Nivolumab for relapsed or refractory Hodgkin lymphoma: real-life experience.

BACKGROUND: Reed-Sternberg cells of classical Hodgkin's lymphoma (cHL) are characterized by genetic alterations at the 9p24.1 locus, leading to over-expression of programmed death-ligand 1 and 2. In a phase 1b study, nivolumab, a PD-1-blocking antibody, produced a high response in patients with relapsed or refractory cHL, with an acceptable safety profile. PATIENTS AND METHODS: We present a retrospective analysis of 82 patients (median age: 30 years; range: 18-75) with relapsed/refractory HL treated with nivolumab in a named patient program from 24 centers throughout Turkey. The median follow-up was 7 months, and the patients had a median of 5 (2-11) previous lines of therapy. Fifty-seven (70%) and 63 (77%) had been treated by stem-cell transplantation and brentuximab vedotin, respectively. RESULTS: Among 75 patients evaluated after 12 weeks of nivolumab treatment, the objective response rate was 64%, with 16 complete responses (CR; 22%); after 16 weeks, it was 60%, with 16 (26%) patients achieving CR. Twenty patients underwent subsequent transplantation. Among 11 patients receiving allogeneic stem-cell transplantation, 5 had CR at the time of transplantation and are currently alive with ongoing response. At the time of analysis, 41 patients remained on nivolumab treatment. Among the patients who discontinued nivolumab, the main reason was disease progression (n = 19). The safety profile was acceptable, with only four patients requiring cessation of nivolumab due to serious adverse events (autoimmune encephalitis, pulmonary adverse event, and two cases of graft-versus-host disease aggravation). The 6-month overall and progression-free survival rates were 91.2% (95% confidence interval: 0.83-0.96) and 77.3% (0.66-0.85), respectively. Ten patients died during the follow-up; one of these was judged to be treatment-related. CONCLUSIONS: Nivolumab represents a novel option for patients with cHL refractory to brentuximab vedotin, and may serve as a bridge to transplantation; however, it may be associated with increased toxicity.

A comparison between allogeneic stem cell transplantation from unmanipulated haploidentical and unrelated donors in acute leukemia.

BACKGROUND: In the absence of a HLA-matched related or matched unrelated donor, allogeneic stem cell transplantation (allo-SCT) from mismatched unrelated donors or haploidentical donors are potential alternatives for patients with acute leukemia with an indication to allo-SCT. The objective of this study was to compare the outcome of allo-SCT from T cell-replete haploidentical (Haplo) versus matched (MUD 10/10) or mismatched unrelated donor at a single HLA-locus (MMUD 9/10) for patients with acute leukemia in remission. METHODS: Two hundred sixty-five adult patients with de novo acute leukemia in first or second remission that received a Haplo-SCT between January 2007 and December 2013 were compared with 2490 patients receiving a MUD 10/10 and 813 receiving a MMUD 9/10. Propensity score weighted analysis was conducted in order to control for disease risk imbalances between the groups. RESULTS: The weighted 3-year non-relapse mortality and relapse incidence were 29 and 30% for Haplo, 21 and 29% for MUD 10/10, and 29 and 25% for MMUD 9/10, respectively. The weighted 3-year leukemia-free survival (LFS) and overall survival (OS) were 41 and 46% for Haplo, 50 and 56% for MUD 10/10, and 46 and 48% for MMUD 9/10, respectively. Using weighted Cox model, both LFS and OS were significantly higher in transplants from MUD 10/10 compared from those in Haplo but not different between transplants from MMUD 9/10 and Haplo. The type of donor was not significantly associated with neither acute nor chronic graft-versus-host disease. CONCLUSIONS: Patients with acute leukemia in remission have better outcomes if transplanted from a MUD 10/10. We did not find any significant difference in outcome between transplants from MMUD 9/10 and Haplo, suggesting that both can be equally used in the absence of a 10/10 MUD. KEY POINT 1: Better outcomes using fully (10/10) matched unrelated donor for allo-SCT in acute leukemia in remission. KEY POINT 2: Similar outcomes after allo-SCT from unmanipulated haploidentical graft or mismatched (9/10) unrelated donor in acute leukemia in remission.

Analysis of cerebral toxoplasmosis in a series of 170 allogeneic hematopoietic stem cell transplant patients.

INTRODUCTION: Cerebral toxoplasmosis is a rare but fatal complication in hematopoietic stem cell transplant patients, which mostly is caused by reactivation of latent disease. METHODS: In this study, we report an analysis of cerebral toxoplasmosis in a series of 170 allogeneic stem cell transplant patients during a 30-month period at our institution. RESULTS: Among these allogeneic stem cell transplant patients, 5 were diagnosed with cerebral toxoplasmosis by brain magnetic resonance imaging and polymerase chain reaction of Toxoplasma gondii DNA. The incidence of cerebral toxoplasmosis was found to be 2.94%. CONCLUSION: Mortality rate is known to be very high in cerebral toxoplasmosis; therefore, it is life saving to diagnose the disease in the early stages and start treatment promptly, especially in high-endemic countries like Turkey.

The role of flow cytometry in the diagnosis of non- Hodgkin's lymphoma, Hodgkin's lymphoma, granulomatous inflammation and reactive lymph node specimens.

PURPOSE: In this study we aimed to compare the flow cytometry (FC) results of patients with B cell lymphoma, T cell lymphoma, Hodgkin's lymphoma, granulomatous inflammation and reactive lymph node and investigate the role of FC in malignant or non malignant conditions. METHODS: Ninety patients were divided into 5 groups according to histopathology results. Patients were compared according to cytokeratin and positivity percentage of the following surface markers: CD45, CD19, CD5, CD19-CD5, CD4, CD8, CD3,CD16-CD56, CD10, CD10-CD19, CD23, CD20, CD4-CD8, CD3-CD16-56, CD30, CD38, kappa and lambda light chains, CD20-CD23. Patients were also compared according to the intensity of the expression (exp) of same markers. ROC curve analysis was performed for CD19+ cell percentage, CD38 exp, kappa/lambda and lambda/kappa ratios. RESULTS: 1) Kappa/lambda and lambda/kappa ratios can distinguish B cell lymphoma from T cell lymphoma, Hodgkin's lymphoma, granulomatous inflammation and reactive lymph node; 2) CD19+ cell percentage can distinguish T cell lymphoma from Hodgkin's lymphoma, granulomatous inflammation and reactive lymph node; 3) CD38 exp can partly distinguish B cell lymphoma from T cell lymphoma, Hodgkin's lymphoma, granulomatous inflammation and reactive lymph node and T cell lymphoma from granulomatous inflammation, T cell lymphoma from reactive lymph node, Hodgkin's lymphoma from reactive lymph node. CONCLUSION: Flow cytometry has a role in distinguishing lymphomas from non malignant lesions.

Similar outcomes using myeloablative vs reduced-intensity allogeneic transplant preparative regimens for AML or MDS.

Although reduced-intensity conditioning (RIC) and non-myeloablative (NMA)-conditioning regimens have been used for over a decade, their relative efficacy vs myeloablative (MA) approaches to allogeneic hematopoietic cell transplantation in patients with AML and myelodysplasia (MDS) is unknown. We compared disease status, donor, graft and recipient characteristics with outcomes of 3731 MA with 1448 RIC/NMA procedures performed at 217 centers between 1997 and 2004. The 5-year univariate probabilities and multivariate relative risk outcomes of relapse, TRM, disease-free survival (DFS) and OS are reported. Adjusted OS at 5 years was 34, 33 and 26% for MA, RIC and NMA transplants, respectively. NMA conditioning resulted in inferior DFS and OS, but there was no difference in DFS and OS between RIC and MA regimens. Late TRM negates early decreases in toxicity with RIC and NMA regimens. Our data suggest that higher regimen intensity may contribute to optimal survival in patients with AML/MDS, suggesting roles for both regimen intensity and graft vs leukemia in these diseases. Prospective studies comparing regimens are needed to confirm this finding and determine the optimal approach to patients who are eligible for either MA or RIC/NMA conditioning.

The effect of calcineurin inhibitors on endothelial and platelet function in renal transplant patients.

BACKGROUND/AIM: Posttransplant cardiovascular mortality is still an important problem in renal transplant patients. In addition to conventional coronary risk factors, coagulation abnormalities play a key role in the hypercoagulable state observed in transplanted patients. Though renal transplantation eliminates cardiovascular disease risk factors by restoring renal function, it introduces new cardiovascular risks derived, in part from immunosupressive medications. We aimed to assess the effect of calcineurin inhibitors on endothelial function, platelet activation and aggregation in renal transplant patients. METHODS: 62 renal transplant were studied. Staging was performed according to immunosuppression regimen. Group 1 (n = 37) were treated with cyclosporine/mycophenolate mofetil/methylprednisolone and Group 2 (n = 25) were treated with tacrolimus/mycophenolate mofetil/methylprednisolone. The control group consisted of 16 healthy subjects (Group 3). Hematological and biochemical tests, asymmetric dimethyl arginine (ADMA), sP-selectin levels and platelet aggregation tests were studied. RESULTS: ADMA levels were higher in Group1 and statistically significant differences were observed compared with those of Group 2 and Group 3 (p < 0.05). Platelet aggregation values induced by all agonists (Adenosine diphosphate (ADP), epinephrine, ristocetin, collagen) were lower in Group 1 than Group 2 and Group 3, but the difference did not reach statistical significance (p > 0.05). There was a negative correlation between cyclosporine level and platelet aggregation values induced by ADP (r = -0.43, p < 0.01), ristocetin (r = -0.40, p < 0.05), epinephrine (r = -0.41, p < 0.05), and collagen (r = -0.43, p < 0.01). sP-selectin levels were appreciably higher in Group 1 and statistically significant differences were observed compared with those of Group 2 (p < 0.05) and Group 3 (p < 0.01). CONCLUSION: The results of our study suggest that CsA induces platelet activation without inducing platelet aggregation. Endothelial dysfunction due to vascular endothelial damage reflected by increases in ADMA values may increase the tendency for thrombotic events in patients who had undergone renal transplantation.

Effects of imatinib mesylate on renin-angiotensin system (RAS) activity during the clinical course of chronic myeloid leukaemia.

The renin-angiotensin system (RAS) is involved in cell growth, proliferation and differentiation in bone marrow in an autocrine-paracrine manner, and it modulates normal and neoplastic haematopoietic cell proliferation. This study aimed to assess expressions of the RAS components, renin, angiotensinogen and angiotensin-converting enzyme (ACE), during imatinib mesylate treatment of patients with chronic myeloid leukaemia (CML). Expressions of RAS components were studied in patients with CML at the time of diagnosis (n = 83) and at 3, 6 and 12 months after diagnosis (n = 35) by quantitative real-time polymerase chain reaction. De novo CML patients had increased ACE, angiotensinogen and renin mRNA levels and these expression levels decreased following administration of imatinib. The RAS activities were significantly different among Sokal risk groups of CML, highlighting the altered biological activity of RAS in neoplastic disorders. The results of this study confirm that haematopoietic RAS affects neoplastic cell production, which may be altered via administration of tyrosine kinase inhibitors such as imatinib mesylate.

Successful treatment of nephrotic syndrome due to systemic AL amyloidosis after autologous stem cell transplantation: renal response is an important therapeutic end point.

Primary systemic (AL) amyloidosis involves vital organs from the early phase of illness, resulting in poor prognosis. Today, high-dose melphalan followed by autologous peripheral blood stem cell transplantation is an effective treatment for systemic AL amyloidosis. We report a patient with nephrotic syndrome due to systemic AL amyloidosis, who was successfully treated with autologous peripheral blood stem cell transplantation. At follow-up 36 months from ASCT, the patient showed a significant improvement in the signs of peripheral neuropathy and reduction in proteinuria without further organ involvement. Due to poor prognosis with conventional therapy, autologous stem cell transplantation should be considered for treatment in patients with systemic AL amyloidosis, and favorable outcome is ensured with achievement of renal response after ASCT.

Calcium channel blockers increase the amount of nitrite production in rabbits without decreasing the responsiveness of platelets to collagen.

By virtue of their ability to increase nitric oxide (NO) production, it is thought that calcium channel blockers (CCBs) may be involved in the inhibition of platelet aggregation. In an attempt to compare the abilities of different groups of calcium antagonists to affect NO generation and platelet aggregation, single doses of the calcium antagonists verapamil, nicardipine and diltiazem were administered to rabbits. It was found that each of these drugs increased the levels of nitrite significantly. It was also found that these drugs had different time courses of action. Of the CCBs used in this study, verapamil was found to induce the greatest increase in nitrite production (about a 4-fold increase over basal levels), peaking at 90 min (P<0.001). Diltiazem and nicardipine (3.5-fold and 2.5-fold increase over basal levels, respectively) were both found to induce increases in NO which peaked at 150 min (P<0.001 and P<0.01 respectively). Each of the drugs was then given at double the original dose; however, nicardipine was the only drug that was seen to further increase nitrite production (P<0.001). Blood samples taken from the animals were analysed using whole-blood aggregometry in order to assess the amount of collagen-induced platelet aggregation. At the time point when NO release was expected to be maximal (150 min), it was found that the collagen-induced platelet responses were not significantly altered in platelets from rabbits that had been treated with either verapamil or nicardipine. In contrast, at the 150-min time point, diltiazem treatment made the platelets hypersensitive to collagen stimulation. The results of this study demonstrate that treatment with calcium channel antagonists increases the levels of NO produced in rabbits, however, this increase in NO production is not accompanied by a decrease in the reactivity of platelets to collagen.

5-Hydroxytryptamine-2A receptor gene (HTR 2 A) candidate polymorphism (T 102 C): Role for human platelet function under pharmacological challenge ex vivo.

Although the environmental and life-style factors influencing individual predisposition to acute myocardial infarction (AMI) have been well documented, little is known on the identity of genetic loci that may contribute to risk for AMI. Recently, genetic studies in patients with nonfatal AMI have suggested an association with the T 102 C polymorphism in the serotonin 5-HT(2A) receptor gene (HTR 2 A). Considering the significant role of the 5-HT(2A) receptor in serotonin-induced platelet responses and the contribution of platelet (patho)physiology to thromboembolic events, we postulated that the increased susceptibility to AMI in patients with the T 102 homozygosity may be attributable, in part, to altered serotonin-mediated platelet function. In a group of healthy volunteers recruited from the Eskisehir region in central Turkey (N=37), we investigated the functional consequences of HTR 2 A T 102 C polymorphism in relation to platelet pharmacodynamics ex vivo. The platelet shape change and aggregation response to serotonin were measured with use of the platelet aggregometry and expressed as aggregometer output (mm). Because the circulating catecholamine hormone epinephrine can augment platelet aggregation, pharmacodynamic response (aggregation and its inhibition by 5-HT(2A) receptor antagonist cyproheptadine) was measured in the presence of both serotonin and epinephrine, to mimic the clinical situation in patients. The mean platelet aggregation was higher by 38% in subjects with T 10 2 homozygosity (T/T genotype, N=13) when compared with the carriers of the 102 C-allele (T/C and the C/C genotypic groups, N=24) (39.5 mm+/-12.3 vs. 28.7 mm+/-16.8, respectively) (mean+/-SD) (p<0.05). On the other hand, neither the serotonin-induced platelet shape change nor the cyproheptadine inhibition of platelet aggregation was influenced by the HTR 2 A T 102 C genetic variation (p>0.05). These findings in healthy subjects may provide a mechanistic explanation for the previously reported genetic association between HTR 2 A and AMI. Further genetic association studies of the 5-HT(2A) receptor in patients with AMI in different populations are warranted.

Assessment of the P-glycoprotein expression by 99mTc-MIBI bone marrow imaging in patients with untreated leukaemia.

The ability of cancer cells to become simultaneously resistant to different drugs is a significant impediment to successful chemotherapy. 99mTc-MIBI has been reported to be a transport substrate for P-glycoprotein (Pgp). The aim of the study was to ascertain the relationship between the degree of 99mTc-MIBI uptake and the level of Pgp expression in patients with newly diagnosed leukaemia. A total of 26 patients (12 female and 14 male; mean age 46.8+/-3.7 years) with newly diagnosed leukaemia were included in the study. None of the patients had been previously treated with chemotherapy. Images were obtained 20 min post-injection of 740 MBq 99mTc-MIBI. Whole-body and planar spot images of the pelvis and thorax were acquired. The uptake of the MIBI in the bone marrow was evaluated using a qualitative and also a quantitative scoring system with determination of the tumour-to-background (T/B) ratios. Flow cytometry was performed for determining the Pgp expression of the blast cells in the bone marrow aspiration samples. There was a statistically significant inverse relationship between the Pgp level in numeric values and both mean qualitative (P<0.001; r=-0.665) and quantitative (P=0.001; r=-0.606) results of 99mTc-MIBI imaging. Both the mean qualitative score and the T/B ratios were higher in patients who were Pgp negative than in those who were Pgp positive (P<0.001 and P<0.001, respectively). These data indicate that an increased level of Pgp expression is correlated with a low accumulation of 99mTc-MIBI in bone marrow of patients with leukaemia. 99mTc-MIBI bone marrow imaging, as a method of functional imaging, can give in vivo information concerning the functional expression of the MDR phenotype in patients with untreated leukaemia.

Tc-99m methoxyisobutylisonitrile bone marrow imaging for predicting the levels of myeloma cells in bone marrow in multiple myeloma: correlation with CD38/CD138 expressing myeloma cells.

The percentage of myeloma cells in bone marrow is subsequently an important index of disease in patients with multiple myeloma (MM). Bone marrow myeloma cells can be detected by strong CD38/CD138 positivity and light scatter characteristics using flow cytometry. The aim of the study was to evaluate the relationship between the degree of Tc-99m methoxyisobutylisonitrile (MIBI) uptake and the percentage of CD38/CD138 expressing myeloma cells in the bone marrow of patients with MM. A total of 15 patients with MM (mean age: 61.7+/-2.4 years; 7 F and 8 M) were included in the study. Tc-99m MIBI imaging was obtained 20 min after injection of 740 MBq Tc-99m MIBI. Planar spot images of the pelvis and thorax were acquired. The uptake of Tc-99m MIBI in the bone marrow was evaluated using a qualitative and also a semiquantitative scoring system for the bone marrow in areas that included the proximal femurs, anterior iliac crest, and sternum. In all patients, flow cytometry was performed for assessing the percentage of CD38/CD138 expressing myeloma cells in the bone marrow samples. There was a statistically significant positive correlation between the percentage of CD38/CD138 expressing plasma cells in bone marrow and both mean qualitative (r=0.689, p=0.005) and semiquantitative (r=0.669, p=0.006) results of Tc-99m MIBI uptake. In conclusion, our results indicate that increased Tc-99m MIBI uptake of bone marrow is related to the percentage of plasma cell infiltration of bone marrow. Tc-99m MIBI bone marrow imaging may be a useful tool for predicting the levels of myeloma cells in bone marrow of patients with MM.

Is there an association of plasma homocysteine levels with vascular involvement in patients with Behçet's syndrome?

OBJECTIVE: To assess whether or not plasma homocysteine levels play a part in vascular involvement in Behçet's syndrome (BS). METHODS: 74 consecutive BS patients fulfilling the criteria of the International Study Group for BS, 35 healthy control (HC) and 14 rheumatoid arthritis (RA) patients on methotrexate (MTX) were studied. BS patients were then classified as those with and without vascular involvement. Fasting plasma homocysteine, folate, and vitamin B12 concentrations were measured by enzyme immunoassay and chemiluminescent immunoassay methods respectively. RESULTS: Plasma homocysteine levels were found to be higher in the BS patients than in the healthy control (16.08 +/- 7.5 vs. 12.9 +/- 6.3 micromol/L, p < 0.03). The homocysteine levels in the RA group on MTX were higher compared with both the BS and HC groups (28.7 +/- 9.9; p < 0.0001). No remarkable difference pertaining to homocysteine levels was found between BS patients with or without thrombosis (p < 0.86). Hyperhomocysteinemia was also detected in 11 out of 22 (50%) of the patients with vascular involvement, which proved to be of no significant difference in comparison with those without vascular involvement (20/52, 38%; chi2 = 0.26, p > 0.05). Active BS smokers exhibited a higher concentration of homocysteine in contrast to non-smoker BS sufferers (20 +/- 8.4 vs 14.1 +/- 6.1 micromol/l; p < 0.004). Smoking was determined to have a positive correlation with vascular involvement (r = 0.26, p < 0.046), as well as with homocysteine levels (r = 0.31, p < 0.012) in BS. Upon logistic regression analysis, smoking was found to have a significant relationship with vascular involvement (odds ratio 3.12 [95% CI 2.02-4.22] p = 0.04). There was no significant difference between the study groups with respect to their B12 vitamin and folate levels. We were unable to make any correlation between homocysteine and vitamin B12 or folate in any of the groups (p > 0.05). CONCLUSIONS: No association was found between homocysteine levels and vascular involvement in our BS patients. We determined that smoking seems to pose a risk for vascular involvement in BS patients.

Effect of cellular DNA content on the prognosis of epithelial ovarian cancers.

OBJECTIVE: To assess the cellular DNA status of epithelial ovarian cancers with regard to clinicopathological findings and its effect on prognosis. MATERIALS AND METHODS: Twenty-six consecutive patients with a diagnosis of epithelial ovarian cancer who had been treated by primary surgery and six courses of platinum-based chemotherapy were enrolled in this study. Second-look laparotomy (SLL) was performed in all cases following confirmation of the clinical remission state. Surgical stage, tumor grade, initial tumor volume, residual tumor volume, histopathologic differentiation, and SLL findings were analyzed in correlation with DNA ploidy and DNA index. DNA analysis was performed via DNA flow cytometry through paraffin-embedded tissue specimens. RESULTS: Of 26 patients, flow cytometric studies revealed 16 aneuploidy cases (61.5%). DNA index values ranged from 1.1 to 1.82 (average 1.29 +/- 0.28). The flow cytometry coefficient of variation mean value was set to 6.7. Taking the cutoff value of 1.2 for DNA indices, a fairly good correlation was detected between DNA ploidy and DNA indices (p < 0.001). The aneuploidy incidence was found to be high in advanced and poorly differentiated tumors (p < 0.05). There was statistically more residual tumor volume in aneuploid tumors during primary cytoreductive surgery and also higher recurrence rates following six courses of chemotherapy compared with diploid tumors (p < 0.05). No significant correlation was detected between the histopathologic subtypes and tumor volume (p > 0.05). Residual tumor volumes were larger in cases with DNA indices of 1.2 yielding higher residual tumor volume following surgery and being in good correlation with SLL results (p < 0.05). The mean survival rates of cases with aneuploid tumor and a DNA index of >1.2 were low compared to those with diploid tumors and DNA indices of <1.2 tumors (p < 0.05). CONCLUSION: DNA ploidy and DNA indices are important prognosticators for malignant epithelial ovarian tumors. They should be evaluated together with the patient's clinical status and other prognostic factors.

Lymphadenitis caused by Scedosporium apiospermum in an immunocompetent patient.

A case of lymphadenitis caused by Scedosporium apiospermum in a 25-year-old immunocompetent woman had been misdiagnosed as tuberculous lymphadenitis. Clinical response to itraconazole therapy was obtained in 6 months; to our knowledge, this is the first report of lymphadenitis caused by S. apiospermum in humans.

Antiphospholipid syndrome associated with intestinal amoebiasis.

We present a case of intestinal amoebiasis with subsequent development of antiphospholipid syndrome, manifested by deep vein thrombosis and pulmonary emboli. Anticardiolipin antibodies (aCL) of IgM type at medium titer and aCL IgG antibody at low titer were determined during the days after the onset of infection. To our knowledge this is the first case of antiphospholipid syndrome associated with amoebiasis to be presented in the literature.