Andrés Gómez-De León

Eltrombopag and high-dose dexamethasone as frontline treatment of newly diagnosed immune thrombocytopenia in adults

Immune thrombocytopenia (ITP) results from platelet destruction and production suppression. Eltrombopag belongs to a new class of thrombopoietin-mimetic drugs that raise platelet counts in ITP patients. We performed a single-arm study to assess the response to a single course of dexamethasone (40 mg by mouth, days 1-4) in combination with eltrombopag (50 mg, days 5-32) in 12 adults with newly diagnosed ITP in an outpatient setting. Median follow-up was 12.5 months. After therapy (day 33), 100% of patients achieved at least ≥30 × 10(9)/L platelets. Four patients relapsed. Complete response at 6 months (platelets ≥100 × 10(9)/L) was achieved in 50% of patients and response at 6 months (platelets ≥30 <100 × 10(9)/L) was achieved in another 25%; relapse-free survival was 66.7% at 12 months (median response duration of 8.3 months). In conclusion, eltrombopag/dexamethasone is a feasible frontline therapy for ITP. This trial is registered at www.clinicaltrials.gov as NCT01652599.

Effective collection of peripheral blood stem cells in children weighing 20 kilogram or less in a single large-volume apheresis procedure

Introduction: Peripheral blood stem cell (PBSC) transplantation has become a routine procedure in pediatric oncology. A special group of PBSC donors are children weighing 20 kg or less. Limited vascular access and low blood volume puts them at a higher risk. Central line placement and a priming apheresis machine are recommended to avoid these complications. Patients and Methods: PBSC collections performed from July 2006 to May 2013 in children weighing less than 20 kg were included. All donors had a central venous catheter (CVC). An apheresis machine was primed with packet red blood cells. Results: Twenty‐seven PBSC collections were performed in 22 children weighing 20 kg or less, 14 for allogeneic and 8 for autologous transplantation, in order to collect at least 2 × 106 CD34+ cells/kg. In the allogeneic group, median age and weight were 3 years (0.8–7) and 15.5 kg (8–20). In the autologous group, median age and weight were 3 years (2–7) and 15.35 kg (12.5–19.5). A single large‐volume apheresis was sufficient to obtain the CD34+ cells needed in 78.5% and 75% of the allogeneic and autologous groups, respectively, with a median 11.84 × 106 and 5.79 × 106 CD34+ cells collected per kilogram of weight of the recipient. No serious complications related to the apheresis procedure or CVC placement occurred. Conclusion: PBSC collection in a single large‐volume apheresis for allogeneic and autologous transplants in children weighing 20 kg or less is a safe and effective procedure when based on standardized protocols. J. Clin. Apheresis 30:281–287, 2015.

Acute Leukemia Characteristics are Different Around the World: the Mexican Perspective

Micro‐Abstract In Mexico, there are no large‐scale studies regarding acute leukemia epidemiology. This multicenter, retrospective study evaluated 1018 patients. A similar prevalence for acute lymphoblastic leukemia versus acute myeloid leukemia was found. Less positivity for the Philadelphia chromosome was observed. Acute myeloid leukemia occurred in younger patients, most frequently as an M3 variant. This study is the largest ever performed in Mexico regarding acute leukemia epidemiology. Background: The incidence of acute leukemia (AL) has increased. Its prognosis is variable and depends on several baseline characteristics with a highly heterogeneous presentation. In Mexico, large‐scale descriptive studies have not yet been published; the objective of this study was to analyze the initial basic characteristics of patients diagnosed with AL in our population. Patients and Methods: In this multicenter, retrospective study, 1018 patients ≥ 16 years of age and diagnosed with AL between 2009 and 2014, were included. We described age, gender, complete blood count, and AL subtype according to flow cytometry analysis. Results: Acute lymphoblastic leukemia (ALL) was as common as acute myeloid leukemia (AML) (51% vs. 49%). The median age was 31 years. Only 9.6% of patients with ALL were positive for the Philadelphia chromosome. No gender differences were observed. The median age at presentation of AML was 43 years. Acute promyelocytic leukemia was the most frequent AML subtype (38.3%), with a median age of 37 years. Conclusion: ALL is equally as frequent as AML in patients ≥16 years of age. Philadelphia‐positive prevalence is less frequent than that reported in literature. AML cases occur in a younger age in comparison with other countries. There is a higher rate of acute promyelocytic leukemia among our patients compared with other non‐Latin American populations. This study is the largest ever performed in Mexico regarding descriptive AL data.

Age Acts as an Adverse Independent Variable for Survival in Acute Lymphoblastic Leukemia: Data From a Cohort in Northeast Mexico

&NA; Acute lymphoblastic leukemia is a highly heterogeneous disease whose clinical course and outcome are strongly influenced by age. A cohort including 377 patients of all ages from a low‐middle income and homogeneous population receiving standardized treatment protocols over a decade was analyzed. Age < 1 and > 20 years was significantly associated with lower overall survival. Infants fared worst. Background: Survival for acute lymphoblastic leukemia (ALL) decreases with age. Patients across all age groups from a homogeneous ethnic and socioeconomic background were studied to document age effect. Material and Methods: Patients diagnosed from 2005 to 2015 at a university hospital in Northeast Mexico were divided into 4 age groups: infants (< 1), children (≥ 1 to < 16), adolescents (≥ 16 to ≤ 20), and adults (> 20 years). Correlation between age at diagnosis and relapse‐free (RFS) and overall survival (OS) was investigated. Results: A total of 377 patients were included. Five‐year RFS and OS for children were 55.6% and 66.9%; for adolescents, 36.0% and 48.3%; for adults, 19.5% and 24.1%, respectively. Differences in RFS and OS between age groups were significant (P < .001, P < .001). In the Cox regression model, all age groups reached statistical significance in univariate analysis of mortality. Conclusion: Age plays a decisive role in clinical evolution of ALL and strongly influences outcome. Age older than 20 represents a progressive high‐risk factor for death.

Impact of the affordability of novel agents in patients with multiple myeloma: Real-world data of current clinical practice in Mexico: Novel Agents for Multiple Myeloma in Mexico

The treatment of multiple myeloma (MM) has become costly and difficult to access for patients living in low‐income to middle‐income countries.

Comparative analysis of iron status and other hematological parameters in preeclampsia

ABSTRACT Objective: To compare serum ferritin (SF) concentrations and other hematological parameters between patients with preeclampsia (PE) and normal pregnant women of the same gestational period who received supplemental iron during pregnancy. Methods: Prospective, comparative, observational pilot study that included 31 women with PE and 30 healthy pregnant women, at 20 weeks’ of gestation. Ferritin, iron and complete blood cell count were compared between groups. Results: In comparison with controls, preeclamptic patients had a higher weight, body mass index, and arterial pressure. Serum ferritin and serum iron were higher in patients with PE (median: 36.5 μg/l vs. 20.9 μg/l and 103.9 μg/dl vs. 90.8 μg/dl) with a significant difference (P = 0.019 and P = 0.345). SF values >40 μg/l correlated with PE (r = 0.281; P = 0.032). A platelet count less than 100 × 109/l was higher in the PE group than in the control group (13% vs. 3%, P = 0.354). Conclusion: Higher SF levels, despite being within normal range, were associated with PE. The incidence of thrombocytopenia was higher in preeclamptic women, however, the remaining hematological parameters were similar in both groups.

Clinical presentation in thrombotic thrombocytopenic purpura: Real-world data from two Mexican institutions

Thrombotic thrombocytopenic purpura (TTP) is a hematologic disease that can be fatal if not treated early. We aimed to describe the clinical characteristics of Mexican patients with idiopathic TTP.

Danazol as First-Line Therapy for Myelodysplastic Syndrome

Background Allogeneic stem cell transplantation (ASCT) represents the only option with a potential cure rate of 30% to 50% in myelodysplastic syndrome (MDS); however, < 5% of patients are optimal candidates for this management. Therapeutic options are limited in patients unsuitable for ASCT. Evidence that androgens might be beneficial in MDS is controversial. We aimed to document the clinical outcomes of patients diagnosed with MDS treated with danazol as first‐line therapy. Patients and Methods We retrospectively reviewed patients diagnosed in our center with MDS according to the World Health Organization 2008 criteria and treated with danazol between 2005 and 2015. Response was defined according to international working group criteria. Results We included 42 patients treated exclusively with danazol. Median dose was 400 mg/d (range, 100‐600 mg/d). Median follow‐up was 12 (range, 3‐76) months. Twenty‐four of these patients (60%) achieved clinical response. Median overall survival was 24 months (95% confidence interval, 5.1‐42). Responders were older than nonresponders (P = .025) and had higher baseline hemoglobin concentration (P = .009). No patients discontinued danazol because of toxicity. Fifteen patients died (35.7%) and 5 progressed to acute myeloid leukemia. Conclusion Danazol as first‐line therapy is an acceptable treatment option with low side effects for patients with MDS who cannot receive ASCT. Micro‐Abstract At present, no standard therapy is available for most patients with myelodysplastic syndrome. In this retrospective study, we analyze data from 42 patients with myelodysplastic syndrome treated with low‐dose danazol. More than half achieved a response. Results show that danazol remains an attractive option because of its low cost and good safety profile in centers with reduced access to novel therapeutic alternatives.

Eltrombopag, low‐dose rituximab, and dexamethasone combination as frontline treatment of newly diagnosed immune thrombocytopaenia

Immune thrombocytopenia (ITP) results from a combination of pathological antiplatelet antibodies, impaired megakaryopoiesis and T cell-mediated platelet destruction. Frontline treatment for newly diagnosed (ND) ITP includes prednisone, intravenous immunoglobulin and anti-D (Lambert & Gernsheimer, 2017). High-dose dexamethasone (HDD) is effective in ~85% of adults, but relapse will occur in ~60% (Wei et al, 2016). Low-dose rituximab (100 mg) has been used for ITP, showing an activity similar to 375-mg/m doses. Sustained response rates of 63–76% have been reported using rituximab plus HDD as frontline therapy (Zaja et al, 2010; G omezAlmaguer et al, 2013). Eltrombopag stimulates thrombopoiesis, but also suppresses T-cell responses to platelet auto-antigens and induces regulatory T cells (Tregs) (Bao et al, 2010). We have used eltrombopag plus HDD as a feasible first-line therapy, albeit relapses occurred in 30% of patients (G omez-Almaguer et al, 2014). The lack of sustained responses in adults with ITP has stimulated the search for treatment that could modify the natural course of, and potentially cure, the disease. Thus, we conducted a single centre pilot study to assess the safety and efficacy of triple therapy, including eltrombopag, low-dose rituximab and HDD. This single arm, open-label, study included ND ITP patients from Hospital Universitario ‘Dr. Jos e Eleuterio Gonz alez’ in Monterrey, Mexico (Clinical trials.gov NCT02834286). Eligible patients were ≥16 years of age, without previous therapy, and ≤30 9 10/L platelets. Bleeding was scored according to the International Working Group (Rodeghiero et al, 2013). Participants were excluded if they had active infection (human immunodeficiency virus, hepatitis), drug-associated thrombocytopaenia, malignancy or were pregnant. Our ethics committee approved the study, which was performed in accordance with the Declaration of Helsinski. Outpatient treatment consisted of eltrombopag 50 mg/day for 28 days (1–28), oral dexamethasone 40 mg/day for 4 days (1–4), and low dose rituximab 100 mg weekly for 4 weeks (days 1, 7, 14, and 21). Eltrombopag was suspended if platelets were ≥ 400 9 10/l. A complete blood count was performed at baseline, on days 3, 5 and 7, and then weekly for 28 days, monthly until month 6, and every 3 months thereafter. Primary outcome was response rate at the end of treatment (day 28). Response and complete response (CR) were defined as an increase in platelet counts ≥30 9 10/l and ≥100 9 10/l, respectively. Secondary outcomes included 2-year relapse-free survival (RFS) considered from the day of initial response until relapse (<30 9 10/l platelets), duration of response (DOR) included the period of time of any responses achieved (CR or response) until relapse. Treatment side effects were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events, v.4 0 (https://evs.nci.nih.gov/ftp1/ CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf). The Kaplan-Meier method was used to calculate probability of RFS; statistical analysis was performed with SPSS software version 20 0 for Mac (IBM, Armonk, NY, USA). Thirteen consecutive patients were enrolled; their characteristics are reported in Table I. Median follow-up was 14 1 months (range 1 4–24). Median platelet count at diagnosis was 4 9 10/l (range 0 8–28). Median bleeding grade was 2 (range 1–3). All patients responded and all but 1 achieved CR during treatment (92%). Median time to response was 4 days (range 3–10) and to CR 9 days (7–22). Five patients received an additional HDD course due to declining platelet counts; two failed to achieve platelets ≥100 9 10/l at evaluation, thus CR rate at day 28 was 84 6% (response: 100%). Two patients achieved platelets >400 9 10/l (days 14 and 21). One patient was lost to follow-up 2 weeks after response evaluation. One patient lost CR and received danazol for 5 months elsewhere, re-achieving CR and currently remains treatment-free. Two patients relapsed 5 and 12 months after diagnosis; 2-year probability of RFS was 79% (Fig 1). Currently, all but the relapsed patients remain treatment-free in CR. Median DOR was 11 months (range 0 5–23). Outpatient treatment was well tolerated. One patient reported mild myalgia, 2 had insomnia, and one had fever related to rituximab. Combination short-duration frontline therapy with the rationale of achieving prolonged remissions has not been attempted previously with these three agents. All patients quickly responded and most reached CR, similarly to previous experience with eltrombopag and rituximab plus HDD (G omez-Almaguer et al, 2013, 2014). The present report can attest to the efficacy of more aggressive therapy early in the course of ITP as it led to an RFS of almost 80% at 12 months that was sustained, in contrast to 66 7% in our previous report with eltrombopag plus HDD (G omez-Almaguer et al, 2014). Our previous experience with rituximab and HDD showed a similar RFS (84%) at 12 months (G omez-Almaguer et al, 2013). Interestingly 3 of the 5 Correspondence

TNF-α increases in the CSF of children with acute lymphoblastic leukemia before CNS relapse.

There is scarce information regarding the concentration of cytokines in cerebrospinal fluid (CSF) of children with acute lymphoblastic leukemia (ALL) and their clinical association with CNS status. A prospective analysis of 40 patients <18years with newly diagnosed ALL was performed. Human cytokine magnetic bead panel assay values of IL-2, IL-4, IL-6, IL-8, IL-10, MCP-1, TNF-α in CSF at diagnosis, end of induction to remission, and 6months after diagnosis were determined. IL-6 and MCP-1 values showed a significant increment at the end of induction. From the whole group 4 (10.0%), patients relapsed to the CNS at a median of 11.48months. A significantly higher value of TNF-α at third determination in these CNS-relapsed patients was documented, 7.48 vs. 2.86pg/mL in 36 children without relapse (p=0.024). TNF-α concentration increased at a median 5.48months before CNS relapse. By receiver-operating characteristic curve (ROC) analysis, the best cut-off point of TNF-α concentration that better predicted CNS relapse was ≥1.79pg/mL. In conclusion an increase in TNF-α concentration on CSF preceded CNS relapse in children with ALL. An increase in MCP-1 and IL-6 was not associated to CNS relapse and appears to result from an inflammatory response after IT injection of chemotherapy.