Chronic Myeloid Leukemia

Treatment

Chronic phase

Conventional chemotherapy

Busulfan (Busulfex, Myleran) and hydroxyurea were the chemotherapeutic agents used most frequently in CML until the development of interferon and more recently tyrosine kinase inhibitors. Busulfan(Drug information on busulfan) is now rarely used.

Hydroxyurea is most frequently used to control the WBC count while confirming the diagnosis of CML. The dose can be adjusted individually to control the WBC count. In some instances, a dose of 10 to 12 g/d may be needed.

Neither busulfan nor hydroxyurea significantly reduces the percentage of cells bearing the Ph chromosome, and, therefore, the risk of transformation to the blastic phase is unchanged. Their use should be limited to temporary control of hematologic manifestations before definitive therapy (eg, imatinib(Drug information on imatinib), stem cell transplantation) is instituted. Once the diagnosis of CML is confirmed, imatinib should be initiated immediately. There is usually no need for or benefit from initially "debulking" with hydroxyurea.

Interferon

Interferon-α can induce a complete hematologic response (Table 2) in 70% to 80% of patients with CML, and with some degree of suppression of Ph chromosome-positive cells (ie, cytogenetic response) in 40% to 60% of patients, which is complete in up to 20% to 25% of patients. Randomized studies have documented a survival advantage for patients treated with interferon-α who achieved a major, and particularly a complete, cytogenetic response.

TABLE 2Response definitions in CML

Patients who achieve a complete cytogenetic response have a 10-year survival rate of 75% or more, compared with less than 40% for those having a partial response and less than 30% for individuals having a lesser or no response.

Interferon and cytarabine(Drug information on cytarabine) (Ara-C) The combination of interferon-α and low-dose Ara-C induced a higher (ie, 40% to 50%) response rate, and possibly a survival advantage.

Approximately 30% of those achieving complete cytogenetic remission with interferon-α may achieve a sustained molecular remission and are probably cured. Among the others, 40% to 60% remain free of disease after more than 10 years despite the presence of minimal residual disease. This has been called "operational cure."'

Formulations of interferon-α attached to polyethylene glycol (PEG) have a longer half-life that allows for weekly administration and may have decreased toxicity.

FIGURE 1Treatment algorithm for chronic-phase CML. Options marked with a question mark define investigational approaches that cannot be considered standard at this time.

Imatinib is a potent inhibitor of the tyrosine kinase activity of bcr-abl and a few other tyrosine kinases, such as PDGF-R (platelet-derived growth factor-receptor) and c-KIT. It has demonstrated significant activity in patients with CML in all phases of the disease, whether they have received prior therapy (with interferon) or they receive imatinib as their initial therapy. Among patients with chronic-phase CML who failed to respond to prior interferon-α therapy, 55% to 85% of patients achieved a major cytogenetic remission, including 45% to 80% with a complete cytogenetic remission. Patients who were deemed to be at high risk on the basis of Sokal scores had a lower rate of complete cytogenetic response (69%) than did patients who were at low risk or intermediate risk (89% and 82%, respectively). Among patients treated in early chronic-phase CML who had not received prior therapy, the rate of complete cytogenetic response is 83%, with an overall survival rate at 8 years of 85%, and an event-free survival of 81%.

Overall and event-free survival rates with imatinib therapy are significantly better than those seen with interferon. Thus, imatinib has become the standard therapy for CML (Figure 1). The proper management of patients receiving imatinib is important to optimize long-term outcome.

Preliminary results of a randomized phase III study comparing 400 mg and 800 mg of imatinib (Gleevec) daily as initial therapy for patients in chronic phase suggested a higher rate of response at earlier time points for patients treated with 800 mg, with a lower rate of transformation by 18 months of follow-up (3.2% vs 1.9%). An update of this same study after 24 months of follow-up showed no difference in the rate of complete cytogenetic response, major molecular response, event-free survival, or progression-free survival between the two cohorts. This result may have been explained in part by the high rate of dose reductions and treatment discontinuation, particularly in the high-dose group. Patients who maintained a dose intensity throughout the study of at least 600 mg had a significantly higher rate of major molecular response. Another randomized study exploring 400 mg and 800 mg of imatinib or imatinib combined with interferon as initial therapy for patients with CML in chronic phase showed an improvement in the time to complete cytogenetic response and major molecular response for patients treated with 800 mg, compared with the other two arms. This result translated into a trend for an improved 5-year progression-free survival (94%), compared with those treated with standard-dose imatinib (87%) or with imatinib plus interferon (91%). The long-term benefit in this study might be due to the fact that dose intensity was maintained at a higher level.

Dose The standard dose of imatinib is 400 mg/day for the chronic phase and 600 mg/day for the accelerated and blastic phases. Dose reductions may be needed in some patients because of toxicity, but doses less than 300 mg/day are not recommended. Available data from the phase I study show a decrease in the probability of response with doses lower than 300 mg/day.

Toxicity Imatinib is generally well tolerated. However, several patients develop grade 1–2 adverse events, including nausea, peripheral or periorbital edema, muscle cramps, diarrhea, rashes, weight gain, and fatigue. These events frequently are minor and either do not require therapy or respond to adequate early intervention. Fluid retention responds to diuretics when indicated; diarrhea can be managed with loperamide or other agents; nausea usually responds to prochlorperazine(Drug information on prochlorperazine), promethazine(Drug information on promethazine), or other agents; muscle cramps can be managed with tonic water or quinine(Drug information on quinine); rash may be managed with antihistamines and/or corticosteroids (topical and/or systemic).

Myelosuppression is the most common grade 3–4 adverse event. Neutropenia can be seen in up to 45% of patients, thrombocytopenia in up to 25% of patients, and anemia in 10% of patients. Treatment is held for grade ≥ 3 neutropenia (neutrophil count < 10⁹/L) or thrombocytopenia (platelet count < 50 × 10⁹/L) and restarted when counts recover above these levels. If the recovery takes longer than 2 weeks, the dose may be reduced. Treatment interruptions and dose reductions are not usually recommended for anemia, neutropenia, or thrombocytopenia grade 1 or 2. Myelosuppression is much more likely to occur during the first 2 to 3 months of therapy and is best managed with treatment interruption and close monitoring. Hematopoietic growth factors (granulocyte colony-stimulating factor [G-CSF, filgrastim(Drug information on filgrastim) (Neupogen)], oprelvekin(Drug information on oprelvekin) [Neumega], and erythropoietin(Drug information on erythropoietin)) have been used successfully to manage prolonged or recurrent myelosuppression, but the long-term safety of this approach needs to be assessed.

Preliminary results of a randomized trial of imatinib vs nilotinib(Drug information on nilotinib) (Tasigna, 400 mg twice daily [BID] or 300 mg BID) as initial therapy for patients with CML in chronic phase were recently reported. The rate of complete cytogenetic response at 12 months was significantly superior for patients treated with nilotinib (78% with 400 mg and 80% with 300 mg) compared with those treated with imatinib (65%; P < .001). A similar advantage in major molecular response was seen (rates at 12 months, 43%, 44%, and 22%, respectively; P < .001). Most important, the rate of transformation at the time of the initial report was significantly lower for patients treated with nilotinib (< 1% for each arm) than for those treated with imatinib (4%). A similar study comparing dasatinib(Drug information on dasatinib) 100-mg daily to imatinib 400-mg daily as initial therapy reported an improved rate of confirmed complete cytogenetic response (77% vs. 66%, P = .007) and major molecular response (46% vs 28%; P < .0001) at 12 months of therapy. This also translated into an improved rate of transformation with dasatinib compared to imatinib (1.9% vs 3.5%). With these results, second-generation tyrosine kinase inhibitors have become standard initial therapy for patients with CML in early chronic phase.

Several studies have investigated the use of interferon combined with imatinib. A French study suggested that the combination resulted in an improved rate of complete molecular response compared to imatinib alone. Two other studies (Hehlmann et al, Cortes et al) did not find such improved response with this combination. Importantly, none of the three studies have shown an improvement in event-free survival, rate of transformation, or overall survival. Thus, the combination of interferon with imatinib remains, at best, investigational.

Monitoring The treatment objective has evolved from hematologic responses (hydroxyurea) to cytogenetic responses (interferon-α), to molecular responses in the imatinib era. All patients have to be evaluated with cytogenetic analysis before the start of therapy, and a baseline quantitative PCR analysis is useful. Conventional cytogenetic analysis is important at baseline and for follow-up because it provides valuable information about the entire karyotype (ie, clonal evolution, cytogenetic abnormalities in Ph chromosome-negative cells) that cannot be obtained with FISH or PCR and has prognostic implications. A cytogenetic analysis every 3 to 6 months during the first year and every 12 to 24 months thereafter is recommended. Quantitative PCR is recommended every 3 to 6 months. It is inappropriate not to follow patients with cytogenetics and real-time PCR. It is important to remember that the only response that has been associated with an improved probability of survival is CCyR. Major molecular response may be associated with an improved event-free survival, but not overall survival.

Duration of therapy At this time, the duration of therapy is unclear. A minority of patients have reached undetectable levels of disease by PCR. Two studies (Ross DM et al, Mahon FX et al) have offered treatment discontinuation to patients with sustained PCR negativity for at least 2 years while on therapy with imatinib. Approximately 60% of patients relapsed after treatment discontinuation. Most relapses occur within the first 6 months and patients have been reported to respond to re-initiation of imatinib. These results suggest that a subset of patients may maintain a molecular remission after discontinuation of imatinib therapy, but the risk of relapse is high. Thus, unless patients are included in clinical trials investigating treatment discontinuation, patients should continue therapy indefinitely.

Imatinib failure The most frequently identified mechanism of resistance to imatinib is the development of mutations at the ABL kinase domain. Mutations are identified in 40% to 60% of patients with imatinib resistance, with the most frequent occurring in the P-loop. Not all mutations confer the same level of resistance to imatinib, and some may be overcome by increased concentrations of imatinib. The most resistant mutation is T315I. P-loop mutations have been reported to be linked to a poor prognosis, but this theory has not been confirmed in all studies, and it is probably more appropriate to consider individual mutations rather than group them by location.

TABLE 3European LeukemiaNet criteria for failure and suboptimal response

Changing therapy based on failure to achieve or losing a molecular response cannot be justified in most instances at the present time. Even when patients who have not achieved a major molecular response after 18 months of therapy have an inferior prognosis compared with those with at least a major molecular response, they still have an 86% probability of event-free survival at 7 years (provided they have a complete cytogenetic response [CCyR]), and, in most instances, the event only represents a loss of cytogenetic response. If the proposed alternative treatment option has any significant risk of mortality or morbidity, the risk may be unnecessary. The clinical significance of the presence of mutations only in patients with an adequate response is still unclear. Thus, mutations should be investigated in patients with clinical evidence of failure. In this setting, a change of therapy is indicated whether a mutation is found or not, but, in some instances, specific mutations may guide the selection of therapy.

The European LeukemiaNet has established criteria for failure and suboptimal response that have become standard (Table 3). These criteria emphasize the response achieved and the time to such response. Patients who meet criteria for failure should be offered therapy with a second-generation tyrosine kinase inhibitor. For patients with suboptimal responses, there are no available data indicating what the optimal management may be, although imatinib dose escalation is usually recommended. There is no available data of the benefit of changing to a second-generaiton tyrosine kinase inhibitor for suboptimal response.

Second-generation tyrosine kinase inhibitors A second generation of tyrosine kinase inhibitors has been developed to overcome resistance to imatinib. Two of these agents have gained regulatory approval (dasatinib and nilotinib [Tasigna]), and others are being developed (bosutinib). Both agents have been shown to inhibit both the wild type BCR-ABL and nearly all of the clinically significant mutants of BCR-ABL, except for the T315I mutation. The results from the initial clinical trials have demonstrated significant clinical activity with both agents.

Dasatinib Dasatinib (Sprycel) is structurally unrelated to imatinib and can bind both the inactive and active configurations of BCR-ABL. In addition, dasatinib is a dual inhibitor that blocks Src and ABL and that is two orders of magnitude more potent than imatinib.

The initial phase II trials of dasatinib used a dose of 70 mg twice daily. Significant clinical activity was seen in patients in all stages of the disease after imatinib resistance or intolerance, with complete cytogenetic responses (CCyRs) in 53% in chronic phase, 33% in accelerated phase, 27% in myeloid blast phase, and 46% in lymphoid blast phase. Duration of response correlates with the stage of disease, with progression-free survival of 57% at 5 years for those in chronic phase and 46% at 24 months in accelerated phase. In contrast, the median progression-free survival was 5.6 and 3.1 months, respectively, for those in the myeloid and lymphoid blast phases.

Some of the most significant adverse events include myelosuppression (grade 3–4 neutropenia and thrombocytopenia in nearly 50% each), pleural effusion, and gastrointestinal hemorrhage (particularly in the advanced stages). Alternative schedules may improve the toxicity profile. In a randomized study, dasatinib administered at 100 mg once daily was associated with significantly less myelosuppression and pleural effusion when compared with 70 mg twice daily (and compared with 50 mg twice daily or 140 mg once daily). The response to therapy was identical, with a trend toward improved progression-free survival with use of 100 mg once daily.

Dasatinib is approved for treatment of patents with CML in all phases of the disease who have experienced resistance to or intolerance of imatinib. The standard dose for patients in chronic phase is 100 mg once daily; 140 mg once daily is recommended for patients in advanced stages. Recently, dasatinib has also been approved for use as initial therapy for patients in chronic phase, with the standard dose also being 100 mg once daily.

Nilotinib Nilotinib was designed based on the imatinib structure and modified to improve its binding to BCR-ABL and to increase its selectivity. These modifications result in an agent at least one order of magnitude more potent than imatinib against BCR-ABL.

Significant activity has been documented in patients treated after imatinib failure with nilotinib (400 mg twice daily) in phase II studies. The rate of CCyR for patients treated in chronic phase after imatinib resistance or intolerance was 44% and for those treated in accelerated phase, 19%. Responses have been durable, with a sustained CCyR at 24 months in 84% of patients treated in the chronic phase. In the accelerated phase, progression-free survival is 57% at 12 months. The most significant toxicities reported have been myelosuppression (grade 3–4 neutropenia or thrombocytopenia in approximately 30%, each), and biochemical abnormalities (elevation of indirect bilirubin, lipase, and glucose) that have been usually transient and asymptomatic. There is also the potential for QTc prolongation (a class effect for all tyrosine kinase inhibitors), although less than 3% of patients have had significant prolongation, most frequently asymptomatic. Nilotinib is currently approved for treatment of patients in chronic or accelerated phase of the disease who have experienced resistance or intolerance to imatinib, and the standard dose for patients treated after imatinib failure is 400 mg twice daily. Recently, nilotinib has also been approved as initial therapy for CML in chronic phase, with the standard dose for this indication being 300 mg twice daily. Nilotinib should be taken on an empty stomach, because food may significantly increase the absorption.

A prognostic model has been developed to predict the probability of response and event-free survival after treatment with second-generation tyrosine kinase inhibitors (dasatinib and nilotinib) after imatinib failure. Among 123 patients treated with these agents, a multivariate analysis identified two factors as being significantly and independently associated with long-term outcome: performance status (adverse feature, ≥ 1) and cytogenetic response with prior imatinib therapy (adverse feature, no prior cytogenetic response). Patients with no, one, and two adverse features had event-free survival probabilities at 24 months of 78%, 49%, and 20%, respectively.

Other agents Other investigational agents are being developed for patients who fail to respond to imatinib therapy. Bosutinib is another Src and ABL inhibitor with activity against most mutants of BCR-ABL. Early results suggest significant activity among patients who fail to respond to imatinib therapy. Bosutinib has minimal or no activity against PDGF-R and KIT, which could lead to decreased toxicity (eg, pleural effusions and myelosuppression); however, this drug has activity against LYN and ABL and has also shown activity in patients who have failed to respond to imatinib and other tyrosine kinase inhibitors. Among 299 patients who received bosutinib after imatinib resistance or intolerance, 47% achieved a CCyR (59% for imatinib-intolerant, 43% for imatinib-resistant). Responses have been durable and are observed across a wide range of mutations, except T315I. The main adverse event is diarrhea and rash (grade 3 in 9% each, leading to treatment discontinuation in 2% and 1%, respectively).

Several agents are being developed to treat patients with the T315I mutation that is resistant to all available agents. They include omacetaxine (homoharringtonine), AP24534 (ponatinib), DCC-2036, MK-0457, XL 228, and PHA-739358 (danusertib). Early results from these trials suggest activity in some patients.

Allogeneic bone marrow transplantation (BMT)

Allogeneic BMT is potentially curative in CML, although relapses and mortality from complications such as chronic graft-vs-host disease (GVHD) may occur many years after transplantation. Results are better for patients in the chronic phase than for those in either the accelerated or blastic phase. Long-term survival rates of 50% to 80% and disease-free survival rates of 30% to 70% can be achieved in the chronic phase. The role of BMT is now changing in view of the results obtained with imatinib.

Predictors of response Early BMT within the first 1 to 3 years after diagnosis may be associated with a better outcome than BMT performed later in the course of disease. Younger patients also have a better outcome than do older patients, with those younger than 20 to 30 years of age having the best prognosis. The use of the EBMT score helps to separate those patients who may have a better outcome from those who may not.

Conditioning regimens, including total-body irradiation (TBI), have been traditionally used, but non–TBI-containing regimens (eg, with busulfan and cyclophosphamide(Drug information on cyclophosphamide)) have produced similar results. More recently, conditioning regimens using pharmacologic targeting of busulfan have been associated with decreased regimen-related toxicity while preserving efficacy. Also, nonmyeloablative conditioning regimens frequently containing purine analogs (mini-BMT) have been tested recently to expand the use of transplants to older patients or to those with medical conditions that preclude conventional BMT.

GVHD The major morbidity from BMT is GVHD. T-cell depletion of the graft can reduce the incidence of this complication, but at the expense of higher relapse and graft failure rates. (For a full discussion of GVHD, see chapter 33.)

Alternatives to matched-related donors For patients who do not have a matched-related donor, matched-unrelated donor transplants are reasonable alternatives. The 9-year experience from the National Marrow Donor Program in 1,432 patients reported a 3-year survival rate of 37.5%. Early transplantation results in better outcome, with patients transplanted in the chronic phase having a 3-year disease-free survival of 63%. The outcome of patients transplanted during the accelerated, blastic, or second chronic phase is inferior.

Relapse after BMT Donor leukocyte infusions are the most effective strategy to treat patients who relapse after BMT. With this strategy, 70% to 80% of patients can achieve a cytogenetic complete response; the best results are achieved when patients are treated during cytogenetic or molecular relapse. Imatinib has also been effective for patients who relapse after BMT. A complete hematologic response in more than 70% of patients, and a cytogenetic response in 58% have been reported, with the best responses obtained in patients relapsing in chronic phase.

Treatment recommendations

The long-term results of imatinib are excellent, with an overall survival of nearly 90% at 8 years. However, at least 35% of patients do not achieve an optimal outcome (ie, do not achieve and maintain at least a CCyR or are intolerant). It is recommended that all patients in chronic phase should be offered standard-dose imatinib (400 mg daily) or second-generation tyrosine kinase inhibitors nilotinib (300 mg twice daily) or dasatinib (100 mg once daily) as initial therapy. The results from recent randomized trials suggest better early results with dasatinib or nilotinib compared with imatinib. Although these results suggest that these should be the preferred options for patients with CML, it is not known yet whether the long- term outcome will be better for patients treated with these agents than for those treated with imatinib with a change to second-generation tyrosine kinase inhibitor only for those who experience failure. A recent analysis suggested that when one accounts for the effective salvage of patients who fail therapy with imatinib by using a second-generation tyrosine kinase inhibitor, the event-free survival improves to at least 88% at 7 years. Patients should be followed closely to determine that the expected results are met at the specified times and treatment changed as soon as a lag in response is identified, particularly in those treated with imatinib (failure probably defined as lack of CCyR at 6 months) (Table 3). Patients showing an optimal response should continue uninterrupted treatment indefinitely. For patients having a suboptimal response, dose escalation is recommended. For patients who fail to respond to imatinib, a change in therapy to one of the second-generation tyrosine kinase inhibitors is indicated.

The role of allogeneic stem cell transplantation in CML has changed, and it is considered mostly a second- or third-line treatment option currently. For patients who fail imatinib therapy, transplantation, or an initial trial with a second-generation tyrosine kinase inhibitor should be considered in most patients. Adequate response at early time points is important, particularly for young patients with a transplant option. If there is no cytogenetic response at 6 months or no major cytogenetic response by 12 months, transplant should be considered. Patients with a T315I mutation or who have failed to respond to two or more tyrosine kinase inhibitors should be considered for stem cell transplantation if adequate candidates. Results with stem cell transplantation are much better when these patients are transplanted in chronic phase; thus, patients with known T315I should be considered for stem cell transplantation in chronic phase if they are optimal candidates for this procedure. Otherwise, they should be included in clinical trials.

Accelerated and blastic phases

Imatinib

Imatinib is also effective for patients with CML in transformation. Seventy-one percent of patients in accelerated phase treated with 600 mg/d of imatinib had a hematologic response. The major cytogenetic response rate was 24%, with 67% having a time to disease progression of 12 months. These results are significantly superior to those achieved using 400 mg/d, making 600 mg/d the standard dose for patients in accelerated phase. In blast phase, 52% of patients achieved a hematologic remission, and 31% achieved a sustained remission lasting at least 4 weeks with imatinib. However, the median response duration is only 10 months, even when considering only patients with sustained remission (ie, lasting at least 4 weeks). Patients with clonal evolution have a lower probability of response and a shorter survival than do patients without clonal evolution when treated with imatinib.

Nilotinib and dasatinib also have significant clinical activity in patients with advanced-stage disease. In accelerated phase, complete hematologic response rates of 26% and 50% have been reported, respectively, and corresponding rates of complete cytogenetic response were 19% and 33%. In blast phase, complete hematologic response was reported in 11% to 13% and 26% to 29% with nilotinib and dasatinib, respectively, and complete cytogenetic responses, in 27% to 46% and 29% to 32%, respectively. Their use should be considered for patients who have failed to respond to prior therapy, including imatinib. Both agents are approved for patients in accelerated phase, but only dasatinib is currently approved for blast phase. However, responses are of shorter duration in patients in advanced stages, particularly among those in the blast phase. Combined use of these agents with other drugs (eg, standard chemotherapy) is being investigated to improve outcomes.

BMT

Compared with results in patients in the chronic phase, results with allogeneic BMT are worse in patients in the accelerated or blast phase, with 4-year survival rates of only 10% to 30%. Patients in the accelerated phase (determined on the basis of clonal evolution only) who undergo BMT less than 1 year after diagnosis have a 4-year probability of survival of 74%. Patients in the blast phase who respond to therapy with a second-generation tyrosine kinase inhibitor should be offered a BMT in the second chronic phase if an adequate donor is available.