Benefits and risks of clofarabine in adult acute lymphoblastic leukemia investigated in depth by multi-state modeling.

BACKGROUND: We recently reported results of the prospective, open-label HOVON-100 trial in 334 adult patients with acute lymphoblastic leukemia (ALL) randomized to first-line treatment with or without clofarabine (CLO). No improvement of event-free survival (EFS) was observed, while a higher proportion of patients receiving CLO obtained minimal residual disease (MRD) negativity. AIM: In order to investigate the effects of CLO in more depth, two multi-state models were developed to identify why CLO did not show a long-term survival benefit despite more MRD-negativity. METHODS: The first model evaluated the effect of CLO on going off-protocol (not due to refractory disease/relapse, completion or death) as a proxy of severe treatment-related toxicity, while the second model evaluated the effect of CLO on obtaining MRD negativity. The subsequent impact of these intermediate events on death or relapsed/refractory disease was assessed in both models. RESULTS: Overall, patients receiving CLO went off-protocol more frequently than control patients (35/168 [21%] vs. 18/166 [11%], p = 0.019; HR 2.00 [1.13-3.52], p = 0.02), especially during maintenance (13/44 [30%] vs. 6/56 [11%]; HR 2.85 [95%CI 1.08-7.50], p = 0.035). Going off-protocol was, however, not associated with more relapse or death. Patients in the CLO arm showed a trend towards an increased rate of MRD-negativity compared with control patients (HR MRD-negativity: 1.35 [0.95-1.91], p = 0.10), which did not translate into a significant survival benefit. CONCLUSION: We conclude that the intermediate states, i.e., going off-protocol and MRD-negativity, were affected by adding CLO, but these transitions were not associated with subsequent survival estimates, suggesting relatively modest antileukemic activity in ALL.

Clofarabine monotherapy in aggressive, relapsed and refractory Langerhans cell histiocytosis.

Over 50% of patients with systemic LCH are not cured with front-line therapies, and data to guide salvage options are limited. We describe 58 patients with LCH who were treated with clofarabine. Clofarabine monotherapy was active against LCH in this cohort, including heavily pretreated patients with a systemic objective response rate of 92.6%, higher in children (93.8%) than adults (83.3%). BRAFV600E+ variant allele frequency in peripheral blood is correlated with clinical responses. Prospective multicentre trials are warranted to determine optimal dosing, long-term efficacy, late toxicities, relative cost and patient-reported outcomes of clofarabine compared to alternative LCH salvage therapy strategies.

Patient-Level Meta-analysis of Clofarabine in Acute Lymphoblastic Leukemia.

INTRODUCTION: Clofarabine monotherapy at a dose of 52 mg/m2 per day was approved in the USA in 2004 for the treatment of relapsed or refractory acute lymphoblastic leukemia (R/R ALL) in patients aged 1-21 years after at least two prior regimens. To address a post-marketing requirement for additional evidence of the clinical benefit of clofarabine in its approved indication, a meta-analysis of patient-level data was conducted. METHODS: A systematic literature review was conducted, using the Dr.Evidence software platform, DOC Search, and Embase, to identify clinical trials with patients with R/R ALL who received clofarabine monotherapy at 52 mg/m2. The primary endpoint was complete remission (CR). Secondary endpoints were overall remission (OR, defined by CR or CR with either incomplete platelet recovery or incomplete neutrophil and platelet recovery), duration of response, overall survival (OS), and safety. RESULTS: A total of 754 patients in 12 clinical studies were analyzed including 682 patients with R/R ALL treated with clofarabine monotherapy at 52 mg/m2; of them, 374 were aged < 22 years (pediatric population). Rates of CR and OR were 16% (95% confidence interval [CI] 7, 26) and 28% (95% CI 20, 37), respectively, in the pediatric population and 12% (95% CI 5, 21) and 21% (95% CI 13, 31) in the overall population. Median OS (evaluable in three studies in pediatric patients) was 3.7 months (95% CI 0.1, 31.4), reaching 10.1 months (95% CI 0.3, 68.9) for those achieving OR. Sensitivity analyses supported these findings. The most frequent grade 3-4 adverse events were liver abnormalities, anemia, diarrhea, and febrile neutropenia. CONCLUSION: In this meta-analysis, CR duration and median OS in pediatric patients with R/R ALL appeared to be slightly longer than in the phase II study. No new safety signals were identified. Results support the use of clofarabine monotherapy in its approved indication.

Vorinostat Combined with Busulfan, Fludarabine, and Clofarabine Conditioning Regimen for Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Acute Leukemia: Long-Term Study Outcomes.

Conditioning regimens play a major role in determining disease outcomes following allogeneic hematopoietic stem cell transplantation (allo-HSCT). The use of i.v. busulfan (Bu) as part of conditioning chemotherapy has been shown to be effective in controlling disease relapse; however, disease relapse remains a major cause of death following allo-HSCT. This study was conducted to determine the long-term outcomes of vorinostat with i.v. Bu plus dual nucleoside analogs clofarabine (Clo) and fludarabine (Flu) in the conditioning regimen for patients undergoing allo-HSCT. This was a rapid dose escalation phase I/II study designed to determine whether the addition of vorinostat would improve the efficacy of standard i.v. Bu/Flu/Clo conditioning regimen. This report presents the long-term disease outcomes of this combination in 68 patients with high-risk leukemia, including 31 (46%) with acute lymphoblastic leukemia (ALL) and 37 (54%) with acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS). Fifty-eight patients (85%) were in morphologic complete remission at time of transplantation, and 38 (56%) received a matched unrelated donor graft. Over the median follow-up of 37.6 months, 29 of the 68 patients died (43%), and the nonrelapse mortality (NRM) rate was 22% (n = 15). The median overall survival and median NRM were not reached. Nineteen patients (28%) experienced disease progression. The median progression-free survival was 36.8 months. Thirty-seven patients (57%) developed grade II-IV acute graft-versus-host disease (GVHD), and 20 patients (31%) developed chronic GVHD. Our results suggest a lack of benefit from adding a short course of vorinostat to i.v. Bu/Flu/Clo conditioning regimens for leukemia patients undergoing allo- HSCT.

Molecular and Pharmacological Bladder Cancer Therapy Screening: Discovery of Clofarabine as a Highly Active Compound.

BACKGROUND: The heterogeneity of bladder cancers (BCs) is a major challenge for the development of novel therapies. However, given the high rates of recurrence and/or treatment failure, the identification of effective therapeutic strategies is an urgent clinical need. OBJECTIVE: We aimed to establish a model system for drug identification/repurposing in order to identify novel therapies for the treatment of BC. DESIGN, SETTING, AND PARTICIPANTS: A collection of commercially available BC cell lines (n = 32) was comprehensively characterized. A panel of 23 cell lines, representing a broad spectrum of BC, was selected to perform a high-throughput drug screen. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Positive hits were defined as compounds giving >50% inhibition in at least one BC cell line. RESULTS AND LIMITATIONS: Amongst >1700 tested chemical compounds, a total of 471 substances exhibited antineoplastic effects. Clofarabine, an antimetabolite drug used as third-line treatment for childhood acute lymphoblastic leukaemia, was amongst the limited number of drugs with inhibitory effects on cell lines of all intrinsic subtypes. We, thus, reassessed the substance and confirmed its inhibitory effects on commercially available cell lines and patient-derived cell cultures representing various disease stages, intrinsic subtypes, and histologic variants. To verify these effects in vivo, a patient-derived cell xenograft model for urothelial carcinoma (UC) was used. Well-tolerated doses of clofarabine induced complete remission in all treated animals (n = 12) suffering from both early- and late-stage disease. We further took advantage of another patient-derived cell xenograft model originating from the rare disease entity sarcomatoid carcinoma (SaC). Similarly to UC xenograft mice, clofarabine induced subcomplete to complete tumour remissions in all treated animals (n = 8). CONCLUSIONS: The potent effects of clofarabine in vitro and in vivo suggest that our findings may be of high clinical relevance. Clinical trials are needed to assess the value of clofarabine in improving BC patient care. PATIENT SUMMARY: We used commercially available cell lines for the identification of novel drugs for the treatment of bladder cancer. We confirmed the effects of one of these drugs, clofarabine, in patient-derived cell lines and two different mouse models, thereby demonstrating a potential clinical relevance of this substance in bladder cancer treatment.

A randomised comparison of FLAG-Ida versus daunorubicin combined with clofarabine in relapsed or refractory acute myeloid leukaemia: Results from the UK NCRI AML17 trial.

The prognosis for younger patients with relapsed acute myeloid leukaemia (AML) is generally dismal. Allogeneic stem cell transplantation is the preferred therapy for these patients. As part of the UK NCRI AML17 trial, daunorubicin/clofarabine (DClo) was compared with fludarabine, cytarabine, granulocyte colony-stimulating factor with idarubicin (FLAG-Ida) in 311 patients designated high-risk following course one of induction therapy, which has previously been reported. We now report the results of the same randomisation in patients who were refractory to two induction courses or subsequently relapsed. A total of 94 relapsed or refractory AML patients, usually less than 60 years of age and with mainly favourable or intermediate-risk cytogenetics, were randomised to receive up to three courses of DClo or FLAG-Ida, with the aim of proceeding to transplant. Complete remission was achieved in 74% of patients with no difference between the arms. Overall, 57% of patients received a transplant with no difference between the arms, likewise overall survival at five years showed no significant difference (21% for DClo vs. 22% for FLAG-Ida). No patient who did not receive a transplant survived beyond 21months. A stratified analysis including the 311 post course 1 high-risk patients who underwent the same randomisation showed a consistent treatment benefit for FLAG-Ida.

Eficacia y seguridad sobre el uso de Clofarabina con quimioterapia en Leucemia linfoblástica aguda o Leucemia mieloide aguda en recaída/refractarios a 1 o más líneas de tratamiento previa, en menores de 21 años, como puente de tratamiento antes de Trasplante de células progenitoras hematopoyéticas / Efficacy and safety on the use of Clofarabine with chemotherapy in leukemia acute lymphoblastic or myeloid leukemia acute relapsed/refractory to 1 or more previous lines of treatment, in children under 21 years, as a treatment bridge before stem cell transplant hematopoietic

ANTECEDENTES: En cumplimiento del inciso e, sobre nuestras funciones como UFETS, que dice: "Evaluar las tecnologías sanitarias ya existentes en la entidad, y proponer estrategias para su uso eficiente y/o reposición", realizamos esta revisión rápida. ESTRATEGIA DE BÚSQUEDA DE INFORMACIÓN: a) Pregunta Clínica: En los pacientes menores de 21 años con leucemia linfoblástica aguda/leucemia mieloide aguda en recaída/refractario a 1 o más líneas de tratamiento previas, ¿Es eficaz y seguro Clofarabina asociada a quimioterapia como terapia puente hacia un trasplante de células progenitoras hematopoyéticas? b) Recolección de los Manuscritos a Revisar: Tipos de estudios: La estrategia de búsqueda sistemática de información científica para el desarrollo del presente informe se realizó siguiendo las recomendaciones de la Pirámide jerárquica de la evidencia propuesta por Haynes y se consideró los siguientes estudios: Guías de práctica clínica.. Documentos Técnicos institucionales. Ensayos fase 2, no randomizados. Estudios Observacionales (cohortes, descriptivos). INFORMACIÓN QUE SOPORTE LA RELEVANCIA PARA LA SALUD PÚBLICA: En las leucemias agudas, de acuerdo a la edad de presentación, se establece su tasa de incidencia y de mortalidad. En la población pediátrica es el cáncer más frecuente comprendiendo aproximadamente más de un tercio (39,8%) de todas las neoplasias malignas, según el Registro de Cáncer de Lima Metropolitana (2013-2015) con una incidencia de 78,44 por millón, cifras mayores respecto al periodo 2010-2012. Según los Datos epidemiológicos del Departamento de Estadística del Instituto Nacional de Enfermedades Neoplásicas (INEN), las leucemias ocupan el cuarto lugar de casos nuevos registrados entre los años 2008-2018; obteniendo en el año 2018 un total de 673 nuevos casos, cifras que se van incrementando cada año. En el periodo 2013-2015 en la población no pediátrica ocurrieron 2047 casos nuevos de leucemias entre los residentes de Lima Metropolitana con una tasa de incidencia estandarizada de 7,1 casos por 100 000 habitantes, representando el 2,9% de todas las neoplasias malignas. Teniendo en cuenta la mortalidad para ambos sexos, las leucemias fueron la séptima causa de muerte por cáncer en Lima Metropolitana, registrándose 1443 muertes por leucemia entre los años 2013 y 2015, correspondiéndole una tasa de mortalidad de 4,8 muertes por 100 000 habitantes. En la población pediátrica, la tasa de mortalidad estandarizada por edad por millón de niños fue de 66,15 para ambos sexos; dichas cifras son mayores a las del periodo 2010-2012. Así como de acuerdo al linaje (linfoide o mieloide) se administra un tratamiento inicial (inducción, consolidación, mantenimiento) buscando una remisión completa de enfermedad). Se debe tomar en cuenta a los pacientes que presentan recaídas de enfermedad (tempranas menor a 12 meses o tardías mayor a 12 meses), como así también a los pacientes refractarios al tratamiento inicial. La importancia de brindar dichos tratamientos de rescate en el mejor momento recae en el estudio de Ko et al (2010)3 , donde se observó la disminución de las tasas de remisión de una cohorte retrospectiva con tasas de respuesta completa (RC) de 44%, 27% y 12%, después de 2, 3 y 4 recaídas respectivamente. El objetivo en los pacientes con recaída/refractariedad es llegar a una remisión completa para proceder a un trasplante de consolidación (Trasplante alogenico, haploidentico o de donante no emparentado). Se cuenta con algunos esquemas de rescate, dentro de los cuales tenemos a la clofarabina asociado con otras drogas de quimioterapia. Mencionar que la clofarabina es un análogo nucleosido de purina, la cual para activarse debe fosforilarse hasta alcanzar un trifosfato, dicha activación desencadenas las siguientes reacciones intracelulares: inhibe la ribonucleotido reductasa, disminuye el ADN polimerasa y también puede promover la apoptosis mediada por la mitocondria. Los dos primeros ejercen una actividad dentro del núcleo celular ocasionando una disminución de la incorporación del ADN, así como la inhibición de la síntesis o reparación del ADN, llevando en su conjunto a la muerte celular. El presente informe analizará la eficacia y seguridad de Clofarabina más quimioterapia como tratamiento en pacientes menores de 21 años con LLA o LMA en recaída/refractariedad a una o más líneas de tratamiento, como terapia puente hacia un trasplante. DISCUSIÓN: Tomando los criterios para un marco de valor de la Health Technology Assessment International (2018)19 para la toma de decisiones y formulación de la recomendación, se describe: Se han encontrado estudios clínicos fase 2, multicéntricos, no aleatorizados, así como 06 estudios retrospectivos de reportes de casos, los cuales han demostrado eficacia y seguridad con el uso de Clofarabina, con una tasa de respuesta global (ORR) entre 40- 50%, sin embargo teniendo en cuenta que el tiempo de la respuesta es corta, requiriendo realizar la terapia puente de consolidación con un Trasplante de células progenitoras (alogénico, Haploidéntico, donante no emparentado) en el menor tiempo posible. Se ha tomado en cuenta dentro de las Tasas de respuesta global (ORR) a los pacientes que alcanzaron Respuesta completa (RC) y Respuesta completa sin recuperación de plaquetas (RCp). Así mismo los datos de EFS y OS no estuvieron bien determinados en todos los estudios, por el tipo de diseño empleado. La importancia recae en administrar dicho régimen de rescate (Clofarabina, Ciclofosfamida, Etoposido) en el mejor momento, tratando de tener un menor número de recaídas para obtener la mejor respuesta en relación a ORR. La población de nuestra institución es similar a la enrolada. Además, el beneficio de administrar el régimen triple con Clofarabina es superior a no administrar ningún medicamento o solo mantener algún manejo paliativo. El impacto económico de esta tecnología para el INEN pareciera no afectarse ya que la población es poca (aproximadamente 04 pacientes al año), además que comparando con otras alternativas de tratamiento como Inmunoterapia (Blinatumomab) o CAR-T cell, las cuales al momento no contamos con ellas en el mercado nacional, son tecnologías de muy alto costo al momento. Luego de la discusión, se comenta que la calidad de la evidencia es baja, sin embargo, el panel concluye que el uso de Clofarabina mas quimioterapia (ciclofosfamida y etoposido) es una opción de tratamiento en pacientes menores de 21 años con LLA o LMA en recaída /refractariedad a 1 o más líneas de tratamiento previas, sirviendo como terapia puente antes del trasplante de células progenitoras. CONCLUSIONES: Dentro de la población de pacientes menores de 21 años con leucemias agudas (linfoblásticas o mieloides), existe un grupo que presenta recaída de enfermedad entre 10-20% y los refractarios entre 2-3%, siendo la sobrevida a 5 años de estos pacientes en un 30-40%; por lo cual es importante el manejo que se dé en estos casos. Se realizó la búsqueda sistemática de la evidencia y se identificaron dos ensayos clínicos fase II no comparativos y 06 estudios observacionales de series de casos, que incluyeron pacientes con una o más líneas de tratamiento previas. Además, se realizó una búsqueda dirigida y se identificó 03 Guías de Práctica Clínica (GPC) y 01 informe de ETS. Las tasas de remisión disminuyen progresivamente conforme aumenta el número de regímenes previos de tratamiento. La terapia triple (Clofarabina, Ciclofosfamida, Etoposido) es el régimen de elección, alcanzado RC y RCp en casi la mitad de los pacientes (40-50%), sin embargo, la duración de respuesta es corta, por lo que se requiere su uso en el momento adecuado. Por no tener adecuadas estrategias metodológicas la evidencia seria de baja calidad. Sin embargo, es una opción de tratamiento necesaria en búsqueda de remisión de enfermedad y llegar al trasplante. Siendo el objetivo de la terapia triple ser una "Terapia puente" para un Trasplante, el uso de Clofarabina debe estar sujeto en dos escenarios: pacientes. En nuestra institución, los pacientes que utilizan Clofarabina son aproximadamente 4 por año. Se debe tener un monitoreo de los pacientes para evaluar respuestas, toxicidades y sobrevida. El costo anual por paciente por uso de Clofarabina seria de S/. 179 200.000. Se cuenta con otras alternativas de tratamiento como terapia puente hacia un trasplante de células progenitoras, como Inmunoterapia (BLINATUMOMAB) o uso de CAR-T CELL, sin embargo, dichos tratamientos aún no están disponibles en nuestro medio, asociado a un mayor costo. Finalmente, en base a la discusión de la mejor evidencia científica disponible con respecto a esta tecnología sanitaria el panel decidió aprobar la clofarabina asociada a otros agentes quimioterapicos (ciclofosfamida y etoposido), como puente de tratamiento antes de trasplante de células progenitoras hematopoyéticas, para el tratamiento de pacientes menores de 21 años con leucemia linfoblástica aguda o leucemia mieloide aguda en recaída o refractariedad a 1 o más líneas de tratamiento previa.

Aptamers Entirely Built from Therapeutic Nucleoside Analogues for Targeted Cancer Therapy.

Owing to the specific and high binding affinity of aptamers to their targets, aptamer-drug conjugates (ApDCs) have emerged as a promising drug delivery system for targeted cancer therapy. However, in a conventional ApDC, the aptamer segment usually just serves as a targeting moiety, and only a limited number of drug molecules are sequentially conjugated to the oligonucleotide, giving a relatively low drug loading capacity. To address this challenge, herein we employ four clinically approved nucleoside analogues, including clofarabine (Clo), ara-guanosine (AraG), gemcitabine (Ge), and floxuridine (FdU), to replace all natural nucleosides in aptamer sequences, generating a series of whole drug-constituted DNA-like oligomers that are termed drugtamers. Similar to their parent aptamers, the obtained drugtamers maintain the targeting capability and can specifically bind to the target receptors overexpressed on the cancer cell surface. With 100% drug loading ratio, active targeting capability, and enzyme-mediated release of active therapeutics, our drugtamers can strongly induce the apoptosis of cancer cells and inhibit the tumor progression, which enables a new potential for a better targeted cancer therapy.

Clofarabine with topotecan, vinorelbine, and thiotepa reinduction regimen for children and young adults with relapsed AML.

Effective reinduction regimens are needed for children with relapsed and refractory acute myeloid leukemia (AML), as outcomes remain poor. Therapeutic options are limited in this heavily pretreated patient population, many of whom have reached lifetime recommended doses of anthracycline chemotherapy. The development of effective non-anthracycline-based salvage regimens is crucial to these patients who are at significant risk of life-threatening cardiotoxicity. We previously reported results of a phase 2 trial of a clofarabine-based regimen with topotecan, vinorelbine, and thiotepa (TVTC) in patients with relapsed acute leukemias. Here we report on an expanded bicenter cohort of 33 patients, <25 years of age, with relapsed/refractory AML treated with up to 2 cycles of the TVTC reinduction regimen from 2007 to 2018. The overall response rate, defined as complete remission or complete remission with partial recovery of platelet count, was 71.4% (95% confidence interval [CI], 41.9-91.6) for those patients in first relapse (n = 14) and 47.4% (95% CI, 24.4-71.1) for patients in second or greater relapse or with refractory disease. Responses were seen across multiple high-risk cytogenetic and molecular subtypes, with 84% of responders successfully bridged to allogeneic stem cell transplantation. The 5-year overall survival for patients in first relapse was 46.2% (95% CI, 19.1-73.3) and 50.0% (95% CI, 26.9-73.1) for patients who responded to TVTC. For pediatric and young adult patients with relapsed/refractory AML, TVTC reinduction compares favorably with currently used salvage regimens and warrants further exploration.

Clofarabine monotherapy in two patients with refractory Langerhans cell histiocytosis.

BACKGROUND: Better therapeutic options other than conventional chemotherapy for pediatric patients with refractory Langerhans cell histiocytosis (LCH) remain undetermined. CASE: We successfully treated two patients with refractory and risk organ negative LCH with clofarabine (CLO) monotherapy after recurrence. We administered total 23 courses of CLO monotherapy in patient 1 and 4 courses in patient 2. Both patients had distinct clinical manifestations but achieved a durable complete response with acceptable adverse effects of transient myelosuppression. CLO monotherapy was still effective when he had the second recurrent lesion after first completion of CLO in patient 1. We could discontinue prednisolone to control his refractory inflammation of LCH after completing CLO chemotherapy in patient 2. CONCLUSION: Although large-scale studies are warranted, CLO monotherapy could be a therapeutic option for high efficacy and feasibility besides other intensive combination chemotherapies or allogeneic hematopoietic stem cell transplantation for refractory LCH without risk organ involvement in children.

The added value of multi-state modelling in a randomized controlled trial: The HOVON 102 study re-analyzed.

Clofarabine is an active antileukemic drug for subgroups of patients with acute myeloid leukemia (AML). Multi-state models can provide additional insights to supplement the original intention-to-treat analysis of randomized controlled trials (RCT). We re-analyzed the HOVON102/SAKK30/09 phase III RCT for newly diagnosed AML patients, which randomized between standard induction chemotherapy with or without clofarabine. Using multi-state models, we evaluated the effects of induction chemotherapy outcomes (complete remission [CR], measurable residual disease [MRD]), and post-remission therapy with allogeneic stem cell transplantation [alloSCT] on relapse and death. Through the latter a consistent reduction in the hazard of relapse in the clofarabine arm compared to the standard arm was found, which occurred irrespective of MRD status or post-remission treatment with alloSCT, demonstrating a strong and persistent antileukemic effect of clofarabine. During the time period between achieving CR and possible post-remission treatment with alloSCT, non-relapse mortality was higher in patients receiving clofarabine. An overall net benefit of treatment with clofarabine was identified using the composite endpoint current leukemia-free survival (CLFS). In conclusion, these results enforce and extend the earlier reported beneficial effect of clofarabine in AML and show that multi-state models further detail the effect of treatment on competing and series of events.

Long-term results of low-intensity chemotherapy with clofarabine or cladribine combined with low-dose cytarabine alternating with decitabine in older patients with newly diagnosed acute myeloid leukemia.

The treatment of older patients with newly diagnosed acute myeloid leukemia (AML) using intensive chemotherapy is associated with treatment intolerance and poor survival. We evaluated two new lower-intensity regimens with clofarabine (n = 119) or cladribine (n = 129) combined with low-dose cytarabine (LDAC) alternating with decitabine. We reviewed response rates by subgroup and long term outcomes of 248 patients with newly diagnosed non core-binding-factor AML treated on two clinical trials investigating double nucleoside-analogue therapy (DNT) alternating with HMA from October, 2008 to April, 2018. Of 248 patients with a median age of 69 years (range, 49-85 years), 102 patients (41%) were ≥ 70 years, and 108 (44%) had adverse karyotype. Overall, 164 patients (66%) responded: 147 (59%) complete remission (CR) and 17 (7%) CR with incomplete count recovery (CRi). With a median follow up of 60 months, median relapse-free and overall survival (OS) were 10.8 and 12.5 months, respectively. The 2-year OS was 29%. Among patients with normal karyotype, the CR/CRi rate was 79% and the median OS 19.9 months. High response rates and OS were observed in patients with mutations in NPM1, FLT3, IDH2, and RUNX1. The 4- and 8-week mortality rates were 2% and 11%, respectively. The backbone of clofarabine or cladribine and LDAC alternating with decitabine was effective and safe for the treatment of older patients with newly diagnosed AML. Incorporating targeted therapies could extend the efficacy of this approach and provide more curative therapeutic options in this AML population.

Effectiveness and Safety of Clofarabine Monotherapy or Combination Treatment in Relapsed/Refractory Childhood Acute Lymphoblastic Leukemia: A Pragmatic, Non-interventional Study in Korea.

PURPOSE: Effectiveness and safety of clofarabine (one of the treatment mainstays in pediatric patients with relapsed/refractory acute lymphoblastic leukemia [ALL]) was assessed in Korean pediatric patients with ALL to facilitate conditional coverage with evidence development. MATERIALS AND METHODS: In this multicenter, prospective, observational study, patients receiving clofarabine as mono/combination therapy were followed up every 4-6 weeks for 6 months or until hematopoietic stem cell transplantation (HSCT). Response rates, survival outcomes, and adverse events were assessed. RESULTS: Sixty patients (2-26 years old; 65% B-cell ALL, received prior ≥ 2 regimen, 68.3% refractory to previous regimen) were enrolled and treated with at least one dose of clofarabine; of whom 26 (43.3%) completed 6 months of follow-up after the last dose of clofarabine. Fifty-eight patients (96.7%) received clofarabine combination therapy. Overall remission rate (complete remission [CR] or CR without platelet recovery [CRp]) was 45.0% (27/60; 95% confidence interval [CI], 32.4 to 57.6) and the overall response rate (CR, CRp, or partial remission [PR]) was 46.7% (28/60; 95% CI, 34.0 to 59.3), with 11 (18.3%), 16 (26.7%), and one (1.7%) patients achieving CR, CRp, and PR, respectively. The median time to remission was 5.1 weeks (95% CI, 4.7 to 6.1). Median duration of remission was 16.6 weeks (range, 2.0 to 167.6 weeks). Sixteen patients (26.7%) proceeded to HSCT. There were 24 deaths; 14 due to treatment-emergent adverse events. CONCLUSION: Remission with clofarabine was observed in approximately half of the study patients who had overall expected safety profile; however, there was no favorable long-term survival outcome in this study.

Mixed Langerhans Cell Histiocytosis and Erdheim-Chester Disease in a Girl: A Rare and Puzzling Diagnosis.

OBJECTIVE: The objective of this study was to report the case of a girl diagnosed as suffering from multisystem, BRAF V600E-positive refractory Langerhans cell histiocytosis (LCH) and coexistent Erdheim-Chester disease (ECD) with perirenal, intracranial involvement and the dramatic response to clofarabine treatment. OBSERVATIONS: Histiocytoses are rare diseases with a broad clinical spectrum. Recent evidence supports a molecular and clinical overlap between LCH and ECD, and mixed LCH/ECD is now a separate entity. However, only a few pediatric cases of mixed disease have been reported in the literature. CONCLUSIONS: In a child with refractory, multisystem histiocytosis and atypical presentations, mixed LCH/ECD should be suspected in the differential diagnosis.

The combination of clofarabine, etoposide, and cyclophosphamide shows limited efficacy as a bridge to transplant for children with refractory acute leukemia: results of a monitored prospective study.

Clofarabine has been shown to effectively induce remission in children with refractory leukemia. We conducted a prospective trial (clinicval.trials.gov NCT01025778) to explore the use of clofarabine-based chemotherapy as a bridge-to-transplant approach. Children with refractory acute leukemia were enrolled to receive two induction courses of clofarabine, etoposide, and cyclophosphamide (CloEC). Responding patients were scheduled for T-cell depleted haploidentical hematopoietic stem cell transplantation (HSCT). The primary objective was to improve survival by achieving sufficient disease control to enable stem cell transplantation. Secondary objectives were to evaluate safety and toxicity. Seven children with active disease entered the study. Two children responded to induction courses and underwent transplantation. Five children did not respond to induction: one died in progression after the first course; two received off-protocol chemotherapy and were transplanted; and two succumbed to progressive leukemia. All transplanted children engrafted and no acute skin graft-versus-host disease > grade I was observed. One child is alive and well 7.5 years after the first CloEC course. One child developed fulminant adenovirus hepatitis and died in continuous complete remission 7 months after start of induction. Two children relapsed and died 6.5 and 7.5 months after enrollment. Infection was the most common toxicity. CloEC can induce responses in some patients with refractory acute leukemia but is highly immunosuppressive, resulting in substantial risk of life-threatening infections. In our study, haploidentical HSCT was feasible with sustained engraftment. No clinically significant organ toxicity was observed. Also, repeating CloEC probably does not increase the chance of achieving remission.

Venetoclax and alvocidib are both cytotoxic to acute myeloid leukemia cells resistant to cytarabine and clofarabine.

BACKGROUND: Cytarabine (ara-C) is the major drug for the treatment of acute myeloid leukemia (AML), but cellular resistance to ara-C is a major obstacle to therapeutic success. The present study examined enhanced anti-apoptosis identified in 3 newly established nucleoside analogue-resistant leukemic cell line variants and approaches to overcoming this resistance. METHODS: HL-60 human AML cells were used to develop the ara-C- or clofarabine (CAFdA)-resistant variants. The Bcl-2 inhibitor venetoclax and the Mcl-1 inhibitor alvocidib were tested to determine whether they could reverse these cells' resistance. RESULTS: A 10-fold ara-C-resistant HL-60 variant, a 4-fold CAFdA-resistant HL-60 variant, and a 30-fold CAFdA-resistant HL-60 variant were newly established. The variants demonstrated reduced deoxycytidine kinase and deoxyguanosine kinase expression, but intact expression of surface transporters (hENT1, hENT2, hCNT3). The variants exhibited lower expression of intracellular nucleoside analogue triphosphates compared with non-variant HL-60 cells. The variants also overexpressed Bcl-2 and Mcl-1. Venetoclax as a single agent was not cytotoxic to the resistant variants. Nevertheless, venetoclax with nucleoside analogs demonstrated synergistic cytotoxicity against the variants. Alvocidib as a single agent was cytotoxic to the cells. However, alvocidib induced G1 arrest and suppressed the cytotoxicity of the co-administered nucleoside analogs. CONCLUSIONS: Three new nucleoside analogue-resistant HL-60 cell variants exhibited reduced production of intracellular analogue triphosphates and enhanced Bcl-2 and Mcl-1 expressions. Venetoclax combined with nucleoside analogs showed synergistic anti-leukemic effects and overcame the drug resistance.

Tisagenlecleucel versus historical standard therapies for pediatric relapsed/refractory acute lymphoblastic leukemia.

Aim: We compared outcomes from a single-arm study of tisagenlecleucel with standard of care (SOC) regimens in pediatric and young adult patients with relapsed/refractory acute lymphoblastic leukemia (ALL). Methods: The analysis included one tisagenlecleucel study, one blinatumomab study, one clofarabine monotherapy study, three studies of clofarabine combination regimens and two studies of other salvage chemotherapy. Matching-adjusted indirect comparison analyses were conducted. Results: After adjusting for baseline characteristics, tisagenlecleucel was associated with significantly prolonged overall survival compared with blinatumomab (hazard ratio [95% CI], 0.32 [0.16-0.64]); clofarabine monotherapy (0.24 [0.13-0.42]); clofarabine combination regimens (0.26 [0.15-0.45]); two salvage therapies (0.15 [0.09-0.25] and 0.27 [0.15-0.49]). Conclusion: The analysis demonstrated tisagenlecleucel was associated with substantially greater survival benefit versus all SOC regimens.