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Autologous stem cell transplantation (ASCT) combined with novel agents is the standard treatment for transplant-eligible, newly diagnosed myeloma (NDMM) patients. Lenalidomide is approved for maintenance after ASCT until progression, although the optimal duration of maintenance is unknown. In this trial, 80 patients with NDMM received three cycles of lenalidomide, bortezomib, and dexamethasone followed by ASCT and lenalidomide maintenance until progression or toxicity. The primary endpoint was the proportion of flow-negative patients. Molecular response was assessed if patients were flow-negative or in stringent complete response (sCR). By intention to treat, the overall response rate was 89%. Neither median progression-free survival nor overall survival (OS) has been reached. The OS at 3 years was 83%. Flow-negativity was reached in 53% and PCR-negativity in 28% of the patients. With a median follow-up of 27 months, 29 (36%) patients are still on lenalidomide and 66% of them have sustained flow-negativity. Lenalidomide maintenance phase was reached in 8/16 high-risk patients but seven of them have progressed after a median of only 6 months. In low- or standard-risk patients, the outcome was promising, but high-risk patients need more effective treatment approach. Flow-negativity with the conventional flow was an independent predictor for longer PFS. Electronic supplementary material The online version of this article (10.1007/s00277-019-03815-7) contains supplementary material, which is available to authorized users.

There is no consensus on treatment strategies for elderly patients with mantle cell lymphoma (MCL). In this prospective phase II study we investigated whether the poor outcome could be improved, with reasonable toxicity, by prolonging the immunochemotherapy. Ten cycles of alternating cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP)/cytarabine (AraC) with eight doses of rituximab (R) were given as induction. The potential synergism of intermediate-dose AraC and fludarabine was tested in cycles 6-8. Induction was followed by bimonthly rituximab maintenance for 2 years. The median age of the 60 included patients was 74 years, and the Mantle Cell Lymphoma International Prognostic Index (MIPI) was intermediate or high risk in 98% of the patients. The overall response rate was 95% (complete response/complete response unconfirmed 87%). The response of 11 patients improved with cycles 6-8 (R-fludarabine-AraC). Progression-free survival was 70% and overall survival 72% at 4 years, respectively. Treatment related mortality was 2%. Severe infections were rare, with only one grade 4 infection. More dose reductions were needed during fludarabine-containing courses as compared to R-AraC. In 20 patients a transient grade 4 neutropenia without severe infections was recorded during maintenance. In conclusion, elderly patients with MCL can be treated relatively intensively with acceptable toxicity.

Biologic and clinical observations suggest that combining imatinib with IFN-α may improve treatment outcome in chronic myeloid leukemia (CML). We randomized newly diagnosed chronic-phase CML patients with a low or intermediate Sokal risk score and in imatinib-induced complete hematologic remission either to receive a combination of pegylated IFN-α2b (Peg–IFN-α2b) 50 μg weekly and imatinib 400 mg daily (n = 56) or to receive imatinib 400 mg daily monotherapy (n = 56). The primary endpoint was the major molecular response (MMR) rate at 12 months after randomization. In both arms, 4 patients (7%) discontinued imatinib treatment (1 because of blastic transformation in imatinib arm). In addition, in the combination arm, 34 patients (61%) discontinued Peg–IFN-α2b, most because of toxicity. The MMR rate at 12 months was significantly higher in the imatinib plus Peg–IFN-α2b arm (82%) compared with the imatinib monotherapy arm (54%; intention-to-treat, P = .002). The MMR rate increased with the duration of Peg–IFN-α2b treatment (< 12-week MMR rate 67%, > 12-week MMR rate 91%). Thus, the addition of even relatively short periods of Peg–IFN-α2b to imatinib markedly increased the MMR rate at 12 months of therapy. Lower doses of Peg–IFN-α2b may enhance tolerability while retaining efficacy and could be considered in future protocols with curative intent.

Introduction: The median progression free survival (PFS) and overall survival (OS) of multiple myeloma (MM) patients have been prolonged due to novel agents combined with ASCT but the median OS in MM is still 7-8 years. Thus, the feasibility of new combinations and dosing of available agents must be investigated. The first proteasome inhibitor (PI), bortezomib (B), combined with elotuzumab and dexamethasone (d) showed superiority to Bd with PFS of 9.7 vs. 6.9 months, respectively, without excessive toxicity (Jakubowiak et al. Blood 2016;127:2833-40). In our study we investigate the safety, feasibility and initial efficacy of a second generation PI carfilzomib (K), SLAMF7 antibody elotuzumab (E) and dexamethasone (D) combination (KED) in relapsed or refractory MM (RRMM) patients. Patients and methods: Forty RRMM patients after 1-3 prior lines will be included in this phase 2 study after written informed consent. The primary endpoint is overall response rate (ORR). In patients achieving at least very good partial remission (VGPR) the quality of response will be assessed with high-sensitivity multicolour flow cytometry (MFC) according to the 8-colour EuroFlow protocol. Carfilzomib is given once weekly 20 mg/m2 on D1C1 and thereafter 70 mg/m2 in 28 day cycles on days 1, 8 and 15 in cycles 1-8 and on days 1 and 15 thereafter combined with weekly elotuzumab 10 mg/kg on days 1, 8 and 15 in cycles 1-2, thereafter on days 1 and 15; dexamethasone 40 mg on days 1, 8, 15 and 22 on cycles 1-8, thereafter on days 1 and 15. Treatment will continue until progression or excessive toxicity. Carfilzomib dose was 20/56 mg/m2 for the first two cycles for the first five patients to evaluate the safety. Additionally, patient samples collected prior to treatment will be comprehensively profiled by whole exome and RNA sequencing and evaluated for ex vivo response to the agents. Together, the study addresses clinical response, ex vivo-in vivo translation, identifies molecular biomarkers for the KED combination and facilitates precision guided clinical trials for RRMM. Results: By the end of July 2018, 11 patients have been enrolled. Median number of prior lines was 2 (1-3). Seven IgG-κ, two IgA-κ and one kappa and lambda light-chain patient are included. After a median of 6 (2-12) cycles ORR is 91% with 3 patients in VGPR (median MFC-MRD of 0,002%), 7 patients in PR, one in MR. Initial molecular characterization highlighted diverse subclonal backgrounds among the treated patients (Figure 1), but interestingly, the best responding VGPR patients displayed mutations to RAS genes in the dominant clones (NRAS 828, 2662; KRAS 733). At least PR was achieved after a median of 1 (1-4) cycle. Three patients have progressed and one patient withdrawn due to suspected thrombotic microangiopathy with manifestation of convulsions and pulmonary embolism. We noticed only one grade 2 infusion reaction after premedication. One patient developed autoimmune hemolytic anemia (AIHA), without red cell antibodies, suspected to be related to elotuzumab. She recovered with steroids and elotuzumab discontinuation and continued Kd without reappearance of AIHA. Another patient had grade 3 liver transaminase elevation but was able to continue treatment with dose reduction of carfilzomib and dexamethasone. Conclusion: To the best of our knowledge this is the first study evaluating the carfilzomib, elotuzumab and dexamethasone combination in RRMM with comprehensive molecular annotations. Among this small group of patients we noticed two unexpected severe adverse events; atypical AIHA and suspected thrombotic microangiopathy. AIHA should be excluded if unexpected anemia will appear during elotuzumab treatment. Preliminary results of this KED combination showed efficacy in patients with clonal RAS mutations and ORR of 91% after the median of two prior treatment lines using weekly carfilzomib dose of 70 mg/m2. Figure 1: Subclonal diversity in patient derived plasma cells. Clonal and subclonal fractions were evaluated by assessing peaks of variant allele frequencies of somatic mutations present in the myeloma plasma cells using kernel density estimation. For each plot, the fraction of cells carrying the mutation is represented on the x axis (1 = 100% of cells), and the probability density on the y axis. The mutated cell fraction (x axis) was calculated by adjusting mutant allele burden by copy number of the mutated loci. Disclosures Silvennoinen: Takeda: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. Tsallos:Novartis: Research Funding. Anttila:Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees. Räsänen:Amgen: Honoraria. Luoma:Amgen: Honoraria. Jantunen:Amgen: Honoraria; Genzyme/Sanofi: Honoraria; Takeda: Honoraria. Heckman:Celgene: Research Funding; Orion Pharma: Research Funding; Novartis: Research Funding.

Objectives Previous studies indicate that 40–50% of patients with chronic myeloid leukemia in prolonged complete molecular remission may discontinue imatinib therapy without imminent relapse. The combination of pegylated interferon-alpha (Peg-IFN-α2b) and imatinib may increase the rate of successful discontinuation. Methods In this pilot study, we prospectively stopped imatinib from patients (n = 12) who had achieved major molecular response (MMR) after ≥12 months of treatment with either imatinib or imatinib+Peg-IFN-α2b. Molecular monitoring was carried out monthly for BCR-ABL1. In addition, analyses of lymphocyte immunophenotype, function, and plasma cytokines were performed. Results In the monotherapy group, 5/6 patients lost MMR within 4 months. One patient remains to date in MR4.0 61 months after discontinuation. In the combination therapy group, 2/6 patients relapsed within 4 months while still receiving Peg-IFN-α2b. Four of six patients were able to discontinue both treatments, but three of these patients relapsed after 3 months. One patient is still in sustained MR4.0 at 58 months off all treatment. All relapsed patients re-responded to imatinib. The two successfully discontinued patients had either an increased number of NK-cells or functionally active T-cells. Conclusions A higher frequency of relapsed patients in our study in comparison with other studies may be due to the shorter duration of imatinib treatment prior to discontinuation. However, in selected patients with an active immune system, even a short duration of TKI therapy (

Introduction The majority of myeloma (MM) patients will relapse or progress in 2-3 years after initial treatment. To prolong remission time several regimens have been investigated for consolidation and maintenance. Minimal residual disease (MRD) has been considered to be a potentially novel primary endpoint in evaluating the efficacy of new therapies. The FMG-MM02 study (NCT01790737) was designed to explore the response to lenalidomide, bortezomib and dexamethasone (RVD) induction, followed by a single ASCT and lenalidomide (LEN) maintenance in newly diagnosed MM patients. The primary endpoint is immunophenotypic remission (IR) and will be compared with molecular remission as a secondary endpoint in sCR patients. Here we present the IR results, comparison with RQ-PCR, and short-term results of other secondary endpoints; improvement of responses during maintenance and PFS. Patients and methods Three RVD cycles consisted of LEN 25 mg/d po on days 1-14, bortezomib 1.3 mg/m2 sc on days 1,4,8,11 and dexamethasone 20 mg po on days 1-2, 4-5, 8-9 and 11-12, followed by MEL200 + ASCT. Three months later patients started LEN 10 mg/d on days 1-21 in 28-day cycles until progression or excess toxicity. Multiparameter flow cytometry (MFC) assays were performed in five Finnish university hospital laboratories. After gating with CD38/CD138/light scatter the expressions of CD45/CD19/CD56/CD27/CD28/CD81/CD117/intracytoplasmic Κ/λ were assessed in all samples at diagnosis and informative markers were used for MFC-MRD analysis. Fifty immunophenotypically abnormal plasma cell events was the lower limit for quantitation in MRD analysis and at least 0.5 x 106 total nucleated cells were needed to reach the sensitivity of 0.01%. Results Overall response rate (ORR) was 86% by intention-to-treat (ITT) after RVD induction. Three months after ASCT 47/80 (59%; ITT) patients had achieved ≥ VGPR and 29/80 (36%) were in IR. Nine patients were withdrawn early due to toxicity. Of the per protocol treated 71 patients 29 (41%) were in IR. After a minimum follow-up of 12 months after ASCT (9 months on maintenance) 38/80 (48%) patients were in at least VGPR and 24/80 (30%) in IR by ITT. Eighteen patients (23 %) have progressed and 4 patients (5 %) have died. From those patients who have continued maintenance 24/44 (55%) patients were in IR. The median follow-up is 22 (2-38) months. Four additional patients have achieved IR during the maintenance and 13 (22%) have upgraded their serological response. The proportion of MM cells among all plasma cells (PC) decreased from the median of 44% (3-100%) to 17% (9-28%) in MFC-positive patients during 9 months of maintenance. The median number of total nucleated cells was 0.7 x 106 in MFC-MRD negative samples resulting in the median sensitivity of < 0.007% of all samples. Fifty percent (11/22) of the samples of sCR/MFC-MRD negative patients were also PCR-negative with the median sensitivity of < 0.0006%. The remaining 50% (11/22) of the samples were still PCR-positive with the median amount of 0.002%. The median PFS for all study patients has not been reached; estimated median PFS is 29 months (95% CI 25-32). Patients (n=24/80, 30%) with high-risk (HR) cytogenetic (del17p, t(4;14), t(14;16) and/or +1q) had significantly shorter PFS (21 months vs. median not reached), p=0.04. ORR of HR patients was 18/24 (75%) and 11/24 (46%) reached IR at least once before relapse. Patients with t(4;14) (n=8), had the worst outcome with the median PFS of only 9 (4-13) months compared to median not yet reached of all other patients or patients without t(4;14), p Conclusion RVD + ASCT + short-term LEN maintenance resulted in 30% IR by ITT but in 55% IR for those who were able to continue protocol treatment. With 9 months of LEN maintenance serological responses improved more than immunophenotypic responses, but the constitution of PCs of MFC-MRD positive patients showed recovery. RVD + ASCT + LEN maintenance seems to benefit most patients without HR cytogenetics. This study confirms previous findings that PCR is one logarithm more sensitive than MFC in MRD assessment. Disclosures Silvennoinen: Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Lecture fee; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Other: Lecture fee. Säily:Celgene: Other: Educational grant for congress participation; Amgen: Other: Educational grant for congress participation. Siitonen:Celgene: Other: Lecture fee; Amgen: Other: Lecture fee. Räsänen:Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene, Amgen: Other: Educational grant for congress participation. Kananen:Celgene, Sanofi Genzyme: Other: Educational grant for congress participation; Amgen: Other: Lecture fee. Lievonen:Novartis: Consultancy; Celgene, Amgen: Honoraria; Takeda, Roche: Other: Educational grant for congress participation; Janssen, Celgene, Amgen, Novartis, Takeda, Roche: Other: Educational grant for congress participation. Pelliniemi:Novartis: Consultancy; Alexion, Novartis, Roche: Other: Lecture fee. Porkka:Celgene: Research Funding. Remes:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees.

Introduction ASCT is the standard treatment in MM for eligible patients < 70 years of age. The median OS has improved from 3-4 to 5-6 years with combination of novel drugs and ASCT. In spite of initial response MM will relapse or progress in the majority of patients in 2-3 years and several consolidation and maintenance treatments are under evaluation. We designed this FMG-MM02 study (NCT01790737) to explore the response of lenalidomide, bortezomib and dexamethasone (RVD) induction, followed by single ASCT and lenalidomide maintenance in newly diagnosed MM patients. The primary endpoint of the study is immunophenotypic remission (IR), and molecular response will be assessed from patients with sCR/IR. The secondary endpoints include safety, improvement of responses during lenalidomide maintenance and PFS. Patients and methods 69 out of 80 included patients proceeded to mobilization after induction with 3 cycles of RVD. Eleven patients (14%) were dropped out due to early toxicity (n=9) or early progression (n=2). The RVD cycle consisted of lenalidomide 25 mg/d po. on days 1-14, bortezomib 1.3 mg/m2 sc. on days 1,4,8 and 11 and dexamethasone 20 mg po. on days 1-2, 4-5, 8-9 and 11-12. Additional nine patients were withdrawn before ASCT due to progression, so actually 60 patients received MEL200+ASCT and lenalidomide maintenance was planned to start three months after ASCT, 10 mg/d on days 1-21 in a 28-day cycle. The multiparameter flow cytometry (MFC) was analyzed from all patients with at least PR response. 53/60 patients have achieved the time-point of three months after ASCT and can be analyzed here. Median follow-up time is 52 (1−115) weeks. Results Forty-five gr 3-4 SAEs were documented in 39 patients during induction; most common were infections (pneumonia, bronchitis) and gastrointestinal disorders. The nine patients with early drop out due to toxicities had following adverse events: severe liver toxicity, amaurosis fugax, neutropenia, severe sepsis-syndrome with rash, simultaneous diagnosis of adenocarcinoma pulmonum, history of prostate cancer, two patients not eligible to ASCT due to infections and one patient died of hepatorenal syndrome. The overall response rate for RVD induction was 86% in intention-to-treat. The primary endpoint, IR, measured by 6-10 color MFC, was achieved at ASCT in 22/69 (32%) of patients who actually received the planned RVD induction and in 22/80 (28%) by intention-to-treat (ITT). The median sensitivity of MFC-MRD-negativity was Three months post-ASCT 24/53 (45%) of evaluable patients had IR with the median sensitivity of MFC-MRD-negativity The achievement of at least VGPR response or IR at ASCT predicts better outcome with estimated PFS of 23.8 months compared to 15.2 months of patients response worse than VGPR (p=0.001) and the respective figures for IR and non-IR are 24.7 and 17.2 months (p=0.016). Patients with t(4;14), t(14;16), n=9, had shorter median PFS (shorter than patients with del 17p), 12.8 months, compared to estimated 20.8 months of other patients (p=0.053). Conclusion One third (28%) of patients achieved an IR after RVD induction, which contrasts with only 14% of serological CR/sCR. This discrepancy most probably results from the rather slow kinetics of paraprotein disappearance. Thus, subsequential samples and sufficient follow-up time are mandatory in evaluation of paraprotein responses. The IR was still predicting favorable outcome and only one of these MFC-MRD negative but paraproteinpositive patients has so far relapsed. In spite of quite high initial IR rate the patients with high-risk cytogenetics relapse quite soon. RVD regimen seems not to overcome their poor prognosis, and these patients clearly need more individual treatment choices. Disclosures Silvennoinen: Amgen: Consultancy, Honoraria; Celgene: Research Funding; Janssen: Research Funding; Genzyme: Honoraria; Sanofi: Honoraria; Research Committee of the Kuopio University Hospital Catchment Area for State Research Funding, project 5101424, Kuopio, Finland: Research Funding. Siitonen:Novartis: Other: charges of EHA congress 2015; Pzizer: Other: charges of EAHAD congress 2015. Putkonen:Celgene: Honoraria; Amgen: Honoraria. Porkka:Celgene: Research Funding. Remes:Roche: Honoraria; Celgene: Honoraria; Janssen: Honoraria. Jantunen:Genzyme: Honoraria; Sanofi: Honoraria; Genzyme: Consultancy.

Introduction Autologous stem cell transplantation (ASCT) is the standard treatment in multiple myeloma (MM) for eligible patients below 70 years of age. The main mobilization treatment in Europe consists of combination of cyclophosphamide (CY) and G-CSF. It is questionable if CY is useful in mobilization. CY as an alkylating agent might also have some negative long-term effects. Bortezomib seems not to have negative impact on autologous stem cell harvesting, but prolonged use of lenalidomide might hamper mobilization. There are only a few studies regarding autologous stem cell mobilization after RVD induction. We designed this randomized study as a substudy of the Finnish Myeloma Group Study (NCT01790737) to compare the results of CY+G-CSF versus G-CSF mobilization in autologous stem cell harvesting. The primary endpoint is the percentage of patients reaching ≥ 3 x 106/kg CD34+ cells (or ≥ 6 x 106/kg for two transplants), with ≤ 2 apheresis after low-dose CY+G-CSF vs. G-CSF mobilization. Secondary endpoints are need for plerixafor, graft cellular composition and engraftment after ASCT. Patients and methods This phase 2 study will include 80 patients below 70 years of age with symptomatic MM and eligible for ASCT. At registration the patients are randomized equally to arm A) CY 2 g/m2 + G-CSF 5 μg/kg or arm B) G-CSF 10 μg/kg. Before mobilization three RVD induction cycles are given. Each 3-week RVD cycle includes lenalidomide 25 mg daily on days 1−14, bortezomib 1.3 mg/m2 subcutaneously on days 1, 4, 8, 11, and dexamethasone 160 mg/cycle. By this schedule the first harvest is estimated to be on day +10 in CY + G-CSF and on day +5 in G-CSF group. Apheresis will start with blood CD34+ level >10 x 106/l. The target cell yields for one and two grafts are ≥ 3 and ≥ 6 x 106 CD34+ cells/kg, respectively, and the minimum for one graft ≥ 2 x 106/kg. Plerixafor is given if B-CD34+ cell count is less than 10 x 106/l on days +10 or +5, respectively, or if the first apheresis product contains < 1 x 106/kg CD34+ cells. G-CSF support is used after ASCT if the number of CD34+ cells in the graft is less than 3 x 106/kg. Engraftment will be assessed by blood neutrophil count > 0.5 x 109/l, and unsupported platelets > 20 x 109/l. Results Fifty-six patients have been included, and the mobilization data for the first 37 patients are available for analysis. The primary endpoint was reached in 90% of the patients (18/20) in arm A and in 82% (14/17) in arm B (p=NS). The median number of apheresis to reach the goal in arms A and B is one (1-3) and two (1−3), respectively (p=0.03). The median number of harvested cells in the two arms is 6.2 (2.2−12.1) and 4.8 (2.9−7.6) x 106/kg, respectively (p The median number of CD34+ cells transplanted, was 4.1 (2.2−7.3) and 3.2 (2.3−4.7) x 106/kg in arms A and B, respectively (p=0.01). In arm A the median neutrophil engraftment was on day +14 (9−28) (16 patients) and in arm B on day +15 (11−25) (15 patients) (p=0.68). The median platelet engraftment days were +13 (8−22) and +11 (8−21) in arms A and B, respectively (p=0.67). At ASCT the response rates in arm A were ≥ VGPR 65% (13/20), PR 25% (5/20), and 10% (2/20) were progressing, and the respective rates for arm B were 70% (12/17), 18% (3/17),and 12 % (2/17). Conclusions Preliminary results of this randomized mobilization substudy with a limited number of patients show no clinically significant differences between the number of harvested CD34+ autologous stem cells. However, in CY+G-CSF group the CD34+ cell target was reached by less aphereses. After short induction course of RVD it seems possible to harvest also for two autografts with G-CSF only mobilization. However, when compared to historical data the CD34+ cell counts in blood and grafts were lower than after bortezomib + dexamethasone induction, and also neutrophil engraftment seemed to be slower after lenalidomide-based induction therapy. We conclude that CY can be omitted in the mobilization regimen for MM patients who have responded to short course of RVD. Disclosures Silvennoinen: Janssen-Cilag: Research Funding; Celgene: Research Funding; Janssen-Cilag: Honoraria; Sanofi: Honoraria; Celgene: Honoraria. Porkka:BMS: Honoraria; BMS: Research Funding; Novartis: Honoraria; Novartis: Research Funding; Pfizer: Research Funding.

Background Rituximab (R) maintenance therapy bimonthly until progression has been shown in a recent randomized study to prolong duration of remission (with median follow-up of 37 months) and overall survival in elderly patients (pts) with MCL after R-CHOP, but not after R-FC, induction therapy (Kluin-Nelemans et al, N Engl J Med 2012; 367:520-31). We have previously reported initial results of 60 elderly pts with MCL treated with induction therapy consisting of 10 cycles of alternating standard CHOP and intermediate-dose AraC (combining fludarabine in 3 cycles) with 8 doses of R, followed by bimonthly R maintenance for 2 years (yrs) (Räty et al. Leuk Lymphoma 2012; 53:1920-8). High response rate to induction therapy with ORR of 95% (CR/CRu 87%) was seen. PFS was 70% and OS 72% at 4 yrs with the median follow-up of 40 months. Herein, we update our results of this prospective study with completed maintenance therapy in all pts with a median follow-up time of 6 yrs for surviving pts. Methods The pts were recruited at 10 Finnish centres during Dec 2004 and Aug 2010. Eligible pts were > 65 yrs old with histologically confirmed newly diagnosed (WHO criteria, CD5+, CD19/20+, Cyclin D1+) and previously untreated stage II-IV MCL with adequate organ functions and performance status (WHO) Results At the time of diagnosis the median age of 60 recruited pts was 74 yrs (range 65-83), 62% were males, 97% had advanced disease (stage III-IV), 77% had good performance status (PS 0-1). Most (87%) had a history of some other notable illness, most typically cardiovascular disease. Another cancer had been diagnosed earlier in 9 pts (prostate n=3, breast n=3, other n=3). The MIPI risk was low in 2%, intermediate in 45% and high in 53% of the pts, respectively. ORR was 95% (CR/CRu n= 52, PR n=5, PD n=2). One patient could not be evaluated for response due to withdrawal of consent after the first cycle. Seven pts did not receive R maintenance (died/progressed/relapsed during induction n=5, withdrawal of consents n= 2). All 12 doses were given to 34 of 53 pts (64%, CR/CRu n=32, PR n=2). Four pts discontinued maintenance due to recurrent infections / neutropenia,10 pts due to relapse and 5 due to other reasons (secondary MDS n=1, general fatigue n=2, unknown n=2). A transient grade 4 neutropenia was seen in 20 pts during maintenance with no serious infections. HZV or VZV infections were recorded in 9 pts. Altogether 22 of responding pts have progressed/relapsed (during induction n=2, during maintenance n=10, during follow-up n=10), 6 of them with isolated CNS relapse. Twenty-one pts have died (sudden cardiac death during induction n=1, progressive MCL n=17, secondary MDS/AML n=1, unknown n=2). At 6 yrs (intention to treat) PFS was 64% (median 97 months, 95% CI 75 – 120 months), EFS 59% (median 95 months, 95% CI 75 – 114 months) and OS 62% (median not reached), respectively. DFS was 72% at 6 yrs (median 91 months, 95% CI 89 – 93 months) for 52 pts in CR/CRu. Two pts have developed secondary MDS (at 27 and 67 months). Eight new cancers (prostate n=3, breast n=1 and skin n=4) have been recorded in 6 patients during maintenance or follow-up. Conclusions Long PFS and OS over 60% at 6 yrs with median DFS of more than 7 yrs can be achieved with prolonged cytarabine-containing immunochemotherapy followed by 2 yrs R maintenance in elderly pts with MCL. Maintenance therapy was well tolerated in general. Transient neutropenia during maintenance was not uncommon, but serious infections were not seen and only 4 pts discontinued maintenance therapy because of recurrent neutropenia or infections. Attention for second malignancies is requested as 9 pts had cancer before MCL diagnosis, MDS/AML was developed in 2 pts and 6 pts showed carcinomas during follow-up in this elderly patient population. Disclosures Räty: Roche Ltd: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline Ltd: Honoraria; Mundipharma: Honoraria. Mikkola:Roche Ltd: Honoraria. Poikonen:Celgene: Speakers Bureau; Amgen: Speakers Bureau; Baxter: Speakers Bureau; Novartis: Speakers Bureau; GlaxoSmithKline: Consultancy; Mundipharma: Honoraria; Novartis: Honoraria. Räsänen:Novartis: Honoraria; Roche Ltd: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; Janssen-Cilag: Honoraria; Amgen: Honoraria; Mundipharma: Honoraria.

Abstract 3280 Poster Board III-1 Background: Imatinib mesylate (IM) 400 mg once daily (OD) is the current standard first-line therapy for CML. Several biological and clinical observations suggest that combining IM with interferon alpha (IFNa) may improve the outcome of treatment. Aim: To compare the effects of standard-dose IM to combination of IM and IFNa in newly diagnosed chronic phase CML patients with an intermediate or low Sokal risk score. The primary end point was to compare the major molecular response (MMR) rate after 12 months between the treatment arms (intention-to-treat analysis). Patients and therapies: In a Nordic CML Study Group (NMCLSG: Denmark, Finland, Norway and Sweden) and Israel multicenter study we randomized 114 newly diagnosed CML patients in complete hematological remission following 3 months of IM 400 mg OD induction therapy. The study arms were IM (Glivec, Novartis) and the combination of IM and IFNa 2b (PegIntron, Schering-Plough). IM dose was fixed at 400 mg OD. IFNa was started at 30 μg/week but could be escalated to 50 μg/week or reduced down to 15 μg/week depending on tolerability. Molecular response was evaluated by blood RQ-PCR for BCR-ABL1 and was expressed on the international scale (IS). Results: As of August 17, 2009, 79 patients were evaluable for primary endpoint and 47 of these were in MMR (59%) The rate of complete cytogenetic response (CCgR) was 68/79 (86%). Nineteen patients (17%) were considered as treatment failures (grade 4 nonhematological adverse event, refusal, loss of CCgR, progression to advanced phase, protocol violation or other reason). Conclusions: A final analysis will be performed when we have complete data on all randomized patients. The comparison by treatment arm on molecular and cytogenetic responses as well as other relevant data (treatment failures, patients off-treatment for protocol violations, refusal or toxicity) will be presented on site. Supported by European LeukemiaNet, WP 4. Disclosures: Simonsson: Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding. BjÖreman:BMS: Consultancy, Honoraria. Mustjoki:BMS: Honoraria. StrÖmberg:Novartis: Honoraria; BMS: Honoraria. Weiss Bjerrum:Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria. Gruber:Novartis: Research Funding. Nagler:Novartis: Consultancy. Porkka:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding.

Tyrosine kinase inhibitor (TKI) imatinib mesylate (IM) is the standard of care for patients with chronic myeloid leukemia (CML). Leukemia-initiating CML stem cells are resistant to TKIs and thus it is unlikely that CML patients will be cured with IM monotherapy. Recent data indicate that in a proportion of CML patients primed with preceding interpheron alpha (IFNα) therapy, IM may be discontinued without rapid leukemia re-expansion. In the Nordic CML study group intermediate and low risk study (IR/LR, NordCML002), newly diagnosed CML patients were randomized after 3 months of IM induction therapy to receive 12 months of either standard IM monotherapy or IM-IFNα combination therapy. In the STOP study (NordCML004) we prospectively discontinued IM and IFNα in IR/LR study patients who achieved major molecular response (MMR) during 12 months of randomized therapy (n=10; IM 5, IM-IFN 5). In this study the monotherapy patients continued imatinib 400mg QD for 6 months while the combination therapy patients stopped IM at study entry and continued IFNα for 6 months. Molecular monitoring by blood RQPCR was done monthly after any drug discontinuation. In the monotherapy group IM was reinitiated when a confirmed loss of MMR was seen. In the IFNα group a rise up to the -2 log (1%) level was allowed before restart. The patients in the monotherapy group had received IM for a median of 23 months (range 21–25 mos) at the time therapy was discontinued. Four of the 5 patients had complete molecular response (CMR); 1 patient had a 3,2 log reduction. No Philadelphia positive (Ph+) cells were detected in either the CD34 positive or the CD34 positive/CD38 negative cell fractions prior to drug discontinuation when analyzed by FISH (n=3, 1000 cells counted). All 5 patients lost MMR rapidly within 4 months. The median time of IM discontinuation was 114 days (range 64–166 days). All evaluable patients re-responded to IM promptly. In the combination therapy group the median duration of IM therapy was 18 months (range 15–19 mos). The patients had used IFNα (Pegintron®) for a median of 14 months (range 12–16 mos). The target dose of 50 μg s.c. once weekly was used by 3 patients and 2 patients used only 20 μg s.c. once weekly due to toxicity. Four of the 5 patients had CMR when they stopped IM; 1 patient had a 3,2 log reduction. As in the monotherapy group no Ph+ cells were detected in the examined stem cell fractions prior to drug discontinuation (n=2). Two of the 5 patients rapidly relapsed within 4 months while still using IFNα corresponding the monotherapy patients. Three patients discontinued all treatment. One patient was in MMR and 2 had log-reductions between 2–3 log units. The latter 2 patients relapsed after 3 months off all treatment. One patient is still in sustained MMR at 18 months off IM and 12 months off all treatment. The median time of IM discontinuation for the combination therapy group is 277 days (range 151– 559+ days). Relapsed patients have started IM monotherapy and all have re-responded. In conclusion, in concord with previous data, discontinuation of IM monotherapy in patients having MMR/CMR resulted in a rapid disease relapse in all patients. However, in 3 out of 5 patients concomitant IFNα enabled IM discontinuation by inducing a state of stable minimal residual disease. One of these patients has been able to discontinue both IM and IFNα and sustain MMR for a considerable time. The occurrence of relapse was not correlated with the number of residual leukemic stem cells as no Ph+ CD34+/CD38- cells were detected prior to drug discontinuation in either group (n=5). Further clinical studies on combinations of TKIs and IFNs are warranted. Elucidating the molecular and immunological mechanisms of priming effects of IFN would enable rational patient selection and putatively result in operational cure of a significant number of CML patients. Figure Figure

Background: The Nordic Lymphoma Group has shown that adding cytarabine (AraC) and rituximab (R) to high dose CHOP and autologous stem cell transplantation increases response rate, event free survival (EFS), progression free survival (PFS) and overall survival (OS) of patients (pts) with MCL < 65 years (Geisler et al, Blood 2008). About 50% of pts with MCL are older than 65 years. Most of them are not candidates for high dose chemotherapy or transplantations and no satisfactory standard treatment is known for them. In this prospective pilot trial for elderly pts we explored the feasibility and efficacy of a prolonged standard dose induction treatment (10 cycles) with potentially synergistic combinations followed by R maintenance. Methods: Eligible were pts with histologically confirmed MCL (WHO criteria), CD5+, CD19/20+, cyclinD1+, age > 65 years, with adequate organ functions and performance status < 4. Induction: standard dose R-CHOP (cycles 1, 3, 5), R-AraC (R 375mg/m2 x 1, AraC 1g/m2 4 doses with 12 hrs intervals, cycles 2, 4), R-AraC with fludarabine (F) (2 doses of F 25 mg/m2, cycles 6 – 8), CHOP (cycles 9–10). Maintenance for pts with CR/PR: R 375 mg/m2 bimonthly x 12. Diagnostic workup included physical examination, CT scan, histological lymph node biopsy, bone marrow aspiration and biopsy, and immunohistology or flow cytometry of the diagnostic material. Endoscopies were performed for symptomatic patients. Responses were evaluated according to revised criteria (Cheson et al JCO 2007) after 5th, 8th, 10th cycles and after that every 6 months. Results: Thirty four pts were recruited. Age median 74 years (67–79 years). Performance status 0 n=12, 1 n=16, 2 n=3, 3 n=3. Stage IIA n=1, IVA n=20, IVB n=13. International prognostic index IPI 2 n=10, 3 n=13, 4 n=9, 5 n=2. Response to induction: CR 23, CRu 6, PR 3, PD 1, not evaluable 1. The response of 7 pts improved with cycles 6 to 8 (R-AraC with F). At diagnosis 32 pts had bone marrow involvement. At best response 24/25 pts with bone marrow involvement studied and CR (n=17), CRu (n=6) or PR (CTscan positive, n=1) were negative in flow cytometry (sensitivity 10−3–10−4). One patient with PR had residual MCL in flow cytometry. Median follow-up time of living patients is 26 months, range 6–43 months. There have been 8 events: progression or relapse 4, secondary AML 1, sudden cardiac death in CR 1, and 2 responding patients withdrew their concents. At 30 months EFS is 72%, PFS 77%, time to progression 85%, and OS 80%. Three pts have discontinued induction after 6,7 or 8 cycles due to toxicity but remain in CR. Infections grade 3 occurred in 8 pts and grade 4 in 1 patient. Eight pts have had transient neutropenia < 0.5 x 109/l during maintenance treatment. Conclusions: Elderly patients with MCL and with good performance status could be treated relatively intensively with moderate toxicity when supported with G-CSF. In historical comparison to CHOP, R, AraC and F increase response rate and prolong PFS, TTP and OS. Flow cytometry is a powerful tool to study bone marrow involvement at diagnosis and minimal residual disease. A longer follow-up is needed to evaluate the maintenance treatment but several patients have developed transient grade 4 neutropenia during maintenance treatment after this induction schedule.