ALBERT

Description: Background. Protein electrophoresis and immunofixation in the serum (SPEP - SIF) and urine (UPEP – UIF) have been routinely used for decades for characterizing and quantifying the M protein in Multiple Myeloma (MM). However, these techniques are notoriously tarnished with inaccuracy, despite improvements in recent years. The most important breakthrough in the field in recent years was the discovery of the Serum Free Light Chain Assay (sFLC), a routine quantitative and automated assay that measures kappa and lambda sFLC, however this was added to / rather than replaced traditional tests in the diagnostic armamentarium of MM. Recently, a new test quantifying paired clonal and non-clonal immunoglobulins (heavy/light chains HLC i.e. IgGκ/IgGλ) in serum was developed. Here we aim to assess the new HLC assays as tools to replace SPEP / IFE during MM patient monitoring Materials and methods. 110 Myeloma treated with pomalidomide and dexamethasone in two IFM studies (IFM 2009-02 in end stage RRMM and IFM 2010-02 in del17p and t(4;14) RRMM ) were included. The criteria for selection were that patients had measurable intact immunoglobulin myeloma according to IMWG criteria (M spike ≥10g/L), using serum and/or urine protein electrophoresis, with exclusion of patients solely measurable on UPEP and sFLC. All sera were collected centrally before initiation of treatment and sequentially every cycle until progression. Hevylite® (HLC) was measured in the biology laboratory of CHRU of Lille, France and results compared to traditional measurements. Along with SPEP, SIF, UPEP, UIF, and sFLC, we have also measured IgA HLC (IgA k and IgA l) and IgG (IgG k and IgG l) and the corresponding difference (clonal - non clonal) and ratio (clonal/non clonal). Results. Overall, 80% were measurable on SPEP with a median serum level of 31g/L (CI95% 19;42), and the remaining also had UPEP measurable myeloma with a median serum level of 0.66g/24h (CI95% 0.4;1.3). The median involved HLC level was 29.7g/L (CI95% 17.6;43.3), the median involved HLC difference clonal - non clonal was 28.8g/L (CI95% 15.6;42.7), the median involved HLC ratio clonal / non clonal was 51.9 (CI95% 18.3;203.9). Since all patients had a measurable intact immunoglobulin-based disease according to IMWG criteria, we have first confirmed that patients had also a measurable disease by HLC. All patients had an abnormal HLC ratio but one patient, who was measurable with an abnormal IgG L involved HLC test. Approximately 32% of patients had an M-spike below 20g/L and/or an electrophoretic migration in beta region meaning in the range of lack of sensitivity of the techniques used, all of whom had a measurable disease using involved HLC level and/or a measurable HLC ratio. We then sought to study the response rate according to HLC, and for that purpose we applied the exact same criteria as to the sFLC-based response criteria recommended by IMWG (e.g. normal ratio is CR and if abnormal ratio, then

Description: Background. Lenalidomide has proved safe and effective in multiple myeloma (MM), particularly in elderly patients. Furthermore, it has been showed that lenalidomide enhanced rituximab-mediated antibody-dependent cell-mediated cytotoxicity. Unexpectedly, lenalidomide (25 mg/d on days 21/28) along with rituximab (375 mg/m²/wk) produced clinically significant acute anemia in patients with WM, most of them received 25mg/day with no improvement when the dose was reduced (Treon et al. CCR, 2009). No cause was attributable to the occurrence of this adverse event. Thus, we sought to perform a study with incremental concentrations of single agent lenalidomide to determine the maximum tolerated dose (MTD) of lenalidomide in WM, and possibly unravel the cause of anemia upon treatment with lenalidomide. Methods. RV-WM-0426 is a multicenter phase I/II dose escalation open label study of lenalidomide in relapse/refractory WM. Lenalidomide was given oral daily 21 / 28 days per cycles for 1 year, at escalated dose of 15 to 20 then 25mg across cohorts of 3 to 6 patients each during the phase 1 part, then followed by 9 patients to recruit in the phase 2 part at the maximum tolerated dose (MTD). The primary endpoint was the MTD, secondary endpoint included response rate (International WM Workshop) and response duration, safety, measurements of free light chain assays, and PFS and OS. Results. 17 patients were enrolled in the study, the median age was 69 (range 48-81), with 7 patients older than 75, 70% were male. 53% had adverse IPSS 3. The median hemoglobin level was 11.2 (95%CI 9.9-12.5), median M spike level 26.5 (95%CI 23-40), 23% had clearance creatinin below 60ml/min. The median number of prior lines was 1 (range 1-8), all patients but 2 exposed to alkylating agents, 30% to nucleoside analogues, 47% to the monoclonal antibody mabthera, none of the patients have had a transplantation. The median time from diagnosis to study entry was 3 years (range 2-15). At the highest dose tested, 20 mg, 2 patients had dose-limiting toxicity, septic syndrome during grade 4 neutropenia and severe fatigue, respectively. The MTD was thus established at the 15 mg/day 21 days out of 28. 7/17 (41%) patients completed one year of single agent lenalidomide at 15mg day 21/28. Single agent lenalidomide in WM provided an overall response (minimal response (MR) and better) on an intent-to-treat basis at 15mg/day of 36%, and an extra 2 patients had a prolonged stable disease (SD). A flare effect (transient initial increase of the M spike) was observed in 5 patients. With a median follow-up of 36 months, 14 have progressed with a median time to progression of 16 months (95%CI 5.5-26), with 35% of patients with a PFS greater than 24 months. One patient died with a 5-year overall survival (OS) of 91%. The most common adverse event (AE ≥ 10%) was fatigue of at least grade 2, reported in 50% of the patients. The incidence rate of grade 3 and greater hematological AE at 15mg was 14% for anemia, 43% for neutropenia, and no thrombopenia observed. 78% experienced a non hematological AE of at least grade 2, but only 2 patients had a grade 3 AE, nephrotic syndrome and cramps. No second primary malignancy (SPM) nor thromboembolic event were reported to date. Only 21% of patients had dose reduction with a median time of 7 months, and 35% had study drug interruption related to an AE with a median time of 4 months. Conclusion. The MTD of lenalidomide is 15mg/day given on days 21/28 in relapse and refractory WM. Lenalidomide is active in the treatment of RRWM and the safety profile appeared manageable, essentially of grade 2 AEs. Future studies may look into combinations to lenalidomide and continuous therapeutic effect in WM at the determined MTD. Disclosures Leleu: Janssen, Celgene, leopharma, Takeda, Amgen, Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Tournilhac:mundipharma: Honoraria, Other, Research Funding; GSK: Honoraria, Other, Research Funding; Roche: Honoraria, Other, Research Funding. Leblond:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Description: Dasatinib (Sprycel®, Bristol-Myers Squibb) is a potent multi-targeted kinase inhibitor (TKI) of BCR-ABL and SRC family kinases. Despite a 33% complete hematological response (CHR) rate in a Phase 2 study in patients with Philadelphia positive (Ph+) acute lymphoblastic leukaemia (ALL) intolerant or resistant to imatinib, the median duration of progression-free survival (PFS) was 3.3 months (Ottmann et al. Blood. 2007;110:2309-2315). Second-generation TKI may thus have a place in the management of these patients. As a European consensus has been reached by the EWALL to adopt a common first-line chemotherapeutic schedule for elderly patients (aged 55 years or more) with Ph-positive ALL, this schedule was used here to test the addition of dasatinib. After a prephase with dexamethasone 10 mg/m2 d-7 to d-3, the induction phase consisted in IV injections of vincristine 1 mg combined with 2 days of dexamethasone 40 mg PO repeated weekly for 4 weeks followed by consolidation cycles including methotrexate 1000 mg/m2 IV d1 (500 mg/m2 over 70y) and asparaginase 10,000 UI/m2 IM d2 (5,000 UI/m2 over 70y) for cycles 1, 3 and 5 alternating with cytarabine 1,000 mg/m2/12h IV d1, d3, d5 (500 mg/m2 over 70y) for cycles 2, 4 and 6. Maintenance phase consisted in 6-MP 60 mg/m2/d and methotrexate 25 mg/m2/week orally 1 month every other month and dexamethasone/vincristine in 2 months intervals during the first year and in 3 months intervals during the second year. Dasatinib (provided by Bristol-Myers Squibb) was administered at 140 mg per day (QD) during the induction period in combination with chemotherapy and at 100 mg/d sequentially with the chemotherapy courses during consolidation and maintenance. BCRABL analysis was performed according to the European Leukemia Net recommendations in two centralized laboratories. A total of 22 patients were included from August 2007 to June 2008. Median age was 71 years (range, 61 to 83), sex ratio (M/F) was 0,46, and median follow-up was 5.8 months. The Ph+ chromosome was associated with complex abnormalities in 58% of cases and 84% of the patients were m-BCR. The CHR rate was 95.2% (20 out of 21 evaluable patients). The only case of induction failure was due to death. The rate of complete molecular remission (CMR) after induction was 33% in blood and 28% in bone marrow and MRD level continued to decrease with time. Only one relapse was observed before the consolidation phase. No other relapse occurred for the 13 patients in CHR still in study after a median follow-up of 3.6 months. One patient died during induction from invasive aspergillosis, 3 deaths occurred in CR, 2 before consolidation due to pulmonary embolism and physical deterioration, and one during maintenance from pneumonia. Serious adverse events (SAEs) were reported in 7 out of 22 patients during induction (31.8%) and in 2 out of 13 patients during maintenance and consolidation (15.3%). SAEs consisted in renal failure (n=3, 2 from acute lysis syndrome and 1 tubular necrosis), invasive aspergillosis (n=1), pulmonary embolism (n=2), pneumonia (n=1), atrial arythmia (n=2), pleural effusion (n=1), microangiopathy (n=1), cytolytic hepatitis (n=1) and physical deterioration (n=1). Eight patients discontinued the study after induction (35%). Primary reasons for discontinuation were SAEs (n=4), death (n=3) and relapse (n=1). The EWALL-PH-01 protocol is highly effective with a 95.2% RCH rate in elderly patients with Ph-positive ALL. Of importance, responses appeared to be durable and MRD level was decreasing over time. An expected 40% rate of SAEs was observed in this elderly population. Reduced doses of therapy are now applied for patients over 70y (20 mg for dexamethasone, 100 mg/d for dasatinib).

Description: This prospective phase II trial (Nov 2011- Dec 2012), supported by the LYSA group, aimed to evaluate the impact on PFS of the RiBVD regimen in newly diagnosed, previously untreated, elderly MCL patients (〉65 years or not eligible for ASCT) (NCT01457144). Inclusion criteria were: WHO 2008 MCL not previously treated, CD20 positive, ECOG 0-2, AA stage II-IV, no CNS involvement or active HBV/HCV/HIV infection. Patients were scheduled to receive a total of 6 cycles of the RiBVD regimen, if they responded (IWG criteria) after 4 cycles. The regimen was administered every 4 weeks with Rituximab 375 mg/m² IV on day(D)1, Bendamustine 90 mg/m² IV on D1 and 2, Dexamethasone 40 mg/m² IV on D2 and bortezomib (Velcade®) 1.3 mg/m² subcutaneously on D1, 4, 8 and 11. Primary prophylaxis with acyclovir was mandatory for Herpes virus reactivation, but there was no recommendation for bacterial prevention. Herein we present preliminary analysis of the trial after 4 RiBVD cycles. Results: A total of 76 patients were included, one was excluded because of HBV active disease and 5 had insufficient data reported in the database. To date we analyzed 70 patients. Patients characteristics: sex ratio M/F 49/21, median age 72 years (y) [64-83] (2 patients were 64 y old), AAstage II/III-IV 5/65, ECOG 0-1/2 59/11, MIPI score low/intermediate/high 3/19/48. Response: 61 responded (ORR=87%), with 19 in PR (26%) and 42 in CR/CRu (60%). Four patients died from pneumonia (n=1), cardiac arrest (n=2) and one following Progressive Multifocal Leukoencephalopathy. Three patients have progressed after 3 cycles. Sixty one patients were analysed by PETscan after 4 cycles, 39 (64%) reached a CR (30 were in CR/CRu and 9 in PR) and 22 remained PET positive (11 patients were in CR/CRu, 10 in PR and 1 stable). RiBVD cycles: 271 cycles were administered out of 280 planned (97%). Twenty four (9%) were delayed, 10 for toxicity. All but one planned Bendamustine doses (n=542) were administered with dosing modified 17 times (3%), mostly for hematological toxicity (n=14). Regarding Bortezomib, 79% (1028/1084) of planned doses were administered, it was prematurely stopped (56, 4%) for neurotoxicity (10 instances) or hematological side effects (46). Rituximab was not administered in 4 instances. Hematologic toxicities: Over the 271 cycles administered, neutropenia was reported in 104 cycles [56 grade 3/4 (g3/4) (21%)], 2.5% with fever; thrombopenia in 181 cycles [41 g3/4 (15%)]; anemia in 210 cycles, [6 g3/4 (2%)]. Non-hematologic toxicities:Reported in 〉10% of the cycles were : allergic reactions (10.3%, g3/4

Description: Abstract 172 Background. Dasatinib (Sprycel®) is a potent inhibitor of BCR-ABL and SRC family kinases. Based on the rapid and clinically meaningful activity observed when dasatinib was used as a single agent a consensus has been reached by the EWALL (European Working Group for Adult ALL) to conduct an international study evaluating the combination of dasatinib and low-intensity chemotherapy in patients with Ph+ ALL aged 55 years or more. Patients and Methods. After a prephase with dexamethasone 10 mg/m2 d-7 to d-3, dasatinib was administered at 140 mg QD (100 mg in patients over 70y) during the induction period in combination with IV injections of vincristine 1 mg and dexamethasone 40 mg 2 days (20 mg over 70y) repeated weekly for 4 weeks. Consolidation cycles consisted of dasatinib 100 mg/d administered sequentially with methotrexate 1000 mg/m2 IV d1 (500 mg/m2 over 70y) and L-asparaginase 10,000 UI/m2 IM d2 (5,000 UI/m2 over 70y) for cycles 1, 3 and 5 and cytarabine 1,000 mg/m2/12h IV d1, d3, d5 (500 mg/m2 over 70y) for cycles 2, 4 and 6. Maintenance phase consisted of dasatinib alternating with 6-MP and methotrexate orally every other month and dexamethasone/vincristine once every 2 months for up to 24 months. Patients were molecularly monitored by a central laboratory for BCR-ABL RTQ-PCR and T315I resistance mutation ASO RTQ-PCR. Results. Seventy one patients were included from August 2007 to study termination in May 2010. Median age was 69.1 years (range: 58–83). Median follow-up was 16.3 months. At diagnosis, the Ph chromosome was associated with other abnormalities (complex, -7, Ph duplication or others) in 64.5% of cases. The CR rate after induction was 90% and 55.7% of the patients achieved a BCR-ABL/ABL ratio ≤0.1% at the time of CR. Failure to achieve CR was mainly related to death (n=5.7%). Serious adverse events (SAEs) during induction were infections (11%), elevated transaminases (7%), hemorrhage (5.6%), renal failure due to tumor lysis syndrome (4.2%) and cardiovascular events (5.6%). Only 2 pleural effusions were observed. During consolidation and maintenance, most frequent SAEs were infections (33.3%). One pleural effusion was observed. Nineteen patients relapsed after a median response duration of 19.2 weeks and 12 of them died. Thirteen patients presented mutations in the BCR-ABL TK domain at relapse (12 T315I, 1 F317L), no mutation was detected in 3 patients and results are pending in 3 patients. T315I ASO RTQ-PCR analysis during follow-up was predictive for relapse. The rise of the T315I signal over 0.1% was always associated with relapse and occurred 1 to 3 months before relapse in 6 of the 12 T315I cases and concomitantly in the 6 remaining patients. Four patients received RIC allogenic stem cell transplantation and were censored at the time of SCT. Median RFS and OS were 22.1 and 27.1 months, respectively. Cytogenetics findings at diagnosis were good predictors for RFS: the median RFS for patients with isolated Ph was not reached while it was 19.2 months in patients with additional cytogenetic abnormalities (p=0.03)). Molecular BCR-ABL transcript level after induction had no effect on RFS. However, a BCR-ABL ratio ≤0.1% after induction and then confirmed during consolidation was significantly associated with a better RFS (5.1 months versus not reached, p=0.006). Conclusions. Dasatinib combined with low-intensity chemotherapy is highly effective in elderly patients with Ph-positive ALL with a 90% CR rate and a 22.1 months RFS. Cytogenetics at diagnosis is a strong predictive factor for RFS. Most relapses were associated with the T315I mutation. Serial monitoring for T315I allowed us to predict for hematological relapse and may offer an opportunity to adapt therapy before relapse. Disclosures: Rousselot: Bristol Myers Squibb: Research Funding. Off Label Use: Dasatinib as first line therapy in Ph ALL.

Description: Background Multiple myeloma with del(17p) and/or t(4;14) are characterized with short survival related to early relapse rate (median TTP

Description: The prognosis of poor risk AML in elderly pts justifies either supportive care only or investigational studies without obvious benefit of post-remission chemotherapies. A phase I study has demonstrated that the combination of azacitidine and lenalidomide is well-tolerated in AML with efficacy superior to that of single-agent therapy in higher-risk MDS (Sekeres JCO2010). The GOELAMS group investigated the efficacy of 12 maintenance cycles alternating monthly azacitidine (sc 75 mg/m²/d1-7) and lenalidomide (10mg/d1-21) every 28 days for pts in CR and compared the results to previous SA2002 and BGMT95 prospective trials which shared the same LIA induction followed by chemotherapy-based maintenance. Between 3/2011 and 2/2013, 117 pts from 27 centers (median age 69 yrs; 60-80, 9 pts ≥ 75) with previously untreated poor prognosis AML were included. Risk factors allowing inclusion were either: i) centrally reviewed (IL) poor risk cytogenetics (n=83) defined as complex karyotype (≥3 abnormalities), monosomal karyotype, t(6;9), del or – 5 or 7, and EVI1 or MLL rearrangement except for t(9;11); ii) preceding MDS (n=52) or iii) secondary leukemia occurring after previous cancer (n=37). Median WBC was 2.9 G/L (0.5-160), 19 pts had WBC 〉 30 G/L. Induction chemotherapy included lomustine 200 mg/m² po d1, Idarabucine 8 mg/m²/d (d1-5), cytarabine 100mg/m²/d CI (d1-7) and G-CSF (d15 to recovery). At the end of induction, CR (excluding CRp) was achieved in 56% (65 pts), 9% died from infection (n=6), cerebral hemorrhage (n=1) or multiorgan failure (n=4) and 35% (41pts) failed to achieve CR. Despite a trend towards a higher CR rate in pts without previous MDS (59% vs 48% CR), CR was not related to any of the risk factors studied. Median follow-up for survivors is 16 months (3-25). Monthly alternating azacitidine-lenalidomide maintenance therapy was started in 65 pts. Except for 1 pt who died during cycle1 of lenalidomide without any obvious explanation, tolerance was good. Median nadir of neutrophils and platelets was 1 and 96 G/L respectively. Grade 3/4 adverse events occurred in 6% of cycles and were due to infection, haemorrhage, hepatitis or fatigue (3%, 1%, 0.5%, 0.5% of cycles respectively). Median CR duration was 4.5 mo (1-23) and 40 pts relapsed. Allogeneic SCT with non myelo-ablative preparative regimen was performed in 4 pts less than 70 years in CR1: 1 is alive in relapse, 2 died of GVH and 1 is in continuous CR. Pts achieving CR had a median OS of 13 mo (95% CI 7.3-18.6), 54% being alive at 1 year and 15% at 2y. In refractory pts, the median OS was 7 mo (95% CI 2.8-11.2) with 32% alive at 1 year (P = 0.0001). OS and DFS reported in the current trial and compared to historical controls are described below: induction results are similar to those observed in the 128 poor risk cytogenetic pts of the previous SA2002/BGMT trials treated with the same LIA induction (CR 58%, early death 15%, failure 27%) but who received maintenance therapy with 6 mini-reinductions (Ida 10mg/m² d1, cytarabine 50 mg/m²x2/d d1-5) and 6MP-MTX for 2years. No significant survival benefit was observed compared to pts with poor risk cytogenetics treated with chemotherapy maintenance in our previous trials. However, pts included in this trial have probably an even worse prognostic than those included in the GOELAMSSA2/BGMT95 trial which excluded AML secondary to MDS and previous cancers. This type of alternating azacitidine/lenalidomide maintenance improves OS and DFS of pts without poor risk cytogenetics (median DFS not reached and 19 mo) and could be randomly compared with conventional chemotherapy maintenance in AML secondary to MDS or cancer but also in older pts with intermediate risk cytogenetics.Median (95% CI)6mo1y2yOS maintenance aza-rev (117)9 mo (7.5-10.5)70%41%17%OS 2002/BGMT95 (128)6 mo (4.1-7.8)54%32%21%DFS maintenance aza-Rev (65)10 mo (2.5-17.4)61%49%8%DFS 2002/BGMT95 (74)9 mo (6.0-11.9)63%43%26%OS poor risk cytogenetic (83) vs other (33)8 mo vs NR P=0.000162% vs 83%27% vs 70%10% vs 60%OS previous cancer (37) vs no cancer (80)9 mo vs 9 mo68% vs 73%44% vs 40%24% vs 17%OS previous MDS (52) vs no MDS(64)12 mo vs 7 mo P=0.00177% vs 65%58% vs 26%27% vs 12%DFS poor risk cytogenetic (44) vs other (20)6 mo vs 19 mo P=0.00748% vs 84%33% vs 67%11% vs 28%DFS previous cancer (20) vs no K(45)8 mo vs 8 mo80% vs 61%46% vs 47%0% vs 13%DFS previous MDS (27) vs no MDS(38)15 mo vs 6 mo, P=0.0874% vs 48%59% vs 32%12% vs 0% Disclosures: No relevant conflicts of interest to declare.

Description: Background Melphalan, prednisone and thalidomide (MPT) is a standard therapy for NDMM recognized worldwide based on a statistically significant advantage in overall survival (OS) and progression-free survival (PFS) vs. MP (Facon Lancet 2007; Fayers Blood 2011; NCCN 2013). The combination of lenalidomide and low-dose dexamethasone (Rd) increased OS with fewer adverse events (AEs) than treatment with lenalidomide and high-dose dexamethasone in NDMM pts (ECOG E4A03) (Rajkumar Lancet Oncol 2010). The FIRST trial is a multicenter, open-label, phase III trial comparing the efficacy and safety of Rd versus MPT in transplant-ineligible NDMM pts. Methods NDMM pts either ≥ 65 years of age, or not candidates for SCT were randomized to one of three arms: Rd in 28-day cycles until disease progression (Arm A), Rd in 28-day cycles for 72 weeks (18 cycles, Arm B), or MPT in 42-day cycles for 72 weeks (12 cycles, Arm C). Assessments by International Myeloma Working Group criteria were done after each cycle. Pts with renal impairment were enrolled; however, pts on dialysis were excluded. Starting doses of lenalidomide and dexamethasone were adjusted based on renal function and age, respectively. Melphalan starting dose was adjusted based on age, absolute neutrophil count, platelet count, and renal function; and thalidomide was adjusted for age. Dose adjustments were permitted for AEs. All pts were required to receive anti-thrombotic prophylaxis. Stratification factors included age, International Stage System, and country. The primary endpoint was a comparison of PFS in Arm A vs. Arm C. Secondary endpoints included OS, overall response rate (ORR), time to response, duration of response (DOR), safety, and quality of life (QOL). A preplanned additional analysis included time from randomization to second progression event or death (PFS2). The final preplanned analysis of independently adjudicated progressive disease (PD) events in Arm A vs. Arm C conducted after 960 events of death or PD, and an interim of OS in 64% of survival events (574/896 events) are presented in this abstract. Comparisons of PFS and all secondary endpoints, including OS for all three arms, will be presented at the meeting. Results A total of 1,623 pts were randomized 1:1:1 in three arms. As of today, 121 pts continue to receive lenalidomide on study (Arm A). The median age was 73 (40.0–92.0) years; 35% pts were aged ≥ 75 years; and 41% of pts had ISS stage 3 disease. After a median follow-up of 37 months, the trial met its primary endpoint (PFS), demonstrating a 28% reduction in risk of progression or death (HR=0.72; p= 0.00006). The preplanned interim analysis of OS demonstrated a 22% reduction in risk of death in favor of Arm A vs. Arm C (HR=0.78, p=0.01685); however, the pre-specified boundary (p

Description: Abstract LBA-6 Background: Multiple myeloma (MM) patients who have become refractory to bortezomib (BORT) and refractory or otherwise ineligible for thalidomide or lenalidomide (LEN) have a poor prognosis, with a median overall survival (OS) of 9 months (Kumar. Leukemia. 2012). There is no standard treatment available for these patients. Pomalidomide (POM) is a novel immunomodulatory drug that has shown activity in LEN- and BORT-refractory patients (Vij. ASCO 2012). MM-003 is an open-label, multicenter, phase 3 trial designed to compare the efficacy and safety of POM + low-dose dexamethasone (LoDEX) vs high-dose dexamethasone (HiDEX) in a population of patients who are refractory to both LEN and BORT. Here we present the final progression-free survival (PFS) and interim OS analysis of MM-003. Methods: Eligible patients with primary refractory or relapsed and refractory disease were enrolled. All patients with documented disease progression during treatment or within 60 days of completing their last myeloma therapy (including ≥ 2 consecutive cycles of LEN and BORT either alone or in combination), were randomized 2:1 to receive either POM + LoDEX (arm A) or HiDEX alone (arm B). Patients progressing on HiDEX had the opportunity to receive POM in the companion trial, MM-003C. Patients in arm A received POM 4 mg on days 1–21 and DEX 40 mg (20 mg for patients 〉 75 years of age) on days 1, 8, 15, and 22 in a 28-day cycle. Patients in arm B received DEX 40 mg (20 mg for patients 〉 75 years of age) on days 1–4, 9–12, and 17–20 in a 28-day cycle. Treatment was continued until progressive disease or unacceptable toxicity. Patients were stratified by age (≤ 75 vs 〉 75 years), disease population (refractory vs refractory and relapsed vs refractory and intolerant [intolerant to BORT only]), and number of prior therapies (2 vs 〉 2). The primary endpoint was PFS; secondary endpoints included safety, OS, overall response rate (ORR; ≥ partial response) by IMWG and EBMT criteria, duration of response, time to progression, and quality of life. OS was to be tested only if PFS would be statistically significant; therefore, alpha was controlled at 0.05 2-sided for both PFS and OS. Results: The Data and Safety Monitoring Board (DSMB) reviewed the protocol-specified final analysis results. 455 patients were randomized from March 2011 to Sept 2012. 302 patients received POM + LoDEX, and 153 patients received HiDEX. At the time of analysis, 45% of patients in arm A and 25% of patients in arm B remained on study. The median number of prior therapies was 5 (range, 1–17). 72% of patients were refractory to both LEN and BORT. At the PFS final analysis, with a median follow-up of 18 weeks, PFS was significantly longer with POM + LoDEX vs HiDEX alone (median 15.7 vs 8.0 weeks; 267 total events; hazard ratio [HR], 0.45; P

Description: Introduction Aplastic anemia (AA) is a rare but potentially life-threatening disease that frequently occurs in older patients. Various therapeutic options can be proposed and data regarding the ideal first line treatment of AA in this ageing population remains scarce. Methods We conducted a retrospective nationwide multicenter study in France to examine current treatments for AA patients over 60 years old within a 10-year period (1/1/2007 to 12/31/2016). Our aims were to evaluate efficacy and tolerance of AA treatment, and to analyze predictive factors for response and survival. Patients who were diagnosed with AA by a bone marrow biopsy at the age of 60 or over were included in the study. Results Over the course of a decade, 88 patients (median age 68.5) were identified in 19 centers, with a median follow-up of 32.1 months; 49% were women, the median Charlson comorbidity index was 2 (range 0-6), the median performance status was 1 (range 0-3), 21% had very severe (vSAA) and 36% severe AA. We analyzed 184 treatment lines which comprised ATG-CsA (33%, including 72% with horse ATG), CsA alone (14%), androgen alone (14%), eltrombopag alone (10%), CsA associated with androgen or eltrombopag (9%), and other treatments (20%). First-line treatment was ATG-CsA for half of patients. Comparisons of patients treated in first line with ATG-CsA, CsA or other treatments revealed that patients receiving ATG-CsA were significantly younger (66 years, vs. 71.5 vs. 71.5, respectively, p=0.007), more frequently female (61%, vs. 50% vs. 27%, p=0.02) and had a lower platelet count (8x109/L, vs. 12x109/L vs. 15x109/L, p=0.025). We found no difference with respect to weight, Charlson comorbidity index score, performance status or disease severity between first line treatment regimens. After first-line therapy, 32% of patients achieved a complete response (CR), and 15% a partial response (PR). After the 181 assessable treatment lines, 19% achieved CR and 19% a PR. Median time until best response was 151 days. The overall response rate (ORR) was 62% with ATG-CsA (70% as a first-line treatment), 35% with CsA alone (39% as first-line), 22% with eltrombopag, and 21% with androgen. The ORR in patients over 70 years receiving ATG-CsA (n=16) was 81% (50% achieving a CR). Responses were significantly better in first line and in patients with good performance status, as well as in those that had received ATG-CsA (ORR of 70% after first-line treatment). In a multivariable analysis using ATG-CsA as a baseline, we found that CsA alone (OR 0.35 (0.13;0.96), p=0.042), eltrombopag (OR 0.12 (0.03;0.54), p=0.0057) and androgens (OR 0.17 (0.05;0.58), p=0.0047) were all individually associated with lower response rates. The main complications were infections (grade III/IV, 35% of treatment lines including 9 deaths (5%)), and renal issues (grade-III/IV, 29%). ATG-CsA was associated with significantly more infectious complications (72% vs. 24%, p