tacrolimus and Leukemia--Myeloid--Acute

Topics: Acute Disease; Adult; Chronic Disease; Drug Eruptions; Female; Graft vs Host Disease; Humans; Immunosuppressive Agents; Leukemia, Myeloid, Acute; Male; Peripheral Blood Stem Cell Transplantation; Risk; Steroids; Tacrolimus; Transplantation Conditioning; Transplantation, Homologous

Graft-versus-host disease (GVHD) has remained the main cause of post-transplantation mortality and morbidity after allogeneic hematopoietic cell transplantation (alloHCT), adding significant economic burden and affecting quality of life. It would be desirable to reduce the rate of GVHD among patients in complete remission (CR) without increasing the risk of relapse. In this study, we have tested a novel conditioning regimen of total marrow and lymphoid irradiation (TMLI) at 2000 cGy, together with post-transplantation cyclophosphamide (PTCy) for patients with acute myeloid leukemia in first or second CR, to attenuate the risk of chronic GVHD by using PTCy, while using escalated targeted radiation conditioning before allografting to offset the possible increased risk of relapse. The primary objective was to evaluate the safety/feasibility of combining a TMLI transplantation conditioning regimen with a PTCy-based GVHD prophylaxis strategy, through the assessment of adverse events in terms of type, frequency, severity, attribution, time course, duration, and complications, including acute GVHD, infection, and delayed neutrophil/platelet engraftment. Secondary objectives included estimation of non-relapse mortality (NRM), overall survival (OS), relapse-free survival, acute and chronic GVHD, and GVHD-relapse-free survival (GRFS). A patient safety lead-in was first conducted to ensure there were no unexpected toxicities and was expanded on the basis of lack of dose-limiting toxicities. The patient safety lead-in segment followed 3 + 3 dose expansion/(de-)escalation rules based on observed toxicity through day 30; the starting dose of TMLI was 2000 cGy, and a de-escalation to 1800 cGy was considered. After the safety lead-in segment, an expansion cohort of up to 12 additional patients was to be studied. TMLI was administered on days -4 to 0, delivered in 200 cGy fractions twice daily. The radiation dose delivered to the liver and brain was kept at 1200 cGy. Cyclophosphamide was given on days 3 and 4 after alloHCT, 50 mg/kg each day for GVHD prevention; tacrolimus was given until day 90 and then tapered. Among 18 patients with a median age of 40 years (range 19-56), the highest grade toxicities were grade 2 Bearman bladder toxicity and stomatitis. No grade 3 or 4 Bearman toxicities or toxicity-related deaths were observed. The cumulative incidence of acute GVHD grade 2 to 4 and moderate-to-severe chronic GVHD were 11.1% and 11.9%, respectively. At a median follow

Topics: Adult; Bone Marrow; Cyclophosphamide; Graft vs Host Disease; Humans; Leukemia, Myeloid, Acute; Lymphatic Irradiation; Middle Aged; Quality of Life; Recurrence; Tacrolimus; Young Adult

Purpose Several open-label randomized studies have suggested that in vivo T-cell depletion with anti-T-lymphocyte globulin (ATLG; formerly antithymocyte globulin-Fresenius) reduces chronic graft-versus-host disease (cGVHD) without compromising survival. We report a prospective, double-blind phase III trial to investigate the effect of ATLG (Neovii Biotech, Lexington, MA) on cGVHD-free survival. Patients and Methods Two hundred fifty-four patients 18 to 65 years of age with acute leukemia or myelodysplastic syndrome who underwent myeloablative HLA-matched unrelated hematopoietic cell transplantation (HCT) were randomly assigned one to one to placebo (n =128 placebo) or ATLG (n = 126) treatment at 27 sites. Patients received either ATLG or placebo 20 mg/kg per day on days -3, -2, -1 in addition to tacrolimus and methotrexate as GVHD prophylaxis. The primary study end point was moderate-severe cGVHD-free survival. Results Despite a reduction in grade 2 to 4 acute GVHD (23% v 40%; P = .004) and moderate-severe cGVHD (12% v 33%; P < .001) in ATLG recipients, no difference in moderate-severe cGVHD-free survival between ATLG and placebo was found (2-year estimate: 48% v 44%, respectively; P = .47). Both progression-free survival (PFS) and overall survival (OS) were lower with ATLG (2-year estimate: 47% v 65% [ P = .04] and 59% v 74% [ P = .034], respectively). Multivariable analysis confirmed that ATLG was associated with inferior PFS (hazard ratio, 1.55; 95% CI, 1.05 to 2.28; P = .026) and OS (hazard ratio, 1.74; 95% CI, 1.12 to 2.71; P = .01). Conclusion In this prospective, randomized, double-blind trial of ATLG in unrelated myeloablative HCT, the incorporation of ATLG did not improve moderate-severe cGVHD-free survival. Moderate-severe cGVHD was significantly lower with ATLG, but PFS and OS also were lower. Additional analyses are needed to understand the appropriate role for ATLG in HCT.

Topics: Adolescent; Adult; Aged; Antilymphocyte Serum; Double-Blind Method; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; HLA Antigens; Humans; Immunosuppressive Agents; Leukemia, Myeloid, Acute; Male; Methotrexate; Middle Aged; Myelodysplastic Syndromes; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prospective Studies; Tacrolimus; Young Adult

A phase 3 clinical trial (BMT CTN 0402) comparing tacrolimus/sirolimus (Tac/Sir) vs tacrolimus/methotrexate (Tac/Mtx) as graft-versus-host disease (GVHD) prophylaxis after matched-related allogeneic hematopoietic cell transplantation (HCT) recently showed no difference between study arms in acute GVHD-free survival. Within this setting of a prospective, multicenter study with uniform GVHD prophylaxis, conditioning regimen, and donor source, we explored the correlation of 10 previously identified biomarkers with clinical outcomes after allogeneic HCT. We measured biomarkers from plasma samples collected in 211 patients using enzyme-linked immunosorbent assay (Tac/Sir = 104, Tac/Mtx = 107). High suppression of tumorigenicity-2 (ST2) and T-cell immunoglobulin mucin-3 (TIM3) at day 28 correlated with 2-year nonrelapse mortality in multivariate analysis (P = .0050, P = .0075, respectively) and in a proportional hazards model with time-dependent covariates (adjusted hazard ratio: 2.43 [1.49-3.95], P = .0038 and 4.87 [2.53-9.34], P < .0001, respectively). High ST2 and TIM3 correlated with overall survival. Chemokine (C-X-C motif) ligand 9 (CXCL9) levels above the median were associated with chronic GVHD compared with levels below the median in a time-dependent proportional hazard analysis (P = .0069). Low L-Ficolin was associated with hepatic veno-occlusive disease (P = .0053, AUC = 0.80). We confirmed the correlation of plasma-derived proteins, previously assessed in single-center cohorts, with clinical outcomes after allogeneic HCT within this prospective, multicenter study.

Topics: Adolescent; Adult; Allografts; Area Under Curve; Biomarkers, Tumor; Drug Therapy, Combination; Enzyme-Linked Immunosorbent Assay; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Acute; Male; Methotrexate; Middle Aged; Myelodysplastic Syndromes; ROC Curve; Sensitivity and Specificity; Sirolimus; Tacrolimus; Transplantation, Homologous; Young Adult

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

Long-term survival rates for older patients with newly diagnosed acute myeloid leukemia (AML) are extremely low. Previous observational studies suggest that allogeneic hematopoietic stem-cell transplantation (HSCT) may improve overall survival (OS) because of lower rates of relapse. We sought to prospectively determine the value of HSCT for older patients with AML in first complete remission.. We conducted a prospective multicenter phase II study to assess the efficacy of reduced-intensity conditioning HSCT for patients between the ages of 60 and 74 years with AML in first complete remission. The primary end point was disease-free survival at 2 years after HSCT. Secondary end points included nonrelapse mortality (NRM), graft-versus-host disease (GVHD), relapse, and OS.. In all, 114 patients with a median age of 65 years received transplantations. The majority (52%) received transplantations from unrelated donors and were given antithymocyte globulin for GVHD prophylaxis. Disease-free survival and OS at 2 years after transplantation were 42% (95% CI, 33% to 52%) and 48% (95% CI, 39% to 58%), respectively, for the entire group and 40% (95% CI, 29% to 55%) and 50% (95% CI, 38% to 64%) for the unrelated donor group. NRM at 2 years was 15% (95% CI, 8% to 21%). Grade 2 to 4 acute GVHD occurred in 9.6% (95% CI, 4% to 15%) of patients, and chronic GVHD occurred in 28% (95% CI, 19% to 36%) of patients. The cumulative incidence of relapse at 2 years was 44% (95% CI, 35% to 53%).. Reduced-intensity conditioning HSCT to maintain remission in selected older patients with AML is relatively well tolerated and appears to provide superior outcomes when compared with historical patients treated without HSCT. GVHD and NRM rates were lower than expected. Future transplantation studies in these patients should focus on further reducing the risk of relapse.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Disease-Free Survival; Drug Administration Schedule; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Leukemia, Myeloid, Acute; Male; Methotrexate; Middle Aged; Neoplasm Recurrence, Local; Prospective Studies; Remission Induction; Tacrolimus; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome; Unrelated Donors; Vidarabine

Children with high-risk acute myelogenous leukemia (AML) (induction failure [IF], refractory relapse [RR], third complete remission [CR3]) have dismal outcomes. Over 80% of AML patients express CD33, a target of gemtuzumab ozogamicin (GO). GO is an active drug in childhood AML but has not been studied in a myeloablative conditioning regimen. We sought to determine the safety of GO in combination with busulfan/cyclophosphamide (Bu/Cy) conditioning before allogeneic hematopoietic stem cell transplantation (alloSCT). GO was administered on day -14 at doses of 3.0, 4.5, 6.0, and 7.5 mg/m(2), busulfan on days -7, -6, -5, -4 (12.8-16.0 mg/kg), and cyclophosphamide on days -3 and -2 (60 mg/kg/day). GVHD prophylaxis consisted of tacrolimus and mycophenolate mofetil. We enrolled 12 patients: 8 IF, 3 RR, 1 CR3; median age: 3 years (1-17); median follow-up: 1379 days (939-2305). Nine received umbilical cord blood (UCB), 2 matched unrelated donors (MUDs) and 1 HLA-matched sibling donor: 3 patients each at GO doses of 3.0, 4.5, 6.0, or 7.5 mg/m(2). No dose-limiting toxicities secondary to GO were observed. Day 100 treatment-related mortality (TRM) was 0%. Myeloid and platelet engraftment was observed in 92% and 75% of patients at median day 22 (12-40) and 42 (21-164), respectively. Median day +30 donor chimerism was 99% (85%-100%). The probability of grade II-IV acute graft-versus-host disease (aGVHD) was 42% and chronic GVHD (cGVHD) was 28%. One-year overall survival (OS) and event-free survival (EFS) was 50% (95% confidence interval [CI], 20.8-73.6). GO combined with Bu/Cy regimen followed by alloSCT is well tolerated in children with poor-risk AML. GO at 7.5 mg/m(2) in combination with Bu/Cy is currently being tested in a phase II study.

Topics: Adolescent; Aminoglycosides; Antibodies, Monoclonal, Humanized; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Antineoplastic Agents; Busulfan; Child; Child, Preschool; Cyclophosphamide; Disease-Free Survival; Female; Follow-Up Studies; Gemtuzumab; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Infant; Leukemia, Myeloid, Acute; Male; Mycophenolic Acid; Myeloablative Agonists; Risk Factors; Sialic Acid Binding Ig-like Lectin 3; Siblings; Survival Rate; Tacrolimus; Tissue Donors; Transplantation Conditioning; Transplantation, Homologous

Posaconazole is a broad-spectrum triazole antifungal available as an oral suspension. Pharmacokinetic data showed a high variability of plasma posaconazole concentrations (PPCs) in patients, suggesting a potential interest in drug monitoring. The aim of our prospective study was to measure the PPCs in prophylactically treated patients to evaluate the impact of different factors on these concentrations. In 40 patients treated prophylactically with posaconazole for acute myeloid leukemia or myelodysplastic syndrome between February 2009 and August 2010, PPCs were measured at day 7 of treatment and then twice weekly. Demographic data, clinical data (including gastrointestinal disorders, comedications, and treatment compliance), caloric and fat intake, and biological data were collected and evaluated. We obtained 275 measurements of PPCs, with a median of 430 ng/ml. PPCs were significantly lower in patients with mucositis (P < 0.001), nausea (P = 0.03), diarrhea (P = 0.03), or vomiting (P = 0.05). PPCs were higher in patients with a higher caloric intake (P = 0.02), while the proportion of fat intake had no influence on PPCs (P = 0.84). The concomitant use of proton pump inhibitors decreased the PPCs (P = 0.02), while the use of tacrolimus increased the PPC (P = 0.03). In the multivariate analysis, the factors influencing the PPCs independently were the concomitant use of tacrolimus (P < 0.001), the presence of mucositis (P = 0.01), and food intake (P = 0.02). Our study confirmed the high variability of posaconazole bioavailability and showed the significant influence of gastrointestinal disorders, food intake, and concomitant medication on the PPCs. However, the optimal PPCs still remain to be defined and correlated with clinical efficacy.

Topics: Adolescent; Adult; Aged; Antifungal Agents; Biological Availability; Chromatography, High Pressure Liquid; Drug Monitoring; Female; Food-Drug Interactions; Gastrointestinal Diseases; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Leukemia, Myeloid, Acute; Male; Middle Aged; Multivariate Analysis; Myelodysplastic Syndromes; Prospective Studies; Spectrophotometry, Ultraviolet; Tacrolimus; Triazoles; Young Adult

Although a combination of i.v. busulfan (Bu) and fludarabine (Flu) is a safe, reduced-toxicity conditioning program for acute myelogenous leukemia/myelodysplastic syndromes (AML/MDS), recurrent leukemia posttransplantation remains a problem. To enhance the conditioning regimen's antileukemic effect, we decided to supplant Flu with clofarabine (Clo), and assayed the interactions of these nucleoside analogs alone and in combination with Bu in Bu-resistant human cell lines in vitro. We found pronounced synergy between each nucleoside and the alkylator but even more enhanced cytotoxic synergy when the nucleoside analogs were combined prior to exposing the cells to Bu. We then designed a 4-arm clinical trial in patients with myeloid leukemia undergoing allogeneic stem cell transplantation (allo-SCT). Patients were adaptively randomized as follows: Arm I-Clo:Flu 10:30 mg/m(2), Arm II-20:20 mg/m(2), Arm III-30:10 mg/m(2), and Arm IV-single-agent Clo at 40 mg/m(2). The nucleoside analog(s) were/was infused over 1 hour once daily for 4 days, followed on each day by Bu, infused over 3 hours to a pharmacokinetically targeted daily area under the curve (AUC) of 6000 μMol-min ± 10%. Fifty-one patients have been enrolled with a minimum follow-up exceeding 100 days. There were 32 males and 19 females, with a median age of 45 years (range: 6-59). Nine patients had chronic myeloid leukemia (CML) (BC: 2, second AP: 3, and tyrosine-kinase inhibitor refractory first chronic phase [CP]: 4). Forty-two patients had AML: 14 were induction failures, 8 in first chemotherapy-refractory relapse, 7 in untreated relapse, 3 in second or subsequent relapse, 4 were in second complete remission (CR), and 3 in second CR without platelet recovery (CRp), 2 were in high-risk CR1. Finally, 1 patient was in first CRp. Graft-versus-host disease (GVHD) prophylaxis was tacrolimus and mini-methorexate (MTX), and those who had an unrelated or 1 antigen-mismatched donor received low-dose rabbit-ATG (Thymoglobulin™). All patients engrafted. Forty-one patients had active leukemia at the time of transplant, and 35 achieved CR (85%). Twenty of the 42 AML patients and 5 of 9 CML patients are alive with a projected median overall survival (OS) of 23 months. Marrow and blood (T cell) chimerism studies at day +100 revealed that both in the lower-dose Clo groups (groups 1+2) and the higher-dose Clo groups (groups 3+4), the patients had a median of 100% donor (T cell)-derived DNA. There has been no secondary g

Topics: Adenine Nucleotides; Animals; Antilymphocyte Serum; Antineoplastic Agents; Arabinonucleosides; Busulfan; Cell Line, Tumor; Clofarabine; Drug Administration Schedule; Drug Resistance, Neoplasm; Drug Synergism; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Injections, Intravenous; Leukemia, Myeloid, Acute; Male; Middle Aged; Myeloablative Agonists; Rabbits; Remission Induction; Survival Analysis; Tacrolimus; Transplantation Conditioning; Transplantation, Homologous; Vidarabine

A calcineurin inhibitor combined with methotrexate is the standard prophylaxis for graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). Everolimus, a derivative of sirolimus, seems to mediate antileukemia effects. We report on a combination of everolimus and tacrolimus in 24 patients (median age, 62 years) with either myelodysplastic syndrome (MDS; n = 17) or acute myeloid leukemia (AML; n = 7) undergoing intensive conditioning followed by HSCT from related (n = 4) or unrelated (n = 20) donors. All patients engrafted, and only 1 patient experienced grade IV mucositis. Nine patients (37%) developed acute grade II-IV GVHD, and 11 of 17 evaluable patients (64%) developed chronic extensive GVHD. Transplantation-associated microangiopathy (TMA) occurred in 7 patients (29%), with 2 cases of acute renal failure. The study was terminated prematurely because an additional 6 patients (25%) developed sinusoidal obstruction syndrome (SOS), which was fatal in 2 cases. With a median follow-up of 26 months, the 2-year overall survival rate was 47%. Although this new combination appears to be effective as a prophylactic regimen for acute GVHD, the incidence of TMA and SOS is considerably higher than seen with other regimens.

Topics: Adult; Aged; Anemia, Hemolytic; Everolimus; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Hepatic Veno-Occlusive Disease; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Myelodysplastic Syndromes; Sirolimus; Survival Rate; Tacrolimus; Transplantation, Homologous

Results of allogeneic hematopoietic stem cell transplantation (HCT) to treat advanced leukemia or myelodysplastic syndrome (MDS) remain poor due to excessive relapse and transplant-related mortality. To improve transplant outcome in this patient population, 43 patients (median age, 46.1 years) with high-risk or advanced lymphoid (n = 5) or myeloid malignancy (n = 38) were prospectively enrolled on a pilot trial of cytoreduction with intravenous busulfan and melphalan followed by an unmodified HLA-A, -B, and -DRbeta1-matched related (n = 18) or unrelated (n = 25) HCT. Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus and methotrexate. Thirty-four patients had > or = 5% blasts at the time of HCT; 12 of these had > 20% blasts. Seventeen patients had unfavorable cytogenetics, 8 patients underwent transplantation for secondary MDS or acute myelogenous leukemia, and 4 patients had relapsed after a previous allogeneic transplantation. Although mucositis was the most significant regimen-related toxicity, requiring the addition of folinic acid rescue and failure to receive all 4 doses of methotrexate in 23 patients, the nonrelapse mortality at 30 and 100 days was low at 0% and 16%, respectively. The cumulative incidence of grade II-IV acute GVHD was 24%, and that of extensive chronic GVHD was 7%. With a minimum follow-up of 18 months, the estimated 3-year overall survival is 37% and the estimated disease-free survival (DFS) is 33%. For 18 patients with MDS (< or = RAEB-2) or high-risk myeloproliferative disorder, the estimated 3 year DFS is 61%. These data demonstrate the curative potential of this regimen in patients with high-risk myeloid malignancies.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Child; Child, Preschool; Female; Hematopoietic Stem Cell Transplantation; Histocompatibility Testing; Humans; Immunosuppressive Agents; Infant; Leukemia, Myeloid, Acute; Male; Melphalan; Methotrexate; Middle Aged; Myelodysplastic Syndromes; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prospective Studies; Survival Analysis; Tacrolimus; Transplantation Conditioning

Topics: Adult; Aged; Antibody Formation; COVID-19; COVID-19 Vaccines; Cyclophosphamide; Female; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Leukemia, Myeloid, Acute; Male; Middle Aged; Retrospective Studies; Tacrolimus; Transplantation Conditioning; Transplantation, Homologous; Young Adult

We report a case of donor-derived diffuse large B-cell lymphoma (DLBCL), which developed 5 years after stem cell transplantation from a human leukocyte antigen (HLA)-haploidentical donor for acute myeloid leukemia (AML). A 51-year-old male was diagnosed with AML with variant KMT2A translocation involving t(6;11)(q13;q23). After 12 cycles of azacitidine treatment, fluorescence in situ hybridization (FISH) for KMT2A split signal indicated that 94% of his bone marrow (BM) cells were positive. He underwent peripheral blood stem cell transplantation (PBSCT) from his HLA-haploidentical son. The preconditioning regimen consisted of fludarabine, busulfan, melphalan, and antithymocyte globulin (ATG). The graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus and short-term methotrexate. On day 28, KMT2A FISH analysis indicated that he had achieved a complete response (CR). He continued to receive tacrolimus for the limited type of cutaneous chronic GVHD. Five years after the transplantation, positron emission tomography/computed tomography (PET/CT) showed an abdominal tumor. The tumor was diagnosed as DLBCL without Epstein-Barr virus. BM aspiration revealed the infiltration of lymphoma cells with t(8;14)(q24;q32). Chimerism analysis showed that both the peripheral blood (PB) and abdominal lymphoma cells were of donor origin. After 4 cycles of salvage chemotherapy, PET/CT showed that a CR had been achieved. He underwent a second PBSCT from an HLA-identical unrelated donor. The preconditioning regimen and GVHD prophylaxis were the same as those for the first PBSCT without ATG. The patient's PB revealed complete second donor-type chimerism, and the patient has maintained a CR since the second transplantation.

Topics: Antilymphocyte Serum; Azacitidine; Busulfan; Epstein-Barr Virus Infections; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Herpesvirus 4, Human; HLA Antigens; Humans; In Situ Hybridization, Fluorescence; Leukemia, Myeloid, Acute; Lymphoma, Large B-Cell, Diffuse; Male; Melphalan; Methotrexate; Middle Aged; Positron Emission Tomography Computed Tomography; Tacrolimus; Transplantation Conditioning

HLA-mismatched hematopoietic stem cell micro-transplantation (MST) is an effective treatment for older patients (≥60 years) with acute myeloid leukemia. Donor selection for MST is broad, ranging from HLA fully mismatched unrelated donors to HLA partially matched related donors. However, the influence of HLA haplotype homozygous donors such donors on MST has not been studied. Such donors has been reported to be associated with a higher risk of graft-versus-host disease (GVHD) in transfusion and cord blood transplantation (CBT). Additionally, sustained complete donor chimerism is rare in MST and usually accompanied by severe acute GVHD and death. Herein, we report the first case of MST using an HLA haplotype homozygous donor. The patient developed persistent complete donor chimerism (donor cells>95%) for 7 months and prolonged isolated thrombocytopenia (PT) for 3 months, after receiving MST from his HLA homozygous son. Grade I acute GVHD presented on day 12 post-MST and it was controlled by timely immunosuppressive treatment. Then he maintained complete molecular remission, complete donor chimerism and mild GVHD for 5 months. However, moderate overlapping GVHD with skin, oral, eyes, and intestinal involvement developed after he self-discontinued Tacrolimus treatment. Fortunately, the GVHD was controlled after intensive anti-rejection therapy and Tacrolimus is now being continued for prophylaxis. This case underscores that HLA haplotype homozygous donors might not be a good choice for MST and GVHD prophylactic should be administrated if such donors have to be selected.

Topics: Chimerism; Graft vs Host Disease; Haplotypes; HLA Antigens; Humans; Leukemia, Myeloid, Acute; Male; Tacrolimus; Unrelated Donors

The distribution of tacrolimus (TAC), an immunosuppressant used during cord blood transplantation (CBT)-one of the haematopoietic stem cell transplantations, to red blood cell (RBC) is approximately 90% in whole blood. In CBT patients, the total RBC count shows dramatic fluctuation due to conditioning before transplantation, including anticancer agents and total body irradiation, as well as RBC transfusions during the treatment period. Therefore, the amount of TAC in whole blood may show wide variation. However, therapeutic drug monitoring (TDM) of TAC has been performed based on the whole blood concentration. In this study, to contribute to TDM of TAC in CBT, we performed the population pharmacokinetic (PPK) analysis of TAC in 56 CBT patients and investigated the factors that affected the concentration of TAC, focusing the variation of RBC count.. A one-compartment model was applied to the observed whole blood TAC concentrations, and a PPK analysis was conducted with a non-linear mixed effect model.. Our final PPK model indicated good robustness and accuracy. In addition, haemoglobin (Hb) level was an influential covariate on Vd, which was expressed as Vd(L) = 91.4 × (Hb/8.2). In this study, our results showed the necessity for the Hb level monitoring during TDM of TAC in CBT patients and provided useful information for improving TDM strategy of TAC.

Topics: Adolescent; Adult; Aged; Cord Blood Stem Cell Transplantation; Drug Monitoring; Erythrocyte Count; Female; Humans; Immunosuppressive Agents; Leukemia, Myeloid, Acute; Male; Middle Aged; Tacrolimus; Young Adult

Ocular graft-versus-host disease (GVHD) is one of the most severe complications of hematopoietic stem cell transplantation. It manifests as an impairment of the ocular surface, such as severe dry eye disease, and deteriorates the recipient's visual function and quality of life. We encountered an "overlap syndrome" of ocular GVHD, which is characterized by the presence of both acute and chronic GVHD symptoms. In this report, we present the treatment progress of the overlap syndrome in a case with ocular GVHD.. A 57-year-old man with acute myeloblastic leukemia underwent hematopoietic stem cell transplantation. Six weeks after the treatment, the recipient complained of eye pain and discharge. He was diagnosed with the overlap syndrome due to low tear volume, severe corneal epithelitis, hyperemia, and a pseudomembrane on the conjunctiva. Immune cells infiltration, fibrinoid degeneration, fibroblastic and spindle-shaped cells, and fibrosis were observed in the pathology of the pseudomembrane. The recipient was treated with topical immunosuppression and pseudomembrane removal. One week after the initial treatment, ocular GVHD improved. Twelve weeks after the treatment, the topical steroid was discontinued due to the elevation of intraocular pressure.. The assessment of conjunctival pseudomembrane in ocular GVHD is important to determine the stage of the case and to assess systemic GVHD. Furthermore, prompt removal of the pseudomembrane after diagnosis is an appropriate management to reduce the symptoms of ocular GVHD. The combination of topical steroids and immunosuppressive agents is suggested to be an effective treatment in management of overlap syndrome.

Topics: Acute Disease; Betamethasone; Chronic Disease; Conjunctival Diseases; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Intestinal Diseases; Leukemia, Myeloid, Acute; Male; Middle Aged; Ophthalmologic Surgical Procedures; Skin Diseases; Tacrolimus

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

A head-to-head comparison of outcomes of unrelated donor allogeneic peripheral blood stem cell transplantation for AML between reduced intensity conditioning (RIC) and myeloablative conditioning (MAC) regimens using thymoglobulin for GVHD prophylaxis is limited. We evaluated outcomes of 122 AML patients who received either busulfan (Bu)/fludarabine (Flu)/low-dose total body irradiation (TBI) as RIC (n = 64, 52%) or Bu/Flu as MAC (n = 58, 48%), and thymoglobulin 4.5 mg/kg total dose between day - 3 to - 1 for GVHD prophylaxis. Grades III-IV acute GVHD (aGVHD) was lower with Bu/Flu/TBI compared with Bu/Flu (6.2% vs 26.1%, p = 0.009). At 1 year, Bu/Flu/TBI was associated with similar chronic GVHD (41.2% vs 44.8%, p = 0.75), OS (61.9% vs 56.9%, p = 0.69), relapse rate (29.9% vs 20.7%, p = 0.24), relapse-free survival (52.8% vs 50%, p = 0.80), non-relapse mortality (17.4% vs 29.3%, p = 0.41), and GVHD-free relapse-free survival (24.2% vs 27.5%, p = 0.80) compared with Bu/Flu. Multivariable analysis did not reveal any difference in outcomes between both regimens. In summary, thymoglobulin at 4.5 mg/kg did not have any adverse impact on survival when used with RIC regimen. Both Bu/Flu/TBI and Bu/Flu conditioning regimens yielded similar survival.

Topics: Aged; Allografts; Antilymphocyte Serum; Busulfan; Female; Graft vs Host Disease; Humans; Immunosuppressive Agents; Infections; Leukemia, Myeloid, Acute; Lymphocyte Depletion; Male; Middle Aged; Mycophenolic Acid; Myeloablative Agonists; Peripheral Blood Stem Cell Transplantation; Progression-Free Survival; Retrospective Studies; T-Lymphocytes; Tacrolimus; Transplantation Conditioning; Treatment Outcome; Unrelated Donors; Vidarabine; Whole-Body Irradiation

Cyclophosphamide (Cy)/etoposide combined with fractionated total body irradiation (FTBI) or i.v. busulfan (Bu) has been the main conditioning regimens for allogeneic hematopoietic cell transplantation (alloHCT) for young patients with acute myelogenous leukemia (AML) eligible for a myeloablative conditioning (MAC) regimen. Recent data has suggested that i.v. Bu could be the preferred myeloablative regimen in patients with myeloid malignancies. However, Bu-based regimens are associated with higher rates of sinusoidal obstruction syndrome. Here we report long-term survival outcomes of patients with AML receiving FTBI combined with Cy or etoposide before undergoing alloHCT at City of Hope (COH). We obtained a retrospective review of a prospectively maintained institutional registry of clinical outcomes in 167 patients (median age, 41 years; range, 18 to 57 years) with AML in first or second complete remission who underwent alloHCT at COH between 2005 and 2015. Eligible patients received a MAC regimen with FTBI (1320 cGy) and Cy (120 mg/kg) for unrelated donor transplantation or etoposide (60 mg/kg) for related donor transplantation. Graft-versus-host disease (GVHD) prophylaxis was provided with tacrolimus and sirolimus. In this retrospective study, 6-year overall survival was 60% and nonrelapse mortality was 15%. The GRFS rate was 45% at 1 year and 39% at 2 years. We also describe late metabolic effects and report the cumulative incidence of secondary malignancies (9.5%). Overall, in this young adult patient population, our results compare favorably to chemotherapy-based (i.v. Bu) conditioning regimens without significant long-term toxicity arising from TBI-based regimens.

Topics: Adolescent; Adult; Busulfan; Cyclophosphamide; Follow-Up Studies; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Middle Aged; Retrospective Studies; Sirolimus; Tacrolimus; Transplantation Conditioning; Whole-Body Irradiation; Young Adult

We sought to determine the occurrence, risk factors, effect of antifungal prophylaxis, and outcomes of invasive fungal infections (IFIs) in patients with acute myeloid leukemia (AML).. We performed a retrospective analysis of all adult patients admitted to the University of Michigan Health System for AML over a 3-year period from 2010 to 2013. We determined comorbidities, hematopoietic cell transplant (HCT) status, antifungal prophylaxis, proven and probable IFI, and outcomes at 12 weeks after initiation of appropriate antifungal therapy.. Of 333 patients in our cohort, 116 of whom had received a HCT, 98 (29%) developed an IFI. Of the 30 (9%) patients who had a proven or probable IFI, 18 had breakthrough infection while on micafungin (n = 5), voriconazole (n = 4), posaconazole (n = 5), or fluconazole (n = 4). Breakthrough IFIs were due to Aspergillus species (n = 11), other molds (n = 4), and Candida species (n = 3). Factors associated with breakthrough IFI were prolonged severe neutropenia (p = .05) and having received tacrolimus (p = .04). Antifungal therapy was successful in 7 of the 18 (39%) patients with breakthrough IFI and 8 of the 12 (67%) patients with non-breakthrough IFI, p = .13. Mortality at 12 weeks was 27%, 5 with breakthrough IFI and 3 with non-breakthrough IFI and was associated with prolonged severe neutropenia, p = .04.. Patients with AML remain at risk for IFI despite the use of several different antifungal agents for prophylaxis. Mortality remains high in patients with AML who develop IFI.

Topics: Adult; Aged; Antifungal Agents; Aspergillus; Candida; Cohort Studies; Female; Humans; Immunosuppressive Agents; Invasive Fungal Infections; Leukemia, Myeloid, Acute; Male; Middle Aged; Mortality; Neutropenia; Retrospective Studies; Risk Factors; Tacrolimus; Tertiary Care Centers

Allogeneic SCT for older patients remains challenging at least in part due to graft-versus-host disease (GVHD) and higher non-relapse mortality (NRM). We conducted a prospective pilot study primarily for older patients undergoing matched unrelated donor (MUD) SCT using a reduced-intensity (RIC) melphalan-based conditioning and post-transplant cyclophosphamide (PTCy)-based GVHD prophylaxis with tacrolimus and mycophenolate mofetil. Twenty-two patients (median age 64, IQR 58, 66) underwent RIC MUD SCT for high-risk hematological malignancies including AML/MDS (73%), CML/MPD (18%), and other (10%). Two (9%) patients had early death; the rest (100%) engrafted. After a median follow-up of 17 months, 11 patients were alive and disease-free with an estimated 2-year progression-free (PFS) and overall (OS) survival of 48%. The cumulative incidences of grades 2-4 and 3-4 acute GVHD (aGVHD) at day + 100 and 2-years were 32 and 4%, and 59 and 24%, respectively. No cases of chronic GVHD (cGVHD) were noted. However, late acute GVHD was observed in 6 (27%) patients. In conclusion, RIC MUD SCT with melphalan-based conditioning and PTCy-based GVHD-based prophylaxis for older patients appears effective in controlling relapse. While cGVHD was not seen and early aGVHD appears controllable, a significant proportion developed late aGVHD responsible for higher NRM seen in these patients.

Topics: Cyclophosphamide; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Mycophenolic Acid; Pilot Projects; Prospective Studies; Tacrolimus; Transplantation Conditioning; Unrelated Donors

To elucidate the mechanisms by which orally administered tacrolimus was not absorbed in a patient following allogeneic hematopoietic stem cell transplantation.. A 17-year-old girl with acute myeloid leukemia underwent HLA-haploidentical peripheral blood stem cell transplantation following fludarabine, busulfan, and total-body irradiation. Graft-vs-host disease prophylaxis was post-transplant cyclophosphamide, followed by intravenous tacrolimus and mycophenolate mofetil. When tacrolimus was switched to oral administration, its blood level declined rapidly, resulting in development of acute graft-vs-host disease, which was ameliorated by switching back to intravenous administration.. To elucidate if impaired tacrolimus absorption could be related to genetic polymorphism of tacrolimus-metabolizing enzymes, we analyzed gene polymorphisms of cytochrome P450 3A4, cytochrome P450 3A5, and multidrug resistance 1 (MDR1). The patient had wild-type cytochrome P450 3A4 (*1/*1) and variant-type cytochrome P450 3A5 (*3/*3), while MDR1 genes (2677A/G, 3435C/C) were wild-type.. Wild-type MDR1 gene product P-glycoprotein expressed in the intestine reduces drug absorption from the gastrointestinal tract and may have contributed to low blood levels of tacrolimus in this patient when tacrolimus was orally administered.

Topics: Administration, Oral; Adolescent; ATP Binding Cassette Transporter, Subfamily B, Member 1; DNA; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Leukemia, Myeloid, Acute; Polymerase Chain Reaction; Polymorphism, Genetic; Tacrolimus

The prognosis of children who relapse after allogeneic hematopoietic cell transplant (alloHCT) for myeloid malignancies remains poor.. To describe the safety and feasibility of post-transplant azacitidine for relapse prevention, we retrospectively reviewed the charts of 18 children undergoing alloHCT for myeloid malignancies.. Post-transplant azacitidine in children is safe and feasible, with most patients successfully receiving all planned cycles. Despite the limitations of a small cohort, low relapse incidence suggests a potential benefit in disease control that warrants further investigation.

Topics: Adolescent; Antimetabolites, Antineoplastic; Azacitidine; Child; Child, Preschool; Female; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Male; Myelodysplastic Syndromes; Neoplasm Recurrence, Local; Prognosis; Remission Induction; Retrospective Studies; Secondary Prevention; Tacrolimus; Transplantation, Homologous; Treatment Outcome; Young Adult

Topics: Adolescent; Antilymphocyte Serum; Child; Child, Preschool; Female; Follow-Up Studies; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Infant; Leukemia, Myeloid, Acute; Male; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Recurrence; Retrospective Studies; Survival Rate; Tacrolimus; Transplantation Conditioning; Treatment Outcome; Young Adult

We present a case of possible transfusion-transmitted Ehrlichia chaffeensis infection in a heavily transfused cord blood transplant recipient, resulting in severe infection and graft loss. Transfusion-transmitted, vector-borne infections in immunocompromised individuals can have severe consequences, and should be considered in hospitalized patients receiving blood products with unexplained fever or sepsis.

Topics: Animals; Anti-Bacterial Agents; Antibiotic Prophylaxis; Blood Transfusion; Cord Blood Stem Cell Transplantation; Ehrlichia chaffeensis; Ehrlichiosis; Female; Graft Rejection; Graft vs Host Disease; Humans; Immunocompromised Host; Immunosuppressive Agents; Leukemia, Myeloid, Acute; Middle Aged; Tacrolimus; Transplantation Conditioning

The coexistence of acute myeloid leukemia (AML) with Behçet's disease (BD) is rare. The optimum treatment for AML-associated BD has not been established. We herein report a patient with BD who developed AML with myelodysplasia-related changes. Induction chemotherapy caused complete remission of the AML but worsened the BD. Thereafter, AML was treated with azacitidine. The BD was steroid-dependent. Tacrolimus was added, which improved the BD. The patient underwent allogeneic hematopoietic stem cell transplantation (HSCT) and remains in complete remission for both diseases. Allogeneic HSCT was found to be a potent therapeutic option for AML-associated BD. In addition, azacitidine and tacrolimus were shown to be a suitable bridging regimen before HSCT.

Topics: Adult; Antimetabolites, Antineoplastic; Asian People; Azacitidine; Behcet Syndrome; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Leukemia, Myeloid, Acute; Male; Myelodysplastic Syndromes; Remission Induction; Tacrolimus; Transplantation, Homologous; Treatment Outcome

New-onset diabetes mellitus after solid-organ transplant makes for complicated tacrolimus immunosuppression. However, tacrolimus-associated diabetic ketoacidosis has not been reported in bone marrow transplant. We report 24-year-old women, hospitalized with diabetic ketoacidosis, 70 days after undergoing a bone marrow transplant with tacrolimus immunosuppression. Clinicians should be wary about tacrolimus levels and the risk of hyperglycemic states after bone marrow transplant as with other solid-organ transplants.

Topics: Bone Marrow Transplantation; Calcineurin Inhibitors; Cyclosporine; Diabetic Ketoacidosis; Drug Monitoring; Drug Substitution; Female; Humans; Immunosuppressive Agents; Leukemia, Myeloid, Acute; Tacrolimus; Transplantation, Homologous; Treatment Outcome; Young Adult

Nontuberculous mycobacterial infections can often occur in individuals with adequate immune function. Such infections typically have cutaneous involvement and are caused by rapidly growing mycobacterium. Other nontuberculous mycobacteria species, like Mycobacterium haemophilum, almost always present as opportunistic infections occurring in severely immunocompromised hosts. Here, we present a complicated and protracted course of diagnosing M. haemophilum lower extremity cutaneous infection in a matched-unrelated donor stem cell transplant recipient.

Topics: Anti-Bacterial Agents; Biopsy; Cellulitis; Ciprofloxacin; Clarithromycin; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunocompromised Host; Immunosuppression Therapy; Immunosuppressive Agents; Leukemia, Myeloid, Acute; Lower Extremity; Middle Aged; Mycobacterium haemophilum; Mycobacterium Infections, Nontuberculous; Opportunistic Infections; Rifabutin; Tacrolimus; Unrelated Donors

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

Central nervous system lomentosporiosis is a rare pathological condition in immunocompromised patients. We describe a fatal case of meningitis caused by Lomentospora prolificans (which was previously named Scedosporium prolificans), after an allogeneic hematopoietic stem cell transplantation (allo-HSCT). To our knowledge, no cases of Lomentospora meningitis following allo-HSCT have been reported previously. Particularly in neutropenic patients, it is important to consider L. prolificans when a fungal infection is suspected and antifungal agents are ineffective.

Topics: Anti-Bacterial Agents; Antifungal Agents; Fatal Outcome; Glucocorticoids; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunocompromised Host; Immunosuppression Therapy; Immunosuppressive Agents; Leukemia, Myeloid, Acute; Male; Meninges; Meningitis, Fungal; Middle Aged; Prednisolone; Scedosporium; Tacrolimus; Tomography, X-Ray Computed; Transplantation, Homologous

There have been few reports on allogeneic stem cell transplantation in patients who have previously undergone solid organ transplantation. The clinical course of such patients is not yet well recognized. Therefore, appropriate immunosuppressive prophylaxis for the rejection of a solid organ graft or for graft-versus-host disease has not yet been established. We present the case of a successful allogeneic stem cell transplantation in a patient who relapsed after a first allogeneic stem cell transplantation for myelodysplastic syndrome and who had previously undergone renal transplantation. The prophylaxis in this case for graft-versus-host disease and rejection of the transplanted kidney was mycophenolate mofetil and tacrolimus. No hyperacute rejection of the transplanted kidney was observed. However, the patient's renal function deteriorated after the cessation of the mycophenolate mofetil and the reduction of the tacrolimus. This deterioration seemed to be due to rejection with humoral immunity of donor lymphocytes, and we were able to control it by resuming the mycophenolate mofetil and local graft irradiation.

Topics: Drug Therapy, Combination; Female; Graft Rejection; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Kidney Transplantation; Leukemia, Myeloid, Acute; Male; Middle Aged; Mothers; Mycophenolic Acid; Myelodysplastic Syndromes; Recurrence; Retreatment; Siblings; Tacrolimus; Tissue Donors; Transplant Recipients; Transplantation, Homologous

Eighty adult patients with acute myeloid leukemia (AML) received peripheral blood T cell-replete HLA haploidentical hematopoietic stem cell transplantation (haplo-HSCT). Disease status at transplantation was either first or second complete remission (CR, n = 69) or relapse/refractory (n = 11). Identical transplant-related procedures with conditioning regimen consisting of fractionated 800 cGy total body irradiation (TBI), fludarabine (30 mg/m(2)/day for 5 days), busulfan (3.2 mg/kg/day for 2 days), and antithymocyte globulin (1.25 mg/kg/day on days -4 to -1) and graft-versus-host disease (GVHD) prophylaxis with tacrolimus and methotrexate were used in all patients. Recovery of neutrophil (median, 11 days) and platelet (median, 10 days) counts was achieved in all patients with full donor chimerism (≥ 99%), and no delayed engraftment failure was observed. The cumulative incidence of grades III to IV acute GVHD and moderate to severe chronic GVHD was 11.2% and 26.3%, respectively. A donor CD8(+) and CD4(+) T cell dose above the median value was significantly associated with the incidences of grades II to IV acute GHVD and moderate to severe chronic GVHD, respectively. After a median follow-up of 28 months for survivors, the 2-year cumulative incidences of relapse (n = 20) and nonrelapse mortality (n = 10) were 26.6% and 12.2%, respectively. Although all but 1 patient in relapse/refractory status died, the 2-year overall and progression-free survival of patients in first CR was 82.5% and 75.1%, respectively. We suggest the strategy of fractionated 800 cGy TBI-based conditioning with unmanipulated peripheral blood stem cell grafts seems feasible with favorable outcomes for adult patients with AML undergoing haplo-HSCT in CR.

Topics: Adolescent; Adult; Aged; Antilymphocyte Serum; Antineoplastic Agents; Busulfan; Female; Graft Survival; Graft vs Host Disease; Haplotypes; Histocompatibility Testing; Humans; Immunosuppressive Agents; Leukemia, Myeloid, Acute; Male; Methotrexate; Middle Aged; Peripheral Blood Stem Cell Transplantation; Prospective Studies; Survival Analysis; Tacrolimus; Transplantation Chimera; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome; Vidarabine; Whole-Body Irradiation

Acute myeloid leukemia is a clonal malignant disorder derived from a small number of leukemic stem cells (LSCs). Rearrangements of the mixed lineage leukemia (MLL) gene are found in acute myeloid leukemia associated with poor prognosis. The upregulation of Hox genes is critical for LSC induction and maintenance, but is unlikely to support malignancy and the high LSC frequency observed in MLL leukemias. The present study shows that MLL fusion proteins interact with the transcription factor PU.1 to activate the transcription of CSF-1R, which is critical for LSC activity. Acute myeloid leukemia is cured by either deletion of PU.1 or ablation of cells expressing CSF-1R. Kinase inhibitors specific for CSF-1R prolong survival time. These findings indicate that PU.1-mediated upregulation of CSF-1R is a critical effector of MLL leukemogenesis.

Topics: Animals; Carcinogenesis; Gene Expression Regulation, Leukemic; Genes, Homeobox; Histone-Lysine N-Methyltransferase; Leukemia, Myeloid, Acute; Mice; Mice, Inbred C57BL; Mice, Transgenic; Myeloid-Lymphoid Leukemia Protein; Neoplastic Stem Cells; Phenylurea Compounds; Prognosis; Proto-Oncogene Proteins; Receptor, Macrophage Colony-Stimulating Factor; Recombinant Fusion Proteins; Signal Transduction; Tacrolimus; Thiazoles; Trans-Activators; Transcription, Genetic; Transcriptional Activation; Up-Regulation

Secondary acute myeloid leukemia is a very rare complication in patients with solid organ transplantation. We report a 62 years old female who received a right single lung allograft for idiopathic pulmonary fibrosis. Her immunosuppression scheme consisted in prednisone, azathioprine, and tacrolimus. Two years after the transplantation, she presented with progressive pancytopenia. Bone marrow aspiration was informed as a M4 acute myeloid leukemia, confirmed by flow cytometry. Cytogenetic study was complex, including alterations in chromosome 5. A secondary acute myeloid leukemia was diagnosed. The patient developed nosocomial pneumonia and died a few days after the diagnosis, without specific treatment. The pathogenesis of acute myeloid leukemia is probably related to the intensive exposure to immunosuppressant, especially azathioprine, in these patients.

Topics: Azathioprine; Bone Marrow; Chromosomes, Human, Pair 5; Fatal Outcome; Female; Humans; Immunosuppressive Agents; Leukemia, Myeloid, Acute; Leukopenia; Lung Transplantation; Middle Aged; Pancytopenia; Tacrolimus

Topics: Adult; Allografts; Cord Blood Stem Cell Transplantation; Female; Graft vs Host Disease; Humans; Immunosuppressive Agents; Leukemia, Myeloid, Acute; Posterior Leukoencephalopathy Syndrome; Purpura, Thrombotic Thrombocytopenic; Tacrolimus

Topics: Bone Marrow Cells; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Leukemia, Myeloid, Acute; Male; Middle Aged; Myelodysplastic Syndromes; Pelger-Huet Anomaly; Tacrolimus

Although graft failure (GF) is a fatal and life-threatening complication of umbilical cord blood transplantation (CBT), the standard treatment has not been established. We describe the case of a 28-year-old man diagnosed with acute myelogenous leukemia with myelodysplasia-related changes harboring a normal karyotype. This patient underwent 2 courses of idarubicin and cytosine arabinose therapy, and 3 courses of high-dose cytosine arabinose therapy. Subsequently, he underwent high-dose chemotherapy (total body irradiation and cyclophosphamide) followed by first CBT. Primary GF occurred after post-immunological reaction and hemophagocytic lymphohistiocytosis, and was diagnosed on day 27 after the first CBT. Therefore, the patient underwent secondary CBT for GF treated with a modified one-day conditioning regimen consisting of fludarabine (30 mg/m(2), 3 days), cyclophosphamide (2 g/m(2)), and total body irradiation (2 Gy), and graft-versus-host disease prophylaxis consisting of mycophenolate and tacrolimus. Consequently, the patient achieved neutrophil engraftment on day 17 after the second CBT. During the clinical course of the second CBT, the main complications were sepsis, BK virus-associated cystitis, and acute graft-versus-host disease (skin, grade 2, stage 3). After these treatments, the patient was disease-free for 39 months. Our case suggests that these treatments may be feasible, safe, and effective for the treatment of patients with GF. This case study may be helpful to physicians who directly care for GF patients, and may provide a future direction for a more efficient treatment modality.

Topics: Adult; Allografts; Cord Blood Stem Cell Transplantation; Graft Rejection; Graft vs Host Disease; Humans; Leukemia, Myeloid, Acute; Male; Mycophenolic Acid; Tacrolimus; Transplantation Conditioning

HLA-haploidentical 2 or 3-loci mismatched families are alternative donors for high-risk patients without HLA-matched donors. We retrospectively reviewed our case series of HLA-halpoidentical hematopoietic stem cell transplantations (haplo-HSCTs). Between Jul 2005 and Dec 2012, 25 patients (median age, 8 y; 13 ALL, 8 AML, 4 others) received haplo-HSCTs because of a worsening prognosis (i.e. induction failure, non-CR, or relapse after prior HSCT). Disease status was CR in 8 and non-CR in 17 patients. The 17 patients received myeloablative conditioning, while the 8 were given reduced-intensity conditioning because of their conditions (e.g. early relapse after prior HSCT). ATG was not administered in all but 3 patients. Tacrolimus and sMTX were used for prophylaxis GVHD and steroids were immediately given to prevent the onset of aGVHD. The 3-year OS and EFS were 35.6±10.0% and 31.3±10.1%, respectively (median follow-up, 49 mo); 14 patients died of their primary disease. Grade 3-4 aGVHD occurred in 7 patients, 2 of whom died of grade 4 aGVHD. Eleven patients had extensive cGVHD. While 4 of the 8 CR patients remained in CR, only 4 of the 17 non-CR patients achieved long-term CR (survival time, 6-89 mo). Haplo-HSCT was tolerable with strict control of infections and GVHD. However, further strategies for non-CR patients appear to be required.

Topics: Adolescent; Child; Child, Preschool; Female; Graft vs Host Disease; Haploidy; Hematopoietic Stem Cell Transplantation; Histocompatibility; HLA Antigens; Humans; Immunosuppressive Agents; Infant; Leukemia, Myeloid, Acute; Male; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Remission Induction; Retrospective Studies; Survival Rate; Tacrolimus; Transplantation Conditioning

Tacrolimus, a macrolide immunosuppressant, is used topically for the treatment of cutaneous manifestations of graft-versus-host disease (GVHD) for rapid, symptomatic relief of pruritus and erythema. Despite the manufacturer's product information reporting minimal systemic effects of topical tacrolimus, this has not been evaluated in patients with cutaneous GVHD and with occlusive dressings. We describe two patients with cutaneous GVHD who developed toxic tacrolimus levels after receiving several applications of tacrolimus ointment along with occlusive dressings to enhance skin effectiveness. The first patient was a 62-year-old woman with a history of acute myelogenous leukemia (AML) who underwent allogeneic bone marrow transplantation and developed chronic GVHD involving 70% of her body surface area. Her GVHD treatment plan consisted of oral corticosteroids, oral tacrolimus, topical corticosteroids, topical tacrolimus 0.1% ointment twice/day, emollient creams, intravenous rituximab, and photopheresis. The patient's tacrolimus trough levels rose rapidly over the course of 6 days from less than 2 ng/ml to 23 ng/ml, despite oral tacrolimus dosage adjustments. The second patient was a 25-year-old man who developed severe, chronic skin GVHD after undergoing allogeneic sibling bone marrow transplantation for AML. In addition to intravenous corticosteroids, corticosteroid creams, and oral tacrolimus, the patient also received topical tacrolimus twice/day with occlusive dressings. Over the course of 2 days, his tacrolimus trough levels increased from 7.10 ng/ml to 22.10 ng/ml. Although improvement was noted in both patients' skin GVHD with application of the occlusive dressings, the practice was discontinued due to increased and erratic systemic tacrolimus absorption. These case reports suggest that substantial use of topical tacrolimus with occlusive dressings in patients with cutaneous GVHD may contribute to increased systemic absorption resulting in toxic tacrolimus levels. Based on the findings from our two patients as well as published case reports, systemic absorption appears to increase with greater skin permeability, skin barrier dysfunction, amount of body surface area applied, and use of occlusive dressings. When one or more of these factors are present, it may be prudent to monitor tacrolimus levels.

Topics: Administration, Cutaneous; Adult; Bone Marrow Transplantation; Dose-Response Relationship, Drug; Female; Glucocorticoids; Graft vs Host Disease; Humans; Immunosuppressive Agents; Leukemia, Myeloid, Acute; Male; Middle Aged; Occlusive Dressings; Skin Absorption; Skin Diseases; Tacrolimus; Transplant Recipients

Topics: Adult; Amsacrine; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Cord Blood Stem Cell Transplantation; Cytarabine; Daunorubicin; Drug Therapy, Combination; Egg Hypersensitivity; Etoposide; Female; Food Hypersensitivity; Graft vs Host Disease; Granulocyte Colony-Stimulating Factor; Humans; Idarubicin; Immunosuppressive Agents; Intestinal Diseases; Leukemia, Myeloid, Acute; Liver Diseases; Male; Middle Aged; Nut Hypersensitivity; Seafood; Tacrolimus; Transplantation Conditioning; Vidarabine

Topics: Akinetic Mutism; Drug Monitoring; Drug Therapy, Combination; Female; Graft vs Host Disease; Humans; Immunosuppressive Agents; Leukemia, Myeloid, Acute; Middle Aged; Neurotoxicity Syndromes; Nuclear Family; Stem Cell Transplantation; Tacrolimus; Treatment Outcome

In our facility, three patients developed tacrolimus (TAC)-induced renal dysfunction after allogeneic hemopoietic stem cell transplantation, although trough levels of TAC were within therapeutic ranges. They received an oral agent of slow-release TAC once a day instead of a regular form oral TAC twice a day. Following treatment with the prolonged-release agent, serum creatinine levels decreased and graft-versus-host disease (GVHD) did not occur. Use of this slow-release formulation may avoid toxic peak concentrations of TAC without the development of GVHD.

Topics: Acute Kidney Injury; Adult; Aged; Delayed-Action Preparations; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Leukemia, Myeloid, Acute; Male; Middle Aged; Tacrolimus

We report a case of encephalopathy seemingly caused by tacrolimus (FK506) in spite of blood concentration near the upper limit of therapeutic range. A 26-year-old man received FK506 to prevent acute graft-versus-host disease after hematopoietic stem cell transplantation. He underwent an intravenous injection of FK506 the day before transplantation (day -1). He developed headache, hypertension, nausea and vomiting from day 2 to day 3. A computed tomography scan showed a low density area with unclear border in the bilateral cerebellar hemispheres. Thereafter, these symptoms improved with discontinuation of FK506, which was strongly suggestive of encephalopathy caused by FK506. The blood concentration of FK506 at the onset of encephalopathy was 21.7 ng/mL. Although this value was slightly higher than the standard therapeutic range (10-20 ng/mL), it was within clinically acceptable range in the early stage after stem cell transplantation. This indicates that even if the blood concentration of FK506 is within the therapeutic range, encephalopathy may develop. In summary, although the blood concentration of FK506 is useful as an indicator for prevention of encephalopathy, we propose careful monitoring not only of the blood concentration but also clinical status for the detection of initial symptoms and prevention of aggravation.

Topics: Acute Disease; Adult; Biomarkers, Pharmacological; Drug Monitoring; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Leukemia, Myeloid, Acute; Male; Myelodysplastic Syndromes; Neurotoxicity Syndromes; Tacrolimus

Topics: Administration, Intravenous; Administration, Oral; Adult; Castor Oil; Drug Delivery Systems; Drug Hypersensitivity; Female; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Leukemia, Myeloid, Acute; Tacrolimus

Topics: Adolescent; Adult; Cord Blood Stem Cell Transplantation; Female; Graft vs Host Disease; Graft vs Leukemia Effect; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; Remission Induction; Tacrolimus; Transplantation Conditioning; Transplantation, Homologous; Young Adult

Topics: Bone Marrow Transplantation; CA-125 Antigen; Carcinoma, Papillary; Erythema; Fatal Outcome; Female; Graft vs Host Disease; Graft vs Tumor Effect; Humans; Leukemia, Myeloid, Acute; Membrane Proteins; Middle Aged; Ovarian Neoplasms; Prednisolone; Tacrolimus

A 45-year-old man with acute myelogenous leukemia (WHO classification, AML with multilineage dysplasia) received allogeneic bone marrow transplantation from an HLA-identical brother in first remission. He became febrile on day 7, and pulmonary failure and multi-organ failure developed subsequently, requiring mechanical ventilation. Chest X-ray and CT scan demonstrated diffuse interstitial shadows, suggesting the development of idiopathic pneumonia syndrome. Administration of methylprednisolone and tacrolimus was effective, but respiratory failure exacerbated along with a decrease in the dose of steroids. Lung biopsy revealed organizing pneumonia with CMV pneumonia. Methylprednisolone and mycophenolate mofetil were instituted, which led to an improvement of lung injury. Intensive immunosuppressive therapy with mechanical ventilation should be considered for the treatment of idiopathic pneumonia syndrome after allogeneic bone marrow transplantation.

Topics: Bone Marrow Transplantation; Drug Therapy, Combination; Humans; Idiopathic Interstitial Pneumonias; Immunosuppression Therapy; Immunosuppressive Agents; Leukemia, Myeloid, Acute; Male; Methylprednisolone; Middle Aged; Mycophenolic Acid; Respiration, Artificial; Syndrome; Tacrolimus; Transplantation, Homologous; Treatment Outcome

Topics: Adult; Bone Marrow Transplantation; Brain Damage, Chronic; Calcineurin; Calcineurin Inhibitors; Cyclosporine; Enzyme Inhibitors; Female; Hippocampus; Humans; Immunosuppressive Agents; Leukemia, Myeloid, Acute; Magnetic Resonance Imaging; Memory Disorders; Neuropsychological Tests; Neurotoxicity Syndromes; Tacrolimus

Topics: Adult; Brain; Brain Diseases; Edema; Female; Humans; Immunosuppressive Agents; Leukemia, Myeloid, Acute; Radiography; Stem Cell Transplantation; Syndrome; Tacrolimus; Treatment Outcome

Topics: Adrenal Cortex Hormones; Chronic Disease; Disease Progression; Graft vs Host Disease; Humans; Immunosuppressive Agents; Leukemia, Myeloid, Acute; Male; Middle Aged; Prognosis; Risk Factors; Stem Cell Transplantation; Tacrolimus

Acute graft-versus-host disease is a common complication after allogeneic stem cell transplantation. It normally affects the skin, liver, and gut. We report a 54-year-old male who developed shortness of breath, cough, and bilateral pulmonary infiltrates in which the work-up failed to demonstrate an infectious etiology 165 days post-HLA-matched allogeneic peripheral blood stem cell transplant. Eighteen days before, his tacrolimus had been tapered and it was subtherapeutic on admission. A transbronchial biopsy showed a perivascular and interstitial lymphocytic infiltrate without evident pathogens on histology or extensive work-up. The clinical picture was suggestive of pulmonary acute graft-versus-host disease. No disease was present elsewhere. Accordingly, the patient was treated with steroids and tacrolimus. After 12 hr on methylprednisolone, his symptoms disappeared with eventual resolution radiologically. Acute graft-versus-host disease of the lung is a very uncommon complication after stem cell transplant, but it should be considered in patients who are at high risk for graft-versus-host disease or developing symptoms soon after discontinuing immunosuppression. Its diagnosis requires work-up to rule out an infectious etiology and a biopsy to confirm histology.

Topics: Acute Disease; Anti-Inflammatory Agents; Graft vs Host Disease; Humans; Immunosuppressive Agents; Leukemia, Myeloid, Acute; Lung; Lung Diseases; Lymphocytes; Male; Methylprednisolone; Middle Aged; Peripheral Blood Stem Cell Transplantation; Pneumonia; Radiography, Thoracic; Steroids; Tacrolimus; Tomography, X-Ray Computed; Transplantation, Homologous

We encountered 2 children with intractable diarrhea after allogeneic hematopoietic stem cell transplantation (SCT). In both cases, salazosulfapyridine (SASP) was administered to treat the diarrhea. One patient was a 14-year-old male with acute myelogenous leukemia who received SCT from a related HLA-identical donor. The leukemia recurred early, and a second SCT from the same donor was performed approximately half a year later. Because intestinal graft-versus-host disease (GVHD) was observed, steroids and octreotide were administered, but the symptoms were not improved. Thereafter, SASP was administered, and the symptoms remitted 9 days later. The other patient was a 12-year-old male with chronic myelogenous leukemia who received SCT from an unrelated HLA-identical donor. Diarrhea and abdominal pain developed early after engraftment and did not respond to either steroids or tacrolimus. Oral administration of SASP was initiated on day 236, and the diarrhea remitted 4 days later without recurrence thereafter. SASP may be effective in children for the digestive system symptoms of chronic GVHD.

Topics: Adolescent; Diarrhea; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Acute; Male; Steroids; Sulfasalazine; Tacrolimus

A patient with an allergy to a macrolide antibiotic was given tacrolimus and developed a sudden cutaneous reaction.

Topics: Anti-Bacterial Agents; Cross Reactions; Drug Eruptions; Erythema; Female; Graft vs Host Disease; Humans; Immunosuppressive Agents; Leukemia, Myeloid, Acute; Middle Aged; Tacrolimus

Twenty adult patients with high-risk leukaemia underwent allogeneic haemopoietic stem cell transplantation after melphalan, busulphan and total body irradiation followed by short-term methotrexate and low-dose cyclosporine or tacrolimus. Three patients developed veno-occlusive disease and no patient developed renal dysfunction. Seven patients experienced grade II-IV acute graft-versus-host disease (aGVHD) and five patients experienced grade III-IV. The 3-year probabilities of relapse and leukaemia-free survival were 22 +/- 11% (95% confidence interval) and 50 +/- 11%, respectively. These data suggest that this preconditioning regimen followed by a low-dose immunosuppressant provided a more anti-leukaemic effect without increased regimen-related toxicity and aGVHD.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Cyclosporine; Disease-Free Survival; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Acute; Melphalan; Middle Aged; Tacrolimus; Whole-Body Irradiation

We report our findings in two cases of steroid-resistant severe acute GVHD after allogeneic BMT successfully treated with FK506 (tacrolimus). An 18-year-old female (patient 1) who underwent BMT from an HLA-identical sibling for ALL in first CR, developed generalized erythema and profuse watery diarrhea, which progressed to acute GVHD of grade III severity, resistant to steroid control. After continuous 24-h administration of FK506, the diarrhea improved within 10 days. Patient 2, a 9-year-old girl with AML who underwent unrelated BMT, had skin, gut and liver lesions of acute GVHD grade IV, which did not respond to high-dose steroid therapy. They were controlled, however, by continuous intravenous infusion of FK506. Both patients are still surviving after more than 1 year without any acute GVHD sequelae or signs of chronic illness. The adverse effects of FK506 were mild and tolerable in both cases. Comparison of our findings with those in the literature suggests that it is important to give FK506 at plasma concentrations as high as 25-35 ng/ml by continuous intravenous infusion for extended periods to control steroid-resistant severe acute GVHD.

Topics: Acute Disease; Adolescent; Bone Marrow Transplantation; Child; Drug Resistance; Female; Graft vs Host Disease; Humans; Immunosuppressive Agents; Infusions, Intravenous; Leukemia, Myeloid, Acute; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Tacrolimus; Transplantation, Homologous