What about complications?
Again click to enlarge. The table relates to grade 3 or 4 adverse events. These are the ones that need to be taken seriously with hospital admission and definitive treatment. The obvious difference between FC and FCR is that adding rituximab causes significantly more neutropenia. As I have previously stated this does not represent bone marrow failure, but increased destruction of neutrophils in the immune complexes cause by antibody reacting with antigen. It need not be viewed as a reason to reduce doses and even as a hazard for future infection. Indeed there were no more infections with FCR than there were with FC, despite the greater incidence of neutropenia.
What about the known rituximab complications? These are primarily to do with the infusion-related cytokine release syndrome. Just one instance in over 400 patients.
Tumor lysis syndrome? Just one instance. Autoimmune hemolytic anemia? Three cases. As I suspected the cyclo and rituximab has cancelled out the fludarabine effect.
Viral and fungal infections? Again penny numbers. It looks to me that in this fit and mostly young population of patients, FCR is well tolerated as a first line therapy. And to be truthful, that is my own experience.
Ten (3%) deaths were related to treatment in the chemotherapy group, and eight (2%) in the chemoimmunotherapy group. Of these, six chemotherapy-treated patients and five chemoimmunotherapy-treated patients died from infections (septicaemia [n=6], pneumonia [n=3], hepatitis B [n=1], and cryptosporidium gastroenteritis [n=1]). In seven patients (three in the chemotherapy group and four in the chemoimmunotherapy group), death occurred before the third treatment course (fatal septicaemia [n=6], sudden cardiac death [n=1]). These early deaths mainly occurred in patients with del 17p, that is unresponsive patients who are in any case highly at risk because of their disease. Virtually all types of treatment damages normal tissue to some extent, but this matters little when the damage to tumor is so much greater that it allows normal tissue to rapidly regrow. It is when both tumor and treatment damage the normal tissue that disaster happens.
In most cases, the underlying cause of death was progressive disease (chemotherapy 48 [56%] of 86, chemoimmunotherapy 33 [51%] of 65). Other fatal events were secondary cancers (chemotherapy 13 [15%], chemoimmunotherapy five [8%]) and causes unrelated to chronic lymphocytic leukaemia, such as myocardial infarction (15 [17%] and 17 [26%], respectively).
There is no mention of patients developing Richter's syndrome or myelodysplastic syndrome. Despite the alarm sounded in some quarters (especially by myself) about the association of these complications with fludarabine usage, I am not surprised that after such short follow up they have not been seen. I would expect them to be late complications and more associated with FCR used as second-line treatment. Indeed we certainly had some concerns about MDS with the REACH trial which used FCR later in the disease.