The Expanding Alphabet String

Newly diagnosed CLL patients are often bewildered by the cryptic acronyms that are very much part of the CLL scene. I have it on my to-do list to publish a glossary of all the acronyms with a short description of what they mean. One of these days I will actually get it done.

But “FCR” is a three letter acronym that deserves special attention. It is a combination of three of our most powerful CLL drugs: fludarabine (a purine analog similar to pentostatin), cyclophosphamide (an alkylating agent similar to chlorambucil) and Rituxan (an anti-CD20 monoclonal – we hope the next generation anti-CD20 monoclonal ofatumumab (Humax-CD20) will get approved soon). Over the past several years M. D. Anderson has taken the lead in conducting large scale Phase – II trials that have demonstrated the oomph of the FCR combination.

When used in chemo naïve patients as frontline therapy, the overall response rates obtained using FCR are impressive; as is the number of people who get CR (“complete response” - desirable, but not the same as the English word CURE). However, bear in mind FCR statistics are not quite as rosy in previously treated patients and life after FCR relapse can be quite challenging with few good options for an encore.

Since FCR is so very potent, can we build on its success? How about making the three letter acronym into a four letter acronym, adding an equally powerful drug called mitoxantrone (spelled a little differently in Europe) to the mix, expanding (and jumbling up) the alphabet string to FCM-R?

What is Logic Behind Adding More Drugs to a Winning Combination?

There is a school of thought that says attacking the cancer from many different directions all at once is the way to go. The idea is that such an attack gives the cancer cells no avenue of escape, kills all of the cancer cells in one fell swoop. The idea is to get aggressive enough to kill the cancer, but stop short of where the patient cries “uncle!”

This is a “Shock and Awe” high-risk approach that may or may not be the best option in indolent cancers such as CLL. More recent information gained from FCR clinical trials suggests even the deepest remissions eventually fail. So far it has not been possible to kill every single last remaining CLL cell by declaring no holds barred chemotherapy war. The stubborn straggler cancer cells eventually grow back and when they do, they have learned a few tricks they did not know before – witness the tough salvage therapy problems presented by patients who relapse soon after completing FCR protocol. But it is also important to remember combinations such as FCR give long lasting remissions to a substantial percentage of chemo naïve patients willing to bring out the big guns right up front.

“Non-overlapping Toxicites”

Researchers love the concept of “non-overlapping toxicities” because based on this idea they can then really turn on the juice. To explain this concept in a way you cannot forget, drug A may cause you to barf, while drug B may cause you to take up semi-permanant residence on the toilet seat. Just so long as the problem associated with each drug is different and does not overlap with the other one, the idea is that you should be able to handle it; there is no increase in the individual pain associated with either of the issues by its lonesome self! On this basis, it is hoped that the toxicities associated with mitoxantrone do not overlap with the toxicities baked into the FCR cake.

What is Mitoxantrone?

Mitoxantrone (brand name Novantrone) has been around a long time, even though it may be new to us in the CLL community. This agent belongs to a group of medicines called cytotoxic antibiotics. Doxorubicin is a well known member of this family, part of the “CHOP” regimen used more frequently by non-Hodgkin’s lymphoma patients. These are synthetic medicines that have been derived from compounds found in certain bacteria and fungi. Mitoxantrone’s exact mechanism of action is unknown but it seems to insert itself into the strands of DNA inside your cells and prevents them from making additional DNA and proteins. All this prevents the cell from growing and therefore it dies. One of its major uses has been for treating AML and multiple sclerosis.

Mitoxantrone is clinically associated with a much lower cardiac toxicity than its better known cousin doxorubicin. I will have more to say about this in my editorial. It is also important to remember mitoxantrone lasts a long time in your body – see the abstract below.

Neurology. 2004 Dec 28;63(12 Suppl 6):S15-8.

Mechanism of action of mitoxantrone

Fox EJ

MS Clinic of Central Texas, 7200 Wyoming Springs Dr., Suite 1100, Round Rock, TX

Mitoxantrone, a synthetic anthracenedione, was developed in the 1980s as a doxorubicin analogue in a program to find a cytotoxic agent with decreased cardiotoxicity compared with doxorubicin. It was approved by the FDA in 1987 for the treatment of adult acute myeloid leukemia and in 1996 for symptomatic hormone-refractory prostate cancer. In 2000, mitoxantrone was approved by the FDA for the treatment of worsening relapsing-remitting multiple sclerosis (MS), secondary progressive MS, and progressive-relapsing MS. Mitoxantrone is taken up rapidly by tissues, from which it is released slowly, and the terminal half-life ranges from 8.9 hours to 9 days. The highest concentrations of the drug are typically found in the thyroid, liver, and heart, and the drug persists in the body for as long as 272 days. Mitoxantrone is effective in reducing disease progression through a variety of different mechanisms of action. For example, it suppresses the proliferation of T cells, B cells, and macrophages. It impairs antigen presentation and decreases the secretion of proinflammatory cytokines. Mitoxantrone enhances T-cell suppressor function and inhibits B-cell function and antibody production. Finally, it inhibits macrophage-mediated myelin degradation. Compared with interferon betas, mitoxantrone has a broad range of actions and has effects on many different types of immune cells.

PMID: 15623664

FCM+R Clinical Trial

OK, we now have some idea what mitoxantrone is, we are duly impressed by its fire power. What can it bring to the FCR party? M. D. Anderson conducted a clinical trial to find out the answer to this question.

Thirty patients recruited for this trial were all previously untreated (“chemo naïve”) patients, the kind that responds best to FCR therapy. There was an age restriction (no one over 70) and aggressiveness of disease was defined almost entirely by the level of beta-2-microglobulin. These patients were not what I would call a tough crowd. The treatment protocol was basic FCR with addition of mitoxantrone. Knowing full well the potential for neutropenia in high impact combinations such as this, pegfilgrastim (brand name “Neulasta”, a longer lasting version of more familiar “Neupogen”) was administered routinely with each cycle. As with the FCR combo, cycles were spaced apart by a month or so and lasted for a total of 6 cycles.

Below is the abstract of a very recent article in Leukemia Research, giving us a first glance of what to expect from this souped-up combination.

Leuk Res. 2009 Jul 29.

Fludarabine, cyclophosphamide, mitoxantrone plus rituximab (FCM-R) in frontline CLL <70 Years.

Faderl S, Wierda W, O’Brien S, Ferrajoli A, Lerner S, Keating MJ.

Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.

Randomized trials demonstrated the superiority of chemoimmunotherapy over chemotherapy in the frontline treatment of CLL. Based on favorable experience with the addition of mitoxantrone (M) to fludarabine (F) plus cyclophosphamide (C), we designed a pilot study testing the combination of FCM plus rituximab (R). Thirty patients with previously untreated, symptomatic CLL, <70 years, and beta-2-microglobulin <twice upper limit of normal were evaluated. Treatment consisted of F 25mg/m(2)/day on days 2-4, C 250mg/m(2)/day on days 2-4, M 6mg/m(2) on day 2, and R 375mg/m(2) on day 1. For cycles 2-6, FCM started day 1 together with R 500mg/m(2). Pegfilgrastim was administered with each cycle. Cycles were repeated every 4-6 weeks. Complete remission (CR) was achieved in 83% of 30 patients, nodular partial response in 10%, and partial response in 3%. The overall response rate was 96%. Sixteen of 24 CR patients (67%) achieved a flow cytometry response with <1% marrow CD5/CD19-positive cells and 13 of 21 CR patients (62%) were MRD-negative by molecular evaluation for clonal IgV(H). With a median follow up of 38.5 months, the median time to treatment failure (TTF) has not been reached. A comparison with a historical group of FCR-treated patients showed no significant differences with respect to response and toxicities. FCM-R is highly active in patients < 70 years with favorable beta-2-microglobulin levels and previously untreated CLL. Outcome does not differ from FCR-treated patients.

PMID: 19646755

Oops! All that fuss and muss, and the “Outcome does not differ from FCR treated patients” !? The authors state there was no difference in toxicities of the FCR+M combo in this trial when compared to their historical database of FCR trials. However, I notice there was very little attention paid to cardiac toxicity, certainly the patients were not monitored for any great length of time after completion of the FCR+M trial. Since we know mitoxantrone lasts for many months in the body, it is reasonable to wonder if there were delayed incidents of cardiac toxicity. Seems to be a bit of “Don’t ask, don’t tell” policy going on here.

While I am on the subject of mitoxantrone trials, here is an abstract from a recent European clinical trial. They seem to have really gone for a record here, increased dosages during the initial FCR+M cycles followed by Rituxan maintenance therapy. As one would expect, the response statistics were impressive. But the authors take pains to report even in their abstract that if you had 17p deletion going in, don’t expect to get a CR from this souped up combo. Patients with good prognostics did well, but those with more aggressive CLL did not. What else is new?

J Clin Oncol. 2009 Aug 24.

Rituximab, Fludarabine, Cyclophosphamide, and Mitoxantrone a New, Highly Active Chemoimmunotherapy Regimen for Chronic Lymphocytic Leukemia.

Bosch F, Abrisqueta P, Villamor N, Terol MJ, González-Barca E, Ferra C, Diaz MG, Abella E, Delgado J, Carbonell F, García Marco JA, Escoda L, Ferrer S, Monzó E, González Y, Estany C, Jarque I, Salamero O, Muntañola A, Montserrat E.

Department of Hematology, Hospital Clínic, Institut de Investigacions Biomèdiques “August Pi i Sunyer”; Department of Hematopathology, Hospital Clinic; Hospital “Duran y Reynals,” L’Hospitalet; Hospital del Mar; Hospital de Sant Pau, Barcelona; Departments of Hematology, Hospital Clínic; Hospital General Universitario; Hospital Dr Peset; Hospital “Arnau de Vilanova”; Hospital “La Fe,” Valencia; Hospital “Germans Trias y Pujol,” Badalona; Hospital Clínico Universitario, Salamanca; Hospital Universitario Puerta de Hierro, Madrid; Hospital Joan XXIII, Tarragona; Hospital “Josep Trueta,” Girona; and Hospital Mutua de Terrassa, Terrassa, Spain.

PURPOSE: The addition of monoclonal antibodies to chemotherapy has significantly improved treatment of chronic lymphocytic leukemia (CLL). Based on excellent results with the chemotherapy-only regimen fludarabine, cyclophosphamide, and mitoxantrone (FCM), we built a new chemoimmunotherapy combination-rituximab plus FCM (R-FCM). We report a phase II clinical trial consisting of an initial treatment with R-FCM followed by rituximab maintenance. PATIENTS AND METHODS: Seventy-two untreated CLL patients age 70 years or younger received rituximab 500 mg/m(2) on day 1 (375 mg/m(2) the first cycle), fludarabine 25 mg/m(2) IV on days 1 to 3, cyclophosphamide 200 mg/m(2) on days 1 to 3, and mitoxantrone 6 mg/m(2) IV on day 1, given at 4-week intervals with up to six cycles supported with colony-stimulating factor. Patients achieving response received maintenance with rituximab 375 mg/m(2) every 3 months for 2 years. RESULTS: The overall response, minimal residual disease (MRD) -negative complete response (CR), MRD-positive CR, and partial response rates were 93%, 46%, 36%, and 11%, respectively. Severe neutropenia developed in 13% of patients. Major and minor infections were reported in 8% and 5% of cycles, respectively. Advanced clinical stage, del(17p), or increased serum beta2-microglobulin levels correlated with a lower CR rate. CONCLUSION: R-FCM is highly effective in previously untreated CLL, with an 82% CR rate and a high proportion of MRD-negative CRs (46%). Treatment toxicity is acceptable. Parameters correlating with a lower response rate were advanced clinical stage, high serum beta2-microglobulin levels, and del(17p). Based on these results, R-FCM warrants further investigation in randomized clinical trials.

PMID: 19704063

Editorial: Why Not Kick It Up Another Notch?

Many of my comments below are abstracted from an earlier article (August 2005) published on our website.  Please refer to it for more details.

Fortunately for us, mitoxantrone has been around for quite a while, and there is a long track record. Its potency is undisputed, along with its siblings doxorubicin, epirubicin, etc. Equally well understood are its potential risks, some of which are not trivial. The single biggest risk factor for use of mitoxantrone is cardiac toxicity. There are maximum life time dosage restrictions on use of this drug.

To see how BC Cancer Agency rates the risk check out this link: B. C. Cancer Agency on Mitoxantrone.

Cardiotoxicity is cumulative across members of the anthracycline (daunorubicin, doxorubicin, epirubicin, idarubicin) and anthracenedione (mitoxantrone)) class of drugs. Patients who have received these drugs are at increased risk of toxicity and should be carefully monitored. The cumulative dose is lower in patients who have received radiation to the mediastinal area or concomitant therapy with other cardiotoxic agents such as cyclophosphamide.”

I have to admit I was taken aback when I read the “Dear Doctor” letter that was sent out by Serono, the company that manufactures Novantrone, a branded version of mitoxantrone. These letters are sent out under FDA mandate, when post marketing surveillance identifies new or increased risks that have not been identified up to that point. Below are some paragraphs abstracted from the letter, pointing out that even in the case of “old” drugs such as this there are new things to be learned. This is serious stuff folks.

April 2005

Dear Healthcare Professional:

This letter is sent to you to supplement previously provided information concerning the risks of cardiotoxicity associated with NOVANTRONE® (mitoxantrone for injection concentrate) treatment for multiple sclerosis (MS) and also provides supplemental information regarding secondary acute myelogenous leukemia (AML) reported in MS patients treated with NOVANTRONE®.

Reports received through post-marketing surveillance, have shown that diminished cardiac function may occur early on in the treatment with NOVANTRONE®. Therefore, the Product Labeling for NOVANTRONE® was updated in March 2005 to state that cardiac monitoring of MS patients should be performed at baseline and prior to administration of every dose of NOVANTRONE®.

The advisory goes on to say

Active or dormant cardiovascular disease, prior or concomitant radiotherapy to the mediastinal/pericardial area, previous therapy with other anthracyclines or anthracenediones, or concomitant use of other cardiotoxic drugs may increase the risk of cardiac toxicity. Cardiac toxicity with NOVANTRONE® may occur at lower cumulative doses whether or not cardiac risk factors are present.

Cardiotoxicity can occur at any time during NOVANTRONE® therapy, and the risk increases with cumulative dose. Congestive heart failure (CHF), potentially fatal, may occur either during therapy with NOVANTRONE® or months to years after termination of therapy. All patients should be carefully assessed for cardiac signs and symptoms by history and physical examination prior to start of NOVANTRONE® therapy. Baseline evaluation of left ventricular ejection fraction (LVEF) by echocardiogram or multi-gated radionuclide angiography (MUGA) should be performed.

We got into a bit of an argument (understatement!) with the researcher in charge of the M. D. Anderson trial because their patient information packet made no mention of potential risk of cardiac toxicity and their clinical trial protocol made no effort to get detailed cardiac history or MUGA scans (mandated by FDA in the letter) of the patients they recruited for the trial. Prior cardiac health was not even part of the selection criteria for inclusion in the trial.   What the heck?!?  This is a classic pattern of not paying attention to mandated rules regarding use of mitoxantron that the FDA deplored in a July 2007 missive.

We stuck to our guns (with help from Dr. Terry Hamblin), writing to the drug company providing financial support (also supplying mitoxantrone for the trial, clearly with financial interest in the trial) as well as the internal review board at M. D. Anderson, requesting that the protocol and inclusion criteria be modified to take potential cardiac toxicity into consideration. There was some push back at our gall and audacity, who-the-heck-did-I-think-I-was etc, but eventually I am happy to report our patient advocacy paid off. The clinical trial inclusion criteria were modified to rule out patients at risk, there was more effort at cardiac screening prior to entry.

All the same, I must confess I could not get commitment from the researchers that they would actively look for cardiac toxicity, or monitor patients long term for delayed onset of cardiac problems. I guess it is just too expensive to do these long term follow-up studies. We will only know by anecdotal stories whether any of the patients who participated in the USA or European mitoxantrone based trials had subsequent cardiac issues.  Please let us know if you participated in these trials and have something to say.

The real sad part of this story? All that fuss, added risk, and the results were no better than plain vanilla FCR. Oh well. Chalk it up to experience.

As for the volunteers who participated in these trials, even though you guys were not thanked for your trouble in either of the two papers cited above, you have our heartfelt thanks and admiration for taking part in these trials. You are our heroes.