Monthly variation in diagnosis of acute lymphoblastic leukemia and survival outcome in children and adults: 15-year trends at a single center

ABSTRACT Background: The date of acute lymphoblastic leukemia (ALL) diagnosis has been studied regarding potential etiologic roles with contrasting results and the issue remains controversial. The principal aim of this study was to analyze monthly variation of ALL diagnosis in a large homogenous Hispanic Latin American cohort over 15 years; its association with survival rates was also assessed. Methods: Clinical files and electronic records of 501 consecutive patients of all ages with ALL in northeastern Mexico over the years of 2004-2018 were scrutinized. Patients were divided into children <18 and adults >18 years. The Chi-square heterogeneity analysis was used to test for non-uniform variation. The Poisson regression analysis was used to fit sinusoidal (harmonic) models to the data, using the month of diagnosis as a covariate in a separate model. Results: During the study period 363 children (72.5%) and 138 adults (27.5%) (p < 0.001) were diagnosed with ALL. Heterogeneity across the months of diagnosis was confirmed (p = 0.019) and the Poisson regression analysis confirmed a significant monthly variation (p < 0.001) (95% CI, 3.024-3.745), a higher annual peak being observed in the month of March (p = 0.002), followed by a second peak in October (p = 0.026). The five-year OS for children was 68.2% (95% CI, 67.64-68.74) and for adults, 43.7% (95% CI, 42.67-44.71) (p < 0.001). No significant association between the month of diagnosis and OS was found (p = 0.789). Conclusion: The monthly variation of ALL diagnosis was documented; these results confirm the heterogeneous behavior of the disease and appear to be consistent with an interplay of environmental and biologic factors. Further studies are needed to examine putative candidate agents.

Influence of minimal residual disease by multiparametric flow cytometry at day 15 of induction in risk stratification of children with B-cell acute lymphoblastic leukemia treated at a referral hospital in southern Brazil

ABSTRACT Background: The minimal residual disease (MRD) is the most important prognostic factor for acute lymphoblastic leukemia (ALL) in children. This study aimed to investigate the influence of detecting the MRD by the multiparametric flow cytometry (MFC) at day 15 (D15) of the induction on the analysis of the risk group classifications of the different childhood ALL treatment protocols used in a referral hospital in southern Brazil. Method: We retrospectively reviewed the medical records of patients with B-cell ALL, aged 1 to 18 years, treated at a hospital from January 2013 to April 2017. Main results: Seventy-five patients were analyzed. Regarding the MRD by the MFC at D15, the analyses showed statistical significance when the MRD was grouped into three categories, < 0.1%, 0.1-10%, and > 10%, with the following distribution: 30.7%, 52.0%, and 17.3%, respectively. There was a significant association between D15 MRD-MFC < 0.1% and the likelihood of dying or relapsing and between D15 MRD-MFC > 10% and the likelihood of dying or relapsing. The cumulative hazard ratio for the relapse of patients with D15 MRD-MFC < 0.1%, 0.1-10%, and > 10% was 19.2%, 59.8%, and 80.1%, respectively. Conclusion: Our analysis suggests D15 MRD-MFC < 0.1% as a cut-off point for patients with more favorable outcomes and that the MRD at D15 in risk classifications is particularly useful for the stratification of patients with a more favorable prognosis.

The Implications of E2A-PBX1 Positivity and Effect of Delayed Intensification Chemotherapy in t(1;19)-positive Childhood Acute Lymphoblastic Leukemia / 대한혈액학회지

PURPOSE: We studied the E2A-PBX1 positivity in t(1;19)-positive childhood acute lymphoblastic leukemia (ALL) patients during chemotherapy and follow-up period to evaluate the clinical implications of minimal residual disease (MRD) and the effect of delayed intensification chemotherapy on long-term survival. METHOD: Fifty-six bone marrow or peripheral blood samples collected retrospectively or prospectively before or during chemotherapy from 14 childhood ALL patients who had t(1;19) or E2A-PBX1 transcript at initial diagnosis were studied for the presence of E2A-PBX1 by RT- PCR. All patients received delayed intensification chemotherapy regardless of standard prognostic grouping for childhood ALL to evaluate its effect on the improvement of long-term survival. RESULTS: There were 11 t(1;19)-positive cases documented by karyotyping and 3 E2A-PBX1 transcript-positive cases amplified by PCR from the initial bone marrow samples. There were 11 cases of FAB L1 and 3 cases of L2. Immunophenotypic classification revealed 10 cases of group V, 2 cases of group IV, and 1 case of group III. Among 11 cases with documented karyotype, 9 cases (81.8%) had der(19)t(1;19) and the other 2 had balanced t(1;19). Fifty-six samples collected at 2 to 7 different time points of 14 patients revealed 4 cases of MRD immediately after completion of induction chemotherapy despite hematologic complete remission. Three of these cases relapsed eventually, and 1 was lost to follow-up. Among 12 cases who received adequate delayed intensificiation chemotherapy, 10 are alive in complete remission. CONCLUSION: MRD detection by RT-PCR amplification of E2A-PBX1 transcript was feasible, and the sample after completion of induction chemotherapy was most informative for the prediction of long-term survival and relapse. The presence of MRD after completion of induction chemotherapy conferred poor prognosis. The addition of delayed intensification chemotherapy to standard chemotherapy regimen could abolish the adverse effect of t(1;19) in childhood ALL patients.

Four Cases of Acute Parotitis in Acute Lymphoblastic Leukemia Patients Developed during Induction Chemotherapy Including L-Asparaginase / 대한소아혈액종양학회지

L-asparaginase is an essential chemotherapeutic agent in the treatment of the acute lymphoblastic leukemia or non-Hodgkin lymphoma with its unique mechanism of action. It has many toxic effects involving multiple organs. The acute parotitis associated with L-asparaginase has been rarely reported. In this report, acute parotitis developed in the 4 acute lymphoblastic leukemia patients who were treated with the induction chemotherapy regimen including L-asparaginase. Mumps was excluded in 3 patients and the evidence of coexisting pancreatitis was observed in 2 patients. The parotid ultrasonography revealed diffuse enlargement in all patients. The symptoms were spontaneously resolved with no specific treatment, and in all cases there was no recurrence of the same disease with later maintenance chemotherapy including L-asparaginase. The possible mechanism of the acute parotitis is not yet clearly understood. But considering its histologic similarity with the pancreas, the depletion of L-asparagine may damage the acinar cells of parotid gland. The acute parotitis is not a well-known side effect of L-asparaginase but it needs to be promptly recognized in order to consider the discontinuation of the L-asparaginase and to exclude any viral infection requiring isolation.

Detection of Minimal Residual Disease by IgH gene rearrangement-PCR in Childhood Acute Lymphoblastic Leukemia / 대한임상병리학회지

BACKGROUND: The IgH gene rearrangement (IgH GR) involving highly specific CDR3 region can be used as a minimal residual disease marker in ALL. The IgH GR-PCR has the advantages of the high positive rate in ALL and the detection of clonal evolution. METHODS: In 30 cases of childhood ALL, the DNA was extracted from the bone marrow aspirates at the diagnosis and during the chemotherapy. The 40 cycle polymerase chain reaction was performed with seven each VH family specific primer and common JH primer. The PCR products were electrophoresed on the agarose gel, and those showing specific bands were electrophoresed on 6M urea 6% polyacrylamide DNA sequencing gel. We compared and analyzed the IgH GR-PCR results, the morphologic diagnosis of the bone marrow and the clinical course. RESULTS: IgH GR was detected in 93.3% (28/30) at the diagnosis and the rest of two cases showed IgH GR during the therapy. IgH GR was detected in all specimens diagnosed as persistence, partial remission and relapse, the 80.0% of hypocellular marrow with persistence of blasts, the 72.7% of hypocellular marrow, and the 59.2% of complete remission. In the complete remission states the patients with IgH GR showed significantly higher relapse rate (26.2%) than those without IgH GR (7.1%) (p=0.019). Number of clones of IgH GR was from one to five. The more number of clones showed the shorter mean survival time (p=0.1172). The usage of VH3 was most frequent (70.0%). IgH GR had been detected average 3.5 months (range 1-12 months) earlier than the morphologic relapse appeared. During the chemotherapy the evolution of IgH GR was observed in the seven cases (23.3%). CONCLUSIONS: The IgH GR-PCR will help the understanding of biological characteristics of leukemic cells, the interpretation of the bone marrow studies after chemotherapy and the plans of further therapy, and can be used as a prognostic indicator in the morphologic complete remission state.