Relapsed or Refractory Adult Acute Lymphoblastic Leukemia

CancerConnect – Relapsed or Refractory Adult Acute Lymphoblastic Leukemia

Charles H. Weaver, MD
10–15 minutes
Home » Leukemia » Relapsed or Refractory Adult Acute Lymphoblastic Leukemia

by Dr. C.H. Weaver M.D. Medical Editor 6/2023

Patients with progressive or relapsed adult ALL remain curable despite failing initial treatment. Patients failing treatment can be divided into two broad categories. Patients who fail to achieve an initial complete disappearance or remission of their cancer following a complete course of remission induction chemotherapy treatment are referred to as “induction failures”. Patients who achieve a complete remission to initial treatment and then experience a cancer recurrence are said to have relapsed leukemia. Relapse of leukemia may occur several months to years after the initial remission; however the majority of relapses occur within two years of initial treatment. Refractory is a term that implies that patients have failed at least one treatment regimen after a relapse.

The standard treatment approach for relapsed or refractory B cell ALL is to attempt to induce a remission again and then consolidate the remission with an allogenic stem cell transplant. 

High-dose chemotherapy and allogeneic bone marrow or blood stem cell transplantation is a treatment strategy that utilizes the administration of high doses of anti-cancer drugs and/or radiation therapy for the purpose of killing the leukemia cells and transplantation of a donors stem cells to “rescue” or restore bone marrow blood and immune cell production. Transplantation is the term for transfer of the tissue (a graft) from one person to another. Allogeneic is the term for a tissue graft from one person to another.

About Allogeneic Stem Cell Transplant.

Remission Induction Treatment 

Reinduction with standard chemotherapy drugs has been effective in producing complete remissions in some patients, but there are no cures without an allogeneic stem cell transplant. Standard-dose chemotherapy can induce a complete remission in 10%-30% of adults, but few patients are cured with chemotherapy alone. The average duration of survival is 5-6 months and less than 5% of adult patients survive 5 years after relapse.

The best treatment is an allogeneic stem cell transplant. A transplant can be performed in first relapse or after an attempt to produce a remission with a chemotherapy regimen different than that used for induction. Patients with adult ALL who receive a related or unrelated donor stem cell transplant in other than first complete remission have a long-term disease-free survival of greater than 30%.1 The best survivals are seen in those patients who achieve a remission with reinduction therapy and the worst survivals are in those who were refractory to attempts to produce a remission.

Regimens Used for Reinduction Treatment

A number of chemotherapy regimens have been developed to induce remissions in patients with relapsed ALL so they can proceed to allogeneic stem cell transplant. More recently precision cancer medicines and immunotherapy have been developed that when used alone or in combination with chemotherapy produce higher remission rates than chemotherapy alone. 

Blincyto (blinatumomab)

Blincyto is a BiTE® antibody construct 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 the first BiTE® antibody construct approved by the US Food and Drug Administration for treatment of ALL and is improving patient outcomes.  Bispecific T cell engager (BiTE®) antibody constructs are a type of immunotherapy are modified antibodies 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.

Besponsa (inotuzumab ozogamicin)

Besponsa consists of a monoclonal antibody, which targets CD22, which is linked to a potent cytotoxic agent called calicheamicin. This drug has been shown to produce remission rates in excess of 50% in ALL and is incorporated into treatment regimens for selected patients.17

CAR-T Cell Therapy

Obecabatagene autoleucel (obe-cel), an investigational autologous CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy is reported to produce significant anti-leukemia responses among adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL).

Among 94 patients who were treated with obe-cel in the phase 2 FELIX clinical trial, 54% achieved a complete remission. At a median follow-up of 9.5 months, 61% of patients who responded continued to remain in remission. A majority of patients experienced cases of cytokine release syndrome and 25% developed immune effector cell-associated neurotoxicity syndrome (ICANS), well known side effects of CAR-T cell therapy.18

 A few of the more common chemotherapy regimens will be listed below:

High-Dose Idamycin® (idarubicin) and Cytosar® (cytarabine):Various doses and schedules of Idamycin and Cytosar have been used to treat relapsed adult ALL over the past two decades. One of the more recent studies reported a complete remission rate of 44% with a median disease-free survival of 6 months.2

Cytosar, Amsidine® (amsacrine) and VePesid® (etoposide): Researchers from France have reported a complete remission rate of 40% with the combination of Cytosar, Amsidine and VePesid in patients with relapsed ALL, with a disease-free survival of 12% at three years.3 All long-term survivors had received an allogeneic stem cell transplant after remission induction.

Arranon: Arranon is a drug which has resulted in a 50% response rate in children with refractory T-cell ALL.5  This drug has now been incorporated into remission induction and consolidation therapy for children with T-cell ALL.6

Clolar: Clolar is a new drug that has been primarily evaluated in children with ALL who relapsed after primary therapy.7

Treatment of Philadelphia Chromosome-Positive ALL

Most current patients with ALL in relapse will have failed Gleevec® (imatinib). However, for patients not receiving up-front Gleevec this drug can be used in salvage regimens. Researchers from France have reported that high-dose Gleevec combined with vincristine and dexamethasone produced complete remissions in 90% of patients with Philadelphia chromosome-positive ALL in relapse.

Some patients with Philadelphia chromosome-positive ALL become refractory to Gleevec due to the development of mutated leukemic clones. However, there are now two drugs currently approved by the US Food and Drug Administration (FDA) for treating adult ALL patients that are refractory to Gleevec: Sprycel® (dasatinib) and Tasigna® (nilotinib). There are other tyrosine kinase inhibitors in the drug development pipeline that have not yet been approved by the FDA, including bosutinib (SK1606).

Sprycel® (dasatinib): Sprycel is a tyrosine kinase inhibitor that is more than 300 times more active than Gleevec for inhibition of Bcr-Abl (the abnormal protein produced by the Philadelphia chromosome). Sprycel can produce complete cytogenetic remissions in patients with ALL who are refractory to Gleevec.8,9 In addition, Sprycel is more effective than Gleevec for the treatment of Philadelphia chromosome-positive ALL that involves the central nervous system (CNS).10 This is because Gleevec does not get into the central nervous system while Sprycel does.

Tasigna® (nilotinib): Tasigna is another tyrosine kinase inhibitor which has more potency than Gleevec. Tasigna produces significant remissions in patients with adult ALL who are refractory to Gleevec.11,12

Strategies to Improve Treatment of Relapsed or Refractory Adult ALL

The development of intensive multi-agent chemotherapy induction regimens, advances in stem cell transplantation, improvements in supportive care, and patient and physician participation in clinical studies have resulted in steady progress in the treatment of adult ALL. The following strategies are currently being evaluated alone or in combination for the purpose of further improving treatment.

New Drug Development: All new drugs for the treatment of patients with ALL are tested first in patients with relapsed or refractory disease. When they are found to be effective, they are then evaluated in remission induction regimens.

New Tyrosine Kinase Inhibitors

Gleevec is a tyrosine kinase inhibitor that was designed specifically for the treatment of leukemia associated with the Philadelphia chromosome abnormality. This drug has revolutionized the treatment of Philadelphia chromosome-positive ALL. However, drug resistance occurs and patients with ALL can fail treatment. Therefore, there is considerable research into the development of new tyrosine kinase inhibitors that can overcome resistance to Gleevec. There are two drugs currently approved by the US Food and Drug Administration (FDA) for treating adult ALL patients that have failed Gleevec: Sprycel® (dasatinib) and Tasigna® (nilotinib). There are other tyrosine kinase inhibitors in the drug development pipeline that have not yet been approved by the FDA, including bosutinib (SK1606).

Bosutinib (SK1606): Bosutinib is a drug that is still in phase I-II testing but it is also more potent than Gleevec. Preliminary studies show that this agent has significant activity in adults with ALL who are refractory to Gleevec.13 Taken together it appears that there will be many new drugs for the treatment of Philadelphia chromosome-positive adult ALL, which may make allogeneic stem cell transplantation less of a necessity.

Monoclonal Antibody Therapy

Monoclonal antibodies directed at tumor antigens have made a major impact in the treatment of cancer over the past two decades. The major advantage of monoclonal antibody therapy is that the toxicities are not the same as for chemotherapy and when added to chemotherapy there is little increase in side effects. There has been little progress in the development of monoclonal antibodies useful for the treatment of adult ALL. However, this situation may be changing. Researchers from New York University have reported that epratuzumab, a humanized monoclonal antibody that targets CD22 antigen, is effective alone or in combination for the treatment of ALL.14 This study showed that epratuzumab could be safely added to chemotherapy with improved responses in patients with advanced ALL. The Children’s Oncology Group plans to add epratuzumab for induction in children with high-risk ALL.

There is emerging evidence that the widely used anti-CD20 antibody Rituxan® (rituximab) has activity in some patients with ALL. A recent study has suggested that CD20 is upregulated in many cases of ALL making this disease a target for Rituxan.[15] There are already reports of children with ALL responding to single-agent Rituxan or Rituxan in combination with chemotherapy.[16] A study from MD Anderson Cancer Center has reported that the addition of Rituxan to intensive chemotherapy improved the outcomes of adult patients with ALL who were CD20-positive.[17] This is expected to be an area of intense research in the near future.

Mylotarg® (gemtuzumab ozogamicin) is an antibody to CD33 that is conjugated (joined) with a cytotoxic (cell-killing) antitumor antibiotic. This antibody conjugate is approved by the US FDA for the treatment of patients with acute myeloid leukemia (AML) who have failed other therapies. A small fraction of patients with ALL also have leukemia cells that are CD33 positive and Mylotarg has been effective in treating children with CD33 positive ALL.[18] Experience with treating adult patients with CD33 positive ALL is limited.

Strategies to improve treatment of patients who fail remission induction are also discussed in the section on Allogeneic Stem Cell Transplant.

References

  1. Kiehl MG, Kraut L, Schwerdtfeger R, et al. Outcome of allogeneic hematopoietic stem-cell transplantation in adult patients with acute lymphoblastic leukemia: No difference in related compared to unrelated transplant in first complete remission. Journal of Clinical Oncology 2004;22:2816-2825.
  2. Tedeschi A, Montillo M, Strocchi E. High-dose idarubicin in combination with Ara-C in patients with relapsed or refractory acute lymphoblastic leukemia: A pharmacokinetic and clinical study. Cancer Chemotherapy Therapeutics Pharmacology 2007;59:771-779.
  3. Reman O, Buzyn A, Lheritier V, et al. Rescue therapy combining intermediate-dose cytarabine with amsacrine and etoposide in relapsed adult lymphoblastic leukemia. Hematology Journal 2004;5:123-129.
  4. Larson RA. Three new drugs for acute lymphoblastic leukemia: nelarabine, clofarabine, and forodesine. Seminars in Oncology 2007;34:513-520.
  5. Berg SL, Blaney SM, Devidas M, et al. Phase II study of nelarabine (compound 506U78) in children and young adults with refractory T-cell malignancies: a report from the Children’s Oncology Group. Journal of Clinical Oncology 2005;20:3376-3382.
  6. Dunsmore K, Devidas M, Borowitz MJ, et al.: Nelarabine can be safely incorporated into an intensive, multiagent chemotherapy regimen for the treatment of T-cell acute lymphocytic leukemia (ALL) in children: a report of the Children’s Oncology Group (COG) AALL00P2 protocol for T-cell leukemia. Blood 2006;108 abstract 1864,
  7. Kearns P, Michel G, Neiken B, et al. BIOV-111 a European phase II trial of clofarabine (Evoltra® in refractory and relapsed childhood acute lymphoblastic leukemia. Blood 2006;108: abstract number 1864.
  8. Brave M, Goodman V, Kaminskas E, et al. Sprycel for chronic myeloid leukemia and Philadelphia chromosome positive acute lymphoblastic leukemia resistant or intolerant of imatinib mesylate. Clinical Cancer Research 2008;14:252-369.
  9. Talpaz M, Shah NP, Kantarjian H, et al. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. New England Journal of Medicine. 2006;354:2531-2541.
  10. Porkka K, Koskenvesa P, Lundan T, et al. Dasatinib crosses the blood-brain barrier and is an efficient therapy for central nervous system Philadelphia chromosome positive leukemia. Blood 2008;112:1005-1012.
  11. Kantarjian H, Giles F, Wunderle L, et al.Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL.The New England Journal of Medicine. 2006;354:2542-2551.
  12. Piccaluga PP, Paolini S, Marinelli G, et al. Tyrosine kinase inhibitors for Philadelphia chromosome positive adult acute lymphoblastic leukemia. Cancer 2007;110:1178-1186.
  13. Gambacorti-Passerini C, Blummedorf T, Kantarjian H, et al. Bosutinib (SKI-606) exhibits clinical activity in patients with Philadelphia chromosome positive CML or AML who failed imatinib. Proceedings from the American Society of Clinical Oncology Conference. Chicago/IL. Abstract # 7006.
  14. Raetz EA, Cairo MS, Borowitz MJ, et al. Chemoimmunotherapy reinduction with epratuzumab with acute lymphoblastic leukemia in marrow relapse: a Children’s Oncology Pilot Study. Journal of Clinical Oncology. 2008;26:3756-3762.
  15. Dworzk MN, Schumich A, Printz D, et al. CD20 up-regulation in pediatric B-cell precursor acute lymphoblastic leukemia during induction treatment: setting the stage for anti-CD20 directed immunotherapy. Blood 2008;Epub on September 9.
  16. Gokbuget N and Hoelzer D, Treatment with monoclonal antibodies in acute lymphoblastic leukemia: current knowledge and future prospects. Annals of Hematology 2004;83:201-2005
  17. E. Jabbour, S. M. O’Brien, D. A. Thomas et al. Inotuzumab ozogamicin (IO; CMC544), a CD22 monoclonal antibody attached to calicheamycin, produces complete response plus complete marrow response (mCR) of greater that 50% in refractory relapse (R-R) acute lymphoblastic leukemia. Journal of Clinical Oncology 29:2011 (supplement, abstract 6507).
  18. Roddie C, Sandhu KS, Tholouli E, et al. Safety and efficacy of obecabtagene autoleucel (obe-cel, AUTO1), a fast-off rate CD19 CAR, in relapsed/refractory adult B-cell acute lymphoblastic leukemia (r/r B-ALL): Top line results of the pivotal FELIX study. Presented at: the American Society of Clinical Oncology (ASCO) 2023 Annual Meeting, held June 2-6, in Chicago, Illinois. Abstract #7000

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