Miguel A. Sanz

Long-term follow-up confirms the benefit of all-trans retinoic acid in acute promyelocytic leukemia

First results of a randomized trial (APL91 trial) and other randomized or non-randomized studies have shown that ATRA followed by chemotherapy significantly increased event-free survival (EFS) and survival, and decreased the incidence of relapse by comparison to chemotherapy alone in newly diagnosed APL. We present here long-term follow-up of the APL91 trial. In this trial, 101 patients had been randomized between ATRA followed by three courses of daunorubicin-AraC chemotherapy (ATRA group) and the same chemotherapy alone (chemotherapy group). Results were reanalyzed 73 months after closing of patient entry. Updated results of APL 91 trial found a Kaplan–Meier estimate of EFS and relapse rate at 4 years of 63% and 31% in the ATRA group, as compared to 17% and 78% in the chemotherapy group (Pu2009=u200910−4 and relative risk 2.95, Pu2009=u200910−4 and relative risk 3.68, respectively). Kaplan–Meier survival at 4 years was 76% in the ATRA group and 49% in the chemotherapy group (Pu2009=u20090.026, relative risk 2.7). In the chemotherapy group, seven of the 27 relapses occurred after 18 months, but no relapse was seen after 43 months. In the ATRA group, four of the 17 relapses occurred after 18 months, including two late relapses (at 58 and 74 months). In the chemotherapy group, 23 of the 25 patients who relapsed achieved a second CR with ATRA, and the Kaplan–Meier estimate of second relapse was 40% at 30 months. In the ATRA group, the 10 patients who relapsed and were retreated with ATRA achieved a second CR. In conclusion, long-term results of APL91 trial confirm the superiority of the combination of ATRA and chemotherapy over chemotherapy alone in newly diagnosed APL, and that ATRA should be incorporated in the front-line treatment of APL.

Prolonged molecular remission after PML/RARα-positive autologous peripheral blood stem cell transplantation in acute promyelocytic leukemia: is relevant pretransplant minimal residual disease in the graft?

The contribution of residual malignant cells contaminating the autologous graft with the occurrence of post-transplant relapse in acute myeloid leukemia (AML) is still unclear. The presence of a specific molecular marker (the PML/RARα rearrangement) in acute promyelocytic leukemia (APL) offers the opportunity to investigate better the pathogenesis of disease recurrence after transplant. We report an APL patient who received high-dose chemotherapy and peripheral blood stem cell (PBSC) autograft in second hematologic remission. Two leukaphereses that tested PML/RARα positive by RT-PCR were obtained during the post-reinduction hematopoietic recovery, while the patient also tested PCR positive in the BM, and was reinfused after myeloablative chemotherapy (BUCY4), when the patient had spontaneously converted to PCR negative in the marrow. At present, he remains in continuous molecular and hematologic remission 22 months after PBSC transplantation. This is the second report of an APL patient who was transplanted in molecular remission with a PML/RARα-positive PBSC autograft. As in the previous report, the prolonged clinical and molecular remission experienced post-transplant suggests that autologous PBSC infusion is still worthy of consideration for patients with APL in spite of the detection of PML/RARα-positive cells in the PBSC collections. Possible underlying mechanisms and the potential role of molecular monitoring of the graft, as well as the host, before and after transplant, in patients with APL undergoing autologous HSCT are also discussed.

Outcome of Second Allogeneic Hematopoietic Cell Transplantation after Relapse of Myeloid Malignancies following Allogeneic Hematopoietic Cell Transplantation: A Retrospective Cohort on Behalf of the Grupo Español de Trasplante Hematopoyetico.

Allogeneic stem cell transplantation (allo-HCT) represents the most effective immunotherapy for acute myeloid leukemia (AML) and myeloid malignancies. However, disease relapse remains the most common cause of treatment failure. By performing a second allo-HCT, durable remission can be achieved in some patients. However, a second allo-HCT is of no benefit for the majority of patients, so this approach requires further understanding. We present a retrospective cohort of 116 patients diagnosed with AML, myelodysplastic syndromes, and myeloproliferative disorders who consecutively underwent a second allo-HCT for disease relapse. The median age was 38 years (range, 4 to 69 years). Sixty-three patients were alive at last follow-up. The median follow-up of the whole cohort was 193 days (range, 2 to 6724 days) and the median follow-up of survivors was 1628 days (range, 52 to 5518 days). Overall survival (OS) at 5 years was 32% (SE ± 4.7%). Multivariate analysis identified active disease status (P < .001) and second allo-HCT < 430 days (the median of the time to second transplantation) after the first transplantation (P < .001) as factors for poor prognosis, whereas the use of an HLA-identical sibling donor for the second allo-HCT was identified as a good prognostic factor (P < .05) for OS. The use of myeloablative conditioning (P = .01), active disease (P = .02), and a donor other than an HLA-identical sibling (others versus HLA-identical siblings) (P = .009) were factors statistically significant for nonrelapse mortality in multivariate analysis. Time to second transplantation was statistically significant (P = .001) in the relapse multivariate analysis, whereas multivariate analysis identified active disease status (P < .001) and time to second transplantation (P < .001) as poor prognosis factors for disease-free survival. This study confirms active disease and early relapse as dismal prognostic factors for a second allo-HCT. Using a different donor at second allo-HCT did not appear to change outcome, but using an HLA-identical sibling donor for a second transplantation appears to be associated with better survival. Further studies are warranted.

Significado pronóstico de los subtipos inmunológicos de la leucemia aguda linfoblástica T del adulto. Estudio de 81 pacientes

Fundamento y objetivo La leucemia aguda linfoblastica (LAL) de fenotipo T incluye 4 subtipos inmunologicos: pro-T, pre-T, timica o cortical y madura. En algunos estudios, los subtipos LAL pro-T y maduro tienen un peor pronostico. El objetivo de este estudio ha sido describir las principales caracteristicas clinicas, los resultados del tratamiento y el pronostico de los subtipos inmunologicos de LAL-T en 81 pacientes adultos incluidos en 2 protocolos del grupo PETHEMA (LAL-96 y LAL-93). Pacientes y metodo Entre 1993 y 2003, se incluyo en 2 protocolos de PETHEMA a 81 pacientes adultos de 22 hospitales espanoles: LAL-96 para pacientes de riesgo estandar y LAL-93 para pacientes de alto riesgo. Se comparo los principales parametros clinicos y biologicos iniciales de cada subgrupo de LAL-T, asi como la rapidez en la respuesta al tratamiento, la tasa de remision completa, la supervivencia libre de enfermedad y la supervivencia global. Resultados De los 64 pacientes evaluables, la distribucion de los subtipos inmunologicos fue: 3 pro-T, 17 pre-T, 22 timica o cortical y 22 madura. Los pacientes con LAL-T madura presentaron afeccion inicial del sistema nervioso central y marcadores mieloides con mayor frecuencia que el resto de los pacientes. Los pacientes con LAL-T madura tuvieron una respuesta significativamente mas lenta al tratamiento que los que presentaban LAL-T pre-T y cortical, pero ello no se tradujo en diferencias significativas en la tasa de remision completa (el 77 frente al 94%) supervivencia libre de enfermedad (el 42 frente al 46%) y la supervivencia global (el 29 frente al 47%). Conclusiones Aunque los pacientes con LAL-T madura respondieron mas lentamente al tratamiento y su supervivencia tendio a ser mas corta, en el presente estudio no se encontraron diferencias estadisticamente significativas en el pronostico de los diferentes subtipos de LAL-T.

Time and Cost of Hospitalisation for Salvage Therapy in Adults with Philadelphia Chromosome-Negative B Cell Precursor Relapsed or Refractory Acute Lymphoblastic Leukaemia in Spain

BackgroundPhiladelphia chromosome-negative (Ph−) relapsed or refractory (R/R) B-cell precursor acute lymphoblastic leukaemia (ALL) is rare, and information on its impact on healthcare systems is scarce.ObjectiveTo quantify the time and reimbursement associated with hospitalisations of patients with R/R ALL in a Spanish hospital.MethodsRetrospective review of medical charts identified patients agedu2009≥u200918xa0years with Ph− R/R ALL hospitalised between 1998 and 2014. Data were collected from the date of first diagnosis of R/R ALL (index) until death or loss to follow-up. The primary endpoint was the proportion of time hospitalised during chemotherapy. Reimbursement associated with hospitalisations (including associated chemotherapy) was also assessed.ResultsThirty-two patients were eligible for inclusion. Their median age was 41xa0years, and 50% had a first remission duration ofu2009≤u20091xa0year; 34% had undergone allogeneic haematological stem-cell transplantation (alloHSCT). Overall, 31 patients had received intensive salvage chemotherapy, during which there were 42 hospitalisations (mean 1.4/patient; mean duration 26xa0days). Patients spent a mean of 71% of the chemotherapy period in hospital. Total mean reimbursement was €26,417 per patient, almost all (€25,723) attributable to inpatient stays (€18,986/hospitalisation). From the index date to death or loss to follow-up (excluding alloHSCT-related hospitalisations), there were 80 hospitalisations (mean duration 24xa0days); mean reimbursement was €16,692 per hospitalisation and €41,730 per patient. AlloHSCT (nu2009=u20098) involved 18 hospitalisations (mean reimbursement €39,782/hospitalisation; €89,510/patient).ConclusionData from this sample of patients suggest that hospitalisations in R/R ALL are lengthy and associated with high costs in Spain.