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Volume 1 Published - 14:00 UTC    08:00 EST    04-December-2000      
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Chronic Myelogenous Leukemia

CTGF (IGFBP-rP2) is specifically expressed in malignant lymphoblasts of patients with acute lymphoblastic leukaemia (ALL).

Unique Identifier: 20411123

Author: Vorwerk P; Wex H; Hohmann B; Oh Y; Rosenfeld RG; Mittler U

Source: Br J Cancer 2000 Sep;83(6):756-60

Address: Department of Pediatric Hematology and Oncology, Otto von Guericke University Magdeburg, E. -Larisch-Weg 17-19, Magdeburg, D-39112, Germany.

    Connective tissue growth factor (CTGF) is a major chemotactic and mitogenic factor for connective tissue cells. The amino acid sequence shares an overall 28-38% identity to IGFBPs and contains critical conserved sequences in the amino terminus. It has been demonstrated that human CTGF specifically binds IGFs with low affinity and is considered to be a member of the IGFBP superfamily (IGFBP-rP2). In the present study, the expression of CTGF (IGFBP-rP2) in human leukaemic lymphoblasts from children with acute lymphoblastic leukaemia (ALL) was investigated. RNA samples from tumour clones enriched by ficoll separation of bone marrow or peripheral blood mononuclear cells (MNC) from 107 patients with childhood ALL at diagnosis and 57 adult patients with chronic myeloid leukaemia (CML) were studied by RT-PCR. In addition MNC samples from children with IDDM and cord blood samples from healthy newborns were investigated as control groups. Sixty-one percent of the patients with ALL (65 of 107) were positive for CTGF (IGFBP-rP2) expression. In the control groups, no expression of CTGF (IGFBP-rP2) in peripheral MNC was detected, and in the group of adult CML patients only 3.5% (2 of 57) were positive for this gene. The role of CTGF (IGFBP-rP2) in lymphoblastic leukaemogenesis requires further evaluation, as does its potential utility as a tumour marker. Copyright 2000 Cancer Research Campaign.

Topotecan-based combination chemotherapy in patients with transformed chronic myelogenous leukemia and advanced myelodysplastic syndrome.

Unique Identifier: 20447643

Author: Park SJ; Kim DW; Kim HJ; Eom HS; Min CK; Lee JW; Min WS; Kim CC

Source: Korean J Intern Med 2000 Jul;15(2):122-6

Address: Catholic Hemopoietic Stem Cell Transplantation Center, Department of Internal Medicine, Catholic University of Korea, College of Medicine, Seoul, Korea.

    BACKGROUND: Patients with transformed chronic myelogenous leukemia(CML) and advanced myelodysplastic syndrome(MDS) have poor prognosis. The aim of this study is to evaluate the feasibility of second chronic phase induction in accelerated phase(CML-AP) or blastic crisis of CML(CML-BC) and remission induction in advanced MDS by combining topoisomerase I inhibitor (topotecan) with topoisomerase II inhibitor(mitoxantrone). METHODS: Twenty-four evaluable patients were entered on this study with a median age of 34 years. Eighteen patients with transformed CML(7 CML-AP, 11 CML-BC) and 6 patients with advanced MDS were treated. Topotecan was administered as 1.5 mg/m2/day by continuous infusion over 24 hours daily for 5 days every 4 to 8 weeks until remission. To enhance the tumoricidal effects, mitoxantrone(12 mg/m2/day, Days 1-3) was added. RESULTS: Eight patients(33%) achieved a complete remission(CR). Four of 7 patients with CML-AP(57%), 2 of 4 patients with CML-lymphoid blastic crisis (-LBC)(50%) and 2 of 6 patients with advanced MDS(33%) had CR lasting more than 45 days(45 to 400 days). There was no CR in the patients with CML-myeloid blastic crisis(-MBC). The dose level of 1.5 mg/m2/day(7.5 mg/m2/course) of topotecan was well tolerated in all patients. Mucositis occurred in 69% of patients (severe in 5%) and diarrhea in 67%(severe in 8%). In addition, there were no new or unexpected toxicities in the patients who were treated at this dose(7.5 mg/m2/course). In patients who recovered their neutrophil count, the absolute neutrophil count(ANC) remained below 500/microL for a period of 13 to 58 days(median 21 days) and the time to ANC recovery was associated with pretreatment severity of bone marrow fibrosis(mainly CML patients). Likewise, in the patients who recovered unsupported platelets, the platelets remained below 20,000/microL for a period of 0 to 37 days (median 19 days). CONCLUSION: The combination of topotecan-mitoxantrone has shown modest activity in CML-AP, CML-LBC and advanced MDS with acceptable toxicities.

The amount of BCR-ABL fusion transcripts detected by the real-time quantitative polymerase chain reaction method in patients with Philadelphia chromosome positive chronic myeloid leukemia correlates with the disease stage.

Unique Identifier: 20439494

Author: Elmaagacli AH; Beelen DW; Opalka B; Seeber S; Schaefer UW

Source: Ann Hematol 2000 Aug;79(8):424-31

Address: Department of Bone Marrow Transplantation, University Hospital of Essen, Germany.

    The use of the real-time reverse-transcription polymerase-chain reaction (RT-PCR) method to quantify BCR-ABL transcripts before and after allogeneic transplant was prospectively studied in 65 patients with chronic myeloid leukemia (CML). The expression of the BCR-ABL transcript was determined and normalized using the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) housekeeping gene product as an endogenous reference. In the single step real-time PCR assay, tenfold serial dilutions of cDNA of the K5652 cell line remained positive down to 100 pg cDNA only. However, molecular relapses of CML after transplant were only safely detectable when a nested real-time PCR assay was performed, which was able to detect 1-10 pg cDNA from a tenfold serial dilution. The median normalized BCR-ABL transcript level was measured as 0.004% in 17 patients with a molecular relapse, 0.4% in 7 patients with a cytogenetic relapse, 2.6% in 36 patients with a stable phase of CML, and 36% in 5 patients with a relapse in a blast crisis. The analyzed median normalized amount of BCR-ABL transcript differed significantly (P<0.001) between the various disease stages. In ten CML patients with relapse, the real-time PCR method was used to monitor the response of various immunotherapies as donor leukocyte infusions, withdrawal of immunosuppression, or interferon-alpha application. The results of the quantitative evaluation of BCR-ABL transcripts reflected very well the clinical effect of the different applied immunotherapies. The new real-time PCR method seems to be a suitable technique for the early detection of relapse after allogeneic transplant in patients with the BCR-ABL transcript. Its ability to distinguish between molecular and cytogenetic relapse (P<0.001) allows early therapeutic decisions.

CML vaccines as a paradigm of the specific immunotherapy of cancer.

Unique Identifier: 20456245

Author: Pinilla-Ibarz J; Cathcart K; Scheinberg DA

Source: Blood Rev 2000 Jun;14(2):111-20

Address: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA.

    T cells are implicated in the effective control of chronic myeloid leukemia (CML). Recently, several clinical observations supported by laboratory data, indicate the presence of CML-specific T cells. Many proteins potentially act as leukemia-specific antigens for MHC-restricted cytotoxicity in CML. These include the bcr-abl fusion protein, myeloid-specific differentiation antigens and minor histocompatibility antigens. There is recent evidence to suggest that bcr-abl junctional peptides are capable of eliciting both CD4 and CD8 responses in normal healthy donors and in patients with CML. Moreover, T cell lines can be generated that react with autologous or HLA-matched fresh CML cells, suggesting that the bcr-abl fusion protein can be processed and expressed in the MHC cell surface molecules. Clinical trials exploiting the new understanding of the immunology of CML are underway.

Late onset cyclosporine-induced cerebral blindness with abnormal SPECT imagings in a patient undergoing unrelated bone marrow transplantation.

Unique Identifier: 20378795

Author: Uoshima N; Karasuno T; Yagi T; Kawamoto S; Hasegawa T; Yasumi M; Murakami M; Teshima H; Nakamura H; Hiraoka A; Masaoka T

Source: Bone Marrow Transplant 2000 Jul;26(1):105-8

Address: Fifth Department of Internal Medicine, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan.

    A 23-year-old woman underwent HLA-matched unrelated BMT for CML. She developed cerebral blindness on day 81. Brain magnetic resonance imaging revealed hyperintensity on a T2-weighted image in the white and gray matter of the right frontal and both occipital lobes. Single-photon emission computed tomography (SPECT) was consistent with a decrease in radionuclide uptake in these areas, suggesting a vasoconstrictive mechanism. A diagnosis of CsA-induced encephalopathy was made and CsA was discontinued. Her vision recovered completely after 24 h and abnormal imaging resolved within 2 weeks. This case demonstrates late onset CsA-induced cerebral blindness with the previously unreported abnormalities on SPECT.

Acute pancreatitis during immunosuppression with tacrolimus following an allogeneic umbilical cord blood transplantation.

Unique Identifier: 20378796

Author: Nieto Y; Russ P; Everson G; Bearman SI; Cagnoni PJ; Jones RB; Shpall EJ

Source: Bone Marrow Transplant 2000 Jul;26(1):109-11

Address: University of Colorado Bone Marrow Transplant Program, Denver, CO 80262, USA.

    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.

Outcome of T cell-depleted transplantation after conditioning with an intensified regimen in patients aged 50 years or more is comparable with that in younger patients.

Unique Identifier: 20378783

Author: Schattenberg A; Schaap N; Preijers F; van der Maazen R; de Witte T

Source: Bone Marrow Transplant 2000 Jul;26(1):17-22

Address: Department of Hematology, University Medical Center St Radboud, Nijmegen, The Netherlands.

    One hundred and thirty-one patients were transplanted for AML-CR1, ALL-CR1 or CML-CP1 after conditioning with 120 mg/kg body weight cyclophosphamide and 2 x 4.5 Gy TBI. Conditioning was intensified with the addition of 42 mg/m2 idarubicin. Grafts were T cell-depleted using counterflow centrifugation. Donors were HLA-identical siblings. We compared outcome of BMT in 109 patients aged less than 50 (median, 35) years with that of 22 patients with an age of 50 years or more (median, 53 years). For the patients aged <50 years, 2-year probabilities of treatment-related mortality, relapse, survival and leukemia-free survival were 26% (95% CI, 17% to 35%), 26% (95% CI, 17% to 35%), 64% (95% CI, 55% to 73%), and 56% (95% CI, 47% to 65%). For the patients aged > or =50 years, these figures were 13% (95% CI, 0% to 30%), 24% (95% CI, 6% to 42%), 66% (95% CI, 46% to 86%), and 67% (95% CI, 47% to 87%), respectively. Outcome did not differ significantly between the two age groups. TRM was within the range of that reported in the literature for recipients of T cell-depleted grafts. We conclude that T cell-depleted transplantation after a conditioning regimen that was intensified with the addition of idarubicin is feasible in patients aged > or =50 years. For this age group of patients, results of nonmyeloablative regimens should be compared with that obtained with T cell-depleted grafts.

Successful allogeneic bone marrow transplant in an HIV-1-positive man with chronic myelogenous leukemia [letter]

Unique Identifier: 20429910

Author: Schlegel P; Beatty P; Halvorsen R; McCune J

Source: J Acquir Immune Defic Syndr 2000 Jul 1;24(3):289-90

    No abstract available.

Detection of a potent humoral response associated with immune-induced remission of chronic myelogenous leukemia.

Unique Identifier: 20432213

Author: Wu CJ; Yang XF; McLaughlin S; Neuberg D; Canning C; Stein B; Alyea EP; Soiffer RJ; Dranoff G; Ritz J

Source: J Clin Invest 2000 Sep;106(5):705-14

Address: Center for Hematologic Oncology, and. Department of Biostatistical Science, Dana-Farber Cancer Institute, and. Department of Medicine, and Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

    The effectiveness of donor-lymphocyte infusion (DLI) for treatment of relapsed chronic myelogenous leukemia (CML) after allogeneic bone marrow transplantation is a clear demonstration of the graft-versus-leukemia (GVL) effect. T cells are critical mediators of GVL, but the antigenic targets of this response are unknown. To determine whether patients who respond to DLI also develop B-cell immunity to CML-associated antigens, we analyzed sera from three patients with relapsed CML who achieved a complete molecular remission after infusion of donor T cells. Sera from these individuals recognized 13 distinct gene products represented in a CML-derived cDNA library. Two proteins, Jkappa-recombination signal-binding protein (RBP-Jkappa) and related adhesion focal tyrosine kinase (RAFTK), were recognized by sera from three of 19 DLI responders. None of these antigens were recognized by sera from healthy donors or patients with chronic graft-versus-host disease. Four gene products were recognized by sera from CML patients treated with hydroxyurea and nine were detected by sera from CML patients who responded to IFN-alpha. Antibody titers specific for RAFTK, but not for RBP-Jkappa, were found to be temporally associated with the response to DLI. These results demonstrate that patients who respond to DLI generate potent antibody responses to CML-associated antigens, suggesting the development of coordinated T- and B-cell immunity. The characterization of B cell-defined antigens may help identify clinically relevant targets of the GVL response in vivo.

Molecular biology. Cancer fighter's modus operandi revealed [comment] [news]

Unique Identifier: 20450093

Author: Marx J

Source: Science 2000 Sep 15;289(5486):1857-9

    No abstract available.

Macrophages and their subpopulations following allogenic bone marrow transplantation for chronic myeloid leukaemia.

Unique Identifier: 20445372

Author: Thiele J; Kvasnicka HM; Beelen DW; Wenzel P; Koepke ML; Leder LD; Schaefer UW

Source: Virchows Arch 2000 Aug;437(2):160-6

Address: Institute of Pathology, University of Cologne, Germany.

    A morphometric and immunohistochemical study was performed on 354 bone marrow trephine biopsies derived from 126 patients with chronic myeloid leukaemia (CML) before and after allogeneic bone marrow transplantation (BMT). The purpose of this investigation was to evaluate the macrophage population, including several subsets and their dynamics in the posttransplant period. In addition to the total CD68+ resident (mature) macrophages the so-called activated fraction identified by its capacity to express alpha-D-galactosyl residues, the pseudo-Gaucher cells (PGCs) and the iron-laden histiocytic reticular cells were also considered. Following immuno- and lectin-histochemical staining morphometric analysis was carried out on sequential postgraft bone marrow specimens at standardized intervals. Compared to the normal bone marrow and calculated per haematopoiesis (cellularity) an overall decrease of about 40-50% in the quantity of CD68+ macrophages and the BSA-I+ subpopulation was detectable in the early posttransplant period (9-45 days after BMT). Noteworthy was the temporal recurrence of PGCs in the engrafted bone marrow, which was not associated with a clonally transformed cell population or leukaemic relapse. Reappearance of postgraft PGCs was most prominent in the first 2 months after BMT. This conspicuous feature was presumed to be functionally associated with a pronounced degradation of cell debris following pretransplant myelo-ablative therapy (scavenger macrophages). Evidence for an activation of the BSA-I+ macrophage subset was derived from the identical carbohydrate-binding capacity shown by the PGCs. In the regenerating haematopoiesis shortly after BMT a significant correlation between the number of BSA-I+ macrophages and erythroid precursor cells was determinable. This result implicates a close functional relationship between postgraft reconstitution of erythropoietic islets and centrally localized activated macrophages. In conclusion, findings emerging from this study included the reappearance of PCGs in the engrafted bone marrow independently of a leukaemic relapse and the significant association of the activated BSA-I+ macrophage subset with the recovery of erythropoiesis.

[Study on nuclear matrix protein in leukemia cells]

Unique Identifier: 20376348

Author: Li J; Ren X; Huang Z

Source: Chung Hua Chung Liu Tsa Chih 1998 Nov;20(6):425-7

Address: First Affiliated Hospital, Sun Yetsen University of Medical Sciences, Guangzhou.

    OBJECTIVE: To compare the composition of nuclear matrix proteins (NMP) between leukemia cells and normal bone marrow cells. METHODS: NMP was isolated by high-salt extration and identified by SDS-PAGE and western blotting. RESULTS: Increase in NMP was demonstrated in acute and chronic myelogenous leukemic cells as well as in the blast phase of chronic leukemia. On SDS-PAGE, NMPs with molecular weight different from what were seen in normal bone marrow cells were present in both acute and chronic myelogenous leukemias. CONCLUSION: Marked changes of NMP, not only in contents but also in compositions, exist in leukemic cells compared with normal bone marrow cells. NMP may serve as a target of chemotherapeutic drugs against leukemia.

Overproduction of BCR-ABL transcripts in human leukemic cell lines K562 and BV173 [letter]

Unique Identifier: 20450119

Author: Moravcova J; Nadvornikova-Muchova S; Brezinova J

Source: Eur J Haematol 2000 Feb;64(2):135-6

    No abstract available.

Ex vivo expansion and characterisation of CD34+ cells derived from chronic myeloid leukaemia bone marrow and peripheral blood, and from normal bone marrow and mobilised peripheral blood.

Unique Identifier: 20450112

Author: Garin MI; Apperley JF; Melo JV

Source: Eur J Haematol 2000 Feb;64(2):85-92

Address: Department of Haematology, ICMS, Hammersmith Hospital, London, UK.

    Ex vivo culture of CD34+ has the potential to provide large numbers of cells for clinical use in autologous and allogeneic transplantation and for experimental research involving genetic manipulation. We evaluated the ex vivo expansion of CD34+ cells obtained from bone marrow (BM) and peripheral blood (PB) of untreated patients with chronic myeloid leukaemia (CML) in the chronic phase and compared these results with those obtained from BM from normal volunteers (NBM) and peripheral blood after mobilising chemotherapy from patients with non-haematological disorders (MPB). Selected CD34+ cells were stimulated with interleukin 1(beta), interleukin IL-3, interleukin IL-6 and stem cell factor. The proliferation observed in patients with CML was similar to that seen in normal donors. CD34+ cells derived from patients with CML are more differentiated than their normal counterparts, as shown by the coexpression of CD34 and CD33 antigens on day 0 (85.6% for CML-BM and 76.8% for CML-PB). The culture conditions allowed a significant expansion of granulocyte-macrophage colony-forming units (CFU-GM) from NBM (33-fold increase) and MPB (22-fold increase), in contrast with CML-derived BM and PB CD34+ cells (2.3-fold increase). These results indicate that the optimal time to harvest ex vivo expanded cells is dependent on a critical compromise between cell numbers and successful retention of their repopulating potential.

Treatment of chronic myeloid leukemia in the blastic phase with fludarabine, cytosine arabinoside and G-CSF (FLAG).

Unique Identifier: 20450690

Author: Tedeschi A; Montillo M; Ferrara F; Nosari A; Mele G; Copia C; Leoni P; Morra E

Source: Eur J Haematol 2000 Mar;64(3):182-7

Address: Division of Hematology, Niguarda Ca Granda Hospital, Milan, Italy.

    The present study was undertaken to evaluate the efficacy of the association of fludarabine plus Ara-C and G-CSF (FLAG) in the treatment of 15 patients with chronic myeloid leukemia in the blastic phase (CML-BP). Patients achieving a partial remission (PR) after the first course received a second FLAG. Complete remission (CR) was consolidated with another FLAG regimen. Patients were then submitted to an individualized program of treatment depending on age and suitable donors. Overall seven patients achieved CR (46.7%), three (20%) showed a primary resistant disease, while three (20%) died during remission induction therapy. Five of them received a consolidation therapy; in two cases further treatment was not performed because of severe toxicity. Median overall survival and disease-free survival were of 7.5 and 4.5 months, respectively. FLAG proved to be effective in achieving a high CR rate in patients with CML-BP. Median overall survival and disease-free survival were not significantly improved compared to previous studies. Nevertheless, the treatment was well tolerated even in a group of heavily pretreated patients, allowing further transplantation opportunities in younger patients.

Essential thrombocythemia transformed to acute myelogenous leukemia with t(3;17)(p24; q12), del(5)(q13q34) after treatment with carboquone and hydroxyurea.

Unique Identifier: 20460230

Author: Tabata M; Imagawa S; Tarumoto T; Ohmine K; Hatake K; Miura Y; Ozawa K

Source: Jpn J Clin Oncol 2000 Jul;30(7):310-2

Address: Department of Hematology, Jichi Medical School, Tochigi, Japan.

    In 1991, a 52-year-old woman was diagnosed as having essential thrombocythemia (ET). She was doing well with continuous medication with carboquone (CQ) and subsequently hydroxyurea (HU). However, substantial leukocytosis with leukemic blast cells, anemia and thrombocytopenia developed in 1996. Analysis of peripheral blood showed 4.4 x 10(3)/microl white blood cells with 82% of leukemic blast cells. These blasts showed negative staining with myeloperoxidase by immunostaining, but the myeloperoxidase was positive by electron microscopic analysis. Cytogenetic analysis of bone marrow cells revealed a t(3;17)(p24; q12), del(5)(q13q34). On the basis of these findings, the leukemic blast cells were classified as acute myelogenous leukemia (AML:M0) in the FAB classification. The causative agent, CQ and HU in secondary leukemia from ET and chromosomal abnormality related to ET blastic crisis (BC) are discussed.

Hydroxyurea treatment for chronic myeloid leukemia during pregnancy.

Unique Identifier: 20445206

Author: Celiloglu M; Altunyurt S; Undar B

Source: Acta Obstet Gynecol Scand 2000 Sep;79(9):803-4

Address: Faculty of Medicine, Department of Obstetrics and Gynecology, Dokuz Eylul University, Izmir, Turkey.

    No abstract available.

Hydroxyurea versus busulphan for chronic myeloid leukaemia: an individual patient data meta-analysis of three randomized trials. Chronic myeloid leukemia trialists' collaborative group.

Unique Identifier: 20452796

Author: Anonymous

Source: Br J Haematol 2000 Sep;110(3):573-6

    Although interferon alpha (IFN) has been shown to prolong survival in chronic myeloid leukaemia (CML), it cannot be used in all patients. Reliable evidence on the relative benefits of busulphan and hydroxyurea is of value in treating those patients who will not receive interferon. Data for each individual patient was sought from trials which randomized patients with CML to hydroxyurea vs. busulphan. Intention-to-treat stratified log rank survival analyses were performed, reporting two-sided P-values. Data were collected on 812 patients in the three trials identified. In the group of 690 patients with confirmed Philadelphia chromosome (Ph)-positive CML, survival at 4 years was 45.1% with busulphan and 53.6% with hydroxyurea, an absolute benefit of 8.5% (95% confidence interval 0. 1-16.9; logrank P = 0.01 over 4 years). There seemed to be no further benefit for hydroxyurea in later years, but there was no apparent delayed adverse effect either. The difference between hydroxyurea and busulphan was not statistically significantly different from the overall result in any subgroup. Survival of patients with Ph-positive CML is better with hydroxyurea treatment than with busulphan.

Monitoring of residual disease and guided donor leucocyte infusion after allogeneic bone marrow transplantation by chimaerism analysis with short tandem repeats.

Unique Identifier: 20452807

Author: de Weger RA; Tilanus MG; Scheidel KC; van den Tweel JG; Verdonck LF

Source: Br J Haematol 2000 Sep;110(3):647-53

Address: Departments of Pathology and Haematology, University Medical Centre, Utrecht, The Netherlands.

    In this study, we analysed the chimaeric status of peripheral blood leucocytes (PBLs) in recipients of allogeneic bone marrow transplantation (BMT) with the use of short tandem repeat (STR) microsatellite markers for monitoring the efficacy of BMT and donor leucocyte infusions (DLIs). A set of four STR markers was used with a highly discrimative capacity between individuals. STRs were detected by polymerase chain reaction (PCR) and were analysed by gene scanning (STR-GS). Between June 1990 and December 1998, 52 patients treated with BMT for chronic myeloid leukaemia (CML) were analysed. Seventeen patients relapsed after BMT and two patients never achieved remission after BMT. Fourteen of the 17 patients achieved a complete donor chimaerism after BMT, as detected by the presence of only donor STR-GS fragments, and in three cases a weak recipient STR-GS signal remained persistently detectable after BMT. A reappearance or increase of recipient STR-GS signals was indicative of relapse, which was mostly detected by STR-GS several months before relapse was diagnosed clinically. Nineteen patients were treated with DLI for reappearance of CML after BMT which resulted in complete remission in 17 patients, concordant with the disappearance of recipient STR-GS signals. More importantly, DLI treatment could be guided based upon the STR-GS data, which prevented unnecessary extra DLI courses that could cause toxicity. This study indicates that STR-GS is an effective and reliable method for monitoring BMT recipients.

Clinical, hematological and cytogenetic characteristics of atypical chronic myeloid leukemia.

Unique Identifier: 20304076

Author: Hernandez JM; del Canizo MC; Cuneo A; Garcia JL; Gutierrez NC; Gonzalez M; Castoldi G; San Miguel JF

Source: Ann Oncol 2000 Apr;11(4):441-4

Address: Department of Hematology, Hospital Universitario and Centro de Investigacion del Cancer, Universidad de Salamanca-CSIC, Spain.

    BACKGROUND: Atypical chronic myeloid leukemia (aCML) is an infrequent chronic myeloproliferative disorder characterized by leukocytosis, absence of Philadelphia chromosome or BCR-ABL rearrangement, and marked myeloid dysplasia. Some cases have an absolute monocytosis but can be distinguished from chronic myelomonocytic leukemia (CMML) by the presence of a higher percentage (> 15%) of circulating immature granulocytes. PATIENTS AND METHODS: In a series of 11 patients with a diagnosis of aCML according to the FAB proposals we have analyzed the most relevant clinical, hematological and cytogenetic characteristics. RESULTS: The median age was 65 years (16-84). All but one case showed, at time of diagnosis, leukocytosis (median WBC was 36 x 10(9)/l), 55% had moderate anemia and 36% had thrombocytopenia. Most cases had marked dysplasia, particularly in the granulocytic lineage (82% of the cases), and all cases showed bone marrow red hypoplasia. Cytogenetic abnormalities were present in 9 out of the 11 patients. Trisomy 8 was observed in three cases and other clonal chromosomal abnormalities included deletions of 5q, 13q, 17p, 12q, and 11q as well as a t(6;8)(p23;q22) translocation. Fluorescence in situ hybridization (FISH) studies failed to demonstrate ETV-6 gene involvement. The median survival time from diagnosis was only 14 months (range 3-56 months). CONCLUSIONS: These data suggest that aCML is a rare disease which is characterized by leukocytosis, with dysgranulopoiesis, BM erythroid hypoplasia, chromosomal, though not recurrent, abnormalities and poor prognosis.

Evidence that specific T lymphocytes may participate in the elimination of chronic myelogenous leukemia.

Unique Identifier: 20429529

Author: Molldrem JJ; Lee PP; Wang C; Felio K; Kantarjian HM; Champlin RE; Davis MM

Source: Nat Med 2000 Sep;6(9):1018-23

Address: Section of Transplantation Immunology, Department of Blood and Marrow Transplantation, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.

    Although the immune system has long been implicated in the control of cancer, evidence for specific and efficacious immune responses in human cancer has been lacking. In the case of chronic myelogenous leukemia (CML), either allogeneic bone marrow transplant (BMT) or interferon-alpha2b (IFN-alpha2b) therapy can result in complete remission, but the mechanism for prolonged disease control is unknown and may involve immune anti-leukemic responses. We previously demonstrated that PR1, a peptide derived from proteinase 3, is a potential target for CML-specific T cells. Here we studied 38 CML patients treated with allogeneic BMT, IFN- alpha2b or chemotherapy to look for PR1-specific T cells using PR1/HLA-A*0201 tetrameric complexes. There was a strong correlation between the presence of PR1-specific T cells and clinical responses after IFN-alpha and allogeneic BMT. This provides for the first time direct evidence of a role for T-cell immunity in clearing malignant cells.

Equivalence of 2 effective graft-versus-host disease prophylaxis regimens: results of a prospective double-blind randomized trial.

Unique Identifier: 20326965

Author: Chao NJ; Snyder DS; Jain M; Wong RM; Niland JC; Negrin RS; Long GD; Hu WW; Stockerl-Goldstein KE; Johnston LJ; Amylon MD; Tierney DK; O'Donnell MR; Nademanee AP; Parker P; Stein A; Molina A; Fung H; Kashyap A; Kohler S; Spielberger R; Krishnan A; Rodriguez R; Forman SJ; Bluzme KG

Source: Biol Blood Marrow Transplant 2000;6(3):254-61

Address: Duke University, Durham, North Carolina, USA.

    We have previously demonstrated a decrease in the incidence of acute graft-versus-host disease (GVHD) with the addition of methotrexate (MTX) to cyclosporine (CSP) and prednisone (PSE) chemotherapy in patients with leukemia. We have now completed a prospective randomized trial comparing the 3-drug regimen (CSP/MTX/PSE, including 3 doses of MTX) to the standard 2-drug regimen (CSP/MTX, including 4 doses of MTX) to investigate the benefit of PSE used up front for the prevention of acute and chronic GVHD. In the trial, 193 patients were randomized and 186 were included in the final analysis. All patients received a bone marrow graft from a fully histocompatible sibling donor. The preparatory regimen consisted of fractionated total-body irradiation (fTBI) and etoposide in all but 13 patients, who received fTBI and cyclophosphamide. The patients were randomized to receive either CSP/MTX/PSE or CSP/MTX. The 2 groups were well balanced with respect to diagnosis, disease stage, age, donor-recipient sex, and parity. In an intent-to-treat analysis, the incidence of acute GVHD was 18% (95% confidence interval [CI] 12-28) for the CSP/MTX/PSE group compared with 20% (CI 10-26) for the CSP/,MTX group (P = .60), with a median follow up of 2.2 years. Overall survival was 65% for those receiving CSP/MTX/PSE and 72% for those receiving CSP/MTX (P = .10); the relapse rate was 15% for the CSP/MTX/PSE group and 12% for the CSP/MTX group (P = .83). The incidence of chronic GVHD was similar (46% versus 52%; P = .38), with a follow-up of 0.7 to 6.0 years. Of interest, 21 patients went off study due to GVHD (5 in the CSP/MTX/PSE group and 16 in the CSP/MITX group [P = .02]), and 11 patients went off study because of alveolar hemorrhage (3 in the CSP/MTX/PSE group and 8 in the CSP/MTX group [P = .22]). The addition of PSE did not result in a higher incidence of infectious complications, bacterial (66% versus 58%), viral (77% versus 66%), or fungal (20% versus 20%), in those receiving CSP/MTX/PSE versus CSP/MTX, respectively. These data suggest that the addition of PSE was associated with a somewhat lower incidence of early posttransplantation complications but did not have a positive impact on the incidence of acute or chronic GVHD or event-free or overall survival.

Trial of IFN or STI571 before proceeding to allografting for CML?

Unique Identifier: 20448466

Author: Hehlmann R

Source: Leukemia 2000 Sep;14(9):1560-2

Address: III. Medizinische Universitatsklinik, Klinikum Mannheim, Universitat Heidelberg, Mannheim, Germany.

    Ten-year survival of IFN-treated low risk CML patients is about 40%, and more in cytogenetic responders. Allografting has a cure rate of up to 75%, but is associated with considerable procedure related morbidity and mortality. One out of three or four is likely not to survive. A comparative quantification of survival after BMT and IFN treatment suggests that a trial of IFN (and possibly STI 571) before proceeding to allografting is a viable, and in low risk patients a probably preferable option.

Biological effects of stroma-derived factor-1 alpha on normal and CML CD34+ haemopoietic cells.

Unique Identifier: 20448479

Author: Durig J; Rosenthal C; Elmaagacli A; Heyworth C; Halfmeyer K; Kasper C; Novotny J; Duhrsen U

Source: Leukemia 2000 Sep;14(9):1652-60

Address: Department of Haematology, University Hospital Essen, Germany.

    We compared the biological effects of the CXC chemokine SDF-1alpha on immunomagnetically purified CD34+ cells isolated from human normal bone marrow (NBM), leukapheresis products (LP) and patients with chronic myeloid leukaemia (CML). LP CD34+ cells showed a significantly stronger migration response to SDF-1alpha (100 ng/ml) than CD34+ cells isolated from the peripheral blood (PB) of CML patients (P < 0.05). The chemotactic response to SDF-1alpha was also reduced in CML BM CD34+ cells in comparison to NBM CD34+ cells but the observed differences were not statistically significant. In analogy to normal CD34+ cells circulating CML PB CD34+ cells were less responsive to SDF-1alpha than their BM counterparts (P < 0.05). Furthermore, SDF-1alpha elicited similar concentration-dependent growth suppressive effects on normal and CML CD34+ cells (P > 0.05) in colony-forming cell assays. We then demonstrated that SDF-1alpha triggers intracellular calcium increases in CD34+ cells and there were no differences in the time course and dose response characteristics of normal and CML CD34+ cells. The reduced migration response to SDF-1alpha in CML CD34+ cells was not due to a down-regulation of the SDF-1alpha receptor CXCR-4 as flow cytometric analysis revealed similar CXCR-4 expression levels on NBM, LP, CML PB and CML BM CD34+ cells (P > 0.05). Finally, no differences in the modulation of CXCR-4 levels in response to SDF-1alpha and serum were observed in CML and normal CD34+ cells. Our data suggest that the impaired chemotactic response of CML CD34+ cells to SDF-1alpha is not caused by a lack or complete uncoupling of CXCR-4, but may be due to an intracellular signalling defect downstream of the receptor.

Abnormal integrin-mediated regulation of chronic myelogenous leukemia CD34+ cell proliferation: BCR/ABL up-regulates the cyclin-dependent kinase inhibitor, p27Kip, which is relocated to the cell cytoplasm and incapable of regulating cdk2 activity.

Unique Identifier: 20442411

Author: Jiang Y; Zhao RC; Verfaillie CM

Source: Proc Natl Acad Sci U S A 2000 Sep 12;97(19):10538-43

Address: Stem Cell Biology Institute and Department of Medicine and Cancer Center, University of Minnesota Medical School, Minneapolis, MN 55455, USA.

    beta(1)-integrin engagement on normal (NL) CD34(+) cells increases levels of the cyclin-dependent kinase inhibitor (cdki), p27(Kip), decreases cdk2 activity, and inhibits G(1)/S-phase progression. In contrast, beta(1)-integrin engagement on chronic myelogenous leukemia (CML) CD34(+) cells does not inhibit G(1)/S progression. We now show that, in CML, baseline p27(Kip) levels are significantly higher than in NL CD34(+) cells, but adhesion to fibronectin (FN) does not increase p27(Kip) levels. p27(Kip) mRNA levels are similar in CML and NL CD34(+) cells and remain unchanged after adhesion, suggesting posttranscriptional regulation. Despite the elevated p27(Kip) levels, cdk2 kinase activity is similar in CML and NL CD34(+) cells. In NL CD34(+) cells, >90% of p27(Kip) is located in the nucleus, where it binds to cdk2 after integrin engagement. In CML CD34(+) cells, however, >80% of p27(Kip) is located in the cytoplasm even in FN-adherent cells, and significantly less p27(Kip) is bound to cdk2. Thus, presence of BCR/ABL induces elevated levels of p27(Kip) and relocation of p27(Kip) to the cytoplasm, which contributes to the loss of integrin-mediated proliferation inhibition, characteristic of CML.

Immunomagnetic selection of CD34(+) cells for transplantation from partially matched family donors in children.

Unique Identifier: 20453686

Author: Toporski J; Turkiewicz D; Kalwak K; Rybka B; Ryczan R; Boguslawska-Jaworska J

Source: Transplant Proc 2000 Sep;32(6):1419-21

Address: Department of Pediatric Hematology and Oncology, Wroclaw University of Medicine, Wroclaw, Poland.

    No abstract available.

[Long-term follow up of chronic myelogenous leukemia patients treated with natural interferon alpha--multi-institutional cooperative study]

Unique Identifier: 20469996

Author: Urabe A; Asano S; Mizoguchi H; Aoki N; Takaku F

Source: Gan To Kagaku Ryoho 2000 Sep;27(10):1541-6

Address: Division of Hematology, NTT Kanto Medical Center.

    The effects on survival in patients with chronic myelogenous leukemia (CML) treated with natural interferon alpha (Sumiferon) were analyzed. The subjects were 131 patients with CML who underwent treatment with Sumiferon between August 1991 and December 1992. Sumiferon was administered more than 8 weeks, and patients were followed for 5 years. In the end, 101 patients were analyzed after 30 patients were dropped from the study because they had received bone marrow transplantation. Survivals from the start of Sumiferon administration were 63.4% at 3 years, 52.5% at 4 years, and 42.6% at 5 years, respectively. Survivals were compared between the 74 patients who received Sumiferon administration with 1 year of diagnosis, and the 27 patients who received Sumiferon administration after more than 1 year from diagnosis. The 50% survivals were 2,089 days and 868 days, respectively (p = 0.0011). It was concluded that early administration of interferon alpha results in a prolonged survival of CML patients.

Natural killer cell dysfunction and apoptosis induced by chronic myelogenous leukemia cells: role of reactive oxygen species and regulation by histamine.

Unique Identifier: 20417778

Author: Mellqvist UH; Hansson M; Brune M; Dahlgren C; Hermodsson S; Hellstrand K

Source: Blood 2000 Sep 1;96(5):1961-8

Address: Hematology Section, Department of Medicine, Institute of Medical Microbiology, Sahlgren's University Hospital, Goteborg, Sweden.

    Natural killer (NK) cells are deficient in patients with chronic myelogenous leukemia (CML), but the mechanisms responsible for the dysfunction are not completely understood. This study reports that CML cells effectively inhibit the baseline and interleukin-2 (IL-2)-induced NK cell cytotoxicity against a CML cell-derived line (K562). A sizable fraction of NK cells subsequently acquired features characteristic of programmed cell death/apoptosis. The CML cell-mediated inhibition of NK cells required triggering of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-mediated formation of reactive oxygen species (ROS) and was prevented by catalase, a scavenger of ROS, and by histamine, acting via H(2)-receptor-mediated inhibition of ROS production in CML cells. In contrast, nonmalignant neutrophilic granulocytes inhibited NK cells via ROS production without the requirement of exogenous NADPH oxidase-triggering stimuli. We propose that paracrine production of ROS may contribute to the dysfunction of NK cells in CML and that histamine may serve as an autocrine inhibitor of ROS formation in leukemic granulocytes. (Blood. 2000;96:1961-1968)

Detailed mapping of methylcytosine positions at the CpG island surrounding the Pa promoter at the bcr-abl locus in CML patients and in two cell lines, K562 and BV173.

Unique Identifier: 20409256

Author: Fajkusova L; Fajkus J; Polackova K; Fulnecek J; Dvorakova D; Krahulcova E

Source: Blood Cells Mol Dis 2000 Jun;26(3):193-204

Address: Faculty Hospital Brno, II. Int. Clin., Jihlavska 20, Brno, CZ-63900, Czech Republic.

    Chronic myelogenous leukemia (CML) is associated with a translocation of the protooncogene c-abl from chromosome 9 to chromosome 22, where it fuses to proximal exons of the bcr gene. The expression of the hybrid gene bcr-abl is regulated by the bcr promoter and results in a translation product with high tyrosine kinase activity. In most CML cases, one of two abl promoters (Pa) is nested within the bcr-abl transcription unit, but appears to be usually silent. Recently, de novo methylation of the Pa region and its correlation with disease progression were reported. As these previous studies were limited to the use of methylation-sensitive restriction endonucleases, our aim here was to obtain a complete map of methylcytosines and its variants in CML patients and in model cell lines. To achieve this, bisulfite conversion of cytosines (but not methylcytosines) to uracils in genomic DNA was employed. After modification, the region of interest was PCR-amplified and the products were cloned and sequenced. The results show methylation at a high level and in a homogenous pattern in the BV173 cell line, corresponding to the translocated abl alleles. Variant methylation observed in K562 cells correlates with multiple bcr-abl loci and an intact chromosome 9. Patients that were methylation-positive in restriction analysis showed sporadic and heterogenous occurrence of methylcytosines in bisulfite modification assays. Corresponding results were obtained using a quantitative Southern analysis of the extent of methylation. We conclude that restriction analysis combined with PCR is able to find rare cases of hypermethylation, e. g., for diagnostic purposes, but does not reflect the dominating level of methylation in Ph-positive cells. Copyright 2000 Academic Press.

Avascular necrosis of the femoral head in chronic myeloid leukemia patients treated with interferon-alpha: a synergistic correlation?

Unique Identifier: 20469239

Author: Kozuch P; Talpaz M; Faderl S; O'Brien S; Freireich EJ; Kantarjian H

Source: Cancer 2000 Oct 1;89(7):1482-9

Address: Department of Leukemia, the University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030-4095, USA.

    BACKGROUND: The objectives of this study were to describe cases of avascular necrosis of the femoral head (ANFH) observed in chronic myeloid leukemia (CML) patients who were treated with interferon-alpha and to review the literature. METHODS: The authors undertook a case review of the M. D. Anderson experience with ANFH occurring in CML patients who were managed with interferon-alpha-based therapy. MEDLINE (from 1966 to November 1999) and CancerLit (from 1983 to November 1999) searches were conducted to identify cases of avascular necrosis (AVN) associated with either CML or interferon-alpha. RESULTS: Three patients with ANFH were identified from the authors' experience. No common features related to the disease or therapy were seen among them, except for the presence of thrombocytosis and loss of response. A literature review revealed seven cases of ANFH associated with CML with or without interferon-alpha-based therapy. ANFH was not reported in association with interferon-alpha use for indications other than the treatment of patients with CML. CONCLUSIONS: ANFH may be the result of an interaction between CML and interferon-alpha therapy. ANFH that occurs in patients with CML who are treated with interferon-alpha should be recognized for treatment implications. Thrombocytosis with consequent microvascular thrombi and avascular necrosis manifesting in susceptible vascular or weight-bearing areas (e.g., the femoral head) may be an associated finding along with loss of response to interferon-alpha therapy.

Autologous peripheral blood stem cell transplantation for chronic myelocytic leukaemia, using unmanipulated grafts.

Unique Identifier: 20454630

Author: Pigneux A; Mahon FX; Reiffers J

Source: Baillieres Best Pract Res Clin Haematol 1999 Mar-Jun;12(1-2):193-8

Address: Service d'Hematologie, Hopital du Haut Leveque, Bordeaux, France.

    In chronic myeloid leukaemia (CML) allogeneic stem cell transplantation can be proposed to a minority of patients who are both less than 50 years of age and have an HLA-identical donor. Recombinant alpha-interferon induces cytogenetic responses (and prolongation of survival) in only 25-40% of patients. Thus, alternative treatments need to be proposed. When performed in chronic phase with unmodified stem cells, autologous stem cell transplantation is followed by cytogenetic responses in about 40% of cases, and some data suggest that these responder patients could have a prolongation of survival. This now needs to be demonstrated prospectively. If so, further studies could be performed in order to define the best source of stem cells (purged or unpurged) to be used.

Normal and leukaemic haematopoiesis in bone marrow and peripheral blood of patients with chronic myeloid leukaemia.

Unique Identifier: 20454631

Author: Frassoni F; Podesta M; Piaggio G

Source: Baillieres Best Pract Res Clin Haematol 1999 Mar-Jun;12(1-2):199-208

Address: Dipartimento di Ematologia, Divisione Ematologia II, Ospedale San Martino, Genoa, Italy.

    In the majority of newly diagnosed patients with chronic myeloid leukaemia (CML), the bone marrow contains consistent numbers of normal Ph-negative surrogate stem cells (LTC-IC) which seem to decline rapidly with time. This is confirmed by mobilization studies showing that early after diagnosis is the optimal time to collect Ph-negative progenitor to be utilized for restoring Ph-negative haematopoiesis. In the marrow of the majority of CML patients at diagnosis Ph-positive LTC-IC are found at a lower frequency than Ph-negative LTC-IC and, unexpectedly, they do not show a tendency to increase with time as long as patients remain in chronic phase. Therefore, the decline of normal haematopoiesis does not seem related to a parallel increase in Ph-positive stem cells.

Autologous peripheral blood haematopoietic stem cell transplantation for chronic myelogenous leukaemia.

Unique Identifier: 20454632

Author: Carella AM; Cavaliere M; Lerma E; Corsetti MT

Source: Baillieres Best Pract Res Clin Haematol 1999 Mar-Jun;12(1-2):209-17

Address: Haematology and ABMT Unit, Azienda Ospedaliera e Cliniche, Universitarie Convenzionate, Ospedale San Martino, Genoa, Italy.

    In these last four decades there has been extraordinary progress in our understanding of the biology of, and therapeutic approach to, chronic myelogenous leukaemia (CML). During these decades new observations arising from studies of the biological behaviour of diploid and leukaemic stem cells and, recently, from clinical investigations have received the most attention. From a clinical point of view, allografting is still the only procedure which is able to cure CML. For patients without HLA-compatible donors, current therapeutic options include conventional chemotherapy (hydroxyurea), interferon-alpha (IFN-alpha) and autografting. While IFN-alpha (+/- low-dose ARA-C) must be considered the first-line therapy, autografting, according to our approach, or other procedures, raises the question of an ideal sequential strategy in the management of CML patients (diploid stem cell mobilization, autografting, IFN-alpha). Because it seems that the diploid haematopoietic reservoir declines with time, it may be desirable to mobilize and collect diploid stem cells in order to store them as soon as diagnosis is possible when the WBC count has been controlled by hydroxyurea.

Leukaemia manifesting as uncontrollable proliferative retinopathy in a diabetic [letter]

Unique Identifier: 20479114

Author: Raynor MK; Clover A; Luff AJ

Source: Eye 2000 Jun;14 ( Pt 3a)():400-1

    No abstract available.

Detection of molecular variants of BCR-ABL gene in bone marrow and blood of patients with chronic myeloid leukemia by reverse-transcriptase polymerase chain reaction (RT-PCR).

Unique Identifier: 20454094

Author: Udomsakdi-Auewarakul C; U-Pratya Y; Boonmoh S; Vatanavicharn S

Source: J Med Assoc Thai 2000 Aug;83(8):928-35

Address: Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.

    Very limited data exists in Thailand regarding the frequency of BCR-ABL leukemic gene and its prognostic implication in Thai CML patients. The objective of this study was to develop a rapid molecular assay for the detection of the two most commonly reported variants of BCR-ABL fusion gene, B2A2 and B3A2 in CML patients. Bone marrow or peripheral blood were used for RNA extraction and reverse-transcribed to cDNA for PCR amplification. 92 per cent of CML patients (91/99) were positive for BCR-ABL gene (61% B3A2 and 31% B2A2). 8/99 CML patients were BCR-ABL-negative. B3A2 and B2A2-positive patients did not have any different clinical and hematological features at presentation although B3A2 patients tended to be slightly older and had higher platelet counts. 71/71 non-CML including other MPD and leukemia cases were all negative for BCR-ABL gene. In conclusion, a rapid RT-PCR assay has now been developed for the detection of this hallmark gene in CML patients. It should be of great value in the differential diagnosis of CML from other diseases. Long-term follow-ups of CML patients with different variants are needed to determine the prognostic importance of each gene variant.

Heterogeneity of delta-aminolevulinic acid-induced protoporphyrin IX fluorescence in human glioma cells and leukemic lymphocytes.

Unique Identifier: 20332859

Author: Eleouet S; Rousset N; Carre J; Vonarx V; Vilatte C; Louet C; Lajat Y; Patrice T

Source: Neurol Res 2000 Jun;22(4):361-8

Address: Departement Laser, Hopital Laennec, Nantes, France.

    Delta-aminolevulinic acid (ALA)-PDT efficacy is particularly dependent on the quality of protoporphyrin IX (PpIX)-induced synthesis. The purpose of this study was to determine the ability of cells from two human cancer types to synthesise PpIX after ALA administration. Biopsies of glioma cells have been obtained from patients with glioblastomas that have or have not been given ALA IV (ex vivo incubation). Peripheral blood lymphocytes, obtained from leukemic patients, have also been ALA-incubated in vitro. In glioma cells, fluorescence heterogeneity was extensive either in ALA infused patients or in ex vivo ALA incubated cells. Mean intensities after 3 h were 110 cts (range 0-340) and 1000 cts (range 0-3600). Similar results were found in leukemic lymphocytes where cell fluorescence varied from 0 to 480 cts with a percentage of fluorescent cells varying with time and from one patient to another. Furthermore, PpIX was not detectable in two patients with CLL. These observations suggest that a marked heterogeneity of ALA uptake and/or PpIX synthesis exists in a given human cancer cell population particularly after systemic administration. Improvements for ALA transformation into PpIX are strongly recommended to ensure the efficacy of ALA/PpIX-PDT.

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