Classification of mature T-cell leukemias.
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Cell Size↗
Biomedical subjects
D Catovsky
Publications and source records attributed to D Catovsky.
A comparison of flow cytometry, bone marrow biopsy, and bone marrow aspirates in the detection of lymphoid infiltration in B cell disorders.
AIMS: To evaluate the diagnostic value of bone marrow aspirates, trephine biopsies (BMB), and flow cytometry (FC) in the assessment of bone marrow infiltration in chronic lymphoid disorders. METHODS: Investigations were carried out in 110 diagnostic and follow up specimens from B cell disorders, namely: chronic lymphocytic leukaemia (CLL; 65), non-Hodgkin's lymphoma (NHL; 39), and hairy cell leukaemia (HCL; 6). A selected panel of monoclonal antibodies was used both for FC and immunohistochemistry. RESULTS: In CLL there was agreement between the three investigations in 71% of samples and in 88% when only FC and BMB were compared. In nine of 65 samples, FC and BMB were positive, although the aspirate was reported as negative. Four BMB negative samples had minimal residual disease (MRD) detected by FC, whereas two samples were positive both on BMB and aspirate but showed no evidence of disease on FC. In NHL, there was agreement between the three investigations in 22 of 39 cases, and in 27 of 39 cases there was agreement between FC and BMB. In eight of 39 NHL cases, FC was negative but the BMB was either positive (five) or uncertain (three), whereas in three of 39, FC was positive but BMB was either negative (one) or uncertain (two). In three of five uncertain BMB, no clonal population was detected by the polymerase chain reaction, whereas in the remaining two cases the nodular aggregates disappeared on further sectioning. CONCLUSIONS: Both BMB and FC are better than bone marrow aspirates for the detection of infiltration in B cell disorders. FC might be slightly more sensitive than BMB to detect MRD in CLL, whereas BMB may be slightly better than FC in NHL.
Adult↗
Chromosomal imbalances in familial chronic lymphocytic leukaemia: a comparative genomic hybridisation analysis.
A subset of B cell chronic lymphocytic leukaemia (CLL) is familial. Lack of large families makes it attractive to exploit methods in addition to genetic linkage analysis for the identification of a susceptibility locus. One strategy that can localise regions of the genome that may harbour tumour suppressor genes is to identify regions of chromosomal imbalance using comparative genomic hybridisation (CGH) analysis. We examined 24 familial CLL cases by CGH analysis. Losses that are documented as arising frequently in sporadic CLL were observed at a comparable frequency in familial CLL. However, gains and losses in two regions of the X chromosome - Xp11.2-p21 and Xq21-qter - appear more common in familial CLL than in sporadic CLL. This suggests these regions may harbour a susceptibility locus for CLL. There is also some evidence that chromosome regions 2p12-p14 and 4q11-q21 may harbour predisposition genes.
Chromosome Aberrations↗
Genetic susceptibility to chronic lymphocytic leukemia.
There is increasing evidence that a subset of chronic lymphocytic leukemia is caused by an inherited predisposition. Here we review the evidence for an inherited predisposition, the characteristics of familial cases and evidence for the involvement of specific genes.
Family Health↗
Detection of cyclin D1 in B cell lymphoproliferative disorders by flow cytometry.
AIMS: To describe and revise a flow cytometric assay for evaluating cyclin D1 overexpression in B cell lymphoproliferative disorders (B-LPDs). METHODS: Cyclin D1 expression was evaluated in 11 healthy controls and 51 patients with B-LPD by flow cytometry using the 5D4 monoclonal antibody. In 25 cases, experiments were repeated up to four times with mononuclear cells (MNC) fixed in ethanol for 1-120 days to evaluate the consistency of cyclin D1 expression. Flow cytometry results were compared with fluorescence in situ hybridisation (FISH) for the t(11;14) translocation in 19 patients and with immunohistochemistry (IHC) using the DCS-6 monoclonal antibody in nine patients. RESULTS: A mean fluorescence intensity ratio (MFIR) of 4.8 was defined as the cut off point for positivity based on cyclin D1 expression in healthy controls (mean + 3 SD). Ten patients overexpressed cyclin D1 by flow cytometry. These included five of eight patients with mantle cell lymphoma, four of 19 with chronic lymphocytic leukaemia, and one with follicular lymphoma. MFIR in the repeat experiments differed less than 25% in 20 of 25 patients and in no cases did it cross the cut off point. There was a good correlation between cyclin D1 expression by flow cytometry and FISH for t(11;14) in 15 of 19 patients and six of nine had concordant results with flow cytometry, FISH, and IHC. CONCLUSION: Cyclin D1 expression remains fairly stable once MNC are fixed in ethanol and the flow cytometric assay can be used for the routine screening of B-LPD. Further comparisons between flow cytometry, IHC, and FISH may be needed to ascertain the diagnostic value of the flow cytometric assay.
B-Lymphocytes↗
Activity of oral fludarabine phosphate in previously treated chronic lymphocytic leukemia.
PURPOSE: A prospective, multicenter, open-label phase II clinical trial was conducted to assess the efficacy and safety of oral fludarabine phosphate. Reference to an historical group of patients treated with the intravenous (IV) formulation allowed the investigators to compare the two formulations. PATIENTS AND METHODS: Efficacy was assessed using the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) and National Cancer Institute (NCI) criteria for complete remission (CR), partial remission (PR), stable disease, or disease progression. Safety monitoring included World Health Organization (WHO) toxicity grading for all adverse events. RESULTS: Seventy-eight (96.3%) of 81 recruited patients with previously treated B-cell chronic lymphocytic leukemia (CLL) received 10-mg tablets of fludarabine phosphate to a dose of 40 mg/m(2)/d for 5 days, repeated every 4 weeks, for a total of six to eight cycles. According to IWCLL criteria, the overall remission rate was 46.2% (CR, 20.5%; PR, 25.6%). The comparative figures using NCI criteria were 51.3% (CR, 17.9%; PR, 33.3%). Overall, 30 incidents of severe adverse events were reported for 22 patients. WHO grade 3 or grade 4 hematologic toxicities included granulocytopenia (53.8%), leukocytopenia (28.2%), thrombocytopenia (25.6%), and anemia (24.4%). Gastrointestinal adverse events were more common with the oral formulation than previously reported with IV fludarabine phosphate. However, these events were generally mild to moderate. CONCLUSION: This study demonstrates that oral fludarabine phosphate has similar clinical efficacy to the IV formulation and a safety profile that is both predictable and essentially similar to that of the IV formulation.
Administration, Oral↗
High remission rate in T-cell prolymphocytic leukemia with CAMPATH-1H.
T-cell prolymphocytic leukemia (T-PLL) is a chemotherapy-resistant malignancy with a median survival of 7.5 months. Preliminary results indicated a high remission induction rate with the human CD52 antibody, CAMPATH-1H. This study reports results in 39 patients with T-PLL treated with CAMPATH-1H between March 1993 and May 2000. All but 2 patients had received prior therapy with a variety of agents, including 30 with pentostatin; none achieved complete remission (CR). CAMPATH-1H (30 mg) was administered intravenously 3 times weekly until maximal response. The overall response rate was 76% with 60% CR and 16% partial remission (PR). These responses were durable with a median disease-free interval of 7 months (range, 4-45 months). Survival was significantly prolonged in patients achieving CR compared to PR or no response (NR), including one patient who survived 54 months. Nine patients remain alive up to 29 months after completing therapy. Seven patients received high-dose therapy with autologous stem cell support, 3 of whom remain alive in CR 5, 7, and 15 months after autograft. Stem cell harvests in these patients were uncontaminated with T-PLL cells as demonstrated by dual-color flow cytometry and polymerase chain reaction. Four patients had allogeneic stem cell transplants, 3 from siblings and 1 from a matched unrelated donor. Two had nonmyeloablative conditioning. Three are alive in CR up to 24 months after allograft. The conclusion is that CAMPATH-1H is an effective therapy in T-PLL, producing remissions in more than two thirds of patients. The use of stem cell transplantation to consolidate responses merits further study.
Adult↗
p53 abnormalities in splenic lymphoma with villous lymphocytes.
The incidence and role of p53 abnormalities have not been reported in splenic lymphoma with villous lymphocytes (SLVL), the leukemic counterpart of splenic marginal zone lymphoma. Because p53 abnormalities correlate with progressive and refractory disease in cancer and isochromosome 17q has been described in SLVL, a low-grade lymphoma that behaves aggressively in a minority of patients, this study investigated p53 changes by molecular and immunophenotypic methods in samples from 59 patients. The p53 deletion was analyzed by fluorescence in situ hybridization, and p53 protein expression was assessed by immunocytochemistry in 35 of 59 cases and by flow cytometry in 20 of 35 patients. Ten patients (17%) had a monoallelic p53 loss, 3 (9%) of 35 nuclear protein expression by immunocytochemistry, and 2 (10%) of 20 by flow cytometry. Two patients had both deletion and protein expression. Direct sequencing of all p53 exons was used to delineate mutations in 9 of 11 patients with an identified abnormality. Mutations, both compromising p53 DNA binding, were identified in the 2 patients with deletion and protein accumulation. Kaplan-Meier analysis revealed a significantly worse survival for patients with p53 abnormalities. Although p53 abnormalities are infrequent in SLVL, they underlie a more aggressive disease course and poor prognosis. (Blood. 2001;97:3552-3558)
Adult↗
TCL1 is activated by chromosomal rearrangement or by hypomethylation.
TCL1 is an oncogene activated by recurrent reciprocal translocations at chromosome segment 14q32.1 in the most common of the mature T-cell malignancies, T-cell prolymphocytic leukemia. It acts to transport Akt1 to the nucleus and enhance Akt1's serine-threonine kinase activity. TCL1 is also expressed in the B-cell malignancy, Burkitt's lymphoma (BL). However, 14q32.1 breakpoints have not been detected in BL, and we therefore investigated in more detail how expression was activated. No evidence for rearrangement near TCL1 was found in BL. Instead, a NotI site adjacent to the TATA box in the TCL1 promoter was found to be unmethylated. By contrast, tumor cell lines not expressing TCL1 were fully methylated at this NotI site, while normal somatic cells were hemimethylated. We also found that TCL1 was expressed in B-cell chronic lymphocytic leukemia (CLL) and the related disorder splenic lymphoma with villous lymphocytes (unlike in normal mature B-cells), and that the NotI site was unmethylated on both alleles. This correlation of repression and methylation was tested in vitro. When cells with both alleles methylated at the NotI site were demethylated, TCL1 expression was induced. These data provide evidence that in mature B-cell malignancies there is an alternative mechanism of TCL1 activation that apparently involves loss of methylation of one promoter allele. We discuss the significance of this for CLL tumorigenesis and for genomewide hypomethylation in CLL.
Base Sequence↗
Cyclin D1 by flow cytometry as a useful tool in the diagnosis of B-cell malignancies.
The translocation (11;14)(q13;q32) and its molecular counterpart the BCL-1 rearrangement are features observed in mantle cell lymphoma (MCL) and less commonly in other B-cell disorders. This rearrangement leads to cyclin D1 overexpression, which may be the main pathogenic event in these tumours and is therefore recognised as a diagnostic marker. We developed a flow cytometry method to detect cyclin D1 overexpression using the monoclonal antibody (MoAb) 5D4, and characterised its frequency in 93 B-cell malignancies. The competitive reverse transcriptase polymerase chain reaction (RT-PCR) for cyclin D1, D2 and D3 was then performed on 40 of these cases to assess the validity of the flow cytometry method. Fluorescence in situ hybridisation (FISH) to detect t(11;14)(q13;q32) was carried out on 31 cases and results were compared with cyclin D1 expression by flow cytometry. Twenty five cases showed cyclin D1 expression using 5D4, including MCL (12/13, 92%), chronic lymphocytic leukaemia (CLL) (4/30), B-prolymphocytic leukaemia (B-PLL) (1/4), splenic lymphoma with villous lymphocytes (SLVL) (4/13), hairy cell leukaemia (HCL) (1/7) and other B-non Hodgkins Lymphoma (B-NHL) (3/15). There was a good correlation between flow cytometry results and RT-PCR in 36/40 cases (90%), and with FISH for t(11;14) in 25/31 cases (80%). We concluded that the detection of cyclin D1 expression by flow cytometry in cell suspensions could be applied routinely to the study of B-lymphoproliferative disorders and may be of value for their diagnosis and management.
Biomarkers, Tumor↗
The natural history and clinico-pathological features of the variant form of hairy cell leukemia.
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Aged↗
Cutaneous presentation of chronic lymphatic leukaemia and response to ultraviolet B phototherapy.
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Ear, External↗
Deletions of D13S25, D13S319 and RB-1 mapping to 13q14.3 in T-cell prolymphocytic leukaemia.
Deletions of 13q14.3 are well known in several malignancies and are thought to be associated with tumour suppressor function. The RB-1 gene is a tumour suppressor gene, but other loci including D13S319 and D13S25 telomeric to this within 13q14.3 are deleted in B-cell chronic lymphocytic leukaemia (B-CLL), multiple myeloma and non-Hodgkin's lymphoma, with varying clinical significance. The fluorescence in situ hybridization screening of 22 patients with T-prolymphocytic leukaemia (T-PLL) for deletions of 13q14.3 revealed loss of D13S25 in 17 cases (mean 40% range 13-98%), with 11 patients having at least a 20% deletion. Mapping the deletions for the RB-1, D13S319,and D13S25 loci revealed D13S25 as the most frequently deleted marker. However, patients with only the D13S25 deletion had low percentages of cells with the deletion (12-13%), suggesting that loss of D13S25 on its own may not provide sufficient growth advantage. The use of the YAC 954c12, which maps immediately adjacent to D13S25, defined the telomeric border of the deletion in some of the cases. Inv(14)(q11q32) and t(14;14)(q11;q32) are characteristic of T-PLL, but are also observed in premalignant T-cell clones in patients with ataxia telangiectasia. Transition to overt leukaemia may result from loss of suppressor function. Thus, 13q14.3 deletions could contribute to the development of overt leukaemia in T-PLL, but the involvement of more than one gene in the region cannot be excluded.
Adult↗
An oxaliplatin-based chemotherapy in patients with relapsed or refractory intermediate and high-grade non-Hodgkin's lymphoma.
This study was designed to assess the efficacy and safety of substituting cisplatin with oxaliplatin in the DHAP (dexamethasone, cytarabine and cisplatin) regimen for patients with relapsed or refractory non-Hodgkin's lymphoma. Twenty-four evaluable patients with intermediate or high-grade non-Hodgkin's lymphoma were treated at 3-weekly intervals with oxaliplatin (130 mg/m2, d 1), cytarabine (2 g/m2 for two doses, d 2) and dexamethasone (40 mg, d 1-4). The median age of the patients was 58 (range 18-70). Histological subtypes were diffuse large B cell, 20; mantle cell, two; anaplastic large cell, one; and peripheral T cell, one. The overall objective response rate (RR) was 50% [95% confidence interval (CI) = 29-71%] including four complete responses and eight partial responses. RR for those patients treated at first relapse was higher than those treated at second and subsequent relapse (77% versus 29%). Grade 3 and 4 toxicity was mainly haematological: anaemia 17%, neutropenia 75% and thrombocytopenia 75%. No grade 4 non-haematological toxicity was reported. No significant renal and neurotoxicity was demonstrated. Median survival was 10.6 months. Probabilities of 1-year progression-free survival and overall survival were 47% (95% CI = 26-66%) and 50% (95% CI = 23-72%) respectively. In conclusion, dexamethasone, cytarabine and oxaliplatin (DHAX) is a novel combination in salvage therapy for relapsed or refractory non-Hodgkin's lymphoma. It has clinically significant activity with an acceptable toxicity profile. Lack of renal toxicity makes DHAX an attractive cytoreductive regimen before high-dose chemotherapy.
Adolescent↗
Transformation of T-cell large granular lymphocyte leukaemia into a high-grade large T-cell lymphoma.
We describe a case of T-cell large granular lymphocyte (LGL) leukaemia that transformed into a large-cell T-cell lymphoma 11 years from diagnosis. A 29-year-old asymptomatic female presented in 1989 with lymphocytosis, neutropenia and mild bone marrow infiltration. The circulating cells were LGL with a CD2+, CD3+, CD8+, CD4-, CD16+, CD56+, CD57- phenotype. In August 2000, she developed fever, a large submandibular mass and hepatosplenomegaly. Biochemistry showed abnormal liver function tests and raised lactate dehydrogenase (LDH) levels. A serological screen for Epstein-Barr virus, cytomegalovirus, human T-lymphotropic virus-I, human herpes virus (HHV)-6 and HHV-7 was negative. Histology of the mass was consistent with the diagnosis of peripheral T-cell lymphoma composed of large cells, and immunohistochemistry showed that the lymphoma cells had a phenotype identical to the mature LGL. Molecular analysis with the polymerase chain reaction (PCR) demonstrated rearrangement of the T-cell receptor (TCR) gamma-chain gene with a band of identical size in both bone marrow mature LGL and lymph node cells. The patient was treated with CHOP (cyclophosphamide, vincristine, doxorubicin and prednisolone), resulting in the disappearance of the mass and improvement of the hepatosplenomegaly, LDH and liver abnormalities. She underwent splenectomy, and spleen histology showed involvement by T-cell LGL leukaemia with no evidence of transformation. This case illustrates that transformation or Richter syndrome may occur in a minority of patients with T-cell LGL leukaemia, a disease that has a benign clinical course in most cases. This is the first case documented by molecular methods of the transformation of the pre-existing clone.
Adult↗
Linkage analysis for major histocompatibility complex-related genetic susceptibility in familial chronic lymphocytic leukemia.
Chronic lymphocytic leukemia (CLL) shows evidence of familial aggregation, but the genetic basis is poorly understood. The existence of a linkage between HLA and Hodgkin lymphoma, another B-cell disorder, coupled with the fact that CLL is frequently associated with autoimmune disease, led to the question of whether the major histocompatibility complex (MHC) region is involved in familial cases of CLL. To examine this proposition, 5 microsatellite markers on chromosome 6p21.3 were typed in 28 families with CLL, 4 families with CLL in association with other lymphoproliferative disorders, and 1 family with splenic lymphoma with villous lymphocytes. There was no evidence of linkage in these families to chromosome 6p21.3. The best estimates of the proportions of sibling pairs with CLL that share 0, 1, or 2 MHC haplotypes were not significantly different from the null expectation. This implies that genes within the MHC region are unlikely to be the major determinants of familial CLL. (Blood. 2000;96:3982-3984)
Adult↗
CLL variants and T-cell-related issues.
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Ataxia Telangiectasia Mutated Proteins↗
Unusual breakpoint distribution of 8p abnormalities in T-prolymphocytic leukemia: a study with YACS mapping to 8p11-p12.
Chromosome 8 abnormalities are seen in 80% of patients with T-cell prolymphocytic leukemia (T-PLL). The abnormalities described are idic(8)(p11),t(8;8)(p11;q12),+8, and 8p+ with the involvement of 8p. To localize 8p11-p12 breakpoints in T-PLL, metaphases from seven cases were karyotyped. Those with idic(8)(p11) and add(8)(p11) were probed with a panel of contiguous YACs derived from 8p11-p12 using fluorescence in situ hybridization (FISH). Analysis of FISH results showed that 8p11-p12 breakpoints cluster into two regions. The first region is telomeric to YAC 899e2, which contains the fibroblast growth factor receptor-1 gene (FGFR1) and appears to cluster within a 1.5-MB YAC 807a2. The second region is more centromeric with breakpoints on either side of YAC 806e9, flanked by YAC 940f10 distally and YAC 910d7 proximally, the latter containing the MOZ gene. These findings showed that a segment of 8p was still present in the isodicentric, but the pattern of clustering does not seem to correspond to a breakpoint affecting a single gene. The clustering regions are likely to be hot spots for recombination and result in idic(8)(p11) and 8p+. These changes point to the pathogenesis of T-PLL involving deletion of a gene sequence on 8p and/or gain of a copy of 8q.
Chromosome Mapping↗