Is there an optimal adjunct therapy to traditional cytotoxic induction?

The traditional cytotoxic induction regimen for acute myeloid leukemia (AML) is seven days of standard-dose cytarabine and three days of an anthracycline antibiotic (such as daunorubicin or idarubicin), commonly known as "7 + 3." Many studies have been conducted to find an additional agent that might improve efficacy. Data from select studies has shown, in certain populations, benefit to adding cladribine, clofarabine and lomustine to a traditional backbone. For mutation-based chemotherapy regimens, midostaurin with 7 + 3 is the current standard of care for FLT3-mutant, younger AML patients. As we learn more about the synergism of molecular agents and traditional anti-cancer treatments, we can hopefully develop novel regimens without abandoning some of the benefits of these mutation agnostic historical therapies.

Análisis de impacto presupuestal de tecnologías para el manejo complementario de quimioterapia en Colombia / Budget impact analysis of technologies for the complementary management of chemotherapy in Colombia

INTRODUCCIÓN: El análisis de impacto presupuestal (AIP) de los medicamentos quimioterapéuticos para el tratamiento de cáncer en Colombia, se desarrolló en el marco del mecanismo técnico científico para la ampliación progresiva del Plan de Beneficios en Salud con cargo a la UPC (PBSUPC) y la definición de la lista de exclusiones, establecido en el artículo 15 de la Ley 1751 de 2015. La quimioterapia tiene un gran impacto en el tratamiento oncológico, la cual es indispensable por su valor terapéutico en varios tipos de cáncer. Esta tecnología puede ser usada sola o junto con otros tratamientos, tales como la cirugía o la radioterapia. La quimioterapia engloba a una gran variedad de fármacos y su objetivo es destruir las células tumorales con el fin de lograr la reducción de la enfermedad, los medicamentos empleados en este tipo de tratamiento se les denomina fármacos antineoplásicos. Cada tipo de tumor canceroso tiene una determinada sensibilidad a estos medicamentos, por lo tanto, es frecuente que el mismo fármaco se pueda emplear en el tratamiento de distintos tumores, variando las dosis o asociándolo a otros fármacos distintos. La quimioterapia puede ser administrada con fines curativos o para aliviar los síntomas y prolongar la supervivencia. La forma de administración de la quimioterapia es por ciclos y esto se logra alternando los periodos de tratamiento con periodos de descanso. Un ciclo es, por lo tanto, el periodo de administración del tratamiento y el de descanso hasta la siguiente administración. El objetivo de este análisis de impacto presupuestal (AIP) es estimar el esfuerzo financiero necesario para la adopción de la quimioterapia en el tratamiento de pacientes con cáncer en Colombia, en un horizonte temporal de tres años. Este documento está conformado por cuatro secciones: en la primera se identifican las tecnologías a evaluar, en la segunda sección se especifica la perspectiva, horizonte temporal y la población sobre la cual se realizó el AIP; en la sección tres se detallan los costos utilizados en el modelo, además de los escenarios planteados por los investigadores; por último, en la sección cuatro se exponen los resultados en los diferentes escenarios planteados Este documento describe la metodología desarrollada para realizar el análisis de impacto presupuestal de 21 tecnologías para el manejo quimioterapéutico del cáncer en Colombia Este informe, sigue los lineamientos propuestos en el Manual para la Elaboración de Análisis de Impacto Presupuestal y en Manual de Participación y Deliberación publicados por IETS. Insumos y método: Esta sección presenta los supuestos, parámetros y métodos utilizados para el modelo de estimación del impacto presupuestal describiendo la siguiente información: Perspectiva: La perspectiva de este AIP es la del tercer pagador el cual en nuestro contexto es el Sistema General de Seguridad Social en Salud (SGSSS). Horizonte temporal: El horizonte temporal de este AIP en el caso base corresponde a un año. Adicionalmente se reportan las estimaciones del impacto presupuestal para los años 2 y 3, bajo el supuesto de inclusión en el PBS en el año 1. Población total: Para el desarrollo de este AIP se parte de la población general afiliada al SGSSS colombiano sin distinción de sexo o edad. ESCENARIOS: Se consideró para la formulación de los escenarios de adopción de las tecnologías evaluadas los siguientes aspectos: 1. Los medicamentos evaluados no son alternativas terapéuticas para las patologías observadas, estas tecnologías sanitarias hacen parte de los protocolos de tratamiento con evidencia científica suficiente que garantizan su efectividad y seguridad clínica y que actualmente se encuentran en las opciones de tratamiento utilizados en la práctica clínica colombiana. 2. Al ser esquemas de tratamiento que hacen parte de protocolos estandarizados de aplicación, sí alguno de los medicamentos es sujeto de recobros ante ADRES, este trámite puede generar barreras de acceso al tratamiento hasta que se efectué la respectiva aprobación. Por lo tanto, no hay certeza de la efectividad clínica si los esquemas de tratamiento son suministrados de forma parcial o incompleta. 3. La elección del esquema de tratamiento obedece a criterios clínicos y a las características evaluadas en el paciente, no se espera una sustitución entre los diferentes esquemas sí se realiza un cambio en el mecanismo de financiamiento. 4. La adopción de las tecnologías evaluadas en este AIP no se espera que se modifiquen de manera importante, debido a que estas tecnologías hacen parte integral de los esquemas de tratamiento y su incorporación en la práctica clínica habitual en el contexto internacional y nacional, data de aproximadamente 10 a 5 años. Tambieén son parte de las opciones de primera línea de tratamiento para estadios tempranos, avanzados y localmente avanzados del paciente diagnosticado con câncer. De acuerdo a las anteriores consideraciones, al incorporar los medicamentos evaluados al PBS con cargo a la UPC, se espera la misma composición del mercado con la adopción de los nuevos medicamentos en el 100% de los tratamientos esperados en la siguiente anualidad. Los resultados esperados en el sistema de salud, en este cambio de financiamiento, se esperan obtener en dos puntos: a) En una mejor oportunidad de acceso a los esquemas de tratamiento en el SGSSS (25). b) En una mejora en la cobertura efectiva de los tratamientos de quimioterapia en pacientes con diagnóstico de cáncer. RESULTADOS: Se muestra el resultado consolidado para las ventiun tecnologías objeto del Análisis de Impacto Presupuestal. La tecnología que genera un mayor impacto es Oxaliplatino, con un valor por persona de $2.363.250,76 usada en 3170 pacientes, para un total de $7.491.504.923,90. El Megestrol es la tecnología con menor impacto, con un costo por persona de $ 383.791,06 y siendo usada en 34 pacientes, tiene un valor total de $ 13.048.896,00. La tretinoina es la tecnología más económica por paciente, con un valor de $ 97.996,50, es usada en 242 personas para un total de $ 23.715.153,00. DISCUSIÓN: En la práctica actual existe un volumen amplio de recobros en el caso de estos medicamentos por usos UNIRS. En algunos casos, los cambios en el mercado farmacéutico, ya sea por el retiro de medicamentos o la llegada de ellos, hace que se modifique indicaciones ya existentes en los registros y que pueden llegar a impactar estos. usos, por ejemplo aquellos casos en los que existe la indicación antineplásico y se cambian por indicaciones especificas, que pueden no considerar condiciones de salud de baja incidencia. Como se ha caracterizado con anterioridad, el mercado de tecnologías sanitarias que se encuentran incluidas al plan de beneficios en salud con cargo a la UPC difiere sustancialmente al mercado de tecnologías sanitarias aún no financiadas por dicho mecanismo. La existencia de las Empresas Administradoras de Planes de Beneficios (EAPB) presume la existencia de un actor que al maximizar su beneficio, es un buen negociador que en cumplimiento de los principios del SGSSS, llega a un precio de equilibrio que maximiza el beneficio social. En cambio, los medicamentos que son sujetos a recobros al ADRES presume un precio fuera de aquel nivel en donde se maximiza al beneficio social, en la medida que no hay una función clara de monopsonio que coteje y negocie un precio de adquisición. En algunos casos puede llegar asumir sobrecostos que las EAPB al ser intermediarias, no tienen incentivos para efectuar un adecuado control. Con el objetivo de estimar el resultado de la incorporación de estos medicamentos al PBS con cargo a la UPC, se asumieron dos escenarios en los cuales la población objetivo del AIP se consideró constante y se asumieron los siguientes supuestos: En el primer escenario se asume que los precios observados en recobros serán el promedio de todas las transacciones de compra en la siguiente anualidad. En el segundo escenario los precios promedio de adquisición de los medicamentos evaluados, corresponden al promedio observado en SISMED como predictor de los precios de equilibrio que pueden generar las EAPB como ente negociador. Se asume que, en promedio, las EAPB son negociadores eficientes que se acercan a un precio de equilibrio que maximiza el bienestar social. Se asume que la población objetivo corresponde al total de posibles pacientes que requieren las tecnologías sanitarias en evaluación, sin que exista demanda insatisfecha para estos esquemas de tratamiento. Para su cálculo, como se presenta en la tabla 09 de los servicios prestados durante el año 2015 y recobrados al FOSYGA en los años 2015 y 2016, se calculó un valor per-cápita de acuerdo con el identificador (cedula de ciudadanía anonimizada) registrado en cada recobro. Luego, este valor es indexado a precios 2016 con el IPC reportado por el DANE a diciembre 31 del año 2015. Este valor será el comparador del precio calculado para cada uno de los medicamentos a partir de SISMED 2016.

Comparison of two transarterial chemoembolization strategies for hepatocellular carcinoma.

AIM: This retrospective study aimed to compare the efficacy of and tolerance to two center-related conventional transarterial chemoembolization (TACE) strategies in the management of unresectable hepatocellular carcinoma (HCC). PATIENTS AND METHODS: All HCC patients in whom TACE was initiated in the two centers from June 2008 to July 2011 were included. The TACE strategy performed in center 1 was "on demand" with selective injections of idarubicin, whereas the TACE strategy in center 2 was based "on scheduled" non-selective injections of epirubicin. Toxicity was evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events v4.0. RESULTS: One hundred and fifty HCC patients were included. Median time to treatment failure was significantly higher in center 1, 13.1 months vs. 7.9 months in center 2 (hazard ratio, 2.32; p<10-3 in multivariate analysis). Median overall survival was 21.1 months in center 1 vs. 18.4 months in center 2 (p=NS). The proportion of grade ≥ 3 adverse events and mean hospitalisation duration for the overall TACE treatment were significantly greater in center 2 than in center 1: 56% vs. 32% (p<0.01) and 14.2 ± 7.2 days vs. 10.3 ± 7.0 days (p<0.01), respectively. CONCLUSION: Our results failed to show any significant survival differences between two center-related TACE strategies but showed a significantly smaller proportion of grade ≥ 3 adverse events and shorter hospitalisation for the overall treatment when the "on-demand" strategy was used.

Antileukemia activity of the combination of an anthracycline with a histone deacetylase inhibitor.

We studied the cellular and molecular effects of the combination of an anthracycline with 2 different histone deacetylase inhibitors (HDACIs): vorinostat (suberoylanilide hydroxamic acid) and valproic acid (VPA). The 10% inhibitory concentration (IC(10)) of idarubicin was 0.5 nM in MOLT4 and 1.5 nM in HL60 cells. Concentrations above 0.675 microM of vorinostat resulted in at least 80% loss of cell viability in both cell lines. Concentrations of 1.5 to 3 mM of VPA induced 50% to 60% loss in viability in HL60 and 80% in MOLT4 cells. The combination of idarubicin with vorinostat at 0.075 microM or VPA at 0.25 mM resulted in at least an additive loss of cell viability in both lines. Vorinostat (0.35 microM) and VPA (0.25 mM) in combination with idarubicin (0.5 nM) resulted in a significant increase in apoptotic cells in MOLT4 cells. The combination resulted in an increase in histone H3 and H4 acetylation at 24 hours, phosphorylated H2AX, as well as in the induction of p21(CIP1) mRNA. No effect on cell cycle transition was observed. Of importance, the cellular and molecular effects observed were independent of the sequence used. In summary, the combination of an anthracycline with an HDACI should have significant clinical activity in patients with leukemia.

Multidrug reverting activity toward leukemia cells in a group of new verapamil analogues with low cardiovascular activity.

The development of refractory disease is often associated with the overexpression of multidrug resistance (MDR) proteins, especially in several hematological malignancies, such as acute myeloid leukemias (AML), multiple myeloma (MM) and non-Hodgkin's lymphomas (NHL). Since the recognition of these proteins, several attempts have been made to modulate their expression and activity (protein kinase C inhibitors, anti-MDR-1 oligonucleotides, pharmacological competitors and transcriptional inhibitors). Six new compounds (MM 36, CTS 4, CTS 9, CTS 12, CTS 27 and CTS 41), derived from verapamil (VRP), were designed and synthesized to improve their MDR-reverting activity and reduce cardiovascular effects. Cytotoxicity (WST-1 methods) and functional (calcein-acetoxymethyl (Calcein-AM)) assays were performed on a resistant cell line K-562/doxR and on the mononuclear cells (MNCs) of patients with AML. Furthermore, the six molecules were tested for their vasodilator, inotropic and chronotropic activity on guinea pig aortic strip and isolated atrium preparations, respectively. Comparison between survival plots and relative ID50, obtained from the K-562/doxR cells treated with Idarubicin (IDA), in the presence or absence of inhibitors, showed that these compounds function well. All the resistance modifying agents potentiated IDA activity inducing a significant reduction (P<0.01) in ID(50) values in comparison to VRP at each of the concentrations tested, but MM 36, CTS 27 and CTS 41 demonstrated the strongest activity. Results obtained from the MNCs were superimposible to K-562/doxR. Further studies on pump functional analysis confirmed the cytotoxic test results: MM 36, CTS 27 and CTS 41 showed a striking inhibition of P-glycoprotein (Pgp) efflux in K-562/doxR and MNCs. Cardiovascular activity of MM 36, CTS 27 and CTS 41, that are the most interesting compounds as MDR inhibitors, followed this course: MM 36>CTS 27>CTS 41, the last one presenting no cardiovascular activity. Chemosensivity to IDA in K-562/doxR cells and AML blasts could be enhanced in vitro by the adjuvant use of the six new VRP analogues. Compared to VRP, all the new compounds presented good MDR-reverting- and reduced cardiovascular activities along with no vasorelaxant effects. The particularly favourable results in some cases (MM 36, CTS 27 and CTS 41) suggests that anti-MDR activity should be further evaluated in clinical trials in patients with myeloid malignancies.

Pharmacokinetic considerations of oral chemotherapy in elderly patients with cancer.

Persons over the age of 65 years are the fastest growing segment of the US population. In the next 30 years they will comprise over 20% of the population. Fifty per cent of all cancers occur in this age group and therefore there will be an expected rise in the total cancer burden. There has been an increasing trend over the past 20 years toward the use of oral chemotherapy. This change has been encouraged by the need to decrease the costs of chemotherapy administration, patient preferences and quality of life issues. Factors that must be considered with oral chemotherapy administration include limitations of saturability of absorption, patient compliance and pharmacokinetic/pharmacodynamic changes which occur in elderly patients. Interpatient variability and drug metabolism, particularly age-related changes in drug metabolism are being studied. The cytochrome P450 system has been intensively studied because of its importance with regard to chemotherapeutic drugs. This article reviews these issues and provides details regarding specific drugs including temozolomide, thalidomide, topotecan, the fluoropyrimidines, etoposide, hydroxycarbamide (hydroxyurea), tamoxifen, and alkylating drugs. Complementary and alternative therapies are also discussed.

LFA-1 and ICAM-1 antibody-idarubicin conjugates separately prolong murine cardiac allograft survival.

Drug antibody conjugates can enhance the activity of monoclonal antibodies (MoAb) and idarubicin-MoAb conjugates have led to tolerance induction with antibodies which are inactive when used alone. It has been reported that, in mice, antibodies to ICAM-1 and LFA-1 have to be used together to induce tolerance to cardiac allografts; here we show that these monoclonal antibodies, conjugated to idarubicin, can lead to tolerance induction to cardiac allografts when used alone.

Improvement of idarubicin induced antitumor activity and bone marrow suppression by theanine, a component of tea.

We have examined the effect of theanine, a specific amino acid in green tea, on idarubicin (IDA)-induced antitumor activity and toxicity. In combination with theanine, IDA (0.25 mg/kg per day x4 days, a dose that does not show antitumor activity) had significant antitumor activity in P388-bearing mice. The IDA concentration in the tumors in the theanine plus IDA group increased to twice the level in the IDA alone group. Furthermore, the decrease in tumor weight caused by IDA at 1.0 mg/kg per day x4 days (at this dose IDA exhibits antitumor activity) was significantly amplified by theanine. The numbers of leukocyte and bone marrow cells decreased significantly on IDA injection. Theanine significantly reversed these changes. These results suggest that theanine selectively moderates the IDA-induced toxicities. Until recently, the antitumor activity and related toxicities of this chemotherapeutic agent in leukemia could not be distinguished. Theanine increases the IDA-induced antitumor activity and ameliorates the toxicities.

[Acute myeloid leukemia in the adult. Results of the National Antineoplastic Drug Protocol at the Hospital del Salvador, 1990-1998]. / Leucemia mieloide aguda del adulto. Resultados del Protocolo Nacional de Drogas Antineoplásica. Hospital del Salvador 1990-1998.

BACKGROUND: The incidence of acute myeloid leukemia is 3 cases per 100,000 inhabitants/year and its five years event free survival is 15 to 20%. Since the incorporation of trans retinoic acid, event free survival of M3 acute myeloid leukemia is 80%. AIM: To report the results of acute myeloid leukemia treatment at the Hospital del Salvador, between 1990 and 1998. PATIENTS AND METHODS: The medical records of 117 patients (66 female, mean age 48.2 years), treated between 1990 and 1998 using PANDA protocol, were retrospectively reviewed. Immunophenotyping was done in 69 patients and cytogenetic studies were done in 65. RESULTS: Sixteen percent of patients had M3 acute myeloid leukemia. The most frequent phenotype was the association of DR, CD34 plus a panmyeloid marker. DR and CD34 were negative in seven of nine patients with M3 acute myeloid leukemia. Cariotype was abnormal in 78% of patients. Complete remission was achieved in 65% of cases with a 13% of failures. Early mortality was 21.3% and decreased to 6.1% in the last three years. Infections and coagulation disorders were the main causes of death. Mean survival was 10.5 months. Five years event free survival was 11%. In M3 acute myeloid leukemia, the figure is 50%. CONCLUSIONS: Treatment results are less effective than protocols that consider more aggressive chemotherapeutic protocols or bone marrow transplantation. The reduction in early mortality is due to a better management of febrile neutropenia.

Sweet's syndrome during treatment with all-trans retinoic acid in a patient with acute promyelocytic leukemia.

A 46 year old male with acute promyelocytic leukemia treated with all-trans retinoic acid (ATRA), developed fever, bilateral erythematous nodules in his axillary area, lower abdomen and inguinal region. Histopathologic examination of the skin biopsy revealed dense neutrophil infiltration in the dermis without vasculitis. The diagnosis of Sweet's syndrome was made. High dose methylprednisolone was administered and the lesions started to improve within 24 hours.

FLAG-idarubicin and allogeneic stem cell transplantation for Ph-positive ALL beyond first remission.

We describe a single centre experience of eight consecutive patients with relapsed or refractory Ph+ ALL treated with the FLAG/idarubicin regimen followed by BMT or PBSCT. Following FLAG/idarubicin, one achieved a partial response and seven CR. All patients subsequently received allogeneic transplants: one sibling BMT, three matched unrelated (MUD) BMT and four sibling PBSCT. Two patients received second transplants with PBSC from their original BM donors following FLA/Ida with no further conditioning. Three patients are alive in CR 9, 24 and 32 months after transplant. Seven of eight patients had a cytogenetic response following FLAG/Ida induction and one of seven became bcr-abl negative. All eight patients had a complete cytogenetic response following transplant. Four of five assessable patients became p190 bcr-abl negative after transplant; three of these subsequently relapsed. Both patients with the p210 bcr-abl transcript remained bcr-abl positive in CR after transplant. FLAG/Ida was well tolerated and appears to be effective in inducing remission in relapsed Ph+ ALL. The use of FDR-containing chemotherapy without further conditioning prior to PBSCT deserves further study in heavily pre-treated patients and, in patients with relapsed ALL following BMT, may be a safer option than DLI (donor lymphocyte infusion) by avoiding the associated risk of aplasia.

Collection of 'normal' blood repopulating cells during early hemopoietic recovery after intensive conventional chemotherapy in chronic myelogenous leukemia.

Twenty-five patients with CML (chronic phase (CP): 15 patients; accelerated phase (AP): 10 patients) at a median of 40 months after diagnosis and ineligible for allogeneic BMT, received an intensive chemotherapy regimen consisting of idarubicin, intermediate-dose ara-C and etoposide (ICE protocol). All patients had previously received alpha-interferon and only two patients had had partial cytogenetic response. During recovery from chemotherapy-induced aplasia, blood progenitors cells (BPC) were harvested by leukapheresis. All metaphases were found to be Ph-negative in the collection of 12 of 25 (48%) patients (CP: 9 of 15 (60%), AP: 3 of 10 (30%)) and a decrease of < 50% Ph-positive metaphases was seen in an additional five (CP: 4 patients; AP: 1 patient). The percentage of complete Ph-disappearance was 66% in patients receiving this procedure within the first 2 years of diagnosis and 30% in those treated after the second year of diagnosis. So far, the Ph-negative collections have been used in 9 patients (CP: 8 patients; AP: 1 patient) as autograft after conditioning with total body irradiation/etoposide/CY. Seven of 9 patients engrafted and 5 are alive and well, Ph-negative at 2+, 3+, 6+, 10+ and 18+ months.

Preclinical investigation of the antitumour effects of anti-CD19-idarubicin immunoconjugates.

Idarubicin (Ida), an analogue of daunomycin, was linked to a mouse monoclonal antibody against the B cell differentiation antigen CD19. Determination of the activity of both the antibody and drug moieties was carried out in vitro using a pre-B cell human acute lymphoblastic leukaemia cell line (NALM-6). A 23% loss in antibody binding and a 20-fold loss in drug activity were observed upon conjugation. Selective cytotoxicity for CD19+ cells, however, was obtained. Measurement of the cytotoxicity, antibody activity and release of the breakdown product, 14-OH-Ida, showed that the conjugates remained stable for more than 100 days after lyophilization and storage at -20 degrees C. In vivo studies were performed in irradiated nu/nu mice bearing NALM-6 tumours. Initial dose response studies with free idarubicin demonstrated that three i.p. doses (every other day) of 10 micrograms resulted in little antitumour activity, but the death of all the animals by day 23. The same treatment regime using 15 micrograms Ida-anti-CD19 conjugate caused the disappearance of four out of five tumours with three complete cures and no evidence of toxicity as assessed by weight loss. Administration of a conjugate of idarubicin with an irrelevant antibody at this dose led to no significant antitumour response. The administration of free drug at a dose of 6 micrograms resulted in a minor antitumour response but high toxicity, whereas injection of Ida-anti-CD19 conjugate at this dose caused no toxicity and a substantial antitumour effect with eradication of two out of five tumours. These results clearly demonstrate that the administration of Ida-anti-CD19 conjugates can result in complete tumour regression in an experimental model. Idarubicin-containing immunoconjugates should be useful for the treatment of patients with non-Hodgkin's lymphoma.