Am J Hematol: Diagnosis, Risk Stratification and Treatment of Hodgkin Lymphoma (2023 Update)

Hodgkin lymphoma (HL) is a malignant proliferative tumor of the lymphatic system, with an incidence of HL accounting for about 10% of all lymphomas in China, and about 8,540 new patients
are diagnosed in the United States each year.
The disease is bimodal and tends to occur in young people aged 15~34 and > 50 years old
.

There are no clear risk factors for HL and the etiology remains unclear; Factors associated with HL include familial factors, viral exposure, and immunosuppression; Same-sex siblings of people with HL have a 10-fold
higher risk of developing the disease.
Familial factors may suggest genetic factors, studies suggest that abnormal immune responses to infection may also play a role in the pathogenesis of HL, epidemiological and serological studies suggest that Epstein-Barr virus (EBV) is associated with the etiology of HL, and EBV genomes
are detected in tumor specimens from HL patients.
While other childhood infectious diseases, including chickenpox, measles, mumps, rubella, and whooping cough, are inversely associated with the risk of HL and may be protective
.
HL is also associated with human immunodeficiency (HIV) infection, as patients with HIV infection have a significantly increased
risk of HL compared with the general population.
Overall, immunosuppressed patients with HL, including HIV-positive patients, present late in the general stage of disease, have uncommon disease sites, and have poor
outcomes after initial treatment.

Over the past four decades, advances in radiation therapy and the increase in combination chemotherapy and targeted immunotherapy have significantly increased cure rates for patients with HL, with more than 80% of newly diagnosed patients younger than 60 years now likely to be cured
.

Professor Stephen M.
Ansell currently works in the Department of Hematology at the Mayo Clinic, where his research focuses on the biology of B-cell malignancies, including Hodgkin lymphoma, Waldenstrom macroglobulinemia, and non-Hodgkin lymphoma, and the role of the
tumor microenvironment in supporting cancer cell growth and survival.
Almost every two years since 2011, Professor Ansell has published a review
of new advances in the diagnosis, risk stratification and treatment of Hodgkin lymphoma in the American Journal of Hematology.
Recently, the 2023 version of the update was released, and it is now compiled as follows for the reference
of teachers.

diagnosis

Most patients with HL present with supraphragmatic lymphadenopathy, typically neck, anterior mediastinum, supraclavicular, and axillary lymph node involvement, and less often
inguinal area involvement.
About one third of patients present with constitutional symptoms (B symptoms), including fever, night sweats, and weight loss, and many patients also present with chronic pruritus
.
HL most commonly affects continuous lymph nodes, but may also affect extranodal tissue through direct invasion or hematogenous dissemination, most commonly involving the spleen, lungs, liver, and bone marrow
.

The initial diagnosis of HL must be made by biopsy, but fine or thick needle biopsy is not sufficient because the structure of the lymph nodes is extremely important
for accurate diagnosis.
HL is a unique malignancy in which tumor cells make up a minority of the cell population, and inadequate biopsy may not allow malignant cells to be included in the
specimen.
To confirm the diagnosis, malignant Reed-Sternberg cells
of follicular center B cell origin should be identified in the cellular environment of normal reactive lymphocytes, eosinophils, and histiocytes.

According to the WHO classification of hematological lymphoid tumors, HL is divided into classic Hodgkin lymphoma (CHL) and nodular lymphocyte-dominated type (NLPHL), the former accounting for about 95%; CHL is divided into four subgroups
: tuberous sclerosis, mixed cell, lymphocytoblastic reduction, and lymphocyte-rich HL.
However, the Clinical Advisory Committee associated with the International Consensus Classification of Mature Lymphomas has recently concluded that nodular lymphocyte-predominant HL requires a new term based on major biological/clinical differences with classical HL and close relationship with T-cell/histiocyte-rich large B-cell lymphoma, and the term "nodular lymphocyte-predominant B-cell lymphoma (NLPBL)" has been suggested, although it remains to be seen
.

Classic Hodgkin lymphoma

The pathologic hallmark of classic HL is the presence of malignant multinucleated giant Reed-Sternberg cells in the background of characteristic reactive cells
.
Painless lymphadenopathy is the most common clinical presentation of classic HL, but each histologic subtype has its own unique clinical features
.
Nodular sclerosis is the most common subtype, more common in adolescents and young adults, and typically presents with localized lesions involving the neck, supraclavicular, and mediastinal region; Mixed-cell HL is more prevalent in children and older age groups, and typically has a later stage and worse prognosis; The incidence of lymphopentic HL appears to be much lower than previously reported, with many cases reclassified as non-HL, a subtype that occurs mainly in older patients and patients with AIDS, and often presents with symptomatic generalized disease without peripheral lymphadenopathy; Lymphocyte-rich CHL is morphologically similar to nodular lymphocyte-predominant HL (see below), but its Reed-Sternberg cells are more consistent
with classical HL immunophenotypes.

Recent studies have found that PD-1 ligands, including PD-L1 (CD274/B7-H1) and PD-L2 (CD273/B7-DC), are overexpressed
on Reed-Sternberg cells.
In cases of PD-L1 and PD-L2 overexpression, most cases have copy number variations and genetic alterations in chromosome 9p24.
1, as well as increased
JAK2 signaling.
PD-L1/PD-L2 alterations are a clear feature of HL and can lead to high expression of PD-L1 or PD-L2 on the cell surface, thereby protecting Reed-Sternberg cells from T-cell-mediated killing
.
Although 9p24.
1 amplification is more common in patients with advanced disease and is associated with shortened progression-free survival in chemotherapy patients, PD-L1 expression and positive MHC II in Reed-Sternberg cells are predictors
of a favorable outcome after PD-1 blockade.

Nodular lymphocytes predominate HL

Nodular lymphocyte-predominant, or the recently proposed NLPBL, is a distinct clinicopathological entity that differs significantly from
classical HL.
Pathologically, lymphocyte-predominant HL lacks typical Reed-Sternberg cells and is instead characterized by a tumor population of larger cells with folded lobulated nuclei, called lymphocytes and histiocytes
.
Unlike classical HL, these cells are CD20+ and are usually CD30 negative
.
Lymphocyte-predominant HL is more common in men, and constitutional symptoms and extranodal disease
are rare at presentation.
Patients typically present with localized lymph node lesions, usually involving the neck region and, rarely
, mediastinum.
The natural history of lymphocyte-predominant HL differs from classical HL in that it has an indolent course and a tendency to relapse in the long
term.

Risk stratification

The main factors determining the choice of initial treatment for patients with HL are the histology of the disease (classical HL or nodular lymphocyte-predominant HL), the anatomical stage of the disease (limited or advanced), the presence of adverse prognostic factors, the presence of constitutional symptoms, and the presence of large masses (> 10 cm in diameter at a single disease site).

During treatment, FDG-PET scans play a prominent role
in deciding whether to complete treatment as planned or to add or remove therapeutic components.
If the interim FDG-PET is negative, the therapeutic dose can be reduced by shortening the number of cycles given, excluding radiotherapy, or eliminating bleomycin to avoid pulmonary toxicity
.
Intensive therapy may be required if mid-term FDG-PET is positive after 2 cycles of treatment, and if PET-positive at the end of treatment may require the addition of consolidation radiotherapy
at the positive site.
A positive PET at any time point may also require repeat biopsy to confirm or rule out ongoing disease
.
Patients who are FDG-PET positive at completion of treatment have a significantly higher
recurrence rate regardless of the results of the CT scan.
In addition, FDG-PET performed early in treatment (after 2 cycles) predicts PFS and OS in patients with HL and is a better predictor of outcomes than staging, extranodal lesions, and other prognostic factors
.

Initial treatment

The current standard of care for HL patients is to use different treatment strategies
for HL patients with good early prognosis, HL patients with poor early prognosis, and patients with advanced HL.
In general, early patients use a comprehensive treatment strategy, that is, in most cases a shortened course of combination chemotherapy followed by invasive field radiation therapy (IFRT), while advanced patients receive a longer course of chemotherapy instead of radiotherapy
.
Novel agents including bubutuximab and anti-PD-1 antibodies are also being included in standard combination therapy
.

HL with good early prognosis

Treatment strategies for early HL (stage I-IIA) have changed
significantly over the past few decades.
Originally extended field radiotherapy was the standard of care, but due to high recurrence rates and significant long-term complications, extended field radiation therapy
involving adjacent lymph nodes is no longer used.
A randomised study comparing patients receiving subpanic nodal radiotherapy with or without ABVD chemotherapy (doxorubicin, bleomycin, vinblastine, dacarbazine) with those receiving ABVD alone found that patients receiving subtotal lymph node radiotherapy had poorer OS and higher
mortality due to non-HL causes.
Therefore, for early stage patients with a good prognosis, short-term chemotherapy (to control occult lesions) combined with IFRT limited to the affected lymph node area is the current standard practice, mostly 2 to 4 cycles of combination chemotherapy followed by IFRT (dose approximately 20 to 35 Gy).

This strategy is based on a four-arm study that randomized patients with early HL with a good prognosis to 2 or 4 cycles of ABVD chemotherapy and 20 or 30 Gy IFRT, with no difference
in treatment response, PFS, and OS in the 4 arms.
Therefore, 2 cycles of ABVD treatment, followed by 20 Gy IFRT, is currently the standard of
care for early prognosis (no adverse risk factors) HL.

HL with poor early prognosis

At present, it is generally believed that stage I and II patients with adverse risk factors should be treated with chemotherapy combined with radiation therapy, but the optimal number of chemotherapy cycles, the optimal chemotherapy regimen, the dose of radiotherapy, and the size of the irradiation field are all controversial
.
These patients often have large mediastinal masses or extranodal lesions, and 4-cycle IFRT plus chemotherapy is generally considered the treatment of choice
.
This conclusion is based on a large clinical study of patients with stage I/IIA HL with adverse factors, in which patients were randomly assigned to receive either 4 cycles of ABVD or 4 cycles of baseline doses of BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) plus 20 or 30 Gy IFRT
。 ABVD plus 20 Gy was found to have a worse freedom from treatment failure (FFTF) than with 30 Gy, but similar outcomes at 20 or 30 Gy in combination with BEACOPP
.
It is concluded that 4 cycles of ABVD plus 30 Gy IFRT are the standard of
care for patients with stage I/IIA HL with adverse factors.

A subsequent study evaluated intensive chemotherapy in this category of patients with poor early prognosis in HL patients receiving 4 cycles of ABVD or 2 cycles of escalating doses of BEACOPP + 2 cycles of ABVD; All patients received 30 Gy IFRT.

No treatment failure favoured the intensive chemotherapy group (5.
6% difference at 10 years), but no difference
in OS.
In addition, there was no difference
in treatment-related mortality or secondary malignancy.

Follow-up studies evaluated whether the inclusion of newer agents such as bubutuximab and PD-1 monoclonal antibody could maintain efficacy and reduce potential toxicity
in these patients.
Novel agents are either given for the first time or as consolidation therapy, and the results suggest that these combination strategies are safe and provide excellent disease control
.
Although the overall outcome for this patient group was very good, randomised studies are needed to confirm that these combinations are consistent with standard regimens and are less
toxic.

Respond to adaptive therapy

To determine the optimal amount of treatment required, several studies have used functional imaging to provide an early indication
of sensitivity to HL chemotherapy.
FDG-PET was mainly used as an interim evaluation of efficacy, and its usefulness was further enhanced by a 5-component scale with high reproducibility.
This method also detects residual active lymphoma
compared to conventional CT.

Results from two large studies illustrate the role of
PET guidance.
The RAPID study, which randomised non-large massed early-stage patients with intermediate PET negative (score 1 or 2) after 3 cycles of ABVD to either the 30 Gy IFRT group or no further treatment, found no significant difference in 3-year PFS and OS between the two groups, but a trend towards poor disease control in patients who did not receive radiotherapy, and the difference became statistically significant (97.
1% vs.
90.
8%)
after excluding patients who did not receive treatment as planned.

The EORTC/LYSA/FIL H10 study compared standard treatment (ABVD and radiation therapy to affected lymph nodes (INRT)) with non-radiation regimens, with further chemotherapy in FDG-PET-negative patients after 2 cycles of ABVD, with an escalation strategy if the patient was PET-positive; Specifically, PET-positive patients switched to 2-cycle increments of BEACOPP and INRT, while PET-negative patients received INRT after ABVD or ABVD
alone.
The authors found that PET response after two cycles of ABVD allowed for early treatment adjustment, as 5-year PFS improved from 77.
4% for standard ABVD + INRT to 90.
6%
for BEACOPP + INRT in PET-positive patients.
However, in PET-negative patients, the 5-year PFS rate was 99.
0% versus 87.
1% in favor of ABVD + INRT in patients with a good prognosis, and 92.
1% vs 89.
6% in favor of ABVD + INRT
in the poor prognosis group.
The non-inferiority
of ABVD alone compared with combination therapy cannot be demonstrated in patients with either a good or poor prognosis.

Thus, combination therapy for patients with early HL achieves excellent disease control, and a higher proportion of patients are cured after initial therapy; However, a large proportion of patients (about 90%) can be cured
with chemotherapy alone.
Therefore, based on these studies, the number of radiotherapy required to achieve an additional cure is between
15% and 30%.
Given these excellent outcomes and the potential long-term toxicity of radiation therapy, many patients may prefer a slightly higher risk of HL recurrence to exclude radiation therapy
.
Overall, outcomes were excellent for both regimens, and small reductions in disease control did not appear to have any adverse effects
on OS in both studies.
But a recent real-world study concluded that while the results of clinical studies can be replicated in some patient subgroups, exclusion of radiation therapy in other subgroups, especially those that do not meet the criteria for the trial, will perform poorly
.

Advanced disease

The challenge for patients with advanced disease (stage IIB-IV) is to increase the number of patients with durable remission while reducing long-term side effects
.
The MOPP regimen (nitrogen mustard, vincristine, procarbazine, prednisone) was originally developed for patients with progression after radiotherapy, and the combined regimen had a 20-year progression-free rate of 54% and OS of 48%.

Although MOPP regimens significantly changed outcomes in patients who had previously died of disease progression, about one-third of patients subsequently relapsed, and a variety of other regimens have since been developed to improve their efficacy
.

ABVD chemotherapy regimens have also shown significant clinical activity and potentially low toxicity
.
A randomized study comparing alternate MOPP ABVD with MOPP alone found that alternating regimens were superior
in CR, PFS, and OS.
Several major randomized studies over the past 20 years have attempted to determine the regimen with the highest efficacy and the
lowest side effects.
The first three studies comparing alternating ABVD with MOPP, ABVD, and MOPP all confirmed the efficacy, relative ease of administration, and acceptable side effects of ABVD-based chemotherapy, making ABVD the preferred choice
for patients with advanced HL.

To further minimize toxicity, the Stanford V regimen incorporates active agents of MOPP and ABVD into a short-dose intensive regimen and combines
this 12-week regimen with radiation therapy.
Many randomized studies have investigated
this protocol compared to ABVD.
Preliminary studies suggest that ABVD may be superior to the Stanford V regimen, but the difference in outcomes may lie in the fact that radiotherapy in the Stanford V group differs
from the initial one.
Two subsequent randomized studies comparing ABVD and Stanford V found similar response rates, no failures, and OS for both regimens, as well as similar frequency of adverse events, but more pulmonary toxicity in ABVD and more
toxicity in other toxicities in Stanford V.

GHSG has also developed new late-stage HL regimens, including standard and dose-escalating BEACOPP
.
A large randomized study comparing alternating COPP (cyclophosphamide, vincristine, methylbenzhydrazine, prednisone) with dose-escalation and standard BEACOPP showed better tumor control and OS with dose-escalating BEACOPP; This result continues to show improved
outcomes with BEACOPP escalation therapy at 10 years of update.
WHILE THESE RESULTS ARE ENCOURAGING, AML AND MDS ARE MORE COMMON
IN PATIENTS TREATED WITH BEACOPP ESCALATION.
A follow-up study compared 6 cycles of ABVD with 4 cycles of incremental BEACOPP followed by 2 cycles of standard BEACOPP, with third arm patients receiving a 6-cycle multi-drug intensive regimen
.
Comparing the ABVD group with the BEACOPP group, it was found that the PFS of the BEACOPP group improved but the OS of the two groups was similar; In addition, BEACOPP is more toxic, but high-risk patients also benefit more
.
Randomized studies have identified the optimal number of BEACOPP cycles required for maintenance therapy to improve outcomes and reduce toxicity, and have shown 6 cycles of incremental BEACOPP to be as effective and less
toxic than 8 cycles of the same regimen.

In a randomized study comparing ABVD and BEACOPP in advanced HL, the authors analysed outcomes after initial treatment and after salvage therapy and found that no freedom from first progression was better in the BEACOPP group, but no second progression rate or OS after completion of all planned treatments (including salvage therapy for patients with residual or disease progression); IN ADDITION, BEACOPP HAD MORE
SERIOUS ADVERSE EVENTS THAN THOSE WITH ABVD.
Therefore, some scholars believe that not all patients need high-intensity initial treatment, because relapsed patients can be saved by subsequent intensive therapy; But others noted that OS was only a secondary endpoint of this study and was small
compared to other similar studies.
IN ADDITION, A META-ANALYSIS THAT INCLUDED ALL COMPARATIVE STUDIES SHOWED A SURVIVAL BENEFIT
OF THE BEACOPP ESCALATION REGIMEN COMPARED WITH ABVD.

To improve clinical outcomes, many studies have used FDG-PET to identify patients who may benefit from intensive or de-escalated therapy, such as the AHL2011 and RATHL studies
.
In the AHL2011 study, patients were randomized to 6 cycles of BEACOPP and PET-driven groups after 2 cycles of BEACOPP (4 cycles of ABVD for PET2-negative patients and 4 cycles of BEACOPP for PET2-positive patients), and long-term follow-up showed similar
PFS and OS in both groups 。 In the RATHL study, patients underwent a mid-term PET scan after 2 cycles of ABVD, negative patients were randomly assigned to receive ABVD or AVD (without bleomycin) for 4 additional cycles, and positive patients continued to receive BEACOPP-14 or incremental BEACOPP intensive therapy
.
In patients with a negative interim PET scan, the 3-year PFS and OS rates were similar
in the ABVD and AVD groups.
The study concluded that removing bleomycin from the ABVD regimen after an interim PET negative did not significantly reduce efficacy
.
Intensive treatment in intermediate-stage PET-positive patients improves outcomes
.

High-dose chemotherapy (HDCT) combined with autologous stem cell transplantation (ASCT) has also been evaluated as part of initial therapy to further improve outcomes
in patients with advanced HL with adverse prognostic factors.
HL patients with advanced poor prognosis who achieve PR or CR after 4 courses of doxorubicin-containing regimens have been found to have the same good outcomes as conventional chemotherapy, with no additional benefit
from premature intensive therapy with HDCT and ASCT.

The strategies discussed above focus on intensive therapy to improve outcomes
in patients with advanced HL.
A recent strategy has been to add novel drugs, including bubutuximab and PD-1 monoclonal antibody
, to standard chemotherapy regimens.
In phase I studies, bubutuximab was initially used in combination with ABVD and subsequently replaced bleomycin, with CR in most patients
.
However, the combination of bubutuximab with bleomycin is significantly pulmonotoxic, leading to contraindications to the simultaneous use of bleomycin and bubutuximab
.
Based on the very high response rate and good tolerability of bubutuximab in combination with AVD chemotherapy, a phase III study comparing ABVD with AVD + vebutuximab resulted in better
PFS and OS for vebutuximab + AVD.
Vebutuximab + AVD neutropenia (requiring growth factor support) and peripheral neuropathy are more common, while pulmonary toxicity is more common
in the ABVD group.
Improvement in OS confirms that bubutuximab plus AVD is now the preferred first-line regimen
for patients with advanced HL.

GHSG also explored vebutuximab + BEACOPP and developed 2 new treatment options, the more conservative variants BrECAPP (vebutuximab, etoposide, cyclophosphamide, doxorubicin, procarbazine, prednisone) and the more fortified variants BrECADD (vebutuximab, etoposide, cyclophosphamide, doxorubicin, dacarbazine, dexamethasone).

A randomized phase II study demonstrated that combination therapy using these combined anti-CD30 targeting methods was feasible and did not compromise the efficacy
of BEACOPP escalation regimens.

Recent studies have also added anti-PD1 monoclonal antibody (excluding bleomycin)
to AVD chemotherapy in the first-line treatment of newly diagnosed, untreated HL patients.
PD-1 monoclonal antibody is given alone for 2 to 3 cycles initially, followed by chemotherapy
or addition.
Both studies showed high CR rates, and PFS also showed good activity and well tolerated combination therapy with immune checkpoint blockade and chemotherapy
.

Treatment of older patients with cHL is challenging because strong treatment regimens
are often not tolerated.
Vibutuximab and PD-1 monoclonal antibody are being used in older patients and can be used alone with a more tolerated chemotherapy regimen or without chemotherapy
.
In a study ≥ patients aged 60 years, patients with advanced cHL received first 2 cycles of vebutuximab monotherapy, followed by 6 cycles of AVD chemotherapy, followed by 4 cycles of bubutuximab
.
The regimen is well tolerated and has excellent 2-year event-free survival, PFS, and OS rates in
older patients.
In older patients, bubutuximab can also be given in combination with drug O without chemotherapy
.
Although the response rate is promising, the long-lasting benefit is not high, and many patients develop disease progression, especially for the duration
of treatment.
These results suggest that the inclusion of novel agents in first-line treatment may be beneficial for older patients, but additional research is needed to optimize the dose and duration
of treatment.

In summary, ABVD chemotherapy is still widely used in patients with advanced HL, but dose-intensive regimens such as BEACOPP escalation
may be considered in advanced patients with a variety of adverse prognostic factors.
However, based on recent data, vebutuximab plus AVD chemotherapy improves OS in patients with advanced HL and is the preferred regimen
for patients with stage III/IV.
In addition, AVD + O drugs also appear to be very promising in the same population, and randomized studies are comparing O + AVD chemotherapy with bubutuximab + AVD chemotherapy
.

Nodular lymphocytes predominate HL

Early nodular lymphocyte-predominant HL is not a candidate for these strategies
.
Patients with a good prognosis of stage IA and no significant risk factors can usually be treated with a post-lymphadenectomy "watch wait" or IFRT at doses of approximately 20 to 30 Gy
.
Patients with more advanced nodular lymphocyte-predominant HL usually receive combination chemotherapy, often in combination with rituximab, because malignant cells express CD20
.

Treatment of relapsed/refractory patients

Despite the high cure rate with initial therapy, approximately 5% to 10% of patients with HL refractory to initial therapy, and 10% to 30% relapse
after achieving an initial complete response.
ASCT followed by HDCT is the standard of
care for many patients who relapse after initial chemotherapy remission.

Primary refractory

HDCT plus ASCT is the preferred option
in patients with a primary refractory (defined as progression or non-response during induction therapy or within 90 days of completion of treatment) usually have a poor clinical course, with low response rates with second-line chemotherapy alone, and long-term disease-free survival in only 5% to 10% of patients.
Many retrospective analyses have shown that patients treated with ASCT have better
long-term outcomes compared with chemotherapy.
One study analysed outcomes in patients with primary progression and found that chemotherapy showed only no failure and poorer
OS compared with those treated with HDCT and ASCT.
Other studies have concluded that patients who receive ASCT after HDCT have better outcomes than chemotherapy, but a significant proportion of these patients still relapse
after HDCT and ASCT.

relapse

Relapse occurs in 10% to 30% of patients after the initial chemotherapy regimen, and patients with disease progression are usually treated with salvage chemotherapy regimens similar to non-HL, and then most transplant-appropriate patients continue to receive ASCT.

However, randomised studies comparing the effectiveness of different conventional salvage chemotherapy regimens have not been conducted, nor have they found optimal salvage regimens
.
Although most salvage regimens have high overall response rates, the goal of salvage therapy is to increase the number of patients who achieve CR, so recent studies have evaluated whether the addition of vebutuximab or anti-PD-1 monoclonal antibody to salvage chemotherapy improves CR rates and increases the number of
patients with subsequent ASCT 。 Bendamustine plus vebutuximab, vebutuximab plus O, vebutuximab plus ICE (ifosfamide, carboplatin, etoposide), vebutuximab plus DHCP (dexamethasone, high-dose cytarabine, cisplatin), K drug + gemcitabine + vinorelbine + doxorubicin liposome, O drug plus ICE can bring high CR rates and successfully bridge most patients to ASCT, and some patients do not even need chemotherapy
。 Despite response to salvage therapy, this treatment alone is inadequate, patients often relapse and subsequently die of disease progression, so patients need to achieve lasting benefit
, often through consolidation regimens that include HDCT and ASCT.

Phase II studies suggest that ASCT after HDCT may result in better long-term disease-free survival than expected with conventional chemotherapy in 30% to 65% of patients, and two subsequent randomized studies have demonstrated improved
outcomes with ASCT therapy after HDCT in patients with recurrent HL compared with conventional salvage chemotherapy regimens.
Patients receiving HDCT in both studies had event-free survival rates of more than 50%
after 3 years.

However, not all patients are candidates for transplantation or would benefit from
ASCT.
Older patients treated with ASCT have increased treatment-related mortality and generally have poorer
event-free survival compared with younger patients.
Some patients continue to progress and undergo tandem ASCT or allogeneic transplantation, including haploid transplantation
.
These therapies are available, but toxicity and relapse are common
.

To prevent or delay post-transplant progression, particularly in patients with adverse risk factors, one study randomized patients after ASCT to brubutuximab consolidation therapy or placebo
.
The median PFS of patients treated with bubutuximab was significantly improved compared with placebo, demonstrating a benefit
of post-transplantation bubutuximab in high-risk patients.
A small study evaluating drug K as consolidation therapy after transplantation in a similar patient cohort with the primary endpoint being that drug K improves PFS at 18 months after ASCT met its primary endpoint, but the benefit of immune checkpoint blockade after ASCT still needs to be demonstrated
in randomized studies.

Treatment options for recurrence after HDCT and ASCT

Patients who progress after ASCT have historically had poor outcomes, but outcomes for HL patients with relapse after ASCT have improved in recent years, largely due to the use of novel agents, including antibody-drug conjugates and PD-1 monoclonal antibodies
.

The CD30-targeting antibody-conjugate vebutuximab is a well-established therapy particularly suitable for HL patients
with relapse after transplantation.
Preliminary studies of post-transplant patients have shown significant clinical activity
.
In a pivotal phase II study of bubutuximab in HL patients with ASCT failure, three-quarters of patients had clinical remission, with CR reaching one-third
.
Clinical response rates with PD-1 and PD-L1 or PDL2 monoclonal antibodies are also very high (see Table 1).

In a recent randomized study, the efficacy of drug K was compared with the efficacy
of bubutuximab for relapsed or refractory classical HL.
The PFS of drug K is significantly improved compared with bubutuximab, supporting PD-1 monoclonal antibody as the preferred regimen
for patients who relapse after ASCT or are not suitable for ASCT.

Other promising approaches in this patient population include combination strategies, CAR T, and new antibody-drug conjugates
.
Vibutuximab has been used in combination with two checkpoint inhibitors, O-drug and ipilimumab, and the triple combination has shown promising efficacy
.
CAR T is still in early development but has been shown to be safe with very promising clinical activity
.
ADCT-301 (camidanlumab tesirine), an antibody-conjugate drug targeting CD25 that conjugates to pyrrolobenzodiazepine dimer toxins, has also observed encouraging clinical activity
in initial studies in patients with relapsed/refractory cHL.

summary

Optimal treatment of HL patients requires accurate diagnosis and careful disease staging, and accurate identification of adverse prognostic factors before risk-adaptive therapy can be implemented to potentially increase the likelihood of cure and limit toxicity
.
Future directions to further improve outcomes for patients with HL lie in combination therapies that include additional novel agents to increase efficacy and the use of novel imaging and peripheral blood molecular tests to minimize the therapeutic exposure
required to cure patients.

References

Stephen M Ansell.
Hodgkin lymphoma: 2023 update on diagnosis, risk-stratification, and management.
Am J Hematol .
2022 Nov; 97(11):1478-1488.
doi: 10.
1002/ajh.
26717.
Epub 2022 Sep 19.