burkitt nhl mainz 2010 - tumorzentrum-muenchen.de · p a1 b1 c1 a2 b2 c2 sc- apheresis (not...

Burkitt NHL Mainz 2010

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Nicola Gökbuget

Goethe University Hospital, Department of Medicine II, Frankfurt GMALL Study Coordinator

German Consortium for Translational Cancer Research

Distribution of NHL Subtypes Harris et al, Ann Oncol, 1999

Dunleavy, Hematol Oncol Clin N Am 30 (2016)

Burkitt‘s Lymphoma Subtypes - I Dunleavy, Hematol Oncol Clin N Am 30 (2016)

Burkitt‘s Lymphoma Subtypes - II

•  Intermediate-sized cells with round nuclei, multiple nucleoli, and a high proliferative index, as measured by Ki- 67 staining.

•  The increased proliferation can cause spontaneous apoptosis leading to the characteristic starry sky pattern present in marrow and lymph nodes

Histology of Burkitt’s Lymphoma Casulo & Friedberg,Curr Hematol Malig Rep (2015)

Biological Characterisation of Mature B-ALL/Burkitt's Lymphoma

Morphology = FAB L3 morphology Immunophenotype sIg +

B-Cell associated antigens + (CD19, CD79a, CD22; 80% CD20+ TdT neg)

Pathology Burkitt‘s Leukemia/Lymphoma "starry sky" pattern CD19, CD20, CD22, and CD79a, and lack CD5 and CD23. Ki-67>95%,c-myc+

Cytogenetics/ mostly t(8;14) – cMYC / IgH Molecular genetics less frequently t(8;22); t(2;8)

in 5-25% EBV genomes in 25-40% associated with HIV-infection


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Gene Expression Profiling in Burkitt‘s Lymphoma Hummel et al, New Engl J Med, 2006

WHO classification: Burkitt‘s Lymphoma includes - classical - atypic (Burkitt-like)

Gene expression analysis -  Typical molecular signature of Burkitt‘s lymphoma identified -  wide variability of histologic appearance (including

lymphoma with DLBCL appearance) -  c-myc translocation not in all cases Conclusion 1. Patients with Burkitt‘s signature identified in DLBCL 2. Patients with c-myc identified in DLBCL

- Poorer outcome with CHOP-based protocols

WHO Classification for Lymphoid Neoplasias Swerdlow et al, Blood 2016


Highlights of changes in 2016 WHO classification of lymphoid, histiocytic, and dendritic neoplasms


Myc as single hit Myc and BCL2 and/or BCL6

Pathogenesis of B-ALL/Burkitt‘s Lymphoma

Hecht et al, JCO, 2000 Blum et al, Blood, 2004

•  C-myc is a Helix-loop-heli leucine zipper transcription factor (BHLH-LZIP) •  C-myc is juxtaposed to immunoglobuline gene loci

- 80%: t(8;14), IgH-c-myc - 20%: t(2;8),t(8;22) kappa or lambda light chain-c-myc

•  C-myc proto-oncogene induces 27 different genes

•  Mutations in TCF3 and/or its negative regulator ID3 are detected in 70% of sporadic and 40% of endemic BL

•  In sporadic BL, ID3 mutations (58%) more common than TCF3 mutations (11%) or mutations of both genes (13%)

•  TCF3: Role in normal B-cell development by regulating the transcription of immunoglobulin and other B-cell-restricted genes

Recurrently mutated genes in aggressive lymphomas determined by RNA-seq Schmitz et al, Nature 2012


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Recurrently mutated genes in aggressive lymphomas determined by RNA-seq Schmitz et al, Nature 2012

CDK-4/6 inhibitor

TCF-3 promotes antigen-independent (tonic) B-cell-receptor signaling Tonic B-cell-receptor signaling sustains BL survival by engaging the PI3 kinase pw

TCF-3 promotes cell-cycle progression by trans-activating CCND3, encoding a D-type cyclin that regulates the G1–S phase transition.

CCND3 mutations stabilize cyclin D3 protein expression and drive proliferation.

BET-Inhibitor

Clinical Characteristics of Burkitt‘s Leukemia/Lymphoma

Mature B-ALL Burkitt‘s NHL (N=148) (N=130)

Male predominance 67% 69%

Older age > 50 34% 24%

WBC > 50,000/µL 13% -

Elevated LDH 100% 56%

Lymphadenopathy 54% 83%

CNS involvement 20% 5%

Extranodal involvement 40% 76%

Population-based data

Castillo, Cancer 2013;119:3672-9

Median age: 49 yrs

US SEER Registry Data On Burkitt‘s

Castillo, Cancer 2013;119:3672-9 US SEER Registry Data On Burkitt‘s



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Prognostic score: 1 point age 40 to 59 yrs

or black race

2 points age 60 to 79 yrs or stage III/IV disease

4 points age 80 yrs 4 risk groups: 0 or 1 points, low risk 2 points, low-intermediate risk 3 points, high-intermediate risk 4 points, high risk


Principles of Therapy

Treatment Design in B-ALL and Burkitt‘s Lymphoma

Important Agents Results in Burkitt‘s NHL (Ziegler 1977) and pediatric studies (Patte 2001, Reiter 1999) •  HD alkylating agents •  HDMTX •  HDAraC

General •  Cell doubling time: 25 hrs (Iversen 1974) •  A prolonged time-period should be covered with

cytostatic drug concentrations: each cell should enter cell cycle once (Murphy 1985)

è 4-5 d cycles è Fractionated drugs or continuous infusion è Short intervals

Rationale for short intensive „non-NHL“ protocols“ incl.

fractionated HD Cyclo/Ifo HDMTX and HDAraC

- Results in Burkitt NHL

(Ziegler et al, 1977) - Results of pediatric procotols

(Patte et al 2001;Reiter et al, 1999) - Results in adult mature B-ALL

Burkitt and High-Grade NHL Dozzo, Adolescent Health, Medicine and Therapeutics, 2017 Features of Current Protocols for Burkitt‘s NHL


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Therapieergebnisse bei Burkitt-Lymphom mit kurzen, intensiven Therapien und Rituximab

Reiter et al, Blood 94 (10):3294, 1999

Diagnoses Total 413

Burkitt 266 B-ALL 56 DLBCL Centroblastic 42 Immunoblastic 6 Mediastinal 8 NHL, not class. B-cell 30

Event Free Survival

GMALL Study B-ALL/NHL 2002

Rationale for B-ALL/NHL Study 2002

Chemotherapy •  Reduction of MTX dose from 3 g/m² to 1.5 g/m² since no improvement but more toxicity in B-NHL90

•  Inclusion of HDAC (cycle C x 2) - to improve antileukemic activity and CNS prophylaxis

Immunotherapy •  anti-CD20 (Rituximab) in combination with chemo cycles - expression of CD20 > 80% in mature B-ALL

Stem cell transplantation •  SC apheresis in pts without donor •  SCT in CR1 for high risk patients ?

A1 B1 P C1 A2 B2 C2

SC- Apheresis

(not obligatory)

antiCD20 antiCD20 antiCD20 antiCD20 antiCD20 antiCD20

Multicentre Study to Optimize Therapy of B-ALL and High-grade Non-Hodgkin’s Lymphoma in Adults

(GMALL B-ALL/NHL 2002)

Patients 15-55 years

Failure of therapy

Salvage SCT (allo, auto, MUD)

antiCD20 antiCD20

End of therapy for

Stage I/II with CR after 2 cycles

MedTU CNS-inv. CRu, PR

Irradiation

1 2 5 8 12 15 18 Weeks

21 24 28

End of therapy after 4 cycles if: stage I/II CR after 2 cycles no extranodal involvement,no Med TU

A1 B1 P C1 A2 B2 C2

SC- Apheresis

(not obligatory)

antiCD20 antiCD20 antiCD20 antiCD20 antiCD20 antiCD20 1

Multicenter Study to Optimize Therapy of B-ALL and High-grade Non-Hodgkin’s Lymphoma in Adults (GMALL-B-ALL/NHL 2002)

Rituximab in combination with Chemotherapy

Patients 15-55 years Failure of therapy


antiCD20 antiCD20

End of therapy in Stage I/II with CR after 2 cycles

MedTU CNS-inv. CRu, PR

Irradiation

1 2 5 8 12 15 18 Weeks

21 24 28

A1 * B1 * P A2 * B2 * A3 * B3 *

antiCD20 antiCD20 antiCD20 antiCD20 antiCD20 antiCD20 1 antiCD20 antiCD20

Patients > 55 yrs

Failure of therapy


Rituximab 375 mg/m2 8x


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GMALL B-ALL/NHL 2002: Patient Flow

Hoelzer et al, Blood 2014

GMALL B-ALL/NHL 2002: Patient Flow


GMALL B-ALL/NHL 2002: Patient Characteristics - I


OS GMALL B-ALL/NHL 2002: Patient Characteristics - II


OS

GMALL B-ALL/NHL 2002: Overall Response and Outcome


Overall Survival Burki- Leukemia / Lymphoma GMALL B-‐ALL/NHL 2002

0.80 ± 0.02 (N=363)



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Progression Free Survival Burki- Leukemia / Lymphoma GMALL B-‐ALL/NHL 2002

0.75 ± 0.03 (N=363)



No CHOP Pretreatment: 0.80 ± 0.02 (N=349) CHOP Pretreatment: 0.77 ± 0.12 (N=14) P=0.99



Male: 0.84 ± 0.02 (N=253) Female: 0.70 ± 0.05 (N=110) P=0.004


Subgruppen- Analysen und Prognosefaktoren

ALTER


≤55 yrs: 0.86 ± 0.02 (N=265) >55 yrs: 0.62 ± 0.05 (N=98) P<0.0001


Faktoren Alter (<> 55) LDH <>250 Stadium 1-‐2 vs 3-‐4 KM-‐Befall ZNS-‐Befall aaIPI (0-‐1 vs 2-‐3) Extranodalbefall Geschlecht

MulYvariat-‐Analyse: Overall Survival

Signifikant 0.0014 HR: 2.5 0.02 HR: 4.4 0.01 HR: 2.4 0.006 HR: 2.2


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European Working Group for Adult ALL (EWALL) EWALL Results in Burkitt‘s Leukemia/Lymphoma

Group N Pts B-ALL/Burkitt Age CR OS

NILG 105 50/54 47 (17-78) 79% 67% Bassan

PETHEMA 127 26/101 44 (15-83) 85% 75% Ribera

PLRG 34 3% B-ALL 37 (18-62) 94% 91% Walewski

Irradiation •  Prophylactic; CNS involv.; Med TU •  Residual tumors

Relapse Localisation Outcome of Burkitt’s Lymphoma after Relapse Short et al, ASH 2016

Hyper-CVAD: 43% ICE: 14% EPOCH: 7% MOAD: 7% Other: 23% SCT: N=6 (3 allo, 3 auto)

N=36 R / R Burkitt Median age: 51 yrs Median time to R/R: 6.6 (0.7-75.3)mo 36% < 6 mo from diagnosis 64% > 6 mo

ORR 38% (CR, n=8; PR, n=3); Late relapse: 61% Early relpase: 0%

Overall Survival

2 pts alive without 1 salvage autologous SCT 1 who had a late relapse 75 months after initial diagnosis and was treated with R-EPOCH

Outcome of Burkitt’s Lymphoma after Relapse Short et al, ASH 2016

Relapse Free Survival

18% at 1 yr

Superior OS Pts who responded: 7.5 vs. 1.5 mo; P<0.001 Late relapse: 5.0 vs 1.4 mo ; P<0.001

Toxizität


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Toxizität B-ALL/Burkitt < 55 yrs


Toxizität B-ALL/Burkitt > 55 yrs

79 73 72 73 58 52 407

29% 52% 76%

43% 42% 33%

49% 31%

A2

37%

72%

62%

43% 18%

27%

49%

28%

1% 12% 21%

1% 14% 38%

3% 21% 22%

1% 3%

8% 18% 2% 1%

16% 30% 13% 21% 9% 17%

Toxizität B-ALL/Burkitt < 55 yrs

1% 1%

2% 1% 1 2 1 1% 1

•  Allopurinol; Uratoxidase bei Patienten mit hohem Risiko eines Tumorlysesyndroms

•  Leukovorin adaptiert an MTX-Spiegel •  Vermeidung von Begleitmedikation, die zu einer bezögerten MTX-

Ausscheidung beitragen können oder potentiell nephrotoxisch sind •  Wässerung vor, während und nach HDMTX Hydration

(Bilanzierung) •  Forcierte Diurese nach MTX •  Urinalkalisierung (Urin-pH >7,5 vor während und nach MTX) •  Tägliche Kontrollen der Nieren- und Leberfunktion •  Mukositisprophylaxe •  Antiinfektiöse Prophylaxe •  G-CSF nach den Zyklen

Maßnahmen der Supportivtherapie bei Burkitt-Lymphom/Leukämie

Critical Issues in the Management of Burkitt’s NHL Dozzo et al, Adolescent Health, Medicine and Therapeutics, 2017 Need to reduce Incidence of Severe Mucositis

Rationale

- Poor quality of life if oIII-IV mucositis

- Need of i.v. morphins

- Entry of pathogens – increase risk of infections ?

- Treatment delays and reduced time-dose-intensity


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Need to reduce Incidence of Severe Mucositis

Options

- Improved supportive care

Risk factors for delayed MTX-elimination

- 3rd space e.g pleural effusion - urine pH<7 - i.v. fluid <3L/m2/24h - overweight - comedication (MTX-interference, nephrotoxic, Vitamin C,

iv. contrast X-ray or CT) - advanced age - baseline hepatic dysfunction - baseline renal insufficiency - intrathecal MTX §  Cave: Orally neutral beverages (no coke,yoghurt,butter milk) §  In case of delayed clearance and/or renal insufficiency:

Carboxypeptidase

Schwartz S, et al., ASH 2006, abstract 2439 Relling MV et al., J Clin Oncol 1994, 12: 1667

NSAR‘s, ß-Lactame, PPI‘s, TMP/SMX, nephrotox. Subst

Need to reduce Incidence of Severe Mucositis

Options

- Reduced dose of MTX Favourable survival in elderly Burkitt‘s NHL (0.5 g MTX) but CNS relapses in eldery B-ALL

-  Reduced infusion time of MTX (4 h vs 24 hrs) HDMTX 4 hr infusion less toxic Equally effective in low risk but less effective in high risk

- Reduction of anthracyclines

- Reduced number of cycles Equally effective in low risk but less effective in high risk Cairo et al, Blood 2007, Patte et al, Blood 2007

- Prophylaxis: G-CSF, Caphosol, Palifermin (KGF)

HIV-positive Burkitt NHL

B-ALL/NHL Protocol in AIDS-associated Burkitt- or Burkitt-like Lymphoma

Hoffmann et al, Leukemia & Lymphoma, 2006

Retrospective multicenter trial in 6 German HIV centers CHOP vs GMALL B-ALL 86/90 (MTX: 0.5 – 3.0 g/m²) CHOP B-NHL90

N 31 20

CD4 >200 43% 78% B-ALL 0 25%

CR 40% 75% Survival 2 y 34% 55% Death on tx 10% 10%

HAART 32% 65% Intensive B-ALL regimen is feasible in HIV infected patients

even in combination with HAART

B-ALL/NHL Protocol in AIDS-associated Burkitt- Lymphoma Oriol et al, Haematologica 2003 Prospective multicenter trial

GMALL B-ALL 90 (MTX: 3.0 g/m²) in HIV+ vs HIV- pts HIV+ HIV-

N 14 39 Age 45 (23-65) 35 (15-74) B-ALL 43% 64% Stage III/IV 57% 23% On HAART 36%

CR 71% 77% Survival 2 y 55% 43%

No difference in outcome between HIV+ vs HIV- pts HAART feasible and probably beneficial


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Therapy in HIV+ Adult Burkitt‘s NHL Summary

§  Improved results with short intensive regimens particularly in advanced stage Burkitt NHL

§  Achievement of CR first goal since long-term survival achievable in CR pts only

§  HAART compatible and probably favourable

§  Prognostic factors (?): - Age - Poor performance - CD4 count < 200, < 100/µl - Later stage - i.v. drug abuse

New approaches: §  Rituximab+chemotherapy feasible in 2 studies

Alternative Strategies ?

N Engl J Med 2013;369:1915-25.

From the Center for Cancer Research, National Cancer Institute, Bethesda

N Engl J Med 2013;369:1915-25.

2013 – N Engl J Med - Series

Study Overview

•  Toxic high-dose chemotherapy may not be necessary to cure Burkitt's lymphoma in adults and patients with immunodeficiency.

•  An infusion-based chemotherapy program with modest toxicity administered mainly in outpatients resulted in an overall survival rate of 90 to 100%.

Dunleavy, Hematol Oncol Clin N Am 30 (2016)

DA-EPOCH-R for HIV-neg

Intrathecal methotrexate 12 mg on day 1 and 5 of cycles 3-6.

SC-EPOCH- RR for HIV-pos

Pts should receive 6 cycles of treatment. If the tumor masses shrink > 20% between the end of cycle 4 and 6, administer two additional cycles.

Pts have at least 3 cycles with 1 cycle beyond CR as determined by combined CT and FDG-PET criteria

EPOCH-R for Burkitt’s Lymphoma


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Dunleavy, Hematol Oncol Clin N Am 30 (2016) EPOCH-R for Burkitt’s Lymphoma

DA-EPOCH-R: 6 cycles in all but one; one patient 9 cycles. 74% received at least dose level 3 37% received dose level 4 SC-EPOCH-RR: 45% received 3 cycles 55% 4 cycles, and doses were not escalated.

Characteristics of the Patients.

Dunleavy K et al. N Engl J Med 2013;369:1915-1925

LR: Resected stage I or abd. stage II IMR: Neither LR nor HR HR: BM >25 a/o. CNS

Kaplan–Meier Estimates of Freedom from Disease Progression and Overall Survival.


Adverse Events.


Risk-Adapted Therapy in Adults with Burkitt Lymphoma: Preliminary Report of a Multicenter

Prospective Phase II Study of DA-EPOCH-R Dunleavy et al, ASH 2015

Inclusion criteria: Newly diagnosed BL Age 18 years or older HIV negative or positive Low-risk (LR): normal LDH, ECOG 0-1, stage I or II, max tumor size < 7cm è 3 cycles of DA-EPOCH-R (no i.th. prophylaxis) High-risk (HR): All other è 6 cycles (i.th. prophylaxis d 1 and 5 on cycles 3-6)



Enrolled: 77 pts Age: 45 (19-78) yrs Male: 82% Stage III or IV: 64% Elevated LDH: 53% CNS: 10% HIV+: 26% LR: 14% HR: 86%


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2 deaths on treatment in the HR arm secondary to infection.

Median follow-up: 25 mo No significant difference: HR vs LR HIV pos vs neg Age ≥ 40y vs < 40y

NR

73%

>40: 40%

Median: 33y Median: 42y

100% c-myc

NR

NR

NR

>ULN: 53% > ULN: 74%

Dunleavy et al

63%

3%

13% 10% LMB HR

50% Bowel

67% III-IV

NR

NR

Dunleavy et al

GMALL B-ALL/B-NHL 2002 Conclusions

• Combination of Rituximab and intensive chemotherapy feasible • Response rate 80-90% in Burkitt

Overall survival ~ 90%

• Improvement in mature B-ALL, less for pts > 55 y à inclusion of HDAC

• Irradiation effective part of therapy • SCT: No prognostic factors à no indication for SCT in CR1 à Stem cell apheresis stopped

• Major toxicity: mucositis à No improvement by caphosol / KGF

Mature B-ALL/Burkitt‘s NHL

Future Prospects Improved molecular characterisation Reduction of toxicity •  De-escalation in good responders and early stages ? •  Improved prophylaxis of mucositis and infections ? Improved outcome in elderly B-ALL •  Intensified CNS prophylaxis •  HDAC based cycle •  Increased Rituximab dose-intensity? Refined response evaluation and risk stratification e.g. •  PET analysis •  MRD analysis (Mussolin et al, JCO 2007)

Reduction of irradiation Application in •  HIV+ pts with Burkitt‘s leukemia/lymphoma Improved salvage therapy – new drugs ?

burkitt nhl mainz 2010 - tumorzentrum-muenchen.de · p a1 b1 c1 a2 b2 c2 sc- apheresis (not...

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