M. Keating

Results of decitabine therapy in the accelerated and blastic phases of chronic myelogenous leukemia.

The aim of the study was to evaluate the activity of decitabine, a hypomethylating agent, in the treatment of patients with chronic myelogenous leukemia (CML) in transformation. Thirty-seven patients with CML in blastic (20 patients) or accelerated phases (17 patients) were treated. Their median age was 52 years; 36 had Philadelphia chromosome-positive disease. Decitabine was given at 100 mg/m2 over 6 h every 12 h × 10 doses (1000 mg/m2) to 13 patients, and at 75 mg/m2 over 6 h every 12 h × 10 doses (750 mg/m2) to 24 patients. In blastic phase, two patients (10%) achieved a complete hematologic response (one with Ph suppression), and three (15%) had a hematologic improvement (marrow CR, platelets <100 × 103/μl), for an overall response rate of 25%. In accelerated phase, six patients (35%) returned to a second chronic phase (two with Ph suppression), one (6%) had a hematologic improvement, and two (12%) had a partial hematologic response, for an overall response rate of 53%. Prolonged myelosuppression was the most significant side-effect. The median time to recovery of granulocytes above 500 /μl was 48 days, and to recovery of platelets above 30 × 103/μl, 31 days. Febrile episodes occurred in 25 patients (68%) including documented infections in 17 patients (46%). Decitabine has promising activity in CML. The most significant side-effect is prolonged myelosuppression. Decitabine may show activity in other myeloid disorders such as acute myeloid leukemia and myelodysplastic syndrome, as well as in other hematologic malignancies, alone or with other drug combinations. Its value in the context of stem cell support should also be investigated.

Phase I study of mitoxantrone plus etoposide with multidrug blockade by SDZ PSC-833 in relapsed or refractory acute myelogenous leukemia.

PURPOSE Expression of the multidrug resistance gene (MDR1) p170 protein is frequent in leukemic blasts from patients with relapsed acute myelogenous leukemia (AML). A phase I study using the nonimmunosuppressive MDR1 blocker SDZ PSC-833 (PSC) in combination with mitoxantrone (MITO) and etoposide (VP) was performed. PATIENTS AND METHODS Starting doses (LVL0) of MITO (3.25 mg/m2/d on days 1 and 3 to 6) and VP (210 mg/m2/d on days 1 and 3 to 5) were 40% of the maximal-tolerated dose (MTD) from a prior study. A 1.5-mg/kg loading dose of PSC was followed by a 120-hour continuous infusion of 10 mg/kg/d on days 2 to 6. Blood samples for PSC, MITO, and VP pharmacokinetics (PK) were taken on days 1 and 3, and samples for MDR1 expression were taken on day 0. RESULTS Severe mucositis developed in all patients at LVL0; therefore, MITO and VP doses were reduced to 2.5 and 170 mg/m2 (LVL-1) for the next seven patients, and this dose proved to be MTD. All LVL0 and three LVL-1 patients had transient elevations in the serum bilirubin level to > or = 4 mg/dL. Serum creatinine level increased to greater than 2 mg/dL in one case. There were no other grade 3 or 4 nonhematologic toxicities observed. The peripheral blood was cleared of leukemia in three LVL0 and four LVL-1 patients. The marrow was cleared of leukemic cells in one LVL0 and five LVL-1 patients, and a significant reduction in marrow leukemic infiltrate was observed in eight of 10. No patient achieved complete remission (CR), and all died of progressive disease (n = 8) or infection (n = 2). MDR1 expression was detected by fluorescent-activated cell sorter (FACS) analysis in five of seven cases. An elevated MDR1 mRNA level was detected by quantitative polymerase chain reaction (Q-PCR) in six of eight cases studied. Clearing of leukemia cells from the marrow occurred in four of six MDR1-positive and one of three MDR1-negative patients. Despite the fact that LVL0 doses had to be reduced due to toxicity, coadministration of PSC did not produce a consistent effect on MITO PK; however, it did repeatedly lead to increased levels of VP in the serum. CONCLUSION We conclude that PSC-MITO-VP is a tolerable regimen with antileukemic activity. Addition of PSC necessitated a 66% reduction in MITO and VP doses from a prior study without PSC.

Emergence of new clonal abnormalities following interferon-alpha induced complete cytogenetic response in patients with chronic myeloid leukemia: report of three cases.

Some cases of hypereosinophilic syndrome and myeloproliferative disorders exhibit common features and thus pose diagnostic and therapeutic problems. We describe a 68-year-old patient who presented with such features and developed lytic lesion in the tibia. Based on our case and a review of literature we suggest that cases like ours should be classified and treated as chronic eosinophilic leukemia (a myeloproliferative disorder) rather than as a hypereosinophilic syndrome or as an atypical chronic myeloid leukemia.

Association between increased body mass index and a diagnosis of acute promyelocytic leukemia in patients with acute myeloid leukemia.

We had observed that several patients with acute promyelocytic leukemia (APL) were markedly obese. Therefore we determined the relationship between obesity and a diagnosis of APL among patients with acute myelocytic leukemia (AML). Between 1980 and 1995 we saw 1245 patients with newly- diagnosed AML of whom 120 had APL. Increasing body mass index (BMI) was strongly associated with a diagnosis of APL (P = 0.0003). Like Douer et al (Blood 1996; 8: 303–313) we found APL to be more frequent in Latinos and younger patients (P < 10−4 for both). Logistic regression indicated that increasing BMI, decreasing age, and Latino origin were each independently associated with a diagnosis of APL (multivariate P values <10−4, <10−4, 0.0035, respectively). Since the mean BMI in the non-APL patients (25.1) resembled that of the general US population, it appears that APL patients are ‘heavy’ and not that non-APL patients are ‘thin’. Five of the APL patients (4.2%) had a BMI >50 (vs none of the other 1125 AML patients). Given the distribution of BMI in the general US population ages 17–74, the probability that five of 120 normal adults would have a BMI >50 is virtually nil. Excluding the five very heavy APL patients does not alter the conclusion that increasing BMI predicted for APL in patients with AML. Although the mechanism is unclear there appears to be an association between increasing BMI and a diagnosis of APL among patients with AML. There may also be an association between APL and obesity.

The hyper-CVAD regimen improves outcome in relapsed acute lymphoblastic leukemia.

Sixty-six adults with refractory acute lymphocytic leukemia received salvage therapy with the ‘hyper-CVAD’ regimen, consisting of eight courses of alternating intensive chemotherapy with growth factor support, followed by oral maintenance chemotherapy. Their outcome was compared with 63 prognostically similar historical control patients treated with high-dose Ara-C plus mitoxantrone with or without GM-CSF. Overall, the complete response rates were similar in the treatment and control groups (29 of 66 (44%) vs 24 of 63 (38%)). There were more patients in the current study with primary resistant disease (10 of 66 (15%) vs one of 63 (2%), P = 0.006), and conversely fewer patients with secondary resistance (19 of 66 (29%) vs 28 of 63 (44%), P = 0.06). Recovery of granulocyte counts above 500/μl was significantly faster in the current study when compared to high-dose Ara-C-treated patients who were given GM-CSF (20 vs 25 days, P = 0.04). Survival was prolonged in the hyper-CVAD-treated patients, with most of the benefit seen in first salvage patients (42 vs 20 weeks, P = 0.016). When only first salvage patients were considered, there was a significant difference in disease-free survival in favor of hyper-CVAD (52 vs 20 weeks, P = 0.008). The hyper-CVAD regimen is a more effective and less toxic salvage regimen for relapsed acute lymphocytic leukemia than high-dose Ara-C-based regimens.

Clinical course and response to treatment of patients with acute myelogenous leukemia presenting with a high leukocyte count

The natural history and response to treatment of 46 patients with acute myelogenous leukemia and a pretreatment leukocyte count of 100,000/μl or higher were reviewed to identify the clinical features and response characteristics to the treatment of this group of patients. While the response rate of 52% was similar to that of patients with lower leukocyte counts, remission durations were shorter and related inversely to the height of the initial leukocyte count and to the number of treatment courses necessary to achieve a complete remission. A high incidence of hemorrhagic deaths was observed during the first 8 days of treatment. These hemorrhages occurred at a time when the leukocyte count was falling secondary to chemotherapy and the platelet count was still greater than 15,000/μl. Pretreatment coagulation disorders and poor performance status were factors associated with this fatal complication. Antimetabolites to rapidly arrest leukemic cell proliferation and leukapheresis to avoid further leukostatic plug formation may be useful immediate measures to reduce the incidence of these fatal hemorrhages until the underlying pathogenic mechanisms have been elucidated.

Prognostic value of plasma interleukin-6 levels in patients with chronic lymphocytic leukemia.

Interleukin 6 (IL‐6) is a B‐cell growth and differentiation factor, which may promote the growth of B‐cell neoplasms. In chronic lymphocytic leukemia (CLL) patients, IL‐6 plasma levels increased in a stage‐dependent manner, suggesting that IL‐6 may be a useful prognostic marker. The purpose of this study is to fully assess the prognostic value of IL‐6 in CLL patients.

Adult acute erythroleukemia: an analysis of 91 patients treated at a single institution

Acute erythroleukemia (AML-M6) is an uncommon subtype of acute myeloid leukemia (AML); it is considered to have a poor prognosis. From 1 January 1980 to 21 May 2008, 91 patients with newly diagnosed AML-M6 were seen at the University of Texas–M.D. Anderson Cancer Center (UT–MDACC). Forty-five patients (50%) had a history of myelodysplatic syndrome (MDS), compared with 41% in our control group (patients with other AML subtypes) (P=0.08). Poor-risk cytogenetics were more common in patients with AML-M6 (61% versus 38%, P=0.001). Complete remission rates were 62% for patients with AML-M6, comparing with 58% for the control group (P=0.35). Median disease free survival (DFS) for patients with AML-M6 was 32 weeks, versus 49 weeks for the control group (P=0.05). Median overall survival (OS) of patients with AML-M6 was 36 weeks, compared with 43 weeks for the control group (P=0.60). On multivariate analysis for DFS and OS, AML-M6 was not an independent risk factor. AML-M6 is commonly associated with a previous diagnosis of MDS and poor-risk karyotype. The diagnosis of AML-M6 does not impart by itself a worse prognosis, and treatment decisions on this disease should be guided by well known AML prognostic factors.

Establishment and characterization of a new mantle cell lymphoma cell line, Mino

Mantle cell lymphoma (MCL) is a distinct type of B-cell non-Hodgkins lymphoma characterized by cyclin D1 overexpression and the cytogenetic abnormality, the t(11;14)(q13;q32). MCL cell lines have been difficult to establish and in vitro studies of these neoplasms are scarce. We describe the establishment and characteristics of a new MCL cell line, Mino. The cells are large, growing singly and in small clumps in vitro. By flow cytometry, the immunophenotype was compatible with MCL (i.e. CD5+CD20+CD23-FMC7+). Conventional cytogenetics showed hyperdiploidy with multiple complex karyotypic abnormalities, but no evidence of the t(11;14), proven to be present only by fluorescence in situ hybridization and polymerase chain reaction (PCR) methods. Western blots showed expression of cyclin D1 but no detectable cyclin D2 and cyclin D3; the retinoblastoma protein was predominantly phosphorylated. There was expression of tumor suppressor gene products including p53, p16(INK4a), and p21(WAF1). Sequencing of the TP53 gene revealed a mutation (codon 147(valine-->glycine)) in exon 5. Epstein Barr virus was absent. In summary, Mino is a new MCL cell line that may be useful to study the pathogenesis of MCL.

Expression of STAT3 and its phosphorylated forms in mantle cell lymphoma cell lines and tumours.

The pathogenesis of mantle cell lymphoma (MCL) is incompletely understood, although cyclin D1 overexpression leading to deregulated cell proliferation is probably important. Recent data suggest that interleukin (IL)‐10 can increase the proliferative activity of MCL cells. STAT3 (signal transducer and activator of transcription 3) is the signal transducer of IL‐10, and STAT3 is activated by phosphorylation. The hypothesis of this study is that STAT3 is activated in MCL. The expression of the two phosphorylated (i.e. active) forms of STAT3, pSTAT3‐tyr (phosphorylated at the tyrosine705 residue) and pSTAT3‐ser (phosphorylated at the serine727 residue), was assessed in four MCL cell lines and 12 MCL tumours using western blots and/or immunofluorescence staining techniques. All MCL cell lines expressed STAT3, but only one had detectable pSTAT3‐tyr and none had pSTAT3‐ser. Addition of IL‐10 rapidly resulted in expression of pSTAT3‐tyr but not pSTAT3‐ser. All eight cases of frozen MCL tumours examined had detectable pSTAT3‐tyr and pSTAT3‐ser. Immunofluorescence studies using four formalin‐fixed, paraffin wax‐embedded MCL tumours demonstrated cytoplasmic localization of STAT3, as opposed to the nuclear localization of the pSTAT3 species. In conclusion, these findings provide evidence that STAT3 is constitutively activated in MCL, supporting the concept that STAT3 signalling may be important in the pathogenesis of these tumours. Copyright