Interim Analysis of a Phase II Pilot Trial of Ruxolitinib Combined with Danazol for Patients with Primary Myelofibrosis (MF), Post Essential Thrombocythemia-Myelofibrosis (Post ET), and Post Polycythemia Vera Myelofibrosis (PV MF) Suffering from Anemia

Abstract Introduction: Approximately 75% of myelofibrosis (MF) patients develop anemia during evolution of the disease process predicting decreased survival. Previous studies exploring the effect of danazol in the treatment of anemia in MF demonstrate responses in anemia of 30-55%. Ruxolitinib has demonstrated improvement in MF related splenomegaly, symptom burden, and even survival yet improvements in cytopenias are uncommon. We designed a phase II multicenter pilot study to evaluate the efficacy and tolerability of combination therapy with ruxolitinib and danazol in MF patients with anemia. Methods: This is a pre-planned interim analysis of a Simon optimum two-stage phase II trial designed to include a minimum of 10 and a maximum of 27 patients. Participants received ruxolitinib 10mg (plat >75 x10x9) BID or 5mg (plat <75 x10 x9) BID with danazol 200mg orally TID. Dose escalation was allowed after completion of 28 days for lack of response or for disease progression. Patients without progression were continued for 6 cycles at 56 days each. Treatment modifications were based on adverse events including thrombocytopenia, leukopenia, and elevation in creatinine and transaminases. Treatment responses were evaluated by the IWG-MRT response criteria (Blood 2013). Patient reported outcome questionnaires (MPN-SAF and EORTC QLQ-C30) were administered at baseline, prior to treatment cycles, and at study discontinuation. Results: Patients: Ten of the 12 evaluable patients enrolled (median age 70.5, range 57-78, M:F ratio 4:1) are included in this analysis. Eight patients had primary MF (PMF), 1 had post essential thrombocytosis (ET) MF, and 1 had post polycythemia vera (PV) MF. Jak2 V617F mutation was positive in 30%. At the time of enrollment 40% had received an erythrocyte transfusion in the last month and all were DIPSS Int-2 or higher. Median baseline hemoglobin was 9.0 g/dL (range 8.3 - 12.4). Median baseline platelet level was 172 x10 (9)/L (range 56 - 346). Most (90%) had received prior therapy and many were refractory to multiple lines of therapy prior to enrollment. Three (30%) patients had previously participated in a JAK inhibitor clinical trial. Tolerability: Among 6 patients who have completed treatment, median duration of treatment was 39 days (range 24-287) with treatment discontinuation due to progression of disease in 2 patients, allogeneic stem cell transplant in 1, alternative treatment in 1, unrelated adverse event (hyponatremia) in 1, and unrelated death (leukemic transformation with intracranial hemorrhage) in 1. Hematologic Grade 3 or > adverse events included anemia (60%), neutropenia (20%), and leukopenia (10%). Non-hematologic Grade 3 or > adverse events included electrolyte abnormalities (20%), edema (10%), infection (10%), and intracranial hemorrhage (10%). Efficacy: Treatment response per IWG-MRT response criteria included stable disease (SD) in 8/10 (80%), clinical improvement in 1/10 (10%), and progressive disease (PD) in 1 (10%). The median change in hemoglobin and platelet count from baseline was -0.05 g/dL (range -0.5 - 1.8) and 28.5 x10(9)/L (range -143 – 118) respectively, however 4/10 (40%) and 7/10 (70%) had improvement at some point during treatment in level of anemia and/or thrombocytopenia. The median follow-up time was 2 months (range 0.9-9.4). Among 6 patients with a baseline and at least one post-baseline MPN-SAF TSS, 2/6 (30%) of patients had at least a 10-point (clinically meaningful) improvement, with 1 of the 2 achieving the stricter 50% improvement from baseline. Responses might have been confounded due to impact of prior therapies. Conclusions: On interim analysis, ruxolitinib and danazol combination therapy demonstrates modest additional clinical benefit, however in a group of exceedingly high risk MF patients with significant anemia and prior single agent JAK inhibitor failures. Preliminary data suggests improvement in anemia and/or thrombocytopenia in some treated patients however only one clinical improvement per IWG-MRT criteria was observed. Combination therapy was well tolerated with no major incremental toxicity attributable to the addition of danazol. Maturation of data is needed to fully evaluate efficacy of ruxolitinib and danazol combination therapy prior to continuation of accrual. Disclosures Mascarenhas: Incyte Corporation: Consultancy, Research Funding; Novartis Pharmaceuticals Corporation: Research Funding. Reeder:Millennium, Celgene, Novartis: Research Funding. Tibes:Seattle Genetics, Inc.: Research Funding. Mesa:Incyte: Research Funding; Novartis: Consultancy; Gilead: Research Funding; Genentech: Research Funding; Promedior: Research Funding; Ns Pharma: Research Funding; Celgene: Research Funding; Lilly: Research Funding; Cti: Research Funding.

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Final Analysis of a Multicenter Pilot Phase 2 Study of Ruxolitinib and Danazol in Patients with Myelofibrosis

Blood ◽

10.1182/blood.v126.23.1618.1618 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1618-1618 ◽

Cited By ~ 6

Author(s):

Krisstina L. Gowin ◽

Heidi E. Kosiorek ◽

Amylou Constance Dueck ◽

John Mascarenhas ◽

Ronald Hoffman ◽

...

Keyword(s):

Board Of Directors ◽

Clinical Improvement ◽

Phase Ii ◽

Research Funding ◽

Patient Specific ◽

Cell Transplant ◽

Jak Inhibitor ◽

Advisory Committees ◽

Prior Therapy ◽

Grade 3

Abstract Introduction: Most myelofibrosis (MF) patients develop anemia during evolution of the disease process predicting decreased survival. Previous studies exploring the effect of danazol for the treatment of anemia in MF demonstrate responses in anemia. In prior randomized-controlled studies, ruxolitinib demonstrated improvements in splenomegaly, symptom burden, and even survival yet improvements in cytopenias were uncommon. We designed a phase II multicenter pilot study to evaluate the efficacy and tolerability of combination therapy with ruxolitinib and danazol in MF patients with anemia. Methods: This was a Simon optimum two-stage phase II trial. Eligible subjects received ruxolitinib, a JAK 1/JAK2 inhibitor, at 10mg (plat >75 x10x9) BID or 5mg (plat <75 x10 x9) BID) representing initial dose reduction for JAK inhibitor naïve patients to minimize cytopenias, in combination with tapered danazol up to 200mg orally TID. Dose escalation was allowed after completion of 28 days for lack of response or for disease progression. Pts without progression continued for 6 cycles at 56 days each. Treatment modifications were allowed for either medication based on emergent adverse events (AE). Treatment responses were evaluated every cycle by IWG-MRT criteria (Blood 2006). Patient reported outcome questionnaires (MPN-SAF, EORTC QLQ-C30) were administered at baseline, prior to treatment cycles, and at study discontinuation. Results: Patients: Fourteen pts enrolled (9 Mayo Arizona, 5 Mount Sinai). Median (Med) age 70.5 (range 43-78), M:F ratio 1.8:1. Ten primary MF, 2 post-essential thrombocythemia MF, and 2 post-polycythemia vera MF. JAK2 V617F positive in 42.9%. DIPSS Low in 1 pt, Int-1 in 1pt, Int-2 in 8 pts, High in 2 pts, and unknown in 2pts. Transfusion dependence in 35.7% at baseline. Med baseline hemoglobin (hgb) was 9.0 g/dL (R: 8.3 - 12.4), platelet (plt)157 x109/L (R:143 - 520). Thirteen pts received prior therapy, with 9 pts (64.2%) on a JAK inhibitor within 3 months of study entry. Tolerability: Nine pts (64.2%) ended active treatment, due to progression of disease in 2 pts (22.2%), adverse event (AE) in 2, pt preference in 2, stem cell transplant in 1, unrelated death in 1, and comorbidity in 1. Med duration of therapy: 91 days (range 24-287). AEs regardless of attrition included: hematologic grade 3 or >: anemia in 7 pts (50%), neutropenia in 2 (14.3%), leukopenia in 1 (7.1%), and thrombocytopenia in 2 (14.3%). Non-hematologic grade 3 or >: electrolyte abnormalities in 3 pts (21.4%), infection in 2 (14.3%), edema in 1(7.1%), hypertension in 1 (7.1%), and intracranial hemorrhage in 1 (7.1%). Efficacy: Of the 5 JAK inhibitor naïve pts, 4 had stable or increasing hgb levels with therapy despite new ruxolitinib therapy. Of the 9 pts on prior JAK inhibitor (5 ruxolitinib, 4 other), 5 (55.5%) and 7 (77.7%) patients had stable or increasing hgb or plt levels, respectively. See Table #1. Four pts (28.6%) had at least 50% improvement from baseline on MPN-SAF TSS (95% CI 8.4%-58.1%). Overall treatment response: (IWG-MRT) stable disease (SD) in 10 pts (71.4%), clinical improvement (CI) in 3 (21.4%) all of which were spleen responses, and progressive disease (PD) in 1 (7.1%). Trial was halted secondary to lack of anemia response. Table 1. Patient Specific Response Patient IWG-MRT Response: Study Cycles (N): Prior therapy (within 3 mo) Hemoglobin Response*: (initial, final g/dL) Platelet Response*: (initial, final 10(9)/L) Ruxolitinib 1 CI-Spleen 5 D (8.8, 7.6) S (221,212) 2 SD 4 D (10.3,7.9) S (54,46) 3 SD 2 S (8.8,8.9) S (82,101) 4 SD 3 I (8.9,9.8) S (441,458) 5 SD 3 S (9.6, 9.5) I (161, 231) JAK Inhibitor: 6 SD 5 Momelotinib S (9.0, 9.2) S (132,113) 7 SD 1 NS-018 D (8.3, 7.1) D (120,43) 8 SD 3 NS-018 D (10.1,9.0) D (138,111) 9 SD 2 LY2784544 S (8.7,9.1) S (56,21) Other: 10 CI-Spleen 9 Procrit I (10.5,11.9) S (153,198) 11 CI-Spleen 7 None I (8.9,10.2) D (338,133) 12 PD 1 Hydroxyurea S (12.4, 12.2) D (310, 82) 13 SD 1 Procrit D (10.1, 8.6) D (192, 71) 14 SD 1 Hydroxyurea S (9.1,8.9) D (346,119 *S=stable (Hgb +/- 0.5g/dL, Plt +/- 50x109, D=decreasing, I=increasing. Conclusions: Although overall well tolerated, the addition of danazol to ruxolitinib therapy has modest incremental efficacy by IWG-MRT criteria. Clinical improvement was observed in 21.4% of treated patients, however responses were limited to spleen reduction. The degree to which danazol may stabilize expected cytopenias is interesting and may require further investigation. Disclosures Hoffman: Promedior: Research Funding; Geron: Consultancy, Membership on an entity's Board of Directors or advisory committees; All Cells, LLC: Consultancy, Membership on an entity's Board of Directors or advisory committees. Mesa:Gilead: Research Funding; Genentech: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; CTI Biopharma: Research Funding; Pfizer: Research Funding; Promedior: Research Funding; NS Pharma: Research Funding; Incyte Corporation: Research Funding.

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Carfilzomib Thalidomide and Dexamethasone Is Safe and Effective in the Treatment of Relapsed/Refractory Multiple Myeloma: An Open Label Phase II Australasian Leukaemia and Lymphoma Group (ALLG) MM 018/ Asian Myeloma Network (AMN) 002 Study

Blood ◽

10.1182/blood-2020-139174 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 39-40

Author(s):

Hang Quach ◽

Simon J Harrison ◽

Je-Jung Lee ◽

Nichloas Murphy ◽

Jae Hoon Lee ◽

...

Keyword(s):

Multiple Myeloma ◽

Adverse Events ◽

Board Of Directors ◽

Phase Ii ◽

Primary Endpoint ◽

Research Funding ◽

Open Label ◽

Advisory Committees ◽

Open Label Phase ◽

Grade 3

Background: The combination of carfilzomib with immunomodulatory drugs (IMiDs) and dexamethasone is active in multiple myeloma (MM). Carfilzomib, thalidomide, and dexamethasone (KTd) has been studied in upfront MM treatment but has not been studied in the setting of relapsed/refractory myeloma (RRMM). The ALLG MM018/ AMN002 is an open-label phase II study of KTd in patients with RRMM. This study was conducted across 16 sites across Australia, New-Zealand, Singapore, South Korea and Taiwan. Method: Patients with RRMM with 1-3 prior lines of treatment were given carfilzomib [K: 20mg/m2 IV cycle 1 days 1 and 2, 56mg/m2 (36mg/m2 for patients age ≥75 years) from cycle 1 day 8 onwards], thalidomide (T: 100mg po nocte) and dexamethasone [dex: 40mg (20mg for patients age ≥75 years) po weekly], in a 28-day cycle. After 12 cycles, T was omitted, and K was given on days 1,2,15,16 and dex days 1,15 every 28-day cycles for a further six cycles. The primary endpoint was PFS. Secondary endpoints were ORR, overall survival, adverse events, and quality of life (QoL). The study had an 80% power to detect a ≥70% PFS at 6.5 months compared to historical ≤50% PFS at 6.5 months expected with Td (Kropff, M. et al. Haematologica 2012), at a significance level of 0.05. Results: This study has completed accrual. Eighty-three patients [median age of 66 years (42-85)] were enrolled with a median follow up of 15.9 (0.9-26) months. ORR rates were 86.4% (≥VGPR 70.2%). Median PFS was 20m (95% CI 15.9-26m). PFS at 6.5 months was 76.2% (95% CI 73.6-84.9%). Median OS has not been reached, and was 75% at 20 months. The most common grade ≥3/4 AEs were peripheral neuropathy (16%), upper respiratory tract infections (12%), dyspnoea (14%), and hypertension (10%). Grade ≥3/4 cardiac AEs occurred in 6%. The median carfilzomib dose that was delivered was 70.7% (32.8-92.6%) of the target dose. Thus far, 41% of patients have completed the intended 18 cycles of treatment. 21% of patients ceased therapy early. The most common reason for early treatment cessation was disease progression (30%) and adverse events (15%). Fifteen patients (18%) have died, 11 were due to MM, two from infection, one from an ischaemic cardiac event, and one from a traffic accident. QoL, as measured by the EQ-5D-5L instrument, remained stable throughout treatment. Conclusion: The ALLG MM018/AMN 002 study has met its primary endpoint. The KTd schedule as outlined in this study is efficacious in patients with RRMM, resulting in a prolonged PFS and a safety profile in line with previous reports for each of carfilzomib and thalidomide. KTd is an active option in jurisdictions where the cost of other IMiDs prohibits regulatory funding. Comparisons of efficacy and adverse events between the Caucasian and Asian populations will be presented at the meeting. Disclosures Quach: Celgene: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Glaxo Kline Smith: Consultancy, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Janssen Cilag: Consultancy, Honoraria; Sanofi: Consultancy, Research Funding. Harrison:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria; CRISPR Therapeutics: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Patents & Royalties: wrt panobinostat; Haemalogix: Consultancy. Augustson:Roche: Other: Support of parent study and funding of editorial support. Campbell:Amgen, Novartis, Roche, Janssen, Celgene (BMS): Research Funding; AstraZeneca, Janssen, Roche, Amgen, CSL Behring, Novartis: Consultancy. Soo:Hanmi: Research Funding. Durie:Amgen, Celgene, Johnson & Johnson, and Takeda: Consultancy.

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A phase I/II study of biweekly XELIRI plus bevacizumab for patients with metastatic colorectal cancer as second-line chemotherapy (BIXER study): Reports of phase I part and interim analysis of phase II part.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.4_suppl.643 ◽

2012 ◽

Vol 30 (4_suppl) ◽

pp. 643-643

Author(s):

Mitsukuni Suenaga ◽

Satoshi Matsusaka ◽

Eiji Shinozaki ◽

Nobuyuki Mizunuma ◽

Kiyohiko Hatake ◽

...

Keyword(s):

Colorectal Cancer ◽

Adverse Events ◽

Phase I ◽

Metastatic Colorectal Cancer ◽

Phase Ii ◽

Interim Analysis ◽

Japanese Patients ◽

Recommended Dose ◽

Grade 3 ◽

Dose Limiting Toxicity

643 Background: Capecitabine is an oral fluoropyrimidine prodrug, which is converted to fluorouracil (5-FU) predominantly in the tumor cells. In Japan, capecitabine is mainly used in combination with oxaliplatin (XELOX) in treatment for metastatic colorectal cancer (mCRC) since its approval in 2009. The results of capecitabine plus Irinotecan (CPT) (XELIRI) with or without bevacizumab (BV) in EU or US patients were previously reported, but not in Japanese. Thus, we conducted this study to assess the safety and efficacy of XELIRI plus BV in Japanese patients with mCRC. Methods: Patients with prior chemotherapy including oxaliplatin and BV for mCRC, wild or hetero type of UGT1A1 *6*28 were eligible for this study. This was a phase I study composed of two steps, and dose limiting toxicity (DLT) was assessed during the first treatment cycle. Treatment comprised capecitabine 1,000 mg/m2 twice daily from the evening of day 1 to the morning of day 8, intravenous CPT 180 mg/m2 on day 1, and BV 5mg/kg on day 1 every two weeks. To evaluate the initial safety, 3-6 patients received XELIRI+BV (CPT 150mg/m2) in step 1, and 6 patients received XELIRI+BV (CPT 180mg/m2) in step 2. If DLT occurred in 1 patient in step1, 3 patients would be newly added to step 1, and if in none of 3 or 1-2 of 6 patients, the step 2 would be started. If DLT occurred in less than or equal to 2 of 6 patients in step 2, phase II study would be proceeded, and if In more than 2 of 6 patients, phase II would be conducted at the recommended dose of step 1. Results: In step 1 and 2 of phase I, initial safety of 9 patients was confirmed without occurrence of DLT. Adverse events observed in step 1 and 2 were: neutropenia in 2 and 1; anorexia in 1 and 1; diarrhea in 1 and 1; stomatitis in 1 and 1; alanine or aspartate aminotransferase increased in 1 and 3, respectively. There was no grade 3 or greater adverse events. Conclusions: In mCRC patients with wild or hetero of UGT1A1*6*28 genotype, safety of biweekly XELIRI+BV was confirmed and recommended dose of CPT-11 was determined as 180mg/m2. Interim analysis of safety of phase II part will be reported at the meeting.

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Safety and Efficacy of Ruxolitinib in Patients with Low Platelets Enrolled in a Phase 3b Expanded-Access Study in Myelofibrosis (MF)

Blood ◽

10.1182/blood.v124.21.1859.1859 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1859-1859 ◽

Cited By ~ 2

Author(s):

Martin Griesshammer ◽

Alessandro M. Vannucchi ◽

Philipp le Coutre ◽

Renato S Tavares ◽

Haifa Kathrin Al-Ali ◽

...

Keyword(s):

Adverse Events ◽

Interim Analysis ◽

Research Funding ◽

Costal Margin ◽

Efficacy Data ◽

Safety And Efficacy ◽

Expanded Access ◽

Daily Dose ◽

Median Daily Dose ◽

Grade 3

Abstract BACKGROUND: Ruxolitinib is a potent JAK1/JAK2 inhibitor that has demonstrated durable reductions in splenomegaly and MF-related symptoms and improved survival compared with placebo and best available therapy in the 2 large phase 3 COMFORT studies. Those studies required baseline platelet (PLT) counts ≥ 100 × 109/L, limiting safety and efficacy data in patients (pts) with lower PLTs; however, thrombocytopenia is frequent in MF. Ongoing phase 2 clinical trials in pts with low PLTs have shown ruxolitinib to be generally well tolerated and to provide efficacy benefits for these pts. To gather additional safety and efficacy data in pts with low PLTs, recruitment for JUMP (JAK Inhibitor Ruxolitinib in Myelofibrosis Patients), a phase 3b expanded-access trial for countries with no access to ruxolitinib outside a clinical trial, was extended to pts with baseline PLT counts ≥ 50 × 109/L. Here, we present safety and efficacy data from a planned interim analysis of ruxolitinib in pts with baseline PLT count ≥ 50 to < 100 × 109/L. METHODS: Eligible pts had high-, intermediate-2, or intermediate-1-risk MF, with a palpable spleen (≥ 5 cm from the costal margin) and baseline PLT counts ≥ 50 × 109/L. The starting doses of ruxolitinib was 5 mg bid for pts with baseline PLTs ≥ 50 to < 100 × 109/L. The primary endpoint was assessment of safety and tolerability of ruxolitinib based on the frequency, duration, and severity of adverse events (AEs). An interim analysis of the safety and efficacy of ruxolitinib in pts with PLTs ≥ 50 to < 100 × 109/L at baseline (low-PLT group) was planned for when the first 50 low-PLT pts had completed 6 mo of therapy; this analysis includes results from the first 6 mo of treatment. The final analysis will be performed after all pts have completed 24 mo of treatment or ended treatment due to commercial availability. RESULTS: At data cutoff (01 January 2014), 50 pts with low PLTs had been treated for 6 mo and are included in this analysis. Pt characteristics were median age, 68.5 years; median palpable spleen length, 15.5 cm below the costal margin; and female, 50.0%. Median (range) baseline hemoglobin (Hb) was 98 g/L (57-149 g/L) and PLT count was 87 × 109/L (68 to 98 × 109/L). Most pts (76.0%) remained on or completed treatment as per protocol at the time of data cutoff. The primary reasons for discontinuation included adverse events (AEs; n = 9) and disease progression (n = 2). The median daily dose was 11.8 mg/day (range, 5.9-40.0 mg/day). Of evaluable pts at week 24, 38.2% (13/34 pts) achieved a ≥ 50% reduction from baseline in palpable spleen length; 38.2% had reductions of ≥ 25% to < 50%. Overall, 44.7% of pts achieved a ≥ 50% reduction from baseline in spleen length at any time. Clinically meaningful improvements in symptoms, as assessed using the FACT-Lymphoma Total Score (the range for the minimally important difference is 6.5 to 11.2 points), were seen as early as week 4 (mean change from baseline, 8.2) and were durable through week 12 (9.6). The most common hematologic grade ≥ 3 AEs were anemia (28.0%) and thrombocytopenia (30%; 4% grade 4); 3 pts discontinued due to thrombocytopenia and 1 due to anemia. Four pts had grade 1/2 hemorrhages (1 conjunctival, 1 gastric, and 2 epistaxis) and 2 pts had grade 3/4 (1 intestinal and 1 esophageal varices). PLT counts decreased slightly from baseline (mean change at nadir, −5.9 × 109/L); 3 pts required PLT transfusions. The mean change from baseline to nadir in Hb was −13.4 g/L. Rates of nonhematologic grade ≥ 3 AEs were low overall (1 pt each), with the exception of pyrexia (6.0%), septic shock (4.0%), and arthralgia (4.0%); 44.0% of pts had ≥ 1 dose modification and 28.0% had ≥ 1 dose interruption. CONCLUSIONS: In this cohort of pts with low PLTs, ruxolitinib demonstrated an AE profile consistent with that previously reported in pts with normal PLTs. As compared to a previous analysis of pts with median baseline PLT counts of 248 × 109/L from this same study (Al-Ali et al. EHA 2014), pts in this low-PLT cohort experienced similar improvements in symptoms (mean change from baseline at week 12, 9.6 vs 11.8) but lower achievement of a ≥ 50% reduction from baseline in spleen length within the first 24 weeks of treatment (44.7% vs 69%), likely due to the lower median daily dose (11.8 mg/day vs 36.8 and 24.0 mg/day for pts with starting doses of 20 and 15 mg bid, respectively). Taken together, these data suggest that low-dose ruxolitinib is generally safe and efficacious in pts with PLTs ≥ 50 to < 100 × 109/L. Disclosures Griesshammer: Roche: Honoraria; Sanofi: Honoraria; Novartis: Honoraria; Shire: Honoraria; Amgen: Honoraria. Vannucchi:Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Research Funding. le Coutre:Pfizer: Honoraria; BMS: Honoraria; Novartis: Honoraria, Research Funding; Ariad: Honoraria. Al-Ali:Celgene: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Gupta:Incyte Corporation: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Foltz:Promedior: Research Funding; Gilead: Research Funding; Incyte: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Janssen: Consultancy. Bouard:Novartis: Employment. Perez Ronco:Novartis: Employment. Ghosh:Novartis: Employment.

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Safety and Efficacy of Combined Ruxolitinib and Thalidomide in Patients with Myelofibrosis: Initial Results of a Phase II Study

Blood ◽

10.1182/blood-2018-99-114125 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 354-354 ◽

Cited By ~ 7

Author(s):

Raajit K. Rampal ◽

Srdan Verstovsek ◽

Sean M Devlin ◽

Eytan M. Stein ◽

Tapan M. Kadia ◽

...

Keyword(s):

Platelet Count ◽

Combination Therapy ◽

Board Of Directors ◽

Phase Ii ◽

Research Funding ◽

Single Agent ◽

Response Assessment ◽

Platelet Response ◽

Advisory Committees ◽

Grade 3

Abstract Background: Among the most frequent and challenging hematologic manifestations of myelofibrosis (MF) are anemia and thrombocytopenia, the presence of which portends an adverse outcome. Few effective modalities to address these cytopenias exist, particularly thrombocytopenia. Further, although the FDA-approved JAK1/2 inhibitor Ruxolitinib (RUX) has demonstrated significant clinical efficacy in MF patients, RUX frequently results in anemia and thrombocytopenia. Thrombocytopenia in particular often results in dose attenuation of RUX. Thalidomide (THAL) is a first-in-class immunomodulatory agent. Studies of THAL in MF patients, alone and with prednisone, have demonstrated improvements in anemia and thrombocytopenia. We therefore sought to examine whether combination of RUX and THAL could result in improvement in both disease-related and therapy-related cytopenias, as well as improve overall disease response in patients with MF. Here we report initial analysis of this study (NCT03069326). Methods: We conducted a multicenter two stage phase II trial designed to assess the effect of RUX and THAL combination in subjects with primary, post-polycythemia vera, or post-essential thrombocythemia myelofibrosis. Patients taking RUX at the time of enrollment must have had less than PR per IWG-MRT/ELN 2013 criteria, or be refractory, to RUX single-agent therapy. Patients must have been taking RUX for a minimum of 3 months, and must have been on a stable dose of RUX for a minimum of 4 weeks immediately prior to enrollment. Treatment-naïve patients received single-agent RUX for 3 months (run-in phase) per label, and went on to combination therapy if they achieved less then a PR per IWG-MRT/ELN criteria. Each cycle of therapy was 28 days. Response assessment was evaluated according to the IWG-MRT/ELN 2013 criteria. Platelet response criteria in patients with baseline thrombocytopenia (less than lower limit of normal) included: Major response (≥75% increase in platelet count), Intermediate Response (≥50% increase) and Minor Response (≥25% increase). Adverse events were assessed using the NCI CTCAE v. 4.0. The primary endpoint was the proportion of treated subjects that achieved a response by IWG-MRT criteria and by platelet response criteria. Results: A total of 25 patients are planned to be accrued. At the time of this writing, a total of 18 patients have been accrued. The median age was 70.5 years (47-85). 8 patients had received prior therapies other than RUX, including imetelstat, momelotinib, danazol, pomalidomide, darbepoetin alpha and sotatercept. 7 patients enrolled to the run-in phase. 14 patients received red blood cell transfusions prior to study enrollment. Evaluation of platelet count in patients with baseline thrombocytopenia demonstrated a significant increase in platelet count at cycle 3 of therapy compared to baseline (Figure 1A and B; P<0.05). An increase in Hgb was observed over successive cycles of combination therapy (Figure 1C and D). 5 of 18 accrued patients completed ≥6 cycles of combined therapy at the time of abstract submission and were thus evaluable for response assessment. The overall response rate in these patients was 80% (4/5 patients). Clinical Improvement (Anemia response and Symptom response) occurred in 3 patients (both responses observed in all 3 patients). Major platelet response was observed in 4 of 5 patients with baseline thrombocytopenia. 1 patient met criteria for spleen response (Table 1). Grade 3/4 non-hematologic adverse events regardless of attribution included; limb edema, diverticulitis, hypertension, syncope. 1 patient experienced a thromboembolic event. 1 patient experienced a grade 3 hematologic AE (neutropenia). Conclusions: The combination of THAL and RUX has demonstrated a promising efficacy signal in this initial analysis of an ongoing phase II study, and appears to be well tolerated. Platelet count increases were observed in all patients who entered study with baseline thrombocytopenia, a response which appears to be maintained in the majority of patients observed 6 months after starting combination therapy. As well, anemia responses were observed in 3 of 5 evaluable patients. Collectively, these data indicate a potential role for this regimen in patients with anemia and/or thrombocytopenia, who otherwise have limited treatment options. Updated data on duration of response and overall response of all accrued patients will be presented. Disclosures Rampal: Constellation: Research Funding; Celgene: Honoraria; Incyte: Honoraria, Research Funding; Jazz: Consultancy, Honoraria; Stemline: Research Funding. Verstovsek:Italfarmaco: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Stein:Celgene: Consultancy; Bayer: Consultancy; Agios: Consultancy; Daiichi Sankyo: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. Kadia:Pfizer: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy; Amgen: Consultancy, Research Funding; Takeda: Consultancy; Takeda: Consultancy; Celgene: Research Funding; BMS: Research Funding; Novartis: Consultancy; Abbvie: Consultancy; Amgen: Consultancy, Research Funding; Celgene: Research Funding; BMS: Research Funding; Jazz: Consultancy, Research Funding; Abbvie: Consultancy; Jazz: Consultancy, Research Funding. Mauro:Bristol-Myers Squibb: Consultancy; Novartis: Consultancy, Research Funding; Pfizer: Consultancy; Takeda: Consultancy. Pemmaraju:SagerStrong Foundation: Research Funding; daiichi sankyo: Research Funding; novartis: Research Funding; abbvie: Research Funding; cellectis: Research Funding; samus: Research Funding; Affymetrix: Research Funding; stemline: Consultancy, Honoraria, Research Funding; celgene: Consultancy, Honoraria; plexxikon: Research Funding. Bose:Blueprint Medicines Corporation: Research Funding; Astellas Pharmaceuticals: Research Funding; Incyte Corporation: Honoraria, Research Funding; Constellation Pharmaceuticals: Research Funding; Celgene Corporation: Honoraria, Research Funding; Pfizer, Inc.: Research Funding; CTI BioPharma: Research Funding.

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A Randomized Phase II Study of Azacitidine Combined with Lenalidomide or with Vorinostat Vs. Azacitidine Monotherapy in Higher-Risk Myelodysplastic Syndromes (MDS) and Chronic Myelomonocytic Leukemia (CMML): North American Intergroup Study SWOG S1117

Blood ◽

10.1182/blood.v124.21.lba-5.lba-5 ◽

2014 ◽

Vol 124 (21) ◽

pp. LBA-5-LBA-5 ◽

Cited By ~ 16

Author(s):

Mikkael A. Sekeres ◽

Megan Othus ◽

Alan F. List ◽

Olatoyosi Odenike ◽

Richard M. Stone ◽

...

Keyword(s):

Bone Marrow ◽

Combination Therapy ◽

Adverse Events ◽

Board Of Directors ◽

Phase Ii ◽

Research Funding ◽

Phase Ii Study ◽

International Prognostic Scoring System ◽

Advisory Committees ◽

N Rates

Abstract Background: Higher-risk MDS and CMML comprise a spectrum of disorders associated with cytopenias, high risk of transformation to acute myeloid leukemia (AML), and truncated survival. Initial treatment with a hypomethylating agent such as azacitidine (AZA) is considered standard of care. Whether addition of the histone deacetylase inhibitor vorinostat (VOR), which acts synergistically with AZA to reactivate epigenetically silenced genes, or addition of lenalidomide (LEN), which impacts the bone marrow microenvironment, improves response rates compared to AZA monotherapy is unknown. Methods: This Phase II study (ClinTrials.gov # NCT01522976) randomized higher-risk MDS (International Prognostic Scoring System (IPSS) Int-2 or High and/or bone marrow blasts >5%) and CMML patients (pts) with <20% blasts to receive AZA (75 mg/m2/d on d1-7 of a 28d cycle), AZA + LEN (10 mg/d on d1-21), or AZA + VOR (300 mg BID on d3-9). Eligibility criteria included: >18 years (yrs), no previous allogeneic transplant, no prior treatment with any of the study drugs, and adequate organ function; therapy-related (t)MDS was allowed. Pts continued treatment until disease progression, relapse, unacceptable toxicity, or lack of response. Dose reductions occurred for unresolved grade >3 adverse events (per NCI CTCAE) or delayed count recovery. The primary endpoint was improvement in overall response rate (ORR), by intention to treat and reviewed centrally, of one of the combination arms vs. AZA monotherapy per 2006 International Working Group MDS response criteria (complete response (CR) + partial response (PR) + hematologic improvement (HI)). Relapse-free survival (RFS) was from time of response. The study had 81% power to detect a 20% improvement in ORR from 35% to 55%. Results: Of 282 pts enrolled from 3/12–6/14, 276 are included in analyses (6 ineligible pts excluded): 92 on the AZA arm, 93 on AZA+LEN, and 91 on AZA+VOR. Baseline characteristics were well-balanced across arms (Table). Pts received a median of 23 weeks of therapy: 25 of AZA; 24 of AZA+LEN; and 20 of AZA+VOR and were followed for a median of 9 months (range: 0-26). Numbers of pts with notable adverse events >grade 3 for AZA:AZA+LEN:AZA+VOR included febrile neutropenia (10:13:13); gastrointestinal disorders (4:11:23); infections (2:3:3); and rash (2:12:1). Responses were assessable in 260 pts (94%). ORR for the entire cohort was 33%: 19% CR, 1% PR, and 13% HI, with a median RFS of 7 months. ORR was similar across study arms: 36% for AZA, 37% for AZA+LEN (p=1.0 vs. AZA), and 22% for AZA+VOR (p=.07 vs. AZA). CR/PR/HI rates across arms were also similar: 23%/0%/13% for AZA; 18%/1%/17% for AZA+LEN (CR p=.47 vs. AZA); and 14%/1%/7% for AZA+VOR (CR p=.18 vs. AZA); rates of bone marrow exams to assess response were 76%, 67%, and 73%, respectively. HI-P/HI-E/HI-N rates were 21%/15%/5% for AZA, 26%/14%/15% for AZA+LEN, and 12%/8%/4% for AZA+VOR. HI-N rates were higher in AZA+LEN vs. AZA (p=.05) but otherwise were similar across arms. Median time to best response across arms was 15 weeks in AZA, 16 weeks in AZA+LEN, and 16 weeks in AZA+VOR. ORR did not vary significantly across arms in subgroup analyses for tMDS, baseline red blood cell (RBC) transfusion dependence, and by IPSS risk group. ORR for CMML pts for AZA:AZA+LEN:AZA+VOR was 33%:53%(p=.15 vs. AZA):12%(p=.41 vs. AZA). Allogeneic transplantation rates were: 7 pts on AZA, 6 on AZA+LEN, and 9 on AZA+VOR. For AZA:AZA+LEN:AZA+VOR, median RFS was: 6:8:11 months (log-rank p=.3 for combination arms vs. AZA, Figure); and for pts on therapy >6 months, it was 7:7.5:13 months (log-rank p=.11 for AZA+VOR, .74 for AZA+LEN vs. AZA). Conclusions: In higher-risk MDS pts, ORR was similar for AZA monotherapy compared to AZA-containing combination arms, though some subgroups may have benefitted from combination therapy. Differences in types of response may have resulted from differential rates of follow-up bone marrow assessments. While a non-significant signal of a DFS advantage for combination therapy was observed, longer-term outcome data are being assessed. Table Table. Figure Figure. Disclosures Sekeres: Boehringer-Ingelheim: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Off Label Use: lenalidomide, vorinostat for higher-risk MDS. List:Celgene Corporation: Consultancy. Gore:Celgene: Consultancy, Research Funding. Attar:Celgene: Consultancy. Erba:Seattle Genetics: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Research Funding; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda Pharmaceuticals International Co.: Research Funding; Astellas Pharma: Research Funding; Celgene: Honoraria, Speakers Bureau.

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A Phase II Study of Ruxolitinib Pre-, during- and Post-Hematopoietic Celltransplantation for Patients with Primary or Secondary Myelofibrosis

Blood ◽

10.1182/blood-2021-146330 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 169-169

Author(s):

Gabriela Hobbs ◽

Haesook T. Kim ◽

AJ S. Bottoms ◽

Michael T. Byrne ◽

Mark A. Schroeder ◽

...

Keyword(s):

Phase Ii ◽

Cumulative Incidence ◽

Interim Analysis ◽

Research Funding ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Free Survival ◽

Grade 3 ◽

Neutrophil Engraftment

Abstract Background: Myelofibrosis (MF) is a lethal hematological malignancy associated with somatic mutations in JAK2, CALR or MPL. Ruxolitinib is the first JAK1/2 inhibitor approved for treatment of MF. Ruxolitinib does not prevent disease progression and thus, allogeneic hematopoietic stem cell transplantation (HSCT) remains the recommended therapy for eligible patients treated with curative intent. Ruxolitinib discontinuation, in preparation for HSCT is challenging as patients experience return of symptoms/splenomegaly. Therefore, ruxolitinib is often continued during and after HSCT in an off-label fashion, yet little is known about the safety of this approach. In addition, ruxolitinib is now utilized to treat steroid refractory acute and chronic graft versus host disease (GVHD) irrespective of underlying disease. Methods: This is a phase II, multi-center, investigator-initiated trial investigating ruxolitinib given pre-, during- and post-HSCT for patients with primary or secondary MF (NCT03427866). The study utilizes ruxolitinib during and after HSCT in MF patients for one year after HSCT. The accrual goal is 48 patients with 1-year GVHD free and relapse free survival (GRFS) as the primary endpoint. Secondary endpoints include overall and progression free survival, engraftment and incidence of acute and chronic GVHD, respectively. Patients are treated with reduced intensity conditioning with fludarabine (30mg/m 2/day x 5 days) and melphalan (100mg/m 2 or 140mg/m 2 x 1). HSCT grafts are with 7/8 or 8/8 HLA-matched peripheral blood stem cells with tacrolimus and methotrexate as standard GVHD prophylaxis. Results: This pre-planned interim analysis includes 26 MF patients who underwent HSCT between September 2018 and January 2021. An interim analysis was included in the trial design to ensure safety of this approach midway through accrual. Median age was 66 (range, 46-75) and 65% were male. 88% had 8/8 matched related grafts, and 92% had intermediate-2 or high DIPSS risk at the time of transplant. 14 (54%) patients were previously treated with ruxolitinib. At HSCT, 58% had JAK2, 12% CALR, 12% MPL, and 35% ASXL1 mutations (Figure A). There were no unexpected toxicities related to ruxolitinib therapy. The most common grade 3/4 hematologic adverse events (AE) were anemia (n=4), thrombocytopenia (n=3). There were few observed grade 3/4 non hematologic AEs and included infection (n=2) and hypertriglyceridemia (n=1). Median time to neutrophil engraftment was 15 days (range 11-38) after HSCT. All but one patient achieved successful neutrophil engraftment. Median day 30 donor all cell chimerism was 100% (range 95-100). Clinical outcomes are summarized in Figure B. With median follow-up among survivors of 12 months (range 3-24), 1-yr GRFS was 65%. OS, PFS, and cumulative incidence of NRM and disease relapse were 77%, 71%, 13% and 17%, respectively (Figure C). There was no grade IV acute GVHD and only one case of grade III acute GVHD. Cumulative incidence of all chronic GVHD and moderate-severe chronic GVHD was 14% and 5%, respectively. There was no severe chronic GVHD and only one patient developed moderate chronic GVHD. As part of the study, next generation sequencing (NGS) was obtained pre- and 100 days post-HSCT. 14 patients have paired samples, including 6 with ASXL1 mutations. All but one patient, who remains in remission at last follow up, no longer had mutations detected by NGS at day 100 (Figure D). Ongoing studies will assess for the presence of low-level mutation not detectable by clinical NGS testing. Discussion: The interim results of our multicenter study demonstrate safety of ruxolitinib administration pre, during and post-HCT with very favorable engraftment rates and no unexpected toxicities of ruxolitinib use. In addition, we demonstrate superior PFS, OS and GRFS compared to historical observations. Incidence of severe acute and chronic GVHD are thus far minimal, indicating excellent GVHD control with prophylactic and continued ruxolitinib use. Figure 1 Figure 1. Disclosures Hobbs: Bayer: Research Funding; Incyte Corporation: Research Funding; Celgene/Bristol Myers Squibb: Consultancy; AbbVie.: Consultancy; Merck: Research Funding; Novartis: Consultancy; Constellation Pharmaceuticals: Consultancy, Research Funding. Byrne: Karyopharm: Research Funding. Defilipp: Incyte Corp.: Research Funding; Regimmune Corp.: Research Funding; Omeros, Corp.: Consultancy; Syndax Pharmaceuticals, Inc: Consultancy. Chen: Gamida: Consultancy; Incyte: Consultancy. OffLabel Disclosure: Will describe the use of ruxolitinib in the ongoing clinical trial.

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An interim analysis of a phase II study of the combination of TACE and sorafenib in patients with unresectable hepatocellular carcinoma in National Cancer Center Korea (COTSUN KOREA, NCT00919009).

Journal of Clinical Oncology ◽

10.1200/jco.2011.29.4_suppl.253 ◽

2011 ◽

Vol 29 (4_suppl) ◽

pp. 253-253 ◽

Cited By ~ 2

Author(s):

J. Park ◽

H. Kim ◽

J. Shim ◽

S. Woo ◽

J. Choi ◽

...

Keyword(s):

Adverse Events ◽

Skin Reaction ◽

Phase Ii ◽

Interim Analysis ◽

Preliminary Evidence ◽

Cancer Center ◽

Close Monitoring ◽

Pugh Class ◽

Grade 3 ◽

Vegfr Inhibitor

253 Background: Transarterial chemoembolization (TACE) is the palliative treatment for patients with unresectable HCC. TACE-induced ischemic injury is known to increase circulating VEGF and related with poor prognosis.The aim of this study is to evaluate efficacy and safety of combined TACE with sorafenib, VEGFR inhibitor in unresectable HCC patients. Methods: This study is a non-randomized, open-labeld, single-arm, phase II investigator-initiated clinical study. Estimated number of subjects was 50 under the assumption of 3.2 months of median time to progression (TTP) with TACE alone. All patients are Child-Pugh class A or superb B. Sorafenib begins to be administered on 3 days after the first session of TACE and will be subsequently administered up to 24 weeks. Efficacy of TACE was evaluated after 4 weeks from TACE by dynamic CT. Repeated TACE is performed “on demand” in case of PR or SD according to CT/MRI evaluation. Results: A total of 50 patients were enrolled for this interim analysis. Male was 84% and mean age was 61.5years. Causes of underlying chronic liver disease were HBV in 28 patients (65.1%). Patients were categorized into modified UICC stage II (15, 30.0%), III (24, 48.0%) and IVA (11, 22.0%). Median follow-up period was 5.3 months (range, 1.0–13.1). The size of index lesions was ranged from 1.0 cm to 13.1 cm, and number of lesions was between 1 and 5. Number of TACE sessions was 1.0 (range, 1–4). Common adverse events (AE) during sorafenib therapy were elevation of serum AST/ALT (96.8%), hypocalcemia (90.0%), thrombocytopenia (84.0%), and hyperbilirubinemia (76.0%). Hand-foot skin reaction was most frequently observed among AE of NCI CTCAE grade 3 or higher (40.0%), followed by elevation of serum ALT (38.0%). Dose reduction of sorafenib was needed most commonly due to hand-food skin reaction (n=29). Median TTP was 5.1 months (range, 3.8–6.3). Conclusions: Adverse events were approved as acceptable by independent monitoring system. Preliminary evidence of antitumor activity was also observed. This trial can be safely performed with close monitoring in inoperable and/or unresectable HCC patients. No significant financial relationships to disclose.

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Combination therapy with vincristine, immunoglobulin and glucocorticosteroid (VIG regimen) is very effective for the management of grade 3/4 or steroid-refractory immune-related adverse events (irAE) secondary to PD-1 blockade.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e14577 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e14577-e14577

Author(s):

Zhan-Hong Chen ◽

Li Wei ◽

Tian-tian Wang ◽

Qu Lin ◽

Xiangyuan Wu

Keyword(s):

Combination Therapy ◽

Adverse Events ◽

Continuous Infusion ◽

Clinical Improvement ◽

Immune Checkpoint ◽

Checkpoint Inhibitors ◽

Inpatient Setting ◽

Improvement Rate ◽

Grade 3 ◽

Steroid Refractory

e14577 Background: The management of grade 3/4 or steroid-refractory immune related adverse events (irAE) is based on a paucity of retrospective data analysis. Our initial experience with the combination therapy with Vincristine (VCR), immunoglobulin (IVIG) and glucocorticosteroid (VIG regimen) showed clinical improvement in a wide variety of irAEs. As a result, we recommend the use of VIG regimen for the management of grade 3/4 or steroid-refractory irAEs. Methods: The character and clinical course of irAEs were abstracted from the medical record and analyzed. The components of VIG regimens are as follows: Methylprednisolone (MP) 2-10mg/kg for 3days, VCR 1.4mg/m2 (≤2mg) continuous infusion for 4-8 hours on day 3 once a week with Immunoglobulin (IVIG) 0.4g/kg for 3-5 days. The dose of MP and IVIG will be reduced quickly after irAE improves. VCR 1.4mg/m2 once a week will be used for 1 to 3 times according to the improvement. Clinical improvement was defined as either: documentation of resolution of symptoms and normalisation of biochemical tests or hospital discharge within 14 days. Results: A total of 25 patients had grade3/4 or steroid-refractory irAEs after receiving immune checkpoint inhibitors and then received VIG regimen. Among them, 22 patients have been significantly improved, with an improvement rate of 88%. Twenty-three patents were treated in the inpatient setting (92%). The index grade 3/4 irAE was pneumonitis in 28%, immune mediated hepatotoxicity(IMH) in 28%, rash/SJS/TEN in 24%, cerebritis in 8 % and one case each of ITP, Near blindness and severe oral mucositis. In 7 patients with severe IMH, the range of total bilirubin was 80-481umol/L and ALT 35-5000u/L. Six patients with IMH recover well but one patient did not recover to normal due to IMH complicated with pneumonitis and TEN . Clinical improvement was noted in 22/25 patients (88%), 11 patients (44%) required a single dose, while 12 patients (48%) required two doses, 2 patients(8%) required three doses of VCR 1.4mg/m2 continuous infusion for 4-8 hours. What is impressive is that the two patients with encephalitis were significantly relieved within 2 weeks after using the VIG regimen. One patient with TEN (SCORETEN 3)was significantly improved and discharged from our hospital 11 days after using the VIG regimen. A patient with near-blind eyesight recovered to normal 3 days after using the VIG regimen. Conclusions: VIG regimen may be an effective therapeutic option for the management of grade3/4 or steroid-refractory irAEs secondary to immune checkpoint blockade. However, randomized trials are needed to better elucidate the efficacy and safety of VIG regimen.

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Bendamustine, Ofatumumab and High-Dose Methylprednisolone (BOMP) in Relapsed/Refractory CLL: Results of a Planned Interim Analysis of the French CLL Intergroup ICLL01 Phase II Trial

Blood ◽

10.1182/blood.v124.21.3341.3341 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3341-3341 ◽

Cited By ~ 3

Author(s):

Sophie de Guibert ◽

Marie-Sarah Dilhuydy ◽

Loic Ysebaert ◽

Laurence Sanhès ◽

Sylvain Choquet ◽

...

Keyword(s):

Adverse Events ◽

Phase Ii ◽

Interim Analysis ◽

Research Funding ◽

Tp53 Mutation ◽

Phase Ii Trial ◽

Risk Group ◽

High Dose ◽

Color Flow ◽

High Dose Methylprednisolone

Abstract Introduction: For relapsed or refractory (R/R) CLL patients (pts), combination of bendamustine and rituximab appears safe and effective (Fischer 2011). Ofatumumab monotherapy gives 58% ORR in heavily pre-treated (median 4 prior lines) R/R CLL pts (Wierda JCO 2010). High doses (HD) steroids are also active in poor prognosis pts with bulky nodal involvement or p53 impairment (Castro 2008, Xu 2010). We report a planned interim analysis of the ICLL01-BOMP phase II trial evaluating the association of Bendamustine, Ofatumumab and high-dose MethylPrednisolone for fit R/R CLL pts after 1-3 previous lines (NCT01612988). Patients and Methods: Primary endpoint was CR rate after 6 cycles (cy) of the BOMP regimen [i.e. bendamustine (70 mg/m2 d1, d2), ofatumumab (1000 mg d1;15 on cy#1-2 and d1 on cy#3-6) and HD methylprednisolone (1 g/m2 d1-3)]. The c#1 was preceded by an ofatumumab (300 mg) prephase. Response evaluation (IWCLL 2008) was done 3 months (m) after the last cy along with blood and bone marrow 10-color flow MRD analysis. Results: Among the 55 pts of this analysis, median age was 64 years (44-76). CIRS-G comorbidity score was 2-6 in 61% and pts had received 2-3 lines in 37% of the cases. Prior FCR-like regimens (50 (91%) patients) had been followed by relapse within 2y in 22/55 and 5/55 pts were fludarabine-refractory (FR). IGVH was unmutated (UM) in (47/52) 90.4%. Karyotypes were complex in 18/46 (39%) cases. Distribution according to FISH hierarchical model was: del(17p) in 15 (27%), del(11q) in 14 (26%), trisomy 12 in 4 (7%), del(13q) in 17 (31%) and normal in 5 (9%). Mutations on the TP53, SF3B1 and NOTCH1 genes occurred in 17 (31%), 14 (26%) and 5 (9%) pts, respectively. According to published risk stratification (Zenz, 2012), 34/55 pts (62%) belonged to the “highest-risk” group with either TP53 disruption (deletion and/or mutation) (n=19) and/or early relapse within 2 years post-FCR (n=22). The remaining patients belonged to either the “high-risk” group (UM-IGVH and/or Highb2mic and/or del11q) accounting for 17 pts (31%) or to the “low-risk” group (or non evaluable) accounting for 4 (7%) pts. Overall, 292 BOMP cy (mean 5.3 cy/pts) were delivered. Safety analysis recorded 158 grade 3-4 adverse events (G3-4/AE) with according to cy: neutropenia: 20.8%, thrombocytopenia: 11.3%, anemia: 2.4%, infection: 5,8%, hyperglycemia: 7,5%, liver enzyme elevation: 1,4%, cutaneous reaction: 1,4%, ofatumumab infusion related reaction: 0,3% and other AE: 3,4%. Overall 43 out of 55 pts (78.2%) had at least one G3-4/AE. Twenty-eight severe adverse events were reported in 20 pts. Treatment interruption before planned 6 cy occurred for pts' decision (n=3), excessive toxicity (n=5) or early progressive disease (PD) (n = 4). Response in the ITT population was 76.4% ORR with 20% CR (n=11), 56.4% PR (n=31 including 5 nPR and 1 CRi), 9.1% stable disease (n=5), 10.9% PD (n=6) and 3.6% (n=3) non evaluable. Blood MRD obtained in 45 pts was negative (<10-4) in 13 (28.8%) cases. Following evaluation, 5 responding pts (9%) had RIC allogeneic (RIC-Allo) transplantation with a persistent remission. With median follow-up of 16.2 (5.1-23.6) months (m) we observed 9 deaths, related to PD (n=5), EBV-induced lymphoproliferation (n=1), PML encephalitis (n=1), sepsis/pancytopenia (n=1) or unknown origin (n=1). We recorded 22 relapses (including 4 Richter Syndromes) resulting in treatment in 17 cases, with a BTK inhibitor in 8 cases. The median OS has not been reached (estimation 84% at 18 m) (Fig 1B). The median PFS was 18.4 m (95%CI, 14.6-22.2) and the median time to next treatment 17.6 m (95%CI, 12.9-22.4). With 5 cases censored at time of RIC-Allo, the PFS (censored analysis) was 17.5 m (95%CI, 13.2-21.8). (Fig 1A) After univariate analysis, ORR was lower in the “highest-risk” (64,6%, p=0.01), del(17p) (40%, p=0.003), TP53 mutation (47.1%, p=0.01) and complex karyotype (61.2%, p=0.024) groups. PFS was shorter in the “highest-risk” (14 m, p=0.046), FR (4.96 m, p<0.001), del(17p) (9.5 m, p=0.017) and TP53 mutation (9.5 m, p=0.007) groups. Conclusion: Relapse treatment of CLL is a challenge especially after prior FCR-like treatments, accounting for >90% of this trial population. These results in terms of response and survival appear noteworthy considering that >60% are “highest-risk” pts. This study provides important information for forthcoming comparison with next emerging CLL therapies. Figure 1 Figure 1. Disclosures de Guibert: Roche: Honoraria. Feugier:Roche: Honoraria. Schuh:Roche, Gilead, GSK, NAPP, Celgene: Honoraria. Leblond:Roche: Honoraria, Speakers Bureau. Tournilhac:mundipharma: Honoraria, Other, Research Funding; GSK: Honoraria, Other, Research Funding; Roche: Honoraria, Other, Research Funding.

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