Rapid Disease Control Research Articles

CDK4/6 inhibitor plus endocrine therapy for hormone receptor-positive, HER2-negative metastatic breast cancer: The new standard of care.

Patients presenting with hormone receptor-positive (HR+ ), human epidermal growth factor receptor 2-negative (HER2- ) metastatic breast cancer (MBC) are usually treated with endocrine therapy (ET), except if there is a concern about endocrine resistance or a need to achieve rapid disease control due to visceral crisis. The combination of CDK4/6 inhibitor + ET has now replaced single-agent ET as the standard first-line treatment; and it can also be considered a standard option in the second-line setting. This review briefly summarizes recently reported efficacy findings from the key phase III clinical trials of CDK4/6 inhibitor + ET in patients with HR+ /HER2- MBC, including evidence that adding a CDK4/6 inhibitor to ET improves overall survival and does so without reducing patients' quality of life. There is still much to learn regarding the use of CDK4/6 inhibitors and how they may be optimally integrated into clinical practice. In particular, there is a need for specific biomarkers that help predict the likelihood of response or resistance to CDK4/6 inhibitor therapy; and for data to guide treatment decisions when a patient's disease progresses on a CDK4/6 inhibitor.

Mitogen-activated protein kinase blockade in melanoma: intermittent versus continuous therapy, from preclinical to clinical data.

Although targeted therapy provides a high response rate and rapid disease control in advanced melanoma, most patients experience disease progression due to acquired resistance mechanisms leading to reactivation of mitogen-activated protein kinase pathway. The purpose of this article is to review the recently published data on the impact of an intermittent versus continuous dosing schedule of BRAF and MEK inhibition in advanced melanoma to determine the best approach in clinical practice. Some preclinical studies have highlighted the concept that drug-resistant cells may also display drug dependency, such that intermittent dosing of targeted therapy may prevent the emergence of lethal drug resistance. Moreover, clinical observations have suggested that repeated treatment after a break or an intervening therapy may provide clinical benefit. However, recent preclinical and clinical studies have also failed to demonstrate an advantage of intermittent dosing and showed a similar efficacy of the intermittent versus continuous regimens of BRAF and MEK inhibitors in mice models and phase 2 clinical trial. Owing to these discordant results, continuous dosing of BRAF and MEK inhibitors remains the optimal therapeutic approach until additional clinical data demonstrate the superiority of another combination or dosing regimen.

Medical Treatment of Cushing's Disease: An Overview of the Current and Recent Clinical Trials.

Cushing's disease (CD) is a serious endocrine disorder characterized by chronic hypercortisolism, or Cushing's syndrome (CS), caused by a corticotroph pituitary tumor, which induces an excessive adrenocorticotropic hormone (ACTH) and consequently cortisol secretion. CD presents a severe clinical burden, with impairment of the quality of life and increase in mortality. Pituitary surgery represents the first-line therapy, but it is non-curative in one third of patients, requiring additional treatments. Among second-line treatments, medical therapy is gradually gaining importance, although the current medical treatments are unable to reach optimal efficacy and safety profile. Therefore, new drugs and new formulations of presently available drugs are currently under clinical investigation in international clinical trials, in order to assess their efficacy and safety in CD, or in the general population of CS. Among pituitary-directed agents, pasireotide, in the twice-daily subcutaneous formulation, has been demonstrated to be an effective treatment both in clinical trials and in real-world studies, and extension studies of the phase II and III clinical trials reported evidence of long-term efficacy with general good safety profile, although associated with frequent hyperglycemia, which requires monitoring of glucose metabolism. Moreover, the most recent once-monthly intramuscular formulation, pasireotide long-acting release (LAR), showed similar efficacy and safety, but associated with potential better compliance profile in CD. Roscovitine is an experimental drug currently under investigation. Among adrenal-directed agents, metyrapone is the only historical agent currently under investigation in a prospective, multicenter, international clinical trial, that would likely clarify its efficacy and safety in a large population of patients with CS. Osilodrostat, a novel agent with a mechanism of action similar to metyrapone, seems to offer a rapid, sustained, and effective disease control of CD, according to recently completed clinical trials, whereas levoketoconazole, a different chemical formulation of the historical agent ketoconazole, is still under investigation in clinical trials, with preliminary evidences showing an effective and safe control of CS. ATR-101 is an experimental drug currently under investigation. Among glucocorticoid receptor-directed drugs, mifepristone has been demonstrated to improve clinical syndrome and comorbidities, especially hypertension and impairment of glucose metabolism, but the occurrence of hypokalemia and in women uterine disorders, due to the concomitant action on progestin receptor, requires caution, whereas the preliminary evidence on relacorilant, characterized by high selectivity for glucocorticoid receptor, suggested good efficacy in the control of hypertension and impairment of glucose metabolism, as well as a good safety profile, in CS. Finally, a limited experience has demonstrated that combination therapy might be an interesting approach in the management of CD. The current review provides a summary of the available evidences from current and recent clinical trials on CD, with a specific focus on preliminary data.

Continuous Clinical Remisssion with High MRD Negativity and High PB and BM MRD Concordance during Venetoclax Monotherapy in R/R CLL Patients

Introduction Venetoclax, a novel BCL2 inhibitor, used either as monotherapy or in combinations, induces rapid disease control , with durable clinical remissions, especially in patients with deep responses. In the Venetoclax era, minimal residual disease(MRD) is a new endpoint in CLL studies. MRD negativity is associated with better clinical outcomes (Jain N, et al. ASH 2019, abstract 186, Tam CS, et al. ASH 2019, abstract 642). Aim We present our single-center MRD data from a cohort of patients with relapsed/refractory(RR) CLL, treated with venetoclax monotherapy. Patients and Methods We collected data from 24 R/R CLL patients who have been treated with venetoclax monotherapy until progression, in the context of VENICE-1 study (NCT02756611) in our department between 11/2016 and 1/2018. MRD was locally evaluated with 10-colour flow cytometry(FC) according to ERIC guidelines, with the cut off of <10-4 (<0.01%) as negative, >10-4-<10-2 (>0.01%-<1%) as low-positive and >10-2 (>1%) cut off as high-positive. Peripheral blood(PB) MRD was assessed every 3-6 months. At week48 (1 year), CT scans were performed for response assessment. Bone marrow (BM) biopsy and BM MRD at week48 were also performed in pts with CT confirmed CR. Results Between 11/2016 and 1/2018, 24 patients started treatment with venetoclax monotherapy. Our patients' baseline characteristics are shown in table 1. Disease responses and patients' treatment status as of end-July 2020 are shown in table 2. Progression free survival(PFS) and overall survival at 34 months is estimated 91.6% and 87.5% respectively. Four patients (16.7%) had to reduce their daily Venetoclax dose due to hematological toxicity: 2 to 300mg due to neutropenia and 2 to 200 and 100mg due to thrombocytopenia. MRD results at week 48 are shown in table 3. Sixteen patients have paired PB and BM MRD results (15 at week 48 and 1 at week 24) with 87.5% concordance (14 patients). In seven MRD negative patients MRD conversion (2 consecutive samples) was observed, after a median time of 16 m(6-28): six patients to low-positive and one to high-positive. The high-positive MRD-converted patient presented clinical relapse at the 2nd high-MRD positive sample, according to iwCLL criteria. One of 6 low-positive MRD-converted patients, became MRD negative again at a later time-point. Conclusion Our single-center data from 24 CLL patients enrolled in the Venice-1 study reveal high concordance of PB and BM MRD at week48. Higher PB MRD negativity rate at week 48 is observed (79.2%) in comparison to Venice trial (Kater A, et al. EHA 2020, S156) due to differences in MRD methodology/number of evaluable patients. Our FC MRD data show that MRD conversion from negative to low-positive may be observed during continuous Venetoclax treatment, without clinical disease progression. This observation, along with high PFS at 34 months (91.5%) confirms the importance of continuing Venetoclax therapy in RR CLL patients when given as monotherapy. Disclosures Kyrtsonis: Genesis pharma SA: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Panayiotidis:Genesis: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Janssen: Honoraria; Gilead: Honoraria; Takeda: Honoraria; Phizer: Honoraria; ASH: Honoraria.

Hyperfractionated Cyclophosphamide-Dexamethasone (HyperCy-Dex) with or without Carfilzomib (Car) in Patients (pts) with Multiple Myeloma (MM)

Hyperfractionated Cyclophosphamide-Dexamethasone (HyperCy-Dex) with or without Carfilzomib (Car) in Patients (pts) with Multiple Myeloma (MM)

Optimizing care for younger women with hormone receptor-positive, HER2-negative metastatic breast cancer.

Treatment strategies for hormone receptor-positive (HR+ ), human epidermal growth factor receptor 2-negative (HER2- ) metastatic breast cancer in young women (<40 years at diagnosis) have traditionally been extrapolated from data obtained from trials conducted either exclusively or predominantly in the postmenopausal setting. These young patients are usually treated with ovarian function suppression (OFS) + endocrine therapy (ET) ± targeted therapy, except if there is a concern about endocrine resistance or a need to gain rapid disease control due to the onset of visceral crisis. This review examines evidence that supports the use of a cyclin-dependent kinase 4/6 inhibitor, in combination with OFS and ET, when treating premenopausal or perimenopausal women with HR+ /HER2- metastatic breast cancer. This includes data from the MONALEESA-7 study (treating only premenopausal/perimenopausal women in the first-line setting), and the results of subgroup analyses from the PALOMA-3 and MONARCH-2 trials. We also consider a number of age-specific challenges that younger breast cancer patients can face, highlighting the importance of a multidisciplinary approach to ongoing care.

THU0188 EFFICACY OF FILGOTINIB IN PATIENTS WITH RHEUMATOID ARTHRITIS WITH POOR PROGNOSTIC FACTORS: POST HOC ANALYSIS OF FINCH 3

Background:Patients (pts) with rheumatoid arthritis (RA) with poor prognostic factors (PPF) are at risk for RA progression if disease activity is not rapidly controlled. In FINCH 3 (NCT02886728), filgotinib (FIL)—an oral, potent, selective JAK1 inhibitor—was effective relative to methotrexate monotherapy (MTX mono) in MTX-naïve patients with ≥1 PPF—erosions, seropositivity for rheumatoid factor (RF) or anti-cyclic citrullinated peptide (CCP), or hsCRP ≥4 mg/L.1Objectives:This post hoc analysis examined FIL efficacy in FINCH 3 pts with multiple PPF.Methods:The global, phase 3, double-blind, active-controlled FINCH 3 study randomised MTX-naïve pts with moderately to severely active RA 2:1:1:2 to oral FIL 200 mg once daily + MTX ≤20 mg weekly, FIL 100 mg + MTX, FIL 200 mg mono, or PBO + MTX up to week (W)52. This subgroup analysis included pts with all 4 of the following PPF at baseline (PPF pts): erosions, seropositivity for RF or anti-CCP, hsCRP ≥4 mg/L, and DAS(28)CRP &gt;5.1. Comparisons were not adjusted for multiplicity.Results:Of 1249 pts randomised and treated in FINCH 3, 510 had all 4 PPF. At baseline, relative to the overall FINCH 3 population, PPF pts had longer mean disease duration (2.4 vs 2.2 years); higher mean hsCRP (27.9 vs 17.5 mg/L), mTSS (17.9 vs 13.3), DAS28(CRP) (6.3 vs 5.7), HAQ-DI (1.76 vs 1.56), CDAI (44.3 vs 39.8), and SDAI (47.1 vs 41.5); and greater frequency of seropositivity for RF (90.6% vs 67.9%), anti-CCP (92.4% vs 68.5%), or both (82.9% vs 59.6%). Efficacy in PPF pts was comparable to data from all FINCH 3 pts (Table, Figures 1–2). PPF pts receiving FIL 200 mg with or without MTX vs MTX mono had higher frequencies of ACR20/50/70 response and greater improvement in HAQ-DI at W24; responses were numerically greater for FIL 200 mg + MTX vs FIL 100 mg + MTX or FIL 200 mg mono (Table) and were evident by W12 (data not shown). Radiographic progression at W24 was lower in PPF pts receiving FIL 200 mg + MTX or FIL 200 mg mono vs MTX mono (Figure 1). Proportions of PPF pts receiving FIL 200 mg with or without MTX who achieved DAS28(CRP) &lt;2.6, CDAI ≤2.8, SDAI ≤3.3, and Boolean remission at W24 (Figure 2) were larger vs pts receiving MTX mono and numerically greater vs pts receiving FIL 100 mg + MTX.Table.Efficacy outcomes in patients with 4 PPF and all FINCH 3 patients at W24FIL 200 mg+ MTXFIL 100 mg+ MTXFIL 200 mg monoMTXmonoPPFAllPPFAllPPFAllPPFAlln1724168520787210166416ACR20, %85.5*81.0***83.580.2*81.678.174.771.4ACR50, %70.3***61.5***58.857.0**59.858.1**48.245.7ACR70, %54.1***43.8***37.640.1***43.7*40.0***28.326.0HAQ-DIa−1.2***−0.94***−1.0*−0.90**−1.0*−0.89*−0.9−0.79aMean change from baseline.*, p &lt;0.05;**, p &lt;0.01;***, p &lt;0.001 vs MTX mono, not adjusted for multiplicity.FIL, filgotinib; mono, monotherapy; MTX, methotrexate; PPF, poor prognostic factors.Conclusion:FIL treatment provided rapid and deep disease control including higher rates of remission and other clinical outcomes, improved physical function, and less radiographic progression compared with MTX alone in MTX-naïve pts with RA with 4 PPF, a population at risk for severe progressive disease. In pts with 4 PPF, W24 remission rates following FIL 200 mg with or without MTX were higher vs MTX mono and numerically higher vs FIL 100 mg + MTX.

Daratumumab (Dara) and hyperfractionated cyclophosphamide (HyperCy)/dexamethasone (Dex) with and without carfilzomib (Car) for the treatment of relapsed/refractory multiple myeloma (RRMM).

e20528 Background: RRMM can be associated with high disease burden and/or end organ damage requiring rapid disease control. Our group has previously published data with hyperCy-bortezomib (bor)-doxorubicin-dex (Tabchi et al. 2019) for such patients (pts). Dara, a monoclonal antibody targeting CD38, has limited overlapping toxicities with cytotoxic chemotherapy, making it an attractive partner for hyperCy-dex. We report our retrospective experience of pts treated with dara-hyperCy-dex ± car. Methods: Between 5/2016-8/2019, 53 pts were treated with dara (16 mg/kg IV d1,8,15,22)-hyperCy (300-350 mg/m2 IV q12h x 6-8 doses d1-3/4)-dex (20-40 mg IV/PO d1-4, 8-11, 15-18, 22-23) alone (27 records), or with car (20 mg/m2 IV d1-2, 27-36 mg/m2 IV d8-9, 15-16) (32 records) on 28 day cycles. Pts received growth factor, anti-fungal, anti-bacterial, anti-viral, and peptic ulcer prophylaxis. High-risk MM (HRMM) was defined by t(4;14), t(14;16), and/or del 17p. Response was assessed by International Myeloma Working Group Uniform Criteria. Overall response rate (ORR) and disease control rate (DCR) were defined as ≥ partial response and ≥ stable disease, respectively. Each instance of treatment (tx) started &gt; 60 days from the previous cycle start date was counted as a separate record. Patient characteristics, progression-free survival (PFS) and overall survival (OS) were assessed per pt, based on earliest administration date. Results: Median age of pts was 61 (26-77) years. Median number of prior therapies was 4 (1-18). Previous exposure to both lenalidomide and pomalidomide (93%), both bor and car (83%), and dara (64%) was frequent. HRMM was present in 20/42 evaluable pts. After a median of 1 cycle (1-5), ORR was 63%, with ≥ very good partial response in 24%. DCR was 86%. Median PFS was 4.3 months. Median OS was 9.7 months. Grade 3-4 hematologic toxicities included 66% neutropenia, 66% anemia, and 68% thrombocytopenia. Grade 3-4 non-hematologic toxicities included 42% febrile neutropenia, 19% bacteremia, and 15% pneumonia. Within 60 days of tx, 7 pts underwent autologous stem cell transplant (ASCT), and 7 pts died. Conclusions: Dara-hyperCy-dex ± car demonstrates a high ORR and DCR in heavily treated and HRMM, allowing bridging of some pts to ASCT. High rates of hematologic toxicity and risk of infection are manageable with twice weekly monitoring for transfusion support, as well as early detection and intervention for infections. Rates of end organ damage reversal will be presented.

Nivolumab (NIVO) + ipilimumab (IPI) + 2 cycles of platinum-doublet chemotherapy (chemo) vs 4 cycles chemo as first-line (1L) treatment (tx) for stage IV/recurrent non-small cell lung cancer (NSCLC): CheckMate 9LA.

9501 Background: NIVO + IPI was shown to improve overall survival (OS) and durability of response vs chemo in 1L advanced NSCLC in CheckMate 227 Part 1, regardless of PD-L1 expression. We hypothesized that a limited course of chemo combined with NIVO + IPI could provide rapid disease control while building on the durable OS benefit seen with dual PD-1 and CTLA-4 inhibition. CheckMate 9LA (NCT03215706) is a phase 3 randomized study evaluating NIVO + IPI + 2 cycles chemo vs chemo in 1L stage IV/recurrent NSCLC. Methods: Adults with tx-naive, histologically confirmed stage IV/recurrent NSCLC, ECOG performance status 0–1, and no known sensitizing EGFR/ALK alterations were randomized 1:1 to NIVO 360 mg Q3W + IPI 1 mg/kg Q6W + chemo (2 cycles) (n = 361) or chemo (4 cycles) alone (n = 358), stratified by PD-L1 (&lt; 1% vs ≥ 1%), sex, and histology (squamous vs non-squamous). Chemo was based on histology. Pts with non-squamous NSCLC in the chemo-only arm could receive optional pemetrexed maintenance. Pts were treated with immunotherapy until disease progression, unacceptable toxicity, or for 2 y. The primary endpoint was OS; the interim analysis using Lan–DeMets alpha spending function with O’Brien–Fleming boundary was planned at ~80% information fraction (ie, after observing ~322 total events). Secondary endpoints included progression-free survival (PFS) and objective response rate (ORR) by blinded independent central review, and efficacy by PD-L1 subgroups. Exploratory endpoints included safety/tolerability. Results: Baseline characteristics were balanced across arms. At a preplanned interim analysis (minimum follow-up 8.1 mo), OS was significantly prolonged with NIVO + IPI + chemo vs chemo (HR 0.69, 96.71% CI: 0.55–0.87; P = 0.0006); statistically significant improvements in PFS and ORR were seen. With longer follow-up (minimum 12.7 mo), NIVO + IPI + chemo vs chemo continued to provide longer OS; median 15.6 vs 10.9 mo (HR 0.66, 95% CI: 0.55–0.80); 1-y OS rates were 63 vs 47%. Clinical benefit was consistent across all efficacy measures in key subgroups including by PD-L1 and histology. Grade 3–4 tx-related adverse events were reported in 47 vs 38% of pts in the NIVO + IPI + chemo vs chemo arms, respectively. Conclusions: CheckMate 9LA met its primary endpoint: a statistically significant improvement in OS was observed with NIVO + NSCLC-optimized IPI + a limited course of chemo vs chemo (4 cycles) in 1L advanced NSCLC. No new safety signals were reported. Clinical trial information: NCT03215706 .

SUN-485 Combined Treatment with Laser Ablation and Tyrosin Kinase Inhibitors. a Novel Multimodality Approach to Locally Advanced Thyroid Cancer?

Background. Direct loco-regional treatments are considered for local control of cervical metastasis of thyroid cancer. In our feasibility study, laser ablation was employed for initial debulking of an unresectable radioiodine-refractory thyroid cancer in a combined treatment with tyrosin kinase inhibitors (TKI). Clinical case. On June 2016, a 69-year-old woman underwent partial resection of a papillary thyroid cancer with extensive tracheal infiltration. On August 2016, whole body scan performed after 131-I treatment (8140 MBq) demonstrated nearly absent thyroid bed uptake. Due to progressive increase of the cervical mass, the patient experienced dysphonia and dysphagia and, after multidisciplinary consultation, was treated with laser ablation (LTA). After local anesthesia, two 300 nm fiberoptics were inserted into the lesion through 21G spinal needles. Two illuminations with 4-watt output power and 3600 Joules energy delivery were peformed with a diode-laser source. LTA resulted in rapid mass volume decrease (28 x12 x16 mm, 2.8 mL, vs 52 x 29 x 29 mm, 22.7 mL) and improvement of pressure symptoms that lasted 6 months. In May 2017, due to initial regrowth of the tumor mass, the patient started therapy with Lenvatinib, at 10-24 mg/day. The cervical tumor burden remained controlled until April 2019, when occurred rapid disease progression and death of the patient. Discussion. These preliminary results suggest that locally-advanced unresectable and radioiodine-refractory thyroid tumors can be managed with preliminary LTA mass debulking, for rapid control of local disease, followed by long-term TKI treatment. References. Mauri G et al. Cardiovasc Intervent Radiol. 2016 Jul; 39(7):1023-30; Park KW et al. Ann Surg Oncol 2011; 18:2564-2568. Schlumberger M et al. NEJM 2015 12; 372(7):621-30.

Oncolytic Adenovirus Armed with BiTE, Cytokine, and Checkpoint Inhibitor Enables CAR T Cells to Control the Growth of Heterogeneous Tumors.

No single cancer immunotherapy will likely defeat all evasion mechanisms of solid tumors, including plasticity of tumor antigen expression and active immune suppression by the tumor environment. In this study, we increase the breadth, potency, and duration of anti-tumor activity of chimeric antigen receptor (CAR) Tcells using an oncolytic virus (OV) that produces cytokine, checkpoint blockade, and a bispecific tumor-targeted Tcell engager (BiTE) molecule. First, we constructed a BiTE molecule specific for CD44 variant 6 (CD44v6), since CD44v6 is widely expressed on tumor but not normal tissue, and a CD44v6 antibody has been safely administered to cancer patients. We then incorporated this BiTE sequence into an oncolytic-helper binary adenovirus (CAdDuo) encoding an immunostimulatory cytokine (interleukin [IL]-12) and an immune checkpoint blocker (PD-L1Ab) to form CAdTrio. CD44v6 BiTE from CAdTrio enabled HER2-specific CAR Tcells to kill multiple CD44v6+ cancer cell lines and to produce more rapid and sustained disease control of orthotopic HER2+ and HER2-/- CD44v6+ tumors than any component alone. Thus, the combination of CAdTrio with HER2.CAR Tcells ensures dual targeting of two tumor antigens by engagement of distinct classes of receptor (CAR and native Tcell receptor [TCR]), and significantly improves tumor control and survival.

Patient-Reported Outcome Data From an Early Rheumatoid Arthritis Trial: Opportunities for Broadening the Scope of Treating to Target.

Treating early, intensively, and to target leads to rapid disease control, preventing joint damage and loss of function in early rheumatoid arthritis (RA). We report the effect of such an approach on patient-reported outcomes and explore the contribution of rapid and persistent disease control to well-being after 1 year of treatment. This study is part of the Care in Early RA trial, a prospective, 2-year, investigator-initiated, randomized controlled trial rooted in daily practice and implementing the treat-to-target principle. Short Form 36 (SF-36) health survey and Revised Illness Perception Questionnaire (IPQ-R) data were collected prospectively. We defined 4 clinical response profiles based on speed and consistency of the treatment response within the first year, defined as the Disease Activity Score in 28 joints using the C-reactive protein level <2.6. Linear regression analyses including these response profiles and treatment type were constructed to predict the SF-36 dimensions of vitality, social functioning, role emotional, and mental health, and the IPQ-R illness perception subscales of consequences, treatment control, and illness coherence at year 1. A total of 333 patients were available for the main analyses, including 140 early persistent responders. Variation in each of the psychosocial outcomes at year 1 was explained mostly by baseline values, followed by the clinical response profiles. Patients with an early persistent response reported significantly higher vitality, more positive beliefs about disease consequences and treatment effect. Treatment type did not matter. Rapid and persistent disease control and not treatment type were associated with favorable patient-reported health and illness perceptions at year 1, but baseline psychosocial variables mattered most. Our data indicate opportunities to broaden the scope of the treat-to-target principle in early RA.

Treatment of Primary Plasma Cell Leukemia with Carfilzomib and Lenalidomide-Based Therapy: Results of the First Interim Analysis of the Phase 2 EMN12/HOVON129 Study

Treatment of Primary Plasma Cell Leukemia with Carfilzomib and Lenalidomide-Based Therapy: Results of the First Interim Analysis of the Phase 2 EMN12/HOVON129 Study

Characterization of Response and Transfusion Independence in Patients with FLT3-Internal Tandem Duplication (FLT3-ITD)-Mutated Relapsed/Refractory Acute Myeloid Leukemia Treated with Quizartinib or Salvage Chemotherapy in the Quantum-R Trial

Characterization of Response and Transfusion Independence in Patients with FLT3-Internal Tandem Duplication (FLT3-ITD)-Mutated Relapsed/Refractory Acute Myeloid Leukemia Treated with Quizartinib or Salvage Chemotherapy in the Quantum-R Trial

Daratumumab for relapsed or refractory AL amyloidosis with high plasma cell burden.

Daratumumab, an anti-CD38 antibody, is effective in AL amyloidosis with low tumor burden. Data of daratumumab treatment in patients with AL amyloidosis but high tumor burden (≥10% bone marrow plasma cells) are limited. We report retrospective data of 10 consecutive patients with high tumor burden treated with daratumumab for relapsed/refractory AL amyloidosis. The median age at diagnosis was 62.3 years; all patients had cardiac involvement, and six (60%) patients had renal involvement. Median bone marrow plasma cell infiltration was 15% (range 10%-40%), and the median difference between involved and noninvolved free light-chains (dFLC) was 446 mg/L (range 102-1392 mg/L). Patients had a median of three prior lines of therapy, including bortezomib in all patients and lenalidomide in seven (70%) patients. The median time to first hematological response was 14 days (range 7-28 days), and the median time to best hematological response was 64 days (range 7-301 days). The hematological overall response was 90%, with high-quality response (≥ very good partial remission [VGPR]) in 70% of the patients. Fifty percent of the patients had a cardiac response after a median of 3.8 months (range 0.7-9.1). Infusion-related adverse events ≤ grade 2 occurred in seven (70%) patients and grade 3 adverse events in one patient. After a median follow-up time of 10 months, eight (80%) patients continued to receive daratumumab. We conclude that daratumumab is a very effective and safe treatment option in AL patients with relapsed/refractory disease and high disease burden at diagnosis. Daratumumab leads to rapid disease control and improvement of organ function.

Therapeutic Strategy According to Differences in Response to Omalizumab in Patients With Chronic Spontaneous Urticaria.

Chronic spontaneous urticaria (CSU) is a heterogeneous condition that can severely impact quality of life. Consequently, rapid disease control is essential. First-line treatment of the symptoms of CSU is the licensed dose of second-generation H1 antihistamines. For second-line treatment, this dose may be increased by up to 4 times. In patients who fail to respond to higher doses of H1 antihistamines, omalizumab for up to 24 weeks is recommended to achieve disease control. After this 24-week period, the patient's response to omalizumab should be assessed in order to identify refractory patients. Optimal management of refractory patients has not been established. Therefore, the aim of the present consensus document, which was drafted by allergists and dermatologists with specific expertise in treating urticaria, was to define specific patient profiles based on differences in their response to omalizumab. We also developed a treatment algorithm based on the specific response profile. After a comprehensive literature review, a group meeting was held to discuss issues related to the therapeutic management of patients with CSU that had not been addressed in previous studies. The experts considered both the available evidence and their own clinical experience with omalizumab. We believe that implementation of the proposed algorithm will optimize management of CSU patients who are refractory to antihistamines, reduce disease-related costs, and improve quality of life.

Dermatitis Herpetiformis: Novel Perspectives.

Dermatitis herpetiformis (DH) is an inflammatory disease of the skin, considered the specific cutaneous manifestation of celiac disease (CD). Both DH and CD occur in gluten-sensitive individuals, share the same Human Leukocyte Antigen (HLA) haplotypes (DQ2 and DQ8), and improve following the administration of a gluten-free diet. Moreover, almost all DH patients show typical CD alterations at the small bowel biopsy, ranging from villous atrophy to augmented presence of intraepithelial lymphocytes, as well as the generation of circulating autoantibodies against tissue transglutaminase (tTG). Clinically, DH presents with polymorphic lesions, including papules, vesicles, and small blisters, symmetrically distributed in typical anatomical sites including the extensor aspects of the limbs, the elbows, the sacral regions, and the buttocks. Intense pruritus is almost the rule. However, many atypical presentations of DH have also been reported. Moreover, recent evidence suggested that DH is changing. Firstly, some studies reported a reduced incidence of DH, probably due to early recognition of CD, so that there is not enough time for DH to develop. Moreover, data from Japanese literature highlighted the absence of intestinal involvement as well as of the typical serological markers of CD (i.e., anti-tTG antibodies) in Japanese patients with DH. Similar cases may also occur in Caucasian patients, complicating DH diagnosis. The latter relies on the combination of clinical, histopathologic, and immunopathologic findings. Detecting granular IgA deposits at the dermal-epidermal junction by direct immunofluorescence (DIF) from perilesional skin represents the most specific diagnostic tool. Further, assessing serum titers of autoantibodies against epidermal transglutaminase (eTG), the supposed autoantigen of DH, may also serve as a clue for the diagnosis. However, a study from our group has recently demonstrated that granular IgA deposits may also occur in celiac patients with non-DH inflammatory skin diseases, raising questions about the effective role of eTG IgA autoantibodies in DH and suggesting the need of revising diagnostic criteria, conceivably emphasizing clinical aspects of the disease along with DIF. DH usually responds to the gluten-free diet. Topical clobetasol ointment or dapsone may be also applied to favor rapid disease control. Our review will focus on novel pathogenic insights, controversies, and management aspects of DH.

Waldenström's macroglobulinemia front line treatment.

Waldenström's macroglobulinemia front line treatment.

Brodalumab in psoriasis: evidence to date and clinical potential.

Brodalumab is a recombinant, fully human monoclonal antibody (IgG2) which binds with high affinity to the interleukin (IL) 17 receptor A (IL17R). Brodalumab is now licensed and approved for the treatment of moderate-to-severe chronic plaque psoriasis in North America and Europe. As the third to market in the class of agents targeting IL-17, we review its place in the expanding armamentarium of cytokine-directed therapies for patients with severe psoriasis. Brodalumab is a highly efficacious therapy for psoriasis, whose mechanism of action is separate from other treatments targeting IL-17. Its use is associated with rapid control of the disease. We suggest that brodalumab is likely to be considered in those patients requiring rapid control of disease, where there is no known history of depression or suicidal ideation.

Biological weapons and health protection against biological terrorism

The possibility of using biological means has become a reality. A biological attack is the deliberate use of living microorganisms or their toxic products to cause disease and death in humans, animals and plants. Methods of biological attack and its main characteristics. Protection against biological attack and its basic articles. Possibilities of protection against biological attack and division of protective measures. Preventive measures and measures for rapid disease control.