Search

Venetoclax combined with intensive chemotherapy shows promise for untreated acute myeloid leukemia (AML), but its integration with the '7+3' regimen remains underexplored. In a phase 1b study (NCT05342584), we assessed the safety and efficacy of venetoclax with daunorubicin and cytarabine in newly diagnosed AML patients. Thirty-four patients (median age 59 years; 62% non-white) received venetoclax at escalating durations (8, 11, or 14 days). Adverse events included febrile neutropenia (100%), sepsis (29%), and enterocolitis (23.5%), with no induction deaths. Median recovery times for neutrophils (>1.0K/uL) and platelets (>100K/uL) were under 30 days. Composite complete remission (CRc) was achieved in 85.3% of patients, with 86.2% being measurable residual disease (MRD)-negative. Responses spanned all ELN2022 risk categories. With a median follow-up of 9.6 (2-20) months, median duration of response, event-free survival and overall survival were not reached. Venetoclax (400 mg) combined with '7+3' chemotherapy was safe and effective in achieving MRD-negative remissions across all durations. Ven dose optimization is being explored in the expansion phase of this trial. Future multicenter studies should confirm our findings., (Copyright © 2025 American Society of Hematology.)

Abstract: A metronomic, low-dose schedule of decitabine and venetoclax was safe and effective in myeloid malignancies with few dose reductions or interruptions in an older diverse population. Median overall survival for patients with acute myeloid leukemia and a TP53-mutation was 16.1 and 11.3 months, respectively. This trial was registered at www.clinicaltrials.gov as #NCT05184842., (© 2024 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Recent advances in graft-versus-host disease (GVHD) prophylaxis including post-transplant cyclophosphamide (PTCy) and abatacept have significantly improved outcomes following HLA-mismatched allogenic hematopoietic stem cell transplantation (allo-HSCT) and have tremendous potential for reducing racial disparities in donor availability. A recent small study employing bone marrow as the source of stem cells showed similar outcomes after 5/8 versus 7/8 matches and is currently being tested in a larger study using peripheral blood stem cells. In this study, we examine real-world alternative donor HSCT options for a minority-predominant cohort in the Bronx, NY, focusing on the availability of lesser-matched (5/8 to 7/8) donors. Records of patients who underwent HLA typing at Montefiore Medical Center (2019 to 2022) were reviewed. The National Marrow Donor Program registry was queried to evaluate the availability of donors with at least 99% likelihood of HLA match at various levels (5/8, 6/8, 7/8, 8/8). Two hundred forty-one patients were included, 70% were non-White. Although the availability of ≥7/8 donors was less common in non-White patients, 100% of patients from each group had at least one or more 5/8 and 6/8 HLA-matched donors and more than 80% of these patients had >100 potential 5/8 and 6/8 HLA-matched donors. There was no statistical difference by race or ethnicity in the mean number of donors at 5/8 and 6/8 HLA-match levels. We demonstrate through real-world data that patients from diverse ethnic and racial backgrounds have access to 5/8 and 6/8 HLA-matched donors for allo-HSCT, potentially eliminating disparities in donor availability and allowing prioritization of other donor selection characteristics such as donor age, sex, ABO, and B leader matching. Further work is needed to study whether the use of mismatched donors offers a more potent graft-versus malignancy effect and optimal GVHD prophylaxis., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Purpose: Venetoclax (VEN) added to the hypomethylating agents (HMA) decitabine or azacitidine is the new standard of care for elderly patients with acute myeloid leukemia (AML) and is being evaluated in myelodysplastic syndrome (MDS). Current dosing of HMA/VEN relies on leukemia suppression through cytotoxicity which also impacts normal hematopoiesis. A regimen using once-weekly low-dose decitabine (LDDec) has demonstrated activity in myeloid malignancies. To overcome the severe myelosuppression often seen with HMA/VEN, we evaluated a once-weekly dosing regimen of VEN and LDDec in elderly and/or frail patients who were felt less likely to tolerate severe myelosuppression., Patients and Methods: This is a retrospective, single-center analysis of patients with AML, MDS, or chronic myelomonocytic leukemia treated with a once-weekly LDDec/VEN regimen. We also compare this regimen with a cohort treated with standard dosing HMA/VEN., Results: In a retrospective cohort of 39 patients, the overall response rate for patients receiving LDDec/VEN for first-line AML and MDS was 88% and 64%, respectively. In patients with TP53 mutations, the composite complete response rate was 71% and the median overall survival was 10.7 months. When compared with 36 patients receiving standard dose HMA/VEN, the LDDec/VEN patients had a longer time on therapy (175 vs. 78 days; P = 0.014) and a trend toward a higher rate of transfusion independence (47% vs. 26%; P = 0.33). Neutropenic fever occurred in 31% of patients, with a median of one hospitalization at any point during treatment., Conclusions: This preliminary clinical experience, although retrospective, provides proof-of-activity of noncytotoxic DNA methyltransferase 1-targeting by allowing frequent, sustained drug exposure often not possible with standard HMA/VEN regimens., (©2023 American Association for Cancer Research.)

Uproleselan (GMI-1271) is a novel E-selectin antagonist that disrupts cell survival pathways, enhances chemotherapy response, improves survival in mouse xenograft and syngeneic models, and decreases chemotherapy toxicity in vivo. A phase 1/2 study evaluated the safety, tolerability, and antileukemic activity of uproleselan (5-20 mg/kg) with MEC (mitoxantrone, etoposide, and cytarabine) among patients with relapsed/refractory (R/R) acute myeloid leukemia (AML). Among the first 19 patients, no dose-limiting toxicities were observed. The recommended phase 2 dose (RP2D) was 10 mg/kg twice daily. An additional 47 patients with R/R AML were treated with uproleselan at the RP2D plus MEC. At the RP2D, the remission rate (complete response [CR]/CR with incomplete count recovery [CRi]) was 41% (CR, 35%), and the median overall survival (OS) was 8.8 months. In a separate cohort, 25 newly diagnosed patients age ≥60 years received uproleselan at the RP2D plus cytarabine and idarubicin (7 + 3). In these frontline patients, the CR/CRi rate was 72% (CR, 52%), and the median OS was 12.6 months. The addition of uproleselan was associated with low rates of oral mucositis. E-selectin ligand expression on leukemic blasts was higher in patients with relapsed vs primary refractory AML and in newly diagnosed older patients with high-risk cytogenetics and secondary AML. In the R/R cohort, E-selectin expression >10% was associated with a higher response rate and improved survival. The addition of uproleselan to chemotherapy was well tolerated, with high remission rates, low induction mortality, and low rates of mucositis, providing a strong rationale for phase 3 randomized confirmatory studies. This trial was registered at www.clinicaltrials.gov as #NCT02306291., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background and Aims: It is unclear whether pre-pouch ileitis heralds an aggressive inflammatory pouch disease in patients with ileal pouch-anal anastomosis [IPAA]. We compared outcomes of patients with pouchitis and concomitant pre-pouch ileitis with those with pouchitis alone., Methods: Patients undergoing IPAA surgery for inflammatory bowel disease, who subsequently developed pouchitis with concomitant pre-pouch ileitis [pre-pouch ileitis group], were matched by year of IPAA surgery and preoperative diagnosis [ulcerative colitis or inflammatory bowel disease-unclassified] with patients who developed pouchitis alone [pouchitis group]. Primary outcomes were development of Crohn's disease [CD]-like complications [non-anastomotic strictures or perianal disease >6 months after ileostomy closure] and pouch failure. Secondary outcomes were need for surgical/endoscopic interventions and immunosuppressive therapy. Log-rank testing was used to compare outcome-free survival, and Cox regression was performed to identify predictors of outcomes., Results: There were 66 patients in each group. CD-like complications and pouch failure developed in 36.4% and 7.6% patients in the pre-pouch ileitis group and 10.6% and 1.5% in pouchitis group, respectively. CD-like complications-free survival [log-rank p = 0.0002] and pouch failure-free survival [log-rank p = 0.046] were significantly lower in the pre-pouch ileitis group. The pre-pouch ileitis group had a higher risk of requiring surgical/endoscopic interventions [log-rank p = 0.0005] and immunosuppressive therapy [log-rank p <0.0001]. Pre-pouch ileitis was independently associated with an increased risk of CD-like complications (hazard ratio [HR] 3.8; p = 0.0007), need for surgical/endoscopic interventions [HR 4.1; p = 0.002], and immunosuppressive therapy [HR 5.0; p = 0.0002]., Conclusions: Pre-pouch ileitis is associated with a higher risk of complicated disease and pouch failure than pouchitis. It should be considered a feature of CD., (© The Author(s) 2020. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

This study describes a computational algorithm to determine vascular permeability constants from time-lapse imaging data without concurrent knowledge of the arterial input function. The algorithm is based on "blind" deconvolution of imaging data, which were generated with analytical and finite-element models of bidirectional solute transport between a capillary and its surrounding tissue. Compared to the commonly used Patlak analysis, the blind algorithm is substantially more accurate in the presence of solute delay and dispersion. We also compared the performance of the blind algorithm with that of a simpler one that assumed unidirectional transport from capillary to tissue [as described in Truslow et al., Microvasc. Res. 90, 117-120 (2013)]. The algorithm based on bidirectional transport was more accurate than the one based on unidirectional transport for more permeable vessels and smaller extravascular distribution volumes, and less accurate for less permeable vessels and larger extravascular distribution volumes. Our results indicate that blind deconvolution is superior to Patlak analysis for permeability mapping under clinically relevant conditions, and can thus potentially improve the detection of tissue regions with a compromised vascular barrier., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Treatment choices for acute myelogenous leukemia (AML) patients resistant to conventional chemotherapies are limited and novel therapeutic agents are needed. IL3 receptor alpha (IL3Rα, or CD123) is expressed on the majority of AML blasts, and there is evidence that its expression is increased on leukemic relative to normal hematopoietic stem cells, which makes it an attractive target for antibody-based therapy. Here, we report the generation and preclinical characterization of SGN-CD123A, an antibody-drug conjugate using the pyrrolobenzodiazepine dimer (PBD) linker and a humanized CD123 antibody with engineered cysteines for site-specific conjugation. Mechanistically, SGN-CD123A induces activation of DNA damage response pathways, cell-cycle changes, and apoptosis in AML cells. In vitro , SGN-CD123A-mediated potent cytotoxicity of 11/12 CD123 + AML cell lines and 20/23 primary samples from AML patients, including those with unfavorable cytogenetic profiles or FLT3 mutations. In vivo , SGN-CD123A treatment led to AML eradication in a disseminated disease model, remission in a subcutaneous xenograft model, and significant growth delay in a multidrug resistance xenograft model. Moreover, SGN-CD123A also resulted in durable complete remission of a patient-derived xenograft AML model. When combined with a FLT3 inhibitor quizartinib, SGN-CD123A enhanced the activity of quizartinib against two FLT3-mutated xenograft models. Overall, these data demonstrate that SGN-CD123A is a potent antileukemic agent, supporting an ongoing trial to evaluate its safety and efficacy in AML patients (NCT02848248). Mol Cancer Ther; 17(2); 554-64. ©2017 AACR ., (©2017 American Association for Cancer Research.)

While antibody-based therapies have emerged as clinically effective approaches for several hematologic and solid malignancies, they have not played a significant role to date in the treatment of acute myeloid leukemia (AML). More recently, improvements in antibody-drug conjugate technology, bispecific antibodies, as well as identification of novel AML antigens have re-invigorated enthusiasm for antibody-based therapies for AML. This review describes experiences with former and existing antibody-based therapies for AML, including unconjugated antibodies, antibody-drug conjugates (ADCs), radio-labelled antibodies, and immune-engaging antibodies, and discusses the promise and challenges associated with each.

Background: Pertussis epidemics have recently emerged across the United States, prompting broad public health recommendations for adult Tdap vaccination (tetanus, diphtheria, acellular pertussis). The impact of immunosuppressive regimens for inflammatory bowel disease (IBD) on vaccine responses to the Tdap vaccine is not known., Methods: We performed a prospective controlled trial between April 2011 and March 2012. Adults with IBD were consecutively stratified based on therapeutic regimen into one of 5 groups: A: no IBD therapy or 5-aminosalicylates alone; B: maintenance biologic monotherapy; C: maintenance immunomodulator monotherapy; D: combined biologic and immunomodulator therapy; and E: healthy age-matched controls. Subjects received Tdap, and serum antibody levels against tetanus toxoid, pertussis toxoid, and filamentous hemagglutinin (FHA) were drawn just before and approximately 4 weeks after vaccination. The primary outcome was the booster response rate to each antigen. Secondary outcomes included the differences in pregeometric and postgeometric mean titers., Results: A total of 98 subjects enrolled, and 84 completed the study. Tetanus response rates were 55%, 56%, 40%, 27%, and 63% across groups A to E, respectively. Group D rates were lower than those of group B (P = 0.02). Postvaccination pertussis toxoid responses were 59%, 72%, 47%, 45%, and 75%, while FHA responses were 86%, 72%, 80%, 64%, and 75% across groups A to E, respectively. Prevaccination and postvaccination geometric mean titer differences for FHA were lower in group D than those in group A (P = 0.05)., Conclusions: Antibody responses to tetanus and pertussis vaccination may be affected by therapeutic drug regimen. Patients with IBD should optimally receive Tdap before starting immunomodulators, particularly when used in combination with anti-tumor necrosis factor alpha agents.

Effective treatment options for adults with therapy-related AML continues to be an area of unmet need. Genetic and molecular changes within these leukemias confer resistance to standard chemotherapy regimens. Emerging developmental therapeutics in this area has focused on several approaches. These include; novel delivery of chemotherapy as well as newer DNA-damaging agents delivered through antibody-drug conjugates, increased use of hypomethylating agents, and molecularly-directed small molecules against specific mutations commonly occurring in secondary AML. Results of this efforts are encouraging, but to date, no clear improvements have been demonstrated in this most difficult to treat population., (Copyright © 2015 Elsevier Inc. All rights reserved.)

There is no effective treatment for relapsed/refractory acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). We conducted a phase I dose escalation trial of SAR103168, a novel multi-targeted kinase inhibitor with activity against the Src kinase family, the BCR-Abl kinase and several angiogenic receptor kinases. Twenty-nine patients 18-83 years old were treated with SAR103168. Pharmacokinetics was characterized by plasma peak concentration (Cmax) at the end of the infusion, followed by a biphasic decline in the elimination profile. Adverse events were as expected for the patient population and there were no individual toxicities specific to SAR103168. Due to the unpredictable nature of drug exposure, the sponsor decided to discontinue the study prior to reaching the maximum tolerated dose.

Background: CPX-351 is a liposome-encapsulated fixed-molar-ratio formulation of cytarabine and daunorubicin that exploits molar ratio-dependent drug-drug synergy to enhance antileukemic efficacy., Methods: This phase II study randomized 125 patients 2:1 to CPX-351 or investigators' choice of first salvage chemotherapy. Patients with acute myeloid leukemia (AML) in first relapse after initial Complete Remission (CR) lasting ≥1 month were stratified per the European Prognostic Index (EPI) into favorable, intermediate, and poor-risk groups based on duration of first CR, cytogenetics, age, and transplant history. Control salvage treatment was usually based on cytarabine and anthracycline, often with 1 or more additional agents. Survival at 1 year was the primary efficacy end point., Results: Patient characteristics were well balanced between the 2 study arms. Improvements in efficacy outcomes were observed following CPX-351, but did not meet prospectively defined statistical criteria for 1-year survival improvement in the overall population. Subset analyses of the EPI-defined poor-risk strata demonstrated higher response rates (39.3% vs 27.6%) and improvements in event-free survival (HR, 0.63; P = .08) and overall survival (HR, 0.55; P = .02). Also, 60-day mortality was lower in the CPX-351 study arm for poor-risk patients (16.1% vs 24.1%)., Conclusions: Taken together, the data suggest possible improved outcomes in CPX-351-treated first relapse AML patients with EPI-defined poor-risk disease., (© 2014 American Cancer Society.)

Purpose: Arsenic trioxide (ATO) is a highly effective agent for the treatment of acute promyelocytic leukemia (APL). QT interval prolongation is common with ATO and can pose a barrier to effective administration. The objective of this study was to characterize the prevalence, management, and clinical consequences of QT prolongation in a large cohort of patients treated with ATO., Patients and Methods: We analyzed 3,011 electrocardiograms from 113 patients with non-APL acute myeloid leukemia and myelodysplastic syndrome who were treated on a previously reported clinical trial. QT intervals were assessed using four different correction formulas, and data were correlated with clinical parameters and treatment with ATO., Results: There were no clinically significant cardiac events in the study population. Of those receiving ATO therapy, 29 patients (26%) had rate-uncorrected QT values above 470 ms and 13 (12%) had values exceeding 500 ms. With the commonly used Bazett rate correction formula, 102 patients (90%) had QTc greater than 470 ms, including 74 (65%) above 500 ms. By using alternative rate correction formulas, only 24% to 32% of patients had rate-corrected QT intervals above 500 ms., Conclusion: QT interval prolongation is common with ATO treatment, but clinically significant arrhythmias are rare and can be avoided with appropriate precautions. Use of the Bazett correction may result in unnecessary interruptions in ATO therapy, and alternative rate correction formulas should be considered for routine electrocardiographic monitoring., (© 2014 by American Society of Clinical Oncology.)

CPX-351 is a liposomal formulation of cytarabine:daunorubicin designed to deliver synergistic drug ratios to leukemia cells. In this phase 2 study, newly diagnosed older acute myeloid leukemia (AML) patients were randomized 2:1 to first-line CPX-351 or 7+3 treatment. The goal was to determine efficacy and identify patient subgroups that may benefit from CPX-351 treatment. Response rate (complete remission + incomplete remission) was the primary end point, with event-free survival (EFS) and overall survival (OS) as secondary end points. The 126 patients entered were balanced for disease and patient-specific risk factors. Overall, CPX-351 produced higher response rates (66.7% vs 51.2%, P = .07), meeting predefined criteria for success (P < .1). Differences in EFS and OS were not statistically significant. A planned analysis of the secondary AML subgroup demonstrated an improved response rate (57.6% vs 31.6%, P = .06), and prolongation of EFS (hazard ratio [HR] = 0.59, P = .08) and OS (HR = 0.46, P = .01). Recovery from cytopenias was slower after CPX-351 (median days to absolute neutrophil count ≥1000: 36 vs 32; platelets >100 000: 37 vs 28) with more grade 3-4 infections but without increase in infection-related deaths (3.5% vs 7.3%) or 60-day mortality (4.7% vs 14.6%), indicating acceptable safety. These results suggest a clinical benefit with CPX-351, particularly among patients with secondary AML, and provide the rationale for a phase 3 trial currently underway in newly diagnosed secondary AML patients. This study is registered at Clinicaltrials.gov as #NCT00788892., (© 2014 by The American Society of Hematology.)

Purpose: Dinaciclib inhibits cyclin-dependent kinases 1, 2, 5, and 9 with a better therapeutic index than flavopiridol in preclinical studies. This study assessed the activity of dinaciclib in acute leukemia both in the clinic and in vitro., Methods: Adults with relapsed/refractory acute myeloid leukemia (n = 14) and acute lymphoid leukemia (n = 6) were treated with dinaciclib 50 mg/m(2) given as a 2-h infusion every 21 days., Results: Most patients had dramatic but transient reduction in circulating blasts; however, no remissions were achieved on this schedule. The most common toxicities were gastrointestinal, fatigue, transaminitis, and clinical and laboratory manifestations of tumor lysis syndrome, including one patient who died of acute renal failure. Dinaciclib pharmacokinetics showed rapid (2 h) achievement of maximum concentration and a short elimination/distribution phase. Pharmacodynamic studies demonstrated in vivo inhibition of Mcl-1 expression and induction of PARP cleavage in patients' peripheral blood mononuclear cells 4 h after dinaciclib infusion, but the effects were lost by 24 h and did not correlate with clinical outcome. Correlative in vitro studies showed that prolonged exposures to dinaciclib, at clinically attainable concentrations, result in improved leukemia cell kill., Conclusions: While dinaciclib given as a 2-h bolus did not exhibit durable clinical activity, pharmacokinetic and pharmacodynamic data support the exploration of prolonged infusion schedules in future trials in patients with acute leukemias.

Treatment options for older patients with acute myeloid leukemia (AML) and for patients with relapsed/refractory AML are limited, and outcomes are poor. Decitabine, a hypomethylating agent, is active in patients with myelodysplastic syndrome (MDS) and AML, but its optimal dose and schedule are unknown. We report the efficacy and safety of repeated 10-day cycles of decitabine 20 mg/m(2) administered intravenously over 1 h in 52 newly diagnosed and 102 relapsed/refractory patients. Repeated 10-day cycles of decitabine produced a complete response (CR) in 40% of newly diagnosed older patients with AML, many of whom had adverse prognostic features. The median overall survival (OS) was 318 days but there was prolonged survival in responders of 481 days. Relapsed/refractory patients had a CR rate of 15.7% with a median OS of 177 days. Extramedullary toxicity was mild and the regimen was well tolerated for ongoing post-remission, outpatient maintenance cycles. Responses were durable for over 1 year.

We present the first reported infection caused by Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacter gergoviae. The patient had leukemia and neutropenia and died of septic shock from KPC-producing E. gergoviae bacteremia. The emergence of KPCs in additional species of Enterobacteriaceae is alarming and may disproportionately affect patients with hematologic malignancies.

Carbapenem-resistant Enterobacteriaceae (CRE) are increasingly prevalent pathogens. However, little is known about their emergence in patients with hematologic malignancies. We identified 18 patients with hematologic malignancies over 3.5 years who developed bloodstream infections (BSIs) caused by CRE. Fourteen BSIs were caused by Klebsiella pneumoniae, three by Enterobacter cloacae, and one was polymicrobial. Initial empirical antimicrobial therapy was active in two patients (11%), and a median of 55 h elapsed between culture collection and receipt of an active agent. Ten patients (56%) died, including nine (69%) of 13 neutropenic patients, with a median of 4 days from culture collection until death. CRE isolates were analyzed for carbapenemase production, β-lactamase genes and outer membrane porin deletions and characterized by multilocus sequence typing and pulsed-field gel electrophoresis (PFGE). Carbapenem resistance mechanisms included Klebsiella pneumoniae carbapenemase production and CTX-M-15 production with an absent outer membrane porin protein. No isolate had ≥95% homology on PFGE, indicating a heterogeneous, non-outbreak population of isolates. CRE BSIs are emerging in patients with hematologic malignancies and are associated with ineffective initial empirical therapy, long delays in administration of active antimicrobials and high mortality rates. New diagnostic, therapeutic and preventive strategies for CRE infections in this vulnerable population are needed.

Forty-eight patients received CPX-351 (liposome-encapsulated cytarabine:daunorubicin at a 5:1 molar ratio) every other day for 3 doses at 10 dose levels. Pharmacokinetic parameters were dose-independent and exhibited low inter-patient variability. CPX-351 showed a negligible distribution phase and prolonged mono-exponential first-order plasma elimination (t(1/2)∼24 h). The plasma ratio of 5:1 was maintained at all dose levels. Nearly all of the detectable cytarabine and daunorubicin in circulation following CPX-351 administration was in the form of liposome encapsulated drug. Dose-dependent hematopoietic effects had early onset with cytopenias at 12 units/m(2), and a gradual increase in frequency and severity, until single induction complete response was achieved at 43 units/m(2). Non-hematologic effects had onset by 24 units/m(2) with shallow dose-response until maximum frequency and severity were observed at the 101-134 units/m(2) dose levels. Single induction response occurred over a 2.3-fold range of doses indicating that CPX-351 may be useful at high doses for patients suitable for intensive chemotherapy and at reduced doses for patients at increased risk of treatment-related mortality. The unique pharmacologic features of CPX-351 contribute to its promising antileukemic efficacy., (Copyright © 2012. Published by Elsevier Ltd.)

This study compares outcomes of low-intensity versus standard-intensity induction strategies for older patients with acute myeloid leukemia at the Weill Cornell Leukemia Program. From 1999 to 2009, 298 adults ≥ 60 years with AML underwent induction chemotherapy with low-intensity and standard-intensity regimens, based on physician and patient preferences and investigational protocol availability. Overall, 33% of the cohort achieved complete remission with initial treatment, 23% with low-intensity induction and 53% with standard-intensity induction (P<0.0001). The median overall survival was 6.5 months and there was no significant difference in overall survival between patients initially treated with a low-intensity regimen compared to those receiving standard-intensity induction. There were no differences in 30- or 60-day mortality between the two groups., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Patients with primary resistant and relapsed acute myeloid leukemia (AML) are rarely cured without undergoing allogeneic stem cell transplantation. What is currently debated is whether a trial of re-induction chemotherapy prior to transplantation is beneficial. Data from multiple retrospective analyses have shown that pretreatment variables are useful in predicting response to salvage chemotherapy. For patients unlikely to respond, re-induction attempts may be detrimental, leading to added organ toxicity and possible increased tumor resistance. Allogeneic transplantation in the setting of active disease is the alternative strategy. Multiple studies have demonstrated the feasibility of this approach, but cure rates have been low with the use of traditional transplant approaches. Newer strategies employing allogeneic transplantation earlier in patients with relapsed or refractory AML, as well as the incorporation of novel and effective antileukemic agents into the transplant conditioning regimen, may lead to better outcomes.

We treated 37 patients with polycythemia vera with imatinib mesylate (IM). The overall response rate was 49%. Thirty percent had a complete response, and 19%, a partial response. Thirty-one patients were treated for >120 days. Frequent side effects included nausea, diarrhea, edema, and skin rash. Whereas IM was effective in controlling erythropoiesis and reducing spleen size it was ineffective in controlling thrombocytosis. Normocellular marrow developed in 4 patients who had a complete response. Progression to overt myelofibrosis occurred in 3. Nevertheless, 6 patients have had a sustained complete response while on IM for >6 years. These patients were young, had high phlebotomy requirements, and only slightly elevated platelet counts. Therefore, we believe there may be a role for IM in patients with these characteristics whose disease cannot be controlled by, or as an alternative to, other myelosuppressive treatments., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Tipifarnib (T) exhibits modest activity in elderly adults with newly diagnosed acute myelogenous leukemia (AML). Based on preclinical synergy, a phase 1 trial of T plus etoposide (E) yielded 25% complete remission (CR). We selected 2 comparable dose levels for a randomized phase 2 trial in 84 adults (age range, 70-90 years; median, 76 years) who were not candidates for conventional chemotherapy. Arm A (T 600 mg twice a day × 14 days, E 100 mg days 1-3 and 8-10) and arm B (T 400 mg twice a day × 14 days, E 200 mg days 1-3 and 8-10) yielded similar CR, but arm B had greater toxicity. Total CR was 25%, day 30 death rate 7%. A 2-gene signature of high RASGRP1 and low aprataxin (APTX) expression previously predicted for T response. Assays using blasts from a subset of 40 patients treated with T plus E on this study showed that AMLs with a RASGRP1/APTX ratio of more than 5.2 had a 78% CR rate and negative predictive value 87%. This ratio did not correlate with outcome in 41 patients treated with conventional chemotherapies. The next T-based clinical trials will test the ability of the 2-gene signature to enrich for T responders prospectively. This study is registered at www.clinicaltrials.gov as #NCT00602771.

Do patients with therapy-related acute myeloid leukemia (t-AML) have a poor prognosis independent of other predictive variables such as cytogenetics or molecular determinants? Limited data exist to answer this question in part because t-AML is often considered together with AML following myelodysplastic syndromes (MDS) in the category of secondary AML. This discussion provides some insight, based primarily on two published retrospective reviews of the German cooperative groups, into the question of whether t-AML is an independent adverse variable., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: Severe thrombocytopenia is a major risk factor for hemorrhage, but platelet function and bleeding risk at low platelet counts are poorly understood, because of the limitations of platelet function testing at very low platelet counts., Objectives: To examine and compare platelet function in severely thrombocytopenic patients with acute myeloid leukemia (AML) or myelodysplasia (MDS) with that in patients with immune thrombocytopenia (ITP)., Methods: Whole blood flow cytometric measurement of platelet activation and platelet reactivity to agonists was correlated with the immature platelet fraction (IPF) and bleeding symptoms., Results: Patients with AML/MDS had smaller platelets, lower IPF and substantially lower platelet surface expression of activated glycoprotein (GP)IIb-IIIa and GPIb, both with and without addition of ex vivo ADP or thrombin receptor-activating peptide, than patients with ITP. In both ITP and AML/MDS patients, increased platelet surface GPIb on circulating platelets and expression of activated GPIIb-IIIa and GPIb on ex vivo activated platelets correlated with a higher IPF. Whereas platelet reactivity was higher for AML/MDS patients with bleeding than for those with no bleeding, platelet reactivity was lower for ITP patients with bleeding than for those with no bleeding., Conclusions: AML/MDS patients have lower in vivo platelet activation and ex vivo platelet reactivity than patients with ITP. The proportion of newly produced platelets correlates with the expression of platelet surface markers of activation. These differences might contribute to differences in bleeding tendency between AML/MDS and ITP patients. This study is the first to define differences in platelet function between AML/MDS patients and ITP patients with equivalent degrees of thrombocytopenia., (© 2011 International Society on Thrombosis and Haemostasis.)

We conducted an open-label phase 1 study exploring the feasibility, safety, and biologic activity of epigenetic priming with decitabine before standard induction chemotherapy in patients with less-than-favorable risk of acute myelogenous leukemia (AML). We directly compared the clinical and DNA-hypomethylating activity of decitabine delivered at 20 mg/m² by either a 1-hour infusion (Arm A) or a continuous infusion (Arm B) for 3, 5, or 7 days before a single, standard induction with infusional cytarabine (100 mg/m² for 7 days) and daunorubicin (60 mg/m² × 3 doses). Toxicity was similar to that of standard induction chemotherapy alone. Although we did not identify a maximum tolerated dose, there was more gastro-intestinal toxicity with 7 days of decitabine priming. Decitabine induced DNA hypomethylation at all dose levels and there was a trend toward greater hypomethylation in CD34(+) bone marrow cells when decitabine was delivered by a short pulse (Arm A). Twenty-seven subjects (90%) responded to therapy: 17 with complete remission (57%) and 10 with partial remission (33%). Of the patients with partial remission to protocol treatment, 8 achieved remission to their next therapy, bringing the overall complete remission rate to 83%. We conclude that epigenetic priming of intensive chemotherapy can be safely delivered in an attempt to improve response rates. This trial was registered at www.clinicaltrials.gov as NCT00538876.

Advanced myelodysplastic syndrome (MDS) carries a poor prognosis. In this phase I/II study, arsenic trioxide was combined with low-dose cytarabine in 49 previously untreated patients with intermediate-2 and high-risk MDS. Complete remission was achieved in 8 (17%) patients, including 3/14 (21%) with treatment-related disease, 4/31 (13%) with unfavorable cytogenetics and 2/36 (6%) with baseline poor performance status. Mortality within the first 4 weeks was 8%. The regimen was active and had a tolerable extramedullary toxicity profile, but it was cumbersome and intensive compared to other currently available treatments., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Purpose: This phase I dose-escalation trial was performed to determine the maximum-tolerated dose, dose-limiting toxicities, and pharmacokinetics of CPX-351., Patients and Methods: CPX-351 induction was administered on days 1, 3, and 5 by 90-minute infusion to 48 relapsed or refractory patients with acute myeloid leukemia (AML) or high-risk myelodysplasia. Doses started at 3 units/m(2) with dose doublings in single-patient cohorts until a pharmacodynamic effect (treatment-related adverse events or reduction in bone marrow cellularity or blast count) was observed, followed by 33% escalations in three patient cohorts until dose-limiting toxicity (DLT) occurred., Results: The maximum-tolerated dose was 101 units/m(2). DLTs consisted of hypertensive crisis, congestive heart failure, and prolonged cytopenias. Adverse events were consistent with cytarabine and daunorubicin treatment. Response occurred at doses as low as 32 units/m(2). Of 43 patients with AML, nine had complete response (CR) and one had CR with incomplete platelet recovery; of patients with acute lymphoblastic leukemia, one of three had CR. Eight CRs were achieved among the 31 patients with prior cytarabine and daunorubicin treatment. CR in AML occurred in five of 26 patients age ≥ 60 years and in five of 17 patients younger than age 60 years. Median half-life was 31.1 hours (cytarabine) and 21.9 hours (daunorubicin), with both drugs and their metabolites detectable > 7 days after the last dose. The targeted 5:1 molar ratio was maintained at all dose levels for up to 24 hours., Conclusion: The recommended dose of CPX-351 for phase II study is 101 units/m(2). Further exploration of efficacy and safety is ongoing in phase II trials in newly diagnosed and first-relapse patients with AML.

It seems strange, but after 40 years of experience using cytosine arabinoside (ara-C) and daunorubicin, leukemia doctors are still unsure as to how much of each drug they should use to treat their patients with acute myeloid leukemia (AML).

A multi-institutional, phase 1 dose-escalation trial of lintuzumab (humanized anti-CD33 antibody; SGN-33, HuM195) was performed in patients with CD33-positive myeloid malignancies. In this study, higher doses than previously tested and prolonged duration of treatment for responding patients were evaluated. Over the dose range of 1.5-8 mg/kg/week, lintuzumab was well tolerated, and a maximum tolerated dose was not defined. The most common adverse event was transient chills with the initial lintuzumab infusion (39%). Responses were observed in 7 of 17 patients with acute myeloid leukemia: morphologic complete remission (n = 4), partial remission (n = 2), and morphologic leukemia-free state (n = 1). Of 14 patients with myelodysplastic syndrome or myeloproliferative diseases, 1 patient had major hematologic improvement and 9 patients had stable disease. In contrast to aggressive conventional chemotherapy, lintuzumab was administered in an ambulatory clinic setting with acceptable toxicity.

The farnesyltransferase inhibitor tipifarnib exhibits modest activity against acute myelogenous leukemia. To build on these results, we examined the effect of combining tipifarnib with other agents. Tipifarnib inhibited signaling downstream of the farnesylated small G protein Rheb and synergistically enhanced etoposide-induced antiproliferative effects in lymphohematopoietic cell lines and acute myelogenous leukemia isolates. We subsequently conducted a phase 1 trial of tipifarnib plus etoposide in adults over 70 years of age who were not candidates for conventional therapy. A total of 84 patients (median age, 77 years) received 224 cycles of oral tipifarnib (300-600 mg twice daily for 14 or 21 days) plus oral etoposide (100-200 mg daily on days 1-3 and 8-10). Dose-limiting toxicities occurred with 21-day tipifarnib. Complete remissions were achieved in 16 of 54 (30%) receiving 14-day tipifarnib versus 5 of 30 (17%) receiving 21-day tipifarnib. Complete remissions occurred in 50% of two 14-day tipifarnib cohorts: 3A (tipifarnib 600, etoposide 100) and 8A (tipifarnib 400, etoposide 200). In vivo, tipifarnib plus etoposide decreased ribosomal S6 protein phosphorylation and increased histone H2AX phosphorylation and apoptosis. Tipifarnib plus etoposide is a promising orally bioavailable regimen that warrants further evaluation in elderly adults who are not candidates for conventional induction chemotherapy. These clinical studies are registered at www.clinicaltrials.gov as #NCT00112853.

Background: Acute myeloid leukemia (AML) carries a dismal prognosis in older patients. In this study, the authors evaluated the safety and efficacy of arsenic trioxide combined with low-dose cytarabine in untreated patients aged >or=60 years with AML., Methods: In a phase 1/2 design, arsenic trioxide was administered intravenously at a dose of 0.25 mg/kg on Days 1 through 5 and on Days 8 through 12, and low-dose cytarabine was given subcutaneously twice daily on Days 1 through 14 in escalating doses to a target of 10 mg/m(2) per dose. Of 64 patients who had pathologically confirmed AML, excluding patients with acute promyelocytic leukemia and using World Health Organization criteria, the median age was 71 years, 10 patients (16%) had treatment-related AML, 40 patients (63%) had an antecedent myelodysplastic syndrome or myeloproliferative disorder, and 35 patients (55%) had unfavorable cytogenetics. Thirty-four patients (53%) had an Eastern Cooperative Oncology Group performance status of 2 or 3., Results: Complete remission was achieved in 21 of 61 patients (34%), including 15 of 50 patients (30%) who had secondary or treatment-related AML, 10 of 33 patients (30%) who had unfavorable cytogenetics, and 6 of 34 patients (18%) who had a poor baseline performance status. The mortality rate within the first 4 weeks was 8%. Neutropenic fever was observed in >80% of patients, and 41% of patients had bacteremia. Nonhematologic toxicity generally was mild and reversible and included fatigue, nausea, diarrhea, rash, peripheral edema, and elevated transaminases. There were no clinically significant cardiac arrhythmias., Conclusions: The addition of arsenic trioxide to low-dose cytarabine appeared to improve responses in elderly patients who had AML compared with either agent alone, and a randomized trial of the combination versus single-agent low-dose cytarabine is ongoing.

The CALGB studied the feasibility and effectiveness of adding oblimersen (G3139; Genasense) to imatinib mesylate (IM) in imatinib-resistant chronic phase chronic myeloid leukemia (CML) patients. We hypothesised that IM resistant CML cells are no longer being driven to proliferate by Bcr/Abl activity alone. Instead, the anti-apoptotic protein Bcl-2 would regulate one of the pathways controlling growth and/or viability. Thus, blocking both Bcr/Abl and Bcl-2 simultaneously would result in hematologic and cytogenetic improvement. Oblimersen was administered via continuous intravenous infusion over 10 days every 21 days, along with daily IM. Doses of both drugs were escalated in 3 cohorts; the initial dose of IM was 600 mg/day. Response was defined as a decrease by >30% in the percentage of t(9;22) metaphase cells. Twelve patients had primary and nine had secondary imatinib resistance. Ten patients received 4 mg/kg/day oblimersen/600 mg IM, six patients received 7 mg/kg/day oblimersen/600 mg IM and five patients received 7 mg/kg/day oblimersen/800 mg IM. Only two (9.5%) patients achieved a decrease by >30% in the percentage of t(9;22) metaphase cells. Although the combination of oblimersen and IM is safe and feasible, we did not observe clinical benefit in these patients with imatinib-resistant CML using these doses and schedule.

Background: Reported median overall survival (OS) in patients with mantle cell lymphoma (MCL) has been reported to be just 3-4 years. As a consequence, first-line treatment has become more aggressive. Single-center studies with R-Hyper-CVAD and/or autologous stem-cell transplant (ASCT) have produced 3-year OS rates >80%, prompting many to adopt their use. We evaluated outcomes from a single-center cohort managed in a more traditional fashion., Methods: We identified patients with MCL evaluated at Weill Cornell Medical Center since 1997, and included those with known date of diagnosis. An online social security database was used to verify survival., Results: We identified 181 patients with MCL, and date of diagnosis could be determined in 111. Three-year OS from diagnosis was 86% [95% confidence interval (CI) 78% to 92%]. Median OS was 7.1 years (95% CI 63-98 months). Adequate information on therapy was available for 75 patients. Only five were treated upfront with (R)-Hyper-CVAD or ASCT while an additional four patients received one of these regimens subsequently. Treatment type had no significant effect on OS., Conclusion: Outcomes with standard approaches can yield similar survival to that achieved with more intensive approaches. Biases may account for the perceived superiority of aggressive strategies.

At present, there is no method available to predict response to farnesyltransferase inhibitors (FTIs). We analyzed gene expression profiles from the bone marrow of patients from a phase 2 study of the FTI tipifarnib in older adults with previously untreated acute myeloid leukemia (AML). The RASGRP1/APTX gene expression ratio was found to predict response to tipifarnib with the greatest accuracy using a "leave one out" cross validation (LOOCV; 96%). RASGRP1 is a guanine nucleotide exchange factor that activates RAS, while APTX (aprataxin) is involved in DNA excision repair. The utility of this classifier for predicting response to tipifarnib was validated in an independent set of 58 samples from relapsed or refractory AML, with a negative predictive value (NPV) and positive predictive value (PPV) of 92% and 28%, respectively (odds ratio of 4.4). The classifier also predicted for improved overall survival (154 vs 56 days; P < .001), which was independent of other covariates, including a previously described prognostic gene expression classifier. Therefore, these data indicate that a 2-gene expression assay may have utility in categorizing a population of patients with AML who are more likely to respond to tipifarnib.