- Email: [email protected]
Chronic lymphocytic leukemia–associated membranous glomerulopathy: Remission with fludarabine
CASE REPORT
Chronic Lymphocytic Leukemia–Associated Membranous Glomerulopathy: Remission With Fludarabine Hesham Butty, MD, Jehad Asfoura, MD, Ferdinando Cortese, MD, Michael Doyle, MD, and Gregory Rutecki, MD ● In some individuals, chronic lymphocytic leukemia (CLL) may be associated with glomerular disease from membranous nephropathy with resultant nephrotic syndrome. CLL is characterized by abnormal immunoregulation with a malignant clonal proliferation of lymphocytes. The association between the abnormal clone and nephrotic syndrome is suggested in some cases by the remission of proteinuria with a reduction in abnormal lymphocyte number after treatment with antineoplastic agents. For the first time, we describe a patient with CLL and associated membranous glomerulopathy whose nephrotic syndrome remitted after treatment with fludarabine, a new purine analogue used in the treatment of refractory CLL. 娀 1999 by the National Kidney Foundation, Inc. INDEX WORDS: Membranous glomerulopathy; chronic lymphocytic leukemia; fludarabine; paraneoplastic nephropathy; nephrotic syndrome.
G
LOMERULAR disease complicated by nephrotic syndrome is a rare complication of malignancy.1,2 It has been described in Hodgkin’s disease and non-Hodgkin’s lymphoma, with solid tumors, and has been rarely associated with leukemia.3 Membranous nephropathy has been the predominant glomerular lesion associated with solid tumors; minimal change glomerulopathy, with Hodgkin’s disease; and either membranoproliferative or membranous glomerulopathy reported as a complication of chronic lymphocytic leukemia (CLL). There are also occasional reports of proliferative, minimal change, or immunotactoid glomerulopathy as well as amyloid or focal sclerosis with CLL.3-5 Nephrotic syndrome is rare enough as a complication of malignancies that the association could occur by chance alone.1 However, the observation that treatment of the malignancy with chemotherapy, or even more importantly, surgical excision, or local radiation for solid tumors results in resolution of nephrotic proteinuria strongly suggests that the glomerulopathy is a paraneoplastic syndrome.1 Furthermore, the demonstration of immunoglobulins and complement in paraneoplastic glomerular lesions suggests that abnormal immunoregulation is responsible for the glomerulopathy. Abnormal immunoregulation occurs frequently in CLL and may lead to autoimmune complications, including immunecomplex renal disease, autoimmune hemolytic anemia, and thrombocytopenia.6 Previously, complete remission of the paraneoplastic nephropathy in CLL has been observed
after therapy with alkylating agents and prednisone, presumably as a result of a reduction in clonal lymphocytes, suggesting a direct role for monoclonal immunoglobulins in the glomerular injury (immunoglobulin [Ig] G, IgM, kappa and lambda light chains).4,7 There have been no controlled studies, however, addressing the response of glomerular disease to treatment for CLL. We describe a patient who developed membranous nephropathy and nephrotic syndrome as a complication of CLL. This individual did not respond to traditional therapy for CLL (alkylating agents and prednisone), but the nephrotic syndrome remitted after treatment with fludarabine—a recent treatment addition for CLL. Fludarabine, a purine analog, has major activity in the treatment of indolent lymphoid malignancies through cytotoxicity against dividing and resting lymphocytes.8 CASE REPORT A white woman presented to her hematologist oncologist January 17, 1989, with easy fatiguability and an increased white blood cell count. Medical history included hypertension treated with a beta-blocker. Physical examination showed
From the Northeastern Ohio Universities College of Medicine (NEOUCOM), Affıliated Hospitals at Canton, OH. Received August 3, 1998; accepted in revised form October 30, 1998. Address reprint requests to Gregory W. Rutecki, MD, Mercy Medical Center, 1320 Mercy Dr, NW, Canton, OH 44708. E-mail: [email protected]
娀 1999 by the National Kidney Foundation, Inc. 1523-6838/99/3302-0034$3.00/0
American Journal of Kidney Diseases, Vol 33, No 2 (February), 1999: E8
1
2
BUTTY ET AL
Fig 1. Peripheral smear with mature lymphocytes (closed arrow) and smudge cells (open arrow).
some small cervical lymph nodes without hepatosplenomegaly. Initial blood work showed a white blood cell count (WBC) of 32,300 with 80% mature lymphocytes (absolute lymphocyte count, 25,840 mm3 ). Peripheral smear showed a predominance of small lymphocytes with smudge cells (Fig 1). Bone marrow aspiration and biopsy were consistent with a diagnosis of chronic lymphocytic leukemia with a dense, mature lymphocytic infiltrate throughout the bone marrow (Fig 2). Flow cytometry performed at a later date corroborated the diagnosis of CLL. That same year, she was started on chlorambucil adjusted according to blood count for progressive adenopathy. Her adenopathy and lymphocytosis improved, and she was continued on this medication without problems until August 1991, when it was discontinued. She was asymptomatic with a stable WBC until December 1993, when she presented with leg edema. White blood cell count then was 20,600 with 67% mature lymphocytes. Her albumin was 2.4 g/dL with a normal blood urea nitrogen creatinine, and a cholesterol of 307 mg/dL. Twenty-four-hour urine protein was 6.7 g, and urine electrophoresis showed albumin without monoclonal proteins. Percutaneous renal biopsy (Fig 3) was consistent with membranous glomerulopathy by light, immunofluorescence, and electron microscopy. The biopsy specimen was not stained for monoclonal proteins. Serial urine proteins and treatment are provided in
Fig 2. Bone marrow aspirate with a monotonous collection of small lymphocytes.
Fig 3. (A) Percutaneous renal biopsy with light (PAS stain) and electron microscopy specimens. Light shows a single glomerulus (arrow) with basement membrane thickening. (B) The EM shows dense subepithelial deposits (arrow) consistent with membranous glomerulopathy.
Fig 4. Intravenous cyclophosphamide was administered May 1994 to July 1994 without effect on the nephrotic syndrome. During therapy, white blood cell count decreased from 19,000 to approximately 10,000. Even though lymphadenopathy cleared, leg edema and other parameters for nephrotic syndrome were unchanged. High-dose steroids were used alone and with cyclophosphamide. In spring 1997, she complained of generalized fatigue, and her hemoglobin decreased to 10 g and white blood cell count increased to 53,900, of which 82% were mature lymphocytes (absolute lymphocyte count, 44,200 mm3 ). Repeat bone marrow aspiration and biopsy again showed diffuse infiltration by mature lymphocytes. Lymphadenopathy was present, but hepatosplenomegaly was absent. Again, there was massive leg edema. At this time, urine protein was 19 g in 24 hours. Based on the increasing number of lymphocytes, anemia, and worsening proteinuria, the patient was started on
REMISSION OF CLL MEMBRANOUS NEPHROPATHY
3
Fig 4. Serial follow-up of proteinuria from July 22, 1994 through January 30, 1998 with therapeutic interventions. (1) Corticosteroids (prednisone) 120 mg every other day; (2) corticosteroids tapered; (3) cyclophosphamide 100 mg every day with 10-mg corticosteroids every other day; (4) cyclophosphamide and corticosteroids discontinued; (5) fludarabine started.
fludarabine as monotherapy. Forty milligrams per day was administered for 5 days, and the cycle was repeated every 3 to 4 weeks. After 2 weeks of therapy, there was a 16-pound weight loss, with disappearance of the leg edema. A total of six cycles of chemotherapy were given. The last was administered on December 8, 1997, with significant improvement in peripheral lymphocytosis, lymphadenopathy, and urine protein excretion (Fig 4). Follow-up continues with a urine protein excretion of 124 mg/d (September 1998); an albumin of 3.4 g/dL; and a cholesterol of 187 mg/dL—all in normal range. Serum creatinine is unchanged at 1.4 mg/dL. Her CLL is in complete remission, with a WBC of 5,400 k/UL and 1,350 k/UL lymphocytes. Flow cytometry shows complete disappearance of the abnormal lymphocytic monoclonality—consistent with remission. The renal biopsy was not repeated.
DISCUSSION
To our knowledge, this is the first report of a patient with CLL and biopsy-proven paraneoplastic membranous nephropathy unresponsive to traditional therapy in whom the nephrotic syndrome remitted after treatment with fludarabine. Fludarabine, a prodrug, is a five-prime monophosphate of 1-beta-D arabinofuranosyl-2-fluoroadenine (F-ara-A).9 After administration, the medication is dephosphorylated and actively transported into cells, where it is transformed into F-ara-ATP. This is a cytotoxic chemical that has a complex mechanism of action. F-ara-A, the active compound of fludarabine, inhibits deacyl nucleotide reductase and is incorporated into cellular DNA with the subsequent inhibition of DNA chain elongation; inhibition of DNA proofreading activities; inhibition of DNA primase and ligase activity—all combining to eventually inhibit DNA synthesis.9,10 It is suspected that the termination of DNA synthesis by F-ara-A results in programmed cell death or so-called apoptosis.
As a result of its cytotoxic activity, fludarabine induces a profound lymphocytopenia.8 A marked decrease in CD4 lymphocytes occurs that may persist for several years, while affecting other mononuclear cell populations (CD5 ), which recover more rapidly. Fludarabine is probably the single most active agent in CLL11,12 and is now recommended as first-line therapy for this disease. It is possible that fludarabine was effective in our patient because it produced a better and more prolonged response in the malignant clone than alkylating agents and steroids. A recent publication described a patient with CLL in whom splenectomy resulted in a complete remission of nephrotic syndrome.13 The remission supports the theory that nephrotic syndrome is a result of diseaseinduced abnormal immune regulation. It is the authors’ suspicion that remission of CLL with fludarabine led to remission of membranous nephropathy. Therefore, because it appears that nephrotic syndrome may be a paraneoplastic manifestation of CLL, and because fludarabine is the most effective drug for the treatment of this disease, it warrants consideration as first-line therapy in CLL-associated glomerular disease. REFERENCES 1. Eagen JW, Lewis EJ: Glomerulopathies of neoplasia. Kidney Int 11:297-306, 1977 2. Alpers CE, Cotran RS: Neoplasia and glomerular injury. Kidney Int 30:465-473, 1986 3. MeLigeyo SO, Notghi A, Thomson D, Anderson JL: Nephrotic syndrome associated with chronic lymphocytic leukemia. Nephrol Dial Transplant 8:461-463, 1993 4. Touchard G, Preud⬘homme JL, Aucouturier P, Giraud
4
C, Gouet D, Yver L, Patte D: Nephrotic syndrome associated with chronic lymphocytic leukemia: An immunological and pathological study. Clin Nephrol 31:107-116, 1989 5. Seney FD, Federgreen WR, Stein H, Kashgarian M: A review of nephrotic syndrome associated with chronic lymphocytic leukemia. Arch Intern Med 146:137-141, 1986 6. Rozman C, Montserrat E: Chronic lymphocytic leukemia. N Engl J Med 333:1053-1057, 1995 7. Moulin B, Ronco PM, Mougenot B, Francois A, Fillastre JP, Mignon F: Glomerulonephritis in chronic lymphocytic leukemia and related B-cell lymphomas. Kidney Int 42:127-135, 1992 8. Cheson BD: Infectious and immunosuppressive complications of purine analogue therapy. J Clin Oncol 13:24312448, 1995 9. Plunkett W, Gandhi V, Huang P, Robertson LE, Yang
BUTTY ET AL
LY, Gregoire V, Estey E, Keating MJ: Fludarabine: Pharmacokinetics, mechanisms of action and rationales for combination therapies. Semin Oncol 20:2-12, 1993 10. Gandhi V, Huang P, Plunkett W: Fludarabine inhibits DNA replication: A rationale for its use in the treatment of acute leukemias. Leukemia and Lymphoma 14(S)2:3-9, 1994 11. Bergmann L: Present status of purine analogues in the therapy of chronic lymphocytic leukemia. Leukemia 11:2934, 1997 (suppl 2) 12. Adkins JC, Peters DH, Markham A: Fludarabine: An update of its pharmacology and use in the treatment of hematological malignancies. Drugs 53:1005-1035, 1997 13. Halimi JM, Lavabre-Bertrand T, Beraud JJ, Canaud B: Nephrotic syndrome associated with chronic lymphocytic leukemic resistant to immunosuppressive drugs: Remission obtained by splenectomy. Clin Nephrol 45:273-276, 1996
Chronic Lymphocytic Leukemia–Associated Membranous Glomerulopathy: Remission With Fludarabine Hesham Butty, MD, Jehad Asfoura, MD, Ferdinando Cortese, MD, Michael Doyle, MD, and Gregory Rutecki, MD ● In some individuals, chronic lymphocytic leukemia (CLL) may be associated with glomerular disease from membranous nephropathy with resultant nephrotic syndrome. CLL is characterized by abnormal immunoregulation with a malignant clonal proliferation of lymphocytes. The association between the abnormal clone and nephrotic syndrome is suggested in some cases by the remission of proteinuria with a reduction in abnormal lymphocyte number after treatment with antineoplastic agents. For the first time, we describe a patient with CLL and associated membranous glomerulopathy whose nephrotic syndrome remitted after treatment with fludarabine, a new purine analogue used in the treatment of refractory CLL. 娀 1999 by the National Kidney Foundation, Inc. INDEX WORDS: Membranous glomerulopathy; chronic lymphocytic leukemia; fludarabine; paraneoplastic nephropathy; nephrotic syndrome.
G
LOMERULAR disease complicated by nephrotic syndrome is a rare complication of malignancy.1,2 It has been described in Hodgkin’s disease and non-Hodgkin’s lymphoma, with solid tumors, and has been rarely associated with leukemia.3 Membranous nephropathy has been the predominant glomerular lesion associated with solid tumors; minimal change glomerulopathy, with Hodgkin’s disease; and either membranoproliferative or membranous glomerulopathy reported as a complication of chronic lymphocytic leukemia (CLL). There are also occasional reports of proliferative, minimal change, or immunotactoid glomerulopathy as well as amyloid or focal sclerosis with CLL.3-5 Nephrotic syndrome is rare enough as a complication of malignancies that the association could occur by chance alone.1 However, the observation that treatment of the malignancy with chemotherapy, or even more importantly, surgical excision, or local radiation for solid tumors results in resolution of nephrotic proteinuria strongly suggests that the glomerulopathy is a paraneoplastic syndrome.1 Furthermore, the demonstration of immunoglobulins and complement in paraneoplastic glomerular lesions suggests that abnormal immunoregulation is responsible for the glomerulopathy. Abnormal immunoregulation occurs frequently in CLL and may lead to autoimmune complications, including immunecomplex renal disease, autoimmune hemolytic anemia, and thrombocytopenia.6 Previously, complete remission of the paraneoplastic nephropathy in CLL has been observed
after therapy with alkylating agents and prednisone, presumably as a result of a reduction in clonal lymphocytes, suggesting a direct role for monoclonal immunoglobulins in the glomerular injury (immunoglobulin [Ig] G, IgM, kappa and lambda light chains).4,7 There have been no controlled studies, however, addressing the response of glomerular disease to treatment for CLL. We describe a patient who developed membranous nephropathy and nephrotic syndrome as a complication of CLL. This individual did not respond to traditional therapy for CLL (alkylating agents and prednisone), but the nephrotic syndrome remitted after treatment with fludarabine—a recent treatment addition for CLL. Fludarabine, a purine analog, has major activity in the treatment of indolent lymphoid malignancies through cytotoxicity against dividing and resting lymphocytes.8 CASE REPORT A white woman presented to her hematologist oncologist January 17, 1989, with easy fatiguability and an increased white blood cell count. Medical history included hypertension treated with a beta-blocker. Physical examination showed
From the Northeastern Ohio Universities College of Medicine (NEOUCOM), Affıliated Hospitals at Canton, OH. Received August 3, 1998; accepted in revised form October 30, 1998. Address reprint requests to Gregory W. Rutecki, MD, Mercy Medical Center, 1320 Mercy Dr, NW, Canton, OH 44708. E-mail: [email protected]
娀 1999 by the National Kidney Foundation, Inc. 1523-6838/99/3302-0034$3.00/0
American Journal of Kidney Diseases, Vol 33, No 2 (February), 1999: E8
1
2
BUTTY ET AL
Fig 1. Peripheral smear with mature lymphocytes (closed arrow) and smudge cells (open arrow).
some small cervical lymph nodes without hepatosplenomegaly. Initial blood work showed a white blood cell count (WBC) of 32,300 with 80% mature lymphocytes (absolute lymphocyte count, 25,840 mm3 ). Peripheral smear showed a predominance of small lymphocytes with smudge cells (Fig 1). Bone marrow aspiration and biopsy were consistent with a diagnosis of chronic lymphocytic leukemia with a dense, mature lymphocytic infiltrate throughout the bone marrow (Fig 2). Flow cytometry performed at a later date corroborated the diagnosis of CLL. That same year, she was started on chlorambucil adjusted according to blood count for progressive adenopathy. Her adenopathy and lymphocytosis improved, and she was continued on this medication without problems until August 1991, when it was discontinued. She was asymptomatic with a stable WBC until December 1993, when she presented with leg edema. White blood cell count then was 20,600 with 67% mature lymphocytes. Her albumin was 2.4 g/dL with a normal blood urea nitrogen creatinine, and a cholesterol of 307 mg/dL. Twenty-four-hour urine protein was 6.7 g, and urine electrophoresis showed albumin without monoclonal proteins. Percutaneous renal biopsy (Fig 3) was consistent with membranous glomerulopathy by light, immunofluorescence, and electron microscopy. The biopsy specimen was not stained for monoclonal proteins. Serial urine proteins and treatment are provided in
Fig 2. Bone marrow aspirate with a monotonous collection of small lymphocytes.
Fig 3. (A) Percutaneous renal biopsy with light (PAS stain) and electron microscopy specimens. Light shows a single glomerulus (arrow) with basement membrane thickening. (B) The EM shows dense subepithelial deposits (arrow) consistent with membranous glomerulopathy.
Fig 4. Intravenous cyclophosphamide was administered May 1994 to July 1994 without effect on the nephrotic syndrome. During therapy, white blood cell count decreased from 19,000 to approximately 10,000. Even though lymphadenopathy cleared, leg edema and other parameters for nephrotic syndrome were unchanged. High-dose steroids were used alone and with cyclophosphamide. In spring 1997, she complained of generalized fatigue, and her hemoglobin decreased to 10 g and white blood cell count increased to 53,900, of which 82% were mature lymphocytes (absolute lymphocyte count, 44,200 mm3 ). Repeat bone marrow aspiration and biopsy again showed diffuse infiltration by mature lymphocytes. Lymphadenopathy was present, but hepatosplenomegaly was absent. Again, there was massive leg edema. At this time, urine protein was 19 g in 24 hours. Based on the increasing number of lymphocytes, anemia, and worsening proteinuria, the patient was started on
REMISSION OF CLL MEMBRANOUS NEPHROPATHY
3
Fig 4. Serial follow-up of proteinuria from July 22, 1994 through January 30, 1998 with therapeutic interventions. (1) Corticosteroids (prednisone) 120 mg every other day; (2) corticosteroids tapered; (3) cyclophosphamide 100 mg every day with 10-mg corticosteroids every other day; (4) cyclophosphamide and corticosteroids discontinued; (5) fludarabine started.
fludarabine as monotherapy. Forty milligrams per day was administered for 5 days, and the cycle was repeated every 3 to 4 weeks. After 2 weeks of therapy, there was a 16-pound weight loss, with disappearance of the leg edema. A total of six cycles of chemotherapy were given. The last was administered on December 8, 1997, with significant improvement in peripheral lymphocytosis, lymphadenopathy, and urine protein excretion (Fig 4). Follow-up continues with a urine protein excretion of 124 mg/d (September 1998); an albumin of 3.4 g/dL; and a cholesterol of 187 mg/dL—all in normal range. Serum creatinine is unchanged at 1.4 mg/dL. Her CLL is in complete remission, with a WBC of 5,400 k/UL and 1,350 k/UL lymphocytes. Flow cytometry shows complete disappearance of the abnormal lymphocytic monoclonality—consistent with remission. The renal biopsy was not repeated.
DISCUSSION
To our knowledge, this is the first report of a patient with CLL and biopsy-proven paraneoplastic membranous nephropathy unresponsive to traditional therapy in whom the nephrotic syndrome remitted after treatment with fludarabine. Fludarabine, a prodrug, is a five-prime monophosphate of 1-beta-D arabinofuranosyl-2-fluoroadenine (F-ara-A).9 After administration, the medication is dephosphorylated and actively transported into cells, where it is transformed into F-ara-ATP. This is a cytotoxic chemical that has a complex mechanism of action. F-ara-A, the active compound of fludarabine, inhibits deacyl nucleotide reductase and is incorporated into cellular DNA with the subsequent inhibition of DNA chain elongation; inhibition of DNA proofreading activities; inhibition of DNA primase and ligase activity—all combining to eventually inhibit DNA synthesis.9,10 It is suspected that the termination of DNA synthesis by F-ara-A results in programmed cell death or so-called apoptosis.
As a result of its cytotoxic activity, fludarabine induces a profound lymphocytopenia.8 A marked decrease in CD4 lymphocytes occurs that may persist for several years, while affecting other mononuclear cell populations (CD5 ), which recover more rapidly. Fludarabine is probably the single most active agent in CLL11,12 and is now recommended as first-line therapy for this disease. It is possible that fludarabine was effective in our patient because it produced a better and more prolonged response in the malignant clone than alkylating agents and steroids. A recent publication described a patient with CLL in whom splenectomy resulted in a complete remission of nephrotic syndrome.13 The remission supports the theory that nephrotic syndrome is a result of diseaseinduced abnormal immune regulation. It is the authors’ suspicion that remission of CLL with fludarabine led to remission of membranous nephropathy. Therefore, because it appears that nephrotic syndrome may be a paraneoplastic manifestation of CLL, and because fludarabine is the most effective drug for the treatment of this disease, it warrants consideration as first-line therapy in CLL-associated glomerular disease. REFERENCES 1. Eagen JW, Lewis EJ: Glomerulopathies of neoplasia. Kidney Int 11:297-306, 1977 2. Alpers CE, Cotran RS: Neoplasia and glomerular injury. Kidney Int 30:465-473, 1986 3. MeLigeyo SO, Notghi A, Thomson D, Anderson JL: Nephrotic syndrome associated with chronic lymphocytic leukemia. Nephrol Dial Transplant 8:461-463, 1993 4. Touchard G, Preud⬘homme JL, Aucouturier P, Giraud
4
C, Gouet D, Yver L, Patte D: Nephrotic syndrome associated with chronic lymphocytic leukemia: An immunological and pathological study. Clin Nephrol 31:107-116, 1989 5. Seney FD, Federgreen WR, Stein H, Kashgarian M: A review of nephrotic syndrome associated with chronic lymphocytic leukemia. Arch Intern Med 146:137-141, 1986 6. Rozman C, Montserrat E: Chronic lymphocytic leukemia. N Engl J Med 333:1053-1057, 1995 7. Moulin B, Ronco PM, Mougenot B, Francois A, Fillastre JP, Mignon F: Glomerulonephritis in chronic lymphocytic leukemia and related B-cell lymphomas. Kidney Int 42:127-135, 1992 8. Cheson BD: Infectious and immunosuppressive complications of purine analogue therapy. J Clin Oncol 13:24312448, 1995 9. Plunkett W, Gandhi V, Huang P, Robertson LE, Yang
BUTTY ET AL
LY, Gregoire V, Estey E, Keating MJ: Fludarabine: Pharmacokinetics, mechanisms of action and rationales for combination therapies. Semin Oncol 20:2-12, 1993 10. Gandhi V, Huang P, Plunkett W: Fludarabine inhibits DNA replication: A rationale for its use in the treatment of acute leukemias. Leukemia and Lymphoma 14(S)2:3-9, 1994 11. Bergmann L: Present status of purine analogues in the therapy of chronic lymphocytic leukemia. Leukemia 11:2934, 1997 (suppl 2) 12. Adkins JC, Peters DH, Markham A: Fludarabine: An update of its pharmacology and use in the treatment of hematological malignancies. Drugs 53:1005-1035, 1997 13. Halimi JM, Lavabre-Bertrand T, Beraud JJ, Canaud B: Nephrotic syndrome associated with chronic lymphocytic leukemic resistant to immunosuppressive drugs: Remission obtained by splenectomy. Clin Nephrol 45:273-276, 1996