ATLANTA – The American Society of Hematology's (ASH) annual meeting embraces, more than many other conferences, both the basic research and the clinical treatment side of diseases their members focus on.

And so Monday's E. Donnall Thomas plenary lecture was on genome sequencing of acute myeloid leukemia (AML) patients, even as companies such as Clavis Pharma ASA were presenting clinical trial updates on AML therapeutics. (See story in this issue.)

Speaker Timothy Ley, of Washington University in St. Louis, summarized his team's goal by recounting the fates of the first two AML patients whose genomes they sequenced. Both had seemingly identical risk profiles when they were first diagnosed: a bone marrow full of blast cells, which are the XX cells that are overproduced in AML, but normal cytogenetics.

One of those two patients died less than two years after her diagnosis. The other has been back at work for several years now, relapse-free.

Ley and his colleagues have now sequenced 50 whole AML genomes and another 150 exomes, and they matched normal genomes from the skin, to answer the question, "Why do patients with the same risk profile have such different outcomes?"

The data from those genomes have begun to yield insights into that question, revealing 23 genes to date that are mutated significantly more often in AML patients than in age-matched controls, which also accumulate mutations in their hematopoietic stem cells as they age. Another 259 genes are mutated recurrently, albeit not significantly. Ley and his team have sorted those mutations into nine distinct pathways and have begun to work out the interactions between those pathways.

To truly answer the question, he told the audience at the lecture, it will be necessary to sequence many more genomes. "There is an enormous amount left to be learned," he said. "Two hundred genomes are not even enough to scratch the surface."

But sequencing more genomes is not the only approach to uncover AML's secrets. In fact, Ley said, "it's still amazing to me how many principles you can learn from one case, well studied."

One example is mutations that his team has seen only once in their studies to date – so-called singletons. The team has seen more than 1 ,000 such singletons in the sequencing so far.

A mutation that occurs in only one of 200 samples would seem like an obvious passenger mutation. "But when you start looking at them," Ley said, some of those singletons are clear candidates for driver mutations despite their relative rarity. "Activating mutations in the Abl kinase – you can't ignore that kind of information."

Another example of rare but important events is subclones that are present at a rare frequency. Such subclones are cancer cells that acquire additional mutations and a further growth advantage compared to the primary tumor.

The details of sequencing methods mean that current technologies can't detect mutations that occur in fewer than 20 percent of cells. Ley said that, initially, his team decided to focus on the frequent mutations.

But, he noted, the mere fact that a subclone arises means that it has a growth advantage, which means that by definition it is relevant to the patient's prognosis.

"If you can detect a subclone, it's outgrowing its parent," he said. "That has got to be trouble."

And it can explain why some patients relapse. Ley showed one clonal evolution diagram of a tumor that gave rise to a subclone with a Ftl3 mutation. After treatment, that subclone became the dominant clone, and the one that ultimately led to the patient's demise.

"To understand AML," Ley concluded, "it is not enough to know the mutations. You also have to know the clones in which they reside."

Also reported at the conference were Phase II results for Ambit Biosciences Inc.'s quizartinib, which inhibits the Flt3-ITD kinase.

Those mutations, Mark Levis, a member of Ambit's clinical advisory board, told reporters at a press conference describing the findings, are "a very nasty subset" of what is an aggressive cancer in the first place. And in the results reported at ASH, Levis' team treated the worst of the worst: patients relapsed or refractory to second-line treatment or a bone marrow transplant.

"These patients were essentially on death row," Levis told reporters. "We don't even have a survival rate to report."

In the AC220 trial, treatment with quizartinib – like many targeted therapies – led to increases in overall survival that were modest at best. But what the drug did do for a fair number of patients was improve their overall states sufficiently to enable them to get stem cell transplants – and that, in turn, improved survival more noticeably.

In other ASH news:

• Alnylam Pharmaceuticals Inc., of Cambridge, Mass., presented new preclinical data from its RNAi therapeutic program for the treatment of hemophilia and other bleeding disorders. Company scientists presented data showing that ALN-AT3, a subcutaneously administered RNAi therapeutic targeting antithrombin (AT), yielded potent, dose-dependent and durable knockdown of AT in nonhuman primates with an up to fourfold increase in thrombin generation. The company also offered preclinical results from its program in hemoglobinopathies. Data showed that ALN-TMP, an RNAi therapeutic targeting Tmprss6, led to disease-modifying effects, including a correction in globin gene expression, in a model of βbeta-thalassemia.

• AMAG Pharmaceuticals Inc., of Lexington, Mass., reported data from two pivotal Phase III trials testing ferumoxytol in subjects with iron deficiency anemia who had failed or could not tolerate oral iron treatment. In study IDA-301, ferumoxytol achieved both primary efficacy endpoints, with more than 80 percent of participants achieving an increase of 2 g/dL or greater in hemoglobin vs. 5.5 percent in the placebo group. Study IDA-302 also hit both primary efficacy endpoints, with subjects in the ferumoxytol arm showing a greater mean increase in hemoglobin of 2.7 g/dL at week five, compared to a 2.4 g/dL increase in the iron sucrose arm. The company also reported patient-reported outcome data from IDA-301 , showing a direct correlation between the rise in hemoglobin and improvement in patient-reported measures of fatigue.

• Ariad Pharmaceuticals Inc., of Cambridge, Mass., disclosed 12-month follow-up data from the pivotal PACE trial of ponatinib, its investigational Bcr-Abl inhibitor, in heavily pretreated patients with resistant or refractory chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia. The study showed that 56 percent of chronic-phase CML patients in the trial, including 70 percent of patients with a T315I mutation, achieved a major cytogenetic response, the primary endpoint for chronic-phase CML patients.

• Astex Pharmaceuticals Inc., of Dublin, Calif., reported Phase I data showing that SGI-110, a second-generation hypomethylation agent, had a differentiated pharmacokinetic profile resulting in an extended half-life and exposure to decitabine as delivered via subcutaneous administration. The ongoing Phase I/II study is testing SGI-110 in patients with relapsed/refractory intermediate or high-risk myelodysplastic syndromes or acute myelogenous leukemia (AML). Of the 17 heavily pretreated AML patients who achieved adequate hypomethylation, five major responses were observed.

• Baxter International Inc., of Deerfield, Ill., disclosed pivotal study results evaluating the safety and efficacy of BAX 326, a recombinant Factor IX protein, for the treatment and prophylaxis of bleeding episodes for patients with hemophilia B older than 12. The Phase I/III study investigated the pharmacokinetics, efficacy and safety of BAX 326 in 73 previously treated patients with severe or moderately severe hemophilia B. Results showed that twice-weekly prophylactic treatment achieved a median annualized bleed rate of 1.99, with 43 percent of patients experiencing no bleeds. The impact of prophylaxis with BAX 326 also translated into statistically significant improvements in physical health-related quality of life.

• Biothera Inc., of Eagan, Minn., said all subjects in a Phase I study of high-risk chronic lymphocytic leukemia responded to the combination therapy of Imprime PGG, Campath (alemtuzumab, Sanofi SA) and Rituxan (rituximab, Biogen Idec Inc. and Roche AG), with 64 percent achieving a complete response. Imprime PGG is an immunomodulatory drug.

• Boehringer Ingelheim GmbH, of Ingelheim, Germany, said preliminary results from the randomized portion of a Phase II study testing volasertib in newly diagnosed patients with acute myeloid leukemia considered ineligible for intensive remission induction therapy showed higher rates of objective response and a trend for longer median event-free survival when given in combination with low-dose cytarabine vs. cytarabine alone. A Phase III study of volasertib plus cytarabine is slated to start in early 2013. In a separate presentation, Boehringer reported results from a post-hoc analysis of the RE-LY trial showing that in patients experiencing a major bleeding event, treatment with Pradaxa (dabigatran etexilate) was associated with lower mortality and a shorter length of stay in intensive care compared to warfarin. The post-hoc analyses compared clinical management and outcomes following major bleeding events associated with both Pradaxa and warfarin in the RE-LY trial alone as well as in a pooled analysis of five Phase III studies in the indications for stroke prevention in nonvalvular atrial fibrillation, acute treatment and secondary prevention of venous thromboembolism.

• Bristol-Myers Squibb Co., of New York, and Abbott, of Abbott Park, Ill., disclosed results from a Phase II, open-label study in patients with previously treated multiple myeloma that evaluated two doses of elotuzumab (10 mg/kg and 20 mg/kg) in combination with lenalidomide and low-dose dexamethasone. In the 10 mg/kg arm, median progression-free survival (PFS) was not reached after 20.8 months of follow-up (N = 36) and the objective response rate (ORR) was 92 percent. Of patients who received elotuzumab at a dose of 20 mg/kg, median PFS was 18.6 months (N = 37) and ORR was 76 percent.

• Celgene Corp., of Summit, N.J., reported Phase I data showing that oral, epigenetic therapy CC-486 (oral azacitidine) in patients with lower-risk myelodysplastic syndromes (MDS) resulted in an overall response rate of 42.3 percent (11 of 26 patients) in the 14-day treatment arm, with a response rate of 37 percent (10 of 27 patients) in the 21-day treatment arm. Patients showing any hematologic improvement totaled 26.9 percent (seven of 26) in the 14-day arm and 29.6 percent (eight of 27) in the 21-day arm. The trial enrolled patients with lower-risk MDS who were red blood cell transfusion-dependent and/or thrombocytopenic.

• Concert Pharmaceuticals Inc., of Lexington, Mass., presented preclinical findings demonstrating that CTP-221, its deuterated S-lenalidomide analogue, exhibited enhanced potency compared to racemic lenalidomide, the active ingredient in Revlimid (lenalidomide, Celgene Corp.), in multiple myeloma and del(5q) myelodysplastic syndromes. CTP-221 consistently demonstrated greater potency in immunomodulatory and antiproliferative in vitro efficacy assays compared to lenalidomide, including a 2.7-fold increase in IL-2 induction in anti-CD3 stimulated peripheral blood mononuclear cells, a 3.7-fold greater inhibition of TNF-alpha production in LPS-stimulated whole blood and a 2.6-fold greater inhibition of proliferation of MM. 1S human multiple myeloma cells.

• Cyclacel Pharmaceuticals Inc., of Berkeley Heights, N.J., presented updated survival data from its Phase III SEAMLESS trial, which tested oral sapacitabine capsules in elderly patients, 70 years or older, with newly diagnosed acute myeloid leukemia who were not candidates for or who refused induction chemotherapy. Nineteen patients, or 41 percent, responded, with 10 complete responses, four partial responses and five major hematological improvements. Median overall survival was 238 days, or about eight months, with 35 percent of patients surviving one year or longer. Among 33 patients who were 75 or older, the median overall survival was 263 days, and 1-year survival was 36 percent.

• Genmab A/S, of Copenhagen, Denmark, reported preliminary safety and efficacy data from the Phase I/II study of daratumumab (HuMax(R)-CD38) in multiple myeloma. Of three patients treated at the final, highest dose level of 24 mg/kg, two achieved a partial response and one achieved a minimal response (MR). Altogether, eight of 12 patients in the study who received daratumumab at a dose level of 4 mg/kg or higher achieved at least an MR. The data showed no major safety issues. The most relevant drug-related adverse events were low-grade infusion-related reactions and a temporary drop in the level of NK cells.

• Geron Corp., of Menlo Park, Calif., reported Phase II results showing that imetelstat, its telomerase inhibitor, produced rapid and durable hematologic and molecular responses in patients with essential thrombocythemia. Data from the first 14 patients, all of whom were refractory to or intolerant of conventional therapies, showed that platelet counts were reduced in all patients (a 100 percent hematologic response rate) and normalized in 13 of 14 patients (a 92.9 percent complete response rate). Data also showed that the allelic burden of the JAK2 V617F gene mutation decreased over time in the seven patients who had such mutations, with substantial reductions that qualified as partial molecular responses achieved in six of seven (85.7 percent) within three to six months of imetelstat treatment. Shares of Geron (NASDAQ:GERN) gained 16 cents, or 15 percent, to close Monday at $1.22.

• Immunomedics Inc., of Morris Plains, N.J., said preclinical data showed that epratuzumab, a humanized antibody targeting the CD22 receptor on B cells, promptly induced the transfer of key proteins associated with the B-cell receptor complex from B cells to other white blood cells such as monocytes, natural killer cells and granulocytes, when bound to the CD22 receptor. Peripheral blood mononuclear cells (PBMCs) from normal donors, systemic lupus erythematosus patients and non-Hodgkin's lymphoma cells spiked into normal PBMCs were used in the study. In a separate presentation, the company reported Phase II data showing that adults with relapsed or refractory acute lymphocytic leukemia had a complete response rate of 50 percent after receiving one cycle of treatment with epratuzumab in combination with clofarabine and cytarabine.

• Infinity Pharmaceuticals Inc., of Cambridge, Mass., reported data from an ongoing Phase I trial of IPI-145, its oral inhibitor of PI3K-delta and PI3K-gamma, in patients with advanced hematologic malignancies, with preliminary results showing the drug to be well tolerated and clinically active in both B-cell and T-cell malignancies, including chronic lymphocytic leukemia, indolent non-Hodgkin's lymphoma, mantle cell lymphoma, Hodgkin lymphoma and T-cell lymphoma. Data also indicated rapid onset of activity, with clinical activity reported for 16 of 19 responders occurring within the first two cycles of treatment. Shares of Infinity (NASDAQ:INFI) gained $4.83, or 21.4 percent, to close Monday at $27.35.

• Millennium: The Takeda Oncology Co., of Cambridge, Mass., reported data from a Phase I/II study of once-a-week MLN9708 in combination with standard-dose lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma (MM). The previously reported Phase 1 portion of the study was a dose-escalation study, and the primary objectives of the ongoing Phase II portion of the study are to determine the combined complete and very good partial response rates (>/= VGPR), safety and tolerability. Of the three patients who have completed 12 cycles, two achieved a complete response (CR) and one achieved a VGPR. The study is ongoing, and patients will continue to be followed to further evaluate the primary and secondary endpoints. In separate news, the firm reported results from two studies evaluating the safety and efficacy of Velcade (bortezomib)-based therapy. A meta-analysis of 23 Velcade-based studies designed to evaluate the efficacy and safety of bortezomib retreatment in 1,051 patients with multiple myeloma showed that, across studies in which overall response rate (ORR) data were available, the pooled, weighted average ORR was 39 percent, including 57 percent in relapsed-only patients and 23 percent in refractory-only patients. The pooled, weighted average median time to progression was 7.5 months, median progression-free survival (PFS) was 5.8 months and median overall survival (OS) was 16.6 months. In addition, a median 54-month follow-up from a Phase III study of bortezomib-melphalan-prednisone-thalidomide followed by maintenance with bortezomib-thalidomide (VMPT-VT) compared to bortezomib-melphalan-prednisone (VMP) in newly diagnosed multiple myeloma patients showed that median OS was not reached in the VMPT-VT arm and was 60.6 months in the VMP arm (p < 0.01). Median PFS was 33.1 months in the VMPT-VT arm compared to 24.8 months in the VMP arm, (p < 0.0001), and median time to next treatment was 46.6 months in the VMPT-VT arm compared to 27.8 months in the VMP arm (p < 0.0001).

• Nimbus Discovery LLC, of Cambridge, Mass., presented preclinical data showing that the IRAK4 inhibitors ND-2110 and ND-2158, when combined with the Bruton's tyrosine kinase inhibitor, ibrutinib, worked synergistically to induce selective cell death in hematological tumors with the activating MyD88 mutation. That genetically defined patient population can be identified in the clinic prior to treatment increasing the potential for positive response. The synergism of IRAK4 and BTK inhibition was demonstrated in both ABC-DLBCL and Waldenström's macroglobulinemia tumor cells.

Scientists at the University of Pennsylvania's (Penn) Perelman School of Medicine reported that nine of 12 leukemia patients who received infusions of their own T cells after the cells had been genetically engineered to attack the patients' tumors responded to the therapy. Participants included 10 adult patients with chronic lymphocytic leukemia and two children with acute lymphoblastic leukemia. Two of the first three adult patients treated with the protocol remain healthy and in full remission more than two years after their treatment with the engineered T cells. In August, Penn signed an exclusive global research and licensing agreement with Novartis AG, of Basel, Switzerland, to study and commercialize the immunotherapy technology. (See BioWorld Today, Aug. 12, 2012.)

• OxiGene Inc., of South San Francisco, presented data from an investigator-sponsored Phase I study using the company's vascular disrupting agent (VDA), OXi4503, in patients with acute myelogenous leukemia (AML). The ongoing open-label, dose-escalating study is evaluating the safety profile, maximum-tolerated dose and biologic activity of OXi4503. Results on five patients with refractory AML showed an overall response of 40 percent, with one patient achieving a marrow complete remission and another achieving partial remission. None of the patients developed dose-limiting toxicities. Adverse events attributable to OXi4503 infusion included bone pain, fever, anemia and thrombocytopenia. University of Florida investigators also presented preclinical data from a study of bone marrow endothelial cells (BMECs) from both healthy subjects and patients with AML treated with various doses of the combretastatins OXi4503 and Zybrestat (fosbretabulin) for 24 and 48 hours. Results showed that both combretastatins impaired BMECs migration and function compared to untreated control. In addition, degradation of microtubule cytoskeleton occurred in BMECs treated with the two combretastatins.

• Pharmacyclics Inc., of Sunnyvale, Calif., reported that its Bruton's tyrosine kinase inhibitor ibrutinib (PCI-32765), as a single agent, demonstrated durable responses for patients older than 65 with treatment-naive chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) and for those with relapsed/refractory (RR) or high-risk disease. In a Phase Ib/II study of 116 patients, the overall response rate (ORR) was 68 percent in elderly treatment-naive patients with an estimated 96 percent progression-free survival (PFS) rate at 26 months. In patients with RR CLL/SLL, including those with HR disease, the ORR was 71 percent with an estimated PFS at 26 months of 75 percent. Adverse events were relatively infrequent, with the most common including diarrhea, fatigue, nausea and rash. A second Phase II study in 40 patients with HR CLL treated with the combination of ibrutinib and rituximab (Rituxan, Biogen Idec and Roche AG) therapy reported an ORR of 83 percent, with 38 of the 40 patients continuing on therapy without disease progression.

• Portola Pharmaceuticals Inc., of South San Francisco, presented data demonstrating limited drug-drug interactions with betrixaban, its oral Factor Xa inhibitor anticoagulant in Phase III development for the prevention of venous thromboembolism in acute medically ill patients with certain risk factors. The company also presented preclinical data for PRT4445, its universal antidote for Factor Xa inhibitor anticoagulants, as well as preclinical results from Syk/JAK inhibitor PRT2070 and from Syk inhibitor PRT0318 in acute lymphoblastic leukemia.

• Sanofi SA, of Paris, said Phase II data showed that treatment with a selective JAK2 inhibitor (SAR302503) reduced spleen size and improved constitutional symptoms in patients with intermediate-2 or high-risk primary or secondary myelofibrosis. Results from that trial support the two doses (400 mg and 500 mg) selected for the SAR302503 Phase III JAKARTA trial that is currently under way.

• Seattle Genetics Inc., of Bothell, Wash., reported results from a Phase I trial of Adcetris (brentuximab vedotin) in combination with chemotherapy in newly diagnosed mature T-cell lymphoma (MTCL) patients, including those with systemic anaplastic large-cell lymphoma (sALCL). Patients received six cycles of Adcetris every three weeks in combination with cyclophosphamide, doxorubicin and prednisone (CHP). Patients who achieved at least a partial remission after completing six cycles of combination therapy were eligible to receive continued single-agent Adcetris for up to 10 additional three-week cycles. The primary endpoints of the trial included defining maximum-tolerated dose of Adcetris in combination with CHP and evaluating safety, with secondary endpoints of response, progression-free survival and overall survival. After completing combination therapy, 100 percent of patients (N = 26) treated with Adcetris plus CHP had an objective response, including 23 (88 percent) with a complete remission.

• Senesco Technologies Inc., of Bridgewater, N.J., reported interim results from the ongoing Phase Ib/IIa study, with no drug-related serious adverse events or disease-limiting toxicities recorded to date. Cohort one of the study was completed in August, and two of the planned three patients in cohort two have completed dosing.

• TetraLogic Pharmaceuticals Inc., of Malvern, Pa., reported preclinical data showing that its small-molecule Smac mimetic drug candidate birinapant induced regressions in two of three childhood acute lymphoblastic leukemia xenografts expressing tumor necrosis factor-alpha, with one of those showing a maintained complete response. Birinapant is in Phase II testing for several solid tumors and a Phase I/II study in acute myeloid leukemia.

• TG Therapeutics Inc., of New York, reported in vitro and in vivo data demonstrating superior efficacy with ublituximab (TG-1101) compared to Rituxan (rituximab, Biogen Idec Inc. and Roche AG) in primary central nervous system lymphomas, including a significant reduction in tumor burden (p = 0.0014) and improvement in survival (p = 0.016). The drug also induced higher levels of ADCC than rituximab in B-cell non-Hodgkin's lymphoma cell lines and caused a higher degree of CDC lysis in patient-derived tumor cells compared to rituximab. The company also presented data from TGR-1202, a selective PI3K delta inhibitor, showing that the drug demonstrated equal efficacy to GS-1101 in regard to in vitro induction of apoptosis and toxicity, as well as in suppressing Akt phosphorylation in chronic lymphocytic leukemia patient cells.

• YM BioSciences Inc., of Mississauga, Ontario, reported updated findings from its 166-patient Phase I/II study of JAK1/JAK2 inhibitor, CYT387, in myelofibrosis. Results showed a 68 percent durable 12-week transfusion independence response rate with a maximal duration of response approaching three years and ongoing. In addition, the percentage of patients requiring transfusions decreased from 44 percent at baseline to fewer than 10 percent at week 40. CYT387 was well tolerated in myelofibrosis patients for dosing periods of up to three years and ongoing, with the most common reported adverse effects including thrombocytopenia; transient, mild dizziness; mild peripheral neuropathy; and abnormalities in liver/pancreas-related laboratory tests.