National Cancer Institute®
Last Modified: September 1, 2002
UI - 12181828
AU - Tsvetaeva NV; Vinogradova OIu; Levina AA; Tsibul'skaia MM; Diagileva OA;
TI - Sokolova MA; Kuznetsov SV; Turkina AG; Khoroshko ND [Clinical significance of erythrocyte ferritin in refractory anemia and chronic myeloid leukemia]
SO - Ter Arkh 2002;74(7):18-22
AIM: To find out if the RBC ferritin elevation can serve as an additional criterion of inefficient erythropoiesis during progression of chronic myeloid leukemia (CML) and in various types of refractory anemia. MATERIAL AND METHODS: The study group consisted of 56 MDS patients and 73 patients at various stages of CML. 20 healthy donors and 105 patients with verified inefficient erythropoiesis (20--with B12 deficiency before and after the treatment, 85--with beta-thalassemia) were the controls. A ferritin level was measured by radioimmunoassay in RBC hemolysates. RESULTS: The RBC ferritin level in all types of refractory anemia was elevated throughout the disease course, increasing with the development of transfusion dependency. The CML progression was also accompanied by RBC ferritin level elevation associated with abnormal erythroid cell accumulation and elevation of intracellular PAS-positive substance (p < 0.05). CONCLUSION: RBC ferritin level elevation can be considered as an additional biochemical criterion of inefficient erythropoiesis that may be useful in differentiation of anemias, adequate therapy selection and follow-up of erythropoiesis.
UI - 12181833
AU - Vinogradova OA; Savchenko VG; Domracheva EV; Liubimova LS; Ol'shanskaia
TI - IuV; Diachenko LV; Parovichnikova EN; Mendeleeva LP; Zakharova AV [Molecular cytogenetic monitoring of chimerism and minimal residual disease in patient with chronic myeloid leukemia after allogenic and syngenic bone marrow transplantation]
SO - Ter Arkh 2002;74(7):38-44
AIM: To study trends in restoration of normal and tumor hemopoiesis after transplantation of allogenic and syngenic hemopoietic cells. MATERIAL AND METHODS: The examination of bone marrow before transplantation and 1, 2, 3, 6, 9 months, 1, 2 and 3 years after bone marrow transplantation (BMT) was made in 25 patients with chronic myeloid leukemia (CML) after allogenic transplantation of the bone marrow (TBM) and 4 patients after syngenic TBM. The method of G-differential staining of chromosomes and fluorescent hybridization in situ (FISH) with DNA probe to centromeric sites X/Y of chromosomes and genes BCR/ABL was used. RESULTS: 56% of CML patients after allogenic BMT were in cytogenetic and clinicohematological remission, 16% developed early cytogenetic recurrence. Single metaphase with t(9;22) were identified in 28%; 14.3% developed late cytogenetic and hematological recurrence. In patients in posttransplantation remission there were from 0.1 to 5.8% cells of the host. The number of cells of the host and the number of BCR/ABL-positive cells correlated significantly. CONCLUSION: The results of 8-year monitoring of chimerism and minimal residual disease validate application of molecular-cytogenetic methods for assessing transplant condition.
UI - 12181416
AU - Barbany G; Hoglund M; Simonsson B; Swedish CML Group
TI - Complete molecular remission in chronic myelogenous leukemia after imatinib therapy.
SO - N Engl J Med 2002 Aug 15;347(7):539-40
UI - 11876544
AU - Murmu N; Mitra S; Das M; Gomes A; Vedasiromoni JR; Ghosh M; Bhattacharya
TI - M; Ghosh P; Biswas J; Bhattacharya S; Sur P Boron compounds against human leukemic cells.
SO - J Exp Clin Cancer Res 2001 Dec;20(4):511-5
AD - Chittaranjan National Cancer Institute, Calcutta, India.
Two new boron compoumds, dihydroxy(oxybiguanido) boron (iii) hydrochloride monohydrate (HB) and guanidine biboric acid adduct (GB) were used in this study to observe the antitumor effect. Leukemic blast cells isolated from chronic myeloid leukemia (CML) patients showed significant cell growth inhibition within twentyfour hours. IC50 of GB and HB was 2mg/ml. The metabolically active cells were found to be inhibited by drug treatment as assessed by MTT test. Inhibition of 3H Thymidine incorporation also supported the above result. In this study we investigated the molecular mechanisms by which HB and GB induce apoptosis in immature blast cells.
UI - 12130516
AU - Roche-Lestienne C; Soenen-Cornu V; Grardel-Duflos N; Lai JL; Philippe N;
TI - Facon T; Fenaux P; Preudhomme C Several types of mutations of the Abl gene can be found in chronic myeloid leukemia patients resistant to STI571, and they can pre-exist to the onset of treatment.
SO - Blood 2002 Aug 1;100(3):1014-8
AD - Unite Inserm U524, Lille, France.
Targeting the tyrosine kinase activity of BCR-ABL represents a very promising therapeutic strategy in chronic myeloid leukemia (CML). Despite strong efficacy of the tyrosine kinase inhibitor STI571, resistance has been observed in a significant proportion of patients in advanced CML stage or in Ph-positive acute lymphoid leukemia (ALL). We investigated in this study the mechanism of resistance to STI571 through point mutations in the tyrosine kinase domain and/or BCR-ABL gene amplification in 24 patients (16 in chronic phase and 8 in accelerated phase of the disease) who obtained no cytogenetic response to STI571 treatment. Screening for the already-described Thr315Ile point mutation in the ABL domain using a reverse transcription polymerase chain reaction restriction fragment length polymorphism (RT-PCR-RFLP) technique, 3 patients showed a proportion of mutated transcript at the time of resistance. The same technique failed to detect mutation at diagnosis, but a specific allele-specific oligonucleotide (ASO)-PCR on DNA for the Thr315Ile mutation and, after sequencing, for 2 newly described Phe311Leu and Met351Thr substitutions, showed the presence of rare mutated cells prior to STI571 therapy. Furthermore, the increased proportion of mutated cells during treatment detected by ASO-PCR strongly suggested clonal selection by the functional inhibiting effect of these mutations. Finally, no BCR-ABL gene amplification was detected by fluorescent in situ hybridization (FISH) in the 24 STI571-resistant patients. Our data support that in CML patients treated with STI571, ABL mutations are not restricted to the accelerated phase of the disease and that, at least in some cases, mutations seem to occur prior to STI571 therapy, probably as second mutational events during the course of CML.
UI - 12130525
AU - Petti MC; Fazi F; Gentile M; Diverio D; De Fabritiis P; De Propris MS;
TI - Fiorini R; Spiriti MA; Padula F; Pelicci PG; Nervi C; Lo Coco F Complete remission through blast cell differentiation in PLZF/RARalpha-positive acute promyelocytic leukemia: in vitro and in vivo studies.
SO - Blood 2002 Aug 1;100(3):1065-7
AD - Hematology section, Regina Elena Cancer Institute, Department of Cellular Biotechnology, University La Sapienza, Rome, Italy.
Acute leukemia with the t(11;17) expressing the PLZF-RARalpha gene fusion is a rare variant of acute promyelocytic leukemia (APL) that has been associated with poor clinical response to all-trans retinoic acid (ATRA) treatment. However, some recent reports have put into question the absolute refractoriness of this leukemia to ATRA. We describe here a patient with PLZF/RARalpha APL who was treated at relapse with ATRA and low-dose hydroxyurea. Complete hematologic remission was obtained through differentiation of leukemic blasts, as proven by morphologic, immunophenophenotypic, and genetic studies carried out in sequential bone marrow samples. Moreover, in vitro studies indicated that blast differentiation was potentiated by the addition of the histone deacetylase inhibitor tricostatin A, but not of hydroxyurea, to ATRA. Our findings indicate that the maturation block may be overcome and terminal differentiation obtained in this leukemia subset and support the view that sensitivity/refractoriness of this form to ATRA should be revisited.
UI - 12130532
AU - Magnusson MK; Meade KE; Nakamura R; Barrett J; Dunbar CE
TI - Activity of STI571 in chronic myelomonocytic leukemia with a platelet-derived growth factor beta receptor fusion oncogene.
SO - Blood 2002 Aug 1;100(3):1088-91
AD - Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA. firstname.lastname@example.org
Platelet-derived growth factor beta receptor (PDGFbetaR) fusion genes have been shown to be critical transforming oncogenes in a subset of patients with chronic myelomonocytic leukemia (CMML). The sensitivity of dysregulated tyrosine kinase oncogenes to the tyrosine kinase inhibitor STI571 (imatinib mesylate) makes it a potentially attractive treatment option in this subset of patients. We have recently cloned a novel member of the PDGFbetaR fusion oncogene family, rabaptin-5-PDGFbetaR. A patient with CMML carrying the rabaptin-5-PDGFbetaR fusion gene underwent allogeneic stem cell transplantation (SCT) and was monitored closely with a sensitive reverse transcriptase-polymerase chain assay to detect the novel fusion gene transcript. After achieving a molecular remission at 5 months after transplantation, 15 months after SCT the patient showed persistent and progressive evidence of molecular relapse. After demonstrating in vitro that cells transformed with this specific fusion oncogene are efficiently killed by STI571, the patient was started on STI571. The patient responded rapidly and entered molecular remission after 6 weeks of therapy, and he continues to be in remission 6 months later. These results suggest that STI571 may be an effective targeted therapy in patients with CMML related to PDGFbetaR fusion oncogenes.
UI - 12130477
AU - Al-Ali HK; Leiblein S; Kovacs I; Hennig E; Niederwieser D; Deininger MW
TI - CML with an e1a3 BCR-ABL fusion: rare, benign, and a potential diagnostic pitfall.
SO - Blood 2002 Aug 1;100(3):1092-3
UI - 12145464
AU - Varadi G; Svirsky O; Nagler A
TI - Successful major surgical recovery of a patient following haploidentical stem cell transplantation for chronic myeloid leukemia in blast crisis and aspergillosis.
SO - Acta Haematol 2002;108(1):29-32
AD - Department of Bone Marrow Transplantation, Hadassah University Hospital, Jerusalem, Israel.
A 44-year-old woman who underwent haploidentical stem cell transplantation (haplo SCT) for chronic myeloid leukemia in blast crisis and aspergillosis was admitted to the emergency room 7 months later because of severe right upper quadrant abdominal pain, fever, leukocytosis and peritoneal signs. Computer tomography disclosed cholecystitis and gallbladder perforation. Within hours, she underwent urgent open laparatomy and cholecystectomy. The postoperative period was uneventful and she was discharged 10 days later without any complications. Currently, she is 2(1/2) years posttransplantation in full hematological, cytogenetic and molecular remission with 100% Karnofsky performance status. Most notably, normal and fast recovery was observed following major surgery 7 months post-haplo SCT which is usually considered to result in long-lasting immunosuppression and malfunction of the immune system.
UI - 12149298
AU - Seiter K; Liu D; Loughran T; Siddiqui A; Baskind P; Ahmed T
TI - Phase I study of temozolomide in relapsed/refractory acute leukemia.
SO - J Clin Oncol 2002 Aug 1;20(15):3249-53
AD - Department of Medicine, Zalmen A. Arlin Cancer Institute, Munger Pavilion Room 250, New York Medical College, Valhalla, NY 10595, USA. email@example.com
PURPOSE: To determine the dose-limiting toxicity and maximum-tolerated dose of temozolomide in patients with acute leukemia. PATIENTS AND METHODS: Twenty patients (16 with acute myelogenous leukemia, two with acute lymphoblastic leukemia, and two with chronic myelogenous leukemia in blastic phase) received 43 cycles of temozolomide. Patients began treatment at two different dose levels: 200 mg/m(2)/d for 7 days or 200 mg/m(2)/d for 9 days. RESULTS: Prolonged aplasia was the dose-limiting toxicity, and the maximum-tolerated dose was 7 days of temozolomide. Overall treatment was well tolerated: hospitalization was required in only nine of 43 courses, and there were no treatment-related deaths. Two patients obtained a complete response, and two others met criteria for complete response except for platelet recovery. Overall, nine of 20 patients had a significant decrease in bone marrow blasts after temozolomide treatment. CONCLUSION: Temozolomide was well tolerated and had significant antileukemic activity when administered as a single agent. Further studies of temozolomide in hematologic malignancies are indicated.
UI - 3132802
AU - Visani G; Patrizi AL; Ricci P; Colombini R; Balducci A; Tosi P; Zaccaria
TI - A; Rosti G; Varotti C Sweet's syndrome: association with accelerated phase of chronic myeloid leukemia.
SO - Acta Haematol 1988;79(4):207-10
AD - Institute of Hematology L.eA. Seragnoli, University of Bologna, St. Orsola Hospital, Italy.
The authors describe a case of Sweet's syndrome in a woman affected with chronic myeloid leukemia. They emphasize the association of the syndrome with a progression of the disease and the complete disappearance of it for 3 years until the present time after allogeneic bone marrow transplantation.
UI - 9477122
AU - Johnson RJ; Smith GM
TI - Mobilisation and reinfusion of Philadelphia negative peripheral blood mononuclear cells in chronic myeloid leukaemia with hydroxyurea and G-CSF.
SO - Leuk Lymphoma 1997 Nov;27(5-6):401-15
AD - Department of Haematology, The General Infirmary at Leeds, Yorkshire, UK.
Unmanipulated autologous transplantation of marrow of peripheral blood stem cells has been performed in small numbers of patients with CML for many years. More recently there has been interest in attempting to 'purge' the autograft of clonal cells as defined by the presence of the Philadelphia chromosome or BCR-ABL rearrangement. One method by which this might be achieved in vivo has been developed in Genoa and involves the administration of high dose chemotherapy and G-CSF followed by peripheral blood stem cell collection. These collections are frequently devoid of Philadelphia positive cells and the hope is that this will enhance the effects of subsequent autograft. We have investigated the use of a less toxic regimen for this procedure using oral hydroxyurea and G-CSF. In this review we describe the background to autografting in CML and the development of strategies to mobilise Philadelphia negative cells into the peripheral blood. We go on to present an update of our data using hydroxyurea and discuss some of the practical and theoretical issues behind the procedure.
UI - 11100752
AU - Fernandez-Jimenez MC; Herraez R; Ojeda E; Hernandez-Navarro F
TI - Sweet's syndrome and accelerated phase of chronic myelogenous leukemia.
SO - Ann Hematol 2000 Oct;79(10):585-7
AD - firstname.lastname@example.org
Sweet's syndrome is a neutrophilic dermatosis characterized clinically by raised, erythematous, tender lesions on the face, neck, upper thorax and extremities. Several diseases have been associated with this entity. We report a case of Sweet's syndrome associated with chronic myelogenous leukemia: a 48-year-old woman who developed recurrent skin lesions 3 years after the diagnosis of chronic myelogenous leukemia. Progression to an accelerated phase of the disease was detected 3 months after the beginning of the skin lesions. This case shows the convenience of evaluation and closer follow-up of patients with chronic myelogenous leukemia who develop skin lesions, especially if these lesions are recurrent.
UI - 11274286
AU - Badid C; McGregor B; Faivre JM; Guerard A; Juillard L; Fouque D; Laville
TI - M Renal thrombotic microangiopathy induced by interferon-alpha.
SO - Nephrol Dial Transplant 2001 Apr;16(4):846-8
AD - Service de Nephrology, Hopital Edouard Herriot, Lyon, France.
UI - 11853786
AU - Griffin JD
TI - Resistance to targeted therapy in leukaemia.
SO - Lancet 2002 Feb 9;359(9305):458-9
AD - Leukemia Program, Dana-Farber Cancer Institute, Boston, MA 02115, USA. email@example.com
UI - 11961207
AU - O'Dwyer M
TI - Multifaceted approach to the treatment of bcr-abl-positive leukemias.
SO - Oncologist 2002;7 Suppl 1():30-8
AD - Leukemia Center, Oregon Health and Science University, Portland, Oregon 97201-3098, USA. Odwyerm@ohsu.edu
Bcr-Abl-positive leukemias include chronic myelogenous leukemia (CML), both myeloid and lymphoid blast-phase CML, and some cases of acute lymphoblastic leukemia. The chimeric bcr-abl gene codes for a tyrosine kinase that is constitutively activated in the leukemic cells and plays the central role in leukemogenesis. Hematologic malignancies, including Bcr-Abl-positive leukemias, also frequently have overactivity of the Ras signaling pathway, leading to abnormal transduction of growth and survival signals. New and investigational therapeutic options that target these specific molecular defects of leukemic cells include the tyrosine kinase inhibitor imatinib mesylate (STI571) and farnesyltransferase inhibitors (R115777, SCH66336), which block localization of Ras proteins to the cell membrane. While single-agent therapy with these new agents may produce hematologic and cytogenetic remissions in patients with Bcr-Abl-positive leukemias, molecular remissions are less common, and resistance may develop. Therefore, the development of a multifaceted therapeutic approach to these leukemias is of great interest. Arsenic trioxide (ATO), which has significant activity in patients with relapsed and refractory acute promyelocytic leukemia, is a potential addition to the therapeutic arsenal. While some of the molecular activities of ATO are specific to acute promyelocytic leukemia, arsenicals also have a broad variety of antineoplastic properties that may be useful in combination therapy with agents that target specific molecular defects of Bcr-Abl-positive leukemias.
UI - 12060123
AU - Branford S; Hughes TP; Rudzki Z
TI - Dual transcription of b2a2 and b3a2 BCR-ABL transcripts in chronic myeloid leukaemia is confined to patients with a linked polymorphism within the BCR gene.
SO - Br J Haematol 2002 Jun;117(4):875-7
AD - Division of Molecular Pathology, Institute of Medical and Veterinary Science, Box 14, Rundle Mall, Adelaide, SA 5000, Australia. firstname.lastname@example.org
We propose a mechanism for dual expression of b2a2 and b3a2 BCR-ABL in chronic myeloid leukaemia (CML). We have identified a BCR allele, present in approximately 29% of the population, which includes an adenine to guanine polymorphism in the putative branchpoint of BCR intron 13. CML patients who expressed both b2a2 and b3a2 transcripts had the allele, which was also associated with alternative transcription of the normal BCR allele. We conclude that the BCR intronic polymorphism is associated with activation of a cryptic branchpoint resulting in reduced efficiency of RNA splicing and exon 14 (b3) skipping in BCR and BCR-ABL.
UI - 12100132
AU - Barker JN; Davies SM; DeFor TE; Burns LJ; McGlave PB; Miller JS;
TI - Weisdorf DJ Determinants of survival after human leucocyte antigen-matched unrelated donor bone marrow transplantation in adults.
SO - Br J Haematol 2002 Jul;118(1):101-7
AD - The University of Minnesota Blood and Marrow Transplant Program, Minneapolis, MN 55455, USA. email@example.com
Unrelated donor (URD) bone marrow transplantation (BMT) in adults can be associated with high non-relapse mortality (NRM). Therefore, factors determining survival in 136 human leucocyte antigen (HLA)-A, B, DRB1-matched adult BMT recipients were reviewed. Fifty-four per cent of patients had chronic myelogenous leukaemia (CML) and 36% had acute leukaemia or myelodysplasia. Graft-versus-host disease (GvHD) prophylaxis was either cyclosporin A (CSA)/methotrexate (64%) or T-cell depletion and CSA/corticosteroids (34%). The probability of donor engraftment by d 45 was 97% (95% CI: 94-100). Incidence of grades III-IV acute GvHD was 18% (95% CI: 12-24) at 100 d, and chronic GvHD was 42% (95% CI: 32-52) at 2 years. At 2 years, 14% (95% CI: 8-20) had relapsed. Multiple regression analysis showed that adverse risk factors for survival were non-CML diagnosis, age > 35 years, diagnosis to transplant time of > 18 months [chronic-phase CML (CML-CP) only]; and grades III-IV acute GvHD. Patients
UI - 12100140
AU - Lewalle P; Meuleman N; Verhest A; Bron D; Martiat P
TI - Infusion of peripheral blood stem cells collected at diagnosis, with maintenance of the treatment, resulted in Ph-negative recovery in a chronic myeloid leukaemia patient in persisting aplasia on STI-571 therapy.
SO - Br J Haematol 2002 Jul;118(1):144-6
AD - Department of Haematology, Institut Bordet, University of Brussels, Belgium.
In advanced chronic myeloid leukaemia patients, STI-571 produces complete haematological response in most cases and cytogenetic response in up to 50%. However, these patients often suffer periods of pancytopenia, which can lead to life-threatening complications, and is probably due to the small number of residual normal stem cells. We have re-infused peripheral blood stem cells collected at diagnosis, in a patient, while maintaining STI-571 treatment. The patient recovered from aplasia, with Philadelphia-negative haematopoiesis. Discontinuing an effective treatment because of persistent aplasia is a major concern; this method circumvents this problem inpatients who have undergone a stem cell harvest at diagnosis.
UI - 12100156
AU - Ohsaka A; Hoshino S; Kobayashi M; Kudo H; Kawaguchi R
TI - Blast crisis of Philadelphia chromosome-positive chronic myeloid leukaemia carrying micro-bcr breakpoint (e19a2 and e191a).
SO - Br J Haematol 2002 Jul;118(1):251-4
AD - Department of Transfusion Medicine, Juntendo University School of Medicine, Tokyo, Japan. firstname.lastname@example.org
We describe two Philadelphia chromosome-positive chronic myeloid leukaemia (Ph-positive CML) patients carrying micro-bcr (micro-bcr) breakpoint, who developed blast crisis within 5 years of diagnosis. Reverse transcription polymerase chain reaction analysis of bone marrow cells using primers specific for the p210BCR-ABL fusion transcript showed aberrant large-sized bands in both cases (986 bp in patient 1 and 1031 bp in patient 2). Sequencing analysis of these products revealed BCR-ABL fusion transcripts with e19a2 in patient 1 and e191a in patient 2. These findings suggest that CML carrying micro-bcr breakpoint may exhibit a similar clinical course to classical CML, and that it may not be a mild form of the disease.
UI - 12100129
AU - Kroger N; Zabelina T; Guardiola P; Runde V; Sierra J; Van Biezen A;
TI - Niederwieser D; Zander AR; De Witte T Allogeneic stem cell transplantation of adult chronic myelomonocytic leukaemia. A report on behalf of the Chronic Leukaemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT).
SO - Br J Haematol 2002 Jul;118(1):67-73
AD - University-Hospital Hamburg, Germany. email@example.com
We report the results of 50 allogeneic transplantations from related (n = 43) or unrelated (n = 7) donors, performed for chronic myelomonocytic leukaemia (CMML) in 43 European centres. The median age at transplant was 44 years (range 19-61). Eighteen patients had excess blasts ranging from 5% to 30% at the time of transplantation. Two graft failures were observed (4%). Neutrophil (> 0.5 x 109/l) and platelet engraftment (> 50 x 109/l) was reached after a median of 17 d (range 11-38) and 27 d (range 11-48) respectively. Acute graft-versus-host disease (GvHD grade II-IV was seen in 35% of patients, while 20% developed severe-acute GvHD grade III/IV. Twenty-six patients (52%) died of treatment-related causes. After a median follow-up of 40 months (range 11-110), the 5-year-estimated overall survival was 21% (95% CI: 15-27%) and the 5-year-estimated disease-free survival (DFS) was 18% (95% CI: 13-23%). Earlier transplantation in the course of disease, male donor, use of unmanipulated grafts, allogeneic transplantation and occurrence of acute GvHD favoured better DFS, but did not reach statistical significance. The 5-year estimated probability of relapse was 49%. The data showed a trend for a lower relapse probability of acute GvHD grade II-IV (24% vs 54%; P = 0.07), and for a higher relapse rate in patients with T cell-depleted grafts (62% vs 45%), suggesting a 'graft-versus-CMML effect'.
UI - 12111626
AU - Karti SS; Ovali E; Ratip S; Cetiner M; Direskeneli H; Bayik M; Akoglu T
TI - Effect of interferon-alpha(2a) on neutrophil adhesion and phagocytosis in chronic myeloid leukemia and Behcet's disease.
SO - Clin Rheumatol 2002 Jun;21(3):211-4
AD - School of Medicine, Karadeniz Technical University, Trabzon 61080, Turkey. firstname.lastname@example.org
Alpha-interferon (alpha-IFN) is implicated in a Behcet's disease (BD)-like syndrome observed in a small number of chronic myeloid leukemia (CML) patients. The effect of alpha-IFN on neutrophil adhesion and phagocytosis in CML patients, BD patients and healthy volunteers was investigated to clarify the reason for this observation. Ten subjects were studied for each group by incubating neutrophils with various doses of alpha-IFN. Basal neutrophil adhesions for CML patients, BD patients and healthy volunteers were similar. However, BD patients had greater basal phagocytosis than CML patients, and both groups had greater basal phagocytosis than healthy volunteers. Neutrophil adhesion and phagocytosis of CML patients increased following incubation with higher doses of alpha-IFN, and phagocytosis approached the high levels observed with BD neutrophils. This study provides evidence that alpha-IFN activates neutrophils in CML patients in a dose-dependent manner, and leads to a neutrophil function profile that resembles BD.
UI - 12149203
AU - Jurcic JG; Larson SM; Sgouros G; McDevitt MR; Finn RD; Divgi CR;
TI - Ballangrud AM; Hamacher KA; Ma D; Humm JL; Brechbiel MW; Molinet R; Scheinberg DA Targeted alpha particle immunotherapy for myeloid leukemia.
SO - Blood 2002 Aug 15;100(4):1233-9
AD - Department of Medicine, Memorial Sloan-Kettering Cancer Center and Weill Medical College of Cornell University, New York, NY 10021, USA. email@example.com
Unlike beta particle-emitting isotopes, alpha emitters can selectively kill individual cancer cells with a single atomic decay. HuM195, a humanized anti-CD33 monoclonal antibody, specifically targets myeloid leukemia cells and has activity against minimal disease. When labeled with the beta-emitters (131)I and (90)Y, HuM195 can eliminate large leukemic burdens in patients, but it produces prolonged myelosuppression requiring hematopoietic stem cell transplantation at high doses. To enhance the potency of native HuM195 yet avoid the nonspecific cytotoxicity of beta-emitting constructs, the alpha-emitting isotope (213)Bi was conjugated to HuM195. Eighteen patients with relapsed and refractory acute myelogenous leukemia or chronic myelomonocytic leukemia were treated with 10.36 to 37.0 MBq/kg (213)Bi-HuM195. No significant extramedullary toxicity was seen. All 17 evaluable patients developed myelosuppression, with a median time to recovery of 22 days. Nearly all the (213)Bi-HuM195 rapidly localized to and was retained in areas of leukemic involvement, including the bone marrow, liver, and spleen. Absorbed dose ratios between these sites and the whole body were 1000-fold greater than those seen with beta-emitting constructs in this antigen system and patient population. Fourteen (93%) of 15 evaluable patients had reductions in circulating blasts, and 14 (78%) of 18 patients had reductions in the percentage of bone marrow blasts. This study demonstrates the safety, feasibility, and antileukemic effects of (213)Bi-HuM195, and it is the first proof-of-concept for systemic targeted alpha particle immunotherapy in humans.
UI - 12171771
AU - Spiers AS
TI - Management of the chronic leukemias: special considerations in the elderly patient. Part III rarer chronic myeloid leukemias.
SO - Hematol 2002 Feb;7(1):1-8
AD - Department of Haematology, John Radcliffe Hospital, Oxford, UK.
The manifestations, diagnosis and management of the rarer chronic myeloid leukemias are reviewed, with special attention to problems that affect elderly patients. The spectrum of disorders includes atypical myeloproliferative syndrome, so-called Ph-negative CGL, chronic myelomonocytic leukemia, and leukemias characterized by chronic proliferation of neutrophil, eosinophil, or basophil leukocytes. These latter are sometimes difficult to differentiate from chronic nonleukemic proliferations of the index cells. Termination in an acute myeloid leukaemia that is usually refractory to treatment may occur in any of the above disorders but is not a constant event.
UI - 12138901
AU - Kawakami K; Miyanishi S; Nishii K; Usui E; Murata T; Shinsato I; Shiku H
TI - A case of acute myeloid leukemia with t(7;11)(p15;p15) mimicking myeloid crisis of chronic myelogenous leukemia.
SO - Int J Hematol 2002 Jul;76(1):80-3
AD - Division of Hematology, Suzuka General Hospital, Mie, Japan. Kawakei@cocoa.ocn.ne.jp
The chromosome aberration t(7;11)(p15;p15) is uncommon but recurrent in leukemia. We experienced a case of acute leukemia with t(7;11)(p15;p15), the hematological appearance of which mimicked myeloid crisis in chronic myeloid leukemia (CML). This case showed splenomegaly, a decreased neutrophil alkaline phosphatase (NAP) score, increased vitamin B12 value, and cells at all stages of neutrophilic maturation in both bone marrow and peripheral blood. We initially had difficulty differentiating acute myeloid leukemia (AML) M2 with marked myeloid differentiation from myeloid crisis of Philadelphia chromosome (Ph)-negative CML. Immature myeloid cells in the peripheral blood disappeared and cytogenetic analysis indicated that marrow cells changed to the normal karyotype after remission induction therapy. Therefore, this case was thought not to be myeloid crisis but AML M2 subtype. The NUP98/HOXA9 fusion transcript was detected by reverse transcription-polymerase chain reaction (RT-PCR) at exon A but not exon B of NUP98.
UI - 12127557
AU - Gonzalez-Medina I; Bueno J; Torrequebrada A; Lopez A; Vallespi T;
TI - Massague I Two groups of chronic myelomonocytic leukaemia: myelodysplastic and myeloproliferative. Prognostic implications in a series of a single center.
SO - Leuk Res 2002 Sep;26(9):821-4
AD - Servicio de Hematologia Clinica, Hospital General Vall d'Hebron, Po Vall d'Hebron 119-129, Barcelona, Spain. firstname.lastname@example.org
The clinical records of 70 patients seen at our hospital between 1976 and 1998 and diagnosed as suffering from chronic myelomonocytic leukaemia (CMML) were reviewed in order to confirm the validity of the classification into two forms of disease that the French-American-British Co-operative Leukaemia Group (FAB) proposed in 1994: myelodysplastic (MD) and myeloproliferative (MP), depending on the peripheral white blood cell count (WBC) (less or more than 13 x 10(9)/l, respectively). After the rejection of incomplete records and lost to follow up patients, our study population consisted of 49 records. Our results confirm that, even though this classification is useful in order to separate two classes of patients, it is not enough to predict the prognosis in an accurate manner. A lot of studies have tried to find some prognostic factors, but the results have been discordant. The multivariate analysis of our group of patients showed three prognostic factors: serum lactate dehydrogenase (LDH) >1.5 times normal level, blasts in bone marrow >5%, and peripheral blood leukocytes >10 x 10(9)/l. A second multivariate analysis led us to distinguish two groups: high risk (2-3 risk factors) and low risk (0-1 risk factors) (median survival 7 and 44 months, respectively) with a very high statistic significance (P<0.0001). This score should be applied to other series of CMML patients in order to confirm its validity.
UI - 12191573
AU - Tsuboi K; Komatsu H; Miwa H; Iida S; Banno S; Wakita A; Nitta M; Ueda R
TI - Lymphoid blastic crisis of chronic myelogenous leukaemia with inv(16)(p13;q22).
SO - Leuk Res 2002 Aug;26(8):771-4
AD - Second Department of Internal Medicine, Nagoya City University Medical School, Mizuho-ku, Nagoya 467-8601, Japan. email@example.com
We report a case of chronic myelogeneous leukaemia (CML) in B-lineage lymphoid blastic crisis (BC) having chromosome abnormality, inv(16)(p13;q22) in addition to Philadelphia chromosome, in 20/20 marrow metaphase. Inv(16)(p13;q22) was not observed in cells of chronic phase or accelerate phase. Abnormalities of chromosome 16, including inv(16)(p13;q22), del(16)(q22) and t(16;16)(p13;q22), have been reported mostly in acute myelomonocytic leukaemia (AML), (FAB M4-Eo), and some in CML-BC and myelodysplastic syndrome (MDS) cases. Most of the cases showed increase of myelomonocytic components and abnormal eosinophils with dysplastic granules in the bone marrow (BM). However, our case was diagnosed as lymphoid BC without increase of myelomonocytic components, although some abnormal eosinophilia was seen. To date, lymphoid BC of CML having inv(16)(p13;q22) abnormality has not been reported. The case presented here could be a clue to understand the pathophysiology of inv(16)(p13;q22) leukaemia.
UI - 12144533
AU - Kim YJ; Kim DW; Lee S; Kim HJ; Kim YL; Hwang JY; Oh IH; Park YH; Lee YK;
TI - Min CK; Kim TG; Han TH; Min WS; Kim CC Comprehensive comparison of FISH, RT-PCR, and RQ-PCR for monitoring the BCR-ABL gene after hematopoietic stem cell transplantation in CML.
SO - Eur J Haematol 2002 May;68(5):272-80
AD - Catholic Hemopoietic Stem Cell Transplantation Center, Catholic University of Korea, #62 Youido-dong, Youngdeungpo-gu, Seoul, Korea (South), 150-713.
The reverse transcriptase-polymerase chain reaction (RT-PCR) was compared with fluorescence in situ hybridization (FISH) and real-time quantitative RT-PCR (RQ-PCR) for minimal residual disease (MRD) monitoring in 266 post-transplant bone marrow samples from 78 patients with chronic myelogenous leukemia (CML). The sensitivities of FISH to BCR-ABL positive samples determined by first-round (1st) RT-PCR, second-round (2nd) RT-PCR, and RQ-PCR were 64.2%, 25.8%, and 20.7%, respectively. The BCR-ABL/ABL ratio by RQ-PCR had a mean of 0.000 13 in the 1st RT-PCR-negative samples and 1.42 in the 1st RT-PCR-positive samples (P<0.001), and means of 0.000 39 and 0.51 in the 2nd RT-PCR-negative and -positive samples (P< 0.001). The mean ratios of BCR-ABL/ABL by RQ-PCR were significantly different in N/N (1st/2nd RT-PCR) or N/P and P/P (P<0.001), but not in N/N and N/P, which showed that the discriminative power of RQ-PCR is confined to the 1st RT-PCR level. In this respect, monitoring of the 1st RT-PCR might be useful for estimating normalized BCR-ABL levels after transplantation. Nested RT-PCR was of limited use, as RQ-PCR quantified the BCR-ABL transcripts in 60 (91%) of 66 samples determined to be negative by 2nd RT-PCR. FISH was significantly correlated with RQ-PCR in FISH-positive samples (n=24, r=0.79, P=0.001). An increase of FISH preceded that of RQ-PCR in a few cases with molecular relapse. By analyzing a large number of samples post-transplant, we found that RQ-PCR might be the most useful assay for MRD monitoring; however, FISH and RT-PCR were found to be useful complementary tools.
UI - 12144534
AU - Dlubek D; Dybko J; Wysoczanska B; Laba A; Klimczak A; Kryczek I; Konopka
TI - L; Lange A Enrichment of normal progenitors in counter-flow centrifugal elutriation (CCE) fractions of fresh chronic myeloid leukemia leukapheresis products.
SO - Eur J Haematol 2002 May;68(5):281-8
AD - Lower Silesian Center for Cellular Transplantation, Institute of Immunology and Experimental Therapy, Polish Academy of Science, Rudolf Weigl 12, 53-114 Wroclaw, Poland.
OBJECTIVES: The aim of this study was to assess the suitability of a technique based on counter-flow centrifugal elutriation (CCE), which should allow one to enrich chronic myeloid leukemia (CML) patients' unstimulated native leukapheresis product (nLP) in CD34+ HLADR- cells and BCR-ABL negative cells. METHODS: Six newly diagnosed CML patients were subjected to leukapheresis, and the products were subfractionated with the use of CCE. nLP and all fractions were studied for the presence of CD34+ cells and a proportion of BCR-ABL fluorescence in situ hybridization (FISH)+ cells. RESULTS: CCE fractions with a high flow rate contained the highest proportion of CD34+ cells [mean (SEM) 6.89% (3.88)]. However, CD34+ cells present in low-rate CCE fractions showed a higher proportion of HLADR-[49.6% (13.5 in 70 mL min-1) and 21.5% (11.6 in 110 mL min-1)] than those in 170 mL min-1[3.2% (2.5)] and "rotor off" [3.4% (1.9)]. This was associated with lower proportions of BCR-ABL FISH+[8.1% (4.8) and 1.9 (1.7)] and smaller BCR-ABL to ABL transcript ratios [0.58 (17) and 0.26 (0.08) in 70 and 110 mL min-1] fractions as compared to 140 and 170 mL min-1 fractions [21.6% (5.2) and 31.6% (15.3) for BCR-ABL FISH+ cells and 0.75 (0.16) and 0.90 (0.24) for BCR-ABL/ABL]. Fractions with the lowest proportions of BCR-ABL-positive cells and the lowest BCR-ABL/ABL transcript ratios (110 mL min-1) contained from 1.3 x 106 to 82.7 x 106 (median: 3.97 x 106) CD34+ cells. CONCLUSIONS: In the present study we have shown that CCE may be used effectively to obtain nLP fractions enriched in normal hematopoietic progenitors.
UI - 12176876
AU - Kantarjian HM; O'Brien S; Cortes JE; Giralt SA; Rios MB; Shan J; Giles
TI - FJ; Thomas DA; Faderl S; De Lima M; Garcia-Manero G; Champlin R; Arlinghaus R; Talpaz M Imatinib mesylate therapy for relapse after allogeneic stem cell transplantation for chronic myelogenous leukemia.
SO - Blood 2002 Sep 1;100(5):1590-5
AD - Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston 77030, USA. firstname.lastname@example.org
Twenty-eight adults with chronic myelogenous leukemia (CML) that had relapsed after allogeneic stem cell transplantation (SCT) received imatinib mesylate (400-1000 mg/d). Disease was in chronic phase in 5 patients, accelerated in 15, and blastic in 8 (7 medullary, 1 extramedullary); median time from transplantation to relapse was 9 months (range, 1-137 months). Thirteen patients had undergone salvage donor lymphocyte infusion (DLI) (median time from DLI to imatinib mesylate therapy, 4 months [range, 2-39 months]). The overall response rate was 79% (22 of 28 patients); the complete hematologic response (CHR) rate was 74% (17 of 23 patients), and the cytogenetic response rate was 58% (15 of 26 patients; complete response in 9 [35%] patients). CHR rates were 100% for chronic phase, 83% for accelerated phase, and 43% for blastic phase. The patient with extramedullary blastic disease achieved complete response. Cytogenetic response rates were 63% (12 of 19 patients) for chronic or accelerated phases (complete cytogenetic response in 8) and 43% for blastic phase (3 of 7 patients). At median follow-up of 15 months, 19 patients were alive, 9 with no evidence of disease. The 1-year estimated survival rate was 74%. Five patients had recurrence of grade 3 (3 patients) or grades 1 to 2 (2 patients) graft-versus-host disease (GVHD). Severe granulocytopenia developed in 43% of patients and thrombocytopenia in 27%; both conditions reversed with dose adjustments of imatinib mesylate. We conclude that imatinib mesylate effectively controlled CML that recurred after allogeneic SCT, but it was associated with side effects including myelosuppression and recurrence of severe GVHD.
UI - 12176881
AU - O'Dwyer ME; Mauro MJ; Kurilik G; Mori M; Balleisen S; Olson S; Magenis
TI - E; Capdeville R; Druker BJ The impact of clonal evolution on response to imatinib mesylate (STI571) in accelerated phase CML.
SO - Blood 2002 Sep 1;100(5):1628-33
AD - Leukemia Center, Oregon Health and Science University Cancer Institute, Portland, USA. email@example.com
In chronic myelogenous leukemia (CML), the development of chromosomal abnormalities in addition to the Philadelphia chromosome (clonal evolution) is considered by many to be a feature of accelerated phase (AP). Imatinib mesylate (STI571), a selective inhibitor of the Bcr-Abl tyrosine kinase, has significant activity in AP CML. As clonal evolution could allow Bcr-Abl independent proliferation, we analyzed its impact on the outcome of 71 AP patients treated with 600 mg of imatinib mesylate. Fifteen patients had clonal evolution alone (AP-CE), 32 had AP features but no evidence of clonal evolution (HEM-AP), and 24 had AP features plus clonal evolution (HEM-AP + CE). Of the AP-CE patients, 73% had a major cytogenetic response, compared with 31% of the HEM-AP patients (P =.043) and 12.5% of the HEM-AP + CE patients (P =.007). Complete cytogenetic responses were seen in 60% of AP-CE patients, compared with 31% of HEM-AP patients (P =.19) and 8% of HEM-AP + CE patients (P <.001). With mean follow-up of 11.2 months, 35% of all patients failed treatment. The lowest estimated rate of treatment failure at 1 year, 0%, was seen in AP-CE patients, compared with rates of 31% for HEM-AP patients and 69% for HEM-AP + CE patients (P =.0004). After 1 year, 100% of AP-CE patients were still alive, compared with 85% of HEM-AP patients and 67.5% of HEM-AP + CE patients (P =.01). In conclusion, in patients with clonal evolution as the sole criterion of disease acceleration, good responses to imatinib are still possible. Once patients have other signs of acceleration, clonal evolution predicts lower response rates and a shorter time to treatment failure.
UI - 12176916
AU - List AF; Kopecky KJ; Willman CL; Head DR; Slovak ML; Douer D; Dakhil SR;
TI - Appelbaum FR Cyclosporine inhibition of P-glycoprotein in chronic myeloid leukemia blast phase.
SO - Blood 2002 Sep 1;100(5):1910-2
AD - Arizona Cancer Center, Tucson, USA.
Chronic myeloid leukemia blast phase (CML-BP) cells commonly express the multidrug transporter, P-glycoprotein (Pgp). To determine whether Pgp inhibition improves treatment outcome in CML-BP, the Southwest Oncology Group performed a randomized, controlled trial testing the benefit of the Pgp modulator, cyclosporin A (CsA). Seventy-three eligible patients were assigned to treatment with cytarabine and infusional daunorubicin with or without intravenous CsA. T