Yu-Yan Hwang

Hepatitis B Reactivation in Patients With Previous Hepatitis B Virus Exposure Undergoing Rituximab-Containing Chemotherapy for Lymphoma: A Prospective Study

PURPOSE Patterns of hepatitis B virus (HBV) reactivation in hepatitis B surface antigen (HBsAg) -negative, antihepatitis B core antigen antibody (anti-HBc) -positive patients with lymphoma receiving rituximab-containing chemotherapy have not been well described. PATIENTS AND METHODS HBsAg-negative, anti-HBc-positive Chinese patients with undetectable serum HBV DNA (< 10 IU/mL), diagnosed with hematologic malignancies and receiving rituximab-containing chemotherapy, were prospectively monitored every 4 weeks for up to 2 years. Entecavir was started when HBV reactivation (defined as detectable HBV DNA) was encountered. RESULTS Among 260 patients receiving rituximab-containing chemotherapy, 63 patients (24.2%) who were HBsAg negative and anti-HBc positive underwent follow-up for a median of 70 weeks (range, 6 to 104 weeks). The 2-year cumulative rate of HBV reactivation was 41.5%, occurring at a median of 23 weeks (range, 4 to 100 weeks) after rituximab treatment. The median HBV DNA level at reactivation was 43 IU/mL (range, 14 to 920 IU/mL). A baseline undetectable antibody to HBsAg (anti-HBs; < 10 mIU/mL) was the only significant risk factor that was positively associated with HBV reactivation (hazard ratio, 3.51; 95% CI, 1.37 to 8.98; P = .009). Patients with negative baseline anti-HBs, compared with those with positive anti-HBs, had a significantly higher 2-year cumulative rate of HBV reactivation (68.3% v 34.4%; P = .012). At HBV reactivation, all patients had normal ALT, and all patients but one were HBsAg negative. Entecavir successfully controlled HBV reactivation in all patients. CONCLUSION A high rate of HBV reactivation was observed in HBsAg-negative, anti-HBc-positive patients undergoing rituximab-containing chemotherapy, with the risk of reactivation significantly higher in anti-HBs-negative patients. Periodic HBV DNA monitoring was an effective strategy in preventing HBV-related complications.

Non-bacterial infections in Asian patients treated with alemtuzumab: a retrospective study of the Asian Lymphoma Study Group

Abstract This retrospective study concerns non-bacterial infections in Asian patients receiving alemtuzumab. The clinical data of 182 patients treated with alemtuzumab alone or alemtuzumab-containing chemotherapy between the years 2003 and 2009 was collected from six Asian countries. Alemtuzumab was used in the setting of frontline (n =48) or salvage (n =90) treatment, and as a part of the conditioning regimen for allogeneic stem cell transplant (n =44). Reactivation of cytomegalovirus (66/182) and varicella zoster virus (25/182), and fungal infection (31/182) including invasive pulmonary aspergillosis, were the most common infectious complications in this retrospective analysis. Thus, we recommend routine prophylaxis with valganciclovir and itraconazole, especially when alemtuzumab is used in the conditioning regimen for allogeneic stem cell transplant. Pneumocystis jirovecii pneumonia (PJP) was found in four patients (3%, 4/122) receiving alemtuzumab as conditioning for stem cell transplant or salvage treatment. Three cases of hepatitis B virus reactivation were found in antigen-negative patients, and 16 cases of tuberculosis were observed. Infection is the major complication of alemtuzumab therapy, and these infectious complications are potentially severe and life-threatening. Based on our retrospective analysis, we have constructed a guideline for antimicrobial prophylaxis in Asian patients receiving alemtuzumab therapy.

Association of Hepatitis B Core-Related Antigen With Hepatitis B Virus Reactivation in Occult Viral Carriers Undergoing High-Risk Immunosuppressive Therapy

OBJECTIVES:Hepatitis B core-related antigen (HBcrAg) is a novel serum marker that correlates with intrahepatic hepatitis B virus (HBV) activity. Its association with HBV reactivation in hepatitis B surface antigen (HBsAg)-negative antibody to hepatitis B core antigen (anti-HBc)-positive patients undergoing high-risk immunosuppressive therapy is undefined.METHODS:HBcrAg was measured in HBsAg-negative, anti-HBc-positive Asian patients with undetectable HBV DNA, who participated in two prospective studies investigating HBV reactivation during rituximab-containing chemotherapy and allogeneic hematopoietic stem cell transplantation (HSCT). Patients were monitored every 4 weeks for up to 2 years, with entecavir started when HBV reactivation, defined as HBV DNA ≥10 IU ml−1, developed.RESULTS:One hundred and twenty-four HBsAg-negative, anti-HBc-positive patients (rituximab, N=62; allogeneic HSCT, N=62) with a median follow-up of 64 weeks (range: 4–104 weeks) were studied. HBV reactivation occurred in 31 patients, with a 2-year cumulative reactivation rate of 40.4%. Serum HBcrAg was detected in 43 (34.7%) patients. Baseline HBcrAg positivity was significantly associated with HBV reactivation (P=0.004, hazard ratio (HR): 2.94, 95% confidence interval (95% CI): 1.43–6.07). HBcrAg-positive patients had a significantly higher 2-year HBV reactivation rate than HBcrAg-negative patients (71.8 vs. 31%, P=0.002). In the rituximab cohort, the HRs for positive HBcrAg and negative antibody to HBsAg for HBV reactivation were 3.65 and 2.84, respectively (P=0.011, 95% CI: 1.35–9.86 and P=0.032, 95% CI: 1.10–7.37, respectively).CONCLUSIONS:Serum HBcrAg positivity is a significant risk factor of HBV reactivation in HBsAg-negative, anti-HBc-positive patients undergoing high-risk immunosuppressive therapy and can potentially have a role in identifying patients who will best benefit from prophylactic nucleoside analogue treatment.

Hepatitis B reactivation in occult viral carriers undergoing hematopoietic stem cell transplantation: A prospective study

Hepatitis B virus (HBV) reactivation in hepatitis B surface antigen (HBsAg)–negative, antibody to hepatitis B core antigen (anti‐HBc)–positive patients after allogeneic hematopoietic stem cell transplantation (HSCT) has not been prospectively studied. HBsAg‐negative, anti‐HBc–positive patients with undetectable HBV DNA undergoing allogeneic HSCT were prospectively monitored every 4 weeks. The primary endpoint was HBV reactivation, defined as detectable HBV DNA (≥10 IU/mL). Secondary endpoints included overall survival, HBsAg positivity, and changes in liver biochemistry and antibody to HBsAg levels. Among 297 allogeneic HSCT recipients, 85 (28.7%) were HBsAg‐negative, anti‐HBc–positive, of whom 62 were recruited and monitored for a median of 48 (4‐104) weeks. The 2‐year cumulative HBV DNA detectability rate was 40.8%, occurring at a median of 44 (8‐100) weeks. Multivariate analysis showed that age ≥50 years (P = 0.004, hazard ratio = 8.2) and chronic graft‐versus‐host disease (P = 0.010, hazard ratio = 5.3) were significantly associated with HBV reactivation. Other clinical parameters, including baseline antibody to HBsAg status, serial changes in antibody to HBsAg levels, and donor serology, were not associated with HBV reactivation. Patients <50 years old and without chronic graft‐versus‐host disease, compared with the remaining patient cohort, had a significantly lower 2‐year cumulative HBV reactivation rate (5.6% versus 65.0%, P = 0.004). Entecavir successfully suppressed HBV DNA to undetectable levels, with no cases developing biochemical hepatitis. Conclusion: HBsAg‐negative, anti‐HBc–positive patients had a high rate of HBV reactivation after allogeneic HSCT, with determinants of HBV reactivation including age ≥50 years and chronic graft‐versus‐host disease; treatment strategies based on these parameters may prevent HBV reactivation and subsequent complications. (ClinicalTrials.gov identifier NCT01481649.) (Hepatology 2017;65:1451‐1461).

Restoration of chemosensitivity by bortezomib: implications for refractory myeloma.

Background. A 59-year-old woman presented to the emergency department with a left rib fracture and was diagnosed with IgA multiple myeloma. The patient underwent autologous bone-marrow transplantation, and 14 months later she developed obstructive jaundice.Investigations. Serum protein electrophoresis, contrast CT of thorax and abdomen, endoscopic retrograde cholangiopancreatography with endoscopic biopsy and pleural biopsy.Diagnosis. Extramedullary plasmacytomas at pancreatic head and pleura.Management. Salvage chemotherapy regimens including bortezomib plus steroid, alkylators plus steroid, bortezomib plus anthracycline and radiotherapy, and combined bortezomib, cyclophosphamide, melphalan and steroid therapy.

Post‐transplant lymphoproliferative diseases in Asian solid organ transplant recipients: late onset and favorable response to treatment

Chan TSY, Hwang Y‐Y, Gill H, Au W‐Y, Leung AYH, Tse E, Chim C‐S, Loong F, Kwong Y‐L. Post‐transplant lymphoproliferative diseases in Asian solid organ transplant recipients: late onset and favorable response to treatment.

Valganciclovir thrice weekly for prophylaxis against cytomegalovirus reactivation during alemtuzumab therapy.

The monoclonal anti-CD52 antibody alemtuzumab is active against chronic lymphocytic leukemia and other low-grade B- and T-cell lymphoproliferative diseases. It is lymphoablative, making patients susceptible to opportunistic infections. Reactivation of cytomegalovirus (CMV) infection occurs in 10–100% of cases, depending on the patient population, the frequency and the sensitivity of the virologic surveillance tests employed.1

Primary treatment of leukemia relapses after allogeneic hematopoietic stem cell transplantation with reduced-intensity conditioning second transplantation from the original donor.

Acute leukemia relapsing after allogeneic hematopoietic stem cell transplantation (HSCT) has dismal outcome. Consecutive consenting patients (acute myeloid leukemia: N = 71; acute lymphoblastic leukemia: N = 37), at a median age of 37 (16–57) years, who had relapsed 7.9 (1.3–132) months post‐HSCT, were treated with three cytarabine‐based intensive regimens as reduced‐intensity conditioning (RIC), followed by infusion of mobilized HSC from the original donors. There were four treatment‐related mortalities (TRMs). Of 104 evaluable cases, 72 patients (67%) achieved complete remission (CR)/CR with incomplete hematologic recovery (CRi). The median overall survival (OS) of the entire cohort was 11.6 months. The OS of patients achieving CR/CRi after the first RIC/HSCT was 18.8 months, as compared with 3.9 months for those not (P < 0.01). For 32 patients with nonremission, 11 received a repeat RIC‐HSCT, leading to CR/CRi in three cases. Therefore, 75/108 (69%) of patients achieved CR/CRi after one or two courses of RIC‐HSCT. Among CR/CRi patients, 48 cases relapsed again after 6.1 (1.0–64.4) months. Thirty cases received a repeat RIC‐HSCT, leading to CR/CRi in 22 patients. Multivariate analyses showed a significant impact of remission duration after initial HSCT (P = 0.026) and the presence of acute graft‐versus‐host disease after RIC‐HSCT (P = 0.011) on CR/CRi. RIC‐HSCT as primary treatment for acute leukemic relapses post‐HSCT induced a high CR rate with low TRM. Optimal postremission treatment remains to be defined. Am. J. Hematol. 88:485–491, 2013.

Low-dose nivolumab induced remission in refractory classical Hodgkin lymphoma

Dear Editor, Immune checkpoint blockade targeting the programmed cell death protein 1 (PD1) is an effective salvage for refractory classical Hodgkin lymphoma (cHL). Two antiPD1 antibodies nivolumab and pembrolizumab are approved for treating relapsed/refractory cHL. In a phase 1 study, 23 patients with relapsed/refractory cHL, with or without prior brentuximab vedotin and/or autologous hematopoietic stem cell transplantation (ASCT), were treated with nivolumab at 3 mg/kg every 2 weeks. Outcome was favorable, with an overall response rate (ORR) of 87% (complete response, CR 17%) [1]. In another phase 2 study, 80 cHL patients failing brentuximab vedotin and ASCT were treated. The ORR was 66% (CR 8%) [2]. At 3 mg/kg every 2 weeks, nivolumab treatment led to significant adverse events (AEs), which occurred in 78–99% (grade ≥3 22–42%) of patients. Studies with pembrolizumab gave comparable results. In a phase 1 study of 31 patients failing brentuximab vedotin with or without prior ASCT, pembrolizumab used at a high dose (10 mg/kg every 2 weeks) resulted in an ORR of 65% (CR 16%). Treatment-related AEs occurred in 21 cases (68%), resulting in drug discontinuation in 2 cases [3]. In a subsequent phase 2 study of 60 similar patients, pembrolizumab was used at 200 mg every 3 weeks. The ORR was 75% (CR 23%) [4]. AEs were fewer, occurring in about 30% of cases. We reported that pembrolizumab used at a lower fixeddose of 100 mg was highly efficacious in relapsed/refractory cHL [5]. Recently, we had the unique opportunity to test the hypothesis that nivolumab used in a low dose might similarly be efficacious. A 33-year-old man presented in 2011 with right cervical lymphadenopathy. Positron emission tomography computed tomography (PET/CT) showed cervical, mediastinal and abdominal lymphadenopathy. Bonemarrowwas normal. Biopsy confirmed mixed cellularity cHL. Treatment with eight cycles of ABVD (adriamycin, bleomycin, vinblastine, dacarbazine) resulted in complete metabolic response (mCR). A year later, the disease relapsed. He received three cycles of DHAP (dexamethasone, cytarabine, cisplatin) and then underwent an ASCT (conditioning: carmustine, etoposide, cytarabine, melphalan). Three years post-ASCT, progressive cervical lymphadenopathy developed. A biopsy the following year confirmed relapse. PET/CT showed widespread lymphadenopathy and bone involvement (Fig. 1a). Concurrently, he developed thrombocytopenia. Bone marrow examination showed megakaryocytic hyperplasia without lymphoma involvement. A diagnosis of immune thrombocytopenia purpura (ITP) was made. Corticosteroid treatment resulted in a brisk platelet response. The patient could not afford brentuximab vedotin, leaving PD1 blockade as his only option. Because of the concern that ITP might be exacerbated, we decided to use the lowest feasible dose of anti-PD1 antibody. Of the two anti-PD1 antibodies, nivolumab was chosen, because it had the smallest dose vial (40 mg) available. Nivolumab was hence used at a fixed dose of 40 mg (about 0.55 mg/kg) every 2 weeks. The patient gave informed consent to treatment. Six days after treatment, the platelet count was 107 × 10/L. However, it dropped precipitously to 7 × 10/L just before the next cycle (Fig. 1b). Intravenous immunoglobulin and prednisolone (1 mg/kg) led * Yok-Lam Kwong ylkwong@hkucc.hku.hk

Valganciclovir suppressed Epstein Barr virus reactivation during immunosuppression with alemtuzumab

BACKGROUND Reactivation of latent herpes viruses occurs with immunosuppression. Alemtuzumab is an antibody targeting CD52, which is expressed on all B- and T-cells. Treatment with alemtuzumab leads to profound T-cell suppression, and reactivation of cytomegalovirus (CMV) and Epstein-Barr virus (EBV) occurs. Valganciclovir is used as an anti-CMV prophylaxis during alemtuzumab therapy. OBJECTIVE To determine if EBV reactivation is decreased with valganciclovir prophylaxis. STUDY DESIGN Plasma EBV DNA was serially quantified by quantitative polymerase chain reaction with a World Health Organization EBV standard in patients receiving alemtuzumab therapy with valganciclovir as anti-CMV prophylaxis. RESULTS Twenty-nine patients were studied. A total of 258 samples were quantified, at a median of 7 (3-25) specimens per patient. Twenty-four patients never had any quantifiable EBV DNA. Five patients (17%) developed EBV reactivation. Two patients had EBV reactivation at very low levels of about 10(3)IU/mL, 3-4 logs lower than those typically found in post-transplant lymphoproliferative diseases. Three patients had EBV reactivation at higher levels of 10(4)IU/mL, which only occurred after two courses of alemtuzumab were administered. EBV reactivation subsided spontaneously in four cases. One patient developed EBV-positive Hodgkin lymphoma, but he had also received previously another potent T-cell suppressing drug fludarabine. CONCLUSION Valganciclovir suppressed EBV reactivation during alemtuzumab therapy. It might be a useful prophylaxis in immunocompromized patient populations at high risk of EBV reactivation.