Genetic alterations and MRD refine risk assessment for KMT2A-rearranged B-cell precursor ALL in adults: a GRAALL study.

KMT2A-rearranged (KMT2A-r) B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is widely recognized as a high-risk leukemia in both children and adults. However, there is a paucity of data on adults treated in recent protocols, and the optimal treatment strategy for these patients is still a matter of debate. In this study, we set out to refine the prognosis of adult KMT2A-r BCP-ALL treated with modern chemotherapy regimen and investigate the prognostic impact of comutations and minimal residual disease (MRD). Of 1091 adult patients with Philadelphia-negative BCP-ALL enrolled in 3 consecutive trials from the Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL), 141 (12.9%) had KMT2A-r, with 5-year cumulative incidence of relapse (CIR) and overall survival (OS) rates of 40.7% and 53.3%, respectively. Molecular profiling highlighted a low mutational burden in this subtype, reminiscent of infant BCP-ALL. However, the presence of TP53 and/or IKZF1 alterations defined a subset of patients with significantly poorer CIR (69.3% vs 36.2%; P = .001) and OS (28.1% vs 60.7%; P = .006) rates. Next, we analyzed the prognostic implication of MRD measured after induction and first consolidation, using both immunoglobulin (IG) or T-cell receptor (TR) gene rearrangements and KMT2A genomic fusion as markers. In approximately one-third of patients, IG/TR rearrangements were absent or displayed clonal evolution during the disease course, compromising MRD monitoring. In contrast, KMT2A-based MRD was highly reliable and strongly associated with outcome, with early good responders having an excellent outcome (3-year CIR, 7.1%; OS, 92.9%). Altogether, our study reveals striking heterogeneity in outcomes within adults with KMT2A-r BCP-ALL and provides new biomarkers to guide risk-based therapeutic stratification.

Factors associated with self-perceived burden to the primary caregiver in older patients with hematologic malignancies: an exploratory study.

OBJECTIVE: Although cancer patients frequently experience self-perceived burden to others, this perception has not been enough studied. The aim of this study was to investigate the prevalence of self-perceived burden to the primary caregiver (SPB-PC) and associated factors in an older patient population with hematologic malignancies at the time of chemotherapy initiation. METHODS: In total, 166 consecutive patients with hematologic malignancies aged ≥65 years were recruited at the time of chemotherapy initiation. Patients' SPB-PC was assessed using a 100-mm visual analogue scale (VAS). Characteristics potentially associated with SPB-PC, including sociodemographic and medical characteristics, physical functioning status (Karnofsky performance score, activities of daily living (ADL)/instrumental ADL), symptoms (fatigue, pain, nausea, quality of life), psychological distress (Hospital Anxiety and Depression Scale (HADS)), perceived cognitive function (Functional Assessment of Cancer Therapy Cognitive (FACT-Cog) Scale), and patients'/primary caregivers' personal relationship characteristics (family tie, support), were assessed. RESULTS: Thirty-five percent of patients reported moderate to severe SPB-PC (VAS ≥ 50 mm). Patients' SPB-PC was associated with lower Karnofsky performance (ß = -0.135, p = 0.058) and ADL (ß = -0.148, p = 0.037) scores, and higher HADS (ß = 0.283, p < 0.001) and FACT-Cog perceived cognitive impairments subscale (ß = 0.211, p = 0.004) scores. The proportion of explained variance was 23.5%. CONCLUSIONS: Health care professionals should be aware that about one third of older cancer patients experience moderate to severe SPB-PC at the time of chemotherapy initiation. They should adapt their support of patients who report such a feeling. Copyright © 2016 John Wiley & Sons, Ltd.

Cognitive compensatory processes of older, clinically fit patients with hematologic malignancies undergoing chemotherapy: A longitudinal cohort study.

OBJECTIVE: Despite the well-known negative impacts of cancer and anticancer therapies on cognitive performance, little is known about the cognitive compensatory processes of older patients with cancer. This study was designed to investigate the cognitive compensatory processes of older, clinically fit patients with hematologic malignancies undergoing chemotherapy. METHODS: We assessed 89 consecutive patients (age ≥ 65 y) without severe cognitive impairment and 89 age-, sex-, and education level-matched healthy controls. Cognitive compensatory processes were investigated by (1) comparing cognitive performance of patients and healthy controls in novel (first exposure to cognitive tasks) and non-novel (second exposure to the same cognitive tasks) contexts, and (2) assessing psychological factors that may facilitate or inhibit cognitive performance, such as motivation, psychological distress, and perceived cognitive performance. We assessed cognitive performance with the Trail-Making, Digit Span and FCSR-IR tests, psychological distress with the Hospital Anxiety and Depression Scale, and perceived cognitive performance with the FACT-Cog questionnaire. RESULTS: In novel and non-novel contexts, average cognitive performances of healthy controls were higher than those of patients and were associated with motivation. Cognitive performance of patients was not associated with investigated psychological factors in the novel context but was associated with motivation and psychological distress in the non-novel context. CONCLUSIONS: Older, clinically fit patients with hematologic malignancies undergoing chemotherapy demonstrated lower cognitive compensatory processes compared to healthy controls. Reducing distress and increasing motivation may improve cognitive compensatory processes of patients in non-novel contexts.

Long-term outcome and prognosis of mixed histiocytosis (Erdheim-Chester disease and Langerhans Cell Histiocytosis).

Background: Erdheim-Chester disease (ECD) is a rare histiocytosis that may overlap with Langerhans Cell Histiocytosis (LCH). This "mixed" entity is poorly characterized. We here investigated the clinical phenotype, outcome, and prognostic factors of a large cohort of patients with mixed ECD-LCH. Methods: This retrospective study was performed at two referral centers in France and Italy (Pitié-Salpêtrière Hospital, Paris; Meyer Children's Hospital, Florence). We included children and adults with ECD diagnosed in 2000-2022 who had biopsy-proven LCH, available data on clinical presentation, treatment and outcome, and a minimum follow-up of one year. Outcomes included differences in clinical presentation and survival between mixed ECD-LCH and isolated ECD; we also investigated response to treatments and predictors of survival in the mixed cohort. Survival was analyzed using the Kaplan-Maier method and differences in survival with the long-rank test. Cox regression models were used to evaluate the potential impact of age and gender on survival and to identify predictors of non-response and survival. Findings: Out of a cohort of 502 ECD patients, 69 (14%) had mixed ECD-LCH. Compared to isolated ECD, mixed ECD-LCH occurred more frequently in females (51 vs. 26%, p < 0.001) and in patients with multisystem disease (≥4 sites). Mixed ECD-LCH more frequently involved long bones (91 vs. 79%, p = 0.014), central nervous system (51 vs. 34%, p = 0.007), facial/orbit (52 vs. 38%, p = 0.031), lungs (43 vs. 28%, p = 0.009), hypothalamic/pituitary axis (51 vs. 26%, p < 0.001), skin (61 vs. 29%, p < 0.001), and lymph nodes (15 vs. 7%, p = 0.028); the BRAFV600E mutation was also more frequent in mixed ECD-LCH (81 vs. 59%, p < 0.001). Targeted treatments (BRAF and/or MEK inhibitors) induced response more frequently than conventional therapies (interferon-α, chemotherapy), either as first-line (77 vs. 29%, p < 0.001) or as any line (75 vs. 24%, p < 0.001). After a median follow-up of 71 months, 24 patients (35%) died. Survival probability was comparable between ECD alone and mixed ECD-LCH (log-rank p = 0.948). At multivariable analysis, age at diagnosis (HR 1.052, 95% CI 1.008-1.096), associated hematologic conditions (HR 3.030, 95% CI 1.040-8.827), and treatment failure (HR 9.736, 95% CI 2.919-32.481) were associated with an increased risk of death, while lytic bone lesions with a lower risk (HR 0.116, 95% CI 0.031-0.432). Interpretation: Mixed ECD-LCH is a multisystem disease driven by the BRAFV600E mutation and targeted treatments are effective. Age at diagnosis, bone lesion patterns, associated hematologic conditions, and treatment failure are the main predictors of death in mixed ECD-LCH. Funding: None.

The use of chemotherapy regimens carrying a moderate or high risk of febrile neutropenia and the corresponding management of febrile neutropenia: an expert survey in breast cancer and non-Hodgkin's lymphoma.

BACKGROUND: The use of chemotherapy regimens with moderate or high risk of febrile neutropenia (defined as having a FN incidence of 10% or more) and the respective incidence and clinical management of FN in breast cancer and NHL has not been studied in Belgium. The existence of a medical need for G-CSF primary and secondary prophylaxis with these regimens was investigated in a real-life setting. METHODS: Nine oncologists and six hematologists from different Belgian general hospitals and university centers were surveyed to collect expert opinion and real-life data (year 2007) on the use of chemotherapy regimens with moderate or high risk of febrile neutropenia and the clinical management of FN in patients aged <65 years with breast cancer or NHL. Data were retrospectively obtained, over a 6-month observation period. RESULTS: The most frequently used regimens in breast cancer patients (n = 161) were FEC (45%), FEC-T (37%) and docetaxel alone (6%). In NHL patients (n = 39), R-CHOP-21 (33%) and R-ACVBP-14 (15%) were mainly used. Without G-CSF primary prophylaxis (PP), FN occurred in 31% of breast cancer patients, and 13% had PSN. After G-CSF secondary prophylaxis (SP), 4% experienced further FN events. Only 1 breast cancer patient received PP, and did not experience a severe neutropenic event. Overall, 30% of chemotherapy cycles observed in breast cancer patients were protected by PP/SP. In 10 NHL patients receiving PP, 2 (20%) developed FN, whereas 13 (45%) of the 29 patients without PP developed FN and 3 (10%) PSN. Overall, 55% of chemotherapy cycles observed in NHL patients were protected by PP/SP. Impaired chemotherapy delivery (timing and/or dose) was reported in 40% (breast cancer) and 38% (NHL) of patients developing FN. Based on oncologist expert opinion, hospitalization rates for FN (average length of stay) without and with PP were, respectively, 48% (4.2 days) and 19% (1.5 days). Similar rates were obtained from hematologists. CONCLUSIONS: Despite the studied chemotherapy regimens being known to be associated with a moderate or high risk of FN, upfront G-CSF prophylaxis was rarely used. The observed incidence of severe neutropenic events without G-CSF prophylaxis was higher than generally reported in the literature. The impact on medical resources used is sizeable.

Fatal Idiopathic Hyperammonemia after Induction Chemotherapy for Acute Myeloid Leukemia.

Idiopathic hyperammonemia is a rare but potentially fatal complication occurring in patients with acute leukemia or bone marrow transplantation. The role of some specific anticancer drugs may be discussed, but the etiology of hyperammonemia is often multifactorial. We report the case of a 40-year-old woman who developed fatal idiopathic hyperammonemia two weeks after induction chemotherapy with idarubicin-aracytine for acute myeloid leukemia. Despite intensive care management and extrarenal epuration, the patient was declared brain dead two days after hyperammonemia onset.

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.

A Belgian consensus protocol for autologous hematopoietic stem cell transplantation in multiple sclerosis.

Multiple sclerosis is considered to be an immune mediated inflammatory disorder of the central nervous system. It mainly affects young, socioeconomic active patients. Although our armamentarium for this disease has significantly evolved in recent years some patients remain refractory to conventional therapies. In these cases, autologous hematopoietic stem cell transplantation can be considered as a therapeutic option. Decreasing morbidity, mortality, and increasing patient awareness have led to rising inquiry by our patients about this treatment option. With the aim of a standardized protocol and data registration, a Belgian working party on stem cell therapy in multiple sclerosis was established. In this paper, we report the consensus protocol of this working party on autologous hematopoietic stem cell transplantation in multiple sclerosis.

Expression of lineage markers using real-time quantitative polymerase chain reaction (RT-qPCR) in normal and in leukemia bone marrow.

BACKGROUND: The study of lineage markers by real-time quantitative polymerase chain reaction (RT-qPCR) at diagnosis enables differentiation between acute myeloblastic leukemia, B- or T-lineage acute lymphoblastic leukemia, without cell sorting. Our objective was to assess the relationship between protein expression and the amount of lineage marker mRNA in acute leukemia samples and to determine whether four lineage markers could be used to differentiate between normal and acute leukemia bone marrow (BM) without cell sorting. METHODS: Quantification of the mRNA of CD19, CD79a, CD3e, and myeloperoxidase was performed by RT-qPCR on 130 acute leukemia BM samples at diagnosis and on 20 BM samples from healthy donors, without cell sorting. Immunophenotyping of leukemia samples was performed after manual gating around the blastic population. RESULTS: Reference values for the four lineage markers were established by RT-qPCR for normal BM. The mRNA expression levels of these four lineage markers allowed the distinction between normal samples and 100% of acute leukemia samples. CONCLUSIONS: With 92% congruence for protein expression and amount of mRNA in acute leukemias, these four lineage markers, essential for diagnosis and subclassification of acute leukemias by flow cytometry, also represent excellent candidate genes when using RT-qPCR technology as a diagnostic tool for molecular cancer class prediction.

Activity and safety of combined rituximab with chlorambucil in patients with mantle cell lymphoma.

We evaluated the combination of rituximab with chlorambucil in patients with mantle cell lymphoma (MCL) not eligible for aggressive therapy. Fourteen patients (male/female: 9/5) were included (two newly diagnosed, 12 relapsed/refractory). The toxicities were neutropenia, thrombopenia and infection. Nine (64%) patients responded; five (36%) achieved complete remission and four (29%) achieved partial remission. The median progression-free survival for responders was 26 months (95% CI, 4-48). Marrow polymerase chain reaction negativity was attained in seven responders. These results suggest that this schedule may have notable antitumour activity in patients with MCL, including patients in relapse after autologous stem cell transplantation.

Differentiation of acute myeloid leukemia from B- and T-lineage acute lymphoid leukemias by real-time quantitative reverse transcription-PCR of lineage marker mRNAs.

BACKGROUND: Flow cytometry of lineage markers is useful in the classification of leukemias. Our aim was to assess whether the study of lineage genes at the RNA level would enable differentiation of acute myeloid leukemias (AMLs) from B-and T-lineage acute lymphoid leukemias (ALLs). METHODS: We measured mRNA of four lineage markers [CD19, CD79a, CD3e, and myeloperoxidase (MPO)] by reverse transcription followed by real-time quantitative (RTQ)-PCR. We investigated 72 acute leukemias (40 AMLs with 23-93% blast cells plus 27 B-lineage ALLs and 5 T-lineage ALLs) defined by morphologic criteria at diagnosis. RTQ-PCR analysis was performed on bone marrow without cell sorting. The expression of each gene was calculated as the difference in the threshold cycle [DeltaCT; CT value of target gene minus CT value of housekeeping gene (Abelson)]. RESULTS: Three patterns of expression were detected. In the first, CD19, CD79a, and MPO mRNAs were less abundant than CD3e. In the second pattern, MPO mRNA was more abundant than the other three mRNAs. In the third, CD19 or CD79a was more highly expressed than CD3e and MPO. The three patterns corresponded to T-ALL, AML, and B-ALL, respectively. The use of cutoffs to establish qualitatively the pattern of coexpression of the four lineage markers provided the same information as the comparison among the four DeltaCT values. Prospective use of the scoring system correctly classified each of 13 additional cases (8 AML, 4 B-lineage ALL, and 1 T-lineage ALL). CONCLUSION: Study of lineage markers at diagnosis by RTQ-PCR allows differentiation of AML from B-ALL or T-ALL without cell sorting, even when the bone marrow contains few blast cells.