RELAPSED/REFRACTORY ALL

DR NAHID AFROZA

PHASE-B

DEPT. OF HAEMATOLOGY

OBJECTIVES

• To define relapse and refractory disease

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• Management of relapse and refractory disease

CASE - 1

• Mr. Torikul

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• 35 year old normotensive nondiabetic male

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• Presented with high grade fever, generalized weakness and bodyache , bilateral neck swelling

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• PBF : Acute Leukaemia with 50% blast

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• BMS : suggestive of Acute Lymphoblastic Leukemia

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• Immunophenotyping revealed : B-ALL

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• Cytogenetics : (-) ve for BCR-ABL study

CASE - 1

• Got his induction chemo with standard BFM (prednisolone, vincristine, daunu , L-asperginase)

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• Following induction he was in morphological partial remission with 6-8% blast

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• MRD was positive with 1.8%

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• The patient was counselled for Hyper CVAD followed by HSCT

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• But due to financial constrain he decided to go for palliative therapy

CASE - 2

• Mr. Hasibur

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• 23 year old normotensive, nondiabetic male

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• Presented with high grade fever, generalized body ache, weakness and multiple bruise in different part of the body

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• BMS reveals ALL with 40% blast

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• Immunophenotyping reveals B-ALL

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• Cytogenetics positive for BCR-ABL

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CASE - 2

• This patient got induction with standard BFM along with dasatinib 140 mg OD

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• Following induction he was morphological partial remission

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• MRD was positive with 1.2%

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• Following that he received 2 cycle of hyper CVAD along with dasatinib

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• After 2 cycle he under went both morphological and immunological remission

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• The patient proceed to allo-HSCT

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INTRODUCTION

• After induction therapy 85-90% of ALL patient go into remission

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• There are subsets that are refractory to induction therapy

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• Many patients with complete remission will have a relapse

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• Only approximately 30-50% will have disease free survival lasting 3 year or longer

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• Conventional standard chemotherapy regimens for adults with relapsed or refractory B-cell ALL are associated with rates of CR
• 31-44% when they are the first salvage therapy after an early relapse and
• 18-25%when they are the second salvage therapy

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CONT…

• Because CR is typically a prerequisite for subsequent allo-HSCT

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• The low rate of CR associated with conventional chemotherapy regimens mean that few adults with relapsed or refractory B-cell ALL proceed to HSCT , which is considered to be the main goal after salvage treatment

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• Because, it is the only potentially curative treatment option.

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DEFINITION

• Relapse – defined as the reappearance of blasts in the blood or bone marrow (›5%) or any extramedullary site after achievement of a CR

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• Refractory - Failure to achieve a CR at the end of induction therapy

CR

• Requires the absence of circulating blasts and absence of extramedullary disease (no lymphadenopathy, splenomegaly, skin/gum infiltration, testicular mass, CNS involvement, other sites of disease)

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• Bone marrow assessment show trilineage haematopoiesis and fewer than 5% blasts

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• Absolute neutrophil count greater than 1.0ₓ 10₉/L

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• Platlet count greater than 100ₓ10₉/L

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• No recurrence should be observed for at least 4 weeks

TREATMENT OPTIONS

CONT…

• Salvage chemotherapy
• Hyper CVAD
• HiDAC
• HiDAC+IDA
• HiDAC+Mitoxantrone
• HiDAC+Fludarabin

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CONT…

• Recently two randomized trials comparing conventional salvage regimens with novel immunotherapy based therapies,
• the tower trial with blinatumomab (targeting CD19) and
• the INO-VATE ALLtrial with inotuzumab ozogamicin(targeting CD22)

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• Demonstrated significantly higher remission rates (up to 80%) for patients with R/R B-precursor ALL treated with either antibody-based therapy.

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• Moreover, these novel treatments showed a favorable toxicity profile compared to conventional chemotherapies and

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• allowed treatment in many in an out patient setting.

CONT…

• Both trials defined a new standard therapy option in patients with R/R B-precursor ALL.

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• Conventional chemotherapy might be still a reasonable option in patients with late relapse.

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• However, with regard to treatment toxicity and option of outpatient treatment, antibody-based therapies should be discussed with the patients, if available.

CONT…

• In patients with R/R Ph + ALL, usually treated with Imatinib as part of the first-line treatment

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• Molecular testing of mutations leading to the resistance to particular tyrosine kinase inhibitors

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• According to these results, a second generation TKI (e.g., Dasatinib or Ponatinib ) should be chosen as salvage therapy.

CAR-T CELL THERAPY

BLINATUMOMAB

• Blinatumomab is a bispecific T-cell–engaging antibody (BiTE)

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• Form a synapse between CD3 T cells and CD19 B cells

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• Causes cytokine release and T-cell proliferation.

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• The cytolytic T cells then induce B-cell apoptosis through pore-forming perforins and proteases.

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• Most adverse events, including cytokine release syndrome(CRS) and neurologic toxicity

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INOTUZUMAB

• Inotuzumab is a CD22-directed antibody linked to calicheamicin

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• Calicheamicin released inside tumor cell

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• It causes double-stranded DNA breaks, that lead to apoptosis

T-CELL ALL

• Treatment options for patients with R/R T- precursor ALL are limited.

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• So far, there is no agreed standard of care in adult with relapsed T-cell ALL.

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• Standard chemotherapy regimens such as FLAG (FLU , Ara-C, and G-CSF) ± idarubicin only result in 30% to 40% response rates with 6 months median OS in responders.

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• Nelarabine as monotherapy or in combination with other chemotherapeutic agents has shown promising response rates and is a reasonable option

NELARABINE

• Nucloside analog

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• 55% response rate in first bonemarrow relapse

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• 27 % response rate in second or greater bone marrow relapse

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• Causes Grade 2 and 3 sensory motor neuropathy and

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• Musculoskeletal pain

CAR-T CELL THERAPY

• Anti-CD19 chimeric antigen receptor (CAR)-expressing T cells

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• Modern cancer immunotherapy

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• Patients T cell genetically modified and reintroduced for eradication malignant B cell

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• Extremely effective against R/R B precursor ALL patients with upto 70-90% response rates reported

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• CAR-T cells have to be evaluated in further prospective trials.

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ADVERSE EFFECT

HSCT

• Myeloablative alloHSCT transplantation is undoubtedly one of the most effective anti ALL therapies available

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• Unfortunately ,it is also the most toxic approach within our therapeutic scope

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• It has played a significant role in the treatment of ALL over many years

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• Reserved for those thought to be at high risk of poor outcome by dint of having poor prognostic factors

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• Wherever a matched sibling donor is available

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• Unrelated donor stem cells being widely available and the use of haploidentical donor cells or umbilical cord blood becoming more routine

CONCLUSION

• The development of antibody-targeted therapies and CAR T cells in R/R ALL has made possible an approach to treatment that is more effective than historical standard chemotherapies.

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• These have significantly improved outcomes in the salvage setting and provided better treatment options.

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• The future of ALL treatment appears to be the use of lower intensity chemotherapy in combination with antibody targeted therapies in the frontline setting to induce higher cure rates while minimizing toxicities.

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• This strategy will also allow more patients to proceed to alloHSCT.

TAKE HOME MESSAGES

• Non chemotherapy approaches are currently in clinical trial for relapsed or resistant ALL

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• If ALL fail to respond to therapy or relapses in adult, survival is generally very poor and allo-HSCT is the only known curative therapy.