International prognostic index, type of transplant and response to rituximab are key parameters to tailor treatment in adults with CD20-positive B cell PTLD: clues from the PTLD-1 trial.

Tailoring treatment by patient strata based on the risk of disease progression and treatment toxicity might improve outcomes of patients with posttransplant lymphoproliferative disorder (PTLD). We analysed the cohort of 70 patients treated in the international, multicenter phase II PTLD-1 trial (NCT01458548) to identify such factors. Of the previously published scoring systems in PTLD, the international prognostic index (IPI), the PTLD prognostic index and the Ghobrial score were predictive for overall survival. None of the scoring systems had a considerable effect on the risk for disease progression. Age and ECOG performance status were the baseline variables with the highest prognostic impact in the different scoring systems. Baseline variables not included in the scoring systems that had an impact on overall survival and disease progression were the type of transplant and the response to rituximab at interim staging. Thoracic organ transplant recipients who did not respond to rituximab monotherapy were at particularly high risk for death from disease progression with subsequent CHOP-based chemotherapy. Patients in complete remission after four courses of rituximab and patients in partial remission with low-risk IPI had a low risk of disease progression. We speculate that chemotherapy might not be necessary in this patient cohort.

Risk factors and prognostic scale for cytomegalovirus (CMV) infection in CMV-seropositive patients after allogeneic hematopoietic cell transplantation.

AIM: We aimed to study the risk factors for first and subsequent cytomegalovirus (CMV) infection among patients who are CMV seropositive and underwent allogeneic hematopoietic cell transplantation (HCT). METHODS: We performed an historical cohort study of all sequential CMV-seropositive patients who underwent allogeneic HCT at a single center. Between May 2007 and December 2012, 121 patients fulfilled inclusion criteria. RESULTS: Multivariate model identified myeloablative preparative regimen (hazard ratio [HR] = 4.297, P = 0.033) and acute graft-versus-host disease (GVHD) prior to infection (HR = 5.091, P = 0.021) as risk factors for first CMV infection. The cumulative incidences of first CMV infection for patients with 0, 1, and 2 risk factors were 52%, 71%, and 91%, respectively. Multivariate analysis identified the diagnosis of lymphoma/myeloma (HR = 3.5, P = 0.049) and GVHD (HR = 1.280, P = 0.045) as risk factors for subsequent CMV infection. High graft CD3 stem cell dose was associated with a trend of lower rate of subsequent CMV infection (HR = 0.543, P = 0.056). The cumulative incidences for subsequent CMV infection in patients with 0, 1, and 2-3 risk factors were 11%, 41%, and 77%, respectively. CONCLUSION: In conclusion, in CMV-seropositive patients, myeloablative conditioning and acute GVHD are risk factors for first CMV infection, while lymphoma/myeloma, ongoing GVHD, and low CD3 graft content are risk factors for subsequent infection.

Subcutaneous administration of rituximab (MabThera) and trastuzumab (Herceptin) using hyaluronidase.

BACKGROUND: Rituximab and trastuzumab were the first therapeutic monoclonal antibodies (mAbs) approved in oncology. Both antibodies are delivered by the intravenous (IV) route, but recently subcutaneous (SC) formulations have been developed. Subcutaneous administration of mAbs can offer substantial patient and resource benefits compared with IV, but SC administration of some mAbs can be limited by drug volume. Recombinant human hyaluronidase (rHuPH20) temporarily degrades hyaluronan, allowing SC delivery of drug volumes that might not otherwise be feasible. METHODS: Clinical trials assessing coformulation of rituximab or trastuzumab with rHuPH20 for SC administration were reviewed. RESULTS: Phase I trials of rituximab SC maintenance therapy in patients with follicular lymphoma and trastuzumab SC in healthy volunteers and patients with early breast cancer have demonstrated substantially shorter administration times and comparable tolerability and pharmacokinetics compared with IV formulations. Rituximab SC 1400-mg and trastuzumab SC 600-mg doses were identified for further study. Phase III clinical data for rituximab SC 1400 mg have shown comparable efficacy to rituximab IV, and initial clinical data suggest comparable efficacy of trastuzumab SC 600 mg and the IV formulation. CONCLUSION: Coformulation with rHuPH20 may enable effective, well-tolerated, cost-effective, and convenient SC administration of rituximab and trastuzumab. Additional studies are ongoing.

Cellular immune function monitoring after allogeneic haematopoietic cell transplantation: evaluation of a new assay.

Managing the patient's immune system after haematopoietic cell transplantation (HCT) is a challenge, mainly in the unstable period immediately after the transplant. Currently there is no standardized non-invasive diagnostic tool for the evaluation of immunological complications such as graft-versus-host disease (GVHD) and for managing the cellular immune function of the transplant recipient. The ImmuKnow assay for cellular immune function monitoring has been incorporated successfully into the clinical follow-up routine of solid organ transplant recipients. This study aims to explore the relevance and potential contribution of immune monitoring using the assay in the setting of HCT. We found that ImmuKnow-level measurement can distinguish between states of immune function quiescence and between events of acute GVHD. ImmuKnow levels were significantly higher in patients going through GVHD than the levels measured for the same patients during immunological stability. Moreover, we demonstrate a patient case where longitudinal monitoring using the ImmuKnow assay provided a trustworthy depiction of the patient's cellular immune function post-HCT. In conclusion, we provide evidence for the potential contribution of the ImmuKnow assay for longitudinal individualized cellular immune function monitoring of patients following HCT. Further studies are necessary in order to establish the optimal practice for utilizing the assay for this purpose.

Outcome of patients with relapsed diffuse large B-cell lymphoma who fail second-line salvage regimens in the International CORAL study.

Salvage chemotherapy followed by autologous stem cell transplantation (ASCT) is the standard second-line treatment for relapsed and refractory diffuse large B-cell lymphoma (DLBCL). However, the strategy is less clear in patients who require third-line treatment. Updated outcomes of 203 patients who could not proceed to scheduled ASCT in the Collaborative Trial in Relapsed Aggressive Lymphoma (CORAL) are herein reviewed. In the intent-to-treat analysis, overall response rate to third-line chemotherapy was 39%, with 27% CR or CR unconfirmed, and 12% PR. Among the 203 patients, 64 (31.5%) were eventually transplanted (ASCT 56, allogeneic SCT 8). Median overall survival (OS) of the entire population was 4.4 months. OS was significantly improved in patients with lower tertiary International Prognostic Index (IPI), patients responding to third-line treatment and patients transplanted with a 1-year OS of 41.6% compared with 16.3% for the not transplanted (P<0.0001). In multivariate analysis, IPI at relapse (hazard ratio (HR) 2.409) and transplantation (HR 0.375) independently predicted OS. Third-line salvage chemotherapy can lead to response followed by transplantation and long-term survival in DLBCL patients. However, improvement of salvage efficacy is an urgent need with new drugs.

Patients with Glanzmann thrombasthenia lacking platelet glycoprotein alpha(IIb)beta(3) (GPIIb/IIIa) and alpha(v)beta(3) receptors are not protected from atherosclerosis.

BACKGROUND: Platelets have been suggested to play a role in the early development of atherosclerosis. As one test of this hypothesis, we assessed whether patients with Glanzmann thrombasthenia who lack platelet glycoprotein alpha(IIb)beta(3) (GPIIb/IIIa) complexes or both alpha(IIb)beta(3) and the more ubiquitous alpha(v)beta(3) cell membrane complexes are protected from development of atherosclerosis. METHODS AND RESULTS: Seven patients with Glanzmann thrombasthenia, 45 to 66 years of age, underwent bilateral carotid artery ultrasonography and screening for risk factors of atherosclerosis. Findings consistent with early atherosclerosis evaluated by measurement of intima-media thickness and presence of atherosclerotic plaques were observed in 6 of the 7 patients. Intima-media thickness values higher than the 75th and 90th percentiles of age- and sex-matched white control subjects of the Atherosclerosis Risk in Communities (ARIC) study were observed in 30 and 8 of 56 carotid artery measurements, respectively. Five of the 6 patients with signs consistent with early atherosclerosis lacked both alpha(IIb)beta(3) and alpha(v)beta(3) complexes and 1 only lacked alpha(IIb)beta(3). CONCLUSIONS: Glanzmann thrombasthenia does not protect affected individuals from development of atherosclerosis.

Donor leukocyte infusions in 140 patients with relapsed malignancy after allogeneic bone marrow transplantation.

PURPOSE: Recipients of allogeneic bone marrow transplants (BMTs) who have relapsed may attain complete remissions when treated with transfusions of leukocytes obtained from the original bone marrow donor. We performed a retrospective study to characterize better this new treatment modality. PATIENTS AND METHODS: We surveyed 25 North American BMT programs regarding their use of donor leukocyte infusions (DLI). Detailed forms were used to gather data regarding the original BMT, relapse, DLI, response to DLI, complications of DLI, and long-term follow-up evaluation. Reports of 140 patients were thus available for analysis. RESULTS: Complete responses were observed in 60% (95% confidence interval [CI], 51.9% to 68.1%) of chronic myelogenous leukemia (CML) patients who received DLI and did not receive pre-DLI chemotherapy; response rates were higher in patients with cytogenetic and chronic-phase relapse (75.7%; 95% CI, 68.2% to 83.2%) than in patients with accelerated-phase (33.3%; 95% CI, 19.7% to 46.9%) or blastic-phase (16.7%; 95% CI, 1.9% to 31.9%) relapse. The actuarial probability of remaining in complete remission at 2 years was 89.6%. Complete remission rates in acute myelogenous leukemia (AML) (n = 39) and acute lymphocytic leukemia (ALL) (n = 11) patients who had not received pre-DLI chemotherapy were 15.4% (95% CI, 9.6% to 21.2%) and 18.2% (95% CI, 6.6% to 29.8%), respectively. Complete remissions were also observed in two of four assessable myeloma patients and two of five assessable myelodysplasia patients. Complications of DLI included acute graft-versus-host disease (GVHD) (60%; 95% CI, 51.4% to 68.6%), chronic GVHD (60.7%; 95% CI, 50.3% to 71.1%), and pancytopenia (18.6%; 95% CI, 12.2% to 25.0%). Pre-DLI characteristics predictive of complete response in CML patients were post-BMT chronic GVHD, pre-DLI disease status of chronic phase, and time interval between BMT to DLI less than 2 years. Acute and chronic GVHD post-DLI were highly correlated with disease response (P < .00001). CONCLUSION: DLI results in complete remissions in a high percentage of patients with relapsed chronic-phase CML. Complete remissions are observed less frequently in patients with advanced CML and acute leukemia. GVHD and pancytopenia occur commonly; GVHD is highly correlated with response.

Secondary malignancies following high dose therapy and autologous hematopoietic cell transplantation-systematic review and meta-analysis.

We performed a systematic review and meta-analysis of randomized controlled trials comparing autologous hematopoietic cell transplantation (HCT) with other treatment modalities to analyze the risk for various secondary malignancies (SMs). Relative risks (RR) with 95% confidence intervals were estimated and pooled. Our search yielded 36 trials. The median follow-up was 55 (range 12-144) months. Overall, the RR for developing SMs was 1.23 ((0.97-1.55), I(2)=4%, 9870 patients). Subgroup analysis of trials assessing TBI-containing preparative regimens and of patients with baseline lymphoproliferative diseases, showed there was a higher risk for SMs in patients given autografts (RR=1.61 (1.05-2.48), I(2)=14%, 2218 patients and RR=1.62 (1.12-2.33), I(2)=22%, 3343 patients, respectively). Among all patients, there was a higher rate of myelodysplastic syndrome MDS/AML in patients given HCT compared with other treatments (RR=1.71 (1.18-2.48), I(2)=0%, 8778 patients). The risk of secondary solid malignancies was comparable in the short term between patients given HCT and patients given other treatments (RR=0.95 (0.67-1.32), I(2)=0%, 5925 patients). We conclude that overall the risk of secondary MDS/AML is higher in patients given autologous HCT compared with other treatments. In the subgroup of patients given a TBI-based regimen and in those with a baseline lymphoproliferative disease, there was a higher risk of overall SMs.

Low molecular weight heparin for the prevention of veno-occlusive disease of the liver in bone marrow transplantation patients.

Hepatic veno-occlusive disease (VOD), a common complication of bone marrow transplantation (BMT), is a result of intensive conditioning by chemo-radiotherapy. Endometrial injury causes fibrin deposition in the affected hepatic venules, leading to abnormal laboratory parameters followed by lethal full-blown disease. Previous studies have shown that unfractionated heparin can prevent VOD in BMT patients. Since low molecular weight heparin (LMWH) preserves the antithrombotic, but not the anticoagulant, activity of unfractionated heparin, we initiated a pilot study to determine the safety of LMWH for the prevention of VOD. Sixty-one patients undergoing BMT (allogeneic, n=24; autologous, n=37) were randomized to receive subcutaneous injection of enoxaparin (40 mg/day x 1) or a placebo prior to BMT conditioning and until day 40 after transplantation or discharge from the hospital. LMWH administration did not influence marrow engraftment, nor was it associated with bleeding tendency. Hemorrhagic events occurred significantly less frequently (P=0.025) were shorter duration (P=0.006) in the LMWH group than in the placebo group. Time to platelet recovery was significantly shorter (16.5 vs 29.6 days, (P=0.0075), and platelet transfusion requirements were lower (p=0.05) in the LMWH patients. VOD parameters occurred less frequently in the experimental group, including duration of elevated bilirubin levels (P=0.01) and incidence of hepatomegaly (P=0.04). LMWH, which seems to enhance platelet recovery, may be safely administrated to BMT patients in an attempt to prevent VOD of the liver.

The insulin-like growth factor system in regulation of normal and malignant hematopoiesis.

The published data available on the insulin-like growth factor (IGF) family of peptides, its receptors and binding proteins in connection with normal and neoplastic hematopoietic processes are reviewed. It is found that nearly all the different hematopoietic cells, either normal or neoplastic, express IGF receptors. The IGFs are involved in normal erythropoiesis, granulopoiesis and lymphopoiesis. IGFs, especially IGF-1, are mitogenic for cell lines of myeloid and lymphoid leukemias and Burkitt's lymphoma. Differentiation of certain immature malignant cell lines is associated with a decrease in the number and affinity of IGF receptors. It might be concluded that the IGFs have an important role in the physiologic and neoplastic processes of the hematopoietic system, and the expanding knowledge of this issue will contribute to the understanding of proliferation and differentiation processes in specific hematologic disorders.

Molecular epidemiology of hematological neoplasms--present status and future directions.

The field of molecular epidemiology, using modern epidemiological approaches and taking the advantage of the advances in molecular biology can provide new tools for the exploration of etiological determinants, either environmental or hereditary, in the development of hematological neoplasms. It is now possible to identify some host susceptibility characteristics, to measure the effective dose of exposure, and to identify early, pre-clinical biological effects, using sensitive and specific biomarkers. The significant variation in the incidence of hematological neoplasms in different geographical areas, races, and age groups, the high rates of familial aggregation in certain populations, the involvement of protooncogenes and tumor suppressor genes in the development of hematological neoplasms, as well as of many environmental agents such as chemicals, radiation, and viruses, support the important role of molecular epidemiology in the investigation of the development of hematological neoplasms.

The MACOP-B and VACOP-B combination chemotherapy for young patients with intermediate-grade non-Hodgkin's lymphoma.

Since the early 1970s, three generations of combination chemotherapy for intermediate-grade non-Hodgkin's lymphomas (NHL) have been developed. One of the third-generation regimens is MACOP-B (methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin). The VACOP-B regimen is a modification of MACOP-B in which methotrexate is omitted and etoposide is added. This study assesses treatment outcome using the MACOP-B and VACOP-B combination chemotherapy in a population of young patients with intermediate-grade NHL treated in a single tertiary hematological center. The files of 45 patients aged 18-55 who were diagnosed as having intermediate-grade NHL (working formulation types F-H) and treated between January 1986 and March 1994 were reviewed. Treatment response, overall survival, disease-free survival and treatment toxicity were determined. The predictive value of the age-adjusted international prognostic index was also assessed. Median follow-up was 80 months in the MACOP-B group and 29 months in the VACOP-B group. The complete response rate was 71% (95% confidence interval CI: 58-84), 4-year overall survival was 74 +/- 7% and 4-year disease-free survival was 79 +/- 8%. No toxicity-related deaths were observed. The main adverse effects were WHO grade 3 or 4 neutropenia (51%), anemia (24%) and mucositis (20%). Only the CR rate was correlated with the Age-Adjusted International Prognostic Index. Mean relative dose intensity was high (95.7%, 95%) CI: 91.7-99.7) and had no correlation with treatment outcome. The MACOP-B and VACOP-B combination chemotherapy regimens were found to be effective and minimally toxic for young patients up to 55 years old with intermediate-grade NHL.

Salvage therapy of refractory and relapsed acute leukemia with high dose mitoxantrone and high dose cytarabine.

We have assessed the outcome of 66 refractory and relapsed acute leukemia patients treated with high dose mitoxantrone and cytarabine. Therapy consisted of a total dose of 40-60 mg/m2 mitoxantrone and 3 g/m2 of cytarabine daily on 5 consecutive days. A total of 28 patients were treated for primary resistant and 38 patients for early or late relapsed leukemia. A total of 35 patients achieved CR. Four patients died during the induction course. Toxicity was acceptable and comparable to other salvage regimens. The median disease-free and overall survivals were 4 and 6 months, respectively. Although this regimen is effective in achieving remission in refractory leukemia, its duration is short.

Postremission therapy with two different dose regimens of cytarabine in adults with acute myelogenous leukemia.

Sixty-seven out of 105 (64%) adults with de novo acute myelogenous leukemia (AML), achieving complete remission after induction chemotherapy, entered two successive postremission treatment protocols. Between 1987 and 1989, 35 patients received an intermediate dose of cytarabine (IDAC) along with other drugs. Between 1990 and 1993, 32 patients received high dose cytarabine (HIDAC) with similar other drugs. Patients treated with IDAC had a median survival of 13.8 months (95% CI 11.2-23.1 months) and a 2 year survival of 34.3 +/- 8.0%. Patients receiving HIDAC had a median survival of 35.5 months (95% CI, lower limit 29.8 months) and a 2 year survival of 71.6 +/- 9.4% (P < 0.002). The 2 year actuarial leukemia-free survival (LFS) was 17.8 +/- 6.6% in the IDAC group and 67.3 +/- 10.0% months in the HIDAC group (P = 0.004). The HIDAC group had a significant 2 year survival advantage over the IDAC group only in patients younger than 45 years. The 2 year survival in the first group was 83.3 +/- 10.8% versus 23.5 +/- 10.3% in the IDAC group (P = 0.0001). In patients older than 45 years, no significant differences in 2 year survival was noticed (52.9 +/- 15.78 versus 44.4 +/- 11.7, P = 0.8). Censoring the 21 patients who underwent bone marrow transplantation (BMT) at BMT did not change significantly the survival analysis of the patients in each group. This study is consistent with previous reports favoring HIDAC intensification in the postremission treatment of young patients with AML.

The next stage: molecular epidemiology.

The traditional approach in epidemiology of relating exposure to an environmental agent such as a drug or infective agent has been to measure an overall risk (i.e., average and then "adjust risk for demographic variables and other confounders"). An attempt is sometimes made to define a "susceptible" subgroup. The analyses are usually based on good statistical methodology rather than an understanding of the interaction of body of host and agent. A twofold risk for 1000 exposed versus nonexposed people could be an average twofold risk for all 1000 exposed or a 20-fold risk for 100 exposed individuals (i.e., a drug-host interaction). Clearly, finding the 100 individuals with a 20-fold risk has much greater clinical importance than a twofold risk for 1000 people. The world of epidemiology may be changing-we may soon be able to define risk based on genetic susceptibility, at least sometimes.

Prospective association of lipoprotein(a) concentrations and apo(a) size with coronary heart disease among men in the Multiple Risk Factor Intervention Trial.

In this nested case-control study, lipoprotein (a) [Lp(a)] concentrations and apo(a) isoform size were measured in serum samples obtained from men participating in the prospective Multiple Risk Factor Intervention Trial (MRFIT). Serum from men aged 35 to 57 years and stored for up to 20 years were analyzed for Lp(a) levels (n=736) and isoform size (n=487), respectively. Cases involved nonfatal myocardial infarctions (MI; n=98), documented during the active phase of the study that ended on February 28, 1982 and coronary heart disease (CHD) deaths (n=148) monitored through 1990. Median Lp(a) levels did not differ between cases and controls and mean apo(a) size did not vary between cases and controls in the entire study population. When adjusted for age and Lp(a) concentration, logistic regression analysis indicated that small apo(a) isoforms were associated with CHD deaths among smokers (OR 3.31; 95% CI 1.07-10.28).

Helicobacter pylori infection and subsequent peptic duodenal disease among young adults.

BACKGROUND: Evidence for a causal relationship between presence of Helicobacter pylori (H. pylori) in gastric mucosa and development of peptic disease is based largely on intervention studies in which eradication of H. pylori led to healing of the lesion. The aim of this study was to assess the importance of H. pylori seropositivity for subsequent development of peptic disease in a prospective study design in young Israelis. METHODS: A nested case-control serum bank study based on a systematic sample of male and female inductees to the Israel Defense Force. Twenty-nine cases of duodenal ulcer or duodenitis of moderate or higher severity, diagnosed between 1986 and 1995, were individually matched for age, sex, ethnicity, education and year of induction, with five healthy controls each. Presence of anti-H. pylori antibodies in the frozen stored sera was determined by ELISA. RESULTS: The geometric mean titre of anti-H. pylori antibodies at baseline was significantly higher in cases (18. 3 U/ml) than controls (6.9 U/ml; P = 0.009). The matched odds ratio for peptic ulcer disease by seropositivity was 3.8 (95% CI : 1.4-10. 2). A stronger association was evident for subjects diagnosed > or =2 years after induction than those diagnosed earlier. The population attributable fraction was 56.6% (95% CI : 15.7-81.1). CONCLUSIONS: Pre-existing infection with H. pylori, as determined by seropositivity, is an important determinant of development of duodenal ulcer or duodenitis in young Israelis, supporting the generalizability of an apparent causal association to diverse populations.