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Leukemia (2003) 17, 1967–1972 & 2003 Nature Publishing Group All rights reserved 0887-6924/03 $25.00 www.nature.com/leu A new multidrug reinduction protocol with , , , dexamethasone, and for relapsed or refractory acute leukemia EA Kolb1 and PG Steinherz1

1Department of Pediatrics at Memorial Sloan-Kettering Center, New York, NY, USA

We report the results of a phase 2 nonrandomized single-arm combination of thiotepa, topotecan, and followed trial of a combination therapy for relapsed or refractory by autologous SCT offers a favorable antitumor effect for leukemia. From January 1999 to June 2002, 28 patients with pediatric solid tumors.22 multiple relapsed or refractory acute leukemia received a 23,24 combination of topotecan, vinorelbine, thiotepa, dexametha- Vinorelbine is a semisynthetic Vinca rosea alkaloid. Early sone, and, for patients with an M3 marrow on day 7, in vitro data suggest that vinorelbine may have a role in the gemcitabine. A total of 14 patients had pre-B-ALL (acute treatment the acute leukemias, although it appears to be less lymphoblastic leukemia), three had T-cell leukemia, nine acute active in acute myeloblastic leukemia (AML) when compared to myeloblastic leukemia (AML), and two biphenotypic leukemia. acute lymphoblastic leukemia (ALL).23,25,26 In adult solid In all, 13 patients achieved a significant response (10 complete tumors, vinorelbine has been used successfully in combination responses and three partial responses). Among the respon- 27 ders, five had pre-B-ALL, two had T-cell leukemias, five had with both gemcitabine and topotecan, but there are no clinical AML, and one had biphenotypic leukemia. In total, 10 of these data to define its role in the treatment of leukemias. patients subsequently underwent hematopoietic stem cell Gemcitabine is a novel deoxycytidine analog with activity in transplantation, and four are alive without disease. One patient hematogenous malignancies. The structure and metabolism of died, while in remission, of complications resulting from an gemcitabine resemble that of .28,29 However, after episode of sepsis and pneumonia that occurred during phosphorylation, gemcitabine achieves higher relative concen- topotecan, vinorelbine, thiotepa, dexamethasone, and gemcita- 30–31 bine (TVTG) reinduction. Other toxicities included grade 4 trations, and is retained longer than cytarabine. In vitro neutropenia in all patients and transient grade 2 hepatotoxicity cytotoxicity data suggest that gemcitabine has significant activity in 10 patients (36%). In summary, we report that 47% of heavily in acute leukemias.32–34 Furthermore, in clinical studies, either pretreated pediatric patients with multiply relapsed or refrac- alone,35–38 or in combination with other agents,39,40 gemcita- tory leukemia achieved a significant response after therapy on bine has activity against human leukemias. the TVTG protocol. Further studies are warranted to evaluate the role of the TVTG combination in the treatment of leukemia. Glucocorticoids are a mainstay in the treatment of pediatric Leukemia (2003) 17, 1967–1972. doi:10.1038/sj.leu.2403097 lymphoid and myeloid leukemias. Dexamethasone may be Keywords: topotecan; thiotepa; vinorelbine; gemcitabine; leukemia preferable to prednisone due to enhanced penetration into the cerebral spinal fluid.41 Many hypothesize that saturation of the glucocorticoid receptor over extended periods of time with high doses of corticosteroids will optimize the antileukemic effect of Introduction these agents. Results of a recent trial at the Dana-Farber Cancer Institute support this hypothesis. They observed enhanced bone marrow and peripheral blood blast response to 18 and 150 mg/ Topotecan is a semisynthetic water-soluble inhibitor of topoi- 2 1–5 m /day dexamethasone when compared to the standard 6 mg/ somerase I, and acts in the S-phase of the . The m2/day.42 unique, cell-cycle-specific effect of topotecan suggests that its We report results of an institutional phase 2 nonrandomized antitumor activity may be schedule dependent. Accordingly, single-arm reinduction protocol, incorporating a combination of results in murine xenograft models of human tumors demon- topotecan, vinorelbine, thiotepa, gemcitabine, and high-dose strate peak activity when the drug is given as a protracted 3 dexamethasone, for patients with multiple relapsed or refractory infusion. Using similar schedules, excellent antitumor activity 6 acute leukemias. While the chemotherapeutic agents employed is observed in L1210 leukemia, an aggressive murine leukemia, all share the dose-limiting toxicity of myelosuppression, they and xenografts of human poor risk acute lymphoblastic 7 8–13 differ in mechanism of action and metabolism. Furthermore, leukemia (ALL). Furthermore, recent clinical trials in adults 14 these are agents not commonly used in current leukemia and children demonstrate that continuous infusion topo- protocols, and they therefore offer potentially novel mechanisms tecan has antileukemia activity. of action, either alone or in combination, against otherwise Preclinical data suggest that the inhibition of topoisomerase I heavily pretreated leukemia cells. The ‘TVTG’ (topotecan, by topotecan will render the cell more susceptible to DNA- 15 vinorelbine, thiotepa, dexamethasone, and gemcitabine) proto- damaging agents. The combination of topotecan, plus either 16 17 18 19 col is designed to induce disease remission that is of sufficient , , , , or 9,11,16,18 duration to identify a matched unrelated stem cell donor, and to cytarabine exhibits antitumor activity in adult patients 9,11,16–18 19 permit hematopoietic stem cell transplantation in a recipient with leukemia and solid tumors. In hematologic free of infections and vital organ dysfunction. malignancies, thiotepa is an active antileukemic agent that is successfully used in the cytoreduction regimens preceding 20,21 allogeneic stem cell transplantion (SCT). Additionally, the Patients and methods

Correspondence: E Anders Kolb, Department of Pediatrics, Memorial Patients with acute leukemias, who had disease recurrence Sloan-Kettering Cancer Center, P.O. Box, 1275 York Avenue, New York, NY 10021, USA; Fax: þ 1 212 717 3239 despite exhausting all conventional therapeutic options, and/or Received 28 March 2003; revised 28 May 2003; accepted 24 June were refractory to conventional therapeutic agents, were eligible 2003 for treatment. Between January 1999 and June 2002, 28 patients Re-induction therapy for refractory leukemia EA Kolb and PG Steinherz 1968 were treated with a combination of topotecan, vinorelbine, graded according to the National Cancer Institute common thiotepa, and dexamethasone, with or without gemcitabine toxicity criteria, version II. according to the Memorial Sloan-Kettering Cancer Center TVTG protocol. All patients had relapsed and/or refractory leukemia, and no patient had therapeutic options of greater curative Results potential. The diagnosis of ALL or AML was made according to the FAB classification. Confirmation of immunophenotype was Among the 28 patients enrolled (Table 2), 19 were male and available prior to treatment. All patients had a normal serum nine female. The mean age at the initial leukemia diagnosis was creatinine, transaminases less than five times normal, and a 8.1 years (range 3 months–21 years), and the mean age at total serum bilirubin less than 1.5 times normal. enrollment was 10.8 years (1–24 years). A total of 14 patients According to institutional guidelines, written informed con- (50%) had Pre-B-cell ALL, three (11%) T-cell ALL, two (7%) sent was obtained from all patients or their guardians before the biphenotypic leukemia, and nine (32%) AML. Three of the nine initiation of therapy. Institutional Review Board approval was cases of AML were secondary to treatment for a previous obtained for the analysis of the results. malignancy (t-AML). A total of 12 patients (43%) had disease The specific schedule and dosages of the prescribed refractory to either first remission induction (n ¼ 3) or refractory is shown in Table 1. Gemcitabine was infused to remission reinduction after the first (n ¼ 6) or subsequent on day 7 if the following criteria were met: there were greater relapse (n ¼ 3). The remaining 16 patients (57%) had a median than 25% leukemic blasts in the day 7 bone marrow or a of two relapses (range 1–9) per patient, including five patients persistence of circulating blasts in the peripheral blood; and who relapsed after myeloablative therapy and subsequent liver transaminases were less than five times normal, with a allogeneic SCT (patients 4, 6, 10, 14, and 19). There were six bilirubin less than 1.5 times normal. Starting on day 7, patients (21%) who received TVTG as the primary remission administration of daily subcutaneous granulocyte colony- reinduction therapy following a first relapse: patient 3 relapsed stimulating factor was initiated and continued until leukocyte while on a high-risk ALL protocol, patient 16 had relapsed AML recovery. Additional courses of TVTG were offered to those after only 6 weeks of remission, patients 18 and 19 experienced patients with a significant response to the first cycle, and an early relapse after primary refractory disease (refers to disease only when the absolute neutrophil count (ANC) exceeded that was refractory to standard initial remission induction 1000/ml and the platelet count exceeded 75,000/ml (Table 1). All therapy, but ultimately these patients did achieve a first patients received either intrathecal or cytara- remission with additional therapy), patient 22 had relapsed bine within 2 weeks of the start of each cycle of TVTG. t-AML, and patient 24 relapsed during consolidation therapy for Subsequent intrathecal chemotherapy was administered at the AML. discretion of the investigator. One patient (patient 21) received In all, 10 of the 28 patients (36%) achieved a CR, one patient intrathecal methotrexate, cytarabine, and thiotepa on days 7, (4%) a PR, two (7%) a PR-P (Table 3), and 15 (53%) had no 14, and 21. response following the first cycle of TVTG. A total of 20 patients A complete response (CR) was defined as no measurable (71%) had either an M3 marrow on day 7, or a persistence of extramedullary disease, and less than 5% blasts in the bone circulating blasts, and 15 subsequently received gemcitabine. marrow (M1 marrow) in a patient with an ANC greater than 500/ Three of these 15 patients achieved a CR (20%), one a PR (7%), ml, and platelet count greater than 75 000/ml. Patients with a and one a PR-P (7%) after gemcitabine. Reasons to not give partial response (PR) had 5–25% bone marrow blasts, with an gemcitabine in the remaining five patients included: hepato- ANC greater than 500/ml, and platelet count greater than 75 000/ toxicity (n ¼ 2), and a decision by the medical providers and ml. It is not uncommon for heavily pretreated patients, especially family that additional therapy would be futile due to rapid those with extensive bone marrow infiltration, to have a progression of disease (n ¼ 3). significant response to therapy but have a delayed recovery of Four of the 14 patients (29%) with pre-B-ALL had a CR and platelet production. Therefore, patients who had an ANC greater one a PR. Two of the three patients with T-cell leukemias had a than 500/ml, a platelet count less than 75 000/ml, and 5–25% CR. Four of the nine patients (44%) with AML (including one leukemic blasts in the bone marrow were defined as having a PR with t-AML) had a CR, and one a PR-P. One of the two patients except platelets (PR-P). Patients who did not meet the above with biphenotypic leukemia had a PR-P (Table 3). Eight of the 13 response criteria were defined as unresponsive (n ¼ 15) and patients with a response received more than one cycle of TVTG were not offered additional courses of TVTG. Toxicities were (mean 3.6 cycles/patient, range 1–5 cycles).

Table 1 TVTG treatment schedule

Dose Day

Topotecan 1 mg/m2/day as a continuous i.v. infusiona 1–5 Vinorelbine 20 mg/m2/day i.v. push 0, 7, 14, 21b Thiotepa 15 mg/m2/day i.v. over 4 h 2 Gemcitabine 10 mg/m2/min continuous i.v. infusion over 6 h. Total dose is 3600 mg/m2/dose 7c Dexamethasone 45 mg/m2/day P.O. or IV divided TID 7–14 G-CSF 5 mcg/kg/day SQ Start day 7 and continue until ANC 4500/ml aAll patients had a central venous catheter with at least two lumens so the infusion of topotecan did not need to be interrupted for the administration of other or blood products. bDay 21 vinorelbine is given only if the ANC is greater that 500/ml. cAdministered if there are greater than 25% leukemic blasts in the bone marrow or a persistence of circulating blasts in the peripheral blood, and if liver transaminases are less than five times normal, with a bilirubin less than 1.5 times normal.

Leukemia Re-induction therapy for refractory leukemia EA Kolb and PG Steinherz 1969 Table 2 Characteristics of patients treated with TVTG (n ¼ 28)

Pt. Diagnosis Age (years) at Sex Prior therapy Disease status diagnosis/at TVTG at enrollment

1 T-cell ALL 9/10 F V, P, As, Dn, Cp, Tg, Ac, HDM, 11 ref 2 Pre-B ALL 11/11 M V, P, As, Dn, Cp, Ac, Mp, M 11 ref 3 Pre-B ALL 14/18 F V, P, As, Dn, Cp, Ac, Mp, M, D, Dx, Tg 1st rel 4 Pre-B ALL 2/5 M V, As, D, Cp, Ac, Mp, M, Tg, Dn, P, RT, TBI/Th/Cp SCT 2nd rel 5 Pre-B ALL 5/9 M V, Dx, As, D, Cp, Ac, Mp, M, Tg, HDM, VP, Flu, RT 2nd rel 6 Pre-B ALL 6/9 M V, Dx, As, D, Cp, P, Ac, Mp, M, Tg, Th, VP, HDM, RT, TBI/Cp SCT 4th rel 7 Pre-B ALL 3/6 F V, Dx, As, D, Cp, Ac, Mp, M, Tg, P, Ida, RT 3rd rel 8 Pre-B ALL 8/8 M V, Dx, As, Mp, M, Ac 2nd rel 9 T-cell ALL 11/12 M V, P, D, As, Mp, M, HDM 1st rel, ref 10 Bp 3/7 F V, Dx, A, D, Cp, Ac, Mp, M, Tg, Dn, P, Ida, If, VP, HDM, TBI/Cp SCT 2nd rel 11 Pre-B ALL 16/20 M V, P, As, D, Cp, Ac, Mp, M, Tg, Dn, AD, 2nd rel 12 AML 2/3 M V, P, As, Dx, Ac, Tg, VP, Dn 1st rel, ref 13 Pre-B ALL 15/16 M V, P, As, Dn, Cp, Ac, Mp, M, Dx, Tg, VP, Th, CRT 2nd rel 14 Pre-B ALL 1/4 M V, P, As, D, Cp, Ac, Mp, M, Tg, Dn, Tm, Flu, TBI/Mel SCT 3rd rel, ref 15 Bp 14/16 M V, Dx, As, D, Cp, Ac, Mp, M, Tg, Dn, P, VP, If, Flu, RT 3rd rel, ref 16 AML 5 months/8 months F Dx, Ac, Tg, VP, Dn 1st rel 17 t-AML 23/23 M Dx, Ac, Tg, VP, Dn 1st rel, ref 18 Pre-B ALL 4/5 F V, Dx, As, D, Cp, Ac, Mp, M, Tg, Dn, P 1st rel, after 1st ref disease 19 AML 2/3 F Dx, Ac, Tg, VP, Dn, As, Ida, Flu, V, P, Cp, M, TBI/Th/Cp SCT 1st rel, after 1st ref disease 20 AML 17/18 M Ac, Tg, Dn, VP, Mito, CSA, GO 1st rel, ref 21 T-cell ALL 8/13 M V, Dx, As, D, Cp, Ac, Mp, M, Tg, Dn, P, If, VP, HDM 9th rel, ref 22 t-AML 20/22 F Dx, Ac, Tg, VP, Dn, Ac 1st rel 23 t-AML 3/8 M Ac, As 11 ref 24 AML 14/17 F Dx, Ac, Tg, VP, Dn, Ac, Cl, VP, 1st rel 25 AML 2/3 M Ac, Tg, Dn, VP, Dx, As, Ida 1st rel, ref 26 Pre-B ALL 4/6 F V, P, As, Dn, Mp, M, VP, Cp, Ac, HDM, 2nd rel 27 Pre-B ALL 21/22 M V, P, As, Dn, Mp, M, Cp, Dx, Ep 1st rel, ref 28 Pre-B ALL 6/8 F V, P, As, M, Mp, D, Cp, Ac 3rd rel Rel, relapse; ref, refactory; 11 ref, prime reference; Bp, biphenotypic leukemia; SCT, stem cell transplantation; Ac, cytarabine; AD, actinomycin D; As, ; Cl, ; Cp, cyclophosphamide; CSA, cyclosporin A; D, ; Dn, ; Dx, dexamethasone; Ep, ; Flu, fludarabine; GO, gemtuzumab ozogamicin; HDM, high-dose methotrexate; Ida, idarubicin; If, ; M, methotrexate; Mel, ; Mito, ; Mp, ; P, prednisone; RT, craniospinal radiation; TBI, total body irradiation; Tg, thioguanine; Th, thiotepa; Tm, ; V, ; VP, etoposide.

Table 3 Description of those patients who demonstrated a response

No. Diagnosis Response to No. of Gem SCT After Current status Follow-up timea TVTG cycles TVTG (months)

1 T-cell ALL CR 2 Yes Alive 32 2 Pre-B ALL CR 2 Yes Alive 10 3 Pre-B ALL CR 5 Yes Died in remission of pneumonitis 13 4 Pre-B ALL CR 2 Yes DOD 3 7 Pre-B ALL CR 2 Yes Died of VOD, in remission 3 11 Pre-B ALL PR 1 Yes Yes Died after graft failure 5 12 AML CR 2 Yes Yesb Alive 9 15 Biphenotypic PR-P 1 Yes No DOD 4.5 20 AML CR 2 Yes Yes DOD 13 21 T-cell ALL CR 2 Yesc Alive 50 22 t-AML CR 1 No DOD 6 23 t-AML PR-P 1 Yes Died of disseminated Aspergillus 17 24 AML CR 1 Yes No Died of complications 1.6 of sepsis that occurred 1 week after TVTG t-AML, therapy related, or secondary AML; SCT, stem cell transplant; CR, complete response; PR, partial response; PR-P, partial response except platelets; DOD, died of disease recurrence, VOD, veno-occlusive disease. aFollow-up time is measured from the start of the TVTG protocol. bThe patient relapsed after the second cycle of TVTG. The patient subsequently achieved remission after therapy with another protocol and was able to undergo an SCT. cPatient received intrathecal therapy with methotrexate, cytarabine, thiotepa, and hydrocortisone concomitantly with TVTG.

Eight of the 10 patients who achieved a CR, and two of the underwent an allogeneic SCT, and are alive and disease free 8, three patients with a PR underwent an allogeneic hematopoietic 19, 30, and 49 months from the start of TVTG, respectively. SCT after TVTG. The median time from achieving a CR to Patient 12 relapsed after the second cycle of TVTG. He again transplant (n ¼ 7) was 3.9 months (range 1.5–10.9 months). Four achieved a remission with idarubicin and cytarabine, and is patients (patients 1, 2, 12, and 21) had a CR after TVTG, currently alive and well after a mismatched SCT. Of the

Leukemia Re-induction therapy for refractory leukemia EA Kolb and PG Steinherz 1970 remaining six patients who were transplanted, two died with allogeneic SCT, and four of these are currently alive and disease- relapsed disease, one viral pneumonitis, one veno-occlusive free. It is interesting to note that remission reinduction with disease, one disseminated aspergillus, and one of complications TVTG was possible regardless of immunophenotype of the associated with graft rejection (Table 3). All transplant-related leukemia cells (Table 3). morbidities were within the range of that which is normally Recent clinical trials of topotecan as a single agent demons- expected in a heavily pretreated cohort of patients, and none trate that the drug has activity in relapsed leukemias.8–10,13,14 could be directly correlated with the prior administration of The maximum tolerated dose of topotecan in a heavily TVTG. pretreated cohort of pediatric patients with refractory leukemia Three patients were not transplanted after a response to TVTG is reportedly 2.4 mg/m2/day for 9 days.14 However, the dose (patients 15, 22, and 24). Patient 24 had hematopoietic recovery employed in the multidrug protocols is necessarily lower and and confirmation of a CR, but the patient died of complications some investigators have successfully used topotecan at a dose of of sepsis and ARDS that occurred during reinduction therapy. 1.25 mg/m2/day in combination with other agents.11,17 In this This is the only TVTG-associated morbidity or mortality that report, seven patients (25%) achieved a CR, and one a PR-P prevented SCT. After an initial PR-P on TVTG, patient 15 opted when topotecan (1 mg/m2/day for 5 days) was used in to go off protocol and receive consolidation therapy with combination with vinorelbine, thiotepa, and dexamethasone fludarabine and cytarabine. No stem cell donor was identified, (ie without the addition of gemcitabine). and the patient died of relapsed disease 4.5 months from the The role of gemcitabine in this combination of drugs is not start of TVTG. Patient 22 refused additional chemotherapy after clear. In total, 15 patients had M3 marrow disease on day 7, and a documented CR. This patient ultimately relapsed and died of received gemcitabine. Three subsequently achieved a CR, one a progressive disease. PR and one a PR-P. Among the patients who received The 13 patients who responded to therapy were evaluated for gemcitabine, ANC recovery (see Table 3) was delayed 9 days hematopoietic recovery following TVTG. The median time to (32 days with gemcitabine, n ¼ 5 vs 23 days without gemcita- achieve an ANC of 500/ml was 27 days (range 6–40 days), and bine, n ¼ 8), and the recovery of the platelet count was delayed median time to achieve a platelet count of 75 000/ml(n ¼ 11) 3 days (32 days with gemcitabine, n ¼ 4 and 29 days without, was 30 days (range 0–48 days). The addition of gemcitabine n ¼ 7). However, only patients with refractory or progressive delayed the recovery of both the ANC and the platelet count disease received gemcitabine, and accordingly were expected (Table 4). Transient grade 1 or 2 hepatic toxicity is documented to have delayed or no recovery of hematopoiesis. Eight patients in 10 patients. Eight of these 10 patients received gemcitabine. experienced grade 2 hepatic toxicity following gemcitabine Three patients died within 1 month of starting therapy with infusion as compared to only two who did not receive TVTG. All three patients had progressive disease on day 7, and gemcitabine. Nonetheless, three CRs, one PR and one PR-P ultimately succumbed to disease and/or sepsis. One patient, as among 15 patients with a slow response to reinduction are mentioned above, developed sepsis and ARDS during cycle 1 of encouraging. Careful consideration of acute toxicities is chemotherapy of TVTG. This patient subsequently died 6 weeks necessary prior to the administration of gemcitabine. after initiation of TVTG, and was in remission at the time. The role of reinduction chemotherapy in multiply relapsed or refractory patients is not an attempt at cure. Long-term remission duration is unrealistic. Without an SCT, sooner or later these Discussion patients will experience disease recurrence. The goal is to administer therapy that will: (1) achieve a clinical response with Patients with multiply relapsed or refractory leukemia have a as little residual disease as possible; (2) maintain the response dismal prognosis. Agents available for salvage therapy are long enough to identify a matched-unrelated stem cell donor; limited by: (1) the development of multidrug resistance in the and (3) permit the patient to undergo an SCT free of infections leukemia cells; and (2) the capacity for these heavily pretreated and vital organ dysfunction. We were able to achieve this goal patients to tolerate the side effects of additional high-dose in 47% of the patients. Unfortunately, one patient with a CR therapy. We present the results of 28 patients treated with a died of complications resulting from ARDS that occurred during protocol containing topotecan, vinorelbine, thiotepa, gemcita- induction. Additionally, two patients, with extensive disease at bine, and dexamethasone. A total of 13 of these patients (47%), the time of enrollment, experienced increased LFTs during the with multiply relapsed or refractory leukemia, achieved either a first week of induction, and were subsequently unable to CR (10 patients) or a PR (three patients) after one cycle of TVTG. potentially benefit from gemcitabine despite an M3 day 7 Additionally, 10 of the 13 patients subsequently underwent marrow. In summary, we report a 47% response rate (36% CR, 11% PR) in patients with multiple relapsed leukemia using a new Table 4 Median hematopoietic recovery after one cycle of TVTG combination of chemotherapeutic agents. Toxicities primarily (n ¼ 13)a include grade 4 neutropenia, which is difficult to assess in the setting of a relapsed leukemia, and transient grade 2 hepatic Parameter Time (days) toxicity. Given the remission reinduction rate in this heavily pretreated cohort of patients, these toxicities are acceptable. ANC greater than 500/ml All patients (n ¼ 13) 27 No gemcitabine (n ¼ 8) 23 Gemcitabine (n ¼ 5) 32 Acknowledgements

Platelets greater than 75 000/ml This work would not be possible were it not for the help of many All patients (n ¼ 11) 30 colleagues. We are especially indebted to Maura Byrnes-Casey, No gemcitabine (n ¼ 7) 29 PNP, Rosemarie Corless, PNP, and Kateri Sullivan, PNP for their Gemcitabine (n ¼ 4) 32 skilled assistance with patient care; and Michael Kellick, RPh for aAnalysis includes only those patients with a CR, PR, or PR-P. his assistance in designing and naming this protocol.

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