“Cost” of Rituxan & Hepatitis

Cost side of B-cell depletion

And I am not talking about dollar costs, even though that too is pretty substantial.  I am talking about the immune system costs.  Over the millennia of our evolution, our bodies developed B-cells as an important part of our overall defenses against pathogens.  And Mother Nature does nothing without a purpose behind it.

Cost side of B-cell depletion via Rituxan therapy

And I am not talking about dollar costs of Rituxan therapy, even though that too is pretty substantial. In this article I am talking about the immune system costs. Over the millennia of our evolution, our bodies developed B-cells as an important part of our overall defenses against pathogens. And Mother Nature does nothing without a purpose behind it.  Getting rid of all your B-cells is not without cost.

Just in case you are a newcomer to CLL and not all that familiar with this most famous monoclonal antibody,  there is little doubt that Rituxan has changed the CLL landscape, for the better.  Just about every other drug (or drug combination) works better if Rituxan is added to the mix.  There is ample proof that FCR works better than FC, and FR works better than F.  The responses are deeper, the remissions are longer and people are enjoying increased overall survival since the age of Rituxan dawned.

Rituxan targets CD20, the marker present on all mature B-cells.  And I mean all mature B-cells, not just the pesky CLL cells.  That means Rituxan therapy targets and facilitates the killing of healthy B-cells, just as well as it targets and facilitates the killing of CLL cells.  The effect of deep seated B-cell destruction can be profound, especially if the Rituxan therapy is continued for many months (years!) as is sometimes done in Rituxan maintenance protocols.  Many of the comments in this article are equally applicable to the other anti-CD20 monoclonal antibody drugs – such as ofatumumab (aka Arzerra, aka Humax-CD20).

Rituxan is not “chemo”.  It is a biologic drug, a monoclonal antibody similar to the immunoglobulins your own body produces. Unfortunately, too many patients equate “not chemo” with “no toxicity”.  Reality is a bit more complicated than that. Rituxan does have some well documented toxicity effects, such as the infusion time side effects that many of you are familiar with.  But there are also some side effects that are not as well publicized and we are only learning about them as we get more hands-on experience with how this drug works in millions of patients undergoing treatment with it.  I thought I would pull together all the not-so-well-publicized risk factors of Rituxan, how it can degrade many aspects of your immune system. Specifically, I would also like to focus on long term Rituxan therapy and risk of hepatitis reactivation.

Downside of Rituxan Maintenance Therapy

There has been a flurry of interest in Rituxan maintenance therapy.  What this means is that after completing “induction therapy” of choice (FCR, FCR Lite, Revlimid, R+HDMP – take your pick of the alphabet soup) Rituxan is administered at regularly scheduled intervals in an attempt to prolong (“consolidate”) the remission obtained by the induction therapy.  There is reasonable grounds for doing this Rituxan maintenance.  Patients undergoing this approach do, in general, have longer remissions – even though the jury is still out on whether they live longer on the whole.  So, if dollars were not an issue, why do we not have all patients undergoing Rituxan maintenance therapy?

You are right, there is a catch. And the catch is that Rituxan maintenance therapy can cause deep and long lasting depletion of immunoglobulins. Low levels of immunoglobulins (especially the IgG variety) leave patients vulnerable to all sorts of infections. The only way to correct it promptly is through intravenous infusion of immunoglobulins (IVIG). This is a blood product painstakingly collected from large quantities of donated blood. It is expensive, often in short supply and there is a non-zero risk associated with infusion of any blood product.

The connection between long term Rituxan therapy and  low immunoglobulins is easy enough to explain.  In a nutshell, mature B-cells grow up to become plasma cells, the factories that produce immunoglobulins.  Another type of B-cell called a “memory B-cell” is particularly important since these wise old B-cells “remember” specific infections they saw in their youth and quickly initiate the production of just the right kind of immunoglobulins if the same infection were to strike again.  Rituxan kills all B-cells, including memory B-cells.  Long lasting Rituxan maintenance means long lasting B-cell depletion, which in turn means  catastrophic loss of plasma cells and their production of immunoglobulins grinds to a halt.

Hypogammaglobulinemia in pts receiving rituximab immunotherapy and the impact of rituximab maintenance.

Citation: J Clin Oncol 28:7s, 2010 (suppl; abstr 8088)

Abstract No: 8088

Author(s): C. Casulo, J. Maragulia, A. D. Zelenetz, Lymphoma Service, Department of Medicine; Memorial Sloan-Kettering Cancer Center, New York, NY

Background: Several randomized studies demonstrated that rituximab maintenance (RM) prolongs PFS (progression free survival) but not OS (overall survival) following induction with rituximab immunotherapy (I) alone or chemoimmunotherapy (CI) in patients (pts) with indolent lymphoma. The long-term impact of rituximab (R) on immune reconstitution has not been well studied; however R has been associated with hypogammaglobulinemia (hypogam) with recurrent infections. This retrospective study sought to evaluate the relationship between R, hypogam, and treatment with intravenous immune globulin (IVIG). Methods: We identified 215 pts treated with R for lymphoma between 12/1998 and 4/2009 and also had quantitative serum immunoglobulin levels (sIg) evaluated prior to and after treatment with R. Data on the use of IVIG was collected. Frequencies were compared using Pearson χ2. Results: Histologies included: DLBCL, N=68; FL, N=42; CLL/SLL, N=38; MZL, N=26; MCL, N=22; other subtypes, N=19. Pts received a median of 6 doses of R (range:2-50). Prior to treatment with R, 85% (183/215) of pts had normal sIg levels and 15% (32/215) had low levels. Histologies among 32 pts with baseline hypogam were well distributed: DLBCL, N=10; CLL/SLL, N=5; FL, N=5; MZL, N=4; MCL, N=2; other, N=6. Of 183 pts with normal sIg levels prior to R, 26.7% (49) received RM while 73.2% (134) received R as I or CI alone. Hypogam was documented in 39% (71/183) of pts with baseline normal sIg levels following R. RM was associated with a higher risk of developing hypogam, 55% (27/49) compared to 33% (44/134) receiving I or CI alone, p=0.006. IVIG was administered to 13% (23/183) of pts with normal baseline sIg. Among patients who received RM, 20% (10/49) received IVIG compared to 10% (13/134) among patients treated with I or CI alone, p=0.05. IVIG for treatment of symptomatic hypogam was administered to 10% (18/183) of pts with normal sIg prior to R therapy. Conclusions: R was associated with developing hypogam in 39% of pts with normal baseline sIg. Pts receiving RM had a significantly higher risk of developing hypogam and requiring IVIG. The risk of symptomatic hypogam should be considered in the use of R maintenance.

B-cells control T-cell diversity

Important as they are, B-cells and their influence on production of immunoglobulins downstream, they are only one part of our complex and amazing immune system.  T-cells are another very important aspect of controlling infections, especially viral infections.  T-cells and their side-kicks NK cells also play a crucial role in controlling secondary cancers.  Drugs such as Campath and fludarabine are justly infamous for depletion of T-cells counts, one of the major reasons why patients treated with these and similar drugs are at higher risk of viral infections, secondary skin cancer etc.

But Rituxan is exquisitely single minded in targeting only CD20, and this marker is only present on B-cells.  Does this mean Rituxan therapy has no effect on T-cell function?  Do we get a free pass on T-cell function by sticking to Rituxan only therapy?  Not quite so fast.

You see, our immune system is designed to work as an inter-connected system of different cell lines working together in harmony.  That is particularly true of B-cells and T-cells.  Both cell lines belong to the general description of lymphatic cells.  In fact, when your routine CBC blood test measures ALC (absolute lymphocyte count), it is measuring the numbers of both B-cells and T-cells.  There is a lot of cross-talk between B-cells and T-cells as they hang out at the local lymph node.  Each cell line influences the number and efficient function of the other.  Take away all the B-cells and the result is that T-cells miss their buddies and pine away.  B-cells are important “antigen presenting cells”, teaching their T-cell counterparts on what to attack.  Without enough B-cells around, T-cells become narrow minded in their focus, unable to deal with the wide repertoire of pathogens they are supposed to combat.  Moral of the story, long term B-cell depletion leads to loss of T-cell diversity, a crucial line of defense in protecting us against a variety of infections.

J Immunol. 2004 Apr 15;172(8):4709-16.

B cell-dependent TCR diversification.

Joao C, Ogle BM, Gay-Rabinstein C, Platt JL, Cascalho M.

Transplantation Biology Program, Mayo Clinic, Rochester, MN 55905, USA.

T cell diversity was once thought to depend on the interaction of T cell precursors with thymic epithelial cells. Recent evidence suggests, however, that diversity might arise through the interaction of developing T cells with other cells, the identity of which is not known. In this study we show that T cell diversity is driven by B cells and Ig. The TCR V beta diversity of thymocytes in mice that lack B cells and Ig is reduced to 6 x 10(2) from wild-type values of 1.1 x 10(8); in mice with oligoclonal B cells, the TCR V beta diversity of thymocytes is 0.01% that in wild-type mice. Adoptive transfer of diverse B cells or administration of polyclonal Ig increases thymocyte diversity in mice that lack B cells 8- and 7-fold, respectively, whereas adoptive transfer of monoclonal B cells or monoclonal Ig does not. These findings reveal a heretofore unrecognized and vital function of B cells and Ig for generation of T cell diversity and suggest a potential approach to immune reconstitution.

PMID: 15067046

Now we know IVIG (intravenous immunoglobulin therapy) serves another function, besides increasing levels of immunoglobulin g.  It can serve to improve T-cell diversity and therefore T-cell function.

Hepatitis

Hepatitis is liver inflammation caused by a group of viruses in most cases, but it can also be due to excessive alcohol consumption and certain medicines. The most common cause of hepatitis is infection by either hepatitis A (HAV) or hepatitis B (HBV) or hepatitis C (HCV).

Hepatitis A (also called infectious jaundice) is usually transmitted by contaminated food and water and so is much more common in third world countries. A vaccine is available that can prevent HAV infection for up to 10 years. Strict personal hygiene and staying away from possibly contaminated food / water are your best defenses.

Hepatitis B (HBV) is transmitted through blood (shared needles, shaving equipment etc), tattoos, unprotected sex with infected individuals etc. HBV infection can be either chronic or acute. In chronic cases the patient is unable to get rid of the virus after initial infection. A vaccine that can protect the individual for the rest of his life against HBV is now available. A million or so people die each year due to complications arising from chronic HBV infection, the largest percentage of them in South-East Asian countries (India!). The approved therapies for HBV infection are interferon and anti-viral drugs such as adefovir, entecavir, lamivudine and telbivudine.

Hepatitis-C viral infection (HCV) is present in roughly 1.5% of the general population in the USA. Here is the kicker: once a person has been exposed to HCV, he will retain trace amounts of this virus in his body for the rest of his life. Once exposed, you are tagged forever – this is the reason why people with prior history of hepatitis may not donate blood. In otherwise healthy people these trace levels of HCV are kept under control by the immune system – a truce of sorts is declared. But when there is a window of opportunity, a time when the immune system is not doing its job, HCV can seize the chance and grow back to full strength. This is called viral reactivation. In the case of HCV, the chief organ attacked is the liver. Liver enzymes (ALT, AST) can go sky high – sometimes fatally high.

“Hepatitis C in the rituximab era”

A recent article in “Blood” as well as an accompanying editorial underlined risk of hepatitis viral reactivation in patients undergoing Rituxan based therapies. You can read both the editorial and the full length article by clicking on the links.

Blood. 2010 Dec 9;116(24):5119-25. Epub 2010 Sep 7.

Hepatic toxicity and prognosis in hepatitis C virus-infected patients with diffuse large B-cell lymphoma treated with rituximab-containing chemotherapy regimens: a Japanese multicenter analysis.

Ennishi D, Maeda Y, Niitsu N, Kojima M, Izutsu K, Takizawa J, Kusumoto S, Okamoto M, Yokoyama M, Takamatsu Y, Sunami K, Miyata A, Murayama K, Sakai A, Matsumoto M, Shinagawa K, Takaki A, Matsuo K, Kinoshita T, Tanimoto M.

Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan. daisukeennishi@yahoo.co.jp

The influence of hepatitis C virus (HCV) infection on prognosis and hepatic toxicity in patients with diffuse large B-cell lymphoma in the rituximab era is unclear. Thus, we analyzed 553 patients, 131 of whom were HCV-positive and 422 of whom were HCV-negative, with DLBCL treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP)-like chemotherapy. Survival outcomes and hepatic toxicity were compared according to HCV infection. The median follow-up was 31 and 32 months for patients who were HCV-positive and HCV-negative, respectively. HCV infection was not a significant risk factor for prognosis (3-year progression-free survival, 69% vs 77%, P = .22; overall survival, 75% vs 84%, P = .07). Of 131 patients who were HCV-positive, 36 (27%) had severe hepatic toxicity (grade 3-4), compared with 13 of 422 (3%) patients who were HCV-negative. Multivariate analysis revealed that HCV infection was a significant risk factor for severe hepatic toxicity (hazard ratio: 14.72; 95% confidence interval, 6.37-34.03; P < .001). An exploratory analysis revealed that pretreatment transaminase was predictive of severe hepatic toxicity. HCV-RNA levels significantly increased during immunochemotherapy (P = .006). These results suggest that careful monitoring of hepatic function and viral load is indicated during immunochemotherapy for HCV-positive patients.

PMID: 2082345

Highlights

This study compared large numbers of patients who had not been previously exposed to hepatitis C with those who had been infected with this virus earlier in their lives and therefore were positive for traces of this virus.  Both groups went on to receive Rituxan based therapies .  Patients who were HCV positive at the start of therapy were at ten times higher risk of severe liver toxicity.  Even in patients with just barely detectable viral load of HCV before start of therapy, reactivation meant significant increase in viral load and thier liver enzymes (AST, ALT) went sky high.  A total of 5% of the patients with HCV reactivation died of liver failure. Liver toxicity (liver cirrhosis) is strongly implicated in causing liver cancer.  Trust me, you do not want to fight CLL and liver cancer at the same time.

The significant increase in liver toxicity observed in Rituxan containing therapies such as R-CHOP compared to plain vanilla CHOP suggests that B-cells and the specific immune function of B-cells (called “humoral” immunity) plays a significant role in controlling chronic HCV viral infection.

The million dollar question is what we do with this information.  When do we start treating HCV positive patients undergoing Rituxan based therapy for the hepatitis virus?  In patients with aggressive B-cell cancers, the authors suggest careful monitoring of liver function of patients with prior history of hepatitis and who are undergoing Rituxan based therapy. Use of antiviral therapy immediately upon detection of hepatitis viral reactivation may prevent full blown disease and liver toxicity, as well as allowing continuation of therapy for the underlying B-cell cancer.

Both the editorial and the article focused mainly on aggressive B-cell cancer such as DLBCL (diffuse large B-cell lymphoma).  CLL patients who undergo Richter’s transformation have similarly aggressive large cell lymphoma.  The study did not look at CLL in particular.  But connecting the dots, it seems clear to me that if are not a stranger to hepatitis, if you have been exposed to one of the many varieties of this virus, you should be sure to discuss this with your doctor before you start therapy – especially if you are contemplating long term use of Rituxan maintenance therapy.

Does Hepatitis infection CAUSE CLL?

There have been intriguing hints of possible links between CLL and prior history of viral infections.  Epstein-Barr virus (EBV) that causes mononucleosis (“glandular fever”) has been suggested as a possible predictor of possible incidence of CLL later in life.  But we have yet to find the smoking gun when it comes to definitive links between viral infection of start of CLL.  Here is a recent article that suggests a link may exist between hepatitis and CLL.

Blood. 2011 Feb 10;117(6):1792-8. Epub 2010 Oct 19.

Hepatitis viruses and non-Hodgkin lymphoma: epidemiology, mechanisms of tumorigenesis, and therapeutic opportunities.

Marcucci F, Mele A.

Centro Nazionale di Epidemiologia, Sorveglianza e Promozione della Salute (CNESPS), Istituto Superiore di Sanità (ISS), Rome, Italy;

Over the past 2 decades considerable evidence has accumulated on the association between hepatitis C virus (HCV) and hepatitis B virus (HBV) and several hematologic malignancies, most notably B-cell non-Hodgkin lymphoma (NHL). In this review we summarize this evidence, address possible mechanisms whereby hepatitis viruses may contribute to lymphomagenesis, and discuss the therapeutic fallouts from this knowledge. Most of this evidence is on HCV, and this is the main focus of the review. Moreover, we mainly address the association with NHL, the most prevalent hematologic malignancy, and the most extensively investigated with regard to an association with hepatitis viruses. Available evidence on the association with other hematologic malignancies is also addressed briefly.

PMID: 2095960

Just because the abstract talks about NHL, don’t assume it does not deal with CLL.  This study includes CLL, considering it a sub-type under the generic catch-all name of NHL.  Risk of developing CLL later on was 250% higher in people who had been infected with hepatitis C (HCV). The authors speculate about the possible mechanism(s) whereby hepatitis infection can precipitate CLL down the road.  Perhaps the increasing incidence of hepatitis can also explain the increased incidence of CLL in ethnic sub-groups which had very few cases of CLL in earlier decades.  If you are interested in reading the full version of this interesting article, send me a personal email and I will help you locate it.

Take-home messages

• Hepatitis is a serious infection. And it is a gift that keeps on giving, since many patients retain traces of the virus for many years, sometimes for the rest of their lives.
• There seems to be a link between loss of B-cell function and reactivation of hepatitis.  Be aware of this “cost” of Rituxan maintenance therapy if you have personal history of hepatitis infection.
• Be sure to tell your doctors about your history of all viral infections. That includes mononucleosis (EBV), jaundice (hepatitis A, B, C), shingles (Herpes zoster), one more episodes of viral pneumonia (cytomegalovirus CMV).  Choice of CLL therapy as well as ways of possibly preventing viral reactivation depends on your doctor being aware of your prior history.  Just because you filled out a lot of paper work several years ago when you first became a patient does not guarantee that your doctor will be fully aware of your viral history when therapy decisions are being made.  It is to your benefit to remind him.
• CLL is a familial cancer. If you are a blood relative of a family cluster of CLL (and other B-cell cancers), you must be aware that you are at increased risk of getting CLL yourself.  In that case it becomes even more important that you avoid the type of high risk behavior that increases your chances of contracting one of these deadly viral infections.  You may also want to explore the modern day hepatitis vaccines available.

Site news

I am back from India and almost recovered from jet lag.  Soon we will be announcing the date of our next CLL Workshop.  Most likely it will be on a Saturday afternoon, early in April.  There is no charge for participating in our workshops and I hope those of you living close to Columbia MD will choose to attend.  Tentatively, this workshop will focus on understanding modern prognostic indicators.