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

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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Prognostic Impact Of Serum Free Light Chain (sFLC) Assay In Newly Diagnosed Multiple Myeloma (MM) Treated With Bortezomib

Blood ◽

10.1182/blood.v122.21.1859.1859 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1859-1859

Author(s):

Paola Tacchetti ◽

Serena Rocchi ◽

Annalisa Pezzi ◽

Elena Zamagni ◽

Lucia Pantani ◽

...

Keyword(s):

Partial Response ◽

Board Of Directors ◽

Median Time ◽

Light Chain ◽

Complete Response ◽

Lower Probability ◽

Prognostic Impact ◽

Newly Diagnosed ◽

Advisory Committees

Abstract Introduction sFLC assay is an important advance in the diagnosis and monitoring of MM, however data on prognostic significance are still limited. Methods We performed a retrospective analysis aimed to investigate the role of sFLC assay as predictor of outcomes in newly diagnosed MM patients (pts) treated up-front with bortezomib based regimens. sFLC assay (Freelite; The Binding Site, Birmingham, UK) was performed by BN II nephelometer (Date Behring, Deerfield, IL, USA). sFLC-k, sFLC-l and sFLC k/l ratio were serially measured at baseline, during treatment and follow-up. sFLC k/l ratios were classified as normal (0.26-1.65) or abnormal (<0.26 or >1.65) according to the IMWG criteria. An involved sFLC level >=100 mg/L, defined by the IMWG criteria as the level to identify a sFLC evaluable disease, was categorized as high. Results We analyzed 110 pts who received first-line bortezomib-based treatments: 67% incorporated into autotransplantation and 33% combined with conventional chemoterapy. The median age was 63 years, 47 pts (43%) were female and 63 (57%) were male. Fifty-eight pts (53%) had IgG heavy chains, 25 (23%) IgA, 1 (1%) IgM and 1 (1%) IgD; 23 pts (21%) had light chain only disease, and 2 pts (2%) had nonsecretory MM. Overall, the involved light chain was kappa in 69 pts (64%), lambda in 36 (33%) and both in 2 (2%), whereas 3 pts (3%) had no detectable light chains. An abnormal sFLC k/l ratio was detected in 91 pts (83%) at baseline, whereas 76 pts (69%) had an involved sFLC >=100 mg/L. The median involved k and l concentrations were 720 and 479 mg/L, respectively. Baseline sFLC >=100 mg/L correlated with higher frequency of Bence Jones isotype (p=0.041), higher beta-2-microglobulin (b2M) (p=0.011), lower hemoglobin concentration (p=0.003) and higher frequency of del(13q) (p=0.016). No correlation was found between high baseline sFLC and other parameters including ISS stage, LDH, bone marrow infiltration, and presence of t(4;14) or del(17p). IMWG response was: 43% stringent complete response (sCR), 11% complete response (CR), 18% very good partial response (VGPR) and 15% partial response (PR). Overall, 83 pts (75%) achieved a normalization of sFLC k/l ratio during treatment. With a median follow-up of 26 months (mos), 36 pts progressed and 17 died. The median time to progression (TTP), progression free survival (PFS) and overall survival (OS) were 46, 46 and 75 mos, respectively. In comparison with a baseline sFLC <100 mg/L, sFLC >=100 mg/L was associated with a reduced rate of sCR/CR (71% vs 48%, p=0.028), a lower probability to normalize sFLC k/l ratio (94% vs 67%, p=0.002) and a shorter median TTP (not reached vs 36 mos, p=0.047) and PFS (not reached vs 35 mos, p=0.034), whereas the OS was similar in the two groups (65 vs 75 mos, p=0.16). By the opposite, pts who achieved a normalization of sFLC k/l ratio during treatment had an extended TTP (53 vs 20 mos, p<0.0001), PFS (53 vs 18 mos, p<0.0001) and OS (not reached vs 75 mos, p=0.0026) in comparison with those who failed this objective. Of the 36 pts who relapsed or progressed, 28 could be assessed for sFLC at relapse. Eleven pts (39%) showed a sFLC escape, defined as an increase of sFLC with no associated increase of intact M protein concentration, that preceded the conventional relapse by a median time of 4 mos. No difference was observed between pts with or without sFLC escape, in terms of time to start second line therapy (1 vs 2 mos, p=0.38) and OS post relapse (p=0.86), whereas sFLC >=100 mg/L at relapse was associated with earlier start of salvage therapy, compared with sFLC <100 mg/L (1 vs 4 mos, p=0.006). A multivariate analysis including age, treatment, b2M, albumin, ISS stage, sFLC and cytogenetic abnormalities identified non-transplant regiments (p<0.001), IIS 3 (p=0.032) and sFLC >=100 mg/L (p=0.047) as variables independently associated with a reduced probability to normalize sFLC k/l ratio. By Cox regression analysis, the normalization of sFLC k/l ratio was an independent factor predicting for extended TTP and PFS (p=0.022 and p=0.001) together with ISS 1-2 (p=0.042 and p=0.007). Conclusions High sFLC at baseline was associated with more aggressive disease characterized by a lower probability to achieve sCR/CR and shorter TTP and PFS. Moreover, high sFLC at relapse predicted for short-lasting asymptomatic phase. By opposite, the achievement of normal sFLC k/l ratio during treatment resulted a considerable prognostic indicator of longer TTP and PFS. Disclosures: Tacchetti: Janssen: Honoraria; Celgene: Honoraria. Zamagni:Janssen-Cilag: Honoraria; Celgene: Honoraria. Brioli:Celgene: Honoraria. Martinelli:Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Pfizer: Consultancy; Ariad: Consultancy. Cavo:Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Onyx: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Millennium: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; 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.

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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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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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Clapd (Clarithromycin, Pomalidomide, Dexamethasone) Therapy In Relapsed Or Refractory Multiple Myeloma

Blood ◽

10.1182/blood.v122.21.1955.1955 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1955-1955 ◽

Cited By ~ 6

Author(s):

Tomer M Mark ◽

Angelique Boyer ◽

Adriana C Rossi ◽

Dennis Kwon ◽

Roger N Pearse ◽

...

Keyword(s):

Partial Response ◽

Board Of Directors ◽

Research Funding ◽

Complete Response ◽

Response Analysis ◽

Muscular Weakness ◽

Advisory Committees ◽

Disease Response ◽

Grade 3

Abstract Background Pomalidomide is a distinct IMiD® immunomodulatory agent with activity in subjects with relapsed or refractory MM (RRMM), including those with prior lenalidomide treatment. We have previously reported that the addition of clarithromycin enhances the anti-myeloma activity of pomalidomide+dexamethasone (Pom/Dex) in the treatment of RRMM (Mark et al, ASH 2012). We now report updated results with extended follow up from a phase 2 trial of large group of patients treated with ClaPd in RRMM. Methods One hundred nineteen patients with heavily pretreated RRMM were enrolled into a single-institution study to investigate the effectiveness and tolerability of ClaPd. Eligible subjects had at least 3 prior lines of therapy, one line of which must have included lenalidomide. ClaPd is clarithromycin 500mg twice daily; pomalidomide 4mg for days 1-21, and dexamethasone 40mg on days 1,8,15,22 of a 28-day cycle. All subjects had thromboprophylaxis with 81mg aspirin daily. Disease response evaluation was performed monthly with immunoelectrophoresis and free light chain analysis; bone marrow biopsy with skeletal imaging was used to confirm MM progression or complete response (CR). Treatment was continued as tolerated by the patient until disease progression. Results One hundred fourteen patients had completed at least 1 cycle of ClaPd and were eligible for disease response analysis at data cut-off. All patients were included in the safety analysis. Patients had undergone a median of 5 (range 3-15) prior lines of therapy. The proportion of patients who were refractory to lenalidomide, refractory to bortezomib, and double (lenalidomide+bortezomib) refractory were 85%, 79%, and 68% respectively. The median number of ClaPd cycles received was 7 (range 1-34). Overall response rate (ORR, ≥PR, entire cohort/double-refractory subgroup) was 61.4/56.4% [stringent complete remission (sCR): 4.4/4%, complete response (CR): 0.9/1.3%, very good partial response (VGPR): 14.9/11.5%, partial response (PR): 41.2/38.5%, minimal response (MR): 7/9%, stable disease (SD): 21.9/21.8%, progressive disease (PD): 9.6/12.8%, ³VGPR rate of 20.2/16.7%]. Clinical benefit (³ MR) was achieved in 68.4/65.4%. Median time to PR and maximum response was 1 (range 1-7) and 2 (range 1-18) cycles, respectively. After a mean follow up time of 11.9 months, 40 patients (34%) remain free from progression, with a median progression free survival of 8.1 months (95% CI: 5.1, 9.8). Median duration of response (DOR) was 9.3 months (95% CI: 7.2,16.1). Median overall survival (OS) has not been reached with 68 patients (57%) alive at last follow-up. Median PFS, DOR, OS were not significantly different in the double-refractory subgroup at 6.3 (CI 4.7, 8.7; p = 0.21), 8.6 (CI 6.5, 16.1; p = 0.87), and 16.8 months (CI 12.4, 28.7; p = 0.11) respectively. The most common (³% grade 3 and 4 toxicities were: neutropenia (49%), thrombocytopenia (39%), anemia (27%), pneumonia (10%), fatigue 8%, and muscular weakness 7%. Febrile neutropenia was uncommon at 2%. There were 6 cases of lower extremity venous thrombosis (5%, 1 grade 1, 4 grade 2, 1 grade 3) and no instances of pulmonary embolism. Mild peripheral neuropathy was present in 32% (19% grade 1, 13% grade 2), 0% grade 3 or 4). Grade 2 congestive heart failure, due to dexamethasone, emerged in 1 subject (0.8%). Four patients (3.3%) withdrew due to treatment related toxicity (1 with Grade 3 muscular weakness, 2 due to Grade 3 fatigue, 1 grade 4 neutropenic sepsis). There was no treatment related mortality. Conclusions ClaPd is a highly effective and tolerable regimen for heavily treated RRMM that has progressed after prior treatments. Response to ClaPd is rapid and sustained at > 8 months in the majority of subjects. The presence of double refractory disease did not significantly impact clinical outcomes. The ORR and PFS compare favorably and toxicity profile is similar to other published reports of Pom/Dex. Disclosures: Mark: Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Onyx: Research Funding, Speakers Bureau. Rossi:Celgene: Speakers Bureau. Zafar:Celgene: Speakers Bureau; Millennium: Speakers Bureau; Onyx: Speakers Bureau. Pekle:Millennium: Speakers Bureau; Celgene: Speakers Bureau. Niesvizky:Millennium: The Takeda Oncology Company: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau.

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Weekly Carfilzomib, Cyclophosphamide and Dexamethasone (wCCyd) in Elderly Newly Diagnosed Multiple Myeloma Patients: Results of a Phase 2 Study

Blood ◽

10.1182/blood.v126.23.1828.1828 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1828-1828 ◽

Cited By ~ 2

Author(s):

Sara Bringhen ◽

Davide Rossi ◽

Alessandra Larocca ◽

Paolo Corradini ◽

Piero Galieni ◽

...

Keyword(s):

Partial Response ◽

Adverse Events ◽

Board Of Directors ◽

Phase 1 ◽

Progression Free Survival ◽

Complete Response ◽

Maximum Tolerated Dose ◽

Phase 2 ◽

Newly Diagnosed ◽

Advisory Committees

Abstract Background Carfilzomib is a novel second generation proteasome-inhibitor with significant anti-MM activity and favorable toxicity profile. In a recent phase 1/2 study in relapsed/refractory patients (pts) a weekly schedule of carfilzomib in combination with dexamethasone showed to be effective (overall response rate of 77%) and safe (ASCO 2015). The ongoing phase 3 ARROW study is comparing once- with twice-weekly carfilzomib. In the newly diagnosed setting, no data are available on weekly carfilzomib. We designed a phase 1/2 study of weekly carfilzomib in combination with cyclophosphamide and dexamethasone (wCCyd) for newly diagnosed MM pts. Results of the dose-escalation phase 1 portion of study were previously reported (Palumbo A et al, Blood 2014), the maximum tolerated dose of weekly carfilzomib was established as 70 mg/m2. Here we report efficacy and safety results of the phase 2 portion of the study. Methods Newly diagnosed pts ineligible for autologous stem-cell transplantation due to age or co-morbidities were enrolled in the phase 2 portion of the study. Pts received IV carfilzomib at the maximum tolerated dose 70 mg/m2 on days 1, 8, 15 combined with oral cyclophosphamide at 300 mg/m2 on days 1, 8, 15 and oral dexamethasone at 40 mg on days 1, 8, 15, 22, in 28-daycycles. After the completionof 9 cycles, pts received 28-day maintenance cycles with carfilzomib at 70 mg/m2 on days 1, 8, 15 until disease progression or intolerance. The primary objectives were to determine the efficacy and safety of wCCyd. The secondary objectives included the evaluation of time to progression, progression-free survival, time to next therapy and overall survival. Response was assessed according to the modified International Uniform Response Criteria. Adverse events (AEs) were graded following NCI-CTCAE v4. Results As of July 15, 2015, 47 newly diagnosed MM pts were enrolled in the phase 2 portion of the study. Median age was 72 years, 23% of pts were older than 75 years, 30% had ISS stage III, 34% had unfavorable FISH profile [t(4;14) or t (14;16) or del17p or amp1]. Toxicityand response data were available in 40 pts, who completed atleast the first cycle; 7 pts were still receiving their first cycle of treatment. Pts received a median of 6 cycles (range 1-9). Overall, 80% of pts achieved at least a partial response, 60% at least a very good partial response, and 28% a near complete response. Responses improved over time (Table 1). During the study, 9 pts progressed or died, the progression-free survival at 1 year was 75%. Grade (G) 3-4 drug-related adverse events included neutropenia (22%, 9 pts), thrombocytopenia (7%, 3 pts), infection (10%, 4 pts), acute pulmonary edema (5%, 2 pts), creatinine increase (5%, 2 pts), fever (2.5%, 1 pt), fatigue (2.5%, 1 pt) and headache (2.5%, 1 pt). G1-2 hypertension was reported in 6 pts (15%). No peripheral neuropathy was reported. Overall, the wCCyd regimen was well tolerated, 4 pts (10%) required carfilzomib dose-reduction (G3 hematologic toxicities [2 pts], G3 headache [1 pt] and G2 fatigue [1 pt]) and 9 pts (22%) required treatment discontinuation due to adverse events (2 infections, 1 acute pulmonary edema, 1 creatinine increase, 1 fever, 1 pt condition, 1 second tumor, 1 pericardial effusion, 1 sudden death). Conclusions This is the first prospective study evaluating once-weekly carfilzomib in treatment-naïve MM. wCCyd therapy appears safe and effective in newly diagnosed MM pts. Responses became deeper with subsequent cycles and toxicities were manageable. The response rate observed with weekly carfilzomib compares favorably with similar studies with standard twice-weekly carfilzomib infusion. Updated results will be presented at the meeting. Table 1. 2nd cycle 6th cycle 9th cycle Complete Response 17% 26% 33% At least near Complete Response 29% 39% 40% At least Very Good Partial Response 66% 82% 87% At least Partial Response 86% 87% 87% Disclosures Bringhen: Janssen-Cilag, Celgene, Novartis: Honoraria; Onyx: Consultancy; Merck Sharp & Dohme: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Use off-label of drugs for the dose and/or schedule and/or association. Larocca:Janssen-Cilag, Celgene: Honoraria. Offidani:Janssen-Cilag, Celgene, Sanofi, Amgen, Mundipharma: Honoraria. Gaidano:Celgene, Onyx: Membership on an entity's Board of Directors or advisory committees. Boccadoro:Sanofi: 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; Onyx Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees. Sonneveld:Janssen-Cilag, Celgene, Onyx, Karyopharm: Honoraria, Research Funding; novartis: Honoraria. Palumbo:Celgene, Millennium Pharmaceuticals, Amgen, Bristol-Myers Squibb, Genmab, Janssen-Cilag, Onyx Pharmaceuticals: Consultancy, Honoraria; Novartis, Sanofi Aventis: Honoraria.

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Children's Oncology Group (COG) AALL0434: Successful Disease Control without Cranial Radiation in Newly Diagnosed T Lymphoblastic Lymphoma (T-LL)

Blood ◽

10.1182/blood-2018-99-113481 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1000-1000 ◽

Cited By ~ 1

Author(s):

Robert James Hayashi ◽

Stuart S. Winter ◽

Kimberly P. Dunsmore ◽

Meenakshi Devidas ◽

Brent Wood ◽

...

Keyword(s):

Bone Marrow ◽

High Risk ◽

Partial Response ◽

Board Of Directors ◽

Complete Response ◽

Newly Diagnosed ◽

Advisory Committees ◽

Risk Patients ◽

To Receive ◽

Standard Risk

Abstract Background: COG AALL0434 evaluated the safety and efficacy of a multi agent chemotherapy backbone containing Capizzi based methotrexate/pegaspargase in newly diagnosed T-LL patients. High-risk patients were randomized to receive the COG augmented BFM (ABFM) regimen with or without Nelarabine. This was part of a larger trial including T-Lymphoblastic Leukemia (T-ALL) patients featuring a 2 x 2 pseudo-factorial randomization at the end of induction using the COG ABFM regimen with a randomization of Capizzi MTX/pegaspargase (C-MTX) verses high dose MTX and a randomization with or without Nelarabine (Nel). Methods: AALL0434 enrolled 277 patients with T-LL (2010-2014). Patients were assigned to two risk categories based upon the degree of bone marrow involvement at diagnosis: (≥1%, High Risk, <1% Standard Risk), and the ability to achieve at least a partial response at the end of induction. Patients with prior steroid treatment were assigned to the high risk group. Both groups were treated using the ABFM C-MTX regimen. High-risk patients were randomized to receive or not receive six, 5-day courses of Nel 650 mg/m2/day. No patients received prophylactic cranial radiation and CNS3 patients were ineligible. Response criteria included, Complete Response (CR): disappearance, Complete Response unconfirmed (CRu): >75% reduction, Partial Response (PR): >50% reduction, of all measurable disease, all without new lesions. Results: At the end of induction, 98.9% of the evaluable patients achieved at least a partial response (30.7% CR, 34.7% CRu, 33.5% PR). For all T-LL patients, the 4-year event free survival (EFS) and overall survival (OS) were 87.0 +/- 2.1% and 90.0+/-1.8%. The 4-year Disease Free Survival (DFS) from end of induction was 90.0+/- 2.1%. There was no difference in DFS observed between the high risk and standard risk groups, (p=0.25) or by treatment regimen (p=0.31). Nel did not show an advantage for high-risk T-LL patients, with 4-year DFS 85.0 +/- 5.6% with Nel (N=60) vs 89.0 +/- 4.7% without Nel (N=58) (p=0.28). Neither stage nor tumor response at the end of four weeks of induction therapy resulted in differences in EFS (p= 0.34 and p= 0.22, respectively). Minimal detectable disease (MDD) of the bone marrow at diagnosis (<0.1%, 0.1-0.99%, >1.0%), used to establish the risk assignment for this trial, failed to demonstrate thresholds at diagnosis that resulted in differences in EFS (p=0.27). Relapse involving the CNS only occurred in 4 patients (1.4%). Overall toxicity and neurotoxicity was acceptable and not significantly different than that experienced from the ALL cohort. There was one observed second malignancy and 5 deaths not from progressive disease. Conclusion: COG AALL0434 produced excellent outcomes in one of the largest trials ever conducted for patients with newly diagnosed T-LL. The COG ABFM regimen with C-MTX provides excellent disease control regardless of stage, or the degree of disease involvement of the bone marrow at diagnosis. Nelarabine did not show an improvement in the outcome, although the trial was underpowered to address this specific question. Disclosures Teachey: Amgen: Consultancy; La Roche: Consultancy. Bollard:Torque: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cellectis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Neximmune: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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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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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)

Blood ◽

10.1182/blood-2021-147218 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3151-3151

Author(s):

Mascha Binder ◽

Axel Matzdorff ◽

Falk Nimmerjahn ◽

Mathias Rummel ◽

Oliver Meyer ◽

...

Keyword(s):

Board Of Directors ◽

Treatment Discontinuation ◽

Sustained Response ◽

High Dose ◽

Newly Diagnosed ◽

Advisory Committees ◽

Platelet Counts ◽

High Dose Dexamethasone ◽

Short Course ◽

History Of

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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Safety and Efficacy of Midostaurin in Combination with High-Dose Daunorubicin in 7+3 Induction for Acute Myeloid Leukemia with FLT3 Mutation

Blood ◽

10.1182/blood-2019-129331 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3896-3896

Author(s):

Yehuda E. Deutsch ◽

Robert Wilkinson ◽

Amanda Brahim ◽

Stephanie Boisclair ◽

Jose Sandoval-Sus ◽

...

Keyword(s):

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Cancer Center ◽

High Dose ◽

Newly Diagnosed ◽

Advisory Committees ◽

Safety And Efficacy ◽

Acute Myeloid

Introduction: Acute myeloid leukemia (AML) is a heterogeneous disease with varied outcomes dependent on patient cytogenetic and mutational status. Thirty percent of adults with newly diagnosed AML have a mutation in the fms-related tyrosine kinase 3 (FLT3) gene. Midostaurin is a small molecule inhibitor that acts on multiple receptor tyrosine kinases, including FLT3. The RATIFY trial showed improved overall survival (OS) and event-free survival in patients treated with daunorubicin and cytarabine (7+3) plus midostaurin (Stone et al, NEJM 2017). In this trial, a dose of daunorubicin 60 mg/m2 was administered. High dose (HD) 90 mg/m2 daunorubicin significantly improved the rate of complete remission and overall survival, including in patients with FLT3-ITD (Luskin et al, Blood 2016). HD daunorubicin has also been shown to be more effective than idarubicin in patients with FLT3-ITD AML (Lee et al, J Clin Oncol 2017). This data raises the question of whether the combination of midostaurin and HD daunorubicin would further improve outcomes of FLT3 mutated AML patients, while maintaining a tolerable safety profile. The objective of this study is to describe the safety and efficacy endpoints of FLT3 mutated AML patients treated with HD daunorubicin plus midostaurin as part of induction therapy. Methods: We retrospectively reviewed clinical and molecular data of patients at Memorial Healthcare System, Moffitt Cancer Center, and Sylvester Cancer Center with newly diagnosed FLT3 mutated AML treated from May 1st, 2017 to July 1st, 2019. Clinical data was abstracted in accordance with institutional review board approved protocol. All patients were induced with HD daunorubicin 90 mg/m2 on days 1-3, cytarabine 100 mg/m2 on days 1-7, and midostaurin 50 mg PO twice daily on days 8-21. Growth factor and antimicrobial support were used per institutional guidelines. Demographics were analyzed using descriptive statistics. OS was analyzed using Kaplan Meier method. Other efficacy outcomes were CR, CRi (assessed according to the European Leukemia Network Criteria for AML), proportion of patients needing re-induction, and proportion of patients who underwent hematopoietic stem cell transplant (HSCT). Safety outcomes were adverse events (AEs) and early (30- and 60-day) mortality. Results: Twenty-six patients were included in the final analysis. Patient characteristics are outlined in TABLE 1. All patients were FLT3 mutated, as confirmed with molecular studies. The FLT3 subtype was ITD (high) in 3 patients, ITD (low) in 16 patients, TKD in 5 patients, and both in 2 patients. Seventy-seven percent of patients achieved a CR/CRi after one induction cycle, and 96.2% attained CR after two induction cycles. Median time to ANC and platelet recovery was 28 and 26 days, respectively. One patient died during the first 60 days, due to Enterococcus sepsis. The most common non-hematological AEs were nausea (77%), diarrhea (62%), mucositis (58%), rash (54%), and increased ALT (54%). Cumulative incidence of relapse in the cohort was 28% (n=7). Four patients relapsed pre-transplant and achieved CR2 with additional therapy. All 7 of these patients had co-occurring mutations of various types. Of the 20 patients who were considered transplant eligible, 13 (65%) underwent HSCT and 4 (20%) are pending transplant. Of the 13 transplanted patients, 3 experienced relapse post-transplant. After a median follow up of 14.5 months, median OS has not been reached. Conclusion: In our multi-center experience, induction with HD daunorubicin, cytarabine, and midostaurin is clinically effective and seems to be well tolerated. Short term mortality was low and AEs were manageable, with no unexpected safety signals. Also, CR/CRi rates were higher than previously reported, suggesting that the combination of HD daunorubicin and midostaurin may improve the outcomes of patients with FLT3 mutated AML. Future analyses with larger patient samples and longer follow up are warranted to further evaluate long-term safety and efficacy for this regimen. Figure Disclosures Sandoval-Sus: Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Bradley:AbbVie: Other: Advisory Board. Talati:Agios: Honoraria; Celgene: Honoraria; Pfizer: Honoraria; Astellas: Honoraria, Speakers Bureau; Daiichi-Sankyo: Honoraria; Jazz Pharmaceuticals: Honoraria, Speakers Bureau. Watts:Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Sallman:Abbvie: Speakers Bureau; Novartis: Speakers Bureau; Jazz: Research Funding; Incyte: Speakers Bureau; Celyad: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding, Speakers Bureau. Sweet:Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Celgene: Speakers Bureau; Jazz: Speakers Bureau; Incyte: Research Funding; Pfizer: Consultancy; Stemline: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees. Lancet:Daiichi Sankyo: Consultancy, Other: fees for non-CME/CE services ; Agios, Biopath, Biosight, Boehringer Inglheim, Celator, Celgene, Janssen, Jazz Pharmaceuticals, Karyopharm, Novartis: Consultancy; Pfizer: Consultancy, Research Funding.

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