mycophenolic-acid and Hematologic-Diseases

Pancreas-kidney transplant is an effective treatment for patients with insulin-dependent dabetes and chronic renal failure. Reduction in technical failure loss and early acute rejection rates contributed to prolong pancreas graft survival. However, drug toxicity affects negatively both short- and long-term follow-ups.. This article reviews the existing literature and knowledge of the immunosuppressive drugs that are frequently used in pancreas transplant, including calcineurin inhibitors, sirolimus, corticosteroids, and mycophenolate. The article also discusses the short- and long-term adverse effects of these drugs. The article also reports and discusses the most relevant in vitro studies, providing additional information to in vivo findings. Some clinically relevant drug interactions with immunosuppressive drugs are also highlighted. Over- and underimmunosuppression effects will not be addressed.. Immunosuppressive regimen after pancreas transplant is very effective and contributed to pancreas allograft survival. However, they present several side effects that are potentiated when drugs are combined. Modifiable and non-modifiable risk factors can aggravate metabolic and toxicological effects of immunosuppressive drugs. It is important to critically analyze the results of clinical studies and investigate new immunosuppressive drugs and/or novel drug combinations. It is equally important to comprehend and interpret experimental data. Therefore, minimization of side effects, based on safe approaches, can prolong pancreas allograft survival.

Topics: Adrenal Cortex Hormones; Bone Diseases; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Gastrointestinal Diseases; Graft Rejection; Graft Survival; Hematologic Diseases; Humans; Hyperkalemia; Hyperuricemia; Immunosuppressive Agents; Mycophenolic Acid; Nervous System Diseases; Pancreas Transplantation; Pneumonia; Renal Insufficiency, Chronic; Sirolimus

There is accumulating evidence indicating that endothelial factors are involved in the pathogenesis of GVHD. We have recently shown that steroid-refractory, but not sensitive, GVHD is characterized by higher pretransplantation serum levels of angiopoetin-2 (ANG2), a hormone mediating endothelial vulnerability. To evaluate whether endothelial vulnerability is a risk factor for GVHD per se or becomes important only when noticeable GVHD is established, we measured ANG2 along with additional serum markers of endothelial stress, including soluble thrombomodulin (sTM), IL-8 (CXCL8), and hepatocyte growth factor (HGF), in patients with no, low-grade, or severe GVHD. Patients with refractory GVHD exhibited elevated serum levels of ANG2, sTM, HGF, and IL-8 posttransplantation compared with patients with sensitive GVHD and patients without GVHD. Pretransplantation ANG2 was the only growth factor correlated with the risk of refractoriness and mortality, and then only within the subset of patients who developed grade III-IV GVHD. In contrast, ANG2 was not predictive of GVHD or nonrelapse mortality (NRM) in patients with no GVHD or low-grade GVHD. These findings provide evidence that endothelial function plays an important role in the pathogenesis of steroid refractoriness in ongoing GVHD; however, endothelial vulnerability does not predict incidence of GVHD.

Topics: Adolescent; Adult; Aged; Endothelium, Vascular; Female; Glucocorticoids; Graft vs Host Disease; Hematologic Diseases; Hematopoietic Stem Cell Transplantation; Hepatocyte Growth Factor; Humans; Immunosuppressive Agents; Incidence; Interleukin-8; Male; Middle Aged; Mycophenolic Acid; Prednisolone; Retrospective Studies; Risk Factors; Thrombomodulin; Transplantation, Homologous; Vesicular Transport Proteins

The optimal graft-versus-host disease (GVHD) prophylaxis after umbilical cord blood transplantation has not been established. Our previous observation using single calcineurin inhibitors revealed a high incidence and severity of early immune-mediated complications, especially for older patients or those with poor performance status.. We conducted a single institute pilot study assessing the safety and effectiveness of mycophenolate mofetil (MMF) and tacrolimus (FK) combination as a GVHD prophylaxis for 29 patients (FK+MMF), and the results were compared with matched-pairs extracted from our historical database who received FK alone as GVHD prophylaxis (control).. FK+MMF group showed superior engraftment rate compared with control group (cumulative incidence until day 60 posttransplant; 90%±0% vs. 69%±1%, P=0.02). A cumulative incidence of severe type preengraftment immune reactions was significantly decreased in FK+MMF group (16%±1%) compared with that of control group (52%±2%, P=0.03), and, remarkably, there was no nonrelapse mortality (NRM) observed up to day 30 posttransplant in FK+MMF group, whereas 21%±1% of NRM was observed in the control group. However, the incidences of acute and chronic GVHD, estimated overall and progression-free survivals were comparable between two groups.. MMF and FK in combination was well tolerated and decreased early NRM possibly by better control of preengraftment immune reactions. Subsequent NRM or disease progression needs to be overcome to further improve survival.

Topics: Acute Disease; Age Factors; Aged; Chronic Disease; Cord Blood Stem Cell Transplantation; Databases, Factual; Disease Progression; Disease-Free Survival; Female; Graft vs Host Disease; Hematologic Diseases; Humans; Immunosuppressive Agents; Incidence; Male; Matched-Pair Analysis; Middle Aged; Mycophenolic Acid; Pilot Projects; Tacrolimus

To improve the outcome of allogeneic stem cell transplantation (allo-SCT) in multiple myeloma as part of first-line treatment, we prospectively investigated the feasibility and efficacy of lenalidomide maintenance. Patients started maintenance 1 to 6 months after nonmyeloablative allo-SCT. Lenalidomide was dosed 10 mg on days 1 to 21 of a 28-day schedule for a total of 24 cycles. Peripheral blood samples were taken to evaluate immune modulating effects. Thirty-five eligible patients were enrolled, and 30 started with lenalidomide. After 2 cycles, 14 patients (47%) had to stop treatment, mainly because of the development of acute graft versus host disease (GVHD). In total, 13 patients (43%) stopped treatment because of development of GVHD, 5 patients (17%) because of other adverse events, and 5 patients (17%) because of progression. Responses improved in 37% of patients, and the estimated 1-year progression-free survival from start of maintenance was 69% (90% confidence interval, 53%-81%). Lenalidomide increased the frequency of human leukocyte antigen-DR(+) T cells and regulatory T cells, without correlation with clinical parameters. In conclusion, lenalidomide maintenance 10 mg daily after nonmyeloablative allo-SCT with unmanipulated graft in multiple myeloma patients is not feasible, mainly because of the induction of acute GVHD. This trial was registered at www.trialregister.nl as #NTR1645.

Topics: Acute Disease; Adult; Aged; Antineoplastic Agents; Combined Modality Therapy; Cyclophosphamide; Cyclosporine; Disease-Free Survival; Drug Eruptions; Feasibility Studies; Female; Graft vs Host Disease; Hematologic Diseases; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Humans; Immunologic Factors; Immunosuppressive Agents; Lenalidomide; Lymphocyte Count; Male; Melphalan; Middle Aged; Multiple Myeloma; Mycophenolic Acid; Prospective Studies; Remission Induction; Thalidomide; Transplantation Conditioning; Transplantation, Autologous; Transplantation, Homologous; Whole-Body Irradiation

A large-scale, controlled clinical study has shown that enteric-coated mycophenolate sodium (EC-MPS) is therapeutically equivalent to mycophenolate mofetil (MMF) in de novo renal transplant patients. Safety and efficacy outcomes from an open-label extension of this core study (n = 122) were compared to those of the MMF arm of two well-controlled randomized studies (RAD B251, n = 141, and RAD B201, n = 150) for the 12- to 36-month posttransplant period. During this period, 33 (27%) EC-MPS patients experienced one or more drug-related adverse event. Sixteen patients (13%) discontinued the extension study due to adverse events. The incidence of all safety parameters was similar in the EC-MPS patients and the MMF-treated patients in the RAD B201 and RAD B251 studies during the 12- to 36-month posttransplant period, as was the frequency of adverse events, infections, malignancies, and hematological abnormalities. During the 24 months of the EC-MPS extension study, four patients died and two lost their graft. Biopsy-proven acute rejection (BPAR) occurred in four patients (3.3%). BPAR, graft loss, and death occurred in a similar proportion of MMF-treated patients in the RAD B201 and RAD B251 studies during months 12 to 36 posttransplant. These findings confirm the safety and efficacy of EC-MPS in maintenance transplant patients at least 1 year posttransplant and suggest that outcomes with EC-MPS are comparable to MMF in this population when used in combination with CsA-ME and steroids.

Topics: Adult; Cytomegalovirus Infections; Female; Follow-Up Studies; Graft Rejection; Hematologic Diseases; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Neoplasms; Postoperative Complications; Tablets, Enteric-Coated; Time Factors

Tacrolimus (FK506)/mycophenolate mofetil (MMF) has been demonstrated to be an effective salvage therapy for steroid-resistant chronic graft-versus-host disease (GVHD), but its effectiveness as prophylaxis for acute GVHD (aGVHD) is unknown. We investigated the safety and efficacy of FK506/MMF in preventing aGVHD and sparing the use of methotrexate and methylprednisolone in childhood and adolescent allogeneic stem cell transplant (AlloSCT) recipients. Thirty-four childhood and adolescent patients (median age, 7 years; range, 0.5-21 years; 24 males and 10 females) undergoing 37 AlloSCTs for malignant (n = 22) and nonmalignant (n = 12) disorders received FK506 (0.03 mg/kg/d by continuous intravenous infusion) and MMF (15 mg/kg per dose orally or intravenously twice daily). Stem cell sources included 22 umbilical cord blood donors (21 unrelated and 1 related), 6 related bone marrow donors, and 9 related peripheral blood donors. Malignant diagnoses included 7 acute lymphoblastic leukemias, 3 acute myeloid leukemias, 1 acute promyelocytic leukemia, 2 non-Hodgkin lymphomas, 4 Hodgkin diseases, 3 chronic myeloid leukemias, and 2 neuroblastomas; nonmalignant diagnoses included 2 beta-thalassemias, 1 sickle cell disease, 4 aplastic anemias, 1 Wiskott-Aldrich syndrome, 1 Hurler syndrome, 2 hemophagocytic lymphohistiocytoses, and 1 myelodysplastic syndrome. The probability of developing grade > or =II aGVHD was 45.4% +/- 9.7% (7 related bone marrow/related peripheral blood; 5 umbilical cord blood), and for chronic GVHD it was 38.1% +/- 19.7%. FK506/MMF was well tolerated. Three patients had grade III to IV neurotoxicity (disorientation and leukoencephalopathy); 4 patients developed grade III to IV nephrotoxicity (all received concomitant nephrotoxins). Patients who achieved target mycophenolic acid levels (1.0-3.5 microg/mL) before day +30 had a significantly reduced incidence of developing grade >/=II aGVHD (16.7% +/- 15.2% versus 100%; P <.02). These results suggest that FK506/MMF is well tolerated and may be a safe and effective methotrexate- and methylprednisolone-sparing alternative GVHD prophylaxis regimen after AlloSCT. Further pharmacokinetic and pharmacodynamic studies are ongoing in pediatric and adolescent AlloSCT recipients to define optimal MMF dosing.

Topics: Adolescent; Adult; Child; Child, Preschool; Drug Resistance; Drug Therapy, Combination; Female; Graft vs Host Disease; Hematologic Diseases; Humans; Immunosuppressive Agents; Infant; Male; Mucopolysaccharidosis I; Mycophenolic Acid; Neuroblastoma; Pilot Projects; Prognosis; Stem Cell Transplantation; Tacrolimus; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome

Topics: Adult; Azathioprine; Gastrointestinal Diseases; Graft Rejection; Hematologic Diseases; Humans; Immunosuppressive Agents; Iran; Kidney Transplantation; Mycophenolic Acid; Time Factors

The objective of this study was to identify the effects of mycophenolate mofetil (MMF) on non-renal manifestations in systemic lupus erythematosus (SLE).. The study population comprised 439 SLE patients from the Korean Lupus Network registry who were followed up annually and completed the baseline survey and two follow-up visits from 2014 to 2018. Disease activity, laboratory markers, and clinical manifestations including mucocutaneous lesions, arthritis, serositis, neurological disorders, and hematologic/immunologic abnormalities were assessed. All variables by group (MMF and non-MMF) effects with time (baseline, 1st follow-up, and 2nd follow-up) were analyzed by generalized estimation equation.. Seventy-two patients were treated with MMF. There was significant difference in frequencies of malar rash, arthritis, renal disorder, and hematologic disorder between MMF and non-MMF groups in total SLE patients. In subgroup analysis of hematologic abnormalities in total patients, frequency of leukopenia was significantly different between the two groups during follow-up (. This study showed that MMF might be a beneficial treatment for hematologic abnormalities, especially leukopenia, in SLE.

Topics: Adult; Depression; Exanthema; Female; Hematologic Diseases; Humans; Lupus Erythematosus, Systemic; Male; Middle Aged; Mycophenolic Acid; Quality of Life; Registries; Republic of Korea

Human herpesvirus 6 (HHV-6) encephalitis/myelitis is now a well-known complication after allogeneic stem cell transplantation (allo-HSCT), particularly after cord blood transplantation (CBT). In this study, we evaluated the risk factors of HHV-6 encephalitis/myelitis.. We evaluated 253 patients who received allo-HSCT from 2007 to 2015 at our institute. HHV-6 encephalitis/myelitis was defined as HHV-6 DNA detection in the cerebrospinal fluid or peripheral blood by polymerase chain reaction in the presence of typical manifestations without other concurrent condition that led to the manifestations.. HHV-6 encephalitis/myelitis occurred in 11 patients (4.5%) (9 encephalitis, 3.7%; 2 myelitis, 0.8%). Multivariate analysis showed that CBT, mycophenolate mofetil (MMF) for graft-versus-host disease prophylaxis, history of allogeneic hematopoietic stem cell transplantation (allo-HSCT), and engraftment syndrome (ES) were significantly associated with incidence of HHV-6 encephalitis/myelitis (P=.025, P=.017, P=.017, and P=.014, respectively).. Although it has been shown that CBT, ES, and history of allo-HSCT are risk factors for HHV-6 encephalitis/myelitis, our study demonstrated MMF is also a risk factor for the disease.

Topics: Adolescent; Adult; Aged; Cord Blood Stem Cell Transplantation; DNA, Viral; Encephalitis, Viral; Female; Graft vs Host Disease; Hematologic Diseases; Hematopoietic Stem Cell Transplantation; Herpesvirus 6, Human; Humans; Immunosuppressive Agents; Incidence; Male; Middle Aged; Mycophenolic Acid; Myelitis; Polymerase Chain Reaction; Risk Factors; Roseolovirus Infections; Transplantation Conditioning; Transplantation, Homologous; Young Adult

Our previous study of 301 patients who received hematopoietic stem cell transplantation (HSCT) from related donors demonstrated the efficacy of mycophenolate mofetil (MMF) for prophylaxis and treatment of graft-vs.-host disease (GVHD). In this study, we investigated the safety and efficacy of MMF in 716 adult patients who received unrelated HSCT. The incidences of Grade II-IV and III-IV acute GVHD in the prophylactic administration group were 38.3% and 14.3%, respectively. These rates were not statistically significant when evaluating the MMF dosage and graft source. The incidences of limited and extensive chronic GVHD were 16.6% and 11.1%, respectively. In the therapeutic administration group, 69.1% of the subjective symptoms for both acute and chronic GVHD improved. With respect to the adverse events, 75 infections and 50 cases of diarrhea were observed, and the frequency of these events increased with increasing MMF dose. The overall survival rate was 36.4% after a median follow-up period of three yr. This study shows that MMF is safe and effective for the prevention and treatment of GVHD in patients who have received HSCT from unrelated donors.

Topics: Adolescent; Adult; Aged; Female; Follow-Up Studies; Graft vs Host Disease; Hematologic Diseases; Hematopoietic Stem Cell Transplantation; Histocompatibility; Humans; Immunosuppressive Agents; Japan; Male; Middle Aged; Mycophenolic Acid; Prognosis; Retrospective Studies; Tissue Donors; Transplantation Conditioning; Transplantation, Homologous; Young Adult

Recent studies have shown that mycophenolate mofetil (MMF) is similar to intravenous cyclophosphamide (IVC) for the treatment of lupus nephritis (LN), but that treatment response may vary according to location and race/ethnicity. Moreover, no studies have been conducted to compare the efficacy of MMF with that of IVC for a Japanese population. We therefore conducted a retrospective study to clarify the efficacy and safety of MMF compared with that of IVC for induction therapy for active LN, classes III and IV, in a Japanese population of 21 patients, 11 of whom received MMF and 10 IVC.. The primary endpoint was expressed as the percentage of responders, who in turn were defined as the patients who met complete or partial response criteria according to the European consensus statement. The secondary endpoints comprised the renal activity component and serological activity.. The primary endpoint was achieved in nine (81.8 %) patients receiving MMF and in four (40.0 %) receiving IVC, with no significant difference between the two groups (p = 0.081), while there was also no significant difference between them in terms of secondary endpoints. However, the MMF group suffered significantly fewer hematologic toxic effects than the IVC group.. MMF may be used as an alternative to IVC for inducing renal remission of LN in Japanese patients.

Topics: Adult; Asian People; Cyclophosphamide; Drug Therapy, Combination; Endpoint Determination; Female; Glucocorticoids; Hematologic Diseases; Humans; Immunosuppressive Agents; Induction Chemotherapy; Injections, Intravenous; Japan; Lupus Nephritis; Male; Mycophenolic Acid; Remission Induction; Retrospective Studies

In the current study, we evaluated a combination of tacrolimus and mycophenolate mofetil (MMF) as GvHD prophylaxis in 50 patients undergoing truly nonmyeloablative (NM; 90 mg/m(2) fludarabine, 2 Gy TBI) hematopoietic SCT (HSCT) from unrelated donors. Median patient age was 51 years (range, 25-67 years). After a median follow-up of 1123 days (range, 47-2729 days), 20 patients (40%) are alive and free from disease. The probabilities of 1-, 2- and 3-year survival were 57, 47 and 39%, respectively. Patients who achieved a remission before HSCT had a significantly better OS compared with those who had active disease (P=0.01). The incidences of grade II-IV and III-IV acute GvHD (aGvHD) were 54% (n=27) and 16% (n=8). Remarkably, using tacrolimus and MMF, the median onset of aGvHD occurred distinctly late on day +66 (range, 12-119 days). A total of 46 patients were evaluable for chronic GvHD (cGvHD). Out of these, 26 (56%) patients developed cGvHD, with 16 (34%) of them showing limited and 10 (21%) showing extensive disease. We conclude that the combination of tacrolimus and MMF as post transplant immunosuppression for patients receiving NM unrelated donor HSCT permits stable engraftment and effective prophylaxis for acute and cGvHD. In particular, the occurrence of severe early-onset aGvHD was attenuated.

Topics: Adult; Aged; Female; Graft vs Host Disease; Hematologic Diseases; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Tacrolimus; Transplantation Chimera; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome; Vidarabine; Whole-Body Irradiation

Mycophenolate mofetil (MMF) in combination with CsA seems to lead to earlier post transplant hematological recovery and less mucositis than MTX, with a similar incidence of GVHD. In this study we analyzed the post transplant outcomes of two cohorts of patients who underwent an HLA-identical sibling reduced intensity conditioning transplantation (allo-RIC) with GVHD prophylaxis consisting of CsA in combination with either MMF or a short course of MTX. We included 145 consecutive allo-RIC transplants performed between April 2000 and August 2007. The median follow-up for survivors was 41 months (4-105 months). The study group included 91 males. Median age was 55 years (range 18-71 years). Diagnoses included myeloid (n=65) and lymphoid (n=80) malignancies. GVHD prophylaxis consisted of CsA/MMF in 52 and CsA/MTX in 93 patients. The conditioning regimen was based on fludarabine in combination with BU (n=59) or melphalan (n=86). The occurrence of grade 2-4 mucositis was higher in the CsA/MTX group than in the CsA/MMF group (57 vs 23%, P=0.001). The cumulative incidence of acute and chronic GVHD was similar, 48 vs 50% and 71 vs 68%, respectively (P>0.7). The 2-year relapse and OS were similar in the CsA/MTX and CsA/MMF groups (29 vs 21%, P=0.3 and 52 vs 51%, P=0.7, respectively). Our results support further prospective studies comparing the use of the CsA/MMF combination with CsA/MTX as GVHD prophylaxis in HLA-identical sibling donor allo-RIC recipients.

Topics: Adolescent; Adult; Aged; Cyclosporine; Drug Therapy, Combination; Female; Graft vs Host Disease; Hematologic Diseases; Hematopoietic Stem Cell Transplantation; HLA Antigens; Humans; Immunosuppressive Agents; Male; Methotrexate; Middle Aged; Mycophenolic Acid; Retrospective Studies; Siblings; Transplantation Conditioning; Transplantation, Homologous; Young Adult

Mycophenolate mofetil (MMF) is an immunosuppressive prodrug approved for use in transplantation. Its active metabolite, mycophenolic acid, is mainly metabolized by UDP-glucuronosyltransferase (UGT) enzymes. In this study, we retrospectively analyzed 74 kidney transplant patients who had been prescribed MMF as part of their immunosuppression regimen. Polymorphisms in UGT1A8 (-999C > T, codon 255A > G, codon 277G > A) were correlated with the occurrence of side effects, such as diarrhea, blood disorders, and infections. The infectious episodes were more frequently observed among individuals receiving MMF (2 g/d) who carryied the variant UGT1A8 codon 277A (P = .031), the haplotype UGT1A8H5 (-999C/codon 55A/codon 277A; P = .02), and the diplotype UGT1A8H2/H5 (-999CC/codon 255AA/codon 277GA; P = .015). The molecular data from this study suggest that UGT polymorphisms may be a factor influencing clinical outcomes among patients receiving MMF for transplant therapy; however, larger studies are warranted.

Topics: Codon; Diarrhea; Glucuronosyltransferase; Hematologic Diseases; Humans; Infections; Kidney Transplantation; Mycophenolic Acid; Polymorphism, Single Nucleotide; Retrospective Studies

Topics: Cell Division; Clinical Trials, Phase III as Topic; Double-Blind Method; Gastrointestinal Diseases; Graft Rejection; Hematologic Diseases; Humans; Immunosuppressive Agents; IMP Dehydrogenase; Incidence; Kidney Transplantation; Lymphocytes; Multicenter Studies as Topic; Mycophenolic Acid; Nucleotides; Randomized Controlled Trials as Topic; Tablets, Enteric-Coated

Toxicities of high-dose conditioning regimens have limited the use of conventional unrelated donor hematopoietic cell transplantation (HCT) to younger, medically fit patients. Based on preclinical studies, an HCT approach has been developed for elderly or medically infirm patients with HLA-matched or mismatched unrelated donors. In this study, 52 patients with hematological diseases were included. Most (88%) had preceding unsuccessful conventional HCT or refractory/advanced disease. Patients were treated with fludarabine 30 mg/m(2)/d from days -4 to -2, 2 Gy total body irradiation on day 0, cyclosporine at 6.25 mg/kg twice daily from day -3, and mycophenolate mofetil at 15 mg/kg twice daily from day 0. Durable donor chimerism was attained in 88% of the patients. By day 28, a median of 100% of CD56(+) cells were of donor origin. Granulocyte and T-cell donor chimerism increased to medians of 100% on day 56 and day 180 (range, 55%-100%), respectively. Acute GVHD, grade II, was seen in 42% (CI, 29%-56%); grade III in 8% (CI, 0%-15%); and grade IV in 13% (CI, 4%-23%) of patients; it was fatal in 9%. The 100-day transplantation-related mortality was 11%. Complete remissions, including molecular remissions, were seen in 45% of patients with measurable disease before transplantation. Mortality from disease progression was 27% at one year. With a median follow-up of 19 months, 18 of the 52 patients (35%) were alive and 25% were in remission. HCT from HLA-matched or mismatched unrelated donors can be performed with a reduced intensity conditioning regimen in patients ineligible for conventional HCT.

Topics: Adult; Aged; Child; Cyclosporine; Female; Graft vs Host Disease; Hematologic Diseases; Hematopoietic Stem Cell Transplantation; Histocompatibility; Histocompatibility Testing; Humans; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Peripheral Blood Stem Cell Transplantation; Remission Induction; Survival Rate; Tissue Donors; Transplantation Chimera; Transplantation Conditioning; Vidarabine; Whole-Body Irradiation