Chronic Myeloid Leukemia following Exposure to Radioactive Iodine (I131): A Systematic Review.

BACKGROUND: Therapy-related leukemia is a term that describes the occurrence of leukemia following exposure to hematotoxins and radiation to emphasize the difference from leukemia that arises de novo. Many agents and host factors contribute to this entity of leukemias. Therapy-related acute myeloid leukemia has an extensive literature review in contrast to therapy-related chronic myeloid leukemia (t-CML). Radioactive iodine (RAI), an established agent in the management of differentiated thyroid carcinomas, has raised concern due to its possible carcinogenic effects. SUMMARY: In this article, we reviewed all the reports from the 1960s to date related to t-CML following RAI on Google Scholar and PubMed. We have identified 14 reports and found that most reports were for men under the age of 60 years with primary papillary thyroid carcinoma and mixed follicular-papillary thyroid carcinoma who developed t-CML mainly between 4 and 7 years after exposure to varying doses of I131. However, the mean dose was 287.78 millicuries (mCi). It was reported that a statistically significant increase in leukemia following RAI therapy (relative risk of 2.5 for I131 vs. no I131). Also, there was a linear relationship between the cumulative dose of I131 and the risk of leukemia. Doses higher than 100 mCi were associated with a greater risk of developing secondary leukemia, and most of the leukemias developed within the initial 10 years of exposure. The precise mechanism through which RAI provokes leukemia is largely unclear. A few mechanisms have been proposed. KEY MESSAGES: Although the risk for t-CML appears to be low based on current reports and does not represent a contraindication to RAI therapy, it should not be disregarded. We suggest including it in the risk-benefit discussion before initiating this therapy. Long-term follow-up for patients is advisable for those who received doses over 100 mCi with a complete blood count, possibly yearly, for the first 10 years. The new onset of significant leukocytosis post RAI exposure should raise the suspicion for t-CML. Further studies are needed to establish or refute a causal relationship.

Deletion of the deISGylating enzyme USP18 enhances tumour cell antigenicity and radiosensitivity.

BACKGROUND: Interferon (IFN) signalling pathways, a key element of the innate immune response, contribute to resistance to conventional chemotherapy, radiotherapy, and immunotherapy, and are often deregulated in cancer. The deubiquitylating enzyme USP18 is a major negative regulator of the IFN signalling cascade and is the predominant human protease that cleaves ISG15, a ubiquitin-like protein tightly regulated in the context of innate immunity, from its modified substrate proteins in vivo. METHODS: In this study, using advanced proteomic techniques, we have significantly expanded the USP18-dependent ISGylome and proteome in a chronic myeloid leukaemia (CML)-derived cell line. USP18-dependent effects were explored further in CML and colorectal carcinoma cellular models. RESULTS: Novel ISGylation targets were characterised that modulate the sensing of innate ligands, antigen presentation and secretion of cytokines. Consequently, CML USP18-deficient cells are more antigenic, driving increased activation of cytotoxic T lymphocytes (CTLs) and are more susceptible to irradiation. CONCLUSIONS: Our results provide strong evidence for USP18 in regulating antigenicity and radiosensitivity, highlighting its potential as a cancer target.

Apocrine adenocarcinoma in the setting of apocrine hidrocystoma of the leg.

Apocrine hidrocystoma is a benign, cystic lesion often presenting in the periorbital region. Apocrine adenocarcinoma is the rare, malignant counterpart occurring mainly in the axilla and anogenital region. There is a paucity of literature on both entities and co-occurrence has been reported in only 5 cases. We present the case of a 48-year-old man with a history of total body irradiation for chronic myelocytic leukemia, diabetes mellitus, and obesity who presented with a calf mass of two years' duration. Epidermal inclusion cyst was presumed and excisional biopsy was carried out. Pathologic analysis revealed apocrine adenocarcinoma in the setting of a precursor apocrine hidrocystoma. Our patient's unique altered immunity and the direct effects of irradiation on the local microenvironment may have resulted in his rare presentation of co-occurrence of apocrine adenocarcinoma within an existing apocrine hidrocystoma. To our knowledge, our patient is the first reported patient with this presentation in the lower extremity.

Central nervous system blast crisis of chronic myeloid leukaemia misdiagnosed as tubercular meningitis.

Chronic Myeloid Leukaemia (CML) presenting with isolated Central Nervous System (CNS) blast crisis is an uncommon entity. A 22-year-old man, diagnosed with chronic phase CML in 2011 and was in haematological and cytogenetic remission until July 2016, had acute onset headache and vomiting with meningeal signs and was admitted elsewhere, investigated by brain imaging and cerebrospinal fluid (CSF) analysis and suspected to have tubercular meningitis, for which steroids and antitubercular medications were started. The patient's sensorium further deteriorated, and Ventriculoperitoneal shunt surgery was done for hydrocephalus by a neurosurgeon. After 2 months of the illness, he was admitted to our hospital with a persistent headache, vomiting and altered sensorium. CSF for cytospin confirmed myeloid blasts. He was still in haematological remission. So, a diagnosis of isolated CNS blast crisis was made. The patient was started on triple intrathecal chemotherapy and cranial radiotherapy. He had improvement with treatment and is still in remission.

Splenic irradiation before hematopoietic stem cell transplantation for chronic myeloid leukemia: long-term follow-up of a prospective randomized study.

In the context of discussions on the reproducibility of clinical studies, we reanalyzed a prospective randomized study on the role of splenic irradiation as adjunct to the conditioning for hematopoietic stem cell transplantation (HSCT) for chronic myeloid leukemia (CML). Between 1986 and 1989, a total of 229 patients with CML were randomized; of these, 225 (98 %; 112 with, 113 without splenic irradiation) could be identified in the database and their survival updated. Results confirmed the early findings with no significant differences in all measured endpoints (overall survival at 25 years: 42.7 %, 32.0-52.4 % vs 52.9 %, 43.2-62.6 %; p = 0.355, log rank test). Additional splenic irradiation failed to reduce relapse incidence. It did not increase non-relapse mortality nor the risk of late secondary malignancies. Comforting are the long-term results from this predefined consecutive cohort of patients: more than 60 % were alive at plus 25 years when they were transplanted with a low European Society for Blood and Marrow Transplantation (EBMT) risk sore. This needs to be considered today when treatment options are discussed for patients who failed initial tyrosine kinase inhibitor therapy and have an available low risk HLA-identical donor.

Lymphoproliferative Disorders in Patients with Chronic Myeloid Leukemia: A Single-Center Case Series.

Lymphoproliferative disorders presenting simultaneously with or subsequent to the occurrence of chronic myeloid leukemia (CML) have rarely been reported. Herein, we report 8 cases of a variety of lymphoproliferative conditions associated with CML at different times during the course of the disease. All 8 patients were treated with tyrosine kinase inhibitors at some point during the course of their illness. The literature regarding the uncommon association of these apparently unrelated disorders is reviewed as well as the possible underlying mechanisms that could be associated with this phenomenon.

Non-selective cation channel-mediated Ca2+-entry and activation of Ca2+/calmodulin-dependent kinase II contribute to G2/M cell cycle arrest and survival of irradiated leukemia cells.

Genotoxic stress induces cell cycle arrest and DNA repair which may enable tumor cells to survive radiation therapy. Here, we defined the role of Ca(2+) signaling in the cell cycle control and survival of chronic myeloid leukemia (CML) cells subjected to ionizing radiation (IR). To this end, K562 erythroid leukemia cells were irradiated (0-10 Gy). Tumor survival was analyzed by clonogenic survival assay and cell cycle progression via flow cytometry. Plasma membrane cation conductance was assessed by patch-clamp whole-cell recording and the cytosolic free Ca(2+) concentration ([Ca(2+)](i)) was measured by fura-2 Ca(2+) imaging. Nuclear activity of Ca(2+)/calmodulin-dependent kinase II (CaMKII) was defined by Western blotting. In addition, the effect of IR (5 Gy) on the cation conductance of primary CML cells was determined. The results indicated that IR (10 Gy) induced a G(2)/M cell cycle arrest of K562 cells within 24 h post-irradiation (p.i.) and decreased the clonogenic survival to 0.5 % of that of the control cells. In K562 cells, G(2)/M cell cycle arrest was preceded by activation of TRPV5/6-like nonselective cation channels in the plasma membrane 1-5 h p.i., resulting in an elevated Ca(2+) entry as evident from fura-2 Ca(2+) imaging. Similarly, IR stimulated a Ca(2+)-permeable nonselective cation conductance in primary CML cells within 2-4 h p.i.. Ca(2+) entry, into K562 cells was paralleled by an IR-induced activation of nuclear CaMKII. The IR-stimulated accumulation in G(2) phase was delayed upon buffering [Ca(2+)](i) with the Ca(2+) chelator BAPTA-AM or inhibiting CaMKII with KN93 (1 nM). In addition, KN93 decreased the clonogenic survival of irradiated cells but not of control cells. In conclusion, the data suggest that IR-stimulated cation channel activation, Ca(2+) entry and CaMKII activity participate in control of cell cycle progression and survival of irradiated CML cells.

Total body irradiation (TBI) in pediatric patients. A single-center experience after 30 years of low-dose rate irradiation.

PURPOSE: To retrospectively analyze patient characteristics, treatment, and treatment outcome of pediatric patients with hematologic diseases treated with total body irradiation (TBI) between 1978 and 2006. PATIENTS AND METHODS: 32 pediatric patients were referred to the Department of Radiation-Oncology at the University of Zurich for TBI. Records of regular follow-up of 28 patients were available for review. Patient characteristics as well as treatment outcome regarding local control and overall survival were assessed. A total of 18 patients suffered from acute lymphoblastic leukemia (ALL), 5 from acute and 2 from chronic myelogenous leukemia, 1 from non-Hodgkin lymphoma, and 2 from anaplastic anemia. The cohort consisted of 15 patients referred after first remission and 13 patients with relapsed leukemia. Mean follow-up was 34 months (2-196 months) with 15 patients alive at the time of last follow-up. Eight patients died of recurrent disease, 1 of graft vs. host reaction, 2 of sepsis, and 2 patients died of a secondary malignancy. RESULTS: The 5-year overall survival rate (OS) was 60%. Overall survival was significantly inferior in patients treated after relapse compared to those treated for newly diagnosed leukemia (24% versus 74%; p=0.004). At the time of last follow-up, 11 patients survived for more than 36 months following TBI. Late effects (RTOG ≥ 3) were pneumonitis in 1 patient, chronic bronchitis in 1 patient, cardiomyopathy in 2 patients, severe cataractogenesis in 1 patient (48 months after TBI with 10 Gy in a single dose) and secondary malignancies in 2 patients (36 and 190 months after TBI). Growth disturbances were observed in all patients treated prepubertally. In 2 patients with identical twins treated at ages 2 and 7, a loss of 8% in final height of the treated twin was observed. CONCLUSION: As severe late sequelae after TBI, we observed 2 secondary malignancies in 11 patients who survived in excess of 36 months. However, long-term morbidity is moderate following treatment with the fractionated TBI at the low-dose rate that was generally used here. Conditioning for bone marrow transplantation without radiation is an attractive option, but is not sufficiently effective to completely replace TBI for the most common pediatric indications.

Growth inhibition by STI571 in combination with radiation in human chronic myelogenous leukemia K562 cells.

Altered radiation responses by STI571 (Imatinib, Glivec), a specific inhibitor of the tyrosine kinase activity of Bcr-Abl, was assessed in K562 chronic myelogenous leukemia cells using growth inhibition and colony formation assays. Flow cytometry, Western blotting, and microscope observation were used to determine cell cycle redistribution, erythroid differentiation, apoptosis, necrosis, senescence, and expression and phosphorylation of effectors downstream from Bcr-Abl as endpoints. STI571 (> or =24-h contact) retarded the growth of K562 cells and elicited reduction in the G(2)-phase content due to an efficient arrest in early S phase rather than to the disruption of the G(2) checkpoint as confirmed by analysis of Lyn and CDK1 phosphorylation. STI571 brought about the inhibitory dephosphorylation of Bcr-Abl and STAT5, but the expression of DNA-PKcs and Rad51 was unaffected and the interaction between radiation and STI571 was strictly additive with regard to induction of apoptosis. Overall STI571 interacted cooperatively with radiation to retard the growth of K562 cells but did not affect intrinsic radiosensitivity. However, STI571 and radiation acted antagonistically with each other with regard to induction of senescence and erythroid differentiation.

Palliative spleen irradiation: can we standardize its technique?

PURPOSE: To explore the pattern of practice of palliative splenic irradiation (PSI) at the National Cancer Institute (NCI), Cairo University. PATIENTS AND METHODS: The medical records of patients referred for PSI during the time period from 1990 to 2005 were retrospectively reviewed. We compared the three most common planning techniques (two parallel opposing, single direct field, anterior and lateral fields). RESULTS: Eighteen patients who received PSI were identified. Thirteen patients were diagnosed as CML and 5 as CLL. The mean age of the patients was 44 (+/-16) years and the majority were men (60%). Spleen enlargement was documented in all cases. The single direct anterior field was the most commonly used technique. The dose per fraction ranged from 25 cGy to 100 cGy. The total dose ranged from 125 cGy to 1200 cGy and the median was 200 cGy (mean 327 cGy). There was no significant difference between CML and CLL patients regarding the dose level. Three out of 5 CLL patients and only one out of 13 CML patients received re-irradiation. All patients showed subjective improvement regarding pain and swelling. There was a significant increase in the hemoglobin level and a significant decrease in the WBC count. The single direct field shows variations in the dose from 56 to 102%; however, it is the simplest and the best regarding the dose to the surrounding normal tissues especially the kidney and the liver. CONCLUSION: PSI has a significant palliative benefit. Although the most widely accepted technique is the 2 parallel opposing anterior-posterior fields, single anterior field is also considered as a suitable option. Higher doses are needed for CLL patients compared to CML patients.

Autologous stem cell transplantation in chronic myeloid leukemia.

Autografting was first attempted for patients with chronic myeloid leukemia (CML) in transformation in order to restore a second chronic phase (CP). The principal rationale for autografting in CP resides on the reduction of the tumor burden and the number of leukemic cells at risk of developing blastic transformation, and the possibility of eradicating already mutated cells. In a European Group for Blood and Marrow Transplantation (EBMT) Registry survey, patients with CML in CP, undergoing autologous stem cell transplantation (auto-SCT) for the first time, had an overall survival of 65% at 5 years from transplant with more than 50% of all patients remaining in CP. The main point made by this retrospective study was that in patients refractory to interferon-alpha (IFN), 70% achieved a cytogenetic response post autografting, which was complete or major in 31%. Since the advent of imatinib, autografting in CML has experienced a substantial decline. Theoretically, there are several possible ways of using auto-SCT in combination with imatinib: (1) to reverse resistance to imatinib; (2) to eliminate a Ph-positive clone bearing a BCR-ABL kinase domain mutation; and (3) to reduce the level of residual disease after a cytogenetic response to imatinib in patients in whom Ph-negative cells had been harvested. The exact role of auto-SCT in the present management of CML remains unanswered.

Renal dysfunction after total-body irradiation. Significance of selective renal shielding blocks.

PURPOSE: A retrospective analysis was conducted on the outcome of total-body irradiation (TBI) followed by bone marrow transplantation (BMT) on leukemia patients. Also studied was the risk of renal dysfunction after TBI/BMT with or without the use of selective renal shielding blocks. PATIENTS AND METHODS: The cases of 109 leukemia patients who received TBI as a component of the conditioning regimen for their BMT were reviewed. They received 12 Gy of TBI in six fractions over 3 consecutive days. Doses to eyes and lungs were reduced to 7 Gy and 8 Gy, respectively, by customized organ shielding blocks. After March 1999, renal shielding blocks were used to constrain the renal dose to 10 Gy. The patients were followed for a median period of 16.6 months (range: 0.3-180.1 months). RESULTS: The 2-year and 5-year overall survival rates were 55.4% and 43.2%, respectively. Renal dysfunction-free rates were different between those with and without renal shielding blocks: 100% and 78.5%, respectively, at 2 years. Overall survivals were not significantly different among these patients: 60.4% and 52.9%, respectively, at 2 years in patients with and without renal shielding blocks (p = 0.53). CONCLUSION: The use of selective renal shielding blocks provided evidence for reducing radiation-induced renal toxicities without decreasing the overall survival rate.

Differences in lethality between cancer cells and human lymphocytes caused by LF-electromagnetic fields.

The lethal response of cultured cancer cells lines K-562, U-937, DG-75, and HL-60 were measured directly after a 4 h exposure to a pulsating electromagnetic field (PEMF, sinusoidal wave form, 35 mT peak, 50 Hz) [Traitcheva et al. (2003): Bioelectromagnetics 24:148-158] and 24 h later, to determine the post-exposure effect. The results were found to depend on the medium, pH value, conductivity, and temperature. From these experiments, suitable conditions were chosen to compare the vitality between K-562 cells and normal human lymphocytes after PEMF treatment and photodynamic action. Both agents enhance necrosis synergistically for diseased as well as for healthy cells, but the lymphocytes are more resistant. The efficacy of PEMF on the destruction of cancer cells is further increased by heating (hyperthermia) of the suspension up to 44 degrees C or by lowering the pH-value (hyperacidity) to pH 6.4. Similar apoptosis and necrosis can be obtained using moderate magnetic fields (B < or = 15 mT 50/60 Hz), but this requires longer treatment of at least over a week. PEMF application combined with anticancer drugs and photodynamic therapy will be very effective.

The modulation of radiation-induced cell death by genistein in K562 cells: activation of thymidine kinase 1.

Ionizing radiation is one of the most effective tools in cancer therapy. In a previous study, we reported that protein tyrosine kinase (PTK) inhibitors modulate the radiation responses in the human chronic myelogenous leukemia (CML) cell line K562. The receptor tyrosine kinase inhibitor, genistein, delayed radiation-induced cell death, while non-recepter tyrosine kinase inhibitor, herbimycin A (HMA) enhances radiation-induced apoptosis. In this study, we focused on the modulation of radiation-induced cell death by genistein and performed PCR-select suppression subtractive hybridization (SSH) to understand its molecular mechanism. We identified human thymidine kinase 1 (TK1), which is cell cycle regulatory gene and confirmed expression of TK1 mRNA by Northern blot analysis. Expression of TK1 mRNA and TK1 enzymatic activity were parallel in their increase and decrease. TK1 is involved in G1-S phase transition of cell cycle progression. In cell cycle analysis, we showed that radiation induced G2 arrest in K562 cells but it was not able to sustain. However, the addition of genistein to irradiated cells sustained a prolonged G2 arrest up to 120 h. In addition, the expression of cell cycle-related proteins, cyclin A and cyclin B1, provided the evidences of G1/S progression and G2-arrest, and their relationship with TK1 in cells treated with radiation and genistein. These results suggest that the activation of TK1 may be critical to modulate the radiation-induced cell death and cell cycle progression in irradiated K562 cells.

Isolated central nervous system blast crisis in chronic myeloid leukemia.

Chronic myeloid leukemia is a myeloproliferative disorder characterized by the presence of the Philadelphia chromosome, t(9:22). Extramedullary blast crisis is a rare event. Imatinib mesylate has become the treatment of choice, especially for patients for whom allogenic stem cell transplantation is not an option. Imatinib produces complete cytogenetic responses in excess of 80%. However, the penetration of the drug and its metabolites into the CNS (Central Nervous System) is poor. Hence for patients who are on prolonged imatinib therapy and continue to have complete cytogenetic responses, the central nervous system may become a sanctuary site. We report a patient who had a complete hematologic and cytogenetic response and presented with headache and vomiting. The MRI showed meningeal enhancement and the CSF (Cerebro Spinal Fluid) examination was positive for blasts. He was started on cranial radiotherapy and triple intrathecal chemotherapy. He showed good symptomatic improvement and cleared the blasts in the CSF. At the end of radiation, he was in complete hematological remission but had 50% marrow metaphases positive for Philadelphia chromosome. As he did not have a matched sibling donor, the dose of imatinib was increased to 600 mg daily. He continues to be in complete hematologic remission at the time of this report.

Enhanced renal toxicity of total body irradiation combined with radioimmunotherapy.

PURPOSE: Total body irradiation (TBI) with and without additional radioimmunotherapy (RIT) was examined for renal toxicity after stem cell transplantation. PATIENTS AND METHODS: Serum creatinine levels of 35 patients (15 female, 20 male, median age 40.5 years, range 17-60 years) after TBI alone and of 23 patients (eight female, 15 male, median age 47, range 16-58 years) after TBI with additional RIT were determined between 10/1997 and 11/1999. TBI was performed by external-beam radiotherapy in six fractions over 3 days with renal doses of 12 Gy in the TBI-alone group and 6 Gy in the group with additional RIT. The mean kidney dose due to the (188)Re-radiolabeled antibody was estimated to be 8.3 Gy (2.3-11.6 Gy). RESULTS: Within 12 months after treatment, creatinine levels increased from 77 mmol/l (SD +/- 11) to 89 mmol/l (SD +/- 20) for TBI alone and from 78 mmol/l (SD +/- 13) to 144 mmol/l (SD +/- 52) for combined TBI and RIT. CONCLUSION: Despite a 50% reduction of the external-beam contribution to the kidney dose, the application of approximately 10 GBq (188)Re-labeled anti-CD66 monoclonal antibody with a calculated renal dose of 8.3 Gy (range 2.3-11.5 Gy) led to renal toxicity, as reported previously. In the absence of a positive dose-response relationship for the (188)Re-labeled antibody, the observation may be explained by an underestimation of the biologically effective dose and the inaccuracy of the dose determination at the glomerular level.

Bilateral optic nerve infiltration in central nervous system leukemia.

PURPOSE: To report the case of a 58-year-old man with sequential bilateral retrolaminar leukemic infiltration of the optic nerves who presented with normal-appearing optic nerves and no optic nerve enhancement. DESIGN: Interventional case report. METHODS: A 58-year-old man with chronic myelogenous leukemia (CML) developed progressive vision loss to no light perception in both eyes over four days. The patient received 14 doses of external beam irradiation and 10 cycles of intrathecal cytarabine. Despite treatment, he developed optic nerve pallor, and visual acuity remained no light perception in both eyes. CONCLUSIONS: In a patient with leukemia, leukemic optic nerve infiltration may occur even with normal-appearing optic nerves and a normal magnetic resonance image. It is important to maintain a high clinical suspicion for optic nerve infiltration so that prompt local irradiation may be initiated.

Cell adhesion-mediated drug resistance (CAM-DR) protects the K562 chronic myelogenous leukemia cell line from apoptosis induced by BCR/ABL inhibition, cytotoxic drugs, and gamma-irradiation.

Integrin-mediated cellular adhesion to extracellular matrix (ECM) components is an important determinant of chemotherapeutic response of human myeloma cells. Here, we demonstrate that when K562 chronic myelogenous leukemia (CML) cells are adhered to fibronectin (FN), they become resistant to apoptosis induced by the BCR/ABL inhibitors AG957 and STI-571, as well as DNA damaging agents and gamma-irradiation. This phenomenon, termed cell adhesion-mediated drug resistance (CAM-DR), was induced by adhesion through the alpha5beta1 (VLA-5) integrin. Phosphotyrosine analysis demonstrates that anti-apoptotic signaling through integrins in K562 cells is independent of the tyrosine kinases activated by BCR/ABL, with the possible exception of an unknown 80 kDa protein. Cytoprotection of FN-adhered CML cells indicates that tumor-ECM interactions may be critical for the emergence of drug-resistant tumor populations and treatment failure in this disease. Antagonists of beta1 integrin-mediated adhesion or corresponding signal transduction elements may sensitize CML cells to chemotherapy and prevent resistance to the novel BCR/ABL kinase inhibitors being used for the treatment of this disease.

Comparison of total body irradiation vs busulfan in combination with cyclophosphamide as conditioning for unrelated stem cell transplantation in CML patients.

We compared fractionated total body irradiation (12 Gy)/cyclophosphamide (120 mg/kg) with busulfan (16 mg/kg)/cyclophosphamide (120 mg/kg) as preparative therapy in unrelated donor stem cell transplantation of CML patients. Fifty patients with CML (1.CP = 46; aP = 4) and a median age of 36 years (range 16-52) were enrolled in this sequential trial between 1994 and 1999. In both groups patients were well balanced with respect to age, disease status, stem cell source and CMV status. All patients received standard doses of cyclosporin A, methotrexate and anti-thymocyte globulin (ATG) as GVHD prophylaxis. No graft failures occurred in either group. The median day of leukocyte engraftment was earlier in the Bu/Cy than in the TBI/Cy group (day 15 vs 17; P = 0.006). The incidence of grade II-IV GVHD was 40% in the TBI/Cy and 36% in the Bu/Cy group, whereas severe grade III/IV GVHD was only observed in 12% of patients in both groups. The incidence of chronic GVHD (limited and extensive) at 1 year was higher in the Bu/Cy arm (65% vs 30%; P = 0.02). More toxicity grade I/II of the liver (88% vs 44%; P = 0.002) and more hemorrhagic cystitis (32% vs 8%; P = 0.02) were observed in the Bu/Cy regimen. Seven relapses in the TBI and no relapse in the Bu/Cy group were observed after a median follow-up of 44 and 15 months, respectively. The estimated 3 year OS and DFS was 72% (95% CI: 55-98%) and 58% (95% CI: 39-77%) in the TBI and 70% (95% CI: 51-89%) for DFS and OS in the Bu/Cy group. We conclude that the anti-leukemic effect of the Bu/Cy regimen seems to be at least as effective as the TBI/Cy combination in unrelated stem cell transplantation of CML patients, with no graft failures, but that it correlates with a higher incidence of liver toxicity, hemorrhagic cystitis and chronic GVHD. Longer follow-up is necessary to determine the late relapse rate and late toxicity.