scholarly journals Orthopedic Toxicity Among Adolescents and Young Adults Treated on DFCI ALL Consortium Trials

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 31-32
Author(s):  
Yannis K. Valtis ◽  
Kristen E. Stevenson ◽  
Andrew E. Place ◽  
Lewis B. Silverman ◽  
Lynda M. Vrooman ◽  
...  
Keyword(s):  
Median Time ◽  
Research Funding ◽  
Chart Review ◽  
Total Joint Replacement ◽  
Massachusetts General Hospital ◽  
Lymphoblastic Leukemia ◽  
Advisory Board ◽  
Competing Risk ◽  
Adolescent And Young Adult ◽  
Adequate Information

Background: Adolescent and young adult (AYA) patients (pts) with acute lymphoblastic leukemia (ALL) have superior outcomes when treated on pediatric regimens. These regimens, which rely heavily on corticosteroids and asparaginase (asp), are known to increase the risk of osteonecrosis (ON). In children older than 10 years (yrs), reported rates of symptomatic ON range from 5-25% (Mattano JCO 2000, Mattano Lancet Onc 2012, Toft Eur J Haematol 2016, Larsen JCO 2016). In adults, the frequency of ON and fractures (fx) are not well described including among those treated on pediatric regimens. In the recently reported C10403 trial (Stock Blood 2019), a 4% rate of ON was reported among patients aged 17-39 yrs. Here, we describe the orthopedic toxicities of AYA pts treated on sequential Dana-Farber Cancer Institute (DFCI) ALL Consortium protocols. Methods: Pts aged 1-50 yrs were treated on four sequential multi-center DFCI ALL Consortium protocols between 2000 and 2018. Additional pts treated as per these protocols at DFCI, Massachusetts General Hospital (MGH), and Boston Children's Hospital (BCH) were identified by chart review. Earlier pts were enrolled on parallel Pediatric 00-001 (2000-2004) and Adult 01-175 (2002-2008) trials while later pts were enrolled on parallel Pediatric 05-001 (2005-2011) and Adult 06-254 (2007-2011) trials. Protocol 00-001 randomized pts between dexamethasone (dex) and prednisone (pred) during consolidation, while the other three trials used dex (all trials used pred during induction). Both 00-001 and 01-175 used native E.Coli asp, while later protocols (05-001, 06-254) used PEG asp for some (05-001, randomized) or all (06-254) pts. All pts were intended to receive 30 weeks of asp during consolidation. Pts aged 15-50 yrs were included in this study. Orthopedic toxicities were extracted from case report forms for trial pts and by chart review for those not on trial. Additional chart review was performed on all pts treated at DFCI, MGH, and BCH to identify surgical events. All pts were combined in the modeling based on the treatment backbone. The 5-yr cumulative incidences (CIs) of ON and fx were estimated and compared using the Gray test. Univariate and multivariable competing risk regression models were constructed with death as a competing risk. Results: A total of 367 pts with a median age of 23 yrs (68% < 30 yrs) were identified. The majority (61%) of pts were male and the median BMI was 24.5 kg/m2 (46% overweight or obese). The median follow-up for pts remaining alive was 5 yrs (range, 0.01-14.1). In total, 60 pts experienced ON (5-yr CI 17%, [95% CI 13-22]) and 40 pts experienced fx (5-yr CI 12%, [8-15]). The median time to develop ON was 1.6 yrs (range, 0.5-7.7). The median time to fx was 1.4 yrs (range, 0.2-5.2). Pts < 30 yrs were significantly more likely to be diagnosed with ON (21%, [16-27]) compared to those aged 30-50 yrs (8%, [4-14], univariate HR 2.77 [1.35-5.65]; p=0.005). Pts treated on PEG-asp based protocols were significantly more likely to be diagnosed with ON (5-yr CI 24% [18-30]) compared to those treated on earlier trials with native E.coli asp (5-yr CI 5% [2-10], HR 5.28 [95% CI 2.24-12.48], p<0.001). These results remained statistically significant in multivariate analysis including treatment backbone, age, BMI, and sex. BMI and sex were not associated with orthopedic toxicity, although there was a trend toward fewer fx in male pts (HR 0.55, [0.29-1.02]). Of the 54 ONs for which adequate information was available, surgery was performed in 25 (46%) and total joint replacement in 18 (33%). Of the 9 fx with adequate information, 3 (33%) required surgery. Conclusions: In a large cohort of AYA ALL pts aged 15-50 yrs treated on a pediatric regimen, orthopedic toxicities were common (17% for ON, 12% for fx at 5 yrs). Younger pts (< 30 yrs) experienced higher rates of ON, as well as pts treated on later-generation PEG-asp protocols which combined dex and PEG asp. Increased rates of orthopedic toxicity in later generation protocols may be driven by the pharmacokinetic drug interaction between PEG asp and dex, leading to higher dex exposure (Yan JCO 2008, Panetta Clin Pharmacol Ther 2009). Increased awareness may be useful in early identification of orthopedic toxicities. Future efforts should focus on further understanding the pathophysiology and risk factors for orthopedic toxicity in ALL AYA regimens and developing prophylactic interventions. Disclosures Place: Novartis: Consultancy, Other: Institutional Research Funding; AbbVie: Consultancy. Silverman:Takeda: Other: advisory board; Servier: Other: advisory board; Syndax: Other: advisory board. Brunner:Acceleron Pharma Inc.: Consultancy; Biogen: Consultancy; Celgene/BMS: Consultancy, Research Funding; Forty Seven, Inc: Consultancy; Jazz Pharma: Consultancy; Novartis: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Xcenda: Consultancy; GSK: Research Funding; Janssen: Research Funding; Astra Zeneca: Research Funding. DeAngelo:Blueprint Medicines Corporation: Consultancy, Research Funding; Forty-Seven: Consultancy; Jazz: Consultancy; Incyte Corporation: Consultancy; Novartis: Consultancy, Research Funding; Shire: Consultancy; Takeda: Consultancy; Abbvie: Research Funding; Glycomimetics: Research Funding; Amgen: Consultancy; Autolos: Consultancy; Agios: Consultancy; Pfizer: Consultancy.

Phase II Study of the Frontline Hyper-CVAD in Combination with Ponatinib for Patients with Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 757-757 ◽  
Author(s):  
Koji Sasaki ◽  
Elias J. Jabbour ◽  
Farhad Ravandi ◽  
Naval G. Daver ◽  
Naveen Pemmaraju ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Median Time ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Advisory Board ◽  
Molecular Response ◽  
Rt Pcr ◽  
Vascular Events

Abstract Background: The combination of tyrosine kinase inhibitors (TKIs) with chemotherapy is highly effective in Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL). Ponatinib is a more potent BCR-ABL inhibitor, and is effective against the T315I clone which commonly causes disease recurrences. The combination of hyper-CVAD with ponatinib may produce better response rates and higher likelihood of eradication of minimal residual disease (MRD) as compared to that reported with other TKIs. Methods: Patients with newly diagnosed Ph+ ALL received 8 cycles of hyper-CVAD alternating with high dose methotrexate and cytarabine every 21 days. Ponatinib was given at 45 mg po daily for the first 14 days of cycle 1 then continuously for the subsequent 7 cycles. Patients in complete response (CR) received maintenance with ponatinib 45 mg daily and vincristine and prednisone monthly for 2 years followed by ponatinib indefinitely. After an increased incidence of vascular toxicities was recognized, patients were offered the option to switch TKIs or to continue with a reduced dose of ponatinib of 30 mg with further decrease to 15 mg in patients in CMR. The evaluation of MRD status was performed by multicolor flow cytometry (FCM), and reverse transcription polymerase chain reaction (RT-PCR). The objective of this study is to evaluate response rates, CR duration, and overall survival (OS), and to assess the safety of this regimen. Rituximab and intrathecal chemotherapy were given for the first 4 courses. Results: To date, 53 patients with untreated Ph+ ALL and 4 patients previously treated (2 patients in CR; 2 patients not in CR) have received a median of 6 cycles (2-8); 11 patients are receiving maintenance in CR; 10 patients underwent allogeneic stem cell transplantation (ASCT) after a median of 4 cycles. Baseline patient characteristics and outcomes are described in table 1. The overall complete cytogenetic response (CCyR), major molecular response (MMR), and complete molecular response (CMR) rates were 100%, 96%, and 79%, respectively. The median time to MMR and CMR were 3 weeks (range, 2-14) and 11 weeks (range, 2- 96), respectively. The median time to MRD negativity by 6-color flow cytometry (FCM) was 3 weeks (range, 3-14). Median time to platelet and neutrophil recovery for cycle 1 was 22 days (range, 17-35) and 18 days (range, 13-29), respectively, and 22 days (range, 0-35) and 16 days (range, 0-28) for subsequent cycles. Grade ≥ 3 toxicity included infections during induction (47%), increased liver function tests (34%), thrombotic events (8%), myocardial infarction (6%), hypertension (15%), skin rash (15%), and pancreatitis (19%). With a median follow up of 33 months (range, 2-51), 44 81(%) patients remain alive and in CR (41 in CR1, and 3 in CR2). Six patients died in CR: 1 patient died in CR from an unrelated cardiac event 4 months after being taken off therapy and placed on imatinib, 1 from multiple organ failure due to sepsis (C2D13), 1 from non-ST elevation myocardial infarction (C2D41; ponatinib 45 mg daily), 1 from potential myocardial infarction (C4D42; ponatinib 30 mg daily), 1 from head injury after a fall (C4D13), and 1 from sepsis post allogeneic stem cell transplantation. Of 44 patients alive at the last follow-up, 20 (46%) patients remained on ponatinib (15 mg daily in 15, and 30 mg daily in 5), 12 (27%) switched to another TKI (9 to dasatinib, 2 to nilotinib, and 1 to imatinib), 8 (18%) underwent ASCT, 3 (7%) relapsed, and 1 (2%) had positive MRD by FCM and RT-PCR. No further vascular events were observed in patients receiving lower doses of ponatinib. The 3-year CR duration and OS rates are 82% and 80%, respectively (Figures 1). Of 10 patients who underwent ASCT while in first CR, 8 patients are alive in CR, 1 died of sepsis in CR, and 1 relapsed and died of disease progression. Landmark analysis at 4 months by ASCT showed no difference in 3-year CR duration (no ASCT, 79%; ASCT, 88%; p=0.48), and 3-year OS (no ASCT, 92%; ASCT, 79%; p=0.31). Conclusion: The combination of hyperCVAD with ponatinib is highly effective in patients with Ph+ ALL. Due to the vascular events observed, the ponatinib dose was modified to 30 mg daily during consolidation with subsequent reduction to 15 mg in patients in CMR without further episode of cardiovascular events. Disclosures Jabbour: ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Pemmaraju:incyte: Consultancy, Honoraria, Research Funding; novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria; stemline: Consultancy, Honoraria, Research Funding; cellectis: Consultancy, Research Funding; affymetrix: Research Funding. DiNardo:Celgene: Research Funding; Agios: Other: advisory board, Research Funding; Abbvie: Research Funding; Daiichi Sankyo: Other: advisory board, Research Funding; Novartis: Other: advisory board, Research Funding. Konopleva:Cellectis: Research Funding; Calithera: Research Funding. Jain:BMS: Research Funding; Celgene: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Novimmune: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria, Research Funding; Abbvie: Research Funding; Infinity: Research Funding; Novartis: Consultancy, Honoraria; Genentech: Research Funding; Seattle Genetics: Research Funding. Wierda:Novartis: Research Funding; Abbvie: Research Funding; Acerta: Research Funding; Gilead: Research Funding; Genentech: Research Funding. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. O'Brien:Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria.

scholarly journals Characterization of Novel Subtypes in B Progenitor Acute Lymphoblastic Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 565-565
Author(s):  
Zhaohui Gu ◽  
Michelle L. Churchman ◽  
Kathryn G. Roberts ◽  
Ian Moore ◽  
Xin Zhou ◽  
...  
Keyword(s):  
Gene Expression ◽  
B Cell ◽  
Transcriptome Sequencing ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Genetic Alterations ◽  
Advisory Board ◽  
The Other ◽  
Cell Maturation ◽  
B Cell Maturation

Abstract Introduction B progenitor acute lymphoblastic leukemia (B-ALL) is a leading cause of childhood cancer death. Many chimeric genes have been identified and led to a refined classification of B-ALL and tailored therapies. Still, up to 30% of B-ALL cannot be classified into established subtypes, and the outcome for many is poor. Methods To identify novel subtypes of B-ALL, we performed integrative genomic analysis including transcriptome sequencing (RNA-seq) of 1,988 cases from St. Jude, Children's Oncology Group and adult cooperative group studies and analyzed chromosomal rearrangements, gene-expression profiles (GEP), somatic mutations and chromosome-level copy-number alterations. Cases lacking known or putative subtype-defining alterations underwent whole genome sequencing. Effects on proliferation and transformation of novel lesions were assessed by retroviral expression in cell lines and point-mutation knock-in mice using CRISPR/Cas9 genome editing. Results Using integrated genetic alterations and gene expression profiling, we classified 23 B-ALL subtypes (Table and Figure). Three groups included cases with similar GEP as canonical subtypes (ETV6-RUNX1, KMT2A-rearranged, and ZNF384-rearranged), but lacking the expected drivers (e.g., ETV6-RUNX1-like, n=42). Eighteen cases (0.9%) had rearrangements of BCL2, MYC and/or BCL6 showing a distinct GEP; they were mostly adults (n=16) with very poor outcome. These alterations, rarely seen in ALL, are identical to those observed in "double/triple hit" lymphoma, and are of pre-B immunophenotype. Eight cases with tightly clustered GEP comprised a novel subtype defined by IKZF1 N159Y missense mutation. N159Y is in the DNA-binding domain of IKZF1, and is known to perturb IKZF1 function, with distinct nuclear mislocalization and induction of aberrant intercellular adhesion. We identified two subtypes with distinct GEP characterized by PAX5 alterations. One, herein termed PAX5 altered (PAX5alt), comprised 148 (7.4%) cases, was characterized by diverse PAX5 alterations including rearrangements (n=57), sequence mutations (n=46) and/or focal intragenic amplifications (n=8). These PAX5 alterations were found in 73.6% of PAX5alt cases and different alteration types were mutually exclusive. Other PAX5 alterations, including deletions and large-scale amplifications were also assessed using SNP array, but were not enriched in the PAX5alt group. Clinically, PAX5alt pediatric and adult patients had favorable (96.8±3.2%) and intermediate (42.1±10.2%) 5-year overall survival (OS), respectively. The other GEP distinct subtype comprised 44 cases, all with PAX5 P80R missense mutations. In 30 of these cases, PAX5 P80R was homozygous due to deletion of the wild-type (WT) PAX5 allele or copy-neutral loss of heterozygosity. Of the other 14 cases with heterozygous PAX5 P80R mutations, 13 had a second frameshift (n=7), nonsense (n=2) or deleterious missense (n=4) PAX5 mutation. Four of the remaining 1,944 cases also had the PAX5 P80R mutation, but all were heterozygous with preservation of a WT PAX5 allele, consistent with the notion that homozygous or compound heterozygous PAX5 P80R mutation is the hallmark of this subtype. Adult PAX5 P80R cases (n=14) showed better 5-year OS (61.9±13.4%) than those in PAX5alt subtype (42.1±10.2%). To examine the effects of PAX5 P80R on B-cell maturation, WT PAX5, PAX5 P80R, V26G and P34Q were expressed in Pax5-/- lineage-depleted bone marrow cells. Expression of WT PAX5, PAX5 V26G and P34Q resulted in near complete rescue of B cell differentiation; however, expression of PAX5 P80R blocked the differentiation at the pre-pro-B stage of B-cell maturation. Further, Pax5 P80R heterozygous or homozygous mice developed pre-B-ALL with a median latency of 166 and 87 days, respectively, with heterozygous mice acquiring alterations on the second allele. In contrast, Pax5+/- mice, and those harboring G183S mutation observed in familial leukemia, do not spontaneously develop B-ALL. Conclusions These results show the utility of transcriptome sequencing in defining subtypes and founding genetic alterations in B-ALL, provide a revised taxonomy of the disease across the age spectrum, and reinforce the central role of PAX5 as a checkpoint in B lymphoid maturation and leukemogenesis. Disclosures McKay: ImmunoGen Inc.: Employment. Tallman:Orsenix: Other: Advisory board; AROG: Research Funding; BioSight: Other: Advisory board; Cellerant: Research Funding; AbbVie: Research Funding; Daiichi-Sankyo: Other: Advisory board; ADC Therapeutics: Research Funding. Stock:Jazz Pharmaceuticals: Consultancy. Konopleva:Stemline Therapeutics: Research Funding. Relling:Shire Pharmaceuticals: Research Funding. Mullighan:Cancer Prevention and Research Institute of Texas: Consultancy; Amgen: Honoraria, Speakers Bureau; Abbvie: Research Funding; Loxo Oncology: Research Funding; Pfizer: Honoraria, Research Funding, Speakers Bureau.

scholarly journals Factors Influencing Time from Initial Presentation to Start of Plasma Exchange (PEX) in Patients with Acute Thrombotic Thrombocytopenic Purpura (TTP)

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 9-10
Author(s):  
Rory McCulloch ◽  
Tom Bull ◽  
Phillip LR Nicolson ◽  
Rebecca J Shaw ◽  
Zara Sayar ◽  
...  
Keyword(s):  
Plasma Exchange ◽  
Median Time ◽  
Research Funding ◽  
Advisory Board ◽  
Initial Presentation ◽  
Red Cell ◽  
Cns Involvement ◽  
Thrombocytopenic Purpura ◽  
Time To Initiation ◽  
Cell Fragments

Background: Acute Thrombotic Thrombocytopenic Purpura (TTP) is a life-threatening medical emergency and plasma exchange (PEX) is the only treatment shown to significantly impact acute mortality (Rock et al, N Engl J Med 1991). Diagnosis can be challenging and therein arrangements for PEX must be made, with most centers in the United Kingdom (UK) having to co-ordinate transfer to a tertiary site. To understand issues affecting practice the trainee research network HaemSTAR conducted a retrospective nationwide review of patients presenting to UK hospitals with TTP against British Society of Haematology clinical guidelines (Scully et al, B J Haem 2012). Analysis was conducted on the time from hospital presentation to initiation of treatment and impact on patient outcomes. Method: Adults ≥18 years presenting to hospital between 1st June 2014 and 1st June 2019 with first episode acute TTP and ADAMTS13 level <10% were identified by local clinicians. Anonymized data of baseline characteristics and treatment times was submitted via an online secure server. Time to PEX was defined as time from receipt of the first full blood count sample in the laboratory to time of plasma release for PEX from blood bank. Where patients were transferred between sites data was linked retrospectively. Results: Data on 148 patients treated at 80 UK hospitals was used for analysis (demographics table 1). 142 patients (96%) received PEX, 67 (47%) at site of presentation and 75 (53%) after hospital transfer. 6 patients died before receiving PEX. 37 patients (25%) received PEX within 8 hrs of hospital presentation, 91 patients (61%) within 24 hrs. 33 patients (22%) commenced PEX more than 48 hrs from presentation. The overall median time to PEX from initial presentation was 15 hours (95% CI 11.3-18.7). Availability of on-site PEX was associated with earlier treatment initiation with median time to PEX for those treated on site 10 hrs (95% CI 7.7-12.3) vs. 21 hrs (95% CI 16.8-25.2) for patients transferred. A blood film comment of red cell fragments significantly impacted time to treatment: in 24 cases with no fragments documented median time to PEX was 110 hrs (95% CI 39-181) vs. 10 hrs (95% CI 8.5-11.5) in cases where fragments were reported (fig 1). On univariate and multivariate analysis age <60 years, hemoglobin (Hb) <100 g/L, presence of fragments, PEX available on-site and admissions occurring after May 2017 were significant predictors for PEX initiation within 8 hrs. PEX within 24 hrs was associated with age <60 years, platelet count <30 x 109/L, Hb <100 g/L and presence of fragments only. The presence of cardiac and/or central nervous system (CNS) involvement was not predictive of time to initiation of PEX (table 1). 96 patients (62%) received steroids within 24 hrs of presentation, 98 of 128 patients with cardiac/CNS involvement (77%) received rituximab within 48 hrs and 12 patients (8%) received platelet transfusion in the absence of major bleeding. 19 patients (12%) died within 30 days of presentation (median time to death 10 days, range 0-23). In 7 of these cases (37%) a delay >24 hrs from presentation to diagnosis was reported despite presence of fragments in 4 cases. Mortality did not correlate with availability of on-site PEX. Discussion: This is the first multi-center record of time to treatment from initial presentation of acute TTP. Results comply with guidance for rapid initiation of PEX with 61% patients commencing within 24 hrs of presentation and, from June 2017, 34% of patients initiating PEX within 8 hrs. The recent increase in early PEX initiation correlates with initiatives to improve treatment pathway efficiency following diagnosis of TTP. Early use of steroids and rituximab correlated with earlier use of PEX indicating where timely diagnosis was made there was good compliance with guidelines. Inappropriate use of platelets appeared attributable to misdiagnosis. Older patients, those with higher platelet counts and Hb and absence of red cell fragments on film report were more likely to experience prolonged time to initiation of PEX. This does not appear related to PEX access, but most likely the difficulty of making TTP diagnosis in this cohort. That 22% of patients initiated PEX over 48 hrs from admission indicates the issue is relatively common and with several deaths occurring in this group we suggest initiatives to increase early diagnosis should be prioritised. Full contributor list: http://haemstar.org/flash-mob-audit-2019/ Disclosures McCulloch: Sanofi: Research Funding. Nicolson:Principia Biopharma: Research Funding; Novartis: Research Funding; Rigel pharmaceuticals: Research Funding; Bayer: Honoraria. Shaw:Octapharma: Research Funding. Scully:Alexion: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; Takeda: Speakers Bureau; Ablynx/Sanofi: Consultancy, Other: Advisory Board, Speakers Bureau; Shire/Takeda: Other: Advisory Board, Research Funding, Speakers Bureau; Novartis: Other: Advisory Board, Speakers Bureau.

Intravesicular Cidofovir in the Treatment of BK Virus-Associated Hemorrhagic Cystitis (BKV-HC) Following Allogeneic Hematopoietic Stem Cell Transplant (HSCT)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2085-2085
Author(s):  
Graham Tooker ◽  
Ashraf Z. Badros ◽  
Jennifer Nishioka ◽  
David Riedel
Keyword(s):  
Viral Load ◽  
Median Time ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Bk Virus ◽  
Response To Treatment ◽  
Cell Transplant ◽  
Initial Report ◽  
Hematopoietic Stem ◽  
Common Diagnosis

Abstract Background: BKV HC is a well-known complication following allo-SCT. Supportive care with bladder irrigation and blood transfusions were the only available treatment. Since our initial report (Bridges B et al. Am J Hematol 2006;81:535), several studies confirmed that intravesicular cidofovir is a potential effective treatment for BKV HC. In this study, we report a large series of consecutive patients who developed BKV HC following allo SCT and received intravesicular cidofovir. Methods: We conducted a retrospective review of allo SCT patients who developed BKV HC and were prescribed intravesicular cidofovir from 2012 to 2017. Results: 33 patients were diagnosed with BKV HC. The median age was 50 years (range=23-73), and 18 (55%) were male. Acute myeloid leukemia (n=12, 35%) was the most common diagnosis followed by non-Hodgkin lymphoma (n=7, 21%) and B cell acute lymphoblastic leukemia (n=4, 12%). Conditioning regimens were myeloablative (n=19, 58%) or reduced-intensity (n=14, 42%); 15 (45%) patients received cyclophosphamide, and 22 (67%) received total body irradiation. The median time to onset of HC symptoms following SCT was 37 days (range: 8-178); 17 (52%) patients had acute graft vs. host disease. HC symptom severity ranged from grade 0-4 (median=2). The median BK urine viral load pre-treatment was 100,000,000 IU/ml. Patients received a median of 2 intravesicular treatments (range=1-7) at a dose of 5 mg/kg. Four patients (12%) were also treated concurrently with intravenous cidofovir. 19 (59%) patients demonstrated complete clinical resolution of symptoms, 9 (28%) demonstrated partial response to treatment, and 4 (13%) had no change in symptoms following treatment. These improvements in clinical status were independent of viral load, though most had reductions in the viral load. The median time to symptom resolution was 17 days (range=7-53; n=28). 82% of patients had no recurrent symptoms of HC. The main side effect of intra-vesicular instillation was increased discomfort and bladder spasms; severe in 3 patients (9%). No patient had impaired renal function directly attributable to intra-vesicular cidofovir. At 12 months after BKV HC diagnosis, 26 (79%) patients were alive. Conclusions: To our knowledge this is the largest study of intravesicular cidofovir for BKV HC reported to date; 77% of patients with BVK HC achieved clinical improvement of symptoms with minimal side effects. Clinical trials of intravesicular cidofovir could provide further evidence for adding intravesicular cidofovir as a standard tool for the treatment of BKV HC. Disclosures Badros: Celgene: Consultancy, Research Funding; Karyopharm: Research Funding; GSK: Research Funding.

Combination of Oral Rigosertib and Injectable Azacitidine in Patients with Myelodysplastic Syndromes (MDS): Results from a Phase II Study

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3167-3167 ◽  
Author(s):  
Shyamala C. Navada ◽  
Guillermo Garcia-Manero ◽  
Katherine P. Hearn ◽  
Rosalie Odchimar-Reissig ◽  
Erin P. Demakos ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Median Time ◽  
Phase Ii ◽  
Median Duration ◽  
Clinical Benefit ◽  
Research Funding ◽  
Standard Dose ◽  
Advisory Board ◽  
Treatment Naïve ◽  
Clinical Benefit Response

Abstract Background: Based on a model suggesting leukemia can be driven by combined effect of mutations in an epigenetic gene (DNMT3) and Ras, the combination of a hypomethylating agent (HMA) such as azacitidine (AZA) and a Ras mimetic such as rigosertib (RIG) may have enhanced activity in both MDS and AML. The mechanism of action for RIG (Athuluri-Divakar et al, Cell 2016) documents its interference with the RAS-binding domains of RAF kinases and inhibition of the RAS-RAF-MEK and the PI3Ks pathways. In vitro, the combination of RIG with AZA was found to act synergistically to inhibit growth and to induce apoptosis of leukemic cells in a sequence-dependent manner (exposure to RIG first, followed by AZA) (Skidan et al, AACR 2006). Rigosertib's low bone marrow toxicity in pre-clinical assays, effective inhibition of human hematopoietic tumor cell lines, and its synergy with AZA suggests the potential value of combination treatment for patients (pts) with MDS. Phase I results of the current clinical study in pts with MDS or AML showed the combination of oral RIG and standard-dose AZA to be well-tolerated with evidence of efficacy (Navada et al, Blood 2014). The phase II portion of the study was initiated to further evaluate the combination in pts with MDS. Methods: Phase II results are presented for HMA-treatment-naïve MDS pts and for those with MDS failing to respond to or progressed on a prior HMA. Oral RIG was administered twice daily on Day 1-21 of a 28-day cycle at the recommended Phase II dose (RPTD: 560 mg qAM and 280 mg qPM). AZA 75 mg/m2/d SC or IV was administered for 7 days starting on Day 8. A CBC was performed weekly and a bone marrow aspirate and/or biopsy were performed at baseline, D29, and then every 8 weeks thereafter. Results: The combination of oral RIG and injectable AZA has been administered to a total of 54 pts, of whom 40 were pts with MDS including HMA-treatment-naïve (N=23) and previously HMA treated pts (N=17). Median age was 66 years (range 25-85); 73% of pts were male; and ECOG performance status was 0, 1, and 2 in 23%, 73%, and 5%, respectively. 17 pts received prior HMA therapy: 12 AZA, 4 decitabine, and 1 both. Patients have received 1-36+ cycles of treatment (median, 6 cycles), with a median duration of treatment of 25 weeks (range 4 to 145+ weeks). 8 (20%) and 2 (5%) of pts have been treated for more than 1 and 2 years, respectively. Table 1 shows the response per IWG 2006 criteria (Cheson, Blood 2006) among 33 evaluable patients. The response per IWG 2006 was complete remission (CR) in 8 (24%), concurrent marrow CR and hematologic improvement (HI) in 9 (27%), marrow CR alone in 7 (21%), and HI alone in 1 (3%). When overall response is defined as CR plus PR plus HI - responses with improvement in marrow function and thus either normalization of the peripheral blood count or lineage improvement - defined here as Clinical Benefit Response - 55% of all evaluable pts and 70% of the evaluable HMA-treatment-naïve patients showed responses meeting these criteria. Median time to initial response was 2 cycles (2.2 months), and median time to best response was 3 cycles (3.3 months). Median duration of response was 8 months for CR, 14.3 months for marrow CR, 7.4 months for erythroid response, 8 months for platelet response, and 6.2 months for neutrophil response. Clinical response is classified by IPSS-R risk categories below. The most frequently reported adverse events are nausea (41%), fatigue (39%), diarrhoea (37%), constipation (37%), dysuria (28%), decreased appetite (28%), haematuria (24%, 8% Grade 3), pyrexia (24%), dizziness (22%), thrombocytopenia (20%), back pain (20%), dyspnoea (20%), and cough (20%). Eight deaths were reported on study with most common causes including infection and progression of disease. Conclusions: The combination oforalRIG and standard-dose AZA was well tolerated in repetitive cycles in pts with MDS. Response per IWG 2006 criteria was observed both in HMA-treatment-naïve patients (85%) and in patients after failure of prior HMA therapy (62%); employing Clinical Benefit Response as the criteria, these groups had 70% and 31% response, respectively. These clinical results confirm the preclinical synergistic interaction with the combination of RIG and AZA reported by Skidan et al, and suggest that the combination can overcome clinical resistance to HMAs. Based on these results, a Phase III study of the combination of oral RIG and AZA in patients with MDS is planned. Disclosures Navada: Onconova Therapeutics, Inc.: Research Funding. Daver:Karyopharm: Honoraria, Research Funding; Pfizer: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Ariad: Research Funding; Otsuka: Consultancy, Honoraria; Kiromic: Research Funding; BMS: Research Funding. DiNardo:Agios: Other: advisory board, Research Funding; Novartis: Other: advisory board, Research Funding; Celgene: Research Funding; Abbvie: Research Funding; Daiichi Sankyo: Other: advisory board, Research Funding. Konopleva:Reata Pharmaceuticals: Equity Ownership; Abbvie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Stemline: Consultancy, Research Funding; Eli Lilly: Research Funding; Cellectis: Research Funding; Calithera: Research Funding. Fenaux:Celgene, Janssen,Novartis, Astex, Teva: Honoraria, Research Funding. Petrone:Onconova Therapeutics, Inc.: Employment. Zbyszewski:Onconova Therapeutics, Inc.: Employment. Fruchtman:Onconova: Employment. Silverman:Onconova Therapeutics, Inc.: Patents & Royalties: Co-Patent holder for the combination of azacitidine and rigosertib, Research Funding.

scholarly journals Association between Sociodemographic, Clinical and Immunophenotypic Variables with Disease Relapse and Survival at 12 Months, in Patients with B-Cell Acute Lymphoblastic Leukemia Treated at a Colombian University Hospital

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4380-4380
Author(s):  
Luis Antonio Salazar ◽  
Sandra Vanesa Rios ◽  
Angela María Peña ◽  
Maria Luna-Gonzalez ◽  
Mario Andrés Arenas ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Survival Function ◽  
Advisory Board ◽  
Overweight And Obesity ◽  
University Hospital ◽  
The Impact

Abstract INTRODUCTION Acute lymphoblastic leukemia (ALL) is a clonal hematopoietic disorder that originates from B or T lymphoid progenitors. It affects more frequently children, but prognosis is worse in adults. ALL has a high incidence in Hispanics (Swords R et al. Blood Cancer J. 2016) and is important to identify baseline clinical, sociodemographic, and cytogenetic characteristics in these patients that are relevant for relapse free and overall survival. Reports of Hispanic patients with ALL outsides of the U.S.A are scare but are important to further characterize the impact of this disease in minority populations. OBJETIVE To describe the association between sociodemographic, clinical and immunophenotypic variables with 12-month relapse free survival (RFS) and overall survival (OS) in patients diagnosed and treated for ALL in a Colombian university hospital (FOSCAL). MATERIALS AND METHODS This is a descriptive observational cohort study that included patients older than 18 years with a confirmed diagnosis of ALL treated in a tertiary university hospital between 2013-2020 and that had at least 12 months follow-up after starting treatment. Baseline sociodemographic, clinical, laboratory and immunophenotypic data were collected. Bivariate analyses of both relapse and mortality cumulative incidences at 12 months, with relative risks (RR) and their 95% Confidence intervals were performed, using either chi-square or Fischer exact test when needed. In a second term, bivariate survival analyses through Kaplan-Meier survival function and Hazard ratios were evaluated, using Cox proportional hazards as the main statistical test. RESULTS Among 128 of include patients, the median age at diagnosis was 34 years (range 0-89 years), 54% were men, 6.2% had type 2 Diabetes Mellitus (T2DM), most had an ECOG PS of 0 (72.7%), 31.8% had splenomegaly, 12% had hepatomegaly and 47% presented without organomegalies. The proportion of patients with overweight and obesity were 26.3% and 22.2% respectively. At diagnosis 80.5% and 8.8% of patients had high risk and standard risk ALL, respectively Forty-eight patients had a FAB classification with 58% being ALL-2 and most of the were unclassified. Most cases (81%) had B-cell immunophenotype, with 55% being pre-B-cell and 32% mature B-cell. Twelve percent of patients were Ph+ B-ALL. At 12 months, the proportion of mortality was 34.4%. Most of the patients (83%) did not have major co-morbidities, however patients with T2DM had a significantly inferior survival at 12 months, HR: 3.68 (95%CI 1.54-8.8 P=0.003), as patients older than 35 years (HR: 2.15, 95%CI: 1.14-4.0, P=0.017) (Table 1). CONCLUSIONS Colombian patients with B-cell ALL have similar clinical, immunophenotypic and cytogenetic (Ph+ prevalence) characteristics as seen in other international cohorts. In our cohort patients older than 35 years and subjects with T2DM had inferior survival at 1 year. Further analyses of socioeconomic factors, molecular features and response to specific regimens are needed to have a better understanding of Colombian B-ALL patients. Figure 1 Figure 1. Disclosures Salazar: Amgen: Research Funding. Peña: Amgen: Research Funding. Sandoval-Sus: BMS: Other: Advisory Board, Speakers Bureau; SeaGen, Janssen, MassiveBio, TG: Other: Advisory Board. Sossa: Amgen: Research Funding.

scholarly journals Pediatric-Inspired Chemotherapy Incorporating Pegaspargase Is Safe and Results in High Rates of MRD Negativity in Adults Ages 18-60 with Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4013-4013 ◽  
Author(s):  
Mark Blaine Geyer ◽  
Ellen K. Ritchie ◽  
Arati V. Rao ◽  
M. Isabella Cazacu ◽  
Shreya Vemuri ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Board Of Directors ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Advisory Board ◽  
Lymphoblastic Lymphoma ◽  
Advisory Committees ◽  
Grade 3

Abstract Introduction: Among adolescents and young adults with (w/) acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LBL), treatment using a pediatric (vs. adult) regimen appears to achieve superior event-free (EFS) and overall survival (OS); this observation has driven increased interest in adapting pediatric regimens for middle-aged adults w/ ALL/LBL. However, greater risk of toxicities associated w/ asparaginase complicates administration of pediatric-inspired regimens in adults. We therefore designed a pediatric-inspired chemotherapy regimen w/ doses of pegaspargase (PEG) rationally synchronized to limit overlapping toxicities w/ other chemotherapeutic agents. Methods: We conducted a phase II multi-center trial in adults ages 18-60 w/ newly-diagnosed Philadelphia chromosome-negative (Ph-) ALL/LBL (NCT01920737). Pts w/ Ph+ ALL or Burkitt-type ALL were ineligible. The treatment regimen consisted of 2-phase induction (I-1, I-2), followed by consolidation w/ 2 courses of alternating high-dose methotrexate-based intensification and reinduction, followed by 3 years of maintenance (Figure 1). PEG 2000 IU/m2 was administered in each of the 6 intensive courses of induction/consolidation at intervals of ≥4 weeks. Minimal residual disease (MRD) was assessed in bone marrow (BM) by multiparameter flow cytometry (FACS) on day (d) 15 of I1 and following I-1 and I-2. Any detectable MRD (even <0.01% of BM WBCs) was considered positive. Toxicities were assessed by CTCAE v4.0. Results: 39 pts were enrolled (30M, 9F), w/ B-ALL (n=28), T-ALL (n=7), B-LBL (n=3), and T-LBL (n=5). Median age at start of treatment was 38.3 years (range 20.2-60.4), w/ 18 pts age 40-60. Grade 3-4 toxicities associated w/ PEG are summarized in Table 1. Grade 3-4 hyperbilirubinemia was observed post-PEG in I-1 in 9 pts, but only recurred thereafter in 1/8 pts resuming PEG. Pts completing consolidation on protocol (n=16) received median of 6 doses of PEG (range, 2-6). Four pts developed hypersensitivity to PEG and subsequently received Erwinia asparaginase. PEG was discontinued in 4 additional pts due to hepatotoxicity (n=2), pancreatitis (n=1), and physician preference (n=1). Of pts w/ available response assessments, 35/36 (97%) achieved morphologic complete response (CR) or CR w/ incomplete hematologic recovery (CRi) following I-1 (n=34) or I-2 (n=1). Both pts not achieving CR/CRi after I-I had early T-precursor ALL; one of these pts was withdrawn from study, and the other (w/ M2 marrow after I-1) achieved CR after I-2. Of the pts w/ ALL (excluding LBL) w/ available BM MRD assessments, 11/28 (39%) achieved undetectable MRD by FACS following I-1; 18/22 (82%) achieved undetectable MRD by FACS following I-2. Of the pts w/ LBL w/ available BM MRD assessments, 7/7 (100%) achieved or maintained undetectable MRD by FACS following I-1 and I-2. Ten pts underwent allogeneic hematopoietic cell transplantation (alloHCT) in CR1. Seven pts experienced relapse at median 15.2 months from start of treatment (range, 5.4-30.4), of whom 6 subsequently underwent 1st (n=5) or 2nd (n=1) alloHCT. Of the 11 pts w/ ALL w/ undetectable MRD following I-1, only one has relapsed. Five patients have died, including 2 pts in CR1 (from sepsis and multi-organ system failure), and 3 pts in relapse. At median follow-up of 22.3 months among surviving pts (range, 1.0-48.1), median EFS and OS (Figure 2A&B) have not been reached (EFS not censored at alloHCT). 3-year EFS was 62.1% (95% CI: 38.4-78.9%) and 3-year OS was 80.0% (95% CI: 57.5-91.4%). Conclusions: PEG can be incorporated into pediatric-inspired chemotherapy regimens w/ manageable toxicity for appropriately selected adults up to age 60 w/ Ph- ALL/LBL. While PEG-related AEs are common, few pts require permanent discontinuation of asparaginase. Grade 3-4 hyperbilirubinemia was common, particularly post-I-1, but recurred infrequently when PEG was continued. Two induction courses resulted in a high rate of MRD negativity post-I-2 and translated to a low rate of relapse. Though further follow-up is required, 3-year EFS is encouraging. Data regarding asparaginase enzyme activity and silent inactivation w/ neutralizing anti-PEG antibody will be presented. Ongoing and future studies will additionally investigate whether incorporating novel therapies (e.g. blinatumomab, nelarabine) into frontline consolidation therapy may reduce risk of relapse among adults receiving PEG-containing regimens. Disclosures Geyer: Dava Oncology: Honoraria. Ritchie:Celgene: Consultancy, Other: Travel, Accommodations, Expenses, Speakers Bureau; NS Pharma: Research Funding; Incyte: Consultancy, Speakers Bureau; ARIAD Pharmaceuticals: Speakers Bureau; Astellas Pharma: Research Funding; Bristol-Myers Squibb: Research Funding; Novartis: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding. Rao:Kite, a Gilead Company: Employment. Tallman:Daiichi-Sankyo: Other: Advisory board; AROG: Research Funding; Cellerant: Research Funding; AbbVie: Research Funding; BioSight: Other: Advisory board; Orsenix: Other: Advisory board; ADC Therapeutics: Research Funding. Douer:Shire: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead Sciences: Consultancy; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Consultancy; Pfizer: Honoraria; Spectrum: Consultancy. Park:Kite Pharma: Consultancy; Juno Therapeutics: Consultancy, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy; Novartis: Consultancy; Shire: Consultancy; Pfizer: Consultancy; Adaptive Biotechnologies: Consultancy.

scholarly journals Ruxolitinib and Lenalidomide As a Combination Therapy for Patients with Myelofibrosis

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1831-1831 ◽  
Author(s):  
Daver Naval ◽  
Jorge E. Cortes ◽  
Elias Jabbour ◽  
Naveen Pemmaraju ◽  
Nitin Jain ◽  
...  
Keyword(s):  
Median Time ◽  
Research Funding ◽  
Dose Adjustment ◽  
Financial Constraints ◽  
Single Agent ◽  
Advisory Board ◽  
Dose Increase ◽  
Median Response ◽  
Board Membership ◽  
Grade 3

Abstract Background: Ruxolitinib (RUX) is a potent and selective inhibitor of the JAK/STAT pathway that significantly abrogates splenomegaly and constitutional symptoms in patients (pts) with myelofibrosis (MF). Lenalidomide (LEN) is a second-generation immunomodulatory agent that may improve MF-associated anemia and thrombocytopenia. RUX and LEN possess complimentary efficacy profiles. Aim:Our single-center phase II open-labeled study was conducted to determine the efficacy and safety of the combination of RUX with LEN in pts with MF. Objective improvements were defined using International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) 2007 criteria. We were cognizant of an overlapping toxicity of the two medications, namely myelosuppression. Methods:Pts received 15 mg RUX orally twice daily in continuous 28-day cycles with 5 mg LEN orally once daily on days 1-21. Dosage was reduced, increased or delayed based on the assessment of efficacy and toxicity. Results: Thirty-one pts were enrolled between October 2011 and August 2013. Twenty-one (68%) had received prior treatment, including 2 with thalidomide. After a med follow-up of 21.6 mo (1.9-27.7), 28 pts remain alive. The median time on study was 14.7 mo (1.8-26.6) and the median number of cycles administered was 15 (1-29). Simultaneous administration of RUX and LEN was difficult. Only 2 (6%) pts have not required a dose interruption/dose adjustment. The median time to first dose interruption/dose adjustment was 56 days (4-360). Among the 29 pts who needed a dose interruption/adjustment, 23 (79%) needed it within 3 months of starting therapy. The first change in 23 (74%) pts was a dose interruption: median time to first dose interruption was 56 days (4-360), with 20 (87%) of the dose interruptions occurring within 3 months of therapy. LEN was held in all 23 pts and 14 (61%) never restarted LEN. RUX was concurrently held in 7 (30%), reduced in 9 (40%), and continued at same dose in 7 (30%). Reasons for the first dose interruption were low platelets (n=8), low absolute neutrophil count (n=3), anemia (n=3), diarrhea (n=3), financial constraints (n=2), deep vein thrombosis (n=1), skin rash (n=1), transaminitis (n=1), and arthralgia/fever (n=1). The first change in 6 (19%) pts was a dose increase (all in RUX): median time to dose increase was 83 days, with 3 (50%) of the increases occurring within 3 months of starting therapy. The reasons for dose increase were leukocytosis (n=2), suboptimal response (n=2), increased spleen size (n=1), and thrombocytosis (n=1). At the time of submission, 18 pts remain on study: 7 on RUX alone and 11 on both medications. IWG-MRT defined clinical improvement (CI) in splenomegaly was noted in 11 (36%) pts. Of note, CI in splenomegaly was seen in 6 of 11 (55%) pts who did not require a dose interruption in the first 3 months. Median time to response was 1.0 mo (0.4-9.1) and median response duration was 19.3 mo (9.4-25.6+). An additional 18 (58%) pts had IWG-MRT defined stable disease. Reasons for discontinuation in 13 pts were lack of response (n=2), infection (n=2), progression (n=1), neuropathy (n=1), renal failure (n=1), diarrhea (n=1), myelosuppression (n=2), concurrent lymphoma (n=1), and financial constraints (n=2). Grade 3/4 myelosuppression was noted in 13 pts. Five pts experienced grade 3/4 non-hematological toxicity (related and unrelated): G3 diarrhea (n=1), G3 edema (n=1), G4 acute kidney injury (n=1), and G3 liver enzyme (n=2). Conclusion: Concomitant administration of RUX with LEN resulted in early dose interruption in a majority of pts. Most pts were unable to restart LEN after dose interruption. Starting the two drugs simultaneously compromised the expected efficacy of RUX alone. A sequential approach with single-agent RUX for the first 3-6 months followed by the addition of the second agent once a steady dose of RUX has been achieved and optimal benefit reached may be a more viable approach for future RUX combination strategies. Table 1: Pt characteristics (N = 31) Characteristic N (%) / [range] Median age, years 66 [37-82] Male 18 (58%) Diagnosis Post-essential thrombocytosis MF Post-polycythemia MF Primary MF 4 (13%) 12 (39%) 15 (48%) Splenomegaly 28 (90%) Median WBC x 109/L 19.0 [4.3-124.9] Median hemoglobin g/dL 11.0 [8.9-17.5] Median platelets x 109/L 250 [27-1898] Peripheral blood blasts ³ 1% 15.0 (48%) JAK2 + 26 (84%) Cytogenetics Diploid 18 (58%) Abnormal 12 (39%) Insufficient metaphases 1 (3%) Disclosures Naval: Incyte: Advisory board membership Other, Research Funding. Pemmaraju:Incyte: Advisory board membership Other. Verstovsek:Incyte: Research Funding.

scholarly journals A Novel Approach to Identifying Septic Shock (SS) in Children with Acute Lymphoblastic Leukemia (ALL) Using Pediatric Health Information System (PHIS) Data: Methods Validation and Incidence Estimation in a National Cohort

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3597-3597
Author(s):  
Viviane C. Cahen ◽  
Yimei Li ◽  
Evanette Burrows ◽  
Caitlin W Elgarten ◽  
Amanda M. DiNofia ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Gold Standard ◽  
Research Funding ◽  
Chart Review ◽  
Lymphoblastic Leukemia ◽  
Medication Administration ◽  
Consensus Conference ◽  
Operating Characteristics ◽  
National Cohort ◽  
Exposure Patterns

Abstract Infectious complications are major contributors to morbidity and mortality in children with leukemia; however, clinical trial reporting is incomplete (Miller 2016 J Clin Oncol). Using administrative data to identify SS events could improve estimates of incidence and clinical impact. However, accurate SS determination is challenging, and the 2005 International Pediatric Sepsis Consensus Conference (IPSCC) definition is often modified for individual studies. ICD-9 codes, assigned at discharge, do not permit precise timing estimates. We hypothesized PHIS resource utilization (RU) codes could identify vasopressor exposures as proxies for IPSCC-defined SS events. We present the operating characteristics of our methods and use the approach to estimate SS incidence for a national cohort. We previously identified and validated a longitudinal cohort of children aged 0-21 with newly diagnosed ALL using PHIS billing and diagnosis codes (Fisher 2014 Med Care), expanded through 12/31/2013. PHIS RU data were used to identify distinct vasopressor exposure patterns hypothesized to represent true SS (Figure 1). Epinephrine alone with asparaginase within ± 3 days was considered anaphylaxis rather than SS. We captured vasopressor patterns occurring ≥7 days from first chemotherapy until the first of: 30 days prior to relapse, 10 days prior to stem cell transplantation, or 3 years from diagnosis. We reviewed charts of all patients with ALL diagnosed from 2004 to 2013 at the Children's Hospital of Philadelphia (CHOP) to establish the SS gold-standard. We assumed true SS events would be associated with blood cultures. Each blood culture triggered a chart review and was classified by IPSCC sepsis criteria. A PHIS RU-defined vasopressor exposure had to be within ±14 days of the chart-defined SS to be considered a true positive. We predicted a patient may meet criteria for a PHIS vasopressor exposure if vasopressors were ordered to the bedside for impending SS but ultimately not administered. For CHOP patients with available electronic medication administration record (MAR) data (1/1/2011-12/31/2013), we assessed whether using vasopressor orders marked as "given" or "given or held at bedside" resulted in different operating characteristics relative to gold standard IPSCC SS events. We calculated sensitivity and positive predictive value (PPV) of PHIS RU exposure patterns for IPSCC SS, then used them to estimate SS incidence for the entire PHIS cohort and for certain risk group subsets. We identified 360 patients common to both PHIS and CHOP chart review cohorts. Chart review revealed 38 events meeting IPSCC SS criteria. PHIS RU data identified vasopressor exposure patterns in 35 of these 38 SS events within ±14 days (sensitivity 92%). PHIS RU data identified an additional 43 vasopressor patterns that did not correlate with a chart review IPSCC SS event (PPV: 35/78, 45%). When considering chart-defined sepsis event of any severity (ie, not restricted to SS), the PPV for PHIS-defined vasopressor events increased to 88%. MAR data were available for 149 patients to delineate whether ordered vasopressors were given or held. Among these 149 patients, 10 SS events met IPSCC criteria by chart review. Restricting RU-identified vasopressor exposure events to patients who actually received vasopressors resulted in sensitivity of 70% and PPV 77%; including orders where vasopressors were given or held, the sensitivity increased to 100% and PPV decreased to 55%. Using PHIS RU vasopressor patterns, we estimated an incidence of 12.6% (95% CI 12.0 - 13.3 %) of patients ever experiencing SS in the PHIS ALL cohort. Infants, children aged ≥10 years, with public insurance, or receiving daunorubicin all had significantly higher SS rates than the cohort baseline (Table 1). PHIS RU-defined vasopressor exposure patterns have a high sensitivity for IPSCC-defined SS but a low PPV. The PPV may be the result of including patients with vasopressors ordered but not given; however, IPSCC-defined SS excludes children with fluid-responsive shock. The low PPV suggests this RU-defined approach results in "overcapture" of SS, but the gold standard definition may be too restrictive. Vasopressor exposure patterns from RU data may identify patients with SS or impending SS that can augment incomplete clinical trial data collection. PHIS RU SS incidence estimates for a national pediatric ALL cohort exceed 12%, with even higher rates in high-risk subgroups. Disclosures Fisher: Merck: Research Funding; Pfizer: Research Funding.

scholarly journals Maintenance and Consolidation Regimens after a Second Autologous Transplant for Multiple Myeloma: A Decade of Experiences

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5700-5700
Author(s):  
Ghulam Rehman Mohyuddin ◽  
Maire Okoniewski ◽  
Osama Diab ◽  
Siddhartha Ganguly ◽  
Al-Ola Abdallah ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Median Time ◽  
Research Funding ◽  
Standard Of Care ◽  
Advisory Board ◽  
Advisory Committees ◽  
Fda Approval ◽  
Novel Drugs ◽  
Significant Difference

Introduction: Autologous stem cell transplant (ASCT) followed by maintenance is the standard of care for eligible patients with multiple myeloma (MM). For patients that relapse, a second ASCT remains a viable option. However, the maintenance regimen to use for such patients remains an unanswered question, particularly in those with prior lenalidomide exposure. We retrospectively analyzed patients receiving two autologous transplants for a diagnosis of MM at our institution from 2008 to 2018 to determine maintenance strategies and outcomes upon completion of a second transplant. Methods: A total of 189 patients received two or more autologous transplants for MM at our institution from 2008 to 2018. Patients with planned tandem transplants, or those that proceeded directly to another transplant without interval progression were excluded. The remaining 135 patients were analyzed. Results: Patient characteristics are shown in Table 1. After first ASCT, 94 out of 135 patients (69.6 %) started maintenance therapy. The most commonly used maintenance regimen was lenalidomide in 63 patients, followed by bortezomib in 12 patients and thalidomide in 10 patients. Median time to initiation of maintenance from the date of transplant was 3.9 months. Overall median progression free survival (PFS) from transplant was 24.7 months with no significant difference between groups that received lenalidomide (median PFS: 21.2 months) or bortezomib (median PFS: 19.2 months, p:0.12). 10 (15.8%) patients discontinued lenalidomide due to toxicity, and 1 patient (8.3%) discontinued bortezomib due to toxicity. The median time from the onset of disease progression post first ASCT to time of second ASCT was 5.8 months. Strategies used post second ASCT includedconsolidation with triplet regimens followed by de-escalation (n=11) versus monotherapy (n=100). Table 2 highlights differing maintenance regimens used after the second ASCT. Median time from second ASCT to initiation of maintenance was 4.0 months. Median PFS post ASCT was 20.7 months. There was no statistically significant difference in PFS between the different regimens used (p=0.26), although there was a numerically higher discontinuation rate due to toxicity with older agents such as lenalidomide and bortezomib compared with newer agents such as daratumumab and pomalidomide. There was no statistically significant difference in the cytogenetic risk profile (p=0.21) or stage at diagnosis (p=0.36) between the groups that received different types of maintenance agents. However, patients receiving daratumumab as maintenance were more likely to have received more lines of therapy (median 5 for Daratumumab vs 3 for Lenalidomide, p=0.0001), and more likely to have previous exposure to daratumumab prior to second ASCT (92% vs 0% for other agents p=0.0001). Patients receiving daratumumab, carfilzomib or triple therapy were more likely to have been refractory to both a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD) (p=0.0001). Despite stratifying for use of newer novel drugs (FDA approval after 2010- pomalidomide, daratumumab, carfilzomib) vs older novel drugs (FDA approval before 2010- lenalidomide, bortezomib, thalidomide), there was no difference in PFS ( 21.2 months vs 20.4 months, p= 0.92), between these groups when used as part of a maintenance strategy. Conclusions: Our data show a variety of maintenance and consolidation regimens are used for patients with MM after their second ASCT. In this single-center, retrospective analysis, there was no clear superiority of a consolidative strategy using triplet over monotherapy, and no superiority of newer agents compared to older agents. This suggests that toxicity, prior therapies and their tolerance may be the more important patient-related factors for consideration when selecting an agent/agents. Randomized, prospective data will be important to ascertain the standard of care in this situation. Disclosures Ganguly: Daiichi Sankyo: Research Funding; Seattle Genetics: Speakers Bureau; Kite Pharma: Honoraria, Other: Advisory Board; Janssen: Honoraria, Other: Advisory Board. McGuirk:Kite Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bellicum Pharmaceuticals: Research Funding; Astellas: Research Funding; Juno Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Fresenius Biotech: Research Funding; Gamida Cell: Research Funding; Pluristem Ltd: Research Funding; ArticulateScience LLC: Other: Assistance with manuscript preparation.

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