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Review Article | | Peer-Reviewed

Refractory and Relapsed Hodgkin Lymphoma: A Comprehensive Review of Biology and Recent Advances in Therapy

Adil Abdelhamed Abbas*
Published in International Journal of Clinical Oncology and Cancer Research (Volume 11, Issue 4)
Received: 4 August 2026     Accepted: 5 September 2026     Published: 15 October 2026
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Abstract

HL accounts for nearly 3% of pediatric cancers. Compared to NLPHL, cHL primarily affects older children and adolescents. The risk-adapted, response-based management approach, which uses combined modality therapy, advances in modern imaging techniques, and careful use of consolidation RT, has led to steady improvements in EFS and OS, with current rates surpassing 90%. However, nearly 10–30% of patients may still experience resistant disease or relapse at different times. Achieving a second CR is generally difficult. Conventional CTR, HD CTR, and ABMT have been the main treatments for several decades. Advanced-stage (stage III and IV) R&R HL generally requires intensive treatment. Meanwhile, treatment for low-stage relapses (stage I and II) require a less intensive approach. The popularity of purely conventional CTR agents is decreasing. Combining one or more of the newer targeted medications, such as brentuximab vedotin, with conventional CTR, or utilizing pure targeted medications to induce second remission, has become standard practice. The treatment outcomes for R&R HL decline with each subsequent relapse. Second and third relapses usually result in much worse outcomes. Depending on the pattern and timing of relapse, the EFS after second-line treatment ranges from 10% to 50%. Many newly identified genetic mutations and molecular pathways are linked to the disease development and progression. Targeting these pathways may help cure patients who do not respond to current therapies. Allogeneic BMT may offer some assistance. The recently developed anti-CD30, CAR T-cell therapy shows promise, especially for patients with refractory disease and those experiencing frequent relapses. In this review, we discuss the mechanisms behind the disease's resistance to treatment and modern approaches to overcoming it.

Published in International Journal of Clinical Oncology and Cancer Research (Volume 11, Issue 4)
DOI 10.11648/j.ijcocr.20261104.11
Page(s) 84-98
Creative Commons

This is an Open Access article, distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium or format, provided the original work is properly cited.

Copyright

Copyright © The Author(s), 2026. Published by Science Publishing Group
Previous article
Keywords

CAR – T Cell Therapy, Chemotherapy, Autologous Blood and Marrow Transplantation, Relapsed and Refractory Hodgkin Lymphoma, Radiotherapy, Targeted Therapy

1. Introduction
HL is a slowly progressive B-cell neoplasm. It commonly involves the central and peripheral LNs and less commonly the lungs, liver, CNS, bone, and bone marrow
[1-6]
.
HL constitutes 10% of all lymphomas and 3% of pediatric neoplasms. The annual incidence is 11-12 cases/million in the 5 -14-year age group. Nearly 5% of younger patients develop the less aggressive NLPHL. The only difference between adult and pediatric HL is in the incidence of the histological subtypes. Classical (cHL) and the NLPHL variants are systemic diseases that require systemic therapy. Both are derived from the B-cell lineage but have distinct immunohistochemical profiles (CD15+ve, CD30+ve, CD20-ve, and CD45-ve for cHL; CD45+, CD30-ve for NLPHL)
[7-11]
.
Before 1960, HL was largely considered a fatal disease. Treatment outcomes have gradually improved. Currently, HL is one of the most curable malignancies. EFS and OS are currently well above 90%. However, 5 - 10% still have refractory disease, and 20 - 30% develop relapses
 [7, 12-16]
.
Patients with R & R HL generally have poor outcomes. Depending on the pattern and timing of relapse, 3-year EFS and OS rates range from 10–50%
[10, 13, 14, 16, 17]
. Generally, patients with primary refractory HL have lower survival rates, with an EFS of 10-15% at 3 years
[16, 18, 19]
.
Currently available treatments for R&R cHL have a low likelihood of inducing a second persistent remission. Therefore, efforts have primarily focused on improving frontline therapy to reduce relapse risk
[18-21]
.
For several decades, conventional CTR regimens have been the primary treatment for R & R HL. Second- and later-line conventional CTR agents have slightly improved survival. HD CTR and ABMT, along with novel targeted medications and Allogeneic BMT (allo BMT), have slightly increased the cure rates. However, long-term toxicities are significant. New targeted molecules, such as anti–CD30 antibody–drug conjugates and PD-1 checkpoint inhibitors, have shown promising results, especially when incorporated into frontline therapy, which has become a standard practice.
[18-21]
.
Most studies on new targeted agents have been conducted in adult patients. However, pediatric and adult HL have similar biology and pathology. Therefore, study results can be safely applied to both adult and pediatric patients. Nonetheless, only pediatric-designed protocols should be used for younger children
[19, 22-24]
.
HD CTR & ABMT remain the primary consolidation therapy for R&R HL. Relapse after ABMT carries a poor prognosis. The use of targeted medications to induce further remission may be effective; however, such remission is often short-lived. A second ABMT may be performed, but the outcomes are often disappointing. Allogeneic BMT offers some hope. CAR T-cell immunotherapy is a newly emerging treatment that has shown efficacy in early clinical trials but is not yet widely used
[21, 25-29]
.
Currently, there is no consensus on the best treatment for R&R NLPHL. Treatment is highly individualized. Generally, except for patients with high–risk relapse, most patients need less intensive CTR to achieve long-term second remissions. The use of rituximab and ofatumumab in patients with relapsed NLPHL has been very successful. Conventional CTR and/or RT have also been generally effective, but data on these approaches remain limited. ABMT is typically reserved for high-risk relapse patients
 [20, 30, 31]
.
In this review article, we will examine a wide range of basic clinical data on cHL and NLPHL. (The term HL is used when the data apply to both subtypes.) In addition to recent advances in the disease's biology, we provide evidence-based information on the recent developments in HL treatment approaches.
2. Frontline Management of Hodgkin Lymphoma
Modern treatment protocols have separated NLPHL from cHL. However, both types are mostly included when it comes to the treatment of relapse. Standard CTR protocols such as OPPA {VCR, PSN, PZN, DOX}, OEPA {VCR, PSN, ETOP, DOX}, MOPP {MCL, VCR, PZN, PSN}, ChlVPP {ChL, VBL, PZN, PSN}, ABVD {DOX, BCN, VBL, DZN} and BEACOPP {BCNU, ETOP, DOX, CPA, VCR, PZN, PSN}, ABVD {DOX, BCN, VBL, DZN} were used to treat the different stages of pediatric and adolescent HL. The later-introduced ABVD has proved a superior outcome and less toxicity. Therefore, until recently, the ABVD regimen was the treatment of choice for patients with newly diagnosed advanced-stage HL. Early-stage HL (stage I and II) patients were treated with fewer cycles of ABVD or one of its modifications. RT was nearly always added to the treatment. The EFS and OS at 5 years were approximately 79% and 88%, respectively. The treatment, however, was associated with significant toxicities
[21, 32-34]
.
To improve efficacy and reduce toxicity, modern treatment strategies use risk stratification and tailor therapy based on response. The patient’s initial risk group is assigned based on strict clinical and radiological criteria using MRI, CT, and FDG–PET scans. Response assessment is determined using preset radiological criteria. CTR regimens are assigned based on the patient’s initial risk group. Treatment is then tailored according to response to induction CTR. RT is given only to patients who show poor response and achieve no CR after completing induction CTR
[16, 35-38]
.
Treatment strategies for pediatric cHL and NLPHL vary significantly across cooperative groups. Therefore, no single standard therapy exists. However, certain principles are agreed upon. Patients with low risk (stage I and stage II without bulky disease or B symptoms) have a low relapse probability. They would receive 2-3 cycles of CTR. Those who achieve CR after induction CTR do not receive RT. The EFS and OS were 85% and 95%, respectively. Patients with intermediate risk (stage I and II with B symptoms and/or bulky disease, and stage III with no B symptoms or bulky disease) would receive 4–5 cycles of CTR. Those who do not achieve CR after 2 cycles of CTR receive 2 additional cycles of CTR followed by RT. RT, however, is omitted in patients who achieve early CR. The treatment results were good, with a 4-year EFS of 86.9% for RERs and 77.4% for SERs (P < 0.001). At 4 years, the OS was 97.8% for RERs and 95.3% for SERs (P < 0.001)
[34, 36, 39]
.
Patients with high–risk disease (stage III and IV, with or without B symptoms and/or bulky disease) have increased relapse probability. Those patients receive 5 cycles of intensive CTR, followed by consolidation RT. Some cooperative groups omit RT for patients who achieve CR after 3 cycles of induction CTR. The EFS at 5 years was 86% for RERs and 83% for SERs (P = 0.85), and the OS was 95%
[12, 40-42]
.
BV is an anti-CD30 antibody-drug conjugate approved by the USA FDA for pediatric and adult patients with R&R HL
[43, 44]
. The significant benefits achieved with BV and the low toxicity profile in treating patients with R&R HL encouraged investigators to move BV and some other targeted agents into frontline therapy. Many newly diagnosed HL treatment protocols, therefore, add BV, PLZ, and NLM to conventional CTR regimens. The COG phase III randomized AHOD1331 trial incorporated BV into AVD-PC {DOX, VCR, DZN, PSN, CPA} regimens to treat stage III and IV cHL. A total of 664 patients received 6 cycles of BV+AVD-PC, and 670 received ABVD. The 6-year EFS was 93.9% (95% CI, 91.6 to 95.5) in the BV+AVD-PC group and 89.4% (95% CI, 86.6 to 91.7) in the ABVD group. Toxicity was minimal in the BV – AVD – PC group. The study showed a clearly higher BV – AVD – PC group FDG – PET scan metabolic response rate at the end of 6 cycles of therapy, resulting in fewer patients receiving RT
[45, 46]
.
3. Predictors of Relapse
The CHIPS for children with newly diagnosed HL was created by the COG based on risk factors derived from the COG AHOD0331 study. Predictors of EFS included advanced-stage HL (stage III and IV), bulky mediastinal disease, fever, and serum albumin <3.5 mg/dL at diagnosis. Each factor was assigned a score of 1. Patients with a CHIPS of 0 have an EFS of 93.1% at 4 years. Those with CHIPS of 1 have an EFS of 88.5%; CHIPS of 2, 77.6%; and CHIPS of 3, 69.2%. A subset of patients with a CHIPS score of 2 or 3 has an EFS of less than 80% at 4 years. This group was considered eligible for early treatment intensification. The CHIPS has proven to be a highly reliable predictor of EFS in HL
 [36, 39]
.
FDG–PET is considered the gold-standard radiologic test for HL. Non–avid FDG–PET at the end of therapy indicates CR and has a good prognosis regardless of residual tumor mass. Any significant residual FDG–PET avidity at the end of therapy may suggest treatment failure and predict higher relapse risk. Negative FDG-PET at the end of treatment has a higher negative predictive value for relapse
[47-49]
.
Jan S et al. retrospectively studied the prognostic significance of the NLR, inflammatory marker levels, and their correlation with B symptoms and disease burden in 64 patients with HL {16 (25%) had B symptoms}. Patients with B symptoms had higher ferritin, monocyte, neutrophil, and NLR levels, and lower lymphocyte counts at presentation (P < 0.0003). Patients with NLR > 3.5 and ferritin > 173 (cutoff < 173 ng/ml) had advanced stage, bulky disease, and B symptoms (P < 0.0001). However, higher ferritin levels and NLR did not predict worse outcomes
[50]
.
The NLR at diagnosis is recognized as a significant independent prognostic factor in many cancers. A retrospective study of 83 HL patients was reported by Hajder J et al. After a median follow-up of 92 months (range, 9-180), 63 patients (80%) achieved CR. An ROC curve was created, with an AUC of 0.655 ± 0.064 (95% CI 0.53-0.724) and a cut-off value of ≥ 4.3. The median OS was 61 months in patients with an NLR > 4.3, compared with 50 months in those with a lower NLR (p < 0.018)
[51]
.
Yan Y et al. retrospectively studied the predictive value of BLNK, measured by immunohistochemistry. The OS and EFS in HL patients with BLNK-positive B lymphocytes (10–49% BLNK expression) were significantly higher
[52]
.
4. Transformation Mechanisms Causing Resistance and Relapse
HL is characterized by a few malignant RS cells surrounded by a mixture of T helper cells, cytotoxic T lymphocytes, and macrophages attracted by cytokines secreted by the tumor cells. These background immune cells secrete anti-apoptotic signals and tumor growth-stimulating factors. Other cells, such as natural killer T lymphocytes, exert antitumor immune responses. However, it is clearly insufficient to halt tumor growth. Specific stromal cells appear to regulate the activity of background immune cells. Therefore, tumor behavior and treatment responses cannot be precisely predicted. Researchers at Martin Luther University in Halle, Germany, proposed a multisystem model that may help simulate HL tumor features and predict behavior. In this model, tumor growth depends on the presence of CSCs, with surrounding stromal cells promoting growth. Immune-regulatory cells mediate this process by suppressing natural killer and cytotoxic T cells. Paradoxically, tumor growth can occur even after therapy, resulting in disease progression or relapse. Therefore, this model may help design new treatment strategies for tumors with strong interactions with the surrounding stroma, such as HL
[53]
.
5. Genetic Profile of Hodgkin Lymphoma
Treatment outcomes for patients with relapsed HL decline with each subsequent relapse, resulting in much poorer outcomes. Novel genetic abnormalities are increasingly identified and are believed to confer resistance. The impact of newly developed targeted medications on these abnormalities remains to be seen.
[21]
.
The limited number of malignant RS cells in cHL tissue makes it challenging to conduct proper genomic studies. However, this issue was recently partially overcome by using advanced laboratory techniques, such as fluorescence-activated cell sorting, to isolate RS cells. Researchers could perform WGS of RS cells and map the sequence of pathological events leading to HL development. Genetic studies using WGS identified driver gene mutations, such as B2M, BCL7A, GNA13, and PTPN1, at early stages of disease progression. Larger chromosomal gains appeared much later. Recent research links HL resistance and relapse to ongoing activation of genomic NF-κB, PI3K/AKT, NOTCH, JAK/STAT, and STAT6 signaling pathways. These somatic mutations and pathways exhibit anti-apoptotic and pro-inflammatory features and are crucial for HL development. These mutations occur more frequently in patients with cHL.
STAT6 is a gain-of-function mutation and is the most common genetic mutation in cHL patients. The mutated STAT6 gene is believed to support RS cell survival and growth. The JAK2/STAT6 signaling pathway regulates gene expression and is activated by lymphotoxin produced by RS cells. The JAK/STAT pathway has been linked to immune evasion by malignant HL cells through the expression of PD-L1 and PD-L2 receptors. Mutations at chromosome 9p24.1 have been shown to upregulate PD-1 and PD-L1 ligands on the HL cell membrane via activation of the JAK/STAT signaling pathway
[11, 21, 54, 55]
.
The genetic pattern in NLPHL is less complex. Typically, malignant tumor cells in NLPHL are found within a lymphocyte-rich microenvironment. In contrast, more aggressive mature B-cell and peripheral T-cell lymphomas show nuclear PLK1 expression. This protein stabilizes MYC (also known as c-myc) and promotes cell proliferation. PLK1 expression correlates with poorer treatment outcomes. Weiss J et al. studied 146 histopathological samples (76 NLPHL and 70 cHL). The analysis revealed 100% PLK1 protein expression in cHL but only 5% in NLPHL tumors. Increased PLK1 expression in cHL patients was linked to advanced stages and higher tumor cell proliferation. The PLK1 pathway presents a potential target for inhibiting tumor growth with PLK1 inhibitors
[56]
.
6. Refractory & Relapsed Hodgkin Lymphoma
Despite the progressive improvement in the initial management of HL, nearly 5-10% of patients still show refractoriness, and 20-30% relapse after initial response to CTR. Relapse is diagnosed in about a quarter of patients with stage III–IV and 10% of those with stage I-II disease. Patients with bulky nodal and extranodal involvement are more likely to relapse. However, this relationship has not been proven in patients with B symptoms.
Unlike lymphoblastic lymphoma and Burkitt’s lymphoma, HL is a relatively slow-growing tumor with limited potential for rapid progression, which is common even in relapse situations. However, the rate of progression increases with each subsequent relapse. The outlook for patients with R&R HL is generally poor. Depending on the pattern and timing of relapse, the 3-year OS ranges from 10% to 50%. The prognosis is particularly bleak for those who experience second and later relapses or show poor response to second-line CTR
[13, 18, 20, 40, 57]
.
6.1. Diagnosis of Relapse
Detecting relapse is usually straightforward, as it can be identified when the patient exhibits symptoms or signs of relapse, or through routine follow-up imaging studies. FDG–PET avidity, however, may persist for up to 1 year after treatment, but in most cases, it is minor and resolves on its own, with the patient remaining in remission. Therefore, careful interpretation of FDG–PET scan avidity is essential. Only scores higher than the normal liver uptake (Deauville score ≥ 4) should be considered positive. Whenever feasible, a tissue biopsy should be performed to confirm residual disease
[18, 20, 47-49]
.
Despite the good yield in detecting disease relapse, the value of routine radiological imaging is questioned. Most treatment protocols recommend routine CT, MRI, and/or FDG–PET scans at regular intervals for 3–5 years. A review of patients treated according to multiple COG trials between 1990 and 2006 has shown that routine radiological monitoring is probably unnecessary. At a median follow-up of 1.7 years, out of 402 HL patients, relapse was diagnosed in 64 (15.9%). Most relapses (47%) were identified after a patient's complaint. Another 17% were found following abnormal clinical examination. The remaining 36% were diagnosed due to abnormal routine imaging scans. Nevertheless, the data confirmed that the timing and method of detecting relapse did not affect survival.
The POG 9425 clinical trial enrolled 212 patients with HL. At a median follow-up of 17.6 months, relapse was diagnosed in 25 (11.6%) patients. In 19 patients (76%), relapse was identified through symptoms, abnormal physical exams, or abnormal lab tests. Two patients (8%) were diagnosed with relapse following routine radiological imaging within the first year, and 4 patients (16%) after the first year of completing therapy. Relapse timing did not significantly affect overall survival
[18, 20, 34, 40, 58]
.
FDG-PET and CT scans have improved diagnostic accuracy, disease staging, and response assessment. However, these tests still have limitations. Genomic characterization of the RS cell is complex. Nonetheless, newer techniques such as single-cell molecular analysis and NGS have identified several tissue mutations. Circulating tumor DNA particles, extracellular vesicles, and cytokines act as liquid biopsies that may help assess treatment response and predict early relapse. Although some liquid biopsy genetic materials have been identified in the laboratory, they have not been widely used clinically
[59]
.
6.2. Patterns of Relapse
According to the AETHERA trial, published in 2018, patients diagnosed with refractory HL, relapse within 12 months, or relapse more than 12 months but with extranodal tissue involvement are classified as high–risk relapse. Patients with relapse more than 12 months after initial treatment and those with limited-stage relapse are classified as low-risk relapse
[57, 60]
.
Dharmarajan KV et al. reported HL relapse patterns in the COG AHOD0031 study. All patients received CTR, but RT was administered only to those with positive FDG–PET. A total of 198 out of 1712 patients (12%) relapsed, while only 14 (0.01%) experienced disease progression. The median time to relapse was 12.8 months. The most common relapse sites were the mediastinum (63%), the supraclavicular fossa (39%), and the neck (32%). The lungs were the most frequent site of extranodal relapse (23%). Patients relapsed at both initial bulky (45%) and non-bulky (55%) sites. However, relapses were more common among patients with initial bulky disease who showed RER without receiving RT. The first relapse occurred either at the same anatomical site of disease (40%) or at that site along with a new site (52%). Only 7% of patients developed relapse at a new location. Patients with SER and those with RER to CTR who were randomized to no RT had higher risk of relapse. Relapse at the previous RT field was uncommon but more frequent within the SER group. Relapse rates were similar across all cHL histological subtypes; however, they were significantly lower in NLPHL patients. Relapses involving extralymphatic sites, such as the liver, were associated with poorer outcomes
[12, 60]
.
6.3. Early Versus Late Relapse
Patients with evidence of active disease at the end of frontline therapy are considered refractory to treatment. Some groups, however, extend this period by 3 months. Patients who relapse between 3 and 12 months are classified as having early relapse, while those who relapse after 12 months of treatment completion are classified as having late relapse. Some patients may present with recurrence of previous symptoms and signs, such as fever, weight loss, and enlarged lymph nodes. As expected, the outcomes of patients with refractory disease are generally worse than those who experience later relapse. The prognosis for patients with late relapse is significantly better than for those with early relapse
[17, 18]
.
6.4. Treatment of Refractory and Relapsed Hodgkin Lymphoma
No single standard CTR regimen exists for treating R&R HL. Several conventional CTR regimens have been used with varying results. Consolidation RT was commonly added, especially to previously non–irradiated sites. Patients with late relapse (> 12 months after treatment completion) may only receive RT for consolidation. Patients with refractory HL and those experiencing early relapse (< 12 months after treatment completion) receive consolidation with ABMT. ABMT should be strongly considered for patients with advanced-stage (stage III and IV) relapse, regardless of the time of relapse.
Over the past two decades, clinical trials have demonstrated the effectiveness of the anti–CD30 antibody–drug conjugate BV and the PD-1/PD-L1 checkpoint inhibitors (PLZ and NLM) as salvage therapies for HL. Researchers are studying newly identified aberrant epigenetic mechanisms in tumors as potential targets for both older and newer anticancer drugs, such as histone deacetylase inhibitors (vorinostat, romidepsin, belinostat, panobinostat) and hypomethylating agents (azacytidine and decitabine). These drugs recently received FDA approval to treat hematological malignancies in children. Targeting the JAK2 gene mutation shows promise. In vitro studies indicate that ruxolitinib is highly effective at inhibiting the JAK2/STAT pathway in HL cells. However, clinical trials have not yet started. Targeting the NF-κB pathway, a transcription factor that controls apoptosis and tumor cell proliferation, with proteasome inhibitors such as bortezomib (BZM) and carfilzomib has shown promise in preclinical trials for multiple myeloma cell lines, but preclinical studies in HL are yet to begin
[62, 63]
.
6.4.1. Conventional Chemotherapy
Dose-intensified, conventional CTR regimens such as DZN, ETOP, CRB, DOX {DECA}, ETOP, CPL, IFO, and Ara C {EPIC}, IFO, CRB, and ETOP {ICE}, BCNU, ETOP, Ara C and MEL {mini-BEAM}, have been used to treat R&R HL for several decades. Although these regimens successfully induced a second remission, toxicity was high, and the results showed no improvement in OS
[41, 44, 64, 65]
.
More biologically based targeted therapies are being studied. Most studies on targeted agents are conducted in adult patients. Pediatric, adolescent, and adult HL have similar biology and pathology. Therefore, clinical study results could be applied to both adult and pediatric patients. However, care is needed, especially for younger patients
[25]
.
Only a few new targeted medications have been developed in the last three decades. Some conventional CTR agents were modified to reduce toxicity. Liposomal and pegylated DOX formulations are in clinical use and have been shown to be less cardiotoxic. The cardioprotective agent dexrazoxane has been shown to reduce cardiomyopathy
[66, 67]
. Amifostine is used as an adjuvant to CBP and has been proven to reduce kidney injury
[67-69]
.
GC is a pyrimidine nucleoside analog, a prodrug that requires activation within tumor cells. Studies have proven GC efficacy in treating HL. A COG phase II study recruited 30 pediatric patients with R&R HL. Patients had at least received 2 prior salvage CTR regimens, and 17 patients (57%) received consolidation ABMT. Patients received three-weekly cycles of VRN (25 mg/m2/dose) and GC (1000 mg/m2/dose). Toxicities were minimal. Nineteen patients had measurable responses (95% CI, 55% to 91%). Six patients (20%) achieved CR, 11 (37%) had VGPR, and 2 patients (7%) had a PR
[70-73]
.
6.4.2. Targeted Medications
There has been a significant shift toward incorporating newer targeted medications into R&R HL treatment regimens, or using them as sole agents. The remission rate after salvage conventional CTR was approximately 60%. The 10-year PFS remains around 50%
[25, 74]
.
BZM is a 26S proteasome inhibitor that stabilizes proteins and small molecules, including NF-κB, which promotes cancer cell survival. The COG-AHOD0521 multicenter, open-label, phase II clinical trial enrolled 26 patients aged < 30 years with R&R HL. Patients received IFO, VRN, and BZM. Patients who achieved CR directly proceeded to ABMT, and those who did not received 2 additional cycles of IFO, VRN, and BZM. Twelve (52%) of the 23 evaluable patients achieved CR. An additional 9 (39%) patients achieved PR after 4 cycles of CTR. All received consolidation ABMT. The 4-year EFS and OS were 68% (95% CI: 45–82%) and 79% (95% CI: 57–91%), respectively
[75]
.
BV is an anti-CD30 antibody-drug conjugate approved by the FDA for patients with R&R cHL, particularly those who have received ABMT
[43, 44]
.
A COG phase I – II, single-arm study recruited 46 patients with R&R HL. All patients received 3 weekly cycles of GC (1000 mg/m2/dose) on days 1 and 8 and BV (1.4-1.8 mg/kg/dose) on day 1. Twenty-four (57%) of the 42 evaluable patients achieved CR after 4 cycles of treatment (95% CI 41-72%). Four patients (10%) showed PR
[34, 72, 73]
.
BM is a nitrogen mustard alkylating agent primarily used as salvage therapy in adult patients with R&R HL, most often in combination with a targeted agent. Pinczés LI et al. studied 41 patients with R&R cHL treated with a median of 3 cycles (1–6 cycles) of BM (90 mg/m2 on days 1 and 2) and BV (1.8 mg/m2 on day 1). The overall response rate was 78%, with 29 patients (70.7%) achieving CR. All 41 patients received ABMT, but unfortunately, 12 (29%) patients developed a second relapse. The 2–year OS and PFS were 93% and 62%, respectively
[76]
.
Forlenza CJ et al. reported the results of a multicenter, retrospective study of 29 pediatric patients with R&R cHL (17 with refractory and 12 with relapsed HL). Patients received 2 – 7 cycles of BV-BM (median 3 cycles). An objective response was achieved in 23 patients (95% CI 60–92%), and 19 patients (66%) achieved CR. Seventeen (17) patients received consolidation ABMT. EFS and OS at 3 years were 65% (95% CI, 46- 85%) and 89% (95% CI, 74- 100%), respectively
[26]
.
Because targeted medications have improved the remission rates (60–70%) and PFS (60%), some centers have eliminated conventional CTR agents and now use only targeted medications to induce remission. Results from these studies show continued improvements in EFS and OS
[25, 74]
.
PD ligands 1 and 2 (PD-1 and PD-2) immune checkpoint inhibitors (PLM and NLM) are FDA-approved and have become a first-line therapy for R&R HL. RS cells are derived from the B-cell germinal center. They exhibit genomic instability and overexpression of PD-1 and PD-2, which enhances their immune-surveillance evasion. PLM and NLM have been shown to improve OS in R&R HL and have a tolerable toxicity profile. They are very beneficial in patients who experience disease progression or poor tolerance to BV
[77]
.
Moskowitz AJ et al. reported the results of a phase II study evaluating PLM, GC, VRN, and liposomal DOX as second-line therapy for 39 patients with R&R cHL. Patients received 2-4 3-weekly cycles of PLM (200 mg/m2) on day 1, plus day 1 and day 8 GC (1,000 mg/m2), VRN (20 mg/m2), and liposomal DOX (15 mg/m2). Thirty-one patients received two cycles, and 8 received 4 cycles. Side effects were minimal. Of the 38 evaluable patients, the CR rate was 95%. Thirty-six patients (95%) received ABMT; all were alive and well 13,5 months (range 2.66-27.06) after therapy
[57]
.
Greve P et al. reported results from adding NLM to BV and BM to treat children with R&R HL. Patients were given 4 to 6 cycles of NLM (3 mg/kg) and BV (1.8 mg/kg) on day 1. Those who were not in CR received 2 additional cycles of BM to achieve CR. Seven patients received ABMT, and 3 received RT. All 10 patients were well and in CR, 25 months after completing therapy
[22]
.
The significant benefits and safety of targeted medications in treating R&R HL have encouraged investigators to move the anti-CD30 drug conjugate BV to frontline therapy. The COG phase III randomized study AHOD1331 incorporated BV into the AVD-PC (DOX, VBL, DZN, PSN, CPA) regimen for de novo stage III and IV cHL. A total of 664 patients received 6 cycles of BV+AVD-PC, and 670 received 6 cycles of ABVD. The 6-year EFS was 93.9% in the BV+AVD-PC group and 89.4% (P < 0.055; 95% CI, 86.6 to 91.7) in the ABVD group. Short- and long-term toxicities were tolerable. The study showed a clearly higher FDG–PET scan response after 6 cycles of BV–AVD-PC therapy, resulting in fewer patients receiving RT
[46]
.
Based on the results of COG AHOD1331, the NCTN S1826 randomized, phase 3 clinical trial evaluated NLM in stage III and IV cHL. They recruited 997 adult and adolescent patients (496 received NLM + AVD and 498 received BV + AVD). At a median follow-up of 2.1 years, the PFS after NLM + AVD was 92% (95% CI, 89 -94%) compared with 83% (95% CI, 79- 86%) after BV + AVD
[45]
.
The COG, in collaboration with the EuroNet–PHL group, is currently running a trial evaluating response to PLM, another PD-1 inhibitor, in newly diagnosed children and adolescents with HL and SER compared with ABVD and OEPA (VCR, ETOP, PSN, DOX)
[78]
.
Chen R et al. reported results from the KEYNOTE–087 study, which recruited 210 adults and adolescents with R&R cHL who relapsed or progressed after second-line CTR, ABMT, and maintenance BV. Patients received single-agent PLM (200 mg) every 3 weeks for 2 years or until disease progression. For a median follow-up of 27.6 months, the ORR was 71.9%. The PR rate was 44.3%. The median duration of response was 16.5 months (range: 0.0 –27.0)
[79]
.
6.4.3. Autologous BMT
Since the approval of anti-CD30 monoclonal antibodies and PD-1 checkpoint inhibitors for treating R&R HL, there has been a noticeable decline in the use of consolidation ABMT and allo BMT. ABMT are often employed to consolidate patients with progressive HL and those with early relapse. Unfortunately, nearly half of these patients still experience further relapses. Currently, ABMT are considered standard of care for patients who do not achieve CR after frontline CTR and those unable to tolerate targeted medications
[24]
.
A randomized clinical trial confirmed ABMT superiority over conventional CTR. Schmitz N et al. reported the results for 161 patients with R&R HL who received 2 cycles of Dex–BEAM CTR. Patients who responded well to Dex–BEAM (CR or VGPR) was randomized to receive either an additional 2 cycles of Dex–BEAM (56 patients) or HD BEAM plus ABMT (61 patients) for consolidation. The 3-year PFS was 55% in patients who received ABMT, compared with 34% in those who received conventional CTR (95% CI, 39.87; P = 0.019)
[23]
.
ABMT is currently the standard consolidation treatment for patients with R&R HL. Recent studies have shown significantly improved survival rates after consolidation with ABMT. Depending on specific predictive risk factors—such as early relapse, advanced disease stage at relapse, or relapse in a previously irradiated field—the 5-year EFS ranges from 43% to 95%. OS, at 10 years, however, is approximately 60%. Patients with a non-avid FDG-PET scan before consolidation ABMT tend to have better EFS and OS. Tandem cycles of ABMT showed no clinical benefit
[80]
.
Most treatment centers use BCNU, ETOP, AraC, MEL {BEAM}, or, less frequently, CPA, BCNU, ETOP (CBV) for conditioning before HSC infusion. Additional consolidation with RT is often needed after ABMT, especially in areas not previously irradiated
[23, 24, 48, 60, 81]
.
Recent data suggest that in the new targeted therapy era, ABMT might be omitted for patients with late (>12 months), limited disease relapse and those with advanced-stage relapse who achieve a rapid CR. However, if these patients have not been previously irradiated, they should receive RT
[23, 57, 60, 61, 74, 82, 83]
.
6.4.4. Radiotherapy
Until the end of the 1960s, high–dose, wide-field RT (36–44 Gy) was part of the standard treatment for HL, resulting in significant early and late toxicities. Over the next two decades, multi-agent CTR was gradually added, the RT dose and field were significantly reduced. Today, RT remains an essential part of HL therapy, but its use has been refined. The modern approach of combining IFRT with CTR and using precise response assessment tools has substantially reduced RT dose, field, and volume without compromising the EFS and OS
[12, 70, 84, 85]
.
Generally, any relapse site that was not previously irradiated requires consolidation RT. However, this has recently been refined, and RT is now limited to previously non–irradiated fields that still show FDG-PET activity after consolidation ABMT, or CTR alone. Re-irradiating a previously treated field is not recommended. However, it may be considered particularly after a long interval (> 12 months) since the initial RT or when a palliative approach is taken. New RT modalities, such as IMRT and Proton Beam therapy, may help deliver RT in such situations
[12, 84, 85]
.
6.4.5. Maintenance Therapy
The 5-year EFS after consolidation with ABMT for R&R HL is nearly 50%. A significant number of patients still progress or develop further relapse. Maintenance BV therapy following ABMT is highly recommended. The multicenter, randomized, double-blind, controlled (ATHERA) phase 3 study recruited 329 R&R HL patients who received salvage CTR followed by ABMT. One hundred and sixty-five patients were randomly assigned to receive 16 cycles of BV (1.8 mg/kg/dose) every 3 weeks, and 164 received placebo. The PFS was significantly better in the BV arm (P = 0.0013, 95% CI 0.40-0.81). More recent clinical trials have shown that NLM and PLM were effective and well tolerated. A phase II clinical trial reported by Armand B et al. recruited 30 patients with R&R HL who received 8 PLM maintenance cycles at 3-week intervals, starting 60 days after ABMT. The PFS and OS at 18 months were 82% and 100%, respectively
[45, 57, 87-89]
.
7. Relapse After ABMT
Relapse after ABMT occurs in nearly 50% of cases and is associated with a poor prognosis. These patients have typically received substantial conventional and possibly targeted therapies. Some patients, however, may be ineligible for ABMT due to prior toxicity. PD1 checkpoint inhibitors, PLM and NLM, and CD30-antibody conjugates—used alone or with conventional CTR- have become first-line therapies for R&R HL, even in patients previously exposed to them. The primary goal of treatment in these cases is often palliative disease control. As a result, some patients respond well, achieving CR or maintaining low-grade active disease as a chronic condition. Complete cure is unrealistic in these situations, though some exceptional cases may be cured. Other options for disease control include allo BMT or CAR T–cell therapy. A second ABMT may be considered, but this is a less favorable option
[29, 77]
.
7.1. Allogeneic Blood and Marrow Transplantation (BMT)
As with ABMT, increased use of BV, PLM, and NLM has led to a decline in consolidation allogeneic BMT in R&R HL. Allogeneic BMT is generally recommended for patients who relapse after HD CTR and ABMT. These patients now typically receive PD-1 inhibitors to induce remission. Emerging data support using consolidation allogeneic BMT as a curative option for patients who do not tolerate or progress after CD30-antibody conjugates and PD-1 inhibitor therapy. The allogeneic BMT procedure should be performed promptly once the patient achieves a meaningful remission. Stem cell sources such as matched related, matched unrelated, and haploidentical donors can be utilized. Conditioning regimens vary between myeloablative and RIC. However, most experts prefer using RIC to minimize toxicity. Maintenance therapy with CD30-antibody conjugates following allogeneic BMT is highly recommended
[60]
.
The survival rates after alloge
neic BMT are modest. The EFS ranges from 20% to 30%, and the OS ranges from 30% to 50%. Martinez C et al. retrospectively reviewed 511 patients with HL who relapsed following ABMT. Treatments included conventional CTR and/or RT in 294 patients (64%), second ABMT in 35 patients (8%), and allogeneic BMT in 133 patients (29%). Patients who relapsed early (< 6 months), had stage IV relapse, bulky tumors, poor performance status, or were over 50 years old had lower OS at 32%. The 5-year OS for patients with no risk factors was 62%
[89]
.
Patients who develop relapse after allogeneic BMT have a very poor prognosis. The treatment options are limited. Therapy is nearly always palliative. Options include palliative targeted medications, such as PLM, NLM, and TKIs, but achieving further remission is often challenging
[60, 90]
.
7.2. Chimeric Antigen Receptor (CAR) T - Cell Therapy
The treatment outcomes for R&R HL remain disappointing. Recent advances in cancer biology have driven progress in cancer immunotherapy and led to new strategies. CAR-T cell therapy targeting the CD19 protein on B-cell lymphocytes has been highly successful in treating B-cell neoplasms, despite safety concerns. Nevertheless, the FDA has approved CAR-T cell immunotherapy for treating adult and pediatric patients with B-cell neoplasms. The same approach has been applied to CD30-positive malignant cells in R&R cHL. BV's success in treating CD30-positive R&R HL has increased interest in pursuing anti–CD30 CAR–T cell therapy as a potential cure. CD30 is part of the tumor necrosis factor family and is expressed on the surface of RS cells in over 97% of cHL cases, with minimal expression on nonmalignant cells. When stimulated, CD30 induces hypoactivation of the MAPK antiapoptotic pathway. Overall, because of the complexity of the tumor microenvironment, CAR–T cell immunotherapy for solid tumors has been less successful
[96]
.
Lymphodepletion before CAR-T cell infusion offers the best chance for CAR–T cell proliferation. CAR-T cell therapy without lymphodepletion was associated with poor outcomes. FLD-containing lymphodepleting regimens produced the best treatment results.
CAR-T cell immunotherapy has become an established therapy for B-cell neoplasms; however, the treatment is associated with potentially serious complications. The most common complications are CRS and ICANS. These complications can be severe and sometimes fatal, but fortunately, severe forms occur in a minority of patients
[96, 97]
.
Tocilizumab is a humanized anti-human IL-6 receptor antibody that binds to both the soluble and membrane-bound IL-6 receptors, hence reducing the inflammatory response caused by excessive cytokine release. Tocilizumab has been approved by the FDA for the treatment of moderate–to–severe, life–threatening CRS. However, the neurologic complication ICANS is mainly treated with corticosteroids
[97, 98]
.
Anakinra is a recombinant, competitive IL-1 receptor antagonist. It competitively binds to IL-1 alpha and beta receptors on the cell surface, thereby reducing the tissue inflammatory response. Anakinra has been approved by the FDA to treat rheumatoid arthritis. However, it has been used off-label as a second-line treatment for CRS and ICANS
[86]
.
Wang et al. reported a phase I clinical trial that enrolled 18 patients with progressive R&R cHL despite prior multiple lines of therapy, including BV and PLM. All patients received salvage anti-CD30 CAR–T cell therapy. Lymphodepletion with FLD and CPA or paclitaxel and CPA. Two patients (11%) developed grade 3 and 4 cardiac and liver toxicities. Seven (39%) patients achieved PR, 6 (33%) had SD, and 5 (25%) had PD
[29]
.
Ramos CA et al. reported the results of a phase I dose-escalation study. No lymphodepletion was used. Nine (9) patients with CD30+ve lymphoma were enrolled (8 with cHL and 1 with anaplastic large B-cell lymphoma). All patients received CAR–T cell products and tolerated the treatment well. The ORR was 33%, with 3 patients achieving CR, 3 achieving SD, and 3 developing PD
[28]
.
Ramos CA et al. reported the results of a phase I/II clinical trial involving 41 patients (age 17 - 69 years) with R&R HL who had experienced multiple relapses. Patients received BM alone, BM and FLD, or CPA with FLD for lymphodepletion. The ORR was 62%. Of the 32 (78%) patients with active disease at the time of CAR T–cell therapy, 19 (59%) achieved CR. Treatment-associated toxicities were minimal. At 1 year, PFS and OS were 36% and 94%, respectively.
The NLPHL malignant cells, however, predominantly express CD45 cell-surface markers but show little to no CD30 expression. To date, researchers have not identified T-cell target molecules for NLPHL
[27, 98]
.
8. Treatment of Relapsed Limited Stage Classical Hodgkin Lymphoma
Patients who develop low-stage (stage 1 & II) relapse (early & late) may benefit from less intensive or more localized therapy. Local surgical resection or RT alone is often followed by relapse. The logical approach is to use conventional CTR or targeted therapy to induce remission. Consolidation with involved field RT is often sufficient to achieve long-lasting remission. However, given the likelihood of further relapses, especially in patients with localized, low-stage disease, some authorities choose to offer consolidation ABMT, especially in patients with early relapse and those who failed to achieve CR following induction CTR or targeted therapy
[60, 91]
.
9. Relapsed Nodular Lymphocytic Predominant Hodgkin Lymphoma
NLPHL accounts for nearly 5% of HL cases. Most patients are young children (aged 3–9 years) who present with early-stage (stages I & II) disease without B symptoms. Few patients develop advanced-stage (stage III & IV) disease and extralymphatic tissue involvement. Depending on the risk factors, treatment options include RT alone, conventional CTR, and targeted medications. Surgical resection as the sole treatment for limited disease has been successful, but with a higher risk of relapse
[20, 30-32]
.
NLPHL usually follows an indolent clinical course. However, because of the minimal therapy approaches applied, relapse is relatively more common than cHL
[20, 30, 91]
.
The overall prognosis of R&R NLPHL is generally better than that for cHL, but disease stage and timing of relapse significantly impact the ultimate outcome.
The optimal treatment for R&R NLPHL is not yet well established. Generally, these patients require less intensive CTR. Aggressive therapy may only be required in a small percentage of patients with advanced (stage III–IV) disease. However, the best therapy depends on several factors, such as relapse timing and prior treatment. CD20 positivity in B–lineage NLPHL cells makes anti-CD20 monoclonal antibodies (rituximab) highly effective. Multiple prospective trials evaluated single-agent rituximab and ofatumumab in patients with R&R NLPHL and showed nearly 100% response rates. However, a significant proportion of patients developed late relapse, especially those with advanced-stage disease. Conventional CTR and/or RT was generally successful
[20, 30, 31, 32, 92, 93]
. Schulz H et al. reported results from the multicenter GHSG study on 4-weekly rituximab (375 mg/m2) in 15 patients with R&R NLPHL. Of the 9 patients with stage I/II disease, 94% responded (5 CR and 4 PR). The 6 patients with stage III/IV disease had an 83% response rate (3 CR and 3 PR). PFS and OS were 55% and 93%, respectively
[94]
. Akhtar S et al. reported 17 patients with R&R NLPHL (12 refractory and 5 relapse) who received ABMT. Five patients had transformed into DLBCL. Salvage CTR consisted of ETOP, PSN, CPL, and Ara-C {ESHAP}. Eight patients received rituximab in addition. The conditioning therapy consisted of BCNU, ETOP, Ara-C, and MEL {BEAM}. The 5–year EFS and OS were 76% and 94%, respectively. Patients who received salvage CTR plus rituximab had a better 5-year EFS than those who did not, [100% versus 56%] (P=0.041)
[31]
. Eichenauer DA et al. reported outcomes for 99 patients with NLPHL who relapsed or progressed after frontline treatment in 12 GHSG studies. With a median follow-up of 11.2 years, relapse occurred at 3.7 years. In front-line therapy, 20% of patients received RT alone. CTR with or without RT in 74%, and CTR with rituximab in 6% of patients. In R&R NLPHL, 37% of patients received single-agent rituximab or RT alone. CTR with or without RT in 74%. CTR with or without rituximab and with or without RT in 27%, and ABMT in 31%. No salvage CTR was given in 4% of patients. The 5-year PFS and OS were 75.6% and 89.5%, respectively. For patients who received single-agent rituximab and RT, PFS and OS were 74.1% and 97.2%, respectively. For patients who received CTR with or without rituximab and/or RT, PFS and OS were 68%, 77.8%, and 84.6% and 89.8% after ABMT, respectively
[93, 94]
.
Transformations between chronic leukemia and lymphoma are not uncommon. In 3–14% of patients, NLPHL may transform into rapidly growing, aggressive lymphomas during relapse. The median time to transformation is 3–8 years. Transformation involves the popcorn-like malignant cells and often results in DLBCL or TCRBCL. Transformation is less common in cHL, which may evolve into a common non-Hodgkin lymphoma, such as mixed unclassifiable B- and T-cell lymphoma, or, rarely, DLBCL. Unlike patients with cHL, transformation in NLPHL can occur many years after therapy, requiring a longer period of follow-up. Treatment generally involves aggressive therapy. Induction CTR using ABVD, BV+AVD (BV, DOX, VBL, DZN), or R-CHOP (rituximab, CPA, DOX, VCR, PSN) may be employed. At least 2 cycles of CTR are administered before consolidation ABMT (for eligible patients) is given. RT is not typically indicated. Patients with CD30 positivity may be considered for CAR-T cell therapy (when available). Allogeneic BMT could be an additional option
[30, 31, 92]
.
The cumulative incidence of NLPHL transformation at 10 years is nearly 6% (95% CI, 4.2-9.6), and the treatment outcomes for patients who transform into DLBCL are generally significantly worse.
[95]
.
10. Conclusion
The standard treatment for patients with R&R HL involves second-line salvage CTR followed by consolidation ABMT. However, despite this toxic regimen, nearly half of patients experience further relapses. Researchers are exploring newly discovered genetic and metabolic pathways as therapeutic targets. CD30 and PD1 checkpoint inhibitors have shown the best results. CAR-T cell therapy targeting CD30 in cHL is a promising emerging treatment. Allogeneic BMT is reserved as a last resort. No CAR-T cell therapy has yet been developed to treat R&R NLPHL. Maintenance BV after consolidation with ABMT and allogeneic BMT offers significant benefits, but it is not yet considered standard.
Abbreviations

HL

Hodgkin Lymphoma

NLPHL

Nodular Lymphocytic Predominant HL

cHL

Classical HL

DLBCL

Diffuse Large B-cell Lymphoma

TCRBCL

T-cell-rich B-Cell Lymphoma

RT

Radiotherapy

CTR

Chemotherapy

R&R

Refractory and Relapsed

IMRT

Intensity-Modulated Radiation Therapy

RIC

Reduced-intensity Chemotherapy

HD

High-Dose

EFS

Event-free Survival

OS

Overall Survival

RER

Rapid Early Response

SER

Slow Early Response

VGPR

Very Good Partial Response

PR

Partial Response

CR

Complete Remission

PR

Partial Remission

SD

Stable Disease

PD

Progressive Disease

ORR

Overall Response Rate

PFS

Progression-Free Survival

AUC

Area Under the Curve

CAR

Chimeric Antigen Receptor

LN

Lymph Nodes

CNS

Central Nervous System

ABMT

Autologous Blood and Marrow Transplantation

ALLOGENEIC BMT

Allogeneic Bone Marrow Transplantation

VCR

Vincristine

PSN

Prednisone

PZN

Procarbazine

DOX

Doxorubicin

ETOP

Etoposide

MCL

Mechlorethamine

ChL

Chlorambucil

GC

Gemcitabine

VRN

Vinorelbine

CPL

Cisplatin

VBL

Vinblastine

DZN

Dacarbazine

BCNU

Carmustine

CPA

Cyclophosphamide

CPL

Cisplatin

IFO

Ifosfamide

Ara C

Cytosine Arabinoside

MEL

Melphalan

BV

Brentuximab Vedotin

BZM

Bortezomib

PLZ

Pembrolizumab

NLM

Nivolumab

BM

Bendamustine

Dex

Dexamethasone

TKIs

Tyrosine Kinase Inhibitors

MRI

Magnetic Resonance Images

CT

Computerized Tomography

FDG–PET

18–Fluorodeoxyglucose Positron Emission Tomography

COG

Children’s Oncology Group

POG

Pediatric Oncology Group

GHSG

German Hodgkin Study Group

CHIPS

Childhood Hodgkin’s International Prognostic Score

FDA

Food and Drug Administration

RS

Reed—Sternberg

CSC

Cancer Stem Cells

NLR

Neutrophil-to-lymphocyte Ratio

ROC

Receiver Operating Characteristic

BLNK

B-cell Linked Protein

WGS

Whole Genome Sequencing

NGS

Next-generation Sequencing

PLK1

Polo-like Kinase 1

PD

Programmed Cell Death
Author Contributions
Adil Abdelhamed Abbas: Conceptualization, Data curation, Methodology, Resources, writing, review and editing.
Conflicts of Interest
The author declares no conflicts of interest.
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    Abbas, A. A. (2026). Refractory and Relapsed Hodgkin Lymphoma: A Comprehensive Review of Biology and Recent Advances in Therapy. International Journal of Clinical Oncology and Cancer Research, 11(4), 84-98. https://doi.org/10.11648/j.ijcocr.20261104.11

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    Abbas, A. A. Refractory and Relapsed Hodgkin Lymphoma: A Comprehensive Review of Biology and Recent Advances in Therapy. Int. J. Clin. Oncol. Cancer Res. 2026, 11(4), 84-98. doi: 10.11648/j.ijcocr.20261104.11

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    Abbas AA. Refractory and Relapsed Hodgkin Lymphoma: A Comprehensive Review of Biology and Recent Advances in Therapy. Int J Clin Oncol Cancer Res. 2026;11(4):84-98. doi: 10.11648/j.ijcocr.20261104.11

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  • @article{10.11648/j.ijcocr.20261104.11,
  author = {Adil Abdelhamed Abbas},
  title = {Refractory and Relapsed Hodgkin Lymphoma: 
A Comprehensive Review of Biology and Recent Advances in Therapy},
  journal = {International Journal of Clinical Oncology and Cancer Research},
  volume = {11},
  number = {4},
  pages = {84-98},
  doi = {10.11648/j.ijcocr.20261104.11},
  url = {https://doi.org/10.11648/j.ijcocr.20261104.11},
  eprint = {https://article.sciencepublishinggroup.com/pdf/10.11648.j.ijcocr.20261104.11},
  abstract = {HL accounts for nearly 3% of pediatric cancers. Compared to NLPHL, cHL primarily affects older children and adolescents. The risk-adapted, response-based management approach, which uses combined modality therapy, advances in modern imaging techniques, and careful use of consolidation RT, has led to steady improvements in EFS and OS, with current rates surpassing 90%. However, nearly 10–30% of patients may still experience resistant disease or relapse at different times. Achieving a second CR is generally difficult. Conventional CTR, HD CTR, and ABMT have been the main treatments for several decades. Advanced-stage (stage III and IV) R&R HL generally requires intensive treatment. Meanwhile, treatment for low-stage relapses (stage I and II) require a less intensive approach. The popularity of purely conventional CTR agents is decreasing. Combining one or more of the newer targeted medications, such as brentuximab vedotin, with conventional CTR, or utilizing pure targeted medications to induce second remission, has become standard practice. The treatment outcomes for R&R HL decline with each subsequent relapse. Second and third relapses usually result in much worse outcomes. Depending on the pattern and timing of relapse, the EFS after second-line treatment ranges from 10% to 50%. Many newly identified genetic mutations and molecular pathways are linked to the disease development and progression. Targeting these pathways may help cure patients who do not respond to current therapies. Allogeneic BMT may offer some assistance. The recently developed anti-CD30, CAR T-cell therapy shows promise, especially for patients with refractory disease and those experiencing frequent relapses. In this review, we discuss the mechanisms behind the disease's resistance to treatment and modern approaches to overcoming it.},
 year = {2026}
}

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  • TY  - JOUR
T1  - Refractory and Relapsed Hodgkin Lymphoma: 
A Comprehensive Review of Biology and Recent Advances in Therapy
AU  - Adil Abdelhamed Abbas
Y1  - 2026/10/15
PY  - 2026
N1  - https://doi.org/10.11648/j.ijcocr.20261104.11
DO  - 10.11648/j.ijcocr.20261104.11
T2  - International Journal of Clinical Oncology and Cancer Research
JF  - International Journal of Clinical Oncology and Cancer Research
JO  - International Journal of Clinical Oncology and Cancer Research
SP  - 84
EP  - 98
PB  - Science Publishing Group
SN  - 2578-9511
UR  - https://doi.org/10.11648/j.ijcocr.20261104.11
AB  - HL accounts for nearly 3% of pediatric cancers. Compared to NLPHL, cHL primarily affects older children and adolescents. The risk-adapted, response-based management approach, which uses combined modality therapy, advances in modern imaging techniques, and careful use of consolidation RT, has led to steady improvements in EFS and OS, with current rates surpassing 90%. However, nearly 10–30% of patients may still experience resistant disease or relapse at different times. Achieving a second CR is generally difficult. Conventional CTR, HD CTR, and ABMT have been the main treatments for several decades. Advanced-stage (stage III and IV) R&R HL generally requires intensive treatment. Meanwhile, treatment for low-stage relapses (stage I and II) require a less intensive approach. The popularity of purely conventional CTR agents is decreasing. Combining one or more of the newer targeted medications, such as brentuximab vedotin, with conventional CTR, or utilizing pure targeted medications to induce second remission, has become standard practice. The treatment outcomes for R&R HL decline with each subsequent relapse. Second and third relapses usually result in much worse outcomes. Depending on the pattern and timing of relapse, the EFS after second-line treatment ranges from 10% to 50%. Many newly identified genetic mutations and molecular pathways are linked to the disease development and progression. Targeting these pathways may help cure patients who do not respond to current therapies. Allogeneic BMT may offer some assistance. The recently developed anti-CD30, CAR T-cell therapy shows promise, especially for patients with refractory disease and those experiencing frequent relapses. In this review, we discuss the mechanisms behind the disease's resistance to treatment and modern approaches to overcoming it.
VL  - 11
IS  - 4
ER  -

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