Interim Results of a Phase II Study of Dasatinib and Prednisone As an Oral, Chemo-Free Induction and Consolidation Regimen for Adults with Newly Diagnosed Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

Background Tyrosine kinase inhibitors (TKIs) combined with intensive chemotherapy as a first-line treatment regimen significantly improved the prognosis of Philadelphia (Ph) chromosomal positive acute lymphoblastic leukemia (Ph+ALL). However, it has been reported that 74% of patients fail to complete 8 cycles of chemotherapy, and the early mortality rate during induction was as high as 13%. Our previous retrospective study determined an oral, chemo-free regimen (dasatinib plus prednisone) as induction and consolidation yields 100% of complete remission (CR) rates in Ph+ ALL with minimal induction death (Li XY, et al. Br J Haematol. 2020;189:e231-e234). To further verify the effectiveness of this completely oral and chemo-free regimen, we conducted a phase II, one-arm and multicenter trial (ChiCTR200038053). Methods Adults ≥16 years of age with new diagnosed Ph+ALL were eligible. Induction (Course I) used dasatinib 100 mg daily on days 1-28 and prednisone 1mg/kg/daily on days 1-21, 0.5 mg/kg/daily on days 22-28. Patients not in CR/CRi received Course I as second induction again. Two courses of consolidation (Course II and III) used dasatinib 100 mg daily on days 1-28 and prednisone 1mg/kg/daily on days 1-7. CNS prophylaxis used intrathecal cytarabine and dexamethasone. Patients 16-65 years old underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) if they had a HLA-matched donor; otherwise they received 6 cycles of hyper-CVAD chemotherapy alternating regimen-B (methotrexate, cytarabine) and regimen-A (cyclophosphamide, doxorubicin, vincristine, dexamethasone). The dose of chemotherapy was reduced by a third in patients 60-70 years old and by half in patients over 70 years. The primary objectives were to determine induced complete remission rate and major molecular response of the dasatinib/prednisone oral, chemo-free regimen. Results To date, 32 patients from 10 centers enrolled. Median age was 54 years (range: 15-84). The dominant BCR-ABL1 isoform was p190 in 72%, p210 in 18%, rare types in 6.3% and not reported in 3.1%. Patients received an average of 2.5 courses of dasatinib/prednisone regimen (Course I-III). Most patients were tolerable the dose of dasatinib, and two patients were reduced to 50mg daily due to severe pleural effusion. Allo-HSCT was performed in 10 patients, 50% after remission and 50% after marrow relapse. As shown in Figure 1, the CR rate was 97% with one induction death due to sepsis. The major molecular response (MMR was defined as: 3-log reduction in BCR-ABL1 transcript) was 50% and the complete molecular response (CMR was defined as: the absence of a detectable BCR-ABL1 transcript with 0.01% sensitivity/4.5-log) was 40% either at 3 months after starting induction or before HSCT, respectively. From Course I to Course II, the CMR increased from 18.5% to 48%, but accompanied by an increase in marrow relapse rates, which were 16% and 18.75% at course II and course III, respectively. Marrow relapse occurred in 9 patients, all occurred within 6 months after starting induction. T315I mutation in ABL1 KD was detected in 5 of 7 marrow relapses (72%). With a median follow up of 232 days (range: 77-392 days), 1-year OS and 1-year event-free survival (events were defined as marrow relapse and death) was 97% and 54%, respectively (Figure 2). The cumulative molecular relapse rate (defined as BCR-ABL1:ABL1 ratio rises after reaching the CMR level) was 35% at 3 months, 48% at 6 months, and 54% at 1 year (Figure 2). Conclusions The chemotherapy-free, oral combination of dasatinib and prednisone appears promising induction efficacy in de novo Ph+ ALL; the high CR rates and acceptable molecular response rates were similar to results reported by GIMEMA LAL2116 study (Foà R, et al. N Engl J Med. 2020;383:1613-1623). However, two subsequent consolidation courses of the chemo-free regimen led to early molecular relapse with T315I mutations, which urged us to modify the study protocol such as strengthening consolidation therapy or incorporating promising drug blinatumomab. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

High STAT5A Expression is Associated with Major Molecular Response Achievement Failure of Chronic Phase Chronic Myeloid Leukemia Patients Receiving Hydroxyurea before Imatinib: A Cross-sectional Study

BACKGROUND: STAT5 is a transcriptional factor which when highly expressed in chronic myeloid leukemia (CML) cells stimulate proliferation and mediate resistance from tyrosine kinase inhibitors, resulting in major molecular response (MMR) failure. STAT5 has two isoforms, STAT5A and STAT5B. However, prolonged use of imatinib appears to only upregulate STAT5A pathway. In addition, the resistance conferred by STAT5A does not extend to other drugs such as hydroxyurea. Hence, STAT5A and STAT5B might have different functions in CML cells. AIM: The objective of the study was to determine the association of STAT5A and STAT5B expression with MMR failure in CML patients. METHODS: This was a cross-sectional study of CML patients in chronic phase with age ≥ 18 years old, receiving IM therapy ≥ 12 months, and previously given hydroxyurea. MMR status was evaluated and patients were categorized as achieved or failed to achieve MMR. Expression levels of STAT5A and STAT5B were conducted using RT-PCR methods. Associations between STAT5A expression, STAT5B expression, hydroxyurea duration, and imatinib duration with MMR achievement were calculated using logistic regression. RESULTS: A total of 118 patients were analyzed; 71.1% failed to achieve MMR. Multivariate logistic regression analysis showed statistically significant association between high STAT5A expression (odds ratio [OR]: 3.852; 95% confidence interval [CI]: 1.420–10.452; p = 0.008), STAT5A/STAT5B interaction (OR: 0.150; 95% CI: 0.038–0.593; p = 0.007), longer hydroxyurea administration (OR: 3.882; 95% CI: 1.023–14.733; p = 0.046), and shorter imatinib administration (OR: 0.333; 95% CI: 0.132–0.840; p = 0.020) with MMR achievement failure. After adjusting STAT5A expression with STAT5A/STAT5B interaction, high STAT5A expression independently increased the likelihood of MMR achievement failure only in high expression STAT5B patients (OR: 3.852; 95% CI: 1.420–10.452; p = 0.008). CONCLUSION: High STAT5A expression which is induced by high STAT5B is associated with MMR achievement failure of chronic phase CML patients who received hydroxyurea before imatinib. Longer duration of hydroxyurea and shorter duration of IM confound of STAT5A expression to MMR achievement failure.

Efficacy and safety of Bosutinib in Patient with Chronic myeloid leukemia who was intolerant to DASTANIB,NILOTUNIB -Case report

Bosutinib is approved as first line therapy for treatment of chronic phase CML and also in patients who are either resistant or intolerant to previous TKI. We present a 59 year old male who was intolerant to 2 TKI but showed excellent hematological and major molecular response to Bosutinib.

Krónikus myeloid leukaemia miatt 2003 és 2019 között a Semmelweis Egyetem Belgyógyászati és Onkológiai Klinikáján kezelt betegek adatainak elemzése

Összefoglaló. Bevezetés: A krónikus myeloid leukaemia a diagnosztika fejlődésének és a tirozin-kináz-gátlók bevezetésének köszönhetően az elmúlt évtizedekben kiváló prognózisú betegséggé vált. Célkitűzés: A betegséggel kapcsolatos ismereteink nagy része klinikai vizsgálatokból származik, emiatt kiemelt szerepük van a nem szelektált beteganyagon végzett elemzéseknek. Módszer: Retrospektív elemzésünkben a Semmelweis Egyetem Belgyógyászati és Onkológiai Klinikáján 2003 és 2019 között tirozin-kináz-gátló kezelésben részesült betegek adatait tekintettük át. Eredmények: Klinikánkon összesen 88 beteg részesült terápiában, közülük 73 beteg az analízis időpontjában is kezelés alatt állt. A betegek 5 éves össztúlélése 86%, 5 éves progressziómentes túlélése 70% volt. 9 beteg halt meg, közülük 2 betegnél a halál oka a progrediáló alapbetegség volt. 38 betegnél volt szükség az első vonalban terápiaváltásra, a váltás oka akkor elsősorban az elégtelen terápiás válasz volt. A későbbi terápiaváltásokra elsősorban intolerancia miatt került sor. Az első vonalban a betegek több mint fele major molekuláris választ ért el, a jelenlegi kezelés mellett a betegek 85%-ánál major molekuláris választ detektáltunk. Megbeszélés: Adataink alapján az intézményünkben kezelt betegek túlélése és a betegek által elért terápiás válasz megfelel a nemzetközi adatoknak. Következtetés: Mivel nem válogatott beteganyagról van szó, a kapott eredmények pontosabb képet adhatnak a krónikus myeloid leukaemia tirozin-kináz-gátlóval történt kezelésének eredményeiről. Orv Hetil. 2021; 162(32): 1297–1302. Summary. Introduction: As a result of advances in diagnostic techniques and the introduction of tyrosine kinase inhibitors, the prognosis of chronic myeloid leukemia has improved over the last decades. Objective: Most of our knowledge about chronic myeloid leukemia results from clinical trials, therefore data derived from non-selected patient population is substantial. Method: Data of chronic myeloid leukemia patients treated with tyrosine kinase inhibitors at the Department of Internal Medicine and Oncology, Semmelweis University, between 2003 and 2019 were analysed retrospectively. Results: 88 patients received treatment, 73 patients were on therapy at the time of the analysis. Overall survival at 5 years was 86%, progression-free survival at 5 years was 70%. 9 patients died, 2 of them due to progressive disease. 38 patients needed 2nd line therapy, the main reason of treatment change was failure of therapy. Subsequent treatment modifications were conducted mostly because of intolerance. More than half of the patients on 1st line treatment reached major molecular response and 85% of the patients on treatment at the end of the analysis are in major molecular response. Discussion: Based on our data, survival and therapeutic response of patients in our center are similar to the international results. Conclusion: This analysis provides real-world data about treatment results of chronic myeloid leukemia in the tyrosine kinase inhibitor era. Orv Hetil. 2021; 162(32): 1297–1302.

Complete hematological and major molecular response through treatment with ultra-low dose Interferon alpha 2 in polycythemia vera: a case report

Early treatment of polycythemia vera with ultra-low-dose interferon-α 2a is well tolerated and results in complete hematologic and major molecular remission and a strong reduction of all symptoms, especially pruritus and fatigue.

Clinical outcomes in patients with Philadelphia chromosome-positive leukemia treated with ponatinib in routine clinical practice—data from a Belgian registry

Data on clinical use of ponatinib are limited. This prospective registry aimed to evaluate outcomes of ponatinib treatment in routine practice over 3 years (2016–2019) in Belgium (NCT03678454). Patients with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) were treated with ponatinib per current label. Fifty patients (33 CML and 17 Ph+ ALL) were enrolled. Fifty-five percent of CML and 29% of Ph+ ALL patients had received ≥3 prior tyrosine kinase inhibitors (TKIs). Reasons for starting ponatinib were intolerance (40%), relapse or refractoriness (28%) to previous TKIs, progression (16%), or T315I mutation (16%). Median follow-up was 15 months for CML and 4.5 months for Ph+ ALL patients. Best response was a major molecular response in 58% of CML and 41% of Ph+ ALL patients. Of 20 patients who started ponatinib due to intolerance to previous TKIs, 9 (64%) CML and 4 (67%) Ph+ ALL achieved a major molecular response. Three-year estimates of overall survival were 85.3% and 85.6%, respectively, in CML and Ph+ ALL patients; estimated progression-free survival was 81.6% and 48.9%. Adverse reactions were reported in 34 patients (68%); rash (26%) and dry skin (10%) were most common. Reported cardiovascular adverse reactions included vascular stenosis (3), arterial hypertension (2), chest pain (1), palpitations (1), and vascular occlusion (1). This Belgian registry confirms results from the PACE clinical trial and supports routine ponatinib use in CML and Ph+ ALL patients who are resistant or intolerant to previous TKIs or with the T315I mutation.

COVID-19 Induced Pancytopenia in a Major Molecular Response CML patient on Dasatinib: A Case Report and Review of Literature

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (COVID-19), has caused a global health crisis. COVID-19 can have a multifaceted presentation. A wide range of complications and outcomes can emerge based on the severity and comorbidities of the infected patient. We report a 42-year-old male with past medical history of CML on Dasatinib (in Major Molecular Response) who was diagnosed with COVID-19 and developed pancytopenia. Our case and review of available reports add to the limited literature available regarding COVID-19 in CML.