ASCO 2013: A Call for New Ways of Thinking

LIVE from ASCO 2013

It's huge.
It's crazy.
It's crowded.

But boy is there a ton of new research to share.

While ibrutinib and idelalisib have kicked open the door to explore new less toxic pathways to control not just CLL, not other B cell cancer, they did not close the door behind them.

Novel pathway inhibitors beyond PI3K and BTK and BCL-2 are being explored and being explored in novel ways with more open access.

New and potentially potent BTK and PI3K inhibitors are in trials now.

Combinations are being considered.

Dr. Wiestner said these new drugs offer us the opportunity to think in new ways.

Hence my disappointment when I hear speakers rightly celebrate the lack of bone marrow suppression with these new targeted therapies, but then got all excited about how that allows them to pile on the old school  bone marrow damaging chemotherapy. Maybe we do need to go in that direction, but can't we try to leverage the low toxicity of these drugs but adding other low toxicity agents to them, offering patients like us gentler and less risky control of our disease.

I like the idea of adding together more than one TKI or adding a monoclonal antibody or an IMID.

In my book, adding in bendamustine or fludarabine or chlorambucil or their ilk should make a significant difference in outcomes to justify the additional downside risk.  

I understand the temptation to revert to tried and true paths. And it might turn out to be the best call. Medicine must be both conservative and progressive.

But we have a sea change, a paradigm shift, happening in CLL. Let's try to keep innovating and exploring using the kind of thinking that got us the breakthroughs with  ibrutinib and idelalisb and ABT-199.

That is the next stage of research that has me excited.

That is the future that I want for all of us.

Live from ASCO 2013: Targeted B cell therapies

Raw review of the first session on targeted B cell therapies.

Typing fast. May have made errors but wanted to get this out

After my bad karma of a weird 35 miles and 16 minute diversion from Orange County to Ontario and then another three hour delay due to weather, I arrive in Chicago four hours late.

Today my karma was good: the hotel and shuttle were perfect. At the meeting 10 minutes early.

ABC diffuse B cell lymphoma DLBCL

NF(kappa)B signaling
Ikk(beta)kinase??

Stuck in the on position

Message from BCR- turns out that BTK is turned on upstream

Ibrutinib binds to site only found in 10 kinases covalent binds to cysteine 481, lasts all day

Inhibits BCR signaling and works other ways when BCR not turned on

Failed in primary refractory disease, worked better in relapsed/refractory

Works great in ABC type as expected Small #s

CD79B mutation 70% response rate, without still 31% response rate-
MYD88 +CD79B 4 of 5 response
MYD88 resistant Poor response??
CARD 11 downstream no response as expected

Pre-clinical trials

Ibrutinib synergizes w PI3K (inhibitor maybe alpha) mTOR, lenalidomide, steroids, chemo

IRAK4 inhibitors???- selective. Works with ibrutinib

BCR Signaling

Other Targets:

• mTOR
• SYK non receptor fostamanib 

BTK inhibitor (ibrutinib)

Little cumulative toxicity- marrow and elsewhere counts stay good

CLL

PFS 96%?  in RX naive (Byrd from ASH 2012) abound 60% in R/R 17 p at 2 yrs

MCL

high response rates 70%
like other biologicals improves the longer patient stays on drug

Other BTKs

CC292 (used to be AVL-292)

Didn't mention but ONO has a BTK inhibitor in early trials that  pre-clinical is strong

More Targets:

PI3K Idelalisib

CLL  significant nodal reduction including those with 17p
Also MCL and others
Little marrow toxicities, some liver enzymes up, pneumonia

Another PI3K
IPI-145 Phase 1 study  Good responses including response in Hodgkin's and T cells!

Dumping of cells from nodes and marrow into the blood (evidence from the marrow is thin- I asked)

Don't get the high WBC when mixed with chemo

EPIGENETICS (Dana Farber)

IN THE NUCLEUS that the actions happens

Sequencing cancer genomes

600,000 events altered, at least 486 important??? ( not sure of #)

Only 15 drugs that targets somatic mutation

Also progression- Need to get to master regulator in nucleus

Histone is critical

HDAC removes markers (placeholders)
Binds zinc  -removes reminder cap
Early w cardiac toxicity


Topical T cells treatment that breaks down when absorbed into blood so less toxicity

Bromodomain inhibitor JQ1

? turns off master growth MYC genes in MM

XANX  bromodomain inhibitors

Dana Farber open-source model of drug discovery.

Questions about how to control cost

That's it for now. I am sure there are mistakes in this. Please forgive. I just wanted to get this out fast in this unedited form to give you a sense of the barrage of information, but later I will of course return to my more editorial style. And videos too soon.

So much happening. So much info. This is all good.

Doctor Turned Patient

I have commented before on the extra advantages and risks of being a healthcare provider, a doctor, facing any serious illness, in my case an indolent (slow) but incurable cancer with a host of nasty complications.

I have also touched on how, with my increased awareness and access, comes the added responsibility of sharing what I have learned and decoding it to make it more widely accessible and digestible.

I plan to discuss this topic over the next few months concerning how I have sailed these troubled waters, but let me start by saying that the more navigational tools I have (think knowledge and friends in high places), the more fellow CLLers in my boat or in sister boats in the convoy ahead and behind me in the race for a cure or at least a long and trouble free voyage, the more friends on the shore with their warning lights and their fog horns to cut through the mist of the unknown and the unseeable, the better are my chances to reach that promised land.  And I plan to bring as many along with me as possible.

Stay strong.

We are all in this together.

Next post will be live from ASCO.

Good News on the Home Front and Sad News at the Hospital

I have managed to stay out of the infusion center where I get my IVIG for a full five weeks and my lab results today were great.

My hemoglobin was the highest it has been in years (14.7) and finally well within the normal range, my platelets were over 400,000 and my ALC was about 1.3 and my WBC around 10.

Maybe it was my wife's Cajun gingerbread with all that blackstrap molasses boosting my iron while my ibrutinib controls my disease and keeps my counts in check, and my cyclosporin and IVIG shut down my ITP.

Whatever it is, it is good news.

As I have preached before, I mustn't get too excited by one blood count. It is the trend that matter. And for my mental health, it is best to smooth out the high and lows, but I wanted share this piece of good news before I head off to ASCO 2103.

With these encouraging results, I am now planning to stretch out my IVIG infusions to every six weeks with my doctor's blessing.  Not so long ago it was every three weeks that I was getting poked and infused. My veins are most thankful for the respite.

On a much more tragic note, last week I lost a colleague, a compassionate and talented surgeon from my local hospital with whom I had worked for decades. He had chosen to keep his CLL and other blood issues more private. We shared many confidence about our battles and I will miss him and the life he gave back to many of our mutual patients though his skilled interventions. 

His last few months were very difficult. Rest in peace, my friend.

This is a cancer that still plays for keeps. It picks no favorites. 

We need to decide wisely on our therapies. We need to get these new drugs to market soon. There are lives in the balance.

ASCO 2013 Abstract: ABT-199 in Relapsed and Refractory CLL Patients

I have posted before on ABT-199. I like this drug because it works. And it is a pill, not an IV.

It is clearly a very potent therapy.

We know that not just from the impressive 85% response rates, even for those difficult to treat 17p del and F refractory patients where an amazing 88% and 75% respectively achieved at least a partial response (PR), but we also know it from its dark's side, namely tumor lysis syndrome (TLS).

Until the dosing was adjusted after the first cohort, the first three patients all had TLS, a life threatening complication (and one die did in this trial) from the massive killing of the cancer overloading the liver and especially the kidneys' ability to prevent all that toxic waste from cell death from building up to dangerous levels.

We need to move carefully, but I am glad that ABT-199 is back in trial after the studies were suspended due to deaths from TLS.

The present approved options for F-refractory and 17p deleted patients are severely limited and these results are very promising.

Complete responses (CR) are only 13%, but that's not bad for any mono therapy, especially in these tough patients.

Our future depends on the researchers taming both the disease and the drugs that we use to treat it.

We also need to constantly recognize the sacrifice of those who bravely jumped into this "first-in-human" phase 1 trials. CLL is not for wimps.

The question I am asking myself is will ABT-199 offer enough of a therapeutic potency edge over the other novel oral therapies such as the gentler inhibitors of BTK and PI3K∂ that will justify its risks and earn a place in our therapeutic arsenal.

Or will its risks become acceptably manageable? Whatever that means.

Still is nice to have more viable choice options for those of us with bad disease.

I hope it move forward. I imagine a time that we will take a cocktail of oral pathway blockers to completely slay our dragon, much as is done today with HIV. Blocking BCL-2 is part of that vision.

Here is the abstract.

Updated results of a phase I first-in-human study of the BCL-2 inhibitor ABT-199 (GDC-0199) in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL).
John Francis Seymour, Matthew Steven Davids, John M. Pagel, Brad S. Kahl, William G. Wierda, Thomas P. Miller, John F. Gerecitano, Thomas J. Kipps, Mary Ann Anderson, David C.S. Huang, David E. Darden, Lori A. Gressick, Cathy E. Nolan, Jianning Yang, Todd A. Busman, Alison M. Graham, Elisa Cerri, Sari H. Enschede, Rod A. Humerickhouse, Andrew Warwick Roberts; Peter MacCallum Cancer Center, Melbourne, Australia; Dana-Farber Cancer Institute, Boston, MA; Fred Hutchinson Cancer Research Center, Seattle, WA; University of Wisconsin Carbone Cancer Center, Madison, WI; The University of Texas MD Anderson Cancer Center, Houston, TX; University of Arizona Cancer Center, Tucson, AZ; Memorial Sloan-Kettering Cancer Center, New York, NY; UC San Diego Moores Cancer Center, La Jolla, CA; Royal Melbourne Hospital; Walter and Eliza Hall Institute of Medical Research, Parkville, Australia; Walter and Eliza Hall Institute of Medical Research, Parkville, Australia; AbbVie, Inc, North Chicago, IL; Royal Melbourne Hospital, Melbourne, Australia
Background: Targeting BCL-2 is a promising strategy for treating CLL, including disease refractory to fludarabine (F), or with (del(17p). ABT-199 is a selective BCL-2 inhibitor with >500-fold higher affinity for BCL-2 (Ki< 0.10 nM) than for BCL-XL (Ki = 48 nM). Methods: Objectives of this Ph I dose-escalation study include evaluations of safety, pharmacokinetics and preliminary efficacy of ABT-199 in patients (pts) with R/R CLL. A single oral dose was given followed by 6 days off drug, before continuous once daily dosing. After cohort 1, the initial dose was reduced and daily dosing modified to include a 2 or 3 step dose-escalation to the target dose for each cohort. Results: As of January 11, 2013, 56 pts have been enrolled; median age 67 y (range 36-86); 41 males; median 3.5 prior therapies (range 1-10). 16 (29%) had del(17p) and 18 (32%) F-refractory CLL. Median follow up is 6.3 months (range 0.03-16.5); 7 pts have been on study for more than 1 yr. 13 pts discontinued; 7 due to PD, 6 for other reasons: tumor lysis syndrome (TLS; 2), other illness (2), thromboembolic event (1), consent withdrawal (1). The most common non-hematological AEs (>15% pts) were nausea (36%), diarrhea (30%), fatigue (25%), upper respiratory tract infection (23%), and cough (16%). Grade 3/4 AEs occurring in > 5 pts were neutropenia 21(38%), thrombocytopenia 6 (11%) and TLS 5 (9%). TLS occurred in 3/3 pts in cohort 1 and 2/53 pts with the modified stepped dosing schedule (DLTs). Additionally, 1 fatal AE occurred within 48 hrs of dose- escalation to 1200 mg in a pt with laboratory evidence of TLS (DLT). 46 of 54 pts (85%) evaluable for efficacy achieved a response to ABT-199; 7 (13%) a CR or CR with incomplete count recovery and 39 (72%) a PR (30 confirmed by consecutive scans). 14/16 (88%) and 12/16 (75%) of pts with del(17p) and F-refractory CLL, respectively, achieved at least a PR. Conclusions: ABT-199 is highly active achieving a 85% overall response rate in R/R CLL, independent of high risk markers such as del(17p) and F-refractory disease. Additional dosing and scheduling modifications are currently being explored to minimize the risk of TLS. Clinical trial information: NCT01328626. 

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ASCO 2013: Press Release and Abstract about Idelalisib (CAL-101 or GS1101) in Treatment Naive CLL Patients

This is why I go to ASCO and ASH and hope to get to Europe for IWCLL. To get the inside scoop on these studies. To talk to the investigators about the data between the lines in their abstracts.

And to hear the good news.

I can't wait to push the presenters to get more of the details, but the overview in the press release is certainly impressive. 

All nine patients with 17p del or mutated P53 responded and three had a CR (complete response).

93% progression-free survival at two years. And I love the fast disappearing B symptoms.  Us patients just seem to feel so much better very quickly on most of these new small molecules.

Now admittedly this is an easy group to treat, all treatment-naive so the number should be good.

The 17% with significant pneumonia is more worrisome to me than the 1 in 4 with elevated liver enzymes. That usually resolves with stopping meds, and one can usually restart at a lower level without recurrent liver issues, but pneumonia can be fatal in CLL.

What I want is more information on those not still on the trial?

Why did the 17 of 64 drop out? What was the cause of the death in the three brave patients?

Why does the abstract say 18 drop outs and four deaths?  I have pasted it at the end

Why are the CR levels so low with this and with ibrutinib? FCR has better numbers, admittedly at a much higher cost.

Does  it really matter that a low level of disease is hanging around? Maybe not? Only time will tell.

Still I am glad to see such strong results with another very active tyrosine kinase inhibitor.

The more potent yet gentle treatment options the better.

The future is looking brighter and brighter for those of us with CLL.

Remember this is a press release from the maker of the drug, so please take a critical look at  what Gilead had to say about their promising new agent and send me your comments on what you like and what  gives you pause:

Gilead Announces Response Data from Phase 2 Study of Idelalisib for Previously Untreated Chronic Lymphocytic Leukemia

-- Regimen Achieves 97 Percent Overall Response Rate with Estimated Progression-Free Survival at 24 Months of 93 Percent --
-- Results from Study 101-08 and Other Idelalisib Clinical Studies to Be Presented at American Society of Clinical Oncology Annual Meeting --

FOSTER CITY, Calif.--(BUSINESS WIRE)--May. 15, 2013-- Gilead Sciences, Inc. (Nasdaq: GILD) today announced results from a Phase 2 study (Study 101-08) evaluating idelalisib (formerly GS-1101), an investigational, targeted, oral inhibitor of PI3K delta, in combination with rituximab for older patients with treatment-naïve chronic lymphocytic leukemia (CLL). This regimen achieved a complete response (CR) rate of 19 percent and an overall response rate (ORR) of 97 percent, with estimated progression-free survival (PFS) at 24 months of 93 percent. Detailed results will be presented during an oral session at the 2013 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago (Abstract #7005).

CLL is a slow-growing cancer that induces the production of too many mature white blood cells. It is the second most common type of leukemia in the United States and can lead to life-threatening complications, including serious infection. Currently, patients with CLL are usually treated first with rituximab in combination with one or more chemotherapy agents.

“New therapies that can drive CLL into remission while potentially avoiding or delaying the need for chemotherapy would represent a much needed clinical advance,” said Susan M. O’Brien, MD, Ashbel Smith Professor of Medicine in the Department of Leukemia at the University of Texas MD Anderson Cancer Center in Houston and a principal investigator of the study. “The high overall response rate and durable disease control observed in this Phase 2 study suggest that idelalisib in combination with rituximab could become an important therapeutic option for CLL patients new to treatment.”

Among the 64 patients in the study, Kaplan-Meier estimated PFS at 24 months was 93 percent. The median time on treatment was 14 months, with 33 patients remaining on treatment. The median time to response was two months. No relapses on study have been reported. The nine patients with chromosome 17p deletion (del 17p) (n=6) or mutation in the TP53 gene (n=3), which have been linked to poor prognosis, all responded to therapy including three with a complete response. Ninety-four percent of patients with thrombocytopenia at baseline responded to treatment (16/17), as did all patients with anemia at baseline (17/17). Of patients with systemic symptoms such as extreme fatigue, fever, night sweats or weight loss (known as “B symptoms”) at baseline, 77 percent (20/26) were asymptomatic by eight weeks.

Patients completing 48 weeks of therapy without progression could continue to receive idelalisib in an extension study. Forty-three patients completed 48 weeks of treatment (21 discontinued – 17 due to adverse events, three due to death and one due to other reasons); 40 patients entered the extension study and 33 remain on treatment.

During the primary and extension study, Grade 3 diarrhea and/or colitis was reported in 33 percent of patients, Grade ≥3 pneumonia in 17 percent and Grade ≥3 transaminase elevations (measure of liver function) in 23 percent of patients.

“These results demonstrate for the first time idelalisib’s potential benefit for patients with a previously untreated hematological malignancy,” said Roy D. Baynes, MD, PhD, Senior Vice President of Oncology and Inflammation Therapeutics at Gilead Sciences. “Based on these promising data, we are now evaluating Phase 3 study designs for idelalisib as part of a frontline treatment regimen for CLL patients.”

Idelalisib’s clinical and safety profile for a number of blood cancers will be characterized in six additional oral or poster presentations at ASCO 2013:

Chronic Lymphocytic Leukemia (CLL)
Final results of a Phase 1 study of idelalisib in patients with relapsed or refractory CLL (Abstract #7003; oral session).
Update on a Phase 1 study of idelalisib in combination with rituximab and/or bendamustine in patients with relapsed or refractory CLL (Abstract #7017; poster session).

Indolent Non-Hodgkin’s Lymphoma (iNHL)
Combinations of the PI3K delta inhibitor idelalisib with rituximab and/or bendamustine are tolerable and highly active in patients with previously treated, indolent non-Hodgkin lymphoma: Updated results from a Phase 1 study (Abstract #8500; oral session).
Final results of a Phase 1 study of idelalisib, a selective inhibitor of PI3K delta, in patients with relapsed or refractory indolent non-Hodgkin lymphoma (Abstract #8526; poster session).

Mantle Cell Lymphoma (MCL)
Final results of a Phase 1 study of idelalisib, a selective inhibitor of PI3K delta in patients with relapsed or refractory mantle cell lymphoma (Abstract #8519; clinical science symposium).
Preliminary results of PI3K delta inhibitor idelalisib treatment in combination with everolimus, bortezomib, or bendamustine/rituximab in patients with previously treated mantle cell lymphoma (Abstract #8501; oral session).

About Study 101-08
Study 101-08 is an open-label, single-arm Phase 2 trial that enrolled 64 treatment- naïve patients ≥65 years old with CLL or small lymphocytic lymphoma (SLL), a less common form of the disease. Patients received intravenous rituximab 375 mg/m2 weekly for eight weeks and oral idelalisib 150 mg twice daily for 48 weeks. The primary endpoint of the study is overall response rate, defined as the proportion of patients achieving a complete or partial response with this regimen (response definitions based on standard criteria). Patients completing 48 weeks of therapy without progression could continue to receive idelalisib in an extension study.

About Idelalisib
Idelalisib is an investigational, targeted, highly selective oral inhibitor of phosphoinositide 3-kinase (PI3K) delta, a molecular target that is critical for the activation, proliferation and survival of B lymphocytes. PI3K delta signaling is hyperactive in many B-cell leukemias and lymphomas and drives proliferation, survival and trafficking to lymphoid tissue. Idelalisib is being developed both as a single agent and in combination with approved and investigational therapies.
Gilead’s clinical development program for idelalisib includes three Phase 3 studies evaluating the drug in combination with approved therapies for patients with previously treated CLL, and two Phase 3 studies of idelalisib in combination with approved therapies for patients with previously treated indolent non-Hodgkin’s lymphoma (iNHL). In addition, combination therapy with idelalisib and GS-9973, Gilead’s novel spleen tyrosine kinase (Syk) inhibitor, is being studied in a Phase 2 trial of patients with relapsed or refractory CLL, iNHL and other lymphoid and hematological malignancies.
Additional information about clinical studies of idelalisib and Gilead’s other investigational cancer agents can be found at www.clinicaltrials.gov. Idelalisib and GS- 9973 are investigational products and their safety and efficacy have not yet been established.

About Gilead Sciences
Gilead Sciences is a biopharmaceutical company that discovers, develops and commercializes innovative therapeutics in areas of unmet medical need. The company’s mission is to advance the care of patients suffering from life-threatening diseases worldwide. Headquartered in Foster City, California, Gilead has operations in North America, Europe and Asia Pacific. 

Abstract # 7005

Background: PI3K-delta is critical for activation, proliferation and survival of B cells and plays a role in homing and retention in lymphoid tissues. PI3Kδ signaling is hyperactive in many B-cell malignancies. Idelalisib is a first-in-class, selective oral inhibitor of PI3Kδ. When combined with R in 19 relapsed/refractory patients with CLL, the ORR was 78% (Coutre, ASH 2012). Methods: Treatment-naive pts ≥65 yrs with CLL or SLL were treated with R 375 mg/m² weekly x 8 and idelalisib 150 mg bid continuously for 48 weeks (primary study). Pts completing 48 wks w/o progression could continue to receive idelalisib on an extension study. Responses and progression were based on investigator assessment using IWCLL criteria (Hallek, Blood 2008). Results: Data is presented here on the first 50 of 64 pts enrolled, 48 CLL/2 SLL, median age 71 yrs (range: 65-89), M/F 70/30 (%), Rai stage III/IV 10/32 (%), nodes ≥5 cm in 16%, WHO 0/1/2 in 34/64/2 (%); del(17p) in 6 pts and del(11q) in 13 pts. 32 pts completed 48 wks (18 discontinued, 11 due to AE, 4 due to death and 3 other); 30 pts entered the extension study and 26 remain on treatment. The median time on treatment was 16 months (range 0.8-27.5). The ORR was 96% with 4% nonevaluable; median time to response was 1.9 mos (range 1.0-6.5). There have been no on-study relapses. The Kaplan-Meier estimated PFS is 91% at 24 mos. Of note, 6/6 pts with del(17p) responded (1 CR, 5 PR) and 3 remain on treatment for more than 21 months. 13/14 (93%) pts with thrombocytopenia and 12/12 (100%) pts with anemia at baseline responded. Of 20 pts with B symptoms at baseline, 13 (65%) were asymptomatic by 8 wks. Most frequent AEs (total%/ ≥G3%) were diarrhea (including reported as colitis) (46/16), pyrexia (42/4), chills (34/0), fatigue (34/2), rash (34/10), pneumonia (30/20) and nausea (28/0). Elevated ALT/AST was seen in 60%, Gr ≥3 in 22%. Conclusions:Idelalisib + R is highly active, resulting in durable disease control in treatment-naïve older pts with CLL. These results support the further development of idelalisib in frontline CLL. Clinical trial information: NCT01203930.

ASH 2012: Dr. David P Steensma: Myelodysplastic Syndrome with a Focus on Secondary MDS in CLL

Dr. David Steensma is a world leader in not only basic laboratory and clinical research on MDS, but also in examining the impact that anemia has on the life of older patients.

MDS or myelodysplastic syndrome is bone marrow failure and in a minority cases, turns into an acute leukemia.

It is not an uncommon complication of CLL, both, as Dr. Steensma explains, secondary to the genetic and epigenetic changes inherent in the disease itself, and to the treatments, especially the alkylating agents that damage the DNA. In CLL, these included chlorambucil (Leukeran), cyclophosphamide (Cytoxan or the C in FCR), and bendamustine (Treanda).

This is a strong argument for younger patients to avoid those drugs known to damage the bone marrow, but Dr. Steensma offers some more subtle analysis and advice.

We also discuss the radiation risk of MDS from all those CT scans we get in clinical trials.

A good friend of mine is now more than two years out post transplant at MDACC for his CLL/MDS combo one-two knockout punch and he is doing great with no molecular evidence of either disease (MRD negative). And very little graft versus disease.  You can read his story at this link.

This is my last video interview from ASH 2012, but ASCO is just around the corner with more news and interviews.

Dr. Steensma clarifies and explains the risk of MDS in simple terms.

Einstein is quoted as saying: "Make things as simple as possible, but not simpler."

Dr. Steensma does exactly that.

Personal Travels

With ASCO (AmericanSociety of Clinical Oncology) and EHA (European Hematology Association) upcoming, a significant backlog of abstracts to review, promised synopsis of critical issues, important editorials, and still some videos from ASH, I am going to grab this moment at the airport in Orlando to update my crazy spring.

First the biggest most important news:

My oldest daughter gave birth this weekend to our second beautiful granddaughter. Mother and baby are doing great (if you don't consider the sleep deprivation), and I am flying to Alameda to meet the newest member of our happy growing family. I can’t wait to hold her and smell her and kiss her.

Sydney Lilah

It is being alive for moments such as this that remind me why I fought so hard to travel across the country a year ago leaving the California sunshine for an Ohio winter, uprooting my wife and myself for months, and risking a new unproven therapy to knock back my CLL and ITP. But my calculated gamble has been an unmitigated success, offering me chances to see so much more than I could have dreamed possible. And no sight will be sweeter than my new grandchild.

Now that baby has safely arrived after a very quick and natural labor and delivery, my schedule is a little more solid.

This frantic spurt of travel started at the end of April with my trip to Columbus, Ohio for my treatment. I stayed a few extra days due to scheduled CT scans, an opportunity to tour of the new hospital and Dr. Byrd’s wonderful lab (the highlight was meeting the bright and enthusiastic PHDs, MDs, and other lab staff), meals with Dr. Byrd and other friends, new and old, and an amazing Mark Rothko exhibit at the Columbus art museum.

Rothko

When back home, I had time to catch a hockey game (Go Kings Go) where the Kings beat St Louis in the Stanley Cup playoffs, before driving up to the Bay area to help my then expectant daughter and son-in-law with the toddler. That didn’t stop me from flying to Vancouver, Canada for a few wonderful days of a west coast all boys high school reunion (UTS or University of Toronto Schools) that included kayaking in Deep Cove, a gondola ride to the snow and the grizzly bears at the top of Grouse Mountain, and poignant memories.

Deep Cove, British Columbia

Now I am writing this post from a plane leaving Orlando where I attended a two day primary care medical conference.

Once back in the bay area, I will be driving back to Orange County for a day or two, then onto San Diego for one day for more learning.

Before the next week is over, and after spending time at the office, getting trained on a new EHR (electronic health record) module, and visiting the infusion lab for my life saving IVIG and a routine check-up with my local CLL doc, Dr. Sharma, I will be leaving for five nights in Chicago to cover ASCO with Andrew Schorr and Patient Power. So far Drs. Byrd and Wierda are aboard for interviews and several other familiar faces are very likely. I will also be interviewing experts on other hematological malignancies and on some solid tumors for Patient Power.

Only two days after ASCO, things get real crazy. I will be driving up to Santa Clara to lecture with Dr. Steven Coutre out of Stanford on anemia and MDS (myelodysplastic syndrome), a too common complication of CLL and its treatment. From there, just hours after I finish, I drive to SFO to fly to Stockholm for only three days to share my experience with ibrutinib from a patient’s perspective just before the EHA meeting (European Hematology Association), then rush back to the bay area the day before I leave for Chicago to see my younger daughter, just back from her delayed honeymoon in Spain and Morocco.

After another brief visit with my daughter, son-in-law and the grandkids in Alameda, the drive to SoCal gets me home in time for more doctors’ visits, clinic hours, a local CLL support group, seeing my son Ben off to Stonehenge for the summer solstice with the Druids, all followed by a two days car trip to La Jolla for more medical education conference, this time on heart failure organized by UCSD.

A week earlier, my son, Will is flying to Israel for 10 days, and I hope to arrange a meeting up with my bone marrow donor.

The next weekend I am in Baltimore for more med. ed., and the extra bonus of catching the Max Weber exhibit at the Baltimore Museum of Art.

This is the last year of my CME cycles in Canada and the USA, and I must squeeze in a lot of hours to meet my requirements. Now I have to overload my credits to catch up before the end of June. Poor planning and other priorities lead to this crisscrossing of the country.

July 3, I have been ask to lead a CLL support group for UCSD on their campus in San Diego.

In between, I have scheduling and planning teleconferences and the Stanley Cup Playoffs.

No more travel is scheduled for July until I need to be back in Columbus, Ohio again in the third week, and I am so looking forward to not leaving home for a few weeks.

This frenetic pace is not sustainable or healthy. I nap often at the hotels and on the planes. I wear an N95 mask and gobs of hand sanitizer. I treat myself to the best vegan meals I can find on the road ( which is not saying much) and I always try to see more of the town that I am visiting than the hotel lobby. In Orlando, I hiked though a lush swamp with catfish and egrets and Spanish moss that was just minutes from the silly shopping malls and alligator miniature golf courses near my hotel. No amusement parks for this traveler.

Shingle Trail, Orlando

Then I took a long nap.

I bring my comfort foods (organic raw nuts and fine Japanese green tea), meet old friends, do work that I love, and have a rare opportunity to make a small but meaningful difference in the world.

This schedule was an extraordinary confluence of opportunities and my inability to say no to spread the word about how cancer treatment is changing. I admit there is desperation to all this journeying, but I know my time is limited and I want every moment to matter.

If I was more at peace, perhaps I could sense the gravity and power found in standing still, like a mountain, like a master, but I am still a breezy soul.

Ibrutinib Research from Dr. Wiestner at the NIH

Below is the press release (PR) from the recent meeting in Washington, DC of the AACR (American Assoc. of Cancer Research) concerning the research by Dr. Wiestner's group at the NIH.

There are a number of things to keep in mind when reading the PR.

First that 29 of 53 patients were 17p del and 30 were relapsed or refractory. These were not the easiest patients to treat.

Second remember this was ibrutinib flying solo. No help from bendamustine or an antibody.

Third this is still early data. We don't know the durability of these fantastic results.

Finally , we learn that the drug is active in all lymphocyte compartments, the blood, the lymph nodes, the spleen, and the marrow.

Please take a look of this data in light of Dr. Wiestner's recent plea that we carefully reassess whether we need to continue with business as usual by insisting more is better and pushing for the "ideal chemo cocktail."

Rather I believe that these new targeted therapies demand that we fully reassess how we treat CLL and we don't just add these molecules to the existing mixes, effective as they are, but  rather we see what they can do on their own, and make slow and logical decisions about what combinations (if any) to consider. 

I like the idea of totally avoiding old school chemo if possible, but only time will tell if that is the wisest approach.

Even mixing two pathway blockers, while mechanistically appealing, is totally unknown territory.

One reason I fear that one reason that chemo or biologicals such as rituximab might get added to these trials (especially true for the very potent and active idelalisib or CAL 101 that where the high counts might linger a bit longer) is that the benign spike seen in the absolute lymphocyte count as the B lymphocyte clone cells exit their protective enclaves in the nodes and marrow and enter the blood stream where they can be counted, may last a long time and makes the early data look weak. Those raised numbers suggest the drug is not working to the uninitiated and it takes works to explain the back story. We all know that is not the case and they are in fact potent therapies, but adding chemo or a mAb solves that short term concern and speeds up the data collection. My questions are: Does it really improve outcome? Does it add unnecessary risk?

Truth is we don't know the answers. That is why we need the trials, but the reported 94% event free survival at 1 year as solo therapy is hard to improve on.

Here is the press release from AACR:

Embargoed for Release:                                                    Media Contact:

1 p.m. ET, April 8, 2013                                                      Jeremy Moore

                                                                                               (215) 446-7109

                                                                                               Jeremy.Moore@aacr.org

                                                                                               In Washington, D.C.
April 6-10, 2013:
(202) 249-4005

Ibrutinib Safe, Effective Against Untreated, Relapsed and Unresponsive Chronic Lymphocytic Leukemia

·      Ibrutinib disrupts the CLL-driving B-cell receptor signaling pathway.

·      Phase II trial showed the drug was well tolerated and effective against CLL regardless of del 17p status.

·      The drug was effective against disease in blood, lymph nodes, spleen and bone marrow.

WASHINGTON, D.C. — The novel drug ibrutinib was well tolerated and highly effective in patients with untreated, relapsed and unresponsive chronic lymphocytic leukemia (CLL), according to phase II data presented at the AACR Annual Meeting 2013, held in Washington, D.C., April 6-10.

“The degree of tumor reduction achieved by once-daily oral therapy was impressive,” said Adrian Wiestner, M.D., Ph.D., investigator and head of the Lymphoid Malignancies Section in the Hematology Branch at the National Heart, Lung, and Blood Institute at the National Institutes of Health (NIH) in Bethesda, Md. “We have seen patients with more than 90 percent reduction of lymph node disease within just two months.” 

Many elderly patients with CLL are unable to tolerate current aggressive standard therapies, and those with a deletion in the short arm of chromosome 17, referred to as “del 17p,” have particularly poor outcomes with chemotherapy. These two CLL patient populations that are enrolled in the NIH phase II study have the greatest need for novel treatment therapies, according to Wiestner.

Ibrutinib is a selective inhibitor of Bruton’s tyrosine kinase, a component of the B-cell receptor signaling pathway that plays a key role in the development and progression of CLL. This study confirms the single-agent antileukemia activity seen in prior phase I/II studies and extends this experience, particularly in del 17p CLL, according to Wiestner.

He and his colleagues enrolled 53 patients with CLL into two cohorts — 29 patients with del 17p and 24 patients without del 17p who were aged 65 years or older. They assigned all patients to 420 mg of ibrutinib daily and evaluated response to the drug at six months and every six months thereafter, until disease progression.

Most adverse events were mild or moderate and included diarrhea, fatigue and rash, severe events occurred in less than 13 percent of the patients.

At six months, 95 percent of patients showed at least a 50 percent reduction in lymph node disease, and all showed reduction in spleen enlargement, with a median reduction of 55 percent. In 26 patients for whom a bone marrow biopsy was done, tumor infiltration decreased by 82 percent. Absolute lymphocyte count decreased by a median of 62 percent. Using standard CLL response criteria, 52 percent of patients had a partial response. At 12 months, the estimated event-free survival rate was 94 percent.

Using blood and tissue samples of lymph nodes collected from 15 patients before and during ibrutinib treatment, Wiestner and his colleagues showed effective inhibition of B-cell receptor signaling and tumor proliferation, which was reduced by more than 80 percent, as measured by Ki67 staining.

“Ibrutinib was highly efficacious as a single agent in patients with untreated, relapsed and unresponsive CLL, irrespective of their del 17p status,” Wiestner said. “Responses appear to be durable, and the drug is effective against the disease in lymph nodes, spleen and bone marrow. This is important because existing therapies often fail to effectively eliminate cancer cells in these tissue sites. Targeted therapy for CLL is becoming a reality, and this new approach will greatly improve the lives of patients with this disease.”

This research was supported by the Intramural Research Program of the National Heart, Lung, and Blood Institute at the NIH.

 

# # #

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About the American Association for Cancer Research

Founded in 1907, the American Association for Cancer Research (AACR) is the world’s first and largest professional organization dedicated to advancing cancer research and its mission to prevent and cure cancer. AACR membership includes more than 34,000 laboratory, translational and clinical researchers; population scientists; other health care professionals; and cancer advocates residing in more than 90 countries. The AACR marshals the full spectrum of expertise of the cancer community to accelerate progress in the prevention, biology, diagnosis and treatment of cancer by annually convening more than 20 conferences and educational workshops, the largest of which is the AACR Annual Meeting with more than 17,000 attendees. In addition, the AACR publishes eight peer-reviewed scientific journals and a magazine for cancer survivors, patients and their caregivers. The AACR funds meritorious research directly as well as in cooperation with numerous cancer organizations. As the scientific partner of Stand Up To Cancer, the AACR provides expert peer review, grants administration and scientific oversight of team science and individual grants in cancer research that have the potential for near-term patient benefit. The AACR actively communicates with legislators and policymakers about the value of cancer research and related biomedical science in saving lives from cancer. For more information about the AACR, visit www.AACR.org. 

On a personal note, I am just back from a wonderful, meaningful high school reunion held in Vancouver, BC  though we all went to an all boys school in Toronto (UTS) three thousand miles away. I am hoping to do one of my personal reflective posts soon, but  because of the important breaking news and backlog of interviews, I have been weak on telling my CLL and life story that is happily boringly stable these days. 

Later this week I will be lecturing in Orlando, Florida. 

No rest.