Treatment of Adult ALL

Vinod Pullarkat, MD, MRCP

Professor

Hematology and Hematopoietic Cell Transplantation

Disclosures

• Consultant for Novartis, Amgen, Jazz

• On the Speakers Bureau for Novartis, Amgen,

Jazz

Epidemiology

• Around 6000 cases annually in the US

• Half the cases in childhood and teen age

• About 75% are B-ALL in adults

• Higher incidence rates in Hispanics (IRR of 1.9 age 20-54)

• Higher incidence of Ph-like subset in Hispanics related to

inherited GATA-3 variant

Pullarkat ST et al. Cancer Epidemiol Biomarkers Prev 2009; 18: 611-5

Perez-Andreu et al. Blood 2015; 125: 680-86

Perez-Andreu et al. Blood 2015; 125: 680-86

Ethnic variation in Ph-like ALL

Average annual age-specific incidence and mortality rates for ALL, 1973-2009, U.S. National Cancer Institute Surveillance

Epidemiology and End-Results (SEER) program (www.SEER.cancer.gov).

Age-specific incidence of ALL

Hunger SP, Mullighan CG. N Engl J Med 2015; 373: 1541

Outcome of pediatric ALL

5-54 yrs

Secular trends of ALL annual relative survival rates in patients diagnosed at 55+ years of age, 1973-2009,

Surveillance, Epidemiology and End-Results Program. (www.SEER.cancer.gov).

55+

Survival of adult ALL

Moorman AV. Blood Rev 2012; 26: 123

Cytogenetics of ALL

Good Risk Intermediate Risk Poor Risk

Hyperdiploidy (51-65 chr)

t(12;21)/ETV6-RUNX1 fusion

t(1;19)(q23;p13.3)

14q32/IGH translocations

Deletion 6q

Abnormal 9p

Abnormal 11q (not MLL translocations)

Dup 1q

Monosomy 7

dic(9;20)(p13;q11

dic(9;12)(p13;p11)

Normal karyotype

Any other abnormality

t(9;22), t(4;11)

Other MLL translocations

iAMP21

Near haploidy (<30 chr)

Low hypodiploidy/triploidy (30-39)/60-78

chr)

t(17;19)(q22;p13.3)

Abnormal 17p

Loss of 13q

Complex karyotype*

*defined as ≥ 5 unrelated chromosomal abnormalities in the absence of other established abnormality

Cytogenetic risk classification

Liu Y-F et al. E BioMedicine 2016;8: 173

Genomics of ALL

Genomics of ALL

Roberts KG Nat Rev Clin Oncol 2015; 12:344

Ph-like ALL

• Gene expression profile similar to BCR-ABL1 (Ph+) ALL

• 10% childhood and up to 30% adult ALL

• More common with Hispanic and native American ancestry

• IKZF1 alterations common

• Activation of various receptor kinases including CRLF2, ABL,

JAK2, EPOR

• Associated with poor outcome

Hunger SP, Mullighan CG. Blood 2015; 125: 3977

Genetics of Ph-like ALL

Outcome of Ph-like ALL

Roberts et al. N Engl J Med

2014; 371: 1005-15

Ph-like ALL in adults

Roberts KG et al. J Clin Oncol 2016; 35: 394

Ph-like ALL in adults

Age group 21-86. Ph-like in 20-30% range

Kinase activating alterations in 88%, CRLF2 rearrangements in 51%

Roberts KG et al. J Clin Oncol 2016; 35: 394

Treat adults like children

• Outcomes of adult ALL are superior when treated with pediatric-

type regimens compared to ‘adult’ regimens e.g. hyper CVAD

• Long term EFS and OS in 60- 70% range

• Results similar for T-cell and pre B-ALL

• Allogeneic HCT cannot be uniformly recommended as

consolidation therapy in newly diagnosed adult ALL

Principles of pediatric-type adult ALL regimens

• Mostly based on Berlin Frankfurt Munster (BFM) backbone

• Multiple cycles of non-cross resistant agents

• Early and frequent CNS prophylaxis

• Repeated doses of L-asparaginase

• Prolonged maintenance

• Less myelosuppression

• Higher cumulative doses of active agents

Adolescents and Young Adults (AYA)

• NCI definition: 15-39 years old

• Better definition : ? Up to Age 60

• Pediatric-type regimens have been safely administered up to

age 60

Pediatric type regimens for AYA

Boissel N, Sender LA. JAYAO 2015; 4: 118

Pediatric vs. adult regimens for AYA with ALL

Boissel N, Sender LS. JAYAO 2015; 4: 118

4 yr OS: 67% (n=92) 4 yr DFS: 69% (n=78)

DeAngelo DJ et al. Leukemia 2015; 29: 526

Age 18-50

DFCI Pediatric ALL consortium regimen

Outcome of USC ALL regimen for Philadelphia–negative patients.

Dan Douer et al. JCO 2014;32:905-911

©2014 by American Society of Clinical Oncology

OS DFS

Age 18-57 yrs

Stock W et al. Proc ASH 2014 Abstract 796

US Intergroup C10403

Kantarjian H et al. Cancer 2004; 101; 2788-2801

Hyper CVAD for ALL

C10403 regimen

USC ALL regimen

Dan Douer et al. JCO 2014;32:905-911

©2014 by American Society of Clinical Oncology

= PEG-asparaginase 2000U/m2

Aldoss I, Pullarkat V . Contemporary management of ALL .

Pullarkat V (Ed)

Jaypee Publishing.

USC ALL regimen

Curran E and Stock W. Blood 2015; 125:3702

1. Aldoss I, Pullarkat V . Contemporary Management of ALL .

Pullarkat V (Ed)

Jaypee Publishing. 2. Douer D et al. J Clin Oncol 2014;32:

905

C10403 USC ALL

Role of asparaginase

• Key drug in pediatric-type adult ALL regimens

• PEG-formulation associated with less hypersensitivity and longer

half life

• Doses of PEG-Asp 2000-2500 U/m2 well tolerated up to 60 years of

age

• Pharmacokinetic dosing may be preferable based on

asparaginase level or asparagine depletion

• Premedication reduces allergic reactions

Stock W et al. Leuk Lymphoma 2011; 52: 2237-2253

Toxicity of asparaginase

Managing asparaginase toxicity

• Hyperbilirubinemia more common in Cycle 1 (OR 22.5) No cases

of hepatic failure in 522 doses administered

• Hepatotoxicity does not preclude readministration of

asparaginase

• Hepatotoxicity was associated with higher BMI and hispanic

ethnicity

• Bleeding and thrombosis extremely rare when cryoprecipitate use

is limited to fibrinogen 60mg/dl. More common in cycle 1

Aldoss I et al. Eur J Haematology 2015 Jun 10. doi:

10.1111/ejh.12600. [Epub ahead of print]

Managing asparaginase toxicity

• Hypersensitivity, clinical pancreatitis and venous thrombosis are

contraindications to retreatment with asparaginase

• Bleeding rare when thrombocytopenia is avoided

• Routine use of cryoprecipitate, FFP and ATIII concentrate is not

required

• Allergic reactions are rare with use of premedications and

steroids

Optimizing asparaginase therapy

• Monitoring asparaginase level; now clinically available

• Hypersensitivity associated with antibody production:

Switch to Erwinia asparaginase

• Silent hypersentivity: ? switch to Erwinia asparaginase

Risk stratification of ALL

• Conventional factors (e.g. age, WBC count, immunophenotype)

have limited value

• High risk cytogenetics include Ph chromosome, hypodiploidy,

MLL rearrangement, iAMP21

• Ph-like ALL and IKZF1 alterations have poor prognosis

• MRD assessment critical in risk stratification

Beldjord et al. Blood 2014; 123: 3739

IKZF1 alterations in ALL

Ph- ALL

P=0.001

MRD to guide ALL therapy

• Detection of disease not detectable by light microscopy

• Detection of Immunoglobulin or T-cell receptor sequences by

PCR based methods or aberrant immunophenotype by multicolor

flow cytometry

• Detection limit in range of 10-3-10-6 (0.1-0.001%)

• Measurement at end of induction-2/Conslidation-1 (day 71-week

16)

• MRD persistence (≥ 10 -4) after consolidation-1 represents a high

risk group

Concordance of FCM vs PCR-based MRD assay

Theunissen P et al. Blood 2017; 129: 347

van Dongen et al. Blood 2015; 125: 3996

MRD

MRD

PCR-based

detection

≥ 10-4

Gokbuget et al Blood 2012; 120: 1868

Gokbuget et al. Blood 2012; 120: 1868

MRD and ALL outcome

All patients

Excluding SCT in CR1

Week 16

Mol failure:

≥10-4

Dhedin et al. Blood 2015; 125: 2486

MRD and ALL outcome

Allo HCT in CR1

• Conventional risk factors do not predict allogeneic HCT outcome

• MRD is the most important predictor of HCT outcome

• Need to identify MRD+ patients who benefit from HCT

• Need to determine benefit of novel therapies in MRD+ patients

prior to HCT

AlloHCT vs. Pediatric-type Chemotherapy Ph-neg ALL in CR1

Seftel et al. Am J Hematol 2016; 91: 322-29.

OS

DFS

RI

TRM

Age 18-50

Surv

ival P

robabili

ty

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Time (Years) from Date of Transplant

0 1 2 3 4 5 6 7 8 9 10 11

Cytogenetic Risk

Good/IntermediatePoor

Surv

ival P

robabili

ty

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Time (Years) from Date of Transplant

0 1 2 3 4 5 6 7 8 9 10 11

Cytogenetic Risk

Good/IntermediatePoor

Cum

ula

tive Incid

ence

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Time (Years) from Date of Transplant

0 1 2 3 4 5 6 7 8 9 10 11

Cytogenetic Risk

Good/IntermediatePoor

Cu

mu

lative

In

cid

ence

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Time (Years) from Date of Transplant

0 1 2 3 4 5 6 7 8 9 10 11

Cytogenetic Risk

Good/IntermediatePoor

OS LFS

RR NRM

HR= 1.13, p = 0.63 HR= 1.23, p = 0.23

HR= 2.50, p = 0.04 HR= 0.93, p = 0.81

Aldoss I et al. BBMT 2016; 22: 1212-7

Cytogenetics and alloHCT outcome

Cytogenetics and alloHCT outcome

Aldoss I et al. BBMT 2016; 22: 1212-7

Treatment of older adults (60y)

• Induction mortality can be high; supportive care during induction is critical

• Infection is a major cause of early mortality

• ? Limiting anthracycline use

• Preferable to avoid asparaginase in induction; can be given in subsequent cycles

• Consideration of RIC HCT in suitable candidates who remain MRD+

DFS OS

Outcome of older adults with ALL

Ribera J-M et al. Leuk Res 2016: 41: 12-20 Age 55yrs

RIC alloHCT for ALL

Mohty M et al. Blood 2010; 116: 4439-43

LFS

RR

N=576, RIC 127, MAC= 449

Age ≥ 45 yrs

NRM

OS

MAC

RIC

RIC for ALL: COH experience

N=24

61.5%

61.5%

21.5%

Stein AS et al. BBMT 2009; 15: 1407-14

21.1%

SWOG S1318

Ph + patients get dasatinib and

steroid induction followed by

dasatinib + blinatumomab

followed by dasatinib

maintenance

Cohort 2

Age ≥ 65

Mature B-cell ALL

• Needs brief duration, high intensity chemotherapy with growth factor support

• Rituximab critical component of such regimens

• CNS therapy critical

• No maintenance phase

• Active regimens include hyper R- CVAD, CODOX/M-IVAC, EPOCH-R

• Late relapses are rare

Hoelzer et al Blood 2014; 124: 3870-79 N=363 Age 16-85

Outcome of mature B-cell ALL

OS PFS

Thomas et al Cancer 2006; 106: 1569-80

Hyper CVAD for mature B-cell ALL

Rituximab

• CD20 expression in 30-50% B-ALL

• Has been used with hyper CVAD and pediatric type

regimens

• EFS improved in randomized study. OS better only

after excluding patients who underwent SCT

• Toxicity profile in ALL needs further study

Rituximab in adult ALL

Age 18-59

16-18 doses

Maury S et al.

N Engl J Med

2016; 375: 1044-53

Rituximab for Ph-neg ALL

Sebastien Maury et al. Blood 2015; 126: 1 (abstract)

Age 18-59

16-18 doses

Treatment of relapsed/refractory ALL

• Goal is to achieve CR with minimal toxicity in order to

proceed to allogeneic HCT in suitable candidates

• Options include chemotherapy reinduction,

blinatumomab, CAR-T cells, immunoconjugates

Outcome of relapsed adult ALL

Oriol A et al. Haematologica 2010; 95: 589-96

T-cell ALL

• Outcome appears similar to precursor B-ALL when

pediatric type regimens are used

• Immunophenotype not useful in assessing prognosis

• HCT outcome also appears similar to pre B-cell ALL

• Limited options for relapsed disease; Nelarabine only

approved agent

Treatment of Ph+ ALL

• Potent activity of TKIs have enabled use of lesser intensity

chemotherapy regimens with lower early mortality

• Allogeneic HCT in CR1 remains standard of care

• Autologous HCT (in patients with MMoR) or continued

chemotherapy with TKI may be option in patients not eligible for

alloHCT

• Role of maintenance TKI after HCT is unclear

Chalandon Y et al. Blood 2015; 125: 3711-19

Treatment of Ph+ ALL

Chalandon Y et al. Blood 2015; 125: 3711-19

Cycle 1 Arm A: VCR, DXM and Imatanib Cycle 1 Arm B: VCR, DXM, DXR, CPM, Imatanib

Treatment of Ph+ALL

Chalandon Y et al. Blood 2015; 125: 3711-19

Pharmacogenomics of ALL therapy

• Results have been conflicting; multiple variants determine

efficacy and toxicity

• TPMT most relevant; requires lowering 6-MP dose by 30-70%

• Other variants could be important eg. SLCO1B1 for MTX toxicity,

CYP3A5 and CEP72 for VCR neuropathy

• Could be important to personalize therapy in future clinical trials

by NGS approach

Bhatia et al. JAMA Oncol 2015; 1: 287-95

6-MP adherence and relapse

New agents for ALL

• Monoclonal antibodies (CD22: epratuzumab )

• Immunoconjugates (CD22: inotuzumab, CD19: denintuzumab)

• Bispecific antibodies (CD19/CD3: blinatunomab)

• CAR-T cells (CD19, CD22, CD123)

• Small molecules (NOTCH1, DOTL1)

Inotuzumab for R/R pre B-ALL

• Calicheamicin-CD22 antibody conjugate

• Calicheamicin released in cells; induces dsDNA breaks

• CD22 expression in 60-85 % of B-ALL

• Phase 2 trial: 58% response rate (CR + CRi) with median remission duration of 7 mo (n=90)

• 40% proceeded to allo HCT

• Weekly schedule was less toxic and associated with less VOD after alloHCT

Kantarjian et al. Cancer 2013; 119: 2728-36

Phase 3 trial of Inotuzumab vs SOC for R/R pre B-ALL

Kantarjian H et al. N Engl J Med 2016; 375: 740

5 mo vs 1.8 mo 7.7 mo vs 6.7 mo

MRD 0.01% :78.4 vs. 28.1

10 of 48 patients who underwent HCT developed VOD

VOD 11% vs. 1%

CR 80.7% vs. 29.4%

Challenges to therapy of adults with ALL

• Most adults treated off protocol

• Lack of adult oncologists’ familiarity with pediatric ALL regimens

• Compliance with oral drugs

• Excessive concern about toxicity

• Therapy in tertiary care centers leads to better outcomes

Future directions

• Integrating novel agents into upfront therapy

• Standardizing approach to poor responders

• Identifying MRD+ patients who can be salvaged with alloHCT

• ? Mininizing chemotherapy side effects in good risk patients

• Application of pharmacogenomic data to guide therapy