Minimal Residual Disease Negative Status At the End of Induction Therapy Is a Potent Prognostic Marker in Adult Non-Ph Acute Lymphoblastic Leukemia: Results of the ALL MRD2002 Study
Authors: Nagafuji Koji , Miyamoto Toshihiro , Eto Tetsuya , Kamimura Tomohiko , Taniguchi Shuichi , Okamura Takashi , Ohtsuka Eiichi , Yoshida Takashi , Higuchi Masakazu , Yoshimoto Goichi , Fujisaki Tomoaki , Abe Yasunobu , Takamatsu Yasushi , Yokota Shouhei , Akashi Koichi , Harada Mine 
Published: October 2019

Abstract
Abstract 2581

Introduction
A clinical indication for allogeneic hematopoietic stem cell transplantation (HSCT) in adult Philadelphia-chromosome negative [Ph (−)] acute lymphoblastic leukemia (ALL) patients in complete remission 1 (CR1) remains to be clarified. An international study showed that matched related donors HSCT for ALL in CR1 provides survival benefits for standard-risk ALL patients compared to chemotherapy (Blood. 2008 111:1827). Minimal residual disease (MRD) status has been reported to be a strong prognostic factor in adult ALL patients (Blood. 2006 107:1116, 2009 113:4153). We prospectively monitored MRD status during induction and consolidation therapy in adult Ph (−) ALL patients to determine a clinical indication for HSCT.

Materials & Methods
From July 2002 to August 2008, 110 adult ALL patients were enrolled in this study. Eligibility criteria included non-L3 ALL, 16–65 years of age, and adequate organ function. Of these patients, 101 were eligible for this study and 59 were Ph (−). The treatment protocol used in this study was modified CALGB 19802. Treatment consisted of 6 courses given in the order of A-B-C-A-B-C, followed by a maintenance phase. Induction chemotherapy (course A) consisted of cyclophosphamide (1,200 mg/m2), daunorubicin (60 mg/m2 × 3), vincristine (VCR) (1.3 mg/m2 (max 2mg) × 4), L-asparaginase (3,000 U/m2 × 6) and prednisolone. Granulocyte colony-stimulating factor was started on day 4 and continued until neutrophil recovery. Consolidation B consisted of mitoxantrone (10 mg/m2 × 2), cytarabine (2,000 mg/m2/day × 4) and intrathecal (IT) administration of methotrexate (MTX). Consolidation C consisted of VCR (1.3 mg/m2 (max 2mg) × 3) and MTX (1,500 mg/m2 × 3) with leucovorin rescue and IT MTX. Patients received maintenance chemotherapy on a monthly basis: prednisolone 60 mg/m2 on days 1–5, VCR (1.3mg/m2 (max 2mg) × 3) on day 1, oral MTX 20 mg/m2 weekly, and oral 6-mercaptopurine 60 mg/m2 daily. MRD status was evaluated after induction therapy (first course A) and after second consolidation therapy (first course C). When MRD statuses after the consolidation were positive, patients were supposed to proceed to HSCT whenever possible.

Results
A total of 59 patients were Ph (−). MRD status of 41 of these patients (69.5%) could be monitored by the major rearrangement patterns of TCRƒÁ, TCRƒÁ, and IgƒÈ chain genes, and secondarily for IgH gene rearrangements (Blood. 1991 77:331), and chimeric RNA analysis (TCRƒÁ n=14, TCRƒÁ n=9, IgƒÈ n=6, IgH n=1, other n=1, E2A-PBX1 n=3, MLL-AF4 n=1). There were 21 male and 20 female patients. The median age was 31.0 (range 17–63 years). The median white blood cell count at presentation was 10,900/ml (range 1,000–408,700). A total of 36 patients (85.7%) achieved CR. The probability of 3-year overall survival and progression-free survival (PFS) were 59.3 % and 48.9 %, respectively. In terms of CR1 status, patients who were MRD (−) after induction therapy (first course A)(n = 22) had a significantly better 3-year PFS compared with those who were MRD (+)(n = 13)(72.2 % vs. 33.6 %, p = 0.011). Those MRD (−) patients also had a significantly lower 3-year probability of relapse compared with MRD (+) patients (27.8 % vs. 58.0 %, p = 0.031). Patients who were MRD (+) after consolidation therapy (n=3) had an ominous prognosis without HSCT (3-year PFS 0%), while the MRD (+) patients with HSCT (n=3) had 66.7 % 3-year PFS. On multivariate analysis, age (≥35 vs. <35 years, HR 4.535, p = 0.007) and MRD status after induction therapy (+ vs. -, HR 5.250, p = 0.009) were significant prognostic factors, whereas WBC count (≥30,000 vs. <30,000, HR 1.502, p = 0.498) was not.

Discussion
HSCT for CR1 ALL has the greatest anti-ALL activity. However, HSCT has higher morbidity and mortality rates than chemotherapy. Thus, HSCT should be avoided in patients who have good prognosis with chemotherapy alone. Our results show that patients with molecular remission after induction therapy have an excellent PFS without HSCT, and patients who are MRD (+) after several consolidation therapies have very poor PFS without HSCT. The present study indicates that MRD status after induction and consolidation therapies is a significant prognostic factor. MRD monitoring is useful to determine a clinical indication of HSCT for patients who achieve CR1. For CR1 patients with MRD (+) status after several consolidation therapies, further intensification of chemotherapy may be possible when HSCT is not a suitable option.

Disclosures:
No relevant conflicts of interest to declare.