Cumulative Dose Of Cyclophosphamide Research Articles

O-088 Effect of low, medium and high risk chemotherapy on the ovarian reserve in children: results of the interim analysis of a prospective multicentric trial (CHANCE)

Abstract Study question How does the ovarian reserve of children diagnosed with cancer recover after chemotherapy that is considered as low or medium risk of future infertility? Summary answer The study showed no evidence that low and medium risk treatments impact the future ovarian function in children. What is known already Acute premature ovarian insufficiency (POI) post childhood cancer treatment is estimated around 6%, varying with treatment type and age at diagnosis. Long-term risk of treatment-related infertility is challenging to assess in this population as most of the data comes from retrospective trials involving adult cohorts of childhood cancer survivors. Benefit of fertility preservation at diagnosis is evident for high risk patients. However, for low or medium risk patients, the lack of knowledge on treatment effect on the ovarian reserve and on marker reliability in children complicates counselling. Study design, size, duration CHANCE is a prospective multicentric observational trial enrolling patients aged between 3 and 14 years at cancer diagnosis. We evaluated factors associated with the risk of future infertility such as hormonal levels, puberty and menstruation, and investigated the fertility preservation strategy. Parameters were assessed at screening, one year post-screening, end of the treatment, and during follow-up (FU) until 18 years of age. An interim analysis was planned considering the duration to reach the final endpoint. Participants/materials, setting, methods Between 2014 and 2023, 144 patients were enrolled. Patients were categorized in 3 groups by cumulative equivalent dose of cyclophosphamide (CED) received: <4000mg/m2 (low), 4000 to 8000mg/m2 (medium) and >8000 mg/m2 (high). Ninety-four patients with at least one year post-treatment follow-up were included in this analysis. Mean age at diagnosis was 8.4±4 years and 38% were prepubertal, with no difference between groups (p = 0.06 and 0.26, respectively). The median time of follow-up was 32.7 months. Main results and the role of chance Patients were categorized as low (n = 58), medium (n = 18) and high (n = 18) risk based on CED. Sarcoma were most frequent in high risk, while leukemia in low/medium risk groups (p < 0.0001). Fertility preservation was performed in 55.6%, 27.8% and 8.6% in high, medium and low risk group, respectively (p < 0.0001). The majority of them underwent ovarian tissue cryopreservation. POI was defined as induced puberty and/or FSH>25IU/l during FU. POI occurred in 10 out of 18 (55.6%) patients in high risk group, while in no patient in the low/medium risk groups except 1 with disease recurrence. POI was associated with high doses of chemotherapy (p < 0.0001) and increased age (p < 0.007). AMH levels significantly decreased in high and medium risk group during treatment. Recovery occurs in medium but not high risk groups (p = 0.84 and 0.02 between screening and values at 1-2 years and >3 years of FU using repeated measures analysis). Low AMH values (<0.5ng/ml) was observed at 2 years of FU in 14.3%, 28.6% and 69.2% of the patients in low, medium and high risk groups respectively. The impact of treatment, particularly in medium risk group, needs confirmation as around 35% of the patients were still prepubertal at the time of the analysis. Limitations, reasons for caution This is an interim analysis of a prospective trial designed to include 275 patients. Data should be cautiously interpreted due to not reaching the calculated optimal power population. Wider implications of the findings Our data confirmed that fertility preservation should be offered to all children and adolescent treated with high risk regimen. We did not provide evidence supporting its benefit for low/medium risk pre-pubertal children. For post-pubertal medium risk patients, fertility preservation may be considered during the FU based on patient decision. Trial registration number NCT02595255

Malignancy in systemic lupus erythematosus: relation to disease characteristics in 92 patients – a single center retrospective study

ObjectiveSystemic lupus erythematosus (SLE) is a chronic autoimmune disease with a variable clinical manifestation, potentially leading to death. Importantly, patients with SLE have an increased risk of neoplastic disorders. Thus, this study aimed to comprehensively evaluate the clinical and laboratory characteristics of patients with SLE and with or without malignancy.MethodsWe conducted a retrospective analysis of medical records of 932 adult Caucasian patients with SLE treated at the University Hospital in Kraków, Poland, from 2012 to 2022. We collected demographic, clinical, and laboratory characteristics, but also treatment modalities with disease outcomes.ResultsAmong 932 patients with SLE, malignancy was documented in 92 (9.87%), with 7 (7.61%) patients experiencing more than one such complication. Non-hematologic malignancies were more prevalent (n = 77, 83.7%) than hematologic malignancies (n = 15, 16.3%). Patients with SLE and malignancy had a higher mean age of SLE onset and a longer mean disease duration than patients without malignancy (p < 0.001 and p = 0.027, respectively). The former group also presented more frequently with weight loss (odds ratio [OR] = 2.62, 95% confidence interval [CI] 1.61–4.23, p < 0.001), fatigue/weakness (OR = 2.10, 95% CI 1.22–3.77, p = 0.005), and fever (OR = 1.68, 95% CI 1.06–2.69, p = 0.024). In the malignancy-associated group, we noticed a higher prevalence of some clinical manifestations, such as pulmonary hypertension (OR = 3.47, 95% CI 1.30–8.42, p = 0.007), lung involvement (OR = 2.64, 95% CI 1.35–4.92, p = 0.003) with pleural effusion (OR = 2.39, 95% CI 1.43–3.94, p < 0.001), and anemia (OR = 2.24, 95% CI 1.29–4.38, p = 0.006). Moreover, the patients with SLE and malignancy more frequently had internal comorbidities, including peripheral arterial obliterans disease (OR = 3.89, 95% CI 1.86–7.75, p < 0.001), myocardial infarction (OR = 3.08, 95% CI 1.41–6.30, p = 0.003), heart failure (OR = 2.94, 95% CI 1.30–6.17, p = 0.005), diabetes mellitus (OR = 2.15, 95% CI 1.14–3.91, p = 0.011), hypothyroidism (OR = 2.08, 95% CI 1.29–3.34, p = 0.002), arterial hypertension (OR = 1.97, 95% CI 1.23–3.23, p = 0.003), and hypercholesterolemia (OR = 1.87, 95% CI 1.18-3.00, p = 0.006). Patients with SLE and malignancy were treated more often with aggressive immunosuppressive therapies, including cyclophosphamide (OR = 2.07, 95% CI 1.30–3.28, p = 0.002), however median cumulative cyclophosphamide dose in malignancy-associated SLE subgroup was 0 g (0–2 g). Interestingly, over a median follow-up period of 14 years (ranges: 8–22 years) a total of 47 patients with SLE died, with 16 cases (5.28%) in the malignancy-associated SLE group and 31 cases (5.73%) in the non-malignancy SLE group (p = 0.76). The most common causes of death were infections (21.28%) and SLE exacerbation (8.51%).ConclusionThe study highlights the relatively frequent presence of malignancies in patients with SLE, a phenomenon that demands oncological vigilance, especially in patients with a severe clinical course and comorbidities, to improve long-term outcomes in these patients.

Malignancy is increased in patients with antineutrophil cytoplasmic antibody-associated vasculitis in China

ObjectiveIt has been reported that in western countries malignancy risk was higher in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) compared with that in the general population. In the current study, we investigated the incidence, spectrum and risk factors of malignancy in Chinese AAV patients.MethodsAAV patients diagnosed from 1995 to 2021 in Peking University First Hospital with a follow-up more than 12 months were recruited. Standardized incidence ratios (SIR) were calculated to describe the risk of malignancy, adjusted for sex, age and follow-up time.ResultsA total of 552 AAV patients were recruited, among which 23 patients had malignancies either preceding or concurrent with AAV diagnosis, and 43 of the remaining 529 patients developed malignancies within 4.3 ± 4.2 years post AAV diagnosis (SIR: 2.24; 95% CI: 1.68–2.99; p < 0.001). Among these 66 patients, twenty different sites of malignancy were observed, lung cancer being most frequent. To get exactly expected malignancies for the calculation of SIR, 529 patients without preceding or concurrent malignancies were included in the following analysis. Lung cancer was still the leading malignancy diagnosis (SIR: 5.01; 95% CI: 3.29–7.62), followed by malignancies in the kidney, bladder, ureter and prostate. Male gender (HR:2.84; 95%CI:1.36–5.96; p = 0.006) and older age (per year, HR:1.04; 95%CI:1.00-1.07; p = 0.038) were significantly associated with increased risk of malignancy. For patients with malignancy developed beyond 5 years after the diagnosis of AAV, a significantly higher malignancy risk was observed in those with a cumulative cyclophosphamide dose over 20.0 g (SIR: 11.54; 95% CI: 4.77–27.93; p < 0.001). Within the first 2 years after the diagnosis of AAV, the risk of malignancy was still significantly higher than that in the general population, but the cumulative cyclophosphamide dose was not significantly associated with malignancy occurrence in this subgroup of patients.ConclusionsMalignancy risk is higher in Chinese AAV patients than that in the general population, with a different malignancy spectrum from western countries. Both the use of cyclophosphamide and AAV per se might be associated with higher incidence of malignancy occurrence.

#1739 Combination rituximab &amp; low-dose IV cyclophosphamide induction therapy for severe multi-system eosinophilic granulomatosis with polyangiitis

Abstract Background and Aims Current guidelines advise rituximab (RTX) or cyclophosphamide treatment for organ-threatening disease in eosinophilic granulomatosis with polyangiitis (EGPA). However, conventional treatment is often limited by partial efficacy, toxicity, high relapse rate and steroid dependency. We investigate the use of a combined RTX, low-dose cyclophosphamide, and steroid regimen for treatment of severe EGPA. Method Single-centre retrospective cohort study of patients treated with a combination induction regimen for severe EGPA (with kidney, cardiac or neurological involvement) between 2012-23. Data reported as median (±IQR) Results Eighteen patients (10 male; age 56 years [52-62]) are included. At treatment, BVAS was 16.3 [14-20], peak eosinophil count 9.3 × 109/L [5-13], C-reactive protein (CRP) 122 mg/L [80-193]. Eleven cases were ANCA positive (10 MPO-, 1 PR3-ANCA.) The proportions of patients affected by active/new respiratory, ENT, neurological, and gastrointestinal disease were 18/18 (100%), 14/18 (78%), 11/18 (61%), and 1/18 (6%), respectively. 11/18 (61%) had cardiac involvement (troponin 10345 ng/L [1240-7621]) and 6/18 (33%) had necrotising glomerulonephritis confirmed by renal biopsy (creatinine 123 µmol/L [83-167]). Cumulative cyclophosphamide dose was 3.5g [3.0-3.5] and total RTX dose was 2g. Initial prednisolone dose was 0.5-1.0 mg/kg/day, and this was rapidly weaned to 5 mg daily at a median time of 6.1 months [3.9-7.2], and 9/18 (50%) had steroids withdrawn completely by 11.7 months [4.6-20.6]. First-line maintenance treatment was azathioprine or MMF. By 6 months, all achieved disease remission as assessed by BVAS (all 0) and improved laboratory parameters: CRP 1 mg/L, eosinophil count 0.1 × 109/L, and ANCA testing negative. In those with renal disease, kidney function improved or stabilised in all (creatinine 95 µmol/L). In those with cardiac disease (11/18), magnetic resonance imaging was performed at baseline and at follow up (median time of 3.7 months) in all patients. Of these, 9/11 (82%) had oedema on initial scan and this improved in all cases; 10/11 (91%) had late gadolinium enhancement at baseline, which persisted in every case, though with significantly lower burden. The median follow-up period was 38 months [14-55]. At 1, 3 and 5 years, 100%, 92% and 76% of patients were in sustained remission (Fig. 1A). Three patients experienced relapse; one patient had major relapse with skin involvement requiring reinduction treatment; two patients had minor ENT relapse requiring retreatment with glucocorticoids. Infection-free survival at 1, 3 and 5 years was 94%, 78%, 62%, respectively (Fig. 1B). There were no deaths. Conclusion This regimen provided rapid disease control in patients with severe multi-system EGPA, including those with life-threatening cardiac manifestations, and enabled rapid glucocorticoid tapering and withdrawal. Disease-free remission was sustained during long-term follow up. Combination induction regimens may have a role in the treatment of organ-threatening disease in EGPA.

#1283 Rituximab in addition to plasma exchange, cyclophosphamide and steroids for treatment of anti-GBM disease

Abstract Background and Aims Anti-GBM disease is a rare antibody-mediated vasculitis, usually treated with plasma exchange (PEX), cyclophosphamide (CYC) and steroids. There are limited data regarding the use of B-cell depleting therapies such as rituximab (RTX). We investigate the use of the addition of rituximab for the treatment of Anti-GBM disease. Method Ten-year (2012-2023) single-centre retrospective cohort study of patients with anti-GBM disease treated with or without rituximab, in addition to standard care, as first-line therapy. A Cox-proportional hazards regression model incorporating age, sex, ANCA status, dialysis need at presentation, lung haemorrhage, CYC (oral or IV) and RTX treatment was used to identify disease/treatment factors associated with outcome (death, end-stage kidney disease [ESKD], infection). Results Forty-five patients are included; baseline demographics, disease characteristics, treatments and outcomes are summarised in Table 1. In the Cox regression model, only increasing age was associated with risk of death (HR 1.08 [95% CI 1.02-1.17]). Age (HR 1.04 [1.01-1.08]), female sex (HR 4.93 [1.80-4.87]), and dialysis need at presentation (HR 5.28 [1.54-17.53]) were associated with ESKD-risk. Increasing age (HR 1.04 [1.00-1.09] and ANCA positivity (HR 3.08 [1.14-8.71]) were associated with risk of infection. The addition of rituximab was not significantly associated with risk of death (HR 0.82 (0.24-2.87), ESKD (HR 1.54 [0.64-3.96]) or infection 2.06 [0.67-5.71]. Conclusion Addition of rituximab to standard treatment for anti-GBM disease was not associated with improved renal outcome or survival benefit. However, rituximab use permitted lower cumulative doses of CYC and reduction in the number of PEX, without an increased risk of infection. Rituximab may have a role as a CYC- and PEX-sparing treatment in patients with anti-GBM disease.

Position statement of the Brazilian society of Rheumatology on mesna use as a preventive therapy for bladder disease in patients with systemic autoimmune diseases and systemic vasculitis under cyclophosphamide treatment

ObjectiveTo review current literature to support the use of mesna as a preventive therapy for hemorrhagic cystitis and bladder cancer in patients with systemic autoimmune diseases and systemic vasculitis treated with cyclophosphamide.Materials and methodsThe search for articles was conducted systematically through MEDLINE, LILACS, Cochrane Library, and Embase databases. Only articles in English were selected. For available records, titles and abstracts were selected independently by two investigators.ResultsEighteen studies were selected for analysis. The known adverse effects of cyclophosphamide were hematological toxicity, infections, gonadal toxicity, teratogenicity, increased risk for malignancy and hemorrhagic cystitis. Long-term toxicity was highly dependent on cyclophosphamide cumulative dose. The risk of bladder cancer is especially higher in long-term exposure and with cumulative doses above 36 g. The risk remains high for years after drug discontinuation. Hemorrhagic cystitis is highly correlated with cumulative dose and its incidence ranges between 12 and 41%, but it seems to be lower with new regimens with reduced cyclophosphamide dose. No randomized controlled trials were found to analyze the use of mesna in systemic autoimmune rheumatic diseases and systemic vasculitis. Retrospective studies yielded conflicting results. Uncontrolled prospective studies with positive results were considered at high risk of bias. No evidence was found to support the use of mesna during the treatment with cyclophosphamide for autoimmune diseases or systemic vasculitis to prevent hemorrhagic cystitis and bladder cancer. In the scenarios of high cumulative cyclophosphamide dose (i.e., > 30 g), patients with restricted fluid intake, neurogenic bladder, therapy with oral anticoagulants, and chronic kidney disease, mesna could be considered.ConclusionThe current evidence was found to be insufficient to support the routine use of mesna for the prophylaxis of hemorrhagic cystitis and bladder cancer in patients being treated for systemic autoimmune diseases and systemic vasculitis with cyclophosphamide. The use may be considered for selected cases.

Unveiling cancer risk in ANCA-associated vasculitis: result from the Turkish Vasculitis Study Group (TRVaS)

To investigate cancer incidence in patients with ANCA-associated vasculitis (AAV), compare it with the age/sex-specific cancer risk of the Turkish population, and explore independent risk factors associated with cancer. This multicenter, incidence case–control study was conducted using the TRVaS registry. AAV patients without cancer history before AAV diagnosis were included. Demographic and AAV-related data of patients with and without an incident cancer were compared. Standardized cancer incidence rates were calculated using age-/sex-specific 2017 Turkish National Cancer Registry data for cancers (excluding non-melanoma skin cancers). Cox regression was performed to find factors related to incident cancers in AAV patients. Of 461 AAV patients (236 [51.2%] male), 19 had incident cancers after 2022.8 patient-years follow-up. Median (IQR) disease duration was 3.4 (5.5) years, and 58 (12.6%) patients died [7 with cancer and one without cancer (log-rank, p = 0.04)]. Cancer-diagnosed patients were older, mostly male, and more likely to have anti-PR3-ANCA positivity. The cumulative cyclophosphamide dose was similar in patients with and without cancer. Overall cancer risk in AAV was 2.1 (SIR) ((1.3–3.2), p = 0.004); lung and head-neck [primary target sites for AAV] cancers were the most common. In Cox regression, male sex and ≥ 60 years of age at AAV diagnosis were associated with increased cancer risk, while receiving rituximab was associated with decreased cancer risk. Cancer risk was 2.1 times higher in AAV patients than the age-/sex-specific cancer risk of the Turkish population population, despite a high rate of rituximab use and lower dose of cyclophosphamide doses. Vigilance in cancer screening for AAV patients covering lung, genitourinary, and head–neck regions, particularly in males and the elderly, is vital.

Herpes zoster in lupus nephritis: experience on 292 patients followed up for 15 years.

To evaluate the prevalence, incidence, and predictors of herpes zoster (HZ) development in lupus nephritis (LN). This retrospective study included 292 LN patients to determine HZ incidence during the last decades and its correlation with LN activity. LN patients with HZ were matched with LN patients without HZ in a 1:2 ratio based on sex, age, year of LN diagnosis, and LN histological class at kidney biopsy to assess HZ risk factors. Statistical tests included t-test, U-test, and Fisher's test. Univariate and multivariate logistic regression analyses were conducted to identify potential risk factors. HZ occurred after LN diagnosis in 66 patients (prevalence 22.6%) with an average of 8.7 years (range 0.2-28.4 years). Although with the potential limitations of the retrospective nature and the extensive duration of the study, the incidence of HZ was 15.6/1,000 person-years, increasing from 6.9 before 1980 to 16.0 in the 1990s and 43.9 after 2010. HZ onset was unrelated to LN activity. LN was active in 43% of cases and quiescent in the other 57% of cases at HZ diagnosis. The percentage of patients who developed lupus flares during the year after HZ (18.9%) was not different from that which occurred during the year before HZ (17.2%, p = 0.804). After excluding confounding factors through matching, the univariate analysis suggested that cyclosporin during induction therapy (p = 0.011) and higher cumulative doses of glucocorticoids (GCs; >50g, p = 0.004), cyclophosphamide (CYC; >5g, p = 0.001), and mycophenolate mofetil (MMF > 1,000 g, p = 0.007) predisposed patients to HZ. Univariate and multivariate analyses revealed a protective role of azathioprine (p = 0.008) and methylprednisolone pulses (p = 0.010) during induction therapy. HZ occurs unpredictably throughout the course of LN, underscoring the importance of continuous monitoring for these patients. In addition, the incidence of HZ seems to have increased in recent decades. Induction therapy with azathioprine and methylprednisolone pulses appears to provide protection, while higher cumulative doses of GCs, CYC, and MMF increase susceptibility.

Mycophenolate mofetil versus cyclophosphamide plus in patients with connective tissue disease-associated interstitial lung disease: Efficacy and safety analysis.

The decision for definitive therapy for the treatment of patients with connective tissue disease-associated interstitial lung disease (CTD-ILD) is difficult. Patients with CTD-ILD received 0.5 g twice a day of mycophenolate mofetil for 2 years (MMF cohort, n = 105) or cyclophosphamide 50 mg once every other day, and the cumulative dose of cyclophosphamide should not exceed 10 g (CYC cohort, n = 140). After complete of treatment (EL), % forced vital capacity (FVC) and % diffusing capacity of the lungs for carbon monoxide were increased in both the MMF and CYC cohorts as compared to before treatment (p < 0.001 for all). There were higher changes in % FVC values and a greater number of patients with significant change in % FVC (>10% change) in the CYC cohort than in the MMF cohort (p < 0.0001 for both) at EL. Patients in the CYC cohort had higher rates of leukopenia, thrombocytopenia, serious adverse effects related to treatment(s), and death than those in the MMF cohort (p < 0.05 for all). Cyclophosphamide plus prednisolone superiorly improved % FVC compared to mycophenolate mofetil plus prednisolone. Mycophenolate mofetil and cyclophosphamide improved pulmonary function. Mycophenolate mofetil is less toxic and increased patient survival.

Tooth Abnormalities and Their Age-Dependent Occurrence in Leukemia Survivors.

The multidrug nature of anticancer treatment and different treatment protocols used in the studies are likely to be a major limitation in establishing real risk factors determining the occurrence of dental abnormalities. The authors aimed to establish a relationship between the duration and the dose of chemotherapy and the number of tooth adverse effects in the group receiving the same treatment. Of the 40 anticancer therapy recipients who attended the outpatient dental clinic, 7 leukemia survivors receiving the treatment according to the ALL IC-BFM 2002 protocol were selected. The study group consisted of four females and three males aged 92 to 207 months at the time of dental examination and 29 to 91 months at leukemia diagnosis. As a result of the clinical and radiological examination, dental abnormalities such as agenesis, tooth size reduction, root abnormalities, and taurodontia were identified, and the medical records of all survivors were reviewed in terms of drugs administered, their doses, and treatment schedules. No correlation was observed between the treatment duration of an intensive therapy, the entire therapy, and the number of tooth abnormalities. No relationship was also found between the number of dental abnormalities and the cumulative dose of vincristine, L-asparaginase, methotrexate, cyclophosphamide, cytarabine, and 6-mercaptopurine. The age at the onset of antineoplastic therapy is likely to be the strongest risk factor for toxic injury during tooth development.

Cumulative cyclophosphamide dose and serum anti-Mullerian hormone levels in adolescent cancer survivors in Indonesia

Background As both the prevalence and survival rates of cancer in children and adolescents has risen, longer-term effects of cancer treatment must be investigated. High-risk gonadotoxic chemotherapeutic agents such as cyclophosphamide may affect the ovarian reserve and impact female adolescent fertility. Anti-Mullerian hormone is a reliable marker to assess ovarian reserve.&#x0D; Objective To assess for a possible correlation between the cumulative dose of cyclophosphamide and serum anti-Mullerian hormone (AMH) levels among adolescent cancer patients.&#x0D; Methods This cross-sectional study included 12-18-year-old adolescent female cancer patients who had experienced menarche and received cyclophosphamide therapy. We recorded the patients’ full history, including menstrual history, computed the cumulative dose of cyclophosphamide received, and measured serum AMH levels. The correlation test was performed to evaluate for a possible correlation between the cumulative dose of cyclophosphamide and ovarian reserve as represented by AMH levels.&#x0D; Results Out of 12 female adolescent cancer patients, three complained of disturbances in their menstrual cycles. Low levels of AMH (&lt;1.5 ng/mL) were noted in five patients. Median cumulative cyclophosphamide dose was 1,000 mg/m2 (range 1,000 to 5,250 mg/m2). Cumulative cyclophosphamide dose was negatively correlated with serum AMH levels, but this correlation was not statistically significant (r=-0.316, P=0.318).&#x0D; Conclusion This study has not been able to show a correlation between cumulative cyclophosphamide dose and serum AMH level. Regular evaluation of fertility and involvement of fertility team is recommended in adolescents receiving high-risk gonadotoxic chemotherapeutic agents.

P-432 Gonadal function and fertility preservation in girls with Hodgkin lymphoma treated according to the EURONET-PHL-C2 Protocol: the fertility add-on study

Abstract Study question What is the gonadotoxic potential of the EURONET-PHL-C2 treatment protocol for female childhood Hodgkin lymphoma patients, and how frequently are co-treatments to preserve fertility applied? Summary answer Treatment-induced amenorrhea (72%) persisted in &amp;gt; 10% of cases. Results on AMH are available by April 2023. Fertility preserving (co-)treatments were applied in 27% of patients. What is known already Current treatment for childhood Hodgkin lymphoma (HL) is highly effective with survival rates exceeding 90%. However, HL treatment affects gonadal function and HL survivors were proven to be at risk of premature ovarian insufficiency. In effort to reduce late effects, treatment protocols were adapted and toxic procarbazine was successfully omitted. The current EuroNET-PHL-C2 protocol aims to reduce use of radiotherapy by intensifying chemotherapy. The cumulative dose of cyclophosphamide is increased by 25% in the intensified treatment-arm, the impact of this change in therapeutic protocol on gonadal function is currently unknown. Therefore, a fertility study was incorporated in the EuroNET-PHL-C2 study. Study design, size, duration This international, prospective, multicenter cohort study is embedded in the EuroNET-PHL-C2 study, an European phase-3 treatment study evaluating the effectivity of HL treatment with OEPA-COPDAC (OEPA: vincristine sulfate (oncovin), etoposide, prednisolone and doxorubicin (adriamycin); COPDAC: cyclophosphamide, vincristine sulfate (oncovin), prednisone and dacarbazine) versus OEPA-DECOPDAC (DECOPDAC: COPDAC with additional doxorubicin and etoposide) in a randomized setting. In the present fertility add-on study, 205 (104 girls, 101 boys) patients were included between January 2017 and September 2021. Participants/materials, setting, methods Female patients, aged &amp;lt;18 years, treated according to the EuroNet-PHL-C2 protocol for classical HL, were recruited across 18 sites (the Netherlands, Belgium, Germany, Austria, Czech Republic). All parents and patients (aged ≥12 years old) provided written informed consent. Serum AMH levels and menstrual cycle were evaluated over time (at diagnosis, during- and directly after treatment, 2 years post-diagnosis) and compared between OEPA-COPDAC and OEPA-DECOPDAC treatment groups. Moreover, use of available fertility preservation treatments was evaluated. Main results and the role of chance In the present analysis, 100 girls were included of whom 88 completed 2 years of follow up. Median age at diagnosis was 15 years (7-18), 8 girls were prepubertal and 92 post pubertal (87% postmenarchal). 17 girls were diagnosed at an early stage of HL (TL1) and 83 in more advanced stages (TL2/TL3, 66% received COPDAC and 33% DECOPDAC). 5 patients (5%) were irradiated in the pelvic area. Of the 46 postmenarchal girls who did not receive hormonal contraceptives during treatment, 33 (72%) experienced treatment-induced amenorrhea, at least 4 (12%) had persisting amenorrhea at 2 years post-diagnosis. 4 girls (22%) who stopped taking hormonal contraceptives after treatment had no (return of) spontaneous cycle. 2 girls (2%) underwent ovariopexy. 4 girls cryopreserved oocytes before treatment and 12 cryopreserved ovarian tissue (OTC). 15 (15%) received GnRH analogues as a co-treatment. Data on AMH-levels up to 2 years post-diagnosis will be available by April 2023. Change in AMH will be evaluated, comparing number of received chemotherapy-cycles (3/4/6), DECOPDAC versus COPDAC and pubertal stage at time of diagnosis. Additional analyses will be performed to assess the impact of applied fertility preservation methods on gonadal function (i.e. AMH levels after OTC or receiving GnRH agonist). Limitations, reasons for caution The current analysis included data up to 2 years post-diagnosis. Potential recovery or late emerging effects of treatment remain unknown. The studied population comprises young girls with diagnosis of HL often concurring with pubertal transition, during which AMH levels naturally rise. SD z-scored will be used to analyze AMH results. Wider implications of the findings The fertility add-on study is the first study to prospectively evaluate reproductive markers in children treated for HL. Study results are highly valuable to determine effect of the proposed new treatment regimen for childhood HL on fertility . Trial registration number Clinicaltrials NCT02684708; EudraCT number 2012-004053-88

#6809 PULSE VERSUS DAILY ORAL CYCLOPHOSPHAMIDE IN ANCA-ASSOCIATED VASCULITIS WITH RENAL INVOLVEMENT: A SINGLE CENTER EXPERIENCE

Abstract Background and Aims We aimed to compare the risk of death, relapse and infections requiring hospital admission of ANCA-associated vasculitis (AAV) patients according to the induction of remission scheme used: daily oral (PO) cyclophosphamide or pulse intravenous (IV) cyclophosphamide. Method We identified all newly diagnosed AAV patients treated with PO or IV cyclophosphamide between January 1998 and December 2022 admitted to the CHVNGE Nephrology Department. Data were analyzed with SPSS v28® using parametric and non-parametric tests and Kaplan Meyer survival analysis. Results We identified 74 cases of de novo vasculitis, 50 of them received PO cyclophosphamide and 24 received IV cyclophosphamide. Median age at presentation was 68,50 ± 16,06 years PO and 68,00 ± 10,41 years IV. Median duration of follow-up was 3,8 years ± 2,98 for both groups, 6,21 years PO and 3,88 years IV. One-year survival was 84% in PO and 91,3% in IV patients; 15 (30%) PO and 5 (20,8%) pulse patients had at least one relapse. Neoplasms occurred in 3 (6%) patients in the PO group and 1 (4,2%) patient in the IV group. The number of patients admitted with one or more infections was 22 (44%) in the PO group and 9 (37,5%) in the IV group. Renal survival was 26 (52%) PO and 15 (62,5%) IV. There was no difference in survival (p = 0,176), renal survival (p = 0,113), risk of relapse (p = 0,283) and infection (p = 0,196) between the two groups. Conclusion There was no difference in renal or overall survival, confirming the previous published data. Contrasting with CYCLOPS, our analysis does not confirm an increased risk of relapse in the IV group. One particularly interesting data is that the number of infections in IV route was lower than PO, corroborating the data on lower cumulative doses and therefore lower risk of infection in previous studies. Potential bias of this study is the small sample of patients enrolled in the two groups and the duration of follow up. Despite the reduction in the cumulative dose of cyclophosphamide, we continue to have significant adverse effects, which can also be explained by the dose of corticosteroid previously used, therefore strategies to reduce the toxicity associated with treatment without compromising efficacy are important goals for future research. Treatments need to be optimized and customized according to the severity of the patient's disease and the risk of recurrence.

#5390 INTENSIFIED B CELL DEPLETION THERAPY IN ANCA-VASCULITIS WITH SEVERE RENAL IMPAIRMENT AS COMPARED TO CONVENTIONAL IMMUNOSUPPRESSION

Abstract Background and Aims Rituximab (RTX) has shown to be an effective induction treatment for small-vessel vasculitides associated with antineutrophil cytoplasm antibodies (AAV) in both newly diagnosed and relapsing patients. However, the role of RTX in the management of the most severe cases of AAV remains to be fully elucidated. The aim of this study was to assess both safety and efficacy of an intensified B-cell depletion therapy (IBCDT) protocol, including RTX, cyclophosphamide (CYC), and methylprednisolone pulses without additional maintenance immunosuppressive therapy in a cohort of 15 AAV patients with the most severe features of AVV renal involvement (as &amp;lt;15 ml/min GFR and histological findings of paucimmune necrotizing glomerulonephritis with more than 50% crescents of non-sclerotic glomeruli at the renal biopsy). Method Results of the IBCDT regimen have been compared to those obtained in a control cohort of 10 patients with AAV treated with a conventional therapy regimen based on oral CYC and steroids followed by a prolonged maintenance therapy with azathioprine (AZA). Plasma exchange was equally employed in the study and the control group. Results Complete clinical remission (BVAS 0) was observed at 6 months in 14 of 15 patients treated with IBCDT (93%). All cases who achieved a complete clinical remission experienced a depletion of peripheral blood B cells at the end of therapy. Of the 10 dialysis dependent patients at onset, 6 subjects (60%) experienced a functional recovery allowing the suspension of dialysis treatment. When compared to the control group, no statistically significant difference was observed in patients treated with IBCDT in terms of overall survival, 6-month therapeutic response rate, and 6-, and 12-month functional renal recovery. The cumulative total dose of CYC in the case group was on average 1 g/patient while in the control group on average 8.5 g/patient (p = 0.00008). Conclusion Despite the retrospective design and relative limited sample size, IBCDT appeared to be safe and had the same efficacy profile when compared to the conventional therapy with CYC plus AZA in the management of the most severe patients with AAV. Additionally, this avoided the need of prolonged maintenance therapy for long, and limited the exposure to CYC with consequent reduced toxicity and drug-related side effect rates.

Efficacy of Gonadotropin-Releasing Hormone Agonist (GnRH-a) in Ovarian Preservation in Females With Systemic Lupus Erythematosus (SLE) Receiving Cyclophosphamide (CYC) [ID: 1375370

INTRODUCTION: Systemic lupus erythematosus (SLE) female patients with severe disease manifestations are treated with cyclophosphamide (CYC), which causes ovarian cytotoxicity. Gonadotropin-releasing hormone agonist (GnRH-a) is often co-administered with CYC to preserve ovarian function and reproductive potential. However, there is a lack of evidence to support this use of GnRH-a. We conducted a retrospective study and questionnaire of SLE patients who received CYC with or without GnRH-a to evaluate its efficacy in preserving ovarian function. METHODS: This study was approved by the IRB of the National Institutes of Health (IRB#:001011). Review of medical records resulted in 50 female SLE patients treated with CYC who were less than 40 year old at the time of treatment: CYC only (n=20, group 1), CYC and GnRH-a (n=30, group 2). These patients were age/gender-matched with 50 SLE patients not treated with CYC (group 3). Data about demographics, SLE disease activity, damage accrual, cumulative CYC exposure, and pregnancy outcomes were collected by chart review. Self-reported questionnaires were used to collect data assessing menses cycles, pregnancies and their outcome, or infertility. RESULTS: There was no significant difference in SLE disease activity, baseline demographics, total damage accrual, or other clinical parameters between groups 1 and 2. The mean cumulative CYC dose was 1.2 g (group 1) and 1.5 g (group 2) (P=.16). Number of pregnancies were similar: mean (SD) group 1=2 (1.6); group 2=1.2 (1.4); group 3=1.3 (1.4) (P=.18). There were more miscarriages in group 1 compared to groups 2 and 3 (P=.015). CONCLUSION: Our data suggest use of GnRH-a improves pregnancy outcomes in SLE patients on CYC, but prospective studies are needed to establish its safety and efficacy.

MO262: Intravenous Cyclophosphamide for High-Risk Primary PLA2R-Positive Membranous Nephropathy

Abstract BACKGROUND AND AIMS The mainstay of treatment for high-risk primary membranous nephropathy (MN) is the cyclic steroid-oral cyclophosphamide (CYC) regimen (modified Ponticelli regimen). However, there has been increasing awareness of serious treatment-related toxicity. Intravenous CYC offers the potential benefit of lower cumulative dose and a lower rate of adverse events. Therefore, we aimed to evaluate the efficacy and safety of intravenous CYC in high-risk primary PLA2R-positive MN. METHOD We retrospectively examined the renal outcome on 1 August 2020 of 40 adult patients [age 57 (interquartile range (IQR) 48–69] years, 70% male, serum creatinine 1.1 (IQR 0.9–1.3) mg/dL) who were diagnosed with MN by kidney biopsy and had positive serum anti-PLA2R ab at diagnosis [median titer 257.3 (IQR 86.4–603.0) RU/mL] during 2016–2019. We included only patients with first episode MN at high risk according to 2021 KDIGO guideline, and who were followed for at least 6 months. All patients received CYC at a dose of 600 mg/m2 every 4 weeks for up to 6 months in conjunction with prednisone at a dose of 0.75 mg/kg daily (up to 60 mg/day) with gradual tapering to 0.5 mg/kg/day by 3 months and 0.1 mg/kg/day by 6 months. The outcomes were as follows: kidney survival defined as kidney replacement therapy (KRT) initiation; partial (proteinuria 0.5–3.5 g/24 h) or complete remission (proteinuria &amp;lt; 0.5 g/24 h and serum albumin ≥ 3.5 g/dL)—whichever came first. RESULTS Patients were followed for a median of 26 (95% CI 19.2–32.7) months, and 27 (67%) patients reached a form of remission with complete remission observed in 15 patients (37%) and partial remission in 12 (30%). Cumulative remission rates were 24% after 6 months, 57% after 12 months and 77% after 24 months. Median time to cumulative remission was 11.0 (95%CI 6.6–15.3) months. Absence of response was observed in 13 patients (33%), three (8%) of whom started KRT after a mean follow-up of 4.2 (95% CI 3.9–4.5) years. Patients who did not respond to immunosuppression had more severe nephrotic syndrome [24 h proteinuria 12.5 (IQR 7.9–15.0) versus 6.1 (IQR 4.0–8.7) g/24 h, P = .002; serum albumin 2.1 (IQR 2.0–2.3) versus 2.4 (IQR 2.0–2.8) g/dL, P = .04] at diagnosis, but similar titer of PLA2R ab [417 (IQR 258–690) versus 185.7 (IQR 85–439) RU/mL, P = .2]. In the Cox proportional hazard model, only lower serum albumin [HR 3.9 (95% CI 1.2–12.3), P = .01] was retained as a risk factor for absence of remission, while 24 h proteinuria [HR 1.0 (95% CI 0.9–1.0), P = .6], baseline PLA2R ab titer [HR 1.0 (95% CI 0.9–1.0), P = .7] and kidney biopsy chronicity index [HR 1.0 (95% CI 0.8–1.2), P = .5] were not. Clinical relapse occurred in 3 of 27 (11%) patients at a mean of 11 months after treatment discontinuation. During the follow-up period five (13%) patients died. Cardiovascular disease (three patients) and infections (two patients) were the main causes of death; apparently not related to CYC treatment. Median cumulative dose of CYC was 7.2g. None of the patients required blood transfusions or granulocyte–colony-stimulating factor for the management of myelosuppression. Two patient developed community-acquired pneumonia after the first CYC dose and required hospital admission. When the infection resolved, immunosuppressive treatment was successfully completed. CONCLUSION Monthly intravenous CYC pulses in patients with high-risk primary PLA2R-positive MN seems to be an effective and safe alternative for treatment. Also, in these patients, lower serum albumin at diagnosis is an early marker for lack of remission.

Long-Term Effects of Cyclophosphamide in Sustained Remission in Childhood Steroid-resistant Nephrotic Syndrome.

Nephrotic syndrome (NS) is a chronic renal disease that can progress into end-stage renal disease within 5 years if no remission occurs. Achieving optimal remission is important to obtain better outcomes of treating childhood steroid-resistant NS (SRNS). This study aimed to determine the survival, long-term outcomes, and factors associated with the sustained remission of SRNS patients after cyclophosphamide therapy. We retrospectively studied 33 children (24 boys) with SRNS treated with cyclophosphamide therapy over 2 years. Relapse-free survival was estimated using the Kaplan-Meier method. The determinants of long-term remission were assessed by univariate and multivariate analyses using Cox's proportional hazard models. The median age at the onset of NS was 3.0 years (range: 7 months to 14.0 years). The median age at the initiation of cyclophosphamide therapy was 5.0 years (range: 1.0-15.0 years). The mean cumulative cyclophosphamide dose was 155.61 ± 16.31 mg/kg body weight. In total, 18 of 33 (54.5%) children remained in remission for 2 years after cyclophosphamide therapy, and 10 of 15 patients who relapsed (66.67%) became steroid sensitive. Relapse-free survival after cyclophosphamide therapy was 78.8%, 69.7%, and 54.5% after 6, 12, and 24 months, respectively. Cox's proportional hazard regression identified no association between remission 2 years after cyclophosphamide therapy and other factors, such as age at the onset of SRNS, type of resistance, hypertension, hematuria, administration route of cyclophosphamide, and cumulative dose (all P >0.05). Cyclophosphamide therapy appeared to be beneficial for children with SRNS for sustaining 2-year remission with a 54.5% relapse-free survival rate.

Treating Patients With ANCA-Associated Vasculitis and Very Severe Renal Injury With an Intensified B Cell Depletion Therapy: Comparison With a Control Cohort Receiving a Conventional Therapy.

Rituximab (RTX), an anti-CD20 monoclonal antibody, has shown to be an effective induction treatment for small-vessel vasculitides associated with antineutrophil cytoplasm antibodies (AAV) in both newly diagnosed and relapsing patients. However, the role of RTX in the management of the most severe cases of AAV remains to be fully elucidated. The aim of this study was to assess both safety and efficacy of an intensified B-cell depletion therapy (IBCDT) protocol, including RTX, cyclophosphamide (CYC), and methylprednisolone pulses without additional maintenance immunosuppressive therapy in a cohort of 15 AAV patients with the most severe features of AVV renal involvement (as <15 ml/min GFR and histological findings of paucimmune necrotizing glomerulonephritis with more than 50% crescents of non-sclerotic glomeruli at the renal biopsy). Results of the IBCDT regimen have been compared to those obtained in a control cohort of 10 patients with AAV treated with a conventional therapy regimen based on oral CYC and steroids followed by a prolonged maintenance therapy with azathioprine (AZA). Plasma exchange was equally employed in the study and the control group. Complete clinical remission (BVAS 0) was observed at 6 months in 14 of 15 patients treated with IBCDT (93%). All cases who achieved a complete clinical remission experienced a depletion of peripheral blood B cells at the end of therapy. Of the 10 dialysis dependent patients at onset, 6 subjects (60%) experienced a functional recovery allowing the suspension of dialysis treatment. When compared to the control group, no statistically significant difference was observed in patients treated with IBCDT in terms of overall survival, 6-month therapeutic response rate, and 6-, and 12-month functional renal recovery. The cumulative total dose of CYC in the case group was on average 1 g/patient while in the control group on average 8.5 g/patient (p = 0.00008). Despite the retrospective design and relative limited sample size, IBCDT appeared to be safe and had the same efficacy profile when compared to the conventional therapy with CYC plus AZA in the management of the most severe patients with AAV. Additionally, this avoided the need of prolonged maintenance therapy for long, and limited the exposure to CYC with consequent reduced toxicity and drug-related side effect rates.

Urotoxicity and safety data of low-dose intravenous cyclophosphamide therapy for rheumatic diseases: A Single-Center retrospective cohort study

Despite its effectiveness in rheumatic diseases, cyclophosphamide (CYC) treatment should be used with caution due to its side effects. CYC is thought to pose a risk in the development of hemorrhagic cystitis and bladder cancer. This study aims to determine the incidence of hemorrhagic cystitis and bladder cancer with intravenous low-dose CYC therapy used in the treatment of rheumatic diseases. A total of 211 adult patients with rheumatic disease treated with intravenous CYC were evaluated in this retrospective study conducted between January 2006 and May 2021. Patient data including cumulative CYC dose, treatment frequency, duration of treatment, side effects, such as hemorrhagic cystitis and bladder cancer were acquired from medical archives. The mean follow-up period was 48.5 (3–180) months, and the mean cumulative CYC dose was 5g (2–19g). None of the patients received mesna therapy concurrent with CYC therapy. 11 patients developed hemorrhagic cystitis (5.2%). Hemorrhagic cystitis was found to be statistically significantly associated with the number of CYC cycles (p=0.04). All patients were asymptomatic. No statistically significant difference was observed between hemorrhagic cystitis, treatment duration, and cumulative dose for CYC therapy in rheumatic diseases. Malignancy developed in 12 patients (5.7%) after CYC treatment. Bladder cancer was observed in 1 patient. According to our findings, the only risk factor for hemorrhagic cystitis in patients receiving CYC was the number of CYC cycles. Intravenous CYC regimen did not cause symptomatic hemorrhagic cystitis. Low-dose IV CYC may be safe in terms of serious urotoxic side effects when used at the appropriate dose, duration and frequency.

Quantification of Long-Term Consequences Associated with Components of the CHOP Chemotherapy Regimen

Introduction: A common chemotherapy regimen for Epstein-Barr virus-driven post-transplant lymphoproliferative disease (EBV + PTLD) following solid organ transplants is cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). Long-term adverse consequences of CHOP, particularly the incidence, timing, and risk factors associated with these events, in any cancer survivor remain poorly understood. In this study, we review the evidence to determine how often long-term consequences associated with the components of CHOP occur.Methods: Potential long-term consequences of CHOP components were identified from the Children's Oncology Group Long-Term Follow-Up (COG LTFU) Guidelines. Abstracts were screened and eligibility was based on reporting data for the identified COG LTFU long-term consequences along with pre-specified criteria (English, systematic review, randomized controlled trial n>100, observation study n>100, case series n>20). Studies that met the inclusion criteria were extracted and synthesized. Quantification of late effects evaluated in >3 studies were reported.Results: Long-term consequences in the 45 studies that met the pre-specified criteria included cardiac toxicity, hormone deficiencies/infertility, secondary leukemia, osteonecrosis (ON), and urotoxicity/bladder cancer. Although none of the studies focused specifically on the CHOP regimen, 30%, 23%, and 15% evaluated alkylating agents (eg, cyclophosphamide), anthracyclines (eg, doxorubicin), and corticosteroids (eg, prednisone), respectively. Time to onset from treatment was as early as 1 year for cardiac toxicity, <5 for infertility, 2 for ON, 3 for secondary leukemia, and 5 for bladder cancer. Longer follow-up times were associated with higher percentages of long-term consequences. For example, cardiac toxicity and hormone deficiencies/infertility affected >20% of patients, and secondary leukemia, ON, urotoxicity/bladder malignancy affected 10-20% of patients (Table 1). A wide range in the incidence and timing of these late effects was observed, likely due to variation in the treatment regimens, follow-up time, and event definition.The synthesized evidence supports that CHOP components increased the risk of long-term consequences in a dose-dependent manner. Cardiac toxicity risk was elevated even at anthracycline doses of <150 mg/m 2 (traditionally considered a ‘safe’ dose range). Hazard ratios (HRs) for heart failure at doses of ≤300 to <400 mg/m 2 were 4.33 and 13.19 for daunorubicin and doxorubicin, respectively. Studies also reported significantly elevated risk of cardiac toxicity in patients with lymphoma treated with anthracyclines (eg, HR of up to 12.2) compared with the sibling cohort. Patients <5 years of age vs ≥5 years of age at exposure had a significantly higher risk of cardiac toxicity (HR of 1.89). Patients exposed to cumulative doses of cyclophosphamide ≥6 g/m 2 had significant reproductive risks. The risk of early menopause was shown to be dose dependent and as much as 27-fold higher in patients treated with both radiation below the diaphragm and alkylating agent chemotherapy. Patients exposed to high-dose cyclophosphamide (>7.5 g/m 2) were at statistically significantly higher risk (odds ratio of 12.0) for diminished ovarian reserve as measured by their Anti-Müllerian hormone level. One study reported 3.8- and 3.2-fold increases in risk of ovarian failure in patients who had been diagnosed with Hodgkin's lymphoma and Non-Hodgkin's lymphoma, respectively. High-doses of anthracyclines and alkylating agents were associated with up to 16-fold increases in risk of secondary leukemia. The risk of bladder cancer significantly increased with increasing dose of cyclophosphamide, with a 6- and 14.5-fold increased risk at cumulative doses of 20‒49 g and ≥50 g, respectively. Intensive corticosteroid therapy was associated with significant risk of ON, with one study showing cancer survivors had a 6.2 times higher likelihood of ON as compared to their sibling comparison group.Conclusions: Patients exposed to components of CHOP have a dose-dependent risk of cardiac toxicity, infertility, secondary leukemia, ON, and bladder cancer that are often significant, impacted a high percentage of patients, and occurred as early as 1 year after treatment. Safe and effective PTLD treatments that potentially avoid these long-term consequences are urgently needed. [Display omitted] DisclosuresWatson: Atara Biotherapeutics: Current Employment, Current holder of individual stocks in a privately-held company. Gadikota: Maple Health Group: Current Employment. Barlev: Atara Biotherapeutics: Current Employment. Beckerman: Maple Health Group: Current Employment.