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Introduction: Initial treatment for hormone-receptor positive (HR+)/human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer (ABC) typically involves endocrine therapy (ET) combined with different targeted agents. When hormonal therapies fail, until recently, the only option available was chemotherapy (ChT), presenting a significant therapeutic challenge. However, the recent introduction of antibody-drug conjugates (ADCs) has provided new treatment alternatives in this context. Sacituzumab govitecan (SG), a novel trophoblast cell-surface antigen 2 (Trop-2)-targeting ADC, has been evaluated following disease progression to ET and ChT in HR+/HER2- ABC., Areas Covered: This review examines the latest clinical trials, including phase I/II and III studies and evaluates the impact of SG on HR+/HER2- ABC. The literature search focused on clinical outcomes, particularly regarding efficacy and safety, comparing them with traditional ChT., Expert Opinion: SG has demonstrated to be an effective treatment for patients with HR+/HER2- ABC after progression to ET and cyclin-dependent kinase 4/6 inhibitors (CDKi) in any setting, and at least two ChT-containing regimens in the advanced setting. With a manageable toxicity profile, SG represents a significant advancement in the treatment landscape for this patient population. However, further research is essential to optimize its application and establish long-term benefits.

Olutasidenib, a potent, selective, oral, mutant isocitrate dehydrogenase 1 (mIDH1) inhibitor, is FDA-approved for relapsed/refractory (R/R) acute myeloid leukemia (AML). Here we report efficacy and safety of olutasidenib in 18 patients with m IDH1 AML who were relapsed (10), refractory (6) or had complete remission with incomplete hematologic recovery (CRi; 2) to a venetoclax combination. Of the 16 patients who were R/R, 4 (25%) achieved complete remission (CR), one (6.3%) achieved CR with partial hematologic recovery (CRh), and 7 (43.8%) achieved a composite complete remission (CRc). Median time to CRc was 1.9 months (range 1-2.8). As of data cutoff (18 June 2021), median duration of CRc was not reached (range, 1.2-NR, ongoing at 30.4+ months). Both patients with CRi at study entry achieved a CR. Safety was consistent with the overall profile of olutasidenib. Olutasidenib offers a valuable treatment option for patients with m IDH1 AML previously treated with venetoclax.

Introduction: Acute myeloid leukemia (AML) treatment has primarily focused on 7 + 3 chemotherapy, but in the last decade there has been a significant increase in new therapies, mostly targeted agents, approved for the treatment of AML. We performed a comparative analysis of the unique safety profile of each of these new agents., Areas Covered: We conducted a review of the current literature on public databases (PubMed, ClinicalTrials.gov, and U.S. Food and Drug Administration) regarding new AML drugs that were approved from 2017 to 2023., Expert Opinion: The diagnosis of AML typically carries a poor prognosis but with an increase in the number of drugs that are now available, patients' outcomes are improving. With novel mechanisms of action, the use of these agents introduces different safety profiles, occasionally with adverse events not previously seen with standard chemotherapy or at different frequencies. An understanding of the drugs available and the safety concerns associated with each one is crucial to selecting the best available option for each patient, and early recognition and appropriate management of drug-related adverse effects.

While TKI are the preferred first-line treatment for chronic phase (CP) CML, alloHCT remains an important consideration. The aim is to estimate residual life expectancy (RLE) for patients initially diagnosed with CP CML based on timing of alloHCT or continuation of TKI in various settings: CP1 CML, CP2 + [after transformation to accelerated phase (AP) or blast phase (BP)], AP, or BP. Non-transplant cohort included single-institution patients initiating TKI and switched TKI due to failure. CIBMTR transplant cohort included CML patients who underwent HLA sibling matched (MRD) or unrelated donor (MUD) alloHCT. AlloHCT appeared to shorten survival in CP1 CML with overall mortality hazard ratio (HR) for alloHCT of 2.4 (95% CI 1.2-4.9; p  = .02). In BP CML, there was a trend toward higher survival with alloHCT; HR = 0.7 (0.5-1.1; p  = .099). AlloHCT in CP2 + [HR = 2.0 (0.8-4.9), p  = .13] and AP [HR = 1.1 (0.6-2.1); p  = .80] is less clear and should be determined on a case-by-case basis.

Acute myeloid leukemia (AML) carries poor survival and high recurrence rate. We conducted a retrospective analysis of AML patients ( N  = 453) treated with chemotherapy only or chemotherapy + hematopoietic cell transplant (HCT) who maintained their first complete remission (CR) for ≥3 years. Prior comorbidities, new comorbidities, secondary malignancies, late relapse, and causes of death (COD) were documented. New comorbidities for chemotherapy only patients ( n  = 304) included renal disease (10%), and osteopenia/osteoporosis (38%) for HCT patients ( n  = 149). Incidence of hypertension was similar in the chemotherapy only cohort and chemotherapy + HCT cohort (14% vs 17%). Secondary malignancies occurred in 13%, commonly skin, prostate and breast cancers. Common COD included: secondary malignancy (4%), HCT complications (3%), and late relapses (5%). Overall, 12% had a late relapse. Median overall survival for chemotherapy only and HCT was 10.7 and 12.7 years, respectively. Long-term AML survivors need routine monitoring for comorbidities, secondary malignancies, and late relapses.

Achievement of MR4.5 (BCR-ABL1 ≤ 0.0032% on international scale) is an important goal of tyrosine kinase inhibitor (TKI) treatment for patients with chronic myeloid leukemia (CML). This study describes treatment patterns by region and assesses time to achieve MR4.5 in patients with CML - chronic phase (CP) treated with second-line nilotinib or dasatinib in 10 countries. A multivariate Cox proportional hazards model was used to assess time to MR4.5 for nilotinib versus dasatinib. The model accounted for the competing-risk event of TKI resistance, included random effects for country clustering, and was adjusted for baseline covariates. The study included 280 patients treated with either nilotinib ( N  = 135 [48%]) or dasatinib ( N  = 145 [52%]) as second-line TKI with median treatment durations of 19.1 and 18.7 months, respectively. Nilotinib was observed to be better in achieving MR4.5 than dasatinib (adjusted hazard ratio = 1.37, 95% CI [1.11, 1.69]) suggesting second-line nilotinib may perform better in achieving MR4.5 than dasatinib.

Considering the risk of arterio-thrombotic adverse events (AEs), ponatinib trials in previously untreated chronic myeloid leukemia chronic phase (CML-CP) were terminated. We conducted a retrospective CML-CP outcome study of patients who discontinued frontline-ponatinib. Among 51 patients who received frontline ponatinib, 38 discontinued because of FDA request and 13 due to AEs. At ponatinib discontinuation, all patients remained in CP with deepest response being CCyR, n  = 7; PCyR, n  = 4; MMR, n  = 14; MR4.5, n  = 26. Of the four patients in PCyR at ponatinib discontinuation, two improved response to CCyR on subsequent TKI. Of seven patients, in CCyR at discontinuation, five improved response to MMR or deeper, one was inevaluable, and another lost response due to treatment noncompliance. With a median follow-up of 39 months, 3-year EFS and OS were 92% and 96%, respectively, indicating favorable long-term outcomes. The cardiac/vascular system AEs with subsequent TKI occurred in patients with prior similar events on ponatinib. AEs occurred up to 9 months post-ponatinib.

ENESTnext (NCT01227577) was a single-arm, multicenter trial evaluating the rate of deep molecular response by 2 years in patients with newly diagnosed (within 6 months) chronic myeloid leukemia in chronic phase (CML-CP) treated with nilotinib 300 mg twice daily. Among 128 enrolled patients, 94 (73%) achieved major molecular response (MMR; BCR-ABL1  ≤ 0.1% on the International Scale [ BCR-ABL1 IS ]) and 34 (27%) achieved confirmed MR 4.5 ( BCR-ABL1 IS ≤0.0032% detectable or undetectable; primary endpoint) by 2 years. Three-month BCR-ABL1 levels were predictive of later responses. In exploratory analyses, digital polymerase chain reaction (PCR) detected BCR-ABL1 in 39.4% of samples from patients with confirmed MR 4.5 and identified further decreases in BCR-ABL1 with continued nilotinib. Safety results, including cardiovascular events, were consistent with those in other nilotinib trials. These results further substantiate the molecular response rates associated with frontline nilotinib therapy and demonstrate the feasibility of monitoring very low BCR-ABL1 transcript levels using digital PCR.

Introduction : Eribulin mesylate is a highly potent anticancer agent approved for use in pretreated metastatic breast cancer (MBC). Clinical trials of eribulin in MBC have demonstrated activity against this tumor type, and a phase 3 study in patients with MBC previously treated with an anthracycline and a taxane showed a significant increase in overall survival (OS) with eribulin versus control regimens. Areas covered : This review presents overviews of the development of eribulin, its pharmacology, and its efficacy in MBC. A detailed review of its safety profile is presented, and the safety of eribulin is compared with other agents commonly used to treat MBC. Expert opinion : As eribulin is the only drug shown to improve OS in patients with pretreated MBC, it is an important treatment option for many patients. Eribulin is currently considered a second-line (Europe) or third-line (United States) therapy, and studies have been examining use in the first-line setting. The use of eribulin in combination with other therapies is beginning to be explored because its manageable safety profile makes it an ideal combination-treatment partner. Emerging eribulin combination-treatment data suggest a manageable toxicity profile, and eribulin is set to be a key drug for the treatment of MBC in the future.

Objective: To examine health and identity differences between older (50+) and younger (< 50) lesbian, gay, bisexual, and transgender (LGBT) veterans., Methods: Participants (N = 254) completed an internet survey assessing depression, anxiety, alcohol use, identity, minority stress, and outness. T tests and logistic regression were used to analyze results., Results: Older LGBT veterans reported less alcohol use (p < .01) than younger counterparts. No age differences in depression or anxiety were reported. Older participants reported LGBT identity as more central to their overall identity (p < .01) and having less minority stress (p < .05), than younger participants., Conclusions: Compared to younger LGBT veterans, older LGBT veterans appeared more resilient over stressors that can impact mental health. Overall older LGBT veterans experienced less alcohol use and reported less minority stress than younger veterans. LGBT identity was more central to older veterans' overall identity than younger Veterans., Clinical Implications: LGBT veterans may experience stressors that can impact mental health, although older LGBT veterans show remarkable resilience. Clinicians should assess sexual orientation and gender identity, as well as veteran status, of patients in order to best evaluate their health risks and strengths.

Ponatinib is a pan-tyrosine kinase inhibitor (TKI) with efficacy in multirefractory CML patients who have failed other TKIs. Despite excellent response rates, resistance or intolerance may develop. We conducted a retrospective review of the outcome of patients with chronic (CP) and accelerated (AP) phase CML refractory to prior TKI who discontinued ponatinib for resistance or intolerance. Nineteen CP patients, discontinued due to resistance (n = 13), toxicity (n = 5) and to pursue stem cell transplantation (n = 1). At discontinuation, 14 were still in CP, three had progressed to AP and two to blast phase (BP). Three CP patients improved their cytogenetic response (CyR) to complete CyR (CCyR), two after SCT and one on omacetaxine. None of the 12 patients, without a major cytogenetic response at ponatinib discontinuation, including all patients treated with subsequent TKIs, responded to therapy. Seventeen AP patients, stopped ponatinib due to resistance (n = 15) or intolerance (n = 2). At discontinuation, 14 were still in AP and three had progressed to BP. Four patients were treated with SCT and one achieved major molecular response. None of the 12 patients treated with non-SCT approaches responded to subsequent therapy. Median survival for all patients was 16.6 months after ponatinib discontinuation (31, 9 and 13 months for patients in CP, AP and BP, respectively). Median survival was 60 months for patients who discontinued ponatinib for toxicity and 11 months for those who discontinued for resistance. Long-term outcome of patients with ponatinib failure are poor with estimated one-year OS and EFS rates of 54% and 40%, respectively. New treatment options are required for this subset of patients.

Background: Hispanic adults aged 55 years and older are the fastest growing ethnic minority group in the United States facing significant mental health disparities. Barriers in accessing care have been attributed to low income, poor education, language barriers, and stigma. Cultural adaptations to existing evidence-based treatments have been encouraged to improve access. However, little is known about mental health treatments translated from English to Spanish targeting anxiety among this Hispanic age group. Objctive: This case study offers an example of how an established, manualized, cognitive-behavioral treatment for adults 55 years and older with generalized anxiety disorder (known as "Calmer Life") was translated to Spanish ("Vida Calma") and delivered to a monolingual, Hispanic 55-year-old woman., Results: Pre- and post-treatment measures showed improvements in symptoms of anxiety, depression, and life satisfaction., Conclusion: Findings suggest Vida Calma is a feasible treatment to use with a 55-year-old Spanish-speaking adult woman., Clinical Implications: Vida Calma, a Spanish language version of Calmer Life, was acceptable and feasible to deliver with a 55-year-old participant with GAD. Treatment outcomes demonstrate that Vida Calma improved the participant's anxiety, depression, and life satisfaction.

Ruxolitinib is the only approved therapy for myelofibrosis (MF). However, its use in patients with myeloproliferative neoplasms (MPN) not participating in clinical studies has been poorly described. We reviewed the medical records of 45 patients (35 MF, 10 others) treated with ruxolitinib at our center, off clinical study, during the year after its approval. Patients had advanced features and were refractory to multiple therapies. Ruxolitinib was effective in reducing splenomegaly (51% response rate) and constitutional symptoms (42% response rate). It controlled blood counts in patients with polycythemia and thrombocythemia but was not effective in patients with non-classic MPNs. Ruxolitinib was an active therapy in patients previously treated with a JAK inhibitor and was safely combined with hypomethylating agents in patients with elevated blasts. Median overall survival was 24 months; 10 patients transformed to acute leukemia. Its use in combination with other active agents should be further explored in clinical studies.

Omacetaxine mepesuccinate is approved by the Food and Drug Administration in the United States for the treatment of chronic myeloid leukemia in chronic or accelerated phase resistant to two or more tyrosine kinase inhibitors. This review summarizes the mode of action, pharmacokinetics, efficacy and safety of omacetaxine mepesuccinate. Omacetaxine mepesuccinate has activity in chronic myeloid leukemia, especially in the chronic phase, regardless of the presence of ABL1 kinase domain mutations. Omacetaxine mepesuccinate has distinct but manageable adverse events profile. Omacetaxine mepesuccinate is a treatment option for a subset of patients with refractory chronic myeloid leukemia.

Recent progress in understanding the biology of acute myeloid leukemia (AML) and the identification of targetable driver mutations, leukemia specific antigens and signal transduction pathways has ushered in a new era of therapy. In many circumstances the response rates with such targeted or antibody-based therapies are superior to those achieved with standard therapy and with decreased toxicity. In this review we discuss novel therapies in AML with a focus on two major areas of unmet need: (1) single agent and combination strategies to improve frontline therapy in elderly patients with AML and (2) molecularly targeted therapies in the frontline and salvage setting in all patients with AML., Competing Interests: Financial and competing interests disclosure: The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Omacetaxine mepesuccinate (Synribo) is an inhibitor of protein synthesis indicated for the treatment of patients with chronic- or accelerated-phase chronic myeloid leukemia (CML) with resistance and/or intolerance to two or more tyrosine kinase inhibitors. Myelosuppression is the most common and clinically significant toxicity experienced by patients treated with omacetaxine. Here, we further examine the patterns of hematologic toxicity observed in clinical trials and describe the approach to management as well as resolution of events. Omacetaxine-related myelosuppression typically occurs more frequently during induction cycles. In general, the myelosuppression observed with omacetaxine treatment is manageable and reversible, and long-term administration is feasible. Careful monitoring, dose delays and reduction in administration days, and appropriate supportive care are critical for successful management of hematologic toxicity. Concerns regarding myelosuppression, observed with many cancer treatments, should not prevent eligible patients from receiving omacetaxine, particularly CML patients with unsatisfactory responses to multiple lines of prior treatment.

This is the largest Latin American study of BCR-ABL mutations in chronic myeloid leukemia (CML) patients, resistant to imatinib (IM). In 195/467 (41%) patients, mutations were detected. The most frequent mutation was T315I (n = 31, 16%). Progression-free (PFS) and overall survival (OS) at 5 years were lower in patients with BCR-ABL mutations (43% vs. 65%, p = 0.07 and 47% vs. 72%, p = 0.03, respectively) and in those with the T315I mutation (p = 0.003 and p = 0.03). OS and PFS were superior in subgroup who switched to second generation inhibitors (SGIs) after IM failure (OS: 50% vs. 39% p = 0.01; PFS: 48% vs. 30% p = 0.02). BCR-ABL mutations conferred a significant poor prognosis in CML patients.

The incidence and pattern of secondary neoplasms in patients with acute promyelocytic leukemia (APL) treated with all-trans retinoic acid (ATRA)-containing regimens is not well described. We compared 160 patients with APL treated with ATRA plus idarubicin (n = 54) or ATRA plus arsenic trioxide (ATO) (n = 106) for the incidence of secondary cancers per unit time of follow-up. Median follow-up times for the two cohorts were 136 and 29 months, respectively. Nine patients developed secondary cancers in the chemotherapy group. These included two breast cancers, three myelodysplastic syndromes/acute myeloid leukemia, one vulvar cancer, one prostate cancer, one colon cancer and one soft tissue sarcoma. A melanoma and one pancreatic cancer developed in the ATO group. We conclude that treatment of patients with APL using the non-chemotherapy regimen of ATRA plus ATO is not associated with a higher incidence of secondary cancers (p = 0.29) adjusted for unit time of exposure.

It is thought that the low incidence of central nervous system (CNS) involvement in acute myeloid leukemia (AML) does not justify routine CNS prophylaxis, as high-dose cytarabine eliminates CNS disease. To investigate whether chemotherapy that does not include high-dose cytarabine increases the risk of CNS involvement, the medical records of 1412 newly diagnosed patients with AML were reviewed. In 1370 patients, lumbar puncture (LP) was performed only if clinically indicated, and CNS disease was detected in 45 (3.3%) patients. Another 42 patients underwent routine LP as part of an investigational protocol, and in eight (19%) CNS disease was detected (p < 0.0001). Risk factors included high lactate dehydrogenase, African-American ethnicity and young age. Patients receiving high-dose cytarabine and those who did not had similar rates of CNS involvement. Disease-free survival (DFS) and overall survival were shorter in patients with CNS involvement. It remains to be determined whether routine CNS prophylaxis would improve DFS.

Two hundred and thirty-five consecutive patients presenting to a single center with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) after breast cancer treatment were compared with matched patients with de novo AML or MDS. There was no significant difference in median overall survival (OS) times between patients with therapy-related AML and those with de novo AML (8.7 months vs.10.2 months; p = 0.17). Patients with therapy-related MDS had slightly lower median baseline platelet counts and a higher frequency of poor cytogenetics than those with de novo MDS, but the two groups had similar OS times (13.6 months vs. 18.9 months; p = 0.06). Multivariate analysis revealed that cytogenetic risk, baseline white blood cell count, age and performance status were predictive for OS time in AML and that cytogenetic risk and performance status were predictive for OS time in MDS. Having therapy-related disease is not an independent risk factor in patients with myeloid neoplasms and with a history of breast cancer. Clinical trials should be designed to serve both populations.

The introduction of tyrosine kinase inhibitors has improved outcomes in Philadelphia chromosome-positive acute lymphoblastic leukemia, yet relapse due to the development of resistance mutations remains a major obstacle. Ponatinib is a novel tyrosine kinase inhibitor designed to overcome single-resistance mutations in the ABL kinase. Three clinical trials confirmed the efficacy of ponatinib in the relapsed and front-line setting in Philadelphia positive acute lymphoblastic leukemia, even in the presence of the T315I mutation, which confers resistance to other tyrosine kinase inhibitors. The rate of relapse appears to be very low when used in combination with chemotherapy, suggesting a role for ponatinib in newly diagnosed patients. A major concern with the use of ponatinib is the associated high risk of life-threatening vascular thrombotic events. Potential strategies to reduce this risk include minimizing the use of ponatinib in patients with significant baseline cardiovascular risk, careful surveillance and treatment of cardiovascular risk-factors and dose reduction of ponatinib.

Omacetaxine mepesuccinate promotes apoptosis by inhibiting the production of short-lived oncoproteins. The efficacy and safety of omacetaxine in patients with advanced chronic myeloid leukemia (CML) previously treated with tyrosine kinase inhibitors were assessed in two phase II trials (CML-202 and CML-203). Fifty-one patients in accelerated phase (AP-CML) and 44 in myeloid blast phase (BP-CML) received subcutaneous omacetaxine 1.25 mg/m(2) twice daily days 1-14 every 28 days until hematologic response/improvement or any cytogenetic response, then days 1-7 every 28 days until disease progression. The primary endpoint was maintenance or attainment of a major hematologic response (MHR). Cytogenetic responses were also evaluated. MHR was 37% in patients with AP-CML and 9% with BP-CML (22% and 5% in those with a history of T315I). Most grade 3/4 adverse events were related to myelosuppression, and were generally manageable. Omacetaxine demonstrates activity and an acceptable safety profile in pretreated patients with advanced CML, irrespective of mutational status.

Abstract With improved outcome for patients with chronic myeloid leukemia (CML) treated with tyrosine kinase inhibitors (TKIs), treatment discontinuation has become increasingly attractive to patients. We analyzed the outcomes of patients who chose to discontinue TKI therapy regardless of their ongoing response. Thirty-five patients with chronic phase CML discontinued TKI in complete cytogenetic response. Of them, 51% discontinued due to adverse effects, 23% due to long complete molecular response (CMR) (> 5 years), 9% due to pregnancy and 17% due to financial problems. After TKI discontinuation, patients were followed for a median of 16 months. Among 27 patients (77%) who discontinued TKIs in CMR, 11 (41%) had a molecular relapse after a median of 3.5 months. In univariate analysis we observed that patients with ≥ 64 months of CMR before TKI discontinuation had superior cumulative proportions of sustained CMR and major molecular response (MMR) at 12 months after discontinuation: 88.9% vs. 45.5% (p = 0.02) and 100% vs. 75% (p = 0.05), respectively. Patients treated with high dose imatinib or second generation TKIs had a higher cumulative proportion of sustained MMR at 12 months after discontinuation than patients treated with standard dose imatinib: 100% vs. 72.2% (p = 0.03), respectively. Of the five patients who stopped TKI in MR(4.5) (molecular response of 4.5-log reduction) one lost cytogenetic response. All three patients who discontinued TKIs in MMR lost cytogenetic response; one progressed to accelerated phase. Thirteen patients (37%) restarted TKIs after loss of response: 11 improved their response, and for two it is too early to assess. Treatment discontinuation can lead to sustained CMR in some patients, but risk of relapse is higher if patients discontinue TKIs when not in CMR.

Introduction: Outcomes for the majority of patients with acute myeloid leukemia (AML) remain poor. Over the past decade, significant progress has been made in the understanding of the cytogenetic and molecular determinants of AML pathogenesis. One such advance is the identification of recurring mutations in the FMS-like tyrosine kinase 3 gene (FLT3). Currently, this marker, which appears in approximately one-third of all AML patients, not only signifies a poorer prognosis but also identifies an important target for therapy. FLT3 inhibitors have now undergone clinical evaluation in Phase I, II and III clinical trials, as both single agents and in combination with chemotherapeutics. Unfortunately, to date, none of the FLT3 inhibitors have gained FDA approval for the treatment of patients with AML. Yet, several promising FLT3 inhibitors are being evaluated in all phases of drug development., Areas Covered: This review aims to highlight the agents furthest along in their development. It also focuses on those FLT3 inhibitors that are being evaluated in combination with other anti-leukemia agents., Expert Opinion: The authors believe that the field of research for FLT3 inhibitors remains promising, despite the historically poor prognosis of this subgroup of patients with AML. The most promising areas of research will likely be the elucidation of the mechanisms of resistance to FLT3 inhibitors, and development of potent FLT3 inhibitors alone or in combination with hypomethylating agents, cytotoxic chemotherapy or with other targeted agents.

Patients with newly diagnosed AML (n = 360) including 137 (38%) with normal karyotype (NK) were evaluated. Overall, 60 (16.6%) patients, including 46 of the 137 (33.5%) NK patients, had NPM1 mutation at baseline. Thirty-nine patients (30 NK) had available NPM1 status at the time of complete remission (CR) and all (100%) were negative for mutated NPM1. Among the patients with mutated NPM1 at baseline, 10/39 overall (25%) and 7/30 NK (23%) patients relapsed. NPM1 status was available for eight patients (six with NK) at the time of relapse. Among them, 7/8 overall (87%) and 5/6 NK (83%) patients had mutated NPM1, while 1/8 overall (12%) and 1/6 NK (16%) patients remained NPM1 wild type. Among the 300 patients (including 91 with NK) with wild type NPM1 at diagnosis, none acquired a mutated NPM1 clone, either at CR or at relapse. We conclude that mutated NPM1 is a stable and reliable prognostic marker in AML and can be used to assess MRD.

Splenectomy may be an effective therapeutic option for treating massive splenomegaly in patients with myeloproliferative neoplasms (MPNs). There are still limited data on its short- and long-term benefits and risks. Efficacy and short-term complications were analyzed in 94 patients with different MPNs who underwent splenectomy at M. D. Anderson Cancer Center. The long-term impact of splenectomy on overall survival (OS) and transformation free survival (TFS) was evaluated in 461 patients with myelofibrosis (MF) seen at M. D. Anderson, including 50 who underwent splenectomy during disease evolution. Splenectomy improved anemia and thrombocytopenia in 47% and 66% of patients, respectively. The most common complications were leukocytosis (76%), thrombocytosis (43%) and venous thromboembolism (16%). Post-operative mortality was 5%. Among patients with MF, splenectomy during disease evolution was associated with decreased OS (hazard ratio [HR] = 2.17, p < 0.0001) and TFS (HR = 2.17, p < 0.0001). This effect was independent of the Dynamic International Prognostic Scoring System. Splenectomy is a possible therapeutic option for patients with MF and other MPNs, and its greatest benefits are related to improvement in spleen pain and discomfort, anemia and thrombocytopenia. However, in patients with MF it appears to be associated with increased mortality.

Introduction: Small-molecule tyrosine kinase inhibitors (TKIs) have revolutionized the management of many malignancies. However, they also have been shown to be associated with a certain degree of cardiovascular side effects that are often reversible., Areas Covered: As the number of new TKIs continues to grow, it is expected that clinicians will be facing the challenge of early detection and 10 management of these side effects while balancing the risk-benefit ratios of continuing with life-saving cancer therapy medications. This review will present the current knowledge related to incidence and proposed mechanisms of cardiovascular side effects of TKIs and also discuss treatment recommendations when available, Expert Opinion: We will present and discuss available data and suggest recommendations related to patient monitoring and early identification of TKIs related cardiovascular toxities.

Two important response criteria in systemic mastocytosis (SM) are the elimination or reduction in percentage of bone marrow mast cells (MCs) and the reduction of serum tryptase levels. We investigated the accuracy of a single time point reduction of bone marrow MCs and serum tryptase level as response criteria in 50 patients with SM with available serial assessments. Bone marrow MC percentage varied significantly, with an average coefficient of variation (CV) of 65% (range, 6-173%) and 44% of patients having a CV higher than the average. The average CV for serum tryptase level was 19% (range, 0-96%), with 36% of patients having a CV higher than average. These wide variations in bone marrow MC burden and serum tryptase level were independent of the administration of SM-directed therapy, type of therapy or disease subtype. Furthermore, the achievement of a single time point therapy-induced bone marrow complete response (no histological evidence of malignant bone marrow MCs) did not correlate with tryptase level or symptomatic improvement. In conclusion, the value of single measurements of bone marrow MC percentage and serum tryptase level as response criteria in SM is not supported by clinical data. Incorporation of an assessment of the degree in reduction of MCs and tryptase, and assessment of response durability, would make response criteria more clinically meaningful., Competing Interests: Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.

The use of interferon-α and allogeneic stem cell transplant and more recently of tyrosine kinase inhibitors (TKIs) have improved the outcome of patients with chronic myeloid leukemia (CML). We performed a population-based study of CML to evaluate relative survival (RS) trend by treatment eras. All instances of CML diagnosed between 1975 and 2009 reported in the Surveillance, Epidemiology and End Results databases were reviewed. The incidence of CML was 1.75/100 000 persons per year and increased with age. The incidence was highest in Detroit and lowest among Asians. The 5-year RS ratios increased from 0.26 in patients diagnosed in 1975-1989 to 0.36 in 1990-2000 and 0.56 in 2001-2009. There was a significant improvement in 5-year RS ratios in the 2005-2009 calendar period compared to the 2001-2004 period (p < 0.05), corresponding to the introduction of second-generation TKIs. Age was the most important prognostic factor for RS, but the improvement in 5-year RS ratios was observed in all age groups except the group aged < 15 years (p > 0.05), including adolescents and young adults and elderly patient groups. There are ethnic and geographic variations in the incidence of CML. The RS improved with each treatment era, with the greatest improvement in all age groups occurring during the TKI era.

The treatment of acute myeloid leukemia has not changed significantly over the last 40 years. Recent progress in understanding the biology of this disease and identification of driver mutations has ushered in a new era of molecular therapeutics. Although a number of molecular markers and pathways have been identified and may serve as potential therapeutic targets, the best studied amongst these include FMS like tyrosine kinase 3 (FLT3), RAS/RAF/MEK/ERK and Janus kinase (JAK-2). In this review we discuss the molecular biology of AML, with a special focus on the above mentioned pathways. We discuss novel molecular targeted therapies that are in preclinical and clinical development. These include AC-220, sorafenib and midostaurin in FLT3 mutated patients; GSK1120212 and MSC1936369B in RAS mutated patients; and INCB018424 in JAK2 mutated patients. Identification of such molecular mutations and appropriate use of targeted therapies, either alone or in combinations, may eventually revolutionize the treatment of AML.

Introduction: The FMS-like tyrosine kinase 3 (FLT3) is highly expressed in acute leukemias. Mutations involving FLT3 are among the most common molecular abnormalities in acute myelogenous leukemia (AML). Available evidence suggests that these molecular lesions confer a shorter disease-free survival and overall survival in patients with intermediate-risk cytogenetics. Therefore, substantial interest in FLT3 as a therapeutic target has led to the development of several promising inhibitors that target this tyrosine kinase., Areas Covered: This review covers the molecular pathways associated with FLT3 activation in patients with AML, the biological rationale for inhibiting FLT3 and recent clinical progress with FLT3 inhibitors for the treatment of AML. Six FLT3 inhibitors undergoing clinical evaluation are discussed. A review of selected published manuscripts on the subject of FLT3 inhibition in AML and a search of the English language manuscripts in PubMed using the index words FLT3 and AML were conducted and articles of interest selected., Expert Opinion: Mutated forms of FLT3, specifically FLT3-internal tandem duplication, have a significant impact on the prognosis of AML patients, particularly those with a normal karyotype. Inhibiting FLT3 may lead to clinical benefit for patients with AML. Newly developed FLT3 inhibitors have shown encouraging activity as monotherapy and in combination with other therapeutic agents.

Earlier use of more potent tyrosine kinase inhibitors such as dasatinib improves response rates for patients with chronic myeloid leukemia (CML). The SRC-ABL Tyrosine Kinase Inhibition Activity Research Trials series displayed dasatinib efficacy in patients with all phases of CML who are resistant or intolerant to imatinib. More recently, dasatinib has been shown to induce rapid and high rates of response and has gained approval for newly diagnosed patients with CML in chronic phase. The future of CML therapy may incorporate more potent tyrosine kinase inhibitors such as dasatinib into initial treatment for newly diagnosed patients. The ability of dasatinib to induce rapid and high rates of response with a low progression to advanced forms of CML may translate into improvements in survival.

Imatinib (IM)-associated myelosuppression is rare in gastrointestinal stromal cell tumors (<10%) but common in chronic myeloid leukemia (CML). Selective inhibition of predominantly Philadelphia chromosome (Ph+) driven hematopoiesis may explain myelosuppression in CML. In the absence of clinical methods to quantitate the Ph+/Ph- progenitor ratio, we hypothesized that the pre-IM percentage of BCR-ABL+ cells measured by fluorescence in situ hybridization (FISH) predicts for myelosuppression. FISH analyses performed within 30 days pre-IM 400 mg/day were analyzed in 89 patients with chronic phase CML at three institutions. Patients who developed grade ≥3 cytopenias had a higher percentage of positive FISH (90% vs. 83%; p = 0.02). Cytopenias lasted a median of 16 days, and all patients but one continued IM, achieved complete hematologic and cytogenetic remissions, and did not experience progression, with a follow-up of 61 months. In conclusion, IM-associated cytopenias are associated with a high pre-IM FISH, are reversible, and do not adversely affect outcomes.

Although imatinib revolutionized the management of chronic myeloid leukemia (CML), recent data indicate a transformation in the treatment approach likely in the near future. The superiority of second-generation tyrosine kinase inhibitors (TKIs) over imatinib in newly diagnosed disease has been recognized. Several investigational agents specific for those patients with the T315I mutation remain under evaluation. In Philadelphia-positive (Ph-positive) acute lymphoblastic leukemia (ALL), the addition of imatinib improved response rates. However, short remission durations with single agent therapy limit the benefit on survival. Early molecular remissions achieved with dasatinib will enable more patients to proceed to stem cell transplant (SCT), with increased likelihood of positive outcomes post-SCT.

Relapse after 5 years of complete remission (CR) is uncommon in acute myeloid leukemia (AML). Among 2347 patients seen between 1980 and 2008, 1366 achieved CR; 942 relapsed. Eleven (1.16% of all relapses) relapsed after a CR of >5 years. The median age was 66 years (range, 37-79). Initial therapy was cytarabine plus anthracycline in six, amsacrine-based in three, and other in two. The median CR1 duration was 81 months (range, 60-137). At relapse, the karyotype was different from the initial finding in five of eight (63%) patients with available data. Treatment for relapse included cytarabine with anthracycline in eight, and other in three patients, with a second CR (CR2) achieved in four (36%). The median CR2 duration was 1 month (range, 0-37), and median survival after relapse was 6.4 months (range, 1-39). Late relapses in AML are infrequent, with poor response to therapy. Karyotype at relapse is frequently different, raising the question of second AML versus relapse with the original clone.

The outcome of adults with acute lymphocytic leukemia (ALL) who achieve a complete response (CR) on salvage therapy is thought to be poor, but not previously analyzed. To define the course of adult ALL post CR on salvage therapy and the effects of pretreatment factors on prognosis. One hundred seventy-two adults with ALL who achieved a second or third CR on salvage therapy were reviewed. Prognostic factors affecting survival were analyzed by multivariate analysis. The median survival post achieving CR for the entire group was 10 months. The estimated 1-year survival rate was 42%. Forty-three patients underwent stem cell transplant in subsequent CR: their median survival was 12 months and the 3-year survival rate was 25%. Independent poor prognostic factors for survival were age  > 55 years, duration of first CR < 12 months, and lactate dehydrogenase levels > 1000 IU/L. This analysis defines the outcome of adult ALL in CR post salvage therapy and the prognostic factors influencing survival. These results could be used in assessing the efficacy of new treatments aimed at improving CR durations and survival post salvage therapy.

The myelodysplastic syndromes (MDS) encompass a heterogeneous group of malignant hematologic disorders characterized by ineffective hematopoiesis, peripheral cytopenias, frequent karyotypic abnormalities and significant risk for transformation to acute myeloid leukemia (AML). The prognosis of patients with intermediate- or high-risk MDS is very poor. This is due to the fact that standard therapeutic options are largely palliative. Neither autologous stem cell transplantation (SCT) nor chemotherapeutic regimens have been shown to prolong survival in patients with MDS. Allogeneic SCT, while potentially curative, is only available to a selected group of patients and is associated with high morbidity and mortality in elderly patients, which constitute the majority of patients with MDS. Hypermethylation of tumor-suppressor genes has been invoked as an important pathogenetic mechanism in MDS. The pyrimidine nucleoside analog azacitidine, which inhibits DNA methyltransferases, has recently become the first therapeutic to prolong survival in patients with MDS, thus changing the natural history of these malignancies. The activity of azacitidine in MDS has spurred the development of combinations of this agent with other epigenetic modifiers for the treatment of MDS and AML.

The identification of aberrant cellular pathways and dysfunctional molecules important in neoplastic transformation has begun to provide us with a number of targets for drug development. It is likely that many of these agents will be incorporated into our existing treatment strategies that include cytotoxic agents. Sorafenib, a multi-kinase inhibitor has been approved in the United States for the treatment of renal cell carcinoma as well as hepatocellular cancer. Its potential role in hematological malignancies, particularly acute myeloid leukemia (AML) is under evaluation. Here we describe the biological pathways in AML that are the potential targets of sorafenib action and discuss the early clinical data with the agent in solid tumors and AML.