Clinical manifestations and treatment of newly diagnosed acute lymphoblastic leukemia in adults

Adult acute lymphoblastic leukemia (ALL) is a heterogeneous disease with distinct biologic and prognostic subgroups. The treatment of adults with ALL has evolved largely from the therapy developed for childhood ALL and, despite differences across regimens, can be broadly classified as including induction, consolidation, maintenance, and central nervous system prophylaxis. Although there has been marked improvement in the outcomes for pediatric patients with ALL, the same success has not yet been realized for adult patients. Some of this difference can be attributed to a greater incidence of unfavorable cytogenetic subtypes in adults than in children. In addition, the ability to tolerate intensive regimens likely plays a role. This article reviews the classification, prognostic features, current treatment programs, and new advances as applied to adult patients with newly diagnosed ALL.     

Management of adult acute lymphoblastic leukemia: moving toward a risk-adapted approach

The vast majority of adults with acute lymphoblastic leukemia (ALL) now achieve remission with current intensive chemotherapy regimens. Nevertheless, most adults with ALL will eventually relapse and die of their disease. Specific clinical and molecular-cytogenetic prognostic factors have been identified that are beginning to provide insights for the development of risk-adapted management strategies that appear to improve survival for several high-risk patient groups, including those with mature B-cell ALL and B-lineage ALL patients with a Philadelphia chromosome. We review standard and some recently described prognostic factors in adult ALL, describe current therapy based on a risk-adapted approach, and look toward the future with a brief discussion of novel, targeted treatments that could be incorporated into postremission strategies to improve survival for adults with ALL.     

Acute lymphoblastic leukemia in adolescents and young adults

Age at diagnosis remains one of the strongest prognostic factors in acute lymphoblastic leukemia (ALL), with older patients having inferior outcomes compared with younger patients. Adolescents and young adults (AYAs) with ALL (age 15–30 years) represent a patient subgroup with distinctive biology whose optimal therapy has yet to be determined. Compared with younger children with ALL, AYAs are more likely to present with unfavorable presenting characteristics (such as high presenting leukocyte counts, T-cell phenotype, and the Philadelphia chromosome). Additionally, AYAs with ALL experience more regimen-related toxicity than younger patients. Recent retrospective studies suggest that patients age 15 to 21 years treated on pediatric ALL regimens have better outcomes than similarly aged patients treated on adult ALL regimens. Pilot prospective studies are under way to test the feasibility of administering pediatric ALL regimens to AYAs with ALL, with promising preliminary results.     

SOHO State of the Art Updates and Next Questions | Asparaginase—Understanding and Overcoming Toxicities in Adults with ALL

The adoption of pediatric-inspired regimens in young adults with newly diagnosed acute lymphoblastic leukemia (ALL) has significantly improved their survival outcomes. Pediatric-inspired regimens in ALL rely profoundly on delivering adequate dosing of non-myelosuppressive drugs of which asparaginase, a bacterial derived agent, is a key component. Asparaginase therapy is associated with a spectrum of unique toxicities that are observed more frequently in adult patients compared to children with ALL, and this observation has contributed to the reluctance of adult oncologists to administer the drug to their patients. Understanding the breadth of asparaginase toxicity and the associated risk factors may help in preventing severe manifestations and allow safer treatment for adults with ALL. In this review, we will discuss the different formulations of asparaginase and the appropriate dosing in adults with ALL. We will further discuss the frequency and risk factors for individual toxicities of asparaginase along with strategies for their prevention and management.     

New agents for the treatment of patients with acute lymphoblastic leukemia

Acute lymphoblastic leukemia (ALL) has a bimodal age distribution with a peak occurring during early childhood and a second peak after age 45. Although all patients are treated with similar intensive chemotherapy regimens, good outcomes have occurred more frequently in children than adults. Most children with ALL have been able to achieve a complete remission (CR) with an induction rate of about 98% and a 5-year estimated event-free survival rate (EFS) rate of about 80%. Unfortunately, the results for adults are less encouraging. Current adult treatment regimens result in CR rates approaching 80%, with EFS at 5 years of only 30% to 40%. Regardless of age, patients with relapsed or refractory ALL have extremely poor outcomes, because CR rates are low and seldom durable. Clearly, new agents are required to improve the outcome of patients with relapsed or refractory 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.     

New approaches to acute lymphoblastic leukemia in adults: where do we go?

The optimization of conventional treatment approaches, such as chemotherapy, stem cell transplantation (SCT), and supportive care, and the exploration of new approaches will hopefully further improve the outcome of adults with acute lymphoblastic leukemia (ALL). Subgroup-adjusted treatment has already greatly improved treatment outcomes in T- and mature B-cell ALL. These approaches should be further refined, for example, in T-ALL with cyclophosphamide and cytarabine, in pro-B ALL with high-dose cytarabine (HdAC), in B-precursor ALL with high-dose methotrexate (HdM) and 6-mercaptopurine (6-MP), and in mature B-ALL with HdM and HdAC. The indications for SCT will be extended to include elderly patients undergoing allogeneic mini-transplants, and tumor eradication will be improved by better conditioning regimens such as radioimmunoconjugates and methods to induce the graft-versus-leukemia (GvL) effect, such as donor leukocyte infusions (DLI) or allogeneic mini-transplants applied after autologous transplants. Molecular therapeutic approaches, for example, those directed against the fusion protein BCR-ABL with ABL-tyrosine kinase inhibitor, are on the way to creating a new avenue for the treatment of ALL. In the future, drug resistance should be exploited as a pretherapeutic test for treatment strategies, but whether multidrug resistance modulation with available drugs will be used in ALL remains open. Evaluation of the pharmacokinetics of cytostatic drugs and the pharmacogenomics of cytostatic agents in adult ALL may contribute to the development of individualized treatment strategies with higher efficacy and lower toxicity. Minimal residual disease (MRD) evaluation is attractive in adult ALL, because it can be determined in a very high percentage of patients. It has been shown to be predictive for relapse and might be of benefit for redefinition of complete remission (CR), for determination of the efficacy of single treatment elements, and for treatment tailoring during the course of disease. New treatment approaches include also several forms of immunotherapy for B- as well as T-lineage ALL; after the demonstration that such approaches are also effective in ALL, their optimal place in the treatment strategy for adult ALL can be determined.     

Studies of minimal residual disease in acute lymphocytic leukemia

During the past 2 decades, there has been considerable progress made in the treatment of childhood and adult lymphocytic leukemia (ALL). Currently, 70% to 90% of adults achieve a complete remission, and 25% to 50% of these patients may experience prolonged disease-free survival and may be cured of their disease. Unfortunately, most adults with ALL will ultimately experience a recurrence and die of their leukemia. Although most children with ALL may now be cured with current therapeutic regimens, the ability to distinguish good-risk patients from those who are likely to relapse has important clinical implications. Relapse, in most pediatric and adult cases, is thought to result from residual leukemia cells that remain following achievement of "complete" remission but are below the limits of detection using conventional morphologic assessment of the bone marrow. Sensitive techniques are now available to detect subclinical levels of residual leukemia, termed minimal residual disease.     

Meningeosis leukaemica in adult acute lymphoblastic leukaemia

This review addresses diagnosis of CNS involvement, incidence and treatment of CNS disease at time of diagnosis, prophylaxis and treatment of CNS relapse and risk factors for meningeal recurrence in adult acute lymphoblastic leukaemia (ALL).At the time of diagnosis meningeosis leukaemica is present in about 6% (1–10%) of the adult ALL patients with a higher incidence in ALL subgroups T-ALL (8%) and B-ALL (13%). With the invention of early additional CNS directed therapy it no longer represents an unfavourable prognostic factor.In the absence of prophylaxis meningeal relapses occur in approximately one third of adults with ALL. A literature review including more than 4000 adult ALL patients showed for the different prophylactic treatment approaches the following CNS relapse rates: intrathecal therapy alone 13% (8–19%), intrathecal therapy and CNS irradiation 15% (6–22%), high dose chemotherapy 14% (10–16%), high dose chemotherapy and intrathecal therapy 8% (2–16%) and high dose chemotherapy, intrathecal therapy together with CNS irradiation 5% (1–12%). It became obvious that the early onset of intrathecal therapy and CNS irradiation and the continuation of intrathecal administrations throughout maintenance are essential. The most favourable results where achieved with high dose chemotherapy combined with intrathecal therapy and/or CNS irradiation. The majority of treatment regimens in adult ALL already include high dose chemotherapy in order to reduce the risk of bone marrow relapse.The outcome of patients with CNS relapse is still poor. Although a remission can be induced in the majority of patients (> 60%) it is usually followed by a bone marrow relapse and the survival is poor (< 5–10%). Bone marrow transplantation might be in adults at present the only curative approach.     

New insights into the pathophysiology and therapy of adult acute lymphoblastic leukemia

Significant advances have been made in the last decade toward a better understanding of the disease pathogenesis and the development of novel therapies that target specific subsets of adult acute lymphoblastic leukemia (ALL). Risk‐adapted strategies are transforming the disease treatment and prognosis. With current treatment regimens, long‐term survival is achieved by approximately 50% of patients with B‐cell ALL, 50% to 60% of patients with Philadelphia chromosome–positive ALL, and approximately 80% of patients with Burkitt's leukemia. Genomic profiling in ALL has identified new prognostic markers, new therapeutic targets, and novel ALL subtypes. These may be amenable to future targeted therapies that can further improve outcomes. The early recognition of early precursor T‐cell ALL, a distinct pathobiological entity with a poor prognosis, is essential for the development of an effective clinical management strategy. The role of monoclonal antibodies and cytotoxic T‐cell therapies continues to be defined. Many of the approaches are currently being evaluated for ALL salvage. Their incorporation into frontline adult ALL therapy, in concomitant or sequential strategies, may increase the cure rates to levels achieved in pediatric ALL and may reduce the need for prolonged intensive and maintenance chemotherapy. Cancer 2015;121:2517–2528 . © 2015 American Cancer Society.     

SOHO State of the Art Updates & Next Questions: Intensive and Non–Intensive Approaches for Adults With Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) was historically considered to be a very poor-risk subtype of ALL. However, with the introduction of highly potent BCR-ABL tyrosine kinase inhibitors (TKIs), Ph+ ALL can now be considered relatively favorable-risk acute leukemia. Considering the high rates of measurable residual disease negativity and excellent long-term survival that has been achieved with regimens incorporating later-generation TKIs and particularly with ponatinib, lower-intensity and even chemotherapy-free regimens are now being evaluated for patients of all ages with Ph+ ALL. The very encouraging early results observed with blinatumomab-based, chemotherapy-free regimens challenge previous notions that all patients with Ph+ ALL should undergo allogeneic stem cell transplantation in first remission, as these regimens are capable of achieving deep and durable remissions without need for transplant in the vast majority of patients, particularly when combined with ponatinib. In this review, we discuss the evolving approach to the treatment of adults with newly diagnosed Ph+ ALL and the major principles that should guide therapy in this disease. We also review the rationale and data supporting the use of novel, chemotherapy-free regimens in Ph+ ALL, and how these approaches may soon become new standards of care.     

Induction therapy of adult acute lymphocytic leukemia without the use of vincristine or prednisone

In the last 30 years, a multitude of treatment regimens for adult acute lymphocytic leukemia (ALL) has been developed. Essentially, all of these regimens use an induction therapy vincristine, prednisone, and an anthracycline intensified with L-asparaginase or cyclophosphamide. Though such regimens induce most patients to enter a remission, relapse is frequent, and most adult patients ultimately die of their disease. The author postulated that further refinements in this approach to induction therapy were unlikely to markedly improve treatment results in this disease. Therefore, the author is studying a new intensive strategy using cytarabine with a single very high dose of mitoxantrone (without vincristine or prednisone) as induction therapy for adult patients with ALL.     

In vitro drug resistance profiles of adult acute lymphoblastic leukemia: possible explanation for difference in outcome to similar therapeutic regimens

Age has important prognostic impact in acute lymphoblastic leukemia (ALL). Adults with ALL have a worse prognosis compared to children. This may be due to different, unfavorable biology, poor treatment tolerance, drug resistance, higher expression of drug resistance related proteins. The lymphoblasts from adult ALL show an increased in vitro resistance to cytotoxic drugs, including prednisolone, dexamethasone, cytosine arabinoside, daunorubicin, L-asparaginase and methotrexate. Glucocorticoid resistance may be a fundamental difference between children, adolescents and adults with ALL, which may underlie different biological aspects and also explain the difference in prognosis. It seems that in vitro resistance to prednisolone with respect to the age might be a continuous variable in ALL patients, except infants. The greater the age, the higher the in vitro resistance to prednisolone. This may be due to induction of various defense mechanisms, such as an activation of P-glycoprotein, which develops throughout the life and protect the human against xenobiotics. Among a number of various drug resistance mechanisms, only several weak differences between adults and children with ALL have been reported including higher P-glycoprotein expression, lower methotrexate polyglutamate accumulation and possibly more often p53 gene mutations in adults. Intrinsic resistance, induction of drug resistance proteins expression during chemotherapy and co-existence of various mechanisms are common phenomena in adult ALL. It seems that age itself, more than drug resistance profile, reflects factors which have direct effect on chemotherapy response in adult ALL.     

Optimal therapy for acute lymphoblastic leukemia in adolescents and young adults

Although the survival rate for adolescents and young adults (AYA) with acute lymphoblastic leukemia (ALL) has steadily improved over the past several decades, it still lags behind that of younger children. This Review explores the reasons for this discrepancy and potential solutions, focusing on patients aged 15-22 years. Recent studies that compared the outcome of AYA patients with ALL treated on pediatric or adult clinical trials have shown substantially better outcomes for this patient population obtained with the pediatric trials. Excellent early results have been obtained for patients with ALL aged up to 40-60 years who were treated in adult study groups with pediatric-based regimens. Targeting biological and socio-political features unique to AYA ALL has reduced the 'AYA gap' and has provided the foundation for basic science and translational and clinical AYA initiatives that are charged with the task of discovering further methods to improve the outcome of AYA with ALL.     

Recent progress in the treatment of acute leukemia

Acute leukemia is classified broadly as either acute myelogenous leukemia (AML) or acute lymphoblastic leukemia (ALL). The main treatments remain remission induction therapy and postremission chemotherapy. The advances in chemotherapy for pediatric patients with ALL have been dramatic, with some 95% achieving complete remission, and long-term survival is 60-80%. Among adults, high long-term survival rates due to improvements in chemotherapy for B-cell type ALL and core binding factor leukemias have been reported. For adult leukemias overall, however, long-term survival rates have stalled at 15-40% despite the high remission rate attained. In most cases this is due to a recurrence. Among the prognostic factors reported for acute leukemia, chromosome type may be cited as the currently most reliable. Acute leukemia patients are classified based on chromosome type, and the postremission therapeutic strategy is considered in terms of an appropriate combination of chemotherapy and hematopoietic stem cell transplant. This accounts for an important part of the treatment given today. Target-based therapies such as all-trans-retinoic acid (ATRA) for AML have brought dramatic improvements in treatment results. The effect of imanitib against Philadelphia chromosome positive ALL, for which the prognosis is poor, is also attracting attention. Moreover, promising new treatment strategies that have been developed, including cord blood transplant, mini-transplant, antibody therapy, and immunotherapy, Clinical studies of PCR and other means to reveal small residual lesions and estimate prognosis are also making progress. In the future it will be possible to identify prognostic factors in genetic tests such as DNA microarrays and single nucleotide polymorphisms, so that the optimum treatment can be selected for individual patients.     

“Society of Hematologic Oncology (SOHO) State of the Art Updates and Next Questions”—Treatment of ALL

The outcome of adult acute lymphoblastic leukemia (ALL) has substantially improved by adopting pediatric-inspired regimens, and approximately half of the patients are nowadays cured. The evaluation of minimal residual disease currently represents the most important prognostic indicator, which drives treatment algorithms, which include allogeneic stem cell transplantation (allo-SCT) allocation. Indeed, for high-risk patients, allo-SCT should be pursued as soon as possible, whereas in standard-risk patients this procedure should be avoided also in light of related toxicity and because there are no significant benefits. Furthermore, better characterization of the molecular genetic events can drive therapeutic decisions: a historical example in this respect is represented by the use of tyrosine kinase inhibitors (TKIs) in Philadelphia chromosome-positive ALL; in the upcoming future, TKIs might be used also in other subgroups, such as breakpoint cluster region/Abelson 1-like cases and others with deregulated tyrosine kinases. Finally, the greatest progress is currently achieved with new immunotherapies targeting frequently expressed surface antigens in ALL. It is also a new chance for elderly ALL patients, so far spared from intensive chemotherapy and allo-SCT. These targeted therapies will substantially change this treatment algorithm and the great challenge is to find optimal sequence of the extended therapy options in an individual patient.     

The Treatment of Adolescents and Young Adults with Acute Lymphoblastic Leukemia

Adolescents and young adult (AYA) patients with acute lymphoblastic leukemia (ALL), 16–40 years of age, were historically not the focus of prospective studies on ALL treatment. This population has unique genetic, immunophenotypic, and clinical features, differing from both pediatric and older adult patients, with outcomes somewhere between these two populations. However, it has been suggested that outcomes (event-free and overall survival) for these patients are better when they are treated with pediatric-inspired therapeutic regimens. This has been attributed to increased dose and frequency of non-myelosuppressive therapy, earlier and more frequent central nervous system prophylaxis, and longer maintenance therapy. However, management by the treating oncologist and adherence by the patients are equally vital. Ultimately, the combination of improved treatment regimens and organizational management are required to improve outcomes of ALL in the AYA population.     

Risk of Thrombosis in Adult Philadelphia-Positive ALL Treated with an Asparaginase-Free ALL Regimen

Background: venous thromboembolism (VTE) is a well-known complication in adults with acute lymphoblastic leukemia (ALL), especially in patients treated with asparaginase (ASNase)-including regiments. However, VTE risk in adult Philadelphia-positive ALL (Ph+ve ALL) patients treated with non-hyperCVAD chemotherapy is unclear. In this study, we examined VTE incidence in adult Ph+ve ALL patients treated with imatinib plus a pediatric-inspired asparaginase (ASNase)-free regimen modified from the Dana Farber Cancer Institute (DFCI) ALL protocol. Methods: a single centre retrospective review of Ph+ve ALL patients treated at Princess Margaret Cancer Center (PMCC) from 2008–2019 with imatinib plus modified DFCI protocol was conducted. Results: of the 123 patients included, 30 (24.3%) had at least 1 radiology confirmed VTE event from diagnosis to the end of maintenance therapy. 86.7% (26/30) of the VTE events occurred during active treatment. Of all VTE events, the majority (53.3%) were DVT and/or PE while another significant portion were catheter-related (40.0%). Major bleeding was observed in 1 patient on VTE treatment with low molecular weight heparin (LMWH). Conclusion: a high VTE incidence (24.3%) was observed in adults Ph+ve ALL patients treated with imatinib plus an ASNase-free modified DFCI pediatric ALL protocol, suggesting prophylactic anticoagulation should be considered for all adult Ph+ve ALL patients including those treated with ASNase-free regimens.     

Autologous stem cell transplantation for acute lymphocytic leukemia in adults

Autologous bone marrow transplantation remains an investigational treatment for adult ALL. Despite many anecdotal studies showing efficacy, the rarity of ALL has prevented the large randomized trials necessary to confirm effectiveness. Candidates for autoBMT include adult patients in first CR with adverse risk factors and all patients who have experienced disease relapse. It remains debatable which preparative regimen is optimal, whether purging is necessary, or if chemotherapy or immunotherapy administered after transplantation can decrease disease relapse. Overall, every effort should be made to enter ALL patients on well-designed randomized multi-institutional trials. These trials should compare autologous transplantation to newer more intensive chemotherapy regimens and should take into account the heterogeneity of ALL. A quality of life analysis should be performed as one high-dose treatment may be less toxic and better tolerated than multiple cycles of consolidation chemotherapy. Strategies aimed at enhancing an autologous graft-versus-leukemia effect after transplantation may enhance long-term survival. Many more studies are needed to further define the optimal role of autoBMT in adult ALL.     

Pediatric-Like Therapy for Adults with ALL

Ten years ago, the first studies comparing the results of adult versus pediatric protocols in adolescents with acute lymphoblastic leukemia (ALL) clearly showed that differences in ALL genetics and treatment tolerance could not be the only reasons for the worse outcome observed in adults with this disease as compared to children. It became evident that intensified pediatric chemotherapy regimens could be associated with better response rates and longer survival in adults as well. During the last decade, the use of pediatric-like or pediatric-inspired protocols in adults allowed markedly improving the outcome of young adult patients aged up from 40 years to 60 years, confirming this initial observation. Administration of pediatric-like therapy in adults is now associated with estimated 5-year overall survival comprised between 60 % and 70 %. In this new context, the risk factors and the place of stem cell transplantation need to be reassessed.