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.

Successful treatment of myelodysplastic syndrome-induced pyoderma gangrenosum.

We report successful treatment of a refractory myelodysplastic syndrome-associated pyoderma gangrenosum with the combination of thalidomide and interferon-alpha2a in a single patient. A non-healing wound developed on a 40-year-old woman's left thumb after minor trauma. Massive ulcerovegetative lesions developed after reconstruction surgery. Histopathological examination of the bone marrow and cytogenetic studies revealed an atypical myeloproliferative/myelodysplastic syndrome. The skin lesions resolved dramatically after two months of thalidomide and interferon-alpha2a combination therapy and the haematological status improved.

cTnT can be a useful marker for early detection of anthracycline cardiotoxicity.

BACKGROUND: The level of serum cardiac troponin-T (cTnT) increases with myocardial damage. We sought to assess whether cTnT level could be a useful marker for the early detection of anthracycline cardiotoxicity. PATIENTS AND METHODS: Forty-one patients who had been scheduled to receive anthracycline-containing combination chemotherapy were included in the study. Serum cTnT levels were measured before (baseline) and after the first cycle of chemotherapy, and again, after the last cycle of chemotherapy. In all patients, the left ventricular ejection fraction (LVEF), fractional shortening (FS), early peak flow/atrial flow velocity (E/A) ratio, and the isovolemic relaxation time (IRT) were measured echocardiographically, both before and after the completion of chemotherapy. RESULTS: LVEF and FS did not change in any patients. In 21 patients (49%), the E/A ratio decreased after therapy as compared to the pre-treatment values. The decrease in E/A ratio was more prominent in patients who were older than the mean age of our study group, which was 44 years. The post-treatment IRT was prolonged compared with the pretreatment IRT (94.0 +/- 2.0 versus 85.6 +/- 10.5 ms, respectively). cTnT levels after completion of therapy were elevated in 14 (34%) patients, and exceeded the upper limit of the normal range (>0.1 ng/ml) in only one patient. cTnT levels measured after completion of therapy were significantly higher, compared with those measured at baseline and after the first cycle of therapy. In the younger age group (< or =44 years old), there was a two-fold decrease in the E/A ratio in those patients whose cTnT levels increased during the therapy, when compared with those whose cTnT levels did not change (21% versus 43%, respectively). CONCLUSION: Increased serum cTnT level can be detected in the early stages of anthracycline therapy and it is associated with diastolic dysfunction of the left ventricle. Therefore, serum cTnT level could be a useful measure for early detection of anthracycline-induced cardiotoxicity.

A patient presenting with spinal cord compression who had two distinct follicular cell type thyroid carcinomas.

A 61-yr-old woman presented with complaints of weakness and pain in her legs. A magnetic resonance imaging showed a 3 x 5.6 x 7.8 cm mass lesion destructing the T1 and T2 vertebral bodies and compressing the spinal cord. The mass was excised surgically. It was follicular carcinoma metastasis of the cervicodorsal region. Then, she underwent a total thyroidectomy. Pathological examination showed two different types of carcinomas in two different focuses; follicular carcinoma in the left lobe and follicular variant papillary carcinoma in the isthmic lobe. After the operation she was given 100 mCi 131I. This is the first report of a patient who had both metastatic follicular carcinoma and follicular variant papillary carcinoma together.

Is there an increased rate of additional malignancies in patients with mantle cell lymphoma?

PURPOSE: To examine the frequency of additional neoplasms preceding and following the diagnosis of mantle cell lymphoma (MCL). PATIENTS AND METHODS: A total of 156 patients with MCL treated on the hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone alternated with methotrexate and cytosine arabinoside (Hyper-CVAD/M-A) program with or without rituximab from 1994 to 2000 were the subjects of this report. RESULTS: These patients were followed for a median time of 26 months, and a total of 32 (21%) additional neoplasms were diagnosed, 21 preceding the diagnosis of MCL and 11 following MCL. After excluding certain types of non-invasive neoplasms, including basal cell carcinoma, meningioma and cervical intraepithelial neoplasia, we observed seven second malignancies after the diagnosis of MCL, and the 5-year cumulative incidence rate of second malignancy was 11%. The observed-to-expected (O/E) ratio was 7/0.07 = 100 [95% confidence interval (CI) 49.3 to 186.6; P <0.0001]. Of the 21 malignancies diagnosed prior to MCL, 16 were invasive and five non-invasive. There were a total of 10 urologic malignancies occurring before or after the diagnosis of MCL was established. CONCLUSIONS: Our findings suggest that there is an increased incidence of second malignancies in patients with MCL. In addition, the high number of cases with urinary tract cancer in our series may substantiate prior reports describing a possible association between lymphoma and urologic malignancies.

Mantle-cell lymphoma.

During the past decade, mantle-cell lymphoma has been established as a new disease entity. The normal counterparts of the cells forming this malignant lymphoma are found in the mantle zone of the lymph node, a thin layer surrounding the germinal follicles. These cells have small to medium-sized nuclei, are commonly indented or cleaved, and stain positively with CD5, CD20, cyclin D1, and FMC7 antibodies. Because of its morphological appearance and a resemblance to other low-grade lymphomas, many of which grow slowly, this lymphoma was initially thought to be an indolent tumour, but its natural course was not thoroughly investigated until the 1990s, when the BCL1 oncogene was identified as a marker for this disease. Mantle-cell lymphoma is a discrete entity, unrelated to small lymphocytic or small-cleaved-cell lymphomas.

Gastric lymphomas in Turkey. Analysis of prognostic factors with special emphasis on flow cytometric DNA content.

BACKGROUND: In contrast to DNA ploidy, to the authors' knowledge the prognostic significance of S-phase fraction (SPF) in gastric lymphomas has not been determined. In the current study, the prognostic significance of various parameters including SPF and DNA aneuploidy were analyzed and some distinct epidemiologic and biologic features of gastric lymphomas in Turkey were found. METHODS: A series of 78 gastric lymphoma patients followed at Hacettepe University is reported. DNA flow cytometry was performed for 34 patients. The influence of various parameters on survival was investigated with the log rank test. The Cox proportional hazards model was fitted to identify independent prognostic factors. RESULTS: The median age of the patients was 50 years. There was no correlation between patient age and tumor grade. DNA content analysis revealed 4 of the 34 cases to be aneuploid with DNA index values < 1.0. The mean SPF was 33.5%. In the univariate analysis, surgical resection of the tumor, modified Ann Arbor stage, performance status, response to first-line chemotherapy, lactate dehydrogenase (LDH) level, and SPF were important prognostic factors for disease free survival (DFS). The same parameters, excluding LDH level, were important for determining overall survival (OS). In the multivariate analysis, surgical resection of the tumor, disease stage, performance status, and age were found to be important prognostic factors for OS. CONCLUSIONS: To the authors' knowledge the current study is the first to demonstrate the prognostic significance of SPF in gastric lymphomas. The distinguishing features of Turkish gastric lymphoma patients are 1) DNA indices of aneuploid cases that all are < 1.0, which is a unique feature; 2) a lower percentage of aneuploid cases; 3) a higher SPF; 4) a younger age distribution; and 5) lack of an age-grade correlation. The authors conclude that gastric lymphomas in Turkey have distinct biologic and epidemiologic characteristics.

Primary breast lymphomas--a retrospective analysis of twelve cases.

This study was undertaken to define the natural history and treatment results of patients with primary breast non-Hodgkin's lymphoma (NHL). Twelve female patients who had been followed at Hacettepe University Hospital between 1973 and 1997 were retrospectively evaluated. All patients presented with breast masses (6 in the right breast and 6 in the left) that had recently enlarged. The most common histologic subtype was diffuse, small cleaved-cell lymphoma. Chemotherapy regimens were employed in 9 patients. Radiotherapy was delivered to the breast and its lymphatics in 8 patients. Lumpectomy, simple or modified radical mastectomy was performed in 5 cases. An objective response was attained with surgery, chemotherapy, or radiotherapy alone in 2, 1, and 1 cases, respectively. Combined modality treatment including either two or three modalities was successful in 7 cases. The median progression-free and overall survival times were 49 and 56 months, respectively. Although primary NHL of the breast is a rare disease compared to carcinoma, it should be considered in the differential diagnosis of breast masses.

Interferon alfa-2b, colchicine, and benzathine penicillin versus colchicine and benzathine penicillin in Behçet's disease: a randomised trial.

BACKGROUND: Sight-threatening eye involvement is a serious complication of Behçet's disease. Extraocular complications such as arthritis, vascular occlusive disorders, mucocutaneous lesions, and central-nervous-system disease may lead to morbidity and even death. We designed a prospective study in newly diagnosed patients without previous eye disease to assess whether prevention of eye involvement and extraocular manifestations, and preservation of visual acuity are possible with combination treatments with and without interferon alfa-2b. METHODS: Patients were randomly assigned 3 million units interferon alfa-2b subcutaneously every other day for the first 6 months plus 1.5 mg colchicine orally daily and 1.2 million units benzathine penicillin intramuscularly every 3 weeks (n=67), or colchicine and benzathine penicillin alone (n=68). The primary endpoint was visual-acuity loss. Analysis was by intention to treat. FINDINGS: Significantly fewer patients who were treated with interferon had eye involvement than did patients who did not receive interferon (eight vs 27, relative risk 0.21 [95% CI 0.09-0.50], p<0.001). Ocular attack rate was 0.2 (SD 0.62) per year with interferon therapy and 1.02 (1.13) without interferon therapy (p=0.0001). Visual-acuity loss was significantly lower among patients treated with interferon than in those without interferon (two vs 13, relative risk 0.13 [95% CI 0.03-0.60], p=0.003). Arthritis episodes, vascular events, and mucocutaneous lesions were also less frequent in patients treated with interferon than in those not receiving interferon. No serious side-effects were reported. INTERPRETATION: Therapy with interferon alfa-2b, colchicine, and benzathine penicillin seems to be an effective regimen in Behçet's disease for the prevention of recurrent eye attacks and extraocular complications, and for the protection of vision.

Treatment of advanced soft tissue sarcomas with ifosfamide and doxorubicin combination chemotherapy.

Our objective was to assess the efficacy of a standard dose ifosfamide and doxorubicin containing regimen in the treatment of advanced soft tissue sarcomas. Forty consecutive patients with a median age of 35.5 years were treated. Ifosfamide was administered at a dose of 2.5 g/m(2)/day as 72-hour continuous infusion with mesna at the same dosage and schedule. Doxorubicin was given at the dose of 60 mg/m(2)/day as 2-hour infusion on day 1. Six patients had a complete response (15%), and 9 (22.5%) had a partial response, fourteen patients (35%) stable disease, and 11 (27.5%) did not respond to chemotherapy. The median duration of response was 13 and 5 months for the complete and partial responders, respectively. The median survival was 37 months. Febrile neutropenia was encountered in 9 cases (22.5%). The present ifosfamide and doxorubicin combination is a moderately effective and well-tolerable regimen in the treatment of advanced soft tissue sarcomas.

Enhanced erythrocyte aggregation in type 2 diabetes with late complications.

We investigated whether erythrocyte aggregation (EA) is enhanced in type 2 diabetic patients who have developed microvascular or macrovascular complications. EA rates at high and low shear rates were analysed in 141 patients with type 2 diabetes who were further divided into 4 subgroups according to the status of diabetic complications and degree of metabolic control. Groups 1 (n = 43) and 2 (n = 23) consisted of well-controlled patients without and with clinically evident late complications, while groups 3 (n = 33) and 4 (n = 42) represented poorly controlled patients without and with these complications, respectively. 124 healthy subjects served as the control group. Mean EA rate was comparable between control subjects and group 1 both at high (2.05 +/- 0.03 vs. 2.14 +/- 0.07, respectively) and low (6.96 +/- 0.02 vs. 7.04 +/- 0.06, respectively) shear rates. Mean EA rate was also comparable between groups 2 and 4 at high (2.76 +/- 0.09 vs. 2.94 +/- 0.07, respectively) and low (8.18 +/- 0.13 vs. 8.41 +/- 0.1, respectively) shear rates. However, EA at both shear rates in groups 2 and 4 were significantly higher than control subjects, group 1 (p < 0.0001) and group 3 (high shear rate EA: 2.76 +/- 0.09 and low shear rate EA: 7.48 +/- 0.07 (p < 0.01). In group 3, EA rates were significantly higher than control subjects and group 1 (p < 0.05) at both shear rates. No significant correlation was found between EA at high and low shear rates and fibrinogen levels in diabetic subgroups and control subjects. The data suggest that patients with type 2 diabetes who had developed clinically evident late complications have enhanced EA regardless of the degree of metabolic control. Whether enhanced EA is a primary phenomenon contributing to the development of these complications or it occurs secondary to their development remains to be clarified.

Serotonin receptor antagonists in prophylaxis of acute and delayed emesis induced by moderately emetogenic, single-day chemotherapy: a randomized study.

In this randomized study, the efficacy of a single dose of three serotonin antagonists were compared in prophylaxis of acute and delayed vomiting induced by moderately emetogenic, single-day chemotherapy in chemotherapy-naïve patients. A total of 54 patients were entered. Eighteen patients received ondansetron, 17 received tropisetron, and 19 received granisetron. Antiemetics were administered as 15-minute intravenous infusion before chemotherapy. Complete control of acute vomiting was achieved in 38.8% with ondansetron, 58.8% with tropisetron, and 73.7% with granisetron. Major response rates were 83.3%, 82.3%, and 89.5%, respectively. For the delayed control of emesis, complete control of delayed vomiting was achieved in 38.8% with ondansetron, 52.9% with tropisetron, and 73.7% with granisetron. The major response rates were 71.8%, 70.5%, and 100%, respectively. The adverse effects were rare and mild in all groups. The authors conclude that there may be clinically important differences among serotonin antagonists used for chemotherapy-induced emesis.

VB-CHEP chemotherapy regimen for aggressive non-Hodgkin's lymphomas.

Despite intensive search for the optimal combination chemotherapy for aggressive non-Hodgkin's lymphoma (NHL), the CHOP (cyclophosphamide, adriamycin, vincristine and prednisolone) regimen is still the standard therapy. We investigated the clinical efficacy of a new combination regimen consisting of vincristine, bleomycin-cyclophosphamide, adriamycin, etoposide and prednisolone (VB-CHEP) in patients with aggressive NHL. A total of 29 patients with aggressive NHL was enrolled into the protocol. Eight patients were consolidated with cisplatin and cytarabine and 5 patients received radiotherapy for bulky disease. Objective response was achieved in 82.8% of the patients. Complete remission (CR) and partial remission rates were 72.4%, and 10.3%, respectively. CR rate was significantly lower in patients with advanced stage, extranodal disease and bone marrow involvement. Median follow-up time is 34+ months; 17 patients are disease-free while 12 died and only 2 patients with CR have relapsed so far. Median response duration is 29+ months and the median survival is 48+ months. The survival rate is 69% in the first year and 66% in the second year. A total of 152 cycles were evaluated for toxicity. Major hematological toxicity was myelosuppression and neutropenia, detected in 50.65%, was mostly grades 1-2. Neutropenic fever occurred in only 11 cycles. The side effects of the consolidation therapy were also acceptable. We conclude that the VB-CHEP regimen with consolidation therapy for high-risk patients may be an effective treatment for advanced stage aggressive NHL.

Bolus and continuous infusion mitoxantrone in newly diagnosed adult acute lymphoblastic leukemia: results of two consecutive phase II clinical studies.

Two consecutive phase II clinical studies were designed to evaluate the efficacy and safety of bolus and continuous infusion (CI) mitoxantrone (MTZ) in 39 patients with newly diagnosed acute lymphocytic leukemia (ALL). MTZ was used as part of the classical ALL induction regimen. Twenty patients were treated with bolus MTZ (10 mg/m2 for 3 days) combined with vincristine and prednisone. The same regimen was given to a second set of 19 patients, except that MTZ was administered as a 24-hr CI. Both groups received bimonthly intensifications with vincristine and prednisone for 3 years, along with oral maintenance therapy. Patients in the CI-MTZ study arm received additional MTZ on the first day of intensification cycles. Seventeen patients (85%) in the bolus arm and 15 patients (79%) in the CI arm achieved complete remission (CR). Median disease-free survivals (DFS) in the bolus and CI groups were 11 and 15 months after median follow-ups of 16 (3.5-96) and 13 (2.3-32) months, respectively. At 2.5 years, DFS rates were 29.4% and 34.4% in the bolus and CI groups (p > 0.05). There were no significant differences between two groups in rates of early death, degree of organ toxicity, or duration of neutropenia and thrombocytopenia. Significant cardiac toxicity was not observed in either group. Bolus or CI administration of MTZ was equally effective and was well tolerated. Neither the mode of administration nor increasing the dose intensity of MTZ by incorporating intensification cycles reduced relapse rates. Development of new antileukemia agents and novel treatment approaches are still needed to improve the high relapse rates in adult ALL once a complete response is achieved.