Leukemia and Lymphoma & Bone Marrow Transplantation

Cardioprotection and Safety of Dexrazoxane in Patients Treated for Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia or Advanced-Stage Lymphoblastic Non-Hodgkin Lymphoma: A Report of the Children’s Oncology Group Randomized Trial Pediatric Oncology Group 9404

Barbara L. Asselin, (2016) JCO, (Link to Abstract)

Dexrazoxane was shown to have some cardioprotective effect if administered with anthracyclines. Some studies have reported a lower anti-tumour effect if administered with chemotherapies and a higher incidence of secondary malignancies. The purpose of this study was to determine the oncologic efficacy, cardioprotective effectiveness, and safety of dexrazoxane added to chemotherapy that included a cumulative doxorubicin dose of 360 mg/m2 to treat children and adolescents with newly diagnosed T-cell acute lymphoblastic leukemia (T-ALL) or lymphoblastic lymphoma.

537 patients were randomly assigned to either receive or not receive dexrazoxane. The 5-year event-free survival did not differ between groups. Of 11 second malignancies, eight occurred in patients who received dexrazoxane (P = .17). The mean left ventricular fractional shortening, wall thickness, and thickness-to-dimension ratio z scores measured 3 years after diagnosis were worse in the doxorubicin-alone group (n = 55 per group; P=0.01 for all comparisons). Mean fractional shortening z scores measured 3.5 to 6.4 years after diagnosis remained diminished and were lower in the 21 patients who received doxorubicin alone than in the 31 patients who received dexrazoxane (22.03

* 20.24; P value 0.001)

Weibull, CE, (2016) Journal of Clinical Oncology (Link to abstract)

There is data from the 1950’s to suggest that relapse might be more frequent in women who get pregnant after treatment for Hodgkin Disease. This is a retrospective study using the Swedish healthcare registry. Adult women with Hodgkin’s Disease were followed for relapse and pregnancy. Pregnancy-related relapse was defined as relapse during or within 5 years of pregnancy. They found fewer pregnancy-associated relapses than predicted thereby providing no evidence that pregnancy is a risk factor for relapse of Hodgkin’s Disease.

* Being a registry-based study, there are weaknesses including the fact that some pregnancies may not have been recorded if they occurred out of country or if there was no in-hospital care. However, this study is pretty decent evidence that clinicians should not advise against pregnancy for fear of relapse of Hodgkin Disease.

Vora, A, (2016) Journal of Clinical Oncology (Link to abstract)

Children with acute lymphoblastic leukemia (ALL) are at risk for relapse from the CNS, and therefore CNS directed therapy has become a mainstay of ALL treatment. Cranial radiotherapy (CRT) is declining in use and gets replaced increasingly by intrathecal therapy and chemotherapy with CNS penetrance such as high dose methotrexate. This is a meta-analysis of the results from all upfront ALL trials in 10 co-operative groups between 1996-2007 looking at whether CRT changes the rate of relapse. None of the trials were randomized to answer this question and each had slightly different indications for using CRT. Overall, there was no difference in outcome between those who received CRT and those who did not. There was a higher incidence of CNS relapse in CNS3 patients who did not get CRT but the overall relapse rate was not different regardless of therapy. The authors suggest that CRT may no longer have a role in the context of modern therapy.

CD 19 CAR T-cells is a new and promising approach to treatment of B-cell malignancies. It is known that prior chemotherapy can alter T-cell numbers. In current trials, patients receive unselected CAR T-cell products with large variation in composition of T-cells subsets (CD4+ /CD8+ naïve, central memory, effector memory). The authors compared the in-vivo potency of CD19 CAR T-cell products prepared from pre- sorted/purified subsets of T-cells. They found that a combination of CAR T-cells derived from CD8+ central memory T-cells and CD4+ naïve / central memory T-cells showed synergistic effect, with superior proliferation of the CD8+ CAR T-cells with enhanced anti-tumor effect. They concluded that the composition of CAR-T-cell products influences function and therapeutic efficacy.

* This study helps to understand one of the variables which affect the efficacy and toxicity of CAR T-cells in individual patients and across studies. The advancement of cell selection methods should enable production of CAR T-cell products with specific cell composition and doses in future.

Mielcarek M, (2016) Blood, (Link to abstract)

GVHD post HSCT is associated with major morbidity and hampers survival. The authors analyzed in a prospective trial of 43 patients (pediatric n=5) with high-risk hematologic malignancies treated on a novel protocol with myeloablative conditioning regimens (TBI containing with 12Gy radiation, n=18, and non-TBI regimen FluBu, n=25) and post-HSCT high-dose cyclophosphamide (50mg/kg on days 3 and 4 post-HSCT). Additional GVHD prophylaxis consisted of cyclosporine A starting on day +5. Graft source was exclusively peripheral stimulated blood. The authors found a relatively high incidence of acute GVHD grade II of 77% but a low incidence of grade III-I

* acute GVHD of 0% and an incidence of chronic GVHD needing systemic immunosuppression of 16%. Non-relapse mortality after 2 years was 14%, relapse-mortality was 17%. TBI was associated with lower relapse incidence but higher cGVHD, whereas BuFlu was associated with lower incidence of cGVHD and lower overall survival (with the two groups being distinct in terms of their age and recurrence risks).

* Post-HSCT high-dose cyclophosphamide was tolerated post myeloablative conditioning regimens and led to a relatively low incidence of cGVHD needing systemic immunosuppression in a mixed adult/ pediatric population.

Karol SE, (2016). Blood. (Link to abstract)

This analysis looks at genetic risk factors for osteonecrosis in patients with ALL, which is a major toxicity with long-term morbidity in patients undergoing treatment for ALL. Age >10 years is a well-known risk factor, but 40% of children affected by osteonecrosis are <10 years. This article evaluated the germline genotype by using whole exome sequencing of 369 patients <10 years with 82 being affected with osteonecrosis. Variants close to three genes (BMP7, PROX1-AS1, and GRID2) were identified as risk factors. Please see as well a previous article from this author looking at genetic risk factors for osteonecrosis in patients with ALL in a cohort of patients from pediatric treatment protocols in Blood. A SNP in the glutamate receptor GRIN3A locus was identified as a risk factor for osteonecrosis (Karol SE, et al. Genetics of glucocorticoid-associated osteonecrosis in children with acute lymphoblastic leukemia. Blood. 2015;126(15):1770–1776). Interestingly, the mutation previously identified in a mixed cohort of patients <10y AND >10 years did not show up as a risk factor in this cohort of patients exclusively <10 years.

FLT3-ITD positive AML is a subset of AML with poor prognosis. The authors examined the effect of bortezomib, a proteasome-inhibitor, on FLT3-ITD positive AML cells in vitro. The authors found that FLT3-ITD positive cells were more sensitive to bortezomib than wild-type cells. This effect was stronger, the higher the FLT3-ITD expression was. The mechanisms identified leading to this sensitivity were through cytotoxic autophagy. FLT3-ITD molecules were identified within autophagosomes which led to MAPK/ ERK, PI3K/ AKT, and STAT5 pathway inhibition and ultimately to cell death. Bortezomib treatment led to sensitivity to a second-generation tyrosine kinase inhibitor with high FLT3 selectivity (quizartinib) in cells that were found to be resistant prior to bortezomib application. Finally, in xenograft mice models, bortezomib led to induction of autophagy and improved survival.

* The results of this study provide a theoretical basis to consider treatment with bortezomib and a tyrosine-kinase inhibitor with high FLT3 selectivity in patients with FLT3-ITD positive AML.

van der Sluis IM, (2016) Haematologica, (Link to abstract)

Asparaginase is an essential component in the treatment of childhood ALL. This article is a consensus of expert opinions on the role of serum asparaginase level assessment, indications for switching asparaginase preparation, and monitoring after change in asparaginase preparation.

* Routine asparaginase activity monitoring for ALL patients has been started in Sickkids recently, it is important to understand the rationale and clinical implications.

Helsmoortel HH, (2016) Blood, (Link to abstract)

Juvenile myelomonocytic leukemia (JMML) is a subtype of leukemia predominantly seen in young children with an aggressive course and poor survival. The authors used gene expression profiling in 82 patients (first 44 children in a discovery cohort, then 38 patients in a validation cohort) affected with juvenile myelomonocytic leukemia (JMML). RNA was analyzed by microarray profiling and identified a subgroup characterized by high LIN28B expression in roughly half the analyzed patients. LIN28B is known as an oncofetal gene regulating self-renewal of embryonic, fetal, and cancer stem cells, suggesting a role in stem cell malignancies. Affected patients expressed high HbF levels but only rare cases of monosomy 7, an event seen in about 25% of all JMML patients. The authors termed this subtype “fetal-like” and found overexpression of genes involved in fetal hematopoiesis and stem cell self-renewal. This subgroup had a worse outcome than other patients, although this was not an independent from other risk factors.

* The authors describe high LIN28B expression as a feature of JMML found in roughly half the cases, which correlated to indicators of fetal hematopoiesis and poor survival. This feature did not pan out to be an independent risk factor though. LIN28B still might be an interesting target as it is under assessment for other cancers and might be an interesting pathway for future treatment protocols.

Brunstein CG, (2016) Blood, (Link to Abstract)

In this article, the authors examined the rate of GVHD in eleven adult patients undergoing double umbilical cord blood (UCB) stem cell transplantation receiving additional UCB-derived T regulatory cells on day +1 from a third UCB graft 4-6/6 matched. The rate of GVHD was compared to contemporary controls (n=22). The authors found low grade II-I

* GVHD on day 100 of 9% in the treatment cohort compared to 45% in controls (p=0.05). At 1 year there were no patients with cGVHD in the treatment group compared to 14% in controls (no statistical comparison provided). No differences in treatment-mortality or relapse were seen.

* In double UCB-HSCT of adult patients with hematological malignancies, the transfusion of T reg from a third UCB graft resulted in low acute and chronic GVHD rates although the numbers in this study were small and therefore definite conclusions cannot be drawn. It would be interested to see a similar approach in children.

Moller, T, (2016) American Journal of Hematology, (Link to abstract)

This study is a randomized control trial studying the applicability of daily spirometry as an early warning tool for pneumonia in patients undergoing treatment for AML, and also explored if the addition of positive expiratory pressure (PEEP) might be effective in preventing the development of pneumonia. 80 adult AML patients were enrolled on the trial and were randomized to daily spirometry with or without PEEP. A FEV1 value of 76-80% was found to be highly sensitive and specific for pneumonia development, and there was a significant decrease in the incidence of pneumonia in the patients who were randomized to the PEEP arm (2.17 per 1000 days vs 6.52 per 1000 days, P = 0.021). The authors suggest that daily self-administered spirometry along with the use of PEEP should be part of the standard of care for AML patients undergoing induction chemotherapy.

* Daily self-administered spirometry may be a useful early warning tool for pneumonia in patients undergoing treatment for AML, and the addition of positive expiratory pressure may help prevent episodes of pneumonia. This approach is not feasible in young pediatric patients and the usefulness in children has not been proven.

Only approximately 50% of patients have steroid-responsive aGVHD.  Pre-HSCT co-morbidity is a critical factor in both probability of developing aGVHD and mortality after it.  Current risk-stratification models do not take into account endothelial factors, including VEGF and thrombomodulin production, and gut microbiota, all of which influence healing and potential for steroid-responsiveness.  A refined Minnesota risk score based on severity of symptoms and number of organ systems involved was recently published.  Serum biomarkers including TNFR1, REG3α, andST2 may also be incorporated in the future. 

* Risk stratification for aGVHD is improving but is not yet able to prognosticate with certainty or help dictate treatment. 

Post transplant cyclophosphamide (PTC) has been shown to successfully modulate GVHD in preclinical models and in the adult population, enabling the patients to be completely off immune suppression on day +5. In this study, 11 pediatric patients were followed prospectively and received PTC for GVHD prophylaxis; they were compared to a retrospectively analyzed control group of 18 patients who received the standard therapy with calcineurin inhibitors. No acute nor chronic GVHD were seen in the PTC group, overall survival and event free survival were similar between the groups, and no significant difference was found with respect to relapse.

* This is the first study in pediatric patients for treatment with single agent post transplant cyclophosphamide for GVHD prophylaxis after matched related SCT for hematological malignancies, showing promising results on a small group of patients that warrant further study. 

This is an analysis of 516 patients with relapsed ALL report based on the cohort of the Nordic Society of Paediatric Haematology and Oncology (NOPHO) treated with the ALL-92 and ALL-2000 protocols, with total of 516 patients with relapsed ALL. Statistically significant adverse prognostic factors included shorter time to relapse (worse if earlier), site of relapse (worse ifbone marrow involvement at relapse involving the bone marrow), age ten years or over at primary diagnosis, unfavorable cytogenetics, Down syndrome, and T-cell lineage with hyperleukocytosis at primary diagnosis. In the whole study population of relapsed ALL patients, the 5-year EFS was 43.7±2.3% and the 5-year OS was 51.5±2.3%. Further subgroup analysis based on time period, risk groups, relapse treatment protocols and HSCT are reported. Analysis of prognostic factors, validation of the current risk stratification and comparison of treatment modalities could be helpful in improving treatment for relapsed childhood ALL.

* Outcomes of relapse ALL in a large population based cohort with long follow up period is presented in this paperOS of this large cohort of relapsed pediatric ALL patients treated on the NOPHO ALL-92 and ALL-2000 was about 50% with confirmation of known adverse risk factors such as older age at diagnosis, unfavorable cytogenetics, T-cell lineage with hyperleukocytosis, Down syndrome, shorter time to relapse, and bone marrow involvement at relapse.

This is a prospective, multicenter, open-label, randomized phase III study with analysis of the use of ATG as part of the myeloablative conditioning regimen for adults with leukemia undergoing allogeneic peripheral-blood HLA-identical sibling stem cell transplant. After 2 years, the cumulative incidence of chronic GVHD was 32.2% in the ATG group and 68.7% in the non-ATG group. Survival rate was similar but the composite end point of chronic GvHD-free survival and relapse-free survival was higher with ATG.

* ATG was effective to prevent chronic GVHD in transplant when using peripheral blood stem cell source in matched sibling stem cell transplants without increasing OS.

The authors report the relative risk of second cancer after treatment for Hodgkin Lymphoma (HL) to be significantly higher than in the general population, particularly for solid tumors. The standardized incidence ratio (SIR) was 4.6 in the study cohort as compared with the general population and remained elevated 35 years after treatment completion. Even though treatment toxicity was reduced over the last decades, the risk of a second malignancy remains largely unchanged. Results showed a small reduction in hematologic malignancies.

*  The risk of second solid cancers did not change within the last 20 years despite reduction of toxicity and more restricted radiation fields.

Kanhatai Chiengthong (2016) Haematologica (Link to abstract)                                                             

This manuscript reports the effect of single nucleotide polymorphisms in ITPA and NUDT15 in a cohort of 82 pediatric ALL patients from Thailand. ITPA polymorphisms showed no difference in 6MP induced myelosuppression, and no difference in cumulative 6MP doses.  Of the NUDT15 c.415 polymorphisms, 70 (85.4%), 10(12.2%), and 2 (2.4%) patients were CC, CT, and TT, respectively. NUDT15 c.415C>T was strongly associated with 6-MP induced early myelosuppression. Adjustment of 6MP doses according to blood counts resulted in lower median cumulative doses in NUDT15 c.415 CT and TT of 45% and 80%, respectively, compared to CC genotype. These results are consistent with results from Korean and Japanese studies (Yang, JCO 2015).

* Dose adjustments of 6MP in ALL treatment based on polymorphisms in TPMT gene is well established. However, these TPMT variants are infrequent in most Asian populations and this article contributes to the understanding of NUDT15 polymorphisms in adjusting 6MP in Asian ethnicities.

The authors performed a genome-wide association study (GWAS) on 1589 individuals with bone marrow stem cell transplantation to identify minor histocompatibility antigen loci mismatched between donors and recipients associated with acute graft versus host disease (aGVHD). All individuals were transplanted with matched grafts on the HLA-A, -B, -C, -DRB1, and -DQB1 loci. They tested their approach on cases with DPB1 mismatch and successfully found a correlation of mismatch and aGVHD occurrence. Three new loci were identified with one within the KRAS gene harboring the strongest correlation. Unfortunately, the authors do not discuss the possible mechanism implicated with this locus variant in GVHD occurrence. Furthermore, the study was performed on a homogeneous Japanese cohort and might not be applicable to other ethnicities.

* Another application of GWAS to identify possible genetic variants associated with clinical features – potentially rendering stem cell transplantation donor search even more complex in the future.

This study aimed to identify genomic changes that could predict treatment-response to chemotherapy and rituximab for Burkitt lymphoma. Forty Burkitt lymphoma patients were analyzed using array-based comparative genomic hybridization, and TP53, TCF3, ID3 and GNA13 mutations were assessed by next generation sequencing. Losses of 11q, 13q, 15q or 17p were associated with poor response to rituximab treatment, shortened PFS and OS. TP53 alterations were associated with shorter PFS and TCF3 alterations were associated with shorter OS.

* Genetic studies could potentially be used for risk stratification of Burkitt lymphoma patients.

IKZF1 deletions in B precursor ALL is linked to unfavorable outcome, with high frequency in Ph+ and Ph-like ALL. The common deletion types DEL 4-7 and DEL 1-8 have proven prognostic value as single lesions.  This is a case control study that looked at other rare variants of IKZF1 deletions to clarify their prognostic role. The study included patients from 9 international study groups, with a total of 134 rare IKZF1 variants and 402 matched controls. Poor EFS was shown in the matched pair analysis in all variant types.

* IKZF1-deletions (including both common and rare variants) may have a role as marker for risk stratification in ALL treatment protocols.

6349 hematopoietic stem cell transplantation (HSCT) donor-recipient pairs (from 1988 to 2006) were examined for clinical and demographic predictors of outcome. The findings were validated in a second cohort of 4690 donor-recipient pairs (years 2007 to 2011). The authors found older donor age to be associated with lower survival in both cohorts. For every 10-year increment in donor age, there was a 5.5% increase in the hazard ratio for overall mortality. Similarly, HLA-matching was correlated with survival. In contrast, sex, parity of donor, and CMV serostatus were not associated with survival.  ABO match seemed to have a modest impact on survival.

* This report further strengthens the association between older age of HSCT donor and lower survival as earlier suggested (http://www.bloodjournal.org/content/98/7/2043). In contrast to other reports (http://www.ncbi.nlm.nih.gov/pubmed/19642176), this analysis did not find an association between sex of donors and outcome.

Hematopoietic stem cell transplantation (HSCT) data from 105 patients who underwent conditioning with a reduced intensity (RIC) protocol using alemtuzumab, fludarabine, and melphalan was collected. Alemtuzumab levels were measured peri HSCT. The authors found a correlation of lower alemtuzumab levels with higher incidence of: acute GVHD, full donor chimerism, faster lymphocyte recovery by day +30. The authors concluded that an optimal alemtuzumab level on day 0 would be in the therapeutic range of 0.2 to 0.4 μleve.

* This report correlates alemtuzumab levels to acute GVHD, donor chimerism, and lymphocyte recovery and suggests to perform targeted drug monitoring trials to test their hypothesis of optimal alemtuzumab levels in RIC HSCT.

Brentuximab vedotin (BV), a chimeric antibody linked to an anti-tubulin agent targets CD-30 or Ki1 antigen. BV has been used in Hodgkin lymphoma and anaplastic large-cell lymphoma (ALCL) in refractory/ relapsed patients with some success. This article shows that CD30 is expressed in about 50% of patients with aggressive systemic mastocytosis or mastocytic leukemia but only in 12% with indolent disease. The authors showed that BV inhibits CD30 expressing cells in vitro and in vivo mouse engraftment models. The effect of BV was enhanced when given with a drug (PKC412) targeting the most common gene mutation in mastocytosis KIT D816V.

* This study suggests that Brentuximab vedotin might be used in systemic mastocytosis with advanced disease.