Yuh Shan Lee

An abnormal nonhyperdiploid karyotype is a significant adverse prognostic factor for multiple myeloma in the bortezomib era.

Multiple myeloma is clinically heterogeneous and risk stratification is vital for prognostication and informing treatment decisions. As bortezomib is able to overcome several high‐risk features of myeloma, the validity of conventional risk‐stratification and prognostication systems needs to be reevaluated. We study the survival data of 261 previously untreated myeloma patients managed at our institution, where bortezomib became available from 2004 for the treatment of relapse disease. Patient and disease characteristics, and survival data were evaluated overall, and with respect to bortezomib exposure. Overall, the international staging system (ISS), metaphase karyotyping and interphase fluorescence in situ hybridization (FISH) were discerning of survival outcomes, where the median for the entire cohort was 5.2 years. However, when stratified by bortezomib exposure, only metaphase karyotyping was still discriminating of long‐term prognosis. The presence of an abnormal nonhyperdiploid karyotype overrides all other clinical and laboratory parameters in predicting for a worse outcome on multivariate analysis (median survival 2.6 years, P = 0.001), suggesting that bortezomib used at relapse is better able to overcome adverse risk related to high tumor burden (as measured by the ISS) than adverse cytogenetics on conventional karyotyping. Metaphase karyotyping provides additional prognostic information on tumor kinetics where the presence of a normal diploid karyotype in the absence of any high‐risk FISH markers correlated with superior survival and could act as a surrogate for lower plasma cell proliferation. Am. J. Hematol., 2010.

Panobinostat in combination with bortezomib in patients with relapsed or refractory peripheral T-cell lymphoma: an open-label, multicentre phase 2 trial

BACKGROUND Patients with relapsed or refractory peripheral T-cell lymphoma have a poor prognosis after conventional chemotherapy. Approved novel agents have only modest single-agent activity in most subtypes of peripheral T-cell lymphoma. Panobinostat is a potent oral pan-deacetylase inhibitor. Findings of many preclinical studies have shown synergistic antilymphoma activity when panobinostat is combined with the proteasome inhibitor bortezomib. We aimed to study the effect of panobinostat and bortezomib in patients with relapsed or refractory peripheral T-cell lymphoma. METHODS In this open-label, multicentre phase 2 trial, we recruited patients aged 21 years or older with relapsed or refractory peripheral T-cell lymphoma who had received at least one previous line of systemic therapy from five tertiary hospitals in Singapore, Malaysia, and South Korea. Patients received 20 mg oral panobinostat three times a week and 1·3 mg/m(2) intravenous bortezomib two times a week, both for 2 of 3 weeks for up to eight cycles. The primary endpoint was the proportion of patients who achieved an objective response in accordance with the International Working Group revised response criteria; analyses were by intention to treat. The study is completed and is registered with ClinicalTrials.gov, number NCT00901147. FINDINGS Between Nov 9, 2009, and Nov 26, 2013, we enrolled 25 patients with various histological subtypes of peripheral T-cell lymphoma. Of 23 patients assessable for responses, ten (43%, 95% CI 23-63) patients had an objective response, of which five were complete responses. Serious adverse events were reported in ten (40%) of 25 patients. Common treatment-related grade 3-4 adverse events included thrombocytopenia (17 [68%]), neutropenia (ten [40%]), diarrhoea (five [20%]), and asthenia or fatigue (two [8%]). We recorded peripheral neuropathy of any grade in ten (40%) patients. INTERPRETATION Combined proteasome and histone deacetylase inhibition is safe and feasible and shows encouraging activity for patients with peripheral T-cell lymphoma. Our findings validate those of preclinical studies showing synergism in the combination and represent a rational way forward in harnessing the full potential of novel agents in peripheral T-cell lymphoma. FUNDING Novartis Pharmaceuticals, Janssen Pharmaceuticals, and Singhealth Foundation.

The impact of time from diagnosis to treatment in diffuse large B-cell lymphoma

Abstract Diffuse large B-cell lymphoma (DLBCL) is a high-grade lymphoma that requires treatment. We retrospectively analyzed the impact of time from diagnosis-to-treatment (TDT) on progression-free survival (PFS) and overall survival (OS) in 581 R-CHOP-treated patients. TDT was defined as the interval between diagnostic biopsy date and day 1 R-CHOP. Cox regression showed stage 3–4 disease (p = .01) and longer TDT (HR 1.13, p =.031) were associated with shorter OS. Eastern Cooperative Oncology Group ≥2 (p = .02), stage 3–4 disease (p < .001), and longer TDT (HR 1.12, p = .028) predicted shorter PFS. The significant interactions between TDT with lactate dehydrogenase (LDH) and with disease stage prompted separate analyses in high versus normal LDH, and stage 3–4 versus 1–2 disease. Longer TDT was associated with shortened PFS and OS only with advanced stage, and, if high LDH was present. Treatment should be started as early as possible for high-tumor burden disease. Delaying treatment in patients with early stage or low LDH does not seem harmful.

Thrombotic microangiopathy during carfilzomib use: case series in Singapore

Carfilzomib is an irreversible proteasome inhibitor and is an effective treatment for multiple myeloma (MM).1, 2 It received US Food and Drug Administration approval based on a single-arm multicenter trial of carfilzomib monotherapy in 266 patients with relapsed MM following at least two prior lines of treatment including bortezomib and immunomodulators.1, 3 Safety analyses from four phase II carfilzomib trials (N=526) that included heavily pre-treated MM patients suggested a favorable risk-benefit profile with no specific signal of thrombotic microangiopathy (TMA) reported. However, serious adverse events of anemia, thrombocytopenia and increased serum creatinine comprised 1.3%, 1.1% and 1.3%, respectively.4 Over 350 subjects have been enrolled in randomized phase III trials in Asian countries. Herein, we report four cases of TMA related to carfilzomib use among 24 patients from 2 tertiary hospitals in Singapore (Table 1). All patients who started carfilzomib had a creatinine clearance >30 ml/min and platelet counts>50 × 109/l at the start of treatment.

Leukaemic presentation of angioimmunoblastic T-cell lymphoma.

A 62-year-old female presented with a 3-month history of poor appetite, cervical lymphadenopathy and an erythematous macular rash over her face, trunk and limbs. A full blood count showed: haemoglobin concentration 118 g/l, white cell count 138 5 9 10/l, lymphocyte count 101 9 10/l and platelet count 146 9 10/l. The lymphocytes were small to medium-sized with scanty, faintly basophilic cytoplasm (image). Peripheral blood flow cytometric immunophenotyping showed an expanded population (82%) of T lymphocytes that were positive for CD3, CD2, CD5 and TCR-ab with aberrant loss of CD7. These cells were negative for CD4/CD8, CD34, CD10 and terminal deoxynucleotidyl transferase. Cervical lymph node biopsy showed extensive effacement by angioimmunoblastic T-cell lymphoma (AITL). Skin and bone marrow biopsies confirmed involvement by T-cell lymphoma. The patient received six cycles of etoposide, doxorubicin, cyclophosphamide, vincristine and prednisone (EPOCH) but had progressive disease 2 months after completing therapy. A leukaemic phase of lymphoma is usually seen in the context of indolent B-cell lymphomas, B and T prolymphocytic leukaemias and, less commonly, aggressive lymphomas such as diffuse large B-cell lymphoma and blastoid mantle cell lymphoma. It is rare in AITL.

Recurrent PD-L1 Structural Rearrangements in Natural Killer/T Cell Lymphoma Patients with Complete Response to PD-1 Blockade Therapy

This study aims to identify recurrent genetic alterations in relapsed or refractory (RR) natural-killer/T-cell lymphoma (NKTL) patients who have achieved complete response (CR) with programmed cell death 1 (PD-1) blockade therapy. Seven of the eleven patients treated with pembrolizumab achieved CR while the remaining four had progressive disease (PD). Using whole genome sequencing (WGS), we found recurrent clonal structural rearrangements (SR) of the PD-L1 gene in four of the seven (57%) CR patients’ pretreated tumors. These PD-L1 SRs consist of inter-chromosomal translocations, tandem duplication and micro-inversion that disrupted the suppressive function of PD-L1 3’UTR. Interestingly, recurrent JAK3-activating (p.A573V) mutations were also validated in two CR patients’ tumors that did not harbor the PD-L1 SR. Importantly, these mutations were absent in the four PD cases. With immunohistochemistry (IHC), PD-L1 positivity could not discriminate patients who archived CR (range: 6%-100%) from patients who had PD (range: 35%-90%). PD-1 blockade with pembrolizumab is a potent strategy for RR NKTL patients and genomic screening could potentially accompany PD-L1 IHC positivity to better select patients for anti-PD-1 therapy.Abstract Natural killer/ T-cell lymphoma (NKTL) patients failing L-asparaginase regimens have extremely poor treatment outcomes. Previous case series showed promising activity when relapsed or refractory NKTL patients were treated with anti-programmed death 1 (PD1) inhibitors. Here, we continue to unravel the molecular profiles with whole-genome sequencing (WGS) on an extended cohort of 11 pembrolizumab-treated patients (median age at diagnosis, 42 years; range, 27-66 years) with a median follow-up of 11 months (range, 2 - 25 months) since starting anti-PD1 therapy. Seven patients achieved complete response (CR) and four patients had progressive disease (PD). Using WGS, we found structural rearrangements of the PD-L1 gene, JAK3-activating mutations and ARID1B homozygous insertion in four, two and one of the CR patients’ tumors, respectively. Interesting, these alterations, especially PD-L1 rearrangements, were absent in the four PD cases. Expression of PD1 ligand (PD-L1) was strong in nine patients (5 CR and 4 PD cases) and weak in two patients (both CR). PD1 blockade with pembrolizumab was a potent strategy for NKTL patients and genomic screening could potentially accompany PD-L1 immunohistochemical screening to better select patients for anti-PD1 therapy.

Outcomes of patients with peripheral t-cell lymphoma in first complete remission: Data from three tertiary asian cancer centers

Peripheral T-cell lymphomas (PTCL) represent a heterogenous group of aggressive non-Hodgkin’s lymphoma, with poorer treatment outcomes compared to that of their B-cell counterparts, using conventional chemotherapy. Despite the lack of randomized data, upfront high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT) has been associated with better treatment outcomes 3 and various guidelines now recommend that patients with chemosensitive PTCL should undergo upfront HDC/ASCT. Consistently, both retrospective and prospective studies suggest that such a strategy appears to benefit patients with responding disease, especially those in first complete remission (CR1). However, it is conceivable that PTCL patients who do achieve CR1 may have more favorable survival outcomes, regardless of the treatment they received. Thus, we performed a retrospective analysis of PTCL patients who attained CR1 following first-line induction therapy to determine the factors that would impact their survival outcomes, including the role of upfront HDC/ASCT. Prospectively maintained T-cell lymphoma databases from the National Cancer Centre Singapore (NCCS)/ Singapore General Hospital (SGH), Samsung Medical Centre, South Korea, and Sun Yat Sen University Cancer Centre, China, were retrospectively reviewed after approval from the institutional review boards of the individual institutions. We included patients with the following histological subtypes: PTCL-not otherwise specified (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL), anaplastic lymphoma kinase (ALK)negative anaplastic large cell lymphoma (ALCL), and monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) , previously known as type II enteropathic T-cell lymphoma, treated with curative intent. To standardize the effect of treatment on outcome, we excluded patients with ALK-positive ALCL because their first-line treatment would not include considerations for upfront HDC/ASCT and patients with natural-killer/ T-cell lymphoma whose treatment may have included upfront allogeneic stem cell transplantation. Upfront HDC/ASCT was not standard practice in any of the participating institutions and left to the discretion of the primary physician or tumor board decisions. We also excluded patients with composite lymphomas, cutaneous T-cell lymphomas and patients who were not treated with curative intent. We then reviewed the clinical characteristics, treatment and survival outcomes of patients who achieved CR1. Patients who had partial response, stable disease and progression of disease were excluded from the analysis. Treating physicians determined the end of treatment response assessments. The exact modality was as per institutional standards, which was either computed tomography or positron-emission tomography scans. Progression-free survival (PFS) was defined as the interval from diagnosis to progression, relapse or death. Overall survival (OS) was defined as the interval from diagnosis to death from any cause. Survival estimates were calculated using the Kaplan−Meier method. Survival curves were compared using the log-rank test. Univariate and multivariate analyses were performed using the Cox proportional hazards model to assess the association between several prognostic factors such as age, stage, international prognostic index (IPI), prognostic index for

Durable remission is achievable with localized treatment and reduction of immunosuppression in limited stage EBV-related plasmablastic lymphoma

Dear Editor, We read with interest the recent letters by Fedele et al. [1] and Yanamandra et al. [2] where plasmablastic lymphoma was successfully treated with a combination of cytotoxic chemotherapy plus either bortezomib or lenalidomide. This is a rare disease, with no prospective randomised trials, and thus no defined standard of care [3]. We present the case of a 78-year-old man who gave a 2week history of a painless enlarging exophytic mass on the upper left oral mucosa. Nineteen years prior to diagnosis, the patient had a cadaveric renal transplant. He was on long-term immunosuppression with prednisolone, ciclosporin, and azathioprine. He had longstanding type 2 diabetes and hypertension with advanced ischaemic heart disease. A 1 cm × 1 cm indurated hyperaemic mass was seen in the oral mucosa. The biopsy showed a diffuse lymphoid infiltrate with sheets of large cells having vesicular chromatin and prominent central nucleoli. Immunostaining for CD20 was negative, cells were lambda light chain restricted, and EBER staining was positive. Cells were also positive for CD30 and CD3, but negative for other T cell markers. Clonal rearrangement was demonstrated by PCR for IGH and IGK, and not for T cell receptors. The diagnosis was thus made of EBV-related PBL. The full blood count was unremarkable and the marrow was uninvolved. EBV quantitative PCR showed 49,150 copies/mL (4.69 log) while HIV serology was negative. A staging PET-CT confirmed localized disease. Following discussion with the renal team, azathioprine was stopped and the ciclosporine dose was reduced. In view of the patient’s significant co-morbidities, the highly aggressive nature of PBL, and the paucity of clinical trial data, a palliative regimen of brentuximab vedotin (BV) [4] with RT was agreed upon. Despite an initial reduction in size, the mass was noted to be growing during the second cycle of BV which was thus discontinued. RT monotherapy was started and was tolerated well apart from mild mucositis. Only 16 of 20 planned fractions were delivered, total 32 Gy, because of an emergency admission to another hospital for a urinary tract infection. Following recovery, the oral mass had disappeared and the mucositis had resolved (Fig. 1). The patient remains in complete remission 2 years after his diagnosis, albeit with persistence of circulating EBV DNA of 22,015 copies/mL (4.34 log). In contrast to the two recently published case reports of plasmablastic lymphoma, our patient had a very limited disease and was not fit for anthracycline-based treatment. Despite disease progression on BV, he achieved a durable complete response with radiotherapy only, highlighting that localized, non-intensive treatment combined with a reduction in immunosuppression can result in very good outcomes in selected cases. * N. F. Grigoropoulos nicholas.francis.grigoropoulos@singhealth.com.sg

Treatment of advanced stage Hodgkin lymphoma – it's all about risk-benefit

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