Intravoxel incoherent motion diffusion-weighted imaging of bone marrow in patients with acute myeloid leukemia: a pilot study of prognostic value

2017 ◽  
Vol 46 (2) ◽  
pp. 476-482 ◽  
Author(s):  
Jinliang Niu ◽  
Wenjin Li ◽  
Hongwei Wang ◽  
Wenqi Wu ◽  
Tong Gong ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Pilot Study ◽  
Diffusion Weighted Imaging ◽  
Myeloid Leukemia ◽  
Prognostic Value ◽  
Intravoxel Incoherent Motion ◽  
Diffusion Weighted ◽  
Acute Myeloid

A Phase I-II Pilot Study of Divalproex Sodium Alone and in Combination with All-Trans-Retinoic Acid (ATRA) in Relapsed or Refractory Acute Myeloid Leukemia.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2799-2799
Author(s):  
Janice L. Gabrilove ◽  
Melanie-Jane McConnell ◽  
Windy Berkofsky-Fessler ◽  
Andres L. Sirulnik ◽  
Sanjay Sharma ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Retinoic Acid ◽  
Pilot Study ◽  
Myeloid Leukemia ◽  
Trisomy 8 ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Marrow Cellularity ◽  
Acute Myeloid

Abstract Valproic acid (VPA), acetylates histones, induces apoptosis and synergizes with All Trans Retinoic Acid (ATRA), in promoting G1 arrest and leukemic cell differentiation in vitro. Based on these observations we designed a Phase I/II pilot study of VPA alone and in combination with ATRA in patients with relapsed, refractory or poor risk acute myeloid leukemia (AML). VPA was initiated at 15mg/kg/day (day 1 IV followed by daily po) and escalated weekly by 10mg/kg (max 60 mg/kg/day) targeted to reach a serum concentration of 80–120mg/ml. For the combination, ATRA was to be added initially at 25mg/M2/day (first 3 patients) and titrated, in the absence of toxicity, to 45mg/M2/day, in two divided doses, following a minimum of 7 days of VPA therapy alone. Treatment was planned to continue for 45 days following achievement of a VPA level of >80mg/ml on two separate, consecutive measurements. To date we have treated 8 patients (7 tAML/MDS, 1 de novo AML) with VPA alone. Two of 8 additional patients to be treated with VPA + ATRA (1 tAML/ET; 1 tAML/MDS), are too early in their treatment upon which to report. Of the VPA alone treated patients, Median age was 63 (range 52–78). No Prior therapy: 3/8 pts; 5F:3M; ECOG PS 0 (1), 1 (5), 2 (2);Cytogenetic abnormalities: normal (1); t(3;18) (1); complex karyotype (6), including trisomy 8 (3), abnormalities of 11 (2) or monosomy 7 (2). Baseline bone marrow blast percentage > 50%; (8); median bone marrow cellularity 84% (range 35–90). Treatment: Median duration of treatment 45 days (range 19–99). Therapy discontinued before 45 days; withdrawl (2); death at home on study (day 33 of treatment), (1); reversible grade 3 toxicity(2). VPA levels: Serum concentrations of VPA of > 80mg/ml was achieved in all patients; Hematologic effects: Changes in CBC: increase in WBC, ANC and blast count (BLC)(3), followed by decrease in WBC and BLC (2); increase in WBC/ANC &decrease in BLC (1); decrease in WBC, ANC and BLC (3); &initial decrease in BLC &increase in ANC (1). Marrow: decrease in marrow cellularity (2)( 90% to 30%); loss of detectable trisomy 8 population (1); &decrease in bone marrow blasts (1) (64% to 5%) was observed. One patient reverted back to MDS, lasting 5 months. Side Effects: somnolence (grade 2–4) was observed in 4/8 patients, and was the major cause of withholding treatment. We also observed a constellation of symptoms (weight gain, fever, elevated WBC, shortness of breath, elevated LDH, bone pain) and chest x-ray findings consistent with &reminiscent of APL syndrome, within seven days of achieving the targeted serum VPA levels (> 80mg/ml), in 2 pts. Decadron was started two days (1) and immediately (1) following the onset of symptoms: signs and symptoms abated quickly &resolved subsequently within three days. In retrospect, one additional patient had comparable symptoms, for which VPA was stopped, following admission to an outside hospital for fever, pulmonary infiltrates and altered mental status. Correlative studies: serial assessment of bulk histone acetylation (H3, H4) was performed in all 8 patients. 7/8 patients showed evidence of histone hyperacetylation in mononuclear cells from peripheral blood, during treatment with VPA. Additional patients are being treated with VPA + ATRA. Analysis of these studies will be forthcoming.

scholarly journals Validation of Low Risk Prognostic Scoring System (LR-PSS) in Patients with Lower Risk IPSS-R Myelodysplastic Syndrome. Results from a Single Center

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4270-4270
Author(s):  
Montserrat Arnan Sangerman ◽  
Helena Pomares ◽  
Esther Alonso ◽  
Mercedes Galiano ◽  
Maite Encuentra ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Scoring System ◽  
Lower Risk ◽  
Myeloid Leukemia ◽  
Prognostic Value ◽  
Low Risk ◽  
Acute Myeloid

Background: Myelodysplastic syndrome (MDS) therapeutic decisions have been traditionally based on the International Prognostic Scoring System (IPSS) (Greenberg et al, Blood 1997) and IPSS-R (Greenberg et al, Blood 2012). Recently, next-generation sequencing genetics has been incorporated into management of MDS, however its use is limited in routine clinical practice. Current prognostic models do not allow the identification of patients with low risk disease (low or intermediate-1 IPSS) and poor prognosis, who could benefit from an early intervention. Garcia-Manero et al (Leukemia 2008) described a specific prognostic scoring system for this subgroup of patients (LR-PSS) based on age ≥60 years, hemoglobin <10g/dl, platelet count <50k/uL or 50-200k/uL, bone marrow blasts ≥4% and unfavorable cytogenetics (non-del(5q), non-diploid). This LR-PSS score system enables the stratification of low risk MDS patients into 3 different risk categories; interestingly, the third category identifies a subgroup of patients with a median overall survival (OS) similar to that of patients classified as intermediate-2 and high risk IPSS. Besides, the IPSS-R described by Greenberg et al (Blood 2012) has demonstrated a strong prognostic value for OS and LFS as compared to the IPSS when applied to different independent series of MDS patients. The prognostic impact of the LR-PSS has not been analyzed in MDS patients with very low-, low- and intermediate IPSS-R scores. Aim: To analyze the prognostic value of Low Risk Prognostic Scoring System(LR-PSS) in a population of lower risk MDS patients (very low, low and intermediate IPSS-R) analyzing as endpoints overall survival (OS) and leukemia free survival (LFS). Methods: A total of 890 consecutive patients with MDS (01/1992-7/2018) diagnosed at the Catalan Institute of Oncology in Barcelona were included in the study. 539 (60%) had available cytogenetics and therefore, IPSS-R could be assessed. 474 (88%) patients were classified as very low, low and intermediate IPSS-R and were included in the study. Results: 178 (37.6%) patients were classified as very low, 219 (46.2%) low and 77 (16.2%) intermediated IPSS-R risk MDS. Median age at diagnosis was 73 years (range 32-101). 332 (70%) were male. According to the 2008 WHO classification, 2.5% CRDU, 7.4% RA, 42.2% RCMD, 13.7% RAEB‐1, 3.6% RAEB‐2, 26.4% CMML and 4.2% MDS‐U with isolated 5q deletion. At diagnosis, median hemoglobin, platelet and bone marrow blast were 11.6 g/dL (5.5-17.1), 157 x109/L (1-1492) and 2 % (0-17), respectively. 84 (17.7%) patients had unfavorable LR-PSS cytogenetics at diagnosis. Median follow up time for survivors was 5.4 years (range 0.25-23.8). At the time of last follow up, 58.4 % (277) had died and 71 (15%) had progressed to acute myeloid leukemia. When the LR-PSS was applied to the very low, low and intermediate IPSS-R subgroups, three well-differentiated prognostic categories could be identified: 103 patients (21.7%) category 1 (scores 0-2); 330 (69.6%) patients category 2 (scores 3-4) and 41 (8.7%) patients category 3 (scores 5-7) with significant different OS and LFS. Median OS for categories 1, 2 and were 7.1 years (95% CI 4.9-9.2), 5.7 years (95% CI 4.7-6.7) and 2.8 years (95% CI 2.1-3.6), p<0.001 (Figure 1), respectively. Rate of progression to acute myeloid leukemia was 10% (10/99), 15% (48/323) and 27% (11/411) for categories 1, 2 and 3, respectively. Summary/Conclusion: When applied to a low risk (very low, low and intermediate) IPSS-R cohort of MDS population, LR-PSS identifies a subgroup of patients with a significantly worse prognosis who could benefit from an early treatment intervention. Disclosures Sureda: Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Gilead: Consultancy; Roche: Honoraria; BMS: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau.

scholarly journals A Pilot/Safety Study of sEphB4-Hsa in Combination with a Hypomethylating Agent for Patients with Relapsed or Refractory Myelodysplastic Syndrome and Acute Myeloid Leukemia Previously Treated with a Hypomethylating Agent

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 40-41
Author(s):  
Caitlin O'Neill ◽  
Akil Merchant ◽  
Parkash S. Gill ◽  
Casey L. O'Connell
Keyword(s):  
Bone Marrow ◽  
Cell Proliferation ◽  
Acute Myeloid Leukemia ◽  
Pilot Study ◽  
Myelodysplastic Syndrome ◽  
Myeloid Leukemia ◽  
Leukemic Cell ◽  
Hypomethylating Agents ◽  
Grade 3 ◽  
Acute Myeloid

Background: Myelodysplastic syndrome (MDS) is a clonal hematopoietic neoplasm that results in bone marrow failure and frequently leads to acute myeloid leukemia (AML). Hypomethylating agents (HMA) are the only FDA-approved treatment for MDS and among few options for chemotherapy-ineligible patients with AML. There are limited options for patients in whom HMA therapy fails and who are not candidates for allogeneic stem cell transplant, so therapies that complement or restore sensitivity to HMAs are needed. Studies have shown increases in bone marrow microvessel density (MVD) and angiogenic markers in patients with MDS and AML. A decrease in MVD has been shown to correlate with response to hypomethylating agents in MDS. A receptor-ligand interaction, comprised of receptor EphB4 and membrane localized ligand EphrinB2, mediates angiogenesis in normal tissue and appears to be a target unique to many cancer types. We have previously shown EphB4 to be highly expressed and a driver of leukemic cell survival in a subset of AML patients. Our group has developed a human fusion protein, sEphB4-HSA, that blocks bidirectional signaling induced by EphB4-EphrinB2 interaction to inhibit tumor cell proliferation and angiogenesis. In phase I clinical trials of sEphB4-HSA in various tumor types, there were no myelosuppressive effects and minimal toxicity. Given its safety in phase I and potential to inhibit leukemic cell proliferation and angiogenesis, we proposed a pilot trial to evaluate the safety of sEphB4-HSA in combination with HMAs in MDS and AML patients who have failed treatment with HMAs. Methods: This pilot study was designed to enroll 6 patients with relapsed/refractory intermediate or high-risk MDS and 6 patients with AML refractory to or relapsed to HMA treatment and who are deemed unfit for chemotherapy. Treatment consisted of sEphB4-HSA 15 mg/kg IV every 2 weeks in combination with the FDA-approved HMA most recently or currently being used for treatment (decitabine 20mg/m2 IV/1hr on days 1 to 5 every 28 days or azacitidine 75mg/m2 SC or IV on days 1 to 7 every 28 days). Patients were treated for as long as they were receiving clinical benefit up to 12 months. The primary endpoint was toxicity and tolerability of sEphB4-HSA in combination with HMA. Toxicity was assessed and graded after each cycle according to the CTCAE version 4. Tolerability was defined as the ability to complete two cycles of treatment without the occurrence of dose-limiting toxicity. A secondary efficacy endpoint was to assess best overall response, based on the IWG Working Group Criteria for MDS and AML, during the first two cycles of treatment. Enrollment was stopped after 7 patients due to expiration of funding. Results: Three patients with intermediate-risk MDS were treated for a median duration of 6 cycles (2-12) and 4 patients with AML were treated for 2 cycles. Median age was 75.5 years (67.9-84.8) and 57.1% were male. HMA included azacitadine in 6 patients and decitabine in one patient. There were no dose-limiting toxicities. There were 8 grade 3/4 events attributed to HMA, which included: neutropenia (2), thrombocytopenia (3), and leukopenia (3). There were 3 grade 3/4 events attributed to sEphB4, which included: febrile neutropenia (1), leukopenia (1), and hypertension (1). Of the MDS patients, 2 had stable disease, 1 patient after 2 cycles and 1 patient after 4 cycles. One patient achieved a hematologic improvement-erythroid after 6 cycles. AML patients had no disease response. Reasons for treatment discontinuation were death (1), disease progression (2), patient's decision (1), physician's decision (2), and hospice (1). Notably, a comparison of bone marrow biopsies at baseline and after 8 weeks of treatment demonstrated a decrease in MVD (Figure 1). Discussion: This pilot study found sEphB4 in combination with HMAs to be tolerable with no significant toxicity beyond that expected with HMA therapy and associated with potential clinical benefit in MDS patients. Improvement in abnormal bone marrow MVD may indicate a potential for sEphB4-HSA plus HMA therapy to alter the malignant microenvironment in MDS/AML. Disclosures No relevant conflicts of interest to declare.

Enasidenib: First Mutant IDH2 Inhibitor for the Treatment of Refractory and Relapsed Acute Myeloid Leukemia

2019 ◽  
Vol 18 (14) ◽  
pp. 1936-1951 ◽  
Author(s):  
Raghav Dogra ◽  
Rohit Bhatia ◽  
Ravi Shankar ◽  
Parveen Bansal ◽  
Ravindra K. Rawal
Keyword(s):  
Clinical Trial ◽  
Bone Marrow ◽  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Adverse Effects ◽  
Blood Cells ◽  
Myeloid Leukemia ◽  
White Blood Cells ◽  
Phase Iii ◽  
Acute Myeloid

Background: Acute myeloid leukemia is the collective name for different types of leukemias of myeloid origin affecting blood and bone marrow. The overproduction of immature myeloblasts (white blood cells) is the characteristic feature of AML, thus flooding the bone marrow and reducing its capacity to produce normal blood cells. USFDA on August 1, 2017, approved a drug named Enasidenib formerly known as AG-221 which is being marketed under the name Idhifa to treat R/R AML with IDH2 mutation. The present review depicts the broad profile of enasidenib including various aspects of chemistry, preclinical, clinical studies, pharmacokinetics, mode of action and toxicity studies. Methods: Various reports and research articles have been referred to summarize different aspects related to chemistry and pharmacokinetics of enasidenib. Clinical data was collected from various recently published clinical reports including clinical trial outcomes. Result: The various findings of enasidenib revealed that it has been designed to allosterically inhibit mutated IDH2 to treat R/R AML patients. It has also presented good safety and efficacy profile along with 9.3 months overall survival rates of patients in which disease has relapsed. The drug is still under study either in combination or solely to treat hematological malignancies. Molecular modeling studies revealed that enasidenib binds to its target through hydrophobic interaction and hydrogen bonding inside the binding pocket. Enasidenib is found to be associated with certain adverse effects like elevated bilirubin level, diarrhea, differentiation syndrome, decreased potassium and calcium levels, etc. Conclusion: Enasidenib or AG-221was introduced by FDA as an anticancer agent which was developed as a first in class, a selective allosteric inhibitor of the tumor target i.e. IDH2 for Relapsed or Refractory AML. Phase 1/2 clinical trial of Enasidenib resulted in the overall survival rate of 40.3% with CR of 19.3%. Phase III trial on the Enasidenib is still under process along with another trial to test its potency against other cell lines. Edasidenib is associated with certain adverse effects, which can be reduced by investigators by designing its newer derivatives on the basis of SAR studies. Hence, it may come in the light as a potent lead entity for anticancer treatment in the coming years.

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