栗山一孝：急性白血病の診断アプローチ. 木崎昌弘編．白血病リンパ腫骨髄腫 今日の診断と治療 第4版．中外医学社, 2011； 98-105．
日本血液学会 日本リンパ網内系学会編：5. 急性リンパ性白血病．造血器腫瘍取り扱い規約 2010年3月第1版.金原出版, 2010； 36-39．
S B Murphy
Childhood non-Hodgkin's lymphoma.
N Engl J Med. 1978 Dec 28;299(26):1446-8. doi: 10.1056/NEJM197812282992606.
Abstract/Text
Steven H. Swerdlow, Elias Campo, at al：WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. WHO Classification of Tumours, Revised 4th Edition, Volume 2. World Health Organization, 2017.
Rita Alaggio, Catalina Amador, Ioannis Anagnostopoulos, Ayoma D Attygalle, Iguaracyra Barreto de Oliveira Araujo, Emilio Berti, Govind Bhagat, Anita Maria Borges, Daniel Boyer, Mariarita Calaminici, Amy Chadburn, John K C Chan, Wah Cheuk, Wee-Joo Chng, John K Choi, Shih-Sung Chuang, Sarah E Coupland, Magdalena Czader, Sandeep S Dave, Daphne de Jong, Ming-Qing Du, Kojo S Elenitoba-Johnson, Judith Ferry, Julia Geyer, Dita Gratzinger, Joan Guitart, Sumeet Gujral, Marian Harris, Christine J Harrison, Sylvia Hartmann, Andreas Hochhaus, Patty M Jansen, Kennosuke Karube, Werner Kempf, Joseph Khoury, Hiroshi Kimura, Wolfram Klapper, Alexandra E Kovach, Shaji Kumar, Alexander J Lazar, Stefano Lazzi, Lorenzo Leoncini, Nelson Leung, Vasiliki Leventaki, Xiao-Qiu Li, Megan S Lim, Wei-Ping Liu, Abner Louissaint, Andrea Marcogliese, L Jeffrey Medeiros, Michael Michal, Roberto N Miranda, Christina Mitteldorf, Santiago Montes-Moreno, William Morice, Valentina Nardi, Kikkeri N Naresh, Yasodha Natkunam, Siok-Bian Ng, Ilske Oschlies, German Ott, Marie Parrens, Melissa Pulitzer, S Vincent Rajkumar, Andrew C Rawstron, Karen Rech, Andreas Rosenwald, Jonathan Said, Clémentine Sarkozy, Shahin Sayed, Caner Saygin, Anna Schuh, William Sewell, Reiner Siebert, Aliyah R Sohani, Reuben Tooze, Alexandra Traverse-Glehen, Francisco Vega, Beatrice Vergier, Ashutosh D Wechalekar, Brent Wood, Luc Xerri, Wenbin Xiao
The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasms.
Leukemia. 2022 Jul;36(7):1720-1748. doi: 10.1038/s41375-022-01620-2. Epub 2022 Jun 22.
Abstract/Text
We herein present an overview of the upcoming 5th edition of the World Health Organization Classification of Haematolymphoid Tumours focussing on lymphoid neoplasms. Myeloid and histiocytic neoplasms will be presented in a separate accompanying article. Besides listing the entities of the classification, we highlight and explain changes from the revised 4th edition. These include reorganization of entities by a hierarchical system as is adopted throughout the 5th edition of the WHO classification of tumours of all organ systems, modification of nomenclature for some entities, revision of diagnostic criteria or subtypes, deletion of certain entities, and introduction of new entities, as well as inclusion of tumour-like lesions, mesenchymal lesions specific to lymph node and spleen, and germline predisposition syndromes associated with the lymphoid neoplasms.
© 2022. The Author(s).
S K Williford, P L Salisbury, J E Peacock, J M Cruz, B L Powell, E S Lyerly, R L Capizzi
The safety of dental extractions in patients with hematologic malignancies.
J Clin Oncol. 1989 Jun;7(6):798-802.
Abstract/Text
Dental disorders have been recognized as major sources of infection in patients with hematologic malignancies (HM). Management of severe dental infections usually includes dental extractions (DE), but the safety of extractions in patients with HM who are at risk for bleeding, sepsis, and poor wound healing has not been well established. In conjunction with an aggressive program of dental care, 142 DE were performed in 26 patients with acute leukemia, myelodysplastic syndromes, and myeloproliferative disorders. Granulocytopenia (less than 1,000 granulocytes/microL) was present during or within ten days following surgery in 14 patients. In these 14 patients (101 DE), the mean granulocyte count was less than 450/microL, with a median duration of granulocytopenia following surgery of 32 days (range, four to 169 days). Thrombocytopenia (less than 100,000 platelets/microL) occurred during or within two days following surgery in 13 patients (80 DE), with a mean platelet count of 63,500/microL. Transfusions were given for platelet counts less than 50,000/microL. All DE were performed without significant complications. Bleeding was minor to moderate and easily controlled with local measures; no patient required transfusion due to hemorrhage. Average maximum temperature 24 hours after DE was 37.7 degrees C. No episodes of bacteremia were documented within ten days of DE. Minor delay in wound healing was observed in two patients. We conclude that DE can be safely performed in patients with HM in combination with aggressive supportive care.
Jacob M Rowe, Georgina Buck, Alan K Burnett, Raj Chopra, Peter H Wiernik, Susan M Richards, Hillard M Lazarus, Ian M Franklin, Mark R Litzow, Niculae Ciobanu, H Grant Prentice, Jill Durrant, Martin S Tallman, Anthony H Goldstone, ECOG, MRC/NCRI Adult Leukemia Working Party
Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993.
Blood. 2005 Dec 1;106(12):3760-7. doi: 10.1182/blood-2005-04-1623. Epub 2005 Aug 16.
Abstract/Text
The international acute lymphoblastic leukemia (ALL) study was designed to prospectively define the optimal therapy for adults 60 years of age or younger with newly diagnosed ALL. All patients received identical induction therapy, and 91% achieved complete remission (CR). Patients 50 years of age or younger with a compatible sibling were assigned to undergo allogeneic transplantation; the others were randomly assigned to autologous transplantation or to consolidation/maintenance therapy for 2.5 years. Patients who did not achieve CR after induction had an overall survival rate of 5% compared with 45% for patients who achieved CR. Factors at diagnosis predictive of overall survival and disease-free survival were age (P = .001), white blood cell count less than 30 x 10(9)/L for B lineage or less than 100 x 10(9)/L for T lineage (P = .001) and immunophenotype, T lineage versus B lineage (P = .001). The data demonstrate that achieving CR with induction therapy is indispensable for long-term survival in adult patients with ALL. Furthermore, with a response rate greater than 90%, the induction regimen was highly efficacious as remission-inducing therapy. This large database has validated several previously identified independent prognostic factors in ALL, such as age, white blood cell count at presentation, cytogenetics, and immunophenotype. However, the achievement of CR within 4 weeks does not appear to be an independent prognostic factor.
Anthony V Moorman, Christine J Harrison, Georgina A N Buck, Sue M Richards, Lorna M Secker-Walker, Mary Martineau, Gail H Vance, Athena M Cherry, Rodney R Higgins, Adele K Fielding, Letizia Foroni, Elisabeth Paietta, Martin S Tallman, Mark R Litzow, Peter H Wiernik, Jacob M Rowe, Anthony H Goldstone, Gordon W Dewald, Adult Leukaemia Working Party, Medical Research Council/National Cancer Research Institute
Karyotype is an independent prognostic factor in adult acute lymphoblastic leukemia (ALL): analysis of cytogenetic data from patients treated on the Medical Research Council (MRC) UKALLXII/Eastern Cooperative Oncology Group (ECOG) 2993 trial.
Blood. 2007 Apr 15;109(8):3189-97. doi: 10.1182/blood-2006-10-051912. Epub 2006 Dec 14.
Abstract/Text
Pretreatment cytogenetics is a known predictor of outcome in hematologic malignancies. However, its usefulness in adult acute lymphoblastic leukemia (ALL) is generally limited to the presence of the Philadelphia (Ph) chromosome because of the low incidence of other recurrent abnormalities. We present centrally reviewed cytogenetic data from 1522 adult patients enrolled on the Medical Research Council (MRC) UKALLXII/Eastern Cooperative Oncology Group (ECOG) 2993 trial. The incidence and clinical associations for more than 20 specific chromosomal abnormalities are presented. Patients with a Ph chromosome, t(4;11)(q21;q23), t(8;14)(q24.1;q32), complex karyotype (5 or more chromosomal abnormalities), or low hypodiploidy/near triploidy (Ho-Tr) all had inferior rates of event-free and overall survival when compared with other patients. In contrast, patients with high hyperdiploidy or a del(9p) had a significantly improved outcome. Multivariate analysis demonstrated that the prognostic relevance of t(8;14), complex karyotype, and Ho-Tr was independent of sex, age, white cell count, and T-cell status among Ph-negative patients. The observation that Ho-Tr and, for the first time, karyotype complexity confer an increased risk of treatment failure demonstrates that cytogenetic subgroups other than the Ph chromosome can and should be used to risk stratify adults with ALL in future trials.
Ching-Hon Pui, William E Evans
Treatment of acute lymphoblastic leukemia.
N Engl J Med. 2006 Jan 12;354(2):166-78. doi: 10.1056/NEJMra052603.
Abstract/Text
J Takeuchi, T Kyo, K Naito, H Sao, M Takahashi, S Miyawaki, K Kuriyama, S Ohtake, F Yagasaki, H Murakami, N Asou, T Ino, T Okamoto, N Usui, M Nishimura, K Shinagawa, T Fukushima, H Taguchi, T Morii, S Mizuta, H Akiyama, Y Nakamura, T Ohshima, R Ohno
Induction therapy by frequent administration of doxorubicin with four other drugs, followed by intensive consolidation and maintenance therapy for adult acute lymphoblastic leukemia: the JALSG-ALL93 study.
Leukemia. 2002 Jul;16(7):1259-66. doi: 10.1038/sj.leu.2402526.
Abstract/Text
In order to improve the disappointing prognosis of adult patients with acute lymphoblastic leukemia (ALL), we applied similar induction therapy as that used for acute myeloid leukemia (AML), ie frequent administration of doxorubicin (DOX). DOX 30 mg/m(2) was administered from days 1 to 3 and from days 8 to 10 together with vincristine, prednisolone, cyclophosphamide and L-asparaginase, followed by three courses of consolidation and four courses of intensification. From December 1993 to February 1997, 285 untreated adult patients with de novo ALL were entered. Of 263 evaluable patients (age 15 to 59; median 31), 205 (78%) obtained complete remission (CR). At a median follow-up period of 63 months, the predicted 6-year overall survival (OS) rate of all patients was 33%, and disease-free survival (DFS) rate of CR patients was 30%, respectively. By multivariate analysis, favorable prognostic factors for the achievement of CR were age <40 and WBC <50 000/microl; for longer OS were age <30 and WBC <30 000/microl; and for longer DFS of CR patients were FAB L1 and ALT <50 IU/l. Among 229 patients who had adequate cytogenetic data, 51 (22%) had Philadelphia (Ph) chromosome. Ph-negative chromosome was a common favorable prognostic factor for CR, longer OS and DFS. DFS was not different between early sequential intensification (n = 48) and intermittent intensification (n = 43) during the maintenance phase. Among CR patients under 40 years old, the 6-year survival was not different between the allocated related allo-BMT group (34 patients) and the allocated chemotherapy group (108 patients). However, among patients with Ph-positive ALL, the survival of patients who actually received allo-BMT was superior to that of patients who received chemotherapy (P = 0.046).
Itsuro Jinnai, Tohru Sakura, Motohiro Tsuzuki, Yasuhiro Maeda, Noriko Usui, Masayuki Kato, Hirokazu Okumura, Taiichi Kyo, Yasunori Ueda, Yuji Kishimoto, Fumiharu Yagasaki, Kosuke Tsuboi, Shigeo Horiike, Jin Takeuchi, Masako Iwanaga, Yasushi Miyazaki, Shuichi Miyawaki, Kazunori Ohnishi, Tomoki Naoe, Ryuzo Ohno
Intensified consolidation therapy with dose-escalated doxorubicin did not improve the prognosis of adults with acute lymphoblastic leukemia: the JALSG-ALL97 study.
Int J Hematol. 2010 Oct;92(3):490-502. doi: 10.1007/s12185-010-0672-z. Epub 2010 Sep 10.
Abstract/Text
We designed a treatment protocol for newly diagnosed adult acute lymphoblastic leukemia (ALL) in the pre-imatinib era, employing intensified consolidation therapy with a total of 330 mg/m² doxorubicin and adopting slightly modified induction and maintenance regimen of the CALGB 8811 study. Of 404 eligible patients (median age 38 years, range 15-64 years), 298 (74%) achieved complete remission (CR). The 5-year overall survival (OS) rate was 32%, and the 5-year disease-free survival (DFS) rate was 33%. Of 256 Philadelphia chromosome (Ph)-negative patients, 208 (81%) achieved CR and the 5-year OS rate was 39%, and 60 of them underwent allogeneic-hematopoietic stem cell transplantation (allo-HSCT) from related or unrelated donors during the first CR, resulting in 63% 5-year OS. Of 116 Ph-positive patients, 65 (56%) achieved CR and the 5-year OS rate was 15%, and 22 of them underwent allo-HSCT from related or unrelated donors during the first CR, resulting in 47% 5-year OS. In Ph-negative patients, multivariate analysis showed that older age, advanced performance status and unfavorable karyotypes were significant poor prognostic factors for OS and higher WBC counts for DFS. The present treatment regimen could not show a better outcome than that of our previous JALSG-ALL93 study for adult ALL.
Oliver G Ottmann, Barbara Wassmann
Treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia.
Hematology Am Soc Hematol Educ Program. 2005;:118-22. doi: 10.1182/asheducation-2005.1.118.
Abstract/Text
Philadelphia chromosome positive (Ph(+)) acute lymphoblastic leukemia (ALL) includes at least one-quarter of all adults with ALL. Until recently, conventional chemotherapy programs that have been effective in other precursor B-cell ALL cases have been unable to cure patients with this diagnosis. Allogeneic stem cell transplantation early in first remission has been the recommended therapy. The availability of imatinib mesylate and other tyrosine kinase inhibitors and small molecules that affect the BCR/ABL signaling pathways may be changing the treatment paradigm and the prognosis for these patients. The results from clinical trials using imatinib in the frontline setting and in relapsed patients as well as preliminary experience treating imatinib-resistant Ph(+) ALL will be described.
薄井紀子: Philadelphia染色体陽性急性リンパ芽球性白血病の新たな治療戦略. 臨床血液 2006；47:294-302．
Donald A Berry, Shouhao Zhou, Howard Higley, Lata Mukundan, Shuangshuang Fu, Gregory H Reaman, Brent L Wood, Gary J Kelloff, J Milburn Jessup, Jerald P Radich
Association of Minimal Residual Disease With Clinical Outcome in Pediatric and Adult Acute Lymphoblastic Leukemia: A Meta-analysis.
JAMA Oncol. 2017 Jul 13;3(7):e170580. doi: 10.1001/jamaoncol.2017.0580. Epub 2017 Jul 13.
Abstract/Text
IMPORTANCE: Minimal residual disease (MRD) refers to the presence of disease in cases deemed to be in complete remission by conventional pathologic analysis. Assessing the association of MRD status following induction therapy in patients with acute lymphoblastic leukemia (ALL) with relapse and mortality may improve the efficiency of clinical trials and accelerate drug development.
OBJECTIVE: To quantify the relationships between event-free survival (EFS) and overall survival (OS) with MRD status in pediatric and adult ALL using publications of clinical trials and other databases.
DATA SOURCES: Clinical studies in ALL identified via searches of PubMed, MEDLINE, and clinicaltrials.gov.
STUDY SELECTION: Our search and study screening process adhered to the PRISMA Guidelines. Studies that addressed EFS or OS by MRD status in patients with ALL were included; reviews, abstracts, and studies with fewer than 30 patients or insufficient MRD description were excluded.
DATA EXTRACTION AND SYNTHESIS: Study sample size, patient age, follow-up time, timing of MRD assessment (postinduction or consolidation), MRD detection method, phenotype/genotype (B cell, T cell, Philadelphia chromosome), and EFS and OS. Searches of PubMed and MEDLINE identified 566 articles. A parallel search on clinicaltrials.gov found 67 closed trials and 62 open trials as of 2014. Merging results of 2 independent searches and applying exclusions gave 39 publications in 3 arms of patient populations (adult, pediatric, and mixed). We performed separate meta-analyses for each of these 3 subpopulations.
RESULTS: The 39 publications comprised 13 637 patients: 16 adult studies (2076 patients), 20 pediatric (11 249 patients), and 3 mixed (312 patients). The EFS hazard ratio (HR) for achieving MRD negativity is 0.23 (95% Bayesian credible interval [BCI] 0.18-0.28) for pediatric patients and 0.28 (95% BCI, 0.24-0.33) for adults. The respective HRs in OS are 0.28 (95% BCI, 0.19-0.41) and 0.28 (95% BCI, 0.20-0.39). The effect was similar across all subgroups and covariates.
CONCLUSIONS AND RELEVANCE: The value of having achieved MRD negativity is substantial in both pediatric and adult patients with ALL. These results are consistent across therapies, methods of and times of MRD assessment, cutoff levels, and disease subtypes. Minimal residual disease status warrants consideration as an early measure of disease response for evaluating new therapies, improving the efficiency of clinical trials, accelerating drug development, and for regulatory approval. A caveat is that an accelerated approval of a particular new drug using an intermediate end point, such as MRD, would require confirmation using traditional efficacy end points.
Nicola Gökbuget, Michael Kneba, Thorsten Raff, Heiko Trautmann, Claus-Rainer Bartram, Renate Arnold, Rainer Fietkau, Mathias Freund, Arnold Ganser, Wolf-Dieter Ludwig, Georg Maschmeyer, Harald Rieder, Stefan Schwartz, Hubert Serve, Eckhard Thiel, Monika Brüggemann, Dieter Hoelzer, German Multicenter Study Group for Adult Acute Lymphoblastic Leukemia
Adult patients with acute lymphoblastic leukemia and molecular failure display a poor prognosis and are candidates for stem cell transplantation and targeted therapies.
Blood. 2012 Aug 30;120(9):1868-76. doi: 10.1182/blood-2011-09-377713. Epub 2012 Mar 22.
Abstract/Text
Quantification of minimal residual disease (MRD) by real-time PCR directed to TCR and Ig gene rearrangements allows a refined evaluation of response in acute lymphoblastic leukemia (ALL). The German Multicenter Study Group for Adult ALL prospectively evaluated molecular response after induction/consolidation chemotherapy according to standardized methods and terminology in patients with Philadelphia chromosome-negative ALL. The cytologic complete response (CR) rate was 89% after induction phases 1 and 2. At this time point the molecular CR rate was 70% in 580 patients with cytologic CR and evaluable MRD. Patients with molecular CR after consolidation had a significantly higher probability of continuous complete remission (CCR; 74% vs 35%; P < .0001) and of overall survival (80% vs 42%; P = .0001) compared with patients with molecular failure. Patients with molecular failure without stem cell transplantation (SCT) in first CR relapsed after a median time of 7.6 months; CCR and survival at 5 years only reached 12% and 33%, respectively. Quantitative MRD assessment identified patients with molecular failure as a new high-risk group. These patients display resistance to conventional drugs and are candidates for treatment with targeted, experimental drugs and allogeneic SCT. Molecular response was shown to be highly predictive for outcome and therefore constitutes a relevant study end point. The studies are registered at www.clinicaltrials.gov as NCT00199056 and NCT00198991.
T Sakura, F Hayakawa, I Sugiura, T Murayama, K Imai, N Usui, S Fujisawa, T Yamauchi, T Yujiri, K Kakihana, Y Ito, H Kanamori, Y Ueda, Y Miyata, M Kurokawa, N Asou, K Ohnishi, S Ohtake, Y Kobayashi, K Matsuo, H Kiyoi, Y Miyazaki, T Naoe
High-dose methotrexate therapy significantly improved survival of adult acute lymphoblastic leukemia: a phase III study by JALSG.
Leukemia. 2018 Mar;32(3):626-632. doi: 10.1038/leu.2017.283. Epub 2017 Sep 15.
Abstract/Text
High-dose methotrexate (Hd-MTX) therapy has recently been applied to the treatment of adult acute lymphoblastic leukemia (ALL) based on pediatric protocols; however, its effectiveness for adult ALL has not yet been confirmed in a rigorous manner. We herein conducted a randomized phase III trial comparing Hd-MTX therapy with intermediate-dose (Id)-MTX therapy. This study was registered at UMIN-CTR (ID: C000000063). Philadelphia chromosome (Ph)-negative ALL patients aged between 25 and 64 years of age were enrolled. Patients who achieved complete remission (CR) were randomly assigned to receive therapy containing Hd-MTX (3 g/m2) or Id-MTX (0.5 g/m2). A total of 360 patients were enrolled. The CR rate was 86%. A total of 115 and 114 patients were assigned to the Hd-MTX and Id-MTX groups, respectively. The estimated 5-year disease-free survival rate of the Hd-MTX group was 58%, which was significantly better than that of the Id-MTX group at 32% (P=0.0218). The frequencies of severe adverse events were not significantly different. We herein demonstrated the effectiveness and safety of Hd-MTX therapy for adult Ph-negative ALL. Our results provide a strong rationale for protocols containing Hd-MTX therapy being applied to the treatment of adult ALL.
Masamitsu Yanada, Jin Takeuchi, Isamu Sugiura, Hideki Akiyama, Noriko Usui, Fumiharu Yagasaki, Tohru Kobayashi, Yasunori Ueda, Makoto Takeuchi, Shuichi Miyawaki, Atsuo Maruta, Nobuhiko Emi, Yasushi Miyazaki, Shigeki Ohtake, Itsuro Jinnai, Keitaro Matsuo, Tomoki Naoe, Ryuzo Ohno, Japan Adult Leukemia Study Group
High complete remission rate and promising outcome by combination of imatinib and chemotherapy for newly diagnosed BCR-ABL-positive acute lymphoblastic leukemia: a phase II study by the Japan Adult Leukemia Study Group.
J Clin Oncol. 2006 Jan 20;24(3):460-6. doi: 10.1200/JCO.2005.03.2177. Epub 2005 Dec 12.
Abstract/Text
PURPOSE: A novel therapeutic approach is urgently needed for BCR-ABL-positive acute lymphoblastic leukemia (ALL). In this study, we assessed the efficacy and feasibility of chemotherapy combined with imatinib.
PATIENTS AND METHODS: A phase II study of imatinib-combined chemotherapy was conducted for newly diagnosed BCR-ABL-positive ALL in adults. Eighty patients were entered into the trial between September 2002 and January 2005.
RESULTS: Remission induction therapy resulted in complete remission (CR) in 77 patients (96.2%), resistant disease in one patient, and early death in two patients, as well as polymerase chain reaction negativity of bone marrow in 71.3%. The profile and incidence of severe toxicity were not different from those associated with our historic chemotherapy-alone regimen. Relapse occurred in 20 patients after median CR duration of 5.2 months. Allogeneic hematopoietic stem-cell transplantation (HSCT) was performed for 49 patients, 39 of whom underwent transplantation during their first CR. The 1-year event-free and overall survival (OS) rates were estimated to be 60.0%, and 76.1%, respectively, which were significantly better than those for our historic controls treated with chemotherapy alone (P < .0001 for both). Among the current trial patients, the probability for OS at 1 year was 73.3% for those who underwent allogeneic HSCT, and 84.8% for those who did not.
CONCLUSION: Our results demonstrated that imatinib-combined regimen is effective and feasible for newly diagnosed BCR-ABL-positive ALL. Despite a relatively short period of observation, a major potential of this treatment is recognized. Longer follow-up is required to determine its overall effect on survival.
Deborah A Thomas, Stefan Faderl, Jorge Cortes, Susan O'Brien, Francis J Giles, Steven M Kornblau, Guillermo Garcia-Manero, Michael J Keating, Michael Andreeff, Sima Jeha, Miloslav Beran, Srdan Verstovsek, Sherry Pierce, Laurie Letvak, August Salvado, Richard Champlin, Moshe Talpaz, Hagop Kantarjian
Treatment of Philadelphia chromosome-positive acute lymphocytic leukemia with hyper-CVAD and imatinib mesylate.
Blood. 2004 Jun 15;103(12):4396-407. doi: 10.1182/blood-2003-08-2958. Epub 2003 Oct 9.
Abstract/Text
Imatinib mesylate, an inhibitor of the Bcr-Abl tyrosine kinase, has modest activity in refractory/relapsed Philadelphia chromosome (Ph)-positive acute lymphocytic leukemia (ALL). Use of concurrent chemotherapy and imatinib mesylate in newly diagnosed Ph-positive ALL was explored. There were 20 patients who received hyper-CVAD (cyclophosphamide, vincristine, Adriamycin, and dexamethasone) and imatinib mesylate followed by imatinib mesylate-based consolidation/maintenance therapy. Of these patients, 11 had de novo disease, 4 were primary failures after induction (without imatinib mesylate), and 5 were in complete remission (CR) after induction (without imatinib mesylate). All 15 patients treated for active disease achieved CR. Within a median of 3.5 months in first CR, 10 patients underwent allogeneic stem cell transplantation (SCT). One patient relapsed after matched related SCT. The other 9 patients remained alive in CR with median follow-up of 12 months after SCT (range, 1+ to 17+ months). Among 10 patients ineligible for (no donor or older age) or refusing allogeneic SCT, 1 patient relapsed after one year. There were 5 patients who remained alive in continuous CR for a median of 20 months (range, 4+ to 24+ months), with 2 older patients dying in CR at 15 and 16 months of comorbid conditions. Molecular CRs were achieved in both groups (SCT or no SCT). Outcome with hyper-CVAD and imatinib mesylate appears better than with prior regimens; continued accrual and longer follow-up of the current cohort is needed.
Isamu Sugiura, Noriko Doki, Tomoko Hata, Ryuko Cho, Toshiro Ito, Youko Suehiro, Masatsugu Tanaka, Shinichi Kako, Mitsuhiro Matsuda, Hisayuki Yokoyama, Yuichi Ishikawa, Yasuhiro Taniguchi, Maki Hagihara, Yukiyasu Ozawa, Yasunori Ueda, Daiki Hirano, Toru Sakura, Masaaki Tsuji, Tsuyoshi Kamae, Hiroyuki Fujita, Nobuhiro Hiramoto, Masahiro Onoda, Shin Fujisawa, Yoshihiro Hatta, Nobuaki Dobashi, Satoshi Nishiwaki, Yoshiko Atsuta, Yukio Kobayashi, Fumihiko Hayakawa, Shigeki Ohtake, Tomoki Naoe, Yasushi Miyazaki
Dasatinib-based 2-step induction for adults with Philadelphia chromosome-positive acute lymphoblastic leukemia.
Blood Adv. 2022 Jan 25;6(2):624-636. doi: 10.1182/bloodadvances.2021004607.
Abstract/Text
The standard treatment for adults with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) in Japan is imatinib-based chemotherapy followed by allogeneic hematopoietic stem cell transplantation (HSCT). However, ∼40% of patients cannot undergo HSCT in their first complete remission (CR1) because of chemotherapy-related toxicities or relapse before HSCT or older age. In this study, we evaluated dasatinib-based 2-step induction with the primary end point of 3-year event-free survival (EFS). The first induction (IND1) was dasatinib plus prednisolone to achieve CR, and IND2 was dasatinib plus intensive chemotherapy to achieve minimal residual disease (MRD) negativity. For patients who achieved CR and had an appropriate donor, HSCT during a consolidation phase later than the first consolidation, which included high-dose methotrexate, was recommended. Patients with pretransplantation MRD positivity were assigned to receive prophylactic dasatinib after HSCT. All 78 eligible patients achieved CR or incomplete CR after IND1, and 52.6% achieved MRD negativity after IND2. Nonrelapse mortality (NRM) was not reported. T315I mutation was detected in all 4 hematological relapses before HSCT. Fifty-eight patients (74.4%) underwent HSCT in CR1, and 44 (75.9%) had negative pretransplantation MRD. At a median follow-up of 4.0 years, 3-year EFS and overall survival were 66.2% (95% confidence interval [CI], 54.4-75.5) and 80.5% (95% CI, 69.7-87.7), respectively. The cumulative incidence of relapse and NRM at 3 years from enrollment were 26.1% and 7.8%, respectively. Dasatinib-based 2-step induction was demonstrated to improve 3-year EFS in Ph+ ALL. This study was registered in the UMIN Clinical Trial Registry as #UMIN000012173.
© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.
Juan-Manuel Sancho, Josep-Maria Ribera, Albert Oriol, Jesus-Maria Hernandez-Rivas, Concepcion Rivas, Concepcion Bethencourt, Ricardo Parody, Guillermo Deben, Jose-Luis Bello, Evarist Feliu, Programa para el Estudio y Tratamiento de Hemopatias Malignas Group
Central nervous system recurrence in adult patients with acute lymphoblastic leukemia: frequency and prognosis in 467 patients without cranial irradiation for prophylaxis.
Cancer. 2006 Jun 15;106(12):2540-6. doi: 10.1002/cncr.21948.
Abstract/Text
Recurrence of acute lymphoblastic leukemia (ALL) in the central nervous system (CNS) confers a poor prognosis, although to the authors' knowledge, only a few studies have analyzed this issue in adults. For the current study, the authors analyzed the frequency, predictive factors, and prognosis of CNS involvement and recurrence in adult patients with ALL who did not receive cranial irradiation for CNS prophylaxis. Four hundred sixty-seven adult patients (age > or = 15 years) with ALL were treated on 4 protocols: ALL-89 (standard-risk and high-risk ALL; n = 108 patients), ALL-93 (high-risk ALL; n = 222 patients), ALL-96 (standard-risk ALL; n = 84 patients), and ALL3-97 (Burkitt leukemia; n = 53 patients). CNS prophylaxis consisted of intrathecal methotrexate, cytarabine, and hydrocortisone together with high-dose systemic methotrexate and cytarabine. The mean age (+/- standard deviation) was 33 years (+/- 16 years), and 272 patients were males. ALL subtypes included an early pre-B phenotype (15%), a common phenotype (45%), a pre-B phenotype (5%), a mature B phenotype (11%), and a T phenotype (24%). CNS involvement at diagnosis was observed in 18 patients (3.9%). Of 159 recurrences, 22 occurred (5.8%) in the CNS (14 isolated and 8 combined). A lactate dehydrogenase level > 1000 U/L was the only factor associated with the risk of CNS recurrence. A complete remission was attained in 7 of 22 patients (32%). The median overall survival after recurrence was 0.7 years for patients with isolated CNS recurrence, 0.13 years for patients with combined recurrence, and 0.41 years for patients with bone marrow recurrence (P = .11). The only 2 survivors underwent stem cell transplantation. The frequency of CNS recurrence in adult patients with ALL who do not receive radiotherapy for CNS prophylaxis was similar to the frequency observed in protocols that included cranial irradiation. A lactate dehydrogenase value >1000 U/L was the only factor found to be associated with CNS recurrence. The prognosis for patients who develop CNS recurrence is poor, identical to that for patients who develop bone marrow recurrence.
Copyright 2006 American Cancer Society.
Xavier Thomas, Jean-Michel Boiron, Françoise Huguet, Hervé Dombret, Ken Bradstock, Norbert Vey, Tibor Kovacsovics, André Delannoy, Nathalie Fegueux, Pierre Fenaux, Aspasia Stamatoullas, Jean-Paul Vernant, Olivier Tournilhac, Agnès Buzyn, Oumedaly Reman, Christiane Charrin, Claude Boucheix, Jean Gabert, Véronique Lhéritier, Denis Fiere
Outcome of treatment in adults with acute lymphoblastic leukemia: analysis of the LALA-94 trial.
J Clin Oncol. 2004 Oct 15;22(20):4075-86. doi: 10.1200/JCO.2004.10.050. Epub 2004 Sep 7.
Abstract/Text
PURPOSE: We analyzed the benefits of a risk-adapted postremission strategy in adult lymphoblastic leukemia (ALL), and re-evaluated stem-cell transplantation (SCT) for high-risk ALL.
PATIENTS AND METHODS: A total of 922 adult patients entered onto the trial according to risk groups: standard-risk ALL (group 1), high-risk ALL (group 2), Philadelphia chromosome-positive ALL (group 3), and CNS-positive ALL (group 4). All received a standard four-drug/4-week induction course. Patients from group 1 who achieved a complete remission (CR) after one course of induction therapy were randomly assigned between intensive and less intensive postremission chemotherapy, whereas those who achieved CR after salvage therapy were then included in group 2. Patients in groups 2, 3, and 4 with an HLA-identical sibling were assigned to allogeneic SCT. In groups 3 and 4, autologous SCT was offered to all other patients, whereas in group 2 they were randomly assigned between chemotherapy and autologous SCT.
RESULTS: Overall, 771 patients achieved CR (84%). Median disease-free survival (DFS) was 17.5 months, with 3-year DFS at 37%. In group 1, the 3-year DFS rate was 41%, with no difference between arms of postremission randomization. In groups 2 and 4, the 3-year DFS rates were 38% and 44%, respectively. In group 2, autologous SCT and chemotherapy resulted in comparable median DFS. Patients with an HLA-matched sibling (groups 2 and 4) had improved DFS. Three-year DFS was 24% in group 3.
CONCLUSION: Allogeneic SCT improved DFS in high-risk ALL in the first CR. Autologous SCT did not confer a significant benefit over chemotherapy for high-risk ALL.
Hillard M Lazarus, Susan M Richards, Raj Chopra, Mark R Litzow, Alan K Burnett, Peter H Wiernik, Ian M Franklin, Martin S Tallman, Lucy Cook, Georgina Buck, I Jill Durrant, Jacob M Rowe, Anthony H Goldstone, Medical Research Council (MRC)/National Cancer Research Institute (NCRI) Adult Leukaemia Working Party of the United Kingdom and the Eastern Cooperative Oncology Group
Central nervous system involvement in adult acute lymphoblastic leukemia at diagnosis: results from the international ALL trial MRC UKALL XII/ECOG E2993.
Blood. 2006 Jul 15;108(2):465-72. doi: 10.1182/blood-2005-11-4666. Epub 2006 Mar 23.
Abstract/Text
Outcome of acute lymphoblastic leukemia (ALL) in adults with central nervous system (CNS) disease at diagnosis is unclear. We treated 1508 de novo ALL patients with 2-phase induction and then high-dose methotrexate with l-asparaginase. Patients up to 50 years old in first remission (CR1) with a matched related donor (MRD) underwent an allogeneic stem cell transplantation (SCT); the remainder in CR1 were randomized to an autologous SCT or intensive consolidation followed by maintenance chemotherapy. Philadelphia chromosome (Ph)-positive patients were offered a matched unrelated donor (MUD) allogeneic SCT. Seventy-seven of 1508 (5%) patients a median age of 29 years had CNS leukemia at presentation; 13 of the 77 (17%) had Ph-positive ALL. Sixty-nine of 77 (90%) patients attained CR1. Thirty-six patients underwent transplantation in CR1 (25 MRD, 5 MUD, and 6 autografts). Eleven of 25 patients with MRD transplantation remain alive at 21 to 102 months, 2 of 5 with MUD at 42 and 71 months, and 1 of 6 with autologous SCT at 35 months. Seven of 27 treated with consolidation/maintenance remain in CR1 56 to 137 months after diagnosis. Overall survival at 5 years was 29% in those with CNS involvement at diagnosis versus 38% (P = .03) for those without. CNS leukemia in adult ALL is uncommon at diagnosis. Adult Ph-negative ALL patients, however, can attain long-term disease-free survival using SCT as well as conventional chemotherapy.
Hervé Dombret, Jean Gabert, Jean-Michel Boiron, Françoise Rigal-Huguet, Didier Blaise, Xavier Thomas, André Delannoy, Agnès Buzyn, Chrystèle Bilhou-Nabera, Jean-Michel Cayuela, Pierre Fenaux, Jean-Henri Bourhis, Nathalie Fegueux, Christiane Charrin, Claude Boucheix, Véronique Lhéritier, Hélène Espérou, Elizabeth MacIntyre, Jean-Paul Vernant, Denis Fière, Groupe d'Etude et de Traitement de la Leucémie Aiguë Lymphoblastique de l'Adulte (GET-LALA Group)
Outcome of treatment in adults with Philadelphia chromosome-positive acute lymphoblastic leukemia--results of the prospective multicenter LALA-94 trial.
Blood. 2002 Oct 1;100(7):2357-66. doi: 10.1182/blood-2002-03-0704.
Abstract/Text
From 1994 to 2000, 154 adults with Philadelphia chromosome-positive (Ph(+)) and/or BCR-ABL(+) acute lymphoblastic leukemia (ALL) were treated according to a prospective trial (median follow-up, 4.5 years) with the aim to study the prognostic value of early response to therapy and the role of stem cell transplantation (SCT) in first complete remission (CR). All patients received a standard induction course followed by a course of mitoxantrone and intermediate-dose cytarabine (HAM). After each course, minimal residual disease was tested by specific reverse transcriptase-polymerase chain reaction (RT-PCR) (median sensitivity, 10(-5)). Allogeneic SCT (if a donor) or autologous SCT (if not) was planned at 3 months in all patients in CR after HAM. CR rates after induction, after HAM, and at 3 months were 53%, 67%, and 62%, respectively. High leukocyte count and m-bcr subtype were the 2 identified bad-prognosis factors for CR at 3 months, both superseded by a poor early response assessed at day 8 of the induction course. HAM-associated salvage rate was higher in patients with M-bcr than in those with m-bcr ALL (55% vs 30%; P =.05). In the 103 patients eligible for SCT, the existence of a donor and the negative BCR-ABL status after HAM were independently predictive of remission duration (P <.001 and.01, respectively) and survival (P =.02 and.01, respectively). Relapse was the most common cause of treatment failure in all patient groups. Allogeneic SCT in first CR is the current best treatment option in adults with the disease. New strategies must be tested during early phases of therapy to increase the rate of BCR-ABL(-) remissions.
K Miyamura, M Tanimoto, Y Morishima, K Horibe, K Yamamoto, M Akatsuka, Y Kodera, S Kojima, K Matsuyama, N Hirabayashi
Detection of Philadelphia chromosome-positive acute lymphoblastic leukemia by polymerase chain reaction: possible eradication of minimal residual disease by marrow transplantation.
Blood. 1992 Mar 1;79(5):1366-70.
Abstract/Text
Minimal residual disease (MRD) in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph1 ALL) who received allogeneic (n = 9) or autologous (n = 6) bone marrow transplantation (BMT) was evaluated by the polymerase chain reaction (PCR) for the bcr-abl transcript. Twelve patients received BMT at the time of hematologic and cytogenetic remission. However, MRD was detected in 8 of 10 patients evaluated. Seven patients, including three who had MRD before BMT, continue to have a disease-free survival 5 to 64 months after BMT. Twenty-one specimens obtained from these patients at various times after BMT did not show MRD. In three patients, MRD detected just before BMT seems to be eradicated by BMT protocol. The other eight patients developed cytogenetic or hematologic relapses 2 to 8 months after BMT. Seven of 14 samples from these patients demonstrated MRD, which preceded clinical relapse by 3 to 9 weeks. Thus, this technique for the detection of MRD appears to be useful for the more precise assessment of various antileukemia therapies and for early detection of leukemia recurrence.
Yves Chalandon, Xavier Thomas, Sandrine Hayette, Jean-Michel Cayuela, Claire Abbal, Françoise Huguet, Emmanuel Raffoux, Thibaut Leguay, Philippe Rousselot, Stéphane Lepretre, Martine Escoffre-Barbe, Sébastien Maury, Céline Berthon, Emmanuelle Tavernier, Jean-François Lambert, Marina Lafage-Pochitaloff, Véronique Lhéritier, Sylvie Chevret, Norbert Ifrah, Hervé Dombret, Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL)
Randomized study of reduced-intensity chemotherapy combined with imatinib in adults with Ph-positive acute lymphoblastic leukemia.
Blood. 2015 Jun 11;125(24):3711-9. doi: 10.1182/blood-2015-02-627935. Epub 2015 Apr 15.
Abstract/Text
In this study, we randomly compared high doses of the tyrosine kinase inhibitor imatinib combined with reduced-intensity chemotherapy (arm A) to standard imatinib/hyperCVAD (cyclophosphamide/vincristine/doxorubicin/dexamethasone) therapy (arm B) in 268 adults (median age, 47 years) with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). The primary objective was the major molecular response (MMolR) rate after cycle 2, patients being then eligible for allogeneic stem cell transplantation (SCT) if they had a donor, or autologous SCT if in MMolR and no donor. With fewer induction deaths, the complete remission (CR) rate was higher in arm A than in arm B (98% vs 91%; P = .006), whereas the MMolR rate was similar in both arms (66% vs 64%). With a median follow-up of 4.8 years, 5-year event-free survival and overall survival (OS) rates were estimated at 37.1% and 45.6%, respectively, without difference between the arms. Allogeneic transplantation was associated with a significant benefit in relapse-free survival (hazard ratio [HR], 0.69; P = .036) and OS (HR, 0.64; P = .02), with initial white blood cell count being the only factor significantly interacting with this SCT effect. In patients achieving MMolR, outcome was similar after autologous and allogeneic transplantation. This study validates an induction regimen combining reduced-intensity chemotherapy and imatinib in Ph+ ALL adult patients and suggests that SCT in first CR is still a good option for Ph+ ALL adult patients. This trial was registered at www.clinicaltrials.gov as #NCT00327678.
© 2015 by The American Society of Hematology.
Farhad Ravandi, Megan Othus, Susan M O'Brien, Stephen J Forman, Chul S Ha, Jeffrey Y C Wong, Martin S Tallman, Elisabeth Paietta, Janis Racevskis, Geoffrey L Uy, Mary Horowitz, Naoko Takebe, Richard Little, Uma Borate, Partow Kebriaei, Laura Kingsbury, Hagop M Kantarjian, Jerald P Radich, Harry P Erba, Frederick R Appelbaum
US Intergroup Study of Chemotherapy Plus Dasatinib and Allogeneic Stem Cell Transplant in Philadelphia Chromosome Positive ALL.
Blood Adv. 2016 Dec 27;1(3):250-259. doi: 10.1182/bloodadvances.2016001495.
Abstract/Text
This multicenter trial was conducted to determine whether the addition of dasatinib to chemotherapy followed by an allogeneic hematopoietic cell transplant (HCT) in patients with Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) was feasible. Patients ≥ 18 and ≤ 60 years of age with newly diagnosed Ph+ ALL received up to 8 cycles of alternating hyperCVAD and high dose cytarabine and methotrexate with dasatinib. Patients with an available matched sibling or unrelated donor underwent an allogeneic HCT in first complete remission (CR1) followed by daily dasatinib starting from day 100. Others received maintenance therapy with vincristine and prednisone for 2 years and dasatinib indefinitely. 97 patients (94 evaluable) with median age of 44 years (range, 20 - 60) and median WBC at presentation of 10 × 109/L (range, 1 - 410 × 109/L) were accrued. 83 (88%) patients achieved CR or CR with incomplete count recovery (CRi) and 41 underwent ASCT in CR1. Median follow-up is 36 months (range, 9 - 63). For the overall population, overall survival (OS), event-free survival (EFS), and relapse-free survival (RFS) at 3 years were 69%, 55%, and 62%, respectively. The 12-month RFS and OS after transplant were 71% and 87%, respectively. Landmark analysis at 175 days from the time of CR/CRi (longest time to HCT), showed statistically superior advantages for RFS and OS (p=0.038 and 0.037, respectively) for the transplanted patients. Addition of dasatinib to chemotherapy and HCT for younger patients with Ph+ ALL is feasible and warrants further testing.
Elias Jabbour, Nicholas J Short, Farhad Ravandi, Xuelin Huang, Naval Daver, Courtney D DiNardo, Marina Konopleva, Naveen Pemmaraju, William Wierda, Guillermo Garcia-Manero, Koji Sasaki, Jorge Cortes, Rebecca Garris, Joseph D Khoury, Jeffrey Jorgensen, Nitin Jain, Joie Alvarez, Susan O'Brien, Hagop Kantarjian
Combination of hyper-CVAD with ponatinib as first-line therapy for patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia: long-term follow-up of a single-centre, phase 2 study.
Lancet Haematol. 2018 Dec;5(12):e618-e627. doi: 10.1016/S2352-3026(18)30176-5.
Abstract/Text
BACKGROUND: The combination of chemotherapy and ponatinib in Philadelphia chromosome-positive acute lymphoblastic leukaemia has the potential to be a new standard of care for the disease; however, long-term efficacy and safety data are needed. Our aim was to evaluate the long-term efficacy and safety of this regimen in patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukaemia in this ongoing phase 2 trial.
METHODS: In our single-centre, phase 2, single-arm trial in the USA, adult patients with previously untreated Philadelphia chromosome-positive acute lymphoblastic leukaemia were sequentially enrolled. Eligible patients had newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukaemia, were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status of 2 or less, a left ventricular ejection fraction above 50%, and adequate hepatic and renal function (serum bilirubin ≤3·0 mg/dL and serum creatinine ≤3·0 mg/dL, unless higher levels were believed to be due to leukaemia at the discretion of the investigator). Patients received eight cycles of 21 days, alternating between two drug combinations: hyper-fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) and high-dose methotrexate and cytarabine. Ponatinib was given orally at 45 mg per day for the first 14 days of cycle 1 then continuously at 45 mg per day for the subsequent cycles. After 37 patients were treated, the protocol was amended to reduce the dose of ponatinib to 30 mg per day at cycle 2, with further reduction to 15 mg once a complete molecular response (defined as absence of quantifiable BCR-ABL1 transcripts) was achieved. Patients in complete remission received maintenance with ponatinib daily (30 mg or 15 mg) indefinitely, and with vincristine (2 mg intravenously on day 1) and prednisone (200 mg orally on days 1-5) monthly for 2 years. The primary endpoint was 3-year event-free survival in the intention-to-treat population. The trial is registered at ClinicalTrials.gov, number NCT01424982, and is ongoing and still enrolling patients.
FINDINGS: 76 patients with a median age of 47 years (IQR 39-61) were enrolled and treated between Nov 19, 2011, and April 4, 2018. The 3-year event-free survival was 70% (95% CI 56-80). The most common grade 3 or 4 adverse events were infection (n=65, 86%), increased transaminases (n=24, 32%), increased bilirubin (n=13, 17%), pancreatitis (n=13, 17%), hypertension (n=12, 16%), bleeding (n=10, 13%), and skin rash (n=9, 12%). Six patients died while still on study treatment. Three patients (4%) died from infection and one (1%) from haemorrhage. Two patients died from myocardial infarction related to early ponatinib use; neither death occurred after protocol revision.
INTERPRETATION: The combination of chemotherapy with ponatinib is effective in achieving long-term remission in patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukaemia. This regimen could represent a new standard of care for this population. A randomised, phase 3 study to evaluate the efficacy of this combination compared with chemotherapy plus earlier-generation tyrosine-kinase inhibitors is warranted.
FUNDING: Takeda Oncology.
Copyright © 2018 Elsevier Ltd. All rights reserved.
Dieter Hoelzer, Nicola Gökbuget, Werner Digel, Thomas Faak, Michael Kneba, Regina Reutzel, Joanna Romejko-Jarosinska, Jacek Zwolinski, Jan Walewski
Outcome of adult patients with T-lymphoblastic lymphoma treated according to protocols for acute lymphoblastic leukemia.
Blood. 2002 Jun 15;99(12):4379-85. doi: 10.1182/blood-2002-01-0110.
Abstract/Text
We treated 45 adult patients with T-lymphoblastic lymphoma (T-LBL) (age range 15-61 years) with 2 protocols designed for adult acute lymphoblastic leukemia (ALL). An encouraging cure rate of 90% was recently reported for T-LBL in children treated with a similar approach. In our study, an 8-drug standard induction was administered over 8 weeks including prophylactic cranial (24 Gy) and mediastinal irradiation (24 Gy) followed by consolidation and reinduction therapy. At diagnosis, 91% of the 45 patients showed a mediastinal tumor and 40% had pleural/pericardial effusions; 73% of the patients had stage III/IV disease. Overall, 42 patients (93%) achieved a complete remission (CR), 2 patients (4%) achieved a partial remission, and 1 patient (2%) died during induction. In patients with stage I-III disease (n = 18) the CR rate was 100% compared with 89% in stage IV (n = 27). There were 15 patients who relapsed (36%) within 12 months. The majority of relapses (47%) occurred in the mediastinum (n = 7) despite mediastinal irradiation with 24 Gy in 6 out of 7 patients. The estimates for overall survival, continuous CR, and disease-free survival at 7 years are 51%, 65%, and 62%, respectively. Stage, age, lactate dehydrogenase, and all other parameters had no influence on achievement of CR or outcome. This study demonstrates in a large cohort of patients with adult T-LBL that a high CR rate and a favorable outcome can be achieved with an ALL-type regimen. Mediastinal recurrence was the major obstacle and further improvement by intensification of chemotherapy, increased dose of mediastinal irradiation (36 Gy), and extended indications for stem cell transplantation seem to be required.
Luciana Annino, Maria Luce Vegna, Andrea Camera, Giorgina Specchia, Giuseppe Visani, Giuseppe Fioritoni, Felicetto Ferrara, Antonio Peta, Stefania Ciolli, Wilma Deplano, Francesco Fabbiano, Simona Sica, Francesco Di Raimondo, Nicola Cascavilla, Antonio Tabilio, Pietro Leoni, Rosangela Invernizzi, Michele Baccarani, Bruno Rotoli, Sergio Amadori, Franco Mandelli, GIMEMA Group
Treatment of adult acute lymphoblastic leukemia (ALL): long-term follow-up of the GIMEMA ALL 0288 randomized study.
Blood. 2002 Feb 1;99(3):863-71.
Abstract/Text
The GIMEMA ALL 0288 trial was designed to evaluate the impact of a 7-day prednisone (PDN) pretreatment on complete remission (CR) achievement and length, the influence of the addition of cyclophosphamide (random I) to a conventional 4-drug induction on CR rate and duration, and whether an early post-CR intensification (random II) by an 8-drug consolidation could improve CR duration. Median follow-up of this study was 7.3 years. From January 1988 to April 1994, among 794 adult (> 12 but < 60 years) patients registered, 778 were eligible. Their median age was 27.5 years; 73% had B-lineage acute lymphoblastic leukemia (ALL) and 22% had T-lineage disease; 18% showed associated myeloid markers; 47 of 216 analyzed patients (22%) had Philadelphia chromosome-positive ALL. Response to PDN pretreatment was observed in 65% of cases. CR was achieved in 627 patients (82%). Resistant patients and induction death rates were 11% and 7%, respectively. Random II was applied to 388 patients with CR; 201 had maintenance alone and 187 had consolidation followed by maintenance. The relapse rate was 60%; isolated central nervous system relapses were 8% of all CRs and 13% of all relapses. Median survival (overall survival [OS]), continuous complete remission (CCR), and disease-free survival (DFS) were 2.2, 2.4, and 2 years, respectively. PDN pretreatment response resulted the main independent factor influencing CR achievement, OS, CCR, and DFS; the addition of cyclophosphamide in induction significantly influenced CR achievement in a multivariate analysis. Neither induction intensification nor early consolidation appeared to influence CCR and DFS duration. For the first time PDN pretreatment response proved to be a powerful factor predicting disease outcome in adult ALL patients.
Elly Barry, Daniel J DeAngelo, Donna Neuberg, Kristen Stevenson, Mignon L Loh, Barbara L Asselin, Ronald D Barr, Luis A Clavell, Craig A Hurwitz, Albert Moghrabi, Yvan Samson, Marshall Schorin, Harvey J Cohen, Stephen E Sallan, Lewis B Silverman
Favorable outcome for adolescents with acute lymphoblastic leukemia treated on Dana-Farber Cancer Institute Acute Lymphoblastic Leukemia Consortium Protocols.
J Clin Oncol. 2007 Mar 1;25(7):813-9. doi: 10.1200/JCO.2006.08.6397.
Abstract/Text
PURPOSE: Historically, adolescents with acute lymphoblastic leukemia (ALL) have had inferior outcomes when compared with younger children. We report the outcome of adolescents treated on Dana-Farber Cancer Institute (DFCI; Boston, MA) ALL Consortium Protocols conducted between 1991 and 2000.
PATIENTS AND METHODS: A total of 844 patients aged 1 to 18 years, with newly diagnosed ALL were enrolled onto two consecutive DFCI-ALL Consortium Protocols. We compared outcomes in three age groups: children aged 1 to 10 years (n = 685), young adolescents aged 10 to 15 years (n = 108), and older adolescents aged 15 to 18 years (n = 51).
RESULTS: With a median follow-up of 6.5 years, the 5-year event-free survival (EFS) for those aged 1 to 10 years was 85% (SE, 1%), compared with 77% (SE, 4%) for those aged 10 to 15 years, and 78% (SE, 6%) for those aged 15 to 18 years (P = .09). Adolescents were more likely to present with T-cell phenotype (P < .001) and less likely to have the TEL-AML1 fusion (P = .05). The incidence of pancreatitis and thromboembolic complications, but not asparaginase allergy, was higher in patients 10 years of age compared with those younger than 10 years. However, there was no difference in the rate of treatment-related complications between the 10- to 15-year and 15- to 18-year age groups.
CONCLUSION: Adolescents were more likely to present at diagnosis with biologically higher risk disease (T-cell phenotype and absence of the TEL-AML1 fusion) and more likely to experience treatment-related complications than younger children. However, the 5-year EFS for older adolescents was 78% +/- 6%, which is superior to published outcomes for similarly aged patients treated with other pediatric and adult ALL regimens. Based on this experience, we currently are piloting our regimen in patients aged 18 to 50 years.
James B Nachman, Mei K La, Stephen P Hunger, Nyla A Heerema, Paul S Gaynon, Caroline Hastings, Leonard A Mattano, Harland Sather, Meenakshi Devidas, David R Freyer, Peter G Steinherz, Nita L Seibel
Young adults with acute lymphoblastic leukemia have an excellent outcome with chemotherapy alone and benefit from intensive postinduction treatment: a report from the children's oncology group.
J Clin Oncol. 2009 Nov 1;27(31):5189-94. doi: 10.1200/JCO.2008.20.8959. Epub 2009 Oct 5.
Abstract/Text
PURPOSE: Patients 16 to 21 years of age with acute lymphoblastic leukemia (ALL) have an inferior outcome compared with younger children, leading some medical oncologists to advocate allogeneic stem-cell transplantation in first remission for these patients. We examined outcome for young adults with ALL enrolled onto the Children's Cancer Group (CCG) 1961 study between 1996 and 2002.
PATIENTS AND METHODS: CCG 1961 entered patients with ALL 1 to 21 years of age with initial WBC count > or = 50,000/microL and/or age > or = 10 years. Randomly assigned therapies evaluated the impact of postinduction treatment intensification on outcome. We examined outcome and prognostic factors for 262 young adults with ALL.
RESULTS: Five-year event-free and overall survival rates for young adult patients are 71.5% (SE, 3.6%) and 77.5% (SE, 3.3%), respectively. Rapid responder patients (< 25% bone marrow blasts on day 7) randomly assigned to augmented therapy had 5-year event-free survival of 81.8% (SE, 7%), as compared with 66.8% (SE, 6.7%) for patients receiving standard therapy (P = .07). One versus two interim maintenance and delayed intensification courses had no significant impact on event-free survival. WBC count more than 50,000/microL was an adverse prognostic factor.
CONCLUSION: Young adult patients with ALL showing a rapid response to induction chemotherapy benefit from early intensive postinduction therapy but do not benefit from a second interim maintenance and delayed intensification phase. Given the excellent outcome with this chemotherapy, there seems to be no role for the routine use of allogeneic stem-cell transplantation in first remission for young adults with ALL.
Wendy Stock, Mei La, Ben Sanford, Clara D Bloomfield, James W Vardiman, Paul Gaynon, Richard A Larson, James Nachman, Children's Cancer Group, Cancer and Leukemia Group B studies
What determines the outcomes for adolescents and young adults with acute lymphoblastic leukemia treated on cooperative group protocols? A comparison of Children's Cancer Group and Cancer and Leukemia Group B studies.
Blood. 2008 Sep 1;112(5):1646-54. doi: 10.1182/blood-2008-01-130237. Epub 2008 May 23.
Abstract/Text
We performed a retrospective comparison of presenting features, planned treatment, complete remission (CR) rate, and outcome of 321 adolescents and young adults (AYAs) ages 16 to 20 years with newly diagnosed acute lymphoblastic leukemia (ALL) who were treated on consecutive trials in either the Children's Cancer Group (CCG) or the Cancer and Leukemia Group B (CALGB) from 1988 to 2001. CR rates were identical, 90% for both CALGB and CCG AYAs. CCG AYAs had a 63% event-free survival (EFS) and 67% overall survival (OS) at 7 years in contrast to the CALGB AYAs, in which 7-year EFS was only 34% (P < .001; relative hazard rate [RHR] = 2.2) and OS was 46% (P < .001; RHR = 1.9). While CALGB AYAs aged 16 to 17 years achieved similar outcomes to all CCG AYAs with a 7-year EFS of 55%, the EFS for 18- to 20-year-old CALGB patients was only 29%. Comparison of the regimens showed that CCG AYAs received earlier and more intensive central nervous system prophylaxis and higher cumulative doses of nonmyelosuppressive agents. There were no differences in outcomes of those who reached maintenance therapy on time compared with those who were delayed. Based on these observations, a prospective study for AYAs with ALL using the more successful approach of the CCG has been initiated.
F Hayakawa, T Sakura, T Yujiri, E Kondo, K Fujimaki, O Sasaki, J Miyatake, H Handa, Y Ueda, Y Aoyama, S Takada, Y Tanaka, N Usui, S Miyawaki, S Suenobu, K Horibe, H Kiyoi, K Ohnishi, Y Miyazaki, S Ohtake, Y Kobayashi, K Matsuo, T Naoe, Japan Adult Leukemia Study Group (JALSG)
Markedly improved outcomes and acceptable toxicity in adolescents and young adults with acute lymphoblastic leukemia following treatment with a pediatric protocol: a phase II study by the Japan Adult Leukemia Study Group.
Blood Cancer J. 2014 Oct 17;4:e252. doi: 10.1038/bcj.2014.72. Epub 2014 Oct 17.
Abstract/Text
The superiority of the pediatric protocol for adolescents with acute lymphoblastic leukemia (ALL) has already been demonstrated, however, its efficacy in young adults remains unclear. The ALL202-U protocol was conducted to examine the efficacy and feasibility of a pediatric protocol in adolescents and young adults (AYAs) with BCR-ABL-negative ALL. Patients aged 15-24 years (n=139) were treated with the same protocol used for pediatric B-ALL. The primary objective of this study was to assess the disease-free survival (DFS) rate and its secondary aims were to assess toxicity, the complete remission (CR) rate and the overall survival (OS) rate. The CR rate was 94%. The 5-year DFS and OS rates were 67% (95% confidence interval (CI) 58-75%) and 73% (95% CI 64-80%), respectively. Severe adverse events were observed at a frequency that was similar to or lower than that in children treated with the same protocol. Only insufficient maintenance therapy significantly worsened the DFS (hazard ratio 5.60, P<0.001). These results indicate that this protocol may be a feasible and highly effective treatment for AYA with BCR-ABL-negative ALL.
Deborah A Thomas, Stefan Faderl, Susan O'Brien, Carlos Bueso-Ramos, Jorge Cortes, Guillermo Garcia-Manero, Francis J Giles, Srdan Verstovsek, William G Wierda, Sherry A Pierce, Jianqin Shan, Mark Brandt, Fredrick B Hagemeister, Michael J Keating, Fernando Cabanillas, Hagop Kantarjian
Chemoimmunotherapy with hyper-CVAD plus rituximab for the treatment of adult Burkitt and Burkitt-type lymphoma or acute lymphoblastic leukemia.
Cancer. 2006 Apr 1;106(7):1569-80. doi: 10.1002/cncr.21776.
Abstract/Text
BACKGROUND: Adult Burkitt-type lymphoma (BL) and acute lymphoblastic leukemia (B-ALL) are rare entities composing 1% to 5% of non-Hodgkin lymphomas NHL) or ALL. Prognosis of BL and B-ALL has been poor with conventional NHL or ALL regimens, but has improved with dose-intensive regimens.
METHODS: To evaluate the addition of rituximab, a CD20 monoclonal antibody, to intensive chemotherapy in adults with BL or B-ALL, 31 patients with newly diagnosed BL or B-ALL received the hyper-fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) regimen with rituximab. Their median age was 46 years; 29% were 60 years or older. Rituximab 375 mg/m(2) was given on Days 1 and 11 of hyper-CVAD courses and on Days 1 and 8 of methotrexate and cytarabine courses.
RESULTS: Complete remission (complete response [CR]) was achieved in 24 of 28 (86%) evaluable patients; 3 had a partial response, and 1 had resistant disease. There were no induction deaths. The 3-year overall survival (OS), event-free survival, and disease-free survival rates were 89%, 80%, and 88%, respectively. Nine elderly patients achieved CR with all of them in continuous CR (except 1 death in CR from infection), with a 3-year OS rate of 89%. Multivariate analysis of current and historical (those treated with hyper-CVAD alone) groups identified age and treatment with rituximab as favorable factors.
CONCLUSIONS: The addition of rituximab to hyper-CVAD may improve outcome in adult BL or B-ALL, particularly in elderly patients.
Copyright 2006 American Cancer Society.
J A Barnes, A S Lacasce, Y Feng, C E Toomey, D Neuberg, J S Michaelson, E P Hochberg, J S Abramson
Evaluation of the addition of rituximab to CODOX-M/IVAC for Burkitt's lymphoma: a retrospective analysis.
Ann Oncol. 2011 Aug;22(8):1859-64. doi: 10.1093/annonc/mdq677. Epub 2011 Feb 21.
Abstract/Text
BACKGROUND: Burkitt's lymphoma (BL) is a highly aggressive B-cell non-Hodgkin's lymphoma (NHL) that may be cured with intensive chemotherapy. The addition of the CD20-directed monoclonal antibody rituximab to CODOX-M/IVAC (cyclophosphamide, vincristine, doxorubicin, and high-dose methotrexate, alternating with ifosfamide, etoposide, and cytarabine) has not been studied despite efficacy in other aggressive CD20-positive NHLs.
PATIENTS AND METHODS: Eighty adult BL patients treated with or without rituximab were identified at our institutions. Response rate, overall survival (OS), and progression-free survival (PFS) are calculated.
RESULTS: There were fewer relapses in rituximab-treated patients (3 of 40 versus 13 of 40, P = 0.01). There was a trend for improvement in outcome favoring rituximab-containing therapy, with 3-year PFS (74% versus 61%) and 3-year OS (77% versus 66%), although these did not reach statistical significance. Advanced age and central nervous system involvement were associated with poorer OS on multivariable Cox regression analysis, adjusting for treatment, human immunodeficiency virus (HIV) involvement, and risk group.
CONCLUSIONS: CODOX-M/IVAC, with or without rituximab, is a highly effective regimen for the treatment of adult BL. Rituximab decreased the recurrence rate and showed a trend in favor of improvement in PFS and OS. HIV-infected patients achieved outcomes comparable with those of their non-HIV-infected counterparts.
Mark Roschewski, Kieron Dunleavy, Jeremy S Abramson, Bayard L Powell, Brian K Link, Prapti Patel, Philip J Bierman, Deepa Jagadeesh, Ronald T Mitsuyasu, David Peace, Peter R Watson, Wahid T Hanna, Christopher Melani, Andrea N Lucas, Seth M Steinberg, Stefania Pittaluga, Elaine S Jaffe, Jonathan W Friedberg, Brad S Kahl, Richard F Little, Nancy L Bartlett, Michelle A Fanale, Ariela Noy, Wyndham H Wilson
Multicenter Study of Risk-Adapted Therapy With Dose-Adjusted EPOCH-R in Adults With Untreated Burkitt Lymphoma.
J Clin Oncol. 2020 Aug 1;38(22):2519-2529. doi: 10.1200/JCO.20.00303. Epub 2020 May 26.
Abstract/Text
PURPOSE: Burkitt lymphoma is an aggressive B-cell lymphoma curable with dose-intensive chemotherapy derived from pediatric leukemia regimens. Treatment is acutely toxic with late sequelae. We hypothesized that dose-adjusted etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone, and rituximab (DA-EPOCH-R) may obviate the need for highly dose-intensive chemotherapy in adults with Burkitt lymphoma.
METHODS: We conducted a multicenter risk-adapted study of DA-EPOCH-R in untreated adult Burkitt lymphoma. Low-risk patients received three cycles without CNS prophylaxis, and high-risk patients received six cycles with intrathecal CNS prophylaxis or extended intrathecal treatment if leptomeninges were involved. The primary endpoint was event-free survival (EFS), and secondary endpoints were toxicity and predictors of EFS and overall survival (OS).
RESULTS: Between 2010 and 2017, 113 patients were enrolled across 22 centers, and 98 (87%) were high risk. The median age was 49 (range, 18-86) years, and 62% were ≥ 40 years. Bone marrow and/or CSF was involved in 29 (26%) of patients, and 28 (25%) were HIV positive. At a median follow-up of 58.7 months, EFS and OS were 84.5% and 87.0%, respectively, and EFS was 100% and 82.1% in low- and high-risk patients. Therapy was equally effective across age groups, HIV status, and International Prognostic Index risk groups. Involvement of the CSF identified the group at greatest risk for early toxicity-related death or treatment failure. Five treatment-related deaths (4%) occurred during therapy. Febrile neutropenia occurred in 16% of cycles, and tumor lysis syndrome was rare.
CONCLUSION: Risk-adapted DA-EPOCH-R therapy is effective in adult Burkitt lymphoma regardless of age or HIV status and was well tolerated. Improved therapeutic strategies for adults with CSF involvement are needed (funded by the National Cancer Institute; ClinicalTrials.gov identifier: NCT01092182).
Anthony H Goldstone, Susan M Richards, Hillard M Lazarus, Martin S Tallman, Georgina Buck, Adele K Fielding, Alan K Burnett, Raj Chopra, Peter H Wiernik, Letizia Foroni, Elisabeth Paietta, Mark R Litzow, David I Marks, Jill Durrant, Andrew McMillan, Ian M Franklin, Selina Luger, Niculae Ciobanu, Jacob M Rowe
In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993).
Blood. 2008 Feb 15;111(4):1827-33. doi: 10.1182/blood-2007-10-116582. Epub 2007 Nov 29.
Abstract/Text
An international collaboration was set up to prospectively evaluate the role of allogeneic transplantation for adults with acute lymphoblastic leukemia (ALL) and compare autologous transplantation with standard chemotherapy. Patients received 2 phases of induction and, if in remission, were assigned to allogeneic transplantation if they had a compatible sibling donor. Other patients were randomized to chemotherapy for 2.5 years versus an autologous transplantation. A donor versus no-donor analysis showed that Philadelphia chromosome-negative patients with a donor had a 5-year improved overall survival (OS), 53% versus 45% (P = .01), and the relapse rate was significantly lower (P < or = .001). The survival difference was significant in standard-risk patients, but not in high-risk patients with a high nonrelapse mortality rate in the high-risk donor group. Patients randomized to chemotherapy had a higher 5-year OS (46%) than those randomized to autologous transplantation (37%; P = .03). Matched related allogeneic transplantations for ALL in first complete remission provide the most potent antileukemic therapy and considerable survival benefit for standard-risk patients. However, the transplantation-related mortality for high-risk older patients was unacceptably high and abrogated the reduction in relapse risk. There is no evidence that a single autologous transplantation can replace consolidation/maintenance in any risk group. This study is registered at http://clinicaltrials.gov as NCT00002514.
C Sebban, E Lepage, J P Vernant, E Gluckman, M Attal, J Reiffers, L Sutton, E Racadot, M Michallet, D Maraninchi
Allogeneic bone marrow transplantation in adult acute lymphoblastic leukemia in first complete remission: a comparative study. French Group of Therapy of Adult Acute Lymphoblastic Leukemia.
J Clin Oncol. 1994 Dec;12(12):2580-7.
Abstract/Text
PURPOSE: Optimal postremission therapy remains controversial in adult patients with acute lymphoblastic leukemia (ALL). In a large multicentric trial (LALA87), we compared allogeneic bone marrow transplantation (BMT) with other postremission therapies (chemotherapy or autologous transplantation) using the result of the human leukocyte antigen (HLA) typing as a random allocation.
PATIENTS AND METHODS: Patient eligibility requirements were as follows: (1) inclusion in LALA87 trial, (2) complete response to induction or salvage therapy, (3) age 15 to 40 years, and (4) at least one potential sibling donor. Patients with an HLA-identical sibling were assigned to the BMT group, while patients without a sibling donor constituted the control group. Allogeneic transplantation was scheduled for patients in the BMT group; in the control group, patients were randomly allocated to receive chemotherapy or autologous transplantation.
RESULTS: Of 284 eligible points, 257 entered the study: 116 were allocated to the BMT group and 141 to the control group. The 5-year survival rates were not statistically significantly different between the two groups. When only patients with high-risk ALL were considered (those with [1] Philadelphia chromosome [Ph1] ALL, [2] null or undifferentiated ALL, or [3] c-ALL with either age greater than 35 years or WBC count > 30 x 10(9)/L or time to achieve complete remission > 4 weeks), overall survival (P = .03) and disease-free-survival (P = .01) were better for the BMT group compared with the control group (5-year overall survival rates, 44% v 20%; 5-year disease-free survival rates, 39% v 14%).
CONCLUSION: Allogeneic transplantation does not improve survival in patients with standard-risk ALL and should be recommended only for patients with adverse prognostic factors.
Nicola Gökbuget, Hervé Dombret, Massimiliano Bonifacio, Albrecht Reichle, Carlos Graux, Christoph Faul, Helmut Diedrich, Max S Topp, Monika Brüggemann, Heinz-August Horst, Violaine Havelange, Julia Stieglmaier, Hendrik Wessels, Vincent Haddad, Jonathan E Benjamin, Gerhard Zugmaier, Dirk Nagorsen, Ralf C Bargou
Blinatumomab for minimal residual disease in adults with B-cell precursor acute lymphoblastic leukemia.
Blood. 2018 Apr 5;131(14):1522-1531. doi: 10.1182/blood-2017-08-798322. Epub 2018 Jan 22.
Abstract/Text
Approximately 30% to 50% of adults with acute lymphoblastic leukemia (ALL) in hematologic complete remission after multiagent therapy exhibit minimal residual disease (MRD) by reverse transcriptase-polymerase chain reaction or flow cytometry. MRD is the strongest predictor of relapse in ALL. In this open-label, single-arm study, adults with B-cell precursor ALL in hematologic complete remission with MRD (≥10-3) received blinatumomab 15 µg/m2 per day by continuous IV infusion for up to 4 cycles. Patients could undergo allogeneic hematopoietic stem-cell transplantation any time after cycle 1. The primary end point was complete MRD response status after 1 cycle of blinatumomab. One hundred sixteen patients received blinatumomab. Eighty-eight (78%) of 113 evaluable patients achieved a complete MRD response. In the subgroup of 110 patients with Ph-negative ALL in hematologic remission, the Kaplan-Meier estimate of relapse-free survival (RFS) at 18 months was 54%. Median overall survival (OS) was 36.5 months. In landmark analyses, complete MRD responders had longer RFS (23.6 vs 5.7 months; P = .002) and OS (38.9 vs 12.5 months; P = .002) compared with MRD nonresponders. Adverse events were consistent with previous studies of blinatumomab. Twelve (10%) and 3 patients (3%) had grade 3 or 4 neurologic events, respectively. Four patients (3%) had cytokine release syndrome grade 1, n = 2; grade 3, n = 2), all during cycle 1. After treatment with blinatumomab in a population of patients with MRD-positive B-cell precursor ALL, a majority achieved a complete MRD response, which was associated with significantly longer RFS and OS compared with MRD nonresponders. This study is registered at www.clinicaltrials.gov as #NCT01207388.
© 2018 by The American Society of Hematology.
Hagop M Kantarjian, Daniel J DeAngelo, Matthias Stelljes, Giovanni Martinelli, Michaela Liedtke, Wendy Stock, Nicola Gökbuget, Susan O'Brien, Kongming Wang, Tao Wang, M Luisa Paccagnella, Barbara Sleight, Erik Vandendries, Anjali S Advani
Inotuzumab Ozogamicin versus Standard Therapy for Acute Lymphoblastic Leukemia.
N Engl J Med. 2016 Aug 25;375(8):740-53. doi: 10.1056/NEJMoa1509277. Epub 2016 Jun 12.
Abstract/Text
BACKGROUND: The prognosis for adults with relapsed acute lymphoblastic leukemia is poor. We sought to determine whether inotuzumab ozogamicin, an anti-CD22 antibody conjugated to calicheamicin, results in better outcomes in patients with relapsed or refractory acute lymphoblastic leukemia than does standard therapy.
METHODS: In this phase 3 trial, we randomly assigned adults with relapsed or refractory acute lymphoblastic leukemia to receive either inotuzumab ozogamicin (inotuzumab ozogamicin group) or standard intensive chemotherapy (standard-therapy group). The primary end points were complete remission (including complete remission with incomplete hematologic recovery) and overall survival.
RESULTS: Of the 326 patients who underwent randomization, the first 218 (109 in each group) were included in the primary intention-to-treat analysis of complete remission. The rate of complete remission was significantly higher in the inotuzumab ozogamicin group than in the standard-therapy group (80.7% [95% confidence interval {CI}, 72.1 to 87.7] vs. 29.4% [95% CI, 21.0 to 38.8], P<0.001). Among the patients who had complete remission, a higher percentage in the inotuzumab ozogamicin group had results below the threshold for minimal residual disease (0.01% marrow blasts) (78.4% vs. 28.1%, P<0.001); the duration of remission was longer in the inotuzumab ozogamicin group (median, 4.6 months [95% CI, 3.9 to 5.4] vs. 3.1 months [95% CI, 1.4 to 4.9]; hazard ratio, 0.55 [95% CI, 0.31 to 0.96]; P=0.03). In the survival analysis, which included all 326 patients, progression-free survival was significantly longer in the inotuzumab ozogamicin group (median, 5.0 months [95% CI, 3.7 to 5.6] vs. 1.8 months [95% CI, 1.5 to 2.2]; hazard ratio, 0.45 [97.5% CI, 0.34 to 0.61]; P<0.001); the median overall survival was 7.7 months (95% CI, 6.0 to 9.2) versus 6.7 months (95% CI, 4.9 to 8.3), and the hazard ratio was 0.77 (97.5% CI, 0.58 to 1.03) (P=0.04). In the safety population, the most frequent grade 3 or higher nonhematologic adverse events with inotuzumab ozogamicin were liver-related. Veno-occlusive liver disease of any grade occurred in 15 patients (11%) who received inotuzumab ozogamicin and in 1 patient (1%) who received standard therapy.
CONCLUSIONS: The rate of complete remission was higher with inotuzumab ozogamicin than with standard therapy, and a higher percentage of patients in the inotuzumab ozogamicin group had results below the threshold for minimal residual disease. Both progression-free and overall survival were longer with inotuzumab ozogamicin. Veno-occlusive liver disease was a major adverse event associated with inotuzumab ozogamicin. (Funded by Pfizer; INO-VATE ALL ClinicalTrials.gov number, NCT01564784.).
Shai Shimony, Yiwen Liu, Yannis K Valtis, Jonathan D Paolino, Andrew E Place, Andrew M Brunner, Lachelle D Weeks, Lewis B Silverman, Lynda M Vrooman, Donna S Neuberg, Richard M Stone, Daniel J DeAngelo, Marlise R Luskin
Nelarabine combination therapy for relapsed or refractory T-cell acute lymphoblastic lymphoma/leukemia.
Blood Adv. 2023 Apr 11;7(7):1092-1102. doi: 10.1182/bloodadvances.2022008280.
Abstract/Text
Nelarabine, an antimetabolite prodrug, is approved as monotherapy for children and adults with relapsed and refractory T-cell acute lymphoblastic leukemia and lymphoma (R/R T-ALL/LBL), although it is often used in combination regimens. We sought to understand differences in efficacy and toxicity when nelarabine is administered alone or in combination. We retrospectively analyzed 44 consecutive patients with R/R T-ALL/LBL; 29 of whom were treated with combination therapy, most with cyclophosphamide and etoposide (23, 79%) and 15 with monotherapy. The median age was 19 years (range, 2-69), including 18 children (<18 years). After a median of 1 (range, 1-3) cycle of treatment, 24 patients (55%) achieved complete remission, 62% (18/29) with combination therapy and 40% (6/15) with monotherapy (P = .21). Most responders (21, 88%) pursued allogeneic stem cell transplant (alloSCT). Overall survival (OS) was 12.8 months (95% confidence interval, 6.93-not reached) in the entire cohort and was higher in the combination therapy than in the monotherapy group (24-month OS, 53% vs 8%; P = .003). The rate of neurotoxicity was similar between groups (27% vs 17%; P = .46) and grade 3/4 anemia and thrombocytopenia were more frequent in the combination group (76% vs 20%; P < .001% and 66% vs 27%; P = .014, respectively). In a multivariate analysis, nelarabine combination therapy and alloSCT post nelarabine were associated with improved OS (hazard ratio, 0.41; P = .04 and hazard ratio, 0.25; P = .008, respectively). In conclusion, compared with monotherapy, nelarabine combination therapy was well tolerated and associated with improved survival in pediatric and adult patients with R/R T-ALL/LBL.
© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.
Shannon L Maude, Theodore W Laetsch, Jochen Buechner, Susana Rives, Michael Boyer, Henrique Bittencourt, Peter Bader, Michael R Verneris, Heather E Stefanski, Gary D Myers, Muna Qayed, Barbara De Moerloose, Hidefumi Hiramatsu, Krysta Schlis, Kara L Davis, Paul L Martin, Eneida R Nemecek, Gregory A Yanik, Christina Peters, Andre Baruchel, Nicolas Boissel, Francoise Mechinaud, Adriana Balduzzi, Joerg Krueger, Carl H June, Bruce L Levine, Patricia Wood, Tetiana Taran, Mimi Leung, Karen T Mueller, Yiyun Zhang, Kapildeb Sen, David Lebwohl, Michael A Pulsipher, Stephan A Grupp
Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia.
N Engl J Med. 2018 Feb 1;378(5):439-448. doi: 10.1056/NEJMoa1709866.
Abstract/Text
BACKGROUND: In a single-center phase 1-2a study, the anti-CD19 chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel produced high rates of complete remission and was associated with serious but mainly reversible toxic effects in children and young adults with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL).
METHODS: We conducted a phase 2, single-cohort, 25-center, global study of tisagenlecleucel in pediatric and young adult patients with CD19+ relapsed or refractory B-cell ALL. The primary end point was the overall remission rate (the rate of complete remission or complete remission with incomplete hematologic recovery) within 3 months.
RESULTS: For this planned analysis, 75 patients received an infusion of tisagenlecleucel and could be evaluated for efficacy. The overall remission rate within 3 months was 81%, with all patients who had a response to treatment found to be negative for minimal residual disease, as assessed by means of flow cytometry. The rates of event-free survival and overall survival were 73% (95% confidence interval [CI], 60 to 82) and 90% (95% CI, 81 to 95), respectively, at 6 months and 50% (95% CI, 35 to 64) and 76% (95% CI, 63 to 86) at 12 months. The median duration of remission was not reached. Persistence of tisagenlecleucel in the blood was observed for as long as 20 months. Grade 3 or 4 adverse events that were suspected to be related to tisagenlecleucel occurred in 73% of patients. The cytokine release syndrome occurred in 77% of patients, 48% of whom received tocilizumab. Neurologic events occurred in 40% of patients and were managed with supportive care, and no cerebral edema was reported.
CONCLUSIONS: In this global study of CAR T-cell therapy, a single infusion of tisagenlecleucel provided durable remission with long-term persistence in pediatric and young adult patients with relapsed or refractory B-cell ALL, with transient high-grade toxic effects. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT02435849 .).
M Schrappe, A Reiter, M Zimmermann, J Harbott, W D Ludwig, G Henze, H Gadner, E Odenwald, H Riehm
Long-term results of four consecutive trials in childhood ALL performed by the ALL-BFM study group from 1981 to 1995. Berlin-Frankfurt-Münster.
Leukemia. 2000 Dec;14(12):2205-22. doi: 10.1038/sj.leu.2401973.
Abstract/Text
Four thousand, four hundred and forty eligible children of up to 18 years of age were treated in four consecutive trials between 1981 and 1995 with the treatment protocols of the Berlin-Frankfurt-Münster (BFM) study group for childhood acute lymphoblastic leukemia (ALL). The probability for event-free survival (pEFS) at 8 years improved from 65.8% in study ALL-BFM 81 to 75.9% in study ALL-BFM 90. The cumulative incidence of recurrences with CNS involvement was 10.1% and 9.3% in studies ALL-BFM 81 and 83, but was reduced to less than 5% in study ALL-BFM 90 (for isolated CNS relapses from 5.3% in study ALL-BFM 81 to 1.1% in study ALL-BFM 90). Four major findings were derived from this series of trials performed by 37 to 96 centers in Germany, Austria, and Switzerland: (1) Reintensification is a crucial part of treatment, even in low risk patients; (2) presymptomatic cranial radiotherapy can be safely reduced to 12 Gy, or even be eliminated if it is replaced by early intensive systemic and intrathecal methotrexate applied; (3) maintenance therapy given a total of 24 months from diagnosis provides a lower rate of systemic relapses than treatment for 18 months; (4) inadequate response to an initial 7-day prednisone window (combined with one intrathecal injection of methotrexate on day 1) defines about 10% of the patients with a very high risk of relapse. For patients with adequate early response (90% of all) an 8-year pEFS of 80% has been achieved in the most recent trial ALL-BFM 90. While it has proven so far to be impossible to improve the outcome for the small group of high risk patients, the number of recurrences could be effectively reduced for the large group of patients responding adequately to the prednisone in vivo sensitivity test. Apart from inadequate prednisone response, patients with hyperleukocytosis, age <1 year, or the presence of the Philadelphia-chromosome (Ph+ ALL) are at a particularly high risk of failure.
M Schrappe, B Camitta, C H Pui, T Eden, P Gaynon, G Gustafsson, G E Janka-Schaub, W Kamps, G Masera, S Sallan, M Tsuchida, E Vilmer
Long-term results of large prospective trials in childhood acute lymphoblastic leukemia.
Leukemia. 2000 Dec;14(12):2193-4. doi: 10.1038/sj.leu.2401977.
Abstract/Text
Stephen P Hunger
Development and refinement of augmented treatment regimens for pediatric high-risk acute lymphoblastic leukemia.
Am Soc Clin Oncol Educ Book. 2012;:611-5. doi: 10.14694/EdBook_AM.2012.32.180.
Abstract/Text
The 5-year survival rate for children and adolescents with acute lymphoblastic leukemia (ALL) is now at least 90%. However, clinical features (age and initial white blood cell count [WBC]), early treatment response, and the presence/absence of specific sentinel genomic lesions can identify subsets of high-risk (HR) ALL patients with a much higher risk of treatment failure. Chemotherapy regimens used to treat HR ALL have been refined over the past 3 decades through randomized clinical trials conducted by the Children's Oncology Group (COG) in North America and the Berlin-Frankfurt-Muenster (BFM) group in Western Europe. Contemporary COG HR ALL treatment regimens were developed from the BFM-76 regimen, with subsequent changes that led to development and refinement of a so-called augmented BFM (ABFM) regimen used today. Although contemporary COG and BFM treatment regimens are not identical, there are many more similarities than differences. With improvements in survival, it has become clear that although the outcome of some patients with HR ALL can be improved by optimizing use of standard cytotoxic chemotherapy agents, this approach has had only limited success for other patient subsets. In contrast, introduction of the tyrosine kinase inhibitor imatinib has led to dramatic outcome improvements for children and adolescents with Philadelphia chromosome-positive ALL. Genomic studies are identifying new sentinel genomic lesions that can serve as potential therapeutic targets, which will likely lead to the testing of novel and/or targeted therapies in more children with HR ALL. Such studies will require increased collaboration between Western European and North American cooperative groups.
R A Larson, R K Dodge, C P Burns, E J Lee, R M Stone, P Schulman, D Duggan, F R Davey, R E Sobol, S R Frankel
A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: cancer and leukemia group B study 8811.
Blood. 1995 Apr 15;85(8):2025-37.
Abstract/Text
The goal of this phase II multicenter clinical trial was to evaluate a new intensive chemotherapy program for adults with untreated acute lymphoblastic leukemia (ALL) and to examine prospectively the impact of clinical and biologic characteristics on the outcome. One hundred ninety-seven eligible and evaluable patients (16 to 80 years of age; median, 32 years of age) received cyclophosphamide, daunorubicin, vincristine, prednisone, and L-asparaginase; 167 patients (85%) achieved a complete remission (CR), 13 (7%) had refractory disease, and 17 (9%) died during induction. A higher CR rate was observed in younger patients (94% for those < 30 years old, 85% for those 30 to 59 years old, and 39% for those > or = 60 years old, P < .001) and in those who had a mediastinal mass (100%) or blasts with a T-cell immunophenotype. Eighty percent of B-lineage and 97% of T-cell ALL patients achieved a CR (P = .01). The coexpression of myeloid antigens did not affect the response rate or duration. Seventy percent of those with cytogenetic or molecular evidence of the Philadelphia (Ph) chromosome and 84% of those without such evidence achieved a CR (P = .11). Patients in remission received multiagent consolidation treatment, central nervous system prophylaxis, late intensification, and maintenance chemotherapy for a total of 24 months. After a median follow-up time of 43 months, the median survival for all 197 patients is 36 months; the median remission duration for the 167 CR patients is 29 months. Favorable pretreatment characteristics relative to remission duration or survival are younger age, the presence of a mediastinal mass or lymphadenopathy, a white blood cell count (WBC) less than 30,000/microL, L1 morphology, T or TMy immunophenotype, and the absence of the Ph chromosome. The estimates of the proportion surviving at 3 years are 69% for patients less than 30 years old, 39% for those 30 to 59 years old, 89% for those who had a mediastinal mass, 59% with WBC less than 30,000/microL, 63% with L1 morphology, 69% for T or TMy antigen expression, and 62% for those who lack the Ph chromosome. Fifteen patients (8%) had no unfavorable prognostic factors and have an estimated probability of survival at 5 years of 100% (95% confidence interval, 77% to 100%). This intensive chemotherapy regimen produces a high remission rate and a high proportion of durable remissions in adults with ALL.
H M Kantarjian, S O'Brien, T L Smith, J Cortes, F J Giles, M Beran, S Pierce, Y Huh, M Andreeff, C Koller, C S Ha, M J Keating, S Murphy, E J Freireich
Results of treatment with hyper-CVAD, a dose-intensive regimen, in adult acute lymphocytic leukemia.
J Clin Oncol. 2000 Feb;18(3):547-61.
Abstract/Text
PURPOSE: To evaluate the efficacy and toxicity of Hyper-CVAD (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone), a dose-intensive regimen, in adult acute lymphocytic leukemia (ALL).
PATIENTS AND METHODS: Adults with newly diagnosed ALL referred since 1992 were entered onto the study; treatment was initiated in 204 patients between 1992 and January 1998. No exclusions were made because of older age, poor performance status, organ dysfunction, or active infection. Median age was 39.5 years; 37% were at least 50 years old. Mature B-cell disease (Burkitt type) was present in 9%, T-cell disease in 17%. Leukocytosis of more than 30 x 10(9)/L was found in 26%, Philadelphia chromosome-positive disease in 16% (20% of patients with assessable metaphases), CNS leukemia at the time of diagnosis in 7%, and a mediastinal mass in 7%. Treatment consisted of four cycles of Hyper-CVAD alternating with four cycles of high-dose methotrexate (MTX) and cytarabine therapy, together with intrathecal CNS prophylaxis and supportive care with antibiotic prophylaxis and granulocyte colony-stimulating factor therapy. Maintenance in patients with nonmature B-cell ALL included 2 years of treatment with mercaptopurine, MTX, vincristine, and prednisone (POMP).
RESULTS: Overall, 185 patients (91%) achieved complete remission (CR) and 12 (6%) died during induction therapy. Estimated 5-year survival and 5-year CR rates were 39% and 38%, respectively. The incidence of CNS relapse was low (4%). Compared with 222 patients treated with vincristine, doxorubicin, and dexamethasone (VAD) regimens, our patients had a better CR rate (91% v 75%, P <.01) and CR rate after one course (74% v 55%, P <.01) and better survival (P <.01), and a smaller percentage had more than 5% day 14 blasts (34% v 48%, P =.01). Previous prognostic models remained predictive for outcome with Hyper-CVAD therapy.
CONCLUSION: Hyper-CVAD therapy is superior to our previous regimens and should be compared with established regimens in adult ALL.
Françoise Huguet, Thibaut Leguay, Emmanuel Raffoux, Xavier Thomas, Kheira Beldjord, Eric Delabesse, Patrice Chevallier, Agnes Buzyn, André Delannoy, Yves Chalandon, Jean-Paul Vernant, Marina Lafage-Pochitaloff, Agnès Chassevent, Véronique Lhéritier, Elizabeth Macintyre, Marie-Christine Béné, Norbert Ifrah, Hervé Dombret
Pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: the GRAALL-2003 study.
J Clin Oncol. 2009 Feb 20;27(6):911-8. doi: 10.1200/JCO.2008.18.6916. Epub 2009 Jan 5.
Abstract/Text
PURPOSE: Retrospective comparisons have suggested that adolescents or teenagers with acute lymphoblastic leukemia (ALL) benefit from pediatric rather than adult chemotherapy regimens. Thus, the aim of the present phase II study was to test a pediatric-inspired treatment, including intensified doses of nonmyelotoxic drugs, such as prednisone, vincristine, or L-asparaginase, in adult patients with ALL up to the age of 60 years.
PATIENTS AND METHODS: Between 2003 and 2005, 225 adult patients (median age, 31 years; range, 15 to 60 years) with Philadelphia chromosome-negative ALL were enrolled onto the Group for Research on Adult Acute Lymphoblastic Leukemia 2003 protocol, which included several pediatric options. Some adult options, such as allogeneic stem-cell transplantation for patients with high-risk ALL, were nevertheless retained.
RESULTS: were retrospectively compared with the historical France-Belgium Group for Lymphoblastic Acute Leukemia in Adults 94 (LALA-94) trial experience in 712 patients age 15 to 55 years. Results Complete remission rate was 93.5%. At 42 months, event-free survival (EFS) and overall survival (OS) rates were 55% (95% CI, 48% to 52%) and 60% (95% CI, 53% to 66%), respectively. Age remained an important bad prognostic factor, with 45 years of age as best cutoff. In older versus younger patients, there was a higher cumulative incidence of chemotherapy-related deaths (23% v 5%, respectively; P < .001) and deaths in first CR (22% v 5%, respectively; P < .001), whereas the incidence of relapse remained stable (30% v 32%, respectively). Complete remission rate (P = .02), EFS (P < .001), and OS (P < .001) compared favorably with the previous LALA-94 experience.
CONCLUSION: These results suggest that pediatric-inspired therapy markedly improves the outcome of adult patients with ALL, at least until the age of 45 years.
