5. CLL

5. CLL
234 235
ICD23 AND iCD54 IN B-CELL CHRONIC LYMPHOCYTIC
LEUKAEMIA. ANALYSIS OF CLINICAL SIGNIFICANCE.
Stefano Molica 1 , Domenico Levato 1 , Matteo Ddl'Olio 2 , Roadla Matcra 2 , Mart*
MioervinP, Angela Danilo 1 , M_Antonictta lorfida 1 , Mario Carotenuto 2 ,
PellegrinoMiato*
'Drvuionc di EmalologU, Azienda Oipcdaliera Tugliese-Ciaccio",
8J100 - Catanzaro, ITALY.
2 Drvmone di Fnnnni^gif IRCCS Ospedtlc 'Cats Sollicvo ddla Soflercnza*.
S. Oiovinni Rotonoo, ITALY.
In 95 B-ccll chrocic lymphocytic tqikcmm (CLL) patient] (44 lUge A, 31 stage
B, 20 stage C.) fbOowed-up in two bcmatological institutions, serum levels of
cither sCD23 or sCD54 were significantly increased in comparison to an agematched
control population. After setting a cutt-off at the mean value for both
these molecules (sCD23, 2834 U/ml; sCD54, 600 ng/ml) a correlation with other
prognostic factor was attempted. Increased levels of sCD23 and iCDJ4 in B-cell
CLL reflected dinico-biologicai parameters representative of either tumor mass
(i.e., clinical stages, pattern of BM invorvrnent, absolute peripheral blood
lymphocytosis) or disease-progression (i.e., lymphocyte doubling time, Ki67
expression on BM lymphocytes, serum thimidine lunate activity). Life expectancy
was significantly shorter in CLL patients with higher sCD23 levels (P < 0.001).
The same applied for those with increased concentrations of sCD54 (P < 0 001).
After adjusting for the most important prognostic factors in CLL (i.e., clinical
stages, BM histologies) sCD23 lost its predictive power. In contrast, sCD54
seemed to be partially independent from either clinical stages or BM histology
Indeed, it could help to isolate two patient subgroups with different prognosis
among stage B patients. After integrating sCD34 into Binet clinical staging
patients could be separated into four groups whose observed/expected (O/E)
ratios were as follows : (I) stage A, 0.37; (II) stage B with jCD54 < 600 ng/ml,
0.51; (HI) stage B with sCD54 > 600 ng/mL 2.63; (IV) stage C, 3.37 (P 3 2-COA cydet
Uroup 1
2(1-1:
21/17
3
oompWa • partial rwrfntai 24(S3%)
nochanoa + progression 14
nacoon (nnu gnoa)
0
22I SH
3-4
Uftlakuk*) (3-4.WHO gndi)
nauroprii 10(20%)
l>ui4jOcytn 4(11%)
lyiHim->'aib0Jx10 a > r ) 22p8%)
Qiji
0J7
0X04
O70
O001
aw
me
aoooi
Conclusion: The standard 2-CDA dosage of 0.7 mg/xg/cyde induced a high response
rate In pretrealed tow grade NHL but was awodatnd with a considerable Incidence ol severe
Infections (pneumonia, staphytococcus septicaemia, nocardknls, brain zoster). The dose
reduction by 30% led lo an Impressive decrease of the Infection risk (2%. enterobacter
septicaemia) whBe an equivalent response rate was maintained. Grade 3-4 myetotoxicity
was acceptable In both groups and other severe adverse effects were rare. The results are
not based on a randomised comparison. Even If we interpret them with the necessary
caution, we conclude that a 2-COA dosage of 0.5 mg/Vg/cyde sc should not be exceeded In
this patient population.
5. CLL 67
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238 239
RESPONSE AND TOXtCtTY OF ClAORBME (2-COA) AS FIRST (JNE
TREATMENT OF LOW-GRADE NON-HOOQKIN'S LYMPHOUAS (NHL).
PRELIMINARY DATA OF AN AUSTRIAN MULTTCENTER TRIAL
MA Fridrfk, G. JflQef, H.J. Klenzar, H,. Hausmaninger O. Krieger. M. Nsubau«r,
C. Gattringer, P. Oppttz, L Schiller, T. Radaskrewtez, W. Unkssch. ARQE Mod.
Tumorther. 1« Dept of Medicine AKH-Unz, A-4020 Unz, Austria, Europe
2-CdA Is an effective drug In heavily pretested low-grade NHL. In these patients
serious Infectious problems were reported. Aim of our trial is to evaluate efficacy
and tojdcity of 2-CdA In untreated pattern* with low-grade NHL
Previously untreated low-grade NHL stags 3 or 4 were eflgtole to the trial. The
protocol was approved by the beat ethics committee*. From June 93 to October
95 51 patients gave Informed consent and were entered to the trial. 2-CdA was
given as a 2-hour infusion 0.12 mgAg dafly for 5 consecutive days. Four treatment
cycles were given every 28 day*. After the last cycle of 2-CdA, patients were
treated with lnterteron-a-2c for one year.
Twenty-eight ol the 40 patients have completed the 2-CdA therapy. Of these patients
one was excluded because o) stage 2 disease, this patient achieved a
partial remission. Median age was 55.4, range 24-74 years. Response rate was
80% (22/26, complete remlsston:19%, 5/26) Alter a median observation period of
110 days (27 to 692 days) 6 relapses occurred after 56, 60,64,138, 259. and 344
days respectively. Four patients died, afl of progressive tymphoma Toxictty WHO*
3 possibly related to 2-CdA occurred in 6 patients (23%) and in 12 of 86 cycles
(13%). Grade 3 toxtaUes were hemalologlcal, except one infection. One WHO* 4
toxfcfty (potyneuropathy) was observed during 86 cycles (1%) ImmurogbouUn G
levels dropped from median 11.90 gA. to 10 89g/L, CD 4 counts from median 0.7
X10VL to 0.112 X10VL After a median time ol 22 months after treatment start the
median CD count still was 0.146xi0*7L Despite this considerable toxictty to CO 4
cells, only 6 Infections were observed during 73 treatment courses (8%)
Conclusions: 2-CdA is an effective treatment In low-grade NHL. Infection rate Is
low and treatment was well tolerated by previously untreated patients.
240 241
2-CHLORODEOXYADENOSINE (2-CDA) IN THE TREATMENT OF PREVIOUSLY
UNTREATED LOW GRADE NON HODGKIN LYMPHOMAS - PRELIMINARY RESULTS
OF A PHASE-ll-STUDY
P. S. Mitrou (I), M. Rummel (IX L. Leimer (2), A. Knuth (3), H. ROckle (4), K. Schumacher
(2), D. Hossfeld (5), L. Bergmann (I). D. Hoelzer(l)
(1) J. W. Goethe-Univeriity Hospital, Medkal Clinic III, Hemitology, Theodor-Stern-Kal 7,
60590 Frankfurt, Germany; (2) RBK Stuttgart; (3) Nordwest Hospital Frankfurt; (4) University
Hospital WOrzburg; (5) UKE Hamburg
2-CdA (2-Chlorodeoxyadenosinc) has been reported lo be an effective treatment in previously
treated low grade lymphomas. Arm of the mullkcnier-study if to evaluate the rale and duration
of remissions and to examine toxlchy and immunosuppressive effects of 2-CdA in low grade
lymphomas as firn line therapy or in first relapse Treatment schedule: 2-CdA 5 mg/m 1 as two
hour infusion day 1-5, for a maximum of six cycles every four weeks. Inclusion criterialymphocytic
and immunocytk (ic) stage III and IV, centrocytic (cc) (mantle zone) slage III and
IV, centroblastk-centrocylic (cb-cc) stage IV, other low grade lymphomas. 41 pu entered the
study. 28 po. are eviluable for response, 9 pu Hill under treatment and 4 pu. not evaluable.
16 out of 28 pu. responded to CdA (table).
CR
PR
NC
Progression
Early death
cb-cc (n-12) cc (n-6) ic (n=5) other entity (n-5)
4*
4
3*
1
-
-
1
1
4*
-
1
4
-
-
-
1 (T-zone)
1 (MALT)
1 (cut T-cell)
1 (Sezary)
1* (T-cell)
F^chutcrbl.C)
stand* fur one
patient treated
in fina rcUpsc
From the results so far 2-CdA seems to hive a delayed antiprolifentive activity which in some
cases can be observed still weeks or months after cessation of chemotherapy. Continuing
improvement of tumor parameters such as regression of bone marrow infiltration, size of
lymph nodes and decrease of monoclonal gammopathtes was delected. Toxicity: Neutropenia
grade 3 occured in IS of 146 evaluable cycles, grade 4 was not observed. Thrombocytopenia
grade 3 occurred in 2 of all evaluable cycles, grade 4 did not occur. CD4-lymphocyles
decreased in every case with a median of 570/ul before treatment, 345/ul after 3 and 225/ul
after 6 cycles. Infections: I reactivated tuberculosis, I bacterial pneumonii and I herpes zoster
Other side effects were not observed. Summary: Because of iu mild unkity the presented
regimen can be administered in an outpatient facility. It is effective in untreated pu. or in first
relapse. From the preliminary results it appears thai cc lymphomas (mantle zone) respond
poorly to CdA compared to other entities. The long-term immunosuppressive effect and hs
consequences are not evaluable so far nor is remission duration.
THREE-DAY THREE-WEEKLY ORAL CLADRIBINE (2-CdA) FOR
CHRONIC LYMPHOCYTIC LEUKEMIA. A PRELIMINARY
REPORT FROM A EUROPEAN PHASE II MULTICENTER
STUDY. Karin Karlsson, Mats StrOmberg, Steven Johnson, Andre 1
Delannoy, Jan Liliemark, Gunnar Juliusson, and Swedish collaborators.
LinkOping, Taunton, Brussels, Stockholm; Sweden, England, Belgium.
In our previous studies of 117 patients with symptomatic chronic
lymphocytic leukemia, five-day monthly cladribine courses resulted in an
overall response rate of two thirds, and half the responses were complete.
The median CR duration was 42 months, and the PR duration 18 months.
However, one third of the patients had major infections, and 13% developed
thrombocytopenia. We therefore embarked on a schedule with lower total
dose per course but the same dose intensity aiming at a reduced loxicity.
From January 1995 through January 1996, 89 symptomatic patients from
Brussels (B), Taunton (UK), and 18 Swedish institutions were entered. Oral
cladribine 10 mg/sqm/day was given days 1 through 3 every 3 weeks, for up
to 10 courses. Stopping criteria were defined at various stages for patients
with certain signs of toxicity, and/or insufficient improvement from therapy.
Thirty-four patients with a median age of 64 (range 41-88) are
currently evaluable for a preliminary analysis. Binet stages were as follows
A:5, B:13, C:16. Twenty-five (74%) were previously untreated. The overall
response rate were 65%, with 7 CR (21%) and 15 PR (44%) after 5 to 10
courses. Seven patients had pneumonia, and one patient developed severe
hemolysis.
The final analysis of the study will tell if this treatment schedule in
combination with defined criteria for stopping therapy will reduce toxicity
with retained response rate as compared to the previously studied regimes.
Studies in multi-institutional settings are required before proceeding into a
phase-Ill comparison of cladribine, fludarabine and chlorambucil for
symptomatic CLL.
2-CHLORODEOXYADENOSINE (2-COA) THERAPY IN HAIRY CELL LEUKEMIA (IICL):
COMPARISON OF 7 DAY CONTINUOUS IV INFUSION WITH A TWO-HOURS IV INFUSION
ON 5 CONSECUTIVE DAYS.
G Vettioef, P. Zachee, P. Vandenberghe, H. Demuynck, J. Maertens, S. Phtaluga C. De Wolf-
Peetets and M. Boogaerts. Department of Hemalology and Pathology, University Hospital,
Leuven, Belgium.
2-CDA is > purlne analogue with excellent activity in HCL. A 7-day continuous i.v. infusion
may be considered standard administration. Since a more convenient route of administration is
desirable, we compared the activity of standard administration ofa single 7-day continuous i.v.
infusion (O.I mg/kg/day) (n-21; newly diagnosed, 6; pretreoted with spleneclomy and/or
interferon-alpha, 15) with an out-patient regimen ofasmgk cycle of 2-CDA (0.1 mg/kg/day) as
a 2-hours i.v. infusion on 5 consecutive days (n-13; newly diagnosed, 8, pretreated, S). All
patients had at least Hb