Results of an AIEOP (Associazione Italiana di Ematologia e Oncologia Pediatrica) Randomized Clinical Trial in Children with Low- and Intermediate-Risk Relapsed Acute Lymphoblastic Leukemia (ALL)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 65-65
Author(s):  
Franco Locatelli ◽  
Marco Zecca ◽  
Gianni Cazzaniga ◽  
Luciana Vinti ◽  
Andrea Biondi ◽  
...  
Keyword(s):  
T Cell ◽  
Maintenance Therapy ◽  
Induction Therapy ◽  
Lymphoblastic Leukemia ◽  
Continuous Treatment ◽  
Unrelated Donor ◽  
Intermediate Risk ◽  
Hematopoietic Stem ◽  
Line Therapy ◽  
To Receive

Abstract Leukemia recurrence remains the main cause of treatment failure in children with ALL. The prognosis of children with relapsed ALL is strongly influenced by the site of relapse, time elapsing between diagnosis and recurrence and by blast cell immune-phenotype. Recently, several groups reported probabilities of disease-free survival (DFS) in the order of 60% for children with low/intermediate-risk ALL in 1st relapse using different approaches. Despite this remarkable progress, the best re-induction and consolidation treatment remains to be defined. We, thus, conducted from 10/2003 to 06/2012 a multicenter randomized trial aimed at comparatively evaluating the efficacy of 2 alternative approaches in centers affiliated to the Italian AIEOP network. Included in the study were patients below the age of 18 experiencing late (i.e. more than 6 months from treatment discontinuation) isolated extramedullary (IEM) relapse (S1 patients, #22) or children with B-cell precursor (BCP)-ALL who had early (i.e. between 18 months from diagnosis and 6 months after completion of front-line treatment) or late combined bone marrow (BM) relapse, late isolated BM relapse of BCP–ALL, and very early (i.e. within 18 months from diagnosis) or early IEM of either BCP-ALL or T-cell ALL (S2 patients, # 255). S2 children were randomized to receive induction therapy consisting of either two multiagent chemotherapy courses, F1 and F2 (ARM-A), according to the ALL-REZ BFM P95/96 trial, or a classical 4-drug continuous reinduction therapy (protocol I-A-IDA, ARM-B). After induction, ARM-A patients were given a continuous treatment element including idarubicin (Protocol II-IDA), followed by 5 additional alternating R1/R2 courses and maintenance therapy (24 months). After induction therapy, ARM-B patients received 8 additional alternating R1/R2 courses and maintenance therapy (24 months, see Figure 1). S1 patients received ARM-A treatment with the exception of only 3 alternating R1/R2 consolidation courses and shorter maintenance therapy (12 months). All S2 children with an available HLA-identical sibling were candidate to receive allogeneic hematopoietic stem cell transplantation (allo-HSCT), while those relapsing within 48 months from diagnosis were eligible to receive the allograft also from an unrelated donor (UD) of BM cells or a suitable UD cord blood unit. For S1 patients, both autologous (auto) and allo-HSCT were considered acceptable post-remissional options; auto-HSCT was also employed in a minority of S2 children relapsing more than 48 months from diagnosis. Of the whole cohort of children, 143 were males and 134 were females; median age at diagnosis and at time of relapse was 5 (range 0.2-17) and 9 (range 1.1-17.9) years, respectively. Among the 255 S2 patients, 127 were allocated to ARM-A and 128 to ARM-B. All S1 children obtained a 2nd complete remission (CR), while the probability of reaching 2nd CR of S2 patients was similar in the 2 randomization arms (95% vs 96%). The 6-year DFS for the 22 S1 children was 75% (confidence interval, CI, 55-94); 13 of these children were given either auto-HSCT (#7) or allo-HSCT (#6), while 9 were treated with chemotherapy only. The 6-year DFS for the 255 S2 children was 65% (CI 57-72); the DFS for ARM-A and ARM-B patients was 60% (CI 48-71) and 69% (CI 60-79), respectively (p=ns). Among S2 patients, 179 received allo-HSCT either from an HLA-identical sibling (#51) or a BM/CB UD (#105) or an HLA-partially matched relative (#23) after T-cell depletion of the graft (TCD haplo-HSCT). Of the remaining 76 children, 12 were given auto-HSCT, while 64 received chemotherapy only. The 6-year DFS for S2 children who did or did not receive allo-HSCT was 66% (CI 58-74) and 58% (CI 38-77), respectively (p=ns). Among allo-HSCT recipients, the 6-year DFS was 59% (CI 42-75), 72% (CI 62-82) and 62% (CI 41-83) for children given HLA-identical sibling, UD or TCD haplo-HSCT, respectively (p=ns). Altogether, these results confirm that a high proportion of children with low-/intermediate-risk relapsed ALL can be rescued by second line therapy, including transplantation. A re-induction course similar to that employed in first-line therapy is as effective as that proposed in the ALL-REZ BFM P95/96 trial. UD-HSCT and TCD haplo-HSCT are suitable and effective alternatives for children candidate to an allograft but lacking an HLA-identical sibling. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Maintenance Therapy with Low-Dose Azacitidine (AZA) after Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for Relapsed or Refractory AML or MDS: A Dose and Schedule Finding Study.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1134-1134 ◽  
Author(s):  
Marcos De Lima ◽  
Leandro de Padua Silva ◽  
Sergio Giralt ◽  
Krishna Komanduri ◽  
Borje S. Andersson ◽  
...  
Keyword(s):  
Maintenance Therapy ◽  
Chronic Gvhd ◽  
Controlled Study ◽  
Unrelated Donor ◽  
Hematologic Toxicity ◽  
Dna Hypomethylation ◽  
Global Methylation ◽  
Hematopoietic Stem ◽  
Number Of Cycles ◽  
To Receive

Abstract Relapse is the major cause of treatment failure after HSCT for relapsed AML. Maintenance therapy may provide an “adjuvant’ support for the allogeneic graft-versus-leukemia effect, decreasing the likelihood of recurrence. AZA is a DNA methyltransferase inhibitor that induces DNA hypomethylation, leading to leukemic cell differentiation and potentially increased tumor immunogenicity. FDA approved doses are however unlikely to be tolerated due to myelosuppression. We hypothesized that AZA will reduce relapse rates, and designed a phase I clinical trial to determine the safest dose and schedule combination. Methods. Eligible were patients (pts) with AML/MDS not in 1st complete remission (CR), not candidates for ablative regimens due to age or comorbidities. Conditioning regimen was gemtuzumab ozogamicin 2 mg/m2, fludarabine 120mg/m2, and melphalan 140mg/ m2. GVHD prophylaxis was tacrolimus/mini-methotrexate (ATG in unrelated donor HSCT). We investigated 4 AZA doses: 8, 16, 24 and 32 mg/m2 SQ daily x 5 starting on day +42, given for 1–4 28-day cycles (schedule). An outcome-adaptive method was used to determine dose and schedule (number of cycles): pts were assigned to a dose/ schedule combination on the basis of the data (organ/hematologic toxicity) from all pts treated previously in the trial. Pts in CR on transplant day+30, with donor chimerism, no grade III/IV GVHD, platelet >10,000/mm3 and ANC >500/mm3 were eligible to receive AZA. Methylation status of long interspersed nuclear elements (LINE) was analyzed by pyrosequencing as a surrogate marker of global DNA methylation (figure). Results. 80 pts were transplanted; 44 (56%) were eligible to receive AZA: 2 refused; 42 pts. (4 too early) received it. Table shows pts characteristics. 88 cycles were delivered at 8 (n=7), 16 (n=5), 24 (n=21) and 32 mg/m2 (n=9). AZA-associated/possibly associated toxicities were grade (gd) I/II or III thrombocytopenia (n=5; n=2), gd I nausea (n=5), gd II fatigue (n=2), gd III transaminase elevation (n=1, AZA + posaconazole), conjunctival erythema (n=1), pruritus (n=1), gd I confusion (n=2), retina hemorrhage (possibly pre-existing), gd II creatinine elevation (n=1), oral ulcers (n=1), papilledema (n=1), and pulmonary hemorrhage (n=1; second HSCT, fungal pneumonia/hepatic VOD during the 1st AZA cycle, evolving with thrombocytopenia/bleeding). Reversible thrombocytopenia was more frequent at 32 mg/m2. Infections: bacteremia, n=5; respiratory, n=6; parainfluenza, n=2, CMV reactivation, n=6. Most pts were 100% donor chimeras at the start of AZA. AZA did not affect GVHD incidence (table). 10 pts have relapsed, 3 while on AZA 16 or 24 mg/m2. Median follow-up is 13 months (3–31; n=26). 12 pts have died, 8 of recurrence, 2 of GVHD, 1 of pneumonia and 1 of unknown causes. Day +100 non-relapse mortality was 6 %; 4 pts died within the first 100 days post HSCT due to relapse (n=2), pneumonia (n=1), and GVHD (n=1). Actuarial 1-year event-free and overall survival is 58% and 72%. No dose was found to significantly affect global methylation (gene specific methylation studies are ongoing). The trial has reached the dose 32 mg/m2 and the projected maximum number of cycles. Thrombocytopenia prevented escalation to the next level (40 mg/m2). Variables N (%) (range) Age: median (range) 60 (24–67) Median number of previous chemotherapy regimens 2 (0 – 5) Cytogenetics Good / Intermediate / bad 1 (3%)/ 22 (58%)/ 15(39%) Previous Allogeneic SCT 7 (18%) Disease status at transplant CR2/CR3 8/2 (26,3%) First Relapse/induction failure 12/13 (66,7%) ≥ second/third relapse 3 (7%) Charlson Comorbidity Index score 0 / 1 4 (10,5%) / 4 (10,5%) 2 / 3 5 (13,2%) / 7 (18,4%) >3 18 (47.4%) Donor type Sibling/unrelated 23/15 (58/42%) Cells Source:PB/BM 73% / 27% Grade II/III Acute GVHD Grade 2 / grade 3 6 (16,7%) / 4 (11%) Chronic GVHD 14 (46,5%) Conclusion. AZA 32 mg/m2 is safe and can be administered for at least 4 cycles to heavily pre-treated pts. with comorbidities. The safety profile indicates that longer periods of administration should be investigated. We will initiate a randomized, controlled study of AZA for one year versus best standard of care (no maintenance therapy) for similarly highrisk patients with AML/MDS. Figure Figure

scholarly journals Long-Term Outcome of Relapsed Acute T-Lymphoblastic Leukemia (T-ALL) in Children and Adolescents

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2580-2580
Author(s):  
Luciana Vinti ◽  
Luisa Strocchio ◽  
Barbara Buldini ◽  
Daniela Silvestri ◽  
Valentino Conter ◽  
...  
Keyword(s):  
Children And Adolescents ◽  
Board Of Directors ◽  
Induction Therapy ◽  
Progressive Disease ◽  
Lymphoblastic Leukemia ◽  
Unrelated Donor ◽  
Primary Therapy ◽  
Advisory Committees ◽  
Hematopoietic Stem ◽  
Long Term Outcome

Introduction Despite improvements in first-line treatment of childhood T-ALL, relapse remains the main cause of treatment failure. Patients with T-ALL experiencing leukemia recurrence have a dismal outcome, mostly due to a failure to achieve a second complete remission (CR) or to subsequent relapse. Assessment of minimal residual disease (MRD) may allow identifying subsets of patients with different prognosis. We analyzed the outcomes of 141 Italian children and adolescents who experienced T-ALL relapse after frontline multicenter AIEOP-BFM ALL treatment trials. Methods: This retrospective study aimed at describing the outcomes of Italian patients with T-ALL who were enrolled in the AIEOP-BFM ALL2000, 2006 and 2009 trials and subsequently experienced disease relapse. Among the 750 T-ALL Italian patients enrolled in the above-mentioned trials, 141 had a disease recurrence (70/251 patients in ALL2000 trial, 29/190 in ALL2006 trial, and 42/309 in ALL2009 trial). Molecular MRD monitoring after induction therapy for leukemia relapse was available for 38 patients. Results: The 141 patients, 113 males and 28 females, had a median age of 9 years at diagnosis (range 1-17) and 10 at relapse (range 2-19). At diagnosis, 7 patients were allocated to the Standard (SR), 45 to the Medium (MR), and 89 to the High Risk (HR) group, respectively. Thirty-four (4 MR and 30 HR patients) of these children were given allogeneic hematopoietic stem cell transplantation (allo-HSCT) in 1st CR and 41 had received central nervous system (CNS) radiotherapy. Relapses were classified as very early (occurring <18 months from diagnosis), early (occurring ≥18 months from diagnosis and <6 months after completion of primary therapy), and late (occurring >6 months after the end of the frontline protocol) in 92, 36, and 13 patients, respectively. Site of relapse was isolated bone marrow (BM) in 74 patients, combined BM/extramedullary (EM) in 23 patients, and isolated EM in 44 patients (involving a single EM site in 37 cases and >1 EM site in 7 cases; CNS was involved in 29 patients). At the time of relapse, 7 patients were treated according to AIEOP ALL REC98 Trial, 57 according to AIEOP ALL REC2003 Trial, while the remaining 77 patients received other combination of chemotherapy. After reinduction/consolidation treatment, 58 patients were given allo-HSCT from either a matched family donor (16) or an unrelated donor (UD, 31 patients, of which 21 from a matched UD and 10 from a mismatched UD) or an HLA-partially matched relative (11). With a median follow-up of 7.5 years (range 2-14), 34 patients are currently alive; 17 of these patients had EM isolated relapse, which was very early in 13 cases, and 17 had BM involvement at relapse, with late relapse in 8 cases. The 8-year overall survival (OS) of the whole cohort was 23.3% (95% CI 16.5-30.7) (Figure 1A). Isolate EM relapse (Figure 1B) and late relapses were associated with a better OS probability. Both factors remained statistically significant in multivariable analysis. Moreover, in univariable analysis a better prognosis was observed in patients treated more recently (i.e., after year 2008) (8-year OS 31.8% vs 16.2%, p=0.01). After allo-HSCT, 29 patients are currently alive, while the remaining 29 patients died from progressive disease (21) or transplant-related causes (8), leading to a 8-year OS for patients given allo-HSCT in 2nd RC of 48.5% (95% CI 34.7-61.0). Of the 83 children given sole chemotherapy, 5 are currently alive, while the remaining 78 died due to progressive disease (53), organ-failure (7), infection (9), or other causes (9). MRD monitoring was performed for 38/97 patients with BM involvement (5 with late, 13 with early, and 20 with very early relapse, respectively). Patients with a post-induction MRD <10-3 showed a reduced incidence of relapse (Figure 1C), resulting into better probability of 8-year OS (Figure 1D) in comparison to patients with higher MRD levels. Conclusions: Our results confirm that T-ALL relapse, especially if involving BM and occurring within 6 months from treatment discontinuation is still associated with poor prognosis, although in the last 10 years a higher proportion of children with relapsed T-ALL has been rescued by second line therapy, including transplantation. In this Italian retrospective cohort, a MRD value >10-3 at the end of induction therapy predicts a miserable outcome, this finding allowing to identify patients eligible to experimental therapies. Figure 1 Disclosures Merli: Novartis: Honoraria; Amgen: Honoraria; Bellicum: Consultancy; Sobi: Consultancy. Rizzari:JazzPharma, Shire, medac , Sigma-Tau, Baxalta, Shire and Servier: Consultancy, Honoraria; Together with study group from Shire, medac , Sigma-Tau, Baxalta, Shire and Servier: Research Funding. Parasole:Servier: Honoraria; Baxalta: Honoraria; Eusapharma: Honoraria. Locatelli:bluebird bio: Consultancy; Miltenyi: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees.

A Successful Re-Induction Regimen for Relapsed Pediatric Acute Lymphoblastic Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 863-863
Author(s):  
Jason Ackerman ◽  
Douglas Hawkins ◽  
Karyn Brundige ◽  
Laura Eisenberg ◽  
Blythe Thomson
Keyword(s):  
Stem Cell ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
B Cell ◽  
Induction Therapy ◽  
Lymphoblastic Leukemia ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Induction Regimen ◽  
First Relapse

Abstract Background: Acute Lymphoblastic Leukemia (ALL) is the most common form of malignancy in children. Advances in treatments have made ALL the disease highly curable; however relapse is the most common form of treatment failure. The prognosis for relapsed ALL is poor, and the ability to achieve a durable second remission is influenced by the length of the initial remission and, potentially, the re-induction therapy chosen. We present a series of 60 pediatric ALL patients with first relapse (54 pre B-cell and 6 T-cell) treated with a standardized four-drug induction therapy followed by either intensification therapy or hematopoietic stem cell transplant (HSCT). Methods: Patients treated at Children’s Hospital and Regional Medical Center, Seattle, WA with a common re-induction regimen for first relapse ALL were reviewed in this IRB-approved retrospective study. Patients included isolated or combined bone marrow (BM) relapse, isolated central nervous system (CNS) relapse alone, or isolated testicular relapse. Re-induction consisted of a four-drug combination of dexamethasone (dex) (day 0-6, 14-20), vincristine (VCR) (weekly for 4 weeks), peg-aspargase (weekly for 4 weeks), and idarubicin (10 mg/m2/day × 2-3 doses) and intrathecal triple (ITT) drug therapy. After achieving second complete remission (CR2), patients proceeded to HSCT or continued chemotherapy at the discretion of the physician. Allogeneic HSCT was total body irradiation based and a variety of stem cell sources. Continuation chemotherapy was alternating blocks every 3 weeks for up to 8 courses: Block A, consisting of dex, VCR, 6-thioguanine (TG), peg-asparagase and methotrexate (MTX) and ITT, and Block B, consisting of etoposide and ifosfamide and ITT. Maintenance chemotherapy with MTX, VCR and TG with cranial, craniospinal or testicular radiation completed the two year regimen. Results: Among the 54 pre-B-cell patients, there were 32 with BM relapse (either isolated or with CNS), 16 CNS relapses, and 6 testicular relapses. CR2 was achieved in 96% of the patients. Two did not achieve remission, dying of toxicity during re-induction. BM (± CNS) Isolated CNS Testicular Duration of CR1 n 3 yr. EFS (95% CI) n 3 yr. EFS (95% CI) n 3 yr. EFS (95% CI) <18 months 5 0% (± 52%) 3 67% (± 54%) - - >18 months 27 39% (± 24%) 13 75% (± 26%) 6 67% (± 38%) Among the patients with BM relapse, the 3 year Event Free Survival (EFS) was 33.2% (95% CI: ± 20.8%). The 3 year EFS for the 18 who proceeded to HSCT was 35.0% (95% CI: ± 27.4%), while 3-year EFS for chemotherapy only patients was 31.7% (95% CI: ± 31.8%). There were 6 patients with T-cell relapsed disease, which were evaluated separately. Their EFS was 0% (95% CI: ±46%) at three years, and 2 failed to achieve CR2. Discussion: We present a large single institution series of patients treated with a common reinduction regimen followed by chemotherapy or HSCT. Although intensive, the regimen was tolerable (less than 4% toxic death rate) and highly successful in achieving CR2. Among the patients with later BM relapse, there was minimal difference in 3-year EFS between chemotherapy and HSCT, offering a reasonable continuation chemotherapy regimen to these patients. Our data confirmed the excellent outcome of isolated CNS and testicular relapse and the poor outcome of very early relapse and T cell disease.

scholarly journals Successful outcome of pre-engraftment COVID-19 in an HCT patient: impact of targeted therapies and cellular immunity

2022 ◽  
Author(s):  
Hoda Pourhassan ◽  
CORINNA LA ROSA ◽  
Flavia Chiuppesi ◽  
Alfredo Puing ◽  
Ibrahim Aldoss ◽  
...  
Keyword(s):  
T Cell ◽  
Cellular Immunity ◽  
Cellular Therapy ◽  
Lymphoblastic Leukemia ◽  
Critical Role ◽  
Humoral Response ◽  
Successful Outcome ◽  
Unrelated Donor ◽  
Hematopoietic Stem ◽  
The Impact

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has emerged as a global pandemic that upended existing protocols and practices, including those for allogeneic hematopoietic stem cell transplantation (HCT). Here we describe the successful clinical course and multiple key interventions administered to an acute lymphoblastic leukemia patient, who tested SARS-CoV-2 positive by RT-PCR on day -1 of matched unrelated donor (SARS-CoV-2 IgG negative) T-cell-replete HCT. This experience allowed for implementing a virologic and immunomonitoring panel to characterize the impact of SARS-CoV-2 on the recipient's nascent humoral and cellular immune response. The finding of robust, functional, and persistent levels of SARS-CoV-2 specific T-cells, starting early after transplant was unexpected, and in combination with the clinical strategy may have contributed to the favorable outcome. Additionally, it is plausible that pre-existing cross-reactive endemic coronavirus immunity in the allogeneic graft reduced recipient susceptibility to COVID-19 disease. This case supports the critical role that T-cell responses may play in mitigating SARS-CoV-2 infection, even in the context of transplant immunosuppression, in which reconstitution of humoral response is commonly delayed. Interventional approaches to transfer SARS-CoV-2-specific cellular immunity such as HCT donor vaccination and adaptive cellular therapy could be of benefit.

Outcome of Early T-Cell Precursor Acute Lymphoblastic Leukemia in AIEOP Patients Treated with the AIEOP-BFM ALL 2000 Study

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3780-3780 ◽  
Author(s):  
Valentino Conter ◽  
Maria Grazia Valsecchi ◽  
Barbara Buldini ◽  
Rosanna Parasole ◽  
Franco Locatelli ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
High Risk ◽  
Induction Therapy ◽  
Lymphoblastic Leukemia ◽  
Cell Precursor ◽  
Hematopoietic Stem ◽  
Phase Ib ◽  
High Risk Patients ◽  
Risk Patients

Abstract Aim: To evaluate the outcome of the Italian Association of Pediatric Hematology and Oncology (AIEOP) patients diagnosed with Early T-cell Precursor (ETP) Acute Lymphoblastic Leukemia (ALL) in the period September 2000-December 2011 and treated in the context of the AIEOP-BFM ALL 2000 Study and the subsequent - very similar – AIEOP ALL R2006 Study. Patients and methods: ETP-ALL was defined by staining negative for CD1a and CD8, mildly positive or negative for CD5 and positive for at least one of CD34, CD117, HLADR, CD13, CD33, CD11b, or CD65 antigens. Treatment consisted of BFM protocol I either with dexamethasone or prednisone in phase IA, 4 HDMTX courses (5 g/sqm over 24 hrs) in non-high risk patients or 3 poly-chemotherapy blocks in high risk patients, delayed intensification based on protocol(s) II or III, protracted intrathecal therapy or cranial radiotherapy, maintenance therapy for a total of 2 years of treatment. Hematopoietic stem cell transplantation (HSCT) was indicated for patients with poor treatment response assessed either morphologically at day +8 (Prednisone Poor Response, PPR) or day +33 (no Complete Remission, CR) or by PCR at day +78 (high-level Minimal Residual Disease, HR-MRD; ≥10-3). Results: Of the 439 T-ALL eligible patients, 34 had ETP ALL. The incidence (7.7%) may be underestimated since the full set of the data needed was not available for all patients. Out of the 34 patients with ETP ALL 14 were at high risk due to PPR; of them, 3 were HR-MRD and 5 did not achieve CR after Phase IA of induction therapy (including one with HR-MRD). Of the remaining 20 patients (all prednisone good responders), 3 patients were at high risk due to resistance to Phase IA and HR-MRD (n=1) or HR-MRD only (n=2). 17/30 patients could not be monitored by MRD due to death in Induction (n=1), or absent (n=10) or inadequate PCR markers (n=6). Of the17 patients monitored by MRD, 13 had HR-MRD at day 33 and 6 of them also at day +78. One patient died during induction therapy. The remaining 33 achieved morphological CR: 27 after phase IA and 6 (those resistant to phase IA) after phase IB of protocol I. Of 12 patients who underwent HSCT, 3 died of HSCT-related complications and 3 relapsed. With a median follow-up of 6.6 years, the 5-year event-free survival (EFS) and Survival in the 34 ETP ALL patients were of 60.9%(SE 8.5) and 66.6%(8.3), versus 71.2%(2.3) and 77.1%(2.1) respectively in the non-ETP patients. The overall cumulative incidence of relapse was 27.3%(7.8) and 22.2%(2.1) in ETP and non-ETP T-ALL patients, respectively (p=0.52). EFS in ETP vs non-ETP patients was respectively 81.9%(9.5) vs 83.8%(2.4) in non high risk patients (p=0.87) and 41.2%(11.9) vs 53.2%(4.0) in high risk patients (p=0.24). Conclusions: The outcome of T-ALL patients treated with BFM-type therapy is comparable in ETP and non-ETP for those with good response to initial chemotherapy; it was slightly, but not significantly, inferior in ETP-ALL patients with poor initial response. Phase IB treatment element is very effective in ETP-ALL, suggesting that intensification with antimetabolite and alkylating agents may be beneficial, while the benefit of HSCT in first CR needs to be further investigated. Disclosures No relevant conflicts of interest to declare.

Unrelated Donor (URD) Hematopoietic Stem Cell Transplantation (HCT) for Adults with Philadelphia Chromosome Negative Acute Lymphoblastic Leukemia (ALL) in First Complete Remission (CR1): A Center for International Blood and Marrow Transplant Research (CIBMTR) Analysis.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3055-3055
Author(s):  
David I. Marks ◽  
Waleska S. Pérez ◽  
Vincent He ◽  
Mei-Jie Zhang ◽  
Armand Keating ◽  
...  
Keyword(s):  
T Cell ◽  
High Risk ◽  
Acute Gvhd ◽  
Lymphoblastic Leukemia ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Term Survival ◽  
Major Barrier ◽  
Hematopoietic Stem ◽  
Risk Of Relapse

Abstract Allogeneic HCT has a growing role in the management of adults with ALL in CR1. Recent large prospective donor vs. no donor analyses show HLA-matched sibling allografting to produce superior outcomes to chemotherapy and its use is unquestioned in the highest risk, Ph+ cohort. Investigators have explored the use of allografting with unrelated donors (URD) for patients with Philadelphia negative ALL in CR1 at high risk of relapse. We report outcomes of URD HCT using myeloablative conditioning in 169 patients with ALL in CR1 transplanted between 1995 and 2004, reported to the CIBMTR by 85 centers in 17 different countries. Median (range) age at HCT was 33 (16–59) years and the median white cell count (WCC) at diagnosis was 31 × 109/L. Fifty percent had a WCC >30 × 109/L, 18% had extramedullary disease, 42% achieved CR >8 weeks from diagnosis, 25% had adverse cytogenetics and 19% had T cell disease. Adverse cytogenetics included t(4;11), hypodiploidy or near triploidy or more than 5 abnormalities. Many patients had multiple high risk factors. Twenty-eight of 41 patients with adverse cytogenetics and 28 of 63 patients who took > 8 weeks to achieve CR had a WCC >30 × 109/L. Cyclophosphamide and total body irradiation (TBI) was used as conditioning in 76% of cases; 80% of patients received >13cGy of TBI. 41% were well matched (no known disparity at HLA A,B,C,DR) and 41% partially matched (1 locus known or likely disparity) with their donors; these are analysed together because of similar outcomes. Eighteen percent of patients were more mismatched (≥2 locus disparity). Univariate outcomes, with a median follow-up of 54 (range, 3–133) months were as follows: Outcomes Probability (95%confidence interval) Acute GVHD @ 100 days, grades II-IV 50 (43–58) Acute GVHD @ 100 days, grades III-IV 25 (19–32) Chronic GVHD @ 5 years 43 (35–51) Transplant-related mortality (TRM) @ 5 years 42 (34–50) Relapse @ 5 years 20 (14–26) Leukemia-free survival @ 5 years 38 (31–46) Overall survival @ 5 years 39 (31–47) In adjusted multivariate analyses, the risk of TRM was significantly higher with mismatched donors (RR = 1.83, p = 0.037) and T cell depletion (TCD) (RR = 2.67, p = 0.002). The risk of relapse was higher (RR = 2.22, p = 0.045) if the WCC at diagnosis was >100 × 109/L. Acute and chronic GVHD did not significantly affect the incidence of relapse (RR = 0.73, p = 0.39 and RR = 0.47, p=0.09 respectively). Factors associated with mortality included WCC >100 × 109/L (RR = 1.80, p = 0.014), >8 weeks to CR1 (RR = 1.77, p = 0.006), CMV seropositivity of donor or recipient (RR = 1.61, p = 0.04), ≥2 locus HLA mismatch (RR = 2.09, p = 0.003) and T cell depleted graft (RR = 2.50, p = 0.003). The major causes of death were relapse (25%), infection (23%) and GVHD (14%). In summary, nearly 40% of patients with high risk ALL in CR1 survive 5 years after URD-HCT. The risk of relapse is modest and TRM is the major barrier to survival. These data indicate that selection of only closely matched URD and better prevention and management of GVHD and infection will be needed to enhance long term survival.

scholarly journals Targeting Interleukin-2-Inducible T-Cell Kinase (ITK) Differentiates GVL and GVHD in Allo-HSCT

2020 ◽  
Vol 11 ◽  
Author(s):  
Mahinbanu Mammadli ◽  
Weishan Huang ◽  
Rebecca Harris ◽  
Aisha Sultana ◽  
Ying Cheng ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Interleukin 2 ◽  
Treatment Strategies ◽  
Receptor Expression ◽  
Hematopoietic Stem ◽  
Target Organs ◽  
Donor T Cells ◽  
Inducible T Cell Kinase

Allogeneic hematopoietic stem cell transplantation is a potentially curative procedure for many malignant diseases. Donor T cells prevent disease recurrence via graft-versus-leukemia (GVL) effect. Donor T cells also contribute to graft-versus-host disease (GVHD), a debilitating and potentially fatal complication. Novel treatment strategies are needed which allow preservation of GVL effects without causing GVHD. Using murine models, we show that targeting IL-2-inducible T cell kinase (ITK) in donor T cells reduces GVHD while preserving GVL effects. Both CD8+ and CD4+ donor T cells from Itk-/- mice produce less inflammatory cytokines and show decrease migration to GVHD target organs such as the liver and small intestine, while maintaining GVL efficacy against primary B-cell acute lymphoblastic leukemia (B-ALL). Itk-/- T cells exhibit reduced expression of IRF4 and decreased JAK/STAT signaling activity but upregulating expression of Eomesodermin (Eomes) and preserve cytotoxicity, necessary for GVL effect. Transcriptome analysis indicates that ITK signaling controls chemokine receptor expression during alloactivation, which in turn affects the ability of donor T cells to migrate to GVHD target organs. Our data suggest that inhibiting ITK could be a therapeutic strategy to reduce GVHD while preserving the beneficial GVL effects following allo-HSCT treatment.

Impact of clostridiodes difficile infection on acute graft-versus-host disease in allogenic transplant patients.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e19027-e19027
Author(s):  
Prasanth Lingamaneni ◽  
Vatsala Katiyar ◽  
Rohit Kumar ◽  
Maha A.T. Elsebaie ◽  
Hashim Mann ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Lymphoblastic Leukemia ◽  
Index Admission ◽  
Unrelated Donor ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Hospitalization Costs ◽  
Acute Graft

e19027 Background: Clostridiodes difficile infection (CDI) is reported to occur up to 9-fold higher in allogenic hematopoietic stem cell transplant (HSCT) recipients compared to the general population of hospitalized patients. This is attributed to disruption of gut microbiome by antibiotics, myeloablative regimens, neutropenia, prolonged hospitalization, and immunosuppressive regimens administered to prevent acute graft-versus-host disease (aGVHD). CDI by disruption of the intestinal microbiome may trigger gastrointestinal aGVHD. Previous studies from HSCT centers have reported conflicting data on the relationship between CDI and subsequent development of aGVHD. Methods: The Nationwide Readmissions Database was queried for admissions of adult allogenic HSCT patients between 2016 and 2018. Those with and without CDI during index admission were compared. Multivariable logistic regression was used to evaluate the primary outcome of risk of aGVHD in the index admission or within 100 days post-engraftment. Results: A total of 13518 allogenic HSCT patients were included in the study. Mean age was 52.4 years. 57.2% of patients were female. The most common underlying diagnoses were acute myeloid leukemia (38%), myelodysplastic syndrome (17%) and acute lymphoblastic leukemia (14%). 11.1% of the index admissions were complicated by CDI. Rates of aGVHD during the index admission or 100 days post-engraftment were similar between CDI and non-CDI groups: 13.8% vs. 12.1%, p=0.19 during index admission and 29.2% vs. 26.1%, p=0.09 during 100 days post-engraftment. Nonetheless, patients with CDI had longer length of hospital stay (34.6 vs 29.8 days, p<0.0001), higher hospitalization costs ($608K vs $506K USD) and greater rate of inpatient mortality (7.3% vs 4.6%, p<0.001). In the multivariate regression analysis, CDI during index admission was not associated with risk of development of aGVHD (Adjusted Odds Ratio 1.14, 95% Confidence Interval 0.87-1.48, p=0.34). Age and unrelated donor HSCT were predictive of risk of aGVHD. Conclusions: CDI during index admission was not predictive of aGVHD during the first 100 days post-allogenic HSCT. HSCT patients are frequency colonized with C.difficile. Diarrhea secondary to CDI may resemble gastrointestinal aGVHD. Therefore, overdiagnosis of CDI in this population is a concern. Antimicrobial stewardship and use of clinical decision support tools have been advocated recently to decrease testing of HSCT patients with C.difficile colonization. Multivariable analysis of risk factors of aGVHD.[Table: see text]

scholarly journals Nasalis típusú extranodalis natural killer T-sejtes lymphoma hazai előfordulása és kezelésével szerzett tapasztalatok

2017 ◽  
Vol 158 (41) ◽  
pp. 1635-1641
Author(s):  
Annamária Bakos ◽  
Árpád Szomor ◽  
Tamás Schneider ◽  
Zsófia Miltényi ◽  
Imelda Marton ◽  
...  
Keyword(s):  
T Cell ◽  
Natural Killer ◽  
Treatment Strategies ◽  
Second Line ◽  
Upper Aerodigestive Tract ◽  
Second Line Therapy ◽  
Hematopoietic Stem ◽  
Non Hodgkin Lymphoma ◽  
Line Therapy ◽  
Natural Killer T

Abstract: Introduction: Extranodal natural killer/T (NK/T) cell lymphoma, nasal type (ENKTL) represents a rare subtype of T-cell lymphomas with aggressive clinical behavior according to WHO 2016 classification. Aim: ENKTL has distinctive geographic distribution with higher incidence in Asia and Latin America (10% of all non-Hodgkin lymphoma cases), than in Europe and North America (<1%). ENKTL tipically origins from nasopharynx and upper aerodigestive tract. Anthracycline-based chemotherapy regimens are largely ineffective in the treatment of ENKTL. Method: Our aims were to evaluate the incidence and treatment strategies of ENKTL patients in Hungarian Haematological Centres between 2003 and 2015. Altogether 20 patients with ENKTL were treated in the 4 haematological hospitals (male:female ratio 12:8, with median 49.5 years of age). Results: Ten patients had localized (stage I–II) disease at the time of the diagnosis. Seventeen patients were treated with chemotherapy (11/CHOP, CHOP-like, 2/HyperCVAD, 1/ProMACECytaBom, 1/SMILE, 2/others), which was completed with involved-field radiation therapy (IFRT) (40–46 Gy) in 6 cases were used. After first-line therapy 9 patients achieved complete remission (CR), 3 patients had partial remission (PR), 3 patients had progressive disease (PD), and 2 patients had stable disease (SD). Median follow-up was 32 (3–113) months. Five patients received second-line therapy for progressive or recurrent disease [2/DHAP, 1/VIM, 1/HyperCVAD, 1/ProMACECytaBom]. None of the patients achieved CR after second-line therapy. Two patients have undergone autologous hematopoietic stem cell transplantation (HSCT) after the first CR. Conclusion: ENKTL treatment is more effective with nonanthracycline-containing regimens. L-asparaginase containing chemotherapy and concurrent or sequential chemo-radiotherapy improves survival and CR rates. Orv Hetil. 2017; 158(41): 1635–1641.

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