Secondary ALL May be Independent of Prior Cytotoxic Therapy

Abstract Background: Little is known about secondary acute lymphoblastic leukemia (ALL). The entity 'secondary ALL', refers to a diagnosis of ALL following a previous malignancy and includes 2 types of patients: those who received chemo-/radio-therapy for their prior malignancy (therapy-associated ALL, t-ALL) and those who did not (antecedent-malignancy ALL, am-ALL). This retrospective single center study describes a cohort of secondary ALL patients and assesses the features of t-ALL and am-ALL. Methods: Patients included in this study were treated for ALL at Memorial Sloan Kettering Cancer Center (MSKCC), in the years 1993-2013. Inclusion criteria were a diagnosis of ALL and a history of any previous malignancy, irrespective of whether therapy was given for the prior malignancy. Patients with Burkitt leukemia or non-melanoma skin cancer were excluded. Fisher's exact test, Wilcoxon rank-sum test and Kaplan-Meier methodology were used. Results: Thirty two patients with secondary ALL were identified representing 3.8% of all ALL patients treated at MSKCC during these 20 years. Among 328 adults (age>21 yrs) the incidence was 8.8%. Of the 32 patients 25% had a history of breast cancer (n=8), 19% lymphoma or myeloma (n=6) and 16% colorectal cancer (n=5). Thirty one of B ALLs (91%) were CALLA positive (CD10+). Thirteen patients (56%) received both chemotherapy and radiotherapy, 6 (26%) only chemotherapy, 2 (9%) - radiotherapy only and another 2 (9%) received radioactive iodine for thyroid carcinoma. In the t-ALL group, 89% of chemotherapy recipients received alkylating agents for their first malignancy and 47% received topoisomerase II inhibitors. The table summarizes the characteristics, complete response (CR) rate and overall survival (OS) of the whole cohort as well as a comparison between t-ALL and am-ALL. No significant difference between groups was found regarding the incidence of B/T ALL, extramedullary disease (EMD), WBC counts, LDH level, incidence of Ph+ ALL, CR rate and OS. The estimated 3- year OS for the entire cohort was 20%. Conclusion: Although as far as we knowthis is the largest reported study of secondary ALL, the overall number is small and should be interpreted with caution. The overall incidence of secondary ALL is not low among adults (8.8%) while secondary T-cell ALL is very rare. In contrast to previous reports, most of the secondary ALLs are CALLA-positive and do not have MLL abnormalities. Radioactive iodine may be associated with development of secondary ALL. The similar characteristics and behavior of t- and am-ALL patients, together with high incidence of family-malignancy in both groups raise the possibility that secondary ALL patients may have an inherent predisposition to develop more than one malignancy and a history of previous therapy may be of lesser importance in the pathogenesis of secondary ALL. Molecular genetic profiling of secondary ALL patients, in the future, may provide insights into this issue. The long-term survival of secondary ALL patients appears similar to other ALL patients of the same age, thus the diagnosis of secondary ALL should not impact on the therapeutic strategy. Abstract 3648 Characteristics of secondary ALL, t-ALL and am-ALL Combined t-ALL am-ALL P N=32 N=23 N=9 Age at 1st malignancy Dx, yrs med. (range) 46 (2.4-83) 44 (2.4-75) 73 (18-83) .01 Age at ALL Dx, yrs med. (range) 55.5 (3.3-83) 52 (3.3-76) 75 (23-83) .01 Male, n (%) 17 (53) 10 (43) 7 (78) .12 Malignancy in 1st degree relative 15/26 (58) 11/19 (58) 4/7 (57) .99 1st malignancy, n (%) .39 Carcinoma 20 (63) 13 (57) 7 (78) Hematologic 5 (16) 5 (22) 0 Other 7 (22) 5 (22) 2 (22) Interdiagnoses interval, yrs med. (range) 5.33 (0.1-28) 7 (0.75-28) 4 (0.1-16) .06 B-ALL, n (%) 28/31 (90) 20/23 (87) 8/8 (100) .55 EMD, n (%) 9 (28) 7 (30) 2 (22) .99 Blood tests at diagnosis WBC, med. (range) 5.2 (0.4-90.6) 6.9 (0.7-68.4) 5.1 (0.4-90.6) .60 ANC, med. (range) 1.2 (0.1-13) 0.95 (0.1-13) 2.1 (0.2-12.1) .76 HgB, med. (range) 10.1 (5.9-14.9) 10.4 (8.1-14.9) 8.6 (5.9-12.8) .23 PLT, med. (range) 48 (11-251) 43 (20-212) 106 (11-251) .49 LDH, med. (range) [N 60-200] 360 (61-866) 371 (61-858) 273 (181-866) .87 Cytogenetics t(9,22) 12 (38) 8 (35) 4 (44) .68 Hyperdiploid 5 (16) 4 (17) 1 (11) - del 7/7p 6 (19) 4 (17) 2 (22) - del11q23 (MLL) 2 (06) 2 (09) 0 - t(4,11) 2 (06) 2 (09) 0 - CR, n (%) 25/26 (96) 18/19 (95) 7/7 (100) .99 OS .97 12 months, (95% CI) 0.49 (0.33-0.72) 0.41 (0.24-0.69) 0.71 (0.45-0.99) 24 months, (95% CI) 0.25 (0.12-0.49) 0.29 (0.14-0.59) 0.14 (0.02-0.88) Disclosures Stein: Seattle Genetics, Inc.: Research Funding; Janssen Pharmaceuticals: Consultancy.

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Chemotherapy Delays Are Associated with Inferior Outcome in Acute Lymphoblastic Leukemia: A Retrospective Study from a Tertiary Cancer Center in South India

Indian Journal of Medical and Paediatric Oncology ◽

10.1055/s-0041-1729513 ◽

2021 ◽

Vol 42 (01) ◽

pp. 051-060

Author(s):

Vineet Agrawal ◽

Smita Kayal ◽

Prasanth Ganesan ◽

Biswajit Dubashi

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Lymphoblastic Leukemia ◽

Univariate Analysis ◽

Cancer Center ◽

Survival Outcomes ◽

Separate Analysis ◽

Term Survival ◽

Free Survival ◽

Intensive Phase ◽

The Impact

Abstract Background Treatment protocols for acute lymphoblastic leukemia (ALL) have evolved over time to give excellent cure rates in children and moderate outcomes in adults; however, little is known how delays in chemotherapy affect long-term survival. Objectives To find the association of delays during different treatment phases on the survival outcomes. Materials and Methods Data from 149 ALL cases treated between 2009 and 2015 were retrospectively analyzed. Treatment course in commonly used protocols was divided into three phases—induction, consolidation (postremission), maintenance, and also a combined intensive phase (induction plus consolidation) for the purpose of analysis, and delay in each phase was defined based on clinically acceptable breaks. Analysis was done to find the impact of treatment delay in each phase on the survival outcomes. Results The median age was 12 years (range, 1–57). Multi-center Protocol-841 (MCP-841) was used for 72%, German Multicenter Study Group for Adult ALL (GMALL) for 19%, and Berlin, Frankfurt, Muenster, 95 protocol (BFM-95) for 9% of patients. Delay in induction was seen in 52%, consolidation in 66%, and during maintenance in 42% of patients. The median follow-up was 41 months, and 3-year survival outcomes for the entire cohort were event-free survival (EFS)—60%, relapse-free survival (RFS)—72%, and overall survival (OS)—68%. On univariate analysis, delay in induction adversely affected EFS (hazard ratio [HR] = 1.78, p = 0.04), while delay in intensive phase had significantly worse EFS and RFS (HR = 2.41 [p = 0.03] and HR = 2.57 [p = 0.03], respectively). On separate analysis of MCP-841 cohort, delay in intensive phase affected both EFS (HR = 3.85, p = 0.02) and RFS (HR = 3.42, p = 0.04), whereas delay in consolidation significantly affected OS with (HR = 4.74, p = 0.04) independently. Conclusion Treatment delays mostly in intensive phase are associated with worse survival in ALL; attempts should be made to maintain protocol-defined treatment intensity while adequately managing toxicities.

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Acute kidney injury and major outcomes in cancer patients with no history of chronic kidney disease (CKD) with coronavirus 2019 (COVID-19) infection.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e18816 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e18816-e18816

Author(s):

Cesar Simbaqueba ◽

Omar Mamlouk ◽

Kodwo Dickson ◽

Josiah Halm ◽

Sreedhar Mandayam ◽

...

Keyword(s):

Mechanical Ventilation ◽

Acute Kidney Injury ◽

Cancer Patients ◽

Clinical Outcomes ◽

Kidney Injury ◽

Hazard Model ◽

Cancer Center ◽

Icu Admission ◽

Significant Difference ◽

History Of

e18816 Background: Acute Kidney Injury (AKI) in patients with COVID-19 infection is associated with poor clinical outcomes. We examined outcomes (hemodialysis, mechanical ventilation, ICU admission and death) in cancer patients with normal estimated glomerular filtration rate (eGFR) treated in a tertiary referral center with COVID-19 infection, who developed AKI within 30 days of diagnosis. Methods: All patient data — demographics, labs, comorbidities and outcomes — were aggregated and analyzed in the Syntropy platform, Palantir Foundry (“Foundry”), as part of the Data-Driven Determinants of COVID-19 Oncology Discovery Effort (D3CODE) protocol at MD Anderson. The cohort was defined by the following: (1) positive COVID-19 test; (2) baseline eGFR >60 ml/min/1.73m2most temporally proximal lab results within 30 days prior to the patient’s infection. AKI was defined by an absolute change of creatinine ≥0.3 within 30 days after the positive COVID-19 test. Kaplan-Meier analysis was used for survival estimates at specific time periods and multivariate Cox Proportional cause-specific Hazard model regression to determine hazard ratios with 95% confidence intervals for major outcomes. Results: 635 patients with Covid-19 infection had a baseline eGFR >60 ml/min/1.73m2. Of these patients, 124 (19.5%) developed AKI. Patients with AKI were older, mean age of 61+/-13.2 vs 56.9+/- 14.3 years (p=0.002) and more Hypertensive (69.4% vs 56.4%, p=0.011). AKI patients were more likely to have pneumonia (63.7% vs 37%, p<0.001), cardiac arrhythmias (39.5% vs 20.7%, p<0.001) and myocardial infarction (15.3% vs 8.8%, p=0.046). These patients had more hematologic malignancies (35.1% vs 19%, p=0.005), with no difference between non metastatic vs metastatic disease (p=0.284). There was no significant difference in other comorbidities including smoking, diabetes, hypothyroidism and liver disease. AKI patients were more likely to require dialysis (2.4% vs 0.2%, p=0.025), mechanical ventilation (16.1% vs 1.8%, p<0.001), ICU admission (43.5% vs 11.5%, p<0.001) within 30 days, and had a higher mortality at 90 days of admission (20.2% vs 3.7%, p<0.001). Multivariate Cox Proportional cause-specific Hazard model regression analysis identified history of Diabetes Mellitus (HR 10.8, CI 2.42 - 48.4, p=0.001) as an independent risk factor associated with worse outcomes. Mortality was higher in patients with COVID-19 infection that developed AKI compared with those who did not developed AKI (survival estimate 150 days vs 240 days, p=0.0076). Conclusions: In cancer patients treated at a tertiary cancer center with COVID-19 infection and no history of CKD, the presence of AKI is associated with worse outcomes including higher 90 day mortality, ICU stay and mechanical ventilation. Older age and hypertension are major risk factors, where being diabetic was associated with worse clinical outcomes.

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275 POSTOPERATIVE COMPLICATIONS DO NOT AFFECT QUALITY OF LIFE AFTER ESOPHAGECTOMY

Diseases of the Esophagus ◽

10.1093/dote/doaa087.59 ◽

2020 ◽

Vol 33 (Supplement_1) ◽

Author(s):

E Jezerskyte ◽

H Laarhoven ◽

M Sprangers ◽

W Eshuis ◽

M Hulshof ◽

...

Keyword(s):

Quality Of Life ◽

Postoperative Complications ◽

Term Survival ◽

Radio Therapy ◽

Significant Difference ◽

Patient Reported ◽

Short And Long Term ◽

Over Time

Abstract Despite the attempts to reduce postoperative complication incidence after esophageal cancer surgery, up to 60% of patients endure postoperative complications. These patients often have a reduced health related quality of life (HR-QoL) and it may also have a negative effect on long-term survival. The aim of this study is to investigate the difference in short- and long-term HR-QoL in patients with and without a complicated postoperative course. Methods A retrospective comparative cohort study was performed with data from the Dutch Cancer Registry (IKNL) and QoL questionnaires from POCOP, a longitudinal patient reported outcomes study. All patients with esophageal and gastroesophageal junction (GEJ) cancer after an esophagectomy with or without neoadjuvant chemo(radio) therapy in the period of 2015–2018 were included. Exclusion criteria were palliative surgery, patients with a recurrence, reconstruction with a colonic or jejunal interposition, no reconstruction and emergency surgery. HR-QoL was investigated at baseline and at 3, 6, 9, 12, 18 and 24 months postoperatively between patients with and without complications following an esophagectomy. Results A total of 486 patients were included: 270 with and 216 without postoperative complications. The majority of patients were male (79.8%) with a median age of 66 years (IQR 60–70.25). Significantly more patients had comorbidities in the group with postoperative complications (69.6% vs 57.3%, p = 0.001). A significant difference in HR-QoL over time was found between the two groups in “choked when swallowing” score (p = 0.028). Patients that endured postoperative complications reported more problems with choking when swallowing at 9 months follow-up (mean score 12.9 vs 8.4, p = 0.047). This difference was not clinically relevant with a mean score difference of 4.6 points. Conclusion Postoperative complications do not significantly influence the short- and long-term HR-QoL in patients following an esophagectomy. Only one HR-QoL domain showed difference over time, however, this was not clinically relevant.

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Varicella Vaccine (VarilRix) in Children with Acute Lymphoblastic Leukemia.

Blood ◽

10.1182/blood.v104.11.4436.4436 ◽

2004 ◽

Vol 104 (11) ◽

pp. 4436-4436

Author(s):

Teresa Jackowska Ass ◽

Robert Wasilewski ◽

Elzbieta Górska ◽

Maria Wasik ◽

Teresa Loch

Keyword(s):

Acute Lymphoblastic Leukemia ◽

B Lymphocytes ◽

Lymphoblastic Leukemia ◽

Varicella Vaccine ◽

White Blood Cells ◽

Healthy Children ◽

Varicella Zoster ◽

Significant Difference ◽

Before And After ◽

History Of

Abstract Background: To assess the effectiveness of vaccination against varicella in children with acute lymphoblastic leukemia (ALL). Methods: 105 children without a history of varicella, were qualified for immunization against varicella with VARILRIX (Oka-strain varicella vaccine). 48 children had ALL and 57 were healthy. 25 of the children with ALL were receiving maintenance therapy, 23 children were after chemotherapy. Results: White blood cells (WBC), lymphocytes, and sub-populations of T- and B-lymphocytes were compared in the healthy and leukemic children before and after vaccination. The ALL children had significantly lower counts of WBC and lymphocytes before vaccination. After vaccination there were no significant differences in the counts of WBC in the healthy and leukemic children. However the ALL children had significantly lower mean counts of lymphocytes. Before vaccination the leukemic children showed a significantly lowered percentage of T-lymphocytes with decreased CD4+ and increased CD8+, what resulted in a lowered CD4 to CD8 ratio. After vaccination, only increased numbers of T CD8+ lymphocytes and a lowered CD4 to CD8 ratio were present while there was no significant difference in CD4. In the healthy and leukemic children alike there was no statistically significant difference between B-lymphocytes (CD 19+) and NK cells. In 10 children (20%), out of the 48 ALL vaccines, varicelliform rash occurred ~1 month after immunization. No adverse effects we observed in healthy children. Seroconversion to varicella-zoster virus was higher in healthy children and ALL children who had skin rash after vaccination. Two ALL children and three healthy ones had varicella one-two years after the vaccination. Those children received only single vaccine doses (double vaccine doses received children above 12 years). Conclusion: Varicella vaccine was safe and immunogenic in leukemic children during maintenance and after chemotherapy.

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Occurence of venothromboembolism (VTE) in patients (pts) with acute lymphocytic leukemia (ALL), Burkitt's leukemia/lymphoma (BL), or lymphoblastic leukemia (LL)

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.7059 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 7059-7059

Author(s):

N. V. Luong ◽

H. M. Kantarjian ◽

S. H. Faderl ◽

D. A. Thomas ◽

K. D. Vu

Keyword(s):

Risk Factors ◽

Lymphoblastic Leukemia ◽

Hormone Replacement ◽

Philadelphia Chromosome ◽

Lymphocytic Leukemia ◽

Pulmonary Vasculature ◽

Cancer Center ◽

Public Health Issue ◽

Female Ratio ◽

History Of

7059 Background: Venous thromboembolism (VTE) is a significant public health issue. Although neoplastic diseases are known risk factors for the development of VTE, little is known about the incidence and predisposing factors of VTE among leukemia patients (pts). Methods: We performed a retrospective study to determine the incidence and risk factors associated with development of VTE among pts with ALL, BL, LL at M. D. Anderson Cancer Center between 1999 and 2005. Medical records of 299 ALL pts were reviewed and analyzed. All computations were conducted using Stata 10. Results: Of the 299 pts with a male/female ratio of 182/117 and a median age of 43 yrs (range 15–83 yrs), 18% had VTE. Recurrent VTE occurred in 10 pts. VTE were identified in upper extremities (59%), lower extremities (30%), pulmonary vasculature (7%), and within venous catheters (4%). In a univariate model, pts with baseline platelet (plt) count 50–99 x 109/L were 2.2 times (95% CI: 1.05–4.55) more likely to develop VTE than pts who had plt >100 x 109/L. Pts aged 40–59 yrs were 2.3 times (95% CI: 1.15–4.59) more likely to develop VTE than pts aged 15–39 yrs. Women were 1.8 times (95%CI: 1.04–3.4) more likely than men to have a VTE. Pts with a history of VTE were 15.2 times (95% CI: 2.97–77.51) more likely to develop a VTE than pts who had no prior VTE history. Pts with > 3 comorbidities were 2.6 times (95% CI: 1.19–5.48) more likely to develop VTE than pts without comorbidities. Pts who used oral contraception or hormone replacement therapy (OCP/HRT) were 2 times (95% CI: 1.07–3.92) more likely to develop VTE than non-users. Pts with Philadelphia chromosome (Ph)-positive ALL were 3 times (95%CI: 1.41–6.17) more likely to develop VTE than pts with Ph-negative ALL. In a multivariate model, significant predictors of VTE were age 40–59 yrs, plt count 50–99 x 109/L, diagnosis of Ph-positive ALL, history of VTE, and OCP/HRT use. Conclusions: Pts with ALL have a high VTE rate. In addition to traditional risk factors, disease-specific features may also predispose pts to higher VTE risk. Further studies should be done in other leukemias to establish guidelines in the prevention and management of VTE in pts with leukemia. [Table: see text]

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Pancreatic ductal adenocarcinoma (PDAC), BRCA: Detailed analysis and outcomes of cohort from Memorial Sloan Kettering Cancer Center (MSK).

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.4_suppl.708 ◽

2020 ◽

Vol 38 (4_suppl) ◽

pp. 708-708

Author(s):

Parisa Momtaz ◽

Catherine Anne O'Connor ◽

Joanne F. Chou ◽

Marinela Capanu ◽

Kenneth H. Yu ◽

...

Keyword(s):

Stage Iv ◽

Ductal Adenocarcinoma ◽

Cancer Center ◽

Clinicopathologic Characteristics ◽

Entire Cohort ◽

Disease Biology ◽

Kaplan Meier ◽

Significant Difference ◽

History Of ◽

Associated Malignancy

708 Background: Given encouraging responses of platinum agents and poly-ADP ribose polymerase inhibitors (PARPi) in BRCA mutated (mut) PDAC, we sought to identify patients (pts) with BRCA mut PDAC treated at MSKCC and to evaluate outcome. Methods: Institutional database at MSK with IRB approval was queried for PDAC germline (g) or somatic (s) BRCA1/2 mut. Genomic profiling, clinicopathologic characteristics and outcomes were collected. Overall survival (OS) from diagnosis was estimated using Kaplan-Meier method. Results: n = 126 with BRCA1/2 mut PDAC were identified between 1/2011-12/2018. n = 77 (61%) male and median age of 62 (range 24-85) at diagnosis. n = 78 (62%) had g BRCA mut (n = 21 BRCA1; n = 57 BRCA2). n = 54 (43%) had a family history of BRCA-related malignancies; 35pts (28%) with a personal history of other BRCA-associated malignancy. n = 66 (52%) AJCC stage IV; of these 43pts (65%) received platinum-based therapy with a partial response (PR) in 35pts (81%); median duration 7 months (m) (range 0.5-39m). n = 40 (32%) received ≥ 4 lines of therapy (range 1-6 lines). n = 44 (35%) received PARPi and 11% (n = 14) received immunotherapy. Median OS for the entire cohort 32.1 m (95% CI 23.9, 42.6). Median OS for stage I-II 49.9m (95% CI 38.5,-); stage III 43m (95% CI 33.9,-) and stage IV 19.1m (95% CI 19.1 16.1,25.8). We did not observe a statistically significant difference in OS between BRCA1 vs BRCA2 pts. Conclusions: BRCA mut PDAC constitutes a small but likely distinct biologic subgroup. Improved OS was notable relative to historical data, possibly due to the integration of platinum and PARPi therapy and possibly due to contribution from disease biology. [Table: see text]

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Implications of Long-Term Survival in Acute Stem Cell Leukemia of Childhood Treated with Composite Cyclic Therapy

Blood ◽

10.1182/blood.v24.5.477.477 ◽

1964 ◽

Vol 24 (5) ◽

pp. 477-494 ◽

Cited By ~ 98

Author(s):

WOLF W. ZUELZER

Keyword(s):

Stem Cell ◽

Lymphoblastic Leukemia ◽

Current Evidence ◽

White Blood Count ◽

Cell Leukemia ◽

Term Survival ◽

Total Survival ◽

Significant Difference ◽

The Mean ◽

Stem Cell Leukemia

Abstract The results of 9 years’ experience with acute stem cell (lymphoblastic) leukemia treated with a combination of steroids and antimetabolites, designated as "composite cyclic therapy" (CCT), are described and their theoretical implications are discussed. In 175 patients surviving at least one month after diagnosis the per cent survivals were: 17.2 months (50 per cent), 27.5 months (25 per cent), and 45.0 months (10 per cent). Six patients were alive in uninterrupted remission at the close of the study, from 4-9 years after diagnosis. The mean survival of the expired patients was 17.7 months, with a median of 14.5 months. The mean duration of the first remission was 15.2 months with a median of 12.5. The therapeutic response in terms of remission rate and total survival was significantly better in stem cell leukemia, as defined cytologically at the time of original diagnosis, than in other types, suggesting that the effect of steroids on the former is at least in part specific for malignant cells of lymphoid origin. A highly significant difference within the group of stem cell leukemia was observed between patients with initially low as compared to high white blood count, the dividing line being at 20,000 cells/mm.,3 the latter having twice the mean survival of the former. Of the 44 patients achieving survival of 2 years or more only one had an initial white count of more than 20,000. In conjunction with chromosome studies published elsewhere these findings suggest that the initial white count is a parameter, possibly of immunologic nature, indicative of the partial retention or complete loss of control over leukemic mutant cells. The possibility is discussed, on the basis of theoretical considerations and the observed role of long first remissions in the total survival time, that conditions and measures taken in the early stages of therapy may be decisive for the ultimate course. The current evidence for the mutational nature of acute leukemia permits the theoretical distinction between remission as the temporary suppression of a mutant stem line as opposed to a "cure" representing its permanent elimination, and to explain occasional apparent cures, including some observed in the present series, on that basis. Clinically, combined cyclic therapy or CCT appears to be superior to the use of single antimetabolites. The withholding of steroids until these drugs become ineffective does not at present appear justified.

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Therapy-related acute lymphoblastic leukemia is a distinct entity with adverse genetic features and clinical outcomes

Blood Advances ◽

10.1182/bloodadvances.2019000925 ◽

2019 ◽

Vol 3 (24) ◽

pp. 4228-4237 ◽

Cited By ~ 5

Author(s):

Caner Saygin ◽

Ashwin Kishtagari ◽

Ryan D. Cassaday ◽

Natalie Reizine ◽

Ilana Yurkiewicz ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Clinical Outcomes ◽

De Novo ◽

Lymphoblastic Leukemia ◽

Small Subset ◽

Distinct Entity ◽

Term Survival ◽

Cytotoxic Therapies ◽

The Impact ◽

Prior Malignancy

Abstract Patients with therapy-related acute lymphoblastic leukemia (t-ALL) represent a small subset of acute lymphoblastic leukemia (ALL) patients who received genotoxic therapy (ie, chemotherapy or radiation) for a prior malignancy. These patients should be distinguished from patients with de novo ALL (dn-ALL) and ALL patients who have a history of prior malignancy but have not received cytotoxic therapies in the past (acute lymphoblastic leukemia with prior malignancy [pm-ALL]). We report a retrospective multi-institutional study of patients with t-ALL (n = 116), dn-ALL (n = 100), and pm-ALL (n = 20) to investigate the impact of prior cytotoxic therapies on clinical outcomes. Compared with patients with pm-ALL, t-ALL patients had a significantly shorter interval between the first malignancy and ALL diagnosis and a higher frequency of poor-risk cytogenetic features, including KMT2A rearrangements and myelodysplastic syndrome-like abnormalities (eg, monosomal karyotype). We observed a variety of mutations among t-ALL patients, with the majority of patients exhibiting mutations that were more common with myeloid malignancies (eg, DNMT3A, RUNX1, ASXL1), whereas others had ALL-type mutations (eg, CDKN2A, IKZF1). Median overall survival was significantly shorter in the t-ALL cohort compared with patients with dn-ALL or pm-ALL. Patients who were eligible for hematopoietic cell transplantation had improved long-term survival. Collectively, our results support t-ALL as a distinct entity based on its biologic and clinical features.

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Pharmacogenetic Outcomes of Pediatric Acute Lymphoblastic Leukemia in Korea

Blood ◽

10.1182/blood.v112.11.5047.5047 ◽

2008 ◽

Vol 112 (11) ◽

pp. 5047-5047

Author(s):

Hyoung Jin Kang ◽

Hyery Kim ◽

Young Jin Seo ◽

Mi Kyung Jang ◽

Yongtaek Oh ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Genetic Polymorphism ◽

Lymphoblastic Leukemia ◽

Individualized Therapy ◽

Treatment Result ◽

Mutant Type ◽

Term Survival ◽

Pediatric Acute Lymphoblastic Leukemia ◽

Korean Patients ◽

Significant Difference

Abstract Treatment result of pediatric acute lymphoblastic leukemia (ALL) has been markedly improved, but treatment related toxicities and relapse are still remaining problems. Genetic polymorphism is an important factor in the effectiveness and toxicity of anti-leukemic drugs and pharmacogenetics are beginning to emerge as useful research filed to solve those problems. In our experience in the treatment of ALL, many Korean patients could not tolerate full dosages of Western protocols. To make basis for individualized therapy with pharmacogenetics, we analyzed major genes implicated in the treatment of ALL. Fourteen genes of total 103 patients with ALL were analyzed with TotalPlex gene amplification methods (Mol Cell Probes.2008. 22: 193). Among the drug related genes (percentage of mutant type) including CYP3A4*1B (0%), CYP3A5*3 (0%), GSTP1 (22.3%), GSTM1 (20.4%), GSTT1 (16.5%), MDR1 exon 21 (76.3%), MDR1 exon 26 (61.2%), MTHFR (64.1%), MTHFR 1298 (29.1%), NR3C1 1088 (0%), RFC 80 (79.6%), TPMT combined genotype (7%), VDR intron 8 (10.7%), VDR FokI (67%), incidence of mutant was higher in GSTM1 deletion, lower in MTHFR 1298, TYMS enhancer repeat, and VDR intron 8 comparing with the data of Western whites (Rocha J.C. et al. Blood 2005). As we had modified the dose of anti-leukemic agents depending on the toxicity during the treatment, we analyzed the relationship between the dose percent of actually administered dose and the distribution of each mutant to find out polymorphisms affecting toxicities of chemotherapeutic drugs. The mean dose percent of mercaptopurine was lower in patients with variant TPMT then those with wild type (33.2% vs. 53.5%, P=0.04), but there was no polymorphism that influenced the dose percent of methotrexate, daunorubicin, doxorubicin, and L-asparaginase. There was no significant difference in the incidence of genotypes between risk groups and individual mutant did not affect long term survival and relapse in Korean patients with ALL. In conclusion, we found some difference in the incidence of mutant genotypes related to the pharmacogenetics of ALL between Korean and Western whites, but there was no individual genetic polymorphism that affect on the treatment outcome. We expect more extensive researches about pharmacogenetics of Korean to establish the basis for individualized therapy with the consideration of ethnical difference.

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Comparative pharmacokinetic studies of three asparaginase preparations.

Journal of Clinical Oncology ◽

10.1200/jco.1993.11.9.1780 ◽

1993 ◽

Vol 11 (9) ◽

pp. 1780-1786 ◽

Cited By ~ 221

Author(s):

B L Asselin ◽

J C Whitin ◽

D J Coppola ◽

I P Rupp ◽

S E Sallan ◽

...

Keyword(s):

Initial Dose ◽

Half Life ◽

Lymphoblastic Leukemia ◽

Pharmacokinetic Studies ◽

Serum Samples ◽

E Coli ◽

Significant Difference ◽

History Of ◽

Repeated Use ◽

Repeated Doses

PURPOSE As part of pharmacologic studies of asparaginase (ASNase), we determined the half-life of ASNase activity and protein, and the effect of dose, repeated doses, different drug preparations, and hypersensitivity reactions on the half-life (t1/2) of serum ASNase activity. PATIENTS AND METHODS We measured ASNase activity (spectrophotometric assay) in serum samples obtained from patients with acute lymphoblastic leukemia (ALL) at various times during their therapy with intramuscular ASNase. ASNase protein was measured by enzyme-linked immunoadsorbent assay (ELISA). RESULTS Studies following the initial dose of Escherichia coli-derived ASNase demonstrated no difference in apparent t1/2 following 25,000 IU/m2 versus 2,500 IU/m2 (1.24 v 1.35 days, P = .2). The apparent t1/2s following maintenance doses of E coli ASNase (middle dose t1/2, 1.28 days, or last dose t1/2, 1.14 days) showed no difference when compared with the initial dose of ASNase (P = .3 to .9). There was no significant difference between the apparent t1/2s of ASNase activity and ASNase protein (n = 8, P = .2 to .6). The serum t1/2 was 0.65 and 5.73 days for patients receiving Erwinia or polyethylene glycol (PEG)-modified E coli ASNase, respectively, as the induction dose. ASNase activity was undetectable in sera of four patients studied in the week following an anaphylactic reaction to E coli ASNase and the t1/2 was significantly shorter in five patients with a history of allergic reaction to E coli ASNase who were studied following a dose of PEG ASNase, (t1/2, 1.80 days). CONCLUSION We conclude that (1) the apparent t1/2 of ASNase is dependent on enzyme preparation used, but is not affected by dose or by repeated use; (2) the apparent t1/2 of E coli ASNase as a protein is the same as the apparent t1/2 of enzymatic activity; and (3) patients who have had a hypersensitivity reaction to E coli ASNase have a decreased apparent t1/2 with both E coli and PEG ASNase.

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