Cyclophosphamide dose adjustment based on body weight and albuminemia in elderly patients treated with R-mini-CHOP.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma in elderly patients, and R-CHOP chemotherapy is the standard treatment protocol for DLBCL. Elderly patients (often defined as 75 years of age) are treated with anticancer drugs with precaution; however, the pharmacokinetics and pharmacodynamics (PK and PD) of these agents have not been thoroughly investigated in this population. In this study, we investigated the PK of cyclophosphamide (CP) and doxorubicin (DOXO) in elderly patients in order to verify if there is an influence of age on the PK of these anticancer drugs. MATERIALS AND METHODS: This is a prospective multi-center clinical trial investigating the PK of CP and DOXO in elderly and very elderly patients with DLBCL treated by R-mini-CHOP regimen. Dose levels were 25 mg/m2, 0.7-1.4 mg/m2, 750 mg/m2, and 375 mg/m2 for DOXO, Vincristine (VCR), CP, and Rituximab, respectively. For PK analysis, 7 time point samples were collected over 48 h post-administration on cycle 3. CP and VCR plasma concentrations were measured using UPLC-MS/MS validated method. DOX plasma concentrations were measured using UPLC coupled with fluorescence detection-validated method. PK-POP modeling has been performed with a non-linear mixed-effect model program (Monolix). RESULTS: 31 patients (15 males and 16 females), 75 to 96 years old, were treated with R-miniCHOP protocol. Among them, 19 patients were treated with VCR. A one-compartment (1cpt) open model with linear elimination adequately described CP concentration-time courses. The population PK parameters for CP were: CL = 3.58 L/h, Vmale = 32.2 L, and Vfemale = 28.7 L. Body weight (BW), albuminemia, and gender demonstrated a significant impact on CP PK. A 2-compartment (2cpt) open model with linear elimination best described DOXO concentration-time courses. The population PK parameters for DOXO obtained for the structural model were: CL = 51.1 L/h, Q = 49.6 L/h, V1 = 29.4 L, V2 = 1,130 L (clearances: CL, Q, volumes of distribution: V1, V2). The main covariate effects on DOXO PK were related to gender, BW, and VCR administration. VCR increases DOXO V1 from 29.4 L to 57.5 L (p = 0.02). No hematologic and cardiac grade 3 or 4 toxicity were recorded. CONCLUSIONS: Usually, in the absence of specific data, the majority of the physicians empirically reduce anticancer drug dose in the elderly patients (Tourani in J Geriatr Oncol 3(1): 41-48, 2012), or even does not treat these very-old patients. A better knowledge of the pharmacokinetics in very-old patients should allow a better dose adjustment based on the most significant physiological factors that modify the pharmacokinetic parameters. In this study, no serious toxicity was observed in these very elderly patients (84.1 years). This indicates that dose adjustment of chemotherapies should not only be based on age and creatinine clearance, but also, based upon appropriate physiological and biological data. Our findings indicate that, CP dose adjustment should be done according to serum albumin levels and patients BW and gender.

[Incidence and clinical characteristics of symptomatic urinary infections in a geriatric hospital]. / Incidence et caractéristiques cliniques des infections urinaires symptomatiques dans un hôpital gériatrique.

UNLABELLED: OBJECTIVES AND SETTINGS: The authors had for aim to study the incidence of symptomatic urinary infections (SUTI) in elderly patients, to describe their clinical and microbiologic characteristics and first-line treatment in a geriatric hospital with 902 beds: 124 in acute care (ACF), 293 in rehabilitation and intermediate-care (RICF), and 485 in long-term-care-facilities (LTCF). METHOD: During two months in 2003, all positive urine cultures detected by the laboratory were sent to the clinician with a questionnaire on clinical signs, diagnosis of SUTI and antibiotic treatment. RESULTS: SUTI was diagnosed in 85 out of 204 positive urine cultures (40%). The incidence of SUTI was 1.86 per 1,000 patient-days (with rates of 2.63, 2.49, 1.41 per 1,000 patients-days for the ACF, RICF, LTCF respectively). For 51 cases (60%) there were only general symptoms, for 24 cases (28.2%) there were only urinary symptoms, and for 10 cases (11.8%) there were both. Escherichia coli and Proteus mirabilis were the main bacterial species involved in 57 and 14% respectively. E. coli strains were 59% resistant to amoxicillin, 55% resistant to amoxicillin-clavulanic acid, and 39% resistant to fluoroquinolones. The main antibiotics were fluoroquinolones, ceftriaxone, and amoxicillin-clavulanate, prescribed respectively in 52.5, 19, and 9% of the cases. CONCLUSION: SUTI was diagnosed in only in 40% of positive urine cultures from elderly patients hospitalized in our hospital. To improve the management of SUTI in this population, we changed our recommendations for diagnosis and treatment.

Dealing with metastatic breast cancer in elderly women: results from a French study on a large cohort carried out by the 'Observatory on Elderly Patients'.

BACKGROUND: Treatment of elderly patients with metastatic breast cancer (MBC) is not clearly defined and seems to vary according to the subjective appreciation of the physician. PATIENTS AND METHODS: After interviewing 107 French specialists qualified in oncology, data concerning 1009 MBC patients were collected: 500 patients were between 65 and 74 years and 509 were >75 years of age. Differences in diagnosis and treatment strategy were analyzed for both age groups to identify the physician's criteria of choice and the eventual use of the geriatric assessment among those criteria. RESULTS: At diagnosis, synchronous metastatic disease was more frequent in patients over 75 years old (52% versus 39%; P<0.001). Physicians indicated that treatment was based on age and on a subjective evaluation of the patient's general status. Sixty-eight per cent of younger patients and only 31% of older ones received chemotherapy (P<0.001). In the older group drug doses were lower than those usually recommended in three-quarters of cases. Only 10% of physicians considered that they under-treat patients using the FEC 50 regimen. Over 75 years of age, hormone therapy was offered to most patients, including 8% with hormone-independent tumors. Geriatric covariates were never considered. Geriatricians rarely, if ever, played a role in the therapeutic decision. CONCLUSIONS: Inclusion of elderly patients with MBC in prospective trials is warranted to define standards of care and reduce heterogeneity in the decision-making process.

[Plasma cell leukaemia]. / La leucémie à plasmocytes.

We report a case of primary plasma cell leukaemia, with an absolute count of plasma cells of 53 Giga/L, diagnosed in a 83-year-old woman. The patient's condition improved, with no circulating plasma cells after 3 weeks of treatment, in response to the combination of thalidomide and dexamethasone administered for 5 days followed by thalidomide alone. The clinical presentation, the morphological, flow cytometric and pathophysiological characteristics of the plasma cell leukaemia and the treatment are summarised in this paper.

[Myelodisplasic syndromes diagnosed in a geriatric hospital: morphological profile in 100 patients]. / Syndromes myélodysplasiques diagnostiqués dans un hôpital gériatrique: profil cytologique de 100 patients.

Myelodysplastic syndrome (MDS) is particularly common in geriatric practice. As few data are available in very elderly patients, we conducted a 54-month retrospective study in patients over 70 years with MDS diagnosed at Hôpital Charles Foix. Patients with cobalamine, folate or iron deficiency were excluded. Regarding biological and morphologic approaches, MDS patients were classified according to the FAB criteria. We then tempted to reclassify the patients according to the WHO criteria. The Bournemouth scoring system was used as a prognostic tool. During the study period, 100 patients were included, 29 males and 71 females, median age 86 +/- 7 years (70-103). At the time of bone marrow sampling, a peripheral blood cytopenia was documented in 64 patients, a bicytopenia in 27 patients and a pancytopenia in 9 patients. Isolated anaemia (Hb < 12 g/dL) was found in 60 patients and isolated thrombocytopenia (< 150 x 10(9)/L) in 4. Macrocytosis (MCV > 100 fL) was observed in 21 % of the cases. According to the FAB criteria, the 100 patients were classified as follows: refractory anaemia (RA): 79%; RA with ringed sideroblasts (RARS): 8%; RA with excess of blasts (RAEB): 8%; RAEB in transformation: 1%; chronic myelomonocytic leukaemia: 4%. According to the WHO classification, the patients were reclassified as follows: RA (unilineage) (with or without ringed sideroblasts): 10%; refractory cytopenia with multilineage dysplasia with or without ringed sideroblasts (RCMD): 73%; RAEB: 7% (RAEB-1 6%, RAEB-21%); MDS/Myeloproliferative disorder: 4%; unclassified (hypocellularity): 5%; acute leukaemia: 1%. In order to estimate prognosis at the time of the bone marrow aspirate, we calculated the Bournemouth'score: 8 patients scored 0,57 scored 1,25 scored 2,8 scored 3 and 2 scored 4. In this geriatric population, 83% cases of MDS are RA or RCMD (with or without sideroblasts); MDS with excess of blasts are uncommon. Thus, elderly patients under study with MDS were diagnosed at an earlier stage of the disease than younger ones from series published in the literature. Due to frequent comorbidities, geriatric patients may be symptomatic for a slight decrease of haemoglobin level. Therefore, elderly patients are investigated as soon as they present with moderate anaemia that may explain the early MDS diagnosis.

[Oral anticoagulation in older patients. Establishment and validation of a new posologic warfarin regimen]. / Anticoagulation orale du sujet âgé. Etablissement et validation d'une grille d'adaptation posologique de la warfarine.

OBJECTIVE: Warfarin is highly effective in preventing thromboembolism and more recent clinical trials have established that adjusted dosing is highly effective in reducing the risk of ischemic stroke in patients with nonvalvular atrial fibrillation. Fear of major hemorrhage frequently dissuades physicians from use of anticoagulants in older people. In addition, the time needed to reach the therapeutic range may be excessively long and delicate in this population. PATIENTS AND METHODS: This study was undertaken in two phases. In the first phase, 20 patients (mean age 84 years) were given 5 mg of warfarin once daily for 3 consecutive days. During the following days, the dose of warfarin was adjusted to reach an International Normalized Ratio (INR) in the therapeutic range (between 2 and 3). The good correlation (r = -0.77, p < 0.01) between the INR on day 4 and the daily maintenance dose was used to establish an algorithm to predict the maintenance dose of warfarin. In the second phase, this algorithm was successfully tested in 94 elderly patients, mean age 84 years (range 74-99). RESULTS: The predicted dose on day 4 was effective in 56% within +/- 0.5 mg and in 92% within +/- 1 mg of the original predicted dose. No hemorrhagic complication occurred during the study. The therapeutic range was reached on day 4 in 63.5% and on day 1 in 91% of the patients. CONCLUSION: We have developed a method of predicting the maintenance dose of warfarin in a very old population based on the INR. This method is safe and easy to use.

Primary plasma cell leukaemia: a report of 18 cases.

Primary plasma cell leukaemia (P-PCL) is a variant of multiple myeloma (MM) first diagnosed in the leukemic phase, with >2000/mm(3) circulating plasma cells (PCs) and plasmacytosis >20% of the white cell count. We investigated the clinical characteristics, therapy, immunophenotype and prognosis factors of 18 patients. Common features at diagnosis were asthenia (seven patients), renal insufficiency (ten patients), bone pain (seven patients), splenomegaly or hepatomegaly (five patients). Hypercalcemia was present at diagnosis in seven patients and was the most potent poor prognosis factor (P<0.05). Most patients (16 out of 18) were treated with an anthracyclin containing regiment; complete remission was attained in one patient and partial remission in 11 patients while six patients had no response. The median survival time from diagnosis was 7 months (2--12, 95% confidence interval), but response to treatment had favorable predictive value (P<0.05). The PCs were usually positive for mature B-cell markers (PCA-1, CD38). They expressed integrins which may increase their binding to endothelial cells and thus participate in PCL physiopathology by favoring plasmocyte extramedullary spread.

A phase II trial of induction and consolidation therapy of acute myeloid leukemia with weekly oral idarubicin alone in poor risk elderly patients.

We have conducted a phase II outpatient trial testing weekly oral administration of idarubicin (ZAVEDOS-ZVD) alone to determine the rate of objective response and toxicity in poor risk acute myeloid leukemia (AML) patients over 60 years of age. The treatment consisted of three phases: induction, with 20 mg/m2 of ZVD on days 1, 8, 15 and 22; consolidation with 20 mg/m2 of ZVD for 4 weeks; and maintenance with six cycles lasting 3 months and consisting of oral 6 mercapto-purine 2 mg/kg/day, 4 days a week for 2 months; subcutaneous cytarabine 1 mg/kg, once a week for 2 months; and oral ZVD 20 mg/m2 on day 1 and day 8 of the third month. In case of failure after induction course, patients received salvage treatment with 4 weekly oral doses of 40 mg/m2 ZVD. Fifty-one patients with a median age of 76 years were enrolled and could receive induction course. Of these 51 patients, 37 could receive subsequent courses, which consisted either of consolidation, or salvage. Only 11 patients underwent maintenance treatment. Sixty-three percent of patients had to be hospitalized during induction, for a median duration of 14.5 days, and 87% required hospitalization during salvage for a median duration of 17.5 days. Only five patients (38%) required hospitalization during consolidation. There were three toxic deaths (6%), two from hemorrhage and one from pulmonary embolism. The overall response rate was 29%, with 12 patients in complete response (25%) and two in partial response (4%). The median overall survival rate is 4 months for the whole population, and the median DFS is 9.6 months among the 14 responding patients. The results of this trial show that this new weekly schedule of oral ZVD chemotherapy is feasible and effective in poor risk elderly patients with AML. This regimen may be helpful for patients unable to tolerate intensive intravenous regimens, and is a real alternative to palliative treatments.

Intensive chemotherapy with idarubicin, cytosine arabinoside, and granulocyte colony-stimulating factor (G-CSF) in patients with secondary and therapy-related acute myelogenous leukemia. Club de Réflexion en Hématologie.

Using a combination of intensive chemotherapy and G-CSF, we conducted a prospective trial designed to improve the complete remission (CR) rate in patients with AML evolving from a primary documented myelodysplastic syndrome (sAML) and therapy-related AML (tAML). Thirty-four patients (median age 61 years) with sAML (25 patients) or tAML (nine patients) entered the study. Induction course consisted of idarubicin (12 mg/m2 of body-surface area per day for 3 days) and intermediate-dose (ID) cytarabine in the 24 younger patients (1 g/m2 of body-surface area as a 2 h infusion every 12 h for 5 days) or standard-dose (SD) cytarabine in the 10 older patients (100 mg/m2 of body-surface area per day as a continuous infusion for 7 days), followed by G-CSF until neutrophil recovery or treatment failure. Nineteen patients (56%, 13/24 in the ID group and 6/10 in the SD group) achieved a CR (14/25 sAML and 5/9 tAML). Early death occurred in four patients, but four additional patients died in CR from treatment-related toxicity (overall toxic death rate 24%). Initial cytogenetics was available in 33 patients. The CR rate was significantly lower in patients with unfavorable cytogenetics compared to patients with intermediate cytogenetics (37% vs 79%). Median remission duration and overall survival were 3 and 9 months, respectively and not different between ID and SD patients. Although the treatment-related toxicity is high, a high CR rate can be obtained in these poor-risk AML patients with the use of intensive chemotherapy in combination with G-CSF, although the role of the latter is still to be proven. Results remain especially poor in patients with unfavorable cytogenetics. New approaches are needed to maintain remission in these high-risk AML patients.

Transmission of Plasmodium falciparum by allogeneic bone marrow transplantation.

We describe a case of Plasmodium falciparum infection in a Comorian patient undergoing BMT. The patient's last visit to an endemic area was 1 year prior to BMT. The donor left the Comoro Islands 2 months before marrow harvesting. They had both had previous episodes of malaria and were seropositive for Plasmodium falciparum. At the time of BMT, blood smears were negative in both the donor and recipient. On day 12 post-BMT the patient was asymptomatic but a blood smear revealed 12.5% parasitemia. We consider that donors and recipients at risk pre-BMT should routinely be given specific treatment before marrow harvesting and conditioning, independent of the appearance of blood smears.

Silica-associated connective tissue disease. A study of 24 cases.

We prospectively studied all patients hospitalized for connective tissue disease (CTD) in our French rheumatology clinic from January 1979 to December 1989. Our aims were 1) to determine if CTDs associated with occupational exposure to silica (Si) are currently observed in a rheumatology clinic, and, if so, 2) to describe the major features of Si-associated CTD, and 3) to specify which individuals are affected by Si-associated CTD. Patients were divided into 2 groups based on their responses to a questionnaire: those who had been exposed to Si, and those who had no occupational exposure to Si. Among the 764 patients with CTD studied, 24 (3%) were patients with Si-associated CTD and 740 (97%) were patients with non-Si-associated CTD. The sex ratio between the 2 groups was significantly different with a high frequency of men and of immigrants in the Si-associated CTD group. Two thirds of the patients exposed to Si were male miners or sandblasters, but the other third had more unusual exposures to Si, which may involve members of all socio-economics sectors and both sexes, such as sculpture or exposure to abrasive powders. Progressive systemic sclerosis (PSS) was significantly more prevalent in the Si-associated CTD group. This group also consisted of patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), dermatomyositis (DM), and other autoimmune diseases. Si-associated CTD was characterized by the frequency of radiologic lung fibrosis, impaired pulmonary function tests, secondary Sjögren syndrome, and antinuclear antibodies. The number of mineral particles and crystalline Si content were raised in all the bronchoalveolar lavage specimens of Si-exposed patients but in none of those of nonexposed patients. In some cases of Si-associated CTD, the disease was reversible after early cessation of Si exposure. Epidemiologic studies are required to confirm our hypothesis that not only PSS and RA but also SLE and DM are associated with occupational exposure to Si. Pending such results, exposure to Si should be sought in the history of any patient with CTD, especially in a male patient with pulmonary signs, and if present, exposure should be stopped. In the meantime, steps should be taken to ensure that workers exposed to Si in all environments have adequate protection.

CT and MR patterns of spinal involvement in Richter syndrome.

Richter syndrome is the transformation of chronic lymphocytic leukemia (CLL) into large cell lymphoma. Besides the involvement of lymph nodes, liver, and spleen, bone lesions occur infrequently. We report one case of a patient with a paraspinous mass and destruction of the vertebra by large cell transformation of CLL seen on CT and MRI. There was nothing specific about the clinical presentation, imaging characteristics, and histopathological pattern of bone biopsy that would allow for confident differentiation from infectious spondylitis.