Hyperuricemia and hyperuricosuria are frequent features of CML at diagnosis or in relapse.406 The need for treatment of hyperuricemia is a function of the elevated pretreatment serum uric acid concentration, blood white cell concentration, spleen size, and dose of cytolytic therapy planned. If these variables suggest a high risk for a significant amount of cell lysis, allopurinol 300 mg/day orally and adequate hydration to maintain a good urine flow should be instituted prior to therapy. Allopurinol is associated with a high frequency of allergic skin reactions and should be discontinued after the blood leukocyte count and spleen size have decreased and the risk of exaggerated cell lysis has passed. If hyperuricemia is extreme, usually over 9 mg/dL, rasburicase can be administered.407 Rasburicase is a recombinant urate oxidase that converts uric acid to allantoin. Rasburicase, unlike allopurinol, reduces the uric acid pool very rapidly, does not result in the accumulation of xanthine or hypoxanthine, and does not require alkalinization of urine facilitating phosphate excretion.408 Although the manufacturer recommends a dose every day for 5 days, several reports have indicated that one injection will produce a rapid and sustained decrease in serum uric acid, significantly decreasing the cost of therapy.409 Another alternative is to use allopurinol for a few days after one injection of rasburicase. A dose of 0.2 mg/kg of ideal body weight of rasburicase intravenously has been used.410
INITIAL CYTOREDUCTION THERAPY
A TKI is now used as initial therapy in patients with CML. In cases where the white cell count is markedly elevated, hydroxyurea can be used prior to or in conjunction with a TKI. If rapid cytoreduction is required because of signs of the hyperleukocytic syndrome, leukapheresis and hydroxyurea often are combined.
Leukapheresis can control CML only temporarily. For this reason, it is rarely used in chronic phase CML and is useful in only two types of patients: the hyperleukocytic patient in whom rapid cytoreduction can reverse symptoms and signs of leukostasis (e.g., stupor, hypoxia, tinnitus, papilledema, priapism),249,250,251 and in the pregnant patient with CML who can be controlled by leukapheresis treatment without other therapy either during the early months of pregnancy when therapy poses a higher risk to the fetus or, in some cases, throughout the pregnancy.411,412 Because of the large body burden of leukocytes in marrow, blood, and spleen, and the high proliferative rate in CML, leukocyte reduction by apheresis is less efficient than in other types of leukemia.249,251 Leukapheresis reduces the burden of tumor cells subject to chemotherapeutically induced cytolysis and thus the production and the excretion of uric acid. In hyperleukocytic nonpregnant patients, leukapheresis is best used in conjunction with hydroxyurea to ensure rapid and optimal reduction in white cell count.
Hydroxyurea 1 to 6 g/day orally, depending on the height of the white cell count, can be used to initiate elective therapy.413 Urgent treatment of extraordinary total white cell counts may require higher doses. The dose of hydroxyurea should be decreased as the total white cell count decreases and usually is given at 1 to 2 g/day when the total white cell count reaches 20 × 109/L. The drug should be temporarily discontinued if the white cell count drops below 5 × 109/L. If hydroxyurea is being used in combination with a TKI, it is usually tapered and discontinued once a hematologic response to the TKI is observed.
Anagrelide can be used for platelet reduction in patients who present with elevated platelet counts. This agent acts directly to decrease megakaryocyte mass, and it can lead to a precipitous fall in platelet counts. In occasional patients who still have significant thrombocythemia after a TKI is initiated, combination with anagrelide is associated with a normalization of platelet counts.414
INITIAL THERAPY WITH A TYROSINE KINASE INHIBITOR
Imatinib mesylate (imatinib) was the first TKI developed, and it was approved by the FDA for initial therapy of CML in 2002. Subsequently, two second-generation TKIs, nilotinib and dasatinib, were approved for initial therapy in 2010. This approval was based upon superior cytogenetic and molecular response rates with nilotinib and dasatinib at benchmark time points and lower rates of conversion to accelerated or blast phase as compared with imatinib. Thus far, an overall survival advantage of dasatinib or nilotinib compared with imatinib has not been shown.415 Third-generation TKIs, bosutinib and ponatinib, are under study. Table 89–2 compares these inhibitors.
Table 89–2.Comparison of Tyrosine Kinase Inhibitors ||Download (.pdf) Table 89–2. Comparison of Tyrosine Kinase Inhibitors
| ||Imatinib (Gleevec) ||Nilotinib (Tasigna) ||Dasatinib (Sprycel) ||Bosutinib (Bosulif) ||Ponatinib (Iclusig) |
|Indications ||First-line therapy (CP, AP, BP); relapsed/refractory Ph+ ALL ||First-line therapy (CP), resistance or intolerance to imatinib (CP and AP) ||First-line therapy (CP), resistance or intolerance to other TKIs (CP, AP, or BP); Ph+ ALL with resistance or intolerance to prior therapy ||Second-line therapy (CP, AP, BP with resistance or intolerance) ||Resistance or intolerance to prior TKI or Ph+ ALL resistant or intolerant to all other TKIs; all T315I + casesI |
|Usual dosing || |
CP 400 mg/day
AP/BP/progression 600–800 mg/day
CP 300 mg BID
AP/BP 400 mg BID
CP 100 mg/day
AP/BP 140 mg/day
|500 mg/day ||45 mg/day |
|Common toxicities (nonhematologic) ||GI disturbance, edema (including periorbital), muscle cramps, arthralgias, Hypophosphatemia, rash ||Rash, GI disturbances, elevated lipase, hyperglycemia, low phosphorus, increased LFTs ||Edema, pleural effusions, GI symptoms, rash, low phosphorus ||GI (diarrhea), rash, edema, fatigue, low phosphorus, elevated LFTs ||HBP, rash, GI, fatigue, headache |
|Other significant toxicities ||Elevated LFTs (usually appear in first month); rare cardiac toxicity reported ||Peripheral vascular disease, PT prolongation, pancreatitis ||Pulmonary arterial hypertension, QTc prolongation || ||Arterial and venous thrombosis, pancreatitis, liver failure, ocular toxicity, cardiac failure |
|Drug–drug interactions || |
CYP3A4 inducers decrease levels
CYP3A4 inhibitors may increase levels
It is an inhibitor of CYP3A4 and CYP2D6
CYP3A4 inhibitors increase levels
CYP3A4 inducers may decrease levels
Inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2D6
Induces CYP2B6, CYP2C8, and CYP2C9
CYP3A4 inhibitors increase levels
CYP3A4 inducer decrease levels
Antacids decrease levels
H2 antagonists/proton pump inhibitors decrease levels
CYP3A inhibitors and inducers may alter levels
Acid-reducing medication may lower levels
|Strong CYP3A inhibitors increased serum levels |
|Administration considerations ||Taken with food ||Taken on empty stomach; avoid food 2 hours before and 2 hours after dose ||Can be taken with or without a meal ||Taken with food ||Taken with and without food |
|Black box warnings ||None ||QT prolongation and sudden death ||None ||None ||Arterial thrombosis; hepatotoxicity |
|Other considerations ||Approved in pediatric patients (340 mg/m2/day) in CP ||Keep potassium, Mg, calcium, phosphorus repleted ||Ascites and pericardial effusion can also occur; has CSF penetration || ||Has activity with T315I mutations; Available in U.S. through ARIAD PASS program |
Imatinib Patients with newly diagnosed, chronic phase CML can be started on imatinib, 400 mg/day by mouth. The goal of imatinib therapy is to decrease the cells bearing the t(9;22) translocation (leukemic cells) to the lowest levels possible, during which process normal (polyclonal) hematopoiesis is restored. The efficacy of imatinib is judged by measuring three benchmarks: hematologic response, cytogenetic response, and molecular response as defined in Table 89–3.416,417 These benchmarks are used to determine its maximal therapeutic effect. The time to achieve a maximal effect is variable, but as long as a patient is having a continued reduction in the size of the leukemic clone as judged by cytogenetic or PCR measurements, and has met response benchmarks, the drug is continued at 400 mg/day. If the patient stops responding before a complete cytogenetic remission or complete molecular remission is achieved, the dose can be increased to 600 mg/day or to 800 mg/day (400 mg every 12 hours), if tolerated. Alternatively, another TKI can be used. About two-thirds of patients who do not have a significant hematologic response or who relapse while receiving imatinib at a dose of 400 mg/day achieve a complete or partial hematologic response with higher doses, but few cytogenetic responses occur.418 Some patients without a cytogenetic response can enter a partial or complete cytogenetic response(CCyR) with higher doses of imatinib. Unfortunately, the responses to higher doses of imatinib in patients lacking a hematologic or cytogenetic response at 400 mg/day usually are transient.419,420
Table 89–3.Definition of a Treatment Response to a Tyrosine Kinase Inhibitor ||Download (.pdf) Table 89–3. Definition of a Treatment Response to a Tyrosine Kinase Inhibitor
|Complete hematologic response (CHR) ||White cell count <10 × 109/L, platelet count <450 × 109/L, no immature myeloid cells in the blood, and disappearance of all signs and symptoms related to leukemia (including palpable splenomegaly) lasting for at least 4 weeks. |
|Minor cytogenetic response (mCyR) ||>35% of cell metaphases are Philadelphia (Ph) chromosome–positive by cytogenetic analysis of marrow cells. |
|Partial cytogenetic response (pCyR) ||1–35% of cell metaphases are Ph chromosome–positive by cytogenetic analysis of marrow cells. |
|Major cytogenetic response (MCyR) ||<35% of cell metaphases contain the Ph chromosome by cytogenetic analysis of marrow cells. |
|Complete cytogenetic response (CCyR) ||No cells containing the Ph chromosome by cytogenetic analysis of marrow cells. |
|Major molecular response (MMR) ||BCR-ABL1/ABL1 ratio <0.1% or a 3-log reduction in quantitative polymerase chain reaction (qPCR) signal from mean pretreatment baseline value, if International Standard (IS)-based PCR not available. |
|Complete molecular response (CMR) ||BCR-ABL1 mRNA levels undetectable by qPCR with assay sensitivity at least 4.5 logs below baseline (IS). |
Several studies have examined use of imatinib at doses higher than 400 mg/day. Patients with newly diagnosed chronic phase CML treated with imatinib, 800 mg/day, administered in two 400-mg doses, every 12 hours, had a frequency of 90 percent CCyR, and 96 percent had at least a major cytogenetic response (MCyR). At a median of 15 months, no patients had progressed and 63 percent showed blood BCR-ABL1/ABL1 percentage ratios of less than 0.05 percent. Twenty-eight percent of patients had undetectable BCR-ABL1 blood levels.421 In one trial, major molecular remission (MMR) at 12 and 24 months was higher in those receiving doses of imatinib greater than 600 mg/day.422 In another trial, patients receiving 400 mg twice per day had a MCyR of 90 and 96 percent at 12 and 18 months, respectively. MMR rates were 48 percent and 54 percent at 6 and 12 months, respectively. These results compared favorably to historical data in the IRIS (International Randomized Study of Interferon) trial studying 400 mg/day of imatinib, but myelosuppression, rash, fatigue, and musculoskeletal symptoms were greater with these higher doses. Responses were, also, more rapid with the higher doses. More edema, gastrointestinal symptoms, rash, and myelosuppression occurred at the higher doses.423 Despite these reports the current starting dose is customarily 400 mg/day, balancing both effectiveness and tolerability in newly diagnosed patients. Moreover, the more rapid response with higher doses of imatinib may not translate into better long-term results.424,425 For example, in another trial, MMR and CCyR at 12 months were not significantly different between standard and high-dose patients, although patients in higher-risk categories based on Sokal scores, fared better with high-dose imatinib.424 (See “Course and Prognosis” below for an explanation of the Sokal Score.)
Doses of imatinib lower than 400 mg/day result in fewer CCyR and a shorter duration of that response. Patients who are older and who have lower body weight may only tolerate a lower dose, but they are less likely to achieve a CCyR.426 If however, a patient is on a lower dose (e.g., 300 mg/day) for a special reason (body size or tolerance level) and achieves a complete hematologic response (CHR) and CCyR within 12 months of onset of therapy, acceptable outcomes without excess toxicity can result.427
Some patients have been followed for up to 8 years on imatinib in the IRIS trial (IFN vs. STI571).428 With median followup of 60 months, the best observed MCyR and CCyR rates were 89 percent and 82 percent, respectively. Only 7 percent had progressed to accelerated or blast phase, and overall survival rate was 89 percent. The best MMR rate was 86 percent during the 8-year followup. No patient with an MMR at 12 months progressed to accelerated or blast phase. By 8 years of follow up on the IRIS trial, 22 percent of patients had discontinued imatinib treatment because of an unsatisfactory response or toxicity, and only 55 percent remained on study. The 5-year probability of remaining in MCyR while receiving imatinib was approximately 60 percent. Achieving a CCyR correlated with progression-free survival, but achieving a MMR conferred no further survival benefit.429
Use of Imatinib in Patients with Variant Chromosomal Translocations or Breakpoints
Patients with variant Ph chromosome translocations have a similar prognosis to that of patients with classic Ph chromosome translocations who are treated with imatinib.430 (See Fig. 89–3 for a diagram of breakpoints.) Patients with the e13a2, p210BCR-ABL translocation respond well to imatinib, with similar rates of complete cytogenetic remission.431 The e13a2 transcript may be more sensitive to imatinib than the e14a2 transcript.432 In a patient with both e1a2 and e14a2 fusion transcripts, only the p210 e14a2 transcript disappeared, whereas the e1a2 transcript persisted during progression to blast phase. No mutation in the kinase domain of ABL1 was found.433 Thus, different clones in a patient may have a different sensitivity to imatinib. Deletions of the derivative chromosome 9 do not influence the response and outcomes in CML chronic phase when using imatinib.434
Response to Imatinib in Children and Older Patients
More than 80 percent of children with chronic phase CML who are treated with imatinib, 260 to 570 mg/m2, enter a complete cytogenetic remission. Imatinib is now approved for use in pediatric patients. Weight gain is the most common side effect of imatinib.435 In patients who were older than age 60 years, similar cytogenetic response rates and survival rates were noted as in younger patients in the late chronic phase who were treated concurrently, suggesting that age is not usually a factor in response.436,437
Side Effects and Special Treatment Considerations
Imatinib is usually tolerated. Most adverse effects are manageable and seldom require permanent cessation of therapy. Reduction to subtherapeutic doses is not recommended; it is better to interrupt therapy for a time.438
Myelosuppression is common, especially at treatment onset when the CML clone accounts for most of the blood cells. Dose reduction to less than 300 mg/day is not advisable for myelosuppression. The drug should be stopped until blood counts recover. G-CSF or GM-CSF can prevent or treat neutropenia.439,440 Platelet transfusion may be used for severe thrombocytopenia. Patients with imatinib-induced chronic cytopenias have inferior responses.441 Myelosuppression is an independent adverse factor for achieving cytogenetic responses with imatinib.442 Erythropoiesis-stimulating agents may be used to raise hemoglobin levels, and their use does not appear to affect CML outcomes, but may increase the risk of thrombosis.443 Severe irreversible marrow aplasias after imatinib exposure can occur.444
The main side effects noted with imatinib include fatigue, edema, nausea, diarrhea, muscle cramps, and rash.445 Elevated hepatic transaminases can occur. Mild transaminase elevations often respond to glucocorticoid use.446 Hepatotoxicity is uncommon, occurring in approximately 3 percent of patients, usually within 6 months of onset of imatinib use. Acute liver failure has been described.447 The severe periorbital edema occasionally observed is postulated to be a drug effect on the function of platelet-derived growth factor receptor (PDGFR) and KIT expressed by dermal dendrocytes. Surgical decompression of severe edema rarely has been required.448 Although no effects on spermatogenesis have been reported, women of childbearing age are at risk of teratogenic effects on their fetus.448
Weight gain is associated with imatinib use.449 Patients with renal impairment require lower doses of imatinib.450 Hypophosphatemia451 and altered bone and mineral metabolism have occurred.452,453 Cutaneous reactions with imatinib therapy occur in approximately 15 percent of patients.454 Except for severe reactions (approximately 5 percent of patients), such as Stevens-Johnson syndrome, exfoliative dermatitis, and erythema multiforme, cutaneous reactions rarely require permanent discontinuation of therapy. With milder reactions, concomitant glucocorticoid therapy or brief discontinuation of imatinib with gradual reintroduction at a lower dose and then a gradual increase in dose can be accomplished.456,457 With very mild cases, concurrent treatment with antihistamine or other symptomatic therapy may be successful. Oral desensitization regimens have been described that allow some patients to continue imatinib therapy. Hair depigmentation458 and hypopigmentation of the skin,459 probably related to the inhibition of the KIT receptor tyrosine kinase by imatinib, have been reported.
Other Effects of Imatinib
Imatinib has been found to cause regression of marrow fibrosis.460 One study found that the extent of marrow fibrosis in CML is not a prognostic factor with imatinib therapy,461 whereas another study observed that although imatinib reverses marrow fibrosis in patients with CML, it does not change the unfavorable prognosis associated with fibrosis.462
Imatinib reverses exaggerated VEGF secretion in patients with CML,463 and it may reverse exaggerated marrow angiogenesis.464 It can reduce marrow cellularity and normalize morphologic features regardless of cytogenetic response. BCR-ABL1–positive cells persist in patients despite prolonged treatment responses with imatinib.465
Pharmacokinetic Considerations During Imatinib Therapy
Mean plasma trough concentration of imatinib and its metabolite, CGP74588, obtained at about 1 month (presumptive steady-state) was 979 ± 530 ng/mL. The rate of CCyR and MMR was higher within the highest quartiles of imatinib trough levels.466 Some therapists suggest that imatinib plasma levels be checked in cases of suboptimal response in order to adjust the dose, but access to this monitoring is not routinely available.467 Comedications and population covariates, such as body weight and white cell count, had no, or minimal, effect on imatinib clearance.468 Patients with CML on hemodialysis have been successfully treated with imatinib.469 Therapy interruptions and nonadherence with oral imatinib usage are common, and patient education and close monitoring are important to ensure compliance.470
Initiation of Therapy with Newer Tyrosine Kinase Inhibitors
Dasatinib Dasatinib is a second-generation oral BCR-ABL1 inhibitor with dual inhibition of ABL1 and SRC.471 It can bind to both the active and inactive conformation of the ABL1 kinase domain, so it may be affected by mutations resulting in resistance.471
Dasatinib was first studied for use in initial therapy in a phase II trial that accrued 62 patients. Ninety-eight percent achieved a CCyR, and the median time to CCyR was 3 months. The MMR rate was 82 percent. Responses were durable, and the recommended treatment schedule based on a safety profile was 100 mg, once daily.472 A randomized, phase III trial compared the efficacy of dasatinib to imatinib.473 In this study, 259 patients received dasatinib, 100 mg/day, and 260 received imatinib, 400 mg/day. After 12 months of followup, the rates of CCyR by 3, 6, and 9 months were 54, 73, and 78 percent, respectively, for patients on dasatinib as compared to 31, 59, and 67 percent, respectively, for those on imatinib. The 24-month CCyR was 80 percent for patients using dasatinib, as compared to 74 percent for those on imatinib. The MMR showed a similar trend, and the median time to MMR was 15 months for those using dasatinib, compared to 36 months for those using imatinib.
Long-term followup data have confirmed faster and deeper responses to dasatinib as compared to imatinib.474 At 4 years, 76 percent of dasatinib-treated patients had attained a MMR (BCR/ABL1 <0.1 percent) as compared to 63 percent using imatinib. At 3, 6, and 12 months, more patients achieved molecular responses using dasatinib than those using imatinib. There were fewer patients who progressed to accelerated or blast phase using dasatinib as compared to imatinib. To date, there is no difference in progression-free survival or overall survival between the two groups.474 In a randomized study, with a minimal followup of 3 years, the proportion of patients with BCR-ABL1 transcript levels less than 10 percent was higher in those using dasatinib as compared to those using imatinib.475 Better responses were observed at 3, 6, and 12 months in the patients using dasatinib. The achievement of an early molecular response was predictive of improved progression-free and overall survival.476
Toxicity of Dasatinib Most grade 3 or 4 adverse events with dasatinib are hematologic and all cell lines can be affected. Some patients may have bleeding from inhibition of platelet aggregation.477 Adverse events noted less frequently with dasatinib than imatinib include nausea, vomiting, myalgia, rash, and fluid retention, including superficial edema. Pleural effusions can be seen with dasatinib use. In one trial, 14 percent of patients had grade 1 or 2 pleural effusions at 24 months, but grade 3 or 4 effusions occurred in only 2 patients. This toxicity did not affect drug efficacy. Dasatinib may also increase the risk of pulmonary arterial hypertension at any time, and this is an indication to discontinue dasatinib.478 Dasatinib may prolong the QTc interval, and it should be used with caution in those who have long QT syndrome or those taking drugs that may lengthen the QT interval.474 Hypophosphatemia was found in 7 percent of cases.474
Dasatinib is metabolized primarily by hepatic cytochrome P450 (CYP) 3A4 enzymes, so inducers of this enzyme may decrease the effective dose, and inhibitors may increase the effective dose. Increases or decreases in administered dose may be needed to compensate for these effects. Antacids can also reduce dasatinib effects.479 Lymphocytosis from the clonal expansion of NK/T cells has occurred during dasatinib treatment.480 In a population of dasatinib-treated patients with large granular lymphocyte expansion, 90 percent had T-cell receptor delta rearrangements, the functional significance of which is unknown.481 Lymph node follicular hyperplasia has been noted on dasatinib therapy.482 Unlike the case with imatinib, dasatinib cellular uptake is not affected by octamer-binding protein-1 (OCT-1) activity, which is a substrate of the efflux proteins, ABCB1 and ABCG2. Resistance to dasatinib is often found with point mutations in ABL1 at residue 315 or 317.
Nilotinib Unlike dasatinib, nilotinib is a selective, orally bioavailable, ATP-competitive inhibitor of BCR-ABL1 which is 20 to 50 times more potent than imatinib in vitro.483 Like imatinib, it does not induce apoptosis in CD34+ CML cells.484 As with dasatinib, nilotinib was first tested as initial therapy in phase II trials,485 which were followed by a randomized phase III trial. In one phase II trial, 51 patients received nilotinib 400 mg, twice a day, and 98 percent entered CCyR and 76 percent had a MMR by 6 months.486 The phase III trial compared nilotinib, 300 mg twice daily, 400 mg twice daily, and imatinib 400 mg daily.487 At 12 months, the MMR which had been chosen as the primary end point, was 44 percent (nilotinib 300 mg dose), 43 percent (nilotinib 400 mg dose), and 22 percent (imatinib 400 mg daily). The CCyR rates were 15 percent higher with nilotinib than imatinib. The rate of progression to accelerated or blast phase was 4 percent at 1 year with imatinib and less than 1 percent with nilotinib. These improvements were observed in each prognostic group based on Sokal risk groups. The patients using either 300 or 400 mg doses had minimal differences, so in 2010, nilotinib was approved at a dose of 300 mg twice daily for initial CML therapy. At 4 years of followup, more patients using either dose of nilotinib achieved a MMR than those using imatinib (73 and 70 percent vs. 53 percent).488 The rates of progression to accelerated and blast phase were also lower for nilotinib than imatinib. The 4-year freedom-from-progression and overall-survival rates were not different between the two groups. MMR rates at 3 years were higher for those patients using nilotinib, 300 mg, twice per day, in the three risk groups of Sokal (low risk, 79 percent; intermediate risk, 76 percent; and high risk, 52 percent progression as compared to those using imatinib (65, 55, and 30 percent progression, respectively).488 There was a reduced incidence of BCR-ABL1 mutations in in patients using nilotinib compared to those using imatinib. Nilotinib use led to fewer (less than half as many) treatment-emergent BCR-ABL1 mutations than did imatinib treatment, and to reduced rates of progression to accelerated phase and blast crisis in patients with these mutations.489
Toxicity of Nilotinib Nilotinib is rarely associated with edema or muscle cramps. Grades 3 and 4 cytopenias were seen in 29 percent of cases in one trial.487 Grade 3 or 4 elevations in lipase, bilirubin, and hyperglycemia were observed in 17, 8, and 12 percent of patients, and hypophosphatemia was seen in 16 percent. QTc prolongation can occur, so one should monitor the electrocardiogram (EKG) readings for 7 days after starting therapy and with dose changes.483 Electrolyte abnormalities should be corrected at outset of treatment. Nilotinib may be associated with an increased risk of peripheral vascular disease, which may be arterial or venous.490 If thrombosis occurs, it should no longer be used for therapy.
Bosutinib and Ponatinib These TKIs are not approved for use in initial therapy. In the one trial, which compared efficacy for bosutinib, 500 mg once daily, with imatinib, 400 mg daily in newly diagnosed chronic phase patients, the primary end point of CCyR at 12 months was 70 percent for bosutinib and 63 percent for imatinib.491,492 Results from followup of MMR rates, transformation rates, and durability of remission are not yet available.
Summary of Tyrosine Kinase Inhibitor Selection for Initial Therapy of Chronic Phase Chronic Myelogenous Leukemia
The goal of initial TKI therapy is to achieve a CCyR within 12 months or no later than 18 months of therapy, and to prevent progression to the accelerated or blast phase. How best to achieve these goals remains controversial. Hence, the National Comprehensive Cancer Network (NCCN) guidelines list imatinib, nilotinib, and dasatinib as all being acceptable TKIs for initial treatment of CML.492 Many clinicians would choose a second-generation TKI, given the rapidity and depth of response and the lower rates of transformation to advanced phases of the disease, but others use imatinib because of the lack of proof of prolongation of survival with nilotinib or dasatinib. In those with intermediate- or high-risk disease as assessed by the Sokal and Hasford models (see “Course and Prognosis” below for details of these scores), nilotinib or dasatinib may be preferred over imatinib to achieve rapid, better responses—the “hit hard, hit early” approach.493 Thus, until survival data are available, any one of the three approved TKIs may be used for initial therapy. Choice of agent may be dependent upon cost considerations, ease of administration, patient risk scores or perceived risk,494 and the drug’s side-effect profile (see Table 89–2).
Defining a Response to Tyrosine Kinase Inhibitors
Table 89–3 contains definitions of hematologic, cytogenetic, and molecular responses. The guidelines for periodic monitoring patients who are in chronic phase and receiving TKI therapy are shown in Table 89–4. The median BCR-ABL1 levels for imatinib-treated patients can decrease over at least 5 years. Table 89–5495 lists the milestones at 3, 6, 12, and 18 months expected of patients as indicators of an appropriate response in patients treated initially with a TKI.434 There is variation in an individual patient’s time to maximal response. Consequently, if a patient has not met those precise milestones but shows a continued decrease in the proportion of Ph chromosome–positive cells on cytogenetic examination of marrow, or if in a CCyR, a continued decrease in the level of the PCR signal for BCR-ABL1 and is near the benchmark, the treatment can be continued. Only (1) failure to meet the benchmarks at 3, 6, or 12 months or (2) loss of response as defined as loss of a CHR or CCyR, (3) development of new cytogenetic abnormalities, (4) acquisition of a BCR-ABL1 mutation, or (5) an increase in the BCR-ABL1/ABL1 ratio of 1-log or more on serial RT-PCR testing or into the range associated with reappearance of the Ph chromosome on G-banding should generate a change in treatment to limit the risk of progression of the disease. Because of the variability in PCR testing, those changes should be confirmed within 1 month. Patients who have 100 percent Ph chromosome–positive cells after 6 months of therapy have a minimal chance of achieving a MCyR or CCyR and may be offered allogeneic stem cell transplantation, if applicable.417,496
Table 89–4.Guidelines for Monitoring of Patients in Chronic Phase Who are Undergoing Tyrosine Kinase Inhibitor Therapy ||Download (.pdf) Table 89–4. Guidelines for Monitoring of Patients in Chronic Phase Who are Undergoing Tyrosine Kinase Inhibitor Therapy
1. At diagnosis, before starting therapy, obtain Giemsa-banding cytogenetics and measure BCR-ABL1 transcript numbers by qPCR using marrow cells. If marrow cannot be obtained, use FISH on a blood specimen to confirm the diagnosis.
2. At 3, 6, 9, and 12 months after initiating therapy, measure qPCR for BCR-ABL1 transcripts. (If qPCR using the International Standard is not available, perform marrow cytogenetics.) If there is a rising level of BCR-ABL1 transcript or 1 log increase after MMR achieved, qPCR should be repeated in 1 to 3 months.
3. At 12 months obtain marrow cytogenetics for cells with Ph chromosome if no CCyR or MMR.
4. Once CCyR is obtained, monitor qPCR on blood cells every 3 months for 3 years and then every 4 to 6 months, thereafter. If there is a rising level of BCR/ABL1 transcripts (1 log increase after MMR achieved), repeat quantitative PCR in 1 to 2 months for confirmation.
5. These guidelines presume continued response to a TKI until CCyR achieved. If this does not occur see text for approach.
6. Mutation analysis should be performed with loss of chronic phase, loss of any previous level of response, inadequate initial response (BCR/ABL1 transcripts >10%) at 3 or 6 months or no CCyR at 12 or 18 months, and a 1-log increase in BCR/ABL after MMR once achieved.
Table 89–5.Milestones for Assessing Response to Tyrosine Kinase Inhibitors417,495 ||Download (.pdf) Table 89–5. Milestones for Assessing Response to Tyrosine Kinase Inhibitors417,495
|Time of Observation (months) ||Disease Response |
|Unsatisfactory ||Suboptimal Response/Warning ||Optimal Response |
|3 ||No CHR and/or Ph+ >95% ||BCR/ABL1 >10% and/or Ph+ 36–95% ||BCR/ABL1 ≤10% and/or MCyR |
|6 ||BCR/ABL1 >10% and/or no MCyR ||BCR–ABL1 1–10% and/or MCyR ||BCR/ABL1 <1% and/or CCyR |
|12 ||BCR/ABL1 >1% and/or no CCyR ||BCR–ABL1 <0.1–1% ||BCR/ABL1 <0.1% |
|18 ||No CCyR ||CCyR if no MMR ||CCyR or MMR |
Achieving a cytogenetic response is associated with progression-free survival in patients treated with imatinib and is an important goal of therapy (97 percent in those with a CCyR vs. 81 percent in those without a MCyR).497 At 5 years of followup, of those patients who achieved CCyR on imatinib in the IRIS study, only 3 percent had progressed to accelerated or blast phase during treatment.428 A CCyR at 1 year may be the major predictor for overall survival and progression-free survival.498 In patients in chronic phase treated with imatinib, nilotinib, or dasatinib, early responses (at 3 months) in BCR-ABL1 transcript reduction or decrease of Ph chromosome frequency predicted for better outcomes as measured by event-free or overall survival. For example, patients with less than 10 percent BCR-ABL1 transcripts at 3 months had a 3-year event-free survival of 95 percent or greater, whereas those with greater than 10 percent transcript level at 3 months had a 61 percent event-free survival.499
Molecular response is determined by the decrease in BCR-ABL1 mRNA by PCR. This is the only means to measure the depth of the response once a CCyR is attained. The achievement of MMR after treatment with imatinib is associated with durable long-term CCyR and a lower rate of disease progression. Only 5 percent of patients achieving a MMR with imatinib lost a CCyR compared to 37 percent who did not achieve that degree of response.500 Also, the 5-year followup of the IRIS trial showed that no patient with a CCyR and MMR at 12 months had progressed to a more advanced phase of the disease.497 The IRIS study 7-year followup also showed that in those with a MMR at that point in time, progression was rare. The estimated event-free survival was 95 percent for those with MMR at 18 months compared with 86 percent in those without a MMR.501 To date, there is no evidence that a change of therapy would improve survival in those with CCyR but not a MMR. In those with stable CCyR after treatment with a second-generation TKI, achievement of MMR may not have significance as a predictor of survival.499
The time taken to achieve MMR is also thought to have prognostic significance. In the IRIS study, the chance of disease progression was higher in those who failed to achieve a 1-log reduction in BCR/ABL1 transcripts by 3 months or a 2-log reduction by 6 months.502 A BCR-ABL1 transcript level greater than 10 percent after 3 months is a significant predictor for long-term outcomes.503 In another analysis, chronic phase patients treated with imatinib 400 mg/day who had BCR-ABL1 transcripts of 9.84 percent or less at 3 months had better overall, progression-free, and event-free survival at 8 years than did those with values of 9.84 percent or greater.503 Also, there is evidence that early molecular response to initial therapy with dasatinib or nilotinib in patients with CML is a predictor of overall response. In one trial with dasatinib, patients with BCR-ABL1 transcripts of 10 percent or less at 3 months had significantly better 5-year progression-free (92 vs. 67 percent) and 4-year overall survival than did those with greater than 10 percent transcripts (95 vs. 83 percent).504 In another study with nilotinib, patients with BCR-ABL1 of 10 percent or less at 3 months also had improved 4-year progression-free survival compared to those with BCR-ABL1 greater than 10 percent at 3 months (95 vs. 85 percent).505 Progression was defined as transformation to accelerated or blast phase.
Rising BCR-ABL1 Transcript Levels Rising BCR-ABL1 transcripts can indicate a new mutation or cytogenetic relapse. A significant change has been defined as either a twofold increase, serially increasing levels, or a 1-log increase.492,495 There are no current recommendations for therapy changes based on an increase in BCR-ABL1 transcripts. Serial increases or increases of 1-log or more should trigger ABL mutational analysis and frequent monitoring of BCR-ABL1 transcripts.
Suboptimal Therapeutic Responses The initial European Leukemia Network guidelines defined suboptimal response as no cytogenetic response at 3 months, less than a partial cytogenetic response (PCyR) at 6 months, a PCyR at 12 months, and less than a MMR at 18 months.495,506 The significance of a suboptimal response is dependent on the cause; for example, this may be insignificant if the result of drug intolerance or noncompliance as opposed to drug resistance (see “Acquired Resistance” below). The significance also depends on time of suboptimal response with earlier time points indicating a worse prognosis. Currently, CCyR and PCyR at 3 months are considered optimal and suboptimal responses. Suboptimal responses are labeled as a “warning” response in the Network guidelines.495 These response levels may trigger ABL mutation analysis or closer monitoring.
Secondary Chromosomal Changes with Tyrosine Kinase Inhibitors
Because of its earlier development, most of these data are obtained with imatinib treatment. Clonal abnormalities in cells lacking a detectable Ph chromosome or BCR-ABL1 rearrangements have been detected in patients undergoing imatinib therapy who previously were treated with IFN-α.507,508 These cytogenetic changes were noted in seven patients at a median of 13 months of imatinib therapy, and trisomy 8 was the most frequent abnormality. All of these patients had MCyRs to imatinib.507 The presence of additional chromosomal abnormalities is considered to be a feature of the accelerated phase of CML. In some patients, clonal evolution may be related to imatinib resistance.509 Clonal abnormalities may be present in up to 10 percent of patients taking imatinib.510 Some of these cases may be associated with a MDS, especially in those patients with previous exposure to cytarabine and idarubicin. The antiproliferative effect of imatinib allows restoration of polyclonal hematopoiesis in CCyR, which could permit the manifestation of a Ph chromosome–negative disorder.511 Some investigators have found that, with the possible exception of +8, +Ph, and i(17), additional chromosomal abnormalities at diagnosis are not associated with an inferior outcome to imatinib therapy.512,513 In contrast, another group found that development of trisomy 8 in patients taking imatinib, while associated with pancytopenia, did not result in signs of disease progression. In a series of 34 CML patients who developed Ph chromosome–negative clones while taking imatinib, the most common abnormalities were trisomy 8 and monosomy 7. In 11 of these patients, no archival evidence of these clones was present before imatinib therapy was initiated, and none of the patients developed myelodysplasia.514 In patients treated at diagnosis with imatinib, 9 percent developed chromosomal abnormalities in Ph chromosome-negative metaphases. These appeared at a median of 18 months, and the most common abnormalities were −Y and +8. Most were temporary and disappeared within 5 months. Only one patient with −7 progressed to acute myelogenous leukemia (AML).515 Cytogenetic clonal evolution may not be an important impediment to achieving a MCyR or CCyR with imatinib, but it is an independent poor prognostic factor for survival of patients in chronic and accelerated phases of CML.516 Imatinib therapy may overcome the poor prognostic significance of derivative chromosome 9 in CML.517
Adherence to Tyrosine Kinase Inhibitor Therapy
Noncompliance with therapy is associated with poorer outcomes. In one trial, patients with a suboptimal response had higher nonadherence (23 percent) than did those with optimal responses (7 percent).518 In another study, adherence was the only independent predictor for achieving a complete molecular response (CMR) on imatinib. Patients with an adherence rate of 85 percent or less had a greater chance of losing their CCyR at 2 years (27 percent) than did those with better adherence (1.5 percent). They, also, had a lower chance of remaining on imatinib.519 Adherence has also been correlated with level of molecular response. In patients using a TKI for about 5 years, median adherence was 98 percent (range: 24 to 100 percent). If adherence was greater than 90 percent, there was a higher probability for a 3-log reduction in BCR/ABL1 transcripts and a CMR. If adherence was less than 80 percent, no MMRs occurred.520 The poor adherence to second-generation TKIs has not been studied for a sufficient duration to determine its impact. Management of side effects is of importance in maintaining a high rate of adherence.
Development of Tyrosine Kinase Inhibitor Resistance
The development of resistance to imatinib is not surprising.521,522 Its specificity and “snug fit” into the ABL1-kinase pocket provide the ideal circumstance for resistance.523 Some cases demonstrate primary resistance to imatinib, and gene profiling has demonstrated differential expression of about 46 genes in responders compared to nonresponders.524 Even in patients with CCyR, malignant progenitors at the LTC-IC stage persist. Chronic phase CML stem cells are resistant to imatinib and are genetically unstable.525 These cells have a high level of BCR-ABL1 transcription, and they are thought to express transporter proteins that result in abnormal imatinib flux.526 Mathematical models suggest that imatinib rapidly eliminates leukemic progenitors, but does not deplete CML stem cells. Such models predict the probability of developing resistant mutations and can estimate the time that resistance will emerge.527 Several potential mechanisms of resistance include BCR-ABL1 amplification in the presence of imatinib, P-glycoprotein–mediated drug efflux, altered drug metabolism, acquisition of BCR-ABL1–independent signaling characteristics, and point mutations in the ABL1 kinase domain that decrease imatinib binding. Each of these mechanisms of resistance may have clinical relevance.
Primary Resistance Primary resistance to imatinib is defined as lack of CHR at 6 months or failure to achieve any level of cytogenetic response at 6 months, a MCyR at 12 months, or a CCyR at 18 months. This may occur in 15 to 25 percent of patients. Primary resistance may often be the result of inadequate plasma concentration because of binding of the drug to proteins, such as albumin or α1-acid glycoprotein. In an analysis of the IRIS study, plasma levels of imatinib following the first month of treatment proved to be a significant predictor for clinical response. Plasma levels are not available for clinical use, however, so these have minimal influence on treatment decisions when responses are not as expected. Only one gene, prostaglandin-endoperoxide synthase 1/cyclooxygenase1 (PTGS1/COX1) was found to differentiate primary imatinib resistance. Eleven genes were associated with secondary resistance after imatinib therapy in those without an ABL1 kinase domain mutation.528 Expression of the OCT-1, which mediates drug influx, is thought to be important for imatinib but not dasatinib effectiveness.529,530 Many CML patients who have a suboptimal response to imatinib have low OCT-1 activity, but this can be overcome with higher doses of imatinib or use of dasatinib, which uptake is not dependent on OCT-1 expression.530 OCT-1 expression is associated with MMR at 12 and 24 months, and it is a predictor of the long-term risk of resistance and of transformation in patients treated with imatinib.531 CML CD34+ cells overexpress the drug transporter ABCG2, and imatinib, dasatinib, and nilotinib are substrates for ABCB1 and ABCG2. Overexpression of MDR1 has been associated with decreased intracellular concentration of imatinib.532
Acquired Resistance Acquired resistance is that which occurs after exposure to TKIs or other treatments. Amplified gene expression and increased BCR-ABL1 protein expression are often reported in resistant patients. Duplication of the Ph chromosome and isodicentric chromosomes are a possible mechanism of resistance to imatinib.533,534
Mutations in the ABL1 kinase domain are a frequent mechanism of resistance. Kinase domain mutations were the only independent predictor for the loss of CCyR and progression when compared to those without a mutation.535 Mutations in the ABL1 kinase domain may predate imatinib treatment,536 and several BCR-ABL1 kinase domain mutants associated with imatinib resistance remain sensitive to the drug, suggesting a need for characterization before a resistant phenotype can be attributed to the given mutation.537 The mutant clone does not always have a proliferative advantage.538 Some of these mutations may lie outside the kinase domain, and more than 40 such mutations have been described. Screening early phase CML patients for mutations before the start of imatinib therapy is not cost-effective because of their low incidence, but in patients with evidence of an increase in CML cells while on imatinib, mutation searches are indicated.539 BCR-ABL1 kinase domain point mutations are rare in those who have had good cytogenetic responses to imatinib, and when detected in that setting, their presence does not always predict relapse.540 Mutations in the ABL1 portion of the BCR-ABL1 oncogene are present in approximately 40 percent of patients who do not achieve a CHR or CCyR to imatinib. ABL1 mutations were found in those patients with both primary and acquired resistance. Amino acid substitutions in seven residues accounted for 85 percent of all mutations associated with resistance.541 The mutations most associated with resistance are Thr315ILe, Gly250Glu, Glu255Lys, and Thr253His substitutions. Few of the described mutations directly affect imatinib binding.542 Mutations in the ABL1–ATP phosphate-binding loop (P-loop) are most closely associated with a poor prognosis,543 and these P-loop mutations predict for disease progression. Overall survival is worse for P-loop and for T315I mutations, but not significantly different when other mutations are present.544
Ultra-deep sequencing approaches have shown that routine Sanger sequencing underestimates BCR-ABL1 mutation in 55 percent of samples where the missed mutations had low abundance.545 Mass spectrometry can detect a 0.05 to 0.5 percent level of mutations, as well.546 For many mutations, the concentration that inhibits 50 percent (IC50) of various TKIs and response have not been documented.547
Second-generation BCR-ABL1 inhibitors (see “Dasatinib and Nilotinib” below) are able to overcome imatinib-resistant mutants, with the exception of the T315I mutations (Table 89–6). Mutations F317L and V299L are resistant to dasatinib and mutations Y253H, E255K, and F359I are resistant to nilotinib. Ponatinib was active against T315I and against other BCR-ABL1 mutations resistant to dasatinib or nilotinib.548 Ponatinib may be effective against individual ABL1 point mutations but may not overcome some compound mutations, which are two or more mutations in the same BCR/ABL1 molecule. Some mutations may be polyclonal as well.549 The T315I mutation results in steric hindrance, which precludes access of some TKIs to the ATP-binding pocket of the ABL1 kinase domain.550 In a series of 27 patients with T315I mutation, survival was dependent on stage of disease, with many of the chronic phase patients described as having an indolent course.551 In addition to ponatinib, agents such as IFN-α and homoharringtonine have also been proposed as therapy for those with the T315I mutation.552
Table 89–6.Prevalent ABL1 Mutations Conferring Resistance to a Tyrosine Kinase Inhibitor ||Download (.pdf) Table 89–6. Prevalent ABL1 Mutations Conferring Resistance to a Tyrosine Kinase Inhibitor
In some cases of resistance associated with imatinib, other signal pathways independent of BCR-ABL1 may become important in cell proliferation.553 These include heat shock protein (hsp) 70,554 survivin,555 LYN kinase,556 SRC,557 and GRB2, among others.558
Dose escalation, combination therapy, and treatment interruption have been proposed as means to overcome drug resistance.559 Combination therapy from the outset560 also has been proposed to prevent development of resistance. Treatment interruption to stop clonal selection of resistant cells has been proposed.557 Gene-expression profiles may be useful to predict the clinical effectiveness of imatinib for CML treatment, thereby allowing individualized therapy from the outset.560 In patients with relapse or resistance, alternative approaches include increasing the dose of imatinib or switching to dasatinib or nilotinib.561 Allogeneic hematopoietic stem cell transplantation is not recommended unless patients have inadequate response or intolerance to multiple TKIs or have the T315I mutation. Mutational analysis is not recommended at diagnosis but is of help in selecting TKI therapy for patients with an inadequate initial response or loss of response to TKI therapy. Mutation type may dictate choice of the next TKI.562
Dose Escalation If the patient is on imatinib, 400 mg/day, dose escalation to 800 mg/day can be tried. This may be most efficacious in patients with cytogenetic relapse who had achieved a cytogenetic response with the initial dose of imatinib, but is not likely to benefit those who have not had a cytogenetic response with imatinib at 400 mg/day.
Second-Generation Tyrosine Kinase Inhibitor Therapy Several TKIs are approved for use in the case of imatinib resistance or intolerance. In general, outcome with each is comparable, so the choice of agent often depends on its side-effect profile or in some cases on mutation type (see Tables 89–2 and 89–6).562
The 3-month molecular response after initiation of a second TKI is also a predictor of overall and event-free survival for those patients in chronic phase when switched from imatinib to another TKI.505 A BCR-ABL1 level of 10 percent or less at 3 months is desirable. In patients treated with nilotinib after imatinib resistance or intolerance, the 4-year progression-free and overall survival was 85 and 95 percent, respectively, if BCR-ABL1 transcripts were 10 percent or less as compared to 42 and 71 percent for those with BCR-ABL1 transcripts greater than 10 percent at 3 months.563
Either dasatinib or nilotinib can be used in cases of imatinib resistance or intolerance. Dasatinib is 325-fold more potent than imatinib; and, as a dual inhibitor of SRC and ABL1 kinases, dasatinib is able to bind to BCR-ABL1 with less-stringent conformational requirements.564 In patients resistant to imatinib, dasatinib, 140 mg/day (70 mg q12h), resulted in a higher proportion of MCyR, CCyR, and MMR than did 800 mg/day (400 mg q12h) of imatinib. Treatment failure was decreased and progression-free survival was improved with dasatinib.565 Unlike imatinib, dasatinib penetrates the blood–brain barrier.566 In long-term followup of 670 patients with imatinib-resistant or intolerant CML, treated with various doses of dasatinib, 28 percent of patients remained on study treatment at 6 years. Survival was in the range of 76 to 83 percent and a MMR was achieved in 45 percent on a dose of 100 mg daily. Molecular and cytogenetic responses at 3 and 6 months were predictive of survival. For those with BCR-ABL1 transcripts less than 10 percent at 3 months, progression-free survival was 68 percent, whereas it was only 26 percent for those with BCR-ABL1 transcripts greater than 10 percent.567 Nilotinib in a dose of 400 mg every 12 hours induced approximately 40 percent of patients who were resistant to or intolerant of imatinib into a MCyR, and approximately 30 percent into a CCyR. Nilotinib, 400 mg BID, is the recommended dose for those intolerant or resistant to imatinib.
Bosutinib and Ponatinib In addition to dasatinib and nilotinib, bosutinib and ponatinib, third-generation TKIs, are active against many of the imatinib-resistant BCR-ABL1 kinase domain mutations and are effective treatment options for CML resistant to standard-dose imatinib. Both were FDA approved for this indication in 2012. Bosutinib is active with F317L, Y253H, and F359C/I/V mutations. Ponatinib is also effective against many mutations resistant to nilotinib or dasatinib and has activity in cases with a T315I mutation (see Table 89–6).
Bosutinib is a dual SRC-ABL1 TKI that resulted in a CCyR in 24 percent and CHR in 73 percent of patients who had used two prior TKIs.568 All mutations except T315I were responsive. It is approved for chronic phase, accelerated phase, or blast phase in those resistant or intolerant to prior TKI therapy. The dose is 500 mg/day, orally, with food. Diarrhea, nausea, decreased platelet count, other gastrointestinal complaints, rash, and anemia were the most common adverse events, and most of these were of low-grade. Bosutinib is not yet approved for use as an initial agent in CML, as it did not demonstrate significant improvement in CCyR rates at 1 year compared to imatinib. It was, however, associated with higher 1-year MMR rates, faster time to response, and less disease progression.491
Ponatinib blocks native and mutated BCR-ABL1 including the gatekeeper mutation T315I. In a phase I dose escalation study, pancreatitis, rash, and myelosuppression were major toxicities. In 12 patients with T315I mutations, 92 percent had a MCyR. In those with accelerated or blast phase, or Ph chromosome–positive ALL, 36 percent had a major hematologic response and 32 percent had a MCyRs. Arterial thrombotic events occurred, however.548 Retrospective analyses of these incidents led to temporary withdrawal of this medication, which is now used primarily in cases of T315I mutation or failure of several other TKIs. If vascular occlusion occurs, therapy should be halted immediately.569 Ponatinib has a black box warning for vascular occlusion, heart failure, and hepatotoxicity.
A third-line TKI should be considered in patients who have failed two prior generations of TKI therapy, but responses tend to be infrequent and are usually not durable, so clinical trials, other agents, or allogeneic hematopoietic stem cell transplantation should be considered. A prior CCyR on either imatinib or subsequent nilotinib or dasatinib therapy was the only predictor of a cytogenetic remission on a third-line therapy.570
Non–Tyrosine Kinase Inhibitor Therapies
Omacetaxine Omacetaxine (homoharringtonine) is a Cephalotaxus alkaloid that has activity against the T315I mutation. Omacetaxine was approved on the basis of a study that recruited patients who had already been on two or more TKIs. In those enrolled in chronic phase, 67 percent had a CHR; a MCyR or a CCyR was achieved in 22 and 4 percent, respectively. Median overall survival was 30 months.570 In those with T315I mutations enrolled on a separate study, MMR was achieved in 17 percent of patients and the T315I clone was reduced in 61 percent of patients.571 The most common side effects with this medication are cytopenias. This agent also has activity in accelerated phase CML, but little in blast phase. It was approved by the FDA in October 2012 for chronic and accelerated phase patients intolerant of other therapy or in cases not responding to two or more TKIs.
Several inhibitors of signal transduction mediators involved in the downstream effects of BCR-ABL have been proposed for use in imatinib-resistant CML. These inhibitors include the JAK2 inhibitor AG490,572 SRC kinase inhibitors, mTOR (mammalian target of rapamycin) inhibitors, such as rapamycin,573 the proteasome inhibitor bortezomib,574,575 histone deacetylators,576,577 PI3K or MEK (mitogen-activated kinase) inhibitors and inhibitors of the WNT/β-catenin pathway thought to be active in CML stem cells. Imatinib resistance often is associated with restored activation of the BCR-ABL1 signal transduction pathway, suggesting that BCR-ABL1 remains a valid target to overcome resistance in these cases.578 BCR-ABL1 point mutations isolated from patients with imatinib-resistant CML are sensitive to inhibitors of the BCR-ABL1 chaperone hsp90, such as geldanamycin.579 Many of these agents have not yet entered clinical trials, but some are in early phase trials, such as inhibitors of the hedgehog pathway, which is activated in CML but not normal hematopoietic stem cells.580 Some are being used in conjunction with imatinib in resistant cases.
Combined Therapy Agents that have been proposed for use in combination to improve response rates or to overcome resistance to imatinib have included IFN-α, cytarabine, omacetaxine multiagent chemotherapy, arsenic trioxide, and decitabine, with some supporting in vitro data.581,582,583,584,585,586 Combining imatinib with chemotherapeutic agents is more myelosuppressive, and final effects on response rates and survival have yet to be determined. This approach is rarely used in chronic phase CML, but is used in accelerated or blast phase or in Ph chromosome–positive acute lymphoblastic leukemia.587
Disease Prognosis and Monitoring During Tyrosine Kinase Inhibitor Therapy
Treatment failure should lead to alterations in therapeutic strategy.588 For patients treated initially with imatinib, BCR-ABL1 expression in cytogenetic responders and nonresponders was similar. BCR-ABL1 expression became significantly different 3 months after treatment and became increasingly different between responders and nonresponders with continued therapy at 6, 9, and 12 months.589
One mode of monitoring patients undergoing TKI therapy is to measure blood counts at least once per month and to obtain marrow samples every 6 months until a complete cytogenetic remission is obtained.590 Thereafter, marrow samples are obtained no more often than yearly to monitor for other clonal abnormalities. Quantitative RT-PCR is performed every 3 months on blood or marrow. A 1-log increase in the level of BCR-ABL1 reactivity, confirmed on a repeat sample at least 1 month later, suggests a loss of response to treatment. In patients who do not have a CHR at 3 months, or a MCyR after 6 to 12 months, other therapeutic options are considered.591 The molecular response after 2 to 3 months of therapy is a strong predictor of clinical and cytogenetic response.592 Sequencing the BCR-ABL1 kinase domain can reveal emergence of resistant clones and is useful if there is an insufficient initial response to imatinib or a second-generation TKI (see Table 89–5) or any sign of loss of response, such as relapse to Ph chromosome–positive status, a 1-log increase in BCR/ABL1 transcript ratio, or loss of a MMR.417
In patients receiving second-generation TKIs as second-line therapy, those who have no cytogenetic response at 3 to 6 months should be considered for allogeneic transplantation or switched to an alternative therapy in a clinical trial. After CCyR is attained, molecular monitoring is recommended every 3 months for 3 years and every 4 to 6 months thereafter.492 After 12 months, those with a MCyR had a significant survival advantage over those with lesser responses.593 Those with BCR-ABL1 transcripts greater than 10 percent following initial imatinib treatment should be switched to dasatinib, nilotinib, or bosutinib. If this is not an option because of cost or availability, high-dose imatinib can be considered, but it also unlikely to have benefit for more than a few months. For those already on a second-generation TKI, a clinical trial or alternative TKI could be tried or patients may continue on the same TKI with very careful followup, as the impact of this benchmark on overall survival is not yet known.492 The 6-month evaluation should identify patients with a poor outcome. For those who have MCyR or BCR-ABL1 of less than 10 percent at 6 months, overall survival was 100 percent as compared to 79 percent for those with no response.594 At 12 and 18 months, CCyR is the optimal response.417 In those who have achieved CCyR, MMR may not be of prognostic significance.595
Rising BCR-ABL1 levels may be associated with an ABL1 mutation or relapse of disease. Those with more than a twofold rise in BCR-ABL1 are more likely to have a mutation.596 A serial rise in the BCR-ABL1 level may also indicate loss of response to therapy.415
OTHER AGENTS USED IN TREATMENT OF CHRONIC PHASE
IFN-α, formerly the most effective agent, is rarely used in the treatment of CML. A CCyR with IFN-α was uncommon (13 percent), but 10-year survival rates in responders were approximately 70 percent.597 CCyRs to IFN-α were stable and durable.598 Approximately 50 percent of complete responders become long-term survivors. Common toxicities of IFN-α use include fatigue, low-grade fever, weight loss, liver function test abnormalities, hematologic changes, and neuropsychiatric symptoms. Overall survival is improved in imatinib-treated patients compared with patients treated with IFN-α or IFN-α plus cytarabine.599 Nevertheless, among all patients who attained a major or CCyR at 12 months, the survival rate was comparable in either case. IFN-α has also been proposed as an immune stimulant to consolidate imatinib remissions because additive effects have been noted.600,601 Conversely, those treated initially with INF-α who achieve a CCyR have an improved molecular response with imatinib.602,603 Some patients intolerant to a TKI may be treated successfully with INF-α.
Use of Other Chemotherapeutic Agents in Chronic Phase
Hydroxyurea The major side effect of hydroxyurea is an extension of its pharmacologic effect, that is, reversible suppression of hematopoiesis, often with megaloblastic erythropoiesis. The median survival of patients with CML treated with hydroxyurea alone is approximately 5 years. Studies with high-dose hydroxyurea indicate that marrow metaphase cells in some patients lose the Ph chromosome either partially or completely after such therapy.604 Hydroxyurea often is used for initial cytoreduction, but it has few other indications in the TKI era of CML therapeutics. Chronic use of hydroxyurea is associated with leg ulcers.605
Cytarabine IFN-α2b combined with cytarabine (20 mg/m2 per day for 10 days per month) in the chronic phase was associated with a greater proportion of MCyRs at 12 months and with greater survival prolongation than was IFN alone.606 Toxicities with these drug combinations were greater, and this combination has been replaced by TKI therapy and is rarely used.
Busulfan Once the mainstay of treatment for the chronic phase, busulfan usage now is rare.607 It is used primarily as part of the preparative regimen for allografting or autografting. It may be used occasionally in older patients who do not tolerate TKIs.
Other Cytotoxic Agents Intensive multidrug regimens have been used in an attempt to eradicate the Ph chromosome–positive clone and, occasionally, have led to prolongation of remission or cure of the disease. This approach did not significantly increase population survival.608
Other Potential Therapeutic Agents in Chronic Phase Chronic Myelogenous Leukemia The farnesyltransferase inhibitors lonafarnib and tipifarnib have been combined with imatinib and have activity after imatinib failure.609,610 The hypomethylation agent decitabine has activity in imatinib refractory CML. INNO-406, a dual BCR-ABL/LYN inhibitor, suppresses the growth of CML cells in the central nervous system.611 MicroRNA approaches may eventually play a role in CML treatment,612 and synthetic BCR-ABL1 small interfering ribonucleic acid (siRNA) has been used in a patient with resistant CML, postallografting with inhibition of BCR-ABL1 noted.613 Ribozymes targeting BCR-ABL1 mRNA have been used as CML treatment,614,615 and these approaches probably will have the most utility for in vitro purging of CML marrow cells before autotransplantation.616,617
Palliative splenic irradiation may be useful occasionally in subjects who have entered the accelerated or advanced chronic phase and are troubled with extreme splenomegaly with splenic pain, perisplenitis, and encroachment of the spleen on the gastrointestinal tract.618 Splenic irradiation may palliate symptoms for a short time.619 Spleen size associated with chronic phase disease usually is decreased with TKI therapy.
Palliative radiotherapy may be useful for extramedullary myeloid sarcomas, which may occur occasionally in bone or soft tissue during the late chronic or accelerated phase.
Splenectomy does not prolong the chronic phase of CML, delay the onset of the accelerated phase, enhance sensitivity to TKIs or chemotherapy, or prolong survival of patients.620 In carefully selected patients with symptomatic thrombocytopenia unresponsive to therapy, mechanical discomfort, hypercatabolic symptoms, and portal hypertension, splenectomy may be useful. Postoperative morbidity from infection, thrombosis, or hemorrhage has been high, with mortality rates up to 10 percent reported.621 Splenectomy performed before allografting has not been found to influence the severity of graft-versus-host disease (GVHD) or survival after allogeneic hematopoietic stem cell transplantation.622
TREATMENT OF CHRONIC PHASE CHRONIC MYELOGENOUS LEUKEMIA DURING PREGNANCY
Treatment of chronic phase CML during pregnancy is sometimes needed to prevent placental insufficiency from hyperleukocytosis. Imatinib may be teratogenic. Normal newborns have been delivered by patients who conceived and ingested imatinib during early pregnancy.623,624,625,626 In 125 women exposed to imatinib during pregnancy, 50 percent delivered normal infants, and 25 percent underwent elective terminations, three of the latter following the identification of fetal abnormalities. Twelve other infants had abnormalities.627 The majority of patients who discontinue imatinib during pregnancy lose their complete hematologic remission and their cytogenetic responses.628 One fetal fatality during pregnancy as a result of a meningocele has been reported. Males treated with imatinib have fathered healthy infants.629 Current recommendations are to practice contraception during treatment with any TKI, or, if pregnant, at the onset of the disease, to consider IFN treatment until delivery.626,630 Imatinib does appear in breast milk.631
IFN can be used during pregnancy with minimum risk of teratogenicity. Eight patients treated with IFN from the first trimester have been described, and each of these pregnancies resulted in normal infants, except for one with mild neonatal thrombocytopenia. All infants had normal growth patterns.632 Hydroxyurea may be useful during the second and third trimester but should be avoided in the first trimester.626,633 Leukapheresis in the first trimester (or longer) also can be used to avoid fetal drug exposure early in pregnancy (see “Leukapheresis” above). It is important to use a TKI after delivery to achieve the best outcome. Further observation may show it to be safe later in pregnancy. Although controversial, stopping and later restarting TKI therapy may not result in as favorable an outcome of therapy as use of IFN or other approaches, initially.626 If conception is desired, attaining a MMR before the TKI therapy is discontinued and a 3-month washout period are recommended.415 The patient should be made aware of the risk for CML progression during the pregnancy.
DISCONTINUATION OF TYROSINE KINASE INHIBITOR THERAPY
Patients responding to TKI therapy are likely to maintain their response. TKIs are associated with a significant symptom burden, however,634 and one-third have persistent moderate to severe symptoms. Persistent CMR is seen in only a minority of patients, and the vast majority of patients on TKIs have minimal residual disease even if their BCR-ABL1 transcripts are undetectable, and this may lead to relapse if the drug is stopped. Thus, in the absence of a clinical trial, life-long therapy with a TKI is recommended.
Some patients in a CMR for 2 years or more have been able to discontinue imatinib without relapse.635,636 Discontinuation of imatinib in 12 patients who had undetectable disease for at least 2 years resulted in six patients having a molecular relapse within 1 to 5 months (imatinib was reintroduced with a response) and six others remaining in CMR for a median of 18 months.637 There are numerous anecdotes of patients relapsing when imatinib was stopped. In patients with intolerable side effects on imatinib, the dose may be reduced in some cases without the loss of a CMR.638 In occasional patients in whom imatinib is stopped, a cytogenetic response of up to 15 months has persisted.639,640,641,642 In a study of 100 patients with a CMR (>5-log reduction in BCR/ABL1 transcripts) for at least 2 years who stopped imatinib, 69 patients had at least 12 months of followup. Of these, 39 percent were stable and 61 percent relapsed, most within the first 6 months. The outcome of stopping was better for those with a lower Sokal risk score at diagnosis.636 In another study, 40 patients were evaluated, and treatment-free remission at 24 months was 47.1 percent for all patients and was higher if patients had prior IFN treatment.635 Female sex and early molecular response predict stable undetectable BCR-ABL1 transcripts in chronic phase CML, the criteria for early stopping.643 In a series of 423 CML patients treated with imatinib, the rate of undetectable BCR/ABL1 transcripts and stable MMR (4.5-log decrease) was 36.5 percent.643 A model to analyze the risk of molecular relapse after cessation of TKIs has been developed.644 Reports of discontinuations, reappearance of the clone, treatment with a second prolonged course of imatinib, discontinuation with retention of MMR at 32 months followup, and retention of CMR in 12.5 percent have been described.645
Discontinuation of nilotinib or dasatinib has not been reported in a significant series, and larger prospective studies will be needed to determine in which patients stopping treatment can be safely attempted. Because early, quiescent Ph chromosome–positive cells (CD34+Lin−) are insensitive to imatinib in vitro,546 at present it is advisable to maintain treatment indefinitely until the criteria for cessation, if any, can be established in clinical trials. Intermittent imatinib dosing has been explored in selected elderly patients with CML without adverse impact on overall and progression-free survival.647
HIGH-DOSE CHEMOTHERAPY WITH AUTOLOGOUS STEM CELL INFUSION
Since the availability of imatinib, autografting in CML is rarely used.648 Ph chromosome–negative stem cells are present in most patients with CML at the time of diagnosis. Techniques that use these cells to reconstitute hematopoiesis after high-dose therapy have been developed.649 Ph chromosome–negative progenitors can be mobilized with G-CSF and collected from the blood of patients who have responded to prior treatment with a TKI.650 Such cells also can be collected after recovery from chemotherapy regimens, such as after idarubicin and cytarabine, followed by G-CSF stimulation.649 G-CSF was used for at least 4 days while imatinib treatment was continued for stem cell mobilization in 58 patients with a CCyR. The cells were collected in two cytapheresis procedures in 74 percent of patients, and the cells of 84 percent of those cytapheresis products were negative for the Ph chromosome.651
In another series, stem cells were mobilized in 32 patients in complete cytogenetic remission after imatinib, with uninterrupted imatinib therapy in 50 percent of patients and with imatinib temporarily withheld in approximately 50 percent. Blood levels of BCR-ABL1 transcripts were not changed by the use of G-CSF.652 In yet another series, 13 of 15 patients were successfully mobilized with G-CSF while receiving imatinib, and 28 percent of stem cell harvests were negative for BCR-ABL mRNA. No change in blood BCR-ABL1 transcript level was noted after stem cell mobilization as assessed by RT-PCR.653 No series of patients autografted with cells mobilized while they were receiving imatinib have been reported.654 Autografting might find a role in cases of imatinib resistance,655 or to reduce the level of residual disease in cases without a molecular response.656 Imatinib can be effective and safe in chronic phase CML patients who have previously undergone autografting,657 although there is an increased frequency of hematologic toxicity.
ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION
Until imatinib became available in 2001, allogeneic transplantation was used in most new patients with CML who were younger than 65 years of age and who had a suitable donor. The advent of imatinib treatment and the projected survival of patients with a complete cytogenetic remission has changed the indications for transplantation in CML.658,659 There has been a marked reduction in number of transplants performed for CML worldwide and a decline in the proportion performed in first chronic phase.660,661 Although no randomized trials of imatinib versus transplantation have been or are likely to be conducted, there is circumstantial evidence that survival is superior for populations of patients treated with drugs who have a CCyR as compared to transplantation.662 Allografting continues to play a role in the treatment of patients, who are refractory or intolerant to serial TKIs, and remains the optimal therapy in those who progress to accelerated or blast crisis in the face of treatment with a series of TKIs.
Patients in the chronic phase of CML who are younger than approximately 70 years and who have an identical twin,663 or a histocompatible sibling,664,665 or access to a histocompatible unrelated donor,666 can be transplanted after intensive therapy, usually with cyclophosphamide and fractionated total-body irradiation (TBI) or a combination of busulfan and cyclophosphamide. Busulfan can be administered as an intravenous preparation and as a single daily dose.667 When targeted steady-state busulfan levels are used, a 3-year survival rate of 86 percent and a disease-free survival rate of 78 percent with no age effect is achieved.668 With nonmyeloablative or “reduced-intensity” conditioning regimens, older patients and those with comorbidities can undergo successful allografting.669 With the success of TKI therapy, allogeneic stem cell transplantation is no longer recommended as a treatment option in chronic phase CML responding to any sequence of TKIs.670 Allogeneic transplant should be considered for patients with disease progression to accelerated or blast phase on TKI therapy. In these cases, TKIs to which the patient has not been previously exposed and for which they do not possess a resistant mutation can be used to bridge or prepare for the transplant.671 Allogeneic transplant can be used in those rare patients who present with blast crisis and in those with T315I mutations who do not respond to ponatinib.672,673 In those who do not respond to their first TKI exposure and are switched to a second TKI, transplantation in chronic phase would be indicated for those patients with BCR-ABL1 transcripts greater than 10 percent or less than a PCyR at 3 and 6 months, minor or no cytogenetic response at 12 months, and only a PCyR at 18 months or cytogenetic relapse at 12 or 18 months.417
Myeloablative Allogeneic Transplants
Stem cell transplantation from HLA-compatible siblings results in engraftment and an actual or projected long-term survival in 45 to 85 percent of recipients.674,675,676 In patients older than age 50 years, survival rates are slightly less at 5 years. The risk of CML relapse is approximately 20 percent, with a plateau of relapse at 5 to 7 years. Transplanted T lymphocytes, especially if activated by a (mild) GVHD, may be an important factor in preventing leukemic relapse. This phenomenon, referred to as graft-versus-leukemia reaction, is thought to suppress the leukemic process through T-cell–mediated cytotoxicity.634 The relative benefit of marrow compared to mobilized blood stem cells as the source of the allograft has not been established.677,678 Mobilized blood stem cells engraft more rapidly but may be associated with more chronic GVHD. The majority of survivors have no evidence of residual leukemia.679
For younger patients who do not have a histocompatible sibling, an unrelated donor or a mismatched family member as a source of stem cells is feasible. When class I HLA genes are typed with molecular methods, an improvement in matching and better outcomes using unrelated donors have been demonstrated and are comparable to those transplanted with a matched-sibling donor. When matched-unrelated donor and sibling donor transplants were compared, unrelated donor transplants had increased risk of graft failure and acute GVHD, but only a slightly poorer survival and disease-free survival. For patients who survived to 1 year, only a slightly inferior disease-free survival was observed.680 The rate of extensive chronic GVHD is up to 60 percent with unrelated donor transplants, but 63 percent disease-free survival in younger CML chronic phase patients has been reported. Cord blood stem cell transplantation from an unrelated donor has also been used in adults with CML.681
Pretransplantation imatinib is not associated with increased transplant-related morbidity or decreased survival, but those who are transplanted with suboptimal response to imatinib or loss of response to imatinib fare worse, probably related to a higher disease burden at the time of transplantation and more aggressive disease.682,683 Second-generation TKIs do not increase transplant-related toxicity.684 Disease status after allografting can be monitored with cytogenetic studies, PCR, or FISH analysis. A positive PCR assay 3 months after allogeneic transplantation has not been found to correlate with an increased risk of relapse compared with PCR-negative patients. A positive assay at 6 months and beyond is associated with subsequent relapse. In one series, 42 percent of patients with a positive PCR assay at 6 to 12 months relapsed versus 3 percent with a negative assay.685 Paradoxically, patients who remain BCR-ABL1 positive more than 36 months after transplantation have little propensity for relapse.685 Serial quantitative RT-PCR analysis of blood specimens has been proposed to distinguish patients destined to relapse.686 Patients who remain in remission have undetectable, low, or falling BCR-ABL1 levels on sequential analysis. After 6 to 9 months, these levels are undetectable in most cases. Recognition of relapse at the molecular level may allow for early therapeutic intervention.
Killer immunoglobulin-like receptors (KIRs) are expressed by NK cells and subpopulations of T cells. NK clones from a single individual can vary substantially in the type of KIR molecules they express. The ligands for several of the inhibitory KIR have been shown to be subsets of HLA class I molecules. Missing KIR ligands in recipients lead to less relapse and increased GVHD based on NK alloreactivity.687 KIR ligand mismatch has also been found to be an important prognostic factor in achieving molecular responses after transplantation for CML.688 Increased frequency of regulatory T cells characterized as CD4+, CD25-high are associated with higher rates of relapse after allografting in CML.689
Nonmyeloablative Allogeneic Transplants
Nonablative regimens have been developed in an attempt to expand the indication for allogeneic transplantation to older patients. These regimens rely on immunosuppressive therapy to allow engraftment of cells that potentially will generate a graft-versus-leukemia effect. These procedures in general are associated with acceptable degrees of engraftment, less mortality, similar rates of GVHD, and possible durable effects on persistent or recurrent disease.690 Approximately 60 percent of patients, mostly in initial chronic phase (median age: 50 years) and transplanted with reduced-intensity conditioning regimens, had a 3-year survival and about one-third had a 3-year progression-free survival.691 Patients no longer in first chronic phase do not fare as well.712 Conditioning regimens include fludarabine and busulfan,693,694 low-dose TBI and fludarabine, and low-dose TBI and cyclophosphamide, but no prospective randomized trials comparing regimens or comparing ablative and nonmyeloablative transplant approaches have been conducted.693,695,696 In one case, imatinib given concurrently with nonmyeloablative stem cell transplantation did not compromise engraftment and resulted in a cytogenetic remission in a patient with CML in blast crisis.697 Whereas nonmyeloablative or reduced intensity regimens are still considered investigational, they can achieve molecular remissions.
USE OF TYROSINE KINASE INHIBITORS AFTER STEM CELL TRANSPLANT
In patients treated with stem cell transplantation before the wide availability of imatinib, complete cytogenetic remissions with imatinib treatment can occur if treated at relapse after allografting and after donor lymphocyte infusion (DLI) fails to give a response. Such remissions may include a molecular response.698 Complete responses after imatinib therapy have been noted in accelerated or blast phase CML persisting after stem cell transplantation.699 In another series, 45 percent of relapsed patients had a CCyR of up to 28 months and without significant GVHD.700 In a series of 28 adults with relapse after allogeneic stem cell transplantation who then received imatinib, the response rate was 74 percent, and the complete cytogenetic remission rate was 35 percent. Five patients had recurrence of GVHD, and 13 had received previous DLI infusions.698 In one series, imatinib was able to generate complete molecular remissions in 26 percent of chronic phase patients after allografting, with full donor chimerism usually observed.701 One study found that more relapsed patients had a molecular remission with DLI at 5 years than with imatinib alone. Most of these patients had cytogenetic relapses only.702 In a retrospective comparison of 37 patients with hematologic or molecular relapse of CML who received imatinib, DLI, or a combination of both in concurrent or sequential regimens, the overall survival was 100, 89, and 54 percent for both modalities, imatinib, alone, and DLI alone, respectively.703 There are few studies examining use of nilotinib or dasatinib for posttransplantation relapses.704
Prophylactic administration of imatinib after transplantation has been used for patients at high risk of relapse.705 Posttransplantation imatinib may also postpone the requirement for DLI with its attendant risks of GVHD and marrow aplasia.706 Some have found that DLI are superior to imatinib therapy in preventing relapse and increasing leukemia-free survival. Posttransplantation imatinib is usually well-tolerated; pancytopenia is the principal toxicity. The cytopenias resolve with doses adjustments or temporary drug discontinuation. Many questions remain regarding the use of posttransplantation TKIs. When should they be started? Which drug is superior? For how long should the drugs be used? Should they only be started in cases of molecular relapse? How can they be best combined with DLI in cases of relapse?
IMMUNOTHERAPY: ADOPTIVE CELL THERAPY FOR POSTTRANSPLANTATION RELAPSE
Substantial evidence indicates that the effectiveness of allografting in CML does not result solely from the eradication of the leukemic clone with high-dose chemoradiotherapy conditioning regimens, but also from adoptive immunotherapy provided by lymphocytes in the allograft, the graft-versus-leukemia effect (see “Myeloablative Allogeneic Transplants” above).707 This phenomenon has been recreated to produce a therapeutic response by infusing the lymphocytes from the stem cell donor after a relapse following allogeneic stem cell transplantation.708,709 The overall response rate to DLI is approximately 75 percent. The response rate is higher when this approach is used early after detecting a relapse by PCR,710 compared to use after a hematologic or cytogenetic relapse. Patients with a short interval between transplantation and DLI have a higher probability of response than patients with longer intervals. Responses are the same with related versus unrelated donors.711 Some patients show a very rapid decline of BCR-ABL1 transcript levels (<6 months after DLI), whereas other patients demonstrate PCR negativity only over a longer period.712 The responses to DLI can be durable.713 Molecular responses can occur in up to two-thirds of patients.714
The main toxicities of DLI have been the induction of GVHD and myelosuppression. Chronic GVHD can occur in up to 60 percent of cases.715 Attempts to diminish these toxicities have included use of CD8-depleted DLIs and infusion of smaller numbers of T cells.716,717 Lower initial cell dose is associated with less myelosuppression, the same response rate, better survival, and less DLI-related mortality, leading to suggestions that the initial dose should not exceed 0.2 × 108 mononuclear cells/kg.718 The initial doses should be lower when matched unrelated donors are used. Immune suppression should first be tapered before DLIs are administered. As noted above, imatinib may synergize with DLI to foster rapid molecular responses after relapse.719