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Clofarabine in pediatric AML
daunorubicin and high-dose cytarabine was well-tolerated in our cohort of patients. Most observed adverse events were as expected (febrile neutropenia and infections, gas- trointestinal symptoms, dermatological manifestations and pain). Our data on infections are comparable to the single agent study in pediatric relapsed AML (67% of patients experienced ≥grade 3 infections).13 The highest dose level, however, appeared not to be tolerable, again due to infectious complications. It might be that the high- er anthracycline dose of 80 mg/m2 DNX can be tolerated in newly diagnosed patients, but this was not assessed in our study. The RP2D of clofarabine (40 mg/m2) was higher compared to the CLOUD study (30 mg/m2/d for 5 days),25 but lower than clofarabine (52 mg/m2/d for 5 days) in combination with 1 gram/m2 of Ara-C without anthracy- clines.24
The ORR of 68% observed with this combination regi- men is extremely encouraging. In addition, this response rate is higher compared than the single-agent study13 and the CLOUD study,25 and is for instance also higher than in our prior study with single-agent Mylotarg.33 Patients with early 1st relapse (n=15) responded in 93%, whereas in the AML 2001/01 study only 70% (treated with FLAG-DNX) and 54% (treated with FLAG) responded, although a dif- ferent definition for response was used (≤ 20% blasts in BM after cycle 1).2 The number of responding patients (3 of 10) who were refractory to FLA-DNX chemotherapy given directly before clofarabine is also interesting, although it cannot be excluded that this was the effect of repeated chemotherapy. This was also observed in the AML 2001/01 study where 20% of patients responded after the second FLAG course who were not in CR after the first course.2 However, we have to consider that, in our cohort, we observed a low response rate among the refractory 1st relapse patients (CR 2 of 10, Cri 1 of 10).
Our response and survival data are in accordance with the data reported for the COG AAML0523 study.24 Of interest, 90% of the patients in this study (that combined cytarabine 1 g/m2 with clofarabine 52 mg/m2) were in 1st relapse, while the remaining 10% of patients had refracto- ry disease. The combination of cytarabine and clofarabine in the COG study resulted in an ORR of 48% in 48 evalu- able patients, and 21 of 23 responders underwent SCT. The overall survival rate at 3 years was 46% for respon-
ders.24 In our study, 10 of 34 patients were still alive at last follow up, with a 2-year pOS 32±8%. This was even high- er in responding patients: 2-year pOS 48±11%.
A phase III, randomized, double-blind, placebo-con- trolled trial was recently published in 320 adults over 55 years of age with relapsed/refractory AML, comparing cytarabine 1 g/m2 plus clofarabine 40 mg/m2 versus cytara- bine with placebo.27 This study showed significantly improved response rates and enhanced EFS in patients treated with clofarabine and cytarabine compared to placebo and cytarabine. However, no significant impact on survival was achieved, probably related to the higher incidence of mortality in the clofarabine arm.27 This is in line with the randomized study performed by Burnett et al.18 However, the recent study from Löwenberg et al.19 did show that intermediate risk AML patients in the clofara- bine arm benefitted compared to cytarabine in the stan- dard arm, including a survival benefit. Children can usual- ly tolerate higher dosages of chemotherapy, certainly when compared to elderly patients, and the dosages used in the adult studies were very low compared to the regi- men that we tested here. Better salvage regimens in relapsed pediatric AML, as summarized in various papers,34,35 including ours, have contributed to better sur- vival rates of patients with pediatric AML in the last decade, together with improved supportive care meas- ures.3
Allogeneic SCT is considered the standard treatment in relapsed pediatric AML in Europe after re-induction with salvage chemotherapy. In our study, 22 patients under- went SCT following the clofarabine combination regi- men. No particular toxicities (e.g. veno-occlusive disease) (data not shown) were noted during the SCT procedure, and pre-treatment with this chemotherapy combination did not preclude a successful SCT procedure.
Pharmacokinetic analysis showed no difference between data obtained with single agent clofarabine in prior studies versus clofarabine in combination in this study. Moreover, we demonstrated that cerebrospinal fluid (CSF) penetration was limited in CSF samples taken approximately 24 h after the last clofarabine infusion. To the best of our knowledge, this study is the first to study CSF penetration of clofarabine.
The results of this trial indicate high efficacy of the com-
Table 4. Response after cycle 1 by disease status and after prior treatment with FLA-DNX.
≥ 2nd relapse
All patients
All patients Pre-treated
Early 1st relapse Refractory 1st relapse
All patients n=34 n=18 n=15
Pre-treated All patients
Pre-treated n=11
10
(100%) 1 (10%) 2 (20%)
3 (30%)
3 (30%)
1 (10%)
All patients n=8
6
(100%) 4 (67%)
2 (33%)
Pre-treated n=7
5
(100%) 3 (60%)
2 (40%)
n=0
n=11
10
(100%) 1 (10%) 2 (20%)
3 (30%)
3 (30%)
1 (10%)
Morphological response
Evaluable CR
CRi
PR
31 15 15
(100%) (100%) (100%)
NEL 00
SD
PD
Treatment failure
6 (19%)
3 (10%)
1 (3%)
5 (33%)
3 (20%)
1 (7%)
5 (16%) 15 (48%) 1 (3%)
1 (7%) 5 (33%)
4 (27%) 9 (60%) 1 (7%)
1 (7%)
FLA: fludarabine, cytarabine (Ara-C); CR: complete remission; DNX: liposomal daunorubicin; n: number; CRi: morphological complete remission with incomplete blood count recovery; NEL: no evidence of leukemia; PR: partial response; SD: stable disease; PD: progressive disease.
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