bluuebunny/crossref_metadata_2025 huggingface dataset:
Extramedullary Infiltrates of AML: Biological and Clinical Features in a Single Centre Experience.
Authors: Carluccio Paola , Pastore Domenico , Liso Arcangelo , Albano Francesco , Mestice Anna , Giannoccaro Margherita , Santodirocco Michele , Mongelli Patrizia , Manduzio Palma , Specchia Giorgina , Liso Vincenzo
Published: April 2020

Extramedullary infiltration (EMI) of malignant myeloid precursor cells in acute myeloid leukemia (AML) may occasionally be a presenting clinical symptom at onset and may develop at any site in the body but most commonly in the gum, skin, central nervous system (CNS) and soft tissue. There is controversy about the prognostic significance of extramedullary disease in AML. The present study examines the incidence, the biological features and prognostic significance of EMI at diagnosis in adult patients with AML. From January 1997 to December 2004, 213 untreated patients with de novo AML were studied. According to Grimwade et al, 14 patients were in the favorable-risk group, 159 in the intermediate-risk group, 25 in the poor risk group and in 15 the karyotype was not available. All patients had been treated with induction therapy according to the GIMEMA protocols including cytarabine, etoposide and idarubicin (15 pts), or mitoxantrone (15 pts) or daunorubicin (183 pts).

Of 213 cases with de novo AML, 29 (14%) had EMI at diagnosis. Ten patients (34.8%) had skin infiltrates, 12 (41.4%) had gum hypertrophy, 5 (17.2%) had CNS involvement and 2 (6.9%) had soft tissue infiltration. No significant differences in terms of sex, age median Hb level and platelets count were found between patients with EMI and patients without EMI. The patients with EMI had higher median WBC counts (27 × 109/L) than patients without EMI (8.5 × 109/L) (p=0.05). The patients with EMI had a higher incidence of the M4/M5 FAB subtype (62%) than patients without EMI (27.4%) (p=0.005). Cytogenetic analysis was performed in patients with and without EMI; none of the abnormal cytogenetic findings was associated with EMI. We evaluated the relationship between the AML blasts surface antigen expression and EMI; the association between CD56/CD4 and CD56/CD14 was more significantly expressed in patients with EMI (35% and 29%, respectively) than without EMI (10.4% and 6.9%, respectively) (p=0.004, p=0.003).

The overall CR rate was 65%; the CR rate was lower in patients with EMI (48.2%) than patients without EMI (76.1%) (p=0.001) and their disease free survival was also shorter (p=0.017); the median duration of CR was 10 and 25 months (range 2–96) in EMI and no EMI group, respectively.

Our data show that a high WBC count, M4/M5 subtype, CD56/CD4 and CD56/CD14 expression are associated with extramedullary infiltrates of AML at diagnosis; the presence of EMI adversely affects the complete response rate to induction chemotherapy and the OS rate. Analysis of the clinical and biologic features in a larger series of adult AML patients is needed to evaluate the allocation of this subgroup in a different or more intensive treatment arm.
Effective Treatment of Biphenotypic Acute Leukemia in Children with Chemotherapy Alone.
Authors: Al-Seraihy Amal S. , Ayas Mouhab , Owaidah Tarek , El-Solh Hassan , Al-Mahr Mohammed , Al-Musa Abdulrahman , Al-Saleh Mahasen S. , Al-Ahmari Ali , Belgaumi Asim F.
Published: April 2020

Biphenotypic acute leukemia (BAL) is now a well-defined entity. However, the outcome of this rare type of acute leukemia is variable and the treatment strategies are controversial. This is a retrospective review analyzing the clinical features and the outcome of BAL cases diagnosed and treated at our institution between January 1999 and December 2004. The diagnosis was based on morphological and cytochemical evaluation, supported with extensive immunophenotyping. The European Group for Immunophenotyping in Leukemia (EGIL) scoring system was utilized to diagnose the BAL. 17 patients (4.1% of 411 ALL patients) were classified as BAL. Of these 15 were B-lymphoid/myeloid and two were T/B-lymphoid. Median age at diagnosis was 7.23 years (range 1.3–14.4 years). Nine patients were male, four had WBC count >100 × 109/L, and 6 (35.3%) had CNS disease. Cytogenetic analysis was available in 14 cases of which three (21.4 %) had a normal karyotype. The most frequent abnormalities were MLL gene rearrangement (n=4; 28.6%) followed by abnormality at the 14q32 locus (n=3; 21.4%; two patients with add(14)(q32) and one t(8:14)(q21:q32)). All patients were treated uniformly, on a modified St Jude TXIII-B high-risk protocol, with agents known to be effective against both lymphoid and myeloid leukemia. They received a 6-drug induction with prednisone, vincristine, daunomycin, asparaginase, etoposide and cytosine arabinoside, followed by consolidation using high-dose methotrexate (2gm/m2) and mercaptopurine. Post remission all patients were eligible for allogeneic bone marrow transplantation (BMT) if a full matched related donor was available. If none was available, patients received continuation therapy consisting of weekly administration of non cross-resistant drug pairs for 120 weeks. All patient achieved remission post induction. Five patients underwent BMT in first remission (CR1), and 12 were treated with chemotherapy (CTX) alone. Two patients in the CTX arm relapsed. Both relapses were extramedullary (isolated CNS in one and lacrimal duct in the other). These patients were reinduced and underwent BMT in CR2. There were no relapses in the BMT arm. No serious acute therapy-related toxicity or infections were noted in the CTX arm. One patient died of BMT- related complications in CR1. With a median follow-up of 2.6 years, the actuarial OS and EFS at 4 years are 71.6 % and 79.5%, respectively. OS and EFS comparing BMT with CTX are 82% v. 74.1% (p=0.5) and 80% v. 79.5% (p=0.84), respectively. We conclude that this chemotherapy protocol is effective and safe in treating BAL. BMT in CR1 may not be needed for these patients.
Incidence of Venothromboembolism (VTE) in Patients (pts) with Acute Lymphocytic Leukemia (ALL), Burkitt’s Leukemia/Lymphoma (BL) or Lymphoblastic Leukemia (LL).
Authors: Vu Khanh D. , Thomas Deborah A. , Hubbard Julie C. , Faderl Stefan , Cortes Jorge , Cabanillas Maria E. , Garcia-Manero Guillermo , O’Brien Susan M. , Kantarjian Hagop
Published: April 2020

Background: Pts with cancer are at increased risk of thromboembolic events with potentially life-threatening consequences. The incidence of VTE in cancer pts has been estimated at 1 in 250. Although most of these episodes are associated with solid tumors, VTE is also observed in pts with acute leukemias, even in the presence of thrombocytopenia. Anticoagulation in this pt population can be particularly problematic if pts are undergoing myelosuppressive chemotherapy. VTE prophylaxis is often not given because of the perceived high risk of bleeding with a presumed low risk of VTE.

Method: As little is known about the incidence and significance of VTE in pts with acute leukemia, we conducted a retrospective chart review of 223 pts with ALL, BL, or LL who received a hyper-CVAD regimen (fractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone alternating with methotrexate and cytarabine) with or without rituximab, maintenance chemotherapy (with L-asparaginase only months #7 & 18), allogeneic stem cell transplant (SCT), or salvage chemotherapy at our institution from November 1999 to May 2005. The median observation period was 112 weeks (range 1–328).

Results: The median age was 51 yrs (range 19–75). 70% were ALL, (50% were Philadelphia positive ALL), 20% Burkitt’s or Burkitt’s-like, and 10% LL. Thirty nine of 223 pts (18%) had confirmed VTE by imaging studies: 12.5% prior to or at the time of diagnosis, 57.5% during consolidation chemotherapy, and 27.5% during maintenance chemotherapy, SCT, or supportive care. Location of VTE varied by site: 3/39 (8%) pulmonary embolus, 16/39 (41%) lower extremity, 2/39 (5%) central venous catheter (CVC), and 18/39 (46%) upper extremity. Two of the 18 with upper extremity VTEs did not have CVC, and an additional 2 had bilateral upper extremity thromboses. The platelet counts were reviewed near the time of VTE diagnosis: 22/39 (56%) had greater than 100 × 109/L, 17/39 (44%) were less than that value, with 76% below 50,000 × 109/L.

Conclusion: Pts with ALL, BL, and LL undergoing therapy are at risk for developing VTE. Thrombocytopenia does not preclude development of VTE. A more detailed analysis will be forthcoming regarding the risk factors for VTE in this pt population, the current medical practices and bleeding complications with VTE prophylaxis and treatment, and the effect on therapy administration and overall survival. Practice guidelines for management of acute leukemia pts with thromboembolic events should be pursued.
Phase I Trial of Sphingosomal Vincristine (SV, Marqibo®) and Dexamethasone in Relapsed or Refractory Acute Lymphocytic Leukemia (ALL).
Authors: Thomas Deborah A. , Kantarjian Hagop M. , Heffner Leonard , Stock Wendy , Garcia-Manero Guillermo , Faderl Stefan , Ferrajoli Alessandra , Giles Francis , Wierda William , Ravandi-Kashani Farhad , Choy Gavin , Berk Gregory I. , O’Brien Susan
Published: April 2020

Delivery of standard therapeutics in formulations which allow increased drug delivery with equivalent or less toxicity may improve outcome. Vincristine is an essential component of ALL therapy. Its cytotoxicity occurs in a time and dose-dependent manner, but the dose needs to be capped at 2 mg to prevent severe neurotoxicity. SV is a form of vincristine encapsulated in sphingomyelin liposomes or “sphingosomes” with an increased circulation half-life of 12 hours compared with 6–12 minutes for free vincristine. In vivo, SV has more anti-tumor activity than free vincristine in mice bearing P388 and L1210 leukemias. A previous study of single agent SV 2.0 mg/m2 given every 2 weeks (without dose capping) was conducted in 16 patients (pts) with relapsed or refractory ALL. Objective responses were observed in 14% (1 complete response [CR], 1 partial response [PR]); 36% had transient reduction in marrow leukemia infiltrate with very minimal toxicity (Thomas et al., Cancer106:1641, 2006). An increase in dose intensity was considered the strategy for future trials. A standard 3 + 3 phase I study of weekly escalating doses of SV (1.5 mg/m2, 1.825 mg/m2, 2 mg/m2, 2.25 mg/m2, 2.4 mg/m2) with pulse dexamethasone (D) 40 mg daily days 1–4 and 11–14 was initiated. Pts with active grade 2 or greater central or peripheral neuropathy (PN) were excluded. Pts were evaluated for dose-limiting toxicities (DLT) after 1 course (defined as 4 weekly doses of SV + D). To date, 36 pts with relapsed/refractory ALL were enrolled. Median age was 34 years (range, 21–62). Median number of prior salvage regimens was 2 (range, 1–3); all pts had prior vincristine. SV was discontinued early for progressive disease (n=5), death due to sepsis (n=3) or other toxicities (n=3). Thus, twenty-five pts (71%) completed 1 full course and were considered evaluable. DLTs were observed at the 2.4 mg/m2 dose level (grade 3 PN, seizure with intracranial hemorrhage, grade 4 hepatotoxicity). The tentative MTD is 2.25 mg/m2 (expansion of cohort ongoing). Expected toxicities included infections related to neutropenia, grade 1–3 constipation, grade 1–2 PN and transient grade 1–3 elevations in hepatic transaminases related to azole antifungal prophylaxis. Six pts (24%) achieved CR (2 at 1.5 mg/m2, 1 at 1.825 mg/m2, 2 at 2.25 mg/m2, 1 at 2.4 mg/m2), 1 a PR (at 2.25 mg/m2), and 3 (12%) hematological improvements (of platelets at 1.825 mg/m2 and 2 mg/m2 or clearance of marrow blasts at 2.25 mg/m2). Five responders proceeded to allogeneic stem cell transplant. In conclusion, SV with pulse dexamethasone demonstrated encouraging activity in relapsed or refractory ALL. Phase II and III studies of SV in ALL are planned.
Bevacizumab Reduces VEGF Expression in Patients with Relapsed and/or Refractory Acute Myeloid Leukaemia (AML) without Clinical Antileukemic Activity.
Authors: Zahiragic Lejla , Schliemann Christoph , Bieker Ralf , Berdel Wolfgang E. , Mesters Rolf M.
Published: April 2020

Angiogenesis is required for tumor growth and metastasis and is an attractive target for cancer therapy. Because of its pivotal role in tumorassociated angiogenesis across a wide range of malignancies, vascular endothelial growth factor-A (VEGF-A) has emerged as a central therapeutic target in cancer.

Neoangiogenesis has been shown to play an important role in the pathogenesis of AML (Padro et al., Blood 2000) and antiangiogenic therapy could constitute a novel strategy for its treatment (Mesters et al., Blood 2001). Autocrine and paracrine secretion of vascular endothelial growth factor (VEGF) in the bone marrow may promote proliferation and survival of leukemic blasts (Fiedler et al., Blood 1997). This concept represented the rationale for the therapeutic application of bevacizumab (BV), a recombinant humanised monoclonal antibody against VEGF, in patients with advanced AML after failure of standard treatment. Nine patients (median age 63 years; range 46–81 years) with relapsed and/or refractory AML not judged medically fit for further intensive chemotherapy were enrolled in this study. All patients received at least one cycle of BV (10 mg/kg body weight), 5 patients received 2 cycles (days 1 and 14) and 2 patients a 3rd cycle (day 35). Treatment was well tolerated, without treatment-related side effects. Two patients had to be withdrawn from drug administration after cycle one due to progressive disease. After treatment with BV none of the patients fulfilled the criteria of a partial response, defined as the clearance of at least 50 % marrow blasts accompanied by increases in platelet counts and haemoglobin values. The level of VEGF expression in the bone marrow determined by immunohistochemistry significantly decreased during treatment with BV (before BV treatment: median of 3.78 arbitrary units (AU) [range 1.5–5.8 AU]; after BV treatment: median of 2.57 AU [range 1.3–5.0 AU]; Wilcoxon test, P<0.05). In contrast, VEGFR-2 expression by leukemic blasts and bone marrow microvessel density did not change significantly. In conclusion, single agent BV has no significant antileukemic activity in relapsed and/or refractory AML.
Compassionate Use of Intrathecal Depot Cytarabine (DepoCyte®) in Central Nervous System (CNS) Involvement in Acute Myeloid Leukemia (AML): Report of 11 Cases.
Authors: Sancho Juan-Manuel , Parker Anne , Deben Guillermo , Bolam Simon , Gimenez Eugenio , Sanchez-Garcia Eva , Piñana Jose-Luis , Pascual Teresa , Mateos Carmen , Fernandez-Abellan Pascual , Palomera Luis , Ribera Josep-Maria
Published: April 2020

Treatment of CNS involvement in patients with AML is based on repetead intrathecal (IT) administrations of chemotherapy, especially methotrexate and cytarabine, until to achieve clearance of blast cells from cerebrospinal fluid (CSF). Recently, the availability of a depot formulation of liposomal cytarabine (DepoCyte®), administered every two weeks by IT route, has demonstrated to be useful for the treatment of neoplastic and lymphomatous meningitis. However, there are few studies that have analyzed its efficacy in the prophylaxis and treatment of CNS involvement in patients with AML. A retrospective review was performed of all cases in which IT depot cytarabine was employed as compassionate therapy for CNS involvement of AML in Spain and United Kingdom. From March 2004 to April 2006, 11 AML cases (2 with acute promyelocytic leukemia [APL]) were recorded. The median (range) age was 46 (18–57) yr and there were 7 females. Six patients had CNS involvement at the time of the diagnosis and the remaining had CNS relapse (first CNS relapse in 4, 2nd relapse in 1). Four out of 6 patients with initial involvement received IT depot cytarabine after one dose of triple IT therapy (TIT) administered during the screening lumbar puncture (one patient received two TIT doses), another received cranial irradiation in addition to IT depot cytarabine, and the remaining was treated only with IT depot cytarabine. The 5 patients with CNS relapse received one TIT dose plus IT depot cytarabine in 3 cases, cranial irradiation plus IT depot cytarabine in one, and only IT depot cytarabine in the remaining. Complete resolution of neurological symptoms was observed in 9 cases and partial response in the remaining 2, whereas clearance of blasts from CSF was observed in 7 evaluable cases. Sustained response was observed in 6 patients (median follow-up 6 [4–23] months) whereas the remaining 5 died from infection (3) or systemic relapse (2), without evidence of neurological progression. The median number of IT depot cytarabine administrations was 3 (1–10). Concurrent dexamethasone therapy (4 mg twice/day/5 days) was administered with each dose of IT depot cytarabine. Side effects included headache (3 patients), fever (1) vomiting (1) and nausea (1). Depot formulation of cytarabine was effective to obtain clearance of blasts cells from CSF in AML patients with CNS involvement or relapse. The administration of depot formulation of cytarabine was well tolerated. This justifies the development of a clinical trial to evaluate the efficacy and safety of IT depot cytarabine in meningeal involvement of AML.
Feasibility Study of Temozolomide Maintenance Therapy in Elderly Patients with AML Following Induction Therapy with High Dose Mitoxantrone and High Dose Ara-C.
Authors: Katragadda Sreedhar , Arshad Muhammad , Liu Delong , Ahmed Nasir , Shi Quihu , Ahmed Tauseef , Seiter Karen
Published: April 2020

With intensive chemotherapy, approximately 50% of elderly patients with AML achieve a complete remission, however essentially all will relapse within 2 years. To date, there is no standard effective postremission therapy for these patients, and most elderly patients tolerate multiple courses of intensive chemotherapy poorly. We previously demonstrated that temozolomide has significant antileukemic activity in patients with relapsed/refractory acute leukemia (Seiter K, et al JCO 2002). In that study 9/20 patients treated had a significant reduction in bone marrow blasts, and 4 patients had a formal complete response. Currently we are evaluating the feasibility and efficacy of temozolomide maintenance therapy administered after one cycle of intensive induction chemotherapy in elderly patients with newly-diagnosed AML. Induction consists of ara-C, 3 gm/m2 daily for 5 days, and mitoxantrone, 80 mg/m2 times one on day 2. Patients achieving complete remission then receive temozolomide 200 mg/m2/d for 7 days every 5 weeks until progression. To date, 30 pts have been treated: median age 69 (range 60–84); M/F: 17/13; prior AHD: 23%; cytogenetics: good: 1, intermediate: 21, poor: 6, insufficient: 2. Response to high-dose ara-C/high-dose mitoxantrone induction: CR: 59%, progression: 24%, aplastic death: 17%. Two pts expired in remission unrelated to temozolomide: pneumonia, 1 pt, c. difficile: 1 pt. Of 17 patients in CR, 15 received temozolomide maintenance. The median number of temozolomide cycles was 2 (range 1–11). 3 pts stopped temozolomide after 1 cycle (1 refused further therapy, 1 had stem cell transplant, 1 died c. diff). Treatment was well tolerated and was administered in the outpatient setting. The median duration of remission is 5.5 months (95% CI: 3.0–9.8 months), and median survival is 7.6 months (95% CI: 5.7–13.3 months) for all patients and 10.2 months (95% CI: 5.6–15.2 months) for patients achieving CR. Temozolomide maintenance is feasible in patients with AML in CR. Further accrual is continuing to assess if remission duration and survival will be improved compared to historical controls.
Sweet’s Syndrome: A Frequently Unrecognized Complication Following Acute Myeloid Leukemia (Aml) Induction Chemotherapy: A Case Report.
Authors: Okura Toru , Aboulafia David M. , Picozzi Vincent
Published: April 2020

Sweet’s syndrome, also known as acute febrile neutrophilic dermatoses, is a distinct clinicopathologic entity of unknown etiology characterized by acute onset of fever, leukocytosis, and cutaneous plaques. It has been associated with a variety of disorders including infections, neoplasms, and autoimmune diseases. Paraneoplastic Sweet’s syndrome is most often associated with hematologic malignancies, including myelogenous leukemia and myelodysplastic syndrome (MDS), are most often associated. Although patients with neutrophilia are most likely to be diagnosed with Sweet’s syndrome, so, too, may patients who are neutropenic post-cytotoxic chemotherapy. Herein, we describe the clinical course of a 60-year-old Caucasian man with a history of high-risk MDS who, after progressing to AML and while neutropenic post-induction chemotherapy, was diagnosed with Sweet’s syndrome. The patient developed a warm, tender, indurated, erythematous lesion over his left anterior chest on day +6 of induction chemotherapy consisting of idarubicin and cytarabine. Despite broad spectrum antibiotics, the lesion darkened, formed blisters, and progressed rapidly to involve much of his left chest. On day +11, his WBC had fallen to 0.7×109cells/l and the wound was surgically debrided due to concern that he had developed necrotizing fasciitis. Surgical samples showed significant dermal infiltration of neutrophils and severe necrosis of skin and subcutaneous tissue, but no pathologic organisms or leukemic cells. Empiric antibiotic coverage was broadened to include amphotericin B, voriconazole, and valganciclovir, but the patient failed to improve. On day +18, he began taking 60mg Prednisone daily and his lesions quickly improved. Although Sweet’s syndrome most often occurs in conjunction with neutrophilia, it may also occur in neutropenic patients who have received systemic chemotherapy. This association with neutropenia is more frequent than is generally appreciated; as many as 20–50% of patients with hematologic malignancies may be diagnosed with Sweet’s syndrome while recovering from therapy-associated neutropenia. Cancer-associated Sweet’s syndrome may be more severe than that seen in patients without malignancy. Lesions may progress from plaques and nodules to vesicular, bullous, and even ulcerative skin lesions, as was seen in our patient. Our case report serves as a reminder that Sweet’s syndrome may occur in the setting of neutropenia and, if diagnosis and treatment are delayed, can lead to a life-threatening complication. Early skin biopsy and histopathologic assessment followed by corticosteroids is essential for recognition and management of this entity.
Remission Induction Treatment for 6 Patients of Jehovah’s Witnesses with De Novo Acute Leukemia.
Authors: Fujita Hiroyuki , Iguchi Mai , Tachibana Takayoshi , Takemura Sachiya , Taguchi Jun , Tanaka Masatsugu , Maruta Atsuo , Ishigatsubo Yoshiaki
Published: April 2020

The treatment of acute leukemia with myelosuppressive chemotherapy usually requires the transfusions of blood and blood products. For religious reasons, Jehovah’s Witnesses (JW) do not consent to the transfusion of blood. We describe here six cases of JW with acute leukemia, who received induction chemotherapy without blood support.

From January 1996 to March 2006, six JW with newly diagnosed acute leukemia received remission induction chemotherapy at Shizuoka Red Cross Hospital or Kanagawa Cancer Center (acute myeloid leukemia (AML) n=5, acute lymphoblastic leukemia (ALL) n=1). All patients refused the consent for transfusions of packed red cells and platelet units and they were never forced accept them.

Remission induction therapy: One patient with M3 received all-trans retinoic acid alone. One ALL patient received prednisolone alone. Three AML patients received the following LVP regimen: L-asparaginase 5000U/sqm div from day 8 to day 21 + vincristine 1.4mg/sqm div day1, 6, 11, 16, 21, 26 + prednisolone 40mg/sqm div from day 1 to day 28, and one AML patient received a low dose of Ara-C regimen (20mg/sqm continuous div from day 1 to day 14).

Results (see Table): Four out of six patients achieved complete remission and two paitents died from cardiac arrest due to severe anemia before hematological recovery. No patients developed fatal bleeding complications, not even long lasting severe thrombocytopenia.

Conclusion: We have demonstrated the feasibility of remission induction therapy for JW with leukemia. This LVP regimen, or steroid based regimen, may be suitable for JW with acute leukemia because myelosuppression is relatively mild. While two patients experienced cardiac arrest due to severe anemia of under 3g/dL of hemoglobin, severe thrombocytopenia can be managed without prophylactic platelet transfusion.

Clinical characteristics of patients Pt#:Age/Sex/FAB/ Karyotype Induction therapy Epo use Nadir in Induction therapy (day) Out come Follow-up from Induction therapy WBC(×109/L) Hb(g/dL) PLT(×109/L) ATRA: All-trans retinoic acid, PSL: Prednisolone, , LDAC: Low dose of Ara-C regimen, Epo: Erythropoietin, CR: Complete Remisson, ED: Early Death, RLPs: Relapse 1: 28/F/M3/t(15;17) ATRA Yes 0.9 (day2) 3.6 (day3) 20 (day2) CR 10Y6M+, 2ndCR 2: 29/F/M1/normal PSL+LVP No 0.6 (day4) 2.4 (day19) 16 (day6) CR 2Y6M, dead in 2nd RLPs 3: 45/F/M2/normal LVP No 0.9 (day22) 3.0 (day30) 8 (day25) CR 2Y1M+, in 1st CR 4: 25/M/M2/t(8;21) LVP Yes 1.2 (day25) 1.5 (day31) 17 (day31) ED 31days 5: 15/F/L1/complex PSL Yes 1.3 (day5) 3.8 (day7) 1 (day4) CR 10M+, in 1st CR 6: 64/M/M2/complex LDAC Yes 0.6 (day6) 2.7 (day21) 1 (day21) ED 23days
The Intention To Treat Analysis of the Different Post Remission Therapy Modalities in AML Patients with the “Intermediate Risk Group (IPG)” Based on Cytogenetics.
Authors: Mun Yeung-Chul , Lee S.M. , Park S.H. , Cho E.K. , Lee J.H. , Jo D.Y. , Kim I.H. , Yoon S.S. , Park S.Y. , Bang S.M. , Min Y.J. , Seo J.J. , Lee M.H. , Kim C.S. , Joo Y.D. , Chung S.Y. , Oh D.Y. , Zang D.Y. , Lee K.H. , Hyun M.S. , Song H.S. , Kim H.S. , Kwon H.C. , Kim H.J. , Park Y.H. , Ahn M.J. , Ahn J.S. , Park K.T. , Bae S.H. , Ryoo H.M. , Yoon H.J. , Kim B.S. , Ghim Thad , Seong Chu-Myong
Published: April 2020

The results of cytogenetics are one of the most important prognostic factors in the prognosis of AML. Three different post remission therapies were given with the IPG based on the MRC definitions using the cytogenetics results. The inclusion criteria included age<65, PS<3 with reasonable organ functions, cardiac ejection fraction>50%, bilirubin<2.0mg/dl, creatinine<2mg/dl in de novo AML and secondary AML. The aims of this prospective intention to treat analysis were to compare the CR, recovery kinetics, DFS and OS in IPG based on cytogenetics with 3 different consolidation treatment modalities described as follows. Three plus seven(Idarubicin 12mg/m2, D1-D3; Ara-C 100mg/m2, D1–D7) were given to de novo AML and secondary AML. HDAC followed by three times of post remission therapy or auto PBPCT followed by two times of post remission therapy was given to IPG. If an HLA-identical sibling were available, then allo BMT was tried after 1st post-remission therapy. The median age of the cohort(Total 194) is 42.5(±17.6) (HDAC(n:89) : 47.6, auto PBPCT(n:51) : 46.6, and allo BMT(n:54) : 30.5). The median days for ANC >500/μl and platelet>20k/μl during induction were 22 days and 21 days respectively. Grade 3~4 toxicities were found in 34.1%, 27.7% and 47.2% during HDAC, auto PBPCT and allo BMT, respetively(p<0.05). The relapse rate and the toxic death rate were 25.8%, 27.5% and 29.6%(p=0.24) and 9.1%, 5.5% and 16.6%(p<0.05) in HDAC, auto PBPCT and allo BMT, respectively. So far, this trial seems to be tolerable in terms of toxicities, during induction and post remission therapies. Among IPG, the auto PBPCT arm had a tendency of superior median survival over the HDAC or allo BMT in terms of OS and LFS without statistical differences(HDAC:17m and 8m, auto-PBPCT:18m and 12m, allograft:15m and 8m). This intention to treat trial, which started in Jan, 2000, has proceeded until now in order to have better statistical power for the subset analysis.
Limited Phase I Trial of Sequential High Dose Cytarabine and Clofarabine (HiDAC→CLOF) in Relapsed or Refractory Acute Myeloid Leukemia.
Authors: Powell Bayard L. , Lovato James , Kimbrough Claire , Lyerly Susan , Galloway-Daniels Sonya , Motley Cathy , Harrelson Robin , Keung Yi Kong , Thakuri Mohan C. , Molnar Istvan , Levitan Denise , Hurd David Duane
Published: April 2020

High dose cytarabine (HiDAC) is the most effective single agent for the treatment of acute myeloid leukemia (AML); clofarabine (CLOF) is also an active agent in AML. Preclinical data suggest synergy between cytarabine and clofarabine. We conducted a two step limited phase I trial of sequential HiDAC (2g/m2 over 3 hours) followed by CLOF (30 or 40 mg/m2 infused over 2 hours), each given daily for 5 days, in adults with AML in first or second relapse or refractory to initial induction chemotherapy. Patients with persistent leukemia on day 12–14 received a second course of HiDAC→CLOF; phase I toxicity evaluation was based on cycle 1 data only. Nine patients (6 men and 3 women) were treated. The median age was 55.5 years (range 29.2 – 68.1). All had relapsed AML; two had prior autologous stem cell transplant. The initial cohort of 3 patients received clofarabine 30 mg/m2 with one dose limiting toxicity (DLT); an additional 3 patients were treated in cohort 1. The second cohort was treated with CLOF 40 mg/m2, the target dose for a planned phase II trial of HiDAC→CLOF. Hematologic toxicities and infections were not considered DLT. In the first cohort (30 mg/m2; n = 6) there was 1 DLT - grade 4 skin rash in a patient who subsequently died on day 17 with sepsis-related multi-organ failure; 3 patients had reversible grade 3 elevations in AST/ALT, 1 had grade 3 skin toxicity. In cohort 2 (40 mg/m2 ; n = 3) there was no DLT; 1 patient had grade 3 AST/ALT; 2 had grade 3 skin. Three of nine patients received a second course of induction HiDACCLOF. Two of six patients in cohort 1 achieved complete remission (CR), 1/3 patients in cohort 2 achieved CRi(CRp). Two of three CR/CRi patients received one course and one received two courses of HiDAC→CLOF induction. Conclusion: HiDAC→CLOF was associated with transient elevation in AST/ALT (4/9) and skin rash (3/9; primarily extensive palmar/plantar); skin toxicity appeared especially prominent in patients with palmar/plantar toxicity during prior therapy with HiDAC. Toxicities (other than skin) were comparable to other salvage regimens for relapsed and refractory AML. This combination is active in relapsed AML with 3/9 CR/CRp. A phase II trial of HiDAC→CLOF is underway; prophylactic intravenous hydrocortisone has been incorporated in an attempt to decrease skin toxicity.
Updated Results of a Phase I Study of Flavopiridol in Acute Leukemias Using a Novel, Pharmacokinetically Derived Schedule: Clinical Activity Including Hyperacute Tumor Lysis Syndrome (TLS), Pharmacokinetics (PK), and Pharmacodynamics (PD).
Authors: Blum William , Klisovic Rebecca B. , Kefauver Cheryl , Johnson Amy , Phelps Mitch , Dalton James T. , Lucas David , Huynh LeNguyen , Liu Shujun , Grever Michael R. , Colevas A.D. , Marcucci Guido , Byrd John C.
Published: April 2020

Flavopiridol is a cyclin-dependent kinase inhibitor that induces apoptosis in acute leukemia cell lines. In earlier studies with flavopiridol in several malignancies, plasma concentrations of flavopiridol were not reached or maintained at sufficient levels to induce apoptosis due to unexpectedly high levels of bound drug in human serum relative to fetal calf serum used in preclinical studies. PK modeling in chronic lymphocytic leukemia (CLL) cells cultured in human plasma in vitro indicated that administering flavopiridol by 30 minute intravenous (IV) bolus followed by 4 hour continuous IV infusion (CIVI) would achieve sustained in vivo plasma drug concentration and time exposure similar to that necessary to induce apoptosis. We designed a phase I dose escalation trial in acute leukemias of single agent flavopiridol given as a 30 minute bolus followed by a 4 hour CIVI on days 1–3 with the ability to repeat cycles every 21 days; 16 patients (pts) have been enrolled to date. Dose escalation was as follows (bolus dose/4 hr CIVI dose in mg/m2): 20/30 (n=3), 30/35 (n=7), 30/50 (n=3), and 40/60 (n=3). Based on prior experience with flavopiridol at our institution in CLL, aggressive measures for the prevention and management of hyperacute tumor lysis syndrome (TLS) were employed. Pts had relapsed/refractory AML (N=12) and ALL (N=4), and were 25–78 yrs old (median age 64 yrs). Average plasma levels were 1.0–2.5 μM at the first three dose levels during the infusion (N=13) and declined with terminal half-lives comparable to previously reported 72 hr and more recent 4.5 hr infusions. Clinically significant TLS occurred in 2/16 pts with chemical evidence of lysis in 4 additional pts. A dose-limiting toxicity (renal failure) occurred at dose level 4 (40 mg/m2 bolus/60 mg/m2 CIVI), and the level is currently being expanded. Treatment was otherwise well tolerated. Downregulation of Mcl-1 protein by standard immunoblotting at 4 and/or 24 hrs was demonstrated in blood and/or bone marrow cells of 6/10 patients Anti-leukemic activity including transient reductions in WBCs/circulating blasts (n=7), bone marrow blasts (n=2), and platelet transfusion independence (n=1) was observed. Two received a second course of therapy, but no pt experienced an objective response by standard criteria. The current dose level exceeds that previously given in ongoing CLL studies; dose escalation to identify the maximum tolerated dose using this pharmacokinetically derived schedule in acute leukemia continues. Given the activity of this drug as a single agent, combination studies with conventional chemotherapy or other novel agents in acute leukemias should be considered.
Arsenic Trioxide-Induced Cell Death Occurs Partially Independent of the Pro-Apoptotic Bcl-2-Family Members Bax and Bak.
Authors: Scholz Christian , Richter Antje , Richter Anja , Dörken Bernd , Daniel Peter T.
Published: April 2020

Arsenic trioxide (As2O3, arsenite) efficiently kills cells from various hematologic malignancies and has successfully been employed for the treatment of acute promyelocytic leukaemia, myelodysplastic syndrome, and multiple myeloma. Investigating the mechanisms of arsenic trioxide-induced cell death, we recently demonstrated that arsenite-mediated cell demise has a partially necrotic phenotype, occurs independently of the extrinsic death receptor pathway of apoptosis, and is not hampered by the absence of functioning caspases. On the contrary, cell death proceeded entirely via an intrinsic, mitochondrial pathway and was efficiently blocked by the anti-apoptotic Bcl-2 family members Bcl-2 or Bcl-xL. Here, we address the role of the pro-apoptotic multi-domain Bcl-2 family members Bax and Bak. By employing different cell lines deficient for Bax and/or Bak, we demonstrate that Bax- or Bak-deficiency as well as the combined absence only partially blocks arsenite-induced cell death. While the detection of an additive effect of the combined Bax-/Bak-deficiency argues for a non redundant function of Bax and Bak, the persistence of a substantial percentage of arsenite-mediated cell demise in different double deficient cell lines nevertheless suggests a mode of arsenic trioxide-mediated cell death independent from these central inducers of apoptotic cell demise. The presented data add to the notion that arsenic trioxide kills tumor cells independent of the apoptotic machinery, and warrants further investigation on the efficacy of this compound in malignancies with deficiencies of the apoptotic cell death pathways.
Advanced Stage Hodgkin Lymphoma: The Predictive Value on Treatment Outcome of Early FDG-PET Scan Is Independent of and Superior to IPS Score.
Authors: Gallamini A. , Hutchings M. , Rigacci L. , Specht L. , Merli F. , D’Amore F. , Nassi L. , Hansen M. , Vitolo U. , Kamper P. , Trentin L. , Stelitano C. , Di Raimondo F. , Sancetta R. , Luminari S. , Viviani S. , Iannitto E. , Levis A.
Published: April 2020

Background: FDG-PET scan performed early during chemotherapy (CT) is a powerful prognostic tool in lymphoma management. This study aimed to compare the predictive value on treatment outcome of the International Prognostic Score (IPS) with that of FDG-PET scan performed after two courses of standard CT in untreated advanced stage (AS) HL patients.

Patients: From December 2001, 202 new AS HL patients were consecutively admitted to 11 Italian and 3 Danish hematological centers, on behalf of Intergruppo Italiano Linfomi and Danish Lymphoma Cooperative Group. The mean age was 35.5 years (14–79), the male/female ratio 105/97; AS (IIB–IVB) was present in 153, and unfavorable stage IIA (> 3 nodal sites involved or sub-diaphragmatic presentation or bulky disease or ESR > 40) in 49. Bulky and extranodal disease was recorded in 71 and 58 patients, respectively. All patients had FDG-PET at baseline (PET-0) and after 2 courses of CT (PET-2). 192 patients were treated with ABVD, 8 with ABVD-like CT, 2 with BEACOPP. 102 patients received consolidation radiotherapy after CT. All patients were given the therapy programmed at baseline, except in case of overt progression.

Results: The mean time from the diagnosis to latest follow-up was 796 days (range 91–1716). 164 patients attained CR while 38 were chemoresistant: 34 showed disease progression during CT and 4 showed early relapse (within 6 months) after CR entry: (+28 – +178 days). 4 out of the 164 pts attaining CR relapsed later than 6 months. In univariate analyses, both PET-2 (p<0.0001) and IPS (p<0.001) were significantly associated with a higher probability of treatment failure. However, in a multivariate analysis only PET-2 was independently predictive of relapse/progression probability (51.0; 95 % C.I. 20.9 – 124.2). The sensitivity of PET-2 for treatment failure was 85%, the specificity 96% and the overall accuracy 94%. The 2-y FFS probability for PET-2 negative and for PET-2 positive patients were 96% and 14%, respectively (log Rank test, p<0.0001; Fig. 1).

Conclusions: so far, FDG-PET after two cycles of CT is the most powerful tool available for predicting treatment outcome in AS HL.

Figure Figure
Identification of Combined Clinical and Biomarker Prognostic Factors in Follicular Lymphoma.
Authors: Foster Cheryl J. , Farmer Patricia L. , Baetz Tara , Brettschneider Julia , Feilotter Harriet E. , LeBrun David P.
Published: April 2020

Follicular lymphoma (FL) is generally an indolent disease, progressing slowly over a period of many years. However, some patients experience a rapid progression or histological transformation to an aggressive lymphoma requiring more aggressive treatment. Identification of these patients at the time of the initial diagnosis would allow more informed decisions to be made regarding clinical management. We investigated whether the expression of specific proteins in FL cells in combination with baseline clinical data could predict for relapse, transformation and survival of patients with follicular lymphoma. A tissue microarray (TMA) was generated of 67 cases of FL diagnosed between 1974 and 2003. Clinical baseline and follow-up data were obtained (median of 58 months). Forty-one patients experienced relapse within the follow-up period and thirty-one individuals transformed to aggressive lymphoma. Median overall survival was 13.6 years. Immunohistochemistry (IHC) staining was obtained for markers routinely used in lymphoma diagnosis, as well as oncogenesis-relevant proteins including p53, bcl-2, bcl-6, mum1, p16 and p65. Evaluations of the presence of benign T-cells, infiltrating macrophages, and the follicular dendritic cell network were also made. Univariate analysis was undertaken using the Kaplan-Meier method in order to assess the prognostic power of various clinical, histological and IHC variables with respect to overall survival, time to transformation and time to relapse. Variables that had prognostic significance (p<0.05) in univariate analysis were included in multivariate models of these end-points. High tumour grade, expression in tumour cells of p16 and lack of bcl-2 predicted shorter transformation-free survival in multivariate analysis. Advanced tumour stage, presence of B symptoms, expression of p53 or p16 in tumour cells, presence of benign T-cells in the tumour environment and integrity of the benign follicular dendritic cell network had independent prognostic power for shorter relapse-free survival. Greater than 5 nodal sites of disease, presence of B symptoms at diagnosis and expression of p53 in lymphoma cells each emerged as significant and independent predictors of overall survival using a Cox regression model. These results indicate that protein-based expression profiling using TMAs in combination with clinical data is a potentially productive means of identifying a prognostic index that can be implemented in the clinical management of follicular lymphoma patients. Further study is required to compare these results to existing clinical prognostic scores.
Utility of FDG-PET and Comparison of FDG-PET and Ga-67 Scintigraphy in Evaluation of B-Cell Indolent Lymphoma.
Authors: Tsukamoto Norifumi , Yokohama Akihiko , Irisawa Hiroyuki , Saitoh Takayuki , Uchiumi Hideki , Matsushima Takafumi , Nojima Yoshihisa , Karasawa Masamitsu , Handa Hiroshi , Murakami Hirokazu
Published: April 2020

18Fluoro-2-deoxyglucose positron emission tomography (FDG-PET) has emerged as an important tool for the management of lymphoma patients, but little information has been reported about its usefulness in indolent lymphoma. The aim of this study was to retrospectively assess the usefulness of FDG-PET, and to compare the sensitivity of FDG-PET with gallium 67 citrated scintigraphy (Ga-67), in identifying disease involvement in patients with indolent lymphoma. We also investigated the relationship between FDG-PET and pathologic diagnosis according to the World Health Organization (WHO) classification system.

A total of 118 cases contemporaneously underwent FDG-PET and CT and/or MRI prior to treatment. The histological diagnoses included follicular lymphoma (FL; n=43), MALT-lymphoma (n=52), splenic marginal zone lymphoma (SMZL; n=10), small lymphocytic lymphoma (SLL; n=5) and mantle cell lymphoma (MCL; n=8). In 88 of these 118 cases, Ga-67 was also performed. The involved disease sites were divided into lymph node regions and extranodal regions. The former group was further divided into four lymph node regions:

head and neck, chest, abdomen and pelvis.

Among the 118 patients, 401 disease sites were included in the analysis. FDG-PET identified disease sites in 171/189 (90%) FLs, 107/126 (86%) MALTs, 7/16 (44%) SMZLs, 10/19 (53%) SLLs and 51/51 (100%) MCLs. In addition, FDG-PET detected more involvement sites than Ga-67 for all disease sites, except for one region each in the MALTs and SMZLs, namely the eyelid and spleen. Ga-67 was able to detect disease sites assessed by FDG-PET in 48/127 (38%) FLs, 44/78 (56%) MALTs, 3/5 (60%) SMZLs, 1/2 (50%) SLLs and 8/27 (30%) MCLs. There were no anatomical differences in the not-detected disease sites between FDG-PET and Ga-67.

In imaging lymphomas before therapy, FDG-PET was informative for FL, MALT, and MCL, but less reliable for SMZL and SLL. Ga-67 was not suitable for indolent lymphoma, in particular FL and MCL. Given the high sensitivity of FDG-PET, this modality is highly recommended for indolent lymphoma. However, for SMZL and SLL, different anatomical imaging modalities such as CT and MRI should be used.

Sensitivity of FDG-PET Histology No.of sites FDG-PET positive % FL 189 171 90 MZL/MALT 126 107 86 MCL 51 51 100 SMZL 16 7 44 SLL 19 10 53 Total 401 346 Comparison of FDG-PET with Ga-67 Histology PET positive Ga-67 positive Ga/PET(%) FL 127 48 39 MZL/MALT 78 44 56 MCL 27 8 30 SMZL 5 3 60 SLL 2 1 50 Total 239 104
Racial Disparities in Diffuse Large B Cell Lymphoma: A VA Population Study.
Authors: Maraboyina Sanjay , Komrokji Rami S. , Haddad Rami Y. , Nahleh Zeina A. , Safa Malek M.
Published: April 2020

Background: Racial disparities in diffuse large B cell non-Hodgkin’s lymphoma (DLBCL) are not well studied. Racial differences in outcome are not well recognized given majority of patients with DLBCL are white. The VA health care system offers a platform to study those racial differences given similar other variables and socioeconomic status among those patients.

Methods: This was a retrospective analysis. The VA Central Cancer Registry (VACCR) database was used to identify patients with DLBCL diagnosed between 1995 and 2005. There are approximately 120 VA medical centers diagnosing and/or treating patients with cancer. The VACCR aggregates the data collected by the medical centers’ cancer registries. Data were extrapolated and analyzed using bio-statistical software SPSS. Variables included age, sex, stage of disease, histology subtype, date of diagnosis, date of last contact, date of relapse, vital status, family history of cancer, tobacco history, alcohol history, Agent orange exposure and whether patients received chemotherapy and or radiation. Independent t test was used for comparing continuous variables and chi square test for categorical variables. Wilcoxon test was used to compare survival among the two groups.

Results: There were 2792 patients with DLBCL at the VA system, 2402 white and 323 black patients. Sixty-seven patients from other racial groups were excluded from this analysis. The mean age of presentation among blacks was 57.8 years compared to 65.7 years among whites (P-value < 0.005). More Black patients had history of alcohol use, and smoking. More white patients had family history of cancer. No differences in histology subtypes were observed. Other baseline characteristics were similar. No difference in stage of disease was noted at presentation. IPI score data were not available. Similar proportion of patients received multi-agent chemotherapy among the two groups, 70 % for blacks and 67% for whites (P-value 0.58). Among blacks 16 % of patients received radiation while 19.5 % white patients did (P-value 0.73). The 5-year overall survival for blacks was 24 % compared to 29% for whites (P-value 0.92, Wilcoxon test). No statistically significant differences in survival were noted between the two races within each clinical stage. Using Cox regression multivariable analysis age, stage and chemotherapy were the only statistically significant independent variables affecting survival.

Conclusions: DLBCL is less common among blacks. Blacks diagnosed with DLBCL are more likely to present at younger age. The treatment and outcome of DLBCL among blacks are not different from whites within the VA system.