Annals of Hematology

The 5-year overall survival (OS) in patients ≥ 60 years old with acute myeloid leukemia (AML) remains < 10%. Clofarabine-based induction (CLO) provides an alternative to low-intensity therapy (LIT) and palliative care for this population, but supporting data are conflicted. Recently, our institution adopted the FLAG regimen (fludarabine, cytarabine, and granulocyte colony-stimulating factor) based on data reporting similar outcomes to CLO in elderly patients with AML unable to tolerate anthracycline-based induction. We retrospectively analyzed the efficacy and safety of patients ≥ 60 years old with AML treated with FLAG or CLO over the past 10 years. We performed a propensity score match that provided 32 patients in each group. Patients treated with FLAG had a higher CR/CRi rate (65.6 vs. 37.5%, P = 0.045) and OS (7.9 vs. 2.8 months, P = 0.085) compared to CLO. Furthermore, FLAG was better tolerated with significantly less grade 3/4 toxicities and a shorter duration of neutropenia (18.5 vs. 30 days, P = 0.002). Finally, we performed a cost analysis that estimated savings to be $30,000–45,000 per induction with FLAG. Our study supports the use of FLAG both financially and as an effective, well-tolerated high-dose treatment regimen for elderly patients with AML. No cases of cerebellar neurotoxicity occurred.

Platelet function disorders (PFD) and Von Willebrand disease (VWD) are among the uncommon causes of bleeding in haematological practice. The inherited variety of PFD includes defects in platelet adhesion, aggregation, secretion and platelet procoagulant activities. VWD is classified into three major categories—type 1 and 3 (quantitative deficiency) and type 2 VWD (qualitative defect). In the present study, the profile and prevalence of inherited PFD and VWD in Indians are described. Two thousand eight hundred patients with history of muco-cutaneous bleeding and other bleeding disorders were investigated. The tests performed included platelet count, bleeding time, PT, APTT, F VIII assay, platelet factor 3 (PF3) availability, platelet aggregation studies, VWF:Ag, VWF:RCo and multimeric analysis. Out of 2,800 patients investigated, a total of 872 (31.1%) were characterized to have either inherited coagulation defects (64.2%) or inherited platelet function disorders (35.8%). Of these 872patients, 312 (35.8%) cases were characterized to have inherited PFD and 94 (16.8%) patients as VWD. Among 312 inherited PFD patients, isolated PF3 availability defect (48.1%) was most common, followed by unclassified PFD (37.2%). Among 94 VWD patients, type 2 VWD was most common (44.7%), followed by type 3 VWD (34.5%) and type 1 VWD (21.3%), respectively. Bleeding manifestations included easy bruising (46%), undue prolonged bleeding from trivial injuries (50% in PFD and type 1 and type 2 VWD and 100% in type 3 VWD), menorrhagia (31%), gum bleeds (22%), epistaxis (55%), haematuria (6%), GI bleeds (11%) and rarely, haematomas and haemarthoses (4%). In conclusion, VWD and inherited platelet function disorders are not uncommon among Indian population presenting with bleeding disorders.

To explore the clinical characteristics and outcomes in Chinese patients with type I cryoglobulinemia (CG), we retrospectively analyzed the clinical data, management, and outcomes of 45 patients diagnosed with type I CG in our hospital from January 2015 to March 2019. In our study, all type I CGs were secondary to hematologic diseases, and monoclonal gammopathy of unknown significance was the most common primary disease, accounting for 48.9% (n = 22). Additionally, B cell non-Hodgkin lymphoma, Waldenström’s macroglobulinemia, and multiple myeloma accounted for 24.4% (n = 11), 20.0% (n = 9), and 6.7% (n = 3), respectively. In patients with type I CG, skin damage was the most common symptom, presenting in 57.8% of the patients, followed by peripheral neuropathy (22.2%) and renal involvement (15.6%). Treatment was initiated in 29 patients (64.4%), and the most common choice was a rituximab-based regimen in 13 patients (44.8%), followed by bortezomib-based regimen in 11 patients (37.9%). Clinical symptoms were significantly improved after treatment, and the clinical remission rate was 86.2%, including 34.5% of complete clinical remission, while the laboratory response rate was 88.9%, including 33.3% of complete response and 55.6% of partial response. The expected 1-year overall survival was 97.8%. In conclusion, for patients with multisystemic involvement, such as skin damage, kidney damage, or peripheral neuropathy, the diagnosis of type I CG should be considered, and the underlying disease needs to be explored. Symptoms and primary diseases should be taken into consideration before choosing initial management.

Colony-stimulating factors (CSFs) have entered the clinical arena. Several investigators have explored, in first clinical phase I studies, different routes of administration to define the optimum biological dose, maximum tolerated dose, toxicity, and pharmacokinetics of these reagents. It has been demonstrated that recombinant human (rh) granulocyte-macrophage CSF (GM-CSF) and granulocyte CSF (G-CSF) can be safely administered over a broad dose range to increase number of circulating granulocytes in man. More recently, GM-CSF and G-CSF have been involved in phase Ib/II studies to assess the granulopoietic responses of patients with granulocytopenia due to various underlying disease states including myelodysplastic syndrome, aplastic anemia, cyclic neutropenia, Kostmann's syndrome, and the acquired immuno-deficiency syndrome. Both factors were also investigated with respect to their potential to prevent chemotherapy induced granulocytopenia or to accelerate recovery from that condition. The short-term effects of rh GM-CSF after autologous bone marrow transplantation for various solid tumors and lymphoid malignancies were assessed as well. In this article we will focus on recent results that have emerged from in vivo studies utilizing CSFs.

We conducted an investigation of 186 randomly selected acute adult leukemia patients in order to examine how far age and subtype of leukemia can be correlated with survival rate. The diagnosis of leukemia was established by cytochemical and cytomorphological techniques. There was an increased frequency of acute myelogenic leukemias in older patients. The age group of the 61–90 year old showed a significant decrease in the survival rate, but at the same time in this age group there was a higher frequency of leukemia types with poor prognosis. Early deaths were correlated with advanced age of patients. There were no long time survivors (with survival rates longer than 4 years after diagnosis) above the age of 57.

Lenalidomide (Len) and dexamethasone (dex) therapy is a standard therapy in patients with multiple myeloma. Elderly or unfit patients may reduce Len or dex doses to prevent toxicities that lead to treatment discontinuation. However, there have been few studies evaluating the efficacy and safety of lower doses of Len and dex. We conducted a phase II study of 1.5-year low-dose Len and dex therapy following melphalan and prednisolone (MP), the number of which cycles was determined by a response within 9 cycles. The Len dose was 10 mg daily and the dex dose was 20 mg weekly, which were continued for 1.5 years. Twenty-one patients were enrolled. The median number of cycles of MP was 3 (range, 2–9). The overall response rate was 81% and a very good partial response or better was achieved in 33.3% of patients. The median follow-up time for survivors was 70.5 months (range, 42–83 months), the median progression-free survival (PFS) was 27 months (95% CI, 21–33 months), and the median overall survival was not reached. Grade 3 or 4 adverse events were observed in 28.6% of patients. In conclusion, the low-dose Len and dex therapy safely achieved comparable efficacies to the standard-dose regimen in elderly patients with newly diagnosed multiple myeloma. UMIN000007889.

DNA methylation is the most common epigenetic modification in the mammalian genome. DNA methylation is governed by the DNA methyltransferases mainly DNMT1, DNMT3A, and DNMT3B. DNMT1 methylates hemimethylated DNA ensuring accurate DNA methylation maintenance. DNMT1 is involved in the proper differentiation of hematopoietic stem cells (HSCs) through the interaction with effector molecules. DNMT1 is deregulated in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) as early as the leukemic stem cell stage. Through the interaction with fundamental transcription factors, non-coding RNAs, fusion oncogenes and by modulating core members of signaling pathways, it can affect leukemic cells biology. DNMT1 action might be also catalytic-independent highlighting a methylation-independent mode of action. In this review, we have gathered some current facts of DNMT1 role in AML and MDS and we also propose some perspectives for future studies.