scholarly journals Dasatinib in the Management of Pediatric Patients With Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

2021 ◽  
Vol 11 ◽  
Author(s):  
Claudio Cerchione ◽  
Franco Locatelli ◽  
Giovanni Martinelli
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Pediatric Patients ◽  
Lymphoblastic Leukemia ◽  
Clinical Approach ◽  
Prognostic Impact ◽  
Intensive Chemotherapy ◽  
Acute Leukemias ◽  
Hematopoietic Stem ◽  
Childhood All

Acute leukemia is the most common cancer in childhood; in particular, acute lymphoblastic leukemia (ALL) represents roughly up to 80% of all cases of acute leukemias in children. Survival of children with ALL has dramatically improved over the last few decades, and is now over 90% (versus 40% of adult patients) in developed countries, except for in infants (i.e., children < 1 year), where no significant improvement was registered. Philadelphia positive ALL (Ph+ALL) accounts for around 3% of cases of childhood ALL, its incidence increasing with patient’s age. Before the era of tyrosine-kinase inhibitors (TKIs), pediatric Ph+ALL showed a worse prognosis in comparison to other forms of ALL, and was managed with intensive chemotherapy, followed, whenever possible, by allogenic hematopoietic stem cell transplantation (HSCT) in first morphological complete remission. TKIs have revolutionized the current clinical approach, which involves combinations of imatinib plus standard chemotherapy that can abrogate the negative prognostic impact conferred by the presence of BCR/ABL1 rearrangement, resulting in the probability of event-free survival (EFS) being significantly better than that recorded in the pre-TKI era. Long-term follow-up confirms these data, questioning the role of a real advantage offered by HSCT over intensive chemotherapy plus TKI in all Ph+ALL pediatric patients. Imatinib was the first generation TKI and the prototype of targeted therapy, but over the years second- (dasatinib, nilotinib, bosutinib) and third-generation (ponatinib) TKIs showed a capacity to overcome resistance to imatinib in Ph+ hematological neoplasms. Given the effectiveness of the first-in-class TKI, imatinib, also the second-generation TKI dasatinib was incorporated in the treatment regimens of Ph+ALL. In this manuscript, we will discuss the role of this drug in pediatric Ph+ALL, analyzing the available data published to date.

scholarly journals The Prevalent, Features and Prognostic Impact of Deletion p16 in Patients with Adult Acute Lymphoblastic Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5351-5351
Author(s):  
Na Xu ◽  
Yulin Li ◽  
Xuan Zhou ◽  
Liu Xiaoli ◽  
Hongsheng Zhou ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Univariate Analysis ◽  
Prognostic Significance ◽  
Prognostic Impact ◽  
Newly Diagnosed ◽  
Wild Type ◽  
Hematopoietic Stem ◽  
Childhood All ◽  
Significant Difference

Abstract Background and objective: Deletion of chromosome 9p21 is a crucial event for acute lymphoblastic leukemia (ALL). 9p21.3 genes encode three cell cycle inhibitory proteins: p15INK4b, p16CDKN2A, and p14ARFT. Recently studies show that p16 (CDKN2A) alleles were hypermethylated at CpG islands in ALL patients and delation p16 was associated with poor prognosis in childhood ALL. However, the prognostic significance of the deletion p16 in adult ALL leukemia is controversial, so the aim of the present study was to investigate the prevalence, feature and specific prognostic relevance of delation p16 in Chinese ALL patients from a single center in China. Patients and Methods: A total of 513 newly diagnosed adult ALL patients were identified retrospectively from the database of ALL between January 2008 and December 2013 at our center. We Detected delation p16 by interphase fluorescence in ituhybridization (I-FISH) and analyzed their clinical data retrospectively. Results: Of 513 cases, the prevalence of having either heterozygous or homozygous p16 deletions was 32%. p16 deletion were identified in 27% of newly diagnosed Philadelphia positive(Ph+) patients by univariate analysis, patients with p16 deletion had no significant difference compared with wild-type patients in terms of sex, age, white blood cells (WBC) count at diagnosis,BM blast percentage,chromosome karyotype,extra infiltration and CR I rate. The patients with p16 deletion was more likely to relapse comparaed with wild-type patients (P=0.03), and at relapse, we found a strong trend in the detection rate of p16 loss (41%) compared with diagnosis (P=0.01), suggesting that loss of this genomic region may be involved in disease progression. Of note, in newly diagnosed Ph+ALL with delation p16 were likely relapse even in the patients who treated with allogeneic hematopoietic stem cell transplantation (P=0.03). In addition, deletion p16 were significantly associated with poor outcomes in terms of overall survival (P=0.01), disease free-survival (P< 0.001), and cumulative incidence of relapse (P< 0.001). Conclusion: In our study, the absence of p16 expression seems to a poor prognostic marker in adult ALL patients. However, how to improve the survival of these patients need further study. Disclosures No relevant conflicts of interest to declare.

A Mechanistic Role For Mir-126, a Hematopoietic Stem Cell Microrna, In Acute Leukemias

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 886-886
Author(s):  
Alice Giustacchini ◽  
Silvia Nucera ◽  
Eric R. Lechman ◽  
Cristiana Fanciullo ◽  
Francesco E Boccalatte ◽  
...  
Keyword(s):  
Stem Cell ◽  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Disease Progression ◽  
Lymphoblastic Leukemia ◽  
Acute Leukemias ◽  
Hematopoietic Stem ◽  
Nsg Mice ◽  
Reporter Vector

Abstract We have recently shown that miR-126 expression faithfully identifies the engrafting fraction of bone marrow (BM) and cord blood (Gentner et al, Sci Transl Med 2010), in which it regulates hematopoietic stem cell (HSC) pool size by modulating cell cycle progression (Lechman et al., Cell Stem Cell 2012). Antagonizing miR-126 expands HSC by enhancing PI3K/AKT signaling, without causing their exhaustion or transformation. By reconstituting mice with lentivirally transduced BM cells ectopically expressing miR-126, we noted differential effects in HSC and progenitors: while miR-126 overexpressing (126OE) HSC were more quiescent and outcompeted by HSC with physiologic miR-126 expression, progenitor subsets were increased in number and proliferated more upon 126OE. In particular, B lymphopoiesis was enhanced, with the appearance of 126OE-vector marked, CD45(low)CD19+Ig(-) B cell progenitors in the peripheral blood. This abnormal population was transiently observed in all 126OE (n=45), but in none of the control mice (n=30), and BM B cell precursors and progenitors from 126OE mice showed significantly reduced levels of apoptosis, as well as a differentiation block at the immature B cell stage. At least part of this effect was due to interference of miR-126 with p53 activation. Consequentially, 20-30% of 126OE mice (as compared to 0% of control mice) followed over 1 year developed vector-marked, high-grade B-cell neoplasms which resembled diffuse large B-cell lymphoma, lymphoblastic lymphoma or acute lymphoblastic leukemia (ALL). Strikingly, by using a tetracycline-regulated, conditional miR-126OE vector, we observed full regression of the expanded abnormal B cell population after switching miR-126 expression off by doxycycline administration, demonstrating that miR-126 is an oncogenic driver in hematologic malignancies. To establish the relevance of miR-126 in human disease, we studied primary samples from patients with acute leukemia. We measured miR-126 expression in blasts from 12 adult patients with acute lymphoblastic leukemia (ALL). miR-126 was highly expressed in all studied cases of ALL (Phil+: n=7, Phil-: n=5), often surpassing the levels found in normal HSC. Unlike in HSC, miR-126 expression was independent from expression of its host gene EGFL7, suggesting an ALL-specific regulation of the miR-126 locus. By exploiting a lentiviral miR-126 reporter vector, we quantified miR-126 activity with single cell resolution after xenotransplantation of miR-126 reporter vector transduced ALL blasts into NSG mice. In 7 out of 12 ALL cases, we identified distinct subpopulations exhibiting different levels of miR-126 activity, and miR-126 (hi) ALL cells were more frequently contained in the CD34+ cell fraction. Moreover, high miR-126 expression correlated with faster and higher ALL engraftment in NSG mice. In acute myeloid leukemia (AML), miR-126 is significantly enriched in leukemic stem cells (LSC) where it governs quiescence and chemotherapy resistance (see abstract by Lechman et al), and analogous studies in ALL are ongoing. To further substantiate the role of miR-126 in AML, we studied miR-126 activity in 11 primary AML cases (4 AML with CBF, core binding factor, mutations; 7 AML with normal karyotype) using the reporter vector technology and the NSG xenotransplantation model. Globally, we found highest miR-126 activity in CBF-mutated AML. However, there was substantial heterogeneity in subpopulations of each single disease. Significantly higher miR-126 levels were found in CD34+, and particularly in CD34+CD38- AML cells, a fraction that is enriched for LSC. To see whether there is a correlation between miR-126 expression and disease progression, we measured miR-126 levels in sorted blasts from paired diagnosis/relapse (n=6) and diagnosis/chemotherapy-refractory (n=8) patient samples. Strikingly, we found a significant up-regulation of miR-126 in the disease progression sample, suggesting a mechanistic role for miR-126 in AML persistence after chemotherapy. In summary, these data support a clinically relevant role of miR-126 in the pathogenesis, treatment response and progession of acute leukemias. Authors AG and SN contributed equally, and LN and BG contributed equally. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Antibiotics in early life and childhood pre-B-ALL. Reasons to analyze a possible new piece in the puzzle

2022 ◽  
Vol 13 (1) ◽  
Author(s):  
T. M. Cardesa-Salzmann ◽  
A. Simon ◽  
N. Graf
Keyword(s):  
Immune Responses ◽  
Early Life ◽  
Lymphoblastic Leukemia ◽  
Antibiotic Use ◽  
Intestinal Microbiome ◽  
Microbial Composition ◽  
Hematopoietic Stem ◽  
Childhood All ◽  
Host Immune Responses

AbstractAcute lymphoblastic leukemia (ALL) is the most common pediatric cancer with precursor B-cell ALL (pB-ALL) accounting for ~ 85% of the cases. Childhood pB-ALL development is influenced by genetic susceptibility and host immune responses. The role of the intestinal microbiome in leukemogenesis is gaining increasing attention since Vicente-Dueñas’ seminal work demonstrated that the gut microbiome is distinct in mice genetically predisposed to ALL and that the alteration of this microbiome by antibiotics is able to trigger pB-ALL in Pax5 heterozygous mice in the absence of infectious stimuli. In this review we provide an overview on novel insights on the role of the microbiome in normal and preleukemic hematopoiesis, inflammation, the effect of dysbiosis on hematopoietic stem cells and the emerging importance of the innate immune responses in the conversion from preleukemic to leukemic state in childhood ALL. Since antibiotics, which represent one of the most widely used medical interventions, alter the gut microbial composition and can cause a state of dysbiosis, this raises exciting epidemiological questions regarding the implications for antibiotic use in early life, especially in infants with a a preleukemic “first hit”. Sheading light through a rigorous study on this piece of the puzzle may have broad implications for clinical practice.

scholarly journals TEL/AML-1 dimerizes and is associated with a favorable outcome in childhood acute lymphoblastic leukemia

Blood ◽  
1996 ◽  
Vol 88 (11) ◽  
pp. 4252-4258 ◽  
Author(s):  
TW McLean ◽  
S Ringold ◽  
D Neuberg ◽  
K Stegmaier ◽  
R Tantravahi ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Chromosomal Translocation ◽  
Fusion Transcript ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Childhood All ◽  
Polymerase Chain ◽  
B Lineage

Abstract Polymerase chain reaction-based screening of childhood acute lymphoblastic leukemia (ALL) samples showed that a TEL/AML1 fusion transcript was detected in 27% of all cases, representing the most common known gene rearrangement in childhood cancer. The TEL/AML1 fusion results from a t(12;21)(p13;q22) chromosomal translocation, but was undetectable at the routine cytogenetic level. TEL/AML1-positive patients had exclusively B-lineage ALL, and most patients were between the ages of 2 and 9 years at diagnosis. Only 3/89 (3.4%) adult ALL patients were TEL/AML1-positive. Most importantly, TEL/AML1-positive children had a significantly lower rate of relapse compared with TEL/AML1-negative patients (0/22 v 16/54, P = .004). Co- immunoprecipitation experiments demonstrated that TEL/AML-1 formed homodimers in vitro, and heterodimerized with the normal TEL protein when the two proteins were expressed together. The elucidation of the precise mechanism of transformation by TEL/AML1 and the role of TEL/AML1 testing in the treatment of childhood ALL will require additional studies.

scholarly journals Phase 2 trial of clofarabine in combination with etoposide and cyclophosphamide in pediatric patients with refractory or relapsed acute lymphoblastic leukemia

Blood ◽  
2011 ◽  
Vol 118 (23) ◽  
pp. 6043-6049 ◽  
Author(s):  
Nobuko Hijiya ◽  
Blythe Thomson ◽  
Michael S. Isakoff ◽  
Lewis B. Silverman ◽  
Peter G. Steinherz ◽  
...  
Keyword(s):  
Stem Cell ◽  
Acute Lymphoblastic Leukemia ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Pediatric Patients ◽  
Overall Response Rate ◽  
Response Rate ◽  
Lymphoblastic Leukemia ◽  
Phase 2 ◽  
Hematopoietic Stem

Abstract The outcomes in children with refractory/relapsed (R/R) acute lymphoblastic leukemia (ALL) are dismal. The efficacy and safety of intravenous clofarabine 40 mg/m2 per day, cyclophosphamide 440 mg/m2 per day, and etoposide 100 mg/m2 per day for 5 consecutive days in pediatric patients with R/R ALL was evaluated in this phase 2 study. The primary endpoint was overall response rate (complete remission [CR] plus CR without platelet recovery [CRp]). Among the 25 patients (median age, 14 years; pre-B cell ALL, 84%; ≥ 2 prior regimens: 84%; refractory to previous regimen: 60%), the overall response rate was 44% (7 CR, 4 CRp) with a 67.3-week median duration or remission censored at last follow-up. Most patients proceeded to alternative therapy, and 10 patients (40%) received hematopoietic stem cell transplantation. Six patients (24%) died because of treatment-related adverse events associated with infection, hepatotoxicity, and/or multiorgan failure. The study protocol was amended to exclude patients with prior hematopoietic stem cell transplantation after 4 of the first 8 patients developed severe hepatotoxicity suggestive of veno-occlusive disease. No additional cases of veno-occlusive disease occurred. The regimen offered encouraging response rates and sustained remission in R/R patients. Future investigation should include exploration of patient selection, dosing, and supportive care. This trial was registered at www.clinicaltrials.gov as #NCT00315705.

Therapy-Related Myelodysplastic Syndrome Following Treatment for Childhood Acute Lymphoblastic Leukemia: Outcome of Patients Registered in the EWOG-MDS 98/06 Studies,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4130-4130
Author(s):  
Brigitte Strahm ◽  
Roland Amann ◽  
Barbara De Moerloose ◽  
Michael Dworzak ◽  
Henrik Hasle ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Myelodysplastic Syndrome ◽  
Treatment Failure ◽  
Lymphoblastic Leukemia ◽  
Univariate Analysis ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Intensive Chemotherapy ◽  
Complex Karyotype ◽  
Childhood All ◽  
Preparative Regimen

Abstract Abstract 4130 Objective: Therapy-related myelodysplastic syndrome (tMDS) following treatment of childhood acute lymphoblastic leukemia (ALL) is one of the most frequently observed secondary malignancies in survivors of childhood cancer. Allogeneic stem cell transplantation (SCT) is the only curative treatment. This analysis was performed to asses the outcome of patients with tMDS following treatment for childhood ALL reported to the EWOG-MDS study group. Patients and Transplant Procedure: Forty-three patients (19 male/24 female) were diagnosed with tMDS between August 1989 and August 2009. The median age at diagnosis was 8.9 yrs (3.4–20.5). The median interval from diagnosis of ALL to the diagnosis of tMDS was 3.3 yrs (1.7–7.0). Five patients did not receive SCT and died due to progressive disease at a median of 5.6 mo after diagnosis. Thirty-eight patients were transplanted. One patient was excluded from the analysis due to insufficient data. In the 37 patients karyotype analysis revealed the following results: normal karyotype (5), abnormalities of chromosome 7 +/− additional aberrations (10), random aberrations (9), structurally complex karyotype (9), failed analysis (4). The highest WHO type was refractory cytopenia (RC) in 4 patients, whereas 33 patients had advanced AML like therapy prior to SCT was employed in 11 patients. Donors were matched siblings (13), matched unrelated volunteers (15), or mismatched or insufficiently typed family or unrelated donors (9). Conditioning consisted of busulfan, cyclophosphamide and melphalan (Bu/Cy/Mel) (23), an alternative busulfan based regimen (6), a radiation based regimen (5) or others (3). Results: After a median follow up of 4.1 (0.5 – 9.4) years, 14 patients are alive in first complete remission (CR). Seventeen patients developed relapse after a median time of 266 days (28 days – 3.4 years). Of these, three patients are alive in CR after a second allograft. Six patients died of transplant-related complications after first (4) or second (2) SCT. In summary, SCT for tMDS following ALL resulted in a probability of event-free and overall survival at 5 years of 0.34 and 0.42, respectively. In univariate analysis, the presence of a structurally complex karyotype, SCT from a mismatched donor and a preparative regimen other than Bu/Cy/Mel were factors predicting a decreased probability of event-free survival. The use of intensive chemotherapy prior to SCT resulted in a trend towards better survival due to a reduction in relapse incidence. In multivariate COX-analysis, a conditioning regimen other than BuCyMel remained the only variable associated with a high risk of treatment failure. Conclusion: Allogeneic SCT with a preparative regimen consisting of Bu/Cy/Mel is feasible and effective in patients developing tMDS following treatment for childhood ALL. Relapse is the main cause of treatment failure and intensive chemotherapy prior SCT may possibly contribute to an improved outcome. Disclosures: Hasle: Pfizer: Research Funding.

Crebbp HAT Domain Mutations Are Frequently Detected in Adult Acute Lymphoblastic Leukemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1419-1419
Author(s):  
Kenji Tokunaga ◽  
Shunichiro Yamaguchi ◽  
Eisaku Iwanaga ◽  
Tomoko Nanri ◽  
Taizo Shimomura ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
B Cell ◽  
Pediatric Patients ◽  
Lymphoblastic Leukemia ◽  
Genetic Alterations ◽  
Adult Patients ◽  
Prognostic Impact ◽  
Pediatric All ◽  
Crebbp Gene

Abstract Abstract 1419 Aims: Molecular pathogenesis of acute lymphoblastic leukemia (ALL) has largely been verified in pediatric patients and the identification of genetic alterations have contributed to stratifying therapeutic applications. In adult patients with ALL, cytogenetic and genetic abnormalities have not sufficiently been elucidated and therapeutic improvement has been hindered. CREB binding protein (CREBBP) is a transcriptional coactivator that interacts with a diverse range of transcription factors and regulates transcription by histone acetylation in hematopoiesis. Mutations of the CREBBP gene are recently found in approximately 2–4% of pediatric patients with ALL. Especially in relapsed cases, the mutations prevail (18–63%) and are possible markers for prediction of relapse in pediatric ALL. In adult patients with ALL, the clinical significance of CREBBP mutations remains to be determined. Here we examined adult ALL patients in an attempt to determine the incidence, clinical characteristics and prognostic impact of the CREBBP mutations. Methods: We investigated 71 adult patients with newly diagnosed ALL treated with JALSG protocols between 1986 and 2010. Age ranged from 15 to 86 years, with a median of 54 years. CREBBP mutations are dominantly identified in histone acetyltransferase (HAT) domain. HAT domain in the CREBBP gene was amplified with RT-PCR using RNA isolated from the peripheral blood or bone marrow mononuclear cells at diagnosis and was subjected to direct sequencing. We compared clinical profiles between patients with and without CREBBPHAT domain mutations. This study was approved by the Institutional Review Boards and informed consent was obtained from each patient according to guidelines based on the revised Declaration of Helsinki. Results: CREBBP HAT domain mutations were detected in 8 of 71 (11.3%) patients: one nonsense mutation, five insertion mutations with frameshifts, and five missense mutations. Two patients harbored biallelic mutations. The mutations at diagnosis in adult patients were seen more frequently than those in pediatric patients ever reported. Such mutations were not completely identical to those detected in pediatric ALL, but were seen in the region within the HAT domain, indicating that such mutations are loss-of-function mutations. The mutations were found in both B-cell (6/53: 11.3%) and T-cell (1/9: 11.1%) ALL, and distributed in patients harboring IKZF1 alterations (3/31: 9.7%) or the BCR-ABL fusion gene (2/19: 10.5%). There were no statistical difference in age, sex, leukocyte, platelet counts and complete remission rate between patients with and without the CREBBP HAT domain mutations. Patients with the mutations had a trend with worse cumulative incidence of relapse (P=0.4637), relapse-free survival (P=0.4195) and OS (P=0.2349) compared to patients lacking the mutations, but statistical significance was not detected in this small cohort. Conclusions: CREBBP HAT domain mutations at diagnosis in adult ALL are found more frequently than in pediatric ALL. This may be one of the mechanisms that adult ALL has been associated with poor OS compared with pediatric ALL. In this study, CREBBP HAT domain mutations were observed in various subtypes of ALL: both B-cell and T-cell ALL, and both Philadelphia chromosome positive and negative ALL. In pediatric ALL, CREBBP mutations were frequently seen in relapsed patients but not in previously untreated patients. These observations suggest that CREBBP mutations play an important role in an additional late event(s) leading to the development and progression of ALL. Our study implies the possibility that mutations of the CREBBP gene are associated with the pathogenesis and prognostic marker of adult ALL and represent specific epigenetic modifiers in adult ALL, serving as potential therapeutic targets. Disclosures: No relevant conflicts of interest to declare.

Prognostic Impact of Bone Marrow B Lymphocyte Precursors (hematogones) Detection in 95 Acute Lymphoblastic Leukemia Cases

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4791-4791 ◽  
Author(s):  
Sylvain P Chantepie ◽  
Audrey Emmanuelle Dugué ◽  
Patrice Chevallier ◽  
Aline Schmidt-Tanguy ◽  
Véronique Salaün ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Prognostic Factors ◽  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Prognostic Impact ◽  
Hematopoietic Stem ◽  
Time Points ◽  
Number Of Patients

Abstract Abstract 4791 Acute lymphoblastic leukemia (ALL) multiparameter flow cytometry (MFC) study of bone marrow aspiration after chemotherapy is crucial for determining minimal residual disease (MRD). Hematogones (HGs) have to be distinguishing from leukemic cells in B-cell subtypes and could be quantify during follow-up. To date, the incidence of Hgs in ALL and their prognostic significance have not been investigated. The aim of this multicenter study was to quantify Hgs after chemotherapy in ALL adult patients and to define its prognostic value. We retrospectively analyzed the incidence of HGs in 95 ALL patients, 71 with B-ALL (75%), 24 (25%) with T-ALL in first line treatment. The median age was 37 years [8–71], 20% had t(9;22) cytogenetic abnormality, and 70% had abnormal karyotype. 4/5-color MFC analysis MRD and HGs were performed at different time point (TP) after diagnosis: TP1 (post-induction, day 45 [41–61], n=78), TP2 (post-consolidation, day 111 [94–144] 25, n=42), TP3 (post-intensification/before hematopoietic stem cell transplantation (HSCT), day 179 [125–268], n=58), TP4 (n=11), TP5 (n=17), TP6 (n=9) after a median of 33, 91 and 167 days after HSCT, respectively. A total of 39 patients (41%) relapsed with a median of 26 months [7.7–47.9]. Forty seven patients (50%) received an HSCT in a complete (98%) or partial remission (2%). At TP1, TP2, TP3, TP4, TP5, TP6, the median HGs [range] were as followed: 0.00 [0.00–6.90]%, 0.30 [0.00–11.2]%, 0.98 [0.00–33.00]%, 0.52 [0.00;23.00]%, 5.50 [0.00;25.00]%, 4.60 [0.00;34.00]%, 5.90 [0.32;11.80]%, respectively. Figure 1 showed the percentage of patients with negative MRD (Figure 1A) and detectable HGs (figure 1B) during the follow up of ALL patients. There is a progressive increase of the percentage of patients with detectable HGs during the time of treatment and follow-up. Interestingly, there was no correlation between age and HGs level while in physiological situation the HGs rate decreases with increasing age. There was a negative correlation between positive MRD and detectable HGs at TP1 (p=0.022) but not at TP3 (p=0.88). In univariate analysis positive MRD at P1 and P3, age (/10), the presence of t(9;22) and absence of HGs at TP3 (figure 2) were bad prognostic factors for relapse free-survival (RFS) and overall survival (OS). The presence of HGs at other different time of evaluation was not associated with a significant decrease of relapse or death. However, patients who had a negative MRD at TP1 and detectable HGs in the bone marrow at TP3 exhibited a better RFS and OS (p=0.018 and p=0.065 respectively). Patients who had negative MRD at TP3 and had detectable HGs at TP3 had also a better RFS and OS (p=0.007 and p=0.011, respectively) compared to patients with negative MRD at TP3 and without HGs (figure 3). In patients who had a positive MRD at TP1, detectable HGs at TP3 identified a subgroup of patient with favorable OS compared to patient with positive MRD at TP1 and without detectable HGs (p=0.072). These results should be taken with cautious because of the decreasing number of patients evaluated at different time points. However, HGs analysis could represent a new area of investigation in search of new prognostic factors in the context of adult ALL. Figure 1. Percentage of patients with (A) negative MRD and (B) detectable HGs at different time points after starting of treatment. Figure 1. Percentage of patients with (A) negative MRD and (B) detectable HGs at different time points after starting of treatment. Figure 2. Overall survival according to HGs status at TP3. Figure 2. Overall survival according to HGs status at TP3. Figure 3. Overall survival in patients with negative MRD at TP3 according to HGs status. Figure 3. Overall survival in patients with negative MRD at TP3 according to HGs status. Disclosures: No relevant conflicts of interest to declare.

Phase II Study of Clofarabine in Pediatric Patients With Refractory or Relapsed Acute Lymphoblastic Leukemia

2006 ◽  
Vol 24 (12) ◽  
pp. 1917-1923 ◽  
Author(s):  
Sima Jeha ◽  
Paul S. Gaynon ◽  
Bassem I. Razzouk ◽  
Janet Franklin ◽  
Richard Kadota ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Phase Ii ◽  
Pediatric Patients ◽  
Lymphoblastic Leukemia ◽  
Single Agent ◽  
Median Number ◽  
Open Label ◽  
Hematopoietic Stem ◽  
Platelet Recovery ◽  
Heavily Pretreated

Purpose To evaluate the efficacy and safety of clofarabine, a novel deoxyadenosine analog, in pediatric patients with refractory or relapsed acute lymphoblastic leukemia (ALL). Patients and Methods In a phase II, open-label, multicenter study, 61 pediatric patients with refractory or relapsed ALL received clofarabine 52 mg/m2 intravenously over 2 hours daily for 5 days, every 2 to 6 weeks. The median age was 12 years (range, 1 to 20 years), and the median number of prior regimens was three (range, two to six regimens). Results The response rate was 30%, consisting of seven complete remissions (CR), five CRs without platelet recovery (CRp), and six partial remissions. Remissions were durable enough to allow patients to proceed to hematopoietic stem-cell transplantation (HSCT) after clofarabine. Median CR duration in patients who did not receive HSCT was 6 weeks, with four patients maintaining CR or CRp for 8 weeks or more (8+, 12, 37+, and 48 weeks) on clofarabine therapy alone. The most common adverse events of grade ≥ 3 were febrile neutropenia, anorexia, hypotension, and nausea. Conclusion Clofarabine is active as a single agent in pediatric patients with multiple relapsed or refractory ALL. The toxicity profile is as expected in this heavily pretreated patient population. Studies exploring rational combinations of clofarabine with other agents are ongoing in an effort to maximize clinical benefit.

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