Clinical implications of measurable residual disease in AML : review of current evidence

Despite the fact that 80% of adult acute myeloid leukaemia patients reach complete morphological remission after induction chemotherapy, many of them relapse. Many studies have shown that detection of minimal residual disease (defined as 'any detectable evidence of persistent leukaemic cells during complete morphological remission') has an added value in prediction of relapse and survival, and is more than just a surrogate marker for already known risk factors in AML. As such, the behaviour of the disease during treatment might become equally or even more important to decide whether or not an upgrade of treatment (such as an allogeneic stem cell transplantation) is necessary to improve outcome. However, there are still many open issues as to what the ideal time point is to measure MRD, which threshold is clinically significant, what sample (peripheral blood or bone marrow) should be used and how we can standardize tests so that results from different labs become comparable. This review gives an overview of currently available evidence regarding technical issues, prognostic impact and MRD-directed treatment in AML

Outcomes of haploidentical stem cell transplantation for chronic lymphocytic leukemia: a retrospective study on behalf of the chronic malignancies working party of the EBMT

Allogeneic hematopoietic stem cell transplantation (HCT) may result in long-term disease control in high-risk chronic lymphocytic leukemia (CLL). Recently, haploidentical HCT is gaining interest because of better outcomes with post-transplantation cyclophosphamide (PTCY). We analyzed patients with CLL who received an allogeneic HCT with a haploidentical donor and whose data were available in the EBMT registry. In total 117 patients (74% males) were included; 38% received PTCY as GVHD prophylaxis. For the whole study cohort OS at 2 and 5 yrs was 48 and 38%, respectively. PFS at 2 and 5 yrs was 38 and 31%, respectively. Cumulative incidence (CI) of NRM in the whole group at 2 and 5 years were 40 and 44%, respectively. CI of relapse at 2 and 5 yrs were 22 and 26%, respectively. All outcomes were not statistically different in patients who received PTCY compared to other types of GVHD prophylaxis. In conclusion, results of haploidentical HCT in CLL seem almost identical to those with HLA-matched donors. Thereby, haploidentical HCT is an appropriate alternative in high risk CLL patients with a transplant indication but no available HLA-matched donor. Despite the use of PTCY, the CI of relapse seems not higher than observed after HLA-matched HCT

A phase 2a randomized clinical trial of intravenous vedolizumab for the treatment of steroid-refractory intestinal acute graft-versus-host disease

Steroid-refractory (SR) acute graft-versus-host disease (aGvHD) remains a significant complication after allogeneic hematopoietic cell transplantation. Systemic corticosteroids are first-line therapy for aGvHD, but apart from ruxolitinib, there are no approved treatments for SR aGvHD. Vedolizumab is approved for treatment of ulcerative colitis and Crohn\u27s disease, and may be effective for treatment of SR intestinal aGvHD. We conducted a phase 2a trial (NCT02993783) to evaluate the clinical efficacy, tolerability, and safety of vedolizumab 300 and 600 mg for SR intestinal aGvHD. This study was terminated before full enrollment was completed because early results failed to demonstrate positive proof-of-concept in efficacy. Before termination, 17 participants had enrolled and an early response in intestinal aGvHD was observed in 11 and eight participants at days 15 and 28, respectively. All adverse events observed were consistent with those expected in a population with SR intestinal aGvHD. Overall, vedolizumab did not meet the primary efficacy endpoint (overall response at day 28), likely owing to premature study drug discontinuation, lack of efficacy, and the competing risks inherent with a population with advanced SR intestinal aGvHD. Nevertheless, this study provides valuable insights into the considerations needed when conducting studies in patients with SR intestinal aGvHD

Plerixafor for autologous peripheral blood stem cell mobilization in patients previously treated with fludarabine or lenalidomide.

Fludarabine and lenalidomide are essential drugs in the front-line treatment of non-Hodgkin lymphoma (NHL) and multiple myeloma (MM), respectively. Data suggests that fludarabine and lenalidomide therapy may have a deleterious effect on stem cell mobilization. In the European compassionate use program, 48 patients (median age 57 years) previously treated with fludarabine (median 5 cycles; range: 1-7 cycles) were given plerixafor plus granulocyte colony-stimulating factor (G-CSF) for remobilization following a primary mobilization attempt. The overall median number of CD34+ cells collected was 2.3 × 10(6)/kg (range: 0.3-13.4). The minimum required number of CD34+ cells (≥2.0 × 10(6)/kg) was collected from 58% of patients in a median of 2 days. Thirty-five patients (median age = 57 years) previously treated with lenalidomide (median 5 cycles; range: 1-10 cycles) were given plerixafor plus G-CSF for remobilization. The overall median number of CD34+ cells collected was 3.4 × 10(6)/kg (range: 1.1-14.8). The minimum required number of CD34+ cells (≥2.0 × 10(6) per kg) was collected from 69% of patients in a median of 2 days. In conclusion, salvage mobilization with plerixafor plus G-CSF is successful in the majority of patients with MM previously treated with lenalidomide. In fludarabine-exposed patients, only 58% of patients will achieve successful salvage mobilization with plerixafor plus G-CSF, suggesting the need for novel mobilization regimens algorithms in this subgroup of patients

EVI1 overexpression in t(3;17) positive myeloid malignancies results from juxtaposition of EVI1 to the MSI2 locus at 17q22

Chromosomal translocations involving the EVI1 locus are a recurrent finding in myeloid leukemia and are associated with poor prognosis. In this study, we performed a detailed molecular characterization of the recurrent translocation t(3;17)(q26;q22) in 13 hematologic malignancies. The EVI1 gene locus was rearranged in all 13 patients and was associated with EVI1 overexpression. In 9 out of 13 patients, the 17q breakpoints clustered in a 250 kb region on band 17q22 encompassing the MSI2 (musashi homologue 2) gene. Expression analyses failed to demonstrate ectopic MSI2 expression or the presence of an MSI2/EVI1 fusion gene. In conclusion, we show for the first time that the t(3;17) is indeed a recurrent chromosomal aberration in myeloid malignancies. In keeping with findings in other recurrent 3q26 rearrangements, overexpression of the EVI1 gene appears to be the major contributor to leukemogenesis in patients with a t(3; 17)

Improved overall survival with Gemtuzumab Ozogamicin (GO) compared with best supportive care (BSC) in elderly patients with untreated acute myeloid leukemia (AML) not considered fit for intensive chemotherapy: final results from the randomized phase III study (AML-19) of the EORTC and gimema leukemia groups

peer reviewe

Prevalence, severity and correlates of fatigue in newly diagnosed patients with myelodysplastic syndromes

The primary objective of this study was to investigate factors associated with fatigue severity in newly diagnosed patients with higher-risk myelodysplastic syndromes (MDS). The secondary objectives were to assess symptom prevalence and to examine the relationships between fatigue, quality of life (QoL) and overall symptom burden in these patients. The analyses were conducted in 280 higher-risk MDS patients. Pre-treatment patient-reported fatigue was evaluated with the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale and QoL was assessed with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30). Female gender (P = 0·018), poor performance status (i.e., ECOG of 2-4) (P < 0·001) and lower levels of haemoglobin (Hb) (P = 0·026) were independently associated with higher fatigue severity. The three most prevalent symptoms were as follows: fatigue (92%), dyspnoea (63%) and pain (55%). Patients with higher levels of fatigue also had greater overall symptom burdens. The mean global QoL scores of patients with the highest versus those with the lowest levels of fatigue were 29·2 [standard deviation (SD), 18·3] and 69·0 (SD, 18·8), respectively and this difference was four times the magnitude of a clinically meaningful difference. Patient-reported fatigue severity revealed the effects of disease burden on overall QoL more accurately than did degree of anaemia. Special attention should be given to the female patients in the management of fatigue

Benefits and risks of clofarabine in adult acute lymphoblastic leukemia investigated in depth by multi-state modeling

Background: We recently reported results of the prospective, open-label HOVON-100 trial in 334 adult patients with acute lymphoblastic leukemia (ALL) randomized to first-line treatment with or without clofarabine (CLO). No improvement of event-free survival (EFS) was observed, while a higher proportion of patients receiving CLO obtained minimal residual disease (MRD) negativity. Aim: In order to investigate the effects of CLO in more depth, two multi-state models were developed to identify why CLO did not show a long-term survival benefit despite more MRD-negativity. Methods: The first model evaluated the effect of CLO on going off-protocol (not due to refractory disease/relapse, completion or death) as a proxy of severe treatment-related toxicity, while the second model evaluated the effect of CLO on obtaining MRD negativity. The subsequent impact of these intermediate events on death or relapsed/refractory disease was assessed in both models. Results: Overall, patients receiving CLO went off-protocol more frequently than control patients (35/168 [21%] vs. 18/166 [11%], p = 0.019; HR 2.00 [1.13–3.52], p = 0.02), especially during maintenance (13/44 [30%] vs. 6/56 [11%]; HR 2.85 [95%CI 1.08–7.50], p = 0.035). Going off-protocol was, however, not associated with more relapse or death. Patients in the CLO arm showed a trend towards an increased rate of MRD-negativity compared with control patients (HR MRD-negativity: 1.35 [0.95–1.91], p = 0.10), which did not translate into a significant survival benefit. Conclusion: We conclude that the intermediate states, i.e., going off-protocol and MRD-negativity, were affected by adding CLO, but these transitions were not associated with subsequent survival estimates, suggesting relatively modest antileukemic activity in ALL.</p