A Phase II Study to Investigate the Efficacy and Safety of Eltrombopag in Combination with Dexamethasone As First-Line Treatment in Adults Patients with Newly Diagnosed Primary ITP (XPAG-ITP)

Abstract BACKGROUND: Eltrombopag is an oral, small-molecule, non-peptide thrombopoietin receptor agonist (TPO-RA) that increases hematopoiesis by inducing proliferation and differentiation of early bone marrow progenitor cells leading to increased platelet production (Erickson-Miller et al., 2010, Sun et al., 2012). Eltrombopag has demonstrated efficacy in adult and pediatric patients with immune thrombocytopenia (ITP) and has a well-established safety profile. It is approved in Europe for the treatment of thrombocytopenia, from 6 months following diagnosis, in patients with primary ITP who are refractory to other treatments (e.g. corticosteroids, immunoglobulins). The efficacy of eltrombopag for achieving hemostatic platelet counts (≥ 50 × 10 9/L) in previously treated adult ITP patients with more than 6 months' disease duration is around 80 % (Wong et al., 2017). However, there is insufficient data on safety and efficacy of TPO-RAs in newly diagnosed ITP patients. AIM: The aim of this trial (NCT04346654; CETB115JDE01) is to compare the ability of eltrombopag in combination with a short course of high-dose dexamethasone to induce a sustained response off treatment in comparison to dexamethasone monotherapy in newly diagnosed primary ITP patients. METHODS: This is a Phase II, multicenter, randomized (1:1), open-label study (see Figure 1). Arm A: Eltrombopag + short course of high-dose dexamethasone Arm B: 1-3 cycles of high-dose dexamethasone Adult patients with newly diagnosed primary ITP who have platelet counts < 30 × 10 9/L and require treatment will be screened, and if eligible, will be randomized to either Arm A or Arm B. The study will be conducted in the following periods: Treatment / Tapering Period: Arm A: Patients will receive eltrombopag in combination with a short course of high-dose dexamethasone beginning at day 1. The dose of dexamethasone will be 40 mg QD (daily; quaque die) for 4 consecutive days and limited to 1 cycle. The starting dose of eltrombopag will be 50 mg QD in order to achieve the target platelet count of ≥ 50 × 10 9/L. Patients who reach platelet counts ≥ 30 × 10 9/L and maintain counts ≥ 30 × 10 9/L during the tapering phase (week 20 - week 26) will be eligible for treatment discontinuation starting from week 26. During the tapering phase, eltrombopag will be decreased by 25 mg every 2 weeks to a minimum dose of 25 mg every other day for all patients. Arm B: Treatment in the control arm consists of 1-3 cycles of high-dose dexamethasone administered orally at a dose of 40 mg QD for 4 consecutive days at 2-4 week intervals. Patients will be treated up to 12 weeks during the treatment period with dexamethasone. If the platelet counts are > 150 × 10 9/L no further course of dexamethasone will be given. Patients who reach platelet counts ≥ 30 × 10 9/L and maintain counts ≥ 30 × 10 9/L after 1-3 cycles of dexamethasone treatment will be eligible for treatment discontinuation. Observation period: After completion of the treatment period, patients will be observed for sustained response off treatment defined as: maintain platelet counts ≥ 30 × 10 9/L after treatment discontinuation and no bleeding events ≥ Grade II and without the use of any rescue therapy until week 52 and week 78 respectively, after study start The study is designed to include 106 adult patients with newly diagnosed primary ITP at 30 sites in Germany. Patients meeting any of the following criteria are not eligible for inclusion in this study: Previous history of treatment for ITP except 3 days of ITP rescue medication within 7 days before study randomization Patients with diagnosis of secondary thrombocytopenia Patients who have life threatening bleeding complications per physician´s discretion Patients with a history of thromboembolic events or known risk factors for thromboembolism The primary objective is the rate of sustained responses off treatment at 52 weeks. Key secondary objectives include the duration of sustained response off treatment, the rate of sustained response off treatment at 78 weeks as well as patient-oriented outcomes for health-related quality of life. Currently, the study is recruiting patients, expected to be completed by 2022. CONCLUSION: This trial will evaluate the potential of eltrombopag in combination with steroids to increase the rate of sustained response off treatment in comparison to steroids alone in patients with previously untreated primary ITP. Figure 1 Figure 1. Disclosures Binder: Deutsche Krebsgellschaft, Medconcept GmbH, event Lab. GmbH: Honoraria, Other: Speaker Activity; Amgen GmbH, Janssen-Cilage GmbH, DGHO, Art tempi, Tumorzentrum Anhalt MD, Uniklinikum Hamburg, Sanofi Aventis: Honoraria, Other: Speaker Activity. Matzdorff: Amgen: Consultancy, Honoraria; Argenx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Grifols: 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; Roche: Current holder of individual stocks in a privately-held company; UCB: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Meyer: Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Grifols: Consultancy, Honoraria; SOBI: Consultancy, Honoraria. Tesanovic: Novartis Pharma GmbH: Current Employment. Sauer: Novartis Pharma GmbH: Current Employment. OffLabel Disclosure: Eltrombopag is approved in Europe for the treatment of thrombocytopenia, from 6 months following diagnosis, in patients with primary ITP who are refractory to other treatments (e.g. corticosteroids, immunoglobulins). In this study Eltrombopag will be administered as first-line therapy in ITP.

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A Phase II Study to Investigate the Efficacy and Safety of Eltrombopag in Combination with Dexamethasone As First-Line Treatment in Adult Patients with Newly Diagnosed Primary ITP (XPAG-ITP)

Blood ◽

10.1182/blood-2020-134318 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 36-37

Author(s):

Axel Matzdorff ◽

Mascha Binder ◽

Falk Nimmerjahn ◽

Oliver Meyer ◽

Mathias J. Rummel ◽

...

Keyword(s):

Treatment Discontinuation ◽

Sustained Response ◽

Adult Patients ◽

High Dose ◽

Newly Diagnosed ◽

Platelet Counts ◽

High Dose Dexamethasone ◽

Short Course ◽

Proliferation And Differentiation ◽

History Of

BACKGROUND: Eltrombopag is an oral, small-molecule, non-peptide thrombopoietin receptor agonist (TPO-RA) that increases hematopoiesis by inducing proliferation and differentiation of early bone marrow progenitor cells leading to increased platelet production (Erickson-Miller et al., 2010, Sun et al., 2012). Eltrombopag has demonstrated efficacy in adult and pediatric patients with immune thrombocytopenia (ITP) and has a well-established safety profile. It is approved in Europe for the treatment of thrombocytopenia, from 6 months following diagnosis, in patients with primary ITP who are refractory to other treatments (e.g. corticosteroids, immunoglobulins). The efficacy of eltrombopag for achieving hemostatic platelet counts (≥ 50 × 109/L) in previously treated adult ITP patients with more than 6 months' disease duration is around 80% (Wong et al., 2017). However, there is insufficient data on safety and efficacy of TPO-RAs in newly diagnosed ITP patients. AIM: The aim of this trial (NCT04346654; CETB115JDE01) is to compare the ability of eltrombopag in combination with a short course of high-dose dexamethasone to induce a sustained response off treatment in comparison to dexamethasone monotherapy in newly diagnosed primary ITP patients. METHODS: This is a Phase II, multicenter, randomized (1:1), open-label study (see Figure 1). Arm A: Eltrombopag + short course of high-dose dexamethasoneArm B: 1-3 cycles of high-dose dexamethasone Adult patients with newly diagnosed primary ITP who have platelet counts < 30 × 109/L and require treatment will be screened, and if eligible, will be randomized to either Arm A or Arm B. The study will be conducted in the following periods: Screening Period: Patients will be screened based on the inclusion and exclusion criteria specified below Treatment / Tapering Period: Arm A: Patients will receive eltrombopag in combination with a short course of high-dose dexamethasone beginning at day 1. The dose of dexamethasone will be 40 mg QD (daily; quaque die) for 4 consecutive days and limited to 1 cycle. The starting dose of eltrombopag will be 50 mg QD in order to achieve the target platelet count of ≥ 50 × 109/L. Patients who reach platelet counts ≥ 30 × 109/L and maintain counts ≥ 30 × 109/L during the tapering phase (week 20 - week 26) will be eligible for treatment discontinuation starting from week 26. During the tapering phase, eltrombopag will be decreased by 25 mg every 2 weeks to a minimum dose of 25 mg every other day for all patients. Arm B: Treatment in the control arm consists of 1-3 cycles of high-dose dexamethasone administered orally at a dose of 40 mg QD for 4 consecutive days at 4 weeks intervals. Patients will be treated up to 12 weeks during the treatment period with dexamethasone. If the platelet counts are > 150 × 109/L no further course of dexamethasone will be given. Patients who reach platelet counts ≥ 30 × 109/L and maintain counts ≥ 30 × 109/L after 1-3 cycles of dexamethasone treatment will be eligible for treatment discontinuation. Observation period: After completion of the treatment period, patients will be observed for sustained response off treatment defined as: maintain platelet counts ≥ 30 × 109/L after treatment discontinuation and no bleeding events ≥ Grade II and without the use of any rescue therapy until week 52 and week 78 respectively, after study start The study is designed to include 106 adult patients with newly diagnosed primary ITP at 25 sites in Germany. Patients meeting any of the following criteria are not eligible for inclusion in this study: Previous history of treatment for ITPPatients with diagnosis of secondary thrombocytopeniaPatients who have life threatening bleeding complications per physician´s discretionPatients with a history of thromboembolic events or known risk factors for thromboembolism The primary objective is the rate of sustained responses off treatment at 52 weeks. Key secondary objectives include the duration of sustained response off treatment, the rate of sustained response off treatment at 78 weeks as well as patient-oriented outcomes for health-related quality of life. Currently, the study is recruiting patients, expected to be completed by 2021. CONCLUSION: This trial will evaluate the potential of eltrombopag in combination with steroids to increase the rate of sustained response off treatment in comparison to steroids alone in patients with previously untreated primary ITP. Disclosures Matzdorff: Novartis Oncology:Consultancy, Other: Honoraria paid to institution;Amgen GmbH:Consultancy, Other: Honoraria paid to institution;Grifols Deutschland GmbH:Consultancy, Other: Honoraria paid to institution;Swedish Orphan Biovitrium GmbH:Consultancy, Other: Honoraria paid to institution;UCB Biopharma SRL:Consultancy, Other: Honoraria paid to institution;Roche Pharma AG:Other: Family stockownership.Binder:DGHO:Honoraria, Other: Speaker Activity;Amgen GmbH:Honoraria, Other: Speaker Activity;Deutsche Krebsgesellschaft:Honoraria, Other: Speaker Activity;Merck Serono GmbH:Honoraria, Other: Speaker Activity;OSHO:Membership on an entity's Board of Directors or advisory committees;Medconcept GmbH:Honoraria, Other: Speaker Activity;Tumorzentrum Anhalt:Honoraria, Other: Speaker Activity;Janssen-Cilag GmbH:Honoraria, Other: Speaker Activity;DFG:Research Funding;Art tempi:Honoraria, Other;Sanofi-Aventis Deutschland:Honoraria, Other;Uniklinikum Hamburg:Honoraria, Other;event lab GmbH:Honoraria, Other: Speaker Activity.Nimmerjahn:Novartis Pharma GmbH:Honoraria.Meyer:Amgen GmbH:Honoraria;Novartis Pharma GmbH:Honoraria;Grifols Germany:Consultancy, Honoraria.Rummel:Roche:Honoraria;Janssen:Honoraria;Novartis Pharma GmbH:Honoraria;Celgene:Consultancy, Honoraria;Amgen GmbH:Honoraria.Tesanovic:Novartis Pharma GmbH:Current Employment.Sauer:Novartis Pharma GmbH:Current Employment. OffLabel Disclosure: Eltrombopag is an oral, small-molecule, non-peptide thrombopoietin receptor agonist (TPO-RA) that increases hematopoiesis by inducing proliferation and differentiation of early bone marrow progenitor cells leading to increased platelet production (Erickson-Miller et al 2010, Sun et al 2012). Eltrombopag has demonstrated efficacy in adult and pediatric patients with ITP and has a well-established safety profile. It is approved in Europe for the treatment of thrombocytopenia, from 6 months following diagnosis, in patients with primary ITP who are refractory to other treatments (e.g. corticosteroids, immunoglobulins).

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Superiority of Lenalidomide-Dexamethasone Versus Thalidomide-Dexamethasone as Initial Therapy for Newly Diagnosed Multiple Myeloma.

Blood ◽

10.1182/blood.v114.22.3884.3884 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3884-3884

Author(s):

Francesca Gay ◽

Suzanne Hayman ◽

Martha Q. Lacy ◽

Francis Buadi ◽

Morie A Gertz ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Initial Therapy ◽

High Dose ◽

Toxicity Profile ◽

Newly Diagnosed ◽

Advisory Committees ◽

Intention To Treat ◽

High Dose Dexamethasone ◽

Grade 3

Abstract Abstract 3884 Poster Board III-820 Background and Objective Thalidomide/dexamethasone (thal/dex) combination has shown high activity in newly diagnosed multiple myeloma (MM) (Rajkumar SV. at al, J Clin Oncol 2006;24:431-436). In newly diagnosed patients, lenalidomide/dexamethasone (len/dex) has demonstrated superiority compared with high-dose dexamethasone alone (Zonder JA et al, Blood 2007;110:77). Although both thal/dex and len/dex are active in newly diagnosed MM, no randomized trial has been reported comparing these two regimens, and unfortunately none are ongoing or planned. We compared the efficacy and the toxicity of thal/dex and len/dex as primary therapy in 411 newly diagnosed MM patients treated at the Mayo Clinic. Patients and methods 411 consecutive patients seen at Mayo Clinic between 2001 and 2008, who received induction with thal/dex (n=183) or len/dex (n=288) were retrospectively studied. Thalidomide was given at a dose ranging from 100 mg/day to 400 mg/day continuously; the lenalidomide dose was 25 mg/day, days 1-21 on a 28-day cycle. All patients received dexamethasone, either at high-dose (40 mg orally on days 1-4, 9-12, and 17-20) or at low-dose (40 mg orally day 1, 8, 15, 22); each cycle was repeated every 4 weeks. In addition, a case-matched subgroup analysis that adjusted for age, gender and transplantation status was performed among patients who received high-dose dexamethasone comparing the thal/dex (n=72) and len/dex (n=72) groups. Outcome was analyzed on an intention-to-treat basis. The Chi-square or the rank sum tests were used to compare variables. Time-to-event analysis was performed using the Kaplan-Meier method and all comparisons were determined by the log-rank test and by the Cox proportional hazards model. Results On intention-to-treat analysis, of 411 patients, 80.3% versus 61.2% patients, respectively in the len/dex group and in the thal/dex group (p < 0.001), achieved at least a partial response. A significant difference between the 2 groups was found in terms of both very good partial response or better (34.2% vs 12.0%, p < 0.001) and complete response rate (13.6% vs 3.3%, p < 0.001). Duration of therapy was significantly longer in len/dex patients as compared to thal/dex patients: 36.7% vs 12.6% of patients who did not stop treatment to receive SCT were still receiving therapy at 1 year (p < 0.001).Time-to-progression was significantly better in the len/dex group than in patients receiving thal/dex (median 27.4 vs 17.2 months, HR 0.64; 95% CI 0.44-0.93; p = 0.019). Similarly, progression-free-survival was significantly higher in len/dex patients (median 26.7 vs 17.1 months, HR 0.69; 95% CI 0.48-0.98; p = 0.036). This translated into an increase in overall survival (OS) (median not reached for len/dex group compared to 57.2 months in thal/dex patients, HR 0.60; 95% CI 0.40-0.92; p = 0.018). Survival advantages were evident in patients presenting with International Staging System Stage (ISS) I/II (HR 0.57; 95% CI 0.32-1.00; p = 0.052) at diagnosis but not in patients with ISS stage III in subgroup analysis. There was a trend toward better OS in len/dex group compared to thal/dex group both for patients who underwent transplant and for patients who did not. A similar rate of patients experienced at least one grade 3 or higher adverse event (57.5% vs 54.6% in len/dex and thal/dex groups, respectively, p = 0.568). However, the toxicity profile was different in the two groups: major grade 3-4 toxicities of len/dex were hematological, in particular neutropenia (14% with len/dex vs 0.6% with thal/dex, p<0.001) while the most common toxicities in thal/dex were venous thromboembolism (15.3% vs 9.2%, p = 0.058) and peripheral neuropathy (10.4% vs 0.9%, p < 0.001). The data on efficacy and safety shown above were also confirmed in the subgroup case-matched analysis which included only high-dose dexamethasone patients. Conclusions This cohort study shows the superiority of len/dex in terms of response rates and survival, compared to thal/dex. The toxicity profile of the 2 regimens is different and len/dex treatment, although more active, was not associated with increased toxicity (grade 3-4 AEs). These data need to be carefully evaluated and randomized prospective phase III studies are necessary to confirm these results and determine the optimal initial therapy for MM. Disclosures: Off Label Use: research drugs in combination to standard care. Lacy:celgene: Research Funding. Gertz:celgene: Honoraria; genzyme: Honoraria; millenium: Honoraria; amgen: Honoraria. Kumar:celgene: Research Funding; millenium: Research Funding; bayer: Research Funding; Novartis: Research Funding; Genzyme: Research Funding. Dispenzieri:celgene: Research Funding. Bergsagel:amgen: Membership on an entity's Board of Directors or advisory committees; genetech: Membership on an entity's Board of Directors or advisory committees; merck: Research Funding; celgene: Membership on an entity's Board of Directors or advisory committees. Witzig:celgene: Research Funding. Fonseca:medtronic: Consultancy; genzyme: Consultancy; celgene: Consultancy; amgen: Consultancy; BMS: Consultancy; otsuka: Consultancy. Greipp:celgene: Research Funding.

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Outcomes of Newly Diagnosed Myeloma Patients Requiring Dialysis: Dialysis Independence Is Associated with Rapid Myeloma Response and Predicts for Longer Survival

Blood ◽

10.1182/blood.v128.22.4492.4492 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4492-4492

Author(s):

Meletios A. Dimopoulos ◽

Maria Roussou ◽

Maria Gavriatopoulou ◽

Despina Fotiou ◽

Dimitrios Ziogas ◽

...

Keyword(s):

Renal Failure ◽

High Risk ◽

Supportive Care ◽

Board Of Directors ◽

Light Chain ◽

Research Funding ◽

High Dose ◽

Newly Diagnosed ◽

Advisory Committees ◽

High Dose Dexamethasone

Abstract Renal failure (RF) is a common severe complication of symptomatic myeloma and may be severe enough to require extrarenal dialysis in approximately 1-5% of newly diagnosed patients. Severe RF is associated with high risk of early death and increased morbidity. Immediate effective anti-myeloma therapy and vigorous supportive care are the cornerstones of management. The use of high cutoff hemodialysis to rapidly reduce the load of nephrotoxic light chains seems to offer limited additional benefit in patients requiring dialysis when treated with bortezomib-based therapies (Cook M et al EHA 2016, Abs P270). However, outside clinical trials, there are limited data focusing on the management and outcomes of NDMM patients requiring dialysis. Thus, we analyzed the outcomes of consecutive newly diagnosed patients with RF requiring dialysis, who were managed and treated in a single center. Between 1995 and 2016, 50 patients (6.2% of 796 consecutive NDMM) who were treated in the Department of Clinical Therapeutics (Athens, Greece) presented with severe RF requiring dialysis. The analysis included all patients who received at least one dose of any therapy. All patients received similar supportive care and dialysis with regular filters. The median age of patients requiring dialysis was 69 years (37-88), 68% were >65 years of age. At presentation 92% had Hb <10 g/dl, 5 (10%) had platelet count <100x109/l, 12 (24%) had hypeprcalcemia (Ca ≥11.5 mg/dl) and 24 (48%) had elevated LDH (≥250 IU/l). All patients had elevated β2-microglobulin (median 21.7 mg/L, range 6-60 mg/l) and all were ISS stage 3. High risk cytogenetics (N=40) were present in 38% and per R-ISS, 75% were R-ISS-3 and 25% R-ISS-2. Myeloma was light chain only in 42%, IgA in 26%, IgG in 30% and IgD in 1 patient (2%); light chain was κ in 38 (64%) and λ in 18 (36%). Among patients who retained urine flow at presentation, median 24h Bence Jones proteinuria was 2.2 gr (range 0.1-8.8 gr). Among patients with available FLCs, median level of involved free light chain (iFLC) was 9080 mg/l (range 119-201000 mg/l). Treatment was bortezomib-based in 41 (82%) patients: 11 (22%) had bortezomib + dexamethasone (VD), 21 (42%) VD + cyclophosphamide (VCD), 8 (16%) VD + thalidomide (VTD), 1 (2%) VD + doxorubicin (PAD). Nine (18%) patients received non-bortezomib containing regimens: 5 (10%) thalidomide plus high dose dexamethasone and 4 (8%) VAD with high dose dexamethasone. Twenty-five (50%) patients became dialysis independent at a median time of 158 days from start of therapy (range 4-336 days). Age ≤65 years was associated with higher probability (75% vs 38%) and shorter time to dialysis independence (51 vs 336 days; p=0.027); no other baseline factors were associated with dialysis independence in univariate analysis. Among patients treated with bortezomib, three-drug combinations (n=30) vs VD alone (N=11) were associated with higher probability of dialysis independence (57% vs 27%; p=0.06). Among patients who became dialysis independent 12 received VCD, 4 VTD, one PAD, 3 VD, 2 MDT, 2 VAD and one T-VAD. Median follow up for all patients was 33 months and median survival was 29 months. Early mortality (within 2 months from start of therapy) was 16%, mostly due to infectious complications. On intent to treat, 64% achieved ≥PR (CR: 6%, VGPR: 32%, PR: 26%); among patients who survived >2 months, ≥PR was achieved by 76%. At 2-month landmark, patients who achieved ≥PR within the first 2 months had higher dialysis independence rates (68% vs 27%, p=0.004). Becoming dialysis independent was associated with a significant improvement in survival (median OS of 63 vs 22 months of patients who remained on dialysis; p=0.002), even after exclusion of early deaths. Notably, the survival of patients who discontinued dialysis was similar to that of the rest of patients (57 months). High dose melphalan (HDM) followed by autologous stem cell transplantation was performed in five patients while on dialysis. Four of them (80%) become dialysis independent approximately one month after HDM. In conclusion, about 6% of NDMM present with renal failure requiring dialysis but half of them can become dialysis independent after bortezomib-based therapy, without the use of special filters, especially if they achieve a rapid myeloma response. VD-based triplets increase the probability of renal response over VD alone and independence from dialysis is associated with a significant improvement in prognosis. Disclosures Dimopoulos: Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genesis: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Terpos:Celgene: Honoraria; Genesis: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Novartis: Honoraria; BMS: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Travel expenses, Research Funding. Kastritis:Takeda: Consultancy, Honoraria; Genesis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria.

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Rituximab Combined with 3 Cycles of High Dose Dexamethasone Improves Response in Patients with Newly-Diagnosed, Persistent, and Chronic Immune Thrombocytopenia (ITP)

Blood ◽

10.1182/blood.v120.21.3345.3345 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3345-3345

Author(s):

Rebecca L. Elstrom ◽

Caroline Seery ◽

Christina Moll ◽

Allison Miller ◽

Julia Gabor ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

High Dose ◽

Newly Diagnosed ◽

Wild Type ◽

Tubulin Gene ◽

Advisory Committees ◽

Optimal Response ◽

High Dose Dexamethasone

Abstract Abstract 3345 Introduction: Adults with newly-diagnosed ITP usually respond to initial prednisone treatment but typically relapse upon its tapering or discontinuation. Patients with persistent/chronic ITP treated with prednisone have an even lower likelihood of a lasting response. Dexamethasone (Dex) has been reported to have curative effects in newly diagnosed patients. Rituximab (Ritux) is thought to be effective in newly diagnosed patients but only yields a long term response in 20–25% of chronic ITP patients. Recently, newly-diagnosed previously-untreated patients received a single cycle of 4 days of Dex 40 mg/day or 4 infusions of 375mg/m2 Ritux combined with Dex. R+Dex in that study yielded a 63% response at 6 months and 34% at 3 years without additional treatment, which was more effective than Dex alone. Methods: Given the additive activity of these two drugs, 59 patients at Weill-Cornell Medical College with ITP of any duration were treated with 4 infusions of 375mg/m2 rituximab and three 4-day cycles of high-dose dexamethasone at 2-week intervals (R+Dex). Optimal response was assessed after 8 weeks as complete remission (CR, platelet count≥100×109/L) or partial remission (PR, 50–100×109/L). Long term outcome was also assessed and both were related to clinical variables. Data was compared to that of rituximab alone using the previous study from our center (Cooper BJH 2004). AIPF values were gathered prior to treatment until 12 weeks after treatment initiation. Results: All but 5 patients had been previously treated with a median of 2 therapies (range 0–7). Assessing optimal response achieved, 44/59 (74.5%) patients responded, with a CR in 64% and a PR in 10%. Only 1/28 patients with ITP < 1yr relapsed (at 12 months). Duration of ITP less than 24 months (p=0.0426) and being an adult predicted better optimal responses (p=0.0154). Of the original 44 responders, 33/59 patients [74% of responding adults and 77% of responding children] had ongoing responses at last f/u at a median of 14 months without the need for further ITP treatment (Figure). Eleven of the 44 relapsed (25%) including the one at 12 months mentioned above. Two additional patients relapsed who had ITP for 1–2 years prior to R+Dex and the other 8 patients who relapsed had ITP for greater than 3 years, 5 of whom had had ITP for 6+ years. Additionally, 53 of the 59 patients were genotyped for β1-tubulin gene. Of the ten patients with heterozygote genotypes, 9 (90%) responded to combination R+Dex treatment and 32 of the 43 wild type patients responded to treatment (p=0.46). There were no overt differences in the AIPF levels over the first 12 weeks between responders and non-responders. No AIPF differences were seen between the heterozygote and wild type patients for the β1-tubulin gene. In our previous study of rituximab alone, 54% of the 57 adult patients responded to rituximab treatment, compared to 86% of the 36 adult patients who responded to R+Dex treatment. R+Dex responders were found to have a longer duration of lower B cell numbers when compared with responders to rituximab alone, preliminarily demonstrating the additive effect of the 2 medications. Adverse events related to R+Dex generally were mild but one patient was hospitalized with colitis, two others experienced serum sickness reactions and dexamethasone was sometimes difficult to tolerate. Conclusion: R+Dex is active and appears clearly superior to rituximab alone in this single-center, pilot study. Adults and patients who have a shorter duration of ITP (< 1–2 years) fare better but children and those with a longer duration of ITP still have a 1/3 chance of a lasting response. The absence of homozygote β1-tubulin SNP's in this population made interpretation of its effect difficult. High dose Dex is not always easy to tolerate but helps maintain the count during the treatment course of 32 days. A prospective, randomized trial is planned. Disclosures: Basciano: Alexion: Consultancy. Ghanima:Roche Pharmaceuticals: Research Funding. Bussel:Amgen: Family owns Amgen stock Other, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cangene: Research Funding; GlaxoSmithKline: Family owns GSK stock, Family owns GSK stock Other, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Research Funding; IgG of America: Research Funding; Immunomedics: Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Shionogi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sysmex: Research Funding; Portola: Consultancy. Off Label Use: The use of romiplostim in pediatric patients was examined in this study.

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Eltrombopag, Low-Dose Rituximab, and High-Dose Dexamethasone Combination for Patients with Newly Diagnosed Immune Thrombocytopenia: A Pilot "Total Therapy" Study

Blood ◽

10.1182/blood.v128.22.1369.1369 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1369-1369

Author(s):

David Gomez-Almaguer ◽

Olga Cantu-Rodriguez ◽

Cesar Homero Gutierrez-Aguirre ◽

Jose Carlos Jaime-Perez ◽

Luz C. Tarin-Arzaga ◽

...

Keyword(s):

Partial Response ◽

Board Of Directors ◽

Low Dose ◽

Complete Response ◽

High Dose ◽

Newly Diagnosed ◽

Advisory Committees ◽

High Dose Dexamethasone ◽

Frontline Therapy

Abstract Introduction: Immune thrombocytopenia (ITP) is an autoimmune disorder that results from platelet destruction and production suppression. Frontline-therapy includes corticosteroids, intravenous immune globulin or anti-D immunoglobulin. Single-agent treatments have not been successful in inducing prolonged remission, as relapse will occur in approximately 50% of patients. Low-dose rituximab (100 mg) has been used for the treatment of ITP, showing an activity almost similar to the 375 mg/m2 standard dose. We and others have reported sustained response rates ranging from 58% to 76% using rituximab plus dexamethasone as a frontline therapy. Eltrombopag is a thrombopoietin nonpeptide mimetic that has been shown to raise platelet count in chronic ITP, and we have previously reported eltrombopag/dexamethasone as a feasible frontline therapy for ITP reaching 100% response rates.The lack of sustained response in many adult patients with newly diagnosed acute ITP has stimulated the search for a treatment that modifies the natural course of the disease. Objetive: We aim to evaluate efficacy, safety, and response duration of low-dose weekly rituximab (100 mg weekly, four doses) plus high-dose dexamethasone (40 mg PO, days 1-4) in combination with eltrombopag (50 mg, days 1-28) as frontline therapy in newly diagnosed primary ITP in an ambulatory setting. Methods: This is an ongoing open-label, single-arm study performed in patients with newly diagnosed ITP from the Hospital Universitario Dr. Jose Eleuterio Gonzalez in Monterrey, Mexico (Clinical trials.gov NCT02834286). Eligible patients are 16 years or older, with bleeding manifestations and/or a platelet count ²30×109/L, without previous treatment. Patients are excluded if they had active infection, pregnancy, or a malignant disease. A complete blood count is performed at baseline, on days 3, 5, 7 and then weekly for 28 days, monthly until month 6, and every 3 months thereafter. Partial and complete responses are defined as an increase in platelet counts ³30×109/L and ³100×109/L, respectively. Results: Ten consecutive patients have been enrolled from March 2015 until July 2016. Median age was 37 years (16-61). Six patients were women (60%) and four were men (40%). Median platelet account at diagnosis was 7 « 109/L (range 1.2-28). Median follow-up has been 7 months (range 1-13). All patients achieved at least a partial response (PR) at a median of 4 days (range 3-14). Complete response (CR) was achieved in 9 patients in a median of 7 days (7-22); all of them were still in CR at the end of treatment (Day 28). One patient lost response at 28 days and received a second high-dexamethasone course maintaining CR. No significant adverse effects have occurred during treatment, only 1 patient reported mild myalgia. No relapses have been documented until now.Currently, 8 patients remain in CR and 2 in PR. Conclusion:This is the first trial evaluating the response of low-dose rituximab in combination with eltrombopag and high-dose dexamethasone in newly diagnosed patients with ITP.Low-dose rituximab in combination with eltrombopag and high dose dexamethasone is a feasible frontline therapy for ITP. This drug combination showed high response rates achieved very rapidly, with a low incidence of side effectsand might represent an attractive option in patients with ITP and substantial bleeding. Table Characteristics and follow-up of patients M: Male, F: Female, CR: Complete Response, PR: Partial Response Table. Characteristics and follow-up of patients. / M: Male, F: Female, CR: Complete Response, PR: Partial Response Disclosures Gomez-Almaguer: Amgen: 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; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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VTE Rates and Safety Analysis of Newly Diagnosed Multiple Myeloma Patients Receiving Carfilzomib-Lenalidomide-Dexamethasone (KRD) with or without Rivaroxaban Prophylaxis

Blood ◽

10.1182/blood-2019-124403 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1835-1835 ◽

Cited By ~ 4

Author(s):

Katrina M Piedra ◽

Hani Hassoun ◽

Larry W. Buie ◽

Sean M. Devlin ◽

Jessica Flynn ◽

...

Keyword(s):

Multiple Myeloma ◽

Venous Thromboembolism ◽

Board Of Directors ◽

Research Funding ◽

High Dose ◽

Newly Diagnosed ◽

Advisory Committees ◽

Cancer Trial ◽

Oncology Research ◽

Increased Risk

Introduction Immunomodulatory agents (IMiD's) are associated with an increased risk of venous thromboembolism (VTE), particularly when combined with high dose steroids. Studies evaluating the use of lenalidomide-bortezomib-dexamethasone (RVD) and carfilzomib-lenalidomide-dexamethasone (KRD) in the frontline setting for multiple myeloma (MM) have reported a 6% and 24% incidence of thrombosis, respectively, despite primary thrombotic prophylaxis with aspirin (ASA) (Richardson, et al. Blood. 2010; Korde, et al. JAMA Oncol 2015). Recent data, including the Hokusai VTE Cancer Trial, have suggested that safety and efficacy of direct oral anticoagulants (DOACs) are preserved in the setting of treatment of solid malignancy-associated thrombosis (Raskob, et al. N Engl J Med. 2018; Mantha, et al. J Thromb Thrombolysis. 2017). Despite this data, there is limited experience and use of DOACs in prevention of thromboses in the setting of hematologic malignancies, specifically MM. After careful review of literature, since early 2018, we changed our clinical practice and routinely placed newly diagnosed MM (NDMM) patients receiving KRD at Memorial Sloan Kettering Cancer Center (MSKCC) on concomitant rivaroxaban 10 mg once daily, regardless of VTE risk stratification. In the following abstract, we present VTE rates and safety data for newly diagnosed MM patients receiving RVD with ASA vs. KRD with ASA vs. KRD with rivaroxaban prophylaxis. Methods This was an IRB-approved, single-center, retrospective chart review study. All untreated patients with newly diagnosed MM, receiving at least one cycle of RVD or KRD between January 2015 and October 2018 were included. The period of observation included the time between the first day of therapy until 90 days after completion of induction therapy. Patients were identified by querying the pharmacy database for carfilzomib or bortezomib administration and outpatient medication review of thromboprophylaxis with rivaroxaban or ASA. VTE diagnoses were confirmed by ICD-10 codes and appropriate imaging studies (computed tomography and ultrasound). Descriptive statistics were performed. Results During the observation period, 241 patients were identified to have received RVD or KRD in the frontline (99 RVD with ASA; 97 KRD with ASA; 45 KRD with rivaroxaban). Baseline characteristics were well distributed among the three arms, with a median age of 60 (30-94) in the RVD ASA arm, 62 (33-77) in the KRD ASA arm, and 60 (24-79) in the KRD rivaroxaban arm. Patients had International Staging System (ISS) stage 3 disease in 13% (N=13), 9.3% (N=9), and 11% (N=5) of the RVD ASA, KRD ASA, and KRD rivaroxaban arms, respectively. Median weekly doses of dexamethasone were higher in both KRD arms, 40 mg (20-40) vs. 20 mg (10-40) in the RVD ASA arm. The average initial doses of lenalidomide were 22 mg in the RVD ASA arm compared to 25 mg in both the KRD ASA and KRD rivaroxaban arms. After querying the pharmacy database, no patients were identified to have a history or concomitant use of erythropoietin stimulating agent (ESA) use. Treatment-related VTE's occurred in 4 patients (4.0%) in the RVD ASA arm, 16 patients (16.5%) in the KRD ASA arm, and in 1 patient (2.2%) in the KRD rivaroxaban arm. Average time to VTE was 6.15 months (Range 5.42, 9.73) after treatment initiation in the RVD ASA group, while it was 2.61 months (Range 0.43, 5.06) in the KRD ASA group and 1.35 months in the KRD rivaroxaban group. Minor, grade 1 bleeding events per the Common Terminology Criteria for Adverse Events (CTCAE) were identified in 1 (1.1%) patient in the RVD ASA arm, 5 (5.2%) patients in the KRD ASA arm, and 1 (2.2%) patient in the KRD rivaroxaban arm. Conclusion More efficacious MM combination therapies have been found to increase the risk of VTE when using ASA prophylaxis, indicating better thromboprophylaxis is needed. We found patients receiving ASA prophylaxis with KRD were more likely to experience a VTE and these events occurred earlier compared to patients receiving ASA prophylaxis with RVD. Importantly, the rate of VTE was reduced to the same level as ASA prophylaxis with RVD when low-dose rivaroxaban 10 mg daily was used with KRD, and without necessarily increasing bleeding risk. Our retrospective data support the development of prospective clinical trials further investigating DOAC use in thromboprophylaxis for NDMM patients receiving carfilzomib-based treatments. Figure Disclosures Hassoun: Novartis: Consultancy; Janssen: Research Funding; Celgene: Research Funding. Lesokhin:BMS: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Janssen: Research Funding; GenMab: Consultancy, Honoraria; Serametrix Inc.: Patents & Royalties; Genentech: Research Funding; Juno: Consultancy, Honoraria. Mailankody:Juno: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Takeda Oncology: Research Funding; CME activity by Physician Education Resource: Honoraria. Smith:Celgene: Consultancy, Patents & Royalties, Research Funding; Fate Therapeutics and Precision Biosciences: Consultancy. Landgren:Theradex: Other: IDMC; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Other: IDMC; Sanofi: Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. OffLabel Disclosure: Off-label use of rivaroxaban for outpatient prophylaxis of venous thromboembolism (VTE) will be explicitly disclosed to the audience.

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Lenalidomide Plus Dexamethasone Versus Lenalidomide Plus Melphalan and Prednisone: A Case-Control Study in Newly Diagnosed Elderly Myeloma Patients.

Blood ◽

10.1182/blood.v114.22.2877.2877 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2877-2877

Author(s):

Francesca Gay ◽

S. Vincent Rajkumar ◽

Patrizia Falco ◽

Shaji Kumar ◽

Angela Dispenzieri ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Low Dose ◽

Case Control Study ◽

Case Control ◽

High Dose ◽

Primary Therapy ◽

Newly Diagnosed ◽

Advisory Committees ◽

Control Study

Abstract Abstract 2877 Poster Board II-853 Background and Objective: In newly diagnosed multiple myeloma (MM) patients, treatment with lenalidomide plus high-dose dexamethasone (RD) was superior to high-dose dexamethasone in terms of both response rates and 1-year progression-free survival (PFS) (Zonder JA et al, Blood 2007;110:77). Preliminary results suggest that the combination lenalidomide plus low-dose dexamethasone (Rd) compared to the RD regimen yields significantly better 2-year overall survival (OS) (Rajkumar SV et al, J Clin Oncol 2008;26:8504). The combination of melphalan, prednisone, and lenalidomide (MPR) has been investigated in a phase I/II study showing promising results (Palumbo A et al, J Clin Oncol 2007; 25:4459-4465). The goal of this case –control study was to compare the efficacy and the toxicity of the lenalidomide/dexamethasone (len/dex) combination vs MPR as primary therapy for newly diagnosed elderly MM patients, to determine the additive value of melphalan compared to a regimen of lenalidomide plus corticosteroid. Patients and methods: Data from 51 newly diagnosed MM patients enrolled in Italy in a phase I/II dose-escalating trial, from January to October 2005, with MPR, were analyzed. For comparison of their outcome, 37 patients were identified among newly diagnosed patients seen at the Mayo Clinic from March 2005 to December 2008 who received len/dex as primary therapy and were enrolled in phase II or III trials. Patients treated with MPR received 9 monthly cycles of oral melphalan (doses ranging from 0.18 to 0.25 mg/kg on days 1-4), prednisone (2 mg/kg on days 1-4) and lenalidomide (doses ranging from 5 to 10 mg/day on days 1-21). After 9 cycles, patients started maintenance with lenalidomide alone (10 mg, days 1-21) until relapse or progression. Patients treated with len/dex received oral lenalidomide (25 mg/day, days 1-21) plus dexamethasone, either at low-dose (n=17) (40 mg orally days 1, 8, 15, 22) or at high-dose (n=21) (40 mg orally on days 1-4, 9-12, and 17-20). Treatment was continued until progression, relapse or unacceptable toxicity, or could be stopped at the physician's discretion. Patients (n=13) were allowed to receive transplant if they wished and were deemed eligible. Outcome was analyzed on an intention-to-treat basis. The Chi-square or the rank sum tests were used to compare variables. Time-to-event analysis was performed using the Kaplan-Meier method and comparisons were determined by the log-rank test and the Cox proportional hazards model. Results: On intention-to-treat analysis, 15.7% versus 23.7% patients, respectively in the MPR and in the len/dex group, (p=0.342) achieved a complete response, and 43.2% vs 47.4%, (p=0.691) achieved at least a very good partial response. Time-to-progression (TTP) (median: 24.7 vs 27.5 in MPR and len/dex groups, respectively; HR 1.04; 95% CI 0.55-1.98; p=0.903), PFS (median: 24.7 vs 27.5 in MPR and len/dex groups, respectively; HR 1.03; 95% CI 0.55-1.92; p=0.926) and OS (2-year OS: 86.2% in MPR group vs 89.1% in len/dex, HR 0.86; 95% CI 0.38-1.98; p=0.730) were not significantly different between the 2 groups. No significant differences in TTP, PFS and OS were reported when MPR patients were compared with the subgroup of patients treated with low-dose dexamethasone plus lenalidomide. Similar results were found when the analysis was restricted to MPR patients and len/dex pair mates receiving lenalidomide plus low/dose dexamethasone, matched according to age and sex, and who did not received transplant. The toxicity profile was different in the two groups. Hematologic grade 3-4 toxicities were more common with MPR compared with len/dex, in particular neutropenia (66.7% vs 21.1%, p < 0.001) and thrombocytopenia (31.4% vs 2.6%, p < 0.001), respectively. Grade 3-4 gastrointestinal events (13.2% vs 2.0%, p= 0.080), thrombotic events (13.2 vs 5.9, p= 0.279) and fatigue (10.5% vs 3.9%, p= 0.395) were more common with len/dex compared with MPR. Conclusion: Results of this case-control study show that both MPR and Rd are efficacious regimens for elderly MM patients. Data need however to be carefully evaluated and randomized control trials are needed to confirm these results. Disclosures: Off Label Use: research drug in combination to standard of care. Kumar:celgene: Research Funding; millenium: Research Funding; bayer: Research Funding; novartis: Research Funding; genzyme: Research Funding. Dispenzieri:celgene: Research Funding. Gertz:celgene: Honoraria; genzyme: Honoraria; millenium: Honoraria; amgen: Honoraria. Lacy:celgene: Research Funding. Musto:celgene: Honoraria. Fonseca:medtronic: Consultancy; genzyme: Consultancy; celgene: Consultancy; amgen: Consultancy; BMS: Consultancy; otsuka: Consultancy. Petrucci:celgene: Honoraria; Janssen Cilag: Honoraria. Greipp:celgene: Research Funding. Boccadoro:jansen Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; pharmion: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Palumbo:Janssen-Cilag: Honoraria; Celgene: Honoraria.

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Achievement of Complete Response Is a Strong Prognostic Factor In Elderly Newly Diagnosed Myeloma: Retrospective Analysis of 1175 Patients

Blood ◽

10.1182/blood.v116.21.1949.1949 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1949-1949

Author(s):

Francesca Gay ◽

Alessandra Larocca ◽

P.W. Wijermans ◽

Sara Bringhen ◽

Tommasina Guglielmelli ◽

...

Keyword(s):

Board Of Directors ◽

Complete Response ◽

New Drugs ◽

Response To Treatment ◽

Maximal Response ◽

High Dose ◽

Newly Diagnosed ◽

Advisory Committees ◽

Best Response ◽

The Impact

Abstract Abstract 1949 Introduction: There is extensive evidence from numerous studies in the transplant setting that achievement of complete response (CR) or at least very good partial response (VGPR) is significantly associated with prolonged progression-free survival (PFS) and overall survival (OS). In elderly myeloma patients CR was a rare event since new drugs has been added to standard melphalan-prednisone (MP). After the introduction of novel agents, CR represents an achievable goal, also outside of the transplant setting. Aims: to assess the impact of response to treatment on time-to-event parameters (PFS and OS) in elderly myeloma patients. Methods: We retrospectively analysed newly diagnosed myeloma patients, older than 65 years old, or younger but not eligible for high-dose chemotherapy and transplant. Patients were enrolled in 3 multicentre randomized European trials of the GIMEMA and Hovon groups, and were treated with MP (n=332), MP plus thalidomide (MPT, n=332), MP plus bortezomib (VMP, n=257) or MP plus bortezomib-thalidomide followed by bortezomib-thalidomide maintenance (VMPT-VT, n=254). PFS, OS and duration of CR were analysed by the Cox proportional hazards model, comparing the two arms by the Wald test and calculating 95% confidence interval (CI). Univariate and multivariate analyses were performed for the following variables: age at diagnosis (>75 vs. ≤75 yrs), International Staging System (ISS) stages, type of chemotherapy and best response achieved. Best response was treated as a time-dependent variable. Results: A total of 1,175 patients, enrolled from November, 2001 to January, 2009, were retrospectively analysed. The best response to treatment was available in 1,136 patients: CR was reported in 195, VGPR in 212, PR in 397. Baseline characteristics according to best response achieved in patients who obtained CR, VGPR or PR were similar. Since response rates vary according to treatment regimens the proportion of patients who received MP, MPT, VMP, and VMPT-VT was different in the different response categories. After a median follow-up of 29 months, PFS was significantly higher in patients who achieved CR compared to those who obtained VGPR (HR 0.16; 95% CI 0.10–0.24; p<0.001) or PR (HR 0.07; 95% CI 0.04–0.13; p<0.001). The advantage in PFS translated into an advantage in OS: patients obtaining CR have a significantly prolonged OS than patients who achieved VGPR (HR 0.15; 95% CI 0.08–0.28; p<0.001) or PR (HR 0.08; 95% CI 0.04–0.16, p<0.001), (table). In multivariate analysis CR achievement was as an independent predictor of longer PFS and OS, regardless of age, ISS stage, and treatment administered. In patients > 75 years, both PFS and OS were shorter as compared to younger patients. Despite these differences, the impact of CR on outcome was identical. In the subgroup of patients > 75 years, PFS was significantly prolonged in patients who achieved CR, compared with those who obtained VGPR (HR 0.26; 95% CI 0.12–0.58, p = 0.001) or PR (HR 0.20; 95% CI 0.10–0.41, p < 0.001). Accordingly, OS was significantly higher in patients who achieved CR, compared with those who obtained VGPR (HR 0.13; 95% IC 0.03–0.58; p = 0.007), or PR (HR 0.12; 95% IC 0.03–0.51, p = 0.004), (table). No significant PFS differences between patients obtaining CR during the first 6 months of treatment or later were seen (HR 1.06; 95% IC 0.49–2.27; p=0.878). Similarly, no OS differences between these two groups were detected (p = 0.676). Duration of CR was comparable in patients who obtained CR during or after the first 6 months of treatment (HR 0.66; 95% CI 0.30–1.45; p = 0.305). Patients whose CR lasted more than 18 months have a significant OS benefit compared to patients who did not (p=0.006). Conclusions: These finding highlight the importance of CR, also outside of the transplant setting, regardless of age, ISS and treatment administered, and support the use of new drugs, also in patients older than 75 years, to achieve and maintain maximal response. Disclosures: Gay: Celgene: Honoraria. Bringhen:Calgene: Honoraria; Janssen-Cilag: Honoraria. Guglielmelli:Celgene: Honoraria; Janssen Cilag: Honoraria. Boccadoro:Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees. Sonneveld:Celgene: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson : Membership on an entity's Board of Directors or advisory committees. Palumbo:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Stable Factor IX Activity Following AAV-Mediated Gene Transfer in Patients with Severe Hemophilia B

Blood ◽

10.1182/blood.v120.21.752.752 ◽

2012 ◽

Vol 120 (21) ◽

pp. 752-752

Author(s):

Andrew Davidoff ◽

Edward GD Tuddenham ◽

Savita Rangarajan ◽

Cecilia Rosales ◽

Jenny McIntosh ◽

...

Keyword(s):

Gene Transfer ◽

Board Of Directors ◽

Normal Values ◽

Factor Ix ◽

Hemophilia B ◽

High Dose ◽

Severe Hemophilia ◽

Advisory Committees ◽

Short Course

Abstract Abstract 752 Introduction: We are conducting a phase I/II clinical trial of factor IX gene transfer for severe hemophilia B. In the trial we are using a serotype-8 pseudotyped self-complementary adeno-associated virus (scAAV) vector expressing a codon-optimized coagulation factor IX (FIX) transgene (scAAV2/8-LP1-hFIXco). We have previously reported the early safety and efficacy of our novel gene transfer approach in six patients with severe hemophilia B following a single peripheral vein infusion of one of three vector doses (low [2×1011 vector particles (vp)/kilogram weight (kg)], intermediate [6×1011 vp/kg], or high dose [2×1012 vp/kg]) (Nathwani et al, NEJM 365:2357–65, 2011). AAV-mediated expression of FIX at 1–6% of normal was established in all six participants with an initial follow-up of between 6–14 months following gene transfer. We now report longer follow-up of these participants, as well as data from two additional participants recently enrolled at the high dose level. Methods: We have now infused scAAV2/8-LP1-hFIXco in eight subjects with severe hemophilia B (FIX activity, <1% of normal values). Vector was administered without immunosuppressive therapy, and participants have now been followed for 3 months to 2½ years. FIX activity, serum transaminases, vector genomes in secretions/excretions, antibodies to FIX and AAV8, and AAV8 capsid-specific T-cells were monitored during the follow-up. Results: Each of the participants currently has AAV-mediated activity of FIX at 1 to 6% of normal levels. These levels have been stable in each during the follow-up period which is now greater than 1½ years for the first six participants. Five of the eight participants have discontinued FIX prophylaxis and remain free of spontaneous hemorrhage; in the other three, the interval between prophylactic injections has increased. None of the participants in the low or intermediate dose cohorts had evidence of transaminitis; each currently has FIX activity of 1–3% for over 1½ years. Of the four participants who received the high dose of vector, one had a transient, asymptomatic elevation of serum aminotransferase levels, which was associated with the detection of AAV8-capsid-specific T cells in the peripheral blood; two others had a slight increase in liver-enzyme levels, the cause of which was less clear. Each of these three participants received a short course of glucocorticoid therapy, which rapidly normalized their aminotransferase levels and maintained FIX levels in the range of 4 to 6% of normal values. The fourth participant has not had transaminitis three months after vector administration. Conclusions: This represents the first successful, long-term, gene therapy-mediated expression of a therapeutic protein from an AAV vector delivered to human liver. Although immune-mediated clearance of AAV-transduced hepatocytes remains a concern, this process may be controlled with a short course of glucocorticoids without loss of transgene expression. Larger numbers of patients followed for longer periods of time are necessary to fully define the benefits and risks and to optimize dosing. However, this gene therapy approach, even with its risk of mild, transient transaminitis, has the potential to convert the bleeding phenotype of patients with severe hemophilia B into a mild form of the disease or to reverse it entirely for a prolonged period of time following vector administration. (ClinicalTrials.gov number, NCT00979238). Disclosures: Chowdary: Novo Nordisk: Consultancy. High:Amsterdam Molecular Therapeutics: ; Baxter Healthcare: Consultancy; Biogen Idec: Consultancy; bluebird bio, Inc.: Membership on an entity's Board of Directors or advisory committees; Genzyme, Inc.: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: ; Sangamo Biosciences: ; Shire Pharmaceuticals: Consultancy.

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Crenolanib, a Type I FLT3 TKI, Can be Safely Combined with Cytarabine and Anthracycline Induction Chemotherapy and Results in High Response Rates in Patients with Newly Diagnosed FLT3 Mutant Acute Myeloid Leukemia (AML)

Blood ◽

10.1182/blood.v128.22.1071.1071 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1071-1071 ◽

Cited By ~ 31

Author(s):

Eunice S. Wang ◽

Richard M. Stone ◽

Martin S. Tallman ◽

Roland B. Walter ◽

John R. Eckardt ◽

...

Keyword(s):

Board Of Directors ◽

Induction Chemotherapy ◽

High Dose ◽

Type I ◽

Cell Transplant ◽

Newly Diagnosed ◽

Advisory Committees ◽

Monosomy 7 ◽

Full Count ◽

Count Recovery

Abstract Background: Crenolanib is a type I oral FLT3 TKI, which inhibits both FLT3-ITD and FLT3-TKD mutations (D835, N841, etc). Crenolanib has a half-life of 6-8 hours and does not accumulate with repeated dosing. Crenolanib does not inhibit c-kit at clinically achievable concentrations, potentially allowing for full count recovery even when combined with myelosuppressive chemotherapy. We report here the first analysis of a phase II trial evaluating the tolerability and efficacy of crenolanib combined with standard induction chemotherapy in patients (pts) with newly diagnosed FLT3 mutant AML. Methods: Pts (≥ 18yrs) (no upper age limit) with newly diagnosed AML characterized by FLT3 (ITD and/or TKD) mutations were enrolled. Pts received standard 7+3 induction with cytarabine 100 mg/m2/d for 7 days and either daunorubicin (<60yrs: 90 mg/m2; ≥60yrs: 60 mg/m2) or idarubicin 12 mg/m2 for 3 days. Crenolanib 100 mg TID was administered starting on day 9 until 72 hrs prior to next chemotherapy. Re-induction was permitted for pts with inadequate leukemia cytoreduction. Up to 4 courses of consolidation consisting of 6 doses of high dose cytarabine (HiDAC) (<60yrs: 3 g/m2; ≥60yrs: 1g/m2) was given, with crenolanib starting on day 7. Eligible pts could proceed to allogeneic stem cell transplant (SCT). Crenolanib maintenance therapy was offered for 1 year after HiDAC or -SCT. Safety and tolerability were assessed as well as anti-leukemic activity. Results: Demographics: Twenty-six pts (14 females, 12 males) with a median age of 55yrs (range 22-74yrs) have received 7+3 followed by crenolanib; nine (35%) pts were ≥ 60yrs. Five pts had initial WBC >100,000/μL (two pts had WBC >200,000). Three pts had AML following antecedent MDS or MPN. Mutational Analysis: Twenty-two pts had either FLT3-ITD (n=19) or FLT3-D835 (n=3) mutations. Genomic sequencing revealed multiple concurrent FLT3 activating mutations in four pts. One pt had a dual-activating kinase domain mutation in trans (D835Y+N841T). Three other pts had FLT3-ITD together with N841 (n=2), I836del (n=2), and V592/593 (n=2). Fifteen (60%) pts had FLT3 and NPM1 mutations, and 11 (52%) had FLT3 and DNMT3A mutations. Five pts (24%) had AML with three mutations (FLT3 + NPM1+ DNMT3A). WIT (WT1, IDH1/2, TET2) mutations were present in 11 (52%) pts. Three pts had trisomy 8; one pt each having monosomy 7, trisomy 4, and t(3;18)del(6q)der(3). Treatment Outcome: Eighteen (69%) pts received induction with cytarabine+daunorubicin (10 pts at 90 mg/m2, 8 pts at 60 mg/m2) and eight pts (31%) received cytarabine+idarubicin. To date, crenolanib has been well-tolerated in combination with chemotherapy. Six pts required crenolanib dose reductions for periorbital edema (n=2), delayed count recovery (n=1), LFT elevation (n=1), nausea (n=1) and rash (n=1). Out of the twenty-five pts evaluable for response, twenty-two (88%) achieved complete remission (CR) with full count recovery after one cycle of induction. Overall CR/CRi rate was 96% (Table 1). Sixteen pts (10 pts< 60yrs; 6 pts≥ 60yrs) have received a total of 26 cycles of consolidation with HiDAC and crenolanib. Twelve pts (46%) have been bridged to allogeneic SCT. With a median follow up of 6 months, only three pts (all > 60yrs) have relapsed. Overall survival is shown in Figure 1. Conclusion: Crenolanib, a type I pan-FLT3 TKI, can be safely combined at full doses with cytarabine/daunorubicin or cytarabine/idarubicin induction and HiDAC consolidation chemotherapy for upfront AML therapy. A high CR rate of 88% with full count recovery was observed after one cycle of induction with an overall CR/CRi rate of 96%. HiDAC consolidation and allo SCT could be administered on schedule. Encouraging anti-leukemic activity has been observed with no relapses in FLT3 mutant AML pts <60yrs. Accrual to this trial continues. Disclosures Stone: Roche: Consultancy; Sunesis Pharmaceuticals: Consultancy; Xenetic Biosciences: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy; Agios: Consultancy; Amgen: Consultancy; Celator: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy; Novartis: Consultancy; Jansen: Consultancy; Pfizer: Consultancy; ONO: Consultancy; Juno Therapeutics: Consultancy; Merck: Consultancy. Eckardt:Arog: Employment, Equity Ownership.

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