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 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.

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 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 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.

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 (hazard ratio [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 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 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 aggressive disease.

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.

Wu and colleagues (2019) examined late mortality in patients with CML who underwent blood transplant or BMT with or without prior TKI therapy. By using data from the Blood or Marrow Transplant Survivor Study, these investigators examined late mortality in 447 patients with CML who underwent BMT between 1974 and 2010, conditional on surviving greater than or equal to 2 years post-BMT. For vital status information, the medical records, the National Death Index, and the Accurint data-base were used. Standardized mortality ratios (SMRs) were calculated using general population age-specific, sex-specific, and calendar-specific mortality rates. Kaplan-Meier techniques and Cox regression were used for all-cause mortality analyses. Cumulative incidence and proportional sub-distribution hazards models for competing risks were used for cause-specific mortality analyses. The 10-year OS rate was 65.7 % and 73 % for those who underwent transplant with and without pre-BMT exposure to TKI therapy, respectively. Patients who underwent transplant with and without pre-BMT TKI experienced SMRs of 6.4 and 6.4, respectively (p = 0.8); and the SMRs were 11.6 and 8.1, respectively, for those with high-risk disease (p = 0.2). Independent predictors of non-CML-related mortality included chronic GVHD (HR, 2.8; 95 % CI: 1.8 to 4.4) and busulfan/cyclophosphamide conditioning (HR, 0.5; 95 % CI: 0.3 to 0.9; reference, total body irradiation/cyclophosphamide conditioning). The 20-year cumulative incidence of CML-related and non-CML-related mortality was 6 % and 36 %, respectively, for the entire cohort. Both CML-related mortality (HR, 1.0; 95 % CI: 0.1 to 12.6) and non-CML-related mortality (HR, 1.3; 95 % CI: 0.6 to 3.1) were comparable for those with and without pre-BMT TKI therapy. The authors concluded that the similar late mortality experienced by patients with CML who underwent transplantation with or without pre-BMT TKIs suggested that allogeneic BMT could be considered in the context of TKI intolerance or non-adherence. The prevention of post-BMT non-CML-related mortality could favorably affect long-term survival.

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.

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 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.

Guidelines from Cancer Care Ontario (Imrie, et al., 2009) state that autologous stem cell transplantation is not recommended for patients with CML.

Appendix

The Hematopoietic Cell Transplantion-Specific Comorbidity Score Calculator is available at the following website:

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Scope of Policy

This Clinical Policy Bulletin addresses hematopoietic cell transplantation for chronic myelogenous leukemia.

Medical Necessity

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.

Experimental and Investigational

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.