AML, acute myeloid leukemia. Chapter 1. B Lineage. T Lineage. Precursor T-ALL. Common ALL. Mature T-ALL. Surface CD3 plus any other T-cell markers. Cytoplasmic IgM. Mature B-ALL. Only thymic T-ALL has excellent outcome with che- motherapy alone. Cytogenetic-Molecular Pro ling. Frequent cytogenetic and molecular abnormalities associated with adult ALL offer insight into the events leading to leukemic progression Table 2 0.
They are of both prognostic and predictive signi cance and have varying frequencies in children and adults, which explains some of the differences in outcomes in these two groups. Children Frequency. Involved Genes. Next-generation sequencing, expression pro- teomics, and oligonucleotide microarrays have trans- formed our understanding of the genomic landscape of ALL and are yielding new molecular subgroups with actionable defects 2 1 - 2 3.
These patients may respond favorably to treatment with hypometh- ylating agents azacitidine or decitabine. Identi cation of these and other molecular and cytogenetic changes in adult ALL drives the development of risk-adapted and targeted therapies, particularly in high-risk groups Table 2 8. Therapy for ALL consists of complex and compre- hensive regimens consisting of several phases: induc- tion, intensi ed consolidation, maintenance, and CNS prophylaxis 9 , 2 9.
Each involves the use of a core group of agents considered the backbone of therapy in a time- and dose-dependent manner, with a goal of restoring normal hematopoiesis, eradicating resistant subclones, providing adequate prophylaxis of sanctuary sites eg, CNS, testicles , and eliminating minimal residual dis- ease MRD during the consolidation and maintenance phases 9 , 3 0.
Combining anthracyclines eg, dauno- rubicin or doxorubicin , vincristine, and dexametha- sone for better CNS penetration , often coupled with cyclophosphamide or asparaginase with growth factor support, represents the cornerstone of ALL induction regimens.
Patients who achieve CR subse- quently transition to the consolidation phase, which, depending on the risk-oriented subtype, may consist of consolidation chemotherapy cytarabine, metho- trexate, cyclophosphamide, and 6-mercaptopurine or allogeneic hematopoietic stem-cell transplantation AHSCT.
Consolidation is followed by prolonged maintenance therapy with daily 6-mercaptopurine, weekly methotrexate, and monthly pulses of vincris- tine and prednisone or dexamethasone, given over 2 to 3 years POMP or DOMP, depending on corticosteroid used 3 0 - 3 2. Although high-dose cytarabine The number of ITs varies according. Ph-like ALL molecular lesions. CRLF2 overexpression flow-cytometry. Non-CRLF2 cases. Poor outcome. Near hypodiploid.
Low hypodiploid. NT5C2 mutations. TP53 mutations. One extensively studied regimen used in treatment of adult ALL is the hyper-CVAD HCVAD regimen, where patients receive hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternat- ing with high-dose methotrexate and cytarabine for a total of eight alternating cycles approximately every 3 to 4 weeks Table 3 0 , 3 1. This is followed by 2 years of POMP maintenance therapy, interspersed with inten- si cation courses during months 6, 7, 18, and The addition of rituximab to short intensive chemo- therapy has also improved outcome in adult Burkitt.
Low-intensity chemotherapy with infused etoposide, doxorubicin, and cyclophos- phamide with vincristine, prednisone, and rituximab EPOCH-R was recently tested in 30 adult patients with Burkitt lymphoma 3 5. There have been several alterations to traditional pro- tocols with further re ning of the disease. The addition of two doses of monoclonal CD20 antibody. Therapy Segment. Dose and Schedule. Induction and intensi ed consolidation. Hyper-CVAD courses 1, 3, 5, and 7.
Methotrexate MTX and high-dose cytarabine courses 2, 4, 6, and 8. CNS prophylaxis. Low risk: 6 IT. High risk: 8 IT. Mature B cell: 16 IT. Maintenance therapy. Supportive care. Ofatumumab is a more potent second-generation anti-CD20 monoclonal antibody that binds to a mem- brane proximal small-loop epitope on the CD20 pro- tein.
Philadelphia-Positive Acute Lymphoblastic Leukemia. Philadelphia-positive ALL used to have a very poor outcome in general. The incorporation of TKIs into treatment regimens has signi cantly improved patient outcomes, as supported by several reports 3 9 - 4 2. Incor- poration of early, daily, and concurrent TKI with chemotherapy has proven more effective than inter- mittent pulses 4 1 , 4 2.
Second-generation TKIs, such as the dual src and abl inhibitor dasatinib, which is more potent than imatinib and crosses the blood-brain barrier 4 3 , have also been investigated in combination with chemotherapy. In an attempt to improve on the outcomes with imatinib, dasatinib was administered at mg daily for 14 days with induction chemotherapy, followed by 70 mg con- tinuous dosing with the consolidation cycles, and at.
Attempting to reduce exposure to cytotoxic che- motherapy by intensifying chemotherapy with TKIs can be very effective but toxic 4 5 , 4 6. Patients in the GRAAPH study were randomized to imatinib mg daily for 4 weeks combined with weekly vincris- tine and dexamethasone versus imatinib mg daily for 2 weeks combined with HCVAD chemotherapy 4 5.
Studies have also evaluated the use of dasatinib and nilotinib with low-intensity chemotherapy 4 6 - 4 8. A third-generation TKI, ponatinib, which has activity against TI, was evaluated in phase I and II trials in patients with Ph-positive leuke- mias and was shown to have signi cant antileukemic activity 4 9 , 5 0.
More recently, 39 patients with newly diagnosed Ph-positive ALL were treated with HCVAD and ponatinib 45 mg daily for 14 days during induction and then continuously thereafter until CCyR and CMR were obtained, when decreases to 30 mg and 15 mg daily could be instituted, respectively. Achieving major molecular. This information suggests that patients with early and sustained molecu- lar response may not need consolidation with AHSCT.
T-Cell Acute Lymphoblastic Leukemia. Adding nelarabine, a selective anti—T-ALL agent may further improve the outcome.
Retrospective studies have shown that pediatric regimens resulted in better outcomes than adult regimens which had deviated signi cantly from the established principles of ALL therapy in pediatric regimens. The Group for Research on Adult Acute Lymphoblas- tic Leukemia GRAALL evaluated a pediatric-inspired regimen in patients up to age 60 years and compared the results to a historical control group treated with an adult regimen. Induction 4 weeks.
IT cytarabine mg within 3 days prior to start of induction. Vincristine 2 mg IV weekly for 4 doses. IT Methotrexate 12 mg during weeks 2 and 5. Extended induction. Vincristine 2 mg IV weekly for 2 doses.
Consolidation 1 8 weeks. Vincristine 2 mg IV during weeks 3 and 4 of each month. IT methotrexate 12 mg weekly for 4 weeks. Consolidation 2 7 weeks.
Vincristine 2 mg IV every 10 days for 5 doses. IT methotrexate 12 mg during weeks 1 and 5. Consolidation 3—part A 4 weeks. Vincristine 2 mg IV weekly for 3 doses.
IT methotrexate 12 mg during week 1. Consolidation 3—part B 4 weeks. Vincristine 2 mg IV during weeks 3 and 4. IT methotrexate 12 mg during weeks 1 and 2. Maintenance 24 months. Vincristine 2 mg IV monthly. IT methotrexate 12 mg every 3 months for the rst 12 months of maintenance. Slow early responders repeat consolidation 2 and consolidation 3A and 3B prior to maintenance therapy. If central nervous system disease is present at start of therapy, then give methotrexate 12 mg IT weekly until negative for blasts, methotrexate 12 mg IT every other week for 8 doses, and then methotrexate 12 mg IT monthly for 6 months.
IT, intrathecal; IV, intravenous. Thus, the toxicity thresh- old can be reached and crossed in the adult population in attempts to reach higher cure rates, limiting the use- fulness of intensifying chemotherapy to the pediatric- inspired strength. A recent US Intergroup study of adolescent and young adult AYA patients median age, 24 years treated with a pediatric-inspired regimen was reported. Presence of MRD at day 28 following initiation of induc- tion therapy and presence of a Ph-like gene expression signature were signi cantly associated with worse EFS and OS.
However, in patients age 25 years and older, the pediatric-inspired regimen was inferior and caused more liver dysfunc- tion, pancreatitis, osteonecrosis, and thrombosis com- pared to HCVAD with CDtargeted therapies.
Hence, HCVAD-based regimens that use the back- bone ALL agents but eliminate or reduce the exposure to asparaginase show similar CR and remission rates and survival outcomes compared with the pediatric- inspired regimens in similar patient populations. Acute Lymphoblastic Leukemia in Elderly Patients. A low- intensity regimen may improve outcome. In a phase II study with inotuzumab ozogamicin and low-intensity hyper-CVD therapy, 26 patients with a median age of 67 years range, years were treated for newly.
Inotuzumab, which is a CD directed monoclonal antibody bound to calicheamicin chemotoxin , was administered at a dose of 1. Role of Allogeneic Stem Cell Transplantation.
However, there has been some debate regarding who should be referred for AHSCT in rst CR based on recent data that indicate that patients with standard-risk disease, and not high-risk disease, bene t the most 6 2. In fact, when controlled for other known risk factors, failure to achieve MRD has emerged as a powerful indicator of future relapse 5 2 and thera- peutic approach ie, AHSCT vs more chemotherapy. Patients who remained MRD positive at the end of consolidation were deemed to be higher risk and underwent AHSCT instead of receiving prolonged maintenance therapy.
In addition to the MRD status, new genomic and immunophenotyping technologies were essential in identifying patients with poor prognosis. Minimal Residual Disease. Postinduction assessment for persistence or reemergence of MRD in patients with ALL is the most important adverse prognostic factor and identi es chemorefrac- tory disease 6 4 , 6 6 , 6 7.
Virtually all adults with ALL and molecular failure exhibit poor prognosis despite con- tinued chemotherapy and are candidates for stem-cell transplantation and targeted therapies 6 8. Blinatumomab is a bispeci c T-cell engaging BiTE antibody and is the rst agent in its class that engages host T cells to the target cell surface antigen—expressing cancer cells.
It contains the variable domains of a CD19 and a CD3 antibody, joined via nonimmuno- genic linker 7 0. Cytotoxic T cells are activated upon binding to CD19, inducing cell death through the per- forin system. Given the pharmacokinetics of the con- struct short half-life and the mechanism of action , continuous infusion over several weeks resulted in signi cantly improved drug activity in ALL and minimization of side effects. Nontransplanted patients had a similar favorable outcome compared to the nine patients who underwent AHSCT.
The prognosis of adult patients with relapsed ALL remains poor, with limited effective therapies avail- able. Relapsed disease carries a median survival of only 24 weeks, and patients who have short duration of rst CR or primary refractory disease do particularly poorly, with a median OS of less than 5 months 7 4. Given that we currently lack agents or regimens that can singularly achieve cure in the relapsed setting, patients should be enrolled on a.
Choice of salvage is contingent upon the previous treatment history, remission dura- tion, ongoing comorbidities, and the relapse-speci c features that may be targetable. Asparaginase could be incorporated into salvage for patients without previous exposure to it. This can be achieved through the augmented HCVAD protocol designed at MDACC, which intensi es the standard vincristine and corticosteroid backbone and adds the pegylated asparaginase 7 5.
Despite the favorable response rate, median OS was 6 months, with some long-term responders. As such, regardless of whether they have received conventional HCVAD previously, this regimen represents a reason- able choice for relapsed patients with good performance status who can tolerate intensive chemotherapy.
Clofarabine is a new-generation purine nucleo- side analog modeled after udarabine and cladribine that is approved as a third-line therapy for pediatric ALL 7 6.
Attempts have been made in both pediatric and adult population to build on its modest activ- ity as a single agent by combining it with other che- motherapeutics 7 7 - 7 9.
In the adult population,. The median OS was 6. It has predominant activity in patients with relapsed T-ALL who have failed two prior regi- mens.
By selectively accumulating in T cells, it lends. The major toxicity of. Vincristine is a standard component of almost. In an effort to optimize its pharmacodynamics and delivery, a liposomal formulation was synthesized. A phase II study evaluated 65 patients with relapsed.
Monoclonal Antibodies. The development of monoclonal antibodies directed against cell surface antigens that are better tol- erated has since led to signi cant improvement in out- comes for a number of malignancies, including ALL.
The median response duration and OS were 9 and 6 months, respectively 8 4. Blinatu- momab causes constitutional symptoms fever, chills that coincide with a rapid rise in activated T cells, leading to secondary cytokine release syndrome CRS. It can be mitigated with the short course of steroids. In a priority review designated by the US Food and Drug Administration, blinatumomab was granted accelerated approval in December for the treat- ment of patients with Ph—negative, relapsed or refrac- tory B-ALL.
Inotuzumab ozogamicin is a CD22 immunocon- jugate linked to calicheamicin, which is a potent cytotoxic inducer of double-strand DNA breaks. Survival was compara-. Among the responders, 22 patients achieved MRD negativity. Survival data are maturing. Chimeric Antigen Receptor T Cells. Autologous T cells can be engineered to express a receptor directed at CD Response can be durable given the ability of T cells to expand and persist in vivo.
As such, chimeric antigen receptor CAR T cells have become an effective approach for targeting lymphoid malignancies 8 7 , 8 8. In another study. Patients responding to this form of ther- apy invariably develop some degree of CRS, which is usually very manageable with steroids or tocilizumab.
Ongoing research is trying to identify the most opti- mal use of this innovative therapeutic strategy. A number of innovative therapies for various stages of. There are several ongoing trials available for patients with ALL at our institution and elsewhere in the frontline and salvage setting Table Trial Characteristics.
ALL Subgroup. Frontline Setting. Salvage Setting. Pre—B-cell ALL. Low-dose inotuzumab 0. Age years. Chimeric antigen receptor CAR T-cell therapies. T-cell ALL. Burkitt leukemia, de novo or relapsed refractory. Philadelphia-positive ALL. Philadelphia-like ALL. Mixed phenotype acute leukemia MPAL , de novo and relapsed. Novel treatment strategies.
Nelarabine single-agent continuous infusion. Intrathecal rituximab in patients with lymphoid malignancies involving the central nervous system. Table Therapy for ALL Subtypes. Subtype of ALL. B-cell ALL. Ph-positive ALL. Ph-like—positive ALL. Mixed phenotype. Adolescent and young adult. Therapeutic capabilities in adult ALL have rapidly reached new heights over the past decade with the introduction of highly promising monoclonal antibodies, immune conju- gates, CAR T cells, and new-generation TKIs.
As many of the newer agents advance through the nal stages of development, we will be seeking to deter- mine optimal combination and order of delivery and the role of cytotoxic chemotherapy in the safest achievement of durable cure rates. Although the role of these agents still continues to be de ned, frontline introduction of most effective therapies can be expected to increase the rate of MRD negativity, optimizing responses and clos- ing the outcome gap separating pediatric from adult ALL.
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Sci Transl Med. Acute myeloid leukemia AML consists of a hetero- geneous group of hematologic neoplasms character- ized by clonal proliferation of myeloid blasts in the peripheral blood, bone marrow, and extramedullary tissues.
Despite advances in our understanding of the molecular biology of AML, its treatment remains chal- lenging and outcomes vary greatly depending on the cytogenetic and molecular features as well as age and comorbidities. Acute myeloid leukemia is thought to be the culmi- nation of genetic mutations and chromosomal aberra- tions within myeloid precursors resulting in disrupted differentiation, excessive proliferation, and suppressed apoptosis of neoplastic cells referred to as blasts.
Over the last several decades, improvements in chemotherapeutic regimens and supportive care have resulted in signi cant but modest progress in treating AML. Davis AT Collection. Davis PT Collection. Murtagh Collection. About Search. Enable Autosuggest. Show Chapters Hide Chapters. Oncology Patient Education Resource Manual. Manual of medical therapeutics. Medical oncology. Medical oncology, surgical oncology, radiation oncology…interventional oncology? Also a good library reference. Overall Grading: Robert J.