessed January 19, 2019.

  30. Pavlu J, Szydlo RM, Goldman JM et al. Three decades of transplantation for chronic myeloid leukemia: what have we learned? Blood 2011; 117(3):755-763.

  31. Piekarska A, Gil L, Prejner W, et al. Pretransplantation use of the second-generation tyrosine kinase inhibitors has no negative impact on the HCT outcome. Ann Hematol. Nov 2015: 94(11):1891-1897.

  32. 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.

  33. Podesta M, Piaggio G, Sessarego M, et al. Autografting with Ph-negative progenitors in patients at diagnosis of chronic myeloid leukemia induces a prolonged prevalence of Ph-negative hemopoiesis. Exp Hematol 2000; 28(2):210-215.

  34. Saglio G, Kim DW, Issaragrisil S et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med 2010; 362(24):2251-2259.

  35. Shen K, Liu Q, Sun J, et al. Prior exposure to imatinib does not impact outcome of allogeneic hematopoietic transplantation for chronic myeloid leukemia patients: a single-center experience in china. Int J Clin Exp Med. 2015; 8(2):2495-2505.

  36. Szatrowski TP.  Progenitor cell transplantation for chronic myelogenous leukemia. Semin Oncol 1999; 26(1):62-66.

  37. U.S. Food and Drug Administration. Tissue and Tissue Products. www.fda.gov/BiologicsBloodVaccines/TissueTissueProducts/.

  38. von Bubnoff N, Duyster J. Chronic myelogenous leukemia: treatment and monitoring. Dtsch Arztebl Int 2010; 107(7):114-121.

  39. 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.

  40. Xu L, Zhu H, Hu J, et al. Superiority of allogeneic hematopoietic stem cell transplantation to nilotinib and dasatinib for adult patients with chronic myelogenous leukemia in the accelerated phase. Front Med. Sep 2015; 9 (3):304-311.

  41. Zhang GF, Zhou M, Bao XB et al. Imatinib mesylate versus allogeneic hematopoietic stem cell transplantation for patients with chronic myelogenous leukemia. Asian Pac J Cancer Prev. 2016; 17(9):4477-4481.

  42. Zhao Y, Luo Y, Shi J, et al. Second-generation tyrosine kinase inhibitors combined with stem cell transplantation in patients with imatinib-refractory chronic myeloid leukemia. Am J Med Sci. Jun 2014; 347(6):439-445.

Policy History:

Medical Policy Group, December 2009 (3)

Medical Policy Administration Committee, February 2010

Available for comment February 5-March 22, 2010

Medical Policy Group, December 2011; Updated Codes 38209, 38210 & 38230 and added Code 38232 – 2012 code updates

Medical Policy Group, December 2011 (4): added Summary section to Key Points and updated References.

Medical Policy Panel, December 2012

Medical Policy Group, December 2012 (3): 2012 update -  NCCN Guidelines section and References.  Policy statement remains unchanged

Medical Policy Panel, December 2013

Medical Policy Group, January 2014 (3):  2013 Updates to Description, Key Points and References; no change in policy statement

Medical Policy Panel, December 2014

Medical Policy Group, January 2015 (3): 2014 Updates to Description, Key Points, and References, no change in policy statement.

Medical Policy Panel, January 2016

Medical Policy Group, March 2016 (2): 2016 Updates Description, Key Points, Approved by Governing Bodies, and References, no change in policy statement.

Medical Policy Panel, January 2017

Medical Policy Group, January 2017 (7): Updates to Description, Key Points, Key Words, and References. Updated policy title and policy statements by removing “stem”, and replaced “myelogenous” with “myeloid” for clarification purposes.

Medical Policy Group, December 2017. Annual Coding Update 2018. Added new CPT code 38222 effective 1/1/18 to the Current Coding section. Updated verbiage for revised CPT codes 38220 and 38221.

Medical Policy Panel, February 2018

Medical Policy Group, March 2018 (7): Updates to Key Points and References. No change in Policy Statement.

Medical Policy Panel, January 2019

Medical Policy Group, February 2019 (3): 2019 Updates to Key Points, Practice Guidelines and Position Statements, References and Key Words: added: hematopoietic cell transplantation. No changes to policy statement or intent.

This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.

This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and pre-procedure review) in Blue Cross and Blue Shield’s administration of plan contracts.

The plan does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. The plan administers benefits based on the member’s contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination.

As a general rule, benefits are payable under health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage.

The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage:

1. The technology must have final approval from the appropriate government regulatory bodies;

2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes;

3. The technology must improve the net health outcome;

4. The technology must be as beneficial as any established alternatives;

5. The improvement must be attainable outside the investigational setting.

Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are:

1. In accordance with generally accepted standards of medical practice; and

2. Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient’s illness, injury or disease; and

3. Not primarily for the convenience of the patient, physician or other health care provider; and

4. Not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that patient’s illness, injury or disease.