Jaroslaw Piszcz

The efficacy and safety of the low-thalidomide dose CTD (cyclophosphamide, thalidomide, dexamethasone) regimen in patients with multiple myeloma--a report by the Polish Myeloma Study Group.

Multiple myeloma (MM) remains an incurable disease, but response rates to new drugs are promising, offering the majority of patients a significant prolongation of overall survival. The objective of this study was to evaluate time to progression (TTP), event-free survival (EFS), and overall survival (OS) in MM patients treated with a combination of cyclophosphamide (CY), thalidomide (THAL) and dexamethasone (DEX). This study included 132 untreated and relapsing/resistant patients treated with the low-thalidomide dose CTD regimen. The patients received CY 500 mg/m(2)i.v. or 625 mg/m(2) orally at day 1, THAL 100mg/day á la longue and DEX 20mg/day at days 1-4 and 8-11, every 28 days. Patients received 6-9 cycles; ORR by 3 months was 59.1%, by 6 months 65.6% and by 9 months 75.6%. In patients responding to CTD therapy (CR, nCR, PR), the probability of survival for 20 months was 89.3%. The outpatient low-thalidomide dose CTD regimen is well tolerated and produces a significant response rate both in untreated and relapsing/resistant MM patients.

Platelet-related fibrinolysis resistance in patients suffering from PV. Impact of clot retraction and isovolemic erythrocytapheresis

Using patients with polycythemia vera (PV) as an experimental model, we evaluated the impact of clot retraction (CR) and architecture of the clot on fibrinolysis. We studied the kinetics of clot retraction and the fibrinolysis rate in whole blood from 48 PV patients and 48 healthy controls. Measurements were performed before and after isovolemic eryhrocytapheresis (ECP). CR was measured by optical method. Clot lysis time (CLT) and maximum clot firmness (MCF) were measured by thromboelastometry in recalcified blood supplemented with t-PA and tissue factor. Compared with healthy controls, CR rate in PV patients was higher (0.0219 vs. 0.0138; p<0.001), the clot volume smaller and MCF elevated (64 vs. 58 mm). CR rate correlated with platelet count (r=0.546; p=0.001) but not with erythrocyte concentration (r=0.192; p>0.3). Compared with healthy controls, CLT in PV patients was significantly prolonged (158 min vs. 71 min). Fibrinolysis rate inversely correlated with CR rate (r=-0.566; p<0.001); MCF (r=-0.704; p<0.001) and platelet count (r=-0.461; p<0.001). As judged by confocal microscope, in comparison to healthy controls, clots formed in blood from PV patients demonstrated booth a distinctly higher degree of crosslinking and possessed thinner fibers. Altered CR, MCF and fibrinolysis speeds were not normalized following the ECP procedure. Tirofiban (a blocker of platelet GPIIb/IIIa receptors), unlike aspirin, normalized abnormal CR and fibrinolysis in blood from PV patients. Collectively, our data indicate that in PV patients, abnormal CR may result in formation of thrombi that are more resistant to fibrinolysis. ECP and aspirin failed to normalize platelet-related fibrinolysis resistance.

Clinical characteristics of patients with chronic eosinophilic leukaemia (CEL) harbouring FIP1L1-PDGFRA fusion transcript--results of Polish multicentre study.

A small subgroup of patients with hypereosinophilic syndrome (HES) demonstrates imatinib‐sensitive fusion transcript—the FIP1L1‐PDGFRA (F/P+). These cases are currently diagnosed as chronic eosinophilic leukaemia (CEL). In this paper, we screened 77 patients to estimate the frequency of FIP1L1‐PDGFRA transcript among patients with unexplained, long‐term hypereosinophilia exceeding 1.5 × 109/L and to analyse the clinical and serological features in F/P+ CEL population. The FIP1L1‐PDGFRA chimeric protein was detectable in 16 (14 males and 2 females) out of 77 examined HES patients (20%) by RT‐PCR. Two patients suffered from cough at diagnosis. Three out of 16 (18%) patients had no organ involvements, in 5‐one organ was affected and in the remaining eight cases—at least two. Eosinophilic organ damage/dysfunction identified splenomegaly in the majority of studied patients. We compared clinical and serological features between CEL F/P+ (n = 16) and HES (n = 61) patients. F/P+ cases had significantly increased WBC and absolute eosinophil count (AEC) at diagnosis (p = 0.008 and 0.02), whereas platelet count was decreased in this population (p = 0.03). Serum B12 and tryptase levels were increased (p = 0.002 and 0.004) in CEL F/P+ patients when compared to HES cases whereas serum IL‐5 levels were significantly increased in the latter group (p = 0.01). Male gender and splenomegaly occurred more frequent in CEL F/P+ population (p = 0.002 and 0.0007, respectively). Additionally, patients with F/P+ CEL (n = 16) were compared with F/P− CEL (n = 8). The latter group, was significantly older, had lower AEC and higher platelet count. In conclusion, significant clinical symptoms are infrequent present and splenomegaly remains the most common organ involvement in patients with CEL expressing F/P fusion transcript. Our study confirmed the long‐term remission on imatinib in this patient population. Copyright

To treat or not to treat: metabolomics reveals biomarkers for treatment indication in chronic lymphocytic leukaemia patients

In chronic lymphocytic leukaemia (CLL), the clinical course of patients is heterogeneous. Some present an aggressive disease onset and require immediate therapy, while others remain without treatment for years. Current disease staging systems developed by Rai and Binet may be useful in forecasting patient survival time, but do not discriminate between stable and progressive forms of the disease in the early stages. Recently ample attention has been directed towards identifying new disease prognostic markers capable of predicting clinical aggressiveness at diagnosis. In the present study serum samples from stable (n = 51) and progressive (n = 42) CLL patients and controls (n = 45) were used with aim to discover metabolic indicators of disease status. First an LC-MS based metabolic fingerprinting method was used to analyse selected samples in order to find a potential markers discriminating aggressive from indolent patients. Ten of these discovered markers were validated on the whole set of samples with an independent analytical technique. Linoleamide (p = 0.002) in addition to various acylcarnitines (p = 0.001–0.000001) showed to be significant markers of CLL in its aggressive form. Acetylcarnitine (p = 0.05) and hexannoylcarnitine (p = 0.005) were also distinguishable markers of indolent subjects. Forming a panel of selected acylcarnitines and fatty acid amides, it was possible to reach a potentially highly specific and sensitive diagnostic approach (AUC = 0.766).

Addition of cladribine to the standard induction treatment improves outcomes in a subset of elderly AML patients. Results of a randomized Polish Adult Leukemia Group (PALG) phase II trial

Intensive induction chemotherapy using anthracycline and cytarabine backbone is considered the most effective upfront therapy in physically fit older patients with acute myeloid leukemia (AML). However, outcomes of the standard induction in elderly AML are inferior to those observed in younger patients, and they are still unsatisfactory. As addition of cladribine to the standard induction therapy is known to improve outcome in younger AML patients. The present randomized phase II study compares efficacy and toxicity of the DAC (daunorubicin plus cytarabine plus cladribine) regimen with the standard DA (daunorubicin plus cytarabine) regimen in the newly diagnosed AML patients over 60 years of age. A total of 171 patients were enrolled in the study (DA, 86; DAC, 85). A trend toward higher complete remission (CR) was observed in the DAC arm compared to the DA arm (44% vs. 34%; P = .19), which did not lead to improved median overall survival, which in the case of the DAC group was 8.6 months compared to in 9.1 months in the DA group (P = .64). However, DAC appeared to be superior in the group of patients aged 60‐65 (CR rate: DAC 51% vs. DA 29%; P = .02). What is more, a subgroup of patients, with good and intermediate karyotypes, benefited from addition of cladribine also in terms of overall survival (P = .02). No differences in hematological and nonhematological toxicity between the DA and DAC regimens were observed.

Nitric oxide scavenging by cell-free hemoglobin may be a primary factor determining hypertension in polycythemic patients

Abstract We tested the hypothesis that hypertension associated with polycythemia vera (PV) may be related to hemoglobin released from erythrocytes (cell-free hemoglobin, fHb). We assessed hematocrit, mean arterial pressure (MAP), blood viscosity, and the level of fHb and nitrite/nitrate (NOx) in the plasma of 73 PV patients and 38 healthy controls. The effect of isovolemic erythrocytapheresis (ECP) on the considered parameters was also studied. From the whole group of PV patients a subset of subjects with normal (normotensive patients, n = 16) and elevated MAP (hypertensive patients, n = 57) can be subtracted. It was found that in comparison with healthy controls, PV patients have significantly (p ≤ 0.01) elevated Hct (0.567 vs. 0.422), blood viscosity (5.45 vs. 3.56 cP), MAP (106.8 vs. 93.8 mmHg), plasma fHb (9.7 vs. 2.8 mg/dL), and NOx levels (34.1 vs. 27.5 μM). Compared with normotensive patients, hypertensive PV patients demonstrated a higher rise in fHb (10.2 vs. 8.0) and plasma NOx levels (35.8 vs. 31.0). In PV patients, fHb positively correlates with MAP (r = 0.489), NOx levels (r = 0.461), hematocrit (r = 0.428), and viscosity (r = 0.393). Blood viscosity positively correlated with hematocrit (r = 0.894), but not with other considered parameters. In PV patients MAP poorly correlated with hematocrit, whereas the correlation between MAP and NOx altered from − 0.325 (healthy control) to + 0.268 (PV patients). ECP procedure was associated with a significant (p < 0.01) reduction of hematocrit, fHb, blood viscosity, and MAP. In the normotensive subgroup of PV patients the ECP procedure did not affect MAP. It can be concluded that accelerated scavenging of nitric oxide by fHb rather than high Hct may be a key factor determining the development of hypertension in PV patients.

Differences and similarities between LC-MS derived serum fingerprints of patients with B-cell malignancies.

Multiple myeloma (MM) and chronic lymphocytic leukaemia (CLL) are closely related B‐cell non‐Hodgkins lymphomas. MM, a plasma cell malignancy, is the second most common haematopoietic cancer in Western countries, with the median survival time of 3–4 years. CLL, a lymphocyte B malignancy, is the most common leukaemia in Western countries. About 25–30% of all CLL patients do not survive the period of 5 years following diagnosis. Both malignancies are complicated, not fully understood and incurable with the current standard treatment. Biologically, MM and CLL may be preceded by associated precursor conditions, that is, monoclonal gammopathy of undetermined significance for MM and its cellular counterpart and monoclonal B‐cell lymphocytosis for CLL. Similarities and differences in the biology of these malignancies prompted us to evaluate their metabolomics in stages requiring chemotherapy. Fingerprinting of serum metabolites by the use of LC‐MS has never been applied in studies on MM and CLL patients. Obtained results revealed metabolites common for both malignancies (e.g. fatty acids, acylcarnitines, sphingolipids, phospholipids, phenylalanylphenylalanine and isoprene) as well as those which render them different (e.g. lysophosphatidylcholines, monoacylglycerols, aminocaproic acid, phenylacetylglutamine).

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.

Thrombocytopenia and perioperative complications after stentless Freedom Solo valve implantation.

BACKGROUND Freedom Solo (FS) stentless bioprostheses have superior haemodynamic performance compared to stented valves; however, the data of thrombocytopenia after FS implantations is disturbing. AIM To compare platelet count and perioperative complications between stentless and stented biological valves in patients undergoing aortic valve replacement. METHODS In 29 patients, FS bovine valves (Sorin Group, Saluggia, Italy) were implanted. Platelet counts were analysed before surgery, on the day of operation, on four consecutive postoperative days (POD) as well as at discharge, and compared to 29 control patients with biological stented porcine valves (Labcor Laboratorios TLBP-A Supra). The analysis of the perioperative variables extracorporeal circulation (ECC), aortic cross clamping (XC) and mechanical ventilation times, as well as blood supply, was performed. RESULTS Initial platelet counts were comparable in both groups. In the FS group, platelet levels on the four consecutive POD were significantly lower. The lowest platelet value (13 × 10³/μL), related to fatal thrombotic thrombocytopenic purpura, was found in one patient from the FS group. ECC as well as XC and mechanical ventilation times, were significantly longer in the FS group, and more blood transfusions in these patients were required. In multiple regression analysis, ECC and XC times did not correlate with platelet count. CONCLUSIONS Implantations of FS stentless bioprostheses are related to significantly lower platelet counts. Severe perioperative complications and their relation to thrombocytopenia need further evaluation.

Secondary acute lymphoblastic leukaemia in a multiple myeloma patient

Secondary acute leukaemia (s-ALL) is a destructive complication in patients who have been previously treated for other cancer. Secondary acute lymphoblastic leukaemia is rarely reported whereas secondary acute myeloid leukaemia is much more common. Chromosomal 11q23 abnormality, frequently detected in therapy-related acute myeloid leukaemia, is the most common cytogenetic alteration in secondary ALL too. However, s-ALL cases without 11q23 abnormality have rarely been described. Furthermore, there are only a few published medical reports describing occurrence of acute lymphoblastic leukaemia in multiple myeloma (MM) patients. We would like to present our experience with a patient with MM, who developed ALL without 11q23 abnormality, nine years after alkylating-agent containing treatment. The course of the disease was complicated by thrombosis that obstructed the possibility of effective treatment. In conclusion, it should be kept in mind that the development of a more aggressive neoplasm related to chemotherapy treatment as well as the inherent genetic instability of normal and abnormal lymphoid progenitors may affect overall survival of an indolent lymphoma patient.