tacrolimus and Leukemia--Myelogenous--Chronic--BCR-ABL-Positive

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

Tyrosine kinase inhibitors (TKI) are an effective treatment option for chronic myeloid leukemia (CML). The most common associated adverse effects of TKI include thrombocytopenia, neutropenia, nausea, vomiting, and diarrhea. Facial edema is a rare adverse reaction that may cause significant psychological burden. Treatment is life-long in many cases therefore it is vital to have options available to manage these adverse effects.. We present a 70-year-old female with a medical history of CML, diabetes, hypertension, and hypercholesterolemia who presented to our dermatology clinic for chief complaint of worsening edematous facial rash beginning after initiation of dasatinib. We were able to achieve significant improvement with a regimen that allowed her to remain on dasatinib.. We treated the patient with a novel, unreported regimen of topical metronidazole 1% gel to be applied every morning and topical tacrolimus 0.1% ointment to be applied twice daily. She had significant improvement with the treatment and was continued on this topical regimen indefinitely.. Previous reports of treatment options available for TKI-associated facial edema include topical and systemic corticosteroids, which can cause long-term side effects int the context of long-term TKI use. Our patient achieved an acceptable reduction in facial edema and rash with our combination regimen of metronidazole gel and tacrolimus ointment. We present the only such case of successful treatment of facial edema associated with a tyrosine kinase inhibitor. We encourage future studies on the efficacy and safety of this regimen to treat this adverse effect.

Topics: Aged; Antineoplastic Agents; Dasatinib; Edema; Exanthema; Face; Female; Gels; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Metronidazole; Ointments; Protein Kinase Inhibitors; Tacrolimus

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adult; Bronchi; Bronchodilator Agents; Bronchoscopy; Dasatinib; Graft vs Host Disease; Humans; Immunocompromised Host; Immunosuppressive Agents; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Mycobacterium Infections, Nontuberculous; Peripheral Blood Stem Cell Transplantation; Protein Kinase Inhibitors; Tacrolimus; Tuberculosis, Pulmonary

The incidence of certain malignancies is significantly higher after organ transplant. However, there are rare reports of chronic myeloid leukemia in the posttransplant setting. The average reported interval between a transplant and the diagnosis of chronic myeloid leukemia is 44 months (range, 10- 96 mo). We report 2 patients with chronic myeloid leukemia within 1 year of a kidney transplant, which is significantly shorter than those previously reported. Both patients were receiving mycophenolate mofetil and tacrolimus for immunosuppression. They were treated with imatinib for chronic myeloid leukemia, and both patients demonstrated an isolated elevation of serum alkaline phosphatase that was directly correlated with imatinib. Despite a potential interaction between the 2 drugs, blood levels of tacrolimus and imatinib were not elevated during the course of treatment. Isolated elevation of alkaline phosphatase in this particular setting has not been reported previously.

Topics: Adolescent; Alkaline Phosphatase; Antineoplastic Agents; Benzamides; Biomarkers; Drug Therapy, Combination; Humans; Imatinib Mesylate; Immunosuppressive Agents; Kidney Transplantation; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Middle Aged; Mycophenolic Acid; Piperazines; Pyrimidines; Tacrolimus; Time Factors; Up-Regulation

Topics: Cardiomyopathies; Fusion Proteins, bcr-abl; Heart Transplantation; Humans; Immunocompromised Host; Immunosuppressive Agents; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukocyte Count; Male; Middle Aged; Philadelphia Chromosome; Platelet Count; Postoperative Complications; Tacrolimus

Oral involvement of chronic graft-versus-host disease (GvHD) is a most distressing and disabling complication of hematopoietic cell transplantation, for which systemic immunosuppression as well as topical corticosteroid treatment may offer only limited symptomatic relief. Here we report encouraging preliminary results with the application of tacrolimus (FK-506) as a 0.1% ointment in three patients with severe oral chronic GvHD, heavily pretreated without success, who experienced rapid, consistent, complete or at least marked, subjective and objective improvement with topical tacrolimus.

Topics: Administration, Topical; Adult; Chronic Disease; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Middle Aged; Mouth Diseases; Tacrolimus; Treatment Outcome

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 5-year-old girl with Ph-positive chronic myelogenous leukemia, who underwent umbilical cord blood transplantation, developed two episodes of electrical status epilepticus while receiving tacrolimus (FK506) then cyclosporin A (CsA), as treatment against graft-versus-host disease. MRI including diffusion weighted MR imaging of the brain revealed abnormalities in the hippocampus and posterior white matter following FK506 and CsA treatment, respectively. While posterior white matter injury has been described with both FK506 and CsA, no previous report describes hippocampal injury from either drug. The MRI changes in the hippocampus in our case suggest possible increased susceptibility to hippocampal injury with FK506.

Topics: Child, Preschool; Cord Blood Stem Cell Transplantation; Epilepsy; Female; Graft vs Host Disease; Humans; Immunosuppressive Agents; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Limbic System; Magnetic Resonance Imaging; Tacrolimus

Topics: Adult; Bone Marrow Transplantation; Female; Graft vs Host Disease; Humans; Hyponatremia; Inappropriate ADH Syndrome; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Tacrolimus; Transplantation, Homologous

A 17-year-old male with chronic myelogenous leukemia in blast crisis received a non-T cell-depleted (TCD) HLA haplo-identical three-loci mismatched hematopoietic stem cell transplant (HSCT) from his mother. Long-term feto-maternal microchimerism was detected by nested polymerase chain reaction with sequence-specific primer typing. The post-transplantation prophylaxis against graft-versus-host disease (GVHD) was tacrolimus with minidose methotrexate. Sustained engraftment was obtained. Acute GVHD (grade 2) developed, but improved rapidly. Bone marrow aspiration on day 120 showed complete remission. Non-TCD HLA haplo-identical HSCT based on feto-maternal microchimerism might be feasible and has important implications in the selection of alternative family donors in HSCT.

Topics: Adolescent; Female; Graft vs Host Disease; Haplotypes; Hematopoietic Stem Cell Transplantation; Histocompatibility; Histocompatibility Testing; Humans; Immune Tolerance; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Methotrexate; Nuclear Family; Tacrolimus; Transplantation Chimera; Treatment Outcome

We report our experience with the combination of anti-thymocyte globulin (ATGAM) and tacrolimus in the treatment of 20 patients with steroid refractory and dependent acute graft-versus-host disease (GVHD) transplanted between August 1996 and February 2000. All patients received cyclosporine-based GVHD prophylaxis. Thirteen patients developed a maximum of grade IV, five grade III and two grade II acute GVHD, with 15 patients being refractory to steroids and five dependent on steroids. Patients were treated with ATGAM (15 mg/kg for 5 d) and tacrolimus (0.025--0.1 mg/kg/d) in addition to continuation of their high-dose steroids and cessation of their cyclosporine. Within 28 d of treatment, we observed eight complete responses (CR), six partial responses (PR) and six with no response. Overall response (CR + PR) was predicted by GVHD severity. Infectious complications occurred in 80% of patients. The median survival was 86.5 d (range, 21--1081 d) with 35% of patients remaining alive. Survival following combination therapy was significantly more likely in men (P < 0.001), skin-only GVHD (P = 0.027), less severe GVHD (P = 0.048), and in responders to tacrolimus and ATGAM (P < 0.001). In conclusion, concurrent introduction of ATGAM and tacrolimus is a promising therapeutic combination for GVHD refractory to steroids and cyclosporine.

Topics: Acute Disease; Adult; Cyclosporine; Drug Therapy, Combination; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Isoantibodies; Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Lymphoma; Male; Methotrexate; Middle Aged; Multiple Myeloma; Myelodysplastic Syndromes; Tacrolimus; Transplantation, Homologous

We present two cases of severe dry eye in patients with chronic graft-versus-host disease (CGVHD) after hematopoietic stem cell transplantation (SCT) who were successfully treated by the systemic administration of FK506 and corticosteroids.. A 29-year-old man with chronic myelogenous leukemia underwent SCT. Oral and lung CGVHD developed on approximately day 130, and dry eye associated with CGVHD was diagnosed on day 168. The patient began receiving cyclosporin A (150 mg/d) for the treatment of oral and lung CGVHD. Treatment with prednisolone (1 mg/kg/d) began on approximately day 300. Oral and lung GVHD improved slightly, but worsened again although systemic administration of cyclosporin A and prednisolone were continued. Cyclosporin A was discontinued, and systemic administration of FK506 was started on day 376. Forty-four days later, marked improvement in the ocular surface and other organs was observed. However, the dry eye worsened while tapering FK506, with no flare of other affected organs. A 43-year-old woman with myelodysplastic syndrome underwent SCT. She received FK506 for prophylaxis of CGVHD. She had mild dry eye before SCT. Oral and intestinal CGVHD developed, and the dry eye worsened significantly on approximately day 150 while tapering FK506. Treatment with prednisolone (1 mg/kg/d) began, and the dose of FK506 was increased. By day 240, the symptoms of dry eye and the findings of the ocular surface markedly improved, and CGVHD in other organs was completely resolved. However, the improvement in the dry eye was lost when FK506 was tapered for the second time.. Systemic administration of FK506 with corticosteroids is an effective treatment of severe dry eye in patients with CGVHD, but long-term administration may be required to achieve a lasting response. These cases also suggest that further investigation into the use of topical FK506 and prednisolone as a maintenance therapy should be pursued.

Topics: Adult; Chronic Disease; Drug Therapy, Combination; Dry Eye Syndromes; Female; Glucocorticoids; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Myelodysplastic Syndromes; Prednisolone; Tacrolimus

FK506-related leukoencephalopathy has been reported to be reversible and readily treated by discontinuation or reduction of FK506. We describe two pediatric cases of FK506-related leukoencephalopathy following allogeneic bone marrow transplantation, which could not be readily controlled. These cases show that FK506-related leukoencephalopathy is not always reversible, and patients may develop epilepsy. Bone Marrow Transplantation (2000) 25, 331-334.

Topics: Acute Disease; Adolescent; Child, Preschool; Cyclosporine; Dementia, Vascular; Electroencephalography; Female; Graft vs Host Disease; Humans; Immunosuppressive Agents; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid; Magnetic Resonance Imaging; Male; Seizures; Tacrolimus

Tacrolimus is increasingly used for graft-versus-host disease (GVHD) prophylaxis and therapy in the allogeneic stem cell transplant (allo-SCT) setting. Pancreatitis, previously described as a side-effect of cyclosporine, has not been reported in allo-SCT recipients receiving tacrolimus. We present here a case of acute pancreatitis in a 28-year-old patient with chronic myelogenous leukemia (CML) who received an unrelated umbilical cord blood transplant (UCBT) and tacrolimus for GVHD prophylaxis. On day +31 post-transplant, she developed severe acute pancreatitis with multiorgan failure, from which she recovered completely. Tacrolimus was the probable cause of pancreatitis in this patient.

Topics: Adult; Female; Fetal Blood; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Multiple Organ Failure; Pancreatitis; Renal Dialysis; Tacrolimus; Tomography, X-Ray Computed; Transplantation, Homologous

Topics: Adult; Bone Marrow Transplantation; Coronary Vessels; Female; Humans; Immunosuppressive Agents; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Myocardial Ischemia; Tacrolimus; Transplantation, Homologous

Diplopia, nystagmus, visual hallucinations, and internuclear ophthalmoplegia developed in a 30-year-old woman 84 days after she received a matched, unrelated bone marrow transplant for chronic myeloid leukemia. A regimen of tacrolimus had been administered since the transplantation was performed. MR imaging revealed bilaterally symmetric regions of signal abnormality with abnormal contrast enhancement in the brain stem. No supratentorial abnormality was present. Tacrolimus therapy was discontinued, and the symptoms resolved. MR imaging that was performed 10 days after tacrolimus was discontinued showed resolution of the abnormalities.

Topics: Adult; Bone Marrow Transplantation; Brain Stem; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Magnetic Resonance Imaging; Neurotoxicity Syndromes; Remission, Spontaneous; 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

A 40-year-old man with chronic myelogenous leukemia in chronic phase received an allogeneic marrow graft from his HLA identical brother. He was conditioned with busulfan (16 mg/kg) and cyclophosphamide (120 mg/kg). Graft-versus-host disease (GVHD) prophylaxis was attempted with cyclosporine A (CYA) and methotrexate. On day 30, weight gain, ascites and hepatomegaly developed in addition to an elevation of total bilirubin (TB). He was diagnosed as having veno-occlusive disease (VOD) and treated conservatively. The TB level increased up to 20.1 mg/dl on day 66, then reduced to 2.1 mg/dl on day 129. By that time ascites and hepatomegaly also had completely resolved. However, on day 134. The TB level started to increase again, when the lesions of chronic GVHD were observed in the eye, the mouth, and the skin. CYA was started on day 142, and FK506 was substituted for CYA on day 161. Despite the improvement of oral and skin lesions, TB level continued to rise, and he died of respiratory failure due to ARDS on day 186. Autopsy revealed both acute and old hepatic VOD lesions, suggesting the occurrence of late-onset VOD which probably contributed to the liver dysfunction observed after clinical resolution of the first episode of VOD.

Topics: Adult; Bone Marrow Transplantation; Busulfan; Chronic Disease; Cyclophosphamide; Cyclosporine; Graft vs Host Disease; Hepatic Veno-Occlusive Disease; Humans; Immunosuppressive Agents; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Methotrexate; Recurrence; Respiratory Distress Syndrome; Tacrolimus

We have examined the effect of FK506 on the Adriamycin sensitivity of the multidrug resistant human chronic myelocytic leukemia cell line (K562/ADM). In K562/ADM cells, 1.0 microgram/ml FK506 reversed the resistance of Adriamycin, and increased the IC50 value for Adriamycin up to 17 fold. However, IC50 value for the parent cells (K562) increased only 1.5 fold. By cell cycle analysis, the accumulation in late S-G2M phase was confirmed on K562/ADM cells, treated with 1.0 microgram/ml FK506 and low-dose of Adriamycin. Cyclosporin A (CsA) could also restored the Adriamycin sensitivity in the K562/ADM cells, as previously reported. 1.0 microgram/ml FK506 as well as CsA significantly increased radioactive Adriamycin accumulation in K562/ADM cells and blocked [3H]azidopien photoaffinity labeling of P-glycoprotein. These results suggest that 1.0 microgram/ml FK506 could reverse the Adriamycin resistance in a MDR human leukemia cells through the interaction with P-glycoprotein.

Topics: Cell Cycle; Doxorubicin; Drug Resistance; Drug Screening Assays, Antitumor; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Tacrolimus; Tumor Cells, Cultured