RESUMO
Asciminib is a myristoyl site BCR::ABL1 inhibitor approved for chronic phase chronic myeloid leukaemia (CP-CML) patients failing ≥2 prior lines of therapy. The Australasian Leukaemia & Lymphoma Group (ALLG) conducted the ASCEND study to assess efficacy of asciminib for newly-diagnosed CP-CML. Patients commenced asciminib 40 mg twice daily (BID) and thereafter were managed according to molecular milestones. Patients with treatment failure, defined as BCR::ABL1 >10% (IS) at 3 or 6 months, or >1% at 12 or 18 months, received either imatinib, nilotinib or dasatinib in addition to asciminib. In patients with suboptimal response, defined as levels of 1-10% at 6 months, >0.1-1% at 12 months, or >0.01%-1% at 18 months, the asciminib dose was increased to 80 mg BID. With a median follow-up of 21 months (range 0-36), 82/101 patients continue asciminib. The most frequent reasons for treatment discontinuation were adverse events (6%), loss of response (4%) and withdrawn consent (5%). There were no deaths; one patient developed lymphoid blast crisis at 6 months. The co-primary endpoints were early molecular response (BCR::ABL1 ≤10% at 3 months), achieved in 93% (96% CI 86-97%), and major molecular response by 12 months achieved in 79%; (95% CI 69.7-86.8%), respectively. The cumulative incidence of MR4.5 was 53% by 24 months. One patient had 2 cerebrovascular events; no other arterial occlusive events were reported. Asciminib as frontline therapy in CP-CML produces high rates of molecular response with excellent tolerance and a low rate of discontinuation for toxicity. (ANZ Clinical Trials Registry ACTRN12620000851965).
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BACKGROUND: Bortezomib, lenalidomide and dexamethasone (VRd) is now the standard-of-care induction therapy for newly diagnosed transplant-eligible multiple myeloma patients, replacing bortezomib, cyclophosphamide and dexamethasone (VCD) therapy. Lenalidomide can negatively impact stem cell yield because of its myelosuppressive effects, although studies have shown that the latter can be overcome with the use of cyclophosphamide for peripheral blood stem cell (PBSC) mobilisation. AIMS AND METHODS: To investigate whether lenalidomide impacts on PBSC mobilisation and to evaluate the optimal mobilisation strategy post VRd induction, we performed a retrospective review of 56 myeloma patients at a single centre who had PBSC mobilisation between January 2019 and March 2021 and compared three cohorts: (i) VCD induction; mobilisation with granulocyte colony-stimulating factor (G-CSF) alone (n = 23); (ii) four cycles VRd induction; mobilisation with G-CSF and cyclophosphamide (G-CSF + Cyclo) (n = 20); and (iii) three cycles VRd induction; mobilisation with G-CSF alone (n = 13). RESULTS: There was no difference in the mean total CD34 count between VCD and VRd patients who had G-CSF mobilisation (6.27 × 106 /kg vs 5.50 × 106 /kg, P > 0.99). VRd patients mobilised with G-CSF + Cyclo achieved higher mean total CD34 counts compared with G-CSF alone (8.89 × 106 /kg vs 5.50 × 106 /kg, P = 0.04). The majority of VRd patients who had G-CSF + Cyclo (19 of 20; 95%) collected sufficient cells for two or more autologous stem cell transplants (ASCTs), regardless of whether this was required, compared with eight of 13 (62%) VRd patients who had G-CSF alone. CONCLUSION: We conclude that successful PBSC mobilisation for at least one ASCT is possible after three cycles of VRd induction using G-CSF alone. The upfront use of a cyclophosphamide-based mobilisation strategy has a role in patients who have had VRd induction, where the aim is to collect enough stem cells for two or more ASCTs.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Mieloma Múltiplo , Células-Tronco de Sangue Periférico , Humanos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/diagnóstico , Bortezomib/uso terapêutico , Lenalidomida/uso terapêutico , Dexametasona/uso terapêutico , Ciclofosfamida/uso terapêutico , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Transplante Autólogo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Mobilização de Células-Tronco HematopoéticasRESUMO
Patients with relapsed/refractory (R/R) higher-risk myelodysplastic syndromes (MDS) have a dismal median overall survival (OS) after failing hypomethylating agent (HMA) treatment. There is no standard of care for patients after HMA therapy failure; hence, there is a critical need for effective therapeutic strategies. Herein, we present the safety and efficacy of venetoclax + azacitidine in patients with R/R MDS. This phase 1b, open-label, multicenter study enrolled patients ≥18 years. Patients were treated with escalating doses of oral venetoclax: 100, 200, or 400 mg daily for 14 days every 28-day cycle. Azacitidine was administered on Days 1-7 every cycle at 75 mg/m2 /day intravenously/subcutaneously. Responses were assessed per modified 2006 International Working Group (IWG) criteria. Forty-four patients (male 86%, median age 74 years) received venetoclax + azacitidine treatment. Median follow-up was 21.2 months. Hematological adverse events of Grade ≥ 3 included febrile neutropenia (34%), thrombocytopenia (32%), neutropenia (27%), and anemia (18%). Pneumonia (23%) was the most common Grade ≥ 3 infection. Marrow responses were seen including complete remission (CR, n = 3, 7%) and marrow CR (mCR, n = 14, 32%); 36% (16/44) achieved transfusion independence (TI) for RBCs and/or platelets, and 43% (6/14) with mCR achieved hematological improvement (HI). The median time to CR/mCR was 1.2 months, and the median duration of response for CR + mCR was 8.6 months. Median OS was 12.6 months. Venetoclax + azacitidine shows activity in patients with R/R MDS following prior HMA therapy failure and provides clinically meaningful benefits, including HI and TI, and encouraging OS.
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Protocolos de Quimioterapia Combinada Antineoplásica , Síndromes Mielodisplásicas , Idoso , Humanos , Masculino , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Azacitidina/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Síndromes Mielodisplásicas/tratamento farmacológico , Neutropenia/induzido quimicamente , Sulfonamidas , Resultado do Tratamento , FemininoRESUMO
The Therapeutic Intensification in De Novo Leukaemia (TIDEL)-II study enrolled 210 patients with chronic phase chronic myeloid leukemia (CML) in two equal, sequential cohorts. All started treatment with imatinib 600 mg/day. Imatinib plasma trough level was performed at day 22 and if <1000 ng/mL, imatinib 800 mg/day was given. Patients were then assessed against molecular targets: BCR-ABL1 ≤10%, ≤1%, and ≤0.1% at 3, 6, and 12 months, respectively. Cohort 1 patients failing any target escalated to imatinib 800 mg/day, and subsequently switched to nilotinib 400 mg twice daily for failing the same target 3 months later. Cohort 2 patients failing any target switched to nilotinib directly, as did patients with intolerance or loss of response in either cohort. At 2 years, 55% of patients remained on imatinib, and 30% on nilotinib. Only 12% were >10% BCR-ABL1 at 3 months. Confirmed major molecular response was achieved in 64% at 12 months and 73% at 24 months. MR4.5 (BCR-ABL1 ≤0.0032%) at 24 months was 34%. Overall survival was 96% and transformation-free survival was 95% at 3 years. This trial supports the feasibility and efficacy of an imatinib-based approach with selective, early switching to nilotinib. This trial was registered at www.anzctr.org.au as #12607000325404.
Assuntos
Benzamidas/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Piperazinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Benzamidas/administração & dosagem , Benzamidas/efeitos adversos , Feminino , Proteínas de Fusão bcr-abl/análise , Humanos , Mesilato de Imatinib , Masculino , Pessoa de Meia-Idade , Piperazinas/administração & dosagem , Piperazinas/efeitos adversos , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Análise de Sobrevida , Resultado do Tratamento , Adulto JovemRESUMO
In the treatment of diffuse large B-cell lymphoma, a persistently positive [18F]fluorodeoxyglucose positron emission tomography (PET) scan typically carries a poor prognosis. In this prospective multi-center phase II study, we sought to establish whether treatment intensification with R-ICE (rituximab, ifosfamide, carboplatin, and etoposide) chemotherapy followed by 90Y-ibritumomab tiuxetan-BEAM (BCNU, etoposide, cytarabine, and melphalan) for high-risk diffuse large B-cell lymphoma patients who are positive on interim PET scan after 4 cycles of R-CHOP-14 (rituximab, cyclophosphamide, doxorubicin, and prednisone) can improve 2-year progression-free survival from a historically unfavorable rate of 40% to a rate of 65%. Patients received 4 cycles of R-CHOP-14, followed by a centrally-reviewed PET performed at day 17-20 of cycle 4 and assessed according to International Harmonisation Project criteria. Median age of the 151 evaluable patients was 57 years, with 79% stages 3-4, 54% bulk, and 54% International Prognostic Index 3-5. Among the 143 patients undergoing interim PET, 101 (71%) were PET-negative (96 of whom completed R-CHOP), 42 (29%) were PET-positive (32 of whom completed R-ICE and 90Y-ibritumomab tiuxetan-BEAM). At a median follow up of 35 months, the 2-year progression-free survival for PET-positive patients was 67%, a rate similar to that for PET-negative patients treated with R-CHOP-14 (74%, P=0.11); overall survival was 78% and 88% (P=0.11), respectively. In an exploratory analysis, progression-free and overall survival were markedly superior for PET-positive Deauville score 4 versus score 5 (P=0.0002 and P=0.001, respectively). Therefore, diffuse large B-cell lymphoma patients who are PET-positive after 4 cycles of R-CHOP-14 and who switched to R-ICE and 90Y-ibritumomab tiuxetan-BEAM achieved favorable survival outcomes similar to those for PET-negative R-CHOP-14-treated patients. Further studies are warranted to confirm these promising results. (Registered at: ACTRN12609001077257).
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma Difuso de Grandes Células B/diagnóstico por imagem , Linfoma Difuso de Grandes Células B/terapia , Tomografia por Emissão de Pósitrons , Adulto , Idoso , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Murinos/uso terapêutico , Carboplatina/administração & dosagem , Carmustina/uso terapêutico , Ciclofosfamida/uso terapêutico , Citarabina/uso terapêutico , Doxorrubicina/uso terapêutico , Etoposídeo/administração & dosagem , Feminino , Fluordesoxiglucose F18 , Humanos , Ifosfamida/administração & dosagem , Linfoma Difuso de Grandes Células B/mortalidade , Masculino , Melfalan/uso terapêutico , Pessoa de Meia-Idade , Podofilotoxina/uso terapêutico , Tomografia por Emissão de Pósitrons/métodos , Prednisona/uso terapêutico , Retratamento , Rituximab/administração & dosagem , Resultado do Tratamento , Vincristina/uso terapêutico , Adulto JovemRESUMO
Most patients with chronic myeloid leukemia (CML) treated with imatinib will relapse if treatment is withdrawn. We conducted a prospective clinical trial of imatinib withdrawal in 40 chronic-phase CML patients who had sustained undetectable minimal residual disease (UMRD) by conventional quantitative polymerase chain reaction (PCR) on imatinib for at least 2 years. Patients stopped imatinib and were monitored frequently for molecular relapse. At 24 months, the actuarial estimate of stable treatment-free remission was 47.1%. Most relapses occurred within 4 months of stopping imatinib, and no relapses beyond 27 months were seen. In the 21 patients treated with interferon before imatinib, a shorter duration of interferon treatment before imatinib was significantly associated with relapse risk, as was slower achievement of UMRD after switching to imatinib. Highly sensitive patient-specific BCR-ABL DNA PCR showed persistence of the original CML clone in all patients with stable UMRD, even several years after imatinib withdrawal. No patients with molecular relapse after discontinuation have progressed or developed BCR-ABL mutations (median follow-up, 42 months). All patients who relapsed remained sensitive to imatinib re-treatment. These results confirm the safety and efficacy of a trial of imatinib withdrawal in stable UMRD with frequent, sensitive molecular monitoring and early rescue of molecular relapse.
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Benzamidas/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Piperazinas/uso terapêutico , Pirimidinas/uso terapêutico , Suspensão de Tratamento , Adulto , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Benzamidas/efeitos adversos , Progressão da Doença , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Mesilato de Imatinib , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Masculino , Pessoa de Meia-Idade , Neoplasia Residual , Piperazinas/efeitos adversos , Pirimidinas/efeitos adversos , Recidiva , Resultado do TratamentoRESUMO
The treatment of acute promyelocytic leukemia has improved considerably after recognition of the effectiveness of all-trans-retinoic acid (ATRA), anthracycline-based chemotherapy, and arsenic trioxide (ATO). Here we report the use of all 3 agents in combination in an APML4 phase 2 protocol. For induction, ATO was superimposed on an ATRA and idarubicin backbone, with scheduling designed to exploit antileukemic synergy while minimizing cardiotoxicity and the severity of differentiation syndrome. Consolidation comprised 2 cycles of ATRA and ATO without chemotherapy, followed by 2 years of maintenance with ATRA, oral methotrexate, and 6-mercaptopurine. Of 124 evaluable patients, there were 4 (3.2%) early deaths, 118 (95%) hematologic complete remissions, and all 112 patients who commenced consolidation attained molecular complete remission. The 2-year rate for freedom from relapse is 97.5%, failure-free survival 88.1%, and overall survival 93.2%. These outcomes were not influenced by FLT3 mutation status, whereas failure-free survival was correlated with Sanz risk stratification (P[trend] = .03). Compared with our previously reported ATRA/idarubicin-based protocol (APML3), APML4 patients had statistically significantly improved freedom from relapse (P = .006) and failure-free survival (P = .01). In conclusion, the use of ATO in both induction and consolidation achieved excellent outcomes despite a substantial reduction in anthracycline exposure. This trial was registered at the Australian New Zealand Clinical Trials Registry (www.anzctr.org.au) as ACTRN12605000070639.
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Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Arsenicais/uso terapêutico , Idarubicina/uso terapêutico , Leucemia Promielocítica Aguda/tratamento farmacológico , Óxidos/uso terapêutico , Tretinoína/uso terapêutico , Adolescente , Adulto , Idoso , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/uso terapêutico , Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Trióxido de Arsênio , Arsenicais/administração & dosagem , Criança , Pré-Escolar , Feminino , Humanos , Idarubicina/administração & dosagem , Quimioterapia de Indução/métodos , Masculino , Pessoa de Meia-Idade , Óxidos/administração & dosagem , Resultado do Tratamento , Tretinoína/administração & dosagem , Adulto JovemRESUMO
INTRODUCTION: Immunosuppressive therapy (IST) with antithymocyte globulin (ATG) and ciclosporin is standard of care for patients with severe aplastic anaemia (sAA) not eligible or suitable for allogeneic stem cell transplant. While patients respond to IST, few achieve complete responses and a significant proportion are refractory or relapse. The addition of eltrombopag, a thrombopoietin-receptor agonist (TPO-A), to IST has been shown to improve haematological responses in sAA. Avatrombopag is a second-generation TPO-A with potential advantages over eltrombopag. However, to date avatrombopag has not been studied in sAA. METHODS AND ANALYSIS: Investigator-initiated, single-arm registry-based Bayesian Optimal Phase II trial of avatrombopag conducted in two cohorts, patients with untreated sAA (FIRST cohort) and in patients with sAA that has relapsed or is refractory to IST (NEXT cohort). In the FIRST cohort, participants receive IST (equine ATG and ciclosporin) plus avatrombopag from day 1 until day 180 at 60 mg oral daily, with dose adjusted according to platelet count. Participants in the NEXT cohort receive avatrombopag at 60 mg oral daily from day 1 until day 180, with or without additional IST at the discretion of the treating clinician.For each cohort, two primary endpoints (haematological response and acquired clonal evolution) are jointly monitored and the trial reviewed at each interim analysis where a 'go/no-go' decision is made by evaluating the posterior probability of the events of interests. ETHICS AND DISSEMINATION: The trial has received ethics approval (Monash Health RES-18-0000707A). The trial conduct will comply with ICH-GCP and all applicable regulatory requirements. The results of the trial will be submitted to a peer-review journal for publication. TRIAL REGISTRATION NUMBER: ACTRN12619001042134, ACTRN12619001043123.
Assuntos
Anemia Aplástica , Benzoatos , Ciclosporina , Hidrazinas , Pirazóis , Tiazóis , Tiofenos , Humanos , Animais , Cavalos , Ciclosporina/uso terapêutico , Imunossupressores/efeitos adversos , Anemia Aplástica/tratamento farmacológico , Teorema de Bayes , Soro Antilinfocitário/uso terapêutico , Terapia de Imunossupressão , Resultado do Tratamento , Ensaios Clínicos Fase II como AssuntoRESUMO
Primary choroidal lymphoma is a rare, slowly progressive intraocular malignancy. Most are low grade B cell lymphomas, often involving tissues adjacent to the choroid such as the subconjunctival space, lacrimal gland or orbit. Ideally, these lesions are biopsied to establish histopathological diagnosis. The most accessible ocular structure is biopsied. Obtaining tissue by transvitreal choroidal biopsy imparts a small but significant risk of ocular morbidity, including the need for multiple surgeries, retinal detachment and vision loss.External beam radiotherapy (EBRT) is a common and effective treatment of low-grade lymphomas. EBRT has been found to very successfully treat primary marginal zone lymphomas of the ocular adnexa, which are typically of the same cell type as most primary choroid lymphomas. Ultra-low dose EBRT, most commonly using a total dose of 4 Gy, has been shown to be as effective as higher doses of radiotherapy for follicular or marginal zone lymphomas. The use of this low dose regimen for conjunctival lymphomas has been recently explored. The role of EBRT, and especially ultra-low dose EBRT, for treatment of primary choroidal lymphoma has been confined to case reports.We describe a case of presumed primary choroidal lymphoma diagnosed on clinical findings alone as the risks of ocular biopsy were deemed too high, and report outcome following treatment with ultra-low dose EBRT.
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Primary CNS lymphoma (PCNSL) in immunocompetent patients is a disease of older adults who are often unsuitable for the high dose therapy or experience substantial morbidity from whole brain radiotherapy. As therapeutic studies in older patients are limited, there is a need for real world data to guide patient care. Here we report a series of 38 consecutive immunocompetent patients with PCNSL treated with curative intent using R-MPV/Ara-C with omission of consolidative radiotherapy in older patients. Outcomes for patients aged < 60 years and > 60 years were similar with overall response rates of 100% vs 85%, (p = .30), 4-year PFS of 81% vs 82% (p = .92) and 4-year OS of 80% vs 77% (p = .52) respectively. This study supports the premise that older patients with PCNSL can be effectively treated with sequential and response-adapted methotrexate (MTX) dosing without the need for WBRT or autologous stem cell transplantation (ASCT).
Assuntos
Neoplasias do Sistema Nervoso Central , Transplante de Células-Tronco Hematopoéticas , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Encéfalo , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/terapia , Terapia Combinada , Citarabina/uso terapêutico , Humanos , Metotrexato/uso terapêutico , Transplante de Células-Tronco , Transplante AutólogoRESUMO
LEOPARD was a single arm, phase II study of lenalidomide (LEN) and alternate day prednisolone maintenance in patients with newly diagnosed multiple myeloma (MM) following autologous stem cell transplantation (ASCT). Sixty patients were enrolled. Estimated median potential follow-up was 44 m, median PFS was 38.3 m, median OS was not reached (landmark 36 m OS: 71.4%). Correlative immunohistochemistry performed on pre-ASCT trephines demonstrated high MM tumor cereblon (total/cytoplasmic) was associated with superior OS (p = .045, p = .031, respectively), whereas high c-Myc was associated with inferior PFS (p = .04). Patients with high cereblon (total/nuclear) were more likely to improve depth of response, whereas patients with high c-Myc were less likely, suggesting alternative/more effective post-ASCT strategies for patients with high c-Myc need identification. Peripheral blood immune profiling (mass cytometry) informed a more sustained response to LEN maintenance, demonstrating enrichment of activated/cytotoxic NK cells and cytotoxic T cells in patients with durable responses, contrasting with enrichment of B-regs in early relapsers.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Mieloma Múltiplo , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Biomarcadores , Humanos , Lenalidomida/uso terapêutico , Quimioterapia de Manutenção , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/tratamento farmacológico , Transplante AutólogoRESUMO
We conducted a trial in 103 patients with newly diagnosed chronic phase chronic myeloid leukemia (CP-CML) using imatinib 600 mg/day, with dose escalation to 800 mg/day for suboptimal response. The estimated cumulative incidences of complete cytogenetic response (CCR) by 12 and 24 months were 88% and 90%, and major molecular responses (MMRs) were 47% and 73%. In patients who maintained a daily average of 600 mg of imatinib for the first 6 months (n = 60), MMR rates by 12 and 24 months were 55% and 77% compared with 32% and 53% in patients averaging less than 600 mg (P = .037 and .016, respectively). Dose escalation was indicated for 17 patients before 12 months for failure to achieve, or maintain, major cytogenetic response at 6 months or CCR at 9 months but was only possible in 8 patients (47%). Dose escalation was indicated for 73 patients after 12 months because their BCR-ABL level remained more than 0.01% (international scale) and was possible in 45 of 73 (62%). Superior responses achieved in patients able to tolerate imatinib at 600 mg suggests that early dose intensity may be critical to optimize response in CP-CML. The trial was registered at www.ANZCTR.org.au as #ACTRN12607000614493.
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Antineoplásicos/administração & dosagem , Proteínas de Fusão bcr-abl/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Piperazinas/administração & dosagem , Pirimidinas/administração & dosagem , Adolescente , Adulto , Idoso , Antineoplásicos/efeitos adversos , Benzamidas , Relação Dose-Resposta a Droga , Feminino , Humanos , Mesilato de Imatinib , Masculino , Pessoa de Meia-Idade , Piperazinas/efeitos adversos , Pirimidinas/efeitos adversos , Fatores de TempoRESUMO
The title "great imitator" refers to conditions which can cause varied manifestations and mimic many diseases. Lymphoma is worthy of this title. We describe three cases of lymphoma in which lymphoma mimicked other diseases causing neurological dysfunction, specifically sarcoidosis, vasculitis and infection respectively. Case 1 was a 66-year-old man with subacute progressive diplopia and gait disturbance and investigations revealing a supratentorial para-falcine soft tissue lesion, mid-thoracic cord enhancement and right axillary mass and an elevated serum ACE. Right axillary mass core biopsy was diagnostic of Burkitt lymphoma. Case 2 was a 50-year-old man with several weeks of constitutional symptoms and development of lower limb weakness and numbness, urinary retention and confusion while in hospital. MRI brain demonstrated multi-territory cerebral infarcts. Intravascular lymphoma was diagnosed on random skin biopsy. Case 3 was a 65-year-old man with several weeks of headache and diplopia on a background of previously treated Burkitt lymphoma. CSF analysis showed a lymphocytic pleocytosis and markedly low glucose with cytologic analysis negative for malignancy. Investigations for an infective cause were negative. FDG-PET demonstrated marked, disseminated spinal and cranial leptomeningeal disease and a multi-focal, intra-dural relapse of Burkitt lymphoma was diagnosed. The varied manifestations in our cases demonstrate the ability for lymphoma to mimic infective, inflammatory, granulomatous (including sarcoidosis) and neoplastic aetiologies. An elevated serum ACE appears insufficiently diagnostic to confirm sarcoidosis and tissue for histological examination should be sought whenever possible. When the diagnosis is uncertain, the possibility of this great imitator should be considered, especially for multi-focal disease.
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Linfoma/patologia , Recidiva Local de Neoplasia/patologia , Sarcoidose/diagnóstico , Vasculite/diagnóstico , Idoso , Diagnóstico Diferencial , Humanos , Linfoma/diagnóstico por imagem , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Pele/patologia , Medula Espinal/patologiaRESUMO
PURPOSE: Oral melphalan and dexamethasone (MDex) were considered a standard of care in light-chain (AL) amyloidosis. In the past decade, bortezomib has been increasingly used in combination with alkylating agents and dexamethasone. We prospectively compared the efficacy and safety of MDex and MDex with the addition of bortezomib (BMDex). METHODS: This was a phase III, multicenter, randomized, open-label trial. Patients were stratified according to cardiac stage. Patients with advanced cardiac stage (stage IIIb) amyloidosis were not eligible. The primary end point was hematologic response rate at 3 months. This trial is registered with ClinicalTrials.gov identifier NCT01277016. RESULTS: A total of 109 patients, 53 in the BMDex and 56 in the MDex group, received ≥ 1 dose of therapy (from January 2011 to February 2016). Hematologic response rate at 3 months was higher in the BMDex arm (79% v 52%; P = .002). Higher rates of very good partial or complete response rates (64% v 39%; hazard ratio [HR], 2.47; 95% CI, 1.30 to 4.71) and improved overall survival, with a 2-fold decrease in mortality rate (HR, 0.50; 95% CI, 0.27 to 0.90), were observed in the BMDex arm. Grade 3 and 4 adverse events (the most common being cytopenia, peripheral neuropathy, and heart failure) were more common in the BMDex arm, occurring in 20% versus 10% of cycles performed. CONCLUSION: BMDex improved hematologic response rate and overall survival. To our knowledge, this is the first time a controlled study has demonstrated a survival advantage in AL amyloidosis. BMDex should be considered a new standard of care for AL amyloidosis.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Amiloidose de Cadeia Leve de Imunoglobulina/tratamento farmacológico , Administração Oral , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bortezomib/administração & dosagem , Bortezomib/efeitos adversos , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Feminino , Humanos , Amiloidose de Cadeia Leve de Imunoglobulina/patologia , Masculino , Melfalan/administração & dosagem , Melfalan/efeitos adversos , Pessoa de Meia-Idade , Intervalo Livre de ProgressãoRESUMO
The management of CML in pregnancy is challenging with the need to balance disease control against potential teratogenic effects of TKI therapy. In this multi-center case-cohort study of 16 women in chronic phase, CML ceased TKI treatment pre- or post-conception during their first pregnancy. Thirteen patients were on imatinib; 9 ceased their TKI prior to conception and 7 ceased at pregnancy confirmation. Twelve patients had achieved either MMR or better at time of TKI cessation. Eleven women lost MMR during pregnancy and two patients lost CHR. Fourteen women reestablished MMR on TKI recommenced. The depth molecular response prior to conception appeared to correlate well with restoration of disease control on TKI recommencement though duration of MMR did not appear to be as important. While interruption of TKI treatment for pregnancy usually leads to loss of molecular response, loss of hematological response is uncommon and disease control is reestablished with resumption of therapy in the majority of women.
Assuntos
Antivirais/uso terapêutico , Interferons/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/prevenção & controle , Inibidores de Proteínas Quinases/uso terapêutico , Adulto , Estudos de Casos e Controles , Estudos de Coortes , Quimioterapia Combinada , Feminino , Seguimentos , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Gravidez , Resultado da Gravidez , Resultado do Tratamento , Adulto JovemAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Linfoma de Burkitt , Linfoma Difuso de Grandes Células B , Rituximab , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma de Burkitt/tratamento farmacológico , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Prednisona/uso terapêutico , Rituximab/uso terapêutico , Vincristina/uso terapêutico , Resultado do TratamentoRESUMO
Following the achievement of deep molecular response on tyrosine kinase inhibitors (TKIs), approximately half of patients with chronic myeloid leukemia (CML) can discontinue TKI and remain in treatment-free remission (TFR). The ALLG CML8 study enrolled 40 imatinib-treated patients with undetectable BCR-ABL1 mRNA (approximately MR4.5). Molecular relapse was defined as detectable BCR-ABL1 on two consecutive tests or any single value >0.1%. With a median follow-up of 8.6 years (range 5.7-11.2 years), 18 patients remain in continuous TFR (45.0%; 95% confidence interval 31.9-63.4%). The latest relapse detected was 27 months after stopping imatinib. No patient progressed to advanced phase. Twenty-two patients met criteria for imatinib re-treatment and all regained undetectable molecular response. Nine patients in long-term TFR were monitored by highly sensitive individualized BCR-ABL1 DNA PCR in a sufficient number of samples to enable more precise quantification of residual leukemia. BCR-ABL1 DNA decreased from a median of MR5.0 in the first year of TFR to MR6.1 in the sixth year of TFR. Our results support the long-term safety and remarkable stability of response after imatinib discontinuation in appropriately selected CML patients. Serial high sensitivity testing provides a new and unexpected finding of gradually reducing CML cells in patients in long-term TFR.
Assuntos
Antineoplásicos/uso terapêutico , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Proteínas de Fusão bcr-abl/metabolismo , Humanos , Assistência de Longa Duração , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/uso terapêutico , RNA Mensageiro/metabolismo , Indução de Remissão , Resultado do TratamentoRESUMO
We describe the case of a 35-year-old man presenting with thrombotic microangiopathy (TMA) and renal impairment following, as he later disclosed, intravenous injection of oral formulation tamper-resistant extended-release oxycodone hydrochloride (Oxycontin). Recurrent misuse of this agent was associated with relapsing TMA despite treatment with terminal complement inhibitor eculizumab. Cases of TMA have been reported in the USA in association with intravenous misuse of extended-release oxymorphone (Opana ER) after the introduction of a new non-crushable formulation in 2012. There are two reported accounts of TMA associated with tamper-resistant Oxycontin, which became available in Australia in 2014. This is the first documented case in which eculizumab was used. This case illustrates the practical diagnostic challenges in identifying TMA disorders, and the importance of a detailed drug history. It also highlights the need to clarify what role, if any, eculizumab therapy has in cases of drug-associated TMA.
Assuntos
Transtornos Relacionados ao Uso de Opioides/complicações , Oxicodona/efeitos adversos , Abuso de Substâncias por Via Intravenosa/complicações , Microangiopatias Trombóticas/induzido quimicamente , Adulto , Analgésicos Opioides/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Inativadores do Complemento/uso terapêutico , Preparações de Ação Retardada , Humanos , Injeções Intravenosas , Masculino , Oximorfona/efeitos adversos , Insuficiência Renal/induzido quimicamente , Insuficiência Renal/tratamento farmacológico , Microangiopatias Trombóticas/tratamento farmacológicoRESUMO
Single agent azacitidine or immunomodulatory drugs are effective in myelodysplastic syndrome (MDS), with differing target mechanisms and toxicities. Objectives of this ALLG MDS3 study in clinically advanced MDS, AMML and low blast AML were to establish safety, response and quality of life of azacitidine and thalidomide. Patients received azacitidine (75mg/m2/d sc 7days every 28 days), and oral thalidomide up to 100mg/d for maximum 12months. Eighty patients registered; median age 68 years (range 42-82), 49% IPSS int2-high. With 36.5 months follow up, patients received median 9 cycles azacitidine, 6.1mths thalidomide. Nonhematologic toxicity grade 3+ in 85%, commonly infections. Overall response rate was 63%; 26% CR were unaffected by IPSS. Median response duration 26.3months; overall survival was 28.1months. This combination azacitidine and thalidomide in clinically advanced MDS, CMML and low-blast AML was tolerable without unexpected toxicity and encouraging responses support further investigation of combination approaches with hypomethylating agent and immunomodulatory drug.