European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia.

The therapeutic landscape of chronic myeloid leukemia (CML) has profoundly changed over the past 7 years. Most patients with chronic phase (CP) now have a normal life expectancy. Another goal is achieving a stable deep molecular response (DMR) and discontinuing medication for treatment-free remission (TFR). The European LeukemiaNet convened an expert panel to critically evaluate and update the evidence to achieve these goals since its previous recommendations. First-line treatment is a tyrosine kinase inhibitor (TKI; imatinib brand or generic, dasatinib, nilotinib, and bosutinib are available first-line). Generic imatinib is the cost-effective initial treatment in CP. Various contraindications and side-effects of all TKIs should be considered. Patient risk status at diagnosis should be assessed with the new EUTOS long-term survival (ELTS)-score. Monitoring of response should be done by quantitative polymerase chain reaction whenever possible. A change of treatment is recommended when intolerance cannot be ameliorated or when molecular milestones are not reached. Greater than 10% BCR-ABL1 at 3 months indicates treatment failure when confirmed. Allogeneic transplantation continues to be a therapeutic option particularly for advanced phase CML. TKI treatment should be withheld during pregnancy. Treatment discontinuation may be considered in patients with durable DMR with the goal of achieving TFR.

A clinical-molecular prognostic model to predict survival in patients with post polycythemia vera and post essential thrombocythemia myelofibrosis.

Polycythemia vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms with variable risk of evolution into post-PV and post-ET myelofibrosis, from now on referred to as secondary myelofibrosis (SMF). No specific tools have been defined for risk stratification in SMF. To develop a prognostic model for predicting survival, we studied 685 JAK2, CALR, and MPL annotated patients with SMF. Median survival of the whole cohort was 9.3 years (95% CI: 8-not reached-NR-). Through penalized Cox regressions we identified negative predictors of survival and according to beta risk coefficients we assigned 2 points to hemoglobin level <11 g/dl, to circulating blasts ⩾3%, and to CALR-unmutated genotype, 1 point to platelet count <150 × 109/l and to constitutional symptoms, and 0.15 points to any year of age. Myelofibrosis Secondary to PV and ET-Prognostic Model (MYSEC-PM) allocated SMF patients into four risk categories with different survival (P<0.0001): low (median survival NR; 133 patients), intermediate-1 (9.3 years, 95% CI: 8.1-NR; 245 patients), intermediate-2 (4.4 years, 95% CI: 3.2-7.9; 126 patients), and high risk (2 years, 95% CI: 1.7-3.9; 75 patients). Finally, we found that the MYSEC-PM represents the most appropriate tool for SMF decision-making to be used in clinical and trial settings.

Myeloproliferative neoplasms and inflammation: whether to target the malignant clone or the inflammatory process or both.

The Philadelphia-negative myeloproliferative neoplasms (MPNs) are clonal disorders involving hematopoietic stem and progenitor cells and are associated with myeloproliferation, splenomegaly and constitutional symptoms. Similar signs and symptoms can also be found in patients with chronic inflammatory diseases, and inflammatory processes have been found to play an important role in the pathogenesis and progression of MPNs. Signal transduction pathways involving JAK1, JAK2, STAT3 and STAT5 are causally involved in driving both the malignant cells and the inflammatory process. Moreover, anti-inflammatory and immune-modulating drugs have been used successfully in the treatment of MPNs. However, to date, many unresoved issues remain. These include the role of somatic mutations that are present in addition to JAK2V617F, CALR and MPL W515 mutations, the interdependency of malignant and nonmalignant cells and the means to eradicate MPN-initiating and -maintaining cells. It is imperative for successful therapeutic approaches to define whether the malignant clone or the inflammatory cells or both should be targeted. The present review will cover three aspects of the role of inflammation in MPNs: inflammatory states as important differential diagnoses in cases of suspected MPN (that is, in the absence of a clonal marker), the role of inflammation in MPN pathogenesis and progression and the use of anti-inflammatory drugs for MPNs. The findings emphasize the need to separate the inflammatory processes from the malignancy in order to improve our understanding of the pathogenesis, diagnosis and treatment of patients with Philadelphia-negative MPNs.

Clinical end points for drug treatment trials in BCR-ABL1-negative classic myeloproliferative neoplasms: consensus statements from European LeukemiaNET (ELN) and Internation Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT).

The discovery of somatic mutations, primarily JAK2V617F and CALR, in classic BCR-ABL1-negative myeloproliferative neoplasms (MPNs) has generated interest in the development of molecularly targeted therapies, whose accurate assessment requires a standardized framework. A working group, comprised of members from European LeukemiaNet (ELN) and International Working Group for MPN Research and Treatment (IWG-MRT), prepared consensus-based recommendations regarding trial design, patient selection and definition of relevant end points. Accordingly, a response able to capture the long-term effect of the drug should be selected as the end point of phase II trials aimed at developing new drugs for MPNs. A time-to-event, such as overall survival, or progression-free survival or both, as co-primary end points, should measure efficacy in phase III studies. New drugs should be tested for preventing disease progression in myelofibrosis patients with early disease in randomized studies, and a time to event, such as progression-free or event-free survival should be the primary end point. Phase III trials aimed at preventing vascular events in polycythemia vera and essential thrombocythemia should be based on a selection of the target population based on new prognostic factors, including JAK2 mutation. In conclusion, we recommended a format for clinical trials in MPNs that facilitates communication between academic investigators, regulatory agencies and drug companies.

Stalled cerebral capillary blood flow in mouse models of essential thrombocythemia and polycythemia vera revealed by in vivo two-photon imaging.

BACKGROUND: Essential thrombocythemia (ET) and polycythemia vera (PV) are myeloproliferative neoplasms (MPNs) that share the JAK2(V617F) mutation in hematopoietic stem cells, leading to excessive production of predominantly platelets in ET, and predominantly red blood cells (RBCs) in PV. The major cause of morbidity and mortality in PV and ET is thrombosis, including cerebrovascular occlusive disease. OBJECTIVES: To identify the effect of excessive blood cells on cerebral microcirculation in ET and PV. METHODS: We used two-photon excited fluorescence microscopy to examine cerebral blood flow in transgenic mouse models that mimic MPNs. RESULTS AND CONCLUSIONS: We found that flow was 'stalled' in an elevated fraction of brain capillaries in ET (18%), PV (27%), mixed MPN (14%) and secondary (non-MPN) erythrocytosis (27%) mice, as compared with controls (3%). The fraction of capillaries with stalled flow increased when the hematocrit value exceeded 55% in PV mice, and the majority of stalled vessels contained only stationary RBCs. In contrast, the majority of stalls in ET mice were caused by platelet aggregates. Stalls had a median persistence time of 0.5 and 1 h in ET and PV mice, respectively. Our findings shed new light on potential mechanisms of neurological problems in patients with MPNs.

Mutations with epigenetic effects in myeloproliferative neoplasms and recent progress in treatment: Proceedings from the 5th International Post-ASH Symposium.

Immediately following the 2010 annual American Society of Hematology (ASH) meeting, the 5th International Post-ASH Symposium on Chronic Myelogenous Leukemia and BCR-ABL1-Negative Myeloproliferative Neoplasms (MPNs) took place on 7-8 December 2010 in Orlando, Florida, USA. During this meeting, the most recent advances in laboratory research and clinical practice, including those that were presented at the 2010 ASH meeting, were discussed among recognized authorities in the field. The current paper summarizes the proceedings of this meeting in BCR-ABL1-negative MPN. We provide a detailed overview of new mutations with putative epigenetic effects (TET oncogene family member 2 (TET2), additional sex comb-like 1 (ASXL1), isocitrate dehydrogenase (IDH) and enhancer of zeste homolog 2 (EZH2)) and an update on treatment with Janus kinase (JAK) inhibitors, pomalidomide, everolimus, interferon-α, midostaurin and cladribine. In addition, the new 'Dynamic International Prognostic Scoring System (DIPSS)-plus' prognostic model for primary myelofibrosis (PMF) and the clinical relevance of distinguishing essential thrombocythemia from prefibrotic PMF are discussed.

Dasatinib induces durable cytogenetic responses in patients with chronic myelogenous leukemia in chronic phase with resistance or intolerance to imatinib.

Dasatinib, a potent inhibitor of BCR-ABL in vitro, is effective for patients with chronic myelogenous leukemia (CML) resistant or intolerant to imatinib. To provide a more definitive assessment of dasatinib in chronic-phase (CP)-CML, we report extended follow-up of a phase II trial, presenting data for the entire patient cohort (N=387). Dasatinib (70 mg) twice daily was administered to patients with imatinib-resistant or -intolerant CP-CML. With median follow-up of 15.2 months (treatment duration, <1-18.4 months), a complete hematologic response was attained or maintained in 91% of patients. A major cytogenetic response (MCyR) was attained or maintained by 59% (52% imatinib resistant and 80% imatinib intolerant); this was complete in 49% of patients (40% imatinib resistant and 75% imatinib intolerant). Of 230 patients achieving an MCyR, 7 experienced disease progression. Fifteen-month progression-free survival was 90% while overall survival was 96%. Grade 3/4 thrombocytopenia and neutropenia were reported in 48 and 49% of patients, respectively. Non-hematologic toxicity (any grade) consisted primarily of diarrhea (37%), headache (32%), fatigue (31%), dyspnea (30%) and pleural effusion (27%). Pleural effusions were classified as grade 3 in 6% of reported events, with no incidence of grade 4. Dasatinib is associated with high response rates in patients with imatinib-resistant or -intolerant CP-CML.

A novel unconventional antigen MPD5 elicits anti-tumor humoral immune responses in a subset of patients with polycythemia vera.

In an effort to define the antigenic mechanism that contributes to beneficial therapeutic outcome in patients with polycythemia vera (PV), we screened a human testis cDNA library with serological cloning derived from sera of three PV patients who had undergone therapeutic-induced remission. As a result, we identified a novel antigen, MPD5, which belongs to the group of cryptic antigens with unconventional genomic intron/exon structure. Moreover, MPD5 elicited IgG antibody responses in a subset of PV patients who had benefited from a variety of therapies--including IFN-alpha, Hydroxyurea, Imatinib mesylate, Anagrelide, and phlebotomy--but not in untreated PV patients or healthy donors, suggesting that MPD5 is a PV-associated, therapy-related antigen. In the granulocytes of PV patients who are responsive to therapy, upregulated MPD5 expression may serve to enhance immune responses. These findings provide new insight into the mechanism underlying regulation of the self-antigen repertoire that elicits anti-tumor immune responses in patients with myeloproliferative diseases, indicating the potential of these self-antigens as targets of novel immunotherapy.

The third International Congress on Myeloproliferative and Myelodysplastic Syndromes.

This meeting was convened by Richard T. Silver and co-chaired by Jerry L. Spivak. It was held from 27 to 29 October 2005 in Washington, DC. Thirty-one invited speakers from seven different countries participated in the conference, which was attended by more than 300 individuals from 23 countries. As in previous years, a clinical symposium for patients, held the day before the symposium, was sponsored by the Cancer Research and Treatment Fund, Inc., New York, NY 10021. This meeting report provides a summary of the five sessions prepared and highlighted by one of the session chairs. In addition to the formal presentations on the biology, clinical aspects and management of these diverse marrow stem cell disorders, there was considerable interest generated because of the availability of several new agents that have been recently approved. A special luncheon satellite symposium was devoted to the dramatic changes in the therapeutic options for the myelodysplastic syndromes, sponsored by MGI Pharma, Inc. The keynote address was presented by Dr. George Q. Daley from Harvard Medical School and the Children's Hospital Medical Center. He reviewed the molecular steps in the formation of the Philadelphia chromosome and some of the newly described mutations leading to resistance to chemotherapy (see Section 4).

Anagrelide is effective in treating patients with hydroxyurea-resistant thrombocytosis in patients with chronic myeloid leukemia.

We report phase II trial results of the use of oral anagrelide hydrochloride for treating 38 patients with hydroxyurea (HU)-resistant thrombocytosis accompanying chronic myeloid leukemia (CML). Anagrelide's efficacy was well established during a phase II study of more than 400 patients with one of the four myeloproliferative disorders: essential thrombocythemia, polycythemia, idiopathic myelofibrosis, and CML. In the last subgroup, there were 114 CML patients with significant thrombocytosis treated with anagrelide. Out of these patients, 38 had symptoms of thrombosis or hemorrhage and had thrombocytosis resistant to HU. They were then treated with anagrelide at an initial dose of 2.0 mg/day, followed by modifications based upon response and toxicity. In all, 71% of these patients responded with platelet reductions of more than 50% in a median time of approximately 4 weeks. The response rate was not influenced by age, gender, or prior thrombosis or hemorrhage. Importantly, the response rate to anagrelide in patients refractory to prior HU was essentially the same as that of the other 76 CML patients. Treatment with anagrelide was well tolerated and without undue toxicity. Reduction of excessive platelet counts by anagrelide sometimes occurring in CML may lead to the prevention of thrombohemorrhagic complications occurring in this clinical setting and is relevant even in those patients in whom imatinib mesylate is primary therapy.

The second international congress on myeloproliferative and myelodysplastic syndromes.

This meeting was convened by Richard T. Silver, M.D. and co-chaired by Jerry L. Spivak, M.D. It was held from 16 to 18 October 2003 in New York City, New York, USA. Thirty-nine invited speakers from nine different countries participated in the conference. There were more than 350 attendees. There were formal presentations and discussions on biology, clinical aspects, and management of patients with these diverse bone marrow stem cell disorders linked by a variable progression to acute myeloid leukemia. Of considerable interest, a clinical symposium exclusively for patients was held the day preceding the meeting at which John Bennett, Tiziano Barbui, Richard Silver, Jerry Spivak, and Ayalew Tefferi spoke on various topics pertaining to these diseases. This proved to be highly informative to the patients who reported that they enjoyed the program immensely. This was sponsored by the Cancer Research & Treatment Fund, Inc. Representatives of the Myelodysplasia Foundation were also present. This meeting report provides a summary of five different sections prepared by one or more of the session chairs. The keynote address was given by Shahin Rafii (Cornell Medical Center). Most appropriately, this talk focused on the expression and activation of angiogenic factors which play a crucial role in the progression of both myeloproliferative disorders and myelodysplastic syndromes (MDS). Among the known factors, vascular endothelial growth tyrosine kinase receptors (VEGF-R1, R2, and R3) support proliferation, survival, and mobility. Rafii's team has demonstrated that these receptors are expressed on subsets of primary hematopoietic cells as well as leukemic cells. Some leukemic cells express both VEGF-A and VEGF-R2, resulting in the generation of an autocrine loop that supports survival and within the osteoblastic zone translocating these cells to the vascular enriched niche for receipt of molecular instructions required for proliferation and differentiation. A pathologic correlation can be seen in some patients with the identification of abnormal localization of immature precursors (ALIP) in the central portions of the medullary cavity. Misplaced megakaryocytes can release pro-fibrotic factors, including platelet derived growth factors and transforming growth factor-beta. Collectively, these data suggest that chronic disregulation of angiogenic factors alter the microenvironment dislocating marrow stem cells that force both proliferation and differentiation in varying degrees, contributing to these hematological disorders.

Pegylated recombinant interferon alpha-2b vs recombinant interferon alpha-2b for the initial treatment of chronic-phase chronic myelogenous leukemia: a phase III study.

Recombinant interferon alpha-2b (rIFN-alpha2b) is an effective therapy for chronic-phase chronic myelogenous leukemia (CML). Polyethylene glycol-modified rIFN-alpha2b is a novel formulation with a serum half-life ( approximately 40 h) compatible with once-weekly dosing. This open-label, noninferiority trial randomized 344 newly diagnosed CML patients: 171 received subcutaneous pegylated rIFN-alpha2b (6 microg/kg/week); 173 received rIFN-alpha2b (5 million International Units/m2/day). Primary efficacy end point was the 12-month major cytogenetic response (MCR) rate (<35% Philadelphia chromosome-positive cells). Modified efficacy analysis included all MCRs >12 months, except for patients discontinuing treatment after 6 months and achieving an MCR on other salvage therapy. The MCR rates were 23% for pegylated rIFN-alpha2b vs 28% for rIFN-alpha2b in the primary efficacy analysis and 26 vs 28% in the prospectively modified efficacy analysis. However, a significant imbalance in baseline hematocrit (HCT), a significant predictor of cytogenetic response (P=0.0001), was discovered: 51 (30%) patients treated with pegylated rIFN-alpha2b had low HCT (<33%) vs 33 (19%) rIFN-alpha2b-treated patients. Among patients with HCT >33%, the MCR rate was 33 vs 31%. The adverse event profile of weekly pegylated rIFN-alpha2b was comparable to daily rIFN-alpha2b. Once-weekly pegylated rIFN-alpha2b is an active agent for the treatment of newly diagnosed CML with an efficacy and safety profile similar to daily rIFN-alpha2b, although statistical noninferiority was not demonstrated.

Efficacy and safety of gemtuzumab ozogamicin in patients with poor-prognosis acute myeloid leukemia.

The objective of this work was to determine the safety and efficacy of gemtuzumab ozogamicin in patients with poor prognosis acute myeloid leukemia (AML). Patients with the following diagnoses/characteristics were treated with 1-3 infusions of gemtuzumab ozogamicin at a dose of 9 mg/m2: (1) relapse of AML < or = 6 months of first complete remission (CR); (2) AML refractory to chemotherapy at initial induction or at first relapse; (3) AML in second or greater relapse; (4) myeloid blast crisis of chronic myeloid leukemia (CML); (5) untreated patients > or = 70 years or > or = 55 years with abnormal cytogenetics (excluding inv 16, t(15;17) and t(8;21)) and/or an antecedent hematologic disorder; (6) refractory anemia with excess blasts in transformation (RAEBT). Forty-three patients, ages 19-84 (mean 62), were treated, including 7 patients with untreated AML age > 70 years, 2 with untreated RAEBT, 14 with AML first salvage (first remission 0-6 months), 15 with AML > or = second salvage and 14 with myeloid blast phase of CML. The overall response rate was 14%, with 4/43 (9%) patients achieving CR and 2/43 (5%) achieving CR without platelet recovery. The most significant toxicity was neutropenic fever, which occurred in 84% of patients. In conclusion, in patients with relapsed/refractory AML, gemtuzumab ozogamicin has a comparable response rate to single-agent chemotherapy and may offer a more favorable toxicity profile.