Common Hematologic Adverse Events Research Articles

Two Year Update of Phase II Trial of Pembrolizumab, Lenalidomide and Dexamethasone As Post -Autologous Stem Cell Transplant Consolidation in Patients with High-Risk Multiple Myeloma

Two Year Update of Phase II Trial of Pembrolizumab, Lenalidomide and Dexamethasone As Post -Autologous Stem Cell Transplant Consolidation in Patients with High-Risk Multiple Myeloma

Results of PAC203: A Randomized Phase 2 Dose-Finding Study and Determination of the Recommended Dose of Pacritinib

Results of PAC203: A Randomized Phase 2 Dose-Finding Study and Determination of the Recommended Dose of Pacritinib

Interim Analysis of Registry of Ruxolitinib Treatment in Patients with Intermediate-2 or High Risk Primary Myelofibrosis (PMF), Post-Polycythemia Vera Myelofibrosis (PPV-MF), or Post-Essential Thrombocythemia Myelofibrosis (PET-MF) in Taiwan

Background Ruxolitinib, an oral JAK 1/JAK 2 inhibitor, has been approved for the treatment of intermediate-2 or high-risk myelofibrosis, including primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (PPV-MF), and post-essential thrombocythemia myelofibrosis (PET-MF) in Taiwan since 2014. This registry aimed to examine the real-world safety profile and treatment pattern of ruxolitinib in Taiwan. Methods This is an observational, multi-center, post-marketing registry study. A total of 98 patients with intermediate-2 or high-risk PMF, PPV-MF, or PET-MF and receiving ruxolitinib (73.5%) or newly initiating ruxolitinib (26.5%) per clinical judgment were enrolled and analyzed in a 2-year follow-up. The primary objective was to collect the safety profile of ruxolitinib under routine practice in Taiwan. Results This interim analysis included results of 98 patients who had received ruxolitinib treatment. The median age was 68.1 years (range, 38 -87 years), 50.0% of patients were male. Of the 98 patients, 51.0% were diagnosed with PMF, 27.1% were PET-MF, and 21.9% were PPV-MF; 70.4% were categorized as Dynamic International Prognostic Scoring System (DIPSS) intermediate-2-risk group and 28.6% were high-risk group when ruxolitinib was initiated. JAK2 mutation was identified in 77.8% of 63 patients examined, while CALR mutation was identified in 6 of the 14 (42.9%) JAK2-unmutated cases. At the time of data cut-off, 23 patients (23.2%) discontinued the study mainly due to death (9.1%), adverse events (2.0%), withdrawal of consent (2.0%), and interruption of ruxolitinib ≥ 3 months (2.0%). The median exposure to ruxolitinib was 14.2 months (range, 0.8 - 37.9 months) from the time of study enrollment. At baseline, 75.4% of patients receiving a starting dose of > 5 - 10 mg bid, 11.2 % receiving > 10 - 15 mg bid, 10.2% receiving 20 mg bid. The prescription appeared to be more conservative than the suggested dose. The dose of 5 - 10 mg bid was prescribed for most patients at study enrollment regardless of different platelet counts (56.5% with platelet counts > 200 × 109/L, 54.5% with platelet counts 100 - 200 × 109/L, 50.0% with platelet counts < 100 × 109/L). The median dose after 6 months was maintained at 10 mg bid. At the time of data cut-off, adverse events (AE) were reported in 77.6% of patients and serious AEs (SAE) observed in 35.7% of patients. The most common non-hematologic AEs (≥ 5% of patients) were infections (pneumonia [9.2%], upper respiratory tract infection [8.2%], urinary tract infection [7.1%]), pyrexia (9.2%), diarrhea (8.2%), hyperkalemia (6.1%), and cough (5.1%). The infections were mainly grade 1/2, without tuberculosis or hepatitis B reactivation reported. Consistent with findings from other ruxolitinib studies, the most common hematologic AEs were anemia (10.2%) and thrombocytopenia (10.2%). However, we observed a lower incidence of anemia and thrombocytopenia compared to other studies (42.2 - 56.3%) and no one discontinued the treatment, indicating that these AEs were tolerable and manageable. Ten patients died but none of them was related to ruxolitinib. Over 48 weeks, ruxolitinib provided a sustained clinical benefit (n = 59), with a significant reduction in MPN-10 total score from 21.4 to 12.0 (P < 0.001). The improvement of symptoms was particularly prominent in naïve patients (change in total score: -12.8, P < 0.001) compared to non-naïve patients (change in total score: -6.1, P = 0.023), especially in itching (-2.7 vs. -0.5, respectively), problems with concentration (-1.8 vs. -0.9, respectively), and filling up quickly when eating (-2.2 vs. -1.1, respectively). In addition, the spleen size was reduced from baseline by 10.9 % in 27 evaluable patients at Week 12 and 16.4% in 13 evaluable patients at Week 24. Conclusions The interim analysis demonstrated that ruxolitinib for patients with intermediate-2 or high-risk myelofibrosis, was well-tolerated in the real-world setting in Taiwan. With a lower starting dose, the incidence of hematological AEs and infection rate appeared to be lower than previous reports. The safety profile was consistent with published data, with neither new safety signal, tuberculosis, nor hepatitis B reactivation detected. Ruxolitinib also provided continuous symptom improvement; however, spleen size reduction, an important goal of ruxolitinib therapy of myelofibrosis, was relatively modest, highlighting the need for dose optimization. Disclosures Hou: Celgene: Research Funding; Abbvie, Astellas, BMS, Celgene, Chugai, Daiichi Sankyo, IQVIA, Johnson & Johnson, Kirin, Merck Sharp & Dohme, Novartis, Pfizer, PharmaEssential, Roche, Takeda: Honoraria. Chen:Novartis: Employment. Lee:Novartis: Employment. Ku:Novartis: Employment.

Interim Analysis of a Phase II Study of the Glutaminase Inhibitor Telaglenastat (CB-839) in Combination with Azacitidine in Advanced Myelodysplastic Syndrome (MDS)

Interim Analysis of a Phase II Study of the Glutaminase Inhibitor Telaglenastat (CB-839) in Combination with Azacitidine in Advanced Myelodysplastic Syndrome (MDS)

Maintenance of Long-Term Undetectable Minimal Residual Disease after Combination of Ibrutinib with Abbreviated Chemotherapy in the Icll-07 Filo Trial

Maintenance of Long-Term Undetectable Minimal Residual Disease after Combination of Ibrutinib with Abbreviated Chemotherapy in the Icll-07 Filo Trial

Comparative Efficacy and Safety of Once Versus Twice Weekly Carfilzomib Based Therapies in Relapsed Refractory Multiple Myeloma- a Systematic Review

Introduction: Carfilzomib use as a single agent or in combination has been shown to improve outcomes in relapsed refractory multiple myeloma (RRMM). Traditionally, carfilzomib has been administered in twice-weekly dosage schemes as compared to the newly approved once-weekly dosage scheme. The once-weekly dosing of carfilzomib is thought to provide same efficacy and has been evaluated in many clinical trials. We have performed a systematic review of comparative efficacy and toxicity profiles of once and twice-weekly carfilzomib dosing schemes in RRMM. Materials and methods: Systematic review was done according to PRISMA statement. PubMed, Embase, AdisInsight, & Clinicaltrials.gov databases were searched, without any filters, using the search terms "Multiple Myeloma" AND "Kyprolis" OR "Carfilzomib". Most recent reports of phase I/II/III clinical trials reporting the clinical efficacy and/or safety of carfilzomib in RRMM were considered for inclusion. After screening of 267 articles, 16 clinical trials (N=2393) evaluating twice-weekly carfilzomib and 4 trials (N=418) evaluating once-weekly dosing schedule were considered for inclusion. Results Once versus (vs.) twice-weekly carfilzomib regimens were evaluated in a total of 406 and 1869 patients, respectively. In our discussion, group-1 refers to patients receiving once weekly carfilzomib while group-2 refers to twice weekly dosing schedule group. For the evaluated population, high risk cytogenetics were reported in 15% (n=60) patients in group-1 and in 17% (n= 317) patients in group-2. The median no. of prior lines of therapy ranged 1-8 in group-1 as compared to 1-20 in group-2. All studies reported the patient responses according to International Myeloma Working Group (IWMG) response criteria. The cumulative overall response rate (ORR) was better in group 1: 70.4% (n= 286) vs. 48% (n= 896). Similarly, more patients in group-1 achieved stringent complete response (sCR) or complete response (CR): 11.5% (n= 47) patients in group 1 vs. 5.2% (n= 99) patients in group 2. The response rates were also non-inferior in group-1 for other responses as overall. In group-1, 30% (n= 123) patients achieved very good partial response (VGPR) compared to 21% (n=389) patients in group-2. The partial response (PR) rate was 28.5% (n= 116) vs. 22% (n= 412) in groups 1 and 2 respectively The rate of minimal response (MR) achievement was comparable in both groups: 5% (n= 21) in group-1 vs. 8% (n= 154) patients in group-2. But lesser proportion of patients in group-1 went on to develop progression of myeloma disease [5.6% (n= 23) vs. 15.6% (n= 293)]. Stable disease (SD) state was achieved by 12.3% (n=50) patients in group-1 compared to 20% (n= 379) patients in group-2. Owing to phase-1 design of most clinical trials evaluating the once-weekly dosing schedule, the survival data is immature at present, but the median progression free survival (PFS) ranged from 1 day to 12.6 months in group-1 while in group 2 it ranged from 3.7-44.4 months. (Table-1) The toxicity profiles were also comparable for both dosing schedules. The most common hematological adverse events (AEs) were anemia and thrombocytopenia and their incidences were 15.7% (n= 64) vs. 25.5% (n= 477) and 13.3% (n= 54) vs. 23.1% (n= 432) in groups 1 and 2 respectively. The most common non-hematological AEs were infections, fatigue, and nausea that were reported in 22% (n= 89), 19% (n= 77), and 17.4% (n= 71) patients in group 1, and 14.5% (n= 272), 19.3% (n= 362), and 19.1% (n= 357) patients in group 2, respectively. Overall, grade 3 or above cardiac AEs were reported in 3.4% (n= 14) patients in group 1 and 3.3% (63/1869) patients in group 2. The most common cardiac AE was hypertension which constituted 50% (n= 7) and 64% (n= 40) of all grade 3 or more cardiac AEs in groups 1 and 2, respectively. Conclusion Achievement of objective response rates for once-weekly carfilzomib appears to be better or at-least similar to twice-weekly carfilzomib regimens. There is paucity of prospective studies comparing once vs. twice-weekly carfilzomib in RRMM which highlights the need for more clinical trials evaluating this regimen. Apart from efficacy and safety profile, once-weekly carfilzomib dosing also carries the potential of becoming a preferred option in terms of lesser financial burden and number of patient visits to the infusion centers. Disclosures Anwer: In-Cyte: Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.

Selinexor, Pomalidomide, and Dexamethasone (SPd) in Patients with Relapsed or Refractory Multiple Myeloma

Selinexor, Pomalidomide, and Dexamethasone (SPd) in Patients with Relapsed or Refractory Multiple Myeloma

Analysis of Predictive Factors for Early Response to Ruxolitinib in 266 Patients with Myelofibrosis from the Polish Adult Leukemia Group (PALG) Registry

Background: Ruxolitinib (RUX), an inhibitor of JAK1/JAK2 kinases, is the only drug approved for the treatment of myelofibrosis (MF). The main clinical effects of RUX therapy include decrease of splenomegaly and reduction of burden of constitutional symptoms. Importantly, predictive factors influencing response and toxicity of RUX are largely unknown. Since 2017 therapy with RUX has been reimbursed in Poland for patients (pts) with MF, and large proportion of these pts has been followed for drug efficacy and tolerance within registry of the Polish Adult Leukemia Group (PALG). Objectives: The primary objective of the study was to identify baseline factors influencing probability of achievement of early response to RUX in MF. Patients and Methods: We retrospectively analyzed outcome of treatment with RUX after 6 months of therapy within the Polish Ministry of Health RUX reimbursement program in pts with primary MF (PMF) and MF secondary to polycythemia vera (post-PV MF) or essential thrombocythemia (post-ET MF). The inclusion criteria to the RUX reimbursement program were as follows: 1) diagnosis of MF confirmed by a recent bone marrow biopsy, 2) intermediate-2 or high risk IPSS, and 3) presence of splenomegaly and constitutional symptoms. Response to RUX was objectively categorized in regard to splenomegaly and MF symptoms. "Spleen Response" was defined as ≥ 50% reduction of the difference between baseline maximal length of spleen and upper limit of normal (120mm) measured by ultrasonography while "Symptoms Response" was defined as ≥50% reduction of the MF constitutional symptoms as assessed by MPN-SAF TSS score. Influence of potential prognostic factors (age, sex, time from MF diagnosis to RUX treatment, PMF vs post-ET MF and post-PV MF, leukocytosis, number of platelets, hemoglobin level, IPSS, DIPSS, grade of fibrosis in bone marrow, genetic status of MF) on probability of response was tested by univariate and multivariate logistic regression. Results: We enrolled 266 MF pts (56.8% PMF, 26.7% post-PV MF, 16.5% post-ET MF) undergoing treatment with RUX in 14 Polish hematology centers. Pts' median age was 67 years (range 21-86), while 59% of the group were females. Thirty-two% of pts were classified as high risk, 56% as intermediate-2 risk and 12% as intermediate-1 risk according to DIPSS score. JAK V617F mutation was found in 83%, CALR in 12%, MPL in 1.5%, and 3.5% of pts were triple negative. The median time from diagnosis of MF to start of RUX therapy was 30 months (range 0-321). At RUX therapy initiation median spleen length was 210 mm (range 100-300), and median symptoms score was 41 (range 4-93). During first six months the therapy has been continued in all but 26 (9.8%) pts in whom the treatment was withdrawn mainly because of lack of effectiveness. The most common hematologic adverse events included anemia (grade ≥3 in 27% of pts) and thrombocytopenia (grade ≥3 in 8% of pts). Major thrombotic events occurred in 3 pts. Among infectious complication 11 upper respiratory tract infections, 4 urinary tract infections, 3 herpes zoster infections, 3 pneumonias of unknown etiology and 1 case of tuberculosis were reported. Regarding the established categories of response to RUX, at 6th month of therapy "Spleen Response" was detected in 50% of patients. The only pre-treatment factor significantly associated with the probability of achievement of "Spleen Response" by multivariable analysis was leukocytosis ≥25 G/L (OR 3.57, 95%CI 1.40-9.06, p=.007). In contrast "Symptoms Response" after 6 months of RUX therapy was found in larger proportion of patients accounting for 77% of the studied population. Multivariable analysis revealed that time-interval between MF diagnosis and RUX start (p=.028) and platelets >200 G/L (OR 2.09, 95%CI 1.16-3.77, p=.014) remained significant predictors of "Symptoms Response". Conclusions: In this study we found that in real life setting efficacy of RUX is more promising, especially in terms of symptoms reduction, and better tolerated, as compared to the results of randomized COMFORT studies. Furthermore, our analysis revealed that simple laboratory parameters such as leukocytosis and platelets number may constitute useful predictors of early response to RUX therapy. Finally, since shorter time interval between MF diagnosis and RUX therapy correlated with better "Symptoms Response", introducing RUX earlier during the course of the disease may be more beneficial for pts. Disclosures Gora Tybor: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Golos:Novartis: Honoraria. Sacha:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Lewandowski:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Niesiobedzka-Krezel:Novartis: Honoraria. Bieniaszewska:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Grzybowska-Izydorczyk:Novartis: Honoraria. Seferynska:Novartis: Honoraria. Patkowska:Novartis: Honoraria. Świstek:Novartis: Honoraria. Jamroziak:Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding.

EPID-07. HEMATOLOGICAL ADVERSE EVENTS IN GLIOBLASTOMA PATIENTS TREATED WITH TEMOZOLOMIDE

Abstract BACKGROUND Temozolomide (TMZ) is the cornerstone for glioblastoma (GBM) treatment. A significant proportion of patients develops hematologic toxicities with limited investigations on outcomes and risk factors for their development. METHODS Our study combines data from the two largest group trials, RTOG 0525 and RTOG 0825, to analyze serious hematologic adverse events (HAE) associated with TMZ therapy for GBM. We analyzed frequency and outcomes of HAE during chemoradiation. RESULTS 1154 patients were evaluated with a median age of 57 years. Over 79% of patients developed HAE during the entire course of GBM treatment. During chemoradiation the most common HAE during chemoradiation was lymphopenia (41.5%), followed by thrombocytopenia (39.0%), and anemia (35.3%). Of these, 34.1% were severe (Grade 3 or 4) and 65.9% were mild (grade 1 or 2). During maintenance the most common HAE was leukopenia (50.7%), followed by neutropenia (50.4%), and lymphopenia (45.3%). MGMT methylation was not associated with HAEs. A history of HAEs during chemoradiation was a protective factor for developing HAEs during maintenance. MGMT methylated and age younger than 50 were protective factors for mortality. Patients that presented HAEs anytime during treatment had a longer overall survival and progression free survival. There was no significant difference in survival between mild or severe HAEs. CONCLUSION HAE are common during chemoradiation with TMZ for GBM, but are more commonly grade 1 or 2 per CTCAE. HAE during GBM treatment is associated with decreased progression free survival and overall survival.

Safety and efficacy findings from the open-label, multicenter, phase 3b, expanded treatment protocol study of ruxolitinib for treatment of patients with polycythemia vera who are resistant/intolerant to hydroxyurea and for whom no alternative treatments are available

Ruxolitinib was recently approved for the treatment of patients with polycythemia vera who are resistant/intolerant to hydroxyurea based on data from the RESPONSE studies. This phase 3b, Expanded Treatment Protocol study (NCT02292446) of ruxolitinib for hydroxyurea-resistant/intolerant patients with polycythemia vera (N = 161: median exposure = 25.1 weeks) further evaluated the safety of ruxolitinib. Adverse events (AEs) led to dose adjustment/interruption in 37.9% of patients and study drug discontinuation in 8.7% of patients. The most common hematologic AEs included anemia and thrombocytosis; while headache and diarrhea were the most frequent nonhematologic AEs. At week 24, 45.3% of patients achieved hematocrit control; hematologic remission was seen in 18% of patients. At least, 50% of reduction in spleen length was achieved in 86.7% of patients from baseline at any time. The observed safety profile of ruxolitinib was consistent and the efficacy results were similar to the observed values in the RESPONSE studies.

Obinutuzumab and ibrutinib induction therapy followed by a minimal residual disease-driven strategy in patients with chronic lymphocytic leukaemia (ICLL07 FILO): a single-arm, multicentre, phase 2 trial

In patients with chronic lymphocytic leukaemia, achievement of a complete response with minimal residual disease of less than 0·01% (ie, <1 chronic lymphocytic leukaemia cell per 10 000 leukocytes) in bone marrow has been associated with improved progression-free survival. We aimed to explore the activity of induction therapy for 9 months with obinutuzumab and ibrutinib, followed up with a minimal residual disease-driven therapeutic strategy for 6 additional months, in previously untreated patients. We did a single-arm, phase 2 trial in 27 university hospitals, general hospitals, and specialist cancer centres in France. Eligible patients were at least 18 years old and previously untreated, and had immunophenotypically confirmed B-cell chronic lymphocytic leukaemia; an Eastern Cooperative Oncology Group (ECOG) performance status score of less than 2; a Binet stage C according to IWCLL 2008 criteria or Binet stage A and B with active disease; no 17p deletion or absence of p53 mutation; and were considered medically fit. In the first part of the study (induction phase), all participants received eight intravenous infusions of obinutuzumab 1000 mg over six 4-weekly cycles and oral ibrutinib 420 mg once per day for 9 months. In part 2, after assessment on day 1 of month 9, patients with a complete response and bone marrow minimal residual disease of less than 0·01% received only oral ibrutinib 420 mg once per day for 6 additional months. Patients with a partial response, or with a complete response and bone marrow minimal residual disease of 0·01% or more, received 6 months of four 4-weekly cycles of intravenous fludarabine, cyclophosphamide, and obinutuzumab 1000 mg, alongside continuing ibrutinib 420 mg once per day. The primary endpoint was the proportion of patients achieving a complete response with bone marrow minimal residual disease less than 0·01% on day 1 of month 16 assessed by intention to treat (ITT). This trial is registered with ClinicalTrials.gov (number NCT02666898) and is still open for follow-up. Between Oct 27, 2015, and May 16, 2017, 135 patients were enrolled. After induction treatment (day 1 of month 9), 130 patients were evaluable, of which ten (8%) achieved a complete response with bone marrow minimal residual disease of less than 0·01% and were assigned to ibrutinib, and 120 (92%) were assigned to ibrutinib plus fludarabine, cyclophosphamide, and obinutuzumab. After minimal residual disease-guided treatment (day 1 of month 16), 84 (62%, 90% CI 55-69) of 135 patients (ITT population) achieved a complete response with bone marrow minimal residual disease of less than 0·01%. The most common haematological adverse event was thrombocytopenia (in 45 [34%] of 133 patients at grade 1-2 in months 1-9 and in 43 [33%] of 130 patients at grade 1-2 in months 9-15). The most common non-haematological adverse events were infusion-related reactions (in 83 [62%] patients at grade 1-2 in months 1-9) and gastrointestinal disorders (in 62 [48%] patients at grades 1 and 2 in months 9-15). 49 serious adverse events occurred, most frequently infections (ten), cardiac events (eight), and haematological events (eight). No treatment-related deaths occurred. Obinutuzumab and ibrutinib induction therapy followed by a minimal residual disease driven strategy is safe and active in patients with previously untreated chronic lymphocytic leukaemia. With longer follow-up, including assessing the evolution of minimal residual disease, if response is maintained, this strategy could be an option in the first-line setting in patients with chronic lymphocytic leukaemia, although randomised evidence is needed. Roche, Janssen.

PB2130 REAL‐WORLD ITALIAN EXPERIENCE OF POMALIDOMIDE IN RELAPSED‐REFRACTORY MYELOMA: RETROSPECTIVE MULTICENTER STUDY BY THE RETE EMATOLOGICA PUGLIESE AND BASILICATA

Background:The POM + LoDEX combination was approved for patients with RRMM who have received at least two prior therapies including lenalidomide and bortezomib.Aims:We report here retrospective analysis of 94 patients with RRMM treated with POM + LoDEX as salvage therapy at 12 hematological centers in the Puglia and Basilicata Network to describe the outcomes and toxicities in a daily practice setting outside clinical trials.MethodsFrom January 2016 to September 2018, 94 patients (60 F and 34 M) were treated in our haematogical Institutions. Sixty‐three patients of them (67%) had relapsed MM and 31 patients (33%) MM refractory to two or more previous treatment lines. The median age was 73 years (range 42‐86). Twenty‐four patients (23,3%) had EMD. Patients received a median 3 previous lines of therapy. The last treatment received was bortezomib‐based regimens in 29% of patients, lenalidomide‐based regimens in 50% of patients, and bendamustine containing regimen in 18% of patients.Results:The median number of cycles administered was 5 (range 1‐27). The ORR was 51%. Higher ORR was recorded in the patient group with relapsed MM compared to those with refractory disease (p &lt;0.05). There were no statistically significant differences in terms of response between patients who had received two or more previous lines of therapy (p NS) and between patients aged over or under 70 years (p 0.25). After median follow‐up of 9.5 months, median TTP and median OS in the ITT population were respectively, 10 months (range 7‐17) and 16 months (range 11‐24). The median TTP was significantly longer in patients who achieved the haematological response (p &lt;0.001) and in patients aged &gt;70 years (p 0.03). The median OS was significantly longer for fit patients (p 0.03). The “disease status”, the “prior exposure to lenalidomide‐based strategies”, the “number of previous lines of therapy” did not influence the TTP and the OS. Multivariate analysis of median TTP identified the “high LDH levels” as negative variable (p &lt;0.001) and the “age &gt;70 years” as positive prognostic factor (p &lt;0.001). Multivariate analysis of median OS identified the “frailty score” and confirmed “high LDH levels” as statistically significant variables (p &lt;0.001). Median TTNT was 30 months (range 18‐30). Neutropenia was the most common hematologic adverse event and occurred in 32% of patients. The most frequent grade 3‐4 non‐haematologic toxicities were fatigue (6%) and infections (4%).Summary/Conclusion:POM + LoDEX resulted in a longer OS and TTP compared to data reported from clinical trials. This advantage was observed mainly in elderly patients and in those with haematologic response and the outcome benefit remained consistent regardless of number of prior and last therapy received. The good toxicity profile and the all‐oral administration of POM + LoDEX make this combination a recommended therapeutic opportunity also in older patients and should be recommended mainly in patients living far from the hospital.

Efficacy and safety of conversion therapy using chemotherapy plus anti-angiogenic therapy in unresectable gastric cancer.

e15510 Background: Conversion therapy has been a promising option for patients with unresectable gastric cancer (GC) (including Phase IV gastric cancer, N3, lymph node fusion and local progression patients). We aimed to investigate the efficacy and safety of S1/oxaliplatin chemotherapy plus apatinib, a novel inhibitor of VEGFR-2, in the conversion therapy for unresectable GC. Methods: This was a single-center, single-arm, open-label study. unresectable GC patients with unresectable factors were eligible for this study. Apatinib (500mg, qd) was administrated continuously, oxaliplatin (130mg/m2) on day 1, and S1 (&lt;1.25m2, 40mg*2/d; 1.25-1.5m2, 50mg*2/d; &gt;1.5m2, 60mg*2/d) on day 1-14 every 3 weeks. Treatment was given for 4-6 cycles preoperatively, but the last cycle did not include apatinib. The primary objective included R0 resection rate and safety profile of preoperative treatment. Results: Total 17 patients were enrolled, the median age was 57 (55.12±10.08) years old. The histological types were mainly signet ring cell carcinoma 10 (58.82%), poorly differentiated adenocarcinoma 5 (29.41%), and moderately differentiated adenocarcinoma 2 (11.76%). Among the 17 patients eligible for preoperative efficacy evaluation, 13 achieved partial response (PR), 3 achieved stable disease (SD), and 1 had progressive disease (PD), the overall response rate (ORR) was 76.5% and disease control rate was 94.1%. Of the 13 pts with PR, 1 refused consents for surgery, 12 patients underwent surgery and 9(75%) achieved R0 resection. During preoperative treatment, the incidence of adverse events (AEs) was 76.5%. The common hematologic AEs were neutropenia (64.7%), leukopenia (64.7%) and hemoglobin decrease (11.8%), and nonhematologic AEs included hyperbilirubinemia (11.8%), hand-foot syndrome (17.6%), oral mucositis (29.4%), fatigue (70.6%), proteinuria (5.9%). Conclusions: Combination of apatinib with S1/oxaliplatin chemotherapy could induce a sufficient conversion rate and achieve a relative high R0 resection rate for initially unresectable GC, with tolerable safety profile. Clinical trial information: ChiCTR-ONC-17010430 trial.

An open label, single-arm, two-stage, multicenter, phase II study to evaluate the efficacy and safety of TLC388 as second-line treatment in subjects with poorly differentiated neuroendocrine carcinomas (TCOGT1Z14).

4101 Background: Therapeutic options for metastatic poorly differentiated neuroendocrine carcinoma (NEC) after prior platinum‐based chemotherapy are unknown. Camptothecin analogs, like topotecan and irinotecan, are approved chemotherapy in small cell lung cancer (SCLC). NEC is considered to have similar biological behavior to SCLC. The aim of this study was to analyze the efficacy of TLC388 (Lipotecan) Hydrochloride, which is a novel camptothecin analog, in pretreated metastatic NEC patients. Methods: This single-arm, 2-stage, phase 2 clinical trial was conducted at 4 community and academic centers in Taiwan. Patients aged 20 years or older enrolled between July 2015 to May 2018 had confirmed metastatic NEC with prior systemic therapy with etoposide plus cisplatin. Patients received intravenous 40 mg/m2 of TLC388 on Days 1, 8 and 15 of a 28-day cycle until disease progression or unacceptable toxic effects. Results: twenty-three patients with a median age of 61 (range, 44-73) years, including 18 men (78%), were enrolled. Patients received a median of 2 (range, 0-6) treatment cycles. Among 20 evaluable patients, three patients showed a stable disease and no patient a complete or partial remission, resulting in a disease control rate of 15%. Median PFS was 1.8 (95% CI, 0.4-15) months and median OS was 4.3 (95% CI, 1.7-15) months. The most common treatment-related hematologic adverse events at grade 3 or higher were leukopenia (22.7%), anemia (31.8%), and thrombocytopenia (18.2%), respectively. Conclusions: TLC388 shows modest antitumor activity in metastatic NEC. Clinical trial information: NCT02457273.

NOVEL-1st: Interim Analysis of a Non-Interventional, Multi-Center Observational Study to Assess the Safety and Efficacy of Nilotinib in Newly Diagnosed Patients with Philadelphia Chromosome Positive (Ph+) Chronic Myelogenous Leukemia in Chronic Phase (CML-CP) in Taiwan

BackgroundThe selective tyrosine kinase inhibitor (TKI) nilotinib has been approved for the treatment of adult patients with newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia in chronic phase (Ph+ CML-CP) globally, including Taiwan. The NOVEL-1st study was conducted to examine the long-term safety and efficacy of nilotinib in this group of patients in routine clinical practice in Taiwan.MethodsThe NOVEL-1st study was a non-interventional, multi-center study. A total of 129 patients with newly diagnosed and previously untreated Ph+ CML-CP were enrolled from 11 centers across Taiwan between January 2013 and June 2016. The follow-up period was 36 months. The primary objective was to collect long-term safety data on nilotinib. Secondary objectives were to evaluate the efficacy of nilotinib by clinical response, disease progression, and survival.ResultsThe median age of the enrolled patients was 49.7 (20.2-89.6) years of whom 58.3% were males. The median duration from CML diagnosis to study enrolment was 25.5 days. Of the 129 enrolled patients, 59 (45.7%) had completed the study, 29 (22.5%) had withdrawn from the study and other patients are still under follow up. The most common reasons included adverse events (AE) (n = 8), discontinuing nilotinib (n = 6), and death (n = 4). All 129 patients were included in the safety analysis, while 122 patients in whom molecular response data were collected were included in the efficacy assessment.At the time of data cut-off, a total of 1,278 AEs were reported by 120 (93.0%) patients, of which 140 (11.0%) AEs in 41 (34.2%) patients were serious and 499 (39.0%) AEs in 40 (33.3%) patients were drug-related. Non-hematological and hematological AEs were consistent with other reports, with no new safety signal detected. Common hematological AEs (incidence ≥ 10 %) included thrombocytopenia (29.5%), anemia (19.4%), and leukopenia (14.0%). Frequent non-hematological AEs (incidence ≥ 10 %) included rash (21.7%), upper respiratory tract infection (19.4%), pruritus (18.6%), cough (17.1%), constipation (14.7%), diarrhea (12.4%), increased alanine aminotransferase (11.6%), increased bilirubin (10.1%), and insomnia (10.1%). Compared to previous studies, we observed lower rates of cardio- or cerebrovascular events (1.6%), fluid retention (2.3%), and hyperglycemia (2.3%) of all grades, but a higher rate of hepatotoxicity (20.9%) was seen in the study population. Five (3.9%) patients expired during the study of whom 2 were due to CML progression.The efficacy outcomes were comparable to other first-line studies of nilotinib. From 3 to 36 months, the rates of clinical response increased over time, from 67.4% to 91.5% for complete hematological response (CHR), 45.0% to 86.0% for complete cytogenetic response (CCyR), 15.5% to 79.1% for major molecular response (MMR), 3.9% to 56.6% for MR4.0 (BCR-ABL ≥ 4 log reduction), and 2.3% to 38.8% for MR4.5 (BCR-ABL ≥ 4.5 log reduction). The median time to CHR, CCyR, MMR, and MR4.0 were 4, 5, 9, and 25 months, respectively (not reached for MR4.5). Early molecular response (EMR), defined as BCR-ABL ≤ 10% at Month 3, was seen in 88.7% of patients. MR4.0 and MR4.5 were significantly higher for patients with deeper EMR, confirming an association between early and long-term deep molecular response. To date, the median OS and PFS were not reached as death and disease progression were only observed in 5 and 2 patients, respectively.ConclusionsThe initial results of NOVEL-1st were comparable to other published first-line studies of nilotinib and demonstrated that nilotinib as a first-line treatment for Ph+ CML-CP patients was well-tolerated and efficacious in the real-world setting. Clinical response was observed as early as 3 months. Early molecular response is a potential predictor of long-term clinical outcome. The final analysis will be conducted when all patients have completed the study. DisclosuresNo relevant conflicts of interest to declare.

Efficacy and Toxicity Profile of Ibrutinib Based Regimens for Refractory Multiple Myeloma: A Systematic Review

BACKGROUND: Despite recent advancements in treatment for multiple myeloma (MM) there is a constant need for newer therapies to tackle the complex issue of relapse and therapy after relapse for patients with MM. Ibrutinib is an oral inhibitor of Bruton tyrosine kinase (BTK), which is overexpressed in the plasma cells. We conducted a comprehensive literature search to analyze the efficacy, dosing and toxicity profile of ibrutinib in relapsed MM.METHODS: Database search using PubMed, EMBASE, Cochrane Library, Web of Science and Clinicaltrials.gov was performed on 06/05/18 (last update) . All clinical trials that used ibrutinib either as monotherapy or in combination regimens in the setting of relapsed and refractory multiple myeloma (RRMM) were included.RESULTS: A total of 388 articles were found on the initial search and after screening, three phase I and II clinical trials qualified for inclusion. Ibrutinib based regimen data (n=155 patients) was analyzed (Table 1). Majority (68%) of the patients were refractory to their previous line of therapy.Ibrutinib Monotherapy: Monotherapy (n=31) with a dose of 420 mg/d to 840 mg/d demonstrated a 0% ORR (overall response rate). A median PFS (progression-free survival) of 0.9 to 2.8 months was noticed with ibrutinib monotherapy. Most common hematological adverse events (HAE) noted were anemia (32%), thrombocytopenia (29%) and neutropenia (13%). All-grade gastrointestinal disturbances (GI) were observed in 90% of cases, fatigue and respiratory infections (RI), each in 39% and muscle spasms in 23% of cases.Ibrutinib + Dexamethasone: The addition of 40 mg dexamethasone to 560 mg/d (n=18) and 840 mg/d (n=43) ibrutinib showed an ORR of 6% and 5% and reported median PFS of 3.7 months and 4.6 months, respectively. Side effects included anemia (26%), thrombocytopenia (23%), and neutropenia (2%). GI toxicity was noted in 82% patients, fatigue in 46%, RI in 15% and muscle spasms reported in 15% patients.Ibrutinib + Carfilzomib: At 560 mg/d dose of ibrutinib, the addition of 27 mg/m2 (n=3) and 36 mg/m2 of carfilzomib (n=5) showed a response of 67% and 40%, respectively. The best response was elicited when 20 mg of dexamethasone was added to 36 mg/m2 of carfilzomib and ibrutinib at a dose of 840 mg/d (n=18; ORR: 71%) and 560 mg/d (n=17; ORR: 71%). The median duration of responses was 12.9 months. Minimal responses were observed in an additional 4 patients giving an overall clinical benefit rate of 76%. At a dose of 36 mg/m2 of carfilzomib, median PFS was reported as 8.1 and 6.4 months at 560 mg/d and 840 mg/d doses of ibrutinib, respectively. Most common HAE were anemia (35%), thrombocytopenia (28%) and neutropenia (9%). Eighty-six percent of patients developed GI disturbances while fatigue and muscle spasms were noted in 53% and 19%, respectively. RI were observed in 51% of patients.Ibrutinib + Bortezomib: The combination of ibrutinib given at 840 mg/d dose with a twice weekly dose of bortezomib 1.3 mg/m2 elicited a response in 46% (n=20) patients, and minimal responses in 4 (21%) patients. Most common GI disturbance was diarrhea (50%). Upper respiratory infections were noted in 30% cases while, asthenia and peripheral edema seen in 20% of cases.Bortezomib/IMiD Refractory Cohort: Patients refractory to prior bortezomib (n=27) showed an encouraging ORR of 73% that was durable for a median of 9.1 months when ibrutinib+carfilzomib+dexamethasone regimen was used. Similarly, another cohort (n=25) of double refractory patients treated with a combination of ibrutinib and dexamethasone demonstrated minimal response in 4 (16%) and disease stabilization in another 5 (20%) patients.High-Risk Cohort: In a population of high-risk cytogenetics (del 17p and/or t[4;14]; n=11) treated with 560 mg/dl to 840 mg/dl of ibrutinib, 36 mg/m2 of carfilzomib and (+/-) 20 mg of dexamethasone showed an ORR of 78%, response was durable for a median of 9.1 months, and achieved a median progression free survival (PFS) of 8.1 months .CONCLUSION: Ibrutinib has demonstrated a promising efficacy (70-80% of ORR in combination regimens) along with an acceptable toxicity profile in the heavily pre-treated and dual drug refractory MM patients. Larger prospective clinical trials are needed to further evaluate its efficacy. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Efficacy and Toxicity Profile of Elotuzumab for Multiple Myeloma: A Systematic Review and Meta-Analysis

Background:Elotuzumab (elo) is a humanized monoclonal antibody, which has been approved by the FDA for use in combination with lenalidomide (lena) and dexamethasone (dexa) in patients (pts) with relapsed and refractory multiple myeloma (RRMM). Elotuzumab is effective as a single agent, as well as in combination for multiple myeloma treatments, supporting the use of elo in pts with RRMM and newly diagnosed multiple myeloma (NDMM) pts.Method:After review of literature using database searches was done on 6/27/18 (Pubmed, Embase, Cochrane Library, Web of Science and Clinical Trials.gov), 9 prospective and 1 retrospective study with 1128 enrolled pts met the inclusion criteria to date in RRMM and 2 clinical trials including 123 pts in NDMM (Table 1). CMA software v.3 was used for meta-analysis. A random-effect model was applied.Result:Regimens used in RRMM: Based on pooled analysis (95% CI), an overall response rate (ORR) of 66% (54-76.2) was calculated in 685 evaluable pts treated with elo based regimens in RRMM (Figure 1). Most common grade (G) ≥ 3 hematological adverse events (HAE) and non-hematological adverse events (NHAE) based on regimen were calculated using pooled analysis in RRMM pts (Table 2). Anemia was noted in 12.1% ( 7.7-18.6) in 559 pts, while neutropenia in 14.5% (7.5-26.4) out of 591 pts and thrombocytopenia (tcp) in 11.9% (7.9-17.4) in 198 evaluable pts. Diarrhea 5.5% (3.6-8.3), pyrexia 2.4% (1.5-4), peripheral neuropathy (PN) 8.4% (3.8-17.8) were measured in 626, 668 and 143 pts respectively.Elotuzumab as monotherapy: 1 study (n=34) evaluated the efficacy of elo as single agent in RRMM. The median age, time from diagnosis and number of prior therapies were 64.5 years (y) (46-87), 4.4 y (0.9-12.8) and 4.5 y (2-10) respectively. It produced an ORR of 1.4% (0.1-19.1 95% CI) in 34 evaluable pts. Adverse events recorded were pyrexia and fatigue in 17.6% and 8.8% pts respectively.Elotuzumab in two drug regimen: In RRMM, 2 clinical trials (n=49) evaluated the efficacy (95% CI) of elo, ORR of 25% (4.1-72.3) was calculated. The best PFS (progression free survival) produced was in combination of elo 20 mg with bortezumib (bort) 1.3mg/m2 of 9.46 months as compared to 1.8 months when elo10mg/kg + dexamethasone (dexa) 28mg was used. In our analysis for safety, common G≥ 3 HAE calculated were, thrombocytopenia 8.7% (3.3-21.1) n=49, neutropenia 10.7 % (3.5-28.4) n=28 pts and anemia 7.1% (1.8-24.5) n=28 pts. NHAE included diarrhea 1.7% (0.1-22.3), PN 10.7% (3.5-28.4), pyrexia 1.7% (0.1-22.3) in 28 evaluable pts each.Elotuzumab in three drug regimen: In RRMM, 10 clinical trials including 602 pts evaluated the efficacy of elo as a part of triple drug regimen, producing an ORR of 72.2% (54-76.2). The best results were produced with the combination of elo 10-20mg/kg + lenalidomide (lena) 25mg + dexa 40mg producing a PFS of 32.2 mo and 28.62 mo in its phase I and II cohorts respectively. Based on pooled analysis (95% CI) common HAE calculated were neutropenia 17.5% (7.6-35.4) in n=563, thrombocytopenia 12.7% (8.2-19.4) in n=149 and anemia 13% (8-20.5) in n=531 pts. Common G ≥ 3 NHAE estimated were diarrhea 5.7% (3.7-8.6), PN 6.6% (2-19.2), pyrexia 2.5% (1.5-4.1) in 598, 115 and 640 pts respectively.Elotuzumab based regimen in NDMM: A currently ongoing clinical trial NCT02272803 has produced promising results in NDMM pts. As a part of three drug regimen with dose of elo 10mg/kg-20mg/kg, lena 25mg, dexa 20mg in 40 pts produced an ORR of 87.5% (73.2-95.8) versus control group of lena 25mg plus dexa 40mg in 42 pts with an ORR of 73.8% (58-86.1). The PFS rate recorded at 1 year was 93% (79-98%) and 91% (73-97%) respectively. The HAE G ≥ 3 included, neutropenia 18% and leukopenia 15%. In another study with 41 pts, elo was used in combination with lena, bort and dexa producing an ORR of 100% and greater than grade 3 adverse events including Tcp 15%, PN 2%.Conclusion:Results produced in our study suggest that elotuzumab is highly effective when used in pts with RRMM and NDMM. Combination regimens for elo produces an ORR ranging from 79-83% with elo + lena+ dexa, proving that the best results were produced by three drug regimens. Large prospective studies are required to evaluate efficacy and safety of elotuzumab in combination therapies. DisclosuresNo relevant conflicts of interest to declare.

Brief report: Clinical experiences after emergency use of daratumumab monotherapy for relapsed or refractory multiple myeloma in real practice.

Despite the recently reported efficacy of daratumumab monotherapy for patients with relapsed or refractory multiple myeloma, outcomes in real practice following daratumumab monotherapy have yet to be investigated. A multi-center retrospective study of 16 Korean patients receiving daratumumab monotherapy for relapsed or refractory multiple myeloma was conducted. The overall response rate was 56.3%. Three patients with creatinine clearance <30 ml/min even achieved an overall response. The median progression-free survival was 2.7 months with 28.9% (95% CI, 9.0-52.8) of 6-month progression-free survival. All infusion-related reactions, including ≥Grade 3 back pain (6.3%) and dyspnea (6.3%), were manageable. The most common hematologic and non-hematological adverse events were anemia (62.5%) and upper respiratory infection (43.8%). ≥Grade 3 bacterial infectious adverse events were identified, including upper and lower respiratory infection (12.5% and 18.8%) and death following sepsis (6.3%). We observed acceptable outcomes of daratumumab monotherapy on relapsed or refractory multiple myeloma patients including even a few subjects with high comorbidity, despite relatively frequent infectious adverse events.

Nab-Paclitaxel and Gemcitabine as First-line Treatment of Advanced or Metastatic Cholangiocarcinoma

Gemcitabine with platinum has limited efficacy for treatment of advanced cholangiocarcinoma, necessitating an evaluation of alternative drug combinations. Recent evidence suggests that paclitaxel may potentiate gemcitabine activity. To evaluate whether gemcitabine plus nanoparticle albumin-bound (nab)-paclitaxel is safe and effective for treatment of advanced cholangiocarcinoma. This single-arm, 2-stage, phase 2 clinical trial was conducted at 23 community and academic centers across the United States and Europe. Patients aged 18 years or older enrolled between September 2014 and March 2016 had confirmed advanced or metastatic cholangiocarcinoma without prior systemic therapy, and had an Eastern Cooperative Oncology Group Performance Status score of 0 to 1 and a Child-Pugh score less than 8. Previous surgery, radiation, or liver-directed therapies were permitted. Patients received intravenous nab-paclitaxel, 125 mg/m2, followed by gemcitabine, 1000 mg/m2, on days 1, 8, and 15 of each 28-day treatment cycle until disease progression or unacceptable toxic effects. The primary outcome was improvement in 6-month progression-free survival (PFS) rate (null and alternative hypotheses of 55% and 70%, respectively) in the evaluable population. Secondary outcomes included median overall survival (OS), PFS, time to progression, best overall response rate, disease control rate, safety and toxicity, and association of change in carbohydrate antigen 19-9 with survival. Seventy-four patients with a median age of 62 (range, 36-87) years, including 44 women (60%), were enrolled. Patients received a median of 6 (range, 1-18) treatment cycles, and the median follow-up was 10.2 (range, 0.6-27.3) months. The observed 6-month PFS rate of 61% (95% CI, 48%-73%) did not favor the alternative hypothesis. Median PFS was 7.7 (95% CI, 5.4-13.1) months, median OS was 12.4 (95% CI, 9.2-15.9) months, and median time to progression was 7.7 (95% CI, 6.1-13.1) months. The confirmed best overall response rate and disease control rate were 30% and 66%, respectively. Hazard ratios for an association between a change in serum carbohydrate antigen 19-9 and median PFS as well as median OS were 2.02 (95% CI, 0.86-4.75) (P = .10) and 1.54 (95% CI, 0.64-3.71) (P = .34), respectively. The most common treatment-related hematologic and nonhematologic adverse events at grade 3 or higher were neutropenia (43%) and fatigue (14%), respectively. Although the trial did not meet its primary efficacy end point, the results indicate that a nab-paclitaxel plus gemcitabine regimen was well tolerated and may be an alternative option to current therapeutic approaches for advanced cholangiocarcinoma. ClinicalTrials.gov identifier: NCT02181634.

Analysis of the activity and safety of weekly low-dose bevacizumab-based regimens in heavily pretreated patients with metastatic breast cancer.

BackgroundCurrently, there are no standard regimens for metastatic breast cancer patients (MBC) who have failed ≥ 3 chemotherapy treatments. The aim of this study was to assess whether weekly low‐dose bevacizumab‐based regimens were well tolerated and would improve efficacy in MBC patients who had failed numerous therapies.MethodsSeventeen patients with MBC who were heavily pretreated with a median of five regimens of therapy (range 1–10) between 2012 and 2016 were included in the analysis. Bevacizumab was administered at a dose of 100 mg intravenously once a week combined with one or two types of chemotherapeutic drugs until confirmed disease progression or an intolerable adverse event was observed. Patient characteristics, objective response rate, clinical benefit rate, progression‐free survival, and toxicity were assessed.ResultsAll 17 patients had been pretreated with taxane‐based and anthracycline‐based chemotherapy. Weekly low‐dose bevacizumab combined with one or two types of chemotherapeutic drugs, which had usually not been previously used (e.g. etoposide, irinotecan, pemetrexed, methotrexate, and nab‐paclitaxel), was administered. Three patients achieved a partial response, while one had stable disease for > 24 weeks, and the clinical benefit rate was 23.5%. Median progression‐free survival was 3.4 months (95% confidence interval 2.0–4.8). The most common hematological adverse events were neutropenia, anemia, and thrombocytopenia. Bevacizumab‐related adverse events included grade 1 bleeding (17.6%) and grade 2 hypertension (5.9%).ConclusionsWeekly low‐dose bevacizumab combined with chemotherapy shows a relatively favorable clinical response and tolerable toxicity, providing a feasible option for heavily pretreated MBC patients.