Interim PET-CT-guided therapy in elderly patients with Hodgkin lymphoma-a retrospective national multi-center study.

Hodgkin lymphoma (HL), a disease of mostly young patients, also peaks in the elderly. Despite the profound improvement in the outcome of young patients, in the elderly, 5-year progression-free survival (PFS) rates are under 70%. Interim PET-CT (iPET) is known to be highly predictive for PFS in young HL patients, but it has not been sufficiently validated in the elderly patient population. In this multi-center collaboration, all consecutive elderly patients (age ≥ 60) diagnosed with HL between 1998 and 2016 were retrospectively reviewed. Baseline characteristics, outcome measures, and iPET results, classified according to the Deauville score, were recorded and analyzed. We identified 78 elderly HL patients (median age 69) who underwent iPET. ABVD was the treatment regimen in 52 (67%) patients. Eighty-three percent of patients had iPET scores of 1-3 while 17% had scores of 4-5. Patients with iPET scores of 1-3 had 5-year PFS and OS rates of 72% and 82% compared with 25% and 45%, respectively, in patients with scores of 4-5 (p < 0.001). Our findings show that iPET is highly predictive of outcome in elderly HL patients and provide evidence that iPET-guided therapy in this patient population may be key to achieving superior treatment outcome.

Two cycles of escalated BEACOPP followed by four cycles of ABVD utilizing early-interim PET/CT scan is an effective regimen for advanced high-risk Hodgkin's lymphoma.

BACKGROUND: Escalated combination therapy with bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone (escBEACOPP) regimen is superior to cyclophosphamide, vincristine, procarbazine and prednisone alternating with doxorubicin, bleomycin, vinblastine and dacarbazine (COPP-ABVD) for advanced-stage Hodgkin's lymphoma (HL) patients. However, the original schedule of eight cycles of escBEACOPP was associated with significant toxicity. This study was conducted in an attempt to reduce the toxicity of the original schedule, while attempting to preserve improved initial tumor control. PATIENTS AND METHODS: Forty-five newly diagnosed patients with advanced-stage HL and International Prognostic Score > or = 3 received two initial cycles of escBEACOPP and then were evaluated by positron emission tomography (PET)/computed tomography scan. If a good imaging response was obtained, they were treated by four cycles of ABVD. RESULTS: Following the first two cycles of escBEACOPP, the overall response was 100% and at the end of all therapy, 40 (89%) patients were in complete response (disappearance of all clinical evidence of disease and PET negativity), three (7%) in partial response (PET-positive residual lesions and a size reduction of the majority of large masses by >50%), while two (4%) had progressive disease. After a median follow-up of 48 months, progression-free survival (PFS) and overall survival at 4 years were 78% and 95%, respectively. The 4-year PFS for early PET-negative patients (n = 31) and early PET-positive patients (n = 13) were 87% and 53%, respectively (P = 0.01). CONCLUSIONS: These data indicate that combined escBEACOPP-ABVD may improve the outcome in patients with high-risk advanced HL. The potential benefit of early-interim PET activity as a guide to continuing therapy in these patients merits further study in the future.

Granulocyte transfusions for neutropenic patients with life-threatening infections: a single centre experience in 47 patients, who received 348 granulocyte transfusions.

INTRODUCTION: The role of granulocyte transfusions (GT) in patients with neutropenia-related infections remains controversial. MATERIALS AND METHODS: A retrospective analysis of 47 neutropenic patients, treated with 348 consecutive GTs for life-threatening infections between 1999 and 2004, is presented. RESULTS: The only grade III-IV toxicity observed in GT recipients was respiratory deterioration (n = 6, 12.8%). The overall infection-related mortality (IRM) approached 38%. Achievement of a neutrophil count of > 700 cells per microl after at least 50% of days of GTs (n = 33, 70%) significantly correlated with reduced IRM (27.3% vs. 64.3%, P < 0.02). GT doses of > 2 x 10(10) neutrophils per bag appeared to increase both neutophil and platelet counts following transfusion. CONCLUSION: GTs are safe and should be considered for patients with life-threatening neutropenic infections. However, prospective randomized studies of GTs are the only way to establish the true role of GTs.

Blood bank protocols for large-scale civilian casualty events: experience from terrorist bombing in Israel.

Terrorist attacks in crowded places cause multiple casualties that are evacuated by quick succession to nearby hospitals. The study goals were to analyse the issues of patient misidentification and excessive blood request and to develop recommendations for the management of such episodes. A retrospective analysis of nine explosion attacks was performed. In nine consecutive events, 450 casualties were reported by the National Ambulance Service, 82 of whom (18%) died on the explosion site and 368 were admitted to nearby trauma centres. Red blood cell units were typed and cross-matched for 70 patients. Seventy-three per cent of the blood supplied over the first 24 h was administered during the first 2 h. The cross-matched/transfused ratio was 2.52 +/- 1.42, reflecting the overestimation of blood requirement in mass casualty episodes. In the mass casualty setup, blood bank personnel should be alert to a potential mistransfusion or a blood collection error. Unidentified patients are subjected to errors due to only one-digit difference in their temporary identification number. Application of the system using an additional sequential four-digit number printed in bold and large size font for patients at admission reduced the possibility of misidentification. Modern technologies, including error-reduction design wristbands, barcode-based system or radiofrequency identification tags may also increase reliability of patient identification in the mass casualty setup.

A prospective randomized trial of itraconazole vs fluconazole for the prevention of fungal infections in patients with acute leukemia and hematopoietic stem cell transplant recipients.

Fluconazole antifungal prophylaxis is standard care in allogeneic hematopoietic stem cell transplant (HSCT) recipients, but this drug lacks anti-Aspergillus activity, the primary cause of invasive fungal infection (IFI) in many transplantation centers. We performed a randomized trial to compare itraconazole vs fluconazole, for prevention of IFIs in patients with acute leukemia (AL) and HSCT recipients. One hundred and ninety-five patients were randomly assigned to either fluconazole or itraconazole antifungal prophylaxis, after stratification into high-risk and low-risk groups. Antifungal prophylaxis was started at the beginning of chemotherapy and continued until resolution of neutropenia, or until amphotericin B treatment was started. IFI occurred in 11 (11%) of itraconazole, and in 12 (12%) fluconazole recipients. Invasive candidiasis (IC) developed in two (2%) itraconazole and one (1%) fluconazole recipients, while invasive aspergillosis (IA) developed in nine (9%) itraconazole and 11(11%) fluconazole recipients. There was no difference in the incidence of total IFI, IC and IA between the two study arms. However, there was a nonsignificant trend towards reduced mortality among patients who developed IA while receiving itraconazole prophylaxis (3/9=33% vs 8/11=73%, P=0.095).

Insect bite-like reaction associated with mantle cell lymphoma: clinicopathological, immunopathological, and molecular studies.

A cutaneous eruption simulating insect bites has been repeatedly described in association with chronic lymphocytic leukemia (CLL). It was only rarely described with mantle cell lymphoma (MCL). Our study was performed to elucidate the clinical, histologic, immunopathological, and molecular characteristics of insect bite like reaction (IBLR) associated with MCL. The clinical presentation and histologic findings in 3 IBLR cases associated with MCL were found to be similar to 3 IBLR cases associated with CLL. The eruptions consisted of itchy erythematous papules, nodules, plaques, and vesicles. Non-vesicular lesions were characterized histologically by normal or mildly spongiotic epidermis. Vesicular lesions were characterized by marked spongiosis and intraepidermal spongiotic vesicles containing eosinophils, or marked subepidermal edema occasionally leading to a dermoepidermal separation. Most of the lesions were characterized by superficial and mid dermal to deep perivascular and interstitial, and occasionally periadnexal, inflammatory-cell infiltrate consisting of mononuclear cells and eosinophils. The densities of the infiltrates varied and the inflammatory-cell infiltrate extended often into the fat lobules. Neutrophils and nuclear dust were found more frequently and abundantly in the IBLR lesions associated with MCL. Immunophenotyping, direct immunofluorescence (DIF) tests, and IgH gene rearrangement studies were performed in the lesions associated with MCL only. The majority of the infiltrating lymphocytes were CD3+, CD5+ and CD43+, more CD4+ than CD8+, and only a small minority was CD20+. The cells did not stain for bcl-1 protein and CD30, and with no evidence of clonality. The DIF test result was negative. The IBLR eruption associated with MCL resembles clinically and histologically IBLR associated with CLL. The eruption seems to be reactive rather than neoplastic, because there is no evidence of MCL involvement in the skin lesions.

Cells from chronic myelogenous leukaemia patients at presentation exhibit multidrug resistance not mediated by either MDR1 or MRP1.

Tetramethylrosamine (TMR) is excluded from P-glycoprotein (MDR1)-enriched cell lines, but it stains efficiently MDR1-poor parent lines. Application of the TMR resistance assay to cells obtained from chronic myelogenous leukaemia (CML) patients revealed, in all individuals, a significant resistance compared with healthy donors (P < 0.001). Cells from the same patients at later phases exhibited a further increase in TMR resistance. Doxorubicin was excluded from all cell samples obtained from CML patients at presentation. The resistance to TMR and doxorubicin was energy-dependent, and was not modulated by inhibitors of MDR1 and multidrug-resistance protein-1 (MRP1). Transcription of mRNAs suspected as relevant to multidrug resistance was assessed using comparative reverse transcription polymerase chain reaction. All cells from the CML patients transcribed high levels of MRP3, MRP4 and MRP5 compared with healthy donors. Low levels of MDR1, MRP1, MRP2, MRP6, lung resistance-related protein and anthracycline resistance-associated protein were equally transcribed in cells from healthy donors and CML patients. These results indicated that neither MDR1 nor MRP1 mediate the resistance in these cells. Our results shed light on a resistance mechanism operative in CML patients, which, together with the resistance to apoptosis, is responsible for the lack of response of CML patients to induction-type protocols used to treat acute myeloid leukaemia patients.

Biology and therapy of secondary leukaemias.

Secondary leukaemias are common, accounting for more than 40% of all patients with acute myeloid leukaemia (AML) or myelodysplastic syndrome (MDS). A clinical history of exposure to haematotoxins or radiation is helpful; however, many older patients are diagnosed with leukaemia with no antecedent history of exposure. These patients' disease show a remarkably similar phenotype to classic therapy-related leukaemia. The specific cytogenetic abnormalities common to MDS, alkylating-agent-related AML and poor-prognosis AML (3q-, -5, 5q-, -7, 7q-, +8, +9, 11q-, 12p-, -18, -19,20q-, +21, t(1;7), t(2;11)), probably reflect a common pathogenesis distinct from that of other de novo AMLs, although the pathogenetic pathway has yet to be elucidated. Possibly, tumour suppressor genes are implicated and genomic instability may be a cause of multiple unbalanced chromosomal translocations or deletions. Typically, these patients are either elderly or have a history of exposure to alkylating agents or environmental exposure 5-7 years prior to diagnosis. Another distinct entity affects the mixed lineage leukaemia (MLL) gene located on 11q23. These account for about 3% of patients with therapy-related leukaemia and have a short latency period from exposure, usually to an inhibitor of topoisomerase II. Other therapy-related patients with t(8:21), inv16 or t(15;17) translocations should be treated as any other de novo AML with similar cytogenetics. In summary, the major prognostic factor is related to the pathogenetic mechanisms of the leukaemia. Cytogenetics and molecular features are a better predictor of outcome than patient history. Patients should receive standard induction therapy. However, the long-term outcome is relatively poor; the best results being obtained among patients undergoing allogeneic transplantation.

Lineage specificity of CBFA2 fusion transcripts.

The CBFA2 gene on chromosome band 21q22 is one of the most commonly translocated genes in leukemia. As with other translocations, those involving CBFA2 are associated with specific disease phenotypes. Only one of the different translocations involving CBFA2, the t(12;21), has been associated with a non-myeloid lineage. Several different CBFA2 fusion transcripts were expressed in the myeloid 32Dcl3 cell line, and show that unlike the myeloid specific fusion transcripts, the lymphoid specific ETV6/CBFA2 transcript is not compatible with myeloid cell differentiation. It is shown that myeloid cells expressing the ETV6/CBFA2 transcript undergo apoptosis in response to a G-CSF differentiation signal. The molecular differences in the cells we studied are characterized using Western blot analysis to show that t(12;21) expressing cells fail to express the G-CSF receptor.

High-dose cladribine therapy for chronic myelogenous leukemia in the accelerated or blast phase.

PURPOSE: A phase II clinical trial was performed to evaluate the effectiveness of high-dose cladribine (2CDA) for treatment of chronic myelogenous leukemia (CML) in the accelerated or blast phase. PATIENTS AND METHODS: Nineteen patients were treated. The median age was 55 years (range, 30 to 73). Six were older than 60 years. Eight had progressed after intensive combination chemotherapy and three after allogeneic or autologous transplantation. For the first course, 16 patients received 2CDA at 15 mg/m2/d intravenously (i.v.) over 1 hour for 5 days. Two received 18 mg/m2 and one received 21.5 mg/m2 daily. The second course was escalated to 20 mg/m2/d in five patients. RESULTS: Rapid cytoreduction of leukemia occurred in the blood, with the nadir at 10 to 12 days. The median WBC count decreased from 36,900/microL before treatment to 500/microL at the nadir and recovered to 5,200/microL at day 30. The median platelet count changed from 113,000/microL to 24,000/microL at the nadir and 71,000/microL at day 30. The complete remission (CR) plus partial remission (PR) rate was 47% (95% confidence interval [CI], 23% to 72%). One 64-year-old man with lymphoid blast phase of CML had a morphologic and cytogenetic CR that lasted 9 months. The median survival for all patients was 34 weeks, and the median survival for the eight responders was 56 weeks (range, 11 to 167). The median number of days spent in hospital over the entire treatment period was 19 (range, 4 to 60). CONCLUSION: High-dose 2CDA therapy provides effective palliation for CML in accelerated or blast phases, even for heavily pretreated patients.

Allogeneic bone marrow transplantation for relapsed and refractory Hodgkin's disease and non-Hodgkin's lymphoma.

The relative benefit of allogeneic bone marrow transplantation (alloBMT) vs autologous BMT (autoBMT) for patients with relapsed or refractory Hodgkin's disease (HD) or non-Hodgkin's lymphoma (NHL) remains uncertain. Toxicity from graft-versus-host disease (GVHD) may diminish the potential benefits both of graft-versus-tumor activity and of receiving uncontaminated donor marrow stem cells. From 1987 to 1995, 27 adults (ages 18-60 years; median 36) underwent alloBMT for lymphoma after failure of standard chemotherapy. Twenty-one had NHL and six had HD (nodular sclerosis). Thirteen patients had primary refractory disease or chemotherapy-resistant relapses; two of these had relapsed after autoBMT. Three patients had untested relapses (one of them had relapsed after autoBMT), and 11 had chemotherapy-sensitive relapses. Twenty-four received HLA-matched bone marrow from a sibling (one twin); three received haploidentical marrow cells. Nine (33%) died from lymphoma. Eleven (41%) died of treatment-related causes. Opportunistic infections were a substantial problem leading to eight of these deaths (30%). Six patients (22%) survive free of lymphoma 17-70 months post-BMT (median, 56 months); four had had sensitive relapses, one had had a resistant relapse, and one had had nontested relapse. Three have chronic GVHD (limited in one; extensive in two). One HD patient who had relapsed after autoBMT remains in remission 19 months after alloBMT. No therapy-related myelodysplasia has been observed. We conclude that alloBMT has substantial morbidity in heavily pretreated lymphoma patients due to acute toxicity, infections and GVHD. However, 22% of our HD/NHL patients have had long-term disease-free survival.

The modulation of plasma lipids and lipoproteins during bone marrow transplantation is unrelated to exogenously administered recombinant human granulocyte-monocyte colony-stimulating factor (rHu GM-CSF).

We evaluated the effect of exogenously administered recombinant human granulocyte-macrophage colony stimulating factor (rHu GM-CSF) on plasma lipid and lipoprotein concentrations in 28 patients undergoing bone marrow transplantation (BMT). Twenty-one received rHu GM-CSF during the immediate post transplantation period (group 1) and seven did not (group 2). All patients received intravenous hyperalimentation starting at the immediate post-transplantation period until 3-5 days post engraftment. Plasma lipids and lipoproteins, liver and renal function tests and blood counts were determined prior to BMT (baseline levels) and during the immediate and late post transplantation periods. In both groups, marked changes of plasma total cholesterol (TC) and high-density lipoprotein cholesterol (HDL-C) concentrations were observed. During the immediate post transplantation period, TC levels decreased by 22.2% and 26.2% in groups 1 and 2, respectively. During the same period, HDL-C levels decreased by 41.4% and 37.5% in these two groups. At the late recovery phase TC and HDL-C resumed pre-treatment levels. These changes were in parallel to the fluctuations in total WBC counts. We conclude, therefore, that BMT has a significant transient effect on plasma lipids and lipoproteins. Although this response is unrelated to the exogenous administration of rHu GM-CSF it may be causally related to endogenous cytokines or other, yet unidentified, factors.

Case series: hyponatremia associated with moderate exercise.

Exercise-induced hyponatremia is commonly believed to be associated only with extraordinary physical efforts, or particularly strenuous exercise. Hyponatremia complicating moderate exercise has not been described previously. The authors describe the characteristics of seven patients with life-threatening hyponatremia associated with mild to moderate exercise. All patients suffered from nausea, vomiting, agitation, and confusion, appearing during or after moderate physical activity. Grand mal convulsions occurred in five of the patients. In laboratory results, hyponatremia was as low as 115 mEq/L, with a relatively high sodium concentration in the urine. High serum creatine kinase activity levels were found in most of the patients. All patients were discharged in good condition, without neurologic sequela. The authors conclude that hyponatremia is a possible complication of moderate exercise, and not only of endurance sports, and that exercise-induced hyponatremia can produce severe neurologic manifestations. The mechanism of the hyponatremia is unclear, but may be due to a hemodynamically inappropriate stimulus for antidiuretic hormone secretion.

Selective discharge of patients with acute myeloid leukemia during chemotherapy-induced neutropenia.

PURPOSE: It is common practice for patients with acute myeloid leukemia (AML) to be observed in hospital during the entire nadir after intensive chemotherapy. In an attempt to lessen the likelihood of developing infections with hospital acquired pathogens, we usually discharge patients upon completion of chemotherapy and follow them as outpatients. They are readmitted if fever develops. We evaluated the feasibility and safety of this practice. PATIENTS AND METHODS: We studied 29 patients with AML (median age 40 years, range 16-63) who were treated with intensive remission-induction and consolidation chemotherapy. Afebrile patients not receiving antibiotics were discharged immediately following chemotherapy and were followed every 3-4 days at the day care unit. Patients were instructed to return immediately if fever rose to 38.2 degrees C or a fever of 38 degrees C persisted for 2 hr. The 29 patients received a total of 86 courses. Following 50 courses, patients were discharged. These 50 ambulatory nadir periods (ANPs) were monitored. RESULTS: Median WBC and platelet counts on discharge were 2,900 per cubic millimeter (range 300-8,300) and 137,000 per cubic millimeter (range 17,000-618,000), respectively. Mean traveling time from the hospital by car was 1.6 hr (range 15 min-3 hr). In three of the 50 ANPs (6%), patients were not readmitted during their entire nadir. During 47 of the ANPs, patients returned to the hospital (because of fever in 44 cases), a mean of 7.2 days (range 1.0-12.7 days) after discharge. In 45 ANPs, patients were readmitted in good general condition. Four patients had life-threatening complications. Two patients were admitted in septic shock due to delay in seeking admission, but rapidly recovered. Two other patients died, one of cardiogenic shock within 24 hr of readmission and one 24 days later. Only one of the 11 gram negative bacteria cultured was resistant to mezlocillin and gentamicin. After 45 ANPs, patients were discharged a mean of 12.2 days (range 5-42 days) following readmission. We estimate that approximately 383 hospital days were saved by this policy, a mean of 7.6 days per patient, representing 16% of total inpatient hospital days. CONCLUSIONS: For AML patients who are reliable and without complicating medical conditions, selected discharge following chemotherapy is a low-risk practice and may reduce the incidence of infection with resistant hospital-acquired pathogens.

Acute promyelocytic leukaemia with t(15;17) following treatment of Hodgkin's disease--a report of 4 cases.

BACKGROUND: Therapy-related acute myeloid leukemia (t-AML) is a recognized entity complicating successful therapy for Hodgkin's disease (HD) and other neoplasias after many years. This risk appears to be related to cumulative exposure to alkylating agents and procarbazine, while drugs affecting DNA--topoisomerase II, such as epipodophyllotoxins and anthracyclines, are also associated with t-AML developing after a much shorter latent period. PATIENTS AND METHODS: Of 56 patients with t-AML or myelodysplasia seen in our institutes during the period 1980-1994 we encountered 5 patients with acute promyelocytic leukemia (APL) all of whom had t(15;17). Four of these had been treated for HD with both chemotherapy and radiotherapy, and one with radiotherapy alone. RESULTS: To the best of our knowledge these appear to be the first cases of t-AML in HD with cytogenetically proven t(15;17). Similarly to other cases of t-APL reported after therapy for neoplasias other than HD, these patients also have a relatively favorable prognosis as seen in de-novo APL. CONCLUSIONS: Although rare, t-APL should be added to the list of late complications of therapy for HD.

Late relapse following autologous bone marrow transplantation for acute myelogenous leukemia: case report and review of the literature.

Most relapses following autologous bone marrow transplantation (BMT) for acute myelogenous leukemia (AML) occur within 18 months. A patient is presented who relapsed 4 years after successful autologous BMT for AML. A review of the literature confirms this to be a rare event and may have been associated with extramedullary relapse of the leukemia.

Lipoprotein profile changes during intense training of Israeli military recruits.

The effect of prolonged strenuous military training on serum lipoproteins was studied in 73 new recruits. Dietary intake, body weight, and average energy expenditure were recorded, and blood samples collected at three time periods before training began (time 0), and after 6 and 12 wk of intense physical activity (times I and II, respectively). There was a significant increase in high density lipoprotein (HDL) cholesterol and a decrease in low density lipoprotein (LDL) cholesterol accompanying an increase of duration and intensity of exercise. HDL increased from 40.5 +/- 7.7 mg.dl-1 at time 0 to 44.5 +/- 9.4 mg.dl-1 at time I and to 52.8 +/- 8.7 mg.dl-1 at time II, and each mean P-value for increases in HDL from time 0-I, I-II, and 0-II were P < 0.0001). For LDL cholesterol, the mean decreases were -1.1, -6.1, and -7.3 mg.dl-1, respectively (P = 0.003 from I-II, and 0.01 from 0-II). These changes did not correlate with weight loss, reduced energy, or fat intake. We conclude that intense physical activity is associated with beneficial changes in the lipoprotein profile in new military recruits during a training period extending over 12 wk.

Activity of fludarabine in refractory chronic lymphocytic leukemia and low grade non-Hodgkin's lymphoma--the Jerusalem experience.

Twenty four patients with refractory chronic lymphocytic leukemia (CLL) and advanced low grade lymphoma (LGL) were treated with Fludarabine given at a dose of 25 mg/m2, intravenously daily for 5 days, every 28 days. Ten of the patients with LGL were in terminal leukemic phase. All patients had received previous chemotherapy, most with multiple regimens. Patients received a mean of 5.1 cycles (range 1-9). 4 patients--one with CLL and 3 with LGL--achieved a complete remission, while 7 LGL and 3 CLL patients had a partial response. Two patients remain in complete remission 23 and 25 months after completion of therapy. One patient underwent successful autologous bone marrow transplantation after achieving a complete remission, while two others had marrow cryopreserved during complete remission. The drug was well tolerated and toxicity was mild. In 9 of the 122 given cycles patients required hospitalization. In conclusion, Fludarabine is active in refractory patients with CLL and LGL and induces complete and partial remissions in some. It seems that Fludarabine could be used as primary therapy in these disorders in the future.