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Leukemia (2001) 15, 1510–1516<br />
© 2001 Nature Publishing Group All rights reserved 0887-6924/01 $15.00<br />
www.nature.com/leu<br />
<strong>Cladribine</strong> <strong>combined</strong> <strong>with</strong> <strong>cyclophosphamide</strong> <strong>and</strong> mitoxantrone as front-line therapy<br />
in chronic lymphocytic leukemia<br />
T Robak 1 , JZ Błoński 1 , M Kasznicki 1 ,JGóra-Tybor 1 , J Dwilewicz-Trojaczek 2 , P Boguradzki 2 , L Konopka 3 , B Ceglarek 3 ,<br />
J Sułek 4 , K Kuliczkowski 5 , D.Wołowiec 5 , B Stella-Hołowiecka 6 , AB Skotnicki 7 , W Nowak 7 , B Moskwa-Sroka 8 ,<br />
A Dmoszyńska 9 <strong>and</strong> M Calbecka 10<br />
1<br />
Department of <strong>Hem</strong>atology, Medical University , Łódź; 2 Department of <strong>Hem</strong>atology, Medical Academy, Warsaw; 3 Institute of <strong>Hem</strong>atology<br />
<strong>and</strong> Blood Transfusion, Warsaw; 4 Department of Internal Medicine, Military Medical Academy, Warsaw; 5 Department of <strong>Hem</strong>atology,<br />
Medical University, Wrocław; 6 Department of Internal Medicine, Medical Academy, Katowice; 7 Department of <strong>Hem</strong>atology, Jagiellonian<br />
University, Kraków; 8 Department of <strong>Hem</strong>atology, City Hospital, Gorzów Wielkopolski; 9 Department of <strong>Hem</strong>atology, University Medical<br />
School, Lublin; <strong>and</strong> 10 Department of <strong>Hem</strong>atology, District Hospital, To<strong>ru</strong>ń, Pol<strong>and</strong><br />
The objective of the study was to determine the effectiveness<br />
<strong>and</strong> the toxicity of a <strong>combined</strong> chemotherapy consisting of cladribine<br />
(2-CdA), mitoxantrone <strong>and</strong> <strong>cyclophosphamide</strong> (CMC<br />
regimen) in the treatment of previously untreated B cell chronic<br />
lymphocytic leukemia (B-CLL). From August 1998 to December<br />
2000 2-CdA was administered at a dosage of 0.12 mg/kg for 3<br />
(CMC3) or 5 (CMC5) consecutive days, mitoxantrone at 10<br />
mg/m 2 on day 1 <strong>and</strong> <strong>cyclophosphamide</strong> at 650 mg/m 2 on day 1<br />
to 62 patients <strong>with</strong> advanced or progressive B-CLL. The cycles<br />
were repeated at 4 week intervals or longer if severe myelosuppression<br />
occurred. Twenty patients received CMC5 <strong>and</strong> 42<br />
patients CMC3. Within the analyzed group an overall response<br />
(OR) rate (CR+PR) of 64.5% (95% CI: 52.7–76.3%) was reported,<br />
including 29.0% CR. There was no difference in the CR rate<br />
between the patients treated <strong>with</strong> CMC5 (30%) <strong>and</strong> CMC3<br />
(28.6%) (P = 0.9), nor in the OR rate (55.0% <strong>and</strong> 69.0%, respectively,<br />
P = 0.3). Residual disease was identified in seven out of<br />
18 (38.9%) patients who were in CR, including two treated <strong>with</strong><br />
CMC5 <strong>and</strong> five treated <strong>with</strong> CMC3 protocols. CMC-induced<br />
grade III or IV thrombocytopenia occurred in 12 (19.4%) of<br />
patients, including four (20%) CMC5-treated <strong>and</strong> eight (19%)<br />
CMC3-treated patients (P = 0.8). Neutropenia grade III or IV was<br />
observed in seven (35%) <strong>and</strong> 11 (26.2%) patients, respectively<br />
(P = 0.8). Severe infections, including pneumonia <strong>and</strong> sepsis,<br />
occurred more frequently after CMC5 (11 patients, 55.0%) than<br />
CMC3 (10 patients, 28.6%) (P = 0.03) Fourteen patients died,<br />
including six treated <strong>with</strong> CMC5 <strong>and</strong> eight treated <strong>with</strong> CMC3<br />
(30% <strong>and</strong> 19%, respectively). Infections were the cause of death<br />
in nine patients, including four in the CMC5 group <strong>and</strong> five in<br />
the CMC3 group. In conclusion, our results indicate that the<br />
CMC programme is an active <strong>combined</strong> regimen in previously<br />
untreated B-CLL patients; its efficiency seems to be similar to<br />
that observed earlier in B-CLL patients treated <strong>with</strong> 2-CdA as<br />
a single agent. However, toxicity, especially after CMC5 administration,<br />
is significant. Therefore, we recommend the CMC3<br />
but not the CMC5 programme for further evaluation. Leukemia<br />
(2001) 15, 1510–1516.<br />
Keywords: cladribine; <strong>cyclophosphamide</strong>; mitoxantrone; CLL;<br />
<strong>combined</strong> therapy; residual disease<br />
Introduction<br />
The newer purine analogs, fludarabine (FAMP), 2-deoxycoformycin<br />
(DCF) <strong>and</strong> cladribine (2-chlorodeoxyadenosine, 2-<br />
CdA), have been synthesized recently <strong>and</strong> introduced into the<br />
treatment of low-grade lymphoid malignancies. 1–3 2-CdA is a<br />
Correspondence: T Robak, Department of <strong>Hem</strong>atology, Medical University<br />
of Łódź, 93-513 Łódź, ul. Pabianicka 62, Pol<strong>and</strong>; Fax: +48<br />
42 6846890<br />
The preliminary results of this study were presented at the 41st Annual<br />
Meetingof the American Society of <strong>Hem</strong>atology, San Francisco, CA,<br />
December 1–5, 2000.<br />
Received 27 Feb<strong>ru</strong>ary 2001; accepted 10 May 2001<br />
nucleoside analog<strong>with</strong> a substituted halogen atom at position<br />
2 in its purine ring, which makes it resistant to deamination<br />
by adenosine deaminase. It is mainly used in the treatment<br />
of hairy cell leukemia, but it is also highly active in chronic<br />
lymphocytic leukemia (CLL), <strong>with</strong> an overall response rate<br />
(OR) <strong>and</strong> complete remission rate (CR) comparable to that<br />
achieved <strong>with</strong> FAMP. 4–7 There are some opinions that 2-CdA<br />
is associated <strong>with</strong> more frequent <strong>and</strong> problematic myelosuppression.<br />
However, direct comparison of both agents in the r<strong>and</strong>omized<br />
study of CLL patients has not been published as of<br />
this time.<br />
Despite the fact that new purine analogs induce a higher<br />
overall response rate <strong>and</strong> a higher CR rate in patients <strong>with</strong><br />
CLL, they do not influence survival time. 5,8 On the other h<strong>and</strong>,<br />
both FAMP <strong>and</strong> 2-CdA administered as single agents can<br />
induce immunophenotypic <strong>and</strong> molecular remission, which is<br />
especially important in younger patients in order to qualify<br />
these patients for bone marrow transplantation <strong>and</strong> offer the<br />
possibility of recovery. 3,9<br />
Combined use of purine analogs <strong>with</strong> other cytotoxic agents<br />
may increase the CR rate <strong>and</strong>, possibly, suppress minimal<br />
residual disease <strong>and</strong> prolongsurvival. Some preclinical studies<br />
<strong>and</strong> early clinical reports may support such a hypothesis. 10–16<br />
Among cytotoxic agents, alkylating d<strong>ru</strong>gs <strong>and</strong> anthracyclines<br />
were the primary c<strong>and</strong>idates for use in combination <strong>with</strong><br />
purine analogs. Synergistic action of 2-CdA <strong>with</strong> <strong>cyclophosphamide</strong><br />
<strong>and</strong> its derivatives has been shown both in in vitro<br />
<strong>and</strong> in vivo experiments. 10,11 These results have been confirmed<br />
recently by early clinical trials, which have shown that<br />
the combination of 2-CdA <strong>with</strong> <strong>cyclophosphamide</strong> <strong>and</strong><br />
prednisone is feasible <strong>and</strong> active in patients <strong>with</strong> CLL <strong>and</strong><br />
other low-grade lymphoid malignancies. 13,14<br />
Mitoxantrone is also a useful d<strong>ru</strong>gin the treatment of lowgrade<br />
lymphomas <strong>and</strong> can be <strong>combined</strong> <strong>with</strong> purine analogs.<br />
17–20 However, the advantage of such a combination in<br />
patients <strong>with</strong> refractory or relapsingdisease over 2-CdA alone<br />
has not yet been proven. Thus, the combination of 2-CdA <strong>with</strong><br />
<strong>cyclophosphamide</strong> <strong>and</strong> mitoxantrone seems to be the logical<br />
conclusion of the clinical studies in which 2-CdA was administered<br />
<strong>with</strong> each independently. In our previous study, 21 we<br />
showed that <strong>combined</strong> treatment <strong>with</strong> 2-CdA, <strong>cyclophosphamide</strong><br />
<strong>and</strong> mitoxantrone (CMC programme) in heavily pretreated<br />
CLL <strong>and</strong> other indolent lymphoma patients is an active<br />
regimen. In this report, we present our experience <strong>with</strong> the<br />
combination of 2-CdA <strong>with</strong> <strong>cyclophosphamide</strong> <strong>and</strong> mitoxantrone<br />
in previously untreated patients <strong>with</strong> B-CLL.
Patients <strong>and</strong> methods<br />
Patients<br />
Between August 1998 <strong>and</strong> December 2000, 62 previously<br />
untreated patients <strong>with</strong> progressive or symptomatic CLL were<br />
treated <strong>with</strong> a <strong>combined</strong> chemotherapy consistingof 2-CdA,<br />
<strong>cyclophosphamide</strong> <strong>and</strong> mitoxantrone. The characteristics of<br />
the patients are shown in Table 1. All of the patients fulfilled<br />
the National Cancer Institute-Sponsored WorkingGroup criteria<br />
for CLL. 22 Pretreatment evaluation included examination<br />
of medical history, physical examination, complete blood cell<br />
count, differential count of WBC, chemical survey, bone marrow<br />
examination <strong>and</strong> se<strong>ru</strong>m immunoglobulin level quantitation.<br />
Cytogenetic analysis was not routinely performed. The<br />
patients had peripheral lymphocytosis greater than 10 × 10 9 /l<br />
<strong>and</strong> more than 30% lymphocytes in normal or hypercellular<br />
bone marrow. The differences between mean values in both<br />
groups of patients were not significant. Cell marker studies<br />
were performed to confirm B cell origin <strong>and</strong> monoclonal proliferation.<br />
All patients were CD5, CD19, CD20 <strong>and</strong> CD23<br />
positive <strong>and</strong> showed monoclonality for light chain immunoglobulin<br />
membrane surface receptors.<br />
The clinical stage of disease was determined at the time of<br />
initiation of the treatment accordingto Rai’s classification. 23<br />
The distribution is shown in Table 1. Patients in stage 0, I <strong>and</strong><br />
II were eligible if they had evidence of active disease, including<br />
progressive lymphocytosis, massive splenomegaly or<br />
bulky lymphadenopathy, recurrent disease-related infections,<br />
weight loss 10% over a 6 month period, temperature of<br />
38°C related to disease or extreme fatigue. Patients <strong>with</strong> poor<br />
performance status (WHO scale 4), active infection, abnormal<br />
liver or renal function <strong>and</strong> Richter’s syndrome were excluded<br />
from the study. The study was approved by Local Ethical Committees<br />
<strong>and</strong> the patients had signed the informed consent<br />
form.<br />
Treatment modality<br />
The doses <strong>and</strong> schedule of the treatment agents were based<br />
on previous studies in cases of CLL relapse, refractory CLL or<br />
low-grade lymphoma. 7,19–21<br />
CMC in untreated CLL<br />
T Robak et al<br />
In the first part of the study, CMC protocol consisted of 2-<br />
CdA administered at a dose 0.12 mg/kg in 2-h i.v. infusion for<br />
5 (CMC5) days, mitoxantrone 10 mg/m 2 i.v. on day 1 <strong>and</strong><br />
<strong>cyclophosphamide</strong> 650 mg/m 2 i.v. on day 1. In the second<br />
part of the study, 2-CdA administration was shortened to 3<br />
days (CMC3) because of excessive hematological toxicity of<br />
CMC5 protocol. The doses of mitoxantrone <strong>and</strong> <strong>cyclophosphamide</strong><br />
were the same as in the CMC5 protocol. 2-CdA<br />
(Biodrybin) was synthesized accordingto the method of Kazimierczuk<br />
et al 24 <strong>and</strong> was commercially available from the<br />
Institute of Biotechnology <strong>and</strong> Antibiotics- Bioton (Warsaw,<br />
Pol<strong>and</strong>).<br />
The cycles were repeated over 28 days for three courses. If<br />
hematological complications (thrombocytopenia 50 × 10 9 /l,<br />
granulocytopenia 0.5 × 10 9 /l) or severe infections developed<br />
the d<strong>ru</strong>gs were re-administered at time intervals longer than<br />
28 days, ranging from 2 to 4 months, until the increase of<br />
hematological parameters or recovery from infections was<br />
noted. If a response had been documented, patients were<br />
treated until maximal response or prohibitive toxicity. If no<br />
response or progression of the disease was observed after<br />
three cycles, the treatment was discontinued. Packed red cells<br />
were transfused for symptomatic anemia or prophylactically<br />
if the hemoglobin level was lower than 7.0 g/dl. Platelets were<br />
administered prophylactically if the platelet count was less<br />
than 15.0 × 10 9 /l. Blood products were irradiated. In order to<br />
prevent hype<strong>ru</strong>ricemia, allopurinol (300 mg/daily) was administered.<br />
No patients received antibiotics or antiviral agents<br />
prophylactically. No patients received hematopoietic growth<br />
factors prophylactically but G-CSF or GM-CSF were administered<br />
if the absolute granulocyte count was less than 1.0 ×<br />
10 9 /l <strong>and</strong> active infection was present.<br />
Response criteria<br />
Treatment effect was monitored by physical examination,<br />
blood count evaluation <strong>and</strong> bone marrow examination before<br />
<strong>and</strong> after every course of chemotherapy. Guidelines for<br />
response were those developed by the NCI-Sponsored WorkingGroup.<br />
22,25 Complete response (CR) required the absence<br />
of symptoms <strong>and</strong> organomegaly, normal complete blood cell<br />
count (absolute neutrophil count 1.0 × 10 9 /l, hemoglobin<br />
1511<br />
Table 1<br />
Clinical characteristics of B CLL patients before CMC treatment<br />
Characteristics All patients CMC5 CMC3<br />
Total 62 20 42<br />
Sex<br />
Male 38 (61.0) 13 (65) 25 (59.5)<br />
Female 24 (39.0) 7 (35) 17 (40.5)<br />
Age in years, median ± s.d. (range) 62.5 (33–77) 63.5 (36–77) 61 (33–76)<br />
Rai stage before CMC<br />
0 1 (1.6) 1 (5) 0<br />
I 8 (12.9) 3 (15) 5 (11.9)<br />
II 18 (29.0) 6 (30) 12 (28.6)<br />
III 20 (32.3) 4 (20) 16 (38.1)<br />
IV 15 (24.2) 6 (30) 9 (21.4)<br />
Median disease duration in months median (range) 8.9 (3.0–156.3) 14.6 (4–26) 8.2 (3.0–156.3)<br />
Mean number of WBC × 10 9 /l (range) 84.0 (5.4–376.0) 103.2 (10.2–606.0) 82.6 (5.4–376.0)<br />
Mean Hb concentration g/dl (range) 12.0 (4.0–17.0) 12.0 (4.0–14.0) 11.0 (5.1–17.0)<br />
Mean number of platelets × 10 9 /l (range) 150 (28–314) 133 (15–231) 174 (28–314)<br />
Leukemia
1512<br />
CMC in untreated CLL<br />
T Robak et al<br />
concentration 11.0 g/dl, platelet count 100 × 10 9 /l <strong>and</strong><br />
bone marrow <strong>with</strong> less than 30% lymphocytes for at least 2<br />
months. Partial response (PR) was considered in the case of a<br />
50% or greater decrease in the size of lymph nodes, liver <strong>and</strong><br />
spleen, <strong>and</strong> peripheral blood findings either identical to those<br />
of CR or improved over pre-therapy values by at least 50%.<br />
The patients who had not achieved CR or PR were classified<br />
as non-responders (NR). Clinical relapse was defined accordingto<br />
Robertson et al 9 as an increase in the absolute lymphocyte<br />
count above 10 × 10 9 /l, more than 50% increase in the<br />
sum of the size of at least two lymph nodes, appearance of<br />
new lymph nodes, more than a 50% increase in the liver or<br />
spleen below the costal margin, the new appearance of palpable<br />
hepatosplenomegaly or development of an aggressive<br />
lymphoma.<br />
Immunophenotype analysis<br />
Immunophenotypingwas performed on peripheral blood <strong>and</strong><br />
bone marrow by flow cytometry usinga simultaneous dualcolor<br />
stainingtechnique before treatment <strong>and</strong> after obtaining<br />
CR, accordingto the method described by B<strong>ru</strong>giatelli et al. 26 A<br />
combination of phycoerythrin (PE)-conjugated <strong>and</strong> fluorescent<br />
isothiocyanate (FITC)-conjugated monoclonal antibodies was<br />
utilized. Residual disease was determined by co-expression of<br />
CD5/CD19 <strong>and</strong> CD5/CD20 on B lymphocytes in conjunction<br />
<strong>with</strong> monoclonality of surface light-chain expression on CD5-<br />
positive B cells. The presence of more than 10% of the total<br />
lymphocytic population co-expressingCD5/CD19 <strong>and</strong><br />
CD5/CD20 <strong>with</strong> monotypic light-chain expression (a : or<br />
: ratio exceeding3:1) was considered positive for residual<br />
disease, accordingto the criteria developed by Robertson et<br />
al. 9<br />
Toxicity monitoring<br />
<strong>Hem</strong>atological toxicity was evaluated according to the criteria<br />
developed by the NCI-Sponsored WorkingGroup. 22 D<strong>ru</strong>ginduced<br />
anemia, thrombocytopenia <strong>and</strong> neutropenia were<br />
diagnosed if after the treatment course a further decrease of<br />
hemoglobin level <strong>and</strong>/or platelets <strong>and</strong> neutrophils numbers<br />
were observed. Other side-effects were assessed <strong>and</strong> monitored<br />
accordingto WHO criteria. 27<br />
Only major <strong>and</strong> moderate infections were recorded, includinglife-threateningepisodes<br />
such as pneumonia <strong>and</strong> disseminated<br />
infections that required oral or parenteral antibiotic<br />
therapy, antifungal <strong>and</strong> antiviral therapy <strong>and</strong>/or hospitalization.<br />
Fever of unknown origin (FUO) requiring parenteral<br />
antibiotic therapy was also recorded as an infectious event.<br />
Infections were reported as CMC related if they developed on<br />
therapy or <strong>with</strong>in 4 months of the completion of the CMC<br />
treatment.<br />
Statistical analysis<br />
Statistical analysis of the differences in the percentages of<br />
responses in patients treated <strong>with</strong> CMC3 <strong>and</strong> CMC5 were<br />
evaluated by the 2 test. Ninety-five percent confidence intervals<br />
for response probability were calculated usingthe<br />
method described by Duffy <strong>and</strong> Santner. 28<br />
Results<br />
Sixty-two patients <strong>with</strong> B-CLL entered the study <strong>and</strong> all of<br />
them were analyzed. The median time from the diagnosis to<br />
CMC administration was 8.2 months (range 4–26). The<br />
characteristics of the patients are presented in Table 1. Twenty<br />
patients were treated accordingto CMC5 protocol <strong>and</strong> 42<br />
received CMC3 chemotherapy. The total number of CMC<br />
courses administered to the entire group of patients amounted<br />
to 237 (84 CMC5 <strong>and</strong> 153 CMC3 courses). The median number<br />
of CMC3 courses was 3.8 (range 1–6), <strong>and</strong> the median<br />
time needed to deliver the total number of cycles was 4.6<br />
months (range 1–8.7). The patients treated <strong>with</strong> CMC5<br />
received from 1 to 6 (median 2.5) courses, <strong>and</strong> the median<br />
time needed to deliver the total number of cycles was 5.7<br />
months (range 1–10.2). In the CMC3 group 8 (19%) patients,<br />
<strong>and</strong> in the CMC5 group 9 (45%) patients, could not reach the<br />
total of three cycles because of early death or severe myelotoxicity.<br />
The criteria for CR were fulfilled in 18 patients (29.0%) <strong>and</strong><br />
PR in 22 (35.5%), giving an overall response rate in 64.5%<br />
(95% CI 52.7–76.3%) of total patients (Table 2). There were<br />
no differences in the frequency of OR between the CMC5-<br />
<strong>and</strong> the CMC3-treated groups (55% <strong>and</strong> 69%, respectively, P<br />
= 0.3). The CR rate was also similar in both groups (30% <strong>and</strong><br />
28.6%, respectively) (P = 0.9). In the group treated <strong>with</strong> CMC5<br />
the patients attainingCR received a median of three courses<br />
(range 2–6) <strong>and</strong> in the group treated <strong>with</strong> CMC3 a median of<br />
three courses (range 2–6) was also administered. CRs were<br />
observed more frequently in the early stages of the disease<br />
(Rai 0, I <strong>and</strong> II) – 11/29 (37.9%) than in the more advanced<br />
stages (Rai III <strong>and</strong> IV) – 7/33 (21.2%) (P = 0.8).<br />
Surface immunophenotypingby flow cytometry usingdualcolor<br />
stainingon peripheral blood <strong>and</strong>/or bone marrow was<br />
performed in patients who achieved CR. Residual disease was<br />
identified in seven out of 18 (38.9%) patients who achieved<br />
remission.<br />
Toxicity<br />
Myelosuppression was the major toxicity of the CMC therapy<br />
(Table 3). Grades III <strong>and</strong> IV neutropenia were observed in 18<br />
(29.0%) out of 62 patients <strong>and</strong> after 30 (12.7%) out of 237<br />
CMC courses. There was no significant difference between the<br />
frequency of severe neutropenia in the 7/20 (35%) patients<br />
treated <strong>with</strong> CMC5 or 11/42 (26.2%) patients treated <strong>with</strong><br />
CMC3 regimens (P = 0.8). <strong>Hem</strong>atopoietic growth factors (G-<br />
CSF or GM-CSF) were administered after four <strong>and</strong> 13<br />
courses, respectively.<br />
The frequency of thrombocytopenia was similar (20% <strong>and</strong><br />
19%) in both groups (P = 0.8). Grade III or IV anemia was the<br />
rarest hematological complication <strong>and</strong> was observed in only<br />
four patients. Autoimmune hemolytic anemia (AIHA)<br />
developed in two patients treated <strong>with</strong> CMC3. These patients<br />
had no clinical or laboratory symptoms of this complication<br />
before CMC treatment.<br />
Severe infections <strong>and</strong> fever of unknown origin (FUO) requiringparenteral<br />
antibiotic therapy occurred more often in<br />
patients treated <strong>with</strong> the CMC5 regimen – 11 patients (55%)<br />
than CMC3 – 10 patients (23.8%) (P = 0.03). The number of<br />
severe infections <strong>and</strong> FUO was also more frequent after CMC5<br />
courses – 15 (17.9%) than CMC3 courses – 12 (7.8%) (P =<br />
0.03). Pneumonia <strong>and</strong> upper respiratory infections (sinusitis<br />
<strong>and</strong> bronchitis) occurred in 23 patients, including12 treated<br />
Leukemia
Table 2<br />
CMC in untreated CLL<br />
T Robak et al<br />
Results of the treatment of B CLL patients <strong>with</strong> CMC accordingto the treatment protocol<br />
1513<br />
Rai All patients (%) CMC5 (%) CMC3 (%)<br />
stage n = 62 n = 20 n = 42<br />
n CR PR NR n CR PR NR n CR PR NR<br />
0 1 1 0 0 1 1 0 0 0 0 0 0<br />
(100.0) (100.0)<br />
I + II 28 10 11 7 9 3 2 4 19 7 9 3<br />
(35.7) (39.3) (26.0) (36.7) (22.2) (44.4) (36.8) (47.4) (15.8)<br />
III + IV 33 7 11 15 10 2 3 5 23 5 8 10<br />
(21.2) (33.3) (45.5) (20.0) (30.0) (50.0) (21.7) (34.8) (43.5)<br />
P value a 0.8 0.4 0.4<br />
Total 62 18 22 22 20 6 5 9 42 12 17 13<br />
(29.0) (35.5) (35.5) (30.0) (25.0) (45.0) (28.6) (40.4) (31.0)<br />
a<br />
P values for responses in different Rai stages.<br />
Table 3<br />
Severe hematological toxicity of the CMC programme<br />
Protocol Neutropenia Thrombocytopenia Anemia<br />
grade III <strong>and</strong> IV grade III <strong>and</strong> IV grade III <strong>and</strong> IV<br />
n (%) n1 (%) n (%) n1 (%) n (%) n1 (%)<br />
CMC5 7 (35.0) 9 (10.7) 4 (20.0) 6 (7.1) 2 (10.0) 4 (4.8)<br />
n = 20<br />
n1 = 84<br />
CMC3 11 (26.2) 21 (13.7) 8 (19.0) 14 (9.2) 2 (4.8) 2 (1.3)<br />
n = 42<br />
n1 = 153<br />
P value for 0.8 0.9 0.7 0.8 0.8 0.2<br />
CMC5 vs CMC3<br />
Total 18 (29.0) 30 (10.3) 12 (19.4) 20 (8.4) 4 (6.5) 6 (2.5)<br />
n = 62<br />
n1 = 237<br />
n, number of patients; n1, number of courses.<br />
<strong>with</strong> CMC5 <strong>and</strong> 11 treated <strong>with</strong> CMC3. Herpes zoster reactivation<br />
<strong>and</strong> herpes simplex infections were observed in 10<br />
patients (two after CMC5 <strong>and</strong> eight after CMC3). Tuberculosis<br />
was diagnosed in one patient after two courses of CMC5.<br />
Other opportunistic infections were not seen.<br />
In four patients, grade III vomiting according to the WHO<br />
classification was observed <strong>and</strong> in one DIC syndrome<br />
developed. Other non-hematological side-effects including<br />
alopecia, abnormal aminotransferases, transient increased<br />
LDH <strong>and</strong> creatinine levels were observed only very rarely<br />
(Table 4). Secondary cancers were observed in two patients<br />
includingone case of pulmonary cancer (adenocarcinoma)<br />
after CMC3 in a patient <strong>with</strong>out the history of tobacco<br />
exposure <strong>and</strong> one case of malignant histiocytosis after CMC5.<br />
Richter syndrome has not been observed to date<br />
The intervals between CMC courses due to myelosuppression<br />
<strong>and</strong>/or infections were prolonged from 4 to 8 weeks in<br />
23 (37%) patients <strong>and</strong> after 38 (16%) courses, including10<br />
patients (18 courses) treated <strong>with</strong> CMC5 <strong>and</strong> 13 patients (20<br />
courses) treated <strong>with</strong> CMC3. In four patients (two treated <strong>with</strong><br />
CMC5 <strong>and</strong> two <strong>with</strong> CMC3), therapy was stopped before the<br />
completion of three courses of treatment because of<br />
prolonged severe myelosuppression.<br />
Altogether, 14 (22.6%) patients died during the study,<br />
includingsix (30%) treated <strong>with</strong> CMC5 <strong>and</strong> eight (19.0%) <strong>with</strong><br />
CMC3. All six patients in the CMC5 group died before completingthree<br />
courses of treatment. In CMC3 group six out of<br />
eight patients died before completing three courses of treatment.<br />
The causes of death are shown in Table 5. Complications<br />
due to infections were the cause of death in nine<br />
patients, includingfour treated <strong>with</strong> CMC5 <strong>and</strong> five after<br />
CMC3 therapy.<br />
Discussion<br />
In spite of intensive research <strong>and</strong> important progress in the<br />
last years, CLL still remains incurable. The results of the r<strong>and</strong>omized<br />
studies published so far indicate that both FAMP <strong>and</strong><br />
2-CdA, applied as first-line therapy, significantly increase the<br />
rate of complete remissions when compared to chlorambucil,<br />
which is still regarded as the gold st<strong>and</strong>ard in CLL treatment. 5,8<br />
However, neither study proved that the higher remission rate<br />
is translated into longer survival. That is why further research<br />
is justified, <strong>with</strong> the objective to increase the remission rate<br />
<strong>and</strong> quality, <strong>and</strong> in this way, to influence survival time. In the<br />
trials finished to date, alkylatingd<strong>ru</strong>gs <strong>and</strong> anthracyclines <strong>with</strong><br />
mitoxantrone were most often <strong>combined</strong> <strong>with</strong> either FAMP or<br />
<strong>with</strong> 2-CdA. 10–18,29,30<br />
Our study is the first, to our knowledge, in which previously<br />
Leukemia
1514<br />
Table 4<br />
CMC in untreated CLL<br />
T Robak et al<br />
CMC-induced grade III <strong>and</strong> IV non-hematological side-effects<br />
Side-effect Total CMC5 CMC3<br />
n = 62 n1 = 237 n = 20 n1 = 84 n = 42 n1 = 153<br />
n (%) n1 (%) n (%) n1 (%) n (%) n1 (%)<br />
Infections <strong>and</strong> FUO 23 (37.1) 37 (15.6) 11 (55.0) 15 (17.9) 10 (23.8) 12 (7.8)<br />
Vomiting grade III or IV 4 (6.5) 7 (3.0) 2 (10.0) 4 (4.8) 2 (4.8) 3 (2.0)<br />
Alopecia 1 (1.6) 1 — 1 1<br />
Aminotransferases increased 1 (1.6) 1 — 1 1<br />
Creatinine increased 1 (1.6) 1 — 1 1<br />
IHD 1 (1.6) 1 — 1 1<br />
DIC 1 (1.6) 1 — 1 1<br />
Secondary neoplasms 2 (3.2) 1 1 1 1 1<br />
n, number of patients; n1, number of courses; FUO, fever of unknown origin; DIC, disseminated intravascular coagulation; IHD, ischemic<br />
heart disease.<br />
Table 5<br />
Cause of death in B CLL patients treated <strong>with</strong> 2-CdA<br />
Cause of death Total CMC5 CMC3<br />
n = 14 n = 6 n = 8<br />
Pneumonia 5 (35.7%) 2 (33.3%) 3 (37.5%)<br />
Septic shock 4 (28.6%) 2 (33.3%) 2 (25.0%)<br />
<strong>Hem</strong>orrhage 1 (7.1%) — 1 (12.5%)<br />
Second neoplasm 2 (14.3%) 1 (16.7%) 1 (12.5%)<br />
Not connected <strong>with</strong> CLL 2 (14.3%) 1 (16.7%) 1 (12.5%)<br />
untreated CLL patients received two other d<strong>ru</strong>gs in combination<br />
<strong>with</strong> 2-CdA: <strong>cyclophosphamide</strong> <strong>and</strong> mitoxantrone<br />
(CMC programme). In this study, the daily doses of 2-CdA<br />
(0.12 mg/kg) were identical in both groups, but the duration<br />
of the treatment was different: 3 days (CMC3) or 5 days<br />
(CMC5). The doses of cyclophosophamide <strong>and</strong> mitoxantrone<br />
were the same in both programmes. Our study indicates that<br />
CMC combination is active in CLL. The CR rate was 29% <strong>and</strong><br />
the OR rate was 64.5%. It should be emphasised, that in spite<br />
of the large proportion of patients who have responded to<br />
treatment, the response rate does not seem greater than in our<br />
earlier studies <strong>with</strong> 2-CdA in monotherapy or <strong>combined</strong> <strong>with</strong><br />
prednisone. 7,8 It is of interest that the shortened administration<br />
time from 5 (CMC5) to 3 (CMC3) days has not resulted in a<br />
lower CR rate (30% <strong>and</strong> 28.6%, respectively) or overall<br />
response rate (55% <strong>and</strong> 69%, respectively). Similarly, we<br />
observed earlier the lack of influence of a shorter administration<br />
time of 2-CdA <strong>with</strong>in a CMC programme on the outcome<br />
in pretreated indolent lymphoma. 21 Previous studies<br />
revealed that the response rate was not lower when 2-CdA or<br />
FAMP were <strong>combined</strong> <strong>with</strong> either <strong>cyclophosphamide</strong>, 14,31–33<br />
mitoxantrone 17,34 or anthracycline. 35<br />
Minimal residual disease (MRD) was evaluated by twocolor<br />
immunophenotypingin the patients who fulfilled morphological<br />
criteria for CR. MRD was identified in seven out<br />
of 18 patients (38.9%). A similar evaluation was performed in<br />
the CLL patients treated <strong>with</strong> 2-CdA in monotherapy <strong>and</strong> MRD<br />
was diagnosed in five out of 17 (29.4%) patients <strong>with</strong> CR. 3<br />
These data indicate that the <strong>combined</strong> therapy <strong>with</strong> CMC does<br />
not appear to reduce the incidence of MRD more than 2-CdA<br />
in monotherapy.<br />
To the best of our knowledge, our study is the first in which<br />
a purine analogwas <strong>combined</strong> <strong>with</strong> two other cytostatics in<br />
patients <strong>with</strong> CLL or low-grade non-Hodgkin’s lymphoma as<br />
first-line treatment. Such combinations were, however,<br />
administered to earlier pretreated patients. 21,36,37 These were<br />
the phase I/II studies that did not prove that the combination<br />
of purine analog<strong>with</strong> <strong>cyclophosphamide</strong> <strong>and</strong> mitoxantrone<br />
seemed more efficient that the monotherapy <strong>with</strong> FAMP or<br />
2-CdA.<br />
An additional aim of our study was the evaluation of the<br />
treatment-related toxicity of the CMC programme. We have<br />
shown that the most important toxic effect of this combination<br />
was myelosuppression. Grade III/IV neutropenia was observed<br />
in 29% of the patients <strong>and</strong> severe thrombocytopenia in 19.4%<br />
of the patients. It should be remembered, though, that myelotoxicity<br />
is the limitingfactor for the administration of any d<strong>ru</strong>g<br />
of the CMC programme when they are applied in monotherapy<br />
or <strong>combined</strong> <strong>with</strong> other cytotoxic agents. Important myelotoxicity<br />
of the CMC programme may indicate the necessity<br />
of reducingthe dose of 2-CdA in this combination, <strong>and</strong> this<br />
supports the CMC3 rather than the CMC5 programme. The<br />
justification of such an approach has also been found in other<br />
studies, where the dose of purine analogin combination was<br />
lower than in monotherapy. 16–18,29,38<br />
The infections were frequent in the patients treated <strong>with</strong> the<br />
CMC programme <strong>and</strong> they were most commonly the cause of<br />
death. These results are consistent <strong>with</strong> the observations from<br />
other studies, which also indicate that infections are frequent<br />
in patients treated <strong>with</strong> purine analogs. 39,40 It should be<br />
emphasized that the frequency of infections was significantly<br />
lower in patients treated <strong>with</strong> CMC3 (23.8%) than in patients<br />
treated <strong>with</strong> CMC5 (55%) (P = 0.02). Betticher et al 41 found<br />
that the reduction in the dose of 2-CdA from 0.7 mg/kg per<br />
cycle to 0.5 mg/kg per cycle in pretreated patients <strong>with</strong> malignant<br />
lymphomas did not decrease the activity of this<br />
compound but greatly reduced the incidence of infections.<br />
Further reduction of myelosuppression <strong>and</strong> infections may<br />
be most likely achieved <strong>with</strong> the prophylactic use of growth<br />
factors followingthe chemotherapy cycle. 42,43 In our study,<br />
G-CSF was applied only as a treatment for severe infections<br />
to the patients <strong>with</strong> neutropenia 1.0 × 10 9 /l. O’Brien et al 42<br />
showed, however, that prophylactic administration of G-CSF<br />
to patients treated <strong>with</strong> FAMP may reduce the incidence of<br />
pneumonia, but does not interfere <strong>with</strong> other infections. It<br />
should also be remembered that prophylactic administration<br />
of hemopoietic growth factors may greatly increase the cost<br />
Leukemia
of treatment. As an alternative, some authors are in favor of<br />
prophylaxis <strong>with</strong> antibacterial <strong>and</strong> antiviral agents in patients<br />
treated <strong>with</strong> purine analogs. 44,45 This approach is intended to<br />
reduce the incidence of opportunistic infections. We have not,<br />
however, observed in our patients infections caused by Pneumocystis<br />
carinii or other opportunistic infections. Such an<br />
approach should also not be recommended because of the<br />
broad spect<strong>ru</strong>m of potential infections that may necessitate the<br />
use of numerous potentially toxic d<strong>ru</strong>gs. 46<br />
In conclusion, <strong>combined</strong> treatment <strong>with</strong> 2-CdA, mitoxantrone<br />
<strong>and</strong> <strong>cyclophosphamide</strong> (CMC programme) shows significant<br />
therapeutic activity in previously untreated patients<br />
<strong>with</strong> CLL. However, the toxicity of the CMC programme is<br />
significant although it is restricted mainly to myelosuppression<br />
<strong>and</strong> infections. The reduction of total dose of 2-CdA per cycle<br />
in the CMC programme does not seem to decrease its antileukemic<br />
activity but significantly reduces the risk of infections.<br />
At present, it is not clear whether the CMC programme is more<br />
efficient in comparison to 2-CdA in monotherapy or the combination<br />
of 2-CdA <strong>with</strong> <strong>cyclophosphamide</strong> in previously<br />
untreated CLL patients. Nevertheless, in our opinion, the<br />
CMC3, but not the CMC5 programme, deserves further<br />
evaluation.<br />
Acknowledgements<br />
This work was supported in part by grant No. 4P05B06019,<br />
from KBN, Warsaw, Pol<strong>and</strong>. We thank Mr Shane Gollop for<br />
the correction of the English version of the manuscript.<br />
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