Association of CD8 + T cells expressing nivolumab-free PD-1 with clinical status in a patient with relapsed refractory classical Hodgkin lymphoma.

A 37-year-old man with refractory classical Hodgkin lymphoma (cHL) underwent PD-1 blockade therapy with nivolumab, which resulted in a partial response. However, treatment was discontinued due to immune-related adverse events (irAEs), including myasthenia gravis and myositis. Retreatment with nivolumab resulted in a complete metabolic response and hepatic irAE. Subsequently, nivolumab was administered at extended dosing intervals. Intermittent infusion of ten doses of nivolumab for a total dose of 2400 mg/body helped control the relapsed/refractory cHL over three years. During nivolumab treatment, disease progression and emergence of irAEs were associated with the proportion of CD8 + T cells expressing nivolumab-free PD-1 relative to the total number of CD8 + T cells. The findings in this nivolumab-sensitive patient highlight the clinical utility of monitoring immune cells expressing nivolumab-free PD-1 in patients with cHL who have been treated with nivolumab and have experienced irAEs.

Doripenem versus meropenem as first-line empiric therapy of febrile neutropenia in patients with acute leukemia: a prospective, randomized study.

Febrile neutropenia is often observed in patients with hematologic malignancies, especially in those with acute leukemia. Meropenem has potent and broad antibacterial activity against gram-positive and gram-negative bacteria, and is recommended as first-line empiric therapy for febrile neutropenia. In contrast, the safety and efficacy of doripenem in patients with febrile neutropenia and hematologic malignancies is limited. In this randomized, prospective, cooperative, open-label trial, we compared doripenem (1.0 g every 8 h) to meropenem (1.0 g every 8 h) as first-line empiric antibacterial treatment of febrile neutropenia. To evaluate efficacy and safety, 133 hospitalized patients with acute leukemia or high-risk myelodysplastic syndrome, who developed febrile neutropenia during or after chemotherapy, were randomized to each drug. Resolution of fever within 3 to 5 days without treatment modification (i.e., the primary endpoint) did not significantly differ between the doripenem and meropenem groups (60.0% vs. 45.6%, respectively; P = 0.136). However, resolution of fever within 7 days of treatment was significantly higher in the doripenem group than in the meropenem group (78.4% vs. 60.2%, respectively; P = 0.037). Similar rates of adverse events (grades 1-2) were observed in both groups. Thus, we conclude that both drugs are safe and well-tolerated for the treatment of febrile neutropenia in patients with acute leukemia or high-risk myelodysplastic syndrome, and that the clinical efficacy of doripenem is noninferior to that of meropenem. UMIN Clinical Trial Registry number: 000006124.

Rapid reduction in BCR-ABL1 transcript predicts deep molecular response in dasatinib-treated chronic-phase chronic myeloid leukaemia patients.

OBJECTIVES: We conducted a phase-II study to evaluate the efficacy and safety of dasatinib in patients newly diagnosed with chronic-phase chronic myeloid leukaemia (CML-CP) in Japan (IMIDAS PART 2 study). METHODS: Seventy-nine patients were administered 100 mg dasatinib once daily. We examined pretreatment and post-treatment influences of various factors. The BCR-ABL1 international scale (IS), halving time (HT) and reduction rate of BCR-ABL1 transcript within the initial 1 or 3 months of therapy (RR-BCR-ABL11m,3m ) were the post-treatment factors investigated to predict the molecular response. RESULTS: The estimated major molecular response (MMR), molecular response 4.0 (MR4.0) and molecular response 4.5 (MR4.5) rates were 77.2%, 49.4% and 35.4%, respectively, at 12 months. Grade 3/4 non-haematologic adverse events were infrequent. Multivariate analysis showed that age >65 years was significantly correlated with MR4.0 and MR4.5 (deep molecular response: DMR) at 12 months. All post-treatment factors at 3 months predicted DMR by univariate analysis. However, RR-BCR-ABL13m was the only significant landmark for predicting DMR by multivariate analysis. CONCLUSIONS: Primary treatment of CML-CP with dasatinib enabled early achievement of MMR and DMR, particularly in elderly patients, with high safety. Furthermore, RR-BCR-ABL13m was found to be a more useful predictor of DMR than HT-BCR-ABL1 and BCR-ABL1 IS.

Successful cord blood transplantation in an adult acute lymphoblastic leukemia patient with congenital heart disease.

Recent advances in surgical corrections and supportive care for congenital heart disease have resulted in increasing numbers of adult survivors who may develop hematological malignancies. Treatments including chemotherapy for such patients may cause serious hemodynamic or cardiac complications, especially in those receiving stem cell transplantation. We present a 29-year-old woman with acute lymphoblastic leukemia and congenital heart disease. She had been diagnosed with pulmonary atresia with an intact ventricular septum at birth, and the anomaly was surgically corrected according to the Fontan technique at age 9 years. Her induction chemotherapy required modifications due to poor cardiac status with Fontan circulation. However, after surgical procedures including total cavopulmonary connection and aortic valve replacement at first complete remission, her cardiac status was significantly improved. Subsequently, she underwent cord blood stem cell transplantation at the third complete remission. She required intensive supportive care for circulatory failure as a pre-engraftment immune reaction and stage III acute graft versus host disease of the gut, but recovered from these complications. She was discharged on day 239, and remained in complete remission at 1-year post-transplantation.

Clinical significance of high-Km 5'-nucleotidase (cN-II) mRNA expression in high-risk myelodysplastic syndrome.

We analyzed cytosolic high-Km 5'-nucleotidase (cN-II) and deoxycytidine kinase (dCK) mRNA expression in bone marrow mononuclear cells (BMMNC) of patients with high-risk myelodysplastic syndrome (MDS) using quantitative real-time polymerase chain reaction (rt-PCR). At diagnosis, the cN-II mRNA expression of patients was higher than that of healthy volunteers, but the dCK mRNA expression showed no significant difference. Patients with ara-C-containing chemotherapies whose BMMNC showed a high level of cN-II expression (greater than the median value) had shorter median overall survival (15 months versus 22 months, p<0.01) and shorter median post-chemotherapy survival (10 months versus 16 months, p=0.012). These data suggest that the expression level of cN-II mRNA might be a prognostic factor of high-risk MDS.

Consensus JH gene probes with conjugated 3'-minor groove binder for monitoring minimal residual disease in acute lymphoblastic leukemia.

Several approaches for the detection of minimal residual disease (MRD) in childhood acute lymphoblastic leukemia (ALL) have shown the importance of determining the level of MRD precisely. In the present study, we tested a new real-time quantitative polymerase chain reaction (RQ-PCR) strategy with minor groove binder (MGB) technology for immunoglobulin heavy chain gene rearrangements by positioning a MGB probe at the germline JH segments and one of the primers at the downstream introns in combination with an allele-specific oligonucleotide (ASO) primer complementary to the VH-DH or DH-JH junctional region. A MGB probe forms extremely stable duplexes with single-stranded DNA targets, allowing the use of shorter probes for hybridization-based assays. Therefore, it shows positional flexibility. We have designed two novel consensus MGB JH germline probes for analyzing all of the germline rearrangements registered in the V BASE database, and demonstrated that the MRD was detectable with the probes in 17 cases of childhood ALL. The actual copy number for the targets and dynamic changes before and after treatment were almost identical between the JH MGB probe and conventional non-MGB probes in each patient. MGB technology will undoubtedly contribute to MRD-PCR studies of childhood ALL.