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Background: The European Society for Medical Oncology (ESMO)-Magnitude of Clinical Benefit Scale (MCBS) has been accepted as a robust tool to evaluate the magnitude of clinical benefit reported in trials for oncological therapies. However, the ESMO-MCBS hitherto has only been validated for solid tumours. With the rapid development of novel therapies for haematological malignancies, we aimed to develop an ESMO-MCBS version that is specifically designed and validated for haematological malignancies., Methods: ESMO and the European Hematology Association (EHA) initiated a collaboration to develop a version for haematological malignancies (ESMO-MCBS:H). The process incorporated five landmarks: field testing of the ESMO-MCBS version 1.1 (v1.1) to identify shortcomings specific to haematological diseases, drafting of the ESMO-MCBS:H forms, peer review and revision of the draft based on re-scoring (resulting in a second draft), assessment of reasonableness of the scores generated, final review and approval by ESMO and EHA including executive boards., Results: Based on the field testing results of 80 haematological trials and extensive review for feasibility and reasonableness, five amendments to ESMO-MCBS were incorporated in the ESMO-MCBS:H addressing the identified shortcomings. These concerned mainly clinical trial endpoints that differ in haematology versus solid oncology and the very indolent nature of nevertheless incurable diseases such as follicular lymphoma, which hampers presentation of mature data. In addition, general changes incorporated in the draft version of the ESMO-MCBS v2 were included, and specific forms for haematological malignancies generated. Here we present the final approved forms of the ESMO-MCBS:H, including instructions., Conclusion: The haematology-specific version ESMO-MCBS:H allows now full applicability of the scale for evaluating the magnitude of clinical benefit derived from clinical studies in haematological malignancies., (Copyright © 2023. Published by Elsevier Ltd.)

The 2010 and 2017 editions of the European LeukemiaNet (ELN) recommendations for diagnosis and management of acute myeloid leukemia (AML) in adults are widely recognized among physicians and investigators. There have been major advances in our understanding of AML, including new knowledge about the molecular pathogenesis of AML, leading to an update of the disease classification, technological progress in genomic diagnostics and assessment of measurable residual disease, and the successful development of new therapeutic agents, such as FLT3, IDH1, IDH2, and BCL2 inhibitors. These advances have prompted this update that includes a revised ELN genetic risk classification, revised response criteria, and treatment recommendations., (© 2022 by The American Society of Hematology.)

Introduction: Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults, but the results for patients with AML are still unsatisfactory. The discovery of new mutations in AML, including IDH mutations, has opened the door for treatment with targeted agents. Ivosidenib is a selective, potent inhibitor of the IDH1 mutant protein., Areas Covered: This review summarizes the mechanism of action, safety profile and efficacy of ivosidenib for patients with IDH1-mutated AML. The authors then provide their expert perspectives on the use of the drug including their future perspectives., Expert Opinion: Ivosidenib is a promising, most probably practice changing, new drug for the treatment of IDH1-mutated AML. Current phase III trials are ongoing to evaluate the addition of ivosidenib to the current standards-of-care. In the near future, more drug combinations are awaited. Challenges for the future include the development of resistance and establishing the duration of maintenance therapy.

Purpose: Leukemic stem cells (LSCs) may harbor important resistance to tyrosine kinase inhibitors in chronic myelogenous leukemia (CML). We identified Philadelphia chromosome (Ph)-positive CD34(+)CD38(-) bone marrow cells (here denoted LSCs) and addressed their response-predictive value in patients with CML (n = 48) subjected to nilotinib in the ENEST1st trial (NCT01061177)., Experimental Design: Two flow cytometry-based cell sorting methods were used with multiparameter-directed CD45- (MPFC) and BCR-ABL1 probe-linked (FISH) identification of Ph-positive cells, respectively., Results: We observed a positive correlation between the proportion of LSCs at diagnosis and established prognostic markers (blast count, spleen size, Sokal score, and hemoglobin). Conversely, a high LSC burden predicted for an inferior molecular response at 3 (MPFC and FISH), 6 (MPFC), 9 (FISH), and 15 months (FISH). During nilotinib therapy, the proportion of LSCs decreased rapidly. At 3 months, a median of only 0.3% LSCs remained among CD34(+)CD38(-) cells, and in 33% of the patients the LSC clone was not detectable anymore (FISH). The response kinetics was similar in LSC fractions as it was in the progenitor and unseparated bone marrow cell fractions., Conclusions: The proportion of LSCs at diagnosis, as analyzed by two independent methodologies, reflects the biology of the disease and appeared as a prognostic and response-predictive marker in patients with CML subjected to first-line nilotinib therapy. Clin Cancer Res; 22(16); 4030-8. ©2016 AACR., (©2016 American Association for Cancer Research.)

Elderly patients with diffuse large B-cell lymphoma (DLBCL) are frequently not treated with standard immunochemotherapy, and this influences survival negatively. The purpose of this study was to gain more insight into treatment decision-making by hematologists. Case vignettes concerning patients with DLBCL were presented to hematologists in the Netherlands. Patient characteristics (age, comorbidity) differed per case. Respondents were asked in each case if they would treat the patient with curative intent by means of full-dose chemotherapy or chemotherapy with dose reduction or if they would not treat the patient with curative intent. The vast majority of respondents would treat an elderly patient diagnosed with DLBCL without a relevant medical history with full-dose chemotherapy irrespective of age. In the presence of comorbidity, lack of social support, cognitive disorders, and untreated depression dose reductions in advance are frequently applied or patients are not treated with curative intent. This is most pronounced for patients aged older than 80 years. Respondents working in a university hospital more frequently refrain form full-dose chemotherapy with curative intent compared to respondents working in tertiary medical teaching hospitals or general hospitals. Patients without a relevant medical history are generally treated with curative intent irrespective of age. Cognitive disorders, comorbidity, and depression reduce the change of being treated with curative intent. This is most prominent in the eldest patient category.

Advances in the understanding of the genetic underpinnings of acute myeloid leukemia are rapidly being translated into novel treatment strategies. Genomic profiling has highlighted the importance of the epigenetic machinery for leukemogenesis by identifying recurrent somatic mutations involving chromatin-modifier proteins. These genetic alterations function as dynamic regulators of gene expression and involve DNA-methyltransferase 3A, methyltransferase DOT1L, enhancer of zeste homologue 2, isocitrate dehydrogenases 1 and 2 and bromodomain-containing proteins. New therapeutic targets are also emerging from further delineation of cell signaling networks in acute myeloid leukemia blasts mediated by PIM kinases, polo-like kinase 1, cell surface protein CD98 and nucleocytoplasmic shuttling receptors, among others. Early results of targeted therapies directed at these molecular mechanisms are discussed in this review and their potential to improve the outcomes of patients by allowing the use of more effective and less toxic treatments.

In a randomized, phase III trial of nilotinib versus imatinib in patients with newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia in chronic phase, more patients had suboptimal response or treatment failure on front-line imatinib than on nilotinib. Patients with suboptimal response/treatment failure on imatinib 400 mg once or twice daily or nilotinib 300 mg twice daily could enter an extension study to receive nilotinib 400 mg twice daily. After a 19-month median follow up, the safety profile of nilotinib 400 mg twice daily in patients switching from imatinib (n=35) was consistent with previous reports, and few new adverse events occurred in patients escalating from nilotinib 300 mg twice daily (n=19). Of patients previously treated with imatinib or nilotinib 300 mg twice daily, respectively, 15 of 26 (58%) and 2 of 6 (33%) without complete cytogenetic response at extension study entry, and 11 of 34 (32%) and 7 of 18 (39%) without major molecular response at extension study entry, achieved these responses at any time on nilotinib 400 mg twice daily. Estimated 18-month rates of freedom from progression and overall survival after entering the extension study were lower for patients switched from imatinib (85% and 87%, respectively) versus nilotinib 300 mg twice daily (95% and 94%, respectively). Nilotinib dose escalation was generally well tolerated and improved responses in about one-third of patients with suboptimal response/treatment failure. Switch to nilotinib improved responses in some patients with suboptimal response/treatment failure on imatinib, but many did not achieve complete cytogenetic response (clinicaltrials.gov identifiers: 00718263, 00471497 - extension)., (Copyright© Ferrata Storti Foundation.)

Background: Elderly patients with non-Hodgkin's lymphoma (NHL) are often not treated with standard immunochemotherapy and this might have a negative impact on their survival. Little is known about the determinants that play a role in treatment decision-making of clinicians regarding elderly patients with NHL. The objective of this study was to gain more insight into these determinants., Methods: A survey was conducted amongst haematologists in the Netherlands. The survey contained questions about comorbidity, polypharmacy, social setting, nutritional status, depression, mild cognitive impairment, dementia, activities of daily living (ADL) and instrumental activities of daily living (IADL) in relation to treatment decisions in elderly NHL patients., Results: Of all comorbidities, respondents designated cognitive disorders and cardiovascular comorbidity as the most important factors when assessing whether an older patient with NHL is eligible for curative treatment. Also in decreasing degree of importance ADL, IADL and depressive disorder are frequently included in treatment decision-making. Almost half of the respondents feel that treatment of the elderly person is complicated as a result of a lack of scientific evidence., Conclusion: Haematologists are aware of coexisting problems in elderly patients and they frequently take comorbidities, cognitive disorders and functional status into consideration in treatment decision-making. Future studies are needed to determine the exact role that these factors should play in the treatment of elderly patients. Furthermore, haematologists feel that treatment of the elderly is complicated and there is a lack of scientific evidence, and therefore older adults should be better represented in clinical trials.

Aminopeptidases represent a class of (zinc) metalloenzymes that catalyze the cleavage of amino acids nearby the N-terminus of polypeptides, resulting in hydrolysis of peptide bonds. Aminopeptidases operate downstream of the ubiquitin-proteasome pathway and are implicated in the final step of intracellular protein degradation either by trimming proteasome-generated peptides for antigen presentation or full hydrolysis into free amino acids for recycling in renewed protein synthesis. This review focuses on the function and subcellular location of five key aminopeptidases (aminopeptidase N, leucine aminopeptidase, puromycin-sensitive aminopeptidase, leukotriene A4 hydrolase and endoplasmic reticulum aminopeptidase 1/2) and their association with different diseases, in particular cancer and their current position as target for therapeutic intervention by aminopeptidase inhibitors. Historically, bestatin was the first prototypical aminopeptidase inhibitor that entered the clinic 35 years ago and is still used for the treatment of lung cancer. More recently, new generation aminopeptidase inhibitors became available, including the aminopeptidase inhibitor prodrug tosedostat, which is currently tested in phase II clinical trials for acute myeloid leukemia. Beyond bestatin and tosedostat, medicinal chemistry has emerged with additional series of potential aminopeptidases inhibitors which are still in an early phase of (pre)clinical investigations. The expanded knowledge of the unique mechanism of action of aminopeptidases has revived interest in aminopeptidase inhibitors for drug combination regimens in anti-cancer treatment. In this context, this review will discuss relevant features and mechanisms of action of aminopeptidases and will also elaborate on factors contributing to aminopeptidase inhibitor efficacy and/or loss of efficacy due to drug resistance-related phenomena. Together, a growing body of data point to aminopeptidase inhibitors as attractive tools for combination chemotherapy, hence their implementation may be a step forward in a new era of personalized treatment of cancer patients.

Insensitivity of chronic myeloid leukemia (CML) hematopoietic stem cells to tyrosine kinase inhibitors (TKIs) prevents eradication of the disease and may be involved in clinical resistance. For improved treatment results more knowledge about CML stem cells is needed. We here present a new flow cytometric approach enabling prospective discrimination of CML stem cells from their normal counterparts within single-patient samples. In 24 of 40 newly diagnosed CML patients residual normal CD34(+)CD38(-) stem cells could be identified by lower CD34 and CD45 expression, lower forward/sideward light scatter and by differences of lineage marker expression (CD7, CD11b and CD56) and of CD90. fluorescent in situ hybridization (FISH) analysis on Fluorescence-activated cell sorting sorted cells proved that populations were BCR-ABL positive or negative and long-term liquid culture assays with subsequent colony forming unit assays and FISH analysis proved their stem cell character. Patients with residual non-leukemic stem cells had lower clinical risk scores (Sokal, Euro), lower hematological toxicity of imatinib (IM) and better molecular responses to IM than patients without. This new approach will expand our possibilities to separate CML and normal stem cells, present in a single bone marrow or peripheral blood sample, thereby offering opportunities to better identify new CML stem-cell-specific targets. Moreover, it may guide optimal clinical CML management.

Tumor-necrosis factor alpha activity has been correlated to ineffective erythropoiesis in lower risk myelodysplastic syndromes. Infliximab (Remicade(®)) is an anti-tumor necrosis factor alpha chimeric antibody that is used in the treatment of patients with rheumatoid arthritis or Crohn's disease. Forty-six patients with myelodysplastic syndromes and a relatively low risk of developing acute leukemia were included in a randomized phase II study assessing the therapeutic activity of two dosages of infliximab administration (3 mg/kg vs. 5 mg/kg). The primary end point was the response rate. Responses were observed in 3 of 22 patients (13.1%) randomized to the 3 mg/kg arm, versus 0 of 21 patients randomized in the 5 mg/kg arm. According to the statistical design of the current study, neither of the two infliximab dose schedules tested showed sufficient activity as a single agent in this cohort of unselected patients with early myelodysplastic syndrome.

The outcome of chronic myeloid leukemia (CML) has been profoundly changed by the introduction of tyrosine kinase inhibitors into therapy, but the prognosis of patients with CML is still evaluated using prognostic scores developed in the chemotherapy and interferon era. The present work describes a new prognostic score that is superior to the Sokal and Euro scores both in its prognostic ability and in its simplicity. The predictive power of the score was developed and tested on a group of patients selected from a registry of 2060 patients enrolled in studies of first-line treatment with imatinib-based regimes. The EUTOS score using the percentage of basophils and spleen size best discriminated between high-risk and low-risk groups of patients, with a positive predictive value of not reaching a CCgR of 34%. Five-year progression-free survival was significantly better in the low- than in the high-risk group (90% vs 82%, P = .006). These results were confirmed in the validation sample. The score can be used to identify CML patients with significantly lower probabilities of responding to therapy and survival, thus alerting physicians to those patients who require closer observation and early intervention.

Three male patients aged 52, 49 and 74 years who were treated with hydroxyurea for chronic myeloid leukaemia (CML) or essential thrombocytosis developed severely painful ulcers on the lower legs and feet after an interval varying from 4 months to 2.5 years. These ulcers only healed after discontinuation of the drug. This is an adverse effect of hydroxyurea that is not infrequently seen but is difficult to recognise. The precise pathogenesis is still unclear but micro-circulatory disorders and a direct cytostatic effect on the epidermal cells probably play a role. Often, the drug has already been used for several years before the ulcers develop. They are resistant to treatment unless the hydroxyurea is stopped. Alternatives to hydroxyurea are imatinib for the treatment of CML and interferon alpha-2a or anagrelide for essential thrombocytosis.

Objective: To determine the average cost-effectiveness ratio of treatment of patients with chronic myeloid leukaemia (CML): with first-line interferon alpha-2a (IFN) or with second-line imatinib following IFN failure., Design: Cost-effectiveness analysis., Method: A general cost-effectiveness analysis was performed using a model. This model consists of two phases: an induction phase of eight months, in which newly-diagnosed patients are treated with either IFN or imatinib, and a chronic treatment phase wherein patients are treated according the result of the induction phase. The model calculated the costs and effects of the treatment. Input for this model was derived from literature and expert opinion. Costs were based on real cost prices and tariffs., Results: Treatment with imatinib resulted in 6.67 quality-adjusted life years (QALYs) and treatment with IFN resulted in 4.98 QALYs. Average costs of treatment with 5 million IU/day of IFN were [symbol: see text] 76,969 and [symbol: see text] 53,257 with 3 million IU/day. For imatinib at 400 mg/day the costs were [symbol: see text] 140,765 per patient. Costs per QALY were [symbol: see text] 15,445, [symbol: see text] 10,687 and [symbol: see text] 21,082, respectively., Conclusion: The addition of imatinib to the treatment options in CML resulted in increased quality-adjusted survival, but also higher costs of treatment.

Three patients suffering from chronic myelogenous leukaemia (CML), a 36-year-old woman in blast crisis, and a 64-year-old woman and a 60-year-old man in the chronic phase, participated in a clinical trial with STI571, a recently developed tyrosine kinase inhibitor with relative specificity for the BCR-ABL kinase. In all three patients, complete haematologic remission occurred within 2 months of the treatment being initiated. Subsequently the patient in blast crisis underwent allogeneic stem-cell transplantation. For the second patient, who had experienced many side effects with the standard treatment, STI571 led to a better quality of life. The third patient reached complete cytogenetic remission after 3 months of treatment. The development of STI571 is a major breakthrough in the treatment of CML. There are few side effects and the short-term results are excellent in specific patient categories. Further research is needed to establish the eventual role of STI571 in the treatment of CML.

Background: Reliable reporting of chemotherapy-induced neurotoxicity is important. The objectives of the current study were to evaluate the differences in the peripheral neurotoxicity sections of several widely used chemotherapy-related toxicity grading systems, and the differences in the way in which observers interpret these scales., Patients and Methods: Two neurologists independently rated the severity of chemotherapy-induced peripheral neuropathy, according to WHO, ECOG, Ajani, and NCIC-CTC criteria in 37 patients., Results: The highest percentage grade 1, grade 2 and grade 3 peripheral neurotoxicity was noted when employing the WHO, Ajani and NCIC-CTC scales, respectively. Percentage inter-observer agreement across all grades of severity ranged from 45.9 (NCIC-CTC) to 83.8 (WHO). The degree of agreement varied from 'poor to fair' to 'substantial'. Percentage inter-observer agreement for the dichotomy grade < or = 2 and grade 3 ranged from 81.1 (NCIC-CTC) to 94.6 (Ajani and WHO), however, exact agreement on grade 3 peripheral neurotoxicity ranged from 0 (Ajani and WHO) to 42% (NCIC-CTC). Percentage interscale agreement for the dichotomy grade < or = 2 and grade 3 varied from 67.6 (WHO and NCIC-CTC) to 100 (WHO and ECOG). Interobserver disagreement of severity grading was partly due to different interpretation of scale parameters., Conclusions: Our results suggest that caution should be used in interpreting results across studies using different scales for neurotoxicity grading in chemotherapy-related peripheral neuropathy. When (multicentre) trials are to be undertaken with potential neurotoxic or neuroprotective agents, consensus should be sought regarding the toxicity rating scale used, and its interpretation by participating physicians.

Prognostic factors to identify patients with high-risk non-Hodgkin's lymphoma (NHL) have recently been developed. We retrospectively investigated the relation between prognostic factors and treatment outcome after autologous bone marrow transplantation (ABMT). From 1984 to 1994, 80 consecutive patients with NHL responding slowly to or relapsing after front-line therapy were treated with high-dose chemotherapy and ABMT. Prognostic factors at the time of diagnosis and of ABMT were related to clinical outcome after ABMT. The cumulative 5-year overall survival (OS) was 51%, progression-free survival (PFS) 41%, and relapse-free survival (RFS) 53%. Absence of B symptoms and intermediate-grade malignancy at first presentation of disease were independently related to prolonged OS (P = 0.02 and P < 0.01, respectively) and prolonged PFS (P = 0.005 and P = 0.01, respectively). At the time of ABMT, first PR or CR, normal LDH levels and tumour stage I + II were associated with prolonged OS (P = 0.0005, P = 0.03 and P = 0.004, respectively). A Coiffier index of 0 or 1, first PR or CR and no extranodal disease involvement were related to prolonged PFS (P = 0.0002, P = 0.005 and P = 0.07, respectively). Treatment-related deaths occurred in 10% of patients. Assessment of disease status, LDH level, tumour stage, extranodal disease involvement and Coiffier index at the time of ABMT is respectively efficient in predicting treatment outcome after ABMT.

The efficacy of chemotherapy in acute myeloid leukaemia (AML) is limited by clinical drug resistance. We determined in vitro resistance to cytosine arabinoside (ARAC), daunorubicin (DNR), mitoxantrone (MITOX), m-amsacrine (AMSA) and etoposide (VP16) in 49 adults with de novo AML using the MTT assay. Results showed that nonresponders to chemotherapy were, in vitro, 2.9-fold more resistant to DNR, but not more resistant to ARA-C, compared to complete responders. However, complete responders who were in vitro resistant to ARA-C had a 4-fold higher risk of relapse (95% CI 1.3-12.5-fold) compared to complete responders in vitro sensitive to ARA-C. With a mean follow-up of 12 months the probability of continuous complete remission (CCR) for patients in vitro sensitive to ARA-C was 61% at 34 months (95% CI 28-82%), whereas all patients in vitro resistant to ARA-C relapsed within 18 months from diagnosis. This difference appeared to be independent of other clinical features such as sex, age, white blood cell count, FAB classification, and CD34 expression. In vitro resistance to DNR was not related to the probability of CCR. We conclude that in vitro drug resistance assessed with the MTT assay appears to be associated with short- and long-term clinical outcome in AML. Confirmatory studies comprising a sufficient number of patients for multivariate analyses should prove whether in vitro resistance to ARA-C will appear to be an independent risk factor.

In patients with hematological malignancies, we prospectively evaluated the use of untunnelled subclavian vein catheters placed either for short term chemotherapy (48 episodes) or for long-term intensive supportive care during pancytopenia (152 episodes). The 200 catheters were placed in 88 different patients. There were 2 placement failures and 2 cases of minor pneumothorax. In 4 episodes ecchymoses and in 1 uncontrollable bleeding from the exit site occurred. The mean time to removal was 25.6 days (range 0-149). There was 1 exit site infection and 26 periods of septicemia, of which 8 were considered catheter associated. All infections responded to appropriate treatment. Irreversible obstruction occurred in 4 and dislodgement in another 4 episodes out of a total number of 11 failures. Patient acceptance was high although repeated placements were frequently undertaken for successive periods of treatment and supportive care. With meticulous sterile techniques of placement and catheter care it seems that untunnelled subclavian vein catheters are reliable and safe in hematooncology.

The feasibility and efficacy of up-front high-dose sequential chemotherapy followed by autologous stem cell transplantation (ASCT) in previously untreated adults (median age 33 years; range 15-64) with Burkitt lymphoma (BL), Burkitt-like lymphoma (BLL) or lymphoblastic lymphoma (LyLy), both without central nervous system or extensive bone marrow involvement was investigated in a multicenter phase II study. Treatment consisted of two sequential high-dose chemotherapy induction courses incorporating prednisone, cyclophosphamide, doxorubicin, etoposide and mitoxantrone, without high-dose methotrexate or high-dose cytarabine. Patients with at least PR went on with BEAM and ASCT. Protocol treatment was completed by 23/27 (85%) BL/BLL and 13/15 (87%) LyLy patients. Median treatment duration until BEAM was 70 (range: 50-116) days. No toxic deaths occurred. Response to treatment was complete response (CR) 81%and partial response (PR) 11%for BL/BLL, CR 73%and PR 20%for LyLy. At a median follow-up of 61 months of patients still alive, six BL/BLL and eight LyLy patients have died. The actuarial 5-year overall and event-free survival estimates are 81 and 73%for BL/BLL vs 46 and 40%for LyLy patients. In conclusion, this short up-front high-dose sequential chemotherapy regimen, followed by ASCT is highly effective in adults with BL/BLL with limited bone marrow involvement, but less so in patients with LyLy.Leukemia (2005) 19, 945-952. doi:10.1038/sj.leu.2403733 Published online 31 March 2005 [ABSTRACT FROM AUTHOR]