Chor-Sang Chim

SMILE for natural killer/T-cell lymphoma: analysis of safety and efficacy from the Asia Lymphoma Study Group

Natural killer/T-cell lymphoma is rare and aggressive, with poor outcome. Optimal treatment remains unclear. A novel regimen dexamethasone, methotrexate, ifosfamide, l-asparaginase, and etoposide (SMILE) showed promise in phase 1/2 studies with restrictive recruitment criteria. To define the general applicability of SMILE, 43 newly diagnosed and 44 relapsed/refractory patients (nasal, N = 60, nonnasal, N = 21; disseminated, N = 6; male, N = 59; female, N = 28) at a median age of 51 years (23-83 years) were treated. Poor-risk factors included stage III/IV disease (56%), international prognostic index of 3 to 5 (43%), and Korean prognostic scores of 3 to 4 (41%). A median of 3 (0-6; total = 315) courses of SMILE were administered. Significant toxicities included grade 3/4 neutropenia (N = 57; 5 sepsis-related deaths); grade 3/4 thrombocytopenia (N = 36); and nephrotoxicity (N = 15; 1 acute renal failure and death). Interim analysis after 2 to 3 cycles showed complete remission rate of 56%, partial remission rate of 22%, giving an overall response rate of 78%. On treatment completion, the overall-response rate became 81% (complete remission = 66%, partial remission = 15%). Response rates were similar for newly diagnosed or relapsed/refractory patients. At a median follow-up of 31 months (1-84 months), the 5-year overall survival was 50% and 4-year disease-free-survival was 64%. Multivariate analysis showed that international prognostic index was the most significant factor impacting on outcome and survivals.

Aberrant gene methylation implicated in the progression of monoclonal gammopathy of undetermined significance to multiple myeloma

Malignant transformation is a multistep process that may involve dysregulation of oncogenes and tumour suppressor genes, and monoclonal gammopathy of undetermined significance (MGUS) is believed to be a precursor of multiple myeloma. To investigate whether aberrant promoter methylation might be involved in the evolution of MGUS to multiple myeloma, we examined the p16, protein tyrosine phosphatase, non-receptor type 6 (SHP1), death-associated protein (DAP) kinase, E-cadherin and oestrogen receptor genes, most being tumour suppressor genes, by methylation-specific polymerase chain reaction. In 32 cases of multiple myeloma and 19 cases of MGUS, significantly more frequent methylation of p16 (p = 0.001), SHP1 (p⩽0.001) and E-cadherin (p⩽0.001) genes was found in multiple myeloma than in MGUS. Methylation of DAP kinase and oestrogen receptor genes was comparable in multiple myeloma and MGUS. In conclusion, methylation of p16, SHP1 and E-cadherin genes might be involved in the progression of MGUS to multiple myeloma.

Use of the oral chelator deferiprone in the treatment of iron overload in patients with Hb H disease

Seventeen non‐transfusion‐dependent Chinese haemoglobin H (Hb H) disease patients (age 29–76 years) with serum ferritin >900 μg/l were treated with deferiprone for up to 18 months. One patient withdrew and data from 16 patients were analysed. Sixteen other Hb H patients with ferritin <900 μg/l, matched for age and genotype, acted as controls. Treatment was well tolerated except for mild arthralgia. Serum ferritin fell with treatment, reaching significance at 6 and 18 months (from 1492·3 ± 901·4 to 519·4 ± 405·4 μg/l at 18 months, P = 0·0008). Nine of 16 patients had levels below 397 μg/l before 18 months. Serum ferritin remained stable 6 months after stopping treatment. In contrast, there was no change in ferritin levels in the control group. Magnetic resonance imaging was used for measurement of liver iron content. Spin echo T1‐signal intensity ratio (T1‐SIR) and gradient echo T2‐signal intensity ratio (T2‐SIR) increased with treatment. T2‐SIR rose from 0·17 ± 0·08 pretreatment to 0·58 ± 0·50 at 2 years (P = 0·0055). Improvement occurred in 12 of 16 patients, reaching normal in three patients. Using echocardiography, peak early diastolic : late diastolic blood flow (E/A) remained unchanged with treatment, but isovolumic relaxation time (IVRT) was prolonged at 2 years indicating mild impairment of diastolic function. All systolic function parameters were normal. A longer treatment period is desirable to demonstrate improvement in cardiac function.

Non-gastric marginal zone B cell lymphoma: clinicopathologic features and treatment results

The optimal treatment strategy and outcome of non-gastric marginal zone lymphoma (MZL) remains undefined. The role of rituximab and fludarabine in MZL has not been critically appraised and compared with conventional chemotherapy. We retrospectively analyzed 81 consecutive patients with non-gastric MZL (mucosa-associated lymphoid tissue lymphoma, n = 66; splenic MZL, n = 11; nodal MZL, n = 4). As a group, the treatment results were favorable, with an overall response rate of 87% and a complete response (CR) rate of 73%. The CR rate was similar for conventional chemotherapy, and rituximab- and fludarabine-containing regimens. However, the relapse rate was significantly decreased in rituximab- and fludarabine-containing regimens. The use of rituximab and fludarabine was associated with acceptable side effects. For splenic MZL, splenectomy was significantly associated with a superior CR rate. Early stage, good performance status, and low international prognostic index risk scores significantly impacted on CR rate and survivals. Rituximab and fludarabine were safe for non-gastric MZL and resulted in more durable remissions.

Epigenetic inactivation of DAPK1, p14ARF, mir-34a and -34b/c in acute promyelocytic leukaemia

Aim TP53 mutation frequently occurs in solid cancers but not haematological cancers including acute promyelocytic leukaemia (APL) characterised by t(15;17). Both DAPK1 and p14ARF positively regulate p53 whereas miR-34a and -34b/c are direct transcriptional targets of p53. We studied if DNA methylation might contribute to inactivation of gene/microRNA (miRNA) in the TP53 tumour suppressor network. Methods Promoter methylation of DAPK1, p14ARF, miR-34a and -34b/c were studied in 10 normal bone marrow samples, NB4 cell line and 60 APL primary samples at diagnosis by methylation-specific PCR (MSP). Results DAPK1, p14ARF, miR-34a and -34b/c were completely unmethylated in normal bone marrow samples. DAPK1, miR-34a and -34b/c were completely methylated in NB4. Treatment of NB4 by 5′-Aza-2′-deoxyctidine resulted in promoter demethylation together with re-expression of DAPK1 and both miRNAs. In primary APL samples, methylation of miR-34b/c was detected in 43% in contrast to absence of methylation of DAPK1, p14ARF or miR-34a. Overexpression of miR-34b in NB4 resulted in inhibition of proliferation. Conclusions Methylation of DAPK1, miR-34a and -34b/c is tumour-specific, and associated with gene/miRNAs silencing. miR-34b/c is a tumour suppressor miRNA in APL. Methylation of miR-34b/c may contribute to APL leukaemogenesis.

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.

Use of fludarabine-containing chemotherapeutic regimen results in durable complete remission of subcutaneous panniculitis-like T-cell lymphoma.

Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare lymphoma. The optimal therapy for SPTCL is undefined and the results of treatment with anthracycline-containing chemotherapy for aggressive cases have remained poor. A 27-year-old woman with multifocal and aggressive CD8+ SPTCL was treated with the purine analog fludarabine in combination with mitoxantrone and dexamethasone (FND). The patient achieved complete remission after one course of treatment. After completion of six courses of FND, the patient has remained in remission for more than 3 years. FND may be an effective treatment for aggressive SPTCL.

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.