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LIVE: Late-breaker coverage from ASH
NEW ORLEANS — Healio.com/HemOnc is reporting live from the ASH Late-Breaking Abstracts, expected to highlight the latest advances in the diagnosis, treatment and prevention of blood disorders, as well as new breakthroughs in research.
10:01 a.m. Session concludes.
9:58 a.m. Furman: In patients with heavily pre-treated relapsed CLL not suitable for chemotherapy, idelalisib added to rituximab improved PFS, ORR and LNR. In summary, idelalisib plus rituximab also demonstrated an acceptable safety profile.
9:57 a.m. Furman: Four deaths in idelalisib arm and 11 in placebo arm. The top five adverse events in the idelalisib arm were pyrexia, fatigue, nausea, chills and diarrhea; however, serious adverse events were seen in both arms.
9:55 a.m. Furman: OS also favored idelalisib (HR=0.28). Adverse events of any grade occurred in 91% of idelalisib-treated patients and 94% of those who received placebo. Any adverse events were found in 91% of the idelalisib arm and 94% in placebo arm.
9:54 a.m. Furman: PFS favored idelalisib in all subgroups analyzed. Overall response was 81% in idelalisib arm vs. 13% in placebo arm. Response rate favored Arm A (idelalisib and rituximab). Percentage of patients with a 50% or greater reduction in lymph node size was 93% in idelalisib and 4% in placebo.
9:53 a.m. Furman: Results from a pre-planned interim analysis showed patients assigned to the combination regimen demonstrated a significant improvement in PFS (median not reached vs. 5.5 months; HR=0.15; 95% CI, 0.08-0.28) compared with those who received rituximab plus placebo. PFS favored idelalisib in all subgroups analyzed. Overall response was 81% in the idelalisib arm vs. 13% in the placebo arm.
9:51 a.m. Furman: 110 patients randomly assigned to each arm. In arm A, 21 discontinued the study. In arm B, 53 discontinued. 81% of patients in the idelalisib arm and 52% in the placebo arm are currently still on the study. Reasons for discontinuation included disease progression, death, adverse events, etc. Three deaths occurred in Arm A and nine deaths in Arm B. Median exposure was 3.8 months for the idelalisib arm and 2.9 months for the placebo arm.
9:50 a.m. Furman: Baseline characteristics were similar in both arms, with a median age of 71 years. Criteria: relapsed CLL, lymphadenopathy, prior therapies, appropriate for non-cytotoxic therapy (the most important criterion) and bone marrow function. Time since diagnosis was 7.8 years in the idelalisib arm and 8.6 years in the placebo arm. Median CIRS score was 8 in both arms.
9:48 a.m. Furman: PFS served as the primary endpoint, with secondary endpoints of ORR, LNR and OS. Treatment arm A (n=110) received rituximab and idelalisib. Treatment arm B (n=110) received placebo/rituximab. Results are from pre-planned interim analysis.
9:47 a.m. All patients received an initial 375-mg/m2 dose of rituximab (Rituxan, Genentech/Biogen Idec). They subsequently received 500 mg/m2 every 2 weeks for four cycles, followed by every 4 weeks for three cycles. Researchers randomly assigned half of the patients to also receive 150 mg idelalisib (Gilead Sciences) twice daily or placebo.
9:46 a.m. Furman and colleagues enrolled 220 patients whose disease progressed less than 24 months after completion of their last therapy. Patients were deemed unfit to receive cytotoxic therapy due to comorbidities, renal dysfunction or cytopenias due to poor marrow reserve.
9:45 a.m. Furman: PI3K-delta impacts multiple critical pathways in CLL. Idelalisib is a novel small molecule inhibitor of PI3K delta isoform that inhibits proliferation and induces apoptosis in CLL. Idelalisib also inhibits homing and retention of CLL cells in lymphoid tissues reducing cell survival.
9:44 a.m. Furman: CLL is an incurable relapsing illness requiring repeated treatment with chemoimmunotherapies. Relapsed CLL is often associated with adverse genetic markers and responds poorly to available therapies. Older patients and those with comorbidities or poor renal/bone marrow function often cannot tolerate standard chemoimmunotherapies.
9:43 a.m. Researchers report research funding and honoraria from, equity ownership in, employment relationships with, and consultant, advisory or board roles with Gilead Sciences.
9:42 a.m. Richard R. Furman, MD, a member of the Lymphoma/Myeloma Service at New York Weill Cornell Medical Center and head of the CLL and Waldenstrom’s macroglobulinemia program at Weill Cornell Medical College, presents LBA-6: A phase 3, randomized, double blind, placebo-controlled study evaluating the efficacy and safety of idelalisib and rituximab for previously treated patients with chronic lymphocytic leukemia.
8:37 a.m. Kronke: Future studies should investigate whether IKZF and IKZF can serve as markers for lenalidomide therapy, as the findings may help in the development of new drugs.
8:33 a.m. Kronke: Having shown IZKF1 and IKZF3 were reduced, we asked what are the biologic consequences of this in multiple myeloma? We found that IKZF3 and IKZF1 was sensitive. However, IKZF3, IKZF2 and IKZF5 was insensitive. We transduced multiple myeloma cells. Myeloma cells IKZF1 and IKZF3 are dependent.
8:31 a.m. Kronke: Next, we analyzed multiple myeloma cell lines and showed lenalidomide decreased IKZF1 and IKZF3 protein levels. We then tested lenalidomide, thalidomide and pomalidomide and observed that all three reduced IKZF1 and IKZF3, but did not change RNA levels.
8:30 a.m. Kronke: Only a very small number of sites are regulated by lenalidomide. We performed CRBN interaction analysis to see which proteins bind to CRBN. We discovered a unique mechanism of action through which lenalidomide promotes binding of two lymphoid transcription factors, IKZF1 and IKZF3, to the CRBN-DDB1 ubiquitin ligase.
8:28 a.m. Kronke: Teratogenicity and multiple myeloma rely on E3 Ubiquitin ligase. Our hypothesis was that thalidomide or lenalidomide modified E3 ubiquitin ligase and results in effect of immunomodulatory drugs. We performed in vivo ubiquitination profiling. We took multiple myeloma cell line and treated with DMSO, thalidomide or lenalidomide.
8:27 a.m. Kronke: Despite more that 500 clinical trials, no other tumor has been found to have similar response. These drugs increased IL-2 and decreased TNF. The exact mechanism for these drugs (lenalidomide, thalidomide and pomalidomide) was unknown until 2010. Subsequent studies in multiple myeloma show CRBN is essential for lenalidomide effect.
8:26 a.m. Kronke: Lenalidomide is an FDA-approved drug for multiple myeloma. Overall response rate is 70% to 90% in first-line treatment in combination with dexamethasone. Also active in myelodysplastic syndrome and B-cell non-Hodgkin's lymphomas.
8:25 a.m. Jan Kronke, MD, of Brigham and Women’s Hospital in Boston presents LBA-5: Lenalidomide promotes CRBN-mediated ubiquitination and degradation of IKZF1 and IKZF3. The researchers report advisory or board roles with Celgene.
8:22 a.m. Righini: 337 patients in this category. 331 patients with complete follow-up. There were seven deaths, but only one VTE during follow-up. Failure rate was 0.1% (95% CI, 0.0-0.7). When taking into account the entire cohort, use of age-adjusted D-dimer cutoff increased proportion of patients in whom PE could be excluded from 28.2% to 40%. Among those 75 or older, age-adjusted cutoff increased proportion of patients in whom PE could be excluded from 6.4% to 30%.
8:21 a.m. Righini: 2,898 patients had non-high or unlikely clinical probability. 57% of patients were female. Average age was 62.1 years. 2,898 patients underwent D-dimer measurement. We had 817 patients with D-dimer level <500 ng/ml. Our results showed VTE during FU: 1/810:0.1% (95% CI; 0.0-0.7). Failure rate was 0.1%. Most interesting was patients with D-dimer levels between 500 ng/ml and age-adjusted cutoff.
8:20 a.m. Righini: 4,960 patients screened. 3,346 patients were included in the study and 3,324 patients were available for analysis. Of those patients with clinical suspicion of PE, those high likely received CTPA and those non-high unlikely received the D-dimer test.
8:19 a.m. Righini: In the prospective management study, patients with a D-dimer value between the usual threshold of 500 mcg/L and their age-adjusted cutoff did not undergo CT pulmonary angiography or treatment. Main outcome variable was the proportion of thromboembolic events in the 3-month follow-up.
8:18 a.m. Proportion of thromboembolic events in 3-month follow-up period in untreated patients served as main outcome variable.
8:17 a.m. Righini: We conducted a 19-center study to validate efficacy of age-adjusted D-dimer cutoff. In our study, consecutive outpatients admitted with a clinical suspicion of PE were eligible.
8:16 a.m. Righini: They derived an age-adjusted D-dimer mcg/L cut-off in patients older than 50 years. This derivation suggested that an easily calculated age-adjusted D-dimer cutoff — the patient’s age multiplied by 10, measured in mcg/L — could increase the proportion of elderly patients in whom PE is ruled out safely.
Marc Righini
8:15 a.m. Righini: D-dimer measurement is an important step in diagnostic strategy of pulmonary embolism. There are some limitations to the test. We tried to increase diagnostic usefulness by changing cutoff of the test. Douma and colleagues proposed an age-adjusted cutoff. A possible solution was proposed: an age-adjusted cutoff derived by a previous retrospective analysis of 5,132 consecutive patients.
8:14 a.m. Marc Righini, MD, MSc, of the division of angiology and hemostasis at Geneva University Hospital and Faculty of Medicine in Switzerland, presents LBA-4: Age-adjusted D-dimer cut-off levels to rule out pulmonary embolism: A prospective outcome study. The researchers report no relevant financial disclosures.
8:12 a.m. Van der Reijden: Our studies have found a dominant negative GFI1b mutation causes Gray Platelet Syndrome Megakaryocytic development disorder and will be able to identify relevant genes that are changed in this disease. This is a broad megakaryocytic developmental disorder. GFI1B is a transcription factor.
8:09 a.m. Van der Reijden: Data shows this mutation indeed causes the disease. GPS increases megakaryocyte progenitors and proliferation. We used flow cytometry, myeloid and erythroid markers and platelet markers. Isolated mutations in GFIB also present in Bernard-Soulier syndrome.
8:08 a.m. Researchers evaluated megakaryocytes of a mouse model expressing the GFI1B mutation and determined they were abnormally sized.
8:07 a.m. Van der Reijden: GFI1B has a partial deletion in zinc finger 5. GFI1BTR acts dominant negative over normal GFI1B.
8:06 a.m. Van der Reijden: Nonsense GFI1B mutation causes autosomal dominant GPS. Sequencing results identified a GFI1B mutation that appeared to be linked to GPS. Another group at ASH has also identified mutation in GFI1B. Analyzing cDNA and CD34+ shows it is clearly expressed at the RNA level. GFI1B includes six zinc fingers, 3-5 are essential for DNA binding.
8:05 a.m. This form of GPS also characterized by megakaryocyte abnormalities. After whole-genome analyses, researchers focused on mutations of one gene, growth factor independence B (GF11B), because of its role in regulating the genes responsible for the development of megakaryocytes, or cells that produce platelets and affect bleeding.
8:03 a.m. Van der Reijden: The researchers analyzed megakarocyte abnormalities and found marked increase in megakaryocytes. Megakaryocytes had stretched morphology rather than normal morphology found in healthy bone marrow. Bone marrow also found hypolobulation of nuclei.
8:01 a.m. Van der Reijden: Reporting on a family that was first reported 45 years ago, researchers analyzed samples of genetic material from members of a large family in the Netherlands with autosomal-dominant GPS. More recently, we reanalyzed patient samples. When we performed electron microscopy, we found both affected and unaffected alpha-granules. Additional tests included measurements of PF4 and beta-TG.
7:59 a.m. Van der Reijden: Gray platelet syndrome is an inherited platelet disorder. Patients with gray platelet syndrome (GPS) have reduced numbers of platelets that are atypically large. A lack of alpha-granules, essential to normal platelet activity, causes them to have a gray appearance. Gray platelets are secreted following activation, causing the disease. Patients often have enlarged platelets and mild-to-moderate thrombocytopenia. GPS is often autosomal recessive and patients have normal megakaryocyte numbers.
Bert A. Van der Reijden
7:58 a.m. Van der Reijden: Work accepted for publication in New England Journal of Medicine and will appear online today.
7:57 a.m. Bert A. Van der Reijden, PhD, presents LBA-3: A dominant-negative GFI1B mutation in gray platelet syndrome. The researchers report no relevant financial disclosures.
7:55 a.m. Nangalia: In summary, we described the mutational landscape of 151 MPN patients. CALR mutations are present in 70% to 84% of JAK2/MPL patients. Sequenced individual colonies for all mutations identified. Data reveal novel biological pathway as target for tumorigenic mutations and will simplify MPN diagnosis.
7:53 a.m. Nangalia: In our c-domain, all were calcium binding and KDEL. All mutations we identified, deletions and insertions were of exact size that led to 1-base frame shift. We were unable to find any increases in cell surface calriticulun in CALR mutant patients compared with healthy controls.
7:50 a.m. Nangalia: Several groups have been searching for genetic basis of JAK-2 negative MPNs. In our data set, two patients identified by standard pipelines to have CALR mutations. We asked if patients with JAK2 or CALR differed in the phenotype. Patients with ET and CALR mutations had higher platelet counts and lower hemoglobin level than JAK2 mutant counterparts.
7:49 a.m. Nangalia: We identified 1,498 mutations of recurrently mutated genes; JAK2 is by far the most-mutated gene. Identified mutations in CHEK2 in three patients. Second most frequently mutated gene was CALR. All mutations were either insertions or deletions in DNA sequence.
Jyoti Nangalia
7:47 a.m. Nangalia: Researchers performed the first large-scale characterization of genetic mutations in 151 patients with myeloproliferative neoplasms via genetic sequencing. They identified novel mutations in regulators of gene activity that previously had not been associated with the disease.
7:45 a.m. Nangalia reports no relevant financial disclosures.
7:45 a.m. Jyoti Nangalia, MBBChir, FRCPath, of the Cancer Genome Project at Wellcome Trust Sanger Institute in Hinxton, United Kingdom, presents LBA-2: The genomic landscape of myeloproliferative neoplasms: Somatic Calr mutations in the majority of JAK2 wild-type patients.
7:44 a.m. Thorsten: To summarize, we have found CALR mutations fill the current gap in understanding the genetic basis of MP. All mutations affect c-terminal domain. Mutant CALR includes cytokine independent growth and activates STAT5. This unique, novel C-terminal in mutant CALR might serve as a target for future therapies.
7:42 a.m. Thorsten: When we look at the clinical data of our patients, we see a significant survival of patients with primary myelofibrosis. Among patients with essential thrombocytopenia, those with CALR mutations demonstrated a lower thrombosis risk than those with JAK2 mutations. CALR mutations fill this gap in understanding genetic basis of MPN. CALR mutations are MPN specific. This has two implications: First, CALR mutations can be used as novel diagnostic markers in MPN.
7:41 a.m. Thorsten: We saw significant survival advantage in CALR-mutant patients with myelofibrosis. Patients with CALR mutation typically had lower white blood cell counts and more elevated platelet levels compared with those who had JAK2 mutations. Patients with essential thrombocytopenia and primary myelofibrosis who had CALR mutations demonstrated longer OS than those with JAK2 mutations.
7:40 a.m. Thorsten: These mutations lead to a frame shift. Mutations in CALR generate a novel C-terminal end of the protein, which is common to all other mutations. CALR has three domains: p-domain, n-domain and c-domain. It is localized to endoplasmic reticulum. It is also found on cytoplasm, cell surface or extracellular matrix.
7:39 a.m. Thorsten: A finding that suggests CALR mutation may be unique to patients with MPNs. Overall, we found 36 different types of CALR mutations. We found 36 different types of CALR mutations, the most common of which were 52 bp deletion (53%) and 5 bp insertion (32%).
7:38 a.m. Researchers then used a PCR-based assay to screen 1,107 patients with MPNs for mutations in exon 9 of CALR. Among patients with wild-type JAK2 or MPL, 67% of those with essential thrombocytopenia and 88% of those with primary fibrosis harbored CALR mutations. So we added another 211 additional patients and found that 67% of ET and 88% of PMF had wild type JAK2 and MPL. CALR mutation was not present in patients with acute myeloid leukemia, chronic myeloid leukemia, myelodysplastic syndrome or chronic myelomonocytic leukemia.
7:37: a.m. Thorsten: They identified novel recurring mutations in the CALR gene encoding for calreticulin in all six patients. All mutations clustered in exon 9. Researchers then used a PCR-based assay to screen 1,107 patients with MPNs for mutations in exon 9 of CALR. Among patients with wild-type JAK2 or MPL, 67% of those with essential thrombocytopenia and 88% of those with primary fibrosis harbored CALR mutations.
7:35 a.m. Thorsten: We still lack knowledge about disease-causing mutation in 40% of patients. We performed advanced genetic sequencing in six patients. Two of the six patients had mutations deletions, and four had insertions.
7:34 a.m. Thorsten: Three classical disease entities in myeloproliferative neoplasms are polycythemia vera, essential thrombocytopenia and primary myelofibrosis. JAK2 gene found in 95% of patients with PV and 50-60% of patients with PM.
7:32 a.m. Klampfl Thorsten, PhD, of CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences in Vienna, Austria, presents LBA-1.
7:30 a.m. Session begins. Drs. Stock and Tisdale open the Late-Breaking Abstract Session.
