Monika Paluszewska

Status of minimal residual disease after induction predicts outcome in both standard and high-risk Ph-negative adult acute lymphoblastic leukaemia. The Polish Adult Leukemia Group ALL 4-2002 MRD Study

The treatment of adults with Philadelphia‐negative acute lymphoblastic leukaemia (ALL) depends on the presence of risk factors including age, white blood cell count, immunophenotype and time to complete remission. In recent years, status of minimal residual disease (MRD) has been postulated as an additional risk criterion. This study prospectively evaluated the significance of MRD. Patients were treated with a uniform Polish Adult Leukemia Group (PALG) 4‐2002 protocol. MRD status was assessed after induction and consolidation by multiparametric flow cytometry. Out of 132 patients included (age, 17–60 years), 116 patients were suitable for analysis. MRD level ≥0·1% of bone marrow cells after induction was found to be a strong and independent predictor for relapse in the whole study population (P < 0·0001), as well as in the standard risk (SR, P = 0·0003) and high‐risk (P = 0·008) groups. The impact of MRD after consolidation on outcome was not significant. The combination of MRD status with conventional risk stratification system identified a subgroup of patients allocated to the SR group with MRD <0·1% after induction who had a very low risk of relapse of 9% at 3 years as opposed to 71% in the remaining subjects (P = 0·001). We conclude that MRD evaluation after induction should be considered with conventional risk criteria for treatment decisions in adult ALL.

Risk factors for breakthrough invasive fungal infection during secondary prophylaxis

BACKGROUND Intensive chemotherapy with severe neutropenia is associated with invasive fungal infections (IFIs) leading to high mortality rates. During leukaemia induction chemotherapy, IFI often prohibited further curative treatment, thus predisposing for leukaemia relapse. Continuing myelosuppressive chemotherapy after diagnosis of IFI has become feasible with the now expanding arsenal of safe and effective antifungals. Secondary prophylaxis of IFI is widely administered, but reliable data on outcome and risk factors for recurrent IFI during subsequent chemotherapy are not available. This study determines risk factors for recurrent IFI in leukaemia patients. METHODS From 25 European cancer centres, 166 consecutive patients with acute myelogenous leukaemia (AML) and a recent history of proven or probable pulmonary IFI were included. Patients were followed for recurrence or breakthrough IFI during the subsequent chemotherapy cycle. RESULTS Of the 166 patients included, 69 (41.6%) were female, the median age was 53 years (range 2-81) the and 3 (1.8%) were <16 years. Recurrent IFI occurred in 26 patients (15.7%). Multiple logistic regressions yielded predisposing factors: duration of neutropenia [per additional day; odds ratio (OR) 1.043, confidence interval (CI) 1.008-1.078], high-dose cytarabine (OR 3.920, CI 1.120-12.706), number of antibiotics (per antibiotic; OR 1.504, CI 1.089-2.086), partial response as outcome of prior IFI (OR 4.037, CI 1.301-12.524) and newly diagnosed AML (OR 3.823, CI 0.953-15.340). Usage of high efficiency particulate air filter appeared protective (OR 0.198, CI 0.036-1.089). CONCLUSIONS Duration of neutropenia, high-dose cytarabine, prior antibiotic therapy and a partial response to the first IFI therapy were risk factors for recurrent IFI and should be considered in AML patients with prior pulmonary IFI undergoing further chemotherapy.

G-CSF Administered in Time-sequenced Setting During Remission Induction and Consolidation Therapy of Adult Acute Lymphoblastic Leukemia has Beneficial Influence on Early Recovery and Possibly Improves Long-term Outcome: A Randomized Multicenter Study

Sixty-four untreated adult acute lymphoblastic leukemia (ALL) patients were randomized to receive chemotherapy alone, n =31 or chemotherapy and granulocyte colony stimulating factor (G-CSF), n =33. During induction patients received G-CSF for 5 days between four weekly Epirubicin+Vcr administrations, starting 36 h after each application and finishing 48 h before the next one with the intention to possibly generate a cell cycle dependent protection of normal hematopoietic progenitors and to stimulate granulopoiesis. The complete remission (CR) rate equaled 94% in the G-CSF group and 87% in controls. Patients who received G-CSF, if compared to the controls, had shorter granulocytopenia during induction and consolidation, displayed a lower infection rate, completed the induction-consolidation quicker and stayed shorter in hospital during induction, p <0.001-0.04. Follow-up at 2 years revealed a rather higher probability of survival (59 vs. 27%, p =0.04 ) and a lower relapse rate (32 vs. 60%) in G-CSF arm than in controls. The beneficial influence of G-CSF administered in time-sequenced fashion on survival needs further confirmation.

Cladribine added to daunorubicin-cytarabine induction prolongs survival of FLT3-ITD+ normal karyotype AML patients.

To the editor: Internal tandem duplication in the FLT3 gene ( FLT3- ITD) has been recognized as a marker conferring poor outcome in patients with normal karyotype acute myeloid leukemia (NK-AML).[1][1] Because of the inferior outcome of FLT3- ITD+ NK-AML patients when treated with standard

FLT3-ITD and MLL-PTD influence the expression of MDR-1, MRP-1, and BCRP mRNA but not LRP mRNA assessed with RQ-PCR method in adult acute myeloid leukemia

Fms-like tyrosine kinase 3–internal tandem duplication (FLT3-ITD) and mixed-lineage leukemia gene–partial tandem duplication (MLL-PTD) are aberrations associated with leukemia which indicate unsatisfactory prognosis. Downstream regulatory targets of FLT3-ITD and MLL-PTD are not well defined. We have analyzed the expression of MDR-1, multidrug resistant protein-1 (MRP-1), breast cancer resistance protein (BCRP), and lung resistance protein (LRP) messenger RNA (mRNA) in relation to the mutational status of FLT3-ITD and MLL-PTD in 185 acute myeloid leukemia (AML) adult patients. The real-time quantitative polymerase chain reaction method was performed to assess the expression of the MDR-1, MRP-1, BCRP, and LRP mRNA, and the results were presented as coefficients calculated using an intermediate method according to Pfaffl’s rule. Significantly higher expressions of MDR-1 mRNA were found in patients who did not harbor FLT3-ITD (0.20 vs. 0.05; p = 0.0001) and MRP-1 mRNA in patients with this mutation (0.96 vs. 0.70; p = 0.002) and of BCRP mRNA in patients with MLL-PTD (0.61 vs. 0.38; p = 0.03). In univariate analysis, the high expression of MDR-1 mRNA (≥0.1317) negatively influenced the outcome of induction therapy (p = 0.05), whereas the high expression of BCRP mRNA (≥1.1487) was associated with a high relapse rate (RR) (p = 0.013). We found that the high expression of MDR-1 (≥0.1317), MRP-1 (≥0.8409), and BCRP mRNA (≥1.1487) significantly influenced disease-free survival (DFS; p = 0.059, 0.032, and 0.009, respectively) and overall survival (0.048, 0.014, and 0.059, respectively). Moreover, a high expression of BCRP mRNA (≥1.1487) proved to be an independent prognostic factor for RR (p = 0.01) and DFS (p = 0.002) in multivariate analysis. The significant correlation between the expression of MDR-1, MRP-1, and BCRP mRNA and FLT3-ITD or MLL-PTD in AML patients requires further investigation.

Mild chronic graft-versus-host disease may alleviate poor prognosis associated with FLT3 internal tandem duplication for adult acute myeloid leukemia following allogeneic stem cell transplantation with myeloablative conditioning in first complete remission: a retrospective study

Internal tandem duplication (ITD) of the FLT3 gene (Fms‐like tyrosine kinase 3) is the most commonly found mutation in acute myeloid leukemia (AML). The significance of FLT3‐ITD at diagnosis was retrospectively estimated for allo‐HSCT (allogeneic hematopoietic stem cell transplantation) outcomes in 140 patients, median age of 38, undergoing allo‐HSCT after myeloablative conditioning in first complete remission of AML. FLT3‐ITD was detected at AML diagnosis in 42/140 (30%) of included into this study patients. At 3 years, relapse incidence (RI) following allo‐HSCT in AML patients with intermediate or normal karyotype was significantly higher in those FLT3‐ITD positive than FLT3‐ITD negative [52.9 vs. 20.4%, P = 0.002]. Additionally, patients with mild chronic graft‐versus‐host disease (cGvHD) had significantly lower RI compared to patients with moderate or severe grade cGvHD or those not experiencing cGvHD, respectively, 4.8 vs. 36.0 vs. 27.8%, P = 0.032. FLT3‐ITD was harboring a poor prognosis in AML with intermediate or normal karyotype and significantly increased risk of relapse following allo‐HSCT. It appears that allo‐HSCT does not cure patients with FLT3‐ITD, unless they develop symptoms of mild cGvHD and graft versus leukemia, which may decrease RI.

Triple transplantation of autologous peripheral blood stem cells each time following conditioning with 100 mg/m2 of melphalan for multiple myeloma patients in poor performance status ☆

Approximately one third of multiple myeloma patients (below 60 years) are diagnosed either in advanced disease or with significant comorbidities. Many other patients referred to transplant centers have already been heavily pretreated with multiple courses of various conventional chemotherapies. These patients are frequently in bad or even grave clinical condition; they are unlikely to survive standard high-dose melphalan (200 mg/m(3)) chemotherapy and autologous hematopoietic stem cell transplantation. Palumbo et al reported a protocol for elderly patients that utilized reduced conditioning (melphalan 100 mg/m(2) three times at 2-month intervals, each time supported by autologous hematopoietic rescue). We have used this protocol as a start to develop a method to induce a remission in the aforementioned subgroup of myeloma patients. Patients with stage III disease and WHO performance status 2 or higher are treated with one or two cycles of cyclophosphamide (2 to 4 g/m(2)) and undergo peripheral blood stem cells collection. Subsequently, they are treated with three to four doses of melphalan (100 mg/m(2)) at 8- to 12-weeks intervals each time supported by infusion of peripheral blood stem cells. To date 13 patients have been entered into the protocol. With one exception of transiently stable disease, the remaining patients obtained at least partial remission and three, complete remission. The compliance was good and better with each subsequent course. For half of the patients the problem was a short duration of response. This method when developed may offer a new treatment alternative for a subgroup of high-risk multiple myeloma patients.

Impact of granulocyte colony stimulating factor administered during induction and consolidation of adults with acute lymphoblastic leukemia on survival: long-term follow-up of the Polish adult leukemia group 4-96 study.

Department of Clinical Oncology, Comprehensive Cancer Centre, Maria Sklodowska-Curie Memorial Institute Branch Gliwice, Gliwice, Poland, Department of Hematology and Bone Marrow Transplantation, Silesian Medical University, Katowice, Poland, Department of Hematology, Institute of Internal Diseases, Gdansk Medical Academy, Gdansk, Poland, Department of Hematology and Bone Marrow Transplantation, Lublin Medical Academy, Lublin, Poland, Department of Hematology, Oncology and Internal Medicine, Warsaw Medical University, Warsaw, Poland, Department of Hematology, Lodz Medical University, Lodz, Poland, Department of Internal Diseases, Institute of Haematology and Blood Transfusion, Warsaw, Poland, Department of Hematology, Institute of Haematology and Blood Transfusion, Warsaw, Poland, and Department of Hematology, Collegium Medicum, Jagiellonian University, Krakow, Poland

Could cytogenetics and minimal residual disease replace conventional risk criteria in adults with Ph-negative acute lymphoblastic leukaemia?

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Pericarditis in Patients with Chronic Graft versus Host Disease

BACKGROUND There are only a few cases of pericarditis complications following allogeneic bone marrow transplantation described in the literature and there are no data available on the risk and frequency of this condition. The aim of this study was to assess the frequency of exudative pericarditis complicating chronic graft-vs-host disease in allogeneic hematopoietic cell transplant recipients. METHODS Retrospective analysis involved a group of 105 patients of the Outpatient Transplantation Service of the Department of Hematology, Medical University of Warsaw, who received transplants in the years 2010-2016 and were evaluated for the years 2014-2016. In this group, 50 patients suffered from chronic graft-vs-host disease (cGVHD), including 24 with moderate or severe disease. Cardiology parameters evaluated included electrocardiography, echocardiography, N-terminal prohormone of brain natriuretic peptide (NT-proBNP), and systematic clinical follow-up. RESULTS Pericarditis was diagnosed in 6 patients (aged 20-56 years) within 4 to 23 months after allogenic hematopoietic stem cell transplantation. All patients suffered from severe cGVHD with involvement of at least 2 organs but none had earlier history of heart disease. All patients had elevated NT-proBNP and demonstrated signs of heart insufficiency grade II or III according to the New York Heart Association. There were no major changes in electrocardiogram. Only 1 patient improved following glucocorticosteroids as monotherapy, while others required complex approaches including tacrolimus plus sirolimus, rituximab, and extracorporeal photopheresis. CONCLUSION Late pericarditis may occur in up to 5% of allogenic hematopoietic stem cell transplantation survivors, primarily affecting patients with moderate and severe grade cGVHD. It requires escalation of immunosuppressive treatment but usually has favorable outcome. Early diagnosis may be achieved by systematic NT-proBNP testing and periodic echocardiograph evaluation.