Malignancies associated with latent Epstein-Barr virus (EBV) are resistant to nucleoside-type antiviral agents because the viral enzyme target of these antiviral drugs, thymidine kinase (TK), is not expressed. Short-chain fatty acids, such as butyrate, induce EBV-TK expression in latently infected B cells. As butyrate has been shown to sensitize EBV(+) lymphoma cells in vitro to apoptosis induced by ganciclovir, arginine butyrate in combination with ganciclovir was administered in 15 patients with refractory EBV(+) lymphoid malignancies to evaluate the drug combination for toxicity, pharmacokinetics, and clinical responses. Ganciclovir was administered twice daily at standard doses, and arginine butyrate was administered by continuous infusion in an intrapatient dose escalation, from 500 mg/(kg/day) escalating to 2000 mg/(kg/day), as tolerated, for a 21-day cycle. The MTD for arginine butyrate in combination with ganciclovir was established as 1000 mg/(kg/day). Ten of 15 patients showed significant antitumor responses, with 4 CRs and 6 PRs within one treatment cycle. Complications from rapid tumor lysis occurred in 3 patients. Reversible somnolence or stupor occurred in 3 patients at arginine butyrate doses of greater than 1000 mg/(kg/day). The combination of arginine butyrate and ganciclovir was reasonably well-tolerated and appears to have significant biologic activity in vivo in EBV(+) lymphoid malignancies which are refractory to other regimens.

Relapse occurs frequently after allogeneic hematopoietic cell transplantation (HCT) for treatment of high-risk Philadelphia chromosome-positive (Ph+) leukemia. Administration of imatinib early after HCT might provide an effective approach for preventing recurrent Ph+ leukemia, but the feasibility of this approach has not been systematically tested. Twenty-two patients, 15 with Ph+ acute lymphoblastic leukemia and 7 with high-risk chronic myelogenous leukemia, were enrolled in a prospective study and given imatinib from the time of engraftment until 365 days after HCT. Before day 90, adults (n = 19) tolerated a median average daily imatinib dose of 400 mg/d (range, 200-500 mg/d), and children (n = 3) tolerated 265 mg/m2/d (range, 200-290 mg/m2/ d). The most common adverse events related to imatinib administration were grade 1-3 nausea, emesis, and serum transaminase elevations. We conclude that imatinib can be safely administered early after myeloablative allogeneic HCT at a dose intensity comparable to that used in primary therapy.

Treatment for steroid-resistant acute graft-versus-host disease (GVHD) has had limited success. ABX-CBL is a hybridoma-generated murine IgM monoclonal antibody against the CD147 antigen, weakly expressed on human leukocytes and up-regulated on activated lymphocytes. A prospective, multicenter, open-label, randomized clinical trial comparing ABX-CBL to antithymocyte globulin (ATG) for treatment of steroid-resistant acute GVHD was conducted in 95 patients at 21 centers. Forty-eight patients received ABX-CBL daily for 14 consecutive days followed by up to 6 weeks of ABX-CBL twice weekly. Forty-seven patients received equine ATG, 30 mg/kg every other day for a total of 6 doses with additional courses as needed. By day 180, overall improvement was similar in the patients receiving ABX-CBL and in those receiving ATG (56% versus 57%, P = .91). Patient survival at 18 months was less favorable on ABX-CBL than on ATG (35% versus 45%), with the 95% confidence interval ruling out that ABX-CBL provides at least a 10.4% improvement. Data from this trial suggest that ABX-CBL does not offer an improvement over ATG in the treatment of acute steroid-resistant GVHD. This prospective, multicenter, randomized clinical trial for steroid-resistant acute GVHD serves as a model for future evaluation of new agents.

Patients receiving warfarin who have unstable control of anticoagulation have a significantly lower intake of dietary vitamin K compared with their stable counterparts. We hypothesized that supplementation with oral vitamin K would improve stability in patients with previously unstable control of anticoagulation. Seventy warfarin-treated patients with unstable anticoagulation control were randomly assigned in a double-blinded fashion to receive a daily amount of 150 mug oral vitamin K or placebo orally for 6 months. Measures of stability of anticoagulation control in the 6-month study period were compared with those in the 6 months immediately prior to it. Vitamin K supplementation resulted in a significantly greater decrease in standard deviation of international normalized ratio (INR) compared with placebo (-0.24 +/- 0.14 vs -0.11 +/- 0.18; P < .001) and a significantly greater increase in percentage time within target INR range (28% +/- 20% vs 15% +/- 20%; P < .01). Anticoagulation control improved in 33 of 35 patients receiving vitamin K supplementation; of these, 19 fulfilled our criteria for having stable control of anticoagulation. However, only 24 of 33 patients receiving placebo demonstrated some degree of improvement, with only 7 patients fulfilling the criteria for having stable control. Concomitant supplementation of vitamin K, perhaps through reducing the relative day-to-day variability in dietary vitamin K intake, can significantly improve anticoagulation control in patients with unexplained instability of response to warfarin.

Millions of women still use postmenopausal hormone therapy (HT). We genotyped 2090 women in Heart and Estrogen/progestin Replacement Study for functional polymorphisms in GP1BA and GP6 and assessed the coronary heart disease (CHD) event rate over 5.8 years of follow-up. In patients receiving placebo, there was an increased CHD death/myocardial infarction (MI)/unstable angina (UA) event rate in carriers of the GP1BA -5C allele (adjusted [adj] P = .006). HT increased the hazard ratio (HR) of CHD events in patients with the GP1BA -5TT genotype by 16% and reduced the HR in patients with the TC+CC genotypes by 46% (adj interaction P < .001). HT reduced the HR in patients with the GP6 13254TT genotype by 17% but increased the HR in patients with the TC+CC genotypes by 35% (adj interaction P < .001). Furthermore, HT increased the HR of CHD events in patients with the GP1BA -5TT plus GP6 13254TC+CC genotypes by 57% and reduced the HR in patients with the GP1BA -5TC+CC plus GP6 13254TT genotypes by 55% (adj interaction P < .001). In postmenopausal women with established CHD, these polymorphisms of platelet genes were predictors of CHD events and significantly modified the effects of HT on CHD risk. It will be important to replicate these findings in other studies.

Following allogeneic hematopoietic stem cell transplantation (alloHSCT), children are at risk of life-threatening pneumococcal infections. Whereas vaccination with polysaccharide vaccines fails to elicit protective immunity in most alloHSC transplant recipients, pneumococcal conjugate vaccines may effectively prevent invasive disease by eliciting T-cell-dependent antibody responses. Here, we report safety and immunogenicity in 53 children immunized with a regimen of 3 consecutive doses of a heptavalent pneumococcal conjugate vaccine (7vPCV) in monthly intervals starting 6 to 9 months after alloHSCT. Immunization was well tolerated with no vaccine-related serious adverse events. Serologic response rates evaluable in 43 patients ranged from 41.9% to 86.0% and 58.1% to 93.0% after 2 and 3 vaccinations, respectively, with 55.8% and 74.4% of patients achieving protective antibody levels to all 7 vaccine serotypes. Our study provides the first evidence that vaccination with 7vPCV is safe and elicits protective antipneumococcal antibody responses in pediatric recipients of related or unrelated donor alloHSC transplants within the first year following transplantation. This trial was registered at www.clinicaltrials.gov as NCT00169728.

Outcomes for older adults with acute myelogenous leukemia (AML) are poor due to both disease and host-related factors. In this phase 2 study, we tested the oral farnesyltransferase inhibitor tipifarnib in 158 older adults with previously untreated, poor-risk AML. The median age was 74 years, and a majority of patients had antecedent myelodysplastic syndrome. Complete remission (CR) was achieved in 22 patients (14%); partial remission or hematologic improvement occurred in 15 patients, for an overall response rate of 23%. The median duration of CR was 7.3 months and the median survival of complete responders was 18 months. Adverse karyotype, age 75 years or older, and poor performance status correlated negatively with survival. Early death in the absence of progressive disease was rare, and drug-related nonhematologic serious adverse events were observed in 74 patients (47%). Inhibition of farnesylation of the surrogate protein HDJ-2 occurred in the large majority of marrow samples tested. Baseline levels of phosphorylated mitogen-activated protein kinase and AKT did not correlate with clinical response. Tipifarnib is active and well tolerated in older adults with poor-risk AML and may impart a survival advantage in those patients who experience a clinical response.

In idiopathic thrombocytopenic purpura (ITP), corticosteroids have been widely recognized as the most appropriate first-line treatment, even if the best therapeutic approach is still a matter of debate. Recently, a single high-dose dexamethasone (HD-DXM) course was administered as first-line therapy in adult patients with ITP. In this paper we show the results of 2 prospective pilot studies (monocentric and multicentric, respectively) concerning the use of repeated pulses of HD-DXM in untreated ITP patients. In the monocenter study, 37 patients with severe ITP, age at least 20 years and no more than 65 years, were enrolled. HD-DXM was given in 4-day pulses every 28 days, for 6 cycles. Response rate was 89.2%; relapse-free survival (RFS) was 90% at 15 months; long-term responses, lasting for a median time of 26 months (range 6-77 months) were 25 of 37 (67.6%). In the multicenter study, 95 patients with severe ITP, age at least 2 years and no more than 70 years, were enrolled. HD-DXM was given in 4-day pulses every 14 days, for 4 cycles; 90 patients completed 4 cycles. Response rate (85.6%) was similar in patients classified by age (<18 years, 36 of 42=85.7%; >or=18 years, 41 of 48=85.4%, P=not significant), with a statistically significant difference between the second and third cycle (75.8% vs 89%, P=.018). RFS at 15 months 81%; long-term responses, lasting for a median time of 8 months (range 4-24 months) were 67 of 90 (74.4%). In both studies, therapy was well tolerated. A schedule of 3 cycles of HD-DXM pulses will be compared with standard prednisone therapy (eg, 1 mg/kg per day) in the next randomized Gruppo Italiano Malattie EMatologiche dell'Adulto (GIMEMA) trial.

Nasal NK/T-cell lymphoma is a rare disease entity with a poor outcome. Expression of antiapoptotic proteins has not been extensively investigated in this entity. Forty-eight patients with nasal T/NK-cell lymphoma who received first-line polychemotherapy (n = 44) or chemoradiotherapy (n = 4) were analyzed for expression of active caspase-3 (aC3), granzyme B protease inhibitor 9 (PI9), and Bcl-2 proteins. Lymphomas were CD3+/CD5-/granzyme B+ and EBV-associated. Median age was 46 years. Stage I/II disease was present in 75% of the cases and an International Prognostic Index (IPI) score less than 1 in 65%. With a median follow-up of 6.3 years, 5-year event-free survival (EFS) and overall survival (OS) rates were 39% and 49%, respectively. Apoptotic index was scored as high in 32% of cases and PI9 expression as positive in 68%, whereas 35% disclosed a high number of aC3+ tumor cells. Univariate analysis showed that absence of PI9 and low apoptotic index were associated with poor outcome, but not aC3 expression nor IPI score. By multivariate analysis, both parameters affected independently EFS (P = .02 and .08, respectively) and OS (P = .009 and .04). In view of its constitutive expression by normal NK cells, it is suggested that loss of PI9 expression in tumor cells may reflect some mechanism associated with progression.

Autologous hematopoietic stem cell transplantation (ASCT) is an increasingly accepted treatment for refractory autoimmune diseases. Refractory celiac disease with aberrant T cells (RCD type II) is unresponsive to available therapies and carries a high risk of transition into enteropathy associated T-cell lymphoma (EATL). This study reports on the feasibility, safety, and efficacy of ASCT in patients with RCD type II. Thirteen patients with RCD type II were evaluated. Seven patients (4 men, 3 women, mean age 61.5 years [range, 51-69 years]) underwent transplantation. After conditioning with fludarabine and melphalan, ASCT was performed. Patients were monitored for response, adverse effects, and hematopoietic reconstitution. All 7 patients completed the mobilization and leukapheresis procedures successfully and subsequently underwent conditioning and transplantation. Engraftment occurred in all patients. No major nonhematologic toxicity or transplantation-related mortality was observed. There was a significant reduction in the aberrant T cells in duodenal biopsies associated with improvement in clinical well-being and normalization of hematologic and biochemical markers (mean follow-up, 15.5 months; range, 7-30 months). One patient died 8 months after transplantation from progressive neuroceliac disease. These preliminary results showed that high-dose chemotherapy followed by ASCT seems feasible and safe and might result in long-term improvement of patients with RCD type II whose condition did not respond promptly to available drugs.

The combination of imatinib with chemotherapy has been recently reported as very promising in patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). During 2004 and 2005, 45 patients with newly diagnosed Ph+ ALL were treated in the Group for Research on Adult Acute Lymphoblastic Leukemia (GRAAPH) 2003 study, in which imatinib was started with HAM (mitoxantrone with intermediate-dose cytarabine) consolidation in good early responders (corticosensitive and chemosensitive ALL) or earlier during the induction course in combination with dexamethasone and vincristine in poor early responders (corticoresistant and/or chemoresistant ALL). Imatinib was then continuously administered until stem cell transplantation (SCT). Overall, complete remission (CR) and BCR-ABL real-time quantitative polymerase chain reaction (RQ-PCR) negativity rates were 96% and 29%, respectively. All of the 22 CR patients (100%) with a donor actually received allogeneic SCT in first CR. At 18 months, the estimated cumulative incidence of relapse, disease-free survival, and overall survival were 30%, 51%, and 65%, respectively. These 3 end points compared very favorably with results obtained in the pre-imatinib LALA-94 trial. This study confirms the value of the combined approach and encourages prospective trials to define the optimal chemotherapy that has to be combined with imatinib and to carefully reevaluate the place of allogeneic SCT in this new context.

We investigated the clinical effects of low-power laser therapy (LPLT) on prevention and reduction of severity of conditioning-induced oral mucositis (OM) for hematopoietic stem cell transplantation (HSCT). We randomized 38 patients who underwent autologous (AT) or allogeneic (AL) HSCT. A diode InGaAlP was used, emitting light at 660 nm, 50 mW, and 4 J/cm2, measured at the fiberoptic end with 0.196 cm2 of section area. The evaluation of OM was done using the Oral Mucositis Assessment Scale (OMAS) and the World Health Organization (WHO) scale. In the LPLT group, 94.7% of patients had an OM grade (WHO) lower than or equal to grade 2, including 63.2% with grade 0 and 1, whereas in the controls group, 31.5% of patients had an OM grade lower than or equal to grade 2 (P < .001). Remarkably, the hazard ratio (HR) for grades 2, 3, and 4 OM was 0.41 (range, 0.22-0.75; P = .002) and for grades 3 and 4 it was 0.07 (range, 0.11-0.53; P < .001). Using OMAS by the calculation of ulcerous area, 5.3% of the laser group presented with ulcers of 9.1 cm2 to 18 cm2, whereas 73.6% of the control group presented with ulcers from 9.1 cm2 to 18 cm2 (P = .003). Our results indicate that the use of upfront LPLT in patients who have undergone HSCT is a powerful instrument in reducing the incidence of OM and is now standard in our center.

We studied the clinical outcomes of 171 adults with hematologic malignancies who received unrelated cord blood transplantation (CBT) as a primary unrelated stem-cell source (n=100), or bone marrow transplant (BMT) or peripheral blood stem-cell transplant (PBSCT) from related donors (n=71, 55 BMT and 16 PBSCT). All patients received myeloablative regimens including 12 Gy total body irradiation. We analyzed the hematologic recovery, and risks of graft-versus-host disease (GVHD), transplantation-related mortality (TRM) and relapse, and disease-free survival (DFS) using Cox proportional hazards models. Significant delays in engraftment occurred after cord blood transplantation; however, overall engraftment rates were almost the same for both grafts. The cumulative incidences of grades III to IV acute and extensive-type chronic GVHDs among CBT recipients were significantly lower than those among BMT/PBSCT recipients. Multivariate analysis demonstrated no apparent differences in TRM (9% in CBT and 13% in BMT/PBSCT recipients), relapse (17% in CBT and 26% in BMT/PBSCT recipients), and DFS (70% in CBT and 60% in BMT/PBSCT recipients) between both groups. These data suggest that unrelated cord blood could be as safe and effective a stem-cell source as related bone marrow or mobilized peripheral blood for adult patients when it is used as a primary unrelated stem-cell source.

To prospectively assess the applicability of reduced-intensity conditioning hematopoietic stem cell transplantation (RIC-HSCT), we wrote a protocol in which all untreated patients 50 years or older with acute myeloid leukemia (AML) and unfavorable cytogenetics would be evaluated during induction for a possible RIC-HSCT in first complete remission (CR1). Ninety-nine of 259 patients entered CR. Fifty-three of the 99 were seen by the Transplant Service with the remainder not seen because of illness, lack/unavailability of siblings, refusal, or, primarily, unclear reasons (21 patients). A donor was identified for 26 patients (21 sibling, 5 unrelated) with RIC-HSCT performed in 14 (13 sibling). Results in consulted patients suggested that 50% or fewer of the 85 patients who did not undergo transplantation were potential transplant candidates. We attempted to find one or more chemotherapy pair-mates for each patient who underwent transplantation based on cytogenetics, age, and a relapse-free survival (RFS) time that was more than or equal to the time from CR1 to RIC-HSCT in the patient who underwent transplantation. Thirty-two of the 39 matches favored (longer RFS) RIC-HSCT and 7, chemotherapy. The probability that the corresponding beta distribution was different than expected (ie, that RIC-HSCT was superior) was 0.99 (P=.004). Results were similar with respect to survival. While RIC-HSCT thus seems of interest, methods are needed to extend its applicability.

Most adults with acute lymphoblastic leukemia (ALL) who achieve complete remission (CR) will relapse. We examined the outcome of 609 adults with recurring ALL, all of whom were previously treated on the Medical Research Council (MRC) UKALL12/ECOG2993 study, where the overall survival (OS) of newly diagnosed patients is 38% (95% confidence interval [CI]=36%-41%) at 5 years. By contrast, OS at 5 years after relapse was 7% (95% CI=4%-9%). Factors predicting a good outcome after salvage therapy were young age (OS of 12% in patients younger than 20 years vs OS of 3% in patients older than 50 years; 2P<.001) and short duration of first remission (CR1) (OS of 11% in those with a CR1 of more than 2 years versus OS of 5% in those with a CR1 of less than 2 years; 2P<.001). Treatment received in CR1 did not influence outcome after relapse. In a very highly selected subgroup of patients who were able to receive HSCT after relapse, some were long-term survivors. We conclude from a large, unselected series with mature follow-up that most adults with recurring ALL, whatever their prior treatment, cannot be rescued using currently available therapies. Prevention of recurrence is the best strategy for long-term survival in this disease.

Although levels of minimal residual disease (MRD) decrease below the detection limit in most adult patients with standard-risk acute lymphoblastic leukemia (ALL) after consolidation treatment, about 30% of these patients will ultimately relapse. To evaluate the power of MRD monitoring as an indicator of impending relapse, we prospectively analyzed postconsolidation samples of 105 patients enrolled in the German Multicenter ALL (GMALL) trial by real-time quantitative polymerase chain reaction (PCR) of clonal immune gene rearrangements. All patients were in hematologic remission, had completed first-year polychemotherapy, and tested MRD negative prior to study entry. Twenty-eight of 105 patients (27%) converted to MRD positivity thereafter, and 17 of 28 (61%) relapsed so far. Median time from molecular (MRD-positive) to clinical relapse was 9.5 months. In 15 of these patients, MRD within the quantitative range of PCR was measured in hematologic remission, and 13 of these patients (89%) relapsed after a median interval of 4.1 months. Of the 77 continuously MRD-negative patients, only 5 (6%) have relapsed. We conclude that conversion to MRD positivity during the early postconsolidation phase in adult standard-risk ALL patients is highly predictive of subsequent hematologic relapse. As a result of the study, as of spring 2006, salvage treatment in the ongoing GMALL trial is intended to be started at the time of recurrence of quantifiable MRD.

Therapy of Hodgkin disease (HD) is designed to prolong progression-free survival and minimize toxicity. The best regimen to achieve this has not yet been defined. A total of 108 patients with newly diagnosed HD and adverse prognostic factors were prospectively studied between 1999 and 2004. They were assigned to therapy according to defined risk stratification. Patients were defined depending on the International Prognostic Score (IPS). Those with IPS of 3 or higher received 2 cycles of escalated therapy, including bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP [EB]). All others received 2 cycles of standard BEACOPP (SB). Subsequent therapy was prospectively assigned following 2 cycles according to results of early interim 67Ga or positron emission tomography/computed tomography (PET/CT). Following a positive interim scan, 4 cycles of EB were administered, whereas 4 cycles of SB were given to patients with a negative scan. The complete remission rate, the 5-year event-free survival (EFS), and overall survival (OS) rates were 97%, 85% and 90%, respectively. Relapse or progression occurred in 27% of patients with interim positive PET/CT versus 2.3% of negative scans (P<.02). Early interim fluorine-18 2-fluoro-2-deoxy-D-glucose (FDG)-PET/CT is a useful tool for adjustment of chemotherapy on an individual basis. Similar EFS and OS rates were observed for patients in both risk groups.

Primary systemic amyloidosis (AL) is an incurable plasma cell disorder. Lenalidomide, especially in conjunction with dexamethasone, is highly active in patients with multiple myeloma. We studied the toxicity and efficacy of lenalidomide in patients with AL. Patients with symptomatic AL, a measurable plasma cell disorder, and adequate hematologic and renal reserve were eligible. Patients received single-agent lenalidomide. If there was no evidence of progression after 3 months or of hematologic response after 3 cycles, dexamethasone was added. Twenty-three patients were enrolled. Thirteen were previously treated. Organ involvement was cardiac (64%), renal (73%), hepatic (23%), and nerve (14%). Within the first 3 cycles of therapy, 10 patients discontinued treatment: 4 early deaths, 3 adverse events, and 3 other causes. With a median follow-up of 17 months, 10 patients responded to treatment. In these patients, responses included 9 hematologic, 4 renal, 2 cardiac, and 2 hepatic. All but one of the responders had dexamethasone added to their treatment program. The most common grade 3 or 4 adverse events at least possibly attributable to lenalidomide were neutropenia (45%), thrombocytopenia (27%), rash (18%), and fatigue (18%). In AL patients, we saw limited activity of single-agent lenalidomide, but significant activity of the combination with dexamethasone, which warrants further investigation.

Building on the prior work of use of pentostatin in chronic lymphocytic leukemia (CLL), we initiated a trial of combined pentostatin (2 mg/m2), cyclophosphamide (600 mg/m2), and rituximab (375 mg/m2) for 65 symptomatic, previously untreated patients. Of 64 evaluable patients, 34 (53%) were high Rai risk, 71% were nonmutated for the immunoglobulin heavy-chain variable region gene, 34% were CD38+, and 34% were ZAP-70+. Thirty patients (52%) had one anomaly detected by fluorescence in situ (FISH) hybridization, and 21 (36%) had complex FISH defects. Thirty-eight patients (58%) had grade 3+ hematologic toxicity but minimal transfusion needs and no major infections. Responses occurred in 58 patients (91%), with 26 (41%) complete responses (CRs), 14 (22%) nodular partial responses (nodular PRs), and 18 (28%) partial responses (PRs). Many patients with a CR also lacked evidence of minimal residual disease by 2-color flow cytometry. Examination of prognostic factors demonstrated poor response in the 3 patients with del(17p). In contrast, we found this regimen was equally effective in young versus older (>70 years) patients and in del(11q22.3) versus other favorable prognostic factors. Thus, this novel regimen of pentostatin, cyclophosphamide, and rituximab for previously untreated patients with CLL demonstrated significant clinical activity despite poor risk-based prognoses, achievement of minimal residual disease in some, and modest toxicity.