A Cheaper, Faster Test for Sickle Cell?
Twelve minutes and 50 cents could be all it takes to diagnose sickle cell disease (SCD), if the sensitivity and specificity results seen with a new rapid, low-cost test hold up in accuracy analyses. The new density-based test developed by researchers from Harvard University takes advantage of the fact that sickle cells are heavier than healthy red blood cells. Slightly larger than a toothpick, the test prototype can be easily administered in the field: after uncapping the capillary tube, pricking the patient’s finger for a blood sample, allowing the blood to wick into the tube, and placing the tube in a centrifuge machine to separate the layers, sickled cells form visibly identifiable layers on the bottom of the thin tube. “The tests we have today work great, but the equipment needed to run them costs in the tens of thousands of dollars, and they take hours to run,” said Ashok A. Kumar, MD, first author of the paper and a postdoctoral fellow in chemistry and chemical biology at the School of Engineering and Applied Sciences at Harvard University. “That’s not [practical for] rural clinics, or even some cities where the medical infrastructure isn’t up to the standards we see in the United States.”
Sources: Kumar A, Patton MR, Hennek JW, et al. Density-based separation in multiphase systems provides a simple method to identify sickle cell disease. Proc Natl Acad Sci. 2014 September 2. [Epub ahead of print]
Harvard University press release, September 2, 2014.
Leukemia Drug Shows Promise for Other Cancers
Dasatinib, a second-generation tyrosine kinase inhibitor approved by the FDA for the treatment of chronic myeloid leukemia (CML), shows promise for treating skin, breast, and several other cancers, according to researchers from Loyola University Chicago Stritch School of Medicine. In CML, the drug targets the protein BCR-ABL; BCR-ABL is similar to Fyn, a protein that is found in these other malignancies. When the drug was used to treat other cancers, researchers found that dasatinib inhibited Fyn’s cell-cell adhesion and migration activity, which prevented cancer cells from migrating and metastasizing.
Source: Fenton SE, Hutchens KA, Denning MF. Targeting Fyn in Ras-transformed cells induces F-actin to promote adherens junction-mediated cell–cell adhesion. Mol Carcinog. 2014 June 29. [Epub ahead of print]
FDA “Fast Tracks” Experimental AML Drug
An experimental IDH2 mutant inhibitor, AG-221 (Agios Pharmaceuticals, Inc.), was recently granted the FDA’s “Fast Track” designation for the treatment of patients with acute myeloid leukemia. AG-221 selectively inhibits the IDH2, or isocitrate dehydrogenase-2, mutation found in a subset of acute myeloid leukemia (AML) patients. The fast-track status is given to medications with the potential to treat serious or life-threatening conditions and address unmet clinical needs. AG-221 is currently being tested in phase I clinical trials in patients with advanced hematologic malignancies. With this new designation, sections of the New Drug Application can be submitted on a rolling basis as data become available.
Source: Agios Pharmaceuticals, Inc. press release. Accessed from: investor.agios.com/phoenix.zhtml?c=251862&p=irol-newsArticle&ID=1939983
Investigational Myeloma Drug Shows Favorable Results
Phase I trial data suggest that treatment with an investigational oral proteasome inhibitor, ixazomib, led to stable disease or better response in 76 percent of patients with heavily pretreated multiple myeloma. In a study population of 60 patients, 15 percent had a “partial or better response” and 60 percent had “stable disease.” All patients had undergone previous treatment with bortezomib and/or carfilzomib, lenalidomide, or stem cell transplantation. Twice-weekly oral ixazomib also appeared tolerable, with no severe neuropathy seen to date.
Source: Richardson PG, Baz R, Wang M, et al. Phase 1 study of twice-weekly ixazomib, an oral proteasome inhibitor, in relapsed/refractory multiple myeloma patients. Blood. 2014 August 14. [Epub ahead of print]
Engineered T Cells in Chemotherapy-Resistant B-Cell Lymphoma
Results from a phase I-IIa clinical trial show successful treatment of diffuse, large B-cell lymphoma (DLBCL) with engineered autologous anti-CD19 CAR T cells in patients with chemotherapy-refractory DLBCL and indolent B-cell malignancies. Of 15 patients with advanced CD19+ B-cell malignancies treated with a single infusion of anti-CD19 CAR T cells, eight achieved complete remission, four achieved partial remissions, one had stable lymphoma, and two were not evaluable for response, according to a research team at the National Cancer Institute. The CAR-expressing T cells were produced from each patient’s own peripheral blood mononuclear cells, using a new cell production process that reduced the preparation time from 24 to 10 days.
Source: Kochenderfer JN, Dudley ME, Kassim SH, et al. Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor. J Clin Oncol. 2014 August 25. [Epub ahead of print]
FDA Expands Approval of Eltrombopag for Severe Aplastic Anemia
On August 26, 2014, the FDA expanded the approved indications for eltrombopag (Promacta®, GlaxoSmithKline) to include treatment of patients with severe aplastic anemia who demonstrated an insufficient response to immunosuppressive therapy. The oral thrombopoeitin receptor agonist has already been approved for the treatment of thrombocytopenia in patients with hepatitis C, and for chronic immune thrombocytopenia patients who demonstrated insufficient response to immunoglobins, corticosteroids, or splenectomy. The FDA’s new approval was based on results from an NHLBI-conducted phase 2 study; 40 percent of this patient population showed hematologic response in at least one lineage (red blood cells, white blood cells, or platelets) at week 12. Among responders, the median red blood cell transfusion–free period was 208 days (range, 15–1,082).
Source: GlaxoSmithKline press release. Accessed from: www.gsk.com/en-gb/media/press-releases/2014/gsks-promacta-eltrombopag-receives-fda-approval-of-an-additional-indication
Updates on Longer-Lasting Hemophilia Treatment Options
Patients with hemophilia A and B may benefit from the less-frequent dosing regimens of two recently FDA-approved fusion protein therapies: recombinant coagulation factor VIII (FVIII) Fc fusion protein (Eloctate™) for hemophilia A and recombinant coagulation factor IX (FIX) Fc fusion protein (Alprolix™) for hemophilia B.
Margaret Ragni, MD, MPH, discussed the safety, efficacy, and clinical implications of these new therapies in a webinar titled “ASH Update on Recent FDA-Approved Therapies for Hemophilia A and B.”*
rFVIIIFc was approved on the basis of results from a phase III pivotal trial that showed that patients with severe hemophilia A who received individualized prophylaxis (25–65 IU/kg every 3–5 days) and those who received weekly prophylaxis (65 IU/kg) had lower annualized bleeding rates (ABR) than those who were treated episodically — to the tune of 92 percent and 76 percent, respectively. Thirty percent of patients who received individualized prophylaxis were also able to lower their bleeding rate while on a five-day interval regimen.
In the phase III trial for rFIXFc, patients with hemophilia B who received 10-day interval dosing (100 IU/kg) had the lowest ABR (1.4), followed by patients in the once-weekly dosing group (50 IU/kg; 3.0). This represented an 87 percent and 83 percent reduction, respectively, in bleeding from the episodic treatment group (20–100 IU/kg). Notably, patients in the 10-day interval group actually received prophylaxis at a median interval of 12.5 days.
In terms of safety, both agents were well-tolerated: adverse events were minor and unrelated to the product (except for one case of painful hematuria in the rFIXFc group).
Both of the agents extended the half-lives of their non-Fc protein counterparts:
- rFVIIIFc: 19 hours (vs. 12.4 hours with rFVIII)
- rFIXFc: 82 hours (vs. 33.8 hours with rFIX)
Speaking about the clinical implications for these new fused proteins, Dr. Ragni noted that the longer duration >1 percent factor level “means we can reduce our treatment frequency and perhaps even avoid ports and ER visits.” The need for less-frequent injections, she added, will also encourage some patients who were not on prophylaxis to consider it.
*ASH, in collaboration with the FDA, offers webinars that feature an unbiased discussion of newly approved hematology therapies. Access recordings of these programs at ASHonDemand.org.