Posted by rob on December 31, 2005 under Uncategorized | 
By Robert Kuttner | December 31, 2005
THE NEW YEAR brings with it congressional midterm elections. Here is an issue that should be a real political gift to the opposition party — the colossal Medicare drug-benefit mess.
It was clear back in 2003, when the Bush administration rammed this bill through the Republican Congress, that the purpose was not to devise an affordable prescription drug program for seniors. Rather the administration wanted to help two friendly industries, the pharmaceutical companies and the HMOs, and to get bragging rights for the 2004 election that President Bush had helped seniors. Few voters would grasp just how bad the law was, since its effective date was deliberately put off until 2006.
Now, as the year of reckoning arrives, the true cynicism of Bush’s program is becoming evident to each senior citizen (or adult child of senior citizen) who attempts to fathom what Bush and the industry lobbyists wrought.
For starters, coverage is woefully inadequate. You pay a $250 deductible and then a 25 percent copay on the first $2,250 of drug benefits each year, plus roughly another $450 a year in premiums. So if your prescriptions cost $2,250 a year, or about $190 a month, you pay $1,200 a year all told and the plan pays just $1,050.
That’s pretty shabby. But then, the truly bizarre feature of the plan kicks in. Coverage simply disappears for the next $2,850 in drug expenses and only picks up again when you have incurred a total of $5,100 in prescription costs. This is the infamous ”hole in the doughnut.”
A great many seniors will never get the coverage because the plan is a bad bargain, and they just won’t sign up. Of if they do sign up, they will run out of the ability to pay enough out of pocket before qualifying for needed benefits. Even with these disgracefully skimpy benefits, the plan is expected to add over half a trillion dollars to the federal budget over the next decade.
Why would anyone have designed such an insane program?
Because the political purpose was never to deliver good benefits. One administration goal, running the program through the private insurance industry, conflicted with the imperative of a clear, cost-effective plan. Seniors must evaluate innumerable competing private plans, each with subtle differences in costs and benefits that make an impenetrable program even less fathomable, and raise total costs because each of these private plans tacks on a profit. This was a case of privatizing something done far more efficiently through a direct government program.
The second administration goal, fattening the drug industry, led to a provision explicitly prohibiting the government from negotiating bulk price discounts from drug companies, as the veterans hospitals do. As a result, according to a study by Families USA, drug prices obtained by the US Department of Veterans Affairs are about 48 percent less on average than those expected to be charged to people enrolled in the Medicare drug program. Among the 20 most widely prescribed drugs for seniors, for instance, a year’s supply of Protonix (for ulcers) costs the VA $253, but the seniors in the Bush Medicare program, which prohibits such bulk discounts, pay a sticker price of $1,080. That will give you ulcers! A year of Zocor, the cholesterol-reducing drug, costs the VA $251. Seniors in Bush’s drug plan get whacked for $1,323.
It was these inflated costs that necessitated some gimmick to keep down the overall cost to taxpayers. Hence the notorious doughnut hole.
If the Democrats have the moxie and the wit, they should propose a straightforward fix, take it to the country in the 2006 elections, and dare Republicans to oppose it:
First, get rid of the costly crazy-quilt of private programs and bring the ”Medicare” drug program back into public Medicare.
Second, allow Medicare to negotiate bulk discounts the way the VA does.
Third, get rid of the doughnut hole, and design a simplified benefit structure with modest copays and then 100 percent coverage after a set annual cap on out-of-pocket costs.
Finally, if the savings from the bulk price discounts are not quite sufficient to cover the costs of filling in the doughnut hole, take back a little of Bush’s tax cuts to the richest 1 percent.
This debate will also remind voters of a useful meta-lesson: A party whose mantra is to hate government, and that sees government mainly as a vehicle for rewarding special-interest allies rather than serving ordinary citizens, can never be trusted to run government competently.
A happier New Year to all.
Robert Kuttner is co-editor of The American Prospect. His column appears regularly in the Globe
Dollars to doughnuts, Bush’s drug benefit is no bargain – The Boston Globe
Posted by rob on December 29, 2005 under Uncategorized |
The investigational drug AMN107 has produced treatment responses in some patients with chronic myeloid leukemia (CML) that does not respond to Gleevec? (imatinib mesylate), as well as in some patients with acute lymphoblastic leukemia (ALL) that is positive for the Philadelphia chromosome. These results were presented at the 47th annual meeting of the American Society of Hematology (ASH).
Chronic myeloid leukemia (CML), also called chronic granulocytic leukemia, is a cancer that originates in the immune cells. It affects approximately 4,600 people annually in the U.S. In the case of CML, large numbers of young immune cells do not mature, resulting in an excess accumulation of these cells. These leukemia cells then crowd the bone marrow and blood, suppressing formation and function of other blood cells normally present in these areas. In addition, the leukemia cells cannot perform their function properly, leaving patients susceptible to infection.
Chronic myeloid leukemia begins with a chronic phase, during which few clinical problems, if any, occur. However, when left untreated, the chronic phase progresses into acute phases; these phases, called the accelerated and blastic phases, are characterized by fast-growing and aggressive cancer. Patients reaching these acute phases have a poor prognosis for long-term survival.
Historically, the only curative option for patients with CML was an allogeneic stem cell transplant. However, treatment-related mortality and side effects can both be substantial in patients undergoing an allogeneic stem cell transplant; researchers have thus focused efforts on curative treatment options that are more easily tolerated.
Philadelphia chromosome-positive CML refers to the majority of cases of CML in which a genetic abnormality, referred to as the Philadelphia chromosome, results in the constantly activated growth of cancer cells. Roughly 30% of adult patients with ALL also have this genetic abnormality.
Gleevec is a biological agent that binds to and slows or stops the uncontrolled growth of cancer cells with this genetic mutation. Unfortunately, a small number of patients who are treated with Gleevec do not achieve anticancer responses; researchers are evaluating novel agents for this group of patients.
AMN107 is an investigational drug that targets the same protein as Gleevec, but through a different mechanism. AMN107 is reported to be significantly more potent than Gleevec. To evaluate AMN107 in the treatment of Gleevec-resistant leukemia, researchers from the MD Anderson Cancer Center in Texas conducted a phase I clinical trial among 119 patients with Gleevec-resistant CML in chronic, accelerated, or blastic phases or Philadelphia chromosome-positive ALL.
Treatment with AMN107 was generally well tolerated and produced notable anticancer activity. Among patients with CML, the rate of cytogenetic response (reduction of genetically abnormal cells) ranged from 22% to 100%, and the rate of hematologic response (normalization of blood cell counts) ranged from 44% to 100%. Among patients with ALL, rate of hematologic response ranged from 10% to 33%.
The researchers concluded that AMN107 has significant activity in patients with Gleevec-resistant CML and possibly in some patients with ALL.
Reference: Kantarjian HM, Ottman O, Cortes J, et al. AMN107, a novel aminopyrine inhibitor of Bcr-Abl, has significant activity in imatinib-resistant chronic myeloid leukemia (CML) or Philadelphia-chromosome positive acute lymphoid leukemia (Ph+ALL). Blood . 2005;106:15a. Abstract # 37.
Investigational Drug Shows Promise in Gleevec?-Resistent CML
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ATLANTA, GA — December 12, 2005 — In an update of a phase 1, dose-escalating study, researchers concluded that the data supports the therapeutic potential of dasatinib in chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL) patients who are imatinib-resistant or intolerant.
Results of the study were presented here on December 10th at the 47th Annual Meeting of the American Society of Hematology (ASH).
Imatinib mesylate (Gleevec) resistance in CML and Philadelphia (Ph) chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) is frequently associated with BCR-ABL mutations that interfere with the ability of imatinib to inhibit BCR-ABL overproduction.
Dasatinib (BMS-354825) is a novel, oral, multitargeted kinase inhibitor, which targets BCR-ABL and Src protein kinase. Src is a signaling protein that specializes in messages that control cell growth. The drug is 325-fold more potent than imatinib in cells transduced with normal BCR-ABL genes, and has demonstrated preclinical activity against 18 of 19 imatinib-resistant BCR-ABL mutations.
In this update by researchers from the University of California, Los Angeles (UCLA) School of Medicine, Los Angeles, California, and the University of Texas MD Anderson Cancer Center, Houston, Texas, the investigators looked at the use of dasatinib in imatinib-resistant or intolerant patients with CML in late chronic phase, accelerated phase, myeloid blast crisis, or lymphoid blast crisis/Ph+ ALL. A blast crisis is the progression of diseases to an acute advanced phase.
Charles Sawyers, MD, director of the Prostate Cancer Program Area at the UCLA Jonsson Cancer Center, and professor of medicine at UCLA School of Medicine, Los Angeles, California, presented data available for 82 patients — 40 CP, 10 AP, 22 MBC, 10 lymphoid blast crisis/Ph+ ALL.
The 40 patients in late chronic phase, with 5 years median duration of CML, were treated with 15 to 180 mg of dasatinib either once-daily QD or BID for a median of 13 months. The rate of complete hematologic response in late chronic phase patients was 93%, while major cytogenetic responses were observed in 45% and complete cytogenetic response in 35%.
In advanced disease, 44 patients have been treated with dasatinib 70 to 240 mg BID for a median of 37 months. The rate of major hematologic response is 81% in accelerated phase, 61% in myeloid blast crisis, and 70% in lymphoid blast crisis/Ph+ ALL. The complete response rate is 45% in accelerated phase, 70% in lymphoid blast crisis/Ph+ ALL, and 35% in myeloid blast crisis.
The overall rates of major cytogenetic responses and complete cytogenetic responses in advanced disease were 43% and 25%, respectively. Cytogenetic responses were seen in patients with a wide spectrum of BCR-ABL mutations, as well as in patients with minimal or no prior cytogenetic response with imatinib.
Responses were durable in late chronic and accelerated phase, but relapses have occurred in the myeloid blast crisis and blast crisis/Ph+ ALL cohorts, often due to dasatinib-resistant BCR-ABL mutations.
“We are encouraged by the results and are looking forward to seeing the results from ongoing phase 2 studies to confirm the effects of dasatinib in patients with all phases of the disease,” Dr. Sawyers said.
[Presentation title: Dasatinib (BMS-354825) in Patients With Chronic Myeloid Leukemia (CML) and Philadelphia Chromosome- Positive Acute Lymphoblastic Leukemia (Ph + ALL) Who Are Resistant or Intolerant to Imatinib: Update of a Phase I Study. Abstract 38]
News – Dasatinib Shown Effective for Treating Two Forms of Leukemia: Presented at ASH
Posted by rob on under Uncategorized |
Offering promise in the battle against cancer, the results from five studies highlighting new advances in the treatment of chronic myeloid leukemia (CML) — a slow-progressing, malignant bone marrow cancer — will be presented at the 47th Annual Meeting of the American Society of Hematology.
“The survival rate for leukemia has improved in the past two decades, thanks to new agents designed to treat patients,” said Brian J. Druker, M.D., Oregon Health and Science University, Portland, Ore. “Continued research will only strengthen our understanding of the disease and support the therapeutic potential of current and developing treatments for chronic myeloid leukemia.”
CML is usually diagnosed by finding a specific chromosomal abnormality called the Philadelphia chromosome (Ph chromosome). The Ph chromosome is the result of translocation — a genetic chromosomal abnormality — between the long arms of chromosomes 9 and 22. The result is that part of the BCR (breakpoint cluster region) gene from chromosome 22 is fused with part of the ABL (abelson leukemia virus) gene on chromosome 9. The translocation takes place in a single bone marrow cell and, through the process of cell division and expansion, results in leukemia, the rapid growth of abnormal white blood cells in the bone marrow, blood, and body tissues.
The discovery of the Ph chromosome marked the first genetic abnormality consistently associated with a particular form of cancer. In addition to CML, Ph chromosome can also be found in some cases of acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML).
Imatinib, which blocks the abnormal protein driving the overproduction of abnormal white blood cells, has become a standard therapy for patients not undergoing stem cell transplantation. It is now demonstrating continued control and reduction in levels of remaining disease in chronic phase CML (CML- CP) patients. However, a number of patients have developed resistance to this treatment because their cancer cells are able to mutate and adapt.
As a result, treatment options for patients with CML continue to expand. Various studies of potential new treatments for CML yield positive results in patients whose disease is resistant to imatinib. Both dasatinib and AMN107 have been shown to be effective in treating patients with CML whose disease has progressed on imatinib.
Continuing Reduction in Level of Residual Disease After Four Years in Patients with Chronic Myeloid Leukemia (CML) in Chronic Phase Responding to First-Line Imatinib (IM) in the IRIS Study [Abstract 163]
A recent report updated results of molecular monitoring of patients in the International Randomized Interferon vs. STI 571 (IRIS) study that prospectively compared imatinib therapy with interferon-alfa plus cytarabine. The IRIS study was initiated in June 2000, and demonstrated that after one year of imatinib treatment, an estimated 40 percent of CML-CP patients taking 400 mg per day achieved a major molecular response (MMR), defined as substantial reduction in BCR-ABL levels. This particular analysis assessed the level of BCR-ABL transcripts after approximately four years of imatinib treatment and showed continuing reduction in transcript levels.
The analysis was based on 101 patients who achieved complete cytogenetic response (CCyR) within one year, received first-line treatment for at least 24 months, and had blood collected for measuring transcript numbers at one year and four years after starting treatment. Results are expressed as a log reduction from a standardized baseline value for untreated patients. This means they are expressed as transcript copy numbers, with a one-log reduction equivalent to a fall from 100 to 10, and a two-log reduction a fall from 100 to one.
At one year, BCR-ABL transcript levels fell by at least three logs in 46 percent of the 101 patients. At the most recent measurement, at or after 44 months from start of study, 75 percent of patients demonstrated a reduction of at least three logs. Of these patients, more than half had already had a three-log reduction at year one, whereas 49 percent had not. Conversely, eight of the 47 patients with three-log reduction at one year had log reductions greater than three at four years. At the one- and four-year points, 20 percent and 36 percent of patients, respectively, achieved four-log reductions.
“The results are gratifying and show that patients in complete cytogenetic response who had an ‘adequate’ reduction in their BCR-ABL transcript levels at one year have a good chance at achieving a much greater reduction after four years of imatinib treatment,” said John M. Goldman, D.M., National Heart,
Lung, and Blood Institute (NHLBI), Bethesda, Md. “This is an important observation because it means that imatinib continues for at least four years to reduce the quantity of residual disease and so promises to offer patients with chronic phase CML very substantial prolongation of essentially normal life, compared with previous therapies.”
Control of Residual Disease in Imatinib (IM) Treated Chronic Myeloid Leukemia (CML) Patients with Peptide Vaccinations: Two Years Follow Up of CMLVAX100 Trial [Abstract 167]
In the past five years, the body of data concerning imatinib has defined its role as an effective first-line therapy for CML-CP patients. However, the persistence of disease in most patients, together with the evidence that discontinuation of imatinib inevitably results in a rapid loss of response, suggests that the cure for CML is unlikely using imatinib alone.
Researchers from the University of Siena in Siena, Italy, looked at the anti-tumor effect of a vaccine (CMLVAX100) targeting the BCR-ABL genes and how it reduced remaining disease in some patients with CML who have reached a maximum response to imatinib. After a median time of 24 months of imatinib treatment, a group of 21 patients showing different degrees of persistent residual disease started vaccinations with CMLVAX100. Vaccine treatment plans included six vaccinations at two-week intervals. In patients who responded to treatment, additional boosts of vaccine were provided every four to six months.
To date, 18 of the 21 patients have completed the immunization regimen, eight of whom received four additional boosts of vaccine. After six vaccinations, six patients with persisting, progressing disease reached a complete response, with three of them achieving an undetectable level of BCR-ABL transcript. In addition, three patients starting vaccinations with persistent molecular disease further reduced their BCR-ABL level, with one reaching molecular negativity. This suggests that CMLVAX100 works effectively with imatinib in CML-CP patients with persistent minimal residual disease.
Of the eight patients who underwent four additional boosts of vaccine, one reached a complete molecular response, five maintained the response obtained after immunization, and two patients (who previously achieved an undetectable level of BCR-ABL transcript) lost the complete molecular response (CMR), but maintained CCyR. This suggests that while beneficial, a six-month interval between boosts could be too long to maintain efficient immune control on residual leukemia cells.
“Although the number of patients who participated in the trial is small, this is a very important study,” said Monica Bocchia, M.D., University of Siena, Siena, Italy. “Researchers have been attempting to develop cancer vaccines for decades, and results in CML patients are a very encouraging step forward.”
Dasatinib (BMS-354825) in Patients with Chronic Myeloid Leukemia (CML) and Philadelphia Chromosome- Positive Acute Lymphoblastic Leukemia (Ph + ALL) Who Are Resistant or Intolerant to Imatinib: Update of a Phase I Study [Abstract 38]
Imatinib resistance in CML and Philadelphia (Ph) chromosome positive acute lymphoblastic leukemia (Ph + ALL) is frequently associated with BCR-ABL mutations that interfere with the ability of imatinib to inhibit BCR-ABL overproduction. Dasatinib (BMS-354825) is a novel, oral, multi-targeted kinase inhibitor which targets BCR-ABL and SRC protein kinases. The SRC protein is a signaling protein that specializes in messages that control the growth of cells. The drug is 325-fold more potent than imatinib in cells transduced with normal BCR-ABL genes, and has demonstrated preclinical activity against 18 of 19 imatinib-resistant BCR-ABL mutants.
In an update of a phase I, dose-escalating study initiated in November 2003, researchers from the University of California, Los Angeles (UCLA) School of Medicine and The University of Texas M. D. Anderson Cancer Center looked at the use of dasatinib in imatinib-resistant or intolerant patients with CML in late chronic phase (CP), accelerated phase (AP), myeloid blast crisis (MBC), or lymphoid blast crisis (LBC)/Ph+ ALL. Data are available for 82 patients (40 CP, 10 AP, 22 MBC, 10 LBC/Ph+ ALL). A blast crisis is the progression of diseases to an acute advanced phase.
The 40 CP patients, with five years median duration of CML, were treated with 15 to 180 mg of dasatinib either once daily (QD) or twice daily (BID) for a median of 13 months. The rate of complete hematologic response (CHR) in CP patients was 93 percent, while major cytogenetic responses (MCyR) were observed in 45 percent and CCyR in 35 percent.
In advanced disease, 44 patients have been treated with dasatinib (70 to 240 mg BID) for a median of 37 months. The rate of major hematologic response (MHR) is 81 percent in AP, 61 percent in MBC, and 70 percent in LBC/Ph+ ALL. The complete response rate is 45 percent in AP, 70 percent in LBC/Ph+ ALL, and 35 percent in MBC.
The overall rates of MCyR and CCyR in advanced disease were 43 percent and 25 percent, respectively. Cytogenetic responses were seen in patients with a wide spectrum of BCR-ABL mutations, as well as in patients with minimal or no prior cytogenetic response with imatinib. Responses were durable in CP and AP patients, but relapses have occurred in the MBC and LBC/Ph+ ALL cohorts, often due to dasatinib-resistant BCR-ABL mutations.
“These data support the therapeutic potential of dasatinib in CML and Philadelphia chromosome positive acute lymphoblastic leukemia patients who are imatinib-resistant or intolerant,” said Charles Sawyers, M.D., Jonsson Cancer Center, UCLA School of Medicine, Los Angeles, Calif. “We are encouraged by the results and are looking forward to seeing the results from ongoing phase II studies to confirm the effects of dasatinib in patients with all phases of the disease.”
Efficacy of Dasatinib (BMS-354825) in Patients with Chronic Phase Philadelphia Chromosome-Positive Chronic Myeloid Leukemia (CML) Resistant or Intolerant to Imatinib: First Results of the CA180013 ‘START-C’ Phase II Study [Abstract 41]
After three years of imatinib therapy, hematologic relapse occurs in seven percent of newly-diagnosed CML patients and 20 percent of CML chronic phase patients after failure to respond to current standard therapy. This is mostly associated with BCR-ABL mutations and/or clonal evolution — the development of chromosomal mutations that occurs in untreated CML and leads to progression of the disease. A previous phase I, dose-escalating study provided early evidence for the safety and efficacy of dasatinib in imatinib-resistant or intolerant patients with CML-CP.
This study (START-C [CA180013]), carried out by a multinational group of 75 investigators, is a follow-up on the use of dasatinib in CP imatinib resistant or intolerant patients.
A total of 394 patients were recruited to this phase II, open-label study. To date, data from 186 patients are available for analysis. Imatinib resistance (n=127) or intolerance (n=59) was defined as a failure to respond to imatinib at maximum tolerated doses or the occurrence of BCR-ABL mutations associated with virtual insensitivity to imatinib. Dasatinib was administered to patients at 70 mg BID, based on phase I data and optimal inhibition of BCR-ABL activity from biomarker analysis. Dose escalation to 90 mg BID was permitted in patients lacking response, and dose reductions to 50 and 40 mg BID were allowed in the event of intolerance. Complete blood counts were obtained weekly for the first 12 weeks, while bone marrow was collected every three months.
Median time from diagnosis of CML was 63.8 months. Prior therapy included imatinib in 100 percent hydroxyurea or anagrelide in 86 percent, and interferon alpha in 70 percent of patients. Approximately 54 percent of patients received imatinib for more than three years.
Within the first six months, 90 percent of patients reached a complete hematologic response (87 percent resistant patients, 97 percent intolerant patients), and 45 percent achieved a major cytogenetic response (
Interim results of Phase II dasatinib studies in advanced disease were also presented. Of the myeloid blast crisis patients resistant to imatinib (n=68), 31 percent reached a major hematologic response, and 29 percent achieved a major cytogenetic response. Of the accelerated phase patients resistant to imatinib (n=99), 59 percent achieved a major hematologic response and 31 percent a major cytogenetic response.
“Despite the short follow-up, significant improvements of hematologic and cytogenetic responses were seen in pretreated CML patients in all phases of the disease, which further supports the activity of dasatinib in BCR-ABL positive leukemia,” said Andreas Hochhaus, M.D., University of Heidelberg, Mannheim, Germany. “This is very encouraging news for patients and should be viewed as a step forward in the treatment of CML.”
AMN107, a Novel Aminopyrimidine Inhibitor of BCR-ABL, Has Significant Activity in Imatinib-Resistant Chronic Myeloid Leukemia (CML) or Philadelphia Chromosome-Positive Acute Lymphoid Leukemia (Ph + ALL) [Abstract 37]
AMN107 is an investigational oral compound which inhibits the activity of specific proteins, including BCR-ABL and 32 of 33 mutant forms of protein responsible for the development of CML. It is 10- to 50-fold more potent than imatinib against BCR-ABL-expressing cell lines, including most imatinib-resistant BCR-ABL mutants.
In research led by The University of Texas M.D. Anderson Cancer Center in Houston and the University of Frankfurt, Germany, 119 patients with imatinib-resistant CML in blast crisis (BC), AP, CP, or Ph+ ALL were treated with AMN107. Initial daily doses ranged from 50 mg QD to 1,200 mg QD, and 400 mg BID to 600 mg BID. Dose escalations occurred in 48 of the 69 patients in the once daily groups, and one patient in the 400 mg BID group escalated to 600 mg BID.
As of June 15, 2005, patients had been treated for a median of 120 days. AMN107 was well-tolerated, and the most common drug-related adverse events were constipation, nausea, and vomiting. Among CML patients who harbored a BCR-ABL mutation prior to treatment, 60 percent achieved a hematologic response and 41 percent achieved a cytogenetic response. In addition, 72 percent of CML patients who had no BCR-ABL mutation prior to taking AMN107 achieved a hematologic response, and 59 percent achieved a cytogenetic response. Ph+ ALL patients who harbored a mutation prior to treatment with AMN107 saw a 33 percent response rate.
“AMN107 was shown to have significant activity in patients with advanced imatinib-resistant CML and Philadelphia chromosome positive acute lymphoblastic leukemia,” said Hagop M. Kantarjian, M.D., The University of Texas M. D. Anderson Cancer Center, Houston, Texas. “Current therapies, though effective, still have many limitations, and new treatment options with proven safety and efficacy can only benefit this patient population.”
###
The American Society of Hematology (www.hematology.org) is the world’s largest professional society concerned with the causes and treatment of blood disorders. Its mission is to further the understanding, diagnosis, treatment, and prevention of disorders affecting blood, bone marrow, and the immunologic, hemostatic, and vascular systems, by promoting research, clinical care, education, training, and advocacy in hematology.
New Studies Identify Advances In Treatment Of Chronic Myeloid Leukemia
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The History Of Glivec
Category: Lymphoma/Leukemia News
Article Date: 27 Dec 2005
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The Glivec (imatinib) story begins with 2 Philadelphia researchers: Peter Nowell, MD, of the University of Pennsylvania School of Medicine, and David Hungerford, MD, of the Institute for Cancer Research. They were able to identify a genetic mutation in patients with CML (chronic myeloid leukaemia) in 1960.(1) The 2 researchers found that a section of DNA was missing from chromosome 22. This alteration soon became known as the Philadelphia (Ph) chromosome and could be detected in approximately 95% of patients with CML. The discovery meant that for the first time ever, scientists had discovered a genetic abnormality linked to a specific kind of cancer. The discovery of the link between the Ph chromosome and CML set off an explosion of research into the genetic causes of cancer.
The Great Shift
The next significant advance in the understanding of CML took place 13 years later through the work of Janet Rowley, MD, and researchers at the University of Chicago. They realised that the missing section of DNA from chromosome 22 (which characterised CML) had shifted to chromosome 9, a phenomenon known as “translocation.”(2) The recognition of this phenomenon paved the way for many later researchers, who have since been able to match dozens of translocations to various cancers. (In 1998, Nowell and Rowley received the Albert Lasker Medical Research Award, which is sometimes called the “American Nobel Prize”, for their work in CML.)
The remainder of the 1970s saw only incremental progress in genetic cancer research. However, in the 1980s, 2 researchers from the California Institute of Technology, David Baltimore, PhD, and Owen N. Witte, MD, identified the principal cause of CML. The Ph chromosome produces an enzyme that plays a central role in aberrant cell growth and division. The enzyme, a fusion protein (Bcr-Abl) that enhances tyrosine kinase activity, changes the cell’s normal genetic instructions. This aberrant enzyme sends out signals through multiple pathways within the cell, resulting in the overproduction of white blood cells in the body. The result is that, while a healthy cubic millimetre of blood contains 4,000 to 10,000 white blood cells, blood from a patient with CML contains 10 to 25 times this amount.(3) The massive increase in the number of white blood cells characterises CML.
Glivec: Realising a Dream
With the groundbreaking discovery that a single enzyme could cause the development of CML, medical researchers faced a rare opportunity. Unlike previous efforts, the genetic target was clear, and the development of a drug that could block Bcr-Abl could proceed rationally. Work soon began in early 1990 on the discovery of Bcr-Abl inhibitors by researchers at Novartis (then Ciba-Geigy).(4,5) The 2 lead researchers, Nicholas Lydon, PhD, and Alex Matter, MD, were particularly optimistic about one promising compound from a pool of several potential agents. However, it had only weak, non-specific activity against Bcr-Abl.
The task of improving this “promising compound” was assigned to 4 Novartis scientists, Drs. Juerg Zimmermann (Medicinal Chemistry), Elisabeth Buchdunger (Cell Biology), Helmut Mett (Screening and Enzymology), and Thomas Meyer (Enzymology). They soon began changing, adding, and deleting certain molecules to alter the original compound’s activity against Bcr-Abl.
After 2 years of painstaking experimentation, the team finally transformed the original compound-a weak, non-specific inhibitor-into a potent, specific inhibitor of Bcr-Abl. This agent effectively blocked the enzyme that leads to the proliferation of white blood cells in patients with CML. Their pioneering work led to a class of compounds with optimised activity against Bcr-Abl and other kinases.(6) The result of this monumental achievement was the filing of the basic patent application covering this class of inhibitors in 1993 and 1995.
Building on the Dream
Building on the enormous experimental achievement of Drs. Zimmermann, Buchdunger, Mett, and Meyer, Novartis began a collaboration in 1994 with Brian Druker, MD, a haematologist and oncologist with an interest in tyrosine kinases and CML. Their work profiled the activity of 2 compounds in cellular models of CML. They found that one compound, which would eventually be known as Glivec, showed selective in vitro activity against the Bcr-Abl protein, and it suppressed the proliferation of Bcr-Abl-expressing cells in vitro and in vivo in one critical study. Of equal significance, the compound did not demonstrate significant activity against normal cells,(7) which immediately distinguished it from traditional cancer treatments. Other researchers subsequently confirmed these findings.(8,9)
Over the next several years, Novartis conducted the additional research needed to start clinical trials, including elaboration of the chemical synthesis, studies of drug formulation, pharmacokinetics, and toxicology screenings.
These studies led to the original reports on this class of inhibitor that were first published by Novartis scientists in 1996.(10-13) While the results from initial oral bioavailability and toxicology studies showed promise, additional refinements were needed. Therefore, pre-clinical development of Glivec soon began, with Lydon directing a multidisciplinary team of scientists. Matter, Lydon, Druker, Baltimore, and Witte would eventually be awarded the 2001 Warren Alpert Foundation Prize for their work with Bcr-Abl. This honour seeks to recognise the full breadth of the development of a therapy-the basic scientific underpinnings, pre-clinical exploration, and clinical trial investigations.
References
1. Nowell PC, Hungerford DA. A minute chromosome in human chronic granulocytic leukaemia. Science. 1960;132:164-172.
2. Rowley D. A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature. 1973;243:290-293.
3. Mughal T, Goldman J. Understanding leukaemia and related cancers. Oxford: Blackwell Science Ltd. 1999.
4. Lydon NB, Adams B, Poschet JF, et al. An E. coli expression system for the rapid purification and characterization of a v-abl tyrosine protein kinase. Oncogene Research. 1990;5:161-173.
5. Geissler JF, Roesel JL, Meyer T, et al. Benzopyranones and benzothiopyranones: a class of tyrosine protein kinase inhibitors with selectivity for the v-abl kinase. Cancer Research. 1992;52:4492-4498.
6. Druker BJ, Lydon NB. Lessons learned from the development of an Abl tyrosine kinase inhibitor for chronic myelogenous leukaemia. J Clin Invest. 2000;105:3-7.
7. Druker BJ, Tamura S, Buchdunger E, et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nature Med. 1996;2:561-566.
8. Deininger MW, Goldman JM, Lydon N, et al. The tyrosine kinase inhibitor CGP57148B selectively inhibits the growth of BCR-ABL-positive cells. Blood. 1997;90:3691-3698.
9. Gambacorti-Passerini C, le Coutre P, Mologni L, et al. Inhibition of the ABL kinase activity blocks the proliferation of BCR/ABL+ leukemic cells and induces apoptosis. Blood Cells Mol Dis. 1997;23:380-394.
10. Buchdunger E, Zimmermann J, Mett H, et al. Inhibition of the Abl protein-tyrosine kinase in vitro and in vivo by a 2-phenylaminopyrimidine derivative. Cancer Research. 1996;56:100-104.
11. Zimmermann J, Caravtti G, Mett H, et al. Phenylamino-pyrimidine (PAP) derivatives: a new class of potent and highly selective PDGF-receptor autophosphorylation inhibitors. Bioorgan Med Chem Lett. 1996;6:1221-1226.
12. Zimmermann J, Buchdunger E, Mett H, et al. Potent and selective inhibitors of the ABL-kinase: phenylamino-pyrimidine (PAP) derivatives. Bioorgan Med Chem Lett. 1997;7:182-192.
13. Zimmermann J, Buchdunger E, Mett H, et al. Phenylamino-pyrimidine (PAP) derivatives: a new class of potent and selective inhibitors of protein kinase c (PKC). Arch Pharm. 1996;329:371-376.
http://www.glivec.com
The History Of Glivec
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PRINCETON, N.J., Dec. 28 /PRNewswire-FirstCall/ — Today, Bristol-Myers
Squibb Company (NYSE: BMY) announced that the Company has completed the
rolling submission of its New Drug Application (NDA) to the U.S. Food and Drug
Administration (FDA) for dasatinib to treat chronic myelogenous leukemia (CML)
in chronic, accelerated or blast phases, as well as Philadelphia chromosome-
positive (Ph+) acute lymphoblastic leukemia (ALL).
The NDA seeks approval of dasatinib – an investigational multi-targeted
kinase inhibitor – to treat adult CML and Ph+ ALL patients with resistance or
intolerance to prior therapy.
Dasatinib was discovered and is being developed by scientists within
Bristol-Myers Squibb laboratories.
About CML and ALL
CML is a slowly progressing cancer of the blood and bone marrow that
usually occurs during or after middle age and rarely occurs in children. ALL
is a rapidly progressing cancer of the blood and bone marrow that usually
occurs in children; although it can occur at any age. The Leukemia and
Lymphoma Society estimates that 4,600 new cases of CML and nearly 4,000 new
cases of ALL will be diagnosed in the United States this year.
About the Philadelphia Chromosome
Approximately 95 percent of people with CML and approximately 25 percent
of adults with ALL have a gene mutation called the Philadelphia chromosome, in
which part of the DNA from one chromosome (chromosome 9) moves to another
chromosome (chromosome 22). This translocation brings together two genes, one
from each chromosome: BCR (breakpoint cluster region) and ABL (Ableson
leukemia virus). The resulting hybrid gene, BCR-ABL, produces an abnormal
protein called Bcr/Abl tyrosine kinase that triggers uncontrolled cell growth.
About Bristol-Myers Squibb
Bristol-Myers Squibb is dedicated to the discovery, development, and
exhaustive exploration of innovative cancer fighting therapies that extend and
enhance the lives of patients living with cancer. More than 40 years ago,
Bristol-Myers Squibb built a unified vision for the future of cancer
treatment. With expertise, dedication and resolve, that vision led to the
development of a diverse global portfolio of anti-cancer therapies that are an
important cornerstone of care today. Hundreds of scientists at Bristol-Myers
Squibb’s Pharmaceutical Research Institute are studying ways to improve
current cancer treatments and identify better, more effective medicines for
the future.
Bristol-Myers Squibb is a global pharmaceutical and related health care
products company whose mission is to extend and enhance human life.
Visit Bristol-Myers Squibb on the World Wide Web at http://www.bms.com.
This press release contains “forward-looking statements” as that term is
defined in the Private Securities Litigation Reform Act of 1995. Such
forward-looking statements are based on current expectations and involve
inherent risks and uncertainties, including factors that could delay, divert
or change any of them, and could cause actual outcomes and results to differ
materially from current expectations. No forward-looking statement can be
guaranteed. Among other risks, there can be no guarantee that dasatinib will
receive regulatory approval or, if approved, will be commercially successful.
Forward-looking statements in this press release should be evaluated together
with the many uncertainties that affect Bristol-Myers Squibb’s business,
particularly those identified in the cautionary factors discussion in Bristol-
Myers Squibb’s Annual Report on Form 10-K for the year ended December 31, 2004
and in our Quarterly Reports on Form 10-Q. Bristol-Myers Squibb undertakes no
obligation to publicly update any forward-looking statement, whether as a
result of new information, future events or otherwise.
SOURCE Bristol-Myers Squibb Company
Web Site: http://www.bms.com
Bristol-Myers Squibb Submits New Drug Application for Dasatinib
Posted by rob on December 23, 2005 under Uncategorized |
Guo XQ, Zhang J, Fu X, Wei Q, Lu Y, Li Y, Yin G, Mao Y, Xie Y, Rui Y, Ying K
Front Biosci. 2006 May 1; 11: 1924-31
Camptothecin (CPT) is a potent inhibitor of DNA topoisomerase I with a wide spectrum of anti-tumor activity. Relatively little information is available regarding the relation of known topoisomerase-mediated DNA damage with other intracellular pathways. To gain an insight into the intracellular molecular mechanisms of Topoisomerase I inhibitor camptothecin-mediated DNA damage leading to cell death, we used a high-density cDNA microarray to assess sensitive early gene expression profiles in SGC7901 (gastric cancer), Hela (cervical adenocarcinoma), K562 (chronic myelogenous leukemia) and HL60 (promyelocytic leukemia) tumor cells stimulated with camptothecin for 1 h at the concentrations of GI50 (50 % growth inhibition after 24 h of treatment). Analysis of the differentially expressed genes obtained 29 response genes common to all four cell lines. Moreover, these cell lines also shared the direction of regulation. Most of these common response genes were functionally related to cell proliferation or apoptosis, and some of them were involved in ATM (ataxia-telangiectasia mutated) and ATR (ATM-and Rad3 related) checkpoint pathways, JNK (c-Jun N-terminal kinase) pathway, the survival phosphatidylinositol (PI) 3 kinase-Akt-dependent pathway, mitochondrial cell death pathway, endoplasmic reticulum (ER)-related cell death pathway, and to ubiquitin/proteasome dependent protein degradation pathway. The data provides evidence for a linkage between topoisomerase-mediated DNA damage and intracellular signaling events, which may facilitate our understanding of the camptothecin mediated molecular mechanisms of action.
Analysis of common gene expression patterns in four human tumor cell lines exposed to camptothecin using cDNA microarray: identification of topoisomerase-mediated DNA damage response pathways.
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I have been in contact with Novartis regarding the situation that so many Medicare patients now face with the large co-payments and deductibles that will be required under the new Medicare prescription drug coverage. Novartis has responded and I will give you a summary of what they have said below. For those patients who will face a serious financial hardship because of the new Medicare program some of the programs listed below may be able to offer some help.
Rob
Contact Novartis PAP
1. If a patient has financial difficulty in being able to pay the co-payments and deductibles to obtain their Gleevec they can call the Novartis PAP number at 800-277-2254 They will try to help patients find ways to make the necessary co-payments so they can continue to receive Gleevec.
Contact PSI
2. Novartis and other drug companies have provided funding to a group called Patient Services Inc. http://www.uneedpsi.org/ which can provide financial assistance for co-payments based upon the severity of medical and financial need. PSI specifically has a program for CML patients, they will consider providing assistance on a case by case basis for both Medicare and non-Medciare patients. They can consider the following types of help:
Premium Assistance Program
# Cobra Payments
# High-risk Payments
# Open-enrollment Payments
# Guaranteed Issue Payments
# Full Assistance or Share-of-Cost
Copayment Assistance Program
# Full Assistance or Share-of-Cost
# Spend down Assistance
Financial Hardship Waiver Program
# Determine eligibility for Copayment Waiver
# Determine eligibility for Compassionate Product
Contact Partnership For Prescription Assistance
An additional site that might be able to also provide assistance to CML patients is:
Partnership For Prescription Assistance
www.pparx.org
They help patients find financial resources through public or private programs.
Posted by rob on December 22, 2005 under Uncategorized |
Park J, Kim S, Oh JK, Kim JY, Yoon SS, Lee D, Kim Y
J Biochem Mol Biol. 2005 Nov 30; 38(6): 725-38
Resistance to imatinib mesylate (also known as Gleevec, Glivec, and STI571) often becomes a barrier to the treatment of chronic myelogenous leukemia (CML). In order to identify markers of the action of imatinib mesylate, we used a mass spectrometry approach to compare protein expression profiles in human leukemia cells (K562) and in imatinib mesylate-resistant human leukemia cells (K562-R) in the presence and absence of imatinib mesylate. We identified 118 differentially regulated proteins in these two leukemia cell-lines, with and without a 1 microM imatinib mesylate challenge. Nine proteins of unknown function were discovered. This is the first comprehensive report regarding differential protein expression in imatinib mesylate-treated CML cells.
Identification of differentially expressed proteins in imatinib mesylate-resistant chronic myelogenous cells.
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Fugazza G, Garuti A, Marchelli S, Miglino M, Bruzzone R, Gatti AM, Castello S, Sessarego M
Cancer Genet Cytogenet. 2005 Dec ; 163(2): 173-5
The cytogenetic studies and molecular evaluation of a Philadelphia chromosome negative chronic myelogenous leukemia patient with trisomy 21 (100% metaphases) and trisomy 9 (50% metaphases) at diagnosis are described. Fluorescence in situ hybridization revealed an atypical location of the BCR/ABL fusion signal on 9q, which was duplicated in cells with trisomy 9 simulating a double Ph. The patient was successfully treated with Glivec (also known as Gleevec; Novartis, Basel, Switzerland) and achieved complete hematological and cytogenetic response as well as a reduction of BCR/ABL transcripts detected by real-time quantitative PCR.
Masked Philadelphia chromosome due to atypical BCR/ABL localization on the 9q34 band and duplication of the der(9) in a case of chronic myelogenous leukemia.
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Millot F, Guilhot J, Nelken B, Leblanc T, De Bont ES, B?kassy AN, Gadner H, Sufliarska S, Stary J, Gschaidmeier H, Guilhot F, Suttorp M
Leukemia. 2005 Dec 8;
A multicentric phase 2 study was conducted to determine the efficiency and the tolerance of imatinib mesylate in children with chronic myelogenous leukemia (CML) in advanced phase of the disease, in relapse after stem cell transplantation, or in case of failure to an interferon alpha-based regimen. In all, 30 children from eight European countries were enrolled. In 18 children assessable for hematologic response, imatinib mesylate induced complete hematologic response in eight (80%) of the 10 patients included in chronic phase and in six (75%) of eight enrolled in advanced phase of the disease with acceptable toxicity. In 27 patients assessable for cytogenetic response, imatinib mesylate induced disappearance of Philadelphia chromosome-positive bone marrow cells in 12 (60%) of 20 children included in chronic phase and in two (29%) of seven included in advanced phase. A reduction of the bcr-abl/abl ratio to less than 10(-4) was achieved in 11 (50%) of the children included in chronic phase. Estimated 12-month overall survival rate was 95% (95% CI, 87-100%) for the patients included in chronic phase and 75% (95%CI, 45-100%) for those enrolled in advanced phase. Imatinib mesylate is well tolerated and molecular remission can be achieved in children with CML.Leukemia advance online publication, 8 December 2005; doi:10.1038/sj.leu.2404051.
Imatinib mesylate is effective in children with chronic myelogenous leukemia in late chronic and advanced phase and in relapse after stem cell transplantation.
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Borthakur G, Kantarjian H, Daley G, Talpaz M, O’brien S, Garcia-Manero G, Giles F, Faderl S, Sugrue M, Cortes J
Cancer. 2005 Dec 8;
BACKGROUND: Lonafarnib (SCH66336) is a nonpeptidomimetic farnesyl transferase inhibitor that has demonstrated significant preclinical activity against chronic myelogenous leukemia (CML) cells and in CML animal models. METHODS: In the current study, the efficacy of lonafarnib was investigated in patients with CML in the chronic or accelerated phase that was resistant or intolerant to imatinib. Thirteen patients with CML in the chronic (n = 6 patients) or accelerated (n = 7 patients) phase were treated with lonafarnib at a dose of 200 mg orally twice daily. Ten patients had failed therapy with imatinib and 3 patients were intolerant to imatinib. The median age of the patients was 62 years (range, 38-80 yrs) and the median time from the diagnosis of CML to therapy with lonafarnib was 5 years (range, 0.3-13 yrs). In addition to imatinib mesylate, all patients had received prior therapy with interferon-alpha and seven patients had received other treatments. The median duration of therapy with lonafarnib was 8 weeks (range, 2-41 wks). RESULTS: Two patients responded. One patient in the accelerated phase of CML returned to the chronic phase, a response that lasted for 3 months. Another patient with chronic phase disease had lowering of the leukocyte count without the need for hydroxyurea and normalization of the differential count that lasted for 5 months. The most common adverse event was diarrhea, which was noted in 11 patients (84%) (Grade >/= 3 in 4 patients; 31%; toxicity was graded according to the National Cancer Institute Common Toxicity Criteria [version 2.0]). Therapy was discontinued in one patient because of diarrhea not responding to dose adjustments. CONCLUSIONS: Single-agent lonafarnib appears to have clinical activity in a small proportion of patients with CML refractory to imatinib. Cancer 2006. (c) 2005 American Cancer Society.
Pilot study of lonafarnib, a farnesyl transferase inhibitor, in patients with chronic myeloid leukemia in the chronic or accelerated phase that is resistant or refractory to imatinib therapy.
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Bornh?user M, Kr?ger N, Schwerdtfeger R, Schafer-Eckart K, Sayer HG, Scheid C, Stelljes M, Kienast J, Mundhenk P, Fruehauf S, Kiehl MG, Wandt H, Theuser C, Ehninger G, Zander AR,
Eur J Haematol. 2006 Jan ; 76(1): 9-17
Objective: To analyse the results of allogeneic haematopoietic cell transplantation (HCT) in patients with advanced stages of Philadelphia chromosome-positive chronic myelogenous leukaemia (CML) who had previously been treated with imatinib mesylate (IM). Methods: We analysed the outcome of 61 patients with CML who had received allogeneic HCT from sibling (n = 18) or unrelated (n = 43) donors after having been treated with IM. Forty-one patients had received IM because of accelerated or blast phase CML. Conditioning therapy contained standard doses of busulfan (n = 25) or total-body irradiation (n = 20) in conjunction with cyclophosphamide in the majority of cases. Sixteen patients received dose-reduced conditioning with fludarabine-based regimens. Results: The incidence of grades II-IV and III-IV graft-versus-host disease was 66% and 38% respectively. The probability of overall survival (OS), disease-free survival (DFS) and relapse at 18 months for the whole patient cohort were 37%, 33% and 24% respectively. The probability of non-relapse mortality (NRM) at 100 d and 12 months was 30% and 46% respectively. Univariate analysis showed that fludarabine-based conditioning therapy, age >/=40 yr and >12 months interval between diagnosis and transplantation were associated with a significantly lower OS and DFS and a higher NRM. Conclusion: These data suggest that although pretreatment with IM is not an independent negative prognostic factor, it cannot improve the dismal prognosis of CML patients at high risk for transplant-related mortality.
Allogeneic haematopoietic cell transplantation for chronic myelogenous leukaemia in the era of imatinib: a retrospective multicentre study.
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J Zhejiang Univ Sci B. 2005 Dec; 6(12): 1141-7
Sun J, Huang H, Zhu YY, Lan JP, Li JY, Lai XY, Yu J
OBJECTIVE: Detecting the expression and mutation of human telomeric repeat binding factor (hTRF1) in 10 malignant hematopoietic cell line cells on the base of determining its genomic structure and its four pseudogenes to clarify if hTRF1 mutation is one of the factors of the activation of telomerase. METHODS: hTRF1cDNA sequences were obtained from GenBank, its genome structure and pseudogenes were forecasted by BLAST and other biology information programs and then testified by sequencing. Real-time RT-PCR was used to detect the expression of hTRF1mRNA in 10 cell line cells, including myelogenous leukemia cell lines K562, HL-60, U-937, NB4, THP-1, HEL and Dami; lymphoblastic leukemia cell lines 6T-CEM, Jurkat and Raji. Telomerase activities of cells were detected by using telomeric repeat amplification (TRAP)-ELISA protocol. PCR and sequencing were used to detect mutation of each exon of hTRF1 in 10 cell line cells. RESULTS: hTRF1 gene, mapped to 8q13, was divided into 10 exons and spans 38.6 kb. Four processed pseudogenes of hTRF1 located on chromosome 13, 18, 21 and X respectively, was named as PsihTRF1-13, PsihTRF1-18, PsihTRF1-21 and PsihTRF1-X respectively. All cell line cells showed positive telomerase activity. The expression of hTRF1 was significantly lower in malignant hematopoietic cell lines cells (0.0338, 0.0108-0.0749) than in normal mononuclear cells (0.0493, 0.0369-0.128) (P=0.004). But no significant mutation was found in all exons of hTRF1 in 10 cell line cells. Four variants were found in part of intron 1, 2 and 8 of hTRF1. Their infection on gene function is unknown and needs further studies. CONCLUSION: hTRF1 mutation is probably not one of the main factors for telomerase activation in malignant hematopoietic disease.
Study on the expression and mutation of human telomeric repeat binding factor (hTRF1) in 10 malignant hematopoietic cell lines.
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Ma X, Ruan G, Wang Y, Li Q, Zhu P, Qin YZ, Li JL, Liu YR, Ma D, Zhao H
Clin Cancer Res. 2005 Dec 15; 11(24): 8592-9
PURPOSE: Chronic myelogenous leukemia (CML) is a disease characterized cytogenetically by the presence of the Philadelphia chromosome. Recent studies suggested that altered PDCD5 expression may have significant implications in CML progression. The aim of this study was to identify single-nucleotide polymorphisms (SNP) within the programmed cell death 5 (PDCD5) promoter region and show their functional relevance to PDCD5 expression as well as their genetic susceptibility to CML.EXPERIMENTAL DESIGN: One hundred twenty-nine CML subjects and 211 healthy controls were recruited for identification of SNPs and subsequent genetic analysis. Luciferase reporter assays were carried out to show the functional significance of the SNPs located in the promoter region to PDCD5 expression. Real-time quantitative PCR and Western blot analysis were done to determine the expression differences of PDCD5 in CML patients with different genotypes.RESULTS: Two SNPs were identified within the PDCD5 promoter. They are -27A>G and -11G>A (transcription start site as position 1), respectively. The complete linkage disequilibrium was found between these two polymorphisms. The frequencies of -27G(+)/-11A(+) genotype and -27G/-11A allele were significantly higher in CML patients than in healthy controls (genotype: 26.36% versus 11.85%, chi(2)=11.75, P HubMed Abstracts
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Rezvani K, Brenchley JM, Price DA, Kilical Y, Gostick E, Sewell AK, Li J, Mielke S, Douek DC, Barrett AJ
Clin Cancer Res. 2005 Dec 15; 11(24): 8799-8807
PURPOSE: Antigens derived from the Wilms’ tumor (WT1) protein, which is overexpressed in leukemias, are attractive targets for immunotherapy. Four HLA-A*0201-restricted WT1-derived epitopes have been identified: WT37, WT126, WT187, and WT235. We determined the natural immunogenecity of these antigens in patients with hematologic malignancies and healthy donor.EXPERIMENTAL DESIGN: To detect very low frequencies of WT1-specific CD8(+) T cells, we used quantitative reverse transcription-PCR to measure IFN-gamma mRNA production by WT1 peptide-pulsed CD8(+) T cells from 12 healthy donors, 8 patients with chronic myelogenous leukemia, 6 patients with acute myelogenous leukemia, and 8 patients with acute lymphoblastic leukemia.RESULTS: Responses were detected in 5 of 8 chronic myelogenous leukemia patients, 4 of 6 patients with acute myelogenous leukemia, and 7 of 12 healthy donors. No responses were detected in patients with acute lymphoblastic leukemia. The magnitude and extent of these CD8(+) T-cell responses was greater in patients with myeloid leukemias than in healthy donors. Clonotypic analysis of WT1-specific CD8(+) T cells directly ex vivo in one case showed that this naturally occurring population was oligoclonal. Using fluorescent peptide-MHC class I tetramers incorporating mutations in the alpha3 domain (D227K/T228A) that abrogate binding to the CD8 coreceptor, we were able to confirm the presence of high-avidity T-cell clones within the antigen-specific repertoire.CONCLUSION: The natural occurrence of high-avidity WT1-specific CD8(+) T cells in the periphery could facilitate vaccination strategies to expand immune responses against myeloid leukemias.
HubMed Abstracts
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Haltrich I, Kost-Alimova M, Kov?cs G, Kriv?n G, Tam?ska J, Klein G, Fekete G, Imreh S
Cancer Genet Cytogenet. 2006 Jan 1; 164(1): 74-80
The virtually obligatory presence of the Philadelphia chromosome may suggest a causal homogeneity, but chronic myelogenous leukemia (CML) is a clinically heterogeneous disease. This may be a consequence of the variable BCR breakpoints on chromosome 22 and of nonrandom secondary chromosomal abnormalities. We present the case of a boy, age 12, investigated in blastic phase of CML. Karyotyping with conventional and multiplex fluorescence in situ hybridization (FISH and M-FISH) karyotyping, complemented with reverse transcriptase-polymerase chain reaction, identified a variant Philadelphia translocation t(9;14;22)(q34;q32;q11) involving a cryptic BCR/ABL fusion with formation of the p190(Bcr-Abl) oncoprotein. M-FISH revealed also an unbalanced jumping translocation of 17q11 approximately qter alternatively present on chromosomes 14 or 20, apparently hithertofore unreported in hematological malignancies. Another secondary aberration, dup(3)(q25q28), was revealed by multipoint interphase FISH (mpI-FISH). Gain of this region is known in adult hematological malignancies and solid tumors, suggesting its general involvement in tumor initiation or progression (or both), regardless of tissue origin.
Jumping translocation of 17q11 approximately qter and 3q25 approximately q28 duplication in a variant Philadelphia t(9;14;22)(q34;q32;q11) in a childhood chronic myelogenous leukemia.
Posted by rob on December 20, 2005 under Uncategorized |
WASHINGTON, DC (Dec. 20, 2005) USSoccerPlayers – Everything was going well for Katie Knudson of Portland, Oregon in the spring of 2001. She loved school and her kindergarten teacher and she had a great 6th birthday party. She loved her dance class and was a very cute ballerina. At school, she loved to run and play with her classmates at recess and in P.E. Then school ended and she was out for summer vacation. What could be better than summer vacation when you are six years old?
Then Katie came down with a summer fever. Nothing too serious, but she was lacking her normal energy, and by the next day it was up to 104 degrees. Her parents, Mark and Karen, decided to take her to the doctor just to be safe. The pediatrician, a wonderful woman who had taken care of Katie since she was born, thought it might be a virus that would run its course in a couple of days. Katie’s Mom was still worried and asked the doctor to order some blood work.
On June 22, 2001 the pediatrician called to ask Katie’s parents to take Katie to the hospital immediately. She asked several times during the call, “is Katie okay” and wanted to know “what is she doing right now?” And then, the pediatrician began to cry and through her tears told Katie’s mother, “we think Katie has leukemia.” That day, Katie’s life and the life of her family took a whole new turn.
Katie spent four days in the hospital, having lots of blood drawn, intravenous fluids pumped into her, and her first bone marrow aspiration – a needle inserted into her hip to test the bone marrow. By the time they had Katie’s fever under control and were ready to send her home, they also had a diagnosis – Chronic Myelogenous Leukemia (CML), a type of leukemia usually found in people over 60 that is extremely rare in young children. Katie may have been the youngest person in the United States with CML in 2001.
As soon as Katie was released from the hospital, she began outpatient chemotherapy. The doctors started with a drug intended to help improve her blood quality without all the side effects associated with more aggressive chemotherapy. During 1995-2001 the three to five (3-5) year survival rate for patients diagnosed with CML was less than 40%. The doctors described the treatment plan for CML – chemotherapy, radiation, and Katie would need a bone marrow transplant before Christmas. The doctors explained both the relatively low survival rate of CML patients and the potential for serious adverse lifelong effects as a result of the treatments for even those who survive.
With no choice apparent, the Knudson family began the search for a bone marrow donor. No family member was a match, but the family was incredibly relieved when they found a suitable unrelated donor. Katie and her family met with the doctors and staff at Doernbecher Children’s Hospital, who would be responsible for the bone marrow transplant. The doctors confirmed Mark and Karen’s fears about the serious long-term health problems associated with some bone marrow transplants.
The doctors then discussed another option with the Knudsons – a new drug, “Gleevec” – that had been approved by the United States Food and Drug Administration (“FDA”) only a few weeks earlier. Gleevec was developed by the pharmaceutical company Novartis. When physician and researcher Brian Druker proposed to conduct clinical trials to see if Gleevec might be effective for treating certain forms of leukemia, Novartis was not willing to bear those costs, so Dr. Druker turned to the Leukemia & Lymphoma Society (the “Society”). The Society funded Dr. Druker’s research and the research was successful. CML was precisely the type of cancer that Gleevec treats, but because CML is so rare in young children, fewer than a dozen children had ever been treated with Gleevec.
Katie started taking Gleevec on August 8, 2001. Every evening after dinner she takes two pills. No aggressive chemotherapy with the profound side effects. No hair loss. No hospitalization. No bone marrow transplant. Regular hospital visits, many bone marrow aspirations – the needles inserted into her hip to test the bone marrow, but in six months the Gleevec had worked – Katie’s leukemia was in remission.
Today, four years later, Katie still takes the Gleevec pills. She still has appointments at the pediatric hematology ward for examinations and twice a year they test her bone marrow, but there have been no signs of the leukemia that changed everything so suddenly in 2001. Katie’s leukemia is not “cured” – and it remains a constant concern that a bone marrow transplant or other treatments will be necessary in the future.
Through all the stress and fear the Knudson family endured, Katie has blossomed. Ballet gave way to soccer as Katie’s favorite activity and now she plays softball and golf as well.
Aware of all that the Leukemia & Lymphoma Society’s funding of Dr. Druker’s research has given them, Katie and her family have committed themselves to giving back. Gleevec meant that Katie Knudson never lost her hair, so she donated her beautiful waist-length brown hair to “Locks of Love,” to help someone else who will have to endure the aggressive chemotherapy the Knudsons have avoided. Katie’s story and her parents’ decision to select Gleevec over the potential cure offered by a bone marrow transplant have been discussed in Newsweek and other national publications.
Katie and her family have become leaders in the cancer community. Katie participates in the Leukemia & Lymphoma Society’s annual “Light the Night” fundraising events. Katie has been a spokesperson and poster child for the Society’s “Pennies for Patients” program, which raises over $10 million per year and reaches six million children in 12,000 schools. Katie has been the “honored hero” for several Team in Training events. She has also been a featured “honored hero” for Soccer Kicks for Cancer, the national program for youth soccer players and teams that was launched in 2005 by the US National Soccer Team players along with the Society and the US Youth Soccer Association. Pictures of Katie with US National Team star Landon Donovan appear in the US National Soccer Team Players website and at the Soccer Kicks for Cancer website. Katie’s artwork is part of the 2006 Leukemia & Lymphoma Society “Twelve Months of Hope” calendar.
After Hurricane Katrina hit the Gulf Coast and the Portland Water Bureau sent people and trucks, one of the mechanics going to New Orleans asked for some yellow Lance Armstrong Livestrong bracelets to distribute to people in New Orleans. Katie and her family responded by providing a bag full of Livestrong bracelets and the red Leukemia & Lymphoma Society bracelets with the message “Relentless,” as in “Relentless for a Cure.”
While Katie and her family have become dedicated to the Leukemia & Lymphoma Society and the cancer community, their commitment has not prevented Katie from having fun doing all the things a ten year-old girl should be doing. She loves to play soccer and her coaches love to see her at practice and on the field. She is not the fastest player on her team or the strongest, but she always does her best and gives 100%. For her teammates and their parents, who know what Katie and her family have been through, Katie contributes something extra – inspiration to everyone else and a reminder of how precious and sometimes how fleeting good health can be. No matter how she plays, she has a smile on her face. But, then, she and her family all have good reasons to smile. The US National Soccer Team Players are privileged to be able to welcome Katie Knudson as a Time In program honoree.
Time In – Katie Knudson
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One night in late October, Dr. Deborah Dunsire endured a fitful night’s sleep.
Dunsire, president and CEO of Millennium Pharmaceuticals Inc. for just three months, was hours away from announcing more than 100 layoffs. She would also tell employees Millennium was ending its promising research into inflammation and redirecting its discovery budget solely toward the pursuit of new cancer treatments.
“We had to look at great people who have done terrific work that helped Millennium be where it is and (then) say to them, ‘Unfortunately you won’t be going forward,’ ” Dunsire said. “That dissonance is what keeps you awake.”
Dunsire announced the cutbacks, moving ahead with an aggressive plan to focus the company primarily on cancer drug development and boost sales efforts for its cancer drug Velcade. It’s a mandate she assumed over the summer after succeeding founder and longtime CEO Mark Levin, who launched Millennium in 1993 as a gene researcher that licensed technology to third parties and then, through acquisitions, transformed it into a drug developer.
Her first step toward a new focus for the company took place in July, when Dunsire executed a plan negotiated before her arrival for Millennium (Nasdaq: MLNM) to give up co-promotion rights to Schering-Plough Corp. (NYSE: SGP) for Integrilin, a cardiovascular drug the companies co-developed. Many of Millennium’s 200 Integrilin sales and marketing jobs subsequently moved to Schering-Plough. That and October’s layoffs will bring Millennium’s employment down to about 1,100 from last year’s 1,500.
Dunsire will be tapping into 17 years of experience with Switzerland’s Novartis AG (NYSE: NVS) and its predecessor companies as she hashes out Millennium’s long-term commercial plans.
She most recently ran Novartis’ North American oncology operations and helped engineer domestic launches of a number of drugs, including the cancer treatment Gleevec in 2001, which has surpassed $1 billion in annual global sales.
Jerry Karabelas, an old boss from that period, said Dunsire is the right executive for the job, even in the wake of the departure of the visionary Levin.
“She’s very smart and focused,” said Karabelas, a partner with Care Capital LLC in New Jersey and a former head of Novartis’ health care division. “She can set and articulate a vision, identify key issues, organize and motivate an organization and direct them to solutions.”
Levin, who continues to serve as a Millennium board member, said the company looked at more than 50 candidates over the last three years before identifying Dunsire as a potential new CEO. Dunsire made strong impressions early on, during an initial airport meeting at the Newark Marriott.
“She was passionate right from the beginning about building a company that would make a big difference in people’s lives,” he said. “And she was focused on building a company for the long term.”
Dunsire’s job won’t be easy. Millennium lost $252.3 million in 2004 even as it reduced red ink and boosted product sales. Losses over the first three quarters of this year hit $154 million, driven in part by restructuring charges left over from the layoff of more than 600 people in 2003 in what also represented a major restructuring and initial narrowing of development focus. Millennium boosted revenue to more than $201.6 million in the third quarter by increasing Velcade sales but also because of one-time revenue sources. Still, clinical trials for three cancer compounds and four inflammation treatments that have made it past the discovery stage are either planned or under way.
The South African-born Dunsire, a former physician who speaks in measured academic language from behind wire-rimmed glasses, said she addresses top decisions by working with and seeking feedback from other executives.
“This business is too complex,” she said. “Any person in this type of role who believes they have all the answers and tries to do it alone, I think, is dangerous.”
And she tries to be transparent about her intentions. Dunsire, 43, ran six town hall-style meetings at Millennium’s headquarters so employees could ask questions about the restructuring. That approach, she said, reflects her overall goals of being quick, honest and clear about her plans.
“I really do believe that when you do something you need to do it well,” she said. “And I absolutely believe if we had tried to continue to do both inflammation and oncology we would have at best been mediocre, and then the whole company suffers.”
Some congratulated the action as necessary for Millennium to achieve its goal of pro forma operating profitability next year.
“She’s doing the right things,” said Christopher Raymond, a Chicago-based analyst with Robert W. Baird & Co.
Dunsire, who now lives in Weston, often works 60 to 70 hours per week, but she also takes time for family, taking road trips with her husband and two children or going swimming and doing “the soccer mom thing.” Dunsire loves orchids (“They are kind of peaceful,” she said) and three grow in her lime-green office. Pictures of her children sit right by her desk, and large modern bookcases display photos from charity events featuring both sides of the political spectrum. At least one includes Dunsire with former President George H.W. Bush and First Lady Barbara Bush. Another photo features Dunsire with Bush’s successor, Bill Clinton, and Sen. Hillary Clinton.
One photo hangs prominently on a side wall: A picture of 50 Gleevec patients celebrating the drug’s launch, all of whom survived because of the medicine she helped launch commercially.
“That’s the reward, really,” she said.
Mark Hollmer can be reached at mhollmer@bizjournals.com.
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A fresh look at the delicate dance of enzymes within living cells has provided insights into how one genetic mutation can lead to three distinct blood disorders.
The discovery ?provides new and important insights into how this gene contributes to the development of myeloproliferative disease,? said D. Gary Gilliland, a Howard Hughes Medical Institute researcher at Brigham and Women’s Hospital and Harvard Medical School. ?It should provide an important foundation for subsequent development of new drugs,? he added.
?Although relatively rare individually, together these disorders are about five times more common than chronic myelogenous leukemia.?
D. Gary Gilliland
The new research results, found in collaboration with biologist Harvey Lodish’s team at the Whitehead Institute for Biomedical Research, were announced December 19, 2005, in an immediate early online publication in the Proceedings of the National Academy of Sciences.
What the teams of scientists are trying to decipher is the molecular explanation for how the protein encoded by this single gene – called JAK2V617F – can be the culprit in three different leukemia-like diseases. They want to know how and why the protein produced by this gene cooperates with other signaling proteins to touch off disease.
The three leukemia-related disorders caused by the mutation are each characterized by abnormal growth of blood system cells. The first, polycythemia vera, involves ultra-high red blood cell counts. The second, essential thrombocythemia, results from excess growth of blood platelets. And the third, myelofibrosis with myeloid metaplasia, stems from abnormal growth of fibroblast cells, making the bone marrow abnormally dense.
Patients who have these disorders are generally older, and there are about 100,000 in the United States. At present, patients with any of the three disorders receive empirically derived drug treatments similar to those used that used to be used to treat chronic myelogenous leukemia (CML).
The three blood disorders can all become dangerous forms of adult leukemia. ?They are technically cancers in their own right,? Gilliland explained. They tend to be slow-growing, and they are sometimes detected before severe symptoms arise, as is true with CML. Although relatively rare individually, together these disorders are about five times more common than CML, Gilliland said.
The research teams hope their findings will help them develop targeted drug therapies for the three disorders, similar to what has already been achieved for CML with the drug Gleevec.
In earlier work, Gilliland and three other teams of investigators found that the damaging mutation in the gene for JAK2V617F occurs later in life – and is acquired rather than inherited. It is not yet known why this single gene mutation causes different disorders in different patients, but it does show that those disorders have much in common. Other, more aggressive leukemias are known to result from different kinds of genetic damage, such as gene rearrangements caused by chromosome breakage.
The two research teams at Harvard and the Whitehead Institute studied the mutation, which occurs in a gene that makes an enzyme called a kinase. This particular kinase is one link in a chain – a kinase cascade ? that sends a signal from the cell surface to the nucleus, spurring a reaction such as cell division.
The kinase is normally pressed into action by the arrival of a molecule that docks with a specific receptor sitting on the cell’s surface. Arrival of the outside signal, like guests ringing a doorbell, sets off a cascade of events inside the cell. The kinase’s job, once the doorbell is rung, is to add a phosphate group to another protein. This sends a message that eventually reaches the nucleus and sets off some action, such as cell division.
The problem is that a strategic mutation can change everything. In these three blood disorders, for example, the mutant gene makes an abnormal kinase, like a faulty doorbell that won’t shut off, and the kinase constantly transmits a signal down the chain of command, whether it’s needed or not. The signal thus spurs abnormal activity – and too much growth causes overgrowth of a particular type of blood cell, leading to leukemia.
The researchers demonstrated that the faulty kinase can only trigger this excessive growth in cells that have its corresponding receptor. Since this receptor is found only in certain types of blood cells, their work helps explain why a mutation in JAK2V617F can trigger three distinct blood disorders – but has not been found to be associated with disorders originating in other types of blood cells.
Although more research is needed, ?these studies advance our understanding of the basis of myeloproliferative diseases,? Gilliland said. ?Ultimately it’s going to lead to curative strategies – we hope.?
HHMI News: Researchers Closer to Understanding How One Mutation Causes Three Different Blood Disorders
