Impact of treatment reduction for childhood acute lymphoblastic leukemia on serum immunoglobulins and antibodies against vaccine-preventable diseases

Background

The consequences of current intensive chemotherapy for childhood acute lymphoblastic leukemia (ALL) for immune defense are a matter of concern. The purpose of this study was to examine the effect of reduced compared with intensive (conventional) ALL chemotherapy on serum immunoglobulin levels and specific antibody concentrations against vaccine‐preventable diseases.

Procedure

Patients treated according to Dutch Childhood Oncology Group ALL 10 protocol were stratified by minimal residual disease to receive reduced (standard risk; SR) or intensive (medium risk; MR) intensification/maintenance treatment. Between November 2004 and July 2009 we compared serum immunoglobulins of 110 patients and specific antibodies against diphtheria toxin, tetanus toxin, and Bordetella pertussis antigens of 41 patients of SR and MR groups during chemotherapy.

Results

Immunoglobulin levels showed significantly different patterns between the SR and MR groups. In the MR group IgG, IgA, and IgM levels decreased towards the end of intensive treatment; in the SR group IgG levels increased while IgA and IgM stabilized. In both groups IgM and IgG levels were most affected. Specific antibody levels against vaccine‐preventable diseases decreased in both groups, but more profound in MR group.

Conclusions

Although reduced chemotherapy is beneficial for immunoglobulin level recovery and might prevent susceptibility for infections, specific antibodies remain decreased. Pediatr Blood Cancer 2012; 58: 701–707. © 2011 Wiley Periodicals, Inc.     

Synchronous occurrence of acute lymphoblastic leukemia and wilms tumor in two patients: underlying etiology and combined treatment plan

Synchronous cancers are extraordinarily rare in pediatric patients and present a therapeutic challenge. Patient A presented with synchronous unilateral Wilms tumor (WT) and standard‐risk (SR) B‐precursor acute lymphoblastic leukemia (ALL). Genetic testing revealed bialleleic BRCA2/FANCD1 mutations. Patient B, after SR B‐precursor ALL induction therapy, was noted on fever workup to have a renal mass; pathology demonstrated lesion indeterminate between WT and nephrogenic rest. Therapy was customized for each patient to treat both cancers. Both patients have ongoing remission from their cancers, without excessive toxicity. We report two regimens for treating synchronous WT and ALL and recommend screening such patients for cancer predisposition.     

Association of clinical trial enrollment and survival using contemporary therapy for pediatric acute lymphoblastic leukemia

While early studies reported superior survival for cancer patients enrolled on clinical trials, recent findings are inconclusive. We investigated the association between enrollment on contemporary trials and event‐free survival (EFS) in pediatric B‐cell acute lymphoblastic leukemia (B‐ALL). In a retrospective cohort of 274 children (1–21 years) treated for B‐ALL from 2008 to 2015, 55.5% enrolled with no disparity in enrollment by age, sex, or ethnicity. Three‐year EFS was similar for enrolled and not enrolled patients (90.1% [95% CI, 82.5–94.5] versus 86.5% [95% CI, 77.7–92.0]). Clinical trial enrollment did not affect pediatric B‐ALL survival, albeit in a limited‐size cohort treated at a single academic institution.     

Spontaneous tumor lysis syndrome in a child with T‐cell acute lymphoblastic leukemia

We report a 5‐year‐old female who presented with unexplained acute renal failure (ARF) and hyperuricemia and who was subsequently diagnosed of T‐cell acute lymphoblastic leukemia (ALL). Peripheral smear was initially unremarkable. She required hemodialysis. Two weeks later, peripheral smear showed 40% blasts and bone marrow demonstrated T‐cell ALL. Our case was the fifth and the youngest case of ALL with spontaneous tumor lysis syndrome. However, in contrast to previous reports in ALL or acute myeloid leukemia, our patient did not have blasts noted on periphereal blood smear and her white blood cell count and serum lactate dehydrogenase level were normal on admission, a time when dialysis‐dependent ARF and severe hyperuricemia were present. Occult hematologic malignancy should be considered in cases of ARF and hyperuricemia of unknown etiology even when peripheral hematologic findings are not informative. Pediatr Blood Cancer 2010;54:773–775. © 2009 Wiley‐Liss, Inc.     

Relapse factors during maintenance therapy of acute lymphoblastic leukemia in children.

A statistical analysis of possible risk factors for relapse during maintenance therapy (MT) for acute lymphoblastic leukemia (ALL) has been performed. The patient material consists of 64 patients. Twenty-six patients were classified as standard risk (SR), 21 as intermediate risk (IR), and 17 as high-risk (HR) patients. Seventeen patients relapsed and 50 patients (78%) are alive at a median observation period of 86 months (range 39-146 months). Mean white blood cell count (mean WBC) based on weekly determinations, duration of treatment interruption, and the number of infectious episodes were calculated in each patient during the first 6 months of MT. In analyses starting at 6 months after the beginning of MT, these factors were related to relapse risk, time to relapse, and time to infection. Using the median WBC value (3.9 x 10(9)/L) of all patients during the first 6 months as a cutoff point, 14 patients with levels higher, and 3 patients with levels lower relapsed (p = .0004). Adjustment of mean WBC for leukemia risk groups had no influence on the analysis. Time to relapse was related to duration of interruption of MT (p less than .01). Time to relapse was not related to leukemia risk groups. Infection frequency was higher in HR patients compared to SR and IR risk patients (p = .04). As WBC level had a prognostic value and was previously shown to be related to 6-mercaptopurine (6-MP) peak plasma concentration, monitoring 6-MP plasma levels during MT could be helpful for optimizing treatment.     

Improvement in CNS protective treatment in non-high-risk childhood acute lymphoblastic leukemia: report from the Japanese Children's Cancer and Leukemia Study Group

BACKGROUND: Prevention of central nervous system (CNS) leukemia by early introduction of therapy to this sanctuary site is an essential component of modern treatment strategy for acute lymphoblastic leukemia (ALL). However, the optimal form of preventive CNS therapy remains debatable. PROCEDURE: To address this issue, we evaluated the efficacy of CNS preventive therapy for 572 children with ALL who achieved complete remission in the Children's Cancer and Leukemia Study Group (CCLSG) ALL874 (1987-1990) and ALL911 (1991-1993) studies. They received risk-directed therapy based on age and leukocyte count. In the ALL 874 study, the non-high-risk (low-risk [LR] + intermediate risk [IR]) patients were randomly assigned to the conventional cranial irradiation (CRT) regimen (L874A and I874A) and the high-dose methotrexate (HDMTX) regimen without CRT (L874B and I874B). The former patients received 18-Gy CRT plus 3 doses of intrathecal (i.t.) MTX and the latter patients received 3 courses of HDMTX at 2 g/m2 plus 13 doses of ITMTX (L874B) or 4 courses of HDMTX at 4.5 g/m2 plus 1 dose of ITMTX (I874B). RESULTS: The 7-year probabilities (+/- SE) of CNS relapse-free survival were 97.3% +/- 2.6% (L874A, n = 41) vs. 90.3% +/- 5.3% (L874B, n = 39) (P = 0.25) in the LR patients, and 100% (I874A, n = 55) vs. 78.5% +/- 6.5% (I874B, n = 54) (P = 0.002) in the IR patients. The corresponding disease-free survival (DFS) rates were 79.4% +/- 6.5% vs. 74.4% +/- 7.3% (P = 0.62) in the LR group and 63.3% +/- 6.8% vs. 58.3% +/- 7.2% (P = 0.66) in the IR group. Thus, the HDMTX regimen could not provide better protection of CNS relapse as compared with the CRT regimen, although their overall efficacy was not significantly different. In the ALL 911 study, intensive systemic chemotherapy with extended i,t, injections of MTX plus cytarabine achieved a high CNS relapse-free survival (98% +/- 1.9% at 7 years) and a favorable DFS (85.5% +/- 5% at 7 years) in the IR patients. The patients in the high-risk (HR) group in both ALL874 and ALL911 studies received the 18-Gy or 24-Gy CRT with intensive systemic chemotherapy. Their 7-year probabilities of CNS relapse-free survival ranged from 88% to 95%, among which the T-ALL patients had a risk of CNS leukemia, which was 3-4 times higher compared with B-precursor ALL patients. CONCLUSIONS: These results indicate that long-term intrathecal CNS prophylaxis as well as appropriate systemic therapy for the non-high-risk patients can provide protection against CNS relapse equivalent to that provided by cranial irradiation.     

Myeloid lineage switch following chimeric antigen receptor T‐cell therapy in a patient with TCF3‐ZNF384 fusion‐positive B‐lymphoblastic leukemia

A pediatric patient diagnosed initially with B‐lymphoblastic leukemia (B‐ALL) relapsed with lineage switch to acute myeloid leukemia (AML) after chimeric antigen receptor T‐cell (CAR‐T) therapy and hematopoietic stem cell transplant. A TCF3‐ZNF384 fusion was identified at diagnosis, persisted through B‐ALL relapse, and was also present in the AML relapse cell population. ZNF384‐rearrangements define a molecular subtype of B‐ALL characterized by a pro‐B‐cell immunophenotype; furthermore, ZNF384‐rearrangements are prevalent in mixed‐phenotype acute leukemias. Lineage switch following CAR‐T therapy has been described in patients with KMT2A (mixed lineage leukemia) rearrangements, but not previously in any patient with ZNF384 fusion.     

Blinatumomab activity in a patient with Down syndrome B‐precursor acute lymphoblastic leukemia

Persistent minimal residual disease (MRD) after consolidation may indicate chemotherapy insensitivity in B‐precursor acute lymphoblastic leukemia (BP‐ALL). Given the strong association of MRD and outcome in non‐Down syndrome (non‐DS) BP‐ALL, it is likely that MRD levels are also of prognostic significance in DS BP‐ALL. We report here the successful use of blinatumomab, a bispecific T‐cell engager antibody construct, in a patient with DS BP‐ALL and persistent MRD at the end of consolidation. Blinatumomab has been shown to have excellent results in patients with relapsed/refractory BP‐ALL. This patient had no significant toxicity and achieved MRD negativity after only one cycle of blinatumomab.     

CD5 positive B‐ALL,a uniquely aggressive subcategory of B‐ALL? A case report and brief review of the literature

CD5 antigen expression in B‐cell acute lymphoblastic leukemia (B‐ALL) is exceptionally rare. There are six detailed case reports in the literature, with only 16 cases described. Case series analyzing the frequency of aberrant B‐ALL immunophenotypes suggest that this variant may occur in as little as 2‐4.5% of all B‐ALL cases, with one series having no CD5⁺ positive cases. Herein we report a case of CD5⁺ B‐ALL in a 15‐year‐old female, and review the previously reported cases. As limited information is available, more data from prospective clinical trials are required to determine whether CD5 positivity portends a poorer prognosis.     

Blinatumomab as a bridge to further therapy in cases of overwhelming toxicity in pediatric B‐cell precursor acute lymphoblastic leukemia: Report from the Israeli Study Group of Childhood Leukemia

Tremendous progress in the therapy of pediatric acute lymphoblastic leukemia (ALL) has been achieved through combination cytotoxic chemotherapy, leading to high cure rates, at the cost of significant life‐threatening toxicity. The bispecific T‐cell engager blinatumomab, recently approved for relapsed/refractory ALL, has a unique nonmyelotoxic toxicity profile. As blinatumomab causes B‐cell depletion, the safety of its use during severe chemotherapy‐induced toxicity is unclear. We report 11 pediatric patients with ALL, treated with blinatumomab following overwhelming chemotherapy‐associated toxicity, with recovery of all patients and successful bridging to further antileukemia therapy. Blinatumomab can be considered for rare patients who cannot tolerate cytotoxic therapy.     

Childhood relapsed acute lymphoblastic leukemia: Biology and recent treatment progress

Acute lymphoblastic leukemia (ALL) is the most frequent cancer in children. Despite remarkable improvement in the prognosis of childhood ALL over the past few decades, the treatment of relapsed ALL is still challenging. The prognosis of first ALL relapse is associated with time of relapse after initial therapy, sites of relapse, and immunophenotype. More recently, response to treatment, which is evaluated by assessment of minimal residual disease (MRD), has been found to be clinically significant in relapsed ALL as well as in the initially diagnosed disease. Utilizing these factors, risk‐oriented treatment stratification for first ALL relapse has been established. In the standard‐risk group for first ALL relapse, intensification of conventional ALL‐type therapy can provide a cure in approximately 70% of patients. It is important to assess MRD after reinduction therapy to determine the indications for stem cell transplantation in the standard‐risk group. In contrast, no standardized therapy has been established for the high‐risk group, which accounts for more than half of relapsed ALL patients. Recent studies have shed light on the clonal origin of relapsed ALL, which usually exists as a minor subclone at the time of initial diagnosis. Clonal selection and evolution take place during chemotherapy, resulting in distinct genetic and epigenetic characteristics of relapsed ALL, some of which are linked to drug resistance, a common and problematic feature of ALL after relapse. To overcome resistance to standard ALL‐type therapy, and considering the heterogeneous biological background of high‐risk relapsed ALL, innovative therapies using new agents are necessary.     

Toxic epidermal necrolysis in a child 6 months post‐hematopoietic stem cell transplantation

TEN is a rare and critical disease mostly caused by drugs. It is mediated by activated CD8+ T cells that cause keratinocyte apoptosis with the assistance of cytokines/chemokines. We herein report a pediatric case of TEN after allogeneic HSCT with precursor B‐cell acute lymphoblastic leukemia (pre‐B‐ALL) in second complete remission. Although we did not evaluate the T‐cell subpopulation in blood or skin lesion of the patient, an imbalanced immune reconstitution after HSCT might additively contribute to the development of TEN.     

Leukemic Cell Lysis by Autologous Lymphocytes in Childhood ALL: Generation of Cytolysis by Lymphocytes Activated With Cultured Non T Non B Leukemic Cell Lines

The lysis of leukemic cells by autologous lymphocytes was studied in the common type of acute lymphoblastic leukemia (ALL) in childhood using the 10-hour⁵¹Cr release assay. Peripheral blood lymphocytes (PBL) from common ALL patients lysed autologous leukemic cells (% lysis: 19–45%), when co-cultivated in vitro with cultured non T non B leukemic cell lines (NALM 16, Reh and NALL 1). The effector cells were cytotoxic T lymphocytes (CTL) possessing Leu-1 and Leu-2a antigens. The effector CTL were cytotoxic not only for autologous leukemic cells but for cultured non T non B leukemic cell lines, whereas they did not lyse human T cell (CCRF-CEM), B cell (Daudi) and natural killer cell lines (SPI-802). Cold target competition assays demonstrated that leukemic cells from childhood common ALL and several non T non B leukemic cell lines shared an antigenic determinant(s) recognized by CTL.     

Evidence for BCR/ABL1‐positive T‐cell acute lymphoblastic leukemia arising in an early lymphoid progenitor cell

BCR‐ABL1‐positive leukemias have historically been classified as either chronic myelogenous leukemia or Ph+ acute lymphoblastic leukemia. Recent analyses suggest there may be a wider range of subtypes. We report a patient with BCR‐ABL1 fusion positive T‐cell ALL with a previously undescribed cell distribution of the fusion gene. The examination of sorted cells by fluorescence in situ hybridization showed the BCR‐ABL1 fusion in the malignant T cells and a subpopulation of the nonmalignant B cells, but not nonmalignant T cells or myeloid or CD34+ progenitor cells providing evidence that the fusion may have occurred in an early lymphoid progenitor.     

Rapid Capture Next‐Generation Sequencing in Clinical Diagnostics of Kinase Pathway Aberrations in B‐Cell Precursor ALL

Comprehensive next‐generation sequencing (NGS) applications have recently identified various recurrent kinase and cytokine receptor rearrangements in Ph‐like B‐cell precursor (BCP) acute lymphoblastic leukemia (ALL) amenable to tyrosin kinase inhibitor treatment. For rapid diagnostics of kinase pathway aberrations in minimal residual disease (MRD) high‐risk BCP‐ALL, we developed a PCR‐independent NGS custom enrichment capture panel targeting recurrent genomic alterations, which allows for the identification of unknown 5′ fusion partner genes and precise mapping of variable genomic breakpoints. Using a standardized bioinformatics algorithm, we identified kinase and cytokine receptor rearrangements in the majority of ALL patients with high burden of postinduction MRD and enrichment of IKZF1 mutation or deletion (IKZF1^del).     

Sequential acquisition of IgH and TCR rearrangements during the preleukemic phase of acute lymphoblastic leukemia in an adolescent patient

Acute lymphoblastic leukemia (ALL) can be preceded by a prodromal phase of bone marrow failure. In serial trephine biopsies in a girl with acquired bone marrow hypoplasia, we have identified a monoclonal B‐cell precursor population characterized by a clone‐specific IgH‐FR3 gene rearrangement. Progression to ALL more than 4 months later was accompanied by acquisition of an additional T‐cell receptor rearrangement. Thus, hypoplastic pre‐ and overt leukemia share a common clonal origin. Prospective biobanking and extended molecular analysis can help to better understand the nature and sequence of genetic events during progression of a covert (pre)leukemic clone. Pediatr Blood Cancer 2011;56:301–303. © 2010 Wiley‐Liss, Inc.     

Treatment‐related mortality in relapsed childhood acute lymphoblastic leukemia

1 Background

Treatment of relapsed childhood acute lymphoblastic leukemia (ALL) is particularly challenging due to the high treatment intensity needed to induce and sustain a second remission. To improve results, it is important to understand how treatment‐related toxicity impacts survival.

2 Procedure

In this retrospective population‐based study, we described the causes of death and estimated the risk for treatment‐related mortality in patients with first relapse of childhood ALL in the Nordic Society of Paediatric Haematology and Oncology ALL‐92 and ALL‐2000 trials.

3 Results

Among the 483 patients who received relapse treatment with curative intent, we identified 52 patients (10.8%) who died of treatment‐related causes. Twelve of these died before achieving second remission and 40 died in second remission. Infections were the cause of death in 38 patients (73.1%), predominantly bacterial infections during the chemotherapy phases of the relapse treatment. Viral infections were more common following hematopoietic stem cell transplantation (HSCT) in second remission. Independent risk factors for treatment‐related mortality were as follows: high‐risk stratification at relapse (hazard ratio [HR] 2.2; 95% confidence interval [CI] 1.3–3.9; P < 0.01), unfavorable cytogenetic aberrations (HR 3.4; 95% CI 1.3–9.2; P = 0.01), and HSCT (HR 4.64; 95% CI 2.17–9.92; P < 0.001). In contrast to previous findings, we did not observe any statistically significant sex or age differences. Interestingly, none of the 17 patients with Down syndrome died of treatment‐related causes.

4 Conclusions

Fatal treatment complications contribute significantly to the poor overall survival after relapse. Implementation of novel therapies with reduced toxicity and aggressive supportive care management are important to improve survival in relapsed childhood ALL.     

Facial manifestations of Epstein–Barr virus‐related lymphoproliferative disease in childhood acute lymphoblastic leukemia in remission: Two atypical presentations

Epstein–Barr virus‐related lymphoproliferative disease (EBV‐LPD) rarely occurs in patients with acute lymphoblastic leukemia (ALL), who have not received hematopoietic transplantation. We describe EBV‐LPD manifesting as facial lesions in two children with ALL in remission. One patient was a 16‐year‐old male with T‐cell ALL with an EBV‐positive angiocentric polymorphous lip lesion presenting as right‐sided facial swelling. The other patient was a 12‐year‐old male with B‐cell ALL with an EBV‐positive polymorphous lymphoplasmacytic infiltrate presenting as bilateral dacryoadenitis. Neither patient had known primary immunodeficiencies. Both cases improved with immunosuppressant de‐escalation. These cases suggest that immunosuppression induced by maintenance chemotherapy is sufficient to promote EBV‐LPD.     

An unusual pattern of B‐cell immunological reconstitution after allogeneic stem cell transplantation: A possible correlation with CMV reactivation?

Abstract: IR after HSCT is a slow process that involves several components of the immune response, and, in allogeneic setting, it can be delayed by GvHD and immuno‐suppressive therapy. Our study on IR post‐HSCT included a child with FA who underwent MUD transplantation. To evaluate B, T and NK cell reconstitution and to investigate the differentiation of B lymphocyte repertoire, this patient was carefully monitored at various time points by IgHCDR3 (third complementarity determining region of the immunoglobulin heavy chain) fingerprinting and by FACS analysis. IgHCDR3 fingerprinting showed a strong oligoclonality of IgM and IgG profiles from day +60 to +180 post‐transplant. CMV reactivation was present at the same time points and overlapped the clonal pattern shown in IgHCDR3 fingerprinting. Immunophenotype analysis showed early repopulation of T and NK cells following HSCT, whereas B cells increased first at one yr post‐transplant. The overlapping of virus reactivation and B‐cell clonal expansion seems to suggest that B lymphocytes may be involved in the CMV immunological response, at least in the early time points after HSCT when the immune repertoire is still reconstituting.     

A Population-Based Study of Childhood Acute Lymphoblastic Leukemia Diagnosed from July 1981 through June 1985 in the Five Nordic Countries

Six hundred and fifty-six children with acute lymphoblastic leukemia (ALL) have been diagnosed in the five Nordic countries (Denmark, Finland, Iceland, Norway and Sweden) during the period from July 1981 through June 1985. Annual incidence of ALL was 3.6/100000 children aged < 15 years, with an incidence for males of 3.8 and for females of 3.4 respectively. Half of the children were younger than 5 years of age at diagnosis, with a peak incidence between 2–3 years of age. The leukemias were classified as Standard Risk (SR), Intermediate Risk (IR) or High Risk (HR) leukemia according to prognostic criteria at diagnosis. The remission rate was 95%. In children 1 year of age with non-B-cell ALL at diagnosis, the Event-Free Survival (EFS) was 0.58; 0.65 for SR-children, 0.51 for IR-children and 0.52 for HR-children. WBC count at diagnosis was the most important prognostic factor and a WBC count of 11-20×10⁹/l was associated with the worst prognosis of all WBC values (EFS=0.30), independent of other prognostic factors. Male sex was the second most important adverse prognostic criterion. The follow-up in January 1986 (observation time 6–54 months), showed that 442 of the 656 children (67%) were in complete continuous remission. The total results indicate a possibility to improve the prognosis for most of the risk groups of ALL with a more intensive treatment.