RESUMO
Based on the lack of differences in progression-free and overall survival after a median follow-up of 93 months in our HOVON-65/GMMG-HD4 trial (German part; n = 395) randomizing VAD induction (vincristin/adriamycin/dexamthasone)/tandem-transplantation/thalidomide-maintenance vs. PAD induction (bortezomib/adriamycin/dexamethasone)/tandem transplantation/bortezomib maintenance, we discern how chromosomal aberrations determine long-term prognosis by different patterns of association with proliferation and treatment-dependent response, whether responses achieved by different regimens are equal regarding prognosis, and whether subpopulations of patients could be defined as treatable without upfront "novel agents" in cases of limited resources, e.g., in low- or middle-income countries. Serum parameters and risk factors were assessed in 395 patients. CD138-purified plasma cells were subjected to fluorescence in situ hybridization (n = 354) and gene expression profiling (n = 204). We found chromosomal aberrations to be associated in four patterns with survival, proliferation, and response: deletion (del) del17p13, del8p21, del13q14, (gain) 1q21+, and translocation t(4;14) (all adverse) associate with higher proliferation. Of these, del17p is associated with an adverse response (pattern 1), and 1q21+, t(4;14), and del13q14 with a treatment-dependent better response (pattern 2). Hyperdiploidy associates with lower proliferation without impacting response or survival (pattern 3). Translocation t(11;14) has no association with survival but a treatment-dependent adverse response (pattern 4). Significantly fewer patients reach a near-complete response or better with "conventional" (VAD) vs. bortezomib-based treatment after induction or high-dose melphalan. These patients, however, show significantly better median progression-free and overall survival. Molecularly, patients responding to the two regimens differ in gene expression, indicating distinct biological properties of the responding myeloma cells. Patients with normal renal function (89.4%), low cytogenetic risk (72.5%), or low proliferation rate (37.9%) neither benefit in progression-free nor overall survival from bortezomib-based upfront treatment. We conclude that response level, the treatment by which it is achieved, and molecular background determine long-term prognosis. Chromosomal aberrations are associated in four patterns with proliferation and treatment-dependent responses. Associations with faster and deeper responses can be deceptive in the case of prognostically adverse aberrations 1q21+ and t(4;14). Far from advocating a return to "outdated" treatments, if resources do not permit state-of-the-art-treatment, normal renal function and/or molecular profiling identifies patient subpopulations doing well without upfront "novel agents".
Assuntos
Aberrações Cromossômicas , Mieloma Múltiplo , Humanos , Mieloma Múltiplo/genética , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/patologia , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Prognóstico , Adulto , Países em Desenvolvimento , Dexametasona/uso terapêutico , Dexametasona/farmacologia , Bortezomib/uso terapêutico , Bortezomib/farmacologia , Talidomida/uso terapêuticoRESUMO
INTRODUCTION: Lung cancer is most common in older patients; despite this, older patients are historically under-represented in clinical studies. Here we present data from GIDEON, a study undertaken in Germany in patients with epidermal growth factor receptor mutation-positive (EGFRm+) non-small cell lung cancer (NSCLC) receiving first-line afatinib. GIDEON enrolled a high proportion of patients aged ≥70 years, providing an opportunity to study afatinib use in older patients. MATERIALS AND METHODS: In GIDEON (NCT02047903), a prospective non-interventional study, patients with EGFRm+ NSCLC received first-line afatinib in routine clinical practice until disease progression, death or intolerable adverse events. Key objectives were twelve-month progression-free survival (PFS) rate and objective response rate (ORR). Overall survival (OS) and safety were also assessed. This post hoc analysis explores outcomes of patients grouped by age (≥70 and <70 years). RESULTS: In the 152 patients enrolled in GIDEON (69.7% female, 64.5%/22.4%/13.2% with Del19/L858R/other exon 18-21 mutations, 33.6% with brain metastases), the median age was 67 years (range 38-89) and 43.4% were aged ≥70 years. In the ≥70 years age group and the <70 years age group, twelve-month PFS rate was 58.9% and 43.9%, median PFS was 17.2 months and 10.6 months, ORR was 72.0% and 76.5%, twelve-month OS rate was 79.1% and 79.2%, 24-month OS rate was 52.0% and 61.7%, and median OS was 30.4 months and 27.4 months, respectively. In the ≥70 years age group and the <70 years age group, grade ≥3 adverse drug reactions (ADRs) were observed in 34.8% and 40.7% of patients, respectively; the most common were diarrhea (13.6% and 14.0%), acneiform dermatitis (7.6% and 7.0%), stomatitis (1.5% and 4.7%) and maculopapular rash (1.5% and 4.7%). DISCUSSION: Patients with EGFRm+ NSCLC aged ≥70 years showed clinical benefit from first-line afatinib with no unexpected safety signals, supporting the use of afatinib in this setting.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Feminino , Idoso , Idoso de 80 Anos ou mais , Masculino , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Afatinib/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Estudos Prospectivos , Quinazolinas/efeitos adversos , Receptores ErbB/genética , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Resultado do TratamentoRESUMO
Lenalidomide (LEN) maintenance (MT) post autologous stem cell transplantation (ASCT) is standard of care in newly diagnosed multiple myeloma (MM) but has not been compared to other agents in clinical trials. We retrospectively compared bortezomib (BTZ; n = 138) or LEN (n = 183) MT from two subsequent GMMG phase III trials. All patients received three cycles of BTZ-based triplet induction and post-ASCT MT. BTZ MT (1.3 mg/m2 i.v.) was administered every 2 weeks for 2 years. LEN MT included two consolidation cycles (25 mg p.o., days 1-21 of 28 day cycles) followed by 10-15 mg/day for 2 years. The BTZ cohort more frequently received tandem ASCT (91% vs. 33%) due to different tandem ASCT strategies. In the LEN and BTZ cohort, 43% and 46% of patients completed 2 years of MT as intended (p = 0.57). Progression-free survival (PFS; HR = 0.83, p = 0.18) and overall survival (OS; HR = 0.70, p = 0.15) did not differ significantly with LEN vs. BTZ MT. Patients with Assuntos
Antineoplásicos/uso terapêutico
, Bortezomib/uso terapêutico
, Transplante de Células-Tronco Hematopoéticas
, Fatores Imunológicos/uso terapêutico
, Lenalidomida/uso terapêutico
, Mieloma Múltiplo/terapia
, Feminino
, Transplante de Células-Tronco Hematopoéticas/métodos
, Humanos
, Quimioterapia de Manutenção/métodos
, Masculino
, Pessoa de Meia-Idade
, Estudos Retrospectivos
, Transplante Autólogo/métodos
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Idoso , Bortezomib/administração & dosagem , Dexametasona/administração & dosagem , Feminino , Seguimentos , Humanos , Masculino , Mieloma Múltiplo/diagnóstico , Prognóstico , Indução de Remissão , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
We investigated subclonal cytogenetic aberrations (CA) detected by interphase fluorescence in situ hybridization (iFISH) in patients with newly diagnosed multiple myeloma (MM) enrolled in the Haemato Oncology Foundation for Adults in the Netherlands (HOVON)-65/German-Speaking MM Group (GMMG)-HD4 phase 3 trial. Patients were either treated with 3 cycles of vincristine, Adriamycin, and dexamethasone or bortezomib, Adriamycin, and dexamethasone and then thalidomide or bortezomib maintenance after tandem autologous transplantation. Subclones were defined either by presence of different copy numbers of the same chromosome loci and/or CA present in at least 30% less and maximally 2/3 of cells compared with the main clone CA. Patients with subclones harbored more frequently high risk (31.0%) or hyperdiploid main clone aberrations (24.8%) than patients with t(11;14) in the main clone (10.1%). Gains and deletions of c-MYC were the only CA that occurred more frequently as subclone (8.1%/20.5%) than main clone (6.2%/3.9%, respectively). Treatment with bortezomib completely overcame the negative prognosis of high-risk CA in patients without subclones, but not in patients with additional subclonal CA. High-risk patients treated without bortezomib showed dismal outcome whether subclones were present or not. Cytogenetic heterogeneity defined by subclonal CA is of major prognostic significance in newly diagnosed MM patients treated with bortezomib within the HOVON-65/GMMG-HD4 trial.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Aberrações Cromossômicas , Mieloma Múltiplo/diagnóstico , Adolescente , Adulto , Bortezomib/uso terapêutico , Humanos , Hibridização in Situ Fluorescente , Pessoa de Meia-Idade , Mieloma Múltiplo/genética , Países Baixos , Prognóstico , Transplante Autólogo , Adulto JovemRESUMO
BACKGROUND: Dermatologic toxicities, especially akne-like skin rash, are the most common side-effects associated with anti-epidermal growth factor receptor (EGFR) therapy. Preemptive treatment with oral tetracyclines is recommended as a standard. Topical prophylactic options have thus far not been compared to tetracyclines. In the current study, we sought to establish an alternative topical treatment. PATIENTS AND METHODS: In this multicentre, randomized, open-label phase II study patients with (K)Ras-wildtype colorectal cancer receiving panitumumab were randomized (1:1) to receive either doxycycline 100 mg b.i.d. (standard arm) or erythromycin ointment 2% followed by doxycycline in case of insufficient activity. The primary endpoint was the percentage of patients developing no skin toxicity ≥ grade 2 at any time during the first 8 weeks of panitumumab treatment. Skin toxicity was assessed using the NCI CTCAE v 4.0. Secondary endpoints comprised the assessment of skin toxicity using a more thorough grading system (WoMo score), evaluation of skin-related (DLQI) and global quality of life (EORTC QLQ C30). RESULTS: In total, 88 patients were included in this trial. 69% of the patients in the erythromycin arm suffered from skin toxicity of grade ≥ 2 versus 63% in the standard arm (P = n.s.). However, as per WoMo score significantly more patients in the erythromycin arm developed moderate or severe skin toxicity at earlier time points. Skin related and overall quality of life was comparable between both arms. CONCLUSIONS: Based on this data erythromycin cannot be regarded as an alternative to doxycycline as prevention of EGFR-related skin toxicity.
RESUMO
To investigate cytogenetic evolution after upfront autologous stem cell transplantation for newly diagnosed myeloma we retrospectively analyzed fluorescence in situ hybridization results of 128 patients with paired bone marrow samples from the time of primary diagnosis and at relapse. High-risk cytogenetic abnormalities (deletion 17p and/or gain 1q21) occurred more frequently after relapse (odds ratio: 6.33; 95% confidence interval: 1.86-33.42; P<0.001). No significant changes were observed for defined IGH translocations [t(4;14); t(11;14); t(14;16)] or hyperdiploid karyotypes between primary diagnosis and relapse. IGH translocations with unknown partners occurred more frequently at relapse. New deletion 17p and/or gain 1q21 were associated with cytogenetic heterogeneity, since some de novo lesions with different copy numbers were present only in subclones. No distinct baseline characteristics were associated with the occurrence of new high-risk cytogenetic abnormalities after progression. Patients who relapsed after novel agent-based induction therapy had an increased risk of developing high-risk aberrations (odds ratio 10.82; 95% confidence interval: 1.65-127.66; P=0.03) compared to those who were treated with conventional chemotherapy. Survival analysis revealed dismal outcomes regardless of whether high-risk aberrations were present at baseline (hazard ratio, 3.53; 95% confidence interval: 1.53-8.14; P=0.003) or developed at relapse only (hazard ratio, 3.06; 95% confidence interval: 1.09-8.59; P=0.03). Our results demonstrate cytogenetic evolution towards high-risk disease after autologous transplantation and underline the importance of repeated genetic testing in relapsed myeloma (EudraCT number of the HD4 trial: 2004-000944-26).
Assuntos
Análise Citogenética , Mieloma Múltiplo/genética , Transplante Autólogo , Aberrações Cromossômicas , Feminino , Humanos , Hibridização in Situ Fluorescente , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/patologia , Mieloma Múltiplo/terapia , Recidiva , Estudos RetrospectivosRESUMO
The prospective, randomized phase III trial GMMG-HD2 aimed at demonstrating non-inferiority of single (Arm A) versus tandem (Arm B) high-dose melphalan followed by autologous transplantation (HDM/ASCT) with regard to 2-year event-free survival (EFS) in newly-diagnosed multiple myeloma (MM) and included 358 evaluable patients [Intention-to-treat population, (ITT), single/tandem HDM/ASCT: n = 177/181]. After a median follow-up of more than 11 years, non-inferiority of single versus tandem HDM/ASCT was demonstrated using the planned non-inferiority threshold of 15% of the 2-year EFS rate. Neither EFS (P = 0·53) nor overall survival (OS) (P = 0·33) differences were observed in the ITT population. In the tandem arm, 26% (n = 47/181) of patients refused a second HDM/ASCT due to non-medical reasons. A per-protocol (PP) analysis, including patients who received the intervention (single/tandem HDM/ASCT: n = 156/93) and patients who did not receive a second HDM/ASCT due to medical reasons (12%, n = 22/181), did not yield differences in EFS (P = 0·61) or OS (P = 0·16). In the ITT and PP set of the tandem arm, the rates of complete responses increased from first to second HDM/ASCT (both P = 0·04). Ten-year OS for the entire ITT was 34% (95% confidence interval: 29-40%). OS after first relapse was significantly shortened in the tandem arm (P = 0·04). In this study single HDM/ASCT was non-inferior to tandem HDM/ASCT in MM.
Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Melfalan/administração & dosagem , Mieloma Múltiplo/terapia , Adulto , Idoso , Terapia Combinada/métodos , Feminino , Seguimentos , Humanos , Masculino , Melfalan/uso terapêutico , Pessoa de Meia-Idade , Mieloma Múltiplo/mortalidade , Agonistas Mieloablativos/administração & dosagem , Agonistas Mieloablativos/uso terapêutico , Estudos Prospectivos , Indução de Remissão/métodos , Análise de Sobrevida , Transplante AutólogoRESUMO
In the multicentre prospective randomized HD2002 trial, rituximab maintenance therapy (375 mg/m(2) every 3 months for 2 years) versus observation was evaluated for CD20(+) B-cell lymphoma. Out of 321 patients [161 randomized to the treatment group (TG), 160 to the observation group (OG)], 295 data sets were evaluable for statistical analysis. Estimated 5-year relapse-free survival (RFS) was 81% in the TG and 70% in the OG (logrank test, P = 0·047). In the diffuse large B-cell lymphoma (DLBCL) subgroup (n = 152), 5-year RFS was excellent, at 87% in the TG and 84% in the OG (logrank test, P = 0·35). Of note, only in male patients of the DLBCL subgroup was RFS significantly superior in the TG in comparison to the OG (5-year RFS: 88% vs. 74%; logrank test, P = 0·05). Cox regression analysis showed a significant interaction between treatment and gender regarding overall survival (OS) (P = 0·006) and RFS (P = 0·02), with a lower hazard in females than males in the OG [OS: hazard ratio (HR) (female:male) = 0·11; 95% confidence interval (CI) = 0·00-1·03; RFS: HR (female:male) = 0·27; 95% CI = 0·05-0·97], and no significant differences between males and females in the TG. We conclude that Rituximab maintenance therapy improves survival in male patients with DLBCL.
Assuntos
Antineoplásicos/administração & dosagem , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Rituximab/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Esquema de Medicação , Feminino , Humanos , Linfoma Difuso de Grandes Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Rituximab/efeitos adversos , Resultado do TratamentoRESUMO
BACKGROUND: Harvest of more than one CD34+ stem cell transplant has become the standard, to ensure the option for a second autologous transplantation in patients with relapsed or progressive multiple myeloma (MM). Additional administration of the CXCR-4 inhibitor plerixafor has been shown to increase the efficiency of CD34+ stem cell harvest. However, the algorithm when to apply plerixafor is still under debate. STUDY DESIGN AND METHODS: In this retrospective study, 46 MM patients were categorized into four groups according to their CD34+ stem cell count in peripheral blood (PB) and mobilization with or without plerixafor: Group A comprised poor mobilizers with CD34+ cell counts of fewer than 20 × 10(6) /L in PB. Group B included inadequate mobilizers with CD34+ cell counts of 20 × 10(6) /L or more in PB and a low CD34+ stem cell yield in the first leukapheresis session. Patients receiving plerixafor preemptively (Group A1) and as a rescue strategy (Group B1) were compared to patients continuing stem cell collection with granulocyte-colony-stimulating factor alone (Groups A2 and B2). RESULTS: In both, the preemptive and the rescue settings, plerixafor enhanced the CD34+ stem cell yield significantly. Poor mobilization and administration of plerixafor was not associated with delayed engraftment. CONCLUSION: Our data demonstrate that administration of plerixafor is safe and effective and facilitates a significantly higher CD34+ stem cell harvest. Based on the presented data, we propose an algorithm for the use of plerixafor for CD34+ stem cell mobilization and harvesting in poor mobilizing myeloma patients.
Assuntos
Fármacos Anti-HIV/administração & dosagem , Mobilização de Células-Tronco Hematopoéticas , Compostos Heterocíclicos/administração & dosagem , Mieloma Múltiplo/terapia , Transplante de Células-Tronco de Sangue Periférico , Adulto , Idoso , Fármacos Anti-HIV/efeitos adversos , Autoenxertos , Benzilaminas , Ciclamos , Feminino , Compostos Heterocíclicos/efeitos adversos , Humanos , Leucaférese/métodos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/sangue , Receptores CXCR4 , Estudos RetrospectivosRESUMO
PURPOSE: The optimal regimen to prevent chemotherapy-induced nausea and vomiting (CINV) for patients undergoing high-dose chemotherapy and autologous stem-cell transplantation (ASCT) is unclear. To evaluate the effect of aprepitant in addition to a standard regimen, we conducted this randomized, placebo-controlled phase III trial. PATIENTS AND METHODS: Patients with multiple myeloma were randomly assigned at a one-to-one ratio to receive either aprepitant (125 mg orally on day 1 and 80 mg orally on days 2 to 4), granisetron (2 mg orally on days 1 to 4), and dexamethasone (4 mg orally on day 1 and 2 mg orally on days 2 to 3) or matching placebo, granisetron (2 mg orally on days 1 to 4), and dexamethasone (8 mg orally on day 1 and 4 mg orally on days 2 to 3). Melphalan 100 mg/m(2) was administered intravenously on days 1 to 2. ASCT was performed on day 4. The primary end point (complete response) was defined as no emesis and no rescue therapy within 120 hours of melphalan administration. Quality of life was assessed by modified Functional Living Index-Emesis (FLIE) questionnaire on days -1 and 6. RESULTS: Overall, 362 patients were available for the efficacy analysis (181 in each treatment arm). Significantly more patients receiving aprepitant reached the primary end point (58% v 41%; odds ratio [OR], 1.92; 95% CI, 1.23 to 3.00; P = .0042). Absence of major nausea (94% v 88%; OR, 2.37; 95% CI, 1.09 to 5.15; P = .026) and emesis (78% v 65%; OR, 1.99; 95% CI, 1.25 to 3.18; P = .0036) within 120 hours was increased by aprepitant. Mean total FLIE score (± standard deviation) was 114 ± 18 for aprepitant and 106 ± 26 for placebo (P < .001). CONCLUSION: The addition of aprepitant resulted in significantly less CINV and had a positive effect on quality of life.
Assuntos
Dexametasona/administração & dosagem , Granisetron/administração & dosagem , Melfalan/efeitos adversos , Morfolinas/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Náusea/prevenção & controle , Vômito/prevenção & controle , Aprepitanto , Dexametasona/efeitos adversos , Método Duplo-Cego , Granisetron/efeitos adversos , Transplante de Células-Tronco Hematopoéticas , Humanos , Morfolinas/efeitos adversos , Mieloma Múltiplo/psicologia , Estudos Prospectivos , Qualidade de Vida , Transplante AutólogoRESUMO
BACKGROUND: Cancer of unknown primary (CUP) now accounts for 2-3% of all fatal cases of cancer in Germany. Histologically, most of these tumors are either adenocarcinoma or undifferentiated carcinoma. Scant data on their clinical features and prognosis are now available, and the published survival times are highly variable. In this article, we document and analyze our own experience with CUP to date. METHOD: We took all 223 patients with CUP (adenocarcinoma or undifferentiated carcinoma) whom we saw in our CUP clinic from 2006 to 2010 as an unaltered sample for retrospective analysis of clinical data and overall survival. We performed the analysis with Kaplan-Meier plotting, log-rank testing, and Cox regression. RESULTS: With a median follow-up time of 32.9 months, the median survival from the time of diagnosis was 16.5 months. Metastases were most commonly found in the lymph nodes, followed by the liver, bones, and lungs. The main pre-treatment prognostic variables that remained significant after adjustment for multiple testing were the Eastern Cooperative Oncology Group (ECOG) score for overall state of health and the number of organ systems involved. These variables were used to construct a practice-oriented risk stratification. CONCLUSION: In patients with adeno- or undifferentiated CUP syndrome, the ECOG score and the number of organ systems involved are important risk factors.
Assuntos
Adenocarcinoma/mortalidade , Adenocarcinoma/secundário , Neoplasias Primárias Desconhecidas/mortalidade , Adulto , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Feminino , Alemanha/epidemiologia , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Prevalência , Modelos de Riscos Proporcionais , Fatores de Risco , Distribuição por Sexo , Taxa de SobrevidaRESUMO
PURPOSE: To construct and validate among patients with multiple myeloma (MM) who were treated with intensive therapy a prognostic index of early MM progression-related death. PATIENTS AND METHODS: Patient-level data from the Intergroupe Francophone du Myélome (IFM) 2005-01 trial (N = 482) were used to construct the prognostic index. The event was MM progression-related death within 2 years from treatment initiation. The index was validated using data from three other trials: the Gruppo Italiano Malattie Ematologiche dell' Adulto (GIMEMA) 26866138-MMY-3006 trial (N = 480), the Programa para el Estudio de la Terapéutica en Hemopatía Maligna (PETHEMA)-GEMMENOS65 trial (N = 390), and the Hemato-Oncologie voor Volwassenen Nederland (HOVON) -65/German-Speaking Myeloma Multicenter Group (GMMG) -HD4 trial (N = 827). RESULTS: The risk of early MM progression-related death was related to three independent prognostic variables: lactate dehydrogenase (LDH) higher than than normal, International Staging System 3 (ISS3), and adverse cytogenetics [t(4;14) and/or del(17p)]. These three variables enabled the definition of an ordinal prognostic classification composed of four scores (0 to 3). Patients with a score of 3, defined by the presence of t(4;14) and/or del(17p) in addition to ISS3 and/or high LDH, comprised 5% (20 of 387 patients) to 8% (94 of 1,139 patients) of the patients in the learning and validation samples, respectively, and they had a very poor prognosis. When applied to the population of 855 patients who had received bortezomib-based induction therapy in the four trials, the prognostic classification was also able to segregate patients into four categories, with a very poor prognosis attributed to patients with a score of 3. CONCLUSION: Our model allows the simple definition of a subgroup of MM patients at high risk of early MM progression-related death despite the use of the most modern and effective strategies.
Assuntos
Cromossomos Humanos Par 14 , Cromossomos Humanos Par 17 , Cromossomos Humanos Par 4 , Deleção de Genes , Transplante de Células-Tronco Hematopoéticas , L-Lactato Desidrogenase/sangue , Mieloma Múltiplo/genética , Mieloma Múltiplo/mortalidade , Translocação Genética , Progressão da Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/enzimologia , Mieloma Múltiplo/patologia , Estadiamento de Neoplasias , Valor Preditivo dos Testes , Prognóstico , Transplante AutólogoRESUMO
PURPOSE: To compare sensitivity of whole-body Computed Tomography (wb-CT) and whole-body Magnetic Resonance Imaging (wb-MRI) with Projection Radiography (PR) regarding each method's ability to detect osteolyses in patients with monoclonal plasma cell disease. PATIENTS AND METHODS: The bone status of 171 patients was evaluated. All patients presented with multiple myeloma (MM) of all stages, monoclonal gammopathy of unknown significance (MGUS) or solitary plasmacytoma. Two groups were formed. Group A consisted of 52 patients (26 females, 26 males) with an average age of 62 years (range, 45-89 years) who received, both, PR and wb-CT as part of their diagnostic work-up. Group B comprised 119 patients (58 females, 61 males) averaging 57 years of age (range, 20-80 years) who received, both, PR and wb-MRI. Two experienced radiologists were blinded regarding the disease status and assessed the number and location of osteolyses in consensus. A distinction was made between axial and extra-axial lesions. RESULTS: In group A, wb-CT revealed osteolyses in 12 patients (23%) that were not detected in PR. CT was superior in detecting lesions in patients with osteopenia and osteoporosis. Compared with PR, wb-CT was significantly more sensitive in detecting osteolyses than PR (p<0.001). This was particularly true for axial lesions. Additionally, CT revealed clinically relevant incidental findings in 33 patients (63%). In group B, wb-MRI revealed lesions in 19 patients (16%) that were not detected in PR. All lesions detected by PR were also detected by wb-MRI and wb-CT. Wb-MRI and wb-CT are each superior to PR in detecting axial lesions. CONCLUSION: Wb-CT can detect 23% more focal lesions than PR, especially in the axial skeleton. Therefore, this imaging method should be preferred over PR in the diagnostic work-up and staging of patients with monoclonal plasma cell disease.
Assuntos
Imageamento por Ressonância Magnética/métodos , Mieloma Múltiplo/diagnóstico , Osteólise/diagnóstico , Imagem Radiográfica a Partir de Emissão de Duplo Fóton/métodos , Tomografia Computadorizada por Raios X/métodos , Imagem Corporal Total/métodos , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/complicações , Variações Dependentes do Observador , Osteólise/etiologia , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Método Simples-CegoRESUMO
While extensive data demonstrated that plerixafor improves stem cell harvest in difficult-to-mobilize patients, economic concerns limit a broader application. We retrospectively assessed the effect of an early plerixafor rescue regimen for mobilization in patients with multiple myeloma. Patients were intended for high-dose chemotherapy followed by autologous peripheral blood stem cell transplantation (ABSCT) and therefore received cyclophosphamide-based mobilization chemotherapy and consecutive stimulation with granulocyte colony-stimulating factor (G-CSF). Fifteen patients with poor stem cell harvest in the first leukapheresis session received plerixafor. Data were compared with a matched historic control group of 45 patients who also had a poor stem cell yield in the first apheresis session, but continued mobilization with G-CSF alone. Patients in the plerixafor group collected significantly more CD34+ cells in total (median 4.9 vs. 3.7 [range 1.6-14.1 vs. 1.1-8.0] × 10(6) CD34+ cells /kg bw; P < 0.05), and also more CD34+ cells per leukapheresis procedure (P < 0.001). Consequently, they required a significantly lower number of leukapheresis procedures to achieve the collection goal (median 2.0 vs. 4.0 [range 2-3 vs. 2-9] procedures; P < 0.001). The efficiency of the collected stem cells in terms of hematologic engraftment after ABSCT was found to be equal in both groups. These data demonstrate that rescue mobilization with plerixafor triggered by a low stem cell yield in the first leukapheresis session is effective. Although the actual economic benefit may vary depending on the local leukapheresis costs, the median saving of two leukapheresis procedures offsets most of the expenses for the substance in this setting. An exemplary cost calculation is provided to illustrate this effect.
Assuntos
Fator Estimulador de Colônias de Granulócitos/farmacologia , Mobilização de Células-Tronco Hematopoéticas/métodos , Compostos Heterocíclicos/farmacologia , Leucaférese/economia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzilaminas , Contagem de Células Sanguíneas , Terapia Combinada , Custos e Análise de Custo , Ciclamos , Ciclofosfamida/administração & dosagem , Avaliação de Medicamentos , Sinergismo Farmacológico , Sobrevivência de Enxerto , Mobilização de Células-Tronco Hematopoéticas/economia , Transplante de Células-Tronco Hematopoéticas/economia , Humanos , Leucaférese/estatística & dados numéricos , Mieloma Múltiplo/sangue , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/terapia , Estudos Retrospectivos , Transplante AutólogoRESUMO
Chromosomal aberrations of plasma cells are well established pathogenetic and prognostic factors in multiple myeloma, but their prognostic implication in systemic light chain (AL) amyloidosis is unclear. Therefore, the aim of this study was to identify prognostic cytogenetic risk factors by interphase FISH in a series of 103 consecutive AL amyloidosis patients treated uniformly with melphalan/dexamethasone as first-line therapy. Detection of gain of 1q21 was predictive for a poor overall survival (OS) (median 12.5 versus 38.2 months, p = 0.002). Hematologic event free survival (hem EFS) for gain of 1q21 was 5.0 versus 8.5 months in median (p = 0.08) and haematologic remission rates (≥VGPR) after three cycles were 5% versus 25% (p = 0.06). Most important, in multivariate concordance analyses the adverse prognosis carried by gain of 1q21 was retained as an independent prognostic factor (OS: p = 0.003, average hazard ratio (AHR) = 3.64, hemEFS: p = 0.008, AHR = 2.35), along with the well established Mayo cardiac staging. Patients with t(11;14) had a longer median OS with 38.2 months versus 17.5 months, though no statistical significance was reached. Deletion 13q14 and hyperdiploidy turned out to be prognostically neutral. In conclusion, we have identified gain of 1q21 as an independent adverse prognostic factor in AL amyloidosis patients treated with standard chemotherapy.
Assuntos
Amiloidose/genética , Cromossomos Humanos Par 1/genética , Dexametasona/uso terapêutico , Melfalan/uso terapêutico , Adulto , Idoso , Amiloidose/tratamento farmacológico , Amiloidose/mortalidade , Duplicação Cromossômica , Intervalo Livre de Doença , Quimioterapia Combinada , Feminino , Humanos , Cadeias Leves de Imunoglobulina/metabolismo , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Modelos de Riscos ProporcionaisRESUMO
Renal impairment is frequent in patients with multiple myeloma and is correlated with an inferior prognosis. This analysis evaluates the prognostic role of renal impairment in patients with myeloma treated with bortezomib before and after autologous stem cell transplantation within a prospective randomized phase III trial. Eight hundred and twenty-seven newly diagnosed myeloma patients in the HOVON-65/GMMG-HD4 trial were randomized to receive three cycles of vincristine, adriamycin, dexamethasone (VAD) or bortezomib, adriamycin, dexamethasone (PAD) followed by autologous stem cell transplantation and maintenance with thalidomide 50 mg daily (VAD-arm) or bortezomib 1.3 mg/m(2) every 2 weeks (PAD-arm). Baseline serum creatinine was less than 2 mg/dL (Durie-Salmon-stage A) in 746 patients and 2 mg/dL or higher (stage B) in 81. In myeloma patients with a baseline creatinine ≥ 2 mg/dL the renal response rate was 63% in the VAD-arm and 81% in the PAD-arm (P=0.31). The overall myeloma response rate was 64% in the VAD-arm versus 89% in the PAD-arm with 13% complete responses in the VAD-arm versus 36% in the PAD-arm (P=0.01). Overall survival at 3 years for patients with a baseline creatinine ≥ 2 mg/dL was 34% in the VAD-arm versus 74% in the PAD-arm (P<0.001) with a progression-free survival rate at 3 years of 16% in the VAD-arm versus 48% in the PAD-arm (P=0.004). Overall and progression-free survival rates in the PAD-arm were similar in patients with a baseline creatinine ≥ 2 mg/dL or <2 mg/dL. We conclude that a bortezomib-containing treatment before and after autologous stem cell transplantation overcomes the negative prognostic impact of renal impairment in patients with newly diagnosed multiple myeloma. The trial was registered at www.trialregister.nl as NTR213 and at www.controlled-trials.com as ISRCTN 64455289.
Assuntos
Antineoplásicos/uso terapêutico , Ácidos Borônicos/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Mieloma Múltiplo/complicações , Mieloma Múltiplo/terapia , Pirazinas/uso terapêutico , Insuficiência Renal/etiologia , Insuficiência Renal/prevenção & controle , Adulto , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Ácidos Borônicos/administração & dosagem , Ácidos Borônicos/efeitos adversos , Bortezomib , Creatinina/sangue , Humanos , Pessoa de Meia-Idade , Mieloma Múltiplo/mortalidade , Pirazinas/administração & dosagem , Pirazinas/efeitos adversos , Indução de Remissão , Insuficiência Renal/mortalidade , Insuficiência Renal/fisiopatologia , Transplante Autólogo , Resultado do TratamentoRESUMO
Solitary plasmocytoma of bone is a rare condition of plasma cell neoplasia that presents as a single lesion. Amyloidoma of the chest wall is an uncommon presentation of solitary tissue amyloid deposition in the absence of systemic light-chain amyloidosis. This report describes a patient with both uncommon conditions. The tumor originated from the spine and invaded the right lung. In this exceedingly rare case, radiotherapy and a two-step resection of the right lower lobe, full-thickness chest wall, diaphragm, and vertebral body of T9 provided local control of the tumor. Spondylodesis of T7 to T11 provided spine stability.
Assuntos
Amiloidose/cirurgia , Neoplasias Ósseas/cirurgia , Plasmocitoma/cirurgia , Neoplasias Torácicas/cirurgia , Procedimentos Cirúrgicos Torácicos/métodos , Parede Torácica , Amiloidose/complicações , Amiloidose/diagnóstico , Biópsia , Neoplasias Ósseas/complicações , Neoplasias Ósseas/diagnóstico , Diagnóstico Diferencial , Humanos , Masculino , Pessoa de Meia-Idade , Plasmocitoma/complicações , Plasmocitoma/diagnóstico , Neoplasias Torácicas/complicações , Neoplasias Torácicas/diagnóstico , Tomografia Computadorizada por Raios XRESUMO
PURPOSE: The aim of this study was to analyze chromosomal aberrations in terms of frequency and impact on time to progression in patients with smoldering multiple myeloma (SMM) on the background of clinical prognostic factors. PATIENTS AND METHODS: The chromosomal abnormalities 1q21, 5p15/5q35, 9q34, 13q14.3, 15q22, 17p13, t(11;14)(q13;q32), and t(4;14)(p16.3;q32) were assessed in CD138-purified myeloma cells by interphase fluorescent in situ hybridization (iFISH) alongside clinical parameters in a consecutive series of 248 patients with SMM. RESULTS: The high-risk aberrations in active myeloma (ie, del(17p13), t(4;14), and +1q21) present in 6.1%, 8.9%, and 29.8% of patients significantly confer adverse prognosis in SMM with hazard ratios (HRs) of 2.90 (95% CI, 1.56 to 5.40), 2.28 (95% CI, 1.33 to 3.91), and 1.66 (95% CI, 1.08 to 2.54), respectively. Contrary to the conditions in active myeloma, hyperdiploidy, present in 43.3% of patients, is an adverse prognostic factor (HR, 1.67; 95% CI, 1.10 to 2.54). Percentage of malignant bone marrow plasma cells assessed by iFISH and combination of M-protein and plasma cell infiltration as surrogates of tumor load significantly confer adverse prognosis with HRs of 4.37 (95% CI, 2.79 to 6.85) and 4.27 (95% CI, 2.77 to 6.56), respectively. In multivariate analysis, high-risk aberrations, hyperdiploidy, and surrogates of tumor load are independently prognostic. CONCLUSION: The high-risk chromosomal aberrations del(17p13), t(4;14), and +1q21 are adverse prognostic factors in SMM just as they are in active myeloma, independent of tumor mass. Hyperdiploidy is the first example for an adverse prognostic factor in SMM of opposite predictiveness in active myeloma. Risk association of chromosomal aberrations is not only a priori treatment dependent (predictive) but is also an intrinsic property of myeloma cells (prognostic).