Sunday, October 19, 2014

ASCO 2014: Dr. Kipps on ABT-199 and more on CLL (chronic lymphocytic leukemia): "Cancer is not an alien from outer space, cancer is us"


More mural work from my son, Ben Koffman

In this final segment of my three part interview from ASCO 2014, my doctor, Dr. Kipps out of the Moore Cancer Center at UCSD, explains as only he can about the competing roles of Bcl-2 and BIM in our malignant B cell clone and how ABT-199 resets that balance in our favor in our malignant B cells.

Here are links to part one and part two of the same interview. They will help set up and give perspective on this longer final segment.

Before you turn off when you hear mention of yet another B cell pathway, please listen to his helpful buttress explanation that explains why this therapy, especially in combinations with other agents, promises a possible cure with no cytotoxic chemotherapy with little collateral damage.

This specific cell death mechanism is particularly active in our malignant B cells. Accordingly, it makes sense as an even more potent target than is blocking B cell communication though the the B-cell receptor (BCR). Blocking BCR activity is likely a major mechanism for the outstanding success of the two newly approved targeted oral agents, idelalisib and ibrutinib. ABT-199 works differently. It works directly on the cell's life and death pathway.

As those who have read my prior post know too well, ABT-199's very potency is its weakness too. It can kill the cancer so fast there is a risk that the kidneys can't keep up with the flood of intracellular toxins spilling out of the millions and millions of lysed (broken down) cancer cells. Tragically, at least two deaths have occurred from this tumor lysis syndrome (TLS), and as a result the whole ABT-199 trial strategy was stopped and than revamped, but it's now back and better.

In other posts, I discussed one tragic death that happened in the trial and argue strongly then that its development be continued and I am so glad that has happened.

But when ABT-199 gets out of trials and into the larger community, I worry that TLS may start to reoccur if the education of the community doctors and their patients is not strong enough.

That, my friends, is one of my major goals here and elsewhere: to inform my fellow patients and providers of the changing landscape in managing CLL so we can make smart decisions and get the care we need.

But ABT-199 has gotten some patients to MRD negative status and even allowed durable disease control long after the med is stopped. That is very exciting and appears to be significantly different from the usual results seen with idelalisib and ibrutinib.

In the past I have argued of reducing the tumor burden with Imbruvica or Zydelig, perhaps with a mAB (monoclonal antibody) such as obinituzumab or rituximab, and then cleaning up any residual disease with ABT-199.

I am happy to say that is now a research direction that is being actively pursued.

It's too early to predict how ABT-199 will fit in the mix, but I predict it will play an important role in the future. The bar already has been set high with the robust responses already seen with the first two approved TKIs. It is not unreasonable to dream that the significant extra kick from ABT-199 or one of the new agents could push us to cure.

So  happy to see more research. We must keep pushing for more evolved therapies that offer cure, not just disease control. (Not that I am complaining about the recent advances that have positively changed my life and that of of so many other CLL patients.)

Later I will comment on the recently announced combination of the PD-1 immune checkpoint inhibitor nivolumab (Opdivo) and the oral BTK inhibitor ibrutinib (Imbruvica) in a phase I/II trial for patients with non-Hodgkin lymphoma (NHL). This is another promising and bold path that has me pretty excited.

But before, we move on, Dr. Kipps has more news for us patients from ASCO 2014.

In the last few minutes of the interview, Dr. Kipps takes a step back and forces us to consider a different perspective on the nature of cancer in general and CLL in particular. He reminds us of cancer's primitive embryonic nature and how ROR1, an embryonic antigen, might be a major player not just in CLL but in other metastatic cancers such as prostrate or ovary too. Thinking about cancer and CLL in this way opens us the possibility for new avenues of research and therapy. The anti-ROR1 mAB is a step in that direction.

When I saw, Dr. Michael Keating from MDACC at the AACR hematology meeting last month in Philadelphia,  he told me he is betting on ROR1 as the path to cure.

When Drs. Kipps and Keating agree, it is worth listening. And considering a ROR1 trial.

Please enjoy my interview with Dr. Kipps.



More soon. (By the way, my ASCO 2014 goatee is long gone.)

This is my crazy season of traveling and teaching, so please forgive my tardiness in posting.

I will be at the LRF conference this Saturday, Oct. 25, 2014 in Manhattan Beach, so please join me and say hello. If you have never attended a LRF conference, they are worthwhile on so many ways. Do come and learn and meet fellow patients.

We are all in this together.

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Saturday, September 27, 2014

ASCO 2014: Dr. Furman Gives us Perspective on Resistance with Ibrutinib in CLL (chronic lymphocytic leukemia)


More of My Son, Ben's Mural Work

ASCO 2014 was only a few months ago, but happily the CLL world is a fast moving place.

Since this video interview with Dr. Rick Furman of Weill Cornell, recorded and edited by Andrew Schorr and his team at Patient Power, idelasilib has been approved for CLL (see this post for discussion of its labeled indication) as predicted by Dr. Furman, and ibrutinib was approved for frontline therapy in 17p deleted patients (see this post).

YEAH to both!

Also in the intervening months, new mathematical models that consider evolution of resistant sub clones have been published by Dr. Burger out of MDACC and a high powered mathematical team headed by Dr. Natalia Komorova out of UCI. (I plan to interview Dr. Komorova as we are practically neighbors in Orange County, CA). Similar research, but this time using deep genetic analysis of the cancer's evolution over time by Dr. Cathy Wu from Dana Farber was presented at AACR 2014 Hematologic Malignancies Conference last week. (I also plan to post on her important research soon.)

The issue of ibrutinib resistance may be becoming an increasingly important issue. More and more of us are doing great with our BTK inhibited, but we still have residual disease and if you are similar to me with bad markers such as clonal diversity, 17p deletion, 11q deletion, and have a history of having been heavily pretreated (I have the first three for sure and many would say the 4th with my bone marrow transplant), then the fear of a resistant sub clone starting to act out, while still not the case for most of us even with the worst of the worst disease, is based on a growing reality of a droopy Kaplan-Meier (KM) Curve. Below are KM plots from OSU published in NATURE at the start of the year that show the downward drift in progression free and overall survival for those of us that are 17p deleted. As you can see the curves are way better than anything else out there, but they are hardly perfect.


This whole resistance issue might be largely obviated in the future by moving the new therapies up to frontline status. Dr. Furman and I both agree that is the direction we need to encourage with appropriate trials and struggles with insurers to pay for these drugs in all treatment naive patients.

Dr. Furman also mentions two exciting new BTK inhibitors, ACP-196 and ONO-4059. Click on the drugs' names to be linked to their phase 1 trials. We are just in the first chapters, but it is looking that the stories they will tell should have very happy endings. Please consider trials that offer these drugs among your treatment options.

Here is my ASCO 2014 interview with Dr. Rick Furman.



As there is a small but significant cohort of FCR patients that do great for years and years, there is a much much larger cohort of patients taking ibrutinib and other small molecules, now based on more than on more than four years of data, that should continue to do well year after year.

I am so happy for all these patients.

But I worry about the minority who won't do well, who will relapse. I am not giving up on my plea: Don't leave us stranded on 3rd base- Get us to the home plate of a cure with a follow up therapy.

We discuss obinutuzumab and ABT-199 as mop up therapies and I think those are smart choices. Maybe it will be cirmtuzumab, a new ROR1 mAB discussed in my recent post with Dr. Kipps from the very same meeting. We will only find out with clinical trials.

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Thursday, September 25, 2014

It's Been Nine Years Since my Diagnosis of CLL (Chronic Lymphocytic Leukemia)


Me (today, the 1st day of the Jewish NewYear 5775 or Sept 25, 2014)

It's been nine years since my diagnosis of CLL and am so happy to be alive and arguably in better health that I was when I received the life changing news in September of 2005.

When I was first told I had an aggressive version of an incurable cancer, I know little about CLL and what I quickly learned was discouraging.

Nothing back in 2005 had yet been shown to add a day to our lives. And the last few years alive with our disease were predicted to be full of misery.

Ibrutinib and idelalisib were just been being born in chemist's vials and were years away from first in human experiments.

I made appointment with our family lawyer to get my affairs in order almost sooner than I started my long term relationship with the wise and kind Dr. Tom Kipps.

I became a raw foodie but couldn't handle it and moved a bit closer to the center to become just a strict and mostly organic vegan. I cut back on my crazy workload and started to work out at the gym with weights for the first time in my life. I worry less and celebrate more.

I got no help with imbibing horrible tasting Chinese herbs that I brewed up myself or from a year of acupuncture. Nothing came of many other well intentioned but ultimately impotent alternative healing approaches, but I sure tried.

The cancer and its complications marched on.

Multiple hospitalizations for life threatening ITP, an emergency splenectomy where I lost half my blood, a failed clinical trial and bone marrow transplant, a move to Columbus, Ohio for the winter 2 and 1/2 years ago to get on an ibrutinib trial at OSU, and here I am, feeling better than ever.

I seen thousands of miles of travel in six continents, two daughters get married, my father's passing, and the birth of my first two granddaughters.

I have learned much from my mistakes and my fortunate choices, and I love to share what my experience, asking a lot of hard questions of the experts, and a ton of late night reading has taught me about surviving.

My hair is grey, my belly's flatter and I sure have learned a lot of hematology for a family doctor.

But best of all, I have met some of the most amazing people ever from all over the world, not despite, but directly because of my cancer.

My battle is hardly over, but I am still out there swinging.

Life is good.

Stay strong my friends. We are all in this together.

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Wednesday, September 24, 2014

ASCO 2014: Dr. Kipps Discusses ROR1 and Information about a New ROR1 Monoclonal Antibody (cirmtuzumab) Trial in Relapsed and Refractory CLL (chronic lymphocytic leukemia)


Mural Detail by my son Benjamin Koffman

I am just back from a very exciting AACR (American Association for Cancer Research) Hematologic Malignancies Conference that was focused on pre-clinical research pointing the way to better therapies in the future for CLL and all blood cancers.


I will be sharing some of the most promising and clinically relevant research from that meeting in Philadelphia over the next several weeks, but first I wanted to post this timely video from ASCO earlier this year with Dr. Tom Kipps out of UCSD as there is now a chance to see how a new promising therapy using cirmtuzumab, an antibody directed at RORI will work in the real world, converting years and years of research into the first in human clinical trial.

If you haven't seen the lead up to our discussion on this brand new and very specific mAb (monoclonal antibody) targeting ROR1, then please revisit this prior post to catch the first part of our interview done in collaboration with my friend Andrew Schorr and his Patient Power team.

Remember that Dr. Kipps is a cutting edge researcher in the field of immunology and this is an immune  therapy. At the AACR meeting in Philadelphia, when I asked the father of FCR, Dr. Michael Keating out of MDACC how I might cure my own CLL, he quickly said ROR1 therapy (both MDACC and UCSD are working on CAR-T directed at ROR1- See this post with Dr. Wierda from back at ASH 2012). For many blood and cancers in general, the path to a cure means inviting an immune therapy onto the team and ROR1 is a very promising and specific target in CLL.

For more background on ROR1 by Dr. Kipps, see this, also from ASH 2012. It's a ton of long and hard bench science to bring these therapies to the bedside. Dr. Kipps has been excited about this for years and it is finally coming to fruition.

I will let Dr. Kipps tell the update of the story.



I love his push for a cure and I love his pneumonia analogy.

Now the trial for relapsed and refractory CLL patients opened recently, not too much later than the hoped for June start date mentioned at ASCO and this new ROR1 antibody, cirmtuzumab is already being used. A few patients have begun the experimental therapy, and though it is way too early to know much of value, so far so good.

Here's the link at clinical trials.gov and here is a news article on the trial.

What I like about this trial that it is an immune therapy with the promise of very little off target damage. I also like that it is so time limited- you get the 4 infusions over 8 weeks are you are done.

The downside risk. This is a Phase 1 first in human trial. Nuff said!

The dose escalation is also a potential turn off in Phase 1 trials as they are always about safety first. The hope is to find the highest dose that is not toxic called the dose limiting toxicity or DTL.

We know from our experience with the tragedies with too rapid a dose escalation with ABT-199 resulting in fatal tumor lysis syndrome (TLS) that slow and easy is the only way to go. Please see this and this and sadly this if you are not familiar with this tragic and instructive story.

The negative consequence of this emphasis on safety is the risk that those in the first few cohort may get too low or a sub-therapeutic dose.

That's why I like that this trial design. I quote from the trial site: "There is intra-patient dose escalation in the first 3 cohorts, followed by the standard 3+3 design for the next 5 cohorts."

What that means is those in the first three groups get a low dose and if they experience no problems a higher and higher dose. After that the dose is fixed for each three patient cohort.

The whole topic of Phase 1 trial design to minimize risk and maximize benefit is complicated and I am no expert, so I welcome comments from those more savvy. This is a link to a nice review article that will help if you want to dig a bit deeper.

Safety comes first and only then is drug efficacy studied more formally in later trials, but that doesn't mean there can be no measurable benefits from this kind of trial. My ibrutinib trial is sort of a phase 1 trial (1b/2) and I see no reason not to expect that this study with reveal positive results and that cirmtuzumab will eventually become an important new weapon in our arsenal to fight CLL.

For relapsed and refractory patients, admission criteria are pretty standard and there is no mention of prior transplant excluding admission to the trial.


ROR1 has been a long long time in coming.

Is it the future? It looks promising and safe in the lab and animal models, but only the clinical trials will tell us for sure.

As I have said before, the science only advances when one of patients facing a tough therapeutic decision decides that joining a clinical trial makes more sense for a host of potential reasons than standard of care. I did and it turned out to be a good bet.

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Monday, September 15, 2014

Personal Good News on the CLL (chronic lymphocytic leukemia) Front at OSU


Selfie with Roy Lichtenstein's wonderful sculpture at the Columbus Ohio Airport 

Perfect weather in Columbus, Ohio and a lovely walk in the woods with OSU friends the day before my OSU clinic morning with Dr. Byrd.

The Columbus airport is in the throes of construction so they have moved the marvelous structure by Ohio State University alumni, Roy Lichtenstein to a more accessible site where I could snuggle up to his flying brush strokes.

At the James Cancer Hospital, my vital signs were all good with my usual healthy low end of normal blood pressure, no fever, slow pulse, and stable weight.

Physical exam revealed no surprises (no enlarged nodes or  organs), and my lab was rock steady. Red blood cells were just the tiniest bit low, platelets were stable in the high 300's, neutrophils were good and my absolute lymphocyte count was 1.2.

My immunoglobulins are still very low except for "my" IGG level. The "my" is in quotations as the source of my normal IGG on the blood test is from many other generous souls whose blood donations were pooled to produce my every seven weeks infusion of IVIG that boost only that one antibody. As of today, there is no known way to raise my poor IGA and IGM levels.

Blood chemistries were all perfect with my happy healthy liver and renal function tests, electrolytes, and blood sugar. Clean living has its rewards. And ibrutinib is less likely to inflame the liver compared to many other cancer therapies.

Everything tested really hasn't changed much in over a year. Rock steady. I like it.

My only complaint is that appointment was at 9 AM and it's 12:30 now and I am still waiting for my magic grey pills (PCI-32765 AKA ibrutinib) to be dispensed so that I can skedaddle. I was hoping to catch a 12:30 flight out, but that is sure not going to happen. There's another flight in a 90 minutes, but it is fully booked. Miss that I will be sitting at the airport for several hours.

Tomorrow, due to a quirk of scheduling, I do it all over again in San Diego at UCSD with Dr. Kipps.

It's all OK, especially when the news is so good.

PS: I  did nab the very last space on an earlier flight (that left late of course) to Chicago from Columbus, then had to race from one side of the airport to the other at O'Hare to snag my standby seat to LAX just as they were announcing the flight was closed, waited forever for the shuttle to my offsite cheaper parking, discovered too late that the 405 freeway home was stopped dead due to a car fire, so I snuck off going around a barrier as I missed the last possible off ramp, and finally made it home  using surface streets for a great vegan dinner and a short refreshing swim. Now time to sleep. Traveling is not for wimps, but life is good.

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Wednesday, September 10, 2014

Dr. Byrd: "We are at an incredibly exciting time for patients and their families with CLL (chronic lymphocytic leukemia)" Let's all bake a cake of cure.


Cake of Cure

OK team, we have taken the first giant step in this moon shot. We've safely landed in a new world of disease control with no chemo. Now get us home.

The real work is just beginning.

We need potent combos of these new wonder drugs to help us stay in the land of remission forever, get off the daily meds, and maybe, just maybe find our decades from now that we have been cured.

We need more trials, trials that use NO chemotherapy. Trials that use drugs from different pharmaceutical companies. Abbvie links with Infinity Pharmacyclics is already working with TG Therapeutics in a clinical trial.We need more of these alliances that break down commercial barriers for the benefit of the patients.

We need brave patients to volunteer. While all of this sound so positive, let's not forget that when Gilead ran a sensible and necessary trial combining its Syk inhibitor, GS-9973 and its better known PI3k inhibitor, idelalisib or Zydelig (click here for the abstract), they concluded: "Despite promising activity in CLL, the combination of GS-9973 and Idelalisib resulted in an unexpectedly high rate of pneumonitis and resulted in stopping dosing of the combination These data need to be considered when designing future investigations combining inhibitors of B cell receptor signaling."

So we can't take anything for granted. These trials need to be carefully designed and monitored. But they are our best path to a cure.

It demands patients and providers and industry and the FDA all fighting together to "bake a cake of cure" for  CLL.

I like it.

Please enjoy this upbeat and realistic one minute video of my doctor, Dr. John Byrd out of OSU.



More soon on ROR1 including an exciting new trial,  and also on challenging paper on new mathematical modeling of ibrutinib resistance.

Good times indeed. Let's have our cake (vegan of course) and eat it.

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Saturday, September 6, 2014

Want to avoid chemotherapy or taking an expensive medication foreverfor your CLL (chronic lymphocytic leukemia)? I may have a clinicaltrial for you.


METHYLPREDNISOLONE

I and many others have railed against chemotherapy for our CLL. It may give us a long remission, or not.  Your mileage will vary and those of us with anything but the best prognostics can be pretty sure that we will relapse too soon for our liking with a nastier clone. FCR may even cure a few very select low risk patients, though that is yet to be proven. But at what cost?  Possible bone marrow damage and immunosuppression leading to low blood counts, infections, and secondary cancers.

Many of us also worry about the risks and cost of being on a life long medication no matter how targeted and patient friendly it might be. This fear is not so much based on any evidence of a problem (as there are not many problems and the data generally keeps getting better as the years roll along), but more based on the opposite: the lack of evidence with any of the new oral agents about their real long term safety, because no one had been on them for more than five years at this time.

So that is why this trial at UCSD with Dr. Januario Castro deserves our consideration. Besides being the innovator in the research on HDMP, Dr. Castro is a super nice guy. Still, entering any trial is a huge decision and by its very nature is full of unknowns.

A PHASE IB/II STUDY OF OBINUTUZUMAB (GA101) IN COMBINATION WITH HIGH-DOSE METHYLPREDNISOLONE (HDMP) IN CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) PATIENTS. (GA101 & HDMP)

The team of Drs. Kipps and Castro and more recently Choi has been a leader for years in innovative less toxic treatments for CLL. HDMP especially in combination with rituximab or ofatumumab has proven efficacy in all flavors of CLL including those of us with the stubborn 17p deletion. Here is link to an article on HDMP+R in frontline therapy. I quote:" With over 3 years of follow-up median progression-free survival was 30.3 months with only 39% of patients requiring additional therapy, and an overall survival was 96%." Similar results have been published here with HPMP + ofatumumab.

There are reasons to believe that this new trial may do even better. Obinutuzumab is a more potent mAb (monoclonal antibody) than its predecessors.  Remember that when it was combined with chlorambucil it proved superior to ritximab: This abstract from NEJM states: "Treatment with obinutuzumab–chlorambucil, as compared with rituximab–chlorambucil, resulted in prolongation of progression-free survival.Its 20.7% complete response rate in combination with wimpy chlorambucil is also encouraging, so it suggests that adding Gazyva to another cytotoxic agent, in this case HDMP makes good sense.


Not that either HDMP or obinutuzumab are without their risks. HDMP can cause a short term increase chance of serious infections, diabetes, fluid retention and psychiatric issues to mention but a few of the possible adverse events. Gazyva can be associated with scary infusion reactions. One definitely needs a team that has experience with this heavy weight arsenal. USCD certainly does. And the good news is that neither therapy is myelosuppressive and neither should have long term sequelae.

The rap against HDMP, justified or not, is that the remissions have not been that durable. This trial hopes to squash that story. But no one knows. That's why it's called a trial.

So are you interested?

The best news is that unlike other trials for attractive therapies where inclusion criteria may be fairly narrow, this trial welcomes nearly all comers. See below. I especially like: A. Documented refusal to be treated with chemotherapy agents.  Do you think patient advocates may have been a factor in kicking open the gate that wide? Here are some of the inclusion criteria copied from clinical trials.gov.

Laboratory parameters as specified below:
  • Hematologic: Hemoglobin > 8 g/dL (may be post-transfusion); platelet count > 40 x103/mm3 (may be post-transfusion). Absolute neutrophil count > 1.0 109 cells/mm3 (Growth factor use is allowed).
  • Hepatic: Total Bilirubin < 3 x ULN, and ALT and AST < 3 x ULN
  • Renal: Creatinine clearance > 30 mL/min (Calculated according to institutional standards or using Cockcroft-Gault formula. Subjects with requirement of hemodialysis will be excluded).

Subjects can be enrolled and treated under this protocol regardless of their CLL treatment history or number of previous treatments. In addition, subjects with history of allogeneic stem cell transplant can be enrolled and treated unless they have active manifestations of graft vs. host disease (GVHD) or chronic illness or infections that will prevent them from completing the study.

Previously untreated subjects that meet ANY of the following criteria: A. Documented refusal to be treated with chemotherapy agents. B. Subjects that are not candidates for treatment with chemotherapy based on poor performance status (ECOG ≥ 2), advance age (> 65 years), Cumulative Illness Rating Scale (CIRS score) ≥ 6 or cytopenias.

These are extraordinarily liberal rules for eligibility for any trial.

I don't know where HDMP+OB will fit in. No-one does. That's why we need this trial. It is particularly attractive to anyone who want to avoid chemo (who doesn't), is willing to document their reluctance, and does not qualify for other non-chemo trials. But it also should appeal to any of us with 17p deletion or any of us who just want to have six months of non-chemo treatment and then hopefully coast for a long long while.

Finally to be clear, I don't have any personal connection with this trial other than my history of being a patient at UCSD. Moreover, while I believe that for some of us, it is worthy of careful review for the reasons I have detailed, the decision about entering any trial must be personal and cautiously weighed. Thankfully there are growing numbers of non-chemo and chemo options out there.

It's all a gamble: hope as I am doing to ride a TKI (ibrutinib) into the happy ever after sunset or whack the CLL hard monthly for half a year and pray that it is so far gone that it ain't ever coming back.


Sunset at Corona del Mar

IF YOU WANT A PERSONAL RESPONSE OR TO JUST STAY IN TOUCH, PLEASE SEND YOUR EMAIL ADDRESS TO BKOFFMANMD@GMAIL.COM AS I OTHERWISE DO NOT RECEIVE THEM.

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