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.

Brentuximab vedotin for relapsed or refractory Hodgkin lymphoma: experience in Turkey.

Current treatment modalities can cure up to 70-80 % of patients with classical Hodgkin lymphoma. Approximately, 20-30 % of patients require further treatment options. Brentuximab vedotin has been approved for the treatment of relapsed and refractory Hodgkin lymphoma. In the present study, we report the experience with brentuximab vedotin as single agent in 58 patients with relapsed or refractory Hodgkin lymphoma. The objective response rate was 63.5 % with 13 complete responders (26.5 %) among 49 patients evaluated at the early phase of treatment (2-5 cycles). Upon treatment prolongation (≥6 cycles), 37 patients achieved a final objective response rate of 32.4 % with 21.6 % of complete and 10.8 % of partial response. Overall survival at 12 months was 70.6 %, and progression-free survival at 12 months was 32.8 %. Median overall survival could not be reached and median progression-free survival was 7 months. While the median duration of response was 9 months in the whole cohort, it was 11.5 months in the complete responders. Complete response rates in patients treated with >3 chemotherapy regimens before brentuximab vedotin were significantly lower (p = 0.016). Fourteen patients were subsequently transplanted. In conclusion, brentuximab vedotin provided a bridge to transplantation in approximately one quarter of the patients. The declining response rates during the course of treatment suggest that transplantation should be implemented early during brentuximab vedotin treatment.

Comparison of chemotherapy and hematopoietic stem cell transplantation pre and postterm DMFT scores: a preliminary study.

AIMS: Chemotherapy is frequently used as a conditioning regimen to destroy malignant marrow cells before transplantation. Xerostomia, dysphagia, altered taste perception, mucositis, soft-tissue ulceration, and infection are common adverse oral effects of chemotherapy. The study was aimed to compare decayed, missing, filled teeth (DMFT) scores before and after hematopoietic stem cell transplantation (HSCT) and chemotherapy. MATERIALS AND METHODS: Thirty-six patients undergoing HSCT were included in the study. A pre-HSCT dental treatment protocol was implemented that consisted of restoration of all active carious lesions, treatment of periodontal infections, and extraction of all teeth with advanced periodontal disease. Upon completion of dental treatment, the importance of rigorous and effective oral hygiene was reemphasized, and patients were recalled 6 months later. DMFT scores were calculated prior to the initiation of HSCT treatment and 6 months after transplantation. STATISTICAL ANALYSIS USED: Regression analysis was used to evaluate the effects of HSCT and chemotherapy on DMFT scores. RESULTS: Wilcoxon T test showed a statistically significant difference in DMFT scores before and after HSCT ( P < 0.001). CONCLUSIONS: DMFT scores were found to increase after chemotherapy and HSCT, suggesting that the risk of infection is higher among HSCT patients when compared to other individuals. The results emphasize the need for dental examinations as an integral part of examination and treatment planning for patients undergoing HSCT and chemotherapy.

The impact of pretransplant hypoalbuminemia on survival in patients with leukemia who underwent allogeneic hematopoietic stem cell transplantation (alloHSCT): a nutritional problem?

OBJECTIVE: Serum albumin level is considered to be a marker reflecting the nutritional status in both healthy subjects and patients with malignancies. In this study we sought to investigate the association between pretransplantation serum albumin levels and prognosis among patients with leukemia who underwent allogeneic hematopoietic stem cell transplantation (alloHSCT). METHODS: We retrospectively analyzed the data of 102 patients who underwent alloHSCT from 2004 to 2010. Pretransplant serum albumin, D-dimer, creatinine, and fibrinogen levels drawn within 10 days before transplantation were obtained from patient files. All parameters were divided into 2 groups: normal levels (group 1) versus abnormal levels (group 2). Our normal range of serum albumin is 3.2-5.2 g/dL; patients with pretransplantation albumin level ≥3.2 g/dL were included in group 1 versus group 2 with <3.2 g/dL. RESULTS: The patients included 42 (41.1%) female and 60 (58.9%) male patients. The diagnoses were acute myeloblastic leukemia in 65 (63.7%) and acute lymphoblastic leukemia in 37 (36.3%). The median age was 26.0 years (range, 13-57). Univariate and multivariate analysis showed that patients with serum albumin levels <3.2 g/dL experienced significantly lower overall survival (OS) compared with ≥3.2 g/dL (hazard ratio [HR] 2.32 [range, 1.23-4.54] and HR 2.70 [range 1.38-5.26], respectively; P = .009). The median (range) OS in group 2 was 230.0 (184.0-544.0) days versus 570.5 (249.5-1,101.0) days in group 1 (P = .007). For disease free survival (DFS) evaluation, univariate and multivariate analysis showed that patients with serum albumin levels <3.2 g/dL had significantly lower values compared with patients with serum albumin ≥3.2 g/dL. (HR 2.17 [range 0.98-4.76] and HR 2.85 [range, 1.25-6.66], respectively; P = .046). The median (range) DFS in group 2 was 184.0 (61.0-524.0) days versus 445.0 (199.0-917.5) days in group 1 (P = .045). Among the patient characteristics the presence of infection was a significant independent variable for worse OS (HR 2.12 [range, 0.98-4.36], P = .036). The other parameters-age, sex, donor status, time to transplant interval, conditioning regimens, HLA status, and number of total infused CD34(+) cells-showed no significant effect on OS and DFS (P = .05). CONCLUSIONS: Pretransplantation decreased serum albumin levels were associated with poor survival in patients with leukemia who underwent alloHSCT.

Langerhans cell sarcoma of the nasopharynx: a rare case.

Langerhans cell sarcoma, a tumour with markedly malignant cytological features that originates from Langerhans cells, is a very rare disease. We report the first case of 39-year-old male with Langerhans cell sarcoma arising in the nasopharynx. We chose the 2-chlorodeoxyadenosine (2-CDA) regimen as first-line chemotherapy, and clinical improvement of Langerhans cell sarcoma was obtained. After the fourth cycle of 2-CDA therapy, however, disease progression was observed, and we administered ESHAP regimen (etoposide, carboplatin, cytarabine, methylprednisolone) as a second-line therapy. After we administered two cycles of ESHAP, however, the patient developed aggressive progression and he died. The importance of immunohistochemical findings is obvious in Langerhans cell sarcoma diagnosis. Considering that Langerhans cell sarcoma behaves in a very malignant fashion, a more aggressive treatment approach is necessary for patients with Langerhans cell sarcoma.

Pre-engraftment syndrome after myeloablative dual umbilical cord blood transplantation: risk factors and response to treatment.

High fevers and/or rashes prior to neutrophil engraftment are frequently observed after umbilical cord blood (UCB) transplantation, and the condition is referred to as pre-engraftment syndrome (PES). Few studies have evaluated the risk factors for and treatment response to PES. Therefore, we retrospectively characterized PES in 57 consecutive engrafted patients (≥ 12 years old) who received myeloablative dual UCB transplantation. All patients received TBI (≥ 13.2 Gy)-based myeloablative conditioning. Tacrolimus (n=35) or CYA (n=22) combined with mycophenolate mofetil was used as GVHD prophylaxis. PES was defined as the presence of non-infectious fever (≥ 38.5 °C) and/or rash prior to or on the day of neutrophil engraftment. The incidence (95% confidence interval) of PES was 77% (66-88%). The incidence of PES was significantly higher in patients who received CYA as a GVHD prophylaxis than those who received tacrolimus (P<0.001), and this association was confirmed in the multivariate analysis. The occurrence of PES did not impact OS or tumor relapse, although it may have increased non-relapse mortality (P=0.071). The incidence of acute GHVD or treatment-related mortality was not influenced by the choice to use corticosteroids to treat PES. This study suggests that use of CYA for GVHD prophylaxis increases the risk of PES following dual UCB transplantation.

Research on and clinical importance of duplications in various chromosomal regions in addition to Philadelphia chromosome in chronic myeloid leukemia.

PURPOSE: To investigate the chromosomal aberrations in chronic myelogenous leukemia (CML), particularly in chromosomal regions which carried 67 genes pertaining to oncogenes, transcription factors, signal transduction, tumor suppressors, apoptosis etc, in addition to Philadelphia (Ph+) chromosome by multiplex ligation-dependent probe amplification (MLPA) method and to compare them with clinical parameters. METHODS: The aberrations were investigated in 48 CML patients receiving imatinib therapy and a group of 15 healthy controls, by using the MLPA method between 2000 and 2009. The obtained results were compared both between patient and control groups and with clinical parameters. RESULTS: Duplication was detected in the fibroblast growth factor receptor 1 (FGFR1) gene of 2 patients, inosine 5' monophosphate dehydrogenase 1 (IMPDH1) gene of 4, postmeiotic segregation increased S. Cerevisiae 2 (PMS2) gene of 1, nuclear factor kappa beta (NFKB) of 5 and T-cell translocation 2 (LMO2) gene of 1 patient. Univariate analysis showed that splenomegaly, advanced age, Sokal risk score (SRS) and the duplications in IMPDH1 and FGFR1 genes significantly shortened 7-year event-free survival (EFS); multivariate analysis showed that only the duplications in IMPDH1 and FGFR1 genes were the factors that significantly affected EFS. No statistically significant correlations were detected between duplications and other clinical parameters. CONCLUSION: Duplications in 4 genes (FGFR1, IMPDH1, PMS2, LMO2) in addition to Ph+ chromosome in CML patients were detected for the first time. This study indicates that chromosomes 7 and 8 should be particularly investigated in more detail in addition to the Ph+ chromosome for better determination of disease prognosis and selection of alternative treatments.

Pretransplant serum ferritin level may be a predictive marker for outcomes in patients having undergone allogeneic hematopoietic stem cell transplantation.

Iron overload increases the risk of infections, veno-occlusive disease and hepatic dysfunction in post-transplant period. Our objective was to investigate the association of pre-transplant ferritin levels with complications and survival after allogeneic hematopoietic stem cell transplantation (alloHSCT).We retrospectively analysed 84 patients' data who had undergone allogeneic HSCT into two groups: patients with a serum ferritin level ≥ 1000 ng/ml, and patients with <1000 ng/ml at the time of HSCT.Cox-regression analysis showed that pre-transplant serum ferritin levels were significantly higher in patients who had at least one infectious event compared with those who had no any infectious event in the post-transplant 100 days (p<0.023). Overall survival (OS) and disease-free survival (DFS) rates were significantly higher in patients with a time-to-tx interval 12 months (p=0.002 and p=0.008 respectively). A higher risk of death was observed in high-ferritin group (hazard ratio=2.27, CI:1.01-5.09, p=0.023 for OS and hazard ratio=2.49, CI:1.12-5.53 p=0.039 for DFS). No significant effect on OS and DFS among groups was observed for variables conditioning regimen, gender and diagnosis. Acute GVHD was more common in patients with a ferritin level ≥ 1000 ng /mL, but this was not statistically significant (p>0.05). There was no statistical significance in both groups (ferritin ≥ 1000 ng /mL and ferritin <1000 ng/mL) for relapse rates (p>0.05). Platelet and neutrophil engaftment day was not found statistically significant compared with both groups (p=0.273 and p=0.882, respectively). Pre-transplant ferritin levels may predict poor outcomes in patients who had undergone allogeneic hematopoietic stem cell transplantation.

Venous thromboembolism risk and thromboprophylaxis among hospitalized patients: data from the Turkish arm of the ENDORSE study.

OBJECTIVES: To evaluate venous thromboembolism (VTE) risk and use of thromboprophylaxis in the acute care hospital setting. METHODS: A total of 1701 patients hospitalized for acute or exacerbated chronic medical illnesses or elective major surgery at 11 different hospitals across Turkey were included in the study. Patients at risk and VTE prophylaxis application were retrospectively identified based on medical charts. RESULTS: According to the American College of Chest Physicians (ACCP) criteria, overall 35.6% (606 of 1701) of the patients were identified to be at VTE risk. Venous thromboembolism-risk was observed in 64.9% of surgical and 23.8% of medical patients, the latter being lower than global Epidemiologic International Day for the Evaluation of Patients at Risk for Venous Thromboembolism in the Acute Hospital Care Setting (ENDORSE) study results; while prophylaxis was prescribed in 39.0% and 38.5% of them, respectively. Contraindication to anticoagulant prophylaxis was observed in 8.7% of medical and 8.8% of surgical patients. CONCLUSIONS: VTE remains a risk factor among patients hospitalized across Turkey, since identification as well as prophylaxis of patients at VTE risk seems to be neglected.

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.

Achondroplasia associated with gonadal dysgenesis.

A 45-year-old woman with short stature and primary amenorrhoea was admitted during a health-screening programme. Physical examination revealed a shortness of proximal legs and arms, short stature and other clinical properties of achondroplasia. Secondary sexual characteristics assessment showed axillary hair stage 5, breast stage 4 and pubic hair stage 5 (Tanner staging). Chromosomal analysis showed a 46XX karyotype. Skeletal X-ray showed small iliac wings and narrow sciatic notches. On pelvic ultrasound examination, the uterus appeared infantile and the ovaries were not visualized. Physical examination and laboratory parameters revealed a diagnosis of hypergonadotrophic hypogonadism. To the authors' knowledge, this is the first case of achondroplasia with gonadal dysgenesis discussed in the literature.