Low-dose Ara-C Research Articles

Treatment of Relapse of AML and MDS after Allogeneic Stem Cell Transplantation Using Low-Dose Chemotherapy, Donor PBSC and GM-CSF: Final Results from a Prospective, Multicenter Phase II Trial by the German Cooperative Transplant Group.

No standard treatment is available for relapse of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) after allogeneic stem cell transplantation (alloSCT). Efficacy of donor lymphocyte transfusion (DLT) was limited, at least in part, by the rapid pace of the disease, overwhelming any allogeneic immune response. However, induction chemotherapy before DLT was complicated by severe toxicity. Based on a pilot trial conducted in Munich, a prospective, multicenter phase II trial for relapsed AML and MDS after alloSCT was initiated in 2000 by the German transplant cooperative group. The study evaluated the sequence of low-dose(ld)AraC for leukemic control (intensive chemotherapy for progressive disease only), transfusion of donor PBSC without immunosuppression as adoptive immunotherapy, and systemic application of GM-CSF. GM-CSF was included, since in combination with other cytokines, it has been able to improve the antigene presentation capacity of myeloid blasts in vitro. Between 2000 and 2006, 41 patients with hematological relapse of AML or MDS >3 months after alloSCT were included. Median age was 47y, 50% had an unrelated donor. Median remission after SCT was 223d (93–1614), median percentage of BM blasts at relapse was 40%. Median follow up was 28 months. Control of leukemic proliferation by ldAraC was achieved in 61%, allowing outpatient care in the majority of these patients. 39% required intensive chemotherapy. Three patients died from infections before donor cell transfusion (DCT), one patient was not transfused due to progressive leukemia. Median time from relapse to DCT was 52 days. 25/34 evaluable patients were found to be free of blasts in BM at d35 after PBSC and were considered initial responders. In an intent-to-treat analysis, overall survival (OS) of the entire cohort at 1 and 2 years from relapse was 41% and 32%. Among initial responders, 1y- and 2y-OS was 68% and 49%. A remission >6months after alloSCT, and control of leukemia by ldAraC prior to DCT were associated with better outcome. At last follow up, 8 patiens were in continous CR, 2 were alive with second relapse, 18 had died from leukemia, and 13 had died in remission or aplasia. In conclusion, ldAraC seems to be effective for initial control of leukemic proliferation in relapsed AML and MDS after alloSCT. A longer duration of post-transplant remission and response to ldAraC may identify patients who will benefit from adoptive immunotherapy. On an intend-to-treat-basis, the overall results of our trial compare favorably to other published strategies; nevertheless, outcome is still unsatisfying and warrants further investigation.

Autophagy Induction of Acute Myeloid Leukemia (AML) Cells after Treatment with Low Dose-Cytarabine (Ara-C) and Enhanced Cytocidal Effect on AML Cells by Combined Treatment with Ara-C Plus Lenograstim.

Autophagy fundamentally refers to a process where cells enclose their own cell organelles with isolated membrane and deliver them to lysosomes for degradation, servicing as a nonspecific degradation mechanism of autologous proteins. Autophagy is induced above basal levels in response to nutrient deprivation or trophic factor withdrawal to sustain metabolism by producing catabolites. In this context, autophagy acts as a cytoprotective mechanism for cells to protect themselves from extracellular stresses. However, in a culture using cells in which autophagy-related genes were suppressed by siRNA and to which an autophagy inhibitor, 3- methyladenine (3-MA), was added, cytotoxic effects of some anticancer agents on cancer cells were diminished. Based on these results, the concept of caspase-independent cell death via autophagy, which is designated as type II programmed cell death (PCD) in contrast to apoptosis as type I PCD, has been receiving increased attention. We here report that treatment of AML cells with low does-Ara-C induces autophagy and enhances its cytocidal effect on AML cells by combined treatment with G-CSF. Treatment of AML cell line U937 cells with 1 to 50 ng/ml of Ara-C induced cell growth inhibition in a dose-dependent manner. Exposure to the higher concentrations of Ara-C (more than 10 ng/ml) induced apoptosis in U937 cells along with formation of apoptotic bodies and caspase-3 activation. However, treatment with the lower concentration of Ara-C (2.5 to 7.5 ng/ml) induced autophagy as assessed by electron microcopy and the punctuated distribution pattern of cytoplasmic microtubule-associated protein 1 light chain 3B (LC3B) by fluorescent immunocytochemistry. Low dose-Ara-C inducing -cell death and -autophagy both were suppressed when the cells were cultured in the presence of 3-MA. This suggests that the autophagic cell death but not the cytoprotective autophagy was induced in response to Ara-C. Combined treatment with G-CSF (lenograstim; 100 ng/ml) plus 2.5 to 7.5 ng/ml of Ara-C, but not plus higher concentrations of Ara-C, resulted in the enhanced cytocidal effect in U937 cells in vitro. These data indicate that combined treatment of Ara-C plus G-CSF has a therapeutic benefit for the AML patients by enhanced cytocidal effect which appears to be mediated via induction of autophagy. In addition, our data appear to explain in part the high response rate of CAG therapy in refractory AML, which consists of low-dose Ara-C in combination with G-CSF and aclarubicin.

Homoharringtonine and Low-Dose Cytosine Arabinoside Combined with G-CSF or GM-CSF Administered in Patients with Advanced Myelodysplastic Syndromes and Relapsed or Refractory Acute Myeloid Leukemia.

According to the FAB classification of myelodysplastic syndromes (MDS), subgroups of refractory anemia with excess blasts(RAEB) and refractory anemia with excess blasts in transformation(RAEB-t) are considered as high-risk MDS or advanced MDS which tend to involve into acute myeloid leukemia(AML). Even though various strategies have been in use, chemotherapy remains the main treatment option. With low remission rates, short duration of remission and high relapse rates, conventional chemotherapy for high-risk MDS and AML transforming from MDS is generally unsatisfactory. Relapsed or refractory AML, geriatric AML and secondary AML have a poor response to the classical induction chemotherapy. Studies indicate that CRs have occurred(8∼56%) at the cost of a high incidence of deaths from toxicity(24%∼64%). Although allogeneic stem cell transplantation could potentially be curative, it is appropriate for only a small subset of patients. This challenges us to work towards new reasonable therapeutic strategies. In vitro, studies have confirmed that granulocyte colony stimulating factor(G-CSF) can enhance the cytotoxic effects of S-phase-specific drugs such as Ara-C by the mechanism of driving myeloid leukemic cells of resting G0-phase into the cell cycle as well as intensifying the metabolism of Ara-C and anthracyclines in the leukemic cell. Recently the regimen of low-dose Ara-C and aclarubicin in combination with G-CSF(CAG regimen) has presented both well-tolerated and highly effective in treating the above categories of AML and MDS. The reported overall CR rate is 35∼75%. We designed a combination chemotherapy of homoharringtonine, low-dose cytarabine and G-CSF or GM-CSF(HAG priming regimen) for remission induction in this study which enrolled 42 patients with advanced MDS or AML between January 2002 and July 2005. 42 patients who received HAG chemotherapy were followed up till April 2006. Clinical and laboratory data of all these patients, which concerned with a)medical interventions including induction chemotherapy, post-remission treatment, and management of complications, etc; b)follow up for conditions of remission, relapse-free survival and overall survival after HAG induction therapy; c)adverse events following HAG induction therapy, were recorded in detail. Among Forty appraisable patients, 20 of them (50%) achieved complete remission (CR), including 66.7% patients with MDS-RAEB and 46.2% patients with refractory or relapsed AML. The fact of 80% patients with AML-M1 achieved CR, demonstrates a better response than those with other subtypes of AML. The overall response rate was 52.5%. After a follow-up of 6—47 months(median 23) from the date of remission, the median times of relapse-free survival and overall survival were 7.0±1.1 and 28±12.3 months, respectively. Meanwhile, these patients aged under 60-year-old who have achieved complete remission and received regular post-remission treatment showed a better survival rate. Myelosuppression was the most significant toxicity. More than 80% of patients experienced neutropenia or thrombocytopenia of grade III to IV after the first induction therapy. The incidences of infection and hemorrhage in the total of 64 induction courses were 43.8%(28/64) and 37.5%(24/64), respectively. Nonhematologic adverse-effects were minimal.

Phase I evaluation of tipifarnib in combination with low-dose Ara-C (LDAC) in high-risk myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML): Interim results

14014 Background: Tipifarnib (T) is a farnesyltransferase inhibitor with clinical activity in MDS and AML. LDAC has utility in the elderly with MDS/AML; hence its use in combination with the investigational agent T to improve outcomes is warranted. Methods: The primary objective of this ongoing phase I, dose finding, multicenter, open-label study was to determine the maximum tolerated dose (MTD) based on dose limiting toxicities (DLT) of T+LDAC observed during the first 28 day cycle. MDS (IPSS Int 1, 2 or High) and untreated AML pts (age =75y or =65y with preceding MDS) or relapsed/refractory AML (age >18y) were included. Planned sample size was up to 57 pts with a traditional 3+3 dose escalation and a minimum of 3 pts enrolled per cohort. T (Dose Level 0) was administered initially at 200mg PO BID x 21 days in combination with LDAC 10mg SC BID x 10 days; both repeated every 28 days. Efficacy will be assessed by bone marrow and peripheral blood count studies. Results: 15 pts have been enrolled to date: 2 MDS (Int 1 n=1, High n=1) and 13 AML (7/13 pts with no previous therapy); all 15 pts were evaluable. Mean baseline characteristics for the entire cohort were: age 76.2y, 67% men, Hb 9.4 ± 0.9 g/dL, WBC 8.7 ± 11.3 x 103/μL, platelets 96.8 ± 96.6 x 103/μL. The observed DLT for T+LDAC was generalized rash seen at Dose Level 3. The MTD was therefore determined to be T 300mg and LDAC 15mg. The most common grade 3/4 adverse events were neutropenia, thrombocytopenia, anemia, and rash. Conclusions: These interim findings show the combination of T at 300mg PO BID x 21 days and LDAC at 15mg SC BID x 10 days to be the MTD in this study. Assessment for efficacy is ongoing. [Table: see text] No significant financial relationships to disclose.

A comparison of low‐dose cytarabine and hydroxyurea with or without all‐trans retinoic acid for acute myeloid leukemia and high‐risk myelodysplastic syndrome in patients not considered fit for intensive treatment

The survival of older patients with acute myeloid leukemia has not improved. Few clinical trials have been available for older patients who are not considered fit for an intensive chemotherapy approach. Between December 1998 and November 2003, as part of National Cancer Research Institute Acute Myeloid Leukemia 14 Trial, 217 patients, who were deemed unfit for intensive chemotherapy were randomized to receive low-dose cytarabine (Ara-C) (20 mg twice daily for 10 days) or hydroxyurea with or without all-trans retinoic acid (ATRA). Low-dose ara-C produced a better remission rate (18% vs 1%; odds ratio [OR], 0.15; 95% confidence interval [95% CI], 0.06-0.37; P = .00006) and better overall survival (OR, 0.60; 95% CI, 0.44-0.81; P = .0009), which was accounted for by the achievement of complete remission (CR) (duration of CR: 80 weeks vs 10 weeks for patients with no CR). Patients who had adverse cytogenetics did not benefit. ATRA had no effect. Toxicity scores or supportive care requirements did not differ between the treatment arms. Older, less fit patients have a poor outcome, and few trials have been conducted in this patient group. Low-dose ara-C treatment was superior to best supportive care and hydroxyurea because it had greater success in achieving CR, and it could represent standard care against which new treatments may be compared in this patient group.

Results of a multicenter phase II trial for older patients with c‐Kit‐positive acute myeloid leukemia (AML) and high‐risk myelodysplastic syndrome (HR‐MDS) using low‐dose Ara‐C and Imatinib

Imatinib (IM) is a potent tyrosine kinase inhibitor of c-Kit. c-Kit is expressed in the majority of patients with acute myeloid leukemia (AML). Whereas clinical trials evaluating monotherapy with IM in AML revealed low response rates, Ara-C and IM showed synergistic effects in vitro. This suggested evaluation of a combination treatment. Low-dose Ara-C (LDAC) combined with IM was tested to determine the efficacy and safety of this regimen. Forty patients from 4 centers with c-Kit-positive AML (n = 34) and high-risk myelodysplastic syndrome (HR-MDS) (n = 6) with a median age of 73 years were enrolled. They were either not eligible for myelosuppressive therapy and/or had recurring/refractory disease. Thirty-eight patients were evaluable for analysis. In 6 of 38 patients a blast response was observed. Eight of 38 patients showed stable disease for more than 2 months. The objective hematologic response rate was low (11%), with 2 patients showing hematologic improvement and 1 each with a partial response (PR) or complete response (CR). Median overall survival was 138 days, with 20% of patients alive after an observation period of 600 days. Study medication was applied in an ambulatory setting with minimal hospitalization time, an early mortality rate of only 18.9%, and a low toxicity rate. LDAC plus IM does not appear to be inferior in older AML patients incomparison with historic controls receiving myelosuppressive therapy. However, this trial also shows that LDAC/IM does not appear to be more effective than LDAC monotherapy in a patient population not selected for appropriate molecular markers.

A Phase II Study (Biov-121) of Clofarabine Monotherapy First Line in Patients Aged 65 Years or Older with Acute Myeloid Leukemia for Whom Standard Intensive Chemotherapy Is Not Considered Suitable.

Background: The treatment of older patients with AML is unsatisfactory and not improving. A substantial proportion of patients are not offered a standard intensive (“3+7”) chemotherapy approach because they are not considered medically fit (Juliusson et al, Leukemia, 2006 (20):42-7). Such patients are usually treated with best supportive care or low-dose Ara-C with a median survival of approximately 3 months. BIOV-121 is an open-label non-randomised multicentre international study of clofarabine, a next generation purine nucleoside analogue, in elderly patients (≥ 65 yrs) with previously untreated acute myeloid leukaemia (AML) who are unsuitable for standard (“3+7”) treatment.Methods: 66 patients aged ≥ 65 with untreated AML (WHO classification) were enrolled in study BIOV-121. Clofarabine was administered at a dose of 30mg/m2 for 5 days repeated every 28–42 days (1 course) for a maximum of 3 courses. All patients were considered unsuitable for standard intensive treatment based primarily on age, comorbidity and/or performance status. The primary endpoint of the study was overall response rate defined as the number of patients achieving a CR, CRi or PR according to the international working group guidelines.Results: 66 patients were recruited with a median age of 71 (range 64–81). 48 patients had de novo and 16 had secondary AML. 72% had an ECOG performance sore of <2; 74% had one or more comorbidities. 31% had an adverse cytogenetic profile; 69% had intermediate cytogenetics (Grimwade D et al Blood 1998). The principal reasons patients were considered unsuitable for standard intensive chemotherapy were age and comorbidity. Nineteen patients achieved a CR; 10 CRi and 3 PR, giving an overall response rate of 48%. 14 patients died (any cause) within 30 days of study start date. The CR/CRi rate in patients over 70 years (49%) was similar to that observed for younger patients (36%). 42% (8/19) of patients with adverse cytogenetics and 31% (5/16) of patients with secondary AML achieved a CR/CRi. The median times to recovery of neutrophils to 1.0 x 109/L and platelets to 100 x 109/L following course 1 were 18 and 27 days respectively. 26% of patients developed neutropenic sepsis. Liver and renal adverse events (NCI CTC grade 3+) were both observed in 23% of patients. The median duration of remission is 6 months; 12 patients have relapsed to date. The median overall survival for all patients is 5 months with a 1 year survival of 26%.Conclusion: A complete response rate of 44% achieved with clofarabine in older AML patients unsuitable for standard intensive treatment is encouraging and potentially superior to the current standard of care, low dose Ara-C. Of note a good proportion of patients with an adverse cytogenetic profile and/or secondary disease achieved a CR/CRi when treated with clofarabine.

Treatment of AML in the Elderly: Who Is “Fit” for Intensive Chemotherapy?.

Currently, increasing attention is being focused on the older patient with AML who is deemed “unfit” for intensive chemotherapy. Indeed a recent population-based study (Juliusson et al, Leukemia 2006 (20), 42–7) showed that only around one half of patients between the ages of 70 and 79 were offered remission induction chemotherapy. Typically the unfit patients are treated with supportive care, low doses of cytosine arabinoside (Ara-C) or with investigational agents. However, there is no strict definition of what constitutes a patient unfit for intensive chemotherapy. The NCRI AML14 trial offered patients the choice of entering an intensive chemotherapy randomisation (where patients received daunorubicin/Ara-C based therapy, n=1273), or a non-intensive randomisation between low dose Ara-C and hydroxyurea (n=217). A randomisation between intensive and non-intensive chemotherapy was attempted but recruited only 8 patients, indicating that clinicians did not appear to be uncertain about which patients should receive which type of treatment. In order to identify which factors were significantly associated with the decision to enter either the intensive or non-intensive approach we performed analyses of the AML14 data. The two principal factors associated with fitness for intensive chemotherapy were age and performance status (both p<0.0001). Other factors influencing the decision were presence of comorbidities (p=0.007), diagnosis (de novo v secondary, p=0.01), lower weight (p=0.04) and heart disease (p=0.04). However, even after adjusting for these factors, clinician was a highly significant predictive variable (p<0.0001), and this significance was retained even if analyses were restricted to those doctors who had entered patients into both parts of the trial. While it is unsurprising that patients deemed unfit for intensive chemotherapy are older, less fit, thinner and with more comorbidities, the high level of significance of clinician as a variable indicates that this characterisation is insufficient. It is likely that clinician is a surrogate variable for other factors currently not routinely collected, although there is also a suggestion that clinicians may not be consistent in who receives intensive treatment. Comparisons of patients treated intensively and those treated non-intensively, even when stratified for prognostic factors, tend to show that intensively treated patients perform better (Wheatley et al., Blood 2005 (106(11)) 199a (Abstract 674)) but it is unclear whether even this stratified comparison is confounded.Conclusion: This study defines factors which differ between patients allocated to an intensive or non-intensive approach. However we identify the clear influence of which physician is involved in the choice as an independent factor. To identify factors (which may be components of the physician's choice) reliably a more comprehensive index is needed for which a prototype will be presented.

Treatment of High Risk MDS and AML Post-MDS with Azacytidine (AZA): Preliminary Results of the French ATU Program.

Background : Following FDA approval of AZA for MDS and activation of a phase III trial randomizing AZA to conventional treatment in higher risk MDS, a compassionate program for the use of AZA (ATU nominative) was started in France for MDS with exclusion criteria for this trial.Patients (pts) : IPSS int-2 and high-risk MDS (and some int-1) with contra-indication to the trial (ie therapy related (t-MDS) or already treated by cytoreductive agents or having progressed to AML or patient refusal), received AZA 75 mg/m/d (d 1–7) (SC) every 4 weeks.Results : From Sept 2004 to May 2006, 90 pts from 31 centres were included, of whom 77 had completed at least one course of AZA : M/F: 52/25, median age 71 y [42–88]. WHO at inclusion : 15 RAEB1, 30 RAEB2, 14 AML post-MDS, 7 CMML, 3 RA, 3 RAS, 2 RCMD, 3 unclassified MDS. 22 pts had previously received intensive Anth-AraC, 9 low dose AraC, 16 EPO and 13 other treatments (alkylators, Arsenic, androgens, Thal) and 1 had t-MDS. 32 (42%), 16 (21%) and 29 (37%) pts had fav, int and unfav karyotype, resp. 37 pts (48%) were IPSS high, 26 pts (34%) int-2 and 14 pts (18%) int-1. Pts received a median of 4 cycles [range 1–16]. Response was generally assessed after 4 cycles, unless pts progressed before. Thus, 16 pts were not yet evaluable for response. Of the remaining 61 pts, 10 (16%) achieved CR (IWG criteria), 15 (25%) achieved PR and 13 (21%) achieved HI (Overall response rate OR=62%). 23 pts (38%) were considered failure of whom 4 died before evaluation and 10 of them were considered failure because early evaluation after only 2 cycles showed stable disease only, and AZA was then stopped. OR was 73%, 57%, 67% and 36% for RAEB1, RAEB2, CMML and AML post-MDS resp (p<0.1); 75%, 56% and 59% for fav, int and unfav karyotype, resp (p=NS). 4/6 pts with monosomy 7 responded (1 CR+3 PR), 2/4 pts with + 8 (1 PR+1 HI) and 13/23 pts with complex karyotype (5 CR+6 PR+2 HI). OR was 56%, 77% and 56% for IPSS high, int-2 and int-1 pts, resp (p=NS) and 50%, 76% in pts previously treated or not by cytoreductive agents resp (p<0.05). Median survival from inclusion was 7 months [range 3–17]. AZA induced myelosuppression lead to dose reduction in 17% pts and hospitalization in 13% pts but was not responsible for any death. Other side effects included frequent local reactions (reversible with local NSAID) (32%), grade I-II gastro-intestinal disorders (39%), unexpected cardiac arythmias (3%).Conclusion : AZA, in this population with overall unfavorable features, gave response rates at least similar to those of CALGB studies, that may have been higher if treatment had not been stopped in some of the pts stable after 2 courses. Pts with unfavorable karyotype (− 7, complex) or + 8 had about 50% response rates. Accrual in this program is continuing. Data on response duration will be presented.

Patients with Acute Myelogenous Leukemia (AML) or High-Risk Myelodysplastic Syndrome (HR-MDS) Treated with Targeted Therapy May Benefit from Prophylactic Measures Against Infections.

Targeted therapy (TT) has emerged as an alternative for patients (pts) 60 years or older with hematologic malignancies. It has been suggested that these approaches produce fewer and less severe side effects than conventional chemotherapy (CC) and could potentially decrease mortality. In the current study, pts with AML or HR-MDS treated with TT and CC were compared with regard to infectious complications and induction mortality. Supportive care measures for pts on CC were given according to our departmental guidelines (protective environment (PE) was offered and antibacterial, antifungal and antiviral prophylaxis were given from D1 to ANC ≥ 500). Pts on TT were given supportive care measures according to protocol requirements. HR-MDS pts: 29 pts were treated with TT and 13 with CC. Pts on TT were significantly older than those on CC (median age: 66(r: 46–85) and 59(r: 17–73) respectively, p=0.02). All 42 pts (TT and CC) had Zubrod performance status (PS) ≤ 2. 16/29 (90%) pts on TT received Decitabine; 2 pts received 5-AZA containing regimens and 1 pt received rosiglitazone + targetrin. Nine pts (69%) on CC had high-dose ara-C (HDAC) containing regimens; 1 pt received cloretazine + hydrea and 3 pts had low-dose ara-C (LDAC) + clofarabine. AML pts: 43 pts were treated with TT and 282 received CC. Pts on TT were significantly older than those on CC (median age: 75(r: 39–86) and 62(r: 17–84) respectively, p<0.001). The majority of the pts in TT (91%) and CC (97%) had PS ≤ 2. Decitabine was given to 40% (17/43) of pts on TT, 25% received 5-AZA containing regimens, 35% had others. HDAC containing regimens were given to 60% of pts on CC and clofarabine and/or LDAC to 40%. Table 1 and 2 show outcome and infectious episodes (IE) in pts with MDS and AML, respectively. Conclusions: Although pts with AML or HR-MDS treated with TT develop significantly fewer number of IE compared to pts treated with CC the severity of such infections lead to similar mortality rate than pts treated with CC. Pts treated with TT may benefit from prophylactic measures against infections.Table 1Outcome in MDSTT (N=29)CC (N=13)Response, n(%)Overall response18(62)8(61)Resistant8(28)4(31)Induction death3(10)1(8)p=0.787Cause of Death, n(%)Infections3(100)1-Progressive disease-1(100)Pts on prophylaxis, n(%)Fungal11(38)12(92)p=0.001Bacterial19(66)9(69)p=0.810Pts in PE, n(%)010(77)p<0.001Pts with IE, n(%)15(52)11(85)p=0.042IE2, n(%)1914Bacterial5(26)2(14)FUO8(42)9(64)Pneumonia unknown origin2(11)3(21)Fungal2(11)0Others2(11)012 aspergillosis, 1 MRSA sepsis2p=nsTable 2Outcome in AMLTT (N=43)CC(N=282)Response, n(%)Overall response12(28)180(64)Resistant27(58)67(24)Induction death6(14)35(12)p=0.779Cause of death, n(%)Infection15(83)20(57)MOF21(14)7(20)Others-8(23)Pts on prophylaxis, n(%)Fungal16(37)260(92)p=0.001Bacterial24(56)282(100)p=0.001Pts in PE, n(%)6(14)214(76)p<0.001Pts with IE, n(%)22(51)247(88)p<0.001IE3, n(%)31405Bacterial7(22)88(22)FUO13(42)202(50)Pneumonia unknown origin6(19)93(23)Fungal1(3)10(2)Virus2(6)6(1)Others2(6)6(1)1TT:sepsis=5, CC:fungal=4, sepsis=162multiorgan failure3p=ns

Effectiveness of Clofarabine in Elderly AML Patients with Adverse Cytogenetics Unfit for Intensive Chemotherapy.

Outcomes for elderly patients with AML are almost uniformly poor, and it has been shown (Wheatley et al., Blood 2005, 106(11) 199a) that patients with adverse cytogenetics have a particularly poor prognosis. Additionally, a large proportion of such patients are considered not to be fit for intensive chemotherapy (Juliusson et al, Leukemia, 2006 (20): 42–7), and given best supportive care, or low-dose Ara-C. The NCRI AML14 trial observed no remissions in 18 patients with adverse cytogenetics treated with Ara-C, and no remissions in 20 patients treated with hydroxyurea. We present here a combined analysis of the BIOV-121 Study, and the UWCM-0001 study. Both studies were for untreated patients over 65 years of age who were not considered fit for chemotherapy. The treatment comprised clofarabine 30mg/m2 on days 1–5 repeated after 28–42 days for up to 3 courses. The primary endpoints were overall response (CR, CRi or PR) and safety.Patients: A total of 95 patients were recruited, of whom 95 received clofarabine 30mg/m2. Twenty-six patients (27%) had adverse cytogenetics.Results: 10/26 patients (38%) achieved either CR or CRi. With a median follow-up of 10 months (range 2–17 months), 1 year survival is 20%, with 19/26 patients having died. At most recent follow-up, 4/10 patients achieving CR or CRi are still alive in remission.Discussion: The remission rate of 38% seen with clofarabine compares favourably, not only with traditional non-intensive approaches (which have failed to induce any remissions in similar sized cohorts), but also to the 42% remission rate seen in patients treated with intensive daunorubicin/Ara-C based chemotherapy in the NCRI AML14 trial. One year survival rates are also encouraging, at 20% compared to 0%, 5% and 23% for patients treated with Ara-C, supportive care, and intensive chemotherapy respectively. Exploratory comparisons of survival between the 30mg clofarabine patients and the three treatment regimens give highly significant survival advantages compared to Ara-C and HU (p=0.0001, p=0.004 respectively) and no significant difference between clofarabine and DA (p=1.0), although confidence intervals in this case are wide.Conclusions: Clofarabine has the ability to induce remissions in patients with adverse cytogenetics, unlike Ara-C and supportive care, and survival in this group is improved. Remission rates and survival are similar to those seen for patients treated with intensive chemotherapy. Clofarabine is clearly worthy of further investigation, and may provide an important treatment option for high risk patients with AML.

Uniform Approach Better Defines Natural History of Transient Myeloproliferative Disorder (TMD) in Down Syndrome (DS) Neonates: Outcomes from Children' Oncology Group (COG) Study A2971.

TMD is solely found in DS infants in the first few months of life & is distinguished from congenital AML primarily by its spontaneous resolution. A2971, the largest study of TMD conducted to date, defines the natural history of this disorder by utilizing uniform observation & treatment guidelines. A total of 136 DS patients (pts) <90 days (d) of age were enrolled from 1999–2004 with median follow-up of 745d(0–2187). Pts were assigned to observation(n=110) or intervention(n=26) arms based upon clinical severity. Median age at diagnosis was 5d(0–58) with median hematologic values of WBC 32,800(4,800 – 259,100), hemoglobin 15(5–22.5), platelets 125K(10–958K), peripheral blasts 25%(0–92) & bone marrow blasts 15%(0–95). Hepatomegaly (HM) was seen in 59%, splenomegaly in 39%, & pleural or pericardial effusion in 10% & 19%. Pts required intervention due to hyperviscosity(11%), blast count >100,000/μl(25%), organomegaly(OM) with respiratory(resp) compromise(43%), CHF(11%), hydrops fetalis(21%), liver dysfunction(43%), renal dysfunction(14%), or DIC(25%). For pts who required intervention(n=29, 21%), 9 pts(31%) received leukopheresis/exchange transfusion (Leuk/Exch). 26(90%) pts received low-dose AraC (3.33 mg/kg/24 hrs continuous infusion on days 0–4) for OM, organ dysfunction causing resp compromise, or continued symptoms after Leuk/Exch. Among all pts, 3-year overall survival(OS) was 77 ± 8% & event-free survival(EFS) was 73 ± 9%. 28 deaths were noted (15 related, 12 unrelated to TMD or therapy, 1 unknown). Median time to TMD resolution (defined as resolution of peripheral/ bone marrow blasts, OM, effusions & organ dysfunction) was 46d(7–757). Peripheral blast resolution was attained in a median of 35d (2–147). To date, 16 pts (12%), including 4 treated with AraC, developed AML/MDS at a median time of 355d(118–888). We identified 3 distinct groups of TMD pts: low risk (without palpable HM or hepatic dysfunction, n=52, 38%), intermediate risk (HM with non-life threatening hepatic dysfunction, n=55, 40%), & high risk (WBC>100K or life threatening cardio-resp compromise due to TMD, n=29, 21%). The OS for low, intermediate & high risk groups was 92 ± 8%, 82 ± 11% & 49 ± 20% and EFS was 83 ± 11%, 64 ± 15% & 36 ± 19%, respectively(p<0.001 for low vs high & intermediate vs high risk groups for OS & EFS). WBC >100K (Hazards Ratio-HR 3.57, p=0.004) & presence of hepatomegaly (HR 3.6, p=0.009) were significant adverse risk factors for OS in univariate analyses. This study confirms that most TMD pts undergo spontaneous resolution of disease without intervention, further clarifies the natural history of TMD, & provides baseline comparisons for upcoming COG trials.

Clofarabine in previously untreated elderly (&gt;65 yrs) AML patients with an unfavourable cytogenetic profile who are considered unfit for standard intensive chemotherapy

6513 Background: Elderly AML patients (&gt;65 yrs) are a very poor prognostic population. Standard treatment achieves an 18% overall response (OR) rate (low dose Ara-C, U.K. AML 14 trial) with no little or no responses observed in high-risk cytogenetic patients. BIOV-121 is a Phase II non-randomized study of clofarabine, a novel, next generation purine nucleoside analogue, in older patients (&gt;65 yrs) with previously untreated acute myeloid leukemia (AML) for whom standard intensive chemotherapy is not considered suitable. Methods: 66 patients aged &gt; 65 yrs with untreated AML were enrolled in study BIOV-121. All patients were considered unfit for standard intensive chemotherapy based primarily on age (&gt; 65 years) and/or performance status. All patients received clofarabine 30mg/m2 for 5 consecutive days repeated every 28 days (1 course) for a maximum of 6 courses. The primary study endpoint was overall response rate (ORR) defined as the number of patients achieving a CR, CRi, or PR according to the international working group guidelines. A preliminary analysis was conducted on both patients with an unfavourable cytogenetic profile (11/44 patients), for whom data was available, and on patients &gt; 70 years of age (36/66 patients). Unfavourable cytogenetic prognostic risk was defined as the presence of a complex karyotype, monosomies of chromosome 5 (del [5q]/5q-), or 3q abnormalities as reported by Grimwade et al (U.K. MRC AML 10 trial). Results: Of 44 patients for whom cytogenetic data was available, 25% (11/44) had an unfavourable cytogenetic prognostic risk profile. The median number of clofarabine courses administered in this patient group was one. With a median age of 68 years the overall response rate (ORR) in this unfavourable cytogenetic patient group was 36% (4/11) with a 27% complete response (CR) rate. 55% (36/66) of patients were aged &gt;70 years. The ORR and CR rate was 56% and 44% respectively in patients aged &gt;70 years. The toxicity of clofarabine was acceptable and manageable in elderly AML patients. Conclusions: Clofarabine appears superior to current standard treatment (low-dose Ara-C) in both unfavourable cytogenetic AML (&gt;65 years) and AML patients &gt; 70 years (all cytogenetic risk groups). [Table: see text]

General Approach to, and Perspectives on Clinical Research in, Older Patients With Newly Diagnosed Acute Myeloid Leukemia

Most patients aged>or=55 to 60 years who are treated for newly diagnosed acute myeloid leukemia (AML) receive a combination of an anthracycline plus cytarabine (ara-C). A principal thesis of this chapter is that such therapy is unsatisfactory for the great majority of such patients. In particular, the >or=15% risk of death in the month following the start of treatment is difficult to justify given median survivals of less than 1 year in the patients who do not die early. Thus, investigational therapy should be recommended for most, if not all, older patients. In patients for whom such therapy is not feasible, low-dose ara-C is a reasonable alternative except for patients with de novo disease and a normal karyotype, who might benefit more from an anthracycline+ara-C combination, and patients with either a poor performance status, abnormal organ function, or age>or=80, for whom supportive/palliative care only is recommended. Distinctions are made between investigational therapies likely associated with lower and higher risks of treatment-related mortality (TRM). The former are preferable initial treatment in patients aged 70 and above, or with abnormal cytogenetics. Three topics are discussed that are likely to be relevant to future clinical research in older patients: the possibility of delaying therapy to gain information about prognosis with initial induction therapy, the clinical value of responses less than conventional complete remission (CR), and the possibility of looking for larger differences between treatments in randomized clinical trials.

Clinical trial of valproic acid and all‐trans retinoic acid in patients with poor‐risk acute myeloid leukemia

Valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, induced in vitro differentiation of primary acute myeloid leukemia (AML) blasts, an effect enhanced by all-trans retinoic acid (ATRA). Clinical responses to VPA were recently observed in patients with myelodysplastic syndrome (MDS). Herein, the authors have described results of a clinical trial with VPA plus ATRA in 26 patients with poor-risk AML. VPA (5-10 mg/kg starting dose) and ATRA (45 mg/m(2)) were administered orally. Low-dose AraC or hydroxyurea were permitted to control leukocytosis. Biologic activity of VPA was confirmed by serial analysis of HDAC2 protein levels in peripheral blood (PB) mononuclear cells. Nineteen of 26 patients completed at least 4 weeks of VPA/ATRA treatment; 7 patients were withdrawn prematurely because of rapidly progressive disease (n = 3) or unacceptable neurologic and cardiovascular toxicity (n = 4). Additional cytoreductive treatment was required in 58% of patients enrolled. Median treatment duration was 3 months. No patient achieved complete remission, one with de novo AML had a minor response, and two patients with secondary AML arising from myeloproliferative disorder (MPD) achieved a partial remission and clearance of PB blasts, respectively. The latter responses were accompanied by profound granulocytosis and erythrocytosis in both patients, reminiscent of the response pattern known from ATRA treatment of acute promyelocytic leukemia. However, cytogenetic analysis of isolated CD34(+) cells and granulocytes did not reveal terminal differentiation of leukemic blasts. Treatment with VPA/ATRA results in transient disease control in a subset of patients with AML that has evolved from a myeloproliferative disorder but not in patients with a primary or MDS-related AML.

Arsenic Trioxide (ATO) Is Safe and Effective in Combination with Low-Dose Ara-C (LDAC) for the Treatment of IPSS-2 Myelodysplastic Syndrome (MDS) and Poor-Prognosis Acute Myeloid Leukemia (AML) in Elderly Patients.

There is no adequate therapy for advanced MDS and elderly AML and treatment outcomes are generally poor. LDAC in elderly AML patients using a variety of dosing schedules results in a CR rate of approximately 20% and possibly improved morbidity and mortality compared to conventional chemotherapy or supportive care. In MDS patients, the CR rates with LDAC are lower, 10–20%, with short duration and no clear benefit over supportive care. On the basis of preclinical data suggesting a possible anti-angiogenic effect of ATO, as well as clinical data showing activity of ATO in MDS, a phase I/II trial of ATO in combination with LDAC was initiated in IPSS-2 MDS and newly-diagnosed, poor-prognosis AML patients. ATO was given at a dose of 0.25 mg/kg for days 1–5 and 8–12. LDAC was dose-escalated from 5 mg/m2 SC BID to the target phase II dose of 10 mg/m2 SC BID for days 1–14 (one treatment cycle). Patients who achieved CR after one treatment cycle were given a second, identical cycle, followed by maintenance treatment of 5 days of LDAC and 2 days of ATO every 28 days. Patients who did not achieve CR after one cycle were given a second cycle beginning between days 21–28, with the addition of ascorbic acid 1g IV within 30 minutes of the ATO infusion. Fifty-seven patients have been enrolled to date, 34 with AML and 23 with MDS. A total of 28 AML and 16 MDS patients are evaluable for response, 38 of whom were treated with the target dose of LDAC. There were no responses in patients treated with less than the target dose. Clinical characteristics of the 28 AML patients include: mean age 75 yrs (range 55–85 yrs; one patient < 60 yrs with AML and multiple medical comorbidities was included); 18 (64%) abnormal cytogenetics; 18 (64%) antecedent hematologic disorder; 4 (14%) secondary disease. CR was achieved in 11 patients (39%), with follow-up 1–8+ mos. Six patients (55%) required 2 treatment cycles to achieve CR. Of the total 34 AML patients, 4 (12%) died of progressive disease prior to day 30 and 1 (3%) died of neutropenic sepsis. Clinical characteristics of the 16 evaluable IPSS-2 MDS patients include: mean age 70 yrs (range 56–84 yrs); 11 (69%) abnormal cytogenetics; 2 (1%) prior therapy with 5-azacytidine. CR was achieved in 4 (25%) patients, follow-up 1–11+ mos. One patient required 2 treatment cycles to achieve CR; there were no therapy related deaths. The regimen was generally well-tolerated, with minimal grade 3/4 non-hematologic toxicity and no significant nausea, emesis, diarrhea or mucositis. Alopecia was not seen. Grade 4 hematologic toxicity was, as predicted, observed in all patients. Fluid retention occurred in 21/34 (62%) of patients. There were no clinically significant drug-related arrhythmias. For AML patients, the combination of ATO and LDAC resulted in a CR rate comparable to conventional chemotherapy, with improved tolerability and induction mortality. Further investigation of this regimen is warranted in both MDS and AML.

Clofarabine and Clofarabine Plus Low-Dose Cytarabine (ara-C) as Induction Therapy for Patients (pts) ≥ 60 Years with Newly Diagnosed Acute Myeloid Leukemia (AML).

Optimal induction therapy for pts ≥ 60 years (yrs) with AML remains undefined. Clofarabine is a purine deoxyadenosine analog with single agent activity in AML. Due to its metabolic and pharmacokinetic properties it is also an ideal agent for biochemical modulation strategies with other nucleoside analogs such as ara-C. In previous trials we reported our experience with clofarabine + intermediate doses of ara-C for salvage and frontline AML pts. To further explore clofarabine in AML, we investigated a lower dose schedule of clofarabine +/− low-dose ara-C (LDAC) in pts ≥ 60 yrs and previously untreated AML. Pts were adaptively randomized (based on history of response in each arm) to receive either clofarabine (C) at 30mg/m2/d i.v. daily d1-5 or clofarabine at 30mg/m2/d i.v. daily d1-5 + LDAC at 20mg/m2/d s.c. daily d1-14. Pts in remission received consolidation therapy q4-7 wks with clofarabine daily on d1-3 +/− LDAC daily on d1-7. Pts with ECOG PS ≥ 3 and/or a history of NYHA ≥ grade 3 heart disease were not eligible. Pts were admitted to a laminar airflow room (“protective environment”) for the duration of the induction. All pts received antibiotic prophylaxis consisting of levaquin, valacyclovir, and itraconazole (or equivalents). No antifungal prophylaxis was given during the days of the clofarabine infusions. Fifty-four pts have been enrolled (C 14; C+LDAC 40). Median age: 71 yrs (range 60–83). An antecedent hematologic disorder (MDS, CMML, NHL) or other malignancy was present in 28 pts (52%). Twenty-four pts (44%) had abnormal cytogenetics of whom 11 (20%) had −5, −7, or 11q23 abnormalities. Flt3 ITD/mutations were found in 7 pts (14%). Forty-four pts are evaluable for response (C 12; C+LDAC 32). Twenty-four pts (55%) achieved CR and 1 (2%) CRp for an overall response rate (ORR) of 57%. Median time to CR: 34 days (25–78). Response by treatment arm: 1) C (n=12): 5 (42%) CR; 2) C+LDAC (n=32): 19 (59%) CR, 1 (3%) CRp, ORR 62% (p=NS for CR rate). Most toxicities were ≤ grade 2 and included nausea/vomiting, diarrhea, fatigue, skin rashes and temporary elevations of transaminases and serum bilirubin. Myelosuppression was ubiquitous and myelosuppression-associated infectious complications were frequent. Nine pts (17%) died during induction (6/40 on C; 3/14 on C+LDAC), of whom 2 died early (≤ 14 days of treatment start): 71 yo female with E. coli sepsis on d12 (C); 83 yo male with pulmonary hemorrhage and pneumonia d14 (C+LDAC). In summary, clofarabine and clofarabine + LDAC show activity in older pts with AML. Its role in elderly AML induction needs to be evaluated further. Myelosuppression-associated complications remain frequent. An update of responses and time-to-event parameters will be presented.

Results of a Multicenter Phase II Trial for Older Patients with c-Kit Positive Acute Myeloid Leukemia (AML) and High-Risk Myelodysplastic Syndrome (HR-MDS) Using Low-Dose Ara-C (LDAC) and Imatinib.

In international multicenter trials, the 5-year overall survival (OS) rate of AML patients older than age 55 ranges from 5–16%. A similar outcome is seen for relapsed/refractory AML patients. As only a minority of these patients appear to benefit from myelosuppressive chemotherapy, new approaches are clearly warranted.Over 70% of AML-patients show expression of the tyrosine kinase (TK) c-Kit on myeloid blasts. c-Kit is involved in activation of proliferation pathways and plays an anti-apoptotic role in normal and malignant hematopoiesis. Imatinib mesylate (IM) inhibits protein TKs including c-Kit, PDGFRs and Abl. Two former studies have investigated IM as a single agent in patients with c-Kit positive AML and HR-MDS suggesting biological activity of IM in a subset of AML patients (Cortes, Cancer 2003; Kindler, Blood 2002). LDAC has been used for MDS and AML to induce differentiation in AML blasts with partial response rates of approximately 30% but without improvement in OS.As synergy between IM and Ara-C has been reported in vitro we conducted a phase II study applying a combination of these two agents.40 patients at 4 centers with a median age of 72 years (range: 42–82 years with 95% of patients >60 y) were enrolled into this study. They either were not eligible for myelosuppressive therapy or had relapsed/refractory disease. Previous therapy included supportive care only, biological agents or < 3 cycles chemotherapy.In median, c-kit positivity of AML blasts from patients included was 67%. 34 patients (85%) were included with AML and 6 patients (15%) with HR-MDS (including CMML). 38 patients were evaluable for this analysis. The overall rate of biological activity was 45% (17 of 38 patients): In 6/38 (16%) patients, a blast response (reduction >50% in PB) was observed while 8/38 patients showed stable disease over a minimum period of 2 months. The objective response rate was low with each 1 patient (3%) showing hematologic improvement, PR and CR, respectively.While more than one third of patients included had a short term course of LDAC/IM only (<4 weeks) due to disease associated morbidity or patient's wish, 3 patients experienced long term progression-free survival of more than 250 days (up to 450 days). Analysis of non-hematologic toxicity revealed 2 patients with a grade III skin rash. Grade I-II toxicity, mainly nausea and loss of appetite occurred in one third of treated individuals.Patients over age 60 show a historical survival benefit of 2.5 months using myelosuppressive chemotherapy versus best supportive care and an early mortality rate of 25% within 6 weeks. Moreover, it has been pointed out that most of the 'benefit-time' (>80%) is spent in hospital. Study medication offered in this trial was applied in an ambulatory setting with minimal hospitalization, an early mortality rate of 21% and a low toxicity rate.In conclusion, combination therapy of LDAC/IM does not appear to be inferior in comparison to myelosuppressive therapy in older AML patients. However, this trial shows that LDAC/IM does not improve substantially the clinical outcome of older patients with AML. Identification of molecular mechanisms for good and long-term responders will be part of further laboratory investigations.

Is Consolidation and/or Maintenance Treatment a Standard Therapy in Elderly AML in First Complete Remission?.

The treatment of elderly patients with acute myeloid leukemia (AML) is very disappointing. Studies have established that if half of the intensivity treated patients achieve complete remission (CR), the high rate of relapse within the first year jeopardize the long term survival. No clearly effective postremission therapy had been established. Therefore we retrospective analyzed 141 elderly patients (>60 yo) in first CR, to evaluate the effectiveness of postremission therapy, consolidation (3+7or 2+5) and/or maintenance (low dose AraC). All patiens received a 3+7 induction therapy. In these 141 patients DFS and OS at 4 years are respectively 14%, and 19%.According to the clinical status of the patient after induction, 20 (14%) patients did not receive therapy after induction, 30 (21%) patients received only maintenance therapy, 53 (38%) patients received only consolidation therapy, and 38 patients (27%) received both consolidation and maintenance therapy. These 4 groups were stratified according to age (< >70 yo) and WBC (< or > 30 x 109/l) (See Tables). The outcome of these patients receiving or not post induction therapy is shown in these Tables.PatientsDFS at 4 yearsOS at 4 yearsConsolidationNo consolidationP valueconsolidationNo consolidationP value< 70yo and WBC< 30x109/l19%13%p=0.0127%13%p=0.0074<70yo and WBC>30x109/l26%0%p=0.0838%0%p=0.05>70 yo and WBC < 30x109/l0%30%p=0.0016%30%p=0.01>70 yo and WBC> 30x109/l2%0%NS4%0%NSOutcome of patients receiving or not consolidation therapy in 4 groups stratified according to age and WBC countIn patients > 70 yo and WBC < 30 x 109/l patients who received consolidation have a poorer prognosis than patients who did not because the mortality in first complete remission (mortality during consolidation) was high (25% versus 0% respectively, P=0.01).PatientsDFS at 4 yearsOS at 4 yearsMaintenanceNo Maintenancep valueMaintenanceNo MaintenanceP value<70yo and WBC<30x109/17%20%NS22%25%NS<70 yo and WBC>30x109/l23%14%p=0.0532%23%NS>70 yo and WBC<30x109/l25%5%p=0.0125%5%p=0.008>70 yo and WBC >30x109/l2%0%NS4%0%NSOutcome of patients receiving or not maintenance therapy in 4 groups stratified according to age and WBC countIn conclusion, in patients < 70 yo consolidation ± maintenance therapy (for DFS in patients with > 30 x109/l) improves the outcome of these patients (DFS and OS). In patients > 70 yo and with WBC < 30 x109/l maintenance therapy without consolidation, improves outcome. In these later patients (> 70 yo and with WBC < 30 x 109/l) consolidation therapy decrease outcome. In patients > 70yo and with WBC > 30 x 109/l, both consolidation and/or maintenance therapy does not improve outcome.

A Pilot Trial of Imatinib, Low-Dose Cytarabine (ara-C) and Idarubicin (Ida) in Patients (pts) with Chronic Myeloid Leukemia (CML) in Myeloid Blastic Phase (BP).

Abstract Although imatinib is the single most effective agent in CML BP, only approximately 30% to 50% of pts achieve a hematologic response, and it is complete (CHR) and durable in 5% or less. Regimens including high-dose ara-C and daunorubicin are associated with remission rates of 20% to 25% in CML BP, a median survival of 3 months, and significant morbidities. Imatinib is additive or synergistic in vitro with ida and ara-C, particularly in imatinib-resistant cell lines. We thus investigated the efficacy of the combination of imatinib 600 mg daily, ara-C 10 mg daily subcutaneous, and Ida 12 mg/m2 IV every 14 days in pts with CML in myeloid BP. Nineteen pts were treated, including 6 who had BP as their first manifestation of CML. Seventeen pts had failed prior imatinib as a single agent and had received a median of 5 prior therapies (range, 1 to 9). Median age was 54 yrs (range, 27–81) and the median WBC was 28.6 x 109/L (range, 3.7 to 240.5), peripheral blood blasts 18% (range, 0 to 82), and bone marrow blasts 36% (range, 2 to 84). Four pts had extramedullary disease. Pts were treated for a median of 10.5 weeks (range, 4 to 124), receiving a median of 2 cycles (range 1 to 28). Fourteen (74%) pts responded, including 9 (47%) who achieved CHR, and 5 (26%) who returned to chronic phase. Four of the pts who achieved CHR also had a cytogenetic response (CGR) (3 complete, 1 minor). Responses lasted for a median of 10 weeks (range, 2 to 89 weeks). Two of 5 pts who failed to respond had a transient hematological improvement (&amp;gt;50% reduction of blasts in peripheral blood). Six pts were able to receive allogeneic BMT (4 in CHR, 1 in CP and 1 still in BP). Treatment was well tolerated and administered on an outpatient basis. Grade 3–4 non-hematological toxicities consisted of fatigue (n=4), vomiting (n=1), bone pain (n=1) and hyperbilirubinemia (n=1). Sixteen (84%) pts required brief hospitalization for neutropenic fever (n=8), bleeding (n=7), pneumonia (n=6), cellulitis (n=2) and CNS disease (n=2). Thirteen pts died: 4 after BMT and 9 due to disease progression. Among these, 4 had achieved CHR and 2 complete CGR. The median survival was 23 wks and 1 year survival rate 26%. In conclusion, the combination with imatinib + low-dose ara-C + Ida is an outpatient, well tolerated regimen that can induce responses in patients with CML BP who have failed imatinib and can be considered as an option to improve patient’s condition, and as a bridge to allogeneic BMT.