Prognostic value of low-level MRD in adult acute lymphoblastic leukemia detected by low- and high-throughput methods

Persistence of minimal residual disease (MRD) after induction/consolidation therapy in acute lymphoblastic leukemia is the leading cause of relapse. The GMALL 07/2003 study used MRD detection by RQ-PCR of clonal immune gene rearrangements with 1x10-4 as discriminating cut-off: levels ≥1x10-4 define molecular failure and MRD-negativity with an assay sensitivity of at least 1x10-4 defines complete molecular response. The clinical relevance of MRD results not fitting in these categories is unclear and termed "molecular not evaluable" (MolNE) towards MRD-based treatment decisions. Within the GMALL 07/03 study, 1019 consecutive bone marrow samples after first consolidation were evaluated for MRD. Patients with complete molecular response had significantly better outcome (five-year overall survival, 5y-OS=85±2%, n=603; five-year disease-free survival, 5y-DFS=73±2%, n=599) compared to patients with molecular failure 5y-OS=40±3%, n=238; 5y-DFS=29±3%, n=208), with MolNE patients in-between (5y-OS=66±4%, 5y-DFS=52±4%, n=178). Of MolNE samples re-analyzed using next-generation sequencing (NGS), patients with undetectable NGS-MRD (n=44; 5y-OS=88±5%, 5y-DFS=70±7%) had significantly better outcome than those with positive NGS-MRD (n=42; 5y-OS=37±8%, 5y-DFS=33±8%). MolNE MRD results are not just borderline values with questionable relevance, but form an intermediate risk group, assignment of which can be further improved by NGS.

Daratumumab and venetoclax in combination with chemotherapy provide sustained molecular remission in relapsed/refractory CD19, CD20, and CD22 negative acute B lymphoblastic leukemia with KMT2A-AFF1 transcript

Relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) has a very poor prognosis with a median overall survival of four to nine months. Achieving a complete molecular response is most often required to obtain a sustained leukemia-free survival after allogeneic hematopoietic stem cell transplantation. Immunotherapies targeting CD19, CD20, or CD22 are very efficient in achieving this goal. However, in the absence of the expression of these immunotherapeutic targets by lymphoblasts, treatment options are extremely scarce. We report the successful treatment of a 26-year-old man who suffered R/R, CD19, CD20, and CD22 negative B-ALL targeting Bcl-2 and CD38 by combining venetoclax and daratumumab with chemotherapy.

Low dose of Dasatinib in chronic myeloid leukemia

The oncoprotein BCR-ABL1 helps with the diagnosis and monitoring the therapeutic response in patients with chronic myeloid leukemia. We describe the case of a 70-year-old woman with chronic myeloid leukemia who did not achieve a molecular response after 12 months of treatment. She was then managed with Dasatinib 70 mg orally twice a day until she reached a complete molecular response. She developed pulmonary toxicity probably due to Dasatinib. The dosage was decreased to 70 mg orally once a day. The patient continues with a complete molecular response with less side effects. In chronic myeloid leukemia, as far as we know, there are no previous reports, after a molecular response with Dasatinib 70 mg twice a day, the maintenance of a good molecular control with a single daily dose. This dose may allow a reduction in toxicity with a better quality of life for patients with chronic myeloid leukemia

A multicenter total therapy strategy for de novo adult Philadelphia chromosome positive acute lymphoblastic leukemia patients. Final results of the GIMEMA LAL1509 protocol

The GIMEMA LAL1509 protocol, designed for adult (≥18-60 years) de novo Ph+ acute lymphoblastic leukemia patients, was based on a dasatinib plus steroids induction - with central nervous system prophylaxis - followed by dasatinib alone in patients in complete molecular response or chemotherapy and/or allogeneic transplantation in patients not reaching a complete molecular response. Sixty patients (median age 41.9 years) were enrolled: 33 were p190+, 18 p210+ and 9 p190/p210+. At the end of induction (day +85), 58 patients (97%) achieved a complete hematologic remission. No deaths in induction were recorded. Eleven patients (18.3%) obtained a complete molecular response. Among non-complete molecular responders (n=47), 22 underwent an allogeneic transplant. Seventeen hematologic relapses occurred (median 7 months, range 3-40.1), 13 during consolidation and 4 post-transplant. ABL1 mutations (5 T315I, 3 V299L, 1 E281K and 1 G254E) were found in 10/13 relapsed cases. With a median follow-up of 57.4 months (range: 4.2-75.6), overall survival and disease-free survival are 56.3% and 47.2%. A better diseasefree survival was observed in patients who obtained a molecular response at day +85 compared to cases who did not. The presence of additional copy number aberrations - IKZF1 plus CDKN2A/B and/or PAX5 deletions - was the most important unfavorable prognostic factor on overall and disease-free survival (p=0.005 and p=0.0008). This study shows that in adult Ph+ ALL long-term survivals can be achieved with a total-therapy strategy based on a chemo-free induction and, in complete molecular responders, also without further systemic chemotherapy. Finally, the screening of additional copy number aberrations should be included in the diagnostic work-up. EudraCT 2010-019119-39

Induction of Effector and Memory Cellular Immunity in a Patient with Long-Term Complete Molecular Response to Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

This case report is about a patient who suffered from Philadelphia chromosome (Ph1)-positive acute lymphoblastic leukemia. The blasts were positive for myeloid-lineage markers including CD13 and CD33, as well as B-cell-lineage markers. Minor bcr-abl1 mRNA was detected by real-time quantitative polymerase chain reaction. Chromosomal abnormality monosomy 7 was also observed, in addition to Ph1. Despite treatment difficulties that were anticipated based on these findings, the patient had long-time complete molecular response (CMR) for approximately 5 years using chemotherapy and two tyrosine kinase inhibitors, imatinib and dasatinib. Lymphocytes were elevated after the patient switched from imatinib to dasatinib, and a T-cell receptor (TCR) V beta gene repertoire analysis revealed oligoclonal expansion of effector and memory cytotoxic T lymphocytes (CTLs), including Wilms tumor 1-specific CTLs. More specifically, the two memory CTLs expressing TCR V beta 3 and V beta 7.1 gradually increased after dasatinib administration. The activation and maintenance of anti-leukemia immunity may have allowed the patient to obtain long-time CMR. These results highlight that obtaining memory CTLs for leukemia cells may lead to safe withdrawal from dasatinib in the patient.

Thromboembolic Risk Reduction and High Rate of Complete Molecular Response with Long-Term Use of Ropeginterferon Alpha-2b in Polycythemia Vera: Results from a Randomized Controlled Study

Introduction: The key treatment goals for polycythemia vera (PV) are to prevent thromboembolic events and minimize the risk of progression, ultimately modifying the natural history of the disease by selectively targeting the malignant clone. In the PROUD-PV/CONTINUATION-PV study, long-term treatment with ropeginterferon alpha-2b (BESREMi®; hereafter ropeg) was compared with standard cytoreductive therapy regarding thromboembolic and other adverse events as well as hematological and molecular parameters over a four-year period. Methods: Cytoreduction-naïve or HU-pre-treated patients aged ≥18 years diagnosed with PV according to WHO 2008 criteria were eligible. A total of 257 patients were randomly allocated to ropeg or hydroxyurea at individualized doses for 12 months in the initial study phase (PROUD-PV). In the ongoing extension phase (CONTINUATION-PV), patients in the hydroxyurea arm were permitted to switch to best available treatment. Efficacy assessments included a longitudinal analysis of complete hematological response (CHR) and complete molecular response (CMR; JAK2V617F was determined using real-time PCR [ipsogen® JAK2 MutaQuant® kit; QIAGEN GmbH]), defined by modified ELN criteria. Discontinued patients were considered non-responders. A data snapshot was performed once all patients reached 48 months of treatment; all available safety data were included. Results: Ninety-five patients in the ropeg arm and 76 in the control arm entered the extension phase. At the time of analysis 139 patients remained on study: 74/95 in the ropeg arm and 65/76 in the control arm. Almost all patients in the control arm (>97% at the last available assessment) continued on HU. The rate of patients in CHR was significantly higher in the ropeg arm than in the control arm in the 4th year (60.6% versus 43.4%; p=0.02), as seen after 2 and 3 years of treatment. In line with this effective control of hematologic parameters by ropeg, a very low rate of major thromboembolic adverse events was observed in the ropeg arm: 0.0%, 0.0% and 1.1% of patients in the 2nd, 3rd and 4th years, respectively. In the control arm, rates of major thromboembolic adverse events in the 2nd, 3rd and 4th year were 0.9%, 1.4% and 0.0%, respectively. The median JAK2V617F allele burden declined from 37.3% at baseline to 9.8% over 4 years in the ropeg arm, whereas in the control group, the median allele burden increased from 38.1% to 43.1% in the same period (p<0.0001). The rate of molecular response (partial or complete) at 48 months was significantly higher among ropeg-treated patients than in the control arm (67.0% versus 25.7%; RR: 2.5 [95% CI: 1.7 to 3.7; p<0.0001]). No patients achieved CMR in the control arm. In the ropeg arm, 13 patients had a JAK2V617F allele burden below the threshold of 1% at month 48, 11 of whom also had a CHR at this time point. An additional 34 patients in the ropeg arm achieved an allele burden <10% at 48 months, suggesting that further patients may reach the <1% threshold with ongoing treatment. In terms of safety, no new signals were detected in the 4th year. Rates of patients with treatment-related adverse events remained similar in the ropeg and control arms in the 4th year (ropeg: 28.7% of patients; control: 22.9%). Disease or treatment-related secondary malignancies reported in the entire study period comprised 2 cases of acute leukemia, 2 cases of basal cell carcinoma and 1 case of malignant melanoma, all in the control group; 1 case of disease-related transformation to myelofibrosis occurred in each treatment arm. Conclusions: Ropeg minimizes the occurrence of thromboembolic events in patients with PV over long-term treatment, without leukemogenic risk. In addition, we show for the first time in a randomized study that, in contrast to hydroxyurea, long-term ropeg treatment is capable of inducing deep molecular responses including CMR, which underscores its disease modifying potential. These results also suggest that selected patients could achieve operational cure (with both CHR and CMR) with ropeg, opening the way for treatment discontinuation. Disclosures Kiladjian: Novartis: Honoraria, Research Funding; AOP Orphan: Honoraria, Research Funding; Celgene: Consultancy. Klade:AOP Orphan Pharmaceuticals AG: Employment. Illés:Takeda, Seattle: Research Funding; Janssen, Celgene, Novartis, Takeda, Roche, Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Mayer:AOP Orphan Pharmaceuticals AG: Research Funding. Krejcy:AOP Orphan Pharmaceuticals AG: Employment. Hasselbalch:Novartis: Research Funding; AOP Orphan Pharmaceuticals: Other: Data monitoring board. Kralovics:Pharma Essentia: Honoraria; MyeloPro Diagnostics and Research: Equity Ownership; AOP Orphan Pharmaceuticals AG: Honoraria, Other: Advisory board; Qiagen: Honoraria; Novartis: Honoraria. Gisslinger:Celgene GmbH: Honoraria; Pharma Essentia: Other: Personal fees; Roche Austria GmbH: Consultancy; Janssen-Cilag: Honoraria; Novartis Pharma GmbH: Consultancy, Honoraria, Research Funding; AOP Orphan Pharmaceuticals: Consultancy, Honoraria, Research Funding; Myelopro GmbH: Consultancy.