Etoposide, dexamethasone, and continuous-infusion cyclophosphamide with g-CSF for VAD-Resistant...
1
170 Letters and Correspondence 5. Hiqsonmez G, Tuncer AM, Giiler E, Tan E, Tekelioglu M: The potential role of high-dose methylprednisolone on the maturation of leukemic cells in children with acute promyelocytic leukemia (APL). Exp Hematol21:599401, 1993. 6. Hamidah HN, Chenog SK, Ainoon 0: In vivo evidence of all-trans-retinoic acid inducing maturation in acute promyelocytic leukemia. Acta Haematol 89:5&5 1, 1993. Etoposide, Dexamethasone,and Continuous-Infusion Cyclophosphamide With G-CSF for VADResistant Multiple Myeloma To the Editor: The combination of vincristine, doxorubicin, and dexam- ethasone (VAD) has been the treatment of choice for patients with resistant multiple myeloma (MM) [I]. This regimen carries a heavy toxicity, and more than 50% of refractory MM are unresponsive [2]. For patients with VAD-resistant MM, options for effective treatment are limited. We have used successfully the combination of etoposide and continous-infusion cyclophosphamide (CY) in two patients with VAD-resistant MM. The treatment regimen was etoposide 80 mgim*iIV over 2 hr on days 1-2. CY 200 mgim’ by continuous IV infusion on days 1-7, dexametha- sone 40 mg IV on days 1-7, and granulocyte-colony-stimulating factor (G-CSF) 5 p,g/kg SC beginning 24 hr after the completion of CY infusion until a white blood cell (WBC) count of >lO,OOO/pI. Recycle every 4 weeks. CASE 1 The patient was a 63-year-old man with MM IgG A, stage IIIB. The patient had progressive disease despite the administration of 2 cycles of melphalan-prednisone, 4 cycles of VCMPiVBAP regimen, and 2 cycles of VAD. On admission, the patient’s performance status (ECOG) was 4, with Hb 5 gidl, creatinine 5.9 mg/dl, calcium 12 mgidl, and a serum M-protein of 12.2 gidl. The bone marrow examination revealed 80% plasma cells. After 4 cycles of etoposide-CY, the patient had a I performance status, no transfusional requirements, normal biochemical profile, and a serum M-protein of 3.6 gidl. The bone marrow plasma cells decreased to 40%. The regimen was well tolerated, and clinical response was evident after the first cycle. The first cycle was given without G-CSF, and the patient had septicemia. Progressive disease developed following 7 months of mainte- nance; the patient died 2 months later. CASE 2 The patient was a 53-year-old man with MM IgG K, stage IIIA. The patient achieved objective response using standard ECOG response criteria after 4 cycles of VCMPiVBAP regimen. Six months later, the patient had unequivocal progression of skeletal disease, and no response was observed despite the administration of 2 cycles of VAD and radiation therapy. On admission, the patient’s performance status (ECOG) was 4, confined to bed with compression fractures of the spine ( L S S I ) , multiple lytic bone le- sions, and severe bone pain (ECOG grade 3). Laboratory data revealed the following: hemoglobin 10 gidl and P,-microglobulin 6 mg/L (normal range 0.6-2. I). The bone marrow examination showed a mean plasma cell per- centage of 70%. After the first cycle of etoposide-CY, the patient had almost no bone pain (ECOG grade 1) and a 1 performance status. p2- Microglobulin and hemoglobin levels returned to normal range, and the bone marrow plasma cells decreased to 30%. This first cycle was adminis- tered without G-CSF, and a pneumonia associated to severe leukopenia developed. The patient received 3 cycles of maintenance and was then treated with high-dose therapy and autologous blood stem cell support. Epipodophyllotoxins and CY have shown antitumor synergism “in vitro” [3]. Using etoposide and high-dose CY with GM-CSF, Dimopoulos et al. 141 reported a 35% responses in patients VAD-resistant MM, but this treatment was associated with considerable toxicity. Leoni et al. [5] admin- istered CY by continuous infusion with teniposide and dexamethasone; they reported a response of 73%. This combination was well tolerated, with bone marrow suppression the major toxicity. We have used a similar approach in treating these two patients with VAD-resistant MM. The combination of etoposide and CY by continuous infusion is certainly capable of producing a significant subjective response just after the first cycle in heavily pretreated patients with a progressive deterioration in performance status. An objective response was produced in both patients after 3 cycles of maintenance. However, relapse developed following 7 months of maintenance in one patient. Serious infections devel- oped in both patients only when G-CSF was not used. The results of this multidrug regimen in these two patients appear to be encouraging. This combination provides a practical salvage regimen for patients with advanced MM, not eligible for aggressive treatments. ENRIC GRAU ESPERANZA REAL MARIA T. TORRECILLAS Departments of Hematology and Pharmacy, Hospital de Vinards, Vinaros, Spain REFERENCES 1. Alexanian R, Dimopoulos M: Drug therapy: The treatment of multiple myeloma. N Engl J Med 330:48&489, 1994. 2. Alexanian R, Barlogie B, Ventura G: Chemotherapy for resistant and relapsing multiple myeloma. Eur J Haematol43(suppI. 51):14&144, 1989. 3. Chang TT, Gulati SC, Chou TC, Vega R, Gandola L, Ezzat Ihrahim SM, Yopp J, Colvin M. Clarkson BD: Synergistic effect of 4-hydroperoxycyclophosphamide and etoposide on a human promyelocytic leukemia cell line (HL-60) demonstrated by computer analysis. Cancer Res 45:243&2439, 1985. 4. Dimopoulos MA, Delasalle KB, Champlin R, Alexanian R: Cyclophosphamide and etoposide therapy with GM-CSF for VAD-resistant multiple myeloma. Br J Haematol 83:24&244, 1993. 5. Leoni F, Ciolli S, Salti F, Teodori P, Ferrini PR: Teniposide, dexamethasone and continuous-infusion cyclophosphamide in advanced refractory myeloma. Br J Haematol77:18&184, 1991. On a Dramatic Response of Refractory Anemia With Excess Blasts in Transformation to 5-Azacytidine To the Editor: Myelodysplastic syndromes (MDS) are a heterogeneous group of hematologic stem cell disorders characterized by ineffective and dysplastic hematopoiesis, resulting in peripheral blood cytopenias [I]. The treatment of these disorders with conventional chemotherapy has not been very successful. This report describes a patient with refractory anemia with excess blasts in transformation (RAEB-T) and severe leucocytosis, who had a dramatic response to 5-azacytidine. A 70-year-old woman presented with fatigue and bruising in August 1991. Examination of the peripheral blood was remarkable for pancytope- nia, with normocytic anemia (Hb = 11 .O g/L), leukopenia (WBC count 2.6 X IO’iL), and thrombocytopenia (86 X 109/L). The bone marrow was hypercellular (8&90%) with 3.6% blasts, an E:G ratio of 1.0:6.5, and dysplastic maturation of the megakaryocytic and granulocytic precursors. The clinical and pathologic findings were consistent with MDS (FAB-type refractory anemia). Her past medical history was significant for breast cancer treated by modified radical mastectomy 25 years earlier; she had never received adjuvant chemotherapy or radiotherapy.
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Transcript of Etoposide, dexamethasone, and continuous-infusion cyclophosphamide with g-CSF for VAD-Resistant...
170 Letters and Correspondence
5. Hiqsonmez G, Tuncer AM, Giiler E, Tan E, Tekelioglu M: The potential role of high-dose methylprednisolone on the maturation of leukemic cells in children with acute promyelocytic leukemia (APL). Exp Hematol21:599401, 1993.
6. Hamidah HN, Chenog SK, Ainoon 0: In vivo evidence of all-trans-retinoic acid inducing maturation in acute promyelocytic leukemia. Acta Haematol 89:5&5 1, 1993.
Etoposide, Dexamethasone, and Continuous-Infusion Cyclophosphamide With G-CSF for VADResistant Multiple Myeloma
To the Editor: The combination of vincristine, doxorubicin, and dexam- ethasone (VAD) has been the treatment of choice for patients with resistant multiple myeloma (MM) [I]. This regimen carries a heavy toxicity, and more than 50% of refractory MM are unresponsive [2]. For patients with VAD-resistant MM, options for effective treatment are limited. We have used successfully the combination of etoposide and continous-infusion cyclophosphamide (CY) in two patients with VAD-resistant MM.
The treatment regimen was etoposide 80 mgim*iIV over 2 hr on days 1-2. CY 200 mgim’ by continuous IV infusion on days 1-7, dexametha- sone 40 mg IV on days 1-7, and granulocyte-colony-stimulating factor (G-CSF) 5 p,g/kg SC beginning 24 hr after the completion of CY infusion until a white blood cell (WBC) count of >lO,OOO/pI. Recycle every 4 weeks.
CASE 1
The patient was a 63-year-old man with MM IgG A , stage IIIB. The patient had progressive disease despite the administration of 2 cycles of melphalan-prednisone, 4 cycles of VCMPiVBAP regimen, and 2 cycles of VAD. On admission, the patient’s performance status (ECOG) was 4, with Hb 5 gidl, creatinine 5.9 mg/dl, calcium 12 mgidl, and a serum M-protein of 12.2 gidl. The bone marrow examination revealed 80% plasma cells. After 4 cycles of etoposide-CY, the patient had a I performance status, no transfusional requirements, normal biochemical profile, and a serum M-protein of 3.6 gidl. The bone marrow plasma cells decreased to 40%. The regimen was well tolerated, and clinical response was evident after the first cycle. The first cycle was given without G-CSF, and the patient had septicemia. Progressive disease developed following 7 months of mainte- nance; the patient died 2 months later.
CASE 2 The patient was a 53-year-old man with MM IgG K, stage IIIA. The
patient achieved objective response using standard ECOG response criteria after 4 cycles of VCMPiVBAP regimen. Six months later, the patient had unequivocal progression of skeletal disease, and no response was observed despite the administration of 2 cycles of VAD and radiation therapy. On admission, the patient’s performance status (ECOG) was 4, confined to bed with compression fractures of the spine ( L S S I ) , multiple lytic bone le- sions, and severe bone pain (ECOG grade 3). Laboratory data revealed the following: hemoglobin 10 gidl and P,-microglobulin 6 mg/L (normal range 0.6-2. I ) . The bone marrow examination showed a mean plasma cell per- centage of 70%. After the first cycle of etoposide-CY, the patient had almost no bone pain (ECOG grade 1) and a 1 performance status. p2- Microglobulin and hemoglobin levels returned to normal range, and the bone marrow plasma cells decreased to 30%. This first cycle was adminis- tered without G-CSF, and a pneumonia associated to severe leukopenia developed. The patient received 3 cycles of maintenance and was then treated with high-dose therapy and autologous blood stem cell support.
Epipodophyllotoxins and CY have shown antitumor synergism “in vitro” [3]. Using etoposide and high-dose CY with GM-CSF, Dimopoulos et al. 141 reported a 35% responses in patients VAD-resistant MM, but this treatment was associated with considerable toxicity. Leoni et al. [5] admin- istered CY by continuous infusion with teniposide and dexamethasone; they reported a response of 73%. This combination was well tolerated, with bone marrow suppression the major toxicity.
We have used a similar approach in treating these two patients with VAD-resistant MM. The combination of etoposide and CY by continuous infusion is certainly capable of producing a significant subjective response just after the first cycle in heavily pretreated patients with a progressive deterioration in performance status. An objective response was produced in both patients after 3 cycles of maintenance. However, relapse developed following 7 months of maintenance in one patient. Serious infections devel- oped in both patients only when G-CSF was not used.
The results of this multidrug regimen in these two patients appear to be encouraging. This combination provides a practical salvage regimen for patients with advanced MM, not eligible for aggressive treatments.
ENRIC GRAU ESPERANZA REAL
MARIA T. TORRECILLAS Departments of Hematology and Pharmacy, Hospital de Vinards, Vinaros, Spain
REFERENCES 1. Alexanian R, Dimopoulos M: Drug therapy: The treatment of multiple myeloma.
N Engl J Med 330:48&489, 1994. 2. Alexanian R, Barlogie B, Ventura G: Chemotherapy for resistant and relapsing
multiple myeloma. Eur J Haematol43(suppI. 51):14&144, 1989. 3. Chang TT, Gulati SC, Chou TC, Vega R, Gandola L, Ezzat Ihrahim SM, Yopp J ,
Colvin M. Clarkson BD: Synergistic effect of 4-hydroperoxycyclophosphamide and etoposide on a human promyelocytic leukemia cell line (HL-60) demonstrated by computer analysis. Cancer Res 45:243&2439, 1985.
4. Dimopoulos MA, Delasalle KB, Champlin R, Alexanian R: Cyclophosphamide and etoposide therapy with GM-CSF for VAD-resistant multiple myeloma. Br J Haematol 83:24&244, 1993.
5. Leoni F, Ciolli S, Salti F, Teodori P, Ferrini PR: Teniposide, dexamethasone and continuous-infusion cyclophosphamide in advanced refractory myeloma. Br J Haematol77:18&184, 1991.
On a Dramatic Response of Refractory Anemia With Excess Blasts in Transformation to 5-Azacytidine
To the Editor: Myelodysplastic syndromes (MDS) are a heterogeneous group of hematologic stem cell disorders characterized by ineffective and dysplastic hematopoiesis, resulting in peripheral blood cytopenias [I]. The treatment of these disorders with conventional chemotherapy has not been very successful. This report describes a patient with refractory anemia with excess blasts in transformation (RAEB-T) and severe leucocytosis, who had a dramatic response to 5-azacytidine.
A 70-year-old woman presented with fatigue and bruising in August 1991. Examination of the peripheral blood was remarkable for pancytope- nia, with normocytic anemia (Hb = 11 .O g/L), leukopenia (WBC count 2.6 X IO’iL), and thrombocytopenia (86 X 109/L). The bone marrow was hypercellular (8&90%) with 3.6% blasts, an E:G ratio of 1.0:6.5, and dysplastic maturation of the megakaryocytic and granulocytic precursors. The clinical and pathologic findings were consistent with MDS (FAB-type refractory anemia). Her past medical history was significant for breast cancer treated by modified radical mastectomy 25 years earlier; she had never received adjuvant chemotherapy or radiotherapy.
