Cyclophosphamide six year followup data + other research about cancer and infertility risk

[dankeen]

https://bora.uib.no/bora-xmlui/bits...esis_2024_rekeland.pdf?sequence=1&isAllowed=y
Fluge & Mellor‘s full follow up paper has not yet been published, but this PHD thesis publishes alot of the data in advance. The slides are from Fluge’s talk at the 2023 Charite conference.

Cyc is impossible to blind, so trials for autoimmune diseases use alternative treatment or historical control groups. At six years there was little difference between rituximab and placebo patients so they can be treated as one large group. This is as good of a control sample as would be found in many studies of cyc for autoimmune disease. Both groups are individually big enough as a control sample.

At six years the cyc patients had improved by an average of 13.7 points more than the combined rtx study patients. There is a 1/20 chance the group difference is pure coincidence. Half of the cyc patients account for most of this difference, improving by an average of 24.4 points more than rtx combined group. This is a huge difference in quality of life.

Fewer cyc patients reported worsening than combined rtx study patients. The sample is too small prove a reduced risk, but it does suggest that the risk is probably not increased.

“At six-year follow-up in the cyclophosphamide group, 44.1% had an SF-36 PF > 70 at six years, compared to 27.6% in the rituximab group and 20.4 % in the placebo group. We chose a cutoff for at 70 points, because that would indicate a substantial improvement. The mean SF-36 PF at baseline was in the range 30-35 (for all groups).

SF-36 PF > 90, i.e., scores close to the normal population range, was achieved by 17.6% of the cyclophosphamide patients, 8.6% of the rituximab patients, and 7.4% of the placebo patients.”

It is difficult to dismiss the group difference as placebo for the following reasons.

1. Average time to first response in cyc patients was five and a half months which is not typical for a placebo effect. There was no prior data that would have made anyone expect this.

2. Cyclophosphamide outperformed rtx & placebo before unblinding. There was more hype and prior data for rituximab which could in theory have promoted a stronger placebo effect than cyclophosphamide.

3. Cyc patients improved by 5 points between 18 months and six years, while rtx active patients declined by about 4. It is understandable that placebo patients would stop improving or relapse after unblinding, but there is no explanation for cyc patients experiencing a long term placebo effect but not rtx active patients.

“In the CycloME study 15.0% worked part-time and no-one worked full-time at baseline. At six years (among 34 participants), six were working part-time and four were working full-time (29.4% in total). In the RituxME trial, four worked part-time, one worked full-time and three were students at baseline (5.3% in total). After six years (among 112 participants), one worked part-time, three worked full-time and two were students (4.5%). Doubling the number of people working part or full-time in the CycloME trial is important both for the patients and society.”

 

[dankeen]

In the cyclome protocol a 70kg/1.8m2 patient would receive six monthly doses of 1280mg for a total of 7.7g. A cancer patient of the same size would receive single doses up to 3500mg. Other cancer regimes combine low doses of cyc with other chemo drugs.

Recent meta studies show that the risk of any cancer following low cumulative doses of cyclophosphamide are much lower than previously believed and is predominantly non melonoma skin cancer. Studies below. Early NMSC is treated by removing the mole. It has a 95% overall survival rate and 99% if caught early which is likely if patients are aware of the risk.

Evolving paradigm of cancer risk following cyclophosphamide 2015
“More recent studies, reflecting treatment periods spanning the 1990s to 2000s, have provided more reassuring findings, showing standardized incidence ratios (SIRs) (i.e. observed number of cancers divided by the expected number) of 1.6–2.1 for all cancer types [6, 7].”excess cancer risk observed was driven mainly by NMSC [6].” It is also important to note that most of the patients in the above study had much higher cumulative doses of cyc than the 7.5G used in the cyclome study. The meta study also states that it cannot control for the use of other carcinogenic immunosuppressants like Aza.

Malignancies in Wegener's granulomatosis: incidence and relation to cyclophosphamide therapy in a cohort of 293 patients
”The risk of malignancies (other than NMSC) was not increased for patients treated with cumulative CYC doses < or = 36 g.”

Malignancies in Patients with Antineutrophil Cytoplasmic Antibody-associated Vasculitis: A Population-based Cohort Study 2020
“There was no increase in incidence of cancers other than SCC for those treated with < 10 g CYC.” Squamus Cell Carcinoma is a type of NMSC.

No increase in cancer incidence detected after cyclophosphamide in a French cohort of patients with progressive multiple sclerosis
I do not know the cumulative doses in the above patient population (paywall) but I can find no MS protocols with cumulative doses less than 10G.

Bladder and kidney cancer following cyclophosphamide therapy for non-Hodgkin's lymphoma
“Within a cohort of 6171 two-year survivors of non-Hodgkin's lymphoma (NHL), 48 patients with secondary cancer of the urinary tract were identified and matched to 136 control subjects with NHL who did not develop a second malignancy.”

“Among patients who received a total amount of cyclophosphamide of less than 20 g, a nonsignificant 2.4-fold risk of bladder cancer was apparent. Significantly elevated sixfold and 14.5-fold risks of bladder malignancy followed cumulative doses of 20–49 g and 50 g or more. For patients given cumulative doses between 20 and 49 g, the absolute risk of bladder cancer is on the order of three excess cancers per 100 NHL patients” This is at 15 year follow-up and no doubt a few more have been diagnosed since.

For arguments sake I will make a linear extrapolation from the above data assuming a mean cumulative dose of (20+49)/2 =34.5g. 34.5/7.5= 4.5 fold dose reduction. 3(excess cancers)/4.5= 0.65 excess cancers per hundred patients for a 7.5g cumulative dose.

However the real number is much lower because the risk is exponential not linear. This is a study using data from the Swedish cancer registry. “The risk of bladder cancer doubled for every 10 g increment in cyclophosphamide”.

The risk of bladder cancer at 7.5G is not zero, but it is so low that it is unlikely there will ever be a study big enough to reach statistical significance.

 

[dankeen]

Another common argument against cyclophosphamide is the risk of infertility and early menopause.
Male fertility risk is significant, but can be easily be preserved by sperm freezing.

A systematic review and meta-analysis of the gonadotoxic effects of cyclophosphamide and benefits of gonadotropin releasing hormone agonists (GnRHa) in women of child-bearing age with autoimmune rheumatic disease

Risk of sustained female infertility and amenorrhea increases with age and cumulative cyc dose, but is minimised with GnRHa. There are varying results in different studies with cumulative cyc doses >5G without GnRHa. Cumulative doses of cyc below 5g are unlikely to produce sustained amenorrhoea in patients under 40 years of age who were NOT treated with GnRHa.

Average female body surface area is 1.6m2 which equates to a cumulative dose of 6.5g for the six dose cyclome protocol. Some patients may choose to reduce the number of doses to balance efficacy with amenorrhoea risk.

A return of periods does not necessarily mean fertility is unharmed. A small study found that most women (without sustained amenorrhea) who tried to get pregnant succeeded. However there is not a big enough sample with data that takes into account intention to conceive to quantify the risk.

I do not know to what extent cyc can bring forward menopause even if it does not cause it immediately.

Use of gonadotropin-releasing hormone agonists for ovarian preservation in patients receiving cyclophosphamide for systemic lupus erythematosus: A meta-analysis
56 patients of an average age of 25.6 were treated with an average cyclophosphamide dose of 8.6g with GnRHa. Sustained amenorrhoea occurred in 2 (3.6%) of patients. One of these patients was age 28 with a cumulative dose of 33g. The other was age 37, but the cumulative cyc dose is unknown.

Seven studies with 218 female patients were included. The ovarian function was preserved in 125/132 (94.6%) of women who received GnRHa concurrently with CYC compared to 50/86 (58%) of women who did not receive GnRHa (OR = 10.3, CI = 4.83–36.29).

In conclusion the risk of sustained amenorrhea is very low for women under 40 who limit cumulative cyclophosphamide dose to 5G and use GnRHa.

 

[dankeen]

“In the CycloME trial, the mean baseline IgG and IgG1 levels were predictive for clinical response, as the levels were significantly lower in the responder group (n=21) compared to non-responders (n=16) (Figure 3). Significantly lower baseline serum IgG levels were also found in responders compared to non-responders in a previous study from our group (61), analysing serum samples from previous rituximab trials (22, 138).”
This fits with my own experience as a cyclophosphamide non responder.
Three months after four doses of cyclophosphamide my Igg is fairly high at 10.8.
It was presumably around 11.5 before.

“In the CycloME trial there were significant but modest decreases of IgG, IgM and IgA during follow up, especially from baseline to 12 months (Figure 3). CD3 (T- cells), CD19 (B-cells) and CD16/56 (NK-cells) lymphocytes in peripheral blood showed significant trends towards ME/CFS severity, with the highest lymphocyte counts in the severe group compared to moderate and mild/moderate (Figure 4). After cyclophosphamide intervention, all subsets of lymphocytes decrease from baseline to 6 months and GLM repeated measures analyses showed significant time effects during follow-up for all subsets (Figure 4), also described by Ahlmann et al (114). CD3, CD4, CD8 T-cells and CD19 B-cells were still lower at 18 months compared to baseline, while NK cells had returned to baseline levels (Figure 4).
The broad effects of cyclophosphamide on different immune cells make it difficult to pinpoint a precise mechanism for the clinical effect observed in ME/CFS. The cytotoxic effects on proliferating cells make inhibition of activated B-cells to plasmablasts and reduction of IgG levels - including autoantibodies - a plausible possibility. The described downregulation of T cells, effects on different subsets of lymphocytes and interactions between immune cells are other possible mechanisms of cyclophosphamide in this disease.”