EXPRESS: Families with Multiple Individuals with Acute Leukemia in Their Pedigrees.

Forty-one families with multiple cases of de novo acute myeloid leukemia (AML), B-cell acute lymphocytic leukemia (B-ALL) or both are presented. The families were randomly collected from physicians, genetic counselors and other sources. Medical records were collected and reviewed for all families. In 17 of the families a parent and child with acute leukemia were identified and in 15 of the pairs the parent and child were of the same sex. Nine grandparent-grandchild affected pairs with AML-AML were identified, occurring in 6 families, and 6 of those pairs were also of the same sex. Anticipation was a common feature of these multigenerational pairs. Twenty families were identified with multiple siblings (none twins) with acute leukemia. This includes 16 sibling pairs and 4 sibling triples. The members of each sibling pair in the AML-AML group and in the B-ALL-B-ALL group were generally of roughly the same age. Curiously, this is not true of those in the AML-B-ALL group. Four of the 41 families had contributions to more than 1 family relationship category. Although inheritance in familial acute leukemia has usually been consistent with an autosomal dominant pattern, these data suggest that an X chromosome gene may be involved in some cases, perhaps in the pseudoautosomal region of the X chromosome as we have reported in familial Hodgkin lymphoma.

Families with non-Hodgkin lymphoma and plasma cell dyscrasias in their pedigrees.

Although reports of familial clustering of hematologic malignancies have appeared for decades, the cause(s) of this uncommon occurrence is still not completely understood. Most modern investigations, however, support a genetic rather than an environmental exposure as a cause of this observation. Most pedigrees of families with familial hematologic malignancies demonstrate age of onset anticipation, with the disease diagnosed at an earlier age in successive generations. The cause of this phenomenon is clear in some familial neurologic disorders (trinucleotide repeat expansion) but not at all clear in familial hematologic malignancies. In preparation for molecular studies of familial clustering of hematologic malignancies, we have collected pedigrees on 738 families and have previously demonstrated anticipation in those with familial plasma cell myeloma, chronic lymphocytic leukemia, Hodgkin lymphoma or non-Hodgkin lymphoma (NHL). Here we present data on 36 families with both plasma cell myeloma and NHL in their pedigrees and demonstrate strong evidence for anticipation in these families. We encourage all health care personnel to ask patients multiple times about family medical history and carefully take note of family histories from individuals with uncommon illnesses and to refer families with clustering of such illnesses for further investigation.

Higher than normal mitochondrial DNA content associated with better outcome in acute promyelocytic leukaemia? Maybe.

Mitochondrial biology may influence the outcome of therapy for acute promyelocytic leukemia if arsenic trioxide is not part of the treatment. Inclusion of arsenic trioxide in the treatment regimen may cancel the adverse impact of certain mitochondrial abnormalities frequently associated with the disease. Commentary on: Pereira-Martins et al. Clinical significance of mitochondrial DNA content in acute promyelocytic leukaemia. Br J Haematol 2023;200:170-174.

Intracellular Cholesterol Pools Regulate Oncogenic Signaling and Epigenetic Circuitries in Early T-cell Precursor Acute Lymphoblastic Leukemia.

Early T-cell acute lymphoblastic leukemia (ETP-ALL) is an aggressive hematologic malignancy associated with early relapse and poor prognosis that is genetically, immunophenotypically, and transcriptionally distinct from more mature T-cell acute lymphoblastic leukemia (T-ALL) tumors. Here, we leveraged global metabolomic and transcriptomic profiling of primary ETP- and T-ALL leukemia samples to identify specific metabolic circuitries differentially active in this high-risk leukemia group. ETP-ALLs showed increased biosynthesis of phospholipids and sphingolipids and were specifically sensitive to inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase, the rate-limiting enzyme in the mevalonate pathway. Mechanistically, inhibition of cholesterol synthesis inhibited oncogenic AKT1 signaling and suppressed MYC expression via loss of chromatin accessibility at a leukemia stem cell-specific long-range MYC enhancer. In all, these results identify the mevalonate pathway as a druggable novel vulnerability in high-risk ETP-ALL cells and uncover an unanticipated critical role for cholesterol biosynthesis in signal transduction and epigenetic circuitries driving leukemia cell growth and survival. SIGNIFICANCE: Overtly distinct cell metabolic pathways operate in ETP- and T-ALL pointing to specific metabolic vulnerabilities. Inhibition of mevalonate biosynthesis selectively blocks oncogenic AKT-MYC signaling in ETP-ALL and suppresses leukemia cell growth. Ultimately, these results will inform the development of novel tailored and more effective treatments for patients with high-risk ETP-ALL. This article is highlighted in the In This Issue feature, p. 587.

CNS involvement in AML at diagnosis is rare and does not affect response or survival: data from 11 ECOG-ACRIN trials.

Central nervous system (CNS) involvement in patients with newly diagnosed acute myeloid leukemia (AML) is rare, and systematic data regarding outcome are scarce. This retrospective study summarized data from 11 consecutive Eastern Cooperative Oncology Group-American College of Radiology Imaging Network (ECOG-ACRIN) clinical trials for patients with newly diagnosed AML. In all, 3240 patients with AML were analyzed, and 36 (1.11%) were found to have CNS involvement at diagnosis. The incidence of CNS disease among the 5 studies with per protocol mandatory lumbar puncture (LP) was similar to the incidence among studies in which LP was performed at the discretion of the investigator (0.86% vs 1.41%; P = .18). There was no significant difference in the rate of complete remission (CR) among patients with CNS involvement and those with other extramedullary disease (EMD) sites or those with no EMD (52.8% vs 59.3%-60%). The median overall survival (OS) for patients who were CNS positive, who had other EMD, or who had no EMD was 11.4, 11.3, and 12.7 months, respectively. There was no difference in OS among patients with CNS involvement, those with other EMD (hazard ratio [HR], 0.96; adjusted P = .84), and those with no EMD (HR, 1.19; adjusted P = .44). In conclusion, the reported incidence of CNS involvement in patients with newly diagnosed AML is low (1.1%), irrespective of whether an LP is mandatory or not. The presence of CNS disease at diagnosis in and of itself does not seem to portend a poor prognosis for achieving an initial CR or for OS.

Prognostic effect of gender on outcome of treatment for adults with acute myeloid leukaemia.

There are conflicting reports in the literature suggesting that one gender or the other has a better survival with acute myeloid leukaemia (AML). The present study was done in an attempt to resolve the issue. The effect of gender was examined on 3546 newly diagnosed patients with AML, including 548 patients with acute promyelocytic leukaemia (APL) enrolled in 10 multi-institutional treatment studies from March 1984 to November 2008. Kaplan-Meier estimates were used to estimate event-time distributions for survival and multivariate models were used to examine the gender effect after adjusting for multiple risk factors. P values were based on two-sided tests. Non-APL female patients had a significantly better overall (OS) but not disease-free survival (DFS) than males, irrespective of age, initial white blood cell count, or dose of daunorubicin. No differences were observed for obese or FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD)-positive patients. Female patients with APL had a significantly better OS and DFS than male patients with APL, and differences in survival were greater for patients with t(15;17) + other cytogenetic abnormalities compared with those with t(15;17) only. Gender is an independent prognostic variable in patients with AML. Whether these survival differences are due to hormonal, genetic or pharmacokinetic differences between the sexes or differential toxin exposure such as smoking is unknown. However, the former seems less likely as patient age did not influence the survival advantage for female patients.

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.

Long-term progression-free survival of patients with metastatic melanoma or renal cell carcinoma following high-dose interleukin-2.

High-dose interleukin-2 (HD IL-2) was approved in the 1990s after demonstrating durable complete responses (CRs) in some patients with metastatic melanoma (mM) and metastatic renal cell carcinoma (mRCC). Patients who achieve this level of disease control have also demonstrated improved survival compared with patients who progress, but limited data are available describing the long-term course. The aim of this study was to better characterize long-term survival following successful HD IL-2 treatment in patients with no subsequent systemic therapy. Eleven HD IL-2 treatment centers identified patients with survival ≥5 years after HD IL-2, with no subsequent systemic therapy. Survival was evaluated from the date of IL-2 treatment to June 2017. Treatment courses consisted of 2 1-week cycles of HD IL-2. Patients were treated with HD IL-2 alone, or HD IL-2 followed by local therapy to achieve maximal response. 100 patients are reported: 54 patients with mM and 46 patients with mRCC. Progression-free survival (PFS) after HD IL-2 ranges from 5+ years to 30+ years, with a median follow-up of 10+ years. 27 mRCC and 32 mM are alive ≥10 years after IL-2. Thus, a small subset of patients with mM and mRCC achieve long-term PFS (≥5 years) after treatment with HD IL-2 as their only systemic therapy. The ability of HD IL-2 therapy to induce prolonged PFS should be a major consideration in studies of new immunotherapy combinations for mM and mRCC.

At three years, patients with acute lymphoblastic leukaemia are still at risk for relapse. Results of the international MRC UKALLXII/ECOG E2993 trial.

Late relapse [>3 years from complete remission (CR)] in acute lymphoblastic leukaemia (ALL), is unusual. Data from the MRC UKALLXII/ECOG E2993 trial are presented to evaluate the incidence and characteristics of late relapse in adult ALL. Of 1,909 patients, 1,752 (92%) achieved CR and among these 757 (43·2%) relapsed; 691 (91·3%) within three years and 66 (8·7%) beyond. Among these 66 patients, median time to relapse was 47 (37-144) months. Relapse beyond three years occurred in 3·8% of all who achieved CR. The cumulative risk of relapse was 40%, 43% and 45% at three, five and ten years respectively. Out of the 1 752 patients who achieved CR, 11·7% underwent autologous and 40·6% allogeneic transplant, while in CR1. Of the autologous patients, 43·2% relapsed early and 3·4% relapsed late. However, among the allogeneic patients, 13·2% relapsed early and only 1·3% late. The five-year overall survival from relapse was 5·8% and 20% in the early and late relapse patients respectively. In conclusion, late relapse in adults with ALL is not uncommon, and is associated with better outcome after relapse compared to early relapse.

The Role of Donor Lymphocyte Infusion (DLI) in Post-Hematopoietic Cell Transplant (HCT) Relapse for Chronic Myeloid Leukemia (CML) in the Tyrosine Kinase Inhibitor (TKI) Era.

Treatment for relapse of chronic myeloid leukemia (CML) following hematopoietic cell transplantation (HCT) includes tyrosine kinase inhibitors (TKIs) with or without donor lymphocyte infusions (DLIs), but the most effective treatment strategy is unknown. This study was performed through the Center for International Blood and Marrow Transplant Research (CIBMTR) database. We retrospectively reviewed all patients reported to the CIBMTR registry from 2002 to 2014 who underwent HCT for CML and were alive 30 days postrelapse. A total of 215 HCT recipients relapsed and were analyzed in the following groups: (1) TKI alone (n = 128), (2) TKI with DLI (n = 48), and (3) DLI without TKI (n = 39). In multivariate analysis, disease status prior to HCT had a significant effect on overall survival (OS). Patients who received a DLI alone compared with a TKI with a DLI had inferior survival (hazard ratio, 2.28; 95% confidence interval, 1.23 to 4.24; P= .009). Those who received a TKI alone had similar survival compared with those who received a TKI with a DLI (P = .81). These data support that despite use of TKIs pretransplantation, TKI salvage therapy continues to provide significant survival following relapse in patients with CML following HCT. These data do not suggest that adding a DLI to a TKI adds an improvement in OS.

Very poor long-term survival in past and more recent studies for relapsed AML patients: The ECOG-ACRIN experience.

This study examines the long-term OS of relapsed AML patients who were enrolled to 9 successive ECOG-ACRIN trials for newly diagnosed AML, during 1984-2008. The objectives were to examine whether there is a trend of improvement in the survival of relapsed AML patients in the more recent studies and to search for prognostic factors that are associated with long-term OS after relapse. A total of 3012 patients were enrolled, 1779 (59.1%) achieved CR1 and of these, 58.9% relapsed. The median follow-up was 9.7 years. The median OS from relapse was 0.5 years and the 5-year OS was 10 (±1)%. These results were similar even for the most recent studies. A multivariate model showed that age, cytogenetics at diagnosis, duration of CR1 and undergoing allogeneic transplantation were significantly associated with OS from relapse. Even among patients who relapsed with better prognostic factors; age < 40 and CR1 > 12 months, there was no significant OS difference between the studies. In conclusion, this large cohort appears to confirm that the survival of AML patients postrelapse continues to be dismal and has not improved during the past quarter of a century.

Core Entrustable Professional Activities in Clinical Pharmacology for Entering Residency: Value of Interprofessional Health-Care Teams in Medication Prescribing and Medication Error Prevention.

In recent years, health care has been increasingly delivered by interprofessional teams in the inpatient, outpatient, and transition-of-care arenas. For many reasons, effective communication between patient-centered care teams and patients is critically important in order to optimize care, ensure patient safety, and prevent medical and medication misadventures. In rapid-paced, high-stress medical environments, it is especially important to carefully evaluate the causes of all misadventures in a manner that avoids assigning blame and identifies the root causes and, through team activity, leads to development of remedies that reduce the likelihood of future misadventures. Using a series of illustrative cases, this paper seeks to bring attention to these issues and provide insights regarding some tools developed to assist in improving patient safety and effective team communication.

Pulmonary Langerhans cell histiocytosis, acute myeloid leukemia, and myelofibrosis in a large family and review of the literature.

BACKGROUND: There is mounting evidence that Langerhans cell histiocytosis (LCH) and acute myeloid leukemia (AML) are hematopoietic neoplasms that arise from the same myeloid precursor cell. In addition, studies suggest a relationship between LCH and primary idiopathic myelofibrosis (MF). Furthermore familial LCH, AML, and MF have each been reported. METHODS: We examined more than 750 pedigrees of familial hematologic malignancies for evidence of familial LCH, AML, and/or MF and identified one family with all three neoplasms, which is presented here. FINDINGS: In four generations of this large family there are five cases of AML in three generations, two cases of LCH in two generations and three cases of MF in two generations. Anticipation of -18 and -6 years was present in the patients with MF, and -8 years in the patients with LCH. Anticipation was also identified between one AML patient pair in generations III and IV (-18 years) and three patients with AML in generations II, III, and IV (-5 years and -10 years). INTERPRETATION: This is the first report of familial LCH, AML, and MF in one family. The pedigree suggests a common basis for these entities, which is further suggested by the presence of anticipation in the pedigree.

Androgen Therapy for Acute Myeloid and Hairy Cell Leukemia.

OPINION STATEMENT: The purpose of this paper is to review the preclinical and clinical rationale for androgen therapy of acute myeloid (AML) and hairy cell leukemia (HCL). A major recent positive study should renew interest in this therapy, which has been reported to be effective in these leukemias for more than 50 years. Hopefully, renewed interest in this approach, which seems promising, will lead to well-designed modern studies that will precisely define a role for androgens in these leukemias. A recent large prospective, randomized study has demonstrated enhanced survival for elderly AML patients who present with WBC counts < 30,000/µL have improved overall survival when androgens are given post-remission, and numerous case reports suggest that androgens frequently restore normal peripheral blood counts in severely pancytopenic patients with HCL. Well-designed prospective studies are needed to precisely define which patients are most likely to benefit from androgen therapy and where in the treatment plan they should be incorporated.

Assessment of Impact of HLA Type on Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation for Chronic Lymphocytic Leukemia.

Chronic lymphocytic leukemia (CLL) is a common hematologic malignancy with many highly effective therapies. Chemorefractory disease, often characterized by deletion of chromosome 17p, has historically been associated with very poor outcomes, leading to the application of allogeneic hematopoietic stem cell transplantation (allo-HCT) for medically fit patients. Although the use of allo-HCT has declined since the introduction of novel targeted therapy for the treatment of CLL, there remains significant interest in understanding factors that may influence the efficacy of allo-HCT, the only known curative treatment for CLL. The potential benefit of transplantation is most likely due to the presence of alloreactive donor T cells that mediate the graft-versus-leukemia (GVL) effect. The recognition of potentially tumor-specific antigens in the context of class I and II major histocompatibility complex on malignant B lymphocytes by donor T cells may be influenced by subtle differences in the highly polymorphic HLA locus. Given previous reports of specific HLA alleles impacting the incidence of CLL and the clinical outcomes of allo-HCT for CLL, we sought to study the overall survival and progression-free survival of a large cohort of patients with CLL who underwent allo-HCT from fully HLA-matched related and unrelated donors at Center for International Blood and Marrow Transplant Research transplantation centers. We found no statistically significant association of allo-HCT outcomes in CLL based on previously reported HLA combinations. Additional study is needed to further define the immunologic features that portend a more favorable GVL effect after allo-HCT for CLL.

Hispanics have the lowest stem cell transplant utilization rate for autologous hematopoietic cell transplantation for multiple myeloma in the United States: A CIBMTR report.

BACKGROUND: Race/ethnicity remains an important barrier in clinical care. The authors investigated differences in the receipt of autologous hematopoietic cell transplantation (AHCT) among patients with multiple myeloma (MM) and outcomes based on race/ethnicity in the United States. METHODS: The Center for International Blood and Marrow Transplant Research database was used to identify 28,450 patients who underwent AHCT for MM from 2008 through 2014. By using data from the National Cancer Institute's Surveillance, Epidemiology, and End Results 18 registries, the incidence of MM was calculated, and a stem cell transplantation utilization rate (STUR) was derived. Post-AHCT outcomes were analyzed among patients ages 18 to 75 years who underwent melphalan-conditioned peripheral cell grafts (N = 24,102). RESULTS: The STUR increased across all groups from 2008 to 2014. The increase was substantially lower among Hispanics (range, 8.6%-16.9%) and non-Hispanic blacks (range, 12.2%-20.5%) compared with non-Hispanic whites (range, 22.6%-37.8%). There were 18,046 non-Hispanic whites, 4123 non-Hispanic blacks, and 1933 Hispanic patients. The Hispanic group was younger (P < .001). Fewer patients older than 60 years underwent transplantation among Hispanics (39%) and non-Hispanic blacks (42%) compared with non-Hispanic whites (56%). A Karnofsky score <90% and a hematopoietic cell transplantation comorbidity index score >3 were more common in non-Hispanic blacks compared with Hispanic and non-Hispanic whites (P < .001). More Hispanics (57%) versus non-Hispanic blacks (54%) and non-Hispanic whites (52%; P < .001) had stage III disease. More Hispanics (48%) versus non-Hispanic blacks (45%) and non-Hispanic whites (44%) had a very good partial response or better before transplantation (P = .005). Race/ethnicity did not impact post-AHCT outcomes. CONCLUSIONS: Although the STUR increased, it remained low and was significantly lower among Hispanics followed by non-Hispanic blacks compared with non-Hispanic whites. Race/ethnicity did not impact transplantation outcomes. Efforts to increase the rates of transplantation for eligible patients who have MM, with an emphasis on groups that underuse transplantation, are warranted. Cancer 2017;123:3141-9. © 2017 American Cancer Society.

Long-Term Response and Possible Cure of Patients With B-Cell Malignancies With Dose-Escalated Rituximab.

Rituximab (R), a chimeric monoclonal antibody targeting CD20 antigen on B-cells, has become a standard of care in the treatment of B-cell malignancies, most often in conjunction with cytotoxic chemotherapy. Activity has been demonstrated in many subtypes of B-cell lymphoma, including diffuse large cell lymphoma, follicular lymphoma (FL), mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), lymphocyte-predominant Hodgkin lymphoma, and Waldenström macroglobulinemia (WM). Additionally, dose escalation of R as a single agent has demonstrated improved activity in previously treated/poor prognosis CLL. We present 4 cases of B-cell malignancy (2 CLL variants/MCL, 1 FL, 1 WM) who received dose-escalated R as a single agent and achieved complete response (3 patients) and stable disease/partial response (1 patient) of 6.5+ to 15+ years duration. They have been off treatment for 6.5+ to 15+ years. Toxicity was minimal, with initial infusion reactions similar to those observed with standard dose infusions. There were no serious treatment-related adverse events or infections. Dose escalated R as a single agent may possibly be curative for some patients with B-cell malignancies, unlike the standard empiric dose of 375 mg/m2, and deserves further study.