Gonadal Function Recovery in Patients With Advanced Hodgkin Lymphoma Treated With a PET-Adapted Regimen: Prospective Analysis of a Randomized Phase III Trial (AHL2011)

PURPOSE The prospective, randomized AHL2011 trial demonstrated that the use of the doxorubicin, bleomycin, vinblastine, and dacarbazine regimen (ABVD) after two cycles of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPPescalated) in early responders on the basis of a positron emission tomography (PET)–driven strategy was safe and minimized toxicity compared with standard 6 BEACOPPescalated cycles. This substudy investigated the benefit of this strategy in gonadal function and fertility in patients under 45 years old. METHODS Ovarian function was assessed by serum measurement of follicle-stimulating hormone (FSH), estradiol, and anti-müllerian hormone in women, and semen analysis, FSH, and testosterone levels were used to evaluate testicular function in men at baseline, end of treatment, and during 5 years of follow-up. RESULTS A total of 145 women and 424 men, enrolled between May 19, 2011, and April 29, 2014, were included. The risk of premature ovarian insufficiency (FSH > 24 IU/L) and of having a low ovarian reserve (anti-müllerian hormone < 0.5 ng/mL) was reduced after treatment in the PET-driven group (odds ratio [OR], 0.20; 95% CI, 0.08 to 0.50; P = .001 and OR, 0.15; 95% CI, 0.04 to 0.56, P = .005, respectively). Both parameters were correlated with age and dose of alkylating agents. However, no significant differences were observed in terms of pregnancy rates. Men in the PET-driven group had a higher recovery rate of sperm parameters after treatment compared with the standard BEACOPPescalated group, as well as a lower risk of severe testicular damage (OR, 0.26; 95% CI, 0.13 to 0.5; P < .0001) and a higher likelihood of achieving pregnancy (OR, 3.7; 95% CI, 1.4 to 9.3; P = .004). CONCLUSION Although both treatments affected ovarian reserve and spermatogenesis, the PET-driven strategy decreased the risk of gonadal dysfunction and infertility in advanced Hodgkin lymphoma.

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Positron Emission Tomography–Driven Strategy in Advanced Hodgkin Lymphoma: Prolonged Follow-Up of the AHL2011 Phase III Lymphoma Study Association Study

Journal of Clinical Oncology ◽

10.1200/jco.21.01777 ◽

2022 ◽

Author(s):

René-Olivier Casasnovas ◽

Reda Bouabdallah ◽

Pauline Brice ◽

Julien Lazarovici ◽

Hervé Ghesquieres ◽

...

Keyword(s):

Positron Emission Tomography ◽

Hodgkin Lymphoma ◽

Emission Tomography ◽

Phase Iii ◽

Second Primary ◽

Second Primary Malignancy ◽

Interim Pet ◽

Positron Emission ◽

Study Results

PURPOSE The AHL2011 study (ClinicalTrials.gov identifier: NCT01358747 ) demonstrated that a positron emission tomography (PET)-driven de-escalation strategy after two cycles of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) provides similar progression-free survival (PFS) and overall survival (OS) and reduces early toxicity compared with a nonmonitored standard treatment. Here, we report, with a prolonged follow-up, the final study results. METHODS Patients with advanced Hodgkin lymphoma (stage III, IV, or IIB with mediastinum/thorax ratio > 0.33 or extranodal involvement) age 16-60 years were prospectively randomly assigned between 6 × BEACOPP and a PET-driven arm after 2 × BEACOPP delivering 4 × ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) in PET2– and 4 × BEACOPP in PET2+ patients. PET performed after four cycles of chemotherapy had to be negative to complete the planned treatment. RESULTS In total, 823 patients were enrolled including 413 in the standard arm and 410 in the PET-driven arm. With a 67.2-month median follow-up, 5-year PFS (87.5% v 86.7%; hazard ratio [HR] = 1.07; 95% CI, 0.74 to 1.57; P = .67) and OS (97.7% in both arms; HR = 1.012; 95% CI, 0.50 to 2.10; P = .53) were similar in both randomization arms. In the whole cohort, full interim PET assessment predicted patients' 5-year PFS (92.3% in PET2–/PET4–, 75.4% [HR = 3.26; 95% CI, 18.3 to 5.77] in PET2+/PET4– and 46.5% [HR = 12.4; 95% CI, 7.31 to 19.51] in PET4+ patients, respectively; P < .0001) independent of international prognosis score. Five-year OS was also affected by interim PET results, and PET2+/PET4– patients (93.5%; HR = 3.3; 95% CI, 1.07 to 10.1; P = .036) and PET4+ patients (91.9%; HR = 3.756; 95% CI, 1.07 to 13.18; P = .038) had a significant lower OS than PET2–/PET4– patients (98.2%). Twenty-two patients (2.7%) developed a second primary malignancy, 13 (3.2%) and 9 (2.2%) in the standard and experimental arms, respectively. CONCLUSION The extended follow-up confirms the continued efficacy and favorable safety of AHL2011 PET-driven strategy, which is noninferior to standard six cycles of BEACOPP. PET4 provides additional prognostic information to PET2 and allows identifying patients with particularly poor prognosis.

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Is Recovery of Gonadal function possible in Very Long-Term Adult Male Survivors of Hodgkin's Lymphoma?

Blood ◽

10.1182/blood.v120.21.2065.2065 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2065-2065

Author(s):

Wendy van Dorp ◽

Ivana van der Geest ◽

Joop Laven ◽

Wim C.J. Hop ◽

Sebastian J.C.M.M. Neggers ◽

...

Keyword(s):

Cancer Survivors ◽

Childhood Cancer ◽

Hodgkin Lymphoma ◽

Adult Male ◽

Alkylating Agents ◽

Childhood Cancer Survivors ◽

Inhibin B ◽

Gonadal Function ◽

Discontinuation Of Treatment

Abstract Abstract 2065 Background: Significant improvements in childhood cancer survival rates over recent decades have increased the importance of long-term treatment effects. Gonadal toxicity is a major complication in survivors of childhood cancer, which can especially occur in Hodgkin Lymphoma survivors, since they have been treated with alkylating agents. Inhibin B levels reflect gonadal function in men, and therefore this marker can be used to identify subgroups of childhood cancer survivors at risk for impaired gonadal function. Hitherto in male childhood cancer survivors, follow-up studies of gonadal function are lacking. Objective: To evaluate possible recovery of gonadal dysfunction over time in adult male survivors. Methods: In this retrospective study, adult male long-term childhood cancer survivors (n=201) of whom 24 (12%) were survivors of Hodgkin lymphoma were included. Serum inhibin B levels were used as a surrogate marker for gonadal function. Results: Median age at diagnosis was 6.0 years (range 0.0–17.5) and discontinuation of treatment was reached at a median age of 8.3 years (range 0.0–20.8). Inhibin B levels were first measured after a median follow-up time of 15.7 years (range 3.0–37.0). Median interval between the first (T1) and second measurement (T2) was 3.3 years (range 0.7–11.3). Median inhibin B level was 127 ng/L (range 5–366) at T1 and 156 ng/L (range 10–507) at T2. Survivors with an inhibin B level at first assessment≥105 ng/L have 50% chance to reach normal inhibin B levels, while this probability of recovery is negligible when the first inhibin B level is below 60 ng/L. The latter group consists of survivors of Hodgkin lymphoma treated with alkylating agents and survivors with an AAD score≥3. Conclusions: Our results suggest that recovery of gonadal function is possible even long after discontinuation of treatment. However, this recovery does not seem to occur in survivors who already reached critically low inhibin B levels after discontinuation of treatment, such as in survivors of a Hodgkin lymphoma treated with alkylating agents. Disclosures: No relevant conflicts of interest to declare.

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Evaluation of Chemotherapy-Induced Ovarian Failure by Sequential Anti-Müllerian Hormone Dosage.

Blood ◽

10.1182/blood.v116.21.3813.3813 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3813-3813

Author(s):

Sabine Tricot ◽

Christine Decanter ◽

Julia Salleron ◽

Louis Terriou ◽

Daniela Robu ◽

...

Keyword(s):

Hodgkin Lymphoma ◽

Ovarian Function ◽

Chemotherapy Regimen ◽

Conflicts Of Interest ◽

Alkylating Agents ◽

Prognostic Score ◽

Ovarian Failure ◽

High Dose ◽

Female Patients

Abstract Abstract 3813 Background. Chemotherapy-induced ovarian failure is one of the most challenging side effects for female patients with lymphoma. For a given patient, it remains difficult to predict if ovarian failure will recover or lead to sterility. Anti-Müllerian Hormone (AMH) reflects primordial follicle depletion and may predict ovarian function recovery. In this study, we prospectively assessed AMH levels during and after treatment of young female patients with lymphoma. Methods. Patients diagnosed with any type of lymphoma and aged below 36 years were eligible. AMH level was measured before chemotherapy, 2 weeks after initiating chemotherapy, 2 weeks before last chemotherapy and every 3 months during 2 years. Median AMH levels at each time point were compared according to the type of chemotherapy regimen (ABVD versus alkylating containing regimen -excluding Dacarbazine-). Results. From April 2004 to May 2010, 100 patients from 7 centers were enrolled of whom 80 are currently evaluable. Diagnosis was Hodgkin lymphoma (n= 65) or non-Hodgkin lymphoma (n=15). Median age was 25 years old (range: 17–36). Forty-eight patients (60.8%) had extended disease and 32 (62%) had at least one risk factor according to validated prognostic score. Chemotherapy regimen consisted of: ABVD (n=51), BEACOPP (n=5), CHOP or CHOP-like (n=11), CHOP followed by BEAM high dose therapy and autologous stem cell transplantation (ASCT) (n=3), or various salvage (MINE or IGEV) followed by BEAM and ASCT (n=10). The median follow up after chemotherapy was 18 months (range 3 – 24 months). The median number of cycles of ABVD was 6 (range: 2–8) whereas for the other regimen, the median cumulative dose of alkylating agents was: cyclophosphamide, 4.5 g/m2; procarbazine, 5.6 g/m2; ifosfamide, 15 g/m2 and melphalan, 140 mg/m2. Baseline AMH was 15 pMol/L (range 4–73). As soon as 2 weeks after chemotherapy, all chemotherapy regimen induced a significant decrease of AMH levels: 5 pMol/L(range 3–45). AMH recovery was significantly different for patients treated with or without alkylating agents (p=0.01) at 6 months (3 v 13 pMol/L) and 12 months (3 v 19 pMol/L) after last chemotherapy. Moreover, at 2 years, patients treated with BEACOPP had persistently low AMH levels (≤3 pMol/L) whereas patients treated with CHOP or CHOP like regimen showed an increasing of AMH levels to 6 (3-34) pMol/L at 1 year after chemotherapy. Patients who underwent ASCT had lower AMH levels than patients treated by alkylating agents without ASCT, yet non significant at 1 year (p=0.09). Three pregnancies were reported 7, 16 and 24 months after last chemotherapy (two patients treated with ABVD and one with CHOP). Conclusion. Sequential AMH profiles during and after chemotherapy were divers. Different AMH profiles were observed for ABVD compared to alkylating-based regimen and also among alkylating-based regimen. AMH recovery started at 6 months after ABVD, at 1 year after CHOP regimen and later for other regimen. Longer clinical follow-up will confirm if no or delayed AMH recovery recovery always reflects severe ovarian failure and will help guiding our decisions of ovarian cryopreservation in the future according to the planned chemotherapy regimen. Disclosures: No relevant conflicts of interest to declare.

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Gonadal function following chemotherapy for Hodgkin's disease: a comparative study of MVPP and a seven-drug hybrid regimen.

Journal of Clinical Oncology ◽

10.1200/jco.1995.13.1.134 ◽

1995 ◽

Vol 13 (1) ◽

pp. 134-139 ◽

Cited By ~ 93

Author(s):

S T Clark ◽

J A Radford ◽

D Crowther ◽

R Swindell ◽

S M Shalet

Keyword(s):

Hodgkin's Disease ◽

Sperm Count ◽

Hodgkin’S Disease ◽

Semen Analysis ◽

Hormone Replacement ◽

Ovarian Failure ◽

Gonadal Function ◽

Early Menopause ◽

Gonadal Dysfunction ◽

Significant Difference

PURPOSE AND METHODS Gonadal function was assessed in 89 patients after chemotherapy for Hodgkin's disease (HD). Thirty-seven patients had received mechlorethamine, vinblastine, prednisolone, and procarbazine (MVPP) and 52 patients, a hybrid combination of chlorambucil, vinblastine, prednisolone, procarbazine, doxorubicin, vincristine, and etoposide (ChIVPP/EVA). Fifty men (MVPP, n = 21; ChIVPP/EVA, n = 29) with a median age of 26 years (range, 16 to 54) and 39 women (MVPP, n = 16; ChIVPP/EVA, n = 23) with a median age of 30 years (range, 15 to 47) were studied at a median of 30 months (range, 4 to 83) following chemotherapy. RESULTS Semen analysis showed azoospermia in 35 of 37 men, and increased serum follicle-stimulating hormone (FSH) levels in this group confirmed severe germinal epithelial damage. Analysis of pretreatment semen in 28 men showed azoospermia in one, oligospermia in four (sperm count < 20 x 10(6)/mL), and a normal sperm count in the remaining 23. In the women, 26 of 34 (76%) with a regular menstrual cycle before commencing chemotherapy became amenorrheic following treatment. Menses returned in 10 women, who had a median age of 25 years (range, 21 to 34), and there were two pregnancies in this group. In the other 16, with a median age of 36 years (range, 27 to 47), amenorrhea persisted and premature ovarian failure was confirmed by increased serum gonadotrophins and reduced estradiol (E2) concentrations. Of the original eight women in whom menses were maintained following treatment, two subsequently developed amenorrhea and the clinical and biochemical features of an early menopause. In total, 18 of 34 women (53%) required hormone replacement therapy for chemotherapy-induced ovarian failure. CONCLUSION There was no statistically significant difference in the frequency or severity of gonadal dysfunction between MVPP- and ChIVPP/EVA-treated patients. We conclude that both of these chemotherapy schedules cause substantial damage to gonadal function in both sexes.

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Faculty Opinions recommendation of Gonadal Function Recovery in Patients With Advanced Hodgkin Lymphoma Treated With a PET-Adapted Regimen: Prospective Analysis of a Randomized Phase III Trial (AHL2011).

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.740347338.793590523 ◽

2021 ◽

Author(s):

Eva Chalas

Keyword(s):

Hodgkin Lymphoma ◽

Phase Iii ◽

Prospective Analysis ◽

Gonadal Function ◽

Phase Iii Trial ◽

Function Recovery

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Effect of Genetic Variation in CYP450 on Gonadal Impairment in a European Cohort of Female Childhood Cancer Survivors, Based on a Candidate Gene Approach: Results from the PanCareLIFE Study

Cancers ◽

10.3390/cancers13184598 ◽

2021 ◽

Vol 13 (18) ◽

pp. 4598

Author(s):

M. Perk ◽

Linda Broer ◽

Yutaka Yasui ◽

Leslie Robison ◽

Melissa Hudson ◽

...

Keyword(s):

Cancer Survivors ◽

Childhood Cancer ◽

Ovarian Function ◽

Meta Analysis ◽

Alkylating Agents ◽

Childhood Cancer Survivors ◽

P Value ◽

Candidate Gene Approach ◽

Gonadal Dysfunction ◽

The Impact

Background: Female childhood cancer survivors (CCSs) carry a risk of therapy-related gonadal dysfunction. Alkylating agents (AA) are well-established risk factors, yet inter-individual variability in ovarian function is observed. Polymorphisms in CYP450 enzymes may explain this variability in AA-induced ovarian damage. We aimed to evaluate associations between previously identified genetic polymorphisms in CYP450 enzymes and AA-related ovarian function among adult CCSs. Methods: Anti-Müllerian hormone (AMH) levels served as a proxy for ovarian function in a discovery cohort of adult female CCSs, from the pan-European PanCareLIFE cohort (n = 743; age (years): median 25.8, interquartile range (IQR) 22.1–30.6). Using two additive genetic models in linear and logistic regression, nine genetic variants in three CYP450 enzymes were analyzed in relation to cyclophosphamide equivalent dose (CED) score and their impact on AMH levels. The main model evaluated the effect of the variant on AMH and the interaction model evaluated the modifying effect of the variant on the impact of CED score on log-transformed AMH levels. Results were validated, and meta-analysis performed, using the USA-based St. Jude Lifetime Cohort (n = 391; age (years): median 31.3, IQR 26.6–37.4). Results: CYP3A4*3 was significantly associated with AMH levels in the discovery and replication cohort. Meta-analysis revealed a significant main deleterious effect (Beta (95% CI): −0.706 (−1.11–−0.298), p-value = 7 × 10−4) of CYP3A4*3 (rs4986910) on log-transformed AMH levels. CYP2B6*2 (rs8192709) showed a significant protective interaction effect (Beta (95% CI): 0.527 (0.126–0.928), p-value = 0.01) on log-transformed AMH levels in CCSs receiving more than 8000 mg/m2 CED. Conclusions: Female CCSs CYP3A4*3 carriers had significantly lower AMH levels, and CYP2B6*2 may have a protective effect on AMH levels. Identification of risk-contributing variants may improve individualized counselling regarding the treatment-related risk of infertility and fertility preservation options.

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Additional Evidence That End-of-Treatment Fluorodeoxyglucose-Positron Emission Tomography Evaluation Is Necessary in Advanced Hodgkin Lymphoma

Journal of Clinical Oncology ◽

10.1200/jco.2018.78.6780 ◽

2018 ◽

Vol 36 (20) ◽

pp. 2124-2125 ◽

Cited By ~ 2

Author(s):

Charles Mesguich ◽

Krimo Bouabdallah ◽

Noël Milpied ◽

Elif Hindié

Keyword(s):

Positron Emission Tomography ◽

Hodgkin Lymphoma ◽

Emission Tomography ◽

Fluorodeoxyglucose Positron Emission Tomography ◽

Positron Emission ◽

End Of Treatment ◽

Fluorodeoxyglucose Positron Emission

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Positron Emission Tomography–Guided Treatment in Early-Stage Favorable Hodgkin Lymphoma: Final Results of the International, Randomized Phase III HD16 Trial by the German Hodgkin Study Group

Journal of Clinical Oncology ◽

10.1200/jco.19.00964 ◽

2019 ◽

Vol 37 (31) ◽

pp. 2835-2845 ◽

Cited By ~ 32

Author(s):

Michael Fuchs ◽

Helen Goergen ◽

Carsten Kobe ◽

Georg Kuhnert ◽

Andreas Lohri ◽

...

Keyword(s):

Positron Emission Tomography ◽

Hodgkin Lymphoma ◽

Early Stage ◽

Hazard Ratio ◽

Emission Tomography ◽

Phase Iii ◽

Deauville Score ◽

Positron Emission ◽

Involved Field ◽

Involved Field Radiotherapy

PURPOSE Combined-modality treatment (CMT) with 2× ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) and small-field radiotherapy is standard of care for patients with early-stage favorable Hodgkin lymphoma (HL). However, the role of radiotherapy has been challenged. Positron emission tomography (PET) after 2× ABVD (PET-2) might help to predict individual outcomes and guide treatment. METHODS Between November 2009 and December 2015, we recruited patients age 18 to 75 years with newly diagnosed, early-stage favorable HL for this international randomized phase III trial. Patients were assigned to standard CMT of 2× ABVD and 20-Gy involved-field radiotherapy or PET-guided treatment, omitting involved-field radiotherapy after negative PET-2 (Deauville score < 3). Primary objectives were to exclude inferiority of 10% or more in 5-year progression-free survival (PFS) of ABVD alone compared with CMT in a per-protocol analysis among PET-2–negative patients (noninferiority margin for hazard ratio, 3.01) and to confirm PET-2 positivity (Deauville score ≥ 3) as a risk factor for PFS among CMT-treated patients. RESULTS We enrolled 1,150 patients. Median follow-up was 45 months. Among 628 PET-2–negative, per-protocol–treated patients, 5-year PFS was 93.4% (95% CI, 90.4% to 96.5%) with CMT and 86.1% (95% CI, 81.4% to 90.9%) with ABVD (difference 7.3% [95% CI, 1.6% to 13.0%]; hazard ratio, 1.78 [95% CI, 1.02 to 3.12]). Five-year overall survival was 98.1% (95% CI, 96.5% to 99.8%) with CMT and 98.4% (95% CI, 96.5% to 100.0%) with ABVD. Among 693 patients who were assigned to CMT, 5-year PFS was 93.2% (95% CI, 90.2% to 96.2%) among PET-2–negative patients and 88.4% (95% CI, 84.2% to 92.6%) in PET-2–positive patients ( P = .047). When using the more common liver cutoff (Deauville score, 4) for PET-2 positivity, the difference was more pronounced (5-year PFS, 93.1% [95% CI, 90.7% to 95.5%] v 80.9% [95% CI, 72.2% to 89.7%]; P = .0011). CONCLUSION In early-stage favorable HL, a positive PET after two cycles ABVD indicates a high risk for treatment failure, particularly when a Deauville score of 4 is used as a cutoff for positivity. In PET-2–negative patients, radiotherapy cannot be omitted from CMT without clinically relevant loss of tumor control.

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