Bone marrow transplantation versus high-dose cytarabine-based consolidation chemotherapy for acute myelogenous leukemia in first remission.

PURPOSE: Despite substantial progress in the treatment of acute myeloid leukemia (AML), fewer than 25% of patients survive free of leukemia for more than 5 years without allogeneic bone marrow transplantation (BMT). In this study we analyzed the results of one or more cycles of high-dose cytarabine-based consolidation chemotherapy as compared with allogeneic BMT in first remission. PATIENTS AND METHODS: The results in 28 adult patients, aged 16 to 45 years, who underwent a closely HLA-matched BMT for AML in first remission were compared with those in 54 consecutive, age-matched, adult patients treated with one or more cycles of high-dose, cytarabine-based consolidation chemotherapy. RESULTS: After a median follow-up of 4 years, the actuarial risk of leukemic relapse was considerably lower in the transplant group than in the group treated with consolidation chemotherapy (32% +/- 26% v 60% +/- 14%; P = .05). Treatment-related mortality, however, was much higher in the group treated with BMT (32% v 6%, P = .002). The actuarial disease-free survival at 5 years was not significantly different for the two groups (45% +/- 24% v 38% +/- 14%). CONCLUSIONS: Our results show that BMT in first remission AML did not offer a disease-free survival advantage over intensive postremission consolidation chemotherapy. Larger studies are needed to identify patients who might benefit most from BMT.

Treatment of resistant disease.

Resistant AML encompasses two groups of patients: those with refractory leukemia and those whose leukemia has relapsed. Refractory leukemia is disease that does not respond to initial induction chemotherapy with cytarabine and an anthracycline. Patients with refractory leukemia are likely to have disease with adverse cytogenetics, a history of antecedent hematologic disturbance, adverse immunophenotypic features, and expression of multiple drug resistance. On the other hand, relapsed leukemia is leukemia that recurs following a CR. The duration of CR greatly affects the patient's prognosis and response to additional treatment. Patients with relapsed leukemia are heterogeneous with variable pretreatment characteristics.

Postremission therapy of acute myeloid leukemia in older adults.

Acute myeloid leukemia (AML) in people over age 60 is characterized by adverse cytogenetic characteristics, prior myelodysplasia, and phenotypic features predictive of poor response to induction chemotherapy and brief leukemia-free survival. Because increased treatment-related toxicity complicates both induction and consolidation chemotherapy, most studies of AML in the elderly focus on induction regimens designed to reduce toxicity. Consolidation usually consists of a repeat cycle of conventional-dose induction chemotherapy. Older patients who achieve complete remission may represent a select population, clinically distinct from patients receiving induction therapy. Regardless of the consolidation regimen, the duration of complete remission is 3 months to 11 months, with long-term leukemia-free survival rates of 10 percent to 28 percent. In the UCLA experience, patients over age 60 who received consolidation, chemotherapy and pretreatment characteristics similar to elderly patients undergoing induction. Postremission treatment varied from standard-dose ara-C to high-dose ara-C consolidation followed by autologous stem-cell transplantation. Leukemia-free survival appears to be longer with high-dose ara-C and autologous stem-cell transplantation. Further randomized studies should be conducted to determine the feasibility of and response to postremission treatment.

Long-term outcome of autologous transplantation of peripheral blood progenitor cells as postremission management of adult acute myelogenous leukemia in first complete remission.

In order to improve leukemia-free survival (LFS) without the treatment-related morbidity of allogeneic bone marrow transplantation or multiple prolonged cycles of consolidation chemotherapy, we evaluated the long-term outcome of autologous transplantation of peripheral blood progenitor cells (PBPCs) as postremission therapy in 129 patients aged 18-71 years (median 49 years) with newly diagnosed acute myelogenous leukemia (AML) in first complete remission (CR1). The median follow-up from remission for surviving patients was 62.2 months (range 3.7-127.9 months). A total of 57 patients were alive and leukemia free at the end of the study. The LFS and overall survival 5 years from remission were 40.2% (+/-9.2%) and 41.4% (+/-9.4%), respectively. The median LFS and overall survival are 17.3 and 23.3 months, respectively. Multivariate analysis identified age as the most significant predictor for both LFS and overall survival. Karyotype was also found to be predictive of outcome. Our results show that autologous transplantation of PBPC procured after a single cycle of high-dose cytarabine-based consolidation chemotherapy for a population of adult patients with AML in CR1 produces a high likelihood of long-term LFS, offering a state of clinical minimal residual disease for the investigation of future therapeutic approaches.

Contribution of chemotherapy mobilization to disease control in multiple myeloma treated with autologous hematopoietic cell transplantation.

In patients with multiple myeloma (MM) undergoing autologous hematopoietic cell transplantation (auto-HCT), peripheral blood progenitor cells may be collected following mobilization with growth factor alone (GF) or cytotoxic chemotherapy plus GF (CC+GF). It is uncertain whether the method of mobilization affects post-transplant outcomes. We compared these mobilization strategies in a retrospective analysis of 968 patients with MM from the Center for International Blood and Marrow Transplant Research database who received an auto-HCT in the US and Canada between 2007 and 2012. The kinetics of neutrophil engraftment (⩾0.5 × 10(9)/L) was similar between groups (13 vs 13 days, P=0.69) while platelet engraftment (⩾20 × 10(9)/L) was slightly faster with CC+GF (19 vs 18 days, P=0.006). Adjusted 3-year PFS was 43% (95% confidence interval (CI) 38-48) in GF and 40% (95% CI 35-45) in CC+GF, P=0.33. Adjusted 3-year OS was 82% (95% CI 78-86) vs 80% (95% CI 75-84), P=0.43 and adjusted 5-year OS was 62% (95% CI 54-68) vs 60% (95% CI 52-67), P=0.76, for GF and CC+GF, respectively. We conclude that MM patients undergoing auto-HCT have similar outcomes irrespective of the method of mobilization and found no evidence that the addition of chemotherapy to mobilization contributes to disease control.

Hematologic aspects of renal insufficiency.

Renal dysfunction gives rise to a variety of hematologic disturbances, including anemia, leukocyte dysfunction, and coagulopathy. The anemia of renal failure has been attributed to a relative deficiency of erythropoietin, but contributing factors include an absolute deficiency of iron or folate. Other contributing factors include heavy metal toxicity, blood loss, and hemolysis. The treatment of the anemia of renal disease has advanced with the development of recombinant human erythropoietin. At doses from 15-500 micrograms/kg triweekly in selected patients, normalization of hemoglobin is presently possible. Transfusion may still have a role in patients with renal disease, although more as preconditioning for renal transplantation. In non-HLA matched transplantation, donor-specific transfusion, as well as immunosuppressives, may exert some benefit in graft survival. The coagulopathy of renal disease consists of an acquired qualitative platelet defect best remedied by dialysis but also treated successfully by cryoprecipitate or DDAVP. Infectious complications of uremia include diminished leukocyte chemotaxis, phagocytosis, and bactericidal activity. Cell-mediated immune defects and hypogammaglobulinemia have also been described. The pathophysiology involved in the protean hematologic manifestations of uremia are discussed; additionally, we describe therapeutic recommendations to deal with anemia, bleeding and infectious complications of renal failure.

Nonmyeloablative approaches to the treatment of sickle hemoglobinopathies.

Significant advances in the field of sickle cell disease (SCD) in recent years have contributed to improving the life expectancy and symptoms of patients with this disease. These health care improvements include the implementation of infectious prophylaxis in children and the modulation of hemoglobin F production with chemotherapy. In spite of these advances, SCD continues to be associated with significant morbidity and mortality. Although standard allogeneic bone marrow transplantation can cure SCD and can halt the progression to end-organ damage, this treatment is associated with greater risk of toxicity and death in older patients and in those with evidence of severe end-organ damage. Nonmyeloablative conditioning regimens based on the use of purine analogs can induce sufficient immunosuppression to allow engraftment after allogeneic stem cell transplantation, resulting in less toxicity than standard conditioning regimens. We describe a clinical trial using a nonmyeloablative chemotherapy conditioning regimen followed by related allogeneic peripheral blood stem cell transplantation that represents a novel approach to the treatment of severe SCD in young adults. This study may afford chimeric engraftment resulting in the resolution or amelioration of disease-related symptoms and in the cessation of progression to organ failure.

A multicenter, randomized trial of fluconazole versus amphotericin B for empiric antifungal therapy of febrile neutropenic patients with cancer.

PURPOSE: To compare the efficacy and safety of fluconazole and amphotericin B as empiric antifungal therapy of febrile neutropenic patients with cancer. PATIENTS AND METHODS: A total of 317 neutropenic patients (<500 cells/mm3) with persistent or recrudescent fever despite 4 or more days of antibacterial therapy were randomly assigned to receive either fluconazole (400 mg intravenously once daily) or amphotericin B (0.5 mg/kg once daily). Patients were evaluated for the efficacy and safety of each drug by clinical criteria, frequent cultures and radiological procedures, and laboratory values. A response was classified as satisfactory at the end of therapy if the patient was afebrile, had no clinical or microbiological evidence of fungal infection, and did not require study termination due to lack of efficacy, drug toxicity, or death. RESULTS: A satisfactory response occurred in 68% of the patients treated with fluconazole (107 of 158 patients) and in 67% of patients treated with amphotericin B (106 of 159 patients). Progressive or new fungal infections during therapy occurred in 13 (8%) patients treated with fluconazole (8 with Candida, 5 with Aspergillus) and in 10 (6%) patients treated with amphotericin B (5 with Candida, 3 with Aspergillus, 2 with other fungi). Adverse events related to study drug (especially fever, chills, renal insufficiency, electrolyte disturbances, and respiratory distress) occurred more often in patients treated with amphotericin B (128 [81%] of 159 patients) than patients treated with fluconazole (20 [13%] of 158 patients, P = 0.001). Eleven (7%) patients treated with amphotericin B but only 1 (1%) patient treated with fluconazole were terminated from the study owing to an adverse event (P = 0.005). Overall mortality (27 [17%] patients treated with fluconazole versus 34 [21%] patients treated with amphotericin B) and mortality from fungal infection (7 [4%] patients treated with fluconazole versus 5 [3%] patients treated with amphotericin B) were similar in each study group. CONCLUSIONS: Intravenous fluconazole can be an effective and safe alternative to amphotericin B for empiric antifungal therapy in many febrile neutropenic patients. However, because fluconazole may be ineffective in the treatment of Aspergillus, patients at risk for that infection should be evaluated by chest radiograph, computed tomographic scanning, and cultures before the use of empiric fluconazole therapy.

Selective depletion of CD8+ cells for prevention of graft-versus-host disease after bone marrow transplantation. A randomized controlled trial.

We performed a prospective randomized, double-blind study to assess the efficacy of selective depletion of CD8+ bone marrow cells in preventing acute graft-versus-host disease (GVHD) in 38 patients undergoing HLA-identical sibling donor bone marrow transplantation for leukemia. All patients received CsA for GVHD prophylaxis. Nineteen patients received marrow depleted of CD8+ cells by ex vivo treatment with anti-leu2, an anti-CD8 mAb and complement; four patients had moderate (grade 1 or 2 acute GVHD) and the only patient who experienced grade 3 manifestations was a technical failure. The control group consisted of 19 patients who received unmodified bone marrow; one patient had grade 1, 4 patients had grade 2, and 10 had grade 3 or 4 acute GVHD. The actuarial incidence of grade > or = 2 acute GVHD was 20 +/- 20% in the CD8-depleted group compared with 80 +/- 18% in the controls (P = 0.004). Death in 5 of the control patients and the single patient in whom CD8 depletion was a technical failure was related to acute GVHD. Graft failure occurred in 2 patients in the CD8-depleted group and in none of the controls. Leukemic relapse occurred in 2 patients receiving CD8-depleted bone marrow and 2 patients in the control group. Seven patients receiving marrow depleted of CD8+ cells are alive and free of leukemia and 9 patients in the control group are alive, 7 of whom remain leukemia-free (P = 0.88). The 3-year actuarial leukemia-free survival is 37 +/- 22% of the CD8-depleted group and 36 +/- 22% for the control group. These results indicate that selective depletion of CD8+ cells from the bone marrow significantly reduces the incidence and severity of acute GVHD.

Abdominal presentation of varicella-zoster infection in recipients of allogeneic bone marrow transplantation.

We report here three recipients of allogeneic bone marrow transplantation in whom visceral varicella-zoster virus infection preceded cutaneous dissemination producing life-threatening complications including hepatitis, pancreatitis and haemorrhage.

Quantitative comparison of multiple myeloma tumor contamination in bone marrow harvest and leukapheresis autografts.

Autologous transplantation is increasingly being used to treat patients with multiple myeloma (MM). Recently, peripheral blood progenitor cell (PBPC) harvest have been preferred over autologous bone marrow (BM) harvests due to reduced engraftment time, ease of attainment, and presumptive reduction of occult tumor involvement. To resolve this latter assumption quantitatively, we have used the unique immunoglobulin (Ig) heavy chain variable region sequence of the patient's myeloma cell as a marker of clonality. Samples from PBPC collections and 'back-up' BM harvests were obtained from 13 patients with MM and analyzed for tumor contamination using patient-specific oligonucleotide primers and the polymerase chain reaction. As expected, the percentage of tumor cells contaminating the BM harvest (median, 0.74%) was higher than in the PBPC specimens (median, 0.0024%). Because of the increased total number of cells required for PBPC transplantation, the increase in total number of contaminating cells in the BM vs PBPC autografts was less pronounced, (BM:PBPC tumor contamination ratios ranging from 0.9 to > 4500; median, 14). This confirms that in most but not all cases unmanipulated PBPC products are preferable over BM harvests as a method of reducing myeloma autograft tumor contamination.

A multicenter, randomized, double-blind comparison of different doses of intravenous immunoglobulin for prevention of graft-versus-host disease and infection after allogeneic bone marrow transplantation.

Intravenous immunoglobulin is approved for use in allogeneic bone marrow transplant recipients for prevention of graft-versus-host disease (GVHD) and infections, but the minimally effective dose has not been established. In this multicenter, randomized, double-blind trial, patients undergoing allogeneic marrow transplantation were randomized to receive 100 mg/kg, 250 mg/kg, or 500 mg/kg doses of intravenous immunoglobulin. Each dose was given weekly for 90 days and then monthly until 1 year after transplant. Six hundred and eighteen patients were evaluated. Acute GVHD (grades 2-4) occurred in 39% of the patients (80 of 206) in the 100 mg/kg group, 42% of the patients (88 of 208) in the 250 mg/kg group, and in 35% of the patients (72 of 204) in the 500 mg/kg group (P = 0.344). Among patients with unrelated marrow donors, a higher dose of intravenous immunoglobulin (500 mg/kg) was associated with less acute GVHD (P = 0.07). The incidences of chronic GVHD, infection and interstitial pneumonia were similar for all three doses of intravenous immunoglobulin. The dose of intravenous immunoglobulin also had no effect on the types of infection, relapse of hematological malignancy or survival. Except for more frequent chills (P = 0.007) and headaches (P = 0.015) in patients given the 500 mg/kg or 250 mg/kg dose of immunoglobulin, adverse events were similar for all three doses. These results suggest that 100 mg/kg, 250 mg/kg, and 500 mg/kg doses of intravenous immunoglobulin are associated with similar incidences of GVHD and infections in most allogeneic marrow transplants. These results should be considered when designing cost-effective strategies for the use of intravenous immunoglobulin in allogeneic marrow transplants receiving other current regimens for prophylaxis of GVHD and infection.

Human herpesvirus 8 (KSHV) contamination of peripheral blood and autograft products from multiple myeloma patients.

Human herpesvirus 8 (HHV-8), also known as Kaposi's sarcoma-associated herpesvirus (KSHV), has recently been identified within the bone marrow dendritic cells of multiple myeloma (MM) patients. This virus contains homologues to human cytokines such as IL-6 that could potentially stimulate myeloma cell growth and contribute to disease pathogenesis. Since mobilization chemotherapy may increase circulating dendritic cell numbers, we searched for HHV-8 in peripheral blood mononuclear cells (PBMCs) before and after mobilization chemotherapy given to MM patients. Furthermore, we determined if autograft purging using the CEPRATE SC device would reduce the percentage of HHV-8 infected stem cell products. Only two of the 39 PBMC samples collected prior to mobilization chemotherapy contained PCR detectable virus, yet nine of 37 PBMCs collected on the first day of leukapheresis had detectable HHV-8 (P = 0.016). HHV-8 was more frequently identified in autograft products before vs after Ceprate SC selection (40% vs 15%, P = 0.016). Although the role HHV-8 plays in myeloma pathogenesis remains unclear, these results imply that mobilization chemotherapy increases the numbers of circulating HHV-8-infected dendritic cells within the peripheral blood. In addition, CD34 selection of autograft products in MM patients may reduce the reintroduction of virally infected cells following high-dose chemotherapy. Bone Marrow Transplantation (2000) 25, 153-160.

A critical reappraisal of gastrointestinal complications of allogeneic bone marrow transplantation.

Gastrointestinal toxicity is a common early complication of allogeneic bone marrow transplants. Etiologies include mucosal damage from pretransplant conditioning, opportunistic infection, and graft-versus-host disease. Because the clinical, laboratory, radiographic, and histological findings of acute graft-versus-host disease are nonspecific, accurate diagnosis is difficult or impossible. We review the differential diagnosis of gastrointestinal complications of bone marrow transplants and implications for therapy.

Autologous bone marrow transplantation in acute leukemia.

Autologous bone marrow transplantation can induce long-term LFS in 20% to 40% of patients with relapsed acute leukemia and should be considered as salvage therapy for patients who lack an HLA-matched donor and for patients over 45. Adult ALL patients and children with ALL in extramedullary relapse beyond second CR should receive alloBMT if at all possible. The role of ABMT in acute leukemia patients in first CR remains unclear despite randomized trials (Table 2). Because protocol deviations, early relapse, and inappropriately high treatment-related mortality unequally affected the ABMT cohort, and because recent randomized trials have used old purging methodologies, it is not possible to conclude that ABMT is not beneficial. More recent studies show that most patients are able to proceed with the intended ABMT and that modern purging may be associated with a treatment-related mortality rate of less then 5%. Immunomodulation and graft engineering uniquely suited to autologous progenitor cells indicate that ABMT should continue to be studied in the management of acute leukemia.

CMV central nervous system disease in stem-cell transplant recipients: an increasing complication of drug-resistant CMV infection and protracted immunodeficiency.

We report on two patients with no active GVHD and on moderate doses of immunosuppressive drugs who unexpectedly developed fatal CMV meningoencephalitis after umbilical cord blood transplantation. A review of these two cases along with nine other cases of CMV central nervous system (CNS) disease after allogeneic SCT that were mostly reported within the last 8 years suggests that this severe complication of CMV infection may be increasing. CMV CNS disease after allogeneic SCT is a late-onset disease (median time of onset, 210 days) and is usually manifested as encephalitis in the absence of other sites of CMV disease. The development of CMV CNS disease is associated with risk factors (T-cell depletion, anti-thymocyte globulin, umbilical cord blood transplantation) that cause severe and protracted T-cell immunodeficiency (8 of 11 cases), a history of recurrent CMV viremia treated with multiple courses of preemptive ganciclovir or foscarnet therapy (11 of 11 cases), and ganciclovir-resistant CMV infection (11 of 11 cases). Despite therapy with a combination of antiviral drugs (ganciclovir, foscarnet and cidofovir), mortality is high (10 of 11 cases). Given this high mortality, extended prophylaxis with current or novel antiviral drugs and strategies to enhance CMV immunity need to be considered in high-risk patients.