Complete Hematologic Response Research Articles

Early minimal residual disease eradication in light chain amyloidosis generates deeper and faster cardiac response

Minimal residual disease (MRD) is of growing interest in light chain (AL) amyloidosis and is associated with higher rates of cardiac response. A new graded cardiac response criteria has been proposed for better assessment of cardiac improvement. We evaluated MRD status in 63 patients with cardiac AL amyloidosis using next generation flow cytometry (sensitivity ≥ 1*10–5) within four cycles after treatment initiation and cardiac response kinetics. All patients were treated with first-line proteasome inhibitor (100%) and predominantly bortezomib (87.3%). The overall early MRD negative rates were 33.3%. Patients who achieved early MRD negativity were less likely to harbor t(11;14) (21.1% vs 57.5%, P = 0.009). The MRD negative rates amongst patients in hematologic complete response were 66.7% (14/21), and in very good partial response 29.2% (7/24). Early MRD negativity was associated with a higher likelihood of achieving ≥ cardiac partial response (≥ CarPR) (66.7% vs 38.1%, P = 0.032) and ≥ cardiac very good partial response (≥ CarVGPR) (38.1% vs 11.9%, P = 0.023) throughout first-line therapy. The cumulative incidence curve of achieving ≥ CarPR (P = 0.034) and ≥ CarVGPR (P = 0.026) showed significant difference between early MRD negative and positive group. After a median follow-up time of 27.2 months, the median progression free survival was longer in early MRD negative group (not reached vs 31.3 months, P = 0.033). Early MRD eradication in cardiac AL amyloidosis generated deeper and faster cardiac organ response.

Phase II trial of imatinib mesylate in patients with PDGFRA/B-negative hypereosinophilic syndrome.

The role of imatinib in PDGFRA/B-negative hypereosinophilic syndromes (HES) is controversial because of the heterogeneity of HES and the scarcity of prospective studies. We conducted a phase II clinical trial to evaluate the efficacy of imatinib in PDGFRA/B-negative HES. Thirty-two patients were treated with imatinib (100-400 mg daily), and the molecular basis of their response was identified using whole-exome sequencing (WES) and whole-transcriptome sequencing (WTS). The haematological response rate was 46.9%, with a complete haematological response (CHR) rate of 18.8%. The median time to response was 1.5 months. Among the six patients who achieved CHR, five maintained it until the 24th cycle of imatinib and one lost response after 20 months. The median progression-free survival was 4.3 months. WES and WTS were conducted for 11 patients. The number of non-silent mutations did not differ between responders and non-responders. Nine differentially expressed genes, including SNORD15A, were downregulated in responders. STAT5B::RARA, PAK2::PIGX, and FIP1L1::CHIC2 fusions were identified in patients with sustained responses, and RNF130::BRAF and WNK1::KDM5A fusions were identified in non-responders. Imatinib, along with an appropriate biomarker, could be a promising option for PDGFRA/B-negative HES.

Long-term safety and efficacy of ropeginterferon alfa-2b in Japanese patients with polycythemia vera.

Ropeginterferon alfa-2b (ropegIFN), a new-generation interferon-based agent, has been approved in Japan for patients with polycythemia vera (PV) who are ineligible for or respond inadequately to conventional treatment. However, long-term outcomes with ropegIFN in Japanese patients have not been reported. This extension of a phase2 study of ropegIFN in Japanese patients with PV aimed to determine its long-term safety/efficacy, and changes over time in JAK2 V617F allele burden. Here, we report data from the phase2 study and subsequent extension over a period of 36months. The primary endpoint was the complete hematologic response (CHR) maintenance rate without phlebotomy (hematocrit value < 45% without phlebotomy during the previous 12weeks, platelet count ≤ 400 × 109/L, and white blood cell count ≤ 10 × 109/L). The CHR maintenance rates were 8/27 (29.6%), 18/27 (66.7%), and 22/27 (81.5%) at 12, 24, and 36months, respectively. No thrombotic or hemorrhagic events occurred. The median allele burden change from baseline was - 74.8% at 36months. All patients experienced adverse events; 25/27 (92.6%) experienced adverse drug reactions (ADRs), but no serious ADRs or deaths occurred. This interim analysis demonstrated the safety and efficacy of ropegIFN over 36months in Japanese patients with PV.

Outcomes of Dose Escalation of Imatinib in Chronic Myeloid Leukemia Patients: A Retrospective Analysis From an Indian University Teaching Hospital.

Chronic myeloid leukemia (CML) treatment in low- and middle-income countries faces significant financial and logistical constraints. In scenarios where second-line tyrosine kinase inhibitors (TKIs) are unavailable or unaffordable, dose escalation of imatinib provides an alternative. This study evaluates the efficacy, safety, and progression-free survival (PFS) outcomes of dose escalation of imatinib in CML patients who experienced suboptimal response or progression on standard doses. A retrospective analysis of 123 CML patients treated at an Indian university teaching hospital from 2013 to 2016 was conducted. Patients who showed progression on a 400 mg dose of imatinib were escalated to 600 mg, and further to 800 mg if required. Demographic data, progression, and toxicity were analyzed. Out of 123 patients, 78 (63.4%) showed a complete hematologic response after dose escalation. The median PFS was 48 months, with a three-year PFS rate of 67%. Notable toxicities included Grade 3/4 neutropenia in 15% and gastrointestinal disturbances in 12%. Comparatively, studies suggest that switching to a second-line TKI in similar settings results in a higher PFS; however, our findings underscore that dose escalation of imatinib remains a viable alternative when financial constraints limit access to second-line therapies. In resource-constrained settings, dose escalation of imatinib can be an effective strategy for managing CML patients who progress on standard doses.

Prognostic value of response to first-line hydroxyurea according to IPSET stratification in essential thrombocythemia.

Hydroxyurea (HU) constitutes the first-line treatment in most patients with essential thrombocythemia (ET), but criteria for changing therapy are not clearly established. The prognostic value of complete hematological response (CHR) and resistance/intolerance to HU was assessed in 1080 patients from the Spanish Registry of ET, classified according to revised IPSET-Thrombosis stratification (Very low- n = 61, Low- n = 83, Intermediate- n = 261, and High-risk n = 675). With a median therapy duration of 5 years, CHR was registered in 720 (67%) patients (1-year probability 51%) and resistance/intolerance in 219 (20%) patients (5-years probability 13%). After correction by other risk factors, High-risk patients achieving CHR showed a reduced risk of arterial thrombosis (HR: 0.35, 95%CI: 0.2-0.6, p = 0.001) and a trend towards lower risk of venous thrombosis (HR: 0.45, 95%CI: 0.2-1.02, p = 0.06) whereas no association was observed for intermediate- or low-risk patients. In comparison with non-responders, intermediate- and high-risk patients achieving CHR had longer survival and lower myelofibrosis incidence. Development of resistance/intolerance to HU, mainly cytopenia, was associated with higher probability of myelofibrosis but no effect on survival or thrombotic risk was demonstrated. In conclusion, CHR with HU is associated with better outcomes and might be an early indicator for selecting candidates to second-line clinical trials.

Factors impeding organ recovery despite a deep haematological response in patients with systemic AL amyloidosis.

Patients with AL amyloidosis can have persistent organ dysfunction despite achieving a haematological complete response (hemCR). We aimed to identify factors for organ non-response among 143 patients who achieved hemCR for ≥6 months. Kidney, heart and liver non-response were observed in 40/117 (34%), 19/68 (28%) and 3/17 (18%) patients respectively. Predisposing factors varied by organ system. Kidney non-responders had more advanced organ dysfunction at diagnosis, whereas heart non-responders had disproportionately more lambda-typic amyloidogenic light chains. Most patients without an apparent reason for organ non-response had detectable residual clonal disease. The interplay of factors impeding organ recovery in AL amyloidosis is complex.

Prognostic impact of cytogenetic abnormalities detected by FISH in AL amyloidosis with daratumumab-based frontline therapy

AbstractWe performed an international retrospective study on 283 patients with light chain (AL) amyloidosis to investigate the prognostic impact of cytogenetic abnormalities by fluorescence in situ hybridization, when treated with frontline daratumumab–based therapy. The cytogenetic subgroups of interest were t(11;14), gain/amp(1q) (hereafter, +1q), hyperdiploidy, deletion(13q), del(17p), and myeloma high-risk (HR) translocations (t[4;14], t[14;16], or t[14;20]). The end points of interest were rate of hematologic complete response (heme-CR), very good partial response (VGPR) or better, and hematologic event-free survival (heme-EFS). The incidence of abnormalities was as follows: t(11;14), 53.4%; deletion (13q), 28.9%; +1q, 22.3%; hyperdiploidy, 19.4%; HR translocations, 6.6%; and deletion(17p), 4.5%. The heme-CR rate by cytogenetic subgroups were as follows: t(11;14) vs no t(11;14), 45.2% vs 41.8% (P=0.597); del(13q) vs no del(13q), 46.8% vs 42.8% (P=0.594); +1q vs no +1q, 30.2% vs 47.9% (P=0.022); hyperdiploidy vs no hyperdiploidy, 39.5% vs 44.9% (P=0.541); HR translocations vs none, 45.5% vs 43.1% (P=0.877); and del(17p) vs no del(17p), 50.0% vs 42.9% (P=0.658), respectively. Similarly, +1q was the only subgroup with a significantly lower VGPR or better rate (64.2% vs 79.0%; P=0.033). At a median follow-up of 19.8 months, the median heme-EFS was 49.6 months (95% CI, 24.7-not reached [NR]), and the 2-year overall survival (OS) was 80.98% (95% CI, 75.6-85.4). The presence of +1q was significantly associated with worse heme-EFS on multivariate analysis (HR 2.06, 95% CI, 1.14-3.71; P=0.017). Notably, there was no adverse prognostic impact of t(11;14) on heme-EFS or OS. In conclusion, +1q is associated with worse outcome in the daratumumab-era. Clinical trials testing novel frontline immunotherapies should be enriched in +1q to further improve outcomes in this subgroup.

Global characteristics and outcomes of autologous hematopoietic stem cell transplantation for newly diagnosed multiple myeloma: A study of the worldwide network for blood and marrow transplantation (WBMT).

Autologous hematopoietic cell transplantation (AHCT) is a commonly used treatment in multiple myeloma (MM). However, real-world global demographic and outcome data are scarce. We collected data on baseline characteristics and outcomes from 61 725 patients with newly diagnosed MM who underwent upfront AHCT between 2013 and 2017 from nine national/international registries. The primary endpoint was overall survival (OS), and the secondary endpoints were progression-free survival (PFS), relapse incidence (RI) and non-relapse mortality (NRM). Median OS amounted to 90.2 months (95% CI 88.2-93.6) and median PFS 36.5 months (95% CI 36.1-37.0). At 24 months, cumulative RI was 33% (95% CI 32.5%-33.4%) and NRM was 2.5% (95% CI 2.3%-2.6%). In the multivariate analysis, superior outcomes were associated with younger age, IgG subtype, complete hematological response at auto-HCT, Karnofsky score of 100%, international staging scoring (ISS) stage 1, HCT-comorbidity index (CI) 0, standard cytogenetic risk, auto-HCT in recent years, and use of lenalidomide maintenance. There were differences in the baseline characteristics and outcomes between registries. While the NRM was 1%-3% at 12 months worldwide, the OS at 36 months was 69%-84%, RI at 12 months was 12%-24% and PFS at 36 months was 43%-63%. The variability in these outcomes is attributable to differences in patient and disease characteristics as well as the use of maintenance and macroeconomic factors. In conclusion, worldwide data indicate that AHCT in MM is a safe and effective therapy with an NRM of 1%-3% with considerable regional differences in OS, PFS, RI, and patient characteristics. Maintenance treatment post-AHCT had a beneficial effect on OS.

A randomized, double-blind, placebo-controlled phase 3 study to assess efficacy and safety of ropeginterferon alfa-2b in patients with early/lower-risk primary myelofibrosis

Primary myelofibrosis (PMF) is the most aggressive of the myeloproliferative neoplasms and patients require greater attention and likely require earlier therapeutic intervention. Currently approved treatment options are limited in their selective suppression of clonal proliferation resulting from driver- and coexisting gene mutations. Janus kinase inhibitors are approved for symptomatic patients with higher-risk PMF. Additionally, most ongoing clinical studies focus on patients with higher-risk disease and/or high rates of transfusion dependency. Optimal treatment of early/lower-risk PMF remains to be identified and needs randomized clinical trial evaluations. Pegylated interferon alfa is recommended for symptomatic lower-risk PMF patients based on phase 2 non-randomized studies and expert opinion. Ropeginterferon alfa-2b (ropeg) is a new-generation pegylated interferon-based therapy with favorable pharmacokinetics and safety profiles, requiring less frequent injections than prior formulations. This randomized, double-blind, placebo-controlled phase 3 trial will assess its efficacy and safety in patients with “early/lower-risk PMF”, defined as pre-fibrotic PMF or PMF at low or intermediate-1 risk according to Dynamic International Prognostic Scoring System-plus. Co-primary endpoints include clinically relevant complete hematologic response and symptom endpoint. Secondary endpoints include progression- or event-free survival, molecular response in driver or relevant coexisting gene mutations, bone marrow response, and safety. Disease progression and events are defined based on the International Working Group criteria and well-published reports. 150 eligible patients will be randomized in a 2:1 ratio to receive either ropeg or placebo. Blinded sample size re-estimation is designed. Ropeg will be administered subcutaneously with a tolerable, higher starting-dose regimen. The study will provide important data for the treatment of early/lower-risk PMF for which an anti-clonal, disease-modifying agent is highly needed.

Unveiling the nephrotoxic profile of BCR-ABL tyrosine kinase inhibitors: A real-world experience in Africa.

The efficacy of BCR-ABL tyrosine kinase inhibitors (TKIs) in treating chronic myelogenous leukemia and other malignancies is well-documented. However, concerns about potential nephrotoxicity have raised questions. This study, conducted at Tikur Anbesa Specialized Hospital (TASH) in Addis Ababa, Ethiopia, aimed to investigate the association between TKIs and renal toxicities. A hospital-based cross-sectional design was used to enroll 260 TASH patients actively receiving BCR-ABL TKIs. Demographic information, diagnoses, treatment details, and laboratory test results were collected for each participant's Electronic Medical Record. The primary goal was to assess adverse renal events, a combination of events of a decrease in estimated glomerular filtration rate (eGFR) exceeding 30% from baseline, significant proteinuria, and a diagnosis of acute kidney injury (AKI) or chronic kidney disease (CKD). A logistic regression model was used to analyze the data and identify factors associated with developing adverse renal events. Our analysis revealed a statistically significant decrease in eGFR following treatment with TKIs. However, the observed rate of adverse renal events (13.1%) was lower than reported in some previous studies. Factors significantly associated with adverse renal events included longer TKI duration, male sex (protective), hypertension, HIV infection, and achieving complete molecular remission and/or a complete hematologic response. No significant associations were found with diabetes mellitus, age, angiotensin-converting enzyme inhibitors use, or baseline creatinine level. While this study found that BCR-ABL TKIs can lead to a decline in eGFR, AKI, and CKD, it also demonstrated that they were relatively safer in our study population.

Light chain only variant of proliferative glomerulonephritis with monoclonal immunoglobulin deposits: a clinicopathological study of three cases

AimsTo explore the clinical and pathological features of light chain only variant of proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID-LC).MethodsFrom January 2010 to December 2022, patients who were diagnosed with...

An open-label, prospective trial to evaluate the efficacy and safety of ixazomib in combination with cyclophosphamide and dexamethasone in patients with newly diagnosed POEMS syndrome.

This open-label, prospective trial evaluated the combination of ixazomib, cyclophosphamide and dexamethasone (ICD) in 12 newly diagnosed POEMS syndrome patients. The study is registered with the Chinese Clinical Trials Registry (ChiCTR2000030072). The treatment protocol consisted of 12 cycles of the ICD regimen compromising ixazomib (4 mg on Days 1, 8 and 15), oral cyclophosphamide (300 mg on Days 1, 8 and 15) and dexamethasone (20 mg weekly). A total of 12 patients received a median of 10 (range: 3-23) cycles of the ICD regimen. The haematological response could be evaluated in 10 patients. The overall haematological response rate was 80% (8/10), with 30% (3/10) achieving complete haematological response, and the overall serum VEGF response rate and neurological response were 100% and 83.3% respectively. Two patients experienced grade 3/4 AEs, including diarrhoea (n = 1) and leukopenia (n = 1). The combination of ixazomib, cyclophosphamide and dexamethasone demonstrated both efficacy and safety in newly diagnosed POEMS syndrome, making it a viable treatment option.

Safety and efficacy of flumatinib as later-line therapy in patients with chronic myeloid leukemia.

To evaluate the efficacy and safety of flumatinib in the later-line treatment of Chinese patients with Philadelphia chromosome-positive chronic-phase chronic myeloid leukemia (CP-CML previously treated with tyrosine kinase inhibitors (TKIs). Patients with CML-CP were evaluated for the probabilities of responses including complete hematologic response (CHR), cytogenetic response, and molecular response (MR) and adverse events (AEs) after the later-line flumatinib therapy. Of 336 enrolled patients with median age 50 years, median duration of treatment with flumatinib was 11.04 (2-25.23) months. Patients who achieved clinical responses at baseline showed maintenance of CHR, complete cytogenetic response (CCyR)/2-log molecular response (MR2), major molecular response (MMR), and 4-log molecular response or deep molecular response (MR4/DMR) in 100%, 98.9%, 98.6%, and 92.9% patients, respectively. CHR, CCyR/MR2, MMR, and MR4/DMR responses were achieved in 86.4%, 52.7%, 49.6%, and 23.5% patients respectively, which showed the lack of respective clinical responses at baseline. The patients without response at baseline, treated with flumatinib as 2L TKI, having no resistance to prior TKI or only resistance to imatinib, with response to last TKI, and with BCR::ABL ≤10% had higher CCyR/MR2, MMR, or MR4/DMR. The AEs observed during the later-line flumatinib treatment were tolerable and consistent with those reported with the first-line therapy. Flumatinib was effective and safe in patients who are resistant or intolerant to other TKIs. In particular, 2L flumatinib treatment induced high response rates and was more beneficial to patients without previous 2G TKI resistance, thus serving as a probable treatment option for these patients.

#1028 Experience with ravulizumab in atypical hemolytic uremic syndrome

Abstract Background and Aims The arrival of eculizumab revolutionized the treatment of Atypical Hemolytic Uremic Syndrome (aHUS). Ravulizumab also offers C5 inhibition, but with 3-4 times longer half- life. We describe the experience with ravulizumab in patients with aHUS in two scenarios: 1. Switching from another C5 inhibitor in stable patients; 2. Direct initiation of therapy with ravulizumab (naïve). Method We present 9 patients with an average age of 42 ± 13 years and weight of 81 ± 12.4 kg. The switch to ravulizumab was initiated 2 weeks after the last dose of eculizumab in switch patients, while in naïve patients it was initiated after excluding other causes of aHUS. The initial dose was 2700 mg, followed by a second dose of 3300 mg after 2 weeks, and subsequently every 2 months. Analytical variables of renal function, hematological parameters, and complement were collected. Results Switch : 6 patients (50% females), 4/6 were transplant recipients (3 on prophylactic treatment). Regarding renal function, 5/6 patients had a complete response with eculizumab (creatinine 1.33 ± 0.32 mg/dL, eGFR 59.5 ± 34.3 mL/min/1.73 m2, proteinuria 115 ± 91.5 mg/g), and all of them had a complete hematological response. After the switch, all patients maintained a complete hematological response, stability of renal function, and serum complement levels. Naïve : 3 cases (2 males); 2/3 required hemodialysis (HD) at presentation. The renal response was complete in two patients and partial in the third (who discontinued HD after 90 days and currently remains stable with stage G3b chronic kidney disease). All three patients had a complete hematological response. Only 3 adverse effects were documented (arthralgia, headache, and rhinitis), with no cases of infection. Conclusion The use of ravulizumab is effective both in maintaining a complete response after switching from eculizumab and as a first-line therapy. The safety profile is comparable, with the main difference being the dosing regimen, as ravulizumab requires fewer administrations and leads to a reduction in direct and indirect costs.

#2622 Very late renal recovery in patient with light chain cast nephropathy: the prognostic value of renal biopsy

Abstract Background and Aims Renal biopsy is not necessary to assess LCCN (Light Chain Cast Nephropathy) in patients with laboratory features suggestive of the disease. However, it has been shown that the histological picture often correlates with renal outcome. We present the case of a 55-year-old man with no significant previous medical history that was evaluated in the emergency department for a stage 3 AKI (sCr 17.3 mg/dl, eGFR 3 ml/min/1.73 m2). Laboratory tests showed a Lambda Micromolecular Myeloma (K chains 44.6 mg/l, λ 4160 mg/l and K/ λ 0.01); Bence Jones not evaluable due to anuria. Bone marrow plasmacytosis was 70%. Method The patient started chemotherapy with Bortezomib and Dexamethasone and hemodialysis thrice a week with a PMMA hemofilter in order to improve the FLC (Free Light Chain) removal rate. After three months of treatment the patient achieved a complete hematologic response but he didn't reach any renal response. In order to assess a more precise renal prognosis a kidney biopsy was performed. The histopathological exam showed a Cast Nephropathy (&amp;lt; 5 casts/mm2) associated with low grade interstitial fibrosis and tubular atrophy (IFTA +1). After 5 cycles with Bortezomib and Dexamethasone, one year after onset, the patient underwent ASCT (Autologous Stem Cell Transplantation). Results In the following months, a progressive increase in renal function allowed us to perform a gradual reduction of dialysis rate, until discontinuation occurred 16 months after disease onset. To date, three years after onset, complete hematologic and renal remission persists with an eGFR of 20 ml/min/1.73 m2. Conclusion Renal biopsy, performed even several months after disease onset, could play a pivotal role in cases of LCCN with a discordance between hematologic and renal response. A low cast number and low IFTA grade are known to be positive prognostic factors for renal outcome and they can predict a renal recovery that sometimes could be exceptionally late.

Frequency of Hematological Response in Patients with Chronic Myeloid Leukemia (Chronic Phase) with Imatinib After Three Months Presenting to CMH Rawalpindi

Objective: To find the frequency of haematological response in patients of chronic myeloid leukaemia (Chronic Phase) after three months of Imatinib Mesylate therapy, presenting to CMH Rawalpindi Study Design: Cross-sectional study. Place and Duration of Study: Department of Oncology Combined Military Hospital, Rawalpindi Pakistan, from Jan to Jun 2020. Methodology: Forty-six patients aged 18 and above within the chronic phase of CML were included. Patients underwent detailed clinical history, examination, baseline investigations, and bone marrow studies at presentation. Enrolled patients were given 400mg of Imatinib, and a complete haematological response was noted at the end of 3 months of therapy. Results: In our study, the age of patients ranged from 18 to 67 years, with a mean age of 47.2+10.6 years. 33(71.7%)were male, and 13(28.3%) were female. 42(91.3%) patients achieved complete haematological response to Imatinib at three months of therapy. Adverse drug reactions exhibited were oedema 18(39.1%), gastrointestinal disturbance 12(26.1%), anaemia 05(10.9%), and skin reactions 03(6.5%). Conclusion: This study has concluded that Imatinib Mesylate is highly effective in treating chronic phase CML at the haematological level and can be considered the drug of first choice in CML-CP.

JAK2 as Predictor of Therapeutic Response in Patients with Chronic Myeloid Leukemia Treated with Imatinib.

Chronic myeloid leukemia (CML) or chronic granulocytic leukemia is a myeloproliferative neoplasm indicated by the presence of the Philadelphia (Ph+) chromosome. First-line tyrosine kinase inhibitor, imatinib, is the gold standard for treatment. However, there has been known unresponsiveness to treatment, especially due to the involvement of other genes, such as the Janus kinase 2 (JAK2) gene. This study aimed to evaluate the relationships between JAK2 levels and complete hematological response (CHR), as well as early molecular response (EMR) after 3 months of imatinib treatment in patients with chronic phase CML. Patients with Ph+ CML in the chronic phase (n = 40; mean age, 40 ± 11 years) were recruited to complete assessments consisting of clinical examination and blood test, including evaluation of complete blood counts and the JAK2 levels, at baseline and following 3 months of therapy with imatinib (at an oral dose of 400 mg per day). Subjects were divided into two groups according to the presence of CHR and EMR. JAK2 gene levels, phosphorylated, and total JAK2 proteins at baseline were significantly lower in the group with the presence of CHR and EMR. In addition, baseline JAK2 levels, including JAK2 gene expression, phosphorylated, and total JAK2 proteins, were negatively correlated with the presence of CHR and EMR. Based on these findings, JAK2 levels may be a potential indicator for evaluating treatment response on imatinib due to its role in the pathophysiology of CML.

Effective Management of Polycythemia Vera With Ropeginterferon Alfa-2b Treatment.

Polycythemia vera (PV) is a myeloproliferative neoplasm. Ropeginterferon alfa-2b is a new-generation polyethylene glycol-conjugated proline-interferon. It is approved for the treatment of PV at a starting dose of 100 µg (50 µg for patients receiving hydroxyurea (HU)) and dose titrations up to 500 µg by 50 µg increments. The study was aimed at assessing its efficacy and safety at a higher starting dose and simpler intra-patient dose escalation. Forty-nine patients with PV having HU intolerance from major hospitals in China were treated biweekly with an initial dose of 250 µg, followed by 350 µg and 500 µg thereafter if tolerated. Complete hematological response (CHR) was assessed every 12 weeks based on the European LeukemiaNet criteria. The primary endpoint was the CHR rate at week 24. The secondary endpoints included CHR rates at weeks 12, 36 and 52, changes of JAK2V617F allelic burden, time to first CHR, and safety assessments. The CHR rates were 61.2%, 69.4% and 71.4% at weeks 24, 36, and 52, respectively. Mean allele burden of the driver mutation JAK2V617F declined from 58.5% at baseline to 30.1% at 52 weeks. Both CHR and JAK2V617F allele burden reduction showed consistent increases over the 52 weeks of the treatment. Twenty-nine patients (63.0%) achieved partial molecular response (PMR) and two achieved complete molecular response (CMR). The time to CHR was rapid and median time was 5.6 months according to central lab results. The CHRs were durable and median CHR duration time was not reached at week 52. Mean spleen index reduced from 55.6 cm2 at baseline to 50.2 cm2 at week 52. Adverse events (AEs) were mostly mild or moderate. Most common AEs were reversible alanine aminotransferase and aspartate aminotransferase increases, which were not associated with significant elevations in bilirubin levels or jaundice. There were no grade 4 or 5 AEs. Grade 3 AEs were reversible and manageable. Only one AE led to discontinuation. No incidence of thromboembolic events was observed. The 250-350-500 µg dosing regimen was well tolerated and effectively induced CHR and MR and managed spleen size increase. Our findings demonstrate that ropeginterferon alfa-2b at this dosing regimen can provide an effective management of PV and support using this dosing regimen as a treatment option.

The Effect and Safety of Flumatinib in Patients with Chronic Myelogenous Leukemia Failed First-and Second-line Treatment

To analyze the efficacy and safety of flumatinib, a second-generation tyrosine kinase inhibitor (TKI) independently developed in China, in patients with chronic myelogenous leukemia in chronic phase (CML-CP) who falied first-line and second-line treatment. The clinical data of 30 CML-CP patients treated with flumatinib in Lianyungang First People's Hospital from January 2020 to September 2022 were collected retrospectively. Among them, 15 patients who received imatinib first-line treatment but failed treatment were included in the second-line group, and the other 15 patients who failed second-line treatment with nilotinib or dasatinib were included in the third-line group. The hematological and molecular responses of the patients in the two groups at 3, 6 and 12 months of treatment, and the event-free survival (EFS) and adverse reactions of patients at the end of follow-up were statistical analyzed. At 3, 6, and 12 months of treatment, 10, 11, and 12 patients in the second line group achieved major molecular response (MMR), which was higher than that of 3, 4, and 5 patients in the third line group (P =0.010, P =0.011, P =0.010). At 3 months of treatment, 12 and 13 patients achieved complete hematological response (CHR) and early molecular response (EMR) in the second-line group, which was higher than that of 9 and 13 patients in the third-line group, but the difference between the two groups was not statistically significant (P =0.232, P =1.000); At 6 and 12 months of treatment, 6 and 7 patients in the second-line group achieved MR4.5, which were higher than of 3 and 2 cases in the third-line group, but the difference was not statistically significant (P =0.427, P =0.713). The hematological adverse reactions of patients in the second-line group during treatment the period were mainly grade 1-2 thrombocytopenia and anemia, and no grade 3-4 of adverse reactions occurred. In the third-line group, there were 2 cases of grade 1-2 thrombocytopenia, grade 1-2 anemia and white blood cell 3 cases were reduced each, 1 case of grade 3-4 anemia, 2 cases of grade 3-4 neutropenia. The non-hematological adverse reactions in the second-line group were rash (2 cases), headache (1 case), diarrhea (1 case), fatigue (1 case), limb pain (1 case). There were 1 cases of diarrhea, 1 cases of nausea, and 1 cases of edema in the third-line group. There was no statistical significance in hematological and non-hematological adverse reactions between the two groups of patients (P >0.05). At the end of follow-up, the EFS rate of patients in the second-line group was higher than that in the third-line group (100% vs 93.3%), but the difference was not statistically significant (P =0.317). The second-generation TKI flumatinib independently developed in China, has good curative effect and safety for CML-CP patients who failed first-line and second-line treatment.

Treatment outcome and germline predictive factors of ropeginterferon alpha-2b in myeloproliferative neoplasm patients.

Studies have shown that some single nucleotide polymorphisms (SNPs) could serve as excellent markers in foretelling the treatment outcome of interferon (IFN) in myeloproliferative neoplasms (MPN). However, most work originated from western countries, and data from different ethnic populations have been lacking. To gain insights, targeted sequencing was performed to detect myeloid-associated mutations and SNPs in eight loci across three genes (IFNL4, IFN-γ, and inosine triphosphate pyrophosphatase [ITPA]) to explore their predictive roles in our cohort of 21 ropeginterferon alpha-2b (ROPEG)-treated MPN patients, among whom real-time quantitative PCR was also performed periodically to monitor the JAK2V617F allele burden in 19 JAK2V617F-mutated cases. ELN response criteria were adopted to designate patients as good responders if they achieved complete hematological responses (CHR) within 1 year (CHR1) or attained major molecular responses (MMR), which occurred in 70% and 45% of the patients, respectively. IFNL4 and IFN-γ gene SNPs were infrequent in our population and were thus excluded from further analysis. Two ITPA SNPs rs6051702 A>C and rs1127354 C>A were associated with an inferior CHR1 rate and MMR rate, respectively. The former seemed to be linked to grade 2 or worse hepatotoxicity as well, although the comparison was of borderline significance only (50%, vs. 6.7% in those with common haplotype, p = 0.053). Twelve patients harbored 19 additional somatic mutations in 12 genes, but the trajectory of these mutations varied considerably and was not predictive of any response. Overall, this study provided valuable information on the ethnics- and genetics-based algorithm in the treatment of MPN.