A nationwide phase II study of delayed local treatment for children with high-risk neuroblastoma: The Japan Children's Cancer Group Neuroblastoma Committee Trial JN-H-11.

PURPOSE: Survival rates of patients with high-risk neuroblastoma are unacceptable. A time-intensified treatment strategy with delayed local treatment to control systemic diseases has been developed in Japan. We conducted a nationwide, prospective, single-arm clinical trial with delayed local treatment. This study evaluated the safety and efficacy of delayed surgery to increase treatment intensity. PATIENTS AND METHODS: Seventy-five patients with high-risk neuroblastoma were enrolled in this study between May 2011 and September 2015. Delayed local treatment consisted of five courses of induction chemotherapy (cisplatin, pirarubicin, vincristine, and cyclophosphamide) and myeloablative high-dose chemotherapy (melphalan, etoposide, and carboplatin), followed by local tumor extirpation with surgery and irradiation. The primary endpoint was progression-free survival (PFS). The secondary endpoints were overall survival (OS), response rate, adverse events, and surgical complications. RESULTS: Seventy-five patients were enrolled, and 64 were evaluable (stage 3, n = 8; stage 4, n = 56). The estimated 3-year PFS and OS rates (95% confidence interval [CI]) were 44.4% [31.8%-56.3%] and 80.7% [68.5%-88.5%], resspectively. The response rate of INRC after completion of the treatment protocol was 66% (42/64; 95% CI: 53%-77%; 23 CR [complete response], 10 VGPR [very good partial response], and nine PR [partial response]). None of the patients died during the protocol treatment or within 30 days of completion. Grade 4 adverse effects, excluding hematological adverse effects, occurred in 48% of patients [31/64; 95% CI: 36%-61%]. Major Surgical complications were observed in 25% of patients [13/51; 95% CI: 14%-40%]. CONCLUSION: This study indicates that delayed local treatment is feasible and shows promising efficacy, suggesting that this treatment should be considered further in a comparative study of high-risk neuroblastoma.

Real-life study on the use of response adapted therapy in patients with Hodgkin Lymphoma: Results from a multicenter experience.

Few data are known regarding the use of interim positron emission tomography (iPET) after the first two cycles (iPET2) of chemotherapy in treatment-naïve classical Hodgkin lymphoma (cHL) in routine clinical practice, and about the real-life adoption of intensification strategies for iPET positive patients. We conducted a multicenter retrospective study on cHL to investigate the use of iPET in the real-life setting, its prognostic role and outcomes of patients early shifted to intensification. Six hundreds and forty-one patients were enrolled (62% had advanced stage). iPET2 was positive in 89 patients (14%) including 8.7% and 17% early and advanced stage patients, respectively (p = 0.003). Among iPET 2 positive cases treatment was immediately modified in 19 cases; in 14 cases treatment was modified after an additional positive iPET4. Overall 56 iPET2 positive patients never received intensified therapies. Most frequently used intensified therapy was autologous stem cell transplantation followed by BEACOPP. After a median follow-up of 72 months, the 5-year progression-free survival (PFS) was 82% with iPET2 positive patients showing a worse PFS compared with iPET2 negative cases: 31% versus 85%. Focusing on advanced stage patients with a positive iPET2, the 5-year PFS was 59% for patients shifted to intensified therapy at any time point versus 61% for patients who never received intensified therapy. Our study confirmed the higher curability of naïve cHL patients in a real-world setting, and the prognostic role of iPET2 in this setting. A poor adherence to response-adapted strategy which however did not translate into a difference in patient outcomes.

Long-time follow-up of patients with untreated peripheral T cell lymphoma following chidamide combined with cyclophosphamide, epirubicin, vindesine, prednisone, and etoposide therapy: a single-center propensity score-matching study

Purpose This is a retrospective, single-center PSM study evaluating the efficacy and safety of chidamide combined with the CHOEP (C-CHOEP) regimen versus the single CHOEP regimen in patients with untreated peripheral T cell lymphomas (PTCL). Patients Patients newly diagnosed with PTCL between January 2015 and June 2021 were recruited, and were 1:1 divided into C-CHOEP and CHOEP groups according to their first-line chemotherapy regimens. The PSM method was used to match the baseline variables to balance the confounding factors. Results A cohort of 33 patients each in the C-CHOEP and CHOEP groups was generated after propensity score-matching (PSM). The complete remission (CR) rates of the C-CHOEP regimen were higher than that of the CHOEP regimen (56.3 vs. 25.8%, p = 0.014), whereas the duration of response of the C-CHOEP group was shorter (median DOR 30 vs. 57 months), resulting in roughly similar progression-free survival (PFS) and (overall survival) OS between the two groups. The responding patients who received chidamide maintenance therapy showed a trend of superior PFS and OS compared with patients who did not receive maintenance therapy. Conclusions The C-CHOEP regimen was well tolerated but failed to show advantages over the CHOEP regimen in patients with untreated PTCL; however, the chidamide maintenance may contribute to a more durable response and stable long-term survival (AU)

Clinicopathological features and prognosis of primary pulmonary rhabdomyosarcoma in middle-aged and elderly patients: a case report and literature review.

To date, only 34 cases of primary pulmonary rhabdomyosarcoma (PPRMS) in the middle-aged and elderly population have been published. However, analyses of the clinicopathological characteristics and prognosis of PPRMS in this population have not been performed. A 75-year-old man visited our hospital because of abdominal pain and discomfort. His serum lactate dehydrogenase, neuron specific enolase, and progastrin-releasing peptide levels were elevated. Positron emission tomography-computed tomography revealed a lobulated mass of 7.6 × 5.5 cm2 in the lower lobe of the left lung with abnormally high fluoro-2-deoxy-d-glucose metabolism. Histologically, the tumor cells were small with little cytoplasm, deep nuclear staining, and heavily stained nuclear chromatin. Immunohistochemically, the tumor cells were positive for desmin, MyoD1 myogenin, synaptophysin, and CD56. Cytogenetic analysis for FOXO1A translocation was negative. Finally, the patient was diagnosed with PPRMS. He received combined chemotherapy with vincristine 1 mg, actinomycin 0.4 mg, cyclophosphamide 0.8 mg; however, only one course of chemotherapy was completed, and the patient died 2 months after diagnosis. PPRMS in middle-aged and elderly people is a highly malignant soft tissue tumor with significant clinicopathological characteristics.

EMACO for treatment of gestational trophoblastic neoplasia: A multinational multicenter study.

OBJECTIVE: To investigate the efficacy and toxicity of etoposide, methotrexate, actinomycin D alternating with cyclophosphamide, and vincristine (EMACO) for treatment of gestational trophoblastic neoplasia, and for factors independently associated with EMACO resistance and disease-specific death in an international cohort. METHODS: Medical records of GTN patients who received EMACO during 1986-2019 from gestational trophoblastic disease centers from four countries including the USA, Thailand, Hungary, and Brazil, were retrospectively reviewed. Among 335 GTN patients, 266 patients who received EMACO as primary chemotherapy were included in the primary treatment group, and 69 patients who received EMACO after relapse/resistance to single-agent chemotherapy were included in the prior treatment group. RESULTS: Three-quarters (76.1%) of all patients achieved remission, and the survival rate was 89%. The prior treatment group had better outcomes than the primary treatment group relative to remission rate (87.0% vs. 73.3%, p = 0.014) and number of EMACO cycles to achieve remission (3 vs. 6 cycles, p < 0.001). Sustained remission increased to 87.2% in EMACO-resistant patients treated with later-line chemotherapy. Number of metastatic organs ≥2 (adjusted odds ratio [aOR]: 2.33, p = 0.049) was the only independent predictor of EMACO resistance among overall patients. Interval from index pregnancy ≥7 months (aOR: 4.34, p = 0.001), and pretreatment hCG >100,000 IU/L (aOR: 2.85, p = 0.028) were independent predictors of EMACO resistance in the high-risk subgroup. The only factor independently associated with disease-specific death was EMACO resistance (aOR: 176.04, p < 0.001). CONCLUSIONS: EMACO is an effective treatment for GTN. Number of metastatic organs and EMACO resistance were the independent predictors of EMACO resistance and disease-specific death, respectively.

NUT Carcinoma in Children and Adolescents: The Expert European Standard Clinical Practice Harmonized Recommendations.

BACKGROUND AND AIMS: Nuclear protein of the testis ( NUT ) carcinoma (NC) is a rare and highly aggressive tumor mainly occurring in adolescents and young adults, defined by the presence of a somatic NUTM1 rearrangement. The aim is to establish internationally harmonized consensus recommendations for the diagnosis and treatment of adolescents and young adults with NC in the framework of the European Reference Network for Paediatric Oncology. METHODS: The European Cooperative Study Group for Pediatric Rare Tumors developed recommendations according to the Consensus Conference Standard Operating procedure methodology and reviewed by external "experts." No evidence of level I to II exists. Recommendations were developed based on published prospective (level III), but more frequently retrospective series (level IV), case reports (level V), and personal expertise (level V). In addition, "strength" of recommendations were categorized by grading (grade A to E). RESULTS: Histology is mandatory for the diagnosis of NC, including immunolabeling with anti-NUT antibodies and molecular biology ( NUTM1 rearrangement) (level V; grade A). Treatment of NC usually combines aggressive approaches in multimodal regimens. Chemotherapy should be considered as first-line treatment (neoadjuvant vincristine-adriamycin-ifosfamide/cisplatin-adriamycin-ifsofamide or vincristine-doxorubicin-cyclophosphamide/ifosfamide-etoposide) for unresectable or metastatic tumor (ie, 3 courses), rapidly followed by local treatment (level IV; grade B). Referral to a specialized surgical oncology center is highly recommended (level V; grade A). In localized NC, a complete microscopic surgical resection should be attempted whenever and as soon as possible, followed by primary irradiation (60 to 70 Gy) and involved lymph nodes area (level IV; grade B). For head and neck tumors, a systematic neck dissection might be considered, even if N0 (level V; grade C). Adjuvant postirradiation chemotherapy is recommended, for a total of 9 to 12 courses (level IV; grade B). For first-line resected tumors, concomitant adjuvant chemotherapy to radiotherapy may be discussed (level IV; grade B). Targeted therapies and immunotherapeutic regimens should be delivered in the setting of prospective trials (level V; grade B). CONCLUSIONS: This project leads to a consensus strategy based on international experience with this very rare disease.

Rabdomiossarcoma de ovário em paciente jovem: Relato de caso / Ovarian rhabdomyosarcoma in a young patient: report of case

O sarcoma de partes moles mais comum na infância é o rabdomiossarcoma. Entretanto a localização ovariana é extremamente rara. Acredita-se que este tumor se origina de células imaturas destinadas a compor o músculo esquelético, porém pode surgir em locais onde tipicamente não há músculo esquelético. O diagnóstico do Rabdomiossarcoma primário de ovário pode causar um dilema entre os clínicos, cirurgiões e patologistas, por se tratar de um tumor muito raro. Após o diagnóstico, é necessária a investigação de possíveis metástases. Este caso trata de uma paciente de 17 anos, submetida a parto cesáreo e, no intraoperatório, foi observado aumento de volume, inespecífico, de ovário direito sendo optado por não abordar naquele momento. De antecedentes pessoais, apresentava ooforectomia esquerda aos 13 anos, por Tumor de células da granulosa juvenil e lobectomia inferior esquerda por malformação adenomatosa cística aos 7 anos. Deu entrada no Pronto Socorro 17 dias após dar à luz com queixa de febre, vômitos e dor abdominal. Foi realizada ultrassonografia de urgência, onde foi visualizada massa sólida em fossa ilíaca direita medindo 14,0 x 11,2 x 10,8 cm. Realizada laparotomia exploradora com anexectomia direita e cito-redução subótima do tumor. O resultado anátomo-patológico demonstrou neoplasia maligna fusocelular com áreas de necrose em ovário. A complementação com o estudo imunohistoquímico concluiu rabdomiossarcoma embrionário. Ela voltou a procurar atendimento no Pronto Socorro dois meses após a abordagem com queixa de vômitos biliosos e epigastralgia. Realizou tomografia computadorizada que identificou recidiva do tumor. Durante a internação, evoluiu com quadro de tromboembolismo pulmonar agudo. Diante disso, foi iniciada terapia com enoxaparina em dose plena e quimioterapia com esquema VAC (Vincristina, Doxorrubicina e Ciclofosfamida). Entretanto, ela apresentou insuficiência de múltiplos órgãos, que culminou com o óbito da paciente. O curso clínico desse caso mostra a rápida progressão e letalidade dessa neoplasia. Além da histopatologia, a idade, o tamanho do tumor, a ressecabilidade, o subtipo histopatológico, a presença de metástase no momento do diagnóstico e a invasão linfonodal influenciam no curso clínico da doença. Palavras-chave: Neoplasias ovarianas. Rabdomiossarcoma. Ovário.

Brentuximab Vedotin with Chemotherapy in Pediatric High-Risk Hodgkin's Lymphoma.

BACKGROUND: In adults with advanced-stage Hodgkin's lymphoma, the CD30-directed antibody-drug conjugate brentuximab vedotin combined with multiagent chemotherapy has been shown to have greater efficacy, but also more toxic effects, than chemotherapy alone. The efficacy of this targeted therapy approach in children and adolescents with Hodgkin's lymphoma is unclear. METHODS: We conducted an open-label, multicenter, randomized, phase 3 trial involving patients 2 to 21 years of age with previously untreated Hodgkin's lymphoma of stage IIB with bulk tumor or stage IIIB, IVA, or IVB. Patients were assigned to receive five 21-day cycles of brentuximab vedotin with doxorubicin, vincristine, etoposide, prednisone, and cyclophosphamide (brentuximab vedotin group) or the standard pediatric regimen of doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide (standard-care group). Slow-responding lesions, defined by a score of 4 or 5 (on a 5-point scale, with scores of 1 to 3 indicating rapid-responding lesions), were identified on centrally reviewed positron-emission tomography-computed tomography after two cycles. Involved-site radiation therapy was administered after the fifth cycle of therapy to slow-responding lesions and to large mediastinal adenopathy that was present at diagnosis. The primary end point was event-free survival, defined as the time until disease progression occurred, relapse occurred, a second malignant neoplasm developed, or the patient died. Safety and overall survival were assessed. RESULTS: Of 600 patients who were enrolled across 153 institutions, 587 were eligible. At a median follow-up of 42.1 months (range, 0.1 to 80.9), the 3-year event-free survival was 92.1% (95% confidence interval [CI], 88.4 to 94.7) in the brentuximab vedotin group, as compared with 82.5% (95% CI, 77.4 to 86.5) in the standard-care group (hazard ratio for event or death, 0.41; 95% CI, 0.25 to 0.67; P<0.001). The percentage of patients who received involved-site radiation therapy did not differ substantially between the brentuximab vedotin group and the standard-care group (53.4% and 56.8%, respectively). Toxic effects were similar in the two groups. Overall survival at 3 years was 99.3% (95% CI, 97.3 to 99.8) in the brentuximab vedotin group and 98.5% (95% CI, 96.0 to 99.4) in the standard-care group. CONCLUSIONS: The addition of brentuximab vedotin to standard chemotherapy resulted in superior efficacy, with a 59% lower risk of an event or death, and no increase in the incidence of toxic effects at 3 years. (Funded by the National Institutes of Health and others; AHOD1331 ClinicalTrials.gov number, NCT02166463.).

Carfilzomibe no tratamento de pacientes com mieloma múltiplo recidivado ou refratário, que receberam terapia prévia / Carfilzomib in the treatment of patients with relapsed or refractory multiple myeloma who have received prior therapy

INTRODUÇÃO: O mieloma múltiplo (MM) é uma neoplasia hematológica maligna caracterizada pela proliferação descontrolada de plasmócitos alterados na medula óssea, resultando na produção aumentada de imunoglobulinas não funcional (proteína monoclonal). O acúmulo destas imunoglobulinas e a interação dos plasmócitos com outras células da medula óssea resultam em anemia, lesões ósseas, infecções, hipercalcemia, injúria renal, fadiga e dor. A incidência mundial informada pelo Globocan é de 2,2 novos casos por 100.000 habitantes em homens e 1,5/100.000 em mulheres, com ocorrência, a nível mundial, de 176 mil novos casos e 117 mil mortes em 2020. Carfilzomibe é um agente antineoplásico, inibidor de proteassoma que se liga seletiva e irreversivelmente nos sítios ativos. Tem atividade antiproliferativa e pró-apoptóticas. PERGUNTA DE PESQUISA: Kyprolis® (carfilzomibe) em combinação com dexametasona é eficaz e seguro no tratamento de pacientes com mieloma múltiplo recidivado ou refratário que receberam uma terapia prévia quando em comparação a bortezomibe, ciclofosfamida, dexametasona, cisplatina, doxorrubicina, doxorrubicina lipossomal, etoposídeo, melfalana, vincristina ou talidomida? EVIDÊNCIAS CLÍNICAS: O demandante realizou as buscas na literatura utilizando as seguintes bases de dados: The Cochrane Library, Medline via PubMed, Literatura Latino-Americana e do Caribe em Ciências da Saúde (LILACS), Centre for Reviews and Dissemination (CRD), o que resultou na inclusão de 14 publicações. Na análise conduzida pela Secretaria Executiva foram consideradas 12 publicações referentes a um ensaio clínico randomizado e uma publicação de revisão sistemática. O estudo ENDEAVOR foi um ensaio clínico de fase III, multicêntrico, aberto, que incluiu 929 participantes randomizados para receber carfilzomibe+dexametasona ou bortezomibe+dexametasona. A mediana de SLP foi 18,7 meses (IC 95%, 15,6 a não estimável) no grupo que recebeu carfilzomibe comparado a 9,4 meses (IC 95%, 8,4 a 10,4) no grupo que recebeu bortezomibe, resultando em uma magnitude de benefício absoluto de 9,3 meses (HR 0,53 [IC95% 0,44 a 0,65]; p< 0,0001). A duração mediana de resposta foi 21,3 meses (IC95% 21,3 a não estimável) no grupo carfilzomibe e 10,4 meses (IC95% 9,3 a 13,8) no grupo bortezomibe. Em ambos os grupos, 98% dos participantes apresentaram eventos adversos (qualquer grau), sendo a anemia (43% versus 28%), diarreia (36,7% versus 40,6%) e febre (32,6% versus 15,4%) os eventos mais frequentes nos grupos carfilzomibe e bortezomibe, respectivamente. Os eventos adversos mais comuns grau 3 ou maior foram reportados em 81,9% dos participantes do grupo carfilzomibe (n=379) e 71,1% no grupo bortezomibe (n=324), sendo a anemia (17,3% no grupo carfilzomibe e 10,1% no grupo bortezomibe), hipertensão (14,9% versus 3,3%), trombocitopenia (12,5% versus 14,7%),os três eventos mais frequentes. Insuficiência cardíaca grau 3 ou superior, foi mais frequente no grupo carfilzomibe (6%) que no grupo bortezomibe (2%.). AVALIAÇÃO ECONÔMICA: O demandante apresentou uma análise de custo-efetividade. Na análise do cenário base, em um horizonte temporal de 30 anos, carfilzomibe acrescentou ganhos incrementais de 1,19 QALY, resultando em uma razão de custo utilidade incremental (RCEI) de R$ 195.310,00 por QALY. No cenário proposto pela Secretária-Executiva (horizonte temporal de 10 anos e valor de utilidade derivada do estudo ENDEAVOR), carfilzomibe gerou benefício de 0,63 QALY, com RCEI de R$ 365.830,00 por QALY. ANÁLISE DE IMPACTO ORÇAMENTÁRIO: Com o desconto apresentado pelo demandante, a incorporação de carfilzomibe ao SUS implica em custos adicionais ao sistema de saúde no montante de aproximadamente R$ 365 milhões em cinco anos. A principal limitação da análise foi a estimativa da população. MONITORAMENTO DO HORIZONTE TECNOLÓGICO: Foram identificadas 10 tecnologias potenciais para compor o esquema terapêutico de pacientes adultos com mieloma múltiplo recidivado ou refratário: Belantamabe mafodotin, Ciltacabtageno autoleucel, Elranatamab, Iberdomida, Idecabtagene vicleucel, Isatuximabe, nivolumabe, selinexor, teclistamab, venetoclax. Tais medicamentos são anticorpo monoclonal ligado a um antineoplásico, anticorpo biespecífico, anticorpo monoclonal, imumodulador, terapias baseadas em células T autólogas geneticamente modificadas (CAR-T), inibidor SINE, ou inibidor de Bcl-2. A maioria não possui registro na FDA, EMA ou Anvisa. CONSIDERAÇÕES FINAIS: Os resultados sugerem eficácia e segurança do carfilzomibe na população elegível, porém, no horizonte temporal de 10 anos, com QALY < 1, RCEI de R$ 365.830,00 por QALY e impacto orçamentário de aproximadamente R$ 17 milhões no primeiro ano de incorporação e R$ 131 milhões no 5º ano da incorporação, totalizando R$ 365 milhões em cinco anos. RECOMENDAÇÃO PRELIMINAR DA CONITEC: Os membros do Plenário presentes na 109ª Reunião Ordinária da Conitec, realizada no dia 08 de junho de 2022, sem nenhuma declaração de conflito de interesse, deliberaram por unanimidade, encaminhar o tema para consulta pública com recomendação preliminar desfavorável à incorporação de carfilzomibe para o tratamento de mieloma múltiplo recidivado ou refratário no SUS. Os membros consideraram a evidência científica boa e favorável ao carfilzomibe, porém, a RCEI e o impacto orçamentário foram considerados muito altos para o tratamento de uma doença que já tem outras opções terapêuticas disponíveis no SUS. CONSULTA PÚBLICA: Entre os dias 08/07/2022 e 27/07/2022 foram recebidas 421 contribuições, sendo 152 pelo formulário para contribuições técnico-científicas e 269 pelo formulário para contribuições sobre experiência ou opinião de pacientes, familiares, amigos ou cuidadores de pacientes, profissionais de saúde ou pessoas interessadas no tema. A maioria foi a favor da incorporação de carfilzomibe no SUS (97% via formulário técnico-científico e 100%). O principal benefício apontado nas contribuições técnico-científicas foi sobre a eficácia, aumento da sobrevida e qualidade de vida, além da disponibilidade de mais uma opção terapêutica e promoção da igualdade no tratamento nos sistemas público e privado de saúde. A empresa detentora do registro do medicamento atualizou o preço do medicamento, e consequentemente os valores do impacto orçamentário e avaliação econômica. No impacto orçamentário o valor ficou em R$ 95,3 milhões em cinco anos. Nas contribuições de experiência e opinião, a totalidade dos respondentes discordou da recomendação preliminar da Conitec. No âmbito das opiniões e experiências positivas, foi mencionada a necessidade de garantir o acesso ao carfilzomibe, especialmente por representar uma alternativa para pacientes recidivados e refratários. Também foi citada a eficácia da tecnologia. Como dificuldades, destacou-se a falta de acesso pelo SUS. Em relação a outros medicamentos, foram mencionados benefícios, mas, também, a eficácia limitada no caso de pacientes recidivados. RECOMENDAÇÃO FINAL DA CONITEC: Os membros do Plenário da Conitec, em sua 112ª Reunião Ordinária, realizada no dia 31 de agosto de 2022, deliberaram por maioria simples, recomendar a não incorporação no SUS de carfilzomibe para o tratamento de pacientes com mieloma múltiplo recidivado ou refratário, que receberam terapia prévia, no SUS. Não houve apresentação de dados clínicos adicionais. Com o preço do medicamento atualizado, ainda assim não se mostrou custo-efetivo. Foi assinado o Registro de Deliberação nº 765/2022. DECISÃO: Não incorporar, no âmbito do Sistema Único de Saúde - SUS, o carfilzomibe para o tratamento de pacientes com mieloma múltiplo recidivado ou refratário, conforme a Portaria nº 107, publicada no Diário Oficial da União nº 184, seção 1, página 75, em 27 de setembro de 2022.

Efficacies of FAEV and EMA/CO regimens as primary treatment for gestational trophoblastic neoplasia.

BACKGROUND: Guidelines recommend etoposide, methotrexate, actinomycin D (EMA)/cyclophosphamide, vincristine (CO) as first-line treatment for high-risk gestational trophoblastic neoplasia (GTN). However, the floxuridine, actinomycin D, etoposide and vincristine (FAEV) regimen is commonly used to treat these patients in China. We conducted a randomised controlled trial to compare the efficacies and toxicities of FAEV and EMA/CO. METHODS: Ninety-four patients with GTN were enrolled between May 2015 and April 2019 and randomly assigned to the FAEV or EMA/CO regimen. The rates of complete remission and relapse and the toxicities were compared in August 2021. RESULTS: Five patients were excluded from the analysis. There were 46 patients in the FAEV group and 43 patients in the EMA/CO group. The complete remission rates following primary treatment were 89.1% and 79.1% (P = 0.193), respectively. The relapse rates were 8.7% and 9.3% (P = 0.604). The apparent incidences of grade 4 myelosuppression were 60.9% and 32.6% (P = 0.008), respectively; however, they became both 32.6% (P = 0.996) after granulocyte colony-stimulating factor support. Other adverse reactions were similar in the two groups. No patient died of disease. CONCLUSION: FAEV has comparable efficacy and toxicity to EMA/CO as the primary treatment for high-risk GTN, and may thus be another first-line choice of chemotherapy. CLINICAL TRIAL REGISTRATION: chictr.org.cn: ChiCTR1800017423.

Extending Treatment Intervals of R-CHOP Therapy Might Be Acceptable for Some Patients with Non-indolent Non-Hodgkin's B-cell Lymphoma.

R-CHOP therapy is generally performed every 3 weeks. We investigated the effects of extending the interval of R-CHOP therapy for > 1 week on the prognoses of patients with non-indolent non-Hodgkin's B-cell lymphoma. Among the 338 patients with non-indolent non-Hodgkin's B-cell lymphoma who received initial chemotherapy at our institution, we focused on 178 patients who received R-CHOP therapy and analyzed the outcomes of the patients stratified by the treatment intervals. The estimated 3-year overall survival (OS) for the entire population was 82.1%. Patients treated at intervals of ≥ 4 weeks were significantly older, and they had significantly longer follow-up periods and lower relative dose intensity. But the estimated 3-year OS was comparable to those treated at <4 weeks (83.3% vs. 80.5% p=0.947). In a multivariate analysis, age and the dose of anti-cancer agents had significant impacts on OS, but there was no significant relationship regarding the treatment intervals. Propensity score matching confirmed the same result. R-CHOP therapy every around 4 weeks could achieve relatively good survival in some selected patients with non-indolent non-Hodgkin's B-cell lymphoma.

Follicular Lymphoma: a Focus on Current and Emerging Therapies

Follicular lymphoma (FL) is the most common indolent lymphoma and is characterized by a relapsing and remitting course. In addition to significant biologic heterogeneity, the clinical trajectory for patients is variable, with some being observed for many years, and others having aggressive disease requiring multiple treatment courses. Unfortunately, FL remains incurable, and continues to cause early mortality. Improved understanding of the genetic and immune biology of FL has led to several FDA-approved therapies in the relapsed and refractory setting, including PI3K inhibitors; immunomodulatory agents; the EZH2 inhibitor, tazemetostat; and anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, axicabtagene ciloleucel. This review outlines the current approach to the diagnosis and treatment of FL with a focus on emerging investigational therapies, including targeted protein inhibitors, antibody-drug conjugates, monoclonal antibodies, bispecific antibodies, and novel combination strategies.

Venetoclax plus dose-adjusted R-EPOCH for Richter syndrome.

Richter syndrome (RS) of chronic lymphocytic leukemia (CLL) is typically chemoresistant, with a poor prognosis. We hypothesized that the oral Bcl-2 inhibitor venetoclax could sensitize RS to chemoimmunotherapy and improve outcomes. We conducted a single-arm, investigator-sponsored, phase 2 trial of venetoclax plus dose-adjusted rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (VR-EPOCH) to determine the rate of complete response (CR). Patients received R-EPOCH for 1 cycle, then after count recovery, accelerated daily venetoclax ramp-up to 400 mg, then VR-EPOCH for up to 5 more 21-day cycles. Responders received venetoclax maintenance or cellular therapy off-study. Twenty-six patients were treated, and 13 of 26 (50%) achieved CR, with 11 achieving undetectable bone marrow minimal residual disease for CLL. Three additional patients achieved partial response (overall response rate, 62%). Median progression-free survival was 10.1 months, and median overall survival was 19.6 months. Hematologic toxicity included grade ≥3 neutropenia (65%) and thrombocytopenia (50%), with febrile neutropenia in 38%. No patients experienced tumor lysis syndrome with daily venetoclax ramp-up. VR-EPOCH is active in RS, with deeper, more durable responses than historical regimens. Toxicities from intensive chemoimmunotherapy and venetoclax were observed. Our data suggest that studies comparing venetoclax with chemoimmunotherapy to chemoimmunotherapy alone are warranted. This trial was registered at www.clinicaltrials.gov as #NCT03054896.

Response-Adapted Postinduction Strategy in Patients With Advanced-Stage Follicular Lymphoma: The FOLL12 Study.

PURPOSE: We compared 2 years of rituximab maintenance (RM) with a response-adapted postinduction approach in patients with follicular lymphoma who responded to induction immunochemotherapy. METHODS: We randomly assigned treatment-naïve, advanced-stage, high-tumor burden follicular lymphoma patients to receive standard RM or a response-adapted postinduction approach on the basis of metabolic response and molecular assessment of minimal residual disease (MRD). The experimental arm used three types of postinduction therapies: for complete metabolic response (CMR) and MRD-negative patients, observation; for CMR and MRD-positive (end of induction or follow-up) patients, four doses of rituximab (one per week, maximum three courses) until MRD-negative; and for non-CMR patients, one dose of ibritumomab tiuxetan followed by standard RM. The study was designed as noninferiority trial with progression-free survival (PFS) as the primary end point. RESULTS: Overall, 807 patients were randomly assigned. After a median follow-up of 53 months (range, 1-92 months), patients in the standard arm had a significantly better PFS than those in the experimental arm (3-year PFS 86% v 72%; P < .001). The better PFS of the standard versus experimental arm was confirmed in all the study subgroups except non-CMR patients (n = 65; P = .274). The 3-year overall survival was 98% (95% CI, 96 to 99) and 97% (95% CI, 95 to 99) in the reference and experimental arms, respectively (P = .238). CONCLUSION: A metabolic and molecular response-adapted therapy as assessed in the FOLL12 study was associated with significantly inferior PFS compared with 2-year RM. The better efficacy of standard RM was confirmed in the subgroup analysis and particularly for patients achieving both CMR and MRD-negative.

Generation and validation of a PET radiomics model that predicts survival in diffuse large B cell lymphoma treated with R-CHOP14: A SAKK 38/07 trial post-hoc analysis.

Functional parameters from positron emission tomography (PET) seem promising biomarkers in various lymphoma subtypes. This study investigated the prognostic value of PET radiomics in diffuse large B-cell lymphoma (DLBCL) patients treated with R-CHOP given either every 14 (testing set) or 21 days (validation set). Using the PyRadiomics Python package, 107 radiomics features were extracted from baseline PET scans of 133 patients enrolled in the Swiss Group for Clinical Cancer Research 38/07 prospective clinical trial (SAKK 38/07) [ClinicalTrial.gov identifier: NCT00544219]. The international prognostic indices, the main clinical parameters and standard PET metrics, together with 52 radiomics uncorrelated features (selected using the Spearman correlation test) were included in a least absolute shrinkage and selection operator (LASSO) Cox regression to assess their impact on progression-free (PFS), cause-specific (CSS), and overall survival (OS). A linear combination of the resulting parameters generated a prognostic radiomics score (RS) whose area under the curve (AUC) was calculated by receiver operating characteristic analysis. The RS efficacy was validated in an independent cohort of 107 DLBCL patients. LASSO Cox regression identified four radiomics features predicting PFS in SAKK 38/07. The derived RS showed a significant capability to foresee PFS in both testing (AUC, 0.709; p < 0.001) and validation (AUC, 0.706; p < 0.001) sets. RS was significantly associated also with CSS and OS in testing (CSS: AUC, 0.721; p < 0.001; OS: AUC, 0.740; p < 0.001) and validation (CSS: AUC, 0.763; p < 0.0001; OS: AUC, 0.703; p = 0.004) sets. The RS allowed risk classification of patients with significantly different PFS, CSS, and OS in both cohorts showing better predictive accuracy respect to clinical international indices. PET-derived radiomics may improve the prediction of outcome in DLBCL patients.

Anticancer properties of vincristine is modulated by microRNAs in acute lymphoblastic leukemia Nalm6 cell line.

Precursor B-cell acute lymphoblastic leukemia (B-ALL), a highly diverse disease, is the most widespread pediatric malignancy characterized by cytogenetic and molecular abnormalities such as altered microRNA (miR) expression signatures. MiRs are a class of short noncoding RNAs. Dysregulation in the expression of miRs plays a crucial role in different types of cancers. Vincristine is an antineoplastic drug with a broad spectrum of activity against different hematologic malignancies and is the first-line treatment for B-ALL. Previous studies have proposed miR-17 and miR-181/b as oncomirs and miR-34/a as a tumor suppressor in Nalm6 cells, thus in the current study, we investigated the effects of vincristine treatment on the expression of miR-17, miR-34/a and miR-181/b expression levels. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide assay was conducted to estimate the optimal concentration of vincristine in the Nalm-6 cell line. Expression of miRs was calculated using real-time PCR. Our results showed significant downregulation of miR-17 (FC = 0.226; P < 0.0004) in Nalm6 cells after vincristine treatment. Conversely, miR-34/a (FC = 4.823; P < 0.0001) was significantly upregulated. Also, the expression of miR-181/b (FC = 0.156; P < 0.3465) was not significantly different between the vincristine treated group and the control group. In conclusion, it is proposed that one of the mechanisms by which vincristine improves B-ALL is by modulating the expression of specific miRs. These specific miRs will serve as good diagnostic and prognostic biomarkers.

Phase 1 study of oral azacitidine (CC-486) plus R-CHOP in previously untreated intermediate- to high-risk DLBCL.

Resistance to standard immunochemotherapy remains an unmet challenge in diffuse large B-cell lymphoma (DLBCL), and aberrant DNA methylation may contribute to chemoresistance. Promising early-phase results were reported with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) plus subcutaneous azacitidine, a hypomethylating agent. In this phase 1 study, we evaluated CC-486 (oral azacitidine) plus 6 cycles of R-CHOP in patients with previously untreated intermediate- to high-risk DLBCL or grade 3B/transformed follicular lymphoma. CC-486 doses of 100, 150, 200, or 300 mg given 7 days before cycle 1 and on days 8-21 of cycles 1-5 were evaluated; additional patients were enrolled in the expansion phase to examine preliminary efficacy. The primary objectives were to determine the safety and the maximum tolerated dose (MTD) of CC-486 in combination with R-CHOP. The most common grade 3/4 toxicities were hematologic, including neutropenia (62.7%) and febrile neutropenia (25.4%); grade 3/4 nonhematologic toxicities were uncommon (<7%). The MTD was not established; 2 patients had dose-limiting toxicities (1 with grade 4 febrile neutropenia; 1 with grade 4 prolonged neutropenia). The recommended phase 2 dose was established as 300 mg. The overall response rate was 94.9%, with 52 patients (88.1%) achieving complete responses. With a median follow-up of 28.9 months, estimated 1- and 2-year progression-free survival rates were 84.1% and 78.6%, respectively. Overall, epigenetic priming with CC-486 before R-CHOP can be delivered with acceptable safety to patients with previously untreated intermediate- to high-risk DLBCL or grade 3B/transformed follicular lymphoma. ClinicalTrials.gov: NCT02343536.

Is it time for PET-guided therapy in follicular lymphoma?

18F-fluorodeoxyglucose positron emission tomography-computed tomography (PET-CT) is now established as the gold-standard imaging modality for both staging and response assessment in follicular lymphoma (FL). In this Perspective, we propose where PET can, and cannot, guide clinicians in their therapeutic approach. PET at diagnosis and pretreatment is important for staging, with greater sensitivity compared with standard CT, and consequent improved outcomes in truly limited-stage FL. Small data sets suggesting that a high baseline standardized uptake value (SUVmax) identifies de novo histologic transformation (HT) have not been corroborated by data from GALLIUM, the largest prospective study to examine modern therapies for FL. Nonetheless, the role of baseline quantitative PET measures requires further clarification. The median survival of patients with newly diagnosed FL is now potentially >20 years. Treatment of symptomatic FL aims to achieve remission and optimize quality of life for as long as possible, with many patients achieving a "functional cure" at the cost of unwanted treatment effects. Several studies have identified end-of-induction (EOI) PET after initial chemoimmunotherapy in patients with a high tumor burden as strongly predictive of both progression-free and overall survival, and EOI PET is being evaluated as a platform for response-adapted treatment. Unmet needs remain: improving the inferior survival for patients remaining PET positive and quantifying the progression-free survival and time to next treatment advantage, and additional toxicity of anti-CD20 maintenance in patients who achieve complete metabolic remission. In the absence of an overall survival advantage for frontline antibody maintenance, the question of using PET to guide the therapeutic approach is more important than ever in the context of the COVID-19 pandemic.