Hans Salwender

Bortezomib Induction and Maintenance Treatment in Patients With Newly Diagnosed Multiple Myeloma: Results of the Randomized Phase III HOVON-65/ GMMG-HD4 Trial

PURPOSE We investigated whether bortezomib during induction and maintenance improves survival in newly diagnosed multiple myeloma (MM). PATIENTS AND METHODS In all, 827 eligible patients with newly diagnosed symptomatic MM were randomly assigned to receive induction therapy with vincristine, doxorubicin, and dexamethasone (VAD) or bortezomib, doxorubicin, and dexamethasone (PAD) followed by high-dose melphalan and autologous stem-cell transplantation. Maintenance consisted of thalidomide 50 mg (VAD) once per day or bortezomib 1.3 mg/m(2) (PAD) once every 2 weeks for 2 years. The primary analysis was progression-free survival (PFS) adjusted for International Staging System (ISS) stage. RESULTS Complete response (CR), including near CR, was superior after PAD induction (15% v 31%; P < .001) and bortezomib maintenance (34% v 49%; P < .001). After a median follow-up of 41 months, PFS was superior in the PAD arm (median of 28 months v 35 months; hazard ratio [HR], 0.75; 95% CI, 0.62 to 0.90; P = .002). In multivariate analysis, overall survival (OS) was better in the PAD arm (HR, 0.77; 95% CI, 0.60 to 1.00; P = .049). In high-risk patients presenting with increased creatinine more than 2 mg/dL, bortezomib significantly improved PFS from a median of 13 months to 30 months (HR, 0.45; 95% CI, 0.26 to 0.78; P = .004) and OS from a median of 21 months to 54 months (HR, 0.33; 95% CI, 0.16 to 0.65; P < .001). A benefit was also observed in patients with deletion 17p13 (median PFS, 12 v 22 months; HR, 0.47; 95% CI, 0.26 to 0.86; P = .01; median OS, 24 months v not reached at 54 months; HR, 0.36; 95% CI, 0.18 to 0.74; P = .003). CONCLUSION Bortezomib during induction and maintenance improves CR and achieves superior PFS and OS.

Administration of bortezomib before and after autologous stem cell transplantation improves outcome in multiple myeloma patients with deletion 17p

In patients with multiple myeloma (MM), risk stratification by chromosomal abnormalities may enable a more rational selection of therapeutic approaches. In the present study, we analyzed the prognostic value of 12 chromosomal abnormalities in a series of 354 MM patients treated within the HOVON-65/GMMG-HD4 trial. Because of the 2-arm design of the study, we were able to analyze the effect of a bortezomib-based treatment before and after autologous stem cell transplantation (arm B) compared with standard treatment without bortezomib (arm A). For allanalyzed chromosomal aberrations, progression-free survival (PFS) and overall survival (OS) were at least equal or superior in the bortezomib arm compared with the standard arm. Strikingly, patients with del(17p13) benefited the most from the bortezomib-containing treatment: the median PFS in arm A was 12.0 months and in arm B it was 26.2 months (P = .024); the 3 year-OS for arm A was 17% and for arm B it was 69% (P = .028). After multivariate analysis, del(17p13) was an independent predictor for PFS (P < .0001) and OS (P < .0001) in arm A, whereas no statistically significant effect on PFS (P = .28) or OS (P = .12) was seen in arm B. In conclusion, the adverse impact of del(17p13) on PFS and OS could be significantly reduced by bortezomib-based treatment, suggesting that long-term administration of bortezomib should be recommended for patients carrying del(17p13).

Bortezomib in combination with intermediate-dose dexamethasone and continuous low-dose oral cyclophosphamide for relapsed multiple myeloma

A phase 2 trial was performed to study the combination of bortezomib (VELCADE®) with intermediate‐dose dexamethasone (DEX), and continuous low‐dose oral cyclophosphamide (CY) in patients with relapsed multiple myeloma (MM). Fifty‐four patients with advanced MM were enroled to receive eight 3‐week treatment cycles with bortezomib 1·3 mg/m2 on days 1, 4, 8, and 11, followed by three 5‐week cycles with bortezomib 1·3 mg/m2 on days 1, 8, 15, and 22. Within all cycles, DEX 20 mg/d was given orally on the day of bortezomib injection and the day thereafter. In addition, patients received CY continuous oral treatment at a dose of 50 mg/d p.o. once daily. Fifty patients completing at least one treatment cycle were evaluable for response. Complete, partial, and minor responses occurred in 16%, 66% and 8% of patients, respectively; overall response rate 90% (efficacy analysis). Median event‐free survival was 12 months, with a median overall survival of 22 months. Adverse events (AE) of grades 3 or 4 occurring in at least 10% of patients comprised leucopenia, infection, herpes zoster, thrombocytopenia, neuropathy and fatigue. Bortezomib combined with DEX and CY is a highly effective treatment for relapsed MM at an acceptable rate of grade 3/4 AE. Antiviral prophylaxis appears to be mandatory.

Prospective Evaluation of Allogeneic Hematopoietic Stem-Cell Transplantation From Matched Related and Matched Unrelated Donors in Younger Adults With High-Risk Acute Myeloid Leukemia: German-Austrian Trial AMLHD98A

PURPOSE To assess the impact of allogeneic hematopoietic stem-cell transplantation (HSCT) from matched related donors (MRDs) and matched unrelated donors (MUDs) on outcome in high-risk patients with acute myeloid leukemia (AML) within a prospective multicenter treatment trial. PATIENTS AND METHODS Between 1998 and 2004, 844 patients (median age, 48 years; range, 16 to 62 years) with AML were enrolled onto protocol AMLHD98A that included a risk-adapted treatment strategy. High risk was defined by the presence of unfavorable cytogenetics and/or by no response to induction therapy. RESULTS Two hundred sixty-seven (32%) of 844 patients were assigned to the high-risk group. Of these 267 patients, 51 patients (19%) achieved complete remission but had adverse cytogenetics, and 216 patients (81%) had no response to induction therapy. Allogeneic HSCT was actually performed in 162 (61%) of 267 high-risk patients, after a median time of 147 days after diagnosis. Graft sources were as follows: MRD (n = 62), MUD (n = 89), haploidentical donor (n = 10), and cord blood (n = 1). The 5-year overall survival rates were 6.5% (95% CI, 3.1% to 13.6%) for patients (n = 105) not proceeding to HSCT and 25.1% (95% CI, 19.1% to 33.0%; from date of transplantation) for patients (n = 162) receiving HSCT. Multivariable analysis including allogeneic HSCT as a time-dependent covariable revealed that allogeneic HSCT significantly improved outcome; there was no difference in outcome between allogeneic HSCT from MRD and MUD. CONCLUSION Allogeneic HSCT in younger adults with high-risk AML has a significant beneficial impact on outcome, and allogeneic HSCT from MRD and MUD yields similar results.

Phase III study of all-trans retinoic acid in previously untreated patients 61 years or older with acute myeloid leukemia.

The purpose of our study was (i) to evaluate the impact of all-trans retinoic acid (ATRA) given as adjunct to chemotherapy and (ii) to compare second consolidation vs maintenance therapy in elderly patients with acute myeloid leukemia (AML). A total of 242 patients aged ⩾61 years (median, 66.6 years) with AML were randomly assigned to ATRA beginning on day +3 after the initiation of chemotherapy (ATRA-arm, n=122) or no ATRA (standard-arm, n=120) in combination with induction and first consolidation therapy. A total of 61 patients in complete remission (CR) were randomly assigned to second intense consolidation (n=31) or 1-year oral maintenance therapy (n=30). After induction therapy the intention-to-treat analysis revealed a significant difference in CR rates between the ATRA- and the standard-arm (52 vs 39%; P=0.05). Event-free (EFS) and overall survival (OS) were significantly better in the ATRA-compared to the standard-arm (P=0.03 and 0.01, respectively). OS after second randomization was significantly better for patients assigned to intensive consolidation therapy (P<0.001). The multivariate model for survival revealed lactate dehydrogenase, cytogenetic risk group, age, and first and second randomization as prognostic variables. In conclusion, the addition of ATRA to induction and consolidation therapy may improve CR rate, EFS and OS in elderly patients with AML.

Bortezomib before and after autologous stem cell transplantation overcomes the negative prognostic impact of renal impairment in newly diagnosed multiple myeloma: a subgroup analysis from the HOVON-65/GMMG-HD4 trial

Renal impairment is frequent in patients with multiple myeloma and is correlated with an inferior prognosis. This analysis evaluates the prognostic role of renal impairment in patients with myeloma treated with bortezomib before and after autologous stem cell transplantation within a prospective randomized phase III trial. Eight hundred and twenty-seven newly diagnosed myeloma patients in the HOVON-65/GMMG-HD4 trial were randomized to receive three cycles of vincristine, adriamycin, dexamethasone (VAD) or bortezomib, adriamycin, dexamethasone (PAD) followed by autologous stem cell transplantation and maintenance with thalidomide 50 mg daily (VAD-arm) or bortezomib 1.3 mg/m2 every 2 weeks (PAD-arm). Baseline serum creatinine was less than 2 mg/dL (Durie-Salmon-stage A) in 746 patients and 2 mg/dL or higher (stage B) in 81. In myeloma patients with a baseline creatinine ≥2 mg/dL the renal response rate was 63% in the VAD-arm and 81% in the PAD-arm (P=0.31). The overall myeloma response rate was 64% in the VAD-arm versus 89% in the PAD-arm with 13% complete responses in the VAD-arm versus 36% in the PAD-arm (P=0.01). Overall survival at 3 years for patients with a baseline creatinine ≥2 mg/dL was 34% in the VAD-arm versus 74% in the PAD-arm (P<0.001) with a progression-free survival rate at 3 years of 16% in the VAD-arm versus 48% in the PAD-arm (P=0.004). Overall and progression-free survival rates in the PAD-arm were similar in patients with a baseline creatinine ≥2 mg/dL or <2 mg/dL. We conclude that a bortezomib-containing treatment before and after autologous stem cell transplantation overcomes the negative prognostic impact of renal impairment in patients with newly diagnosed multiple myeloma. The trial was registered at www.trialregister.nl as NTR213 and at www.controlled-trials.com as ISRCTN 64455289

Central venous catheter (CVC)-related infections in neutropenic patients

Catheter-related infections cause considerable morbidity in hospitalised patients. The incidence does not seem to be higher in neutropenic patients than in non- neutropenic patients. Gram-positive bacteria (coagulase-negative staphylococci, Staphylococcus aureus) are the most frequently cultured pathogens, followed by Candida species. In contrast, Gram-negative bacteria play only a minor role in catheter-related infections. Positive blood cultures are the cornerstone in the diagnosis of catheter-related infections, while local signs of infection are only rarely present. However, a definite diagnosis generally requires the removal of the catheter and its microbiological examination. The role plate method with semiquantitative cultures (Maki) has been established as standard in most laboratories. Other standard procedures use quantitative techniques (Sherertz, Brun-Buisson) and are more sensitive. For therapy of catheter-related infections, antibiotics are administered according to the susceptibility of the cultured organism. Routine administration of gylcopepticed antibiotics is not indicated. Removal of the catheter has to be considered in any case of suspected catheter-related infection and is obligatory in Staphylococcus aureus and Candida infections. Tunnel or pocket infection of long-term catheters is always an indication for removal. In the future, the rate of catheter-related infections in neutropenic patients may be reduced by the use of catheters coated with antimicrobial agents.

Chlorhexidine and silver-sulfadiazine coated central venous catheters in haematological patients—a double-blind, randomised, prospective, controlled trial

BackgroundCentral venous catheters (CVCs) are essential for the intensive care of patients with haematological illness. Catheter-related infections (CRI) are an important problem in modern medicine, which may lead to life-threatening situations, to prolonged hospitalisation and increased cost. In immunocompromised patients suffering from haemato-oncological diseases, CRI is a significant factor for adverse outcome. Several clinical studies have shown that CVCs coated with antiseptics such as chlorhexidine and silver-sulfadiazine (CHSS) reduce the risk of catheter-related bacteraemia. Most studies, however, were performed on intensive care patients not suffering from chemotherapy-induced immunosuppression.Patients and methodsA prospective double-blind, randomised, controlled trial was performed to investigate the effectiveness of CHSS-coated catheters in haemato-oncological patients. A total number of 184 catheters (median duration of placement, 11 days) were inserted into 184 patients (male 115, female 69), of which 90 were antiseptically coated. After removal, all catheters were investigated for bacterial growth.Main resultsCatheters coated with CHSS were effective in reducing the rate of significant bacterial growth on either the tip or subcutaneous segment (26%) compared to control catheters (49%). The incidence of catheter colonisation was also significantly reduced (12% coated vs 33% uncoated). Data obtained show a significant reduction of catheter colonisation in CHSS catheters. There was no significant difference in the incidence of catheter-related bacteraemia (3% coated vs 7% uncoated). However, due to the overall low rate of CRI, we could not observe a significant reduction in the incidence of catheter-related bacteraemia.ConclusionOur data show that the use of CHSS catheters in patients with haematological malignancy reduces the overall risk of catheter colonisation and CRI, although the incidence of catheter-related bacteremia was similar in both groups.

Catheter-related infection and thrombosis of the internal jugular vein in hematologic-oncologic patients undergoing chemotherapy: a prospective comparison of silver-coated and uncoated catheters.

Catheter‐related venous thrombosis is one of the most frequent complications of central venous catheters (CVCs). This complication occurs in 4– 40% of patients with hematologic malignancies receiving conventional chemotherapy after placement of CVCs.

Central venous catheter-related infections in hematology and oncology

Catheter-related infections (CRI) cause considerable morbidity in hospitalized patients. The incidence does not seem to be higher in neutropenic patients than in nonneutropenic patients. Gram-positive bacteria (coagulase-negative staphylococci, Staphylococcus aureus) are the pathogens most frequently cultured, followed by Candida species. Positive blood cultures are the cornerstone in the diagnosis of CRIs, while local signs of infection are not necessarily present. Blood cultures should be taken from peripheral blood and from the venous catheter. A shorter time to positivity of catheter blood cultures as compared with peripheral blood cultures supports the diagnosis of a CRI. In many cases, a definite diagnosis requires catheter removal and microbiological analysis. The role plate method with semiquantitative cultures has been established as standard in most laboratories. Antimicrobial treatment of CRI should be directed by the in vitro susceptibility of the isolated pathogen. Primary removal of the catheter is mandatory in S. aureus and Candida infections, as well as in case of tunnel or pocket infections. Future studies will elucidate whether the rate of CRI in neutropenic patients may be reduced by catheters impregnated with antimicrobial agents.