Abstract 218
Overall survival (OS) for acute leukemia in relapse (RL) or induction failure (IF) treated with HCT is 16–19% (Duval et al., JCO 2010). While randomized studies have shown a dose ...response relationship, with higher doses of radiation resulting in decreased relapse, this benefit is offset by increased treatment related mortality.
To explore the safety and tolerability of targeted radiation treatment in the context of HCT, a phase I trial is being conducted in which escalated doses of targeted whole body radiation is delivered to marrow bearing and lymphoid areas, while sparing non hematopoietic (vital) organs. The transplant preparative regimen is as follows: tomotherapy on days −10 to −6; etoposide 60mg/kg adj bw on day −5 with cyclophosphamide 100mg/kg ideal bw on day −3. The radiation dose was started at 1200cGy delivered in 150 cGy fractions twice a day. As part of the design, the dose of radiation was escalated in increments of 150 cGy until 1500 cGy and then 100 cGy incrementally using cohorts of three until ultimately dose limiting toxicity is reached according to the Bearman and CTCAE 3.0 (for hematologic toxicity) scales. Liver and brain dose was kept at 1200 cGy. Normal organs received 17–62% of the marrow dose (lung 47%, esophagus 35% and oral cavity 28%). All patients received peripheral blood stem cells on day 0. GVHD prophylaxis consisted of tacrolimus and sirolimus.
To date, a total of 26 patients have been transplanted; from 3/14/2008 to 2/9/2012. Additional patient characteristics are as follows:
Age median 33y (20–54y)
AML n=12, ALL Ph- n=10, ALL Ph+ n=2, Biphenotypic n=2
Disease status at HCT, 1RL n=9, 2RL n=2, IF n=15
Cytogenetic risk: intermediate n=13, unfavorable n=8 and information not available n=5
KPS at HCT median 80 (70–100)
Donor source sibling n=13, HLA matched related n=6, mismatched (1 allele) unrelated n=7
WBC at HCT median 1.9 (0.1–14.9)
blasts (blood) at HCT median 0.5% (0–85%)
blasts (marrow) at HCT median 46% (10–85%)
Two patients presented with extramedullary disease at time of HCT.
With a median follow-up for alive patients of 16.1 months (5.3–47.7), the OS and cumulative incidence of relapse/progression at 1 year are 55% (95%CI: 44–65) and 34.6% (95%CI: 17.1–52.9) respectively. Five patients have been treated at 1600 cGy, the current dose level being tested, without reaching DLT. Twenty-two patients (85%) achieved CR at their day 30 post transplant evaluation. Twelve (46%) of patients developed acute GvHD; 5(42%) of these developed grades 3–4. The day 30 and day 100 NRM was 0% and 8% respectively. The most common toxicity across the dose levels tested is grade 2 stomatitis (Bearman Scale). Causes of death were disease progression/persistent disease n=10, GvHD n=2 and infection n=1.
These results are encouraging and suggest that 1) doses of targeted whole body, marrow and lymphoid radiation delivered by Tomotherapy can be safely escalated to 1600 cGy in combination with etoposide and cyclophosphamide (DLT not reached and dose escalation continues); and that 2) a reduction in relapse/progression compared to published reports can be achieved without increasing NRM in this high risk population.
No relevant conflicts of interest to declare.
Abstract 3151▪▪This icon denotes a clinically relevant abstract
Ablative dose total body irradiation (TBI) of 800 cGy in combination with high-dose melphalan (MEL) as part of single cycle autologous ...transplantation (AT) was found to be too toxic, and therefore inferior, in comparison to MEL. We set out to test total marrow irradiation, (TMI), a “sculpted” form of targeted total body irradiation using image-guided intensity modulated helical tomotherapy, given as the sole ablative regimen during the second cycle of tandem AT (TAT) as consolidation in patients with stable/responsive myeloma.
Patients with Durie-Salmon stages I-III multiple myeloma in response or with stable disease, who were ≤ 70 years old and within 18 months from diagnosis, were enrolled. Patients received MEL 200 mg/m2 and AT (cycle 1), and, following recovery, TMI and AT were administered (cycle 2) at a median of approximately 2 months after the first AT. During the phase I part, TMI was tested between 1000 cGy and 1800 cGy given twice daily × 5 days. The maximum tolerated dose (MTD) –as previously reported- was established at 1600 cGy Somlo et al. Clin Cancer Res. 2011; 17 (1):174–82. Following cycle 2 of TAT, maintenance therapy consisted of dexamethasone 40 mg/day × 4 days and an IMiD (first thalidomide, and during the phase II portion, lenalidomide) in a 28-day cycle, administered for 6 cycles for patients in complete response (CR), or for a minimum of 12 cycles for pts not in CR.
54 patients were enrolled (23 females, 31 males). The median age was 54.2 years (range 31.5–66.9). All patients with stage I (7), II (14), III (n=33) multiple myeloma received MEL. Forty-three patients (79.6%) received TMI, 30 at the MTD (6 enrolled at the MTD did not receive TMI). Reversible grade 3 non-hematologic toxicities following TMI at the MTD included febrile neutropenia (5/30), electrolyte abnormalities (7/30), sepsis/infection (5/30), anorexia (2/30), nausea/vomiting (2), fatigue (1), syncope (1). Grade 3 late toxicities include 1 case each of fatigue, nausea, 1 myositis and transaminitis. There were no primary or secondary graft failures, or second malignancies. Of the entire cohort of 54 patients, by intent to treat analysis best responses following TAT included CR (n: 20), very good partial response (VGPR, n:11), partial response (PR, n:16). At a median follow-up of 39 months from first AT, progression-free survival is 55% (95% CI 42–73%) and overall survival is 81% (95% CI 70–94%). For patients treated at the MTD of TMI 1600 cGy, at a median follow-up of 39 months from the first AT, progression-free survival (PFS) is 66% (50–88%), and overall survival (OS) is 80% (65–99%).
TMI of 1600 cGy is feasible as ablative therapy following recovery from high-dose melphalan and AT. CR and VGPR rates are expected to improve with time on maintenance therapy and such data as well as progresion-free and overall survival will be updated. Safety and progression-free and overall survival data are encouraging, and further assessment of the role of TMI is warranted in combination with MEL as part of either single AT, part of TAT, or in comparison of tandem versus single ablative therapy, both in the upfront, and salvage settings.
Off Label Use: IMiDs as maintenance.
Abstract 3467
In recent studies, the incidence of extramedullary (EM) relapse post full-intensity allogeneic hematopoietic cell transplantation (AlloHCT) for AML has been reported to be approximately ...5–15%. However, the incidence and clinical significance of EM relapse following reduced-intensity (RI) AlloHCT has not been studied. To better understand the incidence and predictors of EM relapse following RI-AlloHCT for AML, a consecutive case-series of 246 adult AML patients who underwent RI-AlloHCT from (inception) February 2000 through December 2008 at City of Hope were identified and selected for analysis from a prospective observational research database.
The median patient age was 55 years (range: 19–71) with a fairly balanced gender distribution (male=125, 51%; female=121, 49%). There were 108 (44%) matched related donors and 138 (56%) matched unrelated donors. 221 (90%) of patients received peripheral blood stem cells. The median time from diagnosis to RI-AlloHCT was 6.4 months (range: 0.5–124.8). Disease status at HCT: 1CR/2CR=137(56%), induction failure=40 (16%), relapse=69 (28%). Nine percent (n=22) of patients had a history of EM relapse prior to RI-AlloHCT. Twenty-eight percent of patients (n=68) received a prior auto (n=50) or allo (n=18) HCT. The majority of patients received fludarabine/melphalan conditioning n=227, 92%. GVHD prophylaxis consisted of CSA/MMF=113, 46% or Tacro/Siro=135, 54%. A total of 205 patients were evaluable for cytogenetics. Based on SWOG criteria (2000), there were 10 (5%) favorable, 118 (57.5%) intermediate and 77 (37.5%) unfavorable cytogenetics.
Initial relapse occurred in the BM in 72 (29%) patients and EM sites in 16 (6.5%) patients. The sites were: brain/CSF 5, breast 3, multiple sites 2, spine 1, liver 1, ascites 1, soft tissue 1, testes 1, and bone 1. Three (1%) had concurrent bone marrow/EM relapse. In addition, 6 (2.4%) patients had a second relapse in an EM site. The sites of second or subsequent relapse were: CSF 2, multiple sites 2, spine 1, parietal mass 1. The two-year cumulative incidence of EM relapse was 10.4% (6.8%-15.7%). Treatment for EM relapse included: combined chemo-RT 11, RT and/or chemotherapy followed by second allo/DLI 4, chemotherapy 3, palliative care 3, and RT 1. Time from Allo-HCT to initial EM relapse was 12.2 months (range: 2.8–42.9) and time from HCT to initial BM relapse 6.5 months (range: 1.0–33.3). Overall survival after initial EM relapse was 68.8% (50.3% - 81.5%) at 1-year and 50.0% (37.3% - 61.5%) at 2 years.
Of the risk factors studied (prior EM disease, prior HCT, disease status, cytogenetic risk, and age (<55, >=55)), advanced disease status (IF/RL/>3CR) (HR: 2.8, p=0.04) and unfavorable cytogenetics (HR: 5.2, p<0.01) were found to be predictive of EM relapse.
This is the first report to analyze specifically the incidence of EM relapse of AML post RI-AlloHCT. Our data show that the incidence of incidence EM relapse following RI-AlloHCT is similar to rates reported following ablative AlloHCT. By multivariable analysis, advanced disease and unfavorable cytogenetics were associated with increased risk for EM relapse, also similar to findings in the ablative setting. In conclusion, reduced-intensity conditioning does not appear to be associated with an increased risk of EM relapse. Furthermore, the median time to EM relapse exceeds median time to BM relapse and long-term survival is possible following EM relapse.
No relevant conflicts of interest to declare.
Orderly progression through the cell cycle requires the transcriptional activation of histone genes to support packaging of newly replicated DNA. Induction of human histone gene expression is ...mediated by a co-activation complex containing transcription factor HiNF-P and its cofactor p220NPAT. Here, using cells synchronized in S-phase and in mitosis, as well as serum-stimulated cells, we have investigated how HiNF-P is regulated during the cell cycle and examined its stability relative to p220NPAT. We find that while HiNF-P is maintained at steady-state levels throughout the cell cycle, both HiNF-P and p220NPAT are actively degraded by the proteasome pathway. Importantly, elevation of HiNF-P levels enhances the stability of its co-activator p220NPAT. The HiNF-P-dependent stabilization of p220NPAT may reinforce signaling through the cyclin E/CDK2/p220NPAT pathway and contribute to coordinate control of histone gene expression.
•The total marrow and lymphoid irradiation/cyclophosphamide/etoposide conditioning regimen is safe up to a dose of 2000 cGy•Radiation to off-target critical organs is lower than typically delivered ...by total body irradiation•The results showed an acceptable risk for graft-versus-host disease and were encouraging for disease control
Current conditioning regimens provide insufficient disease control in relapsed/refractory acute leukemia patients undergoing hematopoietic stem cell transplantation (HSCT) with active disease. Intensification of chemotherapy and/or total body irradiation (TBI) is not feasible because of excessive toxicity. Total marrow and lymphoid irradiation (TMLI) allows for precise delivery and increased intensity treatment via sculpting radiation to sites with high disease burden or high risk for disease involvement, while sparing normal tissue. We conducted a phase I trial in 51 patients (age range, 16 to 57 years) with relapsed/refractory acute leukemia undergoing HSCT (matched related, matched unrelated, or 1-allele mismatched unrelated) with active disease, combining escalating doses of TMLI (range, 1200 to 2000 cGy) with cyclophosphamide (CY) and etoposide (VP16). The maximum tolerated dose was declared at 2000 cGy, as TMLI simulation studies indicated that >2000 cGy might deliver doses toxic for normal organs at or exceeding those delivered by standard TBI. The post-transplantation nonrelapse mortality (NRM) rate was only 3.9% (95% confidence interval CI, .7 to 12.0) at day +100 and 8.1% (95% CI, 2.5 to 18.0) at 1 year. The cumulative incidence of grades II to IV acute graft-versus-host disease (GVHD) was 43.1% (95% CI, 29.2 to 56.3) and for grade III and IV, it was 13.7% (95% CI, 6.9 to 27.3). The day +30 complete remission rate for all patients was 88% and was 100% for those treated at 2000 cGy. The overall 1-year survival was 55.5% (95% CI, 40.7 to 68.1). The TMLI/CY/VP16 conditioning regimen is well tolerated at TMLI doses up to 2000 cGy with a low 100-day and 1-year NRM rate and no increased risk of GVHD with higher doses of radiation.
INTERBIO-21
is Phase II of the INTERGROWTH-21
Project, the population-based, research initiative involving nearly 70,000 mothers and babies worldwide coordinated by Oxford University and performed by ...a multidisciplinary network of more than 400 healthcare professionals and scientists from 35 institutions in 21 countries worldwide. Phase I, conducted 2008-2015, consisted of nine complementary studies designed to describe optimal human growth and neurodevelopment, based conceptually on the WHO prescriptive approach. The studies generated a set of international standards for monitoring growth and neurodevelopment, which complement the existing WHO Child Growth Standards. Phase II aims to improve the functional classification of the highly heterogenous preterm birth and fetal growth restriction syndromes through a better understanding of how environmental exposures, clinical conditions and nutrition influence patterns of human growth from conception to childhood, as well as specific neurodevelopmental domains and associated behaviors at 2 years of age.
In the INTERBIO-21
Newborn Case-Control Study, a major component of Phase II, our objective is to investigate the mechanisms potentially responsible for preterm birth and small for gestational age and their interactions, using deep phenotyping of clinical, growth and epidemiological data and associated nutritional, biochemical, omic and histological profiles. Here we describe the study sites, population characteristics, study design, methodology and standardization procedures for the collection of longitudinal clinical data and biological samples (maternal blood, umbilical cord blood, placental tissue, maternal feces and infant buccal swabs) for the study that was conducted between 2012 and 2018 in Brazil, Kenya, Pakistan, South Africa, Thailand and the UK.
Our study provides a unique resource for the planned analyses given the range of potentially disadvantageous exposures (including poor nutrition, pregnancy complications and infections) in geographically diverse populations worldwide. The study should enhance current medical knowledge and provide new insights into environmental influences on human growth and neurodevelopment.
Cardiovascular disease (CVD) risks are increasingly being diagnosed in children and track into adulthood. Growth is associated with CVD risk in adulthood; however, its contribution to CVD risks in ...children facing the obesity epidemic is unclear.
The objective was to assess relations between growth from age 0 to 4 y and CVD status at 4 y in 323 Chilean children with normal birth weight.
From health records we obtained weight and height every 6 mo from age 0 to 3 y and calculated body mass index (BMI; weight/height2). At age 4 y, we measured height, waist circumference, insulin, glucose, and plasma lipids; infant feeding information was provided by the mothers. Outcomes were metabolic score (waist-to-height ratio + glucose + insulin + triglycerides – HDL-cholesterol z scores/5), total cholesterol (TC):HDL cholesterol, and homeostasis model of assessment of insulin resistance.
At 4 y, the prevalence of obesity was 13%. Changes in BMI, particularly from 6 to 24 mo, predicted a higher metabolic score (standardized regression coefficient = 0.29; 95% CI: 0.16, 0.42) but were unrelated to homeostasis model of assessment of insulin resistance and TC:HDL cholesterol. Height changes were not associated with CVD risks at the age of 4 y. Mode of infant feeding was unrelated to CVD status at 4 y; however, in children who were exclusively breastfed at 4 mo, an increase in BMI from 0 to 6 mo was positively associated with TC:HDL cholesterol at 4 y (standardized regression coefficient = 0.24; 95% CI: −0.02, 0.50), whereas in children who were partially or nonbreastfed at 4 mo, it was negatively associated with TC:HDL cholesterol at 4 y (standardized regression coefficient = −0.30; 95% CI: −0.52, −0.08).
In children with normal birth weight and a high prevalence of obesity at 4 y, changes in BMI after 6 mo predicted a higher overall CVD risk at 4 y.
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