ALBERT

Description: INTRODUCTION: Perifosine (peri) is an oral, novel synthetic alkylphospholipid, with multiple effects on signal transduction pathways, including inhibition of Akt and activation of JNK. In vitro studies showed that peri induces cytotoxicity in both MM cell lines and patient (pt) MM cells resistant to conventional therapies, and augments dexamethasone (dex) and bortezomib-induced MM cell cytotoxicity (Hideshima T. et. al. BLOOD 2006). In vivo studies showed antitumor activity in a human plasmacytoma mouse model. Here we report the results of a phase II trial of peri, alone and + dex, in pts with relapsed or relapsed / refractory MM. METHODS: Pts received 150 mg of peri daily for a 21 day (d) cycle, and were assessed every cycle by serum- and/or urine-electrophoresis. Eligible pts had symptomatic relapsed or relapsed / refractory MM. Pts were permitted to receive bisphosphonate treatment. Concomitant steroids (prednisone 〉 10 mg/d), creatinine of 〉 3.0 mg/dL, and hemoglobin 〈 8.0 g/dL within 14 d of enrollment were exclusion criteria. Progressing pts, documented on 2 occasions at least one week apart, had dex 20 mg twice per week added to peri. Toxicities were assessed by NCI-CTCAE, v3.0. RESULTS: 64 pts (35 M/ 29 F, median age 62, range 38–79) have been treated to date. Median lines of prior treatment was 4 (range 1–11); 32 (50%) pts had relapsed and refractory MM. Prior therapy included dex (95%), thalidomide (89%), bortezomib (73%), lenalidomide (30%) and ASCT (61%). Among 48 pts currently evaluable for response, best response (EBMT criteria) to single agent peri after ≥ 2 cycles was MR in 1 pt, stable disease (〈 25% reduction in M-protein) in 22 pts (46%). Dex was added in 37 pts with PD, with 31 pts evaluable for response on the combination as follows: Peri + Dex N (%) Duration (wks) PR 4 (13%) 17, 24, 44+, 46+ MR 8 (25%) 3+, 12+, 19, 21, 25, 30, 32, 55+ Stable Disease 15 (47%) 6+ − 46 (median 12)* *4 pts ongoing at 6, 9, 11 and 24 wks Most common adverse events included nausea (74%, 8% G3); vomiting (61%, 5% G3); diarrhea (65%, 2% G3); fatigue (31%, 2% G3), increased creatinine (51%, 7% G3/4 in the context of PD and light chain nephropathy but reversible) and anemia (63%, 5% G3). 10 pts had G3/4 neutropenia which resolved. Dose reduction was required to 100 mg/d (n=16) or to 50 mg/d (n=4). 9 pts discontinued treatment due to side effects. Attributable toxicities otherwise proved manageable with supportive care and no peripheral neuropathy or DVT seen. CONCLUSION: Perifosine as monotherapy has modest activity, but in combination with dex showed significant activity in pts with relapsed/refractory MM, achieving PR + MR in 38%, and/or stabilization of disease in 47% of evaluable pts to date. It was generally well tolerated, although caution in pts with renal dysfunction is warranted. PK, IHC and gene array studies are ongoing. Other novel studies with peri in combination with bortezomib and with lenalidomide +/−dex are underway.

Description: CD33 is a sialoglycan protein expressed on the vast majority of myeloid malignancies as well as normal myeloid and monocytic progenitors. SGN-33 is a humanized antibody that specifically binds CD33, inducing antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, and antibody-dependent cellular phagocytosis. In prior clinical testing at lower dose levels, this antibody elicited antitumor activity and objective responses in patients with relapsed and refractory acute myeloid leukemia (AML) without dose-limiting toxicity. To further characterize a dose-response relationship, a phase I single-arm dose-escalation trial was performed at 5 trial sites to assess the safety, immunogenicity, pharmacokinetics, and antileukemic activity of SGN-33. Entry criteria included CD33 expression on 〉50% of marrow blasts as determined by flow cytometry. Cohorts of 3–6 patients with advanced myeloid malignancies received intravenous SGN-33 at weekly doses of 1.5 to 8 mg/kg for 5 weeks as outpatients. Clinical response was assessed by bone marrow morphology and hematologic improvement. Patients demonstrating clinical benefit were eligible for additional every other week outpatient infusions. A total of 31 patients [AML (18), MDS (10), and CMML (3)] with a median age of 75 years (range: 52 to 89) were treated with escalating doses of SGN-33. Among AML patients, 6 had antecedent hematologic disorder. Dosing cohorts included 1.5 (6), 2.5 (4), 4 (4), and 8 mg/kg (17). Dose limiting toxicity has not been observed; the most common drug-related adverse event was chills associated with the first infusion (11/31 patients). Infusion reactions were uncommon during subsequent doses. Among adverse events considered related to antibody, none were Grade 4 and two were Grade 3: tumor lysis syndrome documented at 4 mg/kg that resolved swiftly with hydration, and febrile neutropenia observed at 8 mg/kg dose level. No anti-SGN-33 immune responses were detected among the first 15 patients tested. Exposure (AUC) to SGN-33 increased relative to dose and accumulation was documented with repeat dosing. The median time on study was 33 days (range 1–407) and 9 patients have received treatment for more than 56 days. Among 18 patients with AML, 4 have achieved CR and 1 CR with incomplete platelet recovery. To date, stable disease has been observed in 6 MDS patients. In summary, SGN-33 has been well tolerated at doses up to 8 mg/kg/wk, achieving serum SGN-33 exposures approximately twenty times higher than in prior studies. Complete remissions were observed in older patients with AML who were not candidates for intensive therapies. Given the responses observed in the context of an excellent tolerability profile, SGN-33 holds promise, as single agent or as part of combination therapy, for the treatment of patients with myeloid malignancy who are ineligible for aggressive therapy.

Description: Abstract 1198 Risk stratification of plasma cell neoplasms (PCNs) has become an integral part of clinical management along with the rapid advances in treatment. Cytogenetics is widely performed at diagnosis but has a low abnormality detection rate due to poor proliferation of plasma cells (PCs) in culture and inability to identify cryptic translocations. Conventional interphase FISH improves detection sensitivity, but lacks specificity since the percentage of PCs is diluted by the large number of normal bone marrow cells due to the indiscriminative analysis of all cells by FISH. The International Myeloma Working Group recommends all FISH tests for myeloma be PC specific by either PC enrichment or identifying PCs by cytoplasmic immunoglobulin staining (cIg FISH). However, the real benefits of cIg FISH compared to conventional FISH have never been demonstrated in a controlled study. In this objective comparative study, 75 paired samples from patients with PCNs were analyzed concurrently by conventional FISH and cIg FISH with probes for t(4;14), t(11;14), t(14;16), -13/13q (RB1/LAMP1), 17p- (TP53) and CEP3. For conventional FISH, a minimum of 200 nuclei were scored per probe set. For cIg FISH, 100 cIg positive cells were scored per probe with a minimum of 25 cIg+ cells required for conclusive reporting. In this study, 51/75 cases met the above criteria for direct comparison (see Table). cIg FISH results demonstrated an improved overall detection rate [-13/13q: 53% vs. 45%; 17p-: 14% vs. 12%; t(11;14): 25% vs. 24% and t(4;14): 14% vs.12%]. Impressively, cIg FISH quantitatively identified a much higher proportion of abnormal PCs in all cases. The median % of abnormal PCs with all probes was 〉50% by cIg FISH but no more than 10% by conventional FISH. The abnormal PCs detected by cIg FISH were 〉90% of cIg+ cells in 18 cases with at least one probe. In contrast, the abnormal PCs detected by conventional FISH were

Description: Field line resonances have been observed for decades by ground-based and in situ instruments. The driving mechanism(s) are still unclear, although previous work has provided strong grounds that coherent waves in the solar wind may be a source. Here we present further evidence, with the use of multitaper analysis, a sophisticated spectrum estimation technique. A set of windows (dpss tapers) is chosen with characteristics that best suit the width of the narrowband peaks to be identified. The orthogonality of the windows allows for a confidence level (of say 95%) against a null hypothesis of a noisy spectrum, so that significant peaks can be identified. Employing multitaper analysis we can determine the phase and amplitude coherence at the sampling rate of the data sets and, over their entire duration. These characteristics make this technique superior to single windowing or wavelet analysis. A high degree of phase and amplitude (greater then 95%) coherence is demonstrated between a 2.1 mHz field line resonance observed by the SHARE radar at Sanae, Antarctica and the solar wind oscillation detected by WIND and ACE satellites.

Description: All the accessible auroral observations recorded in Chinese and Japanese histories during the interval AD 1840–1911 are investigated in detail. Most of these auroral records have never been translated into a Western language before. The East Asian auroral reports provide information on the date and approximate location of each auroral observation, together with limited scientific information on the characteristics of the auroral luminosity such as colour, duration, extent, position in the sky and approximate time of occurrence. The full translations of the original Chinese and Japanese auroral records are presented in an appendix, which contains bibliographic details of the various historical sources. (There are no known reliable Korean observations during this interval.) A second appendix discusses a few implausible "auroral" records, which have been rejected. The salient scientific properties of all exactly dated and reliable East Asian auroral observations in the interval AD 1840–1911 are summarised succinctly. By comparing the relevant scientific information on exactly dated auroral observations with the lists of great geomagnetic storms compiled by the Royal Greenwich Observatory, and also the tabulated values of the Ak (Helsinki) and aa (Greenwich and Melbourne) magnetic indices, it is found that 5 of the great geomagnetic storms (aa〉150 or Ak〉50) during either the second half of the nineteenth century or the first decade of the twentieth century are clearly identified by extensive auroral displays observed in China or Japan. Indeed, two of these great storms produced auroral displays observed in both countries on the same night. Conversely, at least 29 (69%) of the 42 Chinese and Japanese auroral observations occurred at times of weak-to-moderate geomagnetic activity (aa or Ak≤50). It is shown that these latter auroral displays are very similar to the more numerous (about 50) examples of sporadic aurorae observed in the United States during the interval AD 1880–1940. The localised nature and spatial structure of some sporadic aurorae observed in East Asia is indicated by the use of descriptive terms such as "lightning", "rainbow", "streak" and "grid".