Another Exciting Meeting of the American Society of Hematology (ASH)
I just returned from this year's ASH meeting, held December 4th to 7th in Orlando, Florida. Lots of research progress was reported and many researchers funded by The Leukemia & Lymphoma Society (LLS) were front and center. Mickey was not the star of this show!
I can only review a sampling of the exciting talks, but this is still a long commentary so please find the section(s) most interesting to you - unless, you're like me and find it all riveting!
New findings and new therapies for patients with Chronic Lymphocytic Leukemia (CLL)
Mark Lanasa M.D./Ph.D. of Duke University Medical Center just completed an LLS-funded research project focused on the genetics of CLL carried in families. In a prestigious Education Session at the ASH meeting, he discussed the environmental, immunologic, and inherited factors that play a role in the development of CLL. He also discussed a CLL cell surface molecule called the B-cell receptor (BCR) that promotes leukemia expansion and insensitivity to therapy (chemoresistance).
BCR acts through a series of interacting molecules (a "signaling pathway") that normally control B-cell proliferation and survival. Talks in Oral Sessions addressed various ways to target cancer-promoting abnormalities in this pathway. LLS-funded John Byrd M.D. of The Ohio State University and Jennifer Brown M.D./Ph.D. of Dana Farber Cancer Institute are members of a clinical team that reported promising results for a drug that inhibits PI3 kinase (PI3K) delta, an enzyme upon which BCR signaling depends. CAL-101 is a selective inhibitor of of this enzyme, with more than 200-fold less effect on related PI3K subtypes that seem unimportant in CLL but critical to normal cell functioning. The team reported that CAL-101 caused little toxicity and showed good anti-leukemia activity in a Phase 1 dose-escalation trial that enrolled 37 multiply-treated CLL patients with refractory disease, bulky lymph nodes, and/or high-risk chromosomal features (cytogenetics). High levels of lymph node reduction and prolonged symptomatic tumor control were seen, strongly supporting further evaluations of CAL-101 alone and in combination therapies for CLL patients.
Drs. Brown and Byrd also collaborated with LLS-funded Thomas Kipps M.D./Ph.D. of University of California, San Diego, Nyla Heerema Ph.D. and Michael R. Grever, M.D. of The Ohio State University and colleagues to test another targeted CLL therapy. This drug, alvocidib (flavopiridol), inhibits enzymes known as cyclin-dependent kinases that act in the abnormal BCR signaling pathway in CLL cells. A Phase 1 trial had previously determined the highest safe dose of this new drug. This year, the team reported interim results of an international Phase 2 clinical trial in which nearly half of the planned 165 patients had completed at least 2 cycles of alvocidib therapy. They showed that alvocidib can be safely administered and has durable clinical activity in some fludarabine-refractory CLL patients, including those with bulky lymph nodes and adverse cytogenetics. Laboratory studies will identify drug combinations and treatment schedules that might be even more effective and even less toxic, and develop biomarkers that identify patients most likely to benefit from alvocidib treatments in future trials.
New findings and new therapies for patients with Acute Lymphocytic Leukemia (ALL)
LLS-funded Wendy Stock M.D. of the University of Chicago opened an Education Session with a focus on younger ALL patients (up to age 30), and on the important biological and sociological differences between these patients and older patients with the same disease. Another speaker in this session highlighted the importance of accurately measuring the number of leukemia cells that remain after initial rounds of chemotherapy (known as minimal residual disease, MRD) and concluded that MRD status must be evaluated along with the genetic and biological characteristics of an individual patient's disease in order to devise the best overall treatment plan for that patient. The challenge will be to use the evolving techniques across all treatment centers in order to improve the survival of ALL patients everywhere.
In an Oral Session, Dr. Stock is a member of the team that described the use of Marqibo®, a "nanoparticle" encapsulated formulation of vincristine sulfate (VCR). VCR is a conventional anti-leukemia agent that is widely used in intensive anti-ALL regimens. The new formulation allows higher safe dosing, improves the duration of drug exposure, and enhances drug delivery to cancer sites throughout a patient's body. Two studies, of Marqibo alone versus combined with dexamethasone, enrolled a total of 101 patients with advanced relapsed/refractory ALL who had all previously received standard VCR. The trials showed a combined 20% complete response rate, far better than in previous studies with other "salvage" drugs. Many patients were "bridged" to stem cell transplantation, currently their best chance for cure. Marqibo will now be tested in the frontline setting and in other combination regimens.
T-cell acute lymphoblastic leukemia (T-ALL) is an especially aggressive form of ALL, making high-intensity treatments necessary and exposing patients to high-levels of toxicity, including neurotoxicity associated with methotrexate, standard vincristine, and certain other drugs. LLS-funded Mignon Loh M.D. of the University of California, San Francisco is a member of a team that is testing a new drug, nelarabine, that might replace one or more of these toxic drugs in multi-agent chemotherapies for children with T-ALL. Their ongoing study suggests that nelarabine can have unacceptable toxicity in heavily pre-treated T-ALL patients, but may be well-tolerated in intensive, multi-drug chemotherapies for newly diagnosed patients. Next year, they will be able to report whether nelarabine improves long-term outcomes of young patients with newly diagnosed T-ALL.
New findings and new therapies for patients with Chronic Myelogenous Leukemia (CML)
It seems that second-generation drugs that inhibit the leukemia-causing Bcr/Abl tyrosine kinase are becoming the drugs of choice for community doctors and their CML patients. Neil Shah, M.D./Ph.D. of the University of California, San Francisco updated results of a Phase 3 trial comparing the effects of Sprycel® versus Gleevec® as first-line treatments for adults with chronic phase CML. Results at 18-months were consistent with 12-month data that led the U.S. Food and Drug Administration (FDA) to approve this drug in October, 2010. Sprycel produced more complete remissions, and faster. The trial continues, to compare longer term outcomes.
In another report, the related tyrosine kinase inhibitor, Tasigna®, was also shown to have more rapid and more powerful effects than Gleevec over at least two years of treatment - fewer patients were refractory and fewer patients progressed to accelerated phase/blast crisis CML. As yet there is no difference in overall survival, with about 97% of patients still alive after two years on both treatments in the study.
Despite such high survival with these tyrosine kinase inhibitors, some CML patients do not benefit and need other new treatment options, especially patients whose CML cells carry the so-called T315I mutation in the Bcr/Abl-encoding gene. LLS-funded Michael Deininger M.D./Ph.D. of Oregon Health & Science University and Dr. Shah are members of a team that reported promising results of an ongoing Phase 1 trial of ponatinib, a potent inhibitor of all tested Bcr/Abl mutants, including T315I, and of certain other kinases that are also involved in leukemia formation. The trial enrolled patients with refractory chronic, accelerated, or blast phase CML, Bcr/Abl-positive cases of acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and 4 other blood cancers. A safe dose was determined, with strong evidence of anti-leukemic activity, including early responses in multiply-refractory patients. A Phase 2 study is now planned.
New findings and new therapies for patients with Acute Myelogenous Leukemia (AML)
Most adult AML patients need more effective therapies that produce long-term remissions. Therapies for older AML patients are especially challenging as they generally cannot tolerate highly toxic therapies. An Education Session described the importance of particular molecular and genetic abnormalities in leukemia development and in determining clinical responses to available therapies, including new targeted therapies.
LLS grantee Mark Levis M.D./Ph.D. of the Johns Hopkins University has been a leader in investigations of the "FLT3/ITD" mutations that are relatively common in AML. Abnormal FLT3 kinase is implicated in causing leukemias; laboratory studies have shown that signaling from ITD-mutated FLT3 blocks normal myeloid cell maturation, making fertile ground for the emergence of leukemias since immature cells tend to proliferate more and die less than mature cells. Dr. Levis and his colleagues are testing the selective FLT3 inhibitor, AC220, in an ongoing phase 2 trial for patients with FLT3/ITD AML who are refractory to either primary induction therapy and/or or salvage therapy after relapse. To date, six patients have been treated and leukemia cells were no longer detectable in their blood by Day 8. Marrow blasts were markedly reduced or absent by Day 28 in all cases and FLT3 protein could not be found in the mature blood cells (neutrophils) that seem to have developed form the abnormal blasts. The promising trial continues.
Another oral presentation described the utility of a new formulation of two drugs that are currently the backbone of most AML therapies. CPX-351 encapsulates these drugs, cytarabine and daunorubicin, in a small fat-surrounded package (liposome) to protect the drugs in a patient's blood stream and maintain a drug ratio with optimal anti-tumor activity. Jeffrey Lancet M.D. of H. Lee Moffitt Cancer Center presented positive findings with 12 months of follow-up for a randomized, Phase 2 study comparing CPX-351 to the current standard "7+3" regimen in patients 60 to 75 years of age with newly diagnosed AML. Better responses were seen in CPX-351-treated patients with high-risk AML, including AML cases secondary to previous myeloid malignancies. Of note, LLS is partnering through our Therapy Acceleration Program with the company, Celator, to accomplish a second Phase 2 study in which CPX-351 is being compared to intensive salvage therapy for adult AML patients in first relapse.
New findings and new therapies for patients with other myeloid malignanices
I have mentioned here before the burgeoning field of epigenetics, focused on the small chemical additions that can alter critical gene activities without changing (mutating) the DNA code of those genes. The alterations include the addition of methyl or acetyl chemical groups (known as methylation, acetylation) to DNA and DNA-associated molecules. The importance of abnormal methylation in cancer was first proven in myelodysplastic syndromes (MDS) and the "hypomethylating" drugs Dacogen® and Vidaza® are already FDA-approved as relatively non-toxic treatments for MDS patients.
This year, nearly one-third of all oral presentations concerning MDS were focused on identifying methylation abnormalities and better understanding their functional, prognostic, and therapeutic significance. MDS is characterized by "hypermethylation" of gene activity control regions (known as promoters), relative to normal myeloid cells - the genes are thereby inactivated, which is thought to promote MDS emergence and disease progression. The discovery in MDS (and AML) of mutations in genes involved in DNA methylation is now providing a link between genetics and epigenetics in these disorders. These mutations have prognostic significance in patients and are highlighting new therapy targets.
LLS-funded investigators continue making progress in epigenetics-targeting therapies. For example, Guillermo Garcia-Manero M.D. of M.D. Anderson Cancer Center, Steven Gore M.D. of Johns Hopkins University and Christopher Cogle M.D. of the University of Florida are members of a team studying a new oral form of Vidaza. This form is more convenient than the current intravenously-administered form, and could allow lower dosing on more extended schedules that the researchers think will be more effective. Dr. Garcia-Manero reported that in an ongoing multicenter Phase 1 trial, the maximum tolerated dose has not been reached, the drug is generally well tolerated, and promising clinical responses have already been observed, including complete remissions and hematologic improvements.
Dr. Garcia-Manero also reported results of a Phase 2 trial using Vidaza with Zolinza®, another epigenetics-targeting drug that instead reduces levels of acetylation on DNA-binding proteins. He and his colleagues are testing the combination for patients with previously untreated MDS (INT-1 or above) or AML with bad-risk features, including concomitant HIV disease or malignancy, that would make these patients ineligible for other clinical trials. The drug combination proved safe and effective even in this poor prognosis population, with good clinical responses similar to those previously observed in low-risk patients. The team expressed concerns regarding current eligibility criteria for early phase clinical trials that might benefit patients with no other options. They plan follow-on trials for high-risk and low-risk patients.
Of note, other LLS-funded investigators are developing similarly promising epigenetics-targeting combination treatments for lymphoma patients.
Research progress continues...
... and new treatments, based on new scientific discoveries, are showing promise. There were many other reports from LLS-funded investigators focused on improving our understanding of leukemia biology and improving outcomes for leukemia patients. Stay tuned!