The pattern of bone marrow involvement among chronic lymphocytic leukemia patients and its impact on the disease outcome in Kurdistan Region of Iraq

Abstract Background: There is evidence of a leukemogenic effect of purine analogues, mainly when combined with DNA-damaging agents. Various series report an approximately 5% rate of t-MDS/AML in patients treated with a fludarabine-based regimen. Patients are generally old, and old age is associated with worse outcomes. To date, there is no established standard therapy recommendation for this group of patients, and results of prospective treatment evaluations are scarce. Aim: To determine the characteristics and treatment outcomes of patients with CLL and t-MDS/AML. Methods: We analyzed a group of 6 patients with newly diagnosed t-MDS/AML who were treated in our institution from September 2011 to July 2014. Patients were enrolled in a phase II trial of azacitidine (75 mg/m2 IV daily x 5 days) in combination with vorinostat (200 mg orally three times daily x 5 days) (Arm A) or azacitidine alone (Arm B), with courses repeated every 3-8 weeks. This trial was designed to uniformly treat patients not eligible for other leukemia protocols due to comorbidities. Results: At baseline, all patients had an underlying diagnosis of CLL that was in remission or minimally active. The median percentage of CLL bone marrow involvement was 10% (range 0-60%), and ALC was 0.9 K/uL (range 0.2-9.79). The median number of prior CLL treatments was 2 (range 0-3). All patients had previously received fludarabine-based regimens. The median time from chemotherapy to t-MDS/AML diagnosis was 10 years (range 4-10). All patients were male, and the median age was 72 years (range 52-72). All patients had 3-line cytopenia, with median WBC 2.3 K/uL (range 0.8-8.9), ANC 0.55 K/uL (range 0-1.22), hemoglobin 9.6 G/DL (range 8.3-10.4), platelets 39 K/uL (range 6-80), and bone marrow blast percentage of 5% (range 1-18%). The karyotype was complex in all patients. Molecular studies showed that 3 patients had TP53 gene mutations. Five patients received treatment in Arm A, and only 1 patient was randomized to Arm B. Patients received a median of 4 cycles (range 2-7) and remained in the study for a median time of 216 days (range 86-329) before progression. None of the patients achieved remission, but stable disease was observed in 5 out of 6 patients. At the time of this analysis, 4 patients are dead and 2 are still alive: one discontinued treatment because of prolonged myelosuppression and is receiving best supportive care, and the other is recovering from cycle number 4 of treatment. The median survival in the group from the time of treatment initiation was 10.1 months and from the time of study discontinuation was 3.1 months. Further therapy was attempted in 3 patients without response. Conclusion: This is a group of patients with poor prognostic features. Azacytidine and vorinostat have been previously reported to be a safe combination (Garcia-Manero et al. ASH 2010, abstract 604) and may constitute a reasonable treatment alternative. Further prospective studies involving larger numbers of patients are required. Abstract 5627. Table 1: Baseline Patient Characteristics. Patient Age WBC K/uL Hb G/DL Plt K/uL BM Blast % CLL BM % Cytogenetic Molecular Prior CLL Treatments Treatment Arm Best Response 1 52 11 9.6 6 18 60 -3,-4,-5q,-6,-7, -7p,-12, +16 TP53 mutation 1.FCR x 62. Rituximab + Lenalidomide A NR 2 74 1 10 41 3 10 -3p,-5q,-7,-15,-17,-19 TP53 mutation 1. FCR x 42. FCR x 53. BR x 2 A SD 3 68 2.2 9.4 27 6 30 +7,-7p,t(7,21) Negative 1. FCR x 62. FCR x 4 B SD 4 73 2.3 9.7 39 6 0 +2,-5q,+8,-17,-18,+19,+20,-Y Negative 1. FCR x 6 A SD 5 71 0.8 8.3 39 4 0 +2,+4,t(5;17),+6,-7,-9, +13, +15,-16,-17,+18,+19,-20,+21 Negative 1. FR x 12. BR x43. MEDI-551 A SD 6 74 2.4 10.4 80 1 10 t(1;3),inv3,-5q,-18 TP53 mutation 1. R-CHOP x 62. BR x 13. FCR x 4 A SD WBC: White blood cells, Hb: hemoglobin, Plt: Platelets, BM: Bone Marrow, CLL: Chronic Lymphocytic Leukemia, F: Fludarabine, C: Cyclophosphamide, R: Rituximab, B: Bendamustine, MEDI-551: anti-CD19 antibody, NR: no response, SD: stable disease. Disclosures O'Brien: Amgen, Celgene, GSK: Consultancy; CLL Global Research Foundation: Membership on an entity's Board of Directors or advisory committees; Emergent, Genentech, Gilead, Infinity, Pharmacyclics, Spectrum: Consultancy, Research Funding; MorphoSys, Acerta, TG Therapeutics: Research Funding. Kantarjian:ARIAD, Pfizer, Amgen: Research Funding.

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Diagnostic and Clinical Considerations in Concomitant Bone Marrow Involvement by Plasma Cell Myeloma and Chronic Lymphocytic Leukemia/Monoclonal B-Cell Lymphocytosis: A Series of 15 Cases and Review of Literature

Archives of Pathology & Laboratory Medicine ◽

10.5858/arpa.2011-0696-oa ◽

2013 ◽

Vol 137 (4) ◽

pp. 503-517 ◽

Cited By ~ 24

Author(s):

Christopher L. Alley ◽

Endi Wang ◽

Cherie H. Dunphy ◽

Jerald Z. Gong ◽

Chuanyi M. Lu ◽

...

Keyword(s):

Bone Marrow ◽

B Cells ◽

Chronic Lymphocytic Leukemia ◽

Plasma Cell ◽

Plasma Cells ◽

Correct Diagnosis ◽

Bone Marrow Involvement ◽

Rare Event ◽

Lymphocytic Leukemia ◽

Plasma Cell Myeloma

Context.—Plasma cell myeloma and chronic lymphocytic leukemia are both common hematologic malignancies, sharing many epidemiologic features. Concomitant detection of the 2 conditions poses special diagnostic challenges for the pathologist. Objective.—To describe the pathologic findings in cases of concomitant bone marrow involvement by myeloma and CD5+ monoclonal B cells and to outline the differential diagnostic possibilities, suggest a workup for correct diagnosis, and examine clinical outcome. Design.—Fifteen cases that met the diagnostic criteria were identified from pathology databases at 4 participating institutions. Morphologic findings were reviewed, additional immunohistochemical stains performed, and flow cytometric, cytogenetic, and relevant laboratory and clinical information was summarized. Previously published cases were searched from electronic databases and cross-references. Results.—Most patients (13 of 15) were older males. Often (11 of 15) they presented clinically with myeloma, yet had both monotypic plasma cells and B cells in the diagnostic marrow. In 4 patients, myeloma developed 24 months or later after chronic lymphocytic leukemia. In 7 patients, myeloma and CD5+ B cells showed identical immunoglobulin light-chain restriction. Primary differential diagnoses include lymphoplasmacytic lymphoma, marginal zone lymphoma, and chronic lymphocytic leukemia with plasmacytoid differentiation. CD56 and/or cyclin D1 expression by plasma cells was helpful for correct diagnosis. Most patients in our cohort and published reports were treated for plasma cell myeloma. Conclusions.—Concomitant detection of myeloma and chronic lymphocytic leukemia in the bone marrow is a rare event, which must be carefully differentiated from lymphomas with lymphoplasmacytic differentiation for correct treatment.

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Monoclonal Antibody Therapy of Chronic Lymphocytic Leukemia

Journal of Clinical Oncology ◽

10.1200/jco.2003.09.113 ◽

2003 ◽

Vol 21 (9) ◽

pp. 1874-1881 ◽

Cited By ~ 49

Author(s):

Blanche Mavromatis ◽

Bruce D. Cheson

Keyword(s):

Bone Marrow ◽

Chronic Lymphocytic Leukemia ◽

Opportunistic Infections ◽

Bone Marrow Involvement ◽

Single Agent ◽

Antibody Therapy ◽

Lymphocytic Leukemia ◽

Phase Ii Trials ◽

Routes Of Administration ◽

Chemotherapy Drugs

Chemotherapeutic approaches during the last decade have failed to result in major advances in the outcome of patients with chronic lymphocytic leukemia (CLL). The recent availability of an increasing number of active monoclonal antibodies, immunotoxins, and radioimmunoconjugates (RICs) has stimulated considerable interest in clinical research in CLL. Alemtuzumab was the first antibody approved for CLL on the basis of responses in one third of patients with advanced disease. However, infusion reactions and immunosuppression with opportunistic infections present a challenge that may be overcome with altered schedules and routes of administration. Rituximab has limited activity as a single agent in patients relapsed or refractory after prior chemotherapy; however, response rates seem to be higher in previously untreated patients. More importantly, combinations with chemotherapy drugs such as fludarabine are showing promise in early trials. Newer antibodies in development as single agents and in combinations include apolizumab (Hu1D10), a humanized antibody against an epitope of HLA-DR, and IDEC-152, a primatized anti-CD23 antibody. BL22, an immunotoxin with impressive activity in hairy cell leukemia, is in phase II trials in CLL as well. The safe use of RICs is complicated by the elevated peripheral blood B-cell count, and the extent of bone marrow involvement in CLL; studies will explore the use of agents to eliminate malignant cells from the bone marrow before RIC therapy. It is hoped that the rational development of combinations of the various promising antibodies with chemotherapy and each other will lead to more effective approaches for patients with CLL.

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Immunohistologic study of bone marrow involvement in B-chronic lymphocytic leukemia

Blood ◽

10.1182/blood.v62.6.1289.1289 ◽

1983 ◽

Vol 62 (6) ◽

pp. 1289-1296 ◽

Cited By ~ 53

Author(s):

G Pizzolo ◽

M Chilosi ◽

A Ambrosetti ◽

G Semenzato ◽

L Fiore-Donati ◽

...

Keyword(s):

Bone Marrow ◽

T Cells ◽

Chronic Lymphocytic Leukemia ◽

Peripheral Blood ◽

Bone Marrow Involvement ◽

Lymphocytic Leukemia ◽

Hla Dr ◽

B Lymphoid ◽

T Cell Subpopulations ◽

Cellular Phenotypes

Abstract Bone marrow trephine biopsies from 17 patients with B-chronic lymphocytic leukemia (B-CLL) were studied by immunohistologic techniques in order to investigate the cellular phenotypes of both neoplastic (B-lymphoid) and reactive (T-lymphoid) infiltrates. For this purpose, several heteroantisera and monoclonal antibodies against human Ig isotypes, HLA-DR antigens, and T-cell subpopulations were used in immunofluorescence. The findings were analyzed in relationship to the histologic pattern of involvement, as well as to the immunologic data of cell suspensions from peripheral blood. In all cases, the dominant lymphoid population within the bone marrow infiltrates showed identical phenotypic characteristics of B-CLL cells from the blood (HLA-DR+, mu +, most frequently delta +, kappa +, or lambda +, and weakly RFA-1+). The infiltration by these malignant B cells was diffuse in 5 cases and nodular plus interstitial in 12. The number of T cells (UCHT1+, RFA-1+, mu) was variable (5%-25%) in the different samples, but the values were high when compared to the proportion of T cells in normal bone marrow and in the blood of most patients studied. Furthermore, a clear predominance of T cells exhibiting the inducer phenotype (Leu-3+) was observed in all bone marrow samples, which is in contrast with the findings from peripheral blood, where T cells with the suppressor/cytotoxic phenotype (Leu-2+) were dominant. These data suggest a different blood and tissue distribution of inducer and suppressor/cytotoxic cells in B-CLL, which may have important pathophysiologic significance.

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Three Cases of Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) Involving Cerebrospinal Fluid (CSF)

American Journal of Clinical Pathology ◽

10.1093/ajcp/aqz121.017 ◽

2019 ◽

Vol 152 (Supplement_1) ◽

pp. S111-S112

Author(s):

Anna Shestakova ◽

Jayne Healey ◽

Sheila (Xiaohui) Zhao ◽

Sherif Rezk ◽

Jamie Nakagiri

Keyword(s):

Bone Marrow ◽

Flow Cytometry ◽

Cerebrospinal Fluid ◽

Chronic Lymphocytic Leukemia ◽

Bone Marrow Involvement ◽

Lymphocytic Leukemia ◽

Lymphoid Tissues ◽

Proliferative Index ◽

Cns Involvement ◽

Ki 67

Abstract Background Chronic lymphocytic leukemia (CLL) is a clonal disorder of B lymphocytes, characterized by proliferation of small mature lymphocytes involving the blood, bone marrow, and lymphoid tissues. CLL can rarely involve the central nervous system (CNS), either by involving brain parenchyma or cerebrospinal fluid (CSF). We present a series of three cases with clinically significant involvement of the CNS with CLL. Results During the past 2 years, our medical center managed three patients with CLL who presented with symptomatic CNS involvement, as determined by flow cytometry. The immunophenotypic profile was that of a typical CLL with light chain restricted small B cells positive for CD20 (dim) and coexpressing CD5 and CD23. In addition, two patients had brain involvement by SLL that was confirmed by brain biopsy. Notably, the brain lesions had a mildly elevated Ki-67 proliferative index (10%-30%). Bone marrow was involved in two patients, showing nodular, interstitial, and diffuse patterns. Bone marrow involvement ranged from 60% to 80% and showed very low Ki-67 proliferative index. None of the patients had features suggestive of a CLL transformation. FISH was performed on either bone marrow or CSF and demonstrated that patient 1 had Del11q(ATM) and Dell13q, patient 2 had trisomy 12, and patient 3 had del17(TP53) and IGH rearrangement. All of the patients showed persistent CSF involvement, ranging from 4 to 12 weeks, requiring aggressive treatment with intrathecal chemotherapy. At the end of treatment, all of the patients were clear of CNS involvement as judged by flow cytometry of CSF. Conclusion We report three patients who had persistent involvement of CSF. Only one patient had del17(TP53), a cytogenetic feature that is associated with high-risk CLL. It would be interesting to study clonal evolution of CLL to understand the mechanisms that underlie involvement of the CNS.

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Immunohistologic study of bone marrow involvement in B-chronic lymphocytic leukemia

Blood ◽

10.1182/blood.v62.6.1289.bloodjournal6261289 ◽

1983 ◽

Vol 62 (6) ◽

pp. 1289-1296 ◽

Cited By ~ 7

Author(s):

G Pizzolo ◽

M Chilosi ◽

A Ambrosetti ◽

G Semenzato ◽

L Fiore-Donati ◽

...

Keyword(s):

Bone Marrow ◽

T Cells ◽

Chronic Lymphocytic Leukemia ◽

Peripheral Blood ◽

Bone Marrow Involvement ◽

Lymphocytic Leukemia ◽

Hla Dr ◽

B Lymphoid ◽

T Cell Subpopulations ◽

Cellular Phenotypes

Bone marrow trephine biopsies from 17 patients with B-chronic lymphocytic leukemia (B-CLL) were studied by immunohistologic techniques in order to investigate the cellular phenotypes of both neoplastic (B-lymphoid) and reactive (T-lymphoid) infiltrates. For this purpose, several heteroantisera and monoclonal antibodies against human Ig isotypes, HLA-DR antigens, and T-cell subpopulations were used in immunofluorescence. The findings were analyzed in relationship to the histologic pattern of involvement, as well as to the immunologic data of cell suspensions from peripheral blood. In all cases, the dominant lymphoid population within the bone marrow infiltrates showed identical phenotypic characteristics of B-CLL cells from the blood (HLA-DR+, mu +, most frequently delta +, kappa +, or lambda +, and weakly RFA-1+). The infiltration by these malignant B cells was diffuse in 5 cases and nodular plus interstitial in 12. The number of T cells (UCHT1+, RFA-1+, mu) was variable (5%-25%) in the different samples, but the values were high when compared to the proportion of T cells in normal bone marrow and in the blood of most patients studied. Furthermore, a clear predominance of T cells exhibiting the inducer phenotype (Leu-3+) was observed in all bone marrow samples, which is in contrast with the findings from peripheral blood, where T cells with the suppressor/cytotoxic phenotype (Leu-2+) were dominant. These data suggest a different blood and tissue distribution of inducer and suppressor/cytotoxic cells in B-CLL, which may have important pathophysiologic significance.

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