Use of immunoglobulin replacement therapy in patients with secondary antibody deficiency in daily practice: a European expert Q&A-based review.

INTRODUCTION: Secondary antibody deficiencies (SAD) are often a side effect of specific therapies that target B cells directly or affect the antibody response indirectly. Treatment of immunodeficiency by immunoglobulin replacement therapy (IgRT) is well established in primary antibody deficiencies, although the evidence for its use in SAD is less well established. To fill the gap and provide opinion and advice for daily practice, a group of experts met to discuss current issues and share best practical experience. AREAS COVERED: A total of 16 questions were considered that covered use of a tailored approach, definition of severe infections, measurement of IgG levels and specific antibodies, indications for IgRT, dosage, monitoring, discontinuation of IgRT, and Covid-19. EXPERT OPINION: Key points for better management SID should include characterization of the immunological deficiency, determination of the severity and degree of impairment of antibody production, distinguish between primary and secondary deficiency, and design a tailored treatment protocol that should include dose, route, and frequency of Ig replacement. There remains the need to carry out well-designed clinical studies to develop clear guidelines for the use of IgRT in patients with SAD.

Acalabrutinib Versus Investigator's Choice in Relapsed/Refractory Chronic Lymphocytic Leukemia: Final ASCEND Trial Results.

Acalabrutinib is a Bruton tyrosine kinase inhibitor approved for patients with chronic lymphocytic leukemia (CLL). ASCEND is the pivotal phase 3 study of acalabrutinib versus investigator's choice of idelalisib plus rituximab (IdR) or bendamustine plus rituximab (BR) in patients with relapsed/refractory (R/R) CLL. In the primary ASCEND analysis (median 16.1-month follow-up), acalabrutinib showed superior efficacy with an acceptable tolerability profile versus IdR/BR; here, we report final ~4 year follow-up results. Patients with R/R CLL received oral acalabrutinib 100 mg twice daily until progression or unacceptable toxicity, or investigator's choice of IdR or BR. A total of 310 patients (acalabrutinib, n = 155; IdR, n = 119; BR, n = 36) were enrolled. At median follow-up of 46.5 months (acalabrutinib) and 45.3 months (IdR/BR), acalabrutinib significantly prolonged investigator-assessed progression-free survival (PFS) versus IdR/BR (median, not reached [NR] vs 16.8 months; P < 0.001); 42-month PFS rates were 62% (acalabrutinib) versus 19% (IdR/BR). Median overall survival (OS) was NR (both arms); 42-month OS rates were 78% (acalabrutinib) versus 65% (IdR/BR). Adverse events led to drug discontinuation in 23%, 67%, and 17% of patients in the acalabrutinib, IdR, and BR arms, respectively. Events of clinical interest (acalabrutinib vs IdR/BR) included all-grade atrial fibrillation/flutter (8% vs 3%), all-grade hypertension (8% vs 5%), all-grade major hemorrhage (3% vs 3%), grade ≥3 infections (29% vs 29%), and second primary malignancies excluding nonmelanoma skin cancer (7% vs 2%). At ~4 years follow-up, acalabrutinib maintained favorable efficacy versus standard-of-care regimens and a consistent tolerability profile in patients with R/R CLL.

Ofatumumab with iphosphamide, etoposide and cytarabine for patients with transplantation-ineligible relapsed and refractory diffuse large B-cell lymphoma.

The efficacy of salvage treatment of diffuse large B-cell lymphoma (DLBCL) patients who relapse or progress (rrDLBCL) after initial therapy is limited. Efficacy and safety of ofatumumab with iphosphamide, etoposide and cytarabine (O-IVAC) was evaluated in a single-arm study. Dosing was modified for elderly patients. Patients received up to six cycles of treatment. The primary end-point was the overall response rate (ORR). Patients were evaluated every two cycles and then six and 12 months after treatment. Other end-points included progression-free survival (PFS), event-free survival (EFS), overall survival (OS) and safety. Seventy-seven patients received salvage treatment with O-IVAC. The average age was 56.8 years; 39% had an Eastern Cooperative Oncology Group (ECOG) performance status of at least 3; 78% had disease of Ann Arbor stage 3 or 4; 58% received one or more prior salvage therapies. The ORR for O-IVAC was 54.5%. The median duration of study follow-up was 70 months. The median PFS and EFS were 16.3 months each. The median OS was 22.7 months. Age, ECOG performance status and the number of prior therapy lines were independent predictors of survival. Treatment-related mortality was 15.5%. O-IVAC showed a high response rate in a difficult-to-treat population and is an attractive treatment to bridge to potentially curative therapies.

Long-term Efficacy of Ibrutinib in Relapsed or Refractory Chronic Lymphocytic Leukemia: Results of the Polish Adult Leukemia Study Group Observational Study.

BACKGROUND/AIM: To study the long-term clinical efficacy and tolerability of ibrutinib monotherapy in real-world relapsed and refractory chronic lymphocytic leukemia (RR-CLL) patients outside clinical trials. PATIENTS AND METHODS: Clinical data of 171 RR-CLL patients treated with ibrutinib were collected within the observational study of the Polish Adult Leukemia Study Group. RESULTS: Median patient age was 64 years. Patients were pretreated with 3 (1-10) median lines of therapy, while 42 (24.6%) had 17p deletion. The median observation time was 40 months (range=1-59 months), while median ibrutinib monotherapy reached 37.5 months (range=0.4-59.2 months). Response was noted in 132 (77.2%) patients. The estimated 5-year progression-free survival (PFS) and overall survival (OS) rates were 61.1% (95%CI=49.3-70.9%) and 56.8% (95%CI=45.6-66.6%), respectively. At the time of analysis 97 (56.7%) remained under ibrutinib monotherapy. CONCLUSION: Ibrutinib is clinically effective and tolerable as a monotherapy in real-world RR-CLL patients.

ASCEND: Phase III, Randomized Trial of Acalabrutinib Versus Idelalisib Plus Rituximab or Bendamustine Plus Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia.

PURPOSE: Acalabrutinib, a highly selective, potent, Bruton tyrosine kinase inhibitor, was evaluated in this global, multicenter, randomized, open-label, phase III study in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). METHODS: Eligible patients, aged ≥ 18 years with R/R CLL, were randomly assigned 1:1 centrally and stratified by del(17p) status, Eastern Cooperative Oncology Group performance status score, and number of prior lines of therapy. Patients received acalabrutinib monotherapy or investigator's choice (idelalisib plus rituximab [I-R] or bendamustine plus rituximab [B-R]). The primary end point was progression-free survival (PFS) assessed by an independent review committee (IRC) in the intent-to-treat population. Key secondary end points included IRC-assessed overall response rate, overall survival, and safety. RESULTS: From February 21, 2017, to January 17, 2018, a total of 398 patients were assessed for eligibility; 310 patients were randomly assigned to acalabrutinib monotherapy (n = 155) or investigator's choice (n = 155; I-R, n = 119; B-R, n = 36). Patients had received a median of two prior therapies (range, 1-10). After a median follow-up of 16.1 months (range, 0.03-22.4 months), median PFS was significantly longer with acalabrutinib monotherapy (PFS not reached) compared with investigator's choice (16.5 months [95% CI, 14.0 to 17.1 months]; hazard ratio, 0.31 [95% CI, 0.20 to 0.49]; P < .0001). Estimated 12-month PFS was 88% (95% CI, 81% to 92%) for acalabrutinib and 68% (95% CI, 59% to 75%) for investigator's choice. Serious adverse events occurred in 29% of patients (n = 44 of 154) treated with acalabrutinib monotherapy, 56% (n = 66 of 118) with I-R, and 26% (n = 9 of 35) with B-R. Deaths occurred in 10% (n = 15 of 154), 11% (n = 13 of 118), and 14% (n = 5 of 35) of patients receiving acalabrutinib monotherapy, I-R, and B-R, respectively. CONCLUSION: Acalabrutinib significantly improved PFS compared with I-R or B-R and has an acceptable safety profile in patients with R/R CLL.

Richter syndrome: A rare complication of chronic lymphocytic leukemia or small lymphocytic lymphoma.

BACKGROUND: Richter's syndrome (RS) is a rare complication with an unfavorable prognosis, in which chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) transform into a more aggressive type of lymphoma, most commonly into diffuse large B cell lymphoma (DLBCL) or less often into Hodgkin's lymphoma (HL). OBJECTIVES: The objective of this research paper was to present a retrospective analysis of patients with CLL/SLL whose disease transformed into RS. MATERIAL AND METHODS: The study included 217 patients (100 women and 107 men) with CLL/SLL diagnosed in the years 2006-2015 at the Department of Hematooncology and Bone Marrow Transplantation of the Medical University of Lublin, which transformed into RS. We analyzed clinical, laboratory, immunophenotypic (ZAP-70 and CD38 expression), histopathological, and genetic data (del(17p), del(11q)), which was collected at the time of CLL/SLL diagnosis, and some which was collected at the time of transformation. RESULTS: Richter's syndrome was diagnosed in 4.6% of all CLL and SLL patients. The group of patients with RS consisted of 9 patients with primary CLL and 1 patient with a diagnosis of SLL (8 patients with transformation into DLBCL and 2 patients with transformation into HL). Leukemic lymphocytes showed evidence of peripheral blood lymphocyte membrane expression of ZAP70+/CD38+ (1 patient), of ZAP-70+/CD38- (3 patients), of ZAP-70-/CD38- (1 patient), and of ZAP-70-/CD38+ (5 patients). The deletion of 11q (del(11q)) was documented in 2 patients. In 4 cases, the location of RS was extremely rare (the thyroid gland, liver, skin, bladder, and central nervous system). CONCLUSIONS: Richter's syndrome is a rare, but probable complication of CLL/SLL with an unfavorable prognosis, and it should be taken into account at every stage of the disease, particularly when the course of the disease is aggressive.

Ixazomib significantly prolongs progression-free survival in high-risk relapsed/refractory myeloma patients.

Certain cytogenetic abnormalities are known to adversely impact outcomes in patients with multiple myeloma (MM). The phase 3 TOURMALINE-MM1 study demonstrated a significant improvement in progression-free survival (PFS) with ixazomib-lenalidomide-dexamethasone (IRd) compared with placebo-lenalidomide-dexamethasone (placebo-Rd). This preplanned analysis assessed the efficacy and safety of IRd vs placebo-Rd according to cytogenetic risk, as assessed using fluorescence in situ hybridization. High-risk cytogenetic abnormalities were defined as del(17p), t(4;14), and/or t(14;16); additionally, patients were assessed for 1q21 amplification. Of 722 randomized patients, 552 had cytogenetic results; 137 (25%) had high-risk cytogenetic abnormalities and 172 (32%) had 1q21 amplification alone. PFS was improved with IRd vs placebo-Rd in both high-risk and standard-risk cytogenetics subgroups: in high-risk patients, the hazard ratio (HR) was 0.543 (95% confidence interval [CI], 0.321-0.918; P = .021), with median PFS of 21.4 vs 9.7 months; in standard-risk patients, HR was 0.640 (95% CI, 0.462-0.888; P = .007), with median PFS of 20.6 vs 15.6 months. This PFS benefit was consistent across subgroups with individual high-risk cytogenetic abnormalities, including patients with del(17p) (HR, 0.596; 95% CI, 0.286-1.243). PFS was also longer with IRd vs placebo-Rd in patients with 1q21 amplification (HR, 0.781; 95% CI, 0.492-1.240), and in the "expanded high-risk" group, defined as those with high-risk cytogenetic abnormalities and/or 1q21 amplification (HR, 0.664; 95% CI, 0.474-0.928). IRd demonstrated substantial benefit compared with placebo-Rd in relapsed and/or refractory MM (RRMM) patients with high-risk and standard-risk cytogenetics, and improves the poor PFS associated with high-risk cytogenetic abnormalities. This trial was registered at www.clinicaltrials.gov as #NCT01564537.

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.

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.

Severe sepsis in Poland--results of internet surveillance of 1043 cases.

BACKGROUND: Severe sepsis is a clinical syndrome frequently occurring in intensive care units (ICUs) when systemic infection results in multiorgan dysfunction. No Polish data concerning treatment and prognosis in this group of patients have been available to date. MATERIAL/METHODS: The Polish Working Group for Sepsis introduced in 2003 internet registration of severe sepsis cases treated in ICUs in Poland. Information about severe sepsis were entered including the type of infection, clinical course, methods and results of treatment. RESULTS: From 20.04.2003 to 10.01.2004, 1043 severe sepsis cases were reported by 104 ICUs. Mean age of patients was 59 years. Mean duration of treatment was 19 days, with mortality rate of 55%. In 60% dysfunction of 4 or more organs was diagnosed. In 55% the underlying disease was surgical and abdominal cavity was the primary infection site (47%). Pathogens most likely to cause severe sepsis were G- (48%) and G+ (43%) bacteria, as well as fungi (21%). Positive blood culture was obtained in 45% of patients. Treatment involved antibiotic and support of organ function. Activated protein C was used in 8.2%, causing a reduction of mortality. CONCLUSIONS: Severe sepsis in Polish ICUs develops most frequently in the course of intra-abdominal infections. Dysfunction of 4 or more organs caused observed high mortality (55%) Internet surveillance proved to be useful method of collecting information, widely accepted by personnel of ICUs.

[Cranial fascitis--case report and literature review]. / Zapalenie powi zi czaszkowej--opis przypadku i przeglad pismiennictwa.

Cranial fascitis is a rare disease that is considered as a subset of nodular fascitis. Lauer and Enzinger described the disease for the first time in 1980 as a cranial fascitis of childhood (CFC), based on pathologic findings in nine cases of children from three weeks to six year old. The disease is benign proliferation of immature fibroblasts infiltrating the cranial bones with tendency to form tumor like shapes. Surgery excision gives total cure and recurrence is very rare. We present the case of a twenty years old male patient with head trauma in medical history and two years history of recurrent forehead headache. Performed cerebral computerized tomography and skeleton scintigraphy showed erosion of the lateral parts of both frontal skull bones and upper-lateral parts of the right and left orbital cavity. In general anesthesia, biopsy specimen was taken. After histopathological examination the diagnosis of cranial fascitis was established. Eight months after the diagnosis we observed progression of the skull bones destruction. Therefore our recommended treatment was surgical excision but we did not obtain patient agreement.

[New views on systemic mastocytosis]. / Mastocytoza uogólniona w swietle wspólczesnych pogladów.

Systemic mastocytosis is an uncommon disease characterised by an abnormal increase of mast cell count. The observed symptoms result from bone marrow, gastrointestinal, hepatic, splenic and skin infiltration by mast cells and from release of mast cell active mediators. The aim of our study was to discuss the classification, clinical features and treatment opportunities of systemic mastocytosis, based on review of current literature.