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ABSTRACT: Arsenic trioxide (ATO) is an inorganic arsenic derivative that is very effective against acute promyelocytic leukemia. However, organic arsenic derivatives (OAD) have a more favorable toxicity profile than ATO. We herein characterized dipropil-S-glycerol arsenic (GMZ27), a novel OAD. GMZ27 had potent antiproliferative activity against human acute myeloid leukemia (AML) cell lines that was higher than that of ATO. In contrast to ATO, GMZ27 only marginally induced maturation of leukemia cells and had no effect on the cell cycle. The anti-leukemia activity of GMZ27 against AML cells was independent of the presence of the PML-RARα fusion protein. GMZ27 dissipates mitochondrial transmembrane potential, and induces cleavage of caspase 9 and activation of caspase 3 without altering the expression levels of (BCL-2), BAX and BCL-xl. GMZ27 induces the formation of intracellular superoxide, a reactive oxygen species (ROS) which plays a major role in the antileukemia activity of this OAD. In addition to ROS generation, GMZ27 concomitantly reduces intracellular glutathione which markedly weakens the cellular antioxidant capacity, thus enhancing the detrimental intracellular effects of ROS production. These results indicate that GMZ27 induces apoptosis in AML cells in a PML-RARα-independent fashion, through the induction of ROS production. This activity provides the rationale for the testing of GMZ27 in patients with AML.
Anticancer research 07/2012; 32(7):2871-80. · 1.73 Impact Factor
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Tapan M Kadia,
Hagop Kantarjian,
Steven Kornblau,
Gautam Borthakur,
Stefan Faderl, Emil J Freireich,
Raja Luthra,
Guillermo Garcia-Manero,
Sherry Pierce,
Jorge Cortes,
Farhad Ravandi
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ABSTRACT: BACKGROUND: Activating mutations in RAS are frequently present in patients with acute myeloid leukemia (AML), but their overall prognostic impact is not clear. METHODS: A retrospective analysis was performed to establish the clinical characteristics of patients with RAS-mutated (RAS(mut) ) AML, to analyze their outcome by therapy, and to describe the proteomic profile of RAS(mut) compared with wild-type RAS (RAS(WT) ) AML. RESULTS: Of 609 patients with newly diagnosed AML, 11% had RAS(mut) . Compared with RAS(WT) , patients with RAS(mut) AML were younger (median age, 54 years vs 63 years; P = .001), had a higher white blood cell count (16K mm(-3) vs 4K mm(-3) ; P < 0.001) and bone marrow blast percentage (56% vs 42%; P = .01) at diagnosis, and were less likely to have an antecedent hematologic disorder (36% vs 50%; P = .03). The inv(16) karyotype was overrepresented in patients with RAS(mut) and the -5 and/or -7 karyotype was underrepresented. RAS mutations were found to have no prognostic impact on overall survival or disease-free survival overall or within cytogenetic subgroups. There was a suggestion that patients with RAS(mut) benefited from cytarabine (AraC)-based therapy. Proteomic analysis revealed simultaneous upregulation of the RAS-Raf-MAP kinase and phosphoinositide 3-kinase (PI3K) signaling pathways in patients with RAS(mut) . CONCLUSIONS: RAS mutations in AML may delineate a subset of patients who benefit from AraC-based therapy and who may be amenable to treatment with inhibitors of RAS and PI3K signaling pathways. Cancer 2012. © 2012 American Cancer Society.
Cancer 05/2012; · 4.77 Impact Factor
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ABSTRACT: Arsenic trioxide (ATO) is an inorganic arsenic derivative that is highly effective against PML-RARα-positive leukemia but much less against other hematological malignancies. We synthesized an organic arsenic derivative (OAD),
S-dimethylarsino-thiosuccinic acid (MER1), which offers a superior toxicity profile and comparable in vitro activity relative to ATO. In Swiss Webster mice, maximally-tolerated cumulative dose of MER1 when given IV for 5days was
100mg/kg/d. We demonstrated that MER1 induced apoptosis and dose- and time-dependent inhibition of survival and growth in
a panel of myeloid leukemia cell lines. Unlike ATO, this activity was independent of PML-RARα status and was not associated with induction of myeloid maturation. In NB4 and HL60 cells, MER1 and ATO induced caspase activation
and dissipation of mitochondrial transmembrane potential. At the same time, MER1 induced generation of reactive oxygen species
(ROS) and cell cycle arrest in G2/M phase and proved to be more potent than ATO at inducing apoptosis. ROS generation and
intracellular glutathione levels were key modulators of MER1-induced cytotoxicity as evidenced by abrogation of apoptosis
in myeloid leukemia cell lines pretreated with the disulfide bond-reducing agent dithiothreitol or the radical scavenger N-acetyl-L-cysteine.
Collectively, these data indicate that MER1 induces apoptosis in PML-RARα-positive and -negative myeloid leukemia cells by enhancing oxidative stress. This agent, therefore, combines low in vivo toxicity with formidable in vitro pro-apoptotic ROS-mediated activity, and may represent a novel OAD suitable for clinical development against a variety of
hematological malignancies.
KeywordsMER1-Organic arsenic derivatives-
PML-RARα
-Acute myeloid leukemia
Investigational New Drugs 04/2012; 28(4):402-412. · 3.36 Impact Factor
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Clinical lymphoma, myeloma & leukemia 06/2011; 11 Suppl 1:S1.
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ABSTRACT: Peripheral blood stem cell transplantation (PBSCT) is the most common transplantation procedure performed in medicine. Its clinical introduction in 1986 replaced BM as a stem-cell source to approximately 100% in the autologous and to approximately 75% in the allogeneic transplantation setting. This historical overview provides a brief insight into the discovery of circulating hematopoietic stem cells in the early 1960s, the development of apheresis technology, the discovery of hematopoietic growth factors and small molecule CXCR4 antagonist for stem- cell mobilization, and in vivo experimental transplantation studies that eventually led to clinical PBSCT. Also mentioned are the controversies surrounding the engraftment potential of circulating stem cells before acceptance as a clinical modality. Clinical trials comparing the outcome of PBSCT with BM transplantation, registry data analyses, and the role of the National Marrow Donor Program (NMDP) in promoting unrelated blood stem-cell donation are addressed.
Blood 04/2011; 117(24):6411-6. · 9.90 Impact Factor
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Hatice Duzkale,
Carmen D Schweighofer,
Kevin R Coombes,
Lynn L Barron,
Alessandra Ferrajoli,
Susan O'Brien,
William G Wierda,
John Pfeifer,
Tadeusz Majewski,
Bogdan A Czerniak,
Jeffrey L Jorgensen,
L Jeffrey Medeiros, Emil J Freireich,
Michael J Keating,
Lynne V Abruzzo
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ABSTRACT: We previously identified LDOC1 as one of the most significantly differentially expressed genes in untreated chronic lymphocytic leukemia (CLL) patients with respect to the somatic mutation status of the immunoglobulin heavy-chain variable region genes. However, little is known about the normal function of LDOC1, its contribution to the pathophysiology of CLL, or its prognostic significance. In this study, we have investigated LDOC1 mRNA expression in a large cohort of untreated CLL patients, as well as in normal peripheral blood B-cell (NBC) subsets and primary B-cell lymphoma samples. We have confirmed that LDOC1 is dramatically down-regulated in mutated CLL cases compared with unmutated cases, and have identified a new splice variant, LDOC1S. We show that LDOC1 is expressed in NBC subsets (naive > memory), suggesting that it may play a role in normal B-cell development. It is also expressed in primary B-cell lymphoma samples, in which its expression is associated with somatic mutation status. In CLL, we show that high levels of LDOC1 correlate with biomarkers of poor prognosis, including cytogenetic markers, unmutated somatic mutation status, and ZAP70 expression. Finally, we demonstrate that LDOC1 mRNA expression is an excellent predictor of overall survival in untreated CLL patients.
Blood 02/2011; 117(15):4076-84. · 9.90 Impact Factor
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Hagop Kantarjian,
Farhad Ravandi,
Susan O'Brien,
Jorge Cortes,
Stefan Faderl,
Guillermo Garcia-Manero,
Elias Jabbour,
William Wierda,
Tapan Kadia,
Sherry Pierce,
Jianqin Shan,
Michael Keating, Emil J Freireich
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ABSTRACT: Patients ≥ 70 years of age with acute myeloid leukemia (AML) have a poor prognosis. Recent studies suggested that intensive AML-type therapy is tolerated and may benefit most. We analyzed 446 patients ≥ 70 years of age with AML (≥ 20% blasts) treated with cytarabine-based intensive chemotherapy between 1990 and 2008 to identify risk groups for high induction (8-week) mortality. Excluding patients with favorable karyotypes, the overall complete response rate was 45%, 4-week mortality was 26%, and 8-week mortality was 36%. The median survival was 4.6 months, and the 1-year survival rate was 28%. Survival was similar among patients treated before 2000 and since 2000. A multivariate analysis of prognostic factors for 8-week mortality identified the following to be independently adverse: age ≥ 80 years, complex karyotypes, (≥ 3 abnormalities), poor performance (2-4 Eastern Cooperative Oncology Group), and elevated creatinine > 1.3 mg/dL. Patients with none (28%), 1 (40%), 2 (23%), or ≥ 3 factors (9%) had estimated 8-week mortality rates of 16%, 31%, 55%, and 71% respectively. The 8-week mortality model also predicted for differences in complete response and survival rates. In summary, the prognosis of most patients (72%) ≥ 70 years of age with AML is poor with intensive chemotherapy (8-week mortality ≥ 30%; median survival < 6 months).
Blood 11/2010; 116(22):4422-9. · 9.90 Impact Factor
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Stefano Sacchi,
Hagop M. Kantarjian, Emil J Freireich,
Susan O'brien,
Jorge Cortes,
Mary Beth Rios,
Steve Kornblau,
Francis J. Giles,
Charles Roller,
James Gajewski,
Moshe Talpaz
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ABSTRACT: Preclinical data have shown that all-trans retinoic acid (ATRA) with interferon-alpha (IFN-α) can exert significant suppressive effects on Philadelphia-chromosome (Ph)-positive cells. The aim of this study combining IFN-α, low-dose cytosine arabinoside (ara-C) and ATRA was to increase the proportion of patients achieving a major cytogenetic response, in comparison with a group of 140 patients previously treated with IFN-α plus low-dose ara-C. Forty three patients with Ph-positive CML in early chronic phase were treated with IFN-α 5 MU/m2 sc daily, low-dose ara-C 10 mg sc daily and ATRA 45 mg/m2orally daily, for 7 consecutive days every other week. Overall, 76% of patients achieved a complete hematologic response (CHR). A cytogenetic response was in observed 59% (major in 38% and complete in 17%). Compared with patients treated with IFN-α and low-dose ara-C, those receiving additional ATRA had a lower CHR rate (p. 014), but other response rates were similar. Severe toxicities were common with the triple regimen (64%), mostly related to ATRA therapy. Two patients experienced pseudotumor cerebri; two patients had leukocytosis during the week on ATRA treatment, decreasing during the week off (one suffered a severe asthma-like reaction followed by pulmonary edema, resembling ATRA syndrome). Six patients had other unusual side-effects: aseptic necrosis of the hip (1 patient), ataxic syndrome (1 patient), paranoid syndrome (2 patients), syncopal episodes (1 patient), pure red cell aplasia (1 patient). In conclusion the results of IFN-α and low-dose ara-C combined with ATRA in patients with early CML-chronic phase were disappointing, due to excessive toxicity. Whether different ATRA dose schedules may result in fewer side-effects and improve hematologic and cytogenetic response remains to be determined.
03/2010; 35(5-6):483-489.
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ABSTRACT: The significance of terminal deoxynucleotidyl transferase (TdT) expression in acute myelogenous leukemia (AML) remains controversial. Therefore, we studied TdT expression by flow cytometry in 120 previously untreated patients with AML or myelodysplatic syndrome (MDS) to determine the distribution of TdT-positive blasts and the intensity of TdT expression and to seek clinically significant associations. TdT expression measured by flow cytometry (flow TdT%) was heterogeneous, ranging from 0.1% to 87% (median, 8.5%), and 74 patients (62%) had at least 5% TdT-positive blasts. TdT positivity was associated with the MO or Ml subtype and with expression of CD34 and CD7. No significant correlation was found between TdT expression and type of cytogenetic abnormality or rearrangement of immunoglobulin or T-cell receptor genes. Remission lasted longer in patients with a flow TdT% ≤ 5 than in patients with a flow TdT% ≥ 5 (median, 95 weeks vs 55 weeks, p = 0.02); however, complete remission rates did not differ when patients were classified by initial flow TdT%. Survival was slightly better for patients with flow TdT% less than 5% Among patients with a flow TdT% ≥ 5%, those with a higher TdT intensity survived longer than those with a lower intensity. These data suggest that quantitative TdT measurement may contribute to prognostic estimate in AML patients.
06/2009; 37(3-4):319-331.
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Journal of Clinical Oncology 01/2009; 27(2):304-6. · 18.37 Impact Factor
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Apostolia-Maria Tsimberidou,
Sijin Wen,
Peter McLaughlin,
Susan O'Brien,
William G Wierda,
Susan Lerner,
Sara Strom, Emil J Freireich,
L Jeffrey Medeiros,
Hagop M Kantarjian,
Michael J Keating
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ABSTRACT: Other malignancies have been reported to occur with increased frequency in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). The aim of this study was to determine the frequency, outcomes, and factors associated with other cancers in patients with CLL/SLL.
We reviewed the records of consecutive patients with previously untreated CLL/SLL seen at The University of Texas M. D. Anderson Cancer Center from 1985 to 2005. The number of second cancers observed was compared with the number expected from the Surveillance, Epidemiology, and End Results database.
Among 2,028 patients, 324 (16%) had a history of other cancers and 227 (11.2%) developed other malignancies during the follow-up period. Overall, 625 cancers were observed in 551 patients, including skin (30%), prostate (13%), breast (9%), melanoma (8%), lymphoma (8%), gastrointestinal (9%), lung (6%), and other cancers (17%). The risk of a second cancer was 2.2 times higher than the expected risk. The response rates in patients with and without a history of other cancers were 86% and 92%, respectively (P = .04), and the 5-year survival rates were 70% and 82%, respectively (P < .001). In Cox analysis, independent factors predicting development of new cancers were older age, male sex, and elevated levels of beta2-microglobulin, lactate dehydrogenase, and creatinine. In patients who were treated for CLL/SLL, the treatment regimen did not affect the risk of subsequent cancer (P = .49).
Patients with CLL/SLL have more than twice the risk of developing a second cancer and an increased frequency of certain cancer types. Awareness of risk factors could permit early detection.
Journal of Clinical Oncology 12/2008; 27(6):904-10. · 18.37 Impact Factor
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Emil J Freireich
Clinical advances in hematology & oncology: H&O 12/2008; 6(11):801-4.
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Hagop Kantarjian MD,
O&apos,
Susan Brien,
Jorge Cortes,
William Wierda,
Stefan Faderl,
Guillermo Garcia‐Manero,
Jean‐Pierre Issa,
Elihu Estey,
Michael Keating, Emil J. Freireich,
Hagop Kantarjian,
Susan O'Brien
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ABSTRACT: Major therapeutic progress has been accomplished in leukemia and myelodysplastic syndrome (MDS) over the past 40 years, which may not be fully appreciated by the larger medical community. The objective of this review was to briefly highlight the treatment breakthroughs in leukemia and MDS. Therapeutic progress happened through better understanding of disease pathophysiologies and rational development of targeted agents, like imatinib mesylate in chronic myeloid leukemia (CML), and through astute, empirical discoveries in the clinic, like all-trans retinoic acid and arsenic trioxide in acute promyelocytic leukemia (APL) and chlorodeoxyadenosine in hairy cell leukemia (HCL). Today, the 5- to 10-year survival rates in patients with APL and HCL exceed 80%. In patients with CML, imatinib therapy has been associated with estimated 5- to 7-year survival rates from 85% to 90%. In patients with adult acute lymphocytic leukemia, modern intensive regimens have improved the 5-year survival rates from 20% up to 40%. In patients with chronic lymphocytic leukemia, chemoimmunotherapy recently produced high rates of quality responses and improved long-term outcome. In younger patients with acute myeloid leukemia (AML), the 5-year survival rates range from 40% to 50%, although elderly AML remains a therapeutic challenge. In patients with MDS, it was recently demonstrated that epigenetic therapy with hypomethylating agents improved survival. Much therapeutic progress has been witnessed in leukemia and MDS, and much more is expected to occur soon. Cancer 2008;113(7 suppl):1933–52. © 2008 American Cancer Society.
Cancer 09/2008; 113(S7):1933 - 1952. · 4.77 Impact Factor
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ABSTRACT: It is unknown whether patients with nonleukemic myeloid sarcoma (MS) and those with acute myeloid leukemia (AML) have similar responses to anti-AML treatment. In the current study, the authors addressed this question by matching MS patients with analogous AML patients and comparing their clinical outcomes.
Twenty-three consecutive patients with MS and 1720 consecutive patients with AML were identified who presented at The University of Texas M. D. Anderson Cancer Center from 1990 to 2004. All AML patients and 16 MS patients received cytarabine plus idarubicin or fludarabine as induction remission therapy. Treated MS patients and AML patients were matched according to cytogenetics, age, Zubrod performance status, and time of treatment. Event-free survival (EFS) and overall survival (OS) were compared using Kaplan-Meier analyses.
Complete response rates were 69% in patients with MS and 57% in patients with AML (P = .45). The respective 2-year EFS and OS rates were 32% and 18% (P = .08) and 43% and 29% (P = .11). Matches were identified for 14 MS patients who were paired repeatedly with 91 AML patients to produce 94 matches (3 AML patients were matched twice). EFS was longer in 56 MS pair mates, shorter in 26 pair mates, and similar in 12 pair mates (P = .01; Fisher exact test). OS analyses yielded similar results.
Anti-AML therapy was highly effective in patients with nonleukemic MS. The results from this study emphasize the need to treat patients who have nonleukemic MS with AML-type therapy.
Cancer 08/2008; 113(6):1370-8. · 4.77 Impact Factor
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ABSTRACT: BACKGROUND.It is unknown whether patients with nonleukemic myeloid sarcoma (MS) and those with acute myeloid leukemia (AML) have similar responses to anti-AML treatment. In the current study, the authors addressed this question by matching MS patients with analogous AML patients and comparing their clinical outcomes.METHODS.Twenty-three consecutive patients with MS and 1720 consecutive patients with AML were identified who presented at The University of Texas M. D. Anderson Cancer Center from 1990 to 2004. All AML patients and 16 MS patients received cytarabine plus idarubicin or fludarabine as induction remission therapy. Treated MS patients and AML patients were matched according to cytogenetics, age, Zubrod performance status, and time of treatment. Event-free survival (EFS) and overall survival (OS) were compared using Kaplan-Meier analyses.RESULTS.Complete response rates were 69% in patients with MS and 57% in patients with AML (P = .45). The respective 2-year EFS and OS rates were 32% and 18% (P = .08) and 43% and 29% (P = .11). Matches were identified for 14 MS patients who were paired repeatedly with 91 AML patients to produce 94 matches (3 AML patients were matched twice). EFS was longer in 56 MS pair mates, shorter in 26 pair mates, and similar in 12 pair mates (P = .01; Fisher exact test). OS analyses yielded similar results.CONCLUSIONS.Anti-AML therapy was highly effective in patients with nonleukemic MS. The results from this study emphasize the need to treat patients who have nonleukemic MS with AML-type therapy. Cancer 2008. © 2008 American Cancer Society.
Cancer 07/2008; 113(6):1370 - 1378. · 4.77 Impact Factor
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Hagop Kantarjian,
Susan O'Brien,
Farhad Ravandi,
Jorge Cortes,
Jianqin Shan,
John M Bennett,
Alan List,
Pierre Fenaux,
Guillermo Sanz,
Jean-Pierre Issa, Emil J Freireich,
Guillermo Garcia-Manero
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ABSTRACT: Recent studies have highlighted issues with the International Prognostic Scoring System (IPSS) model in relation to the exclusion of many subgroups that now represent a large proportion of patients with myelodysplastic syndrome (MDS) (eg, secondary MDS, chronic myelomonocytic leukemia [CMML] with leukocytosis, prior therapy) and its lack of applicability to most patients on investigational programs, because many would have received prior therapies and would have had MDS for a significant length of time.
The authors analyzed 1915 patients with MDS who were referred from 1993 to 2005 (including those with CMML, secondary MDS, and MDS with prior therapy). Only 507 patients (26%) had primary MDS without prior therapy (ie, classifiable by the IPSS). Patients were divided randomly into a study group (n = 958) and a test group (n = 957). RESULTS.: A multivariate analysis of prognostic factors in the study group identified the following adverse, independent factors as continuous and categoric values (P<.001): poor performance, older age, thrombocytopenia, anemia, increased bone marrow blasts, leukocytosis, chromosome 7 or complex (>or=3) abnormalities, and prior transfusions. Cutoffs for anemia, thrombocytopenia and blasts, and cytogenetic subsets were different according to the IPSS. The new MDS prognostic model divided patients into 4 prognostic groups with significantly different outcomes. The model was validated in the test group. Applying the prognostic score of the new model within the 4 IPSS risk groups, overall, and in patients who had primary MDS without prior therapy was found to be highly prognostic in each subset. Applying the IPSS within each of the 4 risk groups of the new MDS model was not found to be prognostic.
The new model accounts for duration of MDS and prior therapy. It is applicable to any patient with MDS at any time during the course of MDS.
Cancer 07/2008; 113(6):1351-61. · 4.77 Impact Factor
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Apostolia-Maria Tsimberidou,
Hagop M Kantarjian,
Sijin Wen,
Susan O'Brien,
Jorge Cortes,
William G Wierda,
Charles Koller,
Sherry Pierce,
Mark Brandt, Emil J Freireich,
Michael J Keating,
Elihu H Estey
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ABSTRACT: Serum beta(2) microglobulin (beta2M) is prognostic in other hematologic malignancies; therefore, we evaluated its prognostic significance in acute myeloid leukemia (AML).
Multivariate analyses were used to examine the effect of pretreatment serum beta2M levels on clinical outcomes in patients with AML. beta2M was associated with poorer survival in older but not younger patients. We thus fit separate Cox survival models in patients above and below age 60 years treated with remission induction therapy containing high-dose cytarabine (n = 1,280). In each age group, 50% of the patients were used to develop the model, which was tested in the other 50%. Resampling methods were also used to validate the independent prognostic significance of covariates.
In patients 60 years or older (n = 591), poorer risk cytogenetics; poorer performance status; and higher levels of beta2M, uric acid, and lactate dehydrogenase were each found to independently predict shorter survival and formed the basis of a scoring system. A similar approach was used in patients younger than 60 years (n = 589), with poorer risk cytogenetics, poorer performance status, older age, higher hemoglobin level, and higher leukocyte count predicting a shorter survival and forming the basis of the scoring system. Higher beta2M levels were an adverse independent factor for response, survival, relapse-free survival, and event-free survival in older but not in younger patients.
Serum beta2M levels can help predict outcome in patients > or =60 years with untreated AML, and their use is strongly encouraged.
Clinical Cancer Research 02/2008; 14(3):721-30. · 7.74 Impact Factor
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ABSTRACT: The rates of expected serious adverse events in patients with acute leukemia on chemotherapy far exceed those in patients with solid tumors. Regulatory authorities require similar reporting criteria, which overburden the investigators and infrastructure with unnecessary documentation. To establish a baseline for expected toxicities before and during leukemia therapy, we reviewed 1534 adults with acute myeloid leukemia (AML; excluding acute promyelocytic leukemia) from 1990 to 2006 who received frontline intensive chemotherapy; 723 (47%) were 60 years or older. Prior to therapy, grade 3/4 cytopenias were observed in 86% of patients. All patients developed one or more grade 3/4 cytopenias during therapy, and more than 90% had a febrile episode. Admission to the intensive care unit, mechanical ventilation, and dialysis were required in 28%, 16%, and 7%, respectively. Mortality during induction, 2-week mortality, and 6-week mortality were 20%, 5%, and 16%, respectively. Grade 3/4 renal or hepatic toxicities were observed in 3% and 22% of patients, respectively. Other grade 3 or 4 toxicities were also common before treatment and during therapy. This paper establishes a baseline toxicity rate for patients with AML during induction therapy, and this could be used as a control group for future reference. Guidelines for reporting adverse events in leukemia studies should be revisited.
Blood 12/2007; 110(10):3547-51. · 9.90 Impact Factor
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Apostolia M Tsimberidou,
Sijin Wen,
Susan O'Brien,
Peter McLaughlin,
William G Wierda,
Alessandra Ferrajoli,
Stefan Faderl,
John Manning,
Susan Lerner,
Chinh V Mai,
Alma M Rodriguez,
Mark Hess,
Kim-Anh Do, Emil J Freireich,
Hagop M Kantarjian,
L Jeffrey Medeiros,
Michael J Keating
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ABSTRACT: Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are currently considered the same entity, but controversy remains over whether CLL and SLL should be treated similarly. We assessed whether characteristics of patients with CLL and SLL differ in ways other than the absolute lymphocyte count (ALC) and evaluated treatment outcomes and prognostic factors.
We searched the electronic database for patients with CLL or SLL who presented to The University of Texas M.D. Anderson Cancer Center (Houston, TX) between 1985 and 2005. We reviewed patient records to determine presenting characteristics, treatment, and clinical outcomes. Cox models using training and validation sets of patients and resampling methods were used to develop a model predicting survival.
Among 2,126 consecutive CLL/SLL patients, 312 (15%) had ALC less than 5 x 10(9)/L. Patients with ALC less than 5 x 10(9)/L had lower rates of cytogenetic abnormalities (P = .0002) and higher rates of CD38-positive results (P = .0002) and had mutated immunoglobulin heavy-chain variable region gene status (P = .034). Rates of response, survival, and failure-free survival (FFS) were not different among ALC groups. Regimens that included rituximab and a nucleoside analog were associated with superior rates of response and FFS compared with other therapies, irrespective of ALC. Deletion 17p or 6q with or without other cytogenetic abnormalities, age at least 60 years, beta2-microglobulin at least 2 mg/L, albumin less than 3.5 g/dL, and creatinine at least 1.6 mg/dL were each found to independently predict shorter survival and formed the basis of a scoring system.
Patients with CLL or SLL can be treated similarly. A new prognostic score is proposed.
Journal of Clinical Oncology 11/2007; 25(29):4648-56. · 18.37 Impact Factor
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Emil J Freireich
BMJ (Clinical research ed.). 10/2007; 335(7618):478.
