Treatment-Free Remissions in Newly Diagnosed CP CML Patients Treated with the Combination of Nilotinib + Pegylated Interferon Alpha 2a Versus Nilotinib Alone in the National Phase III Petals Trial

Abstract Aims: Combining 2GTKI+pegylated IFN-a (Peg-IFN) represents an attractive approach for first-line treatment of CP CML, while providing somewhat light additional AEs, it induces high rates of deep molecular responses. We evaluated nilotinib (NIL) alone versus NIL+Peg-IFN in newly diagnosed CP-CML patients (pts) in a randomised phase III trial (PETALs, EudraCT 2013-004974-82) and analysed here the proportion of patients reaching Treatment-Free Remission (TFR) and outcome. Methods: Newly diagnosed CP CML pts ≤65 years, without vascular history were randomized 1:1 to get NIL 300 mg BID alone [M0 to M72 (unless TFR), arm A] vs Peg-IFN alone for 30 days (M-1→M0) 30 mg/wk, prior to NIL 300 mg BID + Peg-IFN 30 mg/wk 2 wks, upgraded to 45 mg/wk thereafter, for up to 2 y (M0 to M24, arm B) followed by NIL alone until M72 unless TFR. The primary endpoint was the rate of MR4.5 by M12, and after amendment, the trial was extended to 72 months follow-up in order to add, as a secondary endpoint, the TFR rate in pts reaching MR4.5 ≥2 y. The trigger for treatment resumption was loss of MMR. All molecular assessments were centralised until M36, and in case of TFR, MR4.5 was centrally confirmed at M0 TFR, and further molecular follow-up was then performed locally. All molecular quantifications are expressed as BCR-ABL1/ABL1 (IS) in % with ≥32,000 copies of ABL1 as control in the central lab and in the local labs all involved to the pluri-annual French external quality controls. Results are analysed in intention-to-treat. Results: As previously reported, 200 pts were randomized (99 in A, 101 in B), 130 M and 35 F in each arm, median age of 46 (18-66) y. The median follow-up (FU) since diagnosis is now 47.5 (33.77-62.39) Mo. and the median FU since discontinuation is 9.86 (5.8-23) Mo. in arm A and 15.57 (12.62-22.77) Mo. in arm B. Sokal and ELTS scores were high in 25% and 2.5%, intermediate in 33% and 16.5% and low in 42% and 81% pts respectively, equally balanced. All pts harboured a "Major" BCR transcript. We have previously shown that by M12, the rate of MR4.5 was 15.9% vs 21.5% (primary endpoint met, p=0.049) and that the overall cumulative incidence of MR4.5 was somewhat superior in arm B (54.6 [43.7-65.5] %) vs A (44 [31.5-54] %), p=0.05. Two pts died, one from myeloid blast crisis before TFR (arm A), one from a solid tumour (arm A). Overall, 40 pts (20%) reached the TFR criteria, 21 in arm A with a median FU of 9.86 (5.8-23) Mo. and 19 in arm B with a median FU since Nilo cessation of 15.57 (12.62-22.77) Mo, partly related to slightly different time for obtaining sustained MR4.5 in favour of arm B (16 vs 13 Mo.). For these 40 pts reaching TFR criteria, there was no statistical difference in terms of age at diagnosis and age at TFR, gender, Sokal, ELTS, FU since diagnosis, undetectability at cessation, BCR-ABL1 levels at 3 Mo. after cessation between the 2 arms. The survival without loss of MMR after cessation is illustrated in Figure 1. It looks superior in arm B over arm A, but did not reach statistical difference (p=0.445), but the FU is very short after cessation yet, especially in arm A. Once NIL was resumed in the pts that failed TFR, all pts recovered MMR within 6 Mo., with no difference between arms (p=1.00). In univariate analysis, we did not identify significant factor impacting on the TFR success (age at cessation, sex, undetectability at cessation, Sokal, ELTS) except the BCR-ABL1 value at M3-TFR (undetectable versus detectable, HR 7.15 [2.06-24.75], p=0.002), and the duration of MR4.5 before discontinuation (HR 1.11 [1.03-1.19], p=0.004). During this TFR phase 7 SAEs were reported in arm A (2 pregnancies, 1 obstructive sleep apnea, 1 fever episode, 1 carotid stenosis and 1 femoral stenosis in the same patient at 2 Mo. after cessation, 1 lung carcinoid tumor) and 2 in arm B (1 persistent atrial fibrillation, 1 cholecystectomy). Conclusions: The combination of NIL + Peg-IFN induces higher MR4.5 rates by M36 in newly diagnosed CP CML pts that may translate in higher successful TFR rates, however a longer follow-up is needed to see consistent significant differences. Updated data will be presented. Figure 1 Figure 1. Disclosures Nicolini: Kartos Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses, Research Funding; Incyte Biosciences: Honoraria, Other: travel, accommodations, expenses, Research Funding, Speakers Bureau; Sun Pharma Ltd.: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria. Etienne: Incyte: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau. Huguet: Novartis: Other: Advisor; Jazz Pharmaceuticals: Other: Advisor; Celgene: Other: Advisor; BMS: Other: Advisor; Amgen: Other: Advisor; Pfizer: Other: Advisor. Guerci-Bresler: Novartis: Speakers Bureau; Incyte: Speakers Bureau. Charbonnier: Incyte: Speakers Bureau; Novartis: Speakers Bureau. Rousselot: Incyte, Pfizer: Consultancy, Research Funding. Deconinck: Stemline Therapetutics: Membership on an entity's Board of Directors or advisory committees; Imunogen: Membership on an entity's Board of Directors or advisory committees; Chugai: Research Funding; Novartis: Research Funding; Pfizer: Other: Travel Grants, Research Funding; Abbevie: Research Funding. Rea: Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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A Phase III Study Of ASCT Vs Cyclophosphamide-Lenalidomide-Dexamethasone and Lenalidomide-Prednisone Maintenance Vs Lenalidomide Alone In Newly Diagnosed Myeloma Patients

Blood ◽

10.1182/blood.v122.21.763.763 ◽

2013 ◽

Vol 122 (21) ◽

pp. 763-763 ◽

Cited By ~ 16

Author(s):

Antonio Palumbo ◽

Francesca Gay ◽

Andrew Spencer ◽

Francesco Di Raimondo ◽

Adam Zdenek ◽

...

Keyword(s):

Stem Cell ◽

Board Of Directors ◽

Research Funding ◽

Phase Iii ◽

Study Endpoint ◽

Newly Diagnosed ◽

Advisory Committees ◽

Grade 3 ◽

To Receive

Abstract Background High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) improves survival in multiple myeloma (MM). The introduction of novel agents challenged the role of ASCT at diagnosis. We conducted a multicenter 2X2 randomized trial comparing conventional chemotherapy plus lenalidomide with ASCT followed by maintenance with lenalidomide-prednisone (RP) or lenalidomide (R) alone in newly diagnosed young MM (NDMM) patients. Methods Eligible patients with NDMM ≤ 65 years were enrolled. All patients received Rd induction (four 28-day cycles of lenalidomide 25 mg day 1–21 and low-dose dexamethasone 40 mg day 1,8,15,22) followed by stem cell mobilization. Patients were randomized to receive consolidation with CRD [six 28-day cycles of cyclophosphamide (300 mg/m2 day 1,8,15), dexamethasone (40 mg days 1,8,15,22) and lenalidomide (25 mg days 1–21)] or MEL200-ASCT (melphalan 200 mg/m2 with stem-cell support). Patients were randomly assigned to receive subsequent maintenance with RP (28-day cycles of lenalidomide 25 mg days 1–21 plus prednisone 50 mg every other day) or R alone (28-day cycles of lenalidomide 25 mg days 1–21). Primary study endpoint was progression-free survival (PFS); secondary endpoints included safety, responses and overall survival (OS). Data cut off was May 30th, 2013. Results Three-hundred and eighty-nine patients were enrolled in the trial. Patient characteristics were well balanced between CRD (n=194) and MEL200-ASCT (n=195), and between R (n=195) and RP (n=194) arms. Median follow-up was 31 months. In the intent to treat (ITT) analysis, the median PFS was not reached with MEL200-ASCT and 28 months with CRD (the respective 3-year PFS was 60% vs. 38%, HR=0.62, 95%CI: 0.49-0.85, P=0.003). Median time from enrolment to maintenance was 14 months. In the population of patients eligible for maintenance, 2-year PFS from the start of maintenance was 73% for RP and 56% for R patients (HR= 0.57, 95%CI: 0.34-0.93; P=0.03). In the subgroup of patients who received MEL200-ASCT, 2-year PFS from the start of maintenance was 83% for patients who received RP and 64% for those who received R alone (HR=0.36 95%CI: 0.15-0.87, P=0.02). In the subgroup of patients who received CRD, 2-year PFS from the start of maintenance was 64% for patients who received RP and 47% for those who received R alone (HR=0.75, 95%CI: 0.40-1.39, P=0.36). At present, no differences in OS were noticed between patients randomised to received CRD or MEL200-ASCT, and between patients who received RP or R maintenance. As expected, the rates of grade 3-4 hematologic (85% vs. 26%, P<0.001) and non-hematologic (35% vs. 19%, P=0.003) adverse events (AEs) were higher in the MEL200-ASCT arm compared with the CRD arm. The main non-hematologic AEs were infections (18% vs. 5%, P=0.001) and gastrointestinal AEs (18% vs. 3%, P<0.001). Rates of grade 3-4 hematologic (8% vs. 7%, P=0.85) and non-hematologic (12% vs. 13%, P=0.88). AEs were similar in the RP and R arms. The main non-hematologic AEs in both RP and R groups were infections (3% vs. 3%). At present, 6 second primary malignancies and 3 cases of cutaneous basalioma have been reported. Conclusions MEL200-ASCT significantly prolonged PFS in comparison with CRD. At present no difference in OS was reported, this may be due to the low number of events and to the length of follow-up. The increase in toxicity with MEL200-ASCT did not adversely impact on efficacy. The addition of prednisone to lenalidomide maintenance significantly reduced the risk of progression in comparison with lenalidomide alone, without increasing the toxicity. Updated data with longer follow-up will be presented at the meeting. Disclosures: Palumbo: Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen Pharmaceuticals: Consultancy, Honoraria; Millenium: Consultancy, Honoraria; Onyx: Consultancy, Honoraria. Gay:Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Spencer:Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Larocca:Celgene: Honoraria. Caravita:Celgene: Honoraria, Research Funding. Petrucci:Celgene: Honoraria. Hajek:Celgene: Honoraria; Celgene: Consultancy. Boccadoro:Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding.

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Bosutinib Vs Imatinib for Newly Diagnosed Chronic Myeloid Leukemia (CML) in the BFORE Trial: 18 Month Follow-up

Blood ◽

10.1182/blood.v130.suppl_1.896.896 ◽

2017 ◽

Vol 130 (Suppl_1) ◽

pp. 896-896

Author(s):

Carlo Gambacorti-Passerini ◽

Michael W. Deininger ◽

Michael J. Mauro ◽

Charles Chuah ◽

Dong-Wook Kim ◽

...

Keyword(s):

Board Of Directors ◽

Primary Endpoint ◽

Cumulative Incidence ◽

Research Funding ◽

Newly Diagnosed ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership ◽

Grade 3

Abstract Introduction: Bosutinib is a potent SRC/ABL tyrosine kinase inhibitor approved for treatment of adults with CML resistant or intolerant to prior therapy. Here we compare the efficacy and safety of first-line bosutinib versus imatinib in patients with chronic phase (CP) CML enrolled in BFORE after ≥18 months of follow-up. Methods: BFORE (NCT02130557) is an ongoing, multinational, open label phase 3 study that randomized 536 patients 1:1 to 400 mg QD bosutinib (n=268) or 400 mg QD imatinib (n=268 [3 not treated]). The prespecified primary endpoint was major molecular response (MMR) rate at 12 months in the modified intent-to-treat (mITT) population, defined as Philadelphia chromosome‒positive (Ph+) patients with e13a2/e14a2 transcripts, and excluding Ph- patients and those with unknown Ph status and/or BCR-ABL transcript type (mITT: BOS, n=246; IM, n=241). Efficacy results refer to the mITT population unless otherwise noted. Results: MMR rate was higher with bosutinib versus imatinib at 18 months (56.9% vs 47.7%; P=0.042). Among all randomized patients (ITT) 18-month MMR rates were higher for bosutinib (56.7% vs 46.6%; P <0.02). Earlier analyses (Table) showed complete cytogenetic response (CCyR) rate by 12 months (77.2% vs 66.4%; P=0.0075) was significantly higher with bosutinib versus imatinib. Rates of BCR-ABL1 transcript ratio ≤10% (International Scale) at 3 months (75.2% vs 57.3%), as well as MR4 at 12 months (20.7% vs 12.0%) and MR4.5 at 12 months (8.1% vs 3.3%), were all higher with bosutinib versus imatinib (all P <0.025). By comparison at 18 months, rates of MR4 (24.4% vs 18.3%) and MR4.5 (11.4% vs 7.1%) were consistent with this trend. Also after ≥18 months follow-up, time to MMR (hazard ratio=1.36, based on cumulative incidence; P=0.0079) and time to CCyR (hazard ratio=1.33; P=0.0049) were shorter for bosutinib (Figure). Cumulative incidence of transformation to accelerated/blast phase disease at 18 months was 2.0% and 2.9% for bosutinb and imatinib, respectively, of which 2 bosutinib and 4 imatinib patients discontinued treatment due to transformation. Additional treatment discontinuations due to suboptimal response/treatment failure occurred in 11 (4.1%) and 35 (13.2%) of bosutinib and imatinib patients, respectively. Dose increases happened in 20% of bosutinib-treated and 31% of imatinib-treated pts There were 2 deaths and 9 deaths in the bosutinib and imatinib arms, respectively. One patient taking bosutinib died within 28 days of last dose, while 4 patients taking imatinib died with that period from last dose. Overall survival at 18 months was 99.6% vs. 96.6% for bosutinib and imatinib groups, respectively. Grade ≥3 diarrhea (8.2% vs 0.8%) and increased alanine (20.9% vs 1.5%) and aspartate (10.1% vs 1.9%) aminotransferase levels were more frequent with bosutinib. Cardiovascular, peripheral vascular, and cerebrovascular events were infrequent in both arms (3.4%, 1.9%, and 0.4% bosutinib vs 0.0%, 1.1%, and 0.8% imatinib; grade ≥3: 1.5%, 0%, and 0.4% vs 0%, 0%, and 0.4%). There were no deaths in the bosutinib arm and 1 death in the imatinib arm due to treatment-emergent vascular events. Treatment discontinuations due to drug-related toxicity occurred in 15.3% and 9.4% of bosutinib and imatinib patients, respectively. Conclusion: After 18 months of follow-up,the MMR benefit seen with bosutinib over imatinib was sustained. These results are in line with observations at 12 months where patients taking bosutinib had significantly higher response rates (primary endpoint) and achieved responses sooner than those on imatinib. Safety data were consistent with the known safety profiles. These results suggest that bosutinib may be an important treatment option for patients with newly diagnosed CP CML. Disclosures Gambacorti-Passerini: Pfizer: Consultancy, Honoraria, Research Funding; BMS: Consultancy. Deininger: Novartis: Consultancy, Research Funding; Pfizer: Consultancy; Celgene: Research Funding; BMS: Consultancy, Research Funding; Gilead: Research Funding; ARIAD: Consultancy; Ariad Pharmaceuticals, Bristol Myers Squibb, CTI BioPharma Corp, Gilead, Incyte, Novartis, Pfizer, Celgene, Blue Print, Galena: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy. Mauro: Bristol-Myers Squibb: Consultancy. Chuah: Avillion: Honoraria; Chiltern: Honoraria; BMS: Honoraria, Other: Travel; Novartis: Honoraria. Kim: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Il-Yang: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Milojkovic: Novartis: Consultancy, Honoraria; Incyte: Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria; BMS: Consultancy, Honoraria; ARIAD: Consultancy, Honoraria. le Coutre: BMS: Honoraria; Pfizer: Honoraria; Incyte: Honoraria; Novartis: Honoraria, Research Funding; ARIAD: Honoraria. García Gutiérrez: Pfizer: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Crescenzo: Pfizer: Employment, Equity Ownership. Leip: Pfizer: Employment, Equity Ownership. Bardy-Bouxin: Pfizer: Employment, Equity Ownership. Hochhaus: Novartis: Research Funding; Pfizer: Research Funding; Incyte: Research Funding; Ariad: Research Funding; MSD: Research Funding; BMS: Research Funding. Brümmendorf: Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Cortes: Sun Pharma: Research Funding; ARIAD: Consultancy, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; BMS: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Teva: Research Funding.

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A Prospective Pilot Study of Ixazomib, Lenalidomide, and Dexamethasone for Patients with Newly Diagnosed or Relapsed/Refractory POEMS Syndrome

Blood ◽

10.1182/blood-2019-127366 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1846-1846

Author(s):

Angela Dispenzieri ◽

Michelle Mauermann ◽

Betsy Laplant ◽

Martha Q. Lacy ◽

Ronald S. Go ◽

...

Keyword(s):

Board Of Directors ◽

Primary Endpoint ◽

Research Funding ◽

Poems Syndrome ◽

Refractory Disease ◽

Newly Diagnosed ◽

Advisory Committees ◽

Impairment Score ◽

Grade 3

Background: POEMS syndrome is a rare paraneoplastic syndrome caused by an underlying plasma cell disorder. The combination of a proteasome inhibitor, an IMiD and corticosteroid is known to be highly effective among patients with myeloma. Methods: We conducted a pilot using a 28-day oral regimen of ixazomib (4 mg days 1, 8, 15), lenalidomide (25 mg days 1-21), and dexamethasone (20 mg days 1, 8, 15, 22). Aspirin and acyclovir were used for prophylaxis. Eligibility included a diagnosis of POEMS syndrome, a plasma VEGF 2x normal, a PS < 3. There were two groups [gp] (intended enrollment 15 per gp): Gp 1, 3 cycles for pts destined for high-dose chemotherapy with stem cell transplant; Gp 2, 13 cycles for patients (pts) who had relapsed or refractory disease. Primary endpoint was VEGF complete response (CR=normalization) after 3 cycles. Secondary endpoints included safety, hematologic response, and overall survival at 3 and 12 months. Other domains including PET response (50% reduction in sum of SUVmax from baseline), clinical responses including neurologic response were also studied. Neurologic assessments were done using the modified neurological impairment score (mNiS+7POEMS), the overall neuropathy limitation scale, and the polyneuropathy disability score. To date, 13 pts enrolled since 10/31/2016-4 to Gp 1 and 9 to Gp 2. 11 pts were analyzed (2 dropped out before receiving any therapy). Data were frozen as of 07/15/2019. Results: Median age was 55; 73% were male. Of the evaluable patients, three were newly diagnosed (Gp 1), and 8 had relapsed or refractory disease (Gp 2). 72% met primary endpoint of VEGF CR (Table). At 3 months, the following improvements were seen: VEGF, 10/11; hematologic, 1/3; PET 1/3; neurologic impairment score, 3/11. By 12-months according to the modified nerve impairment scale, 3/6 had achieved objective improvement and 2/6 stable disease. With a median follow-up of 16 months, 2 patients have died of progressive disease and another patient progressed on therapy (Gp 2) with an extravascular leak progression. 27% of patients had grade 3+hematologic AE; 81% had grade 3-4 non-hematologic AE. These included: rash, respiratory infection, diarrhea, and hypotension in 2 each; atrial fibrillation, edema, dyspnea, and thromboembolism in 1 each. 5 pts had non-objective worsening of their neuropathy. Conclusions: These preliminary results suggest that Ixa-Len-Dex is an effective and tolerable regimen for patients with POEMS syndrome. Longer follow-up will be important to determine durability of this approach and for neurologic assessment given the slow rate of remyelination. Figure Disclosures Dispenzieri: Akcea: Consultancy; Intellia: Consultancy; Janssen: Consultancy; Pfizer: Research Funding; Takeda: Research Funding; Celgene: Research Funding; Alnylam: Research Funding. Lacy:Celgene: Research Funding. Kapoor:Cellectar: Consultancy; Janssen: Research Funding; Glaxo Smith Kline: Research Funding; Takeda: Honoraria, Research Funding; Sanofi: Consultancy, Research Funding; Celgene: Honoraria; Amgen: Research Funding. Leung:Takeda: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; Aduro: Membership on an entity's Board of Directors or advisory committees; Omeros: Research Funding. Dingli:alexion: Consultancy; Karyopharm: Research Funding; Rigel: Consultancy; Millenium: Consultancy; Janssen: Consultancy. Kumar:Takeda: Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Gertz:Proclara: Membership on an entity's Board of Directors or advisory committees; Springer Publishing: Patents & Royalties; Research to Practice: Consultancy; Physicians Education Resource: Consultancy; Abbvie: Other: personal fees for Data Safety Monitoring board; Ionis/Akcea: Consultancy; Alnylam: Consultancy; Prothena Biosciences Inc: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Spectrum: Consultancy, Research Funding; Annexon: Consultancy; DAVA oncology: Speakers Bureau; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; i3Health: Other: Development of educational programs and materials; Amyloidosis Foundation: Research Funding; International Waldenstrom Foundation: Research Funding; Teva: Speakers Bureau; Johnson and Johnson: Speakers Bureau; Appellis: Consultancy; Amgen: Consultancy; Medscape: Consultancy, Speakers Bureau. OffLabel Disclosure: No drugs approved for POEMS syndrome. Ixazomib, lenalidomide and dexamethasone

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Long Term Outcome of Lenalidomide-Dexamethasone (Rd) Vs Melphalan-Lenalidomide-Prednisone (MPR) Vs Cyclophosphamide-Prednisone-Lenalidomide (CPR) As Induction Followed By Lenalidomide-Prednisone (RP) Vs Lenalidomide (R) As Maintenance in a Community-Based Newly Diagnosed Myeloma Population: Updated Analysis of EMN01 Phase III Study

Blood ◽

10.1182/blood.v130.suppl_1.901.901 ◽

2017 ◽

Vol 130 (Suppl_1) ◽

pp. 901-901

Author(s):

Sara Bringhen ◽

Massimo Offidani ◽

Pellegrino Musto ◽

Anna Marina Liberati ◽

Giulia Benevolo ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Phase Iii ◽

Cell Transplant ◽

Newly Diagnosed ◽

Community Based ◽

Advisory Committees ◽

Risk Of Death ◽

Grade 3 ◽

To Receive

Abstract Introduction : Rd and MPR showed to be effective combinations in elderly newly diagnosed multiple myeloma (NDMM) patients (pts). Cyclophosphamide is a less toxic alkylating alternative agent. EMN01 is the first trial to formally compare these three different Lenalidomide-based combinations. Maintenance with Lenalidomide has been recently approved in patients eligible for autologous stem cell transplant (ASCT). Few data are available about the best combination as maintenance in patients not eligible for ASCT. Methods : 662 pts with NDMM were randomized to receive 9 28-day cycles of Rd (lenalidomide 25 mg/day for 21 days; dexamethasone 40 mg on days 1,8,15 and 22 in pts 65-75 years old and 20 mg in those >75 years), MPR (lenalidomide 10 mg/day for 21 days; melphalan orally 0.18 mg/Kg for 4 days in pts 65-75 years old and 0.13 mg/Kg in >75 years pts; prednisone 1.5 mg/Kg for 4 days) or CPR (lenalidomide 25 mg/day for 21 days; cyclophosphamide orally 50 mg/day for 21 days in pts 65-75 years old and 50 mg every other day in >75 years pts; prednisone 25 mg every other day). After induction, pts were randomized to receive maintenance with lenalidomide alone (R; 10 mg/day for 21 days) or with prednisone (RP; R, 10 mg/day for 21 days and P, 25 mg every other day), until disease progression. Results : Pts characteristics were well balanced in all groups; 217 pts in Rd, 217 in MPR and 220 in CPR arms could be evaluated. After a median follow-up of 63.7 months, median PFS was 23.2 months in MPR, 18.9 months in CPR and 18.6 months in Rd (MPR vs CPR p=0.02; MPR vs Rd p=0.08). Median overall survival (OS) was 79.9 months in MPR, 69.4 months in CPR and 68.1 months in Rd (MPR vs CPR p=0.98; MPR vs Rd p=0.64). The most common grade ≥3 adverse event (AEs) was neutropenia: 64% in MPR, 29% in CPR and 25% in Rd pts (p<0.0001). Grade ≥3 non hematologic AEs were similar among arms. At the end of induction, 402 pts were eligible for maintenance, 198 in the RP and 204 in the R groups. PFS from start of maintenance was 22.2 months in the RP group and 17.6 in the R group, with 20% reduced the risk of death/progression for pts receiving RP maintenance (HR 0.81, p=0.07; Figure 1). A subgroup analysis was performed to determine the consistency of RP vs R treatment effect in different subgroups using interaction terms between treatment and cytogenetic abnormalities, ISS, age, sex, induction treatment and response before maintenance (Figure 1). No difference in OS was observed (HR 1.02, p=0.93) but the OS analysis was limited by the low number of events. Median duration of maintenance was 23.0 months in RP pts and 20.5 months in R pts, 14% and 13% of pts discontinued due to AEs, in RP and R groups, respectively. Conclusion : This phase III trial compared 2 different Lenalidomide-containing induction regimens and 2 different Lenalidomide-containing maintenance regimens in an elderly community-based NDMM population. MPR prolonged PFS by approximately 5 months, yet the higher incidence of hematologic toxicity should be carefully considered. The addition of low-dose prednisone to standard lenalidomide maintenance reduced the risk of death/progression by 20%, with a good safety profile. Updated results will be presented at the meeting. Disclosures Bringhen: Mundipharma: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Celgene: Honoraria; Bristol Myers Squibb: Honoraria; Karyipharm: Membership on an entity's Board of Directors or advisory committees. Offidani: celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Musto: Celgene: Honoraria; Janssen: Honoraria. Gaidano: Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Roche: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. De Sabbata: Celgene: Membership on an entity's Board of Directors or advisory committees. Palumbo: Sanofi: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Binding Site: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Genmab A/S: Consultancy, Honoraria, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Employment, Equity Ownership, Honoraria, Research Funding. Hájek: Amgen, Takeda, BMS, Celgene, Novartis, Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria; Pharma MAR: Consultancy, Honoraria. Boccadoro: Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; AbbVie: Honoraria; Mundipharma: Research Funding; Sanofi: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding.

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Routine Use of Gemtuzumab Ozogamicin in 7+3-Based Inductions for All "Non-Adverse" Risk AML

Blood ◽

10.1182/blood-2020-142691 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 36-37

Author(s):

Gavin Hui ◽

Abdullah Ladha ◽

Edna Cheung ◽

Caroline Berube ◽

Steven Coutre ◽

...

Keyword(s):

Board Of Directors ◽

Median Time ◽

Research Funding ◽

Gemtuzumab Ozogamicin ◽

Intermediate Risk ◽

Newly Diagnosed ◽

Myeloablative Conditioning ◽

Advisory Committees ◽

Monosomy 7

Introduction: The addition of gemtuzumab ozogamicin (GO) to 7+3 chemotherapy for newly diagnosed acute myeloid leukemia (AML) has been shown to significantly improve event-free survival (EFS) for cytogenetically favorable-risk AML, with marginal benefit for intermediate-risk AML, and no benefit for cytogenetically adverse-risk AML. Of note, with the exception of mutated FLT3-ITD, little is known about the impact of GO in ELN 2017-defined genotypically adverse-risk AML, and a recent randomized trial found no EFS benefit for 7+3+GO in patients (pts) with genotypically favorable-risk, NPM1-mutated AML. Since 2017, our institution incorporated GO into 7+3-based inductions for all "non-adverse" risk AML pts, as defined by wild-type FLT3 and no abnormalities on rapid FISH analysis for del(5q)/monosomy 5, del(7q)/monosomy 7, and del(20q). We report our experience treating all pts with "non-adverse" risk AML-as defined by this algorithm-with 7+3+GO. Methods: An institutional database was queried in order to identify all pts ≥18 years old who received 7+3-based chemotherapy for newly diagnosed AML between 2017 and 2020; pts who received the FDA-approved fractionated dose of GO were included in the analysis. Data collection included demographic variables, karyotype/FISH, targeted PCR analyses, and multigene NGS panels for AML-related mutations including, but not limited to, mutations in FLT3, NPM1, CEBPA, TP53, RUNX1, and ASXL1. Outcome data included response to induction, relapse, and death, as well as hematopoietic cell transplant (HCT) rates, conditioning regimens, and post-transplant complications. Results: Between January 2017 and July 2020, 96 pts received 7+3-based induction at our institution. Of these, 29 (30%) received 7+3 in combination with GO. Median age at diagnosis was 46 years (range 23-66), with 17 (59%) males. Sixteen (55%) pts had ELN favorable-risk AML (5 [31%] by cytogenetics and 11 [69%] by genotype), 6 (21%) pts had ELN intermediate-risk AML, and 7 (24%) pts had ELN adverse-risk AML (4 [57%] by cytogenetics and 3 [43%] by genotype). Median time from diagnosis to start of induction was 4 days (range 0-43). For cytogenetically adverse-risk pts, median time from diagnostic bone marrow biopsy to receipt of adverse karyotype results was 8 days (7-14). Median time from start of induction to receipt of multigene NGS results for all pts was 15 days (3-32). Overall, 22 (76%) pts achieved remission. All genotypically adverse-risk pts (1 with mutated TP53 and 2 with mutated RUNX1) were refractory to induction, while 3 of 4 (75%) cytogenetically adverse-risk pts (1 with t(6;9), 1 with monosomy 7, and 2 with 11q23 abnormalities) achieved remission. Eight of the 29 (28%) pts proceeded to HCT, including 4 adverse-risk pts. Of the adverse-risk pts, all received myeloablative conditioning prior to HCT and 3 (75%) developed veno-occlusive disease (VOD), with 2 (50%) requiring defibrotide therapy. In favorable/intermediate-risk pts, 4 (18%) proceeded to HCT (2 intermediate-risk pts in first remission and 2 favorable-risk pts in second remission). Of these, 2 (50%) received myeloablative conditioning and 1 (25%) developed VOD. At last follow-up, 23 of 29 pts (79%) remained alive, with a median overall survival not reached (range 1-29 months) and a median EFS of 20 months (9-31). The percentage of ELN favorable-, intermediate-, and adverse-risk pts who remained event-free at last follow-up was 75%, 33%, and 43%, respectively. Discussion: This single-center, retrospective cohort describes the outcomes of pts with "non-adverse" risk AML who received induction chemotherapy with 7+3+GO according to a pre-defined algorithm. Using this algorithm, 30% of all pts receiving 7+3-based inductions received GO. Of these, nearly 25% were ultimately found to have adverse-risk AML as defined by ELN 2017 criteria, largely driven by long turn-around times for karyotyping and NGS multigene panel results. No patient with genotypically adverse-risk AML by ELN criteria responded to induction chemotherapy, and 75% of cytogenetically adverse-risk pts who proceeded to HCT developed VOD. Routine use of 7+3+GO induction outside of the context of cytogenetically favorable-risk AML remains controversial, and further study is needed to define the role of GO, particularly for pts with ELN genotypically adverse-risk AML. Table Disclosures Gotlib: Blueprint Medicines Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Chair of the Response Adjudication Committee and Research Funding, Research Funding; Deciphera: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: co-chair of the Study Steering Committee and Research Funding. Liedtke:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; GSK: Membership on an entity's Board of Directors or advisory committees; Adaptive: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Muffly:Adaptive: Research Funding; Amgen: Consultancy; Servier: Research Funding. Mannis:AbbVie, Agios, Bristol-Myers Squibb, Genentech: Consultancy; Glycomimetics, Forty Seven, Inc, Jazz Pharmaceuticals: Research Funding.

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ENESTnd Update: Continued Superiority of Nilotinib Versus Imatinib In Patients with Newly Diagnosed Chronic Myeloid Leukemia In Chronic Phase (CML-CP)

Blood ◽

10.1182/blood.v116.21.207.207 ◽

2010 ◽

Vol 116 (21) ◽

pp. 207-207 ◽

Cited By ~ 18

Author(s):

Timothy P. Hughes ◽

Andreas Hochhaus ◽

Giuseppe Saglio ◽

Dong-Wook Kim ◽

Saengsuree Jootar ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Clonal Evolution ◽

Molecular Response ◽

Newly Diagnosed ◽

Advisory Committees ◽

Free Survival ◽

Superior Efficacy ◽

Rate Of Progression

Abstract Abstract 207 Background: Results from the phase 3, international, randomized ENESTnd trial have demonstrated the superior efficacy of nilotinib over imatinib with significantly higher rates of major molecular response (MMR), complete cytogenetic response (CCyR), and with significantly lower rates of progression to AP/BC on treatment. Here, we present data with a median follow-up of 18 months. Methods: 846 CML-CP patients were randomized to nilotinib 300 mg twice daily (bid) (n=282), nilotinib 400 mg bid (n=281), and imatinib 400 mg once daily (n=283). Primary endpoint was MMR (≤ 0.1% BCR-ABLIS) rate “at” 12 months, as previously presented. Key secondary endpoint was durable MMR at 24 months. Other endpoints assessed at 24 months include progression to AP/BC (with and without clonal evolution), event-free survival, progression-free survival, and overall survival (OS). Results: With a median follow-up of 18 months, the overall best MMR rate was superior for nilotinib 300 mg bid (66%, P < .0001) and nilotinib 400 mg bid (62%, P < .0001) compared with imatinib (40%). Superior rates of MMR were observed in both nilotinib arms compared with the imatinib arm across all Sokal risk groups (Table). The overall best rate of BCR-ABLIS ≤ 0.0032% (equivalent to complete molecular response, CMR) was superior for nilotinib 300 mg bid (21%, P < .0001) and nilotinib 400 mg bid (17%, P < .0001) compared with imatinib (6%). The overall best CCyR rate was superior for nilotinib 300 mg bid (85%, P < .001) and nilotinib 400 mg bid (82%, P=.017) compared with imatinib (74%). The superior efficacy of nilotinib was further demonstrated using the 2009 European LeukemiaNet (ELN) 12-month milestone in which fewer patients had suboptimal response or treatment failure on nilotinib 300 mg bid (2%, 3%) and nilotinib 400 mg bid (2%, 2%) vs imatinib (11%, 8%). Rates of progression to AP/BC on treatment were significantly lower for nilotinib 300 mg bid (0.7%, P=.006) and nilotinib 400 mg bid (0.4%, P=.003) compared with imatinib (4.2%). The rate of progression on treatment was also significantly lower for nilotinib when including clonal evolution as a criteria for progression (Table). There were fewer CML-related deaths on nilotinib 300 mg bid (n=2), and 400 mg bid (n=1) vs imatinib (n=8). Estimated OS rate (including data from follow-up after discontinuation) at 18 months was higher for nilotinib 300 mg bid (98.5%, P=.28) and nilotinib 400 mg bid (99.3%, P=.03) vs imatinib (96.9%). Both drugs were well-tolerated. Discontinuations due to adverse events or laboratory abnormalities were lowest for nilotinib 300 mg bid (7%) compared with nilotinib 400 mg bid (12%) and imatinib (9%). With longer follow up there has been minimal change in the occurrence of AEs. Minimum 24-month follow-up data for all patients will be presented. Conclusions: With longer follow-up, nilotinib was associated with a significantly lower rate of progression to AP/BC on treatment and lower rates of suboptimal response or treatment failure vs imatinib. Nilotinib resulted in fewer CML-related deaths and a higher OS rate vs imatinib. Nilotinib induced superior rates of MMR, CMR, and CCyR vs imatinib in patients with newly diagnosed CML-CP. Taken together, these data support nilotinib as a new standard of care for patients with newly diagnosed CML. Disclosures: Hughes: Novartis: Honoraria, Research Funding, Speakers Bureau; Bristol-Meyers Squibb: Honoraria, Research Funding; Ariad: Honoraria. Hochhaus:Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Saglio:Novartis: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria. Kim:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. le Coutre:Novartis: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau. Reiffers:Novartis: Research Funding. Pasquini:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. Clark:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Honoraria, Research Funding. Gallagher:Novartis Pharma AG: Employment, Equity Ownership. Hoenekopp:Novartis Pharma AG: Employment. Haque:Novartis: Employment. Larson:Novartis: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding. Kantarjian:Novartis: Consultancy, Research Funding; Bristol Myers Squibb: Research Funding; Pfizer: Research Funding.

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Consolidation with Vtd Significantly Improves the Complete Remission (CR) Rate Following Vtd Induction and Single Autologous Stem Cell Transplantation (auto) in Multiple Myeloma (MM).

Blood ◽

10.1182/blood.v120.21.3096.3096 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3096-3096

Author(s):

Xavier Leleu ◽

Benjamin Hebraud ◽

Guillemette Fouquet ◽

Murielle Roussel ◽

Denis Caillot ◽

...

Keyword(s):

Board Of Directors ◽

Incidence Rate ◽

Relapse Rate ◽

Research Funding ◽

The Other ◽

Newly Diagnosed ◽

Phase 3 ◽

Advisory Committees ◽

Induction Regimen

Abstract Abstract 3096 Background. Several studies have demonstrated the impact of VTd on response rates and PFS either as induction or consolidation regimen. However there are limitations to these studies, especially that no data is available regarding the role of VTd consolidation in the context of bortezomib-triple based VTd induction regimen followed by a single auto. At completion of therapy, the response rate (ORR, PR and better) was 89%, VGPR+CR rate 74%, CR rate 29%, relapse rate and median PFS was 53% and 26 months (median F-up 32 months) in the VTd arm of the phase 3 IFM2007-02 trial conducted for newly diagnosed MM (Moreau et al, Blood 2012). In this study, only a minority of patients had received a consolidation or maintenance. On the other hand, Cavo et al. (Blood 2012) reported 97.5%, 92%, 61%, 39% 3-year progression and 62% estimated 5-year PFS (F-up 43 months) respectively in the VTd arm. VTd was given as induction before and consolidation after double auto in this upfront GIMEMA phase 3 trial (Cavo et al, Lancet 2010). We aimed to assess the efficacy and safety of VTd as consolidation therapy in the context of VTd as induction regimen followed by a single auto (VTd-auto-VTd regimen). Method. This study has included a first group of 121 newly diagnosed MM from 2009 to 2011 across 9 IFM centers. Patients were to be eligible for auto upfront, aged less than 65 and treated with VTd-auto-VTd regimen. The second cohort included MM treated with VTd-auto without consolidation from the IFM2007-02 trial (n=76). A third cohort comprised MM that received upfront a triplet Vd-based combination induction (VCd, VRd) -auto without consolidation (n = 40). Results. In the whole study, the median age was 56 years, the sex ratio was 1,49, 50% had ISS 2 and 3, 22% had adverse FISH [t(4;14); del17p] (similar in the 3 groups). Overall, the ORR was identical in the 3 cohorts at completion of therapy, 104 (86%), 72 (94%) and 32 (80%) for the cohort 1 to 3, respectively. Nevertheless, the CR rate was significantly greater in patients that received a consolidation (cohort 1), as compared to the cohorts 2 and 3 that did not receive any consolidation, 59 (53%) vs. 26 (34%) and 13 (32.5%), respectively (p=0.0001). Interestingly, the CR rates were identical at the end of the induction in the 3 cohorts, 13%, 15% and 22.5%, respectively. With a median follow-up of 25 months, the incidence rate of relapse was significantly greater in the cohort 2 and 3 versus 1, further demonstrating the importance of the consolidation, 25 (21%), 42 (55%) and 13 (32.5%) patients (p=0.0001), respectively; and 9 (8%), 6 (8%) and 8 (20%) had died in cohorts 1 to 3 (p=0.07). The median (95%CI) PFS was not reached in cohort 1, and was 32 (28;36) months and 30 (26;33) months in cohort 2 and 3, respectively. Importantly, 54.5%, 32% and 32% of patients were free of relapse at 32 months in the 3 cohorts, respectively. Similar data were obtained for TTP. The median (95%CI) OS was not significantly different in cohorts 1 to 3, although not reached for the first 2 cohorts and 38 (33;43) months for the 3rdcohort. The 3-year survival was 84%, 91% and 76%, respectively (p=ns). A longer follow up will certainly demonstrate greater survival end points benefit in favor for consolidation. The safety profile of the cohort that contained a consolidation was superimposable to that of the remaining 2 cohorts without consolidation. The incidence rate of hematological EIs of grade 3 and 4 was 4%, 6% and 8% in the 3 cohorts (p=ns), respectively. The incidence rate of neuropathy grade 1–2 and 3–4 was 5% and 2% in the cohort 1 with consolidation, but only 1% occurred during the consolidation. This data compares favorably to the 3% reported in the cohort 2 (Moreau et al. Blood 2012). We have also observed 9 (9%) thromboembolic events (TE), 8 of venous type and 1 arterial. None of them happened during the consolidation, and again, this incidence rate if superimposable to that reported in the IFM2007-02 vTd cohort. Conclusion. This study showed an impressive increase in CR rate in relation to the consolidation that translated into a lower relapse rate. This study also demonstrated that the VTd regimen, used both as induction and consolidation, in the context of a single auto upfront in MM, significantly contributed to improve clinical outcomes with an acceptable toxicity profile. VTd-auto-VTd compared very favorably to the other upfront protocols, and may become in the near future a standard of care in newly diagnosed patients with Myeloma. Disclosures: Leleu: Celgene: Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Sanofi: Honoraria; Onyx: Honoraria, Speakers Bureau; LeoPharma: Honoraria, Speakers Bureau. Off Label Use: Pomalidomide. Roussel:celgene: Honoraria; janssen: Honoraria. Facon:onyx: Membership on an entity's Board of Directors or advisory committees; celgene: Membership on an entity's Board of Directors or advisory committees; janssen: Membership on an entity's Board of Directors or advisory committees; millenium: Membership on an entity's Board of Directors or advisory committees. Attal:celgene: Membership on an entity's Board of Directors or advisory committees; janssen: Membership on an entity's Board of Directors or advisory committees.

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Gene Mutations and Treatment Outcome in CLL Patients Treated with Chlorambucil (Chl) or Ofatumumab-Chl (O-Chl): Results from the Phase III Study COMPLEMENT1 (OMB110911)

Blood ◽

10.1182/blood.v124.21.1992.1992 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1992-1992 ◽

Cited By ~ 1

Author(s):

Eugen Tausch ◽

Christina Galler ◽

Richard Schlenk ◽

Peter Hillmen ◽

Fritz Offner ◽

...

Keyword(s):

Prognostic Factors ◽

Board Of Directors ◽

Research Funding ◽

Cox Regression ◽

Gene Mutations ◽

Phase Iii ◽

Response To Treatment ◽

Prognostic Impact ◽

Advisory Committees

Abstract BACKGROUND: Genomic aberrations and IGHV mutation status are established prognostic factors in CLL. With TP53, NOTCH1, SF3B1, ATM, MYD88, FBXW7, BIRC3 and POT1 recurrently mutated genes were found in CLL and were discussed to associate with disease characteristics and to affect therapy efficacy and outcome. METHODS: We assessed the incidence and impact of gene mutations in the COMPLEMENT1 trial (1st line Chl vs. O-Chl). Pretreatment samples were available from 376 patients (84.1%) and this cohort was representative of the full trial population. Mutations were analyzed by amplicon-based targeted NGS using Illumina Miseq for all coding exons (TP53, ATM, MYD88, FBXW7, BIRC3 and POT1) or hotspot exons (NOTCH1, SF3B1). Additionally, the exact variant frequency was determined. RESULTS: The incidences of gene mutations were: TP53 8.2%, NOTCH1 14.9%, SF3B1 14.1%, ATM 10.9%, MYD88 2.7%, FBXW7 3.5%, POT1 7.7%, and BIRC3 2.7%. Regarding baseline characteristics, we found significant associations: TP53mut with high ß2MG (p=0.01), 17p- (p<0.01), and unmutated IGHV (p=0.01); ATMmut with high WBC (p=0.02), and 11q- (p<0.01); MYD88mut with mutated IGHV (p=0.02); FBXW7mut with 17p- (p=0.02), and +12q (p<0.01). BIRC3mut was only present in IGHV unmutated cases (p<0.01), was more frequent in 11q- (p<0.01), +12q (p=0.05), and in cases with NOTCH1mut (p=0.05). POT1mut was more frequent in NOTCH1mut cases (p=0.02) without associations with any other baseline parameter. Regarding response to treatment, TP53mut was significantly associated with reduced ORR rate (p<0.01). CR rate was not correlated with mutations in the covered genes. At a median follow-up of 31.7 months, there were 249 (66%) events for PFS and 63 (16.8%) events for OS. O-Chl as compared to Chl resulted in significantly improved PFS (median 22.4 vs. 13.1 months, HR 0.54, p<0.01). In univariate analyses, TP53mut (HR 2.07, p<0.01), NOTCH1mut (HR 1.50, p=0.01) and SF3B1mut (HR 1.66, p=0.01) were associated with shorter PFS, whereas ATM and other candidate genes showed no association (ATMmut: HR 1.40, p=0.07). Analyzing both treatment arms separately, TP53mut had an impact on PFS with Chl and O-Chl treatment (HR 1.92, p=0.04 and HR 2.49, p<0.01). Notably, NOTCH1mut was associated with outcome in O-Chl only (HR 2.01, p<0.01 vs. HR 1.14, p=0.59) resulting in a reduced beneficial effect from the addition of Ofatumumab to Chlorambucil treatment. ATMmut and BIRC3mut mutations were only adverse prognostic factors with Chl monotherapy (ATMmut: HR 1.69, p=0.05 vs. HR 1.35, p=0.27; BIRC3mut: HR 2.84, p=0.04 vs. HR 0.99, p=0.99). OS was reduced significantly only in TP53mut cases (HR 3.69, p<0.01). Of note, none of the MYD88mut cases (n=10) had died within the follow-up period. To identify genomic factors of independent prognostic impact, we performed multivariable Cox regression analyses for PFS and OS including treatment arms, 11q-, +12q, 17p-, IGHV and all candidate gene mutations. For PFS, the following independent prognostic factors were identified: O-Chl (HR 0.46, p<0.01), 17p- (HR 3.14, p<0.01), 11q- (HR 1.57, p=0.01), unmutated IGHV (HR 1.43, p=0.02), TP53mut (HR 1.81, p=0.03), NOTCH1mut (HR 1.63, p<0.01) and SF3B1mut (HR 1.54, p=0.02). Regarding OS, only 17p- (HR 4.07, p<0.01), and unmutated IGHV (HR 1.81, p=0.05) were identified as independent adverse prognostic factors with TP53mut showing a trend (HR 2.14, p=0.10). CONCLUSION: We performed mutational analyses for the 8 most frequent mutated genes in CLL in the COMPLEMENT1 trial evaluating 1st line O-Chl against Chl. An independent prognostic impact was identified for TP53mut, NOTCH1mutand SF3B1mut regarding PFS. Notably, NOTCH1mut affected outcome mainly with O-Chl treatment, whereas ATMmut and BIRC3mut were associated with outcome with Chl monotherapy. In multivariate analysis for OS, none of the gene mutations, but the established parameters IGHV and 17p- had independent prognostic impact. Disclosures Tausch: GlaxoSmithKline: Research Funding, Travel support Other. Hillmen:GSK: Honoraria, Research Funding. Offner:GlaxoSmithKline: Honoraria, Research Funding. Janssens:GSK: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Speakers Bureau; Roche: Speakers Bureau; Mundipharma: Speakers Bureau. Mayer:Glaxo: Research Funding; Roche: Research Funding. Panagiotidis:GlaxoSmithKline: Consultancy, Honoraria. McKeown:GlaxoSmithKline: Employment. Gupta:GlaxoSmithKline: Employment. Stilgenbauer:GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Clinical Outcomes of Patients with Newly Diagnosed Multiple Myeloma Receiving Triplet Therapy in the Connect MM® Disease Registry

Blood ◽

10.1182/blood.v126.23.4229.4229 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4229-4229

Author(s):

Jatin J. Shah ◽

Rafat Abonour ◽

Mohit Narang ◽

Jayesh Mehta ◽

Howard R. Terebelo ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Research Funding ◽

Newly Diagnosed ◽

Employment Equity ◽

Advisory Committees ◽

Risk Of Death ◽

Equity Ownership ◽

Triplet Regimen

Abstract Introduction: Triplet therapies are used for treatment (Tx) of both transplant-eligible and -ineligible patients (pts) with newly diagnosed multiple myeloma (NDMM). Actual patterns and outcomes of Tx are not fully understood. Connect MM® is the first and largest multicenter, US-based, prospective observational cohort study designed to characterize Tx patterns and outcomes for pts with NDMM. This analysis describes demographic and disease characteristics of pts who received triplet Tx as an induction regimen and for whom transplant was or was not intended. The analysis explores the relationship of these factors with overall survival (OS) and other efficacy endpoints. Patients and Methods: Pts aged ≥ 18 y with NDMM within 60 days of diagnosis were eligible for enrollment regardless of disease severity, medical history, or comorbidities. Data including transplant intent (yes/no) was collected at baseline; follow-up data was collected quarterly thereafter. Based on the initial intent, 2 groups were identified: patients with intent to transplant who received transplant (TT) and pts with no intent to transplant who did not receive a transplant (NT). Triplet Tx was defined as the combination of ≥ 3 concurrent therapeutic agents in the first course of Tx (within 56 days of study entry). KM analysis adjusted for age was conducted for OS. Because decisions on use of transplant and triplet therapy are influenced by multiple factors, a multivariable Cox regression analysis was performed to evaluate the contribution of the triplet therapy (yes/no) to OS and was adjusted for other variables, including age, comorbidities, and ISS staging. Results: Between September 2009 and December 2011, 1493 pts were enrolled. This analysis was on 1436 pts: 650 pts with transplant intent and 786 pts without transplant intent. The data cutoff date was November 30, 2014, and the median follow-up for overall survival (OS) was 33.8 mos. Of pts with transplant intent, 451 (69%) received transplant (TT) and 199 (31%) did not. Of pts without transplant intent, 62 (8%) received transplant and 724 (92%) did not (NT). The abstract focuses on TT and NT groups only. NT pts tended to be older and have more advanced ISS staging and higher β2-microglobulin levels than TT pts (Table). The most common triplet regimen given during the first course treatment (within 56 days) was lenalidomide, bortezomib, and dexamethasone (RVd). RVd was administered to 34% of the NT pts (76/225) and 59% of the TT pts (152/257). The most common non-triplet regimen was bortezomib and dexamethasone (Vd), which was given to 31% of NT pts (156/499) and 38% of TT pts (73/194). Within the NT group, pts given triplet Tx had a lower risk of death than those who did not receive triplet Tx (P = .0013). The multivariable analysis found triplet Tx to be associated with a 36% reduced risk of death (hazard ratio [HR] = 0.64 [95% CI, 0.50-0.82]; P = .001). ISS disease stage (HR = 1.43 [95% CI, 1.21-1.69]; P < .001) and history of diabetes (HR = 1.38 [95% CI, 1.08-1.78]; P = .012) were negative prognostic factors for OS. Within the TT group, pts who received triplet Tx did not attain an OS benefit (P = .8993), and no baseline characteristics were significantly associated with OS. These results may be limited by other factors not considered that may have influenced physicians' choice of treatment, including the use of maintenance therapy and a short follow-up period of 33.8 months. Conclusions: Triplet Tx as a first regimen is associated with longer OS in pts without transplant intent who did not receive a transplant. RVd and Vd were the most common first Tx regimens, respectively. Continued follow-up of these pts and enrollment of an additional cohort will provide additional data with mature follow-up. Table 1. Table 1. Disclosures Shah: Bristol-Myers Squibb: Research Funding; Array: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium: Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees. Abonour:Celgene: Research Funding, Speakers Bureau. Narang:Celgene: Speakers Bureau. Mehta:Celgene Corporation: Speakers Bureau. Terebelo:Millenium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacylics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Gasparetto:Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium: Honoraria, Other: Export Board Committee, Speakers Bureau. Toomey:Celgene: Consultancy. Hardin:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Srinivasan:Celgene Corporation: Employment, Equity Ownership. Larkins:Celgene Corporation: Employment, Equity Ownership. Nagarwala:Celgene Corporation: Employment, Equity Ownership. Rifkin:Onyx Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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Analysis of Transfusion Dependency Development and Disease Evolution in Patients with MDS with 5q- and without Transfusion Needs at Diagnosis

Blood ◽

10.1182/blood.v128.22.3180.3180 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3180-3180

Author(s):

Felix Lopez-Cadenas ◽

Blanca Xicoy ◽

Silvia Rojas P ◽

Kaivers Jennifer ◽

Ulrich Germing ◽

...

Keyword(s):

Multivariate Analysis ◽

Board Of Directors ◽

Research Funding ◽

Statistical Significance ◽

Univariate Analysis ◽

Rank Test ◽

Advisory Committees ◽

Disease Evolution ◽

Free Survival

Abstract Introduction: Myelodysplastic syndrome with del5q (MDSdel5q) is the only cytogenetically defined MDS category recognized by WHO in 2001, 2008 and 2016 and is defined as a MDS with deletion on the long arm of chromosome 5 and less than 5% of blast cells in bone marrow. It is known that for patients with MDSdel5q and transfusion dependence (TD), Len (LEN) is the first choice of treatment. However, data regarding factors that may impact on the development of TD or disease evolution in patients diagnosed without TD are scanty. In our study a retrospective multicenter analysis on patients with low-int 1 MDSdel5q without TD at diagnosis has been performed in order to answer these questions. Patients and methods: We performed a multicenter collaborative research from the Spanish (RESMD) and German MDS registries. Data from 153 low risk MDSdel5q without TD at diagnosis were retrospectively analyzed. Statistical analysis: Data were summarized using median, range, and percentage. The event of TD was defined as the development of TD according to the IWG criteria (2006) and/or the beginning of a treatment which could modify disease course (LEN or ESA). Transfusion or treatment free survival (TFS), overall survival (OS) and leukemia free survival (LFS) were measured from diagnosis to TD or treatment, the first occurred (or to last follow up if none), last follow up or death from any cause and evolution to AML, respectively. TFS, OS and LFS were analyzed using the Kaplan Ð Meier method. The Log-rank test was used to compare variables and their impact on survival for univariate analysis.Multivariate analysis was performed using Cox's proportional hazards regression model. For comparison of Kaplan Meier curves the long rank test was used, with statistical significance with p<0.05. Statistical analysis was performed using SPSS 20.0. Results: Main clinical and biological characteristics were summarizing in table 1. From the total of 153 patients, finally 121 were evaluable. During the study 56 patients (46.2%) became in TD and 47 (38.8%) did not develop TD but received a modified disease course treatment. In this sense, most of the patients developed relevant anemia regarding those data (103 out of 121 patients, 85%). Median time to TD or treatment (TFS) was 20 months (1-132) from diagnosis. Secondary MDS (p=0.02), thrombocytosis (>350 109/L) (p=0.007), and neutropenia (<1.5 x 109/L) (p=0.02) were associated with poorer TFS. Thrombocytosis and neutropenia retained statistical significance in the multivariate analysis (Table 2). Among the TD patients (N=56), 42 (75%) received treatment: 28 LEN, 7 ESA and 7 other treatments. Among patients that did not develop TD (N=65), 47 (72.3%) received treatment before TD development: 16 LEN, 28 ESA and 3 other treatments. In order to know the evolution of these patients, survival analysis was performed. Median follow up was 58.9 months among alive patients and 57% of them were alive at the time of the last follow up. Estimated OS at 2 and 5 years was 94% and 64%. Regarding Univariate analysis, platelet <100 x 109/L (p=0.03), patients older than 71 years (p=0.001), and progression into AML (p=0.02) were associated with poorer OS. On the contrary, patients who had received treatment showed better OS (p<0.0001). This benefit is more evident among patients receiving LEN, median OS for patients receiving LEN, ESA/other treatments and not treated group was 137 months (CI 95%: 59,4 -215,5), 99,3 months (CI 95%: 46,6 -152) and 57,9 months (CI 95%: 38,2 -77,6), respectively, p<0.0001 (Figure 1). In the multivariate analysis, patients older than 71 years and LEN treatment retained the statistical significant impact on OS (Table 2). Twenty-eight patients (23%) progressed into AML, median time to AML was 35 months (5-122). When univariate analysis was performed, variables with adverse impact on LFS were platelets <100 x 109/L(p=0.019), neutropenia < 0.8 x 109/L (p=0.026), an additional cytogenetic abnormality (p=0.013) while treatment with LEN had a favorable impact (p=0.035). In the multivariate analysis only the presence of additional cytogenetic abnormalities retained statistical significance (Table 2). CONCLUSIONS: Most of the patients with low risk del(5q) MDS and no TD at diagnosis developed symptomatic anemia very early after diagnosis (20 months). Carefully monitoring should be stablished in order to detect this time point. Outcome of this subset of patients could improve after target therapy. Figure 1 Figure 1. Disclosures Del Cañizo: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; janssen: Research Funding; Astex: Membership on an entity's Board of Directors or advisory committees. Díez Campelo:celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Research Funding; Astex: Membership on an entity's Board of Directors or advisory committees.

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