The etiology and pathogenesis of plasma cell myeloma

Szpiczak plazmocytowy (PCM) jest nowotworowym rozrostem komórek plazmatycznych, w którym występują charakterystyczne objawy uszkodzenia narządów, wtórne do procesu nowotworowego. Mimo znacznego postępu w terapii chorych PCM wiedza na temat etiopatogenezy tej choroby pozostaje niekompletna. Do najlepiej udokumentowanych czynników związanych ze zwiększonym ryzykiem zachorowania na PCM należą występowanie gammopatii monoklonalnej o nieokreślonym znaczeniu (MGUS), zaawansowany wiek, płeć męska oraz określona grupa etniczna. Rozwój nowotworu plazmocytowego polega na stopniowej ewolucji od wczesnego i bezobjawowego stadium MGUS, przez objawowy PCM, do końcowej fazy białaczki plazmocytowej. W obecnym modelu patogenezy PCM zakłada się istnienie dwóch odrębnych szlaków inicjujących transformację nowotworową — szlak translokacji z udziałem genów immunoglobulin oraz szlak hiperdiploidii (trisomii). Obok zmian molekularnych w obrębie klonu plazmocytowego kluczową rolę w patogenezie PCM odgrywają interakcje z komórkami mikrośrodowiska szpiku kostnego. Po transformacji nowotworowej, w dalszym etapie progresji PCM, dochodzi do wtórnych zaburzeń molekularnych, które prowadzą do stopniowego uniezależnienia się od mikrośrodowiska szpiku kostnego i zazwyczaj zwiększają agresywność nowotworu. Lepsze poznanie złożonych mechanizmów patogenetycznych PCM w ostatnich latach budzi nadzieję na poszerzenie możliwości terapeutycznych i dalszą poprawę rokowania w przyszłości.Plasma cell myeloma (PCM) is a neoplasm of plasma cells characterized by specific end organ damage. Despite significant progress in the therapy of PCM, knowledge about the etiopathogenesis of this disease remains unsatisfactory. Monoclonal gammopathy of undetermined significance (MGUS), advanced age, male gender and ethnic group belong to best documented factors associated with an increased risk of PCM development. Several stages of PCM evolution from early and asymptomatic MGUS to symptomatic PCM and final stage of plasma cell leukemia were identified. The current model of PCM pathogenesis assumes the existence of two separate pathways initiating neoplastic transformation – the translocations involving immunoglobulin genes and hyperdiploidy (trisomies). Besides molecular changes within atypical plasma cells, interaction with the bone marrow microenvironment plays a key role in the pathogenesis of PCM. After initial transformation, a number of secondary molecular alterations occur at subclonal level leading to gradual independence from bone marrow microenvironment and increase of the aggressiveness of the tumor. It is likely that better understanding of complex mechanisms of PCM pathogenesis will contribute to development of novel therapeutic strategies and further improvement of PCM prognosis in the future

Analysis of ibrutinib efficacy in a subgroup of chronic lymphocytic leukemia patients with 17p deletion: observational study of the Polish Adult Leukemia Group (PALG)

BackgroundThe 17p deletion is regarded as the strongest poor prognostic factor in chronic lymphocytic leukemia (CLL). Results of recently performed clinical trials have suggested that ibrutinib significantly improves the outcome in this patient group.AimThe study aimed at analyzing the efficacy and adverse events profile of ibrutinib monotherapy in CLL patients with 17p deletion treated in routine clinical practice outside clinical trials.Materials and MethodsClinical response and adverse events profile of ibrutinib monotherapy were assessed in thirty-five CLL patients with 17p deletion treated within the ibrutinib named patients program in Poland.ResultsOverall response rate was 80% (28/35 patients) with median observation time of 24.2 months (range 0,1 – 30,9). Complete remission was observed in 5 patients (14.3%), partial remission in 11 (31.4%), partial remission with lymphocytosis in 13 (37.1%), whereas stable disease and progression was noted in 4 (11.4%) and 1 (2.9%) respectively. Response was not assessed in 1 patient. Median progression-free survival was 29.5 months, whereas median overall survival was not reached. Eleven patients died (7 because of infection, 1 of CLL progression, 1 of sudden cardiac death, 1 of disseminated breast cancer and 1 of unknown causes). In 13 patients (37.1%) at least one 3 or 4 grade adverse event occurred. In 11 patients (31.4%) the treatment was temporary withheld or the dose reduced due to adverse events.ConclusionIbrutinib is characterized by high clinical efficacy and acceptable toxicity in CLL patients with 17p deletion in daily clinical practice

Genetically determined telomere length and multiple myeloma risk and outcome

This work was partially supported by intramural funds of Univerity of Pisa and DKFZ; by Fondo de Investigaciones Sanitarias (Madrid, Spain) [PI12/02688 to J. S., PI17/02276 to J.S.]; by Instituto de Salud Carlos III, co-funded by FEDER funds —a way to build Europe—[PI14-00613 to V.M.] and by Agency for Management of University and Research Grants (AGAUR) of the Catalan Government (Barcelona, Spain) [2017SGR723 to V.M.]. Open Access funding enabled and organized by Projekt DEAL.Telomeres are involved in processes like cellular growth, chromosomal stability, and proper segregation to daughter cells. Telomere length measured in leukocytes (LTL) has been investigated in different cancer types, including multiple myeloma (MM). However, LTL measurement is prone to heterogeneity due to sample handling and study design (retrospective vs. prospective). LTL is genetically determined; genome-wide association studies identified 11 SNPs that, combined in a score, can be used as a genetic instrument to measure LTL and evaluate its association with MM risk. This approach has been already successfully attempted in various cancer types but never in MM. We tested the "teloscore" in 2407 MM patients and 1741 controls from the International Multiple Myeloma rESEarch (IMMeNSE) consortium. We observed an increased risk for longer genetically determined telomere length (gdTL) (OR = 1.69; 95% CI 1.36-2.11; P = 2.97 x 10(-6) for highest vs. lowest quintile of the score). Furthermore, in a subset of 1376 MM patients we tested the relationship between the teloscore and MM patients survival, observing a better prognosis for longer gdTL compared with shorter gdTL (HR = 0.93; 95% CI 0.86-0.99; P = 0.049). In conclusion, we report convincing evidence that longer gdTL is a risk marker for MM risk, and that it is potentially involved in increasing MM survival.Univerity of PisaHelmholtz AssociationInstituto de Salud Carlos III PI12/02688 PI17/02276Instituto de Salud Carlos IIIEuropean CommissionFEDER funds-a way to build Europe PI14-00613Agency for Management of University and Research Grants (AGAUR) of the Catalan Government (Barcelona, Spain) 2017SGR723Projekt DEA

Atypical immunophenotype of chronic lymphocytic leukemia

Assessment of the immunophenotype plays a crucial role in the diagnostic process of chronic lymphocytic leukemia (CLL). The expression of CD5, CD19 and CD23 antigens with a concomitant reduction or lack of surface immunoglobulin expression as well as CD22 and CD79b antigens is the basic part of CLL diagnosis. A significant diagnostic challenge is atypical CLL with cells devoid of CD5 or CD23 antigens. The assessment of additional antigens in flow cytometry, especially the CD200 glycoprotein, may facilitate the process of differential diagnosis of atypical CLL from other B-cell lymphoproliferative neoplasms. The results of current studies analyzing the influence of atypical CLL on prognosis are inconclusive. The analysis of a large group of patients with atypical CLL is difficult because of the rare occurrence of CD5(–) or CD23(–) CLL and the misdiagnosis of this disease as other B-cell lymphoproliferative neoplasms. The following paper aims to show how important it is to include atypical CLL in the diagnostic process of this disease and to re-standardize the commonly used immunophenotypic scales for its diagnosis.Assessment of the immunophenotype plays a crucial role in the diagnostic process of chronic lymphocytic leukemia (CLL). The expression of CD5, CD19 and CD23 antigens with a concomitant reduction or lack of surface immunoglobulin expression as well as CD22 and CD79b antigens is the basic part of CLL diagnosis. A significant diagnostic challenge is atypical CLL with cells devoid of CD5 or CD23 antigens. The assessment of additional antigens in flow cytometry, especially the CD200 glycoprotein, may facilitate the process of differential diagnosis of atypical CLL from other B-cell lymphoproliferative neoplasms. The results of current studies analyzing the influence of atypical CLL on prognosis are inconclusive. The analysis of a large group of patients with atypical CLL is difficult because of the rare occurrence of CD5(–) or CD23(–) CLL and the misdiagnosis of this disease as other B-cell lymphoproliferative neoplasms. The following paper aims to show how important it is to include atypical CLL in the diagnostic process of this disease and to re-standardize the commonly used immunophenotypic scales for its diagnosis

Atypical Chronic Lymphocytic Leukemia—The Current Status

A diagnosis of typical chronic lymphocytic leukemia (CLL) requires the presence of ≥5000 clonal B-lymphocytes/μL, the coexistence of CD19, CD20, CD5, and CD23, the restriction of light chain immunoglobulin, and the lack of expression of antigens CD22 and CD79b. Atypical CLL (aCLL) can be distinguished from typical CLL morphologically and immunophenotypically. Morphologically atypical CLL cells have been defined mainly as large, atypical forms, prolymphocytes, or cleaved cells. However, current aCLL diagnostics rely more on immunophenotypic characteristics rather than atypical morphology. Immunophenotypically, atypical CLL differs from classic CLL in the lack of expression of one or fewer surface antigens, most commonly CD5 and CD23, and the patient does not meet the criteria for a diagnosis of any other B-cell lymphoid malignancy. Morphologically atypical CLL has more aggressive clinical behavior and worse prognosis than classic CLL. Patients with aCLL are more likely to display markers associated with poor prognosis, including trisomy 12, unmutated IGVH, and CD38 expression, compared with classic CLL. However, no standard or commonly accepted criteria exist for differentiating aCLL from classic CLL and the clinical significance of aCLL is still under debate. This review summarizes the current state of knowledge on the morphological, immunophenotypic, and genetic abnormalities of aCLL

Polish Experts’ Position Statement on the use of granulocyte colony-stimulating factor in the treatment of chronic lymphocytic leukaemia with venetoclax combined with rituximab

Chronic lymphocytic leukaemia (CLL) is the most common adult leukaemia in Western countries. Venetoclax, a BCL-2 inhibitor, in combination with rituximab is an effective therapeutic option approved for the treatment of refractory and relapsed CLL. Neutropenia diagnosed before or during the above-mentioned therapy is a significant clinical problem, which often involves the need to reduce the dose or temporarily discontinue venetoclax in the initial period of therapy. In Experts’ opinion, the use of granulocyte colony-stimulating factor (G-CSF) during venetoclaxrituximab combined therapy is reasonable in patients with baseline neutrocyte count &lt; 1000–500/mm3 and with high-risk neutropenia. The second important group for the use of G-CSF are patients developing grade 3 asymptomatic neutropenia during venetoclax dose escalation. Using G-CSF can prevent episodes that affect the maintenance of the venetoclax dose intensity and treatment continuity.Chronic lymphocytic leukaemia (CLL) is the most common adult leukaemia in Western countries. Venetoclax, a BCL-2 inhibitor, in combination with rituximab is an effective therapeutic option approved for the treatment of refractory and relapsed CLL. Neutropenia diagnosed before or during the above-mentioned therapy is a significant clinical problem, which often involves the need to reduce the dose or temporarily discontinue venetoclax in the initial period of therapy. In Experts’ opinion, the use of granulocyte colony-stimulating factor (G-CSF) during venetoclaxrituximab combined therapy is reasonable in patients with baseline neutrocyte count < 1000–500/mm3 and with high-risk neutropenia. The second important group for the use of G-CSF are patients developing grade 3 asymptomatic neutropenia during venetoclax dose escalation. Using G-CSF can prevent episodes that affect the maintenance of the venetoclax dose intensity and treatment continuity

Stanowisko polskich ekspertów dotyczące stosowania czynnika stymulującego tworzenie kolonii granulocytów w leczeniu przewlekłej białaczki limfocytowej wenetoklaksem w połączeniu z rytuksymabem

Przewlekła białaczka limfocytowa (CLL) jest najczęstszą postacią białaczki u dorosłych w krajach półkuli zachodniej. Wenetoklaks, inhibitor BCL2, w połączeniu z rytuksymabem stanowi skuteczną opcję terapeutyczną, zatwierdzoną do leczenia opornej i nawrotowej CLL. Neutropenia stwierdzona przed rozpoczęciem lub w trakcie powyższej terapii stanowi istotny problem kliniczny, który niejednokrotnie wiąże się z koniecznością zmniejszenia dawki lub czasowego odstawienia wenetoklaksu w początkowym okresie terapii. Zdaniem ekspertów stosowanie czynnika stymulującego tworzenie kolonii granulocytów (G-CSF) podczas skojarzonego leczenia wenetoklaksem i rytuksymabem jest uzasadnione u chorych z wyjściową liczbą neutrocytów poniżej 1000–500/mm3 oraz obecnością czynników wysokiego ryzyka wystąpienia gorączki neutropenicznej i jej powikłań. Drugą ważną grupą, w której podawanie G-CSF wydaje się uzasadnione, są chorzy, u których podczas zwiększania dawki wenetoklaksu obserwuje się bezobjawową neutropenię 3. stopnia. Stosowanie G-CSF może wówczas zapobiegać wystąpieniu zdarzeń uniemożliwiających utrzymanie zalecanej dawki wenetoklaksu oraz ciągłości leczenia.