Sequential Cis-Platinum and Fludarabine with or without Arabinosyl Cytosine in Patients Failing Prior Fludarabine Therapy for Chronic Lymphocytic Leukemia: A Phase II Study

Patients with chronic lymphocytic leukemia (CLL) who fail fludarabine (Fluda) therapy have a poor response to subsequent salvage regimens and a poor prognosis. This study was undertaken to determine the efficacy and toxicity of a cis-platinum, (cis-p)fluda and arabinosyl cytosine (ara-C) combination in patients who were refractory to fluda or had relapsed following prior fluda therapy for CLL. Forty-one patients who had progressive CLL were treated on study. Eleven patients (27%) were sensitive to fluda and thirty (73%) refractory prior to study entry. Therapy consisted of cis-p 100mg/m² continuous intravenous (IV) infusion over 4 days, fluda 30 m/m² IV over 15 minutes on Days 3 and 4 either given alone (PF) or with ara-C 500 mg/m IV over 1 hour on Day 4 (PFA). The median number of PF or PFA courses received was two. No patient achieved a complete response. Eight patients (19%) achieved a partial response (PR), 28 were taken off study with progressive or refractory disease and 5 had induction deaths. The overall median survival was 6 months, 15 months in responding patients, and 4 months in non-responding patients. Rai stage 1-11 patients had a median survival of 7 months and stage 111-IV patients had a median survival of 3 months. Major toxici-ties (myelosuppression, sepsis, renal failure and tumor lysis syndrome) were frequent.

In conclusion, it can be said that the PF and PFA regimens have equivalent modest activity in patients with progressive CLL following prior fluda therapy, predominantly among patients whose disease was sensitive to fluda at last prior exposure. Ara-C did not add to the activity of the cis-plfluda combination in this study group.     

慢性淋巴细胞白血病分层治疗的长期疗效观察

 目的　分析慢性淋巴细胞白血病（CML）按照分期接受不同治疗方法的临床疗效。方法　对1990年至2007年收治的35例CLL患者的资料进行回顾和随访。35例患者按照Binet分期的不同,A期予干扰素300～600万U／d,每周5次皮下注射;观察6个月,若病情稳定无进展则予300万U每周2～3次长期维持。B、C期患者直接给予FC／FC-R或CHOP／COP方案化疗。化疗间歇期、完全缓解（CR）或部分缓解（PR）后予干扰素长期维持。结果　A期20例患者经干扰素治疗6个月后无一例CR,5例（25 %）达PR,14例（70 %）病情稳定（SD）,1例（5 %）进展到B期。5例PR的患者中有3例在平均36.3个月后复发。在14例SD患者中,8例平均在74个月后进展到B期。27例B、C期患者接受化疗,FC／FC-R化疗组CR 41.2 %,总有效率74.6 %明显优于CHOP／COP组（CR 12.5 %）。A、B、C期患者平均生存时间分别为155.2、100.1、82.9个月,经Kaplan-Meier检验具有统计学意义（P＝0.032）。死亡10例,其中A期2例,B期4例,C期4例。9例死于感染,1例死于大出血。结论　CLL患者应视患者疾病分期及其他预后指标给予个性化治疗,早期患者可予干扰素治疗。长期应用干扰素可能减少感染的发生。     

难治性复发成人急性淋巴细胞白血病的治疗

日的:回顾性分析氟达拉滨(Flu)为主的方案与替尼泊苷 米托蒽醌(MIT)的方案对难治性复发成人急性淋巴细胞白血病(ALL)的疗效及毒副作用.方法:应用替尼泊苷(100 mg/d,5～7 d) MIT(10 mg/d,2 d)的方案和Flu为主的方案[Flu 30 mg/(m2·d),3～5 d,阿糖胞苷(Ara-c)1～2g/(m2·d),5 d;及Flu(50 mg/d,5 d),Ara-c(200 mg/d,5 d),MIT(4 mg/d,4 d)]治疗42例难治复发成人ALL.WBC＜1.0×109/L时使用粒细胞集落刺激因子(G-CSF)5μg/(kg·d)直至WBC＞1.0×109/L.结果:以Flu为主的方案与替尼泊苷 MIT方案(VM)相比:完全缓解(cR)率分别为45%和31.8%,P＞0.05;中性粒细胞最低的中位时间均为第6天,WBC＜1.0×109中位持续时间分别为10 d和7.5 d,P＞0.05;血小板最低的中位时间分别为第10天和第6.5天,P＜0.05;PLT＜20.0×109中位持续时间分别为第6天和第10天,P＞0.05.Flu组非血液学毒副作用显著少于VM组.结论:两组方案对难治复发ALL均有效,Flu方案毒副作用小,骨髓抑制略轻,缓解率较高,尤其对Ph ALL疗效显著.     

In Vitro Effect of Fludarabine, Cyclophosphamide, and Cytosine Arabinoside on Chromosome Breakage in Fanconi Anemia Patients: Relevance to Stem Cell Transplantation

Designing stem cell transplantation (SCT) conditioning regimens for Fanconi anemia (FA) has proved difficult because of hypersensitivity to the DNA cross-linking agents. We performed chromosome fragility tests with 56 FA patients and with 50 non-FA patients with severe aplastic anemia or myelodysplastic syndrome. We evaluated peripheral blood lymphocyte specimens cultured for 72 hours and treated with mitomycin C, diepoxybutane (DEB), cyclophosphamide (CY) metabolites, cytosine arabinoside (Ara-C), and fludarabine (Flu) metabolite (9-beta-D-arabinofuranosyl-2-fluoroadenine [2-F-Ara-A]). The DEB and CY metabolite tests were highly sensitive and specific for FA (P<10(-4)) for both tests), and the number of aberrations per cell for DEB correlated with that for the CY metabolite test (P < 10(-4)) but did not correlate with the number of aberrations per cell for the Ara-C and 2-F-Ara-A tests. The difference in breakage frequencies between FA and non-FA patients for cultures treated with 2-F-Ara-A was not statistically significant. Most of the breakages observed in cells treated with 2-F-Ara-A-and Ara-C were chromatid breaks. It may be possible to determine the appropriate CY dose in the preconditioning regimen for SCT in FA patients on the basis of the in vitro effects on fragility, and Flu or Ara-C may be a safer drug than high-dose CY for conditioning in FA patients.     

Herpes simplex and Epstein-Barr virus lymphadenitis in a patient with chronic lymphocytic leukemia treated with fludarabine

Multiple herpes virus co-infection is a very rare complication in patients with chronic lymphocytic leukemia (CLL). We describe a patient with a CLL who developed an herpes virus lymphadenitis. Inmunohistochemical study was positive for HSV-1, HSV-2, and Epstein-Barr Virus (EBV). The coinfection of EBV with a profile of expresion of viral latent genes type III, is usually seen in inmunodepressed patients. To the best of our knowledge, this is the first reported case of a multiple human herpes virus infection mimicking Richter syndrome.     

A case of hepatosplenic gamma-delta T-cell lymphoma with a transient response to fludarabine and alemtuzumab

Hepatosplenic gamma-delta T-cell lymphoma is a rare, usually fatal lymphoma and available literature on management is sparse. Allografting is probably the only curative option. We describe a further case with a dramatic, though transient response to Fludarabine and Alemtuzumab combination, following a failure of conventional chemotherapy. Given the dreadful prognosis with conventional chemotherapy, it is a regimen worth pursuing as a disease reduction strategy prior to allograft where appropriate.     

Dihydrodiol dehydrogenase in drug resistance and sensitivity of human carcinomas

We previously reported (UroOncology 1:165, 2001) cross-resistance and collateral-sensitivity to 2-chlorodeoxyadenosine (CldAdo) and fludarabine (FaraA), respectively, in a human renal cell carcinoma selected for resistance to 2′-deoxytubercidin (Caki-dTub). Insofar that these drugs generally demonstrate cross resistance rather than collateral sensitivity, we further examined the bases for this phenomenon. Both CldAdo and FaraA induce apoptosis, as the triphosphates, via binding to Apaf-1. In the presence of cytochrome c, this binding leads to activation of procaspase 9 to active caspase 9 that induces apoptosis through its activation of caspase 3. CldAdo and FaraA induced caspase 3 activities in wild type and Caki-dTub cell lines in a dose-dependent manner that paralleled the cross-resistance (CldAdo, 200-fold) or collateral sensitivity (FaraA, 20-fold) with regard to cell viability. The activation of caspase 3 was inhibited by the caspase 9 inhibitor, Z-LEHD-FMK, suggesting that both drugs act via the same pathway. By differential display and direct enzyme analysis, dihydrodiol dehydrogenase (DDH) was observed to be profoundly underexpressed in the Caki-dTub compared to wild-type Caki-1 cells. Stable transfection of the Caki-dTub cells with a vector encoding the enzyme led to partial reversal of the resistance to CldAdo. Resistance to cisplatin has recently been ascribed to overexpression of DDH in a human ovarian carcinoma cell line (Deng et al. in J Biol Chem 227:15035, 2002). It is tempting to speculate a mutation in the Apaf-1 nucleotide binding site that reduces (CldAdo) or increases (FaraA) toxicity in the Caki-dTub cells; however, the recent finding by others in a human ovarian carcinoma cell line suggests that DDH expression mediates the cross-resistance and perhaps, collateral-sensitivity. This work was supported by a National Institutes of Health Grant, DK-41606, from the Institute for Diabetes, Digestive Diseases and Kidney, U.S. Public Health Service.     

Recent progress in the management of chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) is a clonal disease characterized by proliferation and accumulation of small CD5-positive B cells. More than 50% of patients are asymptomatic at diagnosis and usually require no treatment. However, treatment is needed in the advanced and progressive disease. Chlorambucil with or without steroids has been the drug of choice for many years in previously untreated patients with CLL. The purine nucleoside analogs (PNAs), fludarabine (FA), cladribine (2-CdA-chlorodeoxyadenosine) and pentostatin (DCF, 2'-deoxycoformycin) also have been introduced for treatment of CLL. Significantly higher overall response (OR) and complete response (CR) and longer progression free survival (PFS) in patients with CLL treated with FA or 2-CdA have been confirmed in randomized, multicenter trials and more recently in meta-analysis. However, the median survival time did not differ between patients treated with PNA and alkylating agents. Combination therapies with PNAs and cyclophosphamide and especially with cyclophosphamide and rituximab are more active than monotherapy in terms of OR, CR and PFS. Several reports have shown significant activity of alemtuzumab in previously untreated and pretreated patients even when refractory to FA. Alemtuzumab also can be used in CLL as a preparative regimen before stem cell transplantation (SCT) and to eliminate minimal residual disease (MRD). Recently, several new agents have shown promise in treating CLL, including new monoclonal antibodies, agents targeting bcl-2 family of proteins, antisense oligonucleotides and other agents. Moreover, autologous and allogenic hematopoietic cell transplantations are increasingly considered for treatment of patients with CLL. In this review current therapeutic strategies in CLL are presented.     

Synergistic Cytotoxicity of Sorafenib with Busulfan and Nucleoside Analogs in Human FMS-like Tyrosine Kinase 3 Internal Tandem Duplications–Positive Acute Myeloid Leukemia Cells

Clofarabine (Clo), fludarabine (Flu), and busulfan (Bu) are used in pretransplantation conditioning therapy for patients with myeloid leukemia. To further improve their efficacy in FMS-like tyrosine kinase 3 internal tandem duplications (FLT3-ITD)-positive acute myeloid leukemia (AML), we investigated their synergism with sorafenib (Sor). Exposure of FLT3-ITD–positive MV-4-11 and MOLM 13 cells to Bu+Clo+Flu+Sor resulted in synergistic cytotoxicity; no such synergism was observed in the FLT3-wild type THP-1 and KBM3/Bu250⁶ cell lines. The drug synergism in MV-4-11 cells could be attributed to activation of DNA damage response, histone 3 modifications, inhibition of prosurvival kinases, and activation of apoptosis. Further, the phosphorylation of kinases, including FLT3, MAPK kinase (MEK), and AKT, was inhibited. The FLT3-ITD substrate STAT5 and its target gene PIM 2 product decreased when cells were exposed to Sor alone, Bu+Clo+Flu, and Bu+Clo+Flu+Sor. The level of the proapoptotic protein p53 upregulated modulator of apoptosis (PUMA) increased, whereas the level of prosurvival protein MCL-1 decreased when cells were exposed to Bu+Clo+Flu+Sor. The interactions of PUMA with MCL-1 and/or BCL-2 were enhanced when cells were exposed to Bu+Clo+Flu or Bu+Clo+Flu+Sor. The changes in the level of these proteins, which are involved in mitochondrial control of apoptosis, correlate with changes in mitochondrial membrane potential. Bu+Clo+Flu+Sor decreased mitochondrial membrane potential by 60% and caused leakage of cytochrome c, second mitochondria-derived activator of caspases (SMAC)/direct IAP Binding protein with low pI (DIABLO), and AIF from the mitochondria to the cytoplasm, caspase activation, and cell death, suggesting the activation of apoptosis. Analogous, synergistic cytotoxicity in response to Bu, Clo, Flu, and Sor was observed in mononuclear cells isolated from FLT3-ITD–positive AML patients. Although our previous studies were aimed at standardizing the conditioning regimen, the new findings suggest that patients with abnormal expression of FLT3 might further benefit from individualizing treatment through the addition of Sor to Bu+Clo+Flu, thereby providing personalized pretransplantation therapy.