Estudo De Descontinuacao De Fase I/Ii De Imatinibe Apos Pioglitazona (Edi-Pio) Em Pacientes Com Leucemia Mieloide Cronica Em Resposta Molecular Profunda Sustentada - Analise De 5 Anos De Seguimento

Objetivos: avaliar a eficacia e seguranca da pioglitazona utilizada concomitante ao imatinibe antes da descontinuacao do tratamento. Metodos: EDI-PIO (do Estudo de Descontinuacao de Imatinibe em Portugues apos Pioglitazona) e um estudo prospectivo, aberto, de braco unico, fase I/II de descontinuacao. Criterios de inclusao: LMC em fase cronica, tratada com imatinibe por pelo menos 3 anos, com MR 4.5 (Escala Internacional) por 2 anos. Os pacientes receberam pioglitazona 30 mg/dia por via oral por tres meses antes da descontinuacao do imatinibe. Apos a descontinuacao, os niveis de BCR-ABL foram medidos por PCR quantitativo em tempo real mensalmente por 12 meses, a cada dois meses no segundo ano e depois a cada tres meses. O tratamento com imatinibe foi reiniciado na recidiva molecular (amostra unica com valor de PCR >0,1% ou duas amostras consecutivas >0,01%). A sobrevida livre de terapia (SLT) foi calculada a partir da descontinuacao do imatinibe ate a recaida molecular, progressao ou morte por causas relacionadas a LMC. A sobrevida global (SG) foi calculada a partir da descontinuacao do imatinibe ate a ultima consulta ou data de obito por qualquer causa. Registro: Clinicaltrials.gov, NCT02852486. Resultados: Entre junho/2016 e janeiro/2019, foram incluidos 32 pacientes com LMC, com idade mediana de 54 anos (29-77), tratados com imatinibe por um tempo mediano de 9,5 anos (3-16). A duracao mediana de MR4 e MR4.5 foi de 106 e 93 meses, respectivamente. A data de corte desta analise foi 1de julho de 2022. Um paciente deixou o estudo antes da descontinuacao do imatinibe e nao foi analisado para SLT e SG. Nao houve eventos adversos de grau 3 ou 4 relacionados a pioglitazona. A mediana de seguimento dos 31 pacientes que descontinuaram a terapia foi de 61 meses (37-69). 15/31(48%) pacientes apresentaram sintomas relacionados a sindrome de retirada da medicacao. Doze pacientes apresentaram recidiva molecular apos uma mediana de 5 meses (2-30). Nove recaidas ocorreram nos primeiros seis meses e tres em 7, 13 e 30 meses apos a interrupcao do imatinibe. Todos os pacientes com recaida alcancaram resposta molecular maior numa mediana de 3 meses (1,8-4,1). Um paciente desenvolveu um adenocarcinoma do canal anal no terceiro ano apos a descontinuacao e foi tratado com cirurgia e quimioterapia. A SLT foi 71%, 67%, 61% e 61% aos 6,12, 30 e 60 meses, respectivamente. A SG aos 60 meses foi de 95% (IC 95%: 85-100%). Houve 5 casos de COVID-19 entre os 19 pacientes em descontinuacao (26%) e dois suspeitos. Quatro casos foram leves e um paciente em MR4.5 morreu devido a COVID-19 grave. O escore de Sokal baixo risco e a duracao do MR4.5 foram fatores significativos para SLT prolongada (P = 0,032 e 0,012, respectivamente). Discussao: A descontinuacao do tratamento com ITQ na LMC e bem-sucedida em aproximadamente 40-60% dos pacientes que atingem uma resposta molecular profunda e sustentada. Recaidas podem ocorrer devido a persistencia de celulas-tronco leucemicas quiescentes (CTL). A pioglitazona, um medicamento usado no tratamento do diabetes, e um agonista de PPAR gama e reduz a atividade de STAT5, e seus alvos a jusante, HIF2alpha e CITED2, principais guardioes das CTL quiescente. As CLT residuais podem ser gradualmente purgadas dos nichos da medula ossea pela pioglitazona, sendo o racional para a associacao da pioglitazona nesse estudo. Conclusoes: a combinacao de pioglitazona e imatinibe foi segura, sem eventos adversos graves. O seguimento a longo prazo de 5 anos demonstrou respostas moleculares duradouras e estaveis. Financiamento: CAPES (bolsa de mestrado ABPL). Copyright © 2022

Ponatinibe Para Tratamento De Lla Ph+ Recaida: Relato De Caso E Revisao Da Literatura

Objetivos: Descrever caso de paciente com leucemia linfoblastica aguda Ph+, nao elegivel a transplante alogenico de medula ossea, em uso de ponatinibe como terapia de resgate. Material e metodos: Avaliacao de prontuario e pesquisa em base de dados. Resultados: Paciente do sexo feminino, 65 anos de idade, com antecedente de obesidade, asma e nefrolitiase, em investigacao de plaquetopenia, tendo feito uso de prednisona sem incremento da contagem plaquetaria. Avaliacao medular evidenciou leucemia linfoblastica aguda B (LLA-B) com cariotipo normal. Iniciada quimioterapia de inducao com protocolo GRAAL e realizada coleta de BCR-ABL de sangue periferico, que resultou positivo (p190). Diante desse dado, e devido a pandemia de covid-19, com o objetivo de minimizar toxicidades e evitar internacao hospitalar, o tratamento foi modificado para o protocolo GIMEMA LAL, baseado em dasatinibe 140 mg/dia e prednisona. A paciente evoluiu com resposta citomorfologica completa, doenca residual mensuravel negativa e BCR-ABL indetectavel apos 3 meses de tratamento. Nesse periodo, apresentou multiplas intercorrencias - diverticulite aguda, colite pseudomembranosa e artrite (posteriormente diagnosticada com artrite reumatoide). Enviada para avaliacao com equipe de transplante de medula ossea, sendo considerada inelegivel naquele momento devido as comorbidades e decidido por manter inibidor de tirosino quinase. Evoluiu com recaida apos sete meses de uso de dasatinibe, sendo submetida a reinducao com inotuzumabe-mini-Hyper-CVAD. Apos o primeiro ciclo, alcancou resposta citomorfologica completa, porem evoluiu com cefaleia persistente e perda visual a direita. Evidenciada hemorragia intracraniana, sem indicacao de abordagem neurocirurgica. Devido a essa intercorrencia, foi considerada definitivamente inelegivel ao transplante alogenico. Nesse interim, foi pesquisada e detectada a mutacao t315i. Diante da nova informacao e do evento adverso grave, iniciou uso de ponatinibe 30 mg/dia em monoterapia. A paciente segue em uso do medicamento, mantendo resposta citomorfologica completa, com doenca residual mensuravel positiva (0,36% de blastos residuais) e BCR-ABL detectavel apos dois meses de tratamento. Apresenta boa tolerancia ao tratamento, sem toxicidade hematologica ou cardiovascular. Apresentou episodio de diverticulite aguda, sem necessidade de internacao hospitalar. Discussao: Historicamente, LLA-B Ph+ e considerada uma doenca de mau prognostico, com taxas de sobrevida em longo prazo inferiores a 20% na era anterior aos inibidores de tirosino quinase (ITK). Entretanto, com o advento dessa terapia-alvo, os desfechos de pacientes com LLA-B Ph+ tem se equiparado ou mesmo ultrapassado os daqueles sem essa alteracao molecular. No presente caso, a paciente atingiu resposta molecular completa com uso de terapia a base de corticoide e ITK de segunda geracao, tendo evoluido com recaida associada a mutacao T315i. Segue em resposta citomorfologica apos dois meses de ponatinibe, sendo necessario maior periodo de acompanhamento para avaliar a profundidade da melhor resposta, bem como sua duracao. Conclusao: Ponatinibe e opcao terapeutica eficaz e com boa tolerancia para paciente com LLA-B Ph+ (t315i) inelegivel a quimioterapia intensiva. Copyright © 2022

Leucemia Aguda De Fenotipo Misto - Apresentacao Inicial Atipica - Um Relato De Caso

Introducao: Com desafiador tratamento e de diagnostico criterioso, a leucemia aguda de fenotipo misto (LAFM) e uma entidade rara dentro do espectro das leucemias agudas. Requer a presenca imunofenotipica de marcadores de linhagem B (CD19, CD22, CD79a), T (CD3) em conjunto com a linhagem mieloide (mieloperoxidase e diferenciacao monocitica - CD11c, CD14, CD64 ou lisozima). Relato de caso: Paciente masculino, 30 anos, obeso e diabetico tipo 2, hipertrigliceridemia, inicia com febre (38C), dor abdominal em hipocondrio direito e fadiga. Com dois dias de sintomas procura atendimento sendo liberado com sintomaticos. No quarto dia de sintomas houve piora da febre (39degreeC) e da dor, surgindo maculas hiperemiadas pruriginosas pelo corpo, ictericia e coluria. Retornou ao hospital de sua cidade sendo prescrito azitromicina e liberado com suspeita de influenza. No sexto dia de sintomas notou piora da ictericia, procurando, novamente, atendimento. Encaminhado, entao ao servico de referencia da regiao. Interna inicialmente na equipe da gastroenterologia como suspeita de hepatite viral. Na chegada: Hb 14,9, leucocitos 6140 com 2793 neutrofilos, 442 monocitos e 2812 linfocitos, 53 mil plaquetas;AST 57, ALT 733, hiperbilirrubinemia as custas de bilirrubina direta. Com todos os marcadores virais negativos, prosseguiu a investigacao de hepatite. No dia em que realiza ressonancia magnetica, que indicava processo infiltrativo/inflamatorio em figado e rim esquerdo, alem de testar positivo para COVID-19, ha evolucao no hemograma: Hb 10,7, leucocitos 7450 com 1192 blastos, 60 neutrofilos, 2012 monocitos e 4187 linfocitos, 23 mil plaquetas. Com o aparecimento de blastos, piora dos niveis de bilirrubinas e das lesoes de pele, foi realizado imunofenotipagem de sangue periferico que indicava leucemia monocitica aguda. Transferido a equipe da hematologia, sendo realizada biopsia de medula e iniciado protocolo 7 + 3 com substituicao das antraciclinas em falta no mercado por doxorrubicina 45 mg/m2. No terceiro dia da inducao, foi liberado o resultado da imunofenotipagem que confirmava o diagnostico de leucemia aguda de fenotipo misto B/mieloide, marcando CD19, CD22 e CD79a, com diferenciacao monocitica (CD14 e CD64). Cariotipo nao houve crescimento e PCR BCR/ABL negativo. Optado por seguir tratamento com 7 + 3, apresentando medula no D14 aplasiada e medula no D28 com doenca residual minima (DRM) negativa. Realiza tres consolidacoes com altas doses de citarabina (3g/m2). Paciente sustenta DRM negativa, estando em remissao completa. Iniciado manutencao com vincristina, mercaptopurina, metotrexato e prednisona. Aguarda transplante de celulas tronco hematopoieticas (TCTH). Discussao: Com o diagnostico de LAFM, o tratamento requer o maior numero de quimioterapicos, sendo sugerido o uso de protocolos para leucemia linfoblastica aguda. Como ja havia sido instituido o tratamento com doxorrubicina e citarabina, foi optado por seguir protocolo e, na manutencao da remissao completa, terminar as consolidacoes e iniciar a manutencao prevista pelo protocolo HyperCVAD. Devido a ser uma leucemia de alto risco, a realizacao do TCTH e necessaria e, neste caso relatado, a manutencao sera mantida ate a realizacao do transplante. Conclusao: Contudo, por se tratar de doenca rara e com poucos estudos publicados, requer compartilhamento de conhecimentos e condutas para melhora da abordagem. Copyright © 2022

COVID-19 IN PATIENTS WITH CHRONIC MYELOID LEUKEMIA IN TREATMENT-FREE REMISSION: DISEASE SEVERITY AND IMPACT ON TFR STATUS

Background: Severe SARS-CoV-2 infections associated with high mortality rates are reported in a higher percentage of patients (pts) with hematologic malignancies compared to general population. In chronic myeloid leukemia (CML), pts with uncontrolled disease have a higher mortality risk. The impact of SARS-CoV-2 infection on CML pts in treatment-free remission (TFR) has not been studied so far. In particular, as immune control of residual disease may be important for TFR, the concern is that the infection could induce loss of TFR. Aims: To evaluate the outcome of SARS-CoV-2 infection in CML pts in TFR and assess any impact on maintenance of TFR. Methods: From March 2020 to December 2021, the CANDID study organized by the international CML Foundation has collected data on COVID-19 positive CML pts worldwide. Details on the registry were presented recently (Pagano ASH 2021). For this sub-analysis on pts in TFR additional information were collected including;molecular remission status (BCR::ABL1 ratios) before, during and after SARS-CoV-2 infection covering at least 6 months. For molecular analyses, BCR::ABL1 ratios were classified according to Cross et al (Leukemia 2015). In addition, ratios of 0% without indication of sensitivity were allocated as MR4 i.e. 0.01%IS. PCR outlier results were identified using the ROUT method by nonlinear regression with a maximum false discovery rate (FDR) of 1% (Motulsky et al 2006). Time to molecular relapse (MR) was measured from the date of COVID-19 diagnosis to the date of MR defined as loss of major molecular remission (MMR, BCR::ABL1 >0.1%IS) or the date of last molecular test. Molecular relapse-free survival (MRFS) and overall survival (OS) were estimated with the Kaplan-Meier method. The statistical difference between groups was performed using log-rank test. Results: By December 2021, 1050 COVID-19 positive CML pts were registered. 95 pts were in TFR at the time point of SARS-CoV-2 infection of which 89 (93.68%) recovered and 6 deceased (6.32%). Median age of TFR pts was 57 years, male were 51 (53.68%). Median time from CML diagnosis to reporting date was 13 years (range 3.7-27.0 years). TFR duration was 2.83 years in median (range 0.5 months - 10.1 years) including 19 pts with a duration < 1 year. From the 89 recovered TFR pts, 74 pts completed the 6-month follow up (83%), a further 6 pts with molecular follow-up of 3-5 months after COVID-19 diagnosis were still in TFR, 9 pts were lost to follow-up. Of 74 pts with complete reports, 69 pts remained in TFR (93%) and 5 pts lost TFR. For 71 pts, PCR results were obtained before, during and after infection. With the ROUT method 10 pts demonstrated outlier PCR tests, 61 pts demonstrated stable PCR results. There was no statistically significant difference in PCR results before and during/after infection (p>0.2). MRFS for these 71 pts 15 months after COVID-19 diagnosis was 86%. Probability of TFR loss was higher in pts with a TFR duration < 6 months compared to pts with TFR duration >6 months (27% vs 10%, Fig 1A). Additionally, there were no statistically differences in hospitalization rate (16% vs 23%, p=0.12) and severity of COVID-19 symptoms (12.6% vs 12%, p=0.87) comparing TFR and TKI treated pts. OS of COVID-19 positive TFR pts did not differ from COVID-19 positive pts on TKI therapy (HR 1.1, CI 0.47-2.54) (Fig 1B). Summary/Conclusion: In this sub-analysis of the CANDID study, CML pts in TFR had similar severity and survival to CML pts who were on TKI therapy and there was no evidence of an increased risk of TFR loss after SARS-CoV-2 infection.

DISCONTINUATION OF IMATINIB IN PATIENTS FOLLOWED FOR CHRONIC MYELOID LEUKEMIA IN DEEP MOLECULAR RESPONSE

Background: Treatment-free remission (TFR) in CML is defined as achieving a deep molecular remission (DMR) corresponding to molecular remissions of grade 4 or >4. Classically, Imatinib allows it to be achieved in nearly 20% of cases. Aims: We present our experience of stopping Imatib (IMc) (a copy of Imatinib) Methods: Methods and patients This was a study of 25 patients (pts): median age at diagnosis 40 years (9-62) including 2 children and 23 adults, at the time of discontinuation 50 years (18- 73), sex ratio M/F=0.92 (12H/13F);the sokal: 11 pts are intermediate risk, 8 low risk and 6 high risk. According to ELTS, 10 pts low-risk, 10 intermediate-risk, and 5 high-risk, all in chronic phase, all Mbcr/abl and received IMc at 400 mg/day, the first since June 2007 and the last in October 2013. The pts were followed by GeneXpert automated PCR, until deep MR [MMR4 and MMR4.5 ](Xpert BCR-ABL Ultra test) was achieved and maintained for more than 24 months with a hindsight of more than 5 years. Follow-up of discontinuation was done by PCR every month (2 to 3 months during covid-19);resumption of IMc if BCR/ABL transcript > 0.1% and maintenance of IMc discontinuation, if transcript ≤ 0.1% with monitoring. Deep MR (DMR) was completed at a mean of 70 months;2 pts (8.3%) were in MMR4 and 23 pts (91.7%) in MMR4.5. with a median follow-up of 8.5 years (6 - 12 years) . Imatib discontinuation was started in January 2019 Results: Results of discontinuation CHR was maintained in 24 pts, relapse at 6 months in one pt. TFR was lost in 9 pts (36%): [2 pts (20%) at 1 month, 3 pts (30%) at 2 months, 5 pts (50%) at 6 months]. The median duration of TFR was 23.5 months, 16 pts (64%) remained in DMR (2 children and 14 adults), no progression, withdrawal syndrome noted in 36% (9pts) at one month of stopping, mainly musculoskeletal pain in 28% (7pts), skin rash with pruritus in 12% (3 pts), asthenia in12%, palpebral myositis;among patients who presented these events 66.6% (6 pts) are still in TFR. For relapsed patients, the resumption of IMc was effective in 9 patients, with MMR4 and MMR4.5 achieved on average at 6 months, Summary/Conclusion: Comments: the FIT rate is 64% in our cohort, the relapses (9/25) occurred very quickly, during the first 6 months, the duration of impregnation in our patients who lost their TFR was on average 9 years (6-12 years), without difference with the patients who maintained the FIT which is 8.7 years (6- 13). Sokal and ELTS scores had no influence on FIT since 44.4% (4pts) of intermediate, 33.3% (3pts) of low and 2 of high risk relapsed vs 37.5% (6pts) of intermediate, 25% (4pts) of low and 4 of high risk in FIT, an influence of gender since 77.7% of relapses were men, age and even depth of MMR are all potential factors for cessation but the results in our cohort. The results in our cohort do not confirm their influence since 88.8% of our relapses were in MMR4.5 with a median age of 45 years (42-69) Conclusion: The A-STIM and EURO-SKI studies demonstrate that the depth of response before stopping does not play a prognostic factor for a good FIT, which is confirmed by our study;therapeutic impregnation is the only factor ensuring the maintenance of the FIT found in the studies less in our cohort, hence the factors ensuring the maintenance of the FIT in CML are still to be determined, in order to select the eligible patients.

ASCIMINIB PROVIDES DURABLE MOLECULAR RESPONSES IN PATIENTS (PTS) WITH CHRONIC MYELOID LEUKEMIA IN CHRONIC PHASE (CML-CP) WITH THE T315I MUTATION: UPDATED EFFICACY AND SAFETY DATA FROM A PHASE I TRIAL

Background: In pts with CML, the BCR::ABL1 T315I mutation is associated with poor clinical outcomes and confers resistance to previously approved ATP-competitive tyrosine kinase inhibitors (TKIs). Until recently, ponatinib (PON) was the only TKI available for these pts, but its use may be limited by associated cardiovascular events. In the primary analysis of the phase I trial X2101, asciminib-the 1st BCR::ABL1 inhibitor to Specifically Target the ABL Myristoyl Pocket (STAMP)-demonstrated efficacy and a favorable safety profile in heavily pretreated pts with CML with T315I. These results supported the FDA approval of asciminib as a new treatment option for pts with CML-CP with T315I (NCCN 2021). We report updated efficacy and safety data in these pts (data cutoff: January 6, 2021). Aims: Provide updated safety and efficacy data for pts with CML-CP with T315I treated with asciminib monotherapy 200 mg twice daily (BID) after added exposure. Methods: Pts with CML-CP with T315I were enrolled if treated with ≥1 prior TKI and no other effective therapy was available, provided informed consent, and received asciminib 200 mg BID. Results: 48 pts with T315I were included;2 (4.2%) pts had additional BCR::ABL1 mutations at baseline. Eight (16.7%), 15 (31.3%) and 25 (52.1%) pts received 1,2, and ≥3 prior TKIs, respectively. At data cutoff, treatment was ongoing in more than half (27 [56.3%]) of pts;the predominant reason for treatment discontinuation was physician's decision (11 [22.9%]), mainly due to lack of efficacy. Of the 48 pts, 45 were evaluable (BCR::ABL1IS >0.1% at baseline) for major molecular response (MMR);3 were excluded for BCR::ABL1 atypical transcripts. Among evaluable pts, 19 (42.2%) achieved MMR by wk 24 and 22 (48.9%) by wk 96;19 were still in MMR at the cutoff date. Evaluable pts included 26 PON-pretreated and 19 PONnaive pts;34.6% and 68.4%, respectively, achieved MMR by the cutoff date (Table). The probability of pts maintaining MMR for ≥96 wks was 84% (95% CI, 68.1-100.0). Thirteen (28.9%) and 11 (24.4%) pts achieved MR4 and MR4.5, respectively. Twenty (54.1%) and 23 (62.2%) of 37 pts with BCR::ABL1IS >1% at baseline achieved BCR::ABL1IS ≤1% by wk 48 and 96, respectively. The median duration of exposure was 2.08 (range, 0.04-4.13) yrs with more than half (27 [56.3%]) of pts receiving treatment for ≥96 wks;the median daily dose intensity was 398.3 (range, 179-400) mg/day. The safety/tolerability profile of asciminib remained favorable after ≈9 months of added follow-up (Table). The most common (≥5%) grade ≥3 adverse events (AEs) were lipase increase (18.8%, all asymptomatic elevations), thrombocytopenia (14.6%), and vomiting, ALT increase, abdominal pain, hypertension, anemia, neutropenia, and neutrophil count decrease (6.3% each). Arterial occlusive events occurred in 4 (8.3%) pts;none led to dose adjustment/interruption/discontinuation. AEs leading to discontinuation were reported in 2 new pts since the previous data cutoff;both pts discontinued and died due to COVID-19. These were the only study deaths reported in this pt population. Image: Summary/Conclusion: Asciminib monotherapy 200 mg BID exhibited a sustained, favorable safety profile after added exposure with no new safety signals in pts with CML-CP with T315I-a population with high unmet medical need. The clinical efficacy of asciminib is demonstrated by the high proportion of pts achieving durable MMR and BCR::ABL1IS ≤ 1%. The updated analysis confirms asciminib as a treatment option for pts with CML-CP with T315I, including those for whom treatment with PON has failed.

DIAGNÓSTICO DE LEUCEMIA MIELOMONOCÍTICA CRÔNICA EM PACIENTE COM INFECÇÃO PELO NOVO CORONAVÍRUS: RELATO DE CASO

Mulher de 68 anos, hipotireoidea, em uso de levotiroxina, COVID confirmado em exame realizado há 3 dias;deu entrada no pronto atendimento de um hospital de grande porte devido a piora dos sintomas gripais, febre, astenia e dispneia aos esforços com piora progressiva. Apresentava palidez discreta, sem outros achados dignos de nota. À admissão, apresentou leucocitose (Gl 18900/mm³) com desvio à esquerda sem anemia (Hb 13.1 g/dL) ou monocitose, associada a trombocitopenia moderada (98000/mm³). Tomografia de tórax mostrou infiltrado difuso sugestivo de pneumonia por Covid-19. Iniciada dexametasona 6mg/dia e antibioticoterapia empírica (ceftriaxona e azitromicina). Após 3 dias de internação, manteve febre;solicitadas hemoculturas e escalonada antibioticoterapia para Piperacilina-tazobactam. Evoluiu com anemia normocítica e normocrômica discreta (Hb 11.8g/dL), trombocitopenia leve (132000/mm³) e piora de leucocitose (16600/mm³), monocitose (4628/mm³) e surgimento de blastos em hemograma. As hemoculturas fecharam negativas. Devido à piora da leucocitose (Gl 46700/mm³) e da monócitos (9807/mm³) foi solicitada avaliação hematológica;realizada hematoscopia, que evidenciou alterações displásicas nas três séries. Realizada imunofenotipagem de sangue periférico, que mostrou presença de 15,8% de blastos mielóides, CD14- e CD16-, sem basofilia, com desvio à esquerda até promielócitos. Estudo medular inicial foi inconclusivo, com hiperplasia granulocítica e megacariocítica. Após 7 dias de antibioticoterapia, optado por alta hospitalar com proposta de acompanhamento ambulatorial, uma vez que a paciente manteve estabilidade clínica. No seguimento, evoluiu com queixa de astenia;novo hemograma mostrou piora da anemia e da trombocitopenia, assim como piora da leucocitose. Novo estudo medular realizado, com pesquisa da translocação BCR-ABL, mutaçõesJAK2, CALR, MPL e pesquisa de sideroblastos em anel, todos negativos. No mielograma, encontrado hipercelularidade granulocítica com maturação normoblástica, monocitose (13,2%), aumento do blastos(15.4%) e de megacariócitos displásicos. Cariótipo 46, XX, del (20) (q13.1). Biópsia de medula óssea com hiperplasia granulocítica e ausência de fibrose. Diante do exposto, foi feito o diagnóstico de Leucemia mielomonocítica crônica (LMMC-2). Realizado tratamento com azacitidina por 5 ciclos, mantendo leucocitose. No momento, aguardando transplante de medula óssea alogênico. Discussão: A LMMC é uma neoplasia hematológica mieloide com características de ambas as síndromes mielodisplásicas (SMD) e neoplasia mieloproliferativa (NMP), com até um quinto dos casos relacionados a condições inflamatórias/auto-imunes, conforme ilustrado neste caso, onde o seguimento é necessário para o diagnóstico. Trata-se de doença rara, predominante em idosos do sexo masculino. A apresentação varia conforme características mielodisplásicas ou mieloproliferativas, podendo se apresentar como monocitose incidental em indivíduos assintomáticos. Para o diagnóstico, é necessária a exclusão das doenças mieloproliferativas crônicas e de causas reativas, obedecendo os critérios da OMS de 2016. O tratamento varia conforme estratificação de risco e características clínico-laboratoriais mieloproliferativas/mielodisplásicas, com uso de terapia citorredutora ou hipometilante, respectivamente. O transplante alogênico de medula óssea é a única alternativa curativa disponível no momento, no entanto muitos candidatos não são elegíveis devido suas comorbidades.

ESTUDO DE DESCONTINUAÇÃO DO TRATAMENTO DE INIBIDORES DE TIROSINA QUINASE EM PACIENTES COM LEUCEMIA MIELOIDE CRÔNICA COM RESPOSTA MOLECULAR PROFUNDA SUSTENTADA APÓS FASE DE DESCALONAMENTO DE DOSE (DES-LMC) - RESULTADOS PRELIMINARES

Objetivos: Avaliar a efetividade e eficiência de um protocolo de descontinuação de inibidores de tirosina quinase (ITK) em tratamento no Sistema Único de Saúde (SUS) que incluiu uma fase de descalonamento de dose antes da interrupção do tratamento. Materiais e métodos: Estudo prospectivo, em andamento. Critérios de inclusão: LMC em fase crônica, em tratamento com ITK no mínimo há 3 anos, transcritos BCR-ABL típicos, com resposta molecular profunda (RMP) por 2 anos (MR4.5) Exclusão: fase avançada prévia ou atual, resistência prévia, mutações do ABL. Antes da suspensão do tratamento, foi realizado o descalonamento do ITK para 50% da dose atual por 6 meses. Durante a fase de descalonamento foi realizado monitoramento de PCR quantitativo para BCR-ABL (PCRq) mensal. Após a descontinuação do ITK o paciente foi seguido com avaliações clínicas, hemograma e PCRq a cada 4 semanas no primeiro semestre, a cada 2 meses no segundo semestre e no segundo ano e depois a cada 3 meses. A terapia foi reiniciada na perda de RMM (PCRq<0.1%). Resultados: Entre setembro de 2020 e julho de 2021 foram triados 213 pacientes com LMC;28 eram potencialmente elegíveis: 9 não aceitaram participar;19 assinaram o TCLE e um paciente teve falha de screening. A mediana de idade dos 18 participantes foi de 61.5 anos (35-86), 61% homens, 44.4% Sokal baixo risco ao diagnóstico, 15.1% intermediário/alto;81% com transcrito BCR-ABL do tipo b3a2;78% estavam em uso de Imatinibe,11% Dasatinibe,5.5% Nilotinibe e 5.5% Bosutinibe. A mediana da duração do tratamento com ITK até o início do descalonamento foi de 136 meses (46-201);a duração da RM 4.5 foi de 104, 5 meses (27-168);a mediana do tempo entre suspensão e perda de RMM foi de 2.5 meses (2-3). Oito pacientes perderam a RM4.5 durante a fase de descalonamento: destes, 2 perderam RMM, um na fase de descalonamento e outro na fase de descontinuação. Status atual: sete pacientes estão na fase de descontinuação, 8 na fase de descalonamento e 3 pacientes (16.6%) apresentaram recaída molecular. Não houve nenhum evento adverso sério. Dois pacientes tiveram Covid-19 (leve) na fase de descalonamento. Discussão: a descontinuação tem sido proposta como estratégia terapêutica na prática clínica nos pacientes com LMC com RM profunda sustentada. Nesses casos, a chance de sobrevida livre de remissão é de 50%. Poucos estudos avaliaram o efeito da retirada gradual do ITK antes da interrupção. No estudo DESTINY, o descalonamento foi feito por 12 meses, e a sobrevida livre de terapia aos 36 meses foi de 72% nos pacientes com RM4.0. Nos resultados preliminares do nosso estudo, ainda em recrutamento de pacientes, com 10 meses de seguimento, observamos que das 3 recaídas, uma delas ocorreu na fase de descalonamento, em um paciente em uso de nilotinibe em segunda linha e outra em um paciente na segunda tentativa de descontinuação, onde é esperado uma menor chance de sucesso. Conclusões: até o momento o protocolo mostrou-se seguro, com resultados dentro do esperado na literatura. O seguimento a longo prazo e inclusão de novos pacientes nos permitirá avaliar se a estratégia do descalonamento trará vantagem na sobrevida livre de terapia.

An update of safety and efficacy results from phase 1 dose-escalation and expansion study of vodobatinib, a novel oral BCR-ABL1 tyrosine kinase inhibitor (TKI), in patients with chronic myeloid leukemia (CML) and philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ All) failing prior tki therapies

Introduction: Vodobatinib is a novel third generation TKI effective against wild-type and mutated BCR-ABL1 (except T315I) with limited off-target activity. We present updated results from the Phase 1 dose-escalation (DEs) and expansion (DEx) study in CML and Ph+ALL patients (pts) failing ≥ 3 prior TKIs (< 3 prior TKIs if approved TKI is not clinically advised or available);patients with T315I are not eligible (NCT02629692). Methods: This is an open-label, phase 1, multicentre, 3+3 study evaluating maximum tolerated dose (MTD), safety and efficacy of vodobatinib administered once daily in 28 day cycles (dose range: 12 to 240 mg). MTD was established at 204 mg. DEx study enrolled chronic phase CML (CP-CML) patients at 174 mg dose of vodobatinib. Treatment continued until unacceptable toxicity, disease progression, consent withdrawal or death. Adverse events were assessed using NCI-CTCAE v4.03. Results: As of 15 Jul 2021, 52 pts are enrolled in DEs and DEx cohorts. Forty one of these pts received doses from 12 to 240 mg in the DEs cohort;32 chronic phase (CP-CML), 3 accelerated phase CML (AP-CML), 4 blast phase CML (BP-CML), 2 Ph+ ALL. Eleven CPCML pts were enrolled in DEx cohort at 174 mg dose. The baseline demographics and disease history are represented in Table 1. Efficacy: Of the 32 CP-CML pts enrolled in DEs: At baseline, 21 (65%) pts had no cytogenetic response, 4 (12.5%) were in PCyR, 7 (22%) were in CCyR. On vodobatinib therapy, 11(34%) pts achieved CCyR, 3 (9%) achieved PCyR and 7 (22%) maintained baseline CCyR. Baseline major molecular response (MMR) was present in 1 (3%) pt;and 14 pts (44%) achieved MMR on study. Of the remaining 11 pts, 5 (16%) had haematologically stable disease (no CyR and molecular response) and 6 (19%) had disease progression (cytogenetic or hematological) as their best response (Table 2 and 3). Seventeen CP-CML pts had prior ponatinib treatment, of which 11 (65%) had MCyR (4 achieved CCyR, 4 maintained CCyR, 3 achieved PCyR);while 8 (47%) achieved MMR. In the remaining 15 pts ponatinib naïve CP-CML: 10 (66%) had CCyR (7 achieved CCyR, 3 maintained CCyR);with 7 (47%) with MMR (6 achieved, 1 maintained). Two of the 3, AP-CML pts had baseline hematological response (CHR) with absence of cytogenetic and molecular response. The 3 pts further deepened their responses with 1 pt achieving CCyR with MMR and 2 pts in PCyR. Of the 4 BP-CML pts, 2 achieved CHR and 2 patients had disease progression as their best response;Of the 2 Ph+ ALL pts, 1 pt maintained CCyR and MMR while the other reported disease progression as the best response. Median duration of treatment overall was 23 (0.5-51) months [CP-CML 23 (0.5-51);AP-CML 36 (9-40);BP-CML 3 (0.5-18) and Ph+ ALL 4 (0.7-7.3) months]. Twenty one pts continue in study. In the DEx cohort, 1 of the 11 CP-CML pts was in PCyR at baseline. No pts had molecular response. Of the 11 patients, 6 (54 %) pts achieved CCyR, 1(10%) pt achieved PCyR. MMR was achieved by 1 pt (10%). Data is maturing for 1 pt. Median duration of treatment is 16 (0.3-19) months and 10 pts continue in study. Safety: Forty nine of 52 pts reported at least 1 TEAE. Most common any grade TEAEs included thrombocytopenia (33%), cough (19%), anaemia & diarrhoea (17% each). Thirty one pts (60%) reported Grade 3 and 4 treatment emergent AEs: most common were thrombocytopenia (15%), neutropenia and anaemia (12%), increased amylase and lipase (8% each). Ten (19%) pts reported cardiovascular TEAEs (Grade 1: angina pectoris, palpitations, ventricular extra-systoles, arteriosclerosis, hot flush, hypotension, intermittent claudication;Grade 2: hypertension, hypotension;Grade 3: cardiac failure congestive, hypertension);with a Grade 2 hypertension being vodobatinib related. Nineteen pts (37%) reported SAEs;vodobatinib related SAEs were reported in 3 pts (fatal intracranial haemorrhage (ICH), Grade 2 back pain and Grade 3 amnesia reported in 1 pt each). There were 5 deaths on study: 1 was related to use of vodobatinib (1 ICH, confounded by disease progression to blast phase that include extra-medullary sites) and the remaining unrelated (1 sudden death, 1 disease progression, 1 pneumonia fungal, 1 suspected COVID-19). Conclusion: Vodobatinib continues to be associated with favourable long term safety and efficacy in heavily pre-treated CML failing ≥ 3 prior TKIs, including ponatinib. Phase 2 study evaluating vodobatinib in pts failing at least 3 prior lines of therapy, including ponatinib, is ongoing.

Post-immunization multisystemic inflammatory response in non-COVID patient

Case Report Moderna vaccine postvaccination symptoms include local and systemic reactions. Local side effects include pain after injection, erythema, induration, tenderness, and lymphadenopathy. Systemic reactions include fever, headache, fatigue, myalgia, arthralgia, nausea/vomiting, or chills. We describe a case of severe postvaccination symptoms that occurred after administration of Moderna vaccine in an individual with no prior history of COVID infection. Case 73-year-old male with a past medical history of diabetes, atrial fibrillation, hypertension, and hyperlipidemia presented to the Emergency Department secondary to an elevated white blood cell count (WBC). Patient started with weakness, low appetite, fever, chills, and headaches 2 days after receiving the Moderna vaccine. COVID-19 antigen and PCR test were negative. He was hemodynamically stable and afebrile. Laboratories showed WBC of 35.16 K/μL, sodium of 120 mmol/L, alanine transaminase of 84 IU/L, and aspartate transaminase of 116 IU/L. The patient denied having unintentional weight loss, fever, adenopathy, rash, pruritus, new medications, or recent infection. Chest x-ray did not show pleural effusion, consolidation or pneumothorax. Patient was started on broad spectrum antibiotics, and on hypertonic saline, fluid restriction and desmopressin for severe hyponatremia. Liver ultrasound ruled out cirrhosis;his hepatitis panel was negative. Peripheral blood smear showed normocytic anemia, neutrophilia, monocytosis, lymphopenia, and thrombocytosis. Workup for myeloproliferative process including Jak2, CALR, MPL, BCR -ABL, was negative. No bone marrow biopsy was performed as the smear results were considered a reactive process. Blood and urine cultures were negative. The patient was briefly transferred to ICU secondary to worsening hyponatremia, decreased mental status, and acute kidney injury (AKI). He developed erythematous non-pruritic rash on his arms and upper chest on day 13 which resolved after oral antihistamines. Transaminitis, hyponatremia, and AKI resolved, and patient was discharged 18 days later with WBC of 14.42 K/μL. Discussion Post-immunization side effects have been widely described after COVID vaccination. A new entity called adult multisystem inflammatory syndrome (MIS-A) which includes some of those symptoms has been described. Diagnostic criteria include severe illness requiring hospitalization in a person ≥ 21 years, positive COVID test during admission or in the previous 12 weeks, extrapulmonary organ system dysfunction, severe inflammation on laboratory test, and absence of severe respiratory illness. Our patient had characteristics consistent with MIS-A, except for negative COVID test. To our knowledge, there is only one reported case of multisystemic inflammatory syndrome associated with vaccine. Although MIS-A criteria establish that a patient must have a positive COVID test, it is worthwhile examining if there is any role of the vaccination per se on its presentation.

First Interim Analysis of the Italian Dante Study: De-Escalation before Treatment-Free Remission in Patients with Chronic Myeloid Leukemia Treated with First-Line Nilotinib

Introduction: Treatment-free remission (TFR) in chronic myeloid leukemia (CML) is demonstrated to be achievable and recommended for patients (pts) in sustained deep molecular response (sDMR) who can discontinue tyrosine kinase inhibitor (TKI) treatment and maintain responses in ~50% of cases. While the feasibility and safety of TKI cessation have been largely demonstrated, the strategies of TFR optimization are yet to be clarified. Studies (eg. DESTINY) investigating de-escalation, mainly after imatinib, suggested that a stepwise approach may favor TFR outcome. We present the interim results of the phase 2, prospective, multicenter DANTE study (NCT03874858) evaluating de-escalation and TFR in Italian pts with CML in chronic phase (CML-CP) treated with nilotinib (NIL). Methods: Adults with CML-CP treated with NIL 300 mg twice daily (bid) in first-line for ≥3 years who achieved sDMR for ≥1 year (≥MR 4.0;BCR-ABL level ≤0.01% IS) were enrolled in 27 centers. The study consisted of 4 phases: screening (week [wk] −4-0), consolidation (wk 0-48), TFR (wk 48-144), and follow-up (until wk 144). Ongoing treatment with ≥400 mg/day dose was allowed at study entry. During consolidation, pts were treated with NIL 300 mg once daily (qd). At the end of consolidation phase, pts with sDMR entered TFR phase and discontinued NIL;indeed, pts with at least major molecular response (MMR;BCR-ABL ≤0.1% IS), but without sDMR, continued NIL 300 mg qd. At any time, pts with loss of MMR returned to NIL 300 mg bid. During TFR phase, BCR-ABL levels were monitored monthly from wk 52-96, and then every 3 months. Pts on half-dose or full-dose NIL were monitored every 3 months. The primary endpoint is the percentage of pts in full treatment-free remission (FTFR) 96 wks after the start of consolidation phase. FTFR is defined as pts with MMR or better, including those who remained in discontinuation during TFR phase and those who are treated with half the standard dose. Key secondary endpoints include percentage of pts with sDMR at wk 48;TFR rate at wk 96 and 144;BCR-ABL kinetics and safety. The predictive role of digital droplet PCR is also evaluated as an exploratory objective. Results: Overall, 113 pts were screened and 107 entered consolidation phase. This interim analysis included 52 pts who reached the end of consolidation phase by data cut-off period (February 8, 2021). Of these 52 pts, 49 (94.2%) were ongoing by data cut-off and 3 (5.8%) discontinued the study (1 patient due to adverse event (AE) and 2 per patient's decision). Median age at study entry was 49.5 years. Median time from diagnosis was 5.6 years and median dose of prior NIL treatment was 600 mg/day for all pts except one who was on NIL 450 mg/day at baseline. Median duration of last sustained MR4 and MR4.5 were 30 and 16.5 months, respectively. Further details are listed in Table 1. At screening, molecular response categories were MR4.0 in 13.7%, MR4.5 in 23.1% and undetectable MR4.5 in 63.5% of pts. During consolidation phase, 5 (9.6%) pts discontinued prematurely: 2 pts restarted NIL full dose (3.8%) for MMR loss, 2 (3.8%) discontinued for AEs and 1 (1.9%) for pt decision. Overall, 47 pts completed consolidation: of them 40 (76.9%) sustained DMR and 7 (13.5%) maintained MMR but not sDMR. Of the 7 pts not sustaining DMR during consolidation, 6 regained DMR after a median of 4.4 months, while 1 pt was still in MMR by data cutoff. The 2 pts who lost MMR after 5 and 8 months regained MMR and 1 regained DMR by data cutoff after increasing NIL to 300 mg bid. Median time spent in consolidation phase was 11.7 months, and the evolution of response categories over time is shown in Figure 1. During consolidation phase, AEs were observed in 16 pts (30.8%), of them 2 (3.8%) pts had serious AEs: 1 patient had skin ulcers and COVID-19 related pneumonia, while 1 patient had unstable angina. No deaths and disease progressions were observed. Conclusions: DANTE is the first study that showed the safety and feasibility of NIL de-escalation before TFR in CML-CP pts with sDMR. Inter m results suggest that loss of MMR during de-escalation is rare. De-escalation strategy may lead to further improvement of TFR outcome and tolerability and may also preemptively support the identification of pts who may not be ready for discontinuation, with a tailored approach. To date, accuracy in predicting TFR outcome is still low, and the de-escalation setting may sharpen biological and clinical predictive factors, including the potential role of digital PCR. [Formula presented] Disclosures: Breccia: Abbvie: Honoraria;Pfizer: Honoraria;Novartis: Honoraria;Incyte: Honoraria;Bristol Myers Squibb/Celgene: Honoraria. Abruzzese: Incyte: Consultancy, Honoraria;Novartis: Consultancy, Honoraria;Pfizer: Consultancy, Honoraria;Bristol Myers Squibb: Consultancy, Honoraria. Stagno: InCyte: Consultancy, Honoraria;Pfizer: Consultancy, Honoraria, Other: Support for attending meetings and/or travel;Novartis: Consultancy, Honoraria, Other: Support for attending meetings and/or travel, Research Funding. Iurlo: Incyte: Speakers Bureau;Novartis: Speakers Bureau;Pfizer: Speakers Bureau;Bristol Myers Squibb: Speakers Bureau. Sportoletti: AstraZeneca: Consultancy, Honoraria;Janssen: Consultancy, Honoraria;AbbVie: Consultancy, Honoraria. Lemoli: Jazz, Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;AbbVie, Daiichi Sankyo, Servier: Honoraria, Speakers Bureau;Celgene: Other: Support for attending meetings and/or travel. Siragusa: Novartis, CSL, Behring, Amgen, Novonoridsk, SOBI, Bayer: Consultancy, Honoraria, Speakers Bureau. Chiodi: Novartis: Current Employment.

Half: A Prospective Multi-Centre Phase II Clinical Trial Evaluating the Efficacy and Safety of Tyrosine Kinase Inhibitors' Discontinuation after Two-Step Dose Reduction in Patients with Chronic Myeloid Leukemia in Deep Molecular Remission

Background. Treatment-free remission (TFR) has become a new treatment goal for chronic myeloid leukemia (CML) patients. However, usually abrupt tyrosine kinase inhibitors (TKIs) therapy discontinuation has been successful only in about half of eligible patients and it can cause burdening TKI withdrawal syndrome (TWS) in about 30% of them. Moreover, any robust clinical or biological factor predictive for successful TFR has not been identified yet. On top of that, sustainable deep molecular response (DMR) as the main prerequisite for TKI discontinuation attempt is achieved only in 20-40% of patients. The majority of CML patients, therefore, need to be treated with the effective and well-tolerated drug for a long time or even life-long. Study design and methods. With the recognition of all these aspects, we designed a nationwide prospective investigator-initiated phase II clinical trial HALF (ClinicalTrials.gov NCT04147533) in order to evaluate efficacy and safety of TKI discontinuation after previous two-step dose reduction in patients with CML in DMR (Fig. 1). Step-wise TKI dose reduction, i.e. half of the standard during the first 6 months after study entry, and the same dose given alternatively (every other day) during the next 6 months, was derived from pharmacokinetics and experimental data as well as from clinical trials' results. We assume that the step-wise and eventually meaningful TKI dose reduction enables a higher rate of patients achieving successful TFR with less pronounce TWS, or even would represent a more reasonable and safer alternative to the complete and sudden TKI interruption. This unique nationwide academic project has been facilitated by hematological patients care centralization in the Czech Republic. A primary study objective is to evaluate the proportion of patients in major molecular response (MMR) at 6 and 12 months and in TFR at 18, 24, and 36 months after the study enrollment, respectively, and molecular recurrence-free survival at all mentioned time points as well. Main secondary and exploratory objectives are: to evaluate the proportion of patients loosing MMR and in whom MMR and MR4.0 would be re-achieved after TKI re-introduction, time to MMR and MR4.0 re-achievement, FFS, PFS, OS, TWS, and QoL assessment, predictive factors for successful TFR identification, quantification of BCR-ABL1 using digital droplet PCR at both the DNA and mRNA levels, immunological profiling, BCR-ABL1 kinetics mathematical modeling, assessment of TKI pharmacokinetics, clonal hematopoiesis and pharmaco-economics. Results. The study was launched in December 2019;however, due to the COVID-19 outbreak, patients' recruitment started on June 16, 2020. Here, characteristics of the first 74 patients included in the study until April 2021 are presented. There were 37 males and 37 females, with median age at the time of diagnosis of 53 years (range, 23-74) and at the time of the study entry of 67 years (range, 35-86). A median time of CML disease, TKI treatment, and DMR duration before the study initiation was as follows: 9.9 years (range, 4.4-22.5), 9.8 years (range, 4.2-20.2), and 7.3 years (range, 3.2-18.3), respectively. The ELTS score was low, intermediate, high and unknown in 62.2%, 21.6%, 13.5%, and 2.7% of patients, respectively. At the time of study entry, 58 patients (79.5%) were treated with imatinib, 10 (13.7%) with nilotinib, and 5 (6.8%) with dasatinib, respectively, whereas in 63 patients (86.3%) it was in the first line of therapy. With almost half of patients (48.6%), the TKI dose was already reduced at the time of study entry. With 10 (13.5%) patients, interferon-α treatment preceded TKI administration. At the time of this preparation, on July 26, 2021, altogether 102 patients (from planned 150) have been enrolled in the study;48 of them (47.1%) have already moved to the second de-escalation phase and 9 (8.8%) patients to the TFR phase. There were 2 cases of confirmed MMR loss (both in month 8 after the study entry) and no patient experienced symptoms resembling TWS. Conclusions. Despite the COVID-19 pandemic, the HALF study was successfully launched and initiated in the majority of centers, with 102 already included patients and continuing intensive enrolment. Based on our very preliminary results, the step-wise dose reduction seems to be an effective and safe approach. More included patients, longer follow-up and further analyses are needed in order to reach all set up objectives. [Formula presented] Disclosures: Žácková: Angelini: Consultancy, Speakers Bureau;Novartis: Speakers Bureau. Faber: Angelini: Consultancy, Other: conference fees, Research Funding, Speakers Bureau;Bristol-Myers Squibb: Consultancy, Other: conference fees, Research Funding, Speakers Bureau;Novartis: Consultancy, Other: conference fees, Research Funding, Speakers Bureau;Pfizer: Other: conference fees;TERUMO: Other: conference fees. Bělohlávková: Novartis: Consultancy;BMS/Celgene: Consultancy. Horňák: Angelini: Honoraria. Svobodník: Roche: Speakers Bureau;Janssen-Cilag: Speakers Bureau. Machová Poláková: Incyte: Consultancy;Angelini: Consultancy;Novartis: Research Funding. Mayer: Principia: Research Funding.

Identification of a Conserved Intracellular Loop (CIL) Structure That Scaffolds PIP3 to Amplify Oncogenic Signaling during Malignant B-Cell Transformation

Background: Within seconds of antigen-encounter, B-cell receptor (BCR) signaling induces dramatic changes of cell membrane lipid composition, including >40-fold increases of local PIP3-concentrations within lipid rafts. While several structural elements, including pleckstrin homology (PH) domains have been identified as PIP3-binding proteins, the underlying mechanisms that amplify BCR-signaling to assemble large signaling complexes within lipid rafts within 15 to 30 seconds, remained elusive. To understand the mechanistic and biophysical requirements for PIP3 accumulation during normal B-cell activation and acute oncogenic transformation, we identified PIP3-interacting proteins by cell-surface proteomic analyses. Results: In addition to proteins known to bind PIP3 with their PH-domains, we identified the short 133 aa protein IFITM3 (interferon-inducible transmembrane protein 3) as a top-ranking PIP3 scaffold. This was unexpected because IFITM3 was previously identified as endosomal protein that blocks viral infection by stiffening endosomal membranes to firmly contain viral cargo. Previous studies revealed that polymorphisms that lead to the expression of truncated IFITM3 are associated with increased susceptibility to viral infections, including SARS-CoV2. Among known cell membrane lipids, PIP3 has the highest negative charge. Instead of a PH-domain, IFITM3 laterally sequestered PIP3 through electrostatic interactions with two basic lysine residues (K83 and K104) located at the membrane-solution interface. Together with three other basic lysine and arginine residues K83 and K104 form a conserved intracellular loop (CIL), which enable IFITM3 to efficiently capture two PIP3 molecules. Bivalent PIP3-binding of the IFITM3-CIL enables a crosslinking mechanism that results in dramatic amplification of B-cell activation signals and clustering of large signaling complexes within lipid rafts. In normal resting B-cells, Ifitm3 was minimally expressed and mainly localized in endosomes. However, B-cell activation and oncogenic kinases induced phosphorylation at IFITM3-Y20, resulting in translocation of IFITM3 from endosomes and massive accumulation at the cell surface. Ifitm3ˉ /ˉ naïve B-cells developed at normal numbers, however, activation by antigen encounter was compromised. In Ifitm3ˉ /ˉ B-cells, lipid rafts were depleted of PIP3, resulting in defective expression of >60 lipid raft-associated surface receptors and impaired PI3K-signaling. Ifitm3ˉ /ˉ B-cells were unable to undergo affinity maturation and di not contribute to germinal center formation upon immunization. Analyses of gene expression and clinical outcome data from patients in six clinical cohorts for pediatric and adult B-ALL, mantle cell lymphoma, CLL and DLBCL, we consistently identified IFITM3 as a top-ranking predictor of poor clinical outcome. Inducible activation of BCR-ABL1 and NRAS G12D rapidly induced development of B-ALL but failed to transform and initiate B-ALL from Ifitm3ˉ /ˉ B-cell precursors. Conversely, the phospho-mimetic IFITM3-Y20E mutation, mimicking phosphorylation of the IFITM3 N-terminus at Y20 induced constitutive membrane localization of IFITM3, spontaneous aggregation of large oncogenic signaling complexes and readily initiated transformation in a genetic model of pre-malignant B-cells. Conclusions: We conclude that phosphorylation of IFITM3 upon B-cell activation induces a dynamic switch from antiviral effector functions in endosomes to oncogenic signal-amplification at the cell-surface. IFITM3-dependent amplification of PI3K-signaling is critical to enable rapid expansion of activated B-cells. In addition, multiple oncogenes depend on IFITM3 to assemble PIP3-dependent signaling complexes and amplify PI3K-signaling for malignant transformation and initiation of B-lymphoid leukemia and lymphoma. [Formula presented] Disclosures: Weinstock: SecuraBio: Consultancy;ASELL: Consultancy;Bantam: Consultancy;Abcuro: Research Funding;Verastem: Research Funding;Daiichi Sankyo: Consultancy, Research Funding;AstraZeneca: Consultanc ;Travera: Other: Founder/Equity;Ajax: Other: Founder/Equity.

The 15 Year Long-Term Survival of Patients with Chronic Myeloid Leukaemia from 35 Regions of Russian Federation: A Follow up of a Multicenter Observation Study Eutos Osp Initiated By European Leukemia NET

The results of long-term follow-up of patients (pts) with chronic myeloid leukemia (CML) do not lose their importance. Data from routine clinical practice are of particular interest. The use of 1 st (imatinib, IM) and 2nd generation TKI (2G TKI) led to a significant increase in survival, so the probability of death associated with CML could be significantly lower than the probability of death due to common causes of death other than CML. To analyze the overall survival (OS) and causes of mortality in CML pts treated in routine clinical practice in Russian Federation for a long period (>15 years) of time. The long-term follow-up data of the Russian part of the European LeukemiaNet (ELN) OSP EUTOS multicenter observational study were evaluated. The analyzed cohort consisted of 678 Ph/BCR-ABL-positive CML pts from 35 regions of Russia diagnosed in 2002-2006 with IM therapy initiation ≤6 months (mo) after diagnosis. Median (Me) age was 47(range 18-81) years (y), 47% males. Chronic phase, accelerated phase and blast crisis at diagnosis was in 631 (93%), 41(6%) and 6(1%) pts, respectively. The annual number of newly diagnosed pts was as follows: 2002 - 15 pts, 2003 - 38 pts, 2004 - 46 pts, 2005 - 206 pts, 2006 - 302 pts. The last update for 209 pts was done in Jun. 2021;last contact for 100 pts - in 2020, for 39pts - in 2019, for the other - before 2018. The date of the last contact/death could not be established for 14 pts. Statistical analysis included 661 pts, the OS was evaluated by Kaplan-Mayer method using the SAS 9.4 package. In total, 331 (50%) pts of the analyzed cohort were alive with the Me follow-up of 180 (range 2-232) mo or 15 y (range 2 mo-19,3 y). All pts started therapy with IM with 25% switched to 2G TKI in subsequent therapy lines. In total, 218 (66%) pts achieved MR4, 183 (55%) pts got MMR;46 (21%) of these pts with deep molecular response (DMR) were observed in hematology centers of Moscow. The 15-y OS in the total cohort was 63% (CI 59-70%)(fig.1). The OS by age groups was as follows: 18-40yy-75% (CI 73-82%), 40-60yy- 63% (CI 59-70%), 60-80yy- 37% (CI 30-45%). The most complete information was provided by Moscow centers (2 centers, 113 pts). The 15-y OS of pts receiving treatment in Moscow was significantly higher vs pts from other regions (32 centers, 548 pts): 75% vs 60%, p=0,0030 (fig.2). The mortality in the whole cohort of 661 pts was 35% (233 pts). Of these 233 pts, 112(48%) pts deaths were due to CML progression to AP or BP (including non-compliant cases);3pts (1,5%) died after allogenic stem cell transplantation (infection complications);the cause of death was unknown in 50 (21,5%) pts. The highest death rate from CML progression was at 4-9 y of follow-up. Deaths caused by concomitant diseases were in 68 (29%) pts: coronary artery disease/myocardial infarction/heart failure in 42 (62%) of 68 pts, acute ischemic stroke in 10 (15%) pts, second malignancies (Cr- cancer) in 10 (15%) pts (lung tumor, metastatic esophageal Cr, stomach Cr, brain tumor, sigmoid colon Cr, rectal colon Cr, melanoma, renal Cr, breast tumor, other hematological malignancies), accidents - 1 pt, liver cirrhosis - 2 pts, in 2 cases - respiratory virus infections complicated with pneumonia, 1 pt died due to Covid-19. Conclusions. The long-term follow-up of the multicenter study EUTOS OSP in 35 regions of Russian Federation allows not only to characterize the 15-y OS in CML pts but also provides the long-term outlook of the routine clinical practice. Probably, better OS of CML patients receiving treatment in Moscow (2 centers) may be related to organizational issues of interaction with the federal center, better monitoring and timely switching to 2G TKI therapy. The organization and support of multicenter studies may improve the situation with the treatment of diseases of the blood system. [Formula presented] Disclosures: Chelysheva: Novartis Pharma: Speakers Bureau;Pfizer: Speakers Bureau;Pharmstandart: Speakers Bureau;Bristol Myers Squibb: Speakers Bureau. Vinogradova: Pharmstandart: Speakers Bureau;Novartis Phar a: Speakers Bureau;Pfizer: Speakers Bureau;Bristol Myers Squibb: Speakers Bureau. Lomaia: Novartis: Honoraria;Pfizer: Honoraria;BMS: Honoraria;Pharmstandard: Honoraria. Voloshin: Abbvie: Consultancy, Speakers Bureau;Novartis: Consultancy, Speakers Bureau;Astra Zeneca: Consultancy, Speakers Bureau;Pfizer: Consultancy;Biacad: Consultancy, Speakers Bureau. Turkina: Pharmstandart: Speakers Bureau;Pfizer: Speakers Bureau;Bristol Myers Squibb: Speakers Bureau;Novartis Pharma: Speakers Bureau.

Being Present-CML: A Distress Reduction Intervention for Patients with Chronic Myeloid Leukemia Taking Tyrosine Kinase Inhibitors

Background: Tyrosine kinase inhibitors (TKIs) enable patients with chronic phase chronic myeloid leukemia (CP-CML) to achieve similar overall survival to the general population, but can cause side effects that negatively impact quality of life (QOL) and contribute to distress. Since most CP-CML patients remain on TKIs indefinitely, there is a need to develop targeted interventions to address their physical and psychosocial complications. Mindfulness meditation interventions have improved QOL and decreased distress, depression, anxiety, fatigue, and pain in patients with solid tumors;however, such interventions have not previously been evaluated in patients with CP-CML. In Being Present-CML, we sought to determine if a mindfulness meditation-based program is feasible and acceptable to patients with CP-CML, and to explore its preliminary efficacy. Methods: Being Present-CML is a prospective, single-arm clinical trial of an 8-week, online mindfulness meditation-based intervention effective in patients with gastrointestinal cancers (Atreya, et al. PLoS One, 2018). Participants were recruited from a single academic institution. Eligibility included adult patients with CP-CML taking TKIs. Participants were instructed to independently play audio-guided meditations at least 5 times per week on a secure website and to participate in once weekly, instructor-led meditation classes on Zoom in assigned cohorts. Qigong was incorporated into the classes to target fatigue, a common TKI side effect. Class content was recorded and uploaded to the website for those unable to attend live. Feasibility was assessed through measurement of recruitment and attrition. Adherence was determined by web capture. Acceptability was determined by feedback from study surveys and qualitative interviews. Preliminary efficacy was evaluated using patient-reported outcome measures (PROMs) at baseline (week 0) and post-intervention (week 8) using the NCCN Distress Thermometer (DT) and Patient-Reported Outcomes Measurement Information System (PROMIS) short forms for anxiety, depression, fatigue, pain interference, and sleep disturbance. A DT score ≥4 is consistent with moderate to severe distress. PROMIS scores use T-scores where the mean score for the general population is 50 (standard deviation [SD] +/-10);higher scores indicate worse symptoms. Descriptive statistics and two-tailed paired t-tests (p <0.05) were used to summarize the data. Results: Between October 2020-April 2021, 98 eligible participants were approached to participate in the study;88 (89.8%) patients agreed to learn more, and 37 (37.8%) patients provided consent. The median age was 51 (range 23-72), 51.5% (n=19/37) were male, and 89.1% (n=33/37) were non-Hispanic White. At time of study start, 83.7% (n=31/37) had a BCR-ABL1 PCR transcript ≤1% and a median time since diagnosis of 71 months (range 2-234) (Table 1). Of 37 participants, 29 (78.4%) completed end of study procedures;4 (10.8%) dropped out, and 4 (10.8%) did not complete week 8 surveys. The median number of audio meditations listened to per participant was 34 with an average of 4.3 per week. The median number of weekly classes attended and/or recordings viewed per participant was 7 (range 1-8). At baseline, participants had a median DT score of 5 (range 2-8). Average baseline PROMIS scores were slightly worse than the general population in depression (51.4, SD 8.8), anxiety (55.9, SD 7.8), sleep disturbance (51.8, SD 6.9), fatigue (53.9, SD 10.6), and pain interference (52.2, SD 9.9). By week 8, the median DT score improved to 3 (p=0.003) (Figure 1). Post-study PROMIS scores improved in sleep disturbance (p=0.001) and depression (p=0.01) (Figure 2), but not anxiety (p=0.12), fatigue (p=0.10), or pain interference (p=0.98). Of those who conducted post-study interviews, 77% (n=20/26) reported their symptoms during the study were not influenced by the COVID-19 pandemic. Nearly all participants found the study helpful (Figure 3) and would recommend it to others (median score of 8 on a 1-10 scale;10=extremely likely). Concl sions: Patients with CP-CML taking TKIs found the mindfulness meditation-based intervention to be feasible and acceptable. PROM results suggest promise of clinical benefit in this patient population, including patients with well-controlled disease and a long history of CML. A randomized controlled trial is being planned to validate these findings. [Formula presented] Disclosures: Smith: Astellas Pharma: Consultancy, Research Funding;FUJIFILM: Research Funding;Daiichi Sankyo: Consultancy;Revolutions Medicine: Research Funding;AbbVie: Research Funding;Amgen: Honoraria. Shah: Bristol-Myers Squibb: Research Funding. Atreya: Guardant Health: Research Funding;Pionyr Immunotherapeutics: Membership on an entity's Board of Directors or advisory committees;Array Biopharma: Membership on an entity's Board of Directors or advisory committees;Merck: Research Funding;Bristol-Meyers Squibb: Research Funding;Gossamer Bio: Research Funding;Novartis: Research Funding.