2. Activity Faculty Scott C. Howard, MD, MSc University of Tennessee College of Health Sciences Memphis, TN

3. Learning Objectives Upon completion, participants should be able to: Review treatment regimens for patients with relapsed ALL Optimize supportive care for patients who receive relapsed ALL therapy

4. Key Considerations in the Management of Relapsed ALL Relapsed ALL (except for late extramedullary relapse) has a poor prognosis All known-effective agents should be used at first relapse to get the patient into a deep remission before transplant or continuation therapy (depending on donor availability) Great supportive care is as important to optimal patient outcomes as chemotherapy

5. ALL The incidence of ALL is highest among children and decreases with advancing age –Most common form of leukemia in childhood –Only one-fifth of leukemia cases in adults Roughly 80% of patients treated with risk- adapted therapy at diagnosis are cured However, outcomes for patients with relapsed disease are poor PRACTICE PEARL Relapsed ALL (except for late extramedullary relapse) has a poor prognosis

6. When to Suspect Relapsed ALL In general, relapse should be suspected in patients with any of the following: –New neurologic deficits –Testicular mass –Cytopenias of unexpectedly long duration and severity during therapy –Blasts noted on the peripheral blood smear or in the CSF It is essential to confirm relapse before initiating salvage therapy

7. Initial Steps for Patients With Suspected Relapsed ALL Confirmation of the relapse is essential –Flow cytometry –PCR assays

8. Initial Steps for Patients With Suspected Relapsed ALL (cont.) Identify site(s) of relapse –Bone marrow (isolated vs. combined) –CNS –Testes –Other extramedullary sites

9. Factors Affecting Risk Stratification in Relapsed ALL Time to relapse Site of relapse Immunophenotype Response to initial therapy for relapse (ie, MRD after 2 blocks)

10. Defining Risk-Based Groups for Reinduction Therapy Standard-risk treatment group: HSCT not necessary –Late relapse (≥ 36 months from initial diagnosis), AND –B-lineage ALL, AND –MRD ≤ 0.01% after 2 blocks of induction therapy High-risk treatment group: HSCT if possible –Early relapse (< 36 months from initial diagnosis), OR –T-lineage ALL, OR –MRD > 0.01% after 2 blocks of induction therapy

11. Reinduction Therapy for Standard Risk Relapsed ALL *Regimens usually include high-dose methotrexate and high-dose cytarabine. PRACTICE PEARL All known-effective agents should be used at first relapse to get the patient into a deep remission before transplant or continuation Intensive chemotherapy with radiation in some cases Late isolated non-CNS extramedullary relapse (eg, testicular) Intense relapsed induction chemotherapy regimen* followed by consolidation and continuation Bone marrow relapse Intense systemic and intrathecal chemotherapy* with cranial (or craniospinal) radiation Late isolated CNS relapse

12. Reinduction Therapy for High-Risk Relapsed ALL Standard reinduction regimens are not sufficient for patients with high-risk relapsed ALL PRACTICE PEARL All known-effective agents should be used at first relapse to get the patient into a deep remission before transplant or continuation

13. Investigation Into Novel Reinduction Regimens Is Ongoing Current phase 2 study at St. Jude Children’s Research Hospital (NCT01700946) –Examining new approaches to achieve deep remission as early as possible following relapse –Stratifying patients into risk groups to define treatment approach Chemotherapy for standard risk Chemotherapy followed by HSCT for high risk PRACTICE PEARL All known-effective agents should be used at first relapse to get the patient into a deep remission before transplant or continuation

14. Reinduction Therapy for High-Risk Relapsed ALL (cont.) Once CR2 is achieved, initiate intensive chemotherapy followed by HSCT as soon as MRD-negative status is achieved –Recommend HSCT to those with high-risk features –HSCT may be appropriate for some intermediate-risk patients in CR2 If no stem cell donor is available, proceed to consolidation and continuation therapy, as is done for standard-risk ALL PRACTICE PEARL All known-effective agents should be used at first relapse to get the patient into a deep remission before transplant or continuation

15. Relapsed ALL Treatment Algorithm Marrow not involvedMarrow involved Enroll in a clinical trial Early relapse or T-lineage ALL or MRD > 0.01% after initial therapy Late relapse and B-lineage ALL and MRD ≤ 0.01% after initial therapy Standard risk MRD measurement Suspect relapse (New neurologic deficit, blasts on blood smear or in CSF, prolonged cytopenias during therapy) Confirm relapse and identify sites of disease (BMA; neurologic, testicular, and CSF examinations) Regimen for isolated extra-medullary relapse Risk stratify High risk Induction Block II Induction Block I

16. Relapsed ALL Treatment Algorithm SCT Continuation MRD ≤ 0.01% MRD > 0.01% MRD improved No SCT donor MRD worse Consider palliative careConsider experimental therapy Consolidation I Consolidation II Intense block of chemotherapy Standard risk High risk

17. Preventing Toxic Death in Relapsed ALL Management of febrile neutropenia –Empiric antimicrobial therapy –Inpatient admission Antifungal prophylaxis –Consider for all patients receiving chemotherapy –Administer until at least day 75 following allogenic HSCT Avoid antifungals that inhibit cytochrome P450 3A4 isozyme PRACTICE PEARL Great supportive care is as important to optimal patient outcomes as chemotherapy

18. Key Considerations in the Management of Relapsed ALL Relapsed ALL (except for late extramedullary relapse) has a poor prognosis All known-effective agents should be used at first relapse to get the patient into a deep remission before transplant or continuation therapy (depending on donor availability) Great supportive care is as important to optimal patient outcomes as chemotherapy

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