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The Natural Killer Cell Neoplasms: Can we overcome treatmentresistance

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Results comparable to 2001 retrospective study with a CR 55.6%, 5-year OS 55.6 ... Survival data after Allogeneic SCT. Median f/u 34 months. 2-year PFS 34%, OS 40 ... – PowerPoint PPT presentation

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Title: The Natural Killer Cell Neoplasms: Can we overcome treatmentresistance


1
The Natural Killer Cell Neoplasms Can we
overcome treatment-resistance?
  • Jane Chawla, M.D.

2
Case
  • The patient is a 31-year-old Mexican male with a
    PMH of rheumatic fever anemia who presents with
    midepigastric pain, bloating, nausea, vomiting
    and fever for 3 days.
  • CBC WBC 89 / Hgb 14 / Hct 40 / Plt
    133
  • Diff 10 Polys / 2 Bands / 8 Lymphs / 3
    Monos / 77 Others
  • AST 464 GGT 496 TB 3.6 Uric Acid 8
    Coags - wnl
  • ALT 450 AP 438 DB 2.3 LDH 2660
    Cr 1.0
  • Peripheral Smear Medium - large size lymphoid
    cells with variable amounts of basophilic
    cytoplasm, convoluted nuclei, condensed chromatin
    and multiple nucleoli. Some with small
    azurophilic cytoplasmic granules. Morphology
    c/w either NK-cells or atypical (T-LGLs).

3
Further workup
  • Flow cytometry 52 variably-sized cells
  • CD2 / sCD3- / CD3? / CD4- / CD5- / CD7-
    (partial) / CD8(small subset CD10- / CD11b- /
    CD16 / CD33(partial dim) / CD38 / CD45 /
    CD56(subset) / CD57- / CD45RO(variably / CD34-
  • TdT- / MPO- / TIA
  • T-cell receptor gamma ? germline configuration
  • Bone marrow 63 Atypical lymphocytes similar to
    those seen in the peripheral smear.
  • numerous histiocytes with hemophagocytosed RBCs
  • MPO and NSE negative
  • EBV negative
  • CSF cytology negative
  • Cytogenetics 49,XY, complex cytogenetics with
    del(6)(q21q23)

4
Normal NK cell development
Suggests overlap In Phenotypic
Functional characteristics
Common lymphoid progenitors
Tripotential cells T/NK/DC common progenitors
Bright CD56 Dim/neg CD16 Produce ? cytokines
Dim CD56 Bright CD16 ?cytokine production
Oshimi, K. British J of Haematology, 2007.
5
WHO Classification of NK cell neoplasms
  • Blastic NK-cell lymphoma
  • Thought to originate from plasmacytoid dendritic
    cells (CD56/CD4)
  • Extranodal NK/T-cell lymphoma (former aliases
    include polymorphic reticulosis, lethal midline
    granuloma, midline malignant reticulosis,
    angiocentric lymphoma)
  • Nasal type (Arising from the upper aerodigestive
    Tract)
  • Non-nasal type (Arising from an extranodal
    location)
  • Aggressive NK-cell leukemia

6
Extranodal NK/T-cell lymphoma clinical features
  • Median age 50-60 years MgtF
  • Seen primarily in East Asians, Mexicans, South
    Americans with a Native American heritage
  • Consists of 3-9 of malignant lymphomas in
    various Asian countries
  • Fever, malaise, weight loss occur at
    presentation
  • Bone marrow blood involvement occur
  • CNS involvement in 7 at presentation (direction
    invasion or mets)
  • CD56 is a neural adhesion molecule, therefore, NK
    cells have an affinity for nerve tissues
  • Associated with hemophagocytic syndrome

7
Extranodal NK/T-cell lymhoma nasal versus
non-nasal
  • Nasal presentation
  • Nasal, paranasal, upper aerodigestive tracts
    involved gt80 of cases
  • Most often limited stage at presentation
  • Nasal lesions present with mass, nasal
    obstruction, epistaxis and local invasion of
    surounding tissues
  • Metastasizes to same areas from where non-nasal
    form arises
  • Median survival lt 12 months
  • Non-nasal presentation
  • May arise from skin, Gl tract, testis, soft
    tissues other organs
  • Patients with intestinal lesions may develop
    perforation/bleeding
  • Poorer prognosis in non-nasal form
    stage-for-stage when compared to nasal form
  • Median survival lt 4 months

8
NK/T-cell lymphoma diagnosis staging
  • Histology ? medium-sized lymphoid cells with
    cytoplasmic azurophilic granules cells are
    perivascular and exhibit angioinvasion leading to
    tissue necrosis and coagulation
  • CD45sCD3-cCD3?CD56, negative CD13, CD33, CD19
    CD20)
  • Cytotoxic granule-associated proteins, granzyme
    B, TIA-1 and perforin
  • Germ-line configuration of TCR and IGH
  • EBV almost always present in tumor cells
  • Diagnosis often difficult due to massive necrosis
    from vascular occlusion
  • Ann Arbor system difficult to apply to NK/T-cell
    lymphoma that involves primarily extranodal sites
  • IPI for aggressive B-cell neoplasms seems
    inadequate to predict prognosis

9
Aggressive NK-cell leukemia Clinical features
  • MF
  • Median age 30-40 years
  • Disseminated at presentation often with fever,
    jaundice, weight loss, hepatosplenomegaly, and
    lymphadenopathy
  • Homophilic binding of CD56 to tissues expressing
    high levels of this neural cell adhesion molecule
    (skin, testes, GI tracts, neural tissue) may
    explain its propensity to disseminate widely
  • Common complications include liver dysfunction,
    DIC, hemophagocytic syndrome
  • Rapidly progressive, poor prognosis
  • Median survival lt2 months

10
Aggressive NK cell leukemia diagnosis
  • Morphologically slightly immature lymphocytes,
    pale cytoplasm, azurophilic granules, fine
    nuclear chromatin occasional nucleoli
  • sCD3-, CD3?/-, CD56,
  • CD16-/ CD57-
  • Germ-line configuration of TCR and IgH
  • Cytotoxic granule-associated proteins, granzyme
    B, TIA-1 and perforin
  • EBV found in tumor cells
  • Common chromosomal aberration del 6q

11
NK cell leukemia is refractory to treatment
  • Exhibits a relentless progressive course, often
    resistant to traditional chemotherapy
  • Multi-drug resistance gene called P-glycoprotein
    is expressed by NK cells
  • Encodes for protein expressed on cell membrane
    allowing cytotoxic drugs to be extruded
  • Vinca alkaloids anthracyclines rendered
    ineffective

12
Treatment of NK/T-cell LymphomaLocalized Disease
13
Studies involving chemotherapy and XRT for
localized disease
14
Primary XRT Alone for the Treatment of Localized
Disease
  • Retrospective review of 92 pts with Stage I/II
    angiocentric lymphomas (T/NK-cell T-cell
    lymphomas)
  • Treated with 40-60 Gy involved-field XRT with
    median f/u 56 months
  • Initial response rapid with 66.3 CR PR 17.4
  • Patterns of recurrence 50 local recurrence,
    10.9 regional failure, 25 systemic failure
  • In general, T/NK-cell lymphomas were more
    aggressive
  • OS 40.1 DFS 37.8

Kim et al. J Clin Onc, 2000.
15
What do we know about XRT in NK/T- cell lymphomas?
  • XRT is an important modality for localized
    disease
  • Outcomes
  • ORR Ranged from 60-80
  • CR 40-80
  • 5-year OS 40-59
  • Doses ranged from 30-60 Gy
  • Local relapses dosages lt45-50 Gy
  • Initial response rate high, but relapses are
    frequent ? 17-77 (50 most common)
  • Most treatment failures occurred within 1st year
  • Systemic relapses occurred in 25-30 of pts
    treated with XRT alone
  • gt1/2 systemic relapses are NOT associated with
    local recurrences (many early stage pts actually
    have more disseminated disease) How do we
    recognize these patients?
  • Non-nasal lymphomas are usually advanced at
    presentation and early-stage disease disseminates
    rapidly. XRT used only as adjunctive or
    palliative use.

16
Radiation versus chemotherapy as initial treatment
  • You et al ? Retrospective study examining XRT
    (54-60 Gy) versus chemotherapy as initial
    treatment
  • 46 patients received initial ? XRT (n6) vs chemo
    (n40)
  • Chemo pts further stratified into salvage XRT
    (n18) chemo alone (n22)
  • Median f/u 56.9 months
  • 5-year OS and FFS are superior in the intended
    radiotherapy group as compared to the intended
    chemotherapy group
  • Authors recommended front-line use of XRT
  • Only a small number of patients evaluated in a
    retrospective fashion
  • OS / FFS for XRT alone were high compared to
    other studies
  • Did not seem to see high rate of relapse with XRT
    alone as in previous study

17
Treatment outcomes according to modality
Included intended RT Group (n6) those Salvaged
with RT (n18)
Primary XRT group Had superior OS FFS
Included chemo only Group chemo pts Salvaged
with XRT
Small sample size Likely contributed to Inflated
OS/FFS? 40 59 in other studies
18
Outcome of receiving XRT versus never receiving
XRT
5-year OS 49.7 versus 23.0
5-year FFS 48.7 versus 23.0
19
Can sequential CHOP XRT effectively treat
localized disease?
  • Localized intermediate to high-grade NHL can be
    cured by CHOP followed by XRT ? this regimen was
    examined in localized NK/T-cell lymphoma
  • Ribrag et al ? Retrospective study of 20 pts
    compared front-line XRT versus front-line
    CHOP/COP
  • Front-line treatment followed by chemo or XRT in
    some pts
  • Front-line XRT ? CR 100 Front-line chemo
    ? CR 33.3
  • Median survival front-line XRT not reached
    front-line chemo 35 months
  • Suggested that XRT after chemo may be less
    effective
  • Kim et al ? Prospective study of 17 pts receiving
    CHOP x 4 cycles followed by IF XRT (45 Gy)
  • CR 58 3-year OS 59
  • Planned sequential chemoradiotherapy was
    completed in only 35 due to PD on CHOP/COP
  • 2 pts received comcominant XRT Chemo due to
    bleeding from tumor site
  • Authors concluded CHOP prior to IF RT is NOT a
    satisfactory regimen for localized disease

20
Treatment of NK/T-cell LymphomaLocalized
Advanced disease
21
IMEP a new regimen for advanced disease
  • Lee et al prospective study of 26 patients, all
    stages
  • IMEP x 6 cycles (ifosfamide, MTX, etoposide,
    prednisolone) as first-line treatment
  • Group A Localized disease (Stage I/II) ? 16
    patients
  • XRT (45-54 Gy) or salvage chemo ONLY given to
    those who relapsed, progressed, or had residual
    disease
  • Group B Extranasal disease (Stage III/IV) ? 10
    patients
  • Included disseminated primary nasal disease
    primary extranodal disease
  • Those who relapsed were given 2nd line chemo

22
Survival data after IMEP chemotherapy
Group A ? OS (3 yr) 80.4 Median Survival
Not reached
  • Median f/u 24.6 months
  • Group A ? CR 79
  • 2 pts with PR received RT ? both had CR
  • Cummulative CR after IMEP /- XRT was 93
  • Group B ? CR 13
  • No distinction between those with primary nasal
    or those with extranasal disease in this study
  • Of those in CR 64 relapsed received RT

Group B ? OS (3 yr) 30 Median Survival 2.7 mo
23
Conclusions about IMEP chemotherapy
  • IMEP may be superior to CHOP as first-line chemo
  • With CHOP CR 59-63, OS (2-3 years 50 range)
    for Stage I/II disease
  • IMEP /- XRT gt CR 93 3-year OS 80.4
  • Due to high rate of local failure, XRT should be
    done routinely after chemo
  • Those with Stage III/IV disease showed no benefit
    over doxorubicin-based regimens
  • A phase II study planned in Korea with IMEP XRT

24
Salvage Chemo with IMVP-16/Pd
  • Kim et al ? Prospective, phase II study of
    IMVP-16/Pd (similar to IMEP) with relapsed or
    refractory disease after receiving an
    anthracycline-based regimens
  • 32 pts Stage I/II 15 Stage II/IV 17
  • Front-line chemo
  • CHOP 46.9
  • COPBLAM-V 53.1
  • Previous chemosensitivity
  • Sensitive 46.9
  • Refractory 53.1
  • Outcomes (after 59 month follow-up)
  • CR 37.5, ORR 43.8
  • Median TTF 3.7 months
  • OS 8.2 months
  • 5-year OS 24.8

25
IMVP-16/Pd shows activity in chemosensitive
patients
  • Sensitivity to 1st line chemo was most important
    predictor of CR rate, TTF, and OS
  • CR duration was longer in chemosensitive patients
    (not statistically significant due to small
    patient number)
  • Age, B symptoms, stage, LDH, IPI were not
    statistically significant predictors of outcome
  • IMVP-16/Pd showed promise in chemosensitive
    patients but poorly salvaged refractory patients

26
L-asparaginase as a salvage regimen
  • Yong et al (2001) ? Retrospective study examining
    37 patients with NK/T-cell lymphoma
  • Patients treated with CHOP x 2 cycles ?
  • CHOP Responders (n10) ? Received CHOP x 6 more
    cycles local XRT
  • CHOP Refractory patients (n27) ? received
    either L-asparaginase-containing regimen XRT
    (n14) OR salvage regimen (w/o L-asparaginase)
    XRT (n13)
  • CHOP Responders (70 Stage I/II IPI 1-2 CR
    100, 2-year OS 100)
  • CHOP Refractory (82 Stage III/IV IPIgt2 B
    symptoms, angioinvasive dz CR 26 2-year OS
    20)
  • L-ASP Group ? CR 50 2-year OS 50.8
  • No L-ASP Group ? CR 0 2-year OS 0

27
L-asparaginase for CHOP refractory disease
  • Yong et al (2003) ? Prospective study of 18
    patients with disease deemed refractory to CHOP
  • All pts treated with regimen containing
    L-asparaginase (6000 IU/m2), dexamethasone, and
    vincristine (1-6 cycles) XRT
  • Stage II 38.9 Stage III/IV 61.1
  • Results comparable to 2001 retrospective study
    with a CR 55.6, 5-year OS 55.6
  • Yong et al (2006) ? Retrospective study of 46
    patients with NK/T-cell lymphoma
  • Initially treated with CHOP to stratify into
    CHOP-sensitive and CHOP refractory groups
  • 71.7 FAILED CHOP (SD / PD) ? received
    L-asparaginase-based treatment (n33) XRT
  • Stage I/II 58.7 Stage III/IV 41.3
  • 5-year OS 86.3 (Stage I/II) 38.3 (Stage
    III/IV)

28
P-glycoprotein a predictor for CHOP resistance?
  • 12 specimens were examined by immunohistochemical
    staining for anti-P-glycoprotein antibody and
    anti-GSTp antibody
  • For CHOP failure ? 7/8 were P-gp and 5/6 were
    GST p antibody
  • For CHOP responders ? 4 specimens were negative
    for both P-gp GST p antibody

29
Other promising regimens
  • SMILE
  • Dexamethasone, MTX, ifosfamide, L-asparaginase,
    etoposide
  • 6 stage IV relapsed/refractory pts
  • ORR 67, CR 50
  • Bortezomib CHOP
  • 13 pts Stage III/IV T cell/NK cell lymphoma
  • ORR 61.5, (only 3 ENKLs)

30
Does IPI accurately reflect prognosis in
NK/T-cell lymphoma?
  • The prognostic impact of IPI (International
    Prognostic Index) on NK/T-cell lymphomas is
    controversial
  • Previous studies have mixed results on its
    relevance
  • Lee et al ? multicenter, retro-spective review of
    262 pts with NK/T-cell lymphoma
  • Upper Extra-upper aerodigestive tract
    NK/T-cell lymphoma (UNKTL EUNKTL)
  • Localized vs disseminated

31
A new prognostic model is suggested
32
Predicting OS in NK/T-cell lymphoma IPI versus
new prognostic index
International Prognostic Index
Proposed Prognostic Index
(p0.0614)
(p0.8304)
IPI does not discriminate well between low and
low-intermediate groups (p0.0614)
high-intermediate and high groups (p0.8304)
33
Treatment of Aggressive NK-cell Leukemia (ANKL)
  • Due to its rarity, there are mostly case reports
    and small case series in the literature
  • Suzuki et al ? Retrospective review of 22 cases
    of ANKL from 19 collaborating institutions
  • 13 received anthracycline/anthraquinone-containing
    regimens
  • CR 13 PR 3 relapse in all but one
  • Median survival 58 days
  • Presence of B symptoms, IPI category,
    therapeutic response were significant prognostic
    factors
  • No standard treatment regimen is used or
    recommended
  • Some case reports have recommended
    L-asparaginase-based regimens
  • Allogeneic HSCT has been tried with only a few
    successful cases reported

34
Autologous Stem Cell Transplant
35
Autologous HSCT
  • Au et al ? Retrospective study, 18 pts of all
    stages with chemoresponsive disease
  • ASCT in CR1 / CR2 showed significant DFS
    (p0.0027) and OS (p0.0034) over NR/PR group
  • DFS (3-year) 71 (CR1) OS (3-year) 59
    (CR1/CR2)
  • No significant difference in DFS or OS b/w those
    treated in CR1 or CR2
  • Trend toward improved DFS (p0.052) and OS
    (p0.064) for those with ASCT in CR1 versus no
    ASCT

36
Autologous HSCT (continued)
  • Kim et al ? Retrospective study of 16 pts, all
    stages
  • Estimated OS (2-year) 71.3 RFS 25.8
  • Trend toward better survival in those who
    received ASCT compared to historical controls
    (p0.091) (2-year OS in control 56.5)
  • Benefit to ASCT in those with
  • ASCT in CR compared to ASCT with PR/NR (p0.049)
  • Stage III/IV disease (p0.001)
  • Poorest risk groups NK IPI 3,4 AND EUNKTL had
    more prolonged survival with ASCT (not
    statistically significant, p0.055 or p0.056)

37
Allogeneic Stem Cell Transplant
38
Allogeneic HSCT shows promising results
39
Survival data after Allogeneic SCT
  • Median f/u 34 months
  • 2-year PFS 34, OS 40
  • Median time from SCT to progression 1.8 months
  • ORR
  • CST 52 versus RIST 60
  • TRM
  • CST 30 versus RIST 20
  • Relative risk for PFS Multivariate analysis was
    statistically significant for
  • stem cell source (BM vs PB )
  • Age (gt40 vs lt40)
  • Dx (extranodal vs others)

OS (2 yr) 40
40
Conclusions about Allogeneic HSCT
  • Promising results for Allo-HSCT in this patient
    population
  • Of note, 19/28 had active Stage IV disease at the
    time of SCT
  • PFS NOT affected by
  • Sex
  • Stage at time of HSCT
  • Chemosensitivity at time of HSCT
  • CR versus active disease at time of HSCT
  • Type of conditioning regimens
  • The use of TBI in conditioning regimens
  • Donors
  • Acute GVHD
  • Study may lack power due to small sample size
  • TRM was lower in RIST, and RR was equivalent
  • Ultimate timing of Allo-SCT NOT clear

41
Conclusions
  • Common resistance to chemo
  • Poor drug delivery due to tissue necrosis and
    angiodestruction
  • Frequent expression of P-glycoprotein phenotype
  • For localized disease
  • XRT is important for initial treatment
  • XRT alone leads to high rates of relapse
    (including systemic relapse)
  • IMEP may be more effective than CHOP in localized
    disease
  • Not clear whether XRT needs to be given prior to
    chemotherapy
  • For advanced disease
  • IMEP CHOP are minimally effective, especially
    in chemo-refractory pts
  • L-asparaginase-containing regimens have shown
    promise for refractory / relapsed disease
    (whereas IMEP did not)

42
Yet More Conclusions
  • May be able to stratify patients into CHOP
    responders versus CHOP refractory
  • Autologous transplant
  • May be most effective in those in CR1 (or CR2)
  • Trend toward improved survival with ASCT compared
    to none
  • May be beneficial in those with most advanced
    disease (Stage III/IV, NK IPI 3 4, and EUNKTL
    pts)
  • Allogeneic transplant
  • Promising treatment option, especially for
    advanced disease patients
  • Reduced intensity regimens may be equally
    effective and associated with less treatment
    mortality.
  • More prospective, randomized trials are needed

43
Case revisited
  • Initially he received HyperCVAD 1A
  • Complicated by neutropenic fever
  • Upon count recovery he had leukemic cells appear
    in the peripheral blood worsening transaminitis
    and increased LDH
  • Repeat bone marrow showed 50 leukemic cells
  • Adult ALL BFM protocol started (Daunorubicin 60
    mg/m2 IV D1, 2, 3 Vincristine 1.4 mg/m2 IV D1,
    8, 15, 22 PEG-Asparaginase 2000 U/mr IV D15
    Prednisone 60 mg/m2 PO D1-28 Methotrexate 12
    mg IT D 8, 15
  • Pt discharged home but returned 2 weeks later
    with nausea, vomiting, and fever
  • He was febrile to 40.1, hypotensive, tachycardic
    to 140, hypoglycemic in the 20's
  • WBC was 70, LDH 6,000, and LFT's 500s, a TB 7
  • He eventually coded several times and passed away
    about 60 days after initial presentation

44
Resources
  • Kim et al. Angiocentric Lymphoma of the Head and
    Neck Patterns of Systemic Failure After
    Radiation Treatment. J Clin Oncol. 18 2000,
    54-63.
  • Ribrag, V. Early Locoregional High-dose
    Radiotherapy is Associated with Long-term Disease
    Control in Localized Primary Angiocentric
    Lymphoma of the Nose and Nasopharynx. Leukemia.
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  • Kim et al. CHOP followed by involved field
    radiation is it optimal for localized nasal
    NK/T-cell lymphoma? Annals of Oncology. 2001
    12 349-52.
  • You et al. Radiation therapy versus chemotherapy
    as initial treatment for localized nasal natural
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45
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46
Resources
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    transplantation for natural killer-cell lineage
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    methotrexate, etoposide, and prednisolone
    chemotherapy XRT is active in stage I/II
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  • A special thanks to Pooja Paranjpe
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