1. The IgM Flare
2. A Report; Ask the Doctor about IgM and Rituxan
3. About Rituxan in Human Serum
1. THE IgM FLARE
This is a phenomenon seen after treatment with rituximab by patients with maladies characterized by monoclonal IgM. There is evidence of related effects to do with IgM serum factors in rheumatoid arthritis. The major question we hear is “The IgM is high and it won’t go down! What is going on?” Probably you have a flare, but it might also just happen to be that you are expecting serum IgM to drop away faster than it normally does after rituximab (RTX).
Studies: IgM Response to Rituxan Treatment of WM
Arguably, Dr. Steve Treon has drawn most attention to a period of elevated serum IgM in WM patients after treatment with Rituxan. This was described earlier by Dimopoulos and co-workers. It occurred in perhaps 70% of patients they studied. See the Figure. The expression “IgM Flare” is specific reference to the more extreme examples of this very common phenomenon. Let’s take an arbitrary look at the data. Notice that the serum IgM level declines in time with a fairly orderly behavior only after the fist 1-2 months post treatment. In the initial period of 1-2 months, however, we very likely see sustained and magnified IgM within the patients’ serum. Interestingly perhaps, the IgM level remains elevated for half a year post treatment. It may persist at an elevated baseline after treatment, not going down to normal levels. There is a great deal of individual variation.
Figure: Patterns of reduction of monoclonal protein in responding patients after administration of rituximab. Originally published in M.A. Dimopoulos et al; Treatment of Waldenstrom’s macroglobulinemia with rituximab. J Clin Oncol 2002; 20: 2327–2333. Also published in M. A. Dimopoulos et al; “Treatment of Waldenstrom’s Macroglobulinemia with Rituximab: Prognostic Factors for Response and Progression” Leukemia & Lymphoma; 2004: 45 (10): 2057–2061
2. A report: Ask The Doctor About IgM and Rituxan
Message Post: Wed 5/21/2008 12:48 AM
Hello from Down-under. Another long note, but hopefully it will be of some use to someone out there.
Doctors’ Panel Discussion
The ‘Ask the Doctor’ session at the Ed. Forum 2008 dealt with the issue of initial serum IgM level and the possibility of a concept threshold around 5000 mg/dl, above which there might be degraded response to single agent Rituxan treatment. Panelists were Abonour and Gertz – Treon was unable to attend. The primary point of their comments concerned the dubious advisability of using a numerical criterion hanging on a single measurable aspect of a disease to judge the effectiveness of a management scheme. ‘Doctors are better than computers’, they implored.
Basically, they were asking whether a national economy should be considered as being in recession when (1) average citizens cannot afford to house and feed their families, or (2) when some banker’s criterion is satisfied. Who has the measure important to people? Ideally, the two need to be combined in some manner that is both sensitive to individual self-assessment and provides some factual measure. Achieving this is the task of whoever has responsibility overall for management of social expectation and delivery. This is the core of a fundamental disconnect between basic research enquiry that explores and records numerical data inferring detail about a process, compared with an outcome driven philosophy that seeks to deliver quality of life and promote survival. They are two very different issues. An individual must always try to understand the context.
Dr Abonour commented here (and in his address) that apparently small improvement in serum IgM (say 20 to 30%) can deliver important reduction in Hyper-viscosity (amounting to perhaps 50 to 60%). This relieves stresses on the vascular system, the associated bleeding and potential damage to the retina. Dr. Gertz referred to the following study and publication – M. A. Gertz et al; “Multicenter phase 2 trial of Rituximab for Waldenstrom macroglobulinemia (WM): an Eastern Cooperative Oncology Group Study (E3A98)” PMID: 15370249 [PubMed], Leukemia and Lymphoma, 45 (10): 2047-2055 (2004). Here, sixty nine patients were evaluated after a single agent trial 4x375mg/m2 infusion of Rituxan. The overall response rate was 52.2% comprising 27.5% with objective responses and 24.6% with minor responses. Median response duration (27 months) was not significantly different between previously treated and untreated patients. The study was unable to demonstrate any predictive value of initial serum IgM level concerning patient response.
Some Clinical Research
Neither panelist amplified fully the basic point that Rituxan is designed to target the CD20 expressed on B cells and is NOT an agent directed toward the destruction of IgM. For this reason alone, IgM trends can be no more than an indirect measure of the efficacy of Rituxan’s action of the WM cells. Other concurrent measurements are desirable in a numerical study and, above all, additional layers of patient management such as protocol changes should not be introduced unless there are sufficiently large numbers of patients involved in any trials. That has not been the history of trials concerning WM, despite the critical shortages of participants for trials..
The proposition that a response threshold exists for Rituxan treatment of WM appears to originate with a study by M. A. Dimopoulos et al; “Treatment of Waldenstrom’s Macroglobulinemia With Rituximab” J. Clinical Oncology 20: 2327-2333 (2002). Broadly, this reported as follows;
1) The study included 26 patents of whom 12 (44%) achieved at least partial response.
2) The median time to response was 3.3 months, with a range 2.2 to 7.1 months.
3) Patients with initial serum IgM less than 4000mg/dl had significantly higher response rate. Eleven patients out of nineteen (58%) with IgM less than 4K showed response and one out of eight (13%) with IgM above 4K responded.
4) Median time to progression of disease (growing IgM level) was 16 months with a range 6.7 to 24.7 months.
5) Five patients showed more than 75% reduction of IgM level over the observation period, including one with an initial IgM of 4K.
6) Three of the twelve patients who achieved partial response reached the 50% IgM threshold after the second Rituxan treatment, these being patients with 3.5~4K initial IgM.
But the protocol used by Dimopoulos and coworkers involved one set of weekly 4x375mg/m2 infusions followed by a second set of 4x375mg/m2 infusions commenced 3 months after the completion of the first infusion for patients without evidence of disease progression. Further, the results were judged against objective parameters dependent on IgM with only limited clinical context. The criterion set for “partial response” was the achievement of serum IgM level equal to 50% of initial value without correction for IgM flare or other transient effects seen during the course of time. The ‘time to response” was the time from completion of the initial Rituxan Tx to achievement of partial response without correction for intermediate treatment. “Disease progression” was defined as an advancement of 25% in IgM level above the lowest plateau value reached after therapy.
An Interpretation of this Data
What I believe the data show is as follows;
a) Initially Sustained IgM Levels.
Only a quarter of responding patients showed a steady decline in IgM level from the end of the first Rituxan treatment into the observation period. All others showed a period of high and/or growing IgM level followed by leveling and decline of the serum IgM. The duration of the post treatment surge of serum IgM was generally greater for patients with higher initial serum IgM. It extended about two months prior to the onset of decline for the most notable events. Accordingly it dominated the first stage responses.
b) Rates of Rituxan Clearance.
The Rituxan infusion sequence #2 made it impossible to infer what potential really existed in a single series infusion treatment for most patients. Only four responding patients appeared to reach a low plateau in response prior to the second infusion. It would appear these patients were in the category of most rapid clearance for Rituxan, exhibiting serum Rituxan half life in the lower known range between 10 and perhaps 16 days perhaps. The remaining serum Rituxan could be as low as 15% of its initial level by 30 days after the first set of infusions, and perhaps less than 10% at 45 days out. By comparison, median clearance rates of Rituxan would not achieve these levels until 60 and 90 days out, respectively. Slow users would hold on longer, reaching 15% as late as 120 days and 10% at around 180 days consistent with serum Rituxan half life in the order of 36 days. Quite clearly, the commencement of the second set of infusions at 90 days represents a change in protocol and dynamic rather than a repeat of the first test sequence.
The consequence is simple. People who consume the Rituxan most rapidly (half life about 10 days or so) should plateau in some way before the second sequence commences, the median group (half life about 23 days) is likely to be nearly ‘out of steam’ at that time, and the conservatives (with half life about 36 days) will be only just getting started in their responses. These guys need time! But we will not be able to see that from the indirect data – because the dynamic has been disrupted by the second treatment. So it isn’t just a pedantic point at all if the dominating process is actually the rate of Rituxan clearance within that patient.
c) Fast Rituxan Consumers.
Four individuals showed effects consistent with a short range Rituxan half life. They had initial serum IgM values across the full range studied. Three reached stable plateaux at or below the 50% technical response threshold. The other was the only patient in the study whose response to the second Rituxan treatment was tentative. This person was the earliest to show disease progression amongst those who achieved technical response (occurring at ~9 months) and had an initial IgM of about 3800mg/dl.
d) Higher Initial IgM Patients.
All four responding patients whose initial IgM was around 4K achieved IgM reductions of 62.5% or better. Only one of these showed an immediate decline in IgM post infusion. The decline reached 50% reduction of serum IgM by 6 weeks and showed a time to disease progression of ~11 months. In contrast, the patient with the most pronounced delay in the onset of IgM decline was among the most durable of all responses (~24 months) the corresponding pre-treatment IgM level was 4000mg/dl and the depressed level ~750.
e) Overall effects of Pre-treatment IgM Level.
Generally, the total period to disease progression was a biased toward the lower end of the indicated range for higher initial IgM levels. However, we have already seen that one 4K member achieved a particularly long period before disease progression. The reverse was also true. This is the crucial point. The shortest period to progression was actually shown by a patient with amongst the lowest initial IgM levels, ~2300mg/dl.
Moderating the Basis for Prognostication
A subsequent study by Dimopoulos et al is; “Treatment of Waldenstrom’s Macroglobulinemia with Rituximab: Prognostic Factors for Response and Progression” Leukemia & Lymphoma, 45 (10): 2057-2061 (2004). Again, this is a scientists’ paper… about IgM principally and clinical issues later. But this time there are more patients and the data is for a single series of infusions only. Higher initial IgM patients were better represented in the cohort. The analysis looks at supporting measures for interpretation. Unfortunately the data reported are barely robust enough for any scrutiny I would desire to impose.
But importantly, the assertion about the 4K threshold is moderated. The comment now stands that elevated serum monoclonal protein IgM and low serum albumin were the dominant factors associated with shorter time to progression. Presence of two, one or none of these adverse prognostic factors was associated with rapid progression (3.6 months), median (11 months) and longer progression (40 months) after a single 4x375mg/m2 Rituxan treatment.
My conclusion, for what that may be worth, is that IgM alone is not a useful predictor of likely response to Rituxan – whichever trial you base the assessment on. Members at the Ed Forum had responded well to Rituxan from an initial IgM of 6000 and others had various problems from lower levels. Morie Gertz talked of treating patients with IgM of 9000. The most significant numerical indications seem to be for the possible timescales at which disease progression might recommence after treatment, rather than the likelihood of a response. Even then, at least serum IgM and serum albumin must be assessed together. Clinical experience almost certainly includes other combinations of detail in a successful guess of the future. In lay terms, all this seems to say quite simply that if you have a deeply rooted level of disease, or a particularly active variant, your clinical indicators will likely be further from normal and more effort needed to control the WM cells. Your spot on the teeter-totter is defined by those devious little WM cells.
It would be nice to have the real data to evaluate, model and contemplate – particularly if actual serum Rituxan levels were known along the way.
3. About Rituxan in Human Serum
One Further Perspective: Recently, I completed a system analysis (immunatics) model of a series of in vitro studies with Rituxan in laboratory cultures that included serum only, effector cells only (predominantly NK cells) and serum plus effector cells. A brief presentation is at the WM Online Workshop site http://wmscience.wordpress.com/focal-point-2009/making-use-of-models/ . This work shows that the effectiveness of cell depletion varies strongly with the level of CD20 expression in a range consistent with that of WM cells. The process does not run to complete destruction in these laboratory conditions. About 15 to 25% of B-cells survived in these tests and there is some undefined interaction between the cell lysis promoted by complement and NK cells in the presence of serum. Further, it shows greatest sensitivity to actual dynamic conditions in the range consistent with WM B-cells. All of which underscores the difficulty in extrapolating broad conceptual indicators into precise forecasts of actual events. For what it is worth, I attribute this effect to the natural steroid DHEAS in the serum. DHEAS is a known primary stimulant of NK cell cytotoxicity. Its level depend on age, rate of chesterol transformation to hormones, and the level of pro-inflammatory cytokines.
Colin April 2009