mycophenolic-acid and Precursor-Cell-Lymphoblastic-Leukemia-Lymphoma

Infliximab-daclizumab was used to treat acute and chronic liver and gut graft-versus-host disease (GVHD) in two children after standard immunosuppressive therapy failed. Infliximab (10 mg/kg weekly, 4 doses) and daclizumab (1 mg/kg, days 1, 4, 8, 15, and 22) were given over 1 month. In case 1, grade 2 chronic GVHD of the liver developed 1 year after transplantation and failed to improve with tacrolimus, mycophenolate mofetil, and prednisone. In case 2, corticosteroid-unresponsive grade 3 acute liver and gut GVHD developed on day +37. In both patients, GVHD responded to the infliximab-daclizumab regimen without toxicity and immunosuppressive therapy was discontinued.

Topics: Acute Disease; Adrenal Cortex Hormones; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Child; Chronic Disease; Combined Modality Therapy; Daclizumab; Drug Resistance; Drug Therapy, Combination; Graft vs Host Disease; Humans; Immunoglobulin G; Immunosuppressive Agents; Infliximab; Interleukin-2 Receptor alpha Subunit; Intestinal Mucosa; Leukemia, Myelomonocytic, Chronic; Liver; Mycophenolic Acid; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Recurrence; Remission Induction; Reoperation; Tacrolimus; Transplantation, Homologous; Tumor Necrosis Factor-alpha

Clinical efficacy of post-transplantation cyclophosphamide (PTCy) as graft-versus-host disease (GVHD) prophylaxis has been demonstrated in haploidentical and HLA-matched bone marrow but not in unrelated peripheral blood stem cell (PBSC) transplantations. Also, no direct comparisons have been published with current standard of care, combination of antithymocyte globulin (ATG), calcineurin inhibitors, and either methotrexate or mycophenolate mofetil (MMF). Eighty-six adult patients (median age 34 years; range, 18 to 59) with acute myeloblastic and lymphoblastic leukemia underwent unrelated PBSC transplantation with PTCy, tacrolimus, and MMF as GVHD prophylaxis in the single-center trial (clinicaltrial.govNCT02294552). The control group comprised 125 consecutive historical control patients who received ATG, tacrolimus, and methotrexate or MMF. Cumulative incidences of grades II to IV acute (19% versus 45%, P = .0003), grades III to IV acute (4% versus 27%, P < .0001), and chronic GVHD (16% versus 65%, P < .0001) were significantly lower in the PTCy compared with the ATG group. PTCy-based prophylaxis was associated with reduced incidence of nonrelapse mortality (16% versus 36%, P = .005; HR, .55; 95% CI, .34 to .89) and improved overall survival (69% versus 40%, P = .0007; HR, .43; 95% CI, .26 to .70), event-free survival (65% versus 38%, P = .0006; HR, .49; 95% CI, .31 to .78), and GVHD relapse-free survival (52% versus 12%, P < .0001). PTCy-based prophylaxis also had a better safety profile compared with ATG with reduced incidence of veno-occlusive disease, cytomegalovirus reactivation, invasive mycosis, and reduced severity of mucositis. In this study we demonstrated that PTCy in combination with tacrolimus and MMF is a safe and effective GVHD prophylaxis for unrelated PBSC transplantation. Although there are several limitations of the historical control approach, this study suggests the superiority of a PTCy-based approach over an ATG-based prophylaxis.

Topics: Adolescent; Adult; Antilymphocyte Serum; Calcineurin Inhibitors; Cyclophosphamide; Female; Graft vs Host Disease; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Mycophenolic Acid; Peripheral Blood Stem Cell Transplantation; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Premedication; Tacrolimus; Unrelated Donors; Young Adult

Data on pretransplantation minimal residual disease (MRD) and outcomes of umbilical cord blood transplantation (UCBT) are limited. Out of the 143 patients with acute lymphoblastic leukemia (ALL) who underwent UCBT at the University of Minnesota between 2004 and 2010, we evaluated 86 patients with available MRD assessment data by 4- and 8-color flow cytometry analysis immediately before transplantation. Ten patients (11.6%) were MRD-positive, and 76 were MRD-negative (88.4%). Most of the patients (82%) received myeloablative conditioning. GVHD prophylaxis consisted of cyclosporine and mycophenolate mofetil. In multivariate analysis, age, disease status (complete remission [CR] 1 versus CR2/CR3), disease group (precursor B cell ALL versus Philadelphia chromosome-positive ALL versus T cell ALL), and time to transplantation had no impact on relapse. Patients with MRD before UCBT had a greater incidence of relapse at 2 years (relapse rate, 30%; 95% confidence interval [CI], 4%-56%) and lower 3-year disease-free survival (30%; 95% CI, 7%-58%) compared with those without MRD (relapse rate, 16%; 95% CI, 8%-25%; P = .05; disease-free survival, 55%; 95% CI, 43%-66%; P = .02). Our data suggest that in patients with ALL, achieving an MRD-negative state before UCBT improves outcomes.

Topics: Adolescent; Adult; Age Factors; Antineoplastic Agents; Child; Child, Preschool; Cord Blood Stem Cell Transplantation; Cyclosporine; Disease-Free Survival; Female; Fetal Blood; Graft vs Host Disease; Humans; Infant; Male; Middle Aged; Mycophenolic Acid; Neoplasm, Residual; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Secondary Prevention; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome; Unrelated Donors

Hematopoietic stem cell transplantation could improve the prognosis of malignant hematologic diseases. Peripheral blood stem cell transplantation (PBSCT) has been gradually used as an alternative to bone marrow transplantation (BMT). This study was to observe the efficacy of allogeneic PBSCT (allo-PBSCT) or autologous PBSCT (auto-PBSCT) on malignant hematologic diseases.. From Jul. 2003 to May 2006, 53 patients with malignant hematologic diseases underwent PBSCT in the First Affiliated Hospital of Zhengzhou University. PBSCs were mobilized with granulocyte colony-stimulating factor (G-CSF) or chemotherapy combined with G-CSF. Auto-PBSCT group received infusion of CD34+ cells at a median of 3.0x10(6) cells/kg; allo-PBSCT group received infusion of CD34+ cells at a median of 6.2x106 cells/kg. MAC regimen was used in auto-PBSCT group as conditioning regimen; amended BU/CY regimen was used in allo-PBSCT group. Methotrexate (MTX) combined with cyclosporine A (CsA) and MMF was used for graft-versus-host disease (GVHD) prophylaxis. Antilymphocyte globulin (ALG) was used in 1 patient with 1 mismatched locus in allo-PBSCT group.. The median time for neutrophils to reach 0.5x10(9)/L and platelets to reach 20x10(9)/L were 13 days and 19 days in auto-PBSCT group, 12 days and 15 days in allo-PBSCT group. In allo-PBSCT group, grade I-III acute GVHD occurred in 31.4% cases, and chronic GVHD developed in 71.4% cases. The relapse rate was 38.9% in auto-PBSCT group and 5.7% in allo-PBSCT group. The 700-day disease-free survival rate (DFS) was 57.9% in auto-PBSCT group, and 69.5% in allo-PBSCT group.. PBSCT can provide rapid hematopoietic reconstitution. It is a better choice for the cure of malignant hematologic diseases.

Topics: Adolescent; Adult; Antigens, CD34; Antineoplastic Combined Chemotherapy Protocols; Child; Cyclosporine; Disease-Free Survival; Female; Follow-Up Studies; Graft vs Host Disease; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Acute; Male; Methotrexate; Middle Aged; Mycophenolic Acid; Peripheral Blood Stem Cell Transplantation; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Transplantation Conditioning; Transplantation, Homologous; Young Adult

A hematopoietic cell transplantation (HCT) approach was developed for elderly or ill patients with hematologic malignancies that employed nonmyeloablative conditioning to avoid common regimen-related toxicities and relied on graft-versus-tumor effects for control of malignancy. Eighty-nine patients, median age 53 years, were given fludarabine (90 mg/m2) and 2 Gy total body irradiation. Marrow (n = 18) or granulocyte colony-stimulating factor (G-CSF)-stimulated peripheral blood mononuclear cells (G-PBMCs; n = 71) were transplanted from unrelated donors matched for human leukocyte antigen A (HLA-A), -B, -C antigens and -DRB1 and -DQB1 alleles. Postgrafting immunosuppression included mycophenolate mofetil and cyclosporine. Donor T-cell chimerism was higher for G-PBMCs compared with marrow recipients. Durable engraftment was observed in 85% of G-PBMCs and 56% of marrow recipients. Cumulative probabilities of grade II, III, and IV acute graft-versus-host disease (GVHD) were 42%, 8%, and 2%, respectively. Nonrelapse mortality at day 100 and at 1 year was 11% and 16%, respectively. One-year overall survivals and progression-free survivals were 52% and 38%, respectively. G-PBMC recipients had improved survival (57% vs 33%) and progression-free survival (44% vs 17%) compared with marrow recipients. HLA-matched unrelated donor HCT after nonmyeloablative conditioning is feasible in patients ineligible for conventional HCT. G-PBMCs conferred higher donor T-cell chimerism, greater durable engraftment, and better progression-free and overall survivals compared with marrow.

Topics: Adolescent; Adult; Aged; Antibiotics, Antineoplastic; Child; Child, Preschool; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Histocompatibility Antigens Class I; Histocompatibility Testing; Humans; Immunosuppressive Agents; Incidence; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Myelomonocytic, Acute; Lymphocyte Transfusion; Lymphoma, Non-Hodgkin; Male; Middle Aged; Multiple Myeloma; Mycophenolic Acid; Myeloproliferative Disorders; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Survival Rate; Tissue Donors; Vidarabine; Whole-Body Irradiation

Both mismatched unrelated donor (MMUD) and haploidentical (haplo) transplantation are valid options in patients with high-risk acute lymphoblastic leukemia (ALL) lacking a matched donor.. The study compared the outcomes of adult patients with ALL in complete remission (CR) who underwent 9/10 MMUD versus haplo transplantation with posttransplant cyclophosphamide (PTCy) as graft-vs-host disease (GVHD) prophylaxis in 2010-2020.. Outcomes of MMUD and haplo transplants with PTCy-based GVHD prophylaxis for ALL patients in CR are similar, apart from a higher incidence of aGVHD with haplo transplants.

Topics: Acute Disease; Adult; Cyclophosphamide; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; HLA Antigens; Humans; Mycophenolic Acid; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Retrospective Studies; Transplantation Conditioning; Unrelated Donors

The capacity of respiratory viruses to undergo evolution within the respiratory tract raises the possibility of evolution under the selective pressure of the host environment or drug treatment. Long-term infections in immunocompromised hosts are potential drivers of viral evolution and development of infectious variants. We showed that intrahost evolution in chronic human parainfluenza virus 3 (HPIV3) infection in immunocompromised individuals elicited mutations that favored viral entry and persistence, suggesting that similar processes may operate across enveloped respiratory viruses. We profiled longitudinal HPIV3 infections from 2 immunocompromised individuals that persisted for 278 and 98 days. Mutations accrued in the HPIV3 attachment protein hemagglutinin-neuraminidase (HN), including the first in vivo mutation in HN's receptor binding site responsible for activating the viral fusion process. Fixation of this mutation was associated with exposure to a drug that cleaves host-cell sialic acid moieties. Longitudinal adaptation of HN was associated with features that promote viral entry and persistence in cells, including greater avidity for sialic acid and more active fusion activity in vitro, but not with antibody escape. Long-term infection thus led to mutations promoting viral persistence, suggesting that host-directed therapeutics may support the evolution of viruses that alter their biophysical characteristics to persist in the face of these agents in vivo.

Topics: Adult; Binding Sites; DNA Mutational Analysis; Female; Gene Frequency; Graft vs Host Disease; HEK293 Cells; Humans; Immunocompromised Host; Leukemia, Myeloid, Acute; Lung; Lung Diseases; Mutation; Mycophenolic Acid; N-Acetylneuraminic Acid; Parainfluenza Virus 3, Human; Paramyxoviridae Infections; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Receptors, Virus; Sirolimus; Viral Fusion Proteins; Virus Internalization; Young Adult

Haploidentical family donor is universally available and is fast emerging as an alternative donor choice for children with leukemia needing hematopoietic stem cell transplant (HSCT). Here we describe our experience of treating children with acute leukemia by haploidentical HSCT with posttransplant cyclophosphamide (PTCy).. We retrospectively analyzed the outcome data of 17 children with acute leukemia who underwent related haploidentical HSCT. Fifteen were in complete remission (CR) before HSCT: CR1-6, CR2-7, and CR3-2 and 2 were not in remission. Donors were mobilized with granulocyte colony stimulating factor. The conditioning was nonmyeloablative in 4 and myeloablative in 13. All received PTCy 50 mg/kg on days 3 and 4 as graft-versus-host disease (GVHD) prophylaxis along with tacrolimus or cyclosporine and mycophenolate mofetil. A median of 8.94 million of CD34+ cells/kg was infused.. All patients were engrafted for neutrophil and platelets, except 1 child with refractory acute myeloid leukemia disease who relapsed before engraftment. Five children relapsed (4 died and 1 child with CD20-positive leukemia is disease free after Rituximab therapy). There was 1 transplant-related mortality due to grade IV GVHD. Remaining 11 patients are in CR. Acute GVHD was seen in 4 patients. Of 4, 3 children later developed chronic GVHD and all are alive and disease free. Three of 4 children who received nonmyeloablative conditioning have relapsed. Overall survival is 70.5% and event-free survival is 64.7%. Median follow-up of all patients was 393 days.. Haploidentical HSCT with PTCy is a safe and effective therapy for children with acute leukemia. Myeloablative conditioning and chronic GVHD lead to improved disease-free survival.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Combined Modality Therapy; Cyclophosphamide; Cyclosporine; Female; Follow-Up Studies; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Infant; Leukemia, Myeloid, Acute; Male; Mycophenolic Acid; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Remission Induction; Retrospective Studies; Tacrolimus; Tissue Donors; Transplantation Conditioning; Transplantation, Haploidentical

Topics: Adolescent; Busulfan; Child; Child, Preschool; Cyclophosphamide; Cyclosporine; Female; Hematopoietic Stem Cell Transplantation; Humans; Infant; Leukemia; Leukemia, Myeloid, Acute; Male; Mycophenolic Acid; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Retrospective Studies; Treatment Outcome

Mycophenolate mofetil (MMF) is an immunosuppressive agent that is widely used in graft-versus-host disease prophylaxis because of its inhibitory function on T cells and B cells. However, the effect of MMF on natural killer cell reconstitution after allogenic hematological transplantation is largely unknown. The present study examined the effects of different MMF administration durations after haploidentical allo-HSCT on NK cell reconstitution. Ninety patients were enrolled in this study and defined into two groups in term of MMF duration. We found that MMF patients in the long-term MMF group were associated with a poor reconstitution of NK cells and a significantly lower cytotoxicity from day 30 to day 180 post-transplantation. Especially, the long-term MMF group inhibits reconstitution of NKp30 NK subsets, which correlated with higher risk of EBV viremia. Multivariate analysis showed that a better reconstitution of NKp30 cells was associated with lower EBV viremia (HR0.957, p = .04). In vitro experiments demonstrated that the active metabolite of MMF, mycophenolic acid (MPA), inhibited the proliferation and cytotoxicity of NK cells from healthy donors or patients at day 30 post-transplantation. In summary, our findings demonstrated that long-term MMF administration delayed the quality and quantity of NK cells, especially NKp30 subpopulations, which was associated with decreased EBV viremia post allogeneic HSCT.

Topics: Adolescent; Adult; Duration of Therapy; Epstein-Barr Virus Infections; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Herpesvirus 4, Human; Humans; Immune Reconstitution; Immunosuppressive Agents; Killer Cells, Natural; Leukemia, Myeloid, Acute; Male; Middle Aged; Mycophenolic Acid; Myelodysplastic Syndromes; Natural Cytotoxicity Triggering Receptor 3; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Proportional Hazards Models; Transplantation, Homologous; Viremia; Young Adult

In order to examine GvHD prophylaxis in umbilical cord blood transplantation (UCBT) in more detail, we compared transplant outcomes after UCBT for acute leukemia among GvHD prophylaxes using registry data. We selected patients transplanted with a calcineurin inhibitor and methotrexate (MTX)/mycophenolate mofetil (MMF) combination. A total of 1516 first myeloablative UCBT between 2000 and 2012 (Cyclosporine A (CyA) plus MTX, 824, Tacrolimus (Tac) plus MTX, 554, Tac plus MMF, 138) were included. With adjusted analyses, Tac plus MMF showed a significantly higher risk for grade II-IV and III-IV acute GvHD than CyA or Tac plus MTX. Although NRM was similar, Tac plus MMF showed a significantly lower risk of relapse than CyA or Tac plus MTX. A significant difference was observed in the risk of overall mortality (OM) between the MTX-containing group and MMF-containing group. In patients with standard-risk disease, there was no significant difference in the risk of OM in any GvHD prophylaxis. However, in patients with advanced-risk disease, Tac plus MMF showed a significantly lower risk of OM. Therefore, MTX-containing prophylaxis is preferred in UCBT for standard-risk disease, whereas MMF-containing prophylaxis is preferred for advanced-risk disease. A prospective study to identify optimal GvHD prophylaxis for UCBT is warranted.

Topics: Adolescent; Adult; Cord Blood Stem Cell Transplantation; Cyclosporine; Disease-Free Survival; Female; Graft vs Host Disease; Humans; Incidence; Japan; Leukemia, Myeloid, Acute; Male; Methotrexate; Middle Aged; Mycophenolic Acid; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Registries; Survival Rate; Tacrolimus

To retrospectively analyze the efficacy of unrelated umbilical cord blood transplantation (UCBT) with intensified myeloablative conditioning regimen in patients with acute lymphoblastic leukemia (ALL).. From September 2006 to December 2013, a total of 110 consecutive patients with ALL had received UCBT, including 79 male and 31 female patients with a median age of 14(2-51) years, a median weight of 45(12-100)kg. Sixty-one cases were in the first complete remission (CR), 30, 6 and 13 patients in the second, the third CR and advanced stages respectively. The conditioning regimen consisted of total body irradiation, cyclophosphamide and cytarabine (TBI/Cy/Ara-C) in 61 patients, busulfan, cyclophosphamide and fludarabine (BU/Cy/Flu) in 39 patients and BU/Cy/Ara-C in 10 patients. All patients received a combination of cyclosporine (CsA) and mycophenolate mofetil (MMF) for the prophylaxis of graft-versus-host disease (GVHD).. The median amount of total nuclear cells(TNC) and CD34(+) cells were 3.90(1.97-13.50)×10(7)/kg and 2.07(0.40-5.56)×10(5)/kg. The cumulative incidence of sustained donor engraftment was 94.5% (95% CI 94.5%-94.6%) at a median of 18 days after transplantation (range, 12-37 days). The cumulative incidence of platelet recovery at 180 days after transplantation was 82.1% (95% CI 81.8%-82.4%) with a median time to recovery of 40 (range, 15-153) days. Incidences of grade Ⅱ~Ⅳ and Ⅲ~Ⅳ acute GVHD were 21.8% and 10.9% respectively. The cumulative incidence of chronic GVHD was 17.9%. During a median follow up period of 26 (range 6-94) months, the disease free survival (DFS) and overall survival (OS) rates at 3 years were 54.5% and 58.8%, respectively. The transplantation-related mortality (TRM) at 180 days after transplantation was 22.7%. The cumulative incidence of 3-year relapse rate was 18.3% (95% CI 17.9%-18.6%).. UCBT with intensified myeloablative conditioning regimen not only improves the donor engraftment, but also shortens the interval of neutrophil and platelet recovery. It is a safe and effective option for children and adult ALL patients lack of matched related donors.

Topics: Adolescent; Adult; Busulfan; Child; Child, Preschool; Cord Blood Stem Cell Transplantation; Cyclophosphamide; Cytarabine; Disease-Free Survival; Female; Fetal Blood; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Incidence; Male; Middle Aged; Mycophenolic Acid; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; Remission Induction; Retrospective Studies; Survival Rate; Transplantation Conditioning; Treatment Outcome; Vidarabine; Young Adult

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

We retrospectively reviewed 242 patients who received related donor myeloablative peripheral blood hematopoietic cell transplantation. We compared patients who received mycophenolate (MMF)/cyclosporine (CSA) (n = 71), to historical controls who received methotrexate (MTX)/CSA (n = 172). There were no differences in overall survival, nonrelapse mortality, and relapse. The MMF/CSA group had significantly faster neutrophil and platelet engraftment: medians of 13 versus 18 days and 10 versus 14 days, respectively (P = 0.001). The cumulative incidence of acute graft versus host disease (GVHD) (Grades, 2-4) was significantly lower in the MMF/CSA group (45.1 vs. 74.4%, P < 0.001). The MMF/CSA group showed a lower incidence of skin (51.5 vs. 72.1%, P < 0.001) and liver acute GVHD (11.3 vs. 54.2%, P < 0.001) and a higher incidence of lung (42.2 vs. 19.0%, P = 0.045), eye (59.7 vs. 30.1%, P < 0.001), and mouth (72.8 vs. 56.4%, P = 0.001) chronic GVHD but only eye chronic GVHD was confirmed in propensity score matching (PSM) analysis. The incidence of cytomegalovirus (CMV) viremia was higher in the MMF/CSA group (55.8 vs. 39.6%, P < 0.001) but this was not confirmed in PSM analysis. MMF/CSA was identified as an independent favorable factor for acute GVHD (P < 0.001, hazard ratio, 0.41) but as a possible adverse risk factor for CMV viremia as this was not found to be statistically significant in PSM analysis. MMF/CSA in myeloablative matched related donor peripheral blood stem cell transplant is not inferior as GVHD prophylaxis in comparison with MTX/CSA and is associated with faster engraftment but a potentially higher risk of CMV viremia.

Topics: Adolescent; Adult; Antibiotics, Antineoplastic; Cyclosporine; Cytomegalovirus; Cytomegalovirus Infections; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Leukemia, Myeloid, Acute; Male; Methotrexate; Middle Aged; Mycophenolic Acid; Myeloablative Agonists; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; Retrospective Studies; Survival Analysis; Tissue Donors; Transplantation Conditioning; Transplantation, Homologous

Opportunistic infections cause a significant morbidity and mortality in immunocompromised patients. We describe the case of a patient with skin fusariosis and a probable cerebral toxoplasmosis after UCB stem cell transplantation for B-cell acute lymphoblastic leukaemia. Fusarium species (spp) infections are difficult to treat. To date, there has been no consensus on the treatment of fusariosis and the management of its side effects. Given the negative pretransplant Toxoplasma serology in this case, identifying the origin of the Toxoplasma infection was challenging. All usual transmission routes were screened for and ruled out. The patient's positive outcome was not consistent with that of the literature reporting 60% mortality due to each infection.

Topics: Adolescent; Amphotericin B; Cord Blood Stem Cell Transplantation; Dermatomycoses; Diagnosis, Differential; Drug Therapy, Combination; Febrile Neutropenia; Female; Fusariosis; Gibberella; Humans; Mycophenolic Acid; Opportunistic Infections; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyrimethamine; Retreatment; Sulfadiazine; Toxoplasmosis, Cerebral

Topics: Adolescent; Anti-Inflammatory Agents, Non-Steroidal; Antiviral Agents; Cytomegalovirus Infections; Esophageal Diseases; Female; Foscarnet; Humans; Immunocompromised Host; Mycophenolic Acid; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Ulcer

We describe herein the clinical courses and outcomes of 26 patients who received oral mycophenolate mofetil (MMF) for the treatment of steroid-resistant refractory or steroid-dependent acute or chronic graft-versus-host disease (GVHD) in a single institution. In most cases, 1,500 mg/day of MMF is a median dose (range 500-3,000 mg/day) and administered for 116.5 days (range 9-584 days) along with calcineurin inhibitors and steroids. Although 20 patients (77%) showed rapid improvement of GVHD symptoms, of 15 patients, 13 (87%) showed acute GVHD; of 11 patients, 7 (64%) showed chronic GVHD; most patients (54%) experienced infection during MMF administration, including 5 cases with life-threatening infection. Positive cytomegalovirus (CMV) antigenemia was also observed in 19 patients (73%), but no patients developed CMV infection. Within the median follow-up of 12.5 months (range 0.5-67 months), 10 patients (39%) died. This small study demonstrates that MMF offers an alternative tool for rescuing steroid-refractory or steroid-dependent GVHD, but increases the risk of developing life-threatening infection.

Topics: Acute Disease; Adult; Anemia, Aplastic; Chronic Disease; Female; Graft vs Host Disease; Humans; Immunocompromised Host; Immunosuppressive Agents; Infections; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Acute; Male; Middle Aged; Mycophenolic Acid; Myelodysplastic Syndromes; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Retrospective Studies; Risk Factors; Stem Cell Transplantation; Survival Analysis; Transplantation, Homologous; Young Adult

Topics: Adrenal Cortex Hormones; Adult; Biopsy, Needle; Follow-Up Studies; Graft vs Host Disease; Humans; Immunohistochemistry; Lichen Sclerosus et Atrophicus; Male; Mycophenolic Acid; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Scleroderma, Localized; Stem Cell Transplantation; 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 explore the clinical application of human leukocyte antigen (HLA) mismatched hematopoietic stem cell transplantation (HSCT) for malignant hematological diseases using a new GIAC protocol.. One hundred patients with malignant hematological disease received G-CSF mobilization, intensive immunosuppression, ATG and combination of bone marrow and peripheral blood stem cell transplantation at least 1 locus mis-matched hematopoietic stem cell transplant performed with GIAC protocol. The conditioning regimen was intensified and prolonged with combined use of CsA, MMF and ATG for GVHD prophylaxis.. All patients achieved sustained, full donor-type engraftment. The cumulative incidence of grade II approximately IV aGVHD was 48.39%, and grade III approximately IV aGVHD was 12.90%. Thirty-eight patients had cGVHDs which were of extensive type in 11 patients. Twelve patients relapsed, 11 of them were high-risk patients, and 3 returned to CR after donor lymphocyte infusion. Twenty-two patients died, owing to recurrent diseases in 6 and transplant-related complications in 16 cases. Seventy-two patients were alive and disease free, with 1 year disease-free survival probabilities for standard and high risk patients of (83.52 +/- 7.41)% and (47.63 +/- 8.49)%, respectively.. The GIAC protocol for at least 1 locus mismatched hematopoietic stem cell transplantation is relatively safe and efficient for patients with hematological malignancies.

Topics: Adolescent; Adult; Antilymphocyte Serum; Bone Marrow Transplantation; Child; Child, Preschool; Cyclosporine; Female; Graft vs Host Disease; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Histocompatibility Testing; Humans; Immunosuppressive Agents; Leukemia, Myeloid, Acute; Male; Methotrexate; Middle Aged; Mycophenolic Acid; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Transplantation, Homologous

To explore the feasibility of HLA mismatched hemopietic stem cell transplants for the treatment of leukemia.. Between July 2000 and December 2001, seven patients received hemopietic stem cell transplants(HSCT) with HLA mismatched family donors, including 3 chronic myelocytic leukemia (CML), 3 acute nonlymphocytic leukemia (ANLL), and 1 acute lymphocytic leukemia (ALL). Stem cell sources were bone marrow(n = 1) or G-CSF mobilized peripheral blood (n = 6). All the patients were conditioned with busulfan (BU) 12 mg.kg-1 and cyclophosphamide (CY) 3.6 g.m-2, of whom 4 were conditioned with additioned antithymocyte globulin(ATG). Graft versus host disease (GVHD) prophylaxis regimen consisted of cyclosporin-A (CSA), methotrexate (MTX) and mycophenolate mofetil(MMF).. One patients received 3.41 x 10(8) kg-1 mononuclear cells(MNC) from bone marrow; six patients received a mean number of 8.46 x 10(8) kg-1 (4.3 x 10(8)-15.4 x 10(8) kg-1) MNC from peripheral blood. The mean time of ANC > 0.5 x 10(9) L-1 was day 13 (11-16), and BPC > 20.0 x 10(9) L-1 was day 16 (11-23). All the patients got engraftment successfully and attained CR. Acute I-II GVHD occurred in 3(42.9%) patients, no acute III-IV GVHD occurred and extensive chronic GVHD did in 2(28.6%) patients. All the patients were alive and well after 6-24 months' follow-up.. (1) BU/CY plus ATG appears to be an effective conditioning regimen for HLA mismatched allogenic stem cell transplants. (2) G-CSF mobilized peripheral blood stem cells may be the source of stem cells even for HLA mismatched hemopietic stem cell transplants.

Topics: Bone Marrow Transplantation; Cyclophosphamide; Cyclosporine; Graft vs Host Disease; Granulocyte Colony-Stimulating Factor; Histocompatibility Antigens Class II; HLA Antigens; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Acute; Methotrexate; Mycophenolic Acid; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Stem Cell Transplantation; Transplantation Conditioning; Transplantation, Homologous

To explore the hematopoietic and immunologic reconstitution and transplantation-related complications of HLA one locus mismatched unrelated umbilical cord blood transplantation for the treatment of hematological malignancies.. Two children with acute lymphoblastic leukemia received HLA-mismatched unrelated umbilical cord blood transplantation. The conditioning regimens were BU-CTX (case 1) and BU-CTX plus BCNU (case 2). GVHD prophylaxis regimen consisted of cyclosporine (CsA) and mycophenolate mofetil (MMF). The patients received 14.6 x 10(7) nucleated cells/kg with 7.24 x 10(5) CD(34)(+) cells/kg and 16.24 x 10(7) nucleated cells/kg with 21.11 x 10(5) CD(34)(+) cells/kg, respectively.. The two recipients, ANC > 0.5 x 10(9)/L occurred at day 27 and day 17, BPC > 50 x 10(9)/L at day 53 and day 46, the peripheral blood counts normalization at day 60 and day 52, the immune function normalization at day 134 and day 122 and the DNA fingerprinting showing engraftment at day 19 and day 17, respectively. The donor-recipient pair of case 1 was male to female, and the chromosome karyotype of recipients bone marrow and peripheral blood cells showed 100%, 46, XY cells at day 49. Grade II acute graft versus host disease (aGVHD) occurred at day 26 (case 1) and day 21 (case 2). The two recipients have survived for 353 days and 256 days.. The hematopoietic and immunologic reconstitution in umbilical cord blood transplantation were earlier and more durable. The transplantation-related complications were less and aGVHD were milder.

Topics: Child, Preschool; Cyclosporine; DNA Fingerprinting; DNA, Neoplasm; Female; Fetal Blood; Graft Survival; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Histocompatibility Testing; HLA Antigens; Humans; Immunosuppressive Agents; Infant; Male; Mycophenolic Acid; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Transplantation Conditioning

We describe a 55-year-old woman with acute lymphoblastic leukemia (ALL) in the first remission who underwent nonmyeloablative stem cell transplantation with conditioning consisting of low-dose total body irradiation and postgrafting cyclosporine and mycophenolate mofetil. Myelosuppression was mild, but on day 28 her bone marrow showed 8.8% lymphoblasts. We withdrew the cyclosporine, but the patient developed grade 2 acute GVHD and eosinophilia. The proportion of bone marrow lymphoblasts decreased transiently to 1.0% on day 40, but later increased again and the patient died on day 85. Application of this approach to patients with ALL needs to be examined on a large scale.

Topics: Cyclosporine; Female; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Middle Aged; Mycophenolic Acid; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Transplantation Conditioning; Whole-Body Irradiation

6-Mercaptopurine (6MP) cytotoxicity was studied in Molt F4 cells, a T-cell acute lymphoblastic leukemia (ALL) cell line. The effects on cytotoxicity were concentration-dependent. Measurements of intracellular thionucleotide intermediates of 6MP demonstrated a rapid rise of thio-IMP (tIMP) levels, and subsequently a rapid decrease. Thio-GMP (tGMP) and methyl-thio-IMP (Me-tIMP) appeared later in time, and persisted longer. Mycophenolic acid (MPA), a specific inhibitor of IMP dehydrogenase (IMPDH), was used to inhibit the conversion of tIMP into tGMP, thereby decreasing the incorporation of 6MP into DNA. A synergistic effect on cell viability and cell growth was observed when cells were treated with a combination of 2 microM 6MP and 0.5 microM MPA. Also, intracellular Me-tIMP increased 5 times with the combination. Based on the increase of Me-tIMP concentration and the observed synergism between 6MP and MPA, we conclude that methylation of tIMP into Me-tIMP is an important alternative route for 6MP cytotoxicity.

Topics: Cytotoxins; Drug Synergism; Humans; Mercaptopurine; Mycophenolic Acid; Precursor Cell Lymphoblastic Leukemia-Lymphoma; T-Lymphocytes; Tumor Cells, Cultured

Topics: Biotransformation; Carbon Radioisotopes; Cell Division; Cell Line; Cell Survival; Humans; IMP Dehydrogenase; Inosine Monophosphate; Leukemia-Lymphoma, Adult T-Cell; Mercaptopurine; Mycophenolic Acid; Precursor Cell Lymphoblastic Leukemia-Lymphoma