Probability Of Continuous Complete Remission Research Articles

Adults with Philadelphia chromosome-like acute lymphoblastic leukemia frequently have IGH-CRLF2 and JAK2 mutations, persistence of minimal residual disease and poor prognosis.

Philadelphia-like B-cell precursor acute lymphoblastic leukemia (Ph-like ALL) is characterized by distinct genetic alterations and inferior prognosis in children and younger adults. The purpose of this study was a genetic and clinical characterization of Ph-like ALL in adults. Twenty-six (13%) of 207 adult patients (median age: 42 years) with B-cell precursor ALL (BCP-ALL) were classified as having Ph-like ALL using gene expression profiling. The frequency of Ph-like ALL was 27% among 95 BCP-ALL patients negative for BCR-ABL1 and KMT2A-rearrangements. IGH-CRLF2 rearrangements (6/16; P=0.002) and mutations in JAK2 (7/16; P<0.001) were found exclusively in the Ph-like ALL subgroup. Clinical and outcome analyses were restricted to patients treated in German Multicenter Study Group for Adult ALL (GMALL) trials 06/99 and 07/03 (n=107). The complete remission rate was 100% among both Ph-like ALL patients (n=19) and the "remaining BCP-ALL" cases (n=40), i.e. patients negative for BCR-ABL1 and KMT2A-rearrangements and the Ph-like subtype. Significantly fewer Ph-like ALL patients reached molecular complete remission (33% versus 79%; P=0.02) and had a lower probability of continuous complete remission (26% versus 60%; P=0.03) and overall survival (22% versus 64%; P=0.006) at 5 years compared to the remaining BCP-ALL patients. The profile of genetic lesions in adults with Ph-like ALL, including older adults, resembles that of pediatric Ph-like ALL and differs from the profile in the remaining BCP-ALL. Our study is the first to demonstrate that Ph-like ALL is associated with inferior outcomes in intensively treated older adult patients. Ph-like adult ALL should be recognized as a distinct, high-risk entity and further research on improved diagnostic and therapeutic approaches is needed. (NCT00199056, NCT00198991).

BCR-ABL1-like Acute Lymphoblastic Leukemia Is Associated with IKZF1 and JAK2 Alterations and inferior Outcome in Adults

Background: BCR-ABL1-like (Ph-like) B-precursor acute lymphoblastic leukemia (ALL) displays a gene expression profile closely related to B-precursor ALL with t(9;22)(q34;q11). In addition, Ph-like ALL patients (pts) are characterized by distinct genetic alterations and inferior prognosis in pediatric trials. The purpose of this study was the genetic and clinical characterization of Ph-like ALL in adults.Methods: Affymetrix gene expression profiles (GEP) generated from diagnostic bone marrow samples of 306 adult B-precursor and T-ALL pts (median age 41 years, range 16-84 years) were classified as Ph-like ALL according to published algorithms (Roberts et al., Cancer Cell 2012) and separated from BCR-ABL1-positive and B-other ALL pts (BCR-ABL1-negative; non Ph-like). The incidence and genetic characteristics of the Ph-like subset were analyzed in the overall cohort, whereas clinical and outcome analysis were restricted to B-precursor ALL pts treated within GMALL trials 06/99 and 07/03 (n=107). The median age of this population was 30 (16-64) years. The routine diagnostic work-up included immunophenotyping, fluorescent in situ hybridization (FISH) for BCR-ABL1 and KMT2A (MLL) rearrangements, cytogenetics and molecular analyses of BCR-ABL1 translocations and MLL rearrangements. A subgroup of pts with B-precursor ALL was analyzed for CRLF2 alterations by FISH (n=88) and by RT-PCR for the P2RY8-CRLF2 translocation (n=117). Multiplex ligation-dependent probe amplification (MLPA) for common copy number variations (SALSA MLPA probemix P335-B1) and targeted amplicon sequencing of 131 genes recurrently mutated in ALL were performed in BCR-ABL1 positive (n=30), Ph-like (n=16) and B-other ALL pts (n=23).Results: Of the 306 pts, we classified 26 pts (9%) as Ph-like ALL based on their GEP and the absence of the BCR-ABL1 translocation, corresponding to an incidence of 13% (26/207) in B-precursor ALL and 24% (26/110) among BCR-ABL1-negative B-precursor ALL.Nineteen of 107 B-precursor ALL pts treated within the GMALL trials displayed a Ph-like phenotype. There were no significant differences in baseline characteristics like age, sex, white-cell count, hemoglobin or platelet count and risk group in comparison to the B-other subgroup (n=51). All 19 Ph-like pts showed no MLL rearrangement and 58% belonged to the standard risk group. The complete remission rate after induction was similar for Ph-like and B-other pts (96% vs 100%; p>0.05). At 5 years, the Ph-like ALL subgroup had a lower probability of continuous complete remission (RD: 24% vs 63%; p=0.004) and overall survival (OS: 22% vs 56%; p=0.05) compared to B-other ALL pts. After exclusion of pts with MLL rearrangement from the B-other group (n=11), these differences remained significant (RD: 24% vs 62%; p<0.001; OS: 22% vs 64%; p=0.006).MLPA and amplicon sequencing revealed specific genetic alterations associated with the Ph-like ALL subgroup (Figure 1). All pts with IGH-CRLF2 (n=6) were identified in the Ph-like subgroup, whereas all pts with P2RY8-CRLF2 (n=2) were found in the B-other group (p<0.001 and p>0.05, respectively). Additionally, most pts with high CRLF2 expression clustered in the Ph-like ALL subgroup (13/26, 50% vs 8/79, 10% of B-other; p<0.001). Deletions of IKZF1 were significantly more common in Ph-like ALL (13/16, 81%; p=0.003) and in BCR-ABL1 positive ALL (21/30, 70%; p=0.005) in contrast to B-other ALL (7/21, 30%). Mutations in JAK2 were exclusively found in the Ph-like subgroup (0/53, 0% vs 7/16, 44%; p<0.001). In our data set, FISH for IGH-CRLF2 and sequencing of JAK2 was sufficient to identify Ph-like cases with a sensitivity and specificity of 59% and 100%, respectively.Conclusion: Ph-like ALL in adults is associated with inferior survival in a homogenously treated group of pts. Additionally, molecular analysis revealed distinct genetic alterations identifying this specific ALL subtype. Since gene expression analysis could be difficult to be implemented in routine diagnostics our data suggest, that testing for JAK2 mutations and the IGH-CRLF2 translocation could be options for the diagnosis of the Ph-like subtype. Future treatment strategies should be explored to improve the dismal prognosis for these high risk pts. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Moderate Intensive Chemotherapy Including CNS-Prophylaxis with Liposomal Cytarabine Is Feasible and effective in Older Patients with Ph-Negative Acute Lymphoblastic Leukemia (ALL): Results of a Prospective Trial From the German Multicenter Study Group for Adult ALL (GMALL)

Abstract 1493 Few older ALL pts are entered into prospective trials and data on characteristics and outcome are scarce. The GMALL started a prospective trial in older ALL (>55 yrs) in 2003. In Ph-neg ALL a prephase (Dexa, Cyclo, MTX i.th.) was followed by induction I (Dexa, VCR, Idarubicin), induction II (Cyclo, AraC), alternating consolidation with IDMTX (d 1,15) ×3, VM26/AraC ×2, reinduction (VCR, Ida, Cyclo, AraC) and maintenance (MP, MTX) up to 2 yrs. In CD20+ ALL Rituximab ×8 was added. CNS-prophylaxis consisted of i.th. triple combination (MTX, AraC, Dexa) ×4 during induction, ×8 during consolidation/maintenance. The original protocol (group 1) was amended to optimize CNS prophylaxis and consolidation (group 2). I.th. therapy was then performed with liposomal cytarabine, 3x during induction, 3x during consolidation. IDMTX dose was increased from 500 to 1000 mg/m 2 and native E.coli ASP (10.000 U/m 2 ) was added on d2 and d16 of IDMTX. VM26/AraC was replaced by IDAraC (1000 mg/m 2 d1,3,5). In a further amendment the original i.th. prophylaxis was reinserted until final analysis of liposomal AraC became available. Furthermore, after induction, one cycle with pegylated ASP (500 U/m 2 ) (PEG-ASP) was scheduled to evaluate feasibility in older pts (group 3). Results of induction were compared for groups 1–3; outcome analysis was restricted to 1–2 due to still short follow-up for group 3. 268 pts with a median age of 67 (55–85) yrs treated in 94 hospitals were evaluable (180, 43 and 45 pts in groups 1, 2 and 3 resp.). 39% were aged 55–65 yrs, 51% 66–75 yrs and 10% above 75 yrs. 67% had c/pre-B-ALL, 18% pro-B-ALL and 15% T-ALL. WBC was >30/nL in 27%. Poor ECOG status (≥2) before (ECOGb) or after (ECOGa) onset of ALL was described in 7% or 38% resp. 78% had any comorbidity and 9% had a Charlson score (ChS) ≥3. No significant differences were detected between groups 1–3. Overall 76% (N=203) achieved CR after induction, 14% experienced early death (ED) and 10% did not achieve CR. In groups 1–3 CR rates were 72%, 86% and 82% resp. and ED rates 18%, 0% and 11% resp. (p=.03). CR rates were 84%, 74% and 52% in three age groups (p=.002) with ED rates of 7%, 14% and 37% resp. (p=.0004). Immunophenotype and WBC ( 30.000) correlated with CR but not ED rate. ECOGb 0–1 vs ≥2 correlated with CR (82% vs 33%;p Overall survival (OS) at 5 yrs was 23%; 33% at 2 yrs for group 1 and 52% for group 2 resp. (p=.01). Mortality in CR was 6% and 15% of the pts were withdrawn in CR. Probability of continuous complete remission (CCR) was 32% at 5 yrs, 42% and 43% at 2 yrs for group 1 and group 2 resp. (p=>.05). Age (42% vs 37% vs 8%;p=.0007), WBC (43% vs 15%;p With this age adapted regimen a favorable CR rate was achieved in a large patient group with a median age of 67 yrs. CR was increased (86%) and mortality was decreased (0%) significantly with liposomal cytarabine compared to triple i.th. prophylaxis during induction, since the latter probably induced more bone marrow toxicity. Reduced ED contributed considerably to improved OS. Moderate intensive consolidation was feasible and ASP, including PEG-ASP, was well tolerated. Age was correlated with outcome and 75 yrs appears to be the upper limit for this regimen. General condition was an additional highly relevant prognostic factor whereas comorbidity, measured by Charlson score was associated with ED but not with OS. These results encourage further treatment optimisation in older ALL pts, including those with comorbidities, based on comprehensive diagnostics, geriatric assessment, MRD evaluation, intensified consolidation, use of ASP, dose-reduced stem cell transplantation and integration of new, targeted drugs. Disclosures: Goekbuget: Medac: Consultancy, Research Funding, Speakers Bureau; Novartis: Research Funding; BMS: Research Funding; Genzyme: Research Funding; Mundipharma: Research Funding, Speakers Bureau; Glaxo: Research Funding, Speakers Bureau; Micromet/AMGEN: Consultancy; Sigma Tau: Consultancy. Off Label Use: Liposomal cytarabine in prophylaxsis of CNS relapse in ALL.

Adult patients with acute lymphoblastic leukemia and molecular failure display a poor prognosis and are candidates for stem cell transplantation and targeted therapies

AbstractQuantification of minimal residual disease (MRD) by real-time PCR directed to TCR and Ig gene rearrangements allows a refined evaluation of response in acute lymphoblastic leukemia (ALL). The German Multicenter Study Group for Adult ALL prospectively evaluated molecular response after induction/consolidation chemotherapy according to standardized methods and terminology in patients with Philadelphia chromosome-negative ALL. The cytologic complete response (CR) rate was 89% after induction phases 1 and 2. At this time point the molecular CR rate was 70% in 580 patients with cytologic CR and evaluable MRD. Patients with molecular CR after consolidation had a significantly higher probability of continuous complete remission (CCR; 74% vs 35%; P < .0001) and of overall survival (80% vs 42%; P = .0001) compared with patients with molecular failure. Patients with molecular failure without stem cell transplantation (SCT) in first CR relapsed after a median time of 7.6 months; CCR and survival at 5 years only reached 12% and 33%, respectively. Quantitative MRD assessment identified patients with molecular failure as a new high-risk group. These patients display resistance to conventional drugs and are candidates for treatment with targeted, experimental drugs and allogeneic SCT. Molecular response was shown to be highly predictive for outcome and therefore constitutes a relevant study end point. The studies are registered at www.clinicaltrials.gov as NCT00199056 and NCT00198991.

Trisomy 8 in the Light of Recent Cytogenetic Classification Advances. A Study From the French Acute Myeloid Leukemia Intergroup.

Abstract 2594▪▪This icon denotes an abstract that is clinically relevant.Poster Board II-570 Background:Trisomy 8 (+8) is one of the most common cytogenetical abnormality observed in acute myeloid leukemia (AML). The prognostic impact of +8 as sole aberration remains unclear and +8 may be classified either within intermediate- or high-risk subgroups. Recently, the prognostic impact of cytogenetic in AML has been refined by the identification of: 1) favorable genotypes in cytogenetically normal (CN) AML defined by the presence of either NPM1 gene mutation (NPM1m) or CEBPA gene mutation (CEBPAm) and the absence of FLT3 duplication (FLT3/ITD); 2) highly unfavorable AML with monosomal karyotype (MK). The aim of this study was to precise the prognostic impact of: 1) additional +8 in various cytogenetic risk subgroups; and 2) +8 as sole aberration when compared to different CN-AML genotypes. Patients:A total of 2087 patients with AML (AML-M3 excluded) were treated in the LAM-2001, LAM-SA-2002, ALFA-9802 and ALFA-9801 studies from the French AML Intergroup. After central review, cytogenetic analysis was considered successful in 1796 patients. Abnormalities were categorized according to the French AML Intergroup classification. All analysis (complete remission, CR; overall survival, OS; probability of continuous complete remission, %CCR) were stratified on studies. Results:+8 was present in 171/1796 (9.5%) with a similar incidence among the different cytogenetic subgroups: 22/243 fav-risk (9.1%), 99/1121 int-risk (8.8%), and 50/432 unfav-risk (11.6%). The incidence of +8 was significantly higher in MK-AML versus non MK-AML (30/223, 13.5%, p=.04). In none of these subgroups (fav, int, unfav, and MK), the presence of +8 was associated with a significantly different outcome (CR, OS, %CCR). When compared to patients with CN-AML, the 78 patients with +8 as sole anomaly had a similar age, a lower WBC (median WBC: 5 G/L vs 11.5 G/L, p=.004), a similar incidence of FLT3/ITD (22.2% vs 23.7%, 6/27 vs 101/426, p=.99), and a lower incidence of NPM1m (23.8% vs 46.5%, 5/21 vs 187/402, p=.05). In patients with +8 as sole anomaly, prognostic factors associated with a shorter OS were age (p=.01), high WBC (p=.01), and presence of +8 in all analyzed metaphases which was found in 1/3 of patients (p=.05). In those patients, when compared to CN-AML in general, CR rate was similar (88% vs 87%, p=.99), but %CCR and OS were shorter without, however, reaching significance (5y-%CCR: 31.8% vs 45.7%, p=.18). When compared to CN-AML patients with favorable genotypes (NPM1m or CEBPAm w/o FLT3/ITD), patients with +8 as sole anomaly had now a lower CR rate (87% vs 93%, p=.13) and significantly shorter %CCR and OS (5y-%CCR: 37.4% vs 57.8%, p=.05; 5y-OS 35.6% vs 59.0%, p=.05). Conversely, the prognosis of patients with +8 as sole anomaly appeared similar to that of patients with CN-AML w/o favorable genotypes (5y-OS: 32.6%). Conclusion:We report here the largest cohort of patients with +8. Additional +8 is equally distributed among cytogenetic risk subgroups and does not impact prognosis in each of these subgroups. Patients with AML with +8 as sole anomaly have an outcome comparable to that of CN-AML without favorable genotypes, suggesting that these patients should be managed similarly. Disclosures:No relevant conflicts of interest to declare.

Long-term outcome of adults with acute myelogenous leukaemia: results of a prospective, randomized study of chemotherapy with a minimal follow-up of 7 years

In a prospective study running between 1981 and 1983, a group of 156 adult (under 60 years of age) patients with de-novo acute myelogenous leukaemia were randomly assigned to receive a daunorubicin, cytosine arabinoside and thioguanine combination or a regimen containing lower dosages of these drugs but also containing etoposide and vindesine. Patients who entered complete remission received maintenance therapy for 2 years. The survival and remission duration curves of the two groups were exactly superimposable and for this long-term analysis all patients have been considered together. The follow-up times range between 84 and 104 months. Actual survival at 7 years is 15% (95% confidence intervals 9-20%), with a stable curve thereafter. Actual probability of continuous complete remission at 7 years is 22% (95% C.I. 13-31%) with a stable curve beyond that point. These findings, similar to those of the few other studies of chemotherapy with comparable follow-up times, suggest that only a small fraction of adult patients become long-term survivors, irrespective of the precise type or amount of antineoplastic agents administered.

Rituximab for the treatment of acquired antibodies to factor VIII

Rituximab, a monoclonal chimeric antibody to the CD20 antigen, is an effective therapy for the treatment of non-Hodgkin's lymphomas. Moreover, rituximab has also shown to be effective in various autoimmune diseases including spontaneous antibodies to factor VIII. The aim of this study was to assess the efficacy of rituximab treatment of spontaneous inhibitors to factor VIII. We studied the efficacy of rituximab by analyzing the data of 42 previously published cases as well as one so far unpublished case. For comparison, we also analyzed 44 patients treated with cyclophosphamide/prednisone reported in the literature. Treatment with rituximab resulted in an overall rate of complete remission (CR) of 78.6%. Similar results were found when analyzing patients who had (75%) or had not (77%) received previous treatment with other immunosuppressive drugs. The median time to CR was 8.3 weeks. In follow-up 66% of the patients were still in CR after 2 years and the plateau in the Kaplan-Meier analysis suggests that a substantial number of patients had been cured. Among the 44 patients treated with cyclophosphamide/prednisone reported in the literature, the CR-rate was 84.1%, which was slightly higher than that for rituximab. The median time to CR with cyclophosphamide/prednisone treatment was 6.3 weeks, which was similar to that in the rituximab-treated patients; the probability of continuous CR at 2 years was 94%. All in all, both treatment schemes are effective therapies in patients with spontaneous antibodies to factor VIII. Our data analysis is only descriptive and no conclusions can be drawn as to the relative efficacy of the two regimens. However, these data may serve as a useful basis for planning randomized studies to definitively resolve these issues.

In vitro resistance to cytosine arabinoside, not to daunorubicin, is associated with the risk of relapse in de novo acute myeloid leukaemia.

The efficacy of chemotherapy in acute myeloid leukaemia (AML) is limited by clinical drug resistance. We determined in vitro resistance to cytosine arabinoside (ARAC), daunorubicin (DNR), mitoxantrone (MITOX), m-amsacrine (AMSA) and etoposide (VP16) in 49 adults with de novo AML using the MTT assay. Results showed that nonresponders to chemotherapy were, in vitro, 2.9-fold more resistant to DNR, but not more resistant to ARA-C, compared to complete responders. However, complete responders who were in vitro resistant to ARA-C had a 4-fold higher risk of relapse (95% CI 1.3-12.5-fold) compared to complete responders in vitro sensitive to ARA-C. With a mean follow-up of 12 months the probability of continuous complete remission (CCR) for patients in vitro sensitive to ARA-C was 61% at 34 months (95% CI 28-82%), whereas all patients in vitro resistant to ARA-C relapsed within 18 months from diagnosis. This difference appeared to be independent of other clinical features such as sex, age, white blood cell count, FAB classification, and CD34 expression. In vitro resistance to DNR was not related to the probability of CCR. We conclude that in vitro drug resistance assessed with the MTT assay appears to be associated with short- and long-term clinical outcome in AML. Confirmatory studies comprising a sufficient number of patients for multivariate analyses should prove whether in vitro resistance to ARA-C will appear to be an independent risk factor.

High efficacy of the German multicenter ALL (GMALL) protocol for treatment of adult acute lymphoblastic leukemia (ALL) — a single-institution study

Sixty-one consecutive patients with acute lymphoblastic leukemia (ALL) (B-ALL excluded) were treated with the protocol described by Hoelzer et al. [15]. The complete remission (CR) rate was 85% (52/61 patients). Three patients died during induction therapy; six patients were refractory to treatment. The median duration of continuous complete remission (CCR), disease-free survival (DFS), and overall survival was 41.5, 41.4, and 40.8 months, respectively. At 5 years the probability of CCR was 49%, of DFS 43.5%, and of overall survival 41.6%. In the univariate analysis older age (> 35 years, p = 0.01), bcr-abl positivity (p = 0.007), and time to CR (> 4 weeks, p = 0.05) were significantly unfavorable prognostic factors. In the multivariate analysis only age (p = 0.006) and time to CR (p = 0.02) remained significant. Thus, our data confirm the high efficacy of this treatment regimen with regard to CR rate and remission duration.

Relation of 5′-nucleotidase and phosphatase activities with immunophenotype, drug resistance and clinical prognosis in childhood leukemia

Ecto-5′-nucleotidase (ecto-5′NT) catalyzes the extracellular dephosphorylation of nucleotides like IMP. Cytoplasmic 5′NT (cyto-5′NT) and non-specific (e.g. acid- and alkaline) phosphatases (AP) regulate the intracellular degradation of nucleotides. High NT and AP activities might cause a resistance to the thiopurines 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG). We studied the relation between these enzymes and immunophenotype, drug resistance and prognosis in 77 children with acute lymphoblastic leukemia (ALL). Enzyme activities were assessed radiochemically; in vitro drug resistance was measured with the MTT assay. AP activities were higher in T-ALL and B-ALL than in precursor B-ALL. Cyto-5′NT activity was very low in all phenotypes and accounted for a significant proportion of total IMPase activity only in the very immature CD10 cμ − precursor B-ALL. CD10 + ALL cases with high ecto-5′NT activities showed a trend ( p = 0.065) for a lower probability of continuous complete remission than those with a low activity. Ecto-5′NT activity was not related to in vitro drug resistance to 6-TG. A weak correlation was found between in vitro 6-TG resistance and cyto-5′NT and AP activities. We conclude that high ecto-5′NT activities do not cause a resistance to 6-thiopurines in childhood ALL. Some patients have high cyto-5′NT and AP activities associated with 6-thiopurine resistance.

Clinical and prognostic significance of the Philadelphia chromosome in adult patients with acute lymphoblastic leukemia.

Between 1983 and 1991 the Philadelphia chromosome (Ph1) was found in bone marrow and/or peripheral blood cells of 25 adult patients with acute lymphoblastic leukemia (ALL). The Ph1 as sole anomaly was seen in 13 patients, while six patients had additional structural and another six structural and numerical aberrations. Most patients (23/25) received combination chemotherapy according to the BMFT protocols 1/81, 2/84, 3/87, and 4/89. For 25 evaluable patients two early deaths, two treatment failures, two partial remissions (PR), and 19 complete remissions (CR) after phase 1 or 2 of the induction regimen were recorded. Two of these 19 patients who achieved CR are presently disease free, whereas 17 have relapsed after a median duration of remission of 9 months. Actuarial median survival for all patients was 13 months. The probability of continuous complete remission (CCR) after 39 months, as well as that of survival after 40 months, is only 6%. Our results confirm that the presence of the Ph1 is associated with a poor prognosis in adult-ALL patients. Therefore, whenever first CR is obtained and an HLA-identical donor is available, allogeneic bone marrow transplantation (BMT) should be performed at once, the more so, since transplantation in second CR seems to offer no cure. Future studies will have to show whether an intensified cytotoxic therapy can improve the prognosis of Ph1(+)-ALL.

Relation of cellular drug resistance to long-term clinical outcome in childhood acute lymphoblastic leukaemia

The clinical relevance of cellular drug resistance in children with acute lymphoblastic leukaemia (ALL) is unknown. The relation between in-vitro sensitivity to chemotherapeutic drugs at initial diagnosis and long-term clinical outcome was investigated in 44 children with ALL. The short-term MTT assay was used to assess sensitivity to prednisolone, vincristine, colaspase (asparaginase), daunorubicin, and thioguanine (instead of mercaptopurine which is unstable in vitro). For vincristine and colaspase there was no difference in outcome (probability of continuous complete remission) between sensitive and resistant patients. However, the probability of continuous complete remission was significantly lower in patients with resistant cells than in those with sensitive cells for thioguanine (p<0·01), daunorubicin (p<0·02), and prednisolone (p<0·05). For prednisolone there was a significant worsening of the prognosis (p<0·05) from the extremely sensitive patients through an intermediate group to the most resistant group. The prognostic significance of cellular drug resistance was independent of white-blood-cell count, age, sex, and hepatosplenomegaly. Leukaemic cells from boys were more resistant to thioguanine than those from girls. Thus, the short-term highly efficient MTT assay can help to predict long-term response to chemotherapy in childhood ALL.

Acute Leukemia with Normal Platelet Count at Diagnosis

Thirty-six (17.8%) of 202 children with acute lymphoblastic leukemia (ALL) and 2 (3.7%) of 54 children with acute nonlymphoblastic leukemia (ANLL) had a platelet count over 150 x 10(9)/l at diagnosis. Children with ALL and a platelet count over 150 x 10(9)/l were analysed in detail. The ALL patients without thrombocytopenia tended to be male predominant and had less frequent bleeding manifestations (p less than 0.01). These patients without thrombocytopenia had also significantly less marked leukocytosis (p less than 0.01), less severe anemia (p less than 0.05) and lower percentages of bone marrow blasts (p less than 0.05) than those with thrombocytopenia. In addition, ALL patients without thrombocytopenia had a significantly higher probability of continuous complete remission than those with thrombocytopenia (p less than 0.01).

Low Grade Malignant Non-Hodgkin's Lymphomas and Peripheral Pleomorphic T-Cell Lymphomas in Childhood - A BFM Study Group Report

Non-Hodgkin's lymphomas (NHL) are classified as low or high grade malignant lymphomas of either B or T cell origin. Cells of low grade malignant NHL (LG-NHL) of B cell type represent either follicular or postfollicular, cells of LG-NHL of T cell type postthymic maturation stages in the lymphoid differentiation pathway. LG-NHL often fail to undergo long-term complete remission or cure in adults, no matter what type of conventional therapy is applied. In three pediatric therapy studies frequency and probability of continuous complete remission (pCCR) were studied for LG-NHL and peripheral pleomorphic T-cell lymphomas (PTCL). Of 432 evaluated patients only six children (1.4%) were qualified as LG-NHL. LG-NHL of T cell type were diagnosed in three children (one T-zone lymphoma, two PTCL of small cell type), LG-NHL of B cell type in another three cases. Two children presented with nodular type of centroblastic/centrocytic lymphoma (CB/CC), one with lymphoplasmocytoid type of immunocytoma (IC). In addition to the two patients with low grade malignant PTCL, there have been also four children with high grade malignant PTCL. The analysis showed that there was not significant difference for event free survival of children with LG-NHL and HG-NHL, respectively (pCCR: 0.63 and 0.82, p = 0.29). In contrast, when comparing high and low grade PTCL versus all other types of childhood NHL (non-PTCL), a significant difference seems to exist (pCCR for PTCL: 0.44, for non-PTCL: 0.83; p = 0.02). However, for further concisive conclusions more patients are needed for evaluation.

Prognostic significance of surface marker expression on blasts of patients with de novo acute myeloblastic leukemia.

The prognostic significance of the expression of surface membrane antigens on the blasts of 123 consecutive patients with de novo acute myeloblastic leukemia (AML) was evaluated. For this purpose, reactivity of monoclonal antibodies (mAbs) CLB-ERY3 (antiblood-group H antigen), VIM-D5 (CD15), WT1 (CD7), MY7 (CD13), MY9 (CD33), VID-1 (antihuman leukocyte antigen locus DR [anti-HLA DR]), VIM-2 (CDw65L), VIM-13 (CD14), 63D3 (CD14) and anti-TdT with leukemic blast cell populations was prospectively analyzed with respect to the rates of complete remission (CR), continuous complete remission (CCR), and survival. The overall rate of CR was 65%, the 6-year rates of overall CCR and survival were 23% and 13%, respectively (median period of patient observation, 30 months). Of all Abs tested, four (CLB-ERY3, MY7, anti-TdT, and VIM-D5) were found to be of prognostic value. Reactivity of CLB-ERY3, MY7, and anti-TdT was predictive for CR (CLB-ERY3+, 43% v CLB-ERY3-, 73%, P less than .02; MY7+, 59% v MY7-, 91%, P less than .003; TdT+, 28% v TdT-, 71%, P less than .001, respectively) and probability of survival (significantly lower survival rates: CLB-ERY3+, P less than .02; MY7+, P less than .03; and TdT+ cases, P less than .001, respectively). Reactivity of VIM-D5 was significantly associated with a higher probability of CCR (P less than .01). Our results confirm earlier reports on the prognostic significance of expression of CD13 and TdT in AML and indicate CLB-ERY3 (antiblood-group H antibody) and VIM-D5 (CD15) as further markers predictive for the clinical outcome in patients with de novo AML.

Childhood B-cell lymphomas and leukemias. Improvement of prognosis by a therapy developed for B-neoplasms by the BFM study group

In two consecutive therapy studies, the BFM multicenter study group treated 55 children with B-NHL from 1975 until 1981 and another 55 children with B-NHL and 22 with B-ALL since 1981. In the 1975/81 study, a therapeutic regimen which produced excellent results in non-B-NHL and -ALL, emerged to be much less effective in disseminated B-NHL. With this regimen the probability of continuous complete remission (CCR) in advanced disease was 34% only after 7 years. Since 1981, a new therapeutic regimen of higher specificity for B-neoplasias improved the probability of CCR at the present time to 100% in localised B-NHL, to 63% in disseminated B-NHL and even in B-ALL to 49%.

Therapy of acute lymphocytic leukemia in childhood with intermediate dose methotrexate and CNS irradiation. A report of the ALL 77-02 study group.

One hundred and eight children with acute lymphocytic leukemia (ALL) were admitted to a prospective therapeutic regime. Remission induction was achieved in 94% of the cases with vincristine, L-asparaginase, adriamycine and prednisone. One hundred and one patients received three intermediate dose methotrexate (MTX) infusions combined with intrathecal MTX, followed by L-asparaginase 24 h later. High risk (HR) patients (n = 50) were treated in addition with high dose cyclophosphamide and Ara-C over 3 weeks. One hundred and one patients received cranial irradiation (1,800 rads standard risk (SR)-patients, 2,400 rads HR-patients) and intrathecal MTX. Maintenance therapy was performed with the usual two drug combination of daily 6 mercaptopurine (6 MP) and weekly MTX orally. Based on phenotyping 67% of patients had common type ALL, and pre-T or T-cell type in 18%. Six per cent of the patients had leukemic blasts expressing both common ALL and T-cell markers (c/T-type); 9% had acute undifferentiated leukemia (AUL). Out of 108, 101 achieved a complete remission, 6 patients died during induction therapy, 1 was a non-responder and 9 patients relapsed. Of these Four patients died in continuous complete remission (CCR). For 101 patients the 30 months probability of CCR is 0.85 (+/- 0.05). For 51 patients with standard risk CCR probability is 0.98 (+/- 0.03), for 50 patients with high risk indices it is 0.65 (+/- 0.11). Patients with c-ALL have a CCR survival of 0.85 (+/- 0.07), those with T- or pre-T-ALL 0.88 (+/- 0.09), all 5 patients with c/T-ALL alive in CCR. In our study pediatric AUL patients have the most unfavourable prognosis.