Bone Marrow Transplantation (2003) 32, 273–278 & 2003 Nature Publishing Group All rights reserved 0268-3369/03 $25.00 www.nature.com/bmt Acute Leukaemia Stem cell transplantation after salvage therapy with high-dose and amsacrine in adults with high-risk leukaemia

S Tauro1, P Shankaranarayana1, IC Nitu-Whalley2, N Duncan1, G Begum3, JIOCraig 2, RE Marcus2, CF Craddock1 and P Mahendra1

1Bone Marrow Transplant Unit, University Hospital, Birmingham, UK; 2Department of Haematology, Addenbrookes Hospital, Cambridge, UK; and 3Clinical Trials Unit, CRUK Institute of Cancer Studies, Birmingham, UK

Summary: Disease-free survival (DFS) is even poorer in patients developing the blastic phase of chronic myeloid leukaemia Stem cell transplantation (SCT) may be the only curative (CML)3 and those with myelodysplastic syndromes option for patients with relapsed or refractory leukaemia, (MDS),4 and it is common for the disease to be refractory that is,high-risk (HR) leukaemia. Several salvage regi- to standard . Attempts have been made to mens have been used to cytoreduce disease before SCT, risk stratify patients at diagnosis based on characteristic but disease progression or treatment toxicity limits cytogenetic or molecular markers that predict disease numbers of patients receiving SCT. Here,we report our response to treatment, so that those with an increased experience with high-dose cytarabine and amsacrine (Ara- probability of relapse, that is, high-risk (HR) leukaemia amsa) to salvage patients with HR-leukaemia in the may be treated more intensively after induction or context of SCT. A total of 34 patients with HR-leukaemia consolidation therapy.5,6 Nevertheless, a large proportion (20 AML,12 ALL,two advanced CML) received 3 g/m 2/ of patients with HR disease continue to be identified by a day cytarabine for 5 days and amsacrine 200 mg/m2/day failure to respond to standard induction chemotherapy for 3 days. Disease response was observed in 62% of (refractory leukaemia) or disease recurrence following patients. Toxicity was limited to neutropenic fever,one complete remission (CR). patient developed cerebellar toxicity and there was one A number of salvage chemotherapeutic regimens have treatment-related death. A total of 17 patients proceeded been developed in the last 15 years to improve outcomes in to SCT (12 allografts and five autografts). Median patients with HR-leukaemia.7–10 Most regimens contain survival (OS) of all patients was 10.8 months (95% CI cytarabine (Ara-C) at low, intermediate or high doses, 7.8–21). Patients who were consolidated with SCT after along with , amsacrine (amsa), , salvage therapy had a superior median OS of 29.4 months or fludarabine. Although randomised (95% CI 12.5–upper limit not reached, n ¼ 17) than those studies comparing the ability of these different regimens who did not receive SCT (6.7 months,CI 1.5–8.6, to induce CR are lacking, the proportion of patients who Po0.0001). Median disease-free survival with SCT (23 achieve remission, the duration of remission and overall months) was higher than after treatment with salvage survival (OS) appear to be similar in different reports. chemotherapy alone (6.7 months, P ¼ 0.0002). Thus Ara- While response rates (CR2) of up to 89% can be achieved amsa can be used effectively to salvage HR-leukaemia, in patients with AML in first relapse with different enabling further consolidation with SCT. chemotherapy regimens, median survival is only 12 Bone Marrow Transplantation (2003) 32, 273–278. months.10 doi:10.1038/sj.bmt.1704113 In an attempt to improve long-term outcome in patients Keywords: salvage treatment; transplantation; high-risk with HR-leukaemia, stem cell transplantation (SCT) with leukaemia; relapse; refractory an allograft or autograft is the favoured approach, depending on age, performance status and availability of a suitable donor.11,12 Disease relapse, nevertheless, remains a problem even after SCT. It has been suggested that post- transplant outcome may depend on disease status at the Disease relapse after chemotherapy is common in adults time of SCT,12,13 and that patients in haematological with acute myeloid leukaemia (AML) and acute lympho- remission at the time of transplant have superior DFS blastic leukaemia (ALL) and 5-year survival in patients 1,2 and OS. Thus, in an attempt to improve post-transplant treated with chemotherapy alone is unsatisfactory. outcomes, ‘salvage’ regimens have been used to reduce the leukaemic cell burden prior to SCT. In this study, we have retrospectively examined the use of Correspondence: Dr P Mahendra, Bone Marrow Transplant Unit, high-dose Ara-C and amsacrine (Ara-amsa) as a salvage University Hospital Birmingham, NHS Trust, Edgbaston, Birmingham B15 2TH, UK regimen in patients with HR-leukaemia treated at the two Received 16 December 2002; accepted 10 February 2003 participating centres. The use of Ara-amsa to salvage Salvage therapy and transplantation in high-risk leukaemia S Tauro et al 274 refractory or relapsed leukaemia was described over 14 End points years ago7 and this regimen is used extensively in different Duration of survival (OS) and DFS were the end points of centres. Nevertheless, there are not many reports on the study. OS was measured from the time interval between outcomes of patients with HR-leukaemia salvaged with the date of salvage with Ara-amsa until the date of death or Ara-amsa prior to consolidation with SCT. Here, we have last follow-up. DFS was calculated from the date of Ara- studied the efficacy and toxicity of Ara-amsa in the context amsa to the date of relapse (for patients who achieved CR of SCT, and have compared our results with those reported after salvage therapy), death from any cause or last follow- with the use of other salvage regimens prior to transplanta- up for survivors. Treatment-related mortality (TRM) was tion. defined as death occurring in patients in continuing CR.

Patients and methods Statistical methods Survival curves were constructed using the method of Patients Kaplan and Meier and the log-rank test was used to assess Data on patients with HR-leukaemia treated with Ara- differences between groups. Data were analysed using the amsa between 1987 and 2001 at the two centres participat- statistical software SAS (SAS Institute, SAS Circle, North ing in this study were reviewed retrospectively. Patients Carolina, USA). were classed as having HR-disease if they failed to enter CR after two or more courses of induction therapy (primary refractory disease), had relapsed disease after initial CR1 Results with standard induction treatment or if there was a myeloproliferative disorder or myelodysplastic syndrome Patient details preceding the onset of acute leukaemia. Morphological, A total of 34 patients with HR-leukaemia were treated with immunophenotypic and cytogenetic analysis of bone high-dose Ara-C and amsacrine between 1987 and 2001. marrow was performed in all cases at diagnosis as well as Patient characteristics are shown in Table 1. There were 20 to assess response to treatment. males and 14 females with a median age of 28 years (range CR was defined by the presence of a blast cell population 18–63). A total of 12 patients were diagnosed with ALL, 20 of less than 5% of marrow nucleated cells in the presence with AML (including AML M3, HR-MDS and secondary of morphologically normal trilineage haemopoiesis in the leukaemia) and two patients with accelerated phase and marrow. Disease relapse was diagnosed by the re-emer- lymphoid blast transformation of CML, respectively. gence of blasts (45%) in the marrow after an initial CR. Cytogenetic abnormalities were detected in 16 patients The presence of X5% but o30% blasts in the marrow with AML (including t(15;17) in AML M3) and five after treatment indicated partial remission (PR), and patients with ALL (Table 1). One patient had relapsed after patients with persistent myelodysplasia despite the presence an autograft (no. 17), while another (no. 21) with of less than 5% blasts were regarded as having refractory recurrence of ALL had previously received two allografts. disease. All newly diagnosed patients received induction chemother- apy in the context of the Medical Research Council Schedule of salvage regimen (MRC), UK led multicentre clinical trials (Table 1). Patients with HR-leukaemia were treated with amsacrine 200 mg/m2 daily for 3 days and, concurrently, 3 g/m2 Ara-C Response to induction therapy once daily for 5 days. Adjustments in dosage were made if A total of 33 patients were treated with primary induction patients had impaired hepatic or renal function. Amsacrine chemotherapy; one with MDS/sAML (no. 7) had received was infused over 45 min and Ara-C was administered only blood product support. Of the 33 treated patients, over 3 h, with a gap of 24 h between successive doses. 23 (70%) had responsive disease (22 CR +1 PR) and Ophthalmic solution of prednisolone (0.5%) was instilled in 10 (30%) had primary refractory leukaemia (Table 2). both eyes every 2 h from day 1 of treatment until 5 days All patients with ALL had chemosensitive disease (11 CR after completion of chemotherapy, as prophylaxis against and 1 PR), eight patients with AML were refractory to Ara-C-induced conjunctivitis. induction chemotherapy. Both patients with advanced CML also had refractory disease. The median duration to Transplantation after salvage chemotherapy relapse from last CR was 29 months (range 1–89). The two patients who had relapsed after previous SCT (nos. 17 and Following treatment with Ara-amsa, patients with an 21) had been in CR for 89 months (post autograft) and 35 available HLA-matched sibling or unrelated donor received months (post allograft), respectively. an allograft if they were less than 55 years old with good performance status. An autograft was performed in Response to salvage therapy patients who were less than 70 years old, with good performance status, but not eligible for an allograft. Time Following treatment with Ara-amsa, 19/34 (56%) achieved to transplantation was calculated from the date of salvage CR while two patients entered PR (Table 2). Of these therapy. patients with chemoresponsive disease, Ara-amsa had been

Bone Marrow Transplantation Salvage therapy and transplantation in high-risk leukaemia S Tauro et al 275 Table 1 Patient characteristics and induction chemotherapy

No. Age Sex Diagnosis Cytogenetics Induction treatment 1 20 M ALL Normal UKALL X 2 47 F AML(M3) t(15;17) AML X 3 17 F AML(M3) t(15;17) AML X 4 28 M B null ALL Normal UKALL XII 5 22 F T-ALL Normal UKALL XII 6 22 F AML Complex hyperdiploidy AML 12 del 11q,À17,+21+2 7 45 M sAML Complex Supportive 8 35 F AML Normal AML X 9 20 M Pre-B ALL Normal UKALL XII 10 60 M AML t(8;21) AML X 11 24 M ALL High hyperdiploid UKALL XII 12 49 F sAML Unidentified marker and À21 AML 12 13 18 F CML acc ph t(9;17;22) Hydroxyurea, interferon, splenectomy 14 24 M ALL Normal UKALL XII 15 18 F ALL Failed UKALL XII 16 48 M ALL Not available UKALL X 17 42 M sAML t(9;13) AML X 18 33 M ALL Philadelphia positive UKALL XII 19 29 F AML Normal AML X 20 54 F sAML Deletion 13, trisomy 8 AML 12 21 34 M ALL 6qÀ, 11qÀ UKALL X 22 25 F AML Trisomy 8 AML X 23 51 F AML Trisomy 11 AML 12 24 63 M sAML Normal AML 12 25 31 M AML Inv 3, À5 and monosomy 7 AML 12 26 28 M sAML Monosomy 7, t(2;3) AML 12 27 18 M CMLlym Variant Philadelphia Chr UKALL 12 28 18 F AML t(8;21) +del 9q+21 AML 12 29 15 F ALL 7qÀ, amplification AML1 UKALL 12 30 31 M AML Inversion 16 AML X 31 20 M sAML Normal AML 12 32 17 M ALL Del À9p UKALL 12 33 18 M AML(M3) t(15;17) AML 10 34 31 M AML inv 3 AML 12

used as a second-line salvage therapy owing to failure of had drug-rash and nephrotoxicity. The dose of Ara-amsa FLAG and , cytarabine and thioguanine had to be reduced by half and one-third in two patients, (DAT) in one patient (no. 12), cytarabine, doxorubicin respectively, (nos. 2 and 18) during their second course of and etoposide (ADE) and ATRA in another (no. 3) and salvage treatment. phase I induction of UKALL X in a third patient (no. 15). One patient died in remission within 2 months of A total of 14 patients were treated with two courses of receiving salvage treatment (TRM), although the definitive salvage chemotherapy: 10/14 attained CR after one course, cause of death could not be established. one after two courses and three patients had refractory disease. Of the patients with disease response to Ara-amsa, Further treatment 12 had AML (four with primary refractory disease and eight patients in first relapse), eight had ALL and one had After salvage therapy, two patients with chemoresponsive been diagnosed as CML in lymphoid blast crisis. Thus, disease (nos. 1 and 4) were consolidated further with phase 62% of all patients (60% of those with AML and 67% of 1 induction chemotherapy of UKALL 12, along with ALL) exhibited a response to Ara-amsa, but 13 patients intrathecal , whereas one patient (no. 9) was (38%), including five with primary refractory leukaemia, treated with phase 2 induction (UKALL 12). These patients were refractory to salvage treatment. subsequently proceeded to SCT. One patient (no. 18) had a short-lived CR post-Ara-amsa (5 months), but was Toxicity successfully reinduced with FLAG-, achieved CR with and proceeded to SCT. Other patients with Pyrexial episodes (X381C equivalent to a WHOtoxicity refractory disease, however failed to respond to second of Xgrade 2) were a common occurrence in all patients. salvage with ADE (nos. 7 and 13) or FLAG (nos. 6, 11 Culture-positive fevers were, however, uncommon, and 25). although Streptococcus causing meningoencephalitis, and A total of 17 patients (50% of those treated with the sepsis from pseudomonas and enterococcus (VRE) were salvage regimen) proceeded to SCT with an allograft or identified in three patients. Nonhaematological toxicity autograft (Table 2). These included 10 patients with AML included cerebellar toxicity (no. 26) and one patient each and seven patients with ALL. A total of 12 patients

Bone Marrow Transplantation Salvage therapy and transplantation in high-risk leukaemia S Tauro et al 276 Table 2 Duration of remission prior to disease relapse requiring salvage treatment with high-dose Ara-C and amsacrine in patients with HR-leukaemia and outcomes of postsalvage therapy, including details of consolidation with SCT

No. Duration of remission Disease status Transplantation Status at last Cause of death (months) postsalvage follow-up

1 38 CR Siba allograft Alive N/Ab 2 17 CR Autograft Alive N/A 3 18 CR Autograft Alive N/A 4 52 CR Autograft Alive N/A 5 4 PR Sib allograft Dead Disease 6 4 Refractory No Dead Disease 7 N/A Refractory No Dead Disease 8 36 CR No Dead NKc 9 31 CR Autograft Alive N/A 10 27 CR No Alive N/A 11 11 Refractory No Alive N/A 12 Refractory Refractory Sib allograft Alive N/A 13 Refractory Refractory No Dead Disease 14 5 Refractory No Dead Disease 15 48 Refractory No Dead Disease 16 55 Refractory No Dead Disease 17 89 Refractory No Dead Disease 18 PR CR MUD Dead Disease 19 12 CR No Dead Disease 20 Refractory CR No Dead Disease 21 78 PR No Dead Disease 22 31 Refractory Autograft Dead Disease 23 Refractory CR Sib allograft Dead Disease 24 Refractory CR No Dead Disease 25 Refractory Refractory No Dead Disease 26 Refractory Refractory No Dead Disease 27. Refractory CR No Dead Disease 28 8 CR MUDd allograft Alive N/A 29 36 CR Sib allograft Alive N/A 30 8 CR MUD allograft Dead Disease 31 Refractory CR MUD allograft Dead Disease 32 36 CR MUD allograft Dead Disease 33 13 CR MUD allograft Alive N/A 34 Refractory Refractory Sib allograft Dead Disease

aSibling. bNot applicable. cNot known. dMatched unrelated donor.

Table 3 Pretransplant conditioning and timing of SCT in relation received an allograft: six from an HLA-matched sibling and to salvage therapy with Ara-amsa in adults with HR-leukaemia six from an unrelated donor (four AML and one ALL). No. Conditioning Timing of SCT The remaining five patients were treated with autologous (months) transplantation. The median time to SCT was 4 months (range 2–10) from the date of salvage therapy (date of first 1 TBIa/ 6 2 Short BEMb 4 cycle in patients who received two). Details of conditioning 3 Short BEM 2 regimens used for pretransplant conditioning are shown in 4 TBI/etoposide 4 Table 3. Two patients had refractory disease (with normal 5 TBI/cyclophosphamide 4 blood counts) at the time of myeloablative therapy: one 9 TBI/etoposide 4 12 Busulphan/cyclophosphamide 10 received an allograft and the other, an autograft. 18 TBI/cyclophosphamide 8 Of the patients not treated with SCT, 11 had refractory 22 TBI/cyclophosphamide 2 or relapsed disease after Ara-amsa, three did not have 23 //CAMPATHc 2 autologous stem cells or a stem cell donor and one had 28 TBI/cyclophosphamide 2 previously received a sibling allograft on two occasions. 29 TBI/cyclophosphamide 2 30 TBI/cyclophosphamide 4 One patient declined treatment with SCT, while another 31 TBI/cyclophosphamide 5 died in CR (TRM). 32 TBI/cyclophosphamide 4 33 TBI/cyclophosphamide 3 34 TBI/cyclophosphamide 2 Outcomes

aTotal body irradiation. With a mean follow-up of 18.5 months (range 1–76 months, bCarmustine, etoposide, melphalan. median 10 months), the median survival (OS) of all patients cReduced intensity regimen. treated with salvage chemotherapy was 10.8 (95% CI

Bone Marrow Transplantation Salvage therapy and transplantation in high-risk leukaemia S Tauro et al 277 7.8–21). Disease relapse accounted for death in the majority despite a lack of disease response to Ara-amsa died of of patients (Table 2). The median OS of patients treated relapsed leukaemia post-SCT, but the benefit of SCT in with SCT (including those with refractory disease) was 29.4 prolonging OS in HR-AML nevertheless appeared to be months (95% CI 12.5–upper limit not reached) with an maintained (data not shown). expected 3-year survival of 48.4% and this was significantly higher than in patients who did not receive an auto/ allograft (median 6.7 months, 95% CI 1.5–8.6 months, Discussion Po0.0001). Likewise, the expected 3-year survival in patients who did not receive further consolidation with Allogeneic or autologous transplantation may be the only SCT was 6.5% and this was significantly lower than in curative option for eligible patients with relapsed or patients receiving an auto or allograft (Figure 1). As with refractory leukaemia (HR-leukaemia). After transplanta- OS, patients receiving SCT had a longer DFS (23 months, tion, 3 year survival in patients with relapsed AML 95% CI 12.5–upper limit not reached), compared to those receiving an HLA-sibling allograft in CR2 is 44 and 38% not consolidated with salvage chemotherapy alone after an autograft, while corresponding survival figures (P ¼ 0.0002). In the latter group of patients, the median for relapsed ALL are 30 and 34%, respectively.14 Since DFS was identical to the OS. improved outcomes are observed in the absence of residual Numbers of patients with AML permitted a subgroup disease at the time of transplantation,12,13 salvage regimens analysis: median OS in patients with chemosensitive HR- have been used to cytoreduce patients with HR disease AML, that is, those who entered CR or PR after salvage prior to an auto or allograft. While response rates in HR- with Ara-amsa, was 15.4 months (95% CI 9.0–upper limit leukaemia have undoubtedly improved with the use of not reached) compared with 8.8 months (95% CI 3.1–10.8, high-intensity salvage regimens, there is significant toxicity P ¼ 0.06) in those who were refractory to Ara-amsa associated with many of these regimens. Furthermore, not (Figure 2). Two of the three patients who received SCT many eligible patients reach the stage of SCT because of the short duration of remission. In our study, the response rates after Ara-amsa in HR- 100 AML (62%) and toxicity are similar to those reported P<0.001 N previously: combinations of high-dose Ara-C and amsa- 80 Y crine or mitoxantrone have been reported to induce remissions in up to 50% of patients with relapsed or 60 refractory AML,15 although treatment-related deaths were 16 40 reported in 6/52 patients. With the GEMIA protocol, 12 % Alive out of 20 patients with HR-AML were able to achieve CR, 20 although five other patients died of infectious complica- tions. CR rates of 45% have also been achieved with timed- 0 sequential chemotherapy (EMA-86 TSC)17 although a 0 3 6 9 12 15 18 21 24 27 30 33 36 significant toxic risk is associated with its use. Recent Months from Ara-amsa interest has focused on the use of FLAG, with CR rates of Figure 1 Overall survival of patients receiving SCT (Y) as further up to 48% in patients with relapsed and refractory AML 18 consolidation after salvage treatment with Ara-amsa compared to patients and de novo RAEB-t reported in a large series. In patients treated with chemotherapy alone (N). with HR-ALL, the observed response rates of up to 67% with Ara-amsa are comparable to those reported with the use of multiphase reinduction salvage regimens in patients with relapsed or refractory ALL (62%).19 Our remission 100 rates are less impressive than those reported by Martino et al20,21 (78% CR) with the use of a combination 80 chemotherapy (intermediate-dose Ara-C, , mitox- P =0.06 antrone, cyclophosphamide, prednisolone and methotrex- ate). Nevertheless, the proportion of HR-ALL patients 60 no response who proceeded to SCT in the study described by Martino response et al (RELAL-88) was similar to that observed after the use 40 of Ara-amsa in our series. The ability to consolidate patients with SCT following 20 salvage with Ara-amsa was in part due to the relatively

% Surviving disease free low toxicity of the salvage regimen. Although neutropenic fever was a common occurrence, one patient developed 0 self-limiting cerebellar toxicity and there was only one 0 3 6 9 12 15 18 21 24 27 30 33 36 treatment-related death. Thus, up to 50% of patients (10/12 Months from Ara-amsa with HR-AML and 7/12 with HR-ALL) were able to Figure 2 Disease-free survival of patients with AML responding to proceed to SCT. In contrast, only five out of 14 patients in 16 salvage therapy with Ara-amsa (response) compared to patients with CR proceeded to SCT in the GEMIA study and 10/61 salvage refractory disease (no response). patients were able to receive consolidation with SCT after

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