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The original article to which this Erratum refers was published in Cancer (2006) 106(1):120–7.

c‐Src was the first protooncogene described and was among the first molecules in which tyrosine kinase activity was documented. c‐Src has been defined as a common modular structure that participates in much of the crosstalk between the cytoplasmic protein tyrosine kinases and tyrosine kinase receptors. Understanding the structure and function of this important class of protein kinases and elucidating the molecular signaling events mediated by c‐Src are important not only for identifying the critical pathways but also for designing new strategies to block or inhibit the action of these kinases. Despite the large amount of information available on c‐Src, its precise functions in cancer remain to be elucidated. Recently, there has been renewed interest in c‐Src as a molecular target for cancer therapy, and multiple c‐Src inhibitors are entering clinical trials. In this review, the authors describe the function and expression of c‐Src in human malignancies and the novel c‐Src inhibitors and their potential applications for cancer treatment. Cancer 2006. © 2006 American Cancer Society. more...

In the absence of curative options, therapy for aggressive forms of systemic mastocytosis (SM) has relied in the use of cytoreductive agents, mainly interferon‐α (IFN‐α) and cladribine. However, responses are transient and only occur in a subset of patients. Gain‐of‐function mutations at codon 816 of the KIT protooncogene lead to constitutively active Kit receptor molecules, which are central to the pathogenesis of SM. Recent advances in the understanding of the molecular underpinnings of SM have led to the development of small molecules targeting mutant Kit tyrosine kinase isoforms that significantly have widened the range of therapeutic options for patients with SM. Some of these promising agents, such as dasatinib, AMN107, and PKC412, currently are under investigation in clinical trials whereas, others are at different stages of preclinical development. In addition, monoclonal antibodies directed to neoplastic mast cell‐restricted surface antigens constitute a viable option for the treatment of SM that warrants further investigation. Cancer 2006. © 2006 American Cancer Society. more...

Topoisomerase I inhibitors, like topotecan, have activity in myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML). 9‐Nitro‐camptothecin (9‐NC) is a new oral topoisomerase inhibitor with a good safety profile. The aims of the current study were to evaluate the activity and safety of 9‐NC in MDS and CMML.Adults with a diagnosis of MDS (n = 12) and CMML (n = 32) received 9‐NC 2 mg/m2 orally daily 5 days a week, every 4 to 6 weeks.Overall, 5 (11%) patients achieved complete response (CR), 7 (16%) had a partial response (PR), and 6 (14%) had hematologic improvement (HI), for an overall response rate of 41%. The response rate was similar in MDS and CMML. Severe (Grade 3–4) side effects included nausea and vomiting (7%), diarrhea (18%), other gastrointestinal toxicities (5%), and genitourinary toxicities (12%).9‐NC is active in MDS and CMML. The paucity of available therapies in CMML makes 9‐NC a good candidate for further studies as a single agent, or in combination with decitabine, 5‐azacitidine or cytarabine. Cancer 2006. © 2006 American Cancer Society. more...

Alemtuzumab is a humanized monoclonal antibody directed against the cell surface antigen CD52 and has demonstrated activity in chronic lymphocytic leukemia and other CD52‐positive lymphoproliferative disorders. Because CD52 also is expressed on acute leukemic blasts, the authors investigated the safety and efficacy of alemtuzumab in patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).Fifteen patients with CD52‐positive (≥20%), recurrent or refractory acute leukemia (9 patients with AML and 6 patients with ALL) received alemtuzumab at a dose of 30 mg intravenously given 3 times a week (dose escalation during Week 1) for a total of 4 to 12 weeks.The median age of the patients was 39 years (range, 18‐71 years). Patients had received a median of 3 prior therapies (range, 1‐5 prior therapies). Two patients (13%) achieved a bone marrow complete response and 1 patient achieved a substantial reduction in bone marrow blasts. No complete remissions were observed. Ten patients developed disease progression while on study. Alemtuzumab was myelosuppressive in nearly all patients. Infusion‐related toxicities were common, but usually did not exceed Grade 2 (according to the National Cancer Institute Common Toxicity Criteria). Infectious episodes occurred in 13 patients (87%) and included pneumonia (6 patients), bacteremia (11 patients), fungemia (2 patients), and cytomegalovirus reactivation (2 patients).Single‐agent alemtuzumab was found to have limited activity in recurrent or refractory acute leukemia. An evaluation in patients with a better prognosis, in combination with other agents or as part of consolidation therapy, is warranted. Cancer 2006. © 2006 American Cancer Society. more...

Thalidomide is a putative antiangiogenesis agent with activity in several hematologic malignancies.Forty‐four patients who had myelofibrosis with myeloid metaplasia received treatment with thalidomide in a Phase II clinical trial at a dose of 200 mg daily with escalation by 200 mg weekly until the best tolerated dose (maximum, 800 mg) was reached.Seventeen of 41 evaluable patients (41%) who received treatment for at least 15 days had a response. A complete response (without reversal of bone marrow fibrosis) was achieved in 4 patients (10%), a partial response was achieved in 4 patients (10%), and hematologic improvements in anemia, thrombopenia, and/or splenomegaly were observed in 9 patients (21%). Improvements in anemia occurred in 7 of 35 patients (20%) with hemoglobin levels <10.0 g/dL, and improvements in thrombopenia occurred in 5 of 24 patients (21%) with platelet counts <100 × 109/L. Five of 24 patients (21%) became transfusion‐independent. Major or minor regression of splenomegaly was noted in 9 of 29 evaluable patients (31%), and complete regression was noted in 5 patients. Responders had a lower baseline median vascular endothelial growth factor levels (77.9 pg/mL vs. 97.7 pg/mL; P <.01) and higher median basis fibroblast growth factor levels (60.8 pg/mL vs. 37.4 pg/mL; P <.01) compared with nonresponders. Nine patients (22%) had deterioration that was attributed to thalidomide (resolved after withdrawal) with either progressive cytopenias or excessive proliferation. Two patients developed Grade 3 neutropenia with recovery and resumed therapy with dose reductions, and both later achieved a complete response. Dose‐related toxicities included fatigue (50%), constipation (48%), rash or pruritis (37%), sedation (35%), peripheral edema (29%), tremors (23%), peripheral neuropathy (22%), and orthostasis (16%).Thalidomide warrants further evaluation in patients with MMM, particularly in combination regimens, along with the investigation of newer analogs. Cancer 2006. © 2006 American Cancer Society. more...

Adult Burkitt‐type lymphoma (BL) and acute lymphoblastic leukemia (B‐ALL) are rare entities composing 1% to 5% of non‐Hodgkin lymphomas NHL) or ALL. Prognosis of BL and B‐ALL has been poor with conventional NHL or ALL regimens, but has improved with dose‐intensive regimens.To evaluate the addition of rituximab, a CD20 monoclonal antibody, to intensive chemotherapy in adults with BL or B‐ALL, 31 patients with newly diagnosed BL or B‐ALL received the hyper‐fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper‐CVAD) regimen with rituximab. Their median age was 46 years; 29% were 60 years or older. Rituximab 375 mg/m2 was given on Days 1 and 11 of hyper‐CVAD courses and on Days 1 and 8 of methotrexate and cytarabine courses.Complete remission (complete response [CR]) was achieved in 24 of 28 (86%) evaluable patients; 3 had a partial response, and 1 had resistant disease. There were no induction deaths. The 3‐year overall survival (OS), event‐free survival, and disease‐free survival rates were 89%, 80%, and 88%, respectively. Nine elderly patients achieved CR with all of them in continuous CR (except 1 death in CR from infection), with a 3‐year OS rate of 89%. Multivariate analysis of current and historical (those treated with hyper‐CVAD alone) groups identified age and treatment with rituximab as favorable factors.The addition of rituximab to hyper‐CVAD may improve outcome in adult BL or B‐ALL, particularly in elderly patients. Cancer 2006. © 2006 American Cancer Society. more...

The t(3;21)(q26;q22) translocation is associated with myeloid leukemias and results in a chimeric oncoprotein containing AML1/RUNX1 variably fused to EAP, MDS1, and/or EVI1.The current study describes what to the authors' knowledge is the first large case series reported to date of 26 t(3;21)(q26;q22)‐associated leukemias, in which 24 cases arose after chemotherapy. Conventional G‐band karyotyping and flow cytometry immunophenotyping were performed. Reverse transcriptase–polymerase chain reaction (RT–PCR) was performed to detect fusion transcripts between AML1 and EAP, MDS1, or EVI1, followed by DNA sequencing.In all 16 patients with chronic myeloproliferative disorders, including 14 with chronic myelogenous leukemia (CML), the occurrence of t(3;21) heralded myeloid blast transformation. Fifteen (93%) patients had been previously treated with hydroxyurea. Eight patients with chronic myeloproliferative disorders (CMPD) were found to have t(3;21) with t(9;22) as the sole cytogenetic abnormality; in 5 other patients this was accompanied by trisomy 8. Among 10 cases of t(3;21)‐associated acute myeloid leukemia, 8 were secondary tumors after chemotherapy for other neoplasms that had been treated with regimens including fludarabine and 5–fluorouracil in 3 patients each and etoposide in 2 patients. The immunophenotype of the blasts in all 22 tested cases was similar, with uniform expression of myeloid markers and CD34 and variable expression of CD7 and CD9, but minimal morphological myeloid maturation. Dysplastic micromegakaryocytes and bone marrow fibrosis were observed predominantly in CMPD cases. RT–PCR followed by DNA sequencing showed that the AML1‐/MDS1‐/EVI1 (AME) fusion transcript was detected in all 5 cases assessed. Among the patients with CMPD, 8 died of disease (at a median of 6.5 mos) and 5 achieved disease remission with bone marrow transplantation. Among patients with acute myeloid leukemia/myelodysplastic syndrome, 7 died of disease (at a median of 2 mos) and 2 had persistent leukemia with short follow‐up.Activation of AME through t(3;21) defines a highly aggressive, therapy‐related leukemic blast syndrome. Prior treatment with hydroxyurea or other antimetabolites is implicated as a contributory cause. Cancer 2006. © 2006 American Cancer Society. more...

Several staging classification systems, all of which were designed in the preimatinib era, are used for chronic myeloid leukemia (CML). The World Health Organization (WHO) recently proposed a new classification system that has not been validated clinically. The authors investigated the significance of the WHO classification system and compared it with the classification systems used to date in imatinib trials (“standard definition”) to determine its impact in establishing the outcome of patients after therapy with imatinib. In total, 809 patients who received imatinib for CML were classified into chronic phase (CP), accelerated phase (AP), and blast phase (BP) based on standard definitions and then were reclassified according to the new WHO classification system. Their outcomes with imatinib therapy were compared, and the value of individual components of these classification systems was determined. With the WHO classification, 78 patients (10%) were reclassified: 45 patients (6%) were reclassified from CP to AP, 14 patients (2%) were reclassified from AP to CP, and 19 patients (2%) were reclassified from AP to BP. The rates of complete cytogenetic response for patients in CP, AP, and BP according to the standard definition were 72%, 45%, and 8%, respectively. After these patients were reclassified according to WHO criteria, the response rates were 77% (P= 0.07), 39% (P= 0.28), and 11% (P= 0.61), respectively. The 3‐year survival rates were 91%, 65%, and 10%, respectively, according to the standard classification and 95% (P= 0.05), 63% (P= 0.76), and 16% (P= 0.18), respectively, according to the WHO classification. Patients who had a blast percentage of 20–29%, which is considered CML‐BP according to the WHO classification, had a significantly better response rate (21% vs. 8%; P= 0.11) and 3‐year survival rate (42% vs. 10%; P= 0.0001) compared with patients who had blasts ≥ 30%. Different classification systems had an impact on the outcome of patients, and some prognostic features had different prognostic implications in the imatinib era. The authors believe that a new, uniform staging system for CML is warranted, and they propose such a system. Cancer 2006. © 2006 American Cancer Society. The authors investigated the significance of the new World Health Organization classification for chronic myeloid leukemia (CML) and compared it with the classifications used currently in imatinib trials. The results indicated that there is a need for of a new, uniform staging system for CML. more...

Elderly patients (age ≥ 65 years) with acute myeloid leukemia (AML) generally have a poor prognosis. AML‐type therapy results are often derived from studies in younger patients and may not apply to elderly AML. Many investigators and oncologists advocate, at times, only supportive care or frontline single agents, Phase I–II studies, low‐intensity regimens, or ‘targeted’ therapies. However, baseline expectations for outcomes of elderly AML with ‘standard’ AML‐type therapy are not well defined. The aim was to develop prognostic models for complete response (CR), induction (8‐week) mortality, and survival rates in elderly AML, which would be used to advise oncologists and patients of expectations with standard AML type therapy, and to establish baseline therapy results against which novel strategies would be evaluated.A total of 998 patients age ≥ 65 years with AML or high‐risk myelodysplastic syndrome (> 10% blasts) treated with intensive chemotherapy between 1980 and 2004 were analyzed. Univariate and multivariate analyses of prognostic factors associated with CR, induction (8‐week) mortality, and survival used standard methods.The overall CR rate was 45% and induction mortality 29%. Multivariate analysis of prognostic factors identified consistent independent poor prognostic factors for CR, 8‐week mortality, and survival. These included age ≥ 75 years, unfavorable karyotypes (often complex), poor performance (3–4 ECOG [Eastern Cooperative Oncology Group]), longer duration of antecedent hematologic disorder, treatment outside the laminar airflow room, and abnormal organ functions. Patients could be divided into: 1) a favorable group (about 20% of patients) with expected CR rates above 60%, induction mortality rates of 10%, and 1‐year survival rates above 50%; 2) an intermediate group (about 50–55% of patients) with expected CR rates of 50%, induction mortality rates of 30%, and 1‐year survival rates of 30%; and 3) an unfavorable risk group (about 25–30% of patients) with expected CR rates of less than 20%, induction mortality rates above 50%, and 1‐year survival rates of less than 10%.Prognostic models, based on standard readily available baseline characteristics, were developed for elderly patients with AML, which may assist in therapeutic and investigational decisions. These predictive models, based on a retrospective analysis, will require validation in independent study groups. Cancer 2006. © 2006 American Cancer Society. more...

Progressive or higher‐risk myelodysplastic syndrome (MDS) is often treated with intensive chemotherapy regimens used for acute myelogenous leukemia (AML). Patients with MDS are often older and may have contraindications to anthracycline‐based regimens. Topotecan‐cytarabine regimens have shown encouraging results in higher‐risk MDS. The aim of this study was to analyze the long‐term results with topotecan‐cytarabine versus other intensive chemotherapy regimens in higher‐risk MDS.Five hundred ten patients with higher‐risk MDS treated with intensive chemotherapy were reviewed. Their median age was 63 years; 82% had intermediate 2 or high‐risk MDS; 32% had secondary MDS; 40% had chromosome 5 or 7 abnormalities. Therapy was: topotecan‐cytarabine in 77; idarubicin‐cytarabine regimens in 270; topotecan‐cytarabine and cyclophosphamide in 67; fludarabine‐cytarabine in 96. Univariate and multivariate analyses were conducted to evaluate the independent associations of different variables, and most important, the treatment regimen, with complete response, induction mortality, and survival.The overall complete response (CR) rate was 55%, induction mortality 17%, and 5‐year survival rate 8%. The 5‐year survival rate was 11% for patients younger than 65 years old and 17% for patients with a normal karyotype. Among 82 patients younger than 65 years with a normal karyotype, the CR rate was 67%, 5‐year survival rate 27%, and 5‐year CR duration rate 33%. Topotecan‐cytarabine regimens were equivalent to idarubicin‐cytarabine regimens in relation to CR rates and survival rates, but were associated with a lower induction mortality. Multivariate analysis confirmed that treatment regimens were not associated with independent significant differences in CR rates or survival. However, topotecan‐cytarabine regimens were still selected to be associated with lower induction mortality rates.This analysis suggests that topotecan‐cytarabine regimens are equally effective to other AML regimens in higher‐risk MDS and may be less toxic. Topotecan‐cytarabine may be considered a reasonable alternative to idarubicin‐cytarabine in higher‐risk MDS, particularly in older patients with contraindications to anthracyclines. Cancer 2006. © 2006 American Cancer Society. more...

Outcomes with salvage therapy for patients with recurrent or refractory acute lymphocytic leukemia (ALL) are poor, with complete response (CR) rates reported to be 20–30% and a median survival ranging from 2–6 months. New agents are needed to reduce the recurrence rate after frontline chemotherapy. Vincristine is an important component of ALL therapy. In animal models, the encapsulation of vincristine into sphingomyelin liposomes or “sphingosomes” for injection (SV) has improved efficacy compared with conventional vincristine.A Phase II clinical trial of single‐agent SV given at a dose of 2.0 mg/m2 every 2 weeks was conducted in patients with recurrent or refractory ALL. Approximately half of the 16 patients who received SV had a first CR duration of less than 1 year, 19% had failed standard induction chemotherapy, and 50% had Philadelphia chromosome‐positive disease. SV was the first salvage attempt in 69% of the patients.The overall response rate in the 14 evaluable patients was 14% (1 CR and 1 partial response). Five patients (36%) had transient reductions in bone marrow leukemia infiltrate with subsequent regrowth of the leukemia between SV infusions. Toxicity with limited treatment (median number of doses was two; range, one to five doses) was minimal with expected peripheral neuropathy.Further study of SV in patients with ALL is warranted. A Phase I‐II clinical trial of weekly SV with pulse dexamethasone currently is ongoing. Cancer 2006. © 2005 American Cancer Society. more...

The objective of this study was to assess the antitumor activity and toxicity profile of weekly docetaxel in patients with recurrent or metastatic squamous cell carcinoma of the head and neck.Patients with recurrent, metastatic, incurable squamous cell carcinoma of the head and neck were enrolled. Weekly docetaxel (30 mg/m2) was administered for 4 weeks every 5 weeks for a maximum of 6 cycles.The activity and toxicity of docetaxel were assessed in all 38 patients who were entered on the study. No Grade 3–4 toxicities were recorded. No treatment delays were required because of toxicity or dose reductions. Responses were observed in 42% of patients (95% confidence interval, 26–58%). The median duration of response was 8.39 months, the estimated median overall survival was 11.3 months, and the 1‐year survival rate was 39%.The results of this study suggested that weekly docetaxel was an active agent for patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck. Cancer 2006. © 2005 American Cancer Society. more...

Lonafarnib (SCH66336) is a nonpeptidomimetic farnesyl transferase inhibitor that has demonstrated significant preclinical activity against chronic myelogenous leukemia (CML) cells and in CML animal models.In the current study, the efficacy of lonafarnib was investigated in patients with CML in the chronic or accelerated phase that was resistant or intolerant to imatinib. Thirteen patients with CML in the chronic (n = 6 patients) or accelerated (n = 7 patients) phase were treated with lonafarnib at a dose of 200 mg orally twice daily. Ten patients had failed therapy with imatinib and 3 patients were intolerant to imatinib. The median age of the patients was 62 years (range, 38–80 yrs) and the median time from the diagnosis of CML to therapy with lonafarnib was 5 years (range, 0.3–13 yrs). In addition to imatinib mesylate, all patients had received prior therapy with interferon‐α and seven patients had received other treatments. The median duration of therapy with lonafarnib was 8 weeks (range, 2–41 wks).Two patients responded. One patient in the accelerated phase of CML returned to the chronic phase, a response that lasted for 3 months. Another patient with chronic phase disease had lowering of the leukocyte count without the need for hydroxyurea and normalization of the differential count that lasted for 5 months. The most common adverse event was diarrhea, which was noted in 11 patients (84%) (Grade ≥ 3 in 4 patients; 31%; toxicity was graded according to the National Cancer Institute Common Toxicity Criteria [version 2.0]). Therapy was discontinued in one patient because of diarrhea not responding to dose adjustments.Single‐agent lonafarnib appears to have clinical activity in a small proportion of patients with CML refractory to imatinib. Cancer 2006. © 2005 American Cancer Society. more...

Combining therapeutics with single‐agent activity has improved treatment for patients with many malignancies. Debate continues about the impact of treatment on survival in patients with chronic lymphocytic leukemia (CLL). Purine analogues are the most active agents for treatment of patients with CLL. Recently, it was shown that a chemoimmunotherapy regimen combining fludarabine (F), cyclophosphamide (C), and rituximab (R) (FCR) was very effective in treating patients with recurrent and/or refractory CLL. The objective of the current analysis was to determine whether improvements in treatment have had an impact on survival for patients with CLL.Three nonoverlapping, sequential groups of patients enrolled on Phase II studies who received treatment with F (n = 251 patients), FC (n = 111 patients), or FCR (n = 143 patients) were analyzed. Pretreatment characteristics, responses to treatment, and overall survival were compared.Patients who were treated with FCR had a higher complete remission rate compared with patients who were treated with combined F and C or with F alone. Statistically significantly longer estimated median survival was noted for patients who received FCR. A Cox proportional hazards, multivariable model for overall survival that included all patients (n = 505) showed that patients who received FCR had longer survival (P < 0.0001) after adjusting for other significant (P < 0.05) pretreatment characteristics, including age, hemoglobin, β‐2 microglobulin, and the number of prior treatments.The results of this retrospective comparison of patients with recurrent and refractory CLL indicated a higher complete remission rate and the longest estimated survival for patients who were treated with FCR, providing the basis for randomized clinical trials of this regimen. Cancer 2006. © 2005 American Cancer Society. more...

Previous studies have shown that patients with Bcr‐Abl–positive acute lymphoblastic leukemia (ALL) either have primary disease that is refractory to imatinib mesylate or develop disease recurrence after an initial response.The authors investigated the effects of a newly designed Bcr‐Abl inhibitor, AMN107, by comparing its in vitro inhibitory potency on p190 Bcr‐Abl ALL cell lines with that of imatinib.In two Philadelphia (Ph)‐positive ALL cell lines, AMN107 was found to be 30–40 times more potent than imatinib in inhibiting cellular proliferation. AMN107 was also more effective than imatinib in inhibiting phosphorylation of p190 Bcr‐Abl tyrosine kinase in cell lines and primary ALL cells. The inhibition of cellular proliferation was associated with the induction of apoptosis in only one of the cell lines. No activity was observed in cell lines lacking the BCR‐ABL genotype.The results of the current study suggest the superior potency of AMN107 compared with imatinib in Ph‐positive ALL and support clinical trials of AMN107 in patients with Ph‐positive ALL. Cancer 2005. © 2005 American Cancer Society. more...

Although the prognosis is poor for patients with acute myelogenous leukemia (AML) who have disease recurrence after frontline therapy, this is a general reflection of first salvage therapies. The outcome of patients undergoing second salvage therapy in relation to complete response (CR) rates and survival has not been documented. The authors analyzed the outcome of patients with AML undergoing second salvage therapy, and identified prognostic factors associated with response and survival.The records of 594 patients with AML undergoing second salvage therapy from 1980 until 2004 were reviewed. The patient median age was 50 years. Salvage therapy included allogeneic stem cell transplantation (SCT) in 74 patients, standard‐dose cytosine arabinoside (ara‐C) combinations in 30 patients, high‐dose ara‐C combinations in 171 patients, non–ara‐C combinations in 73 patients, and Phase I–II single agents in 246 patients.Overall, 76 patients (13%) achieved CR. The median CR duration was 7 months. The median survival was 1.5 months, and the 1‐year survival rate was 8%. A multivariate analysis of prognostic factors for CR identified the following 6 independent adverse factors: first CR duration < 6 months; second CR duration < 6 months; salvage therapy not including allogeneic SCT; non‐inversion 16 AML; platelet counts < 50 × 109/L, and leukocytosis > 50 × 109/L. Patients were divided into low‐risk (1–2 adverse factors; 8%), intermediate 1 (3 factors; 20%), intermediate 2 (4 factors; 38%), and high‐risk groups (5–6 factors; 33%) with respective CR rates of 54%, 26%, 8%, and 0%. The respective 1‐year survival rates were 36%, 21%, 6%, and 1%. A multivariate analysis for survival identified the following 7 independent adverse factors: first CR duration < 12 months; second CR duration < 6 months; bilirubin level ≥ 1 mg/dL; albumin level < 3 g/dL; age > 60 years; bone marrow blasts ≥ 50%; and year of therapy before 1991. Patients were divided into low‐risk (0–2 adverse factors; 39%), intermediate (3 factors; 27%), and high‐risk groups (≥ 4 factors; 34%) with estimated 1‐year survival rates of 22%, 6%, and 0%, respectively. The respective CR rates were 26%, 8%, and 2%.The current analysis established the outcome and prognostic factors associated with second salvage therapy in AML. It also proposed risk models and groups that could be used for comparison of results of present and future investigational strategies. Cancer 2005. © 2005 American Cancer Society. more...

Hypereosinophilic syndrome (HES) is a rare, disabling, and incurable disease. In this study, a combination of 2‐chlorodeoxyadenosine (2‐CdA) and cytosine arabinoside (ara‐C) chemotherapy was evaluated in patients with HES.Nine patients with HES were treated with ara‐C (1 g/m2) given intravenously over 2 hours at 0 hours, 48 hours, 72 hours, 96 hours, and 120 hours; and 2‐CdA (12 mg/m2 per day) was given as a continuous intravenous infusion over 5 days starting at 24 hours. A second course of the same therapy was administered in patients who had a response.All patients had signs and symptoms of end‐organ involvement. The median time from diagnosis to therapy was 25 months. Seven patients had received prior therapies. Five patients (55%) achieved a complete remission (CR), 1 after receiving 2 courses of therapy. Elimination of eosinophilia was accompanied by the resolution of symptoms. The median disease‐free survival and overall survival after the diagnosis for patients who achieved CR was 26 months and 44 months, respectively. Treatment was tolerated well. Febrile neutropenia occurred in 28% of the 14 courses that were given. The median time to recovery from neutropenia and thrombocytopenia was 17 days and 39 days, respectively.The combined 2‐CdA and ara‐C chemotherapy regimen had activity in patients with HES. Cancer 2005. © 2005 American Cancer Society. more...

Myelofibrosis is associated historically with a poor prognosis in patients with chronic myelogenous leukemia (CML). Its significance in the recent era of effective therapy with imatinib mesylate is unknown.The current study evaluated the significance of the degree of pretreatment myelofibrosis on response and survival with imatinib therapy in patients with newly diagnosed CML. The study group comprised 198 patients with newly diagnosed Philadelphia chromosome‐positive, chronic‐phase CML treated with imatinib mesylate therapy. They were analyzed for the prognostic significance of bone marrow reticulin fibrosis.Severe reticulin (Grade 3–4) fibrosis was observed in 75 patients (38%): Grade 3 in 46 (23%) patients and Grade 4 in 29 (15%) patients. There was a trend towards a lower incidence of a complete cytogenetic response in patients with Grade 4 reticulin fibrosis (76% vs. 89%; P = 0.07), and a significantly worse survival (estimated 3‐year survival rate of 87% vs. 97%; P = 0.04).Although the prognostic significance of severe reticulin fibrosis in patients with newly diagnosed CML receiving imatinib therapy was better, 15% of patients with Grade 4 reticulin fibrosis still had a worse outcome. Cancer 2005. © 2005 American Cancer Society. more...

In 1986, a Phase II trial of recombinant interferon‐α (IFN‐α) was initiated as therapy for patients with essential thrombocythemia (ET).Patients were treated with subcutaneous IFN‐α at a dose of 5 × 106 units/m2 daily. In responding patients, the therapy lasted at least 3 years.Twenty‐three patients (14 females and 9 males; median age, 41 years; age range, 20–63 years) with a median platelet count of 1350 × 109/L were treated. After a median follow‐up of 174 months (14.5 years), 15 of 20 evaluable patients (75%) responded, including 14 patients who achieved a complete hematologic response (CHR) (6 of them with bone marrow remission) and 1 patient who demonstrated a partial response. The median time to response was 6 months (range, 0.5–36 months), and the median response duration was 48 months (range, 5–114 months). Seven patients who achieved a CHR and were taken off therapy after they completed 3 years of maintenance therapy sustained their response for a median of 28 months. No symptoms or signs of thrombosis or hemorrhage were observed in responding patients. Eleven of 14 patients (78%) who achieved a CHR developed a recurrence, and 2 of 5 patients with recurrences who were rechallenged with IFN‐α achieved a second response. The treatment was tolerated relatively well.IFN‐α was safe and effective therapy for patients with ET, and the ability of IFN‐α to reverse disease pathology and possibly modify the clinical course of patients with ET warrants its investigation in larger, prospective trials. Cancer 2005. © 2005 American Cancer Society. more...

The effect of imatinib mesylate on survival in the accelerated phase of chronic myelogenous leukemia (CML) is unknown. The objectives of this study were to update the long‐term experience with imatinib in patients who had accelerated‐phase CML and to compare outcomes with historic experience.The outcomes of 176 patients who received treatment with imatinib were reviewed and compared with the outcomes of 213 historic control patients with accelerated‐phase CML who received treatment with interferon‐α or with other modalities.With imatinib, the complete hematologic response rate was 82% versus a rate ≤ 50% for others, and the complete cytogenetic response rate was 43% versus rates of 0–6% for others. The estimated 4‐year survival rates were 53% with imatinib, 42% with interferon‐α, and 0–21% for others. A multivariate analysis of the total population of 389 patients indicated that imatinib therapy (vs. other therapies) was an independent, favorable prognostic factor for survival (P < 0.0001; hazard rate, 0.62). A subset analysis that included only patients who were treated with imatinib and interferon‐α (276 patients) also identified imatinib as an independent favorable prognostic factor (P < 0.0001; hazard rate, 0.65). The 3‐month cytogenetic response to imatinib was associated with significantly different survival outcomes (P < 0.0001). A multivariate analysis that included pretreatment characteristics and 3‐month cytogenetic response among 150 patients who received imatinib and were alive at 3 months identified only 2 adverse independent prognostic factors: lack of a cytogenetic response at 3 months (P < 0.001) and anemia (hemoglobin < 10 g/dL; P = 0.003). Patients who had neither factor (41%) had an estimated 4‐year survival rate of 88%; in the other patients, the 4‐year survival rate was ≤ 60%. This may have implications in relation to subsequent therapy, because, according to the outcomes of patients who underwent allogeneic transplantation in accelerated phase at the authors' institution and from literature reports, the estimates of 5‐year survival were 25–30%.The current results suggest that imatinib improved survival compared with other therapies in patients with accelerated‐phase CML. Cancer 2005. © 2005 American Cancer Society. more...

Modern intensive chemotherapy regimens have improved the prognosis for patients with adult acute lymphocytic leukemia (ALL). With these regimens, the complete response rates are now reported to be &gt; 80%, and the long‐term survival rates range from 30% to 45%. The current analysis updated the long‐term results with the original hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (Hyper‐CVAD) program, with a median follow‐up time of 63 months.Between 1992 and 2000, 288 patients were treated with Hyper‐CVAD. The median age of the patients was 40 years, and 59 patients (20%) were ≥ age 60 years. The incidence of Philadelphia chromosome (Ph)‐positive ALL was 17%, and the incidence of of T‐cell ALL was 13%.A complete response (CR) was achieved in 92% of patients. The induction mortality rate was 5% (2% if the patient's age was < 60 years, and 15% if the patient's age was ≥ 60 years). With a median follow‐up time of 63 months, the 5‐year survival rate was 38% and the 5‐year CR duration rate was 38%. Multivariate analysis of prognostic factors for CR duration identified the following adverse factors: age ≥ 45 years, leukocytosis ≥ 50 × 109/L, poor performance status (an Eastern Cooperative Oncology Group score of 3–4), Ph‐positive disease, French–American–British L2 morphology, > 1 course to achieve CR, and Day 14 bone marrow blasts > 5%. Patients were divided into low‐risk (risk score 0–1; 37%), intermediate risk (risk score 2–3; 36%), and poor‐risk groups (risk score ≥ 4; 27%) with 5‐year CR duration rates of 52%, 37%, and 10%, respectively.Compared with the previous VAD regimens, Hyper‐CVAD was associated with significantly better CR rates, CR duration, and survival. The long‐term follow‐up results of Hyper‐CVAD were favorable. Comparison of Hyper‐CVAD with other established adult ALL regimens is warranted. Cancer 2004. © 2004 American Cancer Society. more...

The CD52 antigen is a glycoprotein anchored on the cell membrane of mature B and T lymphocytes, monocytes, and eosinophils. Alemtuzumab (CAMPATH‐1H; anti‐CD52) is currently approved for the treatment of patients with refractory chronic lymphocytic leukemia (CLL). The authors investigated the possibility that CD52 may be shed from cells and, once soluble, may bind to injected alemtuzumab, forming immune complexes.The authors used Western blot analysis, immunoprecipitation, and enzyme‐linked immunoadsorbent assay to investigate the presence of soluble CD52 (sCD52) in the plasma specimens of 117 patients with CLL. They also used in vitro mixing experiments to examine the ability of sCD52 to compete with cells and sequester therapeutic alemtuzumab.The authors detected high levels of sCD52 in the plasma specimens of patients with CLL. sCD52 can compete with cells in vitro for binding to alemtuzumab, and can form complexes in patients receiving alemtuzumab. Plasma levels of sCD52 were found to be correlated (r)with Rai stage (P = 0.0001), β‐2‐microglobulin (β‐2M) levels (P = 0.00002), soluble CD23 levels (r = 0.42, P < 0.001), and immunoglobulin mutation status (P = 0.003). In the multivariate analysis adjusted for β‐2M level, patients with sCD52 levels > 2336 nM/L had a nearly 4‐fold increase in risk of death. Higher levels of plasma alemtuzumab were achieved when levels of sCD52 were lower.These data not only demonstrated that sCD52 was detectable and useful in the staging and monitoring of patients with CLL, but also showed that sCD52 formed immune complexes with alemtuzumab and may influence the efficacy and toxicity of alemtuzumab therapy. Cancer 2004. © 2004 American Cancer Society. more...

Reticulin‐stained bone marrow fibrosis is associated with a poor prognosis in patients with chronic myelogenous leukemia (CML). Resolution of fibrosis with therapy may improve patient outcome.The effect of imatinib therapy on bone marrow fibrosis was evaluated in 40 patients with chronic‐phase CML who were treated after interferon‐α failure.Thirty‐one patients (78%) had severe (Grade 3 or 4) reticulin fibrosis prior to therapy. After imatinib therapy was administered for 3 to > 24 months, fibrosis was reduced by at least 2 grades in 19 of the 31 patients (61%) and by at least 1 grade in 34 patients (85%). There was no correlation noted between reduction of fibrosis and cytogenetic response. However, a reduction in fibrosis was found to correlate with a reduction in bone marrow megakaryocytosis (P = 0.002).Treatment with imatinib mesylate appears to reduce CML‐associated bone marrow fibrosis in most patients who are treated during the chronic phase of disease. This effect may be independent of the degree of suppression of Philadelphia chromosome‐positive cells, and may improve prognosis in patients with CML. Cancer 2004. © 2004 American Cancer Society. more...

Imatinib mesylate administration has become standard treatment for patients with chronic myelogenous leukemia (CML). Although the safety profile of imatinib is favorable, Grade ≥ 3 neutropenia (according to the National Cancer Institute Common Toxicity Criteria) occurs in 35–45% of patients with CML in chronic phase who receive standard‐dose imatinib. Myelosuppression results in treatment interruptions, which may compromise responses to imatinib. The authors investigated the ability of granulocyte–colony‐stimulating factor (filgrastim) to reverse imatinib‐associated neutropenia, thereby allowing for more continuous imatinib administration.Thirteen patients with chronic‐phase CML and Grade ≥ 3, imatinib‐induced neutropenia were treated with filgrastim. Treatment with filgrastim was initiated after a median of 22 months from the start of imatinib. Eleven patients received filgrastim 5 μg/kg 1–3 times weekly, and 2 patients received filgrastim 5 μg/kg daily; doses were titrated to maintain an absolute neutrophil count (ANC) ≥ 109/L.Seven of 11 patients (64%) who began treatment with an ANC < 1.5 × 109/L had responses (i.e., their ANC improved to ≥ 2 × 109/L within 21 days); the other 4 patients experienced slower recovery but were able to continue receiving imatinib uninterrupted. Before filgrastim administration was initiated, patients did not receive imatinib (due to neutropenia‐related treatment interruptions) for an average of 21% of the total time since the start of imatinib. This figure decreased to 6% after the start of filgrastim treatment (P = 0.0008). Before filgrastim treatment was initiated, only one patient had achieved a major (partial) cytogenetic response. After the start of filgrastim treatment, five patients had major cytogenetic responses (including two complete responses).The authors concluded that filgrastim may overcome imatinib‐associated neutropenia and allow improved delivery of imatinib. Some patients may experience improvements in their responses to therapy as a result. Cancer 2004. © 2004 American Cancer Society. more...

Myelosuppression occurs in up to 50% of patients with chronic myeloid leukemia (CML) who are treated with imatinib and ≥ Grade 3 myelosuppression is reported in approximately 10% of patients. The authors investigated the prognostic significance of anemia occurring during therapy with imatinib in patients with CML in chronic phase. Of 338 patients treated with imatinib (150 patients after interferon failure and 188 patients with newly diagnosed CML), 230 (68%) developed anemia. In a multivariate analysis, factors associated with an increased probability of developing anemia were a starting hemoglobin level &lt; 12 g/dL, age ≥ 60 years, female gender, higher imatinib dose, and intermediate or high Sokal risk group. Of these 230 patients, 102 patients received treatment with 40,000 U of recombinant human erythropoietin administered subcutaneously once weekly. An increase in the hemoglobin level of ≥ 2 g/dL was achieved in 69 patients (68%) and 22 patients (22%) had an increase of 1–1.9 g/dL. Patients who developed anemia had a trend toward a lower probability of complete cytogenetic remission compared with patients without anemia (68% vs. 77%; P = 0.14), as well as a trend for inferior survival. Patients with anemia and other manifestations of myelosuppression were found to have a significantly worse outcome than those with isolated anemia. The authors concluded that erythropoietin is safe and effective in patients in chronic-phase CML who develop anemia with imatinib therapy. Cancer 2004. © 2004 American Cancer Society. more...

Although central nervous system (CNS) prophylaxis in patients with leukemia has reduced the incidence of CNS disease recurrence, it still is reported to occur in approximately 5–10% of cases, resulting in a median survival of 6 months. Craniospinal irradiation (CSI) has been shown to improve survival in children who develop a CNS recurrence of acute lymphocytic leukemia (ALL). However, to the authors' knowledge, the role of CSI in adults with a CNS recurrence of leukemia is unknown. A retrospective review of adult patients treated with CSI for a CNS recurrence of leukemia identified 16 patients treated between 1986 and 2001. The median age of the patients was 34 years (range, 16–58 years). The diagnoses included seven patients with acute myelogenous leukemia (AML), eight patients with ALL, and one patient with chronic myelogenous leukemia in blast crisis. All patients had achieved a complete disease remission prior to the CNS recurrence. Eleven patients had an isolated CNS recurrence and 5 patients had concurrent disease identified in the blood/bone marrow. The median dose of radiation was 24 grays (Gy) (range, 18–34.5 Gy) to the cranium and 18 Gy (range, 15–30 Gy) to the spine. The median fraction size was 1.8 Gy (range, 1.5–2.0 Gy) to the cranium and 1.5 Gy (range, 1.5–2.0 Gy) to the spine. Fifteen patients were also treated with intrathecal chemotherapy. One patient failed to complete radiation treatment because of disease progression. Thirteen patients achieved a complete response in the cerebrospinal fluid (CSF). The median time to disease progression was 3 months from the first day of CSI and 7 months from CNS recurrence. The median survival was 4 months and 9 months, respectively. No CNS recurrences occurred, but there were 11 bone marrow failures, 2 patients without recurrence at > 5 years, and 3 deaths without a documented site of failure. Thirteen patients had no evidence of disease in the CSF until their death or the time of last follow-up. CSI with or without intrathecal chemotherapy appears to be effective at eliminating leukemia in the craniospinal axis. However, the eradication of disease in the CNS was not found to be effective at preventing disease recurrence in the bone marrow, and despite improved control of disease in the CNS, adult patients with a CNS recurrence still had a poor prognosis. Furthermore, the rapidly fatal course of disease prevented an assessment of the durability of CNS response to irradiation. Cancer 2004. © 2004 American Cancer Society. more...

The myeloproliferative disorders (MPDs) are chronic malignant conditions originating from the clonal expansion of a multipotential hematopoietic stem cell. These diseases include polycythemia vera (PV), essential thrombocythenia, atypical chronic myeloid leukemia, idiopathic hypereosinophilic syndrome (HES), agnogenic myeloid metaplasia with myelofibrosis, and others. Receptor tyrosine kinases—the platelet-derived growth factor receptors (PDGFRs) and c-Kit—and their respective ligands have been implicated in the pathogenesis of MPDs. For example, a constitutively activated PDGFR fusion tyrosine kinase (FIP1L1-PDGFRA) was identified in some patients with HES, a disease characterized by sustained overproduction of eosinophils that has been classified by the World Health Organization as a chronic subtype of the MPDs. Imatinib is a selective inhibitor of PDGFRs, c-Kit, Abl and Arg protein-tyrosine kinases, as well as Bcr-Abl, the oncogenic tyrosine kinase that causes chronic myeloid leukemia. The efficacy of imatinib in treating HES, systemic mast cell disease, chronic myelomonocytic leukemia associated with PDGFRβ fusion genes, and (to a lesser extent) PV and idiopathic myelofibrosis was reviewed from institutional experience and a review of the literature. In 3 studies that involved 11 patients with PV, 10 patients had reductions in phlebotomy with imatinib. Eight studies of 42 patients with HES indicated that 70% achieved complete hematologic remissions with imatinib. Four studies of 6 patients with MPD indicated responses with imatinib in 5 patients. Insight into the molecular pathogenesis of MPDs will improve the definitions of different disease categories and suggests that signal transduction inhibition is likely to be an increasingly important treatment option in the future. Cancer 2004. © 2004 American Cancer Society. more...