Early T-cell precursor leukemia
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- MeSH
- akutní lymfatická leukemie farmakoterapie genetika patologie MeSH
- akutní nemoc MeSH
- buněčný rodokmen genetika MeSH
- genová přestavba MeSH
- histonlysin-N-methyltransferasa genetika MeSH
- indukční chemoterapie metody MeSH
- kineziny genetika MeSH
- lidé MeSH
- lidské chromozomy, pár 11 genetika MeSH
- lidské chromozomy, pár 6 genetika MeSH
- malování chromozomů metody MeSH
- mladiství MeSH
- myeloidní leukemie genetika patologie MeSH
- myosiny genetika MeSH
- protoonkogenní protein MLL genetika MeSH
- translokace genetická * MeSH
- Check Tag
- lidé MeSH
- mladiství MeSH
- ženské pohlaví MeSH
- Publikační typ
- dopisy MeSH
- kazuistiky MeSH
Daratumumab, an anti-CD38 antibody, is used experimentally in the treatment of relapsed acute lymphoblastic leukemia (ALL). We treated five patients suffering from relapsed ALL with daratumumab. Four patients had T ALL, three of whom achieved complete remission (CR) after treatment and underwent stem cell transplant (SCT). Two of them had a second relapse and died 6 and 8 months after SCT, respectively. One transplanted T ALL patient remained in CR2 15 months after relapse. In the remaining T-ALL patient, the disease progressed under daratumumab treatment, and the patient died early after the first relapse. The B-cell precursor ALL patient with a second CD19-negative relapse, whose disease turned out to be resistant to the combination of daratumumab with chemotherapy, later achieved CR3 with inotuzumab ozogamicin, underwent SCT and remained in CR3. Leukemia burden should be monitored after daratumumab, and care should be taken not to misclassify leukemic cells with false negativity of surface CD38; using an antibody reacting with nondaratumumab epitopes is advantageous.
PURPOSE: We aimed to study prognostic factors and efficacy of allogeneic hematopoietic stem-cell transplantation (allo-HSCT) in first remission of patients with noninfant childhood acute lymphoblastic leukemia (ALL) with 11q23/KMT2A rearrangements treated with chemotherapy regimens between 1995 and 2010. PATIENTS AND METHODS: Data were retrospectively retrieved from 629 patients with 11q23/KMT2A-rearranged ALL from 17 members of the Ponte-di-Legno Childhood ALL Working Group. Clinical and biologic characteristics, early response assessed by minimal residual disease at the end of induction (EOI) therapy, and allo-HSCT were analyzed for their impact on outcomes. RESULTS: A specific 11q23/KMT2A translocation partner gene was identified in 84.3% of patients, with the most frequent translocations being t(4;11)(q21;q23) (n = 273; 51.5%), t(11;19)(q23;p13.3) (n = 106; 20.0%), t(9;11)(p21_22;q23) (n = 76; 14.3%), t(6;11)(q27;q23) (n = 20; 3.8%), and t(10;11)(p12;q23) (n = 14; 2.6%); 41 patients (7.7%) had less frequently identified translocation partner genes. Patient characteristics and early response varied among subgroups, indicating large biologic heterogeneity and diversity in therapy sensitivity among 11q23/KMT2A-rearranged ALL. The EOI remission rate was 93.2%, and the 5-year event-free survival (EFS) for the entire cohort was 69.1% ± 1.9%, with a range from 41.7% ± 17.3% for patients with t(9;11)-positive T-ALL (n = 9) and 64.8% ± 3.0% for patients with t(4;11)-positive B-ALL (n = 266) to 91.2% ± 4.9% for patients with t(11;19)-positive T-ALL (n = 34). Low EOI minimal residual disease was associated with favorable EFS, and induction failure was particularly predictive of nonresponse to further therapy and relapse and poor EFS. In addition, EFS was not improved by allo-HSCT compared with chemotherapy only in patients with both t(4;11)-positive B-ALL (n = 64 v 51; P = .10) and 11q23/KMT2A-rearranged T-ALL (n = 16 v 10; P = .69). CONCLUSION: Compared with historical data, prognosis of patients with noninfant 11q23/KMT2A-rearranged ALL has improved, but allo-HSCT failed to affect outcome. Targeted therapies are needed to reduce relapse and treatment-related mortality rates.
- MeSH
- akutní lymfatická leukemie * terapie MeSH
- biologické přípravky * MeSH
- lidé MeSH
- lidské chromozomy, pár 11 MeSH
- lymfoblastická leukemie-lymfom z prekurzorových T-buněk * MeSH
- prognóza MeSH
- recidiva MeSH
- retrospektivní studie MeSH
- reziduální nádor genetika MeSH
- translokace genetická MeSH
- transplantace hematopoetických kmenových buněk * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
A novel immature human T-ALL cell line, UHKT-42, was established from a 12 year old male patient with acute undifferentiated leukemia. The cell line expressed surface CD7, CD5 and cytoplasmic CD3 antigens. All other T-lymphocytic antigens were undetectable on the surface or in the cytoplasm of cultured cells. Expression of the T-cell receptor (TCR) beta, TCR delta, CD3 delta and CD3 epsilon genes was detected by Northern blotting in total cellular RNA extracts, however, the expression of TCR alpha and TCR gamma was undetectable. After stimulation by TPA for 3 days, only the appearance of CD25 (Tac antigen) was detected by immunofluorescence and flow cytometry. Secretion of interleukin-2 (IL-2) into the culture media was also detected after stimulation by PHA or TPA, but not in unstimulated cells. These results suggest that UHKT-42 cells are early precursors of T cells, with TCR beta/delta expression.
- MeSH
- akutní lymfatická leukemie imunologie patologie MeSH
- antigeny CD5 MeSH
- antigeny CD7 MeSH
- CD antigeny metabolismus MeSH
- diferenciační antigeny T-lymfocytů metabolismus MeSH
- dítě MeSH
- lidé MeSH
- nádorové buňky kultivované MeSH
- receptory antigenů T-buněk alfa-beta genetika metabolismus MeSH
- T-lymfocyty * metabolismus patologie MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
Akutní lymfoblastická leukemie (ALL) je nejčastějším zhoubným nádorovým onemocněním u dětí. Její prognóza zaznamenala v průběhu posledních 50 let mimořádné zlepšení v důsledku citlivosti nádorových buněk na kombinovanou chemoterapii, stratifikace terapie dle časné léčebné odpovědi a se zavedením transplantace krvetvorných buněk (hematopoietic stem cell transplantation, HSCT) do léčby pacientů ve vysokém riziku. Přesto prodělává 10‒15 % nemocných relaps leukemie s šancí na vyléčení 30‒50 %, 2‒5 % dětí umírá v důsledku toxicity terapie a děti vyléčené transplantací jsou ohroženy rizikem výskytu pozdních následků léčby zhoršujících kvalitu jejich života. Pokroky v rozvoji metod molekulární genetiky odhalující poškozené signální dráhy v leukemické buňce a následná aplikace metod cílené léčby a imunoterapie jsou nadějí pro zlepšení prognózy dětí ve vysokém riziku, pro snížení toxicity léčby a mají potenciál nahradit v budoucnu HSCT.
Acute lymphoblastic leukemia (ALL) is the most frequent cancer in children. The prognosis improved remarkably during the last 50 years due to chemosensitivity of leukemic cells to combined chemotherapy, stratification of treatment according to early treatment response and the introduction of hematopoietic stem cell transplantation (HSCT) into the therapy of high‑risk patients. Despite this improvement, about 10‒15% of patients suffer from relapse with only 30‒50% chance to be cured, 2‒5% of children die due to treatment toxicity and many patients cured by HSCT suffer from late‑sequelae. Progress in the development of molecular biology methods allows detection of the abnormal signalling pathways in leukemic cells, enabling the application of targeted therapy and immunotherapy. These approaches have a potential to improve treatment results due to the decreased incidence of relapses and toxic deaths, and a potential to substitute HSCT in the future.
The prognostic value of minimal residual disease (MRD) in Philadelphia-chromosome-positive (Ph+) childhood acute lymphoblastic leukemia (ALL) treated with tyrosine kinase inhibitors is not fully established. We detected MRD by real-time quantitative polymerase chain reaction (RQ-PCR) of rearranged immunoglobulin/T-cell receptor genes (IG/TR) and/or BCR/ABL1 fusion transcript to investigate its predictive value in patients receiving Berlin-Frankfurt-Münster (BFM) high-risk (HR) therapy and post-induction intermittent imatinib (the European intergroup study of post-induction treatment of Philadelphia-chromosome-positive acute lymphoblastic leukemia (EsPhALL) study). MRD was monitored after induction (time point (TP)1), consolidation Phase IB (TP2), HR Blocks, reinductions, and at the end of therapy. MRD negativity progressively increased over time, both by IG/TR and BCR/ABL1. Of 90 patients with IG/TR MRD at TP1, nine were negative and none relapsed, while 11 with MRD<5×10-4 and 70 with MRD≥5×10-4 had a comparable 5-year cumulative incidence of relapse of 36.4 (15.4) and 35.2 (5.9), respectively. Patients who achieved MRD negativity at TP2 had a low relapse risk (5-yr cumulative incidence of relapse (CIR)=14.3[9.8]), whereas those who attained MRD negativity at a later date showed higher CIR, comparable to patients with positive MRD at any level. BCR/ABL1 MRD negative patients at TP1 had a relapse risk similar to those who were IG/TR MRD negative (1/8 relapses). The overall concordance between the two methods is 69%, with significantly higher positivity by BCR/ABL1. In conclusion, MRD monitoring by both methods may be functional not only for measuring response but also for guiding biological studies aimed at investigating causes for discrepancies, although from our data IG/TR MRD monitoring appears to be more reliable. Early MRD negativity is highly predictive of favorable outcome. The earlier MRD negativity is achieved, the better the prognosis.
- MeSH
- akutní lymfatická leukemie diagnóza farmakoterapie genetika mortalita MeSH
- analýza přežití MeSH
- bcr-abl fúzní proteiny genetika MeSH
- imatinib mesylát terapeutické užití MeSH
- imunoglobuliny genetika MeSH
- kombinovaná terapie MeSH
- lidé MeSH
- nádorové biomarkery MeSH
- prognóza MeSH
- receptory antigenů T-buněk genetika MeSH
- recidiva MeSH
- reziduální nádor diagnóza genetika MeSH
- výsledek terapie MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Optimal discrimination between leukemic blasts and normal B-cell precursors (BCP) is critical for treatment monitoring in BCP acute lymphoblastic leukemia (ALL); thus identification of markers differentially expressed on normal BCP and leukemic blasts is required. METHODS: Multicenter analysis of CD73, CD86 and CD304 expression levels was performed in 282 pediatric BCP-ALL patients vs. normal bone marrow BCP, using normalized median fluorescence intensity (nMFI) values. RESULTS: CD73 was expressed at abnormally higher levels (vs. pooled normal BCP) at diagnosis in 71/108 BCP-ALL patients (66%), whereas CD304 and CD86 in 119/202 (59%) and 58/100 (58%) patients, respectively. Expression of CD304 was detected at similar percentages in common-ALL and pre-B-ALL, while found at significantly lower frequencies in pro-B-ALL. A significant association (p = 0.009) was found between CD304 expression and the presence of the ETV6-RUNX1 fusion gene. In contrast, CD304 showed an inverse association with MLL gene rearrangements (p = 0.01). The expression levels of CD73, CD86 and CD304 at day 15 after starting therapy (MRD15) were stable or higher than at diagnosis in 35/37 (95%), 40/56 (71%) and 19/41 (46%) cases investigated, respectively. This was also associated with an increased mean nMFI at MRD15 vs. diagnosis of +24 and +3 nMFI units for CD73 and CD86, respectively. In addition, gain of expression of CD73 and CD86 at MRD15 for cases that were originally negative for these markers at diagnosis was observed in 16% and 18% of cases, respectively. Of note, CD304 remained aberrantly positive in 63% of patients, despite its levels of expression decreased at follow-up in 54% of cases. CONCLUSIONS: Here we show that CD73, CD86 and CD304 are aberrantly (over)expressed in a substantial percentage of BCP-ALL patients and that their expression profile remains relatively stable early after starting therapy, supporting their potential contribution to improved MRD analysis by flow cytometry.
- MeSH
- 5'-nukleotidasa analýza biosyntéza MeSH
- antigeny CD86 analýza biosyntéza MeSH
- dítě MeSH
- GPI-vázané proteiny analýza biosyntéza MeSH
- lidé MeSH
- nádorové biomarkery analýza MeSH
- neuropilin-1 analýza biosyntéza MeSH
- pre-B-buněčná leukemie patologie MeSH
- předškolní dítě MeSH
- prekurzorové B-lymfoidní buňky patologie MeSH
- reziduální nádor MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
In a phase 3 clinical study of heavily pretreated adults with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL), overall survival (OS) following blinatumomab, a BiTE (bispecific T-cell engager) immunooncology therapy, was significantly improved vs chemotherapy following induction (cycles 1 to 2). Here we report the efficacy and safety of those who received additional cycles of blinatumomab. Blinatumomab was administered as a continuous IV infusion for 4 weeks in a 6-week cycle. Patients who achieved a bone marrow response (≤5% blasts) or complete remission (full, partial, or incomplete hematological recovery) during induction could receive additional cycles of blinatumomab. OS and relapse-free survival (RFS) for consolidation (cycles 3 to 5) vs no consolidation, and maintenance (cycles ≥6) vs no maintenance were analyzed using Simon-Makuch and Mantel-Byar odds ratios. Of 267 patients who received blinatumomab induction, 86 (32%) entered consolidation and 36 (13%) entered maintenance. Evidence of longer OS was demonstrated among the maintenance group compared with no-maintenance (median OS [95% confidence interval, CI]: not reached for maintenance vs 15.5 months for no maintenance). Median RFS (months; 95% CI) was numerically longer among maintenance group (14.5; 7.1 to 21.9) compared with no-maintenance (9.8; 8.5 to 11.1). A lower incidence of adverse events was seen during maintenance (72.2%) compared with induction (97.2%) and consolidation (86.1%). Adults with R/R ALL who achieved remission following blinatumomab induction had longer survival on continuation therapy than those who discontinued blinatumomab early, supporting the use of blinatumomab as long-term therapy. No new safety signals were reported. This trial was registered at www.clinicaltrials.gov as #NCT02013167.
- MeSH
- akutní lymfatická leukemie * farmakoterapie MeSH
- dospělí MeSH
- konsolidační chemoterapie MeSH
- lidé MeSH
- protilátky bispecifické * terapeutické užití MeSH
- protinádorové látky * terapeutické užití MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
OBJECTIVE: To evaluate the prognostic power of minimal residual disease (MRD) monitored by polymerase chain reaction at defined time points during early treatment in adult patients with acute lymphoblastic leukemia (ALL). METHODS: Seventy-one patients were treated according to the GMALL 07/2003 protocol and evaluated for MRD in bone marrow by specific clonal rearrangements of Ig/TCR in BCR-ABL negative ALL or fusion gene transcript in BCR-ABL positive ALL. RESULTS: Three-year overall survival (OS) was 94% in patients with BCR-ABL negative ALL reaching complete molecular response (CMR) after the first course of chemotherapy (vs. 32% if MRD >10(-4) ; P = 0.001). Patients with CMR prior to the start of consolidation chemotherapy at week 11 had 3-yr OS 82% (vs. 18% if MRD >10(-4) ; P = 0.001). Patients with BCR-ABL positive ALL showed slower MRD dynamics. There was a trend to better OS in patients with ≥ 4 log reduction of BCR-ABL transcript prior to HSCT (92% vs. 50%; P = 0.065). None of the patients with detectable MRD (both BCR-ABL positive and negative) after HSCT survived 3 yr. CONCLUSION: Early MRD kinetics is an important tool for new prognostication models with direct clinical impact irrespective of standard prognostic factors in patients with BCR-ABL negative ALL.
- MeSH
- akutní lymfatická leukemie genetika mortalita patologie terapie MeSH
- analýza přežití MeSH
- bcr-abl fúzní proteiny genetika MeSH
- dospělí MeSH
- genová přestavba MeSH
- geny TcR MeSH
- imunoglobuliny genetika MeSH
- indukce remise MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- prognóza MeSH
- protokoly protinádorové kombinované chemoterapie terapeutické užití MeSH
- reziduální nádor diagnóza genetika MeSH
- senioři MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Přesná analýza karyotypu leukemických buněk hraje významnou roli při diagnostice, klasifikaci, stanovení prognózy a monitorování léčby nemocných s leukémiemi. U dětských ALL byla popsána řada specifických chro- mozómových aberací, které mají velký prognostický význam. K nejdůležitějším patří hyperdiploidie s více než 50 chromozómy a t(12;21), které jsou považovány za příznivý prognostický faktor a t(9;22) a přestavby MLL genu, které korelují se špatnou prognózou. Proto je včasná a přesná detekce těchto aberací velmi důležitá. Metody FISH překonávají některá omezení metod konvenční cytogenetiky a molekulární genetiky a díky své citlivosti umožňují detekovat specifické chromozómové aberace v mitózách i v nedělících se interfázních jádrech. K detekci hyperdi- ploidních buněčných klonů a strukturních přestaveb používáme dvoubarevnou fluorescenci s centromerickými, respektive lokus-specifickými sondami. K analýze složitých komplexních přestaveb používáme malovací sondy a mnohobarevnou fluorescenční in situ hybridizaci (mFISH). Během posledních 8 let jsme různými metodami vyšetřili celkem 275 dětí s ALL. Translokaci t(9;22) jsme nalezli u sedmi a přestavby MLL genu u 14 nemocných z tohoto souboru. Detekcí hyperdiploidních buněk a t(12;21) se zabýváme od roku 1988. Buňky s vysokou hyper- diploidií jsme detekovali u 35 pacientů, 10 z nich mělo v karyotypu další komplexní přestavby. Translokaci t(12;21) jsme detekovali u 37 nemocných a komplexní přestavby jsme prokázali u 22 z nich. FISH se spolu s cytogenetikou a molekulární genetikou stala v dnešní době nezbytnou součástí laboratorních vyšetření u dětí s ALL, a to nejen při diagnostice, ale i v průběhu léčby.
Classical cytogenetic analysis plays an important role in the diagnosis, classificat ion, therapy monitoring and prognosis of patients with leukemia. Many recurrent cytogenetic abnormalities with major prognostic values have been described in childhood ALL. Hyperdiploidy and/or t(12;21) are associated with good prognosis, whereas t(9;22) and/or rearrangements of MLL gene correlate with poor outcome and therefore early detection of these abnormalities is very important. FISH can overcome some limitations of conventional cytogenetic and molecular-genetic analyses and due to high sensitivity specific chromosomal aberrations in mitoses and/or interphase nuclei can be detected. In the Center of Oncocytogenetics of the 3rd Medical Department for assesment of hyperdiploidy and structural rearrangements we use double-color FISH with centromeric and/or locus-specific probes and complex aberrations are ascertained by whole chromosome painting probes and multicolor FISH. Among 275 children with ALL examined during the last 8 years by different FISH methods we found seven patients with translocation t(9;22) and 14 patients with MLL rearrangements in bone marrow cells. Since 1988 we focus on detection of hyperdiploidy and/or t(12;21). High hyperdiploidy was found in 35 children, 10 of them had further complex rearrangements. Translocation t(12;21) was proved in 37 patients and complex rearrangements were found in 22 of them. FISH, cytogenetic and molecular-genetic analyses become obligatory for the first diagnostic examination as well as for monitoring of treatment effect in children with ALL.
- MeSH
- akutní lymfatická leukemie diagnóza MeSH
- chromozomální aberace MeSH
- cytogenetické vyšetření metody MeSH
- dítě MeSH
- finanční podpora výzkumu jako téma MeSH
- genová přestavba MeSH
- hybridizace in situ fluorescenční metody MeSH
- lidé MeSH
- prognóza MeSH
- translokace genetická MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- Publikační typ
- přehledy MeSH
