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Wolach, Ofir; Amitai, Irina; DeAngelo, Daniel J.
doi: 10.1111/bjh.14916pmid: 29076138
Significant advances have been made in recent years in the field of Philadelphia‐negative acute lymphoblastic leukaemia (ALL). New insights into the biology and genetics of ALL as well as novel clinical observations and new drugs are changing the way we diagnose, risk‐stratify and treat adult patients with ALL. New genetic subtypes and alterations refine risk stratification and uncover new actionable therapeutic targets. The incorporation of more intensive, paediatric and paediatric‐inspired approaches for young adults seem to have a positive impact on survival in this population. Minimal residual disease at different time points can assist in tailoring risk‐adapted interventions for patients based on individual response. Finally, novel targeted approaches with monoclonal antibodies, immunotherapies and small molecules are moving through clinical development and entering the clinic. The aim of this review is to consolidate the abundance of emerging data and to review and revisit the concepts of risk‐stratification, choice of induction and post‐remission strategies as well as to discuss and update the approach to specific populations with ALL, such as young adult, elderly/unfit and relapsed/refractory patients with ALL.
Schick, Markus; Habringer, Stefan; Nilsson, Jonas A.; Keller, Ulrich
doi: 10.1111/bjh.14917pmid: 29171017
Identifying and therapeutically targeting cancer cell liabilities is of utmost importance in order to improve the treatment of patients with malignancies of poor prognosis. The MYC family genes (MYC, MYCN and MYCL) are among the most deregulated proto‐oncogenes in human cancer. Aberrant MYC expression is frequently associated with poor prognosis. Although many aspects of MYC‐mediated tumour biology are well characterized, there are currently no effective means for targeting MYC in a specific manner that have been established for clinical use. This review first discusses the role of MYC in the pathogenesis of haematopoietic malignancies, and secondly summarizes how insight into MYC functions could be translated into therapeutic approaches. In particular, we will address the possibilities of taking advantage of MYC‐induced cancer cell vulnerabilities that could be exploited in terms of synthetic lethal interactions.
Giulino‐Roth, Lisa; O'Donohue, Tara; Chen, Zhengming; Bartlett, Nancy L.; LaCasce, Ann; Martin‐Doyle, William; Barth, Matthew J.; Davies, Kimberly; Blum, Kristie A.; Christian, Beth; Casulo, Carla; Smith, Sonali M.; Godfrey, James; Termuhlen, Amanda; Oberley, Matthew J.;
Nozza, Andrea; Terenghi, Fabrizia; Gallia, Francesca; Adami, Fausto; Briani, Chiara; Merlini, Giampaolo; Giordano, Laura; Santoro, Armando; Nobile‐Orazio, Eduardo
doi: 10.1111/bjh.14966pmid: 29048107
Given its anti‐angiogenic activity, lenalidomide may have a role in the treatment of POEMS (Peripheral neuropathy, Organomegaly, Endocrinopathy, Monoclonal plasma cell disorder and Skin changes) syndrome. This prospective, open‐label, pilot study evaluated the combination of lenalidomide + dexamethasone (RD) in 18 POEMS syndrome patients (13 pre‐treated, 5 newly‐diagnosed but ineligible for high‐dose therapy). Treatment consisted of six cycles of lenalidomide (25 mg/day for 21 days followed by 7 days rest) plus dexamethasone (40 mg/once a week). Patients responding after six cycles continued treatment until progression or unbearable toxicity. The primary endpoint was the proportion of patients with either neurological or clinical improvement. The RD combination was considered as deserving further evaluation if 9 of the first 15 patients responded. Ten responses were observed among the first 15 enrolled patients, meeting the primary endpoint. Fifteen of 18 patients (83%) completed six RD cycles: 13 (72%) patients responded and nine had both clinical and neurological improvement. Among the 15 patients who completed the six RD cycles, four were still on treatment after a 25‐month follow‐up. At 39 months of follow‐up, all patients were alive with a 3‐year progression‐free survival of 59%. No patient discontinued RD for toxicity. Overall, the RD regimen showed a high incidence of prolonged symptoms improvement and was well tolerated in most POEMS patients.
Cholujova, Danka; Bujnakova, Zdenka; Dutkova, Erika; Hideshima, Teru; Groen, Richard W.; Mitsiades, Constantine S.; Richardson, Paul G.; Dorfman, David M.; Balaz, Peter; Anderson, Kenneth C.; Jakubikova, Jana
doi: 10.1111/bjh.14974
van der Stoep, M. Y. Eileen C.; Bertaina, Alice; ten Brink, Marloes H.; Bredius, Robbert G.; Smiers, Frans J.; Wanders, Dominique C. M.; Moes, Dirk Jan A.R.; Locatelli, Franco; Guchelaar, Henk‐Jan; Zwaveling, Juliëtte; Lankester, Arjan C.
Showing 1 to 10 of 24 Articles
doi: 10.1111/bjh.14951pmid: 29082519
Treatment with dose‐adjusted EPOCH (etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone) chemotherapy and rituximab (DA‐EPOCH‐R) has become the standard of care for primary mediastinal B‐cell lymphoma (PMBCL) at many institutions despite limited data in the multi‐centre setting. We report a large, multi‐centre retrospective analysis of children and adults with PMBCL treated with DA‐EPOCH‐R to characterize outcomes and evaluate prognostic factors. We assessed 156 patients with PMBCL treated with DA‐EPOCH‐R across 24 academic centres, including 38 children and 118 adults. All patients received at least one cycle of DA‐EPOCH‐R. Radiation therapy was administered in 14·9% of patients. With median follow‐up of 22·6 months, the estimated 3‐year event‐free survival (EFS) was 85·9% [95% confidence interval (CI) 80·3–91·5] and overall survival was 95·4% (95% CI 91·8–99·0). Outcomes were not statistically different between paediatric and adult patients. Thrombotic complications were reported in 28·2% of patients and were more common in paediatric patients (45·9% vs. 22·9%, P = 0·011). Seventy‐five per cent of patients had a negative fluorodeoxyglucose positron emission tomography (FDG‐PET) scan at the completion of DA‐EPOCH‐R, defined as Deauville score 1–3. Negative FDG‐PET at end‐of‐therapy was associated with improved EFS (95·4% vs. 54·9%, P < 0·001). Our data support the use of DA‐EPOCH‐R for the treatment of PMBCL in children and adults. Patients with a positive end‐of‐therapy FDG‐PET scan have an inferior outcome.
Multiple myeloma (MM), a B cell malignancy characterized by clonal proliferation of plasma cells in the bone marrow, remains incurable despite the use of novel and conventional therapies. In this study, we demonstrated MM cell cytotoxicity triggered by realgar (REA; As4S4) nanoparticles (NREA) versus Arsenic trioxide (ATO) against MM cell lines and patient cells. Both NREA and ATO showed in vivo anti‐MM activity, resulting in significantly decreased tumour burden. The anti‐MM activity of NREA and ATO is associated with apoptosis, evidenced by DNA fragmentation, depletion of mitochondrial membrane potential, cleavage of caspases and anti‐apoptotic proteins. NREA induced G2/M cell cycle arrest and modulation of cyclin B1, p53 (TP53), p21 (CDKN1A), Puma (BBC3) and Wee‐1 (WEE1). Moreover, NREA induced modulation of key regulatory molecules in MM pathogenesis including JNK activation, c‐Myc (MYC), BRD4, and histones. Importantly, NREA, but not ATO, significantly depleted the proportion and clonogenicity of the MM stem‐like side population, even in the context of the bone marrow stromal cells. Finally, our study showed that both NREA and ATO triggered synergistic anti‐MM activity when combined with lenalidomide or melphalan. Taken together, the anti‐MM activity of NREA was more potent compared to ATO, providing the preclinical framework for clinical trials to improve patient outcome in MM.
doi: 10.1111/bjh.14960pmid: 29048102
Treosulfan‐based conditioning is increasingly employed in paediatric haematopoietic stem cell transplantation (HSCT). Data on treosulfan pharmacokinetics in children are scarce, and the relationship between treosulfan exposure, toxicity and clinical outcome is unresolved. In this multicentre prospective observational study, we studied treosulfan pharmacokinetics and the drug's relationship with regimen‐related toxicity and early clinical outcome in 77 paediatric patients. Treosulfan dose was 30 g/m2, administered over 3 consecutive days in infants <1 year old (n = 12) and 42 g/m2 in children ≥1 year old (n = 65). Mean day 1 treosulfan exposure was 1744 ± 795 mg*h/l (10 g/m2) and 1561 ± 511 mg*h/l (14 g/m2), with an inter‐individual variability of 56 and 33% in the respective groups. High treosulfan exposure (>1650 mg*h/l) was associated with an increased risk of mucosal [Odds ratio (OR) 4·40; 95% confidence interval (CI) 1·19–16·28, P = 0·026] and skin toxicity (OR 4·51; 95% CI 1·07–18·93, P = 0·040). No correlation was found between treosulfan exposure and the early clinical outcome parameters: engraftment, acute graft‐versus‐host disease and donor chimerism. Our study provides the first evidence in a large cohort of paediatric patients of high variability in treosulfan pharmacokinetics and an association between treosulfan exposure and early toxicity. Ongoing studies will reveal whether treosulfan exposure is related to long‐term disease‐specific outcome and late treatment‐related toxicity.