The role of gemtuzumab ozogamicin in the treatment of acute myeloid leukemia patients

Gemtuzumab Ozogamicin (GO) targets leukemia cells expressing CD33 by means of a monoclonal antibody conjugated to a cytotoxic agent, calicheamicin. GO has been approved in Japan as monotherapy for the treatment of patients with relapsed/refractory acute myeloid leukemia (AML)since 2005. GO administered as a single agent has resulted in overall response rates of about 30% in previously relapsed adult AML. Preliminary data indicate a potential role for GO also as a component of induction or consolidation regimen. Although caution is advised when administering GO within 115 days of a stem cell transplantation (SCT) procedure because of veno-occlusive disease, recent clinical studies overseas suggest that GO can be integrated into reduced-intensity conditioning therapy before allogeneic SCT in patients with relapsed AML. In order to reduce toxicity and improve efficacy, its optimal dose and schedule should be defined by large clinical trials.     

Mitoxantrone, etoposide, carboplatinum and ara-C combination therapy (MECA) in refractory and relapsed acute leukemia

The present study was undertaken to assess the feasibility, toxicity and antileukemic activity of sequential chemotherapy including mitoxantrone, etoposide, carboplatin and intermediate-dose cytarabine in adult patients with refractory and relapsed acute myelogenous (AML) or lymphoid (ALL) leukemia. Fifty-one patients with poor-risk AML and ALL received 64 courses of MECA therapy. The overall response in the entire group was 51% (43% complete remission). The stage of the disease (relapsed or primarily refractory) and the age of the patients did not strongly affect the response rate. MECA therapy was more effective in ALL than in AML, and in those patients who presented at salvage treatment with a bone marrow infiltration lower than 25% blasts. Hematological and extra-hematological toxicities were tolerable and there were 6 deaths related to the treatment (11%). The incidence of documented infectious episodes was 71%. MECA therapy is a safe treatment and has a high antileukemic activity in relapsed and primarily refractory AML or ALL.     

博纳吐单抗治疗急性淋巴细胞白血病的研究进展

近年来,随着免疫治疗和造血干细胞移植技术（hematopoietic stem cell transplantation,HSCT）的发展,急性淋巴细胞白血病（acute lymphoblastic leukemia,ALL）的缓解率逐渐升高,但复发难治性ALL的预后仍旧很差。博纳吐单抗（blinatumomab）作为一个新型的CD3和CD19双特异性抗体在复发难治性ALL中均获得较好的疗效,并于2014年12月被美国食品药品监督管理局（FDA）批准用于复发难治性急性B淋巴细胞白血病（B-cell acute lymphoblastic leukemia,B-ALL）的治疗。博纳吐单抗单药治疗初治ALL及联合化疗药物、酪氨酸激酶抑制剂治疗ALL均可改善患者生存期。本文主要围绕博纳吐单抗的临床试验、不良反应等方面的最新研究进行阐述。      

Inotuzumab Ozogamicin: A Review in Relapsed/Refractory B-Cell Acute Lymphoblastic Leukaemia

The intravenous CD22-directed antibody drug conjugate inotuzumab ozogamicin (Besponsa^®) is approved in several countries including in the USA, EU and Japan, as monotherapy for the treatment of adults with relapsed/refractory B-cell acute lymphoblastic leukaemia (ALL). In adults with relapsed/refractory B-cell ALL who had received one or two prior treatment regimens, inotuzumab ozogamicin was associated with significantly higher rates of complete remission (including complete remission with incomplete haematological recovery) [CR/CRi] than standard therapy in the pivotal INO-VATE ALL trial. Inotuzumab ozogamicin was associated with significantly longer progression-free survival (PFS), duration of remission and higher haematopoietic stem cell transplantation (HSCT) rates than standard therapy. Although there was no significant between-group difference in overall survival duration as per the study design, the 2-year survival probability in the inotuzumab ozogamicin arm was twice that in the control arm. Inotuzumab ozogamicin had an acceptable tolerability profile. Thus, inotuzumab ozogamicin is an important new treatment option for patients with relapsed/refractory CD22-positive B-cell ALL.     

Complete remission with romidepsin in a patient with T‐cell acute lymphoblastic leukemia refractory to induction hyper‐CVAD

T‐cell acute lymphoblastic leukemia (T‐ALL) and T‐cell lymphoblastic lymphoma (T‐LBL) are neoplasms that originate from T‐cell precursors. Outcomes in adult patients with T‐ALL/LBL remain unsatisfactory; early relapse following intensive induction chemotherapy is a concern, and patients with relapsed or refractory disease have a poor prognosis. Romidepsin is a potent, class 1 selective histone deacetylase inhibitor approved for the treatment of patients with peripheral T‐cell lymphoma who have had ≥1 prior therapy and patients with cutaneous T‐cell lymphoma who have had ≥1 prior systemic therapy. Here, we report the case of an adult patient with T‐ALL refractory to induction hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper‐CVAD). Treatment with romidepsin was initiated, and romidepsin in combination with hyper‐CVAD resulted in complete remission, with mild tumor lysis syndrome as the only detectable additional toxicity. The patient eventually underwent allogeneic stem cell transplant while in first complete remission. Prior studies have shown that romidepsin is capable of inducing durable responses with manageable toxicities in patients with mature T‐cell lymphomas. This case study describes the successful use of romidepsin in combination with hyper‐CVAD in an adult patient with refractory T‐ALL and highlights the activity of romidepsin in the T‐cell lineage. The potential of romidepsin‐containing regimens in patients with T‐ALL/LBL deserves further study.     

Synergy of sequential administration of a deglycosylated ricin A chain-containing combined anti-CD19 and anti-CD22 immunotoxin (Combotox) and cytarabine in a murine model of advanced acute lymphoblastic leukemia

Abstract The outcome for patients with refractory or relapsed acute lymphoblastic leukemia (ALL) treated with conventional therapy is poor. Immunoconjugates present a novel approach and have recently been shown to have efficacy in this setting. Combotox is a mixture of two ricin-conjugated monoclonal antibodies (RFB4 and HD37) directed against CD19 and CD22, respectively, and has shown activity in pediatric and adult ALL. We created a murine xenograft model of advanced ALL using the NALM/6 cell line to explore whether the combination of Combotox with the cytotoxic agent cytarabine (Ara-C) results in better outcomes. In our model the combination of both low- and high-dose Combotox and Ara-C resulted in significantly longer median survival. Sequential administration of Ara-C and Combotox, however, was shown to be superior to concurrent administration. These findings have led to a phase I clinical trial exploring this combination in adults with relapsed or refractory B-lineage ALL (ClinicalTrials.gov identifier NCT01408160).     

SOHO State of the Art Updates and Next Questions: Novel Transplant and Post-Transplant Options in Acute Lymphoblastic Leukemia

Allogeneic hematopoietic cell transplantation (alloHCT) is a potentially curative treatment approach for patients with high-risk acute lymphoblastic leukemia (ALL). Despite development of several novel therapies targeting B-cell ALL, alloHCT continues to play an essential role in management, but the identification of patients who are most likely to benefit from alloHCT in first or subsequent remissions continues to evolve. Broader donor options, including haploidentical donors and umbilical cord blood, have enabled alloHCT for more patients, but improvements in front-line therapy and increasing use of high-sensitivity measurable residual disease (MRD) quantification continue to modify the calculus for selecting which patients require transplantation. MRD quantification has become increasingly important as a prognostic indicator, as well as a trigger for therapeutic intervention, since the achievement of MRD negative complete remission is well-established to be associated with improved transplant outcomes. ALL remains the only malignancy with approved therapy for MRD positivity after achievement of remission, and use of Blinatumomab in this setting currently appears to be most effective when used as a bridge-to-transplant, rather than a destination or purely consolidative therapy. Expanding options for those with relapsed/refractory disease, including chimeric antigen receptor (CAR)-T cells, also render more patient in suitably deep remissions to enable alloHCT with a high likelihood of success. It remains unclear whether CAR-T cell therapies may obviate the need for alloHCT in some patients, and currently available data suggest there remains a role for alloHCT after CAR-T. Together, these therapeutic advances appear to be improving post-transplant outcomes. Nevertheless, more remains to be studied regarding how to optimize use of available and emerging cellular and immune modulating therapies to maximize the likelihood of long-term post-alloHCT remission in high-risk ALL.     

Risk and prognosis of central nervous system leukemia in patients with Philadelphia chromosome-positive acute leukemias treated with imatinib mesylate.

PURPOSE: In patients with acute leukemias, a lymphoid phenotype, the presence of a Philadelphia chromosome (Ph), and inadequate central nervous system (CNS)-directed prophylactic therapy are risk factors for CNS involvement. Imatinib mesylate has promising single-agent antileukemic activity in patients with advanced Ph(+) acute leukemias. It was the aim of this analysis to determine the incidence of, and risk factors associated with, meningeal leukemia during imatinib monotherapy. STUDY DESIGN: We analyzed 107 consecutive patients with relapsed or refractory Ph(+) acute lymphoid leukemia (ALL; n = 65) or chronic myeloid leukemia blast crisis (n = 42) who were enrolled in successive Phase II trials of single-agent imatinib and who did not receive routine prophylactic intrathecal chemotherapy. RESULTS: CNS leukemia developed in 13 of 107 patients (12%) and was associated primarily with a lymphoid or bilineage phenotype (12 of 78; 15%) and with imatinib refractory Ph(+) ALL (5 of 19; 26%). Meningeal leukemia did not occur among patients who received prior prophylactic cranial irradiation. The median survival with combined CNS and systemic disease was 108 days (range, 58-141), with no patient surviving long term. In contrast, two of three patients with exclusively meningeal leukemia achieved prolonged molecular remissions with intrathecal chemotherapy, cranial irradiation, and continued imatinib. CONCLUSIONS: Patients with Ph(+) ALL are at considerable risk of meningeal leukemia during imatinib monotherapy and should routinely receive CNS prophylaxis. Although the prognosis with combined meningeal and systemic relapse is dismal, patients with an isolated meningeal relapse may still achieve sustained remissions. The optimal type of CNS-directed treatment and the extent of protection afforded by prophylactic cranial irradiation remain to be defined.     

Teniposide in the treatment of leukemia: a case study of conflicting priorities in the development of drugs for fatal diseases

Teniposide, a semisynthetic epipodophyllotoxin, was found to be highly active against murine leukemias, and the combination of teniposide with cytosine arabinoside (ara-C) was curative in murine leukemia models. The antitumor activity in preclinical models prompted introduction of teniposide into the clinic in 1971. Although teniposide as a single agent rarely produced a complete remission in heavily pretreated leukemia patients, teniposide plus ara-C produced complete remissions in some patients with refractory and relapsed acute lymphoblastic leukemia (ALL). Innovative front-line and salvage regimens using teniposide have been developed that incorporate a multi-drug strategy with early intensification, rotation of drug combinations in maintenance, and regional therapy in an effort to improve the cure rate in leukemia. However, as the complexity of these regimens increases, the contribution of an individual component such as teniposide becomes less clear. Although some of these regimens for newly diagnosed and relapsed ALL are now thought to represent the best available therapy, teniposide remains an investigational agent. In this review, we outline and discuss the conflicts arising from the need to answer drug-specific issues, and, at the same time, facilitate the implementation of innovative, curative regimens.     

Immune evasion strategies of pediatric precursor-B acute lymphoblastic leukemia after allogeneic bone marrow transplantation-a case study

Bone marrow transplantation (BMT) is the primary curative option for refractory/relapsed pediatric acute lymphoblastic leukemia. Although post-transplantation relapse remains a frequent cause of transplantation failure, the mechanisms underlying this are poorly understood. In this study, we compared allogeneic T cell stimulation induced by sequentially obtained precursor-B acute lymphoblastic leukemia (ALL) samples from a single patient with overt graft versus leukemia (GVL) activity. We observed a loss of T cell stimulatory capacity by post-transplantation relapse samples and changes in expression of MHC and the costimulatory molecule CD137 ligand. This study suggests that escape from immune mechanisms after withdrawal of immune suppression is important to ALL progression.     

Systematic Review and Meta-analysis of CD19-Specific CAR-T Cell Therapy in Relapsed/Refractory Acute Lymphoblastic Leukemia in the Pediatric and Young Adult Population: Safety and Efficacy Outcomes

Acute lymphoblastic leukemia (ALL) typically responds better when treated with multiagent chemotherapy in the pediatric and young adolescent populations. Treatment of relapsed/refractory (RR) ALL remains a challenge. Even after stem-cell transplantation and intensive chemotherapy, the prognosis of RR-ALL remains grave. The advent of chimeric antigen receptors has demonstrated promising results in RR-ALL. Chimeric antigen receptor–modified T cells (CAR-T) and engineered T cells are used to target cancer cells. In 2017, the US Food and Drug Administration approved CD19-specific CAR-T (tisagenlecleucel) therapy for RR–B-cell ALL in patients under 25 years old. In this systematic review, we discuss the efficacy and safety of CD19-specific CAR-T therapy in RR–B-cell ALL in the pediatric and young adult population. We searched the PubMed, Embase, Web of Science, Cochrane Library, and clinical trials databases. A total of 448 patients received a CD19-specific CAR-T product, and 446 patients had evaluable data. The age range was 0 to 30 years. The incidence rate of complete remission was 82%. The cumulative incidence of relapse after CD19-specific CAR-T therapy is 36%. Similarly, the incidence rate of grade 3 or higher adverse events of neutropenia, thrombocytopenia, neurotoxicity, infections, and cytokine release syndrome were 38%, 23%, 18%, 29%, and 19%, respectively. Our subgroup analysis shows the incidence rate of minimal residual negative complete remission was 69% with the CD28z costimulatory domain, 81% with the 4-1BB domain, and 77% with fourth-generation CD19-specific CAR-T therapy.     

SOHO State of the Art Updates and Next Questions: Managing Relapsed Mantle Cell Lymphoma

Mantle cell lymphoma (MCL) is a rare subtype of B-cell non-Hodgkin lymphoma i.e., incurable with current therapies. While some patients experience prolonged remissions following initial therapy, most will have a relapsing-remitting course requiring several lines of treatment over the course of their disease. Several targeted therapies are now available to treat patients with relapsed MCL. The Bruton's tyrosine kinase (BTK) inhibitors, including ibrutinib, acalabrutinib, and zanubrutinib, are highly active in MCL and currently approved for treating patients with relapsed disease. Bortezomib and lenalidomide are available as monotherapy or in combination with other agents. Venetoclax is active and can be considered for use in relapsed MCL, although it is not currently approved by regulatory agencies. Chimeric antigen receptor T-cell (CAR-T) therapy with brexucabtagene autoleucel yields high response rates and is now approved for patients with relapsed MCL. Allogeneic stem cell transplant remains an option for a small subset of medically fit and motivated patients who have progressed through multiple lines of therapy, although its use is limited by substantial toxicity. There is currently no standard approach to sequencing therapies for patients with relapsed MCL, and the ability to utilize disease biologic and clinical characteristics to guide treatment decisions in this setting remains limited. In this review, we summarize the current evidence to guide the management of patients with relapsed MCL, review emerging agents and combination therapies that are under investigation, and outline our current treatment approach for these patients.     

Akute Leukämien des Erwachsenen

Background

The prognosis of adult patients with acute leukemia has continuously improved over the years due to the introduction of new diagnostic and therapeutic procedures and progress in the field of supportive therapy.

Methods

This article gives an overview of the currently available options and the clinical approach to the diagnostics and therapy of acute leukemia.

Results

The standardization as well as improvements in diagnostic procedures, in particular by immunocytological and genetic procedures, allow a more rapid determination of the exact diagnosis. In addition to age and performance status of patients, an established panel of cytogenetic and molecular markers allows an individual risk stratification for selecting the most appropriate therapeutic procedure for each patient. In acute myeloid leukemia (AML) younger patients with genetically determined intermediate and poor risk status benefit from allogeneic stem cell transplantation whereas patients in the low risk group are still primarily treated with conventional induction chemotherapy with anthracycline and cytarabine. The poor prognosis of elderly patients with AML has been improved by the development of stem cell transplantation procedures with reduced intensity conditioning and for patients not suitable for stem cell transplantation, the introduction of less toxic demethylating substances allows a substantial improvement in outcome and quality of life compared to cytoreductive therapy alone. The additional role of targeted therapies in AML is still under investigation. In adult patients with acute lymphoblastic leukemia (ALL), the standard systemic therapy still consists of complex cytotoxic regimens which have been modified from pediatric protocols. Biologically and genetically determined subgroups of ALL patients as well as poor responders, who can be identified by the detection of significant molecular determined residual disease (MRD) after standard therapy, benefit from allogeneic transplantation in first remission. In patients with bcr-abl positive ALL, the implementation of first and second generation tyrosine kinase inhibitors has led to rapidly rising response rates and less toxicity. Patients with relapsed ALL may benefit from new molecular options, e.g. bispecific antibodies. Additionally, improved standardization and supportive care, particularly due to the introduction of modern antimycotic agents, increase the treatment options and improve the prognosis of patients with acute leukemia.

Conclusion

The improved diagnostic and therapeutic options for patients with acute leukemia require a complex management. Currently only subgroups of patients benefit from molecular targeted therapeutic strategies. Due to this increasing complexity in the management, patients with acute leukemia should be treated in academic centers and within clinical trials.

     

Phase II trial of amsacrine plus intermediate-dose Ara-C (IDAC) with or without etoposide as salvage therapy for refractory or relapsed acute leukemia

OBJECTIVE: The current trial attempted to evaluate the efficacy and toxicity of a salvage therapy consisting of amsacrine plus intermediate-dose Ara-C (IDAC) with or without etoposide for acute leukemia patients in refractory or relapsed states. METHODS: A total of 51 patients with refractory or relapsed acute leukemia were included in the current trial. Twenty-nine patients with acute myeloid leukemia (AML) received a salvage therapy of amsacrine plus IDAC and etoposide, while 22 patients with acute lymphoblastic leukemia (ALL) received amsacrine plus IDAC. RESULTS: The overall complete remission rate was 55% (45% for AML, 68% for ALL) and the median duration of overall survival was 144 days (95% confidence interval = 101-186 days). Grade 3, 4 infectious toxicities were observed in 43 patients (87%), while treatment-related toxicity, excluding infectious causes, included heart failure from myocarditis (n = 1) and central nervous system toxicity (n = 1). CONCLUSION: A salvage therapy consisting of amsacrine plus IDAC with or without etoposide appears to be safe and an effective bridge therapy into a stem cell transplantation programme for patients with refractory or relapsed acute leukemia.     

Autologous bone marrow transplantation in acute leukemia.

Autologous bone marrow transplantation can induce long-term LFS in 20% to 40% of patients with relapsed acute leukemia and should be considered as salvage therapy for patients who lack an HLA-matched donor and for patients over 45. Adult ALL patients and children with ALL in extramedullary relapse beyond second CR should receive alloBMT if at all possible. The role of ABMT in acute leukemia patients in first CR remains unclear despite randomized trials (Table 2). Because protocol deviations, early relapse, and inappropriately high treatment-related mortality unequally affected the ABMT cohort, and because recent randomized trials have used old purging methodologies, it is not possible to conclude that ABMT is not beneficial. More recent studies show that most patients are able to proceed with the intended ABMT and that modern purging may be associated with a treatment-related mortality rate of less then 5%. Immunomodulation and graft engineering uniquely suited to autologous progenitor cells indicate that ABMT should continue to be studied in the management of acute leukemia.     

Novel Therapeutic Strategies in Adult Acute Lymphoblastic Leukemia – A Focus on Emerging Monoclonal Antibodies

The outcomes in adult B-cell acute lymphoblastic leukemia (ALL) remain inferior to those achieved in pediatric populations. Targeted therapy with monoclonal antibodies may improve outcomes in adult B-cell ALL without significant additive toxicity. Rituximab is the best known monoclonal antibody and is routinely used in combination chemo-immunotherapy for treatment of adult B-cell ALL and Burkitts leukemia. A number of other monoclonal antibodies are currently under investigation for treatment of adult B-cell ALL including unconjugated antibodies (eg., ofatumumab, alemtuzumab and epratuzumab), antibodies conjugated to cytotoxic agents (eg., inotuzumab ozogamycin and SAR3419), antibodies conjugated to toxins such Pseudomonas or Diptheria toxins (eg., BL22 and moxetumomab pasudotox), and T-cell engaging bi-specific antibodies that redirect cytotoxic T lymphocytes to lyse target ALL cells (eg., blinatumomab). In this article we review the therapeutic implications, current status and results of monoclonal antibody-based therapy in adult B-cell ALL.     

成人急性白血病强化治疗67例预后分析

目的：观察成人急性白血病（ＡＬ） 患者完全缓解（ＣＲ） 后强化治疗的效果。方法：对６７ 例ＣＲ后的成人ＡＬ患者进行强化治疗,急性髓细胞性白血病（ＡＭＬ）以中剂量阿糖胞苷（ＩＤ－ Ａｒａ－ Ｃ）方案为主,急性淋巴细胞性白血病（ＡＬＬ）以中剂量氨甲蝶呤（ＩＤ－ ＭＴＸ）方案为主。结果：４８ 例ＡＭＬ患者中位ＣＲ 期１６ 个月,预期３ 年和４ 年无病生存（ＤＦＳ）为３６９％ 和２１１ ％ ;２３ 例（４７９ ％） 患者复发。１９ 例ＡＬＬ 患者中位ＣＲ 期１４ 个月,预期４ 年ＤＦＳ 为３１５％ ;１０ 例（５２６％ ） 患者复发。结论：以ＩＤ－ Ａｒａ－ Ｃ 为主的强化方案及以ＩＤ－ ＭＴＸ 为主的强化方案分别能延长ＡＭＬ及ＡＬＬ患者的ＤＦＳ,降低复发率     

Relapsed acute lymphoblastic leukemia: Current status and future opportunities

Significant improvements in primary therapy for childhood acute lymphoblastic leukemia (ALL) have led to dramatic increases in cure rates over the past few decades. Relapsed ALL, however, remains more common than new diagnoses of many common pediatric malignancies. Outcomes for patients with relapsed ALL remain poor, especially for patients with early bone marrow relapse. However, most relapse patients do achieve a second complete remission, followed by therapeutic options including further chemotherapy and hematopoietic stem cell transplant. The level of minimal residual disease after achieving second remission or before transplant may predict outcomes. The substantial likelihood of achieving second remission with familiar drug combinations may discourage participation in formal relapse studies. The high likelihood of achieving a third remission may discourage participation in single-gent trials of new drugs, despite the critical need for novel agents with activity against resistant disease that may improve outcomes for recurrent ALL.     

Remission induction in adult acute lymphocytic leukemia. Use of vincristine and prednisone alone.

Therapy for acute lymphocytic leukemia (ALL) has been less successful in adults than in children. Many centers treat all adult leukemia with the same regimen. We have used vincristine and prednisone for initial therapy in 14 adults with ALL since 1971 and have followed a treatment regimen developed for childhood ALL for subsequent therapy as well. Complete remissions were attained in 13, and complications and duration of hospitalization were minimized with this nonmyelotoxic regimen. Central nervous system "prophylactic" therapy was also well tolerated in these adult patients. However, remission duration and survival in our series were similar to those reported by others. That complete remission can be attained in a high percentage of adult patients with ALL through use of relatively nontoxic treatment demonstrates the importance of selecting out this group of patients from all adults with acute leukemia.     

靶向PI3K/AKT/mTOR信号通路治疗急性T淋巴细胞白血病的研究进展

急性T淋巴细胞白血病(T-ALL)是来源于胸腺T细胞祖细胞的具有强侵袭性和异质性的血液系统恶性肿瘤。T-ALL约占儿童急性淋巴细胞白血病(ALL)的15%,在成人ALL中的比例约为25%。强化化疗方案的应用使儿童T-ALL患者预后显著提高,但成人及复发耐药T-ALL患者的预后仍较差。研制新型靶向药物特异性阻断T-ALL细胞内生存及耐药相关的异常激活信号通路近年来被认为是治疗成人及复发难治T-ALL患者的新策略。PI3K/AKT/mTOR通路是T-ALL细胞内异常激活信号通路中具有代表性的一条。目前靶向该通路的多种小分子抑制剂已被成功研制,并在治疗T-ALL的研究中取得良好效果。PI3K/AKT/mTOR通路相关抑制剂较传统化疗药物具有更高的特异性和更低的毒副作用,且诸多研究表明其与低剂量化疗药物或其他靶向药物联合治疗T-ALL能发挥协同效应。本综述将总结近年来在PI3K/AKT/mTOR通路与T-ALL相关领域的研究成果,并对基于靶向该通路治疗T-ALL的研究进展一并阐述。