A radiologist's taleHistory: 60 year old male who developed fatigue

and myalgias after TKR in 1999. Over ensuing months developed wheezing and DOE. CXR revealed diffuse pulmonary infiltrates and on CBC had eosinophilia (WBC 12,000/35% eos). Diagnosed with EOSINOPHILIC PNEUMONIA. Treated with steroids and CellCept. Able to taper steroids to 7.5 mg/d and stop CellCept in 12/01. Around the same time WBC increased to 22,000 with lymphocytosis and was referred to Heme/Onc.

A radiologist's tale (cont.)PMHx: HTN, HyperlipidemiaMedications: Prednisone 7.5 mg, Flovent, Advair,

Atenolol, LipitorROS: No B symptoms, occasional DOEPE: Normal except rales at basesLabs:

WBC 22,000 39%N, 60%L, 0%EHgb 14.5Platelets 174,000

A radiologist's tale• BM biopsy was done

• T-cell PLL, small cell variant • Involving 40% of the total cellularity

• Flow cytometry• CD3+, CD2+, CD5+, CD7+, CD4+CD8+, TdT-, CD1-,

CD56-• Cytogenetics

• complex abnormalities with t(11;12) and t(14;21), del(6) in 11/20 cells

• CT scans• Bilateral lung infiltrates, no splenomegaly or

adenopathy

Prolymphocytic LeukemiaT-PLL

T-PLL: A historical perspective

Represents 3% of all T-lymphocyte disorders

Represents 5% of all CLLs, with B-CLL making up the other 95%

T-CLL is old terminology, all T-CLL are really classified as T-PLL due to uniformly poor outcomes

T-PLL WHO Classification:

• Mature T-cell Neoplasm• Disseminated leukemic types

1. T-cell prolymphocytic leukemiaMorphologic variants: small cell

and cerebriform cell2. T-cell granular lymphocytic leukemia (LGL) 3. Adult T-cell leukemia (HTLV1+)

Clinical variants: acute, lymphomatous, chronic, smoldering, Hodgkin-like

4. Aggressive NK-cell leukemia

Clinical Features Median Age 69 (33-91) Splenomegaly 73% Lymphadenopathy 53% Hepatomegaly 40% Skin Lesions 27% Serous effusions 14% WBC > 100,000 75% Anemia 36% Thrombocytopenia 51%

Matutes, et. Al. Blood 78: 3269-3274, A review of 78 British cases

Morphology

Medium sized, monomorphic population of cells High N:C ratio Single prominent nucleolus

• Occasionally irregular with folds or convolutions Agranular cytoplasm with protusions or blebs Small cell variant

• Smaller cells with less prominent nucleolus, but nucleolus is always visible by electron microscopy

Immunophenotype Post-thymic T-cell (HLA-DR -, Tdt -, CD1a-)

unlike T-ALL Negative B cell markers (CD19,20,22) Usually CD2+, CD3+, CD5+, and CD7+ Usually either a CD4+CD8- (47%) or

CD4+CD8+ (15%) T-cell

Cytogenetics 76% with chromosome 14 abnormalities with

breakpoints at q11 and q32inv (14)(q11;q32) 63%t(14;14)(q11;q32)7%

Trisomy 8q and chromosome 7 rearrangements less common

Chromosomes 7 (p13-14, q32-35) & 14 (q11 locus) contain genes that encode for TCR

Some reports that mutations in chromosome 11 that inactivate ATM gene are seen in pts with T-ALL who do not have AT (suggest this is a tumor suppressor gene)

Association with ataxia telangiectasia

Autosomal recessive disorder• Characterized by ataxia, oculocutaneous

telangectasias, immune deficiency, predisposition to malignancies (mainly T cell malignancies)

Mutated ATM gene on chromosome 11q22.3

Patients develop clonal expansions of T cells that may progress to PLL

Differential LGL

• Abundant cytoplasm, many azurophilic granules, rare nucleoli• CD3+, CD8+,CD57+, Half of cases are CD 7-• Rare chromosome 14 abnormalities• 10 year survival about 80%

HTLV+, adult T cell lymphocytic leukemia (ATLL) • Present with hypercalcemia, lymphadenopathy, high white

cell counts, skin involvement, hepatomegaly, and lytic bone lesions

• CD 7-• Rare chromosome 14 abnormalities

Sezary syndrome• Cerebriform nuclei• Half of cases are CD 7-• Rare chromosome 14 abnormalities

Therapy

5 Untreated• 4 patients died 1-2 mos following diagnosis• 1 patient remained untreated for 19 mos, & died 1 mos

after starting therapy for progressive lymphocytosis

32 patients treated with alkylators – 28% PRs

15 patients treated with CHOP – 33% responded with 1 CR lasting 3 months

XRT used in 6 patients – 3 PRs, one lasting 44 mos

Matutes, et. al., Blood 78:3269-3274

Therapy (cont.) Best responses seen with nucleoside

analogues• 50% responses seen with

2'deoxycoformycin (DCF)• 3 CR and 12 PR, CRs lasting 8-12 mos• OS with DCF therapy 10 mos v. 7 mos

Cladribine/Fludarabine/Pentostatin

Mercieca, JCO 12: 2588-2593 45% response rate with 2'deoxycoformycin

(pentostatin) at 4 mg/m2 weekly x 4 and then q 2 weeks until optimal response

10 month duration of response if CR, 6 mos for PRKantarjian, Am. J. Med 90: 223-228

Witzig, Leukemia/Lymphoma 14:137-139 50% responses seen with cladribine and

fludarabine, but duration of response still less then 1 year

Campath-1H Humanized murine monoclonal IgG antibody

to CD52• CD52 present on the majority of normal and

leukemic B- and T-cells, monocytes, and macrophages

Pawson, JCO 15: 2667-2672 11/15 patients all previous treated with DCF had

major responses with CRs in 9, OS 8 mos

Cazin, Blood:94:abstract 552 6/9 with CRs

Campath-1H (cont.)

Multicenter, multinational trial from 5/92-10/99

76 patients enrolled who had failed at least one prior regimen

Dose• Initial infusion: 3 mg IV over 2 hours d1, 10 mg d2,

30 mg d3 • Subsequent treatments:30 mg tiw for 4-12 weeks

Supportive care• Bactrim DS tiw• Famvir 250 bid

Keating, JCO 20:205-213

Campath-1H (cont.)Pt. Characteristics

Median Age 60Male:Female 53:23PS 0:1:2 8:11:13First line therapy

Pentostatin (DCF) 31 (41%)Cladribine/Fludara 18 (24%)

B symptoms 17 (22%)Lymphadenopathy 41 (54%)Splenomegaly 42 (64%)Skin involvement 14 (18%)WBC >100,000 30 (40%)

Keating, JCO 20: 205-213

Campath-1H (cont.)Toxicity Infusion reactions in 62% (fever, chills, rigors,

rashes, hypotension-17%) 15 infections during treatment

• 3 CMV, 3 VZV, 1 RSV pneumonia, 8 bacterial 23 late onset infections occurring after tx

discontinuation, 8 clearly attributable to Campath others occurred with salvage therapy

• 1 RSV, 1 Influenza, 6 bacterial 8 deaths: 2 sepsis, 1 PD, 2 cerebral hemorrhage

due tx induced thrombocytopenia, 1 renal failure, 1 CVA

Keating, JCO 20:205-213

Transplantation Various case series of 1-2 patients

who are still alive up to 2 years after allogeneic transplantation or mini-transplant

Prognostic features

Better outcomeLymphadenopathy p < 0.04

Age less than 50Nucleoside analogue therapy

Worse outcomeHepatomegaly p <0.01

Indolent T-PLL?Garand, et. al. British Journal of Hematology

103: 488-494 78 patients

• 25 had initial stable course• OS 40 months compared to 12 months in the

patients with aggressive course• Median stable phase was 33 months ( > 5 years in

5 patients)• 16 of 25 were untreated in stable phase, with no

difference in progression in treated v. untreated (however, the treated group received chlorambucil – would fludarabine increased survival?)

Indolent PLLGarand, et. al. British Journal of Hematology 103: 488-494 Characteristics of 25 patients with indolent

disease• No organomegaly• Moderate leukocytosis (10 - 52,000)• No cytopenias (2 cases had thrombocytopenia)• No difference in histologic or cytogenetic features• The aggressive subset tended to be CD45RO+ and

CD45RA-, a marker of "memory" T cells, where as the indolent group more like "naïve" T cells

• Authors postulate that different homing properties and adhesion molecules of memory and naïve T –cells may be responsible for aggressive clinical course

A word on B-PLL Incidence is 10% that of CLL Dx requires 55% circulating prolymphocytes Clinical features

• 4:1 males to females, usually high WBC, splenomegaly, rare lymphadenopathy

Variable CD 5 expression Cytogenetics: 17p- (p53 mutations), 14 q+, trisomy 12 often

observed• Occasional c-myc t(2;8) mutations seen as in Burkitts

Tx: alkylators have < 20% response, nucleoside analogues or Campath favored

Overall survival: 3 years

Back to our storyRecommended observation as no cytopenias,

splenomegaly or lymphadenopathy. Patient developed recurrent pneumonias in ensuing months that responded to antibiotics and steroids. Bronchoscopy on 2 occasions revealed T-PLL in lung parenchyma. DOE worsening.

Started fludarabine 8/02

?Any link of eosinophilic pneumonia to T-cell malignancies

Simon, et. Al. NEJM 341: 1112-1120• 16/60 patients with idiopathic eosinophilia had

abnormal T cell clones in peripheral blood (the majority CD3+,CD4+CD8-)

• 3 of these patients eventually developed a malignant T-cell leukemia/lymphoma or Sezary syndrome

• These T-cell clones secreted high levels of interleukin 5 which may have stimulated the eosinophilia