Skuteczność terapii ruksolitynibem u pacjentki z mielofibrozą wtórną do czerwienicy prawdziwej

Przedstawiono przypadek 67-letniej kobiety, u której w 2004 roku rozpoznano czerwienicę prawdziwą, w 2011 roku pojawiły się objawy niedokrwistości hemolitycznej, a w 2016 roku stwierdzono transformację do mielofibrozy. W początkowym okresie rozpoznania czerwienicy prawdziwej (PV) pacjentkę leczono hydroksymocznikiem (HU). Od czasu wystąpienia niedokrwistości hemolitycznej, po odstawieniu HU, otrzymała prednizon i azatioprynę. Dzięki temu leczeniu uzyskano stabilne stężenie hemoglobiny (Hb 8–10 g/dl); pacjentka nie wymagała substytucji koncentratu krwinek czerwonych. Po 12 latach od rozpoznania PV, na podstawie badania patomorfologicznego szpiku kostnego, rozpoznano wtórną mielofibrozę (post-PV MF). W kolejnym 2017 roku, dzięki uzyskaniu dostępu do leku, rozpoczęto terapię ruksolitynibem. Terapię prowadzono łącznie z dalszym leczeniem niedokrwistości hemolitycznej (prednizon, azatiopryna). Stosując to skojarzone leczenie, udało się utrzymać stabilne stężenie Hb; ze względu na ograniczenie nasilenia hemolizy możliwe było zmniejszenie dawki prednizonu. W wyniku trwającej 6 miesięcy terapii uzyskano istotną poprawę jakości życia pacjentki, poprawę parametrów morfologii i zmniejszenie wielkości śledziony. Terapia ruksolitynibem jest prowadzona w pełnej dawce. Przypadek ten ukazuje, że ruksolitynib, mimo swej znanej toksyczności hematologicznej, może być lekiem skutecznym i bezpiecznym u pacjentów z wtórną MF i towarzyszącą hemolizą

ICOS gene polymorphisms in B-cell chronic lymphocytic leukemia in the Polish population

There is strong evidence that altered immunological function entails an increased risk of B-cell chronic lymphocytic leukemia (B-CLL). The main mechanism of an anti-tumor response depends on T-cell activation. Unlike the constitutively expressed CD28, inducible costimulatory molecule (ICOS) is expressed on the T-cell surface after activation. ICOS enhances all the basic T-cell responses to a foreign antigen, namely proliferation, secretion of lymphokines, the upregulation of molecules that mediate cell-cell interaction, and effective help for antibody secretion by B cells. ICOS is essential for both efficient interaction between T and B cells and normal antibody responses to T cell-dependent antigens. It does not upregulate the production of interleukin-2, but superinduces the synthesis of interleukin-10. Our previous results indicated the ICOS gene has a role as a susceptibility locus to B-CLL. Therefore an extended study was undertaken to evaluate the association between four ICOS polymorphisms (which were recently described as functional ones) and susceptibility to B-CLL in the Polish population. A case-control study of 296 individuals, including 146 B-CLL patients, was conducted on four polymorphisms in the ICOS gene. Genotyping of the polymorphisms ICOS ISV1+173T>C (rs10932029), ICOSc.1624C>T (rs10932037), ICOSc.2373G>C (rs4675379), and ICOSc.602A>C (rs10183087) was carried out using allelic discrimination methods with the TaqMan® SNP Genotyping Assay. There were no statistically significant differences in the allele, genotype, or haplotype distributions between B-CLL patients and healthy controls for any of the investigated polymorphic markers in the ICOS gene. However, we noted that patients carrying genotype ICOS ISV1+173T>C [TT], ICOSc.602A>C [AA], ICOSc.1624C>T [CC], and ICOSc.2373G>C [GG] have a decreased frequency of progression to a higher Rai stage during 60-month follow-up (21.35% vs. 40.8%, p = 0.013) compared to other individuals. This indicates that the investigated polymorphisms do not modulate the risk of B-CLL in the Polish population, but are associated with disease dynamics, in particular with the time to Rai stage progression. (Folia Histochemica et Cytobiologica 2011; Vol. 49, No. 1, pp. 49–54

Rekomendacje PALG dotyczące diagnostyki i leczenia przewlekłej białaczki szpikowej w 2013 r.

Tyrosine kinase inhibitors (TKIs) have dramatically improved the results of therapy of chronic myeloid leukemia. However the management with more potent second generation TKIs (2GTKIs) is required for imatinib-intolerant and imatinib-resistant patients. The frontline use of 2GTKIs results in higher rates of deeper and faster responses than with imatinib, it can enable many patients to qualify for participation in studies of treatment-free remission. The BCR/ABL transcript level at 3 months of TKI treatment has become a new prognostic factor. In this paper the recent clinical results of chronic myeloid leukemia therapy with imatinib in first line and with 2GTKIs in first and second line settings are reviewed, and updated PALG recommendations regarding the diagnosis, standard monitoring procedures, definitions of responses and treatment are presented

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

Variations in Suppressor Molecule CTLA-4 Gene Are Related to Susceptibility to Multiple Myeloma in a Polish Population

Various phenotype and functional T-cell abnormalities are observed in multiple myeloma (MM) patients. The aim of this study was to investigate the association between polymorphisms in the gene encoding cytotoxic T-lymphocyte antigen-4 (CTLA-4), a negative regulator of the T-lymphocyte immune response and susceptibility to multiple myeloma in a Polish population. Two hundred MM patients and 380 healthy subjects were genotyped for the following polymorphisms: CTLA-4c.49A>G, CTLA-4g.319C>T, CTLA-4g.*642AT(8_33), CT60 (CTLA-4g.*6230G>A), Jo31 (CTLA-4g.*10223G>T). Our study is the largest and most comprehensive evaluation to date of the association between genetic polymorphisms in the CTLA-4 molecule and multiple myeloma. It was found that CTLA-4c.49A>G[G], CT60[G], and Jo31[G] alleles were more frequently observed in MM patients than in controls (0.50 vs. 0.44, p = 0.03, 0.65 vs. 0.58, p = 0.04, and 0.63 vs. 0.57, p = 0.03, respectively). Moreover, the haplotype CTLA-4c.49A>G[G], CTLA-4g.319C>T[C], CTLA-4g.*642AT(8_33) [8], CT60[G], Jo31[G] including all susceptibility alleles increases the risk of MM about fourfold (OR: 3.79, 95%CI: 2.08–6.89, p = 0.00001). These findings indicate that genetic variations in the CTLA-4 gene play role in susceptibility to multiple myeloma and warrant further investigation through replication studies

Multiple Myeloma Treatment in Real-world Clinical Practice : Results of a Prospective, Multinational, Noninterventional Study

Funding Information: The authors would like to thank all patients and their families and all the EMMOS investigators for their valuable contributions to the study. The authors would like to acknowledge Robert Olie for his significant contribution to the EMMOS study. Writing support during the development of our report was provided by Laura Mulcahy and Catherine Crookes of FireKite, an Ashfield company, a part of UDG Healthcare plc, which was funded by Millennium Pharmaceuticals, Inc, and Janssen Global Services, LLC. The EMMOS study was supported by research funding from Janssen Pharmaceutical NV and Millennium Pharmaceuticals, Inc. Funding Information: The authors would like to thank all patients and their families and all the EMMOS investigators for their valuable contributions to the study. The authors would like to acknowledge Robert Olie for his significant contribution to the EMMOS study. Writing support during the development of our report was provided by Laura Mulcahy and Catherine Crookes of FireKite, an Ashfield company, a part of UDG Healthcare plc, which was funded by Millennium Pharmaceuticals, Inc, and Janssen Global Services, LLC. The EMMOS study was supported by research funding from Janssen Pharmaceutical NV and Millennium Pharmaceuticals, Inc. Funding Information: M.M. has received personal fees from Janssen, Celgene, Amgen, Bristol-Myers Squibb, Sanofi, Novartis, and Takeda and grants from Janssen and Sanofi during the conduct of the study. E.T. has received grants from Janssen and personal fees from Janssen and Takeda during the conduct of the study, and grants from Amgen, Celgene/Genesis, personal fees from Amgen, Celgene/Genesis, Bristol-Myers Squibb, Novartis, and Glaxo-Smith Kline outside the submitted work. M.V.M. has received personal fees from Janssen, Celgene, Amgen, and Takeda outside the submitted work. M.C. reports honoraria from Janssen, outside the submitted work. M. B. reports grants from Janssen Cilag during the conduct of the study. M.D. has received honoraria for participation on advisory boards for Janssen, Celgene, Takeda, Amgen, and Novartis. H.S. has received honoraria from Janssen-Cilag, Celgene, Amgen, Bristol-Myers Squibb, Novartis, and Takeda outside the submitted work. V.P. reports personal fees from Janssen during the conduct of the study and grants, personal fees, and nonfinancial support from Amgen, grants and personal fees from Sanofi, and personal fees from Takeda outside the submitted work. W.W. has received personal fees and grants from Amgen, Celgene, Novartis, Roche, Takeda, Gilead, and Janssen and nonfinancial support from Roche outside the submitted work. J.S. reports grants and nonfinancial support from Janssen Pharmaceutical during the conduct of the study. V.L. reports funding from Janssen Global Services LLC during the conduct of the study and study support from Janssen-Cilag and Pharmion outside the submitted work. A.P. reports employment and shareholding of Janssen (Johnson & Johnson) during the conduct of the study. C.C. reports employment at Janssen-Cilag during the conduct of the study. C.F. reports employment at Janssen Research and Development during the conduct of the study. F.T.B. reports employment at Janssen-Cilag during the conduct of the study. The remaining authors have stated that they have no conflicts of interest. Publisher Copyright: © 2018 The AuthorsMultiple myeloma (MM) remains an incurable disease, with little information available on its management in real-world clinical practice. The results of the present prospective, noninterventional observational study revealed great diversity in the treatment regimens used to treat MM. Our results also provide data to inform health economic, pharmacoepidemiologic, and outcomes research, providing a framework for the design of protocols to improve the outcomes of patients with MM. Background: The present prospective, multinational, noninterventional study aimed to document and describe real-world treatment regimens and disease progression in multiple myeloma (MM) patients. Patients and Methods: Adult patients initiating any new MM therapy from October 2010 to October 2012 were eligible. A multistage patient/site recruitment model was applied to minimize the selection bias; enrollment was stratified by country, region, and practice type. The patient medical and disease features, treatment history, and remission status were recorded at baseline, and prospective data on treatment, efficacy, and safety were collected electronically every 3 months. Results: A total of 2358 patients were enrolled. Of these patients, 775 and 1583 did and did not undergo stem cell transplantation (SCT) at any time during treatment, respectively. Of the patients in the SCT and non-SCT groups, 49%, 21%, 14%, and 15% and 57%, 20%, 12% and 10% were enrolled at treatment line 1, 2, 3, and ≥ 4, respectively. In the SCT and non-SCT groups, 45% and 54% of the patients had received bortezomib-based therapy without thalidomide/lenalidomide, 12% and 18% had received thalidomide/lenalidomide-based therapy without bortezomib, and 30% and 4% had received bortezomib plus thalidomide/lenalidomide-based therapy as frontline treatment, respectively. The corresponding proportions of SCT and non-SCT patients in lines 2, 3, and ≥ 4 were 45% and 37%, 30% and 37%, and 12% and 3%, 33% and 27%, 35% and 32%, and 8% and 2%, and 27% and 27%, 27% and 23%, and 6% and 4%, respectively. In the SCT and non-SCT patients, the overall response rate was 86% to 97% and 64% to 85% in line 1, 74% to 78% and 59% to 68% in line 2, 55% to 83% and 48% to 60% in line 3, and 49% to 65% and 36% and 45% in line 4, respectively, for regimens that included bortezomib and/or thalidomide/lenalidomide. Conclusion: The results of our prospective study have revealed great diversity in the treatment regimens used to manage MM in real-life practice. This diversity was linked to factors such as novel agent accessibility and evolving treatment recommendations. Our results provide insight into associated clinical benefits.publishersversionPeer reviewe

Leczenie ruksolitynibem u chorego na pierwotne włóknienie szpiku oraz małopłytkowość

46-years old male diagnosed with primary myelofibrosis (PMF) was included into therapeutic program of treatment with ruxolitinib. Due to initial thrombocytopenia with basal platelets [PLT] range below 100 G/l, initial dosage of the treatment was reduced according to characteristics of drug. No treatment-related toxicity was noted, the dosage was gradually increased reaching the dose 20 mg twice a day at twelfth week of therapy. Although alleviation of systemic symptoms was reached, lack of diminishment of spleen size demanded by therapeutic program led to cessation of treatment. In group of patients with PMF and secondary thrombocytopenia treatment with ruxolitinib may lead to improvement of patient condition.Przedstawiono przypadek 46-letniego pacjenta z pierwotnym włóknieniem szpiku (PMF) z wyjściową liczbą płytek krwi (PLT) poniżej 100 G/l, którego ze względu na splenomegalię oraz objawy ogólne zakwalifikowano do leczenia ruksolitynibem. Z powodu małopłytkowości początkową dawkę leku zmniejszono zgodnie z charakterystyką produktu leczniczego. Nie obserwowano toksyczności hematologicznej, co pozwoliło na osiągnięcie dawki 2 razy 20 mg w 12. tygodniu terapii. Mimo pozytywnego wpływu na zmniejszenie objawów ogólnych, u chorego nie doszło do wymaganego w programie terapeutycznym zmniejszenia wielkości śledziony w 6. miesiącu leczenia, co skutkowało przerwaniem terapii. Ruksolitynib, mimo potencjalnej toksyczności hematologicznej, może przynosić korzyści terapeutyczne u chorych na PMF i z niską początkową liczbą płytek krwi