CASE REPORT AN UNCOMMON PRESENTATION OF CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) AT DISEASE PROGRESSION. Michael Mian, MD General Hospital of Bolzano

Transcription

1 CASE REPORT AN UNCOMMON PRESENTATION OF CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) AT DISEASE PROGRESSION Michael Mian, MD General Hospital of Bolzano March 12th 2011 Padova

2 DIAGNOSIS Therapy Progression Laboratory Last FUP M. F. *02/1950; m - Judoka - Anamnesis: slight exhaustion, no B-Symptoms. - Medical examination: bilateral laterocervical, sovraclavear and axillary lymphadenopathy (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-mg 2,4 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

3 THERAPY I Therapy Progression Laboratory Last FUP 05/2004: PD (weight loss, hyperleucocytosis, increasing splenomegaly, 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 and abdominal & laterocervical lymphadenopathies) => FISH: del 13q14 28%, mutational analysis: IGHV unmutated 3rd line: 09-12/2009 Fludarabine + Cyclophosphamide x4 cycles (no Rituximab because of recurrent infections): PR

4 THERAPY II Therapy Progression Laboratory Last FUP 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 of the lower extremities: presence of pathologic tissue (2.5 cm) at the level of the diaphysis of the tibia with interruption of the cortical layer. 3) MR right ankle (01/07/2010): presence of a pathologic tissue => 4th line: 06-09/2010 R-Bendamustina (100mg/m2) x4 + start search for a compatible BM donor 24/09/2010: diffuse joint pain, painful swelling at the left forearm and pain of the right elbow (=> radiography: osteloysis), pain when chewing. PET-CT & maxillofacial CT Maxillofacial CT: probable pathologic fracture of the anterior part of the sinus mascellaris extending to the basis of the orbita

5 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 the calcaneus.

6 PROGRESSION OF DISEASE II Therapy Progression Laboratory Last FUP 12/10/2010 (after the 4 th cycle): The patient presents with pain and 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 infiltration of 20% (cytofluorometry 2% of monoclonal B-cells) => Bone marrow biopsy (11/11/2011): No evidence of infiltration of the bone marrow by the known CLL.

7 RADIOGRAPHY (12/10/2010)

8 LBORATORY EXAMS Therapy Progression Laboratory Last FUP - 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 ( ) - Creatinine 0.7 mg/dl ( ) - Absence of Bence-Jones proteinuria. - Absence of monoclonal component in the serumelectrophoresis. - Parathormone was not measured.

9 REVIEW OF THE LITERATURE I (last 30 years) Report # of pts A ge Years After WBC x10^9/l Hb & PLT RS MC Ca++ PTH Treatment McMillian, BMJ f anemia no na +/- +/- Bisphosphonate s + Chlorambucil => PR Rossi, BJH 1990* 2 f+m >7 0 na na na no na na na na Lerner et al, L&L f 2 ++ na yes na ++ death of HC Van de Casteele, Ann Hematol m anemia thromb ocytope nia Briones, L&L f 69 1,8 2 +/- yes IgG k at RS no IgM k ++ red. Bisphosphonate s + CHT => death of HC ++ +/- 1,25(O H)2 D3 normal Steroids + CHOP => death of 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.

10 REVIEW OF THE LITERATURE II (last 30 years) Report Beaudreuil, Cancer 1997 Lazarevic, L&L 2006** Greenfield, Eur J Haematol 2006 # of pts Age 2 73 f +m Years After WBC x10^9/l 1 & 7 L 20 & 42 Hb & PLT na & red. RS MC Ca++ PTH Treatment yes na ++ red. PTH -rp ++ C1: Pam. + CHT => death of septic shock C2: Pam. + CHT => death of septic shock 1 69 m red. yes yes ++ Zoledronate + CHOP => death of MOF 1 81 m 4 na na no IgGk 8g/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-organ failure.

11 OBSERVATIONS Large number of osteoclasts around the tumor mass => secretion of osteoclast activating factor by the tumor cells? Elevated osteoclast count (smaller than normal osteoclasts) and dramatically increase of the eroded surface ratio (4-10 fold of B-BHL without lytic lesions) in 8 patients affected by hematologic malignancies (2 CLL, 4 other NHL, Mb. Waldenstöm) with lytic bone lesions and/or hypercalcemia. The role of numerous local & systemic factors that promote osteoclast activation (IL1, TNF-alpha and beta, IL6, CSFs, 1,25(OH)2 D3, ) in CLL is not clear: 1 case with TNF and IL-6 normal; 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 (1 case associated with diffuse bone reabsorption; 1 case osteolytic bone lesions)

12 LAST FOLLOW UP Therapy Progression Laboratory Last FUP In Trento: - 5th line (11/2010): DHAOX x 1 - Afterwards autoimmunhaemolytic anemia => 4 administrations of rituximab (lastly 21/12/11) per AEA. - Progression of disease with hypercalcemia => monthly Bisphosphonates + C-CHOP - The patient died due to progression of disease after the 3 rd C- CHOP

13 CONCLUSIONS About 11 cases have been described in the last 30 years (5 cases without Richter transformation) => 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 is not strictly associated with hypercalcemia, altered blood counts. Determines a poor prognosis. Probable dysregulation of the microenviroment due to local and/or systemic factors at time of disease progression leading to a elevated localized bone reabsorption by activated osteoclasts. Treatment: bisphosphonates (+ adequate treatment for hypercalcemia if present) + chemotherapy. However, up to now there does not exist any standard treatment for CLL patients with osteolysis and the disease seems to be resistant to immunochemotherapy.

14 ACKNOWLEDGEMENTS Prof. Sergio Cortelazzo (Ospedale di Bolzano) Dr.ssa Cerù Silvia (Ospedale di TN)