Michael Dennis

Azacitidine augments expansion of regulatory T cells after allogeneic stem cell transplantation in patients with acute myeloid leukemia (AML)

Strategies that augment a GVL effect without increasing the risk of GVHD are required to improve the outcome after allogeneic stem cell transplantation (SCT). Azacitidine (AZA) up-regulates the expression of tumor Ags on leukemic blasts in vitro and expands the numbers of immunomodulatory T regulatory cells (Tregs) in animal models. Reasoning that AZA might selectively augment a GVL effect, we studied the immunologic sequelae of AZA administration after allogeneic SCT. Twenty-seven patients who had undergone a reduced intensity allogeneic transplantation for acute myeloid leukemia were treated with monthly courses of AZA, and CD8(+) T-cell responses to candidate tumor Ags and circulating Tregs were measured. AZA after transplantation was well tolerated, and its administration was associated with a low incidence of GVHD. Administration of AZA increased the number of Tregs within the first 3 months after transplantation compared with a control population (P = .0127). AZA administration also induced a cytotoxic CD8(+) T-cell response to several tumor Ags, including melanoma-associated Ag 1, B melanoma antigen 1, and Wilm tumor Ag 1. These data support the further examination of AZA after transplantation as a mechanism of augmenting a GVL effect without a concomitant increase in GVHD.

European development of clofarabine as treatment for older patients with acute myeloid leukemia considered unsuitable for intensive chemotherapy.

PURPOSE Treatment options for older patients with acute myeloid leukemia (AML) who are not considered suitable for intensive chemotherapy are limited. We assessed the second-generation purine nucleoside analog, clofarabine, in two similar phase II studies in this group of patients. PATIENTS AND METHODS Two consecutive studies, UWCM-001 and BIOV-121, recruited untreated older patients with AML to receive up to four or six 5-day courses of clofarabine. Patients in UWCM-001 were either older than 70 years or 60 to 69 years of age with poor performance status (WHO > 2) or with cardiac comorbidity. Patients in BIOV-121 were >or= 65 years of age and deemed unsuitable for intensive chemotherapy. RESULTS A total of 106 patients were treated in the two monotherapy studies. Median age was 71 years (range, 60 to 84 years), 30% had adverse-risk cytogenetics, and 36% had a WHO performance score >or= 2. Forty-eight percent had a complete response (32% complete remission, 16% complete remission with incomplete peripheral blood count recovery), and 18% died within 30 days. Interestingly, response and overall survival were not inferior in the adverse cytogenetic risk group. The safety profile of clofarabine in these elderly patients with AML who were unsuitable for intensive chemotherapy was manageable and typical of a cytotoxic agent in patients with acute leukemia. Patients had similar prognostic characteristics to matched patients treated with low-dose cytarabine in the United Kingdom AML14 trial, but had significantly superior response and overall survival. CONCLUSION 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 impact of dose escalation and resistance modulation in older patients with acute myeloid leukaemia and high risk myelodysplastic syndrome : the results of the LRF AML14 trial

The acute myeloid leukaemia (AML)14 trial addressed four therapeutic questions in patients predominantly aged over 60 years with AML and High Risk Myelodysplastic Syndrome: (i) Daunorubicin 50 mg/m2 vs. 35 mg/m2; (ii) Cytarabine 200 mg/m2 vs. 400 mg/m2 in two courses of DA induction; (iii) for part of the trial, patients allocated Daunorubicin 35 mg/m2 were also randomized to receive, or not, the multidrug resistance modulator PSC‐833 in a 1:1:1 randomization; and (iv) a total of three versus four courses of treatment. A total of 1273 patients were recruited. The response rate was 62% (complete remission 54%, complete remission without platelet/neutrophil recovery 8%); 5‐year survival was 12%. No benefits were observed in either dose escalation randomization, or from a fourth course of treatment. There was a trend for inferior response in the PSC‐833 arm due to deaths in induction. Multivariable analysis identified cytogenetics, presenting white blood count, age and secondary disease as the main predictors of outcome. Although patients with high Pgp expression and function had worse response and survival, this was not an independent prognostic factor, and was not modified by PSC‐833. In conclusion, these four interventions have not improved outcomes in older patients. New agents need to be explored and novel trial designs are required to maximise prospects of achieving timely progress.

A randomized comparison of daunorubicin 90 mg/m2 vs 60 mg/m2 in AML induction: results from the UK NCRI AML17 trial in 1206 patients

Modifying induction therapy in acute myeloid leukemia (AML) may improve the remission rate and reduce the risk of relapse, thereby improving survival. Escalation of the daunorubicin dose to 90 mg/m(2) has shown benefit for some patient subgroups when compared with a dose of 45 mg/m(2), and has been recommended as a standard of care. However, 60 mg/m(2) is widely used and has never been directly compared with 90 mg/m(2). As part of the UK National Cancer Research Institute (NCRI) AML17 trial, 1206 adults with untreated AML or high-risk myelodysplastic syndrome, mostly younger than 60 years of age, were randomized to a first-induction course of chemotherapy, which delivered either 90 mg/m(2) or 60 mg/m(2) on days 1, 3, and 5 combined with cytosine arabinoside. All patients then received a second course that included daunorubicin 50 mg/m(2) on days 1, 3, and 5. There was no overall difference in complete remission rate (73% vs 75%; odds ratio, 1.07 [0.83-1.39]; P = .6) or in any recognized subgroup. The 60-day mortality was increased in the 90 mg/m(2) arm (10% vs 5% (hazard ratio [HR] 1.98 [1.30-3.02]; P = .001), which resulted in no difference in overall 2-year survival (59% vs 60%; HR, 1.16 [0.95-1.43]; P = .15). In an exploratory subgroup analysis, there was no subgroup that showed significant benefit, although there was a significant interaction by FLT3 ITD mutation. This trial is registered at http://www.isrctn.com as #ISRCTN55675535.

Tolerability and Clinical Activity of Post-Transplantation Azacitidine in Patients Allografted for Acute Myeloid Leukemia Treated on the RICAZA Trial

Disease relapse is the major causes of treatment failure after allogeneic stem cell transplantation (SCT) in patients with acute myeloid leukemia (AML). As well as demonstrating significant clinical activity in AML, azacitidine (AZA) upregulates putative tumor antigens, inducing a CD8+ T cell response with the potential to augment a graft-versus-leukemia effect. We, therefore, studied the feasibility and clinical sequelae of the administration of AZA during the first year after transplantation in 51 patients with AML undergoing allogeneic SCT. Fourteen patients did not commence AZA either because of transplantation complications or withdrawal of consent. Thirty-seven patients commenced AZA at a median of 54 days (range, 40 to 194 days) after transplantation, which was well tolerated in the majority of patients. Thirty-one patients completed 3 or more cycles of AZA. Sixteen patients relapsed at a median time of 8 months after transplantation. No patient developed extensive chronic graft-versus-host disease. The induction of a post-transplantation CD8+ T cell response to 1 or more tumor-specific peptides was studied in 28 patients. Induction of a CD8+ T cell response was associated with a reduced risk of disease relapse (hazard ratio [HR], .30; 95% confidence interval [CI], .10 to .85; P = .02) and improved relapse-free survival (HR, .29; 95% CI, .10 to .83; P = .02) taking into account death as a competing risk. In conclusion, AZA is well tolerated after transplantation and appears to have the capacity to reduce the relapse risk in patients who demonstrate a CD8+ T cell response to tumor antigens. These observations require confirmation in a prospective clinical trial.

EBV-associated post-transplant lymphoproliferative disorder following in vivo T-cell-depleted allogeneic transplantation: Clinical features, viral load correlates and prognostic factors in the rituximab era

EBV-associated post-transplant lymphoproliferative disease (PTLD) following Alemtuzumab-based allo-SCT is a relatively uncommon and challenging clinical problem but has not received detailed study in a large cohort. Quantitative-PCR (qPCR) monitoring for EBV reactivation post allo-SCT is now commonplace but its diagnostic and predictive value remains unclear. Sixty-nine patients with PTLD following Alemtuzumab-based allo-SCT were studied. Marked clinicopathological heterogeneity was evident; lymphadenopathy was frequently absent, whereas advanced extranodal disease was common. The median viral load at clinical presentation was 49 300 copies/mL (50–65 200 000 copies/mL) and, notably, 23% and 45% of cases, respectively, had ⩽10 000 and ⩽40 000 copies/mL. The overall response rate to rituximab as first-line therapy was 70%. For rituximab failures, chemotherapy was ineffectual but DLIs were successful. A four-parameter prognostic index predicted response to therapy (OR 0.30 (0.12–0.74); P=0.009] and PTLD mortality (hazard ratio (HR) 1.81 (1.12–2.93) P=0.02) on multivariate analysis. This is the largest detailed series of EBV-associated PTLD after allo-SCT. At clinical presentation, EBV-qPCR values are frequently below customary thresholds for pre-emptive therapy, challenging current paradigms for monitoring and intervention. A four-point score identifies a proportion of patients at risk of rituximab-refractory disease for whom alternative therapy is needed.

Elacytarabine has single-agent activity in patients with advanced acute myeloid leukaemia.

Elacytarabine is a novel cytotoxic nucleoside analogue, independent of nucleoside transporters (e.g. human Equilibrative Nucleoside Transporter 1 [hENT1]) for cell uptake, and mechanisms of action similar to those of cytarabine. This Phase II study assessed the efficacy and safety of elacytarabine in patients with advanced stage acute myeloid leukaemia (AML). Patients received 2000 mg/m2 per d continuously i.v. during days 1–5 every 3 weeks. Patients were matched by six risk factors with historical controls; remission rate (assessed after 1 or 2 cycles) and 6‐month survival were compared. Sixty‐one patients, median age 58 years, were enrolled; 52% had five or six risk factors. The remission rate was 18% (95% confidence interval: 9–30%) vs. 4% in controls (P < 0·0001), 6‐month survival rate was 43%, median overall survival was 5·3 months (vs. 1·5 months); 10 patients (16%) were referred for stem cell transplantation after treatment. Side effects were predictable and manageable. The most common grade 3/4 non‐haematological adverse events were febrile neutropenia, hypokalemia, fatigue, hyponatraemia, dyspnoea and pyrexia. Thirty‐day all‐cause mortality, after start of treatment, was 13% vs. 25% in controls. Elacytarabine has monotherapy activity in patients with advanced AML. This study provides proof‐of‐concept that lipid esterification of nucleoside analogues is clinically relevant.

An operational definition of primary refractory acute myeloid leukemia allowing early identification of patients who may benefit from allogeneic stem cell transplantation.

Up to 30% of adults with acute myeloid leukemia fail to achieve a complete remission after induction chemotherapy - termed primary refractory acute myeloid leukemia. There is no universally agreed definition of primary refractory disease, nor have the optimal treatment modalities been defined. We studied 8907 patients with newly diagnosed acute myeloid leukemia, and examined outcomes in patients with refractory disease defined using differing criteria which have previously been proposed. These included failure to achieve complete remission after one cycle of induction chemotherapy (RES), less than a 50% reduction in blast numbers with >15% residual blasts after one cycle of induction chemotherapy (REF1) and failure to achieve complete remission after two courses of induction chemotherapy (REF2). 5-year overall survival was decreased in patients fulfilling any criteria for refractory disease, compared with patients achieving a complete remission after one cycle of induction chemotherapy: 9% and 8% in patients with REF1 and REF2 versus 40% (P<0.0001). Allogeneic stem cell transplantation improved survival in the REF1 (HR 0.58 (0.46–0.74), P=0.00001) and REF2 (HR 0.55 (0.41–0.74), P=0.0001) cohorts. The utilization of REF1 criteria permits the early identification of patients whose outcome after one course of induction chemotherapy is very poor, and informs a novel definition of primary refractory acute myeloid leukemia. Furthermore, these data demonstrate that allogeneic stem cell transplantation represents an effective therapeutic modality in selected patients with primary refractory acute myeloid leukemia.

A Case of Meningeal Myeloma Presenting as Obstructive Hydrocephalus - A Therapeutic Challenge

Meningeal involvement in myeloma is a rare though recognised complication, and previous treatment strategies have included radiotherapy, intra-thecal and systemic chemotherapy to which there is almost universally a poor response. We report a case of a 60-year-old lady in serological remission with IgG lambda myeloma, presenting with obstructive hydrocephalus due to meningeal infiltration treated with neurosurgical decompression. Such presentation and the treatment strategies are previously unreported, though in view of the ultimate resistance to treatment the prognosis remains poor.

Bullous pyoderma gangrenosum in acute myeloid leukaemia.

A 68-yr-old man with relapsed acute myeloid leukaemia (FAB M5) presented with small, tender, erythematous papules on the dorsal aspects of both wrists, at sites of recent intravenous cannulation. These were initially diagnosed as infective and flucloxacillin was commenced. Subsequently he developed fever and constitutional symptoms. Despite antibiotic escalation the lesions developed into large, exquisitely tender, concentric plaques with well-demarcated, violaceous, serpinginous borders and central necrosis. Similar lesions developed on his left thigh, upper lip and left ear. Microbiology investigations were normal and despite clinical concern that the lesions might represent leukaemic infiltration, recognition of the apparent central necrosis indicated the diagnosis as superficial bullous pyoderma gangrenosum (PG). Punch biopsy revealed inflammatory changes with fat necrosis compatible with PG. Oral prednisolone 1 mg/kg daily was commenced with dramatic regression of the lesions. The association between PG and myeloid malignancy is well established. Typical lesions rapidly enlarge, are tender and violaceous with a well-defined edge and necrotic/ulcerated centre. Histology is non-diagnostic but may exclude doi:10.1111/j.1600-0609.2007.00845.x European Journal of Haematology ISSN 0902-4441