[P0673] CLOFARABINE AS A SALVAGE THERAPY AND A BRIDGE TO
TRANSPLANTATION IN PATIENTS WITH HIGH RISK ACUTE LEUKEMIA AND
RELEVANT COMORBIDITY. A SINGLE CENTRE EXPERICENCE
S Imbergamo1, G Binotto2, C Gurrieri2, T Berno2, F Piazza2, M Ermani2, R Zambello2, G
Semenzato2. 1University of Padua, Padova, Italy; 2University of Padua, Padua, Italy
Backgroud. Acute myeloid leukemia (AML) is an aggressive hematological malignancy and the
outcome of patients with relapsed/refractory disease still remains unsatisfactory. Clofarabine is a
second generation nucleoside analog with efficacy in acute leukemia. Combination therapies of
Clofarabine either with cytarabine arabinoside (ARA-C) in AML or with cyclophosfamide in
acute lymphoblastic leukemia (ALL) are feasible and effective as induction therapy or salvage
treatment. Aims. To determine the efficacy and safety of clofarabine as a salvage therapy and as a
bridge to transplantation in frail patients with unfavourable cytogenetics relapsed/refractory
acute leukemia. Methods. A retrospective analysis was conducted on 21 patients with acute
leukemias treated in our Department. The diagnosis was made according to 2008 WHO criteria.
Median age at diagnosis was 52 years (range 19-76); 12 (57%) patients with relapsed and 9
(43%) with refractory acute leukemias; AML (n: 19)/ALL (n: 2); patients were treated with a
median of 2 prior regimens (range 1-5). Fifteen patients (71.4%) were considered at high, one
intermediate and five (23.8%) low cytogenetic risk. Eighteen patients (86%) had significant
comorbidity (48% had high risk Charlson score index). AML patients received salvage therapy
with ARA-C 1 g/m2 for 5 day and Clofarabine, 40 mg/m2 for 5 days, from day 2 to day 6,
whereas in ALL patients Clofarabine was combined with Cyclophosfamide 400 mg/m2, given for
5 days. Results. Seven patients (33%) achieved complete remission (CR); among these, 3 (14%)
were classified as high risk cytogenetic at the start of therapy. The median DFS was 110.5±179
days (median: 30; range: 3 - 740), while the EFS was 36.8±39.8 (median: 21; range: 3-150).
Neither the DFS nor EFS were significantly associated to cytogenetic risk profile (p=0.96 e
p=0.33, respectively). The DFS was correlated with EFS (Rho=0.61, p=0.003). Eight patients
(38%), three in complete remission and three with persistence of disease, underwent
transplantation. Two cases relapsed after allogeneic bone marrow transplantation (allo-BMT)
and were treated with clofarabine as salvage therapy; the median survival from the beginning of
therapy was 100 days (95% CI: 35-165). The median survival was significantly correlated with
transplantation (log rank, p=0.03), resulting 157 days (95% CI: 86-228) in transplanted patients
versus 58 days (95% CI: 0-134) in non transplanted patients. Side effects with clofarabine
included nausea (49%), transient liver dysfunction (71%), skin rashes (43%), mucositis (31%).
Patients were treated with antibiotic prophylaxis with fluoroquinolones. We documented 13
(61%) febrile neutropenia, 8 (38%) septic shock, 5 (23%) cardiac abnormalities (3 atrial
fibrillation and 2 heart failure). Conclusion. Clofarabine in combination with ARA-C or
Cyclophosphamide represents a promising combination in the treatment of acute leukemias both
as a salvage therapy to induce remission and as a bridge to transplant.
[P1222] CLOFARABINE IN COMBINATION WITH CYTARABINE (ARA-C) FOR
TREATMENT OF RELAPSED/REFRACTORY ACUTE MYELOID LEUKEMIA IN
ADULT PATIENTS
A Malato1, A Santoro1, S Magrin1, R Felice1, D Turri1, R Di Bella1, D Salemi1, F Acquaviva1,
R Scimè1, F Fabbiano1. 1Ospedali Riuniti Villa Sofia-Cervello, U.O. di Ematologia e UTMO,
Palermo, Italy
Introduction. Relapsed/refractory AML patients have a poor prognosis, with CR rates of 1%30%, unless allogeneic hematopoietic stem cell transplantation (HSCT) is an available option.
Although retrospective modeling studies have demonstrated the prognostic value of selected
parameters, responses with salvage therapies remain still poor. 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). However, modifications of
this combination in AML therapy of relapsed/refractory patients warrant further evaluation. Aim.
To determine the efficacy and safety of clofarabine and cytarabine (Ara-C) in adult patients with
relapsed or refractory acute myeloid leukemia (AML). Methods. Patients aged 35-66 years with
refractory/relapsed AML were treated at the dose of clofarabine 30 mg/mq on days 1-5 +
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. Results. Seventeen patients received
clofarabine 30 mg/mq on days 1-5 + cytarabine 1000 mg/mq gg on days 1-5 (their characteristics
are summarized in Table 1), followed by gentuzumab therapy in only three patients. All patients
had relapsed/refractory myeloid leukemia and had received multiple priors tharapies. Two pts
had received a prior hematopoietic stem cell transplant (HSCT). Eight patients achieved a
morphologic complete remission (CR);fourpatients went on to receive allogeneic transplants
after clofarabine/ARA-C salvage. The complete remission rate (CRR) was 52,94%. The Median
of Overall survival for all patients was 59 days (range 23-769), while the media of Overall
survival (OS) was 158,41 days, and we estimated a duration of remission (DOR) as101,50 days
in median (range 3-785), and 260 days in media (we calculated from the first day of remission).
Treatment was complicated by neutropenic fever (n = 9), grade III-IV mucositis (n = 2), skin
rush (n = 2) grade II- III, hepatic transaminase elevations(n = 1). Two patient died of sepsis
during the induction. Conclusions. Combination treatment with clofarabine 30 mg/mq and ARAC 1000 mg/mq in adults pts with refractory or relapsed AML resulted in an ORR of 52,94 %, and
of the 8 patients who achieved a CR, four (50%) proceeded to HSCT (two are still alive and in
complete remission). 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.
[P0072] ORAL CLOFARABINE PLUS LOW-DOSE CYTARABINE IN PREVIOUSLY
TREATED AML AND HIGH-RISK MDS PATIENTS = 60 YEARS OF AGE
M Pagel1, R Sandhu2, T Gooley2, B Scott2, K Shannon-Dorcy3, C Dean2, R Appelbaum2, H
Estey2. 1Fred Hutchinson Cancer Research Center, Seattle, WA, United States of America;
2FHCRC, Seattle, WA, United States of America; 3FHCRC, Seattle, United States of America
Background. For many older patients with AML or high-risk MDS, the risks of standard
induction chemotherapy may outweigh the benefits. The combination of intravenous (IV)
clofarabine and cytarabine (ara-C) appears well tolerated and active in older or relapsed adults
with AML. A randomized trial in untreated patients age ≥60 suggested that IV clofarabine plus
low-dose ara-C (LDAC) was more effective than clofarabine alone. Oral clofarabine offers
advantages to older patients and a phase II trial in higher-risk MDS patients confirmed the drug's
activity, leading us to combine oral clofarabine with LDAC in a dose-escalation phase I/II study
for patients age ≥60 with relapsed/primary refractory AML or high-risk MDS. Aims. Our goals
were to estimate the maximum tolerated dose (MTD) and to assess complete remission (CR)
rates. Methods. Oral clofarabine was administered daily on days 1-5 together with once daily
subcutaneous (SQ) LDAC at 20 mgBID on days 1-10. Adults age ≥60 years with AML or highrisk MDS were eligible if they had primary refractory disease or failed one prior therapy and
disease recurred within 1 year of CR date and had ECOG performance status 0-2. Informed
consent was obtained from all patients. Results. Twenty-nine patients have been enrolled to date.
Median age was 72 (range, 62-82) years. Eight patients (28%) had secondary AML. The median
performance status was 1 (range, 0-2) and median time from diagnosis to trial entry was 12
(range, 2-67) days. Cytogenetics (SWOG criteria) were unfavorable in 13 patients (45%),
intermediate in 9 (31%), favorable in 1 (3%), and unknown in 6 (21%). The MTD of oral
clofarabine when given with LDAC was determined to be 20 mg and the dose-limiting toxicity
was cardiac dysfunction. Number of cycles given: 23 patients - 1 cycle, 4 patients - 2 cycles, 1
patient - 3 cycles, 1 patient - 4 cycles. Twenty-six patients were treated as outpatients and 14
patients were hospitalized during the course of treatment including 11 for fever. Seven patients
(24%) have achieved a CR. Based on previous MD Anderson data (Blood 1996; 88:756), the
expected CR rate with HiDAC, FLAG etc would be 15%. Three patients (10%) achieved CR
with incomplete blood count recovery and 1 (3%) a partial remission. Four of the 10 patients
who achieved CR or CRi have relapsed at a median of 4 months. The other 6 have been in
CR/CRi for a median of 3.5 months (range, 0-13.5 months). Fifteen patients (52%) died after
treatment, 10 due toAML. Conclusions. Oral clofarabine at 20 mg daily for 5 days plus LDAC
appears to be well tolerated and can generally be delivered in an outpatient setting. The CR rate
appears higher than expected. While accrual is on-going, these results warrant further study.
FOR TREATMENT OF RELAPSED/REFRACTORY ACUTE LYMPHOBLASTIC
LEUKEMIA IN ADULT PATIENTS
A Malato1, A Santoro1, R Felice1, D Turri1, S Magrin1, R Di Bella1, R Scimè1, D Salemi1, F
Acquaviva1, F Fabbiano1. 1Ospedali Riuniti Villa Sofia-Cervello, U.O. di Ematologia e
UTMO, Palermo, Italy
Introduction. Relapsed or refractory adult acute lymphoblastic leukemias (ALL) have poor
prognosis. The strategy for treating these patients is through reinduction chemotherapy followed
by allogeneic stem cell transplantation, provided that the toxicity of the salvage regimen is
acceptable. Clofarabine, a next-generation deoxyadenosine analog, has demonstrated significant
activity in children and adults with refractory lymphoid and myeloid leukemia in early clinical
trials and was granted approval for use in children with acute lymphoblastic leukemia in second
or higher relapse. Promising activity of clofarabine in combination with cyclophosphamide, with
DNA damage and apoptosis in both AML and ALL blasts, has been reported (Karp JE et al.
Blood 2007). Aim. We present a series of ten cases in which clofarabine was combined with
cyclophosphamidein adult patients with relapsed or refractory acute lymphoblastic leukemia.
Methods. Patients aged 23-59 years with refractory/relapsedALL were treated at the dose of
clofarabine 10mg/m2 + cyclophosphamide400g/m2 on days 1-3 and 8-10. We evaluated the
overall remission rate (ORR), duration of remission (DOR) and overall survival (OS). Minimal
residual disease (MRD) by molecular targeting was considered in all patients. Results. Nine
patients received clofarabine 10mg/m2 + cyclophosphamide400mg/m2, both on Days 1-5 and 810;one patient received only one cycle. All patients had relapsed/refractory lymphoblastic
leukemia and had received multiple priors tharapies. Eight had pre-B cell ALL, 2 pts had T cell
ALL; two pts had received a prior hematopoietic stem cell transplant (HSCT). Four patients
achieved a complete remission (CR);two patients went on to receive allogeneic transplants after
clofarabine/cyclophosphamide salvage. The median of Overal survival (OS) forall the patients
was 103 days, the media was 172,70days. The overall remission rate (ORR) was 44,4%, and we
estimated a duration of remission (DOR) as 223,25 days in media (we calculated from the first
day of remission). Treatment was complicated by neutropenic fever (n = 4), grade III-IV
mucositis (n = 3), prolonged aplasia >30 days (n = 3). One patient died of sepsis before
completing the regimen. Conclusion. Combination treatment with clofarabine and
cyclophosphamide in adults pts with refractory or relapsed ALL resulted inan ORR of 44%, two
ptsproceeded to HSCT. The safety profile is acceptable in this relapsed/refractory population.
The response rates and durability of remission observed with this regimen were encouraging
given that these patients were highly refractory to prior therapies. However, more studies with
this combination in adults are warranted.