Single agent thalidomide in patients with relapsed or refractory acute myeloid leukaemia

Thalidomide is a putative anti-angiogenesis agent that has significant anti-tumour activity in haematological malignancies with increased bone marrow angiogenesis, including multiple myeloma (MM) and myelodysplastic syndromes (MDS). Increased levels of the mitogen for angiogenesis, vascular endothelial growth factor (VEGF), correlate with worse survival in acute myeloid leukaemia (AML). A phase II trial of thalidomide was conducted in patients with relapsed- or refractory-AML previously treated with cytarabine-containing regimens. A total of 16 patients with refractory- or relapsed-AML were treated with thalidomide 200-800 mg orally daily (median dose 400 mg daily) for a median of 27 d (range, 3-94 d). Overall, one patient (6%) achieved complete remission (CR) lasting for 36 months, and two patients had a transient reduction in marrow blasts from 8% and 7% to less than 5% in both cases. There was no correlation between reduction in levels of angiogenesis markers and response. Toxicities related to thalidomide were significant, and precluded dose escalation beyond 400 mg orally daily in most patients. Although there appears to be some evidence of biological activity, single agent thalidomide is not an optimal choice of therapy for salvaging patients with relapsed- or refractory-AML. Thalidomide analogues with more potent immunomodulatory activities and more favourable toxicity profiles may offer more promise as anti-AML therapy.     

A phase 2 trial of high dose lenalidomide in patients with relapsed/refractory higher‐risk myelodysplastic syndromes and acute myeloid leukaemia with trilineage dysplasia

Limited therapies exist for patients with refractory and relapsed (RR ) higher‐risk myelodysplastic syndromes (HR ‐MDS ) and acute myeloid leukaemia with trilineage dysplasia (AML ‐TD ). High dose (HD ) lenalidomide (50 mg) has activity as frontline therapy in elderly AML but there is limited data in the RR setting. This phase II trial included patients with RR HR ‐MDS or AML ‐TD at 2 doses of lenalidomide (15 or 50 mg) on days 1–28 of 42‐day cycles. The primary endpoint was response rate using the 2006 International Working Group criteria. Overall survival (OS ) was estimated by Kaplan–Meier methods. Of 27 patients enrolled, 59% had HR ‐MDS and 31% AML ‐TD . No patient had isolated del5q; 41% had poor‐risk karyotype. Of 9 patients treated at 15 mg, 56% completed ≥2 cycles with no responses. Of 18 patients treated at 50 mg, 39% completed ≥2 cycles and 11% responded but all experienced grade 3/4 neutropenic fever/infection. The 60‐day mortality rate was 30%. Median OS was 114 days with 19% surviving ≥1 year. The study was terminated due to lack of robust clinical activity. In conclusion, lenalidomide at 15 mg is ineffective in RR myeloid malignancies. Continous high dosing schedules are poorly tolerated and minimally active. Further evaluation should be considered in upfront intensive chemotherapy‐ineligible patients.     

MDR 1 expression is an independent prognostic factor for response and survival in de novo acute myeloid leukaemia

The Multidrug Resistance gene (MDR 1) is frequently expressed in acute myeloid leukaemia (AML). MDR 1 is associated with resistance to chemotherapy in vitro and with a poor response rate in AML. We have investigated the prognostic value of MDR 1 expression in relation to other patient characteristics with respect to response and survival.
One hundred and thirty patients aged 0–88 years were treated for de novo AML with standard induction and consolidation chemotherapy. MDR 1 expression was determined by immunocytochemistry. Univariate and multivariate analyses were conducted to identify prognostic factors for reaching complete remission (CR) and for overall survival from diagnosis, in order to compare MDR 1 with known prognostic factors. Univariate analysis showed that higher MDR 1 expression was an adverse prognostic factor for CR ( P  < 0.001), as was higher age ( P  < 0.001) and unfavourable karyotype ( P  < 0.01). These factors were also negative prognostic factors for overall survival ( P  < 0.001, P  < 0.05 and P  < 0.005, respectively). In the multivariate analysis MDR 1 ( P  < 0.001), higher age ( P  < 0.001) and karyotype ( P  < 0.01) were independent adverse prognostic factors for CR as well as for overall survival ( P  < 0.001, P  < 0.005, P  < 0.001, respectively). Our data indicate that MDR 1 expression is a disease-related unfavourable prognostic factor which has a significant impact on complete remission and overall survival in AML. Analysis of MDR 1 may be used to determine prognosis in individual patients.     

Cladribine combined with high doses of arabinoside cytosine, mitoxantrone, and G-CSF (CLAG-M) is a highly effective salvage regimen in patients with refractory and relapsed acute myeloid leukemia of the poor risk: a final report of the Polish Adult Leukemia Group

Objectives:  Patients with primary refractory AML and with early relapses have unfavorable prognoses and require innovative therapeutic approaches. Purine analogs fludarabine (FA) and cladribine (2-CdA) increase cytotoxic effect of Ara-C in leukemic blasts and inhibit DNA repair mechanisms; therefore its association with Ara-C and mitoxantrone (MIT) results in a synergistic effect. In the current report, we present the final results of multi-center phase II study evaluating the efficacy and toxicity of CLAG-M salvage regimen in poor risk refractory/relapsed AML patients.
Methods:  The induction chemotherapy consisted of 2-CdA 5 mg/m², Ara-C 2 g/m², MIT 10 mg/m², and granulocyte-colony stimulating factor. In the case of PR, a second CLAG-M was administered. Patients in CR received consolidation courses based on high doses of Ara-C and MIT with or without 2-CdA.
Results:  One hundred and eighteen patients from 11 centers were registered; 78 primary resistant and 40 relapsed. Sixty-six patients (58%) achieved CR after one or two courses of CLAG-M, 49 (35%) were refractory, and 8 (7%) died early. WBC >10 g/L and age >34 yr were factors associated with increased risk of treatment failure. Hematological toxicity was the most prominent toxicity of this regimen. The probability of OS at 4 yr was 14% (95% CI 4–23%). OS was influenced by age, WBC >10 g/L and poor karyotype in both univariate and multivariate analyses. The probability of 4 yr DFS was 30% for all 66 patients in CR (95% CI 11–49%). Poor karyotype was the only factor associated with decreased probability of DFS.
Conclusions:  We conclude that CLAG-M is a well-tolerated and highly effective salvage regimen in poor risk refractory/relapsed AML.     

The combination of bortezomib with chemotherapy to treat relapsed/refractory acute lymphoblastic leukaemia of childhood

Achieving complete remission (CR ) in childhood relapsed/refractory acute lymphoblastic leukaemia (ALL ) is a difficult task. Bortezomib, a proteasome inhibitor, has in vitro activity against ALL blasts. A phase I‐II trial, reported by the Therapeutic Advances in Childhood Leukaemia and Lymphoma (TACL ) consortium, demonstrated that bortezomib with chemotherapy has acceptable toxicity and remarkable activity in patients with relapsed ALL failing 2–3 previous regimens. We evaluated bortezomib in combination with chemotherapy in 30 and 7 children with B‐cell precursor (BCP ) and T‐cell ALL , respectively. Bortezomib (1·3 mg/m²/dose) was administered intravenously on days 1, 4, 8, and 11. Chemotherapy agents were the same as those used in the TACL trial, consisting of dexamethasone, doxorubicin, vincristine and pegylated asparaginase. Three patients (8·1%) died due to infections. Twenty‐seven patients (72·9%) achieved CR or CR with incomplete platelet recovery (CR p). Fourteen had minimal residual disease (MRD ) lower than 0·1%. Twenty‐two of 30 BCP ‐ALL patients (73·3%) and 5/7 patients (71%) with T‐cell ALL achieved CR /CR p. The 2‐year overall survival (OS ) is 31·3%; CR /CR p patients with an MRD response had a remarkable 2‐year OS of 68·4%. These data confirm that the combination of bortezomib with chemotherapy is a suitable/effective option for childhood relapsed/refractory ALL .     

A multicentre, open, non-comparative phase II study of a combination of fludarabine phosphate, cytarabine and granulocyte colony-stimulating factor in relapsed and refractory acute myeloid leukaemia and de novo refractory anaemia with excess of blasts in transformation

The primary objective of this study was to determine the complete remission (CR) rate achieved with the FLAG (fludarabine phosphate, cytarabine and granulocyte colony-stimulating factor) regimen in patients with relapsed or refractory acute myeloid leukaemia (AML) or de novo refractory anaemia with excess of blasts in transformation (RAEB-t). Secondary objectives were to evaluate survival and toxicity. Induction treatment consisted of between one and two courses of FLAG. Patients achieving CR received between one and two courses of consolidation treatment. Eighty-three of the 89 patients entering the study were eligible for assessment. CR rates were: 17 out of 21 (81%) in late relapse AML (Group 1), 13 out of 44 (30%) in early relapse/refractory AML (Group 2), and 10 out of 18 (56%) in de novo RAEB-t (Group 3). Thirty-four of the 40 responders (85%) achieved CR after one induction course. Median survival times were 1.4 years, 3 months and 1.6 years in Groups 1, 2 and 3 respectively. Other than myelosuppression, the FLAG regimen was not generally associated with clinically significant toxicity and was well tolerated by most patients including the elderly. The FLAG regimen offers a very effective alternative treatment for CR induction in poor prognosis adult patients with either relapsed or refractory AML or de novo RAEB-t. FLAG delivers high-dose treatment without increasing overall toxicity, an approach which is of particular value in older patients, who constitute the majority in these diseases. It is therefore an important advance in developing new treatment options for these patients.     

Salvage therapy with low-dose cytosine arabinoside in refractory or relapsed acute non-lymphocytic leukaemia:

Abstract: Thirteen patients with de novo acute non-lymphocytic leukaemia (ANLL) refractory to standard chemotherapy for remission induction and 12 patients with ANLL in relapse were treated with low-dose cytosine arabinoside (LD ara-C) 10 mg/m² subcutaneously every 12 hours for 21 days. Five of 13 patients (38%) and 6 of 12 patients (50%), respectively, obtained a complete remission (CR). Of these, 7 patients subsequently relapsed after 2–76 months, while 4 patients remain in CR after 7–131 months. Compared to standard intensive regimens treatment with LD ara-C was rather non-toxic, requiring platelet transfusions and antibiotics in only 6 and 13 cases, respectively. Three patients (12%) died during induction therapy with LD ara-C; 2 had a cerebral haemorrhage and 1 developed anuria following a staphylococcol septicaemia. In conclusion, therapy with LD ara-C may be preferable to more intensive and toxic regimens in the treatment of patients with relapsed or refractory ANLL.     

Treatment of relapsed/refractory acute myeloid leukaemia in adults

The prognosis of relapsed acute myeloid leukaemia (AML) is poor and treatment is challenging. While the most potent treatment modality for patients who achieve a complete remission after relapse is still allogeneic haematopoietic cell transplantation (allo‐HCT), both transplant‐related mortality and relapse rates are high and many patients are not candidates for this approach. After a few decades of relative stasis in this field, a large number of novel approaches have become available to tackle this highly fatal disease. This is mostly due to our improved understanding of disease pathogenesis (including targetable mutations) and the anti‐leukaemia potential of the immune system. Several small‐molecule inhibitors and immunotherapeutic options are being explored in clinical trials and many more are in pre‐clinical phase. Future studies will focus on novel and mechanistically driven combinations, sequential treatments, and low‐toxicity maintenance strategies. While cure of relapsed/refractory AML without allo‐HCT is currently unlikely, treatments are becoming less toxic and remissions are lasting longer.     

Adult acute lymphoblastic leukaemia in Denmark. A national population‐based retrospective study on acute lymphoblastic leukaemia in Denmark 1998–2008

Since July 2008, children and adults 1–45 years, diagnosed with acute lymphoblastic leukaemia (ALL) in Denmark have been treated according to the common Nordic Society for Paediatric Haematology and Oncology ALL2008 protocol. To explore whether this strategy will improve survival compared with historical controls, we performed a retrospective national population‐based study of adult ALL between 1998 and 2008. Patients were identified through the Danish Patobank and the Danish Cancer Registry; data was collected from patient files, and included 277 patients (median age, 47 years, range 15–91 years). The 5‐year projected event‐free survival (pEFS_5y) and overall survival (pOS_5y) for the whole cohort was 27·5% [95% confidence interval (CI) 22·4–33·6] and 34·1% (95% CI 28·7–40·4), respectively. No patient above 65 years survived beyond 5 years from diagnosis. For patients receiving curatively intended treatment, the pEFS_5y and pOS_5y were 36·6% and 44·1%, respectively, with a significantly higher pOS_5y for patients 15–35 years compared with patients 36–65 years (50·7% vs. 38·9%, P = 0·006). Cox multiple regression analysis identified age (Hazard Ratio = 1·7, P < 0·006) as a statistically significant predictor of EFS. The cure rates, not least for the elderly, are unacceptably low, and call for new strategies in the treatment of adult ALL in all age groups.     

A prospective,multicenter phase II study of continuous infusion of FLAG for patients older than 60 yr with resistant acute myeloid leukemia: a comparison with intensive younger patients’ trial

Relapsed or refractory acute myeloid leukemia (R/R AML) in elderly (≥60 yr old) patients were eligible. Induction chemotherapy consisted fludarabine and cytarabine (ARAC) as a 24‐hr CI without idarubicin (C‐FLAG), which was compared with the results of C‐FLAG with idarubicin (CI‐FLAG2) in younger patients’ trial. A total of 33 and 68 patients were enrolled in C‐FLAG and CI‐FLAG2, respectively. CR, CRp, and CRi were achieved in 10 (30.3%), 3 (9.1%), and 2 (6.1%), respectively. When comparing outcomes between C‐FLAG and CI‐FLAG2, there were no difference in terms of CR rate (P = 0.572) and objective response rate (ORR; P = 0.899). Favorable predictors on ORR in C‐FLAG were PB WBC ≤ 20K/uL at salvage (P = 0.024) and early evaluation peripheral BLAST = 0% (P = 0.013) on multivariate analysis. The overall survival of patients who achieve CR/CRp/CRi showed significantly prolonged survival compared with patients who did not in C‐FLAG (P < 0.001) and was a favorable predictor of longer survival by multivariate analysis (P = 0.009). Median overall survival was 3.19 (95% CI, 2.05–4.33) months and similar with that of CI‐FLAG2 (P = 0.841). Attenuated salvage regimen C‐FLGA in elderly patients was as effective as more intensive younger patients’ regimen CI‐FLAG2 in terms of response and survival although elderly patients had more unfavorable clinical characteristics.     

Prognostic significance of the Medical Research Council cytogenetic classification compared with the European LeukaemiaNet risk classification system in acute myeloid leukaemia

Fibrosis has been reported in some patients with immune thrombocytopenia (ITP) treated with thrombopoietin receptor agonists (TPO‐RA). However, fibrosis has also been reported in patients with various stages of ITP, who were TPO‐RA treatment‐naïve. In our study, we looked for fibrosis in bone marrow trephine biopsies taken at initial diagnosis from 32 adult patients with ITP. Ten of the 32 evaluated samples (31·25%) showed increased reticulin (Grade 1–2 on Bauermeister scale and Grade 0–1 on the European Consensus scale), which showed a positive correlation with ethnicity (0·3%) but did not correlate with disease severity, any clinical features or co‐morbidities.