Slow Early Response Research Articles

Exploring the complexity, treatment challenges, and outcomes in pediatric nodular lymphocyte predominant Hodgkin lymphoma: a perspective from a low-middle-income country.

In children, nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is an uncommon subtype of Hodgkin lymphoma. Given the lack of data on the best chemotherapy regimen, there is a knowledge gap in best management. This retrospective study included all pediatric patients with NLPHL diagnosed and treated at the Children's Cancer Hospital, Egypt (2007-2018). We analyzed the clinical characteristics, and treatment outcome according to disease stage (early and advanced), treatment strategy (doxorubicin, bleomycin, vinblastine, and dacarbazine [ABVD] or rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP] and explored the prognostic factors for progression-free survival. The median age at diagnosis was 12 years; 40 (68%) patients had early-stage disease, and 19 (32%) had advanced-stage disease. The median follow-up was 70 months; the 5-year EFS and OS were 75% and 97%, respectively. The 5-year EFS was 78% for early-stage disease and 60% for advanced-stage disease; the 5-year OS was 100% for early-stage disease and 88% for advanced-stage disease. The patients who underwent R-CHOP had a better 3-year EFS (100%) compared with those who underwent ABVD (65%) regimen (P = 0.01). Seventeen (25%) patients relapsed: 9/40 (22%) had early-stage disease, and 8/19 (42%) had advanced-stage disease. Splenic involvement, mediastinal disease, extranodal disease, and slow early response were independent predictors of relapse risk. Pediatric patients with early-stage NLPHL have an excellent prognosis, with a 5-year OS of 100%. However, those with advanced stages had a high relapse rate. R-CHOP was associated with a better response and relapse-free rate than ABVD.

Machine Learning to Predict Interim Response in Pediatric Classical Hodgkin Lymphoma Using Affordable Blood Tests.

Response assessment of classical Hodgkin lymphoma (cHL) with positron emission tomography-computerized tomography (PET-CT) is standard of care in well-resourced settings but unavailable in most African countries. We aimed to investigate correlations between changes in PET-CT findings at interim analysis with changes in blood test results in pediatric patients with cHL in 17 South African centers. Changes in ferritin, lactate dehydrogenase (LDH), erythrocyte sedimentation rate (ESR), albumin, total white cell count (TWC), absolute lymphocyte count (ALC), and absolute eosinophil count were compared with PET-CT Deauville scores (DS) after two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine in 84 pediatric patients with cHL. DS 1-3 denoted rapid early response (RER) while DS 4-5 denoted slow early response (SER). Missing values were imputed using the k-nearest neighbor algorithm. Baseline and follow-up blood test values were combined into a single difference variable. Data were split into training and testing sets for analysis using Python scikit-learn 1.2.2 with logistic regression, random forests, naïve Bayes, and support vector machine classifiers. Random forest analysis achieved the best validated test accuracy of 73% when predicting RER or SER from blood samples. When applied to the full data set, the optimal model had a predictive accuracy of 80% and a receiver operating characteristic AUC of 89%. The most predictive variable was the differences in ALC, contributing 21% to the model. Differences in ferritin, LDH, and TWC contributed 15%-16%. Differences in ESR, hemoglobin, and albumin contributed 11%-12%. Changes in low-cost, widely available blood tests may predict chemosensitivity for pediatric cHL without access to PET-CT, identifying patients who may not require radiotherapy. Changes in these nonspecific blood tests should be assessed in combination with clinical findings and available imaging to avoid undertreatment.

CD371-positive pediatric B-cell acute lymphoblastic leukemia: propensity to lineage switch and slow early response to treatment

AbstractIn the effort to improve immunophenotyping and minimal residual disease (MRD) assessment in acute lymphoblastic leukemia (ALL), the international Berlin-Frankfurt-Münster (iBFM) Flow Network introduced the myelomonocytic marker CD371 for a large prospective characterization with a long follow-up. In the present study, we aimed to investigate the clinical and biological features of CD371-positive (CD371pos) pediatric B-cell precursor ALL (BCP-ALL). From June 2014 to February 2017, 1812 pediatric patients with newly diagnosed BCP-ALLs enrolled in trial AIEOP-BFM ALL 2009 were evaluated as part of either a screening (n = 843, Italian centers) or validation cohort (n = 969, other iBFM centers). Laboratory assessment at diagnosis consisted of morphological, immunophenotypic, and genetic analysis. Response assessment relied on morphology, multiparametric flow cytometry (MFC), and polymerase chain reaction (PCR)-MRD. At diagnosis, 160 of 1812 (8.8%) BCP-ALLs were CD371pos. This correlated with older age, lower ETV6::RUNX1 frequency, immunophenotypic immaturity (all P < .001), and strong expression of CD34 and of CD45 (P < .05). During induction therapy, CD371pos BCP-ALLs showed a transient myelomonocytic switch (mm-SW: up to 65.4% of samples at day 15) and an inferior response to chemotherapy (slow early response, P < .001). However, the 5-year event-free survival was 88.3%. Among 420 patients from the validation cohort, 27 of 28 (96.4%) cases positive for DUX4-fusions were CD371pos. In conclusion, in the largest pediatric cohort, CD371 is the most sensitive marker of transient mm-SW, whose recognition is essential for proper MFC MRD assessment. CD371pos is associated to poor early treatment response, although a good outcome can be reached after MRD-based ALL-related therapies.

Pembrolizumab (pembro) in Children and Young Adults with Low-Risk Classical Hodgkin Lymphoma (cHL) with Slow Early Response (SER) to Front-Line Chemotherapy (chemo): Early Results from the Phase 2 Keynote-667 Study

Background: Pediatric patients (pts) with low-risk cHL achieve high cure rates with standard chemo. However, those with a SER to front-line chemo are at higher risk of relapse than pts with a rapid early response (RER). Current treatment options are also associated with long-term toxicities such as secondary malignancies, cardiovascular disease, and pulmonary and gonadal toxicity. Novel treatment approaches are needed to optimize outcomes while minimizing long-term toxicity. KEYNOTE-667 (NCT03407144) is an open-label, phase 2 study that included an analysis of safety and efficacy of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) induction in pediatric pts with low-risk cHL followed by consolidation with pembro plus AVD and involved-site radiotherapy (ISRT) and pembro maintenance in those with SER to front-line ABVD. We present an interim analysis of pts with low-risk cHL enrolled in this trial. Methods: Eligible pts were 3-25 y old and had newly diagnosed stage IA, IB, or IIA cHL without bulky disease, measurable disease per investigator assessment, and a Lansky Play-Performance Scale ≥50 (aged &amp;lt;16 y) or a Karnofsky score of ≥50 (aged ≥16 y). Pts initially received 2 cycles of induction with ABVD. Response was then assessed by PET/MRI/CT (early response assessment). Pts with RER received nonstudy therapy per treating physician. Pts with SER (Deauville score [DS], 4 or 5) received consolidation with pembro 2 mg/kg up to 200 mg IV Q3W (3-17 y) or 200 mg IV Q3W (18-25 y) in combination with 2 cycles of AVD followed by a late response assessment (LRA) with PET/MRI/CT. All pts with a SER then received ISRT (21.6 Gy for pts with a complete PET response [DS, 1-3]; 30.6-36 Gy for pts with a partial PET response [DS, 4 or 5]) plus maintenance pembro Q3W for up to 17 cycles. Primary end point was ORR by blinded independent central review (BICR) per Cheson 2007 IWG criteria in pts with SER determined at any time after starting pembro and before start of new anticancer therapy. Secondary end points included rate of PET negativity after consolidation, EFS, OS, and safety. Results: 73 pts with low-risk cHL were enrolled, 9 of whom had SER to ABVD induction. 64 pts had a RER and received nonstudy treatment. At data cutoff (March 1, 2023), 2 of 9 pts (22%) with SER had completed consolidation and maintenance therapy, 5 (56%) were ongoing, and 2 (22%) had discontinued, both because of complete response. Median time from enrollment to data cutoff was 8.7 mo (range, 2.2-32.9). Median age was 16 y (range, 7-20), 5 pts (56%) were male, 2 (22%) had Ann Arbor stage I disease, and 7 (78%) had Ann Arbor stage II disease. Pts with SER had received a median of 8 doses of pembro (range, 1-17); median time on pembro was 4.8 mo (range, &amp;lt;0.1-11.3). Of 9 pts who received consolidation therapy with pembro plus AVD, 6 (67%) had a LRA (3 are still in consolidation and have not reached the LRA timepoint), of whom 3 (50%) were PET negative by BICR (2 [33%] were PET negative by investigator review). Of 73 pts who received ABVD induction, 66 (90%) had an AE regardless of causality. 33 pts (45%) experienced grade 3/4 AEs, most commonly (≥10%) neutrophil count decreased (n = 19; 26%) and neutropenia (n = 9; 12.3%). One pt experienced grade 4 febrile neutropenia. Twelve pts (16%) had serious AEs. No pts discontinued treatment or died because of AEs. Treatment-related AEs due to ABVD induction occurred in 59 pts (81%), with grade 3/4 events in 31 (42%). Of the 9 pts with SER to ABVD induction who received consolidation and maintenance therapy, 7 (78%) experienced an AE regardless of causality. Two pts (22%) had grade 3/4 AEs. No serious AEs were reported during consolidation and maintenance therapy, and no pts discontinued treatment or died because of AEs. Treatment-related AEs occurred in 6 pts (67%) who received consolidation and maintenance therapy; with grade 3/4 events in 2 pts (22%). Six pts (67%) experienced AEs related to pembro; most commonly (≥3 pts) anemia, nausea, vomiting (n = 3 each [33%]). Two pts experienced grade 3/4 AEs related to pembro (vomiting, white blood cell count decreased). One pt (11%) experienced an immune-mediated AE (grade 2 hyperthyroidism). Conclusion: Early results from the low-risk cHL cohort of KEYNOTE-667 suggest that induction therapy with ABVD and consolidation with pembro plus AVD had a manageable safety profile. Among the relatively small number of pts with a SER to ABVD, 50% with a LRA had a PET-negative response by BICR and received a reduced dose of RT.

Pembrolizumab (pembro) in Children and Young Adults with High-Risk Classical Hodgkin Lymphoma (cHL) with Slow Early Response (SER) to Front-Line Chemotherapy (chemo): Updated Results from the Phase 2 Keynote-667 Study

Background: cHL is one of the most curable forms of childhood cancer, but patients (pts) who have a SER to initial chemo are at high risk of relapse. The approaches currently used to treat pts with SER, such as dose intensification and radiotherapy (RT), can cause long-term toxicity.An unmet need remains to optimize treatment in pts with cHL and SER while minimizing long-term toxicity. The open-label, phase 2 KEYNOTE-667 study (NCT03407144) is being conducted to evaluate the efficacy and safety of pembro plus chemo in pediatric pts with cHL and SER to front-line chemo. Early analysis of pts in KEYNOTE-667 with high-risk cHL showed that pembro plus cyclophosphamide, vincristine, prednisone/prednisolone, and dacarbazine (COPDAC-28) consolidation had manageable safety and promising antitumor activity, with 66% of pts being spared RT. We present updated results for pts with high-risk cHL and SER. Methods: Pts eligible for the high-risk group were 3-25 y old and had newly diagnosed stage IIEB, IIIEA, IIIEB, IIIB, IVA, or IVB cHL, measurable disease per investigator assessment, and a Lansky Play-Performance Scale ≥50 (&amp;lt;16 y old) or a Karnofsky score ≥50 (≥16 y old). All pts received 2 cycles of induction therapy with vincristine, etoposide, prednisone/prednisolone, and doxorubicin (OEPA). After induction, response was assessed by PET/MRI/CT (early response assessment). Pts with rapid early response received nonstudy therapy. Pts with SER (Deauville score, 4 or 5) received consolidation with pembro 2 mg/kg up to 200 mg IV Q3W (3-17 y) or 200 mg IV Q3W (18-25 y) plus 4 cycles of COPDAC-28. Response was then assessed by PET/CT/MRI (late response assessment [LRA]). Pts with PET positivity at LRA (Deauville score, 4 or 5) received involved-site RT (28.8 Gy) to late PET-positive residua plus maintenance pembro Q3W for up to 17 cycles; pts with PET negativity received maintenance pembro Q3W for up to 17 cycles without RT. The primary end point was ORR by BICR per Cheson 2007 IWG criteria in pts with SER, determined at any time after starting pembro and before start of new anticancer therapy. Secondary end points included PET negativity after consolidation, EFS, OS, and safety. Results: This analysis included 62 pts with high-risk cHL and SER to frontline OEPA. The median time from enrollment to data cutoff (March 1, 2023) was 16.8 mo (range, 2.3-36.4). At the data cutoff, 34 pts (55%) had completed consolidation and maintenance therapy, 23 (37%) were ongoing on treatment, and 5 (8%) had discontinued because of adverse events (AEs; n = 1), progressive disease (n = 2), or withdrawal by pt (n = 2). Median age was 14 y (range, 5-22), 30 pts (48%) were male, 29 (47%) had bulky disease, and 41 (66%) had Ann Arbor stage IV disease. Pts had received a median of 17 administrations of pembro (range, 1-17); the median time on pembro was 11.0 mo (range, &amp;lt;0.1-11.8). Of 62 pts who received consolidation with pembro plus COPDAC-28, 53 (85%) had a LRA (9 are still in consolidation and have not reached the LRA time point), of whom 35 (66%) were PET negative by BICR (37 [70%] PET negative by investigator review). AEs regardless of causality that occurred during consolidation and maintenance were reported in 54 pts (87%), most commonly (≥15%) headache (n = 11; 18%), nausea (n = 11; 18%), cough (n = 10; 16%), COVID-19 (n = 10; 16%), and pyrexia (n = 10; 16%). Grade 3/4 AEs occurred in 21 pts (34%). 13 pts (21%) had a serious AE. No pts died because of AEs. Treatment-related AEs occurred in 38 pts (61%). Grade 3/4 treatment-related AEs occurred in 10 pts (16%). One pt (2%) discontinued treatment because of a treatment-related AE (grade 3 AST increased). Pembro-related AEs occurred in 23 (37%) pts; most commonly (≥5%) hypothyroidism (n = 4; 6%), nausea (n = 3; 5%), and ALT increased (n = 3; 5%). Three pts (5%) experienced grade 3/4 pembro-related AEs. One serious AE was related to pembro (abdominal pain). Six pts (10%) experienced immune-mediated AEs (hypothyroidism, n = 4 [2 grade 1, 2 grade 2]; colitis, n = 1 [grade 2]; pneumonitis, n = 1 [grade 2]). Conclusion: In this updated analysis, consolidation with pembro plus COPDAC-28 continued to have manageable safety and promising antitumor activity in pediatric pts with high-risk cHL and SER to front-line OEPA. Of pts with a LRA, 66% had a PET-negative response and were spared RT. These findings support the results of prior analyses and suggest that adding pembro to COPDAC-28 consolidation may augment responses in the high-risk cHL population.

Improved survival of children and adolescents with classical Hodgkin lymphoma treated on a harmonised protocol in South Africa.

Historic South African 5-year overall survival (OS) rates for Hodgkin lymphoma (HL) from 2000 to 2010 were 46% and 84% for human immunodeficiency virus (HIV)-positive and HIV-negative children, respectively. We investigated whether a harmonised treatment protocol using risk stratification and response-adapted therapy could increase the OS of childhood and adolescent HL. Seventeen units prospectively enrolled patients less than 18years, newly diagnosed with classical HL onto a risk-stratified, response-adapted treatment protocol from July 2016 to December 2022. Low- and intermediate-risk patients received four and six courses of adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD), respectively. High-risk patients received two courses of ABVD, followed by four courses of cyclophosphamide, vincristine, prednisone, and dacarbazine (COPDac). Those with a slow early response and bulky disease received consolidation radiotherapy. HIV-positive patients could receive granulocyte colony-stimulating factor and less intensive therapy if stratified as high risk, at the treating clinician's discretion. Kaplan-Meier survival analysis was performed to determine 2-year OS and Cox regression to elucidate prognostic factors. The cohort comprised 132 patients (19 HIV-positive, 113 HIV-negative), median age of 9.7years, with a median follow-up of 2.2years. Risk grouping comprised nine (7%) low risk, 36 (27%) intermediate risk and 87 (66%) high risk, with 71 (54%) rapid early responders and 45 (34%) slow early responders, and 16 (12%) undocumented. Two-year OS was 100% for low-risk, 93% for intermediate-risk, and 91% for high-risk patients. OS for HIV-negative (93%) and HIV-positive (89%) patients were similar (p=.53). Absolute lymphocyte count greater than 0.6×109 predicted survival (94% vs. 83%, p=.02). In the first South African harmonised HL treatment protocol, risk stratification correlated with prognosis. Two-year OS of HIV-positive and HIV-negative patients improved since 2010, partially ascribed to standardised treatment and increased supportive care. This improved survival strengthens the harmonisation movement and gives hope that South Africa will achieve the WHO Global Initiative for Childhood Cancer goals.

Efficacy and safety of pembrolizumab (pembro) in children and young adults with newly diagnosed classical Hodgkin lymphoma (cHL) with slow early response (SER) to front-line chemotherapy (chemo) in the phase 2, open-label, KEYNOTE-667 study.

10027 Background: Patients (pts) with cHL with SER to initial chemo are at higher risk of relapse, and chemo dose intensification and radiotherapy (RT) can increase the burden of late organ toxicities. The open-label, phase 2 KEYNOTE-667 study (NCT03407144) is evaluating pembro plus chemo in pts with cHL and SER to front-line chemo. Results of an interim analysis in pts with high-risk cHL (group 2) and SER are presented. Methods: Pts were aged 3-17 (children) or 18-25 y (young adults) with newly diagnosed stage IIEB, IIIEA, IIIEB, IIIB, IVA, or IVB cHL. Pts received induction with 2 cycles of vincristine, etoposide, prednisone/prednisolone, and doxorubicin (OEPA). Response was assessed after induction (early) and consolidation (late) therapy by PET/MRI/CT. After induction, pts with rapid early response at the early response assessment (ERA) received nonstudy therapy and pts with SER at ERA received consolidation with 4 cycles cyclophosphamide, vincristine, prednisone/prednisolone, dacarbazine (COPDAC-28) plus pembro 2 mg/kg up to 200 mg IV every 3 weeks (Q3W; aged 3-17 y) or 200 mg IV Q3W (aged 18-25 y). Pts with PET positivity (Deauville score 4-5) after consolidation (late response assessment [LRA]), received involved-site RT (28.8 Gy) to late PET-positive residua; RT was omitted in pts with PET negativity. All pts with SER received maintenance pembro Q3W for a total of 17 doses. Primary end point was ORR by blinded independent central review (BICR) per Cheson 2007 International Working Group criteria in pts with SER. Secondary end points included PET negativity after consolidation and safety. Results: At data cutoff (Sep 02, 2022), median follow-up was 15.3 mo (range, 3.2-30.5); 49 pts with high-risk cHL with SER were included. Median age was 15 y (range, 6-22), 24 (49%) pts had bulky disease, and 31 (63%) had Ann Arbor stage IV disease. 22 (45%) pts completed treatment and 24 (49%) were ongoing on consolidation/maintenance treatment. Median time on pembrolizumab was 10.4 mo (range, 0.5-11.8). 42 (86%) of 49 pts had a LRA, of whom 27 (64%) were PET negative by BICR (30 [71%] PET negative by investigator). All-cause adverse events (AEs) occurred in 42 (86%) pts, with 30 (61%) having a treatment-related AE. Grade ≥3 AEs occurred in 13 (27%) pts, with 7 (14%) having a serious AE. Grade ≥3 treatment-related AEs occurred in 6 (12%) pts. 4 (8%) pts had immune-mediated AEs (2 grade 1 hypothyroidism; 2 grade 2 hypothyroidism). Conclusions: In pediatric pts with high-risk cHL and SER to standard OEPA induction, pembro plus COPDAC-28 consolidation had manageable safety and resulted in 64% of pts having a PET-negative response at end of chemo and being spared RT. These results suggest adding pembro to COPDAC-28 consolidation may augment responses in this high-risk population. Clinical trial information: NCT03407144 .

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: Patients (pts) with cHL with slow early response (SER) to initial chemotherapy (chemo) have a high risk of relapse. Current treatments such as chemo dose intensification and radiotherapy (RT) can increase the risk of secondary malignancies and cause long-term toxicity. KEYNOTE-667 (NCT03407144) is an open-label, phase 2 study being conducted to evaluate pembrolizumab (pembro) plus chemo in pts with cHL and SER to front-line chemo. We present results of an interim analysis of pts with high-risk cHL and SER (group 2). Methods: Pts eligible for group 2 were aged 3–17 (children) or 18–25 y (young adults) with newly diagnosed high-risk (stage IIEB, IIIEA, IIIEB, IIIB, IVA, or IVB) cHL. Pts in group 2 received induction therapy with 2 cycles of vincristine, etoposide, prednisone/prednisolone, and doxorubicin (OEPA). Response was then assessed by PET/MRI/CT. Pts with rapid early response to OEPA received nonstudy therapy and pts with SER to OEPA (Deauville score, 4/5) received consolidation with 4 cycles of cyclophosphamide, vincristine, prednisone/prednisolone, dacarbazine (COPDAC-28) plus pembro 2 mg/kg up to 200 mg IV Q3W (3–17 y) or 200 mg IV Q3W (18–25 y). After consolidation, pts with PET positivity (Deauville score, 4/5 at late response assessment [LRA]) received involved-site RT (28.8 Gy) to late PET-positive residua. RT was omitted in pts with PET negativity. All pts with SER continued to receive pembro Q3W for 17 doses. The primary end point was ORR in pts with SER by blinded independent central review (BICR) per Cheson 2007 International Working Group criteria. Secondary end points included PET negativity at LRA and safety. Results: 49 pts with high-risk cHL with SER to OEPA were included in group 2. The median age was 15 y (range, 6–22), 24 pts (49%) had bulky disease, and 31 (63%) had Ann Arbor stage IV disease. At data cutoff (2 September 2022), the median follow-up was 15.3 mo (range, 3.2–30.5); 22 pts (45%) had completed treatment and 24 (49%) were ongoing on consolidation/maintenance. Median time on pembrolizumab was 10.4 mo (range, 0.5–11.8). 42 pts (86%) had an LRA, of whom 27 (64%) were PET negative by BICR (30 pts [71%] were PET negative by investigator review). Adverse events (AEs) occurred in 42 pts (86%), with grade 3/4 AEs in 13 pts (27%). Serious AEs were reported in 7 pts (14%). No pts died because of an AE. Treatment-related AEs occurred in 30 pts (61%), with grade 3/4 treatment-related AEs in 6 pts (12%). 4 pts (8%) had immune-mediated AEs: 2 grade 1 hypothyroidism and 2 grade 2 hypothyroidism. Conclusions: The results showed that pembro plus COPDAC-28 consolidation had manageable safety and promising efficacy in children and young adults with high-risk cHL and SER to front-line chemo. 64% of pts with a LRA had a PET-negative response and were spared RT. These findings suggest that adding pembro to COPDAC-28 consolidation may augment responses in this high-risk cHL population. Encore Abstract - previously submitted to ASCO 2023 and EHA 2023 The research was funded by: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA Keywords: Hodgkin lymphoma, immunotherapy Conflicts of interests pertinent to the abstract L. Vinti Consultant or advisory role: Amgen, Clinigen Research funding: Merck, Sharp & Dohme Educational grants: Takeda, Neon Other remuneration: Amgen, Takeda F. Fagioli Employment or leadership position: Takeda, Novartis, Jazz Pharmaceuticals, Sanofi Consultant Or Advisory Role: Takeda, Novartis, Jazz Pharmaceuticals, Sanofi Honoraria: Takeda, Novartis, Jazz Pharmaceuticals, Sanofi Educational Grants: Takeda, Novartis, Jazz Pharmaceuticals, Sanofi Other Remuneration: Takeda, Novartis, Jazz Pharmaceuticals, Sanofi D. Plaza Lopez de Sabando Research funding: MERCK J. Landman-Parker Research funding: BMS, MSD J. Shen Employment or leadership position: Merck P. Pillai Employment or leadership position: Merck Stock ownership: Merck P. Marinello Employment or leadership position: Merck Stock ownership: Merck C. Mauz-Koerholz Consultant or advisory role: MSD Research funding: MSD

Prognostic value of chest x-ray- and CT-defined large mediastinal adenopathy in high-risk pediatric Hodgkin lymphoma: A report from the Children's Oncology Group Study AHOD0831.

We compared the prognostic value of chest radiograph (CXR)- and computed tomography (CT)-derived definition of large mediastinal adenopathy (LMA) in pediatric Hodgkin lymphoma (HL). Total 143 patients treated for stage IIIB/IVB HL on COG AHOD0831 were included in this study. Six definitions of LMA were investigated: (i) mediastinal mass ratio on CXR (MRCXR )>1/3; (ii) mediastinal mass ratio on CT (MRCT )>1/3; (iii) mediastinal mass volume on CT (MVCT )>200mL; (iv) normalized mediastinal mass volume (MVCT /thoracic diameter [TD])>1mL/mm; (v) mediastinal mass diameter on CT (MDCT )>10cm; and (vi) normalized mediastinal mass diameter (MDCT /TD)>1/3. Median age at diagnosis was 15.8years (range: 5.2-21.3years). In patients with a slow early response (SER) to chemotherapy, MVCT >200mL, MDCT >10cm, and MDCT /TD>1/3 were associated with worse relapse-free survival (RFS) on MVA, while MRCXR >1/3, MRCT >1/3, and MVCT /TD>1mL/mm trended toward worse RFS; MDCT /TD was the most strongly prognostic for inferior RFS, with a hazard ratio of 6.41 for MDCT /TD>1/3 versus ≤1/3 on MVA (p=.02). LMA according to MVCT >200mL, MDCT >10cm, and MDCT /TD>1/3 is associated with poor prognosis in advanced-stage HL patients with SER. The normalized mediastinal diameter, MDCT /TD>1/3 appears to be the strongest predictor of inferior RFS.

Patterns of Initial Relapse from a Phase 3 Study of Response-Based Therapy for High-Risk Hodgkin Lymphoma (AHOD0831): A Report from the Children's Oncology Group

The Children's Oncology Group protocol AHOD0831, for pediatric patients with high-risk classical Hodgkin lymphoma (cHL), used response-adapted radiation fields, rather than larger involved-field radiation therapy (IFRT) that were historically used. This retrospective analysis of patterns of relapse among patients enrolled in the study was conducted to study the potential effect of a reduction in RT exposure. From December 2009 to January 2012, 164 eligible patients under 22 years old with stage IIIB (43%) and stage IVB (57%) enrolled on AHOD0831. All patients received 4 cycles of doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide (ABVE-PC). Those patients with a slow early response (SER) after the first 2 ABVE-PC courses were nonrandomly assigned to 2 intensification cycles with ifosfamide/vinorelbine before the final 2 ABVE-PC cycles. Response-adapted RT (21 Gy) was prescribed to initial areas of bulky disease and SER sites. Rapid early response (RER) sites without bulk were not targeted. Imaging studies at the time of progression or relapse were reviewed centrally for this retrospective analysis. Relapses were characterized with respect to site (initial, new, or both; and initial bulk or initial nonbulk), initial chemotherapy response, and radiation field (in-field, out-of-field, or both). Of the entire cohort, 140 patients were evaluable for the patterns of failure analyses. To investigate the pattern of failure, this analysis focuses on 23 patients who followed protocol treatment and suffered relapses at a median 1.05 years with 7.97-year median follow-up time. These 23 patients (11 RER and 12 SER) experienced a relapse in 105 total sites (median, 4; range, 1-11). Of the 105 relapsed sites, 67 sites (64%) occurred within an initial site of involvement, with 12 of these 67 sites (18%) at an initial site of bulky disease and 63 of these 67 relapses (94%) occurring in sites that were not fluorodeoxyglucose (FDG)-avid after 2 cycles of ABVE-PC (PET2-negative). Of the 105 relapsed sites, 34 sites (32%) occurred in a new site of disease (that would not have been covered by RT); and, overall, only 4 of 140 patients (2.8%) (occurring in 3 RER and 1 SER) experienced isolated out-of-field relapses that would have been covered by historical IFRT. For a cohort of high-risk patients with cHL patients, most failures occurred in nonbulky, initially involved sites, largely due to response-based consolidation RT delivered to patients with bulky disease. In this analysis, we discovered low rates of failures outside of these modern risk-adapted radiation treatment volumes. Also, FDG uptake on PET2 did not identify most relapse sites.

Long term survival outcome of childhood acute lymphoblastic leukemia treated with modified TXIIIB protocol at South Egypt Cancer Institute

Background: The survival of children with acute lymphoblastic leukemia (ALL) has greatly improved in recent decades. Aim: We aimed at evaluating the outcome of children with ALL and their prognostic factors. Materials & Methods: A prospective study included 200 newly diagnosed pediatric ALL patients from 2009 to 2017. All patients were treated according to the modified total therapy study XIIIB for higher risk ALL adopted from St. Jude Children's Research hospital (SJCRH), USA. Results: Favorable age (< 10 y) and total leucocytic count (TLC) (≥ 50x109/L) occurred in 75% and 69%, respectively. B-precursor ALL represented 82.5%. Central nervous system (CNS) involvement occurred in 4.5%. High-risk patients represented 47%. Complete remission was achieved in 92.5% and was significantly affected by the early morphologic response of BM d15, while it wasn’t related to the phenotype. Eight- year overall survival, disease-free survival, and event-free survival were 77 ± 3%, 70 ± 4%, and 66 ± 3%, respectively. Adverse events included induction deaths (4.5 %(, refractory leukemia (3%), relapse (23.2%), secondary AML (0.5%), and deaths in remission (3.5%). By multivariate analysis, unfavorable age group ≥ 10 years, hyperleukocytosis, and patients with slow early response were the only ones associated with unfavorable impact on the outcome. There was statistical significant difference between standard and high risk for B-precursor ALL but not for T- precursor ALL. Conclusion: We concluded that treating children with ALL through modified TXIIIB protocol improved the survival at our institute than previous and the early response to treatment has a strong implication on the outcome.

Upfront Brentuximab Vedotin and Rituximab with Reduced Toxicity Chemotherapy in Children, Adolescents and Young Adults with Newly Diagnosed Hodgkin Lymphoma

Background: Cure rates for children, adolescents and young adults with Hodgkin Lymphoma remain high, however are limited by significant short and long term toxicity of chemotherapy including effects on cardiac, pulmonary, endocrine and fertility functioning as well as a high rate of secondary malignancy (Canellos GP et al. J Clin Oncol. 2014; 32(3): 163-8; Hochberg J et al. BJH 2009; 144(1):24-40). These effects are compounded by the addition of radiation to therapeutic regimens. Immunotherapy targeting both the Reed Sternberg cell as well as the tumor microenvironment has potential benefit in being able to reduce the burden of traditional chemoradiotherapy treatment. Brentuximab Vedotin and Rituximab have both shown efficacy in relapsed Hodgkin Lymphoma (Younes A et al. J Clin Oncol. 2012; 30(18): 2183-9; Younes A et al. Blood. 2012; 119(18): 4123-8) and are being investigated in up front adult HL clinical trials. We hypothesized that the addition of Brentuximab vedotin (Bv) and Rituximab (R) combined with risk adapted chemotherapy will be safe, well tolerated and effective in children, adolescents and young adults with all stages of newly diagnosed Hodgkin lymphoma while preserving excellent current event free survival with elimination of more toxic chemoradiotherapy.Objectives: To evaluate the safety, tolerability and overall response rate of Brentuximab vedotin and Rituximab in combination with risk adapted chemotherapy in children, adolescents and young adults with newly diagnosed Hodgkin Lymphoma.Methods: Prospective Phase II, non-randomized, risk assigned study (NCT02398240). Eligible patients age 1-30 years with all stages of newly diagnosed classical Hodgkin Lymphoma. Low risk (Stage IA, IIA) patients were given 3 cycles of chemoimmunotherapy consisting of Brentuximab vedotin with Doxorubicin, Vincristine, Prednisone and Dacarbazine (Bv-AVPD). Intermediate (Stage IA bulk/E, IB, IIA bulk/E, IIB, IIIA) and High Risk (Stage IIIA bulk/E, IIIB, IVA/B) patients received either 4 or 6 cycles of Brentuximab vedotin, Doxorubicin, Vinblastine, Dacarbazine and Rituximab (Bv-AVD-R). Early response was measured by PET/CT scan following 2 cycles of chemoimmunotherapy. Definition of Rapid Early Response was PET negative (Deaville ≤2) CR after completion of 1 cycle of chemotherapy for low risk patients and 2 cycles of chemotherapy for intermediate/high risk patients. Slow responders received an additional 2 cycles of Bv-AVD-R for Intermediate Risk or Ifosfamide/Vinorelbine for High Risk patients. Radiation therapy was given ONLY to those patients not in CR at the completion of chemoimmunotherapy, or patients with bulky disease at presentation and found to have a slow early response.Results: Total enrolled to date = 23 patients. Median age = 15yr (range 4-23yr). Total 8 males, 15 females. B symptoms present in 11 patients. Bulky disease at diagnosis in 5 patients. Risk Assignment = 3 low, 13 intermediate, 7 high. Therapy was overall well tolerated with only 3 Grade III or greater toxicity events - 1 episode of GrIII mucositis, 1 episode of GrIII infusion reaction to Brentuximab vedotin, 1 episode GrIII peripheral neuropathy. All Grade III toxicities resolved to <Grade II with appropriate dosing/administration adjustments. Twenty one patients have completed therapy. All 21 patients achieved a complete response to chemoimmunotherapy for a CR = 100%. All 23 patients have been assessed for early response. Twelve (52%) have achieved a rapid early response. One patient has required radiation therapy to date due to the presentation of bulky disease with a slow early response. This patient was in CR prior to the start of radiation. For 21 patients who have completed therapy, the EFS and OS is 100% with a median follow up time of 943 days (32months). (Figure 1)Conclusions: The addition of Brentuximab vedotin and Rituximab to combination risk adapted chemotherapy for newly diagnosed Hodgkin Lymphoma appears to be safe in children, adolescents and young adults. Our early results show significant promise with a CR rate of 100% and 52% rapid early response. We have successfully deleted cyclophosphamide, etoposide, bleomycin and radiation from this treatment regimen. The EFS/OS to date is 100% with a median follow up time of close to three years. Further follow up and a larger cohort is needed to determine long term outcomes of this approach. [Display omitted] DisclosuresCairo:Jazz Pharmaceuticals: Speakers Bureau.

Results of the Full Pediatric, Minimal Residual Disease (MRD)-Oriented Trial LAL-RI/2008 for Adolescents and Young Adults (AYA) with Standard Risk (SR), Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia (ALL)

Background and objective. Full pediatric or pediatric-derived trials constitute the treatment of choice for AYA with SR-ALL. In the MRD era, patients (pts) with SR factors at baseline with poor MRD clearance should be considered as HR patients. The objectives of the full pediatric LAL-RI/2008 trial (NCT02036489) from the Spanish PETHEMA group were to assess the proportion of AYA with SR-ALL at baseline who have HR features based on poor early cytological response and/or poor MRD clearance, and to compare their prognosis with that from those pts who achieve good early cytological response and good MRD clearance.Patients and methods. SR ALL was defined in adolescents (age 15 to 18 years) and young adults (age 19 to 29 years) fulfilling all the following criteria: WBC count ≤30 × 109/L, and absence of t(9;22), t(1;19), t(4;11) or any other 11q23 rearrangements. Induction therapy included vincristine (VCR), prednisone (PDN), daunorubicin (DNR) and native E. coli asparaginase (ASP) for 4 weeks. Pts who achieved complete remission (CR) and MRD<0.1% proceeded to consolidation-1 (high-dose methotrexate [MTX], intermediate-dose ARA-C, etoposide and mercaptopurine [MP]), consolidation-2/reinduction (VCR, dexamethasone, DNR, cyclophosphamide and ASP), maintenance-1 (MP and MTX with monthly reinductions with VCR, PDN and ASP until the end of the 1st year) and maintenance-2 (MP and MTX without reinductions until the end of the 2nd year). CNS prophylaxis consisted of triple intrathecal therapy (MTX, ARA-C and hydrocortisone, 16 doses throughout the treatment). Pts with poor early cytological response (BM blast cells >10% on day 14 of induction), MRD level >0.1% (assessed by flow cytometry) at CR or MRD level >0.05% at any time after CR were considered as high risk (HR) pts and received the ALL-HR trial consisting of intensive chemotherapy followed by allogeneic hematopoietic stem cell transplantation (alloHSCT) (Ribera JM et al. J Clin Oncol 2014; 32:1595-604).Results. Between 2008 and 2017, 79 eligible pts were treated according to the ALL-RI-08 protocol. Median age (range) was 20 years (15-29), 34 (43%) were adolescents and 45 (57%) YA. The mean (SD) WBC count was 10 (9) x109/L, and 73 patients (94%) had B-cell precursor ALL. Two patients are on treatment and 74 out of the remaining 77 (96%) achieved the CR. From the 77 pts, 15 had poor early cytological response, 3 had MRD >0.1% at the time of CR and 1 pt showed reappearance of MRD level >0.05% during maintenance. In all, 19 patients were considered as HR. Of the 58 patients who remained SR and followed the LAL-RI/2008 protocol, 14 relapsed (7 during treatment and 7 off therapy), whereas in the HR group, 3 were resistant, 4 relapsed and 2 died by toxicity (transplant-related in 1 out of 4 pts submitted to alloHSCT). Table 1 shows the DFS, OS and cumulative incidence of relapse (CIR) at 5-yrs for the whole series, the patients remaining SR and those who turned HR. Of note, OS was lower in the HR pts (Figure 1). On comparison with the results of the ALL-RI-96 trial (same inclusion criteria, same treatment but no follow-up by MRD, Ribera JM et al. J Clin Oncol 2008; 26:1843-9), no differences were observed in DFS, OS and CIR (Table 1).ConclusionsTwenty-five percent of AYA pts with SR ALL at baseline are in fact HR based on slow early cytological response to therapy and/or poor MRD clearance. High-risk pts showed lower OS despite being moved to a HR protocol.Supported in part by grants RD12/0036/0029 (RTICC, FEDER), PI14/01971 FIS, Instituto Carlos III, and SGR225 (GRE), Spain. [Display omitted] DisclosuresRibera:Celgene: Honoraria; Gilead: Honoraria; Janssen: Honoraria; Roche: Honoraria; ARIAD: Research Funding, Speakers Bureau; Incyte: Research Funding, Speakers Bureau; Pfizer: Research Funding, Speakers Bureau; Amgen Inc.: Research Funding, Speakers Bureau. Montesinos:Celgene Corporation: Honoraria, Research Funding.

Subsequent malignant neoplasms among children with Hodgkin lymphoma: a report from the Children's Oncology Group

Survivors of Hodgkin lymphoma (HL) have an increased risk of subsequent malignant neoplasms (SMNs). Response-adapted treatment may decrease this risk by reducing exposure to therapy associated with SMN risk. The Children's Oncology Group study AHOD0031 evaluated response-adapted therapy for children and adolescents with intermediate-risk HL. We report the SMNs among 1711 patients enrolled in AHOD0031. Patients were treated with 4 cycles of doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide with or without involved-field radiation therapy (RT). Patients with a slow early response to initial chemotherapy were randomized to 2 additional cycles of dexamethasone, etoposide, cisplatin and cytarabine or no additional chemotherapy, and all received RT. At a median follow-up of 7.3 years, an analysis of SMNs was performed. The 10-year cumulative incidence of SMN was 1.3% (95% confidence interval [CI], 0.6-2.0). SMNs included 3 patients with acute myeloid leukemia (AML), 11 with solid tumors, and 3 with non-Hodgkin lymphoma. Sixteen of 17 patients with an SMN had received combined modality therapy. The standardized incidence ratio for SMN was 9.5 (95% CI, 4.5-15.2) with an excess absolute risk of 1.2 per 1000 person-years. The cumulative incidence of SMNs was higher among patients who received RT (P = .037). In multivariate analysis, RT, B symptoms, and race were associated with SMN risk. Given the latency from exposure, we have likely captured all cases of secondary leukemia and myelodysplastic syndrome (MDS). Longer follow-up is needed to determine the risk of solid tumors. Avoidance of RT without sacrificing disease control should remain a goal for future therapeutic approaches. This trial was registered at www.clinicaltrials.gov as #NCT00025259.

Defining the Inflammatory Plasma Proteome in Pediatric Hodgkin Lymphoma.

Simple SummaryHodgkin lymphoma (HL) is a common type of cancer that is characterized by rare, malignant cells among an inflammatory microenvironment. Specific systemic, inflammatory plasma proteins have demonstrated prognostic significance in adult HL; however, systemic inflammation has not been well-characterized in childhood HL. The aim of our study was to better define the inflammatory pre-therapy plasma proteome and identify plasma proteins associated with clinical features of childhood HL. We measured plasma concentrations of 135 proteins in 56 pediatric subjects with newly diagnosed HL and 47 healthy pediatric controls. We found that the plasma protein profile was distinct from controls, and unique proteins were associated with high-risk disease (IL-10, TNF-α, IFN-γ, IL-8), slow early therapy response (CCL13, IFN-λ1, IL-8), and relapse (TNFSF10). These proteins could be used to improve risk stratification, and thus optimize outcomes and minimize unnecessary toxic exposures for those with childhood HL.Hodgkin lymphoma (HL) histopathology is characterized by rare malignant Reed–Sternberg cells among an inflammatory infiltrate. We hypothesized that characteristics of inflammation in pediatric HL lesions would be reflected by the levels of inflammatory cytokines or chemokines in pre-therapy plasma of children with HL. The study objectives were to better define the inflammatory pre-therapy plasma proteome and identify plasma biomarkers associated with extent of disease and clinical outcomes in pediatric HL. Pre-therapy plasma samples were obtained from pediatric subjects with newly diagnosed HL and healthy pediatric controls. Plasma concentrations of 135 cytokines/chemokines were measured with the Luminex platform. Associations between protein concentration and disease characteristics were determined using multivariate permutation tests with false discovery control. Fifty-six subjects with HL (mean age: 13 years, range 3–18) and 47 controls were analyzed. The cytokine/chemokine profiles of subjects with HL were distinct from controls, and unique cytokines/chemokines were associated with high-risk disease (IL-10, TNF-α, IFN-γ, IL-8) and slow early response (CCL13, IFN-λ1, IL-8). TNFSF10 was significantly elevated among those who ultimately relapsed and was significantly associated with worse event-free survival. These biomarkers could be incorporated into biologically based risk stratification to optimize outcomes and minimize toxicities in pediatric HL.

Sex-Based Disparities in Outcome in Childhood Acute Lymphoblastic Leukemia (ALL): A Children's Oncology Group (COG) Report

BACKGROUND: Survival for children with B and T acute lymphoblastic leukemia (B-ALL, T-ALL) has continued to improve. In past cohorts, boys experienced inferior survival outcomes compared to girls. Though reasons are unknown, previous investigators have suggested that these disparities are explained by imbalances in risk factors, such as a higher proportion of T-ALL among boys. We thus examined whether sex-based disparities persist with modern intensive therapy when adjusted for other risk factors. We also determined if patterns of toxicity and treatment failure varied by sex. METHODS: We identified a cohort of patients age 1-30.99 years enrolled on frontline COG trials for B-ALL (standard risk: AALL0331; high risk: AALL0232) and T-ALL (AALL0434) between 2004-2014. Duration of treatment was sex-dependent, with boys receiving an additional year of Maintenance therapy. A limited number of B-ALL patients (those with slow early response or CNS3 status) underwent cranial radiation, while all intermediate and standard risk T-ALL patients did so. Sex-based differences in the distribution of various prognostic factors were explored, including age at diagnosis, initial white blood cell (WBC) count, central nervous system (CNS) status, leukemia cytogenetics, and end Induction minimal residual disease (MRD). Event-free and overall survival (EFS, OS) were compared between boys and girls using log-rank tests and multivariable Cox regression analyses. Finally, we explored sex-based differences in toxicity rates and in the cumulative incidence of specific causes of treatment failure, including treatment-related mortality (TRM), overall relapse, and subcategories of relapse by site. RESULTS: The study cohort included 8,202 patients with B-ALL [4,463 (54.4%) boys] and 1,562 patients with T-ALL [1,161 (74.3%) boys]. Among B-ALL patients, boys were older than girls and slightly more likely to have unfavorable cytogenetics (Table 1). There was no difference in the distribution of initial WBC or CNS status. Among T-ALL patients, boys were again older than girls, but other prognostic factors did not differ by sex (Table 1). B-ALL boys were less likely to be end induction marrow MRD &amp;lt; 0.01% [3,268 (76.1%) vs. 2791 (78.1%); p=0.04] while T-ALL boys were more likely to achieve end induction MRD &amp;lt; 0.01% [659 (59.0%) vs. 221 (56.8%); p=0.01], although in both cases absolute differences were small. EFS and OS were inferior in B-ALL boys compared to girls (5-year: EFS 84.6%±0.6% vs. 86.4%±0.6%; p=0.003; OS 91.7%±0.4% vs. 92.8%±0.5%; p=0.046). The risk of inferior outcomes among B-ALL boys persisted after adjustment for other prognostic factors in both EFS [hazard ratio (HR) 1.18, 95% confidence interval (1.05-1.33); p=0.003] and OS (HR 1.17 (1.00-1.37); p=0.048). There were no sex-based differences in EFS or OS in T-ALL. When examining specific toxicities and causes of treatment failure, osteonecrosis rates were lower among boys [297/5,624 (5.3%) vs. 281/4,140 (6.8%); p=0.002]. The incidence of TRM did not differ by sex. The incidence of relapse was, however, greater in boys than girls with B-ALL (11.2%±0.5% vs. 9.6%±0.5%; p=0.001). This risk was attributable to a higher incidence of relapses involving the CNS (4.2%±0.3% vs. 2.5%±0.3%; p&amp;lt;0.0001) and in other extramedullary sites, including the testes (1.3%±0.2% vs. 0.7%±0.1%; p= 0.001). Notably, there was no difference in the cumulative incidence of isolated bone marrow relapse (5.4%±0.4% vs. 6.2%±0.4%; p=0.49). Among T-ALL patients, there were no sex-based differences in the cumulative incidence of relapse, either overall or by relapse site. CONCLUSIONS: Small sex-based disparities in ALL outcomes persist despite overall improvements, extended treatment duration, and extra intrathecal therapy in boys. This is mainly attributable to a higher risk of CNS relapse in boys with B-ALL, despite no sex-based differences in initial CNS status, and persists when adjusted for other prognostic risk factors. The lack of sex-based disparities in T-ALL by sex may be in part due to an increased use of CNS radiation, given older studies which observed increases in CNS relapse rates among boys but not girls when radiation was eliminated. Future studies to determine the mechanisms underlying this disparity, including potential sex-based differences in steroid metabolism, are warranted. Disclosures Teachey: Amgen: Consultancy; Sobi: Consultancy; Janssen: Consultancy; La Roche: Consultancy. Dunsmore:Dexcom: Current equity holder in publicly-traded company. Mattano:Melinta Therapeutics: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. Borowitz:Amgen: Honoraria. Raetz:Pfizer: Research Funding; Celgene/BMS: Other. Loh:Pfizer: Other: Institutional Research Funding; Medisix Therapeutics: Membership on an entity's Board of Directors or advisory committees. Hunger:Novartis: Consultancy; Amgen Inc.: Current equity holder in publicly-traded company, Honoraria.

Impact of Asparaginase Discontinuation on Outcome in Childhood Acute Lymphoblastic Leukemia: A Report From the Children's Oncology Group.

Asparaginase (ASNase) is an important component of acute lymphoblastic leukemia (ALL) treatment, but is often discontinued because of toxicity. Erwinia chrysanthemi ASNase (Erwinia) substitution was approved in 2011 for allergic reactions. Erwinia has, however, been intermittently unavailable because of drug supply issues. The impact of Erwinia substitution or complete ASNase discontinuation is unknown. Patients aged 1-30.99 years in frontline Children's Oncology Group trials for B-cell acute lymphoblastic leukemia between 2004 and 2011 (National Cancer Institute [NCI] standard risk [SR]: AALL0331; NCI high risk: AALL0232) were included. The number of prescribed pegaspargase (PEG-ASNase) doses varied by trial and strata. Maintenance therapy did not contain ASNase. Landmark analyses at maintenance compared disease-free survival (DFS) among those receiving all prescribed PEG-ASNase doses versus switching to Erwinia but receiving all doses versus not receiving all ASNase doses. We included 5,195 AALL0331 and 3,001 AALL0232 patients. The cumulative incidence of PEG-ASNase discontinuation was 12.2% ± 4.6% in AALL0331 and 25.4% ± 0.8% in AALL0232. In multivariable analyses, NCI high-risk patients not receiving all prescribed ASNase doses had inferior DFS (hazard ratio [HR], 1.5; 95% CI, 1.2 to 1.9; P = .002) compared with those receiving all prescribed PEG-ASNase doses. Patients with Erwinia substitution who completed subsequent courses were not at increased risk (HR, 1.1; 95% CI, 0.7 to 1.6; P = .69). NCI SR patients who discontinued ASNase were not at elevated risk (HR, 1.2; 95% CI, 0.9 to 1.6; P = .23), except when restricted to those with slow early response, who were prescribed more ASNase because of therapy intensification (HR, 1.7; 95% CI, 1.1 to 2.7; P = .03). Discontinuation of ASNase doses is associated with inferior DFS in higher-risk patients. Our results illustrate the severe consequences of Erwinia shortages.

CSF3R truncation mutations in a patient with B-cell acute lymphoblastic leukemia and a favorable response to chemotherapy plus dasatinib

Activating mutations in the gene encoding for receptor of colony stimulating factor 3 (CSF3R) are drivers of pathogenesis in chronic neutrophilic leukemia (CNL) and atypical chronic myeloid leukemia (aCML). We describe a patient with newly diagnosed B-cell acute lymphoblastic leukemia (ALL) and three unique CSF3R truncating mutations which are predicted to be activating. After a slow early response to induction chemotherapy, dasatinib was added based on data from in vitro experiments demonstrating that dasatinib effectively targets key downstream kinases in CSF3R-mutated CNL/aCML. The patient subsequently achieved complete remission with minimal residual disease negativity that has been durable.

Reducing the Burden of Chemoradiotherapy with the Combination of Brentuximab Vedotin and Rituximab with Reduced Toxicity Chemotherapy in Children, Adolescents and Young Adults with Newly Diagnosed Hodgkin Lymphoma

Background: Cure rates for newly diagnosed Hodgkin Lymphoma remain high through the combined use of chemoradiotherapy. (Hochberg/Cairo Cancer Journal 2018) However, this has resulted in significant adverse physical and psychosocial function that significantly impacts the quality of life among survivors, including cardiotoxicity, neurocognitive deficits, poor quality of life, and secondary malignancies. Pediatric cancer survivor studies have shown significant increases adverse health events following therapy throughout adulthood. Major risk factors for late effects include significant exposure to radiation, anthracyclines, cyclophosphamide, etoposide and bleomycin. (Bhakta et al Lancet 2017, Oeffinger et al NEJM 2006, Gibson et al Lancet Oncol 2018) Immunotherapy targeting the Reed Sternberg cell and tumor microenvironment, including regulatory B-cells, has potential to reduce the burden of traditional treatment. Brentuximab Vedotin, an anti-CD30 antibody-drug conjugate, and Rituximab, a chimeric anti-CD20 monoclonal antibody, have both shown efficacy in relapsed Hodgkin Lymphoma and Brentuximab has gained FDA approval in up front adult HL in combination with standard chemotherapy. (Younes et al JCO 2012, Younes et al Blood 2012, Connors et al NEJM 2018) We hypothesized that the addition of Brentuximab vedotin (Bv) and Rituximab (R) combined with risk adapted chemotherapy will be well tolerated and effective in children, adolescents and young adults with all stages of newly diagnosed Hodgkin lymphoma and will allow for the elimination of more toxic chemotherapies as well as need for radiation. Objectives: To evaluate the safety, tolerability and overall response rate of Brentuximab vedotin and Rituximab in combination with risk adapted chemotherapy in children, adolescents and young adults with newly diagnosed Hodgkin Lymphoma. Methods: Eligible patients 1-30 yrs with all stages of newly diagnosed classical Hodgkin Lymphoma. Patients were risk assigned as either Low (Stage IA, IIA, no bulk), Intermediate (Stage IA bulk/E, IB, IIA bulk, IIB or IIIA) and High Risk (Stage IB bulk/E, II bulk, IIIA bulk, IIIB, IV). Low risk patients were given 3 cycles of Brentuximab vedotin (1.2mg/kg) with Doxorubicin (25mg/m2), Vincristine (1.5mg/m2), Prednisone and Dacarbazine (375mg/m2) on Days 1 and 15. Intermediate and High Risk patients received 4 or 6 cycles of Brentuximab vedotin, Doxorubicin, Vinblastine, Dacarbazine and Rituximab (375mg/m2) on Days 1,2 and 15, 16. (Figure 1) Early response was measured by PET/CT scan. Slow responders, defined by lack of a complete metabolic response or &amp;lt;80% size reduction, received an additional 2 cycles of Bv-AVD-R for Intermediate Risk or Ifosfamide/Vinorelbine for High Risk. Involved Field RT was restricted to only patients with bulk disease with SER and those not in a CR at the end of therapy. Humoral and cellular immunity was measured upon completion of therapy. Results: Total enrolled = 33 patients. Median age = 15yr (range 4-23yr). Total 12 males, 21 females. Risk Assignment = 4 low, 17 intermediate, 12 high. Toxicity = 1 episode of Gr III mucositis, 1 episode of Gr III infusion reaction to Brentuximab vedotin, 2 episode Gr III peripheral neuropathy. All 33 patients achieved a complete response for a CR = 100%. Eighteen patients (58%) achieved a rapid early response. Four patients (only 12%) have required radiation therapy to date due to the presentation of bulky disease with a slow early response. Each of these patients was in CR prior to the start of radiation therapy. At a median follow-up of 18 months, the mean±SEM IgG level, CD19 and CD3 levels were 1097±63, 325±105, and 1273±290, respectively, all within normal range. Furthermore, none of the patients developed agammaglobulinemia or required hospitalization for systemic infection during or following treatment. The EFS and OS is 100% with a mean follow up time of 1320 days (= 44 months, range 3-80). (Figure 2) Conclusions: The addition of Brentuximab vedotin and Rituximab to combination risk adapted chemotherapy (without cyclophosphamide, etoposide or bleomycin) for newly diagnosed Hodgkin Lymphoma appears to be safe in children, adolescents and young adults. Our results show significant promise with a CR rate of 100%, 58% rapid early response and significant reduction in the use of toxic chemotherapy and radiation. The EFS/OS to date is 100% with a median follow up time of greater than 3.5 years. Disclosures Cairo: Osuka: Research Funding; Miltenyi: Other: MTA; Jazz Pharmaceuticals: Other: Advisory Board, Research Funding, Speakers Bureau.

Transient Switch to Myeloid Lineage in Acute Lymphoblastic Leukemia during Induction Therapy: The Role of CD371 Expression and Implication for Minimal Residual Disease Detection

Background Multiparametric flow cytometry (MFC) is critical in the diagnosis and management of pediatric acute lymphoblastic leukemia (ALL), through immunophenotyping (IP), and minimal residual disease (MFC MRD) analysis. The aberrant expression of myeloid markers in B- and T-lineage ALL is a well-known phenomenon. It may be the result of an adaptive mechanism by lineage switch (SW), defined as any variation of blast IP over time. CD371 is a transmembrane glycoprotein usually expressed on normal myeloid cells and most of the myeloid blasts. Aberrant expression of CD371 was observed in DUX4-rearranged B cell precursor ALL (BCP ALL). Aims To investigate the clinical and biological features of CD371 positive (CD371+) pediatric BCP ALL, pointing out its potential implication in MFC MRD monitoring on Day 15. Materials and Methods From June 2014 to January 2017, 862 children with newly diagnosed t(9;22)(q34.1;11.2);BCR-ABL1 negative BCP ALL, were consecutively enrolled in the AIEOP BFM ALL 2009 study by AIEOP centers. Peripheral blood (PB) and bone marrow (BM) samples (SMPs) were processed and analyzed in the Laboratory of Diagnosis and Research of Pediatric Hematology-Oncology, University of Padua, Italy, according to standardized operating protocols designed by the AIEOP BFM Flow Network. At diagnosis, 9 combinations of 8 monoclonal antibodies (MoAbs) were used for IP. MFC MRD (Day 8 on PB, Day 15, 33, and 78 on BM) was performed with 2 combinations of 8 MoAbs from June 2014 to May 2016. Later, a dry 10 colors preformulated tube was adopted for MFC MRD monitoring. Results At diagnosis, CD371 expression was assessed in 823 of 862 (95.5%) SMPs by as many patients (pts; age: 1-17 years; male/female: 446/377). Of those, CD371 was positive in 75 of 823 SMPs (9.1%). CD371 positivity was associated with older age, euploidy, a more immature immunophenotype (B-I as per EGIL classification), and the aberrant expression of CD2 antigen, as well as at least one myeloid marker (Table). CD371+ SMPs showed a stronger expression of CD34, CD45, and CD58 antigens than CD371 negative SMPs (Table). We performed MFC MRD analysis on 207 SMPs of CD371+ BCP ALL (42 on Day 8, 72 on Day 15, 40 on Day 33, and 53 on Day 78). During the first 15 days of Induction therapy, a monocytoid population appeared in 76 SMPs [26 of 42 (61.9%) on Day 8 and 50 of 72 (69.4%) on Day 15]. It was characterized by a strong expression of CD34, CD58 and CD45, reduced expression of CD19, and high SSC. We interpreted that phenomenon as an SW to the myelomonocytic lineage, as previously described in a subtype of BCP ALL expressing CD2 at diagnosis. Myelomonocytic SW displayed 2 different patterns: (a) a single population of blasts with heterogeneous expression of CD19 (strong to dim/negative); (b) 2 distinct populations: the first one with the IP of diagnosis, the second one showing a downregulation of CD19 and CD34, an intensification of CD45, and an increase of SSC (Figure). At the same time points, a clear monocytoid population was visible on May-Grunwald-Giemsa stained smears. The comparison between MFC MRD and PCR MRD data showed a higher concordance when both the populations were included in the final amount of blasts on Day 15 (concordance rate: 89% vs. 82%). SW was transient and disappeared after Day 15, even though chemotherapy was always carried on as per therapeutic ALL protocol. CD371 antigen was an accurate marker of SW in our cohort [sensitivity = 0.93 (95% CI ± 0.06), specificity = 0.98 (95% CI ± 0.005), accuracy = 0.98]. Finally, CD371 positivity was associated with a worse response to Induction therapy, showing a higher proportion of pts enrolled in the high therapeutic risk group of the trial, most frequently due to a slow early response according to PCR MRD on Day 33 and 78 (Table). Conclusions We described a new subtype of pediatric BCP ALL, characterized by the aberrant expression of CD371 and a potential myelomonocytic SW during the first phase of Induction Therapy. Accurate identification of the lineage SW is mandatory to properly assess MFC MRD on Day 15 in these pts, avoiding an underestimation of blast cells. This is particularly important, considering that CD371+ BCP ALL was associated with a poor response to Induction therapy. Even in presence of a prevalent monocytoid population, chemotherapy should be carried on according to a therapeutic protocol for ALL. CD371 antigen should be part of IP diagnosis panel for ALL. A multicenter study of AIEOP BFM Flow Network centers is ongoing. Disclosures Brüggemann: Amgen: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy.