Ming-Chih Chang

Treatment-related myelodysplastic syndrome after temozolomide for recurrent high-grade glioma

In patients with recurrent malignant glioma, treatment-related myelodysplastic syndrome (t-MDS) and acute leukemia are rare adverse effects because the median survival after relapse is limited. We report a 44-year-old woman with t-MDS (refractory anemia with excess blasts) following treatment of recurrent anaplastic astrocytoma with temozolomide (TMZ). A cytogenetic study showed del (3)(q11.1). MDS was diagnosed 8.4 months after beginning TMZ. The disease rapidly evolved into acute leukemia within 1 month after the onset of MDS, and the patient died 1 month later during induction chemotherapy. The prognosis of t-MDS is generally poor. Considering the increasing use of TMZ, which is regarded as a drug with moderate toxicity, careful follow-up with routine blood testing is vital.

A case of tuberculosis-induced hemophagocytic lymphohistiocytosis in a patient under hemodialysis

The insidious onset, but rapid progression of hemophagocytic lymphohistiocytosis is always a diagnostic challenge. Herein, we report the case involving a 58-year-old man with diabetes-related nephropathy on dialysis who presented with fever of unknown origin, pancytopenia, and splenomegaly. A bone marrow smear showed extensive hemophagocytosis and the pathology disclosed granulomatous inflammation with caseous necrosis, suggestive of tuberculosis. Sputum culture and polymerase chain reaction confirmed tuberculosis. The patient exhibited signs of multiple-organ failure that were not reversed with anti-tuberculous medications and corticosteroids. The case reminds us that this is an uncommon clinical scenario, and only a timely diagnosis with prompt treatment results in a favorable outcome.

Clinical outcome of primary gastric lymphoma treated with chemotherapy alone or surgery followed by chemotherapy.

BACKGROUND The role of surgical resection in the treatment of primary gastric lymphoma (PGL) remains unclear. This retrospective study evaluated the clinical outcome of PGL treated with chemotherapy alone or surgery followed by chemotherapy. METHODS During 1986-2003, 59 patients with PGL (other than mucosa-associated lymphoid tissue type lymphoma) were identified from hospital files. The medical records, pathologic sections, radiographic images and treatment modalities of these patients were reviewed. Patients were categorized into localized (stage IE and IIE-1) and advanced (stage IIE-2 or beyond) stage groups. Survival was estimated by the Kaplan-Meier method. RESULTS The study included 55 patients who received treatment at the same institute. Among them, 32 had localized PGL (15 stage IE, 17 stage IIE-1) and 23 had advanced disease. The median survival of the localized stage group was not reached during a mean follow-up of 168.1 +/- 16.7 months (95% confidence interval [CI], 135.4-200.8 months), while that of the advanced stage group was 33.0 +/- 6.8 months (95% CI, 19.7-46.5; p < 0.001, log-rank test). Among patients with localized PGL, the 5-year overall survival rate of those receiving chemotherapy alone (n = 19) or combination therapy (surgery followed by chemotherapy, n = 13) was 73.4% and 87.5%, respectively (p = 0.229). The 5-year disease-free survival was 68.4% and 84.6%, respectively (p = 0.540). However, post-chemotherapy life-threatening hemorrhage occurred in five of the 32 patients (15.6%) in the localized stage group: four in the chemotherapy-alone group, and one in the combination therapy group, all of whom had failed to achieve complete response. CONCLUSION The clinical outcome of localized PGL treated by chemotherapy alone is similar to that treated by surgery followed by chemotherapy in terms of tumor response, disease-free survival and overall survival, suggesting that surgery be reserved for those with residual tumors after chemotherapy.

Activation of CD44 facilitates DNA repair in T-cell lymphoma but has differential effects on apoptosis induced by chemotherapeutic agents and ionizing radiation.

Expression of CD44s (standard form) in malignant lymphoma is a poor indicator of survival. To investigate whether activation of CD44s can protect from cell death, this study compared the extent of apoptosis induced by chemotherapeutic agents and ionizing radiation (IR) on T-lymphoma cell lines in the presence or absence of adherent hyaluronan and monoclonal antibodies (MoAbs). Growth in the presence of adherent ligands enhanced apoptosis induced by dexamethasone (Dex), but protected cells from epirubicin-induced apoptosis. In IR-induced apoptosis, mouse lymphoma cells had resistance against apoptosis when treated with hyaluronan (HA), although acute cell death reached the same plateau regardless of treatment with adherent MoAbs in human lymphoma cell line. However, the post-irradiated repopulation of lymphoma cells was strikingly accelerated in those treated with CD44 adherent ligands. This repopulation process correlated with the remarkable upregulation of proliferating cell nuclear antigen (PCNA), which is a protein involved in DNA repair. Unscheduled DNA synthesis (UDS), a measure of DNA repair, was consistently enhanced in CD44s-stimulated cells after exposure to radiation. The results suggest that the poor prognostic indication of CD44 expression is more a consequence of enhanced DNA repair following genotoxic damage than of direct resistance to apoptosis.

Adult T-cell leukemia/lymphoma in Taiwan: an analysis of 17 patients and review of the literature.

Aim:  We reviewed our experience with adult T‐cell leukemia (ATL), describing the clinical manifestations and outcome in order to facilitate case recognition in the future.

Upfront maintenance therapy with arsenic trioxide in acute promyelocytic leukemia provides no benefit for non-t(15;17) subtype.

Aims:  The optimal maintenance therapy for patients with acute promyelocytic leukemia (APL) who achieved complete remission (CR) and complete consolidation chemotherapy is still controversial. Whether the use of arsenic trioxide (ATO) alone or along with all‐trans retinoic acid (ATRA) improves overall survival (OS) or disease‐free survival (DFS) is still debated.

Germline variations at JAK2 , TERT , HBS1L - MYB and MECOM and the risk of myeloproliferative neoplasms in Taiwanese population

Germline variations at JAK2, TERT, HBS1L-MYB and MECOM have been found to associate with myeloproliferative neoplasms (MPNs) in European populations. Whether these germline variations are associated with MPNs in Taiwanese population is obscure. Here we aimed to evaluate the association of five germline variations (JAK2 46/1 haplotype tagged by rs12343867, JAK2 intron 8 rs12339666, TERT rs2736100, HBS1L-MYB rs9376092 and MECOM rs2201862) and the risk of MPNs in Taiwanese population. A total of 178 MPN patients (109 essential thrombocythemia, 54 polycythemia vera and 15 primary myelofibrosis) were enrolled into this study. The information of 17033 control subjects was obtained from Taiwan Biobank database. The JAK2 46/1 haplotype, JAK2 rs12339666 and TERT rs2736100 were significantly associated with Taiwanese MPNs (P = 3.6×10-19, 1.9×10-19 and 3.1×10-6, respectively), and JAK2V617F-positive MPNs (n=121) (P = 5.6×10-21, 4.4×10-21 and 8.6×10-7, respectively). In JAK2V617F-negative cases (n=55), only the JAK2 46/1 haplotype and JAK2 rs12339666 remained statistically significant (P= 0.009 and 0.007, respectively). When stratified by disease subtypes, the JAK2 46/1 haplotype and JAK2 rs12339666 were significantly associated with all three MPN subtypes, but TERT rs2736100 was only associated with essential thrombocythemia and polycythemia vera. We did not find any association of these five SNPs with CALR mutations in our cohort. Furthermore, the risk alleles of MECOM rs2201862 and HBS1L-MYB rs9376092 were demonstrated to be negatively associated with the risk of developing polycythemia vera. In conclusion, germline variations at JAK2 (both the 46/1 haplotype and rs12339666) and TERT rs2736100 were associated with MPNs in Taiwanese population.Germline variations at JAK2, TERT, HBS1L-MYB and MECOM have been found to associate with myeloproliferative neoplasms (MPNs) in European populations. Whether these germline variations are associated with MPNs in Taiwanese population is obscure. Here we aimed to evaluate the association of five germline variations (JAK2 46/1 haplotype tagged by rs12343867, JAK2 intron 8 rs12339666, TERT rs2736100, HBS1L-MYB rs9376092 and MECOM rs2201862) and the risk of MPNs in Taiwanese population. A total of 178 MPN patients (109 essential thrombocythemia, 54 polycythemia vera and 15 primary myelofibrosis) were enrolled into this study. The information of 17033 control subjects was obtained from Taiwan Biobank database. The JAK2 46/1 haplotype, JAK2 rs12339666 and TERT rs2736100 were significantly associated with Taiwanese MPNs (P = 3.6x10-19, 1.9x10-19 and 3.1x10-6, respectively), and JAK2V617F-positive MPNs (n=121) (P = 5.6x10-21, 4.4x10-21 and 8.6x10-7, respectively). In JAK2V617F-negative cases (n=55), only the JAK2 46/1 haplotype and JAK2 rs12339666 remained statistically significant (P= 0.009 and 0.007, respectively). When stratified by disease subtypes, the JAK2 46/1 haplotype and JAK2 rs12339666 were significantly associated with all three MPN subtypes, but TERT rs2736100 was only associated with essential thrombocythemia and polycythemia vera. We did not find any association of these five SNPs with CALR mutations in our cohort. Furthermore, the risk alleles of MECOM rs2201862 and HBS1L-MYB rs9376092 were demonstrated to be negatively associated with the risk of developing polycythemia vera. In conclusion, germline variations at JAK2 (both the 46/1 haplotype and rs12339666) and TERT rs2736100 were associated with MPNs in Taiwanese population.

Targeted next-generation sequencing identified novel mutations in triple-negative myeloproliferative neoplasms

Mutations in JAK2, MPL and CALR genes have been identified in the majority of myeloproliferative neoplasm (MPN) patients, and patients negative for these three mutations are the so-called triple-negative (TN) MPN. In this study, we examined the mutational profiles of 16 triple-negative MPN patients including 7 essential thrombocythemia (ET), 1 primary myelofibrosis and 8 polycythemia vera (PV). Targeted next-generation sequencing was performed using the ACTOnco Comprehensive Cancer Panel (Ion AmpliSeq Comprehensive Cancer Panel, Life Technologies) to target all coding exons of 409 cancer-related genes. Overall, 30 nonsynonymous somatic mutations were detected in 12 (75%) patients with a range of 1–5 mutations per sample. Notably, one ET patient was found to have JAK2V617F and KITP551L mutations at very low allele frequency. One MPLP70L and 1 MPLM602T mutations were identified each in 1 ET and 1 PV, respectively. Other recurrent mutations were also identified including KMT2C, KMT2D, IRS2, SYNE1, PDE4DIP, SETD2, ATM, TNFAIP3 and CCND2. In addition, germline mutations were also found in some cancer-related genes. Copy number changes were rare in this cohort of TN MPNs. In conclusion, both somatic and germline mutations can be detected in TN MPN patients.

Increased B cell activation is present in JAK2 V617F-mutated, CALR -mutated and triple-negative essential thrombocythemia

Essential thrombocythemia (ET) is a BCL-ABL1-negative myeloproliferative neoplasm. We have reported that increased activated B cells can facilitate platelet production mediated by cytokines regardless JAK2 mutational status in ET. Recently, calreticulin (CALR) mutations were discovered in ~30% JAK2/MPL-unmutated ET and primary myelofibrosis. Here we sought to screen for CALR mutations and to evaluate B cell immune profiles in a cohort of adult Taiwanese ET patients. B cell populations, granulocytes/monocytes membrane-bound B cell-activating factor (mBAFF) levels, B cells toll-like receptor 4 (TLR4) expression and intracellular levels of interleukin (IL)-1β/IL-6 and the expression of CD69, CD80, and CD86 were quantified by flow cytometry. Serum BAFF concentration was measured by ELISA. 48 healthy adults were used for comparison. 19 (35.2%) of 54 ET patients harbored 8 types of CALR exon 9 mutations including 4 (7.4%) patients with concomitant JAK2V617F mutations. Compared to JAK2V617F mutation, CALR mutations correlated with younger age at diagnosis (p=0.04), higher platelet count (p=0.004), lower hemoglobin level (p=0.013) and lower leukocyte count (p=0.013). Multivariate analysis adjusted for age, sex, follow-up period and hematological parameters confirmed that increased activated B cells were universally present in JAK2-mutated, CALR-mutated and triple-negative ET patients when compared to healthy adults. JAK2- and CALR-mutated ET have significantly higher fraction of B cells with TLR4 expression when compared to triple-negative ET (p=0.019 and 0.02, respectively). CALR-mutated ET had significantly higher number of CD69-positive activated B cells when compared to triple-negative ET (p=0.035). In conclusion, increased B cell activation is present in ET patients across different mutational subgroups.

Safety and efficacy of nilotinib in routine clinical practice in patients with chronic myeloid leukemia in chronic or accelerated phase with resistance or intolerance to imatinib: results from the NOVEL study:

Background: Nilotinib, a second-generation tyrosine kinase inhibitor (TKI), is approved for the treatment of patients with chronic myeloid leukemia (CML) in many countries, including Taiwan. Though a number of controlled clinical trials have demonstrated the safety and efficacy of nilotinib, studies assessing the safety and efficacy of nilotinib in routine clinical practice are limited. Methods: The current study was an open-label, single-arm study conducted across 12 centers in Taiwan in adult patients with CML in chronic or accelerated phase with confirmed Ph+ chromosome (or BCR-ABL) and resistant or intolerant to one or more previous TKIs. The primary objective was to collect the long-term safety data in patients treated with nilotinib 400 mg, twice daily for up to 2 years. Results: The study enrolled 85 patients with CML, including 76 in the chronic phase (CML-CP) and 9 in the accelerated phase (CML-AP). Overall, 1166 adverse events (AEs) were reported in 80 patients (94.1%), of which 70 AEs (6%) in 28 patients (32.9%) were serious and 336 AEs (28.8%) reported in 60 patients (70.6%) were drug-related. Common drug-related AEs were thrombocytopenia (21.2%), increased alanine aminotransferase (21.2%) and pruritus (17.7%). Of the 85 patients, 19 switched from imatinib due to intolerance – AEs were resolved in 16 of these 19 patients (84.2%). By 24 months, the cumulative rates of complete cytogenetic response (CCyR), major molecular response (MMR), MR4.0 (BCR-ABL1IS ⩽0.01%) and MR4.5 (BCR-ABL1IS ⩽0.0032%) were 75.3, 56.8, 16.2 and 7.4%, respectively. Patients with CML-CP at baseline had higher overall survival (OS) and progression-free survival (PFS) than those with CML-AP. Conclusion: This is the first study that demonstrated that nilotinib is effective and well-tolerated in patients resistant or intolerant to imatinib in the real-world setting in Taiwan, reflecting effective management of CML by physicians under routine clinical practice in Taiwan.