Differentiation syndrome associated with treatment with IDH2 inhibitor enasidenib: pooled analysis from clinical trials.

ABSTRACT: Treatment with enasidenib, a selective mutant isocitrate dehydrogenase isoform 2 (IDH2) inhibitor, has been associated with the development of differentiation syndrome (DS) in patients with acute myeloid leukemia (AML). Studies on the incidence and clinical features of DS are limited in this setting, and diagnosis is challenging because of nonspecific symptoms. This study assessed the incidence, diagnostic criteria, risk factors, and correlation with clinical response of DS based on the pooled analysis of 4 clinical trials in patients with IDH2-mutated AML treated with enasidenib as monotherapy, or in combination with azacitidine or with chemotherapy. Across the total AML population, 67 of 643 (10.4%) had ≥1 any-grade DS event, with highest incidence in patients who received enasidenib plus azacitidine and lowest incidence in patients who received enasidenib plus chemotherapy (13/74 [17.6%] and 2/93 [2.2%]). The most common symptoms of DS were dyspnea/hypoxia (80.6%) and pulmonary infiltrate (73.1%). Median time to onset of first DS event across all studies was 32 days (range, 4-129). Most patients (88.1%) received systemic steroids for treatment of DS. Evaluation of baseline risk factors for DS identified higher levels of bone marrow blasts and lactate dehydrogenase as independent factors associated with increased grade 3 to 5 DS risk. Overall, these results suggest that DS associated with IDH inhibition is manageable, given the benefits of enasidenib treatment in IDH2-mutated AML. We further characterized enasidenib-related DS in these patients and identified risk factors, which could be used for DS management in clinical practice. These trials were registered at www.ClinicalTrials.gov as # NCT01915498, NCT02577406, NCT02677922, and NCT02632708.

Crenolanib and Intensive Chemotherapy in Adults With Newly Diagnosed FLT3-Mutated AML.

PURPOSE: Crenolanib is a second-generation tyrosine kinase inhibitor with activity against FLT3-ITD- and TKD-mutant AML. We conducted a trial of crenolanib plus intensive chemotherapy in adults with newly diagnosed FLT3-mutant AML. METHODS: Eligible patients were 18 years and older. Induction chemotherapy consisted of cytarabine (100 mg/m2) continuous infusion on days 1-7 and anthracycline (daunorubicin 60-90 mg/m2 or idarubicin 12 mg/m2, once daily) on days 1-3 followed by consolidation with high-dose cytarabine (1-3 g/m2 twice daily on days 1, 3, 5) and/or allogeneic transplant. Crenolanib (100 mg thrice a day) was given from day 9 until 72 hours before the next cycle, after consolidation, and for 12 months after consolidation or transplant. RESULTS: Forty-four patients (median age, 57; range, 19-75 years) were enrolled. Thirty-six had FLT3-ITD, and 11 had FLT3-TKD mutations. European LeukemiaNet 2017 disease risk was favorable in 34%, intermediate in 30%, and adverse in 36%. The overall response rate was 86% (complete remission [CR], 77%; CR with incomplete count recovery [CRi], 9%): 90% in patients 60 years and younger and 80% in older patients. Measurable residual disease-negative CR/CRi rates were 89% and 45%, respectively. With a 45-month follow-up, median overall survival has not been reached and the median event-free survival was 44.7 months. Among younger patients, the estimated 3-year survival was 71.4% with 15% cumulative incidence of relapse. Treatment-related serious adverse events included febrile neutropenia, diarrhea, and nausea. The median time to platelets ≥100,000/µL and absolute neutrophil count ≥1,000/µL during induction was 29 and 32 days, respectively. No new FLT3-mutant clones were detected at relapse in patients completing consolidation. CONCLUSION: Crenolanib plus intensive chemotherapy in adults with newly diagnosed FLT3-mutant AML results in high rate of deep responses and long-term survival with acceptable toxicity. A randomized trial of crenolanib versus midostaurin plus chemotherapy in younger patients is ongoing.

Clinical use of FLT3 inhibitors in acute myeloid leukemia.

Acute myeloid leukemia (AML) is a highly heterogeneous disease. Mutation with internal tandem duplication of fms-like tyrosine kinase-3 (FLT3-ITD) is one of the two most common driver mutations and the presence of FLT3-ITD delivers poor prognosis. A number of ongoing clinical efforts are focused on FLT3 inhibitor use to improve the outcomes of this otherwise difficult leukemia. Midostaurin has been shown to improve outcomes in FLT3-mutated AML in the frontline setting. Several FLT3 inhibitors, especially second-generation agents, have shown clinically meaningful activity in relapsed or refractory AML and in patients not amenable to intensive therapy. In this article, we briefly review the biology of FLT3 in the physiological state and its role in leukemogenesis. We present a detailed review of current clinical evidence of FLT3 inhibitors and their use in the induction, treatment of relapsed or refractory disease, and maintenance setting.

A phase I study of intermediate dose cytarabine in combination with lenalidomide in relapsed/refractory acute myeloid leukemia.

Relapsed/refractory (r/r) Acute Myeloid Leukemia (AML) remains a therapeutic challenge. Cytarabine arabinoside (AraC) forms the backbone of most regimens, with complete responses (CR) ranging from 17 to 20%. Lenalidomide (Len) is approved by the FDA for multiple myeloma and myelodysplasia and has demonstrated activity in AML. We developed a phase I study to evaluate the safety and tolerability of Len in combination with intermediate dose AraC (1.5 g/m(2)/day given on days 1-5) in adults with r/r AML. The maximally tolerated dose for this combination was 10mg daily on days 6-26 of a 28 day cycle. Dose de-escalation from 25mg was required due to rash, liver function abnormalities, and hypokalemia. Of 32 evaluable patients, five achieved CR (16%), 5CRi (16%) and 3 had hematological improvements for an overall response rate of 41% (13/32). Median overall survival (95% confidence interval) for patients treated on study was 5.8 (2.5-10.6) months and disease free survival was 3.4 (2.3-6.2) months. This single institute phase I trial of Len and intermediate dose AraC was associated with marked skin and other toxicities. At the dose and schedule tested, this combination did not appear to result in improved CR over single agent AraC for r/r AML.

Comparison of epigenetic versus standard induction chemotherapy for newly diagnosed acute myeloid leukemia patients ≥60 years old.

Older patients with acute myeloid leukemia (AML) have poor outcomes with standard induction chemotherapy. We retrospectively reviewed our institute's experience with epigenetic (Epi) versus cytarabine- and anthracycline-based intensive chemotherapy (IC) as induction in newly diagnosed AML patients aged 60 years and older. One hundred sixty-seven patients (n = 84, IC; n = 83, Epi) were assessed; 69 patients received decitabine and 14 azacitidine. Baseline characteristics between the IC and Epi patient cohorts were not statistically different except for age, initial white blood cell count, and comorbidity index. Overall response rate (ORR, 50% vs. 28%, respectively, P < 0.01) and complete response rate (CRR, 43% vs. 20%, respectively, P < 0.01) were superior following IC vs. Epi. Although univariate analysis demonstrated longer overall survival after IC (10.7 vs. 9.1 months, P = 0.012), multivariate analysis showed no independent impact of induction treatment. Treatment-related mortality was not statistically different in the two groups. Outcomes of patients with secondary, poor cytogenetic risk, FLT-3 mutated AML, or relapsed/refractory disease after IC or Epi were not significantly different. Outcomes of patients receiving IC versus a 10-day decitabine regimen (n = 63) also were not significantly different. Our results suggest that IC and Epi therapy are clinically equivalent approaches for upfront treatment of older patients with AML and that other factors (feasibility, toxicity, cost, etc.) should drive treatment decisions. Prospective randomized trials to determine the optimal induction approach for specific patient subsets are needed.

Phase II trial of clofarabine and daunorubicin as induction therapy for acute myeloid leukemia patients greater than or equal to 60 years of age.

We designed a phase II study evaluating the upfront combination of clofarabine and daunorubicin in acute myeloid leukemia (AML) patients≥60 years old. The median age of the 21 patients was 69 (range 60-85) years. Fourteen patients (67%) had unfavorable risk features. The principal toxicities were grade ≥3 infections and prolonged myelosuppression. Three (14%) deaths occurred from infectious complications. Six (28.6%) patients achieved complete remission including three (21.4%) of 14 patients with unfavorable AML. The median disease-free survival was 6.8 months and the median overall survival was 11.2 months.

Myelodysplastic syndromes and autoimmune diseases--case series and review of literature.

Our objective was to recognize the association of autoimmune diseases (AD) in patients with myelodysplastic syndromes (MDS) and understand how this association could affect prognosis and management of both diseases. We describe our cohort of 10 patients and 34 patients reported in the English literature in addition to ten cohort studies. Interestingly, four cases showed improvement in AD after 5-azacitidine treatment. The mechanism(s) of the association between AD and MDS are discussed. Treatment could be targeted against AD, MDS or both, though based on recent reports, treating MDS with hypomethylating agents alone could improve the associated AD.

Association of comorbidities with overall survival in myelodysplastic syndrome: development of a prognostic model.

PURPOSE: Patients with cancer often experience comorbidities that may affect their prognosis and outcome. The objective of this study was to determine the effect of comorbidities on the survival of patients with myelodysplastic syndrome (MDS). PATIENTS AND METHODS: We conducted a retrospective cohort study of 600 consecutive patients with MDS who presented to MD Anderson Cancer Center from January 2002 to December 2004. The Adult Comorbidity Evaluation-27 (ACE-27) scale was used to assess comorbidities. Data on demographics, International Prognostic Scoring System (IPSS), treatment, and outcome (leukemic transformation and survival) were collected. Kaplan-Meier methods and Cox regression were used to assess survival. A prognostic model incorporating baseline comorbidities with age and IPSS was developed to predict survival. RESULTS: Overall median survival was 18.6 months. According to the ACE-27 categories, median survival was 31.8, 16.8, 15.2, and 9.7 months for those with none, mild, moderate, and severe comorbidities, respectively (P < .001). Adjusted hazard ratios were 1.3, 1.6, and 2.3 for mild, moderate, and severe comorbidities, respectively, compared with no comorbidities (P < .001). A final prognostic model including age, IPSS, and comorbidity score predicted median survival of 43.0, 23.0, and 9.0 months for lower-, intermediate-, and high-risk groups, respectively (P < .001). CONCLUSION: Comorbidities have a significant impact on the survival of patients with MDS. Patients with severe comorbidity had a 50% decrease in survival, independent of age and IPSS risk group. A comprehensive assessment of the severity of comorbidities helps predict survival in patients with MDS.

Interpretation of cytogenetic and molecular results in patients treated for CML.

The International Randomized Study of Interferon vs. STI571 (IRIS) trial that investigated the use of the tyrosine kinase inhibitor (TKI) imatinib (versus interferon) changed the treatment and outcome of chronic myeloid leukemia (CML). Long-term follow-up of IRIS patients has defined response parameters and methods of tracking residual disease with cytogenetic testing of bone marrow metaphases and molecular monitoring of BCR-ABL transcripts using quantitative reverse-transcriptase polymerase chain reaction. Cytogenetic and molecular responses are now considered useful surrogates for long-term outcome. Early and robust response to imatinib predicts positive long-term outcomes. However, 15-25% of patients fail initial treatment or become intolerant of imatinib and need increased doses or alternate treatment. Second-line treatment with the second-generation TKIs nilotinib and dasatinib have resulted in favorable rates of progression-free survival (PFS) and overall survival. Data from the ENESTnd (nilotinib) and DASISION (dasatinib) trials in newly diagnosed chronic-phase CML patients demonstrated more robust and rapid complete cytogenetic (77-80%) and major molecular responses (43-46%) at 12 months compared with imatinib (65-66% and 22-28%). The relationship between a complete cytogenetic response at 12 months and long-term PFS supports a role for second-generation TKIs as first-line treatment of newly diagnosed chronic-phase CML.

Phase II study of sunitinib malate, a multitargeted tyrosine kinase inhibitor in patients with relapsed or refractory soft tissue sarcomas. Focus on three prevalent histologies: leiomyosarcoma, liposarcoma and malignant fibrous histiocytoma.

Soft tissue sarcomas (STS) represent a diverse group of histologic subtypes with targetable molecular alterations, often treated as a single disease. Sunitinib malate is a multitargeted receptor tyrosine kinase inhibitor active in other solid tumors carrying similar alterations (i.e., imatinib mesylate-refractory gastrointestinal stromal tumors). This single-institution phase II study investigated the safety and efficacy of sunitinib malate in three common STS subtypes. Patients with documented unresectable or metastatic STS (liposarcoma, leiomyosarcoma and malignant fibrous histiocytoma [MFH]), measurable disease, and 3 or less prior lines of therapy were eligible. Treatment consisted of sunitinib malate, 50 mg daily, for 4 weeks every 6 weeks. Forty-eight patients were enrolled, and 35% were heavily pretreated (≥ 2 prior lines of chemotherapy). The safety profile resembled previously known sunitinib malate toxicities. Median progression-free and overall survivals for liposarcoma, leiomyosarcoma, and MFH were 3.9 and 18.6, 4.2 and 10.1 and 2.5 and 13.6 months, respectively. The 3-month progression-free rates in the untreated and pretreated (chemotherapy) patients with liposarcoma, leiomyosarcoma and MFH were 75% and 69.2%, 60%, and 62.5% and 25% and 44.4%, respectively. With the caveats that a minority of patients with potentially indolent or low-grade disease could have been included and the small numbers, a 3-month progression-free rate of >40% suggests activity for sunitinib malate at least in liposarcomas and leiomyosarcomas. Thus, we believe that further investigation in these susceptible STS subtypes is warranted.

Topoisomerase II-α as a predictive factor of response to therapy with anthracyclines in locally advanced breast cancer.

BACKGROUND: Topoisomerase II-α is a molecular target of anthracyclines; several studies have suggested that topoisomerase II-α expression is related to response to anthracycline treatment. The objective of this study was to evaluate if topoisomerase II-α overexpression predicts response to anthracycline treatment in locally advanced breast cancer patients. MATERIAL AND METHODS: Topoisomerase II-α, HER2, estrogen receptor (ER) and progesterone receptor (PR) expression were evaluated by immunohistochemistry in formalin-fixed, paraffin-embedded breast tumors from 111 patients presenting with locally advanced breast cancer between 1995 and 2002. The prognostic value of these markers was analyzed using a multivariate proportional hazards regression model and an interaction analysis between topoisomerase II-α status and dose intensity. RESULTS: Tumors from 40 patients (36%) showed topoisomerase II-α overexpression, 62 patients (56%) for ER, 39 (35%) for PR and 26 (23%) for HER2. There were no significant correlations between topoisomerase II-α expression and response to therapy, progression-free survival (PFS) or overall survival (OS). Anthracycline dose intensity had a significant impact on PFS and OS in patients overexpressing topoisomerase II-α (P=0.010 and 0.027, respectively). Negative PR (P=0.041), positive HER2 (P=0.013) were identified as risk factors in the multivariate model. The multivariate analysis in patients topoisomerase II-α negative shown no significance (HR=0.92, IC 95% 0.39-2.15, P=0.839) while the multivariate analysis in topoisomerase II-α positive, dose intensity shown to be statistically significant (HR=2.725, IC 95% 1.07-6.95, P=0.036). CONCLUSIONS: Our data do not support a correlation between topoisomerase II-α expression in breast cancer patients and improved clinical benefit with anthracycline therapy. However, they do suggest that tumors overexpressing topoisomerase II-α may experience better clinical benefit with higher anthracycline dose intensity.

Prognostic effect of hormone receptor status in early HER2 positive breast cancer patients.

BACKGROUND: This study was conducted to determine the prognostic effect hormone receptor (HR) status in early HER2 positive (HER2+) breast cancer patients, since it has not yet been established whether HR status can be used in the prognosis of patients with (HER2+) breast cancer. PATIENTS AND METHODS: We obtained data from 299 patients with early HER2+ breast cancer who underwent surgery and received standard adjuvant chemotherapy, hormonal therapy and/or radiation between 2000 and 2002 at the Instituto Nacional De Enfermedades Neoplasicas, Perú. Clinical and pathological features were compared. Endpoints analyzed were disease free survival (DFS) and overall survival (OS). RESULTS: Overall, 155 patients were HR-positive (HR+) and 144 were negative (HR-). The two groups had similar characteristics except for histologic grade and extracapsular extension. With a median follow-up of 93 months, 5-year DFS was statistically different between the two groups: 65.0% for (HER2+/ HR-) and 74.6% for the (HER2+/ HR+) patients (p=.045). OS at 5 years was not statistically different between the two groups with 75.5% for (HER2+/ HR-) patients and 82.4% for the (HER2+/ HR+)(p=.140). CONCLUSIONS: Patients with (HER2+/ HR-) breast cancers treated with surgery and standard adjuvant chemotherapy exhibited a statistically worse DFS compared to those with (HER2+/ HR+) tumors. However, OS was similar in both groups.

Safety and efficacy of azacitidine in myelodysplastic syndromes.

PURPOSE: The clinical efficacy, different dosages, treatment schedules, and safety of azacitidine are reviewed. SUMMARY: Azacitidine is the first drug FDA-approved for the treatment of myelodysplastic syndromes that has demonstrated improvements in overall survival and delaying time to progression to acute myelogenous leukemia. The recommended dosage of azacitidine is 75 mg/m(2) daily for 7 days, with different treatment schedules validated. It appears to be well tolerated, with the most common adverse effects being myelosuppression. Several other off-label recommendations were also analyzed. CONCLUSION: Azacitidine is the first DNA hypomethylating agent approved by FDA for the treatment of myelodysplastic syndromes with demonstrated efficacy.

Breast cancer classification according to immunohistochemistry markers: subtypes and association with clinicopathologic variables in a peruvian hospital database.

BACKGROUND: Molecular classification is an excellent prognostic and predictive method in breast cancer (BC). In this study. we evaluated differences in clinicopathologic features and overall survival (OS) in four BC molecular subtypes: luminal A, luminal B, basal cell-like, and HER2/neu. PATIENTS AND METHODS: Immunohistochemical evaluation of estrogen receptor (ER), progesterone receptor (PgR), and HER2 was performed using a Peruvian hospital database of 1198 BC patients who were diagnosed between 2000 and 2002. Overall survival was calculated. RESULTS: Out of 1198 patients with invasive BC, 49.3% were luminal A; 13.2%, luminal B; 21.3%, basal-like; and 16.2%, HER2. The mean of age at diagnosis was 51.5 years for luminal A; 49.6 for luminal B; 49.5 for basal-like; and 49.4 for HER2. The HER2 subtype showed 63.7% positive lymph nodes, 42.3% stage III and 9.7% stage IV cases. Basal subtypes showed the highest prevalence of a poorly differentiated phenotype (70.3%). Average follow-up was 60 months. Five-year OS was significantly different between all 4 groups (P < .0001); luminal A had the highest OS, followed by luminal B, basal-like; and HER2. Results are compared with other population studies. CONCLUSION: This study shows significant differences between the distribution of molecular subtypes and clinicopathologic features. Immunohistochemistry is useful in the clinical management of BC patients.

Current progress in targeted therapy for colorectal cancer.

BACKGROUND: Several molecular targeting agents are available and being used in patients with colorectal cancer, and many others are being tested clinically. METHODS: The authors review and present the biology and use, including predictive testing, of the agents currently approved for use in colorectal cancer as well as current data on several newer tyrosine kinase inhibitors that are undergoing clinical trials. RESULTS: The angiogenesis inhibitor bevacizumab and the two EGFR inhibitors cetuximab and panitumumab are currently the three targeted agents approved in colorectal cancer. Recent studies show that the combined use of bevacizumab and EGFR inhibitors may lead to increased toxicity and inferior outcome. Much remains to be understood regarding these drugs and other targeted therapies as well as the underlying mechanism of tumor resistance or responsiveness to treatment. Their optimal use and sequencing with other treatment modalities such as surgery need to be further refined. CONCLUSIONS: There is a crucial need for identification of predictive markers of response and identification of possible negative interactions between targeted agents so that we can better select patients likely to respond to treatment.