RESUMO
BACKGROUND: Interim PET after two ABVD cycles (iPET2) predicts treatment outcome in classical Hodgkin's lymphoma. To test whether an earlier assessment of chemosensitivity would improve the prediction accuracy, we launched a prospective, multicenter observational study aimed at assessing the predictive value of iPET after one ABVD (iPET1) and the kinetics of response assessed by sequential PET scanning. PATIENTS AND METHODS: Consecutive patients with newly diagnosed classical Hodgkin's lymphoma underwent interim PET scan after one ABVD course (iPET1). PETs were interpreted according to the Deauville score (DS) as negative (-) (DS 1-3) and positive (+) (DS 4, 5). Patients with iPET1 DS 3-5 underwent iPET2. RESULTS: About 106 early (I-IIA) and 204 advanced (IIB-IV) patients were enrolled between January 2008 and October 2014. iPET1 was (-) in 87/106 (82%) or (+) in 19/106 (18%) of early, and (-) in 133/204 (65%) or (+) in 71/204 (35%) of advanced stage patients, respectively. Twenty-four patients were excluded from response analysis due to treatment escalation. After a median follow-up of 38.2 (3.2-90.2) months, 9/102 (9%) early and 43/184 (23%) advanced patients experienced a progression-free survival event. At 36 months, negative and positive predictive value for iPET1 were 94% and 41% (early) and 84% and 43% (advanced), respectively. The kinetics of PET response was assessed in 198 patients with both iPETs. All 116 patients with iPET1(-) remained iPET2(-) (fast responders), 41/82 with IPET1(+) became iPET2(-) (slow responders), and the remaining 41 stayed iPET2(+) (non-responders); progression-free survival at 36 months for fast, slow and non-responders was 0.88, 0.79 and 0.34, respectively. CONCLUSION: The optimal tool to predict ABVD outcome in HL remains iPET2 because it distinguishes responders, whatever their time to response, from non-responders. However, iPET1 identified fast responders with the best outcome and might guide early treatment de-escalation in both early and advanced-stage HL.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Doença de Hodgkin/diagnóstico por imagem , Doença de Hodgkin/tratamento farmacológico , Tomografia por Emissão de Pósitrons/métodos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Bleomicina/administração & dosagem , Quimiorradioterapia , Dacarbazina/administração & dosagem , Doxorrubicina/administração & dosagem , Feminino , Doença de Hodgkin/patologia , Doença de Hodgkin/radioterapia , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Valor Preditivo dos Testes , Vimblastina/administração & dosagem , Adulto JovemRESUMO
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.
Assuntos
Antígenos CD20/imunologia , Linfócitos B/imunologia , Transtornos Linfoproliferativos/tratamento farmacológico , Rituximab/uso terapêutico , Humanos , Transtornos Linfoproliferativos/imunologia , Transtornos Linfoproliferativos/patologia , Pessoa de Meia-Idade , PrognósticoRESUMO
Secondary acute lymphoblastic leukemia (s-ALL) comprises up to 10% of ALL patients. However, data regarding s-ALL outcomes is limited. To answer what is the role of allogeneic hematopoietic cell transplantation (HCT) in s-ALL, a matched-pair analysis in a 1:2 ratio was conducted to compare outcomes between s-ALL and de novo ALL (dn-ALL) patients reported between 2000-2021 to the European Society for Blood and Marrow Transplantation registry. Among 9720 ALL patients, 351 (3.6%) were s-ALL, of which 80 were in first complete remission (CR1) with a known precedent primary diagnosis 58.8% solid tumor (ST), 41.2% hematological diseases (HD). The estimated 2-year relapse incidence (RI) was 19.1% (95%CI: 11-28.9), leukemia-free survival (LFS) 52.1% (95%CI: 39.6-63.2), non-relapse mortality (NRM) 28.8% (95%CI: 18.4-40), GvHD-free, relapse-free survival (GRFS) 39.4% (95%CI: 27.8-50.7), and overall survival (OS) 60.8% (95%CI: 47.9-71.4), and did not differ between ST and HD patients. In a matched-pair analysis, there was no difference in RI, GRFS, NRM, LFS, or OS between s-ALL and dn-ALL except for a higher incidence of chronic GvHD (51.9% vs. 31.4%) in s-ALL. To conclude, patients with s-ALL who received HCT in CR1 have comparable outcomes to patients with dn-ALL.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Condicionamento Pré-Transplante/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Recidiva , Sistema de Registros , Estudos Retrospectivos , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/epidemiologiaRESUMO
UNLABELLED: The aim of the multi-centre retrospective study was to evaluate the efficacy and safety of lenalidomide (LEN) therapy in patients with resistant or relapsed multiple myeloma (MM) as well as in patients with stable disease (LEN used due to neurological complications). The primary endpoint of this study was an overall response rate (ORR). The secondary endpoints were as follows: time to progression (TTP), overall survival (OS) and the safety of drug use. Data were collected in 19 centres of the Polish Multiple Myeloma Study Group. The study group consisted of 306 subjects: 153 females and 153 males. In 115 patients (38.8%, group A), a resistant myeloma was diagnosed; in 135 (44.1%, group B) a relapse, and in 56 (18.3%, group C) a stable disease were stated. In 92.8% of patients, LEN+DEX combination was used; in remaining group, LEN monotherapy or a combination therapy LEN+bortezomib or LEN+bendamustine and other were used. In the entire study group, ORR was 75.5% (including 12.4% patients achieving complete remission [CR] or stringent CR [sCR]). Median time to progression (TTP) was 20 months. Median overall survival (OS) was 33.3 months. The regression model for "treatment response" was on the borderline of statistical significance (p=0.07), however the number of LEN treatment cycles ≥ 6 (R(2)=17.2%), baseline LDH level (R(2)=1.1%) and no ASCT use (R(2)=1.7%) where the factors most affecting treatment response achievement. The regression model for dependant variable--"overall survival"--was statistically significant (p=0.0000004). Factors with the most impact on OS were as follows: number of LEN cycles treatment ≥ 6 (R(2)=16.7%), treatment response achievement (R(2)=6.9%), ß-2-microglobulin (ß-2-M) level (R(2)=4.8%), renal function (R(2)=3.0%) and lack of 3/4 grade adverse events (R(2)=1.4%). SUMMARY: LEN is an effective and safe therapeutic option, even in intensively treated resistant and relapsed MM patients, as well as in patients with stable disease and previous treatment-induced neurological complications. In particular, the number of LEN treatment cycles ≥ 6 was the factor which affected treatment response achievement the most, together with an important impact on OS.
Assuntos
Fatores Imunológicos/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Talidomida/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Progressão da Doença , Feminino , Humanos , Fatores Imunológicos/efeitos adversos , Lenalidomida , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/patologia , Talidomida/efeitos adversos , Talidomida/uso terapêuticoRESUMO
It is unknown whether imatinib prior to myeloablative haematopoietic stem cell transplantation (HSCT) increases transplant-related toxicity. Among the side effects induced by imatinib, myelosuppression and liver injury might worsen HSCT outcomes. We retrospectively analysed engraftment, liver toxicity, acute graft-versus-host disease (aGVHD) incidence and 100-day mortality in 30 patients with BCR/ABL-positive leukaemias who received imatinib before HSCT and compared results of 48 age-matched controls who did not receive preceding imatinib. Both neutrophil and platelet engraftment occurred more rapidly among imatinib patients but the differences adjusted for Gratwohl scale were not statistically significant (P = 0.18 and 0.22, respectively). The adjusted hazards of having liver function tests (LFTs) >1.5 normal increased and the adjusted durations of elevated LFTs were not significantly different. The estimated adjusted difference in mean peak bilirubin values was also not significantly different (P = 0.48). However, the adjusted hazard of increased creatinine >1.5 normal was significantly higher in the imatinib group (HR = 4.09, P = 0.02). The adjusted odds of grades II-IV aGVHD were similar in both groups (OR = 0.86, P = 0.78), and while the adjusted odds of 100-day mortality were lower among imatinib patients, the difference was not significant (OR = 0.65, P = 0.60). These data do not provide any evidence that imatinib preceding HSCT increases acute transplant-related toxicities.
Assuntos
Antineoplásicos/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Piperazinas/administração & dosagem , Pirimidinas/administração & dosagem , Transplante Homólogo , Adolescente , Adulto , Benzamidas , Bilirrubina/sangue , Plaquetas/metabolismo , Creatinina/sangue , Feminino , Sobrevivência de Enxerto , Doença Enxerto-Hospedeiro/sangue , Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Mesilato de Imatinib , Leucemia Mielogênica Crônica BCR-ABL Positiva/sangue , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Fígado/metabolismo , Masculino , Pessoa de Meia-Idade , Neutrófilos/metabolismo , Quimeras de Transplante , Condicionamento Pré-Transplante/métodosRESUMO
Variable regulatory subunits of protein phosphatase 2A (PP2A) modulate activity, substrate selectivity and subcellular targeting of the enzyme. We have cloned a novel member of the B type regulatory subunit family, B delta, which is most highly related to B alpha. B delta shares with B alpha epitopes previously used to generate subunit-specific antibodies. Like B alpha, but unlike B beta and B gamma which are highly brain-enriched, B delta mRNA and protein expression in tissues is widespread. B delta is a cytosolic subunit of PP2A with a subcellular localization different from B alpha and may therefore target a pool of PP2A holoenzymes to specific substrates.
Assuntos
Fragmentos de Peptídeos/genética , Fosfoproteínas Fosfatases/química , Fosfoproteínas Fosfatases/genética , Sequência de Aminoácidos , Animais , Encéfalo/enzimologia , Células COS , Membrana Celular/enzimologia , Clonagem Molecular , Citosol/enzimologia , Dados de Sequência Molecular , Especificidade de Órgãos/genética , Fragmentos de Peptídeos/biossíntese , Fragmentos de Peptídeos/química , Fosfoproteínas Fosfatases/biossíntese , Proteína Fosfatase 2 , RNA Mensageiro/biossíntese , Ratos , Transdução de SinaisRESUMO
Protein phosphatase 2A (PP2A) is a heterotrimeric enzyme consisting of a catalytic subunit (C), a structural subunit (A), and a variable regulatory subunit (B). We have investigated the spatial and temporal expression patterns of three members of the B subunit family, Balpha, Bbeta, and Bgamma, both at the message level by using ribonuclease protection analysis and at the protein level by using specific antibodies. Although A, Balpha, and C protein are expressed in many tissues, Bbeta and Bgamma were detectable only in brain. Balpha, Bbeta, and Bgamma are components of the brain PP2A heterotrimer, because they copurified with A and C subunits on immobilized microcystin. Whereas Balpha and Bbeta are mainly cytosolic, Bgamma is enriched in the cytoskeletal fraction. In contrast to A, C, and Balpha, which are expressed at constant levels, Bbeta and Bgamma RNA and protein are developmentally regulated, with Bbeta levels decreasing and Bgamma levels increasing sharply after birth. RNA and immunoblot analyses of subdissected brain regions as well as immunohistochemistry demonstrated that B subunits are expressed in distinct but overlapping neuronal populations and cellular domains. These data indicate that B subunits confer tissue and cell specificity, subcellular localization, and developmental regulation to the PP2A holoenzyme. The Balpha-containing heterotrimer may be important in general neuronal functions that involve its partially nuclear localization. Holoenzymes containing B likely function in early brain development as well as in somata and processes of subsets of mature neurons. Bgamma may target PP2A to cytoskeletal substrates that are important in the establishment and maintenance of neuronal connections.
Assuntos
Encéfalo/enzimologia , Encéfalo/crescimento & desenvolvimento , Compartimento Celular/fisiologia , Fosfoproteínas Fosfatases/genética , Sequência de Aminoácidos , Animais , Especificidade de Anticorpos , Células COS , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Regulação Enzimológica da Expressão Gênica/fisiologia , Imuno-Histoquímica , Dados de Sequência Molecular , Fosfoproteínas Fosfatases/imunologia , Fosfoproteínas Fosfatases/metabolismo , Fosforilação , Proteína Fosfatase 2 , RNA Mensageiro/análise , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/fisiologia , Frações SubcelularesRESUMO
Conventional approaches to allogeneic stem cell transplantation have used toxic high-dose conditioning therapy to achieve allogeneic engraftment and control of underlying disease. For engraftment purposes, preclinical studies and clinical observations have shown that conditioning regimens can be markedly reduced in intensity, resulting in reduced treatment toxicities. Preclinical canine studies demonstrated that the use of potent pre- and postgrafting immunosuppression allows for reduction in conditioning regimens while facilitating development of stable mixed chimerism. If attenuated conditioning regimens can be successfully translated to human stem cell transplantation, an improved safety profile will allow potentially curative treatment to a more representative patient profile not currently offered such therapy. Mixed chimerism could prove curative of disease phenotype of various nonmalignant disturbances of the hematopoietic and immune systems. For patients with hematopoietic malignancy, spontaneous conversion to full donor hematopoeisis after stem cell transplant may prove curative by virtue of graft versus host reactions directed against the malignancy, however infusion of additional donor lymphocytes may be needed to treat persistent disease.
Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Condicionamento Pré-Transplante/métodos , Animais , Cães , Efeito Enxerto vs Leucemia , Neoplasias Hematológicas/terapia , Humanos , Quimeras de Transplante , Tolerância ao TransplanteRESUMO
BACKGROUND: Stable mixed-donor-host-hematopoietic chimerism can serve as a platform for adoptive immunotherapy. Infusions of donor lymphocytes (DLI) sensitized against hematopoietic cells converted mixed hematopoietic into full-donor chimerism in dog-leukocyte antigen (DLA)-identical littermates. Whether sensitization against tissue of solid organs leads to organ-specific immunity that can be transferred by DLI was unknown and was investigated in these experiments using the kidney as target. METHODS: DLA-identical recipients with established stable mixed-donor-host-hematopoietic chimerism were used. In five pairs, hematopoietic stem-cell transplant (HSCT) donors were sensitized by kidney transplantation from the respective chimeras. In a second group, five HSCT donors received vaccinations that were generated from kidney cells of the respective mixed chimeras. Twenty-eight days after sensitization, DLI were administered to the mixed-hematopoietic chimeras. RESULTS: All HSCT donors rejected their kidney grafts from their mixed-chimeric recipients within 22 to 45 days. DLI caused no sustained graft-versus-kidney effects in the mixed-chimeric recipients. However, DLI donors sensitized by kidney transplantation converted 4 of 5 mixed chimeras into virtually complete (>95%) donor-type chimeras, compared with 1 of 5 mixed chimeras given DLI by vaccination from sensitized donors. CONCLUSION: Although DLA-identical kidney grafts from mixed-hematopoietic chimeras were readily rejected by their HSCT donors, subsequent transfusions of sensitized-donor lymphocytes into mixed chimeras converted mixed to all-donor chimerism but failed to induce graft-versus-kidney effects. Vaccination strategies in lieu of kidney grafts failed to convert mixed chimerism.
Assuntos
Antígenos HLA/imunologia , Transplante de Células-Tronco Hematopoéticas , Imunoterapia Adotiva , Transplante de Rim/imunologia , Quimeras de Transplante/imunologia , Animais , Nitrogênio da Ureia Sanguínea , Creatinina/sangue , Cães , Feminino , Rejeição de Enxerto/diagnóstico por imagem , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/patologia , Doença Enxerto-Hospedeiro/diagnóstico por imagem , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/patologia , Técnicas In Vitro , Rim/diagnóstico por imagem , Rim/patologia , Masculino , Ultrassonografia , Vacinas/farmacologiaRESUMO
AlloPBSC-T is rapidly replacing bone marrow transplantation. The minimum number of progenitor cells required for rapid engraftment following PBSCT is unknown. 12 patients underwent alloPBSC-T during treatment for haematological malignancy. PBSC's were mobilised with Filgrastim (10microg/kg/day sc). The mobilisation was monitored daily by the number of mononuclear cells (MNC) and CD34+ cells in peripheral blood. Collections were normally performed on days 4 and 5, by means of apheresis (Fenwall CS 3000+). No further manipulation of PBSC was performed. A median of 10.15x10(8)/kg MNC (range 5.87-12.24), 9.075x10(6)/kg CD34+ (range 0.78-18.98), 53.85x10(4)/kg CFU-G (range 17.2-138.4), 28.05x10(4)/kg CFU-M (range 4.1-102.2), 115.65x10(4)/kg BFU-E (range 9.1-255.2), 3.65x10(4)/kg CFU-GEMM (range 0.3-10.4) were infused into recipients following BuCyl20 conditioning. Haematopoietic reconstitution was observed in 11 patients. The median number of days to achieve a neutrophil count of 0.5x10(9)/l was 16 (range 12-20), the platelet count of 20x10(9)/l was 12 (range 8-20) and RBC transfusion independence was 11 (range 8-20). 9 recipients developed acute GVHD (3 grade I0, 2 grade II0, 1 grade III0, 3 grade IV0). We found that the number of MNC in PBSC had no influence on the number of progenitors. All the patients who received G-CFU>20x10(4)/kg, BFU-E>60x10(4)/kg and CFU-GEMM>1x10(4)/kg experienced a rapid haematopoietic recovery. No relation was found between the number of reinfused progenitors and the appearance of GVHD.
Assuntos
Hematopoese , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/citologia , Adulto , Contagem de Células , Citaferese , Feminino , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Condicionamento Pré-Transplante , Transplante Homólogo , Resultado do TratamentoRESUMO
A dog model of stable mixed hematopoietic chimerism was established in which leukocyte-antigen-identical littermates receive nonmyeloablative total body irradiation before hematopoietic cell transplantation and postgrafting immunosuppression with mycophenolate mofetil and cyclosporine. Unmodified donor lymphocyte infusion (DLI) into stable mixed chimeras failed to increase donor chimerism, while DLI from donors sensitized to recipient minor-histocompatibility antigens promptly converted all recipients to complete donor chimerism. This established a model for studying approaches to enhance the graft-versus-host (GVH)-effect, a potential surrogate for graft-versus-leukemia activity. We asked if interleukin-2 (IL-2) given after unmodified DLI could result in reliable conversion to complete donor chimerism. IL-2, 4 x 10(5) IU/kg/day, was administered to six mixed chimeric dogs for 14 days. Four dogs received unmodified DLI with IL-2. At 20-40 weeks after DLI, all dogs remained mixed chimeras. For the two recipients of IL-2 only, mixed chimerism also remained unchanged. These results show that IL-2 given with DLI after nonmyeloablative transplantation in dogs is not effective in reliably converting mixed to complete donor chimerism.
Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Interleucina-2/farmacologia , Transfusão de Linfócitos , Quimeras de Transplante/imunologia , Animais , Ciclosporina/uso terapêutico , Cães , Modelos Animais , Condicionamento Pré-Transplante/métodos , Irradiação Corporal TotalRESUMO
Conventional allografting produces considerable regimen-related toxicities that generally limit this treatment to patients younger than 55 years and in otherwise good medical condition. T cell-mediated graft-versus-tumor (GVT) effects are known to play an important role in the elimination of malignant disease after allotransplants. A minimally myelosuppressive regimen that relies on immunosuppression for allogeneic engraftment was developed to reduce toxicities while optimizing GVT effects. Pre-transplant total-body irradiation (200 cGy) followed by post-transplant immunosuppression with cyclosporine (CSP) and mycophenolate mofetil (MMF) permitted human leukocyte antigen (HLA)-matched sibling donor hematopoietic cell engraftment in 82% of patients (n = 55) without prior high-dose therapy. The addition of fludarabine (90 mg/m2) facilitated engraftment in all 28 subsequent patients. Overall, fatal progression of underlying disease occurred in 20% of patients after transplant. Non-relapse mortality occurred in 11% of patients. Toxicities were low. Grade 2-4 acute graft-versus-host disease (GVHD) associated with primary engraftment developed in 47% of patients, and was readily controlled in all but two patients. Donor lymphocyte infusions (DLI) were not very effective at converting a low degree of mixed donor/host chimerism to full donor chimerism; however, the addition of fludarabine reduced the need for DLI. With a median follow-up of 244 days, 68% of patients were alive, with 42% of patients in complete remission, including molecular remissions. Remissions occurred gradually over periods of weeks to a year. If long-term efficacy is demonstrated, such a strategy would expand treatment options for patients who would otherwise be excluded from conventional allografting.
Assuntos
Efeito Enxerto vs Tumor/imunologia , Transplante de Células-Tronco Hematopoéticas/métodos , Condicionamento Pré-Transplante/métodos , Adulto , Animais , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Ciclosporina/uso terapêutico , Progressão da Doença , Cães , Previsões , Facilitação Imunológica de Enxerto/efeitos adversos , Facilitação Imunológica de Enxerto/métodos , Sobrevivência de Enxerto , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Histocompatibilidade , Humanos , Imunossupressores/uso terapêutico , Transfusão de Linfócitos , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Ácido Micofenólico/análogos & derivados , Ácido Micofenólico/uso terapêutico , Neoplasias/terapia , Prednisona/uso terapêutico , Quimera por Radiação , Linfócitos T Citotóxicos/imunologia , Doadores de Tecidos , Condicionamento Pré-Transplante/efeitos adversos , Transplante Homólogo , Resultado do Tratamento , Vidarabina/análogos & derivados , Vidarabina/uso terapêutico , Irradiação Corporal TotalRESUMO
Forty one patients with hairy cell leukemia (HCL) were treated with 2-chloro-deoxyadenosine (2-CdA) administered in various schedules. Complete remission (CR) was achieved in 31 (76%) patients and partial remission (PR) in 9 (22%). The mean duration of remission (CR + PR) was 25.2 months (range 9-45 months). One patient did not respond to therapy. Twelve out of 16 patients (75%) achieved CR after 5-day intravenous infusions of 2-CdA and 19 out of 25 patients (76%) after 7-day courses. In 19 out of 23 patients (82.6%) CR was achieved after intermittent 2-hour infusions and in 12 out of 18 (66.7%) after continuous 24-hour infusion. The differences were not statistically significant. Side effects of 2-CdA were similar in both groups except for infections, which were less frequently observed in the group treated for 5 days. The results of our study suggest that 2-CdA can be effectively administered to patients with HCL using 5-day courses and a 2-hour daily infusion.
Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Cladribina/administração & dosagem , Leucemia de Células Pilosas/tratamento farmacológico , Adulto , Idoso , Antimetabólitos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/uso terapêutico , Cladribina/efeitos adversos , Cladribina/uso terapêutico , Terapia Combinada , Intervalo Livre de Doença , Feminino , Humanos , Fatores Imunológicos/uso terapêutico , Infecções/epidemiologia , Infusões Intravenosas , Interferon-alfa/uso terapêutico , Leucemia de Células Pilosas/cirurgia , Masculino , Pessoa de Meia-Idade , Indução de Remissão , Esplenectomia , Resultado do TratamentoRESUMO
The purpose of our study was to determine the efficacy of 2-chlorodeoxyadenosine (2-CdA) administered in 2-hour intravenous infusions in previously treated patients with low grade non-Hodgkin's lymphoma (LGNHL). We treated 94 LGNHL patients with 2-CdA at a dosage of 0.12 mg/kg/24h in 2-hour intravenous infusion for 5 consecutive days. The treatment consisted of from 1 to 7 courses (median 3), repeated usually at monthly intervals. All patients were refractory to or relapsed after standard chemotherapy. Of these 94 patients 78 (83%) had clinical stage IV of the disease. Complete response (CR) was obtained in 12 (12.8%) and partial response (PR) in 36 (38.3%) giving an overall response rate of 51.1%. In 12 (12.8%) grade 4 thrombocytopenia with haemorrhagic diathesis was noted, grade 4 neutropenia was observed in 12 (12.8%) and infections complicated the course of treatment in 38 (40.4%) patients. 2-CdA treatment was the cause of death of 3 patients. The results of our study show that 2-CdA given in 2-hour infusions is an effective agent in advanced, heavily pretreated patients with LGNHL.
Assuntos
Antineoplásicos/uso terapêutico , Cladribina/uso terapêutico , Linfoma não Hodgkin/tratamento farmacológico , Adulto , Idoso , Antineoplásicos/efeitos adversos , Cladribina/efeitos adversos , Feminino , Humanos , Infusões Intravenosas , Linfoma não Hodgkin/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , RetratamentoRESUMO
The purpose of our study was to determine the effectiveness of 2-CdA in 2-hour intravenous infusions in the treatment of B-CLL. One hundred and ten patients with B-CLL received 1 to 10 courses of 2-CdA (median 2.5) at a dosage of 0.12 mg/kg daily for 5 consecutive days. Eighteen of them were untreated and 92 relapsed or became refractory to previous therapeutic modalities. Complete remission (CR) was achieved in 8 (7.3%) and partial remission (PR) in 35 patients (31.8%) giving an overall response rate of 39.1%. In 3 patients, cross-resistance to fludarabine was noticed. Toxic effects of 2-CdA were more frequently observed in previously treated patients. Hemorrhagic complications due to drug-induced thrombocytopenia were noticed in 25 (22.7%) and severe infections including sepsis in 14 (12.7%) patients.
Assuntos
Antineoplásicos/uso terapêutico , Cladribina/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Adulto , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Cladribina/administração & dosagem , Cladribina/efeitos adversos , Esquema de Medicação , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Infusões Intravenosas , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Recidiva , Vidarabina/análogos & derivados , Vidarabina/uso terapêuticoRESUMO
A 68-year-old male patient with newly diagnosed Waldenström's macroglobulinaemia complicated by severe neutrocytopenia at presentation of the disease was treated with 2-CdA. Partial remission with an increase in neutrocyte count was achieved.
Assuntos
Cladribina/uso terapêutico , Imunossupressores/uso terapêutico , Neutropenia/tratamento farmacológico , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Idoso , Animais , Humanos , Masculino , Camundongos , Neutropenia/etiologia , Macroglobulinemia de Waldenstrom/complicaçõesRESUMO
We have analysed the cellularity, the number of clonogenic cells and their clonogenic efficiency (the number of clonogenic cells/2 x 10(5) MNC) in peripheral blood (PB) and bone marrow (BM) during and after filgrastim (rhG-CSF) mobilization of CD34+ cells in 12 healthy donors for allogeneic stem cell donation. G-CSF was administrated subcutaneously for 5 consecutive days at a dose of 10 micrograms/kg/day. WBC, MNC, CD34+ cell counts, CFU-GM and BFU-E assays in PB were performed at baseline and then daily 12 hours after each G-CSF dose. BM was assayed before start (day 1) and after the last dose (day 6) of G-CSF. Results are given as medians, with ranges in parentheses. In PB the total WBC and MNC increased 7.4-fold (6.0-12.3) and 3.3-fold (1.5-9.4), respectively, reaching a peak of 49.4 x 10(9)/l (32.5-66.6) on day 6 for WBC and 6.28 x 10(9)/l (4.7-13.3) for MNC on day 5. CD34+ cell number reached a peak value of 48.0 x 10(6)/l (45.6-285) on day 6 whereas CFU-GM and BFU-E reached their peaks on day 5, 0.95 x 10(4)/ml (0.05-6.08) and 1.04 x 10(4)/ml, respectively. CFU-MIX, not detectable at baseline, reached a peak of 0.95 x 10(4)/ml (0.006-0.51) on day 5 as well. This was accompanied by an increase in CFU-GM, BFU-E and CFU-MIX clonogenic efficiency: 23-fold (3-150), 9.75-fold (2.2-27.8) and 20-fold (2.5-210), respectively. In BM the total WBC number increased 2.5-fold (1.3-4.9) from the baseline value of 52.6 x 10(9)/l (7.9-137.0) whereas the MNC count increased 2.0-fold (0.81-3.7) from a baseline of 13.6 x 10(9)/l (3.5-54.8). This was, however, not significant. The number of CD34+ cells increased significantly 2.9-fold (0.8-8.3). In 8 donors CFU-MIX were detectable before but not after G-CSF treatment. A similar decrease in CFU-GM and BFU-E clonogenic efficiency occurred but was not significant. CFU-GM and BFU-E numbers did not change. We conclude that the total body numbers of lineage committed progenitors increased during G-CSF administration, which indicate their proliferation in addition to mobilization. The effect of G-CSF on the number of more primitive progenitors in BM is less clear and needs further investigation.
Assuntos
Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/efeitos dos fármacos , Adolescente , Adulto , Contagem de Células Sanguíneas , Células da Medula Óssea/efeitos dos fármacos , Contagem de Células , Ensaio de Unidades Formadoras de Colônias , Feminino , Filgrastim , Células-Tronco Hematopoéticas/citologia , Humanos , Masculino , Proteínas Recombinantes , Fatores de Tempo , Doadores de TecidosRESUMO
We have analysed the clinical course of the 14 consecutive allogeneic peripheral blood stem cell transplantations (PBSCT) and cellular composition of the grafts. Donors were HLA-identical siblings except for the one donor who was only HLA-phenotypically identical brother. Nine of them were sex-mismatched to their recipient. Donors received filgrastim (G-CSF) at a dose of 10 microkilograms/kg for 5 days (4-6). Leukaphereses were started at 5 day to obtain the target dose 4 x 10(6) CD34+ cells/kg recipient weight. Median 24 l of blood (24-36) was processed collecting: 10.3 x 10(8)/kg (6.69-18.8) WBC, 9.9 x 10(8)/kg (5.87-16.02) MNC, 9.72 x 10(6)/kg (0.74-18.98) CD34+ cells, 242.5 x 10(6)/kg (77.9-422) T lymphocytes (CD4+ to CD8+ ratio was 1.5), 76 x 10(6)/kg (24-113) B lymphocytes, 33 x 10(6)/kg (14-88) NK cells and 168.8 x 104/kg (23.1-271.4) CFU-GM with 131.7 x 10(4)/kg (8.4-297.6) BFU-E. Engraftment times to a neutrophil count (ANC) > 0.5 x 10(9)/l was achieved at a median of 15 days (range 10-23) in all patients whereas the platelet count > 20 x 10(9)/l at a median of 14 days (9-19) in all but one patient who received the smallest dose of CD34+ cells. Acute graft versus host disease (GvHD) developed in 8 patients who survived more than 30 days. Most of them (75%) were patients with chronic myeloid leukaemia (CML). In 4 of them GvHD was steroid resistant. Chronic GvHD developed in 3 of 6 evaluable patients. We confirm that allogeneic PBSCT result in rapid and longterm trilineage engraftment. However, the observation of the increasing incidence and severity of acute GvHD in patients with CML will require verification in the larger setting of patients after completion of ongoing clinical trials.
Assuntos
Doadores de Sangue/classificação , Tipagem e Reações Cruzadas Sanguíneas , Doença Enxerto-Hospedeiro/epidemiologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Transplante de Células-Tronco , Adulto , Antígenos CD/análise , Contagem de Células Sanguíneas , Doença Crônica , Esquema de Medicação , Feminino , Filgrastim , Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/prevenção & controle , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Teste de Histocompatibilidade , Humanos , Leucaférese , Masculino , Fenótipo , Proteínas Recombinantes , Células-Tronco/imunologia , Taxa de Sobrevida , Transplante HomólogoRESUMO
We estimated survival time of 56 patients with chronic myelogenous leukemia retrospectively classified according to the model by Kantarjian. Moreover we analysed if there was a correlation between the first-year total dose of busulphan and the size of the spleen during the first year of treatment on the one hand and the patients' survival on the other and if the above factors could enhance the prognostic value of the model by Kantarjian. Although we found such a correlation our preliminary results suggest that the first-year total dose of busulphan and the spleen size do not enhance the prognostic value of the model by Kantarjian.