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The most common BCR-ABL transcripts in chronic myeloid leukemia (CML) are e13a2(b2a2) and e14a2(b3a2). Other transcripts such as e1a2 are rare and their outcome with tyrosine kinase inhibitors (TKI) therapy is undefined. We analyzed 1292 CML patients and identified 14 with only e1a2 transcripts, 9 in chronic phase (CP), 1 in accelerated phase (AP), and 4 in blast phase (BP). Of the CP, 4 achieved complete hematologic response (CHR); 2, complete cytogenetic response (CCyR); 2, partial cytogenetic response (PCyR), and 1 did not respond to imatinib. Five patients progressed to myeloid BP (3), lymphoid BP (1), or AP (1). The AP patient received various TKIs sequentially and achieved only CHR. BP patients received hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, adriamycin, dexamethasone) plus imatinib/dasatinib or idarubicin plus cytarabine (Ara-C); 2 did not respond, 1 had CCyR, and 1 short-lasting complete molecular response (CMR). Overall, cytogenetic responses lasted 3 to 18 months; only 2 achieved major molecular response (MMR) on TKI. P190(BCR-ABL) CML is rare and is associated with an inferior outcome to therapy with TKI. These patients need to be identified as high-risk patients.

Sudden blastic transformation (SBT) has been reported in 0.5% to 2.5% of patients treated with interferon-alpha (IFN-alpha) during the first 3 years of therapy. Imatinib is now standard therapy for patients with chronic myeloid leukemia in chronic phase. We investigated the occurrence of SBT among patients treated with imatinib. Among 541 patients treated with imatinib in chronic phase, 23 developed blast phase, which was of sudden onset (ie, occurring in patients previously in complete cytogenetic remission) in 4 patients (17%; 0.7% of the total), 2 lymphoid and 2 myeloid. Patients with SBT were found to have low-risk features more often at the time of presentation and had achieved optimal response with imatinib. Three of the 4 patients underwent allogeneic stem cell transplantation and achieved a molecular remission. SBT is still a rare event, probably less common than that observed with IFN-alpha therapy. Continuous monitoring of patients treated with imatinib is mandatory.

Molecular abnormalities caused by the hybrid Bcr-Abl gene are causally associated with the development and progression of Philadelphia chromosome-positive (Ph(+)) chronic myelogenous leukemia (CML). Imatinib mesylate (STI571), a specific Bcr-Abl tyrosine-kinase signal-transduction inhibitor, has shown encouraging activity in phase I and II studies of CML. Here, we describe the use of imatinib mesylate to treat 75 patients in blast-phase CML (median age, 53 years; 65 with nonlymphoid and 10 with lymphoid blasts), and compare the results with those of a historical control group treated with standard cytarabine-based therapy. Imatinib mesylate was given as oral doses at 300 to 1000 mg per day and was the first salvage therapy for 47 patients. The objective response rate was 52% (39 of 75 patients: 16 had complete and 3 had partial hematologic response; 12 had hematologic improvement; 7 returned to second chronic phase; and 1 had a complete response in extramedullary blastic disease). Response rates were not different between nonlymphoid and lymphoid groups. The cytogenetic response rate was 16% (12 patients: 5 complete, 3 partial [Ph(+) below 35%], and 4 minor [Ph(+), 34% to 90%]). The estimated median overall survival was 6.5 months; the estimated 1-year survival was 22%. Response to therapy (landmark analysis at 8 weeks) was associated with survival prolongation. Compared with standard cytarabine combinations, imatinib mesylate therapy was less toxic and produced a higher response rate (55% versus 29%, P =.001), longer median survival (7 versus 4 months, P =.04), and lower 4-week induction mortality (4% versus 15%, P =.07). Imatinib mesylate is currently being tested in combination with other drugs to improve the prognosis for blast-phase CML.

Background: Achievement of minimal tumor burden, such as complete response, has been accepted as a surrogate marker for improved survival in many solid and hematologic carcinomas. Several new agents have been approved recently for orphan disease indications or unmet medical needs, based on response analyses. This has not been the case for chronic myelogenous leukemia in the blastic phase (CML-BP), despite its poor prognosis, because response has not been proven to be a valuable endpoint for survival prolongation. The purpose of this study was to analyze the effect of response in CML-BP on survival prolongation. STUDY GROUP AND METHODS In total, 328 patients with CML-BP referred from 1989 to 1999 were studied; 311 patients received therapy for CML-BP, and 275 were evaluable for response. Blastic phase CML was defined by the presence of 30% or more blasts in the blood or bone marrow, or extramedullary disease. Treatment responses were reviewed and categorized as proposed in previous large studies. Four categoric response groups were defined further based on significant differences in outcome: cytogenetic response, hematologic response, bone marrow improvement, and failure. The association of treatment response with survival was evaluated by multivariate and landmark analyses., Results: The association of response with survival was analyzed among the 275 patients who had evaluable responses, and follow-up information was documented. Univariate analysis of pretreatment characteristics found performance status, hemoglobin levels, platelet counts, peripheral blasts, additional chromosomal abnormalities, and blastic phase morphology as showing significant associations with survival (P < 0.1). A multivariate analysis found platelet counts and blastic morphology as independent significant factors associated with survival (P < 0.05). A landmark analysis conducted at 8 weeks from start of therapy showed the beneficial effect of achieving response on survival prolongation (P < 0.001). A repeat multivariate at the 8-week landmark time in the 240 patients alive at that time, which included pretreatment characteristics and treatment response, confirmed the independent significant association of morphology (P = 0.003), platelet counts (P = 0.04), and response (P < 0.001) with survival., Conclusions: Response to therapy is a significant independent factor associated with survival prolongation and maybe an acceptable therapeutic endpoint for approving new treatments in CML-BP., (Copyright 2001 American Cancer Society.)

Background: The prognoses of patients with chronic myelogenous leukemia in blastic phase (CML-BP) are extremely poor. Treatment of patients with nonlymphoid CML-BP is associated with very low response rates, a median survival of 2-3 months, and significant toxicities. The aim of this study was to evaluate the results of therapy in CML-BP with different treatments in relation to response rate, survival, and toxicity., Methods: A total of 162 adults patients with a diagnosis of nonlymphoid CML-BP referred from 1986 to 1997 were included in this analysis. Only first salvage therapy was considered for the purpose of this analysis. The blastic phase of CML was defined by the presence of 30% or more blasts in the blood or bone marrow, or extramedullary disease. Ninety patients were treated with intensive chemotherapy, 31 with decitabine, and 41 with other single agents., Results: Thirty-six patients (22%) had an objective response. Response rates were similar among patients treated with intensive chemotherapy (28%) or with decitabine (26%). In aggregate, other single agents showed objective response rates of 7%. The median duration of remission for all patients was 29 weeks and the median overall survival 22 weeks. Patients treated with decitabine showed a trend toward better survival, despite a higher percentage of older patients (P < 0.004). The median survival times were 29 weeks with decitabine, 21 weeks with intensive chemotherapy, and 22 weeks with other agents. When only older patients were considered, survival was significantly better with decitabine versus other treatments (P < 0.01). A multivariate analysis of prognostic factors for survival confirmed the independent, significant favorable effect of decitabine therapy (P = 0.047). In all groups complications of myelosuppression were the most significant side effects. Severe nonhematologic toxicities were not observed in patients treated with decitabine; they occurred in 20% and 17% of patients treated with intensive chemotherapy or other single agents, respectively., Conclusions: Compared with intensive chemotherapy, decitabine showed favorable results, with similar objective response rates, a better nonhematologic toxicity profile, and a trend for better survival, particularly among older patients. Studies will now attempt to combine decitabine with other promising approaches, such as homoharringtonine, low dose cytarabine, and interferon-alpha, in all CML phases., (Copyright 1999 American Cancer Society.)

Background: Cytarabine is an essential drug for inducing remission of acute myelogenous leukemia, and it is also one the most effective drugs used as salvage therapy for patients with all types of relapsed acute leukemia. Nevertheless, there is considerable room for improvement in the treatment of patients with relapsed leukemia in terms of both the reinduction rate and the duration of response. Fludarabine has been shown to augment responses to cytarabine, possibly by increasing the intracellular concentrations of the active metabolite cytarabine triphosphate. Higher-than-standard doses of mitoxantrone have been shown to augment responses to cytarabine, possibly by increasing the DNA strand breaks induced by topoisomerase II; these strand breaks cannot be effectively repaired in the presence of cytarabine triphosphate. This preliminary study was designed to determine whether moderately high doses of mitoxantrone could be added to the combination of fludarabine and cytarabine in an attempt to improve the combination's antileukemic efficacy., Methods: Fifty-five adults with relapsed or refractory acute leukemia or the blastic phase of chronic myelogenous leukemia (CML) received salvage therapy with the FLAM regimen, which consisted of fludarabine, cytarabine, and increasing doses of mitoxantrone., Results: Even with doses of mitoxantrone escalated to as much as 60 mg/m(2) over 4 days, dose-limiting toxicity was not observed. Overall, the complete response rate was 27.3% (15 of 55 patients, including 4 of 17 with acute myelogenous leukemia [AML], 4 of 12 with acute lymphocytic leukemia [ALL], and 7 of 26 with the blastic phase of CML). The median time to complete response was 42 days. Toxicity other than myelosuppression was manifested primarily as hyperbilirubinemia, which was reversible in all cases. Poor performance status and undifferentiated blastic phase of CML were poor prognostic factors for response to FLAM., Conclusions: The FLAM regimen is an active salvage regimen and should be formally evaluated in Phase II studies of patients with AML, ALL, and the myeloid and lymphoid blastic phases of CML., (Copyright 1999 American Cancer Society.)

Fazarabine has demonstrated a broad spectrum of antitumor activity in experimental models including P388 and L1210 cell lines. Previous phase I clinical trials using a 3-day continuous infusion schedule of Fazarabine have shown myelosuppression to be the dose limiting toxicity in solid tumors. Based on this clinical and preclinical experience we designed a phase I study to determine the toxicity, maximum tolerated dose (MTD), and antileukemic efficacy of Fazarabine using a 3-day continuous infusion schedule in patients with refractory or relapsed acute leukemia or chronic myelogenous (CML) in blastic phase. Adults with a diagnosis of acute leukemia or blastic phase CML who were refractory or had relapsed on salvage chemotherapy were entered on study. Fazarabine was administered as a continuous infusion over 3 days every 3 to 4 weeks. The initial dose was 2 mg/m2/hour x 72 hours. Results showed that the MTD was 425 mg/m2/hour infused over 72 hours every 3 to 4 weeks. At this dose level neurotoxicity and fluid overload were the dose limiting toxicities. Among 71 patients treated, we observed one complete remission, one partial remission and one hematologic improvement. No obvious dose response relationship could be determined. In conclusion, Fazarabine has not shown a beneficial effect in the therapy of acute leukemia. Since 71 patients and 20 dose levels were required to determine the MTD of Fazarabine, a reassessment of our phase I study designs should be considered to provide patients with better potential toxic: therapeutic benefits in such trials.

The aim of the study was to evaluate the activity of decitabine, a hypomethylating agent, in the treatment of patients with chronic myelogenous leukemia (CML) in transformation. Thirty-seven patients with CML in blastic (20 patients) or accelerated phases (17 patients) were treated. Their median age was 52 years; 36 had Philadelphia chromosome-positive disease. Decitabine was given at 100 mg/m2 over 6 h every 12 h x 10 doses (1000 mg/m2) to 13 patients, and at 75 mg/m2 over 6 h every 12 h x 10 doses (750 mg/m2) to 24 patients. In blastic phase, two patients (10%) achieved a complete hematologic response (one with Ph suppression), and three (15%) had a hematologic improvement (marrow CR, platelets <100 x 10[3]/microl), for an overall response rate of 25%. In accelerated phase, six patients (35%) returned to a second chronic phase (two with Ph suppression), one (6%) had a hematologic improvement, and two (12%) had a partial hematologic response, for an overall response rate of 53%. Prolonged myelosuppression was the most significant side-effect. The median time to recovery of granulocytes above 500/microl was 48 days, and to recovery of platelets above 30 x 10(3)/microl, 31 days. Febrile episodes occurred in 25 patients (68%) including documented infections in 17 patients (46%). Decitabine has promising activity in CML. The most significant side-effect is prolonged myelosuppression. Decitabine may show activity in other myeloid disorders such as acute myeloid leukemia and myelodysplastic syndrome, as well as in other hematologic malignancies, alone or with other drug combinations. Its value in the context of stem cell support should also be investigated.

Purpose: The study was undertaken to improve the results of intensive chemotherapy in chronic myelogenous leukemia (CML) in accelerated (CML-AP) and blastic phases (CML-BP) by the addition of granulocyte-macrophage colony-stimulating factor (GM-CSF) as supportive therapy., Patients and Methods: Forty-eight patients were treated with daunorubicin 120 mg/m2 intravenously on day 1, cytarabine (ara-C) 1.5 g/m2/d by continuous infusion over 24 hours for 4 days, and Solu-Medrol (methylprednisolone; The Upjohn Co, Kalamazoo, MI) 100 mg/d for 5 days, followed on day 5 by GM-CSF 125 micrograms/m2/d over 6 hours until recovery of granulocyte count above 2.0 x 10(3)/microliters. Twenty-four patients had CML-BP, and 24 had CML-AP., Results: During remission induction, 45 patients (94%) developed febrile episodes (fever of unknown origin, 23 patients [48%]; documented infections, 22 patients [46%]). The median time to recovery of granulocyte count above 0.5 x 10(3)/microliters was 29 days and to platelet count above 30 x 10(3)/microliters, 28 days. Overall, 14 of 48 patients (29%) achieved a complete hematologic remission (CHR), and seven (15%) reverted to a second chronic phase. CHR was noted in eight of 24 patients with CML-BP (33%), and in six of 24 patients with CML-AP (25%). Cytogenetic responses were observed in 11 patients (23%), but were transient. Sixteen patients developed either fluid retention, hypotension, pleuropericardial effusions, or pericarditis, or a combination of these side effects. These side effects were severe in four patients and are likely to be disease-associated, as a similar regimen of intensive chemotherapy and GM-CSF at the same dose and schedule in acute lymphocytic leukemia was not associated with these side effects., Conclusions: The results pertinent to remission rates, induction mortality, myelosuppression profile and related complications, and overall survival were not significantly improved compared with previous experience. In summary, the results of intensive chemotherapy in CML-transformed phases remain poor, despite the addition of GM-CSF as a supportive measure.