Javier Garcés-Eisele

Improving acute promyelocytic leukemia (APL) outcome in developing countries through networking, results of the International Consortium on APL.

Thanks to modern treatment with all-trans retinoic acid and chemotherapy, acute promyelocytic leukemia (APL) is now the most curable type of leukemia. However, this progress has not yielded equivalent benefit in developing countries. The International Consortium on Acute Promyelocytic Leukemia (IC-APL) was established to create a network of institutions in developing countries that would exchange experience and data and receive support from well-established US and European cooperative groups. The IC-APL formulated expeditious diagnostic, treatment, and supportive guidelines that were adapted to local circumstances. APL was chosen as a model disease because of the potential impact on improved diagnosis and treatment. The project included 4 national coordinators and reference laboratories, common clinical record forms, 5 subcommittees, and laboratory and data management training programs. In addition, participating institutions held regular virtual and face-to-face meetings. Complete hematological remission was achieved in 153/180 (85%) patients and 27 (15%) died during induction. After a median follow-up of 28 months, the 2-year cumulative incidence of relapse, overall survival (OS), and disease-free survival (DFS) were 4.5%, 80%, and 91%, respectively. The establishment of the IC-APL network resulted in a decrease of almost 50% in early mortality and an improvement in OS of almost 30% compared with historical controls, resulting in OS and DFS similar to those reported in developed countries.

Primary thrombophilia in Mexico. II. Factor V G1691A (Leiden), prothrombin G20210A, and methylenetetrahydrofolate reductase C677T polymorphism in thrombophilic Mexican mestizos

We have shown that in Mexican mestizo patients with clinical features of primary thrombophilia, 39% have activated protein C resistance phenotype, 5% protein C deficiency, and 2% protein S deficiency. In the present study, in a group of 37 thrombophilic Mexicans and 50 normal controls, we assessed the factor V G1691A (Leiden), the prothrombin G20210A, and the methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphisms. Four patients were found to be heterozygous for factor V Leiden, 5 heterozygous for the prothrombin 20210, 16 heterozygous, and 6 homozygous for the MTHFR 677. There were four individuals with co‐segregation of alleles: two heterozygotes for the factor V Leiden/prothrombin 20210, one heterozygote for prothrombin 20210/MTHFR 677, and one heterozygote for prothrombin 20210/homozygote for MTHFR 677. For factor V Leiden, prothrombin 20210, and MTHFR 677 mutations, the allele frequencies were respectively 1% (±0.2%, α = 0.05), <1% and 51% (±5%, α = 0.05), with calculated relative risks for thrombosis of 5.94 (P = 0.08), >7.66 (P < 0.05), and 0.44 (P NS), respectively. In Mexican mestizo thrombophilic patients, the low prevalence of the factor V Leiden mutation (10.8%) and the high prevalence of the prothrombin 20210 mutation (13.5%) contrast with those identified in Caucasian thrombophilic patients (21% and 6%, respectively; P < 0.01). On the other hand, the high prevalence of the MTHFR 677 mutation gene both in normal controls (78%) and thrombophilic patients (61%) does not support a role of this mutation in the thrombogenesis of Mexican mestizo patients. Am. J. Hematol. 66:28–31, 2001.

Methotrexate-induced mucositis in acute leukemia patients is not associated with the MTHFR 677T allele in Mexico

Abstract Methylenetetrahydrofolate reductase (MTHFR) has two common variants with reduced activity due to polymorphisms at nucleotides 677 and 1298. Both affect folate metabolism and thus remethylation of homocysteine, but are also thought to affect nucleotide synthesis and DNA methylation. Methotrexate (MTX), which interrupts folate metabolism, is used in the treatment of a variety of diseases including acute lymphoblastic leukemia (ALL), but exerts in some patients toxic effects on fast dividing tissues such as mucosal epithelia. The enhanced toxicity may be due to cooperative effects between MTX and MTHFR variants. Accordingly, it has been reported that carrying the 677T allele of the MTHFR is a risk factor for MTX-associated mucositis. As in the Mexican population, which is characterized by a high prevalence of the 677T MTHFR variant, several of its commonly associated defects have not been observed, we investigated the relationship between MTX toxicity and the 677T allele. Out of 28 patients with ALL (CC: 2, CT: 10, TT: 16), 16 had episodes of MTX-associated mucositis (CC: 0, CT: 6, TT: 10). Neither at the gene level nor at the genotype level was a significant association with mucositis found. It may be postulated that the risk of higher MTX toxicity in patients with decreased MTHFR activity could be neutralized by the normally folate rich diet in Mexico.

More on Geographic Hematology: The Breakpoint Cluster Regions of the PML/RARα Fusion Gene in Mexican Mestizo Patients with Promyelocytic Leukemia are Different from Those in Caucasians

Acute promyelocytic leukemia is characterized the PML/RARalpha chimeric fusion gene, transcript and protein; the breakpoint cluster regions (bcr) in the PML gene may occur in 3 different sites: Intron 6 (bcr1), exon 6 (bcr2) or intron 3 (bcr3). In a 10-year period in a single institution, we studied prospectively the breakpoint cluster regions of the PML/RARalpha fusion gene in 43 Mexican Mestizo patients with APL, and found that the bcr1 represented 62.7%, the bcr2 9.3% whereas the bcr3 27.9%. The prevalence of the bcr1 subtype is significantly higher than that informed in Caucasians and similar to that in Asians; these data are consonant with those described in other Latin-American patients with APL. Since other Asian genetic markers have been found in the Indian component of the Mexican mestizos, it is possible that the Asian immigration into the Americas through the strait of Behring 12,000 years ago may account for a possible genetic susceptibility to suffer certain forms of APL.

Follow up of hemopoietic chimerism in individuals given allogeneic hemopoietic stem cell allografts using an immunosuppressive, non-myeloablative conditioning regimen: A prospective study in a single institution

Thirty consecutive patients were given non-myeloablative stem cell transplants (NST) and posttransplant chimerism was studied by several methods. In 16 individuals definitive proofs of chimerism have been shown: In 10 cases sex chimerism, in 7 cases chimerism shown by means of microsatellites, in 4 cases ABO chimerism, in two cases Rh chimerism and in one HLA-DR chimerism. In addition, in 9 individuals the disappearance of the molecular marker of the leukemia is an indirect evidence of the chimerism, as well as the presence of graft versus host disease (GVHD) in 17 allografted patients. Only in 6 patients no evidence of chimerism could be shown; all of them died as a result of either persistent or relapsing malignancy. Since the early patterns of chimerism may be predictive of either GVHD or graft loss in NST and, since therapeutic intervention (such as donor lymphocytes infusions) is based in the patterns of chimerism, it is possible that chimerism studies in these types of allografts should be ideally done more frequently than in conventional allotransplants.

Primary Thrombophilia in Mexico: A Prospective Study

A group of 102 Mexican Mestizo patients with appropriate clinical features suggestive of primary thrombophilia was prospectively studied. Thirty‐nine percent of them had activated protein C resistance, but only four patients displayed the factor V Leiden mutation. Five percent of the individuals were found to be protein C deficient, whereas 2% had protein S deficiency. No cases of abnormalities in antithrombin III, plasminogen, tissue‐type plasminogen activator or plasminogen activator inhibitor were found. The low prevalence of the activated protein C resistance genotype, probably stemming from the genetic admixture of the Mexican Mestizo group is noteworthy. Am. J. Hematol. 60:1–5, 1999.

Treatment of vitiligo with a chimeric monoclonal antibody to CD20: a pilot study

Five patients with active disseminated vitiligo were given 1 g of a chimeric (murine/human) monoclonal antibody to CD20 in a single intravenous infusion and followed‐up for 6 months. Three of the patients showed an overt clinical and histological improvement of the disease, one presented slight improvement and the remaining patient showed no changes. Improvement was neither associated with changes in laboratory parameters nor to a specific human leucocyte antigen D‐related (HLA‐DR) phenotype. We believe that these preliminary results are encouraging, and further clinical trials should be undertaken. An important aim should be the finding of a marker with a good response to this therapeutic approach.

Tuberculosis-associated fatal hemophagocytic syndrome in a patient with lymphoma treated with fludarabine.

A patient with a stage IV high-grade non-Hodgkins lymphoma who developed a fatal hemophagocytic syndrome is presented: When the patient had achieved complete remission and receiving fludarabine and chlorambucil/prednisone, she developed miliary tuberculosis, the CD4+ T-cell count then being 50/microL; the hemophagocytic syndrome ensuing at this point was fatal. Speculations about the predisposing factors that could have led to this complication are discussed focusing on the severe cellular immunosuppression which developed probably related to the use of fludafabine: it could be useful in the future to use anti-tuberculous prophylaxis in selected patients treated with this purine nucleoside analog.

Primary thrombophilia in Mexico IX: The Glycoprotein IIIa PLA1/A2 Polymorphism is Not Associated With the Sticky Platelet Syndrome Phenotype

Introduction: The sticky platelet syndrome (SPS) seems to be a common cause of thrombosis, although no molecular substrate to explain platelet hyperaggregability has been found. Objective: To analyze an association between the SPS phenotype and the platelet glycoprotein (GP) IIIa PLA1/A2 (human platelet antigen [HPA]-1a/b) gene polymorphism. Methods: Along an 18-month period, Mexican mestizo thrombophilic patients were prospectively accrued. The SPS phenotype was assessed by aggregometry, whereas a tetra-primer amplification refractory mutation system (ARMS) polymerase chain reaction analysis was used to detect the PLA1 and PLA2 alleles. Results: A total of 95 individuals with SPS and 127 healthy donors were studied; in 11 of the donors and 16 of the patients with SPS the A2 allele of the GP IIb/IIIA was found, yielding a weak and nonsignificant association (odds ratio 2.14, 95% CI 0.94-4.85). Conclusion: In Mexican mestizo patients, the platelet GP IIIa PLA1/A2 gene polymorphism does not lead to the SPS phenotype.

Primary thrombophilia in México VII: the V617F mutation of JAK2 is not a frequent cause of thrombosis

Abstract The study of the V617F JAK2 gene mutation has been used to identify the presence of an underlying myeloproliferative disorder (MPD) as the cause of unexplained thrombosis. In a group of 77 consecutive Mexican patients with a clinical marker of a primary thrombophilic condition, we looked for this JAK2 mutation and did not find any individual displaying it. Given these results, we conclude that an undetected MPD is a very improbable cause of thromboses in Mexican mestizos, a population where the prevalence of these disorders has been found to be lower than that found in Caucasian populations. Accordingly, it seems that the investigation for the V617F mutation of the JAK2 gene is not mandatory in all Mexican mestizo patients with unexplained thrombophilia and that this genetic study should be reserved for special cases, such as patients with thrombosis in uncommon sites or patients with cell counts suggesting the presence of an underlying MPD.