september 2019 • vol. 11 • no. 6 the society of …

Journal of THE SOCIETY OF PHYSICIANS OF HONG KONG

www.soPHYSICIANShk.org

香港內科學會THE SOCIETY OF PHYSICIANS OF HONG KONG

Founded 1956

SEPTEMBER 2019 • VOL. 11 • NO. 6

ISSN 2072-4209

EXECUTIVE COMMITTEE

PRESIDENTDr Lam Tat Chung, Paul 林達聰醫生

VICE PRESIDENTProfessor Tsang Wah Tak, Kenneth曾華德教授

HON. SECRETARYDr Chen Yi Tin 陳以天醫生

HON. TREASURERProfessor Wong Chun Yu, Benjamin 王振宇教授

COMMITTEE MEMBERProfessor Brian Tomlinson 湯寧信教授

CHIEF EDITOR Dr Wong King Yan, Matthew 黃敬恩醫生

EDITORSDr Au Wing Yan區永仁醫生

Professor Chan Hin Lee, Henry 陳衍里教授

Dr Chan Tak Hin 陳德顯醫生

Dr Chen Yi Tin 陳以天醫生

Professor Hung Fan Ngai, Ivan孔繁毅教授

Dr Lam Tat Chung, Paul 林達聰醫生

Dr Loo King Fan, Steven 盧景勳醫生

Dr Ng Fook Hong 吳福康醫生

Dr Ting Zhao Wei, Rose丁昭慧醫生

Professor Brian Tomlinson湯寧信教授

Professor Tsang Wah Tak, Kenneth 曾華德教授

Professor Tse Hung Fat 謝鴻發教授

Professor Wong Chi Sang, Martin 黃至生教授

Professor Wong Chun Yu, Benjamin 王振宇教授

Dr Yuen Mae Ann, Michele 袁美欣醫生

CONTENTS

77 Editorial Dr Lam Tat Chung, Paul (林達聰醫生) Dr Wong King Yan, Matthew (黃敬恩醫生)

Pictorial Medical History (21) Dr Lam Tat Chung, Paul (林達聰醫生)

78 Recognizing Immune-Mediated Adverse Events in the Treatment of Hodgkin Lymphoma with Checkpoint Inhibitors

Dr Chen Yi Tin (陳以天醫生)

80 Novel Targeted Therapies for Acute Myeloid Leukaemia

Dr Law Man-Fai (羅文輝醫生) Dr David Chao (趙峻醫生)

84 A Novel Antibody-Drug Conjugate Shows Promise for Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma

Dr Liu Sung Yu, Herman (廖崇瑜醫生)

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SEPTEMBER 2019 Journal of The Society of Physicians of Hong Kong | 77

EditorialEditorial

Dr Lam Tat Chung, Paul (林達聰醫生)FRCP, FRCPsych, FHKAM (Medicine), FHKAM (Psychiatry)Specialist in Psychiatry (Private Practice)President

Dr Wong King Yan, Matthew (黃敬恩醫生)MBBS (HK), MRCP (UK), FHKCP, FHKAM (Med)FRCP RCPS (Glasg), FRCP (Edin)Specialist in Respiratory MedicineChief Editor

It was customary for patients to give votive offerings (in return for the favour given by a deity) by making parts of the body that were cured. These were hung in the wall of the temple.

Pictorial Medical History (21)Dr Lam Tat Chung, Paul (林達聰醫生)FRCP, FRCPsych, FHKAM (Medicine), FHKAM (Psychiatry)Specialist in Psychiatry (Private Practice)President

The full article can be seen at: http://www.hkma.org/english/cme/onlinecme/cme201302main.htm

Votive offering, leg with varicose vein, Epidaurus, Greece, 3rd Century BCE.

I n the first article of this issue, immune-mediated adverse events (IMAEs) are discussed. Immunotherapy or

immuno-oncology has been widely adopted in different types of malignancy, including solid and haematological. Programmed death-1 (PD-1) inhibitors have been used for previously treated cases of classical Hodgkin lymphoma (cHL). A number of extra-haematological organs, such as the lungs, gastrointestinal

tract, liver, skin and kidneys, and endo-crine organs such as the thyroid, can be affected by the activation of the immune response triggered by immunotherapies.In extreme cases, IMAEs can be fatal and, thus, early recognition of effects on seemingly unrelated organs and prompt initiation of steroids may save patients’ lives and reduce damage.

The second article describes the breakthrough treatment approach

for acute myeloid leukaemia involving genomic sequencing and molecular profiling to select the appropriate novel targeted therapy. Clinical trials have dem-onstrated improvements in efficacy and reduced toxicity.

Regarding treatments for diffuse large B-cell lymphoma (DLBCL), cyclo-phosphamide, hydroxydaunorubicin, vincristine and prednisolone, ie, the “CHOP” chemotherapy regimen, was traditionally the core of treatment. More recently, the addition of a biological agent, rituximab, to the traditional chemotherapy backbone has become the gold standard (“R-CHOP”). For cases that prove refrac-tory to R-CHOP therapy, chimeric antigen receptor (CAR) T-cell therapy has been developed but is currently not available locally. However, preliminary results have shown that the addition of a novel humanized monoclonal antibody, as a targeted therapy, to the standard regimen more than doubled the response rate at the cost of cytopenia and neuropathy.

78 | Journal of The Society of Physicians of Hong Kong SEPTEMBER 2019

Recognizing Immune-Mediated Adverse Events in the Treatment of Hodgkin Lymphoma with Checkpoint Inhibitors

Key words:Hodgkin lymphoma (何杰金氏淋巴瘤); Immune checkpoint inhibitors (免疫檢查點抑制劑)

Dr Chen Yi Tin (陳以天醫生)MBChB, MRCP (UK), FRCP (Lond, Edin, Glasg), FHKAM, FHKCPSpecialist in Haematology and Haematological Oncology (Private Practice)Honorary Clinical Associate ProfessorThe Chinese University of Hong Kong

Classical Hodgkin lymphoma (cHL) is characterized by scattered, tumour-initiating Reed-Sternberg cells

surrounded by a dense rosette-like pattern of infiltrating, dysfunctional T cells that are incapable of mediating productive anti-tumour responses. Reed–Sternberg cells suppress T-cell responses by upregulating ligands for the programmed death-1 (PD-1) immunoreceptor. In cHL, Reed–Sternberg cells mediate pathological suppression of antitumour immune responses via increased PD-1 ligand-1 (PD-L1) and PD-1 ligand-2 (PD-L2) expression because of copy number gains in the short arm of chromosome 9 (9p24.1).1 PD-L1/PD-L2 amplifications have been associated with advanced-stage disease at presentation and poor progression-free survival.1

Nivolumab and pembrolizumab are immunoglobulin G4 monoclonal antibodies that act as checkpoint inhibitors by binding to the PD-1 receptor and blocking the inter-action between PD-1 and PD-L1 or PD-L2.

As a result, the ‘brake’ on T-cell activation is released, leading to disinhibition of the immune response and improved control of tumour growth. Clinical trials have shown these agents to have substantial therapeu-tic activity and an acceptable safety profile in patients with relapsed or refractory cHL after multiple prior lines of therapy. However, such disinhibition may also lead to inappropriate T-cell activation against normal tissues and immune-mediated adverse events (IMAEs).

This review focuses on IMAEs reported during the treatment of cHL with two PD-1 checkpoint inhibitors, nivolumab and pembrolizumab. Since these mono-clonal antibodies are only used in the relapsed and/or refractory clinical settings, special consideration is given to the treat-ment history of patients with cHL, as the adverse events associated with earlier lines of therapy may overlap with IMAEs associated with checkpoint inhibitor therapy.

Recognition and management of immune-mediated adverse eventsThe most common IMAEs observed with nivolumab and pembrolizumab in patients with cHL have been rashes and hypo-thyroidism/thyroiditis. Colitis has been reported with lower frequency, although the cases reported have been more severe (grade 3); hepatitis has also been reported at low frequencies. PD-1 checkpoint inhibi-tors are also associated with an increased risk of immune-mediated pneumonitis.2 Infusion-related reactions can occur in up to 14% of patients,3–5 although these are severe in <1% of cases. Infusion reactions requiring immune-modulating medication were reported in 4% of patients with cHL who received nivolumab.5 Notably, pulmo-nary dysfunction is a known complication

of cHL treatment. It is therefore critical that haematologists who treat cHL with immuno-oncology agents can recognize IMAEs, as prompt initiation of cortico-steroid therapy can reduce toxicity and the likelihood of treatment discontinua-tion, thereby decreasing morbidity and mortality.

Diagnosis and management of pneumonitisPneumonitis after checkpoint inhibitor therapy can have variable clinical, radiologi-cal and pathological presentations. Onset may occur early or late in the course of treatment. Patients may be asymptom-atic at the onset or may present with dyspnoea, cough and, less frequently, fever and chest pain.3 Standard treatment guidelines for mild-to-moderate pneumo-nitis recommend chest imaging (chest computed tomography with contrast [pre-ferred] or radiography) every 3–4 weeks or as clinically indicated (mild cases).1,6 Radiographical features may include: a cryptogenic organizing pneumonia-like presentation with discrete patchy or con-fluent consolidation; the appearance of ‘ground glass’ opacities; interstitial mark-ings with interlobular septal thickening; a centrilobular nodular presentation with a bronchiolitis appearance; or a combination of the above.3 Given that the radiographical appearance of pneumonitis is highly varied and can resemble malignant lung infiltra-tion or infection, diagnostic biopsy, via bronchoscopy or video-assisted thoraco-scopic surgery, is essential to distinguish drug-induced pneumonitis from progres-sion of disease or infectious pneumoni-tis.3 Biopsy may reveal granulomatous inflammation, focal fibrin, diffuse alveolar damage, eosinophils or vessels with recanalized thrombi.3 Pneumonitis should


be treated promptly with corticosteroids, although steroid-sparing immunosuppres-sants are used in patients with refractory pneumonitis. Depending on IMAE sever-ity, checkpoint inhibitor therapy should be delayed or stopped entirely.

Immune-mediated colitis and diarrhoeaColitis has been reported in 2–3% of patients, with a median time to onset of 3.5–5.3 months. None of these cases was reported as leading to discontinuation of checkpoint inhibitor therapy. Distinguishing diarrhoea from colitis (radiographical or endoscopic findings of colonic inflamma-tion) is important to help prevent severe or potentially life-threatening complications. Although similar, colitis can be distin-guished from diarrhoea by presentation of abdominal pain, blood and mucus in stools, and fever. Colitis and diarrhoea are treated by prompt administration of corticosteroids.7 Furthermore, checkpoint inhibitor therapy should be withheld or discontinued depending on the severity of colitis. Patients who experience four or more bowel movements above baseline frequency per day (grade 2 or higher) war-rant a pause in treatment and subsequent referral for gastrointestinal evaluation, including colonoscopy with biopsy and possible gastrointestinal-directed treat-ment (eg, budesonide) or systemic corti-costeroid treatment.1

Immune-mediated endocrinopathiesIn trials evaluating treatment of cHL with nivolumab or pembrolizumab, endocrine abnormalities have been observed, specifically consisting of hypothyroidism, hyperthyroidism and thyroiditis. Treatment-related immune-mediated endocrinopa-thies reported in patients treated with pembrolizumab consisted of hypothyroid-ism (12–16%) and thyroiditis (0–6%).4,8 In patients treated with nivolumab for cHL, all-cause immune-mediated endocrinopa-thies reported included hypothyroidism (9%; primary hypothyroidism was reported in 3% of patients), hyperthyroidism (2%),

thyroiditis (<1%), adrenal insufficiency (<1%) and diabetes (<1%).5

In cases of symptomatic thyroiditis, patients may initially develop hyperthyroid-ism that can be treated with beta-blockers. Hypothyroidism develops later and usually requires thyroid hormone replacement.7 Typically, a high thyroid-stimulating hor-mone (TSH) level with low free thyroxine (T4) indicates primary hypothyroidism; a low TSH level with low free T4 indicates hypophysitis; high TSH and triiodothyro-nine/T4 levels indicate hyperthyroidism. Current treatment guidelines recommend measurement of TSH and free T4 levels every 4–6 weeks as part of routine clinical monitoring.1,6 Thyroid hormone replace-ment is effective for the management of hypothyroidism, and beta-blockers, corticosteroids and, in some cases, antithyroid therapy (such as methimazole, carbimazole or propylthiouracil) or perma-nent radioiodine ablation may be used to manage hyperthyroidism.

Adrenal suppression and hypophy-sitis are clinically challenging to diagnose as they may present with symptoms such as fatigue, headache, photophobia, dizzi-ness, nausea or anorexia.1,7 Hypophysitis is diagnosed by biochemical testing of the pituitary–hypothalamus (prolactin), pituitary–thyroid (low or normal TSH with a low free T4) and pituitary–gonadal axes (low luteinizing hormone, follicle-stimulating hormone with low oestradiol or testosterone).

Dermatological, hepatic and renal immune-mediated adverse eventsRash has been reported in 1–9% of patients. Hepatic adverse events associ-ated with PD-1 inhibitors consist mainly of elevations in aspartate aminotransferase and alanine aminotransferase levels.5 Autoimmune hepatitis has been reported in 0.7–1.8% of patients, with a median time to onset of 1–3 months. Renal adverse events with PD-1 inhibitors con-sist mainly of elevated serum creatinine levels. Nephritis has been reported in 0.3–1.2% of patients.

Additional uncommon immune-mediated adverse eventsClinicians should also be aware of other rare (<1% of patients) but potentially severe IMAEs during PD-1 inhibitor therapy. Such IMAEs include pancreatic toxicities, cardiovascular disease (eg, myocarditis), nervous system disorders (eg, myasthenia gravis), ocular toxicity (eg, episcleritis, blepharitis, uveitis), endocrine system disorders (eg, type 1 diabetes mel-litus), severe rashes (eg, Stevens–Johnson syndrome or toxic epidermal necrolysis), and renal (eg, interstitial nephritis) and musculoskeletal disorders (eg, myositis/polymyositis).6,7 Diagnosis and manage-ment of these rare IMAEs is covered in detail in the American Society of Clinical Oncology guidelines.6

ConclusionRecovery from IMAEs is generally expected if clinicians institute timely intervention with corticosteroid therapy; therefore, awareness and recognition of common IMAEs is of utmost importance. Prompt management, with corticosteroid therapy for pneumonitis for instance, may allow patients to quickly recover from IMAEs, restart anti-PD-1 therapy and maintain disease control. Emerging clinical experience with checkpoint inhibitors in cHL will help to guide future management of IMAEs. IMAEs reported in clinical trials of PD-1 checkpoint inhibitors in cHL have so far been predominantly grade 1 or 2 and appear to be generally consistent with those reported in non-haematological malignancies, albeit with some variability.

Consideration of treatment history, with particular attention to organ systems that may be predisposed to toxicities from prior therapies, may aid in early recogni-tion of IMAEs. Only limited data on the treatment of patients with cHL using PD-1 checkpoint inhibitors are currently avail-able. To optimize patient management, further improvements in the understand-ing and treatment of IMAEs are needed.

A complete list of references can be downloaded from www.SOPHYSICIANSHK.org


Novel Targeted Therapies for Acute Myeloid Leukaemia

Key words:Acute myeloid leukaemia (何杰金氏淋巴瘤); Mutationally targeted inhibitors (突變型標靶抑制劑); Pro-apoptotic agents (促凋亡製劑); Targeted therapy (標靶治療)

Dr Law Man-Fai (羅文輝醫生)MBChB, MRCP, FHKAM, FHKCPSpecialist in HaematologyAssociate Consultant, Department of Medicine and TherapeuticsPrince of Wales Hospital

Dr David Chao (趙峻醫生)MBChBResident, Department of Medicine and TherapeuticsPrince of Wales Hospital

A cute myeloid leukaemia (AML) is an aggressive and heterogeneous haematological malignancy. The

disease is particularly difficult to treat in older adults, who account for the majority of patients. Since the 1970s, the treatment regimen has relied on induction chemotherapy that is cytotoxic and suitable only for patients who are fit enough to receive it. Known as the ‘7 + 3’ regimen, the treatment includes 7 days of continuous infusion cytarabine and 3 days of an anthracycline.1

Over the past 40 years, many clinical trials to improve AML treatment have been conducted, with disappointing results, and there has been little change in the standard of care. However, more recently, the landscape of genomic sequencing and targeted therapy has rapidly evolved, leading to advances in molecular profiling and the development of novel targeted therapies for AML.2,3

Molecular mutations in genes, such as FLT3, IDH1/2, NPM1, CEBPA, TP53, RUNX1 and ASXL1, provide important prognostic and therapeutic information in AML. Patients with FLT3-ITD, IDH1/2 and/or CD33+ AML have obtained clinical benefit from targeted therapy. Following these discoveries, a number of new drugs in different classes have been recently approved and are summarized in the Table. These novel therapies, sometimes used in combination with established chemotherapy, have changed the land-scape of AML treatment. This article will focus on the Fms-like tyrosine kinase 3 (FLT3) and B-cell leukaemia/lymphoma-2 (BCL-2) inhibitors, which are available in Hong Kong.

Mutationally targeted inhibitorsFLT3 is a transmembrane tyrosine kinase that has two mutational subtypes: an

internal tandem duplication (ITD), which results in the duplication of three to over 100 amino acids in the juxtamembrane region of the protein, or point mutations in the tyrosine kinase domain (TKD). These mutations are present in approxi-mately 30% of AML patients.4 There are six FLT3 inhibitors currently in clinical development: midostaurin, sorafenib, lestaurtinib, quizartinib, crenolanib and gilteritinib.

Midostaurin is the first FLT3 inhibitor that has demonstrated an overall survival (OS) benefit in combination with induction chemotherapy. In the RATIFY trial, 717 patients aged 18–59 years with FLT3 ITD or TKD mutations were random-ized to receive standard induction che-motherapy or induction with midostaurin 50 mg po BID on days 8 to 22.5 Patients in remission then received high-dose cytarabine consolidation ± midostaurin according to their first treatment arm. The study also included a maintenance phase in which placebo or midostaurin was given for twelve 28-day cycles. Allogeneic transplants were performed if deemed clinically necessary by the treating physician, and midostaurin was not administered post-transplant. The use of midostaurin was associated with a significant improvement in OS; median OS in the midostaurin group was 74.7 months compared with 25.6 months in the placebo group (HR for event or death 0.78; p=0.009) (Figure). The side effect profiles were similar in both groups.5

Pro-apoptotic agentsBCL-2 is an antiapoptotic protein that pro-motes leukaemic blast survival through regulation of the mitochondrial apoptotic pathway. Sensitizer BCL-2 homology 3


(BH3) proteins are antagonists of these antiapoptotic proteins and, therefore, promote apoptosis through mitochondrial outer membrane permeabilization.

Venetoclax is an oral small-molecule BCL-2 inhibitor. It blocks antiapoptotic activity, potentiates the effect of other partnered drugs, and enhances apop-tosis. It demonstrated on-target BCL-2 inhibition by BH3 profiling and yielded an overall response rate of 19% in a single-agent trial in advanced AML.6 In order to take advantage of the drug’s ability to help cells undergo apoptosis in the presence of cytotoxic stress, venetoclax was used in combination with hypomethylating agents, either azacitidine or decitabine, in a cohort of elderly patients who were ineligible for standard induction chemo-therapy. The combinations were well toler-ated, 67% of patients achieved complete

Table. FDA-approved drugs for acute myeloid leukaemia

Drug (mechanism of action) Indication

Midostaurin (FLT3 inhibitor) Treatment of adult patients with newly diagnosed FLT3-positive AML in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation

Gilteritinib (FLT3 inhibitor) Treatment of adult patients who have relapsed or refractory AML with an FLT3 mutation

Venetoclax (BCL-2 inhibitor)In combination with azacitidine or decitabine or low-dose cytarabine for the treatment of newly diagnosed AML in adults who are aged 75 years or older, or who have comorbidities that preclude the use of intensive induction chemotherapy

Ivosidenib (IDH1 inhibitor) Adult patients with relapsed or refractory AML with a susceptible IDH1 mutation

Enasidenib (IDH2 inhibitor) Treatment of adult patients with relapsed or refractory AML with an IDH2 mutation

Gemtuzumab ozogamicin (anti-CD33 monoclonal antibody conjugated to the antibiotic calicheamicin)

Treatment of adults with newly diagnosed CD33-positive AML and for treatment of relapsed or refractory CD33-positive AML in adults and paediatric patients 2 years and older. May be used in combination with daunorubicin and cytarabine for adults with newly diagnosed AML

CPX-351 (liposomal formulation of daunorubicin and cytarabine)

Treatment of adults with newly diagnosed therapy-related AML or AML with myelodysplasia-related changes

AML, acute myeloid leukaemia; FDA, United States Food and Drug Administration; FLT3, Fms-like tyrosine kinase 3; BCL-2, B-cell leukaemia/lymphoma-2; IDH, isocitrate dehydrogenase

remission (CR) and CR with incomplete count recovery (CRi), with a CR + CRi rate of 73% in those taking BCL-2 with hypomethylating agent. The median OS was 17.5 months.7,8 This combination of venetoclax with hypomethylating agents may be a suitable choice of treatment for patients who are elderly or ineligible for standard induction chemotherapy.

Another study, a phase I/II trial, evaluated venetoclax in combination with low-dose cytarabine yielding CR/CRi rates of 35% for secondary AML and 71% for de novo AML.9

The results of these studies are encouraging and have significantly impacted the treatment strategy for elderly patients with AML. There are a number of ongoing studies using venet-oclax in combination with other agents, and they will likely change our treatment

paradigm for this challenging group of AML patients.

ConclusionRecent advances arising from collabora-tion between benchwork and bedside have changed our approach to the treatment of AML. New pharmacologi-cal breakthroughs, such as midostaurin or venetoclax, have transformed the treatment paradigm for this aggressive malignancy. Venetoclax in combination with hypomethylating agents has pro-duced impressive results for elderly AML patients. The new targeted therapies will improve efficacy and minimize toxicity in a disease that has relied on cytotoxic regimens for the past four decades. Such advancements will continue to improve survival and quality of life in patients with AML.


References1. Rai KR, Holland JF, Glidewell OJ, et al. Treatment of acute myelocytic

leukemia: a study by cancer and leukemia group B. Blood 1981;58:1203-1212.2. Lindsley RC, Mar BG, Mazzola E, et al. Acute myeloid leukemia ontogeny

is defined by distinct somatic mutations. Blood 2015;125:1367-1376.3. Papaemmanuil E, Gerstung M, Bullinger L, et al. Genomic classification and

prognosis in acute myeloid leukemia. N Engl J Med 2016;374:2209-2221.4. Stone RM. What FLT3 inhibitor holds the greatest promise? Best Pract

Res Clin Haematol 2018;31:401-404. 5. Stone RM, Mandrekar SJ, Sanford B, et al. Midostaurin plus

chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med 2017;377:454-464.

6. Konopleva M, Pollyea DA, Potluri J et al. Efficacy and biological correlates of response in a phase II study of venetoclax monotherapy in patients with acute myelogenous leukemia. Cancer Discov. 2016; 6:1106-1117

7. DiNardo CD, Pratz KW, Letai A, et al. Safety and preliminary efficacy of venetoclax with decitabine or azacitidine in elderly patients with previously untreated acute myeloid leukaemia: a non-randomised, open-label, phase 1b study. Lancet Oncol 2018;19:216-228.

8. DiNardo CD, Pratz K, Pullarkat V, et al. Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood 2019;133:7-17.

9. Wei A, Strickland SA Jr, Hou JZ, et al. Venetoclax combined with low-dose cytarabine for previously untreated patients with acute myeloid leukemia: Results from a phase Ib/II study. J Clin Oncol 2019;37:1277-1284

Figure. Kaplan–Meier survival curves for median overall survival in the RATIFY trial5

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A Novel Antibody-Drug Conjugate Shows Promise for Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma

Key words:Non-Hodgkin lymphoma (非霍奇金淋巴瘤); Diffuse large B-cell lymphoma (彌漫性大型B細胞淋巴瘤); Anti-CD79b (抗CD79b); R-CHOP chemotherapy (R-CHOP 化療組合); Polatuzumab vedotin

Dr Liu Sung Yu, Herman (廖崇瑜醫生)MBBS (HK) MRCP (UK) FHKAM FHKCP FRCP (Edin, Glas)Specialist in Haematology and Haematological OncologyPrivate Practice

D iffuse large B-cell lymphoma (DLBCL) is an aggressive and common subtype of malignant

lymphoma. The current gold standard of treatment is rituximab, cyclophospha-mide, hydroxydaunorubicin, vincristine and prednisolone, known as R-CHOP. For many decades, cyclophosphamide, hydroxydaunorubicin, vincristine and prednisolone (CHOP), a first-generation combination-chemotherapy regimen, was the standard of care for DLBCL. Attempts to intensify the CHOP regimen were largely unsuccessful, despite a pivotal 1993 study comparing CHOP with sev-eral third-generation regimens, including low-dose methotrexate with leucovorin rescue, bleomycin, doxorubicin, cyclo-phosphamide, vincristine and dexametha-sone, that demonstrated similar efficacy and relatively less toxicity.1 Eventually, at the turn of this century, the addition of rituximab to CHOP became the gold standard.2

Nevertheless, a certain percent-age of patients do not respond well to R-CHOP or relapse shortly after treat-ment, especially in non-germinal centre B-cell (non-GCB), double expressors, double-hit or triple-hit DLBCL. Outcomes for these patients are usually poor.3 Platinum-based salvage therapy is the most commonly used regimen for such cases but usually yields a low response rate and a short duration of remission. Also, although the United States Food and Drug Adminstration (FDA) has approved the use of chimeric antigen receptor (CAR) T-cell therapy for relapsed or refractory DLBCL, this therapy is cur-rently not available locally and its cost would be prohibitive.

Another FDA-approved treatment is a novel first-in-class anti-CD79b antibody for relapsed or refractory DLBCL patients who have had at least two prior lines of treatment. This antibody-drug conjugate (ADC), polatuzumab vedotin, contains a

THE SOCIETY OF PHYSICIANS OF HONG KONG

Anniversary Scientific Meeting (non-members $100)

Date: Nov 10, 2019 (Sunday)

Venue: The Langham Hotel, Peking Road, TST, Kowloon

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humanized monoclonal antibody target-ing CD79b (a B-cell antigen receptor) conjugated to the dolastatin analogue, monomethyl auristatin E (MMAE), via a protease-cleavable linker. Upon adminis-tration, polatuzumab vedotin selectively binds to CD79b, which is abundantly expressed on the surface of B cells. Following internalization and proteolytic cleavage, MMAE binds to tubulin and inhibits its polymerization, resulting in G2/M phase arrest and tumour cell apop-tosis (Figure).

Approval of polatuzumab vedotin was based on Study GO29365, an open-label, multicentre clinical trial con-ducted in a cohort of 80 patients who had received at least one prior regimen. Patients were randomized 1:1 to receive bendamustine and rituximab (BR) or BR plus polatuzumab vedotin (both regimens were given every 3 weeks for up to six cycles). The dosages used in the treat-ment regimens were:

References1. Fisher RI, Gaynor ER, Dahlberg S, et al. Comparison of a standard

regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin’s lymphoma. N Engl J Med 1993;328:1002-1006.

2. Coiffier B, Lepage E, Briere J, et. al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 2002;346:235-242.

3. Friedberg JW. How I treat double-hit lymphoma. Blood 2017; 130:590-596.

4. Wenger M. Polatuzumab vedotin – a potent ADC in NHL. Available at: https://www.roche.com/dam/jcr:fd664a44-06bc-41e0-8ba8-b6 3317e0 f f37/en/ASH _ 2016 _ Michael_Wenger_ F INA L .pdf. Accessed 11 September 2019.

5. Sehn LH, Herrera AF, Matasar MJ, et al. Addition of polatuzumab vedotin to bendamustine and rituximab (BR) improves outcomes in transplant-ineligible patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) versus BR alone: results from a randomized phase 2 study. Blood 2017;130:2821.

Figure. Polatuzumab vedotin, an anti-CD79b antibody conjugated to monomethyl auristatin E, induces apoptosis in DLBCL cells4

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Anti-CD79btargets B-cellmalignancies

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ADC binds to receptor

Variable chain linkercleavable by

lysosomal proteases

ADC, antibody-drug conjugate; DLBCL, diffuse large B-cell lymphoma; MMAE, monomethyl auristatin E

• Rituximab 375 mg/m2 intravenously on day 1 of each cycle;

• Bendamustine 90 mg/m2/day on days 2 and 3 of cycle 1, then on days 1 and 2 of each subsequent cycle; and

• Polatuzumab vedotin 1.8 mg/kg intrave-nously on day 2 of cycle 1, then on day 1 of each subsequent cycle.5

The investigator-assessed best overall response rate (ORR) and complete response (CR) rate were higher with BR plus polatuzumab vedotin versus BR (ORR 70% vs 33%, CR 58% vs 20%, respec-tively) and at primary response assessment (ORR 48% vs 18% and CR 43% vs 15%, respectively).5 The commonest adverse events in the BR plus polatuzumab vedotin group were cytopenias and neuropathy.

In summary, the new anti-CD79b ADC, polatuzumab vedotin, offers promis-ing preliminary results in relapsed or refractory DLBCL patients. It provides an additional option to the existing modali-ties of CAR T-cell therapy or stem cell transplantation.

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print ad 2019.pdf 1 20/9/2019 下午6:27

Recognizing Immune-Mediated Adverse Events in the Treatment of Hodgkin Lymphoma

with Checkpoint Inhibitors

References:

1. Roemer MG, Advani RH, Ligon AH, et al. PD‐L1 and PD‐L2 genetic alterations define classical Hodgkin lymphoma and predict outcome. J Clin Oncol 2016;34:2690-2697.

2. Abdel‐Rahman O, Fouad M. Risk of pneumonitis in cancer patients treated with immune checkpoint inhibitors: A meta‐analysis. Ther Adv Respir Dis 2016;10:183-193.

3. Naidoo J, Wang X, Woo KM, et al. Pneumonitis in patients treated with anti‐programmed death‐1/programmed death ligand 1 therapy. J Clin Oncol 2017;35:709-717.

4. Armand P, Shipp MA, Ribrag V, et al. Programmed death‐1 blockade with pembrolizumab in patients with classical Hodgkin lymphoma after brentuximab vedotin failure. J Clin Oncol 2016;34:3733-3739.

5. Armand P, Engert A, Younes A, et al. Nivolumab for relapsed/refractory classic Hodgkin lymphoma after failure of autologous hematopoietic cell transplantation: Extended follow‐up of the multicohort single‐arm phase II CheckMate 205 trial. J Clin Oncol 2018;36:1428-1439.

6. Brahmer JR, Lacchetti C, Schneider BJ, et al. Management of immune‐related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical OncologyClinical Practice Guideline. J Clin Oncol 2018;36:1714-1768.

7. Naidoo J, Page DB, Li BT, et al. Toxicities of the anti‐PD‐1 and anti‐PD‐L1 immune checkpoint antibodies. Ann Oncol 2015;26:2375-2391.

8. Chen R, Zinzani PL, Fanale MA, et al. Phase II study of the efficacy and safety of pembrolizumab for relapsed/refractory classic Hodgkin lymphoma. J Clin Oncol 2017;35:2125-2132.

september 2019 • vol. 11 • no. 6 the society of …

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