Can Less Intensive Chemotherapy and an Autotransplant Cure Adult T-Cell Acute Lymphoblastic Leukemia?

2019 ◽  
Vol 143 (2) ◽  
pp. 131-139 ◽  
Author(s):  
Elena Parovichnikova ◽  
Vera Troitskaya ◽  
Andrey Sokolov ◽  
Olga Gavrilina ◽  
Zalina Akhmerzaeva ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Blood Cells ◽  
Lymphoblastic Leukemia ◽  
White Blood Cells ◽  
High Dose ◽  
Consolidation Chemotherapy ◽  
Free Survival ◽  
Number Of Patients ◽  
Cell Acute Lymphoblastic Leukemia

T-cell acute lymphoblastic leukemia (T-ALL) is a rare disease usually treated with intensive, high-dose consolidation chemotherapy followed by an allotransplant in a substantial number of patients. The data of the RALL-2009 study on 125 adult T-ALL patients suggest that similar total chemotherapy doses given less intensively over a longer interval without interruptions and with an auto- rather than an allotransplant produce outcomes like current more intensive protocols and an allotransplant: 9-year cumulative incidence of relapse (CIR), leukemia-free survival (LFS), and survival were 24% (95% CI 16–33%), 70% (95% CI 59–79%) and 62% (95% CI 51–72%). In a landmark analysis, subjects achieving a complete remission and receiving an autotransplant had a lower 9-year CIR (9% [95% CI 2–22%] vs. 29% [95% CI 16–43%]; p = 0.0076) and better LFS (91% [95% CI 79–98%] vs. 58% [95% CI 41–74%]; p = 0.0009) and survival (92% [95% CI 77–99%] vs. 60% [95% CI 44–77%]; p = 0.001) compared with subjects not receiving an autotransplant. In a multivariate analysis, white blood cells ≥100 × 109/L at study entry were significantly associated with worse LFS (HR = 2.842 [95% CI 1.131–7.143]; p = 0.0263) and survival (HR = 6.085 [95% CI 1.918–19.3]; p = 0.0022) because of more early deaths (HR = 2.42 [95% CI 1.04–5.67]; p = 0.041). Receiving an autotransplant correlated with a lower CIR (HR = 0.23 [95% CI 0.07–0.73]; p = 0.0136) and better LFS (HR = 0.27 [95% CI 0.08–0.85]; p = 0.0256) and survival (HR = 0.158 [95% CI 0.045–0.550]; p = 0.0037).

The Outcome of Children with T-Cell Acute Lymphoblastic Leukemia: A Single Institution Experience.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4526-4526
Author(s):  
Ali Al-Ahmari ◽  
Asim F. Belgaumi ◽  
Abdelmuniem Al-Dalee ◽  
Mohammed Al-Mahr ◽  
Abdulrahman Al-Musa ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Mediastinal Mass ◽  
Lymphoblastic Leukemia ◽  
Early Response ◽  
Current Treatment ◽  
High Dose ◽  
Childhood All ◽  
Number Of Patients ◽  
Cell Acute Lymphoblastic Leukemia

Abstract Background: T-cell acute lymphoblastic leukemia (T-ALL) constitutes 10% to 15 % of childhood ALL cases in the Western literature. However, higher proportions, up to 40%, have been reported in certain developing countries. While the outcome of childhood T-ALL has improved dramatically over the last decades, by using intensive multi-agent chemotherapeutic regimens, about 30% to 40% of these patients still experience relapses. Patients and methods: Medical records of the 411 pediatric patients (0–13 years old) diagnosed with ALL and treated at our institution between January 1999 and December 2004 were retrospectively reviewed. Result: Fifty-three (12.9%) of the patients had T-ALL. 52 of these were treated according to a multi-drug chemotherapy protocol, based on a modification of the St. Jude Total XIII-B protocol, including high-dose methotrexate (HD-MTX), at 2gm/m2, and non-cross-resistant drug pair administered weekly during the continuation phase. The remaining one patient received a standard ALL therapy with a single delayed intensification and anti-metabolite based maintenance therapy. Early response to induction chemotherapy was assessed using a bone marrow (BM) evaluation at Day-14 of induction. The mean age was 7.1 years and 36 patients (68%) were males. Twenty (39%), out of 51 patients with available results, had CNS involvement. Of these eight (15.5%) were categorized as CNS-3, while 12 (23.5%) were CNS-2. 50% of the patients presented with mediastinal mass. Nine (18%) of the patients with available initial WBC (n=49) had hyperleukocytosis with a WBC >100 × 109/L. 8 out of the 51 patients with a Day-14 evaluation had >5% blasts in the BM. All patients subsequently achieved remission at the end of induction. The 5-year event-free survival (EFS) and overall survival (OS) rates were 63.9% and 76.4%, respectively. 13 (24.5%) patients relapsed at a median time of one year. Six relapses occurred in the BM, 5 isolated-CNS relapses, one CNS+BM and one in the skin+BM. Only 2 of these relapsed patients are long-term survivors. The disease-related and treatment toxicity-related deaths occurred in 11(20.7%) and 2(3.7%) patients, respectively. The initial WBC count, mediastinal mass, CNS status or the Day-14 BM results were not found to impact negatively on the outcome, by multivariate analysis. Conclusion: Our current treatment strategy has resulted in potential cure for about two-thirds of the patients with childhood T-ALL. However, a significant number of patients do fail treatment and novel strategies need to be devised for them. Unfortunately, as specific clinical features that could determine outcome have not as yet been identified, risk stratification, similar to that utilized for precursor-B cell ALL, is not feasible. Further study into risk determining variables at the molecular level, such as activating NOTCH1 mutations, may be promising in predicting outcome and determining treatment intensity in children with T-ALL.

High-Dose Cyclophosphamide for the Treatment of Refractory T-Cell Acute Lymphoblastic Leukemia in Children

2014 ◽  
Vol 36 (5) ◽  
pp. e265-e270 ◽  
Author(s):  
Rachel Kobos ◽  
Neerav Shukla ◽  
Thomas Renaud ◽  
Susan E. Prockop ◽  
Farid Boulad ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
High Dose ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Leukemia In Children

scholarly journals High-dose methotrexate vs. Capizzi methotrexate for the treatment of childhood T-cell acute lymphoblastic leukemia

2018 ◽  
Vol 10 ◽  
pp. 44-51 ◽  
Author(s):  
Wasil Jastaniah ◽  
Naglla Elimam ◽  
Khalid Abdalla ◽  
Aeshah A. AlAzmi ◽  
Mohammed Aseeri ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
High Dose ◽  
High Dose Methotrexate ◽  
Dose Methotrexate ◽  
Cell Acute Lymphoblastic Leukemia

scholarly journals Clinical characteristics and outcomes of patients with pediatric acute lymphoblastic leukemia after induction of chemotherapy: a pilot descriptive correlational study from Palestine

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Ramzi Shawahna ◽  
Sultan Mosleh ◽  
Yahya Odeh ◽  
Rami Halawa ◽  
Majd Al-Ghoul
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
B Cell ◽  
Blood Cells ◽  
Clinical Characteristics ◽  
Lymphoblastic Leukemia ◽  
White Blood Cells ◽  
P Value ◽  
Pediatric Acute Lymphoblastic Leukemia ◽  
Pediatric All

Abstract Objective Pediatric acute lymphoblastic leukemia (ALL) is the most prevalent type of cancer among children. This study was conducted to describe and correlate the clinical characteristics and outcomes of treatment of patients with pediatric ALL in the main referral hospital in Palestine. Results Complete data of 69 patients were included in this analysis. The majority (79.7%) of the patients had B-ALL phenotype. After induction chemotherapy, remission was experienced by the vast majority of the patients and 5 (7.2%) experienced relapses. Cytogenetics for patients with B-ALL phenotype indicated that 10 (18.2%) patients had t(12, 21) translocation, 5 (9.1%) had hyperdiploidy, 4 (7.3%) had t(1, 19) translocation, and 2 (3.6%) had t(9, 22) translocation. The initial white blood cells (p value < 0.001), absolute neutrophils (p value = 0.011), and hemoglobin (p value < 0.001) were significantly lower in patients with B-cell ALL. Platelet counts were significantly lower (p value = 0.012) in patients with splenomegaly and those with bleeding symptoms (p value = 0.008). Presence of palmar pollar was positively associated (p value = 0.035) with T-cell ALL. Presence of hepatomegaly was positively associated (p value < 0.001) with splenomegaly.

scholarly journals Determining the Appropriate Treatment for T-Cell Acute Lymphoblastic Leukemia With SET-CAN/NUP214 Fusion: Perspectives From a Case Report and Literature Review

2021 ◽  
Vol 11 ◽  
Author(s):  
Na Lin ◽  
Zhenghua Liu ◽  
Yan Li ◽  
Xiaojing Yan ◽  
Lei Wang
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Complete Remission ◽  
Ex Vivo ◽  
Lymphoblastic Leukemia ◽  
Recurrent Event ◽  
High Dose ◽  
Delayed Response ◽  
Hematopoietic Stem ◽  
Cell Acute Lymphoblastic Leukemia

SET-CAN/NUP214 fusion is a recurrent event most commonly seen in T-cell acute lymphoblastic leukemia (T-ALL). It is related to resistance to glucocorticoids and chemotherapy; however, the reported prognosis of T-ALL with SET-CAN/NUP214 fusion is diverse, and the optimal treatment option remains undetermined. Here, we present the treatment process of an illuminating case of T-ALL with SET-CAN/NUP214 fusion. The patient showed early resistance to routine VICLP chemotherapy (at 15th day, 79.2% blasts), but the leukemia burden was significantly reduced after 28-day induction chemotherapy (18.85% blasts), even though she still didn’t achieve complete remission (CR) after a second course of high-dose methotrexate (3 g/m2) and pegaspargase. Ex vivo drug sensitivity screening using a panel of 165 kinds of cytotoxic drugs, targeted therapy drugs, combination chemotherapy drugs, etc., was conducted on the refractory leukemia cells, which showed extensive resistance to various regimens. Surprisingly, AML-like scheme DAE scheme (daunorubicin + cytarabine + etoposide) and carfilzomib showed the highest ex vivo inhibition rate. The patient received DAE regimen chemotherapy, and finally achieved complete remission and received allogenic hematopoietic stem cell transplantation (allo-HSCT). According to our own findings and a literature survey, we found that T-ALL patients with SET-CAN/NUP214 fusion usually shows early resistance to chemotherapy, but they have a delayed response, and the CR rate is not compromised; thus, a chemotherapy regimen featuring a 28-day long course, such as that used in GRAALL 2003 or 2005, is recommended for induction therapy. For refractory patients, AML-like therapy such as DAE or CLAG in combination with asparaginase may be beneficial. In addition, carfilzomib may be a useful therapeutic drug and is worthy of further study. Allo-HSCT improves prognosis and we recommend HSCT if possible. Additional chromosomal or molecular events may affect the prognosis, and further investigation is needed. We believe that through proper treatment, the prognosis of patients with SET-CAN/NUP214 fusion can be greatly improved, at least not worse than that of other T-ALL patients.

B Cell Aplasia In a Patient with Relapsed B Cell Acute Lymphoblastic Leukemia Following Re-Induction and Consolidation with Autologous T Cells Genetically Targeted to the CD19 Antigen

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3268-3268
Author(s):  
Marco L Davila ◽  
Clare Taylor ◽  
Xiuyan Wang ◽  
Jolanta Stefanski ◽  
Malgorzata Olszewska ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cells ◽  
Stem Cell ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
B Cell ◽  
Induction Chemotherapy ◽  
Lymphoblastic Leukemia ◽  
High Dose ◽  
Cell Acute Lymphoblastic Leukemia

Abstract Abstract 3268 Despite high initial remission rates following induction chemotherapy, most adults with B cell acute lymphoblastic leukemia (B-ALL) ultimately relapse and the overall prognosis is poor. In light of the overall poor outcomes seen with currently available chemotherapy regimens as well as allogeneic stem cell transplantation, novel and effective treatment approaches are needed for these patients. To this end, we have developed a program utilizing a patient's own T cells genetically modified ex vivo to express a chimeric antigen receptor (CAR), termed 19–28z, specific to the CD19 antigen expressed on normal B cells as well as most B-ALL tumors. In preclinical studies, human T cells modified to express the 19–28z CAR effectively eradicated systemic human B-ALL NALM-6 tumors in SCID-Beige mice. Based on these findings we have recently opened a phase I clinical trial (IRB #09-114) wherein patients with relapsed B-ALL are initially treated with re-induction chemotherapy followed by consolidation with high dose cyclophosphamide (3gm/m2) and a subsequent infusion of autologous T cells genetically modified to express the 19–28z CAR. Herein, we report the initial findings of the first patient treated on this clinical trial. This patient, a 67-year-old male, with B-ALL (normal cytogenetics), achieved a complete remission following induction chemotherapy with mitoxantrone and high-dose cytarabine. The patient remained in remission following treatment with vincristine (consolidation B) and cyclophosphamide (consolidation C). However, he was noted to have relapsed disease following consolidation cycle D with cytarabine and etoposide. At the time of relapse the patient was leukapheresed to obtain autologous T cells, and subsequently achieved a second remission following re-induction with a modified PEG-asparaginase, vincristine, and prednisone regimen. Upon recovery, the patient, as stipulated by the clinical trial, received lymphodepleting consolidation with high dose cyclophosphamide followed, 2 and 3 days later, by a split dose infusion of 3 × 106/kg autologous 19–28z+ T cells, the lowest planned T cell dose on this trial. Over the next 2 weeks, FACS and Q-PCR detected gene-modified T cells in the peripheral blood. Significantly, over the next 5 weeks, despite recovery of neutrophils and T cells, the patient exhibited a persistent B cell aplasia consistent with CD19-targeted cytotoxic activity of the infused autologous 19–28z+ T cells. The patient subsequently received an allogeneic stem cell transplant from a HLA-identical sibling effectively abrogating further analysis of modified T cell function. Despite this limitation, we conclude that following lymphodepleting chemotherapy, modified CD19-targeted T cells exhibit effective anti-CD19 cytotoxic activity, as demonstrated by the persistent B cell aplasia, in the clinical setting. These findings support the promise of this novel adoptive T cell therapy in patients with relapsed B-ALL. Disclosures: No relevant conflicts of interest to declare.

Corrigendum to “BCL11B, FLT3, NOTCH1 and FBXW7 mutation status in T-cell acute lymphoblastic leukemia patients” [Blood Cells Mol. Dis. 50 (2013) 33–38]

2013 ◽  
Vol 51 (1) ◽  
pp. 66-68
Author(s):  
Monika D. Kraszewska ◽  
Małgorzata Dawidowska ◽  
Maria Kosmalska ◽  
Łukasz Sędek ◽  
Władysław Grzeszczak ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Blood Cells ◽  
Lymphoblastic Leukemia ◽  
Mutation Status ◽  
Cell Acute Lymphoblastic Leukemia

scholarly journals Targeting cytokine- and therapy-induced PIM1 activation in preclinical models of T-cell acute lymphoblastic leukemia and lymphoma

Blood ◽  
2020 ◽  
Vol 135 (19) ◽  
pp. 1685-1695 ◽  
Author(s):  
Renate De Smedt ◽  
Julie Morscio ◽  
Lindy Reunes ◽  
Juliette Roels ◽  
Valentina Bardelli ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Tumor Cells ◽  
Integration Site ◽  
Lymphoblastic Leukemia ◽  
Residual Tumor ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Cell Acute Lymphoblastic Leukemia

Abstract T-cell acute lymphoblastic leukemia (T-ALL) and T-cell acute lymphoblastic lymphoma (T-LBL) are aggressive hematological malignancies that are currently treated with high-dose chemotherapy. Over the last several years, the search toward novel and less-toxic therapeutic strategies for T-ALL/T-LBL patients has largely focused on the identification of cell-intrinsic properties of the tumor cell. However, non–cell-autonomous activation of specific oncogenic pathways might also offer opportunities that could be exploited at the therapeutic level. In line with this, we here show that endogenous interleukin 7 (IL7) can increase the expression of the oncogenic kinase proviral integration site for Moloney-murine leukemia 1 (PIM1) in CD127+ T-ALL/T-LBL, thereby rendering these tumor cells sensitive to in vivo PIM inhibition. In addition, using different CD127+ T-ALL/T-LBL xenograft models, we also reveal that residual tumor cells, which remain present after short-term in vivo chemotherapy, display consistent upregulation of PIM1 as compared with bulk nontreated tumor cells. Notably, this effect was transient as increased PIM1 levels were not observed in reestablished disease after abrogation of the initial chemotherapy. Furthermore, we uncover that this phenomenon is, at least in part, mediated by the ability of glucocorticoids to cause transcriptional upregulation of IL7RA in T-ALL/T-LBL patient-derived xenograft (PDX) cells, ultimately resulting in non–cell-autonomous PIM1 upregulation by endogenous IL7. Finally, we confirm in vivo that chemotherapy in combination with a pan-PIM inhibitor can improve leukemia survival in a PDX model of CD127+ T-ALL. Altogether, our work reveals that IL7 and glucocorticoids coordinately drive aberrant activation of PIM1 and suggests that IL7-responsive CD127+ T-ALL and T-LBL patients could benefit from PIM inhibition during induction chemotherapy.

scholarly journals Children’s Oncology Group AALL0434: A Phase III Randomized Clinical Trial Testing Nelarabine in Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia

2020 ◽  
Vol 38 (28) ◽  
pp. 3282-3293 ◽  
Author(s):  
Kimberly P. Dunsmore ◽  
Stuart S. Winter ◽  
Meenakshi Devidas ◽  
Brent L. Wood ◽  
Natia Esiashvili ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Phase Iii ◽  
High Dose ◽  
Newly Diagnosed ◽  
Oncology Group ◽  
Leucovorin Rescue ◽  
Cell Acute Lymphoblastic Leukemia ◽  
To Receive

PURPOSE Nelarabine is effective in inducing remission in patients with relapsed and refractory T-cell acute lymphoblastic leukemia (T-ALL) but has not been fully evaluated in those with newly diagnosed disease. PATIENTS AND METHODS From 2007 to 2014, Children’s Oncology Group trial AALL0434 (ClinicalTrials.gov identifier: NCT00408005 ) enrolled 1,562 evaluable patients with T-ALL age 1-31 years who received the augmented Berlin-Frankfurt-Muenster (ABFM) regimen with a 2 × 2 pseudo-factorial randomization to receive escalating-dose methotrexate (MTX) without leucovorin rescue plus pegaspargase (C-MTX) or high-dose MTX (HDMTX) with leucovorin rescue. Intermediate- and high-risk patients were also randomly assigned after induction to receive or not receive six 5-day courses of nelarabine that was incorporated into ABFM. Patients who experienced induction failure were nonrandomly assigned to HDMTX plus nelarabine. Patients with overt CNS disease (CNS3; ≥ 5 WBCs/μL with blasts) received HDMTX and were randomly assigned to receive or not receive nelarabine. All patients, except those with low-risk disease, received cranial irradiation. RESULTS The 5-year event-free and overall survival rates were 83.7% ± 1.1% and 89.5% ± 0.9%, respectively. The 5-year disease-free survival (DFS) rates for patients with T-ALL randomly assigned to nelarabine (n = 323) and no nelarabine (n = 336) were 88.2% ± 2.4% and 82.1% ± 2.7%, respectively ( P = .029). Differences between DFS in a four-arm comparison were significant ( P = .01), with no interactions between the MTX and nelarabine randomizations ( P = .41). Patients treated with the best-performing arm, C-MTX plus nelarabine, had a 5-year DFS of 91% (n = 147). Patients who received nelarabine had significantly fewer isolated and combined CNS relapses compared with patients who did not receive nelarabine (1.3% ± 0.63% v 6.9% ± 1.4%, respectively; P = .0001). Toxicities, including neurotoxicity, were acceptable and similar between all four arms. CONCLUSION The addition of nelarabine to ABFM therapy improved DFS for children and young adults with newly diagnosed T-ALL without increased toxicity.

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