A multicentre retrospective comparison of central nervous system prophylaxis strategies among patients with high-risk diffuse large B-cell lymphoma.

BACKGROUND: Central nervous system (CNS) relapse in diffuse large B-cell lymphoma (DLBCL) is a devastating complication; the optimal prophylactic strategy remains unclear. METHODS: We performed a multicentre, retrospective analysis of patients with DLBCL with high risk for CNS relapse as defined by two or more of: multiple extranodal sites, elevated serum LDH and B symptoms or involvement of specific high-risk anatomical sites. We compared three different strategies of CNS-directed therapy: intrathecal (IT) methotrexate (MTX) with (R)-CHOP 'group 1'; R-CHOP with IT MTX and two cycles of high-dose intravenous (IV) MTX 'group 2'; dose-intensive systemic antimetabolite-containing chemotherapy (Hyper-CVAD or CODOXM/IVAC) with IT/IV MTX 'group 3'. RESULTS: Overall, 217 patients were identified (49, 125 and 43 in groups 1-3, respectively). With median follow-up of 3.4 (range 0.2-18.6) years, 23 CNS relapses occurred (12, 10 and 1 in groups 1-3 respectively). The 3-year actuarial rates (95% CI) of CNS relapse were 18.4% (9.5-33.1%), 6.9% (3.5-13.4%) and 2.3% (0.4-15.4%) in groups 1-3, respectively (P=0.009). CONCLUSIONS: The addition of high-dose IV MTX and/or cytarabine was associated with lower incidence of CNS relapse compared with IT chemotherapy alone. However, these data are limited by their retrospective nature and warrant confirmation in prospective randomised studies.

"Reversible" myelodysplastic syndrome or ineffectual clonal haematopoiesis? - add(6p) myeloid neoplasm with a spontaneous cytogenetic remission.

Cytotoxic chemotherapy has inherent mutagenic potential and alters the bone marrow microenvironment after therapy. In some cases, this potentiates expansion of an aberrant clone and may lead to a therapy-related myeloid neoplasm if the clone overcomes selective pressure. We present the case of a 43-year-old woman diagnosed with an indolent, therapy-related myeloid neoplasm with an isolated chromosome 6p abnormality following treatment for de novo Acute Myeloid Leukaemia (AML), who manifest a sustained spontaneous cytogenetic remission two years later, possibly due to an ineffectual or non-dominant founding clone. This case reminds us to be mindful of the possibility that clonal haematopoiesis may not always equate to clinically relevant disease, even in the setting of an abnormal clonal karyotype.

Fatal disseminated infection by Scedosporium prolificans during induction therapy for acute leukemia: a case report and literature review.

We report a case of fatal disseminated fungal infection by Scedosporium prolificans which occurred in a patient with acute leukemia during induction chemotherapy. Rapid clinical deterioration despite high-dose empirical amphotericin B highlights both the pathogenicity of this fungus in immunocompromised hosts and its resistance to standard antifungal therapy.

Plerixafor plus pegfilgrastim is a safe, effective mobilization regimen for poor or adequate mobilizers of hematopoietic stem and progenitor cells: a phase I clinical trial.

The safety, kinetics and efficacy of plerixafor+pegfilgrastim for hematopoietic stem and progenitor cell (HSPC) mobilization are poorly understood. We treated 12 study patients (SP; lymphoma n=10 or myeloma n=2) with pegfilgrastim (6 mg SC stat D1) and plerixafor (0.24 mg/kg SC nocte from D3). Six SP were 'predicted poor-mobilizers' and six were 'predicted adequate-mobilizers'. Peripheral blood (PB) CD34(+) monitoring commenced on D3. Apheresis commenced on D4. Comparison was with 22 historical controls (HC; lymphoma n=18, myeloma n=4; poor mobilizers n=4), mobilized with pegfilgrastim alone. Eight (67%) SP had PB CD34(+) count ⩽5 × 10(6)/L D3 post pegfilgrastim; all SP surpassed this threshold the morning after plerixafor. In SP, PBCD34(+) counts peaked D4 6/12 (50%), remaining ⩾5 × 10(6)/L for 4 days in 8/12 (67%). All SP successfully yielded target cell numbers (⩾2 × 10(6)/kg) within four aphereses. After maximum four aphereses, median total CD34+ yield was higher in SP than HC; 8.0 (range 2.4-12.9) vs 4.8 (0.4-14.0) × 10(6)/kg (P=0.04). Seven of twelve (58%) SP achieved target yield after one apheresis. Flow cytometry revealed no tumor cells in PB or apheresis product of SP. Plerixafor+pegfilgrastim was well tolerated with bone pain (n=2), diarrhoea (n=2) and facial paraesthesiae (n=3). Plerixafor+pegfilgrastim is a simple, safe and effective HSPC mobilization regimen in myeloma and lymphoma, in both poor and good mobilizers, and is superior to pegfilgrastim alone.

Therapy-related myelodysplastic syndrome and acute myeloid leukemia following fludarabine combination chemotherapy.

Fludarabine combination chemotherapy achieves high response rates in chronic lymphocytic leukemia (CLL) and indolent lymphoma. The aim of this study was to investigate the incidence and characteristics of treatment-related myelodysplasia and acute myeloid leukemia (t-MDS/AML) after treatment with fludarabine in combination for lymphoproliferative disorders and identify risk factors for its development. In all, 176 patients treated with fludarabine combination were followed for a median of 41 months (range 6-125 months). In all, 19 cases of t-MDS/AML have been identified for an overall rate of 10.8%. Median overall survival post-t-MDS/AML diagnosis was 11 months. Patients developing t-MDS/AML included 11/54 with follicular lymphoma (FL) (crude rate 20.4%), 5/82 with CLL (6.1%) and 3/24 with Waldenstrom macroglobulinemia or marginal zone lymphoma (12.5%). Most patients had other cytotoxic treatments (median 4, range 0-7) but three with FL had fludarabine combination as their only line of treatment. Of the eleven patients (6.3%) who received mitoxantrone with their first fludarabine combination, four (36.4%) developed t-MDS/AML (P=0.007). There was a trend toward prior cytotoxic therapy increasing the risk for t-MDS/AML (P=0.067). Fludarabine combination chemotherapy is associated with a moderate risk of t-MDS/AML particularly when combined with mitoxantrone. This complication should be considered when evaluating the potential benefit of this treatment in lymphoproliferative disorders.

Stem cell factor and high-dose twice daily filgrastim is an effective strategy for peripheral blood stem cell mobilization in patients with indolent lymphoproliferative disorders previously treated with fludarabine: results of a Phase II study with an historical comparator.

Fludarabine exposure leads to impaired peripheral blood stem cell (PBSC) mobilization in indolent lymphoproliferative disorders (LPD). We previously reported that only 34% of fludarabine-exposed patients mobilized successfully using granulocyte-colony stimulating factor (G-CSF; median 10 microg/kg/day) with or without chemotherapy, with unpredictable kinetics and moderate infectious morbidity. Stem cell factor (SCF) plus high-dose twice daily (b.d.) G-CSF may improve mobilization in these patients. SCF 20 microg/kg/day subcutaneously was given from day 1, G-CSF 12 microg/kg b.d. subcutaneously from day 4, apheresis commenced from day 6. Previous study patients served as historical controls. Thirty five patients with indolent LPD were enrolled, median age was 54 years (range 31-66), 66% male, median cumulative prior fludarabine dose was 660 (405-900) mg. Overall, 22 patients (63%) collected >or= 2.0 x 10(6)/kg PBSC (success), compared to 34% controls (odds ratio (OR) 3.2; 95% confidence interval (CI) (1.2, 9.3); P=0.021). Median CD34(+) yield overall was 2.3 x 10(6)/kg (0.53-8.97) from median four (2-6) aphereses. Study patients >or= 50 years mobilized successfully more frequently than controls (58 versus 17%; P=0.0065). Adjusting for age, successful mobilization remained significantly higher in the current study (OR 4.2; 95% CI (1.4, 14.0); P=0.008). SCF/high-dose b.d. G-CSF improves PBSC mobilization efficacy after fludarabine exposure, over mobilization using G-CSF as the mobilizing cytokine. This combined growth factor strategy is a preferred mobilization method for fludarabine-exposed patients.

The diagnosis of idiopathic thrombocytopenic purpura in adults: does bone marrow biopsy have a place?

OBJECTIVE: To assess the value of routine bone marrow biopsy (BMB) in adult patients less than 65 years of age with suspected idiopathic thrombocytopenic purpura (ITP). DESIGN: Retrospective analysis. Data were collected from hospital medical records and laboratory results. SETTING: Large tertiary-level metropolitan teaching hospital, Victoria. PARTICIPANTS: Sixty-six patients who had undergone BMB for investigation of isolated thrombocytopenia between January 1992 and May 1997, according to defined eligibility criteria. RESULTS: Sixty-one of the 66 patients had BMB findings consistent with ITP (i.e., normal or increased numbers of megakaryocytes and other haemopoietic lineages normal). Three of these patients' biopsies incidentally showed reduced or absent iron stores. In the remaining five patients, BMB in four showed mild hypocellularity and the subsequent course in these patients was consistent with chronic ITP. The fifth patient had neutrophil hypersegmentation and giant band cells on BMB, the cause of which was unclear. The subsequent course in this patient has also been consistent with chronic ITP. CONCLUSIONS: Our data suggest that the routine performance of BMB for the diagnosis of ITP is not useful, provided that a thorough clinical history and physical examination are undertaken and that the blood count and peripheral blood smear show no abnormalities apart from thrombocytopenia.

Neutrophil hypersegmentation in iron deficiency anaemia: a case-control study.

Neutrophil hypersegmentation (NH) is an important haematological feature of cobalamin or folate deficiency. As iron deficiency and folate deficiency often occur in the same target groups it is important to establish whether iron deficiency alone is a cause of NH. We report a case-control study which addresses this issue. Two groups of hospital patients were studied. Group 1 comprised 50 patients with iron deficiency anaemia (IDA). Group II comprised 50 control age- and sex-matched patients who were haematologically normal without evidence of iron deficiency from the iron studies. Patients with other factors which could affect the degree of neutrophil segmentation (cobalamin/folate deficiency, renal failure, infection and drug exposures) were excluded from the study. A total of 10 000 neutrophils were examined, 100 from each patient. NH was defined as the presence of five or more five-lobed neutrophils per 100, or any neutrophils with six or more lobes. The results were as follows: IDA, mean neutrophil lobe count 3.36; number of patients with NH 31/50 (62%): controls, mean neutrophil lobe count 2.96, number of patients with NH 2/50 (4%). These differences were statistically significant. We conclude that NH is common in IDA. The mechanism whereby iron deficiency results in NH is not clear.

Factors influencing DRG 210 (hip fracture) reimbursement.

The effect of prospective payment system (PPS) on reducing cost and quality of care is still unknown. Fifty-two patients (mean +/- SD, 82.0 +/- 6.5 years) with hip fracture classified as DRG 210 (hip and femur procedures except major joint, age greater than 69 years and/or complication and/or comorbidity), treated by compression nail were separated into four groups: Group I--no comorbidity, no complications; Group II--no comorbidity but had complications; Group III--with comorbidity but no complications; and Group IV--with both comorbidity and complications. Compared to length of stay (LOS) in Groups I, II and III (mean 26 days), Group IV had significantly increased LOS (mean, 61.5 days) and 81% of the 16 who were day outliers (L.O.S. greater than 40 days). Patients without comorbidity (I & II) even if they did develop complications were not financial losers. Those with comorbidity appear to be high-cost patients as they invariably end up with complications (78%), and reimbursement for Group IV was significantly less, resulting in net loss of this DRG. Our finding demonstrates the importance of preventing complications in patients with comorbidity. Present DRG reimbursement guidelines do not provide sufficient attention to LOS implications of both comorbidity and complications. Ideally, they should be considered as separate factors within the DRG category.

Effects of topical capsaicin on normal skin and affected dermatomes in herpes zoster.

Hyperalgesia and allodynia, lasting for months or even years, occurs in the form of post-herpetic neuralgia in approximately 70% of adults previously infected with the varicella herpes zoster virus. The present study aimed at testing the analgesic desensitising actions and reversibility of repeated application of topical capsaicin on disordered polymodal nociceptors and peptidergic sensory fibres mediating warm and pain sensation. Cutaneous nociceptor desensitisation was measured using the Glasgow automated thermal threshold test (Medelec TTT). For normal subjects (n = 69) the mean forearm warm threshold was 0.15 +/- 0.07 degrees C and the cold threshold was 0.14 +/- 0.10 degrees C. A variable degree of partial desensitisation of herpes-affected skin was found in 15 patients with post-herpetic neuralgia before capsaicin treatment where the mean threshold elevation for warm detection was 1.19 degrees C and 0.7 degrees C for cold detection, compared with the corresponding normal skin. In preliminary studies of 15 patients with post-herpetic neuralgia, good pain relief averaging 30% or 77% occurred in the affected dermatome(s) after 3 to 4 weeks of 0.01% or 0.05% capsaicin cream respectively, applied 3-4 times daily. The warm thresholds, after chronic capsaicin treatment, increased between 0.1 and 7.60 degrees C, the average elevation being 3.69 degrees C. By contrast cold thresholds after capsaicin altered inconsistently and by only an average of 0.08 degrees C. The results suggest that elevation of the warm threshold may indicate the desensitisation achieved by capsaicin treatment of skin polymodal nociceptors. Cold detection, being dependent upon A-delta cold fibre function, is unaffected by capsaicin treatment. There was a poor correlation between pain relief and elevation of warm detection in response to capsaicin treatment. Generally, it was found that those patients with less initial desensitisation to warm detection as a consequence of post-herpetic neuralgia experienced better pain relief after capsaicin was applied. The method used permits determination of the minimum effective desensitising dose of capsaicin, enables patient compliance and progress to be monitored and should allow the prediction of patients likely to achieve the best response to treatment.

Phase I and subsequent phase II study of filgrastim (r-met-HuG-CSF) and dose intensified cyclophosphamide plus epirubicin in patients with non-Hodgkin's lymphoma and advanced solid tumors.

BACKGROUND: To define a maximum tolerated dose (MTD) for the combination of epirubicin and cyclophosphamide with filgrastim (r-met-HuG-CSF) in patients with advanced solid tumors and non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: Thirty-five patients with advanced solid tumors were enrolled in stages I and II. Twenty-one patients were treated in stage I in sequential cohorts of at least three patients at increasing dosage levels of cyclophosphamide and epirubicin, for up to six cycles every 21 days. At the completion of stage I, a MTD for epirubicin was established. Fourteen patients were treated in stage II, in cohorts of three or more. The epirubicin dose remained constant at the MTD dosage from stage I. Cyclophosphamide was further dose-escalated to establish its MTD. Twenty-one patients with previously untreated non-Hodgkin's lymphoma were treated in stage III with the MTD established in the prior stages. RESULTS: The MTD in stage I was epirubicin 150 mg/m2 and cyclophosphamide 1500 mg/m2 with cumulative neutropenia as the dose-limiting toxicity (DLT). Cumulative thrombocytopenia prevented further dose-escalation of cyclophosphamide in stage II. The stage III regimen consisted of six, 21-day cycles of epirubicin 150 mg/m2, cyclophosphamide 1500 mg/m2, vincristine 2 mg, and prednisolone 100 mg for five days with filgrastim support. Nineteen of twenty-one patients (90%) completed six cycles of treatment, eight (38%) without dose reduction. Common toxicity criteria (CTC) grade 4 neutropenia (neutrophil nadir < 0.5 x 10(9)/l) was documented in 85 of 118 cycles (72%). Neutropenic fever was documented in 17 of 21 patients (81%) on at least one occasion. Severe thrombocytopenia (< 25 x 10(9)/l) was seen in fourteen of 118 cycles (12%) and increased with cycle number. There was no significant non-hematological toxicity. CONCLUSION: Significant dose-escalation of epirubicin and cyclophosphamide was possible with filgrastim support. The MTD achieved was approximately double that of standard-dose therapy. This study forms the basis of an ongoing randomized study evaluating dose-intensification in intermediate grade NHL.