Seminars in Hematology
Volume 40, Issue 1 , Pages 79-86, January 2003

Advanced-phase chronic myeloid leukemia☆

Department of Leukemia, The University of Texas, M.D. Anderson Cancer Center, Houston, TX.

Article Outline

Abstract 

Chronic myeloid leukemia (CML) typically runs a biphasic or triphasic course, with diagnoses usually made in the chronic phase (CP). Without effective treatment, patients eventually progress to a blastic phase (BP), frequently through an intermediate or accelerated phase (AP). Because the definition of AP varies among studies, comparisons of outcome and prognosis are difficult. The management of patients in these advanced phases of the disease has been much less satisfactory than that of patients in CP. Treatment with interferon-alfa (IFNα)-based therapy is ineffective for most patients in AP and for all of those in BP. Imatinib mesylate has demonstrated significant activity AP and BP disease, although the results are inferior compared to treatment in CP. In AP, 82% of patients achieve a hematologic response, with 24% achieving a major cytogenetic remission (MCR). Early MCR (within 3 months of diagnosis) provides a survival advantage over patients who do not achieve this response or achieve it later. In BP, 21% of previously treated patients and 36% of previously untreated patients have responded to imatinib, and up to 17% of patients may achieve a major cytogenetic response. However, responses are frequently short-lived. Several agents are being investigated for treatment of advanced-phase CML, including decitabine (DAC), homoharringtonine (HHT), troxacitabine, clofarabine, farnesyl transferase (FTase) inhibitors (FTI), and others. Many have also proven to be synergistic with imatinib in vitro and combination studies are ongoing. Continued investigation of these approaches is needed to improve the long-term prognosis of advanced-phase CML. Semin Hematol 40:79-86. Copyright 2003, Elsevier Science (USA). All rights reserved.

 

Chronic myeloid leukemia (CML) is characterized by a unique cytogenetic abnormality involving the long arms of chromosomes 9 and 22, t(9;22)(q34;q11), known as the Philadelphia chromosome (Ph).17 Clinically, CML is characterized by a biphasic or triphasic course. Of the 85% to 90% of patients diagnosed in the chronic phase (CP), 15% to 20% are asymptomatic. Historically, the median survival has been 4 to 5 years, although current therapeutic interventions (such as interferon-alfa [IFNα]and allogeneic bone marrow transplantation [BMT]) have increased this significantly. Eventually, patients progress to a blastic phase (BP) unless the disease can be eliminated or suppressed effectively before this stage. The prognosis of patients in BP is usually poor, with a median survival of 3 to 12 months. Approximately two thirds of patients will progress to BP through an intermediate or accelerated phase (AP). The prognosis for patients in AP is intermediate, with a median survival of 1 to 2 years.16 Herein we describe the current concepts in the prognosis and management of patients with CML in AP or BP.

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Accelerated phase 

AP is an ill-defined stage of the disease. Different criteria have been proposed to classify AP. Table 1 shows two frequently used classifications.

Table 1. Criteria for accelerated phase
MDACCIBMTR
Blasts (%)≥15≥10
Blasts + promyelocytes (%)≥30≥20
Basophils (%)≥20≥20*
Platelets (×109/L)<100Unresponsive increase or persistent decrease
CytogeneticsCECE
WBC countNADifficult to control, or doubling in <5 days
AnemiaNAUnresponsive
SplenomegalyNAIncreasing
OtherNAChloromas, myelofibrosis
*Basophils + eosinophils.

Abbreviations: MDACC, M.D. Anderson Cancer Center; IBMTR, International Bone Marrow Transplant Registry; WBC, white blood cell; CE, clonal evolution; NA, not applicable.

The criteria used by the International Bone Marrow Transplant Registry (IBMTR) and most of the bone marrow transplant (BMT) literature are less stringent and frequently subjective (for example, failure to control white blood cell count or unresponsive anemia).7, 57 The criteria proposed by Kantarjian et al33 were developed from a multivariate analysis of factors that would independently predict for an inferior outcome to patients in CP. Others have proposed different schema that frequently are intermediate between these two classifications. The criteria used have a significant impact on the results to be obtained with any specific therapy. Savage et al52 analyzed a population of patients with CML who were treated with allogeneic BMT from a human leukocyte antigen (HLA)-identical sibling donor. If patients were classified according to the more stringent criteria of the institution, 205 patients were considered to be in CP with a 5-year probability of survival of 58% and 46 patients were considered in AP with a 5-year probability of survival of 22%. When these same patients were reclassified using the IBMTR criteria, 154 patients were considered to be in CP and 97 in AP. The 5-year probability of survival increased for both groups to 60% and 38%, respectively. This is called the “Will Rogers phenomenon” or “stage migration” and results from moving a subgroup of patients with the worse prognosis from the low-risk group (CP) to the high-risk group (AP) where they now constitute the subgroup with the best prognosis. Thus, it is important to identify the specific parameters being used to define AP, as different criteria are frequently used in the literature, making results difficult to compare. This highlights the importance of developing uniform criteria for AP in order to develop and evaluate prognostic and therapeutic strategies.

Cytogenetic clonal evolution (CE) is a criterion for AP that occurs in 20% to 40% of patients.33, 56 However, in approximately 50% to 70% of cases, transformation occurs without CE.47 The most common recurrent chromosomal abnormalities in CE are trisomy 8 (30% to 40%), an additional Ph chromosome (20% to 30%), and isochromosome 17 (15% to 20%).33 Other abnormalities can occur. Patients who have CE as the only criterion for AP have a significantly better outcome compared to patients who have other criteria for AP, with or without CE. CE categorizes a heterogeneous group of patients with variable prognoses.46 A prognostic system has been developed to try to determine the outcome of patients with CE. From a multivariate analysis of characteristics associated with outcome, three groups with distinct prognosis can be identified (Table 2).

Table 2. Risk classification of clonal evolution10, 46
Suppression of CE
AnyComplete
Risk GroupFeaturesNo.No.%P ValueNo.%P Value
GoodNo chromosome 17 abnormality + abnormal metaphases < 16% + time to clonal evolution ≤ 24 months262285 2285
IntermediateOther than good or poor532955 1834
PoorChromosome 17 abnormality + ≥36% abnormal metaphases, or other accelerated features + ≥16% abnormal metaphases10440 00
.015 <.0001
Patients with CE who have less than 16% metaphases involved with the CE, no chromosome 17 abnormalities, and in whom CE develops within 24 months from diagnosis have the best prognosis, with a median survival of 54 months. In contrast, patients with ≥ 36% metaphases involved with chromosome 17 abnormalities, or those who have other AP features and ≥ 16% metaphases involved with any abnormality have a poor prognosis, with a median survival of 6 to 7 months.46 All others constitute an intermediate group with a median survival of 13 to 24 months. This system has been useful in scoring the probability of response to IFN-based therapy.10 How this system would apply in a population undergoing allogeneic stem cell transplant or imatinib mesylate (STI571, Gleevec, Novartis, East Hanover, NJ) therapy remains to be determined.

Treatment 

The outcome of AP treated with conventional therapy with hydroxyurea is reflected in the median survival of 1 to 2 years, which sets the background to which newer alternatives may be compared. Few studies have addressed treatment of patients with AP as currently defined. Combination chemotherapy with daunorubicin and high-dose cytarabine (ara-C) was reported in a study of 24 patients in AP. Six (25%) achieved a complete hematologic remission (CHR), and five of them had a transient cytogenetic response; four additional patients achieved a second CP.39 Responses were usually transient and the median survival was 8 months.39

IFNα has been effective in the management of patients in CP, but the results in AP are clearly inferior. Only 20% to 30% of patients may have some hematologic response, and cytogenetic responses are rare.34, 38 The addition of ara-C to IFNα improved the response rate to a CHR of 50%, although only 5% had a major cytogenetic response (Ph-positive metaphases ≤ 34%, MCR). Patients with CE may respond to IFNα, and response is associated with a prolonged survival. Among 90 patients with CE treated with IFNα-based therapy, 56 (62%) achieved some suppression of CE, which was complete in 41 (46%). Patients who achieved a complete suppression of CE had a median survival of 66 months, with 51% alive at 5 years.10 The prognostic classification of Majlis et al46 can distinguish three groups of patients with distinct prognoses after treatment with IFNα. Patients in the low-, intermediate-, and high-risk groups had a complete suppression of CE rate of 85%, 34%, and 0%, respectively, and median survivals of 58, 31, and 30 months.10 New formulations of IFNα may have some advantages over conventional IFNα. One of these is pegylated IFN (PEG-IFN), which has a molecule of polyethylene glycol conjugated to IFNα. This modification prolongs the half-life of IFNα, allowing for weekly administration rather than on a daily schedule.25, 58, 69 A phase I study in patients with CML who had failed to respond to IFNα therapy identified the maximum tolerated dose (MTD) of PEG-IFN to be 7.5 μg/kg/wk.58 The predicted area under the concentration-time curve (AUC) comparative dose of PEG-IFN at 0.3 μg/kg/wk is IFNα at 9 MU weekly, thus suggesting improved tolerance with the pegylated formulation. Among the nine patients in AP treated in this study, one achieved a complete cytogenetic remission, one had a partial cytogenetic remission, two had a partial hematologic remission (PHR), and one had disease reversion to CP. Thus, new formulations of IFNα may offer an alternative for patients in AP, particularly in combinations such as with ara-C and with imatinib mesylate.

Imatinib meslyate is a tyrosine kinase inhibitor13, 15 with significant activity in CML.12, 14 Talpaz et al59 recently updated the multicenter, multinational experience using imatinib to treat 235 patients in AP as defined by Kantarjian et al.33 Patients with clonal evolution were not eligible for this study unless they had other criteria for AP. After central review, 181 patients (77%) were confirmed to be in AP, and 66% of them had received prior therapy for AP. The overall response rate (CHR, marrow response, or return to CP) was 82%. Sustained hematologic responses lasting at least 4 weeks were obtained in 125 patients (69%), 61 (34%) of whom achieved a CHR. MCR was achieved in 43 patients (24%) (complete, n = 30 [17%]; partial, n = 13 [7%]).59 The importance of achieving an early MCR was evidenced by a landmark analysis showing that all patients in MCR after 3 months of therapy were alive at the time of the analysis (median follow-up, 11 months) compared with 14 deaths (22%) among patients who had not achieved a MCR 3 months after treatment was started.59 Another important lesson from this study was the dose effect. An earlier phase I study of patients with CML in all phases found that the response rate was proportional to the dose administered, with most responses seen at a dose of ≥ 300mg/d.14 In addition, no MTD could be identified at doses of up to 1,000 g/d. Thus, in the phase II study in AP, patients were initially treated with a starting dose of 400 mg/d, which was later modified to 600 mg/d.59 The higher dose was significantly more effective in terms of remission rate, remission duration, and survival (Table 3).

Table 3. Response to imatinib by dose in patients with CML in accelerated phase
Response by Dose Group (%)
Response400 mg (n = 62)600 mg (n = 119)
Overall hematologic response6571
Complete2737
Marrow response1013
BCP2721
Major cytogenetic response1628
Complete1119
Partial58
Hematologic response at 12 mo5779
Survival at 12 mo6578
No progression at 12 mo4467

Abbreviation: BCP, back to chronic phase.

In a multivariate analysis, hemoglobin levels and dose were the most important predictive factors for time to disease progression. Toxicity was not significantly different with the higher dose and 49% of patients treated at 400 mg and 52% of patients treated at 600 mg required dose reductions.59 A single-institution trial of 237 patients with AP CML (some of them included in the previous study) yielded similar results, with CHR in 80% of patients and MCR in 35%.31 A multivariate analysis identified interval from diagnosis to treatment, spleen size, peripheral blood blasts, and dose as independent variables associated with the probability of achieving MCR. A model was developed based on the number of unfavorable factors present and defined four groups with MCR rates of 68%, 47%, 16%, and 3%.31 Thus, imatinib should be considered the treatment of choice for CML in AP with a recommended dose of 600 mg/d. Ongoing studies are investigating combinations of imatinib with other agents including IFNα, ara-C, idarubicin, arsenic trioxide, and others.

Other drugs have been investigated for patients with CML in AP. Homoharringtonine (HHT) is a plant alkaloid that has demonstrated activity in acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), and myelodysplastic syndrome (MDS).1, 2, 18, 68 In CML in CP it has been used alone or in combination with ara-C after failure on IFNα and in combination with IFNα with or without ara-C in previously untreated early CP.40, 48, 49 The experience in AP is limited, but it has demonstrated activity. Twenty patients with CE as the only criterion for AP were treated with HHT alone.48 Eleven of 16 patients (69%) with active disease achieved CHR and five (29%) PHR; CE resolved in four (25%) of these patients. The other four patients had normal peripheral blood counts but persisting Ph positivity before the start of HHT; two achieved a partial cytogenetic response.48 HHT in combination with ara-C has also been explored in this setting. Among 15 patients with CE as the only criterion for AP, 11 (73%) achieved a CHR and three (20%) a PHR. Three of these patients achieved a MCR (one complete, two partial cytogenetic remissions).40 Five patients had other criteria for AP: three achieved a CHR, including one who achieved a complete cytogenetic remission.40 The availability of a subcutaneous formulation of HHT, and the in vitro synergy with imatinib,54 make further investigations with this agent appealing.

Decitabine (DAC, 5-aza-2'-deoxycytidine) is a hypomethylating agent that has been investigated in AML and MDS.55, 67 Hypomethylating agents are attractive therapeutic options in CML because of the hypermethylation of the Pa promoter of ABL1 and its association with more advanced CML stages29, 70 and with adverse prognosis.4 Seventeen patients with CML in AP were treated with DAC at a dose of 100 mg/m2.36 Nine (53%) had an objective response, with median survival of 58 weeks. At lower doses, cytotoxicity has been minimal and gene-specific hypomethylation was observed. We recently investigated a low-dose, long-exposure schedule in leukemia. Significant activity with minimal toxicity was reported in patients with AML, MDS, and CML; the most effective dose was 15 mg/m2 daily for 10 days.28 This schedule is now being investigated in patients with imatinib-resistant CML in CP, AP, and BP.

Another group of drugs with potential activity in CML are the farnesyl transferase (FTase) inhibitors (FTI). FTase is responsible for a post-translational modification of Ras, which is required to localize Ras to the cellular membrane, a feature required for activation of Ras.3 SCH66336, a nonpeptidomimetic FTI, has shown significant activity in vitro against CML cells and in CML animal models50 and may overcome the resistance to imatinib.27 Clinical studies are starting with these agents, and there is some early indication of activity of these agents in CML. Among six patients in AP treated with a different FTI, R115777, one patient who had failed to respond to imatinib therapy achieved a CHR and a minor cytogenetic response.62 In view of the in vitro synergy of these agents,27 combination studies are being conducted. Several other agents have been investigated and shown minimal or no activity in AP CML, including retinoids, nucleoside analogs, and others.8, 9

BMT as an option in AP CML is discussed elsewhere in this issue. Results in AP are clearly inferior to those reported in CP, with a 5-year probability of survival of 22% to 38%.52 How these data compare with other strategies, particularly imatinib, is difficult to establish because of issues regarding the definitions of AP discussed above, considerations of selection bias for BMT, and the lack of enough long-term follow-up with imatinib. It is probably appropriate to recommend imatinib for all patients in AP as initial therapy and consider transplant or other investigational approaches for those not achieving a MCR at 9 to 12 months. Young patients with available donors in whom the expected 1-year transplant-related mortality is less than 40% could be offered transplant if they do not achieve a MCR after 3 months of therapy.

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Blast phase 

BP is characterized by the presence of ≥ 30% blasts in the peripheral blood or bone marrow, or the presence of extramedullary disease.6, 16 The overall prognosis for patients in BP is poor, with a median survival of 3 to 12 months. Approximately 50% of patients have a myeloid phenotype, 25% a lymphoid, and 25% an undifferentiated phenotype.23 Patients with lymphoid phenotype tend to be younger than those with myeloid transformation.65 The overall prognosis is better for patients with lymphoid phenotype, the median survival being 12 months, compared to 3 to 9 months for myeloid phenotype.37, 65 Nearly two thirds of patients have CE at the time of transformation.65 Features other than immunophenotype associated with decreased probability of long-term survival include CE,65 bone marrow blasts greater than 50%,65 and platelet count ≤ 50 × 109/L.37 Treatment with IFNα has been considered by some as a risk factor for sudden blastic transformation and an argument against the use of nontransplant options. However, the risk of early blastic transformation is only 3% during the first year of therapy,63 and a multivariate analysis identified treatment other than stem cell transplant or IFNα as risk factor for early blastic transformation.65 Still, BP is clearly incurable, as none of the available treatment options have resulted in a significant cure fraction.

Treatment 

Historically, the treatment of BP has been combination chemotherapy similar to that used to treat acute leukemias. Response criteria vary among different studies. In general, CHR is as for acute leukemias: blast count less than 5% in the bone marrow, with no blasts in peripheral blood or evidence of extramedullary disease, neutrophils ≥ 1.5 × 109/L, and platelets ≥ 100 × 109/L. A return to CP is defined as the disappearance of blastic phase features, with less than15% peripheral blood blasts, less than 30% blasts plus promyelocytes, less than 20% basophils, and platelet count greater than 100 × 109/L. The definition of intermediate responses has been more variable. Some proposed definitions include PHR with criteria similar to CHR but with residual splenomegaly (although < 50% of baseline), platelet count greater than 450 × 109/L, and/or the presence of few (≤5%) myelocytes or metamyelocytes in the peripheral blood.37 Marrow response has been defined as a bone marrow blast count <5% with no circulating blasts, neutrophils ≥ 109/L, and platelets ≥ 20 × 109/L with no need for transfusions.53 Most important, the survival advantage of achieving any response has been established in a multivariate analysis,37 thus making it an important goal of therapy and an early objective for clinical trials.

Different ara-C–based regimens, mostly in combination with anthracyclines, have been used in myeloid, undifferentiated, and mixed lineage BP, resulting in overall responses of 20% to 30%.32, 51, 65 Most improvement is transient, with a median survival of 4 to 10 months.32, 51, 65 Response rates in lymphoid BP to ALL-like therapy have are 50% to 60%, but again remissions are usually short.11 Imatinib mesylate is also effective in patients with BP. In a phase I study, 58 patients (15 previously untreated) with BP CML (38 myeloid, 10 lymphoid) or Ph-positive ALL (n = 10) were treated with imatinib at doses of 300 to 1,000 mg/d.12 Twenty-one patients (55%) with myeloid phenotype responded (four CHR) and seven continued in remission after 101 to 349 days of follow-up. Among patients with lymphoid phenotype, 14 (70%) responded (four CHR); all but one (follow-up, 58 days) relapsed.12 A subsequent phase II study further confirmed the efficacy of imatinib. In a multicenter study, 229 evaluable patients (81 previously treated, 148 previously untreated) were treated with imatinib 600 mg daily.53 A response was achieved in 199 patients (52%), and was complete in 35 patients (15%). A MCR was achieved in 37 patients (16%). Responses were sustained (≥4 weeks) in 70 patients (31%) including 18 (8%) with a CHR. The response rate was higher for previously untreated (36%) than for previously treated patients (21%). However, most patients eventually relapsed; the median duration of complete responses was 10 months. Median survival was 7 months (8 months for previously untreated, 6 months for previously treated). A single-institution study in 75 patients with myeloid (n = 65) or lymphoid (n = 10) BP reported objective responses in 36 patients (55%) with myeloid and three of 10 (30%) with lymphoid phenotype.32 CHR was achieved in 15 (23%) and one (10%) patient, respectively. The median survival was 7 months. A comparison of patients with myeloid phenotype treated with imatinib versus historical controls treated with ara-C–based therapy at the same institution demonstrated a significant improvement in response rate, early mortality, and survival with imatinib.32

Despite the positive results, it appears unlikely that imatinib as a single agent will result in significant long-term remissions. Several mechanisms of resistance to imatinib have been described in vitro and in vivo,5, 19, 22, 26, 43, 45, 66 more frequently in patients with BP. Resistance involved bcr/abl overexpression in three of 21 patients, genomic amplification of bcr/abl in two of 21, CE in nine of 24, and point mutations in six of 40.42 When point mutations were identified, they had not been present before imatinib therapy, but developed while on therapy.5, 26 Also, amplification may reverse once imatinib is discontinued in at least some patients.22

Imatinib has synergistic or additive activity with other agents, including IFNα, doxorubicin, daunorubicin, vincristine, ara-C, hydroxyurea, HHT, and etoposide.30, 44, 60, 64 Several imatinib-based combinations are being investigated. Thomas et al combined a highly effective ALL regimen, hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (HyperCVAD),35 with imatinib in treating 18 patients with CML in lymphoid BP (n = 7) or Ph-positive ALL (n = 11).61 A complete response was achieved in all eight with previously untreated Ph-positive ALL, in three of five patients with relapsed Ph-positive ALL, and in five of seven with lymphoid BP CML (one additional patient achieved a second CP).61 With a follow-up time of only 6 months, none have relapsed. The addition of imatinib did not result in additional myelosuppression or nonhematologic toxicity compared with HyperCVAD. The results of other combinations are not yet available. Well-planned long-term studies will determine how best to combine imatinib with chemotherapy to achieve improved long-term results.

Other new drugs have shown promise in BP. Interest in hypomethylating agents has been described above; DAC has been most extensively investigated in CML BP. Thirty-one patients with CML BP were treated with DAC at a dose of 50 to 100 mg/m2 over 6 hours twice daily for 5 days (500 to 1,000 mg per course).51 There were eight (53%) objective responses including two (6%) CHRs. Median survival was 29 weeks. A multivariate analysis identified treatment with DAC (v ara-C–based chemotherapy or other agents) as an independent, favorable factor for survival.51 No early deaths were seen among patients treated with DAC, and the toxicity profile compared favorably with that of other agents, particularly intensive chemotherapy. Lower doses may be more effective in promoting hypomethylation rather than cytotoxicity, and this approach is currently being investigated as single-agent DAC and in combination with imatinib.

Troxacitabine is a novel nucleoside analog that differs from other dideoxycytidines in its L-configuration. L-Enantiomers were not considered as potential antineoplastic agents because they were thought not to be adequate substrates for activating metabolic enzymes. However, troxacitabine has shown significant antineoplastic activity against several solid tumor cell lines and in animal models.24 A recent phase I study of troxacitabine identified activity in patients with relapsed or refractory AML and MDS; one patient with CML in BP treated on this study achieved a second CP.20 A subsequent phase II study included 17 patients with CML in myeloid BP, including six who had failed to respond to imatinib therapy, and nine in second or later relapse.21 Six of 16 evaluable patients (37%) returned to CP. One patient relapsed after 20 months, one died of sepsis in second CP, and four continue in second CP after follow-up times of 2 to 11 months.

FTI have also been investigated in the BP. Among six patients with myeloid BP treated with R115777 at a dose of 600 mg twice daily for 4 weeks every 6 weeks, none responded.62 A phase I study with a schedule of FTI administered for 21 days every 28 days, treated three patients with CML in BP (only two had the Ph chromosome).41 The two patients with Ph-positive BP achieved a complete response. These results, and those observed in AP and CP,62 the in vitro activity of FTI in CML,50 and their possible synergy with imatinib,27 make them attractive options for these patients. Other drugs currently under investigation in CML BP include clofarabine, a novel nucleoside analog; gemtuzumab ozogamycin (Mylotarg, Wyeth, Madison, NJ), an anti-CD33 monoclonal antibody attached to the toxin calicheamicin; and anti-angiogenesis agents such as bevacizumab, an anti–vascular endothelial growth factor monoclonal antibody.

Results with stem cell transplant in BP are still poor, with long-term survival rates of 15% to 20% with current approaches. Patients should probably be treated to achieve CHR or a second CP before a transplant is considered.

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Conclusion 

Although the mechanisms of CML transformation are not well understood, recent therapeutic advances have improved the prognosis of patients in AP and BP. Still, most patients will succumb to their disease. Thus, continued research into these stages of CML is important, and patients should be encouraged to participate in clinical trials.

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☆ Address reprint requests to Jorge Cortes, MD, Associate Professor of Medicine, Department of Leukemia, M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Box 428, Houston, TX 77030.

PII: S0037-1963(03)70045-6

Seminars in Hematology
Volume 40, Issue 1 , Pages 79-86, January 2003

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