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Commentary on Pharma & Biotech Oncology / Hematology New Product Development

Posts from the ‘Lymphoma’ category

Update on ADCs and immunotoxins in hematologic malignancies

By on October 18, 2011

The Cancer Research journal has an interesting review of ADC and immunotoxin technology and their potential role in hematologic malignancies that is well worth reading (see references below).

Fitzgerald et al., (2011) observe that:

Immunotoxins and ADCs are assembled in a number of different ways. Antibody fragments or whole antibodies are combined with either protein toxins or low-molecular-weight toxic drugs. Linkage options include gene fusions (peptide bonds), disulfide bonds, and thioether bonds.

Design goals dictate that immunotoxins and ADCs remain intact while in systemic circulation but disassemble inside the target cell, releasing the toxic payload.

Uncoupling the toxin or drug from the antibody is accomplished by protease degradation, disulfide bond reduction, or hydrolysis of an acid-labile bond. Toxin or drug attachment to the antibody must not interfere with antigen binding.

I was particularly struck by the number of immunotoxins and ADCs currently in clinical development each focused on different targets. The article highlights a number of agents in the clinic, as of January this year.

A quick overview is provided in the table below:

ADC

The good news is that some of these agents have already been approved in the US, although not all have seen a successful launch. While the current rising star from Seattle Genetics and Millennium, brentuximab vedotin (Adcetris), received fast track approval from the FDA in HL and ALCL earlier this year, gemtuzumab ozogamicin (Mylotarg) was voluntarily withdrawn from the US market by Pfizer last summer.  Part of Mylotarg’s problems lay in the early generation linker technology that release the active substance too early, thereby causing more extensive side effects than would be preferred.  Linker technology has evolved considerably since then, which is good news for patients since active drug can now be targeted more precisely where it is most needed.

As the antibody and linkage technology continues to improve, thereby allowing the active drug to be released in the tumour or on the surface of the cancer cells, I would expect to see more of these agents make it to market successfully with fewer toxicities.

One promising agent in this list, moxetumomab pasudotox (MedImmune), had some promising early data presented at ASH in 2010 in relapsed, refractory hairy cell leukemia (HCL) that is worth checking out.

The regular deadline for this years ASH abstracts has already closed, while the late breaker deadline is this month. I’m hoping we will see some more promising data emerge in December.

References:

ResearchBlogging.orgFitzGerald, D., Wayne, A., Kreitman, R., & Pastan, I. (2011). Treatment of Hematologic Malignancies with Immunotoxins and Antibody-Drug Conjugates Cancer Research, 71 (20), 6300-6309 DOI: 10.1158/0008-5472.CAN-11-1374

Upcoming Fall cancer meetings

By on October 11, 2011

November always brings two of my favourite smaller meetings on the oncology calendar, so here’s a quick snapshot of what’s coming soon.

First up is the NY Chemotherapy Foundation Symposium Foundation, also known by many as the Greenspan Meeting, in honour of the late Ezra Greenspan who founded the event. This year, it will be at the Marriott Marquis in Manhattan from November 8-12th. For those interested, here is the 2011 program.

NY Chemotherapy Foundation SymposiumThe annual Greenspan Memorial lecture is usually held at lunchtime on the Thursday of the event and the talks are usually both informative and entertaining. The last two presenters have included experts such as Norman Wolmark on colorectal cancer and Larry Norton on cancer cell seeding.

This year, it is Martine Piccart’s turn and she will be discussing:

“CURE OF HER2 POSITIVE BREAST CANCER WITH NO OR MINIMAL CHEMOTHERAPY AT THE DOOR STEP?”

That should prove to be an provocative talk!

The Greenspan meeting is always useful for practising community oncologists in the Tri-State region because it largely focuses on clinical data (with some new developments in R&D highlights) and where the practice of cancer treatment is changing.

The second meeting I’m attending (they’re virtually back to back) is the AACR Molecular Targets and Cancer Therapeutics conference, also euphemistically known in Pharmaland as the EORTC meeting, although it is co-sponsored by the AACR, EORTC and NCI and alternates between the US and Europe.

AACR Molecular Targets and Cancer Diagnostics 2011This year, it’s in San Francisco and you can view the program here. I’m particularly looking forward to the personalised medicine plenary session, which features luminaries such as:

  • Jose Baselga (MGH)
  • Levi Garraway (DFCI)
  • William Pao (Vanderbilt)

Other interesting talks include:

  • Tona Gilmer (GSK) BRAF and MEK inhibition in melanoma
  • Scott Ebbinghaus (Merck) Dual inhibition of mTOR and IGFR pathways
  • Jean-Pierre Issa (MDACC) Novel agents for epigenetic therapy
  • Christine Eischen (Vanderbilt) Mdm2 regulates DNA repair and chromosome stability
  • Johann de Bono (Marsden) Androgens, biomarkers, and abiraterone

And many many more.

The great thing about this meeting is that there aren’t too many concurrent sessions – I really hate missing interesting presentations because they clash with something else!

If you’re attending either meeting and would like to meet up or say hello, do let me know.

Seattle Genetics announce fast track approval of Adcetris

By on August 22, 2011

This morning, Seattle Genetics announced that the expected fast track approval from the FDA has been forthcoming for brentuximab vedotin (Adcetris) following the recent unanimous ODAC voting in both refractory Hodgkin Lymphoma (HL) and Anaplastic Large Cell Lymphoma (ALCL).  Clearly, the company and the agency have come to agreement on the confirmatory trials as part of the condition of accelerated review.  The final prescribing information (PI) can be found on the Adcetris website.

For those of you looking for more information on Adcetris, please check out the related posts section below for previous reports on this novel ADC therapy.

I missed the conference call this morning announcing the pricing details, but Luke Timmerman from Xconomy had a nice summary:

“The company set the price at $13,500 per dose, given intravenously every three weeks. If patients get eight infusions on average, consistent with clinical trial experience, then it will cost $108,000 per patient.”

Based on the data from the clinical trials, most patients will probably need 7-9 cycles, so this would make the overall course in the $94,500 – $121,500 per treatment range, with $108K being the average based on 8 cycles.  The overall treatment cost will therefore typically be less than the $120K cost of treatment for BMS’s ipilimumab (Yervoy) in metastatic melanoma.

Ever since Dendreon announced the $93K course of treatment for Provenge in asymptomatic castrate resistant prostate cancer (CRPC), there has been a noticeable trend upwards in the cost of treating advanced cancers.  We probably spend more treating the last 6 months of a cancer patients life than any of the other stages combined with incremental rather than dramatic improvements.  In the long run, this is likely to be unsustainable, but for now companies will continue to charge what they think the market will bear.

The good news is that Adcetris offers excellent clinical proof of concept for antibody drug conjugate (ADC) technology and has the distinction of being the first such agent approved, beating Roche’s T-DM1 to market, which has been filed with the FDA for the treatment of HER-2 breast cancer.

In the meantime, we also have several other novel therapies awaiting final review by the FDA.  Aside from T-DM1, Pfizer filed crizotinib for ALK-positive lung cancer and now has a brand name, Xalkori, which I thought sounded rather Vulcan :).  Should these two agents also receive FDA approval in the very near future, 2011 will likely be a bumper year for new cancer drug approvals.

 

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Using social media to improve awareness of clinical trials in rare lymphomas

By on July 8, 2011

Slowly but surely, we are seeing more use of social media in one area where I really think it can help a lot – clinical trials.

Regular readers will know of my passion for use of biomarkers in studies to ensure that the patients most likely to respond and therefore benefit will get treatment, thereby sparing those unlikely to respond of the debilitating systemic side effects. This also helps to reduce false hope and raise more realistic expectations.

I was therefore delighted to see a new video from the folks at MD Anderson Cancer Center where Dr Anas Younes, a lymphoma expert, is explaining about the new trials they have open in a rare form of lymphoma, Peripheral T-Cell Lymphoma (PTCL), with some new agents in development.

The groups stated mission is abundantly clear and admirable:

“Our mission is to improve the cure rate of patients with PTCL and reduce treatment-related toxicity by developing novel targeted therapy using rationally designed small molecules, antibodies and combination regimens of biologic agents.”

Check out the short video below – if you can’t see it, you can click this link to take you directly to it:

PTCL is very rare indeed, but…

  • It is good to see companies invest in clinical trials to continue to improve outcomes
  • Social media sharing through YouTube, Facebook, Twitter and blogs is a great way to aid awareness of clinical trials for those are suffering
  • More awareness will hopefully lead to faster enrolment and earlier readouts that can be publicly shared with all
  • Dr Younes is a fellow believer in targeted agents in a targeted fashion based on the underlying biology of the disease.  Love this – using targeted agents in an untargeted fashion is both silly and a waste of time/research dollars
  • Academia is probably the ideal way to provide this sort of education – are you more likely to believe or be persuaded by a passionate medical specialist from a top cancer center or a pharma company advertising clinical trials?

There has been some excellent research from Pew Internet recently that showed, as Susannah Fox summarised for me via Twitter:

“Most patients say professionals are more helpful than peers for diagnosis, Rx, treatments.”

She has also published another in-depth report that looked at Peer-To-Peer healthcare.  I particularly liked the aims:

“This report shows how people’s networks are expanding to include online peers, particularly in the crucible of rare disease.”

Those online peers could be connections from all walks of life, who like me, like to share fascinating stuff from reputable sources such as Pew Internet, Manhattan Research and top cancer centers such as MD Anderson.  The beauty of social media is that we can all share information and help improve medical education and awareness across a broad church.  As Thomas Friedman said, the world is indeed getting flatter.

For those of you who know someone who has been diagnosed with PTCL or other rare lymphomas and is in need of treatment, do share Dr Younes’ video with them – they may be able to help.

 

 

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Highlights from the European Hematology Association EHA 2011 meeting

By on June 15, 2011

This weekend heralded the sixteenth annual meeting of the European Hematology Association (EHA) conference at the ExCel centre in the London Docklands. Completing back to back ASCO and EHA conferences across two continents will test any delegates stamina!

Like ASCO, this year was a relatively quiet one at EHA, with most of the data already known or presented elsewhere.   There were some gems in the program though.

In the latest video highlights I discuss three things that caught my attention:

  1. Is high dose cytarabine (ara-C) really necessary in AML?
  2. Brentuximab vedotin in anaplastic large cell lymphomas (ALCL)
  3. Adherence with chronic TKI therapy in CML

We have previously covered the excellent data for brentuximab vedotin (Adcetris) in Hodgkin Lymphoma, but the new data presented in ALCL in the poster session was, in ways, even more dramatic as you can see from the before and after pictures included.

You can see from the video, shot on location, that the damp windy weather and rundown surroundings created a rather industrial ambience – not quite the image many may have of the Docklands and Canary Wharf, which is a couple of stops earlier on the Docklands Light Railway (DLR).

Of course, there are unplanned escapades, such as nearly missing the 8am session on Sunday morning after the Jubilee line didn’t begin until 7.20am (first train at 7.35am), then the DLR had a “system failure” at Canning Town. A quick dash down to the adjacent bus station, a frantic climb over a fence in glad rags and a rare taxi was thankfully secured for the mad dash to the ExCel centre!

Still, there is something rather edgy about hosting convention centres in marginal areas in the middle of nowhere-land, quite a trek on the Tube and DLR from the Central London:

All in all, I enjoyed the meeting in my hometown and the more relaxed academic atmosphere after the frenetic pace of ASCO, but by the end of ten days on the road it was nice to return home. It’s not all work and no play though, as you can see from this post about some of the pomp and circumstance that inevitably goes with being in London.

{UPDATE:  The day after this posted, Seattle Genetics announced they have an ODAC scheduled for July 14th.   The PDUFA date is August 30th, so with any luck, we may see this drug approved by the FDA sooner rather than later – great news for patients in the US!}

European Hematology Association meeting 2011

By on June 8, 2011

Well, after just getting back from the American Society of Clinical Oncology (ASCO) meeting in Chicago, I’m heading off to Europe for the European Hematology Association (EHA) meeting – no rest for the wicked!

ASCO was a rather flat meeting this year – the stars were undoubtedly the imatinib 36 vs 12 month data in adjuvant GIST (clearly superior) and Roche/Plexxikon/Daiichi Sankyo’s vemurafenib in BRAF V600E metastatic melanoma. The ipilimumab data was strangely disappointing in the upfront setting – only 2 months improvement in survival when added to DTIC.

On the Sarcoma front, the catch-all nature of the study came back to haunt Merck with an improvement in PFS but no overall survival benefit for ridaforolimus as maintenance therapy after 1-3 cycles of chemotherapy. That filing will likely result in a highly charged ODAC meeting debating the merits of some awkward results.

Ovarian cancer data was a mixed bag – olaparib continues to look promising in this setting, although the Avastin OCEANS data caught a few people by surprise – yet another PFS endpoint met but no overall benefit in survival and the expected incidence in bowel perforations. I think this will likely be reserved for high risk women, if used.

There was a lot of interesting/promising data in phase II, which are too numerous to mention right now – check back as I will be adding some notes on some of the emerging compounds that I liked.

Meanwhile, I’m aggregating the tweets from the hematology meeting using the #EHA11 hashtag – you can track them in the widget below if interested in following along remotely. Most of the tweets from me will likely be on leukemias, lymphomas and multiple myeloma.

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Antibody Drug Conjugates (ADCs) in cancer research: what are they?

By on May 25, 2011

Quite a few questions have hit my inbox recently from people wanting to know more about Antibody Drug Conjugates (ADCs) and how they work.

They basically consist of three things:

  1. Monoclonal antibody
  2. Linker
  3. Cytotoxic agent

Antibody Drug Conjugate (ADC)

Source: Roche

The goal is to create a new molecule that essentially is greater than the sum of its parts by making it more targeted, like a guided missile against the cancer cells.

With normal monoclonal antibodies, they bind to atarget antigen that is a tumor-specific antigen on the surface of a tumour cell. With an ADC, the monoclonal antibody part of the molecule still latches onto the target antigen in the same way, but in this case it now has a powerful cytotoxic attached to potentiate the effect.

As Emeril would say, “Bam!”

You can see a video of how the ADC technology works HERE.

Unfortunately, the site only allows you to watch it there or download the video; it’s not easily sharable with others, short of emailing it.  Sadly, I couldn’t embed it here on the blog post for easy consumption either.

A nicer way would have been to put the educational videos on a company YouTube channel and allow it to be shared through social media via Facebook, Twitter etc. Imagine clicking on a link in Twitter and being taken to YouTube on your iPad, iPhone or Android smartphone?  Or watching an embedded video on someone’s blog post?

That’s a much more fun and immediate way to communicate ideas and technology from a medical or scientific learning perspective than a old fashioned static website.

It is good to see Pharma and Biotech companies active on social media, but they have a long way to go yet in terms of how they can help improve learning about the science behind new cancer research and development in an integrated way that helps the end users, ie the scientists, healthcare professionals, patients in clinical trials and analysts who might be interested.

We really do need to get away from the old web 1.0 world into the 21st century of sharing ideas, tools and medical or scientific information using social media in the web 2.0 era.

That said, there are some advanced ADC’s in clinical development at the moment.  The three leading compounds I’ve come across so far are:

  • Brentuximab vedotin (Seattle Genetics) in Hodgkin Lymphoma (HL) and systemic anaplastic large cell lymphoma (ALCL) targets CD30 and now has a brand name, Adcetris.
  • T-DM1 (Roche/Genentech) in HER2+ breast cancer
  • SGN-75 (Seattle Genetics) in RCC and NHL

Overall though, Roche/Genentech probably have the largest active research in this area, with a large portfolio of agents in development across a multitude of different tumour types.  You can check out this full ADC pipeline here.

Seattle Genetics have a couple of abstracts on their ADCs at ASCO this year and Roche have an abstract on the phase III EMILIA trial comparing T-DM1 with lapatinib plus capecitabine in metastatic breast cancer, all on Monday 6th that I hope to check out, that is if the sessions don’t clash!

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Seattle Genetics brentuximab vedotin accepted for FDA Priority review

By on May 2, 2011

I was delighted to see, amongst all the big news this morning on President Obama and Osama Bin Laden, that there was a little gem for Biotech – Seattle Genetics announced that the FDA have accepted their BLA filings for antibody drug conjugate (ADC), brentuximab vedotin, and awarded Priority status.  The company stated that the Prescription Drug User Fee Act (PDUFA) date is now set for August 30th, based on the Feb 28th filing date.

Two BLA filings were submitted, one for relapsed Hodgkin Lymphoma (HL) and another for relapsed or refractory systemic anaplastic large cell lymphoma (ALCL).  These two hematologic cancers share a commonality, ie CD30, which is the defining marker of the disease and the target for the ADC therapy.

Based on the data we saw at the recent American Society of Hematology meeting in December, the recent NEJM publication, this is very good news indeed for patients.

New treatment options in rare or difficult to treat diseases are always most welcome. With the American Society of Clinical Oncology (ASCO) and European Hematology Association (EHA) meetings both coming up in June, I’m really looking forward to an update of the data and to see how this exciting new concept (antibody drug conjugates) are progressing.

This is an area where I think we will see many more developments in the very near future, with Genentech’s T-DM1 also likely to have data at ASCO in breast cancer.

Mutations in CD20 can cause resistance in rituximab treated lymphoma

By on April 27, 2011

NHL Source: Sanford Health / NCI

A while back, I was discussing Non-Hodgkins Lymphoma (NHL) with someone and we pondered the question, “Why do some patients develop resistance to therapy with rituximab and others do not?”

The answer wasn’t immediately obvious at that time, but this morning I was delighted to spot a published article while browsing Flipboard, a nifty iPad app that brings turgid RSS feeds from journals to life and makes them interesting again.

It turns out that a Japanese group figured out the problem of what, in that Terui et al., (2009) discovered the root cause lay in CD20 mutations, but they they didn’t know the how or what.  This month, in one of the Nature publications, Blood Cancer Journal (Open Access, see references below), the same group have now expanded on their earlier findings.  Mishima et al., (2011) discuss how mutations in CD20 constitute part of the mechanisms that cause resistance rituximab therapy, specifically:

“In this study, we revealed that the binding site of L26 monoclonal antibody is located in the C-terminal cytoplasmic region of CD20 molecule, which was often lost in mutated CD20 molecules.

This indicates that it is difficult to distinguish the mutation of CD20 from under expression of the CD20 protein.”

The basis behind this research is that if “expression of CD20 seemed to have been completely lost for these lymphomas” how can we essentially unhide them?  In non-science speak, it’s as though they are protected by a Klingon-like shield to rituximab.

By finding the binding site on the C20 molecule, the researchers were able to develop new antibodies to the N-terminal region to identify cells that “have CD20 molecules with abnormalities in the C-terminal cytoplasmic region.”

The upshot of all this is that while the resistance is thought to be irreversible, the findings may help us identify patients who need a change in treatment earlier:

“This information may provide important criterion to judge whether it should switch to the treatment such as using second-generation CD20 antibody that is effective against fewer CD20-expressing cells.”

The group suggested that it may also be possible to consider using “using antibody for the different target molecule such as CD22.”

Time will tell what happens here, but these developments are important in our understanding of rituximab resistance in lymphoma.

Notes for PSB Readers:

For those of you with an iPad, you can download Flipboard from iTunes.  Once you have put all RSS feeds from your favourite journals, publications and news sources in to a Feedreader such as Google Reader, you can then import the aggregated feed into Flipboard and browse the articles more easily.

References:

ResearchBlogging.orgMishima, Y., Terui, Y., Takeuchi, K., Matsumoto-Mishima, Y., Matsusaka, S., Utsubo-Kuniyoshi, R., & Hatake, K. (2011). The identification of irreversible rituximab-resistant lymphoma caused by CD20 gene mutations Blood Cancer Journal, 1 (4) DOI: 10.1038/bcj.2011.11

 

 

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Biology of indolent B-cell lymphomas and chronic lymphocytic leukemia

By on April 14, 2011

We all know the importance that inflammation and the immune system plays in the early development of many cancers, but this is not a ubiquitous finding.  Indeed, some hematologic malignancies arise out of immunodeficiency, such as myelomas and chronic lymphocytic leukemia (CLL).  I haven’t written much about this topic in the past, so thought it would be useful to explain some of the underlying biology of CLL given that we can expect new (hopefully positive) data emerge at the American Society of Clinical Oncology (ASCO) meeting in June.

Several studies have shown specifically that immune activation can promote development and progression of lymphoma.  Extranodal marginal zone lymphomas (eMZLs), for example, originate at the site of chronic inflammation under the influence of T-cell help (see Suarez et al., 2006).

Hervé et al., (2005) have previously shown that antigen receptor repertoires exist in B-cell lymphoma and additionally, autoantigen recognition by CLL-derived immunoglobulin may suggest a role for antigen receptor signaling in lymphomagenesis.

In addition, an increase in circulating regulatory T cells (Tregs) has been reported in myeloma, CLL, and other B-cell lymphomas by Breyer et al., (2005) and confirmed by others.  This may well explain why the combination of fludarabine and cyclophosphamide (FC) is a useful strategy in reducing immunosuppression prior to cancer immunotherapy with rituximab (R).  The FCR combination is now very much the bedrock of treatment for patients with CLL and is based on a very solid rationale.

Previous work in 2004 by Christopoulos et al., observed a significant reduction in peripheral T helper cells in patients with untreated FL and eMZL.  The question remains as to what happens to the T-helper cells in untreated CD4+ subpopulations.

Christopoulos et al., (2011) therefore conducted a prospective open label study recently to look at the underlying immune system in patients with CLL or monoclonal gammopathy of unknown significance (MGUS).  According to the Mayo Clinic:

“Monoclonal gammopathy of undetermined significance (MGUS) is a condition in which an abnormal protein (monoclonal protein, or M protein) is in the blood.”

In terms of the selection criteria, patients with prior antineoplastic therapy, including corticosteroids, and patients with evidence for preexisting autoimmunity or immunodeficiency were excluded from the study.

The current study is interesting, because the results demonstrated:

“substantially reduced circulating T helper cells, predominantly naive CD4+ cells, in patients with nonleukemic follicular lymphoma and extranodal marginal zone lymphoma, but not in monoclonal gammopathy and early CLL.”

They went to to say that:

“Gene expression profiling of in vitro–stimulated CD4+ cells revealed an independent second alteration of T helper cell physiology, which was most pronounced in early CLL but also detectable in follicular lymphoma/extranodal marginal zone lymphoma.”

What new therapies are emerging for CLL?

Rituximab has been a very useful addition to the basic FC regimen in CLL.  A number of other therapies are also being evaluated in the disease, including fostamatinib, a SYK inhibitor from AstraZeneca and lenalidomide, a widely used immunotherapy for the treatment of multiple myeloma from Celgene.

Friedberg et al., (2010) published their data on fostamatinib in CLL and NHL last year based on the promising results previously presented at ASCO in 2009.  I wrote about the data at that meeting here for those interested.  Lenalidomide is being evaluated as a maintenance therapy for CLL in clinical trials (see my notes on the previous data presented at ASH) and given it is now 18 months to two years since we saw the initial data, I’m hoping there will be an update in Chicago this year, including some information on the optimal lenalidomide dose (see Wendtner et al., 2010).

Although CLL is a relatively indolent disease, patients can cycle through multiple therapies and combinations over time, so there is still a need for new drugs to mix up the combinations and extend life for this chronic condition further.

A future update will appear on this topic at ASCO in June – watch this space!

References:

ResearchBlogging.orgChristopoulos, P., Pfeifer, D., Bartholome, K., Follo, M., Timmer, J., Fisch, P., & Veelken, H. (2011).  Definition and characterization of the systemic T-cell dysregulation in untreated indolent B-cell lymphoma and very early CLL Blood, 117 (14), 3836-3846 DOI: 10.1182/blood-2010-07-299321

Suarez F, Lortholary O, Hermine O, & Lecuit M (2006). Infection-associated lymphomas derived from marginal zone B cells: a model of antigen-driven lymphoproliferation. Blood, 107 (8), 3034-44 PMID: 16397126

Hervé M, Xu K, Ng YS, Wardemann H, Albesiano E, Messmer BT, Chiorazzi N, & Meffre E (2005). Unmutated and mutated chronic lymphocytic leukemias derive from self-reactive B cell precursors despite expressing different antibody reactivity. The Journal of clinical investigation, 115 (6), 1636-43 PMID: 15902303

Christopoulos P, Follo M, Fisch P, & Veelken H (2008). The peripheral helper T-cell repertoire in untreated indolent B-cell lymphomas: evidence for antigen-driven lymphomagenesis. Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K, 22 (10), 1952-4 PMID: 18385751

Friedberg JW, Sharman J, Sweetenham J, Johnston PB, Vose JM, Lacasce A, Schaefer-Cutillo J, De Vos S, Sinha R, Leonard JP, Cripe LD, Gregory SA, Sterba MP, Lowe AM, Levy R, & Shipp MA (2010). Inhibition of Syk with fostamatinib disodium has significant clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia. Blood, 115 (13), 2578-85 PMID: 19965662

Wendtner CM (2011). Lenalidomide in CLL: What Is the Optimal Dose? Clinical advances in hematology & oncology : H&O, 9 (3), 220-4 PMID: 21475128

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