Worldwide Network for Blood and Marrow Transplantation (WBMT) recommendations for establishing a hematopoietic stem cell transplantation program in countries with limited resources (Part II): Clinical, technical and socio-economic considerations.

The development of hematopoietic stem cell transplantation (HSCT) programs can face significant challenges in most developing countries because such endeavors must compete with other government health care priorities, including the delivery of basic services. While this is may be a limiting factor, these countries should prioritize development of the needed expertise to offer state of the art treatments including transplantation, by providing financial, technological, legal, ethical and other needed support. This would prove beneficial in providing successful programs customized to the needs of their population, and potentially provide long-term cost-savings by circumventing the need for their citizens to seek care abroad. Costs of establishing HSCT program and the costs of the HSCT procedure itself can be substantial barriers in developing countries. Additionally, socioeconomic factors intrinsic to specific countries can influence access to HSCT, patient eligibility for HSCT and timely utilization of HSCT center capabilities. This report describes recommendations from the Worldwide Network for Blood and Marrow Transplantation (WBMT) for establishing HSCT programs with a specific focus on developing countries, and identifies challenges and opportunities for providing this specialized procedure in the resource constrained setting.

Hematopoietic stem cell transplantation activity worldwide in 2012 and a SWOT analysis of the Worldwide Network for Blood and Marrow Transplantation Group including the global survey.

Data on 68 146 hematopoietic stem cell transplants (HSCTs) (53% autologous and 47% allogeneic) gathered by 1566 teams from 77 countries and reported through their regional transplant organizations were analyzed by main indication, donor type and stem cell source for the year 2012. With transplant rates ranging from 0.1 to 1001 per 10 million inhabitants, more HSCTs were registered from unrelated 16 433 donors than related 15 493 donors. Grafts were collected from peripheral blood (66%), bone marrow (24%; mainly non-malignant disorders) and cord blood (10%). Compared with 2006, an increase of 46% total (57% allogeneic and 38% autologous) was observed. Growth was due to an increase in reporting teams (18%) and median transplant activity/team (from 38 to 48 HSCTs/team). An increase of 167% was noted in mismatched/haploidentical family HSCT. A Strengths, Weaknesses, Opportunities, Threats (SWOT) analysis revealed the global perspective of WBMT to be its major strength and identified potential to be the key professional body for patients and authorities. The limited data collection remains its major weakness and threat. In conclusion, global HSCT grows over the years without plateauing (allogeneic>autologous) and at different rates in the four World Health Organization regions. Major increases were observed in allogeneic, haploidentical HSCT and, to a lesser extent, in cord blood transplantation.

Recommendations for the management of sickle cell disease in South Africa.

The spectrum of sickle cell disease (SCD) encompasses a heterogeneous group of disorders that include: (I) homozygous SCD (HbSS), also referred to as sickle cell anaemia; (ii) heterozygous SCD (HbAS), also referred to as sickle cell trait; and (iii) compound heterozygous states such as HbSC disease, HbSß thalassaemia, etc. Homozygous or compound heterozygous SCD patients manifest with clinical disease of varying severity that is influenced by biological and environmental factors, whereas subject with sickle cell trait are largely asymptomatic. SCD is characterized by vaso-occlusive episodes that result in tissue ischaemia and pain in the affected region. Repeated infarctive episodes cause organ damage and may eventually lead to organ failure. For effective management, regular follow-up with support from a multidisciplinary healthcare team is necessary. The chronic nature of the disease, the steady increase in patient numbers, and relapsing acute episodes have cost implications that are likely to impact on provincial and national health budgets. Limited resources mandate local management protocols for the purposes of consistency and standardisation, which could also facilitate sharing of resources between centres for maximal utility. These recommendations have been developed for the South African setting, and it is intended to update them regularly to meet new demands and challenges.

Recommendations for the use of immunoglobulin therapy for immunomodulation and antibody replacement.

Polyvalent immunoglobin, derived from pooled human plasma, can be administered via the intravenous, subcutaneous or intramuscular route. Therapy is standard of care in the treatment of a number of immune-mediated pathologies across disciplines. By volume, the majority is used in neurology (~40%). In primary immunodeficiencies, therapy reconstitutes humoral immunity at replacement doses (0.4 - 0.6 g/kg/month), decreasing infections, and is usually lifelong. However, high doses, usually 2 g/kg total dose over five days, are required for immunomodulation in autoimmune and inflammatory indications. A high-quality evidence base supports use in primary antibody failure, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, acute idiopathic thrombocytopenia, Kawasaki disease andimmunobullous diseases. Low-quality evidence shows benefit in many other uncommon autoimmune and immunodeficient conditions.In South Africa, use of immunoglobulin therapy is restricted and, given the cost involved, will likely remain so. Therefore, the incremental benefit over other forms of immunosuppression, particularly corticosteroids, must be assessed carefully on a case-by-case basis. In most cases, therapy will be second-line or 'rescue' and motivation will be required. This short review aims to provide clinicians with the necessary understanding of the therapy, general considerations for use, and evidence base and quality thereof for well-established indications.

In the absence of clinically significant graft vs. host disease, myeloablative conditioning may allow an effective graft vs. leukaemia effect.

In AML, prevention of GvHD leads to better tolerance of myeloablative therapy. 66 individuals with AML in CR underwent myeloablative conditioning and transplantation with allogeneic PBPC grafts. Median presentation age was 44.5 years. Karyotyping was intermediate in 48% and of unfavourable risk in 36%. For GvHD prophylaxis, PBPC harvests were incubated ex vivo with anti CD52 antibodies. TRM at day 100 and 1 year was 9% and 17%. At a median of 1018 days 65% are alive. Grade >1 GvHD was seen in 11%. GvHD and adverse karyotype were associated with treatment failure. In younger patients preservation of the dose intensity may improve cure rates.

The diagnostic utility of bone marrow biopsies performed for the investigation of fever and/or cytopenias in HIV-infected adults at Groote Schuur Hospital, Western Cape, South Africa.

INTRODUCTION: A bone marrow biopsy is frequently requested in the work-up of patients with human immunodeficiency virus (HIV) infection who present with fever and/or cytopenias in the search for opportunistic infections and malignancies. METHODS: This is a retrospective review of the results of consecutive bone marrow biopsies performed at our institution over a three-year period on HIV-positive patients for the investigation of fever and/or cytopenias. Clinical data, haematological parameters, morphological features, Ziehl-Neelsen staining and microbiological culture results were analysed. The aim of the study was to determine the diagnostic yield of this investigation. RESULTS: Sixty-three males and 84 female patients were included for analysis. The bone marrow biopsy gave a high diagnostic yield of 47% (70 patients) and a unique diagnosis in 33% (49 patients). Immune thrombocytopenic purpura and disseminated mycobacterial infections were the most common unique diagnoses made (14%, respectively), followed by malignancies (4%). In this cohort, four cases of primary bone marrow involvement by Hodgkin lymphoma and one case of involvement by non-Hodgkin lymphoma were diagnosed. CONCLUSION: In our study group, a bone marrow biopsy was a useful investigation with a high diagnostic yield.

Recommendations for the management of adult chronic myeloid leukaemia in South Africa.

INTRODUCTION: Chronic myeloid leukaemia (CML) is a chronic myeloproliferative disorder characterised by a chromosomal translocation between the long arms of chromosomes 9 and 22 [corrected] resulting in the formation of the BCR-ABL fusion gene. The management of CML has undergone major changes over the past decade. Novel treatment approaches have had a dramatic impact on patient outcomes and survival. Nevertheless, these outcomes can only be achieved in the context of expert management, careful monitoring of disease response, appropriate management of adverse events and timeous adjustments to therapy when responses are not achieved within stated time-frames. AIM: With the advent of novel treatments providing molecular responses, both the monitoring and management of CML have become more complicated. The aim of these recommendations was to provide a pragmatic yet comprehensive roadmap to negotiate these complexities. METHODS: Recommendations were developed based on local expert opinion from both the academic and private medical care arenas after careful review of the relevant literature and taking into account the most widely used international guidelines. About five meetings were held at which these recommendations were discussed and debated in detail. RESULTS: A comprehensive set of recommendations was compiled with an emphasis on diagnosis, investigation, treatment and monitoring of disease. Careful attention was given to circumstances unique to South Africa, funding constraints, availability and access to laboratory resources, as well as the effects of concurrent HIV infection. CONCLUSION: Most patients with CML can live a reasonably normal life if their disease is appropriately managed. These recommendations should be of value to all specialists involved in the treatment of haematological disorders.

Reduced-intensity conditioning for severe aplasia using fludarabine and CY followed by infusion of ex vivo T-cell-depleted grafts leads to excellent engraftment and absence of GVHD.

We studied the outcome of individuals with aplastic anaemia (AA) who received reduced-intensity conditioning followed by the infusion of stem cell grafts that had been T-cell depleted ex vivo with alemtuzumab. Consecutive patients with AA who had an HLA-identical sibling received conditioning with fludarabine 30 mg/m(2) daily for 5 days followed by CY 60 mg/kg on 2 consecutive days. Cytokine-mobilized blood grafts were incubated ex vivo with alemtuzumab 'in the bag' and infused without washing. CYA was prescribed until day +90. Engraftment rate, GVHD, EFS and overall survival were studied. Fifteen patients received PBPC grafts. It was the second graft in one of the patients. Ten patients were male and their median age was 23.5 years. The toxicity of the conditioning was minimal. One patient received 1 x 10(7)/kg donor lymphocytes for rising chimerism. At a median of 1107 (294-1778) days, all of them survived with normal blood parameters. None of them developed acute or chronic GVHD. In patients with AA the combination of purine analogue and alkylator leads to rapid engraftment despite T-cell depletion of grafts. This strategy of reduced-intensity conditioning has low toxicity, does not compromise engraftment and seems effective for prevention of GVHD.

Prevention of graft vs. host disease with alemtuzumab 'in the bag' decreases early toxicity of stem cell transplantation and in multiple myeloma is associated with improved long-term outcome.

BACKGROUND: Allogeneic stem cell transplantation in multiple myeloma (MM) is controversial because treatment-related mortality and relapse remain a substantial challenge. METHODS: Patients with symptomatic MM responsive to therapy received myeloablative conditioning with radiotherapy (n=12) or chemotherapy (n=10) followed by infusion of HLA-identical grafts from a sibling. Graft vs. host disease (GvHD) prophylaxis consisted of 'ex vivo' T-cell depletion with CAMPATH-1 antibody. The objective of the study was to determine transplant-related mortality (TRM), GvHD, overall survival (OS) and Disease free Survival (DFS). RESULTS: Twenty-two patients, median age 45 (range 37-56) years, had a median performance status of 1 (0-2). Patients received a median of 23.8 x 10(4)/kg CFU-GM and 4.31 x 10(6)/kg CD34. Median time to engraftment was 13 days. The day-100 and 1-year TRM was 9% and 20%, respectively. Ten patients suffered disease recurrence. Four of eight patients remained in remission after infusions of donor lymphocyte (DLI) containing a median total of 0.67 x 10(8)/kg CD3 cells. Three-year OS was 56%, and 50% remained disease free at a median of 1101 days (range 385-5309). Multiple regression analysis showed that bone marrow (vs. peripheral blood stem cell) (P=0.03), presentation of low albumin (P=0.02) and a higher dose of CAMPATH-1H (P=0.01) were adverse factors for survival. Cox analysis confirmed that a lower CAMPATH-1H dose was associated with improved outcome. DISCUSSION: In chemotherapy-responsive patients with myeloma, T-cell depletion of allogeneic grafts was associated with an acceptable 1-year TRM and seemed to have a favorable impact on long-term survival.

Hematopoietic stem cell transplantation for adults with acute promyelocytic leukemia in the ATRA era: a survey of the European Cooperative Group for Blood and Marrow Transplantation.

We performed a survey of the European Cooperative Group for Blood and Marrow Transplantation to analyze the outcome of 625 acute promyelocytic leukemia (APL) patients transplanted with auto- or allogeneic-hematopoietic stem cell transplantation (autoHSCT, alloHSCT) after 1993, in first (CR1) or in second complete remission (CR2). Leukemia-free survival (LFS) at 5 years in CR1 was 69% for 149 patients autografted and 68% for 144 patients allografted, whereas in CR2, LFS was 51% in 195 autoHSCT and 59% in 137 alloHSCT recipients, respectively. In the group of autoHSCT for CR1 (n=149), higher relapse incidence (RI) was associated with shorter time from diagnosis to transplant (<7.6 months); transplant-related mortality (TRM) was increased in older patients (>47 years), whereas for CR2, longer time from diagnosis to transplant (>18 months) was associated with increased LFS and decreased RI. In the alloHSCT group for CR1 (n=144), age (<33 years) was associated with increased LFS and decreased TRM and for CR2 (n=137), the use of mobilized peripheral blood stem cells was associated with decreased TRM. Female recipient, a female donor to male recipient and transplants performed before 1997 were associated with decreased RI. In conclusion, HSCT still appears to have a role in APL, especially for patients in CR2.

Myeloablative conditioning is well tolerated by older patients receiving T-cell-depleted grafts.

Older age has been linked to increased transplant-related mortality from graft-versus-host disease (GvHD). Depletion of T cells from stem cell grafts seems to protect from complications of GvHD particularly in older patients. After myeloablative conditioning, patients with haematological malignancies received allogeneic grafts from HLA identical siblings. For GvHD prophylaxis, PBPC grafts were treated ex vivo with anti-CD52, and therapeutic doses of cyclosporin until day +90. Survival of patients younger or older than the population age median was analysed. In all, 62 consecutive patients with a median age of 42.5 years were studied. Death was procedure related in 17% and from relapse of malignancy in five. At a median, follow-up is 662 (7-2316) days, 74% survive disease free. The rate of haematopoietic recovery and treatment-related mortality was similar in both groups. A total of 73% of 30 individuals in the younger group and 75% (P=0.8) in the older cohort survive at a median follow-up of 444 and 806 days (P=0.4). GvHD occurred in 13% and was the only adverse factor for survival (P<0.04). Myeloablative conditioning is well tolerated up to the age of 59 in patients receiving T-cell-depleted grafts. This information is useful to more precisely select patients who would benefit most from reduced intensity conditioning schedules.

Radiotherapy-based conditioning is effective immunosuppression for patients undergoing transplantation with T-cell depleted stem cell grafts for severe aplasia.

BACKGROUND: We studied the outcome of individuals with aplastic anemia conditioned with a radiation-containing regimen followed by an infusion of stem cell grafts that had been depleted of lymphocytes with CAMPATH-1H (antiCD52; humanised). METHODS: The conditioning regime consisted of fractionated (f) TBI 8 Gy followed by f total nodal irradiation (TNI) 6 Gy. In addition, patients received CY 60 mg/kg on 2 consecutive days. Cytokine-mobilized peripheral blood grafts from HLA-identical siblings were T-cell depleted with CAMPATH-1H 'in the bag'. CsA was commenced on day -1 and continued until day +90. RESULTS: Seventeen heavily transfused patients with aplastic anemia, median age 18 years (range 14-56 years), were studied. The median time from diagnosis to transplantation was 172 days (range 34-443 days). The median CD34(+) cell number infused was 3.47 x 10(6)/kg (range 1.03-18.4 x 10(6)/kg). All patients engrafted. Recovery was fast and patients reached 0.5 x 10(9)/L polymorphs by median day 11 (range 9-17 days). Toxicity from the conditioning included grade 4 hematologic toxicity in all patients. Another major toxicity was gastrointestinal mucosal damage, which exceeded grade 2 in two instances. One patient developed thrombotic thrombocytopenic purpura, which responded to substitution of CsA with tacrolimus and plasmapheresis. Another patient, who had normal blood counts, died of infection on day 241. Chimerism studies at 6 months post-transplantation confirmed the donor origin of hematopoiesis in all seven patients tested. None of the patients developed acute or chronic GvHD. There was no delayed graft failure and 94% of patients had survived disease free at a median of 1303.5 days (range 216-2615 days) from graft infusion. DISCUSSION: In this cohort of multiply transfused patients, the radiation-containing schedules described in this study led to universal engraftment with limited toxicity despite T-cell depletion. No patient developed GvHD or late graft failure. Lower doses of radiation-containing conditioning should be explored further.

Increasing dose intensity of anthracycline antibiotics improves outcome in patients with acute myelogenous leukemia.

To understand the effect of dose concentration in the overall survival of AML, we conducted a study on the efficacy and toxicity of a drug combination where the dose of daunorubicin was intensified. For this analysis, the outcome of patients entered into two consecutive prospective trials was compared. Inclusion criteria in both arms were identical and consisted of primary AML in adults. Treatment protocol for Cape Town Regimen 4 (CTR-IV) comprised of cytarabine infusion (100 mg/m(2)) and etoposide (100 mg/m(2)), injection daily for 7 days in combination with daunorubicin (45 mg/m(2)) on days 1, 2, and 3. Patients achieving remission were given two further courses of the same chemotherapy and received allogeneic or autologous transplantation. CTR-V was a similar treatment program, except that daunorubicin was escalated on days 1, 2, and 3 to 75 mg/m(2) during induction and to 60 mg/m(2) during a single consolidation. Patients were also offered stem cell transplantation. Between 1990 and 1997, 78 patients (median age 33; range 13-67 years) fulfilled entry criteria and received CTR-IV. From 1998 onwards, 35 patients (median age 36; range 15-66 years) were prospectively enlisted into the CTR-V trial. The patient population in CTR-V had fewer Caucasian individuals (P = 0.02) and had significantly lower presentation hemoglobin (P = 0.0002). Following initiation of induction chemotherapy, 40 patients failed to respond. Among these, 10 patients demised before day 28. Another 30 (25/69 CTR-IV and 5/32 in CTR-V groups; P = 0.01) had leukemia that was resistant to chemotherapy, and all died. Remission was achieved in 59% of patients treated with CTR-IV and 77% of those receiving CTR-V (P = 0.03). CR occurred with a single course in 64% versus 88% (P = 0.02), respectively. There were no differences in the toxicity profile between these two combinations. Disease recurred in 50% and 28% (P = 0.07) of patients. For the 113 individuals, median follow up is 254 (range 19-4,451) and 304 (12-1,702; P = 0.03) days. Survival is 23% and 40%, respectively, favoring patients treated with CTR-V (log rank; P = 0.03). Cox regression analysis showed that treatment group (P < 0.001), FAB type, hemoglobin level, and platelet count were independent factors for response to chemotherapy. Older age and not undergoing myeloablative therapy were the only adverse factors for survival. We conclude that increase in the treatment dose of daunorubicin in patients with AML led to a higher remission rate, particularly with a single course of chemotherapy and had an equivalent toxicity profile. This therapeutic modification is also likely to result in substantial reduction in patient stay in hospital and in the overall expenditure.

Campath-1 Abs 'in the bag' for hematological malignancies: the Cape Town experience.

BACKGROUND: We examined the strategy of T-cell depletion of HLA-identical sibling grafts for the prevention of GvHD, as well as disease control and overall survival. PATIENTS AND METHODS: The myeloablative conditioning was radiation based. The source of stem cells was BM in 62, and cytokine-mobilized PBPC in 68 patients. GvHD prophylaxis was by ex vivo incubation of the stem-cell concentrates with Campath-1G (anti-CD52; n=76) or Campath-1H (n=54). RESULTS: Patients receiving PBPC grafts were older (median 38.5) than those undergoing BMT (median 31; P=0.002). More patients in the PBPC group developed chronic GvHD (p<0.01). While no post-transplant GvHD prophylaxis was given to BMT recipients, prednisone 30 mg daily was prescribed to 12 and CYA for 90 days to a further 32 patients who had received PBPC grafts. Median follow-up was 1055 (range 28-4867) days. Although there was no difference in the survival between patients who received BMT or PBPC, death was from disease recurrence in 16 and nine (p=0.03; chi(2) test) subjects, respectively. Multivariate analysis showed that outcome was particularly favorable in those who were given<20 mg Campath-1 (survival: 28/39 versus 12/29; P=0.01), and in the subgroup of 30 patients who received Campath-1H and post-transplantation CYA. DISCUSSION: In patients receiving BMT, Campath-1 Abs effectively prevent GvHD. For those treated with PBPC grafts, the combination of T-cell depletion and post-transplantation CYA is equally effective, without an obvious increase in disease recurrence.

Intensified myeloablative therapy and autologous stem-cell transplantation for patients with AML: single center experience.

BACKGROUND: Thirty-seven consecutive individuals in CR of AML received intensified conditioning and autologous stem-cell transplantation. METHODS: For those receiving PBSC (n = 28), mobilization protocol was with cyclophosphamide 60 mg/kg followed by G-CSF injection at 5-10 microg/kg; stem cells were harvested by large volume apheresis (6-8 blood volumes) and then cryopreserved. Ablative therapy consisted of fractionated TBI (total 12 Gy), followed by four fractions (1.5 Gy each) of total nodal irradiation (TNI), and CY 120 mg/kg under mesna cover. RESULTS: For individuals transplanted in CR 1 (n = 31) the median time from diagnosis to grafting was 167 (range 92 - 212) days. Patients transplanted with PBSC received high number of CFU-GM x 10(4)/kg (P < 0.01), a difference that was associated with a significantly shorter platelet recovery. While there was no early transplant-associated mortality, in 10 patients death was caused by recurrence of the disease. The median survival is 1746 (range 105-4467) days and 26 (70%) survive disease free, at a median 2207 (range 698-4467) days from transplantation. Multivariate analysis showed that survival of patients with AML-M3, receiving higher CFU-GM (P = 0.04) and without morphological dysplasia (P = 0.01) was longest. DISCUSSION: For patients in remission of AML, transplantation with PBPC appears to be an effective form of intensification, particularly when TBI + TNI (delivering a total of 18 Gy to the axial skeleton) were used as conditioning.

Basic fibroblast growth factor corrects proliferative derangement of bone marrow stroma and CD34(+) population following allogeneic stem cell transplantation.

OBJECTIVE: Following stem cell transplantation (SCT), the integrity of the hematopoietic microenvironment is important for the recovery of bone marrow. We studied the effects of basic fibroblast growth factor (bFGF) on the proliferation of clonogenic progenitors and bone marrow stroma from patients receiving cytokine-mobilized allogeneic stem cell transplants (SCT). MATERIALS AND METHODS: Patient bone marrow mononuclear cells were studied at a minimum of 6 months after transplantation. Control and patient samples were divided into two fractions, one to establish the adherent stroma layers (SL) and the other to select for the progenitor population. SL from normal subjects or from patients were supplemented with 0 (control), 2, or 20 ng/mL bFGF in combination with heparan sulfate, and the resulting area of the dish covered by stroma was quantitated in each group. At 3 weeks of culture, a monocellular suspension was prepared by exposing SL to 0.1% trypsin. Cells then were cultured in the colony-forming unit fibroblast (CFU-F) assay, which was supplemented with 0 (control), 2, or 20 ng/mL bFGF. With the second fraction, CD34(+) cells were selected with paramagnetic beads, and 1 x 10(4) cells were incubated in cross-culture studies on preformed SL from patient or control origin (with or without the addition of bFGF). SL adherent CD34(+) cells were covered with agar and cultured for 6 days. Aggregates of >20 cells were scored as blastic colonies (CFU-bl). RESULTS: At 3 weeks of culture, the median surface area of dishes covered by monoloayers from 13 patients was 40% (range 10-50% vs normal 55%, range 30-60%; p = 0.00006) and improved significantly, matching control values, in dishes supplemented with bFGF. Addition of bFGF to stroma monolayers had no effect on the number of CFU-F in both patient and control samples. Selected CD34(+) cells from patients receiving transplants and cultured on normal stroma gave significantly fewer CFU-bl than control samples (median 36, range 3-121 vs 147, range 10-184; p = 0.006), but colony numbers corrected following exposure to bFGF. Normal CD34(+) cells proliferated poorly on stroma from patients (median CFU-bl 37.5, range 6-84; p = 0.02), but also expanded significantly following bFGF supplementation (104, range 6-117; p = 0.001). CONCLUSIONS: Following SCT, poor SL and CD34(+) proliferation can be corrected by addition of bFGF.

Intravenous and oral itraconazole versus intravenous amphotericin B deoxycholate as empirical antifungal therapy for persistent fever in neutropenic patients with cancer who are receiving broad-spectrum antibacterial therapy. A randomized, controlled trial.

BACKGROUND: Amphotericin B deoxycholate is currently the standard empirical antifungal therapy in neutropenic patients with cancer who have persistent fever that does not respond to antibiotic therapy. However, this treatment often causes infusion-related and metabolic toxicities, which may be dose limiting. OBJECTIVE: To compare the efficacy and safety of itraconazole with those of amphotericin B as empirical antifungal therapy. DESIGN: An open randomized, controlled, multicenter trial, powered for equivalence. SETTING: 60 oncology centers in 10 countries. PATIENTS: 384 neutropenic patients with cancer who had persistent fever that did not respond to antibiotic therapy. INTERVENTION: Intravenous amphotericin B or intravenous itraconazole followed by oral itraconazole solution. MEASUREMENTS: Defervescence, breakthrough fungal infection, drug-related adverse events, and death. RESULTS: For itraconazole and amphotericin B, the median duration of therapy was 8.5 and 7 days and the median time to defervescence was 7 and 6 days, respectively. The intention-to-treat efficacy analysis of data from 360 patients showed response rates of 47% and 38% for itraconazole and amphotericin B, respectively (difference, 9.0 percentage points [95% CI, -0.8 to 19.5 percentage points]). Fewer drug-related adverse events occurred in the itraconazole group than the amphotericin B group (5% vs. 54% of patients; P = 0.001), and the rate of withdrawal because of toxicity was significantly lower with itraconazole (19% vs. 38%; P = 0.001). Significantly more amphotericin B recipients had nephrotoxicity (P < 0.001). Breakthrough fungal infections (5 patients in each group) and mortality rates (19 deaths in the itraconazole group and 25 deaths in the amphotericin B group) were similar. Sixty-five patients switched to oral itraconazole solution after receiving the intravenous formulation for a median of 9 days. CONCLUSIONS: Itraconazole and amphotericin B have at least equivalent efficacy as empirical antifungal therapy in neutropenic patients with cancer. However, itraconazole is associated with significantly less toxicity.

CAMPATH-1 antibodies in stem-cell transplantation.

BACKGROUND: CAMPATH-1 (CD52) Abs have been used in stem-cell transplants for the prevention of GvHD and graft rejection. These complications can effectively be prevented by depletion of T lymphocytes from both donor and recipient. However, donor lymphocytes might contribute an anti-leukemia effect and lymphocyte depletion may exacerbate problems with immune reconstitution. There is a fine balance between the risks of GvHD and host-versus-graft reactions, relapse and infection. METHODS: Clinical outcomes for 4264 patients were reported to a central registry and analyzed by univariate and multivariate methods to determine the superior protocols. Various protocols of lymphocyte depletion were tested, using either CAMPATH-1M (IgM) plus complement or CAMPATH-1G (IgG2b) to treat the donor BM ex vivo and CAMPATH-1G in vivo to treat the recipient. The humanized antibody CAMPATH-1H has recently replaced CAMPATH-1G. A meeting of the clinical collaborators was convened to discuss the results and to review the experiences of individual centers. RESULTS: Interest focused on the use of mobilized PBSC for transplantation and on the use of reduced-intensity conditioning regimens ('mini' or 'non-Correspondence myeloablative' transplants). These approaches are likely to become increasingly important in the future and will allow transplant procedures to be used for relatively older patients. The use of CAMPATH-1G or CAMPATH-1H was associated with a low incidence of GvHD or rejection, though there were some differences that might be related to the longer half-life of the humanized antibody. An unexpected and apparently paradoxical effect of post-transplant CYA was observed - it appeared to reduce the risk of dying from infection after 6 months. Although part of the benefit could be explained by a reduction in GvHD, the effect was still evident when patients with GvHD or graft rejection were excluded from analysis. DISCUSSION: CAMPATH-1H appears to have a useful role in the prevention of graft rejection and GvHD, particularly in patients who are at high risk of these complications. It can equally well be used by admixture with the infused stem cells, or by administration to the patient prior to the transplant. Future studies will seek to understand the mechanism of the CYA effect and to improve the quality of immune reconstitution.

Infectious complications following T-cell depleted hematopoietic stem-cell transplantation.

BACKGROUND: Although sepsis is a common complication during stem-cell transplantation, the prevalence of infections after hematopoietic recovery is less well known. METHODS: We undertook a retrospective analysis of infectious episodes in patients who underwent allogeneic BM (n = 77) or PBSC (n = 29) grafting from HLA identical siblings. T-cell depletion of the stem-cell grafts with anti CD 52 (CAMPATH-1) Abs was employed for the prevention of GvHD. RESULTS: Patients' median age was 30 (4-54) years. Antibiotic prophylaxis was with oral amphotericin, ofloxacin and i.v. or oral acyclovir. Fever was treated empirically with a third generation cephalosporin and aminoglucosides until results of microbiological cultures became available. Six patients died of graft failure. GvHD was observed in 18% but in no case was it > Grade II. Only seven patients did not develop pyrexia during the initial admission or within 60 days following graft infusion. Median duration of pyrexia was 10 (range 2-49) days. A microbial source was detected in 42% and it was Gram (+) in 86%, Gram (-) in 11% and fungal in 3%. In 16 patients, indwelling venous catheters were removed due to severe infection. Subsequent to the recovery of the blood parameters, the most prevalent infection was by herpes varicella/zoster in 20; another 17 developed herpes simplex. In total 40/102 were re-hospitalized for pyrexia, which in four cases was of unknown origin. Bacterial infections with Staphylococcus Aureus and S. Epidermitis were seen in 10 and seven patients respectively. CMV was detected in seven patients. Thirteen patients died of sepsis and in 10, it was related to GvHD or graft failure. Another 20 died following recurrence of the malignancy. Overall, 39 patients died and 63% survived at a median DFS of 1992 (range 623-5092) days. DISCUSSION: We conclude that during the initial neutropenic period the dominant infections are by Gram (+) organisms, often associated with indwelling catheters. Once the BM has recovered, the main morbidity is by viral infections, but Gram+ organisms still remain common bacterial pathogens.