Lenalidomide Maintenance Significantly Improves Survival Figures in Patients with Relapsed Diffuse Large B-Cell Lymphoma (rDLBCL) Who Are Not Eligible for Autologous Stem Cell Transplantation (ASCT): Final Results of a Multicentre Phase II Trial

Abstract Background: Patients (pts) with rDLBCL not eligible for ASCT or experiencing relapse after ASCT have a low likelihood of cure. Single-drug maintenance after salvage therapy may be an attractive strategy to prolong survival in these pts. Lenalidomide (LEN) is a suitable candidate for long-lasting maintenance as it is an oral drug, active against DLBCL, that can be taken for years with an acceptable toxicity profile. Accordingly, we designed a multicentre phase II trial addressing LEN maintenance in pts with chemosensitive relapse of DLBCL not eligible for ASCT or experiencing relapse after ASCT (clinicaltrials.gov NCT00799513). Methods: HIV-neg pts (age ≥18 ys) with histologically-proven de novo or transformed DLBCL and relapsed disease responsive to conventional rituximab-containing salvage therapy were registered and treated with LEN 25 mg/day for 21 days out of 28, until lymphoma progression or unacceptable toxicity. Primary endpoint was 1-year progression-free survival (PFS). Simon's two-stage optimal design was used. To demonstrate a 1-yr PFS improvement from 30% (P0) to 50% (P1), 47 pts (one-sided; α 5%; β 80%) were needed. Maintenance would be considered effective if ≥19 pts were progression-free survivors at 1 yr. Cell of origin was assessed by NanoString Technology and Hans algorithm, and cereblon expression was assessed by immunohistochemistry. Results: 46 of 48 enrolled pts were assessable (median age 72 ys; range 34-86); 36 pts had de novo DLBCL, 10 had transformed DLBCL. All pts were previously treated with anthracycline- and rituximab-based combination, plus ASCT in 6 pts; the median TTP after the prior therapy was 16 months (range 3-121). Thirty-three pts were enrolled at 1st relapse, 13 at 2nd relapse; salvage therapy contained high doses of cytarabine or ifosfamide in two-thirds of cases, and response was complete in 26 pts and partial in 20. Most pts had unfavourable features: IPI ≥2 in 38 (83%) pts, advanced stage in 35 (76%), extranodal disease in 29 (63%), high LDH level in 21 (46%); 28 (61%) pts were older than 70 ys. At a median follow-up of 25 (range 6-87) months, 556 LEN courses were delivered, with an average of 12 courses/pt (range 3-41); 19 pts are still in treatment. LEN was well tolerated: with the exception of neutropenia, grade 3-4 toxicities were uncommon, occurring in ≤3% of delivered courses. Infections were rare, and well controlled with oral antibiotics (grade 1-2 in 8 courses; grade 3 in 3). LEN dose reduction was indicated in 23 pts (transient in 19), and was due to neutropenia (12), rash (7), diarrhoea (2), and neurotoxicity (2); LEN was discontinued in 6 of them. One (2%) pt died of acute toxicity (intestinal infarction) and one due to secondary myelodysplastic syndrome at 56 months of follow-up. Pts with HBV/HCV seropositivity (n=12) or prior ASCT (n=6) did not experience unexpected toxicity after >1 yr of treatment. At one year from trial registration, 28 pts were still progression free, which was significantly higher than the pre-determined efficacy threshold (n≥19). During the whole observation period, there were 21 events: progressive disease in 19 pts, death of toxicity in one, death while off therapy in one, with a 1-yr PFS (primary endpoint) of 70 ± 7%. The duration of response to LEN was longer than response duration after the prior treatment line in 27 (59%) pts, and was twice as long in 15 of them. The benefit of LEN maintenance was observed both in pts with de novo or transformed DLBCL. According to the Hans' algorithm, the 1-yr PFS was 64 ± 11% for GCB-DLBCL and 67 ± 11% for nonGCB-DLBCL (p= 0.67). Results using the Nanostring technique were consistent with the Hans' algorithm, with a concordance rate of 86%. There was no significant association between cereblon expression and PFS. Multivariate analysis confirmed that treatment at first relapse and a prior TTP ≥12 months were independently associated with better PFS. Overall, 33 (72%) pts are alive, with a 1- and 3-yr OS of 81 ± 6% and 71 ± 8%, respectively. Conclusions: With the limitations of a non-randomized design, this trial soundly promotes the use of LEN maintenance in pts with chemosensitive relapse of DLBCL not eligible for ASCT or experiencing relapse after ASCT. LEN was well tolerated in this elderly population, with survival benefit both in pts with de novo or transformed DLBCL, and both in pts with GCB- or nonGCB-DLBCL. These results warrant further investigation of immunomodulatory drugs as maintenance in these high-risk pts. Disclosures Spina: Teva Pharmaceuticals Industries: Membership on an entity's Board of Directors or advisory committees, Other: Speaker Fee; Mundipharma: Membership on an entity's Board of Directors or advisory committees, Other: Speaker Fee. Rusconi:Teva: Consultancy, Other: Congress attendance; Takeda: Consultancy; Janssen: Consultancy, Other: Congress attendance. Couto:Celgene: Employment, Equity Ownership. Ren:Celgene: Employment, Equity Ownership.

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Daratumumab (DARA) Maintenance Therapy Improves Depth of Response and Results in Durable Progression-Free Survival (PFS) Following Dara Plus Cyclophosphamide, Bortezomib, and Dexamethasone (CyBorD) Induction Therapy in Multiple Myeloma (MM): Update of the Lyra Study

Blood ◽

10.1182/blood-2019-122497 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 863-863 ◽

Cited By ~ 4

Author(s):

Robert M. Rifkin ◽

Jason M. Melear ◽

Edward Faber ◽

William I. Bensinger ◽

John M Burke ◽

...

Keyword(s):

Stem Cell ◽

Board Of Directors ◽

Induction Therapy ◽

Safety Profile ◽

Employment Equity ◽

Advisory Committees ◽

Depth Of Response ◽

Equity Ownership ◽

Grade 3

Background: DARA, a human IgGκ monoclonal antibody targeting CD38, is approved in combination with bortezomib, melphalan, and prednisone (VMP) and bortezomib and dexamethasone (Vd) for newly diagnosed MM (NDMM) and relapsed MM (RMM), respectively. CyBorD is a commonly used immunomodulatory drug-sparing regimen for MM. In the LYRA (NCT02951819) study, DARA plus CyBorD (DARA-CyBorD) demonstrated efficacy and a tolerable safety profile at the end of induction. Here, we present updated findings examining the effect of monthly DARA maintenance on the efficacy and safety of DARA-CyBorD in NDMM and RMM. Methods: LYRA is an ongoing, single-arm, open-label, phase 2 study conducted at US community oncology centers. Patients (pts) were aged ≥18 years with documented MM per IMWG criteria, an ECOG performance score (PS) of 0-2, and ≤1 prior line of therapy. Pts received 4-8 induction cycles of DARA-CyBorD (cyclophosphamide 300 mg/m2 PO on Days 1, 8, 15, and 22; bortezomib 1.5 mg/m2 SC on Days 1, 8, and 15; and dexamethasone 40 mg PO or IV weekly [qw]) every 28 days. DARA was given at 8 mg/kg IV on Days 1 and 2 of C1, 16 mg/kg qw from C1D8 through C2, 16 mg/kg q2w for C3-6, and 16 mg/kg q4w for C7-8. After induction, eligible pts could undergo autologous stem cell transplantation (ASCT). All pts received up to 12 maintenance cycles with DARA 16 mg/kg IV q4w. Results: A total of 101 (87 NDMM, 14 RMM) pts were enrolled; 100 (86 NDMM, 14 RMM) pts received ≥1 treatment dose. Median age was 63 years; most pts were white (81%), male (64%), had ECOG PS 0-1 (94%) and had IgG (57%) MM; 36% of pts had high cytogenetic risk, defined as a del(17p), t(4:14) or t(14;16) abnormality. NDMM and RMM pts received a median of 6 and 8 cycles, respectively, of induction therapy. Thirty-nine NDMM pts and 1 RMM pt underwent ASCT. Fifty percent of pts received plerixafor; median stem cell yield for NDMM pts was 6.2 x 106 (range 2-15 x 106) CD34+ cells/kg. A total of 85 (75 NDMM, 10 RMM) pts received ≥1 dose of maintenance treatment; 63 (56 NDMM, 7 RMM) pts have received all 12 maintenance cycles. In NDMM pts, ORR was 87%, with 64% ≥VGPR and 12% ≥CR, by the end of induction. By the end of maintenance, ORR, ≥VGPR and ≥CR rates were 97%, 82% and 51% in NDMM pts who underwent ASCT and 83%, 70% and 30% in NDMM pts who did not receive ASCT. In RMM pts, ORR, ≥VGPR and ≥CR rates were 79%, 71% and 29% by the end of induction and 86%, 71% and 64% by the end of maintenance. At a median follow up of 24.8 mo in NDMM pts and 26.6 mo in RMM pts, median duration of response was not reached (NR). Median PFS (Figure) was NR in NDMM pts, regardless of transplant status, and was 21.7 mo in RMM pts; median OS was NR in NDMM pts and was 30.1 mo in RMM pts. In NDMM pts the 24-mo PFS rate was 89% in pts who underwent ASCT and 72% in pts who did not receive ASCT. The 24-mo OS rate was 90% for NDMM pts. In RMM pts, the 24-mo PFS and OS rates were 48% and 64%, respectively. All treated pts had ≥1 TEAE. Common TEAEs (≥25%) included fatigue, nausea, cough, diarrhea, upper respiratory tract infection, back pain, vomiting, insomnia, dyspnea, constipation, and headache. Grade 3/4 TEAEs were reported in 62% of pts; the most common (≥10%) was neutropenia (14%). Serious TEAEs occurred in 33% of pts; the most common (>2%) were pneumonia, atrial fibrillation and pulmonary embolism. TEAEs led to permanent treatment discontinuation in 7% of pts, with 2% related to treatment. TEAEs resulted in death in 2 pts (nephrotic syndrome, sudden death); both unrelated to treatment. Infusion reactions (IRs) occurred in 56% of pts including grades 1-2 in 52% of pts, grade 3 in 3% of pts and grade 4 in 1% of pts. Most common (>5%) IRs were chills, cough, dyspnea, nausea, pruritus, flushing and nasal congestion. Conclusion: Maintenance with DARA monotherapy for 12 mo increased the >CR rate in NDMM and RMM pts, consistent with observations in prior studies that longer DARA treatment improves depth of response. Importantly, the increase in ≥CR rate was associated with durable PFS and OS. The 24-mo PFS rates in NDMM and RMM pts compare favorably with results for DARA-VMP and DARA-Vd in NDMM and RRMM, respectively. Safety profile was consistent with previous reports of DARA, with no new safety concerns observed with longer follow-up. These data indicate that DARA-CyBorD is a safe, effective MM treatment and that DARA maintenance increases depth of response and achieves durable remissions. Disclosures Rifkin: Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Melear:Texas Oncology: Employment; DARA: Speakers Bureau. Faber:Cardinal Health: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Bensinger:Amgen, Celgene: Other: Personal Fees, Research Funding, Speakers Bureau; Takeda, Janssen: Speakers Bureau; Sanofi, Seattle Genetics, Merck, Karyopharm: Other: Grant. Burke:Gilead: Consultancy; Celgene: Consultancy; Roche/Genentech: Consultancy. Narang:Celgene: Speakers Bureau. Stevens:Astellas: Consultancy. Gunawardena:Janssen: Employment, Equity Ownership. Lutska:Janssen: Employment. Qi:Janssen: Employment. Ukropec:Janssen: Employment, Equity Ownership. Qi:Janssen: Employment. Lin:Janssen: Employment, Equity Ownership. Yimer:Amgen: Consultancy; Clovis Oncology: Equity Ownership; Puma Biotechnology: Equity Ownership; Celgene: Honoraria; Seattle Genetics: Honoraria; Janssen: Speakers Bureau; AstraZeneca: Speakers Bureau.

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Long-Term Safety, Efficacy, and Survival Findings From Comfort-II, a Phase 3 Study Comparing Ruxolitinib with Best Available Therapy (BAT) for the Treatment of Myelofibrosis (MF)

Blood ◽

10.1182/blood.v120.21.801.801 ◽

2012 ◽

Vol 120 (21) ◽

pp. 801-801 ◽

Cited By ~ 21

Author(s):

Francisco Cervantes ◽

Jean-Jacques Kiladjian ◽

Dietger Niederwieser ◽

Andres Sirulnik ◽

Viktoriya Stalbovskaya ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Advisory Board ◽

Extension Phase ◽

Spleen Volume ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership ◽

Grade 3

Abstract Abstract 801 Background: Ruxolitinib is a potent JAK1 & 2 inhibitor that has demonstrated superiority over traditional therapies for the treatment of MF. In the two phase 3 COMFORT studies, ruxolitinib demonstrated rapid and durable reductions in splenomegaly and improved MF-related symptoms and quality of life. COMFORT-II is a randomized, open-label study evaluating ruxolitinib versus BAT in patients (pts) with MF. The primary and key secondary endpoints were both met: the proportion of pts achieving a response (defined as a ≥ 35% reduction in spleen volume) at wk 48 (ruxolitinib, 28.5%; BAT, 0%; P < .0001) and 24 (31.9% and 0%; P < .0001), respectively. The present analyses update the efficacy and safety findings of COMFORT-II (median follow-up, 112 wk). Methods: In COMFORT-II, 219 pts with intermediate-2 or high-risk MF and splenomegaly were randomized (2:1) to receive ruxolitinib (15 or 20 mg bid, based on baseline platelet count [100-200 × 109/L or > 200 × 109/L, respectively]) or BAT. Efficacy results are based on an intention-to-treat analysis; a loss of spleen response was defined as a > 25% increase in spleen volume over on-study nadir that is no longer a ≥ 35% reduction from baseline. Overall survival was estimated using the Kaplan-Meier method. Results: The median follow-up was 112 wk (ruxolitinib, 113; BAT, 108), and the median duration of exposure 83.3 wk (ruxolitinib, 111.4 [randomized and extension phases]; BAT, 45.1 [randomized treatment only]). Because the core study has completed, all pts have either entered the extension phase or discontinued from the study. The primary reasons for discontinuation were adverse events (AEs; ruxolitinib, 11.6%; BAT, 6.8%), consent withdrawal (4.1% and 12.3%), and disease progression (2.7% and 5.5%). Overall, 72.6% of pts (106/146) in the ruxolitinib arm and 61.6% (45/73) in the BAT arm entered the extension phase to receive ruxolitinib, and 55.5% (81/146) of those originally randomized to ruxolitinib remained on treatment at the time of this analysis. The primary reasons for discontinuation from the extension phase were progressive disease (8.2%), AEs (2.1%), and other (4.1%). Overall, 70 pts (48.3%) treated with ruxolitinib achieved a ≥ 35% reduction from baseline in spleen volume at any time during the study, and 97.1% of pts (132/136) with postbaseline assessments experienced a clinical benefit with some degree of reduction in spleen volume. Spleen reductions of ≥ 35% were sustained with continued ruxolitinib therapy (median duration not yet reached); the probabilities of maintaining the spleen response at wk 48 and 84 are 75% (95% CI, 61%-84%) and 58% (95% CI, 35%-76%), respectively (Figure). Since the last report (median 61.1 wk), an additional 9 and 12 deaths were reported in the ruxolitinib and BAT arms, respectively, resulting in a total of 20 (14%) and 16 (22%) deaths overall. Although there was no inferential statistical testing at this unplanned analysis, pts randomized to ruxolitinib showed longer survival than those randomized to BAT (HR = 0.52; 95% CI, 0.27–1.00). As expected, given the mechanism of action of ruxolitinib as a JAK1 & 2 inhibitor, the most common new or worsened grade 3/4 hematologic abnormalities during randomized treatment were anemia (ruxolitinib, 40.4%; BAT, 23.3%), lymphopenia (22.6%; 31.5%), and thrombocytopenia (9.6%; 9.6%). In the ruxolitinib arm, mean hemoglobin levels decreased over the first 12 wk of treatment and then recovered to levels similar to BAT from wk 24 onward; there was no difference in the mean monthly red blood cell transfusion rate among the ruxolitinib and BAT groups (0.834 vs 0.956 units, respectively). Nonhematologic AEs were primarily grade 1/2. Including the extension phase, there were no new nonhematologic AEs in the ruxolitinib group that were not observed previously (in ≥ 10% of pts), and only 1 pt had a new grade 3/4 AE (epistaxis). Conclusion: In COMFORT-II, ruxolitinib provided rapid and durable reductions in splenomegaly; this analysis demonstrates that these reductions are sustained over 2 years of treatment in the majority of pts. Ruxolitinib-treated pts showed longer survival than those receiving BAT, consistent with the survival advantage observed in previous (Verstovsek et al. NEJM. 2012) and current analyses of COMFORT-I, as well as with the comparison of pts of the phase 1/2 study with matched historical controls (Verstovsek et al. Blood. 2012). Disclosures: Cervantes: Sanofi-Aventis: Advisory Board, Advisory Board Other; Celgene: Advisory Board, Advisory Board Other; Pfizer: Advisory Board, Advisory Board Other; Teva Pharmaceuticals: Advisory Board, Advisory Board Other; Bristol-Myers Squibb: Speakers Bureau; Novartis: AdvisoryBoard Other, Speakers Bureau. Kiladjian:Shire: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding. Niederwieser:Novartis: Speakers Bureau. Sirulnik:Novartis: Employment, Equity Ownership. Stalbovskaya:Novartis: Employment, Equity Ownership. McQuity:Novartis: Employment, Equity Ownership. Hunter:Incyte: Employment. Levy:Incyte: Employment, stock options Other. Passamonti:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Barbui:Novartis: Honoraria. Gisslinger:AOP Orphan Pharma AG: Consultancy, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees. Knoops:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Harrison:Shire: Honoraria, Research Funding; Sanofi: Honoraria; YM Bioscience: Consultancy, Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau.

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Complete Molecular and Hematologic Response in Adult Patients with Relapsed/Refractory (R/R) Philadelphia Chromosome-Positive B-Precursor Acute Lymphoblastic Leukemia (ALL) Following Treatment with Blinatumomab: Results from a Phase 2 Single-Arm, Multicenter Study (ALCANTARA)

Blood ◽

10.1182/blood.v126.23.679.679 ◽

2015 ◽

Vol 126 (23) ◽

pp. 679-679 ◽

Cited By ~ 32

Author(s):

Giovanni Martinelli ◽

Hervé Dombret ◽

Patrice Chevallier ◽

Oliver G. Ottmann ◽

Nicola Goekbuget ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Philadelphia Chromosome ◽

Pcr Amplification ◽

Employment Equity ◽

Advisory Committees ◽

T315i Mutation ◽

Equity Ownership ◽

Grade 3

Abstract Introduction. Prognosis of patients (pts) with R/R Philadelphia chromosome-positive (Ph+) ALL is dismal despite the introduction of tyrosine kinase inhibitors (TKI) which may be used as single agents or in combination regimens. Blinatumomab is a bispecific T-cell engaging (BiTE®) antibody construct that has shown antileukemic activity. Among adults with R/R Ph-negative ALL receiving blinatumomab, 43% achieved complete remission (CR) or CR with partial hematologic recovery (CRh) during the first two cycles (Topp MS et al. Lancet Oncol 2015;16:57). We evaluated the efficacy and tolerability of blinatumomab in pts with R/R Ph+ ALL who progressed after or were intolerant to a 2nd or later (2+) generation TKI. Methods. Eligible adult pts (≥18 years) had Ph+ B-precursor ALL and had relapsed after or were refractory to at least one 2+ generation TKI; or were intolerant to 2+ generation TKI and intolerant or refractory to imatinib. All pts had to have >5% blasts in the bone marrow and Eastern Cooperative Oncology Group performance status ≤ 2. Blinatumomab was dosed by continuous IV infusion (4 weeks on/2 weeks off) for up to 5 cycles (9 μg/d on days 1-7 in cycle 1, and 28 μg/d thereafter). The primary endpoint was CR or CRh during the first two cycles; minimal residual disease (MRD) response based on RT-PCR amplification of BCR-ABL per central laboratory, relapse-free survival (RFS), overall survival (OS), and allogeneic hematopoietic stem cell transplant (alloHSCT) rate were key secondary endpoints. Complete MRD response was defined as no RT-PCR amplification of BCR-ABL at a sensitivity of 10-5. Results. Of 45 treated pts, 44 were resistant to 2+ generation TKI; one patient was resistant to imatinib and never exposed to 2+ generation TKI (protocol deviation). 53% of pts were men. Median (range) age was 55 (23-78) years (≥65 years, 27%). Ten pts (22%) had a BCR-ABL gene with T315I mutation. All pts had received prior TKI (dasatinib, 87%; ponatinib, 51%; imatinib, 56%; nilotinib, 36%; bosutinib, 2%), with 60% having received ≥ 2 prior 2+ generation TKI; most pts (96%) had received prior chemotherapy. 38% of pts had ≥ 2 prior relapses and 44% had prior alloHSCT. Efficacy outcomes for key endpoints are shown in the table. 16 pts achieved CR/CRh during the first two cycles for a response rate of 36% (95% CI: 22%, 51%); of those, 14 pts achieved CR, most of them (10/14, 71%) in cycle 1. The patient who never received 2+ generation TKI did not respond to treatment. 12 of the 14 pts (86%) with CR and two of the two pts with CRh achieved a complete MRD response. Among the 10 pts with T315I mutation, four achieved CR/CRh; all four also achieved a complete MRD response. Eight CR/CRh responders (50%) relapsed, three during treatment (including two with CR who did not achieve complete MRD response). One patient died in CR post alloHSCT. Median (95% CI) RFS was 6.7 (4.4, not estimable) months (median follow-up, 9.0 months); median OS was 7.1 (5.6, not estimable) months (median follow-up, 8.8 months). Patient incidence of grade ≥ 3 treatment-emergent adverse events (AEs) was 82%, most commonly febrile neutropenia (27%), thrombocytopenia (22%), anemia (16%), and pyrexia (11%). Five pts had fatal AEs; one (septic shock) was considered treatment-related by the investigator. Three pts discontinued because of AEs. Cytokine release syndrome (CRS) occurred in three pts (all grade 1 or 2). 21 pts (47%) had neurologic events (paraesthesia, 13%; confusional state, 11%; dizziness, 9%; tremor, 9%); three pts had grade 3 neurologic events (aphasia, hemiplegia; and depressed level of consciousness and nervous system disorder), one of which (aphasia) required treatment interruption. Conclusion. In this population of pts with R/R Ph+ ALL who have very poor prognosis after failure of 2+ generation TKI therapy, treatment with CD19-targeted immunotherapy blinatumomab as single agent showed antileukemic activity. AEs were consistent with those previously reported for pts with R/R Ph-negative ALL treated with blinatumomab. Table 1. Table 1. Disclosures Martinelli: Novartis: Speakers Bureau; BMS: Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; ARIAD: Consultancy; Roche: Consultancy; MSD: Consultancy. Dombret:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ottmann:Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ariad: Consultancy, 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, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Goekbuget:Bayer: Equity Ownership; Eusapharma/Jazz: Consultancy, Honoraria, Research Funding; Erytech: Consultancy; Pfizer: Consultancy, Honoraria, Research Funding; Medac: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding; SigmaTau: Consultancy, Honoraria, Research Funding; Kite: Consultancy; Gilead Sciences: Consultancy; Sanofi: Equity Ownership; Amgen: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria. Topp:Astra: Consultancy; Regeneron: Consultancy; Affimed: Consultancy, Research Funding; Roche: Consultancy, Other: Travel Support; Jazz: Consultancy; Pfizer: Consultancy; Amgen: Consultancy, Honoraria, Other: Travel Support. Fielding:Amgen: Consultancy, Honoraria. Sterling:Amgen: Employment, Equity Ownership. Benjamin:Amgen: Employment, Equity Ownership. Stein:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Seattle Genetics: Research Funding.

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Efficacy and Safety of Lenalidomide (LEN) Versus Placebo (PBO) in RBC-Transfusion Dependent (TD) Patients (Pts) with IPSS Low/Intermediate (Int-1)-Risk Myelodysplastic Syndromes (MDS) without Del(5q) and Unresponsive or Refractory to Erythropoiesis-Stimulating Agents (ESAs): Results from a Randomized Phase 3 Study (CC-5013-MDS-005)

Blood ◽

10.1182/blood.v124.21.409.409 ◽

2014 ◽

Vol 124 (21) ◽

pp. 409-409 ◽

Cited By ~ 8

Author(s):

Valeria Santini ◽

Antonio Almeida ◽

Aristoteles Giagounidis ◽

Stephanie Gröpper ◽

Anna Jonasova ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Efficacy And Safety ◽

Employment Equity ◽

Phase 3 ◽

Advisory Committees ◽

Double Blind ◽

Equity Ownership ◽

Grade 3

Abstract Background: Treatment options for RBC-TD pts with lower-risk MDS without del(5q) who are unresponsive or refractory to ESAs are very limited. In a previous phase 2 study, MDS-002 (CC-5013-MDS-002), LEN was associated with achievement of RBC-transfusion independence (TI) ≥ 56 days in 26% of pts with IPSS Low/Int-1-risk MDS without del(5q) (Raza et al. Blood 2008;111:86-93). This international phase 3 study (CC-5013-MDS-005) compared the efficacy and safety of LEN versus PBO in RBC-TD pts with IPSS Low/Int-1-risk MDS without del(5q) unresponsive or refractory to ESAs. Methods: This multicenter, randomized, double-blind, parallel-group phase 3 study included RBC-TD pts (≥ 2 units packed RBCs [pRBCs]/28 days in the 112 days immediately prior to randomization) with IPSS Low/Int-1-risk MDS without del(5q), who were unresponsive or refractory to ESAs (RBC-TD despite ESA treatment with adequate dose and duration, or serum erythropoietin [EPO] > 500 mU/mL). Pts were randomized 2:1 to oral LEN 10 mg once daily (5 mg for pts with creatinine clearance 40–60 mL/min) or PBO. Pts with RBC-TI ≥ 56 days or erythroid response by Day 168 continued double-blind treatment until erythroid relapse, disease progression, unacceptable toxicity, or consent withdrawal. The primary endpoint was RBC-TI ≥ 56 days (defined as absence of any RBC transfusions during any 56 consecutive days). Secondary endpoints included time to RBC-TI, duration of RBC-TI, RBC-TI ≥ 168 days, progression to acute myeloid leukemia (AML; WHO criteria), overall survival (OS), and safety. Baseline bone marrow gene expression profiles were evaluated according to the Ebert signature (PloS Med 2008;5:e35) identified as predictive of LEN response. Clinical trial identifier: CT01029262. Results: The intent-to-treat population comprises 239 pts (LEN, n = 160; PBO, n = 79). Baseline characteristics were comparable across treatment groups; median age 71 years (range 43–87), 67.8% male, and median time from diagnosis 2.6 years (range 0.1–29.6). Pts received a median of 3.0 pRBC units/28 days (range 1.5–9.8) and 83.7% received prior therapy, including ESAs (78.7%). Significantly more LEN pts achieved RBC-TI ≥ 56 days versus PBO (26.9% vs 2.5%; P < 0.001; Table). The majority (90%) of pts with RBC-TI ≥ 56 days responded within 16 weeks of treatment. Median duration of RBC-TI ≥ 56 days was 8.2 months (range 5.2–17.8). Baseline factors significantly associated with achievement of RBC-TI ≥ 56 days with LEN were: prior ESAs (vs no ESAs; P = 0.005), serum EPO ≤ 500 mU/mL (vs > 500 mU/mL; P = 0.015), < 4 pRBC units/28 days (vs ≥ 4 pRBC units/28 days; P = 0.036), and female sex (vs male; P = 0.035). RBC-TI ≥ 168 days was achieved in 17.5% and 0% of pts in the LEN and PBO groups, respectively. The incidence of AML progression (per 100 person-years) was 1.91 (95% CI 0.80–4.59) and 2.46 (95% CI 0.79–7.64) for LEN and PBO pts, respectively, with median follow-up 1.6 and 1.3 years. Death on treatment occurred in 2.5% of pts on either LEN or PBO. The follow-up period was insufficient to permit OS comparison between the 2 groups. Myelosuppression was the main adverse event (AE); in the LEN versus PBO groups, respectively, grade 3–4 neutropenia occurred in 61.9% versus 11.4% of pts, and grade 3–4 thrombocytopenia in 35.6% versus 3.8% of pts. Discontinuations due to AEs were reported in 31.9% LEN and 11.4% PBO pts; among the 51 LEN pts who discontinued due to AEs, 14 discontinuations were due to thrombocytopenia and 8 due to neutropenia. In the subset of pts evaluated for the Ebert signature (n = 203), the predictive power of the signature was not confirmed. Conclusions: LEN therapy was associated with a significant achievement of RBC-TI ≥ 56 days in 26.9% of pts with a median duration of RBC-TI of 8.2 months; 90% of pts responded within 16 weeks of treatment. These data were consistent with response rates seen in the MDS-002 trial. The overall safety profile was consistent with the known safety profile of LEN and these data suggest LEN can be safely and effectively used in this patient population. Figure 1 Figure 1. Disclosures Santini: Celgene Corporation: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Glaxo Smith Kline: Honoraria. Off Label Use: Trial of Lenalidomide in non-del5q MDS. Almeida:Celgene Corporation: Consultancy, Speakers Bureau. Giagounidis:Celgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Vey:Celgene: Honoraria. Mufti:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Buckstein:Celgene: Research Funding. Mittelman:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Platzbecker:Celgene: Research Funding. Shpilberg:Celgene Corporation: Consultancy, Honoraria. del Canizo:Celgene Corporation: Consultancy, Research Funding. Gattermann:Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Ozawa:Celgene: Consultancy, not specified Other. Zhong:Celgene: Employment, Equity Ownership. Séguy:Celgene: Employment, Equity Ownership. Hoenekopp:Celgene: Employment, Equity Ownership. Beach:Celgene: Employment, Equity Ownership. Fenaux:Novartis: Research Funding; Janssen: Research Funding; Celgene: Research Funding.

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Imetelstat Treatment Leads to Durable Transfusion Independence (TI) in RBC Transfusion-Dependent (TD), Non-Del(5q) Lower Risk MDS Relapsed/Refractory to Erythropoiesis-Stimulating Agent (ESA) Who Are Lenalidomide (LEN) and HMA Naive

Blood ◽

10.1182/blood-2018-99-114877 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 463-463 ◽

Cited By ~ 5

Author(s):

David P. Steensma ◽

Uwe Platzbecker ◽

Koen Van Eygen ◽

Azra Raza ◽

Valeria Santini ◽

...

Keyword(s):

Board Of Directors ◽

Lower Risk ◽

Research Funding ◽

Employment Equity ◽

Advisory Committees ◽

Transfusion Independence ◽

Equity Ownership ◽

Grade 3 ◽

Rbc Transfusion

Abstract BACKGROUND: Patients with TD lower-risk (LR)-MDS relapsed or refractory to ESA have limited treatment options. Imetelstat is a first-in-class telomerase inhibitor that targets cells with short telomere lengths and active telomerase, characteristics observed in some MDS patients. IMerge is an ongoing global study of imetelstat in RBC TD patients with LR-MDS (IPSS Low or Int-1). In the first 32 patients enrolled, 8-week TI rate was 34%, with 24-week TI of 16%, and HI-E of 59%. The most frequently reported adverse events were reversible grade ≥3 cytopenias (Fenaux et al EHA 2018 Abstr S1157). Higher response rates were observed in patients (n=13) who were LEN and HMA naïve without del(5q). We report here results in an additional 25 LEN and HMA naïve patients without del(5q), with longer term follow-up of the 13 initial patients meeting the same criteria. METHODS: IMerge is a phase 2/3 trial (NCT02598661) that includes LR-MDS patients with a high transfusion burden (≥4 units / 8 weeks) who are relapsed/refractory to ESA or have sEPO >500 mU/mL. The additional 25 were required to be LEN and HMA naïve and lack del(5q). Imetelstat 7.5 mg/kg was administered IV every 4 weeks. In addition to the key endpoints noted above, secondary endpoints include safety, time to and duration of TI. Biomarkers are also being explored, including telomerase activity, hTERT, telomere length, and genetic mutations. RESULTS: Overall, for the 38 LEN/HMA naïve and non-del(5q) patients, median age was 71.5 years and 66% were men. 63% of patients were IPSS Low and 37% Int-1. Median prior RBC transfusion burden was 8.0 (range 4-14) U, and 71% had WHO 2008 RARS or RCMD-RS. 9/37 (24%) patients with evaluable sEPO levels had baseline level >500 mU/mL. As of July 2018, with a median follow-up of 25.8 months for the initial 13 patients, and 5.2 months for the 25 recently included patients, the 8-week RBC-TI rate was 37% (14/38). Durability of 24-week TI responses was demonstrated, with a median duration of 10 months and the longest ongoing response now >2 years. Among the patients achieving durable TI, all showed a Hb rise of ≥3.0 g/dL compared to baseline during the transfusion-free interval. Response rates were similar in RARS/RCMD-RS (33% [9/27]) and other patients (27% [3/11]), and those with baseline EPO levels >500 mU/mL (33% [3/9]) and ≤500 mU/mL (32% [9/28]). Reversible grade ≥3 neutropenia and thrombocytopenia were each reported in 58% of the patients. Liver function test (LFT) elevations were mostly grade 1/2. Reversible grade 3 LFTelevations were observed in 3 (8%) patients on study. An independent Hepatic Review Committee deemed the observed LFT elevations were not imetelstat-related hepatic toxicities. SUMMARY / CONCLUSIONS: In this cohort of 38 non-del(5q) LR-MDS patients with a high RBC transfusion burden who were ESA relapsed/refractory and naïve to LEN/HMA, single-agent imetelstat yielded a TI rate of 37%, with a median duration of 10 months and limited side effects. Durable responses were characterized by transfusion independence >24 weeks and accompanied by Hb rise. Updated data will be presented. Disclosures Steensma: Takeda: Consultancy; Syros: Research Funding; Otsuka: Membership on an entity's Board of Directors or advisory committees; Onconova: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees; Kura: Research Funding; Janssen: Consultancy, Research Funding; H3 Biosciences: Research Funding; Celgene: Research Funding; Amphivena: Membership on an entity's Board of Directors or advisory committees; Acceleron: Consultancy. Platzbecker:Celgene: Research Funding. Van Eygen:Janssen: Consultancy, Research Funding; Roche: Research Funding; Amgen: Research Funding. Raza:Kura Oncology: Research Funding; Onconova: Research Funding, Speakers Bureau; Celgene: Research Funding; Novartis: Speakers Bureau; Geoptix: Speakers Bureau; Janssen: Research Funding; Syros: Research Funding. Santini:Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; AbbVie: Membership on an entity's Board of Directors or advisory committees; Otsuka: Consultancy; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Research Funding. Germing:Celgene: Honoraria, Research Funding; Janssen: Honoraria; Novartis: Honoraria, Research Funding. Font:Celgene: Membership on an entity's Board of Directors or advisory committees. Samarina:Janssen: Research Funding. Díez-Campelo:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Bussolari:Janssen: Employment, Equity Ownership. Sherman:Janssen: Employment, Equity Ownership. Sun:Janssen: Employment, Equity Ownership. Varsos:Janssen: Employment, Equity Ownership. Rose:Janssen: Employment, Equity Ownership. Fenaux:Roche: Honoraria; Otsuka: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding.

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Long-Term Outcome of Ruxolitinib Treatment in Patients with Myelofibrosis: Durable Reductions in Spleen Volume, Improvements in Quality of Life, and Overall Survival Advantage in COMFORT-I

Blood ◽

10.1182/blood.v120.21.800.800 ◽

2012 ◽

Vol 120 (21) ◽

pp. 800-800 ◽

Cited By ~ 8

Author(s):

Srdan Verstovsek ◽

Ruben A. Mesa ◽

Jason Gotlib ◽

Richard S. Levy ◽

Vikas Gupta ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Survival Advantage ◽

Primary Analysis ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership ◽

Grade 3

Abstract Abstract 800 Background: Ruxolitinib (RUX), an oral JAK1/JAK2 inhibitor, reduced spleen volume (SV), improved myelofibrosis (MF)-associated symptoms and quality of life (QoL), and appeared to exhibit a survival advantage over placebo (PBO) in patients (pts) with MF regardless of JAK2V617F mutation status in the phase III COMFORT-I study. We describe long-term efficacy and safety of RUX from COMFORT-I, with 1 year of additional follow up beyond previously published data. Methods: Eligible pts (N=309) were randomized (1:1) to RUX or PBO. The primary analysis occurred when all pts completed 24 weeks (wks) and when half the pts completed 36 wks of treatment. All pts receiving PBO were eligible for crossover to RUX after the primary analysis; crossover before wk 24 was permitted if pts met protocol-defined criteria for worsening splenomegaly. The proportion of pts with ≥35% SV reduction at 24 wks (primary endpoint) and durability of SV response were assessed. Although symptom burden (measured daily using the modified MF Symptom Assessment Form v2.0) was only measured up to wk 24, QoL continued to be evaluated beyond wk 24 (every 24 wks) using the EORTC QoL Questionnaire-Core 30 (QLQ-C30). Overall survival (OS) was assessed according to original randomized treatment. Results: In this updated analysis, median follow-up of pts randomized to RUX was 102 wks. All pts receiving PBO completed crossover or discontinued within 3 months of the primary analysis. Of 134 pts randomized to RUX who remained on treatment after the primary data analysis, 100 continue on study. Mean SV reduction in pts randomized to RUX was 31.6% at wk 24 and has remained stable with additional follow up through wk 96 (Table). In pts who achieved a ≥35% SV reduction, response was durable, with a median response duration of 108 wks. RUX treatment was also associated with durable improvements in the Global Health Status/QoL (Table) and the 5 functional domains of the EORTC QLQ-C30. Twenty-seven (27) pts randomized to RUX and 41 pts randomized to PBO died, representing a continued OS benefit in favor of RUX (HR=0.58; 95% CI: 0.36, 0.95; P = 0.028; Fig 1) similar in magnitude to that previously reported. OS favored RUX across subgroups including starting dose as well as baseline risk status and hemoglobin (Hgb). Of 34 pts randomized to RUX who discontinued after the primary analysis, 4 discontinued for an adverse event (AE). In pts who continued on RUX, anemia and thrombocytopenia remained the most frequently reported AEs. New onset of grade 3 or 4 anemia and thrombocytopenia was reported in only 12 and 5 pts, respectively. One pt discontinued for anemia. Overall, among all pts randomized to RUX, Grade 3 and 4 anemia regardless of baseline Hgb was reported in 37.4% and 14.8% of pts, respectively. Similarly, Grade 3 and 4 thrombocytopenia was reported in 11.0% and 5.2% of pts, respectively. These rates were similar to those reported in the primary analysis. By wk 36, the proportion of pts receiving red blood cell transfusions decreased to the level seen with PBO and remained stable thereafter (Fig 2). Rates of nonhematologic AEs adjusted for increased follow-up duration remain similar to those seen at the time of the primary data analysis. No additional cases of acute myeloid leukemia (AML) in pts randomized to RUX were reported. Two pts originally randomized to PBO developed AML, 21 and 178 days after crossover to RUX. There continued to be no reports of a withdrawal syndrome after RUX discontinuation. Conclusions: RUX provides durable reductions in SV and improvements in QoL. Although all pts randomized to PBO crossed over to RUX shortly after the primary analysis, with 1 year of additional follow up, RUX continues to be associated with a survival advantage over PBO. RUX continues to be well tolerated; the AE profile with long-term treatment is consistent with that previously reported. The proportion of pts receiving transfusions decreased over time to rates similar to PBO, and there were no reports of a specific withdrawal syndrome or cytokine rebound phenomenon after RUX discontinuation. Disclosures: Verstovsek: Incyte Corporation: Research Funding. Mesa:Incyte: Research Funding; Lilly: Research Funding; Sanofi: Research Funding; NS Pharma: Research Funding; YM Bioscience: Research Funding. Gotlib:Incyte: Consultancy, travel to congress Other. Levy:Incyte: Employment, Equity Ownership. Gupta:Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; YM Biosciences: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofiå]Aventis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Catalano:Incyte: Consultancy. Deininger:Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy; Ariad: Consultancy. Miller:Novartis: Consultancy, Research Funding, Speakers Bureau, development of educational presentations Other; Incyte: development of educational presentations, development of educational presentations Other. Talpaz:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; B.M.S.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Teva: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Winton:Incyte: Consultancy, Honoraria. Arcasoy:Incyte: Research Funding. Lyons:Incyte: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Novartis: Research Funding; Telik: Research Funding. Paquette:Incyte: Consultancy. Vaddi:Incyte: Employment, Equity Ownership. Erickson-Viitanen:Incyte: Employment, Equity Ownership. Sun:Incyte Corporation: Employment, Equity Ownership. Sandor:Incyte Corporation: Employment, Equity Ownership. Kantarjian:Incyte: grant support Other.

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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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Current Results of Lentiglobin Gene Therapy in Patients with Severe Sickle Cell Disease Treated Under a Refined Protocol in the Phase 1 Hgb-206 Study

Blood ◽

10.1182/blood-2018-99-113480 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1026-1026 ◽

Cited By ~ 11

Author(s):

John F. Tisdale ◽

Julie Kanter ◽

Markus Y. Mapara ◽

Janet L. Kwiatkowski ◽

Lakshmanan Krishnamurti ◽

...

Keyword(s):

Gene Therapy ◽

Board Of Directors ◽

Research Funding ◽

Phase 1 ◽

Employment Equity ◽

Advisory Committees ◽

Cd34 Cells ◽

Equity Ownership ◽

Grade 3

Abstract Background β-globin gene transfer has the potential for substantial clinical benefit in patients with sickle cell disease (SCD). LentiGlobin Drug Product (DP) contains autologous CD34+ hematopoietic stem cells (HSCs) transduced with the BB305 lentiviral vector (LVV), encoding β-globin with an anti-sickling substitution (T87Q). The safety and efficacy of LentiGlobin gene therapy is being evaluated in the ongoing Phase 1 HGB-206 study (NCT02140554). Results in the initial 7 patients treated with LentiGlobin DP from steady state bone marrow harvested (BMH) HSCs using original DP manufacturing process (Group A) demonstrated stable HbAT87Q production in all patients, but at levels below the anticipated target. The protocol was thus amended to include pre-harvest RBC transfusions, optimize myeloablation by targeting higher busulfan levels, and use a refined DP manufacturing process (Group B); additionally, HSC collection by plerixafor mobilization/apheresis was instituted (Group C). Data from patients in Group C, treated under the modified protocol with DPs manufactured from plerixafor-mobilized HSCs using the refined process, are reported here. Results in patients in Groups A and B are reported separately. Methods Patients with severe SCD (history of recurrent vaso-occlusive crisis, acute chest syndrome, stroke, or tricuspid regurgitant jet velocity of >2.5 m/s) were enrolled. Patients in Group C received ≥2 months of transfusions to reach Hb of 10 - 12 g/dL and <30% HbS before HSC collection. Patients received 240 μg/kg of plerixafor 4 - 6 hours before HSCs were collected by apheresis and CD34+ cells were transduced with the BB305 LVV at a central facility. Following myeloablative conditioning with busulfan, the DP was infused, and patients were monitored for adverse events (AEs), engraftment, peripheral blood (PB) vector copy number (VCN), HbAT87Q expression, and HbS levels. Summary statistics are presented as median (min - max). Results As of 15 May 2018, 11 Group C patients (age 25 [18 - 35] years) had undergone mobilization/apheresis, 9 patients had DP manufactured (median 1 cycle of mobilization [1 - 3]) and 6 patients had been treated. Cell dose, DP VCN and % transduced cells in the 6 treated patients were: 7.1 (3 - 8) x 106 CD34+ cells/kg, 4.0 (2.8 - 5.6) copies/diploid genome (c/dg) and 81 (78 - 88) % transduced cells. The median follow-up was 3.0 (1.2 - 6.0) months. Patients achieved neutrophil engraftment at a median of 19 (18 - 20) days. Platelet engraftment was achieved at a median of 28 (12 - 64) days in 4 patients; platelet engraftment was pending in 2 patients. Two of 11 patients experienced 4 grade ≥3 AEs associated with plerixafor mobilization/HSC collection: 1 had vaso-occlusive pain and hypomagnesaemia, and the other had vaso-occlusive pain and non-cardiac chest pain. The toxicity profile from DP infusion to last follow-up in the 6 treated patients was consistent with myeloablative conditioning. Febrile neutropenia (n=5) and stomatitis (n=4) were the most common non-hematologic grade ≥3 AEs. Serious AEs were reported in 3 patients post-DP infusion: splenic hematoma, non-cardiac chest pain and mucosal inflammation. To date, there have been no DP-related AEs, graft failure, vector-mediated replication competent lentivirus, or clonal dominance. In the 6 treated patients, PB VCN at last visit ranged from 1.4 - 2.9 c/dg. In the 3 patients with 3 months follow-up, total Hb levels were 11.7 g/dL, 9.8 g/dL and 9.2 g/dL, and HbAT87Q levels were 4.7 g/dL, 3.2 g/dL and 3.5 g/dL. One additional patient with 6 months follow-up was off transfusions and had total Hb of 14.2 g/dL, of which 62% (8.8 g/dL) was vector-derived HbAT87Q and 36% (5.1 g/dL) was HbS. All 4 patients had HbAT87Q (median 39%) levels higher than or equal to HbS (median 31%) at the 3-month visit. Summary HGB-206 protocol changes and refined DP manufacturing have improved the LentiGlobin DP characteristics resulting in significantly improved outcomes. In addition, the HbAT87Q expression is comparable to, or exceeds, HbS levels as early as 3 months post DP infusion. These data support the feasibility of plerixafor-mediated CD34+ cell collection in patients with severe SCD and the efficacy of gene therapy. The safety profile of LentiGlobin gene therapy remains consistent with single-agent busulfan conditioning. Additional data and longer follow-up will determine the clinical effect of increased HbAT87Q/HbS ratios. Disclosures Kanter: Global Blood Therapeutics: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; bluebird bio: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Sancilio: Research Funding; NHLBI: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Apopharma: Research Funding; ASH: Membership on an entity's Board of Directors or advisory committees. Mapara:Incyte: Consultancy. Kwiatkowski:Novartis: Research Funding; bluebird bio: Consultancy, Honoraria, Research Funding; Apopharma: Research Funding; Terumo: Research Funding; Agios Pharmaceuticals: Consultancy, Research Funding. Schmidt:GeneWerk GmbH: Employment; German Cancer Research Center: Employment; bluebird bio: Consultancy. Miller:bluebird bio: Employment, Equity Ownership. Pierciey:bluebird bio: Employment, Equity Ownership. Shi:bluebird bio: Employment, Equity Ownership. Ribeil:bluebird bio: Employment, Equity Ownership. Asmal:bluebird bio: Employment, Equity Ownership. Thompson:Amgen: Research Funding; Celgene: Research Funding; Baxalta/Shire: Research Funding; bluebird bio: Consultancy, Research Funding; Novartis: Research Funding; Biomarin: Research Funding; La Jolla Pharmaceutical: Research Funding. Walters:Sangamo Therapeutics: Consultancy; bluebird bio: Research Funding; ViaCord Processing Lab: Other: Medical Director; AllCells Inc.: Other: Medical Director.

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Multicenter Phase II Trial Addressing Lenalidomide Maintenance in Patients with Relapsed Diffuse Large B-Cell Lymphoma (rDLBCL) Who Are Not Eligible for Autologous Stem Cell Transplantation (ASCT): Efficacy and Safety Results after a Median Follow-up of Five Years

Blood ◽

10.1182/blood-2018-99-116060 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1688-1688

Author(s):

Andres JM Ferreri ◽

Marianna Sassone ◽

Francesco Zaja ◽

Alessandro Re ◽

Michele Spina ◽

...

Keyword(s):

Board Of Directors ◽

Salvage Therapy ◽

Research Funding ◽

Progressive Disease ◽

De Novo ◽

Phase Ii Trial ◽

Efficacy And Safety ◽

Advisory Committees ◽

Observation Period

Abstract Background: Lenalidomide (LENA) maintenance is associated with significantly improved outcome in patients (pts) with chemosensitive relapse of DLBCL not eligible for ASCT or experiencing relapse after ASCT. Preliminary results of a multicentre phase II trial (NCT00799513), reported after a median follow-up of 25 months, showed a 1-yr PFS of 70 ± 7% and a 1-yr OS of 81 ± 6%, with good tolerability (Ferreri AJM, et al. Lancet Haematol 2017). However, LENA was ongoing in 41% of pts at time of analysis, and late side effects and events after maintenance completion remained to be defined. Herein, we report efficacy and safety results of the trial after a median follow-up of 56 (range 27-100) months. Methods: HIV-neg pts (age ≥18 ys) with de novo or transformed DLBCL and relapsed disease responsive to conventional rituximab-containing salvage therapy were registered and treated with LENA 25 mg/day for 21 days out of 28, until lymphoma progression or unacceptable toxicity. A protocol amendment in 2015 allowed physicians to interrupt maintenance after a minimum duration of two years. Primary endpoint was 1-year PFS. Simon's two-stage optimal design was used. To demonstrate a 1-yr PFS improvement from 30% (P0) to 50% (P1), 47 pts (one-sided; α 5%; β 80%) were needed. Maintenance would be considered effective if ≥19 pts were progression-free survivors at 1 yr. Cell of origin was assessed by NanoString Technology (n=23) and Hans algorithm (n=39). Results: Between 3/2009 and 12/2015, we recruited 48 pts; 46 of them were assessable (median age 72 ys; range 34-86); 36 pts had de novo DLBCL, 10 had transformed DLBCL. All pts were previously treated with anthracycline- and rituximab-based combination, plus ASCT in 6 pts. Thirty-three pts were enrolled at 1st relapse; salvage therapy contained high doses of cytarabine or ifosfamide in two-thirds of cases, and response was complete in 26 pts and partial in 20. Most pts had unfavourable features: IPI ≥2 in 38 (83%) pts, advanced stage in 35 (76%), extranodal disease in 29 (63%), high LDH level in 21 (46%); 28 (61%) pts were older than 70 ys. Sixteen pts received ≥2 years of LENA (5 received >2 ys), 30 pts interrupted treatment due to progressive disease (PD; n= 17), toxicity (9) or pt refusal (4) (Table). LENA was well tolerated after an average of 18 courses/pt (range 3-82). With the exception of neutropenia, grade-4 toxicities occurred in <1% of courses. Infections were rare, and well controlled with oral antibiotics (grade 1-2 in 9 courses; grade 3 in 3). LENA dose reduction was indicated in 25 pts (transient in 21), and was due to neutropenia (13), rash (7), diarrhoea (3), or neurotoxicity (2). Three (6%) pts died of toxicity during maintenance (intestinal infarction, meningitis and sudden death) and two pts died due to myelodysplastic syndrome (Table). Grade 4-5 toxicity and SAEs were equally distributed according to maintenance duration (Table). At one year from trial registration, 31 pts were still progression free, which was significantly higher than the pre-determined efficacy threshold (n≥19). During the whole observation period, there were 24 events: progressive disease in 21 pts and death of toxicity in 3, with a 1-yr (primary endpoint) and 5-yr PFS of 67 ± 7% and 50 ± 7%, respectively. The duration of response to LENA was longer than response duration after the prior treatment line in 28 (61%) pts, and was twice as long in 21 (46%) of them. Twenty-six pts were disease-free at the last LENA course (Table), 22 of them remain relapse free after a median observation period from maintenance completion of 26 (8-92) months; 3 of the 4 relapses occurred in pts who received <1 yr of LENA (refusal or SAEs). The benefit of LENA was observed both in pts with de novo or transformed DLBCL. According to the Hans' algorithm, the 4-yr PFS was 50 ± 11% for GCB-DLBCL and 42 ± 11% for nonGCB-DLBCL (p= 0.58). Results using the Nanostring technique were consistent with the Hans' algorithm. Overall, 28 (61%) pts are alive, with a 1- and 5-yr OS of 80 ± 6% and 60 ± 8%, respectively. Conclusions: Long-term results of this trial soundly promotes the use of LENA maintenance in pts with chemosensitive relapse of DLBCL not eligible for ASCT or experiencing relapse after ASCT. LENA was well tolerated in this elderly population, without higher toxicity rates in pts treated for ≥2 years, and with enhanced survival figures. These results warrant further investigation of immunomodulatory drugs as maintenance in these high-risk pts. Table. Table. Disclosures Ferreri: Celgene: Research Funding. Zaja:Abbvie: Honoraria; Takeda: Honoraria; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Amgen: Honoraria; Janssen: Honoraria; Sandoz: Honoraria. Di Rocco:Janssen: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Rusconi:Celgene: Research Funding.

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Results From the ENESTnd Extension Study: Efficacy and Safety of Patients (pts) with Chronic Myeloid Leukemia in Chronic Phase (CML-CP), Treated with Nilotinib 400 Mg Twice Daily (BID) After Suboptimal Response (SoR) or Treatment Failure (TF) to Imatinib 400 Mg Once Daily (QD) or Nilotinib 300 Mg BID

Blood ◽

10.1182/blood.v118.21.114.114 ◽

2011 ◽

Vol 118 (21) ◽

pp. 114-114 ◽

Cited By ~ 2

Author(s):

Andreas Hochhaus ◽

Gert Ossenkoppele ◽

Josy Reiffers ◽

Ming Yao ◽

Hirohiko Shibayama ◽

...

Keyword(s):

Board Of Directors ◽

Dose Escalation ◽

Research Funding ◽

Extension Study ◽

Employment Equity ◽

Advisory Committees ◽

Core Study ◽

Equity Ownership ◽

Grade 3

Abstract Abstract 114 Background: In ENESTnd, nilotinib demonstrated superior efficacy vs imatinib in pts with newly diagnosed CML-CP, including a significantly reduced rate of progression to AP/BC on treatment and a lower rate of SoR/TF. Pts in ENESTnd with SoR/TF on nilotinib 300 mg BID or imatinib could discontinue core study and enter an extension study; entrance was not allowed for intolerance. Here, we report the efficacy and safety of 49 such pts. Methods: 31 pts initially randomized to imatinib 400 mg QD (IM group) and 18 pts to nilotinib 300 mg BID (NIL group) in ENESTnd discontinued due to SoR/TF and received nilotinib 400 mg BID in this study. Progression and deaths in the extension study and after discontinuation of extension treatment have been previously reported as progression events after discontinuation of core ENESTnd treatment and in the OS analysis of ENESTnd. Results: Median time on extension treatment was 6 months (mo) for both groups (range, IM 0.2–24; NIL 1–14); 35/49 pts (71%) remain on study. Median nilotinib dose during extension treatment was equal to planned dose (800 mg/day). In the IM group, 65% of pts escalated imatinib to 400 mg BID prior to extension; 12 pts (46%) not in CCyR at extension entry and 7 pts (23%) not in MMR achieved these responses on extension treatment (table). Of these responders, 7/12 pts (58%) who achieved CCyR and 4/7 pts (57%) who achieved MMR had escalated imatinib to 400 mg BID on core study. In the NIL group, 1 pt (17%) not in CCyR at extension entry and 5 pts (29%) not in MMR, achieved this response on extension treatment. Overall, 4 pts in the IM group progressed to AP/BC (2 on extension treatment, 1 within 1 mo and the other > 12 mo after discontinuation). All 4 pts discontinued core study for TF. Overall, 1 pt in the NIL group progressed to AP/BC (< 1 mo after discontinuation of extension treatment); pt discontinued core study for SoR. The safety of nilotinib 400 mg BID was similar to that in the core study. Grade 3/4 AEs and drug-related AEs leading to discontinuation were reported in 52% and 10% of pts in the IM group. Higher rates of AEs in the first few mo of starting nilotinib in pts previously treated with imatinib were not unexpected as common AEs occur early following initial exposure. In the NIL group, grade 3/4 AEs were reported in 28% of pts and no pt discontinued due to drug-related AEs. No deaths were reported on extension treatment or ≤ 28 days of discontinuation; 4 deaths occurred > 28 days after discontinuation of treatment: 3 were CML-related (2 and 1 deaths in the IM and NIL groups, respectively) and occurred 8–10 mo after discontinuation. Conclusions: Results confirm the efficacy of nilotinib 400 mg BID for pts with CML-CP who had SoR/TF on imatinib, even after imatinib dose escalation. These results suggest that nilotinib 400 mg BID may be efficacious in pts with CML-CP with SoR/TF on nilotinib 300 mg BID, although longer follow-up is required. Whereas dose escalation of imatinib may overcome OCT-1 transporter activity in pts with correspondingly low imatinib plasma levels, nilotinib is not a substrate for OCT-1. The modest (∼16%) increase in nilotinib systemic exposure by dose escalation from 300 to 400 mg BID may benefit some patients with SoR/TF, but requires further evaluation. Currently, dose escalation of nilotinib from 300 to 400 mg BID appears safe with no additional safety signals. The extension study is ongoing and additional follow-up will provide more information moving forward. Disclosures: Hochhaus: Ariad: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Novartis Pharmaceutical: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding. Ossenkoppele:Bristol Myers Squibb: Consultancy, Honoraria; Novartis Pharmaceutical: Consultancy, Honoraria, Research Funding. Gattermann:Novartis: Honoraria, Research Funding. Hughes:Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Saglio:Bristol-Myers Squibb: Consultancy, Speakers Bureau; Novartis Pharmaceutical: Consultancy, Speakers Bureau; Pfizer: Consultancy. Larson:Novartis Pharmaceuticals: Consultancy, Honoraria, Research Funding. Hoenekopp:Novartis Pharmaceutical: Employment, Equity Ownership. Gallagher:Novartis: Employment, Equity Ownership. Yu:Novartis: Employment, Equity Ownership. Blakesley:Novartis Pharmaceutical: Employment. Kantarjian:Pfizer: Research Funding; Novartis: Research Funding; Novartis: Consultancy; BMS: Research Funding.

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