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In Relapsed Or Refractory Diffuse Dührsen et al. Blood Cancer Journal (2021) 11:95 https://doi.org/10.1038/s41408-021-00485-5 Blood Cancer Journal CORRESPONDENCE Open Access Phase I/II trial of lenalidomide, methotrexate, leucovorin, cytarabine, and rituximab (LeMLAR) in relapsed or refractory diffuse large B cell lymphoma Ulrich Dührsen 1, Mareike Tometten2,FrankKroschinsky3, Arnold Ganser4,StefanIbach5, Stefanie Bertram6 and Andreas Hüttmann 1 Dear Editor, ≥2.5 mg/dl, serum aspartate [AST] or alanin amino- Lenalidomide has moderate activity in relapsed or transferase [ALT] >4× upper limit of normal [ULN]), refractory diffuse large B cell lymphoma (r/rDLBCL)1. active hepatitis B or C, human immunodeficiency virus Based on the COMLA regimen used in the 1970s and infection, any other uncontrolled infection, as well as 1980s2, we combined lenalidomide with methotrexate pregnancy and nursing period. All patients gave written (plus leucovorin), cytarabine, and rituximab (LeMLAR) in informed consent. The LeMLAR regimen (Fig. 1) com- a phase I/II trial. Lenalidomide induces apoptosis and cell prised up to six 28-day cycles consisting of lenalidomide cycle arrest in the G0/G1 phase3. After discontinuation, (day 1–21), methotrexate (5–10 min i.v. bolus; day 1, 8, surviving cells start to proliferate and become susceptible 15), leucovorin (four oral 45 mg doses six hours apart, to the S-phase-specific agents methotrexate and cytar- starting 24 h after methotrexate), cytarabine (5-10 min i.v. 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; abine administered in the subsequent cycle. Because of bolus; day 1, 8, 15), and rituximab (375 mg/m², day 1). All – low toxicity for immune effector cells4 6, these drugs are patients received prophylactic enoxaparin (40 mg s.c.). not expected to incapacitate lenalidomide’s indirect In phase I, methotrexate and cytarabine were simulta- mechanisms of action3. neously escalated in a 3 + 3 design in 30 mg/m² or 75 mg/ The study was approved by the ethics committees of the m² steps, respectively. The lenalidomide dose was reduced participating sites and registered under EudraCT no. if chemotherapy could not be escalated beyond level 1. 2012-001891-13 and ClinicalTrials.gov identifier The maximum tolerated dose (MTD) was determined in NCT01788189. The trial protocol is provided in the cycles 1 and 2. Patients without dose-limiting toxicity Supplementary Information. In brief, patients 18 years of (DLT) terminating treatment in cycle 1 or 2 prematurely age or older with relapsed or refractory, biopsy-proven due to disease progression were replaced by new patients. CD20-positive aggressive B cell lymphoma (excluding DLT was defined as neutrophils <0.5 /nl, platelets <25 /nl, mantle cell lymphoma and central nervous system invol- creatinine clearance <60 ml/min, bilirubine ≥3 mg/dl, vement) and a performance status of 0–3 were eligible. serum AST or ALT ≥6× ULN, or mucositis grade ≥3on Exclusion criteria included inadequate organ function day 8 (plus a maximum of 3 extra days), day 15 (plus unrelated to lymphoma (neutrophils <1.0 /nl, platelets ≤6 days), or day 29 (plus ≤7 days). Failure to reach these <75 /nl, creatinine clearance <60 ml/min, bilirubine thresholds at the indicated time-points prevented timely administration of methotrexate and cytarabine. Adverse events requiring dose reduction in cycle 1 or 2, receipt of Correspondence: Ulrich Dührsen ([email protected]) <21 lenalidomide doses per cycle, cycle length >35 days, 1Klinik für Hämatologie, Universitätsklinikum Essen, Essen, Germany and any adverse event preventing continuation according 2 Klinik für Hämatologie, Onkologie, Hämostaseologie und to the protocol were also rated as DLT. Treatment tol- Stammzelltransplantation, Medizinische Fakultät, RWTH Aachen Universität, Aachen, Germany erance was assumed if none of three or only one of six Full list of author information is available at the end of the article © The Author(s) 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a linktotheCreativeCommons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Blood Cancer Journal Dührsen et al. Blood Cancer Journal (2021) 11:95 Page 2 of 4 Table 1 Patient characteristics. Phase I Phase II Number Percent Number Percent Number of patients 22 100% 20 100% Diagnosis Diffuse large B cell 21 95% 20 100% lymphoma Follicular lymphoma 15% –– grade 3b Months from diagnosis, 13 (5–160) n.a. 20 (3–89) n.a. median (range) Patient features Male 14 64% 11 55% Age (years), median 68 (47–81) n.a. 62 (39–82) n.a. (range) Age >60 years 15 68% 11 55% Fig. 1 The LeMLAR protocol. Upper part: Treatment schedule (i.v., ECOG performance status 9 41% 0 0% intravenous; p.o., per os). Lower part: Dose levels for maximum- ≥2 tolerated-dose determination and intrapatient dose escalation. Ann Arbor stage III or IV 19 86% 13 65% ≥2 extranodal lesions 17 77% 9 45% patients experienced DLT. In the absence of DLT, step- Lactate dehydrogenase 18 82% 11 55% wise intrapatient dose escalation was possible after cycle >ULN 2, and again after cycle 4, in both phase I and phase II (Fig. B symptoms 3 14% 0 0% 1). Sample size calculation in phase II was based on a reported objective response rate (ORR) to lenalidomide International prognostic index alone of 20%7. To demonstrate an ORR to LeMLAR of Low 1 5% 6 30% ≥ α 40% at a two-sided of 0.05 and a power of 0.4, 20 Intermediate-low 4 18% 5 25% patients (including 10% drop-outs) were required to be Intermediate-high 5 23% 6 30% treated at the MTD. Responses were assessed after the second and four weeks after the last cycle, using the High 12 54% 3 15% international response criteria for malignant lymphomas8. Previous therapiesa Between January 2013 and May 2018, 37 patients were 1 prior line 7 32% 3 15% registered from four academic sites. One patient withdrew 2 prior lines 5 23% 11 55% consent and two were excluded by their physicians before treatment inception, leaving a total of 34 participants, 3 prior lines 7 32% 5 25% with a median of 2 prior lines of therapy (range, 1–4). 4 prior lines 3 13% 1 5% Twenty-two patients were recruited in phase I (Table 1). Autologous stem cell 4 18% 6 30% With a starting dose of 25 mg lenalidomide, chemother- transplantation apy level 1 was well tolerated. On level 2, two of three Allogeneic stem cell 15%15% patients had a DLT (ALT increase, septicemia). After transplantation reduction of lenalidomide to 20 mg, one DLT was observed among six patients on level 2 (neutro-/throm- Refractory to last 17 77% 13 65% bocytopenia), and two among six patients on level 3 (rash, treatment mucositis). Thus, the MTD was level 2 (lenalidomide Relapse after last 5 23% 7 35% 20 mg, methotrexate 60 mg/m2, cytarabine 150 mg/m2). treatment Phase II comprised eight MTD patients from the phase I ECOG Eastern Cooperative Oncology Group, n.a. not applicable, ULN upper and 12 new patients (Table 1). After two cycles, the ORR limitof normal. was 55%. Five patients achieved a complete remission Note that eight patients from the phase I were also included in phase II. aSee Supplementary Table 1 for regimens. (CR), six a partial remission (PR; one converting into CR Blood Cancer Journal Dührsen et al. Blood Cancer Journal (2021) 11:95 Page 3 of 4 on continued therapy), three had stable disease (SD), four (5/6; Fisher’s exact test p = 0.046). Complete responders progressive diseases (PD), and two were not evaluable (a tended to maintain counts above baseline throughout receipt of only one cycle). The median duration of treatment (Supplementary Table 4). The correlation response (DOR) was 19.4 months, with four long-term between lymphocyte response and tumor response was survivors maintaining their responses for >21–32 months independent of absolute cell numbers, which, in complete (Supplementary Fig. 1). Responses were seen in all of eight responders, ranged from 0.23 /nl to 3.07 /nl at baseline patients without and in three of 12 patients with pro- (normal range, 1.0–3.4). gression on last treatment (median DOR to last treatment, LeMLAR was well tolerated. The most common adverse 9.5 months, range 1–32; Supplementary Table 2). With a event was an infection, occurring in almost half the median follow-up of 31 months, median progression-free patients. Antimicrobial prophylaxis was not mandatory, survival (PFS) and overall survival (OS) were 6.9 and and G-CSF was only given to raise neutrophils from <0.5 12.6 months, respectively (Supplementary Fig. 2). Patients /nl to >1.0 /nl. Systematic antimicrobial prophylaxis and received a median of 4 LeMLAR cycles (range 1–6; more extensive G-CSF use may further improve the median cycle duration, 28 days, range 27–69; median time protocol’s tolerability. ORR (55%) was high. Lymphocytes on lenalidomide, 21 days per cycle, range 7–22; treatment tended to rise in complete responders and fall in non- delays, 22 of a total of 76 cycles [29%]; outpatient responders.
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