S. Wittebol

A randomized phase 3 study on the effect of thalidomide combined with adriamycin, dexamethasone, and high-dose melphalan, followed by thalidomide maintenance in patients with multiple myeloma

The phase 3 trial HOVON-50 was designed to evaluate the effect of thalidomide during induction treatment and as maintenance in patients with multiple myeloma who were transplant candidates. A total of 556 patients was randomly assigned to arm A: 3 cycles of vincristine, adriamycin, and dexamethasone, or to arm B: thalidomide 200 mg orally, days 1 to 28 plus adriamycin and dexamethasone. After induction therapy and stem cell mobilization, patients were to receive high-dose melphalan, 200 mg/m(2), followed by maintenance with alpha-interferon (arm A) or thalidomide 50 mg daily (arm B). Thalidomide significantly improved overall response rate as well as quality of the response before and after high dose melphalan. Best overall response rate on protocol was 88% and 79% (P = .005), at least very good partial remission 66% and 54% (P = .005), and complete remission 31% and 23% (P = .04), respectively, in favor of the thalidomide arm. Thalidomide also significantly improved event-free survival from median 22 months to 34 months (P < .001), and prolonged progression free from median 25 months to 34 months (P < .001). Median survival was longer in the thalidomide arm, 73 versus 60 months; however, this difference was not significant (P = .77). Patients randomized to thalidomide had strongly reduced survival after relapse. This trial was registered on www.controlled-trials.com as ISRCTN06413384.

Thalidomide in induction treatment increases the very good partial response rate before and after high-dose therapy in previously untreated multiple myeloma

Thalidomide as part of initial treatment of multiple myeloma improves pre- and post-transplant response by increasing the proportion of patients achieving a very good partial response. In the prospective phase 3 HOVON-50/GMMG-HD3 trial, patients randomized to TAD (thalidomide, doxorubicin, dexamethasone) had a significantly higher response rate (at least PR) after induction compared with patients randomized to VAD (vincristine, adriamycin, dexamethasone, 72% vs. 54%, p<0.001). Complete remission (CR) and very good partial remission (VGPR) were also higher after TAD. After High Dose melphalan 200mg/m2 response was comparable in both arms, 76% and 79% respectively. However, CR plus VGPR were significantly higher in the patients randomized to TAD (49% vs. 32%, p<0.001). CTC grade 3–4 adverse events were similar in both arms.

Myeloablative allogeneic versus autologous stem cell transplantation in adult patients with acute lymphoblastic leukemia in first remission: a prospective sibling donor versus no-donor comparison.

While commonly accepted in poor-risk acute lymphoblastic leukemia (ALL), the role of allogeneic hematopoietic stem cell transplantation (allo-SCT) is still disputed in adult patients with standard-risk ALL. We evaluated outcome of patients with ALL in first complete remission (CR1), according to a sibling donor versus no-donor comparison. Eligible patients (433) were entered in 2 consecutive, prospective studies, of whom 288 (67%) were younger than 55 years, in CR1, and eligible to receive consolidation by either an autologous SCT or an allo-SCT. Allo-SCT was performed in 91 of 96 patients with a compatible sibling donor. Cumulative incidences of relapse at 5 years were, respectively, 24 and 55% for patients with a donor versus those without a donor (hazard ratio [HR], 0.37; 0.23-0.60; P < .001). Nonrelapse mortality estimated 16% (+/- 4) at 5 years after allo-SCT. As a result, disease-free survival (DFS) at 5 years was significantly better in the donor group: 60 versus 42% in the no-donor group (HR: 0.60; 0.41-0.89; P = .01). After risk-group analysis, improved outcome was more pronounced in standard-risk patients with a donor, who experienced an overall survival of 69% at 5 years (P = .05). In conclusion, standard-risk ALL patients with a sibling donor may show favorable survival following SCT, due to both a strong reduction of relapse and a modest nonrelapse mortality. This trial is registered with http://www.trialregister.nl under trial ID NTR228.

Vincristine, doxorubicin and dexamethasone (VAD) administered as rapid intravenous infusion for first-line treatment in untreated multiple myeloma

We examined the feasibility of achieving a rapid response in patients with previously untreated multiple myeloma by administering vincristine 0.4 mg and doxorubicin 9 mg/m2 as a rapid intravenous infusion for 4 d together with intermittent high‐dose dexamethasone 40 mg (VAD) for remission induction treatment in patients who were scheduled to receive high‐dose therapy. 139 patients (86 male, 53 female; median age 53 years, range 32–65 years; Durie & Salmon stage IIA: 42, IIB: one, IIIA: 89, IIIB: seven) were included in a prospective multicentre study in which VAD was administered as remission induction treatment and was followed by intensified treatment. The response was evaluated according to the criteria of the Eastern Cooperative Oncology Group (ECOG). The results of treatment were evaluable in 134 patients. Five patients died before evaluation. 86 patients (62%) achieved a partial response (PR) and seven patients (5%) achieved a complete response (CR), which equates to a response rate of 67%. The main side‐effect was mild neurotoxicity, which was observed in 18% of the patients. Fever or infections were reported in 27% of the patients. VAD administered as an outpatient regimen, based on rapid intravenous infusion, is an effective induction regimen for untreated myeloma with a 67% response rate and acceptable toxicity.

Intensified chemotherapy inspired by a pediatric regimen combined with allogeneic transplantation in adult patients with acute lymphoblastic leukemia up to the age of 40

Event-free survival (EFS) at 5 years in pediatric acute lymphoblastic leukemia (ALL) is >80%. Outcome in adult ALL is still unsatisfactory, which is due to less cumulative dosing of chemotherapy and less strict adherence to timing of successive cycles. In the present phase II trial, we evaluated a pediatric regimen in adult patients with ALL under the age of 40. Treatment was according to the pediatric FRALLE approach for high-risk ALL patients and characterized by increased dosages of asparaginase, steroids, methotrexate and vincristin. However, allogeneic stem cell transplantation was offered to standard risk patients with a sibling donor and to all high-risk patients in contrast to the pediatric protocol. Feasibility was defined by achieving complete remission (CR) and completion of treatment within a strict timeframe in at least 60% of patients. In all, 54 patients were included with a median age of 26. CR was achieved in 49 patients (91%), of whom 33 completed treatment as scheduled (61%). Side effects primarily consisted of infections and occurred in 40% of patients. With a median follow-up of 32 months, EFS estimated 66% at 24 months and overall survival 72%. These data show that a dose-intensive pediatric regimen is feasible in adult ALL patients up to the age of 40.

Efficacy of escalated imatinib combined with cytarabine in newly diagnosed patients with chronic myeloid leukemia

Background In order to improve the molecular response rate and prevent resistance to treatment, combination therapy with different dosages of imatinib and cytarabine was studied in newly diagnosed patients with chronic myeloid leukemia in the HOVON-51 study. Design and Methods Having reported feasibility previously, we hereby report the efficacy of escalated imatinib (200 mg, 400 mg, 600 mg or 800 mg) in combination with two cycles of intravenous cytarabine (200 mg/m2 or 1000 mg/m2 days 1 to 7) in 162 patients with chronic myeloid leukemia. Results With a median follow-up of 55 months, the 5-year cumulative incidences of complete cytogenetic response, major molecular response, and complete molecular response were 89%, 71%, and 53%, respectively. A higher Sokal risk score was inversely associated with complete cytogenetic response (hazard ratio of 0.63; 95% confidence interval, 0.50–0.79, P<0.001). A higher dose of imatinib and a higher dose of cytarabine were associated with increased complete molecular response with hazard ratios of 1.60 (95% confidence interval, 0.96–2.68, P=0.07) and 1.66 (95% confidence interval, 1.02–2.72, P=0.04), respectively. Progression-free survival and overall survival rates at 5 years were 92% and 96%, respectively. Achieving a major molecular response at 1 year was associated with complete absence of progression and a probability of achieving a complete molecular response of 89%. Conclusions The addition of intravenous cytarabine to imatinib as upfront therapy for patients with chronic myeloid leukemia is associated with a high rate of complete molecular responses (Clinicaltrials.Gov Identifier: NCT00028847).

Lenalidomide (Revlimid) combined with continuous oral cyclophosphamide (endoxan) and prednisone (REP) is effective in lenalidomide/dexamethasone‐refractory myeloma

Lenalidomide (Revlimid ) has significant activity in multiple myeloma through induction of apoptosis, targeting the bone marrow microenvironment, and stimulation of Tand Natural Killer-cell mediated immune responses. Laboratory studies showed that lenalidomide also enhanced the efficacy of various anti-myeloma agents including cyclophosphamide and dexamethasone (Hideshima et al, 2000; Blansfield et al, 2008; van der Spek et al, 2009). Previously, we showed that continuous low-dose oral cyclophosphamide (endoxan) in combination with prednisone had remarkable activity in relapsed multiple myeloma (de Weerdt et al, 2001). To further improve the efficacy of this oral regimen, we undertook a retrospective analysis to evaluate the combination of lenalidomide with continuous low-dose oral cyclophosphamide and prednisone (REP) in 14 lenalidomide/dexamethasone-refractory myeloma patients. The REP regimen consisted of lenalidomide (10 mg; 21 d, followed by 1 week rest), combined with continuous low-dose oral cyclophosphamide (100 mg) and prednisone. Prednisone was started at 20 mg daily and tapered to 10 mg within 8 weeks after start of therapy. This treatment was continued in responding patients and in case of stable disease until disease progression. All patients received aspirin (100 mg daily) as thromboprophylaxis and cotrimoxazol (480 mg daily) as infection prophylaxis. We treated five male and nine female patients with a median age of 65Æ9 years (range: 39Æ6–81Æ2 years). All patients were heavily pre-treated and had received a median of 6 (range: 4–8) previous lines of anti-myeloma therapy including autologous stem cell transplantation in 10 patients (71Æ4%) and allogeneic stem cell transplantation in seven patients (50%). Thalidomide was previously administered to 13 patients (92Æ9%), bortezomib to 13 patients (92Æ9%), and all patients had received alkylating agents, and also lenalidomide plus dexamethasone. In 12 patients REP chemotherapy was started because of progressive disease during treatment with the combination of full dose lenalidomide (25 mg, days 1–21 of a 28 day cycle) and dexamethasone (40 mg, days 1–4 and 15–18) and in two patients because of lenalidomide/dexamethasone-refractory disease and subsequent failure to treatment with oral cyclophosphamide combined with prednisone. Median time from diagnosis to the first REP cycle was 6Æ5 years (range: 3Æ8– 15Æ1 years). A total of 121 cycles of REP were administered with a median number of eight courses (range: 2–18). Response to therapy using the European Group for Blood and Marrow Transplantation criteria (Bladé et al, 1998) was seen in nine patients (64Æ3%), including two patients (14Æ3%) with a complete response (CR), three (21Æ4%) with a very good partial response, two (14Æ3%) with a partial response (PR), and two (14Æ3%) with a minor response (MR) (Table I). Three patients (21Æ4%) had stable disease and two (14Æ3%) patients had progressive disease. Interestingly, in two patients who progressed during treatment with lenalidomide and dexamethasone, treatment with the REP regimen resulted in a CR. Five of 12 patients who obtained response or stable disease progressed. One patient died of progressive disease. With a median follow-up period of surviving patients of 12Æ8 months (range, 4Æ7–19Æ9 months), median progression-free survival was 12Æ2 months and overall survival at 1 year was 92Æ9%. Toxic effects were graded according to the National Cancer Institute’s Common Toxicity Criteria (CTC), version 3 (http:// ctep.cancer.gov/protocolDevelopment/electronic_applications/ docs/ctcaev3.pdf). Four patients experienced CTC grade 3 neutropenia during a total of nine courses and two patients had grade 4 neutropenia during two courses. Pegylated granulocyte colony-stimulating factor was administered in three patients during five cycles for grade 3 neutropenia and on a pre-emptive basis during 11 cycles in two patients who suffered neutropenia during previous therapy with lenalidomide/dexamethasone. CTC grade 3 anaemia occurred in two patients (total of six courses) and grade 3 thrombocytopenia in three patients (total of seven courses). During therapy one patient had a grade 2 upper respiratory tract infection, one patient a grade 2 urinary tract infection, and three patients had grade three infections (all pneumonia). Other CTC grade 3 events were deep venous thrombosis (DVT) in two patients (one patient developed a DVT after stopping aspirin) and nonspecific colitis in one patient. Only one patient experienced (grade 1) bladder irritation, which resolved after dose reduction of cyclophosphamide. One patient permanently stopped treatment because of nonspecific colitis, after which he developed progressive disease. In eight patients, cyclophosphamide dose was reduced to 50%, in seven because of haematological toxicity and in one patient because of bladder irritation. Sedation, worsening of polyneuropathy, Correspondence

Dose finding study of imatinib in combination with intravenous cytarabine: feasibility in newly diagnosed patients with chronic myeloid leukemia

The HOVON cooperative study group performed a feasibility study of escalated imatinib and intravenous cytarabine in 165 patients with early chronic-phase chronic myeloid leukemia (CML). Patients received 2 cycles of intravenous cytarabine (200 mg/m(2) or 1000 mg/m(2) days 1-7) in conjunction with imatinib (200 mg, 400 mg, 600 mg, or 800 mg), according to predefined, successive dose levels. All dose levels proved feasible. Seven dose-limiting toxicities (DLTs) were observed in 302 cycles of chemotherapy, which were caused by streptococcal bacteremia in 5 cases. Intermediate-dose cytarabine (1000 mg/m(2)) prolonged time to neutrophil recovery and platelet recovery compared with a standard dose (200 mg/m(2)). High-dose imatinib (600 mg or 800 mg) extended the time to platelet recovery compared with a standard dose (400 mg). More infectious complications common toxicity criteria (CTC) grade 3 or 4 were observed after intermediate-dose cytarabine compared with a standard-dose of cytarabine. Early response data after combination therapy included a complete cytogenetic response in 48% and a major molecular response in 30% of patients, which increased to 46% major molecular responses at 1 year, including 13% complete molecular responses. We conclude that combination therapy of escalating dosages of imatinib and cytarabine is feasible. This study was registered at www.kankerbestrijding.nl as no. CKTO-2001-03.

Intensive chemotherapy to improve outcome in patients with acute lymphoblastic leukemia over the age of 40: a phase II study for efficacy and feasibility by HOVON

Intensive chemotherapy to improve outcome in patients with acute lymphoblastic leukemia over the age of 40: a phase II study for efficacy and feasibility by HOVON

Quality of life of patients with chronic lymphocytic leukaemia in the Netherlands: results of a longitudinal multicentre study

PurposeTo describe the health-related quality of life (HRQoL) of an unselected population of patients with chronic lymphocytic leukaemia (CLL) including untreated patients.MethodsHRQoL was measured by the EORTC QLQ-C30 including the CLL16 module, EQ-5D, and VAS in an observational study over multiple years. All HRQoL measurements per patient were connected and analysed using area under the curve analysis over the entire study duration. The total patient group was compared with the general population, and three groups of CLL patients were described separately, i.e. patients without any active treatment (“watch and wait”), chlorambucil treatment only, and patients with other treatment(s).ResultsHRQoL in the total group of CLL patients was compromised when compared with age- and gender-matched norm scores of the general population. CLL patients scored statistically worse on the VAS and utility score of the EQ-5D, all functioning scales of the EORTC QLQ-C30, and the symptoms of fatigue, dyspnoea, sleeping disturbance, appetite loss, and financial difficulties. In untreated patients, the HRQoL was slightly reduced. In all treatment stages, HRQoL was compromised considerably. Patients treated with chlorambucil only scored worse on the EORTC QLQ-C30 than patients who were treated with other treatments with regard to emotional functioning, cognitive functioning, bruises, uncomfortable stomach, and apathy.ConclusionsCLL patients differ most from the general population on role functioning, fatigue, concerns about future health, and having not enough energy. Once treatment is indicated, HRQoL becomes considerably compromised. This applies to all treatments, including chlorambucil, which is considered to be a mild treatment.