Complete Molecular Remission Rate Research Articles

ALL-424 Updated Results from the Phase II Study of Blinatumomab in Combination With Ponatinib in Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

Blinatumomab and ponatinib both induce high rates of complete molecular remission (CMR) in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL). Their combination may generate durable responses and decrease the reliance on allogeneic stem cell transplantation (allo-SCT). To evaluate the combination of blinatumomab and ponatinib in patients with Ph-positive ALL. Patients with newly-diagnosed (ND) or relapsed/refractory (R/R) Ph-positive ALL were treated on this phase II trial. Blinatumomab was given for up to 5 cycles at standard doses, and ponatinib was started at 30mg daily during cycle 1, then lowered to 15mg daily upon achieving CMR. Among responders, ponatinib was maintained for a minimum of 5 years. Patients received 12 doses of prophylactic intrathecal chemotherapy. The primary endpoint was the CMR rate in the ND cohort, and the overall response rate (ORR; CR and CRi) in the R/R cohort. Forty-nine patients were treated: 35 ND (median age, 57 years; range, 22-83 years) and 14 R/R (median age, 38 years; range, 24-61 years). Among R/R patients, 43% were in Salvage ≥2. One early death within 4 weeks was observed among ND patients due to intracranial hemorrhage, none among R/R patients. The ORR was 96% in the ND cohort and 92% in the R/R cohort, with respective CMR rates of 85% and 79%. Only one patient with ND disease underwent allo-SCT because of persistently detectable BCR::ABL1 transcript levels; 6 patients (46%) with R/R disease underwent subsequent allo-SCT. After a median follow-up of 11 months (range, 1-46 months), no relapses were observed in the ND cohort with similar 2-year OS and EFS rates of 93%. In the R/R cohort, the estimated 2-year OS and EFS rates were 61% and 42%, respectively. This combination showed a favorable safety profile, with most adverse events of grade 1-2. One patient discontinued ponatinib due to toxicity. The chemotherapy-free combination of blinatumomab and ponatinib demonstrated robust clinical activity in Ph-positive ALL, with high rates of CMR and durable remissions. This strategy will potentially obviate the need for chemotherapy and allo-SCT in many patients, particularly in the frontline setting.

Distinct outcomes, ABL1 mutation profile, and transcriptome features between p190 and p210 transcripts in adult Philadelphia-positive acute lymphoblastic leukemia in the TKI era

BackgroundThe differential signaling and outcome of patients with p190 or p210 transcripts of BCR-ABL1 have been systematically investigated in chronic myeloid leukemia rather than in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL).MethodsWe analyzed the outcomes and ABL1 mutation profiles in 305 consecutive adult patients with Ph+ ALL treated with chemotherapy plus tyrosine kinase inhibitors. We also studied transcriptome features in two newly diagnosed patients with p190 and p210 using single-cell RNA sequencing (scRNA-seq).ResultsP190 and p210 were found in 199 (65%) and 106 (35%) patients, respectively. Compared to patients with p190, a higher white blood cell count (p = 0.05), platelet count (p = 0.047), BCR-ABL1 transcript level (p < 0.001), and lower bone marrow blasts (p = 0.003) were found in patients with p210. Patients with p210 had fewer types of ABL1 mutations (4 vs. 16) and a higher prevalence of T315I and E225K/V mutations (91.3% vs. 68.6%; p = 0.031). Patients with p210 had a similar complete remission rate (91.0% vs. 90.1%; p = 0.805) but a lower complete molecular remission rate at 1 month (9.9% vs. 22.0%; p = 0.031) compared with p190. Patients with p210 had lower 3-year overall survival (OS) and disease-free survival (DFS) rates than those with p190 (3-year DFS: 10.4% vs. 9.2%, p = 0.069, 3-year OS: 44.3% vs. 38.2%, p = 0.018, respectively). Multivariate analysis revealed that p210 was independently associated with worse OS [HR 1.692 (95% CI 1.009–2.838), p = 0.046]. Allogeneic hematopoietic stem-cell transplantation (allo-HSCT) was associated with a better prognosis in patients with p210 (p < 0.0001). In addition, scRNA-seq data showed distinct molecular and cellular heterogeneity between bone marrow cells of the two transcripts.ConclusionsPh+ ALL patients with p190 and p210 had different clinical characteristics, outcomes, ABL1 mutation profiles, and transcriptome features. Allo-HSCT could improve the outcomes of patients with p210.

Combination of ponatinib and blinatumomab in Philadelphia chromosome-positive acute lymphoblastic leukemia: Early results from a phase II study.

7001 Background: Achievement of a complete molecular remission (CMR) is associated with superior outcomes in patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). Ponatinib and blinatumomab both produce high rates of molecular remission in Ph+ ALL. The combination of these two agents may lead to durable responses and reduce the need for allogeneic hematopoietic stem cell transplant (AHSCT). Methods: This is a single-arm phase 2 study in adults with newly diagnosed (ND) or relapsed/refractory (R/R) Ph+ ALL. Patients received up to 5 cycles of blinatumomab as a continuous infusion at standard doses. Ponatinib 30mg daily was given during cycle 1. Ponatinib was decreased to 15mg daily once CMR was achieved. After completion of blinatumomab, ponatinib was continued for at least 5 years in responding patients. Twelve doses of prophylactic intrathecal chemotherapy were administered. For patients with ND Ph+ ALL, the primary endpoint was the CMR rate. For patients with R/R Ph+ ALL, the primary endpoint was the overall response rate (defined as the composite of CR/CRi). Results: Twenty-eight patients were treated (19 FL and 9 R/R). Median age was 59 years (range, 25-83 years); 62 years (range, 34-83 years) in the ND cohort and 36 years (range, 25-61 years) in the R/R cohort. Transcripts were p190 in 69% of patients the ND cohort and 100% in the R/R cohort. Among R/R patients, 44% were in Salvage 2+. No early death within 4 weeks were observed. Overall, 95% of patients responded; the response rate was 100% in the ND cohort and 88% in the R/R cohort. Among responding patients, 86% achieved CMR: 87% in the ND cohort and 86% in the R/R cohort. Median time to CMR was 1 month (range, 1-13 months). None of the patients in the ND cohort underwent AHSCT; 4 patients (44%) with R/R disease underwent subsequent AHSCT. With a median follow-up of 14 months, the estimated 1-year overall survival (OS) rate was 94% and event-free survival (EFS) rate was 81% for the entire study population. In the ND cohort, no patients have relapsed or died, and the 1-year OS and EFS rates were both 100%. In the R/R cohort, 1-year OS and EFS rates were 88% and 55%, respectively. The treatment was well-tolerated. Most side effects were grade 1-2. No patient discontinued ponatinib due to toxicity. One patient discontinued blinatumomab due to recurrent grade 2 tremor. Conclusions: The chemotherapy-free combination of ponatinib and blinatumomab shows encouraging results in Ph+ ALL. The regimen results in high rates of CMR and durable responses, potentially obviating the need for chemotherapy and AHSCT in many patients, particularly when used as frontline therapy. Clinical trial information: NCT03263572.

High Prognostic Value of a 3-Genes Molecular Score in Non-High Risk Acute Promyelocytic Leukemia Treated with AIDA 2000 Protocol: A Retrospective Study from a Regional Register

BACKGROUND AND AIMSNon high risk acute promyelocytic leukemia (APL) patients, as defined by WBC count at diagnosis, have nowadays a very good prognosis when treated with ATRA plus chemotherapy based protocols, with high rate of complete molecular remission after consolidation therapy. However, a small proportion of patients (roughly 10-15%) will eventually relapse, despite the achievement of molecular CR.In the past years, some groups showed that relapse risk could be predicted by testing for some gene alterations, such as FLT3-ITD, or by break point cluster region (BCR) analysis. However, those results were not confirmed in prospective trials.We retrospectively applied a simple 3 gene based molecular panel to low-intermediate risk acute promyelocytic patients, alongside with BCR analysis, in order to develop a risk score.MATERIALS AND METHODSFifty-nine low/intermediate risk APL patients, treated with the Italian age-adapted AIDA protocol from January 1st 2004 to December 31st 2014 in our center were retrospectively included in this study. Median age was 47 years (range 19-88), 16 patients were older than 60 years (27%).BCR analysis was available in all patients, 41 patients showed BCR1/2, whereas 18 patients had BCR3 (30%).Molecular profile included determination of FLT3-ITD mutation, WT1 and BAALC gene expression levels and was available in 38/59 patients (64%); bone marrow sample of diagnosis is available for all other 21 patients for further analysis. Cut-off values for WT1 (20000/abl x 104) and BAALC (450/abl x 104) were arbitrarily chosen after pre-analysis and comparison with our published data.Five patients had FLT3-ITD mutation (13%), 18 (45%) patients had higher WT1 expression levels and BAALC was overexpressed in 9 (24%) patients.Pre-analysis showed that FLT3-ITD, low WT1 levels, high BAALC levels but not the presence of BCR3 were associated with higher relapse risk. A molecular score including those 3 genes was built: 16 patients had no risk factors (42%), 17 patients had one risk factor (45%), 5 had two risk factors (13%).RESULTSFifty-four patients survived induction, all of them achieved CR, in 52 PML/RARα transcript was undetectable after last consolidation therapy. The two patients with molecular persistence of disease received further therapy and then achieved molecular CR. Nine patients (15%) relapsed after a median follow-up of 56 months, 45 patients are alive at the time of analysis (76%). Relapse risk was influenced only by the presence of at least one molecular risk factor (p<0.05), whereas age at diagnosis older than 60 years had only a borderline impact (p=0.105); none of the molecular alterations reached statistical significance if taken alone.Disease free survival (DFS) duration was significantly higher in patients who had none of the molecular risk factor, when compared to patients with at least one (3-years DFS of 100% and 70.8%, respectively, p<0.05, Figure 1). Younger patients had also a longer DFS, with a 3-years DFS of 90.7% and 72% for patients younger or older than 60 years, respectively (p<0.03).Overall survival (OS) analysis led to similar results: patients with no molecular risk factors had a very good outcome when compared to patients with at least one alteration (3-years OS of 100% and 71.5%, respectively, p<0.03). Survival was also influenced by age at diagnosis, as younger patients did significantly better, with 3-years OS of 90% (p<0.05).Again, none of the molecular alterations, if taken alone, had a significant impact on DFS or OS.CONCLUSIONSEven in our small cohort, molecular profile could identify a subset of low-intermediate APL patients at higher risk of relapse, who may take benefit from an intensified consolidation therapy, as it is currently applied to high risk patients defined by WBC at diagnosis. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Nilotinib (Tasigna®) and Chemotherapy for First-Line Treatment in Elderly Patients with De Novo Philadelphia Chromosome/BCR-ABL1 Positive Acute Lymphoblastic Leukemia (ALL): A Trial of the European Working Group for Adult ALL (EWALL-PH-02)

▪Despite a high complete hematologic remission (CHR) rate with imatinib-based therapy, the prognosis of elderly patients (pts.) with Philadelphia positive (Ph+) acute lymphoblastic leukaemia (ALL) is poor, primarily due to relapse. Nilotinib (Tasigna®) is a potent ABL kinase inhibitor (TKI) approved for treatment of chronic and accelerated phase CML, but data on its efficacy in Ph+ ALL are limited. To study the activity of ABL-TKI in the front-line setting, the EWALL (European Working Group for Adult ALL) has developed a joint chemotherapeutic protocol for first-line therapy of elderly Ph+ ALL pts. (aged 55 years or more) that serves as a platform for the addition of targeted therapeutic agents. This chemotherapy backbone was used to test the efficacy and safety of the addition of nilotinib in elderly patients with newly diagnosed Ph+ ALL in a European, investigator-initiated trial.Male or female pts. > 55 years with Ph+ and/or BCR-ABL1 positive ALL were eligible if they had not been previously treated except with corticosteroids, single dose vincristine or three doses of cyclophosphamide, had a WHO performance status of 0-2, adequate organ function and had signed written informed consent. The trial was conducted in accordance with the principles of the Declaration of Helsinki and was approved by the ethics committees of all participating centres. The trial was registered under NCT01528085. After a pre-phase with dexamethasone (Dex) 10 mg/m² d-7 to d-3 (cyclophosphamide 200mg/m² i.v. d-3 to d-1 optional), nilotinib was administered at 400 mg BID starting with induction therapy and given continuously thereafter. During induction, nilotinib was combined with IV injections of vincristine (VCR) 1 mg and Dex 40 mg on 2 days (20 mg over 70y), repeated weekly for 4 weeks. Consolidation cycles consisted of nilotinib 400 mg BID, methotrexate 1000 mg/m² IV d1 (500 mg/m² over 70y) and asparaginase 10,000 UI/m² IV d2 (5,000 UI/m² over 70y) for cycles 1, 3 and 5 and cytarabine 1,000 mg/m²/12h IV d1, d3, d5 (500 mg/m² over 70y) for cycles 2, 4 and 6. Maintenance phase consisted of nilotinib, 6-MP QD and methotrexate once weekly over 1 month every other month, and Dex/VCR in 2 month intervals for up to 24 months of treatment. The primary end-point is the rate of pts. without an event (defined as relapse, death, SAE or study treatment discontinuation) at 12 months, secondary endpoints include the rate of CHR after induction, death during induction or in CHR, event free (and overall survival, the rate of major (MMR) or complete molecular response (CMR) defined by BCR-ABL/ABL ratios < 0.1% and < 0.001%, respectively.As of August 2014, 47 pts. (21 male, 26 female) have been enrolled. Median age is 66 years (55-85 years), twelve pts. are older than 70 years of age. To date, 43 pts. are evaluable for safety and 36 pts. are evaluable for efficacy. The CHR rate is 97% (35 of 36 pts. evaluable for response), one patient was refractory (3%). No patient died during induction therapy. With a median follow-up of 211 days, 31 of 35 evaluable pts. are in CCR and four pts. relapsed, two of whom had discontinued study treatment to undergo allogeneic SCT. 13 of the 36 pts. with documented induction response have discontinued study treatment prematurely, primarily because of transfer to allogeneic SCT (n=7), as explicitly permitted by the protocol. Six pts. discontinued for various other reasons. Eight of 35 CR pts. have completed the consolidation cycles and have entered maintenance phase, five pts. have completed protocol therapy. The rate of complete molecular remission (CMR) after induction (32 pts. evaluable) was 30%, with 2 pts. having undetectable BCR-ABL1 transcripts. During consolidation, 13 of 31 pts. (42%) had a CMR, and BCR-ABL transcripts were undetectable in 9 of 31 pts. (29%). Tolerability has been acceptable, with thirty-four SAEs reported so far, 11 during induction (of 43 pts.), 16 during consolidation (of 37 pts.), 6 during the maintenance phase and one following study discontinuation. Infectious events and neutropenic fever predominated, individual SAEs included metabolic, cardiovascular, neurologic, renal and hepatic events.In conclusion, nilotinib in conjunction with chemotherapy according to the EWALL-PH-02 protocol is well tolerated and highly effective with a 97% CR in elderly pts. with newly diagnosed Ph+ ALL. Molecular response rates are high and MRD levels in responding pts. continue to decrease with time. DisclosuresOttmann:Novartis: Consultancy, Honoraria, Research Funding. Ribera:Novartis: Research Funding. Rousselot:Novartis: Research Funding.

Efficacy and safety analysis of interferon combined with imatinib in treating chronic myeloid leukemia

Imatinib has been recognized as the frontline therapy drug in chronic myeloid leukemia (CML), however, only limited patients could achieve complete molecular remission (CMR). Recent clinical and basic proofs indicated an improved treatment outcome by the combination of interferon and Imatinib. This study was purposed to evaluated systematically the efficacy and safety of interferon plus Imatinib in patients with CML. Data from relative clinical trials were from clinical trial of gov and Cochrane Collaboration. A comprehensive literature search was performed from data bases such as pubMed and EM. The results indicated that 7 clinical trials and 12 research papers met the criteria enrolled in study, included 697 cases in total. The combination group had higher complete cytogenetic remission (CCgR) rate than imatinib alone at 6 months (58% vs 42%; P = 0.0001) and 12 months (74% vs 68%; P = 0.004). The major molecular remission (MMR) rate was also higher in the combination group at 6 months (58% vs 34%; P = 0.0001) and 12 months (66% vs 47%; P < 0.0001). Furthermore, compared with single drug, the combination group had superior CMR rate at 6 months (13% vs 2%; P = 0.0002) and 12 months (14% vs 5%; P = 0.0009). The major adverse effects of combination therapy were rash, asthenia, edema and musculoskeletal events, and combination therapy was more prone to inducing neutropenia, thrombocytopenia and mild anemia. It is concluded that compared with Imatinib alone, the combination of interferon and Imatinib has better clinical efficacy in treating CML with earlier cytogenetic and molecular remission. It is also a safe therapy in spite of slightly weaker tolerance than single drug therapy.

Is Imatinib Maintenance Required for Patients with Relapse Chronic Myeloid Leukemia Post-Transplantation Obtaining CMR? A Pilot Retrospective Investigation

Imatinib can induce complete molecular remission (CMR) in relapse chronic myelogenous leukemia (CML) after allogeneic hematopoietic stem cell transplantation, but it is indefinite whether imatinib is required to maintain CMR. We retrospectively reviewed 37 relapse CML post-transplants treated with imatinib (n = 20) or donor lymphocyte infusion (DLI) (n = 17). The rate of CMR was 85% and 76.47% (P = 0.509) and treatment-related mortality was 0% and 29.4% (P = 0.019), respectively, in imatinib and DLI groups. Fifteen patients obtaining CMR voluntarily ceased imatinib, and did not experience relapse. The 8-year overall survival (OS) after relapse was 85%±8% and 40.3±12.1% (P = 0.017), and disease-free survival (DFS) after relapse was 85%±8% and 40.3±12.1% (P = 0.011), respectively, in imatinib and DLI groups. Imatinib resulted in higher OS and DFS than that of DLI in relapse CML. Imatinib maintenance might not be required for patients with relapse CML post-transplants after they achieved full donor chimerism and CMR.

Clinical and pharmacologic aspects of blinatumomab in the treatment of B-cell acute lymphoblastic leukemia

Acute lymphoblastic leukemia (ALL) in adults remains a challenging disease to treat, and novel therapies are needed. Precursor-B ALL comprises 80% of cases, and the CD19 antigen is expressed in nearly all precursor-B ALL patients. Bispecific T-cell-engaging antibodies are novel bioengineered proteins. The bispecific T-cell-engaging antibody blinatumomab engages polyclonal T cells to CD19-expressing B cells. By binding to both CD3 and CD19, blinatumomab physically brings these T cells in close proximity to malignant B cells and potentiates T-cell-induced cytotoxic cell kill. Blinatumomab requires continuous intravenous infusion due to its short half-life, the need for continuous exposure for the drug to exert sufficient efficacy, and lessened toxicity. A phase II trial of B-cell ALL patients with persistent or relapsed minimal residual disease demonstrated an 80% rate of complete molecular remission. Cytokine-release syndrome and central nervous system events, such as seizures and encephalopathy, are reversible toxicities. Promising results in B-cell ALL with minimal residual disease have led to further evaluation of this drug in newly diagnosed and relapsed B-cell ALL.

Homozygosity for killer immunoglobin-like receptor haplotype A predicts complete molecular response to treatment with tyrosine kinase inhibitors in chronic myeloid leukemia patients

Several recent reports suggest a possible role for killer immunoglobulin-like receptors (KIR) in the onset of chronic myeloid leukemia (CML) and response to therapy with tyrosine kinase inhibitors (TKIs). To explore this hypothesis, we studied KIRs and their human leukocyte antigen class I ligands in 59 consecutive patients with chronic-phase CML (mean age, 53 years; range, 23-81 years) and a group of 121 healthy control participants belonging to the same ethnic group as the patients. The 2-year cumulative incidence of complete molecular response, obtained after a median of 27 months (range, 4-52 months), was 51.2%. An increased frequency of the activating receptor KIR2DS1 (pm = 0.05) and a reduced frequency of the KIR-ligand combination KIR2DS2/2DL2 absent/C1 present (pm = 0.001) were significantly associated with CML. Moreover, KIR repertoires in patients appeared to influence response to TKI therapy. Homozygosity for KIR haplotype A (pm = 0.01), a decreased frequency of the inhibitory KIR gene KIR2DL2 (pm = 0.02), and low numbers of inhibitory KIR genes (pm = 0.05) were all significantly associated with achievement of complete molecular remission. These data suggest that a decrease in properly stimulated and activated NK cells might contribute to the occurrence of CML and indicate homozygosity for KIR haplotype A as a promising immunogenetic marker of complete molecular response that could help clinicians decide whether to withdraw treatment in patients with CML.

1105 - Management of Pediatric Chronic Myeloid Leukemia: Experience from Eastern India

ABSTRACT Imatinib inhibits constitutively active BCR-ABL tyrosine kinase of chronic myeloid leukemia (CML). It is a novel molecule, which inhibits the protein product of this fusion gene and hence has been used in the treatment of CML. In a long term -term study it was found superior to interferon alfa plus cytarabine for newly diagnosed CML in the chronic phase. However, till date there is no major study to evaluate Eastern Indian patients with CML treated with imatinib mesylate. The present study evaluates 138 patients with CML treated with imatinib mesylate. Of these, 33 patients had to be excluded due to various reasons of noncompliance, death and not being fit to receive the drug. Among rest 105 patients, 95 was in chronic phase, 7 in accelerated phase and 3 patients had blast crisis at the time of presentation. Among 105 patients, 45 patients received either interferon alpha or hydroxyurea and other 60 patients were previously untreated. Complete hematological remission rate and major cytogenetic response (CGR) rates were 90% and 50%, respectively after 1 year of treatment. Complete molecular remission rate was 35% after 1 year of treatment. The number of imatinib resistant patients is 8, about 7.6 % of total included patients. The disease free and overall survival at 51 months are 75.5 and 81.5% respectively. Oedema, diarrhoea, abdominal pain, dermatitis, mucositis, neutropenia and thrombocytopenia were some of the major toxicities. After 51 months of follow-up, continuous treatment of chronic-phase CML with imatinib as initial therapy was found to be safe and able to induce durable responses in a high proportion of patients. Thus it can be concluded that imatinib therapy in pediatric patients can replace bone marrow transplantation. Disclosure All authors have declared no conflicts of interest.

Dasatinib (Sprycel®) and Chemotherapy for First-Line Treatment in Elderly Patients with De Novo Philadelphia Positive ALL: Results of the First 22 Patients Included in the EWALL-Ph-01 Trial (on Behalf of the European Working Group on Adult ALL (EWALL))

Dasatinib (Sprycel®, Bristol-Myers Squibb) is a potent multi-targeted kinase inhibitor (TKI) of BCR-ABL and SRC family kinases. Despite a 33% complete hematological response (CHR) rate in a Phase 2 study in patients with Philadelphia positive (Ph+) acute lymphoblastic leukaemia (ALL) intolerant or resistant to imatinib, the median duration of progression-free survival (PFS) was 3.3 months (Ottmann et al. Blood . 2007; 110:2309-2315). Second-generation TKI may thus have a place in the management of these patients. As a European consensus has been reached by the EWALL to adopt a common first-line chemotherapeutic schedule for elderly patients (aged 55 years or more) with Ph-positive ALL, this schedule was used here to test the addition of dasatinib. After a prephase with dexamethasone 10 mg/m2 d-7 to d-3, the induction phase consisted in IV injections of vincristine 1 mg combined with 2 days of dexamethasone 40 mg PO repeated weekly for 4 weeks followed by consolidation cycles including methotrexate 1000 mg/m2 IV d1 (500 mg/m2 over 70y) and asparaginase 10,000 UI/m2 IM d2 (5,000 UI/m2 over 70y) for cycles 1, 3 and 5 alternating with cytarabine 1,000 mg/m2/12h IV d1, d3, d5 (500 mg/m2 over 70y) for cycles 2, 4 and 6. Maintenance phase consisted in 6-MP 60 mg/m2/d and methotrexate 25 mg/m2/week orally 1 month every other month and dexamethasone/vincristine in 2 months intervals during the first year and in 3 months intervals during the second year. Dasatinib (provided by Bristol-Myers Squibb) was administered at 140 mg per day (QD) during the induction period in combination with chemotherapy and at 100 mg/d sequentially with the chemotherapy courses during consolidation and maintenance. BCRABL analysis was performed according to the European Leukemia Net recommendations in two centralized laboratories.A total of 22 patients were included from August 2007 to June 2008. Median age was 71 years (range, 61 to 83), sex ratio (M/F) was 0,46, and median follow-up was 5.8 months. The Ph+ chromosome was associated with complex abnormalities in 58% of cases and 84% of the patients were m-BCR. The CHR rate was 95.2% (20 out of 21 evaluable patients). The only case of induction failure was due to death. The rate of complete molecular remission (CMR) after induction was 33% in blood and 28% in bone marrow and MRD level continued to decrease with time. Only one relapse was observed before the consolidation phase. No other relapse occurred for the 13 patients in CHR still in study after a median follow-up of 3.6 months. One patient died during induction from invasive aspergillosis, 3 deaths occurred in CR, 2 before consolidation due to pulmonary embolism and physical deterioration, and one during maintenance from pneumonia. Serious adverse events (SAEs) were reported in 7 out of 22 patients during induction (31.8%) and in 2 out of 13 patients during maintenance and consolidation (15.3%). SAEs consisted in renal failure (n=3, 2 from acute lysis syndrome and 1 tubular necrosis), invasive aspergillosis (n=1), pulmonary embolism (n=2), pneumonia (n=1), atrial arythmia (n=2), pleural effusion (n=1), microangiopathy (n=1), cytolytic hepatitis (n=1) and physical deterioration (n=1). Eight patients discontinued the study after induction (35%). Primary reasons for discontinuation were SAEs (n=4), death (n=3) and relapse (n=1).The EWALL-PH-01 protocol is highly effective with a 95.2% RCH rate in elderly patients with Ph-positive ALL. Of importance, responses appeared to be durable and MRD level was decreasing over time. An expected 40% rate of SAEs was observed in this elderly population. Reduced doses of therapy are now applied for patients over 70y (20 mg for dexamethasone, 100 mg/d for dasatinib).

Molecular remission to imatinib-IFN-alpha combination or imatinib monotherapy in chronic myeloid leukemia (CML) patients

17512 Background: Continously improving results have been obtained in the control of Philadelphia chromosome (Ph’) positive CML. However, the final goal of molecular remission remains difficult to be obtained, even in the imatinib era. Evaluation of the rate of complete molecular remission (undetectable p210 transcript at RQ-PCR confirmed by NESTED/RT-PCR in at least two subsequent tests over a period of 3 mths or more) to imatinib or to imatinib-IFNa combination as first, second or subsequent line of therapy. Imatinib alone or in combination with IFNa was given as first, second or subsequent line of therapy to a total of 47 patients. In particular, 21 patients were treated at the time of diagnosis with imatinib alone (18,G1) or imatinib-pegilated IFN combination (3,G2). Twenty-three additional patients (G3) received imatinib as second line therapy. Finally, 13 patients were treated with the imatinib-IFNa combination as second (7,G4) or third (6,G5) line therapy, but in two cases IFNa was discontinuated after one month because of intolerance to treatment. Methods: Molecular response was evaluated by NESTED/RT-PCR (Guo JQ et al.; Leukemia:2002;15:2447–53) and RQ-PCR (Gabert J et al. Leukemia:2003;17:2318–57) at time intervals of 3–6 months from the beginning of therapy. Results: Complete molecular remission lasting 3 months or more (range 3–34) was obtained in 15 of 44 evaluable patients (therapy duration = 11 mths, range 11–73).The response rate was higher in patients receiving imatinib- IFNa combination given as first or second line therapy (5/13) than in those given imatinib monotherapy (9/37). In 7 of the 15 complete responders, remission duration lasted more than 12 mths (range 12–34) with 6/7 pts still continuous remission. In further 6 cases continuous remission duration ranged from 3–8 mths while in one case fluctuating negative-positive NESTED/RT-PCR tests have been observed over a period of 65 months. Conclusions: It is not possible to draw any firm conclusion regarding the effect of the imatinib-INFa combination on molecular response because of the small sample size of treated patients. However, our findings suggest an additive effect of imatinib and IFNa in Ph’positive clone control. No significant financial relationships to disclose.

Response to Therapy with Imatinib Mesylate in Patients with CML Is Poor in Non-Caucasian Patients.

Imatinib mesylate is a targeted therapy for chronic myeloid leukemia (CML). All phases of CML are susceptible to imatinib, with more durable responses occurring in patients in chronic phase. Studies in patients with chronic phase CML who have been treated with imatinib have shown a complete hematologic remission (CHR) rate of 97%, a complete cytogenetic remission (CCR) rate of 70%, and a complete molecular remission (CMR) rate of 10%. Racial and ethnic differences have not been extensively studied in relation to cancer outcomes, and no studies to date have demonstrated a difference in outcomes based upon race or ethnicity of patients with CML treated with imatinib.Methods: A retrospective chart review of patients with CML who have been treated with imatinib at the University of Illinois, the Westside VA, and MacNeal hospitals over the past 3 years was performed. Primary endpoints were rates of CHR, CCR, and CMR in Caucasian (C) and non-Caucasian (NC) patients with CML on treatment with imatinib. A secondary endpoint was the correlation of Sokal scores at initiation of imatinib with rates of CHR, CCR, and CMR.Results: 26 charts were reviewed of 7 C and 19 NC patients ( 12 African American, 5 Latino, 1 Indian, 1 Lebanese) in chronic phase CML. For C patients at the initiation of imatinib, mean age was 46 (45 for NC) and mean Sokal score was 0.79 (0.75 for NC). 32% (8/25) of patients had cytogenetic abnormalities in addition to the Philadelphia chromosome, all of whom were NC (50% were pretreated; 29% obtained CCR). Mean duration from diagnosis to treatment with imatinib was 5 months for C and 9 months for NC. Mean length of follow up while on imatinib was 28 months for C and 14 months for NC, with early termination due to lack of follow up, progression of disease, and death. 31% (8/26) of patients (25% C, 75% NC) had received prior treatments with agents such as IFN, AraC, busulfan, anagrelide, homoharrington, and allogeneic SCT. 100% of pretreated C had CCR (vs 33% of pretreated NC). CHR rate was 100% in C (4/4) vs. 87.5% (14/16) in NC. CCR was obtained in 100% of C (6/6) but only 14% (2/14) of NC. CMR rate was noted to be 33% (1/3) in Caucasians compared to 8.3% (1/12) in NC. Low risk Sokal scores were associated with CHR rate of 100% in C (3/3) and 75% (6/8) in NC, as well as CCR rate of 100% in C (5/5) and only 25% (2/8) in NC.Conclusions: NC patients have a poorer response to treatment with imatinib for CML. The discrepancy between complete response rates (most notably the CCR rate) between C and NC patients could be accounted for by differences in the genetic characteristics of the disease, metabolism, or adherence rates. NC patients with low risk Sokal scores also had poorer complete response rates than C patients with the same risk scores. Prospective studies are needed to further evaluate these differences and discern their etiology. Given poor CCR rates, NC patients should be HLA typed soon after diagnosis and considered for transplant if a matched donor is available.