Chronic-Phase Chronic Myeloid Leukemia

Three of the 5 TKIs currently available are licensed for first-line treatment in CML, namely imatinib, dasatinib, and nilotinib. The goal of therapy is to induce deep and durable responses using an agent that can be tolerated in the long term, because for most patients treatment will be lifelong.

The response to TKI therapy is the most important prognostic factor, and is assessed on 3 levels; hematologic, cytogenetic, and molecular. The European Leukemia Network (ELN) have established criteria defining complete hematologic response, complete cytogenetic response (CCyR), and major molecular response (MMR), and require that these responses be achieved by certain time points. Recently updated guidelines use these milestones to stratify response into categories of optimal, warning, and failure. Furthermore, this recent version has incorporated the finding by several groups that an inability to achieve a 10-fold reduction in tumor load by 3 months, as indicated by a real-time, quantitative, reverse transcriptase–polymerase chain reaction (RQ-PCR) result of less than 10%, is associated with a relatively poor long-term survival.

Imatinib is capable of inducing CCyR in the most patients and MMR in many, both of which are associated with prolonged long-term survival. It is this level of efficacy that has led to its adoption as first-line therapy. However, despite its success, by 8 years more than 40% of patients will discontinue imatinib because of intolerance and/or lack or loss of response. The second-generation TKIs (2GTKIs) dasatinib, nilotinib, and bosutinib have now all been used as front-line therapy. Trial data show that their higher potency in inhibiting BCR-ABL1 translates to superiority in achieving cytogenetic and molecular responses. Two large prospective, randomized clinical trials comparing one or other of these agents with imatinib demonstrated prolonged durable remissions, with nilotinib achieving MMR at 3 years in 70% to 73% of patients compared with 53% with imatinib, and dasatinib achieving MMR in 69% compared with 55% with imatinib. Although the data for bosutinib are less mature, similar superiority over imatinib has been demonstrated, with MMR rates of 41% at 12 months compared with 27% with imatinib. In both trials of nilotinib and dasatinib, failure to achieve an RQ-PCR of less than 10% at 3 months was associated with an increased risk of treatment failure. Moreover, in both studies approximately 30% of patients had discontinued their front-line therapy at 3 years, indicating ongoing problems with longer-term efficacy and tolerability.

The 2 main reasons necessitating TKI cessation are intolerance and resistance. Toxicities such as nausea and diarrhea, muscle cramps and arthralgia, edema, and rashes can be common, particularly at the initiation of therapy. Later, patients taking imatinib complain of chronic debilitating fatigue. Typically these side effects are mild and can often be managed with temporary treatment interruption or dose reduction; however, for some they are severe and intolerable, and require cessation of treatment with the particular drug. Dasatinib and nilotinib have some more serious toxicities, only rarely (or never) observed with imatinib, including pleural effusion and pulmonary arterial hypertension on dasatinib and hyperglycemia, abnormal liver function tests, and vascular thrombotic events on nilotinib.

Drug resistance can occur for several reasons. It may be primary, whereby from the outset there is no or little response to the drug, or it can be secondary, developing after a period of initial response. The mechanisms of resistance are beyond the remit of this review, although broadly there are 2 main categories: resistance with an associated kinase domain (KD) mutation and resistance without an identifiable KD mutation. In most cases leukemic cells containing KD mutations are thought to be present at the time of diagnosis and can be observed (or selected) only after nonmutated cells have been killed by the TKI. These mutations (single-nucleotide polymorphisms) may render the protein resistant to 1 or more TKI. Although knowledge of the site of a KD mutation may guide the choice of 2GTKI, many patients will be resistant to their therapy without evidence of a KD.

Patients who fail front-line treatment with imatinib may respond to a change to a 2GTKI. Second-line dasatinib is associated with a 6-year progression-free survival (PFS) of 40% to 50%, with overall survival (OS) on the order of 70%. Of note, in the largest phase II trial of 670 patients, only 28% of those treated with dasatinib remained on the study drug 6 years later. Similar patterns of response are seen in patients treated with nilotinib as second-line therapy following prior imatinib. The largest phase II trial of nilotinib in imatinib-resistant or intolerant patients showed that CCyR was achieved in 45% of patients with OS and PFS at 48 months of 78% and 57%, respectively. Again at 48 months, importantly 70% of patients had discontinued treatment, the most common reason being disease progression. The data from these 2 large studies show that although 2GTKI can induce a durable remission in many patients, most of those who require a 2GTKI will subsequently require an alternative therapy, one of which might be HSCT. Just as 3-month BCR-ABL1 burden is predictive of long-term survival in front-line TKI, the same is true of second-line therapy. Those patients who fail to achieve BCR-ABL1 of less than 10% after 3 months of second-line therapy have a significantly poorer long-term outlook, and the predictive power of such an early assessment could be helpful in the identification of potential HSCT candidates.

Early data on the use of a third-generation TKI, ponatinib, the only drug to be active against the T315I mutation, suggest that approximately 40% of patients resistant or intolerant to multiple TKIs will achieve CCyR, with 27% achieving MMR : while both CCyR and MMR are predictors of prolonged survival, mature data are awaited. In patients with the T315I mutation responses are slightly better, with CCyR and MMR rates of 66% and 56%, respectively; however, about half of these patients will still require alternative treatment. In this circumstance allogeneic HSCT is the only option for long-term survival.

In summary, approximately 10% to 15% of patients presenting in CP will ultimately fail to achieve a durable remission with any TKI ( Fig. 1 ). For these patients, allogeneic HSCT may offer a strategy to achieve long-term remission.

Summary of predicted outcome following tyrosine kinase inhibitor (TKI) treatment in chronic phase of chronic myeloid leukemia. 2G, second-generation; 3G, third-generation.

Advanced-Phase Chronic Myeloid Leukemia

The outcome for patients who present in either AP or BP, or who develop AP or BP while on treatment, is extremely poor. Frequently these patients carry multiple additional nonrandom chromosomal abnormalities, and those previously exposed to a TKI may also harbor KD mutations. In contrast to CP, TKIs have had less impact on the outcome of AP, and very little impact on the outcome of BP disease.

In BP, the median OS has only risen from 3 to 4 months pre-TKI to 7 to 11 months in the post-TKI era. Although often these patients will initially respond to TKI therapy, almost invariably their response is partial and transient, thereby generating a window of opportunity for definitive treatment such as HSCT. HSCT in the second CP offers the best prospect of long-term survival for these patients, with less than 10% achieving long-term survival if transplanted in frank BP. Although TKI treatment may never achieve CCyR and MMR in patients presenting with BP, imatinib can briefly induce hematologic remission in 50% to 70%. For those progressing to BP during treatment with a TKI, cytoreductive chemotherapy in combination with a 2GTKI seems to offer the best prospect of returning the patient to CP, permitting consideration of HSCT.

For AP patients the impact of TKIs is more positive. Imatinib is capable of achieving CCyR in around 60% of patients. 2GTKIs show promise in achieving better responses (MMR 76%), although with only small numbers of patients described to date. At present, durable response rates remain too low to confidently withhold HSCT in eligible patients. Jiang and colleagues suggested a risk-stratification algorithm capable of identifying low-risk patients in whom HSCT conferred no advantage over imatinib (6-year OS 81% vs 100%), but these patients constituted less than 1 in 3 AP patients. The outcome for high-risk patients who did not receive HSCT was dismal (5-year OS 18% vs 100%).

Assessment of Transplant Risk

In the late 1990s the European Group for Blood and Marrow Transplant (EBMT) developed a risk-scoring system for patients with CML based on a data set of more than 3000 patients, at a time when CML was the commonest indication for allogeneic HSCT. This system is based on 5 variables ( Table 1 ) and is a powerful predictor of both survival and transplant-related mortality (TRM), with predicted 5-year OS ranging from 72% to 20% in the low- to high-risk groups, respectively. These data were accumulated from patients who had not been exposed to TKI. Of interest, a recent reanalysis of the EBMT database using patients transplanted after exposure to TKI shows that the score remains prognostic. The EBMT score has been independently validated by the Center for International Blood and Marrow Transplant Research (CIBMTR), and is also valuable in the assessment of patients undergoing a second allogeneic HSCT in CML. In addition to the EBMT score, recent data have shown that comorbidities at the time of transplant significantly affect transplant outcome. The hematopoietic cell transplantation comorbidity index (HCT-CI) has been used to predict non-relapse mortality and OS in many hematologic malignancies. More recently, its use has been validated as an independent predictor of TRM and OS in CML patients undergoing allogeneic HSCT and, importantly, many of the patients used for its validation had been pretreated with TKIs, justifying its use in current practice. This study also identified the presence of an elevated C-reactive protein at the time of admission for transplant, as an independent predictor of increased TRM and reduced OS.

Timing of Transplant

In current practice, TKIs will almost always be the first line of treatment in a newly diagnosed CML patient. However, tools now exist for identifying patients who are likely to fare poorly with first-, second-, and third-generation TKIs. Although prediction of a poor outcome in these patients should not preclude a trial of alternative drugs, it should alert the clinician to the prospect that allogeneic HSCT may offer the best prospect of long-term remission, prompting early discussion about HSCT with the patient in addition to early identification of potential donors. For this reason, the authors would advocate HLA typing and donor identification in patients listed in Table 2 .

In patients with AP or BC, there is no doubt that allogeneic HSCT offers the best prospect of long-term survival, although timing of transplant is crucial. The best possible response must be sought before HSCT, and the time from achieving best response to proceeding to HSCT minimized. Ideally patients should be transplanted as soon as practical after achieving second (or higher) CP.