This study is a retrospective review on the outcomes of patients with therapy-related acute promyelocytic leukemia (APL). Therapy-related APL is rare, and this is a multi-institutional study.
Data on 103 adult patients who were treated between 1991-2015 were collected from 11 study groups and institutions in the US/ Europe. Cox proportional hazards regression model was used to identify prognostic variables for EFS, RFS, and OS.
The study showed difference in outcome based on the APL treatment. None of the patients treated with ATRA alone survived beyond one year. Event-free survival was significantly higher after ATO-based therapy (95%, 95% CI, 82-99%) as compared to CTX/ATRA (78%, 95% CI, 64-87%; P=0.042), if deaths due to recurrence of the prior malignancy were censored.
This was not a prospective study or RCT, therefore possible to have more confounding factors / biases. Further, this study only included adult patients, may not directly be applicable for pediatric oncology patients.
Therapy-related APL appears to have responsiveness to arsenic trioxide based treatments, similar to de novo APL.
Assessment of imatinib as first-line treatment of chronic myeloid leukemia: 10-year survival results of the randomized CML study IV and impact of non-CML determinants
Chronic myeloid leukemia (CML)-study IV was designed to explore whether treatment with imatinib (IMA) at 400 mg/day (n=400) could be optimized by doubling the dose (n=420), adding interferon (IFN) (n=430) or cytarabine (n=158) or using IMA after IFN-failure (n=128). Primary goals were the comparative response and long-term survival analyses of the experimental arms vs IMA 400 mg.
Patients (aged 16-88y) were recruited by 210 centers in Germany, Switzerland, and the Czech Republic. From July 2002 to March 2012, 1551 newly diagnosed CML patients in chronic phase were randomized, 1536 were evaluable. Molecular monitoring of all patients was an integral part of the study from the beginning.
After a median observation time of 9.5 years, 10-year overall survival was 82%, 10-year progression-free survival was 80% and 10-year relative survival was 92%. Survival between IMA 400 mg and any experimental treatment arm was not different. Patients reaching the molecular response milestones at 3, 6 and 12 months had a significant survival advantage. For responders, monotherapy with IMA 400 mg provides a close to normal life expectancy independent of the time to response. The authors concluded that survival with CML is currently more determined by patients’ and disease factors than by initial treatment selection.
This study provided long term outcome data for adult CML patients on long term treatment with imatinib. However, pediatric CML patients were started on treatment at a much younger age compared to this cohort and may need to continue on treatment for a much longer time, therefore this data cannot directly apply to our patients. If the study can have subgroup analysis of the younger adult patients and their long term outcome in next 2 decades, that may be more meaningful for applying our patients.
There is increasing data on long-term outcome data in adult CML patients, but there is still a need for more long-term outcome information on paediatric patients.
CD207+CD1a+ cells circulate in pediatric patients with active Langerhans cell histiocytosis
Langerhans cell histiocytosis (LCH) is seen as a myeloid neoplasm with an important inflammatory component. Pathological CD207+CD1a+cells are found in the lesions among other cell types. This study investigated whether these cells could also be found circulating in the blood in active (AD) and non-active (NAD) disease patients. Further cytokines were measured that had been previously associated with LCH.
Twenty-two patients with LCH were recruited form a single center about half having active disease (AD) and the other half non-active disease (NAD). Plasma, peripheral blood mononuclear cells, and further biochemical values were collected. Flow cytometry was used to differentiate circulating cells. Cytokines were measured in the plasma. AD patients were compared with NAD and healthy adults. Plasma of AD LCH patients was incubated with healthy donor monocytes.
CD207+CD1a+cells were found in the peripheral blood of only AD LCH patients but not NAD LCH patients, healthy adults, umbilical cord blood, or patients affected with disseminated juvenile xanthogranuloma (a non-LCH inflammatory disease). CD11b+ cells were also increased. Previously identified cytokines associated with LCH thymic stromal lymphopoietin (TSLP) and transforming growth factor b (TGF-b) plasma levels were increased in patients with AD LCH compared to NAD LCH. When incubating plasma from AD LCH patients with monocytes of healthy adults, appearance of CD11b+ and CD207+ cells was noted. The authors concluded that CD207+CD1a+cells could be used as markers of AD in LCH.
The sample size used to draw conclusions was small. While the theory is compelling and the findings very promising, they have to be put into the clinical context of LCH patients and measured over time when AD patients become NAD and vice versa.
CD207+CD1a+cells were associated with active disease in LCH patients which is the first time that circulating LCH cells are identified in the peripheral blood and could serve as a disease marker.
Pathophysiology of Chronic Graft-versus-Host Disease and Therapeutic Targets
Zeiser, R et al, 2017, New England Journal of Medicine
Severe viral infection post HSCT are still a major cause of morbidity and mortality. Current antivirals can be ineffective and associated with significant toxicities. Donor-derived virus-specific T cells (VSTs) have been shown to be efficacious but issues include high costs, complex manufacturing and the need of seropositive donors. This study aimed to study VSTs generated from eligible, third-party donors.
Phase 2 study using generated banks of VSTs that recognized five common viral pathogens: EBV, adenovirus (AdV), CMV, BK virus, and human herpesvirus 6.
38 patients with 45 drug-refractory infections received the VST +/- antivirals depending on physician preference. A single infusion produced a cumulative complete or partial response rate of 92% (95% CI, 78.1% to 98.3%) overall and the following rates by virus: 100% for BKV (n = 16), 94% for CMV (n = 17), 71% for AdV (n = 7), 100% for EBV (n = 2), and 67% for HHV-6 (n = 3). Infusions were safe, and only two occurrences of de novo graft-versus host disease (grade 1) were observed.
Small, single centre, adult study thus unknown if these results can be replicated in pediatric HSCT patients. Not an RCT.
New methods to decreased morbidity and mortality associated with viral infections post HSCT are needed and banked VSTs may be a feasible, safe, and effective approach but more studies needed, in particular RCTs on paediatric populations.
Asparaginase-associated pancreatitis in childhood acute lymphoblastic leukaemia: an observational Ponte di Legno Toxicity Working Group study
Asparaginase is an essential drug in the treatment of acute lymphoblastic leukemia, but is also associated with several toxicities, one of the most severe being asparaginase-associated pancreatitis. The aim of this study was to investigate the risk of complications and risk of re-exposing patients with a history of asparaginase-associated pancreatitis to further asparaginase therapy. Other outcomes were investigation of the diagnostic criteria for asparaginase-associated pancreatitis and differences in asparaginase-associated pancreatitis phenotype between patients receiving different types of asparaginase.
This is an observational study, where patient files from 26 trials run by 18 trial groups were reviewed on children diagnosed with t(9;22)-negative acute lymphoblastic leukemia, who within 50 days of asparaginase exposure developed asparaginase-associated pancreatitis.
In this study, 465 patients with asparaginase-associated pancreatitis were included: 26% developed pseudocysts, 21% needed acute insulin therapy, 8% needed mechanical ventilation, and 2% of 458 patients died. Risk of assisted mechanical ventilation, need for insulin, pseudocysts, or death was associated with older age, and having one or more affected vital signs (fever, hypotension, tachycardia, or tachypnoea). 1 year after diagnosis of asparaginase-associated pancreatitis, 11% still needed insulin or had recurrent abdominal pain or both, which were associated with having had a pseudocyst. 96 patients were re-exposed to asparaginase, including 59 after a severe asparaginase-associated pancreatitis. 46% patients developed a second asparaginase-associated pancreatitis.
The high frequency of affected vital signs at diagnosis of asparaginase-associated pancreatitis could be misdiagnosed as having sepsis. Grading of severity was misleading. No dose association or other medication that can cause pancreatitis were examined in this study.
The risk of a second asparaginase-associated pancreatitis was not associated with severity of the first asparaginase-associated pancreatitis and having a second asparaginase-associated pancreatitis was not associated with risk of persisting complications, therefore re-exposure to asparaginase should be determined mainly by the anticipated need of asparaginase for antileukemic efficacy.
Outcome of children with acute leukemia given HLA-haploidentical HSCT after ab T-cell and B-cell depletion
Haploidentical hematopoietic stem cell transplantation (HSCT) is an option for transplantation in patients without a suitable matched donor. CD34+ positive selection is traditionally used to prevent both graft failure and severe graft-versus-host disease (GVHD), but is associated with prolonged lymphopenia and delayed immune reconstitution. Selective depletion of (alpha-beta) T lymphocytes and B cells from a haploidentical donor allows transplantation of both donor hematopoietic stem cells and also committed progenitor cells, NK cells, and (gamma-delta) T lymphocytes to improve post-transplant immune reconstitution and decrease life-threatening infections.
In this prospective trial, children with acute lymphoblastic or myelogenous leukemia without an available matched sibling or unrelated donor were offered a selectively cytoreduced haploidentical transplant. All patients received myeloablative conditioning, anti-T lymphocyte globulin for GVHD prophylaxis and conditioning, and Rituximab for EBV-related PTLD prophylaxis. This cohort was compared to children receiving either a matched sibling or matched unrelated transplant in the same period at the centre.
80 children were enrolled in the cohort; two failed to engraft. No serious acute GVHD occurred, and the overall incidence of limited chronic GVHD was only 5%. Four patients died of treatment-related causes, for a 5-year cumulative incidence of 5%. 19 patients (24%) have relapsed, with 15 in the first year after transplantation; only use of total body irradiation had a significant impact on relapse rate in multivariate analysis. 5-year overall survival was 72%, and this group was comparable to the compared matched sibling and unrelated groups.
Novel approaches such as post-transplantation cyclophosphamide were not evaluated in this regimen, which might allow for decreased intensity of conditioning. Rituximab prophylaxis may have contributed to the low incidence and severity of acute GVHD through recipient B-cell depletion. This was a single-centre trial of a highly specialised graft-manipulation, less experienced centers might not be able to achieve the same quality of graft manipulation.
Even in the absence of post-transplantation pharmacological prophylaxis, patients receiving a selectively (alpha-beta) T-cell and B-cell depleted haploidentical HSC had both a high engraftment rate and a low incidence of GVHD. This type of transplantation offers comparable risks of treatment-related morbidity and mortality and relapse for patients who would otherwise lack a suitable donor.
Central nervous system involvement in acute lymphoblastic leukemia is mediated by vascular endothelial growth factor
Treatment of the central nervous system in acute lymphoblastic leukemia is critical, even in the absence of detectable involvement at diagnosis. This suggests subclinical involvement in many ALL patients at diagnosis. Multiple factors have been evaluated in relation to CNS involvement, which is described as leptomeningeal disease. This study identified vascular endothelial growth factor A (VEGF) as a mediator of CNS involvement of ALL.
The study used the immunodeficient NOD/SCID mouse model to investigate key molecular features of CNS disease in ALL, as a model to study leukemia-cell entry into the CNS. Patient ALL cells were successfully transplanted into these mice, and hematopoietic stem cell and meningeal cell suspensions were evaluated after autopsy. An in vivo component of the study saw mice assigned to receive bevacizumab, an inhibitor of VEGF, or placebo.
Overt leukemia was seen in all transplanted mice, and 9 of 15 developed CNS symptoms. The CNS+ phenotype was maintained with subsequent transplantations, indicating that CNS involvement is intrinsic to the ALL cell. CNS+ ALL was identified as having increased expression of VEGF, which regulates vascular permeability and transendothelial migration in addition to angiogenesis. The overall growth and proliferation of the ALL cells was not affected by VEGF capture in vitro by bevacizumab, but transendothelial ALL cell migration was decreased. This was replicated in vivo, with a clear reduction in CNS leukemia seen in the bevacizumab treated mice, although no reduction in their leukemia was observed.
While 9 mice developed CNS leukemia, this did not correspond to the patients from whom the xenografts were derived. As such, it is difficult to extrapolate completely from the mouse model to the human disease.
ALL cell entry to the CNS is intrinsic to the leukemia, and associated with increased expression of VEGF. Bevacizumab, a VEGF inhibitor, may provide a novel therapeutic strategy to control CNS leukemia.
Arsenic Consolidation Allows Anthracycline Dose Reduction for Pediatric Patients with Acute Promyelocytic Leukemia: Report from the COG Phase III Historical Controlled trial AAML0631
Kutney, MA et al, Journal of Clinical Oncology, 2017
APL0406 demonstrated that all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) were not inferior in adults with acute promyelocytic leukemia (APL). This study reduced anthracyclines by 40% (to decrease risk of cardiotoxicity) and incorporated ATO in treatment for pediatric APL. The aim of this study was to demonstrate safety and tolerability of ATO in consolidation in pediatric patients and maintain same outcomes.
Nonrandomized, multicentre, phase III trial compared to historical data: AIDA 0493: 2-22 years old, de novo APL [t(15:17) confirmed by PML-RAR⍺ PCR]. The treatment protocol similar to AIDA 0493 except ATO 0.15mg/kg/d added to consolidation and cumulative daunorubicin equivalent reduction to 335mg/m2 for standard risk and 385mg/m2 for high-risk instead of 600mg/m2. Designed to detect an 11% decrease in EFS for SR patients.
Patients were enrolled from March 2009 - November 2012, 101 patients were evaluated. 3-year OS was 94% (SR 98%, HR 86%), 3-year EFS was 91% (SR 95%, HR 83%). AAML0631 was non-inferior to previous study. Events in this trial included 3 relapses, 2 second malignancies, and 7 deaths. Cardiac toxicities during ATO: 16% new grade 1 QTc prolongation, 12% grade 2 QTc prolongation, 1 patient grade 3 QTC prolongation, 1 patient grade 1 ventricular arrhythmia, 1 patient left ventricular dysfunction. Off therapy 1 patient grade 1 QTc prolongation, 1 patient grade 2 ventricular arrhythmia. There were no cardiac deaths and minimal liver toxicity.
Historical comparison with AIDA 0493 which enrolled patients between 1993-2000 and only descriptively described HR patients in this study.
Addition of ATO and reduction of anthracyclines in AAML0631 seems to be non-inferior when compared to historical control and minimal adverse events, including cardiac toxicities.
Pretransplant Vitamin D Deficiency Is Associated With Higher Relapse Rates in Patients Allografted for Myeloid Malignancies
Radujkovic, et al, 2017, Journal of Clinical Oncology
Vitamin D has been shown to affect multiple signalling pathways and immune responses. It has been identified that Vitamin D deficiency is common in patients with hematologic malignancy. This is a retrospective cohort study to evaluate the impact of pre-transplant Vitamin D status on outcomes.
Patients undergoing allogeneic hematopoietic stem cell transplantation (alloHSCT) for myeloid and lymphoid malignancies between 2002-2013 at one centre formed the training cohort. The following data was collected: OS, relapse, NRM, disease stage, conditioning, patient age, donor type, recipient/donor sex match, GVHD information. Vitamin D deficiency was defined as 25-hydroxyvitamin D less than 320ng/mL. Validation was performed in a cohort of patients with alloHSCT for AML/MDS between 2009-2013 at different centres (independent cohort).
In the training cohort, 492 patients (age range 17 -75) were assessed and 80% Had Vitamin D deficiency before alloHSCT. Vitamin D deficiency was significantly associated with a higher risk of relapse and inferior overall survival. For ALL, Vitamin D deficiency was associated with significantly inferior OS. For AML, pre-transplant Vitamin D deficiency was only significantly associated with higher risk of relapse. A higher relapse risk was also observed in myeloid diseases in the independent patient cohort.
Retrospective study with risk of confounding bias, such as information about treatment prior to HSCT including length of stay in hospital, infections, complications. Adult study and therefore not directly transferrable to pediatrics. The independent cohort only included patients with AML, thus ALL findings not validated in separate cohort. There was no data providing insight on possible mechanisms leading to the effect on outcome.
In adult patients with hematologic malignancies, Vitamin D deficiency seems to be associated with worse outcomes (OS and/or relapse). Due to minimal risk, vitamin D supplementation seems reasonable to try and prevent deficiency in all patients that will need allo-HSCT.
Neurocognitive outcomes among children who experienced seizures during treatment for acute lymphoblastic leukemia
This article describes the incidence, risk factors, and neurocognitive outcomes for treatment-related seizures among children undergoing treatment for ALL and registered on the St. Jude Total Therapy XV protocol at three time points. This study omitted craniospinal radiation for all treatment groups. Patients with low-risk ALL received triple intrathecal therapy. This was a retrospective review of this patient cohort.
Prospective neuropsychological assessments and MRIs were planned for all patients treated on this protocol (498 patients). Each patient with treatment-related seizure was matched with two cohort patients who did not develop seizures.
Nineteen patients developed seizure (2-year cumulative risk of 3.82 ± 0.86% standard error) and 2 had a prior history of seizures. No risk factors for developing seizures were identified. The intensive chemotherapy on the standard/high-risk arm compared to the low-risk arm may be associated with seizure development but not found to be statistically significant. Problems with attention, working memory, and processing speed were more common in the seizure group. Cognitive deficits persisted 2 years after therapy. Increased rates of leukoencephalopathy on MRI were detected in the seizure group.
An important limitation is the retrospective design. The initial neuropsychological assessment was performed after a dose of high-dose methotrexate, which may not represent a true baseline.
Seizure development during treatment for ALL was found to be associated with neuropsychological changes, even at 2 years post treatment. There may be an association with more intensive therapy. These outcomes should be incorporated in a prospective treatment protocol. This study raises the question whether children who experienced seizures during therapy should be followed more closely by neuropsychology.
Neurocognitive Functioning of Children Treated for High-Risk B-Acute Lymphoblastic Leukemia Randomly Assigned to Different Methotrexate and Corticosteroid Treatment Strategies: A Report from the Children's Oncology Group
Hardy, KK et al, 2017, Journal of Clinical Oncology
Survivors of childhood ALL are at increased risk for a number of late effects due to treatment, individual and environmental factors, including neurocognitive deficits. This study examined whether there was a difference in neurocognitive outcomes based on the treatment administered during a COG protocol for high-risk B-ALL, with the goal of being able to identify those at increased risk to facilitate earlier intervention. Specifically, this study examined the effect of steroid choice and dosage and method of methotrexate administration on intellectual functioning, working memory and processing speed via a randomized control trial.
192 children who had been enrolled on the COG protocol AALL0232 were examined for IQ, working memory and processing speed 8-24 months after the completion of their HR B-ALL therapy. The children had been randomly assigned, during the initial AALL0232 protocol, to receive either prednisone or dexamethasone (during induction), and to receive either four courses of high dose methotrexate with leucovorin rescue or five doses of escalating dose methotrexate (Capizzi) with PEG asparaginase (during interim maintenance).
After controlling for age, gender, race, ethnicity, time since diagnosis and type of medical insurance, there was no significant difference in IQ, working memory or processing speed found 8-24 months post completion of therapy comparing the different treatment groups. However, both, age and type of medical insurance were found to be significant predictors of decreased IQ (P 0.001), age was also found to be associated with decreased processing speed (P = 0.02) and insurance type (public health insurance rather than private or military insurance) with decreased working memory (P 0.001).
Limitations of this study included its small size, as less than 20% of eligible subjects participated, and the generally younger age and less ethnic diversity of patients captured in this trial. The cross-sectional design is also a limitation, as it would be more useful to measure neurocognitive function longitudinally over time. Finally, there are limitations inherent in the tests used to estimate neurocognitive function.
No association between increased neurocognitive late effects and choice of steroid and type of methotrexate administration was found in children who received treatment for high-risk B-ALL; however, there was an increased risk of neurocognitive dysfunction in younger children, and those from a lower socioeconomic status (estimated by type of medical insurance coverage), who might benefit from earlier neurocognitive interventions.
CD33 Splicing Polymorphism Determines Gemtuzumab Ozogamicin Response in De Novo Acute Myeloid Leukemia: Report from Randomized Phase III Children's Oncology Group Trial AAML0531
Lamba, JK et al, 2017, Journal of Clinical Oncology
Gemtuzumab ozogamicin (GO) is a monoclonal antibody targeted against CD33 with known activity in AML. GO was studied in conjunction with standard five-course chemotherapy in the COG AAML0531 trial. A small pilot study indicated that there is an association between a SNP in CD33 (rs12459419) and the patient's response to GO. Specifically, CT and TT SNP genotypes are associated with a loss of exon 2, which contains the GO binding region, while the CC genotype preserves this binding region. The purpose of this study was to quantify the impact of this in patients with AML treated with GO and standard chemotherapy as part of AAML0531.
The COG AAML0531 trial enrolled patients with AML and randomized them to receive either a standard five-course chemotherapy or chemotherapy with the addition of two doses of GO (N=816; 50% received GO). Genotype at the CD33 SNP were determined at diagnosis for all patients.
Of the 816 patients, 415 had the CC genotype, 316 (39%) had the CT genotype and 85 (10%) had the TT genotype. There was no difference in genotype frequency by sex, treatment arm, disease characteristics or receipt of HSCT during treatment; however, there was a significantly higher rate of the SNP in white patients than in black patients (P=0.001). Patients with the CC genotype had a signficantly lower relapse risk in the GO arm of the trial compared to the No-GO arm (26% vs 49%; P=0.001), and higher disease-free survival (65% vs 46%; P=0.004). There was no difference found for the patients with CT or TT genotypes between the two treatment arms for either relapse rate or disease-free survival.
The limitations of this study include the incomplete understanding of the CD33 rs12459419 mechanism of action. Given the complexity of the effects of various promoter regions and other molecular factors, it is important to fully elucidate these mechanisms to understand the implications of the SNP better.
Gemtuzumab Ozogamicin appears to significantly decrease relapse rates and increase disease-free survival in children with AML who also have the CC genotype of the SNP rs12459419. This study raises the question of whether we should target therapy to genotype in AML.
Tregs: hype or hope for allogeneic hematopoietic stem cell transplantation?
Lussana, F et al (2017), Bone Marrow Transplantation
This review on regulatory T cells summarises current concepts and knowledge on their effect in allogeneic stem cell transplantation, particularly in the treatment and prevention of graft versus host disease.
Autologous hematopoietic stem cell transplantation for pediatric multiple sclerosis: a registry-based study of the Autoimmune Diseases Working Party (ADWP) and Pediatric Diseases Working Party (PDWP) of the European Society for Blood and Marrow Transplant
Burman, J et al, (2017), Bone Marrow Transplantation
Approximately 5% of multiple sclerosis (MS) patients are diagnosed before 18 years. Pediatric onset is associated with an earlier disability than patients with adult onset and cognitive impairment is present in about 30%. Disease-modifying drugs are available but a relapsing course is frequent. While autologous hematopoietic stem cell transplantation (HSCT) has been investigated for decades in adults with promising results, there are only very few pediatric patients reported in the literature.
The retrospective multicenter study analyzed data from the European Bone Marrow Registry and identified 22 patients from 7 centers. Additional information was requested from the identified centers by questionnaires.
Data was available for 21 patients, who were included in the study. All patients had been treated with disease-modifying treatments prior to HSCT, 11 with more than one. 20 patients received anti-thymocyte globulin as part of their conditioning regimen. 18 patients had follow-up data available, 2 patients experienced clinical and MR-radiological relapse about two years after HSCT. Another patient was identified as having subclinical disease with enhancing lesions on MRI. 16 patients improved in their disability scores. All patients were alive at last follow-up and only one patient experienced serious HSCT-related complications (sepsis with ICU admission).
This study is limited as a small retrospective study. Follow-up data was not available for all and the median follow-up duration was only 2.8 years. There was no comparison group to relate the outcome after HSCT to a reference group of pediatric MS patients.
Autologous HSCT can be considered as a treatment option in pediatric-onset multiple sclerosis patients where first-line treatment was not effective. However, long-term outcome data are missing and therefore this treatment option still must be considered experimental.
Intent-to-treat leukemia remission by CD19 CAR T cells of defined formulation and dose in children and young adults
Autologous T-cells expressing CD19-specific chimeric antigen receptor (CAR) can induce remission in B-lineage leukemias, specifically refractory ALL, regardless of disease burden. Treatment has been limited by high failure rate in CAR T-cell manufacturing, heterogeneity of response, and treatment associated toxicities.
The authors developed a streamlined manufacturing process for CAR T-cells from a single apheresis product, with a defined 1:1 ratio of CD4/CD8 CAR T cells and selected for high CAR production. Cytokine cocktails were designed to produce homogeneous T-cell differentiation for engraftment fitness. Feasibility of the process, clinical efficacy, and toxicity was evaluated in 45 patients with relapsed or refractory CD19+ ALL. Patients had a varied disease burden and a variable prior treatment history, including some patients who had previously received hematopoeitic stem cell transplantation or CD19 directed therapy.
The manufacturing process was highly successful (100% in minimally pretreated and 93% in heavily pretreated patients), and detectable engraftment was observed in 98% of patients at a median of 10 days. Pretreatment lymphodepletion with both fludarabine and cyclophosphamide was more effective that cyclophosphamide alone. At a median follow up time of 9.6 months, EFS is 50.8% with OS of 69.5%. B-cell aplasia was used as a marker of functional CAR T-cell activity, and observed in 93% of patients - loss of B-cell aplasia was correlated with risk of leukemic relapse, with a hazard ratio of 34. Cytokine release syndrome and neurotoxicity were the most common adverse events, but there were no deaths from toxicity.
While the authors comment in the results about the variable success depending on the lymphodepletion regimen, the actual protocol is not specified in the Methods, nor do they explain how they determined which patients would be given fludarabine. As well, the variety of patients included support the potential role of this therapy in difficult to treat disease, but make it difficult to extrapolate recommendations for any one disease state.
Manufacturing of CAR T-cells using cell purification, enriched transgene expression, and cocktails of recombinant cytokines can reproducibly produce products with therapeutic potency. The use of lymphodepletion with both fludarabine and cyclophosphamide may be associated with better persistence and effect of the CAR T-cells.
Therapy reduction in patients with Down syndrome and myeloid leukemia: the international ML-DS 2006 trial
Children with Down syndrome have an increased risk of myeloid leukemia (ML), the majority of which show a megakaryoblastic subtype and may evolve from transient abnormal myelopoeisis. They are associated with mutations in the GATA1 transcription factor. Excellent cure rates have been achieved, felt to be due to enhanced drug sensitivity in the blasts, but treatment-related mortality remains the major cause of death.
Building on a reduced intensity therapy for children with ML and Down syndrome, the treatment in this BFM trial was further intensity-reduced by excluding etoposide from the consolidation phase of therapy (450 mg/m2 cumulative dose rather than 950 mg/m2), decreased intrathecal cytarabine therapy, and the elimination of maintenance chemotherapy. The aim was to reduce treatment-related toxicity while preserving a high EFS.
170 patients were enrolled from 2006 to 2015, and had an excellent outcome with a 5-year OS of 89% and EFS of 87%. This was not significantly different than the historical control. There was no correlation of outcome noted with cytogenetic abnormalities, although poor early response to therapy (by morphologic assessment) and trisomy 8 was associated with worse prognosis. There were less infectious complications observed compared to the historical control, and the overall treatment related mortality was 2.9% compared to 5%.
The authors comment that there is still no clear evidence of the role of high-dose cytarabine and anthracycline dosing in ML in Down syndrome, such that the approach to risk-adapted therapy used here is only one possible option.
Risk-adapted therapy in myeloid leukemia associated with Down syndrome can reduce toxicity without adversely impacting outcome. Early therapy response may be predictive of treatment outcome and relapse.
Please see the other study published on the same topic by Taub et al. in the same issue of Blood.
Improved outcomes for myeloid leukemia of Down syndrome: a report from the Children's Oncology Group AAML0431 trial
Children with Down syndrome have an increased risk of myeloid leukemia (ML), which generally has unique features such as a megakaryoblastic subtype, preceeding transient abnormal myelopoeisis, and association with mutations in the GATA1 transcription factor. Many have a myelodysplastic phase that preceeds the development of AML. Excellent cure rates have been achieved, but excessive deaths have been observed due to infection and cardiac dysfunction.
The Children's Oncology Group study aimed to adapt therapy for Down syndrome ML to capitalize on the sensitive of blasts to cytarabine (ARAC) and daunorubicin with more effective use of high-dose ARAC and reduced daunorubicin dosing. In the treatment protocol, high-dose ARAC was used earlier in the second induction cycle instead of daunorubicin, resulting in a 25% lower cumulative dose. Minimal residual disease (MRD) testing was performed as an optional biology study.
205 children were enrolled, with a 5 year OS of 93% and EFS of 89.9%. Kaplan-Meier curves demonstrated improved outcomes compared to historical controls for all patients, with statistically significant p-values. MRD showed worse outcomes for those patients with increased levels at the end of the first induction cycle. Toxicity was noted to be highest with the high-dose ARAC in Induction block II, accounting for two-thirds of all grade 3 or higher adverse events.
While outcomes were compared to historical controls, there was no corresponding analysis for toxicity. Although the authors speculated as to the impact of myelosuppression related to the high-dose ARAC, it is difficult to conclude whether the toxicity seen is a significant or important change.
Reduction in daunorubicin and changes in the administration of ARAC were associated with improved EFS and OS in patients with Down syndrome and ML. MRD at the end of Induction I was the only significant predictor of outcome.
Please see the other study published on the same topic by Uffmann et al. in the same issue of Blood.
Monitoring of childhood ALL using BCR-ABL1 genomic breakpoints identifies a subgroup with CML-like biology
This was a retrospective study that analyzed MRD samples of patients treated for childhood Philadelphia-positive ALL or CML in Australia and the Czech Republic. The study was run by a group that has previously shown discrepancies between Ig/TCR-based and BCR-ABL1 transcript based MRD testing for patients with Philadelphia-positive ALL. This study further details the concordance of the MRD methods and looks at related outcomes.
Samples from 48 patients with BCR-ABL1 positive childhood ALL and 3 with CML in blast crisis were analyzed. Each sample had MRD measured by fusion transcript quantification and by clonal Ig/TCR rearrangement. BCR-ABL1 breakpoints were defined by genomic means as opposed to the more standard method of measuring the fusion transcript.
The majority of patients showed good correlation of MRD levels with the different technologies. Genomic (as opposed to transcriptomic) MRD testing also showed differences from Ig/TCR but was consistent with MRD using the BCR-ABL1 fusion-transcript.
Only ALL blasts were BCR-ABL1 positive in patients with concordant MRD. However, in patients with discordant MRD, cell sorting showed the presence of non-blast B-, T- and myeloid cells harbouring the BCR-ABL1 fusion. No significant difference in outcome between patients with concordant and discordant MRD were seen.
Patients were treated on several different trials. The study used a small sample size to compare outcomes. They were unable to identify the genomic breakpoint in 20% of patients.
Different MRD tests yield different results - as expected, PCR-based MRD has a higher sensitivity than flow cytometry-based MRD. The presence of multi-lineage BCR-ABL1 positive cells in patients with discordant MRD suggests that a multipotent hematopoetic progenitor cell is affected similar to CML-like disease. Although different MRD methods yield different results, the clinical significance of this is unclear.
Prognostic significance of flow-cytometry evaluation of minimal residual disease in children with acute myeloid leukaemia treated according to the AIEOP-AML 2002/01 study protocol
Buldini, B et al , 2017, British Journal Of Haematology
In children with acute myeloid leukaemia (AML), assessment of initial treatment response is an essential prognostic factor; methods more sensitive than morphology are still under evaluation. In this study the measurement of minimal residual disease (MRD) was reported by multicolour flow-cytometry (MFC) in one centralized laboratory assessed at the end of each of the 2 courses of induction therapy.
This is a retrospective analysis of 142 children with newly diagnosed AML between May 2003 and May 2011 enrolled in the Associazione Italiana di Emato Oncologia Pediatrica (AIEOP)-AML 2002/01 trial with the aim of evaluating the prognostic role of MFC-MRD. All patients had cytogenetic and molecular characterization at diagnosis and were stratified as either “standard risk” (SR) or “high risk” (HR), according to cytogenetic criteria and response to first induction course.
Bone marrow aspirates were collected after the first induction course in 142 patients; 94 of them were also analyzed after the second induction course.
MRD value ≥0·1% at the end of the first induction course has a relevant power to predict patient outcome. Children with positive MRD after induction remain at higher risk of relapse and have poorer outcomes as compared to those with a negative MRD. Relapse in children with MRD negative disease appeared to be correlated with high risk genetic features.
MFC- MRD can not detect minor subclones of AML which can be cause of relapse.
MFC-MRD has a lower limit of sensitivity of 0.1%.
MRD evaluation can be complemented by presenting features, such as genetic abnormalities or high WBC at diagnosis, with the goals of refining risk stratification and, thus, improving the outcome of children with newly diagnosed AML. This study complements other work done by COG and the BFM showing that end-induction MRD is prognostic in AML.
Progression-free survival of early interim PET-positive patients with advanced stage Hodgkin’s lymphoma treated with BEACOPPescalated alone or in combination with rituximab (HD18): an open-label, international, randomized phase 3 study ... German HSG
Data suggests the use of interim PET assessment during chemotherapy is superior to baseline international prognostic scoring in terms of predicting long-term treatment outcome in patients with Hodgkin’s lymphoma (HL). PET-2 (PET scan after 2 cycles of chemotherapy) has shown a high positive predictive value for patients with advanced HL given ABVD chemotherapy (doxorubicin, bleomycin, vinblastine, dacarbazine). Further, the results of uncontrolled studies suggest there might be a benefit of treatment intensification for patients with advanced HL given ABVD; however, there is no evidence from controlled trials on the prognostic or predictive value of PET-2 for patients given ABVD or BEACOPP.
In this open-label, international, randomized phase 3 trial, patients aged 18-60 years with advanced stage HL were recruited. All patients initially received two courses of BEACOPPescalated. Those patients without progress with PET-positive disease after two courses of BEACOPPescalated (PET2) were randomly assigned (1:1) to receive standard treatment, additional six courses of BEACOPPescalated or six courses of R-BEACOPPescalated.
Consolidating radiotherapy with 30Gy was recommended if a follow up PET showed positive residual disease.
From May 2008-2011, 1100 patients were enrolled, with 440 patients having a positive PET-2 and were randomly assigned to either BEACOPPescalated (220) or R- BEACOPPescalated (220). With a median follow-up of 33 months for PFS, estimated PFS was 91.4% for the BEACOPPescalated group and 93% for those in the R- BEACOPPescalated group (p=0.99).
The chemotherapy regimen itself might have affected the PET-2 imaging results. In contrast to studies with ABVD, patients in this trial received relevant doses of corticosteroids. Additionally, all patients received G-CSF, which can cause false PET-positive findings in the bone marrow and spleen. However, these GCSF effects can usually be discriminated from active lymphoma tissue. The time interval of 3-7 days between the last day of treatment and the PET-2 imaging was relatively short. Finally PET after two courses of BEACOPPescalated took place about two weeks earlier than after treatment with ABVD (6 vs. 8 weeks, respectively).
Additionally, the use of consolidating radiotherapy for patients with PET-8 positive residual disease at the end of chemotherapy (34% of PET-2 positive patients) might have contributed to the unexpectedly good PFS and accordingly, poor positive predictive value of PET-2 in this trial.
However, with regard to the absence of any positive predictive value of PET in this trial, the most important reason is the likelihood and frequency of progression-free survival events, which affects the power of predictive factors generally. Current randomized studies report failure rate of about 30% for ABVD in patients with stage III and IV disease. Thus, the number of PFS events in patients with advanced stage HL given ABVD is about three times higher than after treatment with BEACOPPescalated followed by radiotherapy to PET-8 positive residual disease in the HD18 study.
The analysis does not allow any conclusions on the negative predictive value of PET-2. Although the positive predictive value of PET-2 is poor in this study, a negative PET-2 might still allow the reduction of chemotherapy in PET-2 negative patients.
The addition of rituximab to BEACOPPescalated did not improve the PFS of PET-2 positive patients with advanced stage HL. However, PFS survival for PET-2 positive patients was much better than expected, exceeding even the outcome of PET-2-unselected patients in the previous HD15 trial. Thus, PET-2 cannot identify patients at high risk for treatment failure in the context of the German Hodgkin Study Group standard treatment for advanced stage HL: BEACOPP escalated.
Donor-to-Recipient ABO Mismatch Does Not Impact Outcomes of Allogeneic Hematopoietic Cell Transplantation Regardless of Graft Source
Damodar S, 2017, Biology of Blood and Marrow Transplantation
There is controversy and conflicting reports regarding the influence of ABO mismatch on outcomes of allogeneic stem cell transplants and how to integrate ABO mismatch in the considerations of donor selection. This large retrospective study from the University of Minnesota assesses the impact of ABO mismatch on outcomes of allogeneic transplants from various graft sources.
Transplant outcomes of 1502 patients who underwent SCT from various graft sources between 2000 and 2014 were analyzed.
ABO match status did not significantly influence the outcomes of either engraftment, acute or chronic GVHD or NRM, regardless of stem cell source.
These results suggest that ABO matching should not be a major factor in choosing a donor for allogeneic stem cell transplant.
Childhood Hodgkin International Prognostic Score (CHIPS) Predicts event-free survival in Hodgkin Lymphoma: A Report from the Children’s Oncology Group
Schwartz, CL et al, 2017, Pediatric Blood & Cancer
This study aimed to develop a predictive model for event-free survival (EFS) using upfront clinical data in a retrospective cohort of pediatric/adolescent Hodgkin lymphoma (HL) patients. The predictive model was then used for risk stratification. This study was sponsored by COG/NCI.
This study included 1103 intermediate-risk HL patients registered on COG AHOD0031 who were randomized between an experimental arm or to standard therapy. Patients randomized to the experimental arms were excluded. Independent predictors of EFS were identified and used to create a prognostic score called the Childhood Hodgkin International Prognostic Score (CHIPS). Half of the patient cohort was used as a training group, and the other half was used to validate the CHIPS.
The following criteria were found to be independent predictors of EFS with similar hazard ratios (1.56-2.7): stage 4 disease, large mediastinal mass, low albumin, and fever. 4-year EFS corresponded to a CHIPS score of 0, 1, 2, and 3, respectively: 93.1%, 88.5%, 77.6%, and 69.2%. The CHIPS was able to identify sub-cohorts with different EFS outcomes (EFS 91.5% with CHIPS 0 or 1, EFS 74.9% for CHIPS 2 or 3).
This score was tested in a limited cohort of intermediate-risk patients and therefore might not be extrapolated to low risk or high risk patients. With evolving and improved therapies for HL, it is difficult to say whether this score will still be valid.
The CHIPS provides an easy and inexpensive predictive model for intermediate-risk patients with Hodgkins Lymphoma but it needs to be validated prospectively and with larger patient numbers.
Mercaptopurine Ingestion Habits, Red Cell Thioguanine Nucleotide Levels, and Relapse Risk in Children With Acute Lymphoblastic Leukemia: A Report From the Children's Oncology Group Study AALL03N1.
Landier W et al., (2017) Journal of Clinical Oncology
Children with ALL are given restrictive guidelines on how to take their oral chemotherapy (6-mercaptopurine) in order to maximize medication bioavailability (in the evening, on empty stomach, without dairy) but which may interfere with chemo adherence. Due to the established link between outcome and adherence to oral chemotherapy, the COG conducted a prospective study (AALL03N1; 441 patients) to look at the association of ingestion habits and adherence, red cell thioguanine levels (TGN) and ultimately relapse.
Adherence was measured using a medication event monitoring system that recorded when medication bottles were opened along with questionnaires and institutional outcome data.
After adjusting for other prognostic factors (including adherence), there was no association between ingestion habits and relapse risk or red cell TGN levels. Taking medications at varying times of day was associated with non-adherence (43.8%).
This study was limited by its observational design, lack of data on reasons for varying ingestion patterns along with some missing prognostic information like MRD.
Overly restrictive guidelines around oral chemotherapy administration for children with ALL are not necessary and may in fact contribute to lower medication adherence which is known to be prognostic. The COG chemo guidelines as well as our local practice has changed to promote the importance of consistent medication administration above all else.
Increased proportion of mature NK cells is associated with successful imatinib discontinuation in chronic myeloid leukemia
The study analyzed function and phenotype of T and NK cells in relation to successful tyrosine kinase inhibitor cessation in patients with chronic myeloid leukemia. The study was conducted by the Nordic CML study group as a substudy to EURO-SKI clinical trial.
132 adult patients with CML who were treated with imatinib / dasatinib / nilotinib for at least 3 years and sustained deep molecular response for at least 1 year were included. Patients then had monthly RQ-PCR tests to monitor for loss of major molecular response. Blood samples were drawn before stopping TKI, 1 month and 6 months after and analysed by flow cytometry for basic NK, B and T cell counts and proportions. Additional NK and T cell function and immune phenotype were also studied in 45 patients.
Analysis found that having higher proportion of NK cells at time of imatinib discontinuation was associated with increased molecular relapse-free survival (73% vs 51% at 6 months, hazard ratio 2.17, P=0.02). NK cell phenotype in non-relapsing patients have higher proportion of mature NK cells then early relapsing group.
The study only included adult patients, and results from patients on imatinib were presented only (due to small number for dasatinib and nilotinib). Findings may not be directly applicable to pediatric patients with CML.
This study contributes to understanding on how the functional state of the immune system relates to whether CML patients can discontinue imatinib treatment.
Imatinib discontinuation in chronic myeloid leukemia patients with undetectable BCR-ABL transcript level: A systematic review and a meta-analysis
Tyrosine kinase inhibitors (TKIs) have revolutionized the way in which chronic myeloid leukemia (CML) is treated, but it is unclear when - if ever - it is safe to discontinue TKIs and what the risk of relapse is after discontinuation. This study is a systematic review and meta-analysis of the literature evaluating the incidence of CML relapse following the discontinuation of TKIs in adult patients.
A literature search was performed using MEDLINE and EMBASE, and two independent reviewers performed the study selection. Studies were considered eligible if they included CML patients who discontinued TKIs, were randomized controlled trials or cohort studies and reported clinical outcomes.
15 cohort studies were included in the final analysis, encompassing 509 patients with CML, all who were treated with imatinib. Overall rate of molecular relapse of CML was 51%, with 80% of relapses occurring within the first six months following TKI discontinuation. All patients were still alive at the two year follow up and only one patient in the entire cohort progressed to a blast crisis.
Most of the trials included had only adult patients and none of the trials were RCTs. Furthermore, the confidence intervals calculated for all sub-analyses overlapped and there were a number of questions that were unable to be answered through the data gathered by this study. All patients included in the study were treated with imatinib, and there was no representation of any of the other TKIs commonly used in clinical practice.
TKIs have proven very effective in the management of CML, but questions remain regarding the duration of therapy required. This study showed that it is feasible to discontinue TKI therapy when in complete molecular remission, given that overall survival after two years was 100%, and that nearly half of patients will not relapse following discontinuation. Further study of the timing of TKI discontinuation is required.
Phase I First-in-Human Study of Venetoclax in Patients With Relapsed or Refractory Non-Hodgkin Lymphoma
Davids MS et al, (2017), Journal of Clinical Oncology
This is a phase I adult study of a new inhibitor of BCL-2, an anti-apoptotic protein, called venetoclax. It is of relevance to paediatrics because this target is also thought to be important in paediatric leukaemia/lymphoma and potentially neuroblastoma.
Phase I dose escalation study in patients with non-Hodgkin lymphoma (part of a larger study that also included patients with CLL). Standard phase I inclusion criteria and toxicity grading according to CTCAE.
Maximum tolerated dose was not defined (no dose level exceeded 30% DLT rate). Manageable side effects. Impressive evidence of clinical benefit in context of phase I.
Interesting that despite this being a phase I study with max 6 dose levels, 106 patients were enrolled. Reflects a growing trend for significant expansion within the context of a phase I to demonstrate efficacy once dose has been determined.
BCL-2 inhibitor, venetoclax is a potentially interesting drug for paediatric leukemia/lymphoma and neuroblastoma in the future. A paediatric phase I study will be opening shortly.
Risk–Benefit Analysis of Pediatric-Inspired Versus Hyperfractionated Cyclophosphamide, Vincristine, Doxorubicin, and Dexamethasone Protocols for Acute Lymphoblastic Leukemia in Adolescents and Young Adults
Guzauskas GF et al, (2017), Journal of Adolescent and Young Adult Oncology
This study aimed to estimate the risk–benefit trade-off of a pediatric-inspired regimen compared with hyper-CVAD for first-line treatment of AYA patients with Philadelphia-negative ALL. A quantitative evaluation of the risks and benefits of pediatric versus hyper-CVAD therapy in AYA ALL patients may provide useful guidance for patient-specific treatment decisions and development of treatment guidelines.
This was a retrospective analysis of two studies already published and comparison between the two. This exploratory analysis seems to be the first comparative quantitative assessment of the potential benefits and harms associated with a pediatric-inspired protocol versus a hyper-CVAD protocol for the treatment of Philadelphia-negative AYA ALL
This analysis used a 6-state Markov model to evaluate the risks and benefits of using a pediatric-inspired protocol compared with hyper-CVAD. Patients could transition among the health states at intervals of 1 month, with a total time horizon of 10 years. Patients modeled for the hyper-CVAD protocol were from a single-center, long-term, follow-up study of hyper-CVAD in 288 patients, of whom 17% were Philadelphia chromosome–positive. For the pediatric protocol, comparable patient data were used from a retrospective study of 85 patients treated with a pediatric-inspired regimen (modified Dana Farber Cancer Institute pediatric protocol (DFCI 91-01)). The primary outcomes were total life-years and total quality-adjusted life-years for each regimen.
Treatment with the pediatric-inspired protocol was associated with a 0.04 increase in life-years, but a 0.01 decrease in QALYs at 1 year. By years 5 and 10, the pediatric-inspired protocol resulted in 0.18 and 0.24 increase in life-years and 0.25 and 0.32 increase in QALYs, respectively, relative to hyper-CVAD. The lower quality of life associated with the induction and intensification phases of pediatric treatment was offset by more favorable progression-free survival and overall survival relative to hyper-CVAD.
The authors chose these two studies after systematic literature review because they assessed that they were the most comparable in regard to patient characteristics. However, patients' characteristics were not the same in all respects. Also, they had to make assumptions regarding outcomes in Philadelphia-negative patients, since the hyper-CVAD source included Ph-positive patients. Finally, they didn't compare pediatric-inspired protocol to augmented hyper-CVAD. So the conclusion of the study can bias in favor of pediatric-inspired study.
In the absence of randomized controlled trials comparing these two types of protocols, this retrospective analysis suggests that, compared with hyper-CVAD, pediatric-inspired protocols may increase life-years throughout treatment stages and QALYs in the long term. However, it does not compare pediatric-inspired to augmented hyper-CVAD. It seems to support the use of "more intense" regimens for AYA in order to achieve better outcomes even if there is a higher risk of complications during treatment.
Autologous T cells expressing CD30 chimeric antigen receptors for relapsed or refractory Hodgkin lymphoma: an open-label phase 1 trial
Hodgkin lymphoma (HL) is typically CD30 positive. The authors were looking for a novel treatment for relapsed or refractory disease. CD30 targeting CAR-T cells have not been described prior to this report. This is a phase 1 study describing the feasibility, safety and efficacy of CD30 targeting CAR-T cells.
18 patients with relapsed or refractory HL between the ages of 13-77 years with CD30+ disease (17 HD, 1 ALCL). Patients received one of three conditioning regiments (fludarabine/cyclophosphamide, gemcitabine/cyclophosphamide or paclitaxel/cyclophosphamide) with subsequent infusion of CAR-T cells given over several days. They were eligible for a second infusion of CAR-T cells at recurrence if they had an initial response.
Of 18 patients enrolled, 14 had refractory disease, 4 had relapsed disease that was refractory to prior treatment. There were 2 grade 3/4 toxicities - one patient with elevated ALT, and one with decreased left ventricular systolic function. One patient had anaphylaxis. Out of the 18 patients, there were 7 partial responses and 6 with stable disease. Five patients were previously treated with brentuximab, 1 had PR and 2 had SD after CAR-T cells. Lymph node regions responded the best, lung lesions responded poorly.
Varying conditioning regimens were used prior to infusion. Study included patients who have failed previous CD30 targeted therapy (ie brentuximab), but there were some patients with response. These cells are specifically engineered for the patient, and this is difficult to make available widely.
CD30 targeted CAR-T cells are safe to give and show some efficacy in relapsed/refractory CD30+ve Hodgkin lymphoma in this phase 1 study. Additional studies are needed to further characterise their role in therapy for Hodgkin lymphoma.
Clinical impact of minimal residual disease in children with different subtypes of acute lymphoblastic leukemia treated with Response-Adapted therapy
This study aimed to determine the relevance of MRD assessment at two points during induction therapy. The authours postulated that an early MRD at day 19 could identify a subgroup of very good prognosis leukemia.
This clinical trial was part of the St Jude Total Therapy XV study.
Bone marrow MRD was assessed on days 19 and 46 of induction therapy by flow cytometry, PCR, or both. MRD-based risk classification had 3 levels based on the two time points and not corrected for method of MRD measurement.
A total of 488 children were included in the study.
The mean EFS and OS for global population were respectively 85.8% and 92.5%. MRD level was significantly associated with both EFS, OS and CRR for the global population. Patients with either t(12;21) or hyperdiploid ALL and negative day 19-MRD had particularly good prognosis. A day 19-MRD level >1% was associated with a high mortality rate for the subgroup of T-ALL and NCI standard-risk B-ALL with a respective OS of 68.5% and 76.7%. Day 46-MRD level positivity was predictive of poorer OS and higher risk of relapse for both NCI standard and high-risk B-ALL.
This is a well conducted study with large accrual and long term follow-up allowing the evaluation of 10-year EFS and OS. Philadelphia positive ALL (Ph-ALL) were not included because of the low number (10). The fact that the study did not mandate the method of measuring MRD may have introduced bias.
This study confirmed the relevance of MRD assessment in ALL and the clinical impact of measuring MRD twice in induction. Other groups including COG and AIEOP measure MRD at two time points as well albeit with different chemotherapy backbones. The new very low risk groups identified here may be candidates for therapy reduction. A similar study is already underway in COG (AALL0931).
Treatment of relapse after allogeneic stem cell transplantation in children and adolescents with ALL: the Frankfurt experience
Relapse after allogeneic stem cell transplantation in ALL patients is very challenging to treat and there is no standardized treatment approach. In this study, the latest experience from the Frankfurt group is presented, describing a curative second transplant and an experimental non-transplant approach for treatment of post transplant relapse.
In this single center retrospective study, outcomes of all relapsed pediatric ALL patients treated in Frankfurt between 2005 and 2014 were analysed. The treatment strategy was to treat all patients who were in good clinical condition with high dose chemotherapy or specific immune-therapy to induce remission followed by a second transplant from a haploidentical donor conditioned with clofarabine, cyclophosphamide, etoposide, alemtuzumab and fludarabine. If a second transplant was not clinically feasible, a combination of low dose chemotherapy and donor lymphocyte infusions was offered.
A total of 23 out of 101 pediatric ALL patients relapsed after their first SCT during the study period. Seven patients were treated with a second transplant after responding to salvage chemo/immune therapy, out of which five remained in CR. Ten patients who where not clinically feasible for a second transplant were treated with low dose chemotherapy and DLI out of which four remained in CR. Four-year overall survival for the transplant approach was 56% and for the experimental non-transplant approach 40%.
This is a retrospective single center study with a very limited number of patients and no control group. Treatment group was directed largely by physician decision thereby introducing bias.
The two presented approaches to treat post transplant relapse show encouraging results. Larger prospective studies are warranted.
Phase 1 study of anti-CD22 antibody-drug conjugate pinatuzumab vedotin with/without rituximab in patients with relapsed/refractory B-cell non-Hodgkin lymphoma
This is a phase 1 study using pinatuzumab (anti-CD22 monoclonal antibody conjugated to a microtubule disrupting agent) in relapsed/refractory mature B cell lymphomas and CLL. The aim was to determine the phase 2 dose and evaluate the safety, tolerability, pharmacokinetics and preliminary antitumor activity of pinatuzumab.
This was a phase 1 study with a 3+3 dose escalation design of relapsed/refractory patients with: DLBCL, follicular lymphoma, marginal zone lymphoma or small lymphocytic lymphoma, mantle cell lymphoma or CLL. They did NOT have to have CD22 expressed on tumor cells to be eligible. All patients were >18 years. Initial cohort was enrolled to determine maximum tolerated dose (MTD). An expansion cohort with DLBCL or iNHL was enrolled to determine preliminary efficacy at MTD. An additional cohort was enrolled to determine safety and efficacy of pinatuzumab combined with rituximab. Pinatuzumab was given every 21 days.
91 patients were enrolled, 75 receieved pinatuzumab alone, 16 received pinatuzumab combined with rituximab. Three patients had grade 4 neutropenia at 3.2 mg/kg, one with delayed recovery. Antitumor activity was only seen at doses >= 1.8 mg/kg. The dose selected for phase 2 trials was 2.4 mg/kg every 21 days. Twenty-five percent of patients with DLBCL responded to pinatuzumab (2 CRs and 3 PRs) with PFS of 4 months. There was 1 PR in DLBCL in the group treated with pinatuzumab and rituximab.
This study was done in adult patients (median age was in the 60's) and they did not require demonstration of CD22 expression on tumor cells before enrollment. This makes interpretation of the efficacy results difficult, although one would presume that the majority of the DLBCL patients had CD22 expression. This information is useful to be aware of for relapsed DLBCL (or other mature B cell lymphomas expressing CD22), but may not be directly translatable to the pediatric population.
Pinatuzumab (anti-CD22 conjugated to MMAE) can be given safely and shows some efficacy in patients with DLBCL in the adult population. This could be a potential choice for pediatric patients with mature B cell lymphomas in the future and should be further explored.
The combination of bortezomib with chemotherapy to treat relapsed/refractory acute lymphoblastic leukaemia of childhood
Bertaina A et al, (2017), British Journal of Haematology
Previous Phase I and II studies have shown that bortezomib, a proteasome inhibitor, has acceptable toxicities and a therapeutic effect in patients with relapsed ALL. This study describes the results of a single centre study which looked at the rate of CR in patients with relapsed/refractory ALL who received a combination of bortezomib and standard salvage chemotherapies.
37 pediatric patients (30 with relapsed/refractory B ALL and 7 with relapsed/refractory T ALL), were enrolled in the study. Bortezomib was administered four times in the first month of treatment, in combination with a standard salvage therapy, including dexamethasone, doxorubicin, vincristine, PEG-asparaginase and IT methotrexate. Response to treatment was assessed morphology, cytogenetics and immunophenotyping on day 29.
Twenty-two of 30 B-ALL patients (73%) and five of seven T-ALL patients (71%) achieved CR with the addition of bortezomib to their chemotherapy regimen. Fourteen of the 37 patients had a negative MRD at the end of therapy resulting in a higher 2-year OS of 68.4%. The MRD positive group had dismal survival.
The main limitations of this study include the small sample size, involvement of a single centre and lack of head to head comparison via a randomized control trial.
Bortezomib has been shown to be safe in combination with standard salvage chemotherapy. Where cytotoxic agents such as bortezomib fit in the treatment of relapsed/refractory ALL in the age of immunotherapy is not clear.
Genomic characterization of paediatric acute lymphoblastic leukemia: an opportunity for precision medicine therapeutics
Tasian et al, (2017), British Journal of Haematology
GVHD is a major cause of morbidity and mortality in patients post hematopoietic stem cell transplant (HSCT). Previous studies have indicated that low amounts of regulatory T cells in the grafts were found in patients who developed GVHD. This article is a systematic review of studies which reported the regulatory T cell (Treg) composition of donated grafts to determine if the amount of Tregs in a graft influence clinical outcomes, specifically in regards to GVHD incidence and severity.
A systematic review was done using defined eligibility criteria, and involved both adult and paediatric data. The search was limited to articles published in 2000 and onward. Five reviewers were involved in determining eligible studies. Forty-eight references were identified, describing 14 independent studies and 987 participants.
Consistent reports were found throughout the identified studies. Significant improvement was found in overall survival associated with high Tregs in most studies, as well as significant reduction in acute GVHD incidence; however, no studies showed an effect of Treg number or ratios on the incidence of chronic GVHD. Only 2 studies were included in a meta-analysis for overall survival but high Tregs were associated with increased survival (p = 0.003).
The included studies were conducted at different centres with heterogeneous indications for transplant, recipient demographics and co-morbidities, sources of allografts, conditioning, Treg measurement method, and post-transplant management. Many of the studies included were small and likely under-powered, and there may be a risk of small study and publication bias.
This systematic review indicates a clear and consistent benefit to higher levels of regulatory T cells in allogeneic haematopoietic stem cell transplants. Improvement of Treg/T cell ratios for HSCT allografts could prove to be an effective measuring in decreasing the risk of acute GVHD. Further multi-centre, prospective trials with standardized methods of measuring Tregs are warranted.
In the past couple of decades, acute promyelocytic leukemia (APML) treatment has been revolutionized by the successful use of all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) to the exclusion of cytotoxic chemotherapy. As this regimen is relatively novel, long-term outcomes have not yet been reported.
This is a follow up of 187 patients (age 10 and above) from 3 consecutive MD Anderson trials using ATRA, ATO, and one dose gemtuzumab-ozogamicin to high-risk patients and low risk patients with leucocytosis during induction. A priori primary outcomes were event-free survival (EFS), disease-free survival (DFS), and overall survival (OS). These trials were not randomized.
At 5 years, EFS, DFS, and OS were 87%, 99%, and 89% respectively for the low risk group and 81%, 89%, and 86% for the high risk group. Survival was lower for patients > 60 years of age.
Single centre trial and non-randomized.
These long term outcomes lend further support for ATRA and ATO as standard of care for APML.
In utero cytomegalovirus infection and development of childhood acute lymphoblastic leukemia
Maternal infections during pregnancy are suspected to play a role in the development of childhood ALL through generation of genomic instability. So far, scientific evidence for this theory is controversial. This article addresses the question whether maternal viral infections are associated with ALL. The retrospective case-control study was done as part of the California Childhood Leukemia Study (CCLS).
The study was set up in a two-step approach by (1) screening of the diagnostic bone marrow of 127 ALL and 38 AML patients for presence of viral particles by using a comprehensive next-generation sequencing (NGS)-based viral and bacterial metagenomics assay; and then after identification of candidates: (2) targeted viral DNA sequencing by digital droplet PCR of the candidate pathogens in newborn dried blood spot DNA of 268 ALL cases and 270 healthy controls.
Neonatal cytomegalovirus (CMV) was identified as a candidate in the first part of the study as it was significantly more prevalent in the bone marrow of patients with ALL compared to AML (OR 18, p=0.03). In the second phase, CMV was detected in neonatal dry blood spots of cases and controls and was associated with an increased risk of ALL (OR 3.71, CI 1.56-7.92). In a subgroup analysis, this association was only significant in Hispanics and not in non-Hispanic whites.
This study used two highly sensitive assays (NGS) to detect CMV particles in the bone marrow of ALL and AML patients and by another highly sensitive assay after birth in ALL cases versus healthy controls. The significance of using these techniques clinically for viral detection is unclear. Interesting, the association was not found in a subgroup analysis of non-Hispanic whites which raises questions on the generalizability of the results.
The study contributes to the theory that infections could contribute to the development of ALL with the finding that CMV was more prevalent in dried blood spots after birth of ALL cases.