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Rationale & Objective Data on kidney transplantation outcomes among patients with monoclonal gammopathy of renal significance (MGRS) are lacking. Study Design Case series of patients with MGRS, some of whom received clone-directed therapies before kidney transplantation. Setting & Participants 28 patients who underwent kidney transplantation from 1987 through 2016 after diagnosis with MGRS-associated lesions including light-chain deposition disease (LCDD), C3 glomerulopathy with monoclonal gammopathy (C3G-MG), and light-chain proximal tubulopathy (LCPT). Findings Of the 19 patients with LCDD, 10 were treated before kidney transplantation and 9 were treatment-naive. Among the treated patients with LCDD, 3 (30%) experienced histologic recurrence, 2 (20%) grafts failed, and 2 (20%) died during a median follow-up of 70 (range, 3-162) months after transplant. In the treatment-naive LCDD group, 8 (89%) had histologic recurrence, 6 (67%) grafts failed, and 4 (44%) patients died during a median follow-up of 60 (range, 35-117) months. Of the 5 patients who had a complete response before transplant, none died, and only 1 experienced graft failure, 162 months after transplant. Of 5 patients with C3G-MG, 3 were treatment-naive before transplant. Both patients who were treated before transplant had histologic recurrence, and 1 experienced graft failure and died. Among the 3 patients with treatment-naive C3G-MG, histologic recurrence occurred in all, and graft loss and death were observed in 2 and 1, respectively. In the LCPT group (n = 4), histologic recurrence was observed in all 3 patients who did not receive clone-directed therapies before transplant, and 2 of these patients died, 1 with a functioning kidney. The 1 patient with LCPT who received therapy before transplant did not have histologic recurrence or graft loss and survived. Limitations Small sample size, nonstandardized clinical management, retrospective design. Conclusions Recurrence is very common in all MGRS-associated lesions after kidney transplant. Achieving a complete hematologic response may reduce the risks of recurrence, graft loss, and death. More studies are needed to determine the effects of hematologic response on outcomes for each MGRS-associated lesion.

Monoclonal immunoglobulin deposition disease (MIDD) usually leads to kidney failure. Treatment of patients with a bortezomib-based regimen followed by autologous stem cell transplantation (SCT) has been increasingly used, with improvements in the response rates and allograft outcomes in kidney transplant recipients. The objective of this report was to analyze the outcomes of 6 patients who underwent kidney transplantation in our institution after treatment of MIDD between 2010 and 2019. Monoclonal immunoglobulin deposition disease was initially treated with bortezomib-based therapy followed by high-dose melphalan and autologous SCT with complete hematologic response, although all patients remained on dialysis. During a median follow-up of 20.5 months from kidney transplant (54 months from SCT), 1 patient experienced hematologic relapse and 2 had hematologic progression (one of them with MIDD relapse in the allograft) requiring treatment. The patient with organ relapse received daratumumab monotherapy, achieving complete hematologic response but with graft failure. The other 5 patients had functional grafts with median serum creatinine 1.68 mg/dL. These results support that, in patients with MIDD and sustained complete hematologic response, a kidney transplant can be considered. The optimal approach to treatment of hematologic relapse or recurrence of MIDD after kidney transplant remains to be determined.

Myeloid-derived suppressor cells (MDSCs) represent phenotypically heterogeneous populations that suppress tumor-specific T-cell responses. MDSCs are produced from myeloid precursors in emergent states and are increased in several hematologic malignancies. We evaluated the differences in the levels and prognostic significance of MDSCs according to the clinical status of chronic myeloid leukemia (CML). The percentages and numbers of granulocytic (g)MDSCs and monocytic (m)MDSCs in peripheral blood (PB) and bone marrow (BM) aspirates were determined by five-color flow cytometry (HLA-DR/CD11b/CD15/CD33/CD14). The median BM-gMDSC% and PB-gMDSC% of the CML group were lower than those of the complete hematologic response (CHR) and control groups (P

Chronic myeloid leukemia (CML) is a rare disease among children. A retrospective study was conducted from November 2002 to March 2019 at a single institution in China. A total of 36 pediatric CML patients (25 male and 11 female) were enrolled. Median follow-up time was 51 months (range 8-144), and 5-year overall survival and event-free survival were 95.5 ± 4.4% and 88.9 ± 6.0%, respectively. Among the 25 patients whose response to imatinib mesylate (IM) was regularly monitored, 92.0% achieved complete hematologic response at 3 months, 80.0% achieved complete cytogenetic response at 12 months, and 64.0% achieved major molecular response at 18 months after IM therapy. A higher WBC count at diagnosis was associated with failure to achieve early molecular response (EMR). Height standard deviation score after long-term treatment was significantly and positively correlated with age at diagnosis and at the start of IM therapy. Overall, IM therapy was effective in treating pediatric CML, and WBC count at diagnosis might be an ideal predictor of EMR. Moreover, retardation of height and weight growth due to IM tended to affect patients younger than 9 years old at diagnosis, and longitudinal growth might normalize further into treatment.

Background Myelofibrosis (MF) is a Philadelphia chromosome–negative myeloproliferative neoplasm characterized by progressive bone marrow failure, increased risk of progression to acute myeloid leukemia, and constitutional symptoms. For over 3 decades, various formulations of interferon (IFN) have been used for the treatment of MF, with variable results, and the role of IFN in the treatment of MF is evolving. Patients and Methods For this systematic review and meta-analysis, Medline and Embase via Ovid, Scopus, Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science were searched from inception through March 2019 for studies of pegylated IFN (peg-IFN) and non–peg-IFN in MF patients. The primary outcome of overall response rate was defined as a composite of complete response, partial response, complete hematologic response, and partial hematologic response. Random-effects models were used to pool overall response rate, and metaregression analyses were performed to compare peg-IFN and non-–peg-IFN formulations. Results Among the 10 studies with 141 MF patients included, the overall response rate was 49.9% (95% confidence interval [CI], 30.4-69.3), and there was no statistically significant difference (P = .99) between peg-IFN (50.0%; 95% CI, 26.2-73.9; I2 = 76.9%) and non–peg-IFN (49.6%; 95% CI, 20.5-79.0; I2 = 56.7%). Treatment discontinuation resulting from adverse events was common with non–peg-IFN at 35.8% (95% CI, 3.5-68.1) per year, and less in the one study on peg-IFN (0.5% per year). Conclusion IFN can lead to hematologic improvements in a subset of MF patients, but study quality is limited and heterogenous. Biomarkers predicting response to IFN and formulations with improved tolerability are needed.

Data on the efficacy and safety of interferon (IFN)-α for the treatment of essential thrombocythemia (ET) and polycythemia vera (PV) are inconsistent. We conducted a systematic review and meta-analysis and searched MEDLINE and EMBASE via Ovid, Scopus, COCHRANE registry of clinical trials (CENTRAL), and Web of Science from inception through 03/2019 for studies of pegylated IFN (peg-IFN) and non-pegylated IFN (non-peg-IFN) in PV and ET patients. Random-effects models were used to pool response rates for the primary outcome of overall response rate (ORR) defined as a composite of complete response, partial response, complete hematologic response (CHR) and partial hematologic response. Peg-IFN and non-peg-IFN were compared by meta-regression analyses. 44 studies with 1359 patients (730 ET, 629 PV) were included. ORR were 80.6% (95% confidence interval: 76.6–84.1%, CHR: 59.0% [51.5%−66.1%]) and 76.7% (67.4–84.0%; CHR: 48.5% [37.8–59.4%]) for ET and PV patients, respectively. In meta-regression analyses results did not differ significantly for non-peg-IFN vs. peg-IFN. Annualized rates of thromboembolic complications and treatment discontinuation due to adverse events were low at 1.2% and 8.8% for ET and 0.5% and 6.5% for PV patients, respectively. Both peg-IFN and non-peg-IFN can be effective and safe long-term treatments for ET and PV.

Although no therapies are approved for light chain (AL) amyloidosis, cyclophosphamide, bortezomib, and dexamethasone (CyBorD) is considered standard of care. Based on outcomes of daratumumab in multiple myeloma (MM), the phase 3 ANDROMEDA study (NCT03201965) is evaluating daratumumab-CyBorD vs CyBorD in newly diagnosed AL amyloidosis. We report results of the 28-patient safety run-in. Patients received subcutaneous daratumumab (DARA SC) weekly in cycles 1 to 2, every 2 weeks in cycles 3 to 6, and every 4 weeks thereafter for up to 2 years. CyBorD was given weekly for 6 cycles. Patients had a median of 2 involved organs (kidney, 68%; cardiac, 61%). Patients received a median of 16 (range, 1-23) treatment cycles. Treatment-emergent adverse events were consistent with DARA SC in MM and CyBorD. Infusion-related reactions occurred in 1 patient (grade 1). No grade 5 treatment-emergent adverse events occurred; 5 patients died, including 3 after transplant. Overall hematologic response rate was 96%, with a complete hematologic response in 15 (54%) patients; at least partial response occurred in 20, 22, and 17 patients at 1, 3, and 6 months, respectively. Renal response occurred in 6 of 16, 7 of 15, and 10 of 15 patients, and cardiac response occurred in 6 of 16, 6 of 13, and 8 of 13 patients at 3, 6, and 12 months, respectively. Hepatic response occurred in 2 of 3 patients at 12 months. Daratumumab-CyBorD was well tolerated, with no new safety concerns versus the intravenous formulation, and demonstrated robust hematologic and organ responses. This trial was registered at www.clinicaltrials.gov as #NCT03201965.

Introduction Chronic myeloid leukemia (CML) is an uncommon malignancy in children in which tyrosine kinase inhibitors (TKIs) have significantly improved outcome in recent years. Patients and Methods We performed a retrospective analysis of CML patients (≤ 18 years old) presenting to our center between January 2005 and December 2018 with respect to baseline demographics, response to imatinib, and real-world management of those with a suboptimal response. Results A total of 124 patients were diagnosed with CML with 99 (80%) in the chronic phase. There was a male preponderance (males:females = 3.1:1) with a median age of 13 years. The common presenting clinical features were splenomegaly (90.9%) and fever (51.5%) with a median leukocyte count of 165 × 103/μL. The proportion of patients attaining a complete hematologic response (CHR) at 3 months, a complete cytogenetic response (CCyR) at 12 months, and a major molecular response at 12 months were 79.7%, 54.1%, and 50.9%, respectively. At a median follow-up of 67.4 months, the 5-year overall survival rate and the event-free survival (EFS) rate were 92% ± 3% and 64% ± 6%, respectively. Failure to achieve CCyR at 12 months was associated with poor EFS beyond 1 year (hazard ratio = 2.865, P = .044). Among 15 patients not achieving CHR at 3 months, dose escalation of imatinib resulted in the attainment of CHR in 13 (87%) patients. Seven patients in the cohort had a loss of the established response to imatinib because of documented poor compliance. Conclusion Imatinib remains the frontline treatment of choice in CML with a reasonable outcome in children, especially when financial affordability, availability of second-generation TKIs, and poor compliance still remain major challenges in management. Dose escalation of imatinib remains an option in patients with a suboptimal response.

Malignant cells can increase in number using immune escape mechanisms such as immune checkpoints. In this study, we evaluated the expression of an immune checkpoint programmed death 1 (PD-1) on T-cell subsets in chronic myeloid leukemia (CML). We obtained bone marrow aspirate samples from CML patients and from individuals without evidence of hematologic malignancies (controls). PD-1 expression on T-cell subsets was measured using flow cytometric analysis. PD-1 expression levels on CD8+ T-cells were significantly lower in complete hematologic response (CHR) than in controls, chronic phase, and blast phase (BP). In CML patients receiving imatinib and dasatinib, PD-1 expression levels on CD8+ T-cells were lower than that at diagnosis. PD-1 expression levels on CD8+ T-cells were positively correlated with quantitative levels of the BCR/ABL fusion gene. PD-1 expression levels on CD4+ T-cells were higher in BP than in CHR. PD-1 expression levels on CD4+ T-cells did not differ significantly according to different medications or quantitative BCR/ABL1 fusion gene levels. Low PD-1 expression on CD8+ T-cells might play a role in maintaining CHR in CML patients. Immune monitoring of PD-1 expression on CD8+ T-cells may predict the disease course. In cases of refractory disease or resistance to imatinib or dasatinib, the use of PD-1 inhibitors would be helpful.

We report on 18 patients with myeloid neoplasms and associated tyrosine kinase (TK) fusion genes on treatment with the TK inhibitors (TKI) ruxolitinib (PCM1-JAK2, n = 8; BCR-JAK2, n = 1) and imatinib, nilotinib or dasatinib (ETV6-ABL1, n = 9). On ruxolitinib (median 24 months, range 2-36 months), a complete hematologic response (CHR) and complete cytogenetic response (CCR) was achieved by five of nine and two of nine patients, respectively. However, ruxolitinib was stopped in eight of nine patients because of primary resistance (n = 3), progression (n = 3) or planned allogeneic stem cell transplantation (allo SCT, n = 2). At a median of 36 months (range 4-78 months) from diagnosis, five of nine patients are alive: four of six patients after allo SCT and one patient who remains on ruxolitinib. In ETV6-ABL1 positive patients, a durable CHR was achieved by four of nine patients (imatinib with one of five, nilotinib with two of three, dasatinib with one of one). Because of inadequate efficacy (lack of hematological and/or cytogenetic/molecular response), six of nine patients (imatinib, n = 5; nilotinib, n = 1) were switched to nilotinib or dasatinib. At a median of 23 months (range 3-60 months) from diagnosis, five of nine patients are in CCR or complete molecular response (nilotinib, n = 2; dasatinib, n = 2; allo SCT, n = 1) while two of nine patients have died. We conclude that (a) responses on ruxolitinib may only be transient in the majority of JAK2 fusion gene positive patients with allo SCT being an important early treatment option, and (b) nilotinib or dasatinib may be more effective than imatinib to induce durable complete remissions in ETV6-ABL1 positive patients.

In patients with immunoglobulin light-chain (AL) amyloidosis, depth of hematologic response correlates with both organ response and overall survival. Our group has demonstrated that screening with a matrix-assisted laser desorption/ionization-time-of-flight (TOF) mass spectrometry (MS) is a quick, sensitive, and accurate means to diagnose and monitor the serum of patients with plasma cell disorders. Microflow liquid chromatography coupled with electrospray ionization and quadrupole TOF MS adds further sensitivity. We identified 33 patients with AL amyloidosis who achieved amyloid complete hematologic response, who also had negative bone marrow by six-color flow cytometry, and who had paired serum samples to test by MS. These samples were subjected to blood MS. Four patients (12%) were found to have residual disease by these techniques. The presence of residual disease by MS was associated with a poorer time to progression (at 50 months 75% versus 13%, p = 0.003). MS of the blood out-performed serum and urine immunofixation, the serum immunoglobulin free light chain, and six-color flow cytometry of the bone marrow in detecting residual disease. Additional studies that include urine MS and next-generation techniques to detect clonal plasma cells in the bone marrow will further elucidate the full potential of this technique.

Autologous stem cell transplantation (ASCT) has been an essential part of the treatment armamentarium in light chain (AL) amyloidosis for several decades. Patients who achieve a complete hematologic response following ASCT have a long overall survival. However, only 1 randomized controlled trial compared ASCT with the standard of care used at the time, which was melphalan and dexamethasone, and the results did not support the use of ASCT in AL amyloidosis. These results are of limited significance due to the unexpected high transplant-related mortality (TRM) (24%). TRM is a major concern in AL amyloidosis, but its incidence can be lessened by better patient selection and by patients receiving ASCT in specialized centers. ASCT in AL amyloidosis is performed only in selected patients; approximately 20% of patients with AL amyloidosis are transplant eligible up front or after bortezomib (Velcade) based conditioning. The introduction of newer agents such as bortezomib and daratumumab (Darzalex), which lead to deep responses and have good safety profiles, encourage revisiting the benefit and timing of ASCT in the modern era. This review provides a comprehensive assessment of eligibility criteria for ASCT in AL amyloidosis, conditioning dosing, efficacy in terms of hematologic and organ response, and future areas of research.

Imatinib is now used as the first-line drug to treat CML patient. However, the emergence of resistance to Imatinib in CML patient, the side effect of bone marrow suppression, fluid overload and gastritis are a major limitation of the use of Imatinib in the treatment of CML. This study was conducted to see the therapeutic response and side effect profile of generic Imatinib Mesylate in newly diagnosed CML patients. All cases of CML were given generic Imatinib and followed prospectively with a minimum follow-up of 6 months. They were followed at an interval of 2 weeks till complete hematologic response, thereafter at an interval of 6 to 8 weeks. Cytogenetic and molecular response at the end of one year also evaluated. Among 36 CML patients, 33 were in chronic phase 2 in accelerated phase and 1 in blast crisis while 35 were Philadelphia+ve and 1 was ph–ve at initial presentation. Minimum duration to achieve CHR was 2 week with a mean of 5 weeks. At 3 month except one 35 patients achieved CHR (97%). Out of 36 patients, 27 were subjected for Philadelphia chromosome at one year which shown 23 patients (85.18%) achieved a major cytogenetic response. 8 (38%) patients achieved a major molecular response and one patient (4.76%) was having a complete molecular response at one year. 8 (22.22%) patients developed hematological toxicity to Imatinib with Pancytopenia most common. In conclusion, Generic Imatinib is having an excellent therapeutic response in CML patients although higher response rate may be due to smaller sample size and lesser duration of follow up.

International audience; PurposeTo assess the incidence of BCR‐ABL kinase domain (KD) mutation detection and its prognostic significance in chronic phase chronic myeloid leukemia (CP‐CML) patients treated with tyrosine kinase inhibitors (TKIs).Patients and MethodsWe analyzed characteristics and outcome of 253 CP‐CML patients who had at least one mutation analysis performed using direct sequencing. Of them, 187 patients were early CP (ECP) and 66 were late CP late chronic phase (LCP) and 88% were treated with Imatinib as first‐line TKI.ResultsOverall, 80 (32%) patients harbored BCR‐ABL KD mutations. A BCR‐ABL KD mutation was identified in 57% of patients, who progressed to accelerated or blastic phases (AP‐BP), and 47%, 29%, 35%, 16% and 26% in patients in CP‐CML at the time of mutation analysis who lost a complete hematologic response, failed to achieve or loss of a prior complete cytogenetic and major molecular response, respectively.Overall survival and cumulative incidence of CML‐related death were significantly correlated with the disease phase whatever the absence or presence of a mutation was and for the latter the mutation subgroup (T315I vs P‐loop vs non‐T315I non‐P‐loop) (P

Background: Hasford score is a scoring system which was made in interferon treatment era to assess chronic myelocytic leukemia (CML) prognosis. Complete hematologic response (CHR) is the milestone of prognosis evaluation. CHR achievement will significantly increase survival. Imatinib is a revolutionized treatment that change the prognosis of CML. With the advent of Imatinib, lessened the prognostic impact of the Hasford score to predict prognosis.Materials and Methods: An observational analytic with prospective cohort study conducted in oncology outward division Dr. Soetomo hospital Surabaya, from July until October 2018. Hasford score determined in 32 patients at the beginning of the study, given imatinib and followed up regularly for 3 months to know the hematologic response. Data were analyzed using Fisher exact test which was considered significant if p

Monoclonal gammopathy of undetermined significance (MGUS) may be associated with pathologies with severe neuromuscular manifestations such as sporadic late‐onset nemaline myopathy (SLONM). We describe a difficult to diagnose case of SLNOM with marked clinical improvement after achieving gammopathy complete hematologic response.

Context: The frontline treatment of chronic phase (CP) chronic myeloid leukemia (CML) with nilotinib has resulted in a higher rate of major molecular response (MMR) and complete cytogenetic response (CCyR) at 12 months compared to imatinib but at a higher cumulative cost and increased risk of serious adverse events. A treatment strategy aimed at maintaining long-term efficacy while minimizing both toxicities and costs is needed. Objective: The aim of the study is to evaluate the efficacy and safety of a response-directed switch from nilotinib to imatinib in patients newly diagnosed with CP-CML. Design: This is a single-center, prospective, pilot phase 2 open-label study including adult patients newly diagnosed with CP-CML screened and treated at the American University of Beirut Medical Center in Lebanon. Interventions: Patients were treated with nilotinib 300 mg orally twice daily for 12 months, and those who achieved CCyR were shifted to imatinib 400 mg orally daily, with regular follow-ups at 3, 6, 12 months, and then every 6 months thereafter. Main Outcome Measures: The primary endpoint was to evaluate the efficacy of imatinib in maintaining cytogenetic and molecular responses achieved at 12 months after nilotinib treatment in at least 85% of patients. Results: Thirteen patients were enrolled in the study. Eleven patients completed one year of nilotinib and switched to imatinib 400 mg daily as per protocol. At 3 months, all patients achieved complete hematologic response, with 7 (54%) patients having early molecular response. At 12 months, all patients achieved CCyR, of whom 5 (45%) and 4 (36%) patients achieved MMR and MR4.5, respectively. Three (27%) patients switched back to nilotinib after 18, 24, and 51 months, respectively: one patient lost CCyR after 18 months, and two patients were imatinib-intolerant. After a median follow-up of 60 months, all patients (n=12) were alive and in MMR, 6 (50%) of them in continuous MR4.5. No new safety concerns emerged in the study. Conclusions: These findings suggest that a response-directed switch from nilotinib to imatinib at 12 months is capable of maintaining long-term CCyR, with manageable side effects. This approach warrants further exploration with larger prospective trials.

© The Author(s) 2021., Light chain (AL) amyloidosis is caused by a small B-cell clone producing light chains that form amyloid deposits and cause organ dysfunction. Chemotherapy aims at suppressing the production of the toxic light chain (LC) and restore organ function. However, even complete hematologic response (CR), defined as negative serum and urine immunofixation and normalized free LC ratio, does not always translate into organ response. Next-generation flow (NGF) cytometry is used to detect minimal residual disease (MRD) in multiple myeloma. We evaluated MRD by NGF in 92 AL amyloidosis patients in CR. Fifty-four percent had persistent MRD (median 0.03% abnormal plasma cells). There were no differences in baseline clinical variables in patients with or without detectable MRD. Undetectable MRD was associated with higher rates of renal (90% vs 62%, p = 0.006) and cardiac response (95% vs 75%, p = 0.023). Hematologic progression was more frequent in MRD positive (0 vs 25% at 1 year, p = 0.001). Altogether, NGF can detect MRD in approximately half the AL amyloidosis patients in CR, and persistent MRD can explain persistent organ dysfunction. Thus, this study supports testing MRD in CR patients, especially if not accompanied by organ response. In case MRD persists, further treatment could be considered, carefully balancing residual organ damage, patient frailty, and possible toxicity., This study was supported by a grant from CARIPLO “Molecular mechanisms of Ig toxicity in age-related plasma cell dyscrasias no. 2015-0591”, by a grant from the Black Swan Research Initiative from the International Myeloma Foundation “Automated multidimensional flow cytometry for high-sensitive screening and to monitor response in AL amyloidosis”, by a grant from CARIPLO “Structure–function relation of amyloid: understanding the molecular bases of protein misfolding diseases to design new treatments no. 2013-0964”, by a grant from the Amyloidosis Foundation “Investigating new therapies to treat AL amyloidosis”, and by a grant from Cancer Research UK, FCAECC and AIRC under the Accelerator Award 2017 Program “Early detection and intervention: understanding the mechanisms of transformation and hidden resistance of incurable hematological malignancies”, by a grant from CARIPLO “Harnessing the plasma cell secretory capacity against systemic light chain amyloidosis” (no. 2018-0257), by a grant from the Italian Ministry of Health “Towards effective, patient-tailored anti-plasma cell therapies in AL amyloidosis: predicting drug response and overcoming drug resistance” (GR-2018-12368387). This study has also supported the Centro de Investigación Biomédica en Red—Área de Oncología—del Instituto de Salud Carlos III (CIBERONC; CB16/12/00369, CB16/12/00400, and CB16/12/00489) and the Instituto de Salud Carlos III/Subdirección General de Investigación Sanitaria (FIS No. PI13/02196). G.P. is supported in part by the Bart Barlogie Young Investigator Award from the International Myeloma Society (IMS). P.M. is supported in part by a fellowship grant form Collegio Ghislieri (Pavia). We acknowledge the study coordinator and data manager Anna Carnevale Baraglia.

Introduction: The broadening of targeted and immunotherapeutic strategies markedly impacted on the management of acute lymphoblastic leukemia (ALL). The advent of tyrosine kinase inhibitors (TKIs) changed the history of Philadelphia-chromosome positive (Ph+) ALL. Nowadays, almost all Ph+ ALL patients treated with TKIs achieve a complete hematologic response, and most become minimal residual disease negative. In Ph- ALL, genomic profiling studies have identified a subtype associated with a high relapse risk and a transcriptional profile similar to that of Ph+ ALL, the so-called Ph-like ALL. Given the high prevalence of kinase-activating lesions in this subset, there is compelling evidence from experimental models and clinical observations favoring TKI administration.Areas covered: We discuss the main findings exploring the efficacy of TKIs in ALL.Expert opinion: The use of more potent TKIs will further enhance the inhibitory activity on leukemia cells and increase the possibility of eradicating the disease at a molecular level. In the future, 'combined' approaches of different inhibitors may be considered to prevent/avoid resistance and/or mutations. A rapid identification of Ph-like ALL patients is needed to propose early TKI-based intervention. Several questions remain open, including the initial TKI choice in Ph+ ALL and whether Ph-like ALL patients might benefit from immunotherapy.

Pediatric chronic myeloid leukemia (CML) is a hematopoietic malignancy, treated by tyrosine kinase inhibitor (TKI). Previously, imatinib resistance in CML was treated with nilotinib as a second line. However, in Indonesia, where the options of TKIs are limited, no case has been reported. We describe TKI-resistance of a pediatric CML case in Dharmais Cancer Hospital, Jakarta. A 17-year-old boy presented with loss of complete hematologic response after 4 years of imatinib treatment. Diagnosis of relapsed CML with blast crisis was confirmed, and nilotinib was given accordingly. He achieved hematological and optimal response after 2 weeks and 3 months of treatment, respectively. However, in the 12-month evaluation, he failed to achieve major molecular response and acquired the second resistance to TKI. Since imatinib resistance marks the poor prognosis, initial optimal response of nilotinib treatment remains inconclusive to predict the final outcome.

Background Evans syndrome is a rare autoimmune disorder that is defined by the simultaneous or sequential presence of two or more cytopenias without an obvious underlying precipitating cause. Evans syndrome usually follows a chronic relapsing and remitting course and is quite rare, making it difficult to evaluate in clinical studies. Case report A 66-year-old male patient with a 17-year history of Evans syndrome presented with fulminant autoimmune hemolytic anemia (AIHA). He presented with a markedly elevated C-reactive protein (CRP; 46 mg/L [normal, 0-5 mg/L]) before onset of a decrease in hemoglobin. He required the transfusion of 20 units of red blood cells while awaiting response to aggressive immunosuppressive therapy including high-dose corticosteroids, intravenous immunoglobin therapy, and rituximab. He achieved a complete hematologic response. Results His postdischarge course was complicated by acute cholecystitis requiring laparoscopic cholecystectomy. In addition, his transfusional iron overload requiring 16 phlebotomies to reduce his ferritin level from 4933 μg/L to 326 μg/L, with phlebotomies ongoing every 2 weeks to achieve a ferritin level of less than 100 μg/L. Conclusion Neither transfusional iron overload nor acute cholecystitis are well-recognized complications of a severe episode of AIHA. An elevated CRP has been recently recognized as an important prognostic marker in patients with immune thrombocytopenic purpura and this case suggests a need to evaluate its utility in AIHA.

Introductions : Dasatinib is indicated as a first line, second line and third line tyrosine kinase inhibitor (TKI) in chronic myeloid leukemia (CML). In our center it is used as a second line or third line therapy in BCR-ABL gene positive CML. Methods: It is a retrospective observational therapy done from June 2015 to May 2018. The purpose of the study is to see the response rates using the second line and third line dasatinib after failing or not tolerating imatinib alone or following a sequential therapy with imatinib and nilotinib. Results: A total of 31 (male 56.3%) patients were included in our study. In eighteen patients it was used as a second line TKI and in 13 a third line TKI. Complete Hematologic Response (CHR) was achieved in 93.55%. Best optimal responses were 46.66% and 61.53% in second and third line dasatinib respectively. Major Molecular Response (MMR) was achieved in 35.71% (26.66% and 46.14% in second line and third line dasatinib respectively). For both the groups, the overall survival was 92% and 94 % at 20 months and the event free survival was 70% at 10 months. Conclusions: Dasatinib is effective in achieving MMR and inducing survival benefit in the patients who failed imatinib alone and imatinib and nilotinib. Keywords: chronic myeloid leukemia, dasatinib, imatinib failure or intolerance, imatinib and nilotinib failure or intolerance

The detection and quantification of monoclonal-proteins (M-proteins) are necessary for the diagnosis and evaluation of response in plasma cell dyscrasias. Immunoglobulin enrichment-coupled with matrix-assisted laser desorption ionization time-of-flight mass-spectrometry (MASS-FIX) is a simple and inexpensive method to identify M-proteins, but its clinical generalizability has not yet been elucidated. We compared MASS-FIX to protein electrophoresis (PEL), serum/urine immunofixation-electrophoresis (IFE), and quantitative serum free-light chain (FLC) for the identification of M-proteins in different clinical diagnoses. Paired serum and urine samples from 257 patients were tested. There were six patients for whom s-IFE and FLC ratio were positive and serum MASS-FIX was negative, but when serum and urine MASS-FIX results were combined, only one patient with light chain-MGUS was missed. Serum/urine-MASS-FIX detected M-proteins in 18 patients with negative serum/urine-PEL/IFE and serum-FLC, 10 of whom had multiple myeloma or AL amyloidosis, who were mistakenly thought to have complete hematologic response by serum/urine-PEL/IFE and serum-FLC. Nearly half of the AL amyloidosis patients had atypical spectra, which may prove to be a clue to the diagnosis and pathogenesis of the disease. In conclusion, MASS-FIX has a comparable sensitivity with PEL/IFE/FLC methods and can help inform the clinical diagnosis.

This long-term follow-up of a completed phase 1/2 study assessed the safety and efficacy of bosutinib in Japanese Philadelphia chromosome-positive, chronic phase (CP) or advanced phase (ADV) chronic myeloid leukemia patients who were resistant/refractory or intolerant to prior tyrosine kinase inhibitor treatment. This analysis included 63 patients with a median bosutinib follow-up of 132 weeks (range 3‒372). In the CP second-line (2L) cohort, the cumulative major cytogenetic response (MCyR) and major molecular response (MMR) rates throughout the study were 73 and 53%, respectively. In the CP third-line (3L) cohort, the cumulative MCyR and MMR rates throughout the study were 70 and 40%, respectively. Of the eight ADV patients, MCyR was attained or maintained by 50% of patients, and complete hematologic response was attained or maintained by 25% of patients. Progression-free survival rate and overall survival rate at 96 weeks were, respectively, 91 and 98% in CP2L, 88 and 100% in CP3L, and 33 and 50% in ADV patients. The most common adverse events (50%) reported were diarrhea (95%), nasopharyngitis (57%), and rash (57%). Bosutinib demonstrated durable efficacy and a manageable tolerability profile over long-term use in Japanese patients.ClinicalTrials.gov: NCT00811070.

The standard immunosuppressive therapy (IST) with antithymocyte globulin (ATG) and cyclosporine in treatment of acquired aplastic anemia (AA) results to hematologic response in two thirds of patients, and approximately one third of the responding patients is relapsed. One third of patients have disease that is refractory to IST, with persistent severe cytopenia and a profound deficit in hematopoietic stem cells. In patients with refractory or recurrent disease, the use of alternative immunosuppressive drugs is possible, but the efficacy of the latter does not high. Recent studies have demonstrated the efficacy of eltrombopag in refractory aplastic anemia and in the first line of therapy in combination with IST. It has been shown eltrombopag not only restored the level of platelets, but was associated with multilineage clinical responses. In this study we analyzed the use of eltrombopag in 15 children and young adults with AA: 11 patients in refractory disease, one patient in relapse and three patients in the first line of therapy in combination with IST. The overall efficacy of treatment was 40% (6/15). The main adverse event was moderate and reversible increase of hepatic transaminases (3/15, 20%). A complete hematologic response was achieved in 3/15 patients (20%), and in 2 patients the response is continued after drug withdrawal. Eltrombopag is effective in patients with refractory AA, and it may be an alternative option in patients who do not have suitable donors for hematopoietic stem cells transplantation (HSCT). The first-line treatment with eltrombopag in combination with standard IST in our small group of patients also showed efficacy (60%) and safety.

To compare the efficacy and safety of imatinib and cytarabine (ara-c) combination versus imatinib monotherapy in newly diagnosed patients with chronic phase chronic myeloid leukemia (CML-CP).This prospective, randomized study included adult patients (age18 years) with newly diagnosed CML-CP. Patients received either a single oral dose of imatinib 400 mg/day in combination with a subcutaneous injection of ara-c 20 mg/mOf 30 patients included, 14 were randomized to imatinib + ara-c and 16 to imatinib alone. Complete hematologic response (CHR) at 3 months was higher with imatinib + ara-c vs. imatinib alone (100% vs. 87.5%, P = 0.48). The median time to achieve CHR was significantly (P0.001) lower with imatinib + ara-c (32.07 vs. 23.43 days). Molecular response at 3 months was significantly higher (P = 0.04) with imatinib + ara-c vs. imatinib alone (100% vs. 68.75%). Complete cytogenetic response was also higher with imatinib + ara-c vs. imatinib alone (42.85% vs. 25% at 6 months and 71.4% vs. 62.5% at 12 months). Neutropenia followed by thrombocytopenia and anemia were the most common AEs. Grade 3/4 hematological and nausea events were significantly (P0.05) higher with imatinib + ara-c. Other nonhematological events were not significantly different between the treatments. The median follow-up duration was 20 months (range: 15-23 months).Imatinib with low-dose ara-c can be considered as a potential first-line treatment option for CML-CP.

We report a case of chronic myeloid leukemia in a 52-year-old male expressing a rare e14a3 BCR-ABL1 fusion transcript. Cytogenetic analysis showed the t(9;22) translocation and multiplex RT-PCR detected an atypical fragment of approximately 230 base pairs. Using two primers recognizing exon 10 of BCR and exon 4 of ABL1, a larger PCR product was identified, cloned, sequenced and defined as an e14a3 BCR-ABL1 rearrangement. The patient was treated with nilotinib and monitored measuring cytogenetic and hematological parameters, while BCR-ABL1 transcripts were surveyed by conventional and semi-nested PCR. The patient achieved a complete hematologic response after two months of treatment followed by a complete cytogenetic remission two months later. Furthermore, PCR and semi-nested PCR failed to detect the e14a3 BCR-ABL1 mRNA after 15 and 21 months of nilotinib, respectively.

Primary systemic immunoglobulin light chain (AL) amyloidosis is caused by a plasma cell clone of, usually low, malignant potential that expresses CD38 molecules on their surface. Treatment of AL amyloidosis is based on the elimination of the plasma cell clone. The combination of cyclophosphamide–bortezomib–dexamethasone (CyBorD) is the most widely used and is considered a standard of care; however, complete hematologic response rates and organ response rates remain unsatisfactory. Daratumumab, an anti-CD38 monoclonal antibody, has demonstrated encouraging results, with rapid and deep responses, in patients with relapsed or refractory AL amyloidosis as monotherapy with a favorable toxicity profile. The large phase-III, randomized, ANDROMEDA study evaluated the addition of daratumumab to CyBorD in previously untreated patients with AL amyloidosis and demonstrated that addition of daratumumab can substantially improve hematologic complete response rates, survival free from major organ deterioration or hematologic progression, and organ responses. In this review, we discuss the role of daratumumab in the treatment of AL amyloidosis, its mechanism of action, and the results of ANDROMEDA study that led to the first approved therapy for AL amyloidosis.

Chronic myeloid leukemia (CML) is an orphan disease in Africa because of the inaccessibility to specific treatment and the high cost of diagnosis and monitoring patients. The aim of this study was to report CML treatment response in a developing country in the tyrosine kinase inhibitor era. We conducted a longitudinal study of our cohort of CML patients. Socio-demographic, diagnosis, therapeutic, and treatment response parameters were studied. Sokal score, disease phase at diagnosis, delay from diagnosis to treatment, and treatment response were analyzed for their impact on survival. Fifty-five patients with a diagnosis of CML and who received treatment with imatinib for a minimum of 3 months were included in this study. Median follow-up was 170 patient-years. The sex ratio (M/F) was 1.62 and median age at diagnosis was 42 years. At diagnosis, 85.5 % of the patients were in chronic phase (CP), 12.7 % in accelerated phase (AP), and 1.8 % in blast crisis (BC). Sokal risk score distribution was as follows: low risk 29.8 %, intermediate risk 38.3 %, and high risk 31.9 %. Median time from first symptoms to first medical visit was 6.2 months and median time from first medical visit to cytogenetic and or molecular confirmation was 12.4 months. Mean delay time from first medical visit to imatinib initiation was 12.5 months (95 % CI 6.3-18.7). The complete hematologic response (CHR) at 3 months, the major cytogenetic response (MCR) at 12 months, and the major molecular response (MMR) at 24 months were respectively 82.4, 75, and 25 %. The 2-year overall survival rate was 81 %. Advanced phase at the diagnosis, discontinuation of imatinib therapy over 15 % of the time, lack of CHR at 3 months, lack of MCR at 12 months, and progression of the disease during imatinib therapy were associated with a risk of death (p ≤ 0.05). Our data confirm the improved prognosis of CML treated with imatinib in the setting of a developing country. However, response rates are lower than in developed countries, and additional efforts should be made to facilitate early diagnosis and improve access to TKI, treatment compliance, and regular molecular monitoring of patients.

Over the past decade, a number of changes have occurred in the diagnostic evaluation, management, and long-term follow-up of patients with POEMS syndrome at our institution. This study included 291 patients with POEMS syndrome diagnosed at the Mayo Clinic between 1974 and 2014. Patients diagnosed after 2003 had more features of the syndrome identified at diagnosis and were more likely to receive an autologous transplant (49% versus 8%, P

Background & Aims. Interpretation of key aspects of pathogenesis of chronic myeloid leukemia (CML) and development and introduction of target therapy have changed the prognosis of this once fatal disease dramatically. Results of numerous clinical trials demonstrated substantial superiority of tyrosine kinase inhibitors over previous therapy techniques. At the same time, clinical trials had limitations in patient enrollment, as well as treatment conditions and duration. The analysis of our clinical experience in CML target therapy (over the period from 2003 till 2015) is an important argument for introduction of novel drugs into routine clinical practice. The aim of the study is to analyze our own experience in CML target therapy and to compare our results with clinical trials data. Methods. Outpatient’s cards and case histories of CML patients treated in the Russian Scientific Research Institute of Hematology and Transfusiology over last 12 years were analyzed in this work. Published results of multi-center clinical trials evaluating the use of tyrosine kinase inhibitors in CML were used for a comparative analysis. The primary morbidity rate and the prevalence of CML, results of first and subsequent treatment lines were studied with assessment of survival rates, adverse events, and the nature of the response (hematologic, cytogenetic and molecular). Results. The experience in treatment of 208 CML patients was analyzed. The use of imatinib led to clinical and hematological remission (complete hematologic response) was achieved in 95 % of patients. The frequency of complete cytogenetic responses (CCyR) was 69 %, and that of major molecular responses (MMR) was 58 %. The overall 5-year survival (OS) was 86.4 %, the 10-years OS was 67.5 %. The use of nilotinib during the second line permitted to achieve CCyR in 61 % of patients, and the MMR in 55 % of cases. The two-year OS was 96 % and the 5-year OS was 68 %. CCyR and MMR were achieved in 50 % patients treated with dasatinib during the second line. As for the third line, CCyR was achieved in 50 % of patients and MMR in 25 %. In case of previous imatinib and nilotinib resistance, CCyR was observed only in 36 % of patients and MMR in 18 % of cases. During second-line dasatinib treatment, the 2-year OS was 85 %, and the 5-year OS was 51 %; as for the third line, the results were 75 % and 50 %, respectively. The range and rates of adverse events of the therapy, in general, corresponded to results of clinical trials. Conclusion. The use of tyrosine kinase inhibitors in treatment of CML permits to prolong patient’s life span and quality of life significantly. The use of nilotinib and dazatinib (in case of nilotinib intolerance and/or resistance) could be effective in most patients.

Although clinical improvement is almost universal with therapy in patients with POEMS (an acronym for polyneuropathy, organomegaly, endocrinopathies, monoclonal protein and a variety of skin changes) syndrome, outcomes and management of patients who relapse or progress (R/P) after first-line treatment have not been described. We retrospectively identified 262 patients with POEMS syndrome treated at the Mayo Clinic from 1974 to 2014 and who had follow-up information. The 5-year progression-free survival (PFS) and overall survival (OS) was 58% and 78%, respectively. Median time to R/P was 42 months. Seventy-nine patients (30%) had an R/P, with 52 (19%) experiencing a symptomatic R/P. Eighteen patients relapsed with symptoms or signs that were not documented at diagnosis. Median times to vascular endothelial growth factor, hematologic, radiographic and clinical R/P were 35 months (range, 4-327 months), 72 months (range, 4-327 months), 51 months (range, 4-327 months) and 48 months (range, 6-311 months), respectively. On multivariate analyses, low albumin at diagnosis and failure to achieve a complete hematologic response to first-line therapy were independent risk factors for PFS. Thirty patients had documentation of a second R/P at a median of 26 months from diagnosis of the first R/P. An early R/P was a risk factor for death, but most patients with an R/P had salvageable disease. A majority of patients are still without R/P at 5 years from diagnosis.

Data from 51 patients (23 women) with chronic myeloid leukemia (CML) in blast phase (BP) were analyzed in order to identify prognostic factors for complete hematologic response (CHR) and survival.Forty-four patients experienced disease progression from chronic or accelerated phase, and 7 cases presented as CML-BP. Thirteen patients (25.5%) had extramedullary involvement at diagnosis, and 71% were myeloid BP. Clonal evolution was identified in 53% of the cases, and the abnormalities most frequently observed were isochromosome (17q), double Philadelphia chromosome, and trisomy 8. Forty-five patients received treatment: 60% chemotherapy (CT) alone and 40% CT plus tyrosine kinase inhibitors (TKI) or TKI alone; 42% of them experienced CHR.Median overall survival (OS) in patients whose disease responded to treatment was 7 months (95% confidence interval, 1.7-6.2 months), with a median disease-free survival of 5 months (95% confidence interval, 2.8-5.8 months). One out of 3 patients who underwent hematopoietic stem-cell transplantation remains alive. Multivariate analysis revealed that lymphoid BP and TKI therapy had a statistically significant positive impact as prognostic factors for CHR. In the multivariate analysis, age60 years, hemoglobin 10 g/dL, and complex karyotype were statistically significant negative prognostic factors for OS. There was no statistical significant difference in OS between patients who received only CT (1988-2002) with those treated with CT plus TKI (2003-2013).This is the first study in Mexico to report prognostic factors associated with CHR and OS in patients with CML-BP.

Pendahuluan . Respons hematologi lengkap merupakan bagian tak terpisahkan dari pencapaian target respons sitogenetik lengkap dan respons molekular mayor terapi imatinib mesylate meskipun tidak menentukan prognosis. Respons hematologi lengkap pasien LGK fase kronik di Indonesia lebih rendah daripada kasus LGK fase kronik di dunia (74% vs. 95,3%). Perbedaan ini karena 60% pasien di Indonesia mendapat hidroksiurea lebih dulu. Penelitian ini bertujuan untuk mengetahui faktor-faktor prognostik apa saja yang memengaruhi respons hematologi lengkap pasien LGK fase kronik yang mendapat imatinib mesylate di Indonesia. Metode . Penelitian dilakukan dengan desain kohort retrospektif menggunakan rekam medis pasien leukemia granulositik kronik yang datang berobat ke Klinik Teratai RSCM dan Poli Hematologi RSCM lantai 2 yang mendapat terapi imatinib mesylate sejak Januari 2004-Desember 2011. Hasil . Sebagian besar subjek penelitian laki-laki (61,5%), berumur 26-40 tahun (47,4%), lama diagnosis

Context Imatinib, selective tyrosine kinase inhibitor (TKI), revolutionized treatment of chronic myeloid leukemia (CML) and changed the natural history of the disease. In 2013, a generic formulation came into the Republic of North Macedonia's market and replaced the original formulation, Glivec. Objective The aim of the study is to determine whether the efficacy of the generic Imatinib is the same as the original Imatinib-Glivec in patients treated for chronic myeloid leukemia in North Macedonia in terms of hematological and molecular responses in CML. Design This is an observational retrospective study using medical charts of patients diagnosed with CML in the chronic phase who were previously successfully treated with original Imatinib and subsequently switched to generic Imatinib. The patients were treated with generic Imatinib from the year 2013 to 2020. Patients or other participants 30 patients have been switched from original to generic Imatinib. All of them were receiving Imatinib at a dose of 400 mg/ daily prior and after switching. 17 (56.6%) of all patients were male, 13 (44%) were female. 28 of the patients completed the study, 2 of the patients lost their molecular response and were switched to second-generation TKI-Nilotinib. Results 30 patients have been switched to generic imatinib. Before the switch, all of the patients were in complete hematologic response (CHR), and all of them were in MMR. Patients have received generic Imatinib for a median of 88 months. Molecular response (MR) was decided with BCR-ABL1 gene transcript ratio that is reported as International Scale (IS). Complete hematologic response was accepted as white blood cells Conclusions In our observational series, most of the patients maintained their molecular response. The change from original to generic Imatinib appears to maintain efficacy and maintained CHR and MMR.

Context Tyrosine kinase inhibitors in third-line therapy (TKI-3L) in chronic-phase chronic myelogenous leukemia (CP CML) is effective in a portion of patients. Meanwhile, it is unclear which patients may benefit from TKI-3L. Objective To identify the factors affecting the outcome of TKI-3L therapy in CP CML. Design A retrospective study was conducted in five centers of St. Petersburg and Leningrad Region in 2019. All CP CML patients who ever obtained TKI-3L in these centers were included, except patients (pts) with complete cytogenetic response (CCyR). Results Seventy-three pts (male=26) with baseline median age 51 (25–88) were included in the study. There were 51 (70%) pts without any CyR, including 27 (37%) cases without complete hematologic response in baseline. For other patients, the best baseline cytogenetic response was minimal or minor (mmCyR) in 12 (16%) and partial (PCyR) in 10 (14%). BCR-ABL mutations were detected in 30/73 (42%) cases at any time before TKI-3L. Reasons for switching to TKI-3L were resistance in 56 (77%) or intolerance in 17 (23%). Dasatinib, Nilotinib, Bosutinib, or Ponatinib were used as TKI-3L in 43 (59%), 18 (25%), 9 (12%), and 3 (4%) pts, respectively. The median time of TKI-3L treatment duration was 15 (1–120) months. CCyR was achieved in 8/51 (16%) and 14/22 (64%) pts without CyR and with mmCyR/PCyR, respectively(p=0.001). CCyR subsequently had been lost 5/8 (62.5%) and 5/14 (29%) pts initially without or with any CyR (p=0.01). MMR was achieved in 3/51 (6%) and 6/22 (27%) pts without or with any CyR (p>0.05). Estimated overall 1-year, 3-year, and 5-year OS were 95%, 81%, and 65%, respectively. The median follow-up was 26 (3–136) months. There were 14 (19%) death: 11 due to CML progression and 3 after allo-SCT. All deaths occurred in pts without any CyR at baseline. Transformation to accelerated phase and blast crisis was occurred in 13 (18%) pts only in pts group without any CyR initially. The median time to progression was 15 (6–102) months. The only relevant baseline factor for CCyR, OS, and PFS probability in multivariant analysis was the presence of any CyR at baseline (p Conclusion Initial presence of any CyR was a favorable factor for long-term results of TKI third-line treatment in CP CML. TKI-3L should be considered as an appropriate tool in CML treatment for this group.

Background In this study we aimed to evaluate appropriate time points for mutation analysis of chronic myeloid leukemia. Patients and Methods In total, 961 blood samples obtained from 605 chronic-phase chronic myeloid leukemia patients treated with imatinib were subjected to Sanger sequencing to detect BCR-ABL1 mutations. Mutation frequencies at landmark time points (3, 6, and 12 months) were assessed with 16 landmark responses defined by European LeukemiaNet and 2 additional responses, including a complete hematologic response (CHR) at 3 months and a complete cytogenetic response (CCyR) at 12 months. Results After 12 months of imatinib treatment of 605 patients, 28 (4.6%) patients harbored 33 mutations, including 23 (69.7%) highly resistant T315I and P-loop mutations. Sequencing data from 650 samples were compared with cytogenetic responses. The mutation frequencies in optimal, warning, and failure groups were 0.5% (2/430), 1.8% (2/110), and 19.1% (21/110), respectively. The molecular response was assessed using 956 samples, and the mutation frequencies were 0.7% (3/425), 3.4% (12/358), and 7.6% (14/173) for the optimal, warning, and failure groups, respectively. For the 2 additional responses, the mutation frequencies in patients with CHR at 3 months and with CCyR at 12 months were 0% (0/160) and 1.7% (4/242), respectively. Overall, mutations were frequently detected at 3-month cytogenetic failure (25.0%), 12-month cytogenetic failure (23.2%), and 6-month cytogenetic failure (10.5%) using response–mutation association analysis. Conclusion Irrespective of mutation frequency, failure of achievement of a cytogenetic response should be conducted with appropriate mutation analysis.

Interferon‐α2 reduces elevated blood cell counts and splenomegaly in patients with myeloproliferative neoplasms (MPN) and may restore polyclonal hematopoiesis. Its use is limited by inflammation‐mediated toxicity, leading to treatment discontinuation in 10‐30% of patients. Ruxolitinib, a potent anti‐inflammatory agent, has demonstrated benefit in myelofibrosis (MF) and polycythemia vera (PV) patients. Combination therapy (CT) with these two agents may be more efficacious than monotherapy with either, potentially improving tolerability of interferon‐α2 as well. We report the preliminary results from a phase II study of CT with pegylated interferon‐α2 and ruxolitinib in 50 MPN patients (PV, n = 32; low‐/intermediate‐1‐risk MF, n = 18), the majority (n = 47) being resistant and/or intolerant to interferon‐α2 monotherapy. Objectives included remission (2013 revised criteria encompassing histologic, hematologic, and clinical responses), complete hematologic response (CHR), molecular response, and toxicity. Follow‐up was 12 months. Partial remission (PR) and sustained CHR were achieved in 9% and 44% of PV patients, respectively. In MF patients, complete or partial remission was achieved in 39%, and sustained CHR in 58%. The median JAK2V617F allele burden declined significantly in both groups. Hematologic toxicity was the most common adverse event and was managed by dose reduction. Thirty‐seven serious adverse events were recorded in 23 patients; the discontinuation rate was 20%. We conclude that CT with interferon‐α2 and ruxolitinib is efficacious in patients with low‐/intermediate‐1‐risk MF and, to a lesser extent, in patients with PV. These preliminary results encourage phase III studies as well as a study with CT in newly diagnosed MPN patients.