ALBERT

Description: Background Nowadays, the best evidence for symptomatic patients with Multiple Myeloma (MM) is initial induction therapy with more than two drugs that contains bortezomib. If patients are eligible it is established the use of high dose chemotherapy and autologous stem cell transplantation (ASCT). We do not have to prescribe in Brazilian public health service, due to economic reasons, new drugs such as: bortezomib and lenalidomide. On the other hand, it is known that Cyclophosphamide, thalidomide and dexamethasone (CTD) regimen is an effective primary therapy for MM and it is widely used in some countries such as United Kingdom. We have been prescribing for first line therapy CTD regimen in our clinical practice for approximately 4 years. Thus, we performed a retrospective analysis of patients with MM treated with CTD regimen in the Instituto do Câncer do Estado de São Paulo. Here we present response rate, reduction dose rate, toxicity rate and progression free survival (PFS) and overall survival (OS). Patients and Method We studied 71 patients that were submitted as first line treatment CTD, during 2006-2012. This regimen consists: Cyclophosphamide 500mg orally on days 1, 8, 15; Thalidomide 100mg orally on days 1 to 28 and Dexamethasone 40mg orally on days 1 to 5 and 14 to 18, every 30 days. To sensitive and eligible patients, we have submitted them for  ASCT. PFS and OS were calculated by the Kaplan-Meier method. PFS was calculated from the start of treatment until progression or death or last follow-up and OS until death or last follow-up. GraphPad Prism (v5.0) software was used for statistical calculations, and P values 〈 0.05 were considered to be statistically significant. Results In the 71 patients, 54.2% were male patients, the median age was 57.81 years old (± 7.96). Out of the 71 patients (78.7%), were classified by Durie Salmon staging as IIIA or IIIB and 30% presented stage III for the International Staging System (ISS). Fifty seven (80.2%) were considered eligible for ASCT in the beginning of treatment. Moreover, the evidences of end-organ damage felt related to the plasma cell disorder were: lytic lesions 78.6%; anemia 51.4%, renal failure 20% and hypercalcemia 11.4%. The median of CTD cycles prescribed was 6.44 (± 2.62) and 47.1% were treated in the beginning without adjustment doses. It was evidenced 5.63% deaths related to the treatment. It was observed adjustment doses after 1st cycle in 35.7% of patients due to: peripheral neuropathy 36%, tremor 16%, thrombosis 12%, bradycardia 12% and others 24%. It was observed in 71 patients: 6 (8.45%) stable disease (SD); 4 (5.63%) progressive disease (PD); 26 (36.66%) partial response (PR); 15 (21.1%) very good partial response (VGPR) and 16 (22.53%) complete response (CR), it was not possible to analyze 4 (5.63%) patients due to death. Of total eligible patients to ASCT, 57.62% were submitted for ASCT and in this moment 6.7% have been preparing for ASCT. The median of PFS was 29.2 months (CI 95% 0,22-0,66) and  median of OS was not achieved. It was observed difference in OS between patients with stage III for the ISS: 28,92 months versus (vs) patients with stage I and II median not reached, p = 0.0105. PFS study demonstrated curves that patients responding to CTD at least VGPR (VGPR+CR) presented better median PFS 37.48 months than others patients (PR+PD+SD) 17.93 months, p=0.0018.  Only patients that presented PD and SD response to CTD had a significantly shorter OS median 19.21 months than patients responses at least PR (PR+VGPR+RC) median was not reached, p 〈 0.0001. Conclusion We conclude that CTD is a feasible regimen where is not possible to prescribe new drugs, with acceptable toxicity. Moreover, patients that presented at least VGPR and at least PR to CTD demonstrated better PFS and OS, respectively. Disclosures: No relevant conflicts of interest to declare.

Description: Several trials have demonstrated the feasibility of discontinuation of tyrosine kinase inhibitors (TKI) treatment in chronic myeloid leukemia (CML) patients (pts) with deep molecular response. Aims: to report the results of two Brazilian imatinib (IM) discontinuation trials and to evaluate factors impacting in treatment-free remission (TFR) and treatment-free survival (TFS) after IM discontinuation. Methods:Between September 2016 and January 2019, 60 CML pts were included in two ongoing phase II, single arm, prospective Brazilian discontinuation trials: Pilot Study of Discontinuation in Patients With Chronic Myeloid Leukemia With Deep Molecular Response - Evaluation of Pioglitazone in Treatment-free Remission (TFR) (EDI-PIO UNICAMP)(NCT02852486)and Imatinib Discontinuation in Patients With Chronic Myeloid Leukemia Chronic Phase With Sustained MR4log(USP) (NCT03239886). Inclusion criteria: age 〉18 years, chronic phase, minimum of 3 years of IM therapy, deep molecular response for ≥ 2 years (confirmed by 4 tests in the last 2 years, defined as MR4.0 in USP trial and MR4.5 in EDI-PIO). Patients participating in EDI-PIO trial used pioglitazone 30 mg/day plus IM for 3 months before IM discontinuation (n=30). After discontinuation, pts were monitored by quantitative RQ-PCR monthly in the first year, every 2 months in the second year and every 3 months in the third year. Criteria for IM re-initiation: loss of MMR (in one test), loss of cytogenetic response, loss of hematologic response, disease progression or confirmed loss of MR4.0 (this criteria used only in EDI-PIO trial). TFR was calculated from the date of discontinuation until first event (loss of MMR; IM reintroduction; death any cause or last follow-up); TFS was calculated from the date of IM discontinuation until reintroduction or last follow-up (censoring deaths not related to CML). Adverse events after IM discontinuation were reported according to CTCAE. Results:Data cut-off for analysis was February 2019. In the 1stanalysis 48 pts who discontinued IM in MR4.5 were analyzed. Patient's characteristics from EDIPIO (n=30) and USP (n=18) trials were: 57% vs. 67% male, median age of 55 (29-77) and 56 (33-95) years (29-95) at discontinuation; 16% and 33% had used previously Interferon; median duration of IM treatment of 10 (3-16) vs. 10 (5-15) years; median duration of MMR 95 (30-149) vs. 93 (57-130) months; MR4.0 was 90 (26-135) vs. 89 (30-123) months; and MR4.5 was 76 (23-135) vs. 75 (30-102) months; none variable had statistical difference.One patient died in MMR due to cardiac failure. TFR was 61% (95% CI 47-75) at 20 months. Sixteen (33%) out 48 re-initiated IM (2 with confirmed loss of MR4.0 and 14 with loss of MMR) in a median time of 20 (1-26) months. All relapsed pts recovered MMR after IM reintroduction, in a median time of 2 months (0-4). There was no transformation to advanced phases. No serious adverse events were reported during pioglitazone treatment. In the Cox regression the duration of MMR was associated with a longer TFR HR: 0.96 (beta-) (CI 95%:0.94-0.99, P= 0.006). Gender, age at diagnosis, age at discontinuation, treatment with pioglitazone, Sokal and EUTOS scores, BCR-ABL transcripts type, duration of IM therapy, duration of MR4.0 and MR4.5 and previous use of Interferon did not affect TFR.In the second analysis all 60 pts were included. TFS was 56% and was higher in pts who discontinued IM in sustained MR4.5 vs. MR4.0 (63% vs. 33%, P=0.04)(Figure). The independent factors for TFR in the multivariate analysis by Cox-regression were the duration of MMR [HR: 0.97 (beta-), 95%CI: 0.95-0.98, P=0.001] and intermediate/high risk Sokal [HR 3.14 95%CI: 1.08-9.11, P= 0.035]. Twenty-four out of 60 pts (40%) re-initiated IM (2 with confirmed loss of MR4.0 and 22 with loss of MMR).Adverse events occurred in 38 (63%) pts, 30% attributed to withdrawal syndrome. Some pts presented more than one event. Grade 1-2: arthralgia or muscular pain (17), hyperglycemia (4), hypertriglyceridemia (2), polycythemia (2), hypertension (3), and others (11). Four pts had grade 3-4 event: arthralgia (1), death for cardiac failure (1), abortion and hypertriglyceridemia (1). Conclusions:both trials demonstrated the feasibility and safety of IM discontinuation in pts in sustained deep molecular response. The duration of MMR was associated with a higher TFR and TFS rate. Imatinib discontinuation was more successful in pts in stable MR4.5. Figure Disclosures Pagnano: Pint Pharma: Consultancy; Abbvie: Consultancy; Sandoz: Consultancy. Delamain:Novartis: Honoraria.

Description: Objectives: To estimate the savings and opportunity costs of nilotinib considering treatment free remission after 2nd line treatment of chronic myeloid leukemia (CML) with Nilotinib to fund BCR-ABL molecular test under the Brazilian public healthcare system (SUS) perspective Materials and methods: A budget impact analysis was developed to estimate the savings for the public health system with TFR eligible patients. ENESTop (Mahon FX et al., 2018), an ongoing, single-arm, phase 2 study is the first trial specifically evaluating treatment-free remission (TFR; ie, stopping tyrosine kinase inhibitor [TKI] treatment without a loss of response) in patients with chronic myeloid leukemia in chronic phase (CML-CP) who achieved a sustained deep molecular response after switching from imatinib to nilotinib. In this trial, patients using nilotinib, who had 4.5 log molecular response after at least 24 months of Nilotinib treatment after switching from imatinib, entered into 12 months of consolidation phase and if they maintain MR 4.5 log response (77%), treatment was discontinued as planned in study protocol (57.9% TFR rate at 48 weeks - primary endpoint). A systematic review of the literature was developed over the efficacy of the use of nilotinib in 2nd line for patients diagnosed with CML. Efficacy data used to input the economic model is informed in a published randomized controlled clinical trial (ENESTcmr trial, Hughes TP et al., 2015), a 48 month, open-label, randomized, phase 3 study designed to investigate whether patients with complete cytogenetic response but persistent minimal residual disease on long-term imatinib ( ≥ 2 years prior imatinib) could achieve MR 4.5 log response by switching from imatinib to Nilotinib 400 mg BID. In this study, 33%, 42%, 46% and 52% of patients achieved 4.5 log molecular response by 12, 24, 36 and 48 months of nilotinib treatment after switching from imatinib. The total annual cost in 2017 with nilotinib was extracted from an official Brazilian database (http://paineldeprecos.planejamento.gov.br). Results: Considering that MR 4.5 log response patients will start consolidation in the first year, the economic impact will reduce in BRL 7,2M in the second year year, reaching a saving of BRL 11,4M in the fifth year. The total accumulated saving for the Brazilian public system (SUS) in 5-years was over BRL 38,1M. We also evaluated the necessary investments on BCR-ABL monitoring tests for all CML patients in the public market, as this test is not reimbursed by Brazilian public healthcare system (SUS). We estimated a budget impact of BRL 4.5M per year considering an average of 2 monitoring tests per patient, thus in 5 years an investment of 22,5M in BCR-ABL would be necessary. Discussion: The deep molecular response (MR 4.5 log) in may lead to patient discontinuation in those patients achieving 4.5 log molecular response after at least 24 months of nilotinib treatment and maintaining this response after 12 months. Furthermore, the possibility of TFR with nilotinib will save resources in health sytems allowing to invest in other needs. As demonstrated in this study, savings generated by nilotinib in 2nd line considering the possibility of TFR could allow the incorporation of BCR-ABL test for all CML patients in the public health system (SUS), which is essential in the current management of CML. Conclusion: Nilotinib in 2nd line treatment may generate savings for the public healthcare system (SUS) that could fund the BCR-ABL test for all CML patients. Disclosures Vivona: Novartis: Employment. Leite:Novartis: Employment. Matsuo:Novartis: Employment. Teich:Novartis: Consultancy.

Description: Erdheim-Chester disease (ECD) is a rare histiocytosis that was recently recognized as a neoplastic disorder owing to the discovery of recurrent activating MAPK (RAS-RAF-MEK-ERK) pathway mutations. Typical findings of ECD include central diabetes insipidus, restrictive pericarditis, perinephric fibrosis, and sclerotic bone lesions. The histopathologic diagnosis of ECD is often challenging due to nonspecific inflammatory and fibrotic findings on histopathologic review of tissue specimens. Additionally, the association of ECD with unusual tissue tropism and an insidious onset often results in diagnostic errors and delays. Most patients with ECD require treatment, except for a minority of patients with minimally symptomatic single-organ disease. The first ECD consensus guidelines were published in 2014 on behalf of the physicians and researchers within the Erdheim-Chester Disease Global Alliance. With the recent molecular discoveries and the approval of the first targeted therapy (vemurafenib) for BRAF-V600–mutant ECD, there is a need for updated clinical practice guidelines to optimize the diagnosis and treatment of this disease. This document presents consensus recommendations that resulted from the International Medical Symposia on ECD in 2017 and 2019. Herein, we include the guidelines for the clinical, laboratory, histologic, and radiographic evaluation of ECD patients along with treatment recommendations based on our clinical experience and review of literature in the molecular era.

Description: Introduction: Extranodal natural killer/T cell lymphoma (ENKTL) nasal type is a rare and highly aggressive subtype of lymphoid neoplasia, with a characteristic epidemiology, predominating in the Asian population and some sites in Latin and Central America. Diagnostic pitfalls and the lack of large randomized trials partly explain the unsatisfactory outcomes reported, even with the recent advances such as the incorporation of asparaginase in the frontline regimens and the description of new prognostic factors. Since few reports from Latin America and non-Asian population are available, we conducted this retrospective study to evaluate clinical characteristics and outcomes in a Brazilian referral center. Methods: This is a retrospective single-center study, conducted in an academic center in Brazil. All patients diagnosed with ENKTL from May 1993 to March 2019 were included. Staging was performed according to Ann-Arbor classification. Patients were treated based at discretion of the physician. Survival analysis was performed using the Kaplan-Meier method and log-rank test for comparison. Cumulative incidence of relapse (CIR) was calculated using death as a competitor. Results: A total of 37 patients with ENKTL was included. Median age was 46 years (range, 18 - 84), with male predominance (54%) and Caucasian ethnic majority (87%). Localized disease (Stages I and II) was predominant (81%) and five cases of primary extranasal disease were found. Skin was the most frequent extranasal site affected (60%). Five patients had central nervous system (CNS) disease (3 at diagnosis and 2 during progression/relapse). Tumor site infection at diagnosis was documented in 74%. Only six patients had EBV viral load available at diagnosis, with an median of 650 copies/ml (range, 482 - 997). Other features are summarized in Table 1. Five patients did not receive any regimen (3 subjects died from sepsis before treatment and 2 received only supportive care). Among the treated patients, anthracycline-based regimens (CHOP-like including or not methotrexate) were the most common regimen (16/32, 50%), followed by concomitant chemotherapy/radiotherapy (CCRT) strategy (8/32, 25%). Asparaginase was included in the treatment in 16% of cases (5/32) and 9% received isolated radiotherapy (RT) (3/32). RT was performed in 81%, mostly using sequential strategies (61%). Incidence of febrile neutropenia and grade 3/4 mucositis during treatment was 88% and 65%, respectively. Complete response (CR) rate after the first-line regimen was 62.5% (95% confidence interval [CI]: 43.7 - 78.3) and primary refractory disease was found in 18.7%. Regarding the patients who achieved CR, 5-year CIR was 19.1% (95% CI 6.6 - 36.4). Autologous stem cell transplantation (ASCT) was performed in two cases after achieving a second CR. Median follow-up was 8.7 years, with 5-year OS of 45.9% (95% CI: 31.4 - 67.1) for all patients and 53.9% (95% CI: 38 - 76.5) among the treated group (Figure 1). Albumin level (

Description: Introduction: Asciminib, unlike all approved TKIs that bind to the ATP site of the BCR-ABL1 oncoprotein, is a first-in-class STAMP (Specifically Targeting the ABL Myristoyl Pocket) inhibitor with a new mechanism of action. BOS, an ATP-competitive TKI, has shown clinical efficacy in pts who received ≥2 TKIs and in newly diagnosed CML, in prospective clinical trials. We asked if asciminib could provide superior efficacy to BOS beyond 2nd line, based on the clinical activity of asciminib monotherapy in heavily pretreated pts with CML in a phase 1 study. Methods: Adults with CML-CP previously treated with ≥2 TKIs were randomized 2:1 to asciminib 40 mg twice daily (BID) or BOS 500 mg once daily (QD). Randomization was stratified by major cytogenetic response (MCyR; Ph+ metaphases ≤35%) status at baseline. Pts intolerant of their most recent TKI were eligible if they had BCR-ABL1IS 〉0.1% at screening (19 pts with BCR-ABL1IS 10% or Ph+ 〉65% after 6 months of therapy (asciminib 10.8%, BOS 25.0%). Among the 24 pts who discontinued BOS due to lack of efficacy, 22 switched to asciminib. At baseline, ≥1 BCR-ABL1 mutation was present in 12.7% pts on asciminib (most common: F359C/V) and 17.1% on BOS (most common: M244V, F317L). Median duration of follow-up was 14.9 months from randomization to cutoff. Median duration of exposure was 43.4 wks (range, 0.1-129.9) for asciminib and 29.2 wks (range, 1.0-117.0) for BOS; median relative dose intensity was 99.7% (87-100) and 95.4% (74-100). MMR rate at 24 wks was 25.5% with asciminib and 13.2% with BOS, meeting the primary objective. The between-arm common treatment difference for MMR at 24 wks, after adjustment for MCyR status at baseline, was 12.2% (95% CI, 2.19-22.3: 2-sided P=.029). Among those pts who achieved MMR, median time to MMR was 12.7 wks and 14.3 wks with asciminib and BOS, respectively. At 24 wks, more pts on asciminib (17 [10.8%] and 14 [8.9%]) than on BOS (4 [5.3%] and 1 [1.3%]) achieved deep molecular response (MR4 and MR4.5, respectively). CCyR rate at 24 wks was 40.8% with asciminib vs 24.2% with BOS. Preplanned subgroup analysis showed that the MMR rate at 24 wks was superior with asciminib than BOS across most major demographic and prognostic subgroups, including in pts who received ≥3 prior TKIs, in those who discontinued the prior TKI due to treatment failure, and regardless of baseline cytogenetic response (Figure). Grade ≥3 adverse events (AEs) occurred in 50.6% and 60.5% of pts receiving asciminib and BOS, respectively. The proportion of pts who discontinued treatment due to AEs was lower with asciminib (5.8%) than BOS (21.1%). Grade ≥3 AEs and AEs requiring dose interruption and/or adjustments were reported less frequently with asciminib than BOS (Table 2). Most frequent grade ≥3 AEs (occurring in 〉10% of pts in any treatment arm) with asciminib vs BOS were thrombocytopenia (17.3%; 6.6%), neutropenia (14.7%; 11.8%), diarrhea (0%, 10.5%), and increased alanine aminotransferase (0.6%, 14.5%). On-treatment deaths occurred in 2 pts (1.3%) on asciminib (ischemic stroke and arterial embolism, 1 pt each) and 1 pt (1.3%) on BOS (septic shock). Conclusions: In this first controlled study comparing treatments for resistant/intolerant (R/I) pts with CML, asciminib, a first-in-class STAMP inhibitor, demonstrated statistically significant and clinically meaningful superiority in efficacy compared with BOS (primary objective), deeper MR rates, and a favorable safety profile. These results support the use of asciminib as a new treatment option in CML, particularly in R/I pts who received ≥2 prior TKIs. Disclosures Hochhaus: Novartis: Research Funding; Incyte: Research Funding; Pfizer: Research Funding; Bristol Myers Squibb: Research Funding. Boquimpani:Novartis: Speakers Bureau. Rea:BMS: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees. Minami:Pfizer Japan Inc.: Honoraria; Takeda: Honoraria; Bristol-Myers Squibb Company: Honoraria; Novartis Pharma KK: Honoraria. Lomaia:Bristol Myers Squibb: Speakers Bureau; Pfizer: Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Voloshin:Novartis: Honoraria, Speakers Bureau. Turkina:Pfizer: Honoraria; Novartis Pharma: Honoraria; BMS: Honoraria. Kim:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; ILYANG: Consultancy, Honoraria, Research Funding; Takeda: Research Funding; Sun Pharma.: Research Funding. Apperley:Bristol Myers Squibb: Honoraria, Speakers Bureau; Incyte: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Pfizer: Honoraria, Research Funding, Speakers Bureau. Cortes:Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BioPath Holdings: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Telios: Research Funding; Astellas: Research Funding; Amphivena Therapeutics: Research Funding; Arog: Research Funding; BiolineRx: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Immunogen: Research Funding; Merus: Research Funding; Sun Pharma: Research Funding. Abdo:Novartis: Honoraria; Takeda: Honoraria. Kim:Paladin: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Research Funding. le Coutre:Pfizer: Honoraria; Incyte: Honoraria; Novartis: Honoraria. Saussele:Novartis: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Pfizer: Honoraria. Hughes:BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Chee:Novartis: Other: Travel support for attendance at investigator meeting. García Gutiérrez:Novartis Pharma AG: Consultancy, Honoraria, Other: travel/accommodations/expenses, Research Funding; Pfizer: Honoraria, Other: travel/accommodations/expenses, Research Funding; Incyte: Consultancy, Honoraria, Other: travel/accommodations/expenses, Research Funding. Sasaki:Pfizer Japan: Consultancy; Otsuka: Honoraria; Novartis: Consultancy, Research Funding; Daiichi Sankyo: Consultancy. Aimone:Novartis: Current Employment. Allepuz:Novartis: Current Employment. Quenet:Novartis: Current Employment. Bédoucha:Novartis: Current Employment. Mauro:Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding; Novartis: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding; Takeda: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding; Pfizer: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding; Sun Pharma/SPARC: Research Funding.

Description: INTRODUCTION: Erdheim-Chester Disease (ECD) is a rare histiocytic neoplasm with a heterogenous clinical course with asymptomatic localized course or systemic compromise involving multiples organs causing significant morbidity and mortality. There are few cohorts published however mainly from North America and Europe. Given the scarcity of data on ECD in Latin America, we have established a local registry in the city of São Paulo to collect clinical and biological material of ECD patients. METHODS: We retrospectively collected clinical data on biopsy-proven ECD patients diagnosed and treated at two reference centers for histiocytic disorders (Hospital das Clínicas da Universidade de São Paulo e Hospital Sírio-Libanês, Brazil) from January 2006 to February 2020. RESULTS: Sixteen patients with confirmed diagnosis of ECD were included with median age of 53 years. 75% were males and a median follow-up time of 50 months (7-163). Median time from onset of symptoms to diagnosis was 13 months (0.1-142). Immunohistochemistry (IHC) findings showed positivity for CD68 in 15/16 (94%) and for S100 in 3/16 (19%) patients, no case had CD1a positivity. The most frequent organs involved were: bone (75%), skin (44%), central nervous system (CNS) (44%), lymph nodes (31%), lung (13%), liver (6%), spleen (6%), and gastrointestinal tract (6%) of cases. CNS lesions involvement occurred mostly in the pituitary gland (86%). Twelve of 16 (75%) patients presented disease in more than one organ. Xanthelasma and xanthoma were the most common skin lesions (44%). The most frequent histiocytosis-related clinical manifestations were bone pain (44%) and diabetes insipidus (38%). The most frequent radiologic findings were osteosclerosis in 12/16 (75%) patients, retroperitoneal fibrosis around the kidneys in 6/16 (38%), the coated aorta sign and orbital infiltration were found in 4/16 (25%) of cases. 18FDG/PET-CT was performed in all patients, of whom 13 (81%) had hypermetabolic lesions. BRAF status at diagnosis was available in 13/16 patients using the technique of Sanger in 5/13, pyrosequencing in 3/13, IHC in 3/13 and polymerase chain reaction (PCR) in 2/13. Mutations were detected in only 3/16 (19%) cases. All patients received treatment due to symptomatic disease with a median of two lines of therapy (1-7). Median time between diagnosis and the first treatment was one month. First-line treatments were interferon in 12/16 patients, steroids in 5/16, and each one of thalidomide, vemurafenib and tumoral resection in one patient. Beyond first-line therapy, the most conventional chemotherapy regimens used were cladribine (4/16 patients) and LCH-like etoposide-containing vinblastine, methotrexate and mercaptopurine (2/16 patients). Other treatments included radiotherapy (4/16 patients) and a single patient used cobimetinib, imatinib and infliximab. Median progression free survival (PFS) after the first line treatment was 7.5 months (95% CI 5-10), and median overall survival (OS) was not reached to this date. Time to next treatment was 9 months in patients who did not achieved at least partial response after first line, and 15 months in those who attained it. PFS at 2 years was 45% (95% CI 0.17-0.71), and OS at 2 years was 100%. One patient died due to infection complication after the first cycle of cladribine after 50 months of follow-up. CONCLUSION: To our knowledge, despite the low number of patients, this is the largest Latin American cohort of patients with ECD reported to date. Our findings resemble demographic characteristics, sites of involvement and treatment choices reported by other groups. However, it is noteworthy that the proportion of ECD patients bearing a BRAF mutation (18.8%) was pretty lower than previously reported (approximately 50%). This needs to be taken cautiously due to the small number of subjects and due to technical issues, since all samples analyzed by PCR or Sanger were negative for BRAF mutation. A national registry of histiocytosis is needed to confirm these preliminary data. Disclosures No relevant conflicts of interest to declare.

Description: The management of chronic myeloid leukemia (CML) during pregnancy is a subject of continuous debate and there are few reports on CML outcomes in these women. The aim of the study is to compare progression-free survival (PFS) and overall survival (OS) between women who became pregnant after the diagnosis of CML and those who did not, as well as describing the treatments performed during pregnancy and maternal-fetal outcomes.Methods:Retrospective study, including women under 45 years of age and diagnosis of CML between 1991 and 2018, from the database of the Clinical's Hospital of the University of Medical School of São Paulo and the Cancer Institute of the State of São Paulo-Brazil.Results:100 cases were reviewed and 98 were included for analysis. The PFS and OS of groups A (63 non-pregnant women) and B (35 pregnant women, totaling 46 pregnancies) did not show statistical difference in a median of 11 years of follow-up (p=0.15). In the multivariate analysis, only poor adherence to treatment was identified as an independent risk factor for PFS and OS (HR: 9.7, 95% CI: 1.9-47.7). Comparing women with unplanned pregnancies (group B-UP, n= 21) with group A and considering adherence, PFS was worse in group B-UP without adherence (p

Description: Background Panobinostat (Pano), a pan-histone deacetylase inhibitor, is approved for the treatment of relapsed or relapsed/refractory multiple myeloma (RRMM) in combination with bortezomib and dexamethasone (FVd) in patients who have received ≥2 prior lines of therapy, including bortezomib and an immunomodulatory agent (IMiD). The pivotal phase 3 PANORAMA 1 trial, which used intravenous (i.v.) bortezomib, demonstrated significant progression-free survival benefit with FVd compared with placebo-Vd; however, adverse events (AEs) were also more frequent (San-Miguel J. et al., Lancet Oncol. 2014). The randomized phase 2 PANORAMA 3 study was conducted to optimize FVd by comparing three regimens with varying dose and schedule of Pano and by incorporating subcutaneous (s.c.) bortezomib. Methods PANORAMA 3 (NCT02654990) was a randomized, open-label, international, multicenter phase 2 study conducted in compliance with the Declaration of Helsinki. Eligible patients were ≥18 years old with 1‒4 prior lines of therapy, including an IMiD. Patients refractory to bortezomib were excluded. Patients were randomized 1:1:1 to Pano 20 mg three times weekly (TIW; the currently approved dosing regimen; Days 1, 3, 5, 8, 10, 12), Pano 20 mg twice weekly (BIW; Days 1, 4, 8, 11), or Pano 10 mg TIW (Days 1, 3, 5, 8, 10, 12), all administered in 21-day cycles. Randomization was stratified by number of prior treatment lines (1 vs 2 vs 3 or 4) and by age at screening (≤75 vs 〉75 years). For Cycles 1-4, all patients ≤75 years old received s.c. bortezomib 1.3 mg/m2 BIW (Days 1, 4, 8, 11) and oral dexamethasone 20 mg (Days 1, 2, 4, 5, 8, 9, 11, 12). Patients aged ≤75 years from Cycle 5 onwards, and patients 〉75 years for all cycles, received bortezomib 1.3 mg/m2 weekly (Days 1 and 8) and dexamethasone 20 mg on Days 1, 2, 8, and 9. Patients were treated until progressive disease or death, or until discontinuation due to toxicity or withdrawal of consent. The primary endpoint was overall response rate (ORR; IMWG 2011 criteria) after up to 8 treatment cycles by Independent Review Committee assessment. Secondary endpoints included best response, time to response (TTR), duration of response (DOR) and safety. Results In total, 248 patients were randomized (Pano: 20 mg TIW, N=82; 20 mg BIW, N=83; 10 mg TIW, N=83) and 241 patients received treatment (Pano: 20 mg TIW, N=79; 20 mg BIW, N=82; 10 mg TIW, N=80). Mean (SD) age was 65 (9) years; 55% of patients were male. Overall, patients had a median (range) time since diagnosis of 49 months (7‒242) and a median (range) of 2 (1-4) prior lines of therapy; 17% and 2% of patients were refractory to lenalidomide and pomalidomide, respectively. In total, 68% of patients had relapsed and 32% had relapsed/refractory disease. High-risk molecular findings were present in 15% of patients, with either del(17p) or t (4;14) at screening by fluorescence in situ hybridization. For the Pano 20 mg TIW, 20 mg BIW, and 10 mg TIW arms, respectively, median (range) number of treatment cycles completed was 9 (1; 50), 8 (1; 40) and 7 (1; 39); ORR (95% CI) after up to 8 treatment cycles was 62% (51; 73), 65% (54; 75), and 51% (39; 62); median TTR was 1, 2, and 3 months, with a median (95% CI) DOR of 22 (14, not estimable), 12 (9, 21), and 11 (6, 14.5) months. Best responses are presented in Table 1. In the Pano 20 mg TIW, 20 mg BIW, and 10 mg TIW arms, respectively, treatment-related AEs Grade ≥3 were reported in 78%, 72%, and 54% of patients; serious AEs were reported in 54%, 48%, and 44% of patients; and discontinuations due to AEs occurred in 29.5%, 28%, and 15% of patients, respectively. Most common treatment-emergent AEs (≥20% patients) are presented in Table 2. Grade ≥3 diarrhea occurred in 11.5%, 10%, and 5% of patients, respectively. There were 14 (6%) on-treatment deaths during the study (20 mg TIW, n=5; 20 mg BIW, n=3; 10 mg TIW, n=6), with none causally related to therapy and with 12 of 14 directly attributable to progressive disease. Conclusion In patients with RRMM, the 20 mg TIW and 20 mg BIW dosing regimens provided favorable outcomes, with most durable and deepest responses observed in the 20 mg TIW arm. The rate of AEs, including diarrhea, with Pano 20 mg TIW was lower than those observed with the same dosing regimen in PANORAMA 1, suggesting s.c. administration of bortezomib improves tolerability compared with i.v. administration. Moreover, all three regimens of FVd proved generally manageable; Pano 20 mg TIW had greatest efficacy, while 10mg TIW proved best tolerated. Disclosures Schjesvold: Celgene, Amgen, Janssen, Oncopeptides: Research Funding; Amgen, Celgene, Janssen, MSD, Novartis, Oncopeptides, Sanofi, Takeda: Consultancy; Amgen, Celgene, Janssen, MSD, Novartis, Oncopeptides, Sanofi, SkyliteDX, Takeda: Honoraria. Dimopoulos:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees. Lech-Marańda:Roche, Amgen, Gilead: Speakers Bureau; Roche, Novartis, Takeda, Janssen-Cilag, Amgen, Gilead, AbbVie, Sanofi: Consultancy. Spicka:Celgene, Amgen, Janssen-Cilag, Takeda, Bristol-Myers Squibb, Novartis, Sanofi: Consultancy, Honoraria, Speakers Bureau. Hajek:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria; PharmaMar: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Research Funding; Oncopeptides: Consultancy. Wróbel:Roche: Honoraria, Research Funding; Takeda, Celgene, Janssen, Amgen, AbbVie, Teva, Sandoz: Consultancy, Honoraria. Sureda Balari:Takeda: Consultancy, Honoraria, Speakers Bureau; Merck Sharpe and Dohme: Consultancy, Honoraria, Speakers Bureau; Sanofi: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Gilead/Kite: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Incyte: Consultancy; Celgene: Consultancy, Honoraria; BMS: Speakers Bureau; Roche: Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria. Beksac:Janssen&janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Deva: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Goncalves:Janssen, Takeda, Amgen, Bayer, Novartis, Merck, Bayer, Celgene, GSK, BMS: Research Funding; Janssen: Consultancy, Speakers Bureau. Bladé Creixenti:Celgene: Honoraria; Amgen: Honoraria; Oncopeptides: Honoraria; Takeda: Honoraria; Janssen: Honoraria. Chari:Bristol Myers Squibb: Consultancy; Pharmacyclics: Research Funding; Novartis: Honoraria; Oncopeptides: Consultancy; Takeda: Consultancy, Research Funding; Antengene: Consultancy; Sanofi Genzyme: Consultancy; Seattle Genetics: Consultancy, Research Funding; Secura Bio: Consultancy; Adaptive Biotechnology: Honoraria; Array BioPharma: Honoraria; Karyopharm: Consultancy; Glaxo Smith Kline: Consultancy; Amgen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; The Binding Site: Honoraria. Lonial:JUNO Therapeutics: Consultancy; Merck: Consultancy, Honoraria, Other: Personal fees; Abbvie: Consultancy; GSK: Consultancy, Honoraria, Other: Personal fees; BMS: Consultancy, Honoraria, Other: Personal fees, Research Funding; Janssen: Consultancy, Honoraria, Other: Personal fees, Research Funding; Novartis: Consultancy, Honoraria, Other: Personal fees; Takeda: Consultancy, Other: Personal fees, Research Funding; Amgen: Consultancy, Honoraria, Other: Personal fees; Onyx: Honoraria; Genentech: Consultancy; Karyopharm: Consultancy; Sanofi: Consultancy; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Honoraria. Spencer:Haemalogix: Consultancy, Honoraria, Other: Grant/Research Support; Secura Bio: Consultancy, Honoraria; Pharmamar: Other; Abbvie: Consultancy, Honoraria, Other: Grant/Research Support; Janssen: Consultancy, Honoraria, Other: Grant/Research Support, Speakers Bureau; Roche: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; TheraMyc: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other: Grant/Research Support; BMS: Honoraria, Other: Grant/Research Support, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria; Servier: Consultancy, Other: Grant/Research Support; Takeda: Honoraria, Other, Speakers Bureau; Antegene: Consultancy, Honoraria. Maison-Blanche:Chiesi Pharmaceutical, Sanofi, Novartis: Honoraria. Moreau:Novartis: Honoraria; Sanofi: Consultancy, Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Richardson:Celgene/BMS, Oncopeptides, Takeda, Karyopharm: Research Funding. San-Miguel:Amgen, BMS, Celgene, Janssen, MSD, Novartis, Takeda, Sanofi, Roche, Abbvie, GlaxoSmithKline and Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees.