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Unravelling early colorectal cancer: the links between ROS, DNA methylation and inflammatory responses

By MaverickNY on January 24, 2012

During yesterday’s discussion with Dr Ray DuBois (MD Anderson Cancer Center) about inflammation and methylation, the topic of CpG island methylator phenotype (CIMP) in colorectal cancer (CRC) came up as you can see from the brief audio clip below:

Steve Baylin’s paper sounded most interesting, so I tracked it down – see O’Hagan et al., (2011) in the References below for the direct link.

CIMP is interesting to look at because it can occur in some 30% of colorectal cancer cases and has been previously shown to be an independent predictor of survival with 5FU in early or adjuvant CRC (van Rijnsoever, 2003). It is, therefore, a potentially useful molecular marker in this disease.

In O’Hagan et al’s (2011) current research, they stated:

“We demonstrate that inducing cellular oxidative stress by hydrogen peroxide treatment recruits DNA methyltransferase 1 (DNMT1) to damaged chromatin.”

Essentially, a link between several proteins involved in transcriptional repression to the DNA damage response was observed. A key part of this damage response is reactive oxygen species (ROS), elevated levels of which were shown by Federico et al., (2007) to constitute a key risk state for increased cancer susceptibility. Raised levels of ROS tend to occur as a result of alterations in cellular metabolism and inflammatory responses.

The current research from O’Hagan et al., (2011) takes our understanding of this process further:

“One of the intriguing implications of our data is the potential role for increased levels of cellular ROS that accompany cancer risk states such as inflammation in the formation of cancer-specific aberrant patterns of DNA methylation and transcriptional silencing.”

What is useful from a practical standpoint, is that the current findings build on their existing model, which considers a promoter CpG island, double-strand break DNA damage concept:

“We hypothesize that such localization of the DNMT-PRC4 complex and increase in DNA methylation at low-expression promoter CpG island-containing genes might be more persistent over the course of chronic ROS damage during tumorigenesis, setting up a scenario for the expansion of DNA methylation in the CpG islands involved.”

In other words, Dr Baylin’s lab have shown that chronic inflammation over time may lead to DNA hypermethylation. If we then consider the work from Dr DuBois’s lab discussed yesterday (in Xia et al., 2012), the connection between inflammation, DNA methylation and early development of colorectal cancer starts to make a lot of sense.

Tomorrow, I’ll be looking at early colorectal cancer in more detail and discussing how the roles of BRAF, KRAS and PIK3CA mutations and CIMP may play a role in tumorigenesis in colorectal polyps. Do check back to follow the ongoing story.

References:

O’Hagan, H., Wang, W., Sen, S., DeStefano Shields, C., Lee, S., Zhang, Y., Clements, E., Cai, Y., Van Neste, L., Easwaran, H., Casero, R., Sears, C., & Baylin, S. (2011). Oxidative Damage Targets Complexes Containing DNA Methyltransferases, SIRT1, and Polycomb Members to Promoter CpG Islands Cancer Cell, 20 (5), 606-619 DOI: 10.1016/j.ccr.2011.09.012

Federico A, Morgillo F, Tuccillo C, Ciardiello F, & Loguercio C (2007). Chronic inflammation and oxidative stress in human carcinogenesis. International journal of cancer. Journal international du cancer, 121 (11), 2381-6 PMID: 17893868

Xia, D., Wang, D., Kim, S., Katoh, H., & DuBois, R. (2012). Prostaglandin E2 promotes intestinal tumor growth via DNA methylation Nature Medicine DOI: 10.1038/nm.2608

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New research demonstrates the link between inflammation and early development of colon cancer

Recently, epigenetics has been very much to the forefront with promising new human data in lung and breast cancers.

Nature Medicine

This morning I was therefore thrilled to see some exciting work just published in Nature Medicine Online First from Ray DuBois’s lab at MD Anderson Cancer Center, on the potential role of inflammation and silencing of tumour suppressor genes in early colorectal cancer. Previously, the group looked at the role of COX-2 in intestinal inflammation and colorectal cancer and observed that:

“A large body of evidence indicates that genetic mutations, epigenetic changes, chronic inflammation, diet and lifestyle are the risk factors for CRC.”

Epigenetics is rapidly becoming a crucial and fascinating field of research. Dr DuBois kindly provided an easily understood explanation:

Epigenetics is defined as “the study of heritable changes in genome function that occur without a change in DNA sequence.”

One of the things that many people have trouble with is grasping the difference between mutations (genetic changes) and methylation (epigenetics). I loved Dr DuBois’s quote from Thomas Jenuwein, an epigenetics expert in Vienna:

“The difference between genetics and epigenetics can be compared to the difference between writing and reading a book. Once a book is written the text (genes or DNA sequence) will be the same in all copies distributed to the audience. However, each individual reader of a book may interpret the story slightly differently, with varying emotions and projections…

In a similar manner, epigenetics would allow different interpretations of a fixed template and result in different read-outs dependent on the variable conditions under which the template is interrogated.”

What did the current research show?

In a succinct article, Xia et al., (2012) clearly demonstrated that:

PGE2 promotes intestinal adenoma growth by silencing certain tumor-suppressor and DNA-repair genes.
This process took place through the induction of DNMT1 and DNMT3B specifically.

This research is, however, the first time the connection between inflammation and epigenetic changes has actually been demonstrated scientifically, as Dr DuBois noted:

“This is the first time I know of that there has been such a clear molecular connection between the two, with clear cut effects on the pathway and how it has an effect on the downstream. We never expected the effects on some of the tumor suppressors and mismatch repair genes. That was pretty exciting when we found that effect.”

What was particularly interesting, though, is that they also showed that it might be possible to tackle these issues using an anti-inflammatory drug (celecoxib) and/or a methylating agent (azacitadine). Both of these drugs reduced the size and number of tumours in mice with colorectal cancer in their experiments. In addition, the best responses occurred when both drugs were used together, suggesting a powerful additive effect coud be achieved.

What are the next potential steps from this research?

Obviously finding the link between inflammation and epigenetic changes is important, but there is much work that still needs to be done. Dr DuBois laid out some important next steps:

“Ultimately, what needs to be done is that we need to map out the whole epigenome now under a variety of situations where we apply an inflammatory stimulus or change the state of inflammation because I think it is really telling us something about the underlying mechanisms there.”

We already know from existing research that there is infiltration of immune cells into the tumour microenvironment, and in some situations, that can stimulate the cancer to progress faster:

“One of the ideas that is emerging is that the intestine, especially the large intestine, is in a special niche where it has to respond to this microflora. If there is any breach in the barrier, like adenomas or developing cancers, then that can bring inflammation directly to the tumor microenvironment because of all those bacterial products and other interactions between the microflora and epithelial cells.”

This research is just the beginning – ultimately, we need to think in terms of effective chemoprevention and treatment based on our understanding of the underlying biology:

“It was totally unexpected and I think it is going to lead to some things that will hopefully help, as we do more research, understand better how these interactions occur. Colorectal is a unique situation because it got all those bacteria in the lumen.

There have been some isolated reports about different types of bacteria causing problems, but this really could explain how the genetic somatic mutations interact with the local environment in the colon. We will have to think about ways to intervene to try to prevent or treat the disease more effectively.”

From a clinical standpoint, an obvious follow-on from this research would be to consider a clinical trial for patients who are at extremely high risk for developing colorectal cancer, such as those with a genetic predisposition, to see if combination treatment with these two classes agents (anti-inflammatory and methylating agent or HDAC) would decrease their subsequent risk of developing colorectal cancer.

All in all, some very exciting research to kick off this week and well worth reading.

References:

Wang, D., & DuBois, R. (2009). The role of COX-2 in intestinal inflammation and colorectal cancer Oncogene, 29 (6), 781-788 DOI: 10.1038/onc.2009.421

Xia, D., Wang, D., Kim, S., Katoh, H., & DuBois, R. (2012). Prostaglandin E2 promotes intestinal tumor growth via DNA methylation Nature Medicine DOI: 10.1038/nm.2608

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miRNA as a potential biomarker for early breast cancer

By MaverickNY on January 16, 2012

One way to potentially improve long term cancer statistics is earlier detection, and in high risk patients, appropriate initiation of earlier treatment, since it is well known that the survival in stage II or III breast cancer is noticeably better than that for stage IV metastatic disease.

A critical question then, is how do we improve earlier detection?

There are a number of ways to achieve this:

Imaging techniques
Prognostication
Diagnostics
Biomarkers

Historically, breast cancer has often been picked up using classic, but rather crude, imaging techniques such as mammography and ultrasound, although both have their limitations and challenges. Biopsies are also challenging and invasive, especially in early stage disease when the tumour(s) may be very small. I’m particularly interested in biomarkers because it offers a lot of untapped near-term promise. We know that as tumours begin to develop, they leave tell tall signs and signatures – how can we develop ways to detect these earlier and with greater accuracy than at present?

Source: wikipedia

I was fascinated to read a paper in PLoSONE (open access, see references below) this morning looking at circulating microRNAs (miRNA) as a potential blood based marker for early stage breast cancer detection.

miRNA were defined by Schrauder et al., (2012) as:

“MicroRNAs (miRNAs, miRs) are a class of small, non-coding RNA molecules with relevance as regulators of gene expression thereby affecting crucial processes in cancer development.”

They were first described by Lee et al., (1993) in C. elegans (open access, see references below) and have since been found to be stable in blood, making them ideal biomarker material.

In the current research, the authors set out to determine whether miRNA could discriminate early stage breast cancer (n=48) from healthy controls (n=57) using microarray analysis.

What did the research show?

The initial results appear promising:

“We found that 59 miRNAs were differentially expressed in whole blood of early stage breast cancer patients compared to healthy controls. 13 significantly up-regulated miRNAs and 46 significantly down-regulated miRNAs in our microarray panel of 1100 miRNAs.”

Two of the miRNAs (miR-202, miR-718) were subsequently validated by RT-qPCR in an independent cohort.

What do these results mean?

I thought these results were encouraging, although it should be noted that there is no doubt that blood-based miRNA-profiling is behind the improvements seen in tissue-based miRNA-profiling. The advantage though, of blood-based profiling, is that it clearly offers:

“The potential for early, non-invasive, sensitive and specific BC detection and screening.”

Of course, there is a long way to go yet, although similar early studies have been performed in other tumour types such as lung cancer (Foss et al., 2011; Boeri et al., 2011), ovarian cancer (Häuser et al., 2010) and others.

Using miRNA as a potential biomarker for early detection is not without its challenges, though. Shrauder et al., noted that Chen et al., (2008) observed that:

“Comparing serum and blood cells from the same healthy individual an almost identical miRNA profile can be found, but in cancer patients the profiles differ.”

Other studies have not shown complete congruence in the results or findings, so it may well be a while before some clarity emerges with miRNA as a potential diagnostic, most likely with improved standardisation of sample handling, protocols, detection methods and patients (stage of disease, etc).

That said, miRNA looks to be a promising but fledgling area for biomarker research in the early detection of cancer. No doubt this field will evolve further with new and more sensitive techniques.

References:

Schrauder, M., Strick, R., Schulz-Wendtland, R., Strissel, P., Kahmann, L., Loehberg, C., Lux, M., Jud, S., Hartmann, A., Hein, A., Bayer, C., Bani, M., Richter, S., Adamietz, B., Wenkel, E., Rauh, C., Beckmann, M., & Fasching, P. (2012). Circulating Micro-RNAs as Potential Blood-Based Markers for Early Stage Breast Cancer Detection PLoS ONE, 7 (1) DOI: 10.1371/journal.pone.0029770

Lee, R., Feinbaum, R., & Ambros, V. (1993). The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14 Cell, 75 (5), 843-854 DOI: 10.1016/0092-8674(93)90529-Y

Foss KM, Sima C, Ugolini D, Neri M, Allen KE, & Weiss GJ (2011). miR-1254 and miR-574-5p: serum-based microRNA biomarkers for early-stage non-small cell lung cancer. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer, 6 (3), 482-8 PMID: 21258252

Boeri M, Verri C, Conte D, Roz L, Modena P, Facchinetti F, Calabrò E, Croce CM, Pastorino U, & Sozzi G (2011). MicroRNA signatures in tissues and plasma predict development and prognosis of computed tomography detected lung cancer. Proceedings of the National Academy of Sciences of the United States of America, 108 (9), 3713-8 PMID: 21300873

Häusler, S., Keller, A., Chandran, P., Ziegler, K., Zipp, K., Heuer, S., Krockenberger, M., Engel, J., Hönig, A., Scheffler, M., Dietl, J., & Wischhusen, J. (2010). Whole blood-derived miRNA profiles as potential new tools for ovarian cancer screening British Journal of Cancer, 103 (5), 693-700 DOI: 10.1038/sj.bjc.6605833

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Gene mutation and resistance to chemotherapy in colorectal cancer

By MaverickNY on January 5, 2012

This week’s New England Journal of Medicine (NEJM) contained a fascinating article on how a specific gene mutation known as Transcription factor AP-2 epsilon, TFAP2E–DKK4, appears to be responsible for inducing at least some of the resistance to chemotherapy that occurs during treatment of colon cancer.

At first sight, I wasn’t sure from the abstract if they were referring to either adaptive resistance to therapy or whether genetic changes already present limited the effectivenes of the treatment.

Further reading of the full article more specifically pointed to the latter:

“Epigenetic alterations underlying the pathogenesis of colorectal cancer have been reported by several groups. These alterations include hypomethylation and hypermethylation of DNA as well as histone modifications, all of which have a profound effect on transcriptional gene regulation. The role of these molecular alterations in response prediction and treatment resistance are far less well known.”

For readers interested in more background on histone modifications, check out a previous post on epigenetics first.

What did this research show?

There were a couple of interesting findings in this study, which involved both cell lines and also cancer patients:

“TFAP2E was hypermethylated in 38 of 74 patients (51%) in the initial cohort. Hypermethylation was associated with decreased expression of TFAP2E in primary and metastatic colorectal-cancer specimens and cell lines. Colorectal-cancer cell lines overexpressing DKK4 showed increased chemoresistance to fluorouracil but not irinotecan or oxaliplatin.”

Fluorouracil (5FU) is one of the key bedrocks of chemotherapy when combined with either oxaliplatin (as FOLFOX) or irinotecan (as FOLFIRI), so any epigenetic changes present that limit it’s effectiveness will have a negative impact on the overall treatment response.

The impact of DKK4 was first shown in cell lines by Xi et al., (2006), but this is the first time I think it has been reported in human patients with colon cancer. The research also uncovered some other important findings:

“In the four other patient cohorts, TFAP2E hypermethylation was significantly associated with nonresponse to chemotherapy (P<0.001).”

I’d like to see these results validated on a larger scale, but if replicable, they will have a huge potential impact on clinical practice. If a patient is found to have the TFAP2E mutation, then there will be little point in exposing them to the rigours of chemotherapy with their not inconsiderable side effects if there is little chance of response. A clinical trial or other alternatives such as targeted therapies (EGFR, VEGF) might be a better option in this case.

“Conversely, the probability of response among patients with hypomethylation was approximately six times that in the entire population (overall estimated risk ratio, 5.74; 95% confidence interval, 3.36 to 9.79).”

It’s amazing how just a small change (hypo = positive, hyper = negative in this particular example) can have an enormous potential impact on the probability of response to chemotherapy.

Because the TFAP2E-dependent resistance was found to be mediated through DKK4, the authors suggested that patients who have colorectal cancer with TFAP2E hypermethylation could be approached differently. In other words:

“Specific targeting of DKK4 in these individuals may therefore be an option for overcoming TFAP2E-mediated chemoresistance.”

That, however, may be easier said than done and here’s why – DKK4, or Dickkopf 4, is associated with canonical Wnt signalling and beta-catenin/Tcf-4, which is not the easiest thing to target using currently available approaches. It may be a little while before we see some progress on the R&D front, but certainly the good news is that we at least have some valid targets to aim at.

What do these results mean?

It has long been known that patients vary considerably in their response to treatment and what this research clearly shows us is that genetic changes, specifically the presence of the TFAP2E–DKK4 mutation may explain why some patients with colorectal cancer fare better with chemotherapy than others. In other words, it portends a poorer prognosis and overall response to treatment.

It will be interesting to see if new epigenetic therapies develop in the near future to try and essentially overcome and reverse the histone modifications that impact the treatment response.

References:

Ebert, M., Tänzer, M., Balluff, B., Burgermeister, E., Kretzschmar, A., Hughes, D., Tetzner, R., Lofton-Day, C., Rosenberg, R., Reinacher-Schick, A., Schulmann, K., Tannapfel, A., Hofheinz, R., Röcken, C., Keller, G., Langer, R., Specht, K., Porschen, R., Stöhlmacher-Williams, J., Schuster, T., Ströbel, P., & Schmid, R. (2012). TFAP2E–DKK4 and Chemoresistance in Colorectal Cancer New England Journal of Medicine, 366 (1), 44-53 DOI: 10.1056/NEJMoa1009473

Xi, Y., Nakajima, G., Schmitz, J., Chu, E., & Ju, J. (2006). Multi-level gene expression profiles affected by thymidylate synthase and 5-fluorouracil in colon cancer BMC Genomics, 7 (1) DOI: 10.1186/1471-2164-7-68

ASH 2011 Update #3 – Multiple Myeloma

By MaverickNY on January 4, 2012

Most new developments in cancer research tend to occur in increments, thus we see a fair number of improvements in survival (whether PFS or OS) in the 1-4 month range over the existing standard of care. However, as we saw recently at European Conference for Clinical Oncology (ECCO) in September and the San Antonio Breast Cancer Symposium (SABCS) last month with the BOLERO-2 nad CLEOPATRA trials, every once in a while something comes along that shifts the efficacy curve by six or seven months and people rightly get very excited about this.

Imagine then, an improvement in median overall survival by 13 months? Or rather, 13.3 months to be precise? That’s both very exciting and huge for patients and physicians alike.

What was the drug that produced this stunning seismic shift?

Velcade.

VISTA in newly diagnosed elderly patients with MM

At the 2011 American Society of Hematology (ASH) meeting, Professor Jesús San Miguel (Salamanca, Spain) presented the five year results of the VISTA (VELCADE as Initial Standard Therapy in Multiple Myeloma) study. This trial compared triple therapy with bortezomib, mephalan and prednisone (VMP) to the current standard of care, melphalan plus prednisone (MP) in previously untreated multiple myeloma (MM) patients (N=682) who were ineligible for high-dose therapy.

The analysis demonstrated that after a median follow-up of 60.1 months, the median OS was 56.4 versus 43.1 months for patients randomised to VMP and MP, respectively, giving a significant survival advantage of 13.3 months for the VMP arm (p=0.0004).

This is how the survival curves look:

The Velcade VISTA phase III trial at ASH 2011

Source: Image courtesy of Millennium

Unfortunately, I wasn’t able to see the actual presentation live as it clashed with so many concurrent presentations on the ‘manic Monday’ of the meeting, but I did talk to Prof San Miguel, who excitedly described the findings as “impressive” despite the fact that “the control arm did very well,” however, “we now know that VMP is the best option in this patient population.”

This was one of those rare times when I thought that ‘impressive’ was perhaps an understatement, especially as the majority of patients could be considered elderly, in the 65-75 age range. Based on this eagerly anticipated data and talking to several myeloma thought leaders at the meeting, there is no doubt that VMP will become the new standard of care for upfront treatment in those patients who are ineligible for high dose treatment and a transplant. It’s a result that is full of win all around.

Secondary Primary Malignancies and Revlimid

The other interesting thing about the data was the incidence of secondary primary malignancies (SPM), a topic that was very much to the for last year for Celgene’s lenalidomide (Revlimid).

Dr San Miguel observed that the background incidence in this elderly population is 1.92, based on SEER data. He also noted that in the VISTA trial, the incidence of SPM was 1.66 SPM per 100-patient-years for the VMP arm versus 1.30 for MP alone. This difference wasn’t significant and in fact, both arms were lower than expected from the SEER data, which is reassuring.

Talking of SPMs, I attended Dr Antonio Palumbo (Torino, Italy) presentation on the last day on a retrospective multifactorial analysis of newly diagnosed patients with MM (N=2,283) who had received Revlimid in European clinical trials (N=9). They sought to try and address if we can anticipate when SPMs were most likely to occur and in which combinations. The median follow-up time for in their analysis was 29 months and the median age was 69 years.

Overall, they found 48 secondary cancers including 10 blood cancers and 38 non-blood cancers.

The data clearly showed that the incidence of SPM with IMiDs was higher in melphalan-based regimens than others:

Revlimid:
Dexamethasone ± cyclophosphamide 0.40
Melphalan 0.95

Thalidomide:
Melphalan 1.05

Melphalan only: 0.42

We can see from this analysis that while the IMiDs per se don’t appear to cause SPMs, there is clearly an interaction occurring between the IMiDs and melphalan that increases the risk, although the mechanism for this phenomenon is unknown.

The future is bright for MM

Multiple myeloma is now becoming a very dynamic area of clinical research beyond Velcade, thalidomide and Revlimid.

Other emerging agents include carfilzomib, pomalidomide, MLN9708, perifosine, HDACs (panobinostat, romidepsin, vorinostat) and many others.

No doubt we will hear more about these new agents in development going forward either as new combinations or sequencing of multiple therapies, all of which may lead to a cumulative increase in survival for patients with multiple myeloma.

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AVEO announces front-line data in renal cell cancer for tivozanib

By MaverickNY on January 3, 2012

A very happy New Year everyone! After shaking off the dust of an extended break over the last two weeks, this morning brought plenty of news to kick start 2012.

The most interesting news was AVEO-Astellas’ announcement regarding their VEGF inhibitor, tivozanib, in advanced renal cell cancer (RCC):

“Tivozanib demonstrated superiority over sorafenib in the primary endpoint of progression-free survival (PFS) in TIVO-1, a global, randomized Phase 3 clinical trial evaluating the efficacy and safety of investigational drug tivozanib compared to sorafenib in 517 patients with advanced renal cell carcinoma (RCC).”

The previous front-line trials with sorafenib (Nexavar) and sunitinib (Sutent) were randomised trials that compared the active drug to placebo and interferon respectively, so this is the first head to head study that compares an investigational agent to an approved VEGF therapy. It was a risky study given that the prior phase II trial in RCC compared tivozanib against placebo, meaning AVEO had no idea whether their had a superior agent or not.

What did the data show?

The TIVO-1 study sought to compare tivozanib versus sorafenib in patients with clear cell renal carcinoma who were treatment naïve, ie they had not received prior therapy with either a VEGF or an mTOR inhibitor. The companies announced the topline results from the DSMC analysis:

Tivozanib demonstrated a statistically significant improvement in PFS with a median PFS of 11.9 months compared to a median PFS of 9.1 months for sorafenib in the overall study population.

Tivozanib demonstrated a statistically significant improvement in PFS with a median PFS of 12.7 months compared to a median PFS of 9.1 months for sorafenib in the pre-specified subpopulation of patients who were treatment naïve (no prior systemic anti-cancer therapy); this subpopulation was approximately 70% of the total study population.

Tivozanib demonstrated a well-tolerated safety profile consistent with the Phase 2 experience; the most commonly reported side effect was hypertension, a well established on-target and manageable effect of VEGFR inhibitors.

The data is being submitted as an abstract to ASCO and an FDA filing will also most likely result this year.

No further information was available at this stage on the second point for the treatment-naive and prior therapy groups. The safety profile was reported on the call to be in-line with prior phase II experience, meaning hypertension, a VEGF class effect, was the most common adverse event.

What do these data mean?

There are several points to note from this topline analysis:

The sorafenib arm did better than expected – based on the PI, we would expect around 5.5 months not 9.1 months.
The sunitinib front-line trial showed a median benefit of ~11.0 months, based on the PI giving 47.3 weeks for PFS.
So while the difference in the TIVO-1 study of ~3 months between the two arms is smaller, the absolute PFS benefit for tivozanib is slightly better than sunitinib, although the caveat is that we cannot really compare them clinically without a head to head trial.
We don’t yet know how well Pfizer’s axitinib (Inlyta) will do in the 1st line setting, as only the second-line topline findings were announced in November:

“Axitinib in previously treated patients with metastatic renal cell carcinoma (mRCC), has met its primary endpoint, demonstrating that axitinib significantly extended progression-free survival (PFS) when compared to sorafenib, in the study population.”

My guess is that at this rate, tivozanib and axitinib may well prove to be more similar than different, as the compounds were fairly close preclinically. By this, I mean that with more selective VEGF inhibitors we are likely to see less toxicities from off-kinase inhibition with perhaps similar efficacy to Sutent, than vast improvements in PFS.

Ultimately, the real winner in a very crowded RCC market is going to be a drug with not only superior PFS, but also a cleaner safety profile. It has been shown previously that combining sunitinib with an mTOR such as everolimus (Afinitor) led to unacceptable toxicities and the concept was thereby abandoned after the phase I trial. However, if either tivozanib or axitinib can be safely combined with an mTOR for additional efficacy, then this would be a big plus for both physicians and patients. At the moment, the count is out on that option.

Currently, physicians typically treat patients with Sutent initially and then consider Nexavar, Afinitor or Torisel as second-line therapy, while reserving Votrient (pazopanib), another VEGF inhibitor, for 3rd line given its adverse event and efficacy profile. Sequencing multiple single agents is therefore very much derigeur in RCC. Whether tivozanib or axitinib can change this is an important consideration for the future.

And finally, some observations…

This year’s ASCO is going to be a most interesting meeting for renal cell cancer with data now expected for tivozanib in first and second line expected versus sorafenib, following on from the head to head of axitinib versus sorafenib in second line at last year’s ASCO. I’m not sure when the axitinib front-line data will be available, but it is eagerly awaited given the tivozanib data announcement.

It is interesting that the market is down on the news with AVEO’s shares falling, despite meeting the primary study endpoint. No doubt investors were expecting either a bigger difference between the arms or for the absolute overall PFS value for tivozanib to be greater than 12-12.5 months in the upfront setting.

Part of me would have liked to have seen the safety and efficacy signal of the head to head with sorafenib in a phase 2 trial to see what the real difference between the two was earlier. As it is, the phase 2 was conducted versus placebo, which doesn’t tell us anything about what might be expected in a phase 3 study. It’s always a risk switching horses into the unknown.

Mechanistically though, tivozanib is a VEGF inhibitor in the vein as Sutent, Nexavar, Avastin and Votrient, albeit a more selective one, so there is a limit on what can be expected by blocking a single pathway. Resistance inevitably sets in, so going forward we need to determine what the adaptive resistance pathways to therapy are and then determine what combinations might be feasible to try and overcome them. If this can be done without excessive toxicities, then we can expect the survival to improve further.

Another thing to consider is that previously, AVEO presented some rather promising data on biomarkers of response in their preclinical and phase I RCC data. I’m very keen to see if any subset analysis in the phase III trial will be presented at ASCO and whether the hypothesis stands up in the clinical setting for either the treatment naïve or relapsed patients. If the biomarker can determine who is most likely to respond to tivazanib, then I would expect the PFS to improve in that subset. We must wait and see what, if anything, happens with that.

Finally, for patients moving from 10 to almost 12 months may sound like a small increment in survival, but when we consider the cumulative effect of sequencing multiple drugs, there is no doubt that the efficacy benefits begin to accrue over time. It should not be forgotten than until recently, the choices in RCC were stark. There was either IL-2 (only suitable for a limited number of patients due to severe toxicities) or interferon, which typically had a PFS of approx. 4-5 months.

Since then, in only a few years with several new therapies entering the market, the PFS has already doubled with only single agent therapy; that’s quite an improvement, although we still have a long way to go in understanding the biology of the disease.

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ASH 2011 Update #2 – Non Hodgkins Lymphoma

By MaverickNY on December 21, 2011

I’ve been busy with other things offline since the last blog update from the American Society of Hematology (ASH) meeting in San Diego, but will be catching up on my notes from the conference over the next few days.

In addition, my colleague Pieter Droppert has already posted his topline impressions of the meeting on the companion Biotech Strategy Blog, which readers may be interested in:

Meanwhile, I thought it would be a good idea to look at the pipeline developments in non-Hodgkin’s lymphomas (NHL) that I particulalry liked at ASH:

PI3K inhibitors

Pieter’s choice of PI3K as a hot topic turned out to be rather prescient given that:

a) Intelikine announced last night that the company is being bought by Millennium-Takeda in a deal worth $190M upfront with $120M in additional milestone payments. This is a great transaction all around, enabling clinical development to now begin for Intellikine’s two remaining PI3K-mTOR and selective isoform inhibitors and since Takeda have research facilities locally in San Diego, this will enable work to continue with minimum fuss and relocation.

b) As of this morning, Exelixis announced they have licensed their PI3K-delta inhibitor in preclinical development to Merck. This deal features an upfront payment of $12 million, but the company will be eligible for potential development and regulatory milestone payments for multiple indications of up to $239 million in the future.

Another PI3K inhibitor in the news is Calistoga’s CAL-101 (now owned by Gilead), a delta selective isoform inhibitor being evaluated in indolent NHL. At this meeting, the phase I data was presented in a poster. The patients enrolled to date (n=37) included those with follicular lymphoma, small lymphocytic leukemia and marginal zone lymphomas, all of whom had received prior therapy for their disease. In this study, CAL-101/GS-1101 was given in combination with rituximab and/or bendamustine to determine the safety profile.

The big question is whether the combination with chemoimmunotherapies would lead to added or overlapping toxicities – the authors, de Vos et al., concluded that answer was no and a good efficacy signal was seen:

“GS-1101-based combination therapy with rituximab and/or bendamustine offers major and rapid reductions in lymphadenopathy.”

On the basis of this study and a prior phase I trial that determined the dose (150mg/BID), further continuation of the program in this indication appears warranted:

“The data from this trial will be used to design Phase 3 combination studies of GS-1101 in patients with iNHL.”

Anti-CD20 monoclonal antibodies

Rituximab was the first targeted cancer drug following its approval back in 1997 and has shown how important targeting CD20 has been in lymphomas and more recently, chronic lymphocytic leukemia (CLL). At this meeting, we saw an interesting new development in lymphomas from Roche/Genentech in GA101 (obinutuzumab). This is essentially a follow-on biologic to rituximab. In a previous post prior to ASH, I looked at the key questions that need to be addressed in order to displace rituximab, namely more activity in rituximab refractory patients, more efficacy/better side effect profile up-front or broader activity across several diseases.

What are the key differences between rituximab and obinutuzumab you might ask and does this impart any clinical benefit?

Well, rituximab is a humanised type I monoclonal antibody, whereas obinutuzumab is a humanised type II glyco-engineered antibody, both target CD20. What’s the difference between Type I and II? Well, according to Robak, 2009:

“GA-101 binds with high affinity to the CD20 type II epitope, resulting in the induction of antibody-dependent cytotoxicity that is 5- to 100-fold greater than observed upon treatment with rituximab.”

The proof of the pudding is always in the clinical data, especially randomised head-to-head trials. There were over a dozen abstracts on GA101 at ASH, but the most important one in this context was a phase II GAUSS trial from Sehn et al., which randomised patients with indolent B-Cell NHL to receive either rituximab or obinutuzumab in the relapsed setting:

Gauss trial schematic courtesy of Roche

And the result? The authors concluded that:

“Treatment with GA101 in patientss with relapsed NHL resulted in higher response rates compared to rituximab as assessed by both investigators and the IRF at an early time point.

GA101 was well tolerated, although a higher rate of IRRs was noted, the majority were grade 1/2 in severity and did not result in significant differences in treatment discontinuation.”

Where IRR is infusion related reactions.

This data is promising for obinutuzumab, but still very early – we will still need to see what happens in a larger scale phase III trial with more patients before we can draw more definitive conclusions. That said, I found the GAUSS trial data very encouraging indeed.

Bruton’s Kinase Inhibitors

In the first update, I highlighted how Bruton’s Kinase inhibition (BTK) was one of the exciting new emrging pathways in chronic lymphocytic leukemia (CLL), but new data was also presented on the leading BTK inhibitor, PCI-32765 (Pharmacyclics/J&J), in lymphomas.

The preliminary phase II data in mantle cell lymphoma (MCL) presented by Wang et al., in 48 patients (29 bortezomib-naive, 19 bortezomib-exposed) with a median of two prior treatment regimens (range:1-5).

Initial efficacy data was reported:

“The objective response rate (ORR) is 67% (16/24); ORR is 58% (7/12) in the bortezomib-naive cohort and 75% (9/12) in the bortezomib-exposed cohort.”

The side effect profile seen to date was also described:

“Serious AEs (SAEs) have occurred in 8/39 patients (21%); 2 SAEs (1 rash, 1 febrile neutropenia) were considered potentially related to PCI-32765.”

I thought these results were encouraging – with good tolerability and encouraging signs of efficacy – certainly worthy of exploring in a randomised phase III trial in this indication. This is an agent we are probably going to hear a lot more about in the near future.

And finally…

There were a lot of new developments emerging at this meeting, particularly in the poster sessions and also in both phase I and II trials. It was impossible to keep up with everything, so this post is just a flavour of some of the abstracts either of us did manage to take in.

The challenge, as always, with ASH is their insistence of holding all the critical oral sessions on biology and therapy in leukemias, lymphomas, myelomas and myeloproliferative diseases almost on a single day, making it absolutely impossible to see/hear all the new and exciting data. Monday is, therefore, always a manic day. It’s a strange contrast from the long lulls on the Sunday where some of the oral sessions could have been hosted, perhaps the biology sessions, thereby freeing up a more flexible schedule for the clinical data on Monday. There is some weirdness and also dismay in seeing a biology and clinical session for the same topic (eg CML, Multiple Myeloma, Lymphomas or FLT3 in AML) clashing. Not everyone is a specialist, certainly the community oncologists who attend are not. This is silly scheduling and means that people presenting in a biology session often miss the clinical update for a trial they were a PI in, while attendees like me are regretably forced to choose from one or the other.

Sadly, not everyone can stay until Tuesday morning when a few more key oral sessions that include new data are held, for a meeting that began on Friday. This is issue compounded by no virtual meeting facility, one of ASCO, AACR, ECCO and even the NY Chemotherapy Symposium’s great online service whereby you can catch up with sessions you missed later. For me, this is a critical and integral part of modern cancer meetings.

I hate missing out on great or important data and hope that ASH will seriously consider virtual meeting access for future meetings – it really does help attendees – otherwise if you didn’t catch the sessions they are gone forever! Personally, I was still watching (and enjoying) presentations I missed at AACR and ASCO in July, long after both meetings finished, and really appreciated their excellent webcasts/virtual meetings.

One of the sad things for me was it turned out to be the first time in many years that I skipped the Plenary session as there were some odd choices this year that simply didn’t resonate with me. For example, making Mylotarg, a drug withdrawn by the FDA recently, one of the meeting highlights made little sense to me because:

a) it will have no immediate clinical or even scientific impact for the practising oncologist and
b) there were far more dramatic results that I thought were worthy of broader dissemination

Overall though, this was a good ASH meeting from the point of view of exciting new data in phase I and II trials; clearly the oncology pipelines are beginning to show some early promise, but it was disappointing not to see more of them prominently highlighted. There were quite a few other abstracts I liked, but this overview should give a good flavour of some of the novel agents emerging for the treatment of NHL.

For those wanting information on Hodgkins Lymphomas, I’ll cover those in a separate post as there was too much data to cover both in one post.

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ASH 2011 Update 1: Bruton’s Kinase Inhibitors (BTK)

By MaverickNY on December 15, 2011

This year’s American Society of Hematology (ASH) meeting heralded a wealth of new information on pipeline compounds in early development. Although a lot of people were excited about myelofibrosis and the battle between Incyte’s ruxolitinib and YM Bioscience’s CYT387 (more on these in a separate update), the area that intrigued me most was the Bruton’s Tyrosine Kinase (BTK) inhibitors in B-cell lymphomas.

Background on the science behind the BTK pathway:

I’ve been following these novel agents for a while and was fascinated by two abstracts from the ASCO and ASH meetings last year. It became clear that BTK is a valid target in B-cell lymphomas after Advani et al., (2010) demonstrated at ASCO the effect of BTK inhibitor PCI-32765 monotherapy on responses in patients with relapsed aggressive NHL.1

Later that year, Ponader et al., (2010) showed that PCI-32765 abrogates BCR- and nurselike cell-derived activation of CLL cells in vitro and in vivo.2

Between them, these two abstracts offered a solid rationale for investigating BTK inhibitors in B-cell lymphomas and CLL.

Where are we now with clinical development?

Fast forward to ASH this year, Dr Susan O’Brien presented the initial phase I/II data in chronic lymphocytic leukemia (CLL), which was well worth waiting for the last day of the conference to hear. She took us through the concept of the how the BTK pathway fits into B-cell malignancies:

BTK Source: Dr Susan O’Brien ASH 2011 CLL oral session, reprinted with permission 3

Essentially BTK is a critical part of the BCL pathway that leads to proliferation, so targeting it leads to cell death or apoptosis:

“BTK is a Tec family kinase that is required for B-cell activation mediated by BCR signaling. The essential role of BTK in normal B-cell development is evidenced by the clinical syndrome X-linked agammaglobulinemia, in which BCR signaling is abrogated by mutations in BTK.

Signaling from the BCR is also believed to be required for the maintenance of cell division and survival in B cell malignancies, presumably via downstream phosphorylation of PLC-gamma by BTK, ultimately leading to the activation of the anti-apoptotic transcription factor NF-kB and the kinase ERK.

Additionally, BTK may also play a role in the pathogenesis of B-cell malignancies by regulating integrin-mediated migration and adhesion, through regulation of malignant cell response to lymph node-derived chemotactic factors, such as CXCL12 and CXCL13.”

What does the latest data show?

Here’s a quick overview of the preclinical and clinical data I managed to see at ASH. There were over 2,000 posters over three days, plus a day and a half of simultaneous oral sessions, so it was quite hard to keep up with the sheer volume of it all!

In mantle cell lymphoma (MCL) the preclinical data looked encouraging:

Ponader et al., (2011) provided a nice overview of the initial PCI-32765 preclinical data in mantle cell lymphoma (MCL) in a poster presntation.4

They concluded that MCL cells express surface IgM and BTK, which is involved in BCR signalling. In this study, PCI-32765 successfully blocked BTK function and inhibited MCL proliferation, except in resistant cell lines. The former explains why there were responses in patients, while the presence of the latter suggests that additional BTK independent pathways exist and need to be elucidated.

I think that figuring the mechanisms of resistance out is important because it will help suggest possible rational combinations with BTKi therapy in advanced disease.

In CLL, the initial phase I/II clinical data is early, but promising:

Over the last 18 months, patients with CLL (n=117) have been enrolled into five trials, although the interim data was reported in the two relapsed/refractory arms (asterisked arms) at this conference, at two different dose cohorts of PCI-32765, given orally daily at either 420mg (n=27) or 840mg (n=34):

PCI

Source: Dr Susan O’Brien ASH 2011 CLL oral session, reprinted with permission5

The overall response rate (ORR) of 67-68% for both doses in the relapsed, refractory setting showed impressive activity and a clear sign that the BTK target is a valid one in this setting. Although the CR rate was low (<5%), the majority of patients saw PRs in this setting. Those with bulky disease (common in advanced disease) tended to do better.

There were also dramatic changes in the tumour burden, with the majority of patients seeing a greater than 50% change from baseline. Sustained improvements in blood counts were also reported. What particularly caught my attention was the activity in patients with known poor risk factors such as 11q and 17p deletions, who tend to have noticeably poorer outcomes. Obviously this is only a small phase I/II trial and we will have to see what happens in a larger scale randomised phase III study to see if the results are reproducible.

Typical side effects were diarrhea, cough and fatigue (any grade and grade 2+). The most common grade 3 adverse events were pyrexia, fatigue and diarrhea. Bearing in mind this was a heavily pre-treated population, many of whom had received prior immunotherapy, I thought the results were promising. The downside of immunotherapy is that while it has shown effectiveness, it does leave patients, especially the elderly, rather beaten up. The lack of grade 4 events in CLL was especially encouraging in this group.

What are the main BTK inhibitors in development?

Johnson and Johnson announced they were licensing Pharmacyclics PCI-32765 compound for nearly a $1B just prior to the meeting.6

Based on the data seen over the last two years, I thought they got a steal – this looks like it will be a very promising agent indeed. However, while they are clearly the leading BTK inhibitor, based on the sheer breadth and depth of their program, they aren’t the only one in this niche.

Avila Therapuetics also have a BTKi in early development, AVL-292, but they only have one phase I trial ongoing that I could find. The initial phase I data in B-cell malignancies was also presented in a poster at ASH.7

You can see why J&J licensed the Pharmacyclics agent – it’s much more advanced in the clinic than the others:

BTK
What does all this data mean?

Emerging data on BTK inhibitors has started to show that they produce consistently effective and well tolerated agents in B-cell malignancies such as NHL, MCL and CLL. I think this is a new class we are going to hear a lot more about over the next few years, either alone or in combination with other therapies.

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What’s hot at SABCS – Update 2 – advanced breast cancer

By MaverickNY on December 10, 2011

After a number of basic research and science sessions over the last two days (see the Update 1 post on the science that intrigued me for more details), but the last two days heralded some excellent clinical sessions, in both oral and poster forms. These included the presentation of the much anticipated update to the BOLERO-2 trial, which was also published in the New England Journal of Medicine online and the CLEOPATRA study, also published in the same journal. One of the more impressive posters that caught my eye was the ENCORE 301 study, which provided an update to the entinostat data in ER/PR+ HER2- advanced breast cancer.

Many of you will have read the wire and news articles released in a barrage on Wednesday evening with the NEJM publications ahead of the presentations on Thursday and Friday, but I wanted to put them in context of what we know so far and why these studies are both elegant and important.

Why am I fascinated by these particular studies?

Drug resistance can develop either upfront or is acquired in response to treatment over time. The latter is also known as adaptive resistance, as the tumour evolves certain strategies to ensure it’s survival. This is one reason why many people will have a different response to the same treatment.

In simple terms, if we can figure out ways to:

Either delay the development of resistance up-front in treatment naive patients by enabling more comprehensive pathway suppression
Or switch to a new logical combination regimen once resistance has developed

then we may be able to prolong patient outcomes and survival further. To me, these kind of rational approaches make much more sense than merely throwing random chemotherapy doublets of choice at the problem. These two strategies are very much at the heart of the three impressive studies mentioned above. Let’s look at them in a little more detail.

BOLERO2

BOLERO-2 is the acronym for the breast cancer trials of oral everolimus and the updated safety and efficacy data were reported here at the San Antonio Breast Cancer Symposium (SABCS), although it should be noted that the NEJM article is based on the phase III ECCO data previously presented by Jose Baselga in September.

The trial design, though, remains the exactly same – patients were randomised to receive with everolimus plus exemestane versus placebo plus exemestane to determine whether the mTOR added anything to the AI alone.

The rationale behind this trial is that mTOR is a known cause of resistance to AI therapy, so the combination targets both the ER, which is driving the tumour proliferation, and mTOR targets the adaptive resistance pathway. Shutting down both pathways should lead to improved survival, which we clearly saw at ECCO (6.5 months extra survival as measured by PFS).

The latest data presented by Dr Gabriel Hortobaygi (MDACC) confirmed that the responses continue to be durable, with an improvement in the PFS with the combination arm now up to 11.0 months, up from 10.6 months at ECCO. The results for the exemestane control arm remained the same at 4.1 months. This means that the improvement in survival with the mTOR now offers a median 6.9 months extra benefit. OS had not yet been reached and therefore was not reported.

My view? These are excellent results from a well designed trial with a logical and elegant design given that we know mTOR is one of the adaptive resistance mechanisms to AI therapy and confirm that the original hypothesis was a valid one.

That said, what we don’t know is who will most benefit from the combination i.e. which women are more likely to respond. I’d love to know whether the really good responders had higher mTOR levels or overexpression or whether there is something else that would help us determine the likely responders for several reasons:

mTOR isn’t the only acquired resistant pathway to AI – there are others – so hopefully a way to determine who would be the ideal candidate for mTOR therapy will emerge from retrospective analysis.
A quarter (26%) of both arms received prior chemotherapy – did these women do better or worse when given the AI-mTOR combination compared with those who only received hormonal therapies?
This combination will not be cheap, considering the likely costs of everolimus alone without the AI could easily be ~$7K/month and the cost of exemestane must be added to that.

These points aside, I do think these results are impressive and good news for an advanced population of women who may not want to even consider chemotherapy – the current data suggests that many will get more time with this approach. Expect to see Novartis filing for everolimus approval in advanced breast cancer with the FDA before the year is out.

ENCORE 301

In the same patient population of ER/PR+ HER2- women, there was an update to the phase II ENCORE 301 trial with the HDAC inhibitor, entinostat, that we blogged in more detail at the recent AACR Molecular Targets meeting.

What was new about the data here was an update on the overall survival (OS) data. Remember, in San Francisco the PFS for the entinostat arm (comparable to the everolimus-exemestane arm in BOLERO2) was 8.5 months in the women with high acetylation, an excellent predictive biomarker of response.

Now, I was wondering why the OS has still not yet been met in the BOLERO2 trial here and realised why with the updated entinostat data:

As you can see above, based on a medium follow-up of 23 months, the OS has improved in these patients in the phase II trial from 19.8 to 26.9 months, an improvement of 7.1 months of life.

We’ve all seen so many trials where the benefit is a mere 1-3 months, so to see several trials in advanced breast cancer where the survival is measured in 6-7 months is breathtaking. Long may this trend continue with more rationally designed combinations and robust trial designs!

The entinostat phase II data certainly provides a good efficacy and safety signal to continue development and I was delighted to see that Syndax are moving forward to a confirmatory phase III trial in 2012. I’m very much looking forward to watching how this study progresses, although we obviously won’t know the results for a while.

CLEOPATRA

The CLEOPATRA study looks at a completely different patient population than BOLERO and ENCORE. In this situation, it’s looking at women were treatment naive, not refractory, who also needed to be HER2+ to enter the study.

As discussed in the What’s Hot at SABCS review prior to the meeting, pertuzumab is similar to trastuzumab in that it is a monoclonal antibody to HER2, but also differs in that it acts in a different part of the HER domain from Herceptin and also prevents pairing of HER2 and 3 dimersiation:

HER dimerization, source: NEJM

The idea behind combining pertuzumab and trastuzumab upfront is to enable a more comprehensive shutdown of the HER2 pathway and delay the resistance setting in. By doing this, PFS should increase.

Dr Jose Baslega presented the results of the CLEOPATRA trial for the first time to a packed and highly excited audience in San Antonio. Unfortunately, I wasn’t there as I was en route to the American Society of Hematology (ASH) meeting, but like many, I was eagerly reading the tweets and reactions from the attendees.

The Roche press release summed up the essence of the data nicely:

“The median PFS improved by 6.1 months from 12.4 months for Herceptin and chemotherapy to 18.5 months for pertuzumab, Herceptin and chemotherapy.

Overall survival (OS) data are currently immature, with a trend in favour of the pertuzumab combination.”

In short, another stunning six month leap in survival in an entirely different patient population of advanced breast cancer. This is the sort of data those of us working in the industry live for and hopefully, things will continue to get better because clearly thought leaders such as Martine Piccart (at the the NY Chemotherapy Symposium) and Jose Baselga (at SABCS) are already dreaming and envisioning a world in which women with HER2+ breast cancer can be treated without chemotherapy at all. Now that would be a wonderful thing indeed and I really hope to see it happen sooner rather than later.

One thing that hasn’t been factored into the equation is the antibody drug conjugate T-DM1 and how that relates to pertuzumab and trastuzumab. The phase III trial MARIANNE is currently enrolling patients and may offer us an answer to that question in a couple of years time.

For those of you interested in some expert commentary, the NEJM published an excellent editorial from Dr William Gradisher (Northwestern, Chicago) accompanying the BOLERO2 and CLEOPATRA studies which is well worth reading (see references below).

In summary…

These three studies all show how rationally designed and elegant studies based on solid science can lead to large leaps in improvement in survival in the clinical setting. Roche have already filed the BLA for pertuzumab and Novartis are expected to file everolimus in advanced breast cancer soon. Syndax are already planning their phase III trial for entinostat.

It’s a very good period for ER/PR+ HER2- and HER2+ advanced breast cancers – from that perspective, this year’s San Antonio Breast Cancer Symposium was very uplifting and one of the more exciting meetings of the last five years.

References:

Baselga, J., Campone, M., Piccart, M., Burris, H., Rugo, H., Sahmoud, T., Noguchi, S., Gnant, M., Pritchard, K., Lebrun, F., Beck, J., Ito, Y., Yardley, D., Deleu, I., Perez, A., Bachelot, T., Vittori, L., Xu, Z., Mukhopadhyay, P., Lebwohl, D., & Hortobagyi, G. (2011). Everolimus in Postmenopausal Hormone-Receptor–Positive Advanced Breast Cancer New England Journal of Medicine DOI: 10.1056/NEJMoa1109653

Baselga, J., Cortés, J., Kim, S., Im, S., Hegg, R., Im, Y., Roman, L., Pedrini, J., Pienkowski, T., Knott, A., Clark, E., Benyunes, M., Ross, G., & Swain, S. (2011). Pertuzumab plus Trastuzumab plus Docetaxel for Metastatic Breast Cancer New England Journal of Medicine DOI: 10.1056/NEJMoa1113216

Gradishar, W. (2011). HER2 Therapy — An Abundance of Riches New England Journal of Medicine DOI: 10.1056/NEJMe1113641

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Follow the American Society of Hematology ASH conversations!

By MaverickNY on December 10, 2011

It doesn’t seem a full year since the last American Society of Hematology (ASH) meeting took place, time has certainly flown by!

For those interested, I posted a review what I think will be hot topics at this meeting

In the meantime, to enable easy reading of the tweets and discussions here in San Diego for those both attending and following remotely, I’m aggregating the tweets around the official hashtag, #ASH11.

You can follow the conversations over the weekend through Tuesday in the widget below:

If you have any questions please do add them in the comments below or feel free to tweet me, @maverickny on Twitter.

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