Therapy for ALL consists of complex and comprehensive regimens consisting of several phases: induction, intensified consolidation, maintenance, and CNS prophylaxis (9,29). 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 disease (MRD) during the consolidation and maintenance phases (9,30). Combining anthracyclines (eg, daunorubicin or doxorubicin), vincristine, and dexamethasone (for better CNS penetration), often coupled with cyclophosphamide or asparaginase with growth factor support, represents the cornerstone of ALL induction regimens. This results in complete remission (CR) rates of 70% to 90% and median remission durations of 18 months (30,31). Patients who achieve CR subsequently transition to the consolidation phase, which, depending on the risk-oriented subtype, may consist of consolidation chemotherapy (cytarabine, methotrexate, 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 vincristine and prednisone or dexamethasone, given over 2 to 3 years (POMP or DOMP, depending on corticosteroid used) (30,31,32). Maintenance, which is omitted in mature B-ALL due to high cure rates, may also involve the use of TKIs for patients with Ph-positive ALL. Primary CNS involvement at diagnosis is rare (<10%) but is as high as 50% to 75% at 1 year without prophylactic administration of intrathecal chemotherapy (IT) (31). Although high-dose cytarabine (1-7.5 mg/m2) and methotrexate (5-8 g/m2) successfully penetrate the blood-brain barrier, they are too toxic to serve as the sole CNS prophylaxis. The inclusion of IT prophylaxis (methotrexate, cytarabine, liposomal cytarabine, hydrocortisone, or thiotepa) reduces the incidence of CNS relapse to 4% by allowing sustained therapeutic concentration of the agents in the cerebrospinal fluid. The number of ITs varies according to protocol (usually 8 for standard risk, 12 for Ph positive, and 16 for Burkitt), and in rare cases of extramedullary disease spread (eg, masses or chloromas), IT may even be supplemented by radiation therapy.
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 alternating with high-dose methotrexate and cytarabine for a total of eight alternating cycles approximately every 3 to 4 weeks (Table 1-4) (30,31). This is followed by 2 years of POMP maintenance therapy, interspersed with intensification courses during months 6, 7, 18, and 19. The number of IT injections (two per course) depends on the risk of CNS relapse, which has been identified as high for patients with mature B-ALL. Our current approach is giving 8 ITs for nonmature B-ALL and 16 ITs for mature B-ALL, resulting in a 5-year overall survival (OS) between 38% and 50% (30). Due the improved cure rates of Ph-positive ALL patients, an increase in the CNS relapse rate was observed, which is the reason the protocol was modified to include 12 ITs for Ph-positive ALL.
Table 1-4Doses and Schedule of the Hyper-Cvad Regimen ||Download (.pdf) Table 1-4Doses and Schedule of the Hyper-Cvad Regimen
|Therapy Segment ||Dose and Schedule |
|Induction and intensified consolidation ||Hyper-CVAD (courses 1, 3, 5, and 7) |
| ||• Cyclophosphamide 300 mg/m2 IV over 3 h every 12 h for 6 doses on days 1-3 |
| ||• Mesna 600 mg/m2 as an IV continuous infusion over 24 h daily on days 1-3 (starting approximately 1 h prior to cyclophosphamide and finishing 12 h after the last dose) |
| ||• Doxorubicin 50 mg/m2 IV continuous infusion over 24 h on day 4 |
| ||• Vincristine 2 mg IV on days 4 and 11 |
| ||• Dexamethasone 40 mg daily on days 1-4 and 4-11 |
| ||Methotrexate (MTX) and high-dose cytarabine (courses 2, 4, 6, and 8) |
| ||• MTX 200 mg/m2 IV over 2 h followed by 800 mg/m2 IV over 22 h on day 1 |
| ||• Leucovorin rescue 15 mg every 6 h for eight doses (starting 12 h after completion of MTX) |
| ||• Cytarabine 3 g/m2 IV over 2 h every 12 h for 4 doses on days 2 and 3 |
| ||• Methylprednisolone 50 mg IV twice daily on days 1-3 |
|CNS prophylaxis ||IT MTX 12 mg (6 mg if via Omaya reservoir) on day 2 and cytarabine 100 mg on day 7 of each course |
| ||Low risk: 6 IT |
| ||High risk: 8 IT |
| ||Mature B cell: 16 IT |
|Maintenance therapy ||POMP |
| ||• 6-Mercaptopurine 50 mg orally three times per day |
| ||• MTX 20 mg/m2 orally weekly |
| ||• Prednisone 200 mg orally days 1-5 every month |
| ||• Vincristine 2 mg IV every month |
| ||• Intensification with four additional courses of hyper-CVAD plus MTX/cytarabine |
|Supportive care ||• Antibiotic prophylaxis (levofloxacin, fluconazole, valacyclovir) |
| ||• Hematopoietic growth factor support during induction and consolidation |
| ||• Laminar air flow rooms (for patients ≥60 years old) |
Mature B-Cell and Burkitt Acute Lymphoblastic Leukemia
The addition of rituximab to short intensive chemotherapy has also improved outcome in adult Burkitt and Burkitt-type lymphoma or ALL (29,33,34). Hoelzer and colleagues have recently reported the benefit of adding rituximab to short intensive chemotherapy in 363 patients with Burkitt lymphoma/leukemia; the addition of rituximab resulted in CR and 5-year survival rates of 88% and 80%, respectively (33). Higher rates of survival were reported in adolescents compared to adults and elderly patients (90% vs 84% vs 62%, respectively) (33). Low-intensity chemotherapy with infused etoposide, doxorubicin, and cyclophosphamide with vincristine, prednisone, and rituximab (EPOCH-R) was recently tested in 30 adult patients with Burkitt lymphoma (35). The progression-free survival (PFS) and OS rates were 90% and 100%, respectively. Of note, marrow involvement was present in only 13% of patients, and CNS involvement was present in only 3% of patients (35).
CD20-Positive Pre–B-Cell Acute Lymphoblastic Leukemia
There have been several alterations to traditional protocols with further refining of the disease. Expression of cell surface marker CD20 in adult ALL ranges from 35% to ubiquitous depending on the subtype and has been associated with an inferior prognosis (18). The addition of two doses of monoclonal CD20 antibody (rituximab) administered with the first four cycles of chemotherapy and during maintenance intensification at months 6 and 18 resulted in improved OS in younger patients compared with similar chemotherapy historical controls (75% vs 47% at 3 years; P = .003) (36). Improvement in the 5-year remission duration and survival rates was also reported in patients <55 years old by the German Multicenter Study Group for ALL (GMALL) when rituximab was added to standard induction and consolidation therapy (37).
Ofatumumab is a more potent second-generation anti-CD20 monoclonal antibody that binds to a membrane proximal small-loop epitope on the CD20 protein. A phase II study in CD20-positive pre–B-ALL combined ofatumumab with HCVAD during induction, resulting in a 96% rate of both CR and MRD negativity. At a median follow-up of 14 months, the 1-year PFS and OS rates were 94% and 92%, respectively (38).
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 significantly improved patient outcomes, as supported by several reports (39,40,41,42). Incorporation of early, daily, and concurrent TKI with chemotherapy has proven more effective than intermittent pulses (41,42).
Second-generation TKIs, such as the dual src and abl inhibitor dasatinib, which is more potent than imatinib and crosses the blood-brain barrier (43), have also been investigated in combination with chemotherapy. In an attempt to improve on the outcomes with imatinib, dasatinib was administered at 100 mg daily for 14 days with induction chemotherapy, followed by 70 mg continuous dosing with the consolidation cycles, and at 100 mg daily continuously during the maintenance phase (44). Overall, 94% of patients achieved CR, 96% achieved complete cytogenetic response (CCyR), and 65% achieved complete molecular response (CMR). Allogeneic hematopoietic stem-cell transplantation was performed in 22 patients (12 in first CR and 10 in second CR), with 3-year disease-free survival (DFS) and OS rates of 49% and 61%, respectively.
Attempting to reduce exposure to cytotoxic chemotherapy by intensifying chemotherapy with TKIs can be very effective but toxic (45,46). Patients in the GRAAPH-2005 study were randomized to imatinib 800 mg daily for 4 weeks combined with weekly vincristine and dexamethasone versus imatinib 800 mg daily for 2 weeks combined with HCVAD chemotherapy (45). The CR rate was higher in the low-intensity group due to induction-related mortality in the HCVAD group (7% vs <1%; P = .01). An equal number of patients in each group proceeded to autologous stem cell transplantation and allogeneic stem cell transplantation, and at 3 years, OS was similar between the two arms (53% for low intensity vs 49% for HCVAD; P = .61).
Studies have also evaluated the use of dasatinib and nilotinib with low-intensity chemotherapy (46,47,48). In the EWALL-Ph-01 study, dasatinib with low-intensity chemotherapy was administered to 71 patients with newly diagnosed Ph-positive ALL age ≥55 years (46). Dasatinib was dosed at 140 mg once daily during induction and at 100 mg daily during consolidation, yielding a CR rate of 94%. The estimated 3-year OS was 45%.
Many Ph-positive ALL patients can relapse with threonine-to-isoleucine mutation at position 315 (T315I), which is refractory to imatinib and second-generation TKIs. A third-generation TKI, ponatinib, which has activity against T315I, was evaluated in phase I and II trials in patients with Ph-positive leukemias and was shown to have significant antileukemic activity (49,50). 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. The CR, CCyR, and CMR rates were 100%, 100%, and 74%, respectively. After a median follow-up of 20 months, 1-year PFS and OS were 97% and 87%, respectively (51).
Although current standard of care still advocates AHSCT consolidation in first CR (39), new information regarding the status of MRD in Ph-positive ALL has raised a question as to who should be referred for it. The predictive value of MRD assessment by quantitative reverse transcriptase polymerase chain reaction (RT-PCR) and multiparameter flow cytometry (FCM) was recently assessed in patients with Ph-positive ALL treated with combination chemotherapy and TKIs who did not undergo AHSCT. Achieving major molecular response at 3, 6, 9, and 12 months (P = .02, .04, .05, and .01, respectively) and having negative FCM at 3 and 12 months were associated with improved survival (P = .04 and .001, respectively) (52). This information suggests that patients with early and sustained molecular response may not need consolidation with AHSCT.
T-Cell Acute Lymphoblastic Leukemia
Treatment of adult T-ALL and T-cell lymphoblastic lymphoma (T-LL) results in a long-term survival rate of 40% to 60%, and the outcome is strongly associated with T-cell phenotype (53,54). Adding nelarabine, a selective anti–T-ALL agent may further improve the outcome. In a single-arm, phase II study, 48 patients with newly diagnosed T-ALL or T-LL were treated with HCVAD and neralabine (55). The CR rate was 93%; the 5-year survival rate was 66% after a median follow-up of 41 months. These rates were 38% and 70% for patients with early T-cell precursor (ETP) and mature T-ALL, respectively. Indeed, ETP-ALL is a distinct T-cell entity characterized by the absence of CD1a, sCD3, and CD8 expression; weak CD5 expression; and expression of one or more myeloid or stem cell–associated markers (54). It confers poor prognosis with the use of standard intensive chemotherapy, which results in high rates of remission failure and relapse compared to patients with typical T-ALL (72% at 10 years vs 10% at 10 years). This phenotype is in part a reflection of the higher degree of genomic instability (number and size of genetic defects) that ETP-ALL harbors, with over 60% of adult patients carrying mutations in DNMT3A, FLT3, or NOTCH1, which may allow for tailored induction regimens with targeted therapies (56). Following induction, AHSCT should be considered in first remission for all ETP-ALL patients.
Adolescent and Young Adult Acute Lymphoblastic Leukemia
Retrospective studies have shown that pediatric regimens resulted in better outcomes than adult regimens (which had deviated significantly from the established principles of ALL therapy in pediatric regimens). Pediatric-inspired regimens, such as the Berlin-Frankfurt-Münster (BFM) regimen (Table 1-5), deliver more intensive nonmyelosuppressive agents like vincristine, asparaginase, corticosteroids, and CNS therapy (54,55).
Table 1-5Doses and Schedule of the Augmented Berlin-Frankfurt-Münster (Bfm) Regimen ||Download (.pdf) Table 1-5Doses and Schedule of the Augmented Berlin-Frankfurt-Münster (Bfm) Regimen
|Therapy Segment ||Dose and Schedule |
|Induction (4 weeks) ||IT cytarabine 100 mg within 3 days prior to start of induction |
| ||Daunorubicin 25 mg/m2 IV weekly for 4 doses |
| ||Vincristine 2 mg IV weekly for 4 doses |
| ||Prednisone 60 mg/m2/d orally in divided doses on days 1-28 |
| ||PEG-asparaginase 2,500 international units/m2 IV during week 1 |
| ||IT Methotrexate 12 mg during weeks 2 and 5 |
|Extended induction (2 weeks) ||Daunorubicin 25 mg/m2 IV during week 1 |
| ||Vincristine 2 mg IV weekly for 2 doses |
| ||Prednisone 60 mg/m2/day orally in divided doses for 14 days |
| ||PEG-asparaginase 2500 international units/m2 IV during week 1 |
|Consolidation 1 (8 weeks) ||Cyclophosphamide 1 g/m2 IV during weeks 1 and 5 |
| ||Cytarabine 75 mg/m2 subcutaneously or IV on days 1-4 and 8-11 of each month |
| ||6-Mercaptopurine 60 mg/m2/day orally on days 1-14 of each month |
| ||Vincristine 2 mg IV during weeks 3 and 4 of each month |
| ||PEG-asparaginase 2500 international units/m2 IV during weeks 3 and 6 |
| ||IT methotrexate 12 mg weekly for 4 weeks |
|Consolidation 2 (7 weeks) ||Vincristine 2 mg IV every 10 days for 5 doses |
| ||Methotrexate, starting at 100 mg/m2 and escalating by 50 mg/m2/dose every 10 days for 5 doses |
| ||PEG-asparaginase 2,500 IU/m2 IV during weeks 1 and 4 |
| ||IT methotrexate 12 mg during weeks 1 and 5 |
|Consolidation 3–part A (4 weeks) ||Vincristine 2 mg IV weekly for 3 doses |
| ||Dexamethasone 10 mg/m2/d orally in divided doses on days 1-7 and days 15-21 |
| ||Doxorubicin 25 mg/m2 IV weekly for 3 doses |
| ||PEG-asparaginase 2,500 IU/m2 IV during week 1 |
| ||IT methotrexate 12 mg during week 1 |
|Consolidation 3–part B (4 weeks) ||Cyclophosphamide 1 g/m2 IV during week 1 |
| ||Cytarabine 75 mg/m2 subcutaneously or IV for 4 consecutive days during weeks 1 and 2 |
| ||Thioguanine 60 mg/m2/d orally for 14 days |
| ||Vincristine 2 mg IV during weeks 3 and 4 |
| ||PEG-asparaginase 2,500 IU/m2 IV during week 3 |
| ||IT methotrexate 12 mg during weeks 1 and 2 |
|Maintenance (24 months) ||Vincristine 2 mg IV monthly |
| ||Dexamethasone 6 mg/m2/d orally for 5 days every month |
| ||6-Mercaptopurine 75 mg/m2/d in divided doses |
| ||Methotrexate 20 mg/m2 orally weekly |
| ||IT methotrexate 12 mg every 3 months for the first 12 months of maintenance |
|Supportive care ||Antibiotic prophylaxis (levofloxacin, trimethoprim/sulfamethoxazole [start week 2 of induction], fluconazole, valacyclovir) |
The Group for Research on Adult Acute Lymphoblastic 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. In patients treated with the pediatric-inspired regimen, the CR rate was 93%, and at 42 months, event-free survival (EFS) and OS rates were 55% (95% CI, 48%-52%) and 60% (95% CI, 53%-66%), respectively (57). Although the pediatric-inspired regimen resulted in improved survival compared with the control (66% vs 44%; P < .001), the cumulative incidence of treatment-related death in patients age 40 to 60 years old was 23%, erasing the margin of benefit gained with enhanced activity of pediatric regimens. Thus, the toxicity threshold can be reached and crossed in the adult population in attempts to reach higher cure rates, limiting the usefulness of intensifying chemotherapy to the pediatric-inspired strength.
The UKALL14 study of 91 adults with a median age of 47 years (range, 25-65 years) used PEG-asparaginase at a dose of 1,000 units/m2 on days 4 and 18 during induction, resulting in a CR rate of 66%, with induction-related mortality rate of 20% and hepatotoxicity rate of 56%, prompting the omission of PEG-asparaginase in patients ≥40 years old (58).
A recent US Intergroup study of 318 adolescent and young adult (AYA) patients (median age, 24 years) treated with a pediatric-inspired regimen was reported. With a median follow-up of 28 months, the estimated 5-year EFS and OS rates were 45% and 55%, respectively (59). Presence of MRD at day 28 following initiation of induction therapy and presence of a Ph-like gene expression signature were significantly associated with worse EFS and OS. The Ph-like signature, which was detected in 28% of patients, resulted in 2-year EFS of only 52%, compared to 81% for those without Ph-like disease.
Our internal review of 85 AYA patients up to age 40 (median age, 21 years) treated with pediatric-like augmented BFM showed CR and MRD negativity rates of 94% and 69%, respectively (60). The 5-year CR rate was 58%, and the 5-year OS rate was 62%. Compared with a historical control group of similar patients who received HCVAD with or without rituximab, 3-year OS rates were 72% and 71%, respectively. However, in patients age 25 years and older, the pediatric-inspired regimen was inferior and caused more liver dysfunction, pancreatitis, osteonecrosis, and thrombosis compared to HCVAD with CD20-targeted therapies.
Hence, HCVAD-based regimens that use the backbone 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
Conventional ALL chemotherapy is associated with high mortality rates (30%-35%) during consolidation/maintenance in elderly patients (>60 years) (60). 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, 60-79 years) were treated for newly diagnosed ALL (61). Inotuzumab, which is a CD22-directed monoclonal antibody bound to calicheamicin (chemotoxin), was administered at a dose of 1.3 to 1.8 mg/m2 once with each of the first four courses; doxorubicin was eliminated in induction; cyclophosphamide and steroids were 50% reduced; methotrexate was reduced to 250 mg/m2 on day 1 and cytarabine to 0.5 mg/m2 × 4 on days 2 and 3 of even courses. The overall response rate (ORR) was 96% (CR, 79%; CR with incomplete platelet recovery [CRp], 17%), with all patients with cytogenetic abnormalities achieving CCyR. All responders also achieved MRD-negative status, 75% of which occurred after cycle 1. The 1-year PFS and OS rates were 86% and 81%, respectively. The 1-year survival rate was superior to previous results obtained with HCVAD with or without rituximab in similar patient populations (1-year OS, 81% vs 60%, respectively).
Role of Allogeneic Stem Cell Transplantation
Allogeneic stem cell transplantation has traditionally been reserved for patients with high-risk features including B-lineage with WBC ≥30 × 109/L, T-lineage with WBC ≥100 × 109/L, hypodiploid, Ph-positive, or mixed-lineage leukemia translocation ALL [eg, t(4;11)]. However, there has been some debate regarding who should be referred for AHSCT in first CR based on recent data that indicate that patients with standard-risk disease, and not high-risk disease, benefit the most (62). As an alternative, many centers have incorporated MRD via FCM or RT-PCR after induction or consolidation to stratify patients based on their response to chemotherapy (63). In fact, when controlled for other known risk factors, failure to achieve MRD has emerged as a powerful indicator of future relapse (52) and therapeutic approach (ie, AHSCT vs more chemotherapy). In one study, MRD status at various time points after CR was used to guide treatment in adult patients with ALL (64). 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. Patients who achieved MRD-negative status had a significantly improved 5-year OS (75% vs 33%; P = .001). Furthermore, in a recent update of the GRAALL experience in 423 younger adults with Ph-negative ALL in first remission (265 B-cell precursor ALL and 158 T-ALL patients), postinduction MRD level ≥10−4 and unfavorable genetic characteristics (ie, MLL gene rearrangement or focal IKZF1 gene deletion in B-cell precursor ALL and no NOTCH1/FBXW7 mutation and/or N/K-RAS mutation and/or PTEN gene alteration in T-ALL) were independently associated with worse outcome (65). Therefore, for patients with standard-risk ALL, MRD status should guide the postremission therapy, whereby patients who fail to achieve MRD negativity can be transplanted in first CR. In addition to the MRD status, new genomic and immunophenotyping technologies were essential in identifying patients with poor prognosis. Patient with Ph-like ALL and ETP-ALL should be considered for AHSCT in first CR (24,54).
Postinduction assessment for persistence or reemergence of MRD in patients with ALL is the most important adverse prognostic factor and identifies chemorefractory disease (64,66,67). Virtually all adults with ALL and molecular failure exhibit poor prognosis despite continued chemotherapy and are candidates for stem-cell transplantation and targeted therapies (68).
The Programa Español de Tratamientos en Hematología (PETHEMA) ALL-AR-03 trial in adolescent and adult patients with high-risk Ph-negative ALL showed poor MRD clearance by FCM after early consolidation and identified the pattern of MRD clearance as the only prognostic factor for DFS and OS (69).
Blinatumomab is a bispecific T-cell engaging (BiTE) antibody and is the first 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 nonimmunogenic linker (70). Cytotoxic T cells are activated upon binding to CD19, inducing cell death through the perforin system. Given the pharmacokinetics of the construct (short half-life and the mechanism of action), continuous infusion over several weeks resulted in significantly improved drug activity in ALL and minimization of side effects. Twenty-one patients in hematologic and morphologic CR with persistent or reappearing MRD during consolidation were first studied with a blinatumomab dose of 15 μg/m2/d as a continuous infusion for 28 days every 6 weeks for a total of 4 cycles or proceeded to AHSCT if a donor was available (71). Minimal residual disease conversion following one cycle of therapy was seen in 80% of patients. After a median follow-up of 33 months, 60% of patients remained in CR, with the same percentage of patients experiencing estimated 3-year refractory-free survival (72). Nontransplanted patients had a similar favorable outcome compared to the nine patients who underwent AHSCT.
A recent confirmatory, open-label, multicenter, phase II trial of blinatumomab in 116 patients with MRD-positive B-cell precursor ALL in CR resulted in overall MRD eradication in 80% of patients, almost all (78%) after a single cycle of therapy (73). As a result, the MD Anderson Cancer Center (MDACC) will open a trial evaluating the role of blinatumomab in patients with positive MRD in CR.