Summary A 53-year-old man, who had been treated for penile origin diffuse large B cell type non-Hodgkin lymphoma (NHL), suffered from right femoral pain and dyspnea. Positron emission tomography ...(PET) revealed abnormal accumulation in his right femur and cardiac segments. Transthoracic echocardiography revealed massive localized pericardial effusion with the collapse of both ventricles and the mass-like echo in the left atrium. We performed emergent pericardiocentesis and diagnosed this case as a recurrence of NHL with cardiac metastasis. With the use of transesophageal echocardiography (TEE), we confirmed the mass-like echo around the inter-atrial septum, which directly invaded to the aortic ring and the right atrial wall. In order to evaluate the effect of chemotherapy, we performed TEE and observed the precise changes of intra-cardiac tumor size. With the use of TEE monitoring, we could select the appropriate chemotherapeutic regimen, and the tumor became smaller and finally diminished. The femoral accumulation detected by PET also disappeared. We experienced a case of cardiac metastasis of NHL complicated with left ventricular diastolic collapse due to the massive localized pericardial effusion. TEE is a useful tool to evaluate precisely the efficacy of chemotherapy for intra-cardiac tumors.
Acute leukemia (AL) is characterized by overgrowth of neoplastic hematopoietic precursor cells in the bone marrow. After successful chemotherapy in patients with AL, the growth of leukemic cell is ...thought to be replaced by the recovery of normal hematopoietic cells as a consequence of the activity of anti-cancer agents in eradicating all hematopoietic cells, whether or not they are leukemic cells. However, little is known about the effects of anti-cancer agents on marrow stromal cells, which play a crucial role in supporting hematopoietic cell development. In the present study, we investigated the direct activity of cytosine arabinoside (Ara-C), a key drug for treatment of AL, on human non-leukemic marrow stromal cells by analyzing the effect of Ara-C on gene expression.
Stromal cells were established from 11 patients with no neoplastic hematopoietic precursor cells in the bone marrow. The cells were treated with Ara-C for one week, co-cultured with allogeneic CD34-positive cells, and subjected to colony assay to evaluate their supportive function. A genome-wide DNA microarray analysis was performed to determine Ara-C-induced changes in gene expression in the stromal cells.
Treatment of the stromal cells with Ara-C resulted in a dose-dependent increase in their supportive function. These effects were more evident in the late phase than in the early phase of co-culture with CD34-positive cells, suggesting that Ara-C-treated stromal cells preferably support very immature cells, rather than committed progenitor cells. Furthermore, gene expression profiling with DNA microarrays revealed prominent up-regulation of growth-differentiation factor 15 (GDF15), a divergent member of the transforming growth factor beta superfamily, with concomitant down-regulation of colony-stimulating factor 1 receptor (CSF-1R), both of which are predominantly expressed on macrophages.
Our present study demonstrated that Ara-C directly enhanced the ability of stromal cells to support the development of immature hematopoietic cells, possibly by modulating the function of macrophages in the bone marrow microenvironment. This novel action of Ara-C in the marrow microenvironment may contribute to the better understanding and management of chemotherapy for AL.
We investigated the prognostic effects of frailty and its association with comorbidity in patients with myelodysplastic syndrome (MDS).
This retrospective analysis included 118 consecutive patients ...diagnosed with MDS. Frailty was evaluated using the clinical frailty scale (CFS). Comorbidity was classified using the Charlson comorbidity index (CCI) and MDS comorbidity index (MDS-CI).
On multivariate analysis, CFS (≥ 5 vs. < 5; hazard ratio HR, 3.37; P = .002), CCI (≥ 2 vs. < 2; HR, 2.59; P = .002), and Revised International Prognostic Scoring System (IPSS-R) category (HR, 2.1; P = .009) were independently predictive of overall survival (OS). One-year OS of patients with CFS ≥ 5 or CCI ≥ 2 were significantly worse compared with those with CFS < 5 or CCI < 2 (55% vs. 91%; P < .001; 46% vs. 91%; P < .001, respectively). OS was clearly stratified into 3 groups according to CFS (≥ 5 vs. < 5) and CCI (≥ 2 vs. < 2; P < .001). When comparing these 3 groups, the incidence of infection-related mortality progressively increased with CFS ≥ 5 and/or CCI ≥ 2 (P < .001). This effect was more obvious in patients with lower IPSS-R.
The present study suggests frailty and comorbidity may be patient-related, independent predictive factors of poor prognosis. This could probably be attributed to increasing infection-related mortality with frailty and comorbidity. Combining the evaluation of frailty and comorbidity with IPSS-R might aid in more precise prediction of OS, especially in patients with low risk of MDS.
We retrospectively analyzed the prognostic effects of frailty and its association with comorbidity in patients with myelodysplastic syndrome at a single institute. The incidence of infection-related mortality progressively increased with frailty and comorbidity. Combining the evaluation of frailty and comorbidity might aid in more precise prediction of overall survival owing to good predictive capability for infection-related mortality.
Introduction: Elotuzumab, a humanized IgG1 monoclonal antibody that binds to SLAMF7 expressed on myeloma and natural killer (NK) cells, has a dual mode of action; it causes targeted myeloma cell ...death by directly activating NK cells and enhances NK cell-mediated antibody-dependent cellular cytotoxicity. Elotuzumab combined with lenalidomide and dexamethasone (ELd) has been approved in Japan for the treatment of relapsed/refractory multiple myeloma (RRMM). In a 4-y follow-up of the phase 3 ELOQUENT-2 study (NCT01239797) in patients (pts) with RRMM, ELd demonstrated a sustained 29% reduction in risk of disease progression/death and an overall survival benefit vs Ld (Dimopoulos M et al. Haematologica 2017), consistent with prior reports (Dimopoulos M et al. Br J Haematol 2017). We present the first report on the efficacy/safety of ELd vs Ld in pts with newly diagnosed multiple myeloma (NDMM).
Methods: In this phase 2, open-label, multicenter study (NCT02272803) in Japan enrolling pts with NDMM ineligible for high-dose chemotherapy plus hematopoietic cell transplantation, pts were randomized 1:1 to intravenous elotuzumab (10 mg/kg weekly for Cycles 1 and 2; every 2 wk for Cycles 3-18; 20 mg/kg monthly thereafter) plus Ld or Ld alone, in a 28-d cycle until disease progression or unacceptable toxicity. All pts in the ELd arm received premedication prior to elotuzumab to mitigate infusion reactions (IRs). In the absence of IRs, infusion rate was increased from 0.5-2.0 mL/min at dose 1, and up to a maximum of 5 mL/min (per FDA/EMA labels for ELd in RRMM) by dose 3 of Cycle 1. Primary endpoint was investigator-assessed objective response rate (ORR) with ELd, per International Myeloma Working Group criteria (1-sided α=0.15 for a true response rate >71%). Secondary endpoints included difference in ORR between the arms and progression-free survival (PFS). Safety was an exploratory endpoint.
Results: In total, 40 and 42 pts received ELd and Ld, respectively. At database lock (March 2017; minimum follow-up of 6 mo), 31 (78%) pts in the ELd arm and 25 (60%) in the Ld arm remained on study. At baseline, median (range) age was 72 y (65-83) in the ELd arm and 73 y (62-89) in the Ld arm. Median duration of therapy was 13.0 cycles with ELd and 11.5 cycles with Ld. The most common reason for discontinuation was: ELd (9 pts)-disease progression (4/40 pts 10%); Ld (17 pts)-drug toxicity, adverse events (AEs) unrelated to study drug, and pt request (each with 4/42 pts 10%). The primary endpoint was met: investigator-assessed ORR (Table) was 88% with ELd; lower bound of the 2-sided 70% CI in ORR was 80% (> threshold of 71%). The ORR in the LD arm was 74%. ORR was 13% numerically higher with ELd than Ld. Very good partial response or better was observed for 45% of ELd- and 29% of Ld-treated pts. AEs were reported in 40 (100%) and 41 (98%) pts in the ELd and Ld arms, respectively. The most common (≥20%) AEs for ELd vs Ld included constipation (43% vs 31%), pyrexia (35% vs 7%), rash (28% vs 36%), diarrhea (28% vs 21%), nasopharyngitis (25% vs 26%), dysgeusia (23% vs 19%), malaise (23% vs 2%), peripheral edema (20% vs 14%), neutropenia (20% vs 14%), leukopenia (20% vs 7%), and back pain (18% vs 21%). Grade (G) 3-4 AEs occurred in 31 (78%) and 19 (45%) pts in the ELd and Ld arms, respectively. The most common G3-4 AEs (ELd vs Ld) were neutropenia (18% vs 7%) and leukopenia (15% vs 0%). One IR was reported (ELd): G2 hypersensitivity during the first infusion (2-mL/min infusion rate); elotuzumab infusion was interrupted; the pt did not experience any IRs at subsequent infusions. Thirty-eight pts (95%) received elotuzumab at 5 mL/min (representing 1046/1176 89% infusions) and no IRs were reported at this increased infusion rate. Secondary primary malignancies were reported in 1 pt in each arm (of the rectum and lung with ELd and Ld, respectively). ELd had a comparable safety profile when given at 10 mg/kg weekly or every 2 wk up to Cycle 18, or at 20 mg/kg monthly from Cycle 19 onwards. PFS data are not yet mature.
Conclusions: In this first report of ELd treatment of pts with NDMM, the primary endpoint of ORR was met. ELd had an acceptable safety profile in this pt population, and an increased infusion rate of 5 mL/min, which reduced infusion time and did not induce additional IRs. These data suggested that ELd with a faster infusion rate of 5 mL/min was effective and well tolerated in Japanese pts with NDMM.
Study support: Bristol-Myers Squibb K.K.
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Ohta:Bristol-Meyer Squibb K.K., Celgene K.K., Jansen Pharmaceutical K.K., Novartis Pharma K.K., Ono Pharmaceutical Co. Ltd, Takeda Pharmaceutical Co. Ltd: Honoraria. Hori:Celgene, Fujifilm RI Pharma, Shire Japan: Other: Post-marketing surveillance study fee. Kinoshita:Bristol-Myers Squibb K.K.: Employment. Shelat:Bristol-Myers Squibb: Employment, Equity Ownership. Miyoshi:Bristol-Myers Squibb K.K.: Employment.
Mesenchymal stem cells (MSCs) may modulate inflammatory responses resulting in improvement in inflammatory diseases, as well as tissue regeneration via cellular differentiation. We examined the ...therapeutic effects of exogenously administered MSCs in dextran sulfate sodium (DSS)-induced colitis in rats.
Experimental colitis was produced in inbred male Lewis rats by administration of 4% DSS in drinking water for 7 days. MSCs (5
×
10
6 cells) which were isolated from whole marrow cells and cultured in an optimal medium for MSC outgrowth were administered to the treated rats via the tail vein on days 0, 2, and 4. On day 7, we evaluated colon length, histological changes, and colonic various mRNA expressions by RT-PCR. Localization of MSCs was evaluated using a green-fluorescent cell linker dye. To evaluate the anti-inflammatory action of MSCs, we assayed LPS-induced TNF-α secretion in a co-culture of MSCs and monocytes (THP-1 cells) using ELISA.
MSCs reduced in bloody stools, weight loss, colon shortening, and microscopic injuries. In the rectum of MSCs-treated rats, mRNA expression of TNF-α, IL-1β, and COX-2 decreased to 40, 15, and 15% of their respective control levels. MSCs significantly suppressed mRNA expression of VEGF, HGF, and b-FGF to 40, 25, and 25% of their respective control levels. Green-fluorescent-labeled MSCs were found only within the lamina propria in inflamed regions. LPS-induced TNF-α secretion by THP-1 cells was significantly suppressed by co-culture with MSCs dose-dependently.
We conclude that exogenous MSCs accumulated in inflamed tissues and ameliorated DSS-induced colitis via a local anti-inflammatory action.
Background
Isatuximab, an anti-CD38 antibody, has been widely used in treatments for patients with relapsed/refractory multiple myeloma (MM). Despite its high efficacy, not all patients achieve a ...lasting therapeutic response with isatuximab.
Objective
We tried to identify biomarkers to predict the effectiveness of isatuximab by focusing on the host's immune status before treatment.
Methods
We retrospectively analyzed the cases of 134 relapsed/refractory MM patients in the Kansai Myeloma Forum database who had received only a first isatuximab treatment.
Results
Among the 134 patients, an isatuximab, pomalidomide and dexamethasone (Isa-PD) regimen, isatuximab, carfilzomib and dexamethasone (Isa-KD) regimen and isatuximab and/or dexamethasone (Isa-D) regimen were used in 112, 15 and 7 patients, respectively. The median age at treatment, number of prior treatment regimens, and progression-free survival (PFS) were 71, 6, and 6.54 months, respectively. Multivariate analysis showed that the PFS under the Isa-PD regimen was longer in patients with higher lymphocyte/monocyte ratio (LMR ≥ 4), fewer prior treatment regimens (< 6), and no use of prior daratumumab treatment. The OS under the Isa-PD regimen was longer in patients with higher white blood cell counts (WBC counts ≥ 3000/μL) and higher LMR. The PFS under the Isa-D regimen was longer in patients with fewer prior treatment regimens in univariate analysis, but no parameters were correlated with PFS/OS under the Isa-KD regimen.
Conclusion
We found that the patients with higher LMR (≥ 4) could obtain longer PFS and OS under the Isa-PD regimen. Other cohort studies of isatuximab treatment might be necessary to substantiate our results.
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Introduction
Prognosis of myelodysplastic syndrome (MDS) is influenced by several factors including disease-related factors, treatment options, and patient-related factors. The revised ...International Prognostic Scoring System (IPSS-R) is widely adopted, which is based on disease-related factors. Frailty and comorbidity are clinically important patient-related factors. Recent studies showed that the Charlson comorbidity index (CCI) or MDS-comorbidity index (MDS-CI) has a marked impact on overall survival (OS). Patients with MDS are often of advanced age and frail. There are limited studies that have examined the clinical significance of frailty in patients with MDS. Furthermore, little is known regarding the association between frailty and comorbidity or the mechanisms by which they affect survival. We investigated the prognostic effect of frailty and its association with comorbidity.
Patients and Methods
This retrospective analysis included 118 consecutive patients diagnosed with MDS between June 2007 and May 2016 at Saiseikai Nakatsu Hospital, Japan. Diagnosis was made based on the WHO classification. The following information was collected using our institution's database: WHO classification, age, ECOG Performance Status (PS), IPSS-R score and risk classification, cause of death, albumin, lactate dehydrogenase, and ferritin. Frailty was evaluated using the Rockwood clinical frailty scale (Rockwood et al, 2005). Comorbidity was classified using CCI (Charlson et al, 1987) and MDS-CI (M.G. Della Porta et al, 2011). The primary endpoint was OS. Univariate and multivariate analyses were performed using a Cox proportional hazards regression model and hazard ratio (HR) was calculated to identify significant covariates associated with OS. OS was estimated using Kaplan-Meier method and compared using log-rank test. Cumulative incidences for infection-related mortality were calculated using the cumulative incidence function to account for competing risks. Gray's test was used to evaluate overall differences among cumulative incidence functions.
Results
Patient baseline characteristics are summarized in Table 1. A total of 118 patients (77 males, 41 females) were included. The median age was 73 years (IQR, 65-78). The median IPSS-R score was 4.0 (2.5-6.5) and 41.6% of patients scored high or very high in IPSS-R category. PS was ≥2 in 63 patients (53.4%). Seventeen (14.4%) and six (5.1%) patients received azacytidine and allo SCT, respectively. Seventy-five patients (63.6%) had at least one comorbidity. The most common comorbidities were cardiac diseases (22%), diabetes mellitus (21%), solid tumor (21%), pulmonary disease (18%), and hepatic dysfunction (14%). The median CCI and MDS-CI were 1 (range 0-8) and 1 (0-3), respectively. CCI was ≥2 in 52 patients (44.1%). The median frailty scale was 5 (2-8), and 66 patients (55.9%) had a frailty scale of ≥5. The frailty scale was modestly correlated with CCI (r = 0.43, P < 0.001). The median follow-up period was 362 days (IQR, 178-876). Sixty patients died of which 53.3% died due to infection. The 1-year OS was 68.3%.
Results of univariate and multivariate analyses of OS are summarized in Table 2. On univariate analysis, frailty scale, CCI, MDS-CI, PS, IPSS-R score and category, albumin, and ferritin were significantly associated with shorter duration of OS. On multivariate analysis, frailty scale (≥5 vs <5; HR = 3.54, P = 0.0016), CCI (≥2 vs <2; HR = 2.76, P = 0.0016), and IPSS-R score and category (HR = 1.34, P = 0.00012) were independently predictive of OS. One-year OS of frailty scale ≥5 or CCI ≥2 were significantly worse compared with a frailty scale <5 or CCI <2 (51.4% vs 90.5%, P < 0.001; 44.3% vs 90.2%, P < 0.001, respectively). OS was clearly stratified into three groups according to frailty scale (≥5 vs <5) and CCI (≥2 vs <2) (log-rank, P < 0.001; Figure 1A). Comparing these three groups, the incidence of infection-related mortality progressively increased with the presence of frailty scale ≥5 and/or CCI ≥2 (Gray’s test, P = 0.0004). The incidence of infection-related mortality at 1 year in each group was 32.3%, 8.5%, and 0%, respectively (Figure 1B).
Conclusion
This study suggests that higher frailty and comorbidity may be patient-related, independent poor prognostic factors, which probably depend on increasing infection-related mortality.
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Nakane:Mundipharma KK: Research Funding. Nakamae:Mochida Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Novartis Pharma KK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel/accommodation/meeting expenses, Research Funding. Hino:Pfizer: Honoraria, Research Funding; Alexion: Honoraria, Research Funding; Nippon Shinyaku: Honoraria, Speakers Bureau.
Elotuzumab-based regimens are sometimes selected for multiple myeloma treatment after daratumumab-based regimens. However, there has been insufficient discussion on the efficacy of elotuzumab after ...daratumumab. We used Kansai Myeloma Forum registration data in a multicenter retrospective evaluation of the efficacy of elotuzumab after daratumumab. Overall survival (OS) rate and time to next treatment (TTNT) were significantly worse in the cohort given elotuzumab after daratumumab (Dara cohort, n = 47) than in the cohort with no history of daratumumab administration before elotuzumab (No-Dara cohort, n = 80, OS: P = 0.03; TTNT: P = 0.02; best response: P < 0.01). In the Dara cohort, OS and TTNT rates were worse with sequential elotuzumab use after daratumumab than with non-sequential (OS: P = 0.02; TTNT: P = 0.03). In patients given elotuzumab < 180 days after daratumumab, OS (P = 0.08) and best response (P = 0.21) tended to be worse, and TTNT was significantly worse (P = 0.01), than in those given elotuzumab after ≥ 180 days. These findings were confirmed by subgroup analyses and multivariate analyses. Monoclonal-antibody-free treatment might be preferable after daratumumab-based regimens. If possible, elotuzumab-based regimens should be considered only ≥ 180 days after daratumumab use.
Objective The aim of this study was to investigate the relation of QT dispersion to left ventricular (LV) systolic and diastolic function in patients undergoing anthracycline therapy. Methods We used ...echocardiography to evaluate LV systolic and diastolic function and electrocardiography to evaluate QT dispersion and corrected QT dispersion (QTcD) in patients with hematological diseases, who received anthracycline therapy. Patients Seventy-two patients with hematological diseases who were receiving anthracycline treatment were enrolled in the present study. Results LV end-diastolic diameter or LV end-systolic diameter had a significant positive correlation to QTcD (r=0.35, p<0.01, r=0.43, p<0.01). Also left ventricular ejection fraction of (LVEF) or fractional shortening had a significant negative correlation to QTcD (r=−0.46, p<0.001, r=−0.27, p=0.02). The highest QTcD group had a significantly larger LV end-diastolic diameter or LV end-systolic diameter than the lowest QTcD 48.5±5.7 vs. 44.4±4.5 (mm), p<0.001, 34.1±6.4 vs. 28.8±4.3 (mm), p<0.001 and the highest QTcD group had a significantly lower LVEF than the lowest QTcD 57.5±8.0 vs. 65.5±6.4 (%), p<0.001. On the other hand, none of the diastolic function markers were significantly correlated with QTcD. Conclusion We concluded that increased QTcD is correlated with LV dilation and systolic dysfunction induced by anthracycline therapy, and does not reflect a dispersion of ventricular repolarization or asynchronous motion.
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