case report an uncommon presentation of …solalettura].pdf · an uncommon presentation of chronic...
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CASE REPORTAN UNCOMMON PRESENTATION OF CHRONIC LYMPHOCYTIC
LEUKEMIA (CLL) AT DISEASE PROGRESSION
March 12th 2011Padova
Michael Mian, MDGeneral Hospital of Bolzano
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DiagnosisTherapy
Progression
Laboratory
Last FUP
DIAGNOSIS2001 2002 2003 2004
3 6 9 12 3 6 9 12 3 6 9 12 3 6 9 12
M. F. *02/1950; m
- Judoka
- Anamnesis: slight exhaustion, no B-Symptoms.
- Medical examination: bilateral laterocervical, sovraclavear and axillarylymphadenopathy (max. 2cm). Spleen palpable (1-2 cm).
- Lab: WBC 70,900/ul (N 7%, L 92%), Hb 14,6 g/dl, PLT 190,000/ul,numerous Gumprecht shadows; creatinin 0,9mg/dl; LDH<UNL, beta2-MG2,4 mg/L
- Flow cytometry: CD 19+, CD 20+, CD 22+, CD 23+, CD 5+(CD5+/Cd19+ 93%); lambda 93%
- FISH: absence of del 13q14, del11q23, del 17p13.1, trisomy12
- Ecography of the abdomen: spleen 14 cm, abdominal lymphadenopathy
=> Chronic Lymphocytic Leukemia Rai II, Binet B
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Diagnosis
TherapyProgression
Laboratory
Last FUP
THERAPY I2004 2005 2006 2007
3 6 9 12 3 6 9 12 3 6 9 12 3 6 9 12
05/2004: PD (weight loss, hyperleucocytosis, increasingsplenomegaly, retroperitoneal lymphadenopathy) => PD
⇒1st line: 05-10/2004 Leukeran + Prednisone x12 cycles: SD
⇒ 2nd line: 03-09/2005 start treatment with Fludarabine mono(25mg/m2; q=28) x6: PR
08/2009: PD (Hyperleucocytosis, increasing splenomegaly andabdominal & laterocervical lymphadenopathies) => FISH: del 13q1428%, mutational analysis: IGHV unmutated
⇒3rd line: 09-12/2009 Fludarabine + Cyclophosphamide x4 cycles(no Rituximab because of recurrent infections): PR
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Diagnosis
TherapyProgression
Laboratory
Last FUP
THERAPY II2010
1 2 3 4 5 6 7 8 9 10 11 12
05-06/2010 PD: Increasing spleen size, abdominal lymphadenopathy &extranodal presentation of disease: 1) subcutaneous nodule of the right arm=> excision compatible with localization of the known CLL 2) echography ofthe lower extremities: presence of pathologic tissue (2.5 cm) at the level ofthe diaphysis of the tibia with interruption of the cortical layer. 3) MR rightankle (01/07/2010): presence of a pathologic tissue
=> 4th line: 06-09/2010 R-Bendamustina (100mg/m2) x4 + start searchfor a compatible BM donor
24/09/2010: diffuse joint pain, painful swelling at the left forearm and pain ofthe right elbow (=> radiography: osteloysis), pain when chewing.⇒ PET-CT & maxillofacial CT
Maxillofacial CT: probable pathologic fracture of the anterior part of the sinusmascellaris extending to the basis of the orbita
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PET-CT (28/09/2010)
Several bone lesions: right olecranon, tibial spine, right carpus; left elbow,tibial diaphysis and bilateral tarsal & metatarsali bones as well as thecalcaneus.
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Diagnosis
Therapy
ProgressionLaboratory
Last FUP
PROGRESSION OF DISEASE II2008 2009 2010 2011
3 6 9 12 3 6 9 12 3 6 9 12 3 6 9 12
12/10/2010 (after the 4th cycle): The patient presents with painand swelling of the left forearm.
=> X-Rays: Pathological fracture of radius and ulna.
=> Biopsy of the fracture margin of the forearm (29/10/2011):Infiltration of the bone by the known CLL.=> Bone marrow aspirate (11/11/2011): lymphocyte infiltrationof 20% (cytofluorometry 2% of monoclonal B-cells)=> Bone marrow biopsy (11/11/2011): No evidence ofinfiltration of the bone marrow by the known CLL.
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RADIOGRAPHY (12/10/2010)
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Diagnosis
Therapy
Progression
LaboratoryLast FUP
LBORATORY EXAMS2010 2011
2 4 6 8 10 12 2 4 6 8 10 12 2 4 6 8
- WBC 3,520/ul (N 57%), Hb 12.7 g/dl, PLT 62,000/ul
- Ca++ 9,3mg/dl (8,5 – 10,5)- Alkaline phosphatasis 108 UI/L (30-104)- Uric acid 4.1 mg/dl (2.5-8.0)- Creatinine 0.7 mg/dl (0.8-1.3)
- Absence of Bence-Jones proteinuria.- Absence of monoclonal component in the serum-electrophoresis.- Parathormone was not measured.
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REVIEW OF THE LITERATURE I (last 30years)
Report # ofpts
Age
YearsAfter
Diagnosis
WBCx10^9/l
Hb &PLT
RS MC Ca++ PTH Treatment
McMillian, BMJ 1980 1 f 73 0 28 anemia no na +/- +/- Bisphosphonates + Chlorambucil
=> PR
Rossi, BJH 1990* 2f+m
>70
na na na no na na na na
Lerner et al, L&L 1994 1 f 2 ++ na yes na ++ death of HC
Van de Casteele, AnnHematol 1994
1 m 40 12 341 anemiathrombocytope
nia
no IgM k ++ red. Bisphosphonates + CHT =>death of HC
Briones, L&L 1996 1 f 69 1,8 2 +/- yes IgG kat RS
++ +/-1,25(OH)2 D3normal
Steroids +CHOP => deathof pneumonia
In all reports, patients presented with multiple bone lesions and/or pathologic fractures.MC, Monoclonal Component; PTH, Parathormone; Hb, Hemoglobin; PLT, Platelets; CHT, chemotherapy; HC, hypercalciemia;+/-, normal; ++, elevated; f, female; m, male.
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REVIEW OF THE LITERATURE II (last 30years)
Report # ofpts
Age Years AfterDiagnosis
WBCx10^9/l
Hb &PLT
RS MC Ca++ PTH Treatment
Beaudreuil, Cancer1997
2 73f +m
1 & 7 L 20 &42
na &red.
yes na ++ red.PTH-rP++
C1: Pam. + CHT =>death of septic shockC2: Pam. + CHT =>
death of septic shock
Lazarevic, L&L2006**
1 69 m 1 247 red. yes yes ++ Zoledronate + CHOP=> death of MOF
Greenfield, Eur JHaematol 2006
1 81 m 4 na na no IgGk8g/L
stable
+/- na na
**del(17p), unmutated IGHV genes
MC, Monoclonal Component; PTH, Parathormone; Hb, Hemoglobin; PLT, Platelets; CHT, chemotherapy; HC, hypercalciemia;+/-, normal; ++, elevated; f, female; m, male; Pam, Pamidronate; PTH-rP, parathormone-related peptide; MOF, multi-organfailure.
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OBSERVATIONS
• Large number of osteoclasts around the tumor mass => secretion ofosteoclast activating factor by the tumor cells?
• Elevated osteoclast count (smaller than normal osteoclasts) anddramatically increase of the eroded surface ratio (4-10 fold of B-BHLwithout lytic lesions) in 8 patients affected by hematologicmalignancies (2 CLL, 4 other NHL, Mb. Waldenstöm) with lytic bonelesions and/or hypercalcemia.
• The role of numerous local & systemic factors that promoteosteoclast activation (IL1, TNF-alpha and beta, IL6, CSFs,1,25(OH)2 D3, …) in CLL is not clear: 1 case with TNF and IL-6normal; 2 cases with elevated TNFalpha and elevated IL-6 in 1 case(IL6 was also elevated in control patients without hypercalcemia).
• Parathormone-related peptide could contribute to this process (1case associated with diffuse bone reabsorption; 1 case osteolyticbone lesions)
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Diagnosis
Therapy
Progression
Laboratory
Last FUP
LAST FOLLOW UP
In Trento:
- 5th line (11/2010): DHAOX x 1
- Afterwards autoimmunhaemolytic anemia => 4administrations of rituximab (lastly 21/12/11) per AEA.
- Progression of disease with hypercalcemia => monthlyBisphosphonates + C-CHOP
- The patient died due to progression of disease after the 3rd C-CHOP
2010 2011
2 4 6 8 10 12 2 4 6 8 10 12 2 4 6 8
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CONCLUSIONS
• About 11 cases have been described in the last 30 years (5 cases without Richtertransformation) => lytic bone lesions are a rare complication.
• Lytic bone lesions are a sign of disease progression.
• It occurs in all ages without a specific gender predilection. At time of diagnosis it isnot strictly associated with hypercalcemia, altered blood counts.
• Determines a poor prognosis.
• Probable dysregulation of the microenviroment due to local and/or systemic factorsat time of disease progression leading to a elevated localized bone reabsorption byactivated osteoclasts.
• Treatment: bisphosphonates (+ adequate treatment for hypercalcemia if present) +chemotherapy. However, up to now there does not exist any standard treatment forCLL patients with osteolysis and the disease seems to be resistant toimmunochemotherapy.
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ACKNOWLEDGEMENTS
• Prof. Sergio Cortelazzo (Ospedale diBolzano)
• Dr.ssa Cerù Silvia (Ospedale di TN)