Posted by rob on October 15, 2005 under Uncategorized | 
Dick Shaffer is forever grateful for the doctors and nurses who successfully treated his cancer in a clinical trial two years ago. He never would have met them, however, without the person who suggested he consider an experimental study.
For that reason, Shaffer has vowed to do everything he can to encourage other cancer patients to consider enrolling in clinical trials. He started by joining the Bristol-Myers Squibb Tour of Hope™ team of 24 cyclists who this month completed a 3,300-mile, cross-country bicycle ride aimed at boosting low clinical trial participation nationwide. The tour, led by cancer survivor and seven-time Tour de France winner Lance Armstrong, began in San Diego on Sept. 29 and ended in Washington D.C., on Oct. 8, Shaffer’s 59th birthday.
Riders in four teams of six made the journey by taking turns cycling about 100 miles a day (four or five hours). At the end of a team’s shift, the cyclists were transported to food and lodging and then taken to the next starting point to catch up with their teammates.
The trip was challenging and extremely rewarding, says Shaffer, a retired utility company finance director from upstate New York who has competed in triathlons since 1984. Just a few years before the tour, he was diagnosed with stage 3 esophageal cancer and given the prognosis of a 20% chance of survival – at best.
“This is a celebration for me,” Shaffer says. “It’s a chance to say, ‘in your face, cancer,’ and a chance to tell people there is hope. People need to know that cancer is not always a death sentence, and we need clinical trials because they are the only way to beat cancer in the long run.”
Clinical trial message sent best: patient to patient
Shaffer knew nothing about clinical trials in 2003 when his doctor found a 5-centimeter tumor at the intersection of his esophagus and stomach.
The mass was discovered during a routine physical before Shaffer was to compete in his second Ironman triathlon. He signed up for the competition at the suggestion of his nephew, Mike Siegel, 45, the same person who encouraged him to start training for triathlons 20 years before.
During the physical, Shaffer happened to mention to the doctor that he was having trouble swallowing vitamins. The doctor then ordered an endoscopy and discovered the tumor. Shaffer visited several doctors after that, receiving one poor prognosis after another.
Then Siegel suggested he try a clinical trial. It had worked for him.
Siegel was diagnosed with chronic myelogenous leukemia (CML) in April 1995 and given a 50% chance of survival with standard cancer treatments. Looking for better odds, the then father of three (with twins on the way) sought experimental treatments, therapies only available in clinical trials. Two studies have kept him alive since then, he says. The second trial involved the drug now called Gleevec®, which he continues to take today.
“I watched the twins being born and growing up, and they’re now 10 – and an earful,” says Siegel, who was treated at M. D. Anderson. “So I tell patients, ‘Clinical trials saved my life – twice. Don’t be afraid. Ask about a clinical trial.’”
Taking the leap of faith in a clinical trial pays off
At first, Shaffer resisted that suggestion. He didn’t know anything about clinical trials and was afraid. But then he thought about the people who needed him most, his wife and two young sons, then 8 and 13. He searched for a trial that might lead to a better possibility of survival, and found one at M. D. Anderson.
Entering the study, however, meant moving to Houston for six months and leaving his family behind so his sons could remain in school. “They wanted me home. I’ll never forget the day I said goodbye at the airport,” Shaffer says. “It was hard.”
Shaffer’s wife, Julie, took care of the kids in New York, and Shaffer left for Houston. Fortunately, his sister and brother-in-law moved with him to become his caregivers.
His treatment was aggressive: 12 weeks of chemotherapy (involving a combination of three drugs), 12 weeks of chemotherapy and radiation and, finally, surgery to remove half of his stomach and half of his esophagus.
The medication made him very sick, but he was upbeat during his twice-daily phone calls with his sons. Shaffer even managed to bike during the period he received chemotherapy and radiation. He kept such a positive attitude throughout his treatment that patients and doctors said he made them feel better. “I was so determined to beat this thing, I think,” he says.
Patient’s struggle and journey of hope comes full circle
And that he did. After treatment he reunited with his family, built up his strength and even competed with his wife in the Houston marathon. Next thing he knew he was taking another cue from his nephew, a 2004 cyclist in the Tour of Hope, by becoming a tour member himself.
Siegel joined Shaffer, Armstrong and the rest of the 2005 Tour of Hope team as they rode through the Texas Medical Center for an Oct. 3 stop at M. D. Anderson. Events there included a rally, press conference and a panel discussion about clinical trials.
Siegel was near the rally podium where, as one of the speakers, Shaffer was able to live out his dream of thanking every member of the medical team who helped eliminate his cancer.
His emotional thank-you touched the crowd made up of the public and hundreds of yellow-clad cancer center employees. Shaffer’s former nurses cheered the loudest, holding huge campaign-like signs bearing his photo. Armstrong joked that Shaffer might threaten Houston Mayor Bill White’s re-election bid.
Shaffer just hoped his experience might lead other cancer patients to new treatments that might free them of cancer.
CancerWise – October 2005 – Clinical Trial Patients Spread the Word: Hope
Posted by rob on October 10, 2005 under Uncategorized |
Tefferi A, Spivak JL
Semin Hematol. 2005 Oct ; 42(4): 206-20
Polycythemia vera (PV) is a clonal disorder of unknown etiology involving a multipotent hematopoietic progenitor cell that is characterized by the accumulation of phenotypically normal red blood cells, white blood cells, and platelets in the absence of a definable cause; extramedullary hematopoiesis, marrow fibrosis, and, in a few patients, transformation to acute leukemia can also occur. First described in 1892, the cause of the disease remains unknown and no potentially curative therapy other than bone marrow transplantation is currently available. It is commonly held that PV is a rare disorder, when in fact with a minimum incidence of 2.6 per 100,000 it is more common than chronic myelogenous leukemia (CML) and is particularly prevalent in persons of Ashkenazi Jewish ancestry. However, the incidence of PV is not as high as that of erythrocytosis from other causes collectively, which poses a problem in differential diagnosis when PV presents as isolated erythrocytosis. Characteristic features of PV are erythropoietin (Epo)-independent in vitro erythroid colony formation, as well as hypersensitivity to many other hematopoietic growth factors. Recently, a remarkable association between PV and a somatic point mutation of the JAK2 tyrosine kinase (JAK2 V617F) was described. Functional assays have revealed that JAK2 V617F is capable of inducing constitutive STAT5-mediated signaling in vitro, as well as erythrocytosis in vivo in mice. These data suggest that the JAK2 V617F mutation participates in the pathogenesis of PV. In current clinical practice, two different clinical approaches have been used to diagnose PV. One approach requires establishing the presence of absolute erythrocytosis by directly determining the red cell mass (RCM). A second approach utilizes a RCM-independent diagnostic algorithm based on the serum Epo level and bone marrow histology. Screening for JAK2 V617F can now be added to both diagnostic algorithms. However, it is very clear that some patients with classical PV lack the JAK2 V617F mutation, while some patients with other chronic myeloproliferative disorders such as idiopathic myelofibrosis (IMF) and essential thrombocytosis (ET) also express the JAK2 V617F mutation. Therefore, by necessity, any discussion of PV must take into consideration these companion myeloproliferative disorders, and since erythrocytosis is the single clinical feature that sets PV apart from IMF and ET, it is clear that the presence of the JAK2 V617F mutation cannot by itself establish a diagnosis of PV. Phlebotomy remains the mainstay of therapy for PV. In addition, both aspirin and cytoreductive therapy have been employed to control thrombocytosis and in the case of the latter, leukocytosis and extramedullary hematopoiesis as well. Despite recent progress in the field, several important issues remain controversial. In this review, we will present the areas of agreement, but also point out where the authors’ personal viewpoints differ.
Polycythemia vera: scientific advances and current practice.
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de Vos D
Semin Oncol. 2005 Oct ; 32(5): 437-42
In this chapter, the development of decitabine from its synthesis in 1964 to the submission of a registration file in 2004 is reviewed. The proper application of the unique properties of decitabine took quite some time to elucidate. In addition, the practical handling in the clinic was not easy as the prolonged myelosuppression of decitabine made it difficult to determine the preferred dose and schedule. Laboratory studies on DNA methylation and cell differentiation showed possible applications in solid and hematologic malignancies. However, despite many attempts, results in solid tumors have been disappointing thus far. After thorough investigation, decitabine achieved therapeutic application in myelodysplastic syndrome (MDS), in particular in patients with a poor prognosis. Further indications may include acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), hematopoietic stem cell transplantation, sickle cell anemia, and thalassemia. Whereas most drugs are already at the end of their life cycle after 40 years, decitabine is only at the beginning. Its application will broaden with the increase in knowledge of epigenetic mechanisms and their relationship to drug therapy.
Epigenetic drugs: a longstanding story.
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Rosenfeld CS
Semin Oncol. 2005 Oct ; 32(5): 465-72
This review highlights decitabine as a prototype epigenetic modifying drug to show how the clinical development of epigenetic agents differs from that of traditional cytotoxic chemotherapies. Decitabine, a cytosine analogue, is cytotoxic at high doses but has selective DNA demethylating activity at low doses. The focus of current decitabine investigations is twofold: to elucidate all of the mechanisms of action and to determine the optimal dose, schedule, and concomitant therapies. New phase I trials have identified a “biologically effective dose,” which is 1 to 2 logs lower than the cytotoxic dose. A clinical development program with low-dose decitabine in malignant diseases is focused on myelodysplastic syndrome (MDS), acute myelogenous leukemia (AML), and chronic myelogenous leukemia (CML). A phase III trial in MDS showed objective responses (complete [CR] plus partial [PR] remission) and longer median time to progression to AML or death with decitabine than with supportive care alone. The optimal use of decitabine may be in combination with other agents that promote gene expression, namely, histone deacetylase (HDAC) inhibitors. Optimized decitabine doses and combinations with other epigenetic therapies that can be used at minimally toxic doses provide potentially safer therapeutic options and introduce novel combination therapies.
Clinical development of decitabine as a prototype for an epigenetic drug program.
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Heinemann A, Sturm GJ, Ofner M, Sturm EM, Weller C, Peskar BA, Hartnell A
J Allergy Clin Immunol. 2005 Oct ; 116(4): 820-6
BACKGROUND: Little is known about the mechanisms that regulate the selective recruitment of basophils to sites of allergic inflammation. OBJECTIVE: Here we examine the role of stem cell factor (SCF) in the regulation of basophil function. METHODS: Human basophils were isolated from peripheral blood, and their migration was investigated in chemotaxis assays. Apoptosis was detected by means of annexin V and propidium iodide staining. The expression of cell-surface molecules was measured by means of flow cytometry. RESULTS: SCF amplified the chemotactic responsiveness of human peripheral blood basophils to the chemoattractants eotaxin, monocyte chemotactic protein 2 and macrophage inflammatory protein 1alpha, and C5a, without being chemotactic or chemokinetic by itself. SCF synergized with chemoattractants in causing basophil upregulation of the integrin CD11b, and this effect was inhibited by a c-kit antibody, the tyrosine kinase inhibitor imatinib mesylate (STI-571), and a phosphatidylinositol 3 kinase inhibitor but not by inhibitors of p38 mitogen-activated protein kinase or mitogen-activated protein kinase/extracellular signal-regulated kinase kinase. Basophils bound fluorescence-labeled SCF and expressed its receptor, c-kit, which was markedly upregulated in culture for 24 to 48 hours in the presence of IL-3. Moreover, SCF prolonged basophil survival in concert with IL-3 by delaying apoptosis. These effects of SCF were selective for basophils because chemotaxis and CD11b upregulation of eosinophils or neutrophils were unchanged. CONCLUSION: SCF might be an important selective modulator of basophil function through a phosphatidylinositol 3 kinase-dependent pathway.
Stem cell factor stimulates the chemotaxis, integrin upregulation, and survival of human basophils.
Posted by rob on October 9, 2005 under Uncategorized |
McCandless next stop for army of volunteers
Sunday, October 09, 2005
By Virginia Kopas Joe, Pittsburgh Post-Gazette
At a time when she should be looking forward to high school, Amy Katz is looking for someone to save her life.
Related article
Here’s how to help in donor search
The soon-to-be teenager and her family are searching for a bone marrow donor for Amy, 12, who has leukemia. A transplant is her best hope for a cure.
Amy, an eighth-grader at Jefferson Middle School in Mt. Lebanon, was diagnosed with chronic myelogenous leukemia in autumn 2003, and since that time, she has been in and out of hospitals and must take daily medication. Still, her days are like those of any preteen: homework, music lessons, squabbles with siblings, pestering parents for a cell phone and carrying on the family tradition of cheering on the Mt. Lebanon Blue Devils.
While the family’s health insurance covers the cost of most cancer treatments — father Michael Katz is a financial officer for a Green Tree engineering firm — it does not pay for the $65 to $100 screenings necessary to find a bone marrow donor. In what Amy’s mother, Lisa Katz calls typical of “this amazing place called Pittsburgh,” a volunteer group of more than 100 people, calling themselves Amy’s Army, has held a series of fund-raisers over past two years to help defray the cost of the testing for a bone marrow match for Amy.
One such screening will be held at Temple Ohav Shalom in McCandless on Oct. 23.
Along the way, these volunteers have added 6,000 more people to the national registry and 10 patients from across the nation have found life-saving perfect matches.
Still, none for Amy.
This is one in an occasional series of stories that will track Amy’s progress and her army’s maneuvers. But it is mostly a story about a brave little girl, who in her mom’s words is “working hard to grow up.”
These days, Amy is as much at home seeing her face on posters around town, which advertise Amy’s Army, as she is doing her math homework.
“OK, I really don’t like math, either, but it’s something you have to deal with,” she said matter-of-factly.
This is, after all, a child who stayed calm, cool and collected when she shared a dais with Ben Roethlisberger recently when they were honored at a Breakfast of Champions, sponsored by the Leukemia-Lymphoma Society in Pittsburgh.
“He’s nice. He’s … er … big,” she said.
In mid-September Amy celebrated her bat mitzvah at Temple Emanuel of South Hills in Mt. Lebanon. Wednesday was her 13th birthday.
There was a time when Lisa and Michael Katz didn’t think their middle daughter would see either milestone.
Amy spent the summer of 2003 enjoying the life of a little girl growing up in the suburbs: soccer, swimming and shopping. Sometimes she complained her legs hurt, but her pediatrician wrote it off as “growing pains.” When the pain intensified during a late summer vacation to Ocean City, Md., her mother rushed her home for a blood test.
The result was every parent’s nightmare. Amy was diagnosed with CML, a form of cancer rare in a child. Since then, she has been fighting it with daily 500-milligram doses of Gleevac, a new form of chemotherapy in a pill. At times, the effect of the treatment isn’t pretty, but Amy volunteered to participate in a national study of the drug “because it could help other kids.”
For now, Gleevac keeps the beast at bay. Amy attends school and plays trumpet in the band, is still an A student, and generally feels good except for some joint pain and fatigue that has forced her to give up soccer and tennis.
Her curly blond hair is shorter these days because she donated 10 inches to Locks of Love, a group that provides hairpieces to sick children.
But, don’t let the perpetual smiles of Amy or any of the Katzes fool you: Amy’s only chance for a cure is a stem cell transplant, often called a bone marrow transplant because those cells are found mostly in bone marrow.
As happens in about 70 percent of patients, no family members were a match, even though Amy’s sisters, Jenny, 14, and Katie, 10, are a perfect match for each other. There are some 8 million people currently registered throughout the world to be potential donors and none of those match Amy, either. The family was digesting this news when an Army marched in.
“We had to act. The Katzes were always there for others,” said Kate Rosenthal, of Mt. Lebanon. “Indeed, [Mrs. Katz] was on the front lines for cleanup detail after last September’s floods. The minute it stopped, Lisa was in a Washington County grocery store with a bucket and shovel.”
Ms. Rosenthal is a family friend who belongs to the same synagogue. She has two daughters herself and helped mobilize Amy’s Army.
Now there are about 150 volunteers who work for public awareness and have raised money or gotten grants or corporate partners to help pay for more than 6,000 people to be added to the national registry. To get an idea of how much work has been done, it costs $65 to $100 for each donor test.
“Witness the power of an Army,” said Lisa Desrochers, recruitment director of the HLA Registry, part of the National Bone Marrow donor program.
“Amy’s the face and the story [in Pittsburgh], but this story and the need is repeated everywhere,” she said. “This Army is saving lives.”
Mrs. Katz is a petite blonde with a toothpaste smile of whom Amy is a tintype.
The 40-something exhibits the relentless cheer of a Mt. Lebanon High School football mascot, which is who she was a couple of years ago, and the steely reserve of a marketing executive, which she was until her daughter’s illness,
“This effort is not just for Amy. It is for so many others out there just like her,” Mrs. Katz said. Indeed some 4,000 people with leukemia, aplastic anemia and other blood diseases search the Web site for a donor each day, according to the National Bone Marrow group.
“They, like we, look for hope,” Mrs. Katz said.
“The Army business,” she said in the parlance of a 12-year-old, “is not about me. I am only the messenger.”
For more information about Amy’s Army, visit the Web site: www.amysarmy.org.
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(Virginia Kopas Joe can reached at vkjoe@post-gazette.com or 412.263-1414.)
Bone marrow donor search for Mt. Lebanon girl brings campaign here
Posted by rob on October 8, 2005 under Uncategorized |
Serkova N, Boros LG
Am J Pharmacogenomics. 2005; 5(5): 293-302
Acquired resistance to imatinib mesylate is an increasing and continued challenge in the treatment of BCR-ABL tyrosine kinase positive leukemias as well as gastrointestinal stromal tumors. Stable isotope-based dynamic metabolic profiling (SIDMAP) studies conducted in parallel with the development and clinical testing of imatinib revealed that this targeted drug is most effective in controlling glucose transport, direct glucose oxidation for RNA ribose synthesis in the pentose cycle, as well as de novo long-chain fatty acid synthesis. Thus imatinib deprives transformed cells of the key substrate of macromolecule synthesis, malignant cell proliferation, and growth. Tracer-based magnetic resonance spectroscopy studies revealed a restitution of mitochondrial glucose metabolism and an increased energy state by reversing the Warburg effect, consistent with a subsequent decrease in anaerobic glycolysis. Recent in vitro SIDMAP studies that involved myeloid cells isolated from patients who developed resistance against imatinib indicated that non-oxidative ribose synthesis from glucose and decreased mitochondrial glucose oxidation are reliable metabolic signatures of drug resistance and disease progression. There is also evidence that imatinib-resistant cells utilize alternate substrates for macromolecule synthesis to overcome limited glucose transport controlled by imatinib. The main clinical implications involve early detection of imatinib resistance and the identification of new metabolic enzyme targets with the potential of overcoming drug resistance downstream of the various genetic and BCR-ABL-expression derived mechanisms. Metabolic profiling is an essential tool used to predict, clinically detect, and treat targeted drug resistance. This need arises from the fact that targeted drugs are narrowly conceived against genes and proteins but the metabolic network is inherently complex and flexible to activate alternative macromolecule synthesis pathways that targeted drugs fail to control.
Detection of resistance to imatinib by metabolic profiling: clinical and drug development implications.
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Copland M, Jørgensen HG, Holyoake TL
Hematology. 2005 Oct ; 10(5): 349-59
Chronic myeloid leukaemia (CML) is a clonal disease of stem cell origin that develops when a single pluripotent haemopoietic stem cell acquires the Philadelphia (Ph) chromosome. The unique fusion gene product translated, p210 (Bcr-Abl), is a constitutively active tyrosine kinase that is specific to, and has a central role in the pathogenesis of, CML, making it an atractive target for drug therapy. Imatinib mesylate (IM) is one such therapy that also targets Abl, c-kit and PDGF-R tyrosine kinases. Although IM induces a much higher rate of complete cytogenetic remission (CCR), with improved tolerability and better progression free survival compared to other licensed therapies, resistance is a significant clinical problem. The most common mechanism of IM resistance is mutation of the Bcr-Abl kinase catalytic domain. In addition, molecular persistence in patients in CCR is most likely attributable to persisting Ph(+) stem cells that are insensitive to IM by unknown mechanisms and this is a major focus of current research interest. Current results from pre-clinical in vitro work on novel agents and combination strategies as well as clinical trials including immunotherapy approaches are reviewed. Despite the widespread use of molecularly targeted therapies and the development of new therapeutic drugs and strategies, it is our belief that there is a requirement for further research into and development of stem cell-directed therapies to overcome molecular persistence. It is likely that a combination of molecularly targeted therapies or treatment modalities will finally eliminate the quiescent stem cell population, leading to a “molecular cure” of CML.
Evolving molecular therapy for chronic myeloid leukaemia-are we on target?
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O’hare T, Walters DK, Stoffregen EP, Sherbenou DW, Heinrich MC, Deininger MW, Druker BJ
Clin Cancer Res. 2005 Oct 1; 11(19 Pt 1): 6987-93
PURPOSE: Chronic myeloid leukemia (CML) is effectively treated with imatinib. However, reactivation of Bcr-Abl via kinase domain mutations that reduce sensitivity to imatinib can cause relapse. As combination therapy is frequently used to prevent emergence of resistance, the combination of imatinib with an inhibitor of imatinib-resistant Bcr-Abl mutants (e.g., Src/Abl inhibitors AP23848 and BMS-354825) was investigated.EXPERIMENTAL DESIGN: To test this approach, cellular proliferation and Bcr-Abl tyrosine phosphorylation assays were done on Ba/F3 cells expressing wild-type (WT) Bcr-Abl and four common imatinib-resistant mutants (Y253F, E255K, T315I, and M351T). Colony-forming assays with primary CML cells were also done.RESULTS: Both Src/Abl inhibitors retained full inhibitory capacity when coadministered with imatinib at concentrations above typical clinical levels. For cells expressing WT Bcr-Abl or the marginally imatinib-resistant mutant M351T, inclusion of imatinib at therapeutic levels enhanced the effects of the Src/Abl inhibitors. By comparison, for the highly imatinib-resistant mutants Y253F and E255K, inclusion of imatinib at clinical levels resulted in only a slight enhancement beyond the effects of the Src/Abl inhibitors. None of the inhibitors affected Bcr-Abl T315I cells. Colony-forming assays with primary CML cells yielded analogous results.CONCLUSIONS: Our results indicate that Src/Abl inhibitors are compatible with imatinib and suggest that combined Abl inhibitor therapy is a feasible treatment strategy for patients with CML.
Combined abl inhibitor therapy for minimizing drug resistance in chronic myeloid leukemia: src/abl inhibitors are compatible with imatinib.
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Barnes DJ, Palaiologou D, Panousopoulou E, Schultheis B, Yong AS, Wong A, Pattacini L, Goldman JM, Melo JV
Cancer Res. 2005 Oct 1; 65(19): 8912-9
Chronic myeloid leukemia (CML) starts with the acquisition of a BCR-ABL fusion gene in a single hematopoietic stem cell, but the time to progression is unpredictable. Although the tyrosine kinase inhibitor imatinib mesylate is highly effective in the treatment of CML, its continuous administration is associated with development of resistance, particularly in advanced phase or blast crisis. We investigate here whether a feature of disease progression (i.e., elevated expression of Bcr-Abl in CD34(+) progenitor cells from CML patients in blast crisis) has any bearing on the kinetics of resistance to imatinib. By studying cell lines that exogenously express Bcr-Abl over the range found from chronic phase to blast crisis of CML, we show that cells expressing high amounts of Bcr-Abl, as in blast crisis, are much less sensitive to imatinib and, more significantly, take a substantially shorter time for yielding a mutant subclone resistant to the inhibitor than cells with low expression levels, as in chronic phase. Our data suggest that the differential levels of the Bcr-Abl oncoprotein expressed by CD34(+) CML cells may reflect the extent and duration of their response to imatinib; the relatively high levels of oncoprotein in advanced-phase disease may underlie the observed rapid development of resistance.
Bcr-abl expression levels determine the rate of development of resistance to imatinib mesylate in chronic myeloid leukemia.
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Savani BN, Montero A, Kurlander R, Childs R, Hensel N, Barrett AJ
Bone Marrow Transplant. 2005 Oct 3;
Summary:Donor lymphocyte infusions (DLI) have been the mainstay of treatment for chronic myeloid leukemia (CML) relapsing after allogeneic stem cell transplantation (allo-SCT). Imatinib mesylate (IM) is also effective in these patients. However, advanced phase relapse (APRel) responds poorly with either treatment. To test the possibility that combinations of DLI and IM might be more effective, 37 patients with CML relapsing after allo-SCT between August 1994 and May 2004 were studied. Ten had molecular relapse (MRel), 14 hematological relapse (HRel) and 13 APRel. Thirteen received DLI, 9 IM and 11 DLI+IM. Four patients received DLI+IM but not concurrently. Thirty (81%) patients responded (actuarial survival and current leukemia-free survival of 80.6+/-6.7% and 69.1+/-7.7%). Of 30 patients, 26 are in molecular remission (MR), median follow-up of 1226 days (range 249-3257) since relapse. Ten of 11 patients (including four with APRel) treated with DLI+IM achieved MR in 3 months and all are alive in MR. In contrast, only two of 22 treated with either modality (1/13 DLI and 1/9 IM) achieved MR at 3 months, 15 are alive, 11 in MR. Four patients receiving nonconcurrent DLI+IM are also alive in MR. In conclusion, DLI appears to synergize with IM to induce rapid and durable MR.Bone Marrow Transplantation advance online publication, 3 October 2005; doi:10.1038/sj.bmt.1705167.
Imatinib synergizes with donor lymphocyte infusions to achieve rapid molecular remission of CML relapsing after allogeneic stem cell transplantation.
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Ren H, Guo N, Lu D
Zhonghua Xue Ye Xue Za Zhi. 2001 Dec ; 22(12): 621-4
OBJECTIVE: To explore the feasibility of cord blood transplantation (CBT) for the treatment of adult hematological malignancies and its long-term hematopoiesis reconstitution and transplantation-related complications. METHODS: An 18 years old patient (body weight 75 kg) with chronic myelogenous leukemia in first chronic phase received HLA-identical sibling CBT after conditioning with modified busulfan/cyclophosphamide (Bu/CTX) regimen. The transplanted number of nucleated cells was 1.73 x 10(7)/kg of body weight, and that of CD34+ cells 2. 7 x 10(5)/kg. Cyclosporin A and methylprednisolone were given as prophylaxis against graft versus-host disease (GVHD). RESULTS: The neutrophil count rose to above 0.5 x 10(9)/L on day 18 and platelet count exceeded 50 x 10(9)/L on day 36. Gene analysis showed that bone marrow cells had completely changed to donor’s type on day 80. The patient was diagnosed with grade IV acute hepatic GVHD complicated with CMV infection because of severe jaundice on day 90. After the administration of additional immunosuppressive agents, antiviral agents, plasma exchange and in vitro billirubin adsorption, the complications were well controlled. In the follow-up of 24 months’, the patient’s general condition is good without obvious hepatic dysfunction and Ph chromosome and bcr/abl fusion gene of bone marrow cells were persistently negative. CONCLUSION: It is the first case reported in China that adult patient with leukemia has been successfully treated by allogeneic CBT, and this indicates that CBT is feasible in the treatment of adult patient with leukemia.
[Successful engraftment of HLA-identical sibling cord blood transplantation in an adult with chronic myelogenous leukemia]
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Merzianu M, Medeiros LJ, Cortes J, Yin C, Lin P, Jones D, Glassman A, Kantarjian H, Huh Y
Am J Clin Pathol. 2005 Nov ; 124(5): 1-8
Blast phase (BP) in chronic myelogenous leukemia (CML) frequently is accompanied by cytogenetic abnormalities in addition to t(9;22)(q34;q11.2). We describe 5 patients with CML in blast phase (CML-BP) in which t(9;22) and inv(16)(p13q22) were identified by conventional cytogenetics, with confirmation of BCR-ABL and CBFss-MYH11 by fluorescence in situ hybridization. The morphologic findings at the time of BP resembled de novo acute myeloid leukemia (AML) carrying inv(16)(p13q22), with abnormal eosinophils in the bone marrow and monocytosis in the peripheral blood in all cases. In 1 patient, inv(16)(p13q22) and abnormal eosinophils were detected in the bone marrow 2 months before CML-BP. The clinical course of these patients was similar to patients with CML-BP without evidence of inv(16)(p13q22). These cases illustrate that inv(16)(p13q22) is a form of cytogenetic evolution that rarely occurs in patients with CML at the time of BP. In this setting, unlike de novo AML, inv(16)(p13q22) in CML-BP is not associated with a favorable prognosis.
inv(16)(p13q22) in Chronic Myelogenous Leukemia in Blast Phase.
Posted by rob on October 3, 2005 under Uncategorized |
Wilkins HJ, Crane MM, Copeland K, Williams WV
Am J Hematol. 2005 Oct ; 80(2): 148-57
Hypereosinophilic syndrome (HES) is a rare disorder that is characterized by persistent and marked eosinophilia combined with organ system dysfunction. HES has substantial clinical heterogeneity but can be fatal without treatment, especially in patients who present with a myelodysplastic variant of the disorder. Although the pathophysiology of HES is poorly defined, dysregulation of cytokines (interleukin 5 [IL-5], IL-3, granulocyte-macrophage colony-stimulating factor [GM-CSF]) responsible for the maturation of eosinophils is a primary feature. Of these cytokines, IL-5 appears to have the greatest role in the regulation of eosinophil maturation. There is no Food and Drug Administration-approved treatment for HES as yet; current strategies are designed to lower blood eosinophils and attempt to limit end-organ damage. Historically, corticosteroids and cytotoxic agents have been the mainstays of therapy, with biological response modifiers such as interferon-alpha also effective in some patients. However, despite improvements in survival, available agents have significant limitations in terms of efficacy, tolerability, and long-term toxicity. More recently, new agents directed at specific targets in the pathogenesis of HES have been developed. These include imatinib mesylate, a tyrosine kinase inhibitor, and more recently, mepolizumab, an anti-IL-5 monoclonal antibody. In a small case series of patients, these agents have been shown to produce hematological and clinical responses in patients with HES, although they may be effective in different subsets of patients. These targeted therapies have the potential to improve clinical outcomes and to further the understanding the pathophysiology of this difficult-to-treat condition. Am. J. Hematol. 80:148-157, 2005. (c) 2005 Wiley-Liss, Inc.
Hypereosinophilic syndrome: An update.
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Shelton JG, Steelman LS, Abrams SL, Bertrand FE, Franklin RA, McMahon M, McCubrey JA
Expert Opin Ther Targets. 2005 Oct ; 9(5): 1009-30
Over the past 30 years, a relatively simple growth factor and its cognate receptor have provided seminal insights into the understanding of the genetic basis of cancer, as well as growth factor signalling. The epidermal growth factor (EGF), its cognate receptor (EGFR) and related family members have been shown to be important in normal, as well as the malignant growth of many cell types including: glioblastomata, astrocytomas, medulloblastomata, non-small cell lung carcinoma (NSCLC) and breast cancer. This review summarises the history of the EGFR gene and the v-ErbB oncogene, as well as diverse approaches developed to inhibit EGFR activity. The two most advanced therapies use either small-molecule cell membrane permeable kinase inhibitors or antibodies which prevent receptor activation. Recent clinical trials indicate that certain NSCLC patients have mutations in the EGFR gene which makes them more responsive to kinase inhibitors. These mutations appear to enhance the ability of the ligand to activate EGFR activity and also prolong the binding of the EGFR inhibitor to the kinase domain. Evidence to date suggests that these EGFR mutations in NSCLC occur more frequently in Japan than in the western hemisphere. Although these mutations are correlated with enhanced efficacy to the inhibitors in NSCLC, they can not explain or predict the sensitivity of many other cancer patients to the beneficial effects of the EGFR kinase inhibitors or antibody mediated therapy. As with as other small-molecule kinase inhibitors and susceptible diseases (e.g., imatinib and chronic myeloid leukaemia), resistance to EGFR inhibitors has been reported recently, documenting the requirement for development of multi-pronged therapeutic approaches. EGFR kinase inhibitors are also being evaluated as adjuvants in hormonal therapy of breast cancer – especially those which overexpress EGFR. Genetically engineered antibodies specific for the EGFR family member ErbB2 have been developed which show efficacy in the treatment of primary, and prevent the relapse of, breast cancer. Clearly, the EGF/EGFR signalling cascade has, and continues to play, an important role in the development of novel anticancer targeted therapies.
The epidermal growth factor receptor gene family as a target for therapeutic intervention in numerous cancers: what’s genetics got to do with it?
