Frontline therapies In CLL (Chronic Lymphocytic Leukemia)

In this lively ONCLIVE multi-part series of polite debates among four world class CLL experts (Drs. Byrd, Furman, Ma, and Kipps), I was struck by the conservative approach of the panelists to frontline therapy.

Almost all the discussion in this 13 minute segment is about chemo-immunotherapy (CIT).

Keep on mind that except for patients with 17p deletion where ibrutinib is approved, chemo-immunotherapy is all that is approved for frontline therapy. That said, we all know that many doctors including several on this panel would discuss with their patients other frontline options besides those they discuss on camera, namely FCR (fludarabine, cyclophosphamide and rituximab) or BR (bendamustine-rituximab) or chlorambucil and obinutuzumab.

Dr. Kipps points out the potential advantages of the chlorambucil and obinutuzumab in elderly patients with a less resilient bone marrow. This relatively gentle approach has achieved a 20% complete response rate and a 26.7 month mean progession free survival, much better than the other arms in the trial that lead to its approval. For the details of the study published in the NEJM please click on this link.

Drs. Byrd and Kipps talk glowingly about the very long term benefits of FCR in a small subset of patients with the best prognostic markers: mutated with no other bad prognostic indicators. This is a subject we have visited frequently visited in the past. Here Professor Hallek and I discussed this topic in this post in the context of the role of chemo-immunotherapy (CIT) way back at iwCLL 2013. I am still waiting for the published material on that low risk subgroup that is looking more and more as if they might be CURED!

In this ONCLIVE video, there is also debate on the need to complete all the cycles of FCR to get the full benefit. I fully agree with Dr. Kipps that the evidence suggests getting to MRD (minimal residual disease) negativity is what determines our prognosis and not the number of cycles it takes to get there. I quote from a Blood editorial by Sebastian Böttcher on the original research: "current investigation suggests that the number of treatment cycles also becomes irrelevant as long as MRD negativity can be attained." 
The full text of the original research is accessible here. The authors state in the abstract that:" MRD-negative patients had comparable PFS ( progression free survival) and OS (overall survival), independent of the number of courses received or interim staging. Early MRD eradication may be a desirable goal, prompting consideration of early discontinuation of treatment."

Dr. Furman hastened to point out the potential downside of chemo-immunotherapy and also that the group that did so well is a group that should do well with any therapy.

In this article from the British Journal of Hematology, we learn: "patients treated with purine nucleoside analogues (PNA) had a significantly increased risk of subsequent second LPD (5·2%) compared with patients who had not received PNA (1·9%; P = 0·008)"  PNA are drugs such as fludarabine and LPD are lymphoid cancers.  In fact, they go to stated that the only factor found to be associated with an increased risk of a secondary lymphoma for those us with CLL was prior treatment with chemotherapy.

That certainly does give one pause.

There is also some very interesting comparison of BR versus FCR, a subject that we extensively reviewed in this prior blog post with Dr. Jeff Sharman.  I appreciate Dr. Kipps' careful analysis of the different arms of the trial to ensure that we are really comparing apples to apples.

Give a listen and please share your comments.

Again, thank you ONCLIVE for bringing us this great panel discussion.

ASH 2014: Interview with Dr. Susan O'Brien and Dr. Bruce Cheson on CLL (chronic lymphocytic leukemia)

There is much to report from ASH 2014, and this sweet interview from Medscape offers a short synopsis of some of the highlights.

Over the coming weeks I plan to fill in the details with more comments and videos, but this is a nice and succinct place to start.

There are some priceless moments, thanks to the wise and dry humor of Dr. Cheson and the honest and patient centric attitude of Dr. O'Brien.

First, right up front, I really appreciate that Dr. Cheson points out just how out of date are even the most recent CLL guidelines that were developed only a few years ago.

Are you listening, community oncologists? The published CLL guidelines are out of date.

I am glad he also asked about the secondary malignancies with chemo-immunotherapy, a question too often swept under the carpet in many presentation on CLL treatment. We know there is a small but real risk of MDS or myelodysplastic syndrome (for an explanation of the relationship of MDS and CLL from Dr. Steensma, click here), a difficult to treat form of cancer that presents as bone marrow failure, that may come along as a late and serious complication with FCR (fludarabine, cyclophosphamide, and rituximab), but we don't have much data yet on the risk with BR (bendamustine and rituximab).  Because bendamustine is a DNA damaging alkylating agent similar to chlorambucil (Leukeran) and cyclophosphamide (the C in FCR), it is likely that MDS will also present as a late, but hopefully infrequent ugly complication after BR.

What we do know already is that now that we are living longer with our CLL, we are getting more secondary cancers (click here for a reminder of our risks), especially blood cancers.

Don't miss Dr. Cheson's hand gesture when Dr. O'Brien talks about the minority of patients that do so very well on FCR, a topic that we have visited here more than once (click here to hear Dr. Hallek at  iwCLL discuss who gets the most benefit from FCR).

Another highlight comes right after the honest discussion of the follow up important trial of the two old school chemo-immunotherapies that are duking it out for supremacy in the CLL world, namely the  FCR versus BR (for more on this trial from Dr. Sharman click here). After Dr. O'Brien's honest and upbeat response, Dr. Cheson asks her, quite properly in this era of new treatment options: Do we care?

Yet another interesting moment occurs when he asks Dr. O'Brien to choose between ibrutinib, idelalisib, and ABT-199: If they were all available: Which one would you pick?

She refuses to answer.

Their discussion on the meaning of minimal residual disease or MRD negativity in the era of novel therapies is both informative about what we know but even more so about what we don't know.

Only time and trials will help sort al this out.

Dr. O'Brien has her own hand gesture when she describes just how much above 50% was the progression free survival curve for ABT-199 at 18 months. We need more data. And more time to sort this all out.

I wish I had produced this video. I don't usually see the role of my blog to share what is already available on other websites, but this is good stuff and there was much in it that cried out for commentary and context. I wanted everyone who reads my blog to have the link with it here.

Please enjoy this Medscape Interview:

CLL: It's the Best -- and Most Confusing -- of Times

Thanks for your help and support.

                                          

ASH 2013: Dr. John Pagel Discusses the Risks and Benefits of ABT-199 and TRU-016 or otlertuzumab in CLL (chronic lymphocytic leukemia)

In the final segment of my interview with Dr. Pagel from ASH 2013, he discusses ABT-199 and TRU-016 or otlertuzumab (yet another mouthful for us to poor patients to learn and pronounce).

We have heard much already about ABT-199. Here is a link to a trial reported at last year's ASCO meeting and I have an interview pending from ASH 2013 with Dr. Seymour from Australia. At ASCO later this week, there will more news on ABT-199 with a new dosing schedule to reduce the risks of tumor lysis syndrome (TLS).

TRU-016 is another under reported therapy, a potent monoclonal antibody (MAb), much like rituximab, that is as of now only available in clinical trials. In my opinion it has not received the attention it deserves. Unlike rituximab or ofatumumab or even obinutuzumab that all target CD20, TRU-016 targets CD37. But like CD20, CD37 is also found on most mature B cells, both cancerous and benign and much less so on T cells making it is a good choice for fighting CLL. That's an important difference from Campath that binds to CD52 and destroys both B and T cells. With no T  or B cells to fight infection coupled with our already wimpy immunity, we are high risk for life threatening infections. TRU-016 did not increase infection risk in this small trial.

Here is the ASCO abstract that compares bendamustine with or without TRU-016. The number were very small, but for those who received TRU-016 there was responses in the two patients with 17p mutations but not in the two with 17p deletions. As expected, there were no responses to single agent bendamustine.

And here is Dr. Pagel:



I am hoping to sneak one or two more post before I take off for ASCO 2014 later this week.

CLL (chronic lymphocytic leukemia) Treatment Internationally: We Can't Always Get What We Want

Below is an article from the Brampton Guardian.

This unfortunate CLL patient can't even get bendamustine and rituximab in Ontario, Canada, let alone ibrutinib or idelalisib or ABT-199 or obinutizumab. OHIP, the provincial insurance won't pay for any of it.

Here in the USA, she would automatically qualify for ibrutinib as as second line therapy or she could get her BR or enter a trial or a host of other choices. Not so in Canada.

I am so lucky to be able to have received ibrutinib in a clinical trial long before it was approved.

Others, mostly those wanting a non-chemo first line therapy, have been less fortunate. Still on clinical trials.gov, a quick look found eight open trials for untreated CLL patients with either ABT-199 or ibrutinib or idelalisib or obinutuzumab. And there are many more options using other very promising TKIs and mAbs in development. It's true that you can't be assured that you can get ibrutinib by prescription for frontline treatment, but at least most American untreated patients have many fine options with or without chemo.

When I advocate for more research on the the multi-drug non -chemo treatments for those of us such as myself not in CR after two years of ibrutinib, it is not meant at the expense of those needing other therapies or better access.

I want to see improved access for all of us. One way that might be possible is by following a path such a Professor Hallek outlined at ASH 2013 to limit the duration of therapy and thus control cost. I would just leave out or at least severely restrict the chemo piece of his protocol. His full article is available and well worth reading. It is a thoughtful discussion and one vision of the possible future of CLL treatment.

This is all new territory and we need the trials on untreated patients and we need the trials on relapsed patients and we need the trials on patients not in CR.

Truth is we are barely at the break of dawn of this new era of treatment and we need so many studies to help guide us. We are making this up as we go along.

What we also need to remember is that we are are all in this together and none of us, myself included, should wish for an option that limits another's choices. At least in the USA, we are not at that point.

Canada may be a different story. There is a petition at the end of the attached article. Her denial of care seems cruel, unjust, unscientific, and just plain dumb to me.

I understand that nearly all cancer treatment is expensive. I understand society must make tough choices about how to allocate limited resources. But making choices based solely on arbitrary protocols and short term dollars signs is not good policy, especially when it clearly stands against both the best evidence based medicine and the specific clinical circumstances of the patient.

Truth is that ibrutinib might be a smarter choice than BR for this patient after relapsing only four years post FR. Truth is we learn nothing in this article about the state of her marrow. Can it handle more chemo? We don't even know her FISH. If she is 17p deleted, BR could be a dangerous waste of time and resources, and might leave her worse off than before the therapy.

In the end with CLL, one has to chose which battles to fight. Anne and her oncologist have made their choice and are pushing for BR, so I am assuming they are on their game and have done their due diligence.

Yesterday, I heard from patients in Turkey and China looking in vain for novel therapies. I quote from the latter email discussing ibrutinib: Indeed the medicine cost is too high, and even if it's approved to be imported to China, the market price in China would be still higher (with extremely high custom rate), and yet any imported medicine is out of the range of medical insurance in China.

It's tough for my friends in Europe too. NICE that regulates new drugs in the EU can be very price sensitive and there seems to be be fewer non-chemo trials.

I know how spoiled I am living in the USA. I know how lucky I am to have nabbed a spot in my trial.

I wish everyone everywhere had access to what they needed to be well.

After all, we are all in this together. 

But there is only one of me and I am spread pretty thin already, so I narrow my focus, and try to make sure that at least those of us in North America get the best possible and smartest treatments out there.

The LLS is doing important work on improving access through its patient advocacy and other efforts. They deserves our support. See the photo below.

Brampton woman denied OHIP coverage for life-saving cancer drugs

Brampton Guardian

BRAMPTON — 

Anne Mitchell is fighting an uphill battle.
After four years in remission, the 67-year-old mother of two is gearing up for her second battle with Chronic Lymphocytic Leukemia.
But dealing with cancer isn’t the only obstacle the Brampton woman must overcome. The real challenge now — apart from fighting the illness — is coming up with the money to pay for life-saving drugs.
“My mother can’t receive chemotherapy drugs, purely for bureaucratic reasons,” said Mitchell’s daughter Eleanor Elliott, who has launched on an online petition in a bid to pressure the provincial government to dole out the $52,000 her mother needs for the chemotherapy drugs Bendamustine and Rituximab.

The drugs are covered by OHIP.

Mitchell is being denied coverage based on what family members say is a technicality. Bendamustine is covered for first-time chemotherapy treatments.
But, since Mitchell has undergone chemo before, the drug isn’t covered by OHIP. The other drug, Rituximab, is approved for second line use, but only in tandem with Fludarabine — a drug that Mitchell can’t take because she suffered an extreme, adverse reaction to it during her first bout with chemotherapy.
“The drugs that my mother’s oncologist prescribed are funded by the government. However, in my mother’s case, they have denied her funding,” Elliott said. “If a drug is approved for funding, how can you deny a Canadian citizen access to that drug? How is this possible in our great country that prides itself on universal healthcare?”
In October 2010, doctors treated Mitchell’s cancer with Fludarabine and Rituximab, two very powerful chemotherapy drugs.
Mitchell, who has lived in Bramalea for nearly 40 years, received got through two treatments before the regime was abruptly stopped because of her negative reaction to Fludarabine.
Mitchell was hospitalized for weeks with a severe lung infection that nearly killed her.
Despite that setback, her cancer went into remission and Mitchell and husband John, 68, were looking forward to better days.
But the cancer has returned and doctors believe Mitchell’s fighting chances are good if treated with a combination of Bendamustine and Rituximab.
However, the hefty price tag on those drugs now stands in Mitchell’s way.
Mitchell’s latest chemo treatment was to start April 7. Shortly after arriving in the oncology department at Brampton Civic Hospital, she received news that the $8,700 for the Bendamustine and Rituximab would have to come out of her own pocket.
“I felt complete and utter shock,” said an emotional Mitchell, describing her reaction when told OHIP denied her payment.
Mitchell used a credit card to cover the $4,500 cost for the first round of Bendamustine. She needs six treatments in total and can’t afford the cost.
Elliott said the hospital administered the Rituximab at no charge and has put through an appeal to Ontario’s health ministry for the $4,200.
“I sat in shock as my mother had to pull out a credit card to pay for her treatment,” said Elliott, who is concerned that her parents will be forced to spend their retirement savings on cancer treatments.
With her mother facing an uphill fight, Elliott has taken to social media for support. Her online petition has so far garnered more than 600 signatures, She plans to present the petition to provincial health officials.
Bramalea MPP Jagmeet Singh has offered his support in the form of a letter sent to Ontario Health Minister Deborah Matthews appealing for help

Meanwhile, Elliott has also reached out to the manufacturer of Bendamustine.
According to Elliott, Lundbeck Canada has agreed to cover 20 per cent of the cost of the Bendamustine, but the family will have to pay the cost up front and then apply for a rebate.
But, as Elliott noted, that works out to be just about 10 per cent of the total cost of her mother’s required treatment.
Elliott argues that her mother wasn’t able to complete her first round of chemotherapy and therefore should still be considered a first-time patient.
Falling under the category of first-time chemotherapy patient would make her eligible for the Bendamustine. Elliott also wants Ontario to waive the requirement that OHIP will only cover Rituximab if taken with Fludarabine.
She argues that approved chemotherapy drugs be approved “without discrimination and without bureaucratic intervention that could cost Canadians, like her mother, their lives.”
To view the online petition click here .

ASH 2013: Dr. Claire Dearden Discusses CLL Treatment in the Elderly

One of the nicest doctors in the world of CLL is the English hematologist or should I say haemotologist, Dr. Claire Dearden of the Royal Marsden in London.

At ASH 2013, Dr. Dearden and I reviewed the new studies on the treatment of the most common group in CLL but the most underrepresented in clinical research, namely the elderly patients.

At ASH 2013, several papers made significant progress addressing this gap and that is what we discussed.

We can hear echoes of my discussions with Dr. Jeff Sharman in a recent post on the trial of idelalisib with and without rituximab. In that interview, we focused on the ethics of that placebo controlled trial.

We may also recall that Dr. Jennifer Brown and I discussed in another ASH 2013 post the very exciting trial of chlorambucil alone, with rituximab or with obinutuzumab that Dr. Dearden mentioned.

There was also important information of relevance for this population group in the long awaited study comparing FCR versus BR. For another thoughtful discussion on this, check out Dr. Jeff Sharman's excellent blog post. Here is a link to the actual study data presented at ASH. In the over 65 group, there was no progression free survival (PFS) advantage for FCR over BR despite the former's greater toxicity, especially in this age group. This is news we can use.

But before we get started in deconstructing the data, one of the first issues we must address is exactly how to define old. Turns out there is much research on looking at the biological versus chronological age. The CIRS scale is commonly used to look at co-morbidities, but as Tait Shanafelt out of Mayo Clinic pointed out in his important educational paper at ASH on this topic, we need to look at quality of life, life expectancy (approximately 20 years for those us 65 years old), and frailty. It's not just calendar years.

This is the biggest reason I push for a healthy lifestyle. It is not that a plant based diet and regular exercise will cure our cancer, but we are sure to do better if we have fewer co-morbidities, and living healthy helps with that. We don't need to add diabetes or renal disease or heart trouble to our list of woes that come pre-packaged with CLL. More problems unrelated to CLL lead to more problems related to the CLL.

Here is the interview with Dr. Dearden.


The news is good. Options are improving. I am not thrilled with chlorambucil as the backbone of the therapy, an admittedly gentler but still old school alkylating agent in the same class as bendamustine or cyclophosphamide (cytoxan or the C in FCR) or mustard gas. Just because it's a pill, doesn't mean that it's safe. Moreover, I am sure that the heavy lifting in this trial was done by the immunotherapy agents, rituximab and especially obinutuzumab. But chlorambucil is cheap (as little as $1.50 a day for the lowest dose) and easy to take.  It is very popular in Europe and was a favorite of the late great Dr. Hamblin.

One more point.

As we hear from the end of our discussion, the choices are complex and nuanced. As I have said before and as has been proven in a study out of Mayo, we do better with a CLL expert as part of our team guiding us through our therapeutic decisions.

Finally, Dr. Dearden reminds us of the many unanswered questions and that's why we need more research.

I have been traveling and meeting with fellow CLL friends, but I am back and trying to catch up on a backlog of videos and personal stories and adventures to share.

Stay tuned. Posting should be more frequent over the next month.

ASH 2013: Dr. Jeff Sharman Discusses FCR versus BR in Front Line CLL

In this interview, Dr. Jeff Sharman gives us some understanding of the important trial data presented at ASH 2013 that compares FCR (fludarabine, cyclophosphamide, rituximab), the gold standard chemo-immunotherapy (CIT) to BR (bendamusine-rituximab) the new kid on the block and very popular with community oncologists.

In the excitement and promise of the new era of gentler and more effective oral medications for CLL, there is still a diminishing group of patients that for many reasons will continue to chose a chemo-immunotherapy (CIT) approach.

One possible reason is that for a few patients with excellent prognostic factors, a significant subset of those will reach MRD negativity and for that group FCR produces exceedingly durable remissions, starting to hint a possible cure. A half year of harsh but not the worst therapy, and you're done. Time to get on with your life without any daily pill reminding you that you have CLL.

Professor Hallek discusses this special group in my short interview from iwCLL last year.  I would not be completely dismissive of the value of CIT in those special circumstances.

Sadly insurance coverage and expense will be another reason that we will still see chemo. Older drugs are cheaper than newer drugs.

And even more sadly, patients' and physicians' unawareness of the rapidly changing therapeutic landscape will limit some of us CLLer's option to what our oncologist is most comfortable with it.

A few of us won't be able to tolerate the new oral therapies due to side effects, but as more options and new TKI's are approved I suspect that will be a vanishing small number. There are also the very few patients who have progressed on ibrutinib (the only oral TKI approved for CLL at this time and available by prescription) and an unfortunate group of us who both can not qualify for a trial or who have no access to the new meds because of where they live or their insurance and who need treatment NOW and can not wait for a different option.

That said, the FCR versus BR data welcomed as it is, is hardly the blockbuster news that it would have been a few years ago.

Ibrutinib and idelalisib and ABT-199 and obinutuzumab and others have rightly stolen the spotlight at ASH and elsewhere. Their time has come, and not a moment too soon.

Still CIT is not going to quietly fade away so fast so let's look at this important ASH abstract.

This link gives the data.

This link explains what is meant by the grade of adverse events and reminds us that a grade 3 adverse event is severe or disabling, a grade 4 is life threatening and a grade 5 adverse event is polite medical talk for a side effect that kills the patients. So when we see that on the FCR, we patients had a 90% of a Grade 3 or worst hematologic side effect compared to only two out of three in the BR arm.

The price of this higher that high toxicity and small but real risk of dying from FCR was an impressive 98% overall (ORR) response rate with nearly half of those being CR (complete responses). With BR the ORR is the same but the CR is 38%. MRD (minimal residual disease) negative data was not presented. Progression free survival was better for FCR in those under 65 years old, but not in the older group.

So very impressive results, but significant toxicity. This is an old and too common story with chemo: The more toxic the drug, the better it works. FCR is better in younger patients, but comes with more risks and misery.

New targeted and biological therapies break this paradigm and that is why when we have a choice, we should be putting the emerging therapies high on lists of options.

Remember too that this trial was for front line therapy in fit patients where access to the newer treatments in even more difficult.

Listen to Dr. Jeff Sharman and get his take on this important study. Dr. Sharman is a smart, very busy and compassionate guy who has done much to help the CLL and other blood cancer community and I am grateful for the time he gave for this interview at ASH 2013.



Dr. Sharman has an excellent blog himself where he covers much of the same and even more detail on the trial here.

iwCLL 2013: Dr. Michael Hallek Discusses Clinical Trials in Germany versus the USA and BR versus FCR

Happy New Year.

I am in Alameda, enjoying babysitting my 7 month old and 2 1/2 year old granddaughters. Needless to say, finding a second to get any work done is tough, but the joy of being with them makes my inefficiency a small price to pay.

Today, I am returning to share additional relevant interviews from iwCLL a few months ago.

In the first part of my interview on September 11, the last day of iwCLL 2013, Professor Hallek first discusses some of the differences in clinical trials on either side of the pond.

One subject Prof. Hallek does not mention is the greater willingness of European patients to be randomized in a trial. Canadians and Americans prefer more control in deciding their therapy, and that helps explain the generally lower accrual in North American studies that have two or more randomized arms. I admit that one reason I was drawn to my trial, the official title being,  An Open-label, Phase 1b/2, Safety and Efficacy Study of the Bruton's Tyrosine Kinase (Btk) Inhibitor, PCI-32765, and Ofatumumab in Subjects With Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma and Prolymphocytic Leukemia, was that I was assured that I would be getting PCI-32765, AKA, ibrutinib, AKA, Imbruvica. Phase 3 trials rarely offer that certainty, unless there is a cross-over and that is a big ongoing issue.

Keep in mind that the  calculus of accrual is entirely different when we are looking at the new non-chemo agents, where trials offering some of the exciting new drugs have filled at record rates.

Also don't miss the professor's definition of young.

I like it.

Next, Prof. Hallek, presages with great accuracy what was going to be announced a few months later  in at an abstract presented in New Orleans at ASH 2013, namely that BR is gentler on the marrow, but less effective than FCR. His take on what to do with that data is the real gem in our conversation. Listen to how he describes tailoring of the therapy to the individual patient.

Dr. Jeff Sharman whose interviews have and will continue to pop up here, has a nice review of the ASH data on his excellent blog.

Here is Professor Hallek, who was very busy chairing iwCLL, so I very much appreciate his time.  Sadly when my flight to New Orleans was canceled, I had to also cancel my follow-up interview at ASH, but we get the full story here and from the abstract.

Many, myself included, wonder if the whole question of BR versus FCR is moot as the era of chemo-immunotherapy may be ending in CLL. We have spent many blog posts discussing this issue, and we aren't finished yet.

Here is Professor Hallek:



More soon.

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.

Saying No to Chemo: Non -Chemo Options for CLL, Part 1

This is probably the most common question that I am asked.

"I know that I need therapy, my CLL is taking off, but I don't want any chemo, so what are my options?"

The answer used to be "not much", but not so anymore. Today there are many choice and soon there will be even more.

But before I give my answer, let me give an important preamble and discuss what we are taking off the table when we veto the chemo option.

When fellow CLLers says no chemo please, I take it to mean that they don't want cytotoxic drugs that work by preferentially killing rapidly dividing cells.

For CLL in the USA, we are mostly taking about two classes of medications.

Number one and the backbone of most chemo cocktails is fludarabine that is a classic purine analog that kills by blocking DNA synthesis. Pentostatin and clardribine are similar adenosine analogs that work the same beat. What these cleverly designed drugs do is pretend to be purine, get themselves incorporated into the dividing DNA and completely gum up the work of replication. Nice.

The other class of pure chemo drugs we see a lot of are the direct descendants of the now banned World War I poison, mustard gas or nitrogen mustard. (The story of how its antileukemic powers were accidentally discovered is worthy of its own post). They destroy by attaching an alkyl group to any and all busy DNA, causing aberrant cross links and preventing it from making copies of itself. The more active the DNA, such as in a fast growing cancer, but also in our fast growing gut and skin, the more damage and the greater the kill. This is how the old standard therapy chlorambucil (AKA Leukeran) works. So too cyclophosphamide  (Cytoxan) the big C in FCR, and bendamustine (Treanda) an old communist drug but a new kid on this side of the Berlin Wall.

There are many many others cytotoxic drugs in oncology that play lesser roles in our disease such as vincristine (Oncovin), the V in CVP occasionally used for refractory CLL and just to confuse us, the O in R-CHOP used for Richter's Transformation and many lymphomas.

Oncologists carefully concoct these toxic cocktails with several goals in mind.

First they want to add to the killing power. Cancer is famously adaptive and will rapidly mutate itself right past a block on its road to lusty growth. Blocking it when it turns to either the left or right is a smart strategy. So too is capturing it in a pincer move with the lengthening lists of the toxic chemicals that make up the alphabet soup that we and others get IV to knock the socks off our cancer, and sometimes (but probably never in CLL) kill it for good.

But doesn't adding one drug on top of another inevitably lead to unacceptable toxicities?

Not necessarily so says our clever oncologists. They look for more than just complementary killing. They look for non-overlapping toxicities. CHOP is the poster boy example, a potentially curative cocktail for some lymphomas, where each of the chemo drugs interferes with the DNA in different synergistic ways AND where each drug has a different toxic target (the marrow or nerves or the heart).

Of course, it is never black and white, and dosing and individual sensitivities widely vary.

Hippocrates famously said that the difference between a medicine and a poison is the dose.

Never was this more true than with chemotherapy. Low dose oral chlorambucil is remarkably well tolerated, even in the elderly, but at the proven price of not doing much to extend the life of the patient.

Some chemo drugs are routinely used at low doses for relatively minor skin problems or auto-immune issues.

But the issue is more than the dose. It is also who is getting the dose.

Is there co-morbid heart disease or nerve damage from uncontrolled diabetes? Has the marrow been beaten up and is having a tough time rising again?

That is why it is so important that we stay well otherwise. Cancer is a hard enough fight without the handicap of a bad heart or bronchitic lungs.

Chemotherapy is not "targeted" in the strict sense, but it does preferentially cull the rapidly dividing cells and that is a good thing. In some cancers, it does such a strong job, it can cure. In CLL, while there are no chemo cures, it can and does give many of us years of healthy happy remission.

The majority of us that end up sitting in the infusion chairs for hours and hours report that while CLL chemo is annoying, it was much gentler that expected. No hair loss, little nausea. FCR or BR are wimpy protocols compared to some of the more potent stews used for more aggressive cancers. I know a surgeon who continue to operate all through his treatments with FCR.

Still cytopenias (low blood cell counts) are all too common including anemia, neutropenia with its high serious infection risk, and low platelets. So hand in hand with the chemo might come a partnering dose of a bone marrow stimulant for either red cells (EPOs), white cells (G-CSFs) or platelets (TPO mimetics) each carrying its own set of side effects and worries. Some of us even need transfusions to just keep going. More decisions. More risks. More time. More expense. More worries.

Long term, there also may be a price to pay. The marrow can only take so much before it gives up the ghost. When our marrow stops making enough of the three lineages of our blood cells, we are in dire straits and the only durable way out may be importing a new one AKA an allogeneic hematopoeitic stem cell transplant.

Chemo wallops our immune cells short term, risks of infections shoots up and may stays up for more than a year after fludarabine which is particularly nasty to our T cells.

Insist that your doctor offers you appropriate antimicrobial prophylaxis.

These drugs by design are mutagenic so we hold our breathe when we get our regular PAPs or mammos or PSAs or colonoscopies. We are getting them aren't we? Please see my earlier post on secondary cancers and do the right thing by yourself.

Infections and secondary cancers are the handle and the blade of the our grim reaper's scythe. So anything we can do to keep it reach short and its edge dull is good.

Eating right, exercise, love, sleep, and avoiding chemo are part of that prescription.

Still, when we face a clear and present danger, we must focus on our imminent needs and worry about tomorrow, tomorrow.

And until very recently, the best tools we had for staying alive when our cancer started to rage was a chemo cocktail, and I for one am grateful that these drugs were and are there in our time of need.

It was only a few years ago that we showed that for the first time a combination of chemo and immune therapy in FCR could prolong our lives. We know that those diagnosed with CLL in the 90s live longer than those diagnosed in the 80's, and much of the credit rests at the doorstep of chemotherapy and the modern management of its side effects.

So before we wave goodbye to chemo as some sort of poison concocted by the a cabal of international pharmaceutical companies, the military and medical industrial complex to keep cancer as a big profit center at our expense (believe me I encounter this line of thinking almost daily), let us calmly look at its risks and benefits.

Let's not throw the baby out with the bathwater.

If you have read any of my posts over the last few years, you have seen me vote with my feet and my blood. You know that I am a fan of the emerging small molecules and have tried to avoid chemo in my own personal journey.

All I am asking for is that we have some balance and keep our eyes wide open as we enter this brave new "post-chemo" world.

"Targeted therapies" while they might be compared a smart bombs or drone, they too like their battlefield equivalents, can pick off innocent target either that look like the enemy or are in the wrong place at the wrong time.

As I said, it isn't black and white.

More on non-chemo choices soon.

Brooklyn- The Bottom Line on the North American Educational Forum on Lymphoma

The Lymphoma Research Foundation is to be commended on putting on another first rate conference.

What I like is that while it is totally oriented to help the patients and caregivers in the audience, it tells it like it is.

They may start at the very beginning of the story, for example retelling the very basics on how a mAB (monoclonal antibody such as rituximab) works, but soon they are into the gritty details on how it might be improved upon with the next generation mAB. They don't oversimplify.

Much, but not all is not sugar coated. It does try to be righteously upbeat, but like an an appointment with a good and clever oncologist, you somehow leave feeling positive about the bad news that was just delivered.

So let me hit some headlines.

CART19 therapy (the patient's own T-cells infected with a retrovirus to be re-educated to multiply and to attack B-cells and then re-injected into the same patient) out of U Penn has all the CLLers drooling. You knew that there would be a million questions.

Dr. Bruce Cheson tells it like it is: "The plural of anecdote is not data".

One case reported in NEJM does not signal a cure.

This approach has way too few and is way too new to say anything definite about.

Still it does prove it can be done, not much else. It is a proof of concept study and I am most grateful for its success.

I and others ask how long can you go infection free with no B cells?

Will the remissions hold?

Are there better targets that hit only the CLL cells and not all B lymphocytes? ROR1 for example?

Who is going to pay for this?

Answers are a long ways off.

The next trial will be taking in only 11 volunteers. Unlike nearly all cancer trial, where recruitment can be very slow and difficult, what do bet they will have no problem filling their enrollment? I bet they fill up faster than the pre-orders for the new Iphone.

Dr. Cheson gave the very opinionated and informative breakout talk on CLL.

He is out of Georgetown and has made many important contributions to our knowledge of how to treat CLL. One that he is particularly proud of is his bringing the old East German drug- bendamustine to the USA.

As he points out in communist Germany, bendamustine was developed in the 1960s to be an inexpensive alkylating agent instead of using the then expensive western drugs such as Cytoxan (cyclophosphamide) or Leukeran (Chlorambucil). Those are both off patent now and dirt cheap for a chemo drug. But ironically, we have Treanda (branded bendamustine), a very pricey child of mustard gas that may have some extra oomph in managing CLL and other hematological disorders. The TATA has become the Ferrari.

A short cautionary note before I share his thoughts and slides.

Chaya Venkat may have been the first and the most public, but not the last in understanding and teaching that there is great localism and nepotism in what treatments for CLL we are offered.

If you go to MDACC, you can bet you will be offered FCR and if you show up at Georgetown, expect to see Bendamustine on your infusion schedule.

That is not a bad thing. I want my doc to be very familiar with all the unfamiliar things that might happen to me with my treatment protocol. I want him or her to feel comfortable and upbeat about the therapeutic choice.

So please take into account Dr. Cheson's understandable pride and enthusiasm for his prodigy drug.

He admits that the data is not there yet, but he thinks it is trending to show that BR may be a better front line therapy that FCR.

Here's why.

More patients can get through a full course of therapy of BR than FCR. When you look at the data on FCR, always check how many make it though a full six cycles.

It is safer in patients with renal insufficiency.

There may be less treatment related ALL and MDS. That would be a very good thing.

He believes that auto-immune issues also will be less and that there is less marrow suppression and fewer infections.

Not everyone agrees.

I will post soon on what I learned in Brooklyn on new CLL therapies and transplants and survivorship.

And on the whole ambience and joy in seeing old friends. They even had good vegan food!

I took the redeye on Jet Blue from Long Beach to JFK and stayed awake on Saturday and got up early on Sunday before flying back home and I am glad that I did.

I think all those years as a medical student and intern and resident and fellow has trained me to get by on little sleep.

And to be always be learning.

Waiting for perfect knowledge?

It is always easy to tell when it is too late or too early to start therapy.

It is always easy (at least for me) to second guess any disease management decision.

It is never possible to get it all right and have all the facts.

So what to do?

For me, the answer has always been to get the best information and the best advice from the best people, and then act and stay mindful.

Some choices, such as a transplant, mean that you can't always be aware or mindful. You are just going to be too tired or too sick some of the time. That is where you need a well meshed team of loved ones to be your ombudsmen and of experts to execute the plan. These two groups will keep their eyes on different pieces of the puzzle, but they must communicate. This combo will give you the best chance to handle most of the inevitable bumps on the road so that you can keep moving forward.

Which brings me to another topic.

And another golden nugget:

If you don't know where you are going, you will never get there.

Assuming my chosen path of rituximab and cyclosporin continues to work its biological magic, and my nodes melt away not just where I and Dr. Kipps can palpate, but deep in the darkness of my mesentery, do I pull the trigger on a second transplant, a second shot at a cure and not just a remission?

That would mean a preliminary course of higher octane chemotherapy such as FCR or bendamustine with R or O to further reduce the disease burden and weaken my T cells so that I won't reject the graft as I did last time.

Or do I play out the string a little further in a different direction? Avoid tried and true chemotherapy and engage a newer sexier tango partner, such as one of the tyrosine kinase inhibitor in clinical trial now that doesn't promise a cure, but just a longer and gentler dance.

The risky cure or the unproven promise of a long deep remission?

There is a yet another saying in medicine. This one speaks to the appeal of a new medication.

Better use a new drug soon while it still works.

Is this too cynical an approach? Weren't all medications newborns at some time?

Some "new" drugs (triptans) have grown to be old and trusted friends and other (DES) have been run off leaving behind a trail of shame and tragedy. Some (Penicillin G) have been mostly pushed aside by the newer models, and others (thalidomide) have risen from the dead to find new life in novel therapeutic fields.

So what do I chose?

The devil I know or the devil I don't know?

The honest answer is that I never really know anything fully.

Like the gift of any photograph, I get the truth, but it is always incomplete and always has a built in point of view.

The best I can do is to calmly contemplated the options, purposefully act, and stay aware.

And have my trusty team in place for when I can't.