scholarly journals Unrelated donor transplants in adults with Philadelphia-negative acute lymphoblastic leukemia in first complete remission

Blood ◽  
2008 ◽  
Vol 112 (2) ◽  
pp. 426-434 ◽  
Author(s):  
David I. Marks ◽  
Waleska S. Pérez ◽  
Wensheng He ◽  
Mei-Jie Zhang ◽  
Michael R. Bishop ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Complete Remission ◽  
Lymphoblastic Leukemia ◽  
Cell Depletion ◽  
Unrelated Donor ◽  
T Cell Depletion ◽  
First Complete Remission ◽  
Related Mortality

Abstract We report the retrospective outcomes of unrelated donor (URD) transplants in 169 patients with acute lymphoblastic leukemia (ALL) in first complete remission (CR1) who received transplants between 1995 and 2004. Median age was 33 years (range, 16-59 years). A total of 50% had a white blood cell count (WBC) more than 30 × 109/L, 18% extramedullary disease, 42% achieved CR more than 8 weeks from diagnosis, 25% had adverse cytogenetics, and 19% had T-cell leukemia. A total of 41% were HLA well-matched, 41% partially matched with their donors, and 18% were HLA-mismatched. At 54-month median follow-up, incidences of acute grade 2-IV, III to IV, and chronic graft-versus-host disease were 50%, 25%, and 43%, respectively. Five-year treatment-related mortality (TRM), relapse, and overall survival were 42%, 20%, and 39%, respectively. In multivariate analyses, TRM was significantly higher with HLA-mismatched donors and T-cell depletion. Relapse risk was higher if the diagnostic WBC was more than 100 × 109/L. Factors associated with poorer survival included WBC more than 100 × 109/L, more than 8 weeks to CR1, cytomegalovirus seropositivity, HLA mismatching, and T-cell depletion. Nearly 40% of adults with ALL in CR1 survive 5 years after URD transplantation. Relapse risks were modest; TRM is the major cause of treatment failure. Selecting closely HLA-matched URD and reducing TRM should improve results.

scholarly journals Impact of immune modulation with in vivo T-cell depletion and myleoablative total body irradiation conditioning on outcomes after unrelated donor transplantation for childhood acute lymphoblastic leukemia

Blood ◽  
2012 ◽  
Vol 119 (25) ◽  
pp. 6155-6161 ◽  
Author(s):  
Paul Veys ◽  
Robert F. Wynn ◽  
Kwang Woo Ahn ◽  
Sujith Samarasinghe ◽  
Wensheng He ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Total Body Irradiation ◽  
Lymphoblastic Leukemia ◽  
Cell Depletion ◽  
Unrelated Donor ◽  
T Cell Depletion ◽  
Cox Regression Analysis ◽  
Total Body

AbstractTo determine whether in vivo T-cell depletion, which lowers GVHD, abrogates the antileukemic benefits of myeloablative total body irradiation–based conditioning and unrelated donor transplantation, in the present study, we analyzed 715 children with acute lymphoblastic leukemia. Patients were grouped for analysis according to whether conditioning included antithymocyte globulin (ATG; n = 191) or alemtuzumab (n = 132) and no in vivo T-cell depletion (n = 392). The median follow-up time was 3.5 years for the ATG group and 5 years for the alemtuzumab and T cell–replete groups. Using Cox regression analysis, we compared transplantation outcomes between groups. Compared with no T-cell depletion, grade 2-4 acute and chronic GVHD rates were significantly lower after in vivo T-cell depletion with ATG (relative risk [RR] = 0.66; P = .005 and RR = 0.55; P < .0001, respectively) or alemtuzumab (RR = 0.09; P < .003 and RR = 0.21; P < .0001, respectively). Despite lower GVHD rates after in vivo T-cell depletion, nonrelapse mortality, relapse, overall survival, and leukemia-free survival (LFS) did not differ significantly among the treatment groups. The 3-year probabilities of LFS after ATG-containing, alemtuzumab-containing, and T cell–replete transplantations were 43%, 49%, and 46%, respectively. These data suggest that in vivo T-cell depletion lowers GVHD without compromising LFS among children with acute lymphoblastic leukemia who are undergoing unrelated donor transplantation with myeloablative total body irradiation–based regimens.

Long Term Outcomes of Unrelated Donor Bone Marrow Transplantation in Children with Severe Aplastic Anemia: An Update of the Milwaukee Experience.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3128-3128
Author(s):  
Julie-An Talano ◽  
Bruce Camitta ◽  
Carolyn Keever-Taylor ◽  
Lynnette Anderson ◽  
Caitlin Wallach ◽  
...  
Keyword(s):  
T Cell ◽  
Graft Rejection ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Cell Depletion ◽  
Unrelated Donor ◽  
T Cell Depletion ◽  
Musculoskeletal Problems

Abstract We demonstrated that partially T-cell depleted unrelated donor HSCT for Severe Aplastic Anemia (SAA) is a reasonable treatment option for children and young adults who fail immune suppression therapy. (Margolis et al., 1996, Br J Haematol.)We now report, long term follow up data for 40 patients transplanted for SAA between the years 1986 to 2002. The patient group consisted of 22 males and 18 females, ranging in age from 0.5–24.3 (median 8.5) yrs. Retrospective molecular HLA typing shows that donors were matched for nine patients, and mismatched for 31. Patients were conditioned with cytosine arabinoside, cyclophosphamide, and total body irradiation, as previously described. Some patients additionally received ATG to promote engraftment. The marrow product underwent partial T-cell depletion using an antibody and complement process as described. in the original report. GVHD prevention was with cyclosporine. Three patients did not engraft. All three with non-engraftment died within 60 days of BMT from infectious and hemorrhagic complications. Since employing ATG as part of the conditioning regimen, all patients have engrafted. Of the 37 patients who engrafted the median time to an ANC>500 was 16 (range 8–25) days. Eight patients developed Grade II AGvHD, 1 grade III and 2 grade IV. Of 29 evaluable patients, 12 developed limited chronic GVHD, and 3 developed extensive CGvHD. Twenty-one patients are currently surviving with a follow-up of 4 to 19 yrs. (median 12.7 yrs.). Overall survival is 52% at 12 yrs. Of the 19 patients that died, causes of death included infection n=7, (PCP n=1, CMV n=2, Aspergillus n=1, Adenovirus n=2, PTLD n=1); GVHD n=2; Graft failure n=3; Multiorgan system failure n=2; ARDS n=1; Hemorrhage n=2; VOD n=1; Secondary malignancy n=1 (Hodgkin’s disease n=1). Of the 21 surviving patients, all patients have a Karnofsky score ≥ 90%. The late effects in our survivors include two secondary malignancies (osteosarcoma and vaginal carcinoma in situ); cataracts n=11; growth retardation n=11; gonadal dysfunction n=6; hypothyroidism n=5; cognitive problems n=4; musculoskeletal problems (AVN, osteoporosis) n=7; hyperlipidemia n=3; and renal disease n=2. One patient had a subsequent pregnancy that resulted in a preterm delivery at 26 weeks and a neonatal death. Our experience, now with long follow-up, shows that an intensive conditioning regimen to prevent graft rejection, coupled with partial T-cell depletion of an unrelated donor bone marrow graft to decrease the risk of GVHD, provides for durable survival with an acceptable incidence of acute and chronic GVHD. The relatively low incidence of GVHD is notable in view of the number of patients with donors who had identified HLA disparity. However, there are long-term risks associated with this regimen including secondary malignancies, delayed growth and development, metabolic problems, and musculoskeletal problems. We are encouraged by the recently reported short-term results using regimens for this disease which avoid or limit the use of TBI. Recognizing that many patients have donors with HLA disparity, which increases the risks of graft rejection and GVHD, we believe that combining partial T cell depletion with advanced immunomagnetic methods of graft manipulation and a fludarabine based regimen may allow us to balance the risks of graft rejection, GVHD, and late-effects that are unique to patients with SAA.

Outcome of Hematopoietic Stem Cell Transplantation for Pediatric Acute Lymphoblastic Leukemia in Third Complete Remission (CR3): A Vital Role for Graft-Versus-Host-Disease/Graft-Versus-Leukemia Effect in Survival.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3667-3667
Author(s):  
Adam Gassas ◽  
Kashif Ishaqi ◽  
John Doyle
Keyword(s):  
Stem Cell ◽  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Complete Remission ◽  
Lymphoblastic Leukemia ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Hematopoietic Stem ◽  
Graft Versus Host ◽  
Related Mortality

Abstract Children with acute lymphoblastic leukemia (ALL) who suffer 2 relapses could be salvaged by hematopoietic stem cell transplantation (HSCT) when a suitable stem cell source is available provided they respond to the pre HSCT chemotherapy and at least enter morphological remission. However, these patients are at very high risk for post HSCT relapse and also at a high risk for transplant related mortality (TRM). Our objective, herein, was to review the outcome of children (0–18years) with ALL who received allogeneic HSCT in third complete remission (CR3) at our institution. Between January 1994 – August 2005, twenty-two consecutive children in CR3 received HSCT in the Hospital for Sick Children, Toronto, Canada. Conditioning regimens included single dose of VP16 (60mg/kg infused over 4 hours) and fractionated total body irradiation (TBI; 1200cGy) in six fractions over 3 days (VP16/TBI) in 10 patients (1994–1998) and cyclophosphamide 50mg/kg infused over 1 hour daily for 4 days followed by the same dose of fractionated TBI (CY/TBI) in 12 patients (1999–2005). Graft-versus-host disease (GVHD) prophylaxis included cyclosporine A and a short course of methotrexate for the majority of patients, and all patients were in complete morphological remission prior to HSCT. Median age was 8.4 years (range 3–15.4). Donor source was as follows: matched sibling donor (MSD), 8; matched unrelated donor (MUD) 6; one antigen mismatch related donor (MMRD) 4; one antigen mismatched unrelated donor (MMUD) 3; and one patient received 1 antigen mismatched cord progenitor stem cells. White cell engraftment was successful in all patients at a median of 18 days (range 9–29). Ten patients died of TRM, seven relapsed, one died from other causes and four patients are long term survivors at a median follow up of 3.7 years (range 1–10.2). All patients who did not develop clinical acute or chronic GVHD relapsed and died. Event free survival was (EFS 19% ± 4%). Three out of the 4 survivors received MMUD and all 4 survivors had moderate to severe acute GVHD and three had chronic GVHD, limited in two and extensive in one. Conclusion: Children with ALL in CR3 receiving HSCT are extremely high risk for relapse and transplant related mortality. These children have already relapsed twice and demonstrated chemotherapy resistance and GVL/GVHD plays a key role in leukemia eradication. Although, TRM is high in such patients and GVHD could potentially increase TRM, there are no survivors without GVHD and exploring means of inducing GVHD by reduction of immunosuppressive medications or other means of immunotherapy should seriously be considered in these patients.

Outcome and Toxicities of Modified Augmented Berlin-Frankfurt-Muenster (ABFM) Therapy Used in the Treatment of Acute Lymphoblastic Leukemia in Adolescent and Young Adult Patients, Single Center Experience From Saudi Arabia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3569-3569
Author(s):  
Suhaib Radi ◽  
Anas Merdad ◽  
Mona Al-Dabbagh ◽  
Ahmed Almohanad Absi ◽  
Ahmad Alsaeed ◽  
...  
Keyword(s):  
Overall Survival ◽  
Saudi Arabia ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
High Risk ◽  
Complete Remission ◽  
Fungal Infections ◽  
Lymphoblastic Leukemia ◽  
Inclusion Criteria

Abstract Abstract 3569 Introduction: Acute lymphoblastic leukemia (ALL) is a neoplasm of precursor lymphoid cells known as lymphoblasts. ALL is the most common cancer in children. The prognosis among Adolescents and young adults (AYA) is intermediate between children, who have a very good prognosis with a 5-year survival rate of 80%, and adults, who have a worse prognosis with an overall survival of about 30–50%. We found no studies in Saudi Arabia which assessed the use of a Berlin-Frankfurt-Muenster (BFM) to treat patients in the AYA group. The purpose of this study is to measure the outcome and toxicities of the BFM protocol used in treatment of ALL patients in the AYA population seeking treatment at Princess Noorah Oncology Center (PNOC), at the National Guard Hospital, Jeddah, Saudi Arabia. PNOC is a tertiary referral center for the Western region of the Kingdom of Saudi Arabia. Patients referred between the ages of 14 to 25 were treated according to an augmented modified version of the Berlin-Frankfurt-Muenster (BFM) protocol. Patients' treatments were based on risk factor stratification. High risk category was identified based on the presence of one of following factors: phenotype of the leukemia (i.e. T-cell ALL is considered high risk), lack of response to therapy on day 29 of induction, cytogenetics, presence of extramedullary disease e.g. testicular or CNS disease and whether they have received steroid treatment prior to the first diagnostic marrow. High risk group was treated with doubled blocks of interim maintenance, delayed intensification the first of delayed intensification blocks included a high dose methotrexate at the dose of 5g/m2 which was first started at our center in 2008. Methodology: This study is a retrospective chart review. Patients who met the inclusion criteria within the last five years were included. The inclusion criteria were those with confirmed ALL (excluding mature B cell phenotype) aged between 14 to 25 years, and were treated with the Modified Augmented Berlin-Frankfurt-Muenster (ABFM) therapy protocol. 45 patients were indentified who fulfilled the above criteria 4 were excluded due to the lack of data and loss to follow up. Data were analyzed using SPSS version 19. Results: The mean age of 41 patients treated was 16.4 years (range; 14 – 25 years). Of 41 patients treated, 23 (56%) were males. Only one patient (2%) had CNS involvement at presentation. B cell ALL compromised 61% of the patients while 39% were T cell ALL. All 41 (100%) patients achieved complete remission after induction therapy however two patients (5%) required extended induction to achieve a complete remission status. Five (12.2%) patients relapsed at a median follow up of 30 months. Two (4.9%) patients died while in complete remission from treatment related causes. The probability of Overall Survival (OS) is 95.1% and 87.8% at 2 and 3 years, respectively. The probability of Event-free Survival (EFS) of our 41 patients is 90.2% and 82.9% at 2 and 3 years respectively. Thirty three (81%) patients developed febrile neutropenia with a total of 50 documented episodes. Thirty two (64%) of the febrile neutropenia episodes occurred during induction and re-intensification phases those two blocks were associated with a statistically significant increased risk of neutropenia (P < 0.001)compared to other blocks. Five (12%) of patients developed fungal infections there is one patient who developed two separate episodes of fungal infection. Four fungal infection episodes occurred during induction and re-intensification phases which constituted the highest risk phases for the development of fungal infections. In 38% of febrile neutropenic episodes an infectious agent was identified in 8% of episodes the isolate was a fungus. Eight patients (20%) developed Venous Thromboembolism (VTE) with a total of 9 episodes. Discussion & Conclusion: In our study population the OS & EFS were comparable to other reported groups despite the relatively increased numbers of T cell ALL (39%) patients compared to the reported average of 15–25%. The reported incidence of VTE is similar to the incidence reported by other groups while the incidence of fungal infections is relatively more than we would have expected. Complete remissions, survival, relapse and death rates are comparable to international studies. However new measures are required to lower the increased rates of fungal infections & VTE for future patients. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Factors Predicting Outcome after Allogeneic Stem Cell Transplantation in Primary Refractory Acute Myeloid Leukemia: A Retrospective Analysis of the Gruppo Italiano Trapianto Di Midollo Osseo (GITMO)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 731-731
Author(s):  
Elisabetta Todisco ◽  
Fabio Ciceri ◽  
Boschini Cristina ◽  
Fabio Giglio ◽  
Andrea Bacigalupo ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Median Time ◽  
Myeloid Leukemia ◽  
Cell Depletion ◽  
Unrelated Donor ◽  
T Cell Depletion

Abstract Background The outcome of primary refractory (PRF) acute myeloid leukemia (AML) patients is poor with a minor proportion rescued by allogeneic hematopoietic stem cell transplantation (HSCT). The identification of pre-HSCT variables may help to identify PRF AML most likely to benefit from HSCT. The EBMT group reported factors predicting the outcome of 168 patients with PRF AML receiving an unrelated donor stem cell transplantation; 5-years OS was 22% and factors associated to an improved survival were the numbers of chemotherapy cycles (< 3), bone marrow blast infiltration <38% and patient CMVseropositivity. These clinical findings allowed to define 4 prognostic groups with survival rates ranging between 44% and 0% {Craddock, 2011). We performed a similar analysis focusing on PRF AML patients transplanted in Italy between 1999-2012 with a stem cell graft obtained by a sibling, unrelated donor and cord blood unit. Patients and study design We analyzed the clinical outcome of 242 patients transplanted in 26 GITMO centers. Patients disease status at HCST included PRF AML defined as failure to achieve a complete response (CR) after one or more chemotherapy cycles containing active drugs on AML. The cytogenetic and molecular risk was defined according to the European LeukemiaNet. The main clinical and outcome follow up data were retrieved from the GITMO database. The main end-points of the study were overall survival (OS) and leukemia-free survival (LFS). Results The median age at HSCT was 49 years (18-72) and 55% of patients were male. Before HSCT, 58% received ≤ 2 chemotherapy cycles. Median time from diagnosis to HSCT was 6 months (1-19) and in 85% was ≥ 3 months. An intermediate-II/adverse karyotype was detected in 58% of patients, > 25% marrow blast infiltration or any level of peripheral blood (PB) blasts was found in 60% and a pre-HSCT Karnofsky score < 90 was present in 43%. Donors were HLA identical sibling in 48% and matched unrelated in 19%, related mismatched in 19%, unrelated mismatched in 3% and cord blood in 11%. Anti-CMV antibodies were present in 87% of patients and in 65% of the donors. Conditioning regimen intensity was myeloablative or reduced in 69% and 31%, respectively; 49% of patients received T cell depletion (92% in vivo and 8% ex vivo). Neutrophils and platelets engraftment was achieved in 87% of patients after a median of 17 (9-52) and 17 (3-150) days, respectively. In all, 35 (14%) patients died within 30 days from HSCT. Of 207 patients evaluable for response, 138 (66%) achieved CR after a median time of 32 days (range 16-130) from HSCT and 69 did not (33%). Median survival of patient who achieved CR was 10 months while it was 2 months for those who did not. Seventy patients (51%) relapsed after a median time of 3 months (1-31), 64 died of disease, 6 survived and 2 of these latter reachieved CR. Sixty-eight patients (49%) maintained CR, 34(50%) died and 34 survived. A t the last follow up 42 patients were alive, 36 in CR and 6 with disease with a median follow up of 27 months (range 1,8-14). The median OS of the whole patient cohort was 5,7 months. At 3-years, the OS and LFS was 15% and 23% respectively. AGvHD was registered in 39% of patients (grade > 2 in 30% of cases) while cGVHD occurred in 29% (extended in 44% of cases). The 3-years cumulative incidence of NRM was 17%. By univariate analysis, the number of chemotherapy cycles to achieve CR (≤ 2), the time to HSCT (< 3 months), the cytogenetics risk favorable/intermediate I, the number of marrow blasts < 25% or the absence of blasts in the peripheral blood, the PS ≥ 90 and the lack of any form of T cell depletion, were all associated to a better survival. By multivariate analysis, the number of chemotherapy cycles, (Hazard Ratio (HR): 1.51; 95% confidence interval (CI): 1.04–2.19; P=0.029), the lack of T cell depletion (HR: 1.66; 95% CI: 1.15–2.40; P=0.007), the degree of BM or PB blast infiltration (HR: 1.59; 95% CI: 1.01–2.25; P=0.043), and the PS (HR: 1.46; 95% CI: 1.00–2.14; P=0.048) remained significantly associated with survival. On the basis of this multivariate analysis, we set up a new score predicting a different 3 years OS: score 0 (0 or 1 adverse prognostic factor, with 28% survival), score 1 (2 adverse prognostic factor, 17% survival); score 2 (2 or 3 adverse prognostic factors, 10% survival) (Figure 1) Conclusion The clinical outcome of PRF AML remains poor. The new simple clinical GITMO score helps indentifying patients most likely will benefit or not from the HSCT. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Improved Long Term Survival with Minimal GVHD after Myeloablative Unrelated Donor Stem Cell Transplantation Using In Vitro and In Vivo T Cell Depletion with CAMPATH-1H.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2761-2761
Author(s):  
Peter A. von dem Borne ◽  
Floor Beaumont ◽  
Ingrid Starrenburg ◽  
Machteld A. Oudshoorn ◽  
Geoff Hale ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Cell Depletion ◽  
Unrelated Donor ◽  
T Cell Depletion ◽  
Related Mortality

Abstract In allogeneic stem cell transplantation (SCT) T-cell depletion reduces transplant related mortality by diminishing GVHD. We have investigated a myeloablative regimen for matched unrelated donor SCT using both in vivo and in vitro CAMPATH-1H for effective T-cell depletion, utilising DLI at a later time point for graft versus tumor effect if necessary. Thirty patients (median age 33 years, range 18–48) were transplanted from January 1997 to June 2002. Diagnoses were: CML CP (n=9), CML AP (n=2), AML/MDS (n=9), ALL (n=8), NHL (n=1) and Fanconi anemia (n=1). Six patients had one HLA mismatch, the others were identical for HLA A, B, C, DR and DQ. Conditioning consisted of CAMPATH-1H 5mg/d on days −8 to −4, TBI 6 Gy on days −8 and −7 and cyclofosfamide 60 mg/kg on days −6 and −5. T-cell depletion was performed by in vitro incubation of the graft with 20 mg CAMPATH-1H for 30 minutes (Campath “in the bag”). Post-transplant GVHD prophylaxis consisted of cyclosporine A and methotrexate. The stem cell source was bone marrow in 19 patients (63%) and peripheral blood in 11 patients. One graft failure was observed, all other patients had sustained engraftment of donor cells. Acute GVHD was observed in 12 patients (40%), maximally grade I-II skin. No severe acute GVHD (grade III-IV) was experienced. Limited chronic GVHD developed in 2 patients, resolving after treatment. Only in one patient extensive chronic GVHD developed, which did not resolve. CMV reactivation occurred in 23% of patients, one patient developed CMV disease. No EBV disease was observed. Ten patients received donor lymphocyte infusion (DLI) at a median of 17.4 months after SCT (8 patients with relapsed CML, one patient with relapsed ALL, one patient with autoimmune hemolytic anemia). After DLI acute GVHD grade I-II developed in 4 patients, and GVHD grade III-IV in 3. Chronic GVHD developed in 5 patients, of which 2 extensive, resolving in all except one patient. With a median follow up of 37 (range 21–84) months 17 patients are alive (57%). One of the CML patients shows persistence of molecular disease not responding to increasing doses of DLI. All other patients are in CR with the CML patients in molecular remission. Five patients (17%) died because of relapsed disease (2 AML/MDS and 3 ALL). Treatment related mortality was 26% (1 rejection, 2 GVHD, 1 myocardial infarction, 4 infections). In conclusion, matched unrelated donor SCT following myeloablative conditioning using T-cell depletion with CAMPATH-1H in vivo as well as in vitro results in good engraftment, minimal grade I-II GVHD and an overall survival of 57%. Relapse rate was not increased with this strategy. This regimen appears to be successful for young adults with high-risk malignancies.

scholarly journals A Modified CALGB-10403 in Hispanic Adolescent and Young Adults with Philadelphia -Negative Acute Lymphoblastic Leukemia: Promising Results Despite a High-Rate of Metabolic and Hepatic Toxicities

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1352-1352
Author(s):  
Juan Rangel-Patiño ◽  
Alvaro Cabrero Garcia ◽  
Carolina Balderas-Delgado ◽  
Lauro Fabian Amador ◽  
Yvette Neme Yunes ◽  
...  
Keyword(s):  
Overall Survival ◽  
Young Adults ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
B Cell ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
High Rate ◽  
Related Mortality

Background: Acute lymphoblastic leukemia (ALL) represents 51% of acute leukemias in adults in Mexico. Poor outcomes have been reported, with a 3-year overall survival (OS) of 25.7% in the group of adolescents and young adults (AYA). In ALL, Hispanic ethnicity has been associated with more high-risk features and more treatment-related toxicity. Recently the results of the pediatric-inspired regimen CALGB 10403 in AYA ALL-patients have been published with encouraging results. We modified the original regimen based on the drug-access in Mexico and we incorporate Rituximab in CD20 positive patients. Methods We included patients with newly diagnosed B- or T-cell ALL between 17 and 45 years. Patients with Philadelphia chromosome-ALL were excluded. We enrolled patients from 4 centers in Mexico. We replicated the CALGB 10403 protocol, with the following modifications: replaced pegaspargase (2,500 IU/m2) with E. Coli asparaginase (6,000 IU/m2/day for 6 doses in alternate days). During the delayed intensification we replaced thioguanine 60mg/m2/day with 6-mercapatopurine 60mg/m2/day. We incorporated rituximab 375mg/m2 at D1 and D29 during remission consolidation, D1 and D21 in interim maintenance and D1, D29 and D50 in delayed intensification. The central nervous system (CNS) prophylaxis was given as a triple-drug (methotrexate 12.5mg, cytarabine 60mg and dexamethasone 8mg), with a total of 11 intratecal administrations, 7 during the induction/consolidation courses and 4 during maintenance. Minimal residual disease (MRD) was assessed by flow cytometry after induction and after first consolidation. The aims of this study were to evaluate complete response (CR) rate, progression-free survival (PFS), overall survival (OS), and to assess the safety of this regimen. Result From January 2017 to May 2019 thirty-eight patients (23 men, 15 women) have been enrolled. Median follow-up is 11 months (range 1-30). Median age is 23 years (range 18-41). The 100% of patients are of Hispanic ethnicity. Obesity (BMI≥30) was reported in 18%. Thirty patients had an evaluable karyotype: 83% were normal, and 13% with MLL-rearrangements. The majority were B-cell ALL (90%), and 10% were T-cell ALL. Median WBC was 19.5 x103/mcL (range: 0.7-427.7) and 32% had hyperleukocytosis. Among the B-cell ALL patients, 53% were CD20 positive. CNS disease was presented at diagnosis in only one patient (3%). Thirty-three patients (86%) achieved CR, thirty (81%) after the first induction and three after the extended induction therapy. There was only one death during induction therapy (2.6%). After induction, 41% had negative MRD (&lt;0.01%). Grade 3 /4 hepatic toxicity was reported in 58% patients, hyperglycemia in 24% and hypertriglyceridemia in 34%. The rest of toxicities are summarized in Table 1. During induction ten patients (19%) required dose adjustment because of toxicity. During consolidation, 42% required treatment modifications because of toxicity. After induction, we had no treatment-related mortality. At the last follow-up twenty-three patients continue in the protocol. Four patients already received Allo-SCT. The relapse-rate is 31.2% with half of these patients with CNS-disease at relapse. Nine patients have died: one during induction, six with progression or refractory disease and one after Allo-SCT. The 18-months PFS and OS rates were 80% and 84%, respectively. Median PFS is 23 months (CI 95% 17 to 29 months), and median OS was not been reached. Negative-MRD after induction was associated with excellent outcomes: 18-months OS 100% vs. 45.3%, p=0.008 (figure 1). Obesity was associated with worse OS (18-month 22% vs. 80%, p=0.03) and PFS (22% vs. 79.1%, p=0.026) Conclusion: Mexican patients treated with a modified CALGB 10403 protocol had similar response rates than reported in the original protocol but with more toxicity, mainly hepatic and metabolic. However, induction-related mortality was low and we had no treatment-related toxicity after induction. We presume that the high-rate of toxicities can be related with the genetic and environmental metabolic risk factors plenty described in our population. The modified CALGB showed encouraging results in this Hispanic population, hence we have to explore lower dose schedule based in patient characteristics and asparaginase levels. Disclosures Neme Yunes: Abbvie: Speakers Bureau; Janssen: Speakers Bureau; Novartis: Speakers Bureau. Demichelis:Abbvie: Speakers Bureau; Celgene: Speakers Bureau; AMGEN: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Shire: Speakers Bureau.

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