Beata Stella-Holowiecka

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.

A single weekly dose of imatinib is sufficient to induce and maintain remission of chronic eosinophilic leukaemia in FIP1L1-PDGFRA-expressing patients

Hypereosinophilic syndrome (HES) is defined as chronic, unexplained hypereosinophilia with organ involvement. A subset of HES patients presents an interstitial deletion in chromosome 4q12, which leads to the expression of an imatinib‐responsive fusion gene, FIP1L1‐PDGFRA. These patients are diagnosed as chronic eosinophilic leukaemia (CEL). We treated seven CEL and HES patients, six of which expressed FIP1L1‐PDGFRA, with imatinib using initial daily doses ranging from 100 to 400 mg. In a remission maintenance phase, the patients were treated with imatinib once weekly. All imatinib‐treated patients achieved a complete haematological remission (CHR), and five of the six patients with FIP1L1‐PDGFRA expression exhibited molecular remission. The decreased imatinib doses were as follows: 200 mg/week in three patients, 100 mg/week in two patients and 100 mg/d in the remaining two patients. For remission maintenance, imatinib doses were set at 100 mg/week in five patients and 200 mg/week in two patients. At a median follow‐up of 30 months all patients remained in CHR and FIP1L1‐PDGFRA expression was undetectable in five of the six FIP1L1‐PDGFRA‐expressing patients. These data suggest that a single weekly dose of imatinib is sufficient to maintain remission in FIP1L1‐PDGFRA‐ positive CEL patients.

The results of imatinib therapy for patients with primary eosinophilic disorders.

To the Editor: Primary eosinophilia is considered to be clonal or idiopathic. Clonal eosinophilia occurs in a wide spectrum of hematological malignancies and is demonstrated to be a part of a malignant clone or it can also result from cytokine-secreting T-cell clone (1). Idiopathic hypereosinophilic syndrome (HES) is defined by persistent eosinophilia ‡1.5 · 10/L for at least 6 months, absence of reactive causes of eosinophilia, and evidence of organ damage (2). A subset of patients with FIP1L1-PDGFRA (Fip1-like1-platelet-derived growth factor receptor alpha) -positive HES demonstrated rapid clinical improvement and hematologic/molecular remission after imatinib therapy (3). We report here on eight patients (pts)with primary eosinophilia (four pts HES, two pts chronic eosinophilic leukemia PDGFRA+, one pt MPD-HES (myeloproliferative disorder-hypereosinophilic syndrome), one pt T-cell mediated HES) treated with imatinib at a starting dose of 100 mg daily. There were five male and three female patients, with a median age of 54.5 yr (range 19–65). Median white blood cell count at diagnosis was 14 · 10/L (range 9.7–30.0), with peripheral blood eosinophilia of 6.34 · 10/L (3.9–24) and bone marrow eosinophilic infiltration of 32% (14–47%). Median serum immunoglobulin E (IgE) level was 168 IU (9–1617). Serum vitamin B12 level was in the normal range (median 350 pg/mL). In one patient, flow cytometric analysis of lymphoid cells showed a population of CD2+CD3+CD4+CD8) lymphocytes. On multiplex polymerase chain reaction (PCR) with heteroduplex analysis, this patient revealed TCRab gene rearrangement. The samepatient presented also t(6;11)(21q;23q) on cytogenetic evaluation. Normal karyotype was showed in the remaining seven pts. A FIP1L1-PDGFRAfusion genewas detectable in two of seven pts at diagnosis (28%) by reverse transcription (RT)-PCR.All patients had an associated organ involvement. Because of refractoriness to the primary therapy, imatinib at 100 mg a daywas initiated in all patients. Median time from diagnosis to imatinib commencement was 53 months (4–144). Median serum troponin level before therapy was 0.2 ng/mL (0.0–9.2). A complete hematologic remission defined as peripheral eosinophilia count <0.7 · 10/L was achieved in three pts, all male, after median of 14 d (range 13–65). Two out of three were FIP1L1PDGFRA positive at diagnosis, one patient was not studied for this transcript. One out of two FIP1L1PDGFRA-positive patients also achieved molecular remission at 6 months. In one patient, imatinib was stopped after 7 months, while in complete remission. After 5 months off imatinib, eosinophilia recurred. This patient was not studied for FIP1L1-PDGFRA transcript at diagnosis, but hewas negative at time of relapse. In two other patients (FIP+), who had been in sustained remission for 6 months, imatinib was stopped, but eosinophilia re-appeared within 1 month. All three pts resumed imatinib at 100 mg a day with complete hematologic remission within next 2 weeks of therapy. Soon thereafter imatinib dose was reduced to 100 mg once a week. Median follow-up of treatment is +6 months (+6 to +24). Imatinib is well tolerated and no side effects are present. Currently, all patients receive imatinib as a maintenance at dose 100 mg a week with sustained remission. Figure 1 presents reduction of eosinophilia count during imatinib in responder group. Eur J Haematol 2006: 76: 535–536 doi:10.1111/j.1600-0609.2006.00652.x All rights reserved 2006 The Authors Journal compilation 2006 Blackwell Munksgaard

The early reduction of leukemic blasts in bone marrow on day 6 of induction treatment is predictive for complete remission rate and survival in adult acute myeloid leukemia; The results of multicenter, prospective Polish adult leukemia group study

The aim of this study was to prospectively evaluate the impact of early bone marrow response on complete remission (CR) rate and long-term outcome in adults with acute myeloid leukemia. Bone marrow cytology was assessed on day 6 of induction treatment in 164 patients, revealing the presence of ≥5% blasts in 61 cases. In this subgroup the CR rate was significantly lower compared to the remaining patients (P < 0.00001) resulting in decrease of the overall survival (P = 0.002). Persistence of ≥5% blasts in bone marrow on day 6 of induction is an easily available surrogate marker to be used for treatment decisions.

Zalecenia Polskiej Grupy Szpiczakowej dotyczące rozpoznawania i leczenia szpiczaka plazmocytowego na rok 2012

STRESZCZENIE Nowe leki wprowadzane do leczenia szpiczaka w ostatnich latach pozwalają uzyskac odpowiedź terapeutyczną u przewazającej wiekszości chorych na szpiczaka plazmocytowego. Schematy oparte na talidomidzie i bortezomibie stosowane są obecnie w leczeniu nowo zdiagnozowanych chorych niezaleznie od tego, czy chorzy są kandydatami do chemioterapii duzymi dawkami melfalanu i przeszczepienia krwiotworczych komorek macierzystych, czy nie. W leczeniu chorych opornych na terapie indukującą stosuje sie schematy oparte na lenalidomidzie. Wazną cześcią leczenia chorych na szpiczaka jest leczenie wspomagające i podtrzymujące. W artykule tym przedstawiono rowniez zalecenia dotyczące rozpoznania i leczenia innych dyskrazji plazmocytowych.

Long-term results of the Polish Adult Leukemia Group PALG-CLL2 phase III randomized study comparing cladribine-based combinations in chronic lymphocytic leukemia

Abstract Long-term outcomes following newer therapies for chronic lymphocytic leukemia (CLL) have rarely been reported. This article presents the results of the final analysis of the Polish Adult Leukemia Group PALG-CLL2 study performed 10 years from final patient enrollment. With the extended follow-up time, it was found that cladribine (2-CdA)-based combinations CMC (2-CdA, cyclophosphamide, mitoxantrone) and CC (2-CdA, cyclophosphamide) administered as first-line treatment of progressive CLL resulted in significantly longer progression-free survival, but similar overall survival compared to 2-CdA monotherapy. Furthermore, the risk of potentially fatal late adverse events including infections, autoimmune complications and, particularly, secondary neoplasms was comparable among patients treated with CMC, CC or 2-CdA. The results of our analysis support the importance of long-term outcome monitoring of randomized trials in CLL.

High incidence of ancestral HLA haplotype 8.1 and monoclonal incomplete DH–JH immunoglobulin heavy chain gene rearrangement in persistent polyclonal B-cell lymphocytosis

Dear Editor, Persistent polyclonal B-cell lymphocytosis (PPBL) is a rare, benign, and usually asymptomatic entity, characterized by sustained B-cell CD5 lymphocytosis with normal surface ./1 chains ratio, with bilobulated and/or binuclear cells and elevated serum polyclonal IgM level. The increased frequency of HLA-DR7 haplotype and chromosomal clonal aberrations in particular concerning the chromosome 3 suggest a genetic background of this entity [1, 4]. We studied four women with PPBL, aged 48 to 51 years, for the clonality of rearrangement of immunoglobulin (Ig) and T-cell receptor (TCR) genes in peripheral blood lymphocytes by 14 multiplex PCR reactions with different primers: three VH–JH (IGH), two DH–JH (IGH), two Ig kappa (IGK), one Ig lambda (IGL), three TCR beta (TCRB), two TCR gamma (TCRG), and one TCR delta (TCRD) [5]. Peripheral lymphocytes were also studied with classical cytogenetic and FISH analyses, using 3q/3pspecific probes. All patients and 200 healthy ethnically matched controls were HLA typed for A, B, Cw, and DRB1 genes by PCR-based sequence-specific primer amplification using SSP kits (Olerup, Sweden). Three out of four patients studied were asymptomatic, while one presented recurrent bacterial infections and decreased serum IgA and IgG levels. In all patients studied, peripheral lymphocytosis ranged from 6.1 to 10.5×10/l for a minimum of 5 years, with predominance of CD19/CD5 cells. Binucleated/ bilobulated lymphocytes were present on the blood smear, surface kappa/lambda chains ratios were normal, and serum levels of polyclonal IgM were increased. Cytogenetic studies revealed abnormalities in one patient (+i(3)(q10), +18, i(18)(q10), rob(13;14)(10;q10), with the presence of i(3)(q10) in 10% of interphase nuclei). No patients revealed the monoclonality in IGH VH–JH, IGK, IGL, nor TCR genes, but we found incomplete monoclonal DH7–JH IGH rearrangements in two patients. The observed DH–JH genes rearrangements were not related to other upstream DH or downstream JH genes. HLA typing showed DRB1*07 allele in 2/4 patients and in 58/200 controls (p=0.38). We found significantly higher frequency of Cw*07–B*08– Ann Hematol (2008) 87:597–598 DOI 10.1007/s00277-007-0434-z

Low-dose zinc administration as an effective Wilson’s disease treatment

A case of a 11-yr-long Wilson’s disease treatment in a 16-yr-old boy with neurologic presentation was analyzed and monitored. In the face of severe symptoms of chelator intolerance, a comparatively low dose of 100 mg of zinc has been administered for the entire 11-yr-long treatment. Considerable improvement of clinical status was achieved, with accompanying regression of central nervous system lesion. The parameters of copper metabolism were normalized with effective urine elimination. The low-dose oral zinc intake proved to be therapeutically effective, eliminating further copper tissue toxicity.

Liposomal cytarabine in advanced-stage acute lymphoblastic leukemia and aggressive lymphoma with central nervous system involvement : experience of The Polish Acute Leukemia Group

Department of Hematology and BMT, Silesian Medical University, Katowice, Department of Hematology, Institute of Hematology, Warsaw, Poland, Department of Hematology, Poznan Medical University, Poznan, Department of Hematology, Rzeszow Regional Hospital, Rzeszow, Department of Hematology and BMT, Medical University, Gdansk, Department of Hematology, Medical University, Lublin, and Department of Hematology, Medical University, Białystok, Poland

Red Blood Cell Transfusion Dependency and Hyperferritinemia Are Associated with Impaired Survival in Patients Diagnosed with Myelodysplastic Syndromes: Results from the First Polish MDS-PALG Registry

BACKGROUND Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal stem cell disorders characterized by ineffective hematopoiesis, cytopenias and a risk of progression to acute myeloid leukemia (AML). Anemia is the most frequent cytopenia diagnosed in patients with MDS. Regular RBC transfusions are the only treatment option for about 40% of patients. Transfusion-dependent patients develop secondary iron overload. The influence of serum ferritin (SF) concentration on survival and acute myeloid leukemia transformation in MDS patients remains controversial. The data for the Central European population is scarce and so far there is no description for Poland. OBJECTIVES The aim of this study was to perform a retrospective analysis of the relationship of SF concentration with red blood cell transfusion dependency, survival and transformation to acute myeloid leukemia. MATERIAL AND METHODS We retrospectively evaluated the data of the 819 MDS patients (58% male; median age 70 years) included in the MDS Registry of the MDS Section of the Polish Adult Leukemia Group (PALG). RESULTS Analyses were performed on 190 patients diagnosed with MDS, maximal 6 months before inclusion to the registry in order to avoid selection bias (a shorter survival of higher risk MDS patients). Patients with hyperferritinemia higher than 1000 ng/L vs. patients with SF concentration lower than 1000 ng/L had a median survival of 320 days vs. 568 days, respectively (p log-rank = 0.014). The following factors were found to significantly worsen survival: RBC-transfusion dependence (p = 0.0033; HR 2.67L), platelet transfusion dependence (p = 0.0071; HR 3.321), hemoglobin concentration lower than 10 g/dL (p = 0.0036; HR 2.97), SF concentration higher than 1000 ng/L (p = 0.0023; HR = 2.94), platelet count lower than 10 G/L (p = 0.0081 HR = 5.04), acute leukemia transformation (p = 0.0081; HR 1.968). CONCLUSIONS Taking into account the relatively low number of patients in previous studies exploring hyperferritinemia in MDS, the results of the first Polish MDS Registry provide important insights. Hyperferritinemia higher than 1000 ng/L can be an important indicator of poor prognosis in MDS.