ASH News Daily 2013 - Day 3 - (Page A-16)

Page A-16 ® ASH NEWS DAILY Monday, December 9, 2013 Sickle Cell Disease: New Answers Come With New Questions SICKLE CELL BY JULIE KANTER, MD O ne hundred years ago, Dr. James Herrick first identified sickle cells on a pe- ripheral blood smear from a West Indies dental student. Despite its relatively high prevalence among rare diseases, sickle cell disease (SCD) has remained underfunded and underserved. Patients with SCD are living longer with average lifespans approaching the fifth decade of life. However, the question remains whether quality of life has improved as much as quantity? This year's SCD presentations suggest we have some answers. Dr. Jean Raphael, Baylor College of Medicine, Houston, TX, presented at Saturday's Education Program (repeated Monday at 7:00 a.m.) on the merits of applying the patientcentered medical home (PCMH) to SCD. He described the triple aim of a PCMH: improve quality of care, reduce cost of care, and include the patient experience. Dr. Raphael also explained how pain, the hallmark of SCD, can be managed more ef- CLL «« From Page A-1 Dr. Valentin Goede, German CLL Study Group, presented practice- changing results from the CLL11 trial. Dr. Goede eloquently shared the head-to-head comparison of two chemoimmunotherapy regimens: GA101 plus chlorambucil (GClb) versus rituximab plus Clb (RClb), and an updated analysis of GClb or RClb compared with Clb alone in patients with CLL and comorbidities. Dr. Goede, from the Department of Internal Medicine at the University Hospital Cologne, Cologne, Germany, focuses his research on the prediction and management of age-related vulnerability in elderly lymphoma and leukemia patients. During yesterday's session, Dr. Goede presented the results of this large pivotal phase III trial that enrolled previously untreated CLL patients with significant comorbidities. Patients were randomly assigned to six cycles of 1) Clb alone, 2) GClb, or 3) RClb. The primary endpoint was progression-free survival and the secondary endpoints were response rate, minimal residual disease (MRD), and overall survival (OS). In the final stage-two analysis of GClb versus RClb, treatment arms were similar for baseline characteristics. At a median follow-up of 19 months GClb proved superior fectively in a PCMH. Published articles have already demonstrated that patients with SCD who receive comprehensive care have less acute hospitalization needs. However, as commented by several attendees, problems remain with identifying enough PCMH available to care for the growing adult SCD population. Thus, the PCMH appears to be an answer but also begs further questions. Also on Saturday, Dr. Stella Chou, University of Pennsylvania, Philadelphia, PA, presented her research on the "balancing act" of transfusion therapy in SCD. Dr. Chou described recent results on high-resolution Rh genotyping that helps to explain why allo-immunization has continued in SCD patients receiving blood transfusions despite enhanced antigen matching. Furthermore, she explained that 40 percent of the Rh antibodies found in antigen-positive patients were associated with a delayed transfusion reactions. To prevent these complications, Dr. Chou proposed we should move toward genotyping the Rh antigen. The question becomes whether we will be left with any donors? Until recently, affected patients had only one option (hydroxyurea). However, several presenters revealed early successes in novel therapeutics for SCD. As explained by Dr. Paul Frenette, Albert Einstein College of Medicine, NY, there is an enhanced understanding of the pathophysiology of SCD that has led to new developments in targeted therapies. This augmented understanding of the relationship between the sickled RBC and the microcirculation has led to several new categories of medications. These include anti-adhesion molecules such as GMI-1070, a pan-selectin inhibitor (being presented at 7:15 a.m. on Tuesday by Dr. Laura De Castro, Duke University, Durham, NC) and SelG1, a p-selectin inhibitor (abstract 970 by Dr. Johnathan Stocker, Selexys Pharmaceuticals), and new drugs to target inflammation, including regadenoson, an A2A receptor agonist shown to reduce iNKT cell activation in phase I studies in SCD (abstract 975 by Dr. Joel Linden, La Jolla paring Clb monotherapy to each of the aforementioned chemoimmunotherapy regimens with a median observation of 23 months. Either GClb or RClb was superior to Clb in terms of PFS (GClb versus Clb: HR 0.18, CI 0.13-0.24; RClb vs. Clb: HR 0.44, CI 0.34-0.57). However, most importantly, GClb demonstrated a significant OS advantage over Clb (HR 0.41,CI 0.23-0.74), while RClb did not. The CLL11 trial is pivotal for sevDr. Valentin Goede to RClb in PFS (median PFS 26.7 months vs. 15.2 months, p<0.0001) and achievement of no MRD. Further, a trend toward improved OS was seen with GClb over RClb (HR 0.66, CI 0.41-1.06). Neutropenia was more common with GClb compared with RClb (33% vs. 28%), but no increased risk of infection was noted. Grade three to four infusion-related reactions occurred in 20 percent of the GClb arm compared with 4 percent in the RClb arm and was limited to the first infusion of GClb. Dr. Goede next shared with us the updated stage one analysis of CLL 11, originally presented at the 2013 ASCO Annual Meeting, com- eral reasons. Dr. John Gribben, Barts Cancer Institute in Queen Mary University of London, who introduced this Plenary talk, said, "The investigators are to be commended for the rapid accrual of patients that many thought would be very difficult to enroll into clinical trials." Until now, no other CLL treatment regimen has demonstrated a survival advantage over Clb monotherapy. Dr. Goede and colleagues have unlocked the door to provide an understudied elderly CLL population with safe and effective treatment. Dr. Goede believes that "CLL11 is now reporting on a CLL patient population that is typical for patients treated in routine practice." Surely, most practicing hematologists and oncologists will find the CLL11 trial has an immediate impact in their clinical practice. Dr. Rajasekhar and Dr. Zumberg indicated no relevant conflicts of interest. Institute for Allergy and Immunology. Rounding out treatment options, Dr. Eliane Gluckman, Hospital Saint Louis, Paris, France, reminded attendees that hematopoetic stem cell transplantation (HSCT) is a cure for SCD. Her presentation cited impressive outcomes in sibling-matched transplantations (96% survival) as well as current trials using alternative donors, including matched unrelated donors, umbilical cord blood, and hapoloidentical donors. While HSCT offers immense potential, barriers still remain including the need to expand transplant options to low resource areas, spare fertility, and decrease toxicity. Dr. Jeffrey Chell, the CEO of the NMDP "Be The Match" program and the executive director of the CIBMTR is committed to supporting patients throughout the transplant process so that "financial and social barriers don't prevent curative options." Hopefully this promise will deliver for patients with SCD as we move forward. Dr. Kanter indicated no relevant conflicts of interest. Genes «« From Page A-4 well before an individual is exposed to cancer therapies. The investigators identi- fied seven patients with specific TP53 mutations for whom banked samples were available from several years before the onset of the t-AML/t-MDS. They were then able to identify the specific mutations in these early samples, albeit at very low levels. This important observation suggests a very different model where genotoxic therapies do not necessarily induce TP53 mutations, but rather provide them a selective growth advantage, allowing the clone to expand and potentially further evolve. However, it remains unclear if the patients at risk for cancer may have an enhanced predisposition to develop these random mutations, and thus may start with a higher burden of TP53mutated cells than an average person. These findings open up new opportunities for prevention and potentially early detection of t-MDS and t-AML, which can have a profound effect on patient outcomes. Dr. Kumar indicated no relevant conflicts of interest.

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ASH News Daily 2013 - Day 3

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