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Medically reviewed by Dr. C.H. Weaver M.D. Medical Editor 5/2022

Adult Acute Lymphoblastic Leukemia (ALL) is a malignant disease or cancer of the blood characterized by the rapid uncontrolled growth of abnormal, immature white blood cells known as lymphoblasts. There are ~ 5,000-6,000 adults diagnosed with ALL each year in the US.  

Treatment of adolescents and very young adults with ALL is often carried out using pediatric protocols because of data suggesting better outcomes for this group than when treatment is administered on adult protocols.1 Treatment of children with ALL, including adolescents and young adults, is included in a separate section. Go to Childhood Acute Lymphoblastic Leukemia.

There has been significant progress in treating adult ALL over the past several decades and a majority of patients become long-term survivors and are cured. Recent advances in CAR T cell therapy and the development of BiTE antibody precision medicines have further improved outcomes and the role of these emerging therapies is being evaluated.

In order to understand the best treatment options available for adult ALL, patients should know whether they have a B-cell or T-cell leukemia, the classification or histologic subtype (L1-L3) of leukemia, the initial white blood cell count, and the results of analyses of chromosomes by cytogenetic examination. These are all tests that are performed on a sample obtained from the blood or bone marrow.2 It is important to identify patients with Philadelphia chromosome-positive ALL because there are drugs which are only effective for this subset of adults with ALL. However, this subset of patients represents up to 40% of all elderly patients with ALL.

According to recent study results presented at the 2021 ASCO Annual Meeting, a novel chemotherapy-free regimen resulted in a 100% complete response rate and a 85% complete molecular remission rate in newly diagnosed Philadelphia Chromosome positive ALL patients

The combination of Iculsig (ponatinib) and Blincyto (blinatumomab) was found to be safe and highly effective in patients with newly diagnosed or relapsed/refractory Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL).

ALL has historically been treated with intensive systemic chemotherapy followed by a stem cell transplant to reduce the chance of disease recurrence. The Iculsig-Blincyto combination regimen calls into question the necessity of the more aggressive approach using stem cell transplant.

BCR-ABL is the genetic abnormality that drives Philadelphia chromosome-positive ALL. Ponatinib is a targeted tyrosine kinase inhibitor (TKI) that works by inhibiting proteins called tyrosine kinases on leukemia cells, in particular the abnormal BCR-ABL protein that causes the disease. Ponatinib has an advantage over previous generations of TKIs because it is designed to overcome the T3151 mutation, the most common cause of disease relapse.

This trial sought to evaluate safety and effectiveness of combining Iculsig and Blincyto as initial treatment for Philadelphia chromosome-positive ALL.22

The study evaluated 20 newly diagnosed patients and 10 relapsed/refractory patients patients. Overall, 95% of patients responded to treatment; the response rate was 100% for newly diagnosed patients and 88% for those with refractory disease. The estimated survival rate without cancer progression was 93% for the newly diagnosed patients. In the front-line group, no patients received a stem cell transplant and none have relapsed. For relapsed/refractory patients, the two-year event-free survival rate was 41% and the two-year overall survival rate was 53%. Four patients with relapsed/refractory disease underwent an allogeneic hematopoietic stem cell transplant.

Philadelphia Negative ALL

The treatment of adult ALL occurs in two phases. The initial treatment phase is called remission induction. The goal of remission induction therapy is to achieve a complete remission or disappearance of all detectable leukemia cells in bone marrow, peripheral blood and other sites such as the testes and central nervous system (CNS). After a complete remission is achieved, the second phase of treatment, called post-remission therapy, begins. Post-remission therapy is necessary because despite achieving a complete remission of leukemia with induction treatment, hidden undetectable leukemia cells still exist and the leukemia will return without additional post-remission therapy. Post-remission therapy is often referred to as consolidation.

Remission Induction

Researchers have learned that the best way to cure patients with adult ALL is to administer intensive treatment over a short period of time. The concept is to kill leukemia cells quickly before resistance to the drugs occurs.  Currently, 90% of adults with ALL will achieve a complete remission following initial multi agent chemotherapy treatment.

Current remission induction therapy may involve the use of 4-5 different drugs over approximately one month that may be combined with newer precision cancer medicines.4,5

About Blincyto (blinatumomab)

Blincyto is a precision cancer medicine known as a BiTE® antibody construct that is designed to direct the body’s cell-destroying T cells against target cells expressing CD19, a protein found on the surface of B-cell derived leukemias and lymphomas. Blincyto is approved by the US Food and Drug Administration and its incorporation into the management of ALL is improving patient outcomes.

About BiTE® Technology Bispecific T cell engager (BiTE®) antibody constructs are a type of immunotherapy being investigated for fighting cancer by helping the body’s immune system to detect and target malignant cells. The modified antibodies are designed to engage two different targets simultaneously, thereby juxtaposing T cells (a type of white blood cell capable of killing other cells perceived as threats) to cancer cells. BiTE® antibody constructs help place the T cells within reach of the targeted cell, with the intent of allowing T cells to inject toxins and trigger the cancer cell to die (apoptosis). BiTE® antibody constructs are currently being investigated for their potential to treat a wide variety of cancers.

Study findings presented at the 62nd American Society of Hematology (ASH) Annual Meeting in December 2020 suggest that Blincyto monotherapy should be considered a new standard to be used before allogeneic hematopoietic stem cell transplant in many patients with B-cell precursor acute lymphoblastic leukemia (BCP-ALL). More about Blincyto...

Following remission induction, patients typically require 2-3 weeks for bone marrow blood cell production to recover before proceeding to post-remission therapy.1,2 

Specific Subtypes of Adult ALL

Philadelphia Chromosome-Positive ALL

Up to 40% of adults with ALL have the Philadelphia chromosome in their leukemic cells which connotes an adverse prognosis. This abnormality increases with age, making the treatment of older patients difficult. Adults with Philadelphia chromosome-positive ALL can be treated with the combination of Iculsig (ponatinib) and Blincyto (blinatumomab) or receive long-term maintenance therapy with a TKI.7,8-16,22

T-Cell Leukemia

Multi-agent chemotherapy produces remissions in approximately 40% of patients but most patients ultimately die of progressive disease.9  After blood counts recover following remission induction chemotherapy, a bone marrow examination is repeated to see if a remission has been achieved. If a complete remission is achieved and no further therapy given, over 90% of patients will have a recurrence of leukemia in weeks to months. To prevent recurrence of leukemia, post-remission therapy is initiated immediately after recovery from induction therapy.

A new stem cell transplant conditioning regimen showed that 88% of patients remained in remission one year post-treatment completion, a dramatic increase in relapse-free survival compared to the expected 45%. The regimen added Isotodax (romidepsin) as maintenance therapy post-transplant to both reduce cancer relapse and activate natural killer (NK) cells in the immune system to eliminate any residual cancer cells.23

For patients not in remission, a second remission induction course of treatment can be given immediately or patients can proceed directly to stem cell transplantation, or CAR T cell therapy or  which is currently the most effective way to cure adults failing to achieve a complete remission with initial treatment.

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Post-Remission Treatment

If a complete remission is achieved following remission induction therapy and no further treatment given, over 90% of patients will have a recurrence of leukemia in weeks to months. However, treatment with standard intensive post-remission therapy can now cure a majority of adults with ALL.

Allogeneic Stem Cell Transplantation in First Complete Remission

Utilizing allogeneic stem cell transplantation for post-remission therapy results in cure for up to 50% of young adults if they have a suitable stem cell donor and are transplanted after remission induction chemotherapy. An allogeneic stem cell transplant is a procedure that involves the infusion of donor stem cells into a patient in order to rescue low levels of blood cells caused by high-dose treatment. Adult patients with adverse risk factors may wish to consider treatment with allogeneic stem cell transplant and have an early donor search for an allogeneic stem cell donor performed. It is important for patients with adverse risk factors to identify a suitable allogeneic stem cell donor at the time of diagnosis. To learn more go to Allogeneic Stem Cell Transplant.

A combined US (Eastern Cooperative Oncology Group) and UK study has confirmed that an allogeneic stem cell transplant in first complete remission is the best option for patients with standard- and high-risk ALL who were 65 years of age or younger.2 Patients with Philadelphia chromosome-positive ALL were excluded from this study. This study enrolled 2000 patients with standard- and high-risk ALL over a 13-year period. Patients were offered an allogeneic stem cell transplant in first remission if a donor was available. If no donor was available, patients were randomly allocated to receive prolonged chemotherapy (2.5 years) or an autologous stem cell transplant. The following were the main findings of this study:

  • The complete remission rate for the entire group was 91%
  • The overall 5-year survival for the entire group was 38%
  • Patients in the allogeneic transplant group had a survival at 5 years of 63% compared to 51% for those without a donor.
  • The relapse rate for patients in the transplant group was 39% compared to 62% without a donor.
  • Treatment-related mortality was higher in the allogeneic transplant group especially in those over the age of 35 years.
  • Survival of patients on prolonged chemotherapy was 42% compared to 33% for those randomized to receive an autologous stem cell transplantation.
  • This overall advantage for transplantation was not seen in high-risk patients, defined as age greater than 35 years or high WBC (>30,000 for B-lineage or >100,000 for T-cell lineage).

These authors concluded that allogeneic transplantation in first remission offered the best treatment for standard-risk adult ALL and that there was no advantage to an autologous transplant over consolidation and maintenance chemotherapy.

Only a minority of patients with adult ALL will have a related donor and must resort to using an unrelated donor or umbilical cord blood. Researchers affiliated with the European Bone Marrow Transplant (EBMT) Registry have reported that, for adults with ALL in first remission, allogeneic stem cell transplants from unrelated donors result in similar outcomes to those observed following related allogeneic stem cell transplants.3 These authors reported that the disease-free survival for patients with ALL in first complete remission was 45% following a related donor transplant and 42% following an unrelated donor transplant.

Consolidation and Maintenance Therapy in Specific Subtypes of ALL

Philadelphia Chromosome-Positive ALL

Prior to the development of Gleevec® (imatinib), adult patients under the age of 55 or 65 with no significant co-morbidities were advised to have an allogeneic stem cell transplant in first remission. In the pre-Gleevec era a large French study reported a 3-year survival of patients receiving an allogeneic stem cell transplant of 37%, compared to 12% for patients receiving continued chemotherapy without a transplant.4 Currently all patients with Philadelphia chromosome-positive ALL receive Gleevec indefinitely.

Older Patients with ALL

Hyper-CVAD: A common multi-agent regimen developed at the MD Anderson Cancer Center for the treatment of adult ALL is called hyper-CVAD.6 This regimen includes Cytoxan, Oncovin, Adriamycin, and dexamethasone combined with high doses of methotrexate and Cytosar followed by maintenance with 6-mercaptopurine, Oncovin, methotrexate and prednisone. This is a more aggressive regimen than usual and has different effects depending on age. 

Following remission induction with hyper-CVAD the complete remission rate in older patients was 84% compared to 92% in younger patients. However, the mortality rate during remission induction was 10% for older patients compared 2% for younger patients. In addition 34% of older patients died, usually of infections, while in first complete remission compared to 7% in younger patients. Relapse rates were similar between older and younger patients. Ultimate survival was 25% for older patients and 48% for younger patients. Previous studies with less intensive regimens were associated with a relapse rate of 80% compared to 40% for hyper-CVAD. These data suggest that progress is being made in treating adult ALL but the therapy is associated with an increased rate of non-leukemic deaths in older individuals.

The Importance of Treating the Central Nervous System and Other Sanctuary Sites

Acute lymphoblastic leukemia cells spread into the central nervous system, testicles and other locations not easily reached with chemotherapy. These are often referred to as sanctuary sites. This is because many drugs are unable to penetrate into these areas and destroy the cancer cells. It is important to understand that it is easier to prevent leukemia recurrence than it is to treat leukemia after it recurs in these sites. Prevention of leukemia recurrence can be accomplished by injecting chemotherapy into the central nervous system or by treatment with radiation. This is referred to as central nervous system prophylaxis.

Intrathecal therapy is the term used to describe the injection of drugs into the central nervous system to prevent leukemia recurrence. It is performed by injecting the chemotherapy drugs methotrexate or cytarabine or both through a needle inserted into the spinal canal on several occasions. These same drugs are also effective in preventing CNS relapses when given in high doses intravenously. Current treatment regimens are associated with only a 2-4% incidence of CNS recurrences. Current efforts are directed at preventing CNS relapses without the use of radiotherapy.

Recurrent Acute Lymphoblastic Leukemia

Studies published in The New England Journal of Medicine, and Lancet have reported achieving sustained remissions in children and adults with relapsed/refractory acute lymphoblastic leukemia (ALL) using CD19-targeted chimeric antigen receptor (CAR)-modified T cells.18,21

Anti-CD19 CAR T cell therapy involves genetically modifying a patient’s T cells to express a CAR that is designed to target CD19, a protein expressed on the cell surface of B cell lymphomas and leukemias.18-20

In one clinical study, CAR T was administered to 30 children and adults at the Hospital of the University of Pennsylvania with relapsed or refractory ALL. Of the 30 patients, 26 had relapsed B-cell, 3 had primary refractory B-cell ALL, and 1 had relapsed T-cell ALL expressing the CD19 antigen.

Overall complete disappearance of the ALL was achieved in 90% of patients, and with follow-up of 2 to 24 months, sustained remissions have been observed in 19 patients, with 15 receiving no further treatment.

The ZUMA-3 clinical trial evaluated the CAR T-cell therapy Tecartus® (brexucabtagene autoleucel) in 71 adult patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia leading to FDA approval.  At a median follow-up of 16.4 months, 71% of treated patients achieved a complete response and the average survival duration among all responders had not yet been reached.21

A major side effect of CAR T is cytokine-release syndrome and this was reported in 27% of patients requiring intensive management and support. Cytokine-release syndrome is a documented side effect of CAR T typically starting the day after infusion.19

The researchers concluded that CAR T was effective in treating relapsed and refractory ALL even among patients for whom stem-cell transplantation had failed, and durable remissions up to 24 months were observed are ongoing. Other researchers have confirmed these results and ALL patients with recurrent or refractory disease should be evaluated at a treatment center that offers CAR T cell and stem cell therapies.19,20


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  20. Shah B, Ghobadi A, Oluwole O, et al. Phase 2 results of the ZUMA-3 study evaluating KTE-X19, an anti-CD19 chimeric antigen receptor T-cell therapy, in adult patients with relapsed/refractory B-cell acute lymphoblastic leukemia. J Clin Oncol. 2021;39(15):7002-7002. doi:10.1200/JCO.2021.39.15_suppl.7002