A phase II study of continuous infusion recombinant human granulocyte- macrophage colony-stimulating factor as an adjunct to autologous bone marrow transplantation for patients with non-Hodgkin's lymphoma in first remission

Recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) clearly hastens myeloid recovery in patients with relapsed hematologic malignancies undergoing autologous bone marrow transplantation (ABMT). In efforts to further improve neutrophil engraftment and shorten hospital stay in ABMT patients, rhGM-CSF was administered by a potentially more potent route (continuous infusion) to non-Hodgkin's lymphoma (NHL) patients with better BM reserve (first remission). Time to myeloid engraftment was compared with that of NHL patients treated in first remission at our institution on a similar ABMT protocol but without growth factor support (controls). Median neutrophil engraftment (absolute neutrophil count, 500 cells/microL) in first remission patients treated with rhGM-CSF was 14 days, compared with 22 days in controls (P = .0001). Hospital stays were also significantly reduced for rhGM-CSF patients (P = .0003). Platelet engraftment did not differ between the two groups. Persistent fever and generalized serositis were the primary toxicities. rhGM-CSF, delivered by this route, was efficacious but more toxic than 2-hour rhGM-CSF infusions previously reported by other investigators. Future alterations in both dose and schedule may retain comparable efficacy yet diminish toxicity.     

Randomized trial of protected environment--prophylactic antibiotics in 145 adults with acute leukemia

One hundred and forty-five adults with acute leukemia were randomized to receive remission induction therapy in or out of a protected environment (PE) with prophylactic antibiotics orally (PA) or systemically (SA). Sixty-three patients were randomized in PE and 82 outside a PE. The proportion of patients who survived long enough to receive an adequate trial was higher in the PE (97%) than out (82%) (P = .01). The complete remission (CR) rate was 71% in and 43% out of the PE (P less than .01). Fifty-five patients received PA and 90 received SA. The CR rates were 61% and 45%, respectively. Of the 145 patients, 73 (50%) developed 102 episodes of major infections. Twenty-six of 63 patients in the PE developed major infection compared to 47 of 82 outside a PE (P = .08). The incidence rate of 13% fatal infections in a PE was significantly smaller than the 28% rate outside a PE (P = .04). The number of days with infections at less than 500 neutrophils/mm3 was also significantly lower inside a PE than outside (P less than .01). When comparing patients receiving SA or PA, there was no statistically significant difference in the incidence of infections. Forty-one patients received OAP Chemotherapy and 104 received adriamycin-OAP plus BCG. The CR rate on OAP was 44% compared with 60% on Ad-OAP + BCG. Infection rates were 76% and 40%, respectively (P less than .01). The median survival time was 72 weeks for patients in PE compared with 42 weeks for patients outside a PE (P less than .01). The prophylactic antibiotic regimens were well tolerated by most patients. This prospective randomized study has demonstrated statistically significant advantages for a lowered risk of fatal infection, higher CR rate and longer survival of patients treated in a PE with prophylactic antibiotics compared with patients treated in a conventional hospital room. Also, there was evidence for the superiority of adriamycin-OAP + BCG treatment compared with OAP.     

Increased risk of leukemia relapse with high-dose cyclosporine A after allogeneic marrow transplantation for acute leukemia

Eighty-one patients with acute myeloid leukemia (ANLL, n = 44) or acute lymphoblastic leukemia (ALL, n = 37), aged 10 to 50 years were randomized to receive 1 mg/kg per day (n = 41, group A) or 5 mg/kg per day (n = 40, group B) of cyclosporine A (CyA) from day -1 to day +20 after bone marrow transplant (BMT). All patients received CyA orally thereafter. All patients were prepared with cyclophosphamide (CY) 120 mg/kg and fractionated total body irradiation (TBI), and received unfractionated BM from an HLA-identical sibling. The two groups were comparable for diagnosis, disease status, French-American-British (FAB) classification, WBC count at diagnosis, cytogenetic abnormalities, extramedullary disease before BMT, donor/recipient age and sex, number of cells infused, and number of days with intravenous (IV) CyA. Median follow-up for surviving patients in group A was 983 v 632 days in group B. Patients in group A had lower serum levels of CyA (295 v 686 ng/mL, P = .004), lower bilirubin levels (1.9 v 2.6 mg/dL, P = .07), lower creatinine levels (0.9 v 1.4 mg/dL, P = .06), and a lower proportion of CD8+ cells in the peripheral blood (PB) within day +21 (19% v 28%, P = .07). First day to 0.5 x 10(9)/L neutrophils was comparable in the two groups (13 v 14 days; P = .1). In a Cox model, the actuarial risk of acute graft-v-host disease (GVHD) grade II+, after stratification for age (less than 20 years greater than) was significantly lower in group B patients (0.54, P = .04). The actuarial risk of developing chronic GVHD was comparable (P = .9). Actuarial transplant-related mortality (TRM) at 240 days was 28% and 26% (P = .8) in group A and B: the major cause of death was GVHD in group A (P = .02) and multiorgan toxicity in group B (P = .07). The actuarial risk of relapse at 2 years overall was 20% in group A and 52% in group B (P = .001); it was 9% v 43%, respectively, for patients in first remission (P = .0001) and 48% v 63% for patients in non-first complete remission (CR) (P = .1). Actuarial 2-year disease-free survival (DFS) in group A and B was 58% v 32% (P = .02) for all patients, 71% v 35% (P = .01), in first remissions, and 30% v 23% (P = .2) in advanced disease.(ABSTRACT TRUNCATED AT 400 WORDS)     

Therapeutic use of recombinant human granulocyte-macrophage colony-stimulating factor in neonatal rats with type III group B streptococcal sepsis.

The use of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) as therapy in neonatal sepsis has been proposed because of observed defects in polymorphonuclear leukocyte (PMNL) production and function in infected neonates. Newborn rats were infected intraperitoneally (ip) with type III group B streptococcus (III-GBS) and effects of treatment with rhGM-CSF given ip 7-19 h after infection were studied. Overall mortality was 67% in controls and 37% in animals treated with rhGM-CSF (P = .003). No changes in peripheral blood PMNL number or oxidative metabolic function were found in infected or uninfected animals given rhGM-CSF compared with controls. In uninfected animals, there was an increase in the oxidative burst of peritoneal cells at 3.5 h (P = .043) and in the numbers of peritoneal cells at 3 h (P = .001) in animals receiving ip rhGM-CSF compared with controls. Phagocyte priming, cellular influx into the peritoneum, or both appear to contribute to the decreased mortality observed in this model of rhGM-CSF therapy of III-GBS disease in neonates.     

Autoimmune disease is a risk factor for the development of non-Hodgkin's lymphoma

OBJECTIVE: To investigate the relationship of prior autoimmune disease to the development of non-Hodgkin's lymphoma (NHL). METHODS: Patients with NHL (n = 278) seen from 1993 to 2002 were compared with a group of patients with other hematological disorders (controls, n = 317) seen at the same time. All patients were questioned about prior autoimmune disease. Comparisons between NHL patients and controls were based on analysis of a 2 2 table of counts using Fisher's exact test. Analysis of the effect of autoimmune disease on NHL status, controlling for other risk factors, was performed using logistic regression. RESULTS: Thirty-six (13%) NHL patients had a prior autoimmune disease compared to 5% of controls (p = 0.001). Sixty-nine percent of NHL patients with a prior autoimmune disease were female compared to 43% without a prior autoimmune disease, and this was similar in control patients, 69% and 48%, respectively. Twenty percent of all women with NHL had a history of autoimmune disease compared to 7% of women in the control group (p = 0.001). Nineteen of the NHL patients with autoimmune disease (56%) received immunosuppressive treatment compared to 5 (38%) in the controls. CONCLUSION: Autoimmune disease may account in part for the increase in NHL, especially in women.     

Transplant-related mortality and long-term graft function are significantly influenced by cell dose in patients undergoing allogeneic marrow transplantation

We have studied the impact of cell dose on short- and long-term graft function and outcome in 905 patients undergoing an unmanipulated allogeneic bone marrow transplantation (BMT) from an HLA-identical sibling (n = 735), a one-antigen mismatched related donor (n = 35), or a matched unrelated donor (n = 135). Median number of nucleated cells infused was 3.4 x 10(8)/kg (25th percentile 2.4 x 10(8)/kg, 75th percentile 5 x 10(8)/kg). Patients were stratified according to cells infused in 3 groups: < or = 2.4 x 10(8)/kg (n = 247; low dose); >2.4 x 10(8)/kg and < or = 5 x 10(8)/kg (n = 452; intermediate dose); and >5 x 10(8)/kg (n = 206; high dose). Patients receiving high cell dose had significantly higher platelet counts on days +20, +50, +100, +180, and +365 after BMT (P <.01) and higher white blood cell counts on days +50, +100, and +180 after BMT (P <.01) as compared with other patients. The actuarial 5-year transplant-related mortality (TRM) was 41% versus 36% versus 28% (P =.01); overall survival was 45% versus 51% versus 56% (P =.0008); and disease-free survival was 41% versus 42% versus 48%, respectively, (P =.04) in patients receiving low, intermediate, or high cell dose. The cell dose effect was more pronounced in patients older than 30 years of age, with advanced disease, with chronic myeloid leukemia, and with alternative donors. In multivariate Cox analysis on TRM, cell dose was a significant predictor (P =.002; relative risk 0.6) together with donor type (P =.0001), year of transplantation (P =.0001), conditioning regimen (P =.02), and recipient age (P =.02). In conclusion, transplantation of high marrow cell dose is associated with reduced transplant mortality and improved survival and results in improved graft function both short and long term.     

Total body irradiation, etoposide, cyclophosphamide, and autologous peripheral blood stem-cell transplantation followed by randomization to therapy with interleukin-2 versus observation for patients with non-Hodgkin lymphoma: results of a phase 3 randomized trial by the Southwest Oncology Group (SWOG 9438)

To determine the effect of posttransplantation immunotherapy with IL-2 on the progression-free survival (PFS) and overall survival (OS) of patients with non-Hodgkin lymphoma (NHL) after autologous stem-cell transplantation (PBSCT), patients with previously treated NHL were treated with cyclophosphamide, etoposide, total body irradiation (TBI), and PBSCT. Twenty-eight to 80 days after PBSCT, patients were randomized to IL-2 versus observation. Three hundred seventy-six eligible patients were registered (with 4-year PFS of 34% and 4-year OS of 52%), and 194 eligible patients were randomized to continuous infusion intravenous IL-2 (9 million units/m(2)/day for 4 days followed 5 days later by 1.6 million units/m(2)/day for 10 days) versus observation. In randomized patients, there was no significant difference in PFS (hazard ratio of IL-2 to observation = 0.90; P =.56) or in OS (hazard ratio of IL-2 to observation = 0.88; P =.55). There were no deaths related to IL-2 treatment. Grade 4 IL-2-related toxicities (n = 14) were reversible. These results confirm earlier SWOG findings that cyclophosphamide, etoposide, TBI, and PBSCT can be administered to patients with relapsed/refractory NHL with encouraging PFS and OS. Posttransplantation IL-2 given at this dose and schedule of administration had no significant effect on PFS or OS. This study is registered at www.clinicaltrials.gov as NCT00002649.     

Combination of quinine as a potential reversing agent with mitoxantrone and cytarabine for the treatment of acute leukemias: a randomized multicenter study

A phase III prospective randomized multicenter study was performed to determine whether quinine could improve the response rate of poor-risk acute leukemias (ALs) to standard chemotherapy including a multidrug resistance (MDR)-related cytotoxic agent. The rationale of the study was based on the negative prognostic value of MDR phenotype in ALs and the ability of quinine to reverse this phenotype both in vitro and ex vivo. Three hundred fifteen patients (median age, 49 years; range, 16 to 65) with relapsed (n = 108) or refractory (n = 32) acute myeloblastic leukemia (AML), relapsed (n = 27) or refractory (n = 9) acute lymphoblastic leukemia (ALL), secondary AL (n = 22) or blastic transformation of myelodysplastic syndrome ([MDS] n = 74) or myeloproliferative syndrome ([MPS] n = 43) were randomly assigned to receive mitoxantrone ([MXN] 12 mg/m2/d, days 2 to 5) and cytarabine ([Ara-C] 1 g/m2/12 h, days 1 to 5) alone or in combination with quinine (30 mg/kg/d, days 1 to 5; continuous intravenous infusion beginning 24 hours before MXN infusion). Side effects of quinine were observed in 56 of 161 quinine-treated patients and disappeared in all but four cases after one or two 20% dose decreases. Sera from quinine-treated patients showed increased MXN uptake in an MDR-positive cell line compared with matched sera obtained before quinine infusion. Quinine induced a significant increase in the incidence of nausea, vomiting, mucositis, and cardiac toxicity. A complete response (CR) was observed in 85 of 161 patients (52.8%) from the quinine-treated group versus 70 of 154 patients (45.5%) in the control group (P = .19). The most important differences between quinine and control group CR rates were observed in patients with refractory AMLs and blastic transformation of MDS and MPS. The CR rate was higher in P-glycoprotein-positive cases, although the difference was not significant. Failure of the regimen due to blastic persistence or blast number increase was higher in the control group (61 of 154 patients) than in the quinine group (45 of 161, P = .04). Early death was observed in eight cases (four in each arm) and death in aplasia in 27 cases (20 in quinine group v seven in control group, P = .01). The significant increase of toxicity in the quinine arm could have masked the clinical benefit of MDR reversion in poor- risk ALs.     

Poor response to intensive chemotherapy in de novo acute myeloid leukaemia with trilineage myelodysplasia

Summary. The findings of morphologically dysplastic features in haemopoietic cells in de novo acute myeloid leukaemia (AML) has been named AML with trilineage myelodysplasia (AML/TMDS). We analysed the clinical data, karyotypes, and treatment outcomes of 230 de novo AML patients treated with the Japan Adult Leukaemia Study Group AML-87 protocol. 40 (17%) patients had AML/TMDS. Platelet count was significantly higher ( F =0·006) and bone marrow blasts were fewer ( P =0·01) in the AML/TMDS group than in the AML without TMDS. Abnormal karyotype was shown in 12/30 patients (40%) analysed.
The complete remission (CR) rate for AML/TMDS was significantly lower than AML without TMDS (63% v 81%) ( P =0·01). The overall survival curves showed that the 40 patients with TMDS had a significantly worse survival than the 190 without TMDS ( P =0·0005). AML/TMDS also showed significantly worse disease-free survival (DFS) ( P =0·0001).
Multivariate analysis revealed that the absence of TMDS in AML was the most significant factor in obtaining CR ( P =0·01) and a significant factor in predicting longer DFS ( P =0·04). Our data suggest that AML/TMDS responds poorly to intensive chemotherapy. Further study is required to determine the best treatment strategy for AML/TMDS and the biological differences between AML/TMDS and other types of AML.     

Autologous SCT with a dose-reduced BU and CY regimen in older patients with non-Hodgkin's lymphoma

Autologous SCT is a potentially curative procedure for patients with relapsed lymphoma (NHL). We analyzed the outcomes of 34 patients > or =60 years old, including eight patients > or =70 years old, who received BU and CY and SCT for NHL. Patients received BU 0.8 mg/kg i.v. (n=25) or 1 mg/kg p.o. (n=9) q 6 h x 14 doses and CY 60 mg/kg i.v. q day x 2 days. The median age was 66 (range, 60-78) years. Twenty-two patients had large cell, 10 follicular and two-mantle cell lymphoma. Fifteen patients were in a second or greater CR and 19 patients were in a PR. The median days to ANC >500/microl and platelet count >50,000/microl were 10 and 13 days respectively. The 100-day transplant-related mortality was 0%. Toxicities included interstitial lung disease (n=2), seizures in a patient with CNS lymphoma (n=1), mild veno-occlusive disease (n=2), and transient atrial fibrillation (n=4). With a median follow-up of 40 months, the 2-year overall survival and PFS were 67 and 54% respectively. BU/CY is a well-tolerated conditioning regimen for older patients with NHL. Age alone should not be used as an exclusion criterion for autologous SCT.     

Efficacy of vinorelbine, epirubicin and prednisone combination regimen in pretreated elderly patients with aggressive non-Hodgkin's lymphoma

BACKGROUND AND OBJECTIVES: To assess the efficacy and toxic profile of the NAEPP protocol, a regimen including vinorelbine, epirubicin and prednisone, in a particularly troublesome subset of patients: pretreated elderly patients with aggressive non-Hodgkin's lymphoma (NHL). DESIGN AND METHODS: From November 1998 to January 2000, 20 pretreated patients who had all relapsed after first-line VNCOP-B chemotherapy were enrolled in a phase II trial and treated with the NAEPP regimen: vinorelbine (25 mg/m(2) i.v. on days 1 and 8), epirubicin (40 mg/m(2) i.v. on days 1 and 8), and prednisone (40 mg/m(2) on days 1 and 8) with granulocyte colony-stimulating factor administered at 5 mg/kg/day on days 2-5 and days 9-12. Chemotherapy was repeated every 4 weeks for a total of 6 cycles. RESULTS: Six (30%) patients achieved complete remission (CR) and 7 (35%) had partial responses (PR), giving an overall response rate of 65%. The response rate was not affected either by type of relapse presentation (nodal versus nodal plus extranodal), presence of bulky disease, or time of relapse. No major toxic effects were recorded. INTERPRETATION AND CONCLUSIONS: These preliminary data suggest that the NAEPP regimen is an effective combination with a low toxicity profile in elderly pretreated patients with aggressive NHL. Further trials using NAEPP as a consolidation phase following first-line treatment are needed to establish the advantage in terms of CR rate and relapse-free survival in these patients.     

Allogeneic bone marrow transplantation for acute myeloid leukemia in first remission: a randomized trial of a busulfan-Cytoxan versus Cytoxan-total body irradiation as preparative regimen: a report from the Group d'Etudes de la Greffe de Moelle Osseuse.

From October 1987 to December 1990, 101 patients with acute myeloid leukemia (AML) were randomized to be transplanted in first complete remission (CR1). Preparative regimen including Cytoxan (120 mg/kg) with total body irradiation (CYTBI) (N = 50) or busulfan (16 mg/kg) (BUSCY) (N = 51) was followed by allogeneic bone marrow transplantation (BMT) from an HLA-identical sibling. Mean time between diagnosis and BMT was 119 days. The outcome for CYTBI at 2 years is better for probability of disease-free survival (DFS) (72% v 47%) (P less than .01), survival (75% v 51%) (P less than .02), relapse (14% v 34%) (P less than .04), and transplant mortality (8% v 27%) (P less than .06). In multivariable analysis, higher relapse and decreased survival and DFS were associated with BUSCY regimen, while chronic graft-versus-host disease also influenced independently the probability of relapse. This demonstrates the present limitation of busulfan use in this setting, possibly due to probable individual variations in biodisponibility. Furthermore, besides the anti-leukemic effect of preparative regimens, this trial points out the progress accomplished in BMT management (transplant mortality = 8% in CYTBI) over the last 20 years as well as the effectiveness of transplant in early first CR after CYTBI (DFS = 72% at 2 years).     

The toxicity and efficacy of donor lymphocyte infusions given after reduced-intensity conditioning allogeneic stem cell transplantation

We describe the toxicity and efficacy of donor lymphocyte infusions (DLIs) given to 81 patients (median age, 50 years) after reduced-intensity conditioning (RIC) transplantations performed at 16 centers in the United Kingdom. The diseases treated included non-Hodgkin lymphoma (NHL; n = 29), chronic myeloid leukemia (CML; n = 12), myeloma (n = 11), acute myeloid leukemia (AML; n = 10), and chronic lymphocytic leukemia (CLL; n = 9). Eighty-eight percent received stem cells from sibling donors. The patients received 130 infusions (median, 1; range, 1-4). Indications for DLI were unsatisfactory response/disease progression in 51 patients, mixed chimerism in 18, preemptive in 10, and other in 2. Graft hypoplasia was uncommon (11%). Grade II to IV graft-versus-host disease (GVHD) occurred in 23 of 81 patients (28%) and limited and extensive chronic GVHD in 5 of 69 and 18 of 69 evaluable patients (total incidence 33%). Conversion from mixed to full donor chimerism occurred in 19 of 55 evaluable patients (35%) at a median of 48 days after the DLI; partial responses occurred in 6 patients (total response rate 45%). Eighteen of 51 (35%) patients with measurable disease after stem cell transplantation had a complete response (2 molecular), and 5 a partial response (total response rate 45%). Eleven of 17 evaluable complete responders had full donor chimerism. Eight of 13 patients with follicular NHL had complete responses as did 4 of 12 patients with CML. Clinical and chimeric responses correlated strongly with acute and chronic GVHD. Forty-seven patients (58%) survive at a median of 508 days after transplantation (range, 155-1171 days) with a median Karnofsky score of 90. Thirty-four patients (42%) died at a median of 211 days after transplantation with the major causes being progressive disease (26%) and GVHD (9%). Further systematic studies are required to determine the efficacy and optimum use of DLI for patients with each disease treated by nonmyeloablative stem cell transplantation.     

Radioimmunotherapy with iodine (131)I tositumomab for relapsed or refractory B-cell non-Hodgkin lymphoma: updated results and long-term follow-up of the University of Michigan experience

CD20-targeted radioimmunotherapy is a promising new treatment for B-cell non-Hodgkin lymphoma (NHL). We now provide updated and long-term data on 59 chemotherapy-relapsed/refractory patients treated with iodine (131)I tositumomab in a phase I/II single-center study. Fifty-three patients received individualized therapeutic doses, delivering a specified total-body radiation dose (TBD) based on the clearance rate of a preceding dosimetric dose. Six patients received dosimetric doses only. Dose-escalations of TBD were conducted separately in patients who had or had not undergone a prior autologous stem cell transplant (ASCT) until a nonmyeloablative maximally tolerated TBD was established (non-ASCT = 75 cGy, post-ASCT = 45 cGy). Fourteen additional non-ASCT patients were treated with 75 cGy. Unlabeled antibody was given prior to labeled dosimetric and therapeutic doses to improve biodistribution. Forty-two (71%) of 59 patients responded; 20 (34%) had complete responses (CR). Thirty-five (83%) of 42 with low-grade or transformed NHL responded versus 7 (41%) of 17 with de novo intermediate-grade NHL (P =.005). For all 42 responders, the median progression-free survival was 12 months, 20.3 for those with CR. Seven patients remain in CR 3 to 5.7 years. Sixteen patients were re-treated after progression; 9 responded and 5 had a CR. Reversible hematologic toxicity was dose limiting. Only 10 patients (17%) had human anti-mouse antibodies detected. Long-term, 5 patients developed elevated thyroid-stimulating hormone levels, 5 were diagnosed with myelodysplasia and 3 with solid tumors. A single, well-tolerated treatment with iodine (131)I tositumomab can, therefore, produce frequent and durable responses in NHL, especially low-grade or transformed NHL. (Blood. 2000;96:1259-1266)     

Measles-associated diarrhea in hospitalized children in Lima, Peru: pathogenic agents and impact on growth

Because the causes of measles-associated diarrhea are not well known, 0- to 5-year-old children presenting to the hospital with measles-associated diarrhea (cases, n = 77) or acute diarrhea only (controls, n = 77) were compared. Growth and diarrheal morbidity were evaluated for 1 month after acute illness. Campylobacter jejuni was more frequently isolated from cases (31%) than controls (16%; P = .03). Rotavirus was absent in all cases versus 28% of controls (P less than .001). Incidence density for new episodes of diarrhea was significantly greater in cases (6.5 vs. 4.1; odds ratio, 1.6; confidence intervals, 1.09-2.34; P = .01), as was duration of episodes (3 vs. 2 days, P = .02). Both groups showed similar positive cumulative percentage weight gains throughout follow-up. These data support the theory of measles as a risk factor for developing diarrhea. The bacteriologic and virologic findings may reflect the immunologic response of the host to measles infection.     

Randomized multicenter trial of foscarnet versus ganciclovir for preemptive therapy of cytomegalovirus infection after allogeneic stem cell transplantation

The present study compared foscarnet with ganciclovir for preemptive therapy of cytomegalovirus (CMV) infection after allogeneic blood or marrow stem cell transplantation (SCT). Patients with CMV infection, as detected by weekly antigenemia or polymerase chain reaction (PCR) in blood leukocytes, were randomized to intravenous therapy for 2 weeks with either foscarnet at 60 mg/kg or ganciclovir at 5 mg/kg administered every 12 hours; if CMV infection remained detectable, patients received an additional 2 weeks of intravenous foscarnet at 90 mg/kg or ganciclovir at 6 mg/kg given once daily for 5 days per week, after which therapy was stopped. Primary efficacy endpoint was the occurrence of CMV disease or death from any cause within 180 days after SCT. A total of 213 patients were treated with either foscarnet (n = 110) or ganciclovir (n = 103). Kaplan-Meier estimates of event-free survival within 180 days after SCT were similar in the 2 treatment groups (P =.6). During study treatment, severe neutropenia (< 0.5 x 10(9)/L) occurred in 11 (11%) patients on ganciclovir versus 4 (4%) patients on foscarnet (P =.04), and impaired renal function was observed in 5 (5%) patients on foscarnet versus 2 (2%) patients on ganciclovir (P =.4). Neutropenia or thrombocytopenia required discontinuation of ganciclovir in 6 (6%) patients but in no foscarnet-treated patient (P =.03). After allogeneic SCT, preemptive therapy of CMV infection with foscarnet shows similar efficacy as with ganciclovir, but is associated with a lower proportion of patients who develop severe neutropenia and who require discontinuation of antiviral therapy due to hematotoxicity.     

Fludarabine,ara-C,novantrone and dexamethasone (FAND) in previously treated chronic lymphocytic leukemia patients

BACKGROUND AND OBJECTIVES: The objective of improving the quality of responses of chronic lymphocytic leukemia (CLL) patients has led to the design of protocols that combine fludarabine (FDR) with synergistic drugs. We evaluated the efficacy and toxicity of a schedule that includes fludarabine, ara-C, novantrone and dexamethasone (FAND) for the management of previously treated CLL patients under 60 years old. DESIGN AND METHODS: Thirty-one patients underwent FAND treatment. Twenty-three patients had active disease (relapsed patients: 9; unresponsive to prior therapy: 14). Eight patients had a partial response (PR) to prior therapy and were treated with the aim of further reducing residual disease. The FAND schedule included fludarabine (25 mg/m(2) i.v. days 1-3), ara-C (1 g/m(2) i.v. day 1: 8 patients; days 1-2: 23 patients), novantrone (10 mg/m(2) i.v. day 1) and dexamethasone (20 mg i.v. days 1-3). Infection prophylaxis consisted of fluconazole, acyclovir, trimethoprim/sulfamethoxasole and granulocyte colony-stimulating factor (G-CSF) in the presence of severe neutropenia. RESULTS: A response was observed in 7/14 refractory patients (complete response-CR: 29%), in all 9 relapsed patients (CR: 78%) and in 7/8 patients (CR: 87.5%) treated in PR. Taken together, 18 CRs were obtained and in 14 (78%) this was associated with a flow cytometric remission (CD5+/CD20(weak+) PB lymphocytes: <10%). Severe granulocytopenia occurred after 86 of the 124 administered courses (69%), but only after 10/86 courses (12%) were major infections recorded. In 10/15 mobilized patients (cyclophosphamide + G-CSF: 6 patients; FAND + G-CSF: 9 patients) after FAND > or = 2 x 10(6)/kg CD34+ cells were collected. Nine patients were autografted in CR and showed a longer response duration than the 9 patients in CR who did not receive further therapy after FAND (53 vs 30% at 41 months; p = 0.05). INTERPRETATION AND CONCLUSIONS: FAND associated with extensive infection prophylaxis and G-CSF support is a highly cytoreductive and well-tolerated treatment for CLL patients and in most cases does not hamper subsequent stem cell mobilization.     

Donor natural killer cell allorecognition of missing self in haploidentical hematopoietic transplantation for acute myeloid leukemia: challenging its predictive value

We analyzed 112 patients with high-risk acute myeloid leukemia (61 in complete remission [CR]; 51 in relapse), who received human leukocyte-antigen (HLA)-haploidentical transplants from natural killer (NK) alloreactive (n = 51) or non-NK alloreactive donors (n = 61). NK alloreactive donors possessed HLA class I, killer-cell immunoglobulin-like receptor (KIR) ligand(s) which were missing in the recipients, KIR gene(s) for missing self recognition on recipient targets, and alloreactive NK clones against recipient targets. Transplantation from NK-alloreactive donors was associated with a significantly lower relapse rate in patients transplanted in CR (3% versus 47%) (P > .003), better event-free survival in patients transplanted in relapse (34% versus 6%, P = .04) and in remission (67% versus 18%, P = .02), and reduced risk of relapse or death (relative risk versus non-NK-alloreactive donor, 0.48; 95% CI, 0.29-0.78; P > .001). In all patients we tested the "missing ligand" model which pools KIR ligand mismatched transplants and KIR ligand-matched transplants from donors possessing KIR(s) for which neither donor nor recipient have HLA ligand(s). Only transplantation from NK-alloreactive donors is associated with a survival advantage.