The Age of Monoclonals

MDACC There is little doubt that things have changed in the CLL universe ever since Rituxan made its debut.  While unfortunately this important anti-CD20 monoclonal has low impact as a single agent therapy for CLL patients, there is little doubt that in combination with other conventional chemotherapy drugs it has made a huge difference. Everything seems to work better when Rituxan is around to lend a helping hand.  Among the combination regimens that have become famous are FR (fludarabine + Rituxan), FCR (fludarabine + cyclophosphamide + Rituxan), R+HDMP (Rituxan + high dose methyl prednisolone), R + R (Rituxan + Revlimid), R + B (Rituxan + bendamustine). The list goes on.

By now most of you are probably aware that we have a second generation version of Rituxan, a new anti-CD20 monoclonal that has recently won FDA approval. I have written extensively about ofatumumab (Trade name Arzerra, older name Humax-CD20). You can find the earlier articles by using any of these names as key words in the search box at the top right hand corner of our websites.

Rituxan is not a human protein.  Not 100%.  Part of the molecule derives from mouse protein – hence the nickname of “mouse juice” for this monoclonal.  Arzerra, on the other hand, is fully human protein. There are obvious advantages to this difference.  Some people develop allergic reactions to the mouse protein in Rituxan.  Rituxan hypersensitivity reactions can become very serious – at the very least the patient can no longer use the drug.  But even patients who are allergic to Rituxan may still use Arzerra.

There is also subtle but importance differences in exactly how Rituxan and Arzerra attach to the CD20 marker on B-cells.  It seems Arzerra attaches more strongly, and stays stuck for longer percentage of the time.  Not so Rituxan.  Think of it as Velcro – the stickiness is stronger and better in the case of Arzerra.  There has been some research suggesting that single agent Arzerra works better than single agent Rituxan because of this effect. And in the case of previously treated patients who were fludarabine refractory and Campath ineligible or refractory, ofatumumab did seem to work better than Rituxan.  That finding played a huge role in getting it FDA approval.

So, here is the million dollar question, can we do even better than FCR by using ofatumumab instead of Rituxan?  Is FCO better than the “gold standard” of FCR?

An Important Clinical Trial

This clinical trial is not a direct comparison of FCR versus FCO.  This trial is not the apples to apples comparison I would have liked to see between these two chemoimmunotherapy regimens.  It reports only on FCO;  but fortunately there is now enough evidence about how FCR behaves that we might be able to draw some conclusions based on historical FCR data.  The abstract of this paper is below.  Send me a personal email if you want to read the full text of this article and would like some help in locating it.

Blood. 2011 Apr 15.

Chemoimmunotherapy with ofatumumab, fludarabine, and cyclophosphamide (O-FC) in previously untreated patients with chronic lymphocytic leukemia.

Wierda WG, Kipps TJ, Dürig J, Griskevicius L, Stilgenbauer S, Mayer J, Smolej L, Hess G, Griniute R, Hernandez-Ilizaliturri FJ, Padmanabhan S, Gorczyca M, Chang CN, Chan G, Gupta I, Nielsen TG, Russell CA.

M.D. Anderson Cancer Center, The University of Texas, Houston, TX, United States;

We conducted an international phase II trial to evaluate two dose levels of ofatumumab, a human CD20 monoclonal antibody, combined with fludarabine and cyclophosphamide (O-FC) as frontline therapy for chronic lymphocytic leukemia (CLL). Patients with active CLL were randomized to ofatumumab 500 mg (n=31) or 1000 mg (n=30) day 1, with fludarabine 25 mg/m(2) and cyclophosphamide 250 mg/m(2) days 2-4, course 1; days 1-3, courses 2-6; every 4 weeks for 6 courses. First ofatumumab dose was 300 mg for both cohorts. The median age was 56 years; 13% of patients had 17p deletion; 64% had β2-microglobulin > 3.5 mg/L. Complete response (CR) rate (1996 NCI-WG criteria) assessed by an Independent Review Committee was 32% for the 500-mg and 50% for the 1000-mg cohort; overall response rate (ORR) was 77% and 73%, respectively. Based on univariable regression analyses, β2-microglobulin and number of O-FC courses were significantly correlated (P<.05) with CR, ORR and progression-free survival. Most common CTC grade 3-4 investigator-reported adverse events were neutropenia (48%), thrombocytopenia (15%), anemia (13%) and infection (8%). O-FC is active and safe in treatment-naïve patients with CLL, including in patients with high-risk features. This trial was registered at http://www.clinicaltrials.gov (NCT00410163).

PMID: 21498674

Clinical Trial Details

In this multi-center trial 61 patients were randomly divided into two groups.  The inclusion criteria were pretty straight-forward: previously untreated patients who met the usual guidelines (NCIWG) for start of therapy were eligible, provided they did not have HIV, Richter’s, hepatitis B, central nervous system involvement, significant cardiac disease, uncontrolled infections etc.  In other words, just plain CLL folks ready to start therapy.  The two arms differed only in one item: the amount of ofatumumab they got.

Drug Dosages

There were two arms to this study.  Half the patients got 500 mg of ofatumumab each cycle, the other half got 1,000 mg of ofatumumab per cycle.  Both groups got the same amount of fludarabine and cyclophosphamide.  How did these amounts compare with conventional FCR?  Below is a table that compares the drug dosages.  I used the FCR dosing information from the famous German study that we reviewed before. (Write to me if you want help locating the full length text of this study as well). “Monoclonal” in the table below refers to either ofatumumab or Rituxan, depending of whether you are looking at the FCO columns or the FCR column, respectively.

FCO drug dosages

The drug dosage regimens for both trials are remarkably similar.  Each trial targeted for a total of 6 cycles, each cycle lasting 28 days.  Fludarabine and cyclophosphamide were given on days 1, 2 and 3 of each cycle, at the dosages shown above.  Monoclonal drug (ofatumumab or Rituxan respectively) were given only once each cycle, on the first day.  (Dosages were tweaked around a little for the very first cycle, to make sure patients tolerated the drugs OK).

Notice the units are different for measuring ofatumumab and Rituxan.  In the case of the FCO trial, ofatumumab is measured in milligrams.  Not so the Rituxan in FCR.  There the units are milligrams per meter square (mg/m2).  Don’t get too flummoxed by this little twist.  mg/m2 just means they are also using the patient’s body size, in terms of BSA (body surface area – measured in square meters).  A 180 pound man who is about 5 ft 10 inches tall has a BSA of 2.0 For such an average man, the Rituxan dosage given to him in the FCR trial would have been 500 X 2 = 1,000mg.  So, basically the second arm of the FCO group got the same amount of monoclonal as the FCR patients. The first arm of the FCO group got roughly half the amount of monoclonal as everyone else.

Patient Characteristics

As I said above, this is not a head-to-head comparison of FCO versus FCR.  But in the table below I have tried to consolidate the patient characteristics as best as I can, using information provided in the two papers.

FCO patient characteristics

As you can see, some of the stuff matches and some of it does not.  The FCR trial had far more patients in it (408) than both arms of the FCO trial combined (61 patients).  That has an obvious impact on the robustness of the results.  That said, I was pleased to see roughly the same percentage of the participants in both trials were in late Binet Stage C (33% versus 31%).  For a change, both trials report on modern prognostic indicators such as IgVH gene mutation status, FISH abnormality, CD38 and B2M.  The match is about as good as it gets, considering I am comparing two unrelated trials.  You can make up your own mind how you weigh the different prognostic indicators.

Response to Therapy

This is the punch line, the one that matters to patients and their families.  Once again, I did my best to compare the two trials – but please be aware that I had to do a lot of data consolidation to come up with this chart.

FCO response to therapy

I must also point out that for some reason not all the patients in the FCO trial (either arm) finished all 6 cycles.  In fact, only 39 out of the 61 patients got all six cycles.  The authors note that response to FCO therapy was strongly influenced by how many cycles the patients actually got – I can see how that is quite reasonable, response statistics are strongly influenced by the total amount of drugs the patients got and the duration of their therapy.  For patients who finished all 6 of the planned 6 cycles of FCO, the overall response rate jumped to 92% and the “CR” rate jumped to 56%.

Bottom line, within the limits of this not-apples-to-apples comparison, I think the response statistics immediately after completion of therapy (i.e., the overall response rate and the percentage of CRs) were roughly the same between the FCO and FCR groups – if you make allowance for the fact that a significant portion of the FCO group did not complete all 6 cycles.

The intriguing part is the state of affairs two years after start of therapy.  I am not sure if this is statistically significant or whether it will hold up after more months and years have passed; but a higher percentage of folks who got FCO are still alive, still in remission two years out.  The differences are small, and there is a whole lot of stuff that does not match between the FCO and FCR groups.  For all I know, these differences will be washed out as time goes on.

Adverse Effects

As you would expect, the adverse effect profile between Arm1 (500 mg ofatumumab) and Arm 2 (1,000 mg oftumumab) were slightly different.  Higher drug dosage also meant higher adverse effect profile.  What else is new, you get you bang for the buck.  Here is how hematological toxicity and infections played out in the two arms.

FCO adverse effects

How do the adverse effects compare between FCO and FCR?  Once again I collapsed the two arms of FCO above and compared the numbers against FCR data from the German study.

FCO vs FCR adverse effectsIs there a difference?  Which one is better?  Hard to tell.  There seem to be a tad more infections in the FCR group compared to the folks who got FCO.  On the other hand, there is slightly more hematological toxicity (reduced neutrophils, platelets and red blood cells respectively) in the FCO group.  Is the difference significant in view of the fact that the two groups are not exactly well matched?  I do not think so.

Editorial

How I wish this was a kosher head-to-head comparison of FCO versus FCR comparison.  It is not.  It took a lot of data matching for me to do this comparison.  The two groups were roughly equivalent, but that is not the same thing as two well matched arms nicely randomized by a computer to get either FCR or FCO.

The latest FCO article gives us a first look at how this combination is likely to play out.  But it is good to remember the sample size is small (only 61 patients, divvied up into the two arms getting 500 or 1,000 mg of ofatumumab respectively).  Compared to this rather small number, the German study had more than 400 people in their FCR arm.  But to their credit, both studies report on full prognostic details of their patients.  If you are a glutton for detail, I strongly urge you to read both of the full text articles.

Was there a slam dunk out of the ballpark hit justifying the substitution of ofatumumab in place of Rituxan in this study?  I am afraid not.  Overall response statistics and adverse effect profiles look about the same, if I make allowances for all the ways the two groups are different.  Not enough time has passed yet (only 24 months of observation time since start of therapy with FCO) for us to get a good sense of how these patients will fare down the road.  Will they have longer remissions, will they have longer overall survival?  Only time will tell.  But this much seems obvious:  I think in future the dosage for FCO is going to be the standard dosages of F (25 mg/m2 three times each cycle) and C (250 mg/m2 three times each cycle) and ofatumumab at 1,000 mg, once each cycle.  That puts it just about in the same range as the dosage of F, C and R in the German FCR study.

I guess I am a little disappointed.  I expected to see significantly less toxicity and/or significantly higher percentage of “CR” responses, as a result of substituting “O” for “R”.  That was not the case.  Only time will tell if there is improvement in overall survival and longer remissions as a result of substituting “O” for “R”.

It is good to have a second anti-CD20 monoclonal, if for no other reason than to give Rituxan and its manufacturers some competition.  And for the folks that develop hypersensitivity to the murine component (“mouse juice”) of Rituxan, having access to a fully human protein drug such as ofatumumab is a huge relief. It made a huge difference in the case of my husband. He developed massive allergic reaction to Rituxan and having access to ofatumumab (Humax-CD20 in those days) gave him two extra very precious years.  Bottom line, I do not think we have seen anything here to make FCO the new “gold standard”.  I expect both FCO and FCR will continue to compete for patients and market share, until something else comes along that is better than either of them.

Our message seems to be getting through, the very first group that the authors of this paper thank are the patients who participated in this FCO clinical trial. Please join me in thanking them as well.  How else would you ever learn all these details about FCO chemoimmunotherapy combination?  You owe them, big time.

foxglove