Abstract▪2888▪This icon denotes a clinically relevant abstract
Despite its poor sensitivity to detect bone lesions, its inability to define focal disease in the bone marrow, and its incapacity to ...identify extramedullary disease; skeletal survey remains the gold standard in multiple myeloma (MM). We conducted a prospective clinical study to evaluate novel molecular imaging in MM and its precursors (monoclonal gammopathy of undetermined significance, MGUS; smoldering myeloma, SMM).
We included 10 MGUS, 10 SMM, and 10 MM (2/8; untreated/treated) patients. To define evidence of osteolytic lesions and extramedullary disease, all patients were assessed by skeletal survey, fluorine-18 fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT), 18F-sodium fluoride (18F-NaF) PET/CT. To assess bone marrow vascularity we conducted dynamic contrast enhanced-magnetic resonance imaging (DCE-MRI). Using DCE-MRI, we compared exchange rate constants (contrast agent transit from the extravascular compartment to the intravascular compartment, kep ; movement of contrast agent from plasma to extravascular extracellular space, ktrans) with bone marrow biopsies immunostained with CD34 as measures of microvessel density (MVD).
All but one MGUS patients were negative by 18F-FDG. One had indeterminate uptake in possible early myelomatous lesions but was negative on 18F-NaF. Two MGUS patients had unexplained focal uptake in bone (one in the left orbital sphenoid and another in the left temporal bone) without CT abnormalities. Two SMM patients had abnormalities by PET/CT. One SMM patient had subtle increased 18F-NaF PET uptake in T12 which corresponded to CT, MRI and DCE-MRI abnormalities in this region; 18F-FDG PET and skeletal survey were negative. Another SMM patient had increased 18F-FDG PET uptake in the left clavicle with negative 18F-NaF that was biopsy proven to be consistent with disease. In 8 MM patients, both 18F-FDG and 18F-NaF PET/CT showed mild to moderate positive PET uptake corresponding with CT abnormalities; the remaining 2 MM patients had CT abnormalities, which were 18F-NaF positive, corresponding with skeletal survey, while 18F-FDG PET was negative. Immunohistochemistry and kep were correlated (r=0.64 and p=0.0003), and DCE-MRI showed higher kep levels in MM versus MGUS patients (mean kep 9.4 vs. 5.0; p<0.05); suggesting that increased MVD may be associated with transformation from early precursor disease to frank malignancy. In 2 MGUS patients and 1 SMM patient, DCE-MRI showed focal disease in the bone marrow.
Novel molecular imaging techniques detected evidence of altered bone marrow biology in myeloma precursor disease, which was not found on skeletal survey. Our results emphasize the broad biological and clinical heterogeneity in myeloma precursor disease, and the need for molecularly defined phenotypes. This study provides new avenues for future investigations designed to (1) initiate/monitor early treatment in high-risk myeloma precursor disease and (2) to monitor minimal residual disease and/or to detect early relapse. Detailed imaging, clinical, and molecular data will be presented at the meeting.
No relevant conflicts of interest to declare.
BACKGROUND. c-kit is a receptor tyrosine kinase for the ligand stem cell factor and a member of the PDGF receptor family. c-kit positivity, as defined by the presence of CD117 by flow cytometry (FC) ...in > 20% blasts, is detected in up to 90% of patients with AML, and is a potential target for imatinib, a selective tyrosine kinase inhibitor of c-kit as well as of BCR-ABL, PDGFR, and ARG. Previous reports of treatment with single-agent imatinib at 400 mg/day showed no response in AML (Cortes et al, Cancer 2003), while up to 24% of patients treated with 600 mg/day responded (Kindler et al, Blood 2003, Abstract 3242). Little information is available on the response in AML to imatinib as a single agent at 800 mg/day.
CASE AND DISCUSSION. A 42-year old Caucasian male with relapsed c-kit expressing AML with del(9q), concurrent secondary high-grade (HG) glioma and few remaining therapeutic options presented to our service. He was initially diagnosed with primary oligodendrioglioma in January 2001 and underwent subtotal tumor resection, followed by whole brain radiation therapy, followed by 6 cycles of procarbazine, CCNU, and vincristine (PCV) chemotherapy, and entered complete remission (CR). In December 2002, he was diagnosed with AML M2 with del(9q) and was treated with cytosine arabinoside (Ara-C) and daunorubicin (7+3), followed by 3 cycles of consolidation with HD Ara-C, and entered CR. In March 2004, he had recurrent abnormal magnetic resonance imaging of the brain and HG malignant glioma was diagnosed by stereotactic biopsy. He was started on temozolamide but was unable to tolerate treatment due to pancytopenia, and a bone marrow (BM) at another institution disclosed relapsed AML with 75% blasts. Upon presentation to our institution, a BM examination showed > 90% blasts, 53% of which expressed CD117 positivity by FC. Imatinib therapy was initiated at a dose of 400 mg/day and escalated to 800 mg/day (HD) after lack of response. (Table 1.) The peripheral blood (PB) white blood cell count (WBC) peaked on Day 9 of treatment with imatinib and declined thereafter. On Day 21, blasts were undetectable in the PB and there was a proportional increase of PB neutrophils (PMN). By Day 25, the BM blasts decreased to 50% and only 12% blasts showed positivity for CD117. The patient experienced severe muscle/bone pains at the start of imatinib therapy, which resolved within five days. Response to HD imatinib was also accompanied by dramatic decline in serum LDH. The patient's platelet (PLT) count improved to a peak of 70k on Day 14, declined thereafter, and the patient required PLT transfusion support by Day 31. The patient also received dexamethasone 4 mg q6h for his HG glioma, which remained stable during this time of observation.
CONCLUSION. Our case demonstrates that HD imatinib 800 mg/day has significant preferential activity against the CD117+ AML blasts, is active in a shorter time span than previously reported at lower doses, and should be studied further in combination with other agents in AML. The patient's HG glioma may have been partially stabilized by imatinib as PDGFR overexpression has been reported in secondary glioblastomas.
Table 1.
Imatinib Dose, mg/dayDayWBC x 10-3/uLPMN, %PB Blast, %BM Blast,%BM Blasts CD117 +, %PLT x 10-3/uL-−71.8415> 905334400117.5321--28600759.6540--50800871.0921--418009100.0930--318001411.02225--70800216.3610--31800254.0490–3501213
Blacks are twice as likely to develop and die from multiple myeloma (MM), and are less likely to receive an autologous hematopoietic-cell transplant (AHCT) for MM compared to Whites. The influence of ...race on outcomes of AHCT for MM is not well described. We compared the probability of overall survival (OS), progression-free survival (PFS), disease progression, and nonrelapse mortality (NRM) among Black (N = 303) and White (N = 1892) recipients of AHCT for MM, who were reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) from 1995 to 2005. The Black cohort was more likely to be female, and had better Karnofsky performance scores, but lower hemoglobin and albumin levels at diagnosis. Black recipients were younger and more likely to be transplanted later in their disease course. Disease stage and treatment characteristics prior to AHCT were similar between the 2 groups. Black and White recipients had similar probabilities of 5-year OS (52% versus 47%, P = .19) and PFS (19% versus 21%, P = .64) as well as cumulative incidences of disease progression (72% versus 72%, P = .97) and NRM (9% versus 8%, P = .52). In multivariate analyses, race was not associated with any of these endpoints. Black recipients of AHCT for MM have similar outcomes compared to Whites, suggesting that the reasons underlying lower rates of AHCT in Blacks need to be studied further to ensure equal access to effective therapy.
SPTBN1 mutations cause a neurodevelopmental syndrome characterized by intellectual disability, language and motor delays, autism, seizures and other features. The variants disrupt beta II-spectrin ...function and disturb cytoskeletal organization and dynamics. SPTBN1 encodes beta II-spectrin, the ubiquitously expressed beta-spectrin that forms micrometer-scale networks associated with plasma membranes. Mice deficient in neuronal beta II-spectrin have defects in cortical organization, developmental delay and behavioral deficiencies. These phenotypes, while less severe, are observed in haploinsufficient animals, suggesting that individuals carrying heterozygous SPTBN1 variants may also show measurable compromise of neural development and function. Here we identify heterozygous SPTBN1 variants in 29 individuals with developmental, language and motor delays;mild to severe intellectual disability;autistic features;seizures;behavioral and movement abnormalities;hypotonia;and variable dysmorphic facial features. We show that these SPTBN1 variants lead to effects that affect beta II-spectrin stability, disrupt binding to key molecular partners, and disturb cytoskeleton organization and dynamics. Our studies define SPTBN1 variants as the genetic basis of a neurodevelopmental syndrome, expand the set of spectrinopathies affecting the brain and underscore the critical role of beta II-spectrin in the central nervous system.
We report the first planet discovery from the two-wheeled Kepler (K2) mission: HIP 116454 b. The host star HIP 116454 is a bright (V = 10.1, K = 8.0) K1-dwarf with high proper motion, and a ...parallax-based distance of 55.2 +/- 5.4 pc. Based on high-resolution optical spectroscopy, we find that the host star is metal-poor with Fe/H = -.16 +/- .18, and has a radius R = 0.716 +/- .0024 R_sun and mass M = .775 +/- .027 Msun. The star was observed by the Kepler spacecraft during its Two-Wheeled Concept Engineering Test in February 2014. During the 9 days of observations, K2 observed a single transit event. Using a new K2 photometric analysis technique we are able to correct small telescope drifts and recover the observed transit at high confidence, corresponding to a planetary radius of Rp = 2.53 +/- 0.18 Rearth. Radial velocity observations with the HARPS-N spectrograph reveal a 11.82 +/- 1.33 Mearth planet in a 9.1 day orbit, consistent with the transit depth, duration, and ephemeris. Follow-up photometric measurements from the MOST satellite confirm the transit observed in the K2 photometry and provide a refined ephemeris, making HIP 116454 b amenable for future follow-up observations of this latest addition to the growing population of transiting super-Earths around nearby, bright stars.
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