Background
Brentuximab vedotin (BV) is an antibody drug‐conjugated anti‐CD30 approved for the treatment of adult classical Hodgkin's lymphoma (HL), whereas it is considered as off‐label indication in ...paediatrics. The aim of the study was to evaluate the safety and efficacy of BV to treat patients aged less than 18 years with refractory/relapsed HL.
Materials and methods
In this multicentre, retrospective study, 68 paediatric patients who received at least one dose of BV between November 2011 and August 2020 were enrolled. A median of nine doses of BV were administered as monotherapy (n = 31) or combined with other therapies (n = 37). BV was administrated alone as consolidation therapy after stem cell transplantation (SCT) in 12 patients, before SCT in 18 patients, whereas in 15 patients it was used before and after SCT as consolidation therapy. Median follow‐up was 2.8 years (range: 0.6–8.9 years).
Results
The best response was observed in the 86% of patients; the overall response rate was 66%. The 3‐year progression‐free survival was 58%, whereas the overall survival was 75%. No statistically significant differences between patients treated with BV monotherapy or combination were highlighted. In multivariate analysis, patients with non‐nodular sclerosis HL and not transplanted had an increased risk of failure. Overall, 46% of patients had grade 3–4 adverse events that led to BV discontinuation in five of them.
Conclusion
In conclusion, our study confirms that BV was a safe and effective drug, able to induce complete remission, either as monotherapy or in association with standard therapy.
At present, there is no consensus on whether and how to treat children with molecular relapse of Philadelphia-Positive (Ph+) Acute Lymphoblastic Leukemia (ALL). A “ watch and wait ” strategy is the ...current approach until evidence of hematological recurrence for which there is neither a specific and validate treatment.
We herewith describe the case of a 17.5 years old boy with Ph+ ALL, treated at diagnosis according to the EsPhALL protocol, at low risk, with imatinib at the dosage of 300 mg/mq daily, given continuously from day 15 of Induction until treatment discontinuation. He reach clinical remission at the end of Induction and BCR-ABL1 /10.000 ABL transcript copies progressively reduced from 28,975 at diagnosis to 1 at the end of Induction and negativity of IG/TR molecular minimal residual disease (MDR). After 2 years of treatment and 2.5 years of imatinib, at the end of all therapy he showed 1 copy and negative MRD. Two months after imatinib discontinuation a molecular relapse was observed (257 copies of BCR-ABL1/10.000 ABL). One month later, bone marrow evaluation showed a marked and rapid increase of the fusion gene copies (1227 BCR-ABL1/10.000 ABL copies); conventional cytogenetic was positive (n. 3 of 20 metaphases analyzed) and IG/TR molecular MDR was 1x10-4, consistent with the increase of transcripts copies.
The second-generation tyrosin-kinase inhibitor dasatinib is effective and safe in children, adult and elderly patients affected by Ph+ ALL and it is considered a suitable option in adult ALL resistant or relapsed after imatinib. However, the experience in treating molecular relapse with dasatinib in children is anecdotal. In order to prevent an hematological relapse and to obtain a new molecular remission, dasatinib treatment was purposed.
One month after molecular relapse, a written informed consent was obtained and dasatinib was started, with a dose of 60 mg/mq daily, associated to prednisone (20 mg/mq daily) for the first 21 days, after which dasatinib was given alone at the same dosage. After 1 month of therapy the patient obtained a cytogenetic remission and a rapid decrease of BCR-ABL1 copies, with 40 BCR-ABL1/10.000 ABL copies, further reduced to 17 copies one month later and 6 copies at the last control, after two months, in July 2017. Currently, the boy is continuing dasatinib, without any side effects and enjoying a good quality of life.
Although it is a single case report with a short follow up, we think it is important to share a positive experience on the use of dasatinib after molecular relapse in a children with Ph+ ALL, which resulted rapidly active and well tolerated.
It remains to be defined how long to continue the treatment after obtaining the molecular remission and whether this therapy is sufficient to prevent the hematological recurrence.
Display omitted
No relevant conflicts of interest to declare.
Summary
Burkitt lymphoma (BL) and Diffuse Large B‐Cell Lymphoma (DLBCL) account for most cases of non‐Hodgkin lymphoma (NHL) in childhood. We report the clinical characteristics, outcome and ...prognostic factors in children with BL or DLBCL treated according to the Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) LNH‐97 protocol. Patients aged up to 18 years that were newly diagnosed with BL/DLBCL were included in the study. Therapy consisted of pre‐phase followed by 2–6 high‐dose chemotherapy courses tailored according to lactate dehydrogenase (LDH) value and disease stage. A total of 442 patients (379 BL, 63 DLBCL) were enrolled between 1997 and 2014, of whom 18 failed to achieve remission, 6 experienced treatment‐related death, 2 developed second malignancy and 20 relapsed. At a median follow‐up time of 5 years, overall survival was 93% (±1%) and event‐free survival was 90% (±1%). LDH value above the median value had an independently negative prognostic value (P < 0·0001). However, in the subgroup of 128 patients in which minimal disseminated disease (MDD) was analysed, MDD‐positivity became the only unfavourable prognostic factor for progression‐free survival. Tailored chemotherapy could be extremely effective with limited toxicity. Identification of MDD as a hallmark of a higher risk of treatment failure may provide a target population for treatment intensification by anti‐CD20.
Although children and young adults with Hodgkin's lymphoma usually have a favorable prognosis, patients with primary refractory disease and some subsets of relapsed patients still have a dismal ...outcome. Brentuximab vedotin (BV) in combination with bendamustine may represent a suitable salvage therapy; data on 32 patients aged less than 25 years were retrospectively analyzed. Patients received up to six cycles of treatment of BV 1.8 mg/kg on day 1 and bendamustine 90–120 mg/m2 on days 2 and 3. At the end of treatment, the overall response rate was 81%. The 3‐year overall and progression‐free survivals are 78.1% and 67%, respectively.
Abstract only
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Background: Outcomes for younger patients (pts) with R/R cHL are poor, particularly for those without complete metabolic response (CMR) before autologous transplant (auto-HCT). ...Nivolumab + BV has shown 67% CMR and a high 2-y PFS rate as first salvage in adults with R/R cHL. CheckMate 744 (NCT02927769) is an ongoing phase 2 study for CAYA with R/R cHL, evaluating a risk-stratified, response-adapted approach using nivolumab + BV and, for pts without CMR, BV + bendamustine. In the initial analysis of the standard-risk cohort (R2), the regimen was well tolerated with high CMR rates before consolidation with high-dose chemotherapy plus auto-HCT. We report data from the primary analysis. Methods: Pts were aged 5–30 y and had first-line treatment (tx) without auto-HCT. Risk stratification has been described previously (Harker-Murray, ASH 2018). Pts received 4 induction cycles of nivolumab + BV; pts without CMR by blinded independent central review (BICR) received BV + bendamustine intensification. Pts with CMR at any time could proceed to consolidation off study. Response was per Lugano 2014 criteria. Primary endpoint: CMR rate (Deauville ≤3) per BICR any time before consolidation. Results: At database lock, 44 pts were treated in R2 (median follow up: 20.9 mo); 43 received 4 induction cycles and 11 received intensification. Median age was 16 y (range 9–30); 24 (55%) pts had primary refractory cHL and 20 had relapsed cHL. CMR rates and ORR any time before consolidation and after induction are shown in Table. 1-y PFS rate by BICR was 91% (90% CI 77–96). During induction, 8 (18%) pts experienced grade (G) 3–4 tx-related adverse events (TRAEs); the most common any grade TRAEs were nausea and hypersensitivity (20% each). 1 TRAE led to discontinuation (G3 anaphylaxis). Most tx-related immune-mediated AEs were G1–2 (1 pt had 2 G3 infusion-related reactions). Conclusions: This risk-stratified, response-adapted approach offers a well-tolerated salvage strategy with high CMR rates and no new safety signals for CAYA with R/R cHL. Most pts avoided alkylator exposure prior to consolidation. Further follow up may confirm durability of disease control. Clinical trial information: NCT02927769 . Table: see text
Many studies have reported a more favorable outcome in younger patients with Hodgkin lymphoma (HL). The aims of this study were to find an appropriate age cutoff able to identify low-risk children ...and to describe the natural history of 135 very young patients affected by classic HL (cHL). The best age cutoff was identified at 7 years of age. EFS (p = .0451) and PFS (p = .00921) were significantly better in the group of younger patients. The OS rate at 10 years was 97.0% in the younger group and 92.5% in the older one (p = .0448). However, age was not found to be an independent prognostic factor in multivariate analysis and the better prognosis in younger patients seems to be related to more favorable disease characteristics at presentation.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Purpose
We present the results of an investigation of the role of FDG PET in response evaluation of bulky masses in paediatric patients with Hodgkin’s lymphoma (HL) enrolled in the Italian ...AIEOP-LH2004 trial.
Methods
We analysed data derived from 703 patients (388 male, 315 female; mean age 13 years) with HL and enrolled in 41 different Italian centres from March 2004 to September 2012, all treated with the AIEOP-LH2004 protocol. The cohort comprised 309 patients with a bulky mass, of whom 263 were evaluated with FDG PET at baseline and after four cycles of chemotherapy. Responses were determined according to combined functional and morphological criteria. Patients were followed up for a mean period of 43 months and for each child we calculated time-to-progression (TTP) and relapse rates considering clinical monitoring, and instrumental and histological data as the reference standard. Statistical analyses were performed for FDG PET and morphological responses with respect to TTP. Multivariate analysis was used to define independent predictive factors.
Results
Overall, response evaluation revealed 238 PET-negative patients (90.5%) and 25 PET-positive patients (9.5%), with a significant difference in TTP between these groups (mean TTP: 32.67 months for negative scans, 23.8 months for positive scans;
p
< 0.0001, log-rank test). In the same cohort, computed tomography showed a complete response (CR) in 85 patients (32.3%), progressive disease (PD) in 6 patients (2.3%), and a partial response (PR) in 165 patients (62.7%), with a significant difference in TTP between patients with CR and patients with PD (31.1 months and 7.9 months, respectively;
p
< 0.001, log-rank test). Similarly, there was a significant difference in relapse rates between PET-positive and PET-negative patients (
p
= 0000). In patients with PR, there was also a significant difference in TTP between PET-positive and PET-negative patients (24.6 months and 34.9 months, respectively;
p
< 0.0001). In the multivariate analysis with correction for multiple testing, only the PET result was an independent predictive factor in both the entire cohort of patients and the subgroup showing PR on CT (
p
< 0.01).
Conclusion
After four cycles of chemotherapy, FDG PET response assessment in paediatric HL patients with a bulky mass is a good predictor of TTP and disease outcome. Moreover, in patients with a PR on CT, PET was able to differentiate those with a longer TTP. In paediatric HL patients with a bulky mass and in patients with a PR on CT, response on FDG PET was an independent predictive factor.
Introduction: Classical Hodgkin lymphoma (cHL) is among the most common malignancies in adolescents and young adults. High-dose chemotherapy (HDCT) and autologous hematopoietic stem cell ...transplantation (ASCT) are standard for most patients with relapsed/refractory (R/R) disease. Current salvage therapies are associated with excessive toxicity and variable complete remission rates (Harker-Murray et al, Pediatr Blood Cancer 2014). Novel regimens that increase remission rates and reduce late effects of therapy are needed, particularly for young patients. Nivolumab (nivo) is a fully human IgG4 anti-programmed death-1 monoclonal antibody. Brentuximab vedotin (BV) is a CD30-directed antibody-drug conjugate. In a phase 1/2 study of adults with R/R cHL, the combination of nivo + BV was well tolerated, with a high response rate as first salvage regimen (Herrera et al, Blood 2018). CheckMate 744 (AHOD1721; NCT02927769) is the first risk-stratified, response-adapted, phase 2 study of nivo + BV, followed by BV + bendamustine for suboptimal response, in children, adolescents, and young adults with R/R cHL with low or standard risk of relapse. Here we report preliminary, investigator (INV)-assessed results from the standard-risk (R2) cohort.
Methods: This open-label study enrolled patients aged 5-30 years with pathologically confirmed cHL, excluding nodular lymphocyte-predominant HL, after failure/non-response to first-line therapy and without prior ASCT. Stratification to R2 was based on refractory disease or early relapse; B symptoms, extranodal disease, or extensive disease with radiation therapy (RT) contraindicated at relapse; relapse in a prior RT field; or stage IIIB or IV at initial diagnosis. Patients in R2 received induction (IND) with 4 cycles of nivo + BV. Patients without complete metabolic response (CMR; Deauville score 1-3) received intensification (INT) with 2-4 cycles of BV + bendamustine. Patients with CMR after IND or INT discontinued study treatment, proceeded to HDCT/ASCT, and entered follow-up. Tumors were assessed by INV and blinded independent central review (BICR) per Lugano 2014 criteria (Cheson et al, J Clin Oncol 2014) every 2 treatment cycles. Treatment decisions were based on BICR assessment. The primary endpoint was CMR rate by BICR prior to HDCT/ASCT. Secondary endpoints included INV-assessed response and safety.
Results: At database lock (DBL), 32 patients in R2 had entered IND. Median age was 16 y (range 9-30), 78% were aged <18 y, and 72% were male. Fifteen patients (47%) had relapsed disease and 17 (53%) refractory; 14 (44%) had B symptoms or extranodal disease at relapse. At DBL, 25 patients (78%) had completed IND (4 cycles of nivo + BV); 7 ongoing. At the end of IND, INV-assessed responses were 16 (64%) CMR, 4 (16%) partial metabolic response, and 1 (4%) progressive metabolic disease; 4 (16%) were pending tumor assessment. Based on BICR assessment, 6 patients entered and completed INT; all achieved CMR after 2 cycles of BV + bendamustine. Overall, all evaluable patients achieved CMR by INV after completing IND or INT. At DBL, 18 patients had proceeded to HDCT/ASCT. During IND, 29 patients (91%) had ≥1 adverse event (AE) due to any cause; 7 (22%) grade 3-4. The most common AEs were nausea (53%), diarrhea (31%), and pyrexia (28%). Six patients (19%) had infusion-related reactions (IRRs); 1 (3%) grade 3-4. Four patients (13%) had drug-related serious AEs; 2 (6%) grade 3-4 (1 IRR and 1 activated partial thromboplastin time prolonged). Two patients (6%) had immune-mediated AEs, including 1 grade 3-4 IRR noted above; none had immune-related serious AEs. During INT, 3/6 patients (50%) had AEs; none grade 3-4; most common were nausea (33%) and vomiting (33%); 1 patient (3%) had grade 1 IRR. Overall, no AEs led to discontinuation and there were no deaths.
Conclusion: For children, adolescents, and young adults with standard-risk R/R cHL prior to ASCT, this risk-stratified, response-adapted approach using nivo, BV, and bendamustine resulted in high CMR rates and was well tolerated, making it a promising novel salvage therapy. Most evaluated patients achieved CMR with IND (nivo + BV); all 6 who went to INT (BV + bendamustine) achieved CMR. Updated results based on a planned interim analysis including more patients and BICR-assessed response data will be presented.
Study support: Sponsored by Bristol-Myers Squibb in collaboration with Children's Oncology Group (COG) and EuroNet group.
Leger:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Brugieres:Takeda: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Other: Financial support for SIOP meeting in 2016. Galderisi:Seattle Genetics: Employment, Equity Ownership. Sacchi:Bristol-Myers Squibb: Employment, Equity Ownership. Jou:Bristol-Myers Squibb: Employment, Other: company stock ownership.
The treatment of paediatric Hodgkin lymphoma (HL) has steadily improved over the years, so that 10- years survival exceed 80%. The purpose of this study was to identify prognostic markers for ...relapsed HL that might contribute to optimize therapeutic approaches. To this aim we retrospectively analysed differential protein expression profiles obtained from plasma of children/adolescents with HL (age ranging from 10 to 18 years) collected at diagnosis. We examined the protein profiles of 15 HL relapsed (R) patients compared with 14 HL not relapsed (NR) patients treated with the same LH-2004 protocol. Two dimensional difference in gel electrophoresis (2D-DIGE) revealed significant differences (fold change > 1.5; Student's T-test
<0.01) between R and NR patients in 10 proteins: α-1-antitrypsin chain a, apolipoprotein A-IV precursor; inter-α-trypsin inhibitor heavy chain; antithrombin-III; vitronectin; fibrinogen α, β and γ chains, complement C3, and ceruloplasmin. An up-regulation of fibrinogen α (spots 78, 196, 230, 234, 239) and β (spots 98, 291, 296, 300) chains together with a lower level of α-1-antitrypsin (spots 255, 264, 266, 272, 273) were found in R patients, and this difference was validated by immunoblotting. The functional role(s) of these proteins in the coagulation and inflammation associated with paediatric/adolescent HL progression and relapse deserves further investigations.
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