Role of rituximab in first-line treatment of chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) is a biologically heterogeneous illness that primarily afflicts the elderly. For many decades, the initial therapy for most patients requiring treatment was limited to single-agent alkylator therapy. Within the last two decades, we have seen remarkable progress in understanding the biology of CLL and the development of more effective treatment strategies that have employed monoclonal antibodies, such as rituximab (anti-CD20). Furthermore, recognition of the synergy between fludarabine, cyclophosphamide, and rituximab (FCR) prompted investigators to explore the clinical activity of FCR in Phase II and III trials in patients with relapsed/refractory or previously untreated CLL. On the basis of these findings, the US Food and Drug Administration (FDA) recently approved rituximab in combination with fludarabine and cyclophosphamide for the treatment of patients with relapsed/refractory or previously untreated CD20-postive CLL. Recent data from a randomized Phase III trial has confirmed improved overall survival with FCR in patients with previously untreated CLL. However, FCR is not for everyone. More tolerable regimens using rituximab for the elderly and less fit patients are being pursued in clinical trials. Recent Phase II trials have explored potentially less myelosuppressive approaches by using lower doses of fludarabine and cyclophosphamide, replacing fludarabine with pentostatin, and combining rituximab with chlorambucil. Furthermore new biomarkers predictive of early disease progression have prompted investigators to explore the benefits of early treatment with rituximab combined with other agents. In addition to the proven utility of rituximab as a frontline agent for CLL, rituximab has a favorable toxicity profile both as a single agent and in combination with chemotherapy. The majority of adverse events are Grade 1 and 2 infusion-related reactions (fevers, chills, and rigors) and occur with the first dose of rituximab. The improved tolerability observed with second and subsequent infusions allows for shorter infusion times. Rituximab’s proven activity and favorable toxicity profile has made it an ideal agent for expanding treatment options for patients with CLL, the majority of whom are elderly

Pulmonary Hypertension Is a Frequent Event in Patients with Chronic Myeloid Leukemia Treated with Tyrosine Kinase Inhibitors

Poster presented at American Society of Clinical Oncology in Chicago Illinois. Background: Tyrosine kinase inhibitors (TKI) are the current standard therapy for patients with chronic myeloid leukemia (CML). Fluid retention and pleural effusions have been reported in patients treated with TKIs, particularly with dasatinib. Although TKIs have been shown to reverse pulmonary hypertension (PH) in animal models, there have been some reports of development of reversible PH with dasatinib. Methods: We conducted a retrospective analysis on 401 patients diagnosed with CML in chronic phase (CP) who were treated with TKIs (imatinib, dasatinib, or nilotinib) as initial therapy for CML and had a transthoracic echocardiogram (TTE) done at some point during the course of therapy. PH was diagnosed if the patient had an estimated right ventricular systolic pressure (RVSP) of 35 mm Hg or greater. Secondary causes of PH (systolic or diastolic dysfunction on TTE, chronic obstructive pulmonary diseases [COPD], obstructive sleep apnea [OSA] and pulmonary embolism) were investigated during chart review. Results: Twenty (23%) out of 87 patients had evidence of PH by TTE; median age 57 years, with 46% being males. Six pts (30%) received nilotinib 400mg twice daily, 4 (20%) patients had imatinib (400mg; n=1, 600mg; n=1 and 800mg daily; n=2), and 10 (50%) patients received dasatinib (dose varied 40-140mg daily). Five (25%) patients had coronary artery disease, 9 (45%) had systemic hypertension, 2 (10%) had COPD and 3 (15%) had OSA. Thirteen pts had serial TTE to compare the progression of PH including 6 (7%) who had a TTE prior to starting TKI. Among these 13 pts with serial TTE, 7 had rising RVSP with one patient having mild global hypokinesia, another with diastolic dysfunction and another with OSA. Four of those 7 patients had normal RVSP on their TTE prior to starting therapy. Six other pts had improvement in the RVSP on serial TTE, 4 of them with systemic hypertension. Two of those 6 patients had elevated RVSP on their TTE prior to starting therapy; one pt had no change. Eleven patients had pleural effusions (7 dasatinib, 3 imatinib, 1 nilotinib) associated with PH. Conclusions: TKI therapy is occasionally associated with development of PH, but RVSP may improve spontaneously in some patients. A prospective study is needed to further investigate the relationship between TKIs and the development of PH

Outcome of patients with Philadelphia chromosome-positive chronic myelogenous leukemia post-imatinib mesylate failure

BACKGROUND. The prognosis of patients with chronic myelogenous leukemia (CML) after failure of imatinib mesylate therapy is not well documented. METHODS. The outcome of 420 patients with CML post-imatinib failure (resistance-recurrence in 374; toxicities in 46) were reviewed in relation to survival, overall, and by different therapies. RESULTS. The estimated 3-year survival rates were 72% in 88 patients who progressed in chronic phase, 30% in 130 patients who progressed in accelerated phase, 7% in 156 patients who progressed in blastic phase, and 75% in 37 patients in chronic phase with imatinib intolerance. Survival in chronic phase was better when subsequent therapy was nilotinib or dasatinib vs allogeneic stem cell transplant vs others (estimated 2-year survival rates 100% vs 72% vs 67%; P = .01), but not in accelerated-blastic phase. CONCLUSIONS. Prognosis post-imatinib failure in chronic phase is reasonable; it is poor if the CML phase post-imatinib failure is accelerated or blastic. Cancer 2007. © 2007 American Cancer Society.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/55988/1/22569_ftp.pd

Successful Treatment of Intracranial Hemorrhage with Recombinant Activated Factor VII in a Patient with Newly Diagnosed Acute Myeloid Leukemia: A Case Report and Review of the Literature

Intracranial hemorrhage (ICH) is a common complication in acute myeloid leukemia (AML) patients with an incidence rate of 6.3% [1]. Bleeding disorders related to disseminated intravascular coagulation (DIC) are common complications in AML cases [2]. Recombinant activated Factor VII (rFVIIa [NovoSeven®]) is approved for the treatment of bleeding complications with FVIII or FIX inhibitors in patients with congenital FVII deficiency. Use of rFVIIa for the treatment of acute hemorrhage in patients without hemophilia has been successful [3,4]. Herein, we describe the successful use of rFVIIa in a patient with acute ICH in the setting of newly diagnosed AML

Clinical resistance to crenolanib in acute myeloid leukemia due to diverse molecular mechanisms.

FLT3 mutations are prevalent in AML patients and confer poor prognosis. Crenolanib, a potent type I pan-FLT3 inhibitor, is effective against both internal tandem duplications and resistance-conferring tyrosine kinase domain mutations. While crenolanib monotherapy has demonstrated clinical benefit in heavily pretreated relapsed/refractory AML patients, responses are transient and relapse eventually occurs. Here, to investigate the mechanisms of crenolanib resistance, we perform whole exome sequencing of AML patient samples before and after crenolanib treatment. Unlike other FLT3 inhibitors, crenolanib does not induce FLT3 secondary mutations, and mutations of the FLT3 gatekeeper residue are infrequent. Instead, mutations of NRAS and IDH2 arise, mostly as FLT3-independent subclones, while TET2 and IDH1 predominantly co-occur with FLT3-mutant clones and are enriched in crenolanib poor-responders. The remaining patients exhibit post-crenolanib expansion of mutations associated with epigenetic regulators, transcription factors, and cohesion factors, suggesting diverse genetic/epigenetic mechanisms of crenolanib resistance. Drug combinations in experimental models restore crenolanib sensitivity.This work was supported in part by The Leukemia & Lymphoma Society Beat AML Program, the V Foundation for Cancer Research, the Gabrielle’s Angel Foundation for Cancer Research and the National Cancer Institute (1R01CA183947–01; 1U01CA217862–01; 1U54CA224019-01; 3P30CA069533-18S5). H.Z. received a Collins Medical Trust research grant. S.D.B. was supported by the National Cancer Institute (5R01CA138744-08)

Initial Report of a Phase I Study of LY2510924, Idarubicin, and Cytarabine in Relapsed/Refractory Acute Myeloid Leukemia

Background: The CXCR4/SDF-1α axis plays a vital role in the retention of stem cells within the bone marrow and downstream activation of cell survival signaling pathways. LY2510924, a second generation CXCR4, showed significant anti-leukemia activity in a murine AML model.Methods: We conducted a phase I study to determine the safety and toxicity of LY2510924, idarubicin and cytarabine (IA) combination therapy in relapsed/refractory (R/R) AML. Eligible patients were 18–70 years of age receiving up to salvage 3 therapy. A peripheral blood absolute blast count of < 20,000/μL was required for inclusion. LY2510924 was administered daily for 7 days followed by IA from day 8. Two dose escalation levels (10 and 20 mg) were evaluated, with a plan to enroll up to 12 patients in the phase I portion.Results: The median age of the enrolled patients (n = 11) was 55 years (range, 19–70). Median number of prior therapies was 1 (1–3). Six and five patients were treated at dose-levels “0” (10 mg) and “1” (20 mg), respectively. Only one patient experiencing a dose limiting toxicity (grade 3 rash and myelosuppression). Three and one complete responses were observed at dose-levels “0” and “1,” respectively; the overall response rate (ORR) was 36% (4 of 11 patients). A ≥ 50% decrease in CXCR4 mean fluorescence intensity was observed in 4 of 9 patients by flow cytometry, indicating incomplete suppression of CXCR4-receptor occupancy.Conclusions: The combination of LY2510924 with IA is safe in R/R AML. Dose-escalation to a 30 mg LY2510924 dose is planned to achieve complete blockade of CXCR4 receptor occupancy, followed by expansion phase at the recommended phase 2 dose-level

Secondary cytogenetic abnormalities in core-binding factor AML harboring inv(16) vs t(8;21)

Patients with core-binding factor (CBF) acute myeloid leukemia (AML), caused by either t(8; 21)(q22;q22) or inv(16)(p13q22)/t(16;16)(p13;q22), have higher complete remission rates and longer survival than patients with other subtypes of AML. However, similar to 40% of patients relapse, and the literature suggests that patients with inv(16) fare differently from those with t(8;21). We retrospectively analyzed 537 patients with CBF-AML, focusing on additional cytogenetic aberrations to examine their impact on clinical outcomes. Trisomies of chromosomes 8, 21, or 22 were significantly more common in patients with inv(16)/t(16;16): 16% vs 7%, 6% vs 0%, and 17% vs 0%, respectively. In contrast, del(9q) and loss of a sex chromosome were more frequent in patients with t(8;21): 15% vs 0.4% for del(9q), 37% vs 0% for loss of X in females, and 44% vs 5% for loss of Y in males. Hyperdiploidy was more frequent in patients with inv(16) (25% vs 9%, whereas hypodiploidy was more frequent in patients with t(8;21) (37% vs 3%. In multivariable analyses (adjusted for age, white blood counts at diagnosis, and KIT mutation status), trisomy 8 was associated with improved overall survival (OS) in inv(16), whereas the presence of other chromosomal abnormalities (not trisomy 8) was associated with decreased OS. In patients with t(8;21), hypodiploidy was associated with improved disease-free survival; hyperdiploidy and del(9q) were associated with improved OS. KIT mutation (either positive or not tested, compared with negative) conferred poor prognoses in univariate analysis only in patients with t(8;21)

Superior efficacy of co-targeting GFI1/KDM1A and BRD4 against AML and post-MPN secondary AML cells.

There is an unmet need to overcome nongenetic therapy-resistance to improve outcomes in AML, especially post-myeloproliferative neoplasm (MPN) secondary (s) AML. Studies presented describe effects of genetic knockout, degradation or small molecule targeted-inhibition of GFI1/LSD1 on active enhancers, altering gene-expressions and inducing differentiation and lethality in AML and (MPN) sAML cells. A protein domain-focused CRISPR screen in LSD1 (KDM1A) inhibitor (i) treated AML cells, identified BRD4, MOZ, HDAC3 and DOT1L among the codependencies. Our findings demonstrate that co-targeting LSD1 and one of these co-dependencies exerted synergistic in vitro lethality in AML and post-MPN sAML cells. Co-treatment with LSD1i and the JAKi ruxolitinib was also synergistically lethal against post-MPN sAML cells. LSD1i pre-treatment induced GFI1, PU.1 and CEBPα but depleted c-Myc, overcoming nongenetic resistance to ruxolitinib, or to BETi in post-MPN sAML cells. Co-treatment with LSD1i and BETi or ruxolitinib exerted superior in vivo efficacy against post-MPN sAML cells. These findings highlight LSD1i-based combinations that merit testing for clinical efficacy, especially to overcome nongenetic therapy-resistance in AML and post-MPN sAML

Core-binding factor acute myeloid leukemia with t(8;21) Risk factors and a novel scoring system (I-CBFit)

Background: Although the prognosis of core-binding factor (CBF) acute myeloid leukemia (AML) is better than other subtypes of AML, 30% of patients still relapse and may require allogeneic hematopoietic cell transplantation (alloHCT). However, there is no validated widely accepted scoring system to predict patient subsets with higher risk of relapse. Methods: Eleven centers in the US and Europe evaluated 247 patients with t(8;21) (q22;q22). Results: Complete remission (CR) rate was high (92.7%), yet relapse occurred in 27.1% of patients. A total of 24.7% of patients received alloHCT. The median diseasefree (DFS) and overall (OS) survival were 20.8 and 31.2 months, respectively. Age, KIT D816V mutated (11.3%) or nontested (36.4%) compared with KIT D816V wild type (52.5%), high white blood cell counts (WBC), and pseudodiploidy compared with hyper- or hypodiploidy were included in a scoring system (named I-CBFit). DFS rate at 2 years was 76% for patients with a low-risk I-CBFit score compared with 36% for those with a high-risk I-CBFit score (P <0.0001). Low- vs high-risk OS at 2 years was 89% vs 51% (P <0.0001). Conclusions: I-CBFit composed of readily available risk factors can be useful to tailor the therapy of patients, especially for whom alloHCT is not need in CR1 (ie, patients with a low-risk score)