Ann Hematol (2016) 95:169–171 DOI 10.1007/s00277-015-2524-7
LETTER TO THE EDITOR
Acute promyelocytic leukemia following solid organ transplantation Armin Rashidi 1 & Paul R. Conkling 2 & Stephen I. Fisher 3
Received: 28 September 2015 / Accepted: 5 October 2015 / Published online: 10 October 2015 # Springer-Verlag Berlin Heidelberg 2015
Dear Editor, One year after a cadaveric female donor renal transplantation, a 41-year-old African American man presented to a local physician with a 1-week history of fatigue. He was on tacrolimus, mycophenolic acid, and prednisone. Laboratory tests revealed pancytopenia (WBC 1.4 × 109/μL, hemoglobin 12.5 g/dL, platelets 60×109/μL). This was attributed to medication side effects, mycophenolate was discontinued, and he received filgrastim. One week later, he presented with large ecchymoses on the arms. Laboratory tests showed worsening anemia and thrombocytopenia (WBC 11.8×109/μL, hemoglobin 9.7 g/dL, platelets 41×109/μL) and evidence for disseminated intravascular coagulation (DIC; activated PTT 24 s, INR 1.3, fibrinogen 114 mg/dL, and positive D-dimer). Peripheral blood smear (Fig. 1 inset) and flow cytometry showed 70 % neoplastic promyelocytes with Auer rods that were positive for myeloperoxidase, CD13, CD33, CD34[subset], and CD117[dim] and negative for CD15 and HLA-DR. A diagnosis of acute promyelocytic leukemia (APL) was entertained. All-trans retinoic acid and idarubicin were initiated [1]. Examination of the bone marrow was conf i r m a t o r y a n d t h e k a r y o t y p e w a s 4 6 , X Y, t(15;17)(q24.1;q21)[20]. Fluorescence in situ hybridization
showed a PML-RARA fusion in 71 % and a RARA breakapart in 86 % of cells (Fig. 1). Our patient is the 11th reported case of post-transplant APL (PT-APL), arbitrarily defined as APL occurring after solid organ transplantation (Table 1). Males were more commonly affected (8 of 11 cases) and the median (range) age at diagnosis of PT-APL was 50 (14–62) years. Five cases occurred after renal and six after liver transplantation with a median (range) interval between transplantation and the diagnosis of PT-APL of 2 (1–13) years. Bleeding (7 of 11 cases) was the most common presentation. All patients were on immunosuppressive medication at presentation, consistent with the proposed mechanisms involved in post-transplantation acute myeloid leukemia in general [2], most importantly impaired immune surveillance. The disease was high-risk [3] in 2 of the 10
* Armin Rashidi [email protected] 1
Division of Oncology, Washington University School of Medicine, 660 S. Euclid Ave., Campus Box 8056, St. Louis, MO 63110, USA
2
Virginia Oncology Associates, Eastern Virginia Medical School, Norfolk, VA, USA
3
Pathology Sciences Medical Group, Sentara Laboratory Services, Norfolk, VA, USA
Fig. 1 Fluorescence in situ hybridization and peripheral blood smear. Fluorescence in situ hybridization using a dual-color dual-fusion translocation probe showing t(15;17). The inset shows a leukemic promyelocyte with multiple cytoplasmic Auer rods and many azurophilic granules
170
Ann Hematol (2016) 95:169–171
Table 1
Summary of cases of APL following solid organ transplantation
Ref.
Age/sex/organ/ interval
Presentation
IST
WBC/Hb/Plt/DIC Induction
Outcome
Comments
[4]
41/F/kidney/13 years
Bleeding
GC, Aza
1.5/10/90/NA
Chemo
Death (3.5 m)
add(8)(p21), der(21;21)(q10;q10)
[5]
57/F/liver/2 years
Fatigue, diarrhea
GC, CSA
5.2/10.7/41/+
ATRA
Early deatha
ATRA syndrome
[6]
50/M/liver/2 years
Infection
GC, Tac
1/11/65/+
ATRA/chemo
Early deatha
–
[7]
50/M/kidney/10 years Dyspnea, bleeding
GC, CSA, Aza 8.9/7.1/19/NA
ATRA/chemo
CR (3.3 years) +8,t(13;22)(q12;q13), relapse
[8]
41/M/liver/NA
NA
GC, CSA
1.8/NA/NA/NA
ATRA/chemo
CR (48 m)
–
[9]
14/F/liver/2 years
Tac
77.5/9.8/12/+
ATRA/chemo
CR (14 m)
ATRA syndrome
GC
Pancytopenia, NA
inv(16)
[10]
62/M/liver/6 years
Fatigue, fever, bleeding N/A
ATRA/chemo
CR (14 m)
[11]
41/M/kidney/2 years
Bleeding, weight loss GC, MMF, Tac 1.4/7.4/15/NA
ATRA/chemo
CR (11 m)
–
[12]
50/M/liver/7 years
Bleeding
Tac
ATRA/ATO/chemo CR (22 m)
–
[13]
54/M/kidney/2 years
Bleeding, jaundice
GC, MMF, Tac NA
ATRA/ATO/chemo CR (18 m)
Donor-derived, extramedullary
Fatigue, bleeding
GC, MMF, Tac 1.4/12.5/60/NA
ATRA/chemo
–
Our case 41/M/kidney/1 year
15.4/13.9/103/+
NA
ATO arsenic trioxide, ATRA all-trans retinoic acid, Aza azathioprine, CR complete remission, CSA cyclosporine, DIC disseminated intravascular coagulation (laboratory and/or clinical), F female, GC glucocorticoids, Hb hemoglobin (g/dL), IST immunosuppressive treatment, m month, M male, MMF mycophenolate mofetil, NA not available, Plt platelets (×109 /μL), Tac tacrolimus, WBC white blood cells (×109 /μL) a
Death within 30 days of diagnosis
patients. All four patients with available coagulation results had DIC at presentation. Three patients had additional cytogenetic abnormalities. Induction included ATRA and chemotherapy in seven patients, ATRA, arsenic trioxide (ATO) and chemotherapy in two patients, ATRA alone in one patient, and chemotherapy alone in one patient. Two patients developed ATRA syndrome, one of whom died shortly afterwards and the other one achieved a durable remission. Early death occurred in two patients, and one patient died 3.5 months after diagnosis while in remission. One patient relapsed but was successfully re-treated and achieved a durable remission. In conclusion, we reported the 11th case of APL following solid organ transplantation. The prognosis of patients who survive the initial period after diagnosis seems to be favorable although the small sample size precludes any definitive conclusion. A high degree of vigilance needs to be practiced when patients with a history of solid organ transplantation develop unexplained cytopenias. Given the high fatality of APL when diagnosed late and not treated immediately, any delay in diagnosis may result in catastrophic bleeding and death.
References 1.
2.
3.
4. 5.
6. 7.
8.
Acknowledgments The authors thank Drs. Jennifer Winters and Mark Shenkin for providing the photomicrographs. 9. Compliance with ethical standards Conflict of interest The authors declare that they have no conflict of interest. Funding None
10.
Avvisati G, Lo-Coco F, Paoloni FP et al (2011) AIDA 0493 protocol for newly diagnosed acute promyelocytic leukemia: very long-term results and role of maintenance. Blood 117: 4716–4725 Rashidi A, Fisher SI (2014) Acute myeloid leukemia following solid organ transplantation: entity or novelty? Eur J Haematol 92: 459–466 Powell BL, Moser B, Stock W et al (2010) Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710. Blood 116:3751–3757 Subar M, Gucalp R, Benstein J et al (1996) Acute leukaemia following renal transplantation. Med Oncol 13:9–13 Bodo I, Peters M, Radich JP et al (1999) Donor-derived acute promyelocytic leukemia in a liver-transplant recipient. N Engl J Med 341:807–813 Doti CA, Gondolesi GE, Sheiner PA et al (2001) Leukemia after liver transplant. Transplantation 72:1643–1646 Specchia G, Storlazzi CT, Cuneo A et al (2001) Acute promyelocytic leukemia with additional chromosome abnormalities in a renal transplant case. Ann Hematol 80:246– 250 Camos M, Esteve J, Rimola A et al (2004) Increased incidence of acute myeloid leukemia after liver transplantation? Description of three new cases and review of the literature. Transplantation 77: 311–313 Sato T, Kobayashi R, Iguchi A et al (2005) Acute promyelocytic leukemia after living donor partial orthotopic liver transplantation in two Japanese girls. Leuk Lymphoma 46:1057–1060 Cho YU, Chi HS, Park CJ et al (2008) Two cases of postliver transplant acute myeloid leukemia in Korean adults: review of bibliographies and comparison with post-renal
Ann Hematol (2016) 95:169–171
11.
transplant acute myeloid leukemia. Ann Hematol 87:513– 514 Lai CP, Chang CC, Chung CY, Chen ML (2011) Unusual acute promyelocytic leukemia following de novo renal transplant: case report and literature review. Clin Nephrol 75(Suppl 1):27–31
171 12. 13.
Liu M, Liu J, Liu L et al (2013) A case report of acute myeloid leukemia after liver transplantation. Acta Haematol 129:225–228 Alhuraiji A, Chebbo W, El-Gohary G et al (2015) Donor-derived extramedullary acute promyelocytic leukemia post kidney transplant. Ann Hematol 94:505–507
LETTER TO THE EDITOR
Acute promyelocytic leukemia following solid organ transplantation Armin Rashidi 1 & Paul R. Conkling 2 & Stephen I. Fisher 3
Received: 28 September 2015 / Accepted: 5 October 2015 / Published online: 10 October 2015 # Springer-Verlag Berlin Heidelberg 2015
Dear Editor, One year after a cadaveric female donor renal transplantation, a 41-year-old African American man presented to a local physician with a 1-week history of fatigue. He was on tacrolimus, mycophenolic acid, and prednisone. Laboratory tests revealed pancytopenia (WBC 1.4 × 109/μL, hemoglobin 12.5 g/dL, platelets 60×109/μL). This was attributed to medication side effects, mycophenolate was discontinued, and he received filgrastim. One week later, he presented with large ecchymoses on the arms. Laboratory tests showed worsening anemia and thrombocytopenia (WBC 11.8×109/μL, hemoglobin 9.7 g/dL, platelets 41×109/μL) and evidence for disseminated intravascular coagulation (DIC; activated PTT 24 s, INR 1.3, fibrinogen 114 mg/dL, and positive D-dimer). Peripheral blood smear (Fig. 1 inset) and flow cytometry showed 70 % neoplastic promyelocytes with Auer rods that were positive for myeloperoxidase, CD13, CD33, CD34[subset], and CD117[dim] and negative for CD15 and HLA-DR. A diagnosis of acute promyelocytic leukemia (APL) was entertained. All-trans retinoic acid and idarubicin were initiated [1]. Examination of the bone marrow was conf i r m a t o r y a n d t h e k a r y o t y p e w a s 4 6 , X Y, t(15;17)(q24.1;q21)[20]. Fluorescence in situ hybridization
showed a PML-RARA fusion in 71 % and a RARA breakapart in 86 % of cells (Fig. 1). Our patient is the 11th reported case of post-transplant APL (PT-APL), arbitrarily defined as APL occurring after solid organ transplantation (Table 1). Males were more commonly affected (8 of 11 cases) and the median (range) age at diagnosis of PT-APL was 50 (14–62) years. Five cases occurred after renal and six after liver transplantation with a median (range) interval between transplantation and the diagnosis of PT-APL of 2 (1–13) years. Bleeding (7 of 11 cases) was the most common presentation. All patients were on immunosuppressive medication at presentation, consistent with the proposed mechanisms involved in post-transplantation acute myeloid leukemia in general [2], most importantly impaired immune surveillance. The disease was high-risk [3] in 2 of the 10
* Armin Rashidi [email protected] 1
Division of Oncology, Washington University School of Medicine, 660 S. Euclid Ave., Campus Box 8056, St. Louis, MO 63110, USA
2
Virginia Oncology Associates, Eastern Virginia Medical School, Norfolk, VA, USA
3
Pathology Sciences Medical Group, Sentara Laboratory Services, Norfolk, VA, USA
Fig. 1 Fluorescence in situ hybridization and peripheral blood smear. Fluorescence in situ hybridization using a dual-color dual-fusion translocation probe showing t(15;17). The inset shows a leukemic promyelocyte with multiple cytoplasmic Auer rods and many azurophilic granules
170
Ann Hematol (2016) 95:169–171
Table 1
Summary of cases of APL following solid organ transplantation
Ref.
Age/sex/organ/ interval
Presentation
IST
WBC/Hb/Plt/DIC Induction
Outcome
Comments
[4]
41/F/kidney/13 years
Bleeding
GC, Aza
1.5/10/90/NA
Chemo
Death (3.5 m)
add(8)(p21), der(21;21)(q10;q10)
[5]
57/F/liver/2 years
Fatigue, diarrhea
GC, CSA
5.2/10.7/41/+
ATRA
Early deatha
ATRA syndrome
[6]
50/M/liver/2 years
Infection
GC, Tac
1/11/65/+
ATRA/chemo
Early deatha
–
[7]
50/M/kidney/10 years Dyspnea, bleeding
GC, CSA, Aza 8.9/7.1/19/NA
ATRA/chemo
CR (3.3 years) +8,t(13;22)(q12;q13), relapse
[8]
41/M/liver/NA
NA
GC, CSA
1.8/NA/NA/NA
ATRA/chemo
CR (48 m)
–
[9]
14/F/liver/2 years
Tac
77.5/9.8/12/+
ATRA/chemo
CR (14 m)
ATRA syndrome
GC
Pancytopenia, NA
inv(16)
[10]
62/M/liver/6 years
Fatigue, fever, bleeding N/A
ATRA/chemo
CR (14 m)
[11]
41/M/kidney/2 years
Bleeding, weight loss GC, MMF, Tac 1.4/7.4/15/NA
ATRA/chemo
CR (11 m)
–
[12]
50/M/liver/7 years
Bleeding
Tac
ATRA/ATO/chemo CR (22 m)
–
[13]
54/M/kidney/2 years
Bleeding, jaundice
GC, MMF, Tac NA
ATRA/ATO/chemo CR (18 m)
Donor-derived, extramedullary
Fatigue, bleeding
GC, MMF, Tac 1.4/12.5/60/NA
ATRA/chemo
–
Our case 41/M/kidney/1 year
15.4/13.9/103/+
NA
ATO arsenic trioxide, ATRA all-trans retinoic acid, Aza azathioprine, CR complete remission, CSA cyclosporine, DIC disseminated intravascular coagulation (laboratory and/or clinical), F female, GC glucocorticoids, Hb hemoglobin (g/dL), IST immunosuppressive treatment, m month, M male, MMF mycophenolate mofetil, NA not available, Plt platelets (×109 /μL), Tac tacrolimus, WBC white blood cells (×109 /μL) a
Death within 30 days of diagnosis
patients. All four patients with available coagulation results had DIC at presentation. Three patients had additional cytogenetic abnormalities. Induction included ATRA and chemotherapy in seven patients, ATRA, arsenic trioxide (ATO) and chemotherapy in two patients, ATRA alone in one patient, and chemotherapy alone in one patient. Two patients developed ATRA syndrome, one of whom died shortly afterwards and the other one achieved a durable remission. Early death occurred in two patients, and one patient died 3.5 months after diagnosis while in remission. One patient relapsed but was successfully re-treated and achieved a durable remission. In conclusion, we reported the 11th case of APL following solid organ transplantation. The prognosis of patients who survive the initial period after diagnosis seems to be favorable although the small sample size precludes any definitive conclusion. A high degree of vigilance needs to be practiced when patients with a history of solid organ transplantation develop unexplained cytopenias. Given the high fatality of APL when diagnosed late and not treated immediately, any delay in diagnosis may result in catastrophic bleeding and death.
References 1.
2.
3.
4. 5.
6. 7.
8.
Acknowledgments The authors thank Drs. Jennifer Winters and Mark Shenkin for providing the photomicrographs. 9. Compliance with ethical standards Conflict of interest The authors declare that they have no conflict of interest. Funding None
10.
Avvisati G, Lo-Coco F, Paoloni FP et al (2011) AIDA 0493 protocol for newly diagnosed acute promyelocytic leukemia: very long-term results and role of maintenance. Blood 117: 4716–4725 Rashidi A, Fisher SI (2014) Acute myeloid leukemia following solid organ transplantation: entity or novelty? Eur J Haematol 92: 459–466 Powell BL, Moser B, Stock W et al (2010) Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710. Blood 116:3751–3757 Subar M, Gucalp R, Benstein J et al (1996) Acute leukaemia following renal transplantation. Med Oncol 13:9–13 Bodo I, Peters M, Radich JP et al (1999) Donor-derived acute promyelocytic leukemia in a liver-transplant recipient. N Engl J Med 341:807–813 Doti CA, Gondolesi GE, Sheiner PA et al (2001) Leukemia after liver transplant. Transplantation 72:1643–1646 Specchia G, Storlazzi CT, Cuneo A et al (2001) Acute promyelocytic leukemia with additional chromosome abnormalities in a renal transplant case. Ann Hematol 80:246– 250 Camos M, Esteve J, Rimola A et al (2004) Increased incidence of acute myeloid leukemia after liver transplantation? Description of three new cases and review of the literature. Transplantation 77: 311–313 Sato T, Kobayashi R, Iguchi A et al (2005) Acute promyelocytic leukemia after living donor partial orthotopic liver transplantation in two Japanese girls. Leuk Lymphoma 46:1057–1060 Cho YU, Chi HS, Park CJ et al (2008) Two cases of postliver transplant acute myeloid leukemia in Korean adults: review of bibliographies and comparison with post-renal
Ann Hematol (2016) 95:169–171
11.
transplant acute myeloid leukemia. Ann Hematol 87:513– 514 Lai CP, Chang CC, Chung CY, Chen ML (2011) Unusual acute promyelocytic leukemia following de novo renal transplant: case report and literature review. Clin Nephrol 75(Suppl 1):27–31
171 12. 13.
Liu M, Liu J, Liu L et al (2013) A case report of acute myeloid leukemia after liver transplantation. Acta Haematol 129:225–228 Alhuraiji A, Chebbo W, El-Gohary G et al (2015) Donor-derived extramedullary acute promyelocytic leukemia post kidney transplant. Ann Hematol 94:505–507
