Safety Of Clofarabine Research Articles

DI-073 Effectiveness and safety of clofarabine in paediatric and adult patients in a tertiary hospital

BackgroundClofarabine is a recently marketed drug used in paediatric patients with refractory acute lymphoblastic leukaemia (ALL) after at least two prior chemotherapy regimens. Its safety and effectiveness have not been...

Successful Salvage Treatment With Clofarabine and Cytarabine In Relapsed/Refractory Acute Myeloid Leukemia

ObjectivesRelapsed/refractory AML patients have a poor prognosis; allogeneic hematopoietic stem cell transplantation (HSCT) is the only chance in this setting to achieve long-term disease-free survival (1). It was previously established the activity of clofarabine plus cytarabine in AML relapse (clofarabine dosed once daily for 5 days with 40 mg/m2 followed 4 hours later by ara-C at 1 g/m2 per day)(2).However, modifications of this combination in AML therapy of relapsed/refractory patients warrant further evaluation. Therefore, our goal was to determine the efficacy and safety of clofarabine at lower dosage followed by cytarabine (Ara-C) in adult patients with relapsed or refractory acute myeloid leukemia (AML) and to evaluate the capacity of this regimen as a bridge for HSCT. MethodsPatients aged 18-65 years with refractory/relapsed AML were treated at the dose of clofarabine 30 mg/mq on days 1-5 and cytarabine 1000 mg/mq gg on days 1-5. We evaluated the complete remission rate (CRR), duration of remission (DOR) and overall survival (OS). Minimal residual disease (MRD) by molecular targeting was considered in all patients. ResultsTwenty-five (25) patients aged 29-64 years (median 47), who were fit for allogenetic HCT, received one cycle of 30 minutes infusion of clofarabine 30 mg/mq, followed 4 hours later by 3 hours infusion of intermediate dose cytarabine 1000 mg/mq days 1-5. Only in the first three patients this schedule was followed by gentuzumab. Nine (36%) patients had refractory disease (seven after one induction regimen, one after two previous regimes, one after a prior hematopoietic stem cell transplant (HSCT); 16 (64%) patients were in their first (12 patients) or second relapse (4 patients); among the 12 patients in first relapse, 5 were from an allogeneic stem cell transplant. Fourteen patients (56%) achieved a complete remission (CR), seven (28%) was refractory and 4 (16%) died of treatment related mortality. Eleven (44%) patients underwent (9 in CR) to allogeneic transplants or DLI infusion (3 patients refractory, and 8 patients relapsed), only one patient underwent to autologous transplant. One patient, who was relapsed after prior HSCT, obtained a CR but he developed acute graft vs host disease after therapy and died in molecular CR*. Among all patients underwent HSCT after Clofa/Ara-c salvage, six patients (50%) are still alive and in complete remission, six patients (50%) died because of HSCT complications or AML relapse. The complete remission rate (CRR) was (56,00 %), the median Overall Survival was 5 months for all patients (range 1-38 M), 11 Months for those underwent to tranplantation and 1,5 Months for non transplanted group. Treatment was complicated by neutropenic fever (n=17), grade III-IV mucositis (n=2) , skin rush (n=4) grade II- III, hepatic transaminase elevations (n=2). Two (n=5) patient died before their disease status could be evaluated. ConclusionsThese preliminary results suggest that combination treatment with clofarabine 30 mg/mq and ARA-C 1000 mg/mq is effective in this particularly poor prognosis category of patients, resulting in an ORR very favorably, representing a potential “bridge” toward bone marrow transplant procedures (among the 14 patients who achieved a CR, twelve (85%) proceeded to HSCT, and six are still alive). The safety profile is acceptable in this relapsed/refractory population, and our results are very similar to previous regimes using higher clofarabine dosages. More studies with this combination in adults are warranted. References1 Estey E. Treatment of relapsed and refractory acute myeloid leukemia. Leukemia. 2000;14:476-479. 2. Faderl S et al, “Results of a pase 1-2 study of clofarabine in combination with cytarabine (ara-C)”Blood 2005 [Display omitted] [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.

DGI-027 Effectiveness and Safety of Clofarabine in Paediatric Patients with Acute Leukaemia

Background Clofarabine is a purine nucleoside antimetabolite, a second-generation antineoplastic indicated for the treatment of acute lymphoblastic leukaemia in paediatric patients (≤ 21 years) who have relapsed or are refractory...

Safety of Clofarabine with Multiagent Chemotherapy in Childhood High Risk Relapse of Acute Lymphoblastic Leukemia (Vandevol study of the French SFCE Acute Leukemia Committee).

AbstractAbstract 2570 Background.Current outcome of very early relapse of ALL in children remains poor. Clofarabine, a novel nucleoside analog has proven effective as a single agent in childhood ALL second relapse, providing a CR+CRp ratio of 20 to 28 % (Jeha 2006, Kearns 2006). Clofarabine in combination with cyclophosphamide and Etoposide provided a 44% overal response rate rate in children with advanced ALL (Hijiya 2011) and further multi-drug combinations need to be investigated. The VANDA regimen that has proven effective in high risk ALL and in ALL relapse (Domenech 2008) was used as a template, Cytarabine being replaced by Clofarabine in this combination. Procedure.A phase I study combining escalating doses of Clofarabine with fixed doses of Mitoxantrone, Etoposide, Asparaginase and Dexamethasone was undertaken in children presenting very early (18 months or less after initial diagnosis) medullary or combined ALL relapse or children with second relapse or post transplant relapse. A 3+3 rolling design was used for escalating clofarabine doses with 25% increments from 20 to 40mg/m2/d.Dexamethasone20 mg/m2D1 to D5Clofarabine20 mg/m2 (26, 32, 40)D1 to D5Mitoxantrone8 mg/m2D3, D4Etoposide150 mg/m2D 3, 4, 5E-Coli Asparaginase10 000 UI/m2D7, 9, 11, 13 Results.Sixteen patients were enrolled, eleven in first marrow relapse, four in second relapse. One patient with an initially refractory disease was secondary excluded as he didn’t fulfill the inclusion criteria. Four patients had previously been allografted. Three patients were enrolled at dose level 1 (clofarabine 20 mg/m2), and 3 patients at dose level 2 (clofarabine 26 mg/m2) without any significant dose-limiting toxicity (DLT). Six patients were enrolled at dose level 3 (clofarabine 32 mg/m2), one patient experienced a liver DLT (gamma GT elevation) exceeding 7 days. At the last planned dose level (clofarabine 40 mg/m2), two patients had a grade 3 transaminase elevation exceeding 7 days and 2 patients had a severe fungal infection. Median duration of neutropenia was 20 days (15–31). Other expected toxicities included 3 documented bacterial infections, 3 mucosal toxicities needing parenteral support, one lung aspergillosis, one transient insulin dependant hyperglycemia. There was no toxic death. Out of 15 evaluable patients, 11 (73%) achieved a complete cytological remission (CR). 4 relapses occurred at 1, 1, 2 and 3 months. 6 patients proceeded to allo-SCT with 2 second allografts. One allografted patient died from EBV-PTLD, the others are alive at 2, 13, 13, 15, and 29 months post-transplant. Conclusion.Clofarabine in combination with four major antileukemic drugs appeared feasible and effective in inducing complete remission in those high risk patients. Clofarabine MTD was 32 mg/m2/d for five days and this dose step is currently being expanded to a total of 10 patients, before a phase II study will be proposed for early and very early ALL relapses. Study registered at ClinicalTrials.gov (http://clinicaltrials.gov/ct2/show/NCT01279096). Disclosures:Off Label Use: off label use of clofarabine.

Clofarabine plus cytarabine compared to cytarabine alone in older patients with relapsed or refractory (R/R) acute myelogenous leukemia (AML): Results from the phase III CLASSIC 1 trial.

6503^ Background: This is the first phase III, prospective, randomized, blinded trial to evaluate the efficacy and safety of clofarabine (CLO) in combination with ara-C compared to ara-C alone in o...

Report of a Phase II Study of Clofarabine and Cytarabine in De Novo and Relapsed and Refractory AML Patients and in Selected Elderly Patients at High Risk for Anthracycline Toxicity

To determine the efficacy and safety of clofarabine and cytarabine (Ara-C) in adult patients with relapsed or refractory acute myeloid leukemia (AML) and in elderly patients with untreated AML and heart disease. Patients with relapsed/refractory AML and older patients for whom there was a concern over toxicity from additional anthracyclines received 5 days of clofarabine, 40 mg/m(2) per day i.v. over 1 hour, followed 4 hours later by Ara-C, 1,000 mg/m(2) per day i.v. over 2 hours. Thirty patients were enrolled. The median age was 67 years (range, 38-82 years) and 18 (60%) had received at least one prior therapy. Eleven (37%) patients had a history of cardiovascular disease and were considered to be at high risk for anthracycline toxicity. High-risk cytogenetic abnormalities were present in 14 (47%) patients. The overall response rate (complete remission [CR] plus partial remission) was 53%, including a CR in 14 patients (47%). Responses were observed in all cytogenetic risk groups and in patients who had received up to five prior therapies. The median disease-free survival interval was 9.5 months. The 30-day mortality rate was 20% (de novo AML, 8%; relapsed/refractory AML, 28%). Of the 14 patients achieving a CR, half were able to proceed to curative hematopoietic stem cell transplantation. Clofarabine in combination with Ara-C is effective in both untreated and previously treated patients with AML. In addition, it represents a useful remission induction strategy to serve as a bridge to transplantation in older patients with AML.

Efficacy and safety of clofarabine in relapsed and/or refractory non‐hodgkin lymphoma, including rituximab‐refractory patients

Currently, no standard therapy exists for patients with relapsed and/or refractory non-Hodgkin lymphoma (NHL) who are ineligible for transplantation or who have failed after bone marrow transplantation. The authors of this report investigated the safety and efficacy of clofarabine (CLO) in these patients. In a 2-step, open-label study, CLO (as a 1-hour intravenous infusion given daily for 5 days) was given every 28 days (maximum, 6 cycles). In the phase 1 portion (n = 7; standard 3 + 3 study design), the dose was escalated by 2 mg/m(2) to determine the maximum tolerated dose (MTD). The phase 2 study (n = 26) was initiated at the MTD, and patients were followed until disease progression. Of 33 patients who were enrolled, 31 patients (median age, 69 years) were evaluable; 24% failed after previous stem cell transplantation, and 72% were rituximab-refractory. The MTD for CLO was 4 mg/m(2) . The overall response rate was 42%. Seven patients (23%) achieved a complete response, and 6 patients (19%) achieved a partial response. The median response duration was 5 months. Among the rituximab-refractory patients, the overall response rate was 47% (complete response rate, 28%), and the median response duration was 7 months. At a median follow-up of 14 months, 45% of patients remained alive (median overall survival, 10 months). Toxicity was mainly hematologic (≥60% of patients had neutropenia or thrombocytopenia). Nonhematologic toxicity included tumor lysis syndrome, infection, and renal insufficiency (in 6% of patients each). No treatment-related mortality was observed. Single-agent CLO was active and was tolerated well in patients with refractory NHL, including patients in a rituximab-refractory subset. Reversible myelosuppression was the major toxicity. Study is registered at www.clinicaltrials.gov (NCT00156013).

AAML0523: A Report From the Children's Oncology Group On the Safety of Clofarabine in Combination with Cytarabine in Pediatric Patients with Relapsed Acute Leukemia.

Abstract 3076Poster Board III-13 BackgroundDespite improvements in survival rates for pediatric ALL and AML, many children still relapse with dismal outcomes. It is critical to develop non-anthracycline containing salvage regimens that induce remission and allow for hematopoietic stem cell transplantation (HSCT). Clofarabine is a nucleoside analog that potently inhibits ribonucleotide reductase and DNA polymerase αa. The biochemical modulation of cytarabine by clofarabine via inhibition of ribonucleotide reductase is well established, and this combination has been studied in adults with relapsed AML. Study DesignThe Children's Oncology Group instituted a Phase I/II study testing the combination of clofarabine and cytarabine in pediatric patients with AML in first relapse and ALL in second or subsequent relapse. We report on the toxicity profile in the Phase I portion of the study. Cytarabine was administered on days 1-5 at a dose of 1 gm/m2 and clofarabine was administered on days 2-6 in varying doses. Cytarabine was given 4 hours after the start of clofarabine to optimize the biochemical modulation of ara-CTP. Patients could receive up to 2 cycles on study. The Phase I portion of the study consisted of a single dose escalation/de-escalation of clofarabine with a fixed dose of cytarabine. For each dose level, 10 patients were enrolled. The first cohort of patients received clofarabine at 40 mg/m2/day (the adult single-agent MTD). Based on safety data on the first cohort, the dose of clofarabine would either be escalated to 52 mg/m2/day (single-agent pediatric MTD) or deescalated to a dose of 30 mg/m2/day. The MTD determined in this dose finding phase would determine the dose for the Phase II efficacy portion of the study. ResultsOf the 10 patients enrolled on the first cohort, 8 patients had ALL (6 in second relapse, 2 refractory to reinduction) and 2 had AML. Ten patients completed one cycle and 5 patients completed two cycles. In both cycles, the most common toxicities ≥ Grade 3 were fever/neutropenia (7/15 occurrences), infection (6/15), transaminitis (5/15), abdominal pain (3/15), and hypokalemia (4/15). Two ALL patients with prior HSCT had dose-limiting toxicities (DLT's): one with grade 4 fungal infection and pneumonitis and another with grade 4 fungal infection. Neither patient was on antifungal prophylaxis. The MTD was not met, and 10 patients were enrolled on the second cohort (52 mg/m2): 3 patients with ALL in second relapse and 7 with AML. Ten patients completed cycle 1 and 7 completed two cycles. In both cycles, the most common toxicities ≥Grade 3 were diarrhea (3/17), nausea (3/17), febrile neutropenia (5/17), infection (10/17), hyperglycemia (3/17), and hypokalemia (3/17). In this cohort, one AML patient experienced DLT's of prolonged bone marrow aplasia, Grade 4 hypokalemia, Grade 3 nausea, and Grade 3 dehydration. The table below summarizes count recovery data at both dose levels. The median cycle length for patients without ANC and platelet recovery at the 40 mg/m2 level was 22 and 30 days respectively after one course and 19 and 17.5 days respectively after 2 courses. At the 52 mg/m2 dose level, the median cycle length for patients without ANC and platelet recovery was 20 days for each after one course and 23 and 25 days respectively after 2 courses. These numbers suggest that patients without marrow recovery had progressive disease, received alternate chemotherapy, or proceeded to HSCT prior to count recovery, rather than drug-induced prolonged bone marrow aplasia. ConclusionsThe combination of clofarabine and cytarabine is safe and tolerable in pediatric patients with relapsed acute leukemia. The MTD of clofarabine in combination with cytarabine in pediatric patients with relapsed acute leukemia is 52 mg/m2/day.Dose: 40 mg/m2Course 1Course 2# of patients with recoverymedianrange# of patients with recoverymedianrangeALL patients (n=8)Time to ANC >750/μl (days)52318-3632116-22Time to platelets >75,000/μl (days)32513-28221.521-22AML patients (n=2)Time to ANC >1,000/μl (days)23836-4013333Time to platelets >100,000/μl (days)1363613333Dose: 52 mg/m2Course 1Course 2# of patients with recoverymedianrange# of patients with recoverymedianrangeALL patients (n=3)Time to ANC >750/μl (days)0--0--Time to platelets >75,000/μl (days)0--0--AML patients (n=7)Time to ANC >1,000/μl (days)23324-4215757Time to platelet s >100,000/μl (days)22421-270-- DisclosuresWhitlock:Genzyme: Consultancy.

Complete Response to Clofarabine Is Durable and Correlates with Survival in Previously Untreated Older Adult Patients with Acute Myeloid Leukemia (AML) and Unfavorable Prognostic Factors.

Abstract 2061Poster Board II-38 Background:We have previously reported efficacy and safety of clofarabine in patients = 60 with at least one unfavorable prognostic factor. Retrospective analyses have suggested that survival in AML is related to quality of response. [Estey, Clinical Advances in Hematology Oncology, 2008]. In this report, we present durability and survival data for complete responders in each of the prognostic subgroups in the CLASSIC II trial, and a landmark analysis to evaluate the relationship between complete response and survival. Methods:This single arm, Phase II, open-label study enrolled adults with untreated AML =60 years old with at least one adverse prognostic factor: age =70 years, ECOG performance status (PS)=2; antecedent hematological disorder (AHD); and/or intermediate/unfavorable risk karyotype. Clofarabine was given on days 1-5 at 30 mg/m2 during induction and 20 mg/m2 during re-induction/consolidation. Primary endpoint was ORR (CR + CRp). Secondary efficacy endpoints included duration of remission (DoR), disease-free survival (DFS) and overall survival (OS). Due to interest about outcome of CR alone with respect to remission durability, such secondary endpoints were analysed and are reported below for the overall population and for each prospectively defined prognostic subgroup. Analyses of overall survival (OS) using both best response and landmark timepoints were performed. Landmark analyses eliminate survivorship bias by evaluating the robustness of the relationship between response and survival in patients who survived until a landmark timepoint and using the response at this timepoint for assessment rather than best response. Since this analysis was defined post hoc, 3 analyses of median overall survival in patients who survived at least 30, 45, and 60 days were performed to eliminate time-to-response bias. Results:112 patients were evaluable. For patients with complete response (CR, n=42), median duration of remission (DoR) was 65 weeks (95% CI 41, not estimable [NE]), median disease free survival (DFS) 48 weeks (28, 65), and median overall survival (OS) 72 weeks (53, NE). Patients = 70 years (n=69) had 33% CR, median DoR and DFS 65 weeks (17, NE), and median OS = 48 weeks (48, NE). Patients with ECOG PS2 (n=25) had CR 24%, median DoR 7 weeks (6,NE), median DFS 9 weeks (6, 12), and median OS 16 weeks (12, 33). Patients with AHD (n= 41) had 39% CR; median DoR, DFS, and OS are NE. Patients with intermediate/unfavorable karyotype (n= 108) had 39% CR, median DoR 65 weeks (41, NE), median DFS 48 weeks (28, 65) and median OS 72 weeks (53, NE). Patients with unfavorable karyotype (n=62) had 32% CR, median DoR 56 weeks (28, NE), median DFS 33 weeks (23, 56), and median OS 59 weeks (48, NE). Median OS was 59.1 weeks (95% CI=49.9 weeks, NE) for CR + CRp; 33.4 weeks (95% CI=19.3, 55.0 weeks) for CRp; and15.4 weeks (95% CI=12.0, 29.9 weeks) for non-responders.In the landmark analysis, patients who had a complete response to clofarabine survived longer than non responders (Table 1), regardless of starting point (30, 45, or 60 days). The survival benefit of responders was statistically significant for all time points (p<0.05).Table 1:Sensitivity Analysis of Overall Survival by Complete Response using Landmark AnalysisLandmark Timepoint In DaysNumber of Responders (CR)Median OS for Responders1Number of Non-RespondersMedian OS Non-responders1Hazard Ratio (95% CI; p-value)0 days24272.47019.33.78 (2.15, 6.65; p<0.0001)30 days13NE8836.43.25 (1.17, 9.02; p=0.0234)45 days28NE6835.32.12 (1.09, 4.12; p=0.0266)60 days33NE6132.12.35 (1.25, 4.43; p=0.0082)NE=non-evaluable1Median number of weeks past the landmark time point2Note this analysis uses best response rather than response at landmark Summary/conclusions:CRs were consistent, durable, and associated with survival of > 13 months in all prognostic subgroups except PS2, and complete responders lived longer than non-responders. Achievement of a CR correlates with clinical benefit and survival in older AML patients. Single agent clofarabine is an effective treatment option for older adult patients with untreated AML and unfavorable prognostic factors. Disclosures:Gabrilove:Genzyme: Research Funding. Faderl:Genzyme: Research Funding. Erba:Lilly: Research Funding; Antisoma: Research Funding; Wyeth: Research Funding; Cephalon: Honoraria, Research Funding; MGI Pharma: Honoraria; Pharmion: Honoraria; Celgene: Honoraria; BMS: Honoraria; Novartis: Honoraria, Research Funding; Genzyme: Consultancy, Honoraria, Research Funding; Gemin-X: Research Funding; Kanisa: Research Funding. Claxton:Genzyme: Research Funding. Arellano:Genzyme: Research Funding. Lyons:Celgene: Consultancy; Johnson&Johnson: Consultancy, Honoraria, Speakers Bureau; GlaxoSmithKline: Consultancy, Speakers Bureau; Amgen Inc.: Consultancy, Honoraria, Research Funding, Speakers Bureau; Genzyme: Research Funding. Kovacsovics:Genzyme: Research Funding. Eckert:Genzyme: Employment. Huebner:Genzyme: Employment. Kantarjian:Genzyme: Research Funding.

Oral (po) and Intravenous (iv) Clofarabine for Patients (pts) with Myelodysplastic Syndrome (MDS)

Clofarabine (CLO) is a second generation deoxyadenosine nucleoside analog with activity in pts with acute myeloid leukemia (AML). Early reports also suggested activity in MDS, but the role of CLO in MDS has not been defined. To evaluate the activity and safety of CLO in MDS we designed two phase II studies of IV CLO and PO CLO, respectively. Pts were eligible with MDS and ≥5% blasts or IPSS intermediate-2 and high-risk, CMML, and RAEB-t by FAB. Hematopoietic growth factor support prior to and during the study was permitted. In the IV study pts were adaptively randomized (based on response) to receive CLO 15 or 30 mg/m2 IV over 1 hr. daily × 5 every 4–6 weeks. For the PO study, the starting dose of CLO was 40 mg/m2 orally daily × 5 every 4–6 weeks (oral bioavailability assumed ~ 50%, based on preclinical data), which was decreased to 30 mg/m2 orally daily × 5 after 6 pts had been treated on the higher dose. Sixty-one pts (6 RA/RARS/RCMD, 17 RAEB-1, 16 RAEB-2, 11 CMML, 11 RAEB-t) were treated. Forty-two pts (69%) had high- or intermediate-2 risk disease by IPSS. Thirty-six pts received IV CLO and 25 PO CLO. Median age was 67 yrs (range 25–89) (IV) and 70 yrs (54–86) (PO). Overall, > 80% of pts were older than 60 yrs. Approximately 1/3 of pts had secondary MDS: 13 (36%) (IV) and 8 (32%) (PO), respectively. Seventeen (47%) (IV) and 10 (40%) (PO) of pts had unfavorable cytogenetics (by IPSS definition). Thirty-nine (64%) pts failed prior hypomethylator therapy with either decitabine or azacitidine (22 [61%] pts on IV and 17 [68%] pts on PO CLO). Responses of 60 evaluable pts (one pt refused continuation of therapy on D4 of first course) are summarized in the Table:Response (%)RouteDose (mg/m2)NCRCRpHIPO40/30247 (29)2 (8)3 (13)IV15207 (35)3 (15)-30164 (25)2 (13)-Total-6018 (30)7 (12)3 (5)Six pts (10%) died on study (all IV CLO; most commonly related to infectious complications). All pts were evaluable for toxicities. Common AEs were nausea, vomiting, skin rash, hyperbilirubinemia and transaminase elevations. Toxicities ≥ grade 3 were rare. Acute renal failure occurred in 7 pts (2 IV [15 mg/m2], 3 IV [30 mg/m2], 2 PO). Myelosuppression and hospitalizations for neutropenic fever were common, but prolonged myelosuppression (> 42 days) was rare. In conclusion, CLO has activity in pts with higher-risk MDS. Optimal dose and schedule for PO and IV CLO remain to be defined. Lower doses of CLO are also associated with responses. Additional dose finding trials are underway to define the MTD and DLT of IV and PO CLO in high-risk MDS.

Results of an Exploratory Study of Oral (po) and Intravenous (iv) Clofarabine in Patients with Myelodysplastic Syndrome.

Clofarabine (CLO) is an adenosine nucleoside analog with activity in adult acute myeloid leukemia (AML). Its activity in MDS is less well defined. To evaluate the activity and safety of CLO in MDS we designed two phase II studies with iv CLO and po CLO, respectively. Pts were eligible if they had MDS with ≥ 5% blasts, fell into IPSS intermediate-2 and high-risk groups, or had CMML. No prior intensive chemotherapy or high-dose cytarabine was allowed. Hematopoietic growth factor support was permitted. In the iv study pts were adaptively randomized to receive CLO 15 or 30 mg/m2 iv daily x 5 every 4–6 weeks. The second study used a starting dose of CLO 40 mg/m2 orally daily x 5 every 4–6 weeks (assuming oral bioavailability about 50%), which was then decreased to 30 mg/m2 orally daily x 5. Thirty pts (18 RAEB, 6 RAEB-T, 6 CMML) have been treated. Assignment by IPSS for RAEB and RAEB-T pts: 10 high-risk, 10 intermediate-2, and 4 intermediate-1. Fifteen pts received iv CLO and 15 po CLO. Median age was 68 yrs (range 57–86). Median number of prior therapies was 1 (0–4). Twenty (67%) pts received prior decitabine or azacitidine. Karyotype was abnormal in 24 (80%) pts, including 10 pts with −5/−7 abnormalities. Responses were determined according to International Working Group criteria (IWG). Twenty-seven pts were evaluable for response (2 pts too early, one refused further treatment on day 4 of first course). Eleven (41%) pts responded [7 (26%) CR, 2 (7%) HI, 2 (7%) clinical benefit (CB)] (see table).Response (%)RouteDose (mg/m2)NCRHICBpo406--1 (17)3061(17)2 (33)1 (17)iv3062 (33)--1594 (44)--Response by IPSS: 67% intermediate-1, 44% intermediate-2, 40% high. Twenty-seven pts are evaluable for toxicities. Grade ≥ 3 toxicities occurred in 8 of 13 pts on iv CLO (rash, hyperbilirubinemia, elevated transaminases, elevations of creatinine, acute renal failure) and 4 of 14 pts with po CLO (rash, hyperbilirubinemia, elevated transaminases). Myelosuppression resulting in febrile episodes and hospitalizations with both iv and po CLO was ubiquitous, but prolonged myelosuppression (> 42 days) was rare. In summary, CLO has activity in pts with higher-risk MDS. The optimal dose and schedule for po and iv CLO have not been defined yet. Lower doses of CLO are associated with responses. Correlative PK studies may help to provide further support for optimal dose and route of administration of CLO in pts with MDS.

Phase II Study of Clofarabine and Cytosine Arabinoside in Adult Patients with Relapsed AML and in Elderly Patients with Untreated AML Who Are at High Risk of Anthracycline Toxicity.

PURPOSE: To evaluate the efficacy and safety of clofarabine, a novel deoxyadenosine analog, in adult patients with refractory or relapsed acute myeloid leukemia and in selected elderly patients with untreated AML and heart disease.PATIENTS AND METHODS: In a phase II, open-label trial, 23 patients with de-novo AML, AML evolved from MDS or relapsed AML received a 5 day regimen consisting of clofarabine 40 mg/m2 intravenously over 1 hour followed within 4 hours by Ara-C 1000 mg/m2. The median age was 68 years (range 39–79 years). Fifteen (65%) had received at least one prior cytotoxic regimen (excluding 5-AZA). Significant cardiovascular disease (history of myocardial infarction, bypass grafting, cardiomyopathy) was present in 52% (12/23) prior to therapy.RESULTS: 22/23 received at least one cycle of therapy and 5 received 2 cycles. One early death was due to disease progression. Grade 4 neutropenia developed in all patients. There were no cases of regimen-related cardiac toxicity. Most patients had some degree of edema and third-spacing syndrome. Several developed a significant but reversible acral rash. 20 patients are evaluable for response. The histologic response rate (defined as marrow blasts <5%) is 60% (12/20) consisting of 10 (50%) complete remissions and 2 (10%) partial responses. Complete cytogenetic remissions occurred in 9 patients. Durable remissions and low toxicity allowed some patients to proceed to nonablative allogeneic stem cell transplantation.CONCLUSION: Clofarabine (40mg/m2) and Ara-C (1000mg/m2) x 5 days is an active and well tolerated regimen in myeloid malignancies including “elderly AML”—a distinct entity usually associated with poor response rate and high treatment-related toxicities. Other drug combinations with clofarabine are being explored for use in allogeneic transplant regimens and with other high-risk patient groups.

Phase II Study of Clofarabine in Pediatric Patients With Refractory or Relapsed Acute Lymphoblastic Leukemia

To evaluate the efficacy and safety of clofarabine, a novel deoxyadenosine analog, in pediatric patients with refractory or relapsed acute lymphoblastic leukemia (ALL). In a phase II, open-label, multicenter study, 61 pediatric patients with refractory or relapsed ALL received clofarabine 52 mg/m2 intravenously over 2 hours daily for 5 days, every 2 to 6 weeks. The median age was 12 years (range, 1 to 20 years), and the median number of prior regimens was three (range, two to six regimens). The response rate was 30%, consisting of seven complete remissions (CR), five CRs without platelet recovery (CRp), and six partial remissions. Remissions were durable enough to allow patients to proceed to hematopoietic stem-cell transplantation (HSCT) after clofarabine. Median CR duration in patients who did not receive HSCT was 6 weeks, with four patients maintaining CR or CRp for 8 weeks or more (8+, 12, 37+, and 48 weeks) on clofarabine therapy alone. The most common adverse events of grade > or = 3 were febrile neutropenia, anorexia, hypotension, and nausea. Clofarabine is active as a single agent in pediatric patients with multiple relapsed or refractory ALL. The toxicity profile is as expected in this heavily pretreated patient population. Studies exploring rational combinations of clofarabine with other agents are ongoing in an effort to maximize clinical benefit.

Clofarabine Plus Cytarabine (ARA-C) Combination Is Active in Newly Diagnosed Patients (PTS) ≥ Age 50 with Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS).

Clofarabine is a next-generation deoxynucleoside analog with activity in acute leukemias. As clofarabine effectively inhibits ribonucleotide reductase, it is also suited for biochemical modulation strategies with other nucleoside analogs. In a previous study of clofarabine plus ara-C in pts with relapsed/refractory AML/MDS, we reported a CR rate of 24% (41% OR) (Blood 102:615a, 2003). Cellular pharmacology studies suggested that accumulation of intracellular clofarabine triphosphate resulted in higher ara-CTP accumulation of the leukemia blasts. We conducted a phase II study to investigate the efficacy and safety of clofarabine plus ara-C in pts ≥ 50 yrs with newly diagnosed AML and MDS (≥ 10% marrow blasts). Pts were excluded for ECOG PS > 2, age ≥ 75, and good prognosis karyotypes [t(8;21), inv(16), t(15;17)]. Clofarabine was given at 40mg/m2/d over 1-hour (hr) i.v. daily for 5 days (d2-6) followed 4 hrs later by ara-C at 1g/m2/d over 2-hrs i.v. daily for 5 days (d1-5). Sixty pts (53 AML, 7 RAEB-2 incl. 1 CMML-2) were enrolled and are evaluable. Median age: 61 yrs (range 50–74). Twenty-eight pts (47%) had secondary AML (17 AHD, 11 other malignancies) and 30 pts (50%) had abnormal cytogenetics (−5/−7 in 15, +8 in 10, del(11)(q23) in 3). 31 pts (52%) achieved CR; another 5 pts (8%) achieved CRp. Of 11 pts who received a second induction course, 4 pts (36%) responded (2 CR, 2 CRp). The CR rate was 60% (18/30 pts) in the diploid and 43% (13/30) in the abnormal karyotype group. Median time to CR: 29 days (20–98). 9 deaths (15%) occurred on study of which 4 pts (7%) died during the first course (d10 to d42). Adverse events included transient facial flushing and headaches (< gr. 3) during the infusion, and hyperbilirubinemia (gr. 3 in 3 pts), skin rashes, ↑ SGPT/SGOT, palmoplantar dyserysthesias, pancreatitis (1 pt) and renal failure (1 pt). Our data suggest that clofarabine + ara-C is active in older pts with newly diagnosed AML/high-risk MDS. The toxicity profile is acceptable. An update of time-to-event parameters will be presented.