Diagnostic Utility of Bone Marrow Pathology in Chronic Myeloproliferative Disorders
Richard T. Silver, Ayalew Tefferi in Myeloproliferative Disorders, 2007
Following the recent discovery of an activating JAK2V617F mutation in patients with Philadelphia chromosome–negative (Ph1-) chronic myeloproliferative disorders or neoplasms (MPNs—according to the forthcoming WHO nomenclature), currently a conflict of opinion exists on whether and to which extent conventional methods of diagnosis and classification, such as bone marrow (BM) morphology, are still needed (1). In this context, it is important to note that the mutation has been reported to occur at a strikingly different incidence (2–4) among the various types of clinicopathologically defined conditions. Detection of the JAK2V617F mutation has been described in up to 95% of polycythemia vera (PV) cases and in 30–50% cases of essential thrombocythemia (ET) and primary myelofibrosis (PMF; chronic idiopathic myelofibrosis). The mutation has also been found, although at a much lower frequency, in a minority (5–10%) of cases of chronic myelomonocytic leukemia, chronic myeloid leukemia, myelodysplastic syndromes, and acute myeloid leukemia, as well as in other atypical myeloproliferative disorders (3–6).
Case 37
Atul B. Mehta, Keith Gomez in Clinical Haematology, 2017
Chronic myelomonocytic leukemia is a slowly progressive condition which is usually treated with oral chemotherapy (e.g. hydroxyurea or etoposide). Splenectomy is helpful if patients become transfusion-dependent or if there are symptoms due to an enlarged organ. Transformation to acute leukemia occurs with a median interval of 18–24 months, but intensive chemotherapy is rarely successful. Younger patients should be considered for intensive therapy, possibly followed by bone marrow transplantation; however, this particular patient did not have a suitable donor 5 azacitidine is often helpful. Recent publications have indicated a role for eltrombopag as an orally active agent.
Antitubulin Agents
David E. Thurston, Ilona Pysz in Chemistry and Pharmacology of Anticancer Drugs, 2021
Some examples of well-known PLK1 inhibitors with oral availability and a good level of potency and selectivity toward PLK1 compared to the other PLK family members are shown in Figure 4.29, and some of these have reached the clinic. For example, ON-01910.Na (now known as rigosertib, and with a planned trade name of EstybonTM) is a synthetic benzyl styryl sulfone in development with Onconova Therapeutics. In preclinical studies, treated cells were shown to exhibit multipolar spindles, accumulation in G2/M phase, and spindle and centrosome abnormalities, all consistent with the known mechanism of action. It has reached Phase III clinical trials for the treatment of chronic myelomonocytic leukemia, with the most common side effects determined to be abdominal pain, nausea and vomiting, and fatigue. Based on these encouraging results, in January 2019 the company submitted a Special Protocol Assessment (SPA) request to the FDA for a Phase III study of oral rigosertib combination therapy with azacitidine (VidazaTM) for the treatment of adult patients with treatment-naïve higher-risk myelodysplastic syndrome (MDS). At the time of writing, other clinical studies in different solid tumor types and in B-cell chronic lymphocytic leukemia are underway. Some of the other inhibitors shown in Figure 4.29 reached the clinic, but none has yet progressed to the approval stage. Structures of examples of PKL1 inhibitors.
Immunosuppressive therapy in myelodysplastic syndromes: a borrowed therapy in search of the right place
Published in Expert Review of Hematology, 2018
Rory M. Shallis, Nora Chokr, Maximilian Stahl, Alexander B. Pine, Amer M. Zeidan
Increasing evidence also supports the role of immune dysregulation in the pathogenesis of MDS [7]. Clinical observation has long noted a correlation with disordered immune homeostasis and MDS, and recent retrospective and registry studies have recognized a clear association of MDS and chronic myelomonocytic leukemia (CMML) with the presence of autoimmune disease [8–13]. No dedicated prospective study with serial marrow evaluations has been performed to date to determine whether confirmed autoimmune disease precedes or induces the expansion of myelodysplastic clones and the subsequent development of MDS or whether the converse is true. In a large study of 1408 MDS patients, 28% of patients had an autoimmune disease; a more recent study noted a nearly 50% incidence of such with hypothyroidism being the most common disease with an attributed autoimmune pathogenesis. The prognostic impact of the presence of autoimmune disease in MDS remains controversial with these studies reporting discordant results [8,10]. Investigation into the immune microenvironment as it relates to innate and adaptive immunity has further reinforced the assertion that immune pathways are critical to development of impaired hematopoiesis and ultimately MDS.
Novel therapies for AML: a round-up for clinicians
Published in Expert Review of Clinical Pharmacology, 2020
Mahesh Swaminathan, Eunice S. Wang
The subsequent VIALE-C phase III trial randomized patients to receive either VEN + LDAC or placebo+ LDAC. This study enrolled 211 patients with a median age of 76 years (range 36–93 years) [41], of whom 20% had prior treatment with HMA for MDS/chronic myelomonocytic leukemia. The results of the VIALE-C trial did not meet its primary endpoint (i.e. VEN plus LDAC did not result in statistically significantly improved OS as compared to LDAC alone at the time of primary analysis cut-off date). However, although median OS was not significantly improved following VEN +LDAC (7.2 vs. 4.1 months, HR-0.75 (0.52–1.07), p = 0.11) at the time of primary analysis, subsequent post-hoc data analysis six months later demonstrated a statistically significant OS benefit (HR 0.70 (95% CI 0.50–0.99), p = 0.04). Moreover, VEN + LDAC did appear to result in clinical benefit with a markedly improved overall response rate (CR/CRi of 48%, CR of 27.3%) as opposed to placebo + LDAC (CR/CRi of 13% and CR of 7.4%, respectively) [41]. In addition, patients receiving VEN+LDAC experienced improved quality of life as evidenced by substantially improved rates of red cell (VEN+LDAC 43% vs placebo + LDAC 19%) and platelet transfusion independence (VEN+LDAC 49% vs placebo + LDAC 32%) Table 1. The most frequently reported ≥grade 3 AEs in VEN combination were neutropenia (49%), thrombocytopenia (45%), febrile neutropenia (32%). Tumor lysis syndrome (TLS) was reported in 5.6% of patients Table 2.
The development and clinical use of oral hypomethylating agents in acute myeloid leukemia and myelodysplastic syndromes: dawn of the total oral therapy era
Published in Expert Review of Anticancer Therapy, 2021
Molly Schiffer, Jennifer Zhao, Aubrey Johnson, Jane Lee, Jan Philipp Bewersdorf, Amer M. Zeidan
Myelodysplastic syndromes (MDS) encompass a group of myeloid malignancies characterized by abnormal and ineffective blood cell production in the bone marrow, while acute myeloid leukemia (AML) is characterized by the proliferation of immature myeloid cells in the bone marrow often with cytogenetic and molecular abnormalities [1,2]. The World Health Organization (WHO) 2016 classification of myeloid neoplasms and acute leukemia included chronic myelomonocytic leukemia (CMML) within the MDS/myeloproliferative neoplasms (MPN) overlap category as a myeloid neoplasm that has overlapping features between MDS and MPN [1] Both CMML and MDS cause significant morbidity and mortality on their own terms but also hold the potential of progression to more aggressive forms such as AML.