Ex Vivo Venetoclax Sensitivity Predicts Clinical Response in Acute Myeloid Leukemia in the Prospective VenEx Trial.

The BCL2 inhibitor venetoclax has shown promise for treating acute myeloid leukemia (AML). However, identifying patients likely to respond remains a challenge, especially for those with relapsed/refractory (R/R) disease. We evaluated the utility of ex vivo venetoclax sensitivity testing to predict treatment responses to venetoclax-azacitidine in a prospective, multicenter, phase 2 trial conducted by the Finnish AML Group (VenEx, NCT04267081).

The clinical picture of ERCC6L2 disease: from bone marrow failure to acute leukemia.

Biallelic germ line excision repair cross-complementing 6 like 2 (ERCC6L2) variants strongly predispose to bone marrow failure (BMF) and myeloid malignancies, characterized by somatic TP53-mutated clones and erythroid predominance. We present a series of 52 subjects (35 families) with ERCC6L2 biallelic germ line variants collected retrospectively from 11 centers globally, with a follow-up of 1165 person-years. At initial investigations, 32 individuals were diagnosed with BMF and 15 with a hematological malignancy (HM).

venetoclax sensitivity testing predicts treatment response in acute myeloid leukemia.

The BCL-2 inhibitor venetoclax has revolutionized the treatment of acute myeloid leukemia (AML) in patients not benefiting from intensive chemotherapy. Nevertheless, treatment failure remains a challenge, and predictive markers are needed, particularly for relapsed or refractory AML. Ex vivo drug sensitivity testing may correlate with outcomes, but its prospective predictive value remains unexplored.

Impact of the number of cryopreserved CD34 cells in the infused blood grafts on hematologic recovery and survival in myeloma patients after autologous stem cell transplantation: Experience from the GOA study.

Background: Prospective data on the impact of CD34 cell loss during cryopreservation and the amount of cryopreserved CD34 cells infused after high-dose therapy on hematologic recovery and post-transplant outcome in multiple myeloma (MM) are scarce.

Patients And Methods: This post-hoc study aimed to investigate factors associating with CD34 cell loss during cryopreservation and the effects of the infusion of a very low number (<1.0 × 10 /kg, group A), low number (1-1.

Comparison of CD34 cell mobilization, blood graft cellular composition, and post-transplant outcome in myeloma patients mobilized with filgrastim or pegfilgrastim added to low-dose cyclophosphamide: A prospective multicenter study.

Background: Scarce data exist on the impact of granulocyte-colony stimulating factor (G-CSF) type on the mobilizing capacity of CD34 cells, graft cellular composition, and outcome in myeloma (MM) patients.

Patients And Methods: In this prospective multicenter study, 70 patients with MM received filgrastim (FIL) and 20 patients received pegfilgrastim (PEG) as a G-CSF after low-dose cyclophosphamide. Flow cytometry was used to analyze the mobilization of CD34 cells and cellular composition of blood grafts, hematologic recovery, and survival after auto-SCT according to the G-CSF choice.

Autograft cellular composition and outcome in myeloma patients: Results of the prospective multicenter GOA study.

Background: Autologous stem cell transplantation (auto-SCT) is a widely used treatment option in multiple myeloma (MM) patients. The optimal graft cellular composition is not known.

Study Design And Methods: Autograft cellular composition was analyzed after freezing by flow cytometry in 127 MM patients participating in a prospective multicenter study.

Characterisation of healthcare utilisation and cost of haemophilia care in real-life: A 4-year follow-up study in Finland.

Introduction: Characterisation of outcomes and costs of haemophilia care in common practice settings is essential for evaluation of new treatment options and for developing clinical practices. In Finland, haemophilia care is mostly centralised to University Hospitals, but treatment practices and costs in adult patients have not been systematically evaluated.

Aim: This study was designed to characterise healthcare resource utilisation and treatment costs of adult inhibitor-negative haemophilia patients managed in Finnish University Hospitals.

CD34+ cell mobilization, blood graft composition, and posttransplant recovery in myeloma patients compared to non-Hodgkin's lymphoma patients: results of the prospective multicenter GOA study.

Background: Autologous stem cell transplantation is an established treatment option for patients with multiple myeloma (MM) or non-Hodgkin's lymphoma (NHL).

Study Design And Methods: In this prospective multicenter study, 147 patients with MM were compared with 136 patients with NHL regarding the mobilization and apheresis of blood CD34+ cells, cellular composition of infused blood grafts, posttransplant recovery, and outcome.

Results: Multiple myeloma patients mobilized CD34+ cells more effectively (6.

RVD induction and autologous stem cell transplantation followed by lenalidomide maintenance in newly diagnosed multiple myeloma: a phase 2 study of the Finnish Myeloma Group.

Autologous stem cell transplantation (ASCT) combined with novel agents is the standard treatment for transplant-eligible, newly diagnosed myeloma (NDMM) patients. Lenalidomide is approved for maintenance after ASCT until progression, although the optimal duration of maintenance is unknown. In this trial, 80 patients with NDMM received three cycles of lenalidomide, bortezomib, and dexamethasone followed by ASCT and lenalidomide maintenance until progression or toxicity.

ACTN1 mutations lead to a benign form of platelet macrocytosis not always associated with thrombocytopenia.

The inherited thrombocytopenias (IT) are a heterogeneous group of diseases resulting from mutations in more than 30 different genes. Among them, ACTN1-related thrombocytopenia (ACTN1-RT; Online Mendelian Inheritance in Man: 615193) is one of the most recently identified forms. It has been described as a mild autosomal dominant macrothrombocytopenia caused by mutations in ACTN1, a gene encoding for one of the two non-muscle isoforms of α-actinin.

Blood graft composition and post-transplant recovery in myeloma patients mobilized with plerixafor: a prospective multicenter study.

The composition of autologous blood grafts after cryopreservation, post-transplant hematological recovery up to 1 year and immune recovery up to 6 months as well as outcome was analyzed in 87 patients with multiple myeloma (MM). The patients receiving added plerixafor due to poor mobilization (11%) were compared to those mobilized with G-CSF or cyclophosphamide (CY) plus G-CSF. The use of plerixafor was found to significantly affect the graft composition as there was a significantly higher proportion of the more primitive CD34 cells, higher number of T and B lymphocytes as well as NK cells in the grafts of patients who received also plerixafor.

Impact of lenalidomide-based induction therapy on the mobilization of CD34 cells, blood graft cellular composition, and post-transplant recovery in myeloma patients: a prospective multicenter study.

Background: Lenalidomide is an immunomodulatory drug that is also currently used in transplant-eligible patients with multiple myeloma. Previous studies have suggested a negative impact of lenalidomide on the mobilization of CD34 cells. No data are available regarding the more detailed composition of blood grafts after lenalidomide.

Blood graft cellular composition and posttransplant outcomes in myeloma patients mobilized with or without low-dose cyclophosphamide: a randomized comparison.

Background: Autologous stem cell transplantation is a standard treatment in multiple myeloma (MM). Blood grafts are usually collected after mobilization with granulocyte-colony-stimulating factor (G-CSF) alone or in a combination with cyclophosphamide (CY). There is limited knowledge of the possible effects of different mobilization regimens on blood graft characteristics and posttransplant outcomes.

Clinical Candida krusei isolates remain susceptible during extensive exposure to antifungal drugs.

We have previously reported a Candida krusei outbreak during which a number of our patients were infected or colonized by several different closely related Candida krusei genotypes. The treatment response in many of our patients was at best modest and the patients remained positive for Candida krusei. We speculated that extended exposure to antifungals in patients with an incomplete treatment response might lead to the conditions for selection of drug resistance in the multiple Candida krusei clones.

A cluster of Candida krusei infections in a haematological unit.

Background: Candida krusei infections are associated with high mortality. In order to explore ways to prevent these infections, we investigated potential routes for nosocomial spread and possible clonality of C. krusei in a haematological unit which had experienced an unusually high incidence of cases.

Valproic acid combined with 13-cis retinoic acid and 1,25-dihydroxyvitamin D3 in the treatment of patients with myelodysplastic syndromes.

Valproic acid (VPA), an inhibitor of histone deacetylases, inhibits the growth of leukemia cells and induces their differentiation in vitro. In the present study, VPA in combination with two differentiating agents, 13-cis retinoic acid and 1,25-dihydroxyvitamin D3, was given to 19 previously untreated patients with MDS or CMML. Eight patients had to discontinue treatment before week 16 due to toxicity.

Long-term outcome of intensive chemotherapy for adults with de novo acute myeloid leukaemia (AML): the nationwide AML-92 study by the Finnish Leukaemia Group.

Objective: To investigate the long-term outcome of idarubicin- and cytarabine-based intensive chemotherapy in adult acute myeloid leukaemia (AML).

Patients And Methods: A total of 327 consecutive patients with de novo AML (promyelocytic leukaemia excluded) aged 16-65 yr were recruited into the study between September 1992 and December 2001. The latest follow-up data were collected in October 2006.

An association between manganese superoxide dismutase polymorphism and outcome of chemotherapy in acute myeloid leukemia.

Manganese superoxide dismutase (MnSOD) protects cells against oxidative stress by eliminating superoxides. Hypothetically, decreased MnSOD levels in cancer might lead to increased oxidative stress and, thus, to increased sensitivity of cells to chemotherapy agents. Eighty-nine patients with acute myeloid leukemia (AML) were analyzed for a functional C to T polymorphism of MnSOD, which could potentially lead to decreased enzyme concentrations inside mitochondria.

Increase in Ara-C cytotoxicity in the presence of valproate, a histone deacetylase inhibitor, is associated with the concurrent expression of cyclin D1 and p27(Kip 1) in acute myeloblastic leukemia cells.

The effects of valproate and butyrate were investigated in an acute myeloblastic cell line (OCI/AML-2) on cytotoxicity, cell cycle profile and expression of cell cycle regulating proteins in the presence of cytarabine (Ara-C) and etoposide. As a single agent valproate and butyrate inhibited AML cell growth but did not significantly induce cell death. A dramatic increase in cytotoxicity was observed when combining valproate or butyrate with Ara-C, whereas, co-addition of them with etoposide had much smaller effect on cell death.

Superior effect of 9-cis retinoic acid (RA) compared with all-trans RA and 13-cis RA on the inhibition of clonogenic cell growth and the induction of apoptosis in OCI/AML-2 subclones: is the p53 pathway involved?

In the present study, the effects of 9-cis retinoic acid (RA) and 13-cis RA on acute myeloblastic leukaemia (AML) cell growth and the induction of apoptosis as well as its relationship with bcl-2 and p53 were compared with those of all-trans RA (ATRA). The study was performed with the subclones of the retinoid-sensitive OCI/AML-2 cell line. The most prominent inhibitory effect on clonogenic cell growth and morphological apoptosis was shown by 9-cis RA.

p53-mediated downregulation of Chk1 abrogates the DNA damage-induced G2M checkpoint in K562 cells, resulting in increased apoptosis.

BCR-ABL confers apoptotic resistance to a range of genotoxic agents, and this protection is mediated in part by prolonging the G2 checkpoint. The p53 tumour suppressor protein regulates the transcription of regulatory genes involved in cell cycle arrest and apoptosis. To investigate the effect of p53 on the BCR-ABL-mediated G2M checkpoint response, we transiently transfected the BCR-ABL-positive, p53-negative cell line K562 with wild-type human p53.