Genomics improves risk stratification of adults with T-cell acute lymphoblastic leukemia enrolled in measurable residual disease-oriented trials.

Genetic information has been crucial to understand the pathogenesis of T-cell acute lymphoblastic leukemia (T-ALL) at diagnosis and at relapse, but still nowadays has a limited value in a clinical context. Few genetic markers are associated with the outcome of T-ALL patients, independently of measurable residual disease (MRD) status after therapy. In addition, the prognostic relevance of genetic features may be modulated by the specific treatment used. We analyzed the genetic profile of 145 T-ALL patients by targeted deep sequencing. Genomic information was integrated with the clinicalbiological and survival data of a subset of 116 adult patients enrolled in two consecutive MRD-oriented trials of the Spanish PETHEMA (Programa Español de Tratamientos en Hematología) group. Genetic analysis revealed a mutational profile defined by DNMT3A/ N/KRAS/ MSH2/ U2AF1 gene mutations that identified refractory/resistant patients. Mutations in the DMNT3A gene were also found in the non-leukemic cell fraction of patients with T-ALL, revealing a possible mutational-driven clonal hematopoiesis event to prime T-ALL in elderly. The prognostic impact of this adverse genetic profile was independent of MRD status on day +35 of induction therapy. The combined worse-outcome genetic signature and MRD on day +35 allowed risk stratification of T-ALL into standard or high-risk groups with significantly different 5- year overall survival (OS) of 52% (95% confidence interval: 37-67) and 17% (95% confidence interval: 1-33), respectively. These results confirm the relevance of the tumor genetic profile in predicting patient outcome in adult T-ALL and highlight the need for novel gene-targeted chemotherapeutic schedules to improve the OS of poor-prognosis T-ALL patients.

Results of the compassionate program of inotuzumab ozogamicin for adult patients with relapsed or refractory acute lymphoblastic leukemia in Spain.

INTRODUCTION: The prognosis of relapsed B cell precursor acute lymphoblastic leukemia (B-ALL) is poor and few patients can be successfully rescued with conventional therapies. Inotuzumab ozogamicin (IO), an antibody against the CD22 antigen linked to calicheamicin, has been approved as a rescue treatment in relapsed/refractory (R/R) B-ALL. PATIENTS AND METHODS: This was an observational, retrospective, multicenter study of adult patients included in the Spanish program of compassionate use of IO in centers from the PETHEMA group (Programa Español de Tratamientos en Hematología). RESULTS: Thirty-four patients with a median age of 43 years (range, 19-73) were included. Twenty patients (59%) were refractory to the last treatment, IO treatment was given as ≥3rd salvage treatment in 25 patients (73%) and 20 patients (59%) received allogeneic hematopoietic stem cell transplantation before IO treatment. After a median of 2 cycles of IO, 64% of patients achieved complete response (CR)/complete response with incomplete recovery. The median response duration, progression-free survival and overall survival (OS) were 4.7 (95%CI, 2.4-7.0 months), 3.5 (95%CI, 1.0-5.0 months) and 4 months (95%CI, 1.9-6.1 months) respectively, with better OS for patients with relapsed B-ALL versus refractory disease (10.4 vs. 2.5 months, respectively) (p = .01). There was a trend for better OS for patients with first CR duration >12 months (7.2 months [95%CI, 3.2-11.2] vs. 3 months [95% CI, 1.8-4.2] respectively) (p = .054). There was no sinusoidal obstruction syndrome (SOS) event during IO treatment, but three patients (9%) developed grade 3-4 SOS during alloHSCT after IO treatment. CONCLUSIONS: Our study showed slightly inferior outcomes of the pivotal trial probably due to poorer risk factors and late onset of IO therapy of recruited patients. Our results support early use of IO in relapsed/refractory ALL patients.

Twelve years of experience with miglustat in the treatment of type 1 Gaucher disease: The Spanish ZAGAL project.

We report data from a prospective, observational study (ZAGAL) evaluating miglustat 100mg three times daily orally. in treatment-naïve patients and patients with type 1 Gaucher Disease (GD1) switched from previous enzyme replacement therapy (ERT). Clinical evolution, changes in organ size, blood counts, disease biomarkers, bone marrow infiltration (S-MRI), bone mineral density by broadband ultrasound densitometry (BMD), safety and tolerability annual reports were analysed. Between May 2004 and April 2016, 63 patients received miglustat therapy; 20 (32%) untreated and 43 (68%) switched. At the time of this report 39 patients (14 [36%] treatment-naïve; 25 [64%] switch) remain on miglustat. With over 12-year follow-up, hematologic counts, liver and spleen volumes remained stable. In total, 80% of patients achieved current GD1 therapeutic goals. Plasma chitotriosidase activity and CCL-18/PARC concentration showed a trend towards a slight increase. Reductions on S-MRI (p=0.042) with an increase in BMD (p<0.01) were registered. Gastrointestinal disturbances were reported in 25/63 (40%), causing miglustat suspension in 11/63 (17.5%) cases. Thirty-eight patients (60%) experienced a fine hand tremor and two a reversible peripheral neuropathy. Overall, miglustat was effective as a long-term therapy in mild to moderate naïve and ERT stabilized patients. No unexpected safety signals were identified during 12-years follow-up.

Long-Term Outcomes After Autologous Versus Allogeneic Stem Cell Transplantation in Molecularly-Stratified Patients With Intermediate Cytogenetic Risk Acute Myeloid Leukemia: A PETHEMA Study.

Acute myeloid leukemia (AML) with intermediate risk cytogenetics (IRcyto) comprises a variety of biological entities with distinct mutational landscapes that translate into differential risks of relapse and prognosis. Optimal postremission therapy choice in this heterogeneous patient population is currently unsettled. In the current study, we compared outcomes in IRcyto AML recipients of autologous (autoSCT) (n = 312) or allogeneic stem cell transplantation (alloSCT) (n = 279) in first complete remission (CR1). Molecular risk was defined based on CEBPA, NPM1, and FLT3-ITD mutational status, per European LeukemiaNet 2017 criteria. Five-year overall survival (OS) in patients with favorable molecular risk (FRmol) was 62% (95% confidence interval [CI], 50-72) after autoSCT and 66% (95% CI, 41-83) after matched sibling donor (MSD) alloSCT (P = .68). For patients of intermediate molecular risk (IRmol), MSD alloSCT was associated with lower cumulative incidence of relapse (P < .001), as well as with increased nonrelapse mortality (P = .01), as compared to autoSCT. The 5-year OS was 47% (95% CI, 34-58) after autoSCT and 70% (95% CI, 59-79) after MSD alloSCT (P = .02) in this patient subgroup. In a propensity-score matched IRmol subcohort (n = 106), MSD alloSCT was associated with superior leukemia-free survival (hazard ratio [HR] 0.33, P = .004) and increased OS in patients alive 1 year after transplantation (HR 0.20, P = .004). These results indicate that, within IRcyto AML in CR1, autoSCT may be a valid option for FRmol patients, whereas MSD alloSCT should be the preferred postremission strategy in IRmol patients.

An analysis of the impact of CD56 expression in de novo acute promyelocytic leukemia patients treated with upfront all-trans retinoic acid and anthracycline-based regimens.

Out of 956, there were 95 (10%) CD56+ APL patients treated with PETHEMA ATRA and chemotherapy. CD56+ expression was associated with high WBC, BCR3 isoform, and co-expression of CD2, CD34, CD7, HLA-DR, CD15, and CD117 antigens. CD56+ vs CD56- APL presented higher induction death rate (16% vs 8%, p = .02) and 5-years cumulative incidence of relapse (33% versus 10%, p = .006), irrespectively of the Sanz score (low-risk 47% versus 5%, p < .001; intermediate 23% versus 7%, p < .001; and high-risk 42% versus 21%, p = .007). In the multivariate analysis, CD56 + (p < .0001), higher relapse-risk score (p = .001), and male gender (p = .05) retained the independent predictive value. CD56+ APL also showed a greater risk of CNS relapse (6% versus 1%, p < .001) and lower 5-year OS (75% versus 83%, p = .003). The AIDA-based LPA2012 trial, with an intensified consolidation schedule for CD56+ APL, will elucidate whether an intensified consolidation schedule could mitigate the relapse rate in this setting.

Impact of transplant eligibility and availability of a human leukocyte antigen-identical matched related donor on outcome of older patients with acute lymphoblastic leukemia.

The role of allogeneic hematopoietic cell transplant (allo-HCT) in elderly patients with acute lymphoblastic leukemia (ALL) is unclear. We conducted a prospective study including 110 homogeneously treated patients with ALL aged 50-70 years. Their outcomes were analyzed by intention-to-treat on a donor-versus-no donor basis. Fifty-five patients (50%) underwent human leukocyte antigen (HLA) typing and were considered potential allo-HCT candidates, although only 25 (23%) eventually received an allo-HCT. Among potential allo-HCT candidates, patients with (n = 28) and without (n = 27) an HLA-identical sibling showed similar leukemia-free survival, overall survival (OS) and relapse risk, and the only variable associated with a better outcome was achievement of first complete remission (CR1) after induction therapy. Among the 25 patients who actually received an allo-HCT, the 4-year non-relapse mortality and OS were 42% (95% confidence interval 31-53%) and 37% (95% confidence interval 27-47%), respectively. In conclusion, having an HLA-identical sibling donor was not associated with a better outcome in patients with ALL aged 50-70 years.

[Treatment of neuropathic pain with lacosamide]. / Tratamiento del dolor neuropatico con lacosamida.

INTRODUCTION: Lacosamide is a new antiepileptic drug with a novel mechanism of action, as it selectively promotes the slow inactivation of voltage-dependent sodium channels without affecting fast inactivation. There are studies in the literature regarding its effectiveness in controlling neuropathic pain. CASE REPORTS: We describe the use of intravenous lacosamide in the treatment of three patients with neuropathic pain: a woman with neuropathic pain in the first branch of the right trigeminal nerve during the acute phase of herpes zoster, a woman with central pain secondary to Dejerine-Roussy syndrome due to a malignant brain tumour, and a man with facial pain due to infiltration of the trigeminal nerve by a secondary lymphoma of the central nervous system. In the three cases, the administration of intravenous lacosamide has led to a considerable improvement in pain. The lacosamide dose has been 200 mg/day with excellent tolerability. CONCLUSION: Lacosamide can be an effective and well-tolerated alternative in the treatment of neuropathic pain and, moreover, its intravenous use can achieve pain control faster or be suitable when it is not tolerated orally.

Tratamiento del dolor neuropático con lacosamida / Treatment of neuropathic pain with lacosamide

Introducción. La lacosamida es un nuevo fármaco antiepiléptico con un mecanismo de acción novedoso al favorecer, de forma selectiva, la inactivación lenta de los canales de sodio dependientes del voltaje, sin actuar sobre la inactivaciónrápida. Existen estudios en la bibliografía sobre su eficacia para el control del dolor neuropático.Casos clínicos. Se describe el uso de la lacosamida intravenosa en el tratamiento de tres enfermos con dolor neuropático: una mujer con dolor neuropático en la primera rama del trigémino derecho durante la fase aguda de un herpes zóster, una mujer con un dolor central secundario a un síndrome de Déjerine-Roussy por una neoplasia cerebral y un varón con dolorfacial debido a una infiltración del trigémino por un linfoma secundario del sistema nervioso central. En los tres casos, la administración de lacosamida intravenosa ha significado una llamativa mejoría del dolor. La dosis de lacosamida ha sido de 200 mg/día, con una excelente tolerabilidad. Conclusión. La lacosamida puede ser una alternativa eficaz y bien tolerada en el tratamiento del dolor neuropático y, además, el uso intravenoso puede acelerar el control del dolor o ser adecuado en caso de no tolerar la vía oral (AU)

Introduction. Lacosamide is a new antiepileptic drug with a novel mechanism of action, as it selectively promotes the slowinactivation of voltage-dependent sodium channels without affecting fast inactivation. There are studies in the literature regarding its effectiveness in controlling neuropathic pain. Case reports. We describe the use of intravenous lacosamide in the treatment of three patients with neuropathic pain: a woman with neuropathic pain in the first branch of the right trigeminal nerve during the acute phase of herpes zoster, a woman with central pain secondary to Déjerine-Roussy syndrome due to a malignant brain tumour, and a man with facial pain due to infiltration of the trigeminal nerve by a secondary lymphoma of the central nervous system. In the three cases, the administration of intravenous lacosamide has led to a considerable improvement in pain. The lacosamide dose has been 200 mg/day with excellent tolerability.Conclusion. Lacosamide can be an effective and well-tolerated alternative in the treatment of neuropathic pain and, moreover, its intravenous use can achieve pain control faster or be suitable when it is not tolerated orally (AU)