Relapse and graft vs host disease (GvHD) following alloHSCT are the major causes of treatment (Tx) failure in patients (pts) with MDS and AML. Azacitidine may reduce risk of relapse and GVHD post-allograft (Platzbecker, 2012; de Lima, 2010). Azacitidine up-regulates putative tumor antigens, inducing a CD8+ T cell response that could augment a graft vs leukemia effect (Craddock, 2015). Reported here are interim results of an ongoing phase I/II dose-finding study of CC-486 (oral azacitidine) maintenance Tx post-alloHSCT. To evaluate the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), pharmacokinetics (PK), and safety of CC-486 Tx after alloHSCT. Pts with MDS or AML who have undergone alloHSCT using myeloablative or reduced intensity conditioning with a sibling or unrelated donor with ≤1 antigen mismatch, are eligible. CC-486 Tx begins 42 - 84 days (d) after alloHSCT. A standard 3x3 MTD design is used. This analysis evaluates 4 QD dosing schedules in repeated 28d Tx cycles: CC-486 200 mg or 300 mg x 7d (Cohorts 1 and 2), 150 mg x 14d (cohort 3A), and 200 mg x 14d (Cohort 3). MTD is established if 2 DLTs occur in a cohort during the first 2 Tx cycles (pts are not evaluable if they do not complete 2 Tx cycles for reasons other than a DLT). Pts are followed for toxicity, acute or chronic GvHD, and relapse. CC-486 PK alone and with standard concomitant medications (meds) are evaluated on d1 of Tx cycles 1 and 2. At data cut-off (9-9-2015), 21 pts (AML n=19, MDS n=2) were included; 9 pts (43%) remained on-study (Figure). In cohorts 1 and 2, 6/7 pts had discontinued Tx, 1 completed Tx. Five pts (24%) were not evaluable for DLT: 4 received <2 CC-486 Tx cycles and 1 pt had a dose reduction. Of 6 evaluable pts in Cohort 3, 1 had a DLT (grade 4 neutropenia, grade 3 pneumonia). This pt later died from thrombotic microangiopathy (29x109/L platelets 1 day earlier). The MTD has not been reached. No secondary graft failure occurred. Grade 3-4 AEs were reported in 15 pts; most frequent were vomiting (n=4), thrombocytopenia, diarrhea, and nausea (n=3 each). Azacitidine plasma concentration profiles and PK of CC-486 were similar with or without concomitant meds, and within ranges for similar doses in non-transplant pts (Laille, 2015). Three pts with GvHD at entry had progression of GvHD during Tx. New acute GvHD occurred in 2 pts on Tx and 1 case of chronic GvHD flare occurred during follow-up. Relapse tended to occur early (Figure) and appeared more frequently in the 7d CC-486 cohorts (4/7, 57%) than the 14d cohorts (3/14, 21%). CC-486, at doses of 150 - 300 mg QD x 7d or 14d every 28d, appears safe and generally well tolerated post-transplantation. Azacitidine PK after oral ingestion was not meaningfully altered by concomitant meds. These interim data show relatively low rates of relapse and GVHD in pts with AML or MDS at high risk of relapse but require confirmation in a randomized study.
Dear Sir, We read with interest the recent report of Kihara et al. of POEMS syndrome with Waldenstroms macroglobulinaemia and associated reactive amyloidosis [1] and would like to make two points: Another possible reason for the occurrence of reactive amyloid in POEMS syndrome may be associated Castleman's disease. Castleman's disease is a rare B-cell lymphoproliferative disorder characterized by giant hyperplastic lymph node follicles, capillary proliferation and plasma-cell infiltration. It may be associated with a gammopathy, organomegaly, neuropathy, anaemia, raised inflammatory indices and reactive amyloidosis. Castleman's disease is usually multicentric and has been reported to occur in up to 50% of cases of POEMS syndrome [2, 3]. It may also occur as a unicentric/localized form with associated reactive amyloid. In such, cases resection of the lymph node mass can lead to regression of the amyloid deposits [4]. We would also like to share our recent experience of an unusual case of POEMS syndrome that further extends the phenotype. The patient presented with prolonged facial flushing, which has not previously been described, and was found to have localized Castleman's disease, an association not previously reported. A 34-year-old Caucasian woman presented with a 6-month history of progressive weakness and allodynia of both legs with recurrent episodes of facial flushing in a ‘butterfly’ distribution. The facial flushing occurred unheralded lasting for 24–48 h in the absence of any demonstrable precipitating factors. She did not drink alcohol. There was no history of weight loss and there were no symptoms in the upper limbs. She was found to have a painful symmetrical sensorimotor peripheral neuropathy predominantly affecting the lower limbs and a small enlarged lymph node was palpable in her left axilla. Serum protein electrophoresis revealed a monoclonal gammopathy of the immunoglobulin G (Ig G) lambda type (22.7 g L−1). A comprehensive endocrine screen showed normal or negative values. Cerebrospinal fluid examination revealed a raised protein level of 0.85 g L−1, but normal glucose and no white cells. Nerve conduction studies showed a generalized sensory and motor demyelinating polyneuropathy with evidence of secondary axonal damage in the lower limbs. Full blood count, erythrocyte sedimentation rate (ESR), haemoglobin and renal function were normal, and a detailed vasculitic screen was normal or negative. A skeletal survey demonstrated multiple osteosclerotic lesions in the vertebrae and the pelvis and a bone marrow trephine showed a plasma cell infiltrate with monotypic expression of the lambda light chains, exceeding 10% of the total cell population. Computed tomography (CT) scanning of the thorax, abdomen and pelvis demonstrated splenomegaly. No areas of lymphadenopathy other than the single lymph node in the left axilla were identified. The histology from the isolated enlarged lymph node in the left axilla showed angiofollicular hyperplasia in a pattern consistent with Castleman's disease, hyaline vascular type. Radiolabelled serum amyloid P scintigraphic imaging did not identify evidence of amyloid deposition. A diagnosis of POEMS syndrome and localized Castleman's disease was made according to recognized criteria [2]. Several studies have shown that there is no difference in the final outcome between patients with the complete POEMS syndrome and those with an incomplete form [2, 5]. Although there is one previous report of transient facial flushing [6] mimicking carcinoid syndrome, prolonged idiopathic facial flushing has not previously been reported as a skin manifestation of POEMS syndrome. This patient was also unusual because she had POEMS syndrome and localized Castleman's disease. This has not been previously reported. It has been proposed that the localized and multicentric forms of Castleman's disease are actually two distinct conditions with different clinical features, natural history and responses to treatment, but sharing similar histological features [3]. This case further extends the POEMS syndrome phenotype and illustrates that other clinical features may occur in addition to those of the classical acronym of polyneuropathy, organomegaly, endocrinopathy, M protein and skin changes. Received 21 October 2002; accepted 11 November 2002. Dr S. J. M. Weatherby, University Department of Clinical Neurology, Queen Elizabeth Hospital, Edgbaston, Birmingham, B15 2TH, UK (tel.: +44 (0) 121 472 1311; e-mail: [email protected]).
Summary Azacitidine (AZA) is important in the management of patients with acute myeloid leukaemia (AML) who are ineligible for intensive chemotherapy. Romidepsin (ROM) is a histone deacetylase inhibitor which synergises with AZA in vitro . The ROMAZA trial established the maximum tolerated dose (MTD) of combined ROM/AZA therapy in patients with AML, as ROM 12 mg/m 2 on Days 8 and 15, with AZA 75 mg/m 2 administered for 7/28 day cycle. Nine of the 38 (23·7%) patients treated at the MTD were classified as responders by Cycle 6 (best response: complete remission [CR]/incomplete CR n = 7, partial response n = 2). Correlative next‐generation sequencing studies demonstrated important insights into therapy resistance.
Acute myeloid leukaemia is prevalent in older patients that are often ineligible for intensive chemotherapy and treatment options remain limited with azacitidine being at the forefront. Azacitidine has been used in the clinic for decades, however, we still lack a complete understanding of the mechanisms by which the drug exerts its anti-tumour effect. To gain insight into the mechanism of action, we defined the mutational profile of sequential samples of patients treated with azacitidine. We did not identify any mutations that could predict response and observed lack of a uniform pattern of clonal evolution. Focusing on responders, at remission, we observed three types of response: (1) an almost complete elimination of mutations (33%), (2) no change (17%), and (3) change with no discernible pattern (50%). Heterogeneous patterns were also observed at relapse, with no clonal evolution between remission and relapse in some patients. Lack of clonal evolution suggests that non-genetic mechanisms might be involved. Towards understanding such mechanisms, we investigated the immune microenvironment in a number of patients and we observed lack of a uniform response following therapy. We identified a higher frequency of cytotoxic T cells in responders and higher frequency of naïve helper T cells in non-responders.
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