Richter's Transformation and on the Road Again

Friends,

This week in the Beyond the Basics section of the CLL Society website, we have posted an interview from ASH 2015 with Dr. Januario Castro, although discussing an abstract that was presented at the 2015 iwCLL meeting. We talked about Richter’s Transformation, one of the most aggressive turns that chronic lymphocytic leukemia (CLL) can take and specifically, a clinical trial that will be available soon that uses a non-chemo approach to therapy. You can see that interview here. [http://cllsociety.org/2016/02/richters-transformation-of-cll/]

CLL Meeting in Tampa, FL: For those of you in the Tampa area, there is a CLL patient meeting hosted by the Florida Society of Clinical Oncology (FLASCO) being held on February 11^th at the Embassy Suites Tampa Airport at 5:00 PM. A complimentary buffet dinner will be provided. I’ll be there giving a talk about the importance of support groups. Also, you’ll have the opportunity to ask questions of the expert speakers. Register and find out more information here. [https://www.flasco.org/events/living-with-cll-tampa/]

CLL Meeting in Miami, FL: For those of you in the Miami area, there is a CLL patient meeting hosted by the Florida Society of Clinical Oncology (FLASCO) being held on February 24^th at the Miami Marriott Dadeland at 5:00 PM. A complimentary buffet dinner will be provided. I’m not able to attend this meeting, but you’ll have the opportunity to ask questions of the expert speakers. Register and find out more information here. [https://www.flasco.org/events/living-with-cll-miami/]

CLL Meeting in Atlanta, GA: For those of you in the Atlanta area, we just became aware of another patient meeting in February: Saturday, February 27^th in Atlanta starting at 9:30 AM at the Sheraton Suites Galleria-Atlanta. CLL patients will be sharing their personal stories, and a local CLL expert will be providing a talk on the basics of CLL. You can call 844-482-6815 to register. A complimentary meal and parking will be provided and you are welcome to bring a guest. I will be at the meeting with an exhibit table and will stay afterwards to meet with attendees to discuss the resources available from the CLL Society. I look forward to meeting you there.

Stay strong.

We are all in this together.

Brian Koffman, MD

Volunteer Medical Director of the CLL Society

http://cllsociety.org

http://bkoffman.blogspot.com

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.

XV iwCLL 2013: Interview with Dr. Castro on the Biology of CLL

My long time friend and crusader, Dr. Januario Castro, who works with Dr. Kipps at UCSD, besides caring for CLL and transplant patients, is doing important research into the basic biology of CLL.

He covers some of the novel bench science presented at the first morning in Cologne, Germany for iwCLL 2013.

Before you dismiss this as not being clinically relevant, I humbly suggest you that spend the ten minutes to listen to Dr. Castro making the biology easily accessed and digested. More than that, he points out some of the lingering challenges still facing CLL therapy.

Without this basic research on cancer cell biology, we could not have the amazing progress we have seen in the last few years. As Dr. Jeff Sharman said in a prior interview, the therapies explode when you crack the biology. Without the novel understandings of what is happening in CLL, we would be still be talking only about old school chemotherapy.

In this interview, first Dr. Castro is honest about what we know and don't know about clonal evolution. Next he outlines what was a recurrent theme at the conference, the important regulatory role of very small pieces of RNA called micro or mRNA. Turns out that much of our DNA is busy doing much more than just making proteins. Finally he talks about his own research that he presented on the versatility of the CLL cell, and how he hope to limit its options.



Thanks, Dr. Castro.

So much to share. I will be revisiting some of these same themes to expose some of the controversy and different takes on the same data.

 Stay tuned. A total of ten doctors interviewed over the three days.

iwCLL 2013: Day One

So far iwCLL 2013 has been a very cutting edge and bench science driven conference. Great stuff, but not easy stuff to digest.

Tomorrow that changes with more "clinical" presentations.

I need to sleep and not blog, but expect video interviews when I get home from three of the speakers today: George Calin on micro-RNA, Juan Castro on the micro-environment, and Jan Burger on a review of all the mid morning presentations.

This is important stuff we patients need to understand and the doctors that I interviewed do a great job of making it accessible. This is the basic science that molds the future of therapy that they are discussing.

Spent hours reviewing the many excellent poster presentations.

One tidbit: Notch1 and 11q del may be mutually exclusive. Who knew?

My brain is exploding. So much new information.

I will try to hold your hand as I share over the next several weeks all that I have discovered here in Cologne on day one.

Met many old friends and made some new ones. Working hard on some patient advocacy plans with some of the people here. Stay tuned.

Tomorrow looks to be just as busy or busier with at least three interviews lined up, but everything changes at the last minute.

But my son and I will make the time to get out of the conference center and see the famous cathedral before we leave. That is a must. It is only a short walk (in the rain) from our hotel.

But first I must sleep.

My rough thoughts

This is a rough draft of my notes to myself (and my wife), unedited and uncut to give you a sense of what goes on in my head as I try to sort out the best moves with this crazy thing called CLL.

First what do the nodes mean?

I have two growing nodes in my gut, maybe more. Other nodes are "plumper"

My CT scan shows definite growth. But is it the CLL?

Could it be nothing? Castro said it might be not important and Rai thinks it still might be fibrotic tissue that could grow.

Rai seemed to indicate the lack of any other nodes was particularly critical. At least he asked about it several times and examined me himself. Castro though that all the nodes should grow at once in CLL So does Kipps. Not Tam or Keating.

Steve Forman and the two radiologists say they are evidence of relapse. They offer nothing else to explain the change other than CLL on its way back.

Rick Furman goes in a different direction. He thinks my nodes are growing too fast for CLL and it is important to rule out PTLD, before any cytotoxic treatment. He said my disease is nodal. Acting like a lymphoma.

 

The next issue is the reason for the profound change in my nodes and for my bone marrow becoming and staying MRD negative after the transplant.

Castro and Rai think the T cells may have been a factor, though Rai also suspects that the chemo was definitive. He seemed to waver.

Steve Forman gave me a definite no to the transplant being any factor in my remission.It is all chemo effect. Rick Furman agrees saying that I couldn’t have formed T cells in the time the graft was aboard.

BTW, quoting Rai:” Losing the graft is bad, but it is not a death sentence” Another quote: “ I have gotten to this point remarkably unscathed” Forman:  “The news is good: You did get a complete remission (with the conditioning from transplant)”

 

Next monitoring, testing And the PTLD question.

Steve Forman wants to treat but not too soon and not too late. Not sure his definition of either point, except that the present is too soon. He plans to follow me with CT scans every 3 months for now and slightly less frequent BMB. That could all change after the next tests in June or July. Uninterested in other markers. Also said would treat like any other CLL, when it is time to treat, which is a bit different.

Castro would wait longer on the CT: 4-6 months. Also wants to track using CLU test. Forman does not trust CLU to make a treatment decision.

Rick Furman says B2M is of no use in my case and my CoH cytogenetics are suspect due to the fact they are stimulated tests and don’t capture the CLL cells. Prefers FISH.

Rick Furman wants a work-up for PTLD including EBV PCR (VCA?), monoclonal gammapathy?, T and B cells counts and ratio, mono-spot, peripheral blood gene rearrangement, CD4/CD8 counts, and others. Would biopsy before FRC or similar treatment, even if nodes continued to grow massively. Still could be PTLD. Dr. Furman thinks my CLL is behaving like a lymphoma.

PTLD didn’t come up with the radiologists, Steve Forman, or Castro. Or BTW with Keating or Tam or the German who did study on CT or any of the ASH crowd.

Rai says there is no tests on the blood that are certain for PTLD and besides this is not behaving like PTLD. No systemic symptoms. Would avoid biopsy, too risky and besides I might treat what I find when it is not needed. Rai: “If the biopsy doesn’t kill you, the treatment might”.

Rai said I should be tested less. CT in 2 years. No BMB needed.

 

So the big questions: When to treat and how?

Steve Forman is pretty clear, as mentioned above. When ready, he would do FCR, followed by what Rick Furman calls a “midi” transplant: Melphalan-Flu, hopefully from the same donor (which is unusual).

Rick Furman wants to connect with Dr. David Maloney out of the Hutch and get his take on a DLI. He is not big on transplants, but seeing as I have already had one and done well, then let’s get the most out of it.  He says he doesn’t know about the whole DLI issue and aplastic anemia that Steve Forman raised.

He would do nothing now or Lenalidomide 5 mg. They are doing a trial using Lenalidomide alternating with Thalidomide. Same action, but different toxicities. Thinks it might help GVL and is great for CLL. (BTW he says never stop the acyclovir due to risk of zoster) Test including biopsy before any treatment except Lenalidomide, which he says is so benign. Better treatments in the next few years, so hold off. Not keen on redo or any transplant.

Castro is still keen on the DLI, just not yet. Says it is never too late for DLI. Not worried about aplastic anemia. Not sure the nodes mean anything. Might consider Bendamustine.

Rai would wait until I was symptomatic. Would not test. Treat when B symptoms only, then treat hard Worried I might develop MDS which is very hard to treat with more therapy or a second transplant

Doesn’t like Lenalidomide. Too new, not sure how to use. Risk of getting T cells involved in tumor flare. Dismissive of any treatment, and especially mentioned Bexar and Zevilin as I am a candidate for both with a clean marrow, and they would wipe out the nodes, whatever they are, but they have risks too. He said" Let someone else worry about the nodes".

Kipps like Rick Furman, is biased against transplant. I haven't seen him since December, but he did not recommend treatment then and did not suggest any specific therapy when the time came. He is not keen on CTs and want to rely on his palpation of my nodes and discussed the radiation risk from CT scans.

All sharp caring doctors.

So the way I see it as of today March 25, 2009:

Back to watch and wait. Stop the CT scans every 3 months. Wait for any symptoms.(Maybe recheck in 6-12 months)

Here’s why.

I wanted a DLI. Dr Steve Forman said no despite my mixed chimerism as I was in complete remission MRD negative, so why take the risk.

We were watching carefully to see if I started to relapse; then time to pull the trigger on the DLI.

What happened is that the remission lasted longer than the donor cells. By the time I had relapsed and by Dr. Forman’s evaluation, needed a DLI, my donor cells were down to 0% and it was too late (again according to Dr. Forman).

I am not sure of the rationale to continue with the frequent CT scans.

The downside:

I could miss PTLD or even RT. Possible, but not likely.

My CLL could become more aggressive and harder to get a second complete remission. Recent data suggests that is important for transplant success.

My donor could not be available. The longer I wait, the more likely he won't be in a position to help again. I have only heard the one time from him.

I might have developed co-morbidities that would increase the risk of a second transplant or make it much more risky. I doubt it. I am pretty healthy, but you never know the future. I have sure learned that lesson.

Insurance or government enforced cost savings may make it more difficult to get the second transplant.

The upside:

Fewer CT scans and the radiation risk.

Less worry.

Possibly several long years of remission.

Better treatments. Experience with Bendamustine and Lenolidamide is growing. Humax CD will be approved pretty soon.

Better transplant protocols. The protocol for transplants are evolving. Even the PICC lines are better that 6 months ago.

Truth is that it likely won’t make that much if any difference when we start treatment as to the outcome of treatment.

It is the last one that really tips my hand. At least for now.

"Tell me why it is hard to make arrangements with yourself" Neil Young

Communication breakdown,

It's always the same,

I'm having a nervous breakdown,

Drive me insane!

Led Zeppelin

What's new you've been asking?

You've heard it before. 

Nothing. Nada. Rien du tout. Bupkahs. 

Stillness is not my strength. 

Add to that a communication breakdown and it makes for a frustrating frozen moment. My insurance authorization for my appointment at UCSD was fumbled on the two yard line. In the fourth quarter. With one second left on the clock.

My scheduled appointment for a second opinion on a second transplant is suddenly on hold after office hours on the day before the appointment, waiting for a last minute paperwork reprieve that would allow me to keep the hard to get chance to see the double agent, Dr. Castro, who moves with grace in both the world of CLL and transplant medicine. A rare man in deed. I need his take on the advisability and timing and risky details of second dose of a stranger's stem cells. Or goosing my immune system with lenolidomide, the princely stepchild of thalidomide. That certainly would be entering unknown territory. Or other options I haven't even considered.

There is still a chance I will get the go ahead tomorrow.

In reality, nothing will be decided until the computer that controls an x-ray unit is used to slice through my gut, and using complex algorithms reconstructs my interior geometry. Moving nodes that are less than a half an inch across to begin with will be scanned for any change.  Not by inches, but by millimeters will my future be decided. That CT scan won't happen for another month.

In Vegas, I would be a card counter. I want all the edge I can get.  I want to know what is knowable. I want some to time to compute the odds and then make my move. 

I should still get the information and time I need. 

I am just not good at waiting.