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Graft-versus-host disease (GVHD) is a potentially serious complication ofallogeneic hematopoietic stem cell transplantation (HSCT). Graft-contaminating T cells (donor T cells) arecrucial for the development ofGVHD since they are able to react against the recipient's antigens. In this study we aim toevaluatethepotentialassociation between the IVS3 + 17 T/C gene variation in the CD28 molecule, a T cells costimulatory factor, and the GVHD occurrence in a Tunisian group of recipients of allo-HSCTs. Results show that there is an association between the presence of this polymorphism and the occurrence of grades II-IV acute GVHD (OR: 2.470, I.C: 1.027-5.938, p = 0.043). As for the chronic GVHD, it seems that the studied gene variation has no impact on the occurrence of this complication, which appeared likely to be affected by the HSCT graft source (PBSC: peripheral blood stem cells) (OR: 5.141, I.C: 1.590-16.620, p = 0.006). Based on these data, we believe that the CD28 IVS3 + 17 T/C polymorphism is a significant factor in the pathogenesis of acute GVHD.
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BACKGROUND: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment for acquired aplastic anemia (acquired AA) in young patients. The objective of the study was to compare patient outcomes after Cyclophosphamide and horse antithymocyte globulin (Cy-hATG) versus Fludarabine-cyclophosphamide and rabbit ATG (Flu-Cy-rATG) as part of conditioning regimen in allo-HSCT for acquired AA. RESEARCH DESIGN AND METHODS: Descriptive retrospective study conducted on patients with acquired AA who received allo-HSCT from HLA-matched sibling donors between January 2008 and August 2022 after conditioning regimen with Cy-hATG or Flu-Cy-rATG. RESULTS: A total of 121 patients were enrolled. Cumulative incidence of graft failure was 11.2% in Cy-hATG and 5.3% Flu-Cy-rATG group. There were no significant differences between the two groups in terms of acute GVHD, chronic GVHD, and transplant related mortality. Flu-Cy-rATG group was associated with significantly higher CMV and EBV reactivation(s) compared to Cy-hATG group (p = 0.008 and 0.035, respectively). After a median follow-up of 58 months, estimated overall survival, event-free survival, and graft rejection-free survival were not statistically different between the two groups. CONCLUSIONS: In high-risk population, Flu-Cy-rATG is associated with comparable outcomes to Cy-hATG in allo-HSCT from MSD. However, it seems to be associated with significant risk of viral infections.
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Anemia Aplásica , Suero Antilinfocítico , Ciclofosfamida , Trasplante de Células Madre Hematopoyéticas , Hermanos , Acondicionamiento Pretrasplante , Vidarabina , Humanos , Anemia Aplásica/terapia , Anemia Aplásica/mortalidad , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/métodos , Suero Antilinfocítico/uso terapéutico , Ciclofosfamida/uso terapéutico , Acondicionamiento Pretrasplante/métodos , Masculino , Femenino , Vidarabina/análogos & derivados , Vidarabina/uso terapéutico , Vidarabina/administración & dosificación , Animales , Adolescente , Estudios Retrospectivos , Adulto , Caballos , Conejos , Niño , Trasplante Homólogo , Donantes de Tejidos , Adulto Joven , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/prevención & control , Preescolar , Persona de Mediana EdadRESUMEN
BACKGROUND: Allogeneic hematopoietic stem cell transplantation (ASCT) induces acquired immunodeficiency, potentially altering vaccine response. Herein, we aimed to explore the clinical tolerance and the humoral and cellular immune responses following anti-SARS-CoV-2 vaccination in ASCT recipients. METHODS: A prospective, non-randomized, controlled study that involved 43 ASCT subjects and 31 healthy controls. Humoral response was investigated using the Elecsys® test anti-SARS-CoV-2. Cellular response was assessed using the QFN® SARS-CoV-2 test. The lymphocyte cytokine profile was tested using the LEGENDplex™ HU Th Cytokine Panel Kit (12-plex). RESULTS: Adverse effects (AE) were observed in 69% of patients, encompassing pain at the injection site, fever, asthenia, or headaches. Controls presented more side effects like pain in the injection site and asthenia with no difference in the overall AE frequency. Both groups exhibited robust humoral and cellular responses. Only the vaccine transplant delay impacted the humoral response alongside a previous SARS-CoV-2 infection. Noteworthily, controls displayed a Th1 cytokine profile, while patients showed a mixed Th1/Th2 profile. CONCLUSIONS: Pfizer-BioNTech® anti-SARS-CoV-2 vaccination is well tolerated in ASCT patients, inducing robust humoral and cellular responses. Further exploration is warranted to understand the impact of a mixed cytokine profile in ASCT patients.
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Bortezomib (Vel)- Melphalan 200 mg/m2 (Mel200) (Vel-Mel) has been utilised to intensify conditioning in autologous hematopoietic stem cell transplantation (AHCT) for multiple myeloma (MM). This EBMT registry-based study compared Vel-Mel with Mel200 during upfront AHCT. Between 2010 and 2017, MM patients who received Vel-Mel (n = 292) conditioning were compared with 4,096 Mel200 patients in the same 58 centres. Pre-AHCT, compared to Mel200 patients, Vel-Mel patients had similar International Staging System (ISS) scores and cytogenetic risk profiles; a similar proportion had received bortezomib-based induction (85% and 87.3%, respectively) though they were younger with a better performance status. Vel-Mel patients were more likely to achieve CR post-induction (40.6% vs 20.3%, p < 0.001) and by day 100 of AHCT (CR/VGPR: 70.2 % vs. 57.2%, p < 0.001). There was no difference in 3-year PFS (49% vs 46%, p = 0.06) or early post-AHCT mortality. In multivariable analysis, Vel-Mel associated with inferior PFS (HR: 1.69 (1.27-2.25, p < 0.001) and OS (HR:1.46 (1.14-1.86,p = 0.002), similar to negative effects on PFS of advanced ISS (HR:1.56 (1.33-1.83, p < 0.001), high-risk cytogenetics (HR:1.43(1.18-1.74, p < 0.001) and poor post-induction response(<=PR)(HR: 1.43(1.25-1.62, p < 0.001) Overall, despite superior pre- and post-AHCT responses, there was no improvement in PFS or OS following Vel-Mel. This data supports the findings of the smaller prospective IFM study.
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Trasplante de Células Madre Hematopoyéticas , Mieloma Múltiple , Humanos , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/diagnóstico , Bortezomib/farmacología , Bortezomib/uso terapéutico , Melfalán/farmacología , Melfalán/uso terapéutico , Estudios Prospectivos , Trasplante Autólogo , Protocolos de Quimioterapia Combinada AntineoplásicaRESUMEN
Introduction: New procedures and diagnostic tests in hematopoietic stem cell transplantation (HSCT) are associated with a significant increase in costs. The last cost estimate of allogeneic HSCT done in Tunisia was in 1996 and concerned only direct medical costs. Therefore, an updated cost analysis is needed. Objective: Analysis of direct costs during the first-year post-allogeneic HSCT in two groups of patients: Bone Marrow Transplant (Allo-BMT) and Peripheral Blood Stem Cell Transplant (Allo-PBSCT) and identification of factors leading to interindividual variations in costs in order to compare these costs with the budget allocated by the payer (CNAM). Methods: Pharmacoeconomic retrospective study, concerning patients who underwent allogeneic HSCT in 2013. Clinical and unit cost data were obtained from medical and administration records. Results:This study showed that the average direct cost of allogeneic HSCT in the population during the first year reached 56 638. The average cost of Allo-BMT was 63 612, and Allo-PBSCT was 45 966 (p > 0.05). The initial hospitalization counted for 88% of total direct cost with an average cost of 41 441 in Allo-BMT and 24 672 in Allo-PBSCT (p < 0.05). Direct medical costs represented more than 70% of total direct costs, drugs, and laboratory tests occupied the largest share. Antifungals, antitumors, and antiviral drugs were the most expensive pharmaceutical classes with a mean cost, respectively, of 4 526; 3 737 and 3 268. Some clinical criteria were significantly related to total direct costs like length of aplasia (p < 0.01) and GVHD (p < 0.05). However, the type of blood disease, its risk, length of mucositis, and the treatment protocol have no effect on the costs for all allogeneic patients. Conclusion: Our results showed that the costs of Allo HSCT have exceeded by far the budget allocated by the CNAM to the center, since the 90s to this day. That's why the total reimbursement mechanism should be revised.
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The World Health Organization-designated Eastern Mediterranean region (EMRO) consists of 22 countries in North Africa and Western Asia with a collective population of over 679 million. The area comprises some of the wealthiest countries per capita income and some of the poorest. The population structure is also unique and contrasts with western countries, with a much younger population. The region sits in the heart of the thalassemia belt. Many countries have a significant prevalence of sickle cell disease, and cancer is on the rise in the region. Therefore, the strategic priorities for the growth and development of hematopoietic stem cell transplantation (HSCT) differ from country to country based on resources, healthcare challenges, and prevalent infrastructure. Thirty-one reporting teams to the Eastern Mediterranean Blood and Marrow Transplantation Group have active HSCT programs in 12 countries; allogeneic transplants outnumber autologous transplants, and the proportion of allotransplants for non-malignant conditions is higher in the EMRO region than in Western Europe and North America. The vast majority (99%) of allotransplants are from matched related donors. Matched unrelated donors and other alternate donor transplants are underutilized. The chance of finding a matched related donor for allografts is higher, with a significant chance of finding matched donors among non-sibling related donors. Reasons for relatively lower rates of transplants compared with other countries are multifactorial. Capacity building, development of newer centers, innovative funding, and better utilization of information technology are required to make transplantation as an accessible modality to more patients. Cost-effectiveness and cost-containment, regulation, and ensuring quality will all be priorities in planning HSCT development in the region.
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Trasplante de Células Madre Hematopoyéticas , Humanos , Trasplante de Médula Ósea , Trasplante Homólogo , Región Mediterránea , Europa (Continente)RESUMEN
Hodgkin lymphoma (HL) patients who relapse after autologous-stem-cell- transplantation (auto-SCT) have traditionally had a poor prognosis. We analyzed 1781 adult HL patients who relapsed between 2006 and 2017 after a first auto-SCT. The 4-year overall survival (OS) after relapse continuously increased from 32% for patients relapsing in 2006-2008, to 63% for patients relapsing in 2015-2017 (p = 0.001). The improvement over time was predominantly noted in patients who had an early relapse (within 12 months) after auto-SCT (p = 0.01). On multivariate analysis, patients who relapsed in more recent years and those with a longer interval from transplant to relapse had a better OS, whereas increasing age, poor performance status, bulky disease, extranodal disease and presence of B symptoms at relapse were associated with a worse OS. Brentuximab vedotin (BV), checkpoint inhibitors (CPI) and second transplant (SCT2; 86% allogeneic) were used in 233, 91 and 330 patients respectively. The 4-year OS from BV, CPI, and SCT2 use was 55%, 48% and 55% respectively. In conclusion, the outcome after post-transplant relapse has improved significantly in recent years, particularly in the case of early relapse. These large-scale real-world data can serve as benchmark for future studies in this setting.
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Trasplante de Células Madre Hematopoyéticas , Enfermedad de Hodgkin , Inmunoconjugados , Adulto , Brentuximab Vedotina , Enfermedad de Hodgkin/terapia , Humanos , Inmunoconjugados/efectos adversos , Recurrencia Local de Neoplasia/inducido químicamente , Recurrencia Local de Neoplasia/terapia , Estudios Retrospectivos , Trasplante AutólogoRESUMEN
Aplastic anemia is a relatively rare but potentially fatal disorder, with a reported higher incidence in developing countries in comparison to the West. There are significant variations in epidemiological as well as etiological factors of bone marrow failure syndromes in the developing countries in comparison to the developed world. Furthermore, the management of bone marrow failure syndromes in resource constraint settings has significant challenges including delayed diagnosis and referral, limited accessibility to healthcare facilities, treatment modalities as well as limitations related to patients who require allogeneic stem cell transplantation. Here we will provide a review of the available evidence related to specific issues of aplastic anemia in the developing countries and we summarize suggested recommendations from the Eastern Mediterranean blood and bone marrow transplantation (EMBMT) group and the severe aplastic anemia working party of the European Society of blood and marrow transplantation (SAAWP of EBMT) related to the diagnosis and therapeutic options in countries with restricted resources.
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Anemia Aplásica , Trasplante de Células Madre Hematopoyéticas , Anemia Aplásica/diagnóstico , Anemia Aplásica/terapia , Médula Ósea , Trastornos de Fallo de la Médula Ósea , Trasplante de Médula Ósea , Humanos , Acondicionamiento PretrasplanteRESUMEN
The role of the bone marrow microenvironment in supporting the proliferation and survival of the abnormal plasma cells in multiple myeloma (MM) is well established. Such microenvironment is rich of cytokines like IL-6, TGF-ß, IL-1 and IL-23 which are known to promote the differentiation of Th17 lymphocytes, a T helper subpopulation. Th17 cells secrete IL-17, a cytokine involved in the pathophysiology of several auto-immune diseases. Yet, its involvement in cancers remains unclear. Herein, we aimed to try to understand the role of Th17 lymphocytes in multiple myeloma. Bone marrow samples were prospectively collected from 29 MM patients and 23 healthy bone marrow donors for allograft. Mononuclear bone marrow cells were isolated by Ficoll-Hypaque gradient and CD138+ plasma cells were depleted using magnetic beads. The quantification of Th17 cells was performed by flow cytometry in the CD138 negative cells. The mRNA expression of IL17 and RORc was quantified using real time PCR in the same subset. The mRNA expression of IL17R was analyzed in plasma cells (CD138+ cells). Data obtained from patients and healthy donors were compared by both non-parametric Mann-Whitney U test and Spearman test. A significant increase of IL17 and RORC mRNA expression was found in the bone marrow microenvironment of MM patients compared to healthy donors. Th17 cells were also increased in the bone marrow of MM patients compared to healthy donors. Interestingly, the mRNA expression of IL17R was significantly decreased in MM patients. Yet, no correlation was found between the gene expression IL17, RORC and IL17R and the bone marrow infiltration or the stage of the disease. Collectively, our results suggest the involvement of Th17 cells in the pathophysiology of MM. Such data further support the use of anti-IL-17 antibodies as a therapeutic approach in MM.
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Médula Ósea/inmunología , Mieloma Múltiple/inmunología , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Células Th17/inmunología , Médula Ósea/metabolismo , Expresión Génica , Humanos , Interleucina-17/genética , Interleucina-17/metabolismo , Mieloma Múltiple/genética , Mieloma Múltiple/metabolismo , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , Células Plasmáticas/inmunología , Receptores de Interleucina-17/genética , Receptores de Interleucina-17/metabolismoRESUMEN
AIM: The objective of the study was to estimate the cumulative incidence (CI) of relapse, relapse-free survival (RFS) and overall survival (OS) in ALL patients after a once-a-day fractionated TBI (F-TBI) regimen with 9.9â¯Gy. The secondary objectives were evaluation of short and long-term toxicity and non-relapse mortality (NRM). BACKGROUND: Total body irradiation (TBI), as a part of the conditioning regimen before allogeneic stem cell transplantation (ASCT) for acute lymphoblastic leukemia (ALL), allows disease control by eradicating residual blast cells in the transplant recipient. MATERIALS AND METHODS: Retrospective study conducted in patients with ALL who received between March 2003 and December 2013 a conditioning regimen with F-TBI and chemotherapy. Irradiation was delivered with 3.3â¯Gy once-a-day for three consecutive days. RESULTS: Eighty-seven patients were included. The median age was 19 years (range: 5-49 years). The 3-year CI of relapse was 30%. The estimated 3-year RFS and OS were 54% and 58%, respectively. Cumulative incidence of acute graft-versus-host disease (aGVHD) grade II-IV and chronic GVHD (cGVHD) was 31% and 40%, respectively. Interstitial pneumonitis was observed in 2 patients. The 3-year CI of NRM was 16%. In multivariate analysis, cGVHD was associated with a lower CI of relapse (RRâ¯=â¯0.26, 95% CI: 0.07-0.95, pâ¯=â¯0.04). High-risk cytogenetics was associated with a lower RFS (RRâ¯=â¯2, 95 CI: 1.04-3.84, pâ¯=â¯0.03). Grade II-IV aGVHD was an independent predictor of higher CI of NRM (RRâ¯=â¯6.7, 95% CI: 1.4-31.7, pâ¯=â¯0.02). CONCLUSIONS: Once-a-day F-TBI regimen is effective, safe and practical in patients who underwent ASCT for ALL.
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Hematopoietic Stem Cell Transplantation (HSCT) is the only potentially curative treatment option for the hematologic complications that occur in patients with Fanconi anemia (FA). In this study, we present a retrospective multicenter analysis from the Eastern Mediterranean Blood and Marrow Transplantation Group (EMBMT) of matched related donor HSCT for FA in adolescents and adults transplanted between 1988 and 2015. Forty-five patients received HSCT with a median age at transplant of 18 years, the interquartile range (IQR) (15-23.5); 25 (55.6%) patients were females and 20 (44.4%) were males. Conditioning regimen was fludarabine-based in 29 (64.4%) patients, irradiation-based in five (11.1%) patients, and the remaining patients received other combinations. Indication for HSCT was bone marrow failure in 39 (86.7%) and myelodysplastic syndrome in six (13.3%) patients. Stem cell source was bone marrow in 22 (48.9%), peripheral blood in 20 (44.4%), umbilical cord blood in one (2.2%), and combination of bone marrow and cord blood in two (4.4%) patients. Twenty-seven (60%) patients engrafted and five (11.1%) had primary engraftment failure. The median time to neutrophil engraftment was 14 days (range 10-21 days); median time for platelet engraftment was 17 days (10-33 days). The probability of developing grade II-IV acute GVHD for all patients was 7.0% and chronic GVHD 36.6%. No new malignancies were reported. The OS probability was 53.6% (95% CI, 38.3-68.9%) with a median follow-up of 13 months (95% CI, 1-240). Our HLA-matched related HSCT results in AYA patients with FA compare favorably with other reported international registry data.
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Anemia de Fanconi , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Adolescente , Adulto , Médula Ósea , Anemia de Fanconi/terapia , Femenino , Humanos , Masculino , Estudios Retrospectivos , Acondicionamiento PretrasplanteRESUMEN
The first meeting of the African Blood and Marrow Transplantation (AfBMT) was held in Casablanca from April 19, 2018 to April 21, 2018, with the aim of fostering hematopoietic stem cell transplantation (HSCT) activity in Africa. Out of the 54 African countries, HSCT is available only in six (Algeria, Egypt, Morocco, Nigeria, South Africa, and Tunisia). During this meeting, African teams and international experts from the Worldwide Network for Blood and Marrow Transplantation (WBMT) gathered to share their experience and discussed ways to help fill the gap. Nurses and patients held their meeting in parallel. International support and collaboration can help by providing expertise adapted to local resources and regional population needs. Local engagement including government and private participants are necessary to initiate and develop local HSCT capability.
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Trasplante de Médula Ósea , Trasplante de Células Madre Hematopoyéticas , Congresos como Asunto , MarruecosRESUMEN
Human recombinant granulocyte colony stimulating factor reduces the duration of neutropenia following HLA-identical allogeneic bone marrow transplantation. However, its use remains controversial due to the risk of increasing the incidence of acute graft-versus-host disease (GVHD) and slower platelet recovery. To clarify these risks, we conducted a prospective randomized placebo-controlled trial of filgrastim 5 µg/kg/day i.v. from day 7 post-transplant until neutrophil recovery in 145 consecutive adults undergoing HLA-identical allogeneic bone marrow transplantation, with cyclosporine and methotrexate as GVHD prophylaxis. The primary endpoint was the incidence of acute GVHD; hematological recovery, nonrelapse mortality, and post-transplant complications were secondary endpoints. Filgrastim had no significant effect on the incidence of acute GVHD, platelet recovery, platelet transfusion requirements, chronic GVHD, or survival. Filgrastim accelerated granulocyte recovery significantly (with absolute neutrophil counts >.5â¯×â¯109/L achieved after a median of 16 days versus 23 days for placebo; P < .0001), and reduced both early nonrelapse mortality (2.9% versus 10.5%; P = .042) and the duration of i.v. antibiotic therapy (18 days versus 26 days; P = .001) and hospitalization (27 versus 34 days; P = .017). In conclusion, in this setting, filgrastim reduced significantly the duration of neutropenia, i.v. antibiotic therapy, hospitalization, and early nonrelapse mortality, without increasing the risk of acute and chronic GVHD or relapse, or delaying platelet recovery.
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Trasplante de Médula Ósea/métodos , Filgrastim/uso terapéutico , Fármacos Hematológicos/uso terapéutico , Trasplante Homólogo/métodos , Adolescente , Adulto , Femenino , Filgrastim/farmacología , Fármacos Hematológicos/farmacología , Humanos , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Adulto JovenRESUMEN
A 27-year-old man with severe aplastic anemia underwent bone marrow transplantation from his HLA identical brother in July 2016. Conditioning included ATGAM 30 mg/kg for 3 days and Cyclophosphamide 50 mg/kg for 4 days. The patient received several platelet and red blood cell transfusions before and after the conditioning. The patient received broad spectrum antibiotics and caspofungin because persistant febrile neutropenia without bacteriological or mycological documentation. Hemophagocytic syndrome was diagnosed on day +12. Steroids at 1 mg/kg were started on day +12. Fever resolved the same day but resumed 3 days later associated to intravascular hemolysis with no schizocytes on blood smears and negative DAT. Thick blood film smears performed on day +26 revealed Plasmodium falciparum parasites (parasitemia = 20%). Except the level of parasitemia, there were no signs of gravity. Quinine was started on day 26 at a loading dose of 15 mg/kg followed by 8 mg/kg three times a day for 20 doses. Fever vanished after 2 days. Parasitemia cleared in 3 days and remained negative thereafter. Investigations revealed that the patient was transfused by a red cell unit harvested in a voluntary donor native of a malaria endemic country. PCR for P. falciparum performed in this donor in the frame of investigations was positive. The patient is alive with a normal blood count 1 year after BMT.
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Trasplante de Médula Ósea/efectos adversos , Linfohistiocitosis Hemofagocítica/parasitología , Malaria Falciparum/transmisión , Plasmodium falciparum/efectos de los fármacos , Reacción a la Transfusión/parasitología , Adulto , Anemia Aplásica/complicaciones , Antimaláricos/uso terapéutico , Artemisininas/uso terapéutico , Transfusión Sanguínea , Humanos , Linfohistiocitosis Hemofagocítica/etiología , Malaria Falciparum/tratamiento farmacológico , Malaria Falciparum/parasitología , Masculino , Parasitemia/tratamiento farmacológico , Plasmodium falciparum/aislamiento & purificación , Resultado del TratamientoRESUMEN
Background: Hematopoietic stem cell transplantation (HSCT) is a medically complicated therapy with a long recovery time. In Tunisia, the National Health Insurance Fund (CNAM) covers only the first year post-transplantation, after which the costs are borne by the hospital. Objective: Describe complications that can occur during the second year post-allogeneic HSCT and calculate direct costs in different groups of patients. Methods: In this pharmacoeconomic study, medical records of the second year post-allogeneic HSCT were collected. Studied variables included frequent observed complications and medical and non-medical direct costs. Results: The average total direct cost in the population during the second year post-transplantation was $11,571, 97% of which represents direct medical costs Drugs accounted for the largest share (80%) of total direct costs, dominated by the cost of antifungals (52%) and antivirals (26%) drug . Cytomegalovirus status was seen in 9.3% of patients and was associated with a seven-fold increase in direct costs (p < 0.001).ââIn patients who developed chronic GVHD, the average direct cost was three times higher than for those who did not (p = 0.032). Conclusion: Given the importance of direct costs in the post-transplantation period a review of the hospital financing mechanism and a new convention with the CNAM is crucial.ââ.
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Sustained activation of JAK/STAT3 signaling pathway is classically described in Multiple Myeloma (MM). One explanation could be the silencing of the JAK/STAT suppressor genes, through the hypermethylation of SHP-1 and SOCS-1, previously demonstrated in MM cell lines or in whole bone marrow aspirates. The link between such suppressor gene silencing and the degree of bone marrow invasion or the treatment response has not been evaluated in depth. Using real-time RT-PCR, we studied the expression profile of three JAK/STAT suppressor genes: SHP-1, SHP-2 and SOCS-1 in plasma cells freshly isolated from the bone marrows of MM patients and healthy controls. Our data demonstrated an abnormal repression of such genes in malignant plasma cells and revealed a significant correlation between such defects and the sustained activation of the JAK/STAT3 pathway during MM. The repressed expression of SHP-1 and SHP-2 correlated significantly with a high initial degree of bone marrow infiltration but was, unexpectedly, associated with a better response to the induction therapy. Collectively, our data provide new evidences that substantiate the contribution of JAK/STAT suppressor genes in the pathogenesis of MM. They also highlight the possibility that the decreased gene expression of SHP-1 and SHP-2 could be of interest as a new predictive factor of a favorable treatment response, and suggest new potential mechanisms of action of the therapeutic molecules. Whether such defect helps the progression of the disease from monoclonal gammopathy of unknown significance to MM remains, however, to be determined.
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Mieloma Múltiple/metabolismo , Proteína Tirosina Fosfatasa no Receptora Tipo 11/metabolismo , Proteína Tirosina Fosfatasa no Receptora Tipo 6/metabolismo , Factor de Transcripción STAT3/metabolismo , Proteína 1 Supresora de la Señalización de Citocinas/metabolismo , Médula Ósea/metabolismo , Médula Ósea/patología , Progresión de la Enfermedad , Femenino , Expresión Génica , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Mieloma Múltiple/patología , Mieloma Múltiple/terapia , Estudios Prospectivos , ARN Mensajero/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Transducción de Señal , Resultado del TratamientoRESUMEN
OBJECTIVE/BACKGROUND: The Eastern Mediterranean Blood and Marrow Transplantation (EMBMT) group has accumulated over 31 years of data and experience in hematopoietic stem cell transplantation (HSCT), particularly in hemoglobinopathies, severe aplastic anemia, inherited metabolic and immune disorders, in addition to a wide array of hematologic malignancies unique to this region. A regional update in current HSCT trends is highly warranted. We studied the trends of HSCT activities in World Health Organization-Eastern Mediterranean (EMRO) region, surveyed by the EMBMT, between 2011 and 2012. METHODS: Retrospective analysis of the survey data mainly of cumulative number of transplants, types of transplants (autologous vs. allogeneic), types of conditioning such as myeloablative versus reduced intensity was conducted. Also, trends in leukemias, hemoglobinopathies, severe aplastic anemia, inherited bone marrow failure syndromes, amongst others were analyzed. RESULTS: Twenty-one teams from nine EMRO countries reported their data (100% return rate) to the EMBMT for the years 2011-2012, with a total of 3,546 first HSCT (1,670 in 2011; 1,876 in 2012). Allogeneic HSCT (allo-HSCT) represented the majority (62%) in both years. The main indications for allo-HSCT were acute leukemias (988; 46%), bone marrow failure syndromes (421, 20%), hemoglobinopathies (242; 11%), and immune deficiencies (157; 7%). There was a progressive increase in the proportions of chronic myeloid leukemia cases transplanted beyond first chronic phase (37 [7%] of all chronic myeloid leukemia cases in 2011 vs. 39 [29%] in 2012). The main indications for autologous transplants were multiple myeloma/plasma cell disorders (510; 39%), Hodgkin lymphoma (311; 24%), non-Hodgkin lymphoma (259; 20%), and solid tumors (163; 12%). Reduced intensity conditioning continued to show a progressive decrease over years (9.5% in 2011 vs. 7.9% in 2012), yet remained relatively low compared with contemporary practices in Europe published by EBMT. The vast majority (91%) of allo-HSCT source was from sibling donors with continued dominance of peripheral blood (64%) followed by bone marrow (33%).While umbilical cord blood transplants increased to 4% of allo-HSCT, matched unrelated donor remained underutilized and there was no haplo-identical transplant reported. Large centers with >50 HSCT/year, showed a continued increase in the total number of allo-HSCT over the past 2years that may be related to capacity building issues and require further studies. CONCLUSION: There is a discernable increase of HSCT rate in the EMRO region with a significant expansion in utilization of cord blood transplants and allogeneic peripheral blood-HSCT as a valuable source. However, further research of outcome data and the development of regional donor banks (cord blood and matched unrelated donors) may help to facilitate future planning to satisfy the escalating regional needs and augment collaboration within the EMBMT and globally.