European Bone Research Articles

Prognostic Impact of Recipient and Donor CMV Serostatus in Acute Leukemia Patients After Allogeneic Stem Cell Transplantation At the Era of Preemptive Therapy.

AbstractAbstract 3110 Background:Monitoring and (preemptive) treatment of cytomegalovirus (CMV) infection or disease have been implemented in clinical routine algorithms in patients after allogeneic stem transplantation (allo-SCT) in the early nineties and resulted in a dramatic decrease of CMV disease from 20–30% to less than 5% in recent years. However, a significantly reduced relapse incidence (RI) in acute myeloid leukemia (AML) patients with vs. without early CMV replication has been reported just recently. Larger analyses evaluating the prognostic impact of recipient and donor CMV serostatus - as one of the most important risk factors for CMV infection and disease - are lacking at the era of preemptive treatment of CMV infection. Design and methods:We analyzed the prognostic impact of the (pretransplant) recipient and donor CMV serostatus in 16 628 adult de novo acute leukemia patients who underwent allo-SCT between 1998 and 2009 and are documented in the European Bone Marrow Transplantation (EBMT) database (Cohort I). Additionally, 544 patients with secondary AML (e.g. following myeloproliferative neoplasms) who underwent allo-SCT and were reported to the German Registry for Stem Cell Transplantation (DRST) were analyzed according to the prognostic impact of the CMV serostatus (Cohort II). Finally, 97 acute leukemia patients allografted at the Charité University Hospital (Berlin, Germany) were studied more in detail including other parameters such as kinetics of CMV infection and hematopoietic recipient/donor chimerism (Cohort III). Results:Recipient and/or donor CMV seropositivity was associated with a reduced 2-year leukemia-free survival (LFS) (44% vs. 49%, p<0.001) and overall survival (OS) (50% vs. 56%, p<0.001) in de novo acute leukemia patients (Cohort I). These observations were mainly due to an increased non-relapse mortality (NRM) (23% vs. 20%, p<0.001) and strongest in recipients allografted from a non-HLA identical sibling. However, also higher RI was noted especially for acute lymphoblastic leukemia (ALL), resulting in a markedly decreased 2-year OS (46% vs. 55%, p<0.001) in these patients. The negative prognostic impact of recipient and/or donor CMV seropositivity with respect to LFS, OS, NRM and RI remained in a multivariate Cox regression model including different other parameters (e.g. conditioning type). Conversely, the donor CMV serostatus had no significant prognostic impact among CMV seropositive recipients. Recipient CMV seropositivity was further associated with a significantly increased frequency of death due to interstitial pneumonitis, but decreased incidence of both chronic and II-IV° acute graft-versus-host disease (28% vs. 31%, p<0.001). However, it had no significant impact on the incidence of graft failure. Also in secondary AML (Cohort II) recipient and donor CMV seronegativity was associated with a superior 2-year LFS (48% vs. 41%) and OS (54% vs. 44%), but decreased RI (27% vs. 30%) and NRM (25% vs. 31%). The negative impact of CMV seropositivity of the recipient and/or the donor with respect to OS likewise remained in this cohort of secondary AML in a multivariate Cox regression model (Hazard ratio 1.4, p=0.03). Finally, analysis of cohort III showed that CMV seropositive vs. CMV seronegative patients had a significantly reduced OS even in the absence of CMV antigenemia and less frequently had a complete day +30 hematopoietic chimerism (68% vs. 92%, p=0.02). Conclusion:The recipient and donor CMV serostatus still has an important prognostic effect in acute leukemia patients after allo-SCT - particularly in ALL and those allografted from a non-HLA identical sibling - despite the implementation of most sophisticated techniques for monitoring and (preemptive) treatment of CMV in recent years. The increased RI in cases with CMV seropositivity of the recipient and/or the donor argues against a clinically important ‘virus-versus-leukemia effect′ which has been suggested just recently. Disclosures:No relevant conflicts of interest to declare.

Pomalidomide (POM) with Low-Dose Dexamethasone (LoDEX) in Patients with Relapsed and Refractory Multiple Myeloma (RRMM): Outcomes Based on Prior Treatment Exposure

AbstractAbstract 4070 Background:There are currently limited effective treatment options for patients (pts) with RRMM with prior exposure to lenalidomide (LEN), bortezomib (BORT) and chemotherapy. In a multicenter, randomized phase 2 study, POM with or without LoDEX (n=221) was active in RRMM pts who had received ≥2 prior therapies, including LEN and BORT (Richardson PG, et al. Blood 2011;118:abs 634); activity was also observed in those with disease refractory to LEN, BORT, or both (Vij R, et al. J Clin Oncol 2012;30:abs 8016). Here we characterize outcomes in the POM+LoDEX group (n=113) according to the prior treatment exposure. Methods:Pts with RRMM who had received ≥2 prior therapies, including LEN and BORT, and had progressive disease (PD) within 60 days of their last treatment were randomized (1:1 ratio) to POM+LoDEX (POM, 4 mg/day for days 1–21 of a 28-day cycle; LoDex, 40 mg/week) or POM alone. At randomization, pts were stratified by age, prior number of treatments, and prior thalidomide exposure. At progression, pts receiving POM alone could receive POM+LoDEX at investigator’s discretion. All pts received thromboprophylaxis (daily low-dose aspirin). The endpoints in this study were progression-free survival (PFS), response rates (using European Bone Marrow Transplantation [EBMT] criteria), duration of response, time to response, overall survival (OS), and safety. Response data according to prior therapy were assessed by investigator assessment. Results:All 113 pts assigned to POM+LoDEX had prior exposure to LEN (100%), BORT (100%), and steroids (100%). Most pts had also received prior alkylator therapy (93%), stem cell transplant (SCT) (73%), and thalidomide (THAL) (68%); 49% had received prior anthracyclines. Regimens immediately prior to study entry included BORT (50%), LEN (39%), cyclophosphamide (13%), THAL (8%), vorinostat (8%), carfilzomib (5%), and melphalan (5%). The median number of exposures to LEN and BORT in prior lines was once (range 1–4) and twice (range 1–6), respectively.The majority of pts (80%) had received >3 prior therapies. The overall response rate (ORR) was 48% and 30% in pts who had received ≤3 and >3 prior therapies, respectively. Of the pts who had ≤3 vs > 3 prior therapies, 9% vs 1% pts achieved complete response (CR), 39% vs 29% pts achieved partial response (PR), 9% vs 12% pts achieved minimal response (MR) and 44% vs 36 % pts achieved stable disease (SD), respectively.ORR was 34% and appeared similar regardless of prior exposure to alkylators (33%), anthracyclines (35%), SCT (35%), or THAL (35%). Median duration of response was also similar in pts who had received prior alkylators (8.4 mos), anthracyclines (10.1 mos), SCT (7.7 mos), and THAL (7.7 mos). Of the 69 pts who had a best response of SD or PD to their last prior antimyeloma therapy, 21 pts (12 SD and 9 PD) achieved a PR and 3 pts (1 SD and 2 PD) achieved a CR with POM+LoDEX treatment. Responding pts had longer time to progression (TTP; 11.1 mos) with POM+LoDex compared with the TTP (4.4 mos) observed with their last antimyeloma regimen prior to study.The most common grade 3–4 adverse events in the POM+LoDEX group were neutropenia (41%), anemia (22%), pneumonia (22%), thrombocytopenia (19%), and fatigue (14%). The incidence of at least 1 grade 3–4 adverse event was 100% in pts with ≤ 3 prior therapies, and 88% in pts with >3 therapies. Conclusions:The combination of POM+LoDEX has demonstrated an ORR of 34% in heavily pretreated pts with RRMM who have been previously exposed to LEN, BORT, steroids, and other treatments. Early treatment of POM+LoDEX (≤3 prior therapies) achieved better ORR (48%) compared with pts who received POM+LoDex later (>3 prior therapies; ORR, 30%).TableResponse by EBMT Criteria≤3 Prior Therapies>3 Prior Therapiesn=23n=90ORR, n (%)11 (48)27 (30)CR2 (9)1 (1)PR9 (39)26 (29)MR, n (%)2 (9)11 (12)SD, n (%)10 (44)32 (36) Disclosures:Vij:Onyx: Consultancy, Research Funding; Millennium Pharma: Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau. Off Label Use: Pomalidomide is an investigational drug and is not approved for the treatment of patients with any condition. Hofmeister:Celgene: Advisory Board Other, Honoraria. Richardson:Celgene, Millennium, Johnson & Johnson: Advisory Board Other. Jagannath:Onyx Pharma: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Merck Sharp & Dohme: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Millennium Pharma: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Siegel:Onyx: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau; Millennium Pharma: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau; Celgene: Advisory Board Other, Honoraria, Speakers Bureau; Merck: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau. Baz:Celgene, Millennium, Bristol Myers Squibb, Novartis: Research Funding. Chen:Celgene: Employment, Equity Ownership. Zaki:Celgene: Employment, Equity Ownership. Larkins:Celgene: Employment, Equity Ownership. Anderson:Acetylon, Oncopep: Scientific Founder, Scientific Founder Other; Celgene, Millennium, BMS, Onyx: Membership on an entity’s Board of Directors or advisory committees.

Pomalidomide (POM) with Low-Dose Dexamethasone (LoDex) in Patients (Pts) with Relapsed and Refractory Multiple Myeloma Who Have Received Prior Therapy with Lenalidomide (LEN) and Bortezomib (BORT): Updated Phase 2 Results and Age Subgroup Analysis

Abstract 450 Background: New antimyeloma treatments that re-establish tumor response are required to improve survival for pts with advanced, treatment-refractory MM. The MM-002 phase 2 study evaluated the safety and efficacy of oral pomalidomide, in combination with low-dose dexamethasone (POM+LoDex), in pts with relapsed and refractory multiple myeloma (RRMM) who have who have received ≥2 prior therapies including LEN and BORT (Richardson PG, et al. Blood 2011;118:abs 634). Updated results from March 2012 for pts and the outcomes of subgroup analyses are presented. Methods: Eligible pts with MM who had received at least 2 prior therapies (including LEN and BORT) and had disease progression within 60 days of their last treatment were randomized (1:1 ratio) to either POM+LoDEX (POM, 4 mg/day for days 1–21 of a 28-day cycle; LoDex, 40 mg/week) or POM alone. At progression, pts receiving POM alone could receive POM+LoDEX at investigator9s discretion. Pts aged over 75 years received LoDex, 20 mg/week. All pts received mandatory thromboprophylaxis (daily low-dose aspirin). Pts were stratified within each treatment group according to age. The key efficacy endpoints included the objective response rate using European Bone Marrow Transplantation (EBMT) criteria, duration of response, progression free survival (PFS) and overall survival (OS), and safety. This updated analysis focused on pts on the POM+LoDex arm. Results: The intention-to-treat efficacy analysis included 113 pts in the POM+LoDex group. The mean age of pts treated with POM+LoDex was 64 years (range, 34–88); 99 pts (88%) were aged ≤75 years. Response rates, median duration of response, and age subgroups are presented in the Table. Median PFS and OS were 4.6 months (mos) and 16.5 mos, respectively, in the POM+LoDex group overall. In the age subgroup analysis of pts treated with POM+LoDex, the median PFS was 4.7 mos in pts aged ≤65 years, and 3.7 mos in pts >65 years. Median OS was 19.7 mos in pts aged ≤65 years and 11.8 mos in pts >65 years. The most common grade 3 or 4 adverse events (AEs) occurring in >5% of pts were neutropenia (41%), anemia (22%), pneumonia (22%), thrombocytopenia (19%), fatigue (14%), dyspnea (13%), leukopenia (10%), back pain (10%), and urinary tract infection (9%). AEs led to at least one dose reduction in 26% of pts; neutropenia was associated with a dose reduction in 4% of pts. Overall, 78% of pts who developed grade 3 or 4 neutropenia used G-CSF during study treatment. There were no reports of grade 3 or 4 peripheral neuropathy (PN); grade 1 or 2 PN occurred in 7% of pts treated with POM+LoDex. Deep vein thrombosis (any grade) occurred in 2 pts (2%), both aged ≤65 years. Grade 3 or 4 neutropenia occurred in 46% of pts aged ≤65 years and in 35% of pts aged >65 years. Despite this, only 1 pt in each age group developed febrile neutropenia (2%). The mean relative dose intensity (dose intensity/planned dose intensity) was 0.9 in both pt groups of ≤65 years and > 65 years receiving POM+LoDex. Overall, 21 pts (19%) of the POM+LoDex group died during the study. The most common cause of death was progressive MM (52%; only in 14% of all cases was it due to disease progression); other causes of death (48%) included infections, cerebral/intracranial/subarachonoid hemorrhage, acute respiratory distress syndrome, and suicide in one pt with a history of severe depression. Conclusions: POM, 4 mg/day for days 1–21 of a 28-day cycle in combination with LoDex, is clinically effective and generally well tolerated in pts with RRMM who have received multiple prior treatments including LEN and BORT. POM+LoDex represents an important potential new treatment option for pts with advanced MM and appears active in both younger and older pts, with tolerability similar across different age groups. Phase 3 studies of POM+LoDEX in combination with other agents (e.g. bortezomib) are ongoing. Disclosures: Jagannath:Millennium Pharma: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Merck Sharp & Dohme: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Onyx Pharma: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity9s Board of Directors or advisory committees. Off Label Use: Pomalidomide is an investigational drug and is not approved for the treatment of patients with any condition. Hofmeister:Celgene: Advisory Board Other, Honoraria. Siegel:Onyx: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau; Millennium Pharma: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau; Celgene: Advisory Board Other, Honoraria, Speakers Bureau; Merck: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau. Vij:Onyx: Consultancy, Research Funding; Millennium Pharma: Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau. Lonial:Millennium, Celgene, Novartis, BMS, Onyx, Merck; all

Successful mobilisation of peripheral blood stem cells in children using plerixafor: a case report and review of the literature.

High-dose chemotherapy followed by autologous peripheral blood stem cell (PBSC) support is a salvage therapy for patients with relapsed or refractory malignant disease. Previous chemotherapy treatments, such as alkylating agents, purine analogues and radiotherapy, are known to affect subsequent mobilisation of PBSC1. On the basis of a history of a previously failed mobilisation attempt or the presence of one or more factors predicting an unsuccessful harvest (advanced disease, prior extensive radiotherapy, prolonged treatment with stem cell poisons, advanced age, or extensive bone marrow involvement) these patients have been identified as “predicted poor mobilisers”2. In fact, in about 10 to 30% of patients it is not possible to collect an adequate number of PBSC to support haematopoietic stem-cell transplantation when growth factor alone or in combination with chemotherapy is used for the mobilisation3. Plerixafor is a new agent that inhibits stromal cell-derived factor-1a/CXCR4 binding, resulting in rapid mobilisation of CD34+ cells into peripheral blood and is well recognised as a solution to save adults in whom conventional mobilisation regimens have failed4,5. In this context, in combination with growth factor, plerixafor leads to successful mobilisation in 70% of adult patients with non-Hodgkin’s lymphoma, Hodgkin’s lymphoma and multiple myeloma6. Give the low rate of poor mobilisation in children, few experiences have been reported regarding the use of plerixafor in this context7–11. Since Plerixafor is not yet authorised as a standard mobilising regimen in paediatric patients its administration should be considered as off-label therapy, thus requiring parental informed consent. A European Bone Marrow Transplantation (EBMT) study is currently investigating the off-label use of plerixafor (“Non-interventional study on the off-label transplant use of plerixafor”). Here we describe our experience using plerixafor on demand to mobilise PBSC in a young patient with Hodgkin’s lymphoma.

Report from the first European Bone and Joint Infection Society Travelling Fellowship 2009

Report from the first European Bone and Joint Infection Society Travelling Fellowship 2009

European Bone Marrow Working Group trial on reproducibility of World Health Organization criteria to discriminate essential thrombocythemia from prefibrotic primary myelofibrosis. Haematologica 2012;97(3):360-5 - Comment

Any study of myeloproliferative neoplasms (MPNs) that lacks adequate clinical input is doomed to cause diagnostic uncertainty and increased controversy. In the paper by Buhr et al. published in Haematologica,[1][1] the authors studied 102 cases of essential thrombocythemia (ET) and early primary

European Bone Marrow Working Group trial on reproducibility of World Health Organization criteria to discriminate essential thrombocythemia from prefibrotic primary myelofibrosis. Haematologica 2012;97(3):360-5 - Reply

We are grateful for the critical comments of Thiele et al. because they give us the opportunity to underline the difficulties in applying the current World Health Organization (WHO) classification of thrombocytic myeloproliferative neoplasms and to eliminate potential misunderstandings. 1. The

Consolidative therapy with stem cell transplantation improves survival of patients with mantle cell lymphoma after any induction regimen

Intensive induction regimen followed by high-dose chemotherapy and autologous stem cell transplantation (auto-SCT) is frequently used to improve outcomes in patients with mantle-cell lymphoma. The comparative impact of conventional vs intensive induction regimen before transplantation is unknown. Forty-eight patients with mantle-cell lymphoma receiving SCT at our institution between January 2000 and December 2010 were included in this study. At the time of initial presentation, 43 (89.5%) had stage IV disease and 18 (37.5%) received more than one chemotherapy regimen before transplantation. Forty patients underwent auto-SCT and 7 had allogeneic SCT (allo-SCT); 1 patient had an allo-SCT for relapsed disease after auto-SCT. At the time of this analysis (median follow-up of 6 years from diagnosis and 4 years from transplantation), 40 patients (88%) were alive with a 5-year disease-free survival of 74.8%. Age, disease stage, number of regimens pre-SCT, pre-SCT disease status, and type of SCT had no impact on long-term outcomes. Importantly, there were no differences among the types of induction regimen on outcomes in this cohort receiving SCT. Based on our data, we believe that future studies should focus on strategies to prevent disease relapse rather than comparing induction regimens before stem cell transplantation.

Vantage 095: Vorinostat in Combination with Bortezomib in Salvage Multiple Myeloma Patients: Final Study Results of a Global Phase 2b Trial

Abstract 480 Introduction:Vorinostat (VOR), an oral inhibitor of histone deacetylase (HDAC) class I and class II proteins, affects pathways regulating cell proliferation and apoptosis in a diverse array of tumor types. Phase 1/2 trials in multiple myeloma (MM) have indicated clinical activity of vorinostat, as both a single agent and in combination with bortezomib (BTZ) and immunomodulatory drugs (IMiDs). Materials and methods:The present study (MK-0683 PN095) was an open-label, single-arm phase 2b trial of VOR plus BTZ in BTZ-refractory patients (defined as < 25% response on therapy, or progression during or < 60 days after completion of therapy) and patients considered to be refractory, intolerant, or ineligible for IMiD-based therapy regimens. Eligible patients were aged ≥ 18 years, had measurable secretory MM, had received ≥ 2 prior anti-myeloma regimens, and relapsed or progressed following prior systemic therapy. Patients received 21-day cycles of BTZ (1.3 mg/m2 intravenously [IV]; days 1, 4, 8, and 11) plus oral VOR 400 mg/d on days 1 to 14. If patient had no change as the best response after 4 cycles of treatment or progressive disease after 2 cycles of treatment, oral dexamethasone 20 mg on the day of and day after each dose of BTZ could be added to the treatment regimen. Patients were treated until disease progression, unacceptable toxicities, or withdrawal from the study. The primary endpoint was overall response rate (ORR; ≥ partial response). Secondary and exploratory endpoints included clinical benefit response (ORR + minimal response), overall survival (OS), time to progression (TTP), progression-free survival (PFS), and safety. Responses and progression were determined according to the International Myeloma Working Group criteria and the European Bone and Marrow Transplantation Group criteria. All efficacy data will be confirmed by an Independent Adjudication Committee. Results:Between January 2009 and October 2010, 143 patients were enrolled from 41 centers in 12 countries across Asia-Pacific, Europe, and North America. Median duration of MM for the entire study population was 4.6 years, including 31% whose disease had progressed on or within 60 days of last therapy and 66% whose disease had achieved < 25% response to the regimen immediately preceding study entry. The study population was heavily pretreated, having received a median of 4 prior lines of therapy (range 2–17, ≥ 4 prior regimens: 69%). Prior anti-myeloma agents included 100% BTZ (median 2 prior regimens containing BTZ), 100% IMiDs (thalidomide [85%], lenalidomide [71%], or pomalidomide [4%]), and 74% stem cell transplant. As of July 2011, 142 of the enrolled patients received study medication, with a median exposure of 4 cycles (mean 6.2 cycles; range 1–26 cycles). The most common treatment-emergent adverse events regardless of relationship to study drug were predominantly hematologic and gastrointestinal disorders. Of interest, peripheral neuropathy was infrequent and grade ≥ 3 PN occurred in 2 patients (1.6%). The final efficacy evaluation of the IAC will occur in September 2011. Conclusions:Final data for all primary and secondary endpoints, including response assessment and time-to-event data for PFS/TTP, OS, and duration of response will be available at the annual ASH meeting. Disclosures:Siegel:Millenium: Honoraria, Research Funding, Speakers Bureau; Merck: Honoraria. Off Label Use: Vorinostat, an inhibitor of histone deacetylase, is approved in the US for the treatment of cutaneous manifestations in patients with cutaneous T cell lymphoma (CTCL) who have progressive, persistent or recurrent disease on or following two systemic therapies. Vorinostat is currently under investigation for the treatment of relapsed malignant pleural mesothelioma, relapsed/refractory B cell lymphoma (in combination with other chemotherapy agents), and relapsed/refractory multiple myeloma (in combination with bortezomib and other chemotherapy agents). Dimopoulos:Celgene, Ortho-Biotech: Consultancy, Honoraria. Yoon:NK Bio: Consultancy; Celgene: Consultancy. Kaufman:Merck; Celgene: Research Funding; Millenium; Onxy; Novartis; Keryx: Consultancy. Goldschmidt:Amgen, Novartis, Chugai: Research Funding; Janssen-Cilag, Celgene: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Reece:Merck: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding. Leleu:Janssen Cilag, Celgene, Novartis-Amgen, Leo Pharma, Chugai, Roche: Honoraria, Research Funding. Cavo:Millennium: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Jagannath:Merck: Membership on an entity’s Board of Directors or advisory committees; Celgene: Membership on an entity’s Board of Directors or advisory committees; Millennium: Membership on an entity’s Board of Directors or advisory committees. Graef:Merck: Employment. Houp:Merck: Employment. Sun:Merck & Co., Inc.: Employment. Howe:Merck: Employment. Anderson:Celgene: Consultancy; Millennium: Consultancy; Novartis: Consultancy; BMS: Consultancy; Onyx: Consultancy; Merck: Consultancy; Acetylon: .

Hematopoietic Stem Cell Transplantation in Thalassemia Major. Report from the EBMT Hemoglobinopathy Registry

Abstract 905 Background.Hemopoietic allogeneic stem cell transplantation (HSCT) still remains the only available curative option for β-thalassaemia major. At today more than 3000 transplants have been performed worldwide and registered. We analyze transplant activity and outcome after 20 years of the European Hemoglobinopathy Bone Marrow Transplant (EBMT) Registry. Methods.Data have been analyzed from promise MED-A form. Survival data have been reported with the method of Kaplan-Meier in patients with complete survival data. Results.One hundred and 34 centres from 28 different countries reported their data to the registry. Three thousands and 821 (3821) consecutive first HSCT for patients affected by a hemoglobinopathy have been registered. There were only 364 (10.5%) patients aged 18 years or older. Further analyses were restricted to patients with thalassemia major and to transplants performed after January 1st, 2000. In this latter period 1493 transplants have been performed (median age 7.2 years, range 0.3–45.1) with 133 (9.8%) patients aged 18 years or older.During the last decade 70% of the transplants have been performed in Europe and 30% in Asia and Africa with a trend to an increase activity in these countries compared to previous decades.Of the 1493 transplants performed after January 2000, 1061 (71%) have been performed from an HLA identical sibling donors, 129 (8.6%) from a matched other relative, 57 (3.8%) from a mismatched relative, 210 (14%) from an unrelated donor and in 36 (2.4%) cases donor information were missing. Source of stem cells was bone marrow in 1011 patients (67.7%), peripheral blood in 303 patients (20.3%), cord blood in 60 patients (4%), mixed in 82 patients (5.5%). Source of stem cell was missing in 37 (2.5%).In matched sibling donor transplant recipients overall survival (OS) and thalassemia free survival (TFS) plotted at 91 ± 0.01% and 83 ± 0.01%, respectively. Significant differences have been reported in OS and TFS when related to different age groups as reported in Table 1 (P < 0.001). Conclusion.This analysis confirms allogeneic transplantation is a worldwide diffuse high success curative procedure for β-thalassaemia major. Bone marrow still remains the principal source of stem cells. The large majority of transplants have been performed from a matched sibling donor with a marginal role of other donors. In addition these data demonstrate the trend to not transplant adult patients. In the univariate analyses 14 years old appears as threshold age for best transplant strategy.Table 1:overall survival and thalassemia free survival in 1493 consecutive transplants performed from an HLA identical sibling donor after Jan 1st, 2000 in β- thalassemia patients stratified by age (P <0.001).PatientsOverall SurvivalThalassemia Free Survival<= 2 years960.94 ± 0.030.90 ± 0.032–5 years3880.92 ± 0.020.82 ± 0.025–10 years4730.88 ± 0.020.81 ± 0.0210–14 years2480.94 ± 0.020.83 ± 0.0314–18 years1540.78 ± 0.040.70 ± 0.04> 18 years1330.77 ± 0.040.74 ± 0.04 Disclosures:No relevant conflicts of interest to declare.

Long-Term Experience with Allogeneic Bone Marrow Transplant (BMT) in Chronic Myeloid Leukemia

Abstract 4582 Introduction:Introduction of imatinib mesylate has changed the approach towards bone marrow transplantation in Chronic Myeloid Leukemia (CML). Historically considered as a curative therapeutic option, with a probability of disease free survival ranging from 40 to 60%. Its indicated use has been restricted to patients with treatment failure to prior tyrosin-kinase inhibitors or blast crisis. Objective:To assess the outcome of patients with CML who undergo BMT Materials and methods:66 patients who underwent allogeneic BMT between the years 1994 and 2011 in two health care facilities were analyzed. 63 (93%) were performed between 1994 and 2005. At the time of transplantation, patient status was: 56 patients in 1st Chronic Phase and 10 in advanced phases. Fourteen patients received Unrelated Donor BMT and 37 had Related Donor BMT. Transplant risk was assessed, based on the European Bone Marrow Transplantation (EBMT) score (sc). The conditioning regimens which were used included: for patients in chronic phase, cyclophosphamide (Cy) and busulfan (Bu) and for patients in accelerated phase etoposide (VP 16) was added to the previous regimen, and for unrelated donors BuCy + ATG or alentuzumab was used. Prophylaxis for Graft vs Host Disease (GVHD) was performed with a two-drug regimen (cyclosporine, methotrexate), with or without methylprednisone. Result:66 patients were recorded (28 female/38 male), with a mean age of 35 years at the time of transplantation (range 8–55). The source of Stem Cell was bone marrow in 60 patients and peripheral blood in 6 patients. 43% of patients developed GVHD: (29 patients) according to clinical criteria established by the European Cooperative Group. Overall Survival (OS) was 50% with a mean follow-up of 48 months. Analyzed according to the EBMT risk score, OS was 64% in the 0–2 score group and 31% in patients with a 3–5 score. Procedure-related mortality was 16%, and the most frequent causes included: hepatic veno-occlusive disease, infections, GVHD, and graft failure. Conclusions:BMT in patients with CML has been substantially reduced since the introduction of tyrosin-kinase inhibitors. In our experience, this shows its healing potential with an extended follow-up and a prolonged survival. Disclosures:No relevant conflicts of interest to declare.

Vantage 088: Vorinostat in Combination with Bortezomib in Patients with Relapsed/Refractory Multiple Myeloma: Results of a Global, Randomized Phase 3 Trial

Abstract 811 Introduction:Vorinostat (VOR), an oral inhibitor of histone deacetylase class I and class II proteins, regulates genes and proteins involved in tumor growth and survival. The synergistic effects of VOR and bortezomib (BTZ) have been shown in preclinical studies and were confirmed in independent phase 1 trials in patients with relapsed/refractory multiple myeloma (MM), producing objective response rates (ORRs) of up to 42% and overall clinical benefit of up to 90%. Materials and methods:Eligible patients were aged ≥ 18 years, had measurable secretory MM, had received 1 to 3 prior systemic anti-myeloma regimens, and had an Eastern Cooperative Oncology Group status ≤ 2. Previous exposure to BTZ and the presence of extracellular plasmacytoma were allowed per protocol, but patients with prior resistance to BTZ were excluded. Patients were randomized 1:1 to receive 21-day cycles of BTZ (1.3 mg/m2 intravenously; days 1, 4, 8, and 11) in combination with oral VOR 400 mg/d, or matching placebo, on days 1 to 14. Additional use of corticosteroids for the treatment of MM was not allowed during the trial. Patients were treated until disease progression, unacceptable toxicities, or withdrawal from the study. The primary endpoint for this trial was progression-free survival (PFS; occurrence of 412 PFS events). Secondary and exploratory endpoints included ORR (≥ partial response), clinical benefit response (ORR + minimal response), overall survival, time to progression, patient-reported outcomes questionnaires (QLQ-C30, QLQ-MY20), and safety/tolerability of this novel drug combination. Responses and progression were determined according to the European Bone and Marrow Transplantation Group criteria and will be confirmed by an Independent Adjudication Committee. Results:Between January 2009 and January 2011, 637 patients were enrolled from 174 centers in 33 countries across the globe making this trial one of the largest studies conducted in patients with relapsed/refractory myeloma. Median age of the study population was 62 years (range, 29–86 years). Of the enrolled patients, 59% were male and 56% were Caucasian. Patients had received a median of 2 prior regimens (range, 1–3). Prior anti-myeloma agents included BTZ (24%), thalidomide (56%), lenalidomide (13%), melphalan (56%), and stem cell transplantation (35%). As of July 2011, 635 patients had received study medication, with a median exposure of 7 cycles (mean: 7.6 cycles; range 1–30 cycles). Reported median exposure to BTZ monotherapy in previous phase 3 trials was approximately 5 cycles. Conclusions:The study passed the protocol-specified futility analyses by the independent data monitoring committee in November 2010. Database lock is anticipated in November 2011, and top-line data on primary and secondary endpoints will be available at the meeting. Disclosures:Dimopoulos:Celgene, Ortho-Biotech: Consultancy, Honoraria. Off Label Use: Vorinostat, an inhibitor of histone deacetylase, is approved in the US for the treatment of cutaneous manifestations in patients with cutaneous T cell lymphoma (CTCL) who have progressive, persistent or recurrent disease on or following two systemic therapies. Vorinostat is currently under investigation for the treatment of relapsed malignant pleural mesothelioma, relapsed/refractory B cell lymphoma (in combination with other chemotherapy agents), and relapsed/refractory multiple myeloma (in combination with bortezomib and other chemotherapy agents). Jagannath:Merck: Membership on an entity’s Board of Directors or advisory committees; Celgene: Membership on an entity’s Board of Directors or advisory committees; Millennium: Membership on an entity’s Board of Directors or advisory committees. Yoon:Celgene: Consultancy; NK Bio: Consultancy. Siegel:Millennium: Honoraria, Research Funding, Speakers Bureau; Merck: Honoraria. Lonial:Millennium: Consultancy; Celgene: Consultancy; Novartis: Consultancy; BMS: Consultancy; Onyx: Consultancy; Merck: Consultancy. Hajek:Celgene: Honoraria; Janssen: Honoraria; Merck: Educational lecture. Facon:Janssen: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Merck: Membership on an entity’s Board of Directors or advisory committees. Rosiñol:Celgene: Honoraria; Janssen-Cilag: Honoraria. Blacklock:New Zealand Bone Marrow Donor Registry: Consultancy, Employment; Mercy Hospital, Auckland New Zealand: Consultancy; Leukaemia and Blood Foundation, New Zealand: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Middlemore Hospital: Employment, Research Funding. Goldschmidt:Amgen, Novartis, Chugai: Research Funding; Janssen-Cilag, Celgene: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Palumbo:Merck: Honoraria; Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Amgen: Honoraria; Janssen-Cilag: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Reece:Merck: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding. Graef:Merck: Employment. Houp:Merck Research Laboratories: Employment. Sun:Merck & Co., Inc.: Employment. Eid:Merck Research Laboratories: Employment. Anderson:Celgene: Consultancy; Millennium: Consultancy; Novartis: Consultancy; BMS: Consultancy; Onyx: Consultancy; Merck: Consultancy; Acetylon: founder.

Benefit from autologous stem cell transplantation in primary refractory myeloma? Different outcomes in progressive versus stable disease

Several studies of autologous stem cell transplantation in primary refractory myeloma have produced encouraging results. However, the outcome of primary refractory patients with stable disease has not been analyzed separately from the outcome of patients with progressive disease. In the Spanish Myeloma Group 2000 trial, 80 patients with primary refractory myeloma (49 with stable disease and 31 with progressive disease), i.e. who were refractory to initial chemotherapy, were scheduled for tandem transplants (double autologous transplant or a single autologous transplant followed by an allogeneic transplant). Patients with primary refractory disease included those who never achieved a minimal response (≥ 25% M-protein decrease) or better. Responses were assessed using the European Bone Marrow Transplant criteria. There were no significant differences in the rates of partial response or better between patients with stable or progressive disease. However, 38% of the patients with stable disease at the time of transplantation remained in a stable condition or achieved a minimal response after transplantation versus 7% in the group with progressive disease (P=0.0017) and the rate of early progression after transplantation was significantly higher among the group with progressive disease at the time of transplantation (22% versus 2%; P=0.0043). After a median follow-up of 6.6 years, the median survival after first transplant of the whole series was 2.3 years. Progression-free and overall survival from the first transplant were shorter in patients with progressive disease (0.6 versus 2.3 years, P=0.00004 and 1.1 versus 6 years, P=0.00002, respectively). Our results show that patients with progressive refractory myeloma do not benefit from autologous transplantation, while patients with stable disease have an outcome comparable to those with chemosensitive disease.

European Bone Marrow Working Group trial on reproducibility of World Health Organization criteria to discriminate essential thrombocythemia from prefibrotic primary myelofibrosis

The World Health Organization classification of myeloproliferative neoplasms discriminates between essential thrombocythemia and the prefibrotic phase of primary myelofibrosis. This discrimination is clinically relevant because essential thrombocythemia is associated with a favorable prognosis whereas patients with primary myelofibrosis have a higher risk of progression to myelofibrosis or blast crisis. To assess the reproducibility of the classification, six hematopathologists from five European countries re-classified 102 non-fibrotic bone marrow trephines, obtained because of sustained thrombocytosis. Consensus on histological classification defined as at least four identical diagnoses occurred for 63% of the samples. Inter-observer agreement showed low to moderate kappa values (0.28 to 0.57, average 0.41). The percentage of unclassifiable myeloproliferative neoplasms rose from 2% to 23% when minor criteria for primary myelofibrosis were taken into account. In contrast, the frequency of primary myelofibrosis dropped from 23% to 7%, indicating that the majority of patients with a histological diagnosis of primary myelofibrosis did not fulfill the complete criteria for this disease. Thus, over 50% of cases in this series either could not be reproducibly classified or fell into the category of unclassifiable myeloproliferative neoplasms. World Health Organization criteria for discrimination of essential thrombocythemia from prefibrotic primary myelofibrosis are poorly to only moderately reproducible and lead to a higher proportion of non-classifiable myeloproliferative neoplasms than histology alone.

Competing risks regression for clustered data

A population average regression model is proposed to assess the marginal effects of covariates on the cumulative incidence function when there is dependence across individuals within a cluster in the competing risks setting. This method extends the Fine-Gray proportional hazards model for the subdistribution to situations, where individuals within a cluster may be correlated due to unobserved shared factors. Estimators of the regression parameters in the marginal model are developed under an independence working assumption where the correlation across individuals within a cluster is completely unspecified. The estimators are consistent and asymptotically normal, and variance estimation may be achieved without specifying the form of the dependence across individuals. A simulation study evidences that the inferential procedures perform well with realistic sample sizes. The practical utility of the methods is illustrated with data from the European Bone Marrow Transplant Registry.

High-Dose Therapy and Autologous Stem Cell Transplantation in First Relapse for Diffuse Large B Cell Lymphoma in the Rituximab Era: An Analysis Based on Data from the European Blood and Marrow Transplantation Registry

Autologous stem cell transplantation (ASCT) consolidation remains the treatment of choice for patients with relapsed diffuse large B cell lymphoma. The impact of rituximab combined with chemotherapy in either first- or second-line therapy on the ultimate results of ASCT remains to be determined, however. This study was designed to evaluate the benefit of ASCT in patients achieving a second complete remission after salvage chemotherapy by retrospectively comparing the disease-free survival (DFS) after ASCT for each patient with the duration of the first complete remission (CR1). Between 1990 and 2005, a total of 470 patients who had undergone ASCT and reported to the European Blood and Bone Transplantation Registry with Medical Essential Data Form B information were evaluated. Of these 470 patients, 351 (74%) had not received rituximab before ASCT, and 119 (25%) had received rituximab before ASCT. The median duration of CR1 was 11 months. The median time from diagnosis to ASCT was 24 months. The BEAM protocol was the most frequently used conditioning regimen (67%). After ASCT, the 5-year overall survival was 63% (95% confidence interval, 58%-67%) and 5-year DFS was 48% (95% confidence interval, 43%-53%) for the entire patient population. Statistical analysis showed a significant increase in DFS after ASCT compared with duration of CR1 (median, 51 months versus 11 months; P < .001). This difference was also highly significant for patients with previous exposure to rituximab (median, 10 months versus not reached; P < .001) and for patients who had experienced relapse before 1 year (median, 6 months versus 47 months; P < .001). Our data indicate that ASCT can significantly increase DFS compared with the duration of CR1 in relapsed diffuse large B cell lymphoma and can alter the disease course even in patients with high-risk disease previously treated with rituximab.

Workshop Report on the European Bone Sarcoma Networking Meeting: Integration of Clinical Trials with Tumor Biology

A key workshop was held in The Netherlands in June 2011, hosted by several European bone sarcoma networks and with a broad range of stakeholders from Europe and Australia. The purpose of the meeting was to identify the strengths and weaknesses in current clinical trials for bone sarcomas and to make recommendations as to how to accelerate progress in this field. Two areas of particular interest were discussed. First, all participants agreed upon the importance of tumor biology to understanding clinical responses for all types of bone sarcoma. Various barriers to biobanking tumor and germline specimens were canvassed and are outlined in this paper. Second, there was consideration of the particular challenges of dealing with adolescent and young adult cancers, exemplified by bone sarcomas. Participants recommended greater engagement of both pediatric and adult sarcoma trial organizations to address this issue. Specific opportunities were identified to develop biological sub-studies within osteosarcoma, focused on understanding germ line risk and pharmacogenomics defining toxicity and biological responses. In Ewing sarcoma, it was harder to define opportunities for biological insights. There was agreement that the results for insulin-like growth factor pathway inhibition in Ewing family tumors were disappointing, but represented a clear indication of the need for companion biologic studies to develop predictive biomarkers. The meeting ended with broad commitment to working together to make progress in this rare but important subgroup of cancers.

SP1-57 European bone tumour outcome study (EBTOS): overview of health related quality of life (QOL) in study cohort

IntroductionSurvivors of bone tumours diagnosed in childhood or early adulthood are reported to have more impairment of health related QOL than most other cancer survivor groups. Reports of the relationship...

Abnormal protein bands in patients with multiple myeloma after haematopoietic stem cell transplantation: does it have a prognostic significance?

Abnormal protein bands (APB) unrelated to the original monoclonal protein occasionally appear in serum immunofixation samples from patients with multiple myeloma (MM) following haematopoietic stem cell transplantation (HCT). To investigate the significance of APB, medical records and serum immunofixation patterns of 53 MM patients, who had undergone HCT (49 autologous and 4 allogeneic) at the stem cell transplantation unit of Gazi University Faculty of Medicine, were reviewed. Patients were staged according to Durie-Salmon and International staging systems (ISS) and disease response was determined according to European Bone Marrow Transplantation (EBMT) criteria. Fourteen (26.4%) of the 53 patients developed APBs after HCT. The median time for the appearance and duration of APB was 3 (range 1-24) and 5.5 (range 1.5-14) months, respectively. Probability of overall survival (OS) at the end of the follow-up was 77 and 61.4% in patients with and without APB, respectively (p = 0.334). The median duration of follow-up (767 days (range, 220-2905) vs. 726 days (range, 120-1780) p = 0.545) was not different in patients with and without APB. Probability of progression free survival (PFS) at the end of follow-up was 28.8% in patients with and 27.7% in patients without APB (p = 0.835). PFS (910 days (range 180-2905) vs. 730 days (range 90-1765) p = 0.835) was longer in patients with APB, though without statistical significance. Thus, the occurrence of APB post-transplantation is not associated with any adverse long-term consequences and does not require treatment modification.

Vorinostat Combined with Bortezomib In Patients with Relapsed or Relapsed and Refractory Multiple Myeloma: Update on the Vantage Study Program

AbstractAbstract 1952 Background:Initial clinical response rates have improved significantly with current treatments for multiple myeloma (MM). However, most patients eventually relapse or become refractory to approved agents, prompting the development of additional targeted agents and combination regimens. Vorinostat is a first-in-class oral histone deacetylase inhibitor that regulates the expression of genes and proteins involved in tumor growth and survival, and is approved in the United States for the treatment of patients with advanced cutaneous T-cell lymphoma in whom prior therapies have failed. Bortezomib, a reversible proteasome inhibitor, is approved for the treatment of patients with MM who have received at least 1 prior therapy. The synergistic effects of vorinostat and bortezomib have been shown in preclinical studies and confirmed in Phase I trials in patients with relapsed/refractory (RR) MM, producing objective response rates (ORRs; partial response or better) of up to 42% in all patients (including those with bortezomib-refractory disease) and overall clinical benefit of up to 90%. Methods:Vantage 088 is a global, Phase III, randomized, double-blind study to investigate the safety and efficacy of vorinostat vs placebo in combination with bortezomib in patients with relapsed MM and progressive disease after 1–3 prior antimyeloma regimens. The primary objective is to determine the duration of progression-free survival, with a planned enrollment of 742 patients. Overall survival, time to progression, ORR, tolerability, and patient-reported outcomes (PROs) will be included as secondary and exploratory outcomes. A distinctive aspect of this study design involves the evaluation of PROs using validated instruments, including quality-of-life (QoL) questionnaires for cancer patients (EORTC QLQ-C30) and myeloma patients (EORTC QLQ-MY20) and the EuroQoL-5D, presenting an opportunity to correlate PROs with efficacy and safety data. Interim analysis will take place when at least 126 events have occurred. Vantage 095 is a Phase IIB open-label study to investigate the efficacy and tolerability of vorinostat combined with bortezomib in patients with RR MM who had received ≥2 prior antimyeloma regimens; were refractory to bortezomib; and were relapsed, refractory to, intolerant of, or ineligible for other MM therapies, including immunomodulatory drugs (IMiDs). The primary objective is to determine the ORR, with a planned enrollment of 142 patients.In both studies, patients receive 21-day cycles of intravenous bortezomib (1.3 mg/m2; days 1, 4, 8, and 11) combined with oral vorinostat 400 mg (or matching placebo in Vantage 088) once daily on days 1–14. Efficacy is assessed using European Bone and Marrow Transplantation Group criteria. Adverse events (AEs; including clinical and laboratory events) are assessed and recorded using the National Cancer Institute Common Terminology Criteria for Adverse Events (version 3.0). Results:Vantage 088: As of June 11, 2010, 349 patients (range, 1–17 cycles) were randomized. Patients received a median of 2 prior regimens (range, 1–3 regimens; 25% prior bortezomib, 48% prior thalidomide, and 12% prior lenalidomide).Vantage 095: As of June 11, 2010, 108 patients were enrolled. Patients (median age, 62 y; 57% men; 67% with Eastern Cooperative Oncology Group performance status 1) were heavily pretreated (median prior regimens, 5 [range, 2–17]). Interim efficacy data were reviewed in January 2010 by an independent data monitoring committee (DMC) for the first 43 patients enrolled; the futility threshold was passed, and final results are expected to be available 2Q2011. Conclusion:2 ongoing global, multicenter, investigational trials are evaluating the efficacy and safety of combined vorinostat and bortezomib in patients with RR MM and are rapidly accruing patients. The Vantage 088 trial has passed the initial safety evaluations by the DMC, while interim results from Vantage 095 suggest that combined vorinostat and bortezomib may have clinical activity in patients with RR MM who are refractory to bortezomib and IMiDs and ineligible for other regimens. Disclosures:Siegel:Celgene and Millennium: Advisory Board, Speakers Bureau; Merck: Advisory Board, Consultancy. Off Label Use: Vorinostat Combined with Bortezomib for treatment in Multiple Myeloma. Jagannath:Celgene: Honoraria; Millenium: Honoraria; Ortho Biotech: Honoraria; Onyx Pharma: Honoraria; Merck: Honoraria; Proteolix: Honoraria; Imedex: Speakers Bureau; Medicom World Wide: Speakers Bureau; Optum Health Education: Speakers Bureau; PER Group: Speakers Bureau. Hajek:Janssen-Cilag: Honoraria; Celgene: Honoraria; Merck, Sharp, and Dohme: Honoraria. Dimopoulos:MSD: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ortho Biotech: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lonial:Millennium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Onyx: Consultancy, Research Funding. Graef:Merck Research Laboratories: Employment. Pietrangelo:Merck Research Laboratories: Employment. Lupinacci:Merck Research Laboratories: Employment. Reiser:Merck Research Laboratories: Employment. Anderson:Millennium Pharmaceuticals: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Onyx: Consultancy; Merck: Consultancy; BMS: Consultancy; Acetylon: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.