Real-world status of treatment for lymphoid neoplasms developed during the course of myeloproliferative neoplasms in Japan.

OBJECTIVES: Patients with myeloproliferative neoplasms (MPNs) are at higher risk of developing secondary malignancies. In this study, we focused on patients with MPNs that complicated lymphoid neoplasms. To analyze the real-world status of lymphoid neoplasm treatment in patients with pre-existing MPNs in Japan, we conducted a multicenter retrospective study. METHODS: Questionnaires were sent to collect the data on patients who were first diagnosed with either polycythemia vera, essential thrombocythemia or myelofibrosis and who later were complicated with lymphoid neoplasms defined as malignant lymphoma, multiple myeloma, or chronic lymphocytic leukemia/small cell lymphoma. RESULTS: Twenty-four patients with MPNs complicated by lymphoid neoplasms were enrolled (polycythemia vera, n = 8; essential thrombocythemia, n = 14; and primary myelofibrosis, n = 2). Among these, diffuse large B-cell lymphoma (DLBCL) was the most frequently observed (n = 13, 54.1%). Twelve (92.3%) of the patients with DLBCL received conventional chemotherapy. Among these 12 patients, regarding cytoreductive therapy for MPNs, 8 patients stopped treatment, one continued treatment, and two received a reduced dose. Consequently, most patients were able to receive conventional chemotherapy for DLBCL with a slightly higher dose of granulocyte colony-stimulating factor support than usual without worse outcomes. All 3 patients with multiple myeloma received a standard dose of chemotherapy. CONCLUSION: Our data indicate that if aggressive lymphoid neoplasms develop during the course of treatment in patients with MPNs, it is acceptable to prioritize chemotherapy for lymphoma.

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.

Outcomes of adult patients with early T-cell precursor (ETP) acute lymphoblastic leukemia/lymphoma (ALL) and non-ETP T-ALL.

Early T-cell precursor (ETP) acute lymphoblastic leukemia/lymphoma (ALL) is generally considered to be a high-risk subtype. We retrospectively analyzed the clinical outcomes of adult patients diagnosed with ETP-ALL or other T-cell ALL (non-ETP T-ALL). The subjects were 82 patients (ETP-ALL: n = 18, non-ETP T-ALL: n = 64) for whom relevant immunophenotype data needed for classification were available. ETP-ALL patients were older (median age, 50.5 vs. 33.5 years, P = 0.042) and had less mediastinal involvement (27.8 vs. 73.4%, P < 0.001). The rate of complete remission (CR) with the first induction therapy was significantly lower in the ETP group (33.3 vs. 64.0%, P = 0.03), but the CR rate within 2 cycles of chemotherapy did not differ significantly (61.1 vs. 76.6%, P = 0.232). The 3-year overall survival (OS) rate was also similar in both groups (43.2 vs. 45.8%, P = 0.992). The ETP phenotype had no impact on survival in the transplant group or the non-transplant group. A multivariate analysis identified the male sex as a poor prognostic factor (HR: 4.43, P < 0.01), but not the immunophenotype of ETP. The prognosis for adult patients with ETP-ALL was comparable to that of non-ETP T-ALL patients. However, further studies aimed at improving the remission rate for ETP-ALL are needed.

Lymphoma during pregnancy in Japan: a multicenter retrospective cohort study.

OBJECTIVE: This study was conducted to characterize lymphoma occurring during pregnancy and to investigate the outcomes of the patients and the fetuses. METHODS: Clinical data were gathered retrospectively from 29 patients at 13 participating institutions, and data from 28 eligible patients were analyzed. RESULTS: Six (21%) patients had Hodgkin lymphoma (HL) and 22 (79%) patients had non-Hodgkin lymphoma (NHL). All patients with HL presented with lymphadenopathy, but 15 (68%) of the 22 patients with NHL presented with extranodal sites only. At the median follow-up period of 1325 (range 6-4461) days, the 5-year overall survival rate was 63% for patients with NHL and 100% for patients with HL. Three of the 13 patients who received chemotherapy during pregnancy (23%) developed Pneumocystis jiroveci pneumonia (PCP). There was 1 intrauterine fetal death, 1 spontaneous abortion in the first trimester, and 15 (54%) preterm births. CONCLUSION: This study showed a higher proportion of NHL than HL during pregnancy in Japan, which was inconsistent with the proportions observed in Western countries. The high incidence of maternal PCP and preterm birth suggested the need for improvements in our management of lymphoma during pregnancy.

Fungal biomarker monitoring and CT scans for early detection of invasive fungal disease in neutropenic hematological patients.

OBJECTIVES: By using data from the CEDMIC trial (n = 413), we conducted a post-hoc analysis of the diagnostic value of biomarker monitoring and chest computed tomography (CT) scans for the early detection of invasive fungal disease (IFD) in neutropenic hematological patients. METHODS: IFDs were defined in accordance with the EORTC/MSG definition with some modifications. Biomarkers such as Aspergillus galactomannan (GM) and (1→3)-ß-D-glucan (ßDG) were measured weekly. RESULTS: The positive predictive value (PPV) of GM and ßDG in cases of high-risk treatment were 0.70 and 0.69, while those in low-risk treatment were 0.08 and 0, respectively. All of the positive biomarkers that were measured before the development of fever in low-risk treatment were false positives. The proportion of patients who had abnormal chest CT findings was 19% in persistent fever at 4-6 days, 57% at 7 days or later and 36% in recurrent fever. Sixty-nine percent of the patients who had abnormal findings at 7 days or later did not have abnormalities at 4-6 days. CONCLUSIONS: Afebrile screening of biomarkers in low-risk treatment is not useful. Chest CT should be reevaluated in persistent fever lasting for 7 days or longer even in patients who did not have abnormalities within 6 days.

[Treatment of secondary engraftment failure with granulocyte colony-stimulating factor and eltrombopag after allogeneic peripheral blood stem cell transplantation in adult T-cell leukemia/lymphoma].

A 67-year-old woman diagnosed with adult T-cell leukemia/lymphoma received an induction chemotherapy and showed a partial response. She then underwent allogeneic peripheral blood stem cell transplantation from an HLA-identical sibling donor. Although cyclosporine (CS) was stopped at 120 days after transplantation, chronic graft-versus-host disease (cGVHD) of the skin developed. She was treated with a topical steroid, without exacerbation of the GVHD. She was admitted to our hospital due to the sudden development of pancytopenia at 212 days after the transplantation. She had an EB virus-associated post-transplant lymphoproliferative disorder (PTLD) in the hilum of the lung. The cGVHD of the skin resolved after the administration of prednisolone and CS. However, pancytopenia and PTLD persisted. Treatment with four cycles of rituximab (4×375 mg/m2/week) led to the complete resolution of PTLD, but transfusion-dependent cytopenia did not improve. Secondary engraftment failure was diagnosed, and granulocyte colony-stimulating factor (G-CSF) and eltrombopag (100 mg/day) were administered, leading to gradual improvement of pancytopenia. It was observed that persistent pancytopenia was caused by secondary engraftment failure due to cGVHD in this case. This case suggested that the treatment with G-CSF and eltrombopag is effective for cGVHD-associated secondary engraftment failure.

Improved survival of multiple myeloma patients treated with autologous transplantation in the modern era of new medicine.

New drugs for multiple myeloma (MM) have dramatically improved patients' overall survival (OS). Autologous stem cell transplantation (ASCT) remains the mainstay for transplant-eligible MM patients. To investigate whether the post-ASCT prognosis of MM patients has been improved by new drugs, we undertook a retrospective observational analysis using the Transplant Registry Unified Management Program database in Japan. We analyzed 7323 patients (4135 men and 3188 women; median age, 59 years; range 16-77 years) who underwent upfront ASCT between January 2007 and December 2018. We categorized them by when they underwent ASCT according to the drugs' introduction in Japan: group 1 (2007-2010), group 2 (2011-2016), and group 3 (2017-2018). We compared the groups' post-ASCT OS. The 2-year OS rates (95% confidence interval [CI]) of groups 1, 2, and 3 were 85.8% (84.1%-87.4%), 89.1% (88.0%-90.1%), and 92.3% (90.0%-94.2%) (P < .0001) and the 5-year OS (95% CI) rates were 64.9% (62.4%-67.3%), 71.6% (69.7%-73.3%), and not applicable, respectively (P < .0001). A multivariate analysis showed that the post-ASCT OS was superior with these factors: age less than 65 years, performance status 0/1, low International Staging System (ISS) stage, receiving SCT for 180 days or less post-diagnosis, better treatment response pre-ASCT, later year of ASCT, and receiving SCT twice. A subgroup analysis showed poor prognoses for the patients with unfavorable karyotype and poor treatment response post-ASCT. The post-ASCT OS has thus improved over time (group 1 < 2 < 3) with the introduction of new drugs for MM. As the prognosis of high-risk-karyotype patients with ISS stage III remains poor, their treatment requires improvement.

Predictive and risk factor analysis for bloodstream infection in high-risk hematological patients with febrile neutropenia: post-hoc analysis from a prospective, large-scale clinical study.

OBJECTIVES: Bloodstream infection (BSI) is a frequent complication observed in patients with febrile neutropenia (FN). BSI risk factors and incidence vary depending on chemotherapy types and prophylactic antimicrobial agents. We clarified these issues by post-hoc analysis of a prospective clinical trial cohort for severe FN in hematological malignancy. METHODS: We performed an intention-to-treat analysis of 413 high-risk patients and 1272 blood culture sets. RESULTS: Overall, 356 patients (86.2%) developed FN, and 20.8% had BSI complications. Prophylactic antimicrobials did not prevent complications of FN and BSI, but the incidence of BSIs of Gram-negative (GN) bacteria was lower than in the non-prophylaxis group (23.8% vs. 56.7%). Multinational Association of Supportive Care in Cancer (MASCC) scores < 20 were significantly correlated with the incidence of BSI, whereas MASCC scores > 21 were not (41.7% vs. 17.2%). The only significant risk factors were hypotension and dehydration. axillary temperatures were higher in GN-caused BSIs than in Gram-positive-caused BSIs and in patients with negative blood culture results (38.7 °C vs. 38.2 °C vs. 38.0 °C). The higher the fever, the higher the incidence of BSI and GN bacteremia. CONCLUSIONS: MASCC score and axillary temperature are strong predictors of BSI. Non-administration of prophylactic antimicrobials and GN-caused BSI are correlated. THE CLINICAL TRIAL REGISTRATION NUMBER: UMIN00010411.

Elevation of Early Plasma Biomarkers in Patients with Clinical Risk Factors Predicts Increased Nonrelapse Mortality after Allogeneic Hematopoietic Stem Cell Transplantation.

Early prediction of nonrelapse mortality (NRM) in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) based on the results of laboratory tests is challenging. Thus, there is a need to evaluate biomarkers for prediction of NRM, a major problem that offsets the advantages of allo-HSCT. We tested the validity and efficacy of 2 plasma biomarkers, ST2 and Reg3α, based on the Mount Sinai Acute GVHD International Consortium (MAGIC) algorithm, for early prediction of NRM in Japanese patients who underwent allo-HSCT. We conducted a multicenter retrospective study to analyze the clinical data of 112 patients with hematopoietic malignancies who underwent allo-HSCT. Patient blood samples on day 7 after allo-HSCT were obtained from 6 hospitals. The plasma concentrations of ST2 and Reg3α were used to calculate a 6-month NRM risk score. Based on the scores determined in this study, we identified 64 low-risk patients and 48 high-risk patients for the 6-month NRM. The cumulative incidence of 6-month NRM was 29.2% in the high-risk group and 10.9% in the low-risk group (P < .05). The cumulative incidence of relapse mortality was similar in the high-risk and low-risk patients. The biomarker score was predictive in patients with an unrelated donor, an HLA-mismatched donor, high/very high Disease Risk Index, and Hematopoietic Cell Transplantation Comorbidity Index ≥1. Multivariate analysis identified high biomarker probability as a significant predictor of NRM. The MAGIC algorithm based on blood samples obtained at 7 days after allo-HSCT can identify individuals at high risk for NRM among patients with clinical risk factors for NRM in a Japanese cohort.

Switching from Intravenous to Oral Tacrolimus Reduces its Blood Concentration in Paediatric Cancer Patients.

BACKGROUND/AIM: Tacrolimus is an essential immunosuppressant for successful allogeneic haematopoietic stem cell transplantation (Allo-HSCT). This study aimed to examine the change in the blood concentration of tacrolimus during switching from intravenous to oral administration in allo-HSCT for paediatric cancer to predict the optimal dosage. PATIENTS AND METHODS: We retrospectively examined the medical records of 63 patients who received allo-HSCT and were administered tacrolimus. To compare bioavailability among different dose ranges, the blood concentration was divided by the dose (C/D). RESULTS: Thirty-nine patients (age range=children 1-15 years, adults 17-67 years) were switched to oral administration of tacrolimus. The C/D after switching was significantly lower in children than in adults (p=0.039). There was a strong positive correlation between age and C/D in children, whereas no correlation was observed in adults. CONCLUSION: In paediatric cancer patients, switching tacrolimus administration route may result in reduced blood concentrations. This tendency is more prominent in younger children.

Efficacy and safety of micafungin in empiric and D-index-guided early antifungal therapy for febrile neutropenia; A subgroup analysis of the CEDMIC trial.

OBJECTIVES: The D-index is defined as the area over the neutrophil curve during neutropenia. The CEDMIC trial confirmed the noninferiority of D-index-guided early antifungal therapy (DET) using micafungin to empirical antifungal therapy (EAT). In this study, we evaluated the efficacy and safety of micafungin in these settings. METHODS: From the CEDMIC trial, we extracted 67 and 113 patients who received micafungin in the DET and EAT groups, respectively. Treatment success was defined as the fulfilment of all components of a five-part composite end point. Fever resolution was evaluated at seven days after the completion of therapy. RESULTS: The proportion of high-risk treatments including induction chemotherapy for acute leukemia and allogeneic hematopoietic stem cell transplantation was significantly higher in the DET group than in the EAT group (82.1% vs. 52.2%). The efficacy of micafungin was 68.7% (95%CI: 56.2-79.4) and 79.6% (71.0-86.6) in the DET and EAT groups, respectively. When we focused on high-risk treatments, the efficacy was 69.1% (55.2-80.9%) and 78.0% (65.3-87.7%), respectively (P = 0.30). There was no significant difference in any of the 5 components between the two groups. CONCLUSIONS: The efficacy of micafungin in patients undergoing high-risk treatment was not strongly impaired in DET compared to that in EAT.

D-Index-Guided Early Antifungal Therapy Versus Empiric Antifungal Therapy for Persistent Febrile Neutropenia: A Randomized Controlled Noninferiority Trial.

PURPOSE: Empiric antifungal therapy (EAT) is recommended for persistent febrile neutropenia (FN), but in most patients, it is associated with overtreatment. The D-index, calculated as the area surrounded by the neutrophil curve and the horizontal line at a neutrophil count of 500/µL, reflects both the duration and depth of neutropenia and enables real-time monitoring of the risk of invasive fungal infection in individual patients at no cost. We investigated a novel approach for patients with persistent FN called D-index-guided early antifungal therapy (DET), in which antifungal treatment is postponed until a D-index reaches 5,500 or the detection of positive serum or imaging tests, and compared it with EAT in this multicenter open-label noninferiority randomized controlled trial. PATIENTS AND METHODS: We randomly assigned 423 patients who underwent chemotherapy or hematopoietic stem-cell transplantation for hematologic malignancies to the EAT or DET group. The prophylactic use of antifungal agents other than polyenes, echinocandins, or voriconazole was allowed. Micafungin at 150 mg per day was administered as EAT or DET. RESULTS: In an intent-to-treat analysis of 413 patients, the incidence of probable/proven invasive fungal infection was 2.5% in the EAT group and 0.5% in the DET group, which fulfilled the predetermined criterion of noninferiority of the DET group (-2.0%; 90% CI, -4.0% to 0.1%). The survival rate was 98.0% versus 98.6% at day 42 and 96.4% versus 96.2% at day 84. The use of micafungin was significantly reduced in the DET group (60.2% v 32.5%; P < .001). CONCLUSION: A novel strategy, DET, decreased the use and cost of antifungal agents without increasing invasive fungal infections and can be a reasonable alternative to empiric or preemptive antifungal therapy.

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.

Clinical effects of recombinant thrombomodulin and defibrotide on sinusoidal obstruction syndrome after allogeneic hematopoietic stem cell transplantation.

Sinusoidal obstruction syndrome (SOS) is a lethal complication after hematopoietic stem cell transplantation (HSCT). Defibrotide (DF) is the only drug internationally recommended for SOS treatment in Western countries. Recombinant human soluble thrombomodulin (rhTM), which is promising for the treatment of patients with disseminated intravascular coagulation, is also reported to be potentially effective for SOS. To clarify the safety and efficacy of DF and rhTM, we conducted a retrospective survey of these agents in Japan. Data from 65 patients who underwent allogeneic HSCT and received DF (n = 24) or rhTM (n = 41) for SOS treatment were collected. The complete response rates for SOS on day 100 were 50% and 54% in the DF and rhTM groups, respectively. The 100-day overall survival rates were 50% in the DF group, and 48% in the rhTM group. Several severe hemorrhagic adverse events were observed in one patient in the DF group and five patients in the rhTM group. The main causes of death were SOS-related death, and no patient died of direct adverse events of DF or rhTM. Our results suggest that rhTM, as well as DF, can be effective as a novel treatment option for SOS.

Risk factors and timing of autologous stem cell transplantation for patients with peripheral T-cell lymphoma.

High-dose chemotherapy with autologous stem cell transplantation (HDC-ASCT) is an option for patients with peripheral T-cell lymphoma (PTCL); however, neither prospective nor retrospective studies support proceeding with ASCT upfront, and the timing of HDC-ASCT remains controversial. We retrospectively analyzed the risk factors for outcomes of 570 patients with PTCL, including PTCL not otherwise specified (PTCL-NOS) and angioimmunoblastic T-cell lymphoma (AITL), who received ASCT for frontline consolidation (n = 98 and 75, respectively) or alternative therapies after either relapse (n = 112 and 75) or primary induction failure (PIF; n = 127 and 83) between 2000 and 2015. Significant risk factors for overall survival (OS) after upfront ASCT were a ≥ 2 prognostic index for T-cell lymphoma (P < 0.001) and partial response (PR) at ASCT (P = 0.041) in PTCL-NOS patients, and > 60 years of age (P = 0.0028) and PR at ASCT (P = 0.0013) in AITL patients. Performance status of ≥ 2 at ASCT (P < 0.001), receiving ≥ 3 regimens before ASCT (P = 0.018), and PR at ASCT (P = 0.018) in PTCL-NOS patients and > 60 years of age at ASCT (P = 0.0077) in AITL patients were risk factors for OS after ASCT with a chemosensitive PIF status. Strategies that carefully select PTCL patients may allow identification of individuals suitable for ASCT.

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.