|
|||||||||
|
|
|
|
|
|
|
|
|
|
|
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the Johns Hopkins University, Baltimore, MD;
Southwest Oncology Group Statistical Center, Seattle, WA; University of
New Mexico Hospital, Albuquerque, NM; St. Jude Children's Research
Hospital, Memphis, TN; University of Rochester, Rochester, NY; SUNY
Health Science Center at Syracuse, Syracuse, NY; Kingston General
Hospital, Kingston, Ontario, Canada; University of Miami, Miami, FL;
Mayo Clinic, Rochester, MN; University of Chicago, Chicago, IL; Long
Island Jewish Hospital, New Hyde Park, NY; Puget Sound Oncology
Consortium, Seattle, WA; National Cancer Institute of Canada Clinical
Trials Group, Kingston, Ontario, Canada; National Cancer Institute,
Bethesda, MD; Ohio State University, Columbus, OH.
The nucleoside analogue, pentostatin, has demonstrated high
complete response rates and long relapse-free survival times in patients with hairy cell leukemia, a disease that historically had been
unresponsive to treatment. Long-term data on duration of overall
survival and relapse-free survival and incidence of subsequent
malignancies with this agent are lacking. Patients completing the
treatment phase of a randomized, intergroup study who received
pentostatin as an initial treatment or who crossed over after failure
of interferon alpha were followed for survival, relapse, and diagnosis
of subsequent malignancies. Two hundred forty-one patients
treated with pentostatin as initial therapy (n = 154) or who crossed
over after failure of interferon alpha (n = 87) were followed for a
median duration of 9.3 years. Estimated 5- and 10-year survival rates
(95% confidence interval) for all patients combined were 90%
(87%-94%) and 81% (75%-86%), respectively. In the 173 patients with a confirmed complete response to pentostatin treatment,
5- and 10-year relapse-free survival rates were 85% (80%-91%) and
67% (58%-76%), respectively. Survival curves for patients
initially treated with pentostatin and those crossed over were similar.
Only 2 of 40 deaths were attributed to hairy cell leukemia. The
mortality rate and incidence of subsequent malignancies were not higher
than expected in the general population. Pentostatin is a highly
effective regimen for hairy cell leukemia that produces durable
complete responses. Subsequent malignancies do not appear to be
increased with pentostatin treatment.
(Blood. 2000;96:2981-2986) Hairy cell leukemia is a rare, chronic B-cell
malignancy characteristically unresponsive to traditional cytotoxic
chemotherapy. Historically, hairy cell leukemia had been managed by
splenectomy, but remissions generally were short-lived. In the last
decade, the natural history of hairy cell leukemia has been
significantly altered by the discovery of several highly effective
treatments. Interferon alpha produces high overall objective response
rates but the majority are partial responses.1,2 In
contrast, 2 purine analogues, pentostatin (deoxycoformycin) and
cladribine (2-chlorodeoxyadenosine), have recently been shown to be
active in hairy cell leukemia, with complete response rates greater
than 75% documented in small noncomparative trials.3-9
Several long-term studies with cladribine demonstrate that these
remissions are durable, with 3- to 5-year relapse-free survival rates
of approximately 80%.6,8,10,11
There are little long-term data with
pentostatin.12,13 Because of the promising data shown with
pentostatin in early studies, an intergroup study organized by the
National Cancer Institute was initiated in 1986 to compare the efficacy
and safety of pentostatin and interferon alpha as an initial therapy of
hairy cell leukemia in unsplenectomized patients. In this randomized,
controlled trial, which enrolled patients between December 1986 and
September 1989, patients who did not respond to initial treatment were
crossed over so that they could potentially benefit from the other
treatment arm of the study. The initial report of this study showed
significantly higher complete response rates with pentostatin compared
with interferon alpha (76% vs 11%;
P < .0001).14 With a median follow-up duration of 57 months, remissions with pentostatin appeared to be
durable: 10 of 117 patients responding to pentostatin treatment relapsed compared with 12 of 17 patients responding to interferon alpha
(P < .0001).
With a median follow-up duration of 9.3 years, we now report the
long-term survival results of patients treated with pentostatin on this
study. In view of the concern of a potentially higher risk of secondary
neoplasms in patients with hairy cell leukemia,15,16 the
incidence of secondary malignancies was also evaluated in this study.
Patients and treatment
Patients were randomized to initial treatment with interferon alpha-2a
or pentostatin for 6 months. Patients randomized to interferon alpha-2a
received a self-administered study drug at a dose of
3 × 106 units subcutaneously 3 times per week. Treatment
was continued for 6 months (or less if evidence of progressive
disease). Patients with an objective partial response were treated for
an additional 6 months or until complete response or disease
progression. Patients with progressive disease or stable disease and
those who had experienced toxicity with interferon alpha-2a not
responsive to dose reduction were crossed over to pentostatin.
Patients randomized to pentostatin received a study drug in an
outpatient setting at a dose of 4 mg/m2 every 2 weeks by
rapid intravenous injection. (The initial pentostatin dose could be
reduced based on performance status and subsequent doses could be
reduced based on renal function).8 Patients who achieved a
complete response before 6 months received 2 additional doses of
pentostatin 14 days apart and treatment was then stopped. Patients with
an objective partial response were treated for a further 6 months or
until complete response or disease progression. Patients with
progressive disease or stable disease and those who had experienced
toxicity with pentostatin not responsive to dose reduction were crossed
over to interferon alpha-2a.
Patients whose hairy cell leukemia relapsed or progressed less than 3 months after discontinuing the initial therapy were crossed over to the
alternative therapy. If relapse occurred more than 3 months after
discontinuing the initial therapy, patients were retreated with the
same therapy.
Follow-up assessments
This study was performed in accordance with the ethical standards set forth by the Helsinki Declaration of 1975, as revised in 1983, and with the individual Institutional Review Boards that approved this study. All patients gave signed informed consent before participation. Statistical analyses The objectives of the follow-up phase of this study were to evaluate long-term survival, relapse-free survival, and incidence of subsequent malignancies in patients who received pentostatin as initial or crossover therapy in the randomized phase of the study. All patients were evaluated for survival. Survival was measured from the day of registration for pentostatin therapy until death from any cause (observations were censored for patients last known to be alive). Relapse-free survival was defined as the time interval between the date that complete response was established until first relapse or death from any cause. Observations of relapse-free survival were censored at the date of last contact for patients with no report of relapse who were last known to be alive. Distributions of relapse-free survival and overall survival were estimated by the method of Kaplan and Meier and compared between subgroups using the log rank test.17,18Mortality and cancer incidence after registration for pentostatin therapy were compared with those of the general US population using standardized mortality and incidence ratios (SMRs and SIRs, respectively).19 Expected numbers of deaths were calculated from 1990 age- and sex-specific mortality rates for white patients reported by the National Center for Health Statistics.26 Corresponding cancer incidence rates for 1989-1993 were obtained from the US National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) program.20 Results presented here are based on data available as of April 16, 1999.
Patients One hundred fifty-four eligible patients were randomized to initial pentostatin treatment at study entry. Of the 159 eligible patients randomized to initial interferon alpha-2a treatment, 87 patients failed treatment (84 because lack of response, 3 because toxicity) and were eligible for and crossed over to pentostatin (median time after randomization, 7 months; range, 2-64 months). Thus, a total of 241 patients were evaluable for long-term follow-up with pentostatin. Patients were primarily male, white, and had good performance status. Patients initially randomized to pentostatin and those crossed over from interferon alpha treatment were generally similar in pretreatment demographic and clinical characteristics (Table 1).
Overall survival Of the 241 eligible patients, 40 have died (28 initially treated with pentostatin and 12 cross-overs). For the remaining 201 patients, median duration of follow-up is 9.3 years (range, 19 months-11.6 years, with only 6 having less than 4 years of follow-up). Kaplan-Meier estimates of survival (Table 2) were 90% (95% confidence interval [CI], 87%-94%) at 5 years and 81% (CI, 75%-86%) 10 years after initiation of treatment. Survival outcomes were similar for patients initially treated with pentostatin and those crossed over from interferon alpha-2a treatment (2-tailed log rank P = .59) (Figure 1).
Overall survival was also evaluated according to patient age group
(younger than 55 years of age [n = 121] vs 55 years of age or older
[n = 120]). Ten-year survival rate was 93% (CI, 87%-99%) for
patients younger than 55 years of age compared with 68% (CI, 59%-78%) for patients 55 years of age and older (Figure
2). This difference was statistically
significant in favor of the younger-age patients (2-tailed log rank
P < .0001).
A total of 40 patients died, 7 within 1 year after registration for
pentostatin treatment and 33 after 1 year. The reasons for death are
summarized in Table 3. Of the 40 patients
who died, only 2 deaths were attributed to hairy cell leukemia. (Both
patients had crossed over to pentostatin after failure of interferon
alpha-2a treatment. One patient achieved a complete remission with
pentostatin, which was maintained for 32 months. The other patient was
noncompliant with follow-up studies and was withdrawn from treatment.)
To evaluate the mortality experience of the study patients, an SMR was
calculated and compared with that of the general population. On the
basis of the 1990 age- and sex-specific mortality rates for the white population in the United States,20 the expected number of
deaths among these 241 patients is 38.0. With 40 deaths observed, the SMR for the study cohort is 1.05 (CI, 0.75-1.43).
Relapse-free survival The analysis of relapse-free survival is based on 173 patients who achieved a confirmed complete response (117 after initial treatment with pentostatin and 56 who crossed over from interferon alpha-2a to pentostatin treatment). A total of 32 patients have relapsed (20 initial pentostatin, 12 crossed over), 4 of whom have died (3 initial pentostatin, 1 crossed over); 15 additional patients have died without documented relapse (11 initial pentostatin, 4 crossed over). Estimated 5- and 10-year relapse-free survival rates are 85% (CI, 80%-91%) and 67% (CI, 58%-76%), respectively, with similar outcomes regardless of initial treatment (2-tailed log rank P = .57) (Table 2, Figure 3). Relapse-free survival was also evaluated according to patient age group (younger than 55 years of age [n = 98] vs 55 years of age or older [n = 75]). The 10-year relapse-free survival rate was 77% (CI, 68%-87%) for patients younger than 55 years of age compared with 55% (CI, 40%-70%) for patients 55 years of age and older (Figure 4). This difference was statistically significant (2-tailed log rank P = .012).
Subsequent malignancies Thirty-nine of the 241 eligible patients had documented subsequent malignancies (Table 4). A total of 33 malignancies other than basal/squamous cell skin cancers were reported in 31 patients (23 men), with a median age at first subsequent diagnosis of 66 years (range, 32-84 years) and a median of 3.8 years between the start of pentostatin treatment and diagnosis of malignancy (range, 12 days-9.4 years). Thirteen (42%) of these 31 patients had been crossed over from interferon (IFN) to pentostatin, a somewhat higher proportion than among the remaining patients (74 of 210 patients, or 35%). This increase was attributable to the 8 patients whose subsequent malignancies were hematologic, 5 (63%) of whom had prior IFN (leaving 8 of 23, or 35%, among the patients with solid tumors). The responses of 6 of the 31 patients to pentostatin therapy were unknown: Three were removed from pentostatin treatment because of their subsequent diagnoses, and the assessments of 3 others were inadequate to determine response. Of the remaining 25 patients, 17 (including 15 with solid tumors) had subsequent malignancies diagnosed while their hairy cell leukemia (HCL) was in continuous complete remission from their first pentostatin therapy. Two other malignancies (including one solid tumor) were diagnosed during complete remissions, induced by retreatment with pentostatin on study, in patients whose first pentostatin-induced remissions had ended in relapse. One patient's subsequent malignancy was diagnosed while his hairy cell leukemia was in a partial response that eventually converted to complete remission. The remaining 5 patients' diagnoses occurred after disease progression or failure to achieve complete remission; information on further therapy for HCL in these patients is not available. On the basis of sex- and age-specific incidence rates during 1989-1993 for white patients, as reported by the US SEER registries,20 the expected total number of diagnoses of invasive cancer in this group of patients is 26.3, giving an SIR of 1.26 (95% CI, 0.86-1.77).
Because of uncertainty about whether subsequent diagnoses of lymphoma, myeloma, or leukemia might actually be misdiagnoses of hairy cell leukemia, the expected numbers of total diagnoses (all invasive malignancies) of solid tumors were calculated. When lymphoid and hematologic malignancies were excluded, there were 25 cases of solid tumors diagnosed in 23 patients occurring at a median of 4.1 years after initiation of treatment (range, 12 days-9.4 years). The expected number of diagnoses of solid, invasive tumors is 24.4, giving an SIR of 1.02 (95% CI, 0.66-1.52). Thus, the incidence of overall second malignancies and of solid tumors was not increased among patients treated with pentostatin in this study.
With a median follow-up duration of 9.3 years after initiation of
treatment, this study provides the longest duration of follow-up information in patients treated for hairy cell leukemia. Median overall
and relapse-free survival in this population of previously untreated,
unsplenectomized patients treated with pentostatin has not yet been
reached. Estimated 5- and 10-year overall survival rates of 90% and
81%, respectively, represent a significant prolongation of life in a
disease that remained unresponsive to therapy before the introduction
of purine nucleoside analogues.21 Other long-term data
currently available with pentostatin (median follow-up times of 38-82 months) in hairy cell leukemia show similar long survivals, although in
studies with small numbers of patients (n Remarkably, the mortality experience of the patients in this study did not differ significantly from that predicted for the general population. However, this should not be interpreted as conclusive evidence that hairy cell leukemia has no impact on life expectancy. There may be unknown factors in the selection of patients for this study that introduce bias into their comparison with the general population. In fact, mortality was greater in patients with hairy cell leukemia than in the general population in a retrospective analysis of 350 patients, primarily because of disease-related infections and secondary malignancies.22 However, it should be noted that only 2 patients in the current study subsequently died from hairy cell leukemia. The number of diagnoses of all invasive malignancies and of solid tumors are also consistent with predicted numbers and the SIRs for these events are not significantly greater than 1.0. This is true even though the numbers of reported malignancies may be somewhat inflated by cases of lymphoma, myeloma, or leukemia that might actually be misdiagnoses of hairy cell leukemia. In addition, 3 of 31 patients with subsequent malignancies other than basal/squamous cell skin cancers were diagnosed within 135 days after registration for pentostatin therapy, including one patient who had colon cancer diagnosed 28 days after registration. However, the inclusion of all subsequent diagnoses is conservative (ie, probably inflates the SIRs). Because the SIRs were not significantly greater than 1.0, these data are consistent with the report of no apparent increased incidence of secondary malignancies in other studies of patients with hairy cell leukemia treated with pentostatin.12,13,22,23 Pentostatin is a purine analogue that inhibits the catabolic enzyme, adenosine deaminase, which is responsible for conversion of adenosine to inosine. The exact mechanism by which pentostatin exerts its cytotoxic effects, however, is uncertain, but may include intracellular dATP accumulation, depletion of deoxynucleotides and inhibition of DNA synthesis, depletion of ATP, inhibition of RNA transcription, and other cellular reactions. Long-term studies with cladribine, an adenosine deaminase-resistant purine analogue, also produced long-term remissions.5,7,10,11,24,25 However, direct comparisons of the current results with those produced by cladrabine are difficult, given the differences in the designs of trials with the 2 agents. These studies of cladrabine are either small (approximately 50 patients in each) or have a significantly shorter median follow-up than the 9.3-year median follow-up duration in this study. However, the estimated probability of survival results at 48 months in this trial for the pentostatin patients in this study (93%, 95% CI, 89%-96%) is similar to what has been reported in a large, single-center study with cladrabine (96%, 95% CI, 94%-98%).24 This study provides important long-term data on survival and durability of complete responses with pentostatin in hairy cell leukemia. With a median follow-up of 9.3 years, 83% of patients treated with pentostatin are still alive and only 18% of patients who achieved a complete relapse have relapsed. It is possible that some patients with microscopic evidence of marrow relapse have gone undetected, as the methods of minimal residual disease detection have been refined since the design of this protocol. However, such relapses are of uncertain clinical significance. There has been no increase in secondary malignancies seen over this extended follow-up period from that expected in the general population. Pentostatin has had a significant impact on the management of this disease. With the advent of purine nucleosides, the natural history of hairy cell leukemia has clearly been improved. In fact, few people now actually die of hairy cell leukemia after remission induction. Infection and secondary malignancies had been shown in previous studies to be the leading causes of morbidity and mortality in patients with this disease. More importantly, results with pentostatin in hairy cell leukemia emphasize the impact of achieving a high complete remission on changing the natural history of a malignant disease. Although this rare form of leukemia is exquisitely sensitive to a single agent, novel strategies to effect a high complete response rate in other indolent lymphoid malignancies hopefully will achieve similar success.
We express our appreciation to Linda Mattucci Schiavone, MSc, for editorial assistance.
Submitted February 9, 2000; accepted June 20, 2000.
Supported by National Institutes of Health grants CA38926, CA20319, CA04920, CA46441, CA35117, CA12644, CA58686, CA22433, CA04919, CA20319, CA45377, CA35176, CA46136, CA45200, CA46368, CA35261, CA46113, CA35128, CA35431, CA42777, CA35090, CA12213, CA35192, CA35178, CA35262, CA32734, CA58658, CA46282, CA27057, CA16385, CA13612, CA37981, CA32102, CA11083, CA15488, CA13650, CA21060, CA41287, and CA11028. Financial support for data analysis was provided by Supergen, Inc, San Ramon, CA.
M.R.G. has declared a financial interest in a company whose product was studied in the present work.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Southwest Oncology Group (SWOG-8691), Operations Office, 14980 Omicron Dr, San Antonio, TX 78245-3217.
1.
Golomb HM, Jacobs A, Fefer A, et al.
Alpha-2 interferon therapy of hairy cell leukemia: a multicenter study of 64 patients.
J Clin Oncol.
1986;4:900-905 2. Quesada JR, Reuben JZ, Manning JT, Hersh EM, Gutterman JU. Alpha interferon for induction of remission in hairy-cell leukemia. N Engl J Med. 1984;310:15-18[Abstract]. 3. Spiers AS, Parekh SJ, Bishop MB. Hairy-cell leukemia: induction of complete remission with pentostatin (2'deoxycoformycin). J Clin Oncol. 1984;2:1336-1342[Abstract].
4.
Kraut EH, Bouroncle BA, Grever MR.
Low-dose deoxycoformycin in the treatment of hairy cell leukemia.
Blood.
1986;68:1119-1122 5. Lauria F, Rondelli D, Zinzani P, et al. Long-lasting complete remission in patients with hairy cell leukemia treated with 2-CdA: a 5-year survey. Leukemia. 1997;11:629-632[Medline] [Order article via Infotrieve]. 6. Piro LD, Carrera CJ, Carson DA, Beutler E. Lasting remissions in hairy-cell leukemia induced by a single infusion of 2-chlorodeoxyadenosine. N Engl J Med. 1990;322:117-121.
7.
Hoffman MA, Janson D, Rose E, Rai KR.
Treatment of hairy-cell leukemia with cladribine: response, toxicity, and long-term follow-up.
J Clin Oncol.
1997;15:1138-1142 8. Kraut EH, Bouroncle BA, Grever MR. Pentostatin in the treatment of advanced hairy cell leukemia. J Clin Oncol. 1989;7:168-172[Abstract].
9.
Johnston JB, Eisenhauer EA, Corbett WEN, Scott JG, Zaentz SD.
The efficacy of 2'-deoxycoformycin in hairy cell leukemia: a study of the National Cancer Institute of Canada Clinical Trials Group.
J Natl Cancer Inst.
1988;80:765-769
10.
Seymour J, Kruzrock R, Freireich E, Estey E.
2-chlorodeoxyadenosine induces durable remissions and prolonged suppression of CD4+ lymphocyte counts in patients with hairy cell leukemia.
Blood.
1994;83:2906-2911
11.
Tallman M, Hakimian D, Rademaker A, et al.
Relapse of hairy cell leukemia after 2-chlorodeoxyadenosine: long-term follow-up of the Northwestern University Experience.
Blood.
1996;88:1954-1959
12.
Kraut EH, Grever MR, Bouroncle BA.
Long-term follow-up of patients with hairy cell leukemia after treatment with 2'-deoxycoformycin.
Blood.
1994;84:4061-4063 13. Ribiero P, Bouaffia F, Peaud P-Y, et al. Long term outcome of patients with hairy cell leukemia treated with pentostatin. Cancer. 1999;85:65-71[Medline] [Order article via Infotrieve]. 14. Grever M, Kopecky K, Foucar MK, et al. Randomized comparison of pentostatin versus interferon alpha-2a in previously untreated patients with hairy cell leukemia: an intergroup study. J Clin Oncol. 1995;13:974-982[Abstract].
15.
Kampmeier P, Spielberger R, Dickstein J, Mick R, Golomb H, Vardiman JW.
Increased incidence of second neoplasms in patients treated with interferon alpha 2b for hairy cell leukemia: a clinicopathologic assessment.
Blood.
1994;83:2931-2938
16.
Bernstein L, Newton P, Ross RK.
Epidemiology of hairy cell leukemia in Los Angeles County.
Cancer Res.
1990;50:3605-3609 17. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958;53:457-481. 18. Mantel N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep. 1966;50:163170. 19. Breslow NE, Day NE. Statistical Methods in Cancer Research. Volume II. The Design and Analysis of Cohort Studies. Lyon: International Agency for Research on Cancer; 1987. 20. Ries LAG,Kosary CL,Hankey BF,Harras A,Miller BA, eds. SEER Cancer Sta-tistics Review, 1973-1993: Tables and Graphs. Bethesda, MD: National Cancer Institute; 1996. 21. Golomb HM, Catovsky D, Golde DW. Hairy cell leukemia: a clinical review based on 71 cases. Ann Intern Med. 1978;89:677-683.
22.
Kurzrock R, Strom SS, Estey E, et al.
Second cancer risk in hairy cell leukemia: analysis of 350 patients.
J Clin Oncol.
1997;15:1803-1810
23.
Cheson BD, Vena DA, Barrett J, Freidlin B.
Second malignancies as a consequence of nucleoside analog therapy for chronic lymphoid leukemias.
J Clin Oncol.
1999;17:2454-2460 24. Saven A, Burian C, Koziol JA, Piro LD. Long-term follow-up of patients with hairy cell leukemia after cladrabine treatment. Blood. 1998;1918-1926.
25.
Cheson BD, Sorensen JM, Vena DA, et al.
Treatment of hairy cell leukemia with 2-chlorodeoxyadenosine via the Group C protocol mechanism of the National Cancer Institute: a report of 979 patients.
J Clin Oncol.
1998;16:3007-3015 26. GMWK291 death rates for 12 selected causes by 5-year age groups, race, and sex: United States, 1979-1998. Available at: http://www.cdc.gov/nchswww/datawh/statab/unpubd/mortabs/gmwk291.htm. Accessed April 10, 1999.
© 2000 by The American Society of Hematology.
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
|
 |
|
  F. Ravandi, J. L. Jorgensen, S. M. O'Brien, S. Verstovsek, C. A. Koller, S. Faderl, F. J. Giles, A. Ferrajoli, W. G. Wierda, S. Odinga, et al. Eradication of minimal residual disease in hairy cell leukemia Blood, June 15, 2006; 107(12): 4658 - 4662. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Ravandi and S. O'Brien Chronic Lymphoid Leukemias Other Than Chronic Lymphocytic Leukemia: Diagnosis and Treatment Mayo Clin. Proc., December 1, 2005; 80(12): 1660 - 1674. [Abstract] [PDF]
|
|
|
|
 |
|
 M. A. Weiss, P. G. Maslak, J. G. Jurcic, D. A. Scheinberg, T. B. Aliff, N. Lamanna, S. R. Frankel, S. E. Kossman, and D. Horgan Pentostatin and Cyclophosphamide: An Effective New Regimen in Previously Treated Patients With Chronic Lymphocytic Leukemia J. Clin. Oncol., April 1, 2003; 21(7): 1278 - 1284. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. R. Goodman, C. Burian, J. A. Koziol, and A. Saven Extended Follow-Up of Patients With Hairy Cell Leukemia After Treatment With Cladribine J. Clin. Oncol., March 1, 2003; 21(5): 891 - 896. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Federico, P. L. Zinzani, A. Frassoldati, M. Vinceti, A. Mode, L. Annino, T. Chisesi, G. Pagnucco, R. Invernizzi, M. Spriano, et al. Risk of Second Cancer in Patients With Hairy Cell Leukemia: Long-Term Follow-Up J. Clin. Oncol., February 1, 2002; 20(3): 638 - 646. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
 |
 |
|||||||
 |
 |
 |
 |
 |
 |
 |
 |
||
| Copyright © 2000 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
Top
Abstract
Introduction
50).