Final 3-year Results of the Dasatinib Discontinuation Trial in Patients With Chronic Myeloid Leukemia Who Received Dasatinib as a Second-line Treatment.

INTRODUCTION: We previously reported an interim analysis of the DADI (dasatinib discontinuation) trial. The results showed that 48% of patients with chronic myeloid leukemia in the chronic phase who maintained a deep molecular response (DMR) for ≥ 1 year could discontinue second- or subsequent-line dasatinib treatment safely at a median follow-up of 20 months. However, the results from longer follow-up periods would be much more useful from a clinical perspective. PATIENTS AND METHODS: The DADI trial was a prospective, multicenter trial conducted in Japan. After confirming a stable DMR for ≥ 1 year, dasatinib treatment subsequent to imatinib or nilotinib was discontinued. After discontinuation, the loss of DMR (even of 1 point) was defined as stringent molecular relapse, thereby triggering therapy resumption. The predictive factors of treatment-free remission (TFR) were analyzed. RESULTS: The median follow-up period was 44.0 months (interquartile range, 40.5-48.0 months). The estimated overall TFR rate at 36 months was 44.4% (95% confidence interval, 32.0%-56.2%). Only 2 patients developed a molecular relapse after the 1-year cutoff point. The presence of imatinib resistance was a significant risk factor for molecular relapse. Moreover, high natural killer cell and low γδ+ T-cell and CD4+ regulatory T-cell (CD25+CD127low) counts before discontinuation correlated significantly with successful therapy discontinuation. CONCLUSION: These findings suggest that discontinuation of second- or subsequent-line dasatinib after a sustained DMR of ≥ 1 year is feasible, especially for patients with no history of imatinib resistance. In addition, the natural killer cell count was associated with the TFR.

TAFRO syndrome showing cholangitis on liver biopsy.

TAFRO syndrome is a systemic inflammatory disorder. TAFRO is an acronym that stands for thrombocytopenia, anasarca, fever, reticulin fibrosis, renal dysfunction, lymphadenopathy and hepatosplenomegaly. There are no reports of TAFRO syndrome describing cholangitis on liver biopsy. Herein, we report the first case of TAFRO syndrome with cholangitis. The patient was a 56-year-old man who presented with sudden onset abdominal pain and fever. His symptoms progressed to generalized edema, thrombocytopenia, hepatomegaly, and acute renal failure. Biopsies taken from the mediastinal lymph nodes and bone marrow showed the mixed type of multicentric Castleman's disease and mild reticulin fibrosis, respectively, compatible with TAFRO syndrome. His symptoms were temporarily relieved by steroid pulse therapy and tocilizumab. Fever and anasarca relapsed in a few weeks, however. He was then administered rituximab which resolved his symptoms almost completely.

Discontinuation of dasatinib in patients with chronic myeloid leukaemia who have maintained deep molecular response for longer than 1 year (DADI trial): a multicentre phase 2 trial.

BACKGROUND: First-line imatinib treatment can be successfully discontinued in patients with chronic myeloid leukaemia after deep molecular response has been sustained for at least 2 years. We investigated the safety and efficacy of discontinuing second-line or subsequent dasatinib after at least 1 year of deep molecular response. METHODS: The Dasatinib Discontinuation trial was a prospective multicentre trial done in Japan. Eligible patients taking dasatinib and with confirmed stable deep molecular response were enrolled between April 1, 2011, and March 31, 2012. All patients received dasatinib consolidation therapy for at least 1 year. In those with sustained deep molecular response, dasatinib was discontinued. Patients were followed up every month in year 1 (clinical cutoff), every 3 months in year 2, and every 6 months in year 3 for deep molecular response and immunological profiles. The primary endpoint was the proportion of patients with treatment-free remission at 6 months after discontinuation. Molecular relapse was defined as loss of deep molecular response at any assessment. This study is registered, number UMIN000005130. FINDINGS: 88 patients were enrolled in the consolidation phase, 24 were excluded from the discontinuation phase due to fluctuations in BCR-ABL1 transcript levels. One patient was excluded because of positive expression of major and minor BCR-ABL1 transcripts in chronic myeloid leukaemia cells and the detection of minor BCR-ABL1 transcripts during consolidation. Thus, 63 patients discontinued dasatinib treatment. The 25 patients who were excluded from discontinuation continued to receive dasatinib and none showed disease progression. Median follow-up was 20.0 months (IQR 16.5-24.0). Of the 63 patients who discontinued and were not excluded, 30 patients maintained deep molecular response while 33 patients had molecular relapses, all within the first 7 months after discontinuation. The estimated overall treatment-free remission was 49% (95% CI 36-61) at 6 months. No severe treatment-related toxic effects were seen. Treatment was restarted in the 33 patients with relapse; rapid molecular responses were seen in all 33 patients, of whom 29 (88%) regained deep molecular response within 3 months, as did the remaining four by 6 months. INTERPRETATION: Dasatinib discontinuation after sustained deep molecular response for more than 1 year is feasible. FUNDING: Epidemiological and Clinical Research Information Network (ECRIN).

Complete remission following chemotherapy with low-dose cytosine arabinoside and macrophage colony-stimulating factor/granulocyte colony-stimulating factor in a patient with relapsed acute myeloid leukemia after stem cell transplantation.

The prognosis of patients who relapse with acute myeloid leukemia (AML) after undergoing stem cell transplantation (SCT) is poor. There exist some treatments for relapsed AML; however, almost all treatments are associated with a high level of regimen-related toxicities (RRTs). The RRT of donor lymphocyte infusion is lower than that of other treatments; however, the efficacy of this treatment in treating patients with relapsed AML is lower than that observed in patients with chronic myelomonocytic leukemia. We herein report a case of relapsed AML after SCT in a 65-year-old man. We performed donor lymphocyte infusion; however, it was not effective. We then administered chemotherapy with cytosine arabinoside and macrophage colony-stimulating factor/granulocyte colony-stimulating factor and complete remission was achieved. Since graft-versus-host disease occurred after the administration of low-dose chemotherapy in this case, we speculated that the chemotherapy induced a graft-versus-leukemia effect.

Ubiquitylation of terminal deoxynucleotidyltransferase inhibits its activity.

Terminal deoxynucleotidyltransferase (TdT), which template-independently synthesizes DNA during V(D)J recombination in lymphoid cells, is ubiquitylated by a BPOZ-2/Cul3 complex, as the ubiquitin ligase, and then degraded by the 26 S proteasome. We show here that TdT is ubiquitylated by the Cul3-based ubiquitylation system in vitro. Because TdT could also be ubiquitylated in the absence of Cul/BPOZ-2, we determined that it could also be directly ubiquitylated by the E2 proteins UbcH5a/b/c and UbcH6, E3-independently. Furthermore, the ubiquitylated TdT inhibited its nucleotidyltransferase activity.

Multiple myeloma emerging after prolonged gefitinib treatment for non-small cell lung carcinoma.

The coexistence of lung cancer and multiple myeloma (MM) is rare. A search of the English literature revealed only 5 case reports to date. We describe a case of MM that presented in a 78-year-old lung cancer patient after 20 months of treatment with gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor. We also review previously reported cases of concurrent development of lung cancer and MM.

Neoadjuvant therapy in a patient with clival plasmacytoma associated with multiple myeloma: a case report.

BACKGROUND: Plasmacytoma is a localized mass of metastatic plasma cells. These lesions rarely involve the petroclival region and carry a high risk of progression to MM and poor prognosis. CASE DESCRIPTION: We report a 65-year-old woman who presented with a large clival plasmacytoma causing right trigeminal and abducens nerve palsies and was diagnosed with MM after transsphenoidal biopsy. She underwent neoadjuvant chemoradiotherapy followed by radical resection of the residual tumor. CONCLUSION: We presented our treatment strategy including neoadjuvant chemoradiotherapy followed by radical resection of the lesion. The patient has experienced complete remission, and succeeding MRI revealed no evidence of local recurrence.

Successful reduced-intensity stem cell transplantation with cord blood for a poor-prognosis adult with refractory chronic active epstein-barr virus infection.

A 56-year-old woman with a poor-prognosis chronic active Epstein-Barr virus (CAEBV) infection underwent reduced-intensity stem cell transplantation (RIST) using cryopreserved cord blood (CB). Administration of EBV-seronegative CB cells following a reduced-intensity conditioning regimen was effective and well tolerated. Complete remission with no symptoms, low titers of EBV-related antibodies, and an undetectable level of EBV DNA in peripheral blood mononuclear cells continued for 16 months after RIST. This report is the first of successful RIST with CB for an adult with CAEBV infection. The results also show that a graft-versus-CAEBV effect can be achieved in an allogeneic hematopoietic stem cell transplantation setting.

Constitutional trisomy 8 mosaicism with myelodysplastic syndrome complicated by intestinal Behcet disease and antithrombin III deficiency.

Trisomy 8 is the most common acquired chromosomal abnormality associated with myeloid malignancy. As a constitutional trisomy 8 mosaicism (T8M), it exhibits an extremely variable phenotype. In addition, Behcet disease (BD) has been reported as an unusual complication of myelodysplastic syndrome (MDS). To our knowledge, 12 case reports of various hematologic malignancies in patients with T8M and 18 case reports of MDS with acquired trisomy 8 complicated by BD have been published to date. We report a case of constitutional T8M with MDS complicated by intestinal BD and antithrombin III deficiency.