Part Of Front-line Therapy Research Articles

Allogeneic stem cell transplantation as part of front line therapy for Mantle cell lymphoma.

Mantle cell lymphoma (MCL) is an aggressive form of non-Hodgkin lymphoma that remains incurable for the majority of patients. Allogeneic stem cell transplantation (alloSCT) produces long-term disease-free remissions for around 30-40% patients, however it is reserved for the treatment of relapsed disease. This study examined the use of front line transplantation for young patients in an attempt to improve outcomes. Twenty-five patients received an alloSCT using BEAM [BCNU (carmustine), etoposide, cytarabine, melphalan)-Campath conditioning following permissive induction therapy from both related and unrelated donors. This was a multi-centre prospective trial. Twenty-four of 25 patients engrafted with no non-relapse mortality events by day 100. With a median follow-up of 60·5months, there have been six deaths (3 from MCL). The progression-free survival (PFS) and overall survival were 68% and 80% at 2years and 56% and 76% at 5years. PFS was very similar for both sibling and unrelated transplants and there was no difference in PFS between patients with respect to remission status prior to transplantation. Nine (38%) patients experienced acute graft-versus-host disease (GVHD) and 14 (58%) experienced chronic GVHD, of which 8 were extensive. Front line alloSCT is feasible but should only be considered for patients at high risk of early progression following conventional therapy.

Managing Tumor Lysis Syndrome in the Era of Novel Cancer Therapies

Abstract Tumor lysis syndrome (TLS) is a potentially life-threatening emergency that can develop rapidly after the release of intracellular contents from lysed malignant cells. The advent of novel and targeted therapies that have improved tumor-killing efficacy has the potential to increase the risk of TLS when used as part of front-line therapy. A recent review of TLS risk in patients with hematologic malignancies treated with newer targeted agents highlighted the need to revisit TLS risk stratification and to describe the practical challenges of TLS prevention, treatment, and monitoring. Although this era of rapid development of novel cancer therapies provides new hope for patients with hematologic malignancies, it is essential to be prepared for TLS because monitoring and prophylaxis can almost always prevent severe and life-threatening consequences. Heightened awareness of the development of TLS with novel and targeted agents, accompanied by aggressive hydration and rational, risk-appropriate management, are the keys to successful outcomes.

Efficacy of Novel Agents on Soft-tissue Plasmacytomas in Patients with Relapsed Multiple Myeloma

Introduction: the frequency of soft-tissue plasmacytomas (EMPs) is high in patients with relapsed multiple myeloma (MM). There are two types of plasmacytomas: 1) paraskeletal: originating from focal bone involvement (vertebrae, ribs, sternum, skull) and 2) extramedullary: originating from hematogenous spread (skin, liver, CNS). The reported incidence in relapsed patients is 3-34% for paraskeletal and 3-10% for extramedullary plasmacytomas. The presence of soft-tissue masses is associated with poor prognosis and the efficacy of novel agents is not well established. There are some reports about the lack of efficacy of thalidomide (Blade et al, Br J Haematol 2001; 113: 422-24) while some efficacy has been reported with bortezomib (Rosinol et al, Eur J Haematol 2006;76:405-08) and pomalidomide (Detweiler et al, Leukemia 2011, 25; 906-908). Aim: to analyze the effectiveness of novel drugs (thalidomide, bortezomib, lenalidomide, pomalidomide, carfilzomib) in patients with relapsed MM and EMPs. Patients and Methods: patients with EMPs (paraskeletal or extramedullary) at the time of first or subsequent relapses from our database from Hospital Clinic of Barcelona who were treated with novel agents were analyzed. Only patients receiving the novel drugs in monotherapy or in combination with corticosteroids were included in the analysis. Patients receiving combination therapy including two novel drugs (i.e. VTD, VRD) were excluded. Results: 29 patients (median age 61, M 17/F 12) with relapsed myeloma and EMPs were treated with bortezomib. The median number of previous therapies was one. 22 patients had paraskeletal and 7 extramedullary plasmacytomas. The median number of cycles received was 4. The serological response rate was: 4% CR, 27% PR, 7% MR, 24% SD, 17% PD, 7% early death, 14% non evaluable. The response of the plasmacytomas were: 14% CR, 17% PR, 10% SD, 41% PD, 4% early death, 14% non evaluable. The median PFS from the initiation of bortezomib was 3.9 months. Sixteen patients (median age 49 years, M 6/F 10) were treated with lenalidomide. 13 patients had paraskeletal and 3 extramedullary plasmacytomas. The median number of previous therapies was two. The median number of cycles was 5.5. Serological response was: 38% PR, 12% MR, 19% SD, 19% PD, 12% non evaluable. The plasmacytoma response was: 25% PR, 19% SD, 44% PD, 12% non evaluable. The median PFS from initiantion of lenalidomide was 8.4 months. Nine patients (median age 61 years, 3M/6F) were treated with pomalidomide at relapse. The median number of previous therapies was 4. Two patients had paraskeletal and 7 extramedullary plasmacytomas. The median number of cycles was 2. Serological response rate was: 44% PR, 11% SD, 23% PD, 11% non evaluable. However, none of the patients showed response of the plasmacytomas (11% SD, 77% PD, 11% early death). The median PFS was 1.3 months. 8 patients (median age 49 years, 6M/2F) were treated with thalidomide at relapse. The median number of previous therapies was one. Six patients had paraskeletal and 2 extramedullary plasmacytomas. The median number of cycles of thalidomide received was one. None of the patients showed serological response (25% stable disease (SD), 50% progressive disease (PD), 25% early death) or reduction in the size of the plasmacytomas (50% SD, 50% PD). The median progressive free survival (PFS) from initiation of treatment with thalidomide was 1.6 months. Four patients (median age 62, 2M, 2F) were treated with carfilzomib. The median number of previous therapies was 3. The EMPs type was paraskeletal (1) and extramedullary (3). The median number of cycles administered was one. None patient responded to carfilzomib: serological response rate: 75% SD, 25% PD; plasmacytomas response: 100% PD. The median PFS was 0.7 months. The median survival in the overall series of patients with soft tissues masses at relapse treated with novel agents was 15.2 months. Conclusions: The efficacy of novel drugs in the treatment of EMPs is limited, being the most effective bortezomib and lenalidomide. None of the patients treated with thalidomide, pomalidomide or carfilzomib showed any response of the soft-tissue involvement (paraskeletal or extramedullary). Finally, the presence of plasmacytomas at relapse is associated with poor OS even in the era of novel agents. However, the efficacy of these novel agents as part of front-line therapy is unknown. Disclosures No relevant conflicts of interest to declare.

Efficacy of Novel Agents on Soft-Tissue Plasmacytomas in Patients with Relapsed Multiple Myeloma

Introduction: the frequency of soft-tissue plasmacytomas (EMPs) is high in patients with relapsed multiple myeloma (MM). There are two types of plasmacytomas: 1) paraskeletal: originating from focal bone involvement (vertebrae, ribs, sternum, skull) and 2) extramedullary: originating from hematogenous spread (skin, liver, CNS). The reported incidence in relapsed patients is 3-34% for paraskeletal and 3-10% for extramedullary plasmacytomas. The presence of soft-tissue masses is associated with poor prognosis and the efficacy of novel agents is not well established. There are some reports about the lack of efficacy of thalidomide (Bladé et al, Br J Haematol 2001; 113: 422-24) while some efficacy has been reported with bortezomib (Rosiñol et al, Eur J Haematol 2006;76:405-08) and pomalidomide (Detweiler et al, Leukemia 2011, 25; 906-908).Aim: to analyze the effectiveness of novel drugs (thalidomide, bortezomib, lenalidomide, pomalidomide, carfilzomib) in patients with relapsed MM and EMPs.Patients and Methods: patients with EMPs (paraskeletal or extramedullary) at the time of first or subsequent relapses from our database from Hospital Clínic of Barcelona who were treated with novel agents were analyzed. Only patients receiving the novel drugs in monotherapy or in combination with corticosteroids were included in the analysis. Patients receiving combination therapy including two novel drugs (i.e. VTD, VRD) were excluded.Results: 29 patients (median age 61, M 17/F 12) with relapsed myeloma and EMPs were treated with bortezomib. The median number of previous therapies was one. 22 patients had paraskeletal and 7 extramedullary plasmacytomas. The median number of cycles received was 4. The serological response rate was: 4% CR, 27% PR, 7% MR, 24% SD, 17% PD, 7% early death, 14% non evaluable. The response of the plasmacytomas were: 14% CR, 17% PR, 10% SD, 41% PD, 4% early death, 14% non evaluable. The median PFS from the initiation of bortezomib was 3.9 months. Sixteen patients (median age 49 years, M 6/F 10) were treated with lenalidomide. 13 patients had paraskeletal and 3 extramedullary plasmacytomas. The median number of previous therapies was two. The median number of cycles was 5.5. Serological response was: 38% PR, 12% MR, 19% SD, 19% PD, 12% non evaluable. The plasmacytoma response was: 25% PR, 19% SD, 44% PD, 12% non evaluable. The median PFS from initiantion of lenalidomide was 8.4 months. Nine patients (median age 61 years, 3M/6F) were treated with pomalidomide at relapse. The median number of previous therapies was 4. Two patients had paraskeletal and 7 extramedullary plasmacytomas. The median number of cycles was 2. Serological response rate was: 44% PR, 11% SD, 23% PD, 11% non evaluable. However, none of the patients showed response of the plasmacytomas (11% SD, 77% PD, 11% early death). The median PFS was 1.3 months. 8 patients (median age 49 years, 6M/2F) were treated with thalidomide at relapse. The median number of previous therapies was one. Six patients had paraskeletal and 2 extramedullary plasmacytomas. The median number of cycles of thalidomide received was one. None of the patients showed serological response (25% stable disease (SD), 50% progressive disease (PD), 25% early death) or reduction in the size of the plasmacytomas (50% SD, 50% PD). The median progressive free survival (PFS) from initiation of treatment with thalidomide was 1.6 months.Four patients (median age 62, 2M, 2F) were treated with carfilzomib. The median number of previous therapies was 3. The EMPs type was paraskeletal (1) and extramedullary (3). The median number of cycles administered was one. None patient responded to carfilzomib: serological response rate: 75% SD, 25% PD; plasmacytomas response: 100% PD. The median PFS was 0.7 months. The median survival in the overall series of patients with soft tissues masses at relapse treated with novel agents was 15.2 months.Conclusions: The efficacy of novel drugs in the treatment of EMPs is limited, being the most effective bortezomib and lenalidomide. None of the patients treated with thalidomide, pomalidomide or carfilzomib showed any response of the soft-tissue involvement (paraskeletal or extramedullary). Finally, the presence of plasmacytomas at relapse is associated with poor OS even in the era of novel agents. However, the efficacy of these novel agents as part of front-line therapy is unknown. DisclosuresNo relevant conflicts of interest to declare.

Treatment Patterns and Outcomes Among Patients Who Initiate Therapy for Relapsed/Refractory Multiple Myeloma (RRMM) in Routine Care

BackgroundMultiple myeloma (MM) is the second most common hematologic cancer in adults. Novel agents, including thalidomide, bortezomib, and lenalidomide, have led to improved overall survival (OS) in MM, but the disease remains generally incurable with the majority of patients inevitably relapsing after front-line therapy (FLT). In a multi-center observational analysis of 383 MM patients (treated between 2007 and 2010), median progression-free survival (PFS) and OS from treatment after first relapse were 13 and 35 mos (Durie ASCO 2012; abs 8095). According to NCCN guidelines, retreatment with primary therapy may be considered if relapse occurs more than 6 mos after discontinuation of primary therapy, otherwise a switch in regimen is recommended (NCCN MM Guidelines v.4 2015). Treatment patterns and outcomes in RRMM remain to be elucidated. We examined treatment use, retreatment and therapy switch patterns, and outcomes among patients with RRMM initiating second-line therapy (SLT).MethodsWe conducted a retrospective cohort study using a large, national, US claims database. Adult patients with MM who initiated cancer-specific systemic therapy between Jan 2008 and Feb 2014, without evidence of transplantation, were identified. Newly diagnosed MM patients were followed from the first claim for MM. Continuous enrollment in the health plan for 12 mos pre-diagnosis (with no claim for MM) through at least the start of SLT was required. FLT began with the first claim for MM-directed systemic cancer therapy. Unique agents administered within 90 days of FLT initiation constituted a regimen. Continuation of FLT regimen (or part thereof) or monotherapy within 3 mos of the end of the initial regimen was considered part of FLT. SLT after first relapse for RRMM was identified accordingly: 1) a treatment gap >6 mos between end of FLT and start of a second regimen (retreatment or switch), 2) start of a follow up regimen (retreatment) with a treatment gap of >3 and up to 6 mos after end of FLT, or 3) a switch to another drug combination after FLT regimen. Analyses were conducted from the first claim for SLT. SLT ended at the earliest of start of a new drug, death, or end of study period (Feb 2014). MM drug combinations were based on all unique MM systemic therapy agents received within start and end date for SLT. Vital status information was ascertained from the Social Security Death Index.ResultsWe identified 249 patients with RRMM receiving SLT. Approximately half (49%) were male; 29% and 43% were aged 65-74 and 75 years or older, respectively. SLT regimens were: lenalidomide±dexamethasone (R±d, n=70 [28%]), bortezomib±d (V±d 61 [25%]), other (58 [23%], see Table 1), V+other (25 [10%]), R+other (14 [6%]), V-cyclophosphamide±d (VC±d, 13 [5%]), and VR±d (8 [3%]). The switch and retreatment patterns from FLT to SLT are depicted in Table 1. Among patients with treatment-free interval (TFI, time from end of FLT to start of SLT) >6 mos (n=64) vs ≤6 mos (n=185), 18 (28%) vs 17 (9%) were retreated with the same primary regimen in SLT, respectively. Median duration of SLT was 6.3 (95% CI: 5.6, 6.9) mos (Fig. 1) and of FLT was 6.8 (95% CI: 6.0, 7.8) mos. The 1-year OS probability from initiation of SLT for RRMM was 82% (95% CI: 76%, 86%).ConclusionsAmong patients with RRMM treated in the USA, V- and R-based regimens were the most common at first relapse. The vast majority of patients (91%) with TFI ≤6 mos switched therapy at time of relapse in concordance with NCCN guidelines. The relatively short duration of SLT (median 6.3 mos) in this study compared with PFS from treatment after first relapse (median 13 mos, Durie ASCO 2012; abs 8095) in a cohort of patients with RRMM, suggests that the majority of patients discontinue SLT prior to disease progression. These findings highlight the need for newer SLT regimens that are effective and more sustainable compared with current treatment choices.Table 1Switch and Retreatment Patterns from FLT to SLT among Patients with RRMM. SLTV-basedR-basedVR-basedOtherFLTV-based41 (41%)49 (58%)4 (50%)15 (26%)R-based33 (33%)13 (15%)2 (25%)12 (21%)VR-based9 (9%)6 (7%)2 (25%)19 (33%)Other*16 (16%)16 (19%)0 (0%)12 (21%)Total99 (100%)84 (100%)8 (100%)58 (100%)*Other combinations consisted of a subset of the following agents: cyclophosphamide, melphalan, vincristine, doxorubicin, interferon-alpha, pomalidomide, thalidomide, carfilzomib, dexamethasone, prednisone [Display omitted] DisclosuresRomanus:Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Jhaveri:Sanofi: Equity Ownership; Takeda Pharmaceutical Company Limited: Equity Ownership; Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Labotka:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Henk:Optum (a consulting firm retained by Takeda to conduct the reasearch pertaining to this abstract): Employment. Seal:Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment.

Healthcare Resource Use and Costs Among Patients (pts) with Relapsed/Refractory Multiple Myeloma (RRMM)

BackgroundFew studies have assessed HRU and costs in RRMM. A prior study reported 1-yr total healthcare costs of $113,000 (2013 US $) among non-transplant patients with newly diagnosed MM (DaCosta Byfield ASCO 2015). Real-world data on economic burden in the era of new MM therapeutic options could provide insight for directing efficient resource utilization. We examined HRU and costs associated with second-line therapy (SLT) in RRMM.MethodsWe identified adult pts with MM between Jan 2008 and Feb 2014 in a large, national, healthcare claims database of commercially insured and Medicare Advantage beneficiaries. Newly diagnosed pts were followed from first claim for MM (+12-mo wash out period). Pts with continuous enrollment from 12 mos pre-diagnosis through 12 mos post-initiation of SLT for RRMM were included (including pts who died within 12 mos post SLT start). Those with a claim for transplants were excluded. Front-line therapy (FLT) began with the first claim for MM-directed systemic cancer therapy. Unique agents administered within 90 d of FLT initiation constituted a regimen. Continuation of FLT regimen (or part thereof) or monotherapy within 3 mos of the end of the initial regimen was considered part of FLT. SLT after first relapse for RRMM was identified accordingly: 1) a treatment gap >6 mos between end of FLT and start of a 2nd regimen (retreatment or switch), 2) start of a follow-up regimen (retreatment) with treatment gap >3 and ≤6 mos after end of FLT, or 3) a switch to another drug combination after FLT. The first claim for SLT was the index date. Healthcare costs and HRU were determined for the 1-yr period following SLT start. Healthcare costs were calculated as total reimbursed amount to the provider paid by the health plan, the pt, and other payers, including treatment with subsequent lines of therapy if falling within the 1-yr period. Drug and drug-administration costs were captured from a) all pharmacy claims for MM-directed systemic therapy, and b) medical claims with CPT codes indicating chemotherapy drug administration if, on the same date of service, there was a claim with a HCPCS for any drug of interest.ResultsWe identified 160 of 249 pts receiving SLT. The majority (55%) were female, 72% were aged ≥65 yrs, 10% received triplet SLT, and 53% were enrolled in a Medicare Advantage plan. Most common SLT regimens were bortezomib- (39%) or lenalidomide-based (38%) (Table 1).RRMM pts averaged 58 ambulatory visits and 1.2 hospitalizations in the yr following start of SLT, with 5.1 ICU and 7.9 non-ICU days. Mean 1-yr healthcare costs were $123,922 with 59% of total costs attributable to non-drug costs (mean: $72,718; Table 2).ConclusionsThe healthcare and economic burden of illness among pts with RRMM receiving SLT is substantial. The main cost driver in RRMM was non-drug related. While this research did not examine indirect costs, rates of ambulatory visits and hospitalization days occurring within 1 yr of the start of SLT were high and likely correlated with indirect costs to both the pt and caregiver. New treatment options with a more favorable side-effect and efficacy profile may mitigate this burden. At study completion, a statistical analysis will be conducted to assess the determinants and drivers of economic burden in RRMM.Table 1RRMM pt Characteristics and SLT patternsTotal (N=160)n (%)*Died during 1-yr following start of SLT36 (22.5)Age, yrs<6545 (28.1)65-7445 (28.1)≥7570 (43.8)Male72 (45)Insurance typeCommercial76 (47.5)Medicare Advantage84 (52.5)SLT regimensBortezomib-based62 (38.8)IMiD-based60 (37.5)Bortezomib + IMiD3 (1.9)Other†35 (21.9)Start of a new regimen within 1 yr (3rd line)68 (42.5)*unless otherwise noted †including cyclophosphamide, melphalan, vincristine, doxorubicin, interferon-alpha, pomalidomide, thalidomide, carfilzomib, dexamethasone, prednisone ‡among non-censored ptsTable 2Healthcare costs and encounters among pts with RRMM after initiation of SLT1-yr healthcare costs (2014 US$)Mean (SD)(N=160)Total123,922 (114,052)Drug51,204 (40,997)Non-drug72,718 (102,169)Total123,922 (114,052)During SLT81,590 (90,151)After 3rd Line initiation*33,573 (64,832)SLT end to start of 3rd Line8,759 (28,046)Healthcare encounters per ptAmbulatory visits58.5 (32.6)ER visits1.7 (2.2)Hospitalizations1.2 (1.7)Inpatient length of stay, days13.0 (26.6)Non-ICU7.9 (21)ICU5.1 (12.7)*censored at 12 mos after SLT initiation DisclosuresRomanus:Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Seal:Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Jhaveri:Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment; Takeda Pharmaceutical Company Limited: Equity Ownership; Sanofi: Equity Ownership. Labotka:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Henk:Optum (a consulting firm retained by Takeda to conduct the reasearch pertaining to this abstract): Employment.

Predictors of Second-Line Treatment Choice with Triplet Therapy in Routine Care Among Patients with Relapsed/Refractory Multiple Myeloma (RRMM)

BackgroundBeginning with the IFM 2005-04/MMVAR trial, three-drug combinations (TCs) have demonstrated superior clinical outcomes compared with two-drug regimens among patients with RRMM (Garderet JCO 2012). TCs are emerging as the standard of care at first relapse. We assessed factors that influenced treatment choice with TCs in a cohort of patients with RRMM who were managed in routine care.MethodsWe identified adult patients with MM between January 2008 and February 2014 in a large, national, US healthcare claims database of commercially insured and Medicare Advantage beneficiaries. Newly diagnosed patients were followed from the first claim with an ICD-9 code for MM (with a 12-month wash-out period). To ensure completeness of claim history, patients with continuous enrollment from 12 months pre-diagnosis through at least initiation of second-line therapy (SLT) for RRMM were included. Those with claims for transplants were excluded. Front-line therapy (FLT) began with the first claim for MM-directed systemic cancer therapy. Unique agents administered within 90 days of FLT initiation constituted a regimen. Continuation of FLT regimen (or part thereof) or monotherapy within 3 months of the end of the initial regimen was considered part of FLT. SLT after first relapse for RRMM was identified accordingly: 1) a treatment gap >6 months between end of FLT and start of a second regimen (retreatment or switch), 2) start of a follow-up regimen (retreatment) with a treatment gap of >3 and up to 6 months after end of FLT, or 3) a switch to another drug combination after FLT regimen. The first claim for SLT was the index date. SLT ended at the earliest of: start of a new drug, death, or end of study period (February 2014). Patients were grouped into those receiving one-/two-(1-2) vs three-/four-drug (3+) combinations based on the number of unique cancer therapy agents received within the start and end date of SLT. A logistic multivariable model was used to identify factors independently associated with receipt of 1-2 vs 3+ SLT regimens.ResultsBaseline characteristics among 249 RRMM patients on SLT are shown in Table 1 according to receipt of 1-2 vs 3+ SLT regimens. Among 62 patients who initiated SLT in 2013-14, 14 (23%) received a 3+ SLT regimen (vs 19 (10%) prior to 2013). Adjusting for gender and CRAB symptoms (hypercalcemia, renal insufficiency, anemia, and bone disease), predictors of 3+ SLT included: younger age (<65 years), early relapse (time to next therapy [TTNT], interval from start of FLT to start of SLT, <6 months), 3+ agents in FLT and index year of SLT initiation (in 2013-14). Charlson Comorbidity Index (CCI) was not independently associated with receipt of 3+ SLT.ConclusionsA majority of patients do not receive triplet-based SLT in routine care. Younger age, and not comorbidity status, appears to be the discriminatory patient characteristic for triplet therapy choice. Introduction of triplets with a favorable toxicity profile and assessment for comorbidity status in routine practice represent steps towards optimizing treatment choices in RRMM.Table 1Baseline Characteristics among Patients with RRMM According to SLT Type (N=249)N (%)Monotherapy/Doublet (1-2) (N=216)Triplet/Quadruplet (3+) (N=33)Total (N=249)TTNT<6 months44 (20.4%)14 (42.4%)58 (23.3%)≥6 months172 (79.6%)19 (57.6%)191 (76.7%)Age, years<6553 (24.5%)17 (51.5%)70 (28.1%)65-7464 (29.6%)8 (24.2%)72 (28.9%)≥7599 (45.8%)8 (24.2%)107 (43%)Male105 (48.6%)16 (48.5%)121 (48.6%)CCI060 (27.8%)10 (30.3%)70 (28.1%)152 (24.1%)3 (9.1%)55 (22.1%)2+104 (48.1%)20 (60.6%)124 (49.8%)CRAB symptoms147 (68.1%)26 (78.8%)173 (69.5%)Number of agents in FLT regimen1-2147 (68.1%)12 (36.4%)159 (63.9%)3+69 (31.9%)21 (63.6%)90 (36.1%)Table 2Predictors of 3+ SLT in RRMM (N=249)Odds Ratio (OR) for 3+ vs 1-2 SLT(95% CI for OR)Age, years<65 65-74 ≥753.10 1.36 Reference(1.13 - 8.51)* (0.45 - 4.09) -Male1.13(0.51 - 2.51)Index year2008-2012 ≥2013Reference 3.42- (1.42 - 8.21)**TTNT, months≥6 <6Reference 2.54- (1.05 - 6.17)*CRAB symptoms at baseline1.69(0.63 - 4.58)CCI0 1 2+Reference 0.41 0.98- (0.10 - 1.62) (0.39 - 2.46)Number of agents in FLT regimen1-2 3+Reference 2.77- (1.20 - 6.42)**significant at 5%; **significant at 1% DisclosuresRomanus:Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Jhaveri:Takeda Pharmaceutical Company Limited: Equity Ownership; Sanofi: Equity Ownership; Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Labotka:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Henk:Optum (a consulting firm retained by Takeda to conduct the reasearch pertaining to this abstract): Employment. Seal:Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment.

Gray Zone Lymphoma (GZL) with Features Intermediate Between Classical Hodgkin Lymphoma (cHL) and Diffuse Large B-Cell Lymphoma (DLBCL): Analysis of Tumor Immunophenotype (IP) and Critical Examination of Therapy with Associated Impact on Outcome

Background: The WHO recognizes a category of B-cell lymphoma unclassifiable with features intermediate between DLBCL and cHL, also known as GZL. This is a challenging disease entity to treat due to disease heterogeneity and lack of pathologic or clinical prognostic indicators as well as absence of standard management guidelines for untreated or relapsed/refractory patients (pts).Methods: We performed a multicenter retrospective analysis of newly diagnosed GZL pts treated from 2001-2012 across 19 North American academic centers. Diagnosis was established by institutional expert pathology review. This work is an expansion and update of prior reported data (Evens AM et al, ASH 2013, #847) with 16 cases added to the original report. Additionally, new data were examined including histopathologic and IP analysis and detailed frontline and salvage therapy. Prognostic factors associated with survival on univariate and multivariate Cox regression analyses were examined.Results: Characteristics of 112 GZL pts included: median age 39 years (19-86); M:F 1.8:1; ECOG PS 0-1 87%; B symptoms 40%; anemia 59%; hypoalbuminemia 30%; bulky disease (≥10cm) 24%; non-mediastinal presentation 57%; bone marrow pos 11%; Stage III/IV 52%; IPI 0-2 77%; and IPS 0-2 in 81%. The most prevalent tumor IPs were: 93% CD20+ (100/108), 91% CD30+ (98/108), 78% CD79+ (43/55), 97% Pax5+ (67/69), 97% Oct2+ (27/28), and 94% MUM1+ (32/32). CD15 (44%, 45/101) and CD45 (69%, 48/70) were variable. Only 13% and 24% of pts were CD10+ (4/30) and EBV+ (13/55), respectively. Notably, IP did not differ based on clinical presentation (ie, mediastinal vs non-mediastinal). The most common frontline treatments were R-CHOP n=52, ABVD +/- R n=34, and R-EPOCH n=11. 71% of CD20+ pts were treated with rituximab as part of frontline therapy. At 31-month median follow-up, 2-year PFS and OS for all pts were 40% and 88%, respectively. The only pathologic factor correlating with outcome was CD20 positivity (PFS: HR 0.34, 95% CI 0.16-0.73, P=0.006). Characteristics correlating with PFS were anemia (HR 0.51, 95% CI 0.29-0.91, P=0.022), low albumin (HR 0.57, 95% CI 0.32-1.00, P=0.05), and IPI (continuous: HR 1.48, 95% CI 1.19-1.82, P=0.0003). For therapy, 2-year PFS and OS for R-CHOP were 46% and 84%, respectively; ABVD+/-R 25% and 96%, respectively; and R-EPOCH 68% and 83%, respectively (Fig. 1). R-EPOCH predicted improved PFS (0.047), however this effect was abrogated after controlling for IPI, anemia and hypoalbuminemia (P=0.2). Pts who received rituximab with frontline therapy had improved 2-year PFS (51% vs 19%, respectively, P=0.012). Interestingly, the significance of CD20 persisted on Cox regression controlling for rituximab (rituximab HR 0.55, 95% 0.33-0.93, P=0.025; CD20 0.35, 95% CI 0.16-0.75, P=0.007). Furthermore, the effect of rituximab remained significant after controlling for IPI, anemia, and hypoalbuminemia (HR 0.35, 95% CI 0.18-0.69, P=0.002). Overall, 58% of pts relapsed with median time to relapse of 7 months (0-64); the mean number of salvage therapies was 3. Regimens at 1st relapse included: R-ICE (n=33), R-ESHAP (n=6), R-EPOCH (n=7), ABVD (n=1) and brentuximab vedotin (n=4). Beyond first relapse, the most common treatments were: brentuximab vedotin (n=7) and radiation (n=5). 61% of relapsed pts proceeded to stem cell transplantation (SCT) (38% allogeneic, 62% autologous). 20/27 (74%), 20/32 (63%), and 3/3 (100%) of pts who relapsed after frontline ABVD, R-CHOP and R-EPOCH, respectively, had SCT at relapse. 2-year OS was superior for pts who had SCT (88% vs 67%, P=0.014; Fig. 2), which persisted on multivariable regression (SCT: HR0.14, 95% CI 0.02-0.95, P=0.044; IPI continuous: HR 2.04, 95% CI 1.00-4.16, P=0.05; anemia: HR 2.40, 95% CI 0.32-18.25, P=0.4; low albumin: HR 5.54, 95% CI 1.08-28.44, P=0.04).Conclusions: To the best of our knowledge, this represents the largest series of GZL reported to date. Presence of CD20 appeared to be an independent prognostic factor and treatment with a rituximab-based DLBCL-specific regimen for frontline therapy was associated with the most optimal PFS. In addition, pts who underwent SCT at relapse appeared to have superior OS, however caution should be given to this finding given likely selection bias. Continued examination of this unique lymphoma is warranted. [Display omitted] [Display omitted] DisclosuresBartlett:Seattle Genetics, Inc.: Other, Research Funding; Takeda Pharmaceuticals International Co.: Research Funding; Pfizer: Research Funding; Pharmacyclics: Research Funding; Novartis: Research Funding; MedImmune: Research Funding; Celgene: Research Funding; ImaginAb: Research Funding; Genentech: Research Funding; Janssen: Research Funding; AstraZeneca: Research Funding. Mato:Genentech, Celgene, Millenium: Speakers Bureau. Advani:Seattle Genetics, Inc.: Research Funding, Travel expenses Other; Genentech: Research Funding; Janssen Pharmaceuticals: Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding; Takeda International Pharmaceuticals Co.: Research Funding. Blum:Janssen, Pharmacyclics : Research Funding.

Subcutaneous bortezomib incorporated into the bortezomib-thalidomide-dexamethasone regimen as part of front-line therapy in the context of autologous stem cell transplantation for multiple myeloma

High-dose therapy plus autologous stem cell transplantation (ASCT) is considered the standard of care for the front-line treatment of younger patients with multiple myeloma.[1][1] Response rates to induction therapy prior to ASCT have significantly increased through the use of novel agent-based

Clinical Characteristics, Chromosomal Abnormalities and Outcomes in Very Elderly Patients with Multiple Myeloma: The IFM Experience

AbstractAbstract 204 Background:The incidence of multiple myeloma (MM) considerably increases with age. At least half of all MM patients are older than 70 years of age and 20 to 30% are older than 80 years of age. Furthermore, the number of elderly patients with MM is likely to increase due to the increasing life-expectancy of the general population. Between 2010 and 2030 the accrual annual incidence is expected to be about 50%. Until recently no survival improvment was seen in patients over 75 years. We aimed to describe the clinical and cytogenetic characteristics of this group of patients, and define their clinical outcome. Methods:We selected within the IFM database all patients with symptomatic MM older than 75 years of age with available clinical data, characterized for the most common chromosomal rearrangements, treated between 05/2000 and 10/2010. In terms of survival and chromosomal abnormalities a comparison was performed with 770 patients aged between 65 and 75 years issued from the IFM database during the same period of time. Results:651 patients older than 75 years (75 - 94) centrally analyzed for chromosomal abnormalities, the incidence were 37% for del(13), 8.3% for t(4;14) and 6.1% for del(17p). Incidence of del(13) and t(4;14) were significantly lower than for patients under 65 years (45% and 14.3% respectively) and also for patients between 65 and 75 years (43.6% and 10.9% respectively) (p 0.004 and < 0.0001, ref Avet-Loiseau H. et al, abstract ASH meeting Blood 2011 ). The incidence of del(17p) was stable among age. Treatment modalities and follow-up data were available for 335 patients. The median age was 79 years and 40% were older than 80 years. Isotypes were the following: IgG 59% of patients, IgA in 23% and light chain in 16% of the cases respectively. The median beta 2 microglobulin was 5.2 mg/l (1.6 – 54.1), 45% of patients presented with ISS 3 and 18% of patients had renal impairment at time of diagnosis (creatinine value >160 micromol/L). Frontline therapy consisted of melphalan + prednisone (MP) in 72 patients (21.5 %), MP + thalidomide in 179 patients (53 %), MP + bortezomib in 26 patients (8%), lenalidomide and dexamethasone in 52 patients (15.5 %) and 6 patients (2 %) were treated in a semi-intensive approach including autologous stem cell transplantation. Overall, the median progression free survival (PFS) was 20.5 months (CI 95% 21.1–24.8) and the median overall survival (OS) was 37.6 months (CI 95% 28–46.3). This PFS was not different as compared with patients treated in between 65 and 75 years of age (median 23 months CI 95% 21.1–24.8). Nevertheless, OS was significantly higher in this latter group of patients (median 51 months CI 95% 45.1–59.2, p < 10-4) suggesting better salvage therapies in younger patients and the impact of potential comorbidities. In patients older than 75 years of age, both t(4;14) and del(17p) adversely impact PFS and OS. Conclusion:Our survival results compare very favorably with those recently reported in the same population, with OS usually inferior to 24 months (ref Ludwig H et al., J Clin Oncol, 2010;28:1599–1605). This is attributed to the routine use of novel agents thalidomide, bortezomib, and lenalidomide, as part of frontline therapy, but also at the time of relapse. Treatment strategies should be specifically tailored to very elderly patients to optimize tolerability and efficacy. Disclosures:Hulin:janssen: Honoraria; celgene: Honoraria. Off Label Use: carfilzomib as part of frontline therapy in myeloma. Roussel:celgene: Honoraria; janssen: Honoraria. Kolb:janssen: Honoraria; celgene: Honoraria.

Utilization of EBV DNA Copy Number Monitoring in Extranodal NK Lymphoma, Nasal Type in Non Asian Patients

AbstractAbstract 5088 Introduction.Extranodal NK/T-cell lymphoma, nasal type (ENKL) is a common type of non-Hodgkin's lymphoma (NHL) in Asia and Latin America but is rare in the West. Epstein-Barr Virus (EBV)-encoded RNA (EBER) is detected in most cases of ENKL. Measurement of EBV-DNA copy number (EDCN) in peripheral blood (PB) via polymerase chain reaction (PCR) has been shown in Asian patients to be a useful marker for monitoring tumor burden, response to treatment and disease recurrence (Suzuki, 2011; Ito, 2012), but data in Western patients are lacking. We conducted a pilot, retrospective study of EDCN measurements in Western patients with ENKL, nasal type. Methods.A retrospective review of an IRB-approved patient database identified 13 consecutive patients with ENKL, nasal type, diagnosed between July 1999 and August 2011. Inclusion criteria were based on WHO criteria. Six patients were diagnosed at outside institutions, received initial therapy locally and presented to OSU for evaluation after treatment or at relapse. All pathology specimens were reviewed at OSU. In situ hybridization was used to evaluate EBER expression. PB samples were serially obtained from patients at multiple time points (first visit, longitudinal, last follow up) and analyzed in real time. The Artus™ EBV PCR assay was used for EBV-DNA, extracted from EDTA plasma. 200 uL of patient plasma and 2. 5uL of internal control were processed using the EasyMAG™ sample processor. Quantification of EDCN was done using the EBV TM Master which specifically amplifies a 97bp region of the EBNA-1 gene and the ABI PRISM™ 7500 system. The amplicon was detected by measuring the FAM fluorescence. Quantification of EBV-DNA in the patient’s sample was compared to five known standards supplied by Acrometrix. The standards range from 500 to 10, 000, 000 copies/mL. Outcomes including complete response (CR), partial response (PR) and relapse/progression of disease (PD) were assessed according to the Cheson criteria. Categorical data, such as gender, race, stage of disease at diagnosis, number of treatments received and best response were summarized as frequency counts and percentages. Quantitative data, such as age, LDH, WBC, hemoglobin, platelet, were summarized as medians and ranges. Estimates of progression- free survival and overall survival were obtained using the Kaplan-Meier method. Results.Demographics, pathology, treatment, and outcome data will be provided. For all patients, involved field radiation therapy (IFRT) was part of front line therapy. Figure 1 shows EDCN for 12 evaluable patients. Three patients (1a, 2a, 3a) had elevated EDCN at diagnosis, which normalized with treatment, and remained undetectable at last follow up. All 3 patients achieved CR, 2 patients after initial therapy and 1 patient after allogeneic hematopoietic stem cell transplant (HSCT). Three patients (1b, 2b, 3b) had undetectable EBV-DNA at diagnosis, throughout treatment, and at last follow up. Three patients (1c, 2c, 3c) had no EBV-DNA measurements initially, but all 3 had rapidly increasing EDCN prior to progression and death. Three patients (1d, 2d, 3d), whose disease status and EDCN was documented at multiple time points on long term follow up are analyzed in detail. In patient 1d EBV-DNA was undetectable at diagnosis and at first and second progression, but increased rapidly at third progression and prior to death. Patient 2d had undetectable EBV-DNA at diagnosis, but after front line therapy failure EDCN increased and then closely paralleled clinical response. Following allogeneic HSCT, the EDCN increased rapidly to >10E6 copies/mL, prior to radiographic or clinical evidence of relapse. Patient 3d had elevated EDCN at diagnosis, which normalized with therapy, rose prior to clinically overt first relapse, and normalized again with SMILE chemotherapy. Conclusions.Elevated EDCN was found in the PB of many non Asian patients with ENKL, nasal type at diagnosis and should be studied prospectively as an adjuvant diagnostic marker, particularly in cases where biopsy is inconclusive or delayed. Serial changes in PB EDCN closely paralleled clinical response in many of the patients. EDCN elevation preceded clinical or radiological evidence of active disease in some patients, prompting further diagnostic work up. The value of serial monitoring of EDCN should be studied prospectively and be included in clinical trials of new therapies for ENKL, nasal type in the U. S. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Improved response with post‐ASCT consolidation by low dose thalidomide, cyclophosphamide and dexamethasone as first line treatment for multiple myeloma

The use of consolidation or maintenance to improve disease response, and hence clinical outcome, following autologous stem cell transplantation (ASCT) remains the subject of intense clinical research. We carried out a single-arm study to assess the toxicity and efficacy of a short block of consolidation therapy with cyclophosphamide, low dose thalidomide and dexamethasone (CTD) in patients within 6 months following ASCT, as part of frontline therapy for symptomatic multiple myeloma. Forty-five patients who had not progressed were enrolled on the study, and 43 completed treatment on protocol. This regimen was well tolerated soon after ASCT, with only grade 1/2 toxicity apart from neutropenia, and no long-term sequelae. Importantly, CTD consolidation improved the depth of response in treated patients, increasing the complete/very good partial response rate from 44% at 3 months, to 72% at 12 months, which was significantly higher compared with a historical group of control patients (P = 0·002). There was a trend to longer progression-free survival that favoured the study group. Consolidation therapy did not adversely affect subsequent disease response to salvage therapies at relapse. We conclude that CTD consolidation may be a useful, non-toxic and cost-effective strategy to deepen disease response following ASCT, and deserves further study in a randomized trial.

Upfront thiotepa, busulfan, cyclophosphamide, and autologous stem cell transplantation for primary CNS lymphoma: a single centre experience

Treatment of primary central nervous system lymphoma (PCNSL) with high-dose methotrexate-based chemotherapy and whole-brain radiotherapy (WBRT) is associated with high rates of relapse and severe neurotoxicity. In an attempt to improve upon these poor results, we treated 21 patients with PCNSL aged 34–69 years (median 56) with high-dose thiotepa, busulfan, cyclophosphamide (TBC) and autologous stem cell transplant (ASCT) as part of front-line therapy, without WBRT. Patient characteristics included: Karnofsky performance status (KPS) <70% (n = 17), age >60 years (n = 8), deep brain involvement (n = 16). Treatment-induced neurotoxicity was not observed in any of these patients. Currently, 11 of 21 patients (52%) are alive and progression-free at a median follow-up of 60 (7–125) months post-ASCT. Causes of death included progressive PCNSL (n = 4), progressive systemic lymphoma (n = 1), early treatment-related mortality (TRM, n = 3) and two late deaths from pneumonia 3 years post-ASCT. All patients who died of TRM were over 60 years of age and had poor performance status. In conclusion, TBC/ASCT offers potential long-term progression-free survival without neurotoxicity when used as part of upfront therapy for PCNSL. However, efforts to reduce TRM through improved patient selection and possibly through decreased intensity of the TBC regimen for older or less fit patients are recommended.

Treatment of Molecular and Clinical Relapse of Acute Promyelocytic Leukemia (APL) with Arsenic Trioxide: Results of the European Registry of Relapsed APL

AbstractAbstract 15Arsenic trioxide (ATO) is presently regarded as the best treatment option in relapsed PML-RARA+ acute promyelocytic leukemia (rAPL). However, given the relative rarity of relapses following standard front-line APL therapy, the optimal management of this group of patients remains to be firmly established. For this reason, and in order to ensure homogeneity in patient data collection and gain insights into the epidemiology and clinical aspects of rAPL, a European registry of rAPL was established in 2008 under the auspices of the European LeukemiaNet (ELN). Patients with a genetically confirmed (PML-RARA+) molecular or clinical relapse of APL occurring from January 2003 onwards were eligible for registration using uniform CRFs. Management of relapse was at the discretion of the treating physician, but could be based on the treatment recommendations developed by an expert panel provided on the ELN website (www.leukemia-net.org/content/). By 15 July 2010, 122 cases of rAPL had been registered by participants of 7 European countries (Spain, Italy, UK, France, Germany, Greece, Poland) representing the starting group of this ongoing initiative open for participation. In 80 pts (69 in first, 11 in 2nd and later relapse), information was available on ATO salvage therapy. At time of first diagnosis median age was 43 years (14-77); all pts had received all-trans retinoic acid (ATRA) and anthracyclines ± ara-C as first-line therapy. No patients received ATO as part of front-line therapy. According to Sanz Score, 26% were low risk, 45% intermediate and 29% high risk. 39% of pts had the bcr1/2 and 61% the bcr3 isoform of PML-RARA. Median duration of first remission was 493 days (93d to 5.7 years). The usual dosage of ATO was 0,15mg/kg/day, or regimens with the same cumulative dose were used. ATO induction therapy was combined with ATRA (45 mg/m2/day) in 40% of pts and during the consolidation cycle in 50% of pts, respectively. The median duration of ATO (± ATRA) for induction was 30 days and for consolidation 25 days. CNS relapses were treated with intrathecal application of methotrexate ± ara-C ± hydrocortisone and ATO. Among the 69 pts with first relapse, there were (Group A) 25 molecular and (Group B) 42 hematological relapses (bone marrow), in three pts combined with CNS involvement. Two pts had isolated CNS or extramedullary relapse. Main characteristics of pts at start of induction therapy in Group A vs. B were: median WBC count (x109/L) 4.4 (1.9-6.2) vs. 2.3 (0.5-102) (p=0.015); median platelet count (x109/L) 178 (40-392) vs. 87 (9-273) (p=0.0007); median Hb (g/L) 14 (10.6-15.7) vs. 12 (7.6-14.8) (p=0.0008). In Group A, none of the pts had coagulopathy compared to 8 of 25 (32%) pts with coagulopathy in Group B (p=0.004). In Group A, ATO therapy was not complicated by hyperleukocytosis and no episodes of differentiation syndrome were observed. In Group B, 9 (21%) pts had suspected or manifest differentiation syndrome (p=0.02), and additional chemotherapy was administered in 14 (33%) pts to control hyperleukocytosis. Other toxicities were rare and had no significant influence on therapy. In Group A, the rate of 2nd molecular remission after induction was 52% (13 of 25 pts) and after consolidation therapy 64%. No pt died. In Group B, 39 (88%) pts achieved 2nd CR, 2 (5%) pts were resistant and 3 (7%) pts died early from cerebral bleeding. Second molecular remission was reached in 12 of 32 (38%) pts after induction and in 62% after consolidation. Information on postconsolidation therapy was available in 45 pts of Group A and B. Of these, 14 pts underwent allogeneic, 18 pts autologous transplantation and 13 pts further therapy with ATO ± gemtuzumab ozogamicin. 11 of the 45 (24%) pts relapsed (median 2nd remission duration 10 months, 4 to 26), and 9 deaths were reported between 9 and 14 months after the end of consolidation therapy. In pts with 2nd and later relapse, despite previous exposure to ATO, further responses with this agent were observed. Conclusions:ATO is an effective therapy for all stages of relapsed APL. The results argue in favor of serial PML-RARA monitoring in front-line therapy of APL to allow early treatment of emergent relapses, avoiding hyperleukocytosis and risk of death due to bleeding and differentiation syndrome. Furthermore, the favorable toxicity profile of ATO seems to benefit the feasibility of subsequent transplantation. Disclosures:Lengfelder:Cephalon: Research Funding. Fenaux: CELGENE, JANSSEN CILAG, AMGEN, ROCHE, GSK, NOVARTIS, MERCK, CEPHALON: Honoraria, Research Funding.

Primary Plasma Cell Leukemia: Results of a Retrospective Italian Multicentric Survey.

Abstract 2885Poster Board II-861 Background:Epidemiological and clinical information on Primary Plasma Cell Leukemia (pPCL) are rarely reported. Aims:To evaluate in patients (pts) with pPCL the clinical features, the prognostic factors, and the efficacy of treatments. Patients and Methods:A multicenter retrospective cohort study was carried out between January 2000 and December 2008 in 26 Italian hematology divisions. A total of 128 cases of PCL were collected, and 73 of them (57%) were classified as primary (M/F 43/30). Results:The median age was 63 years (range 32-86). At diagnosis the median values of peripheral blood plasma cells and bone marrow plasma cell infiltration were 2.7 × 10 9/L (range 0.4-49.9) and 80% (range 37-100), respectively. The median values of hemoglobin, white blood cell count, and platelet counts were 9.1 g/dl (range 4.8-12.9), 13.7 × 10 9/L (range 1.3-56.7), 116 × 10 9/L (range 8-428), respectively. Extramedullary disease was present in ten cases (14%) and included testis, muscular, neuromeningeal, and cutaneous localization. At diagnosis, 64 pts (88%) had at least one CRAB sign, namely 35 pts (48%) had low hemoglobin level, 20 pts (27%) calcium ≥11 mg/dl, 32 pts (44%) creatinine ≥2 mg/dl, and 47 pts (64%) had osteolysis. In 41 pts (56%) cytogenetic study was performed, revealing an unfavourable karyotype in 17 (23%), in 13 of them del(13q-). Seventy-two pts received front-line therapy (1 died early, receiving only support treatments and steroids), that included antracycline-containing regimens in 36 pts (50%), and single alkylating agents in 17 pts (24%, 9 cyclofosfamide and 8 melphalan). In 11 of them Bortezomib (BTZ, n= 7) or Thalidomide (THAL, n= 4) were also employed. Finally, 19 pts (26%) received BTZ (4) or THAL (5) or both (10) as unique treatment. Twenty-one pts (29%) underwent autologous stem cell transplantation (SCT) as part of front-line therapy, followed by allogeneic-SCT in four cases; two additional pts underwent only allogeneic-SCT. A complete or partial remission after front-line therapy was achieved in 20 pts (27%) and 19 pts (26%) respectively (overall response rate 53%). The median overall survival (OS) was 13.1 months (range 0.5-75.8); 30.6 months (range 4.7-75.8) in responder pts and 4.2 months in non-responder ones (range 0.5-75.6, univariable hazard ratio, HR, 0.28, 95% CI 0.11-0.39). In the responder pts the median progression free survival (PFS) was 17.2 months (range 1.4-72.1). Of note, in SCT pts the median OS and PFS were 38.1 months (range 4.8-75.8) and 25.8 months (range 1.4-72.1) respectively, with a significant advantage with respect to non-transplanted pts in OS (median 9.1 months, range 0.5-75.6, HR 0.28, 95% CI 0.16-0.52) and in PFS (median 7.3 months, range 1.7-17.7, HR 0.29, 95% CI 0.04-0.44). The low number of allo-SCTs did not allow a reliable separate statistical analysis. A multivariable Cox proportional hazard regression analysis showed that OS was influenced by lack of initial response (HR 2.62, 95% CI 1.04-6.57), albumin <3 g/dl (HR 3.33, 95% CI 1.64-6.76), and SCT (HR 0.34, 95% CI 0.12-0.98). Pts with hypercalcemia at diagnosis had a shorter PFS (HR 4.0, 95% CI 1.04-15.24); the PFS was favourably influenced by SCT (HR 0.05, 95% CI 0.009-0.28). Overall, the use of BTZ and/or THAL did not influence the OS and PFS. Conclusions:pPCL is a highly aggressive lymphoprolipherative malignancy, characterized by a poor prognosis and a low response rate to conventional therapy. The use of high-dose chemotherapy followed by autologous or allogeneic-SCT is a very effective therapy leading to 66% increase in the OS and to 95% increase in PFS in respect to non-transplanted pts. Apparently, the use of novel drugs such as BTZ and THAL did not produce a further amelioration in the patient outcome. However, those latter findings should be taken with caution, given the relatively low number of treated pts. Disclosures:No relevant conflicts of interest to declare.

Melphalan + Prednisone Versus Melphalan + Prednisone + Thalidomide in Induction Therapy for Multiple Myeloma in Elderly Patients: Final Analysis of the Dutch Cooperative Group HOVON 49 Study

Introduction: The Dutch cooperative group HOVON started a randomised phase III study in elderly patients with multiple myeloma (MM) in September 2002 comparing the standard Melphalan and Prednisone (MP) treatment with the combination Melphalan, Prednison and Thalidomide (MPT) (HOVON 49 study). Patients with previous untreated multiple myeloma > 65 years of age with a stage IB or higher were candidates for this trial.Melphalan was given in a dose of 0.25 mg/kg and prednisone 1 mg/kg for 5 days every 4 weeks. Thalidomide was given daily in a dose of 200 mg.. A maximum of 8 cycles was planned. In case of ongoing improvement of response further therapy was allowed till a plateau phase was reached. When a good response and a plateau phase was reached the patients on MPT received maintenance therapy with Thalidomide 50 mg/day until disease progression. Responses were assessed using the IMWG criteria. The primary endpoint was Event Free Survival (EFS). Progression Free Survival (PFS), Overall Survival (OS) and Response Rate (RR) were secondary endpoints. The study was powered for 420 patients. However accrual decreased significantly after the publications of 2 other trials comparing MP with MPT. Therefor the HOVON monitoring board decided to stop the trial when 344 patients had been included.Results: 344 patients from 59 centers were registered. 11 patients were not eligible and 3 patients were excluded for lack of signed informed consent or insufficient data at the time of evaluation. The 333 remaining patients, had been randomized to MP (n=168)and MPT (n=165. The arms were well matched for age, sex, stage of the disease, performance status and type of M-protein.The best response on protocol with MPT was 66% (CR 2%, VGPR 28% and PR 36%) as compared to 47% with MP (CR 2%, VGPR 8% and PR 37%), respectively (p<0.001). RR after three cycles of MPT was 52% as compared with only 32% with MP. That the quality of the responses seen in the Thalidomide treated group was better, is clear from the PFS after CR or PR; median 14 months vs 10 months (p<0.0002). At two years the PFS after CR/PR was 32% vs 12% for MPT vs MP respectively. There was a significant difference for the primary endpoint EFS in favour of the MPT arm; 13 versus 9 months (p< 0.001). Also the PFS was clearly in favour of MPT (p<0.02; median 10 months versus 13 months). The PFS after 2 years was 33% versus 19%.). For patients in CR vs PR the median PFS was 14 and 10 months respectively (p<0.0002). The median OS was 37 months vs 30 months (p=0.16).Toxicity: Grade 2,3 and 4 toxicity of any type was seen in 60% of the patients in the MP arm and in 88% of the MPT patients. This difference was mainly due to grade 2 and grade 3 neurotoxicity. No differences between the two arms were seen for other toxicities. Death during protocol treatment was 31% in the MP arm and 39% in de MPT arm. After three cycles only 36% of the patients used the full Thalidomide dose and after 6 cycles this was only 28%. Only one third of the patients received cycle 3 of Melphalan as planned according the protocolConclusions: In this randomised phase III study the addition of Thalidomide to MP resulted in a significant better RR. The quality of the responses (number of VGPR and PFS after CR/PR) and time to response were in favour of MPT. EFS and PFS were significantly better in MPT treated patients. Thalidomide added significantly to the toxicity (mainly neurotoxicity) of the treatment. We were unable to confirm the positive effect with Thalidomide as part of front-line therapy on OS perhaps probably because a substantial number of the MP patients received Thalidomide as the second line therapy. Moreover the study might be underpowered due to premature stopping of the inclusion.

High‐dose chemotherapy with autologous stem cell rescue for children with recurrent malignant brain tumors

High-dose chemotherapy (HDCT) with autologous stem cell rescue (ASCR) has been reported to be effective in treating children with recurrent central nervous system (CNS) malignancies. To evaluate the efficacy and toxicities of HDCT and ASCR, the medical records of 27 children with recurrent CNS malignancies who received such therapy at St. Jude Children's Research Hospital between 1989 and 2004 were reviewed. The median age at diagnosis was 4.5 years (range, 0.4-16.6 years) and that at ASCR was 6.7 years (range, 1.1-18.5 years). Diagnoses included medulloblastoma (13 patients), primitive neuroectodermal tumor (3 patients), pineoblastoma (2 patients), atypical teratoid rhabdoid tumor (2 patients), ependymoma (3 patients), anaplastic astrocytoma (2 patients), and glioblastoma multiforme (2 patients). The 5-year overall and progression-free survival (PFS) rates were 28.2% and 18.5%, respectively. The 5-year PFS rate for patients aged<3 years at diagnosis (57.1%) was significantly better than older patients (5.0%) (P=.019). Among the 6 long-term survivors (5 with M0 disease and 1 with M3 disease at diagnosis), 5 received both radiotherapy and HDCT as part of their salvage regimen; 4 were aged<3 years at diagnosis and had received chemotherapy only as part of frontline therapy. Two patients died of transplant-related toxicities; 44% experienced grade 3 or 4 transplant-related toxicities (toxicities were graded according to the National Cancer Institute Common Toxicity Criteria). HDCT with ASCR is not an effective salvage strategy for older children with recurrent CNS malignancies. The significantly better outcome in the younger cohort was most likely related to the use of radiotherapy as part of the salvage strategy.

Thalidomide In Multiple Myeloma: Past, Present and Future

Thalidomide was introduced in the treatment of multiple myeloma in the late 1990s. Following the initial results, which demonstrated dramatic response rates in heavily pretreated patients, a number of Phase II studies have confirmed the efficacy of this agent in relapsed patients. However, a high incidence of side effects at the dosage initially recommended (400 mg/day) justified further studies with lower doses of thalidomide given alone or in combination with dexamethasone or chemotherapy. Thalidomide is currently considered as one of the most active agents in relapsed myeloma. Recent studies have demonstrated that thalidomide could also be used as part of frontline therapy. The combination of thalidomide plus dexamethasone as initial therapy appears to be slightly superior to dexamethasone alone or to vincristine-doxorubicine-dexamethasone, but with an increased risk of deep vein thrombosis. Maintenance with thalidomide after autologous transplantation appears to increase the complete remission rate and to prolong progression-free survival. The combination of thalidomide plus melphalan and prednisone is superior to the classical melphalan-prednisone regimen in elderly patients, and will become the standard of care. Thalidomide has been registered in the USA in combination with dexamethasone in newly diagnosed patients, but is not yet registered in the European Union. Its use is currently challenged by bortezomib and by thalidomide's analog lenalidomide.

Multiple Myeloma

High-dose therapy with stem cell transplantation (SCT) and novel targeted therapies (thalidomide, its more potent analogues, and bortezomib) represent two approaches for overcoming resistance of multiple myeloma (MM) cells to conventional therapies. While it is now clear that dose-intensification improves the outcome in younger patients, long-term remissions are obtained in a minority of patients. Therefore, the impact of novel agents as part of front-line therapy is the objective of ongoing trials. Gene expression profiling (GEP) will help to improve the management of MM not only by identifying prognostic subgroups but also by defining molecular pathways that are associated with these subgroups and that are possible targets for future therapies. In Section I, Dr. John Shaughnessy describes recent data obtained with GEP of CD138-purified plasma cells from patients with MM. His group has already shown that overexpression of the Wnt signaling inhibitor DKK1 by MM plasma cells blocks osteoblast differentiation and contributes to the development of osteolytic bone lesions. Recent data allow identification of four subgroups of MM in which GEP is highly correlated not only with different clinical characteristics and outcome but also with different cytogenetic abnormalities. In addition, abnormal expression of only three genes (RAN, ZHX-2, CHC1L) is associated with rapid relapses. In the context of intensive therapy with tandem autotransplantations, this model appears to be more powerful than current prognostic models based on standard biologic variables and cytogenetics. Understanding why the dysregulation of these three genes is associated with a more aggressive behavior of the disease will help to define new therapeutic strategies. In Section II, Dr. Jean-Luc Harousseau presents recent results achieved with tandem autologous SCT (ASCT) and with reduced intensity conditioning (RIC) allogeneic SCT. ASCT is now considered as the standard of care in patients up to 65 years of age. The IFM (Intergroupe Francophone du Myelome) has recently shown that double ASCT is superior to single ASCT. Current results of three other randomized trials confirm that double ASCT is superior, at least in terms of event-free survival. However, patients with poor prognostic features do poorly even after tandem ASCT. Strategies to further improve the outcome of ASCT include more intensive therapies and the use of novel agents such as thalidomide and immunomodulatory analogs (IMiDs) or bortezomib. Results of allogeneic SCT remain disappointing in MM even with T cell-depleted grafts. Preliminary results of a strategy combining ASCT to reduce tumor burden and RIC allogeneic SCT are encouraging, although the follow-up is still short. However, again, patients with chromosome 13 deletions have poor results with RIC. Longer follow-up of ongoing multicentric studies will help to clarify the indications of RIC. In Section III, Dr. Paul Richardson summarizes current knowledge of novel targeted therapies in MM. A better understanding of interactions between MM cells and bone marrow stromal cells and of the signaling cascades whereby cytokines mediate proliferation, survival, drug resistance and migration of MM cells provide the rationale for testing novel agents in relapsed/refractory MM. Increased angiogenesis coupled with the known anti-angiogenesis activity of thalidomide justified its use in refractory MM. The remarkable responses initially achieved prompted a number of clinical studies in different indications and the development of more potent IMIDs. Among them CC-5013 (Revlimid) has been tested in Phase I/II studies and a randomized Phase III study has just been completed. Blockade of NF-kappa B using the proteasome inhibitor bortezomib (Velcade) may mediate anti-MM activity by inhibiting interleukin (IL)-6 production in stromal cells and other mechanisms of action have been shown in preclinical studies. Based on the promising results of the Phase II trial, a large randomized trial of bortezomib versus dexamethasone has been completed. Studies of bortezomib combined with other drugs are ongoing. Arsenic trioxide has a number of properties showing that it targets MM cells interacting with the microenvironment. Clinical studies are ongoing as well. Other agents in MM have already been or will probably be translated soon from the bench to the bedside.

Novel therapies in multiple myeloma.

The discovery of the activity of thalidomide in myeloma in the late 1990s transformed the therapy of myeloma dramatically. Apart from providing a useful treatment option for patients with myeloma, it has spurred clinical investigation of several other nonchemotherapeutic agents for this disease. These active, promising agents include CC-5013 (a thalidomide analog) and bortezomib (a proteasome inhibitor), as well as other agents, such as arsenic trioxide, ENMD 0995 and 2-methoxyestradiol. Preliminary data show that a number of these agents are active in treating disease that has relapsed after conventional chemotherapy as well as after high-dose therapy and transplantation, and some agents are active even after other novel agents have failed. The only novel drug that is commercially available currently is thalidomide, which has a therapeutically relevant benefit at all stages of the disease. A therapeutic trial of thalidomide is essential for all patients with myeloma. There are in vitro and in vivo data showing synergy between some of the novel agents. Although these novel drugs are typically used for treating disease that is refractory to or has relapsed after cytotoxic therapy, it is likely that they will start being used as part of frontline therapy, either by themselves or in combination with chemotherapy.