Atypical CML: diagnosis and treatment.

Atypical chronic myeloid leukemia (aCML) is included in the group of myelodysplastic/myeloproliferative neoplasms by the International Consensus Classification and has been renamed as MDS/MPN with neutrophilia by the fifth edition of World Health Organization classification. It is always characterized by morphologic identification of granulocytic dysplasia with >10% circulating immature myeloid cells, 2 distinguished features that differentiate this disease among the others. Somatic mutations may help to diagnose but are not specifically pathognomonic of the disease, with the most detected including ASXL1, SETBP1, NRAS, KRAS, SRSF2, and TET2 and with low-frequency CBL, CSF3R, JAK2, and ETNK1. The genomic landscape of aCML has been recently unravelling, revealing that SETBP1 and ETNK1 are usually not ancestral but secondary events associated with disease progression. Unfortunately, until now, no consensus on risk stratification and treatment has been developed: Mayo Clinic prognostic score identified as adverse events age >67 years, hemoglobin level <10  g/dL, and TET2 mutations. Although some possible genetic markers have been identified, allogeneic transplant remains the only curative strategy.

Characteristics, primary treatment, and survival of MDS/MPN with neutrophilia: a population-based study.

Myelodysplastic and myeloproliferative neoplasms (MDS/MPN) with neutrophilia, until recently called atypical chronic myeloid leukemia (aCML), being part of the MDS/MPN is a very rare disease with poor prognosis. Although emerging data reveal its cytogenetic and molecular profile, integrated survival and treatment data remain scarce. We analyzed a cohort of 347 adult patients diagnosed with MDS/MPN with neutrophilia, registered in the Netherlands Cancer Registry between 2001 and 2019. Our demographic baseline data align with other cohorts. We observed cytogenetic aberrations exclusively in patients aged >65 years, with trisomy 8 being the most common abnormality. We identified 16 distinct molecular mutations, with some patients (16/101) harboring up to 3 different mutations; ASXL1 being the most frequent one (22%). In a multivariable Cox regression analysis, only age, hemoglobin level and allogeneic hematopoietic stem cell transplant (alloHSCT) were associated with overall survival (aged >65 years; hazard ratio [HR] 1.85; P = .001 and alloHSCT HR, 0.51; P = .039). Because no other treatment modality seemed to affect survival and might cause toxicity, we propose that all patients eligible for alloHSCT should, whenever possible, receive an allogeneic transplant. It is imperative that we strive to improve outcomes for patients who are not eligible for alloHSCT. Tackling this challenge requires international collaborative efforts to conduct prospective intervention studies.

CSF3R-mutant chronic myelomonocytic leukemia is a distinct clinically subset with abysmal prognosis: a case report and systematic review of the literature.

Chronic myelomonocytic leukemia (CMML) is a myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) chacaterized by persistent peripheral blood monocytosis, hypercellular bone marrow and dysplasia at least in one myeloid lineage. CMML shares much of its molecular landscape with other myeloid neoplasms, while differs from others such as chronic neutrophilic leukemia (CNL), given the high frequency of CSF3R mutations in the latter. In this article, we report a case of CSF3R-mutated CMML and dissect this rare entity by reviewing the medical literature, with the intent to understand how this rare mutation shapes CMML's clinical and morphological phenotype. CSF3R-mutated CMML emerges as a rare entity meeting the ICC/WHO diagnostic criteria for CMML and simultaneously showing clinical-pathological and molecular traits of CNL and atypical chronic myeloid leukemia, rising an important and difficult diagnostic and therapeutical issue.

CCND2 mutations in atypical chronic myeloid leukemia: a report of two cases.

Atypical chronic myeloid leukemia (aCML) is a rare MDS/MPN disease characterized by the absence of BCR::ABL1 rearrangement and well known typical mutations associated with myeloproliferative disorders. Mutational landscape associated with this disease was recently described with frequent involvement of SETBP1 and ETNK1 mutations. CCND2 mutations have not been frequently detected in MPN or MDS/MPN patients. We describe two cases of aCML with two CCND2 mutations in 280 and 281 codons which rapidly develop progressive characteristics, and we reviewed the literature about this unfavorable association, suggesting a role as a new possible marker of aggressive disease.

Myelodysplastic/myeloproliferative neoplasm with neutrophilia (atypical chronic myeloid leukemia-aCML).

A case of myelodysplastic/myeloproliferative neoplasm with neutrophilia (aCML) with SETBP1 and ASXL1 mutations.

Atypical chronic myeloid leukemia and myelodysplastic/myeloproliferative neoplasm, not otherwise specified: 2023 update on diagnosis, risk stratification, and management.

DISEASE OVERVIEW: Atypical chronic myeloid leukemia (aCML) and myelodysplastic/myeloproliferative (MDS/MPN) neoplasms, not otherwise specified (NOS), are MDS/MPN overlap neoplasms characterized by leukocytosis, in the absence of monocytosis and eosinophilia, with <20% blasts in the blood and bone marrow. DIAGNOSIS: aCML, previously known as aCML, BCR::ABL1 negative, was renamed as aCML by the ICC classification, and as MDS/MPN with neutrophilia by the 5th edition of the WHO classification. This entity is characterized by dysplastic neutrophilia with immature myeloid cells comprising ≥10% of the white blood cell count, with prominent dysgranulopoiesis. MDS/MPN-NOS consists of MDS/MPN overlap neoplasms not meeting criteria for defined categories such as chronic myelomonocytic leukemia (CMML), MDS/MPN-ring sideroblasts-thrombocytosis (MDS/MPN-RS-T), and aCML. MUTATIONS AND KARYOTYPE: Cytogenetic abnormalities are seen in 40-50% of patients in both categories. In aCML, somatic mutations commonly encountered include ASXL1, SETBP1, ETNK1, and EZH2 whereas MDS/MPN-NOS can be further stratified by mutational profiles into CMML-like, MDS/MPN-RS-T-like, aCML-like, TP35-mutated, and "others", respectively. RISK STRATIFICATION: The Mayo Clinic aCML model stratifies patients based on age >67 years, hemoglobin <10 g/dl, and the presence of TET2 mutations into low-risk (0-1 points) and high-risk (>2 points) groups, with median survivals of 18 and 7 months, respectively. MDS/MPN-NOS patients have traditionally been risk stratified using MDS risk models such as IPSS and IPSS-R. TREATMENT: Leukocytosis and anemia are managed like lower risk MPN and MDS. DNMT inhibitors have been used in both entities with suboptimal response rates. Allogeneic stem cell transplant remains the only curative strategy but is associated with high morbidity and mortality.

ETNK1 mutation occurs in a wide spectrum of myeloid neoplasms and is not specific for atypical chronic myeloid leukemia.

BACKGROUND: ETNK1 mutation has been suggested as a useful tool to support the diagnosis of atypical chronic myeloid leukemia. ETNK1 mutations, however, occur in other myeloid neoplasms. METHODS: The authors assessed the clinicopathologic and molecular genetic features of 80 ETNK1-mutated myeloid neoplasms. RESULTS: Thirty-seven neoplasms (46%) were classified as myelodysplastic syndrome, 17 (21%) were classified as myelodysplastic/myeloproliferative neoplasm, 14 (18%) were classified as acute myeloid leukemia, and 12 (15%) were classified as myeloproliferative neoplasm. ETNK1 mutations were detected at the first test in 96% of patients, suggesting that ETNK1 mutation is an early event in pathogenesis. ETNK1 mutations represented the dominant clone in 63% of patients and was persistently dominant in 93%. The variant allele frequencies were usually higher in acute myeloid leukemia and increased upon leukemic transformation. ETNK1 mutation was accompanied by coexisting mutations in all patients, with ASXL1 (50%), TET2 (25%), EZH2 (24%), RUNX1 (24%), and SRSF2 (24%) mutations being the most common. Neoplasms with ETNK1 mutations were associated with morphologic dysplasia, increased blasts, myelofibrosis, and noncomplex karyotypes. With a median follow-up of 16.5 months, 30 patients died, 44 had persistent disease, and four achieved complete remission after stem cell transplantation. CONCLUSIONS: ETNK1 mutation is present in various myeloid neoplasms, often as an early event and a dominant clone and always with concurrent mutations. It may play an important role in the pathogenesis and progression of myeloid neoplasms by causing DNA damage and inducing other mutations and genomic instability, and it may serve as a potential therapeutic target. ETNK1 mutation is not disease-specific and should be interpreted with caution to classify myeloid neoplasms.

CNL and aCML should be considered as a single entity based on molecular profiles and outcomes.

Chronic neutrophilic leukemia (CNL) and atypical chronic myeloid leukemia (aCML) are rare myeloid disorders that are challenging with regard to diagnosis and clinical management. To study the similarities and differences between these disorders, we undertook a multicenter international study of one of the largest case series (CNL, n = 24; aCML, n = 37 cases, respectively), focusing on the clinical and mutational profiles (n = 53 with molecular data) of these diseases. We found no differences in clinical presentations or outcomes of both entities. As previously described, both CNL and aCML share a complex mutational profile with mutations in genes involved in epigenetic regulation, splicing, and signaling pathways. Apart from CSF3R, only EZH2 and TET2 were differentially mutated between them. The molecular profiles support the notion of CNL and aCML being a continuum of the same disease that may fit best within the myelodysplastic/myeloproliferative neoplasms. We identified 4 high-risk mutated genes, specifically CEBPA (ß = 2.26, hazard ratio [HR] = 9.54, P = .003), EZH2 (ß = 1.12, HR = 3.062, P = .009), NRAS (ß = 1.29, HR = 3.63, P = .048), and U2AF1 (ß = 1.75, HR = 5.74, P = .013) using multivariate analysis. Our findings underscore the relevance of molecular-risk classification in CNL/aCML as well as the importance of CSF3R mutations in these diseases.

[BCR-ABL1 negative chronic myeloid leukemia: report of two cases]. / Leucemia mieloide crónica atípica BCR-ABL1 negativa: reporte de 2 casos.

BCR-ABL1 negative atypical chronic myeloid leukemia (aCML) is a rare type of myeloproliferative / myelodysplastic syndrome characterized by leukocytosis and proliferation of dysplastic neutrophilic precursors in the absence of positivity for the BCR-ABL1 fusion gene. We report a 66-year-old woman and a 57-year-old man with aCML, who initially presented with general malaise and weight loss, associated with anemia, thrombocytopenia, and leukocytosis with left shift and dysplasia in the neutrophil series. Both evolved unfavorably after admission and died a few days later due to multiple organ failure.

Leucemia mieloide crónica atípica BCR-ABL1 negativa: reporte de 2 casos / BCR-ABL1 negative chronic myeloid leukemia: report of two cases

BCR-ABL1 negative atypical chronic myeloid leukemia (aCML) is a rare type of myeloproliferative / myelodysplastic syndrome characterized by leukocytosis and proliferation of dysplastic neutrophilic precursors in the absence of positivity for the BCR-ABL1 fusion gene. We report a 66-year-old woman and a 57-year-old man with aCML, who initially presented with general malaise and weight loss, associated with anemia, thrombocytopenia, and leukocytosis with left shift and dysplasia in the neutrophil series. Both evolved unfavorably after admission and died a few days later due to multiple organ failure.

Myelodysplastic/myeloproliferative neoplasms-unclassifiable with isolated isochromosome 17q represents a distinct clinico-biologic subset: a multi-institutional collaborative study from the Bone Marrow Pathology Group.

Classification of myeloid neoplasms with isolated isochromosome i(17q) [17p deletion with inherent monoallelic TP53 loss plus 17q duplication] is controversial. Most cases fall within the WHO unclassifiable myelodysplastic/myeloproliferative neoplasms (MDS/MPN-U) category. The uniformly dismal outcomes warrant better understanding of this entity. We undertook a multi-institutional retrospective study of 92 adult MDS/MPN-U cases from eight institutions. Twenty-nine (32%) patients had isolated i(17q) [MDS/MPN-i(17q)]. Compared to MDS/MPN without i(17q), MDS/MPN-i(17q) patients were significantly younger, had lower platelet and absolute neutrophil counts, and higher frequency of splenomegaly and circulating blasts. MDS/MPN-i(17q) cases showed frequent bilobed neutrophils (75% vs. 23%; P = 0.03), hypolobated megakaryocytes (62% vs. 20%; P = 0.06), and a higher frequency of SETBP1 (69% vs. 5%; P = 0.002) and SRSF2 (63% vs. 5%; P = 0.006) mutations that were frequently co-existent (44% vs. 0%; P = 0.01). TP53 mutations were rare. The mutation profile of MDS/MPN-U-i(17q) was similar to other myeloid neoplasms with i(17q) including atypical chronic myeloid leukemia, chronic myelomonocytic leukemia, myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis, myelodysplastic syndrome and acute myeloid leukemia, with frequent concomitant SETBP1/SRSF2 mutations observed across all the diagnostic entities. Over a median follow-up of 52 months, patients with MDS/MPN-i(17q) showed a shorter median overall survival (11 vs. 28 months; P < 0.001). The presence of i(17q) retained independent poor prognostic value in multivariable Cox-regression analysis [HR 3.686 (1.17-11.6); P = 0.026] along with splenomegaly. We suggest that MDS/MPN-i(17q) warrants recognition as a distinct subtype within the MDS/MPN-U category based on its unique clinico-biologic features and uniformly poor prognosis.

A rare case of atypical chronic myeloid leukemia associated with t(8;22)(p11.2;q11.2)/ BCR-FGFR1 rearrangement: A case report and literature review.

Myeloid/lymphoid neoplasm with t(8;22)(p11.2;q11.2)/BCR-FGFR1 is an extremely rare diagnosis, with few reported cases to date. In contrast to other FGFR1-partner rearrangements that are associated with chronic eosinophilic leukemia, acute myeloid leukemia, and/or lymphoblastic lymphoma, patients with BCR-FGFR1 have a myeloproliferative disorder that closely resembles chronic myeloid leukemia (CML). The current report describes a rare case of a 61 year old man with an atypical CML phenotype associated with t(8;22)(p11.2;q11.2)/BCR-FGFR1. A literature review is presented to enhance the awareness of this rare diagnostic entity.

Correlation analysis of long non-coding RNA TUG1 with disease risk, clinical characteristics, treatment response, and survival profiles of adult Ph- Acute lymphoblastic leukemia.

BACKGROUND: Long non-coding RNA taurine-upregulated gene 1 (lncRNA TUG1) is reported to be involved in the progression and development of several malignancies; however, its role in Philadelphia chromosome-negative acute lymphoblastic leukemia (Ph- ALL) is unknown. The present study aimed to explore the correlation of lncRNA TUG1 with disease risk, disease condition, and prognosis of adult Ph- ALL. METHODS: Total 101 adult Ph- ALL patients and 40 bone marrow (BM) donors were included, followed by detection of BM monocyte cell lncRNA TUG1 expression by reverse transcription-quantitative polymerase chain reaction. According to the quantiles of lncRNA TUG1 expression in Ph- ALL patients, these patients were divided into four tiers: tier 1 (ranked in 0%~25%), tier 2 (ranked in 25%~50%), tier 3 (ranked in 50%~75%), and tier 4 (ranked in 75%~100%). RESULTS: LncRNA TUG1 was upregulated in Ph- ALL patients compared with healthy donors. Further analysis indicated that in Ph- ALL patients, higher lncRNA TUG1 tier was correlated with the presence of central nervous system leukemia, increased white blood cell level, and bone marrow blasts. Furthermore, higher lncRNA TUG1 tier was negatively associated with complete remission (CR) within 4 weeks, total CR, and allogeneic hematopoietic stem cell transplant achievement. In addition, higher lncRNA TUG1 tier was associated with decreased disease-free survival and overall survival, which was further verified to be an independent factor by Cox's regression analysis. CONCLUSION: lncRNA TUG1 presents potential to be a novel biomarker for disease risk assessment and survival surveillance in Ph- ALL management.

Clinicopathologic correlates and natural history of atypical chronic myeloid leukemia.

BACKGROUND: There are limited data on the clonal mechanisms underlying leukemogenesis, prognostic factors, and optimal therapy for atypical chronic myeloid leukemia (aCML). METHODS: The authors evaluated the clinicopathologic features, outcomes, and responses to therapy of 65 patients with aCML. The median age was 67 years (range, 46-89 years). RESULTS: The most frequently mutated genes included ASXL1 (83%), SRSF2 (68%), and SETBP1 (58%). Mutations in SETBP1, SRSF2, TET2, and GATA2 appeared at variant allele frequencies (VAFs) greater than 40%, whereas other RAS pathway mutations were more likely to appear at low VAFs. The acquisition of new, previously undetectable mutations at transformation was observed in 63% of the evaluable patients, with the most common involving signaling pathway mutations. Hypomethylating agents (HMAs) were associated with the highest response rates but with a short duration of response (median, 2.7 months). Therapy with ruxolitinib was not associated with clinically significant responses as a single agent or in combination with an HMA. Allogeneic stem cell transplantation was the only therapy associated with improved outcomes (hazard ratio, 0.144; 95% CI, 0.035-0.593; P = .007). Age, platelet counts, bone marrow blast percentages, and serum lactate dehydrogenase (LDH) levels were independent predictors of survival and were integrated in a multivariable model that allowed the prediction of 1- and 3-year survival. CONCLUSIONS: aCML is characterized by high frequencies of ASXL1, SRSF2, and SETBP1 mutations and is associated with a high risk of acute myeloid leukemia transformation. Response and survival outcomes with current therapies remain poor. The incorporation of age, platelet counts, bone marrow blast percentages, and LDH levels can allow survival prediction, and allogeneic stem cell transplantation should be considered for all eligible patients.

Genetics and Pathogenetic Role of Inflammasomes in Philadelphia Negative Chronic Myeloproliferative Neoplasms: A Narrative Review.

The last decade has been very important for the quantity of preclinical information obtained regarding chronic myeloproliferative neoplasms (MPNs) and the following will be dedicated to the translational implications of the new biological acquisitions. The overcoming of the mechanistic model of clonal evolution and the entry of chronic inflammation and dysimmunity into the new model are the elements on which to base a part of future therapeutic strategies. The innate immune system plays a major role in this context. Protagonists of the initiation and regulation of many pathological aspects, from cytokine storms to fibrosis, the NLRP3 and AIM2 inflammasomes guide and condition the natural history of the disease. For this reason, MPNs share many biological and clinical aspects with non-neoplastic diseases, such as autoimmune disorders. Finally, cardiovascular risk and disturbances in iron metabolism and myelopoiesis are also closely linked to the role of inflammasomes. Although targeted therapies are already being tested, an increase in knowledge on the subject is desirable and potentially translates into better care for patients with MPNs.

Molecular genetics of MDS/MPN overlap syndromes.

The myelodysplastic/myeloproliferative neoplasms (MDS/MPN) are a heterogenous group of myeloid malignancies hallmarked by clinicopathologic features that overlap with myelodysplastic syndromes and myeloproliferative neoplasms. Formally recognized by the World Health Organization, this group includes the entities chronic myelomonocytic leukemia, juvenile myelomonocytic leukemia, atypical chronic myeloid leukemia, MDS/MPN with ring sideroblasts and thrombocytosis and MDS/MPN, unclassifiable. Advancements in next generation sequencing have begun to unravel the molecular underpinnings of these diseases, identifying an array of recurrently mutated genes involved in epigenetic regulation, RNA splicing, transcription, and cell signaling. Despite molecular overlap with other myeloid malignancies, each entity displays a unique spectrum of somatic mutations supporting their unique pathobiology and clinical features. Importantly, molecular profiling is becoming an integral tool utilized in routine clinical practice. This review summarizes our current understanding of the molecular pathogenesis of overlap syndromes and details the impact of somatic mutations in diagnostic, prognostic, and therapeutic decision-making.

Atypical Chronic Myeloid Leukemia: Where Are We Now?

Atypical chronic myeloid leukemia, BCR-ABL1 negative (aCML) is a rare myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) with a high rate of transformation to acute myeloid leukemia, and poor survival. Until now, the diagnosis has been based on morphological grounds only, possibly making the real frequency of the disease underestimated. Only recently, new insights in the molecular biology of MDS/MPN syndromes have deepened our knowledge of aCML, enabling us to have a better molecular profile of the disease. The knowledge gleaned from next generation sequencing has complemented morphologic and laboratory WHO criteria for myeloid neoplasms and can provide greater specificity in distinguishing aCML from alternative MDS/MPN or MPNs. The most commonly mutated genes (>20%) in aCML are SETBP1, ASXL1, N/K-RAS, SRSF2, and TET2, and less frequently (< 10%) CBL, CSFR3, JAK2, EZH2, and ETNK1. Several of these mutations affect the JAK-STAT, MAPK, and ROCK signaling pathways, which are targetable by inhibitors that are already in clinical use and may lead to a personalized treatment of aCML patients unfit for allogeneic transplant, which is currently the only curative option for fit patients. In this review, we present two emblematic clinical cases and address the new molecular findings in aCML and the available treatment options.

Atypical CML- the role of morphology and precision genomics.

Atypical chronic myeloid leukemia is an esoteric myeloid malignancy with features of both myeloproliferative and myelodysplastic syndromes. This disease is characterized primarily by morphologic-based criteria, and has clinical and molecular features overlapping with other myeloid malignancies. No one molecular abnormality is specific, and multiple mutations are often present in various combinations, due to the malignant multi-step clonal evolution of myeloid malignancies. In this review, we will address what we know about atypical chronic myeloid leukemia; evaluate how the molecular landscape in myeloid malignancies overlaps, and discuss what we can learn by incorporating individualized precision genomic strategies.

Casos atípicos e14a3 (b3a3) en el gen de fusión BCR-ABL de la leucemia mieloide crónica en Cuba / Rare cases of e14a3 (b3a3) BCR-ABL fusion in chronic myeloid leukemia in Cuba

Introducción: La leucemia mieloide crónica es un desorden clonal maligno de células madres hematopoyéticas pluripotentes que se caracteriza por la presencia del cromosoma Filadelfia, consecuencia de la traslocación cromosómica recíproca entre los brazos largos de los cromosomas 9 y 22. El resultado de esta alteración cromosómica es un gen de fusión que contiene las uniones b2a2 (e13a2) o b3a2 (e14a2). En la mayor parte de los casos, las células de la leucemia mieloide crónica expresan uno de los dos transcritos (b2a2 o b3a2); sin embargo, el 5 por ciento de los pacientes tienen ambos tipos de ARNm como resultado de empalmes alternativos. Se han encontrado otros transcriptos como e19a2, e2a2, e1a3, e6a2, e13a3(b2a3), y e14a3(b3a3), que ocurren con menos frecuencia. Objetivo: Describir el comportamiento de dos pacientes con leucemia mieloide crónica que presentan un trascripto BCR/ABL atípico. Casos clínicos: En el estudio molecular por reacción en cadena de la polimerasa cualitativo realizado a los dos pacientes, se observó un punto de ruptura del gen de fusión BCR/ABL poco frecuente, el cual se correspondía al transcripto e14a3 (b3a3). Estos pacientes iniciaron tratamiento con mesilato de imatinib a dosis de 400 mg diarios. Al primer paciente a los dos meses de tratamiento se le detectó crisis blástica, por lo que se le cambió el tratamiento a nilotinib 400 mg diarios que mantiene hasta la actualidad. La segunda paciente mantuvo igual tratamiento, aunque en ocasiones ha sido necesario incorporar tratamiento citorreductor con hidroxiurea por presentar leucocitosis. Conclusiones: Los pacientes con BCR/ABL a3 presentan un curso más benigno de la enfermedad. Aunque en los pacientes estudiados no se observó una respuesta satisfactoria al tratamiento pues presentaron diversas complicaciones(AU)

Introduction: Chronic myeloid leukemia is a malignant clonal disorder of pluripotent hematopoietic stem cells and characterized by the presence of the Philadelphia chromosome, which is the product of a reciprocal translocation between the long arms of chromosomes 9 and 22. The result of this chromosomal alteration is a fusion gene that contains the e13a2 (b2a2) and e14a2 (b3a2) junctions. In most cases, chronic myeloid leukemia cells express one of the two transcripts (b2a2 or b3a2); however, 5 percent of patients have both types of mRNA, as a result of alternative junctions. Other transcripts have been identified, such as e19a2, e2a2, e1a3, e6a2, e13a3 (b2a3), and e14a3 (b3a3), which occur less frequently. Objective: To describe the behavior of two patients with chronic myeloid leukemia who have an atypical BCR-ABL transcript. Clinical cases: In a qualitative molecular study of polymerase chain reaction carried out with two patients, a BCR-ABL fusion gene breakpoint was observed, which corresponded to the e14a3 (b3a3) transcript. These patients started treatment with imatinib mesylate at a dose of 400mg/d. At two months, the first patient had a diagnose of blast crisis, so the treatment was changed to nilotinib at a dose of 400mg/d, which the patient maintained to date. The second patient maintained the same treatment, although it was sometimes necessary to incorporate cytoreductive treatment with hydroxyurea due to leukocytosis. Conclusions: Patients with BCR-ABL a3 present a more benign evolution of the disease. However, a satisfactory response to treatment was not observed in the patients studied, as long as they presented various complications(AU)