Large Granular Lymphocytic Leukemia: What We CLL Patients Can Learn from a Novel Therapy for a T Cell Cancer

This week in Blood there was a very interesting article published on a very rare form of blood cancer, LGLL or large granular lymphocytic leukemia.

The abstract stated:

T-cell large granular lymphocyte leukemia (LGLL) is a rare clonal disease often associated with rheumatoid arthritis (RA) and manifests chiefly as neutropenia and recurrent infections. Immunosuppressive agents are the mainstay of treatment, but long-term remissions are rare. We report 2 cases of LGLL in patients with RA successfully treated with rituximab, a monoclonal antibody specific of B cells and approved for treating RA. The first patient experienced a complete LGLL remission that was sustained during the 8-year follow-up after the first rituximab infusion. In the second patient, rituximab therapy was followed by immediate neutropenia recovery and then by marked shrinkage of the LGLL clone 1 year later. The paradoxical efficacy of this specific anti–B-cell drug on a monoclonal T-cell disease suggests that some cases of LGLL may be reactive manifestations of chronic autoantigen stimulation rather than true malignancies.

I added the bold because this jamming on of reactive pathways with all its nasty downstream consequences is similar to what we are trying to block with BTK and PI3K inhibitors in CLL. In CLL, we are trying to shut down the constitutively stimulated B cells by blocking their pro-survival communication, proliferative, and homing instincts.

Further down is the report we find:

As illustrated by our first patient, T-cell LGLL is frequently associated with concomitant low-grade B-cell dyscrasias, such as monoclonal gammopathy of unknown significance or chronic lymphocytic leukemia, suggesting that a common antigen may drive both T- and B-cell proliferation.

That is powerful talk. Yet to be proven, but worthy of more research.

Maybe that is why anti-T cells therapies such as ciclosporin help some in CLL, yours truly included. 

Everything in the complex immune system is so connected.

The whole Blood article is short and I recommend it.

This type of creative systemic thinking is exactly what will be needed to completely and finally shut done the monoclonal B cell factory that is CLL. We may need to read the green tea leaves in more than our CLL teacups to find our answers. We need to look at the research being done in other liquid and solid cancers. Some of the fantastic new immune therapies in metastatic melanoma as detailed in my prior post from ASCO 2013 immediately come to mind as future paths to pursue. 

Last, but not least, and while the issue may be just semantic and this is only two cases, all of us with  CLL would much prefer to live with a "reactive manifestations of chronic autoantigen stimulation rather than true malignancies", especially if such labeling leads to better therapeutic approaches and better outcomes.

I am off to Germany on Monday for iwCLL. Send me your burning thoughts and questions that I might share with all the CLL gurus gathered in Cologne.

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THE PLAN: More of the same

So here's the plan.

As of today. It could change tomorrow.

This is mostly a medical post, so those who aren't CLL or transplant aficionados might want to skim it quickly or skip to the last few paragraphs.

As you know from my spotty posting, my status has been delightfully boring with little new to report.

To understand what I am planning to do, it is important to see it for what it is: more of the same.

Let's go back to last spring when I started down this very smooth path.

Allow me to briefly summarize my journey over the last 12 months.

Almost two years post transplant, my platelets had fallen again, this time over four weeks from 242,000 to 32,000 in May 2010 despite low dose IVIG infusions (30 grams) twice a month.

With the platelet crash I was re-staged to be sure it was ITP.

It was.

My CT scan showed the largest cluster of nodes was way too big: 6.4 x 3.4 cm. on the right side of my mesentery. The flow cytometry showed CLL was back in my peripheral blood again. My ALC was normal but my atypical lymph count had reached 12%. Red cells were fine and I could feel some small palpable nodes in my neck, but nothing worrisome.

So besides the ITP, it was all too clear that the CLL was stealthily but forcefully on the move again.

Yucch.

That's when it was decided to go back to what had worked so well before my transplant, the unusual but magic mix of ciclosporin (CSP) 150 mg twice a day and some heavy cycles of rituximab (R) at 500/M2 weekly x 6. And continue the IVIG unchanged.

It worked quickly. My platelets jumped up immediately and were soon a non-issue again.

As of now, my ITP as measured by my platelet count seems to be stable or even trending upward with numbers often well above the amazing level of 400,000, and never below 270,000 for almost a year now. The therapy is working great for ITP!

After the first cycle of rituximab, my follow up CT scan in September 2010 showed my largest node was 3.8 x 1.7 cm, still much too big, but also much better. My ALC was low to low-normal ranging from 0.52 to 0.79, likely from the R wiping out all my B cells. My bone marrow showed about 5-10% CLL on the biopsy and 3% by flow cytometry.

Not just my ITP, but my CLL was responding to this non-chemo therapy as it had done before.

So I did a second round of 6 weekly doses of rituximab starting in October and finishing late in November. During this time, I also had to reduce the CSP because of its well known nasty side effects when my uric acid jumped to 9.4 (really should be less than 6 but we can accept as high as 8) and when my blood pressure shot up. Thankfully renal function (creatinine and eGFR) stayed in the normal range this time, unlike my last CSP scare.

I eventually readjusted my BP meds and halved the CSP to 75 mg twice a day, which is my present dose. Uric acid is fine again, creatinine has climbed a touch but is still normal, and my BP is great to high normal. It depends on who is checking it. It is always great at my office and alway borderline at the cancer center.

Not a perfect portrait, but not bad. I can't imagine what these renal parameters would be if I wasn't vegan. I do believe my anti-inflammatory diet moderates some of the toxicity of my disease and its treatments.

My ALC is now up to normal ranging from 0.7 to 1.2.

My Hgb has dipped as low as 12.7 but last week was a robust 15. It fluctuates between a bit low and low normal. My red cells are always slightly too big or macrocytic, but it is not progressive.

The few tiny nodes that never went away in my neck after the first round of R therapy didn't change much with the second hit of monoclonal antibody, but they were tiny.

The bone marrow biopsy on March 30 showed 3% CLL on flow, and < 5% on the biopsy. Even better than 6 months earlier. It also showed some mild hypocellularity (30%), which means it may have been beaten up more than I realize with the transplant. FISH studies for the usual suspects for MDS and CLL were negative. All in all a very good result.

The next important piece of the puzzle is the imaging.

Here there is a new wrinkle in the strategy. I am switching to MR. My hospital has just installed a new more powerful machine, and although the details won't be as precise as on a CT, it will be good enough for a new baseline. Truth is that I don't need to know if my nodes are 1.9 or 2.2 cm but I do need to know if they are 2 or 4 cm. All future imaging will be on this same machine, and hopefully this will eliminate the Morton's fork of too much radiation or not enough information. The scan will be in mid June.

What I do know is that my palpable nodes are definitely growing very slowly. Kipps agrees. Is it because of the reduction of the CSP as the nodes seemed to enlarge after the last drop in dosage, or is that the R finally wearing off (it has been 6 months since the last infusion), or is it just what it is.

Unless the MR finds the bad or good extreme of either massive nodes or no nodes, I will be doing 6 weeks of R again in late June through early August. 6-12 weeks later I will repeat the MR.

During this time I will continue on the same dose of CSP and then try to stretch out the IVIG to three weeks between treatments which will also spare my veins, which are getting a little inflamed from years of abuse by the IV nurses.

I hope to make only one change at a time so I can monitor the effect.

After that, I will try to reduce the CSP to 50 mg twice a day, but I am nervous about going lower than that. Rai is not keen on my stopping the ciclosporin, ever.

After that more R again in 6 months and another BMB and MR scan somewhere in there, depending on how things go this summer.

If this is smelling a lot like rituximab maintenance with the every six month dosing, it might be.

But I believe it is more than that because clearly the CSP has anti-leukemic properties proven in the test tube and a few published cases and at least twice in this little body of mine. It is a novel low toxicity combination therapy that probably should be better studied.

I believe this approach is using CSP and R to treat to goal, to shrink those mesenteric nodes.

Maybe I will need to add something like AMD3100 or CAL 101 to get the B cells out of the nodes, but I will cross that bridge if and when I need to.

Imagine no chemotherapy and getting a complete remission!

The plan:

More R, slowly reduce the CSP, and stretch out the IVIG, but don't totally stop either, and watch the nodes in the gut with a MR instead of a CT.

So I can avoid more chemo.

So I can feel well longer without damaging my marrow or likely making my cancer more aggressive or resistant and only mildly mangling my immunity.

So I can stay out of the 5th floor of City of Hope for a second transplant a little longer .

So I can wait out a possible cure without burning too many bridges.

So I can hug and hold my first grandchild, a girl due in July without dreading every cough or drool.