Thomas S. Y. Chan

PD1 blockade with pembrolizumab is highly effective in relapsed or refractory NK/T-cell lymphoma failing L-asparaginase

Natural killer (NK)/T-cell lymphomas failing L-asparaginse regimens have no known salvage and are almost invariably fatal. Seven male patients with NK/T-cell lymphoma (median age, 49 years; range, 31-68 years) for whom a median of 2 (range, 1-5) regimens (including l-asparaginase regimens and allogeneic hematopoietic stem-cell transplantation [HSCT] in 2 cases) failed were treated with the anti-programmed death 1 (PD1) antibody pembrolizumab. All patients responded, according to various clinical, radiologic (positron emission tomography), morphologic, and molecular (circulating Epstein-Barr virus [EBV] DNA) criteria. Two patients achieved complete response (CR) in all parameters. Three patients achieved clinical and radiologic CRs, with two having molecular remission (undetectable EBV DNA) but minimal EBV-encoded RNA-positive cells in lesions comprising predominantly CD3+CD4+ and CD3+CD8+ T cells (which ultimately disappeared, suggesting they represented pseudoprogression) and one having detectable EBV DNA despite morphologic CR. Two patients achieved partial response (PR). After a median of 7 (range, 2-13) cycles of pembrolizumab and a follow-up of a median of 6 (range, 2-10) months, all five CR patients were still in remission. The only adverse event was grade 2 skin graft-versus-host disease in one patient with previous allogeneic HSCT. Expression of the PD1 ligand was strong in 4 patients (3 achieving CR) and weak in 1 (achieving PR). PD1 blockade with pembrolizumab was a potent strategy for NK/T-cell lymphomas failing l-asparaginase regimens.

Allogeneic haematopoietic SCT for natural killer/T-cell lymphoma: a multicentre analysis from the Asia Lymphoma Study Group

Eighteen patients (men=14; women=4) with natural killer (NK)/T-cell lymphomas (CR1, N=9; CR2, N=7; PR, N=1; progressive disease, N=1) undergoing allogeneic haematopoietic SCT (HSCT) (myeloablative, N=14; reduced intensity, N=4) were analyzed. With a median follow-up of 20.5 months, the 5-year OS was 57% and 5-year EFS was 51%. The use of the SMILE regimen pre-HSCT was the most important positive prognostic indicator, resulting in significantly superior OS and EFS (P<0.01). Acute GVHD had a significant negative impact on OS (P=0.03). CR1 and CR2 patients had similar survivals, but all patients who were not transplanted in remission died. Chronic GVHD, International Prognostic Index, disease stage, primary sites of involvement, conditioning regimen and source of HSC did not affect survival. Although allogeneic HSCT leads to reasonable survival for NK/T-cell lymphoma patients, results need to be compared with those in patients receiving L-asparaginase-containing regimens. Novel prognostic models incorporating biomarkers, such as circulating EBV DNA, are needed to identify high-risk patients who may benefit from allogeneic HSCT.

Pembrolizumab for relapsed anaplastic large cell lymphoma after allogeneic haematopoietic stem cell transplantation: efficacy and safety

Dear Editor, Antibody treatment targeting the programmed cell death protein 1 (PD1) is rapidly becoming an important strategy against Hodgkin lymphoma [1]. However, recipients of allogeneic haematopoietic stem cell transplantation (HSCT) are typically excluded from clinical trials. Negative signalling via PD1 after ligation with its ligand PDL1 is regarded to play an important part in ameliorating cytotoxic T cell-mediated graftversus-host disease (GVHD) [2], implying that PD1 blockade after allogeneic HSCT might incite or exacerbate GVHD. Notwithstanding these concerns, PD1 blockade has been tested in allogeneic HSCT recipients, which to date is confined to relapsed Hodgkin lymphoma. Two anti-PD1 antibodies nivolumab and pembrolizumab have been used. For nivolumab, in 10 of 14 reported cases who were evaluable [3–5], 3 patients developed GVHD, 1 case grade IV in severity. Four patients achieved complete response (CR). For pembrolizumab, only three patients have been reported. In the first two cases, no GVHD was observed, and one patient achieved CR [6]. In the third patient, despite achieving CR, grade IV GVHD developed, leading to death [7]. No data hitherto exist for patients with other lymphomas treated with anti-PD1 antibodies after allogeneic HSCT. A 35-year-old woman presented with stage IV anaplastic lymphoma kinase-negative anaplastic large cell lymphoma (ALCL), which did not respond to 6 cycles of ProMACECytaBOM (prednisolone, doxorubicin, cyclophosphamide, etoposide, cytarabine, bleomycin, methotrexate). However, CR was achievedwith three courses of a regimen comprising cisplatin, ifosfamide, gemcitabine, etoposide and L-asparaginase, together with local radiotherapy. She then underwent an autologous HSCT, with cyclophosphamide, carmustine and etoposide as conditioning. The lymphoma relapsed 11 months afterwards. Because lymphoma cells expressed CD30, the anti-D30 antibody brentuximab vedotin was administered, which resulted in CR after five courses. She then received an allogeneic HSCT from a volunteer unrelated donor (mismatched at one HLA-DR locus), with cyclophosphamide and total body irradiation as conditioning. Two episodes of acute GVHD involving the skin and intestine developed, which responded to corticosteroids. Three months post-HSCT, the lymphoma relapsed again. Analysis of peripheral blood showed complete donor DNA chimerism. Re-biopsy confirmed CD30 expression on lymphoma cells. Three cycles of brentuximab vedotin and bendamustine were administered. Re-assessment positron emission tomography computed tomography (PET/CT) scan showed disease progression in the left lung, and supraclavicular, mediastinal and upper abdominal lymph nodes (Fig. 1a). Transbronchial biopsy confirmed persistent lymphoma, with concomitant invasion by yeast-like fungal organisms. Under a named-patient programme, she gave consent to treatment with pembrolizumab (2 mg/kg), with liposomal amphotericin as antifungal coverage. Transaminases started to rise 10 days after the first dose of pembrolizumab. There was otherwise no evidence of GVHD. Methylprednisolone was given at 2 mg/kg/day, which at one point was escalated to 500 mg/day for a day, and then 250 mg/day for a week. Transaminases peaked at the end of the third week of treatment, and then gradually recovered (Fig. 1b), becoming normal by the end of the fifth week. The second dose of * Yok-Lam Kwong ylkwong@hkucc.hku.hk

PD1 blockade with low-dose nivolumab in NK/T cell lymphoma failing l -asparaginase: efficacy and safety

Dear Editor, Extranodal natural killer (NK)/T cell lymphoma is an aggressive malignancy. Effective regimens for this lymphoma contain L-asparaginase. For patients failing L-asparaginase-containing regimens, there are no useful conventional salvage approaches [1]. We recently reported that blockade of programmed cell death protein 1 (PD1) on effector T cells with the anti-PD1 antibody pembrolizumab was highly efficacious in NK/T cell lymphoma failing L-asparaginase [2]. Anti-PD1 antibodies are off-label non-reimbursed drugs for NK/T cell lymphomas. Not every patient can afford pembrolizumab. Since employing PD1 blockade as an option for NK/T cell lymphomas failing L-asparaginase, we have with informed consent treated three patients who could only afford another anti-PD1 antibody nivolumab, which if given at 40 mg (the smallest vial available) every 2 weeks (Q2W) was much cheaper than pembrolizumab. Patient 1 was a 59-year-old man with stage IV disease involving the nasal cavity, right testis and bone marrow (Table 1). Initial treatment with an L-asparaginase-containing regimen for three cycles resulted in complete response (CR), as assessed by 18F-fluorodeoxyglucose (FDG) positron emission tomography computed tomography (PET/CT). However, he presented with fever, facial skin infiltration, pancytopenia, and ataxia after the fourth course. Magnetic resonance imaging (MRI) showed lymphomatous infiltration of the cerebellum and dorsal midbrain (Fig. 1a). Biopsy of bone marrow and skin confirmed lymphoma relapse. Cerebrospinal fluid also showed lymphoma cells. Nivolumab was started. Shortly after the first dose, his mental state worsened and bilateral vocal cord palsy developed, requiring emergency tracheostomy. Interestingly, the facial skin lesion then totally regressed. MRI brain repeated 10 days after the second dose of nivolumab showed stable disease (Fig. 1a). However, his genera l physique deter iorated and he died from Stenotrophomonas maltophilia chest infection. Patient 2 was a 43-year-old man with stage II disease involving the nasopharynx and cervical lymph nodes, who achieved CR with SMILE (Table 1) and sandwiched radiotherapy (50 Gy). He presented 3.5 years later with gastrointestinal bleeding. CT scan showed a distal jejunal lesion with adjacent lymphadenopathy. Histology of the resected tumor confirmed lymphomatous recurrence. PET/CT scan showed residual FDG-avid foci after the operation (Fig. 1b). Nivolumab was started. PET/CT scan after four doses of nivolumab showed no FDG-avid lesions (Fig. 1b). He has since received five additional doses, and is asymptomatic. Patient 3 was an 80-year-old woman with stage IV disease and widespread cutaneous infiltration. After six courses of an L-asparaginase-containing regimen (Table 1), CR was achieved. The lymphoma relapsed 3 months later, and there was a delay before the patient sought treatment. She was admitted in a moribund state. PET/CT scan showed hypermetabolic hepatosplenomegaly, generalized lymphadenopathy, and extensive skin lesions (Fig. 1c). Nivolumab was given. Approximately a week afterwards, there was fever associated with a mild hyperbilirubinemia, hypofibrinogenemia, and increased D-dimer; which could be consistent with grade I cytokine release syndrome (CRS) [3]. These problems subsided with * Yok-Lam Kwong ylkwong@hkucc.hku.hk

Disseminated fusarium infection after ibrutinib therapy in chronic lymphocytic leukaemia

Dear Editor, A 46-year-old man presented in 2007 with generalized lymphadenopathy. A diagnosis of small lymphocytic lymphoma/ chronic lymphocytic leukaemia (CLL) with marrow involvement was made. He was treated with 6 cycles of fludarabine, mitoxantrone and dexamethasone and achieved a complete remission (CR). The disease relapsed in 2010, and he was treated with 6 cycles of rituximab, cyclophosphamide, epirubicin, vincristine and prednisolone, followed by consolidation with ibritumomab tiuxetin. In 2014, there was disease recurrence, presenting as generalized lymphadenopathy and marrow infiltration with anaemia and thrombocytopenia. Fluorescence in situ hybridization (FISH) showed a deletion of 11q23. Six cycles of obinutuzumab and bendamustine were given. However, pancytopenia due to marrow infiltration persisted. Because of neutropenia, he was put on maintenance itraconazole (200 mg twice daily) and regular injections of granulocyte colony stimulating factor to increase the neutropil count. After a brief period of stable disease, progressive lymphadenopathy then developed. He was started on the Bruton tyrosine kinase inhibitor ibrutinib at 420 mg daily. Itraconazole had to be stopped because of liver function derangement. Patient gave informed consent to treatment. Six weeks after commencement of ibrutinib, he developed unremitting fever. Full blood count showed haemoglobin: 7.4 g/dL; white cell count: 37.7 × 10/L (neutrophil: 0.5 × 10/L, lymphocyte 36.9 × 10/L); and platelet count: 24 × 10/L. There was also profound hypogammaglobulinaemia (immunoglobulin A, IgA: 9 mg/dL; IgG: 483 mg/dL; IgM: 15 mg/dL). Physical examination showed multiple skin lesions, including a plaque with a necrotic centre in the right calf (Fig. 1a), and ulcerated nodules in the right submandibular region, left shoulder and left knee (Fig. 1b). Biopsy of the left knee skin lesion showed infiltration of inflammatory cells (Fig. 1c), and Grocott stain showed the presence of fungal elements (Fig. 1d). Culture from blood and the biopsied tissue was negative. Polymerase chain reaction followed by sequencing of the internal transcribed spacer region confirmed that the fungus belonged to the Fusarium solani species complex. He was treated with oral voriconazole (400 mg twice daily for 1 day then 200 mg twice daily). Defervescence was achieved a week after voriconazole therapy and he was discharged. Six weeks later, the neutrophil count started to rise and skin lesions gradually subsided. Voriconazole has since been continued as secondary prophylaxis. Sixteen months after commencement of ibrutinib, he has normal blood counts and complete regression of all nodal lesions. Fusarium spp. are important hyaline moulds that can cause serious infections in immunocompromised hosts. They are ubiquitous in the environment, distributed widely in soil, plants and water systems [1]. The infection ranges from superficial (fungal keratitis, onychomycosis) to invasive (sinusitis, pneumonia) and disseminated. In patients with haematological malignancies, infection is typically invasive and disseminated [2]. Neutropenia and defects in T cell immunity are the important underlying risks. In a recent study from three countries over a 66-month period, 76 cases of fusariosis were * Yok-Lam Kwong ylkwong@hkucc.hku.hk

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.

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.

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.

Pembrolizumab and lenalidomide induced remission in refractory double-hit lymphoma

Dear Editor, B cell lymphomas with concurrent rearrangements of BCL2 andMYC are often referred to as double-hit lymphomas [1]. It is an aggressive neoplasm characterized by rapid lymphoma cell proliferation, resulting in a large tumor load, B-symptoms, and a high incidence of bone marrow infiltration and central nervous system (CNS) involvement [1]. Response to conventional regimens such as R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) is poor, with about 60 % of patients dying within 6 months and a 5year survival of less than 10 % [2]. Increasing the dose intensity of chemotherapy may result in better progression-free survival, but overall survival is not improved [3]. For refractory double-hit lymphomas, there is no known effective treatment. Novel therapeutic strategies are needed. A 51-year-old man presented with massive abdominal, pelvic, and cervical lymphadenopathy. Biopsy of the cervical lymph node showed follicular lymphoma, grade 1–2. There was disease progression during treatment with rituximab and bendamustine. After four courses of R-CHOP, positron emission tomography computed tomography (PET/CT) showed good response. However, he presented with back pain and right sciatica after the fifth course. Magnetic resonance imaging showed infiltrative lesions in the right paraspinal and pyriformis muscles, and multiple deposits in the left occipital, and right frontal and parietal regions. A biopsy of the paraspinal mass showed a high-grade B cell lymphoma, with histological features intermediate between diffuse large B cell lymphoma (DLBCL) and Burkitt lymphoma. Neoplastic cells were BCL2-positive, MYC-positive, CD20-negative, and BCL6-negative. Fluorescence in situ hybridization showed MYC rearrangement in 70 % of cells. Overall features were consistent with evolution of follicular lymphoma to a doublehit lymphoma. High-dose methotrexate and cytarabine were given, but there was rapid disease progression with right testicular involvement. Further treatment with multiple regimens (dexamethasone, methotrexate, ifosfamide, etoposide) (cisplatin, ifosfamide, gemcitabine, etoposide, dexamethasone) (mitoxantrone, cytarabine) was ineffective. There was disease progression in multiple nodal areas and the right testicle (Fig. 1A). Lenalidomide (10mg daily, escalated to 15mg daily 1 week later) and the anti-PD1 antibody pembrolizumab (100 mg every 3 weeks) were given with informed consent. Because of painful testicular enlargement, one dose of cyclophosphamide (1 g) was administered after the first course for symptomatic control. There was gradual improvement of systemic disease after the second course. However, diplopia and dysarthria developed, and lymphoma cells were found in the cerebrospinal fluid (CSF). Intrathecal methotrexate and cytarabine (twice weekly) and one dose of thiotepa (30mg/m) resulted in complete resolution of CNS symptoms and clearance of lymphoma cells from the CSF. PET/CT performed after three cycles of pembrolizumab showed complete metabolic response of all systemic lesions (Fig. 1B). The patient has since received another course of treatment and remains asymptomatic. He is currently evaluated for a matched-sibling allogeneic hematopoietic stem cell transplantation. Reported data of pembrolizuamb in aggressive B cell lymphomas are very scanty. In refractory primary mediastinal B cell lymphoma (N = 10) [4], with pembrolizumab used at 10 mg/kg every 2 weeks, the overall response rate (ORR) * Yok-Lam Kwong ylkwong@hkucc.hku.hk

Antifungal drug usage in haematologic patients during a 4‐year period in an Asian university teaching hospital

Invasive fungal disease (IFD) is an important problem complicating the therapy of haematologic patients.