Case Report Thrombotic Microangiopathy of Hyperacute Onset After Autologous Peripheral Blood Stem Cell Transplantation in Malignant Lymphoma

Bone Marrow Transplantation, (1998) 21, 1263–1266  1998 Stockton Press All rights reserved 0268–3369/98 $12.00 http://www.stockton-press.co.uk/bmt Case report Thrombotic microangiopathy of hyperacute onset after autologous peripheral blood stem cell transplantation in malignant lymphoma

K Togitani, K Takeyama, T Yokozawa, M Andoh, M Narabayashi, Y Kobayashi, T Takenaka and K Tobinai

Department of Medical Oncology, National Cancer Center Hospital, Tokyo, Japan

Summary: Case report

Bone marrow transplant-associated thrombotic A 52-year-old man was diagnosed as having stage IV per- microangiopathy (BMT-TM), usually associated with ipheral T cell lymphoma involving retroperitoneal lymph thrombocytopenia, microangiopathic haemolytic anae- nodes, liver, spleen, and bone marrow in May 1994. He mia (MAHA) and renal insufficiency, has been reported received several regimens of combination chemotherapy to occur approximately 5–6 months after BMT. We (MACOP-B, consisting of methotrexate, doxorubicin, report a case of relapsed malignant lymphoma compli- cyclophosphamide, vincristine, prednisolone and bleomy- cated by BMT-TM of hyperacute onset, which has never cin; CHOP, consisting of cyclophosphamide, doxorubicin, been described in the literature. Our patient, a 52-year- vincristine and prednisolone; CHOP-bleo, consisting of old male, developed MAHA with gross haematuria, CHOP with bleomycin), which produced some response, thrombocytopenia, lactate dehydrogenase elevation and but his disease progressed and he was referred to our hospi- renal insufficiency 2 days after autologous PBSC trans- tal in April 1996. Salvage chemotherapy consisting of eto- plantation following high-dose chemotherapy. Support- poside, methylprednisolone, high-dose cytarabine and cis- ive treatment, ie glucocorticoid, fresh frozen plasma and platin (ESHAP)3 produced a partial response. The harvested haemodiafiltration were given, and thereafter the BMT- PBSC which were enriched for CD34+ cells were cryopre- TM gradually improved. In heavily pretreated patients, served as previously described.4 Organ function remained caution should be exercised for possible occurrence of within normal limits before the patient received HDC the BMT-TM of hyperacute onset. with PBSCT. Keywords: thrombotic microangiopathy; hyperacute In August 1996, he was treated with high-dose carbopla- onset; PBSCT; high-dose chemotherapy tin (200 mg/m2/day (total dose 1000 mg/m2)), cyclophosphamide (1200 mg/m2/day (total dose 6000 mg/m2)), etoposide (250 mg/m2/day (total dose 1250 mg/m2)) and dexamethazone (40 mg/day (total dose 200 mg)) on 5 con- Thrombotic microangiopathy (TM) in association with secutive days (days Ϫ7toϪ3). Vomiting and diarrhoea BMT (BMT-TM) has been reported by several investi- observed during the HDC were considered maximal grade 1,2 gators. In the setting of allogeneic BMT, not only con- 2 toxicities according to the National Cancer Institute Com- ditioning therapy, but also CsA, GVHD and cytomegalo- mon Toxicity Criteria. Mild proteinuria developed on day virus (CMV) infection are incriminated as possible factors Ϫ3. A febrile episode occurred on day Ϫ2, and empiric 1,2 in the pathogenesis of BMT-TM. In autologous BMT, antibiotic therapy was started. On day 0, mild lactate 2 conditioning therapy has been proposed as a cause. dehydrogenase (LDH) elevation (566 U/l, normal range Although conditioning-associated TM is generally thought 234–484 U/l) was observed. His post-transplant course is 2 to occur approximately 5–6 months after BMT, we report shown in Figure 1. Abrupt onset anaemia (Hb 101 g/l, Ht a case of hyperacute onset (during high-dose chemotherapy 29%) and thrombocytopenia (6 × 109/l) were recognized on (HDC)) TM following autologous PBSC transplantation day 2, and other laboratory values were LDH, 1268 U/l; (PBSCT). Such hyperacute onset BMT-TM has never been haptoglobin, Ͻ0.01 g/l; direct antiglobulin test, negative; reported in the literature. prothrombin time, 10.7 s (normal range 10.8–13.0 s); acti- vated partial thromboplastin time, 27.1 s (normal range 20– 35 s); fibrin split products, normal; serum creatinine, 80 mm/l (normal range 44–97 mm/l); 2+ reaction for albumin and 3+ reaction for red blood cells in the urine; proteinuria, 8.2 g/day. A peripheral blood smear showed 6.4% schisto- Correspondence: K Tobinai, Department of Medical Oncology, National cytes, and a diagnosis of TM was made. Because severe Cancer Center Hospital, 5–1-1, Tsukiji, Chuo-ku, Tokyo 104, Japan neutropenia was persistent, we did not perform a plasma Received 3 October 1997; accepted 28 January 1998 exchange but administered four units of fresh frozen plasma Thrombotic microangiopathy of hyperacute onset K Togitani et al 1264 HDC / PBSCT

Haptoglobin FFP Prednisolone

CHDF with FUT 3000 600 LDH

2000 Creatinine 400 µ 1000 200 Creatinine ( m / l ) LDH ( U / l ) PLT transfusion 0

140 RBC transfusion 140 120 120 100

100 / l ) 80 9 Hb 80 60 PLT count PLT ( x1 0 Hb ( g / l ) 40 60 20 Plts 40 0 0 50 100 200 300 Days after PBSCT

Figure 1 Clinical course of the present patient.

(FFP) per day and prednisolone (1 mg/kg) empirically. On BMT-TM. Table 1 shows the characteristics of the 27 day 3, gross haematuria began, and we thus administered patients with BMT-TM (26 reported cases6–11 and the human haptoglobin concentrates to prevent renal toxicity present case12) who underwent autologous transplants con- due to massive intravascular haemolysis. ditioned without TBI. The median onset of the BMT-TM When his WBC recovered (5.8 × 109/l) on day 9 with G- in these cases was 5 months after transplantation, but only CSF support, he suffered from generalized edema, his body one patient conditioned with CY, BCNU and etoposide weight rose by about 10 kg, and a chest X-ray showed car- (CBV) presented with BMT-TM 11 days after PBSCT.12 diomegaly and pulmonary congestion. We therefore began The severity of BMT-TM in that patient was grade 4, continuous haemodiaﬁltration (CHDF) with nafamostat according to the grading system of BMT-TM proposed by mesilate (FUT) as an anticoagulant. After the initiation of Zeigler and colleagues.12 The patient did not respond to a the CHDF and FUT therapy, LDH values and transfusion cryosupernatant plasma exchange (PE) or to Staphylococcal requirements gradually decreased. The CHDF was stopped protein A immunoabsorption (SPAI). In our patient, the on day 38. Signs of haemolysis disappeared over 3 months onset of BMT-TM was much earlier than in the previously and the last platelet transfusion was given on day 78. The reported cases (Table 1). The severity of the BMT-TM in patient was discharged from hospital on day 169. His lab- our patient was grade 3 at diagnosis and subsequently wors- oratory values 11 months after the onset of BMT-TM were ened to grade 4 (maximal percentage of schistocytes in the as follows: Hb, 83 g/l; PLTS, 57 × 109/l; LDH, 424 U/l; peripheral blood was 11.3%). serum creatinine, 180 mm/l; BUN, 13.2 mm/l. Because the interval between the last administration of the ESHAP regimen and the onset of TM was very short in the present patient (ie 5 weeks), the anticancer agents Discussion utilized in the ESHAP regimen and the HDC could have operated additively in the pathogenesis of the BMT-TM. In Byrnes et al1 recently reviewed more than 90 cases of addition, there remains a possibility that the prior ESHAP BMT-TM. It is thought to occur at a median interval of regimen might have directly caused the TM. Vascular tox- 5–6 months after BMT, more frequently after allogeneic icity associated with some anticancer agents is well- transplantation.1,2 TBI has been reported to be an important known,13 and mitomycin C, cisplatin, carboplatin and bleo- causal factor of BMT-TM.1 Therefore, BMT-TM without mycin in conventional doses have been described as causal TBI preparation has been regarded as unusual. However, agents of TM. The acute form of cancer chemotherapy- recently Fisher and colleagues5 reported that 15 (2.6%) of associated haemolytic uremic syndrome (C-HUS) is charac- the 581 breast cancer patients who underwent autologous terized by a fulminant course with marked microangi- transplants conditioned without TBI developed late onset opathic changes, severe haemolysis and thrombocytopenia, Thrombotic microangiopathy of hyperacute onset K Togitani et al 1265 Table 1 Cases of thrombotic microangiopathy after autologous hematopoietic stem cell transplantation conditioned without TBI

Age/ Diagnosis Conditioning Onset Speciﬁc therapy Outcome Ref. Sex (months or (months or days afterPE FFP SPAI IVIg VCR days after AHSCT) onset)

58/M NHL BCNU/CY/Ara-C 6 m ++8d 6 59/M NHL BCNU/CY/Ara-C 7 m ++ 15 m* 6 45/M NHL BCNU/CY/Ara-C 6 m ++3m 6 32/F NHL BCNU/ETP/Ara-C/CY 4 m ++ 15 m* 7 44/F NHL BCNU/ETP/Ara-C/CY 3 m not speciﬁed 7 m 8 48/F Cancer of CBDCA/CY/Thiotepa 4 m + 16 m* 9 fallopian tube 36/M GCT CBDCA/Cy/Thiotepa 6 m + 3d 9 33/M HD BCNU/ETP/Ara-C/CY 6 m +++10 m* 9 34/M HD BCNU/ETP/Ara-C/CY 8 m conservative only 12 m* 10 NA Breast cancer CY/CDDP/BCNU 4 m 80 m* 5 NA Breast cancer CY/CDDP/BCNU 5 m ++ 61 m* 5 NA Breast cancer CY/CDDP/BCNU 3 m 3 m 5 NA Breast cancer CY/CDDP/BCNU 7 m +++2m 5 NA Breast cancer CY/CDDP/BCNU 6 m 7 d 5 NA Breast cancer CY/CDDP/BCNU 9 m ++ 2m 5 NA Breast cancer CY/CDDP/BCNU 3 m + 2d 5 NA Breast cancer CY/CDDP/BCNU 3 m +++2m 5 NA Breast cancer CY/CDDP/BCNU 5 m + 1m 5 NA Breast cancer CY/CDDP/BCNU 3 m ++ 1m 5 NA Breast cancer CY/CDDP/BCNU 3 m + 1m 5 NA Breast cancer CY/CDDP/BCNU 5 m ++ 6m* 5 NA Breast cancer CY/CDDP/BCNU 4 m ++2m 5 NA Breast cancer CY/CDDP/BCNU 6 m ++ 1m 5 NA Breast cancer CY/CDDP/BCNU 5 m ++ 3m* 5 40/M NHL MCNU/CBDCA/ETP/CY 4 m ++4m* 11 67/F NHL CY/BCNU/ETP 11 d ++ No response 12 52/M NHL CBDCA/CY/ETP/Dexa 2 d + 12 m* This case

M = male; F = female; NA = not applicable; NHL = non-Hodgkin’s lymphoma; GCT = germ cell tumor; HD = Hodgkin’s disease; ETP = etoposide; CBDCA = carboplatin; CDDP = cisplatin; MCNU = ranimustine; Dexa = dexamethazone; AHSCT = autologous hematopoietic stem cell transplantation; PE = plasma exchange; FFP = fresh frozen plasma; SPAI = Staphylococcal protein A immunoabsorption; IVIg = intravenous immunoglobulin; VCR = vincristine; d = day; m = month. *Indicates surviving patient. and rapidly progressive renal failure. In light of the hyper- FUT might have shown some efficacy by inhibiting acute onset and clinical severity, the BMT-TM in this complement activation.15 patient is thought to have characteristics similar to those of In conclusion, the present case indicates that BMT-TM acute form C-HUS. can occur during or immediately after HDC. In heavily Although haemolysis and elevated LDH could be multi- pretreated patients, possible occurrence of the BMT-TM of factorial and due to repeated transfusions, infection and G- hyperacute onset should be considered. CSF administration, the present case is thought to fulfil the minimum criteria of TM5 as follows: (1) evidence of microangiopathic haemolysis with schistocytes on periph- Acknowledgements eral blood smear, an elevation in serum LDH levels and a persistent decline in haematocrit; (2) sudden decrease in We thank the medical, nursing and laboratory staffs of the platelet counts which persisted for at least 2 weeks; (3) National Cancer Center Hospital for their excellent cooperation. negative direct and indirect antiglobulin tests; and (4) nega- This study is partly supported by the Grants-in-Aid for Cancer tive testing for disseminated intravascular coagulation. Research (8S-1, 9–10) from the Ministry of Health and Welfare There has been no effective therapy against fulminant of Japan. BMT-TM and acute onset C-HUS, although some pilot studies regarding cryosupernatant PE and SPAI have shown promising results.5,6,8,9,12 BMT-TM in the present patient References gradually improved after administration of FFP and glucocorticoid, and other supportive measures. We used nafamo- 1 Byrnes JJ, Hussein AM. Thrombotic microangiopathic syn- dromes after bone marrow transplantation. Cancer Invest stat mesilate (FUT) as the anticoagulant during CHDF, 1996; 14: 151–157. because it has been reported to be useful for haemodialysis 2 Pettitt AR, Clark RE. Thrombotic microangiopathy following in patients with a high risk of bleeding such as those with bone marrow transplantation. Bone Marrow Transplant 1994; thrombocytopenia.14 As the haemolysis in our patient obvi- 14: 495–504. ously improved after the initiation of CHDF (Figure 1), 3 Rodriguez MA, Cabanillas FC, Velasquez W et al. Results of Thrombotic microangiopathy of hyperacute onset K Togitani et al 1266 a salvage treatment program for relapsing lymphoma: MINE drome after high dose chemotherapy with autologous stem cell consolidated with ESHAP. J Clin Oncol 1995; 13: 1734–1741. support. Cancer 1995; 76: 2338–2342. 4 Kohno A, Takeyama K, Narabayashi M et al. Low-dose gra- 10 Raybon KB, Snyder MJ, Halvorson RD. Hemolytic uremic nulocyte colony-stimulating factor enables the efficient collec- syndrome after autologous BMT without TBI. Bone Marrow tion of peripheral blood stem cells after disease-oriented, con- Transplant 1996; 17: 897–898. ventional-dose chemotherapy for breast cancer, malignant 11 Ohno E, Ohtsuka E, Iwashita T et al. Hemolytic uremic syn- lymphoma and germ cell tumor. 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Semin Oncol 1992; 19: irradiation. Am J Nephrol 1993; 13: 167–170. 580–596. 8 Carlson K, Smedmyl B, Hagberg H et al. Hemolytic uremic 14 Akizawa T, Koshikawa S, Ota K et al. Nafamostat mesilate: syndrome and renal dysfunction following BEAC (BCNU, a regional anticoagulant for hemodialysis in patients at high etoposide, ara-C, cyclophosphamide) Ϯ TBI and autologous risk for bleeding. Nephron 1993; 64: 376–381. BMT for malignant lymphomas. Bone Marrow Transplant 15 Miyata T, Fujita Y, Inagi R et al. Effectiveness of nafamostat 1993; 11: 205–208. mesilate on glomerulonephritis in immune-complex diseases. 9 Lelie H, Baars JW, Rodenhuis S et al. Hemolytic uremic syn- Lancet 1993; 341: 1353.