Similar efficacy outcomes with peripheral blood stem cell versus bone marrow for autologous stem cell transplantation in acute myeloid leukemia: Long-term follow-up of the EORTC-GIMEMA randomized AML-10 trial.

We report here the long-term follow-up of the only prospective randomized trial of autologous hematopoietic stem cell transplantation (auto-HSCT) with peripheral blood stem cells (APBSCT) versus auto-HSCT with bone marrow (ABMT) in acute myeloid leukemia (AML) patients in first remission (CR). We observed that among patients alive and still in CR 5 years after planned auto-HSCT, approximately 10% of the patients died in the following 10 years. This stresses the need for long-term close surveillance of AML patients after auto-HSCT. Further, long-term follow-up of the trial confirms that APBSCT was comparable to ABMT in term of disease-free-survival and overall survival.

Impact of the type of anthracycline and of stem cell transplantation in younger patients with acute myeloid leukaemia: Long-term follow up of a phase III study.

We provide a long-term evaluation of patients enrolled in the EORTC/GIMEMA AML-10 trial which included a total of 2157 patients, 15-60 years old, randomized to receive either daunorubicin (DNR, 50 mg/m2 ), mitoxantrone (MXR, 12 mg/m2 ), or idarubicin (IDA, 10 mg/m2 ) in addition to standard-dose cytarabine and etoposide for induction chemotherapy and intermediate dose cytarabine for consolidation. Younger patients who reached complete remission with complete (CR) or incomplete (CRi) recovery were then scheduled to receive an allogeneic hematopoietic stem cell transplantation (HSCT). That was if they had a HLA-identical sibling donor; in all other cases, an autologous HSCT had to be administered. At an 11-year median follow-up, the 5-year, 10-year and 15-year overall survival (OS) rates were 33.2%, 30.1% and 28.0%, respectively. No significant difference between the three randomized groups regarding OS was observed (P = .38). In young patients, 15-45 years old, no treatment difference (P = .89) regarding OS was observed, while in patients 46-60 years old, MXR and IDA groups had a trend for a longer OS as compared to the DNR group (P = .029). Among younger patients without a favorable MRC cytogenetic risk subgroup who achieved a CR/CRi after induction chemotherapy, those with a HLA-identical sibling donor had higher 10-year and 15-year OS rates than those without. In older patients who reached CR/CRi, the long-term outcomes of those with or without a donor was similar. In conclusion, long-term outcomes of the study confirmed similar OS in the three randomized groups in the whole cohort of patients.

A prospective observational study to assess clinical decision-making, prognosis, quality of life and satisfaction with care in patients with relapsed/refractory multiple myeloma: the CLARITY study protocol.

BACKGROUND: Treatment decision-making in patients with relapsed/refractory multiple myeloma (RRMM) is challenging for a number of reasons including, the heterogeneity of disease at relapse and the number of possible therapeutic approaches. This study broadly aims to generate new evidence-based data to facilitate clinical decision-making in RRMM patients. The primary objective is to investigate the prognostic value of patient self-reported fatigue severity for overall survival. METHODS: This multicenter prospective observational study will consecutively enroll 312 patients with multiple myeloma who have received at least 1 prior line of therapy and are considered as RRMM according to the International Myeloma Working Group (IMWG) criteria. Eligible RRMM participants will be adults (≥ 18 years old) patients and will be enrolled irrespective of comorbidities and performance status. At the time of study inclusion, data to calculate the frailty score are to be available. Patients will be followed up for 30 months and patient-reported outcome (PRO) assessment is planned at baseline and thereafter at 3, 6, 12, and 24 months. The following PRO validated questionnaires will be used: the European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30), the EORTC QLQ-MY20 and the EORTC QLQ-INFO25. Satisfaction with care and preference for involvement in treatment decisions will also be evaluated. Clinical, laboratory and treatment related information will be prospectively collected in conjunction with pre scheduled PRO assessments. Cox regression analyses will be used to assess the prognostic value of baseline fatigue severity (EORTC QLQ-C30) and other patient-reported health-related quality of life parameters. DISCUSSION: Clinical decision-making in RRMM is a challenge and outcome prediction is also an important aspect to enhance personalized treatment planning. Given the paucity of PRO data in this population, this prospective observational study aims to provide novel information that may facilitate patients' management in routine practice. TRIAL REGISTRATION: This trial is registered as identifier NCT03190525 .

Physicians' attitude towards selection of second line therapy with nilotinib and dasatinib in chronic myeloid leukemia patients.

We investigated factors that physicians consider of most importance in the selection of second line tyrosine kinase inhibitors treatments (TKIs) in chronic myeloid leukemia patients (CML).

Enhanced and aberrant T cell trafficking following total body irradiation: a gateway to graft-versus-host disease?

Pre-transplant conditioning regimens play a major role in triggering graft-versus-host disease (GVHD). This study investigated the effect of irradiation on donor T cell trafficking to lymphoid and non-lymphoid tissues by comparing the migration of carboxy-fluorescein diacetate succinimidyl ester-labelled, naïve donor T lymphocytes in vivo in irradiated and non-irradiated syngeneic mice recipients. Recruitment of adoptively transferred naïve T cells to secondary lymphoid organs was increased in irradiated mice and naïve T cells also aberrantly localized to non-lymphoid tissues. Irradiation also induced aberrant effector memory T cell migration into lymph nodes and their localization to homing-privileged non-lymphoid sites, such as the gut. The presence of a minor histocompatibility mismatch further enhanced the aberrant accumulation of T cells in both lymphoid and non-lymphoid tissue, whilst their migratory pattern was not modified as compared to fully matched irradiated recipients. These effects correlated with decreased permeability of, and the secretion of chemotactic factors by the endothelium. Our findings are consistent with the possibility that excessive, dysregulated extravasation of T cells induced by irradiation promotes the development of GVHD.

Chimeric Antigen Receptor T-cell Therapy in Hematologic Malignancies and Patient-reported Outcomes: A Scoping Review.

The inclusion of patient-reported outcome (PRO) measures in chimeric antigen receptor (CAR) T-cell therapy research is critical for understanding the impact of this novel approach from a unique patient standpoint. We performed a scoping review to map the available literature on the use of PRO measures in CAR T-cell therapy studies of patients with hematologic malignancies published between January 2015 and July 2022. Fourteen studies were identified, of which 7 (50%) were investigational early-phase trials, 6 (42.9%) were observational studies, and 1 (7.1%) was a pilot study. The EQ-5D and the PROMIS-29 were the 2 most frequently used PRO measures, being included in 6 (42.9%) and 5 (35.7%) studies, respectively. Despite differences in study designs, there seems to be evidence of improvements over time since CAR T-cell infusion in important domains such as physical functioning and fatigue, at least in patients who respond to therapy. Overall, the studies identified in our review have shown the added value of PRO assessment in CAR T-cell therapy research by providing novel information that complements the knowledge on safety and efficacy. However, there are several questions which remain to be answered in future research. For example, limited evidence exists regarding patient experience during important phases of the disease trajectory as only 4 (28.6%) and 5 (35.7%) studies provided information on PROs during the first 2 weeks from CAR T-cell infusion and after the first year, respectively. Time is ripe for a more systematic implementation of high-quality PRO assessment in future clinical trials and in real-life settings of patients treated with CAR T-cell therapy.

Health-related quality of life in patients with acute promyelocytic leukemia: a systematic literature review.

Introduction: Remarkable advances have been made in acute promyelocytic leukemia (APL) research over the past decades and many patients can now also be cured without traditional chemotherapy. Therefore, the assessment of health-related quality of life (HRQoL) and other types of patient-reported outcomes (PROs) is highly relevant in the current APL treatment landscape.Areas covered: A systematic literature review was performed to identify APL studies assessing HRQoL that were published over the last 15 years. Eligible studies were evaluated on a predetermined data extraction form including information on the study design, PRO measure used, as well patient characteristics and summary of HRQoL findings. For descriptive purposes, selected studies were grouped and discussed based on the type of treatment: standard chemotherapy only versus those also including more recent targeted arsenic trioxide (ATO)-based strategies.Expert opinion: Inclusion of HRQoL in APL research was important to better understand the benefit-risk profile of intravenous ATO compared to traditional chemotherapy. While some information on HRQoL and symptoms in APL survivors treated with standard chemotherapy is available, the long-term effects of ATO therapy on patients' HRQoL are largely unknown. Additionally, future studies are needed to evaluate the potential advantages of oral ATO over intravenous administration.

Cytogenetic and molecular responses in chronic phase chronic myeloid leukaemia patients receiving low dose of imatinib for intolerance to standard dose.

Imatinib mesylate is the gold standard treatment of chronic myeloid leukaemia (CML) and 400 mg/day is considered the standard dose. Although it is generally well tolerated, some patients require temporary drug discontinuation and permanent dose reduction because of haematological or non-haematological toxicities. Whether or not reduced doses are effective as the standard dose in inducing and/or maintaining complete cytogenetic and molecular response is not clear. We report the outcome of 45 CML patients in early (17) and late (28) chronic phase (CP) in whom, within a series of 250 patients treated with imatinib, reduced the dose of the drug after experiencing adverse events. Median time interval between the start of therapy and dose reduction was 58 days, whereas median administered dose was 300 mg/day. At 6 months from reduction, major cytogenetic responses (MCRs) were observed in 67% of patients, with 58% being complete cytogenetic remission (CCR), and complete molecular response (CMR) were obtained in 18% of patients. At 12 months, all patients who had obtained MCR reached CCR: this was significantly higher in low risk patients (87%) versus non-low risk patients (66 and 46%), and in early phase (82%) versus late phase (53.5%). CMR and major molecular response (MMR) were detected in 20 and 22% of patients, respectively. Low dose imatinib appears effective in patients with intolerance to standard dose, even though long-term effects remain to be established.

Quality of patient-reported outcome reporting in randomised controlled trials of haematological malignancies according to international quality standards: a systematic review.

Patient-reported outcome (PRO) endpoints are increasingly considered for inclusion in randomised controlled trials (RCTs) involving patients with haematological malignancies. The aim of our systematic review was to investigate the quality of PRO reporting across these RCTs. We searched Ovid MEDLINE, Embase, the Cochrane Library, and PubMed for English language articles published between Jan 1, 2014, and Jan 31, 2019. Eligible articles were RCTs of cancer-directed therapy in adult patients with haematological malignancies that reported on PRO measures in the primary publication or in a subsequent publication, with a comparison of PROs among treatment groups. A total of 3678 records were assessed, and 71 RCTs, enrolling 24 701 patients, were included in our systematic review. Most RCTs (n=65 [92%]) had PRO measures as a secondary or exploratory endpoint. A PRO hypothesis and relevant PRO domains were specified in 36 (51%) RCTs. Statistical approaches for dealing with missing data were documented in 26 (37%) RCTs. Quality of PRO reporting was higher in RCTs citing the Consolidated Standards of Reporting Trials Statement-PRO extension (CONSORT-PRO) than in those not citing this checklist, as evidenced by the International Society for Quality of Life Research score (median score in studies citing the CONSORT-PRO extension [n=4] was 89 [IQR 75-94] vs 61 [44-78] in those not citing this extension). Independent factors significantly associated with higher reporting included having PROs as a primary endpoint (p=0·008) and the presence of a subsequent publication on PROs (p<0·0001). International guidelines for designing, reporting, and analysing PRO data are now available to further improve overall study quality. Our findings can help investigators to focus on key aspects most in need of attention when reporting PROs in future trials of haematological malignancies.

Comorbidities and FLT3-ITD abnormalities as independent prognostic indicators of survival in elderly acute myeloid leukaemia patients.

Elderly acute myeloid leukaemia (AML) patients have a dismal prognosis due to biological features of disease in itself and to presence of comorbidities. Aim of this study was to evaluate the prognostic impact of comorbidity prognostic score systems applied in our population of patients. as well as other clinical-biological features. We retrospectively considered the outcome of 120 patients aged >65 years diagnosed as having AML between January 2001 and December 2005. Comorbidities were evaluated by using Charlson comorbidity index (CCI), Hematopoietic cell transplantation comorbidity index (HCTCI) and a score proposed by Dombret et al. in 2007. Median patient age was 67 years. Forty-six patients were treated with intensive chemotherapy and 23 reached a complete remission. Seventy-four patients received only supportive therapies or low-dose chemotherapy. Multivariate analysis showed the effects of leukocytosis (p = 0.0013), antecedent Myelodysplastic syndrome (MDS) (p = 0.011), FLT3 abnormalities (p = 0.032), CCI (p = 0.0037) and Dombret et al. score (p = 0.045) as independent prognostic parameters for survival. Based on these variables we were able to stratify patients in low and high risk, with different median overall survival: patients were considered as low risk if they had none or only one of the above mentioned adverse factors for survival, with a median overall survival of 447 days. Patients with two or more adverse factors were categorized as high risk: this subgroup had a median overall survival of 227 days (p = 0.001). Comorbidities are independent factors that influence survival. Application of CCI and Dombret score may help to better identify patients at diagnosis who can benefit from intensive chemotherapy.

Isolated thrombocytosis as first sign of chronic myeloid leukemia with e6a2 BCR/ABL fusion transcript, JAK2 negativity and complete response to imatinib.

Since very few unusual BCR/ABL fusion transcripts in chronic myeloid leukemia have been reported, no clear evidence exists concerning their clinical and prognostic implications. We describe here a CML case with normal karyotype at standard cytogenetics and an atypical e6a2 BCR/ABL fusion transcript, presenting at diagnosis isolated thrombocytosis and mild leukopenia; the patient, who was tested negative for JAK2 mutation, obtained a complete response to imatinib. The few previous observations from literature are also reviewed.

Ocular side effects in chronic myeloid leukemia patients treated with imatinib.

Imatinib mesylate is a selective inhibitor of the bcr/abl, c-kit and PDGF receptor tyrosine kinases. Its ocular toxicity is little known with mild periorbital oedema being the most commonly reported side effect. We here describe our experience on ocular complications in imatinib treated Ph+ CML patients, which consisted of a wide spectrum of adverse effects ranging from periobital oedema to serious adverse events such as glaucoma.

Rituximab associated to imatinib for coexisting therapy-related chronic myeloid leukaemia and relapsed non-Hodgkin lymphoma.

Philadelphia positive (Ph+) chronic myeloid leukaemia (CML) presenting synchronously or following non-Hodgkin lymphoma (NHL) has only rarely been reported. Herein, we refer on a case of Ph+ CML occurring after a breast cancer and a NHL with multiple relapses. After obtaining complete cytogenetic remission with imatinib, the patient presented a new NHL relapse, that was treated with rituximab concomitantly to imatinib. Therapy was well tolerated and the patient is presently alive in complete remission of either NHL and CML. We also reviewed the literature relating the uncommon association of these two unrelated diseases.

How should we assess patient-reported outcomes in the onco-hematology clinic?

PURPOSE OF REVIEW: The improvement of clinical outcomes in hematologic malignancies has paved the way for a more systematic patient-reported outcomes (PROs) assessment in routine clinical practice. PROs help to narrow the gap between patients' and healthcare professionals' view of patient health and treatment success. This review outlines key aspects of planning and performing PRO assessments in daily routine such as the selection of PRO instruments, electronic PRO data collection, and the presentation and interpretation of PRO results. RECENT FINDINGS: A substantial body of literature has demonstrated that careful planning, adequate logistics, and elaborate methodology allow to successfully integrate the patients' experience in routine care. Several examples exist of the clinical benefits of systematically collecting PRO information in daily care of patients with solid tumors. These include improved patient-physician communication, better symptom management, and, in patients with advanced disease, also fewer hospitalizations and prolonged survival. However, sparse evidence based data are available for patients with onco-hematologic diseases. SUMMARY: Data collected through PRO instruments provide unique information that complements traditional clinical examinations and may help improving patients' management in clinical practice. Major efforts are now needed to implement PRO instruments in daily practice of patients with hematologic malignancies.

The value of quality of life assessment in chronic myeloid leukemia patients receiving tyrosine kinase inhibitors.

The development of the oral tyrosine kinase inhibitors (TKIs) to treat chronic myeloid leukemia (CML) is one of the great triumphs of cancer research. Although the efficacy of TKIs has dramatically improved the disease-specific overall survival rate, the prevalence of CML is increasing worldwide. Currently, CML patients receive prolonged (even lifelong) treatment, and over the last decade, clinical decision making has become challenging. Therefore, consideration of the effects of TKI therapies on patients' quality of life (QoL) and symptom burden (ie, patient-reported outcomes [PROs]) is now critical to more robustly inform patient care and improve health care quality. Over the last 5 years, a number of studies have generated valuable PRO data, for example, on long-term QoL effects of imatinib therapy or symptom burden of patients switching from imatinib to second-generation TKIs. PRO findings are important, as they provide a unique patient perspective on the burden of the disease and treatments effects. We will review main evidence-based data on the use of PROs in clinical research and highlight the importance of methodological rigor of PRO assessment. Also, we will describe the potential value of using PRO assessment in routine clinical practice, for example, to facilitate timely management of side effects. Areas for future research will also be discussed.