Abstract
Clofarabine has shown activity and tolerability in older patients with acute myeloid leukemia (AML). We investigated the safety and tolerability of an oral formulation of clofarabine for consolidation therapy of patients aged 60 and older with AML. In this phase I study, twenty-two patients older than 60 years with AML in first complete remission were treated once daily with oral clofarabine for 14 or 21 days of a 28 day cycle, for up to 5 cycles. Dose escalation from 1 mg to 6 mg daily using a 3 + 3 design was used to determine dose-limiting toxicities (DLT), the maximum tolerated dose (MTD), and tolerability of oral clofarabine. No DLTs or Grade 3-4 nonhematologic toxicities were observed. The primary toxicities were hematologic, including uncomplicated grade 3-4 neutropenia (50%) and thrombocytopenia (50%). Given that myelosuppression necessitating dose delays/reductions was observed more commonly at higher doses, the recommended phase II dose is 2 mg daily for 21 of 28 days. At doses equal to or greater than 2 mg, the median relapse-free survival was 28.35 months. Oral clofarabine was well-tolerated with encouraging activity in patients older than 60 years. Further investigation of oral clofarabine as a consolidation and/or maintenance therapy in AML for older individuals is warranted. (ClinicalTrials.gov:NCT00727766).
INTRODUCTION
The prognosis of patients aged 60 and greater with acute myeloid leukemia (AML) is poor with traditional therapy. Several factors contribute to the poor outcomes observed in elderly patients, including a lower baseline performance status, an increased incidence of unfavorable cytogenetics, the presence of antecedent hematologic disorders, and increased incidence of the multidrug resistance (MDR) phenotype (1-4). However, older age remains an independent poor prognostic indicator (1-3, 5). For elderly patients deemed fit for induction therapy who achieve a complete remission (CR), there is no standard recommendation for post-remission therapy (2, 6). More intensive, cytarabine-based consolidation regimens in patients over 60 years old are characterized by high relapse rates and poor tolerability (6-8). Reduced-intensity conditioning allogeneic stem cell transplantation is an option for consolidation in older adults, although currently only utilized in a minority of patients who achieve a CR after standard induction (9). Prolonged, lower intensive therapies may be more tolerable in the elderly population but have shown varying degrees of efficacy. For example, when less intensive outpatient therapy combining cytarabine with an anthracycline was compared to a more intensive consolidation strategy for post-remission therapy, better outcomes for the less intensive, ambulatory arm were reported (10). Studies of post-remission, low intensity regimens with DNA hypomethylating agents demonstrate feasibility and tolerability, although relapse rates are high (11, 12). Low dose interleukin-2 immunotherapy as a post-remission strategy in elderly patients was not shown to improve outcomes (6, 13). Although post-remission combination histamine dihydrochloride and interleukin-2 therapy demonstrated improved leukemia-free survival in a trial for patients aged ≥ 18 years, this strategy has not been widely adopted (6, 14). Continued studies of less toxic, more effective consolidation strategies for the elderly population with AML are needed.
Clofarabine (2-chloro-2’-fluoro-deoxy-9-ß-D-arabinofuranosyladenine) is a nucleoside analog designed to optimize the favorable pharmacokinetic properties of fludarabine and cladribine while minimizing toxicity (15). Clofarabine is superior to fludarabine in inhibiting ribonucleotide reductase and superior to cladribine in the inhibition of DNA polymerase alpha (16). The IV formulation of clofarabine has shown acceptable tolerability and single-agent activity in older patients with AML (17-20). Clofarabine therapy in previously untreated elderly AML patients deemed unfit for intensive therapy resulted in a CR rate of 48%,(18) and in a study of patients over 60 with at least one unfavorable prognostic factor the overall response rate (CR + CRp) was 46% (17). Clofarabine has also demonstrated activity and tolerability in combination with cytarabine in frontline therapy for elderly patients with AML, with CR rates as high as ~60% (21-23). Substitution of a fluorine at the C-2’-position of its arabinofuranosyl moiety increases the stability of clofarabine in gastric acid and thus may lead to increased oral bioavailability as compared to other nucleoside analogs (24). Clofarabine administered by the oral route demonstrated anti-tumor activity in preclinical xenograft mouse models (25, 26). Furthermore, in preclinical mouse models, prolonged oral administration of clofarabine demonstrated increased anti-tumor effect compared to shorter duration IV administration. A recent report demonstrated tolerability and encouraging efficacy of oral clofarabine for the treatment of relapsed/refractory non-Hodgkin lymphoma (27).
We hypothesized that prolonged administration of low-dose oral clofarabine may improve disease control without excessive toxicity in elderly patients with AML. Thus, we designed a phase I trial to investigate extended dosing of the oral formulation of clofarabine for consolidation therapy in adults aged 60 years or greater. The objective of this phase I dose escalation study was to determine the maximum tolerated dose (MTD), dose limiting toxicities (DLT), and tolerability of oral clofarabine for consolidation therapy of AML in first complete remission after cytotoxic induction regimens.
METHODS
Patient Eligibility
Patients aged 60 years or older with a diagnosis of non-M3 AML according to WHO criteria in morphologic complete remission (CR) following intensive induction chemotherapy (such as anthracyclines plus cytarabine or cladribine plus cytarabine ± mitoxantrone) were eligible. Up to one cycle of consolidation therapy was permitted prior to enrollment. Other eligibility criteria included: Eastern Cooperative Oncology Group (ECOG) performance status of 0-2; adequate hepatic (serum total bilirubin ≤1.5X upper limit of normal [ULN], AST/ALT≤2.5 ULN, and alkaline phosphatase ≤2.5 ULN ) and renal function (creatinine ≤1.0 or estimated glomerular filtration rate (GFR) >60 mL/min/1.73 m2); absence of concomitant chemotherapy, radiation, or immunotherapy; absence of severe concurrent disease, organ dysfunction, or uncontrolled active infection; or absence of active gastrointestinal disease that may affect the ability to absorb oral clofarabine. Treatment with “low-intensity” agents such as lenalidomide and decitabine were permitted prior to induction chemotherapy and prior therapy with purine analogs was permitted. All patients were required to provide written informed consent. The study protocol, registered at ClinicalTrials.gov, number: NCT00727766 was approved by the Human Research Protection Office at Washington University.
Study Design and Treatment Plan
This was a single institution, phase I, open label, dose escalation study. The primary objective was to define dose limiting toxicities (DLT) and maximal tolerated dose (MTD) of oral clofarabine for consolidation therapy in elderly patients in remission. Six cohorts were tested (1mg X 14 days; and 1 mg, 2mg, 3mg, 4mg, and 6mg X 21 days of a 28 day cycle) with clofarabine administered orally once daily. Patients could receive up to five cycles in the absence of disease progression or unacceptable toxicity. The absolute neutrophil count (ANC) was required to be ≥ 1000 /mm3 and platelets ≥75,000 /mm3 prior to initiation of each cycle without growth factor or transfusional support. During treatment, CBCs and serum chemistries were collected weekly during the first 4 cycles. Transfusions and prophylactic antibiotics were administered according to institutional standards. Growth factors were not administered routinely to patients during the study.
DLT and Dose Escalation Rules, and Dose Reductions
The dose escalation phase was conducted with a 3 +3 design. The MTD was to be defined at the dose level at which ≤ 1 of 6 patients experienced a DLT. Patients who did not receive all cycle 1 doses and did not experience a DLT, were considered unevaluable and replaced. A DLT was defined as one the following adverse events that was considered at least possibly related to clofarabine treatment occurring during the first cycle of treatment: Grade 4 neutropenia for ≥ 14 days or grade 3-4 neutropenia with infection; Grade 4 thrombocytopenia for ≥ 7 days or grade 3-4 thrombocytopenia with bleeding; or any Grade 3-4 non-hematologic event with the exception of drug-related fever, anorexia, or adequately treated nausea, vomiting, or diarrhea. All toxicities were graded according to the National Cancer Institute Common Terminology Criteria version 3.0. Any cycle could be delayed for up to 28 days for grade 2 creatinine or bilirubin elevation, ≥ grade 3 non-hematologic toxicity other than skin rash, grade 4 skin rash, or to allow platelet and neutrophil count recovery (to ANC ≥ 1000/ mm3 and platelets ≥ 75,000/ mm3). After the DLT observation period, dose reductions by one dose level were allowed. Only one dose reduction was permitted except for the 6 mg cohort, where two dose reductions were permitted. Clofarabine treatment was discontinued for toxicity requiring cycle delays greater than 28 days or more than the permitted number of dose reductions. The 3 mg and 4 mg cohorts were expanded to 6 patients each to better evaluate toxicities of cumulative cycles.
Statistical Methods
The demographics, clinical characteristics, and toxicities were summarized using descriptive statistics. Overall survival (OS) and relapse-free survival (RFS) were defined as the time lapse between the date of the first dose of clofarabine to the date of death (for OS) or documented relapse (for RFS), or the most recent follow-up date. The Kaplan-Meier (KM) product limit method was used to generate the empirical survival probability. The KM curve was plotted and median survival time and survival probabilities accompanied with 95% CI were reported.
RESULTS
Patient Characteristics
Twenty-five patients enrolled on study, and 22 completed at least one cycle of clofarabine and were considered evaluable for response. Three enrolled patients did not complete cycle 1 secondary to disease relapse. Characteristics of the 22 treated patients are shown in Table I. The median age was 67, with the majority of patients between 65-69 years old (54.4%), and male (68.2%). Baseline cytogenetic findings are detailed in Table I. Overall, the majority of patients had a normal karyotype (68.2%); of these, most patients had the wild-type NPM gene without the presence of the FLT3 gene internal tandem duplication (ITD) (46.7%). Six patients (27.3%) had AML with MDS-related changes and 2 patients (9.1%) had therapy-related AML.
Table I.
Baseline patient demographic and clinical characteristics
| Patients (n=22) | ||
|---|---|---|
| Characteristic | No. | % |
| Age | ||
| Median | 67 | |
| Range | 60-76 | |
| 60-64 | 5 | 22.7 |
| 65-69 | 12 | 54.4 |
| >=70 | 5 | 22.7 |
| ECOG | ||
| 0 | 8 | 36.4 |
| 1 | 8 | 36.4 |
| 2 | 6 | 27.3 |
| Induction Regimen | ||
| 7+3 | 18 | 81.8 |
| Other1 | 4 | 18.2 |
| Received 1 cycle HiDAC | ||
| Yes | 8 | 36.4 |
| No | 14 | 63.6 |
| AML type | ||
| De novo | 14 | 63.6 |
| AML with MDS-related changes2 | 6 | 27.3 |
| Therapy-related | 2 | 9.1 |
| Cytogenetics | ||
| Normal karyotype | 15 | 68.2 |
| +8 | 1 | 4.5 |
| Inv (16)(p13.1q22) | 1 | 4.5 |
| Complex | 1 | 4.5 |
| Other3 | 3 | 13.6 |
| Not available | 1 | 4.5 |
| Patients (n=15) | ||
|---|---|---|
| No. | % | |
| Molecular Genetics4 | ||
| Mutated NPM and FLT3-ITD | 2 | 13.3 |
| Wild-type NPM and FLT3-ITD | 2 | 13.3 |
| Wild-type NPM without FLT3-ITD | 7 | 46.7 |
| Not available | 4 | 26.7 |
Abbreviations:ECOG, Eastern Oncology Cooperative Group; HiDAC, High-dose cytarabine; AML, acute myeloid leukemia; MDS, Myelodysplastic syndrome; ITD, internal tandem duplication
CLAM (cladribine, cytarabine, mitoxantrone, filgrastim), n=3; CLAG (cladribine, cytarabine, filgrastim), n=1
includes previous history of MDS, and /or AML with multilineage dysplasia
Cytogenetics were as follows: t (7;11)(p15;15) (n=1); trisomy 13 (n=1); 46 XY, add(13p11.2)(n=1)
In patients with normal cytogenetics. CEBPA was not available.
DLTs and MTDs
The dose escalation and number of patients treated at each dose is shown (Table II). No DLTs occurred in this trial. However, enrollment in the 6 mg dose cohort was halted after the first patient required two dose reductions for persistent cytopenias. Thus, although a MTD remains undefined, the 6 mg dose was felt to be excessively myelosuppressive when administered for multiple cycles. Additional patients were added in the 3 mg and 4 mg dose cohorts to better evaluate myelosuppression and tolerability at these doses.
Table II.
Summary of treatment administration
| Dose and Schedule | Median No. Cycles | Range of Cycles | Patients Requiring Dose Reductions | Patients With Delayed Count Recovery1 |
|---|---|---|---|---|
| 1 mg × 14 days | 3 | 1-5 | 0/3 | 0/3 |
| 1 mg × 21 days | 5 | 2-5 | 0/3 | 0/3 |
| 2 mg × 21 days | 5 | 1-5 | 0/3 | 0/3 |
| 3 mg × 21 days | 4 | 1-5 | 1/6 | 2/6 |
| 4 mg × 21 days | 3 | 2-5 | 2/6 | 1/6 |
| 6 mg × 21 days | 4 | 4 | 1/1 | 0/1 |
Attributable to clofarabine. Delayed count recovery defined as > 28 days of absolute neutrophil count <1000/mm3, or platelets <75,000/mm3, which required drug discontinuation.
Safety and Tolerability
The 1 mg and 2 mg cohorts were well-tolerated and did not require dose reductions or clofarabine discontinuation for drug toxicity (Tables II-III). In the 3 mg cohort, 1 of 6 patients required dose reduction for hematologic toxicity and 2 patients had prolonged cytopenias (defined as >28 days with an absolute neutrophil count [ANC] <1000/mm3 or platelets <75,000 /mm3) requiring drug discontinuation (Table II). The median number of cycles completed in the 3 mg cohort was 4 (range 1-5). In the 4 mg cohort, 2 patients required dose reductions for hematologic toxicity and one patient had prolonged cytopenias requiring drug discontinuation. The median number of cycles completed at the 4 mg dose was 3 (range 2-5) (Table II). Overall, 15 patients completed ≥ 3 cycles and of these, 9 patients completed all 5 planned cycles. In total, the median number of cycles completed was 3.5. For the 13 patients who did not complete the 5 planned cycles, the following reasons were cited: relapsed disease (n=6); hematologic toxicity (n=3); allogeneic stem cell transplant at the discretion of the treating physician (n=2), and patient choice (n=2).
Table III.
Patients with Grade 1-2 drug-related toxicity occurring in at least 10% of patients overall (N=22)
| 1 mg × 21 d (n=3) | 1 mg × 21 d (n=3) | 2 mg × 21 d (n=3) | 3 mg × 21 d (n=6) | 4 mg × 21 d (n=6) | 6 mg × 21 d (n=1) | Total (N=22) | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| No. | % | No. | % | No. | % | No. | % | No. | % | No. | % | No. | % | |
| Hematological | ||||||||||||||
| Hemoglobin | 1 | 33.3 | 0 | 0 | 1 | 33.3 | 1 | 16.7 | 1 | 16.7 | 1 | 100 | 5 | 22.7 |
| Leukocytes (WBC) | 1 | 33.3 | 2 | 66.7 | 2 | 66.7 | 0 | 0 | 2 | 33.3 | 0 | 0 | 7 | 31.8 |
| Lymphopenia | 2 | 66.7 | 1 | 33.3 | 0 | 0 | 1 | 16.7 | 0 | 0 | 0 | 0 | 4 | 18.2 |
| Neutrophils (ANC) | 0 | 0.0 | 1 | 33.3 | 2 | 66.7 | 1 | 16.7 | 1 | 16.7 | 0 | 0 | 5 | 22.7 |
| Platelets | 1 | 33.3 | 3 | 100 | 1 | 33.3 | 1 | 16.7 | 2 | 33.3 | 0 | 0 | 8 | 36.4 |
| Constitutional | ||||||||||||||
| Fatigue | 0 | 0 | 1 | 33.3 | 1 | 33.3 | 5 | 83.3 | 3 | 50 | 0 | 0 | 10 | 45.5 |
| Gastrointestinal | ||||||||||||||
| Anorexia | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 16.7 | 2 | 33.3 | 0 | 0 | 3 | 13.6 |
| Constipation | 0 | 0 | 0 | 0 | 1 | 33.3 | 0 | 0 | 3 | 50 | 0 | 0 | 4 | 18.2 |
| Diarrhea | 1 | 33.3 | 1 | 33.3 | 1 | 33.3 | 0 | 0 | 3 | 50 | 0 | 0 | 6 | 27.3 |
| Nausea | 1 | 33.3 | 1 | 33.3 | 1 | 33.3 | 3 | 50 | 3 | 50 | 1 | 100 | 10 | 45.5 |
| Vomiting | 1 | 33.3 | 0 | 0 | 0 | 0 | 1 | 16.7 | 2 | 33.3 | 0 | 0 | 4 | 18.2 |
| Metabolic/Laboratory | ||||||||||||||
| Hypoalbuminemia | 0 | 0 | 0 | 0 | 1 | 33.3 | 0 | 0 | 3 | 50 | 1 | 100 | 5 | 22.7 |
| Elevated Alkaline Phosphatase | 1 | 33.3 | 0 | 0 | 2 | 66.7 | 0 | 0 | 1 | 16.7 | 0 | 0 | 4 | 18.2 |
| Hypobilirubinemia | 0 | 0 | 0 | 0 | 1 | 33.3 | 0 | 0 | 2 | 33.3 | 1 | 100 | 4 | 18.2 |
| Hypocalcemia | 0 | 0 | 1 | 33.3 | 2 | 66.7 | 0 | 0 | 0 | 0 | 0 | 0 | 3 | 13.6 |
| Hyperkalemia | 0 | 0 | 0 | 0 | 2 | 66.7 | 0 | 0 | 1 | 16.7 | 0 | 0 | 3 | 13.6 |
| Elevated SGOT (AST) | 0 | 0 | 1 | 33.3 | 2 | 66.7 | 1 | 16.7 | 1 | 16.7 | 0 | 0 | 5 | 22.7 |
| Elevated SGPT (ALT) | 0 | 0 | 1 | 33.3 | 1 | 33.3 | 1 | 16.7 | 1 | 16.7 | 0 | 0 | 4 | 18.2 |
| Hyponatremia | 1 | 33.3 | 0 | 0 | 0 | 0 | 1 | 16.7 | 1 | 16.7 | 0 | 0 | 3 | 13.6 |
| Neurological | ||||||||||||||
| Dizziness | 0 | 0 | 1 | 0 | 0 | 1 | 16.7 | 2 | 33.3 | 0 | 0 | 4 | 18.2 | |
| Pain | ||||||||||||||
| Abdominal | 0 | 0 | 0 | 0 | 0 | 1 | 16.7 | 2 | 33.3 | 0 | 0 | 3 | 13.6 | |
Note: Toxicity was graded using the National Cancer Institute Common Terminology Criteria, version 3.0. Toxicities occurring multiple times in the same patient were coded once at the highest grade.
Overall, oral clofarabine was well-tolerated with adverse events most commonly related to hematologic toxicity. Related adverse events are shown in Tables III and IV by dose level. The most common (>30%) non-hematologic drug-related adverse effects were grade 1-2 fatigue (45.5%) and nausea (45.5%). No grade 3-4 drug-related non-hematologic toxicities occurred. Hematologic grade 3-4 toxicities increased with the dose of clofarabine, as expected (Table IV). Although at least one patient in each dose level experienced grade 3-4 neutropenia and/or thrombocytopenia, neither bleeding nor infection was a significant complication of treatment, even at doses ≥ 3 mg/day , where 50-100% of patients experienced at least one incident of grade 3-4 neutropenia and 66.7-100% patients experienced at least one incident of grade 3-4 thrombocytopenia. Only one incident of grade 2 infection (Clostridium difficile colitis) associated with normal or Grade1 or 2 neutrophils was thought to be possibly related to treatment, and occurred in a patient treated at the 2 mg/day dose. No deaths occurred during the first 30 days of starting clofarabine therapy. Given that Grade 3-4 myelosuppression occurred in the majority of patients receiving ≥ 3 mg/day (Table IV), and that dose reductions and/or delayed count recovery requiring drug discontinuation occurred in 50% of the 3 mg and 4 mg dosing cohorts (Table II), the optimal dose of clofarabine was identified as 2 mg/day for 21 days of a 28 day cycle.
Table IV.
Drug-related Grade 3-4 toxicity by dosing schedule
| 1 mg × 14 d (n=3) | 1 mg × 21 d (n=3) | 2 mg × 21 d (n=3) | 3 mg × 21 d (n=6) | 4 mg × 21 d (n=6) | 6 mg × 21 d (n=1) | Total (n=22) | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| No. | % | No. | % | No. | % | No. | % | No. | % | No. | % | No. | % | |
| Hematological | ||||||||||||||
| Hemoglobin | 0 | 0 | 0 | 0 | 0 | 0 | 3 | 50 | 5 | 83.3 | 0 | 0 | 8 | 36.36 |
| Leukocytes (WBC) | 0 | 0 | 0 | 0 | 0 | 0 | 5 | 83.3 | 4 | 66.6 | 1 | 100 | 10 | 45.45 |
| Lymphopenia | 0 | 0 | 1 | 33.3 | 2 | 66.7 | 2 | 33.3 | 6 | 100 | 1 | 100 | 12 | 54.55 |
| Neutrophils (ANC) | 1 | 33.3 | 1 | 33.3 | 0 | 0 | 5 | 83.3 | 3 | 50 | 1 | 100 | 11 | 50 |
| Platelets | 0 | 0 | 0 | 0 | 1 | 33.3 | 5 | 83.3 | 4 | 66.7 | 1 | 100 | 11 | 50 |
Survival
Relapse-free and overall survival was measured from the date of the first dose of clofarabine. As we found the dose of 2 mg daily to be well-tolerated, response data was evaluated for the entire study cohort (n=22, receiving any dose of clofarabine), and for those subjects receiving ≥ 2 mg daily. Overall, the median relapse-free survival (RFS) for the entire study cohort was 28.4 months (95% confidence interval [CI] [6.54 months, not reached]). Similarly, for patients receiving ≥ 2 mg, median RFS was 28.4 months [95% CI (6.5 months, not reached)] (Figure 1A). The median overall survival (OS) for the entire cohort was 35.9 months (95% CI [14.3 months, not reached]) with a median follow-up time of 13.3 months (range, 1.2-39 months). The median OS survival for patients receiving ≥ 2 mg was not attained (95% CI [14.3 months, not reached]), with a median follow-up time of 13.3 months (range, 1.2-31 months) (Figure 1B). Four patients, all of them receiving ≥ 3 mg of clofarabine, received an allogeneic stem cell transplant at the discretion of the treating physician. There were long-term survivors among the patients who were not transplanted (n=18), with a median RFS of 13.31 months (95% CI [2.8 months, not reached]) and a median OS of 35.9 months (95% CI [9.7 months, not reached]) (Figure 1C). It should be noted that the majority of patients in the study (19 patients, or 86.3%) would be categorized as being in the intermediate-I or –II risk groups based on available cytogenetic and molecular information (2) (Table I). In addition, 7 of 19 intermediate risk patients had therapy-related AML or AML with myelodysplasia-related changes. Finally, up to one cycle of high-dose cytarabine consolidation was permitted prior to enrollment (Table I). As expected, neither OS nor RFS were significantly different between the group treated with one cycle of cytarabine consolidation (n=8) versus the group that was not (n=14) (p=0.29 and p=0.76, respectively).
Figure 1.
Kaplan Meier analysis of (A) relapse-free survival and (B) overall survival for patients receiving ≥ 2 mg of clofarabine. The median relapse-free survival was 28.4 months (95% CI [6.5 months, not reached]) and the median overall survival was not attained (95% CI [14.3 months, not reached]), with a median follow-up time of 13.3 months. (C) Kaplan Meier analysis of overall survival for patients who did not receive an allogeneic stem cell transplant (n=18). The median OS was 35.9 months (95% CI [9.7 months, not reached]). The dashed line represents the 95% confidence intervals.
DISCUSSION
Current options for therapy for elderly patients with AML who achieve remission are limited by poor tolerability and/or high relapse rates, and as such, no definitive post-remission recommendations exist. We report the results of a phase I study of the oral formulation of clofarabine as post-remission consolidation therapy for elderly patients with AML. This is one of the first studies of oral clofarabine evaluating mainly AML patients. We find the dose of 2 mg daily for 21 days of a 28 day cycle to be well-tolerated. The primary toxicities were hematologic, but incidences of grade 3-4 neutropenia and thrombocytopenia were uncomplicated by infection or bleeding, and the administration of low doses of oral clofarabine evaluated thus far appears tolerable and feasible in the outpatient setting. However, this was a Phase I study with 3-6 patients per dose level, and safety and tolerability of oral clofarabine as an outpatient consolidation/maintenance regimen will need to be monitored in further trials.
This study of oral clofarabine supports previous observations that a less intensive post-remission regimen is feasible in the elderly population, with toxicity profiles as well as preliminary evidence of activity, that compare favorably to prior lower intensity regimens studies (10-13). Furthermore, standard intensive post-remission, cytarabine-based consolidation in patients older than 60 are plagued by short remission durations (9 months (7), with a four year disease-free probability of 16% (8)) and toxicity, with patients often unable to tolerate more than 1 course (8). A recent post hoc analysis of older patients with AML treated with clofarabine induction followed by post-remission IV clofarabine consolidation (20 mg/m2 IV days 1-5 of a 28 day cycle, with up to 5 cycles) demonstrated the feasibility of administering this consolidation regimen in the outpatient setting, although the most common adverse events included nausea, vomiting, diarrhea, febrile neutropenia, edema, hypokalemia, and pneumonia (17, 20, 28). While hematologic toxicity was frequent in the oral clofarabine regimen reported here, there were no episodes of febrile neutropenia and a low incidence of infection observed. Our toxicity data are similar to those reported recently in a phase I trial of oral clofarabine for relapsed/refractory non- Hodgkin lymphoma, with frequent grade 3-4 neutropenia (53%) and thrombocytopenia (27%), but low rates of neutropenic fever (3%), grade 3-4 infection (10%), and other ≥ grade 3 adverse events (27). Furthermore, oral clofarabine was associated with encouraging activity, as the median relapse-free survival was 28.35 months and the median overall survival was not attained with a median follow-up time of 13.3 months, at doses of clofarabine of 2 mg daily or higher. However, the majority of patients in this study fell into an intermediate cytogenetic risk group, and four patients received allogeneic stem cell transplants. The relative lack of patients with adverse risk cytogenetics, and transplantation of a subset of patients likely contributed to the encouraging outcome data we observed. Additional studies with a larger number of patients are needed to further assess efficacy.
Evidence suggests that elderly patients achieving a CR after intensive induction therapy have limited long-term survival in the absence of an allogeneic stem cell transplant (reviewed in (29)). However, allogeneic stem cell transplants are currently only utilized for a minority of older patients who achieve a CR after standard induction (9). Improving the tolerability of post-CR consolidation therapies to preserve patient performance status may make allogeneic stem cell transplantation feasible for a larger number of elderly patients. The toxicity profile of oral clofarabine for post-remission consolidation demonstrated thus far suggests its feasibility as a strategy to bridge to allogeneic stem cell transplantation, which could be explored in future studies. In this study, four patients did receive allogeneic stem cell transplantation post-clofarabine consolidation, underscoring the potential usefulness of this approach.
In summary, this phase I trial, the first study of oral clofarabine for AML, demonstrates that oral clofarabine at a dose of 2 mg daily for 21 days of a 28 day cycle was well-tolerated and further supports the feasibility of less intensive, more tolerable regimens for post-remission therapy in elderly AML. Phase II clinical trials to further evaluate the efficacy of oral clofarabine for post-remission regimens for elderly patients with AML are warranted.
ACKNOWLEDGEMENTS
Clofarabine and funding for the trial were provided by Genzyme. The authors thank the Alvin J. Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital for the use of core facilities which are supported in part by National Cancer Institute (NCI) Cancer Center Support grant P30 CA91842. Research reported in this publication was supported by the Washington University Institute of Clinical and Translational Sciences grant UL1 TR000448 from the National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health (NIH). The content is solely the responsibility of the authors and does not necessarily represent the official view of the NIH. MAJ was supported by NIH grants T32-HL007088 and K12 HL087107.
Footnotes
Trial registration: ClinicalTrials.gov identifier: NCT00727766
AUTHORSHIP
CNA was the principal investigator and takes primary responsibility for the paper; MAJ, MGM, CNA designed research; MAJ and CNA analyzed research; CNA, GLU, PW, JFD, AC, KSG, and RV recruited the patients, TR and NB coordinated the research; RL participated in the statistical analysis; MAJ and CNA wrote the paper; all authors reviewed the manuscript, provided critical feedback, and reviewed and approved the final version for submission. Conflict-of-interest disclosure: CNA is on the advisory boards of Alexion, Ariad, and Novartis, and the speakers bureau of Teva Pharmaceuticals.
DISCLOSURES
The remaining authors declare no competing financial interests.
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