Jerzy Wojnar

Imatinib therapy prior to myeloablative allogeneic stem cell transplantation

Summary:It is unknown whether imatinib prior to myeloablative haematopoietic stem cell transplantation (HSCT) increases transplant-related toxicity. Among the side effects induced by imatinib, myelosuppression and liver injury might worsen HSCT outcomes. We retrospectively analysed engraftment, liver toxicity, acute graft-versus-host disease (aGVHD) incidence and 100-day mortality in 30 patients with BCR/ABL-positive leukaemias who received imatinib before HSCT and compared results of 48 age-matched controls who did not receive preceding imatinib. Both neutrophil and platelet engraftment occurred more rapidly among imatinib patients but the differences adjusted for Gratwohl scale were not statistically significant (P=0.18 and 0.22, respectively). The adjusted hazards of having liver function tests (LFTs) >1.5 normal increased and the adjusted durations of elevated LFTs were not significantly different. The estimated adjusted difference in mean peak bilirubin values was also not significantly different (P=0.48). However, the adjusted hazard of increased creatinine >1.5 normal was significantly higher in the imatinib group (HR=4.09, P=0.02). The adjusted odds of grades II–IV aGVHD were similar in both groups (OR=0.86, P=0.78), and while the adjusted odds of 100-day mortality were lower among imatinib patients, the difference was not significant (OR=0.65, P=0.60). These data do not provide any evidence that imatinib preceding HSCT increases acute transplant-related toxicities.

Homozygosity for human leucocyte antigen-C ligands of KIR2DL1 is associated with increased risk of relapse after human leucocyte antigen-C-matched unrelated donor haematopoietic stem cell transplantation.

Human leucocyte antigen (HLA)‐C molecules regulate the function of natural killer cells and may be subdivided into two groups, C(1) and C(2), based on their specificity for inhibitory killer immunoglobulin‐like receptors. We analysed the impact of the HLA‐C genotype on outcome of HLA‐C‐matched unrelated donor haematopoietic stem cell transplantation (URD‐HSCT) recipients. HLA‐C(2) homozygous patients (n = 18) had lower probability of overall survival (P = 0·01) and disease‐free survival (P = 0·02), resulting from increased relapse rate (P = 0·02) when compared with both HLA‐C(1) homozygous (n = 43) and HLA‐C(1),C(2) heterozygous (n = 50) subgroups. Patients lacking HLA‐C(1) should, therefore, be considered at increased risk of relapse following HLA‐C‐matched URD‐HSCT.

Activating killer immunoglobulin-like receptor incompatibilities enhance graft-versus-host disease and affect survival after allogeneic hematopoietic stem cell transplantation.

Objectives:  Killer immunoglobulin‐like receptors (KIRs) regulate function of natural killer (NK) cells and a subset of T cells. In this study, we prospectively evaluated the impact of donor and recipient activating KIR genes on outcome of allogeneic hematopoietic stem cell transplantation (alloHSCT) for patients with hematological malignancies.

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.

Treosulfan and fludarabine low-toxicity conditioning for allogeneic haematopoietic stem cell transplantation in chronic myeloid leukaemia

Allogeneic haematopoietic stem cell transplantation (alloHSCT) is the only treatment of proven long‐term efficacy in chronic myeloid leukaemia (CML), although high non‐relapse mortality (NRM) observed after conventional myeloablative conditioning limits its applicability. This phase II trial evaluated the efficacy and toxicity of a new preparative regimen consisting of treosulfan 3 × 14 g/m2 and fludarabine 5 × 30 mg/m2, in patients with CML in chronic phase. Among the 40 patients included, 18 received alloHSCT from a sibling and 22 from an unrelated donor. All patients engrafted with 92·5% of cases achieving complete donor chimaerism by day +100. All but one patient had achieved complete cytogenetic remission on day +100. Grade III or IV non‐haematological toxicities included: neutropenic fever (10%), nausea/vomiting (10%), elevated liver enzymes (5%) and infection (2·5%). The incidence of grade II–IV acute graft‐versus‐host disease (GVHD) was 22·5% and extensive chronic GVHD, 14%. The 2‐year probability of overall survival, leukaemia‐free survival and NRM was 85%, 82·5% and 15% respectively. At 1 year post‐transplant, 85% of survivors had a Karnofsky index of 100%. We concluded that treosulfan and fludarabine conditioning is a low‐toxicity regimen with high anti‐leukaemic potential that seems feasible in CML patients referred for alloHSCT.

Outcome of HLA-matched related allogeneic hematopoietic stem cell transplantation for patients with acute leukemia in first complete remission treated in Eastern European centers. Better results in recent years

The goal of this study was to analyze results and to determine factors affecting outcome of HLA-matched hematopoetic stem cells transplantation (MRD-HSCT) for patients with acute leukemia transplanted in first complete remission in Eastern European countries. Six hundred forty HSCT were performed between 1990 and 2006 for adults with acute myeloid (n = 459) and lymphoblastic (n = 181) leukemia. Two-year leukemia-free survival (LFS), nonrelapse mortality (NRM), and relapse incidence were 58 ± 2%, 19 ± 2%, and 23 ± 2%, respectively. The cumulative incidence of NRM decreased from 22 ± 2% for patients treated between 1990 and 2002 to 15 ± 3% for transplantations performed between 2003 and 2006 (p = 0.02), despite increasing recipient age. In a multivariate analysis, time of HSCT affected both NRM and LFS. Among other prognostic factors, the use of TBI decreased relapse incidence and increased the LFS rate. We conclude that results of MRD-HSCT for acute leukemia in Eastern Europe improved over time as a consequence of decreased NRM. The use of TBI containing regimens appears advantagous.

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

Sequential recovery of NK cell receptor repertoire after allogeneic hematopoietic SCT

Alloreactivity of natural killer (NK) cells contributes to the GVL reaction after allogeneic hematopoietic SCT (allo-HSCT). However, various procedure-related factors may affect NK cell maturation and their ability to recognize and kill leukemic cells. In this study, we prospectively evaluated expression of NK cell inhibitory receptors in 83 adults treated with myeloablative, killer cell Ig-like receptor (KIR)-ligand-matched allo-HSCT. NK cell maturation was evaluated by comparing the phenotypic patterns after allo-HSCT with the donor ones. The frequencies of KIR3DL1 were comparable to the donor ones on day +28, while they decreased significantly starting from day +100. The expression of KIR2DL2/3 was significantly lower in patients compared with donors up to day +100. The expression of KIR2DL1, despite continues growth, remained significantly decreased for 1 year after allo-HSCT. NKG2A was over-expressed up to day +180. Within 1 year after allo-HSCT, the NK cell phenotypic pattern tended to recapitulate the donor type. The process was disturbed by the use of steroids with significant differences observed on days +56 (P=0.01) and +100 (P=0.04). Up to day +100, reconstitution of NK cell receptor repertoire correlated with the absolute numbers of circulating CD3+, CD3+CD4+ and CD3+CD8+ cells. Our observations should be taken into account when trying to predict potential benefit from NK cell alloreactivity.

Galectin Targeted Therapy in Oncology: Current Knowledge and Perspectives

The incidence and mortality of cancer have increased over the past decades. Significant progress has been made in understanding the underpinnings of this disease and developing therapies. Despite this, cancer still remains a major therapeutic challenge. Current therapeutic research has targeted several aspects of the disease such as cancer development, growth, angiogenesis and metastases. Many molecular and cellular mechanisms remain unknown and current therapies have so far failed to meet their intended potential. Recent studies show that glycans, especially oligosaccharide chains, may play a role in carcinogenesis as recognition patterns for galectins. Galectins are members of the lectin family, which show high affinity for β-galactosides. The galectin–glycan conjugate plays a fundamental role in metastasis, angiogenesis, tumor immunity, proliferation and apoptosis. Galectins’ action is mediated by a structure containing at least one carbohydrate recognition domain (CRD). The potential prognostic value of galectins has been described in several neoplasms and helps clinicians predict disease outcome and determine therapeutic interventions. Currently, new therapeutic strategies involve the use of inhibitors such as competitive carbohydrates, small non-carbohydrate binding molecules and antibodies. This review outlines our current knowledge regarding the mechanism of action and potential therapy implications of galectins in cancer.

The role of inflammation in colon cancer pathogenesis

The results of the latest research more and more bind development of neoplasms with the chronic inflammation. Inflammatory process creates microenvironment promoting development of neoplasms; as a result, malignant process start to develop in places, where chronic inflammation proceeds or regeneration of tissues takes place. Inflammatory cells not only create suitable microenvironment for development of neoplasms, but also excrete number of cytokines and growth factors promoting survival of a neoplasmatic cell and avoiding its apoptosis, promoting neoangiogenesis and metastases formation. Moreover, cytokines and other pro-inflammatory factors modulate expression of genes important in cancerogenesis, they also activate NFκB-dependent signaling pathways, which favor neoplasmatic cells to avoid apoptosis. On the other hand, oxidative stress accompanying chronic inflammation may promote mutagenesis, enabling that way the neoplasm development. The same cells and metabolic pathways are engaged in inflammatory and neoplasmatic processes, and development of cancer may be a consequence of loss of control over tissue regeneration during resolution of chronic inflammation. The role of most important cells and metabolic pathways in inflammatory process, which may lead to colon cancer, was discussed in this paper.