No abstract

Clofarabine is active and generally well tolerated in this patient group. It is worthy of further evaluation in comparative trials and might be of particular use in patients with adverse cytogenetics.

The treatment of older patients with acute myeloid leukaemia, who are not considered suitable for conventional intensive therapy, is unsatisfactory. Low-dose Ara-C(LDAC) has been established as superior to best supportive care, but only benefits the few patients who enter complete remission. Alternative or additional treatments are required to improve the situation. This randomised trial compared the addition of the immunoconjugate, gemtuzumab ozogamicin (GO), at a dose of 5 mg on day 1 of each course of LDAC, with the intention of improving the remission rate and consequently survival. Between June 2004 and June 2010, 495 patients entered the randomisation. The addition of GO significantly improved the remission rate (30% vs 17%; odds ratio(OR) 0.48 (0.32-0.73); P=0.006), but not the 12 month overall survival (25% vs 27%). The reason for the induction benefit failing to improve OS was two-fold: survival of patients in the LDAC arm who did not enter remission and survival after relapse were both superior in the LDAC arm. Although the addition of GO to LDAC doubled the remission rate it did not improve overall survival. Maintaining remission in older patients remains elusive.

No abstract

Late-onset erythropoietic protoporphyria (EPP) is a rare complication of myelodysplastic syndrome (MDS) but has not been described in association with a myeloproliferative disorder (MPD). EPP is normally an inherited disorder characterized by photosensitivity that starts in early childhood and results from overproduction of protoporphyrin secondary to ferrochelatase (FECH) deficiency. Severe liver disease occurs in 1% to 2% of patients. Here we report that severe photosensitivity and cholestatic liver disease in a patient with a myeloproliferative disorder was caused by excess protoporphyrin production from a clone of hematopoietic cells in which one FECH allele had been deleted. Our observations suggest that the usual explanation for the association of late-onset EPP with MPD and MDS is acquired somatic mutation of one FECH allele in bone marrow and show for the first time that the consequent overproduction of protoporphyrin may be severe enough to cause acute liver damage. IntroductionErythropoietic protoporphyria (EPP) is an uncommon inherited disorder of heme biosynthesis that results from partial deficiency of ferrochelatase (FECH). It is characterized clinically by childhood onset of lifelong photosensitivity and biochemically by overproduction of protoporphyrin in erythropoietic cells with accumulation of protoporphyrin in erythrocytes, plasma, skin, and liver. 1 Clinical expression of EPP normally requires inheritance of an FECH mutation trans to a lowexpression FECH allele, 2-4 which is present in 13% of the United Kingdom population. 4 In 1% to 2% of patients with EPP, deposition of protoporphyrin in the liver leads to progressive liver failure, usually after at least a decade of photosensitivity. 1,5,6 Late onset of photosensitivity is rare in EPP. 1 Only 10 patients have been reported in whom symptoms started after the age of 40 years, 7-10 7 of whom also had refractory anemia with ring sideroblasts (RARS) or other myelodysplastic syndromes (MDSs). In one patient, EPP was recently shown to be caused by proliferation of a clone of hematopoietic cells in which one allele of the FECH gene had been deleted. 9 Here we describe a patient with a myeloproliferative disorder (MPD) who developed severe photosensitivity and cholestatic liver disease. We postulated that these complications were caused by an acquired somatic mutation of the FECH gene in his hematopoietic cells. Study designA 62-year-old man was diagnosed with polycythemia vera (PV) and hyperuricemia (hemoglobin concentration, 17.5 g/L; hematocrit, 0.513 [51.3%]; leukocyte count, 11.1 ϫ 10 9 /L; platelet count, 191 ϫ 10 9 /L; red cell volume, 34.2 mL/kg [136% of predicted]; plasma volume, 34.4 mL/kg [92.6% of predicted]). Bone marrow examination was consistent with a myeloproliferative disorder (MPD), showing increased cellularity, no excess blasts, no ringed sideroblasts, and normal cytogenetics. He was treated with hydroxyurea, venesections, and allopurinol. Thirty-three months later, an increase in his white cell count (73 ϫ 10 9 /L; 79% neutr...

The MRC AML15 Trial is primarily for patients with any form of AML who are under 60 years. One of the questions addressed was whether the addition of the immunoconjugate, Gemtuzumab Ozogamicin (GO) to induction (course 1) and/or consolidation (course 3) is beneficial. In induction patients are randomised to receive either DA (Daunorubicin/Ara-C) or ADE (Ara-C/Daunorubicin/Etoposide) or FLAG-Ida (Fludarabine/Ara-C/Idarubicin/G-CSF) and in consolidation either MACE (Amsacrine/Etoposide) or HD Ara-C (3.0g/m2 or 1.5g/m2 per dose). Our prior pilot trial had shown that GO 3mgs/m2 could be safely added to day 1 of each of these treatments (Kell et al Blood102, 4277–4283). Here we report the preliminary results of the effect of combining GO with induction chemotherapy. This randomisation achieved its recruitment target and was closed on 30 June 2006. All other comparisons in the trial, including GO in consolidation, remain open. Patients: A total of 1115 patients were randomised between July 2002 and June 2006. The median age was 49 (range 0–71) years: 53% of patients were male: 92% (n=1027) had de novo disease: 95% had WHO performance score of <2: 43% received DA, 43% FLAG-Ida, and 14% ADE. (Recruitment to ADE+GO opened in June 2005). Patients with WBC > 30 x 109/l and LFT’s > normal were initially excluded but admitted from March 2004. APL patients were not eligible for entry. 15% of patients with data had favourable 71% intermediate, and 14% adverse cytogenetics. Over 83% were CD33 positive. Results: The overall remission rate was 85% with no differences between the arms for GO vs no GO in CR (85% vs 85%) induction death (8% vs 7%) or resistant disease (7% vs 8%). There was a modest increase in mucositis on the GO arm in course 1 only (p=0.04) and increased AST and Alt toxicity in C1 (p=.002; p=.03) but no difference in bilirubin grades. GO patients used more platelets (19 vs 14; p<0.0001), but not red cells, and had more days on IV antibiotics (20.6 vs 18.6 p=0.001). The haemopoietic recovery and days in hospital were similar. With a median follow-up of 15 months (range 0–45), there is no significant difference in deaths in CR (GO vs no GO): 36 vs 45 (HR 0.75; CI.49–1.16 p=0.2), but relapse was reduced: 37% vs 52% at 3 years (HR 0.70 (0.52–0.92) p=0.01) resulting in an improved DFS: 51% vs 40% at 3 years (HR 0.72 (0.56–0.91) p=0.008). There is so far no significant difference in OS (53% vs 46% at 3 years; HR 0.91(0.73–1.14) p=0.4). Conclusion: This preliminary analysis of 1115 randomised patients indicates that the addition of GO to induction chemotherapy can reduce the relapse risk without adding significant extra toxicity and this has significantly improved the DFS in the GO arm. Longer follow up is required to determine the impact on survival.

A multicenter phase II study was initiated to investigate the efficacy, toxicity and tolerability of an oral regimen of 9-cis retinoic acid (9CRA) as a differentiation-inducing agent stimulating both retinoic acid receptor (RAR) and retinoic X receptor (RXR). Thirty patients with myelodysplastic syndromes (MDS) were enrolled into the study. The MDS subtypes were distributed as follows: 14 refractory anaemia (RA), four refractory anaemia with ringed sideroblasts (RARS), and 12 refractory anaemia with excess blasts (RAEB). The age ranged from 40 to 81 years (median 70). None of these had previously received treatment for MDS other than supportive therapy. 9CRA (Alitretinoin capsules, kindly provided by Allergan-Ligand Retinoid Therapeutics) was given daily at 60 mg/m 2 p.o. for 1 week, followed by an intra-patient escalation to 100 mg/m 2 during the second week, up to a maximum of 140 mg/m 2 . The planned treatment duration was 48 weeks. Twenty-five were available for assessment. One patient (4%) with RA achieved complete hematological remission. Four (16%), two with RA, two with RAEB, had minor responses resulting in decreased transfusion requirements or increased neutrophils. Thus, the overall response rate was 20% in evaluable patients with MDS and 17% in the study group on an intention-to-treat basis. The most frequent side-effects included headache (77%), dry skin (57%), arthralgias (30%), and rash (23%). In conclusion, although modest responses were noted in this study, the treatment tolerability was suboptimal. It is conceivable that a lower dosage schedule may be efficacious and better tolerated so enabling prolonged exposure which may be required to induce a differentiation effect. Leukemia (2000) 14, 1583-1588.

582 We previously showed in the MRC AML15 Trial (Burnett et al JCO 2011:29(4):369-77 that 70% of younger patients with AML derived a 10% survival benefit by the addition of the immuno-conjugate, Gemtuzumab Ozogamicin (GO) (Mylotarg™), to induction chemotherapy. In a second trial (AML16 non-intensive) its addition to Low dose Ara-C doubled the CR rate but did not improve OS (Burnett et al. Blood 2010:116 (21): Abstract 18). We now report the result of the NCRI AML16 (Intensive) Trial in which older patients were randomised to receive, or not, GO 3mg/m2 on day 1 of course 1 of induction chemotherapy. Patients were randomised to two courses of DA (daunorubicin/ara-C) or DClo (daunorubicin/clofarabine), followed, or not, by a 3rd course (DA) with or without Azacytidine maintenance. Between December 2006 and July 2010, 1115 patients were randomised to the GO vs no GO comparison from 149 centres in the UK & Denmark. The median age was 67 years (range 51–84). 806 had de novo AML, 194 secondary disease and 115 high risk MDS (>10% marrow blasts). Of the 806 patients with cytogenetic data, 33 were favourable/629 intermediate/204 adverse risk (Grimwade et al, Blood 1998: 92:2322-33). 96% of those allocated GO received it. The overall response rate was 69% (CR 60%; CRi 9%) with 52% of patients achieving response after course 1. Overall survival at 4 years was 17% with a median follow up of 29.5 months (range 0.5–54.6 months).CR%CRi%ORR%Res Dis %Ind Death %30d mortality %60d mortality %GO629711712915No GO5810682111814p-value0.180.30.070.40.80.8 Induction Results: There was no significant difference in blood count recovery kinetics; other toxicities and resource usage were not significantly increased with the exception that for course 1 nausea and oral toxicity were marginally higher with GO, more platelet transfusions were given (13.7 vs 9.6 mean units; p<0.001), and marginally more days of IV antibiotics (mean 19.2 days v 18.1 days p=0.03). There were no significant differences for course 2 of treatment. Relapse/RFS/OS: The rate of relapse was significantly reduced (GO vs no GO: CIR at 2 years 61% vs 70%; p=0.004), leading to significantly better RFS (28% vs 23% at 2 years; p=0.03), and survival from CR and OS were significantly better on the GO arm (2 year survival from CR 47% vs 39%; p=0.02; 2 year OS 35% vs 29%; p=0.04). While the benefit appeared lower in patients with secondary disease or with adverse cytogenetics (GO vs no GO 2 year OS 19% vs 21% and 13% vs 6%) compared to those with de Novo disease or intermediate cytogenetics (2 year OS 38% vs 32% and 41% vs 36%), as was seen in our previous AML15 trial, in this trial there was no significant evidence of interaction between treatment and any demographics or underlying chemotherapy. Conclusion: The addition of GO to induction chemotherapy did not lead to unacceptable increases in toxicity. It improved disease control and delivered a significant OS benefit for older patients overall. While there is no significant interaction, the greater benefit in patients with de novo disease or intermediate risk cytogenetics is consistent over the 2228 patients randomised in the AML15 and AML16 trials. Disclosures: Burnett: Pfizer: Consultancy. Off Label Use: Gemtuzumab Ozogamicin in AML.