Leukemia In Blastic Phase 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.

Outcomes of Olverembatinib Based Regimen in Patients with Philadelphia Chromosome-Positive Advanced Leukemias: A Real-World, Single-Center Experience

Background Philadelphia chromosome-positive (Ph+) advanced leukemias including chronic myeloid leukemia blast phase and acute lymphoblastic leukemia have poor outcomes. Olverembatinib, a novel BCR-ABL tyrosine kinase inhibitor, has anti-tumor activity in Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia cells(CML) and tumor models, is currently approved for treating resistant CML patients with T315I mutation by the National Medical Products Administration in China, and in phase Ib clinical trials in the US for ponatinib resistant and/or intolerant CML patients. Olverembatinib also inhibited p-KIT, p-AKT, p-ERK1/2, and p-STAT3 to a higher extent than ponatinib, and suppresses pre-B ALL cells through inhibition of the SRC kinase and PI3K/AKT pathways and may be a potential therapeutic agent for the management of pre-B ALL. However, the efficacy of Olverembatinib based regimen in Philadelphia chromosome- positive advanced leukemias is still unknown. Methods We conducted a retrospective study on patients with Philadelphia Chromosome- Positive Advanced Leukemias including Ph+ CML (n=11) and Ph+ ALL (n=5) who received a Olverembatinib-based regimens in our center. Results The trial included 11 patients with Ph+ CML and 5 patients with Ph+ ALL who had relapsed after transplantation. Among the 11 CML patients, there were 2 CML-AP, 6 chronic myeloid leukemia-myeloid blast phase (MBP), 2 chronic myeloid leukemia-lymphoblastic bast phase(LBP), 1 chronic myeloid leukemia- myeloid and lymphoblastic mixed blast phase. Median age was 34 years and the median follow-up time was 4 months. Also, two (18.2%) CML-AP patients were treated witholverembatinib alone. Six (54.5%) CML-BP patients were treated with olverembatinib in combination with demethylating agents. And two patients with LBP received VDP and stem cell transplantation (SCT)-based regimens combined with olverembatinib. Treatment for patients with chronic myeloid leukemia- myeloid and lymphoblastic mixed blast phase is consistent with patients with MBP. The overall response rate of 8 evaluable patients was 100%. CR/CRi rate was 100%, and CCyR/PCyR rates 62.5% vs 37.5%, respectively. In addition, 6 patients achieved major molecular responses (MMR). the remaining three patients were not yet due for evaluation. Of 5 patients with ph+ ALL that relapsed after transplantation, 1patient was treated with blinatumomab and olverembatinib, 2 patients were treated with intensive chemotherapy and olverembatinib followed by donor lymphocyte infusion(DLI), The treatment for the remaining 2 patients was Anti-CD19 chimeric antigen receptor T cell (CAR-T) technology followed by olverembatinib, and this 5 Ph+ ALL patients achieved complete molecular remission(CMR). In addition, treatment-related adverse reactions included cytopenias, skin pigmentation, proteinuria and high triglycerides, all grades less than 2. No deaths have occurred. Conclusion Olverembatinib-based regimens show encouraging activity and safety in very heavily pre-treated, advanced Ph+ leukemias.

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.

Poster: CML-451: Outcomes of Allogeneic Stem Cell Transplant in Chronic Myeloid Leukemia Blast Phase: A Single Center Experience from South India

Poster: CML-451: Outcomes of Allogeneic Stem Cell Transplant in Chronic Myeloid Leukemia Blast Phase: A Single Center Experience from South India

CML-451: Outcomes of Allogeneic Stem Cell Transplant in Chronic Myeloid Leukemia Blast Phase: A Single Center Experience from South India

Context: Blast phase (BP) remains a significant challenge in the treatment of chronic myeloid leukemia (CML). Currently, allogeneic stem cell transplant (AlloSCT) remains the best chance of cure for BP, with 3-year survival ranging from 35–40%. Outcomes of AlloSCT are better when performed in the second chronic phase. Objective: There is limited contemporary data of AlloSCT in CML-BP from resource-limited settings. We hereby present our experience of AlloSCT in patients with CML-BP Design: Retrospective study of CML-BP patients who underwent AlloSCT between October 2017 to July 2019. Median follow-up was 24 months. Setting: Tertiary institution with developing transplant unit. Patients or Other Participants: Seven CML-BP (WHO criteria) patients underwent AlloSCT at our center after reverting to chronic phase. Interventions: All patients received myeloablative conditioning and stem cells harvested from peripheral blood. Main Outcomes Measures: Leukemia-free survival (LFS) was defined as the time from the AlloSCT to relapse or death due to any cause. Overall survival (OS) was the time from AlloSCT to death due to any cause. Results: The median age was 40 years (range, 9–52), and the male-to-female ratio was 5:2. Four patients had de novo BP; the subtype of BP was lymphoid in three, myeloid in three, and mixed phenotypic (B/myeloid) in one. The median time from the diagnosis to ASCT was 6 (3–12) months. The median CD34+ dose was 7.6 (range, 6.6–8.9) x106 cells/kg. Peri-transplant toxicities within the first 100 days included febrile neutropenia with septic shock in three, cytomegalovirus (CMV) reactivation in three, ≥ grade 3 mucositis in two patients, secondary graft failure (SGF) in one, and poor graft function (PGF) in one. In both patients who had a haploidentical donor transplant, one had SGF and one had PGF. Day 100 transplant-related mortality (TRM) was observed in two patients, disseminated infections being the cause of death for both. Post-AlloSCT, all living patients received dasatinib maintenance starting at a median of 50 (47–60) days. On the last follow-up on April 30, 2021, two-year PFS and OS were 43% and 57%, respectively. Conclusions: AlloSCT can result in promising survival for carefully selected patients of CML-BP, especially with a matched sibling donor. The adverse outcome for both the haplo-transplant patients underscores the need for careful donor selection and reflects the initial learning curve. None of the authors have any relevant conflicts of interest to declare.

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

Mucormycosis in patients with hematological diseases: seven cases reports and literature review

目的探讨血液病合并毛霉菌病患者的临床特征、诊治与转归，提高对该病的认识。方法回顾性分析2012年9月至2018年9月7例血液病合并毛霉菌病患者的临床资料，分析其临床特征、治疗过程和转归。结果7例血液病合并毛霉菌病患者中，男4例，女3例，中位年龄36（19~79）岁。基础疾病：急性髓系白血病2例，急性B淋巴细胞白血病、外周T细胞淋巴瘤、慢性髓性白血病急髓变、骨髓增殖性肿瘤及重型再生障碍性贫血（移植后）各1例。毛霉菌病临床类型：4例为肺型，1例为鼻眶脑型，1例为皮肤型，1例为播散型。7例患者均通过活检组织病理确诊。治疗药物为两性霉素B、两性霉素B脂质体及泊沙康唑。手术治疗4例，其中3例术中彻底清除病变组织，1例仅行局限性清除。治愈2例，好转1例，死亡4例。结论血液病合并毛霉菌病患者临床表现及影像学表现多样，死亡率高，确诊主要依赖于组织病理学。早期诊断、控制基础疾病、改善免疫抑制状态、尽早行有效的抗真菌药物治疗及彻底的手术清创治疗是提高血液病合并毛霉菌病患者生存率的关键。

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.

Regular Prophylactic Donor Lymphocyte Infusion Is Effective and Safe to Prevent Relapse after Hematopoietic Cell Transplantation in High-Risk Patients

BackgroundDonor lymphocyte infusion (DLI) is the mainstream therapy for the prevention and treatment of relapse following hematopoietic cell transplantation (HCT). The efficacy of DLI for patients with acute leukemia, however, is limited in previous studies. This may be due to the more rapid proliferative capacity of malignant cells in acute leukemia, since a full response to DLI often requires months. Moreover, DLI is more effective when there is less disease burden to eradicate. Therefore, patients with high risk of relapse may take advantage of an early DLI after HCT. In this study, we applied an early prophylactic DLI in high relapse-risk patients with negative MRD (MRD-) after HCT.Patients and MethodsFrom July 2013 to December 2015, 56 adult patients with high relapse-risk in our center were admitted in this study. High relapse-risk was defined as failure to attain a complete remission (CR) after two cycles of induction therapy (primary induction failure), more than second complete remission (¡ÝCR2), no complete remission before HCT, or increasing MRD before HCT detected by flow cytometry (FCM) or real-time quantitative PCR (RQ-PCR). All patients received modified busulfan/cyclophosphamide¨Cbased myeloablative conditioning regimen. Rabbit antithymocyte globulin was administered for patients receiving unrelated donor HCT or haploidentical HCT. All patients received graft-versus-host disease (GVHD) prophylaxis consisting of cyclosporine A, methotrexate and low-dose mycophenolate mofetil. Post-HCT MRD was monitored at regular intervals with FCM or RQ-PCR. All patients achieved negative MRD post-HCT in our study.ResultsIn total, 56 patients (median age, 36, range, 17-46; 66.1% male) with high relapse risk were included in our study. 15 patients had acute lymphoblastic leukemia; 25 had acute myeloid leukemia; 5 had chronic myelogenous leukemia blast phase; the rest hadT-cell lymphoblastic lymphoma, myelodysplastic syndromes with refractory anemia with excess blasts-2, and peripheral T-cell lymphoma. Among them, 37 (66.1%) received haploidentical-HCT, 16 (28.6%) received matched sibling donor-HCT, and three (5.4%) received unrelated donor-HCT. The median time from HCT to DLI was 82 days (range, 47-160). After a median follow-up of 21 months (range, 7-34), the overall survival (OS) at two years was 78.4%; the disease-free survival (DFS) at two years was 75.4%, with relapse rate of 13.3%. Clinical characteristics were subjected into univariate Cox analysis for OS or relapse rate to find prognostic factors. Neither donor type nor disease type had significant impact on OS or relapse rate in our study. Of note, four patients relapsed after the first DLI underwent chemotherapy combined with a second DLI. Unfortunately, this strategy failed to treat relapse in all of the four patients.The main concern following DLI is the emergence of GVHD. In our study, 19 of the 56 patients (33.9%) developed aGVHD after DLI, mostly Grade I to Grade II (n = 15, 78.9%). cGVHD was observed in 25 of the 56 patients (44.6%), mostly with limited manifestations (n = 20, 80%). Among the deceased 11 patients, only one patient died secondary to GVHD complications due to bronchiolitis obliterans.ConclusionsFor patients with high risk of relapse following HCT, this study indicates that early administration of DLI is effective and safe to prevent relapse. Regular application of DLI for negative MRD patients post-HCT with high relapse risk may be a feasible strategy to prevent future relapse. [Display omitted] DisclosuresNo 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)

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.

Imatinib-Based Chemotherapy for Newly Diagnosed BCR–ABL Positive Acute Lymphoblastic Leukemia: Japan Adult Leukemia Study Group (JALSG) Ph+ALL208 Study

Introduction:The outcome of BCR–ABL positive acute lymphoblastic leukemia (ALL) has drastically improved since the introduction of imatinib. We recently reported the clinical results of the Japan Adult Leukemia Study Group (JALSG) ALL-202 study at the 51th ASH Annual Meeting. Most patients (97.1%) achieved complete remission (CR) and 9% of them relapsed within 100 days after CR. In addition, 60% of patients received allogeneic stem cell transplantation during their first CR, and the 3-year overall survival (OS) rate was 57%. We now present the data of the subsequent JALSG Ph+ALL208 study, where we have modified a part of consolidation therapy to prevent early relapse after achieving CR.Methods:The JALSG Ph+ALL208 study was a phase 2 trial for patients newly diagnosed with BCR–ABL positive ALL. Imatinib at a dose of 600 mg/day was administered from day 8 to day 42 combined with daunorubicine (DNR), cyclophosphamide (CPM), vincristine (VCR) and prednisolone (PSL) for induction therapy. Consolidation therapy comprised course 1 (C1: high-dose methotrexate and high-dose cytarabine with imatinib for 18 days) and course 2 (C2: DNR, CPM, VCR, and PSL with imatinib for 20 days). C1 and C2 were repeated alternately for 4 cycles. After consolidation therapy, allogeneic stem cell transplantation (allo-SCT) was recommended if a suitable stem cell donor was identified. Those ineligible for allo-SCT, due to the lack of a suitable donor and/or comorbidity, received maintenance therapy comprising VCR, PSL and imatinib for 2 years from the date they achieved CR. Seventy patients were enrolled between October 2008 and December 2010. Of these, two patients were excluded because they were diagnosed with chronic myeloid leukemia blast phase. Therefore, 68 patients newly diagnosed with BCR–ABL positive ALL were included in this study. The median age was 49 years (18–64 years) and 41% were >54 years.Results:With this treatment regimen, 65 patients achieved CR (95.6%) and only 1% of them relapsed within 100 days after CR. Finally, 35/40 patients (81%) <55 years-old=“” and=“” 8=“” 28=“” 19=“”>54 years-old were able to receive allo-SCT in their first CR (13 from a sibling donor, 23 from an unrelated bone marrow donor, and 7 from unrelated cord blood). The 3-year OS and disease-free survival (DFS) rates were estimated at 62% and 52%, respectively. Three early deaths occurred during the induction course. One patient (51 years) died of pulmonary bleeding on day 9, another patient (59 years) died of sepsis on day 15, and the third patient (62 years) died of cerebral hemorrhage on day 15. Grade 3 or 4 non-hematologic adverse events including febrile neutropenia and liver dysfunction was reported in 60.3% and 11.8% of the patients, respectively. Twelve patients relapsed after achieving CR with a median time of 307 (64–1053) days. Moreover, 6/43 patients who received allo-SCT relapsed with a median time of 346 (149–602) days. The probability of DFS at 3 years was 72% for patients who underwent allo-SCT in CR compared to only 21% for patients without allo-SCT (p = 0.0004)(Figure.1).Conclusion:We conclude that imatinib-based chemotherapy produced a very high CR rate, thus allowing a high proportion of patients to prepare for allo-SCT, particularly patients 55 years. Moreover, the intensified consolidation therapy reduced the rate of early relapse after induction therapy and resulted in a higher rate of DFS after allo-SCT. [Display omitted] DisclosuresHatta:Bristol Myers Squibb: Honoraria. Miyazaki:Novartis: Honoraria. Ohnishi:Novartis: Honoraria.

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.

T-Lymphoblastic Leukemia With t(9;22): Blast Phase of Chronic Myelogenous Leukemia or BCR-ABL- Positive T-Acute Lymphoblastic Leukemia?

T-acute lymphoblastic leukemia/lymphoma (T-ALL) as chronic myelogenous leukemia blast phase (CML-BP) is rare. BCR-ABL–positive T-ALL is extremely rare. In patients without previous/concurrent history of CML, it is difficult to differentiate these 2 entities. Herein we report 3 cases of T-ALL with t(9;22) and review the literature. Case 1 was a 6-year-old girl with leukocytosis and splenomegaly. She was diagnosed with …