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Background: The phase 3 GIMEMA-MMY-3006 trial, which compared bortezomib, thalidomide, and dexamethasone (VTD) combination therapy with thalidomide and dexamethasone (TD) as induction therapy before and consolidation therapy after double autologous haematopoietic stem-cell transplantation (HSCT) for newly diagnosed multiple myeloma, showed the superiority of the triplet regimen over the doublet in terms of increased complete response rate and improved progression-free survival. We report the results from the final analysis of the study. Methods: In this randomised, open-label, phase 3 study, patients aged 18–65 years with previously untreated symptomatic multiple myeloma and a Karnofsky Performance Status of 60% or higher were enrolled at 73 centres in Italy. Patients were randomised (1:1) by a web-based system to receive three 21-day cycles of thalidomide (100 mg daily orally for the first 14 days and 200 mg daily thereafter) plus dexamethasone (total 320 mg per cycle; 40 mg on days 1–2, 4–5, 8–9, and 11–12 in the VTD regimen, and 40 mg on days 1–4 and 9–12 in the TD regimen), either alone (TD group) or with bortezomib (1·3 mg/m2 intravenously on days 1, 4, 8, and 11; VTD group). After double autologous HSCT, patients received two 35-day cycles of either the VTD or TD regimen, according to random assignment, as consolidation therapy. The primary outcome was the rate of complete response and near complete response after induction (already reported). In this updated analysis we assessed long-term progression-free survival and overall survival (secondary endpoints of the study) with an extended 10-year median follow-up, and analysed the variables influencing survival. Analysis was by intention to treat. The study is registered with ClinicalTrials.gov, NCT01134484. Findings: Between May 10, 2006, and April 30, 2008, 480 patients were enrolled and randomly assigned to receive VTD (241 patients) or TD (239 patients). Six patients withdrew consent before start of treatment. 236 (99 [42%] women) in the VTD group and 238 (102 [43%] women) in the TD group were included in the intention-to-treat analysis. The data cutoff date for this analysis was May 31, 2018. Median follow-up for surviving patients was 124·1 months (IQR 117·2–131·7). The 10-year progression-free survival estimate for patients in the VTD group was 34% (95% CI 28–41) compared with 17% (13–23) for the TD group (hazard ratio [HR] 0·62 [95% CI 0·50–0·77]; p

Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by the expansion of a P/G-A mutated hematopoietic stem cell. An immune-mediated origin has been suggested for this disease. Because HLA genes represent a susceptibility factor for autoimmunity, we investigated HLA genotype in 42 Italian PNH patients compared with 301 control subjects of the same ethnic origin. A significantly increased frequency of the HLA class I alleles A*0201 (p < 0.05), B*1402 (p < 0.001), and Cw*0802 (p < 0.005), and of the HLA class II DRB1*1501 (p < 0.01) with the Linked DQB1*0602 (p

We are now left with the third paradox unsolved: namely, how can a hematopoietic PNH clone expand? On one hand, one might surmise that such a clone has an intrinsic growth advantage; i.e., it is aggressive, just like a leukemic clone. However, several lines of evidence militate against this notion. First, in patients with PNH, PNH clone(s) can co-exist for years or decades with apparently normal hematopoietic cells: thus, the PNH clone, having expanded, does not take over (as a leukemic clone would do). Second, patients who have had PNH for years may sometimes recover spontaneously; but the PNH clone is still present years after this self-cure has occurred (Hillmen et al. 1995xHillmen, P, Lewis, S.M, Bessler, M, Luzzatto, L, and Dacie, J.V. N. Engl. J. Med. 1995; 333: 1253–1258Crossref | PubMed | Scopus (493)See all ReferencesHillmen et al. 1995). We infer that, when conditions change, the PNH clone not only stops expanding, but may actually regress in relation to non-PNH hematopoietic cells. Third, in chimeric mice produced by knocking out PIG-A in embryonic stem cells, the resulting PNH red blood cells, far from prospering, tend to disappear rather quickly after birth (Kawagoe et al. 1996xKawagoe, K, Kitamura, D, Okabe, M, Taniuchi, I, Ikawa, M, Watanabe, T, Kinoshita, T, and Takeda, J. Blood. 1996; 87: 3600–3606PubMedSee all ReferencesKawagoe et al. 1996).The rate of expansion of a PNH clone might be influenced by the existence of other as yet unknown genetic changes in addition to PIG-A mutations. At any rate, the facts we have listed, seen in the context of the close relationship between PNH ad AA, have led to the hypothesis that PNH cells might have a conditional growth or survival advantage in an environment which is injurious to hematopoietic cells through a GPI-mediated mechanism (Rotoli and Luzzatto 1989xRotoli, B and Luzzatto, L. Bailliere's Clin. Haematol. 1989; 2: 113–138Abstract | Full Text PDF | PubMed | Scopus (110)See all ReferencesRotoli and Luzzatto 1989; see Figure 2Figure 2). For instance, if the damage was caused by autoreactive T cells or by natural killer cells, as has been suggested to be the case in AA (Rosenfeld and Young 1991xRosenfeld, S.J and Young, N.S. Blood Rev. 1991; 5: 71–77Abstract | Full Text PDF | PubMed | Scopus (1)See all ReferencesRosenfeld and Young 1991), we could speculate that this happens by virtue of these cells triggering an apoptotic pathway by interacting with a GPI-linked molecule normally present on the surface of hematopoietic stem cells. Under this hypothesis it is obvious that PNH cells, being invulnerable to this special kind of injury, would be at an advantage as long as the offending T cells or natural killer cells are present; whereas they would revert to being neutral or even at a disadvantage once such offending cells are no longer present. In this respect, one cannot help noting that much of the biochemical work on GPI-linked molecules has sprung from the study of the variable surface glycoprotein (VSG) of trypanosomes (14xMasterson, W.J, Doering, T.L, Hart, G.W, and Englund, P.T. Cell. 1989; 56: 793–800Abstract | Full Text PDF | PubMed | Scopus (160)See all References, 8xFerguson, M.A, Homans, S.W, Dwek, R.A, and Rademacher, T.W. Science. 1988; 239: 753–759Crossref | PubMedSee all References). In that instance, the functional role of the GPI anchor seems clearly to consist of making it easy for the parasite to shed its VSG coat and thus evade immune attack by host antibodies (Cross 1990xCross, G.A.M. Annu. Rev. Immunol. 1990; 8: 83–110Crossref | PubMedSee all ReferencesCross 1990). In PNH cells there may be an advantage for the cell in not having GPI-linked molecules on its surface, in order to evade a different sort of immune attack. Thus, PNH and AA might in fact give us a new handle for elucidating the functional role of GPI-linked molecules in mammalian cells which, in spite of a wealth of recent information (see in Cardoso-de-Almeida et al. 1994xCardoso-de-Almeida, M.L, Mendonca-Previato, L, Ramalho-Pinto, F.J, da Silva, A.M, and Travassos, L.R. J. Med. Biol. Res. 1994; 27: 115–562PubMedSee all ReferencesCardoso-de-Almeida et al. 1994), has remained rather elusive. In the meantime, we should consider that a PIG-A mutation may be a blessing in disguise, because it enables a patient who otherwise would have AA to survive, although at the price of having PNH (Luzzatto and Bessler 1996xLuzzatto, L and Bessler, M. Curr. Opin. Hemat. 1996; 3: 101–110Crossref | PubMedSee all ReferencesLuzzatto and Bessler 1996).Figure 2A Model for the Pathogenesis of PNHIn this cartoon the dark red circles are normal hematopoietic stem cells, on which the green prongs represent GPI-linked surface molecules. The pink circles are stem cells in which a PIG-A mutation prevents insertion in the membrane of any of the protein molecules that are normally GPI-linked. A black bracket symbolizes a hypothetical molecule which, upon binding to a GPI-linked protein, can cause damage to the stem cell. Panel 1 represents a normal bone marrow, in which an occasional cell with a PIG-A mutation may exist. In Panel 2, normal cells are suffering damage, whereas cells lacking GPI-linked molecules (i.e., PNH cells) are not affected and may grow. At this stage the patient may manifest symptoms of bone marrow failure (AA), and the PNH clone would be picked up by appropriate tests. In Panel 3, as a result of selection, the majority of stem cells are PNH cells. At this stage the patient has overt PNH. If the PNH clone had not grown, by this time the patient would have instead severe AA. Based on Rotoli and Luzzatto 1989xRotoli, B and Luzzatto, L. Bailliere's Clin. Haematol. 1989; 2: 113–138Abstract | Full Text PDF | PubMed | Scopus (110)See all ReferencesRotoli and Luzzatto 1989.View Large Image | View Hi-Res Image | Download PowerPoint SlideIn conclusion, PNH shares with leukemias several features of clonal disorders and, since it can evolve to leukemia, it may still teach us something about leukemogenesis. On the other hand, whereas leukemic cell proliferation is, by definition, unconditionally aggressive, PNH cell proliferation is conditioned by the environment. In this respect PNH can be also seen as a remarkable exception to the golden rule that in every disease process, no matter how protean, we ought to be able to pinpoint a single primary agent. It seems instead that two different causes are required to give the clinical phenotype of PNH: one (A) that we now fully understand, namely a somatic mutation in the PIG-A gene; and one (B) that we can only define as a specific mode of bone marrow failure. The implications of this by now testable model are that A alone would produce PNH clones of no clinical significance, which may be lurking in normal people, whereas B alone would give, of course, the clinical picture of AA. It is only when A and B co-exist in the same person that we see the clinical phenotype of PNH.

Summary A review of recent information on the abnormalities of the blood cell membrane in paroxysmal nocturnal haemoglobinuria (PNH) is presented, with a detailed analysis of biochemical and flow cytometry findings. The complex patterns observed in the various cell lineages of which the PNH clone consists are described, and a simplified monoclonal antibody panel is defined for diagnostic purposes. Available data on in vitro culture of progenitor cells and on the recent establishment of PNH cell lines are summarized. Finally, we discuss speculative hypotheses on the growth advantage of the PNH clone.

255 patients with acute non-lymphoid leukaemia (ANLL), observed between October 1984 and June 1987, entered a chemotherapy regimen consisting of induction therapy with cytarabine in combination with idarubicin (IDA/ARA) or daunorubicin (DNR/ARA), followed by consolidation with four courses of IDA+ARA plus 6-thioguanine (6-TG) or DNR+ARA+6-TG and a 6 month maintenance therapy with 6-TG and ARA. The median age was 62 years (range 55–78 years) and 33 were aged more than 70 years. The treatment groups were comparable for median age, FAB type, performance status and initial blood counts. 249 patients were randomised, 124 to the IDA/ARA arm and 125 to the DNR/ARA arm. Complete remission was achieved in 50 patients (40%) on the IDA/ARA treatment program and 49 patients (39%) on DNR/ARA. No definite differences were found between patients receiving IDA/ARA and those treated with DNR/ARA as far as complete response (CR), overall survival, failure free and relapse free survival are concerned. 74% of the complete responders in the IDA/ARA arm and 51% in the DNR/ARA arm achieved CR after a single course of treatment. Resistant leukaemia was observed in 13.7% of the patients in the IDA/ARA arm and in 31.2% in the DNR/ARA one, whereas hypoplastic death occurred in 29% and 14.4%, respectively. In conclusion, our data failed to show any advantage of idarubicin over daunorubicin even though there is some evidence that IDA, despite the higher toxicity, is more rapid in eradicating leukaemia as proved by the higher CR rate obtained after one course of induction.

The binding of thrombin to human platelets is markedly affected by buffer conductivity. As conductivity is decreased from 13.5 mS to 3 mS using buffers containing monovalent anions, thrombin binding increases; below this value, thrombin binding decreases. For the multivalent anion containing solutions studied, including EDTA, phosphate, and citrate buffers, as conductivity falls thrombin binding increases to a maximum level at 1.5 mS and thereafter declines. Addition of thrombin to anti-coagulated blood does not result in significant binding to platelets due to the high non-optimal conductivity of plasma, the anticoagulant solution, and various plasma inhibitors.