Dasatinib 140 mg once daily versus 70 mg twice daily in patients with Ph‐positive acute lymphoblastic leukemia who failed imatinib: Results from a phase 3 study

Dasatinib 70 mg twice daily is indicated for Philadelphia chromosome‐positive acute lymphoblastic leukemia (Ph+ ALL) intolerant or resistant to imatinib. In patients with chronic‐phase chronic myelogenous leukemia, once‐daily dosing has similar efficacy with improved safety, compared with twice‐daily dosing. A phase 3 study (n = 611) assessed the efficacy and safety of dasatinib 140 mg once daily versus 70 mg twice‐daily in patients with advanced phase chronic myelogenous leukemia or Ph+ ALL resistant or intolerant to imatinib. Here, results from the Ph+ ALL subset (n = 84) with a 2‐year follow‐up are reported. Patients were randomly assigned to receive dasatinib either 140 mg once daily (n = 40) or 70 mg twice daily (n = 44). The rate of confirmed major hematologic response with once‐daily dosing (38%) was similar to that with twice‐daily dosing (32%). The rate of major cytogenetic response with once‐daily dosing (70%) was higher than that with twice‐daily dosing (52%). Compared with the twice‐daily schedule, the once‐daily schedule had longer progression‐free survival (median, 3.0 months versus 4.0 months, respectively) and shorter overall survival (median, 9.1 months versus 6.5 months, respectively). Overall safety profiles were similar between two groups, with nonhematologic adverse events being mostly grade 1 or 2. Pleural effusion was less frequent with once‐daily dosing than with twice‐daily dosing (all grades, 18% versus 32%). Notably, none of the differences between the two schedules was statistically significant. Compared with the 70 mg twice daily, dasatinib 140 mg once daily had similar overall efficacy and safety in patients with imatinib‐resistant or intolerant Ph+ ALL. (clinicaltrials.gov identifier: NCT00123487). Am. J. Hematol. 2010. © 2009 Wiley‐Liss, Inc.     

Oral ciclopirox olamine displays biological activity in a phase I study in patients with advanced hematologic malignancies

The antimycotic ciclopirox olamine is an intracellular iron chelator that has anticancer activity in vitro and in vivo. We developed an oral formulation of ciclopirox olamine and conducted the first‐in‐human phase I study of this drug in patients with relapsed or refractory hematologic malignancies (Trial registration ID: NCT00990587). Patients were treated with 5–80 mg/m² oral ciclopirox olamine once daily for five days in 21‐day treatment cycles. Pharmacokinetic and pharmacodynamic companion studies were performed in a subset of patients. Following definition of the half‐life of ciclopirox olamine, an additional cohort was enrolled and treated with 80 mg/m² ciclopirox olamine four times daily. Adverse events and clinical response were monitored throughout the trial. Twenty‐three patients received study treatment. Ciclopirox was rapidly absorbed and cleared with a short half‐life. Plasma concentrations of an inactive ciclopirox glucuronide metabolite were greater than those of ciclopirox. Repression of survivin expression was observed in peripheral blood cells isolated from patients treated once daily with ciclopirox olamine at doses greater than 10 mg/m², demonstrating biological activity of the drug. Dose‐limiting gastrointestinal toxicities were observed in patients receiving 80 mg/m² four times daily, and no dose limiting toxicity was observed at 40 mg/m² once daily. Hematologic improvement was observed in two patients. Once‐daily dosing of oral ciclopirox olamine was well tolerated in patients with relapsed or refractory hematologic malignancies, and further optimization of dosing regimens is warranted in this patient population. Am. J. Hematol. 89:363–368, 2014. © 2013 Wiley Periodicals, Inc.     

自体外周血干细胞移植治疗血液恶性肿瘤231例临床观察

目的观察自体外周血干细胞移植(APBSCT)治疗血液恶性肿瘤的疗效。方法2001年3月至2007年2月对第三军医大学新桥医院231例血液恶性肿瘤患者施行APBSCT,其中急性淋巴细胞白血病(ALL)45例,急性髓性白血病(AML)34例,非霍奇金淋巴瘤(NHL)100例,霍奇金淋巴瘤(HD)31例,多发性骨髓瘤(MM)21例,观察临床疗效和并发症。结果除1例ALL外,230例患者移植后造血功能均快速重建。ALL首次完全缓解(CR1)28例患者中无病存活(DFS)13例,带病存活4例,死亡11例;ALL二次缓解(CR2)17例患者中DFS3例,带病存活4例,死亡10例。AMLCR120例患者中DFS11例,带病存活3例,死亡6例;AMLCR214例患者中DFS6例,带病存活2例,死亡6例。NHLCR159例患者中DFS43例,带病存活7例,死亡9例;NHLCR230例患者中DFS18例,带病存活5例,死亡7例;NHL未缓解(NR)11例患者中DFS2例,带病存活4例,死亡5例。HDCR110例患者中DFS10例;HD部分缓解(PR)15例患者中DFS12例,带病存活3例;HD疾病复发(RE)6例患者中DFS3例,带病存活2例,死亡1例。MM21例患者中DFS7例,带病存活6例,死亡8例。结论APBSCT是一种安全有效的血液肿瘤治疗方法。     

Phase I study of evofosfamide,an investigational hypoxia‐activated prodrug,in patients with advanced leukemia

Tumor hypoxia causes resistance to radiation and chemotherapy. Evofosfamide (TH‐302) has exhibited specific hypoxia‐dependent cytotoxicity against primary acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) samples in vitro. Based on these findings, a Phase I study of evofosfamide was designed for patients with relapsed/refractory leukemia (NCT01149915). In this open‐label study, patients were treated with evofosfamide as a 30–60 min/day infusion on Days 1–5 of a 21–day cycle (Arm A, n = 38) or as a continuous infusion over 120 hr over Days 1–5 of a 21‐day cycle (Arm B, n = 11). Forty‐nine patients were treated including 39 (80%) with AML and 9 (18%) with ALL. Patients had received a median of five prior therapies. In Arm A, the dose‐limiting toxicities (DLTs) were grade 3 esophagitis, observed at a dose of 550 mg/m². The maximum tolerated dose (MTD) was a daily dose of 460 mg/m². In Arm B, the DLTs were grade 3 stomatitis and hyperbilirubinemia, observed at a daily dose of 460 mg/m². The continuous infusion MTD was a daily dose of 330 mg/m². Hypoxia markers HIF‐1α and CAIX were highly expressed in leukemic bone marrow and were significantly reduced after evofosfamide therapy. The combined overall response rate in Arms A and B was 6% (2 CR/CRi and 1 PR), with all responses seen in Arm A. Evofosfamide has shown limited activity in heavily pretreated leukemia patients. Further evaluation investigating evofosfamide in combination with cytotoxic or demethylating agents is warranted. Am. J. Hematol. 91:800–805, 2016. © 2016 Wiley Periodicals, Inc.     

Phase I trial of low dose decitabine targeting DNA hypermethylation in patients with chronic lymphocytic leukaemia and non‐Hodgkin lymphoma: dose‐limiting myelosuppression without evidence of DNA hypomethylation

Targeting aberrant DNA hypermethylation in chronic lymphocytic leukaemia (CLL) and non‐Hodgkin lymphoma (NHL) with decitabine may reverse epigenetic silencing in B‐cell malignancies. Twenty patients were enrolled in two phase I trials to determine the minimum effective pharmacological dose of decitabine in patients with relapsed/refractory CLL (n = 16) and NHL (n = 4). Patients received 1–3 cycles of decitabine. Dose‐limiting toxicity (DLT) was observed in 2 of 4 CLL and 2 of 2 NHL patients receiving decitabine at 15 mg/m² per d days 1–10, consisting of grade 3–4 thrombocytopenia and hyperbilirubinaemia. Six patients with CLL received decitabine at 10 mg/m² per d days 1–10 without DLT; however, re‐expression of methylated genes or changes in global DNA methylation were not observed. Therefore, a 5‐day decitabine schedule was examined. With 15 mg/m² per d decitabine days 1–5, DLT occurred in 2 of 6 CLL and 2 of 2 NHL patients, consisting of grade 3–4 neutropenia, thrombocytopenia, and febrile neutropenia. Eight patients had stable disease. In 17 patients, there were no significant changes in genome‐wide methylation or in target gene re‐expression. In conclusion, dose‐limiting myelosuppression and infectious complications prevented dose escalation of decitabine to levels associated with changes in global methylation or gene re‐expression in CLL and NHL.     

Results of a phase I‐II study of fenretinide and rituximab for patients with indolent B‐cell lymphoma and mantle cell lymphoma

Fenretinide, a synthetic retinoid, induces apoptotic cell death in B‐cell non‐Hodgkin lymphoma (B‐NHL ) and acts synergistically with rituximab in preclinical models. We report results from a phase I‐II study of fenretinide with rituximab for B‐NHL s. Eligible diagnoses included indolent B‐NHL or mantle cell lymphoma. The phase I design de‐escalated from fenretinide at 900 mg/m² PO BID for days 1–5 of a 7‐day cycle. The phase II portion added 375 mg/m² IV rituximab weekly on weeks 5–9 then every 3 months. Fenretinide was continued until progression or intolerance. Thirty‐two patients were treated: 7 in phase I, and 25 in phase II of the trial. No dose‐limiting toxicities were observed. The phase II component utilized fenretinide 900 mg/m² twice daily with rituximab. The most common treatment‐related adverse events of grade 3 or higher were rash (n  = 3) and neutropenia (n  = 3). Responses were seen in 6 (24%) patients on the phase II study, with a median duration of response of 47 months (95% confidence interval, 2–56). The combination of fenretinide and rituximab was well tolerated, yielded a modest overall response rate, but with prolonged remission durations. Further study should focus on identifying the responsive subset of B‐NHL .     

Combination trial of duvelisib (IPI-145) with rituximab or bendamustine/rituximab in patients with non-Hodgkin lymphoma or chronic lymphocytic leukemia

Duvelisib, a potent δ- and γ-PI3K inhibitor, is a potential therapeutic for hematologic malignancies. Rituximab and bendamustine have demonstrated activity in non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Combining duvelisib with either rituximab alone or rituximab and bendamustine may improve response rates and remission durability. We conducted this Phase one study in relapsed/refractory NHL and CLL patients. During expansion, each arm enrolled to disease-specific cohorts to assess efficacy. Arm one received rituximab 375 mg/m² IV weekly for two 4-week cycles plus duvelisib until progression/intolerance. Arm two received rituximab 375 mg/m² IV Day one, bendamustine 90 mg/m² IV (NHL patients) or 70 mg/m² IV (CLL patients) Days one-two for six cycles, plus duvelisib until progression/intolerance. Duvelisib doses of 50 mg and 75 mg BID were tested during dose escalation. Forty-six patients (27 NHL, 19 CLL) were treated. The adverse events of the drug combinations were consistent with single agent toxicities. The most common AEs were neutropenia (47.7%), fatigue (41.3%), and rash (41.3%). A duvelisib expansion dose of 25 mg BID was chosen based on the monotherapy phase one study, IPI-145-02, which confirmed that dose for further clinical development. Overall response rate was 71.8%. Median progression-free survival was 13.7 months. Median overall survival has not been reached, but 30-month overall survival probability was 62%. Duvelisib combined with rituximab, or bendamustine and rituximab did not appear to increase toxicities beyond the known safety profile of the individual agents. Further study is needed to determine if these combinations improve efficacy.     

Intracellular lactic dehydrogenase and phosphohexose isomerase activity in leukaemia and malignant lymphoma

Intracellular activities of total lactic dehydrogenase (LDH) and phosphohexose isomerase (PHI) were investigated in the leukaemic cells of 14 patients with acute myeloid leukaemia (AML), five with chronic myeloid leukaemia (CML), seven with acute lymphoblastic leukaemia (ALL), 19 with chronic lymphocytic leukaemia (CLL), 16 with leukaemic non-Hodgkin's lymphoma (NHL) and in the lymphocytes of 14 normal persons. Intracellular total LDH-activity of the blasts of AML and ALL was in the same range as the normal lymphocytes. Patients with CLL and NHL had significantly lower levels ( P <0.01) of total intracellular LDH than the controls. Intracellular PHI activity was consistently lower in the lymphoid malignancies (ALL, CLL, NHL) than in normal lymphocytes ( P <0.05), or in leukaemic myeloblasts ( P <0.01). The intracellular LDH/PHI index of the leukaemic lymphoblasts was significantly elevated as compared to lymphocytes from normal subjects ( P <0.0001) or to leukaemic cells from patients with AML ( P <0.001), with CLL ( P < 0.0001) or with NHL ( P < 0.001). The patients with CLL and NHL, on the other hand, had significantly lower levels of LDH/PHI ratio than the normal subjects ( P <0.0001 and P <0.025 respectively).     

Efficacy and safety of the third-generation chloroethylnitrosourea fotemustine for the treatment of chemorefractory T-cell lymphomas

Patients with recurring T‐cell non‐Hodgkin lymphoma (T‐NHL) are incurable and candidate for investigational agents. Here, we report on five patients with T‐NHL refractory to multiple chemotherapy lines, including in all cases alkylators and gemcitabine, who received the third‐generation chloroethylnitrosourea fotemustine at a dose of 120 mg/m² every 21 d, up to eight courses. Median actual dose intensity was 79%; toxicity was manageable and mainly hematological. One complete remission, one partial remission, two protracted disease stabilization, and one transient, minor response were achieved. Time to progression ranged from 48 to 240+ d. This is the first evidence ever reporting the activity of fotemustine in end‐stage T‐NHL. Formal studies with this agent are warranted in T‐cell malignancies.     

Clofarabine,idarubicin, and cytarabine (CIA) as frontline therapy for patients ≤60 years with newly diagnosed acute myeloid leukemia

Clofarabine is a second generation nucleoside analogue with activity in adults with acute myeloid leukemia (AML). A phase I trial of clofarabine, idarubicin, and cytarabine (CIA) in relapsed and refractory AML had shown an overall response rate (ORR) of 48%. To explore this combination further, we conducted a phase II study of (CIA) in patients with newly diagnosed AML ≤60 years. Patients ≥18–60 years with AML and adequate organ function were enrolled. Induction therapy consisted of clofarabine (C) 20 mg m^?2 IV daily (days 1–5), idarubicin (I) 10 mg m^?2 IV daily (days 1–3), and cytarabine (A) 1 g m^?2 IV daily (days 1–5). Patients in remission received up to six consolidation cycles (C 15 mg m^?2 × 3, I 8 mg m^?2 × 2, and A 0.75 g m^?2 × 3). Fifty‐seven patients were evaluable. ORR was 79%. With a median follow up of 10.9 months, the median overall survival (OS) was not reached, the median event‐free survival (EFS) was 13.5 months. Most toxicities were ≤grade 2. Four week mortality was 2%. In subgroup analysis, patients ≤40 years had better OS (P = 0.04) and EFS (P = 0.04) compared to patients >40 years. Compared to historical patients treated with idarubicin and cyarabine (IA), the OS and EFS were significantly longer for CIA treated patients. In multivariate analysis, CIA retained its favorable impact on OS compared to IA. Thus, CIA is an effective and safe therapy for patients ≤60 years with newly diagnosed AML. Am. J. Heamtol. 88:961–966, 2013. © 2013 Wiley Periodicals, Inc.     

A phase 1/2 study of carfilzomib in Japanese patients with relapsed and/or refractory multiple myeloma

We conducted a phase 1/2 study of single‐agent carfilzomib in Japanese patients with relapsed/refractory multiple myeloma. Safety, pharmacokinetics and pharmacodynamics of carfilzomib were examined in phase 1. The primary endpoint in phase 2 was the overall response rate (ORR). Carfilzomib was administered in a twice‐weekly, consecutive‐day dosing schedule. In Phase 1, doses of 15 or 20 mg/m² were administered on this schedule or 20 mg/m² on Days 1 and 2 of Cycle 1 and then 27 mg/m² in the 20/27 mg/m² cohort. Patients had a median of five prior therapies, including bortezomib and an immunomodulatory agent. The dose level did not reach the maximum tolerated dose. The most common adverse events were haematological. Notably, carfilzomib either induced new hypertension (n = 4) or aggravated previously existing hypertension (n = 6) in 10 of 50 patients. Four of the eight patients who previously experienced peripheral neuropathy (PN) experienced a recurrence with carfilzomib use, but no new cases of PN occurred. The ORR of the 20/27 mg/m² 40 patient cohort was similar to that in the pivotal US study. The dose was efficacious and tolerable in heavily pre‐treated Japanese patients; however, meticulous control of hypertension may be necessary for further carfilzomib use.     

Phase II study of ifosfamide, etoposide, and oxaliplatin (IFETOx) chemotherapy for relapsed or refractory non-Hodgkin’s lymphoma

As part of an effort to develop a more effective and safe treatment for relapsed or refractory non-Hodgkin’s lymphoma (NHL), we conducted a phase II study of the oxaliplatin, etoposide, and ifosfamide (IFETOx) regimen. Patients with relapsed or refractory NHL and a performance status of 0–2 were eligible. The IFETOx consisted of etoposide at 100 mg/m² on days 1–3, oxaliplatin at 130 mg/m² on day 2, and ifosfamide 5,000 mg/m² on day 2, every 21 days. The primary endpoint was the overall response rate (ORR) for IFETOx regimen. A total of 23 eligible patients were enrolled. The median age was 58 years (range 19–76 years), and the male-to-female ratio was 15:8. The disease status was as follows: 15 patients had relapsed and 8 patients were refractory to treatment. The ORR for IFETOx chemotherapy was 65.2 %. In the 15 patients who responded to the protocol treatment, five underwent hematopoietic stem cell transplantation. The 2-year probability of progression-free survival and overall survival rates were 51.4 and 56.1 %, respectively. Grade 3/4 neutropenia was observed in 73.9 % of the patients. No significant renal impairment was observed. In conclusion, IFETOx chemotherapy shows a tolerable toxicity profile and efficacy as a salvage treatment regimen for relapsed or refractory NHL.     

血液肿瘤患者FLT3/ITD基因突变的检测及临床意义

目的检测血液肿瘤患者FLT3/ITD基因突变,探讨其突变的临床意义。方法2001—2005年对南方医科大学南方医院血液科332例血液肿瘤患者,采用聚合酶链反应(PCR)方法检测FLT3/ITD基因突变。结果FLT3/ITD基因突变阳性率分别为急性髓性白血病(AML)22.3%(23/103)、慢性髓性白血病急变期(CML-BC)6.5%(2/31)、骨髓增生异常综合征(MDS)5.6%(2/36)和急性淋巴细胞白血病(ALL)2.6%(2/76)。而慢性髓性白血病慢性期(CML-CP)、慢性淋巴细胞白血病(CLL)、多发性骨髓瘤(MM)和非霍奇金淋巴瘤(NHL)均未发现FLT3/ITD基因突变。FLT3/ITD基因突变阳性AML患者外周血WBC计数及骨髓白血病细胞比例显著高于FLT3/ITD基因突变阴性AML患者(P<0.05),FLT3/ITD基因突变阳性AML患者完全缓解后18个月内累计复发率(63.6%)显著高于FLT3/ITD基因突变阴性AML组(27.7%)(P<0.05)。结论FLT3/ITD基因突变检测对血液肿瘤预后有一定意义;FLT3/ITD基因突变AML患者预后差。     

All-trans retinoic acid plus low doses of cytarabine for the treatment of “poor-risk” acute myeloid leukemias

Summary Thirteen refractory/resistant AML patients no suitable for additional aggressive chemotherapy, were treated with a combination including all -trans retinoic acid (45 mg/m² sine die) and low doses of Ara-C (20 mg/m² subcutaneously, twice in a day, days 1–10, every 28 days). Ten patients were évaluable; 8 of them achieved a complete remission, two patients with an important tumor burden, failed to achieve a response. One complete remission patient relapsed after 7 months but is still receiving the same therapy and is now in partial remission. We believe this combination effective as inducer of complete remission in those AML patients which cannot tolerate additional heavy treatments. The role of tumor burden in affecting response to therapy remains to be still evaluated.     

Combination of liposomal daunorubicin (DaunoXome), fludarabine, and cytarabine (FLAD) in patients with poor-risk acute leukemia

Sixty-two patients with high-risk acute leukemia were treated with the FLAD regimen [3 days of treatment with fludarabine 30 mg/m², cytarabine (AraC) 2 g/m², and liposomal daunorubicin 80 mg/m²]. The acute myeloid leukemia (AML) patients were either refractory to standard induction regimens (8), were in first or second relapse (13), or received therapy as first-line treatment [21 patients, 16 were above 60 years of age and 5 had post-myelodysplastic syndrome (MDS) AML]. The acute lymphoblastic leukemia (ALL) patients were treated for relapsed (7) or refractory disease (10). Three patients had chronic myeloid leukemia (CML) in the blastic phase. FLAD was well tolerated by most patients. Ten major infectious complications were recorded while no signs of cardiac toxicity were observed. Five patients (8%) died before day 28 with hypocellular marrow, mainly of infection or hemorrhage, and response could not be evaluated. Complete response rate was 62% and 69% among AML patients treated at diagnosis or for relapsed disease, respectively, and 59% among the ALL patients. Furthermore, FLAD managed to overcome the negative impact of poor prognosis karyotype in ALL patients, since five of the seven patients with t(9;22) or complex karyotype achieved complete remission (CR). Nine patients underwent bone marrow transplantation (BMT). Among the AML patients who were treated at diagnosis or for relapse, the median duration of CR was 7 months (range: 2–18) and 8 months (range: 2–26), respectively. Median survival among these patients was 8 (range: 1–40) and 12 (range: 1–30) months, respectively. Similar values were found in ALL patients. In conclusion, FLAD may be an effective alternative treatment for patients with relapsed AML and for patients with ALL who failed first-line therapy.     

Fludarabine,cytarabine, and attenuated‐dose idarubicin (m‐FLAI) combination therapy for elderly acute myeloid leukemia patients

We performed a phase II trial to evaluate the efficacy and safety of the modified fludarabine, cytarabine, and attenuated‐dose idarubicin (m‐FLAI) regimen in elderly acute myeloid leukemia (AML) patients. Elderly (≥60 years) AML patients who had not previously received chemotherapy were enrolled in the study. Patients received two consecutive cycles of m‐FLAI chemotherapy as an induction. The m‐FLAI regimen comprised fludarabine (25 mg/m², days 1–4), cytarabine (1,000 mg/m², days 1–4), and attenuated‐dose idarubicin (5 mg/m², days 1–3). The primary end point was complete remission (CR) rate. Secondary end points were overall survival (OS), event‐free survival (EFS), and treatment‐related mortality (TRM). There were 108 patients (median age 68.4 years, M:F = 64:44) enrolled in the study. CR was achieved in 56.5% of patients, and the TRM rate was 21.3%. Median OS and median EFS were 10.2 and 6.6 months, respectively. The mortality at 30 and 60 days was 15 and 21%, respectively. Performance status and comorbidity did not have prognostic value in this patient cohort. Bone marrow expression of CD117 was associated with increased EFS and OS. m‐FLAI is an effective induction regimen for previously untreated AML in elderly patients. In addition, bone‐marrow CD117 expression is an independent favorable prognostic factor in elderly AML patients. (ClinicalTrials.gov number, NCT01247493). Am. J. Hematol. 2013. © 2012 Wiley Periodicals, Inc.     

BCR‐ABL1 molecular remission after 90Y‐epratuzumab tetraxetan radioimmunotherapy in CD22+ Ph+ B‐ALL: proof of principle

Although targeted therapies are used increasingly in hematologic malignancies, we are unaware of any prior studies of radioimmunotherapy (RAIT) in B‐acute lymphoblastic leukemia (ALL), even though this radiosensitive tumor expresses CD22, potentially a good target for this approach. Here, we report a patient with Philadelphia chromosome‐positive B‐ALL in third relapse who received RAIT with ⁹⁰yttrium (⁹⁰Y)‐labeled anti‐CD22 epratuzumab tetraxetan. Seven weeks after initiating therapy, the patient achieved a BCR‐ABL1 molecular remission documented by RT‐qPCR, which is now continuing at 6 months while awaiting an allogeneic hematopoietic stem cell transplant. ⁹⁰Y‐Epratuzumab tetraxetan may be a promising therapeutic option for CD22⁺ B‐ALL patients.     

The pattern of mutational involvement of RAS genes in human hematologic malignancies determined by DNA amplification and direct sequencing

DNA from 161 patients with various forms of hematologic malignancies were investigated for mutations in exons 1 and 2 of the N-RAS, K-RAS and Ha-RAS gene by direct sequencing of DNA amplified in vitro by the polymerase chain reaction. Mutations involving either codons 11, 12, or 13 of the N-RAS gene were identified in 18 of the 161 patients. The relative frequencies of N-RAS gene mutations in these hematologic disorders was as follows: acute myelogenous leukemia (AML), 15%; acute lymphoblastic leukemia (ALL), 14%; myelodysplastic syndromes, 24%; and myeloid and lymphoid blast crisis of chronic myelogenous leukemia (CML), 3%. No correlation was observed between the presence of mutations and cytologic features or immunophenotype of these malignancies. Mutations involving codons 12 or 13 were equally prevalent, with a glycine to aspartic acid substitution being the most frequently encountered change. A single T-ALL case had a codon 11 mutation resulting in substitution of alanine with threonine. We failed to find mutations in exons 1 and 2 of the K-RAS or Ha-RAS genes in any case except a single AML with a mutation in codon 61 of the K-RAS gene. Also, no mutations were identified in chronic phase of CML, chronic lymphocytic leukemia. Ph1 positive ALL, non-Hodgkin's lymphoma, Hodgkin's disease, or multiple myeloma. These results indicate that RAS mutations, especially those involving exon 1 of the N-RAS gene, are frequent only in a subset of hematologic malignancies.     

Prognostic factors for outcome in patients with refractory and relapsed acute lymphocytic leukemia treated with inotuzumab ozogamicin,a CD22 monoclonal antibody

Inotuzumab ozogamicin was found to be highly active in patients with refractory‐relapsed acute lymphocytic leukemia (ALL), with an overall response rate of 58% and a median survival of 6.3 months. Identifying factors associated with different outcomes on inotuzumab therapy may help select patients for this treatment and advice of prognosis. A total of 89 patients treated with inotuzumab on previous studies were analyzed. Inotuzumab was given at 1.3–1.8 mg/m² intravenously (IV) × 1 every 3–4 weeks or weekly (0.8 mg/m² day 1, 0.5 mg/m² days 8 and 15) every 3–4 weeks. Pretreatment factors associated with achieving marrow complete response (CR) and with survival were analyzed using standard statistical methods. The median survival of patients with at least marrow CR was 9.2 months versus 3.4 months for those without marrow CR (P < 0.001). By multivariate analysis, a high peripheral blood absolute blast count and low platelet count were independently associated with a lower likelihood of achieving at least marrow CR. Baseline characteristics independently associated with worse survival included adverse cytogenetics [complex karyotype, translocation (4;11), translocation (9;22), abnormal chromosome 17], disease beyond first salvage, and high peripheral blood absolute count. Patients with 0, 1–2, or 3 adverse factors had a median survival of 39+, 7.5, and 2.4 months, respectively. Our current analyses identified a subset of adult patients with ALL in whom outcome of therapy with inotuzumab ozogamicin can be differentially predicted. Am. J. Hematol. 90:193–196, 2015. © 2014 Wiley Periodicals, Inc.