Consolidation Therapy After ASCT in Hodgkin Lymphoma: Why and Who to Treat?

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Consolidation Therapy After ASCT in Hodgkin Lymphoma: Why and Who to Treat?

Introduction

The combined use of effective multidrug chemotherapy regimens and radiation over the past few decades has led to significant improvements in the prognosis of Hodgkin lymphoma, making achievement of a cure a clinical reality for the majority of patients.1 With current therapies, long-term tumor control may be achieved in 70%-80% of patients.1 However, a subset of patients do not respond to frontline therapy or relapses following initial response. For these patients with relapsed/refractory disease, the treatment options have been limited and prognosis has been poor, underscoring the need for novel therapeutic approaches.1

Brentuximab vedotin (ADCETRIS®) is an antibody-drug conjugate that comprises an anti-CD30 monoclonal antibody (SGN-30) attached by a protease-cleavable dipeptide linker to a microtubule-disrupting agent, monomethyl auristatin E, which has shown remarkable antitumor activity in patients with advanced Hodgkin lymphoma.2 Single-agent brentuximab vedotin demonstrated considerable efficacy in a pivotal phase 2 study of 102 patients with advanced Hodgkin lymphoma who had received previous autologous stem-cell transplantation (ASCT), resulting in an objective response rate (ORR) of 75% and a complete response (CR) rate of 34%, which were durable and associated with long-term survival.2,3 In addition to its previous approval for advanced Hodgkin lymphoma, brentuximab vedotin was also recently approved in the European Union as consolidation therapy in patients at increased risk for relapse or progression following ASCT, based on the results of the AETHERA trial.4

In July 2016, an expert roundtable was convened to discuss consolidation therapy as an emerging treatment approach in the management of patients with advanced Hodgkin lymphoma and the practice implications of this strategy. Roundtable participants included 3 key opinion leaders in Hodgkin lymphoma: (1) Andreas Engert, MD, Professor, Internal Medicine, Haematology, and Oncology, University Hospital of Cologne, Cologne, Germany; (2) Anton Hagenbeek, MD, PhD, Professor, Hematology, University of Amsterdam, Amsterdam, the Netherlands; and (3) Anna Sureda, MD, PhD, Head, Hematology Department and Hematopoietic Stem Cell Transplant Programme, Institut Català d’Oncologia–Hospital Duran I Reynals, Barcelona, Spain. This panel deliberated on the current evidence for consolidation therapy with brentuximab vedotin in patients with Hodgkin lymphoma, as well as on major considerations in the identification of risk factors for relapse following ASCT that inform patient selection for consolidation treatment with brentuximab vedotin. This publication is a synthesis of the discussions and recommendations of these experts, with the overall goal of communicating the evolving trends in the management of patients with Hodgkin lymphoma.

Rationale for Consolidation Therapy

The current standard of care for the majority of patients with advanced Hodgkin lymphoma after relapse is high-dose chemotherapy followed by ASCT for chemosensitive candidates (Figure 1).5 Unfortunately, approximately 50% of these patients will subsequently relapse.6 Putting this relapse rate in perspective, the panel clarified that, by calculating from the time of first relapse, only a small proportion of patients (approximately 25%-30%) achieve durable remission or cure after relapse or primary refractoriness. Risk factors that identify patients who are most likely to benefit from ASCT include low tumor burden at diagnosis, receiving an autograft after a long CR, and having no detectable disease at ASCT.7

figure1_cps1161_specialissue

Historically, the prognosis for patients who relapse following ASCT has been poor, with a median postprogression survival of 1.3 years and a median overall survival (OS) of 2.4 years.8 No standard treatment options have been available for patients who relapse following high-dose chemotherapy and ASCT.5 The use of chemotherapy following ASCT has been associated with CR rates of only up to 17%.9 Until the recent approval of brentuximab vedotin as consolidation therapy following ASCT, several treatment strategies, including tandem transplantation, intensification of conditioning regimen, and consolidation chemotherapy, have not improved outcomes in this setting.10

Although reduced-intensity conditioning allogeneic stem-cell transplantation (alloSCT) may be curative in a significant proportion of eligible patients, it is not regarded as a standard treatment approach in Hodgkin lymphoma.5 Noting that other very effective and less toxic therapies such as brentuximab vedotin or checkpoint inhibitors have recently become available, Dr Sureda indicated that alloSCT in patients with high transplant risk or high comorbidity index should be avoided.

The expert panel agreed that relapse after high-dose chemotherapy and ASCT not only has adverse implications in terms of prognosis, but is also associated with substantial physical burden because of the need for additional treatment, which is compounded by increased hospitalizations and outpatient visits. Importantly, there is also a considerable psychologic burden associated with prognosis and treatment, as well as the impact of missed workdays for patients and caregivers.

Taking into account all of these factors, the panel agreed that a clear medical need exists in Hodgkin lymphoma for effective treatment options that result in sustained disease control after ASCT and relapse prevention in patients at increased risk for relapse.

Current Evidence for Consolidation Therapy

Although the concept of consolidation therapy is relatively new in Hodgkin lymphoma, the panel indicated that a large body of evidence supports the successful implementation of consolidation in hematologic malignancies, including acute myeloblastic leukemia and multiple myeloma. In myeloma, consolidation after ASCT typically refers to a short period of intensive treatment with a single agent or a combination of agents.11 Despite presently being restricted to clinical trials, it is regarded as an emerging strategy for providing sustained disease control, improving depth of response, preventing repeated relapses, and, importantly, increasing rates of minimal residual disease (MRD) negativity.11 In acute myeloblastic leukemia, higher doses of cytosine arabinose as postremission consolidation therapy have been shown to cure up to 40% of younger adults, although there is no consensus on the standard regimen to use.12

The panel experts defined MRD as viable Hodgkin cells that remain following the achievement of “complete” remission, but are below the limits of detection using conventional assessments such as 18F-fluorodeoxyglucose positron emission tomography (PET); MRD is hypothesized to be a predictor of relapse and overall outcome. However, they clarified that no validated techniques are yet available and that a PET scan is currently the most sensitive way to analyze MRD. Considerable research efforts are underway to identify soluble factors as biomarkers of MRD and to develop sensitive assays to measure it. In the context of standard chemotherapy and ASCT for Hodgkin lymphoma, the panel defined consolidation as a short, intense, active treatment that is intended to cure the patient by eliminating MRD still present after the last therapy. In contrast, the experts clarified that the primary goal of maintenance therapy, a postremission strategy used in many cancer types to improve outcomes, is to maintain response until disease relapse/progression or unacceptable side effects using a less intense and long-term treatment. Overall, the panel noted that it is a matter of semantics whether treatment is delivered in 2 months or 12 months, and that the main goal of therapy at this treatment juncture is to eradicate any residual malignant cells that survived high-dose chemotherapy to prevent relapse.

The randomized, double-blind, placebo-controlled, phase 3 AETHERA trial evaluated whether patients with an increased risk for relapse following ASCT would benefit from early consolidation therapy with brentuximab vedotin as a way of extending the effect of transplantation and preventing relapse.10 In this trial, 329 patients with histologically confirmed classical Hodgkin lymphoma, who had undergone high-dose chemotherapy and ASCT, were randomized to receive 16 cycles of brentuximab vedotin (N = 165) or placebo (N = 164), administered intravenously every 3 weeks and initiated 30 to 45 days after transplantation. Eligible patients must have achieved CR, partial remission (PR), or stable disease (SD) after pretransplantation salvage therapy, and ≥1 of the following risk factors for post-ASCT progression needed to be present: (1) primary refractory Hodgkin lymphoma (defined as progression or no CR after frontline treatment); (2) relapsed or progressive disease within 12 months of frontline therapy; or (3) extranodal involvement upon initiation of pre-ASCT salvage therapy. Patients in both treatment groups received a median of 15 cycles once every 3 weeks.10

At a median follow-up of 30 months, consolidation with brentuximab vedotin therapy following ASCT was associated with a significant improvement in the primary end point of progression-free survival (PFS) in patients with Hodgkin lymphoma (median PFS, 42.9 months [95% confidence interval (CI), 30.4-42.9] with brentuximab vedotin vs 24.1 months [95% CI, 11.5-not estimable] with placebo; hazard ratio [HR], 0.57; P = .0013) by independent review.10 The estimated 2-year PFS rate in the brentuximab vedotin group was significantly higher than that in the placebo group (63% vs 51%; Figure 2).10 Prespecified subgroup analysis showed that this PFS benefit also extended across patient subgroups, including response to salvage therapy pre-ASCT, age, Hodgkin lymphoma status after frontline therapy, B symptoms after frontline therapy, and extranodal involvement pre-ASCT.10

figure2_cps1161_specialissue

Updated 3-year results of the AETHERA trial showed sustained improvement in PFS in the brentuximab vedotin group compared with the placebo group, with a PFS rate per investigator of 61% versus 43%, respectively (95% CI, 53-68 vs 36-51, respectively).13 The panel suggested that the emerging plateau in the PFS curves potentially indicate that the majority of patients with Hodgkin lymphoma may be cured with consolidation therapy, based on evidence that relapses typically occur within the first 2 years of treatment.

Updated results also showed that among patients who relapsed and went on to receive subsequent therapy (N = 139), 84% of those in the placebo group received single-agent brentuximab vedotin therapy and achieved an ORR of 67%.13

The panel also addressed the lack of a difference in OS between the 2 treatment groups in the AETHERA trial, which they attributed mainly to the confounding effect of the crossover trial design and the efficacy of the salvage therapy that patients received. Since PFS is not influenced by such effects, the panelists agreed that PFS was the best true measure of the activity of brentuximab vedotin in this trial. They also pointed out that the trial was not statistically powered to demonstrate a difference in OS. Moreover, it was noted that the presence of 1 risk factor alone may not have been sufficient to define high-risk disease in the study population, potentially limiting the impact of the results. In the study, the placebo group also demonstrated a PFS rate of approximately 50% at 24 months,10 which is not consistent with a true high-risk patient population.

In terms of safety, the most common treatment-emergent adverse events (all grades) in the brentuximab vedotin group included peripheral neuropathy (56%) and neutropenia (56%), with grade 3 peripheral neuropathy reported in 10% of patients (there were no grade 4 events) and grade 3/4 neutropenia in 29% of patients. In addition, 1 patient developed febrile neutropenia, and grade 3 or higher severe infections were reported in 7% of patients in the brentuximab vedotin group.10 The median time to onset of peripheral neuropathy in the brentuximab vedotin group was 13.7 weeks. Peripheral neuropathy either resolved or improved in 85% of patients who experienced the event, with a median time to resolution of 23.4 weeks. Overall, 23% of patients discontinued brentuximab vedotin therapy because of peripheral neuropathy, and 31% required dose modification (dose reduction or delay).10 Sweetenham and colleagues reported that during the extended follow-up of the trial, symptoms of peripheral neuropathy continued to improve or resolve.13

Neutropenia resulted in dose delays in 22% of patients treated with brentuximab vedotin, but did not require dose reductions or treatment discontinuation. It was managed with growth factor support, with 25% of patients in the brentuximab vedotin group receiving this intervention.10

The panel emphasized that the timing of consolidation therapy is critical for optimal patient outcomes. Dr Hagenbeek explained that consolidation therapy was initiated 30 to 45 days after transplantation in the AETHERA trial, to eradicate the remaining residual malignant cells and achieve maximum benefit. Dr Engert elaborated that “In patients who are destined to relapse, treatment delay may create an environment for proliferation of residual cancer cells, resulting in a larger tumor load.” Supporting this design element of the study, it was revealed that early differences between the 2 treatment arms may be discerned in the survival curves of the trial, indicating that brentuximab vedotin was effective in decreasing very early relapses following transplantation. However, the panel cautioned that consolidation therapy should not be initiated too early and that treatment should be dictated by the patient’s hematologic recovery following transplantation, so that the autologous stem cell graft is not jeopardized.

Overall, given the curative potential of the combined strategy of brentuximab vedotin consolidation therapy following ASCT observed in the AETHERA trial, the panel concurred that it was a clinically meaningful evidence-based treatment for patients with advanced Hodgkin lymphoma.

Patient Selection Criteria for Consolidation Therapy

To guide clinical treatment decisions, to determine which patients are most likely to benefit from treatment, and to avoid unnecessary treatment in those who will not benefit, it is critical to identify reliable risk factors.7 In the AETHERA trial, the 3 risk factors selected to define patients at increased risk for relapse were: (1) primary refractory Hodgkin lymphoma; (2) relapsed or progressive disease within 12 months; and (3) extranodal involvement on initiation of pre-ASCT salvage therapy.10 Dr Sureda noted that more rigorous studies on prognostication were not available when the AETHERA trial was designed, and that the choice of risk factors was based on the best available information at that time. She also noted that PET imaging results were not included among the risk factors in AETHERA, because the study was designed before this modality was widely available in all the countries that were part of the study group consortium.

The consensus of the panel was that 2 of the 3 risk factors were subjective measures of risk and may be difficult to apply in clinical practice. Diagnosing extranodal disease was considered to be challenging even for experts in the field of Hodgkin lymphoma. Dr Engert noted that patients who experienced residual disease after initial treatment would qualify for the AETHERA trial and this may be inappropriate, because many patients with Hodgkin disease still have residual disease after frontline treatment.

Much discussion among the panel experts revolved around which patient population, based on risk stratification, benefited from consolidation therapy in the AETHERA trial. Data showed that the greatest PFS benefits were observed in patients with pre-ASCT responses of PR (HR, 0.459) or SD (HR, 0.390); those with extranodal disease at relapse despite pre-ASCT PET negativity (HR, 0.378) or CR (HR, 0.507); and those with ≥2 risk factors for progression (HR, 0.412), including those who had achieved CR before transplantation (HR, 0.504).13 Importantly, although the presence of 1 of the 3 risk factors was deemed sufficient for study inclusion, the experts noted that in the subgroup analysis, it was unclear whether patients with 1 risk factor benefited from consolidation therapy, and they expressed concern about the potential for overtreatment in this subset. The panel noted that interpretation of results of the subgroup analysis must be made with caution, because the patient numbers in each subgroup were less than those in the total patient population. Therefore, larger studies are warranted to validate these results.

Since the AETHERA trial was conducted, several ongoing research efforts have focused on identifying new prognostic biomarkers in advanced Hodgkin lymphoma. In newly diagnosed advanced disease, the International Prognostic Score, a retrospectively constructed clinical model based on 7 clinical risk factors, is the best validated clinical risk stratification index for predicting the outcome of patients and is commonly used for prognostication purposes.14 By contrast, in relapsed/refractory disease, treatment stratification based on prognostic factors is not standard clinical practice. Nonetheless, several clinical biomarkers and functional imaging are increasingly being shown to have prognostic value in this setting. These risk factors may identify a subset of patients with advanced Hodgkin lymphoma who are at increased risk for relapse and who may potentially be candidates for consolidation therapy.

Current efforts to improve risk prognostication in advanced Hodgkin lymphoma are building upon previous work conducted by European and US researchers. In 2001, the German Hodgkin Study Group (GHSG) developed a comprehensive risk score based on data from 422 patients who relapsed after frontline treatment. Time to relapse, clinical stage at relapse, and anemia (<105 g/L for women, <120 g/L for men) were identified as risk factors for freedom from second treatment failure and OS.15 In the United States, the Memorial Sloan Kettering Cancer Center group also developed a scoring system based on results of a 2-step protocol of dose-dense and dose-intense second-line chemotherapy, followed by high-dose chemoradiotherapy and ASCT. It identifies 3 risk factors for event-free survival: (1) CR duration of 1 year or primary refractory disease; (2) extranodal involvement of less than 1 year; and (3) B symptoms at relapse.16

More recently, the GHSG developed a prognostic score for PFS after ASCT using a comprehensive set of >20 previously described risk factors in a large population of patients (N = 1045) with relapsed/refractory Hodgkin lymphoma.17 Multivariate analysis determined that 5 clinical risk factors were significant: (1) stage IV disease; (2) time to relapse ≤3 months; (3) Eastern Cooperative Oncology Group (ECOG) performance status ≥1; (4) bulk ≥5 cm; and (5) inadequate response to salvage chemotherapy.17 Dr Engert noted that each of these factors represents a different dimension that impacts patient outcomes. For example, stage IV disease indicates advanced stage, relapse within 3 months denotes aggressive disease, and ECOG stage shows the patient’s condition. Using these risk factors, a prognostic score was computed, which allowed delineation of 4 different prognostic groups, each with a distinct PFS rate.17

Regarding the potential eligibility of the 4 risk groups identified by the GHSG for consolidation therapy with brentuximab vedotin, the panel agreed that the discriminatory ability of this risk model represented an important step forward from a clinical perspective. Dr Engert indicated that based on the 5-year PFS rate in each of the risk groups, it was clear the group with 0 risk factors should not be treated, whereas the groups with ≥2 risk factors would be eligible for treatment. Although the presence of 1 risk factor was associated with a statistically significant difference in PFS and OS, he noted that there may be opportunities for improved prognostication in this group, given the advances in emerging technologies, and he recommended the evaluation of other factors, such as PET positivity. It was suggested that, in the future, MRD measurement and PET imaging may be useful in this setting in addition to the 5 clinical risk factors identified by the GHSG. Current evidence indicates that PET is an emerging determinant of disease that may discriminate between good and poor responders in Hodgkin lymphoma.14

Taken together, appropriate patient selection is clearly important to identify those who may or may not benefit from consolidation therapy with brentuximab vedotin; however, it is less apparent which risk factors are reliable and can be easily applied to clinical practice. Based on current evidence, patients with ≥2 risk factors and relapse <12 months are associated with the highest probability of relapse following ASCT, and are, therefore, candidates for consolidation therapy.

Other Considerations

The expert panel concurred that the communication of recent advances in the management of advanced Hodgkin lymphoma to the broader hematology and oncology community is critical for optimal application in clinical practice. In Europe, these advances will most likely be adopted into national guidelines before they are included in European Society of Medical Oncology guidelines. The panel suggested that the initiation of discussions on consolidation therapy at large international oncology meetings–including the annual European Hematology Association and the International Symposium on Hodgkin Lymphoma meetings–as well as the dissemination of information via online and print media, will facilitate increased awareness of important emerging data.

Conclusions

The panel agreed that brentuximab vedotin is a novel therapeutic option for consolidation therapy in patients with Hodgkin lymphoma who are at increased risk for relapse. Dr Sureda noted that, “a significant portion of patients who have a chemosensitive relapse have not been cured with what we conceive as the standard of care. And in this setting, consolidation strategies are very much welcomed and potentially indicated from a clinical point of view.” However, the panel noted that it is important to select patients who are at increased risk for relapse, to prevent these occurrences as well as to avoid overtreatment in patients who may not benefit from additional therapy. Although potential risk factors that may identify those at higher risk have been determined, more clarification is needed on which of these factors can be reliably and readily implemented into clinical practice. The risk model developed by the GHSG represents an important step toward improved prognostication; however, the panel agreed that additional opportunities may exist to better define those patients most likely to benefit.

Overall, the expert consensus was that the current level of evidence supports the establishment of consolidation therapy with brentuximab vedotin as a standard of care for patients with Hodgkin lymphoma at increased risk for relapse or progression following ASCT.

References

  1. Engert A. Non-Hodgkin’s lymphoma: who needs consolidation treatment? Lancet. 2015;385:1810-1812.
  2. Younes A, Gopal AK, Smith SE, et al. Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin’s lymphoma. J Clin Oncol. 2012;30:2183-2189.
  3. Chen R, Gopal AK, Smith SE, et al. Five-year survival data demonstrating durable responses from a pivotal phase 2 study of brentuximab vedotin in patients with relapsed or refractory Hodgkin lymphoma. Presented at: 57th American Society of Hematology (ASH) Annual Meeting & Exposition; December 5-8, 2015; Orlando, FL. Abstract 2736.
  4. Adcetris (Brentuximab vedotin). Summary of Product Characteristics (SmPC). Denmark: Takeda Pharma A/S; 2016.
  5. Eichenauer DA, Engert A, Dreyling M; on behalf of the ESMO Guidelines Working Group. Hodgkin’s lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2011; 22(suppl 6):vi55-vi58.
  6. Kuruvilla J, Keating, Crump M. How I treat relapsed and refractory Hodgkin lymphoma. Blood. 2011;117:4208-4217.
  7. Sureda A, Constans M, Iriondo R, et al; for The Grupo Español de Linfomas/Trasplante Autólogo de Médula Osea (GEL/TAMO) Cooperative Group. Prognostic factors affecting long-term outcome after stem cell transplantation in Hodgkin’s lymphoma autografted after a first relapse. Ann Oncol. 2005;16:625-633.
  8. Arai S, Fanale M, deVos S, et al. Defining a Hodg­kin lymphoma population for novel therapeutics after relapse from autologous hematopoietic cell transplant. Leuk Lymphoma. 2013;54:2531-2533.
  9. Crump M. Management of Hodgkin lymphoma in relapse after autologous stem cell transplant. Hematology Am Soc Hematol Educ Program. 2008:326-333.
  10. Moskowitz CH, Nadamanee A, Masszi T, et al; for the AETHERA Study Group. Brentuximab vedotin as consolidation therapy after autologous stem-cell transplantation in patients with Hodgkin’s lymphoma at risk of relapse or progression (AETHERA): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2015;385:1853-1862.
  11. Krishnan A, Vij R, Keller J, et al. Moving beyond autologous transplantation in multiple myeloma: consolidation, maintenance, allogeneic transplant, and immune therapy. Am Soc Clin Oncol Educ Book. 2016;35:210-221.
  12. Schiffer CA. Optimal dose and schedule of consolidation in AML: is there a standard? Best Pract Res Clin Haematol. 2014;27:259-264.
  13. Sweetenham J, Walewski J, Nadamanee A, et al. Updated efficacy and safety data from the AETHERA trial of consolidation with brentuximab vedotin after autologous stem cell transplant (ASCT) in Hodgkin lymphoma patients at high risk of relapse. Presented at: 57th American Society of Hematology (ASH) Annual Meeting & Exposition; December 5-8, 2015; Orlando, FL. Abstract 3172.
  14. Venkataraman G, Mirza MK, Eichenauer DA, Diehl V. Current status of prognostication in classical Hodgkin lymphoma. Br J Haematol. 2014;165:287-299.
  15. Josting A, Franklin J, May M, et al. New prognostic score based on treatment outcome of patients with relapsed Hodgkin’s lymphoma registered in the database of the German Hodgkin’s lymphoma study group. J Clin Oncol. 2002;20:221-230.
  16. Moskowitz CH, Nimer SD, Zelenetz AD, et al. A 2-step comprehensive high-dose chemoradiotherapy second-line program for relapsed and refractory Hodg­kin disease: analysis by intent to treat and development of a prognostic model. Blood. 2001;97:616-623.
  17. Bröckelmann PJ, Müller H, Casasnovas O, et al. Risk factors and a prognostic score for progression free survival after treatment with autologous stem cell transplantation (ASCT) in patients with relapsed or refractory Hodgkin lymphoma (rrHL). Presented at: 57th American Society of Hematology (ASH) Annual Meeting & Exposition; December 5-8, 2015; Orlando, FL. Abstract 1978.

Active Ingredient: brentuximab vedotin

Please refer to Summary of Product Characteristics (SmPC) before prescribing.

INDICATIONS

ADCETRIS® is indicated for the treatment of adult patients with relapsed or refractory CD30+ Hodgkin lymphoma (HL):

  1. following autologous stem cell transplant (ASCT) or
  2. following at least two prior therapies when ASCT or multi-agent chemotherapy is not a treatment option.

ADCETRIS is indicated for the treatment of adult patients with CD30+ HL at increased risk of relapse or progression following ASCT.

ADCETRIS is indicated for the treatment of adult patients with relapsed or refractory systemic anaplastic large cell lymphoma (sALCL).

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS

ADCETRIS is contraindicated for patients with hypersensitivity to brentuximab vedotin and its excipients. In addition, combined use of ADCETRIS with bleomycin is contraindicated as it causes pulmonary toxicity.

SPECIAL WARNINGS & PRECAUTIONS

Progressive multifocal leukoencephalopathy (PML): John Cunningham virus (JCV) reactivation resulting in PML and death can occur in patients treated with ADCETRIS. PML has been reported in patients who received ADCETRIS after receiving multiple prior chemotherapy regimens.

Patients should be closely monitored for new or worsening neurological, cognitive, or behavioral signs or symptoms, which may be suggestive of PML. Suggested evaluation of PML includes neurology consultation, gadolinium-enhanced magnetic resonance imaging of the brain, and cerebrospinal fluid analysis for JCV DNA by polymerase chain reaction or a brain biopsy with evidence of JCV. ADCETRIS dosing should be held for any suspected case of PML and should be permanently discontinued if a diagnosis of PML is confirmed.

Pancreatitis: Acute pancreatitis has been observed in patients treated with ADCETRIS. Fatal outcomes have been reported. Patients should be closely monitored for new or worsening abdominal pain, which may be suggestive of acute pancreatitis. Patient evaluation may include physical examination, laboratory evaluation for serum amylase and serum lipase, and abdominal imaging, such as ultrasound and other appropriate diagnostic measures. ADCETRIS should be held for any suspected case of acute pancreatitis. ADCETRIS should be discontinued if a diagnosis of acute pancreatitis is confirmed.

Pulmonary toxicity: Cases of pulmonary toxicity, some with fatal outcomes, have been reported in patients receiving ADCETRIS. Although a causal association with ADCETRIS has not been established, the risk of pulmonary toxicity cannot be ruled out. New or worsening pulmonary symptoms should be promptly evaluated and treated appropriately.

Serious infections and opportunistic infections: Serious infections such as pneumonia, staphylococcal bacteremia, sepsis/septic shock (including fatal outcomes), and herpes zoster, and opportunistic infections such as Pneumocystis jiroveci pneumonia and oral candidiasis have been reported in patients treated with ADCETRIS. Patients should be carefully monitored during treatment for emergence of possible serious and opportunistic infections.

Infusion-related reactions (IRR): Immediate and delayed IRR, as well as anaphylaxis, have occurred with ADCETRIS. Patients should be carefully monitored during and after an infusion. If anaphylaxis occurs, administration of ADCETRIS should be immediately and permanently discontinued and appropriate medical therapy should be administered. If an IRR occurs, the infusion should be interrupted and appropriate medical management instituted. The infusion may be restarted at a slower rate after symptom resolution. Patients who have experienced a prior IRR should be premedicated for subsequent infusions. IRRs are more frequent and more severe in patients with antibodies to ADCETRIS.

Tumor lysis syndrome (TLS): TLS has been reported with ADCETRIS. Patients with rapidly proliferating tumor and high tumor burden are at risk of TLS. These patients should be monitored closely and managed according to best medical practice.

Peripheral neuropathy (PN): ADCETRIS treatment may cause PN, both sensory and motor. ADCETRIS-induced PN is typically cumulative and reversible in most cases. Patients should be monitored for symptoms of PN, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain, or weakness. Patients experiencing new or worsening PN may require a delay and a dose reduction or discontinuation of ADCETRIS.

Hematological toxicities: Grade 3 or Grade 4 anemia, thrombocytopenia, and prolonged (equal to or greater than one week) Grade 3 or Grade 4 neutropenia can occur with ADCETRIS. Complete blood counts should be monitored prior to administration of each dose.

Febrile neutropenia: Febrile neutropenia has been reported. Patients should be monitored closely for fever and managed according to best medical practice if febrile neutropenia develops.

Stevens-Johnson syndrome (SJS): SJS and toxic epidermal necrolysis (TEN) have been reported with ADCETRIS. Fatal outcomes have been reported. If SJS or TEN occurs, treatment with ADCETRIS should be discontinued and appropriate medical therapy should be administered.

Gastrointestinal (GI) complications: GI complications, some with fatal outcomes, including intestinal obstruction, ileus, enterocolitis, neutropenic colitis, erosion, ulcer, perforation and hemorrhage, have been reported. New or worsening GI symptoms should be promptly evaluated and treated appropriately.

Hepatotoxicity: Elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) have been reported. Serious cases of hepatotoxicity, including fatal outcomes, have also occurred. Liver function should be tested prior to treatment initiation and routinely monitored in patients receiving ADCETRIS. Patients experiencing hepatotoxicity may require a delay, dose modification, or discontinuation of ADCETRIS.

Hyperglycemia: Hyperglycemia has been reported during trials in patients with an elevated body mass index (BMI) with or without a history of diabetes mellitus. However, any patient who experiences an event of hyperglycemia should have their serum glucose closely monitored.

Anti-diabetic treatment should be administered as appropriate.

Renal and hepatic impairment: There is limited experience in patients with renal and hepatic impairment. Available data indicate that MMAE clearance might be affected by severe renal impairment, hepatic impairment, and by low serum albumin concentrations. The recommended starting dose in patients with hepatic impairment or severe renal impairment is 1.2 mg/kg administered as an intravenous infusion over 30 minutes every 3 weeks. Patients with renal or hepatic impairment should be closely monitored for adverse events.

Sodium content in excipients: This medicinal product contains a maximum of 2.1 mmol (or 47 mg) of sodium per dose. To be taken into consideration for patients on a controlled sodium diet.

INTERACTIONS

Patients who are receiving a strong CYP3A4 and P-gp inhibitor, concomitantly with ADCETRIS may have an increased risk of neutropenia and should be closely monitored. Co-administration of ADCETRIS with a CYP3A4 inducer did not alter the plasma exposure of ADCETRIS but it appeared to reduce plasma concentrations of MMAE metabolites that could be assayed. ADCETRIS is not expected to alter the exposure to drugs that are metabolized by CYP3A4 enzymes.

PREGNANCY: Women of childbearing potential should be using two methods of effective contraception during treatment with ADCETRIS and until 6 months after treatment. There are no data from the use of ADCETRIS in pregnant women, although studies in animals have shown reproductive toxicity. ADCETRIS should not be used during pregnancy unless the benefit to the mother outweighs the potential risks to the fetus. If a pregnant woman needs to be treated, she should be clearly advised on the potential risk to the fetus.

LACTATION (breast-feeding): There are no data as to whether ADCETRIS or its metabolites are excreted in human milk, therefore a risk to the newborn/infant cannot be excluded. With the potential risk, a decision should be made whether to discontinue breast-feeding or discontinue/abstain from therapy with ADCETRIS.

FERTILITY: In nonclinical studies, ADCETRIS treatment has resulted in testicular toxicity, and may alter male fertility. Men being treated with this medicine are advised not to father a child during treatment and for up to 6 months following the last dose.

ADVERSE REACTIONS

Serious adverse drug reactions were: pneumonia, acute respiratory distress syndrome, headache, neutropenia, thrombocytopenia, constipation, diarrhea, vomiting, nausea, pyrexia, peripheral motor neuropathy, peripheral sensory neuropathy, hyperglycemia, demyelinating polyneuropathy, tumor lysis syndrome, and Stevens-Johnson syndrome.

In the clinical studies of ADCETRIS, adverse reactions defined as very common (≥1/10) were: infection, upper respiratory tract infection, neutropenia, PN (sensory and motor), cough, dyspneoa, diarrhea, nausea, vomiting, constipation, abdominal pain, alopecia, pruritus, myalgia, arthralgia, fatigue, chills, pyrexia, infusion-related reactions and weight decreased. Adverse reactions defined as common (≥1/100 to <1/10) were: Sepsis/septic shock, herpes zoster, pneumonia, herpes simplex, anemia, thrombocytopenia, hyperglycemia, dizziness, demyelinating polyneuropathy, ALT/AST increased, rash, and back pain.

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