WVCI ASH 2012 Abstracts

ASH abstracts are out.  I recently posted on how to carefully evaluate the news.  Over next several weeks I want to draw attention to those abstracts that I think are most noteworthy.  In the meantime, I thought I would put the links to the studies our center has participated in.  Most of these represent collaborations with leaders in CLL and NHL.  It has been a good year in CLL/NHL and I think we are really on the verge of substantial change in the field.

Ibrutinib Is an Irreversible Molecular Inhibitor of Interleukin-2 Inducible Kinase: Expanding Therapeutic Potential and Modulating a Th1 Selective Pressure in CD4 T-Cells

Combinations of the Phosphatidylinositol 3-Kinase-Delta (PI3Kδ) Inhibitor Gs‑1101 (CAL-101) with Rituximab and/or Bendamustine Are Tolerable and Highly Active in Previously Treated, Indolent Non-Hodgkin Lymphoma: Results From a Phase I Study

Variation in Health-Related Quality of Life by Line of Therapy of Patients with Chronic Lymphocytic Leukemia

The Bruton’s Tyrosine Kinase (BTK) Inhibitor Ibrutinib (PCI-32765) Promotes High Response Rate, Durable Remissions, and Is Tolerable in Treatment Naïve (TN) and Relapsed or Refractory (RR) Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL) Patients Including Patients with High-Risk (HR) Disease: New and Updated Results of 116 Patients in a Phase Ib/II Study

Combinations of the Selective Phosphatidylinositol 3-Kinase-Delta (PI3Kdelta) Inhibitor GS–1101 (CAL-101) with Rituximab and/or Bendamustine Are Tolerable and Highly Active in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL): Results From a Phase I Study

A Phase 2 Study of Brentuximab Vedotin in Patients with Relapsed or Refractory CD30-Positive Non-Hodgkin Lymphomas:  Interim Results

The Bruton’s Tyrosine Kinase Inhibitor Ibrutinib (PCI-32765) Is Active and Tolerated in Relapsed Follicular Lymphoma

How I treat Diffuse Large B Cell Lymphoma (DLBCL)

In contrast to the debate about how to select initial treatment for patients with follicular lymphoma, treatment in DLBCL is considerably more straight forward.  These two lymphomas represent the most commonly diagnosed subtypes of NHL.  For further questions about thedifferent types of NHL link here.

Most patients with DLBCL are going to be treated with R-CHOP.  I have a lengthy post about this regimen that describes the regimen in detail for the interested reader.  There are a number of considerations that may individualize therapy for some patients so it is not just a blanket – one size fits all.

When R-CHOP is the selected regimen, several important questions need to be asked.  The first question is “how many cycles.”  In most patients the answer will be six.  I normally repeat CT scans after cycles two, four, and six.  If the patient still has measurable disease and it continues to shrink between cycles four and six – I will occasionally go to eight cycles – but that is definitely the minority of patients.  You cannot continue R-CHOP indefinitely because the “H” which stands for “hydroxydoxorubicin” aka “Adriamycin” can be hard on the heart and you can only give so many doses before running into long term cardiac issues.

For the less common patient who shows up with “limited stage” (ie. Stage I or stage II disease mostly in one spot), you can consider a shorter duration of R-CHOP when combined with radiation.  Usually 3 cycles followed by radiation is enough.  Sometimes that is more difficult when the site of disease is less agreeable to radiation such as in the colon.

I will also use radiation in patients who present with stage III, or IV disease provided there was one spot that was particularly bulky at the start (>10cm) but this is a little more controversial.  This tends to reduce the likelihood that disease will relapse at the same site of disease, but does not necessarily prevent distant spread of the lymphoma.

The next question is whether a patient is at risk for their lymphoma coming back in their brain.  Since chemotherapy does not get into the brain very well, it is a site of relapse in a minority of high risk patients.  This includes patients whose initial disease started in the testicle, the nasal sinuses, or someone who has a lot of disease outside of their lymph nodes (what we call extra-nodal disease).  For those patients with high risk of CNS relapse, we have the option of administering a shot of a drug called methotrexate by way of a lumbar puncture.  When done by our radiology colleagues using fluoroscopy, this doesn’t typically bother a patient too much. 

The problem with methotrexate is that we really don’t have a lot of confidence that it works particularly well.  It is one of those things we do by convention when what is really needed is a change of convention.  Some docs will actually give a much higher dose of methotrexate into a vein.  The dose in this situation typically requires the patient be admitted to the hospital for a few days.  This may be a more effective strategy, but obviously a lot more difficult to perform.

There are circumstances where R-CHOP may not be a good idea for a patient.  In patients with prior exposure to Adriamycin (perhaps for a breast cancer many years ago), or who are starting with a bad heart to begin with, you may need to substitute the Adriamycin for something more “heart friendly.”  Sometimes these substitutions are done for patients that you think might be a little too old or fragile to handle R-CHOP.   I did recently treat a 92 year old with DLBCL giving him six cycles of R-CHOP.  Granted, he was still out there chopping wood – but another example of where age does not equal limitation.  He is two years out from therapy now and just celebrated his 70^th anniversary – way cool!

There are a number of ways to do swap things around.  I know some docs who use a different formulation of Adriamycin known as “Doxil” which is more heart friendly.  Others have used a drug with a lot of similarities to Adriamycin known as mitoxantrone.  Unfortunately, this substitution reduces efficacy and it isn’t totally clear that it protects the heart all that much.  I have periodically used a substitute for Adriamycin known as etoposide.  The published study for this is pretty old and I cannot be certain it is a great substitute.  I try to use R-CHOP as much as I can, but sometimes you just have to avoid the Adriamycin.

Another key group of patients for whom I choose a different path are the patients with “double hit” lymphoma.  I need to explain some biology here.  There are common DNA abnormalities in DLBCL.  The most common is where a gene known as BCL-6 gets abnormally activated by getting the chromosomes rearranged, resulting in excessive protein.  This can happen with other genes including BCL-2 or Myc.  When a lymphoma has two of these (most commonly Myc and one of the others), we think these patients do not do as well as our more common “single hit” DLBCL.  Most scientists agree this group is considered “higher risk” but what to do about it is less agreed upon and subject of practice patterns not necessarily scientifically proven to be any better.

When Myc in locked on, the cells cannot stop dividing.  We see exceptionally highly proliferative tumors in this setting.  We can measure a “Ki67” which is just a marker for dividing cells.  While normal DLBCL might be anywhere from 40-80% of cells staining positive, Myc affected cells are almost always > 90%.  Myc is also a hallmark of a particularly aggressive version of lymphoma known as Burkitt’s lymphoma.  Unfortunately, if you show microscopic slides of very aggressive lymphomas to a bunch of pathologists, you will find a surprising degree of disagreement as to whether a lymphoma is Burkitt’s or DLBCL.  In fact there is even a new category known as “Aggressive B Cell lymphoma with features indeterminant between Burkitt’s and DLBCL.”  The main point for me, is that we sometimes under-diagnose either double hit lymphoma or it’s close cousin Burkitt’s and instead call it DLBCL.

Clinical science gets a little thin here so please do not take the following as the only acceptable strategy.  For those patients with highly proliferative tumors, I will use a regimen that has been studied in both DLBCL as well as Burkitt’s.  The regimen is known as “R-EPOCH”  A lot of the letters (as well as the drugs) are actually the same.  In fact, there is only one new drug – etoposide.  The main difference is that all the drugs are infused over four days through a pump followed by some injections on day five.  This is different than R-CHOP which is commonly given over just one day.

Since the regimen is good in Burkitt’s as well as DLBCL, I use it when there is gray area with the diagnosis.  I cannot say that this is definitively the right thing to do but I know a number of academic physicians who do the same.  There is a large research study currently comparing R-EPOCH to R-CHOP but it is accruing slowly and I don’t know if it will ever give us the answer as to which regimen is the best. 

R-EPOCH is also my preferred regimen for those patients with HIV who have been diagnosed with DLBCL.  This is a unique subpopulation that used to be a lot more common than it is today.  There have been a number of studies using this regimen in this setting.

Hopefully that should cover a number of questions about how to select a front line regimen in DLBCL.  It is not meant to be a replacement for your own doctors advice but hopefully give you confidence that your doc is on the right track.  I hope I’ve highlighted where things are pretty clear and where they are controversial so that any differences in strategy might be explainable.

Thanks for reading!

Jeff