Health-related quality of life in transplant ineligible newly diagnosed multiple myeloma patients treated with either thalidomide or lenalidomide-based regimen until progression: a prospective, open-label, multicenter, randomized, phase 3 study

Data on the impact of long term treatment with immunomodulatory drugs (IMiD) on health-related quality of life (HRQoL) is limited. The HOVON-87/NMSG18 study was a randomized, phase 3 study in newly diagnosed transplant ineligible patients with multiple myeloma, comparing melphalan-prednisolone in combination with thalidomide or lenalidomide, followed by maintenance therapy until progression (MPT-T or MPR-R). The EORTC QLQ-C30 and MY20 questionnaires were completed at baseline, after three and nine induction cycles and six and 12 months of maintenance therapy. Linear mixed models and minimal important differences were used for evaluation. 596 patients participated in HRQoL reporting. Patients reported clinically relevant improvement in global quality of life (QoL), future perspective and role and emotional functioning, and less fatigue and pain in both arms. The latter being of large effect size

Inferior outcome of addition of the aminopeptidase inhibitor tosedostat to standard intensive treatment for elderly patients with aml and high risk mds

Treatment results of AML in elderly patients are unsatisfactory. We hypothesized that addition of tosedostat, an aminopeptidase inhibitor, to intensive chemotherapy may improve outcome in this population. After establishing a safe dose in a run-in phase of the study in 22 patients, 231 eligible patients with AML above 65 years of age (median 70, range 66–81) were randomly assigned in this open label randomized Phase II study to receive standard chemotherapy (3+7) with or without tosedostat at the selected daily dose of 120 mg (n = 116), days 1–21. In the second cycle, patients received cytarabine 1000 mg/m2 twice daily on days 1-6 with or without tosedostat. CR/CRi rates in the 2 arms were not significantly different (69% (95% C.I. 60–77%) vs 64% (55–73%), respectively). At 24 months, event-free survival (EFS) was 20% for the standard arm versus 12% for the tosedostat arm (Cox-p = 0.01) and overall survival (OS) 33% vs 18% respectively (p = 0.006). Infectious complications accounted for an increased early death rate in the tosedostat arm. Atrial fibrillation w

Case report : Coxiella burnetii vascular infection and lymphoma in the Netherlands

Objectives and design: Non-Hodgkin lymphoma has been linked to infection with Coxiella burnetii, potentially through overproduction of IL-10 during infection with C. burnetii. Materials and methods: Description of a case report. Results: We describe a patient with retroperitoneal non-Hodgkin lymphoma and vascular infection with C. burnetii. Immunofluorescence staining and fluorescence in situ hybridization targeting specific C. burnetii 16S rRNA were performed on the retroperitoneal lymphoma tissue sample obtained at diagnosis of NHL. Both were strongly positive for the presence of C. burnetii. Conclusions: This case provokes questions regarding a potential association between C. burnetii and NHL, and underlines the importance of further exploration of this association

Sequential versus combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (CAIRO): a phase III randomised controlled trial

The optimum use of cytotoxic drugs for advanced colorectal cancer has not been defined. Our aim was to investigate whether combination treatment is better than sequential administration of the same drugs in patients with advanced colorectal cancer. We randomly assigned 820 patients with advanced colorectal cancer to receive either first-line treatment with capecitabine, second-line irinotecan, and third-line capecitabine plus oxaliplatin (sequential treatment; n=410) or first-line treatment capecitabine plus irinotecan and second-line capecitabine plus oxaliplatin (combination treatment; n=410). The primary endpoint was overall survival. Analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov with the number NCT00312000. 17 patients (nine in the sequential treatment group, eight in the combination group) were found to be ineligible and were excluded from the analysis. 675 (84%) patients died during the study: 336 in the sequential group and 339 in the combination group. Median overall survival was 16.3 (95% CI 14.3-18.1) months for sequential treatment and 17.4 (15.2-19.2) months for combination treatment (p=0.3281). The hazard ratio for combination versus sequential treatment was 0.92 (95% CI 0.79-1.08; p=0.3281). The frequency of grade 3-4 toxicity over all lines of treatment did not differ significantly between the two groups, except for grade 3 hand-foot syndrome, which occurred more often with sequential treatment than with combination treatment (13%vs 7%; p=0.004). Combination treatment does not significantly improve overall survival compared with the sequential use of cytotoxic drugs in advanced colorectal cancer. Thus sequential treatment remains a valid option for patients with advanced colorectal cance

Thalidomide before and after autologous stem cell transplantation in recently diagnosed multiple myeloma (HOVON-50) : long-term results from the phase 3, randomised controlled trial

Background: In patients with recently diagnosed multiple myeloma, the HOVON-50 phase 3 trial showed improved event-free survival for thalidomide-containing induction and maintenance regimens (in conjunction with high-dose melphalan and autologous stem cell transplantation [auto-SCT]) after a median of 52 months of follow-up, by comparison with regimens containing classical cytotoxic drugs. In this follow-up analysis, we aimed to determine the long-term effects of thalidomide in induction and maintenance therapy in multiple myeloma. Methods: In this open-label, phase 3 randomised controlled trial, patients with recently diagnosed multiple myeloma were recruited from 44 Dutch and Belgian hospitals. Participants had been diagnosed with multiple myeloma of Durie-Salmon stage II or III and were aged 18–65 years. Patients were randomly assigned (1:1) either to receive three 28-day cycles of vincristine (0·4 mg, intravenous rapid infusion on days 1–4), doxorubicin (9 mg/m2, intravenous rapid infusion on days 1–4) and dexamethasone (40 mg, orally on days 1–4, 9–12, and 17–20; control group); or to receive the same regimen, but with thalidomide (200–400 mg, orally on days 1–28) instead of vincristine (thalidomide group). No masking after assignment to intervention was used. Patients were randomly assigned to groups, stratified by centre and treatment policy (one vs two courses of high-dose melphalan and auto-SCT). After stem cell harvest, patients received one or two courses of 200 mg/m2 melphalan intravenously with auto-SCT. Patients with at least a partial response to high-dose melphalan and auto-SCT were eligible for maintenance therapy, starting 2–3 months after high-dose melphalan. Patients in the control group received maintenance therapy with interferon alfa (3 × 106 international units, subcutaneously, three times weekly). Patients in the thalidomide group received thalidomide as maintenance therapy (50 mg, orally, daily). Maintenance therapy was given until relapse, progression, or the occurrence of adverse events. The primary endpoint of the study was event-free survival (EFSc; censored at allogeneic stem cell transplantation), analysed by intention to treat. The study is closed for enrolment and this Article represents the final analysis. This trial was registered with the Netherlands Trial Register, number NTR238. Findings: Between Nov 27, 2001 and May 31, 2005, 556 patients were enrolled in the study, of whom 536 (96%) were eligible for evaluation and were randomly allocated (268 [50%] to the control group and 268 [50%] to the thalidomide group). These 536 patients were assessed for the primary endpoint of EFSc. At an extended median follow-up of 129 months (IQR 123–136), EFSc was significantly longer in the thalidomide group compared with the control group (multivariate analysis hazard ratio [HR] 0·62, 95% CI 0·50–0·77; p<0·0001). Thalidomide maintenance was stopped because of toxicity in 65 (42%) of 155 patients in the thalidomide group (neuropathy in 49 [75%] patients, skin reactions in four [6%] patients, fatigue in two [3%] patients, and as other symptoms [such as abdominal pain, pancreatitis, and dyspnoea] in ten [15%] patients). 24 (27%) of 90 patients in the control group discontinued protocol treatment during maintenance therapy with interferon alfa because of toxicity (five [21%] patients with psychiatric side-effects, five [21%] patients with flu-like symptoms, four [17%] patients with haematological toxicity [thrombocytopenia and leucocytopenia], three [13%] patients with skin reactions, and seven [29%] patients with other symptoms [such as infections, cardiomyopathy, and headache]). The frequency of second primary malignancies was similar in both groups. There were 23 second primary malignancies in 17 patients in the control group and 29 second primary malignancies in 24 patients in the thalidomide group. There were 19 treatment-related deaths in the control group, and 16 treatment-related deaths in the thalidomide group. Interpretation: Our data indicate that thalidomide-based treatment could be a treatment option for patients with multiple myeloma who are eligible for auto-SCT who live in countries without access to proteasome inhibitors or lenalidomide. However, careful follow-up and timely dose adjustments are important to prevent the development of thalidomide-induced neurotoxicity. Funding: The Dutch Cancer Foundation

Thalidomide before and after autologous stem cell transplantation in recently diagnosed multiple myeloma (HOVON-50):long-term results from the phase 3, randomised controlled trial

Background: In patients with recently diagnosed multiple myeloma, the HOVON-50 phase 3 trial showed improved event-free survival for thalidomide-containing induction and maintenance regimens (in conjunction with high-dose melphalan and autologous stem cell transplantation [auto-SCT]) after a median of 52 months of follow-up, by comparison with regimens containing classical cytotoxic drugs. In this follow-up analysis, we aimed to determine the long-term effects of thalidomide in induction and maintenance therapy in multiple myeloma. Methods: In this open-label, phase 3 randomised controlled trial, patients with recently diagnosed multiple myeloma were recruited from 44 Dutch and Belgian hospitals. Participants had been diagnosed with multiple myeloma of Durie-Salmon stage II or III and were aged 18–65 years. Patients were randomly assigned (1:1) either to receive three 28-day cycles of vincristine (0·4 mg, intravenous rapid infusion on days 1–4), doxorubicin (9 mg/m2, intravenous rapid infusion on days 1–4) and dexamethasone (40 mg, orally on days 1–4, 9–12, and 17–20; control group); or to receive the same regimen, but with thalidomide (200–400 mg, orally on days 1–28) instead of vincristine (thalidomide group). No masking after assignment to intervention was used. Patients were randomly assigned to groups, stratified by centre and treatment policy (one vs two courses of high-dose melphalan and auto-SCT). After stem cell harvest, patients received one or two courses of 200 mg/m2 melphalan intravenously with auto-SCT. Patients with at least a partial response to high-dose melphalan and auto-SCT were eligible for maintenance therapy, starting 2–3 months after high-dose melphalan. Patients in the control group received maintenance therapy with interferon alfa (3 × 106 international units, subcutaneously, three times weekly). Patients in the thalidomide group received thalidomide as maintenance therapy (50 mg, orally, daily). Maintenance therapy was given until relapse, progression, or the occurrence of adverse events. The primary endpoint of the study was event-free survival (EFSc; censored at allogeneic stem cell transplantation), analysed by intention to treat. The study is closed for enrolment and this Article represents the final analysis. This trial was registered with the Netherlands Trial Register, number NTR238. Findings: Between Nov 27, 2001 and May 31, 2005, 556 patients were enrolled in the study, of whom 536 (96%) were eligible for evaluation and were randomly allocated (268 [50%] to the control group and 268 [50%] to the thalidomide group). These 536 patients were assessed for the primary endpoint of EFSc. At an extended median follow-up of 129 months (IQR 123–136), EFSc was significantly longer in the thalidomide group compared with the control group (multivariate analysis hazard ratio [HR] 0·62, 95% CI 0·50–0·77; p<0·0001). Thalidomide maintenance was stopped because of toxicity in 65 (42%) of 155 patients in the thalidomide group (neuropathy in 49 [75%] patients, skin reactions in four [6%] patients, fatigue in two [3%] patients, and as other symptoms [such as abdominal pain, pancreatitis, and dyspnoea] in ten [15%] patients). 24 (27%) of 90 patients in the control group discontinued protocol treatment during maintenance therapy with interferon alfa because of toxicity (five [21%] patients with psychiatric side-effects, five [21%] patients with flu-like symptoms, four [17%] patients with haematological toxicity [thrombocytopenia and leucocytopenia], three [13%] patients with skin reactions, and seven [29%] patients with other symptoms [such as infections, cardiomyopathy, and headache]). The frequency of second primary malignancies was similar in both groups. There were 23 second primary malignancies in 17 patients in the control group and 29 second primary malignancies in 24 patients in the thalidomide group. There were 19 treatment-related deaths in the control group, and 16 treatment-related deaths in the thalidomide group. Interpretation: Our data indicate that thalidomide-based treatment could be a treatment option for patients with multiple myeloma who are eligible for auto-SCT who live in countries without access to proteasome inhibitors or lenalidomide. However, careful follow-up and timely dose adjustments are important to prevent the development of thalidomide-induced neurotoxicity. Funding: The Dutch Cancer Foundation

Melphalan, prednisone, and lenalidomide versus melphalan, prednisone, and thalidomide in untreated multiple myeloma

The combination of melphalan, prednisone and thalidomide (MPT) is considered standard therapy for newly diagnosed patients with multiple myeloma (NDMM) who are ineligible for stem-cell transplantation. Long term treatment with thalidomide is hampered by neurotoxicity. Melphalan, prednisone and lenalidomide, followed by lenalidomide maintenance therapy showed promising results, without severe neuropathy emerging. We randomly assigned 668 NDMM patients, ineligible for stem-cell transplantation, between nine 4-weekly cycles of MPT followed by thalidomide maintenance until disease progression or unacceptable toxicity (MPT-T) and the same MP regimen with thalidomide being replaced by lenalidomide (MPR-R). This multicenter, open-label, randomised phase 3 trial was undertaken by HOVON and the NMSG. The primary endpoint was progression-free survival (PFS). The accrual for the study was completed in October 19, 2012. 318 patients were randomly assigned to receive MPT-T and 319 MPR-R. After a median follow up of 36 months PFS with MPT-T was 20 months (95% CI 18-23 months) versus 23 months (95% CI 19-27 months) with MPR-R (HR 0.87 [0.72-1.04], p=0.12). Response rates were similar, with ≥VGPR 47% and 45% respectively. Hematological toxicity was more pronounced with MPR-R, especially grade 3 and 4 neutropenia: 64 versus 27%. Neuropathy ≥ grade 3 was significantly higher in the MPT-T arm; 16% versus 2% in MPR-R, resulting in a significant shorter duration of maintenance therapy (5 versus 17 months in MPR-R), irrespective of age. MPR-R has no advantage over MPT-T concerning efficacy. The toxicity profile differed with clinically significant neuropathy during thalidomide maintenance versus myelosuppression with MPR