Outcomes of Low-Intensity Treatment of Acute Lymphoblastic Leukemia at Butaro Cancer Center of Excellence in Rwanda

Purpose Children with acute lymphoblastic leukemia (ALL) in low-income countries have disproportionately lower cure rates than those in high-income countries. At Butaro Cancer Center of Excellence (BCCOE), physicians treated patients with ALL with the first arm of the Hunger Protocol, a graduated-intensity method tailored for resource-limited settings. This article provides the first published outcomes, to our knowledge, of patients with ALL treated with this protocol. Methods This is a retrospective descriptive study of patients with ALL enrolled at BCCOE from July 1, 2012 to June 30, 2014; data were collected through December 31, 2015. Descriptive statistics were used to calculate patient demographics, disease characteristics, and outcomes; event-free survival was assessed at 2 years using the Kaplan-Meier method. Results Forty-two consecutive patients with ALL were included. At the end of the study period, 19% (eight) were alive without evidence of relapse: three completed treatment and five were continuing treatment. Among the remaining patients, 71% (30) had died and 10% (four) were lost to follow-up. A total of 83% (25) of the deaths were disease related, 3% (one) treatment-related, and 13% (four) unclear. Event-free survival was 22% (95% CI, 11% to 36%), considering lost to follow-up as an event, and 26% (95% CI, 13% to 41%) if lost to follow-up is censored. Conclusion As expected, relapse was the major cause of failure with this low-intensity regimen. However, toxicity was acceptably low, and BCCOE has decided to advance to intensity level 2. These results reflect the necessity of a data-driven approach and a continual improvement process to care for complex patients in resource-constrained settings.

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Chemotherapy in 998 unselected childhood acute lymphoblastic leukemia patients. Results and conclusions of the multicenter trial ALL-BFM 86

Blood ◽

10.1182/blood.v84.9.3122.3122 ◽

1994 ◽

Vol 84 (9) ◽

pp. 3122-3133 ◽

Cited By ~ 414

Author(s):

A Reiter ◽

M Schrappe ◽

WD Ludwig ◽

W Hiddemann ◽

S Sauter ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Risk Group ◽

Lymphoblastic Leukemia ◽

Multicenter Trial ◽

Low Risk ◽

Event Free Survival ◽

Free Survival ◽

Risk Patients ◽

To Receive

Abstract In trial ALL-BFM 86, the largest multicenter trial of the Berlin- Frankfurt-Munster (BFM) study group for childhood acute lymphoblastic leukemia (ALL), treatment response was used as an overriding stratification factor for the first time. In the previous trial ALL-BFM 83, the in vivo response to initial prednisone treatment was evaluated prospectively. A blast cell count of > or = 1,000/microL peripheral blood after a 7-day exposure to prednisone and one intrathecal dose of methotrexate (MTX) identified 10% of the patients as having a significantly worse prognosis. In trial ALL-BFM 86 patients with > or = 1,000/microL blood blasts on day 8 were included in an experimental branch EG. Patients with < 1,000/microL blood blasts on day 8 were stratified by their leukemic cell burden into two branches, Standard Risk Group (SRG) and Risk Group (RG). SRG patients received an eight- drug induction followed by consolidation protocol M (6-mercaptopurine, high-dose [HD] MTX 4 x 5 g/m2) and maintenance. RG patients were treated with an additional eight-drug reinduction element. For EG patients protocol M was replaced by protocol E (prednisone, HD-MTX, HD- cytarabine, ifosfamide, mitoxantrone). All patients received intrathecal MTX therapy; only those of branches RG and EG received cranial irradiation. In branch RG, patients were randomized to receive or not to receive late intensification (prednisone, vindesine, teniposide, ifosfamide, HD-cytarabine) in the 13th month. During the trial reinduction therapy was introduced in branch SRG, because in the follow-up of trial ALL-BFM 83 the randomized low-risk patients receiving reinduction did significantly better. Nine hundred ninety- eight evaluable patients were enrolled, 28.6% in SRG, 61.1% in RG, 10.3% in EG. At a median follow-up of 5.0 (range 3.4 to 6.9) years, the estimated 6-year event-free survival was 72% +/- 2% for the study population, 58% +/- 5% in branch SRG for the first 110 patients without reinduction therapy, 87% +/- 3% for the next 175 patients with reinduction therapy, 75% +/- 2% in branch RG, and 48% +/- 5% in branch EG. Late intensification did not significantly affect treatment outcome of RG patients; however, only 23% of the eligible patients were randomized. Prednisone poor response remained a negative prognostic parameter despite intensified therapy. The results confirmed the benefit of intensive reinduction therapy even for low-risk patients. The strategy of induction, consolidation, and intensive reinduction may offer roughly 75% of unselected childhood ALL patients the chance for an event-free survival.

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Changing the Fate of Children with Acute Lymphoblastic Leukemia (ALL) in a Limited Resources Setting

Blood ◽

10.1182/blood-2019-132205 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5075-5075

Author(s):

Yajaira Valentine Jimenez-Antolinez ◽

Julia Esther Colunga Pedraza ◽

José Eduardo Mares-Gil ◽

Emma Lizeth Estrada ◽

Jesus Mauricio Gonzalez-Diaz ◽

...

Keyword(s):

Overall Survival ◽

Acute Lymphoblastic Leukemia ◽

Relapse Rate ◽

Lymphoblastic Leukemia ◽

Limited Resource ◽

Outcome Evaluation ◽

Event Free Survival ◽

Free Survival ◽

Early Relapse

Introduction Pediatric acute Lymphoblastic Leukemia (ALL) patients have about 90% overall survival (OS) in developed countries. However, many children in low-middle income countries (LMIC) do not have access to appropriate drugs at optimal doses, a multidisciplinary medical team, laboratory resources for diagnosis and follow-up, and appropriate support therapy for morbidities and treatment-related toxicities. A 50-60% five-year OS has been reported in children with ALL in Mexico, and our center is not the exception. This low survival rate has pushed Mexican centers to develop strategies highlighting collaboration between centers with economic, research and teaching resources ("Mexico en Alianza con St. Jude MAS"), and outpatient treatment. However, each center must adapt their chemotherapy protocol to its own supplies and possibilities. We report the results of a risk adapted therapy protocol in a limited-resource treatment setting. Materials and Methods All pediatric patients with a diagnosis of ALL from January 2017 to December 2018 were classified according to risk as shown in Figure 1. Depending on risk classification, modifications to the induction, consolidation and intermediate maintenance regimens were made. The higher the risk, the higher the intensity of the regimen, as defined by the number of anthracycline doses, the presence or absence of high-dose methotrexate, and the duration of the consolidation and maintenance phases (Table 1). Demographic data is reported using distribution analysis, and the Kaplan-Meier method is used to analyze and predict overall survival, event-free survival (EFS) and relapse. Our results were compared with previous results from our institution. Results There were 35 male and 25 female patients; median age at diagnosis was 5.5. B-cell and T-cell lymphoblastic leukemia was the diagnosis in 57 (95%), and 3 (5%) patients, respectively, with a follow-up of 16 (8-30) months. Twenty-three (38%), 21 (35%), and 16 (26%) children were classified as high, intermediate and low risk ALL, respectively. After one week of corticosteroids 46 (77%) of patients had a good response. At the end of induction 53 patients had an evaluable MRD (88%), out of which 9 were positive (17%). Median follow-up was 16 (0.6-30) months. Mortality at induction was 6 (10%) patients. Very early relapse was observed in 3(5%) of patients. Estimated 2-year relapse rate was 6%, event-free survival was 84.1%, and OS was 85%. A comparison of results obtained with previous regimens (protocols 1 and 2) and the risk-adapted treatment (protocol 3) is observed in Table 2. Conclusions The implementation of a modified chemotherapy regimen based on adjusted stratification risk was associated to improved responses as reflected by MRD. A decrease in very early relapse rate to 5%, without increasing the toxicity and death during induction was observed. Periodic and prospective outcome evaluation in a limited-resource setting is fundamental to adjust and to standardize therapy. Long-term follow-up of this patient group is required to compare OS and EFS at 5 years. This is a preliminary report, but it seems that we are changing the fate of Mexican children with ALL. Disclosures Gomez-Almaguer: Amgen: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Teva: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau.

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Excellent Outcome of Children with Down Syndrome (DS) and Acute Lymphoblastic Leukemia (ALL) Treated on Dana-Farber Cancer Institute (DFCI) ALL Consortium Protocols 00-001 and 05-001

Blood ◽

10.1182/blood.v128.22.761.761 ◽

2016 ◽

Vol 128 (22) ◽

pp. 761-761

Author(s):

Uma H. Athale ◽

Maneka Puligandla ◽

Kristen E. Stevenson ◽

Barbara L. Asselin ◽

Luis A. Clavell ◽

...

Keyword(s):

Down Syndrome ◽

Acute Lymphoblastic Leukemia ◽

De Novo ◽

Lymphoblastic Leukemia ◽

Event Free Survival ◽

Free Survival ◽

Children With Down Syndrome ◽

Dana Farber Cancer Institute ◽

Induction Failure

Abstract Background Children with Down syndrome (DS) and acute lymphoblastic leukemia (ALL) are shown to have increased therapy-related morbidity and mortality. Hence, therapy modifications and/or dose-reductions are common treatment strategies for this patient (pt) population. Dana-Farber Cancer Institute (DFCI) ALL Consortium protocols have used same risk-stratified treatment for children with and without DS and ALL. Aim: To define the toxicity profile and outcome of children with DS and de novo ALL treated on DFCI ALL Consortium therapy protocols 00-001 and 05-001 using therapy identical to non-DS patients. Methods: Demographic, clinical and outcome data of DS and non-DS patients enrolled on the DFCI ALL protocols 00-001 (2000-2004) and 05-001 (2005-2011) were analyzed. Risk categorization and protocol therapy have previously been described (J Clin Oncol 2013; 31:1202-10; Lancet Oncol 2015;16:1677-90). On both protocols, DS ALL pts were treated identically to non-DS pts without any dose reduction or modification, except for the option for DS ALL pts to receive 3 doses of leucovorin after IT methotrexate. Fisher's exact test was used to compare toxicities in the DS and non-DS pts and Gray test was used to compare the cumulative incidence of fracture and osteonecrosis. Overall survival (OS) was defined as time from registration to death. Event-free survival (EFS) was defined as time from registration to first event (defined as induction failure, relapse, second malignant neoplasm (SMN) or death due to any cause). Induction failure and induction death were included as events at time zero. Disease-free survival (DFS) was defined as time from complete remission (CR) to relapse, SMN or death. Pts without an event were censored at the last known follow-up. The Kaplan-Meier method was used for survival estimation and Greenwood's formula for calculation of 95% confidence interval (CI) of survival estimates. Outcome of DS patients was also examined using Ponte di Legno (PdL) risk group [Low risk (LR) was defined as age at diagnosis ≤ 6 yr. and white cell count < 10X109/L and, remainder as high risk (HR)].(Blood 2014;123:70-7). Two-sided p values <0.05 were considered significant. Results: Of 1286 eligible pts aged 1-18 yrs. with de novo ALL enrolled on protocols 00-001 and 05-001, 38 (3%) had DS. There was no difference in demographic or presenting clinical features between DS and non-DS ALL pts except immunophenotype (absence of T-ALL in DS vs 11.7% in non-DS, p=0.017) and presence of high hyperdiploidy (51-65 chromosomes) (8.8% in DS vs 25.1% in non-DS, p=0.027) (Table 1). Two DS-ALL pts withdrew from the study after achieving CR. There was no difference in the CR rates (DS: 100% vs non-DS: 95.2%, p=0.47) or proportion of pts with low end of induction minimal residual disease (MRD) between DS and non-DS groups (p=0.73). Toxicities were comparable except DS pts had significantly higher rates of ≥Grade 3 mucositis (data available for protocol 05-001 only) (DS: 52.0% vs. non-DS: 12.0%, p<0.001), non-CNS thrombosis/bleed (18.4% vs. 8.2%; p=0.036), and seizure (15.8% vs. 4.7%, p=0.010). DS pts also had marginally higher rate of bacterial and fungal infections (55.3% vs. 41.3%, p=0.096) (Table 2). All 38 DS pts achieved a CR and there were 4 relapses with 1 death due to disease. There were no treatment-related deaths in DS-ALL pts. With a median follow-up of 6.2 yrs. the 5-yr EFS, DFS, and OS of DS pts were similar to non-DS pts (90.7% [81.1-100.0] vs. 83.7% [81.7-85.9]; 90.7% [81.1-100.0] vs. 87.4% [85.5-89.3]; 97.1% [91.8-100.0] vs. 91.4% [89.8-93.0]), with the 95% CI overlapping for each comparison (Figures 1a and 1b). There was no difference in outcomes of DS-ALL PdL LR pts (n=13) compared to PdL HR pts (n=25) (5-yr EFS 90.0% [73.2-100.0]. vs. 91.0% [79.9-100.0]; 5-yr OS 100.0% [100.0-100.0] vs. 95.8% [88.2-100.0]). Conclusion: DS pts treated on DFCI ALL Consortium protocols without dose reduction or modifications achieved similar outcomes to non-DS pts. DS pts had a higher frequency of mucositis, infection, and seizures, but did not experience any treatment-related deaths. Other than a higher risk of thrombotic complications, they did not develop excessive toxicity to asparaginase. The low rates of relapse and toxicity-related mortality support the approach of unified therapy protocol for DS and non-DS ALL pts with emphasis on supportive care interventions to prevent toxicities. Overall and event free survival Overall and event free survival Disclosures Asselin: Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Sigma Tau Pharamceuticals: Consultancy.

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L-Asparaginase Toxicity in the Treatment of Children and Adolescents with Acute Lymphoblastic Leukemia

Journal of Clinical Medicine ◽

10.3390/jcm10194419 ◽

2021 ◽

Vol 10 (19) ◽

pp. 4419

Author(s):

Madalina-Petronela Schmidt ◽

Anca-Viorica Ivanov ◽

Daniel Coriu ◽

Ingrith-Crenguta Miron

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Children And Adolescents ◽

Lymphoblastic Leukemia ◽

Event Free Survival ◽

Long Term Outcomes ◽

Term Survival ◽

Free Survival ◽

The Impact

Asparaginase is a basic component of chemotherapy in pediatric acute lymphoblastic leukemia (ALL) and has played a crucial role in improving the long-term survival of this disease. The objectives of this retrospective study were to elucidate the toxicity profile associated with asparaginase in children and adolescents with ALL, to analyze the impact of each type of toxicity on long-term outcomes, and to identify risk factors. We analyzed the medical charts of 165 patients diagnosed with ALL at Sf. Maria Iasi Children’s Hospital from 2010 to 2019 and treated according to a chemotherapeutic protocol containing asparaginase. The median duration of follow-up was 5 years (0.1–11.5 years). Groups of patients with specific types of toxicity were compared to groups of patients without toxicity. We found the following incidence of asparaginase-associated toxicity: 24.1% clinical hypersensitivity, 19.4% hepatotoxicity, 6.7% hypertriglyceridemia, 4.2% hyperglycemia, 3.7% osteonecrosis, 3% pancreatitis, 2.4% thrombosis, and 1.2% cerebral thrombosis. Overall, 82 patients (49.7%) had at least one type of toxicity related to asparaginase. No type of toxicity had a significant impact on overall survival or event-free survival. Being older than 14 years was associated with a higher risk of osteonecrosis (p = 0.015) and hypertriglyceridemia (p = 0.043) and a lower risk of clinical hypersensitivity (p = 0.04). Asparaginase-related toxicity is common and has a varied profile, and its early detection is important for realizing efficient and appropriate management.

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Prognostic Significance of Blasts in the Cerebrospinal Fluid Without Pleiocytosis or a Traumatic Lumbar Puncture in Children With Acute Lymphoblastic Leukemia: Experience of the Dutch Childhood Oncology Group

Journal of Clinical Oncology ◽

10.1200/jco.2005.03.9727 ◽

2006 ◽

Vol 24 (15) ◽

pp. 2332-2336 ◽

Cited By ~ 64

Author(s):

D. Maroeska W.M. te Loo ◽

Willem A. Kamps ◽

Anna van der Does-van den Berg ◽

Elisabeth R. van Wering ◽

Siebold S.N. de Graaf

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Lumbar Puncture ◽

Cox Regression ◽

Lymphoblastic Leukemia ◽

Prognostic Significance ◽

Event Free Survival ◽

Free Survival ◽

Cox Regression Analysis ◽

Significant Difference

Purpose To determine the significance of blasts in the CSF without pleiocytosis and a traumatic lumbar puncture in children with acute lymphoblastic leukemia (ALL). Patients and Methods We retrospectively studied a cohort of 526 patients treated in accordance with the virtually identical Dutch protocols ALL-7 and ALL-8. Patients were classified into five groups: CNS1, no blasts in the CSF cytospin; CNS2, blasts present in the cytospin, but leukocytes less than 5/μL; CNS3, blasts present and leukocytes more than 5/μL. Patients with a traumatic lumbar puncture (TLP; > 10 erythrocytes/mL) were classified as TLP+ (blasts present in the cytospin) or TLP− (no blasts). Results Median duration of follow-up was 13.2 years (range, 6.9 to 15.5 years). Event-free survival (EFS) was 72.6% (SE, 2.5%) for CNS1 patients (n = 304), 70.3% (SE, 4.7%) for CNS2 patients (n = 111), and 66.7% (SE, 19%) for CNS3 patients (n = 10; no significant difference in EFS between the groups). EFS was 58% (SE, 7.6%) for TLP+ patients (n = 62) and 82% (SE, 5.2%) for TLP− patients (n = 39; P < .01). Cox regression analysis identified TLP+ status as an independent prognostic factor (risk ratio, 3.5; 95% CI, 1.4 to 8.8; P = .007). Cumulative incidence of CNS relapses was 0.05 and 0.07 in CNS1 and CNS2 patients, respectively (not statistically significant). Conclusion In our experience, the presence of a low number of blasts in the CSF without pleiocytosis has no prognostic significance. In contrast, a traumatic lumbar puncture with blasts in the CSF specimen is associated with an inferior outcome.

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The Importance of Hypersensitivity in Childhood Acute Lymphoblastic Leukemia

Blood ◽

10.1182/blood.v124.21.5242.5242 ◽

2014 ◽

Vol 124 (21) ◽

pp. 5242-5242

Author(s):

Yesim Oymak ◽

Sultan Aydin Koker ◽

Tuba Hilkay Karapinar ◽

Dilek Ince ◽

Yilmaz Ay ◽

...

Keyword(s):

Overall Survival ◽

Acute Lymphoblastic Leukemia ◽

Lymphoblastic Leukemia ◽

Survival Rates ◽

Dramatic Improvement ◽

Event Free Survival ◽

Free Survival ◽

Erwinia Asparaginase ◽

Overall Survival Rates

Abstract Background Acute lymphoblastic leukemia (ALL) remains the most common pediatric malignancy in the world. Overall survival rates have increased from 30% in the 1960s to 90% in past 10 years. Enabling this dramatic improvement are the multi-agent chemotherapeutic regimens in which asparaginase is cornerstone. Unfortunately, hypersensitivity to asparaginase has been a commonly-reported adverse event, associated with inferior outcomes in ALL. Methods Between January 1, 2005 and December 31, 2012, 97 patients were enrolled in the study. Selection criteria included those were diagnosed with ALL and given the ALL-BFM-2000 protocol at Dr. Behcet Uz Children's Hospital. Data regarding age at diagnosis, sex, follow-up duration, hypersensitivity of L- asparaginase, status of relapse and outcome were gathered from the patients’ files. The event-free survival (EFS) and the overall survival (OS) of the patients who developed and did not develop hypersensitivity to L- asparaginase were compared. Peg-asparaginase was given to patients who developed L- asparaginase hypersensitivity, and erwinia asparaginase was given if the patients developed peg-asparaginase. The asparaginase activity could not be measured. Kaplan mayer test was used to calculate the EFS and the OS. Results A total of 97 patients were evaluated. Thirty-two were standard risk, 49 were moderate risk, and 15 were high risk. 61 patients were male, and 36 were female. The median age (range) at diagnosis was 5 (1-15) years. Median (range) follow-up duration was 5.1 (0.08-7.3) years. Of the 97 patients, 28 (29.2%) developed L-asparaginase hypersensitivity. The event-free survival was 84.5 ± 4.6%, and 62.6 ± 9.4% for patients who developed and did not develop hypersensitivity, respectively (p=0.01). The overall survival rates were 89.2 ± 3.9 % and 74.6 ± 8.3% for patients who developed and did not develop hypersensitivity, respectively (p=0,07). Figure 1. Event-free survival. The five years EFS±SE for the patients who developed and did not develop native L- asparaginasehypersensitivity were 84.5 ± 4.6% and 62.6 ± 9.4%, respectively (p=0.01). Figure 1. Event-free survival. The five years EFS±SE for the patients who developed and did not develop native L- asparaginasehypersensitivity were 84.5 ± 4.6% and 62.6 ± 9.4%, respectively (p=0.01). Conclusions This study demonstrated that EFS was lower in patients with L-asparaginase hypersensitivity than those without hypersensitivity, although there were no differences in terms of OS. All of the patients with hypersensitivity received a sufficient dose of peg-asparaginase or erwinia asparaginase according to the ALL-BFM-2000 protocol. The lower EFS for patients who were switched to peg-asparaginase because of L- asparaginase may be explained by silent inactivation of peg-asparaginase. If the activity of asparaginase could not be measured, it could be preferable to switch to erwinia asparaginase. Disclosures No relevant conflicts of interest to declare.

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Immunologic, cytogenetic, and clinical characterization of childhood acute lymphoblastic leukemia with the t(1;19) (q23; p13) or its derivative.

Journal of Clinical Oncology ◽

10.1200/jco.1994.12.12.2601 ◽

1994 ◽

Vol 12 (12) ◽

pp. 2601-2606 ◽

Cited By ~ 66

Author(s):

C H Pui ◽

S C Raimondi ◽

M L Hancock ◽

G K Rivera ◽

R C Ribeiro ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Lymphoblastic Leukemia ◽

Childhood Acute Lymphoblastic Leukemia ◽

Event Free Survival ◽

Balanced Translocation ◽

Free Survival ◽

Antigen Profile ◽

Treatment Responses

PURPOSE To evaluate the immunophenotypes, karyotypes, and clinical features, including treatment responses, of patients with childhood acute lymphoblastic leukemia (ALL) and either a t(1;19)(q23;p13) or a der(19)t(1;19)(q23;p13) translocation. PATIENTS AND METHODS The lymphoblasts of 45 patients with a balanced translocation, t(1;19) or its derivative form, der(19)t(1;19), were analyzed by cytogenetic and immunologic methods for differences that might suggest distinct subtypes of ALL. This cohort was treated in four consecutive clinical trials with a median overall follow-up duration of 7 years. RESULTS A pre-B immunophenotype was found in 10 cases with the balanced t(1;19) and 31 with the unbalanced der(19)t(1;19). The four remaining cases, each with a derivative t(1;19), were classified as early pre-B ALL. The characteristic surface antigen profile of the 41 pre-B cases was CD19+/CD10+/CD22+/CD34-/CD20+/-, whether the translocation was balanced or derivative. In contrast to the four early pre-B cases, which had hyperdiploid karyotypes (> 50 chromosomes), the pre-B cases were primarily pseudodiploid. Comparison of presenting clinical and laboratory features, as well as event-free survival, failed to disclose any differences that would warrant separation of pre-B cases with a balanced or derivative translocation. However, neither subgroup responded to therapy as well as patients with early pre-B ALL, each of whom remains in complete remission for > or = 3 years. CONCLUSION The t(1;19) and the der(19)t(1;19) identify a relatively homogeneous group of patients with pre-B ALL, who can be expected to respond similarly to intensive chemotherapy. The exceptional cases have an early pre-B phenotype with hyperdiploid karyotypes and appear to have favorable prognosis.

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Bony Morbidity in Children Treated for Acute Lymphoblastic Leukemia

Journal of Clinical Oncology ◽

10.1200/jco.2001.19.12.3066 ◽

2001 ◽

Vol 19 (12) ◽

pp. 3066-3072 ◽

Cited By ~ 170

Author(s):

Adam J. Strauss ◽

Joyce T. Su ◽

Virginia M. Kimball Dalton ◽

Richard D. Gelber ◽

Stephen E. Sallan ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Lymphoblastic Leukemia ◽

Older Children ◽

Event Free Survival ◽

Free Survival ◽

Increased Risk ◽

High Incidence ◽

Pediatric All ◽

Male Sex

PURPOSE: Corticosteroids are widely used in the treatment of acute lymphoblastic leukemia (ALL). To determine the frequency of corticosteroid-associated bony morbidity in children with ALL, we retrospectively evaluated the incidence of fractures and osteonecrosis (ON) on two consecutive pediatric ALL protocols. PATIENTS AND METHODS: One hundred seventy-six consecutive children were treated for ALL between 1987 and 1995 at the Dana-Farber Cancer Institute and Children’s Hospital. Prednisone was used as the corticosteroid during postremission therapy from 1987 to 1991, and dexamethasone was used from 1991 to 1995. Medical records for all patients were reviewed to assess the occurrence of fractures and ON. RESULTS: With a median follow-up of 7.6 years, the 5-year cumulative incidence (CI) ± SE of any bony morbidity for the 176 patients was 30% ± 4%, with a 5-year CI of fractures of 28% ± 3% and of ON of 7% ± 2%. With multivariate analysis, independent predictors of bony morbidity included age 9 to 18 years at diagnosis (P < .01), male sex (P < .01), and treatment with dexamethasone (P = .01). Dexamethasone was associated with a higher risk of fractures (5-year CI, 36% ± 5% v 20% ± 4% with prednisone; P = .04), but not ON (P = .40). The 5-year event-free survival for the 176 patients was 79% ± 3%. CONCLUSION: Children treated for ALL had a high incidence of fractures and ON. Older children, boys, and patients receiving dexamethasone were at increased risk for the development of bony morbidity. Future studies should attempt to minimize corticosteroid-associated bony morbidity without compromising clinical efficacy.

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Risk Factors in Childhood Acute Lymphoblastic Leukemia: A Single Center Experience in a Developing Country.

Blood ◽

10.1182/blood.v106.11.4475.4475 ◽

2005 ◽

Vol 106 (11) ◽

pp. 4475-4475

Author(s):

Sema S. Anak ◽

Leyla Agaoglu ◽

Arzu Akcay ◽

Ebru T. Saribeyoglu ◽

Didem Y. Atay ◽

...

Keyword(s):

Risk Factors ◽

Bone Marrow ◽

Acute Lymphoblastic Leukemia ◽

High Risk ◽

Lymphoblastic Leukemia ◽

Event Free Survival ◽

Free Survival ◽

Risk Patients ◽

Pediatric All

Abstract Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy, with the survival rates up to 80–90%, but in high-risk patients the survival rate is still unsatisfactory. The aim of this study is to analyze the pediatric ALL data of a single pediatric university center between 1987–2005 retrospectively to identify risk factors effecting the event free survival (EFS). In order to determine the risk factors possibly effecting the survival, we analyzed gender, age, physical examination findings, blood cell count, FAB morphology, immunophenotyping results, translocations and extramedullary involvement. During the same period, chemotherapy regimens used and response to these protocols were also analyzed. A total of 372 cases [220 male (60%) and 151 female (41%)] were diagnosed and treated in our center between 1987–2005. The age distribution was as follows: 7% patients under 2 years, 68% between 2–10 years, 25% above 10 years of age. At diagnosis, 76% patients had a hemoglobin level <10gr/dl, 56% WBC >10.000/mm3, 74% platelet <100.000/mm3. Primary CNS involvement was positive in 2.5%, mediastinal mass in 8% of all patients. The morphological subtypes were as follows: L1 64%, L2 32%, L3 4%. Immunophenotypic results revealed T ALL in 22%, mature B ALL in 8% and B ALL (common, pre B, proB) in 70%. All patients received CCG modified BFM protocol (80% of all patients) until 1999. Since then high-risk patients were treated with the augmented BFM protocol and L3 patients BFM NHL 95 Protocol, while standard risk patients continued to get the CCG modified BFM protocol. The remission rate at day 33 was 97.8%. Eighty-one patients relapsed (68% patients isolated bone marrow, 16% bone marrow + extramedullary, 9% CNS, 7% testes). According to the univariate analysis of our patient population, the factors negatively effecting the EFS were age <1 year, hepatomegaly >2cm., white blood cell >50.000/mm3 and platelet count <20.000/mm3, L3 FAB morphology, ≥M2 bone marrow status at day 14; CD3, HLADR, CD45 and Tdt negativity. According to the multivariate analysis the most important negative risk factors effecting the EFS were age <1 year, hepatomegaly >2cm. and ≥M2 bone marrow status at day 14 and CD 45 negativity. After a follow up of 72±59 months (1–300 months) 58% of patients are alive & well, 28% were lost to follow up and 14% patients succumbed to death. Overall survival (OS) for 60&120 months follow up were 83%, 83% and event free survival (EFS) 72%, 70% respectively. In conclusion, in ALL patients risk assessment is very important to conduct appropriate therapy. Identifying such factors and implementing risk adapted therapy will improve our treatment results decreasing the toxicity rates in pediatric ALL. Therefore treatment of all ALL patients still remains a challenge.

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Efficacy and Toxicity of Pegaspargase and Calaspargase Pegol in Childhood Acute Lymphoblastic Leukemia: Results of DFCI 11-001

Journal of Clinical Oncology ◽

10.1200/jco.20.03692 ◽

2021 ◽

pp. JCO.20.03692

Author(s):

Lynda M. Vrooman ◽

Traci M. Blonquist ◽

Kristen E. Stevenson ◽

Jeffrey G. Supko ◽

Sarah K. Hunt ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Residual Disease ◽

Lymphoblastic Leukemia ◽

Lymphoblastic Lymphoma ◽

Event Free Survival ◽

Free Survival ◽

Induction Dose ◽

Dosing Strategies ◽

Asparaginase Activity

PURPOSE Dana-Farber Cancer Institute Acute Lymphoblastic Leukemia (ALL) Consortium Protocol 11-001 assessed efficacy and toxicity of calaspargase pegol (calaspargase), a novel pegylated asparaginase formulation with longer half-life, compared with the standard formulation pegaspargase. METHODS Patients age 1 to ≤ 21 years with newly diagnosed ALL or lymphoblastic lymphoma were randomly assigned to intravenous pegaspargase or calaspargase, 2,500 IU/m2/dose. Patients received one induction dose. Beginning week 7, pegaspargase was administered every 2 week for 15 doses and calaspargase every 3 week for 10 doses (30 weeks). Serum asparaginase activity (SAA) (≥ 0.1 IU/mL considered therapeutic) was assessed 4, 11, 18, and 25 days after the induction dose and before each postinduction dose. RESULTS Between 2012 and 2015, 239 eligible patients enrolled (230 ALL, nine lymphoblastic lymphoma); 120 were assigned to pegaspargase and 119 to calaspargase. After the induction dose, SAA was ≥ 0.1 IU/mL in ≥ 95% of patients on both arms 18 days after dosing. At day 25, more patients had SAA ≥ 0.1 IU/mL with calaspargase (88% v 17%; P ˂ .001). Postinduction, median nadir SAAs were similar (≥ 1.0 IU/mL) for both arms. Of 230 evaluable patients, 99% of pegaspargase and 95% of calaspargase patients achieved complete remission ( P = .12), with no difference in frequency of high end-induction minimal residual disease among evaluable patients with B acute lymphoblastic leukemia (B-ALL). There were no differences in frequencies of asparaginase allergy, pancreatitis, thrombosis, or hyperbilirubinemia. With 5.3 years median follow-up, 5-year event-free survival for pegaspargase was 84.9% (SE ± 3.4%) and 88.1% (± SE 3.0%) for calaspargase ( P = .65). CONCLUSION Every 3-week calaspargase had similar nadir SAA, toxicity, and survival outcomes compared with every 2-week pegaspargase. The high nadir SAA observed for both preparations suggest dosing strategies can be further optimized.

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