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•Little data is available on Quality of Life (QoL) of patients with AML treated with decitabine.•Current QoL findings support the use of lower intensity decitabine, compared to the current standard of care in fit older patients with AML.

Introduction

An urgent need for new treatment modalities is emerging in elderly patients with acute myeloid leukemia (AML). We hypothesized that targeting VEGF might furnish an effective treatment modality in this population. Elderly patients with AML were randomly assigned in this phase 2 study (n = 171) to receive standard chemotherapy (3 + 7) with or without bevacizumab at a dose of 10 mg/kg intravenously at days 1 and 15. In the second cycle, patients received cytarabine 1000 mg/m2twice daily on days 1-6 with or without bevacizumab. The complete remission rates in the 2 arms were not different (65%). Event-free survival at 12 months was 33% for the standard arm versus 30% for the bevacizumab arm; at 24 months, it was 22% and 16%, respectively (P= .42). The frequencies of severe adverse events (SAEs) were higher in the bevacizumab arm (n = 63) compared with the control arm (n = 28; P= .043), but the percentages of death or life-threatening SAEs were lower in the bevacizumab arm (60% vs 75% of SAEs). The results of the present study show that the addition of bevacizumab to standard chemotherapy does not improve the therapeutic outcome of older AML patients. This trial is registered as number NTR904 in The Nederlands Trial Register (www.trialregister.nl).

Maintaining results of successful induction therapy is an important goal in multiple myeloma. Here, members of the International Myeloma Working Group review the relevant data. Thalidomide maintenance therapy after autologous stem cell transplantation improved the quality of response and increased progression-free survival (PFS) significantly in all 6 studies and overall survival (OS) in 3 of them. In elderly patients, 2 trials showed a significant prolongation of PFS, but no improvement in OS. A meta-analysis revealed a significant risk reduction for PFS/event-free survival and death. The role of thalidomide maintenance after melphalan, prednisone, and thalidomide is not well established. Two trials with lenalidomide maintenance treatment after autologous stem cell transplantation and one study after conventional melphalan, prednisone, and lenalidomide induction therapy showed a significant risk reduction for PFS and an increase in OS in one of the transplant trials. Maintenance therapy with single-agent bortezomib or in combination with thalidomide or prednisone has been studied. One trial revealed a significantly increased OS with a bortezomib-based induction and bortezomib maintenance therapy compared with conventional induction and thalidomide maintenance treatment. Maintenance treatment can be associated with significant side effects, and none of the drugs evaluated is approved for maintenance therapy. Treatment decisions for individual patients must balance potential benefits and risks carefully, as a widely agreed-on standard is not established.

The role of thalidomide for previously untreated elderly patients with multiple myeloma remains unclear. Six randomized controlled trials, launched in or after 2000, compared melphalan and prednisone alone (MP) and with thalidomide (MPT). The effect on overall survival (OS) varied across trials. We carried out a meta-analysis of the 1685 individual patients in these trials. The primary endpoint was OS, and progression-free survival (PFS) and 1-year response rates were secondary endpoints. There was a highly significant benefit to OS from adding thalidomide to MP (hazard ratio = 0.83; 95% confidence interval 0.73-0.94, P= .004), representing increased median OS time of 6.6 months, from 32.7 months (MP) to 39.3 months (MPT). The thalidomide regimen was also associated with superior PFS (hazard ratio = 0.68, 95% confidence interval 0.61-0.76, P< .0001) and better 1-year response rates (partial response or better was 59% on MPT and 37% on MP). Although the trials differed in terms of patient baseline characteristics and thalidomide regimens, there was no evidence that treatment affected OS differently according to levels of the prognostic factors. We conclude that thalidomide added to MP improves OS and PFS in previously untreated elderly patients with multiple myeloma, extending the median survival time by on average 20%.

Complete response (CR) was an uncommon event in elderly myeloma patients until novel agents were combined with standard oral melphalan-prednisone. This analysis assesses the impact of treatment response on progression-free survival (PFS) and overall survival (OS). We retrospectively analyzed 1175 newly diagnosed myeloma patients, enrolled in 3 multicenter trials, treated with melphalan-prednisone alone (n = 332), melphalan-prednisone-thalidomide (n = 332), melphalan-prednisone-bortezomib (n = 257), or melphalan-prednisone-bortezomib-thalidomide (n = 254). After a median follow-up of 29 months, the 3-year PFS and OS were 67% and 27% (hazard ratio = 0.16; P< .001), and 91% and 70% (hazard ratio = 0.15; P< .001) in patients who obtained CR and in those who achieved very good partial response, respectively. Similar results were observed in patients older than 75 years. Multivariate analysis confirmed that the achievement of CR was an independent predictor of longer PFS and OS, regardless of age, International Staging System stage, and treatment. These findings highlight a significant association between the achievement of CR and long-term outcome, and support the use of novel agents to achieve maximal response in elderly patients, including those more than 75 years. This trial was registered at www.clinicaltrials.govas #NCT00232934, #ISRCTN 90692740, and #NCT01063179.

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/m2, followed by maintenance with α-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.

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.nlunder trial ID NTR228.

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/m2 or 1000 mg/m2 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/m2) prolonged time to neutrophil recovery and platelet recovery compared with a standard dose (200 mg/m2). 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.

We evaluated the role of rituximab during remission induction chemotherapy in relapsed aggressive CD20+ non-Hodgkin lymphoma. Of 239 patients, 225 were evaluable for analysis. Randomized to DHAP (cisplatin-cytarabine-dexamethasone)-VIM (etoposide-ifosfamide-methotrexate)-DHAP (cisplatin-cytarabine-dexamethasone) chemotherapy with rituximab (R; R-DHAP arm) were 119 patients (113 evaluable) and to chemotherapy without rituximab (DHAP arm) 120 patients (112 evaluable). Patients in complete remission (CR) and partial remission (PR) after 2 chemotherapy courses were eligible for autologous stem-cell transplantation. After the second chemotherapy cycle, 75% of the patients in the R-DHAP arm had responsive disease (CR or PR) versus 54% in the DHAP arm (P = .01). With a median follow-up of 24 months, there was a significant difference in failure-free survival (FFS24; 50% vs 24% vs, P < .001), and progression free survival (PFS24; 52% vs 31% P < .002) in favor of the R-DHAP arm. Cox-regression analysis demonstrated a significant effect of rituximab treatment on FFS24 (HR 0.41, 95% confidence interval [CI] 0.29-0.57 versus 0.51, 95% CI 0.37-0.70) and overall-survival (OS24: HR 0.60 [0.41-0.89] vs 0.76 [0.52-1.10]) when adjusted for time since upfront treatment, age, World Health Organization performance status, and secondary age-adjusted international prognostic index. These results demonstrate improved FFS and PFS for relapsed aggressive B-cell NHL if rituximab is added to the re-induction chemotherapy regimen.

We evaluated the role of rituximab during remission induction chemotherapy in relapsed aggressive CD20+non-Hodgkin lymphoma. Of 239 patients, 225 were evaluable for analysis. Randomized to DHAP (cisplatin-cytarabine-dexamethasone)-VIM (etoposide-ifosfamide-methotrexate)-DHAP (cisplatin-cytarabine-dexamethasone) chemotherapy with rituximab (R; R-DHAP arm) were 119 patients (113 evaluable) and to chemotherapy without rituximab (DHAP arm) 120 patients (112 evaluable). Patients in complete remission (CR) and partial remission (PR) after 2 chemotherapy courses were eligible for autologous stem-cell transplantation. After the second chemotherapy cycle, 75% of the patients in the R-DHAP arm had responsive disease (CR or PR) versus 54% in the DHAP arm (P= .01). With a median follow-up of 24 months, there was a significant difference in failure-free survival (FFS24; 50% vs 24% vs, P< .001), and progression free survival (PFS24; 52% vs 31% P< .002) in favor of the R-DHAP arm. Cox-regression analysis demonstrated a significant effect of rituximab treatment on FFS24(HR 0.41, 95% confidence interval [CI] 0.29-0.57 versus 0.51, 95% CI 0.37-0.70) and overall-survival (OS24: HR 0.60 [0.41-0.89] vs 0.76 [0.52-1.10]) when adjusted for time since upfront treatment, age, World Health Organization performance status, and secondary age-adjusted international prognostic index. These results demonstrate improved FFS and PFS for relapsed aggressive B-cell NHL if rituximab is added to the re-induction chemotherapy regimen.

The Dutch-Belgian Hemato-Oncology Cooperative Group and the Swiss Group for Clinical Cancer Research (HOVON-SAKK) collaborative study group evaluated outcome of patients (pts) with acute myeloid leukemia (AML) in first remission (CR1) entered in 3 consecutive studies according to a donor versus no-donor comparison. Between 1987 and 2004, 2287 pts were entered in these studies of whom 1032 pts (45%) without FAB M3 or t(15;17) were in CR1 after 2 cycles of chemotherapy, received consolidation treatment, and were younger than 55 years of age and therefore eligible for allogeneic hematopoietic stem cell transplantation (allo-SCT). An HLA-identical sibling donor was available for 326 pts (32%), whereas 599 pts (58%) lacked such a donor, and information was not available in 107 pts. Compliance with allo-SCT was 82% (268 of 326). Cumulative incidences of relapse were, respectively, 32% versus 59% for pts with versus those without a donor (P< .001). Despite more treatment-related mortality (TRM) in the donor group (21% versus 4%, P< .001), disease-free survival (DFS) appeared significantly better in the donor group (48% ± 3% versus 37% ± 2% in the no-donor group, P< .001). Following risk-group analysis, DFS was significantly better for pts with a donor and an intermediate- (P= .01) or poor-risk profile (P= .003) and also better in pts younger than 40 years of age (P< .001). We evaluated our results and those of the previous MRC, BGMT, and EORTC studies in a meta-analysis, which revealed a significant benefit of 12% in overall survival (OS) by donor availability for all patients with AML in CR1 without a favorable cytogenetic profile.

The myelodysplastic syndromes (MDSs) are heterogeneous with respect to clinical characteristics, pathologic features, and cytogenetic abnormalities. This heterogeneity is a challenge for evaluating response to treatment. Therapeutic trials in MDS have used various criteria to assess results, making cross-study comparisons problematic. In 2000, an International Working Group (IWG) proposed standardized response criteria for evaluating clinically significant responses in MDS. These criteria included measures of alteration in the natural history of disease, hematologic improvement, cytogenetic response, and improvement in health-related quality of life. The relevance of the response criteria has now been validated prospectively in MDS clinical trials, and they have gained acceptance in research studies and in clinical practice. Because limitations of the IWG criteria have surfaced, based on practical and reported experience, some modifications were warranted. In this report, we present recommendations for revisions of some of the initial criteria.

We compared the efficacy of intensified chemotherapy followed by myeloablative therapy and autologous stem cell rescue with intensified chemotherapy alone in patients newly diagnosed with multiple myeloma. There were 261 eligible patients younger than 66 years with stage II/III multiple myeloma who were randomized after remission induction therapy with vincristine, adriamycin, dexamethasone (VAD) to receive intensified chemotherapy, that is, melphalan 140 mg/m2 administered intravenously in 2 doses of 70 mg/m2 (intermediate-dose melphalan [IDM]) without stem cell rescue (n = 129) or the same regimen followed by myeloablative therapy consisting of cyclophosphamide, total body irradiation, and autologous stem cell reinfusion (n = 132). Interferon-α–2a was given as maintenance. Of the eligible patients, 79% received both cycles of IDM and 79% of allocated patients actually received myeloablative treatment. The response rate (complete remission [CR] plus partial remission [PR]) was 88% in the intensified chemotherapy group versus 95% in the myeloablative treatment group. CR was significantly higher after myeloablative therapy (13% versus 29%; P = .002). With a median follow-up of 33 months (range, 8-65 months), the event-free survival (EFS) was not different between the treatments (median 21 months versus 22 months; P = .28). Time to progression (TTP) was significantly longer after myeloablative treatment (25 months versus 31 months; P = .04). The overall survival (OS) was not different (50 months versus 47 months; P = .41). Intensified chemotherapy followed by myeloablative therapy as first-line treatment for multiple myeloma resulted in a higher CR and a longer TTP when compared with intensified chemotherapy alone. However, it did not result in a better EFS and OS.

p16 and p15, 2 inhibitors of cyclin-dependent kinases, are frequently hypermethylated in hematologic neoplasias. Decitabine, or 5-Aza-2′-deoxycytidine, reverts hypermethylation of these genes in vitro, and low-dose decitabine treatment improves cytopenias and blast excess in ∼50% of patients with high-risk myelodysplastic syndrome (MDS). We examined p15and p16 methylation status in bone marrow mononuclear cells from patients with high-risk MDS during treatment with decitabine, using a methylation-sensitive primer extension assay (Ms-SNuPE) to quantitate methylation, and denaturing gradient gel electrophoresis (DGGE) and bisulfite-DNA sequencing to distinguish individually methylated alleles. p15 expression was serially examined in bone marrow biopsies by immunohistochemistry. Hypermethylation in the 5′ p15 gene region was detected in 15 of 23 patients (65%), whereas the 5′ p16 region was unmethylated in all patients. Among 12 patients with hypermethylation sequentially analyzed after at least one course of decitabine treatment, a decrease in p15 methylation occurred in 9 and was associated with clinical response. DGGE and sequence analyses were indicative of hypomethylation induction at individual alleles. Immunohistochemical staining for p15 protein in bone marrow biopsies from 8 patients with p15 hypermethylation revealed low or absent expression in 4 patients, which was induced to normal levels during decitabine treatment. In conclusion, frequent, selectivep15 hypermethylation was reversed in responding MDS patients following treatment with a methylation inhibitor. The emergence of partially demethylated epigenotypes and re-establishment of normal p15 protein expression following the initial decitabine courses implicate pharmacologic demethylation as a possible mechanism resulting in hematologic response in MDS.

This study investigated the feasibility of allogeneic (alloSCT) and autologous stem cell transplantation (ASCT) as postconsolidation therapy for patients with myelodysplastic syndromes (MDSs) or acute myeloid leukemia after MDS. Patients with a histocompatible sibling were candidates for alloSCT and the remaining patients for ASCT. Remission-induction therapy consisted of 1 or 2 courses with idarubicin, cytarabine, and etoposide, followed by one intensive consolidation course with cytarabine and mitoxantrone. Initially, bone marrow cells were used for ASCT. Subsequently, mobilized blood stem cells were used in an attempt to shorten posttransplantation hypoplasia. With a median follow-up of 3.6 years the 184 evaluable patients showed a 4-year survival rate of 26% and a median survival of 13 months. The remission-induction chemotherapy induced complete remission (CR) in 100 patients (54%). The 4-year disease-free survival (DFS) rate was 29% and the median DFS was 12 months. Twenty-eight of 39 patients (72%) with a donor were allografted in CR-1, including 2 patients who underwent transplantation in CR-1 without a consolidation course. Thirty-six of 59 patients (61%) without a donor received ASCT in CR-1. The 4-year DFS rates in the group of patients with or without a donor were 31% and 27%, respectively. The 4-year survival rates from CR were 36% and 33%, respectively. This large prospective study shows the feasibility of both alloSCT and ASCT. This treatment approach leads to a relatively high remission rate, and the majority of patients in remission received the SCT in CR-1. The ongoing study investigates whether this approach is better than treatment with chemotherapy only.

Standardized criteria for assessing response are essential to ensure comparability among clinical trials for patients with myelodysplastic syndromes (MDS). An international working group of experienced clinicians involved in the management of patients with MDS reviewed currently used response definitions and developed a uniform set of guidelines for future clinical trials in MDS. The MDS differ from many other hematologic malignancies in their chronicity and the morbidity and mortality caused by chronic cytopenias, often without disease progression to acute myeloid leukemia. Whereas response rates may be an important endpoint for phase 2 studies of new agents and may assist regulatory agencies in their evaluation and approval processes, an important goal of clinical trials in MDS should be to prolong patient survival. Therefore, these response criteria reflected 2 sets of goals in MDS: altering the natural history of the disease and alleviating disease-related complications with improved quality of life. It is anticipated that the recommendations presented will require modification as more is learned about the molecular biology and genetics of these disorders. Until then, it is hoped these guidelines will serve to improve communication among investigators and to ensure comparability among clinical trials.

In the human promyelocytic cell line HL60, we observed both a strong procoagulant activity (PCA) on the cell membrane and proteolytic activity in the lysate of these cells. Because these cell-line cells are susceptible to differentiation to either a more mature granulocytic or monocytic form, we were able to study the hypothesis that the combination of PCA and proteolytic activity is confined to the promyelocyte. This may explain the severe coagulopathy seen in patients with acute promyelocytic leukemia. Cell differentiation in a myeloid direction induced by retinoic acid or DMSO led to a diminished PCA, while not affecting the fibrinolytic activity. On the other hand, monocytic differentiation obtained by culturing the cells in the presence of 1; 25 dihydroxy vitamin D3 led to the complete disappearance of the proteolytic activity of the cell lysate, although the procoagulant activity was still present. Furthermore, we found that the elastase activity almost disappeared after monocytic differentiation. We also studied the PCA, proteolytic activity, and elastase activity of blast cells of patients with acute myeloid leukemia. Only in patients with acute promyelocytic leukemia did we observe both a strong PCA and fibrinolytic activity. This supports our hypothesis that the combination of these activities is unique to the promyelocyte and may explain the observed bleeding complications in patients with acute promyelocytic leukemia.

We conducted a prospective randomized multicenter clinical trial comparing the effects of granulocyte-macrophage colony-stimulating factor (GM-CSF ) as an adjunct to intensive chemotherapy in patients of 61 years and older with untreated newly diagnosed acute myeloid leukemia (AML). Patients were randomized to either receive daunomycin-cytosine arabinoside with GM-CSF or daunomycin-cytosine arabinoside (control arm). Based on the rationale that GM-CSF might sensitize the leukemic cells to the cytotoxicity of chemotherapy as well as enhance white blood cell regeneration, GM-CSF was given during chemotherapy as well as after chemotherapy. Patients were treated with one, and in case of a partial response, with two remission induction cycles. When a complete remission was attained they received one additional cycle of consolidation therapy. Of 318 evaluable patients with a median age of 68 years, 157 were randomized to receive GM-CSF and 161 were assigned to control therapy. The effect of GM-CSF on treatment was evaluated according to intention-to-treat. Complete remission was achieved in 56% of the patients in the GM-CSF group and 55% of the control patients (P = .98). Recovery of neutrophils was significantly faster in GM-CSF–treated patients. The median time of recovery of neutrophils towards 0.5 × 109/L was 23 days in the GM-CSF group versus 25 days in the control group (P = .0002) with the percentages of patients who recovered being 81% and 71%, respectively. With a median follow-up of 36 months, the probabilities of survival at 2 years after randomization were estimated at 22% for individuals assigned to the GM-CSF treatment as well as for control patients (P = .55). Disease-free survival at 2 years compared 15% and 19% for the two treatment groups (P = .69). The number of nights spent in the hospital, number of transfusions, and frequencies and types of hemorrhages and infections did not differ either. The cytogenetic results at diagnosis of this study in elderly AML shows that there is a relatively high numerical representation of patients with abnormal cytogenetics (55% of documented cases), who showed significantly inferior response rates and survival duration. We conclude that, except for a faster neutrophil recovery, GM-CSF during and after induction chemotherapy does not improve the clinical outcome of elderly patients with AML.

An International Prognostic Index (IPI) for patients with aggressive non-Hodgkin's lymphoma (NHL) has recently been published. The IPI is based on pretreatment clinical characteristics and developed on clinical trial patients, classified as intermediate grade according to the Working Formulation (WF). We applied this IPI in a population-based registry of NHL patients. This registry does not have the restrictions that usually hold for patients in clinical trials, eg, with respect to age and performance status. Moreover, it covers all the three WF classes (low, intermediate, and high). The IPI turned out to be of prognostic value for response rate and survival in our unselected cohort of 744 patients, as well. In each of the three WF classes separately, the four IPI classes showed going from low to high substantially decreasing response rates and survival percentages. For our cohort of WF intermediate grade patients 5-year survival levels were lower in all four IPI classes (59%, 34%, 14%, and 10%, respectively), probably reflecting the selection of clinical trial patients in the original study (73%, 51%, 43%, and 26%).

Serum neural cell adhesion molecule (NCAM) has been described as a prognostic marker in multiple myeloma (MM). Both C-reactive protein (CRP) and beta 2-microglobulin (beta 2M) are established prognostic markers in MM. We tested the diagnostic value of these markers in 212 serum samples of patients with paraproteinemia registered prospectively in a population-based registry. Sixty patients had MM and 152 had other monoclonal gammopathies (hematologic diseases [48], paraneoplastic disease [35], autoimmune disease [15], and monoclonal gammopathy of undetermined significance [56]). CRP and beta 2M had wide and overlapping ranges in all diagnostic categories. However, serum neural cell adhesion molecule (NCAM) was low (< 20 U/mL) in all but 4 of 152 nonmyeloma cases and high (> or = 20 U/mL) in 31 (52%) of the 60 MM cases. Two patients with non-Hodgkin's lymphoma, 1 with chronic lymphatic leukemia, and 1 with autoimmune disease had serum NCAM values between 20 and 30 U/mL. In a discriminant analysis in which serum NCAM, CRP, beta 2M, paraprotein type and concentration, hemoglobin, leukocyte and thrombocyte counts, creatinine, corrected calcium, lactate dehydrogenase, and alkaline phosphatase were included, paraprotein type and concentration and serum NCAM turned out to be the best combination of parameters predicting whether a patient had MM, with 89% of cases being correctly classified. Even without bone marrow and x-ray examinations, serum NCAM, in combination with paraprotein type and concentration, can differentiate between MM and nonmyeloma patients.

Introduction:

Ossenkoppele: J&J: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Roche: Honoraria; Karyopharm: Consultancy, Research Funding; Novartis: Research Funding.

Claus: Roche: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria, Other: Travel Funding. Becker:BMS: Honoraria; Novartis: Honoraria. Lübbert:Ratiopharm: Other: Study drug valproic acid; Janssen-Cilag: Other: Travel Funding, Research Funding; Celgene: Other: Travel Funding.

Sonneveld: SkylineDx: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Research Funding; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Salwender:Celgene: Honoraria; Janssen Cilag: Honoraria; Bristol Meyer Sqibb: Honoraria; Amgen: Honoraria; Novartis: Honoraria. Blau:MSD: Honoraria; Celgene: Honoraria, Research Funding; AMGEN: Honoraria; JAZZ pharm: Honoraria; BMS: Honoraria; Shire: Honoraria; Baxalta: Honoraria; Janssen: Honoraria, Research Funding. Zweegman:celgene: Honoraria, Research Funding; takeda millennium: Honoraria, Research Funding; onyx: Honoraria. Weisel:Noxxon: Consultancy; Janssen Pharmaceuticals: Consultancy, Honoraria, Other: Travel Support, Research Funding; Novartis: Other: Travel Support; Onyx: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other: Travel Support; BMS: Consultancy, Honoraria, Other: Travel Support; Celgene: Consultancy, Honoraria, Other: Travel Support, Research Funding. Broijl:Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Scheid:Janssen: Honoraria; Celgene: Honoraria. Potamianou:Janssen: Employment. Hose:Takeda: Other: Travel grant; EngMab AG: Research Funding. Kersten:takeda millennium: Research Funding; janssen: Honoraria, Research Funding; roche: Honoraria, Research Funding. Duehrsen:Alexion: Honoraria; janssen: Honoraria. Lokhorst:Janssen: Honoraria, Research Funding; Genmab: Honoraria, Research Funding; Amgen: Honoraria. Goldschmidt:celgene: Honoraria, Research Funding; janssen: Honoraria, Research Funding; novartis: Honoraria, Research Funding; chugai: Honoraria, Research Funding; onyx: Honoraria, Research Funding; millennium: Honoraria, Research Funding; BMS: Honoraria, Research Funding.

Kersten: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees. Vellenga:Janssen: Research Funding. Bos:celgene: Research Funding. Lokhorst:Genmab: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Sonneveld:Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding.

De Greef: Celgene: Consultancy. Van de Loosdrecht:celgene: Honoraria, Research Funding; alexion: Research Funding.

We investigated if bortezomib during induction and maintenance improves survival in newly diagnosed Multiple Myeloma (MM).827 eligible patients with newly diagnosed symptomatic MM were randomized to receive induction therapy with VAD (vincristine, doxorubicin, dexamethasone; n=414) or PAD (bortezomib, doxorubicin, dexamethasone; n=413) followed by high-dose melphalan (HDM) and autologous stem cell transplant (ASCT). Maintenance consisted of daily thalidomide 50 mg (VAD) or 2-weekly bortezomib 1.3 mg/m2 i.v. (PAD) for 2 years. The primary analysis was progression-free survival (PFS) adjusted for ISS stage. We here report long-term results of this trial (P. Sonneveld et al., J Clin Oncol 2012;30:2946-2955).The number of eligible patients, patient characteristics and disease characteristics are similar to those reported before. The response rates during protocol treatment have improved slightly since all patients have now completed treatment: CR+nCR 49% vs 35%, VGPR 26% vs 21% and ≥PR 91% vs 83% (PAD vs VAD).After a median follow-up of 67 months, 111 of patients treated with VAD and 131 of patients treated with PAD were progression-free and alive. Progression-free survival (PFS) defined as time from randomization until progression, relapse or death (censored at date of alloSCT, if applicable), was superior with PAD when adjusted for ISS, (HR=0.78, 95% CI [0.66-0.91], P=.002) and in multivariate analysis (HR=0.76 (95% CI [0.64-0.90], P=.001). For the secondary endpoint overall survival (OS) the PAD arm was superior when adjusted for ISS (HR=0.80, 95% CI [0.65-1.00], P=.047) as well as in multivariate analysis (HR=0.78, 95% CI [0.63-0.97], P=.027). Landmark analysis from start of maintenance for PFS did not show a significant difference between Thalidomide and Bortezomib maintenance, however, for OS the PAD arm was superior (P=.035) (HR=0.71, 95% CI [0.52-0.98]). Subgroup analysis performed on patients with renal failure at presentation (serum creatinine ≥2 mg/dL; 45 VAD, 36 PAD) showed that the PAD arm was significantly superior for PFS (HR=0.44, 95% CI [0.26-0.75], P=.003) and OS (HR=0.38, 95% CI [0.21-0.69], P<.001). 35/45 (78%) patients treated with VAD had died as compared with 16/36 (44%) patients with PAD. In bortezomib treated patients with serum creatinine ≥2 mg/dL OS and PFS were not significantly different from those in bortezomib-treated patients with normal renal function. Analysis for the effect of study group, concentrating on the difference of single HDM (sHDM, HOVON policy) vs double HDM (dHDM, GMMG policy) with ASCT indicated that dHDM was not superior across treatment arms for PFS, but in multivariate analysis remained superior for OS (HR=0-72, 95% CI [0.58-0.90], P=.004). Comparison of study group and treatment arms for OS at 5 years indicated that PAD plus dHDM was superior (72% vs 59% (PAD+sHDM) vs 63% (VAD+dHDM) vs 56% (VAD+sHDM), logrank P=.004. When patients were classified by prognostic characterization by FISH and ISS (K. Neben et al. Blood 2012;119:940-948) subgroup analysis in patients treated with dHDM showed that in the VAD arm, PFS was significantly lower in intermediate risk (IRi) (HR 2.26, 95% CI [1.42-3.58], P<0.001) and poor risk (PRi) (HR 5.02, 95% CI [2.89-8.73], P<0.001) as compared to good risk (GRi), while in the PAD arm the HR for PRi was 2.04, 95% CI [1.20-3.48], P=0.009, and for IRi 1.26, 95% CI [0.82-1.92], P=0.29. These data suggest that with PAD+dHDM only high-risk remains an independent unfavourable group for PFS. For OS a comparable difference was observed. Finally, the actuarial probability to develop a second primary malignancy was not different between treatment arms (PAD 3% at 5 years vs VAD (5%), P=.22).Bortezomib during induction and maintenance improves CR and achieves superior PFS and OS. Subgroup analysis after long follow-up confirms the favourable outcome in patients with renal failure. Comparison of study subgroup analysis suggests that bortezomib treatment combined with double intensive treatment may be beneficial for PFS/OS.This trial has been registered as NTR213; EudraCT no. 2004-000944-26; ISRCTN: 64455289.This trial was supported by the Dutch Cancer Foundation, the German Federal Ministry of Education and Research and an unrestricted grant from Janssen-Cilag-Ortho Biotech. The GMMG study group received further grants to support this trial by Novartis, AMGEN, Chugai and Roche.Sonneveld: Janssen-Cilag: Honoraria; Celgene: Honoraria; Onyx: Honoraria; Janssen-Cilag: Research Funding; Millenium: Research Funding; Onyx: Research Funding; Celgene: Research Funding. Salwender:janssen: Honoraria. Weisel:Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria. Schmidt-Wolf:janssen: Research Funding; novartis: Honoraria. van de Velde:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Lokhorst:Genmab A/S: Consultancy, Research Funding; Celgene: Honoraria; Johnson-Cilag: Honoraria; Mudipharma: Honoraria. Goldschmidt:janssen: Honoraria, Research Funding; amgen: Research Funding; novartis: Honoraria, Research Funding; chigai: Honoraria, Research Funding; roche: Honoraria, Research Funding.

The randomised, open-label, phase III trial HOVON-50 was designed to evaluate the effect of thalidomide during induction and maintenance in newly diagnosed multiple myeloma patients. The previous analysis showed that thalidomide improved the primary endpoint EFS, but had no impact on OS (Lokhorst et al; Blood 2010 115: 1113-1120).Patients with Salmon & Durie stage II or III, age 18-65 years inclusive, were randomly assigned to arm A: 3 cycles of VAD (Vincristine, Adriamycin, Dexamethasone) or to arm B, 3 cycles of TAD (Thalidomide 200 orally, days 1-28 instead of Vincristine) Thalidomide was given from day 1 until 2 weeks before the stem cell mobilization with CAD (Cyclophosphamide 1000 mg/m2 iv day 1)and G-CSF. After induction therapy patients received 1 or 2 courses of high dose Melphalan (HDM) 200 mg/m2 with autologous stem cell rescue followed by maintenance therapy with alpha-Interferon (Arm A) or Thalidomide 50 mg daily (arm B) until relapse or progression. Between November 27, 2001 and May 31, 2005, 556 patients were randomised of which 536 patients were eligible for evaluation. As of July 2013 the median follow up of the 201 patients still alive is 99 months, range 65 – 130 months.The best responses achieved on protocol after extended follow-up were improved and significantly higher in the patients randomized to thalidomide: ≥ PR 88% vs 80 % (p<0.01), at least VGPR 66 % vs 55% (p<0.01), CR 31% vs 24 % (p=0.04), respectively. Similar to the previous analysis thalidomide improved EFS (censored at allo-SCT) from median 22 months to 33 months,; HR = 0.63, 95% CI [0.51 - 0.78], p<0.001) and PFS from median 25 to 33 months (HR =0.70, 95% CI [0.58 - 0.84], p<0.001). After 5 years of randomization the overall OS curvesdiverged and thalidomide improved median OS from 65 to 75 months. 10 years from randomization 27 % of patients randomized to alpha-Interferon are still alive and 35% of patients randomized to Thalidomide. For OS multivariate analysis showed prognostic significance for the whole group of patients for LDH (HR=1.52, 95% CI [1.15-2.00], P= 0.004) and ISS (HR=1.31, 95% CI [1.11-1.53, P=0.001]. For the secondary endpoint OS the thalidomide arm was superior when adjusted for covariates in multivariate analysis (HR = 0.80, 95% CI [0.64 – 0.99], P=0.045).The incidence of second primary malignancies (SPM) was similar between the two arms, as well as the actuarial probability to get an SPM within 5 years from start of the therapy (5-6%) or 10 years (9-10%)After long term follow-up thalidomide in induction and maintenance treatment and in combination with HDM improves the quality of response and achieves superior EFS and OS. No increased incidence of SPM was observed as compared to patients not receiving thalidomide. This trial was registered on www. Trialregister.nl as NTR238 and was supported by the Dutch Cancer Foundation.Lokhorst: Genmab A/S: Consultancy, Research Funding; Celgene: Honoraria; Johnson-Cilag: Honoraria; Mudipharma: Honoraria. Minnema:Janssen Cilag: Consultancy, Honoraria. Sonneveld:Janssen-Cilag: Honoraria; Celgene: Honoraria; Onyx: Honoraria; Janssen-Cilag: Research Funding; Millenium: Research Funding; Onyx: Research Funding; Celgene: Research Funding.

Decitabine has been approved for the treatment of myelodysplastic syndromes (MDS) in the United States and acute myeloid leukemia (AML) in older patients in Europe. The definitions of MDS and AML differ between the FAB and WHO classification, mainly with regards to patients with 20 to 30% blasts in blood or bone marrow having MDS according to the FAB classification (i.e. refractory anemia with excess blasts [RAEB] or RAEB in transformation), but AML according to the WHO. In the phase III trial 06011, we compared low-dose decitabine with best supportive care (BSC) in patients ≥60 years with MDS according to the FAB classification (Lübbert et al., J Clin Oncol. 2011;29:1987-96). Here, we examine trial 06011 for the efficacy and safety of decitabine in patients with AML according to WHO and low proliferation, i.e., blast counts of 20 to 30%.Patients were randomly assigned to receive decitabine or BSC. Decitabine 15 mg/m2 was given intravenously over 4 hours every 8 hours for 3 consecutive days in 6-week cycles, with a maximum of 8 cycles. Results were evaluated every 2nd cycle. In case of complete remission (CR) at least 2 further courses were administered. Primary endpoint was overall survival (OS). Response rates (CR; PR, partial remission; HI, hematologic improvement; PD, progressive disease), progression-free survival (PFS; time from random assignment to PD, relapse or death), AML-free survival (AMLFS; time from random assignment to AML according to FAB [>30% bone marrow blasts] or death), and toxicity were secondary endpoints.Applying the WHO criteria to the 233 patients enrolled onto the trial, 164 had MDS and 50 had AML with blast counts of 20 to 30%. The remaining 19 patients were excluded from the present analyses. They comprised 14 patients with chronic myelomonocytic leukemia, 2 with AML and ≥40% blasts, and 3 with no blast counts available.Among the AML patients, 27 were in the decitabine and 23 in the BSC arm. In both arms, the median age was 70 years. Of the patients in the decitabine arm, 59% received 3 or more treatment cycles. Response rates in the decitabine and the BSC arm were as follows: CR, 11% vs 0%; PR, 11% vs 0%; HI, 11% vs 0%; and PD, 37% vs 74%. Compared with the patients receiving BSC, those receiving decitabine had longer PFS (P=0.008; Table 1). However, this did not translate into a significantly improved AMLFS or OS of the decitabine treated patients, although median OS was 9.8 months, compared to 5.9 months among patients receiving BSC only (Table 1). With regard to toxicity differences between the decitabine and BSC arms, grade 1-2 nausea was observed in 46% vs 14% and grade 3-4 febrile neutropenia in 19% vs 0%.Among the MDS patients, those receiving decitabine (n=78) had a longer PFS (P=0.07) but similar AMLFS and OS compared to the patients receiving BSC only (n=86; Table 1). The impact of decitabine on PFS, AMLFS and OS did not significantly differ between the AML and MDS patients (Table 1). Response rates among the MDS patients in the decitabine and BSC arms were as follows: CR, 14% vs 0%; PR, 4% vs 0%; HI, 18% vs 2%; and PD, 23% vs 66%.Our data point to the clinically relevant efficacy of decitabine given in the 3-day schedule among patients with AML and low blast counts, particularly by delaying progression or relapse. No impact of decitabine, compared to BSC or low-dose cytarabine, on OS in older patients with AML and 20 to 30% marrow blasts (median, 8.0 vs 6.1 months) has been previously also reported by Kantarjian et al. (J Clin Oncol. 2012;30:2670-7). In that study, decitabine was given with 20 mg/m2/day on 5 days every 4 weeks; PFS was not presented. The prolonged PFS that we observe may be used for example as non-intensive bridge to allogeneic stem cell transplantation after reduced-toxicity conditioning. Due to the post-hoc nature of our analyses and the relatively small patient numbers, further studies appear warranted to fully establish the benefit of decitabine in AML patients with low blast counts.Rüter: Boehringer-Ingelheim: Employment. Platzbecker:Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Giagounidis:Celgene: Consultancy, Honoraria. Selleslag:Celgene: Consultancy; Novartis: Consultancy; Amgen: Consultancy. Baron:Genzyme: Honoraria.

No relevant conflicts of interest to declare.

No relevant conflicts of interest to declare.

Bortezomib (1.3 mg/m2) combined with Lenalidomide (10–25 mg) and Dexamethasone (VRD) is effective in newly diagnosed and relapsed multiple myeloma (MM). Reported data on the effect of these drugs in relapse/refractory MM are available from the APEX and MM-009/MM-010 trials, respectively. These trials, however, were performed in patients with 2–8 prior regimens.This investigator sponsored two-step phase 2 HOVON trial was designed to evaluate escalated dosages of Bortezomib (B) given once weekly and daily Lenalidomide (L) combined with weekly Dexamethasone (D) (eVRD) followed by Lenalidomide maintenance in an homogenous group of patients with symptomatic MM in first relapse. The goal was to explore the maximum tolerated dose of this combination in order to achieve a durable second remission.Dose levels were B 1.3 mg/m2, L 10 mg, (level 1); B 1.6 mg/m2, L 10 mg (level 2); B 1.6 mg/m2, L 15 mg (level 3); B 1.6 mg/m2, L 20 mg (level 4). D dose was 20 mg days 1–2, 8–9, 15–16 in all dose levels. Inclusion criteria were symptomatic MM ISS stage 1–3, aged 18–80 in first relapse after initial treatment. The primary endpoint was response (complete response (CR) according to IMWG criteria, very good partial response (VGPR), partial response (PR), together overall response (ORR)) with Progression-free Survival (PFS), overall survival (OS) and toxicity as secondary endpoints.Eighty-one patients were included, i.e. 15 patients in dose levels 1, 2 and 3, followed by 66 in the phase 2 part. This report is based on 12 patients in the dose escalation phase and the first 42 patients in the phase 2 part. Median age was 67 yrs, with ISS stages 1 (56%), 2 (40%) and 3 (5%). 37/54 patients had received HDM followed by stem cell transplant as part of first-line treatment. The MTD was reached at dose level 3 when the maximum of 3 SAEs in 5 patients was observed. After establishment of the MTD, the phase 2 part of the trial was performed with B 1.6 mg/m2 once weekly for 3 weeks, L 20 mg days 1–21 and D 20 mg days 1–2, 8–9, 15–16, for 8 cycles of 28 days followed by L maintenance 10 mg days 1–21 of a 28 days cycle. The median number of cycles was 6 in the dose-escalation phase and 7 cycles in phase 2. 7/12 (58%) patients in the dose-escalation phase and 23/42 (55%) patients in phase 2 started lenalidomide maintenance. Reasons for premature discontinuation of the protocol treatment were toxicity (14%), progression (24%), no response (5%) or other (14%). Polyneuropathy grade 3–4 occurred in 19% with a median time to maximum PNP of 123 days. Hematological toxicity grade 3 and 4 was observed in 29 % of patients In the phase 2 part including 42 patients the ORR was 92 %, ≥VGPR 64% and CR/nCR 30%. Median time to response was 1.1 cycles. At a median follow-up of 13.6 months PFS at 18 months was 52% and OS 76%. Among predetermined risk factors ISS stage, prior HDM/ASCT and achieved response on protocol, depth of response was the only significant factor which was associated with PFS (p<0.001) and OS (p<0.001), Eight patients died from progressive MM (n=4) or other causes (n=4). One second primary malignancy was observed in dose level 3.Escalated VRD followed by Lenalidomide maintenance is effective and feasible in patients with first relapse MM. We will present an updated follow-up at ASHThis trial was registered as Eudract nr 2007–002533–37. Unrestricted grants and study drug were provided by Janssen and Celgene.Sonneveld: Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Onyx: Honoraria, Research Funding.

The “monosomal karyotype” cytogenetic subgroup (MK+), as defined by Breems et al. (1) encompasses mostly complex karyotypes (CK, >3 abnormalities) and is associated with very poor outcome in AML (1, 2) and MDS (3). Discussions are ongoing regarding treatment response prediction, and a prognosis-modifying effect within the CK+ AML subgroup (1, 4). In a study of 227 AML pts >60 years, 38 of whom were MK+, we found that particularly pts with at least 2 monosomal autosomes (MK2+, by definition also CK+) appeared to benefit from DAC (5). We now applied this question to higher-risk MDS pts randomized to either DAC or Best supportive care (BSC) in the 06011 trial (6) which explicitly enrolled pts with IPSS poor-risk cytogenetics.Of 233 randomized pts, 206 had cytogenetics informative for MK status: 63 had normal cytogenetics (CN), 143 had cytogenetic abnormalities (CA) without MK (MK-, n=73) or with MK (MK+, n=70). This last group was further subdivided into pts with 1, 2 or at least 3 monosomal autosomes (MK1, MK2, MK3+, n=17, 22, 31, resp.). Endpoints were overall survival (OS), progression-free survival (PFS) and response rate (RR, complete and partial remissions, hematologic improvement). Analysis was based on the intent-to-treat principle.As recently published (6), in the overall 233 pts, PFS was significantly improved in the DAC arm as compared to BSC (median 0.55 vs 0.25 years, hazard ratio [HR] 0.68, p=0.004), but not OS (HR 0.88), probably due to post-progression treatments, suboptimal DAC schedule and treatment duration as possible confounders. In the 206 pts with informative cytogenetics, significant improvement in outcome with DAC vs. BSC was also seen for PFS (p=0.022, HR 0.72, Table 1) but not OS (HR 0.93). The improvement of PFS with DAC vs BSC was quite pronounced in the 63 pts with CN (HR 0.55, p=0.03), but less impressive and not significant in the 143 pts with CA (HR 0.76, p=0.11). When subdividing the latter by MK categories, pts with either 2 (MK2) or more than 2 (MK3+) monosomal autosomes also had significantly prolonged PFS with DAC, reflected in RR of 67% in MK2 and 33% in MK3+ DAC-treated pts (Table 1). This effect was not obvious in the MK1 subgroup, where the PFS outcome was favorable in both treatment groups, and in the MK− subgroups, either without (“MK−/CK−”) or with complex karyotype (“MK−/CK+”), the latter having a very poor outcome in both treatment groups. With caution (considering the limited size of some subgroups), these results support our observation that AML pts with a complex karyotype harboring 2+ monosomies can gain benefit from this hypomethylating agent.This first randomized trial addressing the predictive value of the MK genotype in the presence of 2+ monosomies embedded in a complex karyotype demonstrates a very rapid deterioration of MDS pts receiving BSC (within <6 weeks from randomization with 3+ monosomies). DAC treatment mitigated the negative effect of these karyotypes. We speculate that this effect is linked to the distinct mechanism of action of the hypomethylating agent DAC (7), and that with a different DAC schedule and longer treatment duration, these effects might be observed also on OS.No relevant conflicts of interest to declare.

Wijermans: Centocor Ortho Biotech Research & Development: Research Funding. Janssen:Novartis: Consultancy.

Although outcomes have improved for patients (pts) with multiple myeloma (MM), relapsed/refractory MM remains associated with short survival and constitutes an unmet medical need. Glucocorticoids (GCs) are an important component of MM therapy; however, resistance is common. In preclinical models, interleukin-6 (IL-6) promotes the proliferation and survival of MM cells in the context of the bone marrow microenvironment and protects these cells from GC-induced apoptosis. Therefore, blocking IL-6 may disrupt resistance and restore sensitivity to GCs. Here, we report the final results from a Phase 2 open-label, non-randomized study that evaluated the safety and efficacy of siltuximab (S), a monoclonal antibody targeting soluble human IL-6, in combination with high-dose dexamethasone (D) in pts with relapsed and relapsed/refractory MM.Pts with measurable, secretory disease who had received at least 2 prior lines of therapy, one of which contained bortezomib, and progressed during or after their last line of treatment were eligible. Other key eligibility criteria included a creatinine clearance ≥20 mL/min, platelets ≥50,000/mm3, and neutrophils ≥1,000/mm3. S was administered 6 mg/kg IV on days 1 and 15 of a 28-day cycle and oral D 40mg once daily, on days 1–4, 9–12, and 17–20 for a max of 4 cycles; days 1–4 for subsequent cycles. The first 14 pts received S alone for the initial 1 to 2 cycles; 10 pts had D added for progressive disease post-Cycle 1 or suboptimal response post-Cycle 2. 39 subsequent pts received S+D concurrently as none of the first 14 pts achieved ≥PR while on S monotherapy. The primary endpoint was overall response rate (ORR, CR+PR) using EBMT criteria. Secondary endpoints were time to progression (TTP), progression-free survival (PFS), overall survival (OS), and incidence of AEs and SAEs.Forty-nine pts received S+D. The median age was 65 yrs (range 43–89) and 43% of pts were female. The median disease duration was 4 yrs (range 0.7–13.2). Pts were heavily pretreated, having received prior bortezomib (100%), steroids (100%), IMIDs (90%), alkylating agents (91%) and ASCT (65%). The median number of prior lines of therapy was 4 (range 2–9); 86% had disease that was refractory to the last prior line. Of the 44 pts with prior D exposure, 32 (73%) were refractory to the last D-containing regimen. The median duration of therapy was 4 cycles (99 days). Of the 47 pts evaluable for response, the ORR by EBMT criteria was 17% (0 CRs, 8 PRs); the ORR + minimal response (MR) rate was 23.4% (N=11). Using IMWG criteria, the ORR + MR rate was 27.7% (9 PRs, 4 MRs). Of the 11 pts with at least MR by EBMT criteria, 5 pts were refractory to the last D-containing regimen and 7 experienced less than MR on a prior D-containing regimen. The median duration of response was 5.9 months (181 days, 95% CI: 147, 365). Three pts had a long-lasting response of 9 months or more. For all 49 pts, the median PFS was 3.7 months (114 days, 95% CI: 84, 148) and median OS was 20.4 months (621 days, 95% CI: 347,984). AEs occurring in ≥25% of pts were thrombocytopenia, fatigue, anemia, abnormal hepatic function, neutropenia, diarrhea, peripheral edema, dyspnea and dizziness. 74% of pts experienced a grade ≥3 AE; the most frequent non-hematologic grade ≥3 AEs were fatigue (8%), abnormal hepatic function (8%), and pneumonia (6%). Grade 4 hematologic toxicities were thrombocytopenia (12%), neutropenia (4%) and anemia (2%). 25% of pts discontinued treatment due to an AE. Twenty (41%) of the 49 pts experienced ≥1 SAE. The most frequently occurring SAEs were pneumonia (8%), thrombocytopenia (6%), septic shock, anemia, and hemolytic anemia (4% each). Five pts died during the study; 3 due to progressive disease, 2 due to infection (nosocomial infection, septic shock).The combination of siltuximab with dexamethasone was well tolerated. Although the ORR was modest in this relapsed/refractory patient population, responses were seen in pts with MM refractory to prior dexamethasone-containing therapy, suggesting that siltuximab may be able to at least partially overcome dexamethasone resistance in some cases. Overall, these results provide a rationale for further studies of siltuximab in combination with dexamethasone-based MM therapy.Voorhees: MedImmune: Consultancy; Pfizer: Research Funding; Centocor Ortho Biotech: Research Funding; Celgene: Research Funding; Merck: Research Funding. Off Label Use: Siltuximab for the treatment of multiple myeloma. Manges:Centocor Ortho Biotech: Research Funding. Sonneveld:Millennium Pharmaceuticals: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Onyx: Consultancy, Research Funding. Jagannath:Merck: Honoraria; Millennium Pharmaceuticals: Honoraria; Johnson and Johnson Pharmaceuticals: Consultancy; Celgene: Consultancy, Honoraria; Centocor Ortho Biotech: Research Funding. Somlo:Onyx: Consultancy; Millennium: Consultancy; Celgene: Consultancy, Speakers Bureau; Centocor Ortho Biotech: Research Funding. Krishnan:Celgene: Speakers Bureau; Millennium Pharmaceuticals: Speakers Bureau; Centocor Ortho Biotech: Research Funding. Lentzsch:Celgene: Consultancy, Research Funding; Onyx: Consultancy; Genzyme: Consultancy; Centocor Ortho Biotech: Research Funding. Frank:Centocor Ortho Biotech: Research Funding. Zweegman:Centocor Ortho Biotech: Research Funding. Wijermans:Centocor Ortho Biotech Research & Development: Research Funding. Rijnbeek:Ortho Biotech Oncology Research and Development: Employment. Qin:Johnson & Johnson Pharmaceutical Research & Development, LLC: Employment. Cornfeld:Ortho Biotech Oncology Research and Development: Employment. Xie:Ortho Biotech Oncology Research & Development: Employment. Thomas:Centocor Ortho Biotech: Research Funding; Millennium Pharmaceuticals: Research Funding; Celgene: Research Funding; Novartis: Research Funding; Immunomedics: Research Funding.

Wijermans: Centocor Ortho Biotech Research & Development: Research Funding.

The membrane of erythrocytes is composed of a bilayer of phospholipids and cholesterol. It is strengthened by a membraneskeleton consisting of the proteins spectrin, ankyrin, pallidin, band 3 and band 4.1. Hereditary elliptocytosis (HE) is caused by mutations in the spectrin protein, resulting in a typical elliptocytic shape. These cells have a decreased deformability and a shortened lifespan. Most mutations in HE are located in the head to head self association site of the α- and β dimers of spectrin.HE Patients with heterozygous mutations in α spectrin show little or no hemolysis because α spectrin is synthesized in an excess relative to β spectrin. In the heterozygous situation, plenty of normal wild type α spectrine (Wt α) is available for incorporation in to the membraneskeleton. In Hereditary Pyropoikilocytosis (HPP) with its bizarre shapes, a second mutation in the α spectrin is present, in addition to the HE mutation. It is responsible for a defect in the synthesis of α spectrin, resulting in the production of 50% functional α spectrin. This mutation is called LELY (Low Expression LYon). Thus, when the LELY mutation is located in trans on the allele in respect to the HE allele, the expression of the Wt α spectrin protein is reduced. As a consequence, more abnormal HE spectrin will be incorporated in to the membraneskeleton. This enhanced expression of the HE mutation results in an unstable membraneskeleton of the HPP cell.The deformability of erythrocytes is measured using the ektacytometer LORRCA Maxsis of Mechatronics (Hoorn, The Netherlands). DNA was isolated from white blood cells from peripheral blood. The HE mutations are found by a PCR of the α spectrin exons where most mutations exists for HE, followed by DNA sequencing using the ABI prism genetic analyzer from Applied Biosystems. The LELY mutation is proven by a PCR of exon 40 of the α spectrin gene followed by RFLP agarose gel electrophoresis.(59 G/A) mutation and the LELY mutation are present. In addition to these Exon 2 and LELY mutations, a third mutation in Exon 6 (103 T/C) is found in the α spectrin of brother E.α spectrin is synthesized and incorporated into the membraneskeleton. The same mutations hold for brother E., but he has HPP. This is attributed to a third additional mutation in Exon 6 of the α spectrin gene. This Exon 6 mutation is located in trans to the Exon 2 mutation that in turn is in cis with the LELY mutation. Like in brother W. the expression of the Exon 2 mutated spectrin is reduced due to the LELY mutation. However relatively more of the Exon 6 mutated α spectrin comes available for the dimerization with β-spectrin resulting in an unstable membrane skeleton, causing the HPP of brother E.The B. family is examined for the presence of HE or HPP (figure 1). Brother E. has clinical symptoms, poikilocytes and a typical ektacytometric deformability matching HPP. Brother W. and his daughter N. have no clinical symptoms but elliptocytes and an ektacytometric deformability typical for HE. In all affected individuals the same Exon 2.The combination of Exon 2 and LELY mutations normally leads to HPP. Concerning brother W. and his daughter N. this is not the case. They have a mild form of HE. The explanation for this finding is, that the Exon 2- and LELY mutation are located in a cis rather than in a trans position on the α spectrin gene (figure 1). In that case the mutated Exon 2 is less expressed and more Wt.No relevant conflicts of interest to declare.

The monosomal karyotype (MK+) has recently been identified as the single most adverse cytogenetic prognosticator of AML outcome (1, 2). We made the recurrent - and seemingly paradoxical - observation that MDS/AML patients (pts) with complex karyotypes (CK+) including monosomy 7 showed encouraging responses to decitabine (DAC, ref.s 3, 4). We now evaluated a large cohort of AML pts >60 years ineligible for induction chemotherapy treated on a single phase II multicenter DAC study (trial 00331) for the effect of the MK+ genotype upon outcome.Comparisons of response rate (RR), i.e. attainment of complete and partial remissions (CR/PR) and overall survival (OS) were performed in 179 treatment-naive AML pts with available cytogenetics (median age 72 years) treated with DAC as described (ref. 3, given over 72 hours, every 6 weeks), for up to 4 courses, followed by “maintenance” with 3 daily 1-hour infusions of DAC 20 mg/m2 every 4–6-weeks. Median white blood cell counts prior to treatment was 7.500/μl (range 0.5–241,000), 79% had a performance status ECOG >1. Cytogenetic risk groups are shown in Table 1. All karyotypes were centrally reviewed and scored for MK (A.H.). Analyses were adjusted for the parameters which had a strong effect on outcome in multivariate analyses of RR and OS, i.e., performance status (on RR and OS) and platelet counts (on OS).By the established definition of MK+, i.e either 1 autosomal monosomy and at least one structural change (MK1) or 2 or more autosomal monosomies (MK2), 39/179 patients were scored as MK+, with chromosomes 7 (n=17), 17 (n=17), and 5 (n=8) being most frequently lost. 17 pts had a single monosomy, as part of a median of 5 abnormalities (range, 2–21), 22 pts had multiple monosomies (median 3, range 2–11), as part of a median of 9.5 abnormalities (range, 4–17). As shown in Table 1, abnormal cytogenetics (AA) were associated with a lower RR and OS compared to pts with normal karyotype. When analyzing pts with AA (n=123) according to the presence (n=39) or absence of MK+ (n=84), MK+ patients had a higher RR than MK-, irrespective of a CK+ genotype. Since it has been shown by several groups that multiple monosomies may herald an even worse prognosis of AML than single monosomy, it was notable that pts with multiple monosomies (MK2, n=22) had a 45% RR and 25% 1-year OS (Fig. 1) compared with 24% and 12% in those with a single monosomy (MK1, n=17), both comparisons p=0.11.Patients with normal-karyotype AML had a better outcome with DAC treatment than those with chromosomal abnormalities. Patients with single or even multiple monosomies still appeared to respond to this treatment, supporting our previous, surprising observation that pts with highly complex karyotype including monosomies may benefit from DAC. Because of a lack of control group in our trial, it is difficult to hypothesize if this encouraging result may be related to modes of action of DAC which differ from low-dose chemotherapy, e.g., with cytarabine. The role of MK will be further studied prospectively in a randomized clinical trial in the same patient population (NCT00867672), and retrospectively in a randomized trial of higher-risk MDS patients treated with either DAC or Best Supportive Care (EORTC 06011).Off Label Use: Decitabine is approved for treatment of different types of MDS, in the present study its activity in AML of older patients was studied. Germing:Celgene: Consultancy, Research Funding.

There is extensive evidence from numerous studies in the transplant setting that achievement of complete response (CR) or at least very good partial response (VGPR) is significantly associated with prolonged progression-free survival (PFS) and overall survival (OS). In elderly myeloma patients CR was a rare event since new drugs has been added to standard melphalan-prednisone (MP). After the introduction of novel agents, CR represents an achievable goal, also outside of the transplant setting.to assess the impact of response to treatment on time-to-event parameters (PFS and OS) in elderly myeloma patients.We retrospectively analysed newly diagnosed myeloma patients, older than 65 years old, or younger but not eligible for high-dose chemotherapy and transplant. Patients were enrolled in 3 multicentre randomized European trials of the GIMEMA and Hovon groups, and were treated with MP (n=332), MP plus thalidomide (MPT, n=332), MP plus bortezomib (VMP, n=257) or MP plus bortezomib-thalidomide followed by bortezomib-thalidomide maintenance (VMPT-VT, n=254). PFS, OS and duration of CR were analysed by the Cox proportional hazards model, comparing the two arms by the Wald test and calculating 95% confidence interval (CI). Univariate and multivariate analyses were performed for the following variables: age at diagnosis (>75 vs. ≤75 yrs), International Staging System (ISS) stages, type of chemotherapy and best response achieved. Best response was treated as a time-dependent variable.A total of 1,175 patients, enrolled from November, 2001 to January, 2009, were retrospectively analysed. The best response to treatment was available in 1,136 patients: CR was reported in 195, VGPR in 212, PR in 397. Baseline characteristics according to best response achieved in patients who obtained CR, VGPR or PR were similar. Since response rates vary according to treatment regimens the proportion of patients who received MP, MPT, VMP, and VMPT-VT was different in the different response categories. After a median follow-up of 29 months, PFS was significantly higher in patients who achieved CR compared to those who obtained VGPR (HR 0.16; 95% CI 0.10–0.24; p<0.001) or PR (HR 0.07; 95% CI 0.04–0.13; p<0.001). The advantage in PFS translated into an advantage in OS: patients obtaining CR have a significantly prolonged OS than patients who achieved VGPR (HR 0.15; 95% CI 0.08–0.28; p<0.001) or PR (HR 0.08; 95% CI 0.04–0.16, p<0.001), (table). In multivariate analysis CR achievement was as an independent predictor of longer PFS and OS, regardless of age, ISS stage, and treatment administered. In patients > 75 years, both PFS and OS were shorter as compared to younger patients. Despite these differences, the impact of CR on outcome was identical. In the subgroup of patients > 75 years, PFS was significantly prolonged in patients who achieved CR, compared with those who obtained VGPR (HR 0.26; 95% CI 0.12–0.58, p = 0.001) or PR (HR 0.20; 95% CI 0.10–0.41, p < 0.001). Accordingly, OS was significantly higher in patients who achieved CR, compared with those who obtained VGPR (HR 0.13; 95% IC 0.03–0.58; p = 0.007), or PR (HR 0.12; 95% IC 0.03–0.51, p = 0.004), (table). No significant PFS differences between patients obtaining CR during the first 6 months of treatment or later were seen (HR 1.06; 95% IC 0.49–2.27; p=0.878). Similarly, no OS differences between these two groups were detected (p = 0.676). Duration of CR was comparable in patients who obtained CR during or after the first 6 months of treatment (HR 0.66; 95% CI 0.30–1.45; p = 0.305). Patients whose CR lasted more than 18 months have a significant OS benefit compared to patients who did not (p=0.006).These finding highlight the importance of CR, also outside of the transplant setting, regardless of age, ISS and treatment administered, and support the use of new drugs, also in patients older than 75 years, to achieve and maintain maximal response.Gay: Celgene: Honoraria. Bringhen:Calgene: Honoraria; Janssen-Cilag: Honoraria. Guglielmelli:Celgene: Honoraria; Janssen Cilag: Honoraria. Boccadoro:Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees. Sonneveld:Celgene: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson : Membership on an entity's Board of Directors or advisory committees. Palumbo:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees.

This independent trial was designed to evaluate the efficacy of bortezomib (B) during induction and maintenance on progression-free survival (PFS) in patients with newly diagnosed symptomatic MM, who were candidates for high-dose therapy. Patients were randomly assigned to 3 cycles of standard VAD (arm A) or PAD (Arm B); PAD was dosed as B 1.3 mg/m2, days 1,4,8,11, doxorubicin 9 mg/m2, days 1–4, dexamethasone 40 mg, days 1–4, 9–12, 17–20). Patients received one (HOVON) or two (GMMG) high-dose melphalan (HDM) 200 mg/m2 with ASCT. Maintenance consisted of thalidomide (T) 50 mg daily (arm A) or B 1.3 mg/m2, 2-weekly (arm B) for 2 years. Primary endpoint was PFS, other endpoints were complete response (CR) (EBMT), immunofixation positive CR (nCR), VGPR pre-and post HDM and survival (OS). The protocol specified analysis was intention-to-treat and censored for patients who received allo-SCT after HDM1 (n=46). We report the analysis of the first 626 randomized patients. The final analysis of all patients will be presented at the meeting.13 patients were excluded (7 not eligible, 6 not evaluable). The two arms (A:n=305;B:n=308) were well balanced for age, Salmon/Durie stage II/III, renal failure (11%), and serum B2M. Medium follow-up is 40 months. 89% of patients completed induction and HDM1. In GMMG after HDM1 80% of patients received 2nd HDM. Full dose B could be administered in 82% of patients. Polyneuropathy (PNP) WHO gr 3+4 occurred in 7% (arm A) and 16% (arm B). 204 (67%, arm A) and 174 (57%, arm B) patients started maintenance. 64% of patients tolerated full dose B and 27% reduced dose. 47% of patients on B maintenance went off protocol because of toxicity (9%), progression (29%) or other (9%). In contrast 64 % on T maintenance went off protocol because of toxicity (31%), progression (31%) or other (2%).nCR/CR rates were 7/9% (arm A) vs 9/21% (arm B) at 3 months after HDM-1 and 12/26% (arm A) vs 12/38% (arm B) on protocol. ≥VGPR in arm-A vs arm-B were 40% vs 60% after HDM-1 and 61% vs 75% on protocol. PFS was superior in arm B (HR 0.81, p=0.047; adjusted for ISS: HR 0.81, p=0.056). PFS at 36 months was 42% (arm A) vs 46% (arm B). Multivariate Cox regression showed treatment arm (p=0.037), IgA (p=0.007), ISS stage (p=0.007), WHO Performance Status (p<0.0001), del13/13q- (p=0.015) and study group (2nd HDM) (p=0.015) as significant PFS variables. Patients treated with bortezomib had a better OS (HR 0.74, p=0.048), with study arm, WHO, IgA, ISS stage and del13/13q- as significant variables. Subgroup analysis of response at 12 months showed no impact on PFS and an impact of VGPR/nCR/CR on OS only in arm A. Adverse cytogenetic markers (p<0.05) in the combined group were 13q14, 17p-, t(4;14) for PFS and OS. Detailed FISH data are reported separately. The response and survival data of the subgroup analysis are given below. We conclude that B achieves high nCR/CR during induction, that B maintenance is well tolerated and is associated with additional responses. Bortezomib achieves superior PFS and results in an improvement of survival.This trial (EudraCT no. 2004-000944-26) was supported by the Dutch Cancer Foundation, the German Federal Ministry of Education and Research and a grant from Janssen-Cilag.Sonneveld: celgene: Membership on an entity's Board of Directors or advisory committees; janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; millennium: Membership on an entity's Board of Directors or advisory committees. Off Label Use: bortezomib, induction treatment prior to high dose therapy. Schmidt-Wolf:celgene: Membership on an entity's Board of Directors or advisory committees; janssen-Cilag: Research Funding. van de Velde:Johnson & Johnson: Employment, Equity Ownership. Delforge:celgene: Membership on an entity's Board of Directors or advisory committees; janssen-cilag: Membership on an entity's Board of Directors or advisory committees. Weisel:orthobiotech: Consultancy, Membership on an entity's Board of Directors or advisory committees; celgene: Membership on an entity's Board of Directors or advisory committees. Scheid:orthobiotech: Honoraria. Goldschmidt:celgene: Honoraria, Research Funding; amgen: Honoraria, Research Funding; novartis: Honoraria, Research Funding; orthobiotech: Honoraria, Research Funding; roche: Honoraria, Research Funding.