melphalan and Infections

Treatment of chronic granulomatous disease (CGD) with myeloablative bone marrow transplantation is considered risky. This study investigated complications and survival according to different risk factors present at transplantation. The outcomes of 27 transplantations for CGD, from 1985 to 2000, reported to the European Bone Marrow Transplant Registry for primary immunodeficiencies were assessed. Most transplant recipients were children (n = 25), received a myeloablative busulphan-based regimen (n = 23), and had unmodified marrow allografts (n = 23) from human leukocyte antigen (HLA)-identical sibling donors (n = 25). After myeloablative conditioning, all patients fully engrafted with donor cells; after myelosuppressive regimens, 2 of 4 patients fully engrafted. Severe (grade 3 or 4) graft-versus-host disease (GVHD) disease developed in 4 patients: 3 of 9 with pre-existing overt infection, 1 of 2 with acute inflammatory disease. Exacerbation of infection during aplasia was observed in 3 patients; inflammatory flare at the infection site during neutrophil engraftment in 2: all 5 patients belonged to the subgroup of 9 with pre-existing infection. Overall survival was 23 of 27, with 22 of 23 cured of CGD (median follow-up, 2 years). Survival was especially good in patients without infection at the moment of transplantation (18 of 18). Pre-existing infections and inflammatory lesions have cleared in all survivors (except in one with autologous reconstitution). Myeloablative conditioning followed by transplantation of unmodified hemopoietic stem cells, if performed at the first signs of a severe course of the disease, is a valid therapeutic option for children with CGD having an HLA-identical donor.

Topics: Adolescent; Adult; Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Antilymphocyte Serum; Bone Marrow; Busulfan; Cause of Death; Child; Child, Preschool; Cyclophosphamide; Europe; Female; Genetic Heterogeneity; Graft vs Host Disease; Granulomatous Disease, Chronic; Hematopoietic Stem Cell Transplantation; Humans; Infection Control; Infections; Inflammation; Male; Melphalan; Neutrophils; Survival Analysis; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome; Vidarabine

Topics: Amyloid; Amyloidosis; Anemia; Antineoplastic Agents; Clinical Trials as Topic; Cyclophosphamide; Hodgkin Disease; Humans; Immunodiffusion; Immunoelectrophoresis; Immunoglobulin G; Immunoglobulin M; Immunoglobulins; Infections; Leukemia, Lymphoid; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Melphalan; Multiple Myeloma; Prognosis; Pyelonephritis

Patients with transplant-ineligible relapsed and refractory multiple myeloma (RRMM) have a short life expectancy, especially when they have failed both the proteasome inhibitor and immunomodulator therapies. This study aimed to assess the efficacy and safety of pomalidomide, cyclophosphamide, and dexamethasone (PCd) in elderly patients with RRMM. This phase 2 clinical trial recruited 55 elderly patients with RRMM. The patients underwent a 28-day treatment cycle: pomalidomide (4 mg/day on days 1-21, administered orally) and cyclophosphamide (400 mg/day on days 1, 8, and 15; administered orally) plus dexamethasone. The median (range) age of the patients was 73.3 (64-86) years, and 8 (14.5%) patients who were ≥ 80 years old. Eight (14.5%) and 31 (56.4%) patients exhibited stage III (revised international staging system) and frail status (simplified frailty scale), respectively. The overall response rate (ORR) and clinical benefit rate (CBR) of PCd therapy were 58.2% and 72.7%, respectively. The median PFS and median overall survival (OS) were 6.90 months (95% CI, 4.7-9.0) and 18.48 months (95% CI, 9.4-27.6), respectively. The incidence rate of grade ≥ 3 non-hematological toxicities was 70.8%. In particular, the incidence rate of primary infection was 45.4%, including 21.8% for pneumonia, 9.0% for sepsis, and 14.6% for febrile neutropenia. In conclusion, PCd is an effective regimen for elderly patients with RRMM who had failed both bortezomib and lenalidomide treatments, but in whom the treatment-associated infection is the main cause of morbidity and mortality.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Cyclophosphamide; Dexamethasone; Drug Resistance, Neoplasm; Febrile Neutropenia; Female; Frail Elderly; Frailty; Hematologic Diseases; Humans; Incidence; Infections; Kaplan-Meier Estimate; Lenalidomide; Male; Melphalan; Middle Aged; Multiple Myeloma; Myeloma Proteins; Prednisone; Progression-Free Survival; Recurrence; Republic of Korea; Thalidomide

The combination of bortezomib, melphalan, and prednisone is a standard treatment for patients with newly diagnosed multiple myeloma who are ineligible for autologous stem-cell transplantation. Daratumumab has shown efficacy in combination with standard-of-care regimens in patients with relapsed or refractory multiple myeloma.. In this phase 3 trial, we randomly assigned 706 patients with newly diagnosed multiple myeloma who were ineligible for stem-cell transplantation to receive nine cycles of bortezomib, melphalan, and prednisone either alone (control group) or with daratumumab (daratumumab group) until disease progression. The primary end point was progression-free survival.. At a median follow-up of 16.5 months in a prespecified interim analysis, the 18-month progression-free survival rate was 71.6% (95% confidence interval [CI], 65.5 to 76.8) in the daratumumab group and 50.2% (95% CI, 43.2 to 56.7) in the control group (hazard ratio for disease progression or death, 0.50; 95% CI, 0.38 to 0.65; P<0.001). The overall response rate was 90.9% in the daratumumab group, as compared with 73.9% in the control group (P<0.001), and the rate of complete response or better (including stringent complete response) was 42.6%, versus 24.4% (P<0.001). In the daratumumab group, 22.3% of the patients were negative for minimal residual disease (at a threshold of 1 tumor cell per 10. Among patients with newly diagnosed multiple myeloma who were ineligible for stem-cell transplantation, daratumumab combined with bortezomib, melphalan, and prednisone resulted in a lower risk of disease progression or death than the same regimen without daratumumab. The daratumumab-containing regimen was associated with more grade 3 or 4 infections. (Funded by Janssen Research and Development; ALCYONE ClinicalTrials.gov number, NCT02195479 .).

Topics: Adult; Aged; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Disease-Free Survival; Female; Follow-Up Studies; Humans; Infections; Intention to Treat Analysis; Kaplan-Meier Estimate; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Survival Rate

Topics: Administration, Intravenous; Adult; Aged; Busulfan; Female; Humans; Infections; Male; Melphalan; Middle Aged; Multiple Myeloma; Stem Cell Transplantation; Stomatitis; Transplantation Conditioning; Transplantation, Autologous; Venous Insufficiency; Young Adult

The phase 3 FIRST (Frontline Investigation of REVLIMID + Dexamethasone Versus Standard Thalidomide) trial demonstrated that lenalidomide plus low-dose dexamethasone (Rd) until disease progression (Rd continuous) is an effective treatment option for transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM). Given genetic differences between Asian and Western populations, this subanalysis of the FIRST trial examined the safety and efficacy of Rd (given continuously or for 18 cycles [Rd18]) and MPT (melphalan, prednisone, thalidomide) in 114 Asian patients from Mainland China, South Korea and Taiwan. Efficacy and safety with Rd continuous in Asian patients were consistent with those in the overall study population. The overall response rates were 77·8% for Rd continuous, 57·5% for MPT and 65·8% for Rd18. The risk of progression or death was reduced by 39% with Rd continuous versus MPT and by 35% with Rd continuous versus Rd18. Rd continuous improved the 3-year survival rate compared with MPT (70·2% vs. 56·4%) and Rd18 (58·1%). Common grade 3/4 adverse events in the Rd continuous and MPT arms were neutropenia (25·0% vs. 43·6%), infection (19·4% vs. 28·2%) and anaemia (19·4% vs. 15·4%), respectively. Thromboembolic event rates were low, and no second primary malignancies were observed. Rd continuous is safe and effective in transplant-ineligible Asian patients with NDMM.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Asia; Asian People; Dexamethasone; Disease Progression; Disease-Free Survival; Female; Humans; Infections; Lenalidomide; Male; Melphalan; Middle Aged; Multiple Myeloma; Neutropenia; Prednisone; Remission Induction; Thalidomide; Treatment Outcome

Panobinostat is a histone deacetylase inhibitor that has shown synergistic preclinical anti-myeloma activity when combined with other agents, recently exhibiting synergy with the alkylating agent melphalan (Sanchez et al., Leuk Res 35(3):373-379, 2011). This phase 1/2 trial investigated the safety and efficacy of panobinostat in combination with melphalan for relapsed/refractory multiple myeloma patients. There were four different trial treatment schedules due to tolerability issues, with the final treatment schedule (treatment schedule D) consisting of panobinostat (15 or 20 mg) and melphalan (0.05 or 0.10 mg/kg), both administered on days 1, 3, and 5 of a 28-day cycle. A total of 40 patients were enrolled; 3 in treatment schedule A, 9 in schedule B, 7 in schedule C, and finally 21 schedule D. Patients had been treated with a median of four regimens (range, 1-16) and two prior bortezomib-containing regimens (range, 0-9). Maximum-tolerated dose was established at 20 mg panobinostat and 0.05 mg/kg melphalan in treatment schedule D. Overall, 3 patients (7.5 %) achieved ≥partial response (two very good PRs and one PR) while 23 exhibited stable disease and 14 showed progressive disease. All three responders were enrolled in cohort 2 of treatment schedule B (panobinostat 20 mg thrice weekly continuously with melphalan 0.05 mg/kg on days 1, 3, and 5). Neutropenia and thrombocytopenia were common, with 30.8 and 23.1 % of patients exhibiting ≥grade 3, respectively. Panobinostat + melphalan appears to have tolerability issues in a dosing regimen capable of producing a response. Care must be taken to balance tolerability and efficacy with this combination.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Disease Progression; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Gastrointestinal Diseases; Hematologic Diseases; Humans; Hydroxamic Acids; Indoles; Infections; Kaplan-Meier Estimate; Male; Maximum Tolerated Dose; Melphalan; Middle Aged; Multiple Myeloma; Panobinostat; Recurrence; Salvage Therapy

Graft contamination has been blamed for causing relapse in children with high-risk neuroblastoma (HRNB) after autologous hematopoietic stem cell transplantation (HSCT).. We report the long-term results of hematopoietic reconstitution, post-transplant complications, and clinical outcome of 44 children with HRNB treated with busulfan/melphalan high-dose chemotherapy followed by transplantation of purged CD34+ immunoselected autologous peripheral HSCT. Minimal residual disease (MRD) of grafts was evaluated by anti-GD2 immunofluorescence or tyrosine hydroxylase reverse transcriptase-polymerase chain reaction (RT-PCR).. Contaminating neuroblasts were found in 19/38 grafts (50%) before CD34+ positive selection, and none after (technique sensitivity of one cell in 10(5)). A median of 6.5 × 10(6) CD34+ cells/kg (range 0.8-23.7) were transplanted with only 2% of TRM. Neutrophils and platelet recovery occurred within a median of 12 days (range 9-47) and 44 days (range 12-259), respectively, without any secondary graft failure. Twenty-three percents of patients experienced a sepsis (10/44) and 14% a pyelonephritis (6/44). Recurrence of varicella zoster virus occurred in 21% of patients (9/44). Negative RT-PCR MRD within the leukapheresis product and cis-retinoic acid therapy were significantly and independently associated to a better survival (P < 0.05). Overall and event-free survivals at 5 years post-transplant were at 59.3% and 48.3% respectively.. Besides high rates of manageable infections due to late immune recovery, transplantation with CD34+ immunoselected grafts in HRNB children was feasible and did not affect long-term hematopoiesis.

Topics: Antigens, CD34; Busulfan; Child; Follow-Up Studies; Hematopoiesis; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Humans; Immunomagnetic Separation; Infections; Leukapheresis; Melphalan; Neoplasm, Residual; Neuroblastoma; Survival Analysis; Transplantation, Autologous

The individual risk of infection and requirements for medical treatment after high-dose chemotherapy have been unpredictable. In this prospective, multicenter, open-label study we investigated the potential of granulocyte colony-stimulating factor (G-CSF) responsiveness as a predictor. A total of 168 patients with multiple myeloma or lymphoma received a single dose of subcutaneous G-CSF (lenograstim, 263 μg) after high-dose chemotherapy. Highly variable leukocyte peaks were measured and grouped as low (quartile 1; leukocytes 100-10 100/μL), medium (quartile 2; leukocytes > 10 100-18 300/μL), and high (quartiles 3/4; leukocytes > 18 300-44 800/μL). G-CSF responsiveness (low vs medium vs high) was inversely correlated with febrile neutropenia (77% vs 60% vs 48%; P = .0037); the rate of infection, including fever of unknown origin (91% vs 67% vs 54%; P < .0001); days with intravenous antibiotics (9 vs 6 vs 5; P < .0001); and antifungal therapy (P = .042). In multivariate analysis, G-CSF responsiveness remained the only factor significantly associated with infection (P = .016). In addition, G-CSF responsiveness was inversely correlated with grade 3/4 oral mucositis (67% vs 33% vs 23%; P < .0001). G-CSF responsiveness appears as a signature of the myeloid marrow reserve predicting defense against neutropenic infection after intensive chemotherapy. This study is registered at http://www.clinicaltrials.gov as NCT01085058.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Female; Granulocyte Colony-Stimulating Factor; Humans; Infections; Lenograstim; Lymphoma; Male; Melphalan; Middle Aged; Multiple Myeloma; Multivariate Analysis; Neutropenia; Peripheral Blood Stem Cell Transplantation; Predictive Value of Tests; Prognosis; Prospective Studies; Recombinant Proteins; Risk Factors; Young Adult

Haploidentical SCT (HaploSCT) has been most commonly performed using a myeloablative, TBI-based preparative regimen; however, the toxicity with this approach remains very high. We studied the feasibility of a reduced-intensity conditioning regimen in a phase II clinical trial using fludarabine, melphalan and thiotepa and antithymocyte globulin (ATG) for patients with advanced hematological malignancies undergoing T-cell depleted HaploSCT. Twenty-eight patients were entered in the study. Engraftment with donor-derived hematopoiesis was achieved in 78% of patients after a median of 13 days. Six patients experienced primary graft failure, three out of four tested patients had donor-specific anti-HLA antibodies (DSA) (P=0.001). Toxicity included mostly infections. A total of 21 out of 22 patients with AML/myelodysplastic syndrome (MDS) achieved remission after transplant (16 with relapsed/refractory AML). Five out of the 12 patients (42%) with AML/MDS with <15% BM blasts survived long term as compared with none with more advanced disease (P=0.03). HaploSCT with this fludarabine, melphalan and thiotepa and ATG RIC is an effective, well-tolerated conditioning regimen for patients with AML/MDS with low disease burden at the time of transplant and allowed a high rate of engraftment in patients without DSA. Patients with overt relapse fared poorly and require novel treatment strategies.

Topics: Adolescent; Adult; Antilymphocyte Serum; Child; Female; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Infections; Leukemia, Myeloid, Acute; Male; Melphalan; Middle Aged; Myeloablative Agonists; Myelodysplastic Syndromes; Survival Rate; T-Lymphocytes; Thiotepa; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome; Vidarabine; Young Adult

Dexamethasone alone increases life expectancy in patients with relapsed multiple myeloma (MM); however, no large randomized study has compared dexamethasone and dexamethasone-based regimens with standard melphalan-prednisone in newly diagnosed MM patients ineligible for high-dose therapy. In the Intergroupe Francophone du Myélome (IFM) 95-01 trial, 488 patients aged 65 to 75 years were randomized between 4 regimens of treatment: melphalan-prednisone, dexamethasone alone, melphalan-dexamethasone, and dexamethasone-interferon alpha. Response rates at 6 months (except for complete response) were significantly higher among patients receiving melphalan-dexamethasone, and progression-free survival was significantly better among patients receiving melphalan (P < .001, for both comparisons), but there was no difference in overall survival between the 4 treatment groups. Moreover, the morbidity associated with dexamethasone-based regimens was significantly higher than with melphalan-prednisone, especially for severe pyogenic infections in the melphalan-dexamethasone arm and hemorrhage, severe diabetes, and gastrointestinal and psychiatric complications in the dexamethasone arms. Overall, these results indicated that dexamethasone should not be routinely recommended as first-line treatment in elderly patients with MM. In the context of the IFM 95-01 trial, the standard melphalan-prednisone remained the best treatment choice when efficacy and patient comfort were both considered. These results might be useful in the context of future combinations with innovative drugs.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Disease-Free Survival; Female; Humans; Infections; Interferon-alpha; Male; Melphalan; Multiple Myeloma; Neoplasm Staging; Patient Selection; Prednisone; Survival Analysis; Treatment Outcome

We undertook a comparative study of Pegfilgrastim vs. Filgrastim after high-dose melphalan and autologous peripheral blood stem cell transplantation (APBSCT) in multiple myeloma (MM) patients. Thirty-seven consecutive patients were randomly assigned to receive a single 6 mg dose of Pegfilgrastim on day 1 post-transplant (n = 18 patients) vs. daily subcutaneous injections of Filgrastim 5 microg/kg (n = 19 patients) starting on day 5 post-transplant. The median duration of grade 4 neutropenia in the Pegfilgrastim and Filgrastim groups was 5 and 6 d, respectively (P = ns). The results for the two groups were also not significantly different for time to neutrophil and platelet recovery, but incidence of febrile neutropenia (61.1% vs. 100%, P = 0.003) and duration of febrile neutropenia (1.5 d vs. 4 d, P = 0.005), were lower in the Pegfilgrastim arm. After initial haematopoietic reconstitution, we observed significantly higher value of leukocytes x 10(9) L on day 15 (6.0 vs. 2.7, P = 0.004), in the Pegfilgrastim group compared with the Filgrastim group. This study shows that a single injection Pegfilgrastim can be used with safety and efficacy similar to those provided by daily injections of Filgrastim and it is associated with a decrease incidence of infectious events after APBSCT in MM patients.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Dacarbazine; Female; Filgrastim; Granulocyte Colony-Stimulating Factor; Hematopoiesis; Humans; Infection Control; Infections; Male; Melphalan; Middle Aged; Multiple Myeloma; Myeloablative Agonists; Neutropenia; Nimustine; Peripheral Blood Stem Cell Transplantation; Polyethylene Glycols; Recombinant Proteins; Recovery of Function; Time Factors; Transplantation, Autologous; Vincristine

CBV and BEAM are the two most frequently used regimens for patients with lymphoma undergoing autologous hematopoietic stem-cell transplantation (ASCT). This study compared their morbidity and transplant-related mortality (TRM) in 113 patients with non-Hodgkin's lymphoma (69) and Hodgkin's disease (44) undergoing ASCT between 1990 - 2004. CBV (cyclophosphamide, 6000 mg m(-2); VP-16, 750 mg m(-2); and high-dose BCNU, 800 mg m(-2)) was administered to 75 patients and 38 received BEAM (BCNU, 300 mg m(-2); VP-16, 800 mg m(-2); cytarabine, 800 mg m(-2); melphalan, 140 mg m(-2)). Patients in the BEAM group had a significantly higher median age (p = 0.002) and were more heavily treated before ASCT (p = 0.003). More patients showed active disease at transplant in the BEAM group (p = 0.04). Sinusoidal obstruction syndrome (SOS) was more frequent in the CBV group (11% vs 0%, p = 0.048). There were 20 (18%) transplant-related deaths, 18 in the CBV and two in the BEAM group. Infectious complications (12 patients, seven with pneumonia) and SOS (four) were the most frequent causes of death. The cumulative incidences of TRM were 25% in the CBV and 7% in the BEAM group (p = 0.02). CBV thus produced a higher incidence of SOS and TRM than BEAM in this series.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cyclophosphamide; Cytarabine; Etoposide; Female; Hematopoietic Stem Cell Transplantation; Hepatic Veno-Occlusive Disease; Humans; Infections; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Lymphoid; Male; Melphalan; Middle Aged; Morbidity; Mortality; Podophyllotoxin; Transplantation Conditioning; Transplantation, Autologous

Melphalan & Prednisone (MP) is considered as the standard therapy for Multiple Myeloma (MM) patients not eligible for high-dose therapy. Here, we report the results of a phase I-II study to evaluate the feasibility and efficacy of the association of PLD to the conventional MP regimen during the first six cycles of the front-line therapy for untreated MM patients older than 70. Thirty patients were included in the study with a median age of 77 years (71-84) and a M/F ratio of 17/13. The phase I of the study demonstrated that the maximum tolerable dose of PLD in this setting was 30 mg/m(2), so it was the final dose evaluated in the study. Twenty-nine patients were valuable for response, which was: complete in 4 (14%) partial in 15 (52%) minor/no changes in 7 (24%) and progressive in 3 (10%). The median progression free survival (PFS) was 24 months. The median overall survival (OS) has not been reached yet, with a 3-year probability for OS and PFS of 52 and 37%, respectively. Haematological toxicity was frequent but usually weak/moderate (grades 1 & 2 of the WHO scale) and it was resolved only with dose delays. Infection was a relatively frequent event (30% of patients), but only in 4 cases it was of grade 3. No cases of palmar-plantar erythrodysesthesia were observed. In conclusion, pegylated liposomal doxorubicin can be safely added to the other chemotherapeutic drugs in the treatment of elderly MM patients, which can be very useful for patients in whom novel agents are not tolerated or inefficient.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Doxorubicin; Female; Humans; Infections; Male; Maximum Tolerated Dose; Melphalan; Multiple Myeloma; Polyethylene Glycols; Prednisone; Survival Rate; Treatment Outcome

Sixteen patients with stage III multiple myeloma (MM) and a median age of 51 years were treated with autografting followed by reduced intensity conditioning allotransplantation (RICT). Nine patients are alive in remission at a median of 30 months after their transplants, one patient is alive in relapse and 6 patients died of progressive disease (5) or extensive chronic graft-versus-host disease, infections and progressive disease (1). We suggest that this two-step approach is feasible and it has strong anti-myeloma activity.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Cyclophosphamide; Disease Progression; Disease-Free Survival; Feasibility Studies; Female; Graft vs Host Disease; Granulocyte Colony-Stimulating Factor; Humans; Immunosuppressive Agents; Infections; Male; Melphalan; Middle Aged; Multiple Myeloma; Peripheral Blood Stem Cell Transplantation; Postoperative Complications; Remission Induction; Salvage Therapy; Survival Analysis; Transplantation Conditioning; Transplantation, Autologous; Transplantation, Homologous; Treatment Outcome; Vidarabine; Whole-Body Irradiation

A nonmyeloablative conditioning regimen was investigated in 47 patients with hematological malignancy receiving allogeneic progenitor cells from matched, unrelated donors. The median patient age was 44 years. The majority of patients had high-risk features, including having failed a prior transplantation (29 individuals). Twenty of the transplants were mismatched for HLA class I and/or class II alleles. Recipient conditioning consisted of 20 mg CAMPATH-1H on days -8 to -4, 30 mg/m(2) fludarabine on days -7 to -3, and 140 mg/m(2) melphalan on day -2. Graft-versus-host disease (GVHD) prophylaxis was with cyclosporine A alone. Primary graft failure occurred in only 2 of 44 evaluable patients (4.5%). Chimerism studies in 34 patients indicated that the majority (85.3%) attained initial full donor chimerism. Only 3 patients developed grade III to IV acute GVHD, and no patients have yet developed chronic extensive GVHD. The estimated probability of nonrelapse mortality at day 100 was 14.9% (95% confidence interval [CI], 4.7%-25.1%). With a median follow-up of 344 days (range, 79-830), overall and progression-free survivals at 1 year were 75.5% (95% CI, 62.8%-88.2%) and 61.5% (95% CI, 46.1%-76.8%), respectively. In summary, a nonmyeloablative regimen incorporating in vivo CAMPATH-1H is effective in promoting durable engraftment in most patients and in reducing the risk of severe GVHD following matched unrelated donor transplantation.

Topics: Adolescent; Adult; Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Antineoplastic Combined Chemotherapy Protocols; Female; Graft Survival; Graft vs Host Disease; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Infections; Male; Melphalan; Middle Aged; Survival Analysis; Tissue Donors; Transplantation Chimera; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome; Vidarabine

Sixty-five patients with hematological malignancies (25 multiple myeloma, 18 Hodgkin's disease, 22 non-Hodgkin's lymphomas) who received a carmustine-based regimen followed by autologous PBPC transplantation, were studied retrospectively to evaluate the incidence of post-transplant non-infective pulmonary complications (NIPCs), risk factors predictive of NIPCs, and response to steroids. Carmustine (BCNU) given i.v. at a dose of 600 mg/m2 was combined with etoposide and cyclophosphamide in 40 patients (BCV regimen) and with etoposide and melphalan in 25 patients (BEM regimen). Seventeen of 65 patients (26%) had one episode of NIPCs. The median time to NIPCs was 90 days (52-289). Factors that increased the risk of developing NIPCs on multivariate analysis were female sex (P < 0. 001) and BCV regimen (P < 0.05). All patients with NIPCs received prednisone at a dose of 1 mg/kg body weight for 10 days then tapered by 5 mg every two days; complete response to steroids was achieved in 15 of 17 patients; one unresponsive patient died of interstitial pneumonia. BCNU given at the dose of 600 mg/m2 is well tolerated when associated with melphalan and etoposide. In females and in patients receiving BCNU with cyclophosphamide, a BCNU dose reduction may be advisable. Bone Marrow Transplantation (2000) 25, 309-313.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Child; Child, Preschool; Combined Modality Therapy; Cyclophosphamide; Etoposide; Female; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Infant; Infections; Lung Diseases; Male; Melphalan; Middle Aged; Retrospective Studies; Transplantation, Autologous

High-dose immunoablative chemotherapy with autologous haematopoietic cell support might be beneficial in the treatment of intractable forms of MS. We mobilised PBPC in 11 patients with secondary progressive MS and finally eight patients were grafted after high-dose BEAM chemotherapy with either in vitro or in vivo T cell depletion. Median EDSS and SNRS scores at the time of inclusion were 6.5 (6.5-7.5) and 56 (44-65), respectively. PBPC mobilisation was safe with no serious adverse effects, and without significant aggravation of disability. One patient improved significantly (by 1.0 point on EDSS) after the mobilisation. Two mobilisation failures were observed. No life-threatening events occurred during the transplantation. All grafted patients, except one, at least stabilised their disability status. One patient improved significantly (by 1.5 points on EDSS), two patients improved slightly (by 0.5 points on EDSS), one patient worsened by 1.0 point on the EDSS in 10 months. Improvement occurred with a delay of 2-4 months. Median EDSS and SNRS of grafted patients at the last follow up were 6.5 (5.5-8.5) and 64 (39-73), respectively with median follow-up of 8.5 months. Further follow-up is needed to determine the disease course after complete immune reconstitution. Bone Marrow Transplantation (2000) 25, 525-531.

Topics: Adolescent; Adult; Antigens, CD; Antineoplastic Combined Chemotherapy Protocols; Carmustine; CD4-CD8 Ratio; Cytarabine; Etoposide; Female; Fever; Follow-Up Studies; Graft Survival; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Infections; Leukapheresis; Lymphocyte Subsets; Magnetic Resonance Imaging; Male; Melphalan; Middle Aged; Multiple Sclerosis; Neutropenia; Prognosis; Severity of Illness Index

Interferon (IFN) has demonstrated activity in the treatment of patients with multiple myeloma. A previous Eastern Cooperative Oncology Group (ECOG) study suggested that the rates of complete response (CR) and survival were increased with a regimen that alternated IFN with chemotherapy. The current study was designed to evaluate the effect of adding alternating cycles of IFN or early intensification with high dose cyclophosphamide (HiCy) to the VBMCP regimen for the treatment of multiple myeloma patients.. From February 1988 to May 1992, the ECOG entered previously untreated patients with active multiple myeloma on a study in which they were randomized to VBMCP (vincristine 1.2 mg/m(2) administered intravenously [i.v.] on Day 1, BCNU 20 mg/m(2) i.v. on Day 1, melphalan 8 mg/m(2) administered orally [p.o.] on Days 1-4, cyclophosphamide 400 mg/m(2) i.v. on Day 1, and prednisone 40 mg/m(2) p.o. on Days 1-7; 5-week cycles) or VBMCP + rIFN(alpha2), the latter given at 5 Mu/m(2) 3 times a week starting on Day 22 of each 6-week cycle after 2 initial cycles of VBMCP. Patients younger than 70 years were also randomized to a third treatment that substituted cyclophosphamide 600 mg/m(2) i.v. on Days 1-4 and prednisone 100 mg/m(2) p.o. on Days 1-4 for cycles 3 and 5 of VBMCP (VBMCP + HiCy). Treatment was continued for 2 years.. Of the 653 patients entered, 628 were eligible for the study. All were evaluated for response. With median follow-up for surviving patients of 54 months, the median survival duration was 42 months-1 year longer than usually reported for melphalan combined with prednisone. A comparison of the three regimens revealed no significant difference in the rates of survival or objective response (OR). However, CRs were increased among patients treated with VBMCP + rIFN(alpha2) compared with VBMCP alone (18% vs. 10%, P = 0.03). Patients treated with VBMCP + rIFN(alpha2) had a longer response duration than patients treated with VBMCP alone (30 vs. 25 months, P = 0.035). There was a greater response rate with the IFN regimen among elderly patients (OR and CR = 67% and 31%, respectively) and patients with immunoglobulin A (IgA) myeloma (OR and CR = 83% and 29%, respectively). Severe infections were seen as often with VBMCP as with VBMCP + rIFN(alpha2) (13% vs. 15%), but they were more frequent with VBMCP + HiCy (25%).. VBMCP + rIFN(alpha2) yields a higher rate of CR and a longer response duration than VBMCP alone but appears to make no difference in the rates of overall response or survival compared with VBMCP or VBMCP + HiCy. The superior ability of VBMCP + rIFN(alpha2) induction therapy to produce CR and more durable responses, as well as its activity in older patients and in those with IgA myeloma, suggest that this therapy has important biologic activity in myeloma and merits further clinical investigation.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cardiovascular Diseases; Carmustine; Cyclophosphamide; Hematologic Diseases; Humans; Infections; Interferon Type I; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Recombinant Proteins; Survival Analysis; Vincristine

The aim of this phase II study was to determine the feasibility of using two (tandem) courses of high-dose alkylating agents with bone marrow or peripheral blood progenitor cell support in women with stage IV breast cancer. Women with stage IV breast cancer who had achieved a CR or PR during conventional chemotherapy were enrolled in a phase II trial of high-dose cyclophosphamide 7500 mg/m2 and thiotepa 675 mg/m2 (C+T) followed within 180 days by high-dose melphalan (M) 140 mg/m2. Bone marrow and/or GM-CSF mobilized peripheral blood hematopoietic progenitor cells were used to support high-dose C+T and high-dose M. Twenty-seven women were enrolled in this trial. The median age was 45 years (range 32-56). The median PS was 0 and all patients had achieved either a CR (4/27, 15%) or PR (23/27, 85%) to conventional chemotherapy. All 27 women underwent high dose C+T. The predominant toxicities were mucositis (81%), and diarrhea (81%); two patients (7%) died from infectious complications. Following C+T, the median time to hematologic recovery for neutrophils (ANC > 500 cells/mu 1) was 12 days and for platelets (>20 000 cell/mu 1), 23 days. Following C+T, 18 of 22 patients received high dose M; the predominant toxicities were nausea, vomiting (70%), and mucositis (91%). The median time to hematologic recovery for the ANC was 13 days and for platelets, 18 days. The overall response after high dose C+T and high dose M was 67% (CR, 15/27 patients (56%) and PR* (complete resolution of all measurable disease but persistent lytic disease or positive bone scan) 3/27 patients (11%). With median follow-up of 24 months, the actuarial freedom from relapse or treatment failure is 56% at 24 months. At 30 months 56% of patients are alive. For patients who achieve a CR or PR* the actuarial freedom from relapse or treatment failure at 24 months is 88%. In women with stage IV breast cancer who attain a CR or PR to conventional chemotherapy, tandem high-dose chemotherapy with ABMT can lead to prolonged relapse-free survival.

Topics: Adult; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Breast Neoplasms; Cyclophosphamide; Disease-Free Survival; Feasibility Studies; Female; Follow-Up Studies; Gastrointestinal Diseases; Hematopoietic Stem Cell Transplantation; Humans; Infections; Leukocyte Count; Life Tables; Melphalan; Middle Aged; Palliative Care; Remission Induction; Survival Analysis; Thiotepa; Treatment Outcome

Topics: Amyloid; Amyloidosis; Anemia; Antineoplastic Agents; Clinical Trials as Topic; Cyclophosphamide; Hodgkin Disease; Humans; Immunodiffusion; Immunoelectrophoresis; Immunoglobulin G; Immunoglobulin M; Immunoglobulins; Infections; Leukemia, Lymphoid; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Melphalan; Multiple Myeloma; Prognosis; Pyelonephritis

High-dose BEAM chemotherapy (BCNU, etoposide, Ara-C, and melphalan) followed by autologous hematopoietic stem cell transplantation is frequently used as consolidative therapy for patients with recurrent or refractory Hodgkin or non-Hodgkin lymphoma. The BEAM regimen has traditionally been administered over 6 days in the hospital, with patients remaining hospitalized until hematologic recovery and clinical stability. In an effort to reduce the length of hospitalization for these patients, our institution has transitioned from inpatient (IP) to outpatient (OP) administration of BEAM conditioning. Here, we report the results of an analysis of the feasibility, cost, complications, and outcomes for the initial group of patients who received OP BEAM compared to a prior cohort of patients who received IP BEAM. Patient and disease characteristics were comparable for the two cohorts, as were engraftment kinetics. Length of hospital stay was reduced by 6 days for the OP cohort (P < 0.001), resulting in a cost savings of more than $17,000 per patient. Fewer complications occurred in the OP cohort, including severe enteritis (P = 0.01), organ toxicities (P = 0.01), and infections (P = 0.04). Overall survival rate up to 3 years posttransplant was better for the OP cohort (P = 0.02), likely due to differences in posttransplant therapies. We conclude that OP administration of BEAM conditioning is safe and may offer significant advantages, including decreased length of hospitalization, reduced costs, decreased risks for severe toxicities and infectious complications, and likely improvement in patient satisfaction and quality of life.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Combined Modality Therapy; Cost-Benefit Analysis; Cytarabine; Female; Follow-Up Studies; Health Care Costs; Hematopoietic Stem Cell Transplantation; Humans; Infections; Kaplan-Meier Estimate; Lymphoma; Male; Melphalan; Middle Aged; Outpatients; Podophyllotoxin; Transplantation Conditioning; Transplantation, Autologous; Young Adult

We defined the epidemiology and clinical predictors of infection in patients with multiple myeloma (MM) receiving immunomodulatory drugs (IMiDs), proteasome inhibitors (PI) and autologous haematopoietic stem cell transplant (ASCT) in a large longitudinal cohort study. Clinical and microbiology records of patients with MM diagnosed between January 2008 and December 2012 were reviewed to capture patient demographics, characteristics of myeloma and infections (type, severity, outcomes). Conditional risk set modelling was used to determine clinical predictors of infection. One hundred and ninety-nine patients with MM with 771 episodes of infection were identified. 44·6% of infections were clinically defined, 35·5% were microbiologically defined and 19·9% were fever of unknown focus. There was a bimodal peak in incidence of bacterial (4-6 and 70-72 months) and viral infections (7-9 and 52-54 months) following disease diagnosis. Chemotherapy regimens high-dose melphalan [hazard ratio (HR) = 2·07], intravenous cyclophosphamide (HR = 1·96) and intensive combination systemic chemotherapy (HR = 1·86) and cumulative doses of corticosteroid (HR = 3·06 at highest dose) were independently associated with increased risk of infection overall (P < 0·05). IMiDs and PI and other clinical factors were not independently associated with increased risk of infection. New approaches to prevention and treatment of infection should focus upon identified periods of risk and treatment-related risk factors.

Topics: Adrenal Cortex Hormones; Aged; Antineoplastic Combined Chemotherapy Protocols; Autografts; Cyclophosphamide; Female; Follow-Up Studies; Hematopoietic Stem Cell Transplantation; Humans; Immunologic Factors; Infections; Male; Melphalan; Middle Aged; Multiple Myeloma; Risk Factors

Topics: CD4-Positive T-Lymphocytes; Female; Humans; Infections; Male; Melphalan; Multiple Myeloma; Stem Cell Transplantation

Neutropenia following high-dose chemotherapy is associated with a substantial risk of infectious complications. The aim of this study was to identify variables in residual leukocyte subsets during neutropenia that are predictive for neutropenic fever.. Residual leukocytes in the peripheral blood on day 5 after autologous blood stem cell transplantation were analyzed by three-color flow cytometry in 55 consecutive patients with multiple myeloma. Furthermore, the number of T cells transfused with the autografts was determined.. Neutrophil counts at day 5 and neutrophil engraftment were similar in patients with and without neutropenic fever. Low absolute lymphocyte, CD4(+) CD28(+) and CD45RO(+) CD28(+) counts at day 5 were associated with neutropenic fever. T-cell counts at day 5 correlated with the CD3(+) cell number in the graft.. Our data show that the absolute lymphocyte, CD4(+) CD28(+) and CD45RO(+) CD28(+) counts play a role in host defense during severe neutropenia. The T-cell number in the graft may help to identify patients at high risk of neutropenic infections.

Topics: Aged; CD28 Antigens; CD4-Positive T-Lymphocytes; Cell Count; Female; Humans; Immunophenotyping; Infections; Male; Melphalan; Middle Aged; Multiple Myeloma; Neutropenia; Prognosis; Prospective Studies; Risk; Stem Cell Transplantation; Transplantation, Autologous

Topics: CD4-Positive T-Lymphocytes; Female; Humans; Infections; Male; Melphalan; Multiple Myeloma; Stem Cell Transplantation

Treatment-related mortality (TRM) is not uncommon in patients after the first course of vincristine-doxorubicin-dexamethasone (VAD) chemotherapy,but quite rare after melphalan-prednisolone (MP). This motivated us to compare the rates of TRM after the first course of VAD with those after the first course of MP. We retrospectively assessed survival and TRM in 179 patients treated for multiple myeloma with either MP or VAD. Survival was similar in two groups (P 50.463 in log-rank test). However, TRM was significantly higher inpatients after the first course of VAD (11 in 100 patients, 11.0%) than that after the first course of MP (1 in 79, 1.3%; P 5 0.010). Poor performance status (P 5 0.004) and advanced age (P 5 0.009) before treatment were independent significant factors associated with TRM after the first course of induction therapy. Pyogenic infection was the major cause of TRM after VAD (9 in 11, 81.8%). We concluded that VAD should be cautiously used as induction therapy in multiple myeloma patients, especially in elderly and/or those with poor performance status.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Doxorubicin; Female; Follow-Up Studies; Hemorrhage; Humans; Incidence; Infections; Kidney; Kidney Diseases; Male; Melphalan; Multiple Myeloma; Neoplasm Staging; Prednisone; Retrospective Studies; Survival Analysis; Vincristine

Since 1997, 32 newly diagnosed multiple myeloma patients responsive to DAV chemotherapy were autografted with idarubicin-intensified busulphan-melphalan (ida-bu-mel). Main endpoints of the study were transplant-related toxicity, overall survival (OS) and progression-free survival (PFS). The results were compared with a historical control group of 38 patients treated with the 'standard' bu-mel regimen. Concerning time to engraftment, no significant difference was observed between the two groups, while toxicity was significantly higher in the intensive conditioning group, regarding grade IV mucositis, duration of profound neutropenia, incidence of infections and platelet requirement. Five-year OS and PFS are 73 versus 78% and 37 versus 48% for the intensive and standard regimen, respectively (p value not significant). The ida-bu-mel schedule appears to be a feasible and effective regimen for newly diagnosed multiple myeloma patients; nevertheless, no apparent benefit in OS and PFS arises from the comparison with a historical control treated with standard bu-mel, which is better tolerated and at least equally effective.

Topics: Adult; Antibiotics, Antineoplastic; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Dacarbazine; Female; Graft Survival; Humans; Idarubicin; Infections; Male; Melphalan; Middle Aged; Mucositis; Multiple Myeloma; Neutropenia; Nimustine; Peripheral Blood Stem Cell Transplantation; Transplantation Conditioning; Transplantation, Autologous; Vincristine

Severe infections related to treatment are common in patients with multiple myeloma (MM). Genetic polymorphisms of the immune system may influence the risk of infections. Mannan-binding lectin (MBL) is part of the innate immune system, and individuals homozygous for wild-type MBL encoding gene (MBL2) have a well-functioning MBL pathway of complement activation, in contrast to individuals carrying one or two variant alleles. We evaluated 113 courses of high-dose melphalan and autologous stem cell transplantation (ASCT) in patients with MM. Patients homozygous for wild-type MBL2 had a significantly reduced risk of septicaemia during the ASCT procedure compared with patients carrying variant MBL2: Odds Ratio (OR) 0.19 (95% CI: 0.04-0.77), (P=0.02) in multivariate analysis. The risk of Common Toxicity Criteria grade 3-4 infections in general was not affected by wild-type MBL2: OR 1.20 (95% CI: 0.52-2.78), (P=0.67). The findings indicate that MBL to some extent protects against the most severe infections during ASCT.

Topics: Adult; Aged; Female; Hematopoietic Stem Cell Transplantation; Humans; Immunity; Infections; Male; Mannose-Binding Lectin; Melphalan; Middle Aged; Multiple Myeloma; Polymorphism, Genetic; Retrospective Studies; Risk; Transplantation, Autologous

Reduced-intensity regimens (RIRs) are being used with increasing frequency in patients with non-Hodgkin's lymphoma (NHL) undergoing allogeneic transplantation. The impact of dose reduction on relapse and survival has not been extensively studied. We performed a retrospective analysis of 88 patients conditioned with conventional myeloablative regimens (CMRs) (n = 48) and an RIR (n = 40) of fludarabine 125 mg/m(2) and melphalan 140 mg/m(2). Compared with the patients receiving CMR, those receiving RIR were older, had more often failed autologous transplantation, and had more frequently received peripheral blood and unrelated donor transplants. Graft-versus-host disease prophylaxis was provided with cyclosporine + methotrexate +/- prednisone for the CMR and with cyclosporine + mycophenolate +/- methotrexate for the RIR. The relapse rate was significantly lower in the patients receiving CMR than in those receiving RIR (13% vs 28%; P = .05). The 1-year transplantation-related mortality rate was 33% for CMR and 28% for RIR (P = .40). Kaplan-Meier 2-year overall survival and progression-free survival were 52% and 46% for CMR versus 53% and 40% for RIR (P = not significant). Using cumulative incidence functions based on competing risks, univariate analysis, and treatment-related prognostic factors, we found that higher treatment intensity (P = .03; relative risk [RR] = 35%) and absence of previous autologous transplantation (P = .0007; RR = 20%) were associated with a lower relapse rate. Using a Cox univariate proportional hazards model, we found that chemosensitive disease at transplantation (P = .05; RR = 57%) and absence of previous autologous transplantation (P = .002; RR = 37%) were associated with improved survival. Our observation of similar survival in the patients receiving CMR and those receiving RIR confirms that RIRs are feasible alternatives for high-risk patients with NHL; however, the data suggest that reduced treatment intensity and previous autologous transplantation are associated with increased relapse.

Topics: Adolescent; Adult; Aged; Busulfan; Cause of Death; Cohort Studies; Cyclophosphamide; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Female; Graft vs Host Disease; Hepatic Veno-Occlusive Disease; Humans; Infections; Kaplan-Meier Estimate; Lung Diseases, Interstitial; Lymphoma, Follicular; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Mantle-Cell; Lymphoma, Non-Hodgkin; Lymphoma, T-Cell; Male; Melphalan; Middle Aged; Peripheral Blood Stem Cell Transplantation; Postoperative Complications; Proportional Hazards Models; Reoperation; Retrospective Studies; Risk Factors; Survival Analysis; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome; Vidarabine; Whole-Body Irradiation

Although nonmyeloablative conditioning regimen transplantations (NMTs) induce engraftment of allogeneic stem cells with a low spectrum of toxicity, graft-versus-host disease (GVHD) remains a significant cause of morbidity and mortality. In vivo T-cell depletion, using alemtuzumab, has been shown to reduce the incidence of GVHD. However, this type of maneuver, although reducing GVHD, may have an adverse impact on disease response, because NMTs exhibit their antitumor activity by relying on a graft-versus-malignancy effect. To explore the efficacy of alemtuzumab compared with methotrexate (MTX) for GVHD prophylaxis, we have compared the results in 129 recipients of a sibling NMT enrolled in 2 prospective studies for chronic lymphoproliferative disorders. Both NMTs were based on the same combination of fludarabine and melphalan, but the United Kingdom regimen (group A) used cyclosporin A plus alemtuzumab, whereas the Spanish regimen (group B) used cyclosporin A plus MTX for GVHD prophylaxis. Patients receiving alemtuzumab had a higher incidence of cytomegalovirus (CMV) reactivation (85% versus 24%, P <.001) and a significantly lower incidence of acute GVHD (21.7% versus 45.1%, P =.006) and chronic GVHD (5% versus 66.7%, P <.001). Twenty-one percent of patients in group A and 67.5% in group B had complete or partial responses 3 months after transplantation (P <.001). Eighteen patients in group A received donor lymphocyte infusions (DLIs) to achieve disease control. At last follow-up there was no difference in disease status between the groups with 71% versus 67.5% (P =.43) of patients showing complete or partial responses in groups A and B, respectively. No significant differences were observed in event-free or overall survival between the 2 groups. In conclusion, alemtuzumab significantly reduced GVHD but its use was associated with a higher incidence of CMV reactivation. Patients receiving alemtuzumab often required DLIs to achieve similar tumor control but the incidence of GVHD was not significantly increased after DLI.

Topics: Adult; Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Antineoplastic Combined Chemotherapy Protocols; Cyclosporine; Disease-Free Survival; Female; Graft vs Host Disease; Graft vs Tumor Effect; Hematologic Neoplasms; Humans; Immunosuppressive Agents; Incidence; Infections; Life Tables; Lymphoproliferative Disorders; Male; Melphalan; Methotrexate; Middle Aged; Peripheral Blood Stem Cell Transplantation; Prospective Studies; Spain; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome; United Kingdom; Vidarabine

Register data suggest that patients with Hodgkin's disease (HD) given high-dose therapy (HDT) with peripheral blood progenitor cells (PBPC) have a less favourable prognosis as compared to those given bone marrow as stem cell support. Since this can be due to infusion of tumour cells contaminating the PBPC grafts, we initiated a feasibility study in which PBPC grafts from HD patients were purged by CD34(+) cell enrichment. Controversy exists about whether the use of CD34(+) enriched stem cells leads to a delayed haematological and immune reconstitution. We compared these parameters, including risk of infections and clinical outcome after HDT, in patients with HD given either selected CD34(+) cells or unmanipulated PBPC as stem cell support. From October 1994 to May 2000, 40 HD patients with primary refractory disease or relapse were treated with HDT and supported with either selected CD34(+) cells (n = 21) or unmanipulated PBPC (n = 19) as stem cell support. All patients had chemosensitive disease at the time of transplantation. A median of 5.8 (range 2.7-20.0) vs 4.5 (range 2.3-17.6) x 10(6) CD34(+) cells per kilo were reinfused in the CD34(+) group and PBPC group, respectively. No difference was observed between the two groups with regard to time to haematological engraftment, reconstitution of B cells, CD56(+) cells and T cells at 3 and 12 months and infectious episodes after HDT. Two (5%) treatment-related deaths, one in each group, were observed. The overall survival at 4 years was 86% for the CD34(+)group and 74% for the PBPC group with a median follow-up of 37 months (range 1-61) and 46 months (range 4-82), respectively (P = 0.9). The results of this study demonstrate that the use of CD34(+) cells is safe and has no adverse effects either with respect to haematological, immune reconstitution or to infections after HDT.

Topics: Adolescent; Adult; Antigens, CD34; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Dexamethasone; Etoposide; Feasibility Studies; Female; Follow-Up Studies; Graft Survival; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Hodgkin Disease; Humans; Infections; Male; Melphalan; Middle Aged; Neutropenia; Radiotherapy, Adjuvant; Retrospective Studies; Risk; Safety; Salvage Therapy; Survival Analysis; Survival Rate; Transplantation Conditioning; Treatment Outcome

Infectious complications were retrospectively analyzed in 129 transplants, performed in 90 patients, to identify characteristics that qualify breast cancer patients for outpatient-based PBSCT. Thirty-one cases (24%) did not develop fever. Of the remaining 98 cases, 84.7% developed fever during severe neutropenia. On univariate analysis, disease stages II-III, first PBSCT, mucositis grades II-IV and the use of two alkylators were associated with a higher risk of fever development. The latter two factors also affected fever occurrence on multivariate analysis. A longer median time to fever onset was observed in patients conditioned with single as compared to double alkylating agent-containing regimens (respectively 8th vs 6th day, P < 0.00001). As compared with metastatic breast cancer (MBC), high risk breast cancer showed a 2.3-fold increased risk of developing early fever during neutropenia (CI 2.3-3.8), remaining the only variable still significant on multivariate analysis (P = 0.0039). Combination antibiotic therapy was equivalent to single agent therapy. Patients suffering from microbiologically documented fever were at higher risk of undergoing second-line antibiotic therapy. In conclusion, MBC patients treated with a conditioning regimen containing only one alkylating agent and adequate prophylaxis for mucositis may qualify for outpatient-based PBSCT on the basis of a lower risk of infection.

Topics: Adult; Aged; Ambulatory Care; Anti-Bacterial Agents; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carboplatin; Combined Modality Therapy; Cyclophosphamide; Docetaxel; Drug Therapy, Combination; Female; Fever; Hematopoietic Stem Cell Transplantation; Humans; Immunocompromised Host; Infection Control; Infections; Inflammation; Melphalan; Middle Aged; Mitoxantrone; Mucous Membrane; Multivariate Analysis; Neutropenia; Paclitaxel; Patient Selection; Retrospective Studies; Risk; Taxoids; Thiotepa; Transplantation Conditioning

Multiple-cycle high-dose therapy with autologous hematopoietic progenitor cell (AHPC) support has been used to deliver dose-intensive therapy. We have used this approach as well as single-cycle high-dose therapy in treating patients with metastatic breast cancer. We present the outcomes of multiple-cycle high-dose therapies and compare them with those resulting from single-course high-dose therapies performed at a single institution. Fifty-five patients received 4 cycles of intensive chemotherapy with AHPC support. Three multicycle regimens were sequentially applied. Twenty patients were enrolled to receive 4 cycles of high-dose mitoxantrone, thiotepa, and cyclophosphamide. Nineteen subsequent patients received this regimen modified by the incorporation of paclitaxel. Sixteen patients received 2 cycles of high-dose melphalan, thiotepa, and paclitaxel and 2 cycles of mitoxantrone, thiotepa, and paclitaxel. The results of all 3 multiple-cycle therapies are compared with those of 55 contemporaneous patients with metastatic breast cancer who received a single course of high-dose cyclophosphamide and thiotepa or cyclophosphamide, cisplatin, and BCNU (carmustine) with hematopoietic cell rescue. Multiple-cycle therapy was associated with more infectious complications, increased transfusion requirements, and increased hospital admissions. However, there were no significant differences in outcomes between the groups. For 55 patients who received multiple-cycle therapy, the actuarial 3-year overall survival rate was 36% (95% confidence interval [CI] 23%-49%); freedom from progression and event-free survival were both 15% (CI 5%-25%). The median time to disease progression and median survival were 1.0 and 1.6 years, respectively. For the 55 patients who underwent a single course of high-dose therapy, the 3-year overall survival was also 36% (CI 18%-54%), whereas freedom from progression and event-free survival were both 19% (CI 7%-31%). The median time to progression and median survival were 0.8 and 2.2 years, respectively. Within the constraints of this patient population, the outcomes of 4 cycles of high-dose therapy with AHPC support were not superior to those resulting from single courses of high-dose therapy in the treatment of patients with metastatic breast cancer.

Topics: Adjuvants, Pharmaceutic; Adult; Antineoplastic Combined Chemotherapy Protocols; Blood Transfusion; Breast Neoplasms; Carmustine; Cisplatin; Combined Modality Therapy; Cyclophosphamide; Disease Progression; Dose-Response Relationship, Drug; Female; Hematopoietic Stem Cell Transplantation; Humans; Infections; Melphalan; Middle Aged; Mitoxantrone; Paclitaxel; Survival Rate; Thiotepa; Time Factors; Transplantation, Autologous

Autologous peripheral stem cell transplantation (APSCT) is increasingly used for various hematologic malignancies and solid tumors. The objective of this study was to analyze the immune reconstitution after APSCT and see if there was any correlation with diagnosis, age, type of high-dose therapy, CD34(+) selection of the autograft and double vs single APSCT.. Lymphocyte subset recovery was studied in 46 consecutive patients with hematologic malignancies and breast cancer, who underwent APSCT. Eleven patients with multiple myeloma received tandem autografts. Thirty-one patients were given total body irradiation (TBI) as part of the high-dose treatment. Eighteen patients received a CD34(+) selected graft. The percentage and absolute numbers of lymphocyte populations, T-cells (CD2(+), CD3(+)), B-cells (CD19(+)), NK cells (CD56(+ )CD3(-) and CD16(+)CD3(-)) and T-cell subpopulations (CD4(+), CD8(+), CD4(+)CD45RA(+), CD4(+ )CD45RO(+), CD4(+)DR(+), CD8(+ )CD45RO(+), CD8(+)DR(+)), were monitored with flow cytometry during the first year after APSCT.. The total B-cell (CD19(+)) and T-cell (CD3(+)) counts were reconstituted to normal levels 2-4 months after APSCT. All patients had a low CD4/CD8 ratio during the observation period, related to both a low number of CD4(+) cells and elevated numbers of CD8(+) cells. The low number of CD4(+) cells was due to a persistently low level of naive CD4(+)CD45RA(+) cells. A high proportion of the CD8+ cells displayed a phenotype compatible with activated T-cells (CD8(+)DR(+)) up to 10 months after autografting. The number of NK cells (CD56(+)3(-) or CD16(+)3(-)) reached normal values within one month post-transplant. No single variable, such as diagnoses, age, TBI as part of the high-dose treatment, tandem autografting or CD34(+) selection of the graft, influenced the immune or hematopoietic reconstitution and no correlation with documented infectious complications was found.. Despite heterogeneity of diseases, age, initial treatment and high-dose regimens, lymphocyte subset analysis did not reveal any differences in hematopoietic or immune reconstitution. All patients had a low CD4(+)/CD8(+) ratio during at least the first year post-transplant, caused by a persistent increase of CD8(+) lymphocytes and a constant reduction of CD4(+) lymphocytes, making the patients susceptible to infections for a prolonged period of time post-transplant.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Diseases; Breast Neoplasms; Carmustine; Cell Lineage; Combined Modality Therapy; Cytarabine; Disease Susceptibility; Female; Graft Survival; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Infections; Lymphocyte Count; Lymphocyte Subsets; Lymphopenia; Male; Melphalan; Middle Aged; Podophyllotoxin; Sweden; Transplantation Conditioning; Transplantation, Autologous

Limited data are available concerning feasibility and toxicity of progenitor cell mobilization and high-dose therapy (HDT) supported by peripheral blood stem cell transplantation (PBSCT) in elderly patients (>/=60 years) with non-Hodgkin's lymphoma (NHL). From 1995 to 1999, 17 elderly NHL patients (median age 63 years, range 60-70) entered our HDT program and were mobilized with CY (4 g/m2) followed by G-CSF. Mobilization was successful in 13 patients, who then received BEAM or BEAC followed by PBSCT. The feasibility and toxicity of progenitor cell mobilization and HDT in the elderly patients were compared with experiences in 62 NHL patients <60 years (median 46 years, range 16-59), who received the same mobilization protocol and of whom 48 patients received HDT supported by PBSCT. No significant differences were observed between these groups in the success rate of progenitor cell mobilization, in the number of CD34-positive cells collected or in the number of aphereses needed. HDT appeared to be somewhat more toxic in the elderly patients: a higher peak CRP value (P = 0.08) and longer in-hospital stay (P = 0. 05) were observed. No differences were found in transplant-related mortality or severe organ toxicity between these age groups except for oral mucositis grade >2, which tended to be more common in the elderly patients (P = 0.07). We conclude that progenitor cell mobilization and HDT supported by PBSCT is also feasible in selected elderly patients with NHL. Bone Marrow Transplantation (2000) 26, 737-741.

Topics: Adolescent; Adult; Age Factors; Aged; Antigens, CD34; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cyclophosphamide; Cytarabine; Disease Progression; Etoposide; Female; Graft Survival; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Humans; Infections; Lymphoma, Non-Hodgkin; Male; Melphalan; Middle Aged; Podophyllotoxin; Survival Rate; Time Factors; Transplantation Conditioning

We conducted a pilot study in 20 patients with high-risk or recurrent/refractory non-Hodgkin's lymphoma (NHL) using high-dose sequential chemotherapy (HDSC) and autologous hematopoietic cell transplantation (AHCT). After cytoreduction with standard salvage therapy, HDSC/AHCT was administered in 4 phases at 2- to 4-week intervals. Phase 1 consisted of cyclophosphamide 7 g/m2 followed by granulocyte colony-stimulating factor (G-CSF) at 10 microg/kg per day and leukapheresis upon recovery from white blood cell nadir. The hematopoietic cell product was enriched by Percoll gradient separation and purged with a B-cell or T-cell monoclonal antibody panel and complement. Phase 2 consisted of methotrexate 8 g/m2 with leucovorin rescue and vincristine 1.4 mg/m2. Phase 3 was etoposide 2 g/m2 with G-CSF 5 microg/kg per day. In phase 4, the preparative regimen of mitoxantrone 60 mg/m2 and melphalan 180 mg/m2 was administered followed by AHCT. The NHL histologies were diffuse large cell, follicular/diffuse mixed, small noncleaved cell, T-cell-rich B-cell, lymphoblastic, and peripheral T cell. The remission status was first partial remission (PR1; n = 1) or beyond first complete remission (post-CR1; n = 19). Of the 20 patients enrolled, 11 proceeded through all 4 phases. Nine were removed from the study after the first or second phase because of progressive disease (n = 5), poor hematopoietic cell mobilization (n = 1), excessive toxicity (n = 2), and chronic active hepatitis C (n = 1). Treatment-related toxicities in the remaining 11 transplant recipients were cardiomyopathy, hemorrhagic cystitis, persistent cytopenias, acute renal failure, abnormal liver function test results, and infectious complications. There were no treatment-related deaths. Eight of the 11 transplant recipients were alive, 6 without disease, at a median follow-up of 2.7 years. The estimated median 2-year event-free survival was 55%, and overall survival was 70%. We conclude that HDSC/AHCT in refractory/recurrent NHL is associated with considerable acute and chronic toxicities. Given the toxicity profile, efficacy data were not sufficiently promising to warrant further study.

Topics: Acute Kidney Injury; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Diseases; Bone Marrow Purging; Cardiomyopathies; Chemical and Drug Induced Liver Injury; Combined Modality Therapy; Cyclophosphamide; Cystitis; Disease Progression; Disease-Free Survival; Drug Administration Schedule; Etoposide; Female; Follow-Up Studies; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Hemorrhage; Humans; Infections; Leucovorin; Life Tables; Lymphoma, Non-Hodgkin; Male; Melphalan; Methotrexate; Middle Aged; Mitoxantrone; Pilot Projects; Salvage Therapy; Survival Analysis; Survival Rate; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome; Vincristine

This study reports a large cooperative experience in myeloablative therapy and bone marrow rescue undertaken to define better the outcome of children with disseminated neuroblastoma after megatherapy. Between 1984 and 1993, 135 children underwent myeloablative therapy with bone marrow transplantation (BMT) in nine Italian Centres. One hundred and seventeen children received unpurged autologous BMT, five allogeneic BMT and 13 peripheral blood progenitor cells as rescue. Of these 135 children, 57 were in 1st CR, 11 in 2nd or subsequent CR, 42 in 1st PR, and 25 had more advanced disease. Twelve children (9%) died of toxicity, 86 relapsed or progressed at 1-68 months (median 7 months) and 80 of these subsequently died of progressive disease. Forty-three children are still alive with 37 in continuous remission at a median of 65 months (30-123 months) after BMT. Overall and disease-free survival at 8 years are 28.5% (s.e. 4.3) and 26% (s.e. 4), respectively. Disease-free survival is 34.6% (s.e. 6.7) for the patients grafted in 1st complete remission, 23.6% (s.e. 6.6) for patients grafted in 1st partial remission, 36.4% (s.e. 14.5) for patients grafted in 2nd or subsequent CR, and 8% (5.4) for patients with advanced disease. We conclude these data confirm that early toxicity of myeloablative therapy is manageable and that myeloablative therapy with bone marrow rescue may contribute to an improved long-term survival of children with disseminated neuroblastoma but the objective of cure of all patients remains distant.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Combined Modality Therapy; Disease-Free Survival; Female; Humans; Infant; Infant, Newborn; Infections; Italy; Liver Diseases; Male; Melphalan; Neuroblastoma; Registries; Survival Analysis; Survival Rate; Transplantation Conditioning; Treatment Outcome; Vincristine; Whole-Body Irradiation

Carboplatin and melphalan are two drugs whose toxicity profile makes them suitable for use in high doses followed by stem cell rescue. We report the use of high-dose carboplatin, with the dose based on glomerular filtration rate (GFR), combined with melphalan followed by autologous stem cell rescue in children with advanced stage or chemoresistant solid tumours. Thirty children were treated. After multiagent induction chemotherapy before BMT, 13 were in CR, five in VGPR, 11 in PR and one had progressive disease. They received melphalan, 180 mg/m2 and carboplatin, followed by autologous stem cell rescue. The dose of carboplatin was varied by GFR rather than fixed by surface area. The dose given ranged from 0.7 to 2.6 g/m2. Haematological and gastrointestinal toxicities were severe. Life-threatening or fatal toxicity was attributable to opportunistic infection in two cases and regimen-related in two cases. Of the 30 patients, 15 are alive and 13 disease-free at 4-36 months post-BMT. This simple two-drug combination has been used as consolidation of initial remission for patients with high-risk tumours. The toxicity is severe but tolerable. Use of a carboplatin dose based on GFR should optimise effectiveness in patients with good renal function and avoid excessive toxicity where renal function is impaired.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Diseases; Carboplatin; Child; Child, Preschool; Disease-Free Survival; Female; Glomerular Filtration Rate; Hematopoietic Stem Cell Transplantation; Humans; Infant; Infections; Kidney Diseases; Male; Melphalan; Neoplasms; Neuroblastoma; Treatment Outcome

Among 62 children over 1 year of age at diagnosis, who were treated for stage IV neuroblastoma, 33 entered complete remission (CR) or good partial remission (GPR) after conventional therapy and received high-dose chemotherapy (HDC) with in vitro purged autologous bone marrow transplantation (ABMT) as consolidation therapy. The HDC was a combination of carmustine (BCNU), teniposide (VM-26), and melphalan. Thirty-three patients received one course of this regimen, and 18 received two courses. At present, 16 of the 33 grafted patients are alive in continuous CR, with a median follow-up of 28 months. Toxicity of this regimen was tolerable, principally marked by bone marrow depression and gastrointestinal (GI) tract complications. Four complication-related deaths were observed. Relapse post-ABMT occurred most often in the bone marrow. Under this treatment, actuarial disease-free survival is improved compared with that observed under conventional therapy.

Topics: Abdominal Neoplasms; Adolescent; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Diseases; Bone Marrow Transplantation; Carmustine; Child; Child, Preschool; Cisplatin; Combined Modality Therapy; Cyclophosphamide; Doxorubicin; Etoposide; Gastrointestinal Diseases; Humans; Infant; Infections; Melphalan; Neuroblastoma; Teniposide; Thoracic Neoplasms; Transplantation, Autologous; Vincristine