Hemopoietic cell transplantation as curative therapy of myelodysplastic syndromes and myeloproliferative disorders.

Hemopoietic cell transplantation (HCT) is presently the only therapy with curative potential for myelodysplastic syndromes (MDS) and myeloproliferative disorders (MPD). Among patients with less advanced MDS, 3-year survival figures of 65-80% are achieved with human leukocyte antigen (HLA)-identical related and unrelated donors. The probability of relapse is less than 5%.

Optimization of conditioning for marrow transplantation from unrelated donors for patients with aplastic anemia after failure of immunosuppressive therapy.

In 87 patients with aplastic anemia who failed to respond to immunosuppressive treatment, we determined the minimal dose of total body irradiation (TBI) required when added to antithymocyte globulin (ATG, 30 mg/kg x 3) plus cyclophosphamide (CY, 50 mg/kg x 4) to achieve engraftment of unrelated donor marrow. TBI was started at 3 x 200 cGy, to be escalated or deescalated in steps of 200 cGy depending on graft failure or toxicity. Patients were aged 1.

Reduced incidence of acute and chronic graft-versus-host disease with the addition of thymoglobulin to a targeted busulfan/cyclophosphamide regimen.

To reduce the incidence of graft-versus-host disease (GVHD), we added Thymoglobulin (THY) to dose-adjusted oral busulfan plus cyclophosphamide (targeted BUCY). The starting dose of THY was 4.5 mg/kg given over days -3, -2, and -1, escalated in steps of 1.

Evidence of donor-derived hematologic malignancies after hematopoietic stem cell transplantation.

Increasing the upper age limit for recipients of hematopoietic stem cell transplantation (HCT) naturally has also increased the age of the corresponding related donor population. Because aging is a risk factor for malignancies, the risk of transferring preexisting malignant or premalignant hemopoietic clones in the process of HCT might be expected to increase as well. Anecdotal clinical cases of malignancies derived from donor cells in patients undergoing HCT have been published since 1971.

Nonmelanoma skin and mucosal cancers after hematopoietic cell transplantation.

Purpose: To evaluate the incidence of and risk factors for basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) in survivors of hematopoietic cell transplantation (HCT).

Patients And Methods: The impact of patient-, disease-, treatment-, and toxicity-related factors on risk of BCC and SCC was determined in a retrospective cohort study of 4,810 patients who received allogeneic HCT and who survived for at least 100 days.

Results: Among allogeneic HCT recipients, 237 developed at least one skin or mucosal cancer (BCC, n = 158; SCC, n = 95).

Transplant strategies for patients with myelodysplastic syndromes.

Purpose Of Review: Hematopoietic cell transplantation offers potentially curative therapy for patients with myelodysplastic syndrome. The median patient age at diagnosis, however, is about 70 years, which has limited the application of conventional hematopoietic cell transplantation. In addition, the optimum timing of transplantation remains controversial.

The clinical spectrum of acute graft-versus-host disease.

Acute graft-versus-host disease (GVHD), initiated by the reaction of donor T lymphocytes against nonshared recipient antigens, typically leads to a clinical syndrome characterized by cutaneous eruptions and intestinal and hepatic dysfunction. These three organ systems are considered in the clinical grading of acute GVHD. However, other targets may be involved.

Protection of human and murine hepatocytes against Fas-induced death by transferrin and iron.

Recent studies in a murine model show that transferrin (Tf) interferes with Fas-mediated hepatocyte death and liver failure by decreasing pro-apoptotic and increasing anti-apoptotic signals. We show here in vitro in murine and human hepatocyte cell lines and in vivo in mice that Fas-induced apoptosis is modulated by exogenous Tf and iron. The results obtained with iron-free Tf (ApoTf), iron-saturated Tf (FeTf), and the iron chelator salicylaldehyde isonicotinoyl hydrazone (SIH) in its iron-free and iron-saturated (FeSIH) forms indicate that apoptosis-modulating effects of Tf are not mediated by iron alone.

Optimization of transplant regimens for patients with myelodysplastic syndrome (MDS).

Myelodysplastic syndrome (MDS) is a hemopoietic stem cell disorder that is potentially curable by transplantation of normal hemopoietic stem cells. The optimum timing, however, and the best conditioning strategy have remained controversial. Both conventional and reduced-intensity/nonmyeloablative regimens have been used successfully.

Myeloablative vs nonmyeloablative allogeneic transplantation for patients with myelodysplastic syndrome or acute myelogenous leukemia with multilineage dysplasia: a retrospective analysis.

Transplant outcome was analyzed in 150 patients with myelodysplastic syndrome (MDS) or acute myelogenous leukemia transformed from MDS (tAML) conditioned with nonmyeloablative or myeloablative regimens. A total of 38 patients received nonmyeloablative regimens of 2 Gy total body irradiation alone (n=2) or with fludarabine (n=36), 90mg/m2. A total of 112 patients received a myeloablative regimen of busulfan, 16mg/ kg (targeted to 800-900 ng/ml), and cyclophosphamide 120 mg/ kg.

Hematopoietic stem cell transplantation for myelofibrosis.

Myelofibrosis with myeloid metaplasia (MMM) is a clonal disorder resulting from the proliferation of aberrant hematopoietic progenitors. Hence MMM is curable if the abnormal clone can be eradicated and replaced by normal cells from healthy donors. Myeloablative allogeneic transplantation results in high rates of durable engraftment and cure in approximately 50% of patients.

Allogeneic hematopoietic cell transplantation for chronic myelomonocytic leukemia.

We evaluated the outcomes of allogeneic hematopoietic cell transplantation (HCT) in 43 patients with chronic myelomonocytic leukemia. Patients were classified according to the French-American-British and World Health Organization classifications, as well as the International Prognostic Scoring System and the M.D.

Cyclophosphamide and antithymocyte globulin as a conditioning regimen for allogeneic marrow transplantation in patients with aplastic anaemia: a long-term follow-up.

A total of 81 severe aplastic anaemia patients, aged 2-63 years, received human leucocyte antigen-matched related marrow grafts after cyclophosphamide + antithymocyte globulin followed by postgrafting methotrexate + cyclosporin. Median follow-up was 9.2 years.

NF-kappaB and FLIP in arsenic trioxide (ATO)-induced apoptosis in myelodysplastic syndromes (MDSs).

Tumor necrosis factor (TNF)-alpha, a potent stimulus of nuclear factor-kappaB (NF-kappaB), is up-regulated in myelodysplastic syndrome (MDS). Here, we show that bone marrow mononuclear cells (BMMCs) and purified CD34+ cells from patients with low-grade/early-stage MDS (refractory anemia/refractory anemia with ring sideroblasts [RA/RARS]) have low levels of NF-kappaB activity in nuclear extracts comparable with normal marrow, while patients with RA with excess blasts (RAEB) show significantly increased levels of activity (P = .008).

Hemopoietic cell transplantation for the myelodysplastic syndromes.

Myelodysplastic syndromes (MDS) are hemopoietic stem cell disorders, and hemopoietic stem cell transplantation is currently the only therapeutic modality with curative potential. Among patients with less advanced/low-risk MDS (<5% marrow blasts), 3-year survivals of 65--70% are achievable with HLA-identical related and unrelated donors. The overall probability of disease recurrence in these patients is <5%.

A phase I/II study of mycophenolate mofetil in combination with cyclosporine for prophylaxis of acute graft-versus-host disease after myeloablative conditioning and allogeneic hematopoietic cell transplantation.

Abstract In a phase I/II study, the combination of cyclosporine (CSP) and mycophenolate mofetil (MMF) was investigated as graft-versus-host disease (GVHD) prophylaxis after myeloablative conditioning and hematopoietic cell transplantation from an HLA-matched sibling donor. In phase I, 3 groups, each with 10 or 11 patients, received MMF (15 mg/kg) from day 0 to day 27 at decreasing dose intervals of every 12, 8, and 6 hours to determine a safe and effective total daily dose. At the 45 mg/kg/d dosage level, 4 of 11 patients developed only grade II GVHD, and a concentration at steady state of mycophenolic acid (the active moiety of MMF) consistent with a therapeutic range described for solid-organ transplantation was achieved.

Low-dose cyclophosphamide conditioning for haematopoietic cell transplantation from HLA-matched related donors in patients with Fanconi anaemia.

Allogeneic haematopoietic cell transplantation (HCT) is effective therapy for Fanconi anaemia (FA). FA patients do not tolerate conditioning with 200 mg/kg of cyclophosphamide (Cy), typically used in aplastic anaemia. We previously published results of studies in which Cy doses were gradually reduced from 200 to 100 mg/kg.

Ablative allogeneic hematopoietic cell transplantation in adults 60 years of age and older.

Purpose: To evaluate outcomes of ablative allogeneic hematopoietic cell transplantation (HCT) in older patients with hematologic malignancies.

Patients And Methods: We treated 52 patients from 1979 to 2002 with a median age of 62.8 years (range, 60.