Blastic Phase Of Chronic Myelocytic Leukemia Research Articles

Management and outcome of patients with chronic myeloid leukemia in blast phase in the tyrosine kinase inhibitor era – analysis of the European LeukemiaNet Blast Phase Registry

Blast phase (BP) of chronic myeloid leukemia (CML) still represents an unmet clinical need with a dismal prognosis. Due to the rarity of the condition and the heterogeneity of the biology and clinical presentation, prospective trials and concise treatment recommendations are lacking. Here we present the analysis of the European LeukemiaNet Blast Phase Registry, an international collection of the clinical presentation, treatment and outcome of blast phases which had been diagnosed in CML patients after 2015. Data reveal the expected heterogeneity of the entity, lacking a clear treatment standard. Outcomes remain dismal, with a median overall survival of 23.8 months (median follow up 27.8 months). Allogeneic stem cell transplantation (alloSCT) increases the rate of deep molecular responses. De novo BP and BP evolving from a previous CML do show slightly different features, suggesting a different biology between the two entities. Data show that outside clinical trials and in a real-world setting treatment of blast phase is individualized according to disease- and patient-related characteristics, with the aim of blast clearance prior to allogeneic stem cell transplantation. AlloSCT should be offered to all patients eligible for this procedure.

A Phase I Trial of Activated Donor-Derived Marrow Infiltrating Lymphocytes to Treat Relapsed Hematologic Malignancies after Allogeneic Transplantation with Post-Transplantation Cyclophosphamide As Graft-Versus-Host Disease Prophylaxis

Background: Donor lymphocyte infusion (DLI) or a second allogeneic transplant (HCT) are the only curative treatments for hematologic malignancies relapsing after initial HCT. Both approaches lack significant efficacy and may cause considerable toxicity. Post-transplant cyclophosphamide (PTCy) used as graft-versus-host disease (GVHD) prophylaxis eliminates alloreactive T cells and enriches for tumor-specific T cells in the bone marrow. We hypothesized that expanded, donor-derived marrow infiltrating lymphocytes (alloMILs) collected post-HCT could restore antitumor immunity in relapsed recipients without the additional GVHD and toxicity seen with DLI or second HCT. Methods: We conducted a phase I dose-escalation trial (NCT02342613) of expanded alloMILs to treat bone marrow infiltrating hematologic malignancies relapsing after HCT with PTCy. Key inclusion criteria were age ≥ 18 years; relapsed hematologic malignancy ≥ 6 months after HLA matched or mismatched HCT with PTCy; donor CD3 + chimerism ≥ 30% in the peripheral blood; and lack of immunosuppressant use for 2 weeks prior to alloMILs harvest. Enrolled patients underwent salvage chemotherapy prior to or after alloMILs harvest to control the disease during the expansion process. Harvested bone marrow mononuclear cells were co-incubated with anti-CD3/CD28 beads and IL-2 for 7 to 14 days until the target CD3 + dose was reached. Given the differential risk of GVHD with matched versus mismatched DLI, dosing progressed from 1 x 10 7 to 5 x10 7 CD3 + cells/kg for matched HCT recipients and 1 x 10 6 to 5 x10 7 CD3 + cells/kg for mismatched HCT recipients. The primary endpoint was the feasibility of the product, defined as: successful harvest; expansion; infusion; and absence of grade III-IV acute GVHD for 90 days after infusion. Evaluation for HLA loss was performed using next-generation sequencing (NGS) of HLA loci. Single cell RNA sequencing (scRNAseq) was performed using 10x Genomics technology, Cell Ranger (v6.0.2), and Seurat (v4.3.0). Results: Thirty-two patients enrolled and underwent bone marrow harvest. Two patients were inaspirable, and five patients were not expanded due to low cell counts or high tumor volume. Twenty-five patients underwent alloMILs expansion, of which five failed to expand. Twenty patients received an infusion and six received a second infusion. Of the twenty patients receiving an infusion, eleven had multiple myeloma (MM) or plasma cell leukemia; five had acute myeloid leukemia (AML); one had chronic myeloid leukemia in blast phase; and three had chronic lymphocytic leukemia. Harvest, expansion, and infusion were well tolerated with minimal adverse events. No patient developed acute or chronic GVHD after infusion. Dosing advanced to the highest level of 5 x10 7 CD3 + cells/kg in both the mismatched and matched HCT cohorts. At day 60, the overall response rate (composite of complete (CR) and partial responses) was 40 percent (8/20) in the entire cohort; 33.3 percent (2/6) in the myeloid cohort (Figure 1A); 30 percent (3/10 evaluable patients) in the MM cohort; and 66.7 percent (2/3) in the lymphoid cohort. One MM patient achieved sustained > 2 years long CR and one AML patient is in ongoing CR, both of whom received alloMILs with no or minimal disease followed by maintenance therapy. HLA loss analysis was performed on pre-expansion samples from three AML patients receiving a mismatched HCT and alloMILs. Both non-responders in this cohort had loss of the host mismatched HLA haplotype. ScRNAseq on pre-expansion samples from ten AML patients, eleven MM patients, and four AML patients in remission after HCT (control) yielded 197 522 total cells and 32 587 CD8 + T cells. CD8 + T cells expressing a senescent-like gene signature previously associated with dysfunctional tumor killing in AML patients (Mazziotta et al ASH 2022) were associated with non-response primarily in AML patients (observed log2 fold change -2.48 compared with responders; FDR = 0.0017) (Figure 1B). Conclusions: AlloMILs demonstrated feasibility, a favorable safety profile, and early evidence of clinical activity in patients with measurable residual disease. The maximum dose of 5 x10 7 CD3 + cells/kg was reached, and no patient developed acute or chronic GVHD. HLA loss and CD8 + T cell senescence may be associated with non-response in AML patients. A clinical trial utilizing alloMILs as maintenance therapy for patients with measurable residual disease is in development.

Acute Leukemias of Ambiguous Lineage presenting in Extramedullary Location – Unusual and Challenging Diagnoses: A Report of Two Cases

Abstract Introduction/Objective Acute leukemias of ambiguous lineage are uncommon, accounting for <1% of all leukemias, and extramedullary presentations of these leukemias are rare. Methods/Case Report We report two cases of acute leukemia of ambiguous lineage presenting in extramedullary sites. Case 1 is a 41-year-old female who presented with right cervical lymphadenopathy and fatigue. Laboratory and imaging studies showed leukopenia, anemia, and abnormal cervical, supraclavicular, axillary, mediastinal, and abdominal pelvic lymphadenopathy. Biopsy of the axillary lymph node revealed sheets of morphologic blasts. Flow cytometry showed the blasts were of mixed phenotype, with T-cell differentiation supported by CD3 and TdT, and myeloid subpopulation supported by myeloperoxidase and lysozyme. Both these populations were negative for CD10, CD20, CD4, CD8, CD34, CD138, CD1a, CD79a. The morphology and immunophenote establish the diagnosis of T/myeloid mixed-phenotype acute leukemia, not otherwise specified. Case 2 is a 65-year-old female who presented with bilateral lower extremity weakness. Multiple lytic lesions involving the thoracic and cervical spine were detected by imaging. Biopsy of a T12 vertebral lesion revealed sheets of large malignant cells. Extensive immunohistochemical workup revealed positivity for CD45 (weak), CD4, and CD43, supporting a diagnosis of hematopoietic neoplasm of likely hematopoietic origin. Subsequent evaluation eventually led to discovery of chronic myeloid leukemia in blast phase with undifferentiated blasts, BCR-ABL1 positive, originally presenting as extramedullary acute leukemia with undifferentiated blasts. Results (if a Case Study enter NA) NA. Conclusion These cases highlight the challenges of diagnosing peripheral solid tumors of unknown origin. Extramedullary presentation of acute leukemia of ambiguous lineage are particularly challenging and, although rare, include phenotypes ranging from mixed phenotype to undifferentiated types.

Allogeneic Stem Cell Transplantation in Patients with Philadelphia Chromosome-Positive Acute Myeloid Leukemia in Japan

Allogeneic Stem Cell Transplantation in Patients with Philadelphia Chromosome-Positive Acute Myeloid Leukemia in Japan

Diagnostic challenges of de novo acute leukemia with positive BCR-ABL1 fusion: Case report and review of literature

A 32-year-old female was admitted because of an acute course of gum bleeding and fatigability. On complete blood cell counts, bicytopenia was evident. Morphologic evaluation of the peripheral blood smear and bone marrow materials revealed remarkable involvement by two separate blastic populations (myeloid/B-cell lymphoid). Karyotyping, fluorescence in situ hybridization, and molecular analysis showed positive Philadelphia chromosome and BCR-ABL1 (p210) fusion. chronic myeloid leukemia in blast phase (CML-BP) versus mixed phenotype acute leukemia was critically debated as to which the final diagnosis should be assigned.

Safety and Efficacy of Blinatumomab in Patients with Central Nervous System (CNS) Disease: A Single Institution Experience

Safety and Efficacy of Blinatumomab in Patients with Central Nervous System (CNS) Disease: A Single Institution Experience

Prognostic factors and survival outcomes in patients with chronic myeloid leukemia in blast phase in the tyrosine kinase inhibitor era: Cohort study of 477 patients.

Outcomes in patients with chronic myeloid leukemia in blast phase (CML-BP) are historically dismal. Herein, the authors sought to analyze the characteristics, prognostic factors, and survival outcomes in patients with CML-BP in the tyrosine kinase inhibitor (TKI) era. A total of 477 patients with CML-BP were treated with a TKI at some point during the course of their CML. Cox proportional hazard models identified characteristics that were predictive of survival. Overall survival and failure-free survival were assessed. Optimal cutoff points for specific parameters were identified using classification and regression tree (CART) analysis. The median age of the patients was 53 years (range, 16-84 years) and 64% were male. Approximately 80% of patients initially were diagnosed in the chronic phase of CML at a median of 41 months (range, 0.7-298 months) before transformation to CML-BP. De novo CML-BP occurred in 71 patients. Approximately 72% of patients received TKI therapy before CML-BP. The initial therapy for CML-BP included a TKI alone (35%), a TKI with chemotherapy (46%), and non-TKI therapies (19%). The median overall survival was 12 months and the median failure-free survival was 5 months. In multivariate analysis, myeloid immunophenotype, prior TKI, age ≥58 years, lactate dehydrogenase level ≥1227 IU/L, platelet count < 102 K/μL, no history of stem cell transplantation, transition to BP from chronic phase/accelerated phase, and the presence of chromosome 15 aberrations predicted for a significantly increased risk of death. Achievement of major hematologic response and/or complete cytogenetic response to first-line treatment was found to be predictive of better survival. The combination of a TKI with intensive chemotherapy followed by stem cell transplantation appeared to confer the best outcome. Patients with CML-BP continue to pose a therapeutic challenge, have dismal outcomes, and require newer treatment approaches. Cancer 2017;123:4391-402. © 2017 American Cancer Society.

Safety, Pharmacokinetics, and Efficacy of BP-100-1.01 (Liposomal Grb-2 Antisense Oligonucleotide) in Patients with Refractory or Relapsed Acute Myeloid Leukemia (AML), Philadelphia Chromosome Positive Chronic Myelogenous Leukemia (CML), Acute Lymphoblastic Leukemia (ALL), and Myelodysplastic Syndrome (MDS)

Background: Essential to cancer cell signaling, the growth receptor bound protein-2 (Grb-2) is evolutionarily conserved and utilized by oncogenic tyrosine kinases including Bcr-Abl to activate Ras, ERK, and AKT. BP-100-1.01is a neutrally-charged, liposome-incorporated antisense designed to inhibit Grb-2 expression.Aim: To define the safety, maximum tolerated dose (MTD), optimal biologically active dose, pharmacokinetics and anti-leukemia activity of BP-100-1.01 in patients (pts) with hematologic malignancies.Methods: This is a standard 3+3 phase I dose-finding study in pts with relapsed or refractory acute myeloid leukemia (AML), chronic myeloid leukemia in blast phase (CML-BP), acute lymphoblastic leukemia (ALL) and myelodysplastic syndrome (MDS). The starting dose was 5 mg/m2 twice weekly, IV over 2-3 hours for 28 days. Dose escalation proceeded through 5, 10, 20, 40, 60, and 90 mg/m2.Uponcompletion of single agent phase 1, combination of cytarabine 20 mg SubQ BID x 10 days + 60 mg/m2 of BP-100-1.01 was studied (Cohort 1B). Flow cytometric analysis was performed on peripheral blood samples from cohorts 3, 4, 5, 6 and 1B collected at baseline, on day 15 and at end-of-treatment (EOT). Fluorescent-labeled antibodies specific for Grb-2 or phosphorylated Erk (pErk) were utilized to determine Grb-2 protein levels and pErk levels in CD33-expressing cells.Results: A total of33 pts were included (13 in Cohort 1, 6 in Cohort 2, 3 each in Cohorts 3, 4, 5, and 4 in cohort 6). One patient has been treated in cohort 1B. The median age was 64 yrs (range, 32-89) and diagnoses were AML (n=24), CML-BP (n=5) and MDS (n=4). The median number of prior therapies was 4 (range, 1- 8). Of 33 pts, 21 were evaluable and 11 failed completion of a full 28-Day cycle due to disease progression (with no toxicity) and were replaced, per protocol. Only one pt (treated at 5 mg/m2) experienced dose limiting toxicity (DLT), grade 3 mucositis and hand-foot syndrome, while receiving concurrent hydroxyurea for proliferative CML-BP. The patient had a previous history of hydroxyurea-induced mucositis. Being the first patient to receive BP-100-1.01, these toxicities were considered possibly related to BP-100-1.01. The cohort was expanded to a total of 6 pts. No other DLTs have been noted in any pt. Among 21 evaluable pts, 11 experienced at least a 50% reduction in peripheral or bone marrow blasts from baseline. Additionally 2 pts with improvement in leukemia cutis lesions received 1 cycle each. Furthermore, 6 pts demonstrated transient improvement (n=3) and/or stable disease (n=3). Among the 21 evaluable pts, a median of 1 cycle was administered (1-5): Four pts received 2 cycles, 3 pts received 5 cycles, and all others received 1 cycle. Notably one pt (treated at 5 mg/m2)with CML-BP showed a significant reduction in blasts from 81% to 5%. Due to leptomeningeal disease progression therapy was discontinued before a full cycle. The 1st patient treated in cohort 1B achieved CR after 1 cycle. The patient did not experience any DLTs, but came off study due to failure to thrive in the context of dementia.The levels of Grb-2 and pErk proteins were indicated by their respective median fluorescent signals and are shown in the table. Median fluorescent signals of Grb-2 and pErk on days 15 and EOT were compared to baseline. On day 15 Grb-2 levels decreased by >25% in 7 out of 12 samples tested, and pErk levels by >25% in 6 out of 12 samples. The average decrease in Grb-2 levels was 61% (range: 47 to 85%) and in pErk levels 52% (range: 28 to 82%). On the last measured sample (EOT or day 22), BP-100-1.01 decreased >25% Grb-2 levels in 11 out of 13 samples, and >25% pErk levels in 7 out of 13 samples. The average decrease in Grb-2 levels was 49% (range: 28 to 91%) and in pErk levels was 52% (range: 27 to 91%).Table 1Patient NumberGrb-2 decrease (Day 15)pErk decrease (Day 15)Grb-2 decrease (Day 22 or EOT)pErk decrease (Day 22 or EOT)02200570023032845024562847350256382549102647000027NSNS3427028003054029575165a0a030545543470310000032855491630336135320346342400NS = no sample collectedaFewer cells were used in the analysis of this sample than other samples, because this sample had less cells than other samplesConclusions: BP-100-1.01, at dose range 5 mg/m2 to 90 mg/m2 is well tolerated with no MTD yet identified. There is suggestion of Grb-2 target protein down-regulation, and possible anti-leukemia activity. DisclosuresKonopleva:Novartis: Research Funding; AbbVie: Research Funding; Stemline: Research Funding; Calithera: Research Funding; Threshold: Research Funding. Tari:Bopath Holdings: Employment. Cortes:BerGenBio AS: Research Funding; Teva: Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Ambit: Consultancy, Research Funding; Arog: Research Funding; Celator: Research Funding; Jenssen: Consultancy.

Prognostic Factors, Response to Treatment, and Survival in Patients With Chronic Myeloid Leukemia in Blast Phase: A Single-Institution Survey.

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, age > 60 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.

Cytologic findings of hematologic malignancies in bronchoalveolar lavage fluid

Bronchoalveolar lavage (BAL) is often performed in leukemia and lymphoma patients with pulmonary infiltrates, mainly to rule out infection. However, malignant hematopoietic infiltrates are uncommon and a comprehensive cytologic study has not yet been performed. We retrospectively reviewed all BAL samples from our institution for the past 22years (November 1992-October 2014). There were 37 cases of hematologic malignancies identified on BAL specimens (21 female patients and 16 male patients, age 22-80 years). Eighteen patients (49%) had pneumonia-like symptoms at the time of initial diagnosis of their malignancy, including fever, dyspnea, respiratory distress/hypoxia, and cough. The biopsy-proven cases were 25 leukemia (12 acute myeloid leukemia, 6 acute promyelocytic leukemia, 2 acute monocytic leukemia, 2 acute myelomonocytic leukemia, 1 chronic myeloid leukemia in blast phase, 1 large granular leukemia, and 1 plasma cell leukemia), 11 lymphoma (8 diffuse large B-cell lymphoma, 1 mantle cell lymphoma, 1 natural killer/T-cell lymphoma, and 1 T-cell lymphoma), and 1 multiple myeloma. Chest X-ray findings included opacities, consolidation, and interstitial edema. Four patients had BAL specimens with concomitant microorganisms. Eighteen patients subsequently died (2 days to 4years), 15 were alive (3 weeks to 8 years of follow-up), and 4 were lost to follow-up. BAL is especially important in distinguishing inflammatory/infectious processes from neoplastic disorders because many patients with hematologic malignancies can have pneumonia-like symptoms as part of their initial disease presentation. Causative pathogens are identified in only a minority of malignant BAL specimens from these patients. Lung involvement in patients with hematologic malignancies carries a poor prognosis.

A Rare Case of Chronic Myeloid Leukemia At a Patient with Achondroplasia

The coincidence of chronic myeloid leukemia (CML) and achondroplastic dwarfism is very rare. A 40-year old man with achondroplastic dwarfism was diagnosed with chronic myeloid leukemia in blastic phase with a Sokal index of 1.34. Standart dose imatinib treatment was immediately started after the diagnosis.

Clinicopathological Study Of 12 Cases Of EBV-Associated Post-Transplant Lymphoproliferative Disorder (PTLD) After Allogeneic SCT: A Single Institution Analysis Of 825 Transplants Including 572 Cord Blood Transplants In Toranomon Hospital

BackgroundEBV-associated post-transplant lymphoproliferative disorder (EBV-PTLD) is uncommon but one of serious complications after allogeneic stem cell transplantation (SCT). However, there has been little literature published on clinicopathological feature of it. MethodWe retrospectively investigated 825 cases of allogeneic SCT (unrelated bone marrow (uBM) 159, related peripheral blood (rPB) 94, cord blood (CB) 572) at Toranomon Hospital between January 2006 to November 2012. EBV-PTLD was defined as histologically confirmed Epstein-Barr virus (EBV) positive lymphoproliferative disorder developed after allogeneic SCT. ResultsWe identified 12 cases of EBV-PTLD in our cohort. Cumulative incidence of EBV-PTLD at 2 years was 1.5%. Median time from allogeneic SCT to the diagnosis of EBV-PTLD was 6.4 (2.5-26) months. Eight patients were male and median age at the diagnosis of EBV-PTLD was 58.5 years (28-66). Underlying diseases were acute myeloid leukemia (n=5), myelodysplastic syndrome (1), acute lymphoblastic leukemia (2), adult T cell leukemia-lymphoma (1), aplastic anemia (2) and chronic myeloid leukemia in blastic phase (1). Conditioning regimens were fludarabine-based (n=10) and TBI/CY (n=2). None had an antithymocyte globulin-containing regimen. Donor sources were uBM (n=1) and CB (11). EBV serology before allogeneic SCT was tested in 11 and all were positive. Patients who received CB showed higher incidence of EBV-PTLD compared to those in non-CB cohort (2.2% vs 0.6%, p < 0.01), although patients characteristics was different between them. One patient developed PTLD after third allogeneic SCT. All but one patients had a history of acute graft-versus-host disease (aGVHD) of grade I (n=2), grade II (6) and grade III (3), respectively. Chronic GVHD was observed in 6 patients. Eight patients were on immunosuppressive therapy (IST) with calcineurin inhibitors and/or steroids when EBV-PTLD was suspected for the first time. Although lymphadenopathy was detected by CT scan in 7 patients, surface lymph nodes were swollen in only 3 patients. Initial manifestations were fever in 8, and diarrhea in 5 patients. EBV-PTLD was diagnosed from lymph nodes (n=3), skin (3), bone marrow (2), stomach/duodenum (1), colon (2), and lung (1), respectively. Histological feature was monomorphic (n=4), polymorphic (2), early lesion (4), and unknown (2), respectively. LMP1 and EBNA2 was positive in 40% (4/10) and 30% (3/10), suggesting latency status of I in 50% (6/12), II in 8.3% (1/12), III in 25% (3/12), and unknown in 16.7% (2/12). EBV DNA of 100 copies/microL or above was detected in peripheral blood in all of the EBV-PTLD cases. The treatment for EBV-PTLD were rituximab alone (n=3), rituximab plus reduction of IST (6), rituximab plus cytotoxic chemotherapy (1), and observation alone(2). Although 8 patients achieved response, 2 patients suffered a relapse of EBV-PTLD. With a median follow up of 27.5 (4.1-47.7) months, 2-year overall survival was 46.9% after diagnosis of EBV-PTLD. Eight patients died and 4 are alive without relapse of EBV-PTLD. Causes of death were EBV-PTLD (n=2), relapse of underlying disease(3), infectious disease(2), and aGVHD(1). ConclusionTwelve cases of EBV-PTLD were identified in 825 transplants. Cumulative incidence of EBV-PTLD at 2 years was 1.5%. The incidence of EBV-PTLD after CB transplant was higher than that after non CB transplant, although we have to take into consideration that patients feature was different between them. Response to rituximab and/or reduction of IST was observed in 8 patients with a 2-year overall survival rate of 46.9%. Patients with prior aGVHD and with longer duration of immunosuppressive therapy may have an increased risk of developing EBV-PTLD. Since the initial manifestations were often equivocal, and survival rate after diagnosis is not high, having EBV-PTLD in mind as one of the possibilities is critical for prompt diagnosis. Disclosures:No relevant conflicts of interest to declare.

Safety, Pharmacokinetics, and Efficacy Of BP-100-1.01 (Liposomal Grb-2 Antisense Oligonucleotide) In Patients With Refractory Or Relapsed Acute Myeloid Leukemia (AML), Philadelphia Chromosome Positive Chronic Myelogenous Leukemia (CML), Acute Lymphoblastic Leukemia (ALL), and Myelodysplastic Syndrome (MDS)

BackgroundEssential to cancer cell signaling, the adaptor protein growth receptor bound protein-2 (Grb-2) is evolutionarily conserved. With SH2/SH3 domains and lacking enzyme activity, Grb-2 is utilized by oncogenic tyrosine kinases such as Bcr-Abl to activate Ras, ERK, and AKT during cancer progression. Thus, Grb2 suppression has therapeutic potential. BP-100-1.01 is a neutrally-charged, liposome-incorporated antisense designed to inhibit Grb-2 expression. AimTo define the safety, maximum tolerated dose, optimal biologically active dose, pharmacokinetics and anti-leukemia activity of BP-100-1.01 in patients (pts) with hematologic malignancies. MethodsThis is a standard 3+3 phase I dose-finding study in pts with relapsed or refractory acute myeloid leukemia (AML), chronic myeloid leukemia in blast phase (CML-BP), acute lymphoblastic leukemia (ALL) and myelodysplastic syndrome (MDS). The starting dose was 5 mg/m2 twice weekly, intravenously (IV) over 2-3 hours for 28 days. Dose escalation has proceeded through 10, 20, 40, and 60 mg/m2 and will proceed to 90 and 135 mg/m2. Flow cytometric analysis was performed on peripheral blood samples from Cohorts 3, 4, & 5, collected prior to study initiation (baseline), on day 15 and on end-of-treatment day (EOT). Commercially available fluorescent-labeled antibodies specific for Grb-2 or phosphorylated Erk (pErk) were utilized to determine Grb-2 protein levels and pErk levels in CD33-expressing cells. ResultsA total of 28 pts were included (13 in Cohort 1, 6 in Cohort 2, and 3 each in Cohorts 3, 4, and 5). The median age was 62 yrs (range, 32 - 89) and diagnoses were AML (n=19), CML-BP (n=5) and MDS (n=4). The median number of prior therapies was 4 (range, 1 to 8). Of 28 pts, 18 were evaluable and 10 failed completion of a full 28-Day cycle due to disease progression (with no toxicity) and were replaced, per protocol. Only one pt experienced dose limiting toxicity (DLT), grade 3 mucositis and hand-foot syndrome, while receiving concurrent hydroxyurea for proliferative CML-BP. The patient had a previous history of hydroxyurea-induced mucositis. Being the first patient to receive BP-100-1.01, these toxicities were considered possibly related to BP-100-1.01. The cohort was expanded to a total of 6 pts. No other drug related toxicities have been noted in any of the pts treated. No other DLT have occurred. Among 18 evaluable pts, 9 experienced at least a 50 percent reduction in peripheral or bone marrow blasts from baseline. Furthermore, 5 pts demonstrated transient improvement and/or stable disease, 3 of whom received a total of 5 cycles each while 2 pts with improvement in leukemia cutis lesions received 1 cycle each. The remaining patients received 1 cycle each. Notably patient 002 with CML-BP showed a significant reduction in blasts from 81% to 5%. Due to leptomeningeal disease progression he discontinued therapy before a full cycle.The levels of Grb-2 and pErk proteins were indicated by their respective median fluorescent signals and are shown in the table. The median fluorescent signals of Grb-2 and pErk on days 15 and EOT were compared to baseline. On day 15, BP-100-1.01 decreased Grb-2 levels in 5 out of 8 samples tested, and pErk levels in 4 out of 8 samples. The average decrease in Grb-2 levels was 55% (range: 47 to 63%) and the average decrease in pErk levels was 54% (range: 28 to 82%). On EOT day, BP-100-1.01 decreased Grb-2 levels in 7 out of 8 samples, and pErk levels in 6 out of 8 samples. The average decrease in Grb-2 levels was 42% (range: 28 to 57%) and the average decrease in pErk levels was 50% (range: 27 to 91%). ConclusionsPreliminary results suggest that BP-100-1.01, at dose range 5 mg/m2 to 60 mg/m2 is well tolerated with no MTD yet identified. There is suggestion of Grb-2 target protein down-regulation, and possible anti-leukemia activity. Accrual continues with cohort 6 open at 90 mg/m2. Disclosures:Tari:Bio-Path Holdings: Employment, Equity Ownership.

Twice Daily Fludarabine and Cytarabine Combination (BID-FA) Is Effective in Pts with De Novo Acute Myeloid Leukemia (AML), Relapsed/Refractory (R/R) AML, High-Risk Myelodysplastic Syndromes (MDS), and Blast Phase Chronic Myeloid Leukemia (CML-BP)

AbstractAbstract 4939 Background:High dose cytarabine containing regimens are still considered standard options for pts (pts) with AML relapsing after a first complete remission (CR1) lasting more than 12 months. No standard options exist for pts relapsing after shorter remission duration or with primary refractory disease. We conducted a phase II study assessing the efficacy and safety of twice daily fludarabine and cytarabine (BID FA) in pts with R/R AML, high-risk MDS and CML-BP. Pts and Methods:147 pts with de Novo AML, R/R AML, intermediate-2 and high-risk MDS, and CML-BP, with a performance status of 3 or less, as well as normal organ functions were eligible. Pts were scheduled to receive fludarabine 15 mg/m2 intravenously (IV) q12 hrs on days 1 to 5 as well as cytarabine at the dose of 0. 5 g/m2IV over 2 hrs q12 hrs on days 1 to 5. GO was administered at the dose of 3 mg/m2 IV on day 1 for the first 70 pts enrolled. Courses were repeated every 4 to 6 weeks for a maximum of 7 courses. Pts with CML-BP were allowed to receive concomitant tyrosine kinase inhibitors. Four pts with AML who had FLT3 mutation were allowed to receive BID FA and sorafenib. Results:A total of 147 pts were treated. The median age was 63 years (range, 20 to 85 years). 131 (89%) had AML, 7 (5%) had high-risk MDS, and 9 (6%) had CML-BP. Of the 131 AML pts, 17 (12%) were de novo AML, 50 (38%) were in first salvage: first CR duration (CRD1) of less than 12 months in 39 pts (29%), and more than 12 months in 11 (9%) pts. Cytogenetic studies showed diploid karyotype in 52 pts (35%) and unfavorable chromosomal abnormalities involving chromosomes 5 and 7 in 30 pts (20%). 128 pts (87%) had a PS ≥1. Sixty-four pts (44%) had failed previous intensive chemotherapy, while 21 (14%) had failed targeted and hypomethylating agents. Forty-three (29%) pts had failed both. Overall, 34 pts (23%) achieved a complete remission (CR) and 8 (6%) achieved a CR without platelet recovery (CRp), for an overall response rate (ORR) of 29%. 6 pts received reinduction therapy, of which 3 achieved a CR. The CR rates for AML pts with frontline therapy, with relapsed AML with CRD1 ≥12 months, relapsed AML with CRD1< 12 months, and R/R AML beyond first salvage were 47%, 64%, 21%, and 14%, respectively. In CML-BP, 2 (22%) of 9 pts had objective responses (1 CR, 1 CRp). 1 of the 7 pts with MDS responded (Table 1). The treatment was well tolerated with only 7 of the pts experiencing grade 3 and 4 toxicities including mainly skin rash and increased liver enzymes. The overall 4-week mortality rate was 13%. With a median follow-up of 24 months (range, 10 to 33), 20 patients (14%) remained alive. The overall 6-month survival rate was 44%. The median overall survival (OS) and event free survival (EFS) were 5 months (range, 0. 1 to 33) and 1 month (range, 0. 1 to 33), respectively. The median CR/CRp duration was 12 months. Median OS for pts with de novo AML, a CRD1≥12 months, pts with CRD1<12 months and pts receiving second salvage and beyond were 8, 12, 5, and 4 months respectively. Median EFS for pts with de novo AML, a CRD1≥12 months, pts with CRD1<12 months and pts receiving second salvage and beyond were 3, 7, 1 and 1 month respectively. Conclusion:BID FA appears to be active with an ORR of 29% in a heavily pre-treated population. This combination is safe with a low rate of 4-week-mortality of 13%.Table 1:Overall response by disease and subset groupsPercentageStatusNORCRCRPDe novo AML17594712S1, CRD1≥ 12 months1164640S1, CRD1< 12 months3926215≥S26419145Disease14729236AML13130255MDS714140CML-BP9221111GOYes7030264No7727216OR=objective response; CR=complete remission; CRp=complete remission without platelet recovery; S1=salvage 1; S2=salvage 2; CRD1=first complete remission duration; AML=acute myeloid leukemia; MDS=myelodysplastic syndrome; CML-BP=chronic myeloid leukemia in myeloid blast phase; GO=gemtuzumab ozogamicin.Table 2:Comparison to historical data% ORRParameterBIDFAExpectedS1, CRD1 ≥ 12 months6450S1, CRD1 < 12 months2611≥ S2197S1=salvage 1; S2=salvage 2; CRD1=first complete remission duration. Disclosures:No relevant conflicts of interest to declare.

Twice-Daily Fludarabine and Cytarabine Combination With or Without Gentuzumab Ozogamicin is Effective in Patients With Relapsed/Refractory Acute Myeloid Leukemia, High-Risk Myelodysplastic Syndrome, and Blast- Phase Chronic Myeloid Leukemia

We evaluated the efficacy and safety of the combination of twice-daily fludarabine and cytarabine (BIDFA) in patients with refractory/relapsed acute myeloid leukemia (AML), high-risk myelodysplastic syndromes (MDS), and chronic myeloid leukemia in myeloid blast phase (CML-BP). One hundred seven patients were enrolled. Overall, 27 (26%) patients responded with a complete remission (CR) rate of 21% and CR without platelet recovery (CRp) of 5%. The overall 4-week mortality rate was 9%. In conclusion, BIDFA is active and safe in heavily pretreated patients with myeloid malignancies. The purpose of this study was to evaluate the efficacy and safety of the combination of twice-daily fludarabine and cytarabine (BIDFA) in patients with refractory/relapsed acute myeloid leukemia (AML), high-risk myelodysplastic syndromes (MDS), and chronic myeloid leukemia in myeloid blast phase (CML-BP). One hundred seven patients with refractory/relapsed AML, intermediate and high-risk MDS, and CML-BP, with a performance status of 3 or less and normal organ function were treated. Patients received fludarabine 15 mg/m(2) intravenously (IV) every 12 hours on days 1 to 5 and cytarabine 0.5 g/m(2) IV over 2 hours every 12 hours on days 1 to 5. Gemtuzumab ozogamicin (GO) was administered at 3 mg/m(2) IV on day 1 in the first 59 patients. Patients with CML-BP were allowed to receive concomitant tyrosine kinase inhibitors. Overall, 27 (26%) patients responded with a complete remission (CR) rate of 21% and CR without platelet recovery of 5%. The overall 4-week mortality rate was 9%. The CR rates for patients with relapsed AML with first CR duration greater than or equal to 12 months, relapsed AML with first CR duration less than 12 months, and refractory/relapsed AML beyond first salvage were 56%, 26%, and 11%, respectively. With a median follow-up of 7 months, the 6-month event-free survival, overall survival, and complete remission CR duration rates were 18%, 35%, and 70%, respectively. BIDFA is active with an overall response rate of 26% in a heavily pretreated population. This combination is safe with a low 4-week mortality rate of 9%.

Nilotinib is effective in imatinib-resistant or -intolerant patients with chronic myeloid leukemia in blastic phase

Nilotinib is a selective inhibitor of BCR-ABL approved for use in newly diagnosed and imatinib-resistant or -intolerant patients with chronic myeloid leukemia (CML) in chronic phase. In this study, 400 mg of nilotinib was administered twice daily to the patients with myeloid (MBP, n=105) or lymphoid blastic phase (LBP, n=31) CML. After a minimum follow-up of 24 months, major hematologic responses were observed in 60% (MBP) and 59% (LBP) of patients. Major cytogenetic responses (MCyR) were attained in 38% (MBP) and 52% (LBP) of patients; and complete cytogenetic responses in 30% and 32%, respectively. Median duration of MCyR was 10.8 (MBP) and 3.2 months (LBP). Median overall survival was 10.1 (MBP) and 7.9 (LBP) months with 12- and 24-month survival of 42% (MBP 44%, LBP 35%) and 27% (MBP 32%, LBP 10%), respectively. Twelve MBP patients and two LBP patients received subsequent stem cell transplantation. Myelosuppression was frequent, with grade 3/4 neutropenia, thrombocytopenia, and anemia in 68%, 63% and 47% of patients, respectively. Grade 3/4 hypophosphatemia, hyperbilirubinemia and lipase elevation were observed in 15%, 11% and 11% of patients, respectively. Nilotinib has significant efficacy in patients with BP CML, but given the limited long-term survival of these patients, novel agents are needed.

Effect of Low-Dose Cytarabine and Aclarubicin in Combination with Decitabine and Granulocyte Colony-Stimulating Factor Priming on the Outcome of Patients with Myeloid neoplasms

Abstract 5047 PurposePatients older than 60 years with acute myeloid leukemia (AML) or with chronic myeloid leukemia in blast phase (CML-BC) or myelodysplastic syndrome (MDS) have non-intensive treatment options because of the lack of effectiveness and the toxicity of available therapies. We investigated the efficacy and toxicity of the low-dose cytarabine and aclarubicin in combination with hypomethylating agent decitabine and granulocyte colony-stimulating factor priming as induction therapy in MDS, CML-BC and older patients with AML. Patients and MethodsWe described 28 consecutive patients (median age 65.5 years, range 49–78 years with MDS (n= 7) or AML (n= 17), or CML-BC (n=4). Among them, Seventeen were cases of AML (10 previously untreated AML, 3 bone marrow relapse, 2 extramedullary relapse and 1 MDS-AML); 4 were cases of CML-BC who were resistant to imatinib or nilotinib therapy and 7 were cases of MDS. Cytogenetic analysis was performed in all the patients, showing 7 patients had cytogenetic aberrations. All patients were treated with decitabine 15 mg/m2 intravenously for 5 consecutive days (d1-5) in combination with cytarabine 10 mg/m2 q12h for 7 days (d3-9) and aclarubicin 10mg every day for 4 days (d3-6) and granulocyte colony-stimulating factor (G-CSF) 300μg every day (d 0–9) priming (D-CAG). G-CSF was withdrawn when the white blood cell count (WBC) >20×109/L. Hydroxyurea or in combination with homoharringtonine 1mg/d intravenously was treated until WBC was <10×109/L before decitabine was given. CML-BC patients continued to be treated with imatinib or nitotinib during the D-CAG. Response was assessed by weekly complete blood count and bone marrow biopsy was taken at the time of recovery of peripheral hemogram or 3–4 weeks later after each course. Patients with MDS and AML continued to receive the second cycle. All of patients underwent baseline and efficacy evaluations. ResultsFifteen older patients with AML (median 68 years, range 60–78 years) were enrolled. Among those patients, 10 were in previously untreated AML, 3 bone marrow relapse, 1 extramedullary relapse and 1 secondary AML. The overall response rate (ORR) was 86.7% (13/15) in all older patients, 80.0% (8/10) in patients with previously untreated AML, and the complete rate (CR) was 73.3% after one cycle. 3 older patients with bone marrow relapse achieved. Two patients with extramedullary relapse achieved partial remission (PR) after one cycle. Two fourth of patients with high WBC more than 100×109/L at the time of diagnosis achieved CR. 7 patients with MDS (6 high-risk MDS, 1 RCMD) achieved the therapy. 3/5 patients achieved the CR or 2/5 PR. Other 2 high-risk MDS patients with refractory to convenient regimens such as CAG and HA had non-response to D-CAG regimen. All of the CML-BC patients received the one cycle of D-CAG regimen. Three fourth CML-BC patients achieved the CR and one stopped disease progression. All patients completed the treatment and there was no induction mortality. Grade 4 neutropenia and thrombocytopenia was universal. Median duration of granulocyte recovery (0.5×109/L) was 13 days(4–20), and that of platelet recovery (×109/L) was 10 days(2–16).The platelets rose above 600×109/L in 5 patients and all counts returned to the normal range with a week and there were no thrombotic complications including one patient with atrial fibrillation. The most common toxicities were myelosuppression, febrile neutropenia. ConclusionD-CAG regimen as the induction therapy seemed to be a safe and effective regimen for patients with untreated/relapsed AML, MDS and CML-BC, including older patients, and it has well tolerance. Disclosures:No relevant conflicts of interest to declare.

Twice Daily Fludarabine and Cytarabine Combination Is Effective in Patients with Relapsed/Refractory Acute Myeloid Leukemia, High-Risk Myelodysplastic Syndromes, and Blast Phase Chronic Myeloid Leukemia,

Abstract 3629 Background:High dose cytarabine containing regimens are still considered standard options for patients (pts) with AML relapsing after a first CR lasting more than 12 months. In a phase I study, 65 patients received fludarabine 15 mg/m2 every 12 hours and cytarabine 0.5 g/m2. Five days of administration were found to be safe and effective with a CR rate of 28%. Aim: This phase II study was conducted to evaluate the efficacy and safety of the combination of twice daily fludarabine and cytarabine (BIDFA) in patients with refractory/relapsed (R/R) acute myeloid leukemia (AML), high-risk myelodysplastic syndromes (MDS), and chronic myeloid leukemia in myeloid blast phase (CML-BP). Methods: Pts with R/R AML, intermediate-2 and high-risk MDS, and CML-BP, whose disease relapsed or was refractory to frontline and/or salvage therapy were eligible. Pts with performance status 0–3 and adequate organ function, received fludarabine 15 mg/m2 intravenously (IV) q12 hours on Days 1 to 5 and cytarabine 0.5 g/m2 IV over 2 hours q12 hours on Days 1 to 5. Gentuzumab ozogamycin (GO) was administered at 3 mg/m2 IV on day 1 in the first 59 pts. Pts with CML-BP were allowed to receive concomitant tyrosine kinase inhibitors. Results: 107 pts were enrolled. The median age was 62 years (range, 19 to 85). 93 pts had AML, 5 had high-risk MDS, and 9 had CML-BP. All pts had received prior therapy. 65 (61%) pts had failed previous intensive chemotherapy, while 42 (39%) had failed targeted and hypomethylating agents. Cytogenetics analysis showed diploid karyotype in 36 (33%) and unfavorable chromosomal abnormalities involving chromosome 5 and 7 in 22 (21%). Of the 107 pts, 52 were in first salvage: first CR duration of less than 12 months in 43 (40%) pts, and more than 12 months in 9 (9%). Overall, 22 pts (21%) achieved complete remission (CR) and 5 (5%) achieved a complete remission without platelet recovery (CRp), for an overall response rate (ORR) of 26% (Table 1). The CR rates for patients with relapsed AML with first CR duration (CRD1) ≥12 months, relapsed AML with CRD1< 12 months, and R/R AML beyond first salvage were 56%, 26%, and 11%, respectively. These compare favorably with the expected response rates in matched cohorts treated at our institution where the ORR were 50%, 11%, and 7%, respectively. A multivariate analysis identified the following 3 factors to be independent adverse prognostic factors for response: abnormal karyotype (versus diploid), second salvage (versus first salvage regardless of the duration of the first CR), and older age (Table 2). With a median follow-up of 7 months, the 6-month event-free survival, overall survival, and complete remission duration (CRD) rates were 18%, 35%, and 70%, respectively. Abnormal karyotype, older age, an increasing in the peripheral blood blasts percentage, and low platelets count (<30 × 109/L) were independently associated with a significant worse overall survival. The most common side effects observed were gastro-intestinal toxicities, including nausea, vomiting, diarrhea, and mucositis. The overall 4-week mortality rate was 9%. Conclusion: BIDFA is active with an ORR of 26% in a heavily pre- treated population. This combination is safe with a low rate of 4-week-mortality of 9%.Table 1:Response by disease and subset groupsStatusNPercentageORCRCRPOverall10726215S1, CRD1≥ 12 months956560S1, CRD1< 12 months4330255≥S25516115DiseaseAML9327234MDS5000CML-BP9221111GOYes5930273No4819136Table 2:Multivariate analysis of prognostic factors for response and survivalCharacteristicResponseEFSOSORp-valueHRp-valueHRp-valueAbnormal cytogenetic0.310.0062.43<0.0013.997<0.001≥S20.290.0082.31<0.001NSOlder age0.970.021.020.0021.020.009Increasing PB blasts percentageNS1.010.0081.010.001Platelets <30 × 109/LNSNS1.010.04OR=objective response; EFS=event-free survival; OS=overall survival; OR=odds ration; HR=hazard ratio; S2=salvage 2; PB=peripheral blood; NS=not significant Disclosures:No relevant conflicts of interest to declare.

Dasatinib in imatinib‐resistant or imatinib‐intolerant chronic myeloid leukemia in blast phase after 2 years of follow‐up in a phase 3 study

In a phase 3 study, the authors assessed the effects of dasatinib at doses of 140 mg once daily and 70 mg twice daily in patients who had either chronic myeloid leukemia (CML) in advanced phases or Philadelphia chromosome-positive acute lymphoblastic leukemia and were resistant or intolerant to imatinib. In the current report, the results for patients with CML in blast phase after 2 years of follow-up are reported. Patients were stratified according to whether they had CML in myeloid blast phase (MBP-CML) or in lymphoid blast phase (LBP-CML) and were randomized (1:1) within each stratum to receive either oral dasatinib 140 mg once daily or 70 mg twice daily. In patients with MBP-CML, the major hematologic response rate was 28% for both regimens; and, in patients with LBP-CML, the major hematologic response rate was 42% for once-daily dasatinib and 32% for twice-daily dasatinib. The major cytogenetic response rates were 25% for once-daily dasatinib and 28% for twice-daily dasatinib in patients with MBP-CML, and the respective rates in patients with LBP-CML were 50% and 40%. The overall survival rate at 24 months was 24% for once-daily dasatinib and 28% for twice-daily dasatinib in patients with MBP-CML, and the respective values in patients with LBP-CML were 21% and 16%. Adverse events indicated a trend toward improved tolerability for the once-daily regimen. The current results suggested that dasatinib 140 mg once daily had similar efficacy and improved tolerability relative to the 70-mg twice-daily regimen in patients with imatinib-resistant, blast phase CML.

Chronic myeloid leukemia in blast phase associated with t(3;8)(q26;q24)

We previously reported a recurrent t(3;8)(q26;q24) translocation involving EVI1 in five patients with myelodysplastic syndrome or acute myeloid leukemia. Here we report the same structural abnormality in a case of chronic myeloid leukemia in blast phase. The t(3;8)(q26;q24) occurred several months after the initial diagnosis of chronic myeloid leukemia, while the patient was being treated with a tyrosine kinase inhibitor. We confirmed rearrangement of EVI1 by fluorescence in situ hybridization assay using a dual-color break-apart probe set that spans the EVI1 region. Our findings demonstrate that, similar to other recurrent translocations involving 3q26, such as t(3;3) and t(3;21), the t(3;8)(q26;q24) is implicated not only in myelodysplastic syndrome and acute myeloid leukemia, but also in progression of chronic myeloid leukemia. These findings extend the known disease spectrum associated with this cytogenetic aberration.