Molecular classification improves risk assessment in adult BCR-ABL1-negative B-ALL.

Genomic classification has improved risk assignment of pediatric, but not adult B-lineage acute lymphoblastic leukemia (B-ALL). The international UKALLXII/ECOG-ACRIN E2993 (#NCT00002514) trial accrued 1229 adolescent/adult patients with BCR-ABL1- B-ALL (aged 14 to 65 years). Although 93% of patients achieved remission, 41% relapsed at a median of 13 months (range, 28 days to 12 years). Five-year overall survival (OS) was 42% (95% confidence interval, 39, 44). Transcriptome sequencing, gene expression profiling, cytogenetics, and fusion polymerase chain reaction enabled genomic subtyping of 282 patient samples, of which 264 were eligible for trial, accounting for 64.5% of E2993 patients. Among patients with outcome data, 29.5% with favorable outcomes (5-year OS 65% to 80%) were deemed standard risk (DUX4-rearranged [9.2%], ETV6-RUNX1/-like [2.3%], TCF3-PBX1 [6.9%], PAX5 P80R [4.1%], high-hyperdiploid [6.9%]); 50.2% had high-risk genotypes with 5-year OS of 0% to 27% (Ph-like [21.2%], KMT2A-AFF1 [12%], low-hypodiploid/near-haploid [14.3%], BCL2/MYC-rearranged [2.8%]); 20.3% had intermediate-risk genotypes with 5-year OS of 33% to 45% (PAX5alt [12.4%], ZNF384/-like [5.1%], MEF2D-rearranged [2.8%]). IKZF1 alterations occurred in 86% of Ph-like, and TP53 mutations in patients who were low-hypodiploid (54%) and BCL2/MYC-rearranged (33%) but were not independently associated with outcome. Of patients considered high risk based on presenting age and white blood cell count, 40% harbored subtype-defining genetic alterations associated with standard- or intermediate-risk outcomes. We identified distinct immunophenotypic features for DUX4-rearranged, PAX5 P80R, ZNF384-R/-like, and Ph-like genotypes. These data in a large adult B-ALL cohort treated with a non-risk-adapted approach on a single trial show the prognostic importance of genomic analyses, which may translate into future therapeutic benefits.

Special considerations in the management of adult patients with acute leukaemias and myeloid neoplasms in the COVID-19 era: recommendations from a panel of international experts.

The ongoing COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 is a global public health crisis. Multiple observations indicate poorer post-infection outcomes for patients with cancer than for the general population. Herein, we highlight the challenges in caring for patients with acute leukaemias and myeloid neoplasms amid the COVID-19 pandemic. We summarise key changes related to service allocation, clinical and supportive care, clinical trial participation, and ethical considerations regarding the use of lifesaving measures for these patients. We recognise that these recommendations might be more applicable to high-income countries and might not be generalisable because of regional differences in health-care infrastructure, individual circumstances, and a complex and highly fluid health-care environment. Despite these limitations, we aim to provide a general framework for the care of patients with acute leukaemias and myeloid neoplasms during the COVID-19 pandemic on the basis of recommendations from international experts.

Role of reduced-intensity conditioning allogeneic hematopoietic stem-cell transplantation in older patients with de novo myelodysplastic syndromes: an international collaborative decision analysis.

PURPOSE: Myelodysplastic syndromes (MDS) are clonal hematopoietic disorders that are more common in patients aged ≥ 60 years and are incurable with conventional therapies. Reduced-intensity conditioning (RIC) allogeneic hematopoietic stem-cell transplantation is potentially curative but has additional mortality risk. We evaluated RIC transplantation versus nontransplantation therapies in older patients with MDS stratified by International Prognostic Scoring System (IPSS) risk. PATIENTS AND METHODS: A Markov decision model with quality-of-life utility estimates for different MDS and transplantation states was assessed. Outcomes were life expectancy (LE) and quality-adjusted life expectancy (QALE). A total of 514 patients with de novo MDS aged 60 to 70 years were evaluated. Chronic myelomonocytic leukemia, isolated 5q- syndrome, unclassifiable, and therapy-related MDS were excluded. Transplantation using T-cell depletion or HLA-mismatched or umbilical cord donors was also excluded. RIC transplantation (n = 132) stratified by IPSS risk was compared with best supportive care for patients with nonanemic low/intermediate-1 IPSS (n = 123), hematopoietic growth factors for patients with anemic low/intermediate-1 IPSS (n = 94), and hypomethylating agents for patients with intermediate-2/high IPSS (n = 165). RESULTS: For patients with low/intermediate-1 IPSS MDS, RIC transplantation LE was 38 months versus 77 months with nontransplantation approaches. QALE and sensitivity analysis did not favor RIC transplantation across plausible utility estimates. For intermediate-2/high IPSS MDS, RIC transplantation LE was 36 months versus 28 months for nontransplantation therapies. QALE and sensitivity analysis favored RIC transplantation across plausible utility estimates. CONCLUSION: For patients with de novo MDS aged 60 to 70 years, favored treatments vary with IPSS risk. For low/intermediate-1 IPSS, nontransplantation approaches are preferred. For intermediate-2/high IPSS, RIC transplantation offers overall and quality-adjusted survival benefit.

Measuring health-related quality of life in leukemia: the Functional Assessment of Cancer Therapy--Leukemia (FACT-Leu) questionnaire.

OBJECTIVE: Develop and validate a health-related quality-of-life (measure for patients with acute and chronic leukemia. METHODS: The study consisted of two phases: scale construction and scale validation. For the item-generation phase, a summary of the literature combined with qualitative results from item-generation interviews with 29 acute or chronic leukemia patients and 16 health care providers yielded an initial item pool reflecting leukemia-specific concerns and symptoms. Items underwent iterations of review and reduction according to defined retention criteria to support content validity, as defined by priority concerns of patients. Seventeen final leukemia-specific items were combined with the Functional Assessment of Cancer Therapy-General to create the FACT-Leukemia (FACT-Leu) scale. For the validation phase, 79 individuals with acute or chronic leukemia completed questionnaires at three time points. RESULTS: All FACT-Leu subscale and aggregated scores showed high internal consistency (αs ranging from 0.75 to 0.96). Test-retest reliability was adequate for all subscales (intraclass correlation range 0.765-0.890). The FACT-Leu scale demonstrated good convergent validity, with significant correlations with quality-of-life criteria and performance status, in the expected direction. FACT-Leu subscale scores were significantly different among the three performance status change groups, suggesting good responsiveness to change. CONCLUSIONS: The FACT-Leu scale is a valid, reliable, and efficient measure of leukemia-specific health-related quality of life for acute and chronic disease.

Shortcomings in the clinical evaluation of new drugs: acute myeloid leukemia as paradigm.

Drugs introduced over the past 25 years have benefitted many patients with acute myeloid leukemia (AML) and provided cure for some. Still, AML remains difficult to treat, and most patients will eventually die from their disease. Therefore, novel drugs and drug combinations are under intense investigation, and promising results eagerly awaited and embraced. However, drug development is lengthy and costs are staggering. While the phase 1-phase 2-phase 3 sequence of clinical drug testing has remained inviolate for decades, it appears intrinsically inefficient, and scientific flaws have been noted by many authors. Of major concern is the high frequency of false-positive results obtained in phase 2 studies. Here, we review features of phase 2 trials in AML that may contribute to this problem, particularly lack of control groups, patient heterogeneity, selection bias, and choice of end points. Recognizing these problems and challenges should provide us with opportunities to make drug development more efficient and less costly. We also suggest strategies for trial design improvement. Although our focus is on the treatment of AML, the principles that we highlight should be broadly applicable to the evaluation of new treatments for a variety of diseases.

Evaluation of serious adverse drug reactions: a proactive pharmacovigilance program (RADAR) vs safety activities conducted by the Food and Drug Administration and pharmaceutical manufacturers.

BACKGROUND: The Food and Drug Administration (FDA) and pharmaceutical manufacturers conduct most postmarketing pharmaceutical safety investigations. These efforts are frequently based on data mining of databases. In 1998, investigators initiated the Research on Adverse Drug events And Reports (RADAR) project to investigate reports of serious adverse drug reactions (ADRs) and prospectively obtain information on these cases. We compare safety efforts for evaluating serious ADRs conducted by the FDA and pharmaceutical manufacturers vs the RADAR project. METHODS: We evaluated the completeness of serious ADR descriptions in the FDA and RADAR databases and the comprehensiveness of notifications disseminated by pharmaceutical manufacturers and the RADAR investigators. A serious ADR was defined as an event that led to death or required intensive therapies to reverse. RESULTS: The RADAR investigators evaluated 16 serious ADRs. Compared with descriptions of these ADRs in FDA databases (2296 reports), reports in RADAR databases (472 reports) had a 2-fold higher rate of including information on history and physical examination (92% vs 45%; P<.001) and a 9-fold higher rate of including basic science findings (34% vs 4%; P = .08). Safety notifications were disseminated earlier by pharmaceutical suppliers (2 vs 4 years after approval, respectively), although notifications were less likely to include information on incidence (46% vs 93%; P = .02), outcomes (8% vs 100%; P<.001), treatment or prophylaxis (25% vs 93%; P<.001), or references (8% vs 80%; P<.001). CONCLUSION: Proactive safety efforts conducted by the RADAR investigators are more comprehensive than those conducted by the FDA and pharmaceutical manufacturers, but dissemination of related safety notifications is less timely.

Growth factors in leukemia.

The role of myeloid growth factors, such as granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor, in the management of acute myeloid and acute lymphoblastic leukemias has been evaluated extensively in multiple clinical trials. Growth factors have been given before, concurrently, or sequentially with chemotherapy with the goal of reducing the duration of neutropenia and consequently the incidence and severity of infections, and improving the rate of remissions and overall survival. They also have been studied as chemotherapy-sensitizing agents in an effort to recruit dormant myeloid stem cells into the sensitive phase of the cycle. Additionally, growth factors, shown to stimulate proliferation and differentiation of leukemia cells in vitro, were evaluated as monotherapy in patients with acute leukemia. Most studies show modest improvement in the duration of the neutropenia, which does not consistently correlate with the severity of infection, rate or duration of remissions, or disease-free and overall survival. Attempts to enhance the chemosensitivity of the leukemic cells and decrease drug resistance failed to improve the rate of remission and survival in several large series. However, more recent reports suggested an improved outcome in younger patients with acute myeloid leukemia with normal karyotype. Several anecdotal case reports have shown that growth factor monotherapy can induce a complete remission in patients with acute leukemia. Data from the published clinical trials do not seem to support emergence of drug-resistant leukemia, worsening toxicity, and bone marrow failure with growth factor administration.

Comprehensive assessment of genetic and molecular features predicting outcome in patients with chronic lymphocytic leukemia: results from the US Intergroup Phase III Trial E2997.

PURPOSE: Genomic features including unmutated immunoglobulin variable region heavy chain (IgVH) genes, del(11q22.3), del(17p13.1), and p53 mutations have been reported to predict the clinical course and overall survival of patients with chronic lymphocytic leukemia (CLL). In addition, ZAP-70 and Bcl-2 family proteins have been explored as predictors of outcome. PATIENTS AND METHODS: We prospectively evaluated the prognostic significance of a comprehensive panel of laboratory factors on both response and progression-free survival (PFS) using samples and data from 235 patients enrolled onto a therapeutic trial. Patients received either fludarabine (FL; n = 113) or fludarabine plus cyclophosphamide (FC; n = 122) as part of a US Intergroup randomized trial for previously untreated CLL patients. RESULTS: Complete response (CR) rates were 24.6% for patients receiving FC and 5.3% for patients receiving FL (P = .00004). PFS was statistically significantly longer in patients receiving FC (median, 33.5 months for patients receiving FC and 19.9 months for patients receiving FL; P < .0001). The occurrence of del(17p13.1) (hazard ratio, 3.428; P = .0002) or del(11q22.3) (hazard ratio, 1.904; P = .006) was associated with reduced PFS. CR and overall response rates were not significantly different based on cytogenetics, IgVH mutational status, CD38 expression, or p53 mutational status. Expression of ZAP-70, Bcl-2, Bax, Mcl-1, XIAP, Caspase-3, and Traf-1 was not associated with either clinical response or PFS. CONCLUSION: These results support the use of interphase cytogenetic analysis, but not IgVH, CD38 expression, or ZAP-70 status, to predict outcome of FL-based chemotherapy. Patients with high-risk cytogenetic features should be considered for alternative therapies.

Quantitative real-time RT-PCR analysis of PML-RAR alpha mRNA in acute promyelocytic leukemia: assessment of prognostic significance in adult patients from intergroup protocol 0129.

The potential prognostic value of quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR [qrtPCR]) measurements of PML-RAR alpha mRNA in acute promyelocytic leukemia was retrospectively assessed before treatment and at 3 posttreatment intervals in 123 patients on intergroup protocol 0129. The primary measure was the PML-RAR alpha(GAPDH) normalized quotient (NQ), that is, PML-RAR alpha mRNA copies divided by glyceraldehyde-3'-phosphate dehydrogenase (GAPDH) mRNA copies. Only samples with more than 2.5 x 10(5) copies of the housekeeping gene GAPDH mRNA (detection sensitivity exceeding 10(4)) were considered NQ evaluable. With RNA from low-density selected cells, paired peripheral blood (PB) and bone marrow samples (n = 140) had comparable NQs (P <.001). Before treatment, high NQ was associated with short-form PML-RAR alpha (P <.001), but not with white blood cell count or clinical outcome. Following treatment, NQ was lower in all-trans retinoic acid-induced complete remission (CR) than chemotherapy-induced CR (P =.018) and at first test after consolidation chemotherapy (P =.037). After consolidation chemotherapy, patients with NQ exceeding 10(-5) had 4.1-fold increased relapse risk (P =.008); however, 73% of patients who experienced relapse had NQ lower than 10(-5). In the follow-up period (FUP), any NQ exceeding 10(-5) and 10(-6) had 17.5-fold and 7.6-fold increased relapse risk, respectively (P <.001), while no gradation of relapse risk (approximately 18%) could be identified at NQ lower than 10(-6), including NQ(-). These results indicate that qrtPCR monitoring of PML-RAR alpha NQ can identify patients at high risk of relapse and suggest that clinically practical PB NQ monitoring at more frequent FUP intervals may improve predictive accuracy for relapse or continuing CR in patients with persistent, fluctuating minimal residual disease levels.