Intermediate-dose melphalan (IDM) combined with G-CSF (filgrastim) is an effective and safe induction therapy for autologous stem cell transplantation in multiple myeloma

Twenty-one previously untreated multiple myeloma (MM) patients and 10 previously treated patients with refractory or relapsed disease received two or three cycles of intermediate-dose melphalan (70 mg/m²) (IDM), administered intravenously every 6 weeks. Seven previously untreated patients received three and all other patients received two courses of IDM. The objective of the study was to reduce the toxicity of high-dose melphalan (140 mg/m²) (HDM) while maintaining its cytotoxic efficacy and secondly to ensure the possibility of collecting sufficient numbers of peripheral blood stem cells (PBSC) for transplantation. 18 (85%) previously untreated patients responded, of whom four achieved CR (18%). In addition five out of 10 previously treated patients with refractory or relapsed disease responded although bone marrow toxicity in this category was a major drawback. Toxicity was moderate, consisting of alopecia and moderate bone marrow suppression: the granulocyte count dropped below 0.5 × 10⁹/l and platelets below 25 × 10⁹/l for a median of 8 and 6 d, respectively. No serious infections occurred and the majority of patients attended the out-patient clinic. In 12/14 previously untreated patients sufficient peripheral blood CD34⁺ cells for harvest were present in the repopulation phase after the first IDM. In nine patients peripheral blood stem cells were collected and eight patients have undergone succesful transplantation.
Repeated IDM followed by filgrastim is highly effective in untreated MM and may be safely administered to reduce tumour load prior to PBSC collection. Autologous stem cells harvested after repeated IDM have a full long-term repopulating capacity.     

Bortezomib, low-dose intravenous melphalan, and dexamethasone for patients with relapsed multiple myeloma

This multicenter phase I/II study investigated the maximum tolerated dose (MTD), safety, and efficacy of low dose intravenous (IV) melphalan in combination with bortezomib for patients with relapsed multiple myeloma (MM). Patients received bortezomib 1·3 mg/m² on days 1, 4, 8, and 11 and escalating doses of IV melphalan (2·5–10·0 mg/m²) on day 2 of a 28-day cycle for a maximum of eight cycles. Dexamethasone 20 mg was added for progressive or stable disease. Fifty-three patients were enrolled. The MTD was defined at melphalan 7·5 mg/m² and bortezomib 1·3 mg/m². The overall response rate (ORR) was 68% (23% complete or near-complete responses [CR/nCR]) whilst at the MTD ( n  = 33) the ORR was 76% (34% CR/nCR). After median follow-up of 17 months, the median progression free survival was 10 months, rising to 12 months at the MTD ( P  < 0·05 vs. non-MTD regimens). The median overall survival was 28 months, but was not yet reached at the MTD. Grade 3/4 adverse events included thrombocytopenia (62%), neutropenia (57%), infection (21%), and neuropathy (15%). Bortezomib and low-dose IV melphalan combination therapy is a safe and highly effective regimen for patients with relapsed MM. These data suggest further investigation of this combination is warranted.     

Granulocyte colony-stimulating factor given in addition to interferon-α to mobilize peripheral blood stem cells for autologous transplantation in chronic myeloid leukaemia

In order to potentially mobilize and harvest the Ph⁻ cells observed in most patients with chronic myeloid leukaemia (CML) during interferon-α (IF-α) therapy, G-CSF (filgrastim), 5 μg/kg/d, was administered subcutaneously together with IF-α to 30 CML patients in haematological remission but with various degrees of cytogenetic remission, after IF-α therapy. Peripheral blood stem cells (PBSC ) were harvested using standard aphereses from day 5 of G-CSF. Patients underwent one to four (median three) aphereses. Median total yields/kg were 7.6 (range 3.8–25) × 10⁸ MNC, 3.4 (0–140) × 10⁶ CD34⁺ cells, and 17 (1.1–107) × 10⁴ CFU-GM. No patient had a significant increase in the percentage of Ph⁺ cells in the bone marrow under G-CSF therapy. The percentage of Ph⁺ cells in apheresis products tended to decrease between the first and the last apheresis ( P  = 0.05). 14 patients who were not responsive to IF-α were transplanted after conditioning with busulphan 16 mg/kg and melphalan 140 mg/m². Median time to neutrophils > 0.5 × 10⁹/l was 20 d (16–114 d) and to platelets > 50 × 10⁹/l 18 d (12–149 d). Nine patients had a major cytogenetic response post graft, which correlated with the amount of Ph⁺ cells reinfused with the graft ( P  = 0.02). We conclude that this procedure is feasible, allowing the harvest of enough PBSC, some of them Ph⁻ in patients who responded to IF-α, to allow autologous transplantation.     

CD34+ cell immunoselection from G-CSF-alone-primed peripheral blood in children with low body mass

Summary. We report the data of CD34⁺ cell immunoselection from peripheral blood after G-CSF-alone mobilization (lOμg/kg/d s.c.) in nine children with neuroblastoma (median age 4 5 years (2-8), median body weight 16kg (10-20). Leukaphereses were carried out on a Cobe Spectra separator and two consecutive harvests (4 blood volumes processed) were used for immunoselection on a Ceprate(tm) column. The yield of CD34⁺ cells in the purified fraction was 50% (23-80), with a median number of 2.8xl0⁶ CD34+ cells/kg (1-9-4). All patients were reinfused with selected CD34⁺ cells after busulfan 600 mg/m²+ melphalan 180mg/m² and achieved successful haemopoietic recovery.     

Impact of Baseline Renal Function on Outcomes of Renal Artery Stenting in Hypertensive Patients

Renal artery stenting may improve blood pressure (BP) and renal function in resistant hypertension patients; however, benefit may differ depending on the degree of renal dysfunction. The authors analyzed 67 consecutive patients receiving stenting for obstructive renal artery disease between 2002 and 2005. Patients were categorized as normal or mildly impaired according to estimated glomerular filtration rate (eGFR) (≥60 mL/min/1.73 m²), moderately impaired (eGFR 30 to 59 mL/min/1.73 m²), and severely impaired (eGFR <30 mL/min/1.73 m²). In patients with eGFR ≥60, systolic BP did not significantly improve from baseline. However, in patients with an eGFR between 30 and 59 mL/min/1.73 m², systolic BP decreased by 12 mm Hg at 6 months (P=.02) and 14 mm Hg at 12 months (P=.01). Greater benefit was observed in patients with eGFR <30 mL/min/1.73 m², with a 16 mm Hg (P=.10) and 21 mm Hg (P=.02) decrease at 6 and 12 months, respectively. Renal function was stable across all groups. Renal artery stenting reduced BP and produced greatest benefit in patients with baseline impaired renal function.     

IDA-FLAG (idarubicin, fludarabine, cytarabine, G-CSF), an effective remission-induction therapy for poor-prognosis AML of childhood prior to allogeneic or autologous bone marrow transplantation: experiences of a phase II trial

A phase II trial was designed to explore the potential feasibility and efficacy of a reinduction therapy consisting of fludarabine, cytarabine, idarubicin and granulocyte colony stimulating factor (G-CSF) for acute myelogenous leukaemia (AML) patients with poor prognosis.
Twenty-three patients aged 1.2–17.5 years with refractory ( n  = 3), relapsed ( n  = 19) or secondary ( n  = 1) AML were treated with the IDA-FLAG regimen, a combination therapy of idarubicin (days 2–4, 12 mg/m²/d), fludarabine (days 1–4, 30 mg/m²/d), cytarabine (days 1–4, 2000 mg/m²/d) and G-CSF (day 0 up to ANC > 1 × 10⁹/l, 400 μg/m²/d). They received a total of 37 courses of IDA-FLAG and/or FLAG (IDA-FLAG without idarubicin). 17/23 patients achieved a complete remission (CR) with a median duration of 13.5 months (1–39 months), one patient showed a partial remission, and five were nonresponders while in CR, 11 patients underwent bone marrow or PBSC (peripheral blood stem cells) transplantation. Overall, nine patients remain in continuous complete remission with a median duration of 17.5 months (9.5–39 months). The toxicity of the IDA-FLAG courses was more severe than for the FLAG courses with marked neutropenia and thrombocytopenia (for IDA-FLAG: median 22.5 and 25 d respectively; for FLAG: median 10.5 and 14 d respectively). Pulmonary infections were the main nonhaematological toxicity. One patient died in CR from invasive aspergillosis.
The IDA-FLAG regimen produced a CR of >12 months in more than half of the patients and can be recommended as a therapeutic option prior to allogeneic or autologous bone marrow transplantation.     

A randomized trial of maintenance interferon following high-dose chemotherapy in multiple myeloma: long-term follow-up results

High-dose chemotherapy (melphalan) with autologous marrow stem cell support (AMSCS) results in high response rates in multiple myeloma (MM), with up to 50% of patients achieving complete remission. However, these remissions are generally not durable. As the cytokine interferon alpha has been shown to prolong partial response following conventional chemotherapy, this trial was conducted to evaluate its role following high-dose chemotherapy. 85 patients were randomly assigned to maintenance treatment with interferon alpha, 3 × 10⁶ units/m² subcutaneously three times weekly until relapse or no further treatment following recovery from high-dose chemotherapy (melphalan 140–200 mg/m² or busulphan 16 mg/kg) combined with AMSCS. At 5.8 years following the accrual of the last patient in this trial, 38 patients had died, 17 in the interferon arm and 21 in the control arm. The median progression-free survival (PFS) in the 42 patients randomized to interferon alpha was 46 months versus 27 months in the controls. Both overall survival and PFS, which were highly significant at median follow-up of 52 months, have now ceased to be significant, because most patients have ultimately succumbed to their disease. Interferon was tolerated by the majority of patients with very good compliance. Toxicity consisted mainly of flu-like symptoms and malaise which were usually self-limiting. The results of such a pilot study should be carefully interpreted and the benefits of interferon should be confirmed in larger multi-centre studies in the setting of minimal residual disease following autologous transplantation.     

Australian Leukaemia Study Group Myeloma II: a randomized trial of intensive combination chemotherapy with or without interferon in patients with myeloma

The Australian Leukaemia Study Group has performed a randomized trial of interferon α-2A (Roferon-A) as a co-induction agent together with intensive combination chemotherapy and as maintenance following completion of 12 cycles of induction treatment. When used as a co-induction agent, interferon-α did not improve response rates, time-to-treatment failure, or overall survival. Patients who had interferon together with intensive combination therapy (PCAB: prednisone 60 mg/m² days 1–5, cyclophosphamide 600 mg/m² day 1, BCNU 30 mg/m² day 1, doxorubicin 30 mg/m² day 1, repeated every 28 d for a total of 12 cycles) had more leucocyte and granulocyte toxicity and received a lower dose intensive of cytotoxic drugs than those patients who received PCAB without interferon.   There was a trend towards prolongation of plateau phase which did not reach significance. Interferon, however, did improve the survival of patients who achieved plateau; for those patients interferon was associated with a 33% decrease in the rate of death after adjusting for initial beta-2 microglobulin level.     

Factors influencing collection of peripheral blood progenitor cells following high-dose cyclophosphamide and granulocyte colony-stimulating factor in patients with multiple myeloma

We treated 103 multiple myeloma (MM) patients with 7 g/m² cyclophosphamide (Cy) followed by 300 μg G-CSF/d to harvest peripheral blood progenitor cells (PBPC). PBPC autografts containing > 2.0 × 10⁶ CD34⁺ cells per kg body weight were obtained at the first attempt from 90/100 evaluable patients. The most significant factor predicting impairment of PBPC collection was the duration of previous melphalan treatment ( P  < 0.0001). In multivariate discriminate analysis, treatment with melphalan during the most recent chemotherapy cycles prior to mobilization ( P  = 0.0727) and previous radiotherapy ( P  = 0.0628) had a marginally significant negative influence on the efficacy of PBPC collection. We found no reduced functional capacity of CD34⁺ cells to restore haemopoiesis after myeloablative treatment related to the duration of melphalan exposure. At the time of best response to conventional treatment, a median paraprotein reduction of 21% was achieved following high-dose cyclophosphamide (HD-Cy). Two heavily pretreated patients died and one patient developed pulmonary toxicity W.H.O. grade IV following HD-Cy. Potential transplant candidates should undergo mobilization and harvesting of PBPC before melphalan-containing treatment. Combinations of haemopoietic growth factors and their dose modifications should be investigated to improve PBPC collection, to allow a dosage reduction of the mobilization chemotherapy.     

A randomized phase II study of BB-10010: a variant of human macrophage inflammatory protein-1α for patients receiving high-dose etoposide and cyclophosphamide for malignant lymphoma and breast cancer

Macrophage inflammatory protein-1α (MIP-1α) is a chemokine that can inhibit the cell cycle progression of both primitive haemopoietic and epidermal progenitor cells. This property could potentially be exploited to attenuate both the myelosuppressive effects of chemotherapy as well as mucositis. We evaluated both the biological and clinical effects of BB-10010, a genetically engineered variant of MIP-1α, in patients with malignant lymphoma or breast cancer receiving high-dose etoposide (VP 3.6 g/m²) and cyclophosphamide (Cy 200 mg/kg). 52 patients were randomized to one of three cohorts. Cohort A received no BB-10010; cohorts B and C received 10 μg/kg and 100 μg/kg of BB-10010, respectively. All patients received post-chemotherapy G-CSF. BB-10010 was well tolerated. There were no significant differences between groups in recovery to an ANC > 0.5 × 10⁹/l, 1 × 10⁹/l or 1.5 × 10⁹/l, the number of days with an ANC < 0.5 × 10⁹/l, days to a platelet count >50 × 10⁹/l or 100 × 10⁹/l, or the incidence and severity of mucositis. There was no evidence of any effect of BB-10010 on colony-forming cell (CFC) or long-term culture-initiating cell (LTC-IC) mobilization, cycling activity in the marrow or on chemotherapy-induced changes in CFC or LTC-IC number both of which were in the normal range by 22 d after completion of the chemotherapy. To our knowledge this is the first report of a myelointensive regimen having no apparent long-term effect on the LTC-IC compartment. In summary, BB-10010 is safe when used in patients receiving high-dose therapy but has no effect on reducing the toxicity of such therapy.     

Phase I trial of fludarabine, bortezomib and rituximab for relapsed and refractory indolent and mantle cell non-Hodgkin lymphoma

Based on the hypothesis that bortezomib may potentiate fludarabine activity by inhibiting DNA repair, we designed a phase I trial using this combination with rituximab in patients with relapsed and refractory indolent and mantle cell non-Hodgkin lymphoma. Twenty-four patients were enrolled. Non-Hodgkin lymphoma subtypes included 12 patients with follicular lymphoma, four with marginal zone lymphoma, three with lymphoplasmacytic lymphoma, three with mantle cell lymphoma and two with small lymphocytic/chronic lymphocytic leukaemia. Fludarabine and bortezomib were escalated in cohorts of three patients. Rituximab was added to the maximum tolerated dose of fludarabine and bortezomib and added significant dose-limiting myelosuppression. The maximum tolerated dose was fludarabine 25 mg/m² on days 1–3, bortezomib 1·3 mg/m² on days 1, 4, 8, 11, with rituximab 375 mg/m² on day 1 administered every 21 d. Clinical responses were observed in 11 patients, five of whom were refractory to their most recent treatment regimen. Six additional patients had stable disease for a median of 10 months (range 4–30+). Cumulative myelosuppression and neuropathy was observed. The combination of fludarabine, bortezomib, and rituximab appears to be an active regimen with manageable toxicity for relapsed NHL.     

Quinine improves the results of intensive chemotherapy in myelodysplastic syndromes expressing P glycoprotein: results of a randomized study

Intensive chemotherapy produces a lower complete remission (CR) rate in the myelodysplastic syndromes (MDS) than in de novo acute myeloid leukaemia (AML), possibly due in part to a higher incidence of P glycoprotein (PGP) expression in MDS blast cells. We designed a randomized trial of intensive chemotherapy with or without quinine, an agent capable of reverting the multidrug resistance (mdr) phenotype, in patients aged  65 years with high-risk MDS. Patients were randomized to receive mitoxantrone 12 mg/m²/d days 2–5 + AraC 1 g/m²/12 h days 1–5, with (Q⁺) or without (Q⁻) quinine (30 mg/kg/d). 131 patients were included. PGP expression analysis was successful in 91 patients. In the 42 PGP-positive cases, 13/25 (52%) patients in the Q⁺ group achieved CR, compared to 3/17 (18%) patients in the Q⁻ group ( P  = 0.02) and median Kaplan-Meier survival was 13 months in the Q⁺ group, and 8 months in the Q⁻ group ( P  = 0.01). No life-threatening toxicity was observed with quinine. In conclusion, the results of this randomized study show that quinine increases the CR rate and survival in PGP-positive MDS cases treated with intensive chemotherapy.     

Haematological reconstitution following high dose and supralethal chemo-radiotherapy using stored, non-cryopreserved autologous bone marrow

S ummary . Eighteen patients with small cell carcinoma of the lung received high dose cyclophosphamide (180–200 mg/kg) intensification following five pulses of 'CHOP' chemotherapy (cyclophosphamide 750 mg/m² i.v., adriamycin 50 mg/m² i.v., vincristine 1·4 mg/m² i.v., prednisolone 40 mg orally for 5 d). They received infusions of autologous bone marrow which had been stored at 4°C for 34 h. Pancytopenia was predictable in onset and its duration acceptable. Recovery of neutrophils to greater than 1·0 × 10⁹/l was achieved in 17·5 ± 0·9 d (mean ± SEM) and platelets to greater than 100 × 10⁹/l in 17·5 ± 0·8 d. Four patients with acute myeloid leukaemia in complete remission received intensification with the supralethal combination of cyclophosphamide and total body irradiation followed by infusion of autologous marrow which had been stored at 4°C for 54 h. Haematological reconstitution in these patients was acceptable but slower (greater than 1·0 × 10⁹/l neutrophils between days 26 and 40; greater than 20 × 10⁹/l platelets between days 23 and 77). Except in one case, normal peripheral counts were attained in all patients.
It is concluded that bone marrow stored at 4°C for up to 54 h is a simple and practical source of viable stem cells which have the capacity for acceptable haematological reconstitution.     

Clofarabine, cyclophosphamide and etoposide as single-course re-induction therapy for children with refractory/multiple relapsed acute lymphoblastic leukaemia

The safety and efficacy of the combination clofarabine/cyclophosphamide/etoposide were evaluated in children with advanced acute lymphoblastic leukaemia (ALL). The study enrolled 25 paediatric patients (median age 12·5 years) with either refractory ( n  = 17; 68%) or multiple relapsed ( n  = 8; 32%) ALL to receive clofarabine 40 mg/m², cyclophosphamide 400 mg/m² and etoposide 150 mg/m², daily for 5 consecutive days. No patient died from treatment-related complications. The most common adverse events were febrile neutropenia, mucositis and reversible liver toxicity; no case of liver veno-occlusive disease was reported. The overall remission rate was 56%: 13 patients (52%) achieved complete remission (CR) and one (4%) CR without platelet recovery (CRp). In seven of the 13 (54%) patients achieving CR, remissions were of sufficient duration to allow patients to receive allogeneic haematopoietic stem cell transplantation. The probability of CR/CRp was greater in the 17 patients with B cell precursor ALL than in the eight with T-ALL (76% vs. 12%, respectively, P  <   0·01). The 18-month overall survival probability was 39% and 0% in patients who did or did not respond to the treatment, respectively ( P  <   0·01). These data suggest that the clofarabine/cyclophosphamide/etoposide regimen is well tolerated and can induce clinical response in a relevant proportion of children with refractory/multiple relapsed ALL.     

Changes in coagulation and fibrinolysis in childhood ALL: a two-step dose reduction of one E. coli asparaginase preparation

The influence of two different E. coli asparaginase (ASP) preparations on fibrinolytic proteins in childhood ALL was recently reported, demonstrating a clearly significant association between ASP activity and haemostatic changes. Since the Bayer preparation is no longer available for treatment of large series of patients with ALL, the present study was designed to prospectively evaluate coagulation and fibrinolytic changes in leukaemic children receiving different doses of Medac ASP, which is now available for treatment of childhood ALL. Leukaemic children in whom ASP Medac was administered at 3 d intervals in a two-step dose reduction (5000 IU/m², n  = 10; 2500 IU/m², n  = 15) were compared with children who had received Bayer ASP 10 000 IU/m² in the same time schedule in a former randomized trial; at the same venipuncture, blood samples for coagulation studies were obtained before each ASP administration together with serum samples for pharmacoinetic monitoring. Compared with Bayer ASP 10 000 IU/m², patients receiving Medac ASP 5000 IU/m² showed significantly decreased values of fibrinogen, plasminogen, and α2-antiplasmin, along with significantly enhanced thrombin generation. Improvement occurred in children treated with 2500 IU/m² Medac ASP; α2-antiplasmin and D -dimer no longer differed from the Bayer group. Since both patient groups showed complete asparagine depletion during the course of ASP administration, the lower dosage of 2500 IU/m² administered at 3 d intervals should guarantee the specific metabolic therapy for ALL, leading to depletion of the circulating pool of asparagine.     

Cladribine combined with high doses of arabinoside cytosine, mitoxantrone, and G-CSF (CLAG-M) is a highly effective salvage regimen in patients with refractory and relapsed acute myeloid leukemia of the poor risk: a final report of the Polish Adult Leukemia Group

Objectives:  Patients with primary refractory AML and with early relapses have unfavorable prognoses and require innovative therapeutic approaches. Purine analogs fludarabine (FA) and cladribine (2-CdA) increase cytotoxic effect of Ara-C in leukemic blasts and inhibit DNA repair mechanisms; therefore its association with Ara-C and mitoxantrone (MIT) results in a synergistic effect. In the current report, we present the final results of multi-center phase II study evaluating the efficacy and toxicity of CLAG-M salvage regimen in poor risk refractory/relapsed AML patients.
Methods:  The induction chemotherapy consisted of 2-CdA 5 mg/m², Ara-C 2 g/m², MIT 10 mg/m², and granulocyte-colony stimulating factor. In the case of PR, a second CLAG-M was administered. Patients in CR received consolidation courses based on high doses of Ara-C and MIT with or without 2-CdA.
Results:  One hundred and eighteen patients from 11 centers were registered; 78 primary resistant and 40 relapsed. Sixty-six patients (58%) achieved CR after one or two courses of CLAG-M, 49 (35%) were refractory, and 8 (7%) died early. WBC >10 g/L and age >34 yr were factors associated with increased risk of treatment failure. Hematological toxicity was the most prominent toxicity of this regimen. The probability of OS at 4 yr was 14% (95% CI 4–23%). OS was influenced by age, WBC >10 g/L and poor karyotype in both univariate and multivariate analyses. The probability of 4 yr DFS was 30% for all 66 patients in CR (95% CI 11–49%). Poor karyotype was the only factor associated with decreased probability of DFS.
Conclusions:  We conclude that CLAG-M is a well-tolerated and highly effective salvage regimen in poor risk refractory/relapsed AML.     

The impact of dose escalation and resistance modulation in older patients with acute myeloid leukaemia and high risk myelodysplastic syndrome: the results of the LRF AML14 trial

The acute myeloid leukaemia (AML)14 trial addressed four therapeutic questions in patients predominantly aged over 60 years with AML and High Risk Myelodysplastic Syndrome: (i) Daunorubicin 50 mg/m² vs. 35 mg/m²; (ii) Cytarabine 200 mg/m² vs. 400 mg/m² in two courses of DA induction; (iii) for part of the trial, patients allocated Daunorubicin 35 mg/m² were also randomized to receive, or not, the multidrug resistance modulator PSC-833 in a 1:1:1 randomization; and (iv) a total of three versus four courses of treatment. A total of 1273 patients were recruited. The response rate was 62% (complete remission 54%, complete remission without platelet/neutrophil recovery 8%); 5-year survival was 12%. No benefits were observed in either dose escalation randomization, or from a fourth course of treatment. There was a trend for inferior response in the PSC-833 arm due to deaths in induction. Multivariable analysis identified cytogenetics, presenting white blood count, age and secondary disease as the main predictors of outcome. Although patients with high Pgp expression and function had worse response and survival, this was not an independent prognostic factor, and was not modified by PSC-833. In conclusion, these four interventions have not improved outcomes in older patients. New agents need to be explored and novel trial designs are required to maximise prospects of achieving timely progress.     

The addition of liposomal doxorubicin to bortezomib, thalidomide and dexamethasone significantly improves clinical outcome of advanced multiple myeloma

Relapsed/refractory myeloma has a poor outcome because of multi-drug resistance, patient low-performance status and toxicity of conventional chemotherapy. To improve results, standard chemotherapeutics and drugs targeting the microenvironment are applied at the same time. Bortezomib, by inhibiting proteasome function, may enhance chemosensitivity to other drugs and overcome drug-resistance. Notably, doxorubicin and bortezomib may reciprocally increase their efficacy. Thus, to improve outcome whilst minimizing therapy-related toxicity, liposomal doxorubicin was added to a bortezomib-based combination. From January 2004, relapsed/refractory myeloma patients referred to our Institution received bortezomib 1·0 mg/m² i.v. twice weekly for 2 weeks in a 28-d cycle for up to six cycles, oral dexamethasone 24 mg with the standard scheduling and thalidomide 100 mg continuously (VTD). From January 2005, liposomal doxorubicin, 50 mg/m² (30 mg/m² for patients older than 75 years), was added on day 4 of each cycle [VTD plus Myocet (MyVTD)]. In total, 70 patients were treated: 28 received VTD and 42 MyVTD. Baseline demographic and clinical characteristics were similar between the two groups. Toxicity was manageable although more pronounced with MyVTD. The overall response rate (81% vs. 50%, P  = 0·009), time to progression (19 vs. 11 months, P  = 0·01) and progression-free survival (15 vs. 8 months, P  = 0·001) were significantly higher with MyVTD regimen, suggesting an improved quality of response.     

A population pharmacokinetic model for pegylated-asparaginase in children

We analysed 1221 serum activity measurements in 168 children from the Berlin-Frankfürt-Münster acute lymphoblastic leukaemia studies, ALL-BFM (Berlin-Frankfürt-Münster) 95 and ALL-BFM REZ, in order to develop a pharmacokinetic model describing the activity-time course of pegylated (PEG)-asparaginase for all dose levels. Patients received 500, 750, 1000 or 2500 U/m² PEG-asparaginase on up to nine occasions. Serum samples were analysed for asparaginase activity and data analysis was done using nonlinear mixed effects modelling (NONMEM Vers. VI, Globomax, Hanouet, MD, USA). Different linear and nonlinear models were tested. The best model applicable to all dosing groups was a one-compartmental model with clearance (Cl) increasing with time according to the formula: Cl=Cl_i * e ^{(0·0793 * t )} where Cl_i = initial clearance and t  = time after dose. The parameters found were: volume of distribution ( V ) 1·02 ± 26% l/m², Cl_i 59·9 ± 59% ml/d per m² (mean ± interindividual variability). Interoccasion variability was substantial with 0·183 l/m² for V and 44·7 ml/d per m² for Cl, respectively. A subgroup of the patients showed a high clearance, probably due to the development of inactivating antibodies. This is the first model able to predict the activity-time course of PEG-asparaginase at different dosing levels and can therefore be used for developing new dosing regimens.     

Successful treatment of primary central nervous system lymphoma in an elderly patient

The successful treatment of an elderly patient with primary central nervous system lymphoma is described. A 74-year-old Japanese man with left hemiplegia and consciousness disturbance presented in December 2001. His performance status was Grade 4. Computed tomography of the brain revealed a tumor in the right paraventricle. A biopsy of the brain confirmed the diagnosis of non-Hodgkin lymphoma (diffuse large, B cell type). Radiographic examinations did not detect any other lesions outside the brain. Primary central nervous system lymphoma was diagnosed. Chemotherapy was initiated in January 2002 using intravenous administration of methotrexate (600 mg/m², 6-h infusion, day 1) combined with etoposide (25 mg/m², continuous infusion, day 2–5), doxorubicin (5 mg/m², continuous infusion, day 2–5), vincristine (0.2 mg/m², continuous infusion, day 2–5), cyclophosphamide (350 mg/m², 2-h infusion, day 6) and dexamethazone (6 mg/body, 1-h infusion, day 1–6), with intrathecal administration of methotrexate (15 mg/body, day 8) and prednisolone (10 mg/body, day 8). Four courses of chemotherapy were completed without severe toxicities, followed by whole-brain radiotherapy (25 Gy). Complete remission was achieved, and the patient became alert with normalized movement of the left extremities. Despite poor prognostic factors (old age, low performance status), the patient was successfully treated as such and was still in remission without neurotoxicity in May 2004. The combination of methotrexate-based chemotherapy and radiotherapy with appropriate dose modification may improve the outcome in elderly patients with this disease since supportive therapy; CHOP, a combination of cyclophosphamide, doxorubicin, vincristine and prednisolone; and solo radiotherapy are usually not effective.