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Blood, Vol. 94 No. 2 (July 15), 1999:
pp. 448-454
Clinical Characteristics and Outcome of Young Chronic Lymphocytic
Leukemia Patients: A Single Institution Study of 204 Cases
By
Francesca R. Mauro,
Robert Foa,
Diana Giannarelli,
Iole Cordone,
Sabrina Crescenzi,
Edoardo Pescarmona,
Roberta Sala,
Raffaella Cerretti, and
Franco Mandelli
From the Dipartimento di Biotecnologie Cellulari ed Ematologia and
Dipartimento di Medicina Sperimentale e Patologia, University "La
Sapienza" of Rome, Rome, Italy; and the Dipartimento di Scienze
Biomediche ed Oncologia Umana, University of Turin, Turin, Italy.
 |
ABSTRACT |
A retrospective analysis on chronic lymphocytic leukemia (CLL)
patients  55 years observed at a single institution was performed with the purpose of characterizing the clinical features and outcome of
young CLL and of identifying patients with different prognostic features. Over the period from 1984 to 1994, 1,011 CLL patients (204 [20%] 55 years of age and 807 [80%] >55 years of age) were observed. At diagnosis, younger and older patients displayed a similar
distribution of clinical features, except for a significantly higher
male/female ratio in younger patients (2.85 v 1.29;
P < .0001). Both groups showed an elevated rate of
second primary cancers (8.3% v 10.7%), whereas the occurrence
of Richter's syndrome was significantly higher in younger patients
(5.9% v 1.2%; P < .00001). Younger and older
patients showed a similar overall median survival probability (10 years) but were characterized by a different distribution of causes of
deaths: CLL unrelated deaths and second primary malignancies
predominated in the older age group, whereas the direct effects of
leukemia were prevalent in the younger age group. Although younger and
older patients displayed a similar survival, the evaluation of the
relative survival rates showed that the disease had a greater adverse
effect on the expected survival probability of the younger population.
Multivariate analysis showed that for young CLL patients only dynamic
parameters, such as lymphocyte doubling time and other signs of active
disease, were the independent factors that significantly influenced
survival probability (P = .00001). A prolonged
clinico-hematologic follow-up allowed us to identify two subsets of
young CLL patients with a different prognostic outcome: a group of
patients (40%) with long-lasting stable disease without treatment and
an actuarial survival probability of 94% at 12 years from diagnosis
and another group (60%) with progressive disease and a median survival
probability of 5 years after therapy. For the latter patients, the
therapeutic effect of innovative therapies with curative intents needs
to be investigated in prospective, comparative clinical trials.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
CHRONIC LYMPHOCYTIC leukemia (CLL) is the
most common leukemia of the elderly people in the western world, with
only 10% to 15% of patients diagnosed while less than 50 years of
age.1,2 In the last decade, retrospective studies, mainly
multicentric, have focused on patients who are 50 years old or
less.2-6 Montserrat et al2 demonstrated that
the clinical features of these young patients do not differ
significantly from those of elderly patients and that traditional
clinical factors, such as stage, blood lymphocyte count, lymphocyte
doubling time (LDT), and bone marrow histology, bear the same known
predictive effect on survival. However, at present, there is only
limited information about the outcome of young patients after therapy.
Dhodapkar et al4 reported in 39 treated young patients an
overall actuarial median survival of 67 months; in patients refractory
to alkylating drugs, this rate decreased to only 19 months. More
recently, Seymour et al7 reported that the survival of 91 poor prognosis CLL patients 55 years old unresponsive to fludarabine
or relapsing after fludarabine-induced remission was very low.
Although for elderly patients a traditional conservative management is
a realistic and reasonable strategy, for younger patients this approach
may prove unsatisfactory. Thus, there is a general agreement that young
patients should deserve curative therapeutic efforts. Although purine
analogues, in particular fludarabine, have proven capable of inducing a
consistent proportion of complete responses (CR),8-10
residual disease is generally still present even in apparent complete
responders, suggesting that in most, if not all, cases the leukemic
clone is not eradicated. An increasing number of autologous and
allogeneic cell transplants has been attempted in younger patients with
poor prognosis CLL.11-16 The limited data available appear
promising, because both autologous and allogeneic transplants can
effectively induce long-term disease-free survival and in some cases
the molecular disappearance of the leukemic clone.16 Thus,
the question that becomes relevant is which subset of young CLL
patients may benefit from intensive therapeutic programs?
We report here a retrospective study performed on a series of 204 young
CLL patients 55 years of age observed at a single institution from
1984 onwards. The upper cut-off age for the definition of young CLL
patients was extended to 55 years, because this is the normally adopted
limit for the inclusion of patients into intensive chemotherapeutic
programs. The objective of this study was to characterize the clinical
features and the outcome of young (55 years) CLL patients and to
identify patients for whom the outcome was so poor to justify the
potential toxicity of more intensive therapeutic programs.
| |
MATERIALS AND METHODS |
Patients.
Over the period from 1984 to 1994, 204 CLL patients 55 year of age or
younger were observed at the Dipartimento di Biotecnologie Cellulari ed
Ematologia of the University "La Sapienza" of Rome (Rome, Italy).
During the same period, 807 CLL patients greater than 55 years of age
were also observed, leading to an overall total of 1,011 cases included
in this series. The cytomorphological and immunological diagnostic
criteria recommended by the National Cancer Institute (NCI; Bethesda,
MD)17 were applied to all patients included in
this study. Bone marrow biopsy was performed in the majority of younger
patients (170/204), and the pattern of marrow infiltration was
evaluated according to the criteria suggested by Rozman et
al.18 The clinical stage was defined according to
Rai19 and Binet.20 The clinical and
hematological features of smouldering CLL described by Montserrat et
al21 were considered for stage A patients. LDT was
evaluated according to the criteria proposed by Montserrat et
al.22
A group of patients did not double their lymphocyte count within 12 months from diagnosis, but showed during this period other signs of
active disease (AD) as defined by the NCI17 (marrow failure, high and progressive lymphocyte counts, and massive increase of nodal and/or spleen size) that required therapy. For the purpose of
this study, we identified these patients as patients with AD. We
evaluated the clinical and prognostic characteristics of such patients,
as well as of those with an LDT of 12 months and >12 months.
Patients were treated in the presence of advanced stage or progressive
disease according to the NCI recommendations for therapy17 and independently of age. Patients with advanced stages were treated at
the time of diagnosis, whereas earlier stage patients were treated only
at the time of disease progression. Response to therapy was assessed
according to the NCI criteria.17 One hundred twenty-three young patients and 399 old patients required treatment. The majority of
young (67%) and old patients (90%) received chlorambucil associated with prednisone as first-line therapy, whereas fludarabine associated with prednisone was administered to 26% of younger patients and to 7%
of older patients; different therapy schedules (CHOP, CVP, and CTX)
were used in the remaining cases. A second-line therapy was
administered to 52% of the younger patients and to 35% of the older
patients. Fludarabine was used as second-line therapy in a similar
proportion of younger (14%) and older (16%) patients.
With regard to mortality, active leukemia, associated infections,
Richter's syndrome, marrow failure, and second primary cancers were
considered as CLL-related causes of death. The clinical characteristics and survival probability of the 204 younger patients were compared with
those of the 807 older patients of our series.
Statistical analysis.
The corrected  2 test was applied to compare groups.
Survival curves were calculated according to Kaplan and
Meier23 and compared with the log-rank test.24
To evaluate the relative significance of some prognostic factors, the
multiple regression model of Cox was applied.25 The set
variables analyzed were as follows: age (55 v >55 years),
sex (male v female), stage according to Rai's classification
(0 v I+II v III+IV), signs of disease progression (LDT
>12 v 12 months v AD), bone marrow histology (nondiffuse v diffuse), and lymphocyte count (<50 × 109/L v 50 × 109/L).
The expected survival probability of the age- and sex-matched Italian
population was calculated on the basis of the life expectancy obtained
from the Italian 1986 lifetables and the relative survival rates were
calculated according to the method of Ederer et al.26
| |
RESULTS |
Patients' characteristics.
The overall proportion of young CLL patients 55 years of age in our
series of 1,011 cases was 20% (204 patients). Eleven percent (108 patients) were 50 years of age and 9% (96 patients) were between 50 and 55 years of age; 93 patients (9%) were between 40 and 50 years of
age, whereas 15 (1.5%) were less than 40 years of age. During the
period from 1984 to 1994, a median of 20% young patients per year has
been observed. The clinical features of both younger and older CLL
patients are reported in Table 1. When the
male (M) and female (F) distribution among younger and older patients
was compared, a significantly higher M/F ratio was noted in the former
group: 2.85 compared with 1.29 for older patients (P < .0001). Within young CLL patients, 74% (151/204) were males, whereas
in the group greater than 55 years of age, the percentage of males
decreased to 56% (454/807). An inverse correlation between M/F ratio
and age was observed. Younger and older patients showed similar median
values of peripheral blood lymphocytes, a similar proportion of
patients with clinical signs of progressive disease (LDT and AD), and
no difference in the distribution of clinical stages and bone marrow
patterns of lymphocyte infiltration. Furthermore, the same proportion
of smouldering CLL was observed among younger (34%) and older (33%)
patients (Table 1). No differences in the above-noted parameters were recorded between patients less than 50 years of age and patients between 50 and 55 years of age.
Treatment.
Forty percent of young patients (81) have so far not required
treatment, whereas 60% of patients (123) have been treated. All
advanced-stage patients were treated at diagnosis, whereas 48%
(74/154) of stage A patients were treated at the time of disease progression after a median time of 23 months from diagnosis. Only 24%
of young patients with smouldering features of CLL progressed and were
subsequently treated. The overall response rate (complete and partial
responses) to first- and to second-line therapy was 86% and 32%,
respectively. Forty-nine percent of the older patients (399) required
treatment. The proportion of stage A (40%) and of smouldering CLL
(18%) patients that progressed and required treatment, as well as the
overall response rate to first-line therapy (87%) and to second-line
therapy (36%), was similar to those of the younger age group.
Second primary cancers and Richter's syndromes.
The rate of second primary cancers within the overall series of 1,011 CLL patients was 10.2% (104): 8.3% (17) for younger patients and
10.7% (87) for older patients (P = not significant [NS]).
Skin cancers were observed only in the older age group, in which they
represented the most frequent type of tumor (2.1%). Other tumors
recorded only among elderly patients were prostate, larynx, pancreas,
and brain malignancies. Excluding the latter, the neoplasias most
frequently encountered in both groups of patients were
gastrointestinal, lung, kidney, bladder, and mammary cancers. Three
cases of acute myeloid leukemia were observed, 2 in young patients
previously treated with fludarabine and 1 in an old patient previously
treated with chlorambucil. A similar overall rate of second cancers was
documented among treated and untreated patients (50/522 [9.5%]
v 54/489 [11%]; P = NS). Twenty-two patients (2.2%) developed Richter's syndrome, in the form of a large-cell lymphoma in
18 cases (1.8%) and in the form of a Hodgkin's disease in 4 (0.4%).
Younger patients showed a significantly higher rate of Richter's
syndrome than did older patients (5.9% v 1.2%; P < .00001).
Survival analysis.
At the time of this analysis, 21% of patients (208) of the whole
series have died: 26% within the younger patients group and 19%
within the older patients group. As expected, CLL-unrelated deaths were
significantly greater in older than in younger patients (P < .0001). With regard to the CLL-related causes of deaths, an overall
rate of 98% for young patients and of 72% for old patients was
observed (P < .0001). The distribution of the different
CLL-related causes of deaths varied significantly according to age. The
rate of deaths due to neoplasia was 4% in young patients and 14% in the older patients (P < .05). Conversely, the proportion of
deaths considered as directly due to progressive CLL was significantly greater in younger than in older patients (85% v 49%;
P < .0001; Table 2).
The overall actuarial median survival from diagnosis for both groups of
patients was similar (10 years). Patients less than 50 years of age and
between 50 and 55 years of age displayed a similar survival trend.
Both young and old CLL patients showed a 10-year survival rate
significantly lower compared with the expected survival probability of
the age- and sex-matched Italian population: 55 years of age: controls 96.2% versus CLL 45.3%; greater than 55 years of age: controls 81.7% versus CLL 54.8%. When the relative survival rates were calculated, younger patients showed a lower relative survival rate
compared with older patients (47% v 67%).
Stage according to Rai's classification and Binet's classification,
bone marrow histology, lymphocyte count, LDT value, or the presence of
AD (Fig 1) showed a significant prognostic
effect on survival by univariate analysis
(Table 3). Male and female young patients
showed a similar survival probability. The multiple regression analysis
of Cox was applied to evaluate the relative prognostic significance on
survival of clinical stage (Rai's classification), bone marrow
histology, lymphocyte count, and signs of disease progression (LDT and
AD). In the group of older patients, two variables emerged as
independent prognostic parameters of statistical significance: stage
(P < .01) and signs of disease progression (LDT and AD;
P = .0001; Table 3). The same analysis performed in the group
of younger patients showed that only signs of disease progression (LDT
and AD) entered the modal at a highly significant level (P = .00001; Table 3). This means that, in the subset of young patients,
only dynamic parameters indicative of disease progression showed a
significant and independent value in predicting survival.
The overall median survival probability from the start of therapy for
the 123 treated younger patients was lower, although not significantly,
than that of the 399 treated older patients (5 v 7 years;
P = .14). No significant differences were observed when all
non-CLL-related causes of death were removed. The median survival
probability of young patients from the start of a second-line therapy
was 28 months. The projected survival probability of stable and
untreated stage A patients was 94% at 12 years
(Fig 2).
| |
DISCUSSION |
This study has been performed with the objective of better defining in
a large series of CLL followed at a single institution the incidence of
young CLL patients as well as their clinical and prognostic features.
Our main purpose was to identify young CLL patients with a poor
prognostic outcome who could be eligible for more aggressive
therapeutic strategies. Within our overall series of 1,011 CLL, the
proportion of patients 55 years of age was 20%. During the period
from 1984 to 1994, we have observed a progressively increasing number
of newly diagnosed CLL matched by a constant rate of about 20% young
patients per year. As previously described,2-6 younger and
older patients showed at diagnosis a similar distribution of clinical
features: stage, lymphocyte count, bone marrow histology, LDT, and AD.
The only unexplained difference between the two age groups was a
significantly higher male/female ratio in the younger group that could
be accounted for by a hypothetical protective endocrine
effect in young female subjects.
The association of a second primary malignancy with CLL is well known.
A recent epidemiological study performed on approximately 10,000 CLL
patients reported to tumor registries participating in the NCI
Surveillance, Epidemiology and End Results (SEER) Program27 reported a significantly increased risk of developing second cancers in
CLL patients, with an overall incidence of 8.7% that is similar to the
one observed in the present series. Second primary cancers occurred at
a not statistically different rate in both age group patients and did
not appear to be influenced by the effect of previous therapy. This
finding suggests that the disease-related immunodeficiency state of CLL
that most likely predisposes to the development of second malignancies
is independent of treatment and of age. The simultaneous occurrence of
a leukemia of the elderly and of a second cancer before 55 years of age
strongly suggests that some patients may have an increased risk of
developing early a tumor due to individual predisposing factors. The
rate of Richter's syndrome (2.2%) recorded in our series is
comparable to that reported by Robertson et al.28 Younger
patients showed a Richter's syndrome rate fivefold higher than older
patients. It should be recalled that the rate of lymphomas in the old
age group is possibly underestimated, because very old patients with
advanced and unresponsive disease are not always submitted, for ethical
reasons, to surgical biopsies.
The overall median survival probability of young patients was 10 years,
which is in line with the range of median survival values for young
patients included in other series.2-4,29,30 Stage,
peripheral blood lymphocytes, marrow histology, LDT, and AD correlated
significantly with survival in univariate analysis. However, in
multivariate analysis, LDT and AD (parameters indicative of early
disease progression) represented the only independent factors capable
of significantly predicting survival for young CLL
patients. As previously reported by us and by
others,31,32 bone marrow histology lost its prognostic
value when tested in multivariate analysis. Paradoxically, young age
did not represent a survival advantage, because both younger and older
patients showed a similar survival probability. However, causes of
deaths directly related to CLL progression predominated significantly in the younger age group, and the evaluation of the relative survival rates showed a greater impact of the disease on survival in the younger
than in the older age group. These findings indicate that a diagnosis
of CLL implies a more adverse effect on survival in younger people than
in older people.
Sixty percent of younger patients required treatment, and the majority
of them have obtained a clinical response to first-line therapy. The
median survival probability of younger patients from the start of first
line therapy was 5 years, which is lower, although not significantly,
compared with that of 7 years for the older patients. On the other
hand, a substantial group of young patients (40%) with an extremely
good prognostic likelihood could be identified within stage A patients
with stable disease: 94% of them are projected long-term survivors at
12 years from diagnosis without treatment. Such a different outcome for
patients with an apparently identical disease clearly indicates that
age is not a priori a sufficient reason to treat every young CLL
patient early after diagnosis. This finding suggests that, for both
younger and older patients, the same therapeutic policy should be
recommended: stage A patients should be treated only at the time of
disease progression, whereas advanced-stage patients require treatment
earlier. This is in agreement with the lack of survival advantage in
the early treatment of all stage A CLL patients reported in the
past33 and recently confirmed in a large randomized
study.34 Cytogenetic markers, molecular abnormalities, and
serologic molecules (soluble CD23 and interleukin-2 [IL-2] receptor,
 2-microglobulin, etc) within large prospective studies
could provide helpful prognostic information for a better
identification at diagnosis of patients with stable or progressive disease.
Whereas young CLL patients with early stage disease should not be
treated, young CLL patients with progressive disease have to be
considered for more effective treatment programs, because the
achievement of a better quality response may translate into a longer
relapse-free survival duration.35-37 Despite the high activity of fludarabine, no significant advantage of this drug compared
with other regimens on the long-term survival and cure of CLL has so
far been recorded.36,38 However, the possibility of
obtaining complete responses with little residual disease allows the
design of postinduction therapies, such as stem cells autologous transplantation, monoclonal antibodies, or other biologic agents. Since
the first reports of Rabinowe et al11 and Khouri et
al,13 an increasing number of patients have undergone
allogeneic or autologous bone marrow transplants and have been referred
to the transplant registries.15,39 At the present time,
there are insufficient data to establish whether transplant procedures
may improve the survival of CLL patients. However, the finding of cases
with long-lasting undetectable disease at the molecular level, both
after allogeneic and autologous transplant, is promising.16 Moreover, recent experiences indicate the feasibility of intensive therapies followed by transplant procedures also in patients greater than 50 years of age and the possibility of using autologous peripheral stem cells in young CLL patients responsive to nucleoside
analogues.40,41 The poor prognosis of the younger CLL
patients who require therapy should encourage to investigate the
benefit of such potentially eradicative programs.
Taken together, the results of the present study indicate that,
although the two age groups show similar CLL features at diagnosis and
overall survival, the disease itself appears to have a more adverse
effect on the expected survival of younger individuals. Two different
prognostic subsets of young CLL patients could be clearly identified: a
group of 40% of patients with long-lasting stable disease without
treatment and a group of 60% of patients with progressive disease and
low survival probability after therapy. For the latter patients, the
therapeutic effect of innovative treatment modalities with curative
intents needs to be investigated in prospective, comparative clinical trials.
| |
FOOTNOTES |
Submitted December 2, 1998; accepted March 21, 1999.
Supported by ROMAIL (Italian Association Against Leukemia-Section of
Rome) and by Istituto Superiore di Sanità, Italy-USA project on
"Therapy of Tumors," Rome, Italy.
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to Francesca R. Mauro, MD, Dipartimento di
Biotecnologie Cellulari ed Ematologia, University "La Sapienza,"
Via Benevento, 6, 00161 Rome, Italy.
| |
REFERENCES |
1.
Catovsky D, Foa R:
The Lymphoid Leukaemias. London, UK, Butterworths, 1990.
2.
Montserrat E, Gomis F, Vallespi T, Rios A, Romero A, Soler J, Alcalá A, Morey M, Ferrán C, Díaz-Mediavilla J, Flores A, Woessner S, Batlle J, Gonzáles-Aza C, Montserrat R, Reverter JC, Rozman C:
Presenting features and prognosis of chronic lymphocytic leukemia in younger adults.
Blood
78:1545, 1991[Abstract/Free Full Text]
3.
Pangalis GA, Reverter JC, Boussiotis VA, Montserrat E:
Chronic lymphocytic leukemia in younger adults: Preliminary results of a study based on 454 patients. IWCLL/Working Group.
Leuk Lymphoma
5:175, 1991 (suppl 1)
4.
Dhodapkar M, Tefferi A, Su J, Phyliky RL:
Prognostic features and survival in young adults with early/intermediate chronic lymphocytic leukemia (B-CLL): A single institution study.
Leukemia
7:1232, 1993[Medline]
[Order article via Infotrieve]
5.
De Rossi G, Mandelli F, Covelli A, Luciani M, Martelli M, Resegotti L, Alberti A, Cajozzo A, Deriu L, De Biasi R, Broccia G, Abbadessa A, Caronia F, Leone P:
Chronic lymphocytic leukemia (CLL) in younger adults: A retrospective study of 133 cases.
Hematol Oncol
7:127, 1989[Medline]
[Order article via Infotrieve]
6.
Molica S, Brugiatelli M, Callea V, Morabito F, Levato D, Nobile F, Alberti A:
Comparison of younger versus older B-cell chronic lymphocytic leukemia patients for clinical presentation and prognosis. A retrospective study of 53 cases.
Eur J Haematol
52:216, 1994[Medline]
[Order article via Infotrieve]
7.
Seymour JF, Robertson LE, O'Brien S, Lerner S, Keating MJ:
Survival of young patients with chronic lymphocytic leukemia failing fludarabine therapy: A basis for the use of myeloablative therapies.
Leuk Lymphoma
18:493, 1995[Medline]
[Order article via Infotrieve]
8.
Keating MJ, Kantarjian H, O' Brien S, Koller C, Talpaz M, Schachner J, Childs CC, Freireich EJ, McCredie KB:
Fludarabine: A new agent with marked cytoreductive activity in untreated chronic lymphocytic leukemia.
J Clin Oncol
9:44, 1991[Abstract/Free Full Text]
9.
Keating MJ, O'Brien S, Kantarjian H, Plunkett W, Estey E, Koller C, Beran M, Freireich EJ:
Long-term follow-up of patients with chronic lymphocytic leukemia treated with fludarabine as a single agent.
Blood
81:2878, 1993[Abstract/Free Full Text]
10.
Robertson LE, Huh YO, Butler JJ, Pugh WC, Hirsch-Ginsberg C, Stass S, Kantarjian H, Keating MJ:
Response assessment in chronic lymphocytic leukemia after fludarabine plus prednisone: Clinical, pathologic, immunophenotypic and molecular analysis.
Blood
80:29, 1992[Abstract/Free Full Text]
11.
Rabinowe SN, Soiffer RJ, Gribben JG, Daley H, Freedman AS, Daley J, Pesek K, Neuberg D, Pinkus G, Leavitt PR, Spector NA, Grossbard ML, Anderson K, Robertson MJ, Mauch P, Chayt-Markus K, Ritz J, Nadler LM:
Autologous and allogeneic bone marrow transplantation for poor prognosis patients with B-cell chronic lymphocytic leukemia.
Blood
82:1366, 1993[Abstract/Free Full Text]
12.
Michallet M, Corront B, Hollard D, Gratwohl A, Milpied N, Dauriact C, Brunet S, Soler J, Jovet JP, Esperou Bordeau H, Arcese W, Witz F, Moine A, Zwaah FE:
Allogeneic bone marrow transplantation in chronic lymphocytic leukemia: 17 cases reported from the EBMTG.
Bone Marrow Transplant
7:275, 1991[Medline]
[Order article via Infotrieve]
13.
Khouri IF, Keating MJ, Vriesendorp HM, Reading CL, Przepiorka D, Huh YO, Andersson BS, van Besien KW, Mehra RC, Giralt SA, Ippoliti C, Marshall M, Thomas MW, O'Brien S, Robertson LE, Deisseroth AB, Champlin RE:
Autologous and allogeneic bone marrow transplantation for chronic lymphocytic leukemia: Preliminary results.
J Clin Oncol
12:748, 1994[Abstract]
14.
Michallet M, Archimbaud E, Juliusson G, Bastion Y, Sutton L, Cahn JY, Neidhard EM, Fière D, Coiffier B, Gahrton G, Binet JL:
Autologous transplants in chronic lymphocytic leukaemia: Report of 11 cases.
Br J Haematol
87:172, 1994 (suppl 1)
15.
Michallet M, Archimbaud E, Bandini G, Rowlings PA, Deeg HJ, Gahrton G, Montserrat E, Rozman C, Gratwohl A, Gale RP:
HLA-identical sibling bone marrow transplantation in younger patients with chronic lymphocytic leukemia.
Ann Intern Med
124:311, 1996[Abstract/Free Full Text]
16.
Provan D, Bartlett-Pandite L, Zwicky C, Neuberg D, Maddocks A, Corradini P, Soiffer R, Ritz J, Nadler LM, Gribben JG:
Eradication of polymerase chain reaction-detectable chronic lymphocytic leukemia cells is associated with improved outcome after bone marrow transplantation.
Blood
88:2228, 1996[Abstract/Free Full Text]
17.
Cheson BD, Bennett JM, Rai KR, Grever MR, Kay NE, Schiffer CA, Oken MM, Keating MJ, Boldt DH, Kempin SJ, Foon KA:
Guidelines for clinical protocols for chronic lymphocytic leukemia: Recommendations of the National Cancer Institute-Sponsored Working Group.
Am J Hematol
29:152, 1988[Medline]
[Order article via Infotrieve]
18.
Rozman C, Montserrat E, Rodriguez-Fernandez JM, Ayats R, Vallespi T, Parody R, Ríos A, Prados D, Morey M, Gomis F, Alcalá A, Gutiérrez M:
Bone marrow histologic pattern. The best single prognostic parameter in chronic lymphocytic leukemia: A multivariate survival analysis of 329 cases.
Blood
64:642, 1984[Abstract/Free Full Text]
19.
Rai KR, Sawitsky A, Cronkite EP, Chanana AD, Levy RN, Pasternak BS:
Clinical staging of chronic lymphocytic leukemia.
Blood
46:219, 1975[Abstract/Free Full Text]
20.
Binet JL, Auquier A, Dighiero G, Chastang C, Piguet H, Goasguen J, Vaugier G, Potron G, Colona P, Oberling F, Thomas M, Tchernia G, Jacquillat C, Boivin P, Lesty C, Duault MT, Monconduit M, Belabbes S, Gremy F:
A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis.
Cancer
48:198, 1981[Medline]
[Order article via Infotrieve]
21.
Montserrat E, Viñolas N, Reverter JC, Rozman C:
Natural history of chronic lymphocytic leukaemia: On the progression and prognosis of early clinical stages.
Nouv Rev Fr Haematol
30:359, 1988
22.
Montserrat E, Sanchez-Bisono J, Viñolas N, Rozman C:
Lymphocyte doubling time in chronic lymphocytic leukaemia: Analysis of its prognostic significance.
Br J Haematol
62:567, 1986[Medline]
[Order article via Infotrieve]
23.
Kaplan EL, Meier P:
Non-parametric estimation from incomplete observation.
J Am Stat Assoc
53:457, 1958
24.
Peto R, Pike MC, Armitage P:
Design and analysis of randomized clinical trials requiring prolonged observation of each patients. Analyses and examples.
Br J Cancer
35:1, 1977[Medline]
[Order article via Infotrieve]
25.
Cox DR:
Regression models and life tables.
J R Stat Soc
34:187, 1972
26.
Ederer F, Axtell MA, Cutler SJ:
The relative survival rate: A statistical methodology.
Natl Cancer Inst Monogr
6:101, 1961
27.
Travis LB, Curtis RE, Hankey BF, Fraumeni JF Jr:
Second cancers in patients with chronic lymphocytic leukemia.
J Natl Cancer Inst
84:1422, 1992[Abstract/Free Full Text]
28.
Robertson LE, Pugh W, O'Brien S, Kantarjian H, Hirsch-Ginsberg C, Cork A, McLaughlin P, Cabanillas F, Keating MJ:
Richter's syndrome: A report on 39 patients.
J Clin Oncol
11:1985, 1993[Abstract/Free Full Text]
29.
Lee JS, Dixon DO, Kantarjian HM, Keating MJ, Talpaz M:
Prognosis of chronic lymphocytic leukemia: A multivariate regression analysis of 325 untreated patients.
Blood
69:929, 1987[Abstract/Free Full Text]
30.
De Lima M, O'Brien S, Lerner S, Keating MJ:
Chronic lymphocytic leukemia in the young patient.
Semin Oncol
25:107, 1998[Medline]
[Order article via Infotrieve]
31.
Mauro FR, De Rossi G, Burgio VL, Caruso R, Giannarelli D, Monarca B, Romani C, Baroni CD, Mandelli F:
Prognostic value of bone marrow histology in chronic lymphocytic leukaemia. A study of 335 untreated cases of a single institution.
Haematologica
79:335, 1994
32.
Geisler CH, Hou-Jensen K, Myhre Jensen O, Tinggaard-Pedersen N, Mork Hansen M, Hansen NE, Holm M, Egelund Christensen B, Drivsholm A, Boye Nielsen J, Thorling K, Andersen E, Larsen JK, Kragh Andersen P:
The bone-marrow infiltration pattern in B-cell chronic lymphocytic leukemia is not an important prognostic factor.
Eur J Haematol
57:292, 1996[Medline]
[Order article via Infotrieve]
33.
Catovsky D, Richards S, Fooks J, Hamblin TJ:
CLL trials in the United Kingdom: MRC trial 1, 2 and 3.
Leuk Lymphoma
5:105, 1991 (suppl 14)
34.
Dighiero G, Maloum K, Desablens B, Cazin B, Navarro M, Leblay R, Leporrier M, Jaubert J, Lepeu G, Dreyfus B, Binet JL, Travade P, and for The French Cooperative Group on Chronic Lymphocytic Leukemia:
Chlorambucil in indolent chronic lymphocytic leukemia.
N Engl J Med
338:1506, 1998[Abstract/Free Full Text]
35.
Brugiatelli M, Claisse JF, Lenormand B, Morabito F, Callea V, Malloum K, Chevret S, Binet JL, Dighiero G, Travade P:
Long-term outcome of B-cell chronic lymphocytic leukaemia patients in clinical remission phase evaluated at phenotypic level.
Br J Haematol
97:113, 1997[Medline]
[Order article via Infotrieve]
36.
The French Cooperative Group on CLL, Johnson S, Smith AG, Loffler H, Osby E, Juliusson G, Emmerich B, Wyld PJ, Hiddemann W:
Multicentre prospective randomised trial of fludarabine versus cyclophosphamide, doxorubicin and prednisone (CAP) for treatment of advanced-stage chronic lymphocytic lekaemia.
Lancet
347:1432, 1996[Medline]
[Order article via Infotrieve]
37.
Keating MJ, O'Brien S, Lerner S, Koller C, Beran M, Robertson LE, Freireich EJ, Estey E, Kantarjian H:
Long-term follow-up of patients with chronic lymphocytic leukemia (CLL) receiving fludarabine regimens as initial therapy.
Blood
92:1165, 1998[Abstract/Free Full Text]
38.
Rai KR, Peterson B, Eias L, Shepherd L, Hines J, Nelson D, Cheson B, Kolitz J, Schiffer CA:
A randomized comparison of fludarabine and chlorambucil for patients with previously untreated chronic lymphocytic leukemia.
Blood
88:141a, 1996 (abstr, suppl 1)
39.
Michallet M, Archimbaud E, Rowlings PA, Horowitz MM, Apperley J, Gratwohl A, Gale RP:
Hematopoietic stem cell transplant for chronic lymphocytic leukemia.
Bone Marrow Transpl
17:S3, 1996 (abstr, suppl 1)
40.
Meloni G, Mauro FR, Proia A, Vignetti M, Guglielmi C, De Fabritiis P, Foà R, Mandelli F:
Peripheral blood stem cell transplantation in CLL patients in remission after fludarabine therapy. A feasibility study, in
Dicke KA,
Keating A
(eds):
Autologous Marrow and Blood Transplantation. Proceedings of the 8th International Symposium. Arlington, TX, 1997Charlottesville, NCCarden Jennings1997177
41.
Itälä M, Pelliniemi TT, Rajamäki A, Remes K:
Autologous blood cell transplantation in B-CLL: Response to chemotherapy prior to mobilization predicts the stem cell yield.
Bone Marrow Transplant
19:647, 1997[Medline]
[Order article via Infotrieve]
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TOP
ABSTRACT
INTRODUCTION
