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P Moreau,
J Bladeé,
S V Rajkumar,
O Sezer,
H Goldschmidt, X Leleu,
S K Kumar,
C Hulin,
J H Lee,
J Crowley, [......],
S K Klein,
P Sonneveld,
G Morgan,
J S Miguel,
D Siegel,
J Feather,
P G Richardson,
R Orlowski,
A Hoering,
A Palumbo
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H Avet-Loiseau,
B G M Durie,
M Cavo,
M Attal,
N Gutierrez,
J Haessler,
H Goldschmidt,
R Hajek,
J H Lee,
O Sezer,
B Barlogie, J Crowley,
R Fonseca,
N Testoni,
F Ross,
S V Rajkumar,
P Sonneveld,
J Lahuerta,
P Moreau,
G Morgan
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ABSTRACT: The combination of serum β2-microglobulin and albumin levels has been shown to be highly prognostic in myeloma as the International Staging System (ISS). The aim of this study was to assess the independent contributions of ISS stage and cytogenetic abnormalities in predicting outcomes. A retrospective analysis of international studies looking at both ISS and cytogenetic abnormalities was performed in order to assess the potential role of combining ISS stage and cytogenetics to predict survival. This international effort used the International Myeloma Working Group database of 12 137 patients treated worldwide for myeloma at diagnosis, of whom 2309 had cytogenetic studies and 5387 had analyses by fluorescent in situ hybridization (iFISH). Comprehensive analyses used 2642 patients with sufficient iFISH data available. Using the comprehensive iFISH data, combining both t(4;14) and deletion (17p), along with ISS stage, significantly improved the prognostic assessment in terms of progression-free survival and overall survival. The additional impact of patient age and use of high-dose therapy was also demonstrated. In conclusion, the combination of iFISH data with ISS staging significantly improves risk assessment in myeloma.Leukemia advance online publication, 26 October 2012; doi:10.1038/leu.2012.282.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 10/2012; · 8.30 Impact Factor
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ABSTRACT: The concept of applying all active therapeutic agents in Total Therapy (TT) clinical trials for newly diagnosed multiple myeloma was pursued with the intent of developing curative treatment. The results of TT1 (n=231), TT2 (n=668) without or with thalidomide and TT3 with added bortezomib (n=303) have been reported. An update with median follow-up times of 17.1, 8.7 and 5.5 years, respectively, is provided. Conditional overall survival (OS) analysis from a 4-year landmark was applied to account for earlier protocol failure owing to disease aggressiveness and toxicities. Cumulative relative survival was computed in the context of age- and gender-matched US population, and interval-specific relative survival ratios were estimated to determine times to normal survival expectation. Based on Cox model-adjusted statistics, OS, progression-free survival and complete-response duration all improved with the transitions from TT1 to TT2 to TT3; improvement was also evident from time-to-progression estimates, 4-year conditional survival data and cumulative relative survival. Interval-specific relative survival normalized progressively sooner, reaching near-normal levels with TT3 in patients who attained complete response. Thus, a strategy using all myeloma-effective agents up-front seems effective at preventing, in progressively larger patient cohorts over time, the outgrowth of resistant tumor cells that account for ongoing relapses.Leukemia advance online publication, 13 July 2012; doi:10.1038/leu.2012.160.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 06/2012; · 8.30 Impact Factor
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S K Kumar,
J H Lee,
J J Lahuerta,
G Morgan,
P G Richardson, J Crowley,
J Haessler,
J Feather,
A Hoering,
P Moreau, [......],
P Sonneveld,
D Siegel,
J Bladeé,
H Goldschmidt,
S Jagannath,
J S Miguel,
R Orlowski,
A Palumbo,
O Sezer,
S V Rajkumar
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 05/2012; 26(5):1153. · 8.30 Impact Factor
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S Z Usmani,
B Nair,
P Qu,
E Hansen,
Q Zhang,
N Petty,
S Waheed,
J D Shaughnessy,
Y Alsayed,
C J Heuck,
F van Rhee,
T Milner,
A Hoering,
J Szymonifka,
R Sexton,
J Sawyer,
Z Singh, J Crowley,
B Barlogie
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ABSTRACT: To determine whether primary plasma cell leukemia (PPCL) remains a high-risk multiple myeloma feature in the context of contemporary therapy and gene-expression profiling (GEP), we reviewed records of 1474 patients with myeloma, who were enrolled in Total Therapy protocols or treated identically off protocol. A total of 27 patients (1.8%) were classified as having PPCL. As a group, these patients more often had low hemoglobin, high beta-2-microglobulin, high lactate dehydrogenase, low albumin and cytogenetic abnormalities. Among 866 patients with GEP results, the PPCL group more often had disease that was classified as high risk, and in CD-1 and MF molecular subgroups. Regardless of the therapeutic protocol, patients with PPCL had shorter median overall survival (OS; 1.8 years), progression-free survival (PFS; 0.8 years) and complete response duration (CRD; 1.3 years) than the remainder, whose clinical outcomes had improved markedly with successive protocols. Multivariate analyses of pretreatment parameters showed that PPCL was a highly significant independent adverse feature linked to OS, PFS and CRD. In GEP analyses, 203 gene probes distinguished PPCL from non-PPCL; the identified genes were involved in the LXR/RXR activation, inositol metabolism, hepatic fibrosis/hepatic stellate-cell activation and lipopolysaccharide/interleukin-1-mediated inhibition of RXR function pathways. Different treatment approaches building on these genomic differences may improve the grave outcome of patients with PPCL.Leukemia advance online publication, 18 May 2012; doi:10.1038/leu.2012.107.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 04/2012; · 8.30 Impact Factor
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S K Kumar,
J H Lee,
J J Lahuerta,
G Morgan,
P G Richardson, J Crowley,
J Haessler,
J Feather,
A Hoering,
P Moreau, [......],
D Siegel,
J Bladé,
H Goldschmidt,
S Jagannath,
J S Miguel,
R Orlowski,
A Palumbo,
O Sezer,
S V Rajkumar,
B G M Durie
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ABSTRACT: Promising new drugs are being evaluated for treatment of multiple myeloma (MM), but their impact should be measured against the expected outcome in patients failing current therapies. However, the natural history of relapsed disease in the current era remains unclear. We studied 286 patients with relapsed MM, who were refractory to bortezomib and were relapsed following, refractory to or ineligible to receive, an IMiD (immunomodulatory drug), had measurable disease, and ECOG PS of 0, 1 or 2. The date patients satisfied the entry criteria was defined as time zero (T(0)). The median age at diagnosis was 58 years, and time from diagnosis to T(0) was 3.3 years. Following T(0), 213 (74%) patients had a treatment recorded with one or more regimens (median=1; range 0-8). The first regimen contained bortezomib in 55 (26%) patients and an IMiD in 70 (33%). A minor response or better was seen to at least one therapy after T(0) in 94 patients (44%) including ≥ partial response in 69 (32%). The median overall survival and event-free survival from T(0) were 9 and 5 months, respectively. This study confirms the poor outcome, once patients become refractory to current treatments. The results provide context for interpreting ongoing trials of new drugs.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 07/2011; 26(1):149-57. · 8.30 Impact Factor
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S K Kumar,
J H Lee,
J J Lahuerta,
G Morgan,
P G Richardson, J Crowley,
J Haessler,
J Feather,
A Hoering,
P Moreau, [......],
Isabelle Vande Broek,
Karin Vanderkerken,
Robert Vescio,
David Vesole,
Anders Waage,
Michael Wang,
Donna Weber,
Jan Westin,
Keith Wheatley,
Jeffrey Zonder
[show abstract]
[hide abstract]
ABSTRACT: Promising new drugs are being evaluated for treatment of multiple myeloma (MM), but their impact should be measured against the expected outcome in patients failing current therapies. However, the natural history of relapsed disease in the current era remains unclear. We studied 286 patients with relapsed MM, who were refractory to bortezomib and were relapsed following, refractory to or ineligible to receive, an IMiD (immunomodulatory drug), had measurable disease, and ECOG PS of 0, 1 or 2. The date patients satisfied the entry criteria was defined as time zero (T0). The median age at diagnosis was 58 years, and time from diagnosis to T0 was 3.3 years. Following T0, 213 (74%) patients had a treatment recorded with one or more regimens (median=1; range 0–8). The first regimen contained bortezomib in 55 (26%) patients and an IMiD in 70 (33%). A minor response or better was seen to at least one therapy after T0 in 94 patients (44%) including partial response in 69 (32%). The median overall survival and event-free survival from T0 were 9 and 5 months, respectively. This study confirms the poor outcome, once patients become refractory to current treatments. The results provide context for interpreting ongoing trials of new drugs.Keywords: multiple myeloma; relapse; natural history; survival
Leukemia 07/2011; 26(1):149-157. · 9.56 Impact Factor
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B G M Durie,
B Van Ness,
C Ramos,
O Stephens,
M Haznadar,
A Hoering,
J Haessler,
M S Katz,
G R Mundy,
R A Kyle,
G J Morgan, J Crowley,
B Barlogie,
J Shaughnessy
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ABSTRACT: Bone disease in myeloma occurs as a result of complex interactions between myeloma cells and the bone marrow microenvironment. A custom-built DNA single nucleotide polymorphism (SNP) chip containing 3404 SNPs was used to test genomic DNA from myeloma patients classified by the extent of bone disease. Correlations identified with a Total Therapy 2 (TT2) (Arkansas) data set were validated with Eastern Cooperative Oncology Group (ECOG) and Southwest Oncology Group (SWOG) data sets. Univariate correlates with bone disease included: EPHX1, IGF1R, IL-4 and Gsk3beta. SNP signatures were linked to the number of bone lesions, log(2) DKK-1 myeloma cell expression levels and patient survival. Using stepwise multivariate regression analysis, the following SNPs: EPHX1 (P=0.0026); log(2) DKK-1 expression (P=0.0046); serum lactic dehydrogenase (LDH) (P=0.0074); Gsk3beta (P=0.02) and TNFSF8 (P=0.04) were linked to bone disease. This assessment of genetic polymorphisms identifies SNPs with both potential biological relevance and utility in prognostic models of myeloma bone disease.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 09/2009; 23(10):1913-9. · 8.30 Impact Factor
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Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 09/2008; 22(8):1650. · 8.30 Impact Factor
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M Pineda-Roman,
M Zangari,
F van Rhee,
E Anaissie,
J Szymonifka,
A Hoering,
N Petty, J Crowley,
J Shaughnessy,
J Epstein,
B Barlogie
[show abstract]
[hide abstract]
ABSTRACT: Bortezomib (V) was combined with thalidomide (T) and dexamethasone (D) in a phase I/II trial to determine dose-limiting toxicities (DLT's) and clinical activity of the VTD regimen in 85 patients with advanced and refractory myeloma. The starting dose of V was 1.0 mg/m(2) (days 1, 4, 8, 11, every 21 day) with T added from cycle 2 at 50 mg/day, with 50 mg increments per 10 patient cohorts, to a maximum dose of 200 mg. In the absence of DLT's, the same reiteration of T dose increases was applied with a higher dose of V=1.3 mg/m(2). D was added with cycle 4 in the absence of partial response (PR). Ninety-two percent had prior autotransplants, 74% had prior T and 76% abnormal cytogenetics. MTD was reached at V=1.3 mg/m(2) and T=150 mg. Minor response (MR) was recorded in 79%, and 63% achieved PR including 22% who qualified for near-complete remission. At 4 years, 6% remain event-free and 23% alive. Both OS and EFS were significantly longer in the absence of prior T exposure and when at least MR status was attained. The MMSET/FGFR3 molecular subtype was prognostically favorable, a finding since reported for a VTD-incorporating tandem transplant trial (Total Therapy 3) for untreated patients with myeloma (BJH 2008).
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 08/2008; 22(7):1419-27. · 8.30 Impact Factor
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ABSTRACT: Cytogenetic studies were performed as part of all diagnostic and surveillance bone marrow examinations in 956 newly diagnosed patients with multiple myeloma (MM) receiving total therapy (TT) protocols and in 1085 previously treated patients enrolled in non-TT protocols. In both groups, cytogenetic abnormalities (CA) were present in one-third at baseline and persisted in 14% prior to first and 10% prior to second transplant (TT, 5%; non-TT, 15%); post-transplant detection rates increased progressively with time, from 7% within 6 months to 21% within 24 months to 28% at relapse. According to multivariate analyses, overall survival was adversely affected by the presence of CA at baseline (hazard ratio (HR)=7.20, P<0.001) and the development of CA both prior to (HR=3.28, P<0.001) and after first transplant (HR=6.24, P<0.001), whereas suppression of CA pretransplant was favorable (HR=0.38, P<0.001). The presence of CA at relapse further distinguished patients with a short median post-relapse survival of only 11 versus 47 months in those without CA (P<0.0001). Post-relapse survival was independently adversely affected by the detection of CA both at baseline (HR=1.35, P=0.044) and relapse (HR=2.47, P<0.001). Collectively, these results underscore the importance of monitoring for CA and attest to the favorable prognostic consequences of CA suppression with effective therapy.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 04/2008; 22(4):850-5. · 8.30 Impact Factor
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B G M Durie,
J-L Harousseau,
J S Miguel,
J Bladé,
B Barlogie,
K Anderson,
M Gertz,
M Dimopoulos,
J Westin,
P Sonneveld, [......],
R Alexanian,
G Tricot,
M Attal,
G Merlini,
R Powles,
P Richardson,
K Shimizu,
P Tosi,
G Morgan,
S V Rajkumar
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ABSTRACT: New uniform response criteria are required to adequately assess clinical outcomes in myeloma. The European Group for Blood and Bone Marrow Transplant/International Bone Marrow Transplant Registry criteria have been expanded, clarified and updated to provide a new comprehensive evaluation system. Categories for stringent complete response and very good partial response are added. The serum free light-chain assay is included to allow evaluation of patients with oligo-secretory disease. Inconsistencies in prior criteria are clarified making confirmation of response and disease progression easier to perform. Emphasis is placed upon time to event and duration of response as critical end points. The requirements necessary to use overall survival duration as the ultimate end point are discussed. It is anticipated that the International Response Criteria for multiple myeloma will be widely used in future clinical trials of myeloma.
Leukemia 10/2006; 20(9):1467-73. · 9.56 Impact Factor
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ABSTRACT: The main purpose of this paper is to present the results of a randomized trial comparing the effects of two chemotherapy regimens on the Quality of life (QOL) of patients with advanced non-small-cell lung cancer (NSCLC). Trials in advanced stage disease represent an important treatment context for QOL assessment. A second purpose of this paper is to examine methods for handling the level of missing data commonly observed in the advanced stage disease context.
Patients were randomized to receive cisplatin plus vinorelbine or carboplatin plus paclitaxel. The QOL of 222 patients was assessed with the Functional Assessment of Cancer Therapy-Lung (FACT-L) prior to randomization; follow-up assessments occurred at 13 and 25 weeks. Three methods were used to analyze the QOL data: (1) cross-sectional analysis of four patient categories (improved, stable, missing, and declined) based on changes in the FACT-L score, (2) a mixed linear model, and (3) a pattern mixture model. The longitudinal analyses addressed two potential data biases.
Questionnaire submission rates were 91% at baseline, 68% at 13 weeks, and 47% at 25 weeks. The cross-sectional and mixed linear model analyses did not show significant differences by treatment arm in patient-reported QOL. The pattern mixture model analysis, more appropriate given non-ignorable missing data, also found no statistically significant effect of treatment on patient QOL.
We present a sensitivity analysis approach with multiple methods for analyzing treatment effects on patient QOL in the presence of substantial, non-ignorable missing data in an advanced stage disease clinical trial. We conclude that the two treatment arms did not differ statistically in their effects on patient QOL over a 25-week treatment period.
Quality of Life Research 04/2002; 11(2):115-26. · 2.30 Impact Factor
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ABSTRACT: We summarize the Southwest Oncology Group (SWOG) experience with standard therapy for multiple myeloma by reviewing and updating data from seven consecutive SWOG trials. Some modest progress has been made since the introduction of melphalan and prednisone (MP) for induction therapy, using regimens that involve vincristine and doxorubicin, and which save alkylating agents for possible later high-dose therapy. For maintenance, it appears that prednisone plays a useful role. We demonstrate the use of the data collected in these trials with a proposed new staging system.
Seminars in Hematology 08/2001; 38(3):203-8. · 3.99 Impact Factor
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K Kelly, J Crowley,
P A Bunn,
C A Presant,
P K Grevstad,
C M Moinpour,
S D Ramsey,
A J Wozniak,
G R Weiss,
D F Moore,
V K Israel,
R B Livingston,
D R Gandara
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ABSTRACT: This randomized trial was designed to determine whether paclitaxel plus carboplatin (PC) offered a survival advantage over vinorelbine plus cisplatin (VC) for patients with advanced non--small-cell lung cancer. Secondary objectives were to compare toxicity, tolerability, quality of life (QOL), and resource utilization.
Two hundred two patients received VC (vinorelbine 25 mg/m(2)/wk and cisplatin 100 mg/m(2)/d, day 1 every 28 days) and 206 patients received PC (paclitaxel 225 mg/m(2) over 3 hours with carboplatin area under the curve of 6, day 1 every 21 days). Patients completed QOL questionnaires at baseline, 13 weeks, and 25 weeks. Resource utilization forms were completed at five time points through 24 months.
Patient characteristics were similar between the groups. The objective response rate was 28% in the VC arm and 25% in the PC arm. Median survival was 8 months in both arms, with 1-year survival rates of 36% and 38%, respectively. Grade 3 and 4 leukopenia (P =.002) and neutropenia (P =.008) occurred more frequently on the VC arm. Grade 3 nausea and vomiting were higher on the VC arm (P =.001, P =.007), and grade 3 peripheral neuropathy was higher on the PC arm (P <.001). More patients on the VC arm discontinued therapy because of toxicity (P =.001). No difference in QOL was observed. Overall costs on the PC arm were higher than on the VC arm because of drug costs.
PC is equally efficacious as VC for the treatment of advanced non--small-cell lung cancer. PC is less toxic and better tolerated but more expensive than VC. New treatment strategies should be pursued.
Journal of Clinical Oncology 08/2001; 19(13):3210-8. · 18.37 Impact Factor
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R Desikan,
B Barlogie,
J Sawyer,
D Ayers,
G Tricot,
A Badros,
M Zangari,
N C Munshi,
E Anaissie,
D Spoon,
D Siegel,
S Jagannath,
D Vesole,
J Epstein,
J Shaughnessy,
A Fassas,
S Lim,
P Roberson, J Crowley
[show abstract]
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ABSTRACT: High-dose therapy (HDT) has increased complete remission (CR) rates and survival in multiple myeloma (MM). We now report on continuous CR (CCR) and associated prognostic factors in 1000 consecutive patients receiving melphalan-based tandem HDT. Five-year CCR was 52% among 112 CR patients without chromosome 13 (triangle up13) abnormalities and with beta-2-microglobulin </= 2.5 mg/L, C-reactive protein </= 4 mg/L, and pre-HDT standard chemotherapy </= 12 months. Of all 390 CR patients without triangle up13 abnormalities, 35% enjoyed 5-year CCR but none of 54 with triangle up13 abnormalities. triangle up13 abnormalities, present in overall 16%, reduced 5-year event-free survival from 20% to 0% and overall survival from 44% to 16% (both P <.0001). CR and a second HDT cycle applied within 6 months both extended event-free and overall survival significantly, justifying further pursuit of HDT, especially toward curing non-triangle up13 MM. (Blood. 2000;95:4008-4010)
Blood 07/2000; 95(12):4008-10. · 9.90 Impact Factor
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Journal of Clinical Oncology 12/1999; 17(11 Suppl):22-4. · 18.37 Impact Factor
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[show abstract]
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ABSTRACT: We investigate a resampling method for bias correction in group sequential designs with censored survival data using logrank testing. The method draws nested bootstrap samples of different sizes from the observed data in order to mimic the large sample independent increment property of statistics resulting from sequential designs. The motivation for this problem came from the very positive results and early termination of a randomized clinical trial for nasopharyngeal cancer co-ordinated by the Southwest Oncology Group.
Statistics in Medicine 11/1999; 18(19):2635-44. · 1.88 Impact Factor
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[show abstract]
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ABSTRACT: We develop a method for constructing adaptive regression spline models for the exploration of survival data. The method combines Cox's (1972, Journal of the Royal Statistical Society, Series B 34, 187-200) regression model with a weighted least-squares version of the multivariate adaptive regressi on spline (MARS) technique of Friedman (1991, Annals of Statistics 19, 1-141) to adaptively select the knots and covariates. The new technique can automatically fit models with terms that represent nonlinear effects and interactions among covariates. Applications based on simulated data and data from a clinical trial for myeloma are presented. Results from the myeloma application identified several important prognostic variables, including a possible nonmonotone relationship with survival in one laboratory variable. Results are compared to those from the adaptive hazard regression (HARE) method of Kooperberg, Stone, and Truong (1995, Journal of the American Statistical Association 90, 78-94).
Biometrics 04/1999; 55(1):204-13. · 1.83 Impact Factor
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B Barlogie,
S Jagannath,
K R Desikan,
S Mattox,
D Vesole,
D Siegel,
G Tricot,
N Munshi,
A Fassas,
S Singhal, [......],
E Anaissie,
D Dhodapkar,
S Naucke,
J Cromer,
J Sawyer,
J Epstein,
D Spoon,
D Ayers,
B Cheson, J Crowley
[show abstract]
[hide abstract]
ABSTRACT: Between August 1990 and August 1995, 231 patients (median age 51, 53% Durie-Salmon stage III, median serum beta-2-microglobulin 3.1 g/L, median C-reactive protein 4 g/L) with symptomatic multiple myeloma were enrolled in a program that used a series of induction regimens and two cycles of high-dose therapy ("Total Therapy"). Remission induction utilized non-cross-resistant regimens (vincristine-doxorubicin-dexamethasone [VAD], high-dose cyclophosphamide and granulocyte-macrophage colony-stimulating factor with peripheral blood stem cell collection, and etoposide-dexamethasone-cytarabine-cisplatin). The first high-dose treatment comprised melphalan 200 mg/m2 and was repeated if complete (CR) or partial (PR) remission was maintained after the first transplant; in case of less than PR, total body irradiation or cyclophosphamide was added. Interferon--2b maintenance was used after the second autotransplant. Fourteen patients with HLA-compatible donors underwent an allograft as their second high-dose therapy cycle. Eighty-eight percent completed induction therapy whereas first and second transplants were performed in 84% and 71% (the majority within 8 and 15 months, respectively). Eight patients (3%) died of toxicity during induction, and 2 (1%) and 6 (4%) during the two transplants. True CR and at least a PR (PR plus CR) were obtained in 5% (34%) after VAD, 15% (65%) at the end of induction, and 26% (75%) after the first and 41% (83%) after the second transplants (intent-to-treat). Median overall (OS) and event-free (EFS) survival durations were 68 and 43 months, respectively. Actuarial 5-year OS and EFS rates were 58% and 42%, respectively. The median time to disease progression or relapse was 52 months. Among the 94 patients achieving CR, the median CR duration was 50 months. On multivariate analysis, superior EFS and OS were observed in the absence of unfavorable karyotypes (11q breakpoint abnormalities, -13 or 13-q) and with low beta-2-microglobulin at diagnosis. CR duration was significantly longer with early onset of CR and favorable karyotypes. Time-dependent covariate analysis suggested that timely application of a second transplant extended both EFS and OS significantly, independent of cytogenetics and beta-2-microglobulin. Total Therapy represents a comprehensive treatment approach for newly diagnosed myeloma patients, using multi-regimen induction and tandem transplantation followed by interferon maintenance. As a result, the proportion of patients attaining CR increased progressively with continuing therapy. This observation is particularly important because CR is a sine qua non for long-term disease control and, eventually, cure.
Blood 02/1999; 93(1):55-65. · 9.90 Impact Factor
