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A case of blast clearance on sorafenib in relapsed FLT3-ITD acute myeloid leukemia: Evidence of efficacy continues to mount
Leukemia Research 34 (2010) e268–e269
Contents lists available at ScienceDirect
Leukemia Research journal homepage: www.elsevier.com/locate/leukres
Letter to the Editor A case of blast clearance on sorafenib in relapsed FLT3-ITD acute myeloid leukemia: Evidence of efficacy continues to mount 1. Introduction Sorafenib, a multi-targeted tyrosine kinase inhibitor FDA approved for the treatment of advanced renal cell carcinoma and hepatocellular carcinoma, inhibits the FLT3 (fms-like tyrosine kinase receptor-3) protein on the surface of acute myeloid leukemia (AML) cells and has been utilized in a compassionate use, single agent setting by German physicians to treat relapsed FLT3-ITD positive AML with success [1]. A different FLT3 inhibitor, lestaurtinib, produced negative results in relapsed FLT3-ITD positive AML [2]; however, a recent report demonstrates that more selective FLT3 inhibitors (sorafenib) have greater in vitro activity than less selective FLT3 inhibitors (lestaurtinib) in relapsed AML samples [3]. We present a case of sorafenib use in relapsed FLT3-ITD positive AML which supports both the in vitro finding and the in vivo efficacy demonstrated in the German report. 2. Case report A 48-year-old white male without significant past medical history was diagnosed with normal karyotype, FLT3-ITD positive AML after complaint of easy bruising was investigated with complete blood count with differential followed by bone marrow aspiration/biopsy. The initial complete blood count demonstrated a leukocyte count of 29,000 cells/mcL with 41% peripheral blood blasts, hemoglobin of 6.2 g/dL, and platelet count of 15,000 cells/mcL. The bone marrow had 100% cellularity with 39% blasts. Flow cytometry revealed a population of blasts expressing CD13 and CD33 with lesser expression of CD34, CD117, CD4, CD7, and HLA-DR. Enzyme cytochemistry revealed myeloperoxidase and nonspecific esterase staining in approximately 50% of blasts, indicating a myelomonocytic phenotype. Induction chemotherapy with idarubicin 12 mg/m2 intravenously (IV) daily days 1–3, cladribine 5 mg/m2 IV daily days 1–5, and cytarabine 200 mg/m2 IV daily days 1–7 was begun. A bone marrow aspiration/biopsy 6 weeks later at a time of normal complete blood count other than mild anemia with hemoglobin 11.2 g/dL demonstrated no residual leukemic blasts, and the FLT3-ITD molecular mutation was absent, indicating a morphologic and molecular complete remission. HLA typing of the patient was performed; however, a matched sibling was not available and a suitable HLA matched donor could not be found. The patient subsequently underwent an uneventful consolidation course with high dose cytarabine (3 g/m2 IV every 12 h for 12 doses) and idarubicin 12 mg/m2 IV daily days 1–3. He was readmitted 3 weeks later for a second consolidation course with the same dose of high dose cytarabine but etoposide 100 mg/m2 IV daily days 1–3 was substituted for idarubicin given a reduction of ejection 0145-2126/$ – see front matter © 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.leukres.2010.03.046
fraction from 69% pre-treatment to 53%. The patient tolerated therapy well, was discharged day 23, and on day 85 the complete blood count was normal. The patient followed in the outpatient clinic, and day 115 he was asymptomatic but complete blood count with differential revealed a leukocyte count of 18,000 cells/mcL with 33% blasts. Relapsed acute myeloid leukemia was diagnosed and he underwent a bone marrow aspiration/biopsy. The aspirate was significant for 90% cellularity with 72% blasts. The karyotype was normal and FLT3ITD mutation was present. He was not a candidate for a clinical trial at our center. The patient was hospitalized and re-induction chemotherapy with high dose cytarabine and etoposide (same dose and schedule as consolidation course #2) was initiated. Compassionate use sorafenib was obtained but therapy was not initiated. On day 14, the peripheral blood leukocyte count was 100 cells/mcL with 4% blasts; bone marrow aspiration/biopsy revealed 10–20% cellularity with 100% blasts. Interestingly, the karyotype was now abnormal in four of 11 metaphase cells from the bone marrow culture. Three of four cells contained t(14;16)(q22;q24), one of the three cells had an additional t(X;1)(p22.1;q12), and the fourth cell had a t(1;14)(q12;q22) with a t(14;7)(q32;q11.2). In the last two cells, 1q12 and 14q22 are involved in two different translocations from the original clone indicating a jumping translocation which is known to be associated with genome instability. Sorafenib at 400 mg oral daily was started after the bone marrow was performed. Peripheral blood blasts were absent on the day 15 peripheral smear, 15 h after the first dose of sorafenib. Sorafenib was increased on day 17 to 400 mg oral bid, and he tolerated therapy well with only grade 1 diarrhea. He was discharged day 23 with a leukocyte count of 600cells/mcL, absolute neutrophil count (ANC) of 520 cells/mcL, and platelet count of 11,000 cells/mcL. A mismatched double umbilical cord hematopoietic stem cell transplant was recommended given the disease relapse, but the patient decided to seek a second opinion. After several weeks, the patient agreed to the mismatched double umbilical cord hematopoietic stem cell transplant. A pretransplant bone marrow aspiration/biopsy was performed day 37 post re-induction while the patient was still platelet transfusion dependent with an ANC of 560 cells/mcL. It revealed a 5% cellular bone marrow with no residual acute myeloid leukemia by morphology. The jumping translocations seen on the day 14 bone marrow were absent with a normal karytoype, but the FLT3-ITD mutation was still present, indicating a morphologic and cytogenetic remission with evidence for disease molecularly.
3. Discussion We describe a patient who achieved morphologic and cytogenetic clearance of leukemic blasts from the peripheral blood and bone marrow with early relapsed, FLT3-ITD positive acute myeloid leukemia which had evolved to a complex karyotype. Although the
Letter to the Editor / Leukemia Research 34 (2010) e268–e269
patient still has molecular evidence of persistent FLT3 positivity, this may be a clinically important result for a patient undergoing a subsequent allogeneic hematopoietic transplant, as the status of leukemia at the time of transplantation affects likelihood of relapse. Based on the results of a prior study in which the leukemic cell mass (product of percent bone marrow biopsy cellularity and percent blasts on manual aspirate differential) on day 14 of high dose cytarabine was correlated with eventual disease outcome [4], we believe that our patient’s leukemic cell mass of 1000–2000 on day 14 was unlikely to result in complete remission with chemotherapy effect alone, although the etoposide was added in our patient’s case. The temporal profile of peripheral blood blast clearance, with the percentage of blasts in peripheral blood being 5, 16, 13, 7, 12, 3, 4, consecutively on days 8 through 14, suggested a plateau effect of the peripheral blood blast clearance with chemotherapy. The initiation of sorafenib on day 15 was temporally related to no further detectable peripheral blood blasts from that day forward. Supporting an effect of sorafenib is the clearance of peripheral blood, and, in some cases, bone marrow blasts by the German authors [1]. Importantly, a recent phase I/II study supports a potential synergistic effect of the combination of sorafenib and chemotherapy in both relapsed and untreated FLT3-ITD positive AML patients, with three out of seven relapsed and 14 out of 15 untreated patients achieving a complete remission [5]. It appears that the hints of efficacy seen in a compassionate use setting have been further confirmed, which should give hematologic oncologists a feeling of cautious optimism moving forward. Conflicts of interest All authors have no conflict of interest to report. Acknowledgements None. Funding: none. Contributions: M.F. contributed in the acquisition of data, references, data analysis and drafting the article. J.R. and P.P. are
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responsible for the important intellectual content of the article as well as final approval of version to be submitted. References [1] Metzelder S, Wang Y, Wollmer E, Wanzel M, Teichler S, Chaturvedi A, et al. Compassionate use of sorafenib in FLT3-ITD-positive acute myeloid leukemia: sustained regression before and after allogeneic stem cell transplantation. Blood 2009;113:6567–71. [2] Levis M, Ravandi F, Wang ES, Baer MR, Perl A, Coutre S, et al. Results from a randomized trial of salvage chemotherapy followed by lestaurtinib for FLT3 mutant AML patients in first relapse [abstract]. Blood, ASH Ann Meet Abstr 2009;114 [22: abstract 788]. [3] Pratz KW, Sato T, Murphy KM, Stine A, Rajkhowa T, Levis M. FLT3-mutant allelic burden and clinical status are predictive of response to FLT3 inhibitors in AML. Blood 2010;115:1425–32. [4] Preisler HD, Raza A, Azarnia N, Rakowsky I, Barcos M, Browman G, et al. Changes in the characteristics of the bone marrow during therapy for acute nonlymphocytic leukemia: relationship to response to remission induction therapy. Eur J Cancer Clin Oncol 1985;21(5):563–71. [5] Ravandi F, Cortes JE, Jones D, Faderl S, Garcia-Manero G, Konopleva MY, et al. Phase I/II study of combination therapy with sorafenib, idarubicin, and cytarabine in younger patients with Acute Myeloid Leukemia. J Clin Oncol 2010 [epublished March 8].
Mark J. Fesler ∗ John M. Richart Paul J. Petruska Department of Internal Medicine, Division of Hematology and Medical Oncology, Saint Louis University, Saint Louis, MO, USA ∗ Corresponding
author at: Department of Internal Medicine, Division of Hematology and Medical Oncology, Saint Louis University Cancer Center, 3655 Vista Avenue, West Pavilion, Saint Louis, MO 63110, USA. Tel.: +1 314 577 8854; fax: +1 314 773 1167. E-mail address: [email protected] (M.J. Fesler) 27 March 2010 Available online 24 April 2010
Contents lists available at ScienceDirect
Leukemia Research journal homepage: www.elsevier.com/locate/leukres
Letter to the Editor A case of blast clearance on sorafenib in relapsed FLT3-ITD acute myeloid leukemia: Evidence of efficacy continues to mount 1. Introduction Sorafenib, a multi-targeted tyrosine kinase inhibitor FDA approved for the treatment of advanced renal cell carcinoma and hepatocellular carcinoma, inhibits the FLT3 (fms-like tyrosine kinase receptor-3) protein on the surface of acute myeloid leukemia (AML) cells and has been utilized in a compassionate use, single agent setting by German physicians to treat relapsed FLT3-ITD positive AML with success [1]. A different FLT3 inhibitor, lestaurtinib, produced negative results in relapsed FLT3-ITD positive AML [2]; however, a recent report demonstrates that more selective FLT3 inhibitors (sorafenib) have greater in vitro activity than less selective FLT3 inhibitors (lestaurtinib) in relapsed AML samples [3]. We present a case of sorafenib use in relapsed FLT3-ITD positive AML which supports both the in vitro finding and the in vivo efficacy demonstrated in the German report. 2. Case report A 48-year-old white male without significant past medical history was diagnosed with normal karyotype, FLT3-ITD positive AML after complaint of easy bruising was investigated with complete blood count with differential followed by bone marrow aspiration/biopsy. The initial complete blood count demonstrated a leukocyte count of 29,000 cells/mcL with 41% peripheral blood blasts, hemoglobin of 6.2 g/dL, and platelet count of 15,000 cells/mcL. The bone marrow had 100% cellularity with 39% blasts. Flow cytometry revealed a population of blasts expressing CD13 and CD33 with lesser expression of CD34, CD117, CD4, CD7, and HLA-DR. Enzyme cytochemistry revealed myeloperoxidase and nonspecific esterase staining in approximately 50% of blasts, indicating a myelomonocytic phenotype. Induction chemotherapy with idarubicin 12 mg/m2 intravenously (IV) daily days 1–3, cladribine 5 mg/m2 IV daily days 1–5, and cytarabine 200 mg/m2 IV daily days 1–7 was begun. A bone marrow aspiration/biopsy 6 weeks later at a time of normal complete blood count other than mild anemia with hemoglobin 11.2 g/dL demonstrated no residual leukemic blasts, and the FLT3-ITD molecular mutation was absent, indicating a morphologic and molecular complete remission. HLA typing of the patient was performed; however, a matched sibling was not available and a suitable HLA matched donor could not be found. The patient subsequently underwent an uneventful consolidation course with high dose cytarabine (3 g/m2 IV every 12 h for 12 doses) and idarubicin 12 mg/m2 IV daily days 1–3. He was readmitted 3 weeks later for a second consolidation course with the same dose of high dose cytarabine but etoposide 100 mg/m2 IV daily days 1–3 was substituted for idarubicin given a reduction of ejection 0145-2126/$ – see front matter © 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.leukres.2010.03.046
fraction from 69% pre-treatment to 53%. The patient tolerated therapy well, was discharged day 23, and on day 85 the complete blood count was normal. The patient followed in the outpatient clinic, and day 115 he was asymptomatic but complete blood count with differential revealed a leukocyte count of 18,000 cells/mcL with 33% blasts. Relapsed acute myeloid leukemia was diagnosed and he underwent a bone marrow aspiration/biopsy. The aspirate was significant for 90% cellularity with 72% blasts. The karyotype was normal and FLT3ITD mutation was present. He was not a candidate for a clinical trial at our center. The patient was hospitalized and re-induction chemotherapy with high dose cytarabine and etoposide (same dose and schedule as consolidation course #2) was initiated. Compassionate use sorafenib was obtained but therapy was not initiated. On day 14, the peripheral blood leukocyte count was 100 cells/mcL with 4% blasts; bone marrow aspiration/biopsy revealed 10–20% cellularity with 100% blasts. Interestingly, the karyotype was now abnormal in four of 11 metaphase cells from the bone marrow culture. Three of four cells contained t(14;16)(q22;q24), one of the three cells had an additional t(X;1)(p22.1;q12), and the fourth cell had a t(1;14)(q12;q22) with a t(14;7)(q32;q11.2). In the last two cells, 1q12 and 14q22 are involved in two different translocations from the original clone indicating a jumping translocation which is known to be associated with genome instability. Sorafenib at 400 mg oral daily was started after the bone marrow was performed. Peripheral blood blasts were absent on the day 15 peripheral smear, 15 h after the first dose of sorafenib. Sorafenib was increased on day 17 to 400 mg oral bid, and he tolerated therapy well with only grade 1 diarrhea. He was discharged day 23 with a leukocyte count of 600cells/mcL, absolute neutrophil count (ANC) of 520 cells/mcL, and platelet count of 11,000 cells/mcL. A mismatched double umbilical cord hematopoietic stem cell transplant was recommended given the disease relapse, but the patient decided to seek a second opinion. After several weeks, the patient agreed to the mismatched double umbilical cord hematopoietic stem cell transplant. A pretransplant bone marrow aspiration/biopsy was performed day 37 post re-induction while the patient was still platelet transfusion dependent with an ANC of 560 cells/mcL. It revealed a 5% cellular bone marrow with no residual acute myeloid leukemia by morphology. The jumping translocations seen on the day 14 bone marrow were absent with a normal karytoype, but the FLT3-ITD mutation was still present, indicating a morphologic and cytogenetic remission with evidence for disease molecularly.
3. Discussion We describe a patient who achieved morphologic and cytogenetic clearance of leukemic blasts from the peripheral blood and bone marrow with early relapsed, FLT3-ITD positive acute myeloid leukemia which had evolved to a complex karyotype. Although the
Letter to the Editor / Leukemia Research 34 (2010) e268–e269
patient still has molecular evidence of persistent FLT3 positivity, this may be a clinically important result for a patient undergoing a subsequent allogeneic hematopoietic transplant, as the status of leukemia at the time of transplantation affects likelihood of relapse. Based on the results of a prior study in which the leukemic cell mass (product of percent bone marrow biopsy cellularity and percent blasts on manual aspirate differential) on day 14 of high dose cytarabine was correlated with eventual disease outcome [4], we believe that our patient’s leukemic cell mass of 1000–2000 on day 14 was unlikely to result in complete remission with chemotherapy effect alone, although the etoposide was added in our patient’s case. The temporal profile of peripheral blood blast clearance, with the percentage of blasts in peripheral blood being 5, 16, 13, 7, 12, 3, 4, consecutively on days 8 through 14, suggested a plateau effect of the peripheral blood blast clearance with chemotherapy. The initiation of sorafenib on day 15 was temporally related to no further detectable peripheral blood blasts from that day forward. Supporting an effect of sorafenib is the clearance of peripheral blood, and, in some cases, bone marrow blasts by the German authors [1]. Importantly, a recent phase I/II study supports a potential synergistic effect of the combination of sorafenib and chemotherapy in both relapsed and untreated FLT3-ITD positive AML patients, with three out of seven relapsed and 14 out of 15 untreated patients achieving a complete remission [5]. It appears that the hints of efficacy seen in a compassionate use setting have been further confirmed, which should give hematologic oncologists a feeling of cautious optimism moving forward. Conflicts of interest All authors have no conflict of interest to report. Acknowledgements None. Funding: none. Contributions: M.F. contributed in the acquisition of data, references, data analysis and drafting the article. J.R. and P.P. are
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responsible for the important intellectual content of the article as well as final approval of version to be submitted. References [1] Metzelder S, Wang Y, Wollmer E, Wanzel M, Teichler S, Chaturvedi A, et al. Compassionate use of sorafenib in FLT3-ITD-positive acute myeloid leukemia: sustained regression before and after allogeneic stem cell transplantation. Blood 2009;113:6567–71. [2] Levis M, Ravandi F, Wang ES, Baer MR, Perl A, Coutre S, et al. Results from a randomized trial of salvage chemotherapy followed by lestaurtinib for FLT3 mutant AML patients in first relapse [abstract]. Blood, ASH Ann Meet Abstr 2009;114 [22: abstract 788]. [3] Pratz KW, Sato T, Murphy KM, Stine A, Rajkhowa T, Levis M. FLT3-mutant allelic burden and clinical status are predictive of response to FLT3 inhibitors in AML. Blood 2010;115:1425–32. [4] Preisler HD, Raza A, Azarnia N, Rakowsky I, Barcos M, Browman G, et al. Changes in the characteristics of the bone marrow during therapy for acute nonlymphocytic leukemia: relationship to response to remission induction therapy. Eur J Cancer Clin Oncol 1985;21(5):563–71. [5] Ravandi F, Cortes JE, Jones D, Faderl S, Garcia-Manero G, Konopleva MY, et al. Phase I/II study of combination therapy with sorafenib, idarubicin, and cytarabine in younger patients with Acute Myeloid Leukemia. J Clin Oncol 2010 [epublished March 8].
Mark J. Fesler ∗ John M. Richart Paul J. Petruska Department of Internal Medicine, Division of Hematology and Medical Oncology, Saint Louis University, Saint Louis, MO, USA ∗ Corresponding
author at: Department of Internal Medicine, Division of Hematology and Medical Oncology, Saint Louis University Cancer Center, 3655 Vista Avenue, West Pavilion, Saint Louis, MO 63110, USA. Tel.: +1 314 577 8854; fax: +1 314 773 1167. E-mail address: [email protected] (M.J. Fesler) 27 March 2010 Available online 24 April 2010