Post-Transplant Pulmonary Function Abnormalities Nadir At Five Years and Then Fully Normalize by the Second Decade in Allogeneic Stem Cell Transplantation Survivors

Abstract Abstract 247 Background: The presence of minimal residual disease (MRD) after allogeneic stem cell transplantation (SCT) for Ph+ ALL is highly predictive of eventual relapse. Imatinib (IM) has very limited efficacy in hematologic relapse of Ph+ALL, but may prevent leukemia recurrence if started when the leukemia burden is still very low and detectable only by molecular techniques. The optimal time for starting IM post transplant and the prognostic relevance of different bcr-abl transcript levels in relation to time after SCT have not been established. Aims: To determine the impact of post-transplant IM, given either prophylactically or after detection of bcr-abl transcripts (pre-emptively), on the overall incidence of MRD, remission duration, long-term treatment outcome and tolerability in pts. who underwent SCT for Ph+ALL in complete remission. Study Design: In a prospective, randomized multicenter trial, previously transplanted Ph+ ALL pts. (n=55) were assigned to receive imatinib prophylactically (n=26) or pre-emptively (n=29). SCT was performed in CR1 in 23 pts. and 27 pts. in the two groups, respectively. Five pts.were transplanted in CR2. Serial assessment of bcr-abl transcripts was performed by quantitative RT-PCR and additionally by nested-RT-PCR if the sensitivity of the qRT-PCR was below the quantitative range. Confirmatory testing of a second independent sample was not required, to reduce the risk of treatment delays. Samples were considered PCR negative only if the ABL copy number exceeded 104. Imatinib administration was scheduled for one year of continuous PCR negativity. Results: IM was started in 24/26 pts. allocated to prophylactic IM and in 14/29 pts. in the pre-emptive arm. The majority of pts. received IM 400 mg/d (26/38 pts.), the other 12 pts. 600 mg IM daily. IM was started a median of 48 d after SCT in the prophylactic arm and 70 d after SCT with pre-emptive therapy. After a median follow-up of 30 mos. and 32 mos., respectively, 82% and 78% of pts. are alive in ongoing CR, 4 pts. died in CR. Five pts. transplanted in CR1 and 2/5 pts. transplanted in CR2 have relapsed (median follow-up 9 mos. and 10.5 mos., respectively). The frequency of MRD positivity was significantly lower in pts. assigned to prophylactic imatinib (10/26; 40%) than those in the pre-emptive treatment arm (20/29; 69%) (p=0.046 by chi2 test). Only 9 of 29 pts. assigned to pre-emptive imatinib remained continuously PCR negative after SCT, with a median follow-up of 32 months (18–46 months) after SCT. The median duration of sustained, uninterrupted PCR negativity after SCT is 26.5 months with prophylactic and 6.8 months with pre-emptive administration of imatinib (p=0.065). The probability of remaing in CHR after SCT was significantly lower in partients who remained MRD negative after SCT (p=0.0002). Analysis of the kinetics of molecular relapse showed that detection of bcr-abl transcripts within 100 days of transplant, despite rapid initiation of IM, was associated with a significantly inferior EFS compared to first detection of MRD positivity more than 100 days after SCT. IM was discontinued prematurely in 54% pts. receiving imatinib prophylactically and in 64% of pts. receiving imatinib pre-emptively, mostly due to gastrointestinal toxicity. Accordingly, the time to IM discontinuation was 245 d and 191 d in the prophylactic and the pre-emptive treatment arms, respectively. Despite this early discontinuation rate, overall survival in the two treatment groups was 80% and 74.5% after 5 years, with no significant difference by log rank test (p=0.84). Conclusions: Prophylactic administration of imatinib significantly reduces the incidence of molecular relapse after SCT. Both interventional strategies are associated with a low rate of hematologic relapse, durable remissions and excellent long-term outcome in patients with Ph+ ALL. The presence of MRD both prior to and early after SCT identifies a small subset of patients with a poor prognosis despite post-transplant imatinib, and warrants testing of alternative approaches to prevent hematologic relapse. Disclosures: Schuld: Novartis: Employment. Goekbuget:Micromet: Consultancy. Ottmann:Novartis Corporation: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding.

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Mutational Profiling Of Myeloid Malignancies For Prediction Of Disease Relapse Following Allogeneic Stem Cell Transplantation

Blood ◽

10.1182/blood.v122.21.2096.2096 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2096-2096

Author(s):

Alan M Hanash ◽

Sean M. Devlin ◽

Molly Maloy ◽

Kristina M. Knapp ◽

Vincent A. Miller ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Allogeneic Stem Cell Transplantation ◽

Peripheral Blood ◽

Disease Relapse ◽

Post Transplant ◽

Mutational Profiling ◽

Idh Mutations ◽

Flt3 Mutations

Abstract Disease relapse remains the greatest cause of mortality following allogeneic stem cell transplantation (SCT). Improved predictive markers are needed to identify patients most likely to benefit from SCT. Several mutations reported recently in MDS and AML have potential prognostic importance, however the relevance of these mutations to clinical outcome after SCT is poorly understood. In order to evaluate mutations present in transplant patients and provide an initial assessment of their clinical significance, we performed next-generation sequencing of myeloid malignancies from 55 patients (23 MDS, 32 AML) treated with SCT at MSKCC from 2010-2013. Median recipient age was 56 (20-69); 22/55 patients were transplanted in remission. Stem cell sources were CD34-selected (36) or unmanipulated (14) peripheral blood, unmanipulated marrow (2), or cord blood (3). 40/55 allografts were HLA matched (20 related, 20 unrelated). Sequencing was performed on peripheral blood or marrow aspirates in patients with >20% blasts (AML) or >20% dysplastic cells (MDS). Adaptor ligated sequencing libraries were captured with two custom baitsets targeting 374 cancer-related genes and 24 genes often rearranged for DNA-seq, and 272 genes often rearranged for RNA-seq. Captured libraries were sequenced to high depth (Illumina HiSeq), averaging >590X for DNA and >20,000,000 total pairs for RNA. Statistics included cumulative incidence functions for relapse, Kaplan-Meier estimates for relapse-free survival (RFS), and outcome comparison with a permutation-based logrank test. Only mutations observed in at least 5 patients were analyzed. No adjustments were made for multiple comparisons. Median follow-up of survivors was 16.2 months (5.5-32.8). We detected genetic variants in each patient, suggesting the utility of this approach for identifying somatic mutations to track minimal residual disease (MRD) post-SCT. Six patients had known FLT3 mutations detected by a CLIA-certified test; all 6 of these mutations were identified by the sequencing platform. In addition, 3 FLT3 mutations and 1 FLT3 amplification were identified in patients who previously tested FLT3 negative. We identified 13 patients with IDH mutations (5 IDH1, 8 IDH2), eight with NPM1 mutations (all in AML), and 10 with DNMT3A mutations. We identified MAP kinase pathway mutations in 12 patients, including NRAS (7), KRAS (5), and NF1 (4), and we identified mutations in novel genes previously implicated in MDS/AML, including STAT4, CASP8, APC, and ALK. We next evaluated if specific mutations were associated with SCT outcome. Patients with IDH mutations (all of whom had normal karyotype) demonstrated significantly less relapse than patients with wild-type (WT) IDH (1 yr incidence: 0% vs 29%, p=.027, Fig 1). This translated into improved RFS (p=.037) in patients with IDH mutant AML (Fig 2). Treatment-related mortality (TRM) was similar with and without IDH mutations, suggesting the improved outcome was due to reduced relapse. For FLT3, 5/10 patients with FLT3 abnormalities relapsed. All 5 that relapsed were IDH WT. In contrast, IDH mutations were present in 4/5 FLT3+ AMLs that did not relapse, suggesting that IDH mutations may predict for improved SCT outcomes in patients with intermediate cytogenetic risk AML and in patients with FLT3 mutations. Mutant KRAS correlated with reduced overall survival in AML (p=.008), but the significance of this was unclear due to the absence of relapses and high TRM, including infection and GVHD, in this group. We also evaluated disease progression in 2 AML patients who relapsed post-transplant with archived samples collected pre-SCT and at relapse. In both patients we observed a distinct mutational profile pre and post-transplant consistent with clonal evolution. Of note, 1 patient gained a NF1 mutation post-SCT, while the other patient lost a NF-1 mutation, although when detected, both mutations were present at a frequency less than 10%. In summary, we performed mutational profiling in SCT patients using a novel high throughput platform, which allowed us to identify clinically relevant mutations, including some not detected by clinical laboratory testing. Notably, we found that IDH mutations may predict for favorable outcome after SCT, even in FLT3 mutant AML. These data suggest that mutational profiling can identify clinically relevant biomarkers pre-SCT and identify mutations for tracking MRD. Disclosures: Miller: Foundation Medicine, Inc: Employment. Lipson:Foundation Medicine, Inc: Employment. Stephens:Foundation Medicine, Inc: Employment. Otto:Foundation Medicine, Inc: Employment. Yelensky:Foundation Medicine, Inc: Employment. Nahas:Foundation Medicine, Inc: Employment. Wang:Foundation Medicine, Inc: Employment. Levine:Foundation Medicine, Inc: Consultancy.

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