TREATMENT Chronic Myeloid Leukemia
The introduction of TKI therapy, first in the form of imatinib mesylate in 2001, has revolutionized the treatment and prognosis in CML. Before 2000, allogeneic SCT was frontline therapy, when available, because of its potentially curative capacity. Otherwise, patients were offered interferon α therapy (approved for the treatment of CML in 1986), which had modest benefits (improving survival from a median of 3–4 years with hydroxyurea-busulfan to a median of 6–7 years), but also significant side effects. Other alternatives included hydroxyurea, busulfan, and other nonspecific chemotherapies. With TKI therapy, the estimated 10-year survival in CML is 85%. Since 2001, six agents have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of CML. These include five oral BCR-ABL1-selective TKIs: imatinib (Gleevec), nilotinib (Tasigna), dasatinib (Sprycel), bosutinib (Bosulif), and ponatinib (Iclusig). Imatinib 400 mg orally daily, nilotinib 300 mg orally twice a day (on an empty stomach), and dasatinib 100 mg orally daily are approved for frontline therapy of CML. All three are also approved for salvage therapy (nilotinib 400 mg twice daily), in addition to bosutinib (500 mg daily) and ponatinib (45 mg daily). Imatinib, dasatinib (140 mg daily), bosutinib, and ponatinib are also approved for the treatment of CML transformation (accelerated and blastic phase), whereas nilotinib is only approved for chronic and accelerated phase. Dasatinib, nilotinib, and bosutinib are referred to as second-generation TKIs; ponatinib is referred to as a third-generation TKI. The sixth approved agent is omacetaxine (Synribo), a protein synthesis inhibitor with presumed more selective inhibition of the synthesis of the BCR-ABL1 oncoprotein. It is approved for the treatment of chronic- and accelerated-phase CML after failure of two or more TKIs, at 1.25 mg/m2 subcutaneously twice a day for 14 days for induction and for 7 days for consolidation-maintenance. Nilotinib is similar in structure to imatinib but 30 times more potent. Dasatinib and bosutinib are dual SRC-ABL1 TKIs (dasatinib is reported to be 300 times more potent and bosutinib 30–50 times more potent than imatinib). Ponatinib is effective against wild-type and mutant BCR-ABL1 clones. It is unique in being the only currently available BCR-ABL1 TKI that is active against T315I, a gatekeeper mutant resistant to the other four TKIs (Table 15-2).
Imatinib, nilotinib, and dasatinib are all acceptable frontline therapies in CML. The long-term results of imatinib are very favorable. The 8-year follow-up results show a cumulative complete cytogenetic response rate (occurring at least once) of 83%, with 60–65% of patients being in complete cytogenetic response at 5-year follow-up. The estimated 8-year event-free survival rate is 81%, and the overall survival rate is 85%. Among patients continuing on imatinib, the annual rate of transformation to accelerated-blastic phase in years 4–8 is <1%. In two randomized studies, one comparing nilotinib 300 mg twice daily or 400 mg twice daily with imatinib (ENEST-nd) and the other comparing dasatinib 100 mg daily with imatinib (DASISION), the second-generation TKIs were associated with better outcomes in early surrogate endpoints, including higher rates of complete cytogenetic responses (85–87% vs 77–82%), major molecular responses (65–76% vs 46–63%), and undetectable BCR-ABL1 transcripts (IS) (32–37% vs 15–30%), and lower rates of transformation to accelerated-blastic phase (2–4% vs 6%). However, neither study showed a survival benefit with second-generation TKIs (median follow-up times of 4–5 years). This may be because salvage therapy with other TKIs (following close observation and treatment change at progression) provides highly effective salvage therapy that rebalances the negative effect of the relapse.
Salvage therapy in chronic phase with dasatinib, nilotinib, bosutinib, or ponatinib is associated with complete cytogenetic response rates of 30–60% of patients, depending on the salvage status (cytogenetic vs hematologic relapse), prior response to other TKIs, and the mutations at the time of relapse. Complete cytogenetic responses are generally durable, particularly in the absence of clonal evolution and mutations. Ponatinib is the only TKI active in the setting of T315I mutation, with complete cytogenetic response rates of 50–70%. The estimated 3- to 5-year survival rates with new TKIs as salvage are 70–80% (compared with <50% before their availability). For example, with dasatinib salvage after imatinib failure in chronic-phase CML, the major molecular response rates were 40–43%, the estimated 6-year survival rates were 74–83%, and progression-free survival rates were 40–51%. Thus, TKIs in the salvage setting have already reduced the annual mortality from the historical rate of 10–15% to ≤5%.
The goal of CML therapy is viewed differently in the context of research versus standard practice. In current practice, functional cure, defined as survival with CML similar to survival among normal individuals, is the current goal of therapy. CML is now considered an indolent disease, which, with appropriate TKI therapy, treatment compliance, careful monitoring, and early change to other TKIs as indicated, can be associated with close to normal survival. Therefore, in standard practice, achievement and maintenance of a complete cytogenetic response are the aims of therapy, because complete cytogenetic response is the only treatment-related factor associated with survival prolongation. Lack of achievement of a major molecular response (protects against events; associated with longer event-free survival) or of negative BCR-ABL1 transcripts (offers the potential of TKI interruption on investigational studies) should not be considered indications to change TKI therapy or to consider allogeneic SCT. A general practice rule is to continue the particular TKI chosen at the most tolerable dose schedule not associated with grade 3–4 side effects or with bothersome chronic side effects, for as long as possible, until either cytogenetic relapse or the persistence of unacceptable side effects. These two factors (i.e., cytogenetic relapse and intolerable side effects as judged by the patient and treating physician) are the indicators of “failure” of a particular TKI therapy. Because of the increasing prevalence of CML (cost of TKI therapy) and the emerging long-term low rates of significant organ toxicities, the ultimate goal of CML therapy in the research setting is to achieve eradication of the disease (molecular cure) that is prolonged and durable, with recovery of nonneoplastic, nonclonal hematopoiesis off TKI therapy. The first step toward this aim is to obtain the highest rates of undetectable BCR-ABL1 transcripts lasting for at least 2 or more years.
Recommendations provided by the National Comprehensive Cancer Network (NCCN) and by the European LeukemiaNet (ELN) discuss optimal/expected, suboptimal/warning, and failure response scenarios at different time points of TKI treatment duration. Unfortunately, they may have been misinterpreted in current practice, because oncologists often report that their aim of treatment is the achievement of major molecular response and disease eradication. Significantly, a substantial proportion of oncologists consider a change of TKI therapy in a patient in complete cytogenetic response if they note “loss of major molecular response” (increase of BCR-ABL1 transcripts ([IS] from <0.1% to >0.1%). This perception may be the result of confusion regarding the NCCN and ELN guidelines, which have been updated often as a result of maturing data and have multiple treatment endpoint considerations. Although such endpoints have been suggested by these recommendations as possible criteria for failure, it is important to emphasize that no randomized study has yet shown that a change of TKI treatment in patients with complete cytogenetic response because of a loss of major molecular response, versus changing at the time of cytogenetic relapse, has been shown to improve survival. This is likely because of the high efficacy of salvage TKI therapy at the time of cytogenetic relapse.
Side effects of TKIs are generally mild to moderate, although with long-term TKI therapy, they could affect the patient’s quality of life. Serious side effects occur in less than 5–10% of patients. With imatinib therapy, common mild to moderate side effects include fluid retention, weight gain, nausea, diarrhea, skin rashes, periorbital edema, bone or muscle aches, fatigue, and others (rates of 10–20%). In general, second-generation TKIs are associated with lower rates of these bothersome adverse events. However, dasatinib is associated with higher rates of myelosuppression (20–30%), particularly thrombocytopenia, and with pleural (10–25%) or pericardial effusions (≤5%). Nilotinib is associated with higher rates of hyperglycemia (10–20%), pruritus and skin rashes, and headaches. Nilotinib is also associated with rare events of pancreatitis (<5%). Bosutinib is associated with higher rates of early and self-limited gastrointestinal complications like diarrhea (50–70%). Ponatinib is associated with higher rates of skin rashes (10–15%), pancreatitis (5%), elevations of amylase/lipase (10%), and vasospastic/vasoocclusive events (10–20%). Nilotinib and dasatinib may cause prolongation of the QTc interval; therefore, they should be evaluated cautiously in patients with prolonged QTc interval on electrocardiogram (>470–480 ms), and drugs given for other medical conditions should have relatively smaller or no effects on QTc. These side effects can often be dose-dependent and are generally reversible with treatment interruptions and dose reductions. Dose reductions can be individualized. However, the lowest estimated effective doses of TKIs (from different studies and treatment practices) are imatinib 300 mg daily; nilotinib 200 mg twice daily; dasatinib 20 mg daily; bosutinib 300 mg daily; and ponatinib 15 mg daily.
With long-term follow-up, rare but clinically relevant serious toxicities are emerging. Renal dysfunction and renal failure (creatinine elevations >2–3 mg/dL) are observed in 2–3% of patients and reverse with TKI discontinuation and empirical use of other TKIs. Pulmonary hypertension has been reported with dasatinib (<1–2%) and should be considered in a patient with shortness of breath and a normal chest x-ray (echocardiogram with emphasis on measurement of pulmonary artery pressure). This may be reversible with dasatinib discontinuation and occasionally the use of sildenafil citrate. Systemic hypertension has been observed more often with ponatinib therapy, as well as other TKIs. Hyperglycemia and diabetes have been noted more frequently with nilotinib. Finally, mid- and small-vessel vasoocclusive and vasospastic events have been reported at low but significant rates with nilotinib and ponatinib and should be considered possibly TKI-related and represent indications to interrupt or reduce the dose of the TKI. These events include angina, coronary artery disease, myocardial infarction, peripheral arterial occlusive disease, transient ischemic attacks, cerebral vascular accidents, Raynaud’s phenomenon, and accelerated atherosclerosis. Although these events are uncommon (<5%), they are clinically significant for the patient’s long-term prognosis and occur at significantly higher rates than in the general population (5–20 times more often). ALLOGENEIC STEM CELL TRANSPLANT
Allogeneic SCT, a curative modality in CML, is associated with long-term survival rates of 40–60% when implemented in the chronic phase. It is associated with early (1-year) mortality rates of 5–30%. Although the 5- to 10-year survival rates were reported to be around 50–60% (and considered as cure rates), about 10–15% of patients die in the subsequent 1–2 decades from subtle long-term complications of the transplant (rather than from CML relapse). These are related to chronic graft-versus-host disease (GVHD), organ dysfunction, development of second cancers, and hazard ratios for mortality higher than in the normal population. Other significant morbidities include infertility, chronic immune-mediated complications, cataracts, hip necrosis, and other morbidities affecting quality of life. The cure and early mortality rates in chronic-phase CML are also associated with several factors: patient age, duration of chronic phase, whether the donor is related or unrelated, degree of matching, preparative regimen, and others. In accelerated-phase CML, the cure rates with allogeneic SCT are 20–40%, depending on the definition of acceleration. Patients with clonal evolution as the only criterion have cure rates of up to 40–50%. Patients undergoing allogeneic SCT in second chronic phase have cure rates of 40–50%. The cure rates with allogeneic SCT in blastic phase CML are ≤15%. Post–allogeneic SCT strategies are now implemented in the setting of molecular or cytogenetic relapse or in hematologic relapse/transformation. These include the use of TKIs for prevention or treatment of relapse, donor lymphocyte infusions, and second allogeneic SCTs, among others. TKIs appear to be highly successful at reinducing cytogenetic/molecular remissions in the setting of cytogenetic or molecular relapse after allogeneic SCT. Choice and Timing of Allogeneic SCT
Allogeneic SCT was considered first-line CML therapy before 2000. The maturing positive experience with TKIs has now relegated its use to after first-line TKI failures. An important question is the optimal timing and sequence of TKIs and allogeneic SCT (whether allogeneic SCT should be used as second- or third-line therapy). Among patients who present with or evolve to blastic phase, combinations of chemotherapy and TKIs should be used to induce remission, followed by allogeneic SCT as soon as possible. The same applies to patients who evolve from chronic to accelerated phase. Patients with de novo accelerated-phase CML may do well with long-term TKI therapy (estimated 8-year survival rate 75%); the timing of allogeneic SCT depends on their optimal response to TKI (achievement of complete cytogenetic response). Among patients who relapse in chronic phase, the treatment sequence depends on several factors: (1) patient age and availability of appropriate donors; (2) risk of allogeneic SCT; (3) presence or absence of clonal evolution and mutations; (4) patient’s prior history and comorbidities; and (5) patient and physician preferences (Table 15-3). Patients with T315I mutations at relapse should be offered ponatinib and considered for allogeneic SCT (because of the short follow-up with ponatinib). Patients with mutations involving Y253H, E255K/V, and F359V/C/I respond better to dasatinib or bosutinib. Patients with mutations involving V299L, T315A, and F317L/F/I/C respond better to nilotinib. Comorbidities such as diabetes, hypertension, pulmonary hypertension, chronic lung disease, cardiac conditions, and pancreatitis may influence the choice for or against a particular TKI. Patients with clonal evolution, unfavorable mutations, or lack of major/complete cytogenetic response within 1 year of salvage TKI therapy have short remission durations and should consider allogeneic SCT as more urgent in the setting of salvage. Patients without clonal evolution or mutations at relapse and who achieve a complete cytogenetic response with TKI salvage, have long-lasting complete remissions and may delay the option of allogeneic SCT to third-line therapy. Finally, older patients (age 65–70 years or older) and those with high risk of mortality with allogeneic SCT may forgo this curative option for several years of disease control in chronic phase with or without cytogenetic response (Table 15-3). Historically, before the availability of TKIs, patients without cytogenetic response on interferon α or hydroxyurea had expected short median survival times (2–3 years) with expected rapid disease transformation. The maturing experience with TKIs suggests a different course, whereby patients may remain in chronic phase on TKI-based therapies (combinations including hydroxyurea, cytarabine, decitabine, and others), with or without cytogenetic response, for many years. Table 15-3 summarizes a general guidance to the choice of TKIs versus allogeneic SCT. MONITORING THERAPY IN CML
Achievement of complete cytogenetic response by 12 months of imatinib therapy and its persistence later, the only consistent prognostic factor associated with survival, is now the main therapeutic endpoint in CML. Failure to achieve a complete cytogenetic response by 12 months or occurrence of later cytogenetic or hematologic relapse is considered as treatment failure and an indication to change therapy. Because salvage therapy with other TKIs reestablishes good outcome, it is important to ensure patient compliance to continued TKI therapy and change therapy at the first sign of cytogenetic relapse. Patients on frontline imatinib therapy should be closely monitored until documentation of complete cytogenetic response, at which time they can be monitored every 6 months with peripheral blood FISH and PCR studies (to check for concordance of results), or more frequently if there are concerns about changes in BCR-ABL1 transcripts (e.g., every 3 months). Monitoring by molecular studies only is reasonable in patients who are in major molecular response. Cytogenetic relapse on imatinib is an indication of treatment failure and need to change TKI therapy. Mutational analysis in this instance helps in the selection of the next TKI and identifies mutations in 30–50% of patients. Mutational studies in patients in complete cytogenetic response (in whom there may be concerns of increasing BCR-ABL1 transcripts) identify mutations in ≤5% and are therefore not indicated. Earlier response has been identified as a prognostic factor for long-term outcome, including achievement of partial cytogenetic response (BCR-ABL1 transcripts ≤10%) by 3–6 months of therapy. Failure to achieve such a response on imatinib therapy has been associated with significantly worse survival in some studies (particularly when second-generation TKIs were not readily available as salvage therapy), but not in others (when they were).
The use of second-generation TKIs (nilotinib, dasatinib) as frontline therapy changed the monitoring approach slightly. Patients are expected to achieve complete cytogenetic response by 3–6 months of therapy. Failure to do so is associated with worse event-free survival, transformation rates, and survival. However, the 3- to 5-year estimated survival among such patients is still high, around 80–90%, which is better than what would be anticipated if such patients were offered allogeneic SCT at that time. Thus, this adverse response to therapy is considered a warning signal, but it is not known whether changing therapy to other TKIs at that time would improve longer term outcome. TREATMENT OF ACCELERATED AND BLASTIC PHASES
Patients in accelerated or blastic phase may receive therapy with TKIs, preferably second- or third-generation TKIs (dasatinib, nilotinib, bosutinib, ponatinib), alone or in combination with chemotherapy, to reduce the CML burden, before undergoing allogeneic SCT. Response rates with single-agent TKIs range from 30 to 50% in accelerated phase and from 20 to 30% in blastic phase. Cytogenetic responses, particularly complete cytogenetic responses, are uncommon (10–30%) and transient in blastic phase. Studies of TKIs in combination with chemotherapy are ongoing; the general experience suggests that combined TKI-chemotherapy strategies increase the response rates and their durability and improve survival. In CML lymphoid blastic phase, the combination of anti-ALL chemotherapy with TKIs results in complete response rates of 60–70% and median survival times of 2–3 years (compared with historical response rates of 40–50% and median survival times of 12–18 months). This allows many patients to undergo allogeneic SCT in a state of minimal CML burden or secondary chronic phase, which are associated with higher cure rates. In CML nonlymphoid blastic phase, anti-AML chemotherapy combined with TKIs results in CR rates of 30–50% and median survival times of 9–12 months (compared with historical response rates of 20–30% and median survival times of 3–5 months). In accelerated phase, response to single TKIs is significant in conditions where “softer” accelerated phase criteria are considered (e.g., clonal evolution alone, thrombocytosis alone, significant splenomegaly or resistance to hydroxyurea, but without evidence of high blast and basophil percentages). In accelerated phase, combinations usually include TKIs with low-intensity chemotherapy such as low-dose cytarabine, low-dose idarubicin, decitabine, interferon α, hydroxyurea, or others. OTHER TREATMENTS AND SPECIAL THERAPEUTIC CONSIDERATIONS Interferon α
Interferon α was a standard of care before 2000. Today, it is considered in combination with TKIs (an investigational approach), sometimes after CML failure on TKIs, occasionally in patients during pregnancy, or as part of investigational strategies with TKIs to eradicate residual molecular disease. Chemotherapeutic Agents
Hydroxyurea and busulfan were commonly used chemotherapeutic agents in the past. Hydroxyurea remains a safe and effective agent (at daily doses of 0.5–10 g) to reduce initial CML burden, as a temporary measure in between definitive therapies, or in combination with TKIs to sustain complete hematologic or cytogenetic responses. Busulfan is often used in allogeneic SCT preparative regimens. Because of its side effects (delayed myelosuppression, Addison-like disease, pulmonary and cardiac fibrosis, myelofibrosis), it is now only rarely used in the chronic management of CML. Low-dose cytarabine, decitabine, anthracyclines, 6-mercaptopurine, 6-thioguanine, thiotepa, anagrelide, and other agents are useful in different CML settings to control the disease burden. Others
Splenectomy is occasionally considered to alleviate symptoms of massive splenomegaly and/or hypersplenism. Splenic irradiation is rarely used, if at all, because of the postirradiation adhesions and complications. Leukapheresis is rarely used in patients presenting with extreme leukocytosis and leukostatic complications. Single doses of high-dose cytarabine or high doses of hydroxyurea, with tumor lysis management, may be as effective and less cumbersome. Special Considerations
Women with CML who become pregnant should discontinue TKI therapy immediately. Among 125 babies delivered to women with CML who discontinued TKI therapy as soon as the pregnancy was known, three babies were born with ocular, skeletal, and renal malformations, suggesting the uncommon teratogenicity of imatinib. There are no or little data with other TKIs. Control of CML during pregnancy can be managed with leukapheresis for severe symptomatic leukocytosis in the first trimester and with hydroxyurea subsequently until delivery. There are case reports of successful pregnancies and deliveries of normal babies with interferon α therapy and registry studies in essential thrombocytosis of its safety, but interferon α can be antiangiogenic and may increase the risk of spontaneous abortions.
Patients on TKI therapy may develop chromosomal abnormalities in the Ph-negative cells. These may involve loss of chromosome Y, trisomy 8, 20q–, chromosome 5 or 7 abnormalities, and others. Most chromosomal abnormalities disappear spontaneously on follow-up and may be indicative of the genetic instability of the hematopoietic stem cells that predispose the patient to develop CML in the first place. Rarely, abnormalities involving chromosomes 5 or 7 may be truly clonal and evolve into myelodysplastic syndrome or acute myeloid leukemia. This is thought to be part of the natural course of patients in whom CML was suppressed and who live long enough to develop other hematologic malignancies.