12th Congress of the European Hematology ... - Haematologica

0364
CLINICAL EFFICACY OF OXALIPLATIN, FLUDARABINE, CYTARABINE, AND RITUXIMAB
COMBINATION THERAPY IN PATIENTS WITH RICHTERS SYNDROME OR
FLUDARABINE-REFRACTORY CHRONIC LYMPHOCYTIC LEUKEMIA:
RESULTS OF A PHASE I-II CLINICAL TRIAL
A.M. Tsimberidou, 1 W.G. Wierda, 1 W.W. Plunkett, 1 S. O'Brien, 1
T.J. Kipps, 2 J.R. Brown, 3 S. Lerner, 1 H.M. Kantarjian, 1 M.J. Keating1 1 U. T. M. D. Anderson Cancer Center, HOUSTON; 2 UCSD Moore's Cancer
Center, SAN DIEGO; 3 Dana-Farber Cancer Institute, BOSTON, USA
Background. Oxaliplatin is a platinum compound that covalently binds
DNA, inducing DNA intra- and interstrand cross-links. Fludarabine and
cytarabine act synergistically to inhibit excision repair of DNA crosslinks.
The clinical efficacy of oxaliplatin in patients with Richter’s syndrome
(RS) and fludarabine-refractory chronic lymphocytic leukemia
(CLL) has not been investigated previously. We conducted a phase 1-2
trial of oxaliplatin, fludarabine, cytarabine, and rituximab (OFAR) in
these diseases. Aims. The objectives of this trial were to identify a safe,
tolerated dose and any dose-limiting toxicities (DLT) of oxaliplatin, to
assess pharmacodynamic endpoints (phase 1), and to assess the complete
(CR) and partial remission (PR) rates for the OFAR regimen (phase 2).
Methods. The OFAR regimen consisted of increasing doses of oxaliplatin
(17.5, 20, or 25 mg/m 2 /d), days (D) 1-4 (phase 1); 30 mg/m 2 of fludarabine,
D2-3; 1 g/m2 of cytarabine, D2-3; 375 mg/m 2 of rituximab, D3 on
course 1 and D1 on subsequent courses; and 6 mg of pegfilgrastim, D6,
every 4 weeks for a maximum of 6 courses. Prophylaxis for PCP pneumonia
and DNA virus were given. DLT was defined as any non-hematologic,
treatment-related toxicity > grade (G) 3. Results. From November
2004 to January 2007, 64 patients (26 RS, 38 fludarabine-refractory
CLL) were treated with OFAR (phase 1, 19 pts). The highest tolerated
oxaliplatin dose identified was 25 mg/m 2 . No DLT was observed. Pharmacodynamic
analyses demonstrated enhanced leukemia cell killing by
oxaliplatin in the presence of fludarabine and cytarabine. For patients
with RS and CLL, the median ages were 66 yrs (range, 41-78) and 62 yrs
(range, 34-78) and the median numbers of prior therapies were 3 (range,
0-10) and 4 (range, 1-11), respectively. Among patients with fludarabinerefractory
CLL, 24 (63%) had Rai stage 3-4. The median number of
OFAR cycles was 2 (range, 1-6). Sixty patients are currently evaluable for
response. The overall response rates were 44% (11 of 25; CR= 3, PR= 7)
in RS and 43% (15 of 35; CR=1, nodular CR= 2, PR=12) in fludarabinerefractory
CLL. Responses included 9 of 22 (41%) patients with 17p
deletion, 5 of 9 (56%) patients with 11q deletions, 5 of 5 (100%) patients
with trisomy 12, 2 of 5 (40%) patients with 13q deletions, and 4 of 12
(33%) patients with no genomic aberrations. Fifteen of 31 (48%) patients
with tumors greater than 5 cm compared to 9 of 27 (33%) patients with
tumors less than or equal to 5 cm (tumor size was not recorded in 2
patients) responded to OFAR therapy (p=0.16). Toxicities were mainly
hematologic, but no prolonged myelosuppression was observed. Grade
3-4 infections occurred in 14 patients. Conclusions. OFAR is clinically
active in patients with Richter’s syndrome and fludarabine-refractory
CLL. These results are encouraging and warrant further investigation of
the OFAR regimen in the treatment of these disorders.
12 th Congress of the European Hematology Association
0365
ERADICATON OF MINIMAL RESIDUAL DISEASE IN CHRONIC LYMPHOCYTIC LEUKEMIA IS
ASSOCIATED WITH PROLONGED SURVIVAL. LONG TERM FOLLOW UP OF PATIENTS
TREATED WITH ALEMTUZUMAB
H.A. Sayala, 1 P. Moreton, 2 B. Kennedy, 3 G. Lucas, 4 M. Leach, 5
S.M.B. Rassam, 6 A. Haynes, 7 J. Tighe, 8 D. Oscier, 9 C. Fegan, 10
A.C. Rawstron, 1 P. Hillmen1 1 HMDS, Leeds General Infirmary, LEEDS; 2 Pinderfields general Hospital,
WAKEFIELD; 3 Leicester Royal Infirmary, LEICESTER; 4 Manchester royal Infirmary,
MANCHESTER; 5 Stobhill Hospital, GLASGOW; 6 Maidstone Hospital,
KENT; 7 Notingham City Hospital, NOTTINGHAM; 8 Aberdeen Royal Infirmary,
ABERDEEN; 9 Royal Bournemouth Hospital, BOURNEMOUTH; 10 University
Hospital Wales, CARDIFF, United Kingdom
Eradication of minimal residual disease (MRD) in chronic lymphocytic
leukemia (CLL) is increasingly emerging as a desirable therapeutic end
point predicting for better outcome. The monoclonal antibody alemtuzumab
(Mabcampath) is licensed for the treatment of patients with
CLL refractory to fludarabine-based therapies and results in the eradication
of MRD in a proportion of patients. We previously published a
series of ninety one (74 men and 17 women, median age 58 years [range,
32 to 75 years]) relapsed CLL patients who received a median of 9 weeks
(range 1 to 16 weeks) of alemtuzumab treatment between 1996 and
2003 (Moreton et al, J Clin Oncol 2005 May 1;23(13):2971-9). 44 were
refractory to purine analogues. Responses to alemtuzumab according to
National Cancer Institute sponsored working group response criteria
were complete remission (CR) in 32 patients (36%), partial remission
(PR) in 17 patients (19%), and no response (NR) in 42 patients (46%).
Detectable CLL to a level of less than a single CLL cell in 10,000 leucocytes,
assessed by four-colour MRD flow cytometry, was eradicated
from the blood and marrow in 18 patients (20%). 8/18 of these patients
were refractory to prior therapy with purine analogues (fludarabine
refractory). We report here the results of long term follow up of this
cohort of patients after a median follow up of 7.3 years (range 4 to 10.6
years). Median survival was significantly longer in those patients achieving
MRD negative responses compared with those who had detectable
CLL at the end of therapy (MRD positive CR, PR, or NR). The median
survival for all 18 MRD negative responders has not been reached but
was 87 months for the 8 fludarabine-refractory patients who achieved
MRD negativity following alemtuzumab. Overall survival for the 18
patients with MRD-negative remissions was 72% at 79 months (see Figure
1). Patients achieving an MRD positive complete response had a
median survival of 41 months, an MRD positive partial response a median
survival of 30 months and non-responders a median survival of 15
months. The median treatment-free interval prior to alemtuzumab for
the 18 MRD negative patients was 6 months (range 1 to 28 months). We
conclude that alemtuzumab can induce MRD negative remissions in
CLL resulting in a clear survival advantage with 72% patients alive 10
years after alemtuzumab therapy.
Figure 1. Over survival of subgroups by response.
haematologica/the hematology journal | 2007; 92(s1) | 131