Assessment of ifosfamide, gemcitabine, vinorelbine and prednisone (IGEV) regimen as salvage treatment for relapsed or refractory pediatric classical Hodgkin lymphoma

Introduction

Hodgkin lymphoma (HL) has an excellent prognosis in pediatric patients. However, up to 25% of the cases experience recurrence, necessitating salvage chemotherapy (1). Commonly utilized salvage regimens in pediatrics comprise various chemotherapeutic agents followed by high-dose chemotherapy and autologous stem cell transplantation (ASCT), demonstrating overall survival (OS) rates of up to 70% (2). The ICE regimen, comprising ifosfamide, carboplatin (or cisplatin), and etoposide, is used by many centers to treat patients with relapsed or refractory HL, exhibiting a good response rate. However, the toxicities associated with this regimen, including the risk of secondary malignancies, have prompted the exploration of more effective and less toxic reinduction therapies (3). The IGEV regimen, consisting of ifosfamide, vinorelbine, gemcitabine and prednisone was first introduced in 2001 for the treatment of adults with relapsed or refractory HL. The treatment has demonstrated significant efficacy, characterized by a high response rate, favorable mobilization potential, acceptable hematological toxicity, and an absence of toxicity-related deaths (4-6). IGEV has demonstrated efficacy not only in adults but also in pediatric patients, with an overall response rate (ORR) of 100%, excellent stem cell mobilization potential, and acceptable toxicity (2). In addition, advances in the understanding of the tumor microenvironment have led to the introduction of promising targeted therapies for relapsed or refractory classical HL, including the antibody-drug conjugate brentuximab vedotin and immune checkpoint inhibitors (7). The high economic burden associated with such a type of treatment presents significant challenges, especially in low- and middle-income countries, where access to such therapies may be limited due to financial constraints and availability issues. The primary objectives of the present study are to evaluate ORR, assess the toxicity profile, and examine the potential for stem cell mobilization after administering the IGEV regimen in pediatric patients with relapsed or refractory HL. Few studies have investigated the use of the IGEV regimen in pediatric patients, and most of these are from high-income countries. Our study provides data from a low- and middle-income country, offering a new perspective on its use in resource-limited settings. This helps to fill a gap in current literature by assessing its outcomes and feasibility in a different healthcare context. We present this article in accordance with the STROBE reporting checklist (available at https://aol.amegroups.com/article/view/10.21037/aol-25-3/rc).

Methods

Study design

This retrospective study included patients diagnosed with relapsed or refractory HL who received the IGEV regimen as second-line treatment at the Children Cancer Hospital Egypt (CCHE) between August 2021 and December 2022. Data collection was completed in June 2024. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. It was approved by the institutional research board committee of CCHE (No. 40/2023) with no need for informed consent as it is a retrospective study. Eligible patients were aged 1–18 years at the time of diagnosis, with confirmed pathology of classical HL; selection bias was minimized by including consecutive patients. Relapse was confirmed by a new tissue biopsy. The study cohort, included cases of primary refractory, early, and late relapses. There were no specific comorbidities, excluding IGEV treatment. Patients with nodular lymphocyte-predominant HL were excluded from the study because they had distinct clinic-pathologic features and a treatment algorithm.

Treatment protocol

The IGEV regimen was administered in an inpatient setting, consisting of ifosfamide at 2,000 mg/m²/day infused over 24 hours (days 1–4), vinorelbine at 25 mg/m²/dose (days 1 and 5), gemcitabine at 800 mg/m²/day intravenously (IV) (days 1 and 4), and oral prednisolone at 100 mg/day (days 1–4). Anti-emetics were routinely administered; however, no prophylactic antimicrobial agents were provided to the patients, with the exception of trimethoprim/sulfamethoxazole. No specific dose modification guidelines were predefined prior to its administration. Subsequent cycles were administered after hematologic recovery. Peripheral blood stem cell (PBSC) harvesting was done after achieving remission (2–6 cycles) using subcutaneous filgrastim (10 mcg/kg/d), or filgrastim plus cyclophosphamide (2 gm/m² IV over one hour). PBSC was deemed successful if the total CD34⁺ cell count was ≥2.5×10⁶ cells/kg. The conditioning regimen used post-IGEV was BEAM consisting of bendamustine at 200 mg/m²/day IV on day −8 and day −7, etoposide at 200 mg/m²/day IV on days −6 to −3, cytarabine at 400 mg/m²/day IV on days −6 to −3, and melphalan at 140 mg/m² on day −2 (8). Involved field radiotherapy (IFRT) was administered as a consolidation treatment for patients who underwent ASCT during the post-transplant period, as well as for those who were considered low-risk (LR) at the time of relapse (total dose 1,980 cGy in 11 fractions) to all sites initially involved at the time of relapse. The detailed treatment pathway is shown in Figure 1.

Figure 1 The detailed treatment pathway. ASCT, autologous stem cell transplantation; BEAM, bendamustine, etoposide, cytarabine, melphalan; CMR, complete metabolic response; CR, complete response; IFRTH, involved field radiotherapy; IGEV, ifosfamide, gemcitabine, vinorelbine, prednisone; PD, progressive disease; PET, positron emission tomography; PET2, PET after the first 2 cycles of IGEV; PET4, PET after 4 cycles of IGEV; PR, partial response; SD, stable disease.

Patient data

Initial disease characteristics, first-line chemotherapy, and relapse metrics were retrospectively collected from electronic medical records, including relapse timing, number of salvage chemotherapy cycles, response to the salvage regimen, adverse events and outcomes of ASCT. Reported toxicities were also analyzed. Relapse was categorized as primarily refractory if it occurred within three months of the end of treatment or during therapy, early if it occurred between 3 and 12 months after therapy ended, or late if it occurred more than 12 months after therapy had ended (9). Information bias was reduced by using a standardized data collection form.

Risk stratification at relapse

We have implemented an updated approach for the management of patients with relapsed and primary refractory classic HL. They were classified at the time of diagnosis of relapse/refractory disease into two risk categories: LR and standard-risk (SR), based on a recent recommendation from the EuroNet pediatric HL group 2020 (9). All patients were classified into these risk levels based on prognostic criteria at the time of relapse, as detailed in Table S1. Only patients who met the LR criteria were exempt from ASCT and received standard-dose chemotherapy and consolidation radiotherapy.

Assessment of response

Disease assessment was performed by fluorodeoxyglucose positron emission tomography-computed tomography (FDG PET-CT) after the first 2 and 4 cycles of IGEV therapy. Complete response (CR) was defined as complete metabolic response, Deauville score (DS) 1–3 in PET-CT as per the EuroNet pediatric HL group 2020 recommendation (9-11). Partial response (PR) as incomplete metabolic response DS >3 with reduced uptake compared with baseline PET-CT. Stable disease (SD) was defined as DS >3, with no significant change in FDG uptake compared with baseline PET-CT. Progressive disease (PD) was defined as DS >3 with increased FDG uptake or new lesions compared to baseline PET-CT. The ORR was calculated as the sum of CR plus PR.

Engraftment assessment

Engraftment was defined as the first day on which an absolute neutrophil count (ANC) of 0.5×10⁹/L was achieved, persisting for a minimum of three days following the initial nadir post-PBSC transplant.

Toxicity assessment

Adverse events were classified based on the Common Terminology Criteria for Adverse Events (CTCAE), version 5. Only grades 3 and 4 were reported for hematologic toxicities. All grades of hypersensitivity were documented. Fever, all forms of infection, and any toxicity requiring dosage modification were assessed.

Statistics

All statistical analyses were performed using IBM SPSS Statistics, version 20. Kaplan-Meier survival curves were used to estimate event-free survival (EFS) and OS. Differences between survival curves were assessed using the log-rank test. Categorical variables were compared using the chi-square test or Fisher’s exact test, as appropriate. Continuous variables were compared using the independent samples t-test for normally distributed data, or the Mann-Whitney U test for non-normally distributed data. Quantitative variables were summarized using mean, median, and range. Age was used as a grouping variable, while all other variables were treated as continuous. A P value of less than 0.05 was considered statistically significant. Additionally, R software (version 4.4.1) was used to perform survival analyses. Given the small sample size (n=40) in this retrospective study, controlling for confounders was limited. However, subgroup analysis based on age was conducted to account for potential differences in outcomes. Further multivariable adjustments were not feasible due to the sample size, but descriptive analyses were carefully reviewed to identify potential confounding factors. Patients with missing information were excluded from specific analyses involving those variables. Sensitivity analyses were not conducted due to the small sample size, which limits the ability to explore alternative assumptions in the data without compromising statistical power. However, future studies with larger cohorts may be required to confirm the robustness of these findings. EFS was defined as the time from the first relapse or progression to the occurrence of any of the following events: disease progression, relapse, or a switch to another salvage regimen due to inadequate response—specifically defined as stable or PD following IGEV therapy. Switching therapy due to toxicity was not considered an event. OS was defined as the time from the first relapse or progression to death or the last follow-up. Patients were censored at the date of their last follow-up if no event (relapse, progression, or death) had occurred by that time. Loss to follow-up was defined as the absence of any clinical contact or documentation for a period of six consecutive months, despite scheduled follow-up visits and efforts to reach the patients or their family.

Results

The total number of patients with relapsed or refractory HL during the period from August 2021 to December 2022 at CCHE was 44; 4 were excluded as they received ICE upon physician preference, the remaining 40 patients received IGEV as a second-line treatment following their first relapse. Most variables had complete data. Missing values were minimal and occurred in toxicity grading for only 2 patients. The patients’ characteristics at the initial presentation are listed in Table 1. The median age was 12 years (range 3–17 years). The male-to-female ratio was 1.3, and most patients exhibited nodular sclerosis (NS) pathology (80%). A significant percentage of patients presented with B symptoms (55%), bulky disease (45%), extranodal disease (47.5%), involvement of three or more nodal sites (85%), and advanced-stage disease (62%) at initial diagnosis. The EuroNet-PHL-C2 protocol was administered as the first-line treatment in 90% of patients, whereas the remaining 10% received the ABVD regimen (doxorubicin, bleomycin, vinblastine, and dacarbazine). Initially, only 25% of the cohort received radiotherapy due to having positive FDG PET-CT after the 1st 2 cycles of the frontline therapy. Among the 40 cases studied, 16 (40%) experienced late relapse, 15 (37.5%) presented with primary refractory disease, and 9 (22.5%) experienced early relapse. All relapses were confirmed by biopsy and occurred at the same sites of the initial disease involvement. The IGEV regimen was administered to patients as the first salvage therapy, followed by ASCT for those who exhibited a response to the treatment and met the criteria for transplantation. The ORR to IGEV regimen before ASCT was 70%, with 17 patients (42.5%) achieving CR and 11 patients (27.5%) exhibiting PR after two cycles of chemotherapy. Furthermore, five patients (12.5%) demonstrated SD, whereas the remaining seven patients (17.5%) displayed PD, demonstrated on FDG PET-CT following two cycles of treatment. The characteristics of patients who achieved CR or PR after 2 cycles of IGEV in comparison with those who had SD or PD are listed in Table 2. Out of the 28 patients who had good ORR after the 1st 2 cycles of IGEV, either CR or PR, 14 patients (50%) unfortunately experienced a second relapse while waiting for apheresis or transplantation. For these patients, the average duration from achieving CR to disease progression during the waiting period was 5.5 months (range: 1.5–14.2 months). Among the 24 patients who underwent ASCT in our study, seven achieved CR or PR with the IGEV regimen and subsequently underwent successful CD34⁺ stem cell mobilization followed by ASCT. The remaining 17 patients required a switch to an alternative chemotherapy regimen due to a second relapse prior to ASCT. In the subgroup of seven patients who proceeded to ASCT after IGEV, stem cell collection was completed after one apheresis session in four patients and after two sessions in the remaining three. Regarding the timing of stem cell collection, it was performed after the third cycle of IGEV in one patient, after the fourth cycle in two patients, and after the sixth cycle in four patients, as shown in Table 3. The median CD34⁺ cell yield among these seven patients was 5.8×10⁶ cells/kg (range, 2.9×10⁶–12.8×10⁶ cells/kg), collected after a median of seven days following the administration of subcutaneous filgrastim alone or in combination with cyclophosphamide. Engraftment occurred at a median of 17 days (range, 12–26 days) following stem cell reinfusion. Patients who were classified as having low-risk at relapse (6 patients) were not indicated for transplantation as they had late relapse, did not receive radiotherapy during the front-line treatment, and achieved CR after 2 cycles of IGEV chemotherapy. Patients who had stable or PD following 2 cycles of IGEV (12 patients) were switched to another salvage regimen to achieve CR. Patients’ characteristics, at initial presentation, relapse, response to IGEV and outcome are listed in Table S2. The median follow-up duration for the entire cohort was 37.5 months [range: 10–96 months; interquartile range (IQR): 29–50.5 months]. The 2-year OS and EFS for our cohort were 86% and 34%, respectively, as shown in Figure 2. During the study, three children died. Two of the deaths were due to respiratory failure secondary to measles infection. Both patients had been vaccinated prior to their initial cancer diagnosis; however, their immunocompromised status following intensive chemotherapy may have contributed to their susceptibility and the severity of the infection. The third patient died due to PD. The 2-year EFS for patients with negative and positive PET-CT after two cycles of IGEV chemotherapy were 49.9% and 21.7%, respectively (P=0.01), as demonstrated in Figure 3. A statistically significant difference was observed in EFS regarding the timing of relapse. The 2-year EFS rates were 52.2%, 33.3%, and 13.3% for patients with late, early relapses and refractory disease, respectively (P=0.010), as shown in Figure 4. Figure 5 provides an overview of patient responses to the IGEV regimen, the number of patients who required alternative treatments, those who proceeded to ASCT, and the final outcomes across the study population. Adverse events were generally mild, with one patient experiencing a grade II allergic reaction to gemcitabine in the form of a skin rash. Only one patient required dose modification. This patient developed peripheral neuropathy, which led to the omission of vinorelbine from the fourth cycle of the IGEV regimen. In contrast, another patient who developed neurotoxicity due to ifosfamide, manifesting as seizures, was switched entirely to an alternative regimen (brentuximab-bendamustine). Furthermore, gemcitabine-induced pseudocellulitis was reported in two patients; it was diagnosed clinically but not confirmed histologically and it does not recur with subsequent gemcitabine doses. It was managed with short course of steroids without any dose modification. Febrile neutropenia of grade 3–4 was observed in nine patients who required hospital admission in 8 patients, with two patients exhibiting neutropenic enterocolitis, but there was no documented bloodstream infection nor need for intensive care admission. Oral mucositis was observed in two patients, classified as grade 2 in one patient and grade 4 in the other.

Figure 2 OS and EFS for the whole cohort. 2-yr, 2-year; CI, confidence interval; EFS, event-free survival; OS, overall survival; Surv., survival.

Figure 3 EFS for the patients according to PET-CT results after 2 cycles of IGEV. CI, confidence interval; CT, computed tomography; EFS, event-free survival; IGEV, ifosfamide, gemcitabine, vinorelbine, prednisone; PET, positron emission tomography.

Figure 4 EFS for the patients in relation to the time of relapse. CI, confidence interval; EFS, event-free survival.

Figure 5 Flow chart of patient responses to the IGEV regimen, the number of patients who required alternative treatments, those who proceeded to ASCT, and the final outcomes. ASCT, autologous stem cell transplant; CR, complete response; IGEV, ifosfamide, gemcitabine, vinorelbine, prednisone; PD, progressive disease; RTH, radiotherapy.

Discussion

ASCT is recognized as the standard treatment for pediatric patients with relapsed or refractory classical HL. The primary goal of any salvage chemotherapy regimen in this setting is to achieve adequate disease control or response to allow for successful transplantation. While the optimal salvage regimen has not been universally defined, several protocols are in use, and their selection typically depends on ORR, toxicity profile, and stem cell mobilization potential. Among these, the IGEV regimen has been recommended as first-line salvage option within the EuroNet Pediatric Hodgkin Lymphoma Group, as supported by the group’s treatment guidelines and clinical experience (9). Additional reports have supported the efficacy and tolerability of IGEV in the salvage setting, highlighting its role in achieving adequate disease control with acceptable toxicity and good stem cell mobilization, making it a viable option for pediatric HL patients eligible for ASCT (2,12,13).

A pediatric study conducted at our institution (14) compared the efficacy and toxicity profiles of two salvage regimens, ICE vs. gemcitabine and vinorelbine (GV) in children with relapsed or refractory HL. Although the ICE regimen demonstrated a higher ORR than the GV regimen (54% vs. 29%, respectively), it was associated with significant toxicities. Reported adverse events included marked myelosuppression, grade 3–4 hematologic toxicities, infectious complications, prolonged hospitalizations for supportive care, septic shock, and admissions to the intensive care unit (ICU). Given that approximately 90% of our patients received frontline therapy according to the EuroNet Pediatric Hodgkin Lymphoma Group’s protocol, and considering the significant toxicity associated with the ICE regimen observed in our patients, evaluating an alternative salvage approach was essential. The EuroNet Group recommends the IGEV regimen as the preferred first-line salvage treatment due to its use of non-cross-resistant agents and lack of cumulative dose-dependent toxicity (9). Therefore, we evaluated the safety and efficacy of the IGEV regimen in our patient population. Compared to the ICE regimen, the IGEV regimen demonstrated a more favorable toxicity profile, with lower rates of febrile neutropenia, septic shock, bloodstream infections, ICU admissions, and hospitalizations for supportive care, as shown in Table 4. In our cohort, only eight patients developed grade 3 or 4 febrile neutropenia requiring hospital admission, with an average hospital stay of 7 days (range, 5–10 days). These findings suggest that the IGEV regimen may reduce the need for hospital-based care, which is particularly important in low- and middle-income countries where healthcare resources and inpatient bed availability are limited. Given its lower toxicity and reduced requirement for intensive supportive measures, IGEV may represent a practical, effective, and potentially preferable treatment option for children with relapsed HL in resource-constrained settings. In our study, two patients developed gemcitabine-induced pseudocellulitis, which improved with the use of non-steroidal anti-inflammatory drugs and topical corticosteroids. The literature on gemcitabine-associated pseudocellulitis remains limited, and the condition is often under-recognized, leading to misdiagnosis and unnecessary antibiotic use. A few case reports in adult patients have described histologically confirmed pseudocellulitis following gemcitabine administration (15,16), highlighting the importance of awareness and accurate diagnosis in clinical practice. The proportion of refractory patients in our cohort (37.5%) was slightly lower than that reported by Marr et al. (50%) but similar to the 39.6% reported by Santoro et al., as shown in Table 5 (2,17). For response assessment, our study used a broader definition of CR, considering a DS of 1–3, while Marr et al. used a stricter criterion, defining CR as DS 1–2. Usually, a broader definition would lead to higher rates of CR and ORR. However, our ORR of 70% was still lower than Marr et al.’s 100%, despite our more inclusive criteria. This difference is likely due to a higher number of patients with poor response in our group. The small sample size in Marr et al.’s study (n=12) limits direct comparison. Our larger cohort (n=40) showed an ORR that is reasonably comparable to the 81% reported in the larger study by Santoro et al. (n=91), making this comparison more appropriate. In our cohort, most patients underwent stem cell mobilization after 4 to 6 cycles of IGEV, in contrast to Marr et al., where mobilization typically occurred after cycles 1 or 2. This later timing may have influenced the stem cell yield, as prolonged chemotherapy exposure can impair hematopoietic stem cell reserve and mobilization efficiency. Our median CD34⁺ yield was 5.8×10⁶ cells/kg, which is notably lower than that reported in Marr et al. (12.5×10⁶) and Santoro et al. (10.3×10⁶). In our analysis, only 12% of the patients with late relapses developed PD after IGEV, compared to 44% and 33% for those with early relapse and primary refractory disease, respectively. Moreover, there was a statistically significant difference between EFS in relation to time of relapse, indicating the poor response and survival outcomes for patients with early relapse and primary refractory disease, and highlighting the urgent need for targeted agents. The mobilization potential of a salvage regimen is a critical factor in selecting a pre-transplant regimen. In the reported cohort, IGEV regimen bridged 7 patients into ASCT after achieving CR with successfully collecting CD34⁺ cells through 1–2 apheresis procedures. Post-transplant, all patients underwent consolidation radiotherapy and achieved complete remission, as evaluated by CT at end of the treatment. According to Magagnoli et al., the IGEV regimen followed by a fixed dose of lenograstim demonstrates high efficacy in the mobilization of CD34⁺ cells. In their phase II trial involving 90 patients, successful mobilization was achieved in 99% of cases. The study reported that mobilization targets of more than 3×10⁶ or 6×10⁶ CD34⁺ cells/kg were reached, depending on whether patients underwent single or tandem high-dose chemotherapy. Furthermore, approximately two-thirds of the patients achieved sufficient cell yield with only a single apheresis procedure (13). In our study, according to the definition of EFS mentioned in the methodology section, patients who were switched to another salvage regimen due to inadequate response to IGEV were considered to have experienced an event, even if they later achieved remission and remained alive. This definition likely contributed to the relatively lower EFS observed in comparison to OS, as it captures early treatment failure regardless of long-term outcomes. In contrast, OS reflects survival regardless of subsequent therapies, which in our cohort included access to alternative salvage chemotherapy regimens [e.g., dexamethasone, high dose cytarabine and cisplatin (DHAP), checkpoint inhibitors, brentuximab vedotin, and, in selected cases, successful ASCT following second-line therapy]. Palliative options were also available, such as oral etoposide (VP-16), for patients with limited therapeutic options. This study has several important limitations that should be acknowledged. First, as a retrospective analysis, it is inherently prone to selection and documentation biases. Although the decision to administer the IGEV regimen followed institutional protocol, only four patients in our cohort received an alternative salvage regimen due to physician preference, which may have further contributed to selection bias. Furthermore, toxicity data were extracted from medical records, which may not consistently capture the full range or severity of adverse events, potentially resulting in underreporting or incomplete documentation. Second, although the median follow-up duration in our cohort was 37.5 months, we emphasize the need for extended follow-up to identify potential late relapses and long-term treatment effects, which are particularly relevant in pediatric HL. Third, although ASCT is the standard of care following successful salvage therapy, only 24 of the 34 patients eligible for transplant in our study proceeded to ASCT. This was primarily due to logistical challenges, including a shortage of transplant beds and intermittent unavailability of essential drugs and equipment required for the procedure. These limitations may have contributed to treatment delays, which could partly explain the relatively high rate of PD observed after IGEV and prior to ASCT in some cases. The impact of these delays on patient outcomes warrants further investigation in future prospective studies.

Conclusions

In conclusion, the IGEV regimen demonstrated adequate efficacy as a salvage treatment in our cohort. Patients who responded to this regimen achieved favorable clinical outcomes, and most were able to achieve successful stem cell collection. Given its lower toxicity and reduced need for hospital admission and supportive care, IGEV may represent an effective and potentially preferable option for children with relapsed HL, particularly in resource-limited countries. Additionally, LR patients who show a good response to IGEV may be able to avoid transplantation and its associated toxicities while still achieving favorable outcomes. Further studies involving larger cohorts and the incorporation of novel targeted agents are needed to refine and optimize treatment strategies for this patient population.

Acknowledgments

We are exceptionally thankful to all our patients and their families.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://aol.amegroups.com/article/view/10.21037/aol-25-3/rc

Data Sharing Statement: Available at https://aol.amegroups.com/article/view/10.21037/aol-25-3/dss

Peer Review File: Available at https://aol.amegroups.com/article/view/10.21037/aol-25-3/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://aol.amegroups.com/article/view/10.21037/aol-25-3/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. It was approved by the institutional research board committee of Children Cancer Hospital Egypt (CCHE) (No. 40/2023) with no need for informed consent as it is a retrospective study.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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