ALBERT

Description: Multiple myeloma (MM) is the second most common hematologic malignancy. Presently, the majority of suitable MM patients who undergo high-dose melphalan therapy followed by autologous peripheral blood stem cell transplantation (PBSCT) fail to achieve a complete response (CR). This suggests that treatment options following autologous transplantation are needed. Moreover, there is a need to determine the optimal role of maintenance therapy following PBSCT in MM. Over time, Bortezomib (B) has been shown to be an active agent in the treatment of newly diagnosed, and relapsed or refractory MM. Therefore, the primary objective of this study was to determine the efficacy of B treatment after high-dose melphalan therapy followed by PBSCT in MM. Fifty patients (pts) were enrolled between March 2004 and November 2007, and 47 were evaluable (2 pts ineligible and 1 pt data pending). Pts received B 1.3 mg/m2 IV on Days 1, 4, 8, and 11 of each 21-day cycle. Pts were treated for 4 cycles or until evidence of disease progression or intolerable toxicity. If an improvement in response was noted after Cycle 4, pts could receive up to 4 additional cycles. To reduce the incidence of varicella zoster infection, antiviral prophylaxis (acyclovir 400 mg PO BID) was taken for the duration of the study. The median patient age was 56 years (range, 39–74), 82% were white, and 68% were male. The majority of pts (64%) had ECOG PS 0, 44% were Durie-Salmon Stage IIIA prior to induction therapy. Forty percent had symptomatic IgG-kappa multiple myeloma. Of all pts, 74% had a single transplant, while 24% had tandem transplants (2% [n=1 pt] data pending). Sixty-eight percent of pts had a PR and 18% had a MR following their transplant(s). While on study, pts received a median of 4 cycles (range, 2–8) of therapy with B. Efficacy results for the evaluable population are: CR 4%, unconfirmed (u) CR 4%, PR 21%, uPR 17%, MR 11%, and No Change 36%. Median time-to-treatment failure was 5.8 months (mos) (range, 0.2–19.4). There were 2 on-study deaths (sepsis and PD). Grade 3–4 treatment-related toxicities reported in 〉1 pt were thrombocytopenia (15%), asthenia (10%), neutropenia or neuropathy (8% each), peripheral neuritis (6%), and nausea (4%). Twenty patients discontinued study treatment due to toxicity (22%), pt request (6%), disease progression, ineligibility, and intercurrent illness/protocol deviation (4% each). 26 pts (52%) completed the study; 4 pts are still on study (8%). Sixteen pts started new treatment; median time from start of study treatment to the start of new treatment was 5.2 mos (range, 1.5–17.6 mos). The study was closed earlier than the planned due to the widespread availability of B, and the inability to find B-naïve patients. Bortezomib given after high-dose melphalan therapy and autologous PBSCT was well-tolerated with manageable adverse events. Updated cytogenetic analysis will be available for presentation.

Description: Paroxysmal Nocturnal Hemoglobinuria (PNH) is an acquired clonal stem cell disease, characterised by intravascular hemolysis, bone marrow failure and lifethreatening thromboses. The median survival is 10–15 years, with the average age of presentation being in the 30’s. Symptoms include hemoglobinuria, fatigue, anemia, venous and arterial thromboses, recurrent pain, renal impairment, erectile dysfunction and pulmonary hypertension. The care of a patient with PNH is complex and challenging, as many experience chronic symptoms with periods of acute exacerbations. Historically the management of PNH included bone marrow transplant, blood transfusion and administration of additional supportive therapies, all necessitating regular visits to the hospital. Eculizumab, a monoclonal antibody that binds to the C5 complement component inhibiting the activity of terminal complement and thus preventing the destruction of red blood cells has dramatically altered the management of hemolytic PNH. Clinical trials of eculizumab demonstrated the resolution of the majority of symptoms and complications of PNH and resulted in its approval in the UK in June 2007. Eculizumab is administered as a 30 minute intravenous infusion every 14 days, and under the terms of its current EU licence, must be administered by a healthcare professional. In view of the rarity of PNH there are relatively few specialist Centres for the disease resulting in, patients travelling long distances for review and treatment. In view of the dramatic improvement in symptoms on eculizumab many patients are able to return to a near normal lifestyle. In the UK, Leeds Teaching Hospitals with Healthcare at Home have developed a home infusion programme that ensures safe administration of eculizumab in the patient’s home at a time convenient to them, leading to enhanced treatment-associated convenience for patients and their families. Patients then only attend the PNH Centre every 3 months to ensure appropriate monitoring and patient education. A recent survey of patients reports a reduction in treatment-associated burden for PNH patients and their families when receiving infusions at home. 46 patients responded to the survey with just over half receiving eculizumab. Of the 21 patients at the time receiving home infusions 19 found this more convenient than the hospital. Home treatment allows flexibility and for some, the return to full-time employment, with the associated financial benefits and improvement in psychological well-being. Of the 21 patients on home care 7 stated there ability to work was transformed with a further 10 having great improvement. Whilst the purpose of the survey was not to address financial burden, the home infusion programme has anecdotally reduced the financial burden on the patient and their family by eliminating the need for time off work, allowing return to full-time employment, and eliminating the cost of travel to and from the hospital for treatments. No patients reporting negative impact, including effect on social life and family relationships, whilst 15 experienced improvement or complete transformation in both areas. The patients reported confidence in the homecare programme, knowing that a very close working relationship existed between the expert hospital and homecare teams. This innovative programme of medication delivery by a dedicated home nursing team allows patients who have previously struggled to cope with their illness to lead a near normal life with an associated enhancement in quality of life. Patients are able to carry on with activities of daily life, including work, recreational activities and holidays, whilst at the same time ensuring compliance with treatment and therefore allowing maximum therapeutic benefit.

Description: The RUNX1 (AML1) gene is a transcription factor that regulates expression of genes involved in hematopoietic cell differentiation. It is a gene located on chromosome 21 at q22. Genetic alterations of RUNX1 whether through loss-of-function point mutations, translocation or amplification are known to impact myeloid differentiation and trigger leukemic transformation in particular with respect to myelodysplasia and acute myeloid leukemia. However, while there are many articles describing the impact of these types of RUNX1 genetic alterations, there is a paucity of information regarding loss of the entire RUNX1 gene. The case in this abstract highlights the significance of understanding loss of the RUNX1 gene. An 87 year old patient presented for evaluation for anemia and leukopenia. Flow cytometric evaluation revealed 26% myeloid blasts and confirmed a diagnosis of acute myeloid leukemia (AML). The cytogenetic findings demonstrated a translocation between chromosomes 17 and 21 −t(17;21)(q11.2;q22). The dilemma then was to determine if this was a variant of the traditional t(15;17) associated with acute promyelocytic leukemia or a variant of the t(8;21) associated with the M2 subtype of AML. FISH studies determined that there was no involvement of the RARA gene and no evidence of a RUNX1/ETO rearrangement. However, there was a complete loss of RUNX1 on the abnormal chromosome 21. Thus, what appeared to be a balanced translocation included a cryptic loss of RUNX1. While this may be an interesting case presentation the more pertinent question is what is the impact of the RUNX1 loss? This case prompted a review of the data on complete loss of the RUNX1 gene which while limited suggests that RUNX1 loss on its own is not leukemogenic. This poster presents the data and implication of complete loss of RUNX1, the role of this loss in leukemogenesis and patient management.

Description: This study presents various statistical methods for exploring and summarizing spatial extremal properties in large gridpoint datasets. Extremal properties are inferred from the subset of gridpoint values that exceed sufficiently high, time-varying thresholds. A simple approach is presented for how to choose the thresholds so as to avoid sampling biases from nonstationary differential trends within the annual cycle. The excesses are summarized by estimating parameters of a flexible generalized Pareto model that can account for spatial and temporal variation in the excess distributions. The effect of potentially explanatory factors (e.g., ENSO) on the distribution of extremes can be easily investigated using this model. Smooth spatially pooled estimates are obtained by fitting the model over neighboring grid points while accounting for possible spatial variation across these points. Extreme value theory methods are also presented for how to investigate the temporal clustering and spatial dependency (teleconnections) of extremes. The methods are illustrated using Northern Hemisphere monthly mean gridded temperatures for June–August (JJA) summers from 1870 to 2005.

Description: The Brier score is widely used for the verification of probability forecasts. It also forms the basis of other frequently used probability scores such as the rank probability score. By conditioning (stratifying) on the issued forecast probabilities, the Brier score can be decomposed into the sum of three components: uncertainty, reliability, and resolution. This Brier score decomposition can provide useful information to the forecast provider about how the forecasts can be improved. Rather than stratify on all values of issued probability, it is common practice to calculate the Brier score components by first partitioning the issued probabilities into a small set of bins. This note shows that for such a procedure, an additional two within-bin components are needed in addition to the three traditional components of the Brier score. The two new components can be combined with the resolution component to make a generalized resolution component that is less sensitive to choice of bin width than is the traditional resolution component. The difference between the generalized resolution term and the conventional resolution term also quantifies how forecast skill is degraded when issuing categorized probabilities to users. The ideas are illustrated using an example of multimodel ensemble seasonal forecasts of equatorial sea surface temperatures.

Description: Verification is an important part of any forecasting system. It is usually achieved by computing the value of some measure or score that indicates how good the forecasts are. Many possible verification measures have been proposed, and to choose between them a number of desirable properties have been defined. For probability forecasts of a binary event, two of the best known of these properties are propriety and equitability. A proof that the two properties are incompatible for a wide class of verification measures is given in this paper, after briefly reviewing the two properties and some recent attempts to improve properties for the well-known Brier skill score.

Description: A global database of infrared (IR) land surface emissivity is introduced to support more accurate retrievals of atmospheric properties such as temperature and moisture profiles from multispectral satellite radiance measurements. Emissivity is derived using input from the Moderate Resolution Imaging Spectroradiometer (MODIS) operational land surface emissivity product (MOD11). The baseline fit method, based on a conceptual model developed from laboratory measurements of surface emissivity, is applied to fill in the spectral gaps between the six emissivity wavelengths available in MOD11. The six available MOD11 wavelengths span only three spectral regions (3.8–4, 8.6, and 11–12 μm), while the retrievals of atmospheric temperature and moisture from satellite IR sounder radiances require surface emissivity at higher spectral resolution. Emissivity in the database presented here is available globally at 10 wavelengths (3.6, 4.3, 5.0, 5.8, 7.6, 8.3, 9.3, 10.8, 12.1, and 14.3 μm) with 0.05° spatial resolution. The wavelengths in the database were chosen as hinge points to capture as much of the shape of the higher-resolution emissivity spectra as possible between 3.6 and 14.3 μm. The surface emissivity from this database is applied to the IR regression retrieval of atmospheric moisture profiles using radiances from MODIS, and improvement is shown over retrievals made with the typical assumption of constant emissivity.