Cyclosporine A alleviates severe anaemia associated with refractory large granular lymphocytic leukaemia and chronic natural killer cell lymphocytosis

Large granular lymphocytic (LGL) leukaemia and chronic natural killer cell lymphocytosis (CNKL) are chronic indolent disorders often associated with neutropenia and constitutional symptoms. Severe anaemia occurs in about 20% of patients and is currently treated with corticosteroids followed by oral cyclophosphamide in non-responders. 30% of patients fail initial measures, and salvage therapy is inadequate. We describe three transfusion-dependent patients (two with T-LGL leukaemia, one with CNKL) refractory to corticosteroids, cyclophosphamide, and in one case fludarabine. Cyclosporine A (CSA) initiation resulted in prompt transfusion-independence and was well tolerated in all patients, making it an attractive alternative therapy for this disorder.     

Early lymphocyte recovery predicts superior survival after autologous hematopoietic stem cell transplantation for patients with primary systemic amyloidosis.

PURPOSE: Absolute lymphocyte count recovery at day 15 (ALC-15) post-autologous stem cell transplantation (ASCT) is a powerful prognostic indicator for survival for multiple hematologic malignancies and metastatic breast cancer. The relationship of ALC-15 with clinical outcomes in primary systemic amyloidosis is unknown. EXPERIMENTAL DESIGN: We evaluated 145 consecutive patients with primary systemic amyloidosis who underwent ASCT at the Mayo Clinic from 1996 to 2003. The ALC-15 threshold was set at 500 cells/microL based on our previous observations. RESULTS: The median patient follow-up was 22 months (range, 3-87 months). Higher hematologic complete response was observed in patients with an ALC-15 > or = 500 cells/microL compared with patients with an ALC-15 < 500 cells/microL (41% versus 21%, P < 0.0008, respectively). The median overall survival and progression-free survival times were significantly better for the 59 patients that achieved an ALC-15 > or = 500 cells/microL compared with 86 patients with ALC-15 < 500 cells/microL (not reached versus 53 months, P < 0.0003 and not reached versus 27 months, P < 0.0001, respectively). Multivariate analysis showed ALC-15 to be an independent prognostic factor for overall survival and progression-free survival. CONCLUSIONS: ALC-15 > or = 500 cells/microL is associated with significantly improved clinical outcomes following ASCT in patients with primary systemic amyloidosis.     

Prediction of early (4-week) mortality in acute myeloid leukemia with intensive chemotherapy

The progress with intensive chemotherapy and supportive care measures has improved survival in patients with newly diagnosed acute myeloid leukemia (AML). Given the recent development of effective low intensity therapies, an optimal decision on the therapy intensity may improve survival through the avoidance of early mortality. We reviewed the outcome of 3728 patients with newly diagnosed AML who received intensive chemotherapy between August 1980 and May 2020. Intensive chemotherapy was defined as a cumulative cytarabine dose ≥ 700 mg/m² during induction therapy. We divided the whole cohort into a training and validation group at a 3:1 ratio. The population was divided into a training (2790 patients) and a validation cohort (938 patients). The median age was 55 years (range, 15-99). Among them, 442 patients (12%) had core-binding factor AML. Binary logistic regression identified older age, worse performance status, hyperbilirubinemia, elevated creatinine, hyperuricemia, cytogenetic abnormalities other than CBF and -Y, and pneumonia as adverse prognostic factors for an early 4-week mortality. This risk classification for early mortality was verified in the validation cohort of patients. In the validation cohort of more recently treated patients from 2000 to 2017, the 4-week mortality rates with intensive chemotherapy were 2%, 14%, and 50% in the low-, high-, and very high-risk group, respectively. The mortality rates with low intensity therapies were 3%, 9%, and 20%, respectively. The risk classification guides treatment intensity by the assessment of age, frailty, organ dysfunction, cytogenetic abnormality, and infection to avoid early mortality.     

The effects of anagrelide on human megakaryocytopoiesis

Anagrelide, an inhibitor of platelet aggregation, decreases the number of platelets in normal subjects and in patients with myeloproliferative disorders. We describe studies aimed at discovering the general mechanism(s) by which anagrelide acts. We examined three hypotheses: (1) anagrelide shortens platelet survival, (2) anagrelide inhibits the proliferation of megakaryocytic-committed progenitor cells (CFU-M), and (3) anagrelide inhibits maturation of megakaryocytes. We observed that anagrelide did not shorten platelet survival. Proliferation of CFU-M in vivo was not affected by anagrelide, although high concentrations of anagrelide inhibited CFU-M in vitro . In-vivo and in-vitro anagrelide altered the maturation of megakaryocytes, causing a decrease in their size and changing other morphometric features. We conclude that anagrelide decreases the number of platelets primarily by interfering with the maturation of megakaryocytes.     

Imatinib for systemic mast-cell disease

Imatinib has shown to be effective against malignant disease driven by ckit. We prospectively treated 12 adults with symptomatic systemic mast-cell disease at a dose of either 100 mg or 400 mg per day. Of the ten patients who we could assess for response, five (50%) had a measurable response to the drug, four of whom had important mast-cell cytoreduction and two who had complete clinical and histological remission. In the five patients with eosinophilia, three had complete clinical and haematological remission. The other two, who did not respond to treatment, were the only patients with the ckit D816V mutation. Our results suggest that imatinib either inhibits the growth-promoting role of wild type ckit, or targets an oncogenic kinase.     

Long-term analysis of the palliative benefit of 2-chlorodeoxyadenosine for myelofibrosis with myeloid metaplasia

OBJECTIVE: Therapeutic splenectomy in myelofibrosis with myeloid metaplasia (MMM) may result in extreme thrombocytosis and leukocytosis and accelerated hepatomegaly. We previously described initial palliative benefit from 2-chlorodeoxyadenosine (2-CdA) in such instances. The purpose of this study is to provide long-term follow-up on the durability of response in the initial cohort and in additional subsequent cases. METHODS: We retrospectively identified patients with histologically confirmed MMM who had palliative therapy with 2-CdA. Clinical characteristics and information on subsequent clinical course were abstracted at the time of diagnosis of MMM and at initiation of 2-CdA therapy until death. RESULTS: To date, we have used 2-CdA as palliative therapy in 14 patients with MMM. After a median of four cycles of therapy, responses for hepatomegaly occurred in 56% of patients, thrombocytosis 50%, leukocytosis 55%, and anemia 40%. Cytopenias were frequent but usually transient and without clinical consequence. Responses occurred usually by the second cycle; median duration of response was 6 months (range, 2-19) after completion of 2-CdA therapy. CONCLUSION: This study confirmed relevant and frequently durable palliation of symptoms in about half the patients. 2-CdA is a reasonable palliative option in postsplenectomy patients with MMM who have problematic myeloproliferation.     

A contemporary approach to the diagnosis and management of polycythemia vera

The natural history of polycythemia vera (PV) includes an increased lifetime risk of thrombohemorrhagic complications and disease transformation into myelofibrosis with myeloid metaplasia and acute myeloid leukemia. The latter is the primary reason for the shortening of survival that becomes significant after the first decade of disease. Historic nonrandomized studies have suggested that aggressive phlebotomy improves survival in PV. However, prospective randomized studies have failed to demonstrate a better treatment than phlebotomy alone, in terms of survival. However, the addition of cytoreductive therapy to phlebotomy in high-risk patients with PV may reduce the risk of recurrent thrombosis. Other disease features of PV include aquagenic pruritus and microvascular disturbances such as erythromelalgia. This review outlines a practical approach to diagnosis, in addition to treatment of life-threatening and non-life-threatening complications of PV.     

Platelet-rich plasma serotonin levels in chronic myeloproliferative disorders: evaluation of diagnostic use and comparison with the neutrophil PRV-1 assay

In a prospective study of 109 subjects, an enzyme-linked immunosorbent assay (ELISA) was used to measure platelet-rich plasma (PRP) serotonin levels in patients with polycythaemia vera (PV; n = 27), essential thrombocythaemia (ET; n = 14), myelofibrosis with myeloid metaplasia (MMM; n = 30), secondary or spurious polycythaemia (SP; n = 22) and controls (n = 16). Nine study subjects who were taking a selective serotonin reuptake inhibitor (SSRI) all displayed a markedly decreased PRP serotonin level (median, 24.2 ng/10(9) platelets; range, 0-49.3) and were therefore excluded from further analysis. Among the remaining 100 subjects, the median and range of PRP serotonin levels, in ng/10(9) platelets, was significantly lower in MMM (89.5; 0-278.3), PV (204.8; 0-496.0) and ET (385.3; 136.8-1025.7) compared with both SP (608.8; 369.0-1780.1) and controls (567.2; 359.9-1071.1). Neutrophil polycythaemia rubra vera-1 (PRV-1) expression was concurrently assayed by real-time polymerase chain reaction in 69 patients (23 PV, 17 SP, 12 ET, seven MMM, 10 controls). PRP serotonin measurement performed as well as the PRV-1 assay in distinguishing PV from SP (93% vs. 86% test accuracy). The current study suggests that PRP serotonin concentration might be considered as one of the several biological markers that complement each other for the diagnosis of PV.