Results of the Treatment for Relapsed Acute Lymphoblastic Leukemia (ALL) in Childhood

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4339-4339
Author(s):  
Myriam Ruth Guitter ◽  
Elizabeth M Alfaro ◽  
Jorge Rossi ◽  
Marta Gallego ◽  
Cristina Alonso ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Childhood All ◽  
New Therapeutic Approaches ◽  
High Doses ◽  
Null Response ◽  
The Moment ◽  
Se 33

Abstract Abstract 4339 INTRODUCTION: Relapses occur in 25–30% of childhood ALL. We evaluated the outcome of this group of patients (pts) according to the duration of the 1st CR, immunophenotype and site of relapse in our Institution. PATIENTS AND METHODS: From Sept’94 to Aug’09, 245 ALL relapses were diagnosed: 73 cases were not evaluable due to: different treatments received (n: 36), palliative care (n: 26) and insufficient data (n: 11); 172 pts were evaluable (54 F/118 M), with a mean age at the moment of the relapse of 9.8 (range 1.8–20.8) years. Induction therapy combined a pre-phase with 10 days of prednisone and 1 block of high doses of chemotherapy, followed by 5 blocks of similar intensity, CNS or testicular (preventive/therapeutic) radiotherapy, and weekly rotational maintenance, until completing two years from the moment of diagnosis. High-risk relapsed pts who had an available identical donor received HSCT. RESULTS: Immunophenotype was B-cell precursor (Bcp) in 89% of the pts and T-cell in 11 %. The duration of the 1st CR was <18 mo in 41 (24%), 18–36 mo in 79 (46%), >36 mo in 52 (30%) pts. The sites of relapse were bone marrow (BM) in 106 pts (61%), combined bone marrow (cBM) in 27 pts (17%) and isolated extramedullar in 39 pts (22%). The response to induction was: CR 134 pts (78%), death during induction 20 pts (12%) and partial/null response 18 pts (10%). Among the 134 pts who achieved CR, 69 (52%) presented a second relapse at 18,8 (r 0.7–88.8) mo from the 2nd CR, 10 (7%) died in CR and 1 developed a 2nd neoplasm. With a mean follow-up of 49 (r 2–155) mo, 54 pts remain in CR, 37 of them out of therapy. Of the 26 pts who received HSCT, 12 relapsed and 3 died in CR. The EFSp (SE) for the total group of pts was 25 (3)% and LFS probability (SE) 33 (4)%; for Bcp relapses it was 28%, and for T relapses 6% (P=0.0025); for BM+cBM cases it was 21%, and 40% for extramedullar (P=0.0061). However, testicular relapses achieved EFSp of 80%, and 12% for the remaining extramedullar cases (P=0.0004). The EFSp for relapses at <18mo of 1st CR was 5%, between 18–36 mo 25% and >36 m 41% (P=0.0001). CONCLUSIONS: The immunophenotype, the duration of the 1st CR and site of relapse significantly influenced the EFSp. Isolated testicular relapses achieved the best EFSp. HSCT is an eligible option for a small group of pts. New therapeutic approaches must be developed to improve outcome of most of relapsed ALL patients. Disclosures: No relevant conflicts of interest to declare.

Effects of G-CSF On Acute Lymphoblastic Leukemia.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2564-2564
Author(s):  
Jordan Basnett ◽  
Adam Cisterne ◽  
Kenneth F Bradstock ◽  
Linda J Bendall
Keyword(s):  
Bone Marrow ◽  
Disease Progression ◽  
Microarray Analysis ◽  
Environmental Changes ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Hematopoietic Stem ◽  
Childhood All ◽  
Extracellular Matrix Components ◽  
The Impact

Abstract Abstract 2564 G-CSF is commonly used to treat chemotherapy-induced neutropenia and for the mobilization of hematopoietic stem cells for transplantation in patients with leukemia. Administration of G-CSF has profound effects on the bone marrow microenvironment including the cleavage of molecules required for the maintenance of lymphopoiesis, including CXCL12 and VLA-4. We have recently reported that G-CSF results in the dramatic suppression of B-lymphopoiesis. This, together with previous reports by ourselves, and others, showing that disruption of CXCL12 or VLA-4 slow the progression of B-lineage ALL lead us to consider that G-CSF may similarly antagonize the progression of ALL. To explore this possibility, we examined the impact of G-CSF administration on six human ALL xenografts using a NOD/SCID mouse model. Mice were engrafted without radiation and G-CSF commenced when 1% of the bone marrow consisted of ALL cells. G-CSF was administered twice daily for 10 days, at which time all animals were culled and leukemia assessed in the blood, bone marrow and spleens. Surprisingly G-CSF was found to increase disease progression in two of xenografts investigated (1345 and 0398, referred to as G-CSF responsive xenografts hereafter), while the remainder demonstrated a small reduction in leukemia, with one showing a statistical significant decrease. No evidence for a direct mitogenic effect of G-CSF could be demonstrated in any of the xenografts using exogenous G-CSF in vitro cultures in the presence or absence of human or murine stromal support. Consistent with these findings, and previous reports, little to no G-CSF receptor was detected by flow cytometry or microarray analysis of xenografts. Microarray analysis of the xenografts revealed significant differences in gene expression between the G-CSF responsive xenografts and the remainder of the samples. A total of 83 genes were expressed at a higher level and 127 genes at a lower level in the G-CSF responsive xenografts. The more highly expressed genes included cell cycle regulators (eg cyclin A1), adhesion molecules (eg ALCAM), extracellular matrix components and surface receptors. Perhaps the most interesting was the exclusive expression of the acetylcholine receptor (cholinergic receptor, nicotinic, beta 4, nAChRb4) in the G-CSF responsive cases. Analysis of a large public dataset of childhood ALL samples revealed significantly higher expression of this gene in ALL samples with rearranged MLL (p<0.03). However, small numbers of cases in all ALL subgroups had greater than an 2 fold higher expression compared to normal B cell progenitors. The role of nAChR in the response of ALL cells to micro-environmental changes induced by G-CSF remains to be determined, however, nAChR has known roles in cell proliferation and inhibition of apoptosis. Furthermore G-CSF is known to induce acetylcholine production in other tissues. In summary, G-CSF inhibited leukemia progression in the majority of patient xenografts, however, in a subset of samples G-CSF accelerated disease progression. Clinically, G-CSF administration to ALL patients has not been associated with any major adverse outcomes. However our data suggest that a small subset of patients may experience accelerated disease. Identification of features associated with adverse responses to G-CSF will permit the identification of patients for whom G-CSF may present a risk for increased disease progression. Disclosures: No relevant conflicts of interest to declare.

Flow Cytometric Leukemic Blasts Detection in Cerebrospinal Fluid of Children with Acute Lymphoblastic Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3799-3799
Author(s):  
Mette Levinsen ◽  
Hanne Vibeke Marquart ◽  
Line Groth-Pedersen ◽  
Thomas Leth Frandsen ◽  
Birgitte Klug Albertsen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cerebrospinal Fluid ◽  
Acute Lymphoblastic Leukemia ◽  
Conflicts Of Interest ◽  
Leukocyte Count ◽  
Lymphoblastic Leukemia ◽  
Leukemic Cells ◽  
Newly Diagnosed ◽  
Childhood All ◽  
Blast Count

Abstract Background: Central nervous system (CNS)-directed treatment has reduced risk of CNS relapse for childhood acute lymphoblastic leukemia (ALL), which accounts for 30-40% of initial relapses. Compared with CNS-negative patients, patients with CNS leukemia (>5 leukocytes/µL cerebrospinal fluid (CSF) and lymphoblasts) suffer from more CNS+ relapses. Conventional cytology (CC) is specific (>95%), but nonsensitive (<50%), since leukocytes in CSF decay within few hours after lumbar puncture. Method: We prospectively assessed centralised multi-parameter flow cytometry (FCM) of fixated CSF versus local CC in Nordic/Baltic childhood ALL. Diagnostic samples from 172 children aged 0-18 years with de novo and eight children with relapsed ALL were investigated in 297 CSF samples from 180 patients. Kinetics of disappearance of leukemic cells in the CSF was evaluated until day 15. Antibody-combinations reflected the immunophenotype of leukemic blasts in bone marrow. Result: Of 172 newly diagnosed patients, 51 (30%) had CSF involvement by FCM, while CC was positive in 16 patients (9%) (p<0.001). CSF involvement was detected by both FCM and CC in four of eight patients with relapse (50%). Among newly diagnosed patients, samples positive by FCM and CC had higher leukemic blast count compared to samples positive by FCM only (medians: 0.545 (range: 0.005-4.801) versus 0.016 (range: 0.003-1.38) leukemic blasts/µL; p<0.001). Among newly diagnosed patients with samples positive by FCM and CC, the CSF blast count was related to the CSF leukocyte count (rs=0.82; p=0.001). Compared to newly diagnosed patients who were FCM-negative, those with FCM-positivity had higher WBC (median: 37 versus 9 x 109/L; p<0.001), were younger (medians: 3 versus 5 years, p=0.04), and more often had T-cell ALL (12/51 (24%) versus (6/121 (5%), p<0.001). Five (16%) of 31 newly diagnosed patients with FCM detected blasts at diagnosis and available data at day 15 still had CSF leukemic blasts on day 15. So far the two patients who later developed CNS and/or bone marrow relapse were positive by flow (1.38 and 0.178 blasts/µL), but CNS negative by CC or had CSF leukocyte count <5/µL and lymphoblasts on CC, respectively. Conclusion: Leukemic blasts are present in spinal fluid of one third of newly diagnosed ALL. CSF involvement is associated with other higher risk characteristics. The prognostic value of these findings awaits prospective evaluation. Disclosures No relevant conflicts of interest to declare.

Characterization of CD9-CXCL12-CXCR4 Expression in Biological Subtypes of Childhood ACUTE Lymphoblastic Leukemia: Preliminary Findings and Future Perspectives

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5278-5278 ◽  
Author(s):  
Valeria Iachelli ◽  
Nellina Andriano ◽  
Paola Bonaccorso ◽  
Manuela La Rosa ◽  
Emanuela Cannata ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Prognostic Marker ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Single Gene ◽  
Cxcr4 Expression ◽  
Late Relapse ◽  
Childhood All ◽  
Normal Expression

Abstract Background. Although the prognosis of acute lymphoblastic leukemia (ALL) has improved considerably in recent years, some cases still exhibit therapy-resistance and late relapse. CD9-CXCL12-CXCR4 pathway has been implicated in hematopoietic and leukemic stem cell homing, promoting cell adhesion and survival in bone marrow stromal niches and mediating cell dissemination to secondary lymphoid organs. We characterized the CD9-CXCL12-CXCR4 expression in specific biological subgroups of childhood ALL, comparing, in some cases, diagnosis vs relapse, in order to investigate the role of these genes, in the process of leukemia relapse and to preliminarily evaluate their impact as prognostic markers, even for those subtypes with well-established good outcome. Materials and Methods. We analyzed bone marrow (BM) samples from 68 children with ALL, 3 cases with chronic myeloid leukemia, as control for t(9;22) positive leukemia, and 4 healthy donors (HDs). Patients were enrolled and treated at our Center from 2000 to 2010. We reverse-transcribed 500 ng of patients' diagnostic RNA and performed a Real-time PCR using the SYBRTM Green PCR Master Mix (Applied Biosystems®), calculating the median fold-changes (MFCs) among different reactions and comparing with HDs. GUS gene mRNA was used as an internal positive control, showing no significant variation in our experiments. Each PCR experiment was carried out in duplicate. Sequences of oligonucleotides used for experiments, together with RQ-PCR protocol were previously published (Gandemer V. et al Leukemia Research 2010) Results. We analyzed for CD9, CXCL12 and CXCR4 expression 39 children with t(12;21) positive ALL, 12 cases with t(1;19) positive ALL, 8 cases with t(9;22) positive ALL, and 9 cases resulted negative for chromosomal translocation screening. Among the t(12;21) positive ALL we found that CD9 was overexpressed in 13 out of 39 patients (33%), CXCL12 in 14 out of 39 (35%) and CXCR4 in 9 out of 39 (23%), respectively. We noted that in 2 cases who presented a late relapse, one (CT13) showed a normal expression of the analyzed genes, conversely the other case (CT24), who suffered from a isolated extramedullary relapse, showed a high overexpression of CD9. In the t(1;19) subgroup we found only one case with overexpression of both CD9 and CXCR4 genes, respectively. Moreover we noted that comparing diagnosis vs relapse in one case, we observed a dramatic increased expression of CXCL12 (CT70 diagnosis 3,33 FCs vs relapse 38 FCs). In the subgroup of children with t(9;22) positive ALL, we observed an extremely high expression of the CD9-CXCL12-CXCR4 genes. In particular, we found an overexpression of CD9 in 4 out of 8 (50%) cases with this subtype of ALL; interestingly, all these case showed a BM relapse. One of these (CT56) showed an overexpression of all the three pathway's components. As negative counterpart, we also analyzed three cases with a t(9;22) positive CML, finding a normal expression of all genes. In order to determine this pathway's expression in children presenting an ALL without known chromosomal aberration, we analyzed other 9 cases. In only one (CT44) we found an overexpression of both CD9 and CXCL12. This patient suffered from an early relapse (<24 months from diagnosis). Conclusions. Our preliminary findings demonstrated that the CD9-CXCL12-CXCR4 pathway is mainly altered in children with t(12;21) and t(9;22) positive ALL. In the latter subgroup we found a linear correlation between overexpression and impending relapse, confirming that this pathway can be potentially used as prognostic marker. Among t(1;19) positive ALL, we found few cases with single gene aberration. More importantly, we found an overexpression of one or two pathway's components in diagnostic samples of those cases, who presented a subsequent relapse. These data need to be confirmed in a larger population and will pave the way to identify new prognostic marker and/or therapeutic target, since CXCR4 has already antagonist drugs in clinical use, showing very recent promising results (Randhawa S et al. British Journal of Hematology 2016). Disclosures No relevant conflicts of interest to declare.

scholarly journals Patterns of hematopoietic chimerism following bone marrow transplantation for childhood acute lymphoblastic leukemia from volunteer unrelated donors

Blood ◽  
1996 ◽  
Vol 87 (7) ◽  
pp. 3027-3031 ◽  
Author(s):  
K Molloy ◽  
N Goulden ◽  
M Lawler ◽  
J Cornish ◽  
A Oakhill ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Mixed Chimerism ◽  
Childhood All ◽  
Low Level ◽  
Progressive Return ◽  
Hematopoietic Chimerism ◽  
Serial Samples

Hematopoietic chimerism was analyzed in serial bone marrow samples taken from 28 children following T-cell depleted unrelated donor bone marrow transplants (UD BMT) for acute lymphoblastic leukemia (ALL). Chimeric status was determined by polymerase chain reaction (PCR) of simple tandem repeat (STR) sequences (maximal sensitivity, 0.1%). At least two serial samples were examined in 23 patients. Of these, two had evidence of complete donor engraftment at all times and eight showed stable low level mixed chimerism (MC) (<1% recipient hematopoiesis). All 10 of these patients remain in remission with a minimum follow-up of 24 months. By contrast, 13 patients demonstrated a progressive return of recipient hematopoiesis. Five of these relapsed (4 to 9 months post BMT), one died of cytomegalovirus pneumonitis and seven remain in remission with a minimum follow-up of 24 months. Five children were excluded from serial analysis as two serial samples were not collected before either relapse (3) or graft rejection (2). We conclude that as with sibling transplants, ex vivo T depleted UD BMT in children with ALL is associated with a high incidence of MC. Stable donor engraftment and low level MC always correlated with continued remission. However, detection of a progressive return of recipient cells did not universally correlate with relapse, but highlighted those patients at greatest risk. Serial chimerism analysis by PCR of STRs provides a rapid and simple screening technique for the detection of relapse and the identification of patients with progressive MC who might benefit from detailed molecular analysis for minimal residual disease following matched volunteer UD BMT for childhood ALL.

Immunological Shift On Day 15 of Remission Induction in Children with CD10-Positive B-Cell Precursor ALL Treated by ALL-MB 2008 Protocol.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2650-2650
Author(s):  
Alexander Popov ◽  
Tatiana Verzhbitskaya ◽  
Grigory Tsaur ◽  
Egor Shorikov ◽  
Leonid Saveliev ◽  
...  
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
B Cell ◽  
B Lymphocytes ◽  
Fluorescence Intensity ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Remission Induction ◽  
Cell Precursor ◽  
Childhood All

Abstract Abstract 2650 Poster Board II-626 Statement. Flow cytometric (FC) minimal residual disease (MRD) monitoring during remission induction is a strong tool for prediction of outcome in children with acute lymphoblastic leukemia (ALL) of B-cell precursor (BCP) origin. Antigens' expression changes during treatment. Immunological shift can significantly complicate MRD detection. Immunophenotypical changes could vary during antileukemic treatment. Aim. To compare CD19, CD10, CD34, CD20, CD45 and CD58 expression at diagnosis and on day 15 of remission induction of currently applied ALL-MB 2008 treatment protocol and to evaluate significance of this changes for FC MRD monitoring. Patients and methods. Since November 2008 till July 2009 38 cases of childhood ALL were enrolled onto ALL-MB 2008 trial in Pediatric Oncology and Hematology Center in Ekaterinburg. Among them 22 patients were selected for present study as they fulfilled following criteria: had CD10-positive BCP-ALL and were MRD-positive ≥ 10−4 on day 15. MRD detection in bone marrow was performed by 9-color FC. We compared mean fluorescence intensity (MFI) values at diagnosis and on day 15. We also analyzed changes in CD19, CD20, CD45 and CD58 expression by normal B-lymphocytes on day 15 because at this time-point B-lineage regeneration is absent in bone marrow and MRD has to be discriminated only from mature B-cells. Coefficient of variation (CV) of fluorescence intensity and percentage of positive cells were used for evaluation of cells' distribution changes. Results. At diagnosis we found significant differences in antigen expression between tumor cells and B-lymphocytes. CD10, CD34, CD58 overexpression and CD19, CD20, CD45 underexpression by leukemic blasts were noted. On day 15 CD10, CD34 and CD58 were downmodulated (p = 0,0030, p = 0,0007 and p = 0,0017 respectively) while CD19, CD20 and CD45 were upmodulated (p = 0,0033, p = 0,0273 and p = 0,0001 respectively). At the same time CD20, CD45 and CD58 expression by mature B-lymphocytes decreased (p = 0,0013, p = 0,0130 and p = 0,0067 respectively) while CD19 was stable (p = 0,1060). Hence malignant and normal cells became closer on dot plots. On day 15 significant differences in CD10, CD34, CD20, CD45 and CD58 between blasts and lymphocytes were still presented. CD19 expression by leukemic cells on day 15 became higher than by mature B-cells (median MFI = 20284, range1587-34505 and median MFI = 15823, range 811–30882, p = 0,0196). Cells' distribution by CD10 and CD34 became more heterogeneous (p = 0,0364 and p = 0,0008 respectively), CD45 expression became more homogeneous (p = 0,0003) while CD20 and CD58 expression CV didn't change significantly (p = 0,1913 and p = 0,3443 respectively). CD20- and CD45-positive cells' percentage increased (p = 0,0015 and p = 0,0002 respectively) and CD34-positive cells' percentages decreased (p = 0,0003). Discussion. Changes in antigens' expression could complicate MRD detection so far as they decrease immunophenotypical differences between tumor blasts and mature B-lymphocytes. Interestingly, disparity of our results and previously shown data was found. Differences in immunological shift could be partially explained by differences in induction intensity of ALL-MB 2008 and international protocols. Conclusion. Significant immunological shift occurred on day 15 of ALL-MB 2008 remission induction. These antigens' expression changes have to be taken into account by the researcher for the successful FC MRD monitoring. Disclosures: No relevant conflicts of interest to declare.

Long-Term Sequelae and Late Effects In Childhood Acute Lymphoblastic Leukemia (ALL) Survivors: A Single AIEOP Center Experience

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1720-1720 ◽  
Author(s):  
Rosanna Parasole ◽  
Fara Petruzziello ◽  
Antonia De Matteo ◽  
Argia Mangione ◽  
Gaia Sepe ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Late Effects ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Late Effect ◽  
Cranial Radiotherapy ◽  
Childhood All

Abstract The advent of more intensive chemotherapy and the improvement of supportive cares have dramatically changed the natural history of childhood acute lymphoblastic leukemia (ALL), with current estimated 5-year overall survival of about 80%. The increased survival rate and the establishment of follow-up survey for long term survivors (LTS) have allowed the identification of late chemo-radiotherapy adverse effects on psychological and general health. We retrospectively evaluate the incidence and type of sequelae and / or late effects in a cohort of 301 childhood ALL LTS, followed in a single pediatric AIEOP center. From June 1986 to June 2013, 301 LTS (154 male and 147 female), aged <18 years at ALL diagnosis, were followed-up by a multidisciplinary team. The surveillance protocol is summarized in Figure 1. The timing of follow-up (FU) was modified, case by case, in relation to the appearance of adverse events or organ diseases. Survivors' results were compared with chronic medical and psychological conditions of siblings (n=89). Mean FU time (time from the stop therapy to the last control) was 6 years (range 1.8-26.8 years). The majority of LTS were teenager or young adults : 35% ranged between 15 and 20 years; 19.7% was more than 21 years old and the 45.3% was less than 14 years old. During FU, 16 late recurrences (5.3%) were identified and 3 secondary malignancies (0.99%) such as one mesenteric paraganglioma and two Acute Myeloid Leukemia in second complete remission ALL LTS. 40 patients (13.3%) received cranial radiotherapy during treatment. 39 LTS (13%) reported at least one sequelae. The most frequent sequelae were neurological and orthopedic (6% and 3% respectively) as summarized in Figure 2 151 LTS (50.17%) presented at least one late effect as showed in Figure 3. In our experience at least one late effect occurred in 50.17% of LTS; these late complications affect negatively the quality of life of survivors. Endocrine-metabolic events are the most frequent late effect (34,5%). 13% of LTS have at least one sequelae mainly neurological and orthopedic. Prevention and/or early identification of complications during follow-up survey of LTS are crucial in order to decrease the long-term health risks associated with curative treatment for childhood ALL. Disclosures: No relevant conflicts of interest to declare.

ETV6/RUNX1-Postitive Childhood Acute Lymphoblastic Leukemia (ALL): Do Additional Aberrations Influence Treatment Response and Outcome?

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2403-2403
Author(s):  
Maria Ampatzidou ◽  
Stephanos I. Papadhimitriou ◽  
George Paterakis ◽  
Loizos Petrikkos ◽  
Dimitrios Pavlidis ◽  
...  
Keyword(s):  
Prognostic Markers ◽  
Conflicts Of Interest ◽  
Fusion Gene ◽  
Lymphoblastic Leukemia ◽  
Clonal Diversity ◽  
Early Response ◽  
Response To Treatment ◽  
Childhood All ◽  
Biological Features

Abstract ETV6/RUNX1 rearrangement, being the most common genetic abnormality in childhood ALL, is combined with controversial prognostic behavior and frequent late relapses, indicating the need for identification of additional prognostic markers. In our study, we examined the relation between ETV6/RUNX1 and presenting clinical/biological features, co-existing subclones/secondary aberrations, early response to treatment (MRD) and their impact on outcome in a pediatric cohort of 133 ALL pts , treated in one Center over a 12-year period. Data from 133 newly diagnosed ALL pts(83 males) with a median age of 5.1 yrs(range 1.2-16.7), have been retrospectively recorded and analyzed. Pts were consecutively diagnosed and homogeneously treated on BFM based protocols during the years 2000-2011. FISH evaluation using commercial probe sets was performed for the detection of ETV6-RUNX1, E2A-PBX1, BCR-ABL fusion genes, MLL gene rearrangements as well as ETV6, RUNX1, CDKN2A/2B and other gene duplications, deletions or amplifications. Twenty seven pts (27/133, 20.3%) were tested positive for the t(12;21)(p13;q22) translocation(16 males), with a median age of 3.9 yrs(range 2.0-16.7). Immunophenotype revealed 22/27 common (81.5%) and 5/32 pre-B cases (18.5%). All pts were characterized as GPR and treated in the IR Arm. 8/27 (29.6%) were positive for the ETV6/RUNX1 fusion gene only with no secondary aberrations. 19/27 ETV6/RUNX1-positive pts (70.4%) harbored additional structural or numerical genetic abnormalities while 8 of those pts showed presence of subclones with multiple patterns of additional ETV6 and RUNX1 aberrations. The most common abnormalities were del12p13(37%), 3-6x21q22(22.2%), del9p21(18.5%), +21(14.8%), and 2-3xETV6/RUNX1(18.5%). On day 15, 13/27 ETV6/RUNX1+ pts (48.1%) presented with FCM-MRD(d15) values≥10-3 while the corresponding percent among IR ETV6/RUNX1- pts was 46.9%. Out the 8 pts with sole t(12;21)(p13;q22) translocation, only 25%(2/8 pts) presented with MRD(d15)>10-3 while among the 19 pts with additional aberrations, the corresponding percent was 52.6% (10/19). Interestingly, referring only to ETV6/RUXN1+ pts with subclones, the percent reflecting MRD(d15)>0.1% rises to 87.5% (7/8 pts). Among the 14 pts with no MRD(d15) detection only 1/14 appeared with clonal heterogeneity. 3/27 pts (11.1%) relapsed, in a median time of 30.3 months (median follow-up time 64 months). Common features of all relapses were sub-clonal diversity at diagnosis, del(9p21) and MRD(d15) positivity. 5-year RFS for the ETV6/RUNX1+ subgroup was 86.4%±7.4 vs 87.7%±3.5 for ETV6/RUNX1- pts. The presence of the ETV6/RUNX1 fusion gene as a favorable genetic marker did not seem to have a statistically significant impact on the probability of relapse (p=0.906). The 5-year RFS for those with MRD≥0.1% was limited to 67.3% ±16.0, while the corresponding rate for MRD- pts reached 100%. ETV6/RUNX1+ childhood ALL is characterized by extreme heterogeneity and the prognostic value of the fusion itself varies, depending on coexisting clinical and biological features. In our series, the presence of additional genetic aberrations/subclones (such as del9p21 or ETV6/RUNX1 duplication) and impaired FCM-MRD clearance, influences patient outcome. Longer follow-up is needed in order to further validate these initial results. FISH and FCM data may help establish new prognostic markers to predict relapse and refine risk stratification. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Igh-V(D)J NGS-MRD Measurement in Pediatric B-Acute Lymphoblastic Leukemia

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4923-4923
Author(s):  
Suying Lu ◽  
Jia Zhu ◽  
Junting Huang ◽  
Juan Wang ◽  
Feifei Sun ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Induction Therapy ◽  
Bone Marrow Cells ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Clinicopathological Characteristics ◽  
Marrow Cells

Abstract Introduction B-acute lymphoblastic leukemia (B-ALL) is the most common cancer of childhood. Early response to induction chemotherapy is one of the important prognostic factors in B-ALL. However, the analytic sensitivity for flow cytometry (FC) is only 10 -4. The feasibility of using next-generation sequencing (NGS) of immunoglobulin for the determination of minimal residual disease (MRD) in B-ALL has been demonstrated. This study aimed to investigate the performance of NGS techniques measuring immunoglobulin heavy chain (IgH)-variable, diversity, and joining (V[D]J) clonal rearrangements compared with FC in detecting MRD for children with B-ALL and to predict the clinical outcome of B-ALL patients. Methods Newly diagnosed younger than 18 years old B-ALL patients who received the treatment strategy of South China children's leukemia Group (SCCLG)-ALL 2016 were recruited. DNA extracted from bone marrow cells at all available time points for each patient was submitted to Simcere diagnostics for sequencing using Illumina NovaSeq platform. We performed IgH V(D)J NGS and FCM on the bone marrow serially obtained at diagnosis (D0), 15 days at induction therapy (D15), 33 days at induction therapy (D33) and then at the end of induction therapy (EOI). We defined MRD positive (MRD +) by IgH V(D)J NGS and FCM as more than 1 blast cell among 10 4 and 10 6 bone marrow cells, respectively. The sensitivity of MRD detection by IgH V(D)J NGS and FCM, and the association of MRD status with clinicopathological characteristics were investigated. Statistical analysis was performed through SPSS Statistics 22. Enumeration data and correlation between MRD data and clinicopathological characteristics were compared by Chi-square test or Fisher's exact test. This trial was registered at www.clinicaltrials.gov as # NCT04977895. Results As of July 27, 2021, 22 patients (median age, 4.5 years; range, 3.0-7.3) were enrolled in the study. Three patients (13.6%) had a t (9;22) translocation consistent with Philadelphia chromosome positive disease. According to risk stratifications, 8 (36.4%), 8 (36.4%), and 2 (9.1%) patients were classified as low risk (LR), intermediate risk (IR), and high risk (HR) groups, respectively. The remaining 4 patients are still under treatment and have not been classified. We identified leukemic IgH clones in 100% of the diagnostic samples and 68.2% (15/22) of the patients were polyclonal. In 11 patients whose samples of all the four timepoints (D0, D15, D33, EOI) have been tested in parallel by FCM and IgH V(D)J NGS, the frequencies of patients with MRD + were 30.4% vs. 90.9% at D15 (P＜0.05) by FCM and IgH V(D)J NGS. IgH V(D)J NGS MRD monitoring could identify MRD + patients with frequency of 45.5% and 18.2% among patients achieved MRD negativity by FCM at D33 (P＜0.05) and EOI (P = 0.46). With an MRD detection limit of 10 -6, 90.9% (10/11), 36.4% (4/11) and 18.2% (2/11) patients were MRD negative by FCM but positive by the NGS test at D15, D33 and EOI, respectively. This suggested that the sensitivity of IgH V(D)J NGS was significantly higher than that of FCM. Correlation of the measured MRD between the two methods in the entire cohort (r = 0.7934, P &lt; 0.0001) as well as in the concordant cases (r = 0.5558, P = 0.0032) was very high. There was a high discordant rate with NGS identifying more patients MRD + at this threshold. Furthermore, NGS MRD was positive but the FCM MRD was negative in 13 samples (P &lt; 0.0001). In addition, positive MRD status of D33 by NGS was significantly associated with the age of B-ALL patients, patients under 6 years more frequently harbored detectable MRD compared with those ≥ 6 years old (87.5% vs. 11.1%, P &lt; 0.01). There was no patient relapsed after a medium follow-up of 10.5 months. Conclusions We demonstrated the higher sensitivity of IgH-V(D)J NGS in MRD detection of B-ALL, which implies that NGS MRD monitoring could be helpful for more accurate risk stratifications and more precise treatment according to risk stratifications. Further study with a larger sample size and a longer follow-up period is need. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals The Platelet Millionaire: A Rare Cause of Thrombocytosis in an Adolescent

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5391-5391
Author(s):  
Ritika Walia ◽  
Theresa Sepulveda ◽  
Sharon Wretzel ◽  
Philip H Brandt
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Biopsy ◽  
Primary Care Physicians ◽  
Conflicts Of Interest ◽  
Abdominal Ultrasound ◽  
Cell Transplant ◽  
Peripheral Smear ◽  
Hematopoietic Stem ◽  
Marrow Fibrosis

Objectives: Primary myelofibrosis is rare in pediatrics, often manifesting as persistent idiopathic thrombocytosis.Transitions from pediatric to adult medical care can be complicated by workup requiring invasive procedures. J.M., an 18-year-old healthy male, presented for excessive gingival bleeding after wisdom tooth extraction. Workup revealed persistent thrombocytosis to 1,165K, prompting a referral to hematology-oncology. A peripheral smear was notable for many platelets but normal RBC morphology. He had splenomegaly on abdominal ultrasound and a decreased von-Willebrand's activity to antigen ratio, suggesting acquired vWD. A bone marrow biopsy was advised; however, J.M. became lost to follow up for over 9 months owing to self-reported anxiety about the procedure. He remained asymptomatic in this interim until he re-presented to clinic for easy bruising, with no other evidence of bleeding at the time. The biopsy was pursued, revealing hypercellular marrow for age with left shifted granulocytic and erythroid maturation, abnormal megakaryocytes, and 3% blasts. This was consistent with primary early myelofibrosis (PMF), positive for MF-1, CALR, and TP53 mutations and negative for JAK2 and BCR-ABL. He was transitioned to adult hematology, maintained on baby aspirin, and referred for potential allogeneic hematopoietic stem cell transplant (HSCT). PMF is characterized by marrow fibrosis due to secretion of fibroblast growth factor by clonally proliferative megakaryocytes. It is a disease of adulthood, with 67 years being the median age at diagnosis. Only 100 cases have been reported in children, most of which are secondary to AML, ALL or other malignancies.1 Most patients present with complications of extramedullary hematopoiesis or bleeding.2 Diagnosis is suggested by a leukoerythroblastic picture on peripheral smear and confirmed with a bone marrow biopsy "dry tap" revealing marrow fibrosis.3 Prognosis in pediatric PMF is difficult to predict but outcomes tend to be worse;4 TP53 mutation is rare and based on limited adult studies may portend a poorer prognosis.5 Our young patient with this rare mutation was therefore referred for HSCT evaluation. Further complicating this case was J.M.'s anxiety, which delayed definitive diagnosis by biopsy. He only agreed to it when, at the med-peds clinic, the concept of local pain management was discussed. Anticipation of upcoming procedures by primary care physicians and close follow-up is especially important for patients transitioning from pediatric to adult providers. Disclosures No relevant conflicts of interest to declare.

scholarly journals Study of Some Biochemical Parameters in Iraqi Children with Acute Lymphoblastic Leukemia

2015 ◽  
Vol 12 (2) ◽  
pp. 371-378
Author(s):  
Baghdad Science Journal
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Biochemical Parameters ◽  
Serum Proteins ◽  
Lymphoblastic Leukemia ◽  
White Blood Cells ◽  
Total Serum ◽  
Childhood All ◽  
Marrow Cavity ◽  
Increased Risk

Leukemia or cancer of the blood is the most common childhood cancer, Acute lymphoblastic leukemia (ALL), is the most common form of leukemia that occurs in children. It is characterized by the presence of too many immature white blood cells in the child’s blood and bone marrow, Acute lymphoblastic leukemia can occur in adults too, treatment is different for children. Children with ALL develop symptoms related to infiltration of blasts in the bone marrow, lymphoid system, and extramedullary sites, such as the central nervous system (CNS). Common constitutional indications consist of fatigue (50%), pallor (25%), fever (60%), and weight loss (26%). Infiltration of blast cells in the marrow cavity and periosteum often lead to bone pain (23%) and disturbance of normal hematopoiesis. Thrombocytopenia with platelet counts less than 100,000 are seen in approximately 75% of patients. About 40% of patients with childhood ALL present with hemoglobin levels less than 7 g/dL. Although leukocyte counts greater than 50,000/mm3 occur in 20% of cases, neutropenia defined as an absolute neutrophil count less than 500 is common at presentation and is associated with an increased risk of infection. The aim of this study was to investigate the differentiations in some biochemical parameters (Hb, PCV, total serum proteins Aspartate amino transferase(AST), Alanin amino transferase (ALT), and Malondialdehyde (MDA) in blood which can be conceder as a marker of ALL. Samples were collected from 50 patients (between 1-16 years old) diagnosed with ALL after one month treatment with induction therapy, compared with 30 control samples taken from healthy persons at the same age . The ALT and MDA showed a significant increase p < 0.001 and p

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