tacrolimus and Precursor-Cell-Lymphoblastic-Leukemia-Lymphoma

Eosinophilic folliculitis (EF) comprises classic eosinophilic pustular folliculitis (EPF), human immunodeficiency virus (HIV)-related EF, and infantile EPF subtypes. A fourth proposed subtype describes EF associated with hematologic malignancy. Recently, EF has occurred after bone marrow or stem cell transplantation (SCT).. We report a unique case of EF after haploidentical allogeneic SCT for acute lymphoblastic leukemia (ALL) and review the literature for similar cases.. A 56-year-old, HIV-negative ALL patient presented with an intensely pruritic papulopustular eruption. He had undergone haploidentical allogeneic SCT 65 days earlier, which he had tolerated well. Histopathology revealed a moderately dense perifollicular and perivascular lymphocytic infiltrate with many eosinophils extending from the superficial dermis to the subcutaneous fat. Fungal stains were negative. These findings were highly consistent with EF.. Therapy with a class II topical corticosteroid ointment, oral doxepin, and emollients achieved near-resolution of the lesions within eight weeks. Transition to topical tacrolimus 0.1% ointment applied twice daily to residual lesions yielded complete clearance by 12 weeks with mild post-inflammatory hyperpigmentation. The patient's ALL remains in remission.. A fourth proposed subtype of EF is associated with HIV-negative hematologic disease. This subtype is distinguished by a predictable timeframe to presentation and a relatively rapid response to therapy. Although EF is an important consideration in all patients with hematologic malignancy, clinically heightened suspicion is warranted during the 2-3 months after transplant.

Topics: Adrenal Cortex Hormones; Doxepin; Eosinophilia; Folliculitis; Histamine Antagonists; Humans; Immunosuppressive Agents; Male; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Stem Cell Transplantation; Tacrolimus

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

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

A 5-year-old African-American male was diagnosed with nephrotic syndrome (NS). Because of concomitant leukopenia, bone marrow aspiration was performed, which did not demonstrate a hematological malignancy. The patient received standard daily steroid therapy for treatment of NS. Steroid resistance at 5 weeks of therapy led to a renal biopsy, which documented focal segmental glomerulosclerosis (FSGS). He was begun on cyclosporin A (CsA) and later switched to tacrolimus because of side-effects of CsA. Seven months after the initial diagnosis of NS, the patient was diagnosed with acute lymphoblastic leukemia (ALL). The patient is in complete remission of ALL and partial remission of NS with continued nephrotic-range proteinuria. Review of the literature shows four other cases of pediatric ALL after NS. No particular immunosuppressive agent seemed to be causative in the evolution of ALL. Although the exact mechanism for development of ALL after NS is unknown, the incidence of leukemia may be increased after immunosuppressive therapy when used in this context.

Topics: Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child, Preschool; Cyclosporine; Dexamethasone; Glomerulosclerosis, Focal Segmental; Humans; Immunosuppressive Agents; Male; Nephrotic Syndrome; Polyethylene Glycols; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Remission Induction; Tacrolimus; Treatment Outcome; Vincristine

Reports of cases of mycobacterial infections after SCT are rare. We report a 30-year-old female with a cutaneous infection of Mycobacterium fortuitum 30 months after allogeneic bone marrow transplantation for acute lymphoblastic leukemia. The patient was successfully treated with surgical debridement followed by oral minocycline and clarithromycin. Mycobacterial infections should be considered in SCT patients with undiagnosed refractory chronic cutaneous infection, and surgical debridement is useful for the diagnosis and treatment of such infections.

Topics: Adult; Bone Marrow Transplantation; Clarithromycin; Combined Modality Therapy; Cyclosporine; Debridement; Drug Therapy, Combination; Female; Graft vs Host Disease; Humans; Immunocompromised Host; Immunosuppressive Agents; Methotrexate; Minocycline; Mycobacterium fortuitum; Mycobacterium Infections, Nontuberculous; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Remission Induction; Skin Ulcer; Tacrolimus; Transplantation Conditioning; Transplantation, Homologous

Dipeptidyl peptidase 4 (DPP-4; also known as CD26), a transmembrane receptor expressed on T cells, has a costimulatory function in activating T cells. In a mouse model, down-regulation of CD26 prevented graft-versus-host disease (GVHD) but preserved graft-versus-tumor effects. Whether inhibition of DPP-4 with sitagliptin may prevent acute GVHD after allogeneic stem-cell transplantation is not known.. We conducted a two-stage, phase 2 clinical trial to test whether sitagliptin plus tacrolimus and sirolimus would reduce the incidence of grade II to IV acute GVHD from 30% to no more than 15% by day 100. Patients received myeloablative conditioning followed by mobilized peripheral-blood stem-cell transplants. Sitagliptin was given orally at a dose of 600 mg every 12 hours starting the day before transplantation until day 14 after transplantation.. A total of 36 patients who could be evaluated, with a median age of 46 years (range, 20 to 59), received transplants from matched related or unrelated donors. Acute GVHD occurred in 2 of 36 patients by day 100; the incidence of grade II to IV GVHD was 5% (95% confidence interval [CI], 1 to 16), and the incidence of grade III or IV GVHD was 3% (95% CI, 0 to 12). Nonrelapse mortality was zero at 1 year. The 1-year cumulative incidences of relapse and chronic GVHD were 26% (95% CI, 13 to 41) and 37% (95% CI, 22 to 53), respectively. GVHD-free, relapse-free survival was 46% (95% CI, 29 to 62) at 1 year. Toxic effects were similar to those seen in patients undergoing allogeneic stem-cell transplantation.. In this nonrandomized trial, sitagliptin in combination with tacrolimus and sirolimus resulted in a low incidence of grade II to IV acute GVHD by day 100 after myeloablative allogeneic hematopoietic stem-cell transplantation. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT02683525.).

Topics: Adult; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Leukemia, Myeloid; Male; Middle Aged; Myelodysplastic Syndromes; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; Sirolimus; Sitagliptin Phosphate; Survival Analysis; Tacrolimus; Transplantation, Homologous; 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

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

Sirolimus has activity against acute lymphoblastic leukemia (ALL) in xenograft models and efficacy in preventing acute graft-versus-host disease (aGVHD). We tested whether addition of sirolimus to GVHD prophylaxis of children with ALL would decrease aGVHD and relapse. Patients were randomized to tacrolimus/methotrexate (standard) or tacrolimus/methotrexate/sirolimus (experimental). The study met futility rules for survival after enrolling 146 of 259 patients. Rate of Grade 2-4 aGVHD was 31% vs 18% (standard vs experimental, P = .04), however, grade 3-4 aGVHD was not different (13% vs 10%, P = .28). Rates of veno-occlusive disease (VOD) and thrombotic microangiopathy (TMA) were lower in the nonsirolimus arm (9% vs 21% VOD, P = .05; 1% vs 10% TMA, P = .06). At 2 years, event free survival (EFS) and overall survival (OS) were 56% vs 46%, and 65% vs 55% (standard vs experimental), respectively (P = .28 and .23). Multivariate analysis showed increased relapse risk in children with ≥0.1% minimal residual disease (MRD) pretransplant, and decreased risk in patients with grades 1-3 aGVHD (P = .04). Grades 1-3 aGVHD were associated with improved EFS (P = .02), whereas grade 4 aGVHD and extramedullary disease at diagnosis led to inferior OS. Although addition of sirolimus decreased aGVHD, survival was not improved. This study is registered with ClinicalTrials.gov as #NCT00382109.

Topics: Adolescent; Child; Child, Preschool; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Infant; Male; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Sirolimus; Tacrolimus; Transplantation Conditioning; Transplantation, Homologous; Whole-Body Irradiation; Young Adult

We aimed to evaluate the safety and efficacy of fludarabine (FLU) and pharmacokinetic-targeted busulfan (BU) as conditioning regimen for hematopoietic cell transplantation (HCT) in adult patients with acute lymphoid leukemia (ALL). Forty-four patients with ALL (27 in first complete remission [CR1] and 17 in more advanced disease stage: 4 with primary induction failure [PIF], 12 in CR2, and 1 in CR3) received FLU and pharmacokinetic-targeted BU as preparative therapy for HCT. Grafts were T-replete, filgrastim-mobilized peripheral blood stem cells (PBSC). Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus (TAC) and short-course methotrexate in 36 patients, TAC and sirolimus in 3, and TAC and mycophenolate mofetil in 5. Primary engraftment was achieved in all 44 patients. The cumulative incidence of transplant-related mortality (TRM) was 2% (95% confidence interval [CI] 0%-16%) at 100 days and 18% (95% CI 10%-34%) at 2 years. The 2-year cumulative incidence of relapse was 19% (95% CI 8%-41%) for those transplanted in CR1, and 48% (29%-80%) for those with more advanced disease. After a median follow-up of 32 months (range: 15-69 months), the 2-year overall survival (OS) was 54% (95% CI 39%-69%). Relapse-free survival (RFS) at 2 years was 63% (95% CI 45%-81%) for patients transplanted in CR1 and 34% (95% CI 11%-57%) for patients transplanted in more advanced disease. When compared to irradiation-containing regimens, FLU and PK-targeted BU appear safer and similarly effective in controlling ALL, providing a treatment option for adult patients with ALL.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Disease-Free Survival; Female; Follow-Up Studies; Graft Survival; Graft vs Host Disease; Humans; Immunosuppressive Agents; Male; Methotrexate; Middle Aged; Peripheral Blood Stem Cell Transplantation; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Retrospective Studies; Survival Rate; Tacrolimus; Transplantation Conditioning; Transplantation, Homologous; Vidarabine

Sirolimus has been shown to have activity against human acute lymphoblastic leukaemia at serum levels used for immunosuppression. We hypothesized that the addition of sirolimus to a tacrolimus/methotrexate graft-versus-host disease (GVHD) prophylaxis regimen would decrease relapse after haematopoietic stem cell transplantation and initiated a phase I/II study to demonstrate safety, feasibility, and efficacy. The study cohort included 18 patients in high-risk (HR) first complete remission (CR1), 16 in HR CR2, 17 in intermediate risk (IR) CR2, and 12 in CR3+. The 2-year event-free survival (EFS) of the cohort was 66% (standard error 6.4). EFS of risk groups was 74%, 81%, 44% and 46% for CR1, IR CR2, HR CR2 and CR3+ patients respectively, and did not differ by stem cell source. Cumulative incidence of acute GVHD grade II-IV and III-IV was 38% and 21% respectively, while the cumulative incidence of chronic GVHD was 32%. Cumulative incidence of transplant-related mortality and relapse was 10% and 25% respectively. Significant toxicities included veno-occlusive disease [seven patients (11%)], transplant-associated microangiopathy (three patients), and idiopathic pneumonitis (one patient). In summary, sirolimus-based GVHD prophylaxis can be given safely in this population and early survival results are promising. A phase III trial to test whether sirolimus decreases relapse and improves outcome after transplantation for ALL is ongoing.

Topics: Adolescent; Child; Child, Preschool; Epidemiologic Methods; Female; Graft Survival; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Infant; Male; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; Sirolimus; Tacrolimus; Treatment Outcome; Young Adult

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

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

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

Topics: Acute Kidney Injury; Anti-Inflammatory Agents; Diuretics; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Male; Methylprednisolone; Middle Aged; Nephrotic Syndrome; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Rituximab; Tacrolimus; Transplantation, Homologous

Acute lymphoblastic leukemia (ALL) is associated with poor survival in older adults, and allogeneic hematopoietic cell transplant (HCT) with reduced-intensity conditioning (RIC) has been an increasingly used strategy in this population. At City of Hope we conducted a retrospective analysis of 72 patients who underwent allogeneic HCT with fludarabine and melphalan (FluMel) as the conditioning regimen between 2005 and 2018, from either a matched sibling or fully matched unrelated donor while in complete remission. Tacrolimus and sirolimus (T/S) were used as graft-versus-host disease (GVHD) prophylaxis. Overall survival and progression-free survival at 4 years post-HCT were 58% and 44%, respectively. The cumulative incidences of relapse/progression and nonrelapse mortality at 4 years were 34% and 22%, respectively. Patients with Philadelphia chromosome-positive (Ph+) ALL had a significantly lower cumulative incidence of relapse/progression (20% versus 48% for patients with Ph-negative status, P = .007). In conclusion, RIC HCT with FluMel conditioning and T/S GVHD prophylaxis was associated with favorable outcomes in patients with Ph+ ALL and should be considered as a viable consolidative therapy for adult patients with ALL.

Topics: Aged; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Retrospective Studies; Sirolimus; Tacrolimus; Transplantation Conditioning; Vidarabine

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

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

The prognostic relevance of cytogenetics at diagnosis on the outcome of allogeneic hematopoietic stem cell transplantation (alloHCT) for adult acute lymphoblastic leukemia (ALL) remains unclear. We retrospectively analyzed outcomes of 333 adult ALL patients who underwent alloHCT at our institution over a 10-year period. Patients were classified according to disease status at transplantation (complete response [CR] 1 [n = 202] or > CR1) and according to cytogenetic risk, defined as good (2%), intermediate (42%), poor (46%), or unknown (10%) based on available outcome data for each of the cytogenetic abnormalities. Three-year overall survival (OS), leukemia-free survival (LFS), and relapse incidence (RI) were 55.7%, 47.9% and 27.5%, respectively; 1-year nonrelapse mortality (NRM) was 17.3%. For patients undergoing alloHCT in CR1, 3-year OS, LFS, and RI were 69.8%, 62.3%, and 17.1%, respectively. In multivariable analysis, cytogenetic risk did not impact OS or LFS for the whole cohort or for patients who underwent transplantation in CR1. Disease status at alloHCT was an independent predictor for LFS (CR1 versus others: hazard ratio [HR], 3.17; P < .01) and OS (CR1 versus others: HR, 2.90; P < .01). Graft-versus-host disease prophylaxis with tacrolimus/sirolimus was associated with a low NRM of 11.5% in the alloHCT recipients in CR1. Our data indicate that cytogenetic risk is not an independent predictor of outcomes in alloHCT performed to treat adult ALL.

Topics: Adolescent; Adult; Aged; Chromosome Aberrations; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Male; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Premedication; Prognosis; Retrospective Studies; Risk Assessment; Sirolimus; Tacrolimus; Transplantation, Homologous; Young Adult

Cancer risk associated with topical calcineurin inhibitors (TCIs) remains unclear.. To evaluate the association between TCIs and cancer among patients with atopic and endogenous eczema.. Incident cancers were identified from the National Cancer Registry. Data were analyzed using the Cox proportional hazards model to estimate hazard ratios (HRs) and 95% confidence intervals.. 880 unique cases of cancer developed in 66 176 patients from 2004 to 2012. The adjusted HRs for overall malignancy were 0.82 (95%CI 0.44-1.39) for tacrolimus-exposed and 1.30 (95%CI 0.59-2.45) for pimecrolimus-exposed. The only significant cancer association observed was lymphoid leukemia among the tacrolimus-exposed: HR 7.58 (95%CI 1.64-25.8). All affected patients had young-onset B-cell leukemia. Subgroup analysis of pediatric patients (≤16 years) showed significant association between tacrolimus use and B-cell leukemia: HR 26.4 (95%CI 4.77-146).. In this first Asian study on the risk of TCIs and malignancies, we do not find an association between use of tacrolimus and pimecrolimus in atopic and endogenous eczema and the overall development of malignancies. However, the use of topical tacrolimus was found to be associated with the development of B-cell acute lymphoid leukemia in pediatric eczema patients; further studies are required to investigate if a true association indeed occurs.

Topics: Administration, Topical; Asian People; Calcineurin Inhibitors; Child; Cohort Studies; Eczema; Female; Humans; Immunosuppressive Agents; Male; Neoplasms; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Risk; Tacrolimus

Primary graft failure occurred after cord blood transplantation for a patient with acute lymphoblastic leukemia. The second transplantation was performed using haploidentical peripheral blood. The conditioning regimen consisted of fludarabine (day -1; 30 mg/m(2)), cyclophosphamide (day -1; 2,000 mg/m(2)), and total body irradiation (day -1; 2 Gy). The immunosuppressants contained tacrolimus, prednisolone, and rabbit anti-thymocyte globulin (day -3 to -2; total dose: 3.75 mg/kg). The engraftment was confirmed on day 9. Both acute and chronic graft-versus-host disease were controllable. The present regimen appears to be suitable for immediate management, fast engraftment, and the durable control of complications.

Topics: Graft vs Host Disease; Haplotypes; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Male; Melphalan; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Tacrolimus; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome; Vidarabine

We report on 27 patients with Down syndrome (DS) and acute lymphoblastic leukemia (ALL) who received allogeneic hematopoietic cell transplantation (HCT) between 2000 and 2009. Seventy-eight percent of patients received myeloablative conditioning and 52% underwent transplantation in second remission. Disease-free survival (DFS) was 24% at a median of 3 years. Post-transplant leukemic relapse was more frequent than expected for children with DS-ALL (54%) than for non-DS ALL. These data suggest leukemic relapse rather than transplant toxicity is the most important cause of treatment failure. Advancements in leukemia control are especially needed for improvement in HCT outcomes for DS-ALL.

Topics: Adolescent; Adult; Allografts; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Child; Child, Preschool; Combined Modality Therapy; Cyclosporine; Disease-Free Survival; Down Syndrome; Genetic Predisposition to Disease; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Infant; Kaplan-Meier Estimate; Living Donors; Myeloablative Agonists; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; Registries; Remission Induction; Retrospective Studies; Salvage Therapy; Tacrolimus; Transplantation Conditioning; Treatment Outcome; Whole-Body Irradiation

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

Candida krusei is an important agent of opportunistic infections that often displays resistance to several antifungals. We describe here the in vivo acquisition of resistance to voriconazole (VRC) by C. krusei isolates recovered from a leukemia patient during a long period of VRC therapy. In order to mimic the in vivo development of VRC resistance, a susceptible C. krusei isolate was exposed daily to 1 μg/ml of VRC in vitro. Interestingly, after 5 days of exposure to VRC, a MIC of 4 μg/ml was achieved; this value remained constant after 25 additional days of treatment with VRC and also after 30 consecutive days of incubation in VRC-free medium. Our objective was to determine the associated molecular resistance mechanisms, such as expression of efflux pump genes and ERG11 gene mutations, among the resistant strains. Synergistic effects between the efflux blocker tacrolimus (FK506) and VRC were found in all of the resistant strains. Moreover, ABC1 gene expression increased over time in both the in vivo- and in vitro-induced resistant strains, in contrast to the ABC2 and ERG11 genes, whose expression was invariably lower and constant. ERG11 gene sequencing showed two different types of mutations, i.e., heterozygosity at T1389T/C, corresponding to synonymous mutations, in C. krusei strains and a missense mutation at position T418C, resulting in a change from Tyr to His, among resistant C. krusei clinical isolates. This study highlights the relevance of ATP-dependent efflux pump (namely, Abc1p) activity in VRC resistance and describes new mutations in the ERG11 gene among resistant C. krusei clinical isolates.

Topics: Adult; Antifungal Agents; Antineoplastic Agents; ATP-Binding Cassette Transporters; Candida; Candidiasis; Drug Resistance, Fungal; Fluconazole; Fungal Proteins; Gene Expression; Humans; Male; Mutation; Opportunistic Infections; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Sterol 14-Demethylase; Tacrolimus; Voriconazole

Nephrotic syndrome (NS) associated with hematopoietic stem cell transplantation (HSCT) is usually related to chronic graft-versus-host disease (GVHD) and invariably occurs later than 100 days after transplantation. Here, we report the case of a 6-year-old boy who presented with NS only 61 days after cord blood stem cell transplantation (CBSCT). At 4 years old he was diagnosed with acute lymphoblastic leukemia and underwent bone marrow transplantation. Six months later, a recurrence was noted in the thymus, which required CBSCT at the age of 6. Acute GVHD and hemophagocytic syndrome occurred on day +13 and day +15, respectively, and were successfully treated with tacrolimus and a steroid. After tacrolimus was switched from intravenous infusion to oral administration, NS occurred on day +61. Complete remission was achieved in 3 weeks by resuming steroid treatment. Dry erythema with pigmentation and elevation of Th2 cytokine level suggest that NS in this case was also related to chronic GVHD. To our knowledge, this is the earliest occurrence of NS after HSCT. Hematologists and nephrologists should be aware that this condition may occur even in early periods after HSCT.

Topics: Bone Marrow Transplantation; Child; Child, Preschool; Cord Blood Stem Cell Transplantation; Graft vs Host Disease; Humans; Male; Nephrotic Syndrome; Pleural Effusion; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Recurrence; Remission Induction; 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: Administration, Cutaneous; Adolescent; Chronic Disease; Dry Eye Syndromes; Graft vs Host Disease; Humans; Inflammation; Male; Ointments; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Tacrolimus; Treatment Outcome

A 64-year-old woman underwent allogeneic peripheral blood-derived stem cell transplantation for acute lymphocytic leukemia. She complained of dyspnea and was admitted to hospital 116 days after transplantation. Because of positive serum testing for the Aspergillus antigen and antibody, and ground-glass opacity in the right upper lobe on high-resolution computed tomography (HRCT), we made a diagnosis of pulmonary aspergillosis and administered an antifungal agent. Although tests for the Aspergillus antibody became negative and the ground-glass opacities disappeared, her dyspnea persisted. Progressive bronchiectasis was seen on HRCT, predominantly in the lower lobes. A pulmonary function test showed mixed impairment. We made a diagnosis of bronchiolitis obliterans after chronic graft versus host disease (GVHD). Prednisolone and an increased dose of tacrolimus (FK506) were administered, but type II respiratory failure progressed and she died 2 months after admission. On HRCT, each lobe was graded for bronchiectasis using a scale: 0 = normal, 1 = less than 2 x the diameter of an adjacent pulmonary artery, 2 = 2 - 3 x the diameter of an adjacent pulmonary artery, and 3 = more than 3 x the diameter of an adjacent pulmonary artery. A total score was calculated by summing the scores of all the lobes (maximum 15). In this case, the total score increased rapidly from 0 to 13 in 2 months.

Topics: Bronchiectasis; Bronchiolitis Obliterans; Chronic Disease; Disease Progression; Fatal Outcome; Female; Graft vs Host Disease; Humans; Middle Aged; Peripheral Blood Stem Cell Transplantation; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Respiratory Insufficiency; Severity of Illness Index; Tacrolimus; Tomography, X-Ray Computed; Transplantation, Homologous

A major complication following hematopoietic stem cell transplantation is graft versus host disease. Cutaneous manifestations of chronic graft versus host disease (cGVHD) are varied and this condition impacts patient outcomes and quality of life. We describe two cases of lichen sclerosus et atrophicus-like cGVHD developing in patients after hematopoietic stem cell transplantation. Both patients presented clinically with patches of pigmentary changes and scaling that displayed classic histologic features of lichen sclerosus et atrophicus. The skin is a frequent target organ of cGVHD and often the presenting location of the disease, making dermatologists key in recognition and management. It has been proposed that cutaneous cGVHD is a spectrum of disease and the lesions may evolve through various stages. Lichen sclerosus et atrophicus-like cGVHD may represent a phase in this continuum or a distinct sub-type of disease. Remaining cognizant of the potential manifestations of disease is key for prompt recognition and proper treatment.

Topics: Clobetasol; Combined Modality Therapy; Diagnosis, Differential; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Hydrocortisone; Immunosuppressive Agents; Leukemia, Promyelocytic, Acute; Lichen Sclerosus et Atrophicus; Lymphocyte Transfusion; Male; Middle Aged; Photopheresis; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Tacrolimus; Triamcinolone

Topics: Child; Cyclosporine; Female; Humans; Neurotoxicity Syndromes; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Stem Cell Transplantation; Tacrolimus

Calcineurin-inhibitor-induced pain syndrome (CIPS), a rare complication seen in patients with organ transplants, is associated with the use of calcineurin inhibitors (CIs) such as cyclosporine (CSP) and tacrolimus (FK). Patients with this syndrome usually present with severe leg pain. This case report demonstrates the successful pain control of this pain syndrome in a 42-year-old female patient who had been given CIs (FK and CSP) as an immunosuppressive agent after a bone marrow transplant. Twenty-one days after the transplantation, she complained of severe pain in her bilateral lower extremities; this lasted several weeks, and was resistant to ordinary analgesics such as intramuscular pentazocine, intravenous morphine, and even oral nifedipine, which is generally accepted as an effective analgesic agent for the pain in this syndrome. Due to the presence of allodynia, our patient's pain had neuropathic pain-like characteristics, unlike the pain in previously reported patients with other organ transplants. Her pain was successfully relieved by the administration of oral amytriptyline, clonazepam, oxycodone, and intravenous lidocaine, all of which ordinarily have an analgesic effect on neuropathic pain. CIPS in patients with hematopoietic stem cell transplants treated with FK may have a mechanism by which neuropathic pain may develop that is different from that in patients with other organ transplants.

Topics: Adult; Bone Marrow Transplantation; Calcineurin Inhibitors; Female; Humans; Immunosuppressive Agents; Leg; Pain; Pain Management; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; Syndrome; Tacrolimus; Treatment Outcome

Topics: Adolescent; Diabetes Mellitus, Type 2; Humans; Immunosuppressive Agents; Male; Postoperative Complications; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Stem Cell Transplantation; Tacrolimus

The calcineurin inhibitors (CIs) cyclosporine A and tacrolimus are essential for graft-versus-host disease prophylaxis but are associated with adverse effects, including neurotoxicity. We report a case of irreversible CI-induced neuropathic pain following allogeneic hematopoietic stem cell transplantation. The patient developed dysesthesia, electric shock-like pain, and severe itching followed by intractable analgesic-resistant pain in the lower extremities. There were no abnormal radiographic findings, and there was no improvement with a reduction of CI dosage or with administration of a calcium channel blocker. These clinical findings are similar to but inconsistent with CI-induced musculoskeletal pain syndromes previously reported in organ transplantation.

Topics: Adult; Calcineurin Inhibitors; Cyclosporine; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Pain; Peripheral Nervous System Diseases; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Radiography; Tacrolimus; Transplantation, Homologous

Tacrolimus is widely used for the prophylaxis and treatment of graft-versus-host disease after allogeneic hematopoietic stem cell transplantation (HSCT) and graft rejection in solid organ transplantation. The metabolism of tacrolimus has been reported to be impaired in association with liver dysfunction, mostly as documented in liver transplant recipients. Hepatic veno-occlusive disease (VOD) is one of the serious complications after allogeneic HSCT. It is characterized by jaundice, fluid retention, and painful hepatomegaly, caused by endothelial cell injury resulting from the toxicity of the conditioning regimen. The impaired metabolism of tacrolimus in hepatic VOD has not previously been reported in the literature. Here, we report the notable alteration in the metabolism of tacrolimus in two patients with hepatic VOD, in whom the half-lives of tacrolimus were markedly prolonged (288 and 146 h).

Topics: Cord Blood Stem Cell Transplantation; Endothelium, Vascular; Female; Hepatic Veno-Occlusive Disease; Humans; Immunosuppressive Agents; Liver; Liver Diseases; Male; Middle Aged; Myelodysplastic Syndromes; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Tacrolimus; Transplantation Conditioning

A 26-year-old male with acute lymphoblastic leukemia (ALL) in its second complete remission received an unrelated bone marrow transplantation (UBMT) following cyclophosphamide plus total body irradiation conditioning. The patient relapsed 7 months after the BMT. He received a second UBMT from a different donor 15 months after the initial UBMT. Conditioning for the second UBMT consisted of busulphan, melphalan, and anti-thymocyte globulin. The regimen was well tolerated, and engraftment was achieved. Both acute and chronic graft-versus-host diseases occurred but were successfully controlled with immunosuppressive drugs. He is alive and disease-free 29 months after the second UBMT. This is the first report of a successful second UBMT for ALL that had relapsed after the first UBMT and for which a different donor was used.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Azathioprine; Bone Marrow Transplantation; Cyclophosphamide; Daunorubicin; Drug Therapy, Combination; Female; Graft vs Host Disease; Humans; Immunosuppressive Agents; Living Donors; Male; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Recurrence; Remission Induction; Tacrolimus; Transplantation Conditioning; Transplantation, Homologous; Vincristine

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

Topics: Adult; Bone Marrow Transplantation; Bronchiolitis Obliterans; Female; Graft vs Host Disease; Humans; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Tacrolimus