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This study shows the long-term updated outcomes of a multicenter retrospective study which analyzed 843 patients with myelodysplastic syndrome (MDS) who underwent transplantation with an HLA-identical sibling donor with either reduced-intensity conditioning (RIC) in 213 patients, or standard myeloablative conditioning (MAC) in 630 patients. In multivariate analysis, the 13-year relapse rate was significantly increased after RIC (31% after MAC vs 48% in RIC; HR, 1.5; 95% CI, 1.1–1.9; P=0.04), but with no differences in overall survival (OS) (30% after MAC vs 27% in RIC; P=0.4) and PFS (29 vs 21%, respectively, P=0.3). Non-relapse mortality was higher in MAC (40 vs 31%; P=0.1), especially in patients older than 50 years (50 vs 33%, P<0.01). In addition, long-term follow-up confirms the importance of other variables on 13-year OS, mainly MDS risk category, disease phase, cytogenetics and receiving a high donor cell dose, irrespective of the conditioning regimen used.

Consensus Panel 5 (CP5) of the 11th International Workshop on Waldenstrom's Macroglobulinemia (IWWM-11; held in October 2022) was tasked with reviewing the current data on the coronavirus disease-2019 (COVID-19) prophylaxis and management in patients with Waldenstrom's Macroglobulinemia (WM). The key recommendations from IWWM-11 CP5 included the following: Booster vaccines for SARS-CoV-2 should be recommended to all patients with WM. Variant-specific booster vaccines, such as the bivalent vaccine for the ancestral Wuhan strain and the Omicron BA.4.5 strain, are important as novel mutants emerge and become dominant in the community. A temporary interruption in Bruton's Tyrosine Kinase-inhibitor (BTKi) or chemoimmunotherapy before vaccination might be considered. Patients under treatment with rituximab or BTK-inhibitors have lower antibody responses against SARS-CoV-2; thus, they should continue to follow preventive measures, including mask wearing and avoiding crowded places. Patients with WM are candidates for preexposure prophylaxis, if available and relevant to the dominant SARS-CoV-2 strains in a specific area. Oral antivirals should be offered to all symptomatic WM patients with mild to moderate COVID-19 regardless of vaccination, disease status or treatment, as soon as possible after the positive test and within 5 days of COVID-19-related symptom onset. Coadministration of ibrutinib or venetoclax with ritonavir should be avoided. In these patients, remdesivir offers an effective alternative. Patients with asymptomatic or oligosymptomatic COVID-19 should not interrupt treatment with a BTK inhibitor. Infection prophylaxis is essential in patients with WM and include general preventive measures, prophylaxis with antivirals and vaccination against common pathogens including SARS-CoV-2, influenza, and S. pneumoniae.

The consensus panel 2 (CP2) of the 11th International Workshop on Waldenström's macroglobulinemia (IWWM-11) has reviewed and incorporated current data to update the recommendations for treatment approaches in patients with relapsed or refractory WM (RRWM). The key recommendations from IWWM-11 CP2 include: (1) Chemoimmunotherapy (CIT) and/or a covalent Bruton tyrosine kinase (cBTKi) strategies are important options; their use should reflect the prior upfront strategy and are subject to their availability. (2) In selecting treatment, biological age, co-morbidities and fitness are important; nature of relapse, disease phenotype and WM-related complications, patient preferences and hematopoietic reserve are also critical factors while the composition of the BM disease and mutational status (MYD88, CXCR4, TP53) should also be noted. (3) The trigger for initiating treatment in RRWM should utilize knowledge of patients’ prior disease characteristics to avoid unnecessary delays. (4) Risk factors for cBTKi related toxicities (cardiovascular dysfunction, bleeding risk and concurrent medication) should be addressed when choosing cBTKi. Mutational status (MYD88, CXCR4) may influence the cBTKi efficacy, and the role of TP53 disruptions requires further study) in the event of cBTKi failure dose intensity could be up titrated subject to toxicities. Options after BTKi failure include CIT with a non-cross-reactive regimen to one previously used CIT, addition of anti-CD20 antibody to BTKi, switching to a newer cBTKi or non-covalent BTKi, proteasome inhibitors, BCL-2 inhibitors, and new anti-CD20 combinations are additional options. Clinical trial participation should be encouraged for all patients with RRWM.

Peripheral T-cell lymphoma carries a poor prognosis. To document a possible graft-versus-lymphoma effect in this setting, we evaluated the impact of immunomodulation in 63 patients with peripheral T-cell lymphoma who relapsed after allogeneic transplant in 27 SFGM-TC centers. Relapse occurred after a median of 2.8 months. Patients were then treated with non-immunologic strategies (chemotherapy, radiotherapy) and/or immune modulation (donor lymphocyte infusions (DLI) and/or discontinuation of immunosuppressive therapy). Median overall survival (OS) after relapse was 6.1 months (DLI group: 23.6 months, non-DLI group: 3.6 months). Among the 14 patients who received DLI, 9 responded and 2 had stable disease. Among the remaining 49 patients, a complete response accompanied by extensive chronic GvHD was achieved in two patients after tapering of immunosuppressive drugs. Thirty patients received radio-chemotherapy, with an overall response rate of 50%. In multivariate analysis, chronic GvHD (odds ratio: 11.25 (2.68–48.21), P=0.0009) and skin relapse (odds ratio: 4.15 (1.04–16.50), P=0.043) were associated with a better response to treatment at relapse. In a time-dependent analysis, the only factor predictive of OS was the time from transplantation to relapse (hazards ratio: 0.33 (0.17–0.640), P=0.0009). This large series provides encouraging evidence of a true GvL effect in this disease.

Analysis of the patients treated in the international, multicenter phase II PTLD‐1 trial with sequential treatment with four courses of rituximab followed by four cycles of three‐weekly CHOP suggests that tailoring treatment based on patient baseline characteristics and response to treatment at interim staging might improve outcomes of patients with posttransplant lymphoproliferative disorder even further.

Tailoring treatment by patient strata based on the risk of disease progression and treatment toxicity might improve outcomes of patients with posttransplant lymphoproliferative disorder (PTLD). We analysed the cohort of 70 patients treated in the international, multicenter phase II PTLD-1 trial (NCT01458548) to identify such factors. Of the previously published scoring systems in PTLD, the international prognostic index (IPI), the PTLD prognostic index and the Ghobrial score were predictive for overall survival. None of the scoring systems had a considerable effect on the risk for disease progression. Age and ECOG performance status were the baseline variables with the highest prognostic impact in the different scoring systems. Baseline variables not included in the scoring systems that had an impact on overall survival and disease progression were the type of transplant and the response to rituximab at interim staging. Thoracic organ transplant recipients who did not respond to rituximab monotherapy were at particularly high risk for death from disease progression with subsequent CHOP-based chemotherapy. Patients in complete remission after four courses of rituximab and patients in partial remission with low-risk IPI had a low risk of disease progression. We speculate that chemotherapy might not be necessary in this patient cohort.

The authors show that an algorithm assessing Epstein‒Barr virus viral load, and responding with decreasing immunosuppression and rituximab, is highly effective in controlling posttransplant lymphoproliferative disorder in heart transplant patients.

Up to 35% of posttransplant lymphoproliferative disorder (PTLD) cases occur within 1 year of transplantation, and over 50% are associated with Epstein–Barr virus (EBV). EBV primary infection and reactivation are PTLD predictive factors, but there is no consensus for their treatment. We conducted a prospective single-center study on 299 consecutive heart-transplant patients treated with the same immunosuppressive regimen and monitored by repetitive EBV viral-load measurements and endomyocardial biopsies to detect graft rejection. Immunosuppression was tapered on EBV reactivation with EBV viral loads >105copies/mL or primary infection. In the absence of response at 1 month or a viral load >106copies/mL, patients received one rituximab infusion (375 mg/m2). All patients responded to treatment without increased graft rejection. One primary infection case developed a possible PTLD, which completely responded to diminution of immunosuppression, and one patient, whose EBV load was unevaluable, died of respiratory complications secondary to PTLD. Compared with a historical cohort of 820 patients, PTLD incidence was decreased (p = 0.033) by a per-protocol analysis. This is the largest study on EBV primary infection/reactivation treatment, the first using rituximab following solid organ transplantation to prevent PTLD and the first to demonstrate an acceptable tolerability profile in this setting.

Le carcinome de Merkel (CCM) est un cancer de la peau agressif principalement induit par le polyomavirus à cellules de Merkel. L’avènement des inhibiteurs de point de contrôle immunitaire constitue une avancée majeure pour le traitement des patients CCM au stade métastatique inopérable. Cependant, des résistances primaires ou secondaires à ces thérapies surviennent chez 75 % des patients, soulignant le besoin de développer de nouveaux traitements. Dans ce contexte, l’objectif de cette étude est d’évaluer les performances thérapeutiques d’un nouvel anticorps couplé à une drogue (ADC) ciblant le CD56, nommé Adcitmer, dans un modèle préclinique de CCM.

In an international analysis of solid organ transplant recipients with primary central nervous system posttransplant lymphoproliferative disease, the authors find that the disease is associated with renal transplantation, typically occurs late and retains EBV positivity, and the dominant prognostic factor for survival is response to first‐line therapy.

We performed a multicenter, International analysis of solid organ transplant (SOT)-related primary central nervous system (PCNS) posttransplant lymphoproliferative disease (PTLD). Among 84 PCNS PTLD patients, median time of SOT-to-PTLD was 54 months, 79% had kidney SOT, histology was monomorphic in 83% and tumor was EBV+ in 94%. Further, 33% had deep brain involvement, 10% had CSF involvement, while none had ocular disease. Immunosuppression was reduced in 93%; additional first-line therapy included high-dose methotrexate (48%), high-dose cytarabine (33%), brain radiation (24%) and/or rituximab (44%). The overall response rate was 60%, while treatment-related mortality was 13%. With 42-month median follow-up, three-year progression-free survival (PFS) and overall survival (OS) were 32% and 43%, respectively. There was a trend on univariable analysis for improved PFS for patients who received rituximab and/or high-dose cytarabine. On multivariable Cox regression, poor performance status predicted inferior PFS (HR 2.61, 95% CI 1.32–5.17, p = 0.006), while increased LDH portended inferior OS (HR 4.16, 95% CI 1.29–13.46, p = 0.02). Moreover, lack of response to first-line therapy was the most dominant prognostic factor on multivariable analysis (HR 8.70, 95% CI 2.56–29.57, p = 0.0005). Altogether, PCNS PTLD appears to represent a distinct clinicopathologic entity within the PTLD spectrum that is associated with renal SOT, occurs late, is monomorphic and retains EBV positivity.

Published data on transplantation in Waldenstrom's macroglobulinemia (WM) are still limited. We present a retrospective multicentric study of 27 WM patients who underwent 19 autologous (median age, 54 years) and 10 allogeneic (median age, 46 years) transplantations. Median time between diagnosis and transplantation was 36 months; 66% of patients had received three or more treatment lines and 72 % had chemosensitive disease. High-dose therapy (HDT) and autologous transplantation induced a 95% response rate (RR), including 10 major responses. With a median follow-up of 18 months, 12 patients are alive at 10 to 81 months and eight are free of disease progression at 10 to 34 months. The toxic mortality rate (TRM) was 6%. Allogeneic transplantation was preceded by HDT in nine patients and by a nonmyeloablative regimen in one patient. The RR was 80%, including seven major responses. With a median follow-up of 20.5 months, six patients are alive and free of progression at 3 to 76 months. Four patients died, all from toxicity, resulting in a TRM of 40%. HDT followed by autologous transplantation is feasible in WM, even in heavily pretreated patients, with some prolonged responses but a high relapse rate. Conversely, allogeneic transplantation is more toxic, but likely induces a graft-versus-WM effect and may, for some patients, result in long-term disease control. Semin Oncol 30:291-296. © 2003 Elsevier Inc. All rights reserved.

Intensive sequential chemotherapy with mitoxantrone, 12 mg/m2/d on days 1 through 3, etoposide, 200 mg/m2/d as a continuous infusion on days 8 through 10, and cytarabine, 500 mg/m2/d as a continuous infusion on days 1 through 3 and 8 through 10 was administered to 72 patients aged less than 60 years with previously treated acute myelogenous leukemia (AML). Forty patients had refractory AML (nonresponse to prior therapy, early first relapse, or multiple relapse) and 32 had late first relapse. Sixty-one percent of patients, with a 95% confidence interval (CI) ranging from 49% to 72%, achieved complete remission (CR), including 45% (CI: 30% to 62%) of refractory patients and 81% (CI: 64% to 93%) of late first relapse patients. Twenty-nine percent of patients (CI: 19% to 41%) did not respond to therapy and 10% (CI: 4% to 19%) died from therapy-related toxicity. Median duration of aplasia was 30 days. Nonhematologic WHO grade 3 or more toxicity included sepsis (57% of patients), vomiting (10%), mucositis (35%), diarrhea (7%), skin rash (6%), and hyperbilirubinemia (11%). Postinduction therapy was attempted in 36 of 44 CR patients: 16 of them received a second course of the same regimen, 7 received maintenance chemotherapy, 4 underwent autologous bone marrow transplantation (BMT), and 9 allogeneic BMT. At a median follow-up of 20 months, 23 of the 44 complete remitters have relapsed, 1 to 14 months after achievement of CR, including 19 of 31 patients not undergoing BMT. Median survival is 7 months with 16% (CI: 4% to 28%) projected survival at 47 months. Median disease-free survival is 6 months with 21% (CI: 3% to 39%) of CR patients projected to remain disease-free at 46 months. Twenty-six percent (CI: 13% to 43%) of the evaluable patients who did not receive transplantation had inversion of CR duration. Among patients younger than 50 years, there was no significant difference in disease-free survival between patients receiving postinduction chemotherapy and those receiving BMT. We conclude that this chemotherapy regimen is highly efficient and could be used as first-line therapy in young patients with AML.

Eighteen French centers reported 133 autologous stem cell transplantations performed after first remission induction in multiple myeloma. The source of stem cell was marrow (81 cases), blood (51 cases) or marrow plus blood (1 case). The immediate outcome after transplantation was 49 (37%) complete remissions (CRs) (13 maintained, 36 achieved), 61 (46%) partial remissions, 17 failures and 5 toxic deaths. With a median follow-up of 35 months, the median remission duration was 33 months, the median time to treatment failure was 22 months. The median survival was 46 months overall, 54 months for the 103 patients responding to primary treatment, and 30 months for the 30 nonresponders. In univariate analysis, the outcome was influenced by age, Ig isotype, initial beta 2 microglobulin level, response to initial chemotherapy, plasma cell marrow involvement at the time of harvest, albumin and beta 2 microglobulin level at the time of transplantation, and CR achievement after transplantation. In multivariate analysis, the most important prognostic factor was the quality of response after transplantation. The conditioning regimen and the source of stem cell had no significant impact on immediate and long-term results. Maintenance therapy with interferon alpha did not appear to prolong remission duration or survival. Autologous stem cell transplantation is an effective consolidation for patients responding to primary treatment and a salvage therapy for some nonresponding patients. This approach has to be compared to conventional chemotherapy in prospective randomized studies. The critical impact of CR achievement on survival implies new strategies to increase the CR rate.

The macrophage-secreted 92-kDa type IV collagenase and metalloproteinases play a critical role in cell microenvironment regulation and cell movement. HIV infection of macrophages might be capable of deregulating the expression of these gelatinases. Hence, human monocyte-derived-macrophages were infected by lymphotropic HIV-1/Lai and monocytropic HIV-1/DAS isolates. Gelatinase activity and gelatinase and inhibitor (TIMP, α2M) biosyntheses were evaluated in supernatants and cellular extracts. Our data suggest that HIV infection facilitates gelatinase secretion and intracellular inhibitor retention. These argue for the increase of free proteinase that could degrade barriers, which would permit cell movement and viral dissemination into tissues.

Aim: In order to assess the influence of total-body irradiation (TBI) on the outcome and incidence of complication after bone marrow transplantation (BMT), we retrospectively analyzed our patients treated for acute leukemia and conditioned with TBI prior to BMT. Patients and Methods: Between 1980 and 1993, 326 patients referred to our department with acute non-lymphoblastic leukemia (ANLL, n=182) and acute lymphoblastic leukemia (ALL, n=144) in complete remission underwent TBI either in single dose (190 patients: 10 Gy administered to the midplane, and 8 Gy to the lungs [STBI]) or in 6 fractions (136 patients: 12 Gy on 3 consecutive days, and 9 Gy to the lungs [FTBI]) before BMT. The male-to-female ratio was 204/122 (1.67), and the median age was 30 years (mean: 30 ± 11, range: 3 to 63). The patients were analyzed according to 3 instantaneous dose rate groups: 118 patients in the LOW group (≤0.048 Gy/min), 188 in the MEDIUM group (> 0.048 and ≤ 0.09 Gy/min), and 20 in the HIGH group (> 0.09 cGy/min). Conditioning chemotherapy consisted of cyclophosphamide (CY) alone in 250 patients, CY and other drugs in 54, and 22 patients were conditioned using combinations without CY. Following TBI, allogeneic and autologous BMT were realized respectively in 118 and 208 patients. Median follow-up period was 68 months (mean: 67 ± 29, range: 24 to 130 months). Results: Five-year survival, LFS, RI and TRM rates were 42%, 40%, 47%, and 24%, respectively. Five-year LFS was 36% in the STBI and 45% in the FTBI group (p = 0.17). It was 36% in the LOW group, 42% in the MEDIUM group, and 30% in the HIGH group (p > 0.05). Five-year RI was 50% in STBI, 43% in FTBI, 55% in LOW, 41% in MEDIUM, and 44% in HIGH groups (STBI vs. FTBI, p = 0.48; LOW vs. MEDIUM, p = 0.03: MEDIUM vs. HIGH, p = 0.68). TRM was not influenced significantly by the different TBI techniques. When analyzing separately the influence of fractionation and the instantaneous dose rate either in ANLL or ALL patients, no difference in terms of survival and LFS was observed. Fractionation did not influence the 5-year RI both in ANLL and ALL patients. However, among the patients with ANLL, 5-year RI was significantly higher (58%) in the LOW group than the MEDIUM group (31%, p = 0.001), whereas instantaneous dose rate did not significantly influence the RI in ALL patients. The 5-year TRM rate was significantly higher in allogeneic BMT group both in ANLL (37%) and ALL (37%) patients than those treated by autologous BMT (ANLL: 15%, ALL: 18%: p = 0.002 and 0.02, respectively). The 5-year estimated interstitial pneumonitis (IP) and cataract incidence rates were 22% and 19%, respectively, in all patients. IP incidence seemed to be higher in the HIGH group (46%) than the MEDIUM (19%, p = 0.05) or LOW (25%, p = 0.15) groups. Furthermore, cataract incidence was significantly influenced by fractionation (STBI vs. FTBI, 29% vs. 9%; p = 0.003) and instantaneous dose rate (LOW vs. MEDIUM vs. HIGH, 0% vs. 27% vs. 33%; p &lt; 0.0001). Multivariate analyses revealed that the best factors influencing the survival were 1st CR (p = 0.0007), age ≤ 40 years (p = 0.003), and BMT after 1985 (p = 0.008). The RI was influenced independently only by the remission status (p = 0.0002). On the other hand, the TRM rate was lower in patients who did not experience graft-vs.-host disease (GvHD, p &lt; 0.0001), and in those treated after 1985 (p = 0.0005). GvHD was the only independent factor involved in the development of IP (p = 0.01). When considering the cataract incidence, the only independent factor was the instantaneous dose rate (p = 0.0008). Conclusion: The outcome of BMT patients conditioned with TBI for acute leukemia was not significantly influenced by the TBI technique, and TRM seemed to be lower in patients treated after 1985. On the other hand, cataract incidence was significantly influenced by the instantaneous dose rate.

We report a new inhibitory activity of CD8+CD57+ peripheral blood lymphocytes from allo-bone marrow transplant patients. Positively selected CD8+CD57+ lymphocytes act as potent inhibitors of allospecific cytolytic T lymphocyte and lymphokine activated killer cell cytolytic activities. These suppressor cells are mature T cells expressing the CD2, 5, 7, CD3-TcR alpha beta complex, and lack natural killer cell markers as well as cytolytic function. Their inhibitory activity on both cytolytic processes and T-cell proliferation is mediated by a non- antigen-specific soluble factor released by CD8+CD57+ cells in culture supernatants. Preliminary characterization suggests that the CD8+CD57+ cells' inhibitory activity is mediated by a low molecular weight, glycosylated factor as indicated by its less than 1S coefficient of sedimentation and its binding to concanavalin A lectin.

Posttransplant lymphoproliferative disorders (PTLD), developing after immunosuppressive therapy in human organ-graft recipients, are, for the most part, Epstein-Barr virus-induced. The earlier the diagnosis is made, the greater the potential for reversibility. The chest radiographs and CT scans of 10 patients with thoracic locations of PTLD were reviewed. Mediastinal (n = 3) and hilar adenopathy (n = 2), pulmonary nodules (n = 8), and pleural thickening or effusion (n = 4) were encountered. The incidence of partial resolution with clinical remission (n = 4) appears to be noteworthy, and in all likelihood is related to the extensive necrosis (n = 5) that is frequently seen. Slow regression, transitory deterioration in one case, and localization only on the graft side in two cases, were observed. These morphological and evolutionary peculiarities must be known in order to optimize the diagnosis, and thus the prognosis, of these very original disorders.

Major expansions of CD8^hi+CD57⁺ T lymphocytes frequently occur during human immunodeficiency virus (HIV) infection and after transplantation. To investigate mechanisms of such cell expansion, we compared the activation and functional status of CD8^hi+CD57⁺ and CD57^- peripheral blood lymphocytes (PBL) from normal, bone marrow transplantation (BMT) and HIV⁺ donor. The CD8^hi+CD57⁺PBL from BMT and HIV⁺ donors preferentially displayed CD38 and HLA-DR activation markers without correlation between CD8^hi+CD57⁺ percentages and HIV load, the CD45RA⁺ isoform in all ex vivo conditions but acquired CD45RO after in vitro expansion, CD11b and CD11c in BMT and HIV⁺ donors but decreased expression of CD62-L, VLA-2 and VLA-6. The CD8^hi+CD57⁺ cells were positive for perforin and granzyme B and spontaneously mediated cytolytic activity in a CD3-redirected assay. In contrast the inhibitor of cytolytic functions (ICF) produced by CD8^hi+CD57⁺ cells down-modulated the CD3-redirected cytolytic activity but only at low levels of CD3 cross-linking. While CD3-triggering induced a low, if any, short-term proliferation of CD8⁺CD57⁺ cells, this subset could be amplified after long-term stimulation either with mitogens or with HIV antigens, thereby enriched in HIV-specific T cells producing tumor necrosis factor-α. Altogether these data suggest that CD8^hi+CD57⁺ cells represent a terminal differentiation state of activated effector cytotoxic T lymphocytes which are enriched in antigen-specific T cells and down-modulate their own cytolytic potential, thus participating in a negative control of effector cell functions during persistent viral infections or transplantations.

Major expansions of CD8hi+CD57+ T lymphocytes frequently occur during human immunodeficiency virus (HIV) infection and after transplantation. To investigate mechanisms of such cell expansion, we compared the activation and functional status of CD8hi+CD57+ and CD57-peripheral blood lymphocytes (PBL) from normal, bone marrow transplantation (BMT) and HIV+ donors. The CD8hi+CD57+ PBL from BMT and HIV+ donors preferentially displayed CD38 and HLA-DR activation markers without correlation between CD8hi+CD57+ percentages and HIV load, the CD45RA+ isoform in all ex vivo conditions but acquired CD45RO after in vitro expansion, CD11b and CD11c in BMT and HIV+ donors but decreased expression of CD62-L, VLA-2 and VLA-6. The CD8hi+CD57+ cells were positive for perforin and granzyme B and spontaneously mediated cytolytic activity in a CD3-redirected assay. In contrast the inhibitor of cytolytic functions (ICF) produced by CD8hi+CD57+ cells down-modulated the CD3-redirected cytolytic activity but only at low levels of CD3 cross-linking. While CD3-triggering induced a low, if any, short-term proliferation of CD8+CD57+ cells, this subset could be amplified after long-term stimulation either with mitogens or with HIV antigens, thereby enriched in HIV-specific T cells producing tumor necrosis factor-alpha. Altogether these data suggest that CD8hi+CD57+ cells represent a terminal differentiation state of activated effector cytotoxic T lymphocytes which are enriched in antigen-specific T cells and down-modulate their own cytolytic potential, thus participating in a negative control of effector cell functions during persistent viral infections or transplantations.

T-cell prolymphocytic leukemia (T-PLL), a rare form of mature T-cell leukemias, and ataxia telangiectasia clonal proliferation, a related condition occurring in patients suffering from ataxia telangiectasia, have been associated to translocations involving the 14q32.1 or Xq28 regions, where are located the TCL1 and MTCP1 putative oncogenes, respectively. The MTCP1 gene is involved in the t(X;14)(q28;q11) translocation associated with these T-cell proliferations. Alternative splicing generates type A and B transcripts that potentially encode two entirely distinct proteins; type A transcripts code for a small mitochondrial protein, p8MTCP1, and type B transcripts, containing an additional open reading frame, may code for 107 amino-acid protein, p13MTCP1. The recently cloned TCL1 gene, also involved in translocations and inversions associated with T-cell proliferations, codes for a 14-kD protein that displays significant homology with p13MTCP1. We have generated rabbit antisera against this putative p13MTCP1 protein and screened for expression of p13MTCP1 normal lymphoid tissues and 33 cases of immature and mature lymphoid T-cell proliferations using a sensitive Western blot assay. We also investigated the MTCP1 locus configuration by Southern blot analysis. The p13MTCP1 protein was detected in the three T-cell proliferations with MTCP1 rearrangements because of t(X;14) translocations, but neither in normal resting and activated lymphocytes nor in the other T- cell leukemias. Our data support the hypothesis that p13MTCP1 and p14TCL1 form a new protein family that plays a key role in the pathogenesis of T-PLL and related conditions.

We report on 71 consecutive patients with de novo myelodysplastic syndromes referred to physicians belonging to the Societe francaise de greffe de moelle from 1982 through 1991 and transplanted with marrow from HLA-identical siblings. There were 16 cases of refractory anemia, 27 of refractory anemia with excess of blast cells, and 28 of refractory anemia with excess of blast cells in transformation. Seventeen patients had received cytoreductive chemotherapy before the graft. The disease progressed in 17 patients between diagnosis and grafting. Twenty-three patients are alive with a median follow-up of 6 years, whereas 24 died from relapse and 24 from transplant-related complications. Kaplan-Meier estimates of event-free survival, relapse and transplant-related mortality at 7 years were 32%, 48%, and 39%, respectively. The log-rank test and Cox's model revealed better outcome among young patients, patients in an early stage of the French-American- British (FAB) classification or with a low percentage of marrow blasts before transplantation, patients who did not undergo cytoreductive chemotherapy before transplantation, and patients conditioned with total body irradiation and cyclophosphamide. The high rate of relapse in advanced FAB stages has led us to graft patients earlier in the course of the disease, and we are currently conducting a multicenter, randomized study to determine the value of intensive chemotherapy before grafting in patients with an excess of marrow blasts.

A major expansion of CD8+57+ lymphocytes expressing an alpha-beta T- cell receptor (TCR) is frequent after bone marrow transplantation (BMT). We examined the clonality of the TCR beta gene repertoire in these expanded CD8+57+ cells after allogeneic or autologous BMT. We performed a polymerase chain reaction (PCR) analysis of the V beta chain usage in CD8+57+ cells purified from nine BMT recipients with a series of oligonucleotides specific for 20 V beta gene families. PCR products from selected TCR beta gene rearrangements were sequenced. The CD8+57+ cells from eight of nine patients used a restricted set of V beta families, with a marked predominance of two to three V beta gene families per patient, whereas the control autologous CD57- subset expressed the whole 20 V beta families. A direct sequencing analysis confirmed the V beta 16 and V beta 17 clonality in six patients, showing a striking homology in the CDR3 sequences of the V beta 16 products. The CD8+57+ cells, but not the CD57- cells, displayed an oligoclonal pattern of TCR rearrangements as shown by PCR analysis of TCR gamma gene rearrangements. Such an oligoclonal expansion of CD8+57+ cells, using a restricted set of the V beta gene families, may result from a specific TCR stimulation of a limited number of T-cell clones in BMT recipients.

Sixty-three patients with high tumor mass multiple myeloma were treated with high-dose chemotherapy and total body irradiation supported by autologous blood stem cell transplantation. After high-dose therapy, they were monitored for a median of 44 months. Seven patients died early from toxicity. All the other patients, including those whose disease was resistant to previous therapies, showed a tumor mass reduction. At 6 months postengraftment, 40 (71%) of the surviving patients had minimal residual disease and 11 (20%) were in apparent complete remission. During follow-up, 25 out of the 63 (39%) patients relapsed and 16 of these died; 31 (49%) had a sustained remission. The median overall and event-free survival times after transplantation were 59 and 43 months, respectively. The initial serum beta 2-microglobulin value (> or < 2.8 mg/L) and length of previous therapy (> or < 6 courses of chemotherapy) were the only significant prognostic factors. In all surviving patients, blood stem cell autograft provided satisfactory and sustained haematopoietic reconstitution most often within 15 days. High dose chemoradiotherapy followed by autologous blood stem cell transplantation is thus an important therapeutic option for young patients with aggressive multiple myeloma.

In order to assess the value of MRI in the diagnosis and follow-up of intra-ocular lymphoma, a rare form of primary non-Hodgkin's lymphoma of the central nervous system, we retrospectively reviewed fifteen patients.All patients had ophthalmic investigations and 13 underwent ocular sampling. MR examinations of the brain and globes were performed in all cases and five patients underwent stereotactic brain biopsy. Six patients were treated with chemotherapy and/or radiotherapy, and nine with high-dose chemotherapy, followed by autologous bone marrow transplantation in five cases. MR follow-up was available in all cases.All 15 patients had chronic uveitis which preceded the diagnosis and abnormal funduscopic findings. Three had a mild or severe neurologic deficit. Initial MRI showed brain lymphoma lesions in six cases and a choroido-retinal tumour in one. MR brain lesions were multiple in four cases. They appeared as contrast-enhanced infiltrating areas (n=11) or expansive masses (n=3); two lesions appeared as infiltrating high-signal T2 areas but were unenhanced on T1 with GdDTPA.The diagnosis was based on vitrectomy in 11 cases and on stereotactic brain biopsy in four. Of the twelve lumbar punctures which were performed one was positive. Contrast enhancement disappeared during treatment in all cases, but isolated signal abnormalities persisted. The long-term outcome of such lesions in patients with an intact blood-brain barrier is not yet known. Ocular relapses occurred in 14 patients and CNS recurrences in four. Three patients died from CNS failure (n=1) or relapse (n=2), five are alive in partial remission, five are in complete remission and two died in remission from other causes. Follow-up ranges from 12 to 78 months (median 36 months).MRI usually failed to detect intra-ocular lesions but identified clinically occult brain lesions and served to guide stereotactic brain biopsy when other samples were negative. MRI is the most sensitive follow-up method during treatment, even when the blood-brain barrier is intact.

ABSTRACTEchinocandin drugs are widely used for the treatment of candidemia. Resistance is considered rare, and only a few cases of breakthrough candidiasis in patients receiving echinocandin have been reported worldwide. We report here for the first time a Candida kefyrisolate that acquired echinocandin resistance very rapidly after the initiation of caspofungin treatment for candidemia. We characterized the FKSgene mutation responsible for the resistance via the comparison of isolates sampled before and during treatment.

Le carcinome à cellules de Merkel (CCM) est un cancer cutané neuroendocrine rare mais agressif. Les inhibiteurs de points de contrôle immunitaire ont révolutionné le traitement des patients atteints de CCM de stade IV, la moitié des cas ne répondent pas à cette thérapie. L’expression du CD56 a été observée dans 66 % des CCM confirmant la pertinence de cette cible thérapeutique. Le but de cette étude est d’évaluer les performances thérapeutiques d’un nouvel immunoconjugué ciblant le CD56 dans un model préclinique de CCM. La reconnaissance spécifique du CD56 et l’internalisation de l’immunoconjugué a été démontrée. L’évaluation in vitro a confirmé un effet cytotoxique de l’immunoconjugué sur les lignées de CCM (IC50 comprise entre 1 et 10nM) et l’effet sur le cycle cellulaire a été démontré. Pour finir, l’impact sur la croissance tumorale a été mis en évidence dans un modèle de xénogreffe de CCM.Pour conclure, l’immunoconjugué présente une cytotoxicité spécifique dans un modèle préclinique de CCM. Cette molécule est une option thérapeutique prometteuse pour les patients atteints de CCM en échec de traitement ou en combinaison avec les inhibiteurs de points de contrôle immunitaire.

Arterial and venous thromboembolic events represent frequent and life-threatening complications in homocystinuric patients and are responsible for their early deaths. Reduced levels of antithrombin III activity in homocystinuric patients have recently been reported. So, high plasma L-homocysteine concentration could play a role in the low antithrombin III activity level. In the present study, we have studied the relationship between total plasma homocysteine and inhibitors of blood coagulation levels in 16 patients with malignancies who received bone marrow grafts. There were no correlations between homocysteine values and inhibitors of blood coagulation levels. So, while the defect in amino acid transsulfuration that is responsible for homocystinuria can directly affect the synthesis or activity of some clotting factors, homocysteine concentration is not responsible for this effect.

BackgroundChronic lymphocytic leukaemia and mantle cell lymphoma have a new standard of care: ibrutinib (metabolised by CYP3A4/5 and P-glycoprotein inhibitor). Cardiovascular (CV) adverse events are characterised by atrial fibrillation (AF) (5%–13.8%), bleeding event (BE) (grade 3 or 4 about 3%–4%) and hypertension. CV pre-treatment evaluation is not required in the ibrutinib summary of product characteristics.PurposeEvaluate whether the CV risks are considered regarding the prescription of ibrutinib and measure cardiovascular adverse event occurence during treatment.Material and methodsA retrospective analyse was conducted including patients with ibrutinib initiation in our Haematology Department from May 2014 to July 2017. A demographic, clinical and biological database including adverse events, CV evaluation and potential drug interactions was constituted consulting all the medical records. The incidence of AF and BE and the CHA2DS2-VASc score were calculated.ResultsFifty-fivemedical records were analysed. Thirty-six patients (65%) had at least one CV risk factor and 14 patients (25%) had at least one initial cardiac examination (ECG/Holter, echocardiography, cardiology consultation). Twenty-one patients (38%) had CV monitoring during their treatment. Four patients developed AF (1 to 7 months after starting the treatment) and were treated with anti-arrhythmics and anti-coagulants (one patient with CHA2DS2-VASc<2). Among these, three patients had initial cardiologic examination because of their CV risk factor and one had no cardiac examination. Twenty-four patients (44%) had at least one BE, five of these were under anti-platelet medication. Three patients developed hypertension and one had myocardial infarction. Drug-drug interactions were detected in four patients who had BE and one that developed AF (implicating verapamil, irbesartan and posaconazole).ConclusionOur results show that cardiac pre-treatment examinations are rarely performed (25%) despite our patients’ CV risk factors. With 7.2% of AF, this risk is not negligible considering the limited cohort. A part of serious BE could have been prevented, as concomitant drugs, especially CYP3A4 inhibitor, seem to play a role in CV adverse event occurrence. As a result of drug interactions and CV consequences, which can lead to serious outcomes, a multidisciplinary consultation including a haematologist, cardiologist and pharmacist, should be established at the initiation and during treatment by ibrutinib.References and/or Acknowledgements1. Byrd JC, et al. 2014.2. Brown JR, et al. 2017.No conflict of interest

La GVH aiguë de type Lyell est difficile à distinguer du Lyell médicamenteux. À partir de l’analyse de données d’une cohorte avec application des scores d’imputabilité médicamenteuse (ALDEN) et pronostique (SCORTEN), le but de cette étude était de dégager des paramètres permettant d’orienter vers GVH-Lyell versusLyell.