Marek Hus

Production of Proangiogenic Cytokines During Thalidomide Treatment of Multiple Myeloma

Recently a growing number of studies have suggested the efficacy of thalidomide (THAL) in the treatment of relapsed or resistant multiple myeloma. Some of these studies indicate that the thalidomide antimyeloma effect is associated with decreased vessel density. Here we first present our experience with THAL treatment and then focus on the determination of the role of proangiogenic cytokines during THAL therapy. Thirty relapsing or resistant multiple myeloma (MM) patients were treated with THAL at a median dose of 400 mg/daily. Eighteen responded to THAL therapy and 12 were resistant or intolerant to THAL. We determined the plasma level of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) as the main biological parameters associated with tumour angiogenesis. In addition I1-6 and TNF α levels were also assayed. Assessment of peripheral blood (PB) and bone marrow (BM) cytokine levels were done before and during THAL treatment at weeks 4 and 8 of therapy. In the responder group VEGF, bFGF I1-6 and TNF α concentrations were significantly decreased after four weeks of therapy both in PB and BM. In the non-responder group no significant changes in bFGF and VEGF levels were observed. However, a significant increase in IL-6 and TNF concentrations was evident. We conclude that the significant decrease of VEGF, bFGF, I1-6 and TNF α concentrations reflected response to THAL therapy. Also it seems that VEGF is a better marker of response to treatment than bFGF.

Therapy-related peripheral neuropathy in multiple myeloma patients

This review discusses the most common issues concerning multiple myeloma (MM)‐related peripheral neuropathy (PN). This is an important MM complication, observed in up to 54% of newly diagnosed patients, caused by the disease itself or its treatment. Although its aetiology is largely unknown, a number of mechanisms are suspected. It is important to know the neurological status of a patient, as many new antimyeloma medicines can trigger or exacerbate any pre‐existing neuropathy. Examples include thalidomide‐induced and bortezomib‐induced PN (TiPN and BiTN, respectively), which are key MM treatment options. TiPN is usually sensory and sensorimotor, whereas BiPN is typically sensory. The mechanisms of chemotherapy‐induced neurotoxicity in MM are well known; thalidomide seems to induce PN through its antiangiogenic properties, whereas bortezomib neurotoxicity is connected with disrupted calcium homeostasis. TiPN incidence ranges from 25% to 75%, and its prevalence and severity appears to be dose‐dependent. BiPN incidence is almost 40% and is dose‐related as well. Poor (25%) reversibility of TiPN prompted the recommendations for dose and exposure reduction, whereas BiPN cases are mostly reversible (64%). Peripheral sensory neuropathy is very rare in patients receiving bendamustine monotherapy. Because of this favourable toxicity profile, bendamustine may be considered a promising option for combination therapies in pre‐existing PN in myeloma patients. Considering the lack of curative therapy for treatment‐emergent PN, prevention is a key management strategy in MM patients. All patients should be evaluated for PN before the administration of a neurotoxic drug, and those under treatment should be closely monitored by a neurologist. Copyright

Additional genetic abnormalities significantly worsen poor prognosis associated with 1q21 amplification in multiple myeloma patients

We investigated the prognostic value of amp(1q21) alone and in combination with other abnormalities in newly diagnosed myeloma patients. The study group consisted of 104 patients treated with various induction regimens, mostly thalidomide based (87 patients). Amp(1q21) was detected in 49 (47.1%) of patients; in 26 (25.0%) cases, it was combined with del(13q14), in 7 (6.7%) with del(17p13) and in 15 (14.4%) with t(4;14)(p16;q32). The response rate was significantly better in amp(1q21)‐negative than in amp(1q21)‐positive patients (74.5% vs 55.1%, p = 0.025; complete response 18.2% vs 4.1%, p = 0.024). The median progression‐free survival (PFS) was 33.9 months in patients without amp(1q21) and 10.3 months with this aberration (p = 0.002). The presence of additional abnormalities resulted in significantly shortened PFS when compared with patients with isolated amp(1q21): coexisting del(13q14) resulted in 7.8 vs 29.0 months of PFS (p = 0.024) and del(17p13) resulted in 4.0 vs 24.9 months of PFS (p = 0.034). The presence of amp(1q21) significantly influenced overall survival (OS) as well as PFS resulting in the median OS of 26.6 vs 62.4 months (p = 0.018) in patients without amp(1q21). The presence of additional genetic abnormalities significantly affected OS when compared with patients carrying isolated amp(1q21): for del(13q14) 18.9 vs 58.4 months (p = 0.004) and for del(17p13) 12.0 vs 46.5 months (p = 0.036). On multivariate analysis amp(1q21), del(13q14) and del(17p13) were found to be an independent adverse predictors of shorter PFS and OS. Our results showed that the presence of amp(1q21) was associated with poor prognosis. Moreover additional genetic abnormalities made PFS and OS further shortened. Copyright

Thalidomide, dexamethasone and lovastatin with autologous stem cell transplantation as a salvage immunomodulatory therapy in patients with relapsed and refractory multiple myeloma

The treatment of patients with multiple myeloma usually includes many drugs including thalidomide, lenalidomide and bortezomib. Lovastatin and other inhibitors of HMG-CoA reductase demonstrated to exhibit antineoplasmatic and proapoptotic properties in numerous in vitro studies involving myeloma cell lines. We treated 91 patients with relapsed or refractory multiple myeloma with thalidomide, dexamethasone and lovastatin (TDL group, 49 patients) or thalidomide and dexamethasone (TD group, 42 patients). A clinical response defined of at least 50% reduction of monoclonal band has been observed in 32% of TD patients and 44% of TDL patients. Prolongation of overall survival and progression-free survival in the TDL group as compared with the TD group has been documented. The TDL regimen was safe and well tolerated. The incidence of side effects was comparable in both groups. Plasma cells have been cultured in vitro with thalidomide and lovastatin to assess the impact of both drugs on the apoptosis rate of plasma cells. In vitro experiments revealed that the combination of thalidomide and lovastatin induced higher apoptosis rate than apoptosis induced by each drug alone. Our results suggest that the addition of lovastatin to the TD regimen may improve the response rate in patients with relapsed or refractory myeloma.

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

Assessment of red blood cell distribution width as a prognostic marker in chronic lymphocytic leukemia

Red blood cell distribution width (RDW) is a quantitative measure of the variability in size of circulating erythrocytes. It was recently reported that RDW is a prognostic factor for infection diseases, cardiovascular and pulmonary diseases, as well as some neoplasms. Moreover, RDW is remarkably strong predictor of longevity, including all causes of death, for adults aged 45 years and older. To explain this occurrence it was proposed that persistent IGFs/mTOR signaling is one of the factors that play a role in affecting the RDW and mortality. The above observations induced us to analyze the prognostic role of RDW in chronic lymphocytic leukemia (CLL) being the most frequent type of adult leukemia in Western countries. The obtained results have shown that RDW may be considered as a potential CLL prognostic marker. Elevated RDW level at the moment of diagnosis was associated with advanced disease and presence of other poor prognostic factors. It is also connected with overall survival indicating shorter time in patients with elevated RDW. It is possible that the presently observed correlation between mortality and RDW of the CLL patients is affected by their metabolic (IGF-1/mTOR driven)- rather than chronological- aging. The patients with high level of RDW are expected to have an increased persistent level of IGF-1/mTOR signaling. Within the framework of personalized therapy, these CLL patients therefore would be expected to be more sensitive to the treatment with mTOR inhibitors.

Changes in T-cell subpopulations and cytokine network during early period of ibrutinib therapy in chronic lymphocytic leukemia patients: the significant decrease in T regulatory cells number

B cell receptor (BCR) stimulation signal plays an important role in the pathogenesis of chronic lymphocytic leukemia (CLL), and kinase inhibitors directed toward the BCR pathway are now the promising anti-leukemic drugs. Ibrutinib, a Bruton tyrosine kinase inhibitor, demonstrates promising clinical activity in CLL. It is reported that ibrutinib, additionally to directly targeting leukemic cells, also inhibits the interactions of these cells with T cells, macrophages and accessory cells. Assessment of these mechanisms is important because of their non -direct anti-leukemic effects and to identify possible side effects connected with long-term drug administration. The aim of this study was to assess the in vivo effects of ibrutinib on T-cell subpopulations and cytokine network in CLL. The analysis was performed on a group of 19 patients during first month of ibrutinib therapy. The standard multicolor flow cytometry and cytometric bead array methods were used for assessment of T-cell subsets and cytokines/chemokines, respectively. The data obtained indicates that Ibrutinib treatment results in changes in T-cell subpopulations and cytokine network in CLL patients. Particularly, a significant reduction of T regulatory cells in peripheral blood was observed. By targeting these populations of T cells Ibrutinib can stimulate rejection of tumor cells by the immune system.

Efficacy and toxicity of compassionate ibrutinib use in relapsed/refractory chronic lymphocytic leukemia in Poland: analysis of the Polish Adult Leukemia Group (PALG)

El_ zbieta Iskierka-Ja_ zd_ zewska, Marek Hus, Krzysztof Giannopoulos, El_ zbieta Mądro, Jadwiga Hołojda, Magdalena Piotrowska, Jan M. Zaucha, Weronika Piszczek, Agnieszka Szeremet, Małgorzata Wojciechowska, Paweł Steckiewicz, Wanda Knopi nska-Posłuszny, Marek Osowiecki, Joanna Drozd-Sokołowska, Beata Kumiega, Sławomira Kyrcz-Krzemie n, Janusz Hałka, Marek Dudzi nski, Paulina Wieszczy, Tadeusz Robak, Krzysztof Warzocha and Krzysztof Jamroziak Department of Hematology, Medical University of Lodz, Copernicus Memorial Hospital, Lodz, Poland; Department of Haematooncology and Bone Marrow Transplantation, Medical University of Lublin, Lublin, Poland; Experimental Hematooncology Department, Medical University of Lublin & Hematology Department, St. Johns Cancer Center, Lublin, Poland; Department of Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland; Department of Hematology, Specialist District Hospital, Legnica, Poland; Department of Hematology, Cracow University Hospital, Cracow, Poland; Department of Oncological Propaedeutics, Medical University of Gdansk, Gdansk, Poland & Gdynia Oncology Center, Gdynia, Poland; Department of Hematology, Copernicus Hospital, Torun, Poland; Department of Hematology, Blood Neoplasms and Bone Marrow Transplantation, Wroclaw Medical University, Wroclaw, Poland; Department of Hematology, Specialist District Hospital, Olsztyn, Poland; Department of Hematology, Holycross Cancer Center, Kielce, Poland; Department of Hematology, Independent Public Health Care of the Ministry of the Internal Affairs with the Oncology Centre, Olsztyn, Poland; Department of Lymphoid Malignancies, Maria Sklodowska-Curie Memorial Institute and Oncology Centre, Warsaw, Poland; Department of Hematology, Oncology and Internal Diseases, Medical University of Warsaw, Warsaw, Poland; Department of Haematooncology, Oncology Centre of the Podkarpackie Province, Brzozow, Poland; Department of Hematology and Bone Marrow Transplantation, Silesian Medical University Hospital SPSKM, Katowice, Poland; Department of Hematology, Military Institute of Medicine, Warsaw, Poland; Department of Hematology, Specialist District Hospital, Rzeszow, Poland; Department of Gastroenterology, Hepatology and Clinical Oncology, Medical Center for Postgraduate Education, Warsaw, Poland

New drugs in multiple myeloma – role of carfilzomib and pomalidomide

Carfilzomib (CFZ), an epoxyketone with specific chymotrypsin-like activity, is a second-generation proteasome inhibitor with significant activity in patients with relapsed and refractory multiple myeloma. On July 20, 2012, the US Food and Drug Administration approved CFZ to treat patients with multiple myeloma who have received at least two prior therapies including bortezomib (BORT) and an immunomodulatory agent and have demonstrated disease progression on or within 60 days of completion of the last therapy. Cytogenetic abnormalities did not appear to have a significant impact on the CFZ activity. Carfilzomib was well tolerated and demonstrated promising efficacy in patients with renal insufficiency. Pomalidomide (POM) (CC-4047) is a novel immunomodulatory derivative (IMID) with a stronger in vitro anti-myeloma effect compared with “older” IMIDs – thalidomide and lenalidomide (LEN). On February 8, 2013, the US Food and Drug Administration approved POM (Pomalyst, Celgene) for the treatment of MM patients who have received at least two prior therapies including LEN and BORT and have demonstrated progression on or within 60 days of completion of the last therapy. Pomalidomide is a novel IMID with significant anti-myeloma activity and manageable toxicity. This compound has shown high efficacy in MM patients who were resistant to prior use of LEN/BORT as well as in patients with a high-risk cytogenetic profile. Carfilzomib and POM have very high efficacy and will be used also in first line therapy in future.

1q21 amplification with additional genetic abnormalities but not isolated 1q21 gain is a negative prognostic factor in newly diagnosed patients with multiple myeloma treated with thalidomide-based regimens

In this study we assessed the prognostic value of amp(1q21) alone and in combination with del(17p13), del(13q14) and t(4,14)(p16;q32) detected by fl uorescence in situ hybridization(FISH) in newly diagnosed patients with MM treated with thalidomide-based induction regimens. Th e primary endpoints were response rate after fi rst-line therapy, PFS and OS.