Laura C. Michaelis

Hydroxyurea, azacitidine and gemtuzumab ozogamicin therapy in patients with previously untreated non-M3 acute myeloid leukemia and high-risk myelodysplastic syndromes in the elderly: results from a pilot trial.

Elderly patients with acute myeloid leukemia (AML) and high-risk myelodysplastic syndromes (MDS) have a poor prognosis due to low response rates (26–46%) to standard chemotherapy and high treatment-related mortality (11–31%). In this Phase II study, we used a combination of hydroxyurea (HU), azacitidine and low dose gemtuzumab ozogamicin (GO) to assess its efficacy and toxicity in this group of patients. Twenty patients with non-M3 AML and MDS were treated with this regimen. The treatment was begun with HU 1500 mg orally twice daily to lower white blood cell count below 10,000/μL, followed by azacitidine 75 mg/m2 subcutaneously for 7 days and GO 3 mg/m2 on day 8. Patients who achieved complete remission (CR) received a consolidation course. The median age of patients was 76 years. Eleven patients (55%) were treated in the outpatient setting. Fourteen (70%) achieved a CR, three of which were incomplete (CRi). The median duration of remission was 8 months and median survival was 10 months. Performance status of 0–1 was associated with high complete response rate. Overall toxicity was acceptable with only one (5%) early death due to disease progression. The combination of HU, azacitdine and GO appears to be a safe and effective regimen in the treatment of AML and high risk MDS in the elderly. These results need to be confirmed in a larger cohort of patients.

Outcomes of Allogeneic Hematopoietic Cell Transplantation in Patients with Myelofibrosis with Prior Exposure to Janus Kinase 1/2 Inhibitors

The impact of Janus kinase (JAK) 1/2 inhibitor therapy before allogeneic hematopoietic cell transplantation (HCT) has not been studied in a large cohort in myelofibrosis (MF). In this retrospective multicenter study, we analyzed outcomes of patients who underwent HCT for MF with prior exposure to JAK1/2 inhibitors. One hundred consecutive patients from participating centers were analyzed, and based on clinical status and response to JAK1/2 inhibitors at the time of HCT, patients were stratified into 5 groups: (1) clinical improvement (n = 23), (2) stable disease (n = 31), (3) new cytopenia/increasing blasts/intolerance (n = 15), (4) progressive disease: splenomegaly (n = 18), and (5) progressive disease: leukemic transformation (LT) (n = 13). Overall survival (OS) at 2 years was 61% (95% confidence interval [CI], 49% to 71%). OS was 91% (95% CI, 69% to 98%) for those who experienced clinical improvement and 32% (95% CI, 8% to 59%) for those who developed LT on JAK1/2 inhibitors. In multivariable analysis, response to JAK1/2 inhibitors (P = .03), dynamic international prognostic scoring system score (P = .003), and donor type (P = .006) were independent predictors of survival. Among the 66 patients who remained on JAK1/2 inhibitors until stopped for HCT, 2 patients developed serious adverse events necessitating delay of HCT and another 8 patients had symptoms with lesser severity. Adverse events were more common in patients who started tapering or abruptly stopped their regular dose ≥6 days before conditioning therapy. We conclude that prior exposure to JAK1/2 inhibitors did not adversely affect post-transplantation outcomes. Our data suggest that JAK1/2 inhibitors should be continued near to the start of conditioning therapy. The favorable outcomes of patients who experienced clinical improvement with JAK1/2 inhibitor therapy before HCT were particularly encouraging, and need further prospective validation.

Age-related differences in disease characteristics and clinical outcomes in polycythemia vera

Abstract The natural history and prognosis for young patients with polycythemia vera (PV) in the post-JAK2 V617F era are not well defined. Therefore, we retrospectively analyzed disease characteristics and clinical outcomes in 120 patients ≤ 45 years and 84 patients ≥ 65 years at diagnosis. Despite lower white blood counts (9.2 vs. 13.4 × 109/L, p = 0.004) and a lower JAK2 V617F allele burden (51% vs. 66%, p = 0.015), younger patients with PV had comparable rates of vascular complications compared to older patients (27% vs. 31%, p = 0.64). However, splanchnic vein thrombosis occurred more frequently in younger patients (13% vs. 2%, p = 0.0056). Myelofibrotic and leukemic transformation, the most serious complications of myeloproliferative neoplasms (MPN), occurred with similar frequencies in young versus older patients (15% vs. 10%, p = 0.29). Prevention or delay of these complications is currently the most urgent challenge in the care of younger patients with PV.

Phase II Trials Published in 2002: A Cross-Specialty Comparison Showing Significant Design Differences between Oncology Trials and Other Medical Specialties

Purpose: Phase II trials play an essential role in drug development pathway, and their conclusions often impact the decision to embark on large, pivotal trials. However, the determination of agent activity is highly dependent on trial design. Formal comparisons of phase II trial designs across medical specialties are uncommon. We hypothesized that there are significant differences in the design of trials conducted by oncologists and those conducted by other medical and surgical specialties. Experimental Design: We screened MEDLINE for the abstracts of phase II trials published in 2002. All abstracts were analyzed and classified by a priori defined variables, including study type, intervention, subspecialty, journal impact factor, method of control, and study conclusions. Results: Our search yielded 703 abstracts of phase II trials published in 2002. A total of 586/703 (83%) were trials on antineoplastic agents. Twenty percent (143/703) of the trials included explicit control subjects. Oncology trials, as compared with all trials done by other specialties, were significantly less likely to use control subjects (13% versus 56%, P < 0.001) and were less likely to conclude that the investigational intervention was safe and efficacious and/or worthy of additional investigation (76% versus 89%, P < 0.01). Conclusions: There are significant differences in the phase II trials published in oncology compared with those conducted by other medical and surgical specialties. The impact that such differences have on the efficiency of drug development should be investigated.

Rearrangements of the MLL gene are influenced by DNA secondary structure, potentially mediated by topoisomerase II binding

The location of MLL translocation breakpoints within therapy‐related acute myeloid leukemia linked to drugs targeting Topoisomerase II and infant acute leukemia (IAL) are biased toward the intron 11–exon 12 region of MLL, although lacking a comprehensive explanation. To address this, blood samples were taken from breast cancer and lymphoma patients receiving Topoisomerase II inhibitor therapy. Inverse PCR analysis was used to interrogate the exon 12 region of MLL for rearrangements. Eleven of 19 observed translocations showed breakpoint junctions restricted to a single 5 bp location within exon 12. A similarly restricted distribution (11/20 breakpoint junctions) was observed in TK6 cells exposed to either estrogen (linked to IAL) or anti‐CD95 antibody. The translocation hotspot was at the 5′ edge of a 10‐bp tract matched with a perfect palindrome, 101 bp distant. A high stringency Topoisomerase II consensus sequence binding site was noted at the geometric midpoint of the palindromes. Ligation‐mediated PCR to screen TK6 cells exposed to anti‐CD95 antibody showed 14/37 (38%) of DNA breaks adjacent to the 5′ palindrome and 10/37 (27%) at the 3′ partner. We propose a model whereby Topoisomerase II facilitates the organization of nuclease‐sensitive secondary structures, stabilized by palindrome association, which are prone to rearrangement.

Mechanisms of thrombogenesis in polycythemia vera

Thrombotic and cardiovascular events are among the leading causes of death for patients with polycythemia vera (PV), and thrombosis history is a key criterion for patient risk stratification and treatment strategy. Little is known, however, about mechanisms of thrombogenesis in patients with PV. This report provides an overview of thrombogenesis pathophysiology in patients with PV and elucidates the roles of conventional and nonconventional thrombotic risk factors. In addition to several conventional risk factors for thrombosis, clinical data have implicated increased hematocrit and red blood cell adhesiveness, activated platelets, leukocytosis, and elevated JAK2(V617F) allele burden in patients with PV. Furthermore, PV-related inflammation may exacerbate thrombogenesis through varied mechanisms, including endothelial damage, inhibition of natural anticoagulant pathways, and secretion of procoagulant factors. These findings suggest a direct link between myeloproliferation and thrombogenesis in PV, which is likely to provide new opportunities for targeted antithrombotic interventions aimed at decreasing PV-related morbidity and mortality.

Successful autologous stem cell collection in patients with chronic myeloid leukemia in complete cytogenetic response, with quantitative measurement of BCR-ABL expression in blood, marrow, and apheresis products

Imatinib mesylate is the initial therapy of choice for chronic myeloid leukemia in chronic phase (CML-CP), but in some patients, the disease becomes resistant to imatinib. Autologous stem cell transplantation using cells collected while in complete cytogenetic response (CCyR) may represent a therapeutic option for these patients. We mobilized and collected autologous CD34+ stem cells from 20 CML-CP patients in CCyR, 19 of whom were taking imatinib, and measured BCR-ABL expression in the apheresis products, blood and bone marrow using real-time quantitative PCR (RQ-PCR). Stem cells were mobilized with G-CSF 10 µg/kg daily for 5 days. In patients whose initial collection was <2×106 CD34+ cells/kg, G-CSF dose was increased to 10 µg/kg twice daily on the second attempt, and imatinib was held for 14 days if a third attempt was necessary. All 20 patients successfully mobilized the target yield of 2 to 5×106 CD34+ cells/kg; 16 reached target yield with the first mobilization. The median number of CD34+ cells collected was 4.4 (range, 2.0 – 8.4)×106/kg in a median of 3 (range, 2 – 6) apheresis days. Of 17 patients whose stem cell products were evaluable by RQ-PCR, 11 (65%) had ≥1 daily product with undetectable BCR-ABL; 4 of these (24%) had no detectable BCR-ABL in any apheresis products. BCR-ABL expression in apheresis products was correlated with levels of expression in the blood and marrow prior to mobilization. No patient has yet required transplantation. With median follow-up of 18 months, all patients remain in CCyR and 9 of 16 (54%) have undetectable BCR-ABL in the most recent blood and marrow sample.

Trends in anemia management in lung and colon cancer patients in the US Department of Veterans Affairs, 2002–2008

PurposeIn 2007, growing concerns about adverse impacts of erythropoiesis-stimulating agents (ESAs) in cancer patients led to an FDA-mandated black box warning on product labeling, publication of revised clinical guidelines, and a Medicare coverage decision limiting ESA coverage. We examined ESA therapy in lung and colon cancer patients receiving chemotherapy in the VA from 2002 to 2008 to ascertain trends in and predictors of ESA use.MethodsA retrospective study employed national VA databases to “observe” treatment for a 12-month period following diagnosis. Multivariable logistic regression analyses evaluated changes in ESA use following the FDA-mandated black box warning in March 2007 and examined trends in ESA administration between 2002 and 2008.ResultsAmong 17,014 lung and 4,225 colon cancer patients, those treated after the March 2007 FDA decision had 65% (lung OR 0.35, CI95% 0.30–0.42) and 53% (colon OR 0.47, CI95% 0.36–0.63) reduced odds of ESA treatment compared to those treated before. Declines in predicted probabilities of ESA use began in 2006. The magnitude of the declines differed across age groups among colon patients (p = 0.01) and levels of hemoglobin among lung cancer patients (p = 0.04).ConclusionsUse of ESA treatment for anemia in VA cancer care declined markedly after 2005, well before the 2007 changes in product labeling and clinical guidelines. This suggests that earlier dissemination of research results had marked impacts on practice patterns with these agents.

Risk stratification in myelofibrosis: the quest for simplification

Risk-stratification systems in hematologic malignancies can serve a myriad of clinical and research purposes. They facilitate rational bedside discussion regarding the likely trajectory of a disease, provide an objective screen to ensure clinical trial enrollment reproducibility, and help guide

Recent developments in the treatment of older individuals with acute myeloid leukemia: 2014.

Purpose of reviewThe treatment of acute myeloid leukemia (AML) in older persons remains a tremendous clinical challenge. AML in older patients is more often associated with biologically unfavorable features, and these patients are less likely to tolerate or accept intensive therapy. There have not been substantial improvements in outcome for this group of patients despite decades of research. In this review, we summarize the most substantial contributions in the past 2 years. Recent findingsThere have been three major research themes in the recently published literature for older patients with AML: methods to predict response to therapy, models to predict toxicity of therapy in older, less-fit patients, and investigation of novel agents for AML patients with either newly diagnosed or relapsed disease. An unexpected recent finding has been the observation that complete remission in this disease may not necessarily translate into an overall survival advantage, and conversely, survival benefit has been demonstrated without any improvement in complete remission. SummaryAlthough anthracycline and cytarabine-based therapy remains the standard of care for older patients with AML, this option remains suboptimal for the vast majority of patients. We argue for a national research agenda that may help to accelerate progress for older people with AML.