Annual Meeting Proceedings Part 1 - American Society of Clinical ...

6616 General Poster Session (Board #24C), Mon, 1:15 PM-5:15 PM
Epigenetically induced expression of CD30 in T-PLL: A rationale for the use of
brentuximab vedotin. Presenting Author: Zainul Hasanali, Penn State Hershey
Medical Center, Hershey , PA
Background: T-cell prolymphocytic leukemia (T-PLL) is characterized by high
lymphocyte counts, skin involvement and enlarged organs. Treatment with
alemtuzumab (alem) induces complete remission (CR) in �50% of patients,
duration is short (median: 6 mos). Therapy with the histone deacetylase
inhibitors (HDACi) vorinostat (SAHA) or romidepsin (romi) and cladribine
(2-CdA), may augment mAb activity. Methods: Five T-PLL patients were studied
(Table). Diagnosis was made by pathology, flow cytometry and TCR studies. Alem
(30 mg sq d1,3,5) and 2-CdA (5mg/m2 d1-5), followed by alem, 2-CdA and
SAHA (400mg qdX5days) or romi (14mg/m2d 1,8,15) was given. One patient
with skin lesions expressed CD30 and received brentuximab vedotin (SGN-35).
Results: All patients achieved CR (mean: 10; median: 8 mos). Relapsed patients
responded with repeat dosing. Genes assayed indicate involvement of the MAPK
pathway (p53, DUSP2, TRIB1, C/EBP). mRNA expression of the membrane receptor
CD30 (TNFRSF8) increased following therapy in 4/5 patients (mean: 14; Range:
1.3-69 fold). CD30 protein was confirmed by IHC and Western blotting. One patient
with relapsed T-PLL involving skin had a dramatic clearing of lesions and blood counts
after one dose of SGN35. Conclusions: Therapy with HDACi and 2-CdA overcomes
resistance and augments clinical activity of alem and SGN-35, as evidenced by
derepression of CD30 and response to treatment. We present a rationale for
epigenetic resensitization to mAbs and their drug conjugates (ADC) in T-PLL. A
prospective multicenter clinical trial is warranted.
Patient characteristics.
Age, years
Range 64-77
Median 71
Sex
Male 3
Female 2
Karnofsky score 90% (5)
WBC at diagnosis
Range 120-300
Median 211
Peripheral blood flow
CD4� 5
CD8� 2
CD2� 5
CD5� 5
CD7� 5
Treatment
Alemtuzumab 5
Cladribine 5
Vorinostat 3
Romidepsin 1
Brentuximab vedotin 1
TCR-rearrangement 5
Remission 5/5 (100%)
Remission duration (months)
Pt 1 16, 8�
Pt 2 8, 5, 4
Pt 3 6*
Pt 4 13, 1*
Pt 5 6, 3�
Current status
Alive 2
Hematologic remission 2
CD30 mRNA expression fold change after initial treatment
Pt 1 �69.0
Pt 2 �1.3
Pt 3 -3.5
Pt 4 �11.8
Pt 5 �2.8, �4.2†
Average �11.8
Std. dev. -/� 27.3
* Patient deceased with no evidence of disease.
† Fold change after treatment of relapse.
6618 General Poster Session (Board #24E), Mon, 1:15 PM-5:15 PM
The prognostic role of serum albumin in patients receiving induction
chemotherapy for acute myeloid leukemia (AML). Presenting Author:
Hossein Sadrzadeh, Massachusetts General Hospital/Harvard Medical
School, Boston, MA
Background: Serum albumin has been investigated as a prognostic tool in
the care of patients with hematologic malignancies, including multiple
myeloma and myelodysplastic syndromes. However, its prognostic utility in
patients with AML is unknown. We hypothesized that a lower serum
albumin is associated with worse outcomes following induction chemotherapy
for AML. Methods: We conducted a retrospective medical record
review of 166 adult, non-promyelocytic AML patients who had received
induction chemotherapy at Massachusetts General Hospital from 1992 to
2007. Patient characteristics were summarized as numbers and percentages
for categorical variables. The Kaplan Meier method was used to
estimate median disease-free survival (DFS) and overall survival (OS). We
dichotomized our patients by serum albumin �3 and �3, and determined
the association of albumin with 60-day survival and complete remission
(CR) rate using Fisher’s exact test. Association of albumin with DFS and OS
was summarized using Cox regression in both univariate and multivariable
analyses. Results: Of 166 patients, 125 (75%) achieved CR and 143
(86%) were alive at 60 days following diagnosis. After risk-adjusting for age
and LDH, we found that a serum albumin level �3 mg/dL was associated
with decreased 60-day survival (OR 0.30, p�0.015) and CR rate (OR 0.41,
p�0.02) compared to patients with serum albumin �3. There was no
association between serum albumin and DFS (p�0.88) or OS (p�0.31). As
expected, younger age was associated with better induction outcomes.
Conclusions: Serum albumin was negatively associated with short-term
outcomes in patients receiving induction chemotherapy. A serum albumin
level less than 3, clinically relevant to oncologic patients, was associated
with a significantly decreased CR rate and lower 60-day survival after
induction chemotherapy. This data suggests that serum albumin, a
surrogate commonly used for nutritional status and suppressed in inflammatory
comorbid states, has prognostic utility for AML patients undergoing
induction chemotherapy.
Leukemia, Myelodysplasia, and Transplantation
445s
6617 General Poster Session (Board #24D), Mon, 1:15 PM-5:15 PM
A seasonal pattern of presentation in younger patients with de novo acute
myeloid leukemia (AML). Presenting Author: Benjamin Jacob Drapkin,
Massachusetts General Hospital/Harvard Medical School, Boston, MA
Background: Seasonal variation in AML has been studied in a wide variety of
populations and locations, with primarily negative results. These investigations
may have been undermined by the heterogeneity of the disease, as de
novo and secondary AML can vary in disease presentation and trajectory,
likely reflecting distinct pathogenesis.We investigated seasonal variation in
the incidence of AML diagnosed at Massachusetts General Hospital (MGH)
from 1992 through 2011, focusing on de novo disease among younger
patients. Methods: We assembled a database of 511 biopsy-proven cases of
adult-onset AML (age � 18 years), from the MGH electronic medical
record, using a systematic search algorithm with IRB approval. We
subdivided this database into three cohorts: (1) de novo AML diagnosed
prior to age 50 (2) de novo AML diagnosed after age 50, and (3) secondary
AML, preceded by chemotherapy, myelodysplasia or myeloproliferative
disease. Diagnosis dates were grouped into quarters (Jan-Mar, Apr-Jun,
Jul-Sep, Oct-Dec). Divergence of quarterly incidence from a null hypothesis
of uniformity was evaluated by chi square analysis. Results: Among patients
under 50-years-old with de novo AML, we found a 44% increase in
incidence between October and December (Table, p�0.04). There was no
significant variation throughout the rest of the calendar year. Furthermore,
the incidence of both de novo AML diagnosed after age 50 and secondary
AML conformed to a uniform quarterly distribution. As expected, the
majority of AML patients under age 50 demonstrated intermediate-risk
cytogenetics, most frequently normal karyotype. Conclusions: We found a
significantly increased incidence of de novo AML in younger patients
between the months of October and December, diagnosed at MGH from
1992 through 2011. This may reflect a local environmental or infectious
exposure that is not relevant to the pathogenesis of AML in older patients or
those in whom AML develops due to prior therapy or previous hematological
disorder. Investigation of this exposure is ongoing.
Quarter All cases Under 50 y/o Over 50 y/o Secondary
Jan-Mar 23% 17% 26% 23%
Apr-Jun 25% 23% 25% 27%
Jul-Sep 25% 24% 24% 26%
Oct-Dec 27% 36% 26% 24%
Total patients 511 108 182 221
p value 0.51 0.04 0.97 0.77
6619^ General Poster Session (Board #24F), Mon, 1:15 PM-5:15 PM
Initial characterization of the toxicity and efficacy of elacytarabine (CP-
4055), a novel antileukemic agent, using a multidimensional exposureresponse
relationship model. Presenting Author: Murray P. Ducharme,
Learn and Confirm Inc., Quebec, QC, Canada
Background: Elacytarabine (CP-4055), an elaidic acid ester of ara-C, is a
novel antineoplastic agent developed to treat hematologic malignancies
(HM). It is metabolized to active ara-CTP and inactive ara-U. In 3 studies,
diverse elacytarabine monotherapy doses and regimens were given to
patients with advanced HM and solid tumours. This analysis aimed to 1)
describe the pharmacokinetics (PK) of elacytarabine in these patients and
2) investigate the relationship between PK and toxicity and efficacy in HM.
Methods: Population PK analyses were run with ADAPT 5 (ITS) and
included 146 patients given a 2h, 4h or 120h continuous infusion (CIV) of
elacytarabine. Elacytarabine, ara-C and ara-U plasma concentrations (Cp)
were simultaneously modeled and explained. Standard model discrimination
criteria were used to select the best model. With the model, different
dosing regimens were simulated to find average exposure and % of patients
with efficacious or toxic exposure. A multi-dimensional exposure-response
relationship (MDERR) was developed with pre-clinical and clinical data.
Results: The best model was a 2-compartment (CPT) model with linear
elimination and formation rates for the metabolism of elacytarabine to
ara-C. Mean PK parameters were Vc � 4.12 L/m2 ,CL�5.27 L/h/m2 and
T1/2 � 7.57 h. Elacytarabine PK included a peripheral CPT with a
non-linear distribution process to reflect saturable binding to red blood
cells, otherwise its PK was linear. Ara-C and ara-U PK were described by 2and
1-CPT linear models, respectively. The MDERR model related efficacy
and toxicity thresholds to elacytarabine dosing regimens, and indicated
that a 120 h CIV dosing regimen is preferable, allowing elacytarabine to
exceed efficacious Cp for longer than the other investigated regimens. A
minimum dose of 1000 mg/m2 /day is needed for most patients to receive
efficacious exposure. Conclusions: Elacytarabine is a promising antileukemic
agent for patients with advanced HM. Its PK, toxicity and efficacy
were characterized in patients given diverse dosing regimens. An MDERR
model, which will be further refined or confirmed in upcoming clinical
trials, was proposed.
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