IGH-Mediated Translocations, Recurrent in Classic Hodgkin Lymphoma, Frequently Correlate with an Aggressive Behavior

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2922-2922
Author(s):  
Iwona Wlodarska ◽  
Daan Dierickx ◽  
Ursula Pluys ◽  
Kathleen Doms ◽  
Carlos Graux ◽  
...  
Keyword(s):  
Aggressive Behavior ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
Lymphoblastic Leukemia ◽  
Cell Phenotype ◽  
First Case ◽  
Classic Hodgkin Lymphoma ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Bcl2 Protein

Abstract Genetic studies of classic Hodgkin lymphoma (cHL) are hampered by a low content of neoplastic Reed-Stenberg cells (RSCs) in tumor mass. Therefore, cytogenetic features of cHL remain poorly characterized. Previous interphase FISH (iFISH) studies, however, suggest that RSCs which carry 'crippling' IGH mutations and lost B cell phenotype, are recurrently featured by t(IGH)-related rearrangements (PMID: 17079453, 18940474). Recently, we have identified 14q32/IGH aberrations in karyotypes of two patients with nodular sclerosis HL (NSHL) analyzed at time of relapse. The first case showed the classic follicular lymphoma-associated t(14;18)(q32;q21)/IGH-BCL2 rearrangement which correlated with expression of the BCL2 protein (as demonstrated by immunohistochemistry). The second case revealed inv(14)(q11q32)/IGH-CEPBE, originally identified in B cell acute lymphoblastic leukemia. To identify additional cHL cases with 14q32/IGH aberrations and check whether these rearrangements correlate with clinical outcome, we screened by RSC-focused iFISH: (i) 46 relapsed cHL, (ii) 40 cHL with a long-term remission, and (iii) 60 prospective cases. Altogether, IGH rearrangements were detected in 28 patients, including 17 representing the former group (35.4%), four cases representing the second group (10%) and seven prospective cases (11.6%). FISH pattern of LSI IGH suggested a reciprocal t(14q32/IGH) in 20 cases, nonreciprocal t(14q32/IGH) in four cases, inv(14q32/IGH) or ins(14q32/IGH) in three cases and interstitial del(14q32/IGH) in one case. Twenty six cases were further analyzed by iFISH with break-apart (BA) assays for BCL2, BCL3, BCL6 and MYC. In three cases with a presumed inv(14)/ins(14), CEPBE BA was applied. Altogether, we have identified the IGH-BCL2 rearrangement in two cases, including the index case with t(14;18), and the IGH-CEPBE rearrangement in the case with inv(14). All the remaining cases showed a non-rearranged status of the examined loci. The cases were additionally examined with the JAK2/PDLs (9p24) probes; amplification of signals was observed in six cases (21.5%) and FISH pattern suggestive of the PDLs rearrangement was found in two cases (7%). The majority of patients (18/28) with t(14q32/IGH) were diagnosed with NSHL. There were 18 male and 10 female patients in age ranging from 18 to 91 years (mean 50). Patients presented with both early (10/26) and advanced (16/26) stage (two not staged). All were treated with chemotherapy with or without radiotherapy, except for two patients who were subjected to a palliative treatment. After induction therapy, complete and partial remission was achieved in 17 and 5 patients, respectively. Thirteen patients are alive (11 without disease and 2 with disease); 13 patients died, including 11 whose death was related with a disease, and two are lost for follow up. In summary, we confirmed that chromosomal aberrations involving 14q32/IGH occur recurrently in cHL. These rearrangements rarely target BCL2 and CEPBE, and do not affect BCL3, BCL6 and MYC, the oncogenes frequently affected in B-NHL. Interestingly, 17 out of 21 (81%) patients with t(14q32/IGH) and long follow up showed an aggressive behavior. Our study allows a new insight into the pathogenesis of cHL and might help in further stratification of cHL patients. Disclosures Graux: Amgen: Honoraria; Celgene: Honoraria; Novartis: Honoraria.

scholarly journals Pre-B cell acute lymphoblastic leukemia in the newborn

Blood ◽  
1984 ◽  
Vol 64 (5) ◽  
pp. 1064-1066
Author(s):  
CM Spier ◽  
CR Kjeldsberg ◽  
R O'Brien ◽  
J Marty
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Lymphoblastic Leukemia ◽  
Cell Phenotype ◽  
Cell Marker ◽  
Ultrastructural Studies ◽  
Congenital Leukemia ◽  
Laboratory Techniques ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Marker Studies

Leukemia in the newborn is an infrequent disease that has not been well defined using modern laboratory techniques. We describe two infants, one at birth and one at four weeks, with acute lymphoblastic leukemia. The blasts from each patient were studied in great detail, using a battery of cytochemical and immunologic procedures in addition to ultrastructural studies. Immunologic cell marker studies, not previously reported in congenital leukemia, showed the lymphoblasts from each infant to be of the pre-B cell phenotype. Each infant relapsed, one after a 17-week clinical remission and the other after a 44-week remission. The former has died while the latter is in a second remission. The subtype of pre-B cell acute lymphoblastic leukemia (ALL) which in childhood appears to confer an unfavorable prognosis, may have the same significance in neonatal ALL.

The first case of elderly TCF3-HLF-positive B-cell acute lymphoblastic leukemia

2019 ◽  
Vol 60 (11) ◽  
pp. 2821-2824 ◽  
Author(s):  
Reina Takeda ◽  
Kazuaki Yokoyama ◽  
Miho Ogawa ◽  
Toyotaka Kawamata ◽  
Tomofusa Fukuyama ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Lymphoblastic Leukemia ◽  
First Case ◽  
Cell Acute Lymphoblastic Leukemia

scholarly journals Pre-B cell acute lymphoblastic leukemia in the newborn

Blood ◽  
1984 ◽  
Vol 64 (5) ◽  
pp. 1064-1066 ◽  
Author(s):  
CM Spier ◽  
CR Kjeldsberg ◽  
R O'Brien ◽  
J Marty
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Lymphoblastic Leukemia ◽  
Cell Phenotype ◽  
Cell Marker ◽  
Ultrastructural Studies ◽  
Congenital Leukemia ◽  
Laboratory Techniques ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Marker Studies

Abstract Leukemia in the newborn is an infrequent disease that has not been well defined using modern laboratory techniques. We describe two infants, one at birth and one at four weeks, with acute lymphoblastic leukemia. The blasts from each patient were studied in great detail, using a battery of cytochemical and immunologic procedures in addition to ultrastructural studies. Immunologic cell marker studies, not previously reported in congenital leukemia, showed the lymphoblasts from each infant to be of the pre-B cell phenotype. Each infant relapsed, one after a 17-week clinical remission and the other after a 44-week remission. The former has died while the latter is in a second remission. The subtype of pre-B cell acute lymphoblastic leukemia (ALL) which in childhood appears to confer an unfavorable prognosis, may have the same significance in neonatal ALL.

scholarly journals Safety and Efficacy of Tisagenlecleucel (CTL019) in B-Cell Acute Lymphoblastic Leukemia in Children, Adolescents and Young Adults: The French Experience

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3876-3876 ◽  
Author(s):  
Marie-Emilie Dourthe ◽  
Florence Rabian ◽  
Karima Yakouben ◽  
Aurélie Cabannes ◽  
Florian Chevillon ◽  
...  
Keyword(s):  
T Cells ◽  
B Cell ◽  
Disease Burden ◽  
Lymphoblastic Leukemia ◽  
Car T Cells ◽  
Car T ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Grade 3 ◽  
High Disease Burden

Objectives: Tisagenlecleucel (CTL019) is a chimeric antigen receptor T cell- therapy that reprograms autologous T cells to target CD19+ leukemia cells, approved in the US (2017) and in the EU (2018). This study reports the feasibility, safety and efficacy of CTL019 in patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL) treated in Robert-Debré and Saint-Louis University Hospitals (Assistance Publique-Hôpitaux de Paris/Université de Paris). Methods: Patients (pts) with an apheresis performed between march 1, 2016 and june 15, 2019, included in sponsored-clinical trials or treated within the French compassionate program or with the commercial product, were analyzed. All infused pts received a fludarabine-cyclophosphamide based lymphodepletion before a single infusion of CAR-T cells (2 to 5 x 106 CTL019/kg if less than 50 kg; a fixed dose of 1 to 2.5 x 108 CTL019/kg if > 50 kg) Results: 55 pts were referred from 25 French centers. Forty-one pts with a median number of relapses of 2 (range, 1-5) were infused with CTL019 at a median age of 18.2 y (range, 1-29.2). Eight pts were not infused due to progressive disease (n=4), screen failure (n=3) or fatal septic shock (n=1). Six pts were waiting to be infused at time of analysis. Out of the 41 infused pts, 26 had a prior history of allogeneic SCT (63%), 11 had received blinatumomab (27%). Among the 40 pts evaluable at one month post-infusion, 38 were in CR/CRi (95%) (one progression at day 5 after infusion and one toxic death at D6), 35/38 (92.1%) being clone-specific Ig-TCR MRD negative. After 3 months 21 out of 26 evaluable pts (81%) had a negative MRD. The 5 remaining MRD positive pts did relapse. No pt underwent allogeneic HSCT while in CR after CTL019 infusion. Median event free survival (EFS) and overall survival (OS) were not reached with a median follow up of 7.2 months (range, 0.2-36.3). The 18-month OS probability was 80% (95%CI, 58%-92%). The 18-month EFS probability was 58 % (95%CI, 37%-74%). Ten pts relapsed after a median time of 3.4 months (range, 1.9-10): 3 relapses were CD19+ and 5 CD19- (4 out of these 5 pts had a preexposure to blinatumomab), 2 being of undetermined status. Loss of B-cell aplasia (BCA) occurred in 9 pts after a median time of 3 months (range, 2-12), followed by relapse for 2 pts (one concomitant with loss of BCA and one 7 months later). Three pts received a second infusion of CTL019 for loss of BCA with no further expansion of CAR-T cells. Prior treatment with blinatumomab was a significant predictive factor for relapse (HR=6.082, 95%CI, 1.2-30, p=0.0005) in a univariate analysis. There was a trend toward increased risk of relapse with increased disease burden (≥ 5%) before lymphodepletion regimen (HR=2.4, 95%CI, 0.7-8, p=0.14). Twenty-two pts experienced a CRS (≥ grade 3: n=13, all ≥ 10 y). ICU was required for 14 pts (34%). One 29 year-old pt died of an uncontrollable CRS at day 6. Ten pts received tocilizumab, 4 pts siltuximab and 9 pts corticosteroids. Age ≥ 10 y (p=0.04) and a high disease burden just before lymphodepletion (marrow blasts ≥ 5%) (p=0.01) were associated with a higher risk of CRS ≥ grade 3. Nine neurological events have been reported, being reversible except in 2 cases (one death in combination with grade 5 CRS-cf supra-, one HHV6-related encephalitis with neurological sequelae). Among the 9 pts who presented neurological events, 8 experienced CRS grade ≥ 3 (RR=17.2, 95%CI, 3.22-100.3, p=0.0001). By day 28, unresolved neutropenia grade ≥ 3 was reported for 13 pts. G-CSF treatment was required in 21 pts overall. Thrombocytopenia grade ≥3 was reported for 14 pts. Conclusion: CTL019 confirms its efficacy with a high response rate after infusion and very encouraging early outcomes in a cohort of pts heavily pretreated for refractory or multiply relapsed B-ALL. Persistent remissions with a potential for cure were observed without additional HSCT, relapses occurring within the first year after infusion of CTL019. Accurate assessment of a potentially deleterious effect of Blinatumomab preexposure notable on CD19 negative relapse will need more pts and a longer follow-up. Toxicity profile was tolerable and manageable thanks to collaboration between intensivists, neurologists and hematologists. The identification of severe CRS predictive risk factors (high disease burden just before lymphodepletion and age ≥ 10 y) points towards the reinforcement of toxicity monitoring and treatment anticipation in these cases. Disclosures Boissel: NOVARTIS: Consultancy. Baruchel:NOVARTIS: Consultancy.

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