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Alert Number 232

Rituxan: Delayed Onset Neutropenia

Date: May 11, 2007

There have been nagging concerns over the past few years regarding delayed onset neutropenia associated with Rituxan therapy in some patients. There were scattered cases documented in the published literature, and I was hearing from several patients with anecdotal stories of unexplained neutropenia several weeks or even months after completion of Rituxan therapy. Based more on my gut sense evaluation of this anecdotal feedback from our members than formal post-market surveillance guidance from the FDA or the manufacturer, we published our heads-up article on this subject way back in 2003. Here is a link to that original article:

Neutropenia in Patients Treated with Rituximab

Looks like we read the tea-leaves right even back then, in keeping an eye out for this potential complication. The very recent (February 2007) article in prestigious “Annals of Oncology” (see abstract below) finally confirms what I have long suspected. Delayed onset neutropenia is far more common than was officially documented. In this credible retrospective study, a whopping 24.9% of the patients developed neutropenia (absolute neutrophil count less than 1,000), at a median of 106 days after completion of therapy. One out of four! That is not trivial or within statistical error.

Neutropenia is not something to take lightly, since it is often associated with increased risk of infections. CLL patients have poor B-cell function, compromised T-cell function as a result of the CLL and many of the therapies that go with it, low to non-existing immunoglobulin levels – we are well short of a full deck when it comes to fighting infections.  Healthy neutrophil counts are all the more important for our guys. This surprisingly high percentage of patients who developed late onset neutropenia certainly takes something away from the image of Rituxan as a low toxicity drug. No free lunch here, folks.

I am struck that all too often, anecdotal feedback from our large membership sounds the alarm bells for me far sooner than official reports. We had a similar situation with regard to epo drugs (Procrit, Epogen, Aranesp etc). Our warning article on the Dark Side of Epo was published in 2003, and sounds almost prescient in view of the flood of warnings in the past few months. Keep that feedback coming folks. It may not get much respect from the officialdom since it is “only” anecdotal patient information but to my thinking we are ahead of the curve by several years by sharing our information. We also have more skin in this game, I am sure you agree - this stuff is not just of academic interest to us.

Below are some other articles on our website that deal with potential adverse effects associated with Rituxan therapy. The first link below gives an overview of all the issues that have been identified thus far.

Rituxan: Important New Adverse Effects
Alert Number 49 - Rituxan Warning: Hepatitis Reactivation
Rituxan in the News: Risk of Hepatitis-B Reactivation with Rituxan Therapy

Be well, stay smart.



Ann Oncol. 2007 Feb;18(2):364-9.

A high incidence of late-onset neutropenia following rituximab-containing chemotherapy as a primary treatment of CD20-positive B-cell lymphoma: a single-institution study

Nitta E, Izutsu K, Sato T, Ota Y, Takeuchi K, Kamijo A, Takahashi K, Oshima K, Kanda Y, Chiba S, Motokura T, Kurokawa M.

Department of Hematology and Oncology, Graduate School of Medicine, University of Tokyo, Japan.

BACKGROUND: Late-onset neutropenia (LON) has been reported following rituximab-containing chemotherapy. Its incidence and risk factors, however, have not been extensively studied.
PATIENTS AND METHODS: We retrospectively reviewed the medical records of 107 patients treated with rituximab-containing chemotherapy as a primary treatment of CD20-positive B-cell lymphomas and identified cases with LON as defined by the neutrophil count of <or=1.0 x 10(9)/l without an apparent cause after the recovery of neutrophil count following completion of the intended chemotherapy.
RESULTS: With a median follow-up of 411 days, 23 patients developed LON out of the 107 at a median of 106 days after the last chemotherapy. Cumulative incidence of LON among the total patients was 24.9%. The median neutrophil count nadir was 0.61 x 10(9)/l. The LON episodes were generally self-limited, and filgrastim was administered in one patient. Including this patient, there were no serious infectious episodes in the cases with LON. In multivariate analysis, intensive chemotherapy regimens including high-dose therapy followed by autologous hematopoietic stem cell transplantation (ASCT) and high-dose methotrexate-containing regimens without ASCT were a risk factor for LON.
CONCLUSION: This study suggests that LON is a frequent complication of rituximab-containing intensive chemotherapy.

PMID: 17079695

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