Acute Lymphoblastic Leukemia Treatment Protocols

Treatment Protocols

Treatment protocols for acute lymphoblastic leukemia (ALL) are provided below, including general treatment recommendations and commonly used treatment recommendations, as well as information on central nervous system (CNS) prophylaxis, the prognosis for various subtypes of ALL, the role of stem cell transplantation in ALL, treatment of relapse, and supportive care.

The treatment regimen for patients with ALL is determined primarily by the Philadelphia chromosome status of the leukemia and the age of the patient. Patients with Philadelphia chromosome–positive ALL receive atyrosine kinase inhibitor (TKI) in combination with chemotherapy. Younger adults are treated with pediatric-style regimens. Patients aged 15-39 years are referred to as "AYA" (adolescent and young adult) are eligible for these more intensive protocols. Patients with Burkitt leukemia/lymphoma are treated with regimens specific for this diagnosis.

General treatment principles

• Treatment recommendations for patients who are diagnosed with acute lymphoblastic leukemia (ALL) include induction, consolidation and maintenance therapy along with CNS prophylaxis^{[1, 2, 3, 4, 5]}
• Patients receive induction therapy with combinations of drugs, including vincristine, prednisone, cyclophosphamide, doxorubicin, and L-asparaginase, which are given over 4-6wk
• Patients then receive consolidation (intensification) with multiagent therapy additionally, including cytarabineand methotrexate; there is no role for radiation or surgical treatment in patients in the induction phase
• Maintenance therapy includes 6-mercaptopurine, methotrexate, steroids, and vincristine; intrathecal methotrexate is administered throughout
• Newer studies with intensive multiagent chemotherapy (ie, the CALGB [Cancer and Leukemia Group B]- 8811 and hyper-CVAD [hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone] regimens and the ALL-2 regimen) plus the addition of tyrosine kinase inhibitors for Philadelphia chromosome-positive ALL and rituximab for CD20-positive ALL have resulted in 3-y survivals of 50% or more in adults

Treatment recommendations commonly used for acute lymphoblastic leukemia

Philadelphia chromosome–negative ALL in the older adult (age ≥40 y):

• Standard multiagent chemotherapy regimen (eg, CALGB 8811 [daunorubicin, vincristine, prednisone, pegaspargase, cyclophosphamide])
• Consider dosage reduction in patient ≥60 y (evaluate end-organ reserve, end-organ dysfunction, and performance status) or with substantial comorbidities

Philadelphia chromosome–positive ALL in the older adult (age ≥40 y):

• Chemotherapy (eg, hyper-CVAD) plus TKI; consider allogeneic stem cell transplantation if an appropriate donor is available and the patient has a good performance status and no or limited comorbidities; if transplantation is not feasible, continue multiagent chemotherapy and a TKI
• Consider TKI plus corticosteroids in patient ≥65 y (evaluate end-organ reserve, end-organ dysfunction, and performance status) or with substantial comorbidities

Philadelphia chromosome–negative ALL in the AYA (age 15-39 y):

• Pediatric-style intensive multiagent chemotherapy regimen

Philadelphia chromosome–positive ALL in the AYA (age 15-39 y):

• Chemotherapy plus TKI, followed by allogeneic stem cell transplantation if an appropriate donor is available; if transplantation is not feasible continue multiagent chemotherapy and a TKI

Frequently used treatment regimens

The following regimens can be used for patients diagnosed with acute lymphoblastic leukemia. Patients can also be admitted into clinical 

trials

, which is strongly recommended.

Standard-intensity regimens (older adults):

Hyper-CVAD/methotrexate-cytarabine includes the following^[5] :

Cycles 1, 3, 5, and 7 (3-4wk between cycles):

• Cyclophosphamide 300 mg/m² IV over 2h every 12h for 6 doses starting on day 1 plus mesna 600 mg/m²/day continuous IV infusion on days 1-3, starting 1h before plus
• Cyclophosphamide (continue until 12h after last dose of cyclophosphamide) plus  vincristine 2 mg IV on days 4 and 11 plus doxorubicin 50 mg/m² IV over 2-24h on day 4 plus dexamethasone 40 mg PO on days 1-4 and 11-14

Cycles 2, 4, 6, and 8 (3-4wk between cycles):

• Methotrexate 200 mg/m² IV over 2h followed by 800 mg/m² IV over 22h on day 1 plus
• Cytarabine 3 g/m² (1 g/m² for patients older than 60y) IV over 2h every 12h for 4 doses starting on day 2plus
• Leucovorin 15 mg every 6h for 8 doses beginning 12h after the completion of methotrexate infusion, and increased to 50 mg IV every 6h if methotrexate levels are > 20 µmol/L at 0h, are > 1.0 µmol/L at 24h, or are > 0.1 µmol/L at 48h after the end of methotrexate infusion, until levels are < 0.1 µmol/L plus
• Methylprednisolone 50 mg IV every 12h beginning on day 1

Maintenance chemotherapy (for up to 2y):

• 6-mercaptopurine 50 mg PO 3 times daily plus  methotrexate 20 mg/m² PO weekly plus  vincristine 2 mg IV monthly plus prednisone 200 mg PO daily for 5d monthly (with vincristine)

Supportive care during hyper-CVAD:

• Ciprofloxacin 500 mg PO BID plus fluconazole 200 mg PO daily plus acyclovir 200 mg PO BIDplus filgrastim 10 µg/kg SC daily, starting on day 5 of hyper-CVAD and on day 4 of high-dose methotrexate and cytarabine^[5]

The CALGB 8811 ALL regimen includes the following^[1] :

Course I: Induction (4wk):

• Cyclophosphamide 1200 mg/m² (800 mg/m² if patients older than 60y) IV on day 1 plus daunorubicin 45 mg/m²/day (30 mg/m²/day if patients older than 60y) IV on days 1-3 plus vincristine 2 mg IV on days 1, 8, 15, and 22 plus prednisone 60 mg/m²/day PO on days 1-21 (days 1-7 if patients older than 60y)plus L-asparaginase 6000 U/m² SC on days 5, 8, 11, 15, 18, and 22

Course II: Early intensification (4wk/cycle, for 2 cycles):

• Intrathecal methotrexate 15 mg on day 1 plus  cyclophosphamide 1000 mg/m² IV on day 1 plus 6-mercaptopurine 60 mg/m²/day PO on days 1-14 plus cytarabine 75 mg/m²/day SC on days 1-4 and 8-11plus  vincristine 2 mg IV on days 15 and 22 plus  L-asparaginase 6000 IU/m² SC on days 15, 18, 22, and 25

Course III: CNS prophylaxis and interim maintenance (12wk):

• Cranial radiation 2400 cGy on days 1-12 plus  intrathecal methotrexate 15 mg on days 1, 8, 15, 22, and 29 plus  6-mercaptopurine 60 mg/m²/day PO on days 1-70 plus  methotrexate 20 mg/m² PO on days 36, 43, 50, 57, and 64

Course IV: Late intensification (8wk):

• Daunorubicin 30 mg/m² IV on days 1, 8, and 15 plus  vincristine 2 mg IV on days 1, 8, and 15 plus dexamethasone 10 mg/m²/day PO on days 1-14 plus  cyclophosphamide 1000 mg/m² IV on day 29plus 6-thioguanine 60 mg/m²/day PO on days 29-42 plus  cytarabine 75 mg/m²/day SC on days 29-32 and 36-39

Course V: Prolonged maintenance (until 24mo from diagnosis):

• Vincristine 2 mg IV on day 1 plus  prednisone 60 mg/m²/day PO on days 1-5 plus  methotrexate 20 mg/m² PO on days 1, 8, 15, and 22 plus  6-mercaptopurine 80 mg/m²/day PO on days 1-28; repeat all every 4wk

Central nervous system (CNS) prophylaxis

• Patients with ALL have an increased chance of CNS involvement; therefore, intrathecal (IT) methotrexate is given as CNS prophylaxis
• CNS prophylaxis consists of methotrexate 12 mg IT (6 mg if via the Ommaya reservoir) on day 2 and cytarabine 100 mg IT on day 8 of each cycle
• Patients with a high risk for CNS disease (mature B-cell , high proliferative index, and/or lactate dehydrogenase level > 600 U/L [normal range, 25–225 U/L]) receive 16 IT methotrexate treatments
• Patients with low lactate dehydrogenase (LDH) and unknown proliferative index receive 8 treatments of intrathecal methotrexate

Philadelphia chromosome (Ph)-positive ALL

• In the past, the prognosis for patients with Ph+ ALL was very poor; however, advances have brought about an improved outcome for this subtype of ALL with treatment that includes tyrosine kinase inhibitors
• Use of high-dose cytarabine induction regimens has resulted in a higher complete remission rate compared with that seen with traditional ALL regimens
• For example, using ALL-2 induction (cytarabine 3 g/m² IV over 3h daily for 5d and mitoxantrone 80 mg/m² on day 2), patients with Ph+ ALL obtain a rapid hematologic, cytogenetic, and molecular remission^[6]
• Ph+ ALL is characterized by the BCR-ABL fusion (usually p190), which is a target of several tyrosine kinase inhibitors
• Currently, imatinib, dasatinib, and ponatinib are tyrosine kinase inhibitors approved by the FDA for treatment of Ph+ ALL
• Although these tyrosine kinase inhibitors (TKIs) have activity as single agents, they are best used in combination with multiagent chemotherapy regimens^{[7, 8, 9, 10]}
• For example, the addition of imatinib (600 mg PO daily) to hyper-CVAD increased the 3-y rate of complete remission duration to 68%, compared with 24% of patients treated with hyper-CVAD without imatinib^[10]
• Likewise, the addition of dasatinib (140 mg PO daily) to hyper-CVAD resulted in complete remissions in 94% of patients^[11] ; after a median follow-up of 14mo, the median disease-free survival had not been reached
• Ponatinib has shown a 41% major hematologic response in Ph+ ALL after failure or intolerance to dasatinibor nilotinib, including in patients with the T315I mutation^[12] Because of its high risk for thromboembolic events, it is indicated for patients with T315I-positive, Ph+ ALL for whom no other TKI therapy is indicated.^[13]

CD-20-positive ALL

• CD-20 is an adverse prognostic factor in ALL
• In 143 adults with Ph-negative B-cell precursor (BCP) ALL treated in the Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) 2003 trial, CD20 positivity was associated with a higher cumulative incidence of relapse at 42mo, independent of the ALL high-risk subset^[14]
• Rituximab is a monoclonal antibody that targets CD20; a trial with hyper-CVAD and rituximab 375 mg/m² on days 1 and 11 of cycles 1, 3, 5, and 7 and on days 1 and 8 of cycles 2, 4, 6 and 8 resulted in a complete remission rate of 86%; and 3-y overall survival (OS), event-free survival, and disease-free survival rates were 89%, 80%, and 88%, respectively^[15]

Mature B-cell ALL

• Mature B-cell ALL is characterized by a high proliferative index, very high LDH, and strong CD20 positivity
• The prognosis of mature B-cell ALL is poor when disease is treated with traditional ALL regimens
• However, the prognosis has improved with the use of cyclical dose-dense chemotherapy that includes rituximab and aggressive intrathecal prophylaxis^[15]

Treatment of ALL in AYA

• The prognosis of ALL is dramatically better in children than in adults
• It is unclear to what degree this difference is due to intrinsic differences in the leukemic cells that occur in these 2 populations versus the intensity of therapy given
• Older patients have poor tolerance of high-dose therapies, and as such, many of the regimens designed for adults are less intensive than those given in children
• However, younger adults, particularly those younger than 39y, are able to tolerate similar doses as children
• For this reason, clinical trials are now ongoing to determine if the prognosis of ALL in adults can be improved by giving pediatric-style regimens in the younger-adult population^{[16, 17, 18]}

Pediatric-style chemotherapy regimens:

• GRAALL-2003^[19]
• COG AALL-0434^[20]
• CCG-1961^[21]
• CALGB 10403^[22]
• DFCI regimen^[23]

Role of stem cell transplantation

• Stem cell transplantation represents the most intensive postremission therapy and potentially increases a patient's chance for cure
• Although autologous stem cell transplantation has lower treatment-related mortality than allogeneic transplantation, the relapse rate is higher than for patients receiving allogeneic stem cell transplantation^{[3, 24, 25, 26]}
• However, patients undergoing allogeneic stem cell transplantation frequently develop complications from graft versus host disease that can affect long-term survival as well as quality of life
• The GOELAL02 trial evaluated the impact of early allogeneic bone marrow transplantation or delayed unpurged autologous stem cell transplantation for patients with ALL who had no human leukocyte antigen (HLA)–matched sibling donor or who were older than 50y^[24]
• Inclusion criteria included at least 1 of the following: age older than 35y; non–T-ALL; leukocytosis > 30,000/mm³; t(9;22), t(4;11), or t(1;19); or failure to achieve complete remission after 1 induction course; among 198 patients, the median age was 33y
• For patients younger than 50y, allogeneic bone marrow transplantation significantly improved the 6y OS (75% vs 40% after autologous stem cell transplantation)
• The LALA trial analyzed the benefits of a risk-adapted postremission strategy in adult lymphoblastic leukemia and evaluated stem cell transplantation for high-risk patients^[3]
• Patients in the higher-risk group who had a sibling donor underwent allogeneic transplantation; the remaining patients received either an autologous stem cell transplant or postremission chemotherapy
• Overall, allogeneic stem cell transplantation improved disease-free survival; however, autologous stem cell transplantation did not confer a significant benefit over chemotherapy

Treatment of relapse

• The prognosis for patients who experience relapse after front-line therapy is poor, with very few patients surviving long term; the best outcome is obtained if patients achieve a second remission and then proceed to allogeneic stem cell transplantation
• Patients who are in complete remission within 4wk of starting therapy have a better prognosis^{[27, 28, 29]}
• Most of the chemotherapy regimens used for front-line therapy of ALL can be used in the salvage setting; however, response rates are low and remission durations are short
• Tavernier et al reported the results of treatment of first relapse for patients entered on the LALA-94 trial^[30] ; 187 patients (44%) achieved a second complete remission
• The median disease-free survival was 5.2mo, with a 5-y disease-free survival of 12%; factors predicting a better outcome after relapse were any transplant performed in second complete remission (CR), a first CR duration > 1y, and platelet level > 100 x 10⁹/L at relapse; risk groups defined at diagnosis and treatment received in first CR did not influence the outcome after relapse; best results were obtained in a subset of patients who were eligible for allogeneic stem cell transplantation
• In the second salvage setting, O'Brien et al noted that the complete remission rate was only 18% and the median survival was 3mo^[31] ; prognostic factors that were associated with survival were duration of first complete remission, percentage of bone marrow blasts, platelet count, and albumin level
• Clofarabine is a purine nucleoside metabolic inhibitor approved for the treatment of pediatric patients aged 1-21y with relapsed or refractory ALL after at least 2 prior regimens; in this patient population, the dosage is 52 mg/m²/day IV over 2h for 5d; adult patients are treated at a lower dose, no more than 40 mg/m²/day for 5d^[32]
• Nelarabine is approved for the treatment of patients with T-cell ALL and T-cell lymphoblastic lymphoma who have not responded to or have relapsed following treatment with at least 2 chemotherapeutic regimens; recommended dose of nelarabine in adults is 1500 mg/m² IV over 2h on days 1, 3, and 5 repeated every 21d^[33]
• Vincristine liposomal (Marqibo) was approved in August 2012 by the FDA for treatment of Ph-negative ALL patients in second or greater relapse or whose disease has progressed following 2 or more antileukemia therapies; initial dosage regimen is 2.25 mg/m2 IV infusion over 1 h every 7d^[34]

Supportive care

Leukapheresis:

• Patients with a markedly elevated WBC count, especially > 100,000/mm³, are at risk for leukostasis
• Symptoms include dyspnea due to pulmonary infiltration and altered mental status due to CNS effects; patients should receive emergency leukapheresis to rapidly reduce the WBC count

Treatment of tumor lysis syndrome:

• Patients with ALL are at risk for tumor lysis syndrome
• High-risk factors include elevated WBC count, especially > 50,000/mm³; marked elevation of LDH, especially > 1000 U/L; baseline hyperuricemia; and baseline renal dysfunction
• Patients should receive aggressive hydration and allopurinol; high-risk patients should also receive uricolytic agents (ie, rasburicase)

Treatment of infections:

• Most patients are neutropenic and immunocompromised
• Afebrile patients usually receive prophylactic antibiotics, such as ciprofloxacin (or levofloxacin) andacyclovir (or valacyclovir), and an azole antifungal (posaconazole, voriconazole, itraconazole, orfluconazole) during induction therapy
• Febrile neutropenic patients require prompt initiation of broad-spectrum antibiotics
• Suggested regimens include a third- or fourth-generation cephalosporin or carbapenem with or withoutvancomycin
• Antibiotics can be modified based on response to therapy; additional antibiotics might be needed for resistant organisms (eg, vancomycin-resistant enterococci [VRE]) or suspected fungal infections

Blood bank support:

• Patients should receive leukodepleted, irradiated blood products to reduce the risk of transfusion-associated graft versus host disease, cytomegalovirus (CMV) transmission, and febrile transfusion reactions
• Most patients are anemic and require red cell transfusion support
• Patients usually receive packed red cells when the hemoglobin is < 8 g/dL
• Patients with significant respiratory and cardiac disease might require transfusion at a higher hemoglobin level
• Patients are frequently thrombocytopenic; patients receive platelet transfusions when the platelet count is < 10,000/mm³
• Patients being seen less than daily will receive platelet transfusions at a higher threshold (20,000/mm³)
• Patients with active bleeding will be transfused to a platelet count of 50,000/mm³; patients with CNS hemorrhage should be transfused to a platelet count of 100,000/mm³

Special considerations

Immunophenotype for ALL^{[14, 35, 36]} :

• Prognostic factors for ALL include age older than 30y (worse with increasing age)
• White blood cells (WBC) > 30,000/mm³ for B cell; WBC > 100,000/mm³ for T cell
• For precursor B-cell, the prognosis is worse for CD10-negative (common ALL antigen [CALLA]-negative) cases
• For precursor T-cell, the prognosis is worse for pro-, pre-, and mature-T subtypes (CD1a-, CD3-/CD3+), compared with the CD1a+ cortical/thymic phenotype

Cytogenetics for ALL^{[37, 38, 39]} :

• Patients with ALL can have abnormalities of chromosome number as well as balanced translocations
• Patients with a normal karyotype and those with isolated 9p/CDKN2A-CDKN2B deletions have had a relatively favorable (standard) prognosis
• Patients with 6q deletions, miscellaneous karyotype, and hyperdiploid karyotype have had an intermediate prognosis
• Patients with t(9;22)/BCR/ABL1, t(4;11)/MLL/AF4, and t(1;19)/TCF3/PBX1 have had an unfavorable prognosis
• Previously, t(9;22)(q34;q11) was considered high risk; however, outcomes have improved considerably with the addition of TKIs targeting BCR-ABL to chemotherapy