Adrian Copplestone

Dyskeratosis Congenita (DC) Registry: identification of new features of DC

Dyskeratosis congenita (DC) is an inherited disorder characterized by skin pigmentation, nail dystrophy and mucosal leucoplakia. In 1995 a Dyskeratosis Congenita Registry was established at the Hammersmith Hospital. In the 46 families recruited, 76/83 patients were male, suggesting that the major form of DC is X‐linked. As well as a variety of noncutaneous abnormalities, the majority (93%) of patients had bone marrow (BM) failure and this was the principal cause (71%) of early mortality. In addition to BM hypoplasia, some patients also developed myelodysplasia and acute myelod leukaemia. Pulmonary abnormalities were present in 19% of patients. In affected females the phenotype was less severe. Some female carriers of X‐linked DC had clinical features. Carriers of X‐linked DC showed skewed X‐chromosome inactivation patterns (XCIPs), suggesting that cells expressing the normal DC allele have a growth/survival advantage over cells that express the mutant allele. Linkage analysis in multiplex families confirmed that the DKC1 gene, responsible for the X‐linked form of DC, is located within Xq28 and facilitated its positional cloning. The high incidence of BM failure in association with a wide range of somatic abnormalities together with the ubiquitous expression of DKC1 suggest that, as well as having a critical role in normal haemopoiesis, this gene has a key role in normal cell biology.

Atypical lymphocyte morphology: An adverse prognostic factor for disease progression in stage A CLL independent of trisomy 12

We studied 270 patients with Binet stage A chronic lymphocytic leukaemia looking for adverse prognostic factors. In a multivariate analysis the following features were found to be risk factors for disease progression: atypical lymphocyte morphology (defined as either > 10% prolymphocytes or > 15% lymphocytes with cleaved nuclei or lymphoplasmacytoid cells); more than two karyotypic abnormalities; lymphocyte count > 30 × 109/l; lymphocyte doubling time < 1 year; enlargement of one or more lymph node groups.

Results of a Randomized Trial of Chlorambucil Versus Fludarabine for Patients With Untreated Waldenström Macroglobulinemia, Marginal Zone Lymphoma, or Lymphoplasmacytic Lymphoma

PURPOSE Treatment options for patients with Waldenström macroglobulinemia (WM) and closely related disorders include alkylating agents, purine analogs, and monoclonal antibodies. No large randomized studies have yet been reported comparing any of these approaches. PATIENTS AND METHODS The randomized WM1 study (Trial Comparing Chlorambucil to Fludarabine in Patients With Advanced Waldenström Macroglobulinemia) was undertaken in 101 centers in five countries enrolling 414 eligible patients (339 with WM, 37 with non-mucosa-associated lymphoid tissue marginal zone lymphoma, and 38 with lymphoplasmacytic lymphoma) who were randomly assigned to receive chlorambucil or fludarabine. The primary end point was the overall response rate (ORR). RESULTS On the basis of intent-to-treat analysis, the ORR was 47.8% (95% CI, 40.9% to 54.8%) in the fludarabine arm versus 38.6% (95% CI, 32.0% to 45.7%) in the chlorambucil arm (P = .07). With a median follow-up of 36 months (interquartile range, 18 to 58 months), median progression-free survival (PFS), and duration of response (DR) were significantly improved in the fludarabine arm compared with the chlorambucil arm: PFS, 36.3 versus 27.1 months (P = .012) and DR, 38.3 versus 19.9 months (P < .001). In patients with WM, median overall survival (OS) was not reached in the fludarabine arm versus 69.8 months in the chlorambucil arm (95% CI, 61.6 to 79.8 months; P = .014). Grade 3 to 4 neutropenia was significantly higher among patients treated with fludarabine (36%) compared with patients treated with chlorambucil (17.8%; P < .001). Second malignancies were significantly more frequent in the chlorambucil arm with 6-year cumulative incidence rate of 20.6% versus 3.7% in the fludarabine arm (P = .001). CONCLUSION In the complete intent-to-treat study population, fludarabine significantly improved PFS compared with chlorambucil, and in patients with WM, it improved OS.

HEPARIN-INDUCED THROMBOCYTOPENIA IN PREGNANCY

Reisner. Y., Kapor, N.. Kirkpatrick, D., Pollack, M.S.. Dupont. B.. Good. R.A. & O’Reilly, R.J. (1981) Transplantation for acute leukaemia with HLA-A and B non identical parenteral marrow cells fractionated with soybean agglutinin and sheep red blood cells. Lancet, ii, 327-331. Slavin, S., Waldmann. H.. Cividalli, G., Naparstek. E.. Steiner-Salz. D.. Michaeli. J., Galun, E.. Weiss, L., Samuel, S.. Moreckl. S., Bar, S.. Brautbar. C.. Weshler, Z.. Hale, G.. Rachmilewihz, E.A. & Reisner, logy, 63. 221-230. Y. (1 985) Prevention of graft-versus-host disease in allogenic bone marrow transplantation for leukemia by T cell depletion in vitro prior to transplantation. Transplantation Proceedings. 17 ,465467 . Trigg, M.E., Billing, R., Sondel. P.M.. Exten. R.. Hong, R.. Bozdech. MJ.. Horowitz. S.D.. Finlay. J.L.. Moen, Longo. W., Erickson. C. & Peterson, A. (1985) Clinical trial depleting T lymphocytes from donor marrow for matched and mismatched allogenic bone marrow transplants. Cancer Treatment Reports. 69, 377-386. Waldmann. H.. Hale, G.. Cividalli. G., Weshler. Z., Manor. D.. Rachmilewitz, E.A., Polliak, A,. Or. R., Weiss. L., Samuel. S.. Brautbar. C. & Slavin. S. (1 984) Elimination of graft-versus-host disease by in vitro depletion of alloreactive lymphocytes with a monoclonal rat anti-human lymphocyte antibody Campath-1 . Lancet. ii, 4 8 3 4 8 6 .

Type C TP53-CDKN1A pathway dysfunction occurs independently of CDKN1A gene polymorphisms in chronic lymphocytic leukaemia and is associated with TP53 abnormalities.

Deletions and/or mutations of TP53 are associated with poor prognosis in patients with chronic lymphocytic leukaemia (CLL), even when these abnormalities are not present in the predominant clonal population (Rossi et al, 2014). Dysfunction of the TP53-CDKN1A (p21) pathway correlates strongly with TP53 structural abnormalities (Carter et al, 2004; Best et al, 2008), however 9 5% of unselected CLL cases have been reported to have an impaired CDKN1A response to DNA damage despite normal TP53 upregulation, termed Type C dysfunction (Johnson et al, 2009). In the UK CLL4 trial, Type C dysfunction was documented in 13/278 (4 7%) of patients at entry and was associated with short progression-free survival (Lin et al, 2012). In half of these cases, Type C dysfunction was associated with two polymorphisms of CDKN1A (p21) in the absence of structural abnormalities of TP53; namely C/A (Ser/Arg) at CDKN1A codon 31 (CDKN1A-cod31) and C/C rather than C/T in the 30UTR (Johnson et al, 2009). We carried out CDKN1A genotyping in 208 samples from a series of 418 cases on which TP53 functional and structural data was available. TP53-CDKN1A function was assessed as previously described (Best et al, 2008) using the classifications of Carter et al (2004). Of 418 cases analysed, 290 (69 4%) showed normal function and 13 (3 1%), 76 (18 2%) and 39 (9 3%) showed Type A, B and C dysfunction respectively (Fig 1A). The relative incidence of dysfunctional cases was not significantly different between our series and that of Johnson et al (2009) (v = 3 542, 2 degrees of freedom, P =