Phase I Trial of Total Marrow and Lymphoid Irradiation Transplantation Conditioning in Patients with Relapsed/Refractory Acute Leukemia

Abstract Abstract 198 Fludarabine in combination high-dose busulfan (Bu) is an effective myeloablative preparative regimen for allogeneic stem cell transplantation. At doses used, however, fludarabine has only modest anti-leukemic activity. Clofarabine (Clo) is a second-generation purine nucleoside antimetabolite with significant single agent activity in patients with AML and ALL. The novel combination of Clo with Bu may provide improved disease activity safely. Therefore, we conducted a phase I trial to determine the maximum tolerated dose (MTD) of Clo in combination with Bu in patients with high-risk acute leukemia. Patients received i.v. Bu (Busulfex) 0.8 mg/kg q 6 hrs on days −6 to −3 and Clo at 30–60 mg/m2/day on days −6 to −2 in successive cohorts. Stem cells were infused day 0. GvHD prophylaxis included sirolimus plus tacrolimus starting day −2 to day 100, tapering to day 180. Patients were eligible if they were 18–60 years, had primary refractory or relapsed and refractory AML or ALL, or were in CR2 or higher, had Karnofsky performance status ≥70%, and adequate organ function. Donors were HLA-matched related (5/6 or 6/6 antigen-matched) or unrelated (10/10 allele-matched). Toxicity was scored using the Common Terminology Criteria for Adverse events, version 3.0. Dose limiting toxicity (DLT) was defined as any grade 3–4 non-hematologic toxicity that did not resolve to grade 2 or less by day 30. A total of 15 patients were treated at 4 Clo dose levels, 30 (n=3), 40 (n=3), 50 (n=3), and 60 mg/m2 (n=6). Seven males and 8 females of median age 48 (30–58) years, with AML (n=13) or ALL (n=2) were treated. At transplant, leukemia was relapsed and refractory (n=8), primary refractory (n=6), or in CR2 (n=1). Median number of lines of treatment failed before transplant was 2 (1–3). Median marrow blasts at transplant was 12% (3%–83%). Hematopoietic cell transplants were from related (n=9) and unrelated (n=6) donors. All patients engrafted. Median time to neutrophils >0.5×109/l was 16 (12–20) days, and to platelets >20×109/l was 15 (10–42) days. One patient treated at the 30 mg/m2 dose level failed to achieve platelets > 20×109/l. No DLT was observed. Transient Grades 3–4 non-hematological toxicities were evenly distributed across all 4 dose levels, and included vomiting (n=3), mucositis (n=9), hand-foot syndrome (n=1), and elevation of AST/ALT (n=10). Grades 3–4 elevation of AST/ALT occurred in 2 of 3 patients treated at 30 mg/m2, 3 of 3 at 40 mg/m2, 2 of 3 at 50 mg/m2, and 3 of 6 patients at 60 mg/m2 dose levels. AST/ALT peaked at day −1 or 0 and returned to baseline in all patients by day 10, with no long-term sequelae. There was no correlation between Clo dose and peak AST/ALT. One patient developed acute renal failure at the 60 mg/m2 dose on day +12 in association with elevated tacrolimus levels, although the creatinine subsequently normalized. Two patients, both at the 30 mg/m2 dose, developed mild veno-occlusive disease of the liver which was self-limiting. One treatment-related death due to sepsis was observed at day +104 in a patient treated at the 30 mg/m2 dose. Thirteen of 15 patients were in CR by day 30; 2 patients, treated at 40 mg/m2 and 50 mg/m2, respectively, failed to achieve CR. Day 100 mortality was 0. With a median follow-up of 313 days, the 1-year relapse-free survival was 51% ± 15%, and the 1-year overall survival was 61% ± 14%. Clo at doses as high as 60 mg/m2/day × 5 days in combination with Bu 3.2 mg/kg/day × 4 days is well tolerated and demonstrates promising efficacy in a very-high risk acute leukemia population. The MTD has not been reached. We recommend Phase II testing of Clo 60 mg/m2/day × 5 days in combination with high-dose Bu as a myeloablative regimen for allogeneic stem cell transplantation in patients with acute leukemia. Disclosures: No relevant conflicts of interest to declare.

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Phase I Evaluation of Prolonged-Infusion Gemcitabine With Irinotecan for Relapsed or Refractory Leukemia or Lymphoma

Journal of Clinical Oncology ◽

10.1200/jco.2002.08.166 ◽

2002 ◽

Vol 20 (13) ◽

pp. 2995-3000 ◽

Cited By ~ 20

Author(s):

Adam J. Bass ◽

Jon P. Gockerman ◽

Eve Hammett ◽

Carlos M. DeCastro ◽

David J. Adams ◽

...

Keyword(s):

Confidence Interval ◽

Acute Leukemia ◽

Phase I ◽

Phase I Trial ◽

Overall Response Rate ◽

Response Rate ◽

Total Duration ◽

Hematologic Malignancies ◽

Prolonged Infusion ◽

Induction Regimen

PURPOSE: To estimate the maximum-tolerated duration of infusion of gemcitabine at 10 mg/m2/min in combination with irinotecan at 40 mg/m2 daily for 3 days in the treatment of relapsed or refractory acute leukemia or lymphoma. PATIENTS AND METHODS: Patients with leukemia or lymphoma were escalated in separate strata. Stratum I consisted of 11 patients, median age of 47 years (range, 18 to 68 years), with relapsed or refractory leukemia. Stratum II contained nine patients, median age of 48 years (range, 39 to 68 years), who had refractory non-Hodgkin’s lymphoma. Patients received irinotecan at 40 mg/m2 daily for 3 days, beginning just before the first dose of gemcitabine. Gemcitabine was given at 10 mg/m2/min, with the total duration adjusted following a modified continuous reassessment model. RESULTS: Severe myelosuppression and stomatitis/esophagitis were the most serious hematologic and nonhematologic toxicities. Several patients developed febrile neutropenia, nausea, or vomiting. In both strata, the maximum recommended duration of infusion of gemcitabine was 12 hours delivered at 10 mg/m2/min (7,200 mg/m2). The overall response rate for one cycle of this therapy in this phase I trial for patients with leukemia was 18% (95% confidence interval, 8% to 45%), and for those with lymphoma, 33% (95% confidence interval, 17% to 66%). CONCLUSION: A prolonged infusion of gemcitabine at 10 mg/m2/min for 12 hours with 3 days of irinotecan at 40 mg/m2/d is a tolerable induction regimen for patients with acute leukemia or lymphoma. Stomatitis/esophagitis should be anticipated; however, this regimen may induce responses in patients with difficult-to-treat hematologic malignancies.

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Phase I trial of interleukin-2 after unmodified HLA-matched sibling bone marrow transplantation for children with acute leukemia

Blood ◽

10.1182/blood.v87.4.1249.bloodjournal8741249 ◽

1996 ◽

Vol 87 (4) ◽

pp. 1249-1254 ◽

Cited By ~ 33

Author(s):

N Robinson ◽

JE Sanders ◽

MC Benyunes ◽

K Beach ◽

C Lindgren ◽

...

Keyword(s):

Bone Marrow ◽

Bone Marrow Transplantation ◽

Acute Leukemia ◽

Phase I ◽

Marrow Transplantation ◽

Phase I Trial ◽

Acute Gvhd ◽

Interleukin 2 ◽

Allogeneic Bone ◽

Matched Sibling

Allogeneic bone marrow transplantation (BMT) for advanced acute leukemia is associated with a high risk of relapse. It is postulated that interleukin-2 (IL-2) administered after BMT might induce or amplify a graft-versus-leukemia effect and thereby reduce the relapse rate. To identify an IL-2 regimen for testing this hypothesis, a phase I trial of IL-2 (Roche) was performed in children in complete remission (CR) without active graft-versus-host disease (GVHD) off immunosuppressive agents after unmodified allogeneic matched-sibling BMT for acute leukemia beyond first remission. Beginning a median of 68 days after BMT, 17 patients received escalating doses of induction IL-2 (0.9, 3.0, or 6.0 x 10(6) IU/m2/d representing levels I, II, and III) for 5 days by continuous intravenous infusion (CIV). After 6 days of rest, they received maintenance IL-2 (0.9 x 10(6) IU/m2/d) for 10 days by CIV infusion. Levels I and II were well-tolerated, but, of 6 patients at level III, 1 developed pulmonary infiltrates, 1 developed hypotension (both resolved), and 1 died of bacterial sepsis and acute respiratory distress syndrome. Grade II acute GVHD developed in 1 patient at level I and 1 at level III. The maximum tolerated dose of induction IL-2 was level II. IL-2 induced lymphocytosis, with an increase in CD56+ and CD8+ cells. Ten patients remain in CR at 5+ to 67+ months. Thus, a regimen of IL-2 has been identified that did not induce a high incidence of acute GVHD when administered to children after unmodified allogeneic BMT. Its clinical activity will be assessed in a phase II trial.

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Phase I Trial of Belinostat and Bortezomib in Patients with Relapsed or Refractory Acute Leukemia, Myelodysplastic Syndrome, or Chronic Myelogenous Leukemia in Blast Crisis - One Year Update

Blood ◽

10.1182/blood.v120.21.3588.3588 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3588-3588

Author(s):

Beata Holkova ◽

Prithviraj Bose ◽

Mary Beth Tombes ◽

Ellen Shrader ◽

Wen Wan ◽

...

Keyword(s):

Adverse Events ◽

Acute Leukemia ◽

Myelodysplastic Syndrome ◽

Phase I ◽

Chronic Myelogenous Leukemia ◽

Dose Level ◽

Phase I Trial ◽

Blast Crisis ◽

Myelogenous Leukemia ◽

Acute Leukemias

Abstract Abstract 3588 Although reports of synergistic interactions between proteasome and histone deacetylase (HDAC) inhibitors in acute leukemias have been limited, they are well described in B-cell malignancies (e.g., myeloma and lymphoma). Nevertheless, preclinical findings have shown striking synergism between the HDAC inhibitor belinostat (previously PXD-101) and the proteasome inhibitor bortezomib, administered at low (sub-micromolar) concentrations, in cultured and primary acute myeloid leukemia (AML) and acute lymphocytic leukemia cells (Dai Y et al. Br J Haematol. 2011). These findings prompted initiation of a phase I trial, using a 3+3 design, with the primary objective of determining the maximum tolerated dose (MTD) for the combination of bortezomib and belinostat in patients with relapsed or refractory acute leukemia, myelodysplastic syndrome (MDS), or chronic myelogenous leukemia in blast crisis (CML-BC). To date, 25 patients with the following disease types have been treated: acute leukemia (n=19), MDS (n=4), and CML-BC (n=2). The male:female ratio was n=11 (44%):14 (56%); the median age was 62 (range 27–83) years; ECOG performance scores ranged from 0–2; and the median number of prior therapies was 2 (range 1–5). The schedule of administration was belinostat, 30 minutes intravenous (IV) infusion, on days 1–5 and 8–12; and bortezomib, IV bolus, preceding belinostat on days 1, 4, 8, 11; on a 21-day cycle. Dose levels were, in mg/m2(bortezomib/belinostat): 1.0/500 (n=6); 1.3/500 (n=6); 1.3/650 (n=4); 1.3/850 (n=3); 1.3/1000 (n=4); 1.3/1200 (n=2). The study is currently enrolling to dose level 6 (1.3/1200). No dose-limiting toxicities (DLTs) have been observed to date. Non-DLT ≥ grade 2 (CTCAE version 4) treatment-related adverse events have included: fatigue (grade 2, 36%), leukopenia (grade 4, 12%), nausea (grade 2, 12%), peripheral sensory neuropathy (grade 2, 12%), and thrombocytopenia (grade 3, 20%). No serious adverse events have occurred at an unexpected frequency or severity. Two deaths have occurred due to disease progression, and one death has occurred due to a cerebrovascular accident that was related to pre-existing comorbidities and not to study-therapy. Of the 25 patients treated, 22 have been evaluable for response, 2 are too early to evaluate, and 1 patient was not evaluable for response. There have been 2 partial responses (PRs) and 1 complete response (CR) in this heavily pretreated population. The CR was achieved at dose level 1 in a patient with biphenotypic acute leukemia refractory to 7+3 and Flag-IDA. The patient proceeded to allogeneic hematopoietic stem cell transplantation (SCT) after 4 cycles of treatment. In addition, 1 patient with CML-BC had stable disease (SD) by protocol criteria but a CR with incomplete blood count recovery (CRi) by standard criteria, and is undergoing evaluation for allogeneic hematopoietic SCT. The patient is currently in cycle 8 at dose level 4. One of the PRs was achieved in a patient with AML transformed from MDS (2 prior regimens); after 4 cycles of treatment at dose level 5, the patient proceeded to allogeneic hematopoietic SCT. The second PR was achieved in an AML patient after cycle 2; a bone marrow biopsy revealed chronic myelomonocytic leukemia, and the response was deemed sufficient to proceed to allogeneic hematopoietic SCT. Also of note, a patient with AML transformed from MDS is currently on treatment in cycle 5 at dose level 5 with SD. An additional 6 patients have had SD, and 11 patients have had progressive disease. Correlative studies examining pre- and post-treatment leukemic blast expression of nuclear RelA, Bim, Bcl-xL, and XIAP are ongoing. Collectively, these findings indicate that a regimen combining belinostat and bortezomib is well tolerated in patients with relapsed or refractory acute leukemia, MDS, or CML-BC and shows evidence of activity. The MTD has not yet been reached. Pending identification of the MTD, phase II evaluation of this therapeutic strategy, should determine its activity more definitively. Disclosures: No relevant conflicts of interest to declare.

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Preliminary results of a phase I trial with dose escalated lenalidomide (L) in separate cohorts of relapsed acute leukemia (AL) or chronic lymphocytic leukemia (CLL): evidence of activity in acute myeloid leukemia (AML) and toxicity in CLL at starting dose

Journal of Clinical Oncology ◽

10.1200/jco.2008.26.15_suppl.7075 ◽

2008 ◽

Vol 26 (15_suppl) ◽

pp. 7075-7075 ◽

Cited By ~ 1

Author(s):

W. G. Blum ◽

L. A. Andritsos ◽

A. J. Johnson ◽

R. B. Klisovic ◽

C. Kefauver ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Chronic Lymphocytic Leukemia ◽

Acute Leukemia ◽

Phase I ◽

Myeloid Leukemia ◽

Phase I Trial ◽

Lymphocytic Leukemia ◽

Preliminary Results ◽

Starting Dose ◽

Acute Myeloid

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Phase I trial and pharmacokinetic study of high-dose clofarabine and busulfan and allogeneic stem cell transplantation in adults with high-risk and refractory acute leukemia

Leukemia ◽

10.1038/leu.2010.319 ◽

2011 ◽

Vol 25 (4) ◽

pp. 599-605 ◽

Cited By ~ 27

Author(s):

S S Farag ◽

L L Wood ◽

J E Schwartz ◽

S Srivastava ◽

R P Nelson ◽

...

Keyword(s):

Stem Cell ◽

High Risk ◽

Stem Cell Transplantation ◽

Acute Leukemia ◽

Phase I ◽

Cell Transplantation ◽

Allogeneic Stem Cell Transplantation ◽

Pharmacokinetic Study ◽

Phase I Trial ◽

High Dose

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A phase I clinical trial of 2-chlorodeoxyadenosine in pediatric patients with acute leukemia.

Journal of Clinical Oncology ◽

10.1200/jco.1991.9.3.416 ◽

1991 ◽

Vol 9 (3) ◽

pp. 416-422 ◽

Cited By ~ 60

Author(s):

V M Santana ◽

J Mirro ◽

F C Harwood ◽

J Cherrie ◽

M Schell ◽

...

Keyword(s):

Acute Leukemia ◽

Phase I ◽

Phase I Trial ◽

Fungal Infections ◽

Lymphoblastic Leukemia ◽

Phase Ii Trials ◽

Heavily Pretreated ◽

Blast Cells ◽

Steady State Levels

To evaluate its toxicity and clinical efficacy in children with relapsed or refractory leukemia, we performed a phase I trial of 2-chloro-2'-deoxy-adenosine (2-chlorodeoxyadenosine; 2-CDA) given as a continuous 5-day infusion at doses of 3 to 10.7 mg/m2/d. In this study of 31 children with acute leukemia, the only dose-limiting toxicity was myelosuppression. At the highest dose level, three of seven patients developed fatal systemic bacterial or fungal infections. At dose levels above 6.2 mg/m2/d, significant oncolytic responses occurred in all patients. In addition, there was a significant correlation between both the responsiveness by cell type and dose of 2-CDA, such that more oncolytic responses were noted in acute myeloid leukemia (AML) patients than acute lymphoblastic leukemia (ALL) patients (P = .02). Although this was a phase I trial in heavily pretreated patients with refractory disease, two AML patients treated at 5.2 and 10.7 mg/m2/d, respectively, had complete hematologic responses, and one patient treated at 10.7 mg/m2/d had a partial response. In addition, there was a dose-response relationship in all patients with improved cytoreduction of peripheral blast cells at higher doses of 2-CDA. In vitro evaluation of 2-CDA uptake and anabolism by leukemic blast cells from 22 patients demonstrated that 2-chloro-2'-deoxyadenosine (Cld-AMP) and 2-chloro-2'-deoxyadenosine 5'-striphosphate (CldATP) reached concentrations close to steady-state levels within 1 hour. Intracellular nucleotide disappearance rates were high with half-lives of 1.29 and 2.47 hours for CldAMP and CldATP, respectively. This suggests that continuous infusion is necessary to maintain the desired plasma concentration. The results of this study confirm the antileukemic activity of 2-CDA and the lack of prohibitive nonhematologic toxicity. Phase II trials in patients with AML and ALL are warranted.

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