Daunorubicin or Not During the Induction Treatment of Childhood Standard-Risk B-Cell Precursor Acute Lymphoblastic Leukemia (SR-BCP-ALL): The Randomized Fralle 2000-A Protocol

Abstract Abstract 135 From December 2000 to June 2010, 1201 children with SR-BCP-ALL (age: 1–9 years, WBC<50 G/L, CNS-, no MLL rearrangement, no BCR-ABL, no Down syndrome) were included in the FRALLE 2000-A multicenter protocol. At a MFU of 60 months, 1195 patients are evaluable. An ETV6-RUNX1 fusion transcript was documented in 28% of the pts (329 out of 1173 evaluable pts). Induction regimen: prednisone prephase +IT MTX, dexamethasone (DEX) 6 mg/m2/d, vincristine (VCR), native E.coli L-asparaginase ASPA: 6000 IU/m2 × 9 infusions). Response was assessed at D8 (blood, good if < 1000 blasts/mm3), D21 (bone marrow morphology, good if less than 5% blasts, so-called M1) and end of induction D35 (bone marrow morphology and DNA-based PCR for Ig/TCR rearrangements MRD). A D21 M1 marrow was observed in 1132 pts (94.7%). Out of these, 1128 pts were randomized to receive daunorubicin (DNR; 40 mg/m2 at D22 and D29) [560 DNR(+) pts] or not [568 DNR(-) pts]. Pts with D21 M2/M3 marrow (n= 61; 5%) were not randomized and received two infusions of DNR. Two pts died before D21. Pts with D21 M1 marrow (A1 group) received after induction a 12 week-consolidation based on VCR, DEX, mercaptopurine (6-MP) and oral methotrexate (MTX), followed by a 1st delayed intensification (reduced “Protocol II”, including a total of 75 mg/m2 of doxorubicin), an interphase therapy (VCR, DEX, 6-MP, MTX), and a triple drug only-2nd delayed intensification (DI°2) (VCR, MTX 100 mg/m2, ASPA 20000 IU/m2; 4 cycles). A 24-month maintenance was then applied, including 12 VCR-DEX pulses the first year. A total of 18 intrathecal injections of MTX was given. Only the rare patients with D21 M3 marrow and/or EOI MRD level ≥1% (n= 47, 4%)(A3 group) received an intensified treatment after CR with 3 block-consolidation, intensified interphase with 6 cycles of MTX 5 g/m2 and a second DI (“reduced protocol II”). No pt received CNS irradiation. Results: 1. Overall efficacy: No leukemic induction failure was observed; 4 induction deaths (0.3%) occurred leading to a 99.7% CR rate. Only 30 out 1097 evaluable pts (2.7%) had a decisional EOI MRD ≥ 1%. Eighty-two relapses have been observed (BM: 47, CNS+: 24, BM+CNS: 9, testis: 2). For the whole population 5-year EFS is 91.5% (95%CI: 89.8–93.3), 5-year OS is 97.4% (95%CI: 96.4–98.4). 5-yr EFS and OS for the A1 and A3 groups are 93.1% vs. 61.2% (p<0.0001), and 98.3% vs. 84.2% respectively (p<0.0001). Five-year DFS of the 30 pts with MRD ≥1% is 58.8% (95%CI: 41.7–82.8). Five-year EFS of the children with ETV6-RUNX1 fusion transcript is 96.6% (95%CI: 94.4–98.8). 2. Overall toxicity: 5 non leukemic deaths have been observed after CR (0.4%). Other main toxicities were attributable to ASPA (CNS thrombosis: 1.5%, grade 3–4 pancreatitis: 0.8%, allergic reaction-all grades- during DI °2: 70%). Six cases of secondary neoplasms were observed (AML: 5 pts, astrocytoma: 1 pt). 3. Randomization: 5y EFS and OS from randomization was 92.9% and 97.2% for D21 M1 pts DNR(+) versus 93.3% and 98.2% for D21 M1 DNR(-) pts (p= 0.89 and p= 0.85, respectively). Interestingly EOI MRD levels in the two arms were not different at the sensitivity cut-off of 10−2 (p=0.93) or 10−3(p= 0.74). 4. Prognostic factors: For the whole population, age < 6 years, WBC < 20.000/mm3, ETV6-RUNX1 positivity, as well as D21 marrow M1 and EOI MRD levels of 10−2 and 10−3 were all associated to EFS in univariate analysis. In multivariate analysis remain only WBC < 20.000/mm3 (p=.001), ETV6-RUNX1 positivity (p=.02), EOI MRD levels ≤ 10−3 (p=1.4×10−5). Considering only randomized pts (D21M1 pts) age <6 (p=.004), WBC < 20.000/mm3 (p=.04), ETV6-RUNX1 positivity (p=.01), EOI MRD levels ≤ 10−3(p=.002) remain as independent prognostic factors in multivariate analysis. Conclusions: Very good results were obtained with this VCR-DEX-ASPA oriented protocol. SR-BCP ALL pts which represents around 55 % of all children with ALL can be cured with a modest dose of anthracyclin (75 mg/m2). A further decrease in therapy based on the identified prognostic factors could be proposed. Intensification of the chemotherapy for the rare SR pts with a very high MRD has salvaged half of these pts but the addition of new drugs and/or HSCT is now to be evaluated. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

Experience of a Brazilian Institution with Adult Acute Lymphoblastic Leukemia: Clinical, Laboratory and Prognosis in 102 Patients.

Blood ◽

10.1182/blood.v108.11.4447.4447 ◽

2006 ◽

Vol 108 (11) ◽

pp. 4447-4447

Author(s):

Edilson D. Pinheiro-júnior ◽

Elvira R.P. Velloso ◽

Beatriz Beitler ◽

Gracia A. Martinez ◽

Monika Conchon ◽

...

Keyword(s):

Multivariate Analysis ◽

Complete Remission ◽

Clinical Laboratory ◽

Lymphoblastic Leukemia ◽

Univariate Analysis ◽

Treatment Protocol ◽

Rank Test ◽

Induction Treatment ◽

Induction Phase ◽

Adverse Factor

Abstract ALL is an aggressive bone marrow neoplasm, mainly associated with a poor outcome in adult patients. The aim of this study is to describe clinical, laboratory and prognostic factors in 102 patients treated in one institutional department from 1990 to 2005, retrospectively. Adult ALL subtype L3 (FAB) or B-IV (EGIL) was excluded. Statistical analysis was done by SPSS 10.0.The association of features and prognosis was assessed by Pearson’s chi-square. OS and DFS curves were constructed by Kaplan-Meier method and the differences were analyzed by the log-rank test. Mean age was 30,6 (12 to 82) years and 55,9% was male. Clinical findings, at diagnosis, were fatigue (55,9%), splenomegaly (56,9%), hepatomegaly (54,6%), lymphadenopathy (52,6%), fever (38,8%), bone pain (28,6%), bleeding (27,5%) and headache (15,3%). Involvement of CNS was detected in 11(10,8%) patients and testicular involvement was observed in one patient. Cutaneous infiltration occurred in one patient immunophenotyping T-IV(group b). Kidney and pulmonary infiltration, documented by biopsy, was found in 2 and 1 patients respectively. At diagnosis; mean blood values were 8,5g/dl, 84.341/mm3 and 76.275/mm3 for hemoglobin, leukocytes and platelets respectively. 98,7% of the patients presented with lymphoblasts in peripheral blood. FAB classification was L1 and L2, 50% each. B and T-ALL was observed in 69,7% and 30,2% respectively. One case was identified as biphenotypic B and T leukemia. Karyotype analysis was performed in 40 cases, Ph chromosome was identified in 20% (8/40) of the cases. Others abnormalities were hyperdiploid karyotype (6/40); t(4;11) in 2 cases; t (1;19) and t(10;11) each one with 1 case. Patients were treated with different protocols: BFM 86 modified (BFM 86M) in 47,1% (48/102) of the patients, OPAL86 and OPAL87 protocols (Linker e cols) in 45,1% (46/102) and CHOP in 7,8% (8/102). Ten patients died in early induction phase and 70,6% (65/92) were in complete remission after induction treatment. Age less than 35 years (p=0.021), CNS not infiltrated (p= 0.022) and immunophenotyping B1 and B3 (p=0.018) were associated with a better induction response in a univariated analysis. The first two parameters were associated with a high probability of complete response (p=0.041 and 0.034, respectively) in a multivariate analysis. In a median follow up of 49 months, we have observed a four-years OS of 30,4% (median 19 months). Univariate analysis of OS showed that age less than 35 and mainly less than 18 years (p=0.01), absent bleeding and hepatomegaly at diagnosis (p=0.0022; p=0.029), early time to complete remission (p=0.0001) and treatment protocol BFM 86M (p=0.0034) were associated with better survival. In a multivariate analysis age >35y, presence of hepatomegaly or bleeding at diagnosis were associated with poor OS, and were used to created a prognosis score. Patients with none to one adverse factor have a significantly better survival than patients with more than one (p=0.0001). We have observed in our population a DFS of 27% in 4 years with a median DFS of 18,9 months. Only fever, at diagnosis, was an adverse factor related to DFS in univariate analysis (p=0.0057).

Download Full-text

Low Prevalence of T-Cell Lymphoblastic Leukemia/Lymphoma in an Adult Hispanic Population: A Report of the Acute Leukemia Working Group (GTLA)

Blood ◽

10.1182/blood-2020-142639 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 5-6

Author(s):

Luis Felipe Rubalcava-Lara ◽

Emmanuel Almanza Huante ◽

Roberta Demichelis ◽

Juan Rangel-Patiño ◽

Andres Gomez-De Leon ◽

...

Keyword(s):

T Cell ◽

Acute Leukemia ◽

Conflicts Of Interest ◽

Lymphoblastic Leukemia ◽

Univariate Analysis ◽

Rank Test ◽

Induction Treatment ◽

P Value ◽

Cell Transplant ◽

Hispanic Population

Introduction: The proportion of Acute lymphoblastic T cell leukemia/lymphoma (T-ALL/LBL) in Latinamerica (LA) is about 13% [Quiroz, 2018], compared with 25% of other publications [Litzow,2015]. In the largest leukemia series of adult Mexican population, the incidence of T-ALL was merely 2.9% with a -SG. The main objective of this study was to describe the epidemiological characteristic and survival of T-ALL in 4 reference oncology centers in Mexico. Methods: Retrospective cohort study from 2014 to 2019 in all consecutive, newly diagnosed T-ALL patients defined by flow cytometry (FC). The primary end point was to assess the survival of T-ALL in a Hispanic population. Baseline characteristics were grouped in tables and summarized as medians and ranges. Sub-groups were compared using chi-square test for binary variables and Mann-Whitney U test for quantitative variables. The Overall Survival (OS) analysis was made using Kaplan-Meier curves and comparison between groups was performed using the log-rank test with a significant P value less than 0.05 with 95% confidence interval. Results: A total of 47 patients were identified, which represent 11.1% of all acute leukemia the median of age was 30 years. The 83.7% being identified in the adolescent young-adult (AYA) group. Counterintuitively a 44.9% had a previous comorbidity (diabetes, hypertension, dyslipidemia) considering the range of age. The 85% had a low risk of mortality using the modified Charlson index, the median count of leukocytes was 36 x 109 (range 6.78-117) and 28% presented with initial hyperleukocytosis, the median LDH was 605 UI/l (range 343-1451). Applying the European Group for the Immunological Classification of Leukemias criteria: 28% were cortical T, 41.7% were mature and approximately 30% were be classified as early. Applying the early T-P (ETP) definition a total of 10 cases were identified (22.2% prevalence). The use of hyperCVAD and pediatric inspired regimens shared the same rate (41.3%), strikingly there is still a 17.4% of patients that received other type of chemotherapy for diverse reasons (economic, shortage of treatment, patient or physician preference) being the CHOP-inspired schemes the most used. The rate of complete response (CR) at 4 weeks after induction was 68.2% with 54.2% having a negative minimal residual disease (MRD). After 8 weeks a total of 34 (77.3%) patients achieved CR, with 63.6% and 66.7 % maintaining negative MRD at 16 weeks and after consolidations, respectively. Only 38.3% were able to complete the full induction treatment without a dose adjustment due to toxicity. A total of 8 (19.5%) were refractory to initial frontline treatment and eventually 23 (60.5%) relapsed, with a total of 10 patients presenting with CNS infiltration at relapse. A total of 6 patients received an allogenic stem cell transplant (ASCT), with 4 of them being alive and in CR at the 100 days cutoff. The median OS was 16 months (CI 95% 11.4-21.09) and 38.8% of our population was alive at the 24 months cutoff. This time period was drastically reduced for the non-AYA population who had a OS of 7.69 months (CI 95% 0-21.24) and 21.9% a 24 months progression free survival (PFS), compared with 16.6 months (CI 7.41-25.81) and 41.6% 24 months PFS. In the univariate analysis refractoriness to induction (p 0.039) and higher number of cycles (p 0.02) were associated with worse outcome. Conclusions: The T-ALL predominantly affects AYA populations while its incidence in our country appears to be lower even in large oncologic concentration centers. The proportion of ETP was slightly higher than that reported in other studies. Lower CR rates with a low frequency of ASCT in comparison to those reported in high income countries was observed, probably associated with the delay in implementation of pediatric-inspired regimens and lack of access to ASCT. Disclosures No relevant conflicts of interest to declare.

Download Full-text

What Is the Appropriate Dose Attenuation System of RCHOP for Elderly DLBCL Patients? - A Single Institutional Analysis in 115 Cosecutive Patients From Japan -

Blood ◽

10.1182/blood.v120.21.3639.3639 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3639-3639

Author(s):

Akira Tanimura ◽

Risen Hirai ◽

Atsushi Sato ◽

Miki Nakamura ◽

Masataka Takeshita ◽

...

Keyword(s):

Multivariate Analysis ◽

Prognostic Factors ◽

Elderly Patients ◽

Conflicts Of Interest ◽

Univariate Analysis ◽

International Prognostic Index ◽

Prognostic Index ◽

B Cell Lymphoma ◽

Age Related

Abstract Abstract 3639 Background: The combination therapy of RCHOP [rituximab (R), cyclophosphamide (CY), doxorubicin (DOX), vincristine (VCR), and prednisone (PSL)] is a standardized treatment for diffuse large B-cell lymphoma (DLBCL). However, its clinical outcome is worse in elderly patients because of comorbidities, age-related decrease in organ function, and impaired drug metabolism. If possible, the dose of RCHOP in elderly patients and patients with comorbidities should be adjusted appropriately. Since 2005, we have used a unified dose attenuation system for RCHOP according to the age and comorbidities of patients. This study retrospectively verified this system. Patients/Methods: We analyzed 115 consecutive DLBCL patients treated at our institute from September 2001, when rituximab was approved in Japan, to December 2010. From September 2001 to August 2005, 33 patients received dose adjustment of RCHOP according to the physician's discretion (PHY group). From September 2005, 82 patients received RCHOP according to the unified dose attenuation system (UNI group). In the UNI group, patients younger than 60 years received the standard RCHOP dose [R, 375 mg/m2; CY, 750 mg/m2; DOX, 50 mg/m2; VCR, 1.4 mg/m2 (max 2.0 mg/body); PSL, 100 mg/m2]. In patients older than 60 years, the doses of CY, DOX, VCR, PSL, and R were attenuated as shown in Table 1. In addition to age, the doses of CY, DOX, and VCR were adjusted according to organ functions (Table 2). The two groups were compared statistically. Results: The median age of patients was 70 years (range, 38–91), with 70.4% of patients classified as stage III or IV DLBCL, 40.4% with an international prognostic index (IPI) score of 0–2, and 70.2% with a ECOG performance status (PS) of 0 or 1. Low serum albumin levels (under normal range) were observed in 50.5% patients, and a high Charlson comorbidity index (CCI) score of >1 was found in 58.3%. The characteristics of the patients in the two groups were almost similar. The UNI system was completed in 94% of patients. The complete response (CR) rate was 63% in all patients (UNI group, 73%; PHY group, 39%; P = 0.0006). Univariate analysis revealed that better prognostic factors for CR were a low IPI score, better PS, and the UNI group. In the multivariate analysis, only the UNI group was a significantly better prognostic factor for CR. With a median follow-up of 26 months, the 5-year event-free survival (EFS) and overall survival (OS) were 39.3% and 68% in all patients, 43% and 72% in the UNI group, and 27% and 59% (5-year EFS; P = 0.0083, 5-year OS; P = 0.16) in the PHY group, respectively. Multivariate analysis showed that better prognostic factors for EFS were a low IPI score, a low CCI score, and the UNI group, and that for OS were low IPI and low CCI scores. In elderly patients aged >70 years (N = 59), the CR rates were 81% and 13% in the UNI and PHY groups, respectively (P = 0.0004), with OS in the UNI group being longer than that in the PHY group (72% vs. 59%; P = 0.02; Fig.1). In the UNI group, patient age did not affect the CR rate (<70, 71% vs. 70–79, 83% vs. >79, 79%; P = 0.56) or 5-year OS (<70, 76% vs. 70–79, 70% vs. >79, 66%; P = 0.58). The actual dose of CY, DOX, and VCR compared with the standard RCHOP dose was 64% and 26%, 63% and 16%, and 63% and 21% in the UNI and PHY groups, respectively. Disease progression during treatment, discontinuation of therapy, and death during treatment were observed in 10% and 15%, 5% and 24%, and 5% and 3% in the UNI and PHY groups, respectively. Nineteen patients (23%) from the UNI group died over a median follow-up of 15 months, while 15 patients (45%) of the PHY group died over a median follow-up period of 29 months. Lymphoma-related deaths were 12 (14%) in the UNI group and 8 (24%) in the PHY group. Five secondary primary malignancies (SPM) were observed (1 colon cancer and 1 breast cancer in the PHY group, and 1 lung cancer and 2 myelodysplastic syndrome in the UNI group). Four deaths were related to SPM. Conclusion: The unified dose attenuation system determined by the patients' age and comorbidities may achieve an effective dose level and better prognosis in elderly DLBCL patients. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

Validation of MRD Quantification By Flow Cytometry for Pediatric BCP ALL Relapsed Patients Treated on the Intreall Protocol

Blood ◽

10.1182/blood.v126.23.1414.1414 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1414-1414 ◽

Cited By ~ 1

Author(s):

Ester Mejstrikova ◽

Julie Irving ◽

Leonid Karawajew ◽

Marian Case ◽

Jenny Jesson ◽

...

Keyword(s):

Bone Marrow ◽

Flow Cytometry ◽

Clinical Decision Making ◽

Conflicts Of Interest ◽

Residual Disease ◽

Lymphoblastic Leukemia ◽

Induction Treatment ◽

High Dose ◽

Risk Patients ◽

To Receive

Abstract At acute lymphoblastic leukemia (ALL) relapse, about 40% of children can be salvaged with intensified multi-agent, high dose chemotherapy and in very high risk patients, with additional stem cell transplantation (SCT). To improve on this, the International BFM Study Group has led a consortium of 19 countries to develop the world's largest trial for relapsed ALL (IntReALL). Standard risk patients will be randomized to receive the ALL-REZ BFM 2002 or UK ALL R3 therapy and post induction will be randomised to receive the additional targeted anti-CD22 drug, Epratuzumab, during consolidation, to clear residual disease. Children with end of re-induction MRD positive bone marrow will undergo SCT following consolidation. Both ALL-REZ BFM 2002 and UK ALL R3 used MRD PCR-based quantification of clonal Ig/TCR rearrangements, with different cut offs (10-3 for ALL-REZ BFM 2002 and 10-4 for UK ALL R3) and this is the reference assay for IntReALL. However, flow MRD may also play a role for patients without PCR targets. Flow MRD relies on the discrimination of leukaemic blasts from hematogones and this can be hampered depending on the degree of haematopoietic regeneration which varies depending on the treatment protocol and is especially important after intensive induction treatment in relapsed protocols. Thus, prospective MRD quantification of patients entered onto the UKALLR3 and ALL-REZ BFM 2002 clinical trials was performed by a standardised, quality assured, 4-8colour Flow MRD assay in end of re-induction bone marrow aspirates, by laboratories in the IBFM FLOW consortium (n=221). Flow MRD in both treatment protocols was classed as a prospective biological add on study and not used for clinical decision making. Median MRD levels were 0.026 +/-9.9% SD for BFM versus 0.027+/-18% SD for UK protocols, with comparative MRD positivity rates of 45% versus 54%, respectively. Comparison with MRD levels as assessed by molecular analysis of antigen receptor gene rearrangements was performed in 170 samples (BFM,128; UK R3, 42). The Spearman rank correlation of all samples was 0.90 (p<0.0001) for patients treated on the BFM protocol, compared to 0.82 (p<0.0001) for those on UK ALL R3. Risk category concordance was 88% (ALL-REZ BFM) and 88% (UKALLR3). For the 21 discordant samples, 5 were MRD positive by flow but negative by PCR and 17 were negative by flow and positive by PCR. When analysing the accuracy, with which flow MRD classified specimens identically as PCR, the sensitivity of flow MRD in the ALL-REZ BFM protocol was 81% (cut off 0.1%) and in UK ALL R3 was 79% (cut off 0.01%). Specificity values were 93% versus 100%, respectively. Although sample processing and quantification of MRD differ between PCR and FC MRD, in both re-induction protocols, there was good correlation of MRD levels assessed by flow cytometry and PCR, validating the use of Flow MRD as a method of choice in patients without PCR targets in the IntReALL trial. Flow MRD also has the advantage of enabling levels of CD22 to be assayed on MRD cells, prior to treatment with Epratuzumab. This research has received funding from the European Union's Seventh Framework Programme for research, technological development and demonstration under grant agreement no 278514 - IntReALL", Deutsche Kinderkrebsstiftung for its funding support of the ALL-REZ BFM 2002 clinical trial and the minimal residual disease studies by PCR and the Deutsche Jose Carreras Leukämiestiftung for support of the international principal investigator, Leukaemia and Lymphoma Research and North East Children's Cancer Research Fund, NT 13462-4, NV15-28525A, NV15-26588A, UNCE 204012. Disclosures No relevant conflicts of interest to declare.

Download Full-text

Frequency of IKZF1 Deletions in a Peruvian Population with B-Cell Acute Lymphoblastic Leukemia

Blood ◽

10.1182/blood-2020-137122 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 11-11

Author(s):

Daniel J Enriquez ◽

Rachel J. Mitchell ◽

Krisztina Zuborne Alapi ◽

Elizabeth Cervantes ◽

Karina Cancino ◽

...

Keyword(s):

Bone Marrow ◽

Acute Lymphoblastic Leukemia ◽

B Cell ◽

Conflicts Of Interest ◽

Lymphoblastic Leukemia ◽

Dominant Negative ◽

White Blood Count ◽

Induction Treatment ◽

Wild Type ◽

Cell Acute Lymphoblastic Leukemia

Frequency of IKZF1 Deletions in a Peruvian Population with B-cell Acute Lymphoblastic Leukemia Background: B-cell Acute Lymphoblastic Leukemia (B-ALL) is an aggressive disease with worse outcomes in older patients, and latino ethnicity. Additionally, Latino populations are at higher risk of developing B-ALL.IKZF1is an essential lymphoid transcription factor with deletions (ΔIKZF1)implicated in treatment failure and relapses. We aimed to evaluate the frequency ofIKZF1deletions in a cohort of Peruvian patients with newly diagnosed B-ALL. Methods: We collected diagnostic bone marrow samples from 41 consecutive patients with B-ALL diagnosed between 2015-2019 at Instituto Nacional de Enfermedades Neoplasicas (INEN; Lima, Peru). Bone marrow samples were cryopreserved prior to induction treatment. DNA was extracted using High Pure PCR Template Preparation Kit (Roche) at INEN. Samples with adequate DNA were screened forΔIKZF1by multiplex endpoint PCR covering four main deletions - dominant negative Δ4-7 or the loss of function Δ2-7, Δ4-8, and Δ2-8 IKZF1 deletions at UCL Cancer Insitute (London, UK) using the primers described by Caye et. al. We analyzed outcomes byIKZF1status. Results: Forty-one cases were enrolled during the study period. Clinical characteristics are presented in Table 1. Median age was 20 years[1-63]. Fifteen∆IKZF1cases (37%) were detected (67%BCR-ABL1 negand 33%BCR-ABL1pos).Cases withΔIKZF1were older than those with wild-typeIKZF1(median age 31 vs 13 years, p=0.002). Median presenting white blood count (WBC) was 48 x109/L [R:2-218], with a higher WBC inΔIKZF1compared to wild-type (87 vs 24 x109/L, p=0.001). The most frequent deletion was ∆4-7 (sevenBCR-ABL1 negand threeBCR-ABL1 pos) additional deletions are described in table 2. All patients received intensive 'pediatric-based' treatment, 21 with BFM-2009 and 19 with the CALGB 10403 protocol. CR rates after induction were 67% and 92% for∆IKZF1and wild-type cases, respectively. Eleven (73%) of patients with∆IKZF1subjects (73%) were MRD positive by flow cytometry after induction compared to 11 (44%) among wild-type. At a median follow-up of 2 years EFS was 38% in the∆IKZF1group and 58% in the wild type group, correspond OS was 38% and 58%, respectively. Conclusion: A high frequency of IKZF1 deletions was found in a Peruvian population with B-ALL and was associated with older age and higher presenting white blood counts. Prospective studies with larger Latino population are warranted to confirm this finding. Disclosures No relevant conflicts of interest to declare.

Download Full-text

Clinical Significance of Additional Cytogenetic Abnormalities (ACA) at Disease Progression in Patients with High-Risk Myelodysplastic Syndrome (MDS) Treated with Azacitidine

Blood ◽

10.1182/blood-2019-127956 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5434-5434

Author(s):

Chiaki Naito ◽

Hiroaki Shimizu ◽

Yuri Miyazawa ◽

Takuma Ishizaki ◽

Akihiko Yokohama ◽

...

Keyword(s):

Multivariate Analysis ◽

Prognostic Factors ◽

High Risk ◽

Disease Progression ◽

Lymphoblastic Leukemia ◽

Univariate Analysis ◽

Philadelphia Chromosome ◽

Complex Karyotype ◽

Cytogenetic Abnormalities ◽

Cytogenetic Changes

Background: Although cytogenetic abnormalities at diagnosis are recognized as one of the most important prognostic factors in MDS patients, their cytogenetic findings are not stable and ACA are sometimes acquired in their clinical courses. We recently described that ACA acquisition at relapse was found in 40% and associated with the lower second complete remission (CR) rate and the inferior overall survival (OS) rate in adult patients with acute myeloid leukemia (AML) and Philadelphia chromosome-negative acute lymphoblastic leukemia (Ph-negative ALL). However, this clinical impact of ACA acquisition has not been elucidated in high-risk MDS patients during azacitidine treatment. So, we conducted this retrospective study to address this unsolved issue. Patients and methods: Of the 63 patients who were diagnosed as high-risk MDS according to French-American-British classification and were treated with azacitidine between 2012 and 2019, 34 whose cytogenetic data both at diagnosis and disease progression were available were included in this study. Treatment response to azacitidine was evaluated based on international working group response criteria for myelodysplasia. Cytogenetic changes between the time of diagnosis and disease progression were classified into four groups: (1) no change, (2) ACA was acquired at time of disease progression, (3) cytogenetic abnormalities observed at diagnosis were reduced or had disappeared at the time of disease progression, and (4) cytogenetic abnormalities observed at diagnosis were reduced or had disappeared, and completely different ACA was acquired at the time of disease progression. In this study, groups 2 and 4 were defined as those with ACA acquisition. OS was defined as the interval from the date of disease progression to the date of death. Fisher's exact test was used to compare binary variables. OS was estimated with the Kaplan-Meier method and compared using the log-rank test. The Cox proportional hazard model was used for multivariate analysis of prognostic factors. The potential factors evaluated in this analysis were age, gender, blast count in bone marrow (< or => 10%), karyotype (complex or not), revised international prognostic scoring sysytem (high/high-intermediate or not), and response to azacitidine (CR/partial remission or not). Values of p < 0.05 were considered to indicate statistical significance. Results: Of the 34 patients included in this study, 25 were male and 9 were female, and the median age was 66 years (range, 38-78 years). According to the definition described above regarding cytogenetic changes between the time of diagnosis and disease progression, 11 (32%), 14 (41%), 0 (0%), and 9 (26%) patients were categorized into group 1, 2, 3, and 4, respectively; thus, 23 patients (67%) acquired ACA at disease progression with a higher incidence in comparison with that of AML and Ph-negative ALL patients. In univariate analysis, only complex karyotype at treatment initiation was extracted as a significant predisposing factor for ACA acquisition at disease progression (100% vs. 47.6%, respectively; p = 0.002). Among 14 patients (nine and five in patients with and without ACA acquisition, respectively) received chemotherapy after disease progression, only two (14.3%) achieved CR (one and one, respectively). Although the OS rates after disease progression were not significantly different between patients with and without ACA acquisition (19.3% vs. 32.0% at one year, respectively; p = 0.256), in multivariate analysis, only ACA acquisition was identified as a negative prognostic factor of OS after disease progression (hazard ratio: 3.21, p = 0.043). Conclusion: These findings suggested that ACA acquisition at disease progression is frequently observed in high-risk MDS patients treated with azacitidine, especially in those harboring complex karyotype, and is associated with poor prognosis even after azacitidine failure, just like AML and Ph-negative ALL. As clinical impacts of ACA acquisition are common among multiple hematologic malignancies, to clarify the biological basis of ACA acquisition might contribute to the development of novel therapeutic strategies. Disclosures Handa: Ono: Research Funding.

Download Full-text

Children with NCI Standard Risk Acute Lymphoblastic Leukemia (ALL) and TEL-AML1 or Favorable Chromosome Trisomies Are Almost Certain to Be Cured with Graduated Intensity Therapy: Results of the CCG - 1991 Study.

Blood ◽

10.1182/blood.v114.22.320.320 ◽

2009 ◽

Vol 114 (22) ◽

pp. 320-320 ◽

Cited By ~ 1

Author(s):

Yousif Matloub ◽

Bruce C. Bostrom ◽

Anne L Angiolillo ◽

Meenakshi Devidas ◽

Nyla A. Heerema ◽

...

Keyword(s):

Bone Marrow ◽

Overall Survival ◽

Conflicts Of Interest ◽

Lymphoblastic Leukemia ◽

Fusion Transcript ◽

Event Free Survival ◽

Free Survival ◽

Therapy Regimen ◽

B Lineage ◽

Standard Risk

Abstract Abstract 320 Three thousand fifty four children with NCI standard-risk (SR) ALL were enrolled on CCG-1991; 2075 non-T ALL eligible patients were randomized and began treatment with IT cytarabine, vincristine, dexamethasone, and pegylated asparaginase. Bone marrow status was assessed at Day 7, 14, and 28 of Induction. Slow early responders (Day 7/14 M3-M3 and M3-M2; or M2 at Day 28 Induction) and patients with unfavorable cytogenetics were non-randomly assigned to a COG augmented BFM therapy regimen (N Engl J Med 1998; 338:1663).Thirteen hundred and thirty patients were analyzed for the presence of trisomy 4 and trisomy 10 (DT); and 1041 patients were evaluated for the presence of TEL/AML1 (ETV6/RUNX1) (TEL) fusion transcript. Twenty four percent of patients were positive for DT, and 41% were positive for TEL. Among the randomized subset, 23.8% had DT, and 40.8% had TEL. Six year event-free survival (EFS) and overall survival (OS) rates are given in the tables below for all patients and also separately for the randomized patients, by DT and TEL status. There was a significant different in EFS and OS between patients that were DT+ vs. DT- and also between patients that were TEL+ vs. TEL-.The overall 6-year EFS and OS for all patients with B-lineage ALL are 88.1±1.1% and 94.7±0.8%; and for the randomized patients they are 89.4±2.4% and 95.9±0.8%. We conclude that COG risk-adapted therapy is curative for patients with NCI-SR criteria and DT and/or TEL. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

Assessment of Frailty Measures and Their Effect on Survival in a Population of Patients Registered At Marche Region Multiple Myeloma (MM) Registry

Blood ◽

10.1182/blood.v118.21.2873.2873 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2873-2873 ◽

Cited By ~ 1

Author(s):

Massimo Offidani ◽

Claudia Polloni ◽

Laura Corvatta ◽

Riccardo Centurioni ◽

Giuseppe Visani ◽

...

Keyword(s):

Multiple Myeloma ◽

Multivariate Analysis ◽

Prognostic Factors ◽

Conflicts Of Interest ◽

Univariate Analysis ◽

Final Outcome ◽

Bone Lesions ◽

Single Patient ◽

Marche Region ◽

Frail Patients

Abstract Abstract 2873 International staging system (ISS) and cytogenetics are the main prognostic factors of Multiple Myeloma (MM) but they reflect biologic characteristics of disease without taking into account individual host features. On the contrary, clinical characteristics of single patient could be substantial as to various points of view. For instance, in elderly MM patients, novel therapies reduction or interruption due to toxicity represent the major cause of unsatisfactory outcome. Therefore, it was empirically suggested different schedule of drugs in these “frail” patients but, how the “frailty” should be assessed in every single patient, is still unsettled. Advanced age, poor performance status (PS) and comorbidities are usually applied to recognize the “frailty” but it is not well known which of them are really prominent and whether these parameters, adjusted for conventional prognostic factors, still affect final outcome. We analyzed a population of symptomatic MM diagnosed from 2007 to 2010 included in the Marche Region MM Registry, to assess the frequency of “frailty” features, such as age, PS, comorbidities, cytopenias, renal insufficiency (RI) and lytic bone lesions, and their role on the overall survival (OS) when adjusted for prognostic factors. Comorbidities were scored according to Charlson Comorbidity Index (CCI) that split patients in 4 categories according to number and type of comorbidity. Patients were treated with transplant or standard therapy according to their eligibility. Overall, 88% of patients were treated with new drug-based therapies and 12% with MP. Median age of the 266 patients analyzed was 73 years (range 38–90). Twenty-four percent of patients had IgA MM, fifty patients (23%) had ISS stage=3 and 29/166 (17.5%) had unfavourable cytogenetics. Regarding “frailty” measures, 38% of patients had > 75 years, 39% had PS=2–4, 34% had 1 or more comorbidities. The most frequent comorbidities were hypertension (35%), heart diseases (22%), diabetes (15%), neurological diseases (16%), COBP (8%), secondary malignancies (8%) and chronic renal failure (6%). CCI ≥1 was detected in 51%. Increasing comorbitities number and CCI were associated with increased age although 37% of patients aged less than 65 years had CCI ≥2. Moreover, 35% had at least 2 cytopenias, 76% had bone disease and 14% had RI. Fifty patients (19%) died during follow-up. OS at 3 years was 74%. Univariate analysis performed on the total population determined age > 65 years (p=0.065), PS=2–4 (p<0.001), Hb < 10 g/dl (p=0.035), ISS=3 (p=0.017), unfavourable cytogenetics (p=0.074), cytopenias (p=0.024), RI (p=0.036) and CCI=1–3 (p=0.005) as factors that significantly decrease OS. Multivariate stepwise analysis selected ISS=3 (HR=1.6; p=0.033), PS=2–4 (HR=2.5; p=0.007) and CCI=1–3 (HR=2.1; p=0.028) as factors affecting worse OS. To obtain a clinical applicable prognostic model, we assigned 1 point to each unfavourable finding such as PS=2–4 or CCI=1–3. A “frailty score” (FS) was thus developed as low (0 point), intermediate (1 point) and high (2 points). Patients in the low category had 91% OS at 3 years vs 83% in the intermediate one (p=0.205) vs 36% in the high category (p< 0.0001). According to these results we performed a multivariate analysis adding FS (0–1 vs 2) to the above frailty covariates and to prognostic factors. This analysis was carried out splitting patients in two subgroups according to the age ≤65 years or older; high FS was recognized in 10% and 30% of subgroups, respectively. In younger patients, multivariate analysis selected ISS=3 (median OS 41.5 months vs NR; HR=5.2; p=0.006) and FS=2 (median OS 46.5 vs NR; HR=5.5; p=0.024;) as factors diminishing OS whereas only FS=2 (HR=3.5; p=0.002) affects worse survival in older ones. Patients with FS=2 had a median survival of 27 months vs NR in patients with FS=0-1. This study demonstrated that, behind biologic features of MM, host characteristics are of utmost importance regarding final outcome prediction. Two easy, reliable and not time-consuming measures normally used in clinical practice such as PS and CCI, scored as we found, seem to be very useful tool to identify frail patients independently by age or other single frailty parameter. These findings maybe used to try to explain why outcome of some patients poorly improved despite new-drugs introduction and should be taking into account planning future clinical trials. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

ID1 Expression Correlates with CEBPA Mutational Status and Is Not An Independent Risk Factor in Cytogenetically Normal AML,

Blood ◽

10.1182/blood.v118.21.3554.3554 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3554-3554

Author(s):

Katharina Wagner ◽

Frederik Damm ◽

Michael A Morgan ◽

Felicitas Thol ◽

Haiyang Yun ◽

...

Keyword(s):

Multivariate Analysis ◽

Prognostic Factors ◽

Prognostic Factor ◽

Conflicts Of Interest ◽

Univariate Analysis ◽

High Expression ◽

Prognostic Impact ◽

Mutational Status ◽

Negative Prognostic Factor ◽

Cebpa Mutations

Abstract Abstract 3554 Background: Acute myeloid leukemia with normal karyotype (CN-AML) is a heterogenous disease. During the last years, mutations in several genes (e.g. NPM1, FLT3, CEBPA, WT1, IDH1, IDH2) have been identified which are involved in the pathogenesis of AML and affect the prognosis of these patients. Moreover, deregulated expression of genes such as MN1, BAALC, ERG and WT1 was demonstrated to be predictive of outcome in CN-AML. Recently, high expression of the ID1 gene was described as a negative prognostic factor in AML (Tang et al. Blood 2009, 114:2993–3000). Aims: We have shown that C/EBPα, a transcription factor encoded by the CEBPA gene, binds to a regulatory element in the promoter region of the ID1 gene and regulates ID1 expression in leukemic cells (Wagner et al. Proc Natl Acad Sci USA 2006, 103:6338–6343). Therefore, we wanted to analyze the prognostic impact of ID1 expression in CN-AML in the context of other molecular markers, in particular CEBPA mutations. Methods: ID1 expression was quantified normalized to ABL by real time RT-PCR in 269 patients (age 16–60 years) with CN-AML treated with intensive double induction and consolidation therapy within the AMLSG 295 and 0199 trials (NCT00209833). The patients were also analyzed for mutations in the genes NPM1, FLT3, CEBPA, WT1, IDH1 and IDH2. Median follow up was 79 months. Results: Expression of ID1 varied over a 3-log range. High expression of ID1 (ID1high, defined as > median expression level) was significantly associated with the presence of a FLT3 -ITD or an IDH2 mutation and WT1 wildtype. Moreover, ID1 expression was closely associated with CEBPA mutational status. Altogether, 41 patients (15%) harboured a CEBPA mutation (24 monoallelic and 17 biallelic mutations). ID1 expression in the CEBPA wildtype patients was significantly higher than in patients with monoallelic CEBPA mutations and these patients had a significantly higher ID1 expression compared to patients with biallelic CEBPA mutations (p = 0.001). ID1high patients had a trend to a lower complete remission (CR) rate (74% vs. 84%; p = 0.07), but in multivariate analysis only blast clearance on day 15 after induction 1, age and WT1 SNP rs16754 were independent predictors for the achievement of CR. In univariate analysis, ID1high patients had an inferior overall survival (OS) compared to patients with low expression (median OS 29 vs. 78 months, 5 year OS 39% vs. 53%, p = 0.026). ID1high status was an independent negative prognostic factor in multivariate analysis when analyzed together with NPM1, FLT3 -ITD, WT1, IDH1, IDH2, extramedullary disease and platelet counts (HR 1.51; 95% CI 1.06–2.19). However, when also CEBPA mutational status was entered into the model, ID1 expression lost its prognostic impact and the only independent prognostic factors were age, platelets, CEBPA mutations, NPM1 /FLT3 -ITD risk group and WT1 SNP rs16754. Likewise, ID1high patients had a trend to an inferior relapse-free survival (RFS; HR 1.36, 95% CI 0.96–1.93, p = 0.086) in univariate analysis. However, in multivariate analysis including CEBPA mutational status, ID1 expression had no impact on RFS and the only prognostic factors for RFS were NPM1 and CEBPA mutations and WT1 SNP rs16754. In CEBPA wildtype patients, ID1 expression had no impact on CR-rate, OS or RFS in univariate or multivariate analysis. Conclusions: CEBPA mutations seem to deregulate ID1 expression in CN-AML. Therefore, ID1 expression is not an independent prognostic factor in CN-AML. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

An Early Thymic Precursor Phenotype Predicts Outcome Exclusively in HOXA-Overexpressing Adult T-ALL: A GRAALL Study

Blood ◽

10.1182/blood.v126.23.808.808 ◽

2015 ◽

Vol 126 (23) ◽

pp. 808-808 ◽

Cited By ~ 1

Author(s):

Jonathan Bond ◽

Tony Marchand ◽

Aurore Touzart ◽

Agata Cieslak ◽

Amélie Trinquand ◽

...

Keyword(s):

Bone Marrow ◽

Multivariate Analysis ◽

Acute Lymphoblastic Leukemia ◽

Cancer Cell ◽

Conflicts Of Interest ◽

Residual Disease ◽

Lymphoblastic Leukemia ◽

Underlying Mechanism ◽

Cell Transplant ◽

Survival Differences

Abstract Introduction: Gene expression studies have consistently identified a HOXA positive (HOXAPos) subgroup of T-cell acute lymphoblastic leukemia (T-ALL) (Ferrando et al, Cancer Cell 2002, Soulier et al, Blood 2005, Homminga et al, Cancer Cell 2011). It is however unclear if HOXAPos T-ALL constitutes a distinct and homogeneous clinical entity, and the biological consequences of HOXA over-expression have not been systematically examined. Methods: We identified and characterized the biological characteristics and clinical outcome of 55 HOXAPos cases among a cohort of 209 adult T-ALL patients who were uniformly treated as part of the Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL)-2003 and -2005 studies. Results: HOXAPos patients had higher rates of an early thymic precursor (ETP)-like immunophenotype (38% v 13.9%, p = 0.0008), early bone marrow chemoresistance (59.3% v 40.8%, p = 0.026) and positive minimal residual disease (MRD, 51.5% v 23.5%, p = 0.01) than the HOXANeg group. These differences were due to a particularly high frequency of chemoresistant ETP-ALL among HOXAPos cases harboring leukemic fusion proteins that trans-activate the HOXA locus (e.g. PICALM-MLLT10, SET-NUP214). Strikingly, the presence of an ETP-like immunophenotype conferred marked differences in outcome within the HOXAPos group (5 year event-free survival (EFS) 25% for HOXAPos ETP v 52.2% for HOXAPos non-ETP, p = 0.02), which were mirrored by corresponding increases in cumulative incidence of relapse (CIR, 57.1% v 25%, p = 0.01, Figure 1). In contrast, these survival differences were not seen in the HOXANeg patients, where ETP and non-ETP cases had similar 5 year EFS (54.9% v 50%, p = 0.73) and CIR (34.5% v 41.2%, p = 0.57). Multivariate analysis revealed that early bone marrow chemosensitivity was the clinico-biological covariate that had the strongest prognostic interaction with HOXA status. HOXA positivity conferred significant decreases in both the EFS and CIR of chemoresistant patients (p = 0.053 and 0.039 respectively), that was independent of white blood cell count (WCC), stem cell transplant (SCT), ETP phenotype, EGIL classification, and our recently reported risk classifier that integrates the prognostic effects of mutations of NOTCH1, FBXW7, RAS and PTEN (Trinquand et al, J Clin Oncol 2013). There were corresponding marked survival differences within the HOXAPos cohort between chemoresistant and chemosensitive cases. These disparities were not seen in the HOXANeg group, indicating that the prognostic value of chemosensitivity in adult T-ALL is specific to HOXAPos patients. Discussion: Our data show that clinico-biological phenotype is intimately linked to the underlying mechanism of HOXA locus deregulation, and we identify HOXA overexpression as a novel prognostic variable in ETP-ALL. Multivariate analysis suggests that this poor outcome is strongly related to intrinsic treatment resistance, and that this effect is exclusive to the HOXAPos cohort. Patients in the GRAALL-2003 and -2005 studies received enhanced induction and/ or salvage therapy in the event of poor early treatment response. Our results suggest that pediatric regimen-based intensification provides significant survival benefits for HOXANeg chemoresistant cases. In contrast, these modifications are inadequate for therapeutic rescue of the majority of HOXAPos chemoresistant ETP-ALL. The dramatically inferior prognosis of this group mandates consideration for alternative treatments in future clinical trials. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

Download Full-text