Multiple myeloma. New treatment options.

Before proceeding to treatment selection for multiple myeloma, it is important to exclude monoclonal gammopathy of unknown significance or any similar smouldering or indolent type of myeloma not requiring immediate chemotherapy. In patients with active myeloma, pretreatment prognostic classification is important for appropriate balancing of the risks and benefits of particular treatment options. For example, conventional chemotherapy such as melphalan/prednisone may be appropriate for an elderly patient with active stage III myeloma, whereas high dose chemotherapy with or without bone marrow transplantation or cytokine support may be considered for the patient under age 45 with even earlier stage disease. A variety of options are now available for patients with relapsing or resistant disease, particularly using agents with potential for reversal of multi-drug resistance. The use of interferon-alpha as maintenance following initial response to chemotherapy is important for prolongation of remission, duration and potentially survival. A variety of supportive measures are also helpful including the use of epoetin (erythropoietin) to improve refractory anaemia and bisphosphonates for the inhibition of ongoing bone resorption. With the availability of various treatment options, it has become important for patients to be evaluated by a specialist in the field.

Poor prognosis acute myeloid leukaemia treated by matched unrelated donor marrow transplant without preceding total body irradiation.

Two patients with acute myeloid leukaemia, one in relapse after autologous bone marrow transplantation (BMT) (aged 52 years) and the other with primary resistant disease secondary to previously treated malignancy, have received marrow transplants from matched unrelated donors. Cytoreductive conditioning in both cases was with high-dose combination chemotherapy alone. Engraftment was aided by the administration of total lymphoid irradiation together with in vivo antilymphocyte antibody prior to marrow infusion. Both patients survive in complete remission, currently at 12 and 15 months post-BMT respectively. The avoidance of total body irradiation in BMT patients at high risk of early treatment-related mortality may be advantageous.

Refractory anaemia terminating in a combined lymphoproliferative and myeloproliferative disorder.

We report a case of non-sideroblastic refractory anaemia which evolved to a double lymphomyeloproliferative disorder. At presentation, bone marrow appearances and peripheral blood pancytopenia without myelomonocytosis were consistent with a diagnosis of non-sideroblastic refractory anaemia. Subsequently, the patient developed pronounced myelomonocytosis and lymphocytosis with prolymphocytes. Light and transmission electron microscopy as well as surface marker studies were compatible with a diagnosis of prolymphocytic transformation of chronic lymphocytic leukaemia/prolymphocytic leukaemia associated with myelomonocytic leukaemia. The pathogenesis of such double lympho-myeloproliferative disorders is discussed in the light of the evidence for common lymphoid and myeloid progenitor cells and some recent advances in the immunology of the myelodysplastic syndromes.

Acute thrombocytopenia following ingestion of indomethacin.

A case of acute thrombocytopenia with shortened platelet survival following ingestion of indomethacin is reported. Drug history and absence of infection exclude both the role of other agents and an acute episode of idiopathic thrombocytopenia. The patient exhibited a poor response to immunosuppressive treatment and a slow resolution of the thrombocytopenia.

[Monoclonal gammopathies: differential diagnosis with bone marrow biopsy]. / Le gammopatie monoclonali: diagnostica differenziale su biopsia osteomidollare.

Aim of the present study is to examine the morphological aspects of monoclonal gammopathies (GM) detectable by bone marrow biopsy. With reference to Multiple Myeloma (MM), the more important disease of this group from a clinical standpoint, other conditions will be later evaluated. Particular attention will be given to Monoclonal Gammopathy of Undetermined Significance (MGUS) that still today is characterized by wide shadows concerning both ethiology and evolution significance.

Model for antenatal diagnosis of beta-thalassaemia and other monogenic disorders by molecular analysis of linked DNA polymorphisms.

Polymorphisms of DNA restriction sites within the human fetal globin genes have been used to identify chromosomes that carry beta-thalassaemia genes in individuals heterozygous for this disease. This has allowed an antenatal diagnosis for beta-thalassaemia to be carried out by observation of the pattern of the inherited polymorphism of a linked DNA sequence not involved in the genetic pathogenesis of the disease. In the populations we have investigated there is no constant pattern of polymorphism that segregates with the beta-thalassaemia gene. The use of linked polymorphisms should, therefore, be applicable to antenatal diagnosis both of beta-thalassaemia and of any other single-gene defect for which there is a DNA probe specific for a sequence linked to the affected locus.

Thalassaemia as a model of recessive genetic disease in the community.

In order to gain understanding of some of the problems of genetic counseling for a severe recessive disease in England, a Greek Cypriot extended family including 87 living members and known to be transmitting a beta-thalassaemia gene was investigated for the extent and the sources of their knowledge about thalassaemia. 42% of members tested carried beta-thalassaemia trait: nearly half were already aware of this, but only 10% of the non-carriers were aware of their status. The study illustrated many of the difficulties in conveying accurate counselling to a whole community and the need for active involvement of all health workers, especially general practitioners. This study is also relevant to the approaching possibility of genetic counseling for cystic fibrosis.

Hairy cell leukemia without splenomegaly nor myelofibrosis in a patient with gastric adenocarcinoma: early phase of the disease or a variant?

The first case of patient affected both by gastric carcinoma and hairy cell leukemia (HCL) is reported. From a clinical standpoint, this 54-year old man presented with striking leukopenia without splenomegaly. From a morphological point of view, the infiltration by leukemic cells occurred in the hypoplasic areas of the bone marrow biopsy (BMB) without increase in reticulin fibers. From these observations the authors deduce that: 1) BMB in many cases is the only morphologic tool for diagnosis and prognosis of HCL; 2) probably the "hypoplasic" variant of HCL will become more frequent, because of the increasing indication to BMB in course of pancytopenia, even in absence of splenomegaly; 3) our case is probably related more to an early phase of the disease than to a distinct variant. In addition, we propose that the co-existence of an aggressive solid tumor and HCL could be related to the immunosuppressive action by hairy cells.

Locoregional intrasplenic chemotherapy for hypersplenism in myelofibrosis.

A 79-year-old patient with post-polycythaemic myelofibrosis presented with severe hypersplenism. After splenic artery catheterization, cytosine arabinoside was given intrasplenically from November 1999 to March 2000 for 5 d/month at 10 mg/m2 and increased each month by 10 mg/m2. It was then administered by continuous infusion until June 2000, starting at 20 mg/m2/d and tapering by 5 mg/m2 every 2 weeks to a final daily dose of 5 mg/m2/d. The drug was then stopped. The spleen had decreased to one third of the initial volume. Clinical conditions and haematological indices improved substantially. Intrasplenic therapy could be a new therapeutic tool for hypersplenism in chronic idiopathic and post-myeloproliferative myelofibrosis.

Functions of T cells and recruitment of cellular response after in vitro mitogenic stimulation of lymphocytes in chronic lymphocytic leukaemia.

In vitro stimulation of peripheral blood lymphocytes from ten patients with chronic lymphocytic leukaemia (CLL) was investigated under various culture conditions. It was confirmed that the mitogenic reactivity of whole cell populations (PBL) was delayed and depressed. When CLL rosette-forming cells (RFC) were stimulated, their 3H-thymidine uptake was increased, but the pattern of the response was similar to that of whole PBL, thus suggesting some impairment of these cells. Furthermore, in order to evaluate the possible recruitment of B cells, generally thought to be unresponsive, some co-culture experiments were performed in which 10(4) normal lymphocytes and 10(5) CLL whole PBL or RFC-depleted cell populations were stimulated with mitogens. An amplified response of the CLL lymphocytes was obtained in all co-cultures, and this effect was more evident when specific T cell stimulants were used; autologous CLL T lymphocytes, on the contrary, failed to display such a 'synergic' effect. These results indicate that normal lymphocytes are able to recruit a large number of CLL lymphocytes in the mitogenic response; furthermore, the fact that in co-cultures of CLL T-depleted fractions a better response was obtained with T cell mitogens suggests that the definition of CLL as a clonal expansion of unresponsive 'B' lymphocytes may be inadequate.

In vitro proliferative response of chronic lymphocytic leukemia.

The peripheral blood lymphocytes of 13 previously untreated chronic lymphocytic leukemia (CLL) patients showed a decreased and delayed response in vitro to plant mitogens (PHA and PWM) and specific antigens (PPD and MLC). In addition, the serum of these patients inhibited the mitotic reactivity of both autologous and homologous normal lymphocytes. Since incubation with CLL serum did not affect the SRBC-rosetting capacity of normal lymphocytes, we believe that CLL serum interferes with some metabolic stage in blastogenesis rather than at the level of mitogen membrane interaction. The in vitro transformation of lymph node, bone marrow and peripheral blood lymphocytes in some of these patients was also investigated. Stimulation of peripheral blood cells with plant mitogens resulted in a more serious impairment of the response than that found with bone marrow and lymph node cells. This could be explained by the fact that, although CLL is a widespread lymphoproliferative disorder, some preferential homing of normally reactive cells in the bone marrow and lymph nodes cannot be excluded. Finally, since no stimulation was observed in mixed leukocyte cultures (MLC), our experiments provide evidence that no antigenic differences are detectable in CLL lymphoid populations.

Combined treatment with high-dose methotrexate, vincristine and procarbazine, without intrathecal chemotherapy, followed by consolidation radiotherapy for primary central nervous system lymphoma in immunocompetent patients.

OBJECTIVES: To assess the feasibility and the activity, as well as the efficacy to treat meninges, of chemotherapy (CHT) containing high-dose methotrexate (HD-MTX) followed by radiation therapy (RT), without intrathecal CHT, in patients with primary central nervous system lymphoma. METHODS: Eligibility criteria were histologically proven diagnosis, disease limited to the CNS, age < or = 70, ECOG performance status < or = 3, HIV-negative and no prior treatment. Thirteen patients (1996-1999; median age 54 years) received two courses of vincristine 1.4 mg/m2 day 1, MTX 3 g/m2 days 3 and 10 and procarbazine 100 mg/m2 days 1-14 every 4 weeks. Patients who achieved a complete remission were referred to RT, those with progressive disease were excluded from further study; all the remaining patients received a third course of CHT followed by RT. RESULTS: Twelve patients responded to CHT (overall response rate = 92%, complete response rate = 77%): 9 underwent consolidation RT, 3 did not. Two patients experienced severe acute toxicity; lethal pulmonary thromboembolism and transient renal failure. Five patients relapsed: 2 after CHT and 3 after RT. Relapse was local in all cases, with a case of concomitant hepatic involvement. No cases of ocular or meningeal relapse were observed. In contrast to high-dose cytarabine-containing CHT, salvage therapy with temozolomide produced good results. Two patients died of treatment-related neurotoxicity. Six patients are alive with a median follow-up of 17 months, and a 2-year overall survival (OS) of 61%. The median survival of the 9 patients who completed the planned treatment is 25+ months with a 2-year OS of 80%. CONCLUSIONS: HD-MTX, procarbazine and vincristine followed by RT, without intrathecal therapy, produce similar results with respect to other HD-MTX-containing regimens. These results seem to suggest that adequate meningeal treatment is possible without intrathecal drug delivery, even in CSF-positive patients. Corroborating data from a larger series are, however, necessary. Temozolomide should be tested in relapsed patients in a phase II prospective trial.

Interferon is effective in hairy-cell leukaemia.

Seventeen patients with hairy-cell leukaemia (HCL) and peripheral cytopenias were given human lymphoblastoid interferon (Wellferon), 3 megaunits daily or 6 megaunits on alternate days intramuscularly, for 4-24 weeks. Twelve of the patients had undergone splenectomy, three had no palpable spleen and had therefore not been offered surgery, and two patients with substantial splenomegaly were given interferon (IFN) as treatment of first choice. Toxic effects were minor except in one patient who experienced a severe form of somnolence syndrome. In all patients hairy cells (HCs) were cleared from the blood and platelet and Hb levels improved in 2-14 weeks. Neutrophils were improved in 14/17 of the patients. In the two patients with splenomegaly, the spleen became impalpable after 5-8 weeks therapy, and haematological improvement occurred at 12-14 weeks. HC infiltration of the marrow was reduced in all patients, but was complete (less than 5%) in only two, both of whom had impalpable spleens. Immunological surface-marker studies confirmed that light-chain-restricted B cells disappeared from the blood in parallel with the clearance of morphological HCs. There was no evidence of HC maturation and no increase in phenotypic NK cells. T cells were moderately reduced and the relatively greater reduction of Leu 2a+ suppressor cells resulted in increased Leu 3a+/2a+ helper/suppressor ratios in 11/17 of the patients. Early experience in the six patients who have stopped IFN suggests that, after an initial further increase in Hb and neutrophil levels, HCs gradually return with slow deterioration of haematological parameters. Interferon is now the treatment of choice for patients becoming cytopenic post-splenectomy or for patients without splenomegaly. IFN is effective first-line therapy in patients with splenomegaly, but further work is needed to establish whether the agent should replace splenectomy in such patients. Some form of maintenance or re-treatment therapy will probably be necessary.