Acute Leukemia Relapse after Hematopoietic Stem Cell Transplantation: The Good, the Bad, and the Ugly of Isolated Extramedullary Relapse in a Latin American Population.

Hematopoietic stem cell transplantation (HSCT) is an effective therapy for acute leukemia (AL). Relapse represents the main cause of mortality. Isolated extramedullary relapse (iEMR) is atypical and has been related to better outcomes. Here we describe the clinical characteristics and outcomes of AL relapse after HSCT in our study population and analyze the impacts of different types of relapse on survival outcomes. This retrospective, multicenter study included 124 patients age ≥15 years with AL who underwent HSCT between 2004 and 2019. At diagnosis, 66.1% of the patients had lymphocytic AL, 19.7% presented with high-risk features, and 18.5% had extramedullary disease (EMD). At HSCT, 83.1% of the patients were in complete remission (CR), and 44.8% had negative measurable residual disease (MRD). The vast majority of donors were related (96%), including 48.4% HLA-matched and 47.6% haploidentical. Myeloablative conditioning was provided to 80.6% of patients. The median overall survival (OS) was 15 months (95% confidence interval [CI] 9.9 to 20.1 months). Factors associated with improved OS were adolescent and young adult (AYA) patient (P = .035), first or second CR (P = .026), and chronic graft-versus-host disease (GVHD) (P < .001). Acute GVHD grade III-IV (P = .009) was associated with increased mortality. The median relapse-free survival was 13 months (95% CI, 7.17 to 18.8 months); early disease status (P = .017) and chronic GVHD (P < .001) had protective roles. Sixty-eight patients (55%) relapsed after HSCT, with a median time to relapse of 6 months (95% CI, 3.6 to 8.4 months). iEMR was reported in 16 patients (23.5%). The most commonly involved extramedullary sites were the central nervous system and skin. Compared to patients with bone marrow relapse, all patients with iEMR had a diagnosis of acute lymphoid leukemia (P = .008), and 93.8% belonged to the AYA group; regarding pre-HSCT characteristics, iEMR patients had higher rates of negative MRD (P = .06) and a history of EMD (P = .009). Seventy-seven percent of relapsed patients received additional treatment with curative intent. The median OS after relapse (OSr) was 4 months (95% CI, 2.6 to 5.4 months). Factors related to increased OSr included lymphoid phenotype (P = .03), iEMR (P = .0042), late relapse (≥6 months) (P = .014), receipt of systemic therapy including second HSCT (P < .001), and response to therapy (P < .001). Rates of relapse and iEMR were higher than those previously reported in other studies. Advanced disease, reduced-intensity conditioning, and a diminished graft-versus-leukemia effect were factors influencing these findings. At relapse, presenting with iEMR after 6 months and receiving intensive therapy with adequate response were associated with better outcomes. Our results strongly suggest that a personalized approach to treating patients with HSCT is needed to counterbalance specific adverse factors and can positively impact clinical outcomes.

Global methylation and promoter-specific methylation of the P16, SOCS-1, E-cadherin, P73 and SHP-1 genes and their expression in patients with multiple myeloma during active disease and remission.

Tumor suppressor gene promoter CpG island methylation is a well-recognized mechanism in cancer pathogenesis, but its role in multiple myeloma (MM) is controversial. The present study investigated the methylation status and expression of P16, suppressor of cytokine signaling 1 (SOCS-1), P73, E-cadherin and Src homology region 2 domain-containing phosphatase 1 (SHP-1), as well as global methylation in patients with MM during active disease and remission. Bone marrow samples were obtained from 43 patients at the Multiple Myeloma Clinic, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (Mexico City, Mexico) during active disease and remission. Methylation-specific polymerase chain reaction and ELISA were performed on bisulfite-treated or untreated DNA to determine promoter-specific or genomic methylation, respectively. Gene expression was measured using reverse-transcription polymerase chain reaction. The results indicated that SOCS-1 methylation occurred more frequently during active disease than remission [29 vs. 3.2% (P=0.021)] and was associated with more advanced forms of the disease [international staging system (ISS) 3, 16.67% vs. ISS 1, 8.3% (P=0.037)]. SHP-1 methylation during active disease was associated with a lower probability of survival at 39-month follow up (median), 52.5 vs. 87.5% (P=0.025). The percentage of methylation was associated with active disease at remission, but this was not significant. Global hypomethylation at remission was a negative predictor factor for overall survival (OS). The results indicated that methylated P16, SOCS-1 and SHP-1 were associated with clinical variables of poor prognosis in MM, likewise the persistence of global hypomethylation at remission. The negative impact on OS of global hypomethylation at remission must be confirmed in a larger sample. Future studies are necessary to investigate whether patients with global hypermethylation at remission should receive more aggressive treatments to improve their OS.

Importance of CD117 in the Assignation of a Myeloid Lineage in Acute Leukemias.

The correct classification of acute leukemias (AL) is an essential part in the evaluation of any patient with this disease. Historically, CD117 has been an important asset in the diagnosis of patients with mixed-phenotype acute leukemia (MPAL). In an attempt to simplify the diagnosis of MPAL with fewer and more lineage specific markers, the World Health Organization (WHO) proposed in 2008 a new criteria for the diagnosis of this type of AL, which excluded CD117 from the myeloid markers that are utilized to diagnose MPAL. In order to assess whether CD117 is necessary in the diagnosis of MPAL, we evaluated the sensitivity and specificity of CD117 for acute myeloid leukemia (AML) in 331 patients with AL. The calculated sensitivity of CD117 for AML was 85.88% (103/120), while the specificity was 83.9% (177/211). Besides myeloperoxidase (MPO), which was used as the gold standard in differentiating AML from other type of ALs, the most specific markers for AML in our study were CD14 and CD64 (99.5 and 95.6%). Although the specificity of CD117 in this study is not as high as CD14 and CD64, markers concomitantly used in this this study and in the WHO classification, based on the results of other researches (i.e. the specificity of CD117 for AML was 100% in one study) and due to the fact that its specificity for AML in this study is relatively high, we recommend the use CD117 in assigning a myeloid lineage in MPAL.

Expression of HER2/Neu in B-Cell Acute Lymphoblastic Leukemia.

BACKGROUND: The expression of HER2/neu in B-cell acute lymphoblastic leukemia has been reported in previous studies. OBJECTIVE: The objective of this research was to study the expression of HER2/neu on the blasts of patients with acute leukemia from the Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran. METHODS: From June 2015 to February 2016, a HER2/neu monoclonal antibody was added to the panel of antibodies that we routinely use in patients with acute leukemia. An expression of ≥ 30% was considered positive. RESULTS: We studied 33 patients: 19 had de novo leukemia (57.6%), three (9.1%) were in relapse, and in 11 (33.3%) their status could not be specified. Seventeen patients (51.5%) were classified as B-cell acute lymphoblastic leukemia with a median expression of HER2/neu of 0.3% (range 0-90.2). Three patients with B-cell acute lymphoblastic leukemia were positive for HER2/neu: 89.4%, 90.9%, and 62.4%. The first and third patient had de novo B-cell acute lymphoblastic leukemia. The second patient was in second relapse after allogeneic stem cell transplant. All three patients were categorized as high-risk at the time of diagnosis. CONCLUSIONS: In the studied Mexican population, we found a positive expression of HER2/neu in 17% of the B-cell acute lymphoblastic leukemia patients, similar to previous studies in which the expression was found in 15-50%.

Impact of Aberrant Antigens in the Outcome of Patients with Acute Leukemia at a Referral Institution in Mexico City.

BACKGROUND: Patients with acute leukemia can express aberrant markers, defined as antigens that are normally restricted to a different lineage. The reported significance and frequency of these markers is inconclusive. We assessed the frequency and impact of aberrant markers in patients with acute leukemia in a referral institution in Mexico City. METHODS: We included 433 patients, diagnosed and treated between 2005 and 2015 in our institution. RESULTS: Aberrant markers were expressed in 128 patients (29.6%); CD13 and CD33 were the most frequent aberrant markers in patients with acute lymphoblastic leukemia, while CD7 and CD19 were the most frequent in patients with acute myeloid leukemia. In the univariate analysis, the group with aberrant markers had a lower disease-free survival when compared with the aberrant-free group (8 vs. 13 months) (p = 0.03). Aberrant expression of CD10, CD20, and CD33 correlated with a worse outcome in a statistically significant manner. In the multivariate analysis, male gender, lymphoid lineage, secondary leukemia, high risk at diagnosis, and the presence of aberrant markers had a significantly negative impact on disease-free survival. CONCLUSION: The use of more aggressive treatment strategies could be considered in patients with acute leukemia and an aberrant expression of CD10, CD20, and CD33.

Mixed-phenotype acute leukemia: suboptimal treatment when the 2008/2016 WHO classification is used.

BACKGROUND: Different criteria have been used to diagnose mixed-phenotype acute leukemia (MPAL), which has impacted the number of individuals diagnosed with this pathology. Better outcomes have been reported when using acute lymphoblastic leukemia (ALL)-type chemotherapy in the treatment of MPAL. METHODS: We compared the outcome of 4 groups of patients with MPAL. Group 1 included patients diagnosed using the 2008/2016 World Health Organization (WHO) classification; group 2 included patients diagnosed using the European Group for the Immunological Characterization of Leukemias (EGIL) criteria; group 3 included patients diagnosed using either the EGIL or the 2008/2016 WHO criteria; and group 4 was comprised of patients diagnosed with MPAL using the EGIL classification only. RESULTS: We found a significantly worse disease-free survival (groups 1-4) and overall survival (OS) (groups 2 and 3) when comparing MPAL patients to other acute leukemia (AL) patients. A significantly better OS was obtained in patients (groups 2-4) treated with ALL-type chemotherapy compared to acute myeloid leukemia (AML)-type regimens. CONCLUSION: In light of these results, and because a trend (P=0.06) was found with regard to a better OS in group 4 when compared to other AL patients, an argument can be made that the 2008/2016 WHO classification is underpowered to diagnose all MPAL cases, potentially resulting in the suboptimal treatment of some individuals with AL.

Diagnosing and treating mixed phenotype acute leukemia: a multicenter 10-year experience in México.

Mixed phenotype acute leukemia (MPAL) in adults represents nearly 2 to 5 % of all acute leukemia cases. There are two large studies throughout the world and only case reports and small series have been reported in Latin America. This study retrospectively analyses the clinical characteristics and survival of 27 patients with MPAL evaluated in three medical institutions of Mexico. All cases meet World Health Organization 2008 criteria; 70.3 % of patients had B lymphoid/myeloid lineage MPAL. Induction chemotherapy protocols included 7 + 3 hyper-CVAD, high-density schedules, and pediatric-like regimens such as New York II and total XI. Complete remission was achieved in 23/27 patients (85.2 %). Only one patient died due to chemotherapy-induced aplasia during remission induction (5.2 %). In 68 % of cases, we were able to administer maintenance therapy as a regimen in lymphoblastic leukemia. At the time of analysis, 70.4 % of the patients in the entire cohort had died mainly as result of disease progression (73.6 %). Disease-free survival was 13 months (95 % CI, 9.6-16.3 months) and overall survival was 14.8 months (95 % CI 13.4-16.27). Survival rates are low and standardized therapy for the management of this type of leukemia is still lacking. This is the largest series reported in Mexico and to the best of our knowledge in Latin America.