mycophenolic-acid and Leukemia--Myeloid

Enterocytozoon bieneusi microsporidiosis is an emerging disease in immunocompromised patients. We report 2 cases of this disease in allogeneic hematopoietic stem cell transplant patients successfully treated with fumagillin. Thrombocytopenia occurred but without major adverse events. Modifications of immunosuppression could be avoided when E. bieneusi is rapidly identified and fumagillin therapy is started promptly.

Topics: Adult; Antifungal Agents; Cyclohexanes; Enterocytozoon; Fatty Acids, Unsaturated; Female; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Leukemia, Myeloid; Male; Microsporidiosis; Middle Aged; Mycophenolic Acid; Platelet Count; Prednisone; Sesquiterpenes; Thrombocytopenia; Treatment Outcome

Increasing numbers of patients are receiving haplo-identical stem cell transplantation (haplo-SCT) for treatment of acute leukemia with reduced intensity (RIC) or myeloablative (MAC) conditioning regimens. The impact of conditioning intensity in haplo-SCT is unknown.. We performed a retrospective registry-based study comparing outcomes after T-replete haplo-SCT for patients with acute myeloid (AML) or lymphoid leukemia (ALL) after RIC (n = 271) and MAC (n = 425). Regimens were classified as MAC or RIC based on published criteria.. A combination of post-transplant cyclophosphamide (PT-Cy) with one calcineurin inhibitor and mycophenolate mofetil (PT-Cy-based regimen) for graft-versus-host disease (GVHD) prophylaxis was used in 66 (25%) patients in RIC and 125 (32%) in MAC groups. Patients of RIC group were older and had been transplanted more recently and more frequently for AML with active disease at transplant. Percentage of engraftment (90 vs. 92%; p = 0.58) and day 100 grade II to IV acute GVHD (24 vs. 29%, p = 0.23) were not different between RIC and MAC groups. Multivariable analyses, run separately in AML and ALL, showed a trend toward higher relapse incidence with RIC in comparison to MAC in AML (hazard ratio (HR) 1.34, p = 0.09), and no difference in both AML and ALL in terms of non-relapse mortality (NRM) chronic GVHD and leukemia-free survival. There was no impact of conditioning regimen intensity in overall survival (OS) in AML (HR = 0.97, p = 0.79) but a trend for worse OS with RIC in ALL (HR = 1.44, p = 0.10). The main factor impacting outcomes was disease status at transplantation (HR ≥ 1.4, p ≤ 0.01). GVHD prophylaxis with PT-Cy-based regimen was independently associated with reduced NRM (HR 0.63, p = 0.02) without impact on relapse incidence (HR 0.99, p = 0.94).. These data suggest that T-replete haplo-SCT with both RIC and MAC, in particular associated with PT-Cy, are valid options in first line treatment of high risk AML or ALL.

Topics: Acute Disease; Adult; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Cytarabine; Disease-Free Survival; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid; Male; Melphalan; Middle Aged; Multivariate Analysis; Mycophenolic Acid; Neoplasm Recurrence, Local; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Retrospective Studies; Transplantation Conditioning; Treatment Outcome

28 patients with high-risk acute lymphoblastic (ALL) or acute myelogenous leukemia (AML) underwent nonmyeloablative stem cell transplantation (NST) from HLA-identical donors because of one or several contraindications against myeloablative conditioning. Out of 28 patients, nine (32%) had pulmonary or hepatosplenic infiltrates due to invasive fungal infections (IFI) before NST. Out of a total of 28 patients, 17 (61%) had uncontrolled leukemia before NST. Conditioning was performed with fludarabine 180 mg/m(2), busulfan 8 mg/kg and antithymocyte globulin 40 mg/kg. After NST, fever of unknown origin, sepsis or pneumonia developed in 18/28 patients (64%) overall. IFI reactivated in 3/9 patients after NST. Out of, 28 patients, 13 (46%) had late onset of acute graft-versus-host disease (GvHD), which developed at a median of 83 days after NST. GvHD frequently developed after donor lymphocyte infusions. After a median follow-up of 8 months (2-46 months), 14/28 patients (50%) have died from relapse and 1/28 patients (4%) has died from sepsis. Among 28 patients, 13 (46%) are alive in complete remission (CR). Six of 17 patients (35%) with uncontrolled disease and 7/11 patients (63%) with CR before NST are alive in CR. Probability of overall survival at 2 years is 38%. In summary, NST offers a therapeutic alternative to patients with high-risk ALL or AML, who have contraindications against conventional high-dose conditioning. Low NRM was encountered despite high morbidity, but relapse rate was high. Therefore, controlled studies are necessary to elucidate the place of NST in the therapy of high-risk acute leukemias.

Topics: Acute Disease; Adult; Antilymphocyte Serum; Busulfan; Contraindications; Cyclosporine; Female; Follow-Up Studies; Graft Survival; Graft vs Host Disease; Humans; Immunosuppressive Agents; Infection Control; Infections; Leukemia, Myeloid; Male; Middle Aged; Mycophenolic Acid; Mycoses; Myeloablative Agonists; Peripheral Blood Stem Cell Transplantation; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Risk; Survival Rate; T-Lymphocytes; Transplantation Conditioning; Treatment Outcome; Vidarabine; Whole-Body Irradiation

To evaluate the efficacy of combination of mycophenolate mofetil (MMF) with cyclosporine (CsA) and methotrexate (MTX) on prophylaxes of acute graft-versus-host disease (GVHD) in HLA-matched allogeneic peripheral blood stem cell transplantation (allo-PBSCT).. Thirty-nine patients with acute leukemia (n = 21) and chronic myeloid leukemia (n = 17) and severe aplastic anemia (n = 1) were treated with allo-PBSCT from HLA matched siblings (n = 36) or unrelated donors (n = 3). Twenty-six patients were in CsA + MTX group. CsA was given at a dosage of 2 mg.kg(-1).d(-1) by continuous intravenous injection for 24 h, since on day(-1) and injection of CsA was changed to oral administration of CsA around day 18. CsA was tapered by 10% per week after day + 90. MTX was given at the dosage of 15 mg at day + 1, and 10 mg at day + 3, + 6 and + 11, respectively. Thirteen patients were included in MMF + CsA + MTX group with the same dosage of CsA and MTX as above but omitted at day + 11. MMF of 2 g/day was added orally from day + 1 to day + 28 post transplantation.. All patients in both groups were successfully engrafted. The days of recovery of neutrophils and platelets were not significantly different between two groups (P > 0.05). The incidence of acute GVHD in MMF + CsA + MTX group (7.6%) was significantly lower than that in CsA/MTX group (46.2%, P < 0.05). Incidence of grade II approximately IV GVHD in MMF group was 0 while that in control group was 23.0%. The incidence of severe mucositis was lower in MMF group (15.4%) than in the control group (30.8%) (P < 0.05).. The regimen of MMF + CsA + MTX for prevention of acute GVHD in allo-PBSCT is more efficient than that of CsA + MTX, without adversely affecting the engraftment and relapse rate.

Topics: Acute Disease; Adult; Anemia, Aplastic; Blood Platelets; Chronic Disease; Cyclosporine; Drug Therapy, Combination; Female; Follow-Up Studies; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Incidence; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid; Male; Methotrexate; Middle Aged; Mouth Mucosa; Mycophenolic Acid; Neutrophils; Transplantation, Homologous; Treatment Outcome

Inosine 5'-monophosphate (IMP) dehydrogenase catalyzes the rate-limiting reaction of guanine nucleotide biosynthesis and has been implicated in the reaction of cell growth and differentiation. We investigated the ability of mycophenolate mofetil, a prodrug of mycophenolic acid, to induce differentiation in HL-60 and U937 leukemic cells as well as in fresh leukemia cells from patients with non-lymphocytic leukemia. Treatment with mycophenolate mofetil reduced the intracellular guanosine 5'-triphosphate (GTP) levels and induced morphologic and functional differentiation in HL-60 and U937 cells dose-dependently. HL-60 and U937 cells developed macrophage-like cytoplasm as well as the expression of CD11b and CD14 antigens and the ability to oxidize nitroblue tetrazorium (NBT). These changes became evident when the intracellular GTP levels decreased to approximately 20-30% of the untreated control level and were abrogated by the addition of guanosine. In the fresh leukemic cells, differentiation induction was shown in the cells derived from seven of 13 patients. The fresh leukemia cells responding to mycophenolate mofetil revealed significant higher positivity to CD11b, CD14, and NBT before treatment and significantly reduced intracellular GTP levels after treatment compared to the non-responding cells. These findings suggest that mycophenolate mofetil induces differentiation in HL-60 and U937 cells and some fresh leukemia cells with moderate tendency to maturation, by causing a decrease in the intracellular GTP levels. Mycophenolate mofetil could be a promising differentiation inducer in vivo.

Topics: Adult; Aged; Antineoplastic Agents; Cell Differentiation; Female; HL-60 Cells; Humans; Leukemia, Myeloid; Male; Middle Aged; Mycophenolic Acid; Myelodysplastic Syndromes; Tumor Cells, Cultured; U937 Cells

The effects of three different nucleotide biosynthesis inhibitors were tested on differentiation and purine/pyrimidine metabolism in HL60 cells. On the three nucleotide biosynthesis inhibitors, acivicin and mycophenolic acid were able to differentiate HL60 cells, while alanosine failed to do so. Differentiation of HL60 cells by acivicin and mycophenolic acid was associated with substantial decreases in both the guanylate and adenylate pools and appeared to be dependent on the state of depletion of intracellular GTP. Simultaneous addition of guanosine or guanine to mycophenolic acid-treated cells restored the GTP pool and prevented differentiation from occurring. Adenine or adenosine had no such effect, while hypoxanthine and inosine partially reversed the differentiation. In acivicin-treated cells, simultaneous addition of guanine caused partial prevention of differentiation. Even though treatment of HL60 cells with alanosine resulted in the depletion of guanylates, this effect was secondary to the depletion of adenylates and developed only upon prolonged exposure. In all the inhibitor-treated cells the activities of the key regulatory enzymes of de novo purine biosynthesis were affected. Even though the measurable activity of hypoxanthine/guanine phosphoribosyl transferase was enhanced in inhibitor-treated cells, the activity of the salvage pathway was inhibited in mycophenolic acid and alanosine-treated cells. Besides de novo purine nucleotide biosynthesis, de novo pyrimidine nucleotide biosynthesis was also inhibited in inhibitor-treated cells. The inhibition of purine and pyrimidine nucleotide biosynthesis in mycophenolic acid, acivicin and alanosine-treated cells resulted in an increase in the steady-state concentration of PRPP. Since purine and pyrimidine nucleotides play an important role in the synthesis of important macromolecules, it can be suggested that depletion of guanine ribonucleotide as a result of inhibition of early de novo purine biosynthesis, or due to specific inhibition of de novo guanine nucleotide biosynthesis, may be an obligatory step in the initiation of differentiation in mycophenolic acid and acivicin-treated HL60 cells.

Topics: Alanine; Cell Differentiation; Cell Division; Formates; Hematopoiesis; Humans; Hypoxanthine; Hypoxanthines; In Vitro Techniques; Inosine Monophosphate; Isoxazoles; Leukemia, Myeloid; Mycophenolic Acid; Phosphoribosyl Pyrophosphate; Purines; Pyrimidines; Reactive Oxygen Species; Tumor Cells, Cultured

Topics: Administration, Oral; Adult; Aged; Antibiotics, Antineoplastic; Caproates; Carcinoma; Esophageal Neoplasms; Female; Hodgkin Disease; Humans; Injections, Intraperitoneal; Injections, Intravenous; Leukemia, Lymphoid; Leukemia, Myeloid; Lymphoma, Large B-Cell, Diffuse; Male; Middle Aged; Multiple Myeloma; Mycophenolic Acid; Stomach Neoplasms