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    <recommendedItem id="20100101_19_461"
                     title="Limited Benefit Seen in CML Drug, FDA Says"
                     score="0.015"
                     href="http://www.medpagetoday.com/HematologyOncology/Leukemia/tb/18390?impressionId=1265790513080"
                     
      &lt;p&gt;WASHINGTON  --  Chronic myeloid leukemia (CML) patients who are resistant to imatinib (Gleevec) had a low response rate to treatment with omacetaxine (Omapro), according to Food and Drug Administration (FDA) reviewers.&lt;/p&gt;

&lt;p&gt;The FDA released its assessment of omacetaxine, made by ChemGenex Pharmaceuticals, in preparation for a meeting of an outside panel of oncology experts who will recommend whether the agency should approve the drug for imanitib-resistant CML patients with a Bcr-Abl T3151 mutation.&lt;/p&gt;
    &lt;p&gt;That meeting, original scheduled for Wednesday, was postponed when the federal government closed most Washington area offices because of snow. An FDA spokesman said no new date has been set.&lt;/p&gt;


&lt;p&gt;The agency does not have to follow the advice of its advisory panels, but it usually does.&lt;/p&gt;
&lt;p&gt;The Oncologic Drugs Advisory Committee will look at data from manufacturer ChemGenex&apos;s lone trial, which tested the safety and efficacy of subcutaneously administered omacetaxine in the target population.&lt;/p&gt;
&lt;p&gt;The trial divided 66 patients into disease stage cohorts of &quot;chronic phase,&quot; &quot;accelerated phase,&quot; or &quot;blast phase,&quot; and gave them 1.25 mg/m&lt;sup&gt;2&lt;/sup&gt; subcutaneous omacetaxine twice daily for 14 days every 28 days until hematologic response for induction therapy.&lt;/p&gt;
&lt;p&gt;If a patient achieved a complete hematologic response, hematologic improvement, or any cytogenetic response, the patient was transitioned to a maintenance does twice daily for seven days every 28 days.&lt;/p&gt;
&lt;p&gt;Researchers found: &lt;ul&gt; &lt;li&gt;For the chronic phase cohort of 40 patients, the major cytogenetic response rate was 15%, and the median duration of response was 7.7 months. &lt;/li&gt; &lt;li&gt;After a mean of nine months, 86% of the 49 chronic patients who were no longer controlling their diseases with imatinib had achieved a complete hematological response. &lt;/li&gt; &lt;li&gt;For the &quot;accelerated phase&quot; cohort of 16 patients, the major cytogenetic response rate was 6%, and the complete hematological response rate was 31%, with a median of duration of response of 22 weeks. &lt;/li&gt; &lt;li&gt;No patients responded in the more severe &quot;blast&quot; group, indicating omacetaxine works best among patients who are not as sick.&lt;/li&gt; &lt;li&gt;Overall, about 27% of patients achieved a major cytogenetic response, defined as absence of Bcr-Abl mutation in at least 35% of cells. About 18% of the patients had achieved a complete cytogenetic response, defined as all cells appearing to have lost the Bcr-Abl mutation.&lt;/li&gt; &lt;/ul&gt;&lt;/p&gt;
&lt;p&gt;&quot;The response rate observed in the efficacy study was low,&quot; FDA reviewers concluded in documents released in advance of Wednesday&apos;s meeting.&lt;/p&gt;
&lt;p&gt;However, ChemGenex researchers said, &quot;These results demonstrate that omacetaxine is an effective and durable therapy with rapid onset of action for CML patients with the Bcr-Abl T315I mutation.&quot;&lt;/p&gt;
&lt;p&gt;The most common adverse events in the trial were thrombocytopenia, anemia, diarrhea, and neutropenia.&lt;/p&gt;
&lt;p&gt;The FDA reviewers cited a number of concerns with the ChemGenex study, noting that the company planned to enroll 100 patients but submitted efficacy data from only 66, and then continued to enroll additional patients after the prespecified data cutoff.&lt;/p&gt;
&lt;p&gt;Also, the reviewers said there is no commercially available test to detect the T3151 mutation. And, although it was a requirement of the study that the patients have a confirmed T3151 mutation, the mutation status of 35% of the patients in the trial was not confirmed.&lt;/p&gt;
&lt;p&gt;There are currently no approved drugs that have been found to be effective at treating CML patients with the T315I mutation.&lt;/p&gt;
&lt;p&gt;&quot;Omacetaxine offers an important therapeutic option for the treatment of CML patients who have the T315I mutation, a population that has a clear unmet medical need and no proven treatment options,&quot; ChemGenex researchers wrote in the company&apos;s briefing document.&lt;/p&gt;

    </recommendedItem>
    <recommendedItem id="20100101_19_342"
                     title="Stem Cell Transplant Source Does Not Affect Long-Term Leukemia Outcomes (CME/CE)"
                     score="0.009"
                     href="http://www.medpagetoday.com/HematologyOncology/Leukemia/tb/18220?impressionId=1265790513080"
                     
      Ten-year survival rates after allogeneic stem-cell transplant in leukemia patients were the same whether the cells came from donors&apos; bone marrow or peripheral blood, researchers conducting a randomized trial said.&lt;br&gt;
&lt;br&gt;Among 329 patients participating in the trial, overall survival was 49.1% for those receiving peripheral blood progenitor cell transplants versus 56.5% among those receiving bone marrow transplants (&lt;em&gt;P&lt;/em&gt;=0.27), reported Birte Friedrichs, MD, of Charite-Campus Benjamin Franklin in Berlin, Germany, and colleagues online in &lt;em&gt;Lancet Oncology&lt;/em&gt;.&lt;br&gt;
&lt;br&gt;There was also no significant difference over the long term in performance status, ability to work, hematopoietic function, development of bronchiolitis obliterans, or secondary malignancy rates.&lt;/p&gt;
&lt;p&gt;Ten-year leukemia-free survival rates were somewhat better with bone marrow transplant in patients with acute myeloid and acute lymphoblastic leukemia (AML, ALL) but the differences did not reach statistical significance. There was no apparent difference in disease-free survival for those with chronic myeloid leukemia (CML).&lt;/p&gt;
&lt;p&gt;But significantly more transplants involving peripheral blood progenitor cells led to chronic graft-versus-host disease (GVHD), seen in 73% of patients compared with 56% among those receiving bone marrow transplants (&lt;em&gt;P&lt;/em&gt;=0.021).&lt;/p&gt;
&lt;p&gt;As a result, significantly more patients receiving peripheral blood cell transplants were on immunosuppressant therapy five years postprocedure (26% versus 12%, &lt;em&gt;P&lt;/em&gt;=0.024).&lt;/p&gt;
&lt;p&gt;Noting that subgroup analyses did show notable differences in survival in patients with acute leukemias, Friedrichs and colleagues added, &quot;These data alone do not currently support the return to bone marrow transplantation for specific indications, but we believe that long-term data from other randomized trials should be collected.&quot;&lt;/p&gt;
&lt;p&gt;Patients in the study were participating in a parallel-group trial of the two transplant types, with transplants conducted from 1995 to 1999. Participants were adults up to age 55 with CML in second remission or newly diagnosed ALL or AML.&lt;/p&gt;
&lt;p&gt;Specific overall and leukemia-free survival rates for leukemia subtypes after 10 years were: &lt;ul&gt; &lt;li&gt;ALL: 32.9% overall and 28.3% disease-free with bone marrow transplant, 18.2% overall and 13.0% disease free with peripheral blood transplant (&lt;em&gt;P&lt;/em&gt;=0.071 and 0.12, respectively)&lt;/li&gt; &lt;li&gt;AML: 65.3% overall and 62.3% disease-free with bone marrow transplant, 52.3% overall and 47.1% disease-free with peripheral blood transplant (&lt;em&gt;P&lt;/em&gt;=0.24 and 0.16, respectively)&lt;/li&gt; &lt;li&gt;CML: 61.1% overall and 40.2% disease-free with bone marrow transplant, 56.8% overall and 48.5% disease-free with peripheral blood transplant (&lt;em&gt;P&lt;/em&gt;=0.81 and 0.60, respectively)&lt;/li&gt; &lt;/ul&gt;&lt;/p&gt;
&lt;p&gt;The failure to find significant differences may have been related to small patient numbers in these subgroups: 64 with AML, 19 with ALL, and 89 with CML.&lt;/p&gt;
&lt;p&gt;Transplant types were performed at equal rates in patients with AML and CML, but the randomization was unbalanced in ALL patients, with 15 of 19 receiving bone marrow transplants.&lt;/p&gt;
&lt;p&gt;Chronic GVHD was the most common cause of death in the study, killing nine patients (of whom six received peripheral blood progenitor cell transplants). Six patients died of recurrent leukemia. The remaining nine deaths were distributed among several causes including hemorrhage, bronchial cancer, suicide, and traffic accident.&lt;/p&gt;
&lt;p&gt;Patients with chronic GVHD after peripheral blood cell transplants were more likely to have skin, liver, and oral mucosal involvement compared with GVHD following bone marrow transplant, with relative risks ranging from 1.49 to 1.85.&lt;/p&gt;
&lt;p&gt;Factors significantly associated with better overall survival included a diagnosis of ALL (HR 2.90 versus other diagnoses, &lt;em&gt;P&lt;/em&gt;&amp;lt;0.0001), age of 40 or more (HR 1.55 versus age under 40, &lt;em&gt;P&lt;/em&gt;=0.009), and use of total body irradiation instead of a chemotherapy-only myeloablative regimen before transplant (HR 1.55, &lt;em&gt;P&lt;/em&gt;=0.014).&lt;/p&gt;
&lt;p&gt;The researchers noted that many of their findings, including the apparent benefit of preparative total body irradiation, were consistent with earlier studies.&lt;/p&gt;
&lt;p&gt;Limitations to the study included loss to follow-up of 26 patients, lack of detailed data on surviving participants&apos; quality of life, and changes in treatment since the study began.&lt;/p&gt;
&lt;p&gt;Friedrichs and colleagues noted that the introduction of tyrosine kinase inhibitors and new approaches to pretransplant conditioning have altered practice significantly.&lt;/p&gt;
&lt;div style=&quot;float:left;border-style:solid;border-width:1px;border-color:#8dabbc;font-family:arial;font-size:12px;background-color:#DBE9F2;padding:5px;&quot;&gt;&lt;p&gt;No external funding for the study was received.&lt;/p&gt;&lt;p&gt;No potential conflicts of interest were reported.&lt;/p&gt;&lt;/div&gt;&lt;div style=&quot;clear:both;&quot;&gt;&lt;/div&gt;
    </recommendedItem>
    <recommendedItem id="20100101_19_167"
                     title="Stem Cells from Cord Blood Pass Early Test (CME/CE)"
                     score="-0.005"
                     href="http://www.medpagetoday.com/HematologyOncology/Leukemia/tb/17998?impressionId=1265790513080"
                     
      The first reported clinical use of ex vivo-expanded stem cells from umbilical cord blood led to rapid engraftment in patients with high-risk acute leukemia, investigators found.&lt;br&gt;
&lt;br&gt;Activation of the Notch signaling pathway with a bioengineered protein led to a 164-fold increase in CD34+ cells. Infusion of the expanded stem-cell population into leukemia patients after myeloablation reduced the time to neutrophil recovery and the time to engraftment by 50%, according to a report published online in &lt;em&gt;Nature Medicine&lt;/em&gt;.&lt;br&gt;
&lt;br&gt;After a mean follow-up of about a year, seven of 10 patients remained alive with no evidence of disease and with sustained complete engraftment, wrote Colleen Delaney, MD, of the Fred Hutchinson Cancer Research Center in Seattle, and colleagues.&lt;br&gt;
&lt;br&gt;&quot;The real ground-breaking aspect of this research is that we have shown that you can manipulate stem/progenitor cells in the lab with the goal of increasing their numbers,&quot; Delaney said in a statement.&lt;p&gt;&lt;/p&gt;
&lt;p&gt;&quot;When given to a person, these cells can rapidly give rise to white blood cells and other components of the blood system.&quot;&lt;/p&gt;
&lt;p&gt;Delayed engraftment after cord-blood transplantation is thought to result from an inadequate population of progenitor cells in the graft, the authors wrote. Delayed engraftment can lead to early transplant-related morbidity and mortality.&lt;/p&gt;
&lt;p&gt;Culture strategies that increase the number of viable progenitors would expand the applicability of cord-blood for transplantation.&lt;/p&gt;
&lt;p&gt;The phase I results reported by Delaney and colleagues had their origin in work begun more than a decade ago by co-investigator Irwin D. Bernstein, also of Fred Hutchinson. The Seattle group identified a potential role for the Notch signaling pathway in hematopoiesis by detecting the human &lt;em&gt;Notch 1&lt;/em&gt; gene in CD34+ human hematopoietic precursors. They subsequently demonstrated enhanced self-renewal of repopulating cells in response to retrovirus-mediated expression of an active form of Notch 1.&lt;/p&gt;
&lt;p&gt;Further study showed that activation of Notch receptors by immobilized Notch ligand had a profound effect on growth and differentiation of mouse marrow progenitor cells. Incubation of human cord-blood progenitors with immobilized ligand led to a 100-fold increase in CD34+ cells.&lt;/p&gt;
&lt;p&gt;&quot;Overall, these observations demonstrated that Notch signaling has a key regulatory role in hematopoiesis and suggest that Notch ligands will be useful reagents for improving ex vivo culture of stem/progenitor cells,&quot; the authors wrote.&lt;/p&gt;
&lt;p&gt;As a prelude to the phase I clinical study, investigators cultured cord-blood CD34+ progenitors in the presence of immobilized Notch ligand for as long as three weeks, resulting in 138- to 163-fold expansion of the cell population. Validation studies of the culture system showed consistent expansion of the CD34+ population by more than 150-fold.&lt;/p&gt;
&lt;p&gt;When given to immunodeficient mice, ex vivo-expanded CD34+ cells resulted in repopulation with markedly enhanced kinetics and magnitude.&lt;/p&gt;
&lt;p&gt;The phase I study involved patients whose leukemia was in morphologic remission at the time of transplant. The patients ranged in age from 3 to 43.&lt;/p&gt;
&lt;p&gt;Myeloablative therapy consisted of whole-body irradiation, cyclophosphamide, and fludarabine. Each patient received one unmanipulated and one expanded cord-blood graft. All patients received standard prophylaxis for graft versus host disease (GVHD). Expansion of CD34+ cells prior to infusion averaged 164-fold.&lt;/p&gt;
&lt;p&gt;The median time to an absolute neutrophil count (ANC) &amp;#8805;100 cells/&amp;#181;L was nine days, compared with 19 days for a similar group of patients who received two unmanipulated cord-blood grafts.&lt;/p&gt;
&lt;p&gt;The median time to ANC &amp;#8805;500 cells/&amp;#181;L was 16 days in nine evaluable patients, compared with 26 days in patients who received two unmanipulated grafts.&lt;/p&gt;
&lt;p&gt;Nine of 10 patients had successful engraftment in an average of 14 days, whereas engraftment required an average of 28 days in patients who received unmanipulated cord-blood grafts.&lt;/p&gt;
&lt;p&gt;One patient had primary graft rejection. Peripheral blood analysis on day seven showed a predominance of donor-cell engraftment from the expanded-cell graft.&lt;/p&gt;
&lt;p&gt;Among evaluable patients, one had acute grade 3 GVHD, and all the others had acute grade 2 GVHD. In all cases patients responded to therapy. Three patients developed chronic limited GVHD, but no patient had chronic extensive GVHD.&lt;/p&gt;

&lt;p&gt;Results of the phase I study give reason for excitement about the potential for using cord blood-derived stem cells to treat leukemia, said Peter Emanuel, MD, director of the Winthrop P. Rockefeller Cancer Institute in Little Rock, Ark.&lt;/p&gt;
&lt;p&gt;&quot;Investigators from [Seattle] appear to have given us the next big leap forward in advances for stem cell transplants, that being the methods to culture cord blood in the laboratory so that the stem and immature cells will &apos;take root&apos; more rapidly when infused back into patients,&quot; said Emanuel, who was not involved in the study. &quot;This is significant for patient safety as it shortens the time period when they are at risk for life threatening infection.&quot;&lt;/p&gt;

&lt;div style=&quot;float:left;border-style:solid;border-width:1px;border-color:#8dabbc;font-family:arial;font-size:12px;background-color:#DBE9F2;padding:5px;&quot;&gt;&lt;p&gt;The authors had no disclosures.&lt;/p&gt;&lt;/div&gt;&lt;div style=&quot;clear:both;&quot;&gt;&lt;/div&gt;
    </recommendedItem>
    <recommendedItem id="20090101_19_3952"
                     title="ASH: New CML Drug Overcomes Resistance Mutation (CME/CE)"
                     score="-0.005"
                     href="http://www.medpagetoday.com/MeetingCoverage/ASHHematology/tb/17343?impressionId=1265790513080"
                     
      &lt;p&gt;NEW ORLEANS  --  Promising preliminary findings from a small study suggest a possible treatment for imatinib (Gleevec)-resistant chronic myeloid leukemia (CML), researchers reported here.&lt;/p&gt;
&lt;p&gt;Researchers had already identified the the cause of resistance  --  the T3151 mutation  --  and now they may have a fix for the problem that has become the Achilles&apos; heel of CML therapy, Jorge Cortes, MD, professor of medicine at the University of Texas, M.D. Anderson Cancer Center.&lt;/p&gt;
&lt;p&gt;The investigational drug, omacetaxine, being developed by ChemGenex Pharmaceuticals Limited, based in Menlo Park, Calif., and Melbourne, Australia, &quot;represents a new potential therapy for patients with T315I-positive chronic myeloid leukemia,&quot; Cortes said at the American Society of Hematology meeting.&lt;/p&gt;
&lt;p&gt;That hopeful note emerged from a study designed to evaluate the safety and efficacy of subcutaneously administered omacetaxine in patients with imatinib resistant T315I Philadelphia chromosome-positive chromin myeloid leukemia. Patients were given 1.25 mg/m&lt;sup&gt;2&lt;/sup&gt; subcutaneous omacetaxine twice daily for 14 days every 28 days until hematologic response for induction therapy.&lt;/p&gt;
&lt;p&gt;For maintenance therapy, patients were dosed twice daily for seven days every 28 days.&lt;/p&gt;
&lt;p&gt;Although the mean follow-up time was short, Cortes said the early results revealed a number of promising findings including: &lt;ul&gt; &lt;li&gt;After a mean of nine months follow-up, 86% of the 49 chronic phase patients in the study who no longer were controlling their disease with imatinib had achieved a complete hematological response.&lt;/li&gt;  &lt;li&gt;About 27% of patients had achieved a major cytogenetic response, defined as absence of Bcr-Abl mutation in at least 35% of cells.&lt;/li&gt; &lt;li&gt;Roughly 18% of the patients had achieved a complete cytogenetic response  --  all the cells appear to have lost the Bcr-Abl mutation.&lt;/li&gt; &lt;/ul&gt;&lt;/p&gt;
&lt;p&gt;The median age of the patients in the study was 58 years, and ranged from 19 to 83. Their median time diagnosed with chronic myeloid leukemia was 54 months. Imatinib failed to control the disease in all the patients; 79% had failed two or more prior tyrosine kinase inhibitors. The presence of baseline T315I mutation was confirmed in all patients.&lt;/p&gt;
&lt;p&gt;Cortes said the study did not have a control arm because there is no established treatment for patients whose disease has progressed despite use of imatinib and other tyrosine kinase inhibitors in the face of the T315I mutation.&lt;/p&gt;
&lt;p&gt;He explained that omacetaxine, which is not approved in the U.S. or Europe, has been used to treat leukemia in China for many years and it appeared to work against the mutation in the laboratory.&lt;/p&gt;
&lt;p&gt;&quot;What is encouraging is that we are seeing that patients are able to respond to this therapy,&quot; he said at a press briefing here. &quot;It is self-administered subcutaneously and we have seen that it is very well tolerated.&quot;&lt;/p&gt;
&lt;p&gt;&quot;One can draw a parallel between the acquisition of antibiotic resistance in bacterial infections and the development of drug resistance due to a mutation in this case which blocks the binding of drugs like imatinib to the active site in chronic myeloid leukemia cells,&quot; said Richard Larson, MD, professor of medicine at the University of Chicago, who acted as a moderator at the press briefing.&lt;/p&gt;
&lt;p&gt;He said omacetaxine and other drugs in the development pipeline will be important in treating even small groups of patients.&lt;/p&gt;
&lt;p&gt;&quot;It is fair to say that therapeutic breakthroughs never occur quickly enough to help everyone. The good news is there are a lot of new agents in the pipeline. The challenge is that each subset of disease becomes smaller,&quot; Larson said.&lt;/p&gt;
&lt;div style=&quot;float:left;border-style:solid;border-width:1px;border-color:#8dabbc;font-family:arial;font-size:12px;background-color:#DBE9F2;padding:5px;&quot;&gt;&lt;p&gt;The trial was funded by ChemGenex.&lt;/p&gt;&lt;p&gt;Cortes disclosed financial relationships with ChemGenex.&lt;/p&gt;&lt;p&gt;Larson disclosed grant/research support from Amgen, Bristol-Myers Squibb, Celgene, Hana Bioscience, Novartis, Kanisa, and Telik. He has served as a consultant for BioCryst, Genta, GlaxoSmithKline, Hana Bioscience, Merck, Sharpe and Dohme, Novartis, and Xanthus.&lt;/p&gt;&lt;/div&gt;&lt;div style=&quot;clear:both;&quot;&gt;&lt;/div&gt;
    </recommendedItem>
    <recommendedItem id="20090101_1_356"
                     title="CML Survival with Gleevec Remains High"
                     score="-0.005"
                     href="