Targeted next generation sequencing and identification of risk factors in World Health Organization defined atypical chronic myeloid leukemia.

Atypical chronic myeloid leukemia (aCML) is an aggressive myeloid neoplasm with overlapping features of myelodysplastic syndromes (prominent granulocytic dysplasia) and myeloproliferative neoplasms (neutrophilic leukocytosis). We studied 25 molecularly-annotated and World Health Organization defined aCML patients; median age 70 years, 84% males. Cytogenetic abnormalities were seen in 36% and gene mutations in 100%. Mutational frequencies were, ASXL1 28%, TET2 16%, NRAS 16%, SETBP1 12%, RUNX1 12%, ETNK1 8%, and PTPN11 4%. Fifteen patients (60%) had >1 mutation, while 9 (36%) had ≥3. The median overall survival (OS) was 10.8 months and at last follow up (median 11 months), 17 (68%) deaths and 2 (8%) leukemic transformations were documented. On univariate analysis, survival was adversely impacted by advanced age (P = .02), low hemoglobin (P = .01), red blood cell transfusion dependence (P = .03), high white blood cell count (P = .02), TET2 (P = .03), NRAS (P = .04), PTPN11 (P = .02) mutations and the presence of ≥3 gene mutations (P = .006); ASXL1, SETBP1, and ETNK1 mutations did not impact OS. In multivariable analysis, advanced age (P = .003) [age >67: HR 10.1, 95% CI 1.3-119], low hemoglobin (P = .008) [HB< 10 gm/dL: HR 8.2, 95% CI 1.6-23.2] and TET2 mutations (P = .01) [HR 8.8, 95% CI 1.6-47.7] retained prognostic significance. We then used age >67 years, hemoglobin <10 gm/dL and the presence of TET2 mutations (each counted as one risk factor) to create a hazard ratio weighted prognostic model; effectively stratifying patients into two risk categories, low (0-1 risk factor) and high (≥2 risk factors), with median OS of 18 and 7 months, respectively.

Response to blinatumomab or inotuzumab ozogamicin for isolated extramedullary relapse of adult acute lymphoblastic leukemia after allogeneic hematopoietic cell transplantation: a case study.

Isolated extramedullary relapse (EMR) without bone marrow relapse (BMR) after allogeneic hematopoietic cell transplantation (allo-HCT) is a rare condition in patients with acute lymphoblastic leukemia (ALL), and the role of immunotherapeutic agents for these patients remains unclear. We analyzed treatment outcomes of blinatumomab or inotuzumab ozogamicin (INO) as first- or second-line salvage therapy in nine patients with Philadelphia chromosome-negative B-cell precursor ALL presenting with isolated EMR after previous allo-HCT. In seven patients receiving blinatumomab as first-line salvage therapy, 4 (57.1%) achieved complete remission (CR). Among the three patients without remission after blinatumomab, two switched to INO and subsequently showed responses {one CR and one partial response [PR]}, and one switched to multiagent chemotherapy that led to CR. In the two patients receiving first-line salvage therapy with INO, one showed PR and the other achieved CR. Overall, 6 (66.7%) of nine patients achieved CR, and five of them proceeded to allo-HCT in CR. The median overall survival after relapse was 27.8 months. In conclusion, both blinatumomab and INO showed good response rates and a safe bridging role to second allo-HCT in patients with isolated EMR. However, clinical differences between isolated EMR and EMR with BMR remain to be elucidated.

Current and evolving understanding of atypical chronic myeloid leukemia.

Atypical chronic myeloid leukemia (aCML) is a BCR-ABL1 negative myelodysplastic (MDS)/myeloproliferative (MPN) neoplasm with poor overall survival. The current 2016 WHO classification of myeloid neoplasms allows clinicians to more accurately differentiate aCML from its similar MDS/MPN overlap and MPN counterparts. In addition, the advent of next-generation sequencing has expanded our understanding of the molecular pathogenesis of aCML and its therapeutic potential. Hematopoietic stem cell transplant (HSCT) remains the first consideration in the treatment algorithm for aCML, however, with the advances in mutational analysis, opportunities for targeted therapy have expanded. In this review, we highlight the current classification, diagnostic criteria, and molecular pathogenesis of aCML. We also discuss the therapeutic implications of the heterogeneous molecular fingerprint of aCML focusing on emerging targeted therapies, specifically ruxolitinib, dasatinib, and trametinib. Future disease management will rely on clinical trial development focused on new mutational drug targets, combination therapies, and signaling pathway dysregulation.

Philadelphia chromosome-negative chronic myelogenous leukemia and chronic myelomonocytic leukemia.

Philadelphia chromosome (Ph)-negative chronic myelogenous leukemia (CML) and chronic myelomonocytic leukemia (CMML) are heterogeneous disorders characterized by various degrees of proliferation, dysplasia, maturation arrest, and monocytosis. In this article, the clinical, laboratory, molecular, and therapeutic aspects of the disease entities are reviewed.

The occurrence of Philadelphia chromosome (Ph) negative leukemia after hematopoietic stem cell transplantation for Ph positive chronic myeloid leukemia: implications for disease monitoring and treatment.

Chronic myeloid leukemia (CML) is a clonal neoplastic disorder, characterized by t(9;22)(q34;q11) that results in the formation of the Philadelphia chromosome (Ph) and the BCR/ABL fusion gene. Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for CML. Much of its therapeutic efficacy is attributed to a graft-versus-leukemia (GVL) effect exerted by donor-derived lymphoid cells against the Ph positive (Ph+) clone. Post-HSCT monitoring by cytogenetic and molecular detection of the Ph+ clone is necessary, so that pre-emptive immunologic or pharmacologic treatment may be administered at an early stage of relapse. However, under rare circumstances a second Ph negative (Ph-) leukemia may evolve post-HSCT. The pathogenetic possibilities included leukemia arising from donor-derived hematopoietic stem cells (HSCs), or transformation of residual recipient-derived Ph- HSCs that have survived the conditioning chemotherapy and radiotherapy. Recipient-derived Ph- leukemia may be related to genetic alterations that precede the onset of CML, or myelotoxic effects of the HSCT conditioning regimen. The diagnosis of Ph- relapses requires detailed investigations by conventional karyotyping, fluorescence in-situ hybridization (FISH), and molecular analysis; as well as chimerism studies that help to document the donor or recipient origin of the leukemia. Although uncommonly reported in the past, Ph- relapses may in fact be more frequent if leukemic relapses post-HSCT are more thoroughly evaluated with these investigations. The recognition of Ph- relapses are important in several ways. Ph- relapses cannot be identified by monitoring investigations targeting the Ph+ clone, so that the early detection of Ph- leukemia is usually not possible. Furthermore, Ph- relapses will not respond to therapeutic strategies effective against the Ph+ CML clone.

Atypical chronic myelogenous leukemia following immunosuppressive therapy for severe aplastic anemia.

Late clonal complications of aplastic anemia (AA) such as acute leukemia, myelodysplastic syndromes or paroxysmal nocturnal hemoglobinuria have been recognized for a long time. To our knowledge, chronic myelogenous leukemia (CML) as a late complication of severe aplastic anemia has as yet not been reported. We report here a case of AA treated successfully with antilymphocytic globulin and cyclosporin in whom Ph1 negative, BCR/ABL negative CML developed 8 years after diagnosis of AA. This case of atypical, secondary CML was refractory to treatment with interferon alpha and hydroxyurea.

Clinical and biological aspects of Philadelphia-negative/BCR-negative chronic myeloid leukemia.

The Philadelphia (Ph) chromosome was the first chromosomal abnormality associated with a specific leukemia, chronic myeloid leukemia (CML). This chromosome arises from the t(9;22)(q34;q11) translocation which results in the juxtaposition of the bcr gene and the abl proto-oncogene. This BCR/ABL fusion gene encodes for a hybrid protein with the capacity of oncogenic transformation of hematopoietic cells. Nonetheless, very few myeloproliferative disorders (about 10%) included under the generic term of CML have no Ph chromosome. Half of these Ph-negative CML have the BCR/ABL fusion gene (BCR-positive) and are considered equivalent to Ph-positive CML. In contrast, the patients without detectable BCR/ABL fusion (BCR-negative) fulfil the criteria for atypical CML (aCML) of the French-American-British (FAB) classification, despite considerable variability at the individual level. Due to the very small number of patients with precise cytological descriptions already published, cooperative studies focused on aCML are warranted to draw definitive conclusions and to provide some pointers on physiopathology.

[A model of the interclonal interactions in chronic myeloleukemia]. / Model' mezhklonal'nykh vzaimodeistvii pri khronicheskom mieloleikoze.

A new model of chronic myelogenous leukemia (CML) pathogenesis based on the idea of some cellular clones dominance over the others at the stem cells level is described. The model gives good explanations to all basic clinical variants of CML as well as to all well-known cytological phenomena to be found recently in this type of leukemia. The most probable mechanisms which might be responsible for the above-mentioned phenomenon of dominance between different cellular clones are discussed.

[The chronic Philadelphia chromosome-negative myeloproliferative syndrome I. Pathogenesis and pathophysiology]. / Det kroniske Philadelphia-kromosom-negative myeloproliferative syndrom I. Patogenese og patofysiologi.

In polycythaemia vera (PV) the erythroid progenitors proliferate autonomously independently of the circulating erythropoietin. The progenitors are hypersensitive to various growth factors, including insulin-like growth factor 1, which inhibits apoptosis in erythroid and myeloid progenitor cells. No change has been found in the erythropoietin (EPO) receptor. Thrombopoietin (Tpo) regulates the production of haematopoietic progenitor cells, particularly of platelets. By inhibiting apoptosis, this growth factor may be responsible for the autonomous proliferation of the megakaryocyte cell lineage in PV and idiopathic myelofibrosis (IMF), which are featured by highly elevated circulating Tpo levels. Thrombopoietin may also be involved in the pathogenesis of myelofibrosis and development of extramedullary haematopoiesis. Both fibrogenesis and angiogenesis in the bone marrow, spleen, and liver develop secondary to the release of various growth-promoting factors from the megakaryocyte cell lineage. The lesion of the pluripotent stem cell in PV and IMF seems to imply several defects, including lack of or decreased expression of the Tpo receptor, alterations in the sensitivity of progenitor cells to various growth factors, and alterations in important gene systems (Bcl-2), which govern cell survival. Essential thrombocytosis seems to be a heterogeneous disease entity, as about 50% of the patients have polyclonal haematopoiesis.

Perspectives on the impact of JAK-inhibitor therapy upon inflammation-mediated comorbidities in myelofibrosis and related neoplasms.

Chronic inflammation is suggested to contribute to the Philadelphia-chromosome-negative myeloproliferative neoplasm (MPN) disease initiation and progression, as well as the development of premature atherosclerosis and may drive the development of other cancers in MPNs, both nonhematologic and hematologic. The MPN population has a substantial comorbidity burden, including cerebral, cardiovascular, pulmonary, abdominal, renal, metabolic, skeletal, autoimmune, and chronic inflammatory diseases. This review describes the comorbidities associated with MPNs and the potential impact of early intervention with anti-inflammatory and/or immunomodulatory agents such as JAK-inhibitors, statins, and IFN-α to inhibit cancer progression and reduce MPN-associated comorbidity impact. Early intervention may yield a subset of patients who achieve minimal residual disease, thereby likely reducing the comorbidity burden and improving the cost-effective socioeconomic profile.

Transformation of refractory anemia with excess of blasts into acute myelogenous leukemia with Ph-negative chronic myelogenous leukemia-like characteristics.

We report a 56 year old patient with acute myelogenous leukemia (FAB classification: M2), in whom the number of mature myeloid cells similar to those seen in Ph-negative chronic myelogenous leukemia increased markedly 2 months after the diagnosis of refractory anemia with excess of blasts (RAEB). This is a rare case of leukemic evolution as a terminal event of RAEB.