Abnormalities In Marrow Cells Research Articles

IN VIVO MOBILIZATION OF KARYOTyPICALLY NORMAL PERIPHERAL BLOOD PROGENITOR CELLS IN HIGH‐RISK MDS, SECONDARY OR THERAPY‐RELATED ACUTE MYELOGENOUS LEUKAEMIA

We have previously reported that mobilization of Philadelphia (Ph) chromosome-negative progenitors is possible in a significant number of Ph1-positive acute lymphoblastic leukaemia (ALL) and chronic myelogenous leukaemia (CML) patients. In this pilot study we employed the same approach for patients with RAEB-t, secondary AML (sAML) and therapy-related AML (t-AML). All patients except one had double or complex cytogenetic abnormalities in marrow cells before mobilization therapy. All patients received an idarubicin-containing regimen (mini-ICE protocol) followed by rh-G-CSF and the first leukapheresis was performed as they were recovering from aplasia. In six out of nine patients the leukapheresis product was entirely karyotypically normal, combined with a significant number of CFU-GM. CD34+ cells and LTC-IC. Recovery time from mobilization therapy was short and no patient died as a result of the procedure. To date, three patients have undergone autografting using their karyotypically normal collections, of which two (sAML) are alive with karyotypically normal marrow a few months after autografting.

Allogeneic marrow grafts from donors with congenital chromosomal abnormalities in marrow cells

To determine whether siblings with chromosomal abnormalities in marrow cells which are associated with cellular defects (e.g. Down syndrome or heterozygosity for Fanconi syndrome) are suitable donors for allogeneic bone marrow transplants, we have reviewed the patient files at the Fred Hutchinson Cancer Research Center (FHCRC) and carried out a survey among member centres of the International Bone Marrow Transplant Registry (IBMTR). The 57 of 253 (23%) member centres which responded to the survey reported seven transplants from donors with the following conditions: Down syndrome (n = 2), suspected heterozygotes for Fanconi syndrome (n = 3), and 47,XXX syndrome (n = 2), among a total of 5,561 allogeneic transplants from HLA-identical siblings. Adding the three cases seen at the Fed Hutchinson Cancer Research Center among 2,927 HLA-identical sibling transplants during 1992 resulted in 10 transplants among 8,488 cases transplanted overall: four with Down syndrome, four suspected of being heterozygous for Fanconi syndrome, and two trisomy X. Three out of four grafts from siblings with Down syndrome had complications, including poor graft function (n = 2) and graft failure (n = 1). Two of four recipients of marrow from presumed Fanconi syndrome heterozygotes presented with poor graft function and a third recipient developed graft failure after initial evidence of engraftment. The two patients given marrow from siblings with 47,XXX syndrome engrafted uneventfully. The experience reported here shows a low frequency of encountering an HLA-identical sibling donor who has chromosomal abnormalities in marrow cells consistent with Down syndrome or heterozygosity for Fanconi syndrome, about one case among 1,000 transplants. The much higher than expected incidence of graft problems with marrow from such a donor would make it reasonable to look either for an alternative marrow donor or consider an autologous transplant, in case a sibling marrow donor with Down syndrome or heterozygosity for Fanconi syndrome is encountered, although a donor with trisomy X seems acceptable.

Chromosome abnormalities in acute lymphoblastic leukemia

Less information is available on the cytogenetic abnormalities in marrow cells of patients with acute lymphoblastic leukemia (ALL) than on abnormalities in acute nonlymphocytic leukemia (ANLL); nonetheless, some patterns of karyotypic change in ALL are evident. Even with banding, about 50% of patients appear to have a normal karyotype. The modal chromosome number tends to be higher in ALL than in ANLL. Every patient with B-cell ALL has had an abnormality of one chromosome No. 14 that involved the translocation of material to the end of the long arm. Among seven reported cases, the translocation was from 8q in three patients and 11q in one. Cells with a haploid or near-haploid (24–35) chromosome number have been reported in five patients with ALL and in four patients in a lymphoid blast crisis of chronic myelogenous leukemia. The karyotype in the four ALL patients whose cells were analyzed with banding was remarkably consistent. All patients had the haploid number, usually with both sex chromosomes, plus an additional No. 10, 18, and 21. Evolution of the karyotype, which occurs in the leukemic cells of about 50% of patients, involves cells of patients who had an initially normal or an initially abnormal karyotype. The evidence regarding a correlation between the presence of an abnormal clone prior to treatment and response to treatment is contradictory at present. Some chromosome abnormalities, such as the presence of a Philadelphia (Ph 1) chromosome, a 14q+ chromosome, or a haploid clone, are associated with a relatively short survival.

The marks of preleukaemia

The term preleukaemia suggests a state which precedes true leukaemia and can be clearly distinguished from it. However, since there are no absolute criteria of what constitutes leukaemia, it is impossible to draw a sharp demarcation line between the disease and any pathological processes leading up to it. Preleukaemia can thus only be diagnosed retrospectively. The discovery of acquired cytogenetic changes is often believed to indicate the imminence or presence of malignancy. In this paper the question is posed if clonal abnormalities in marrow cells denote preleukaemia and forecast the later development of leukaemia. Details are presented of the case of a man with lymphosarcoma whose marrow, when first seen before treatment, was mildly hypoplastic; but without abnormal chromosomes. The lymphoma was controlled by chemo- and radiotherapy, but 7 mth after treatment was discontinued, the patient developed pancytopenia. A hypodiploid clone was now observed in the marrow, and additional hyperdiploid and polyploid lines were found 4 mth later, together with the clear features of acute granulocytic leukaemia. This case showed the concurrent development of leukaemia and of chromosome abnormalities. It is contrasted with others where clonal changes were found in haematologically abnormal patients but leukaemia failed to develop, and with a second group in which leukaemia followed longstanding blood dyscrasias but without any observable chromosome abnormalities. It was concluded that new cytogenetic techniques are required before the precise rattionship between leukaemia and its pathological antecedents can be properly assessed.