ABSTRACT
We report on a 28-year old female patient with fever and severe respiratory insufficiency requiring mechanical ventilation. Cytomegalovirus pneumonia was diagnosed by bronchoalveolar lavage, and antiviral therapy was initiated. However fever persisted and laboratory workup showed pancytopenia and elevated liver enzymes. Additional blood tests demonstrated a markedly elevated ferritin level and high concentrations of inflammatory cytokines. A diagnosis of hemophagocytic lymphohistiocytosis was made and immunosuppressive therapy was started. The patient's condition and laboratory values improved rapidly.
Subject(s)
Cytomegalovirus Infections/diagnosis , Ferritins/blood , Fever of Unknown Origin/etiology , Liver Function Tests , Lymphohistiocytosis, Hemophagocytic/diagnosis , Pancytopenia/etiology , Pneumonia, Viral/diagnosis , Respiratory Insufficiency/etiology , Adult , Antiviral Agents/therapeutic use , Bone Marrow Examination , Cyclosporine/therapeutic use , Cytokines/blood , Cytomegalovirus Infections/drug therapy , Diagnosis, Differential , Drug Therapy, Combination , Etoposide/therapeutic use , Female , Ganciclovir/therapeutic use , Humans , Immunosuppressive Agents/therapeutic use , Lymphohistiocytosis, Hemophagocytic/drug therapy , Pneumonia, Viral/drug therapy , Prednisone/therapeutic use , Tomography, X-Ray ComputedABSTRACT
The T-lineage phenotype of childhood acute lymphoblastic leukaemia (ALL) is associated with an increased relapse-risk and in vitro resistance to drugs as compared to a precursor B phenotype. Antiapoptotic isoforms of p73 that lack part of the transactivation (TA) domain (DeltaTA-p73, i.e. p73Deltaex2, p73Deltaex3, p73Deltaex2/3 and DeltaN-p73) may cause resistance to anticancer agents through inhibition of p53 and/or proapoptotic p73 family members (TA-p73). We demonstrate in our study that the expression of total p73 mRNA was higher in childhood T-ALL compared to controls (P=0.004). In T-ALL, the relative contribution of antiapoptotic DeltaTA-p73 (88%) was larger than of proapoptotic TA-p73 (12%). Leukaemic cells of T-ALL patients expressing higher levels of antiapoptotic p73 were more resistant to the DNA-damaging drug daunorubicin compared to cells of patients with low or negative expression or these isoforms (P(trend)=0.045). Interestingly, p73Deltaex2 was the most abundantly expressed antiapoptotic isoform in daunorubicin-resistant patient cells (44% of total p73). No association was found between high expression of proapoptotic TA-p73 or antiapoptotic DeltaTA-p73 and relapse-risk. Our results suggest that childhood T-ALL is associated with a high expression of DeltaTA-p73. These isoforms may play a role in cellular resistance to DNA-damaging drugs in children at initial diagnosis of T-ALL.
Subject(s)
DNA-Binding Proteins/genetics , Leukemia-Lymphoma, Adult T-Cell/genetics , Nuclear Proteins/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Adolescent , Cell Lineage , Child , Child, Preschool , DNA Methylation , Drug Resistance, Neoplasm , Genes, Tumor Suppressor , Humans , Infant , Leukemia-Lymphoma, Adult T-Cell/drug therapy , Loss of Heterozygosity , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Protein Isoforms , RNA, Messenger/analysis , Tumor Protein p73 , Tumor Suppressor ProteinsABSTRACT
MLL rearranged acute lymphoblastic leukemia (MLL) is an aggressive type of acute lymphoblastic leukemia (ALL), diagnosed predominantly in infants (<1 years of age). Since current chemotherapy fails in >50% of patients with MLL, new therapeutic strategies are desperately needed. For this, understanding the biological features characterizing MLL is necessary. Analysis of gene expression profiles revealed that the expression of the tumor suppressor gene FHIT is reduced in children with MLL rearranged ALL as compared to ALL patients carrying germ line MLL. This finding was confirmed by quantitative real-time PCR. In 100% of the infant MLL cases tested, methylation of the FHIT 5'CpG region was observed, resulting in strongly reduced mRNA and protein expression. In contrast, FHIT methylation in infant and non-infant ALL patients carrying germ line MLL was found in only approximately 60% (P< or =0.004). FHIT expression was restored upon exposing leukemic cells to the demethylating agent decitabine, which induced apoptosis. Likewise and more specifically, leukemic cell death was induced by transfecting MLL rearranged leukemic cells with expression vectors encoding wild-type FHIT, confirming tumor suppressor activity of this gene. These observations imply that suppression of FHIT may be required for the development of MLL, and provide new insights into leukemogenesis and therapeutic possibilities for MLL.
Subject(s)
Acid Anhydride Hydrolases/genetics , Gene Silencing , Myeloid-Lymphoid Leukemia Protein/genetics , Neoplasm Proteins/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Cell Line, Tumor , CpG Islands/genetics , DNA Methylation , Gene Expression Profiling , Gene Rearrangement , Histone-Lysine N-Methyltransferase , Humans , Infant , Precursor Cell Lymphoblastic Leukemia-Lymphoma/diagnosis , RNA, Messenger/genetics , Reverse Transcriptase Polymerase Chain ReactionABSTRACT
Clinical heterogeneity within t(12;21) or TEL/AML1-positive ALL (25% of childhood common/preB ALL) indicates that additional genetic changes might contribute to outcome. We studied the relation between additional genetic changes in TEL(ETV6) and AML1(RUNX1) (FISH), drug sensitivity (MTT assay) and clinical outcome in 143 DCOG and COALL-treated t(12;21)-positive ALL patients. Additional genetic changes in TEL and AML1 were present in 83% of the patients, and consisted of (partial) deletion of the second TEL gene (70%), an extra AML1 gene (23%) or an extra der(21)t(12;21) (10%). More than one additional change was observed in 20%. Disease-free survival (pDFS) of DCOG patients without additional genetic changes (4 years pDFS +/- s.e. 53 +/- 17%) and of those with an extra der(21)t(12;21) (60 +/- 22%) is poorer than that of compared to patients with other additional genetic changes in TEL or AML1 (79 +/- 6%; P-trend = 0.02). This was mainly due to the occurrence of early relapses within 2.5 years after the first diagnosis. Similar observations were found in the COALL cohort, albeit not significant owing to limited follow-up. Multivariate analysis including age, WBC and genetic abnormalities in TEL and/or AML1 showed that especially, in vitro resistance to prednisolone (hazard ratio 5.78, 95% CI 1.45-23.0; P=0.01) is an independent prognostic factor in DCOG- and COALL-treated t(12;21)-positive ALL.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Chromosomes, Human, Pair 12 , Chromosomes, Human, Pair 21 , Core Binding Factor Alpha 2 Subunit/genetics , Oncogene Proteins, Fusion/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Translocation, Genetic , Disease-Free Survival , Drug Resistance, Neoplasm , Humans , In Situ Hybridization, Fluorescence , Treatment OutcomeABSTRACT
The T-lineage phenotype in children with acute lymphoblastic leukaemia (ALL) is associated with in vitro drug resistance and a higher relapse-risk compared to a precursor B phenotype. Our study was aimed to investigate whether mutations in the ATM gene occur in childhood T-lineage acute lymphoblastic leukaemia (T-ALL) that are linked to drug resistance and clinical outcome. In all, 20 different single nucleotide substitutions were found in 16 exons of ATM in 62/103 (60%) T-ALL children and 51/99 (52%, P = 0.21) controls. Besides the well-known polymorphism D1853N, five other alterations (S707P, F858L, P1054R, L1472W, Y1475C) in the coding part of ATM were found. These five coding alterations seem to occur more frequently in T-ALL (13%) than controls (5%, P = 0.06), but did not associate with altered expression levels of ATM or in vitro resistance to daunorubicin. However, T-ALL patients carrying these five coding alterations presented with a higher white blood cell count at diagnosis (P = 0.05) and show an increased relapse-risk (5-year probability of disease-free survival (pDFS) = 48%) compared to patients with other alterations or wild-type ATM (5-year pDFS = 76%, P = 0.05). The association between five coding ATM alterations in T-ALL, their germline presence, white blood cell count and unfavourable outcome may point to a role for ATM in the development of T-ALL in these children.
Subject(s)
Cell Cycle Proteins/genetics , DNA-Binding Proteins/genetics , Leukemia-Lymphoma, Adult T-Cell/drug therapy , Leukemia-Lymphoma, Adult T-Cell/genetics , Polymorphism, Single Nucleotide , Protein Serine-Threonine Kinases/genetics , Tumor Suppressor Proteins/genetics , Adolescent , Adult , Aged , Antibiotics, Antineoplastic/pharmacology , Ataxia Telangiectasia Mutated Proteins , Case-Control Studies , Child , Child, Preschool , Daunorubicin/pharmacology , Disease-Free Survival , Drug Resistance, Neoplasm/genetics , Female , Gene Expression Profiling , Genetic Predisposition to Disease , Humans , Infant , Leukemia-Lymphoma, Adult T-Cell/pathology , Leukocyte Count , Male , Middle Aged , Phenotype , Prognosis , Reverse Transcriptase Polymerase Chain Reaction , Risk FactorsABSTRACT
PURPOSE: To confirm the prognostic value of a drug resistance profile combining prednisolone, vincristine, and l-asparaginase (PVA) cytotoxicity in an independent group of children with acute lymphoblastic leukemia (ALL) treated with a different protocol and analyzed at longer follow-up compared with our previous study of patients treated according to the Dutch Childhood Leukemia Study Group (DCLSG) ALL VII/VIII protocol. PATIENTS AND METHODS: Drug resistance profiles were determined in 202 children (aged 1 to 18 years) with newly diagnosed ALL who were treated according to the German Cooperative Study Group for Childhood Acute Lymphoblastic Leukemia (COALL)-92 protocol. RESULTS: At a median follow-up of 6.2 years (range, 4.1 to 9.3 years), the 5-year disease-free survival probability (pDFS) rate +/- SE was 69% +/- 7.0%, 83% +/- 4.4%, and 84% +/- 6.8% for patients with resistant (PVA score 7 to 9), intermediate-sensitive (PVA score 5 to 6), and sensitive (SPVA score 3 to 4) profiles, respectively (sensitive and intermediate-sensitive v resistant, P =.05). Resistant patients were at increased risk of an early event (nonresponse or relapse within 2.5 years of diagnosis) compared with sensitive and intermediate-sensitive patients (P =.03). The profile did not identify patients at higher risk of late relapse, which was also observed for DCLSG ALL-VII/VIII patients now analyzed at a median of 7.5 years of follow-up (range, 4.4 to 10.8 years). Despite being nondiscriminative for late relapses, the resistant profile was still the strongest prognostic factor for COALL-92 patients in a multivariate analysis including known risk factors (P =.07). CONCLUSION: Drug resistance profiles identify patients at higher risk of early treatment failures and may, therefore, be used to improve risk-group stratification of children with ALL.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Patient Selection , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Adolescent , Antineoplastic Agents, Hormonal/administration & dosage , Antineoplastic Agents, Phytogenic/administration & dosage , Asparaginase/administration & dosage , Chi-Square Distribution , Child , Child, Preschool , Disease-Free Survival , Drug Resistance, Multiple , Drug Resistance, Neoplasm , Drug Screening Assays, Antitumor/standards , Female , Humans , Infant , Male , Predictive Value of Tests , Prednisolone/administration & dosage , Risk , Statistics, Nonparametric , Vincristine/administration & dosageABSTRACT
The German Co-operative Study Group COALL for treatment of acute lymphoblastic leukemia (ALL) in childhood started the first trial in 1980. This report gives an overview of the long-term results of the four consecutive studies COALL-82, COALL-85, COALL-89 and COALL-92. Besides improvement in long-term survival major objectives were reduction of treatment-related toxicity by transferring asparaginase (ASP) from induction therapy to intensive phase and omitting CNS irradiation by stepwise increase of the initial white blood count (WBC) up to 50 x 10(9)/l (exception T-ALL) as criterion for irradiation. In study COALL-85 in high risk patients slow vs rapid rotational treatment was randomized. In study COALL-92 initial response to daunorubicin (DNR) as a 1-h vs 24-h infusion and its prognostic value was investigated. Furthermore, 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) were randomized in maintenance treatment. In total, 1191 eligible patients were enrolled. Induction treatment without ASP has been shown to be as effective and less hazardous than the former four-drug induction. CNS control could be obtained in most without cranial irradiation (CNS relapse-free survival >95%). The leukemic cell kill with a 24-h DNR infusion was equivalent to that of a 1-h infusion. DNR response was of less prognostic significance than prednisone response. The rapid rotation regimen failed to improve outcome as well as 6-TG in maintenance treatment. However, intensification of systemic treatment resulted in an increase in overall event-free survival (EFS) to approximately 80% which is comparable to other groups.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Clinical Trials as Topic , Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy , Child , Child, Preschool , Combined Modality Therapy , Female , Follow-Up Studies , Humans , Infant , Male , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/radiotherapy , Treatment OutcomeABSTRACT
Resistance to anthracyclines is related to a poor prognosis in childhood acute lymphoblastic leukemia (ALL). Resistance to this class of drugs may (partly) be reversed by modulating agents, as has been demonstrated in a variety of cell lines. However, it is unknown which modulators may be of clinical benefit in childhood ALL. Therefore, we studied the modulating effect of PSC 833, cyclosporin A (CsA), verapamil (Vp) and genistein on daunorubicin (DNR) cytotoxicity, accumulation and retention in childhood ALL cells. DNR cytotoxicity was determined using the MTT assay; DNR accumulation, DNR retention and the expression of P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP) and major vault protein/lung resistance protein (LRP) were determined by flow cytometry. In the majority of samples PSC 833 (19/26), CsA (22/26) and Vp (15/18) sensitized the cells to DNR whereas genistein made 25 out of 26 samples more resistant to DNR. The sensitizing effect on the cytotoxicity of DNR was median 1.2-fold using 2 microM PSC 833 (P = 0.025), 1.5-fold using 4 microM CsA (P = 0.003) and 1.6-fold using 6 microM Vp (P = 0.012) whereas the adverse effect of 25 microM genistein was median 1.8-fold (P < 0.0001). No relationship was found between the sensitizing effect of PSC 833, CsA or Vp and the degree of DNR resistance. In contrast, the adverse effect of genistein was largest in DNR sensitive samples (P = 0.003). The effect of each modulator on the cytotoxicity of DNR did not differ between initial and relapse ALL samples although the latter were median 1.4-fold more resistant to DNR (P = 0.005). Modulation of DNR cytotoxicity was not correlated with changes in the accumulated and retained intracellular DNR content or with the expression of P-gp, MRP and LRP. Besides genistein, PSC 833, CsA and Vp incidentally made ALL cells more resistant to DNR. CsA stimulated the leukemic cell survival in seven out of 26 samples, a phenomenon that was not related to the degree of DNR resistance. In conclusion, PSC 833, CsA and Vp but not genistein may be used to sensitize cells to DNR in childhood ALL. The data also indicate that not all patients may have a therapeutic benefit from these modulators. Therefore, an in vitro culture assay may be necessary to screen for patients who may benefit by a modulator in their therapy.
Subject(s)
Antibiotics, Antineoplastic/pharmacokinetics , Cyclosporine/pharmacology , Cyclosporins/pharmacology , Daunorubicin/pharmacokinetics , Genistein/pharmacology , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Verapamil/pharmacology , ATP Binding Cassette Transporter, Subfamily B, Member 1/analysis , ATP-Binding Cassette Transporters/analysis , Cell Survival/drug effects , Drug Resistance, Neoplasm , Humans , In Vitro Techniques , Multidrug Resistance-Associated Proteins , Precursor Cell Lymphoblastic Leukemia-Lymphoma/metabolismABSTRACT
Infants with acute lymphoblastic leukemia (ALL) are more resistant to chemotherapeutic drugs than older children with ALL, except for Ara-C. Drug resistance mechanisms in infant ALL, however, remain unknown. Possibly, multidrug resistance (MDR) proteins like P-glycoprotein, MDR-associated protein (MRP1), lung resistance-related protein (LRP/MVP) and the breast cancer resistance protein (BCRP) play a role. Accordingly, we measured the mRNA levels of these proteins in infants (n=13) and non-infants (n=13) with ALL, using quantitative RT-PCR. Infants expressed 2.4-fold less BCRP mRNA (P=0.009) than non-infants with ALL. MDR1, MRP1 and LRP/MVP expression did not differ between both groups. MDR gene expression levels did not correlate to prednisolone, vincristine, daunorubicin or Ara-C cytotoxicity, except for BCRP expression, which correlated with resistance to Ara-C (Rs=0.53, P=0.012), suggesting that Ara-C might be a BCRP substrate. However, culturing patients ALL cells in the presence of the BCRP inhibitor Ko143 had no effect on Ara-C sensitivity. Inhibiting Bcrp1 in the Mdr1a-, Mdr1b- and Mrp1-deficient and Bcrp1-overexpressing mouse cell line Mef3.8/T6400, also did not modulate Ara-C cytotoxicity. Therefore, we conclude that Ara-C is not a substrate for BCRP and that MDR proteins do not play a significant role in drug resistance in infant ALL.
Subject(s)
ATP-Binding Cassette Transporters/genetics , Antimetabolites, Antineoplastic/metabolism , Cytarabine/metabolism , Drug Resistance, Multiple/genetics , Drug Resistance, Neoplasm/genetics , Neoplasm Proteins/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics , ATP Binding Cassette Transporter, Subfamily G, Member 2 , Animals , Antineoplastic Agents/pharmacology , Cell Survival/drug effects , Cells, Cultured , Child , Child, Preschool , Fibroblasts/metabolism , Gene Expression Regulation, Leukemic , Humans , Infant , Mice , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/metabolism , RNA, Messenger/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Topotecan/pharmacology , Vault Ribonucleoprotein Particles/geneticsABSTRACT
In vitro resistance to anthracyclines is related to a poor prognosis in childhood acute lymphoblastic leukemia (ALL), but the underlying mechanisms are poorly understood. Using flow cytometry, we studied the contribution of daunorubicin (DNR) accumulation and retention, cell size, expression of the major vault protein/lung resistance protein (LRP), P-glycoprotein (P-gp) and multidrug resistance-associated protein (MRP) to the cytotoxicity of DNR (by MTT assay) in childhood ALL. The accumulated and retained DNR content was not related to the degree of DNR resistance, nor did the content differ between 53 initial and 20 relapse ALL samples (P >0. 05), although the latter were median two-fold more resistant to DNR (P = 0.004). Leukemic cell volume correlated with resistance to the anthracyclines DNR (Rs 0.32, P = 0.012) and idarubicin (Rs 0.46, P = 0.011) but not to other classes of drugs such as prednisolone, vincristine, L-asparaginase and etoposide. Relapsed patients had 1. 5-fold larger cells than patients at initial diagnosis of ALL (P = 0. 001). After cell volume correction, the intracellular DNR concentration was lower in relapsed compared with initial ALL cells (eg 60 min accumulation, P = 0.003). Moreover, the intracellular DNR concentration inversely correlated with DNR resistance, both in the accumulation (Rs -0.44, P < 0.001) and retention (Rs -0.33, P = 0. 016) test condition. The accumulated DNR concentration inversely correlated with expression of LRP (Rs -0.36, P = 0.012) but not with P-gp and MRP. Expression of LRP, but not of P-gp and MRP, significantly correlated with DNR resistance in childhood ALL (Rs 0. 33, P = 0.03). In conclusion, the intracellular DNR concentration and the expression level of LRP may contribute to DNR resistance in childhood ALL. The strength of the correlations also indicates that resistance to anthracyclines can not be explained by one single mechanism.
Subject(s)
Antibiotics, Antineoplastic/pharmacokinetics , Daunorubicin/pharmacokinetics , Neoplasm Proteins/physiology , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Vault Ribonucleoprotein Particles/physiology , Drug Resistance, Multiple , Drug Resistance, Neoplasm , Humans , Precursor Cell Lymphoblastic Leukemia-Lymphoma/metabolism , Tumor Cells, CulturedABSTRACT
Acute lymphoblastic leukemia (ALL) in infants under 1 year is strongly associated with translocations involving 11q23 (MLL gene), CD10-negative B-lineage (proB) immunophenotype, and poor outcome. The present study analyses the relationship between age, MLL rearrangements, proB-lineage, and in vitro drug resistance determined using the MTT assay. Compared to 425 children aged over 1 year with common/preB (c/preB) ALL, the 44 infants were highly resistant to steroids (for prednisolone (PRED) more than 580-fold, P=0.001) and L-asparaginase (L-ASP) (12-fold, P=0.001), but more sensitive to cytarabine (AraC) (1.9-fold, P=0.001) and 2-chlorodeoxyadenosine (2-CdA) (1.7-fold, P<0.001). No differences were found for vincristine, anthracyclines, thiopurines, epipodophyllotoxines, or 4-hydroperoxy (HOO)-ifosfamide. ProB ALL of all ages had a profile similar to infant ALL when compared with the group of c/preB ALL: relatively more resistant to L-ASP and PRED (and in addition thiopurines), and more sensitive to AraC and 2-CdA. Age was not related to cellular drug resistance within the proB ALL group (<1 year, n=32, vs >/=1 year, n=19), nor within the MLL-rearranged ALL (<1 year, n=34, vs >/=1 year, n=8). The translocation t(4;11)(q21;q23)-positive ALL cases were more resistant to PRED (>7.4-fold, P=0.033) and 4-HOO-ifosfamide (4.4-fold, P=0.006) than those with other 11q23 abnormalities. The expression of P-glycoprotein, multidrug-resistance protein, and lung-resistance protein (LRP) was not higher in infants compared to older c/preB ALL patients, but LRP was higher in proB ALL and MLL-rearranged ALL of all ages. In conclusion, infants with ALL appear to have a distinct in vitro resistance profile with the proB immunophenotype being of importance. The role of MLL cannot be excluded, with the t(4;11) being of special significance, while age appears to play a smaller role.
Subject(s)
Antineoplastic Agents/pharmacology , DNA-Binding Proteins/genetics , Drug Resistance, Neoplasm , Gene Rearrangement , Immunophenotyping , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Proto-Oncogenes , Transcription Factors , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Age Distribution , Drug Screening Assays, Antitumor , Female , Histone-Lysine N-Methyltransferase , Humans , In Vitro Techniques , Infant , Infant, Newborn , Male , Myeloid-Lymphoid Leukemia Protein , Neoplasm Proteins/metabolism , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology , Vault Ribonucleoprotein Particles/metabolismABSTRACT
The clinical course of a 17-year-old patient who suffered from chronic neutropenia without cyclic variation since the age of 2 is presented. The bone marrow showed absent granulopoiesis and yielded very few colony-forming units (CFU-GM) in vitro with maturation up to segmented neutrophils. Incubation with cyclosporin A (CyA) increased CFU-GM markedly. Such an increase was not found after incubation of normal bone marrow with CyA in vitro. The patient also responded to CyA in vivo and maintained adequate granulocyte counts for 7 months when she became neutropenic again. She subsequently responded to high doses of prednisolone. The clinical course and bone marrow studies suggest that the defective granulopoiesis is due to an immunologically mediated mechanism sensitive to CyA and prednisolone. Other findings in this patient, such as impaired natural killer (NK) cell activity and random and chemotactic leukocyte motility, could further point to an imbalance in the regulation of hematopoiesis. Neutropenia, NK cell defect and impaired chemotaxis may be pathogenetically connected.
Subject(s)
Cyclosporine/therapeutic use , Neutropenia/drug therapy , Adolescent , Autoimmune Diseases/drug therapy , Bone Marrow/pathology , Cell Differentiation/drug effects , Cells, Cultured , Chemotaxis, Leukocyte , Chronic Disease , Colony-Forming Units Assay , Cyclosporine/pharmacology , Female , Hematopoietic Stem Cells/drug effects , Hematopoietic Stem Cells/pathology , Humans , Killer Cells, Natural/pathology , Neutrophils/pathology , Prednisolone/therapeutic use , Respiratory Burst , Stimulation, Chemical , T-Lymphocytes/pathologySubject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Leukemia, Lymphoid/drug therapy , Adolescent , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Child , Child, Preschool , Combined Modality Therapy , Drug Administration Schedule , Drug Evaluation , Drug Resistance , Female , Humans , Infant , Leukemia, Lymphoid/radiotherapy , Male , Remission InductionSubject(s)
Antineoplastic Agents, Hormonal/metabolism , Dexamethasone/metabolism , Leukemia, Myeloid/metabolism , Precursor Cell Lymphoblastic Leukemia-Lymphoma/metabolism , Receptors, Glucocorticoid/metabolism , Acute Disease , Bone Marrow/chemistry , Child , Drug Resistance, Neoplasm , Humans , In Vitro Techniques , Leukemia, Myeloid/blood , Leukemia, Myeloid/drug therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/blood , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , TemperatureABSTRACT
In this study, the long-term outcome of 1818 patients treated in five consecutive clinical trials (the cooperative study group for childhood acute lymphoblastic leukaemia (COALL) 82, 85, 89, 92 and 97) from 24 cooperating centres in Germany is reported. The probability of event-free survival (pEFS) improved significantly from the first two trials conducted in the 1980s (COALL 82 and COALL 85) to the three trials conducted in the 1990s (COALL 89, 92 and 97) (P=0.001). Through all COALL studies, age > or =10 years and initial white blood cell count (WBC) > or =50 x 10(9)/l and pro-B immunophenotype were of significant prognostic relevance. A refinement of risk assessment has been achieved by in vitro drug sensitivity testing in COALL 92 and 97. In patients with very sensitive leukaemic cells, therapy could be reduced without loss of efficacy. In COALL 97, a further improvement in risk stratification was gained by the molecular assessment of minimal residual disease (MRD) under treatment, which proved to have a superior prognostic effect when compared with in vitro drug sensitivity testing. Importantly, the gradual reduction in central nervous system (CNS) irradiation led to a decreased incidence of brain tumours as a second malignancy. In general, the prevention of treatment-related late effects will be one of the major issues in future studies. It remains to be shown whether prolonged infusions of anthracyclines, which have been implemented into the COALL studies after equal efficacy compared with short-time infusions was confirmed, will be associated with fewer cardiac late effects. Another way to prevent late effects may be a more refined risk assessment allowing for a reduction in cumulative treatment burden. A great challenge in the future will be to improve the overall treatment results, which very likely can only be achieved by the identification of molecularly defined subgroups to which novel, rational therapeutic strategies can be applied.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cranial Irradiation , Neoplasm Recurrence, Local/therapy , Neoplasm, Residual/therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy , Adolescent , Child , Child, Preschool , Combined Modality Therapy , Female , Follow-Up Studies , Humans , Immunophenotyping , Infant , Leukocyte Count , Male , Neoplasm Recurrence, Local/diagnosis , Neoplasm, Residual/diagnosis , Precursor Cell Lymphoblastic Leukemia-Lymphoma/diagnosis , Prognosis , Remission Induction , Risk Factors , Survival Rate , Time Factors , Treatment OutcomeABSTRACT
Assessment of minimal residual disease (MRD) has acquired a prominent position in European treatment protocols for patients with acute lymphoblastic leukemia (ALL), on the basis of its high prognostic value for predicting outcome and the possibilities for implementation of MRD diagnostics in treatment stratification. Therefore, there is an increasing need for standardization of methodologies and harmonization of terminology. For this purpose, a panel of representatives of all major European study groups on childhood and adult ALL and of international experts on PCR- and flow cytometry-based MRD assessment was built in the context of the Second International Symposium on MRD assessment in Kiel, Germany, 18-20 September 2008. The panel summarized the current state of MRD diagnostics in ALL and developed recommendations on the minimal technical requirements that should be fulfilled before implementation of MRD diagnostics into clinical trials. Finally, a common terminology for a standard description of MRD response and monitoring was established defining the terms 'complete MRD response', 'MRD persistence' and 'MRD reappearance'. The proposed MRD terminology may allow a refined and standardized assessment of response to treatment in adult and childhood ALL, and provides a sound basis for the comparison of MRD results between different treatment protocols.
Subject(s)
Precursor Cell Lymphoblastic Leukemia-Lymphoma/diagnosis , Flow Cytometry , Fusion Proteins, bcr-abl/genetics , Gene Rearrangement , Genes, Immunoglobulin , Humans , Neoplasm, Residual/diagnosis , Polymerase Chain Reaction , Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapyABSTRACT
BACKGROUND: Daunorubicin (DNR) is one of the most important drugs in treatment of acute lymphoblastic leukemia (ALL). Prolonged infusions of anthracyclines are less cardiotoxic but it has not been investigated whether the in vivo leukemic cell kill is equivalent to short-term infusions. PROCEDURE: In the cooperative treatment study COALL-92 for childhood ALL 178 patients were randomized to receive in a therapeutic window a single dose of 36 mg/m (2) DNR either as a 1-h (85 patients) or 24-h infusion (93 patients). Daily measurements of white blood cell count (WBC) and peripheral blood smears for seven days could be evaluated centrally in 101 patients (1-h: 43 patients, 24-h: 58 patients). RESULTS: The proportional decline of blasts at day 7 after DNR infusion showed no statistically significant difference between the two treatment arms. At day 3 the median percentage of blasts was less than 10%, at day 7 less than 2% for either the 1-h or 24-h infusion. Twelve patients (1-h: 5 patients, 24-h: 7 patients) had an absolute number of more than 1000 blasts per mul peripheral blood (PB) at day 7 after DNR infusion (DNR poor responders). Kaplan-Meier analysis showed an equal probability of EFS for the short- and long-term infusion group (24-h: 83%+/-5; 1-h: 81+/-6) after a median observation time of 12.3 years. CONCLUSIONS: We conclude that in children with ALL a 24-h infusion of DNR has the same in vivo cytotoxicity for leukemic cells as a 1-h infusion. This offers the possibility to use prolonged infusions with hopefully less cardiotoxicity without loss of efficacy.
Subject(s)
Antibiotics, Antineoplastic/administration & dosage , Cell Survival/drug effects , Daunorubicin/administration & dosage , Leukocyte Count , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Adolescent , Antibiotics, Antineoplastic/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Child , Child, Preschool , Daunorubicin/adverse effects , Disease-Free Survival , Drug Administration Schedule , Female , Humans , Infant , Infusions, Intravenous , Injections, Spinal , Long-Term Care , Male , Mercaptopurine/administration & dosage , Mercaptopurine/adverse effects , Methotrexate/administration & dosage , Methotrexate/adverse effects , Thioguanine/administration & dosage , Thioguanine/adverse effects , Treatment OutcomeABSTRACT
UNLABELLED: Polyethylene glycol conjugated asparaginase (PEG-ASNase) can be substituted in cases of hypersensitivity to native Escherichia coli asparaginase. We measured asparagine (asn) levels in plasma after a single dose of 2,500 IU/m(2) i.v. PEG-ASNase (Oncaspar) in consolidation treatment of ALL and compared those with data from the previous protocol COALL-05-92. This protocol was similar to COALL-06-97, except that children had been given 45,000 IU/m(2) C-ASNase instead of PEG-ASNase. PATIENTS AND METHODS: Between May 2000 and December 2001 seventy-one children (38 boys, 33 girls) with newly diagnosed ALL treated according to the multicenter protocol COALL-06-97 were investigated in this study. Four hundred and seventy-four plasma samples (71 patients) were analysed by ion exchange chromatography after column derivatization with o-phthaldialdehyde. For comparison data (350 plasma samples) from 51 patients treated according to the protocol COALL-05-92 were available. The same method for detection of asn in plasma was used. RESULTS: The median asparagine level in plasma after 2,500 IU/m(2) PEG-ASNase i.v. was below the limit of detection for at least 5 weeks in 81 % of the patients. When divided into high risk (HR) and low risk (LR) group, HR patients who had previously received one dose more of C-ASNase showed a markedly shorter depletion than the LR patients compatible with a higher risk of antibody formation and consequent silent inactivation after a higher number of exposures to ASNase. In the previous protocol COALL-05-92 median asn levels in plasma after 45,000 IU/m(2) native C-ASNase i.v. were below the limit of detection for at least 5 weeks in 65 % of the patients. CONCLUSIONS: 2,500 IU/m(2) PEG-ASNase led to an equally long depletion of asn in plasma as did 45,000 IU/m(2) native C-ASNase i.v. used in COALL-05-92.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Asparaginase/administration & dosage , Asparagine/blood , Polyethylene Glycols/administration & dosage , Precursor Cell Lymphoblastic Leukemia-Lymphoma/blood , Adolescent , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Child , Child, Preschool , Chromatography, Ion Exchange , Dose-Response Relationship, Drug , Drug Hypersensitivity/immunology , Drug Hypersensitivity/prevention & control , Female , Half-Life , Humans , Infant , Infusions, Intravenous , Male , Multicenter Studies as Topic , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Randomized Controlled Trials as Topic , Treatment OutcomeABSTRACT
Two children developed multiple melanocytic naevi after polychemotherapy administered for acute lymphoblastic leukaemia in one and for non-Hodgkin lymphoma in the other. Induction of naevi does not seem to be related to specific agents used in chemotherapy, but rather to the immunosuppression resulting from multiple-agent chemotherapy. There are reports in the literature of both intrinsically and iatrogenically immunosuppressed patients who have developed multiple melanocytic naevi.