Omission Of Bleomycin Research Articles

Invited commentary on “The impact of bleomycin deficit on survival in Hodgkin's lymphoma patients: A retrospective study”

The article “The impact of bleomycin deficit on survival in Hodgkin's lymphoma patients: A retrospective study” have presented the experience of AVD chemotherapy regimen in newly diagnosed Hodgkin's lymphoma (HL) in a single center in Brazil. Though being a small retrospective study, results from this study have provided the medical community a real-world data on HL in Brazil. ABVD has remained the standard of care for patients of newly diagnosed HL both in early and advance stages. Newer targeted molecules have also come for use in novel combinations with existing drugs. However, in a situation of temporary scarcity of bleomycin due to lack of supply during 2017 in Brazil led to use of incomplete ABVD regimen without bleomycin, i.e. AVD for HL. However, Soldi et al. utilized the opportunity to retrospectively study if the omission of bleomycin leads to subnormal treatment or unwarranted effects.

P1089: BRENTUXIMAB VEDOTIN, NIVOLUMAB, DOXORUBICIN, AND DACARBAZINE (AN+AD) FOR ADVANCED STAGE CLASSIC HODGKIN LYMPHOMA: PRELIMINARY SAFETY AND EFFICACY RESULTS FROM THE PHASE 2 STUDY (SGN35 027 PART B)

Background: Brentuximab vedotin (BV) and nivolumab are both active and well-tolerated in patients (pts) with classical Hodgkin lymphoma (cHL) and were previously studied in first salvage (overall response rate [ORR] 85%; complete response [CR] 67%) (Advani 2021) and as firstline (1L) therapy in older adults (ORR 95%; CR 79%) (Yasenchak 2019). The combination of BV plus nivolumab demonstrated promising activity as a frontline treatment option for pts over 60 yrs of age with cHL (Friedberg 2018). Additionally, in pts with non-bulky Stage I or II cHL, treatment with BV plus doxorubicin and dacarbazine (AD) resulted in a CR rate of 97% at end of treatment (EOT), as well as a promising 4-year progression-free survival (PFS) estimate of 91%. There were no cases of ≥Grade 3 peripheral neuropathy and only 9% were Grade 2 (Abramson 2021). Aims: This abstract will present the preliminary safety and efficacy results from Part B of the SGN35-027 study, which enrolled pts with Ann Arbor Stage II cHL with bulky mediastinal disease (defined as a single node or nodal mass ≥10 cm as determined by CT imaging), or Stage III or IV cHL. Methods: SGN35-027 (NCT03646123) is an open-label, multiple part, multicenter, phase 2 clinical trial. Pts received up to 6 cycles of AN+AD (consisting of BV 1.2 mg/kg, nivolumab 240 mg, doxorubicin 25 mg/m2, and dacarbazine 375 mg/m2). All study drugs were administered by IV infusion on Days 1 and 15 of each 28-day cycle. The primary endpoint was CR rate at EOT. Key secondary endpoints included safety, tolerability, ORR, and PFS. Disease response and progression was assessed by investigators using the Lugano Classification Revised Staging System for nodal non-Hodgkin and Hodgkin Lymphomas (Cheson 2014) and Lymphoma Response to Immunomodulatory Therapy Criteria (LYRIC) (Cheson 2016) at Cycle 2 and EOT. Results: In Part B, 58 pts were enrolled and 57 pts received at least 1 dose of study treatment. Of these 57 pts, 30 (53%) were male, 27 (47%) were female, 50 (88%) were white, 46 (81%) were not of Hispanic or Latino/a or Spanish origins, and 54 (95%) were <65 years old. Median age was 35 yrs (range: 19-78 yrs); 30% had Stage II cHL with bulky mediastinal disease, while 18% and 51% had Stage III and IV cHL, respectively. Of 58 pts enrolled, 52 (90%) completed treatment and 4 (7%) discontinued due to AEs. The most frequently reported TEAEs were nausea, fatigue, and diarrhea (70%, 51%, and 46% of pts, respectively). Grade 3 or higher TEAEs were reported in 30 pts (53%), with neutropenia and increased ALT in 5 pts (9%) being the most frequent. Treatment-related AEs occurred in 98% of pts; the most frequent were nausea, fatigue, and peripheral sensory neuropathy (65%, 46%, and 39% of pts, respectively). Treatment-related SAEs occurred in 8 pts (14%), of which pneumonitis was the most common (3 pts [5%]). Immune-mediated AEs were observed in 18 pts (32%), and hypothyroidism (4 pts [7%]) was the most frequently reported. No febrile neutropenia was observed, and there were no Grade 5 AEs. Preliminary results show at EOT, 52 pts had a response to treatment (ORR 93% [95% CI:82.7-98.0]), with 49 pts having a complete response (CR rate: 88% [95% CI: 75.9-94.8]). Summary/Conclusion: Preliminary results demonstrate that AN+AD has promising clinical activity and is well-tolerated, with no new safety signals observed. The omission of bleomycin and vinblastine may have contributed to the absence of certain AEs, such as febrile neutropenia. AN+AD may provide another active treatment option for patients with 1L advanced cHL.

The EHA Research Roadmap: Malignant Lymphoid Diseases.

The EHA Research Roadmap: Malignant Lymphoid Diseases.

Brentuximab Vedotin, Nivolumab, Doxorubicin, and Dacarbazine (AN+AD) for Advanced Stage Classic Hodgkin Lymphoma: Preliminary Safety Results from the Single-Arm Phase 2 Study (SGN35-027 Part B)

Brentuximab Vedotin, Nivolumab, Doxorubicin, and Dacarbazine (AN+AD) for Advanced Stage Classic Hodgkin Lymphoma: Preliminary Safety Results from the Single-Arm Phase 2 Study (SGN35-027 Part B)

SWOG S1826: A Phase III, Randomized Study of Nivolumab Plus AVD or Brentuximab Vedotin Plus AVD in Patients with Newly Diagnosed Advanced Stage Classical Hodgkin Lymphoma

SWOG S1826: A Phase III, Randomized Study of Nivolumab Plus AVD or Brentuximab Vedotin Plus AVD in Patients with Newly Diagnosed Advanced Stage Classical Hodgkin Lymphoma

Current Treatment Options for Older Patients with Hodgkin Lymphoma.

Older adults with Hodgkin lymphoma (HL), commonly defined as age ≥ 60years, represent approximately 20% of the total HL population. Historically, they have significantly inferior outcomes compared with younger patients. The cause of this is multifactorial, including biologic differences (e.g., mixed cellularity and EBV-related disease); high incidence of advanced stage disease; and frequency of comorbidities and decreased organ reserve leading to poorer tolerability of therapy with increased toxicity, including treatment-related mortality. Pretreatment evaluation for older HL patients should entail a geriatric assessment (GA), with evaluation of functional status and comorbidities (e.g., geriatric cumulative illness rating scale, CIRS-G) to determine fitness. Furthermore, treatment selection should be based in part on GA, with fit older patients receiving curative chemotherapy-based regimens and unfit or frail patients considering less intensive or non-chemotherapy-based platforms. Additionally, there may be consideration for pre-phase of therapy (e.g., pulse steroids) in order to improve performance status. The inclusion of anthracycline therapy appears important, while bleomycin-containing regimens (e.g., ABVD) may be associated with prohibitive pulmonary toxicity, and intensive therapies such as BEACOPP are too toxic. benefit ratio/benefit ratio, a priori omission of bleomycin may also be considered (i.e., AVD), especially for patients older than 70years of age. In addition, newer regimens for older HL patients integrating novel therapeutic agents into frontline treatment have emerged as effective and tolerable options. Data incorporating brentuximab vedotin sequentially before and after AVD chemotherapy represent the best-reported outcomes in older HL patients to date. In the relapsed/refractory setting, salvage chemotherapy regimens followed by autologous stem cell transplantation should be considered for fit patients, while less intensive treatment, including the use of novel targeted agents, is an option for unfit or frail patients. In this review, we examine the epidemiology, importance of GA, and current treatment options for older HL patients.

Partial omission of bleomycin for early-stage Hodgkin lymphoma patients treated with combined modality therapy: Does incomplete ABVD lead to inferior outcomes?

Classical Hodgkin lymphoma (HL) patients achieve excellent outcomes; therefore, treatment de‐escalation strategies to spare toxicity have been prioritized. In a large randomized trial of early‐stage HL patients, omission of chemotherapeutic agents including bleomycin from the standard ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) regimen was not found to be noninferior; however, the effect of partial omission is unknown. We investigated the effect of bleomycin omission on outcome for 150 early‐stage HL patients. At 8 years, freedom from relapse was 99% for both patients who received complete or incomplete bleomycin, which is reassuring for patients requiring bleomycin omission due to toxicity.

Treatment strategy for newly diagnosed classical Hodgkin lymphoma: current achievements using interim PET-guided therapy

Interim positron emission tomography (iPET-2)-guided therapy following two cycles of ABVD chemotherapy has been developed for newly diagnosed classical Hodgkin lymphoma (cHL) patients in several prospective trials. In localized-stage cHL, radiotherapy cannot be omitted, even in iPET-negative patients after two or three cycles of ABVD, whereas two cycles of escalated BEACOPP regimens followed by involved nodular radiotherapy (30 Gy) is a useful treatment option for iPET-2 positive patients after two cycles of ABVD. In advanced-stage cHL, approximately 20% of cases were iPET-2 positive, and the switch to BEACOPP-based regimens was reported as a useful treatment option, with 3-year progression-free survival of approximately 60-65%, in iPET-2-positive patients in three clinical trials. Furthermore, the switch to AVD (omission of bleomycin after two cycles of ABVD) is a reasonable treatment option in iPET-2-negative patients, particularly those at risk for bleomycin lung toxicity in advanced-stage cHL. This review summarizes the current evidence regarding interim PET-guided therapy for newly diagnosed cHL patients.

An evaluation of brentuximab vedotin as a treatment option for stage III/IV Hodgkin lymphoma

ABSTRACTIntroduction: Outcomes of patients with classical Hodgkin lymphoma are excellent, and the intent of frontline therapy for even advanced-stage disease has been curative. This review summarizes the role of brentuximab vedotin in the upfront treatment of advanced stage classical Hodgkin lymphoma in the context of reducing therapy-related toxicity without compromising the high cure rate.Areas covered: Strategies to reduce bleomycin-induced lung toxicity include a response-adapted approach investigated in the RATHL study and a replacement of bleomycin with brentuximab vedotin in frontline chemotherapy regimens. In both studies, omission of bleomycin in the non-standard arms decreased the rate of pulmonary toxicity while maintaining high progression-free survival and overall survival rates.Expert opinion: The approval of A+AVD in North America offers a new bleomycin-free regimen for the treatment of advanced-stage HL, but it must be balanced against a risk-adapted approach. Recently presented subset analyses raise a question about which patients benefit most from this therapy.

Partial Omission of Bleomycin for Early Stage Hodgkin Lymphoma Patients Treated with Combined Modality Therapy: Does Incomplete ABVD Lead to Inferior Outcomes?

Partial Omission of Bleomycin for Early Stage Hodgkin Lymphoma Patients Treated with Combined Modality Therapy: Does Incomplete ABVD Lead to Inferior Outcomes?

Pharmacogenomic Prediction of Bleomycin-Induced Pneumonitis in South East Asian Hodgkin Lymphoma Patients

BackgroundHodgkin lymphoma (HL) accounts for 15% of all cancer diagnosis in young adults. Standard of care is ABVD (Adriamycin, Bleomycin, Vinblastine, Dacarbazine), which has resulted in overall cures of 70-90%. In the setting of HL, bleomycin is still one of the cornerstones in its treatment with the omission of bleomycin in the randomized trial of GHSG HD13 showing poorer outcomes. A major complication of HL treatment is Bleomycin induced pneumonitis (BIP) occurring in 0.4-28% of patients, with up to 10% mortality. Currently, we are unable to predict which patients are more prone. Given that human genomic variations underlie both disease susceptibility and drug response, uncovering genetic biomarkers predisposing to BIP is imperative to predicting and preventing BIP.MethodsIn this first pharmacogenomics study of BIP in South-East Asian patients, we perform both candidate gene and GWAS analyses. 96 HL patients were recruited from the National University Cancer Institute, Singapore (NCIS). BIP was clinically characterized and graded by CTCAEv4. Genetic association analysis was performed by regression (additive model) accounting for non-genetic predictor variables.ResultsAge at the start of bleomycin treatment, sex, genetic ancestry, concomitant chemotherapy treatment, treatment with G-CSF, stage of HL disease, pretreatment creatinine clearance, weight, chest irradiation and smoking history did not differ significantly between patients with and without BIP. The total number of treatment cycles (P=0.006) , cumulative exposure (P=0.01) and total exposure (P=0.028) were significantly lower in the BIP group as Bleomycin was omitted from further chemotherapy regimens once BIP was diagnosed.We independently replicated the association of HFE rs1799945 (H63D) with BIP (Cases: 15.38% vs Controls: 1.72%, P=0.0069, OR(95%CI)=2.89 (1.88-88.59)), while BLMH rs1050565 was not associated with BIP (P=0.92, OR(95%CI)=1.07 (0.29-3.93)). H63D carriers have 12.44 (1.98-78.17) times the odds of developing BIP compared to non-carriers (P=0.0088). We uncover a significant association of H63D with the severity of BIP (P=0.00087). HIST1H1T rs198846, a downstream variant in LD with H63D was also associated with BIP and its severity. H63D was predicted to be highly pathogenic (CADD Score=24.40) and at the top 1% of the most deleterious mutations in the human genome.The GWAS uncovered 4 novel genetic biomarkers with suggestive evidence of association with BIP (Unknown locus on Chr 17, MRC2 rs8072984, TMEM260 rs1124062 and KIF26B rs12747330). MRC2 rs8072984 is involved with remodeling of extracellular matrix, and defects in this could cause poor lung remodeling after bleomycin insult. TMEM260 rs1124062 and KIF26B rs12747330 are both involved with renal anomalies and development suggesting that defects in these could affect bleomycin clearance.ConclusionThis is the first pharmacogenomics study of BIP in South East Asian patients, looking at both candidate gene and GWAS analyses. Our results suggest that iron regulation could be the driver in the etiopathogenesis of BIP, supporting the utility of H63D testing in the risk stratification of patients receiving Bleomycin. Moreover, GWAS analyses have discovered 4 novel markers that suggest an association with BIP, which will be further evaluated and should be independently replicated in a larger cohort. DisclosuresChng:Celgene: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Takeda: Consultancy, Honoraria, Other: Travel, accommodation, expenses; Janssen: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Merck: Research Funding; Amgen: Consultancy, Honoraria, Other: Travel, accommodation, expenses; Aslan: Research Funding.

Delivery of chemotherapy for testicular cancer in routine practice: A population-based study

IntroductionMaintenance of chemotherapy dose intensity is a cornerstone of management in testicular germ cell tumors. We describe chemotherapy delivery and outcomes of patients in routine practice. MethodsThe Ontario Cancer Registry was linked to electronic records of treatment to identify patients diagnosed with testicular cancer treated with orchiectomy and chemotherapy from 2005 to 2010. We describe chemotherapy delivery and dose intensity. Overall survival was measured from the start of chemotherapy. ResultsDuring the study period, 552 new cases of testicular cancer were treated with orchiectomy and chemotherapy; drug/regimen details were available for 475 (86%) cases. The study population included 324 patients with nonseminoma and 151 with seminoma. The majority of patients were treated with bleomycin, etoposide, and cisplatin (BEP) (83%, 394/475) or etoposide and cisplatin (EP) (6%, 30/475); 89% (379/424) received 3 to 4 cycles of treatment. Thirty two percent of all BEP patients (125/394) had at least 1 dose omission of bleomycin; this rate increased to 51% of patients treated with BEP × 4. Eight percent (33/397) of evaluable BEP/EP patients had a dose reduction/omission of cisplatin and 21% (82/397) had a dose delay of >6 days. Among the BEP/EP cases, 44% (174/397) had reduced chemotherapy dose intensity. Five-year overall survival for all cases was 95%. ConclusionsAlmost half of patients treated with BEP/EP chemotherapy in routine practice have some form of reduced chemotherapy delivery. Despite this, long-term survival in the general population is very high. Further studies are required to understand the extent to which dose delivery might influence outcomes.

Outcomes of Chemotherapy Treatment in Elderly Patients with Hodgkin Lymphoma

Introduction: Hodgkin lymphoma (HL) is a common lymphoid malignancy accounting for approximately 10 percent of all lymphomas. In the United States (US), the incidence of HL has a bimodal distribution curve with peaks at age 20 years and a second peak at approximately age 65 years. Age of diagnosis is an important prognostic marker in HL with younger patients having superior outcomes. Patients diagnosed at greater than age 60 years are considered elderly. Prior analyses of HL treatment in elderly patients have revealed worse outcomes in this population with reported 5-year progression free survival (PFS) and overall survival (OS) from 30-45% and 40-60% ranges, respectively (Evens, Blood 2012). The most common first line treatment for HL is doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). Elderly patients are thought to have higher risk of bleomycin toxicity and worse outcomes with treatment in comparison to younger patients. Omission of bleomycin or doxorubicin from chemotherapy regimens administered to elderly patients is not uncommon. This study evaluated treatment outcomes of HL in an elderly U.S. Veteran population.Methods: The VHA database was used to identify patients diagnosed with HL using ICD-03 codes C000-C8099, 9651, 9652, 9653-9655, 9663-9667, 9650, 9661-9662, and 9659. Data was available from the Veterans Affairs Central Cancer Registry (VACCR) from October 1st, 2001-December 31st 2013. Data was obtained on patient demographics, weight, height, other clinical characteristics, date of diagnosis and HL directed treatments. Chemotherapeutic agents patients received were collected from the VACCR data and missing data was abstracted using chart review. Patients who received at least one dose of any chemotherapy for HL were considered to have received chemotherapy. Of patients who received chemotherapy, those who received at least one dose of bleomycin or doxorubicin were included in the bleomycin and doxorubicin groups respectively. Patients less than age 60 years were excluded. Patients greater than age 60 years were stratified by age into age groups 61-69 and ≥70 years. Overall survival was measured from date of diagnosis to date of death. Kaplan-Meier method for overall survival was used to evaluate each treatment group. Cox proportional hazard model was used to evaluate risk of death after adjusting for age (61-69 years used as reference) and chemotherapy used (bleomycin or doxorubicin).Results: There were 1,135 unique HL patients [632 (56%) patients ≤ age 60 years, 503 (44%) patients >age 60 years] identified in the VHA database. For patients age years >60, 389 patients (77%) received chemotherapy; with 226 (58%) patients age years 61-69 and 163 (42%) age years ≥70. Bleomycin was administered to 177 (78%) patients age years 61-69 and 106 (65%) patients age years ≥70 (p=0.037). Doxorubicin was administered to 198 (88%) patients age years 61-69 and to 122 (75%) patients age years ≥70 (p=0.0012). Cox proportional hazards analysis demonstrated that patients ≥70 years had a worse overall survival (HR = 1.71; 95% CI 1.276-2.293) in comparison patients age 61-69 years. After adjusting for age and chemotherapy, treatment with doxorubicin (HR 0.67; 95% CI 0.416-1.084) or bleomycin (HR 0.77; 95% CI 0.512-1.192) was associated with an improved survival.Conclusions: This retrospective analysis represents the largest cohort of elderly HL patients with detailed treatment information reported to date. Advanced age (age ≥70 years) was confirmed to be a poor prognostic factor. The chemotherapy agents used in elderly patients also differed by age with less doxorubicin and bleomycin administered to patients age ≥70 years in comparison to those age years 61-69. While not statistically significant, this study demonstrated improved survival in patients receiving bleomycin or doxorubicin regardless of age. Further analyses adjusting for patient comorbidities, evaluating for treatment related toxicity (i.e. pulmonary toxicity) and accounting for cause specific mortality are pending. DisclosuresReagan:Seattle Genetics: Research Funding. Carson:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.

Response-adapted frontline therapy for Hodgkin lymphoma: are we there yet?

Treating Hodgkin lymphoma by using chemotherapy with or without radiotherapy is highly successful, with substantially fewer deaths from lymphoma than from other causes in recent studies of both early-stage and advanced-stage disease. Long-term toxicity is a major consideration in this context, and recent trials have used functional imaging with [18F]fluorodeoxyglucose (FDG) positron emission tomography early in the course of treatment (interim PET) to assess response and modulate subsequent therapy. In early-stage disease, this has allowed omission of consolidation radiotherapy after a good response to doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) chemotherapy, and trials have shown that this can be done without detriment to overall survival, despite a small increase in rates of recurrence of ∼5%. Conversely, escalation to more intensive chemotherapy with bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) for those with positive interim PET scans seems to be an effective strategy with improved disease control. In advanced-stage disease, several groups have elected to start treatment with ABVD and escalate to BEACOPP or myeloablative therapy for patients who remain PET positive after 2 cycles, which gives rates of disease control of ∼65%. De-escalation by omission of bleomycin and consolidation radiotherapy after a negative interim PET scan seems safe with no increase in recurrence rate, but the performance of interim PET after ABVD is suboptimal, especially for those with very advanced disease at presentation; recurrence rates after a negative scan are ∼15%. The negative predictive value of PET is higher after escalated BEACOPP chemotherapy, and the approach of initially treating with BEACOPP and de-escalating to ABVD for those with negative interim PET scans shows promising early results. Response-adapted therapy has yielded important results for patients with Hodgkin lymphoma and is becoming established as a standard approach.

Adapted Treatment Guided by Interim PET-CT Scan in Advanced Hodgkin’s Lymphoma

BackgroundWe tested interim positron-emission tomography–computed tomography (PET-CT) as a measure of early response to chemotherapy in order to guide treatment for patients with advanced Hodgkin’s lymphoma.MethodsPatients with newly diagnosed advanced classic Hodgkin’s lymphoma underwent a baseline PET-CT scan, received two cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) chemotherapy, and then underwent an interim PET-CT scan. Images were centrally reviewed with the use of a 5-point scale for PET findings. Patients with negative PET findings after two cycles were randomly assigned to continue ABVD (ABVD group) or omit bleomycin (AVD group) in cycles 3 through 6. Those with positive PET findings after two cycles received BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone). Radiotherapy was not recommended for patients with negative findings on interim scans. The primary outcome was the difference in the 3-year progression-free survival rate between randomized groups, a noninferiority comparison to exclude a difference of 5 or more percentage points.ResultsA total of 1214 patients were registered; 937 of the 1119 patients (83.7%) who underwent an interim PET-CT scan according to protocol had negative findings. With a median follow-up of 41 months, the 3-year progression-free survival rate and overall survival rate in the ABVD group were 85.7% (95% confidence interval [CI], 82.1 to 88.6) and 97.2% (95% CI, 95.1 to 98.4), respectively; the corresponding rates in the AVD group were 84.4% (95% CI, 80.7 to 87.5) and 97.6% (95% CI, 95.6 to 98.7). The absolute difference in the 3-year progression-free survival rate (ABVD minus AVD) was 1.6 percentage points (95% CI, −3.2 to 5.3). Respiratory adverse events were more severe in the ABVD group than in the AVD group. BEACOPP was given to the 172 patients with positive findings on the interim scan, and 74.4% had negative findings on a third PET-CT scan; the 3-year progression-free survival rate was 67.5% and the overall survival rate 87.8%. A total of 62 patients died during the trial (24 from Hodgkin’s lymphoma), for a 3-year progression-free survival rate of 82.6% and an overall survival rate of 95.8%.ConclusionsAlthough the results fall just short of the specified noninferiority margin, the omission of bleomycin from the ABVD regimen after negative findings on interim PET resulted in a lower incidence of pulmonary toxic effects than with continued ABVD but not significantly lower efficacy. (Funded by Cancer Research UK and Others; ClinicalTrials.gov number, NCT00678327.)

Doxorubicin, Vinblastine and Dacarbazine with or without Bleomycin for Older Patients with Early Stage Favorable Hodgkin Lymphoma: An Analysis of the German Hodgkin Study Group (GHSG) HD10 and HD13 Trials

IntroductionBleomycin is commonly omitted from the ABVD regimen (doxorubicine, vinblastine, dacarbazine and bleomycin) in older Hodgkin Lymphoma (HL) patients due to excessive toxicity, particularly bleomycin-induced lung toxicity (BLT). Very recently, however, the GHSG HD13 trial indicated that the omission of bleomycin from the ABVD regimen has a negative impact on efficacy (Behringer et al., EHA 2014). Given the high rate of BLT in older patients, the role of bleomycin in the ABVD regimen for this particular group of patients is still unclear. We therefore analyzed feasibility, toxicity and efficacy of ABVD or AVD in 287 older early stage favorable HL patients.MethodsAs described in detail previously elsewhere, HD10 and HD13 were prospective, randomized international multicenter trials including early stage favorable HL patients defined as stages I and II without any of the GHSG risk factors (Engert et al. NEJM 2010). For the present study, we focused on older HL patients (≥60 years), who were randomized to receive either 2 cycles ABVD (2 x ABVD) or AVD, in both cases followed by either 20 or 30 Gy involved-field radiotherapy (IF-RT). To estimate cumulative BLT, we also analyzed older HL patients who received 4 x ABVD followed by IF-RT in the HD10 trial.Results287 patients with a median age of 65 years (range 60-75) were included with an equal distribution of gender, IPS scores, histology and age between the treatment groups.Treatment consisted of 2 x ABVD in 137 patients (HD10 and HD13), 2 x AVD in 82 patients (HD13), and 4 x ABVD in 68 patients (HD10). Pulmonary function test (PFT) prior to therapy was available for 117 patients (HD13 only) showing impaired PF in 14 (26%) and 9 (15%) of the patients randomized to receive ABVD or AVD, respectively.Although patient numbers were too small to draw statistically sound conclusions, in our analysis, patients treated with AVD tended to receive higher relative dose intensity than patients treated with 2 x ABVD. Early termination of chemotherapy was only observed in 1 patient of each treatment arm.Overall, frequency of grade III-IV adverse events was similar for both patient groups. Respiratory adverse events were rare even in patients receiving 2 cycles of bleomycin (1 and 0 cases with 2 x ABVD and AVD, respectively). However, BLT occurred in 6 patients (9%) receiving 4 cycles ABVD and was lethal in half of the affected patients. PFTs or (chest x-ray) within two years after therapy were available for 80 HD13 patients and showed pathological results for 2 patients each out of 34 and 46 patients treated with 2 x ABVD or AVD, respectively.Regarding the efficacy, patient numbers were far too small for testing on (non-)inferiority of the AVD regimen as done in the HD13 trial. However, differences in PFS and OS were about the same magnitude as observed in the HD13 trial (Behringer et al., submitted), indicating that the effect of bleomycin on efficacy observed in this trial does also hold true for the subgroup of older patients.ConclusionIn this study of 219 older early stage favorable HL patients treated with 2 cycles of either ABVD or AVD, no significant effect of bleomycin on the incidence and severity of adverse events was detectable. In contrast, the additional 67 older patients receiving 4 x ABVD had more grade III/IV toxicity and a strikingly higher rate of BLT, indicating a cumulative toxicity of bleomycin in older HL patients. DisclosuresOff Label Use: Everolimus in relapsed or refractory Hodgkin Lymphoma. von Tresckow:Novartis: Honoraria, Research Funding; Takeda: Honoraria, Travel grants, Travel grants Other. Borchmann:Takeda: Honoraria, Research Funding, Travel grants Other.

Bleomycin induced flagellate erythema: Revisiting a unique complication

Bleomycin induced flagellate dermatitis is a rare and unique adverse effect. With the declining use of bleomycin, this complication is becoming increasingly infrequent in common clinical practice. We herein describe a case of a 22-year-old Indian male with Hodgkin's lymphoma, Ann Arbor stage IIBEX developing flagellate dermatitis following 1(st) cycle of chemotherapy with ABVD regimen. The diagnostic dilemma in the illustrative case underscores the importance of awareness and prompt identification and treatment of this dermatological toxicity in limiting morbidity in patients undergoing bleomycin based combination chemotherapy. In patients having severe rash, bleomycin should be expeditiously discontinued. Omission of bleomycin does not compromise the treatment outcome in the majority of patients with Hodgkin's lymphoma.

Prognostic impact of bleomycin-induced pneumonitis on the outcome of Hodgkin’s lymphoma

Bleomycin-induced pneumonitis (BIP) has been well described in Hodgkin's lymphoma (HL) patients. The impact of BIP on patients uniformly treated with adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) is not clear; previous studies have included patients treated with both ABVD and hybrid regimens. We reviewed our experience with BIP in HL to better understand the impact of BIP on overall survival. One hundred and eighty four consecutive patients who were treated with ABVD for newly diagnosed HL were eligible for retrospective review. BIP was defined by the presence of pulmonary symptoms, bilateral interstitial infiltrates on chest X-ray, computed tomography or presence of lung fibrosis on transbronchial lung biopsy, and the absence of infection. Patients were required to meet all three criteria to be included in the BIP group. BIP was observed in 28 patients (15%). A low albumin level and the use of colony granulocyte stimulating factor were associated with a higher risk of developing BIP. Age, smoking history, and underlying lung function were not predictive of BIP. Importantly, patients with BIP had similar rates of 5-year overall survival compared to unaffected patients. There were no deaths from BIP. Omission of bleomycin from subsequent treatment did not adversely affect the outcomes.

Analysis of long-term treatment outcomes and toxicty of HL

e19536 Background: Prognosis of patients with Hodgkin lymphoma (HL) has substantially improved but therapy of HL can however contribute to delayed toxicity. Long term treatment outcomes of HL in our local population were evaluated. Methods: Clinical and treatment data was prospectively collected from all patients with a histological diagnosis of HL. Patients were all fully staged with CT scan and bone marrow biopsy. Results: On the basis of 217 patients seen at the National Cancer Centre Singapore between 1990–2008, we found that there was a peak in young adulthood with 103 patients who were diagnosed before the age of 30 (48%), median age of presentation 32 (range 17–84). Patients who were young (&lt; 30 years) were more likely to present with nodular sclerosis HL (p=0.0001). Treatment outcomes were comparable to other published series, 85% of cases received ABVD based treatment. 5 year OS for early stage HL was 92% and 88% for advanced stage HL. Overall FFTF was 93% at 5 years. Of note, comparing patients with early stage (Stage I/ II) HL (n=114) who had ABVD 4 cycles followed by involved field radiotherapy (IFRT) with those who received 6–8 cycles of ABVD, there was no difference in OS, FFTF (p= 0.99, 0.48 respectively). Bulky early stage HL who received 6 cycles of ABVD and IFRT had better FFTF rates than those who had just 4 cycles of ABVD followed by IFRT (p=0.06). In contrast, patients patients with advanced HL (Stage III/ IV) (n=70) who completed 6–8 cycles of ABVD did not benefit from additional IFRT even in the presence of bulky disease (n=15). Acute toxicities included that of bleomycin induced pneumonitis (BIP) seen in 15% of cases. Neither the omission of bleomycin nor the presence BIP adversely affected treatment outcomes. Hematological malignancies were seen in 1% of survivors appearing after a median of 7.3 years. Hypothyroidism was noted in 3% of cases. Conclusions: 1) Epidemiology of HL in Singapore is increasingly similar to that of developed countries with a peak in young adults. 2)Young age was predictive of a nodular sclerosis subtype 3) Abbreviated chemotherapy using 4 cycles of ABVD followed by IFRT performed similarly to 6 cycles of ABVD in early stage HL, but in patients with bulky disease this may not be sufficient. 4) BIP occurred in 15% of cases. BIP and the omission of bleomycin did not adversely affect treatment outcomes. No significant financial relationships to disclose.

Flagellate erythema due to bleomycin

A 48-year-old woman, recently diagnosed with classical Hodgkin lymphoma stage 3B, developed an intensely itchy rash 1 week after her first cycle of doxorubicin, bleomycin, vincristine, dacarbazine (ABVD) chemotherapy. The eruption subsided with a course of prednisolone 40 mg daily for 4 d, but recurred after the third chemotherapy cycle, despite the omission of bleomycin. She was referred to dermatology at this stage. Examination showed an extensive violaceous and erythematous excoriated rash with a striking linear configuration and post-inflammatory hyperpigmentation, typical of flagellate erythema. Clobetasol proprionate cream twice daily was prescribed with good response. After 1 week, the inflammatory lesions had settled, leaving residual hyperpigmentation that was expected to settle with time. There has been no recurrence at 3 months follow-up. Flagellate erythema is a cutaneous side effect of bleomycin or its derivative peplomycin. The term ‘flagellate’ derives from the Latin flagellum, referring to the characteristic whip-like appearance. It is also rarely associated with ingestion of shiitake mushrooms, dermatomyositis and adult-onset Still’s disease. All methods of administration of bleomycin may cause the rash, occurring from 12 h to as long as 6 months after drug administration. The rash usually subsides 3–4 months following discontinuation of the drug. It is unusual that our patient had a relapse after chemotherapy omitting bleomycin, suggesting a possible unusual recall phenomenon, particularly as flagellate erythema has not been described with the other drugs in the ABVD regime. Treatment includes topical or systemic corticosteroids and oral antihistamines. The length of treatment depends on clinical response. The mechanism for the peculiar linear nature of this reaction remains uncertain.