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For patients with indolent non-Hodgkin lymphoma who fail initial anti-CD20–based immunochemotherapy or develop relapsed or refractory disease, there remains a significant unmet clinical need for new therapeutic approaches to improve outcomes and quality of life. 177Lu-lilotomab satetraxetan is a next-generation single-dose CD37-directed radioimmunotherapy (RIT) which was investigated in a phase 1/2a study in 74 patients with relapsed/refractory indolent non-Hodgkin B-cell lymphoma, including 57 patients with follicular lymphoma (FL). To improve targeting of 177Lu-lilotomab satetraxetan to tumor tissue and decrease hematologic toxicity, its administration was preceded by the anti-CD20 monoclonal antibody rituximab and the “cold” anti-CD37 antibody lilotomab. The most common adverse events (AEs) were reversible grade 3/4 neutropenia (31.6%) and thrombocytopenia (26.3%) with neutrophil and platelet count nadirs 5 to 7 weeks after RIT. The most frequent nonhematologic AE was grade 1/2 nausea (15.8%). With a single administration, the overall response rate was 61% (65% in patients with FL), including 30% complete responses. For FL with ≥2 prior therapies (n = 37), the overall response rate was 70%, including 32% complete responses. For patients with rituximab-refractory FL ≥2 prior therapies (n = 21), the overall response rate was 67%, and the complete response rate was 24%. The overall median duration of response was 13.6 months (32.0 months for patients with a complete response). 177Lu-lilotomab satetraxetan may provide a valuable alternative treatment approach in relapsed/refractory non-Hodgkin lymphoma, particularly in patients with comorbidities unsuitable for more intensive approaches. This trial was registered at www.clinicaltrials.gov as #NCT01796171.

For patients with indolent non-Hodgkin lymphoma who fail initial anti-CD20–based immunochemotherapy or develop relapsed or refractory disease, there remains a significant unmet clinical need for new therapeutic approaches to improve outcomes and quality of life. 177Lu-lilotomab satetraxetan is a next-generation single-dose CD37-directed radioimmunotherapy (RIT) which was investigated in a phase 1/2a study in 74 patients with relapsed/refractory indolent non-Hodgkin B-cell lymphoma, including 57 patients with follicular lymphoma (FL). To improve targeting of 177Lu-lilotomab satetraxetan to tumor tissue and decrease hematologic toxicity, its administration was preceded by the anti-CD20 monoclonal antibody rituximab and the “cold” anti-CD37 antibody lilotomab. The most common adverse events (AEs) were reversible grade 3/4 neutropenia (31.6%) and thrombocytopenia (26.3%) with neutrophil and platelet count nadirs 5 to 7 weeks after RIT. The most frequent nonhematologic AE was grade 1/2 nausea (15.8%). With a single administration, the overall response rate was 61% (65% in patients with FL), including 30% complete responses. For FL with ≥2 prior therapies (n = 37), the overall response rate was 70%, including 32% complete responses. For patients with rituximab-refractory FL ≥2 prior therapies (n = 21), the overall response rate was 67%, and the complete response rate was 24%. The overall median duration of response was 13.6 months (32.0 months for patients with a complete response). 177Lu-lilotomab satetraxetan may provide a valuable alternative treatment approach in relapsed/refractory non-Hodgkin lymphoma, particularly in patients with comorbidities unsuitable for more intensive approaches. This trial was registered at www.clinicaltrials.govas #NCT01796171.

Survival of patients with high-risk diffuse large B-cell lymphoma (DLBCL) is suboptimal, and the risk of central nervous system (CNS) progression is relatively high. We conducted a phase 2 trial in 139 patients aged 18 to 64 years who had primary DLBCL with an age-adjusted International Prognostic Index (aaIPI) score of 2 to 3 or site-specific risk factors for CNS recurrence. The goal was to assess whether a dose-dense immunochemotherapy with early systemic CNS prophylaxis improves the outcome and reduces the incidence of CNS events. Treatment consisted of 2 courses of high-dose methotrexate in combination with biweekly rituximab (R), cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP-14), followed by 4 courses of R-CHOP-14 with etoposide (R-CHOEP) and 1 course of high-dose cytarabine with R. In addition, liposomal cytarabine was administered intrathecally at courses 1, 3, and 5. Coprimary endpoints were failure-free survival and CNS progression rates. Thirty-six (26%) patients experienced treatment failure. Progression occurred in 23 (16%) patients, including three (2.2%) CNS events. At 5 years of median follow-up, failure-free survival, overall survival, and CNS progression rates were 74%, 83%, and 2.3%, respectively. Treatment reduced the risk of progression compared with our previous trial, in which systemic CNS prophylaxis was given after 6 courses of biweekly R-CHOEP (hazard ratio, 0.49; 95% CI, 0.31-0.77; P = .002) and overcame the adverse impact of an aaIPI score of 3 on survival. In addition, outcome of the patients with BCL2/MYC double-hit lymphomas was comparable to the patients without the rearrangements. The results are encouraging, with a low toxic death rate, low number of CNS events, and favorable survival rates. This trial was registered at www.clinicaltrials.gov as #NCT01325194.

Survival of patients with high-risk diffuse large B-cell lymphoma (DLBCL) is suboptimal, and the risk of central nervous system (CNS) progression is relatively high. We conducted a phase 2 trial in 139 patients aged 18 to 64 years who had primary DLBCL with an age-adjusted International Prognostic Index (aaIPI) score of 2 to 3 or site-specific risk factors for CNS recurrence. The goal was to assess whether a dose-dense immunochemotherapy with early systemic CNS prophylaxis improves the outcome and reduces the incidence of CNS events. Treatment consisted of 2 courses of high-dose methotrexate in combination with biweekly rituximab (R), cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP-14), followed by 4 courses of R-CHOP-14 with etoposide (R-CHOEP) and 1 course of high-dose cytarabine with R. In addition, liposomal cytarabine was administered intrathecally at courses 1, 3, and 5. Coprimary endpoints were failure-free survival and CNS progression rates. Thirty-six (26%) patients experienced treatment failure. Progression occurred in 23 (16%) patients, including three (2.2%) CNS events. At 5 years of median follow-up, failure-free survival, overall survival, and CNS progression rates were 74%, 83%, and 2.3%, respectively. Treatment reduced the risk of progression compared with our previous trial, in which systemic CNS prophylaxis was given after 6 courses of biweekly R-CHOEP (hazard ratio, 0.49; 95% CI, 0.31-0.77; P= .002) and overcame the adverse impact of an aaIPI score of 3 on survival. In addition, outcome of the patients with BCL2/MYCdouble-hit lymphomas was comparable to the patients without the rearrangements. The results are encouraging, with a low toxic death rate, low number of CNS events, and favorable survival rates. This trial was registered at www.clinicaltrials.govas #NCT01325194.

Reduced sexual function may have negative implications on health related quality of life among lymphoma survivors. A national cross-sectional study among long-term lymphoma survivors after high-dose therapy with autologous stem-cell transplantation auto-SCT treated during 1987–2008 was conducted in 2012–2014. The current study explored sexual functioning among these survivors. Sixty-six percent (n= 159) of eligible men with complete questionnaire data were included, median age was 55 years. The Brief Sexual Function Inventory (BSFI) was used to assess sexual function and sexual satisfaction, compared with age-matched controls. In addition, sexual problems were defined based on predetermined cutoff values for BSFI domain scores. Sexual drive and erections firm enough to have sexual intercourse were reported to be present only a few days or less last month among 30% and 41% of survivors, respectively. Sexual satisfaction was reported by 39% of survivors. The survivors had significantly lower scores on all BSFI domains and an increased risk of problems with sexual drive and erection compared with controls. In multivariable models, cardiovascular disease was significantly associated with worse erectile function, while age > 55 years, chronic fatigue, and physical inactivity were significantly associated with lower sexual functioning overall. Chronic fatigue and anxiety were related to lower sexual satisfaction.

Sexual function in female lymphoma survivors after high-dose therapy with autologous stem-cell transplantation (auto-SCT) is largely unstudied. Female lymphoma survivors treated with auto-SCT in Norway 1987–2008 were eligible participants (n= 157). A multi-item questionnaire including a complete Sexual Activity Questionnaire was returned by 70% (n= 110) of the women. A comparison to age-matched normative controls was performed. Sexual inactivity was equal among survivors and controls. The survivors reported personal issues more frequent as reason for inactivity compared with controls (44% vs. 28%, p= 0.04). The sexually active survivors reported more sexual discomfort, greater reduction in frequency of sexual activity, and more sex-related tiredness compared with controls (pvalue and effect size [95% confidence interval]; p≤ 0.001, 0.70 [0.44, 0.97], p= 0.03, −0.29 [−0.55, −0.03] and p≤ 0.001, 0.64 [0.37, 0.90], respectively). Sexual activity was related to older age (odds ratio (OR) 0.58 [0.43, 0.82] per 10 years), being in a relationship (OR 28.6 [6.9, 118.9]) and hormonal replacement therapy (OR 6.0 [1.49, 24.2]). Tiredness in relation to sexual activity was associated with younger age, chronic fatigue and mental distress. Sexual inactivity due to personal issues was more frequent and among those sexually active, a higher rate of sexual dysfunction exists among auto-SCT survivors compared with controls. Hence, sexual function should be addressed at regular timepoints during the cancer trajectory.

The main objective of the MCL3 study was to improve outcome for patients not in complete remission (CR) before transplant by adding 90Y-ibritumomab-tiuxetan (Zevalin) to the high-dose regimen. One hundred sixty untreated, stage II-IV mantle cell lymphoma patients <66 years received rituximab (R)–maxi–CHOP (cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone) alternating with R-high-dose cytarabine (6 cycles total), followed by high-dose BEAM/C (bis-chloroethylnitrosourea, etoposide, cytarabine, and melphalan or cyclophosphamide) and autologous stem cell transplantation from 2005 to 2009. Zevalin (0.4 mCi/kg) was given to responders not in CR before transplant. Overall response rate pretransplant was 97%. The outcome did not differ from that of the historic control: the MCL2 trial with similar treatment except for Zevalin. Overall survival (OS), event-free survival (EFS), and progression-free survival (PFS) at 4 years were 78%, 62%, and 71%, respectively. For responding non-CR patients who received Zevalin, duration of response was shorter than for the CR group. Inferior PFS, EFS, and OS were predicted by positron emission tomography (PET) positivity pretransplant and detectable minimal residual disease (MRD) after transplant. In conclusion, positive PET and MRD were strong predictors of outcome. Intensification with Zevalin may be too late to improve the outcome of patients not in CR before transplant. This trial was registered at www.clinicaltrials.govas #NCT00514475.

The main objective of the MCL3 study was to improve outcome for patients not in complete remission (CR) before transplant by adding 90Y-ibritumomab-tiuxetan (Zevalin) to the high-dose regimen. One hundred sixty untreated, stage II-IV mantle cell lymphoma patients <66 years received rituximab (R)–maxi–CHOP (cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone) alternating with R-high-dose cytarabine (6 cycles total), followed by high-dose BEAM/C (bis-chloroethylnitrosourea, etoposide, cytarabine, and melphalan or cyclophosphamide) and autologous stem cell transplantation from 2005 to 2009. Zevalin (0.4 mCi/kg) was given to responders not in CR before transplant. Overall response rate pretransplant was 97%. The outcome did not differ from that of the historic control: the MCL2 trial with similar treatment except for Zevalin. Overall survival (OS), event-free survival (EFS), and progression-free survival (PFS) at 4 years were 78%, 62%, and 71%, respectively. For responding non-CR patients who received Zevalin, duration of response was shorter than for the CR group. Inferior PFS, EFS, and OS were predicted by positron emission tomography (PET) positivity pretransplant and detectable minimal residual disease (MRD) after transplant. In conclusion, positive PET and MRD were strong predictors of outcome. Intensification with Zevalin may be too late to improve the outcome of patients not in CR before transplant. This trial was registered at www.clinicaltrials.gov as #NCT00514475.

Multiple myeloma (MM) is characterized by accumulation and dissemination of malignant plasma cells (PCs) in the bone marrow (BM). Gene expression profiling of 2 MM cell lines (OH-2 and IH-1) indicated that expression of PRL-3, a metastasis-associated tyrosine phosphatase, was induced by several mitogenic cytokines. Cytokine-driven PRL-3 expression could be shown in several myeloma cell lines at both the mRNA and protein levels. There was significantly higher expression of the PRL-3 gene in PCs from patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering myeloma (SMM), and myeloma than in PCs from healthy persons. Among 7 MM subgroups identified by unsupervised hierarchical cluster analysis, PRL-3 gene expression was significantly higher in the 3 groups denoted as “proliferation,” “low bone disease,” and “MMSET/FGFR3.” PRL-3 protein was detected in 18 of 20 BM biopsies from patients with MM. Silencing of the PRL-3 gene by siRNA reduced cell migration in the MM cell line INA-6, but had no detectable effect on proliferation and cell-cycle phase distribution of the cells. In conclusion, PRL-3 is a gene product specifically expressed in malignant plasma cells and may have a role in migration of these cells.

Multiple myeloma (MM) is characterized by accumulation and dissemination of malignant plasma cells (PCs) in the bone marrow (BM). Gene expression profiling of 2 MM cell lines (OH-2 and IH-1) indicated that expression of PRL-3, a metastasis-associated tyrosine phosphatase, was induced by several mitogenic cytokines. Cytokine-driven PRL-3 expression could be shown in several myeloma cell lines at both the mRNA and protein levels. There was significantly higher expression of the PRL-3gene in PCs from patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering myeloma (SMM), and myeloma than in PCs from healthy persons. Among 7 MM subgroups identified by unsupervised hierarchical cluster analysis, PRL-3gene expression was significantly higher in the 3 groups denoted as “proliferation,” “low bone disease,” and “MMSET/FGFR3.” PRL-3 protein was detected in 18 of 20 BM biopsies from patients with MM. Silencing of the PRL-3gene by siRNA reduced cell migration in the MM cell line INA-6, but had no detectable effect on proliferation and cell-cycle phase distribution of the cells. In conclusion, PRL-3 is a gene product specifically expressed in malignant plasma cells and may have a role in migration of these cells.

The bone disease in multiple myeloma is caused by an uncoupling of bone formation from bone resorption. A key difference between patients with and patients without osteolytic lesion is that the latter have fewer and less active osteoblasts. Hepatocyte growth factor (HGF) is often produced by myeloma cells and is found at high concentrations in the bone marrow of patients with multiple myeloma. Here we show that HGF inhibited bone morphogenetic protein (BMP)–induced in vitro osteoblastogenesis. Thus, HGF inhibited BMP-induced expression of alkaline phosphatase in human mesenchymal stem cells (hMSCs) and the murine myoid cell line C2C12, as well as mineralization by hMSCs. Furthermore, the expression of the osteoblast-specific transcription factors Runx2 and Osterix was reduced by HGF treatment. HGF promoted proliferation of hMSCs, and the BMP-induced halt in proliferation was overridden by HGF, keeping the cells in a proliferative, undifferentiating state. BMP-induced nuclear translocation of receptor-activated Smads was inhibited by HGF, providing a possible explanation of how HGF inhibits BMP signaling. The in vitro data were supported by the observation of a negative correlation between HGF and a marker of osteoblast activity, bone-specific alkaline phosphatase (rho = -0.45, P = .008), in sera from 34 patients with myeloma. These observations suggest that HGF inhibits bone formation in multiple myeloma.

The bone disease in multiple myeloma is caused by an uncoupling of bone formation from bone resorption. A key difference between patients with and patients without osteolytic lesion is that the latter have fewer and less active osteoblasts. Hepatocyte growth factor (HGF) is often produced by myeloma cells and is found at high concentrations in the bone marrow of patients with multiple myeloma. Here we show that HGF inhibited bone morphogenetic protein (BMP)–induced in vitro osteoblastogenesis. Thus, HGF inhibited BMP-induced expression of alkaline phosphatase in human mesenchymal stem cells (hMSCs) and the murine myoid cell line C2C12, as well as mineralization by hMSCs. Furthermore, the expression of the osteoblast-specific transcription factors Runx2 and Osterix was reduced by HGF treatment. HGF promoted proliferation of hMSCs, and the BMP-induced halt in proliferation was overridden by HGF, keeping the cells in a proliferative, undifferentiating state. BMP-induced nuclear translocation of receptor-activated Smads was inhibited by HGF, providing a possible explanation of how HGF inhibits BMP signaling. The in vitro data were supported by the observation of a negative correlation between HGF and a marker of osteoblast activity, bone-specific alkaline phosphatase (rho = −0.45, P= .008), in sera from 34 patients with myeloma. These observations suggest that HGF inhibits bone formation in multiple myeloma.

Kolstad: Nordic Nanovector: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Roche: Research Funding. Illidge:Nordic Nanovector: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Research Funding; Takeda: Consultancy, Honoraria. Hajek:Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding. Jurczak:European Medicines Agency: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Consultancy; Acerta: Consultancy, Research Funding; Sandoz-Novartis: Consultancy; Afimed: Research Funding; Bayer: Research Funding; BeiGene: Research Funding; Celgene: Research Funding; Epizyme: Research Funding; Gilead: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Nordic Nanovector: Research Funding; Merck: Research Funding; Morphosys: Research Funding; Pharmacyclics: Research Funding; Servier: Research Funding; Roche: Research Funding; TG Therapeutics: Research Funding. Rojkjaer:Nordic Nanovector: Employment. Østengen:Nordic Nanovector: Employment.

Leppä: Roche: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Research Funding; Bayer: Research Funding; Janssen: Consultancy, Research Funding; Celgene: Consultancy. Silva:Gilead Sciences: Research Funding; Abbvie, Gilead Sciences, Janssen, BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche, Janssen, Celgene: Other: Travel Support; Roche, Janssen: Other: Institution's payment for consultancy. Hagberg:Roche: Honoraria. Lugtenburg:takeda: Consultancy, Research Funding; servier: Consultancy, Research Funding; roche: Consultancy; BMS: Consultancy; Celgene: Consultancy; Sandoz: Consultancy; GenMab: Research Funding. Walewski:Roche, GSK/Novartis, Takeda, and Janssen-Cilag: Research Funding; Roche, Celgene, Takeda, Janssen-Cilag, and Servier: Honoraria; Roche, Celegene, Takeda, Janssen-Cilag, and Servier: Membership on an entity's Board of Directors or advisory committees. Hopfinger:Janssen: Honoraria; Gilead: Honoraria, Research Funding; GlaxoSmithKline: Honoraria; Celgene: Honoraria; Novartis: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Jantunen:Amgen: Honoraria; Genzyme/Sanofi: Honoraria; Takeda: Honoraria. Steidl:Seattle Genetics: Consultancy; Juno Therapeutics: Consultancy; Tioma: Research Funding; Bristol-Myers Squibb: Research Funding; Nanostring: Patents & Royalties: patent holding; Roche: Consultancy. Gascoyne:NanoString: Patents & Royalties: Named Inventor on a patent licensed to NanoString Technologies. Scott:Celgene: Consultancy, Honoraria; Janssen: Research Funding; Roche: Research Funding; NanoString: Patents & Royalties: Named Inventor on a patent licensed to NanoString Technologies, Research Funding.

Introduction:Most indolent NHL patients (pts) have advanced stage disease at diagnosis, and no curative therapy exists. The mainstay of both first- and second-line (2L) therapy is anti-CD20 chemo-immunotherapy, and although initially effective, most pts relapse, with median PFS decreasing markedly after 2L and 3rd-line therapies. In addition, many pts eventually develop resistance to rituximab (RTX)/RTX-containing regimens, thus therapeutic targets other than CD20 are important. Those who develop resistance to RTX, especially the elderly, need new treatment approaches. With a median age at diagnosis of 67 (seer.gov), NHL is a disease of the elderly, who are at risk of developing cumulative myelosuppression, cardiac toxicity, and severe infections with currently available therapies. CD37 is highly expressed (>90%) in B-cell NHL, providing an alternative target to CD20. Lutetium (177Lu) lilotomab satetraxetan (Betalutin®) is a beta-emitting anti-CD37 ARC in a ready-to-use formulation. LYMRIT 37-01 is a phase I/II open-label, multicenter, dose-escalation study to determine the safety, pharmacokinetics (PK), and preliminary efficacy of a single dose of Betalutin in pts with relapsed iNHL, and to establish a recommended phase II dose (RP2D). We present updated efficacy and safety data for the phase I/IIa part of the study (Part A) as of 22 June 2018; all pts have ≥ 6 months (m) of follow-up, except for 3 (will be completed in August).

[§ share last authorship]

The incidence of indolent NHL (iNHL) is increasing, with approximately 63,000 new cases per year in the US. The highest unmet medical need is for rituximab (RTX)-refractory patients (pts), with inferior 5 year overall survival rates for RTX-refractory follicular lymphoma (FL) vs all FL pts (58% vs 87.7%) (Abdollahi S et al. Blood 2008; www.seer.cancer.gov). Many pts develop resistance to RTX or RTX-containing regimens, thus targets other than CD20 are important. CD37 is highly expressed (>90%) in most B-cell NHL, providing an alternative target to CD20. Lutetium (177Lu) lilotomab satetraxetan (Betalutin®) is a novel beta-emitting anti-CD37 antibody radionuclide conjugate (ARC) in a ready-to-use formulation that is being evaluated in a phase I/II, open-label, dose-escalation study (LYMRIT 37-01) to determine the safety and preliminary efficacy of Betalutin® monotherapy in pts with relapsed/refractory NHL, and establish a recommended phase II dose (RP2D). Lilotomab (cold antibody) pre-dosing was determined to be essential to optimize Betalutin® biodistribution and safety, and dosimetry data indicate less bone marrow (bm) uptake of Betalutin® with lilotomab pre-dosing with no impact on tumor absorbed dose (Blakkisrud et al. J Nucl Med 2017). Arms 1 and 4 are evaluating 2 different lilotomab pre-doses (Arm 1 - 40 mg; Arm 4 -100mg/m2) with escalating doses of Betalutin®. We provide here an update on safety/efficacy for the 2 arms.

Leppa: Roche: Honoraria, Other: Travel expenses, Research Funding; Janssen: Research Funding; Bayer: Research Funding; Mundipharma: Research Funding; Amgen: Research Funding; Takeda: Honoraria, Other: Travel expenses; CTI Life Sciences: Honoraria; Merck: Other: Travel expenses. Joergensen:Amgen: Research Funding; Mundipharma: Research Funding. Mannisto:SOBI: Honoraria; Pfizer: Honoraria; Gilead: Other: Travel expenses; Celgene: Other: Travel expenses; Novartis: Other: Travel expenses; Amgen: Other: Travel expenses; Takeda: Honoraria, Other: Travel expenses; Roche: Honoraria, Other: Travel expenses. Jerkeman:Gilead: Research Funding; Celgene: Research Funding; Mundipharma: Research Funding; Amgen: Research Funding; Janssen: Research Funding. Holte:Amgen: Research Funding; Mundipharma: Research Funding.

Introduction:Survival of patients with high-risk diffuse large B-cell lymphoma (DLBCL) is suboptimal, and the risk of early central nervous system (CNS) progression is high. Here we present the final results from a Nordic phase II study, where dose-dense chemoimmunotherapy including early systemic CNS prophylaxis with high dose methotrexate (HD-Mtx), further intensified by intrathecally (IT) administered liposomal cytosine arabinoside (AraC), was given.

Abstract 57

Newly diagnosed stage II-IV MCL patients < 66 years received induction immunochemotherapy with alternating cycles of R- (rituximab) maxi-CHOP and R-Ara-C to a total of 6 cycles. Evaluation of pretransplant response with CT scans and bone marrow was performed after 5 cycles. PET/CT pretransplant was recommended, but would not influence treatment. Responding patients by NCI criteria underwent in-vivo purged stem cell harvest after the 6th cycle (Ara-C + 2 doses of rituximab). Patients in CRu or PR received a standard dose Zevalin (0.4 mCi/kg) one week prior to high-dose therapy with BEAM or BEAC while CR patients received the high-dose chemotherapy without Zevalin. Follow-up included CT-scans, bone marrow and blood sampling for at least 5 years, including PCR for minimal residual disease or molecular relapse. Patients in solely molecular relapse received preemptive therapy with 4 weekly doses of rituximab, as in the MCL2 study.161 consecutive patients were included from 2005–2009, with characteristics similar to that of the MCL2 trial with a median age of 57 years (28–65), a male predominance and the majority in stage IV with bone marrow involvement. Only 12 out of 161 patients (7 %) did not receive a transplant, 6 due to stem cell harvest failure, 2 due to toxicity and 4 due to no response to induction treatment. Before transplant 50% were in CR, 17% in CRu, and 30% in PR. Only four out of 161 patients (2 %) did not respond to induction treatment. After a median follow-up of 3.2 years the projected 5-year overall and event free survival, and time to progression were 71, 55 and 65% respectively and the MCL2 and MCL3 curves were superimposable. Of the 69 candidates to Zevalin in CRu/PR according to protocol, 65 (94%) actually received this treatment. There was no significant difference in time to progression for patients in CRu and PR pretransplant between MCL2 and MCL3, indicating no effect of late intensification with Zevalin in MCL3 in this patient group. Interestingly, a positive pretransplant PET scan proved to be a strong negative predictor for outcome. Lack of benefit from addition of Zevalin to the high-dose regimen was shown for both PET-positive and PET-negative patients. In a multivariate analysis of the impact of clinical response, PET positivity and zevalin treatment, only PET positivity pretransplant had independent significance (p=0.0003 HR=3.412 (95% confidence limits 1.744 – 6.673).The treatment-related mortality was 3 %. Side-effects were similar to that previously reported for MCL2, and we did not find that Zevalin added any toxicity. Of the 3 patients who developed secondary MDS/AML posttransplant, two had received Zevalin and one had not.The MCL3 data confirm the good results and tolerability of the Nordic regimen. However, the late intensification with Zevalin, albeit non-toxic, did not prolong the time to progression for patients in only CRu or PR pretransplant. A positive PET prior to transplant was shown to be a strong negative predictor for outcome. The concept of late intensification may be too late in poor responders. In consequence, up-front intensification with increasing use of high-dose AraC for MIPI high-risk patients is used in the subsequent, now ongoing Nordic-British MCL5 study.Arne: Bayer Schering Pharma: Research Funding. Geisler:Roche, Schering: Consultancy, Research Funding.

The ACT trial (ACT-1, younger patients aged 18–60 yrs and ACT-2, elderly patients aged >60 yrs) is the first international randomized phase III trial in newly diagnosed primary systemic peripheral T-cell lymphoma (PTCL). It tests, in both younger and elderly patients, the efficacy of the addition of alemtuzumab (ALZ) to 6 courses of bi-weekly CHOP followed, only in younger patients (ACT-1), by high-dose therapy with autologous stem cell rescue. A dose reduction amendment tapering the cumulative ALZ dose from 360 mg (30 mg on days 1 and 2 of CHOP courses 1–6) to 120 mg (30 mg on day 1 of CHOP courses 1–4), respectively, was introduced early on due to two cases of systemic fungal infection (Blood 2011,118;4110). To date, the trial has accrued a total of 186 patients (ACT-1 n=98; ACT-2 n=88).Here, we present the results from the first interim efficacy and safety analysis of the ACT-1 trial based on the first 68 randomized patients.Of the 68 patients, 63 had a complete set of treatment data. The median follow-up was 15 months (range 0.5–42 months). Thirty-two patients belonged to the experimental arm (exp) and 31 to the standard arm (std). Of the 32 patients treated according to exp, 4 received the higher dose of ALZ and 28 the lower. Treatment arms were well balanced with regard to main prognostic features such as age (std: median 53 yrs, range 21–60 yrs; exp: median 50 yrs, range 22–64 yrs; p=0.705), IPI subgroups (std: low 10%, low-intermediate 51%, intermediate-high 29%, high 10%; exp: low 12%, low-intermediate 44%, intermediate-high 19%, high 25%; p=0.392), advanced clinical stage (std: stage III-IV 94%; exp: 97%; p=0.613), performance status ECOG>1 (std: 23%; exp: 28%; p=0.613), elevated LDH (std: 68%; exp: 69%; p=0.932), presence of B-symptoms (std: 68%; exp: 75%; p=0.524), bulky disease (std: 13%; exp: 13%; p=1.0) and bone marrow involvement (std: 39%; exp: 31%; p=0.535). Histological subtypes were also similarly distributed among both treatment arms (std: PTCL-NOS 55%, AILT 23%, other 22%; exp: PTCL-NOS 56%, AILT 28%, other 16%). No cases of anaplastic large cell PTCL (regardless of ALK-protein status) were included. Neither of the treatment cohorts showed significant treatment delay. The median duration of chemotherapy (calculated for 5 bi-weekly cycles of an expected cumulative duration of 70 days) for non-ALZ vs. ALZ-treated patients was 73 vs. 81 days, respectively. No suspected unexpected serious adverse reactions (SUSARs) were reported. Grade 4 leucopenia was more frequent in ALZ-treated patients (std: 24%, exp: 69%; p=0,001), whereas grade 3–4 anemia and grade 3–4 thrombocytopenia were not significantly different between treatment arms (anemia, std: 19%, exp: 31%; p=0,278; thrombocytopenia, std: 20%, exp: 12%, p=0,682). Non-hematological toxicity unrelated to infectious complications was mild and had a similar frequency in both arms. The number of serious adverse events (SAEs) per patient was 0.86 for patients treated at post-amendment ALZ dose levels, representing a significant reduction compared to the pre-amendment value (3.25), and 0.46 for patients treated in the control arm (p=0.002). The frequency of bacterial and fungal infections (grade ≥3) was similar in both treatment arms. ALZ treated patients had more viral events (9/32; 28% vs. 3/31; 10%), mainly (6 out of 9) consisting of asymptomatic cytomegalovirus reactivations. The overall (non-arm specific) 1-year event-free survival (primary end-point), progression-free survival and overall survival were 55% (95% CI: 42%-67%), 54% (95% CI: 42%-67%) and 78% (95% CI: 67%-88%), respectively.The safety profile of the current standard and experimental treatment schedules, as well as the interim outcome results, support a continuation of the trial. A final analysis will be performed in Q2 2015.Jantunen: Genzyme: Has participated in EU Leadership meeting organized by Genzyme as well as Medical Advisory Board meeting organized by Genzyme Other, Honoraria.

Abstract 747This icon denotes a clinically relevant abstract

From May 2007 to October 2010, 66 newly diagnosed primary central nervous system lymphoma (PCNSL) patients (M/F ratio 1: 1) were enrolled. Younger patients (≤65 yrs; N=39) received 6 three-weekly cycles of chemotherapy consisting of: high-dose (HD)-methotrexate (MTX) (cycles 1, 2, 4 and 5), HD-cytosine arabinoside (AraC) (cycles 3 and 6) in addition to Rituximab (cycle 1 only), ifosfamide (cycles 1 and 4), cyclophosphamide (cycles 2 and 5), vincristine (cycles 2 and 5), vindesine (cycles 3 and 6), and dexamethasone (all 6 cycles). Depocyte® was delivered intratechally during the HD-MTX cycles. Elderly patients (66–75 yrs; N=27) received an identical Rituximab-containing 1st cycle. Cyclophosphamide and ifosfamide were replaced by temozolamide (cycles 2 to 6), which was also given as maintenance in patients with chemosensitive disease, and vincristine was omitted. No radiotherapy was given. Response was determined after the 2nd, 4th and 6th chemotherapy cycle by cerebral MRI and assessed according to International Primary CNS Lymphoma Coordinating Group criteria. The primary endpoint was overall survival (OS), secondary endpoints were progression-free survival (PFS), overall response rate (ORR), systemic toxicity and neurotoxicity assessed as Mini Mental State Examination (MMSE) and Functional Independence Measure (FIM).The median age was 64 yrs overall, 55 yrs (range 40–65) for younger and 70 yrs (range 66–75 years) for elderly patients. In 56 patients, the International Extranodal Lymphoma Study Group prognostic score was: 0–1 (N=5), 2–3 (N=36) and 4–5 (N=15). In the remaining 10 patients, lumbar puncture was not performed in five and spinal fluid protein concentration not reported in additional five cases. Response assessment after completion of induction treatment was performed in 43 out of 66 patients and showed complete remission (CR/CRu) in 30 patients, partial remission (PR) in 5 and progressive disease (PD) in 8. The ORR was 53 %. In 23 patients, response could not be evaluated due to early progression (n=8), toxic death (n=4), poor performance (n=3), neurotoxicity (n=5), or other causes (n=3). Of the 27 elderly patients, 15 continued to maintenance therapy. Of these, 14 have completed the maintenance schedule. Remission status at month 3 was CR in 13 and PD in 1 patient.With a median follow-up of 11.1 months (range 0.6–40.2) the 3-yr OS was 54.6% with no significant difference between younger and elderly patients (56.4% vs 51.9% respectively, p=0.32). The 3-yr PFS was 35.1% (32.9% in younger and 38.2 % in elderly patients; p=0.96). There were four septic deaths. Grade 3–4 hematological toxicity was seen in 79 % of the patients. Arachnoditis-like symptoms occurred in 13 patients. In all but two patients, the symptoms resolved within less than a week. MMSE and FIM were recorded both before and after therapy in 32 patients. Scores improved in 18 and 20 patients, respectively.In conclusion, the schedule applied in the present study led to a 3 yr PFS of 35%. Surprisingly, no significant outcome difference was found between the younger and the elderly patients. The majority of treatment failures were due to early progressive disease under induction therapy. Although the follow-up of our study is short, de-escalation of induction treatment intensity by introduction of a less toxic agent as temozolomide, and its subsequent use in a maintenance schedule may explain a possible survival benefit of this strategy in elderly patients.No relevant conflicts of interest to declare.

Systemic peripheral T-cell lymphomas (PTCL) are malignancies responding poorly to conventional therapy. To evaluate the efficacy of a dose-dense approach consolidated by upfront high-dose chemotherapy supported by autologous stem-cell transplantation (HDT/ASCT) in PTCL, the Nordic Lymphoma Group conducted the, so far, largest PTCL-restricted prospective phase II study in previously untreated systemic PTCL. This is the final report of the NLG-T-01 study with a 5-years median follow up.Patients with previously untreated systemic PTCL aged 18–67 years were included. ALK-positive anaplastic large cell lymphoma (ALCL) cases were excluded. An induction regimen of six cycles of bi-weekly cyclophosphamide, doxorubicin, etoposide, vincristin and prednisone (CHOEP) was given. Age-based (>60 yrs) omission of etoposide was recommended. If in complete or partial remission, patients received high-dose chemotherapy with carmustine, etoposide, cytarabine and melphalan/cyclophosphamide (BEAM/BEAC) followed by HDT/ASCT.A total of 166 patients with previously untreated PTCL were enrolled. Of these, 160 were histopathologically confirmed and included the following subtypes: PTCL-not otherwise specified (PTCL-NOS) (n=62; 39%), ALK-negative ALCL (n=31; 19%), angioimmunoblastic lymphoma (AIL) (n=30; 19%), enteropathy-associated T-cell lymphoma (n=21; 13%), panniculitis-like (n=6; 4%), T/NK nasal-type (n=5; 3%), and hepatosplenic (n=5; 3%). The M/F ratio was 2.0 and the median age 57 yrs (range 22–67 yrs). The majority of the cases presented with advanced-stage disease (81%), B-symptoms (59%) and elevated s-LDH (62%). Nevertheless, 71% of all patients had a good performance score (PS) (WHO 0–1) at inclusion. With regard to the International Prognostic Index (IPI), risk factor distribution was as follows: 1 factor n=45 (28%), 2 factors n=52 (32%), 3 factors n=30 (19%), 4–5 factors n=33 (21%). Of the 160 patients, a total of 114 (71%) underwent HDT/ASCT with 90 in complete remission at 3 months post-transplant. Early failures occurred in 26% of the patients. The treatment related mortality was low (4%). At a median follow-up of 60 months, 83 patients were alive. The median follow-up for deceased patients (N=77) was 9 months. The consolidated 5-yr overall (OS) and progression-free survival (PFS) values for the entire cohort were 51% and 44%, respectively. Best results were obtained in ALK-negative ALCL with 5-yr OS and PFS of 70% and 61%, respectively. IPI was a useful overall prognostic discriminator for the low/low-intermediate vs. intermediate-high/high groups with regard to 5-yr OS (p=0,047) and 5-yr PFS (p=0,029). If applied separately to each of the four major subtypes, IPI had a predictive value for OS in AIL (p=0,02) and for PFS in both AIL (p=0,02) and PTCL-NOS (p=0,03). The clinicopathological parameters that showed a significant impact on OS and PFS were: female gender (correlated with a better outcome), age (analyzed as continuous variable), PS≥2 (correlated with adverse outcome), and cytotoxic phenotype (correlated with adverse outcome in AIL). All these parameters retained their prognostic value at multivariate level, except for cytotoxic phenotype, where multivariate analysis could not be performed because of too small numbers.Dose-dense induction followed by HDT/ASCT is well tolerated and leads to long-term PFS in 44% of patients with systemic PTCL. This represents an encouraging outcome, particularly considering the high median age and adverse risk profile of the present study population. Therefore, based on these results, dose-dense induction and HDT/ASCT should be considered in transplant-eligible PTCL patients.Jantunen: Genzyme: Honoraria.

The ACT trial (ACT-1 and −2) tests the addition of alemtuzumab (ALZ) to 6 courses of bi-weekly CHOP (A-CHOP-14) followed, in younger patients (ACT-1), by high-dose therapy with autologous stem cell transplant (HDT/ASCT) in newly diagnosed primary systemic peripheral T-cell lymphoma (PTCL). To date, the trial has accrued a total of 131 patients (ACT-1 n=72; ACT-2 n=59). Here, we present the first planned interim safety analysis of the ACT-1 trial based on the first 51 randomized patients.The aim of the present analysis is to report on the feasibility of a dose-dense chemo-immunotherapy schedule combining ALZ and bi-weekly CHOP followed by HDT/ASCT in ‘de novo' PTCL patients.Results contain two data subsets corresponding to ALZ dose levels prior and subsequent to a dose-reduction amendment tapering ALZ dose from 360 mg (30 mg on days 1 and 2 of each CHOP course) to 120 mg (30 mg on day 1 of CHOP courses 1–4), respectively. Of the 51 randomized patients, 43 had a complete set of evaluable data and represent the background for the present set of results. Of these, 5 received the higher ALZ dose, 17 the lower and 21 belonged to the antibody-void control arm. Treatment arms were well balanced with regard to histological subtypes, IPI sub-groups, and single prognostic factors. Neither of the two treatment cohorts, and for the experimental one irrespective of ALZ dose level, showed significant treatment delay. The median duration of chemotherapy (calculated for 5 bi-weekly cycles of an expected cumulative duration of 70 days) for non-ALZ vs. ALZ-treated patients was 73 vs. 81 days, respectively. No suspected unexpected serious adverse reactions (SUSARs) were reported. Grade 3–4 leucopenia and anemia were more frequent in ALZ-treated patients (71% vs 29% and 47% vs 14%, respectively), whereas no difference was seen in terms of thrombocytopenia (17% vs 18%). Non-hematological toxicity unrelated to infectious complications was similar in the two groups. At the higher ALZ dose level, two cases of systemic fungal infection were reported, of which one (verified as being aspergillosis) with fatal outcome in a patient with pre-existing type II diabetes and steroid-requiring chronic obstructive pulmonary disease. These two events prompted the ALZ dose-reduction amendment, which led to a significant drop in the number of serious adverse events (SAEs) for ALZ-treated patients (SAE/patient pre-amendment: 2.6, post-amendment: 0.76) to a level comparable with the control arm (SAE/patient pre-amendment: 0.67, post-amendment: 0.44). With regard to the types of infection (≥grade 2), there was a similar frequency in reported fungal infections between the two treatment cohorts, bacterial infections were more often reported in the standard treatment arm (55% vs 46%), while the opposite was observed for viral infections (29% vs. 35%). Among the latter, there were 8 cases of cytomegalovirus reactivation among ALZ-treated patients, of which only two were clinically symptomatic and regressed upon specific treatment.In conclusion, the early-on impression of a SAE decrease subsequent to the ALZ dose-reduction amendment (applied on both ACT-1 and ACT-2) has been further confirmed by a larger cohort of patients treated at the lower ALZ dose level. The number of adverse events in the two study arms is now fairly comparable and adds further useful information to the previous reports on feasibility of stem cell harvest (Blood 2010;116: 2395) and hematopoietic recovery (Ann Oncol 2011;22(s4): 476) in ‘de novo' PTCL patients treated with a dose-dense ALZ-CHOP regimen followed by HDT/ASCT.Walewski: 4SC AG: Consultancy. Jantunen:Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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No relevant conflicts of interest to declare.

No relevant conflicts of interest to declare.

No relevant conflicts of interest to declare.

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Abstract 3565

Abstract 3566

As in the MCL1 and 2 studies newly diagnosed stage II-IV MCL patients ≤ 65 years were included. Induction treatment was identical to that of the MCL2 study with alternating cycles of maxi-CHOP-rituximab (3 cycles) and Ara-C-rituximab (3 cycles). Response evaluation was done after cycle 5. PET/CT was recommended, but could not influence the response evaluation, which was done according to the International Workshop criteria. Responders underwent in vivo purged harvest of stem cells after cycle 6 (Ara-C + 2 doses of rituximab). Patients in CRu or PR received a standard dose 90Y-Ibritumomab tiuxetan (0.4 mCi/kg) one week prior to the BEAM/BEAC, CR patients received BEAM/BEAC alone. Patients are followed by CT-scans, bone marrow and blood samples, including PCR for minimal residual disease or molecular relapse. For molecular relapse preemptive treatment with 4 standard doses of rituximab, as in the MCL2 study3, is given.The planned accrual of 160 patients was reached in June 2009. The patient characteristics are similar to those of the MCL2 trial with a median age of 57 years (28-65), the majority male (80%) and in stage IV (89%) with bone marrow involvement (74%). The response rates pre-transplant so far compare favorably with data from MCL2 with 50% in CR, 18% in CRu, and 28% in PR. Only 4 out of 128 evaluable patients did not respond (3%) and there was one case (1%) of treatment-related mortality during induction therapy. While it is still too early to assess the impact of the 90Y-Ibritumomab tiuxetan on the progression-free survival, the side effects were similar to those of the MCL2 study including a treatment related mortality of 4%. Fifty-five patients in CRu or PR have so far been treated with 90Y-Ibritumomab tiuxetan, with no indication of any added toxicity. Only 12 out of 133 patients (10%) have not undergone transplant, 5 due to stem cell harvest failure, 3 due to toxicity and 4 due to non response to induction treatment. PET-scan prior to transplant was positive in 2% of CR patients, 20% of CRu patients and 54% of PR patients. Patients with a positive PET-scan pre-transplant had a 36% chance of achieving a molecular remission post-transplant, compared to 92% of cases with a negative PET-scan (p<0.001)The high response rates after induction treatment achieved in the MCL2 study are confirmed in the present study. Adding 90Y-Ibritumomab tiuxetan to high-dose chemotherapy for responding patients not in CR prior to transplant is feasible and does not increase toxicity. A negative PET-scan prior to transplant predicts for a molecular remission after the transplant.Andersen et al, Eur J Cancer, 2002, 38: 401-408Geisler et al, Blood, 2008, 112: 2687-2693Andersen et al J Clin Oncol 2009 epub ahead of pressKolstad: Bayer Schering Pharma: Research Funding. Geisler:Bayer Schering Pharma: Research Funding.

Abstract 932

Multiple myeloma is a hematological malignancy characterized by accumulation of malignant plasma cells in the bone marrow. Most patients develop osteolytic lesions, caused by an uncoupling of bone formation from bone resorption. In patients with osteolytic lesions the osteoblasts are fewer and less active. HGF (Hepatocyte Growth Factor) is produced by the malignant plasma cells and is found at high concentrations in the bone marrow of most patients with multiple myeloma. In this study we show that HGF inhibited BMP-induced expression of alkaline phosphatase and mineralization in human mesenchymal stem cells (MSC) and the murine myoid cell line C2C12. Furthermore, the expression of the osteoblast-specific transcription factors Runx2 and Osterix was reduced by HGF treatment. HGF inhibited BMP-induced differentiation of MSC partly by keeping the cells in a proliferative, undifferentiated state. The in vitro data was supported by the observation of a negative correlation between HGF and a marker of osteoblast activity, bone specific alkaline phosphatase (rho=−0,45, p=0,008), in sera from 34 myeloma patients. These observations suggest that HGF inhibits bone formation in multiple myeloma.

Multiple myeloma is a hematological malignancy characterized by accumulation of malignant plasma cells in the bone marrow. Most patients develop osteolytic lesions, caused by an uncoupling of bone formation from bone resorption. In patients with osteolytic lesions the osteoblasts are fewer and less active. HGF (Hepatocyte Growth Factor) is produced by the malignant plasma cells and is found at high concentrations in the bone marrow of most patients with multiple myeloma. In this study we show that HGF inhibited BMP-induced expression of alkaline phosphatase and mineralization in human mesenchymal stem cells (MSC) and the murine myoid cell line C2C12. Furthermore, the expression of the osteoblast-specific transcription factors Runx2 and Osterix was reduced by HGF treatment. HGF inhibited BMP-induced differentiation of MSC partly by keeping the cells in a proliferative, undifferentiated state. The in vitro data was supported by the observation of a negative correlation between HGF and a marker of osteoblast activity, bone specific alkaline phosphatase (rho=−0,45, p=0,008), in sera from 34 myeloma patients. These observations suggest that HGF inhibits bone formation in multiple myeloma.

We examined the role of the hepatocyte growth factor (HGF) receptor c-Met in multiple myeloma by applying a novel selective small-molecule tyrosine kinase inhibitor, PHA-665752, directed against the receptor. Four biological sequels of HGF related to multiple myeloma were studied: (1) proliferation of myeloma cells; (2) secretion of interleukin-11 from osteogenic cells; (3) migration of myeloma cells; and (4) adhesion of myeloma cells to fibronectin. We also examined effects of the c-Met inhibitor on intracellular signaling pathways in myeloma cells. PHA-665752 effectively blocked the biological responses to HGF in all assays, with 50 % inhibition at 5-15 nM concentration and complete inhibition at around 100 nM. PHA-665752 inhibited phosphorylation of several tyrosine residues in c-Met (Y1003, Y1230/1234/1235, and Y1349), blocked HGF-mediated activation of Akt and p44/42 Mitogen-activated protein kinase (MAPK), and prevented the adaptor molecule Gab1 from complexing with c-Met. In the HGF-producing myeloma cell line ANBL-6, PHA-665752 revealed an autocrine HGF/c-Met-mediated growth loop. The inhibitor also blocked proliferation of purified primary myeloma cells, suggesting that autocrine HGF/c-Met-driven growth loops are important for progression of multiple myeloma. Conclusions: Collectively, these findings support the role of c-Met and HGF in the proliferation, migration, and adhesion of myeloma cells and identify c-Met kinase as a therapeutic target for treatment of patients with multiple myeloma.

We examined the role of the hepatocyte growth factor (HGF) receptor c-Met in multiple myeloma by applying a novel selective small-molecule tyrosine kinase inhibitor, PHA-665752, directed against the receptor.