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PubMed2005

Efficacy and toxicity of intermediate-dose amphotericin B lipid complex as a primary or salvage treatment of fungal infections in patients with hematological malignancies.

We treated 74 adults with a hematological malignancy and documented or suspected invasive fungal infection (IFI) with amphotericin B lipid complex (ABLC) at 3 mg/kg/day. Forty-five patients (61%) received upfront therapy and 29 patients (39%) received salvage therapy for their IFI. Forty-eight of 71 evaluable patients responded [complete responses in 40 (56%) and partial responses in 8 (11%)] and 15 (21%) died as a consequence of the IFI. Response rates in invasive aspergillosis were 33 out of 49 (67%) for probable/definite cases and 6 out of 11 (55%) for invasive candidiasis. In 40 patients with neutropenia-associated IFI, rapid neutropenic recovery ( < 10 days from study entry) was essential for response to therapy (90% vs. 32%, P < 0.01). Treatment was well tolerated, with 15% infusions followed by infusion-related adverse events, nephrotoxicity in 7% of patients and 11% of withdrawals due to toxicity. These data suggest that intermediate-doses of ABLC may be of similar efficacy than higher doses with less toxicity, making it a cost-effective alternative worthy of study in future trials.

Adult↗

PubMed2004

Update on the proteasome inhibitor bortezomib in hematologic malignancies.

The ubiquitin-proteasome system plays a crucial role in eukaryotic cells in maintaining protein homeostasis. Through the disruption of a variety of pathways and cell cycle checkpoints, proteasome inhibition leads to apoptosis and in experimental models can overcome chemoresistance. Bortezomib is the first of its class of proteasome inhibitors tested in humans that showed promising activity in several tumor types, and especially in hematologic malignancies, in phase I studies. The remarkable results obtained in phase II studies in multiple myeloma (MM) led to its fast-track approval by the US Food and Drug Administration in May 2003 for relapsed MM. More recent observation also revealed promising activity in non-Hodgkin's lymphoma. This review will explore the rationale for the use of bortezomib in hematologic malignancies as well as provide an update on the results of ongoing studies and future directions for the use of this new agent in hematologic malignancies. The mechanism of action of bortezomib and its nonoverlapping toxicity profile make it a very appealing drug for combination with other chemotherapeutic or biologic agents. Bortezomib represents an excellent example of how progress in understanding the biology of cancer cells can impact clinical practice and lead toward a new era of rational therapeutics.

Antineoplastic Agents↗

PubMed1989

Chromosomal differences between acute nonlymphocytic leukemia in patients with prior solid tumors and prior hematologic malignancies. A study of 14 cases with prior breast cancer.

A cytogenetic study of 14 patients with secondary acute nonlymphocytic leukemia (S-ANLL) with prior treatment for breast cancer is reported. The chromosomes recurrently involved in numerical or structural anomalies are chromosomes 7, 5, 17, and 11, in decreasing order of frequency. The distribution of the anomalies detected in this sample of patients is similar to that observed in published cases with prior breast or other solid tumors, though anomalies of chromosome 11 were not pointed out, but it significantly differs from that of the S-ANLL with prior hematologic malignancies. This difference is principally due to a higher involvement of chromosome 7 in patients with prior hematologic malignancies and of chromosomes 11 and 17 in patients with prior solid tumors. A genetic determinism involving abnormal recessive alleles located on chromosomes 5, 7, 11, and 17 uncovered by deletions of the normal homologs may be a cause of S-ANLL. The difference between patients with prior hematologic malignancies or solid tumors may be explained by different constitutional mutations of recessive genes in the two groups of patients.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1997

Partially mismatched blood cell transplants for high-risk hematologic malignancy.

Eleven patients with high-risk hematologic malignancy received cryopreserved but otherwise unmanipulated blood cell transplants (BCT) from partially mismatched family members in whom progenitor cells had been mobilized by G-CSF. Donors were mismatched by up to one antigen in the GVH direction and up to three antigens in the rejection direction. Outcomes were compared with those of 22 patients receiving BCT from fully matched donors. Two mismatched patients died without engraftment on day 21 and 32. One had rejected bone marrow from the same donor, the other was mismatched by two antigens in the rejection direction and received the lowest dose of CD34+ cells. Median time to granulocyte engraftment was 21.5 (range 16-33) days for the mismatched group compared with 16 (11-28) days for the matched group (P = 0.01). No correlation was found between CD34+ cell dose and time to granulocyte or platelet recovery. In the mismatched and matched BCT groups respectively, the risk of grade II-IV acute graft-versus-host disease (GVHD) was 73% vs 28% (P = 0.001) and of chronic GVHD 100% vs 78% at 18 months (P = 0.01). The relationship of T cell dose to acute GVHD could only be evaluated in the matched group and no correlation was found. One of 11 mismatched patients and eight of 22 matched patients had relapse or persistent disease. Disease-free survival at 1 year was similar at 55% for mismatched and 50% for matched BCT. These results indicate that allogeneic BCT from partially mismatched family members is accompanied by a high incidence of GVHD but may result in comparable survival to BCT from fully matched donors.

Adolescent↗

PubMed2000

Hematologic malignancies: selected abstracts and commentary.

ASCO 2000 did not offer revolutionary new advances in the treatment of hematologic malignancies. However, reports at the meeting built incrementally on gains established over the past several years. The meeting continued to highlight advances in the targeted therapy of hematologic malignancies. Excitement abounds regarding the clinical development of STI 571, a rationally designed tyrosine kinase inhibitor, for the treatment of chronic myelogenous leukemia. Studies further defined the role monoclonal antibody treatment for non-Hodgkin's lymphoma and more mature data were presented on both unconjugated antibody therapy and radioimmunoconjugates. In disease detection, important data were presented to clarify the role of positron emission tomography scans in the staging and follow-up of lymphoid malignancies. The following review summarizes key abstracts presented at the 2000 ASCO meeting and will elaborate on the implications of these findings for disease management.

Antibodies, Monoclonal↗

PubMed2001

Mutation analysis of the FAS and TNFR apoptotic cascade genes in hematological malignancies.

OBJECTIVE: The existence of properly functioning apoptotic pathways is of utmost importance in the maintenance of a normal cell count. Several groups have searched for mutations in the FAS receptor, a well-characterized apoptotic protein carrying a death domain, and reported the existence of rare mutations in multiple myeloma, T-acute lymphoblastic leukemia (T-ALL), and adult T-cell leukemia. Our aim was to expand these searches by looking for mutations in the death domains of FAS, FADD, TNFR, TRADD, and RIP, in the promoter region of FAS, and in the protease domain of caspase 10, in a larger variety of hematological malignancies, some of which express an apoptosis-resistant phenotype. METHODS: We extracted RNA and DNA samples from 92 hematological malignancies: chronic lymphocytic leukemia (CLL; 31 cases), chronic myelogenous leukemia (CML; 28 cases), essential thrombocythemia (ET; 8 cases), acute lymphocytic leukemia (ALL; 6 cases), acute myeloblastic leukemia (AML; 6 cases), hairy-cell leukemia (HCL; 3 cases), Burkitt's lymphoma (3 cases), polycythemia vera (PV; 3 cases), myelofibrosis (2 cases), and chronic myelomonocytic leukemia (CMML; 2 cases) and performed PCR-SSCP and sequence analysis on these samples. RESULTS: Five polymorphic patterns were found: three in the death domain of the FAS gene in CML patients, one in the promoter of this gene in a CLL patient, and the fifth in the death domain of the TRADD gene in a CML patient. No mutations, altering amino acids, were found in these genes in any of the aforementioned malignancies. CONCLUSIONS: These observations imply that mutations in the death domains of FAS, FADD, TNFR, TRADD, and RIP and in the protease domain of caspase 10 are not a major cause for failure of apoptosis in hematological malignancies, mainly CML and CLL. Regulatory and epigenetic abnormalities in these apoptotic cascade members and aberrations in other components of all death machinery should be looked for.

Apoptosis↗

PubMed2001

Drug resistance in hematologic malignancies.

Drug resistance eventually occurs in most hematologic malignancies treated with chemotherapy. The mechanisms responsible for drug resistance include expression of transporters of xenobiotics of the adenosine triphosphate-binding cassette protein superfamily (P-glycoprotein, multidrug resistance associated proteins, breast cancer resistance protein), modifications of enzymes like deoxycytidine kinase, and defects in chemotherapy-induced apoptosis. The efforts to overcome this drug resistance have been focused, thus far, on modulation of P-glycoprotein. Several compounds were manufactured for this purpose, and phase III trials of PSC833, one of the most potent P-glycoprotein inhibitors, are completed. The emergence of modulators with several adenosine triphosphate-binding cassette protein targets, like GG120918 (inhibiting P-glycoprotein and breast cancer resistance protein) and VX710 (inhibiting P-glycoprotein and multidrug resistance associated protein 1), are of clinical interest in malignancies often expressing several efflux pumps simultaneously. Another approach is the use of "furtive" drugs like liposomal or nanoparticular anthracyclines.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMedDate not supplied

Autologous blood stem cell transplantation as intensive consolidation therapy in hematological malignancies.

Ten consecutive patients (pts), suffering from hematological malignancies (5 NHL, 3 ANLL and 2 HD), received high doses of radio-chemotherapy and autologous peripheral blood stem cell (PBSC) transplantation. Seven of them were in 1st CR, two in 3rd CR and one in refractory status. The recruitment of PBSC was performed during the conventional non-intensive schedule of therapy. The median interval between the remission and the transplant was 6 months (3-15). The pts received a median of 0.96 x10(9) MNC/Kg b.w. and of 3.8 x10(4) CFU-GM/Kg b.w. Hemopoietic recovery occurred promptly and the median number of days to reach WBC greater than 1.0 x10(9)/L was 10 (7-15), PMN greater than 0.5 x10(9)/L was 12 (10-34), platelets greater than 50 x10(9)/L was 13 (10-41) and reticulocytes greater than 20 x10(9)/L was 12 (10-15). Three pts relapsed after 14, 12 and 6 months, respectively. Two of them achieved a further remission and one died. The remaining seven, are alive and disease-free with a follow-up of 11 months (range 2-27).

Adolescent↗

PubMed1986

[Early phase II trial of bestrabucil in hematological malignancies].

Thirty-three patients with various hematological malignancies were treated with Bestrabucil, the benzoate of an estradiol-chlorambucil conjugate, at doses of 50-300 mg daily p.o., consecutively. Nineteen patients had previously received chemotherapy. Of 29 evaluable patients, there were one CR and three PRs among 6 patients with chronic lymphocytic leukemia, two CRs and one PR among 4 patients with malignant lymphoma, two PRs among 3 patients with adult T-cell leukemia, one PR among 4 patients with macroglobulinemia, one PR for one patient with essential thrombocythemia, and one PR for a patient with chronic myelocytic leukemia. Main side effects included G1 symptoms (14%), estradiol-related symptoms (24%) and myelosuppression (32%).

Adult↗

PubMed1983

[Phase II study with methyl-6[[[2-chloroethyl) nitrosoamino] carbonyl] amino]-6-deoxy-alpha-D-glucopyranoside (MCNU) in hematological malignancies].

A total of 117 cases with hematological malignancies were treated with MCNU at doses of 70-100 mg/m2. Following are the results obtained. 1. MCNU showed a marked depression of cells in the cases with CML, polycythemia vera and thrombocythemia. The low level of cells was maintained for 2 to 7 months. 2. A good response was observed in several cases with blastic crises of CML. 3. No response was observed in two cases with acute leukemia. 4. Although a fair response was observed in several cases with malignant lymphoma or multiple myeloma, moderate bone marrow suppression was observed in a majority of the cases.

Adult↗

PubMed1994

Applications of in situ hybridization in the study of hematologic malignancies.

In situ hybridization is a molecular technique that can be useful in the study of hematologic malignancies. Thus far, the most extensive uses have been in the detection of viral sequences and in the detection of chromosomal alterations. Other applications such as the identification of various cellular gene products are more limited, but with improvements in the sensitivity and reliability of methods for ISH, their use will become more widespread. Information provided by ISH contributes to our understanding of the pathophysiology and etiology of hematologic malignancies. In the future, ISH may be used routinely in the evaluation of leukemias and lymphomas.

DNA, Viral↗

PubMed1990

Serum deoxythymidine kinase as a progressive marker of hematological malignancy.

The levels of serum deoxythymidine kinase (s-dTK) were investigated for 127 patients suffering hematological malignancy by a sensitive method using [125I]-iododeoxy-uridine as substrate. It was found that the deoxythymidine kinase activity in the sera of these patients was higher than the normal levels in adults. It was also found that the levels of s-dTK in the progressive stage were much higher than those in the indolent stage. These results suggest that high levels of s-dTK in hematological malignancy may reflect the extent of disease and that this activity may be derived from proliferating leukemic cells. The deoxythymidine kinase activity in the extracts derived from cultured cell lines and clinical specimens indicated that leukemic cells contained much higher activity than normal cells.

Biomarkers, Tumor↗

PubMed2003

Invasive aspergillosis in patients with hematologic malignancies.

Invasive aspergillosis is an increasingly common and often fatal opportunistic fungal infection in patients with hematologic malignancies. Prolonged and profound neutropenia remains a key risk factor for the development of invasive aspergillosis. However, qualitative deficiencies in host immune responses resulting from prolonged corticosteroid therapy, graft-versus-host disease, and cytomegalovirus infection are important risk factors for the recurrence and progression of Aspergillus infections after bone marrow recovery. Early diagnosis of invasive aspergillosis remains a challenge, and few tools are available for monitoring its course once the diagnosis is established. Even with the recent introduction of new antifungal therapies, mortality in patients with invasive aspergillosis remains high, and uniformly effective prophylaxis or preemptive therapeutic strategies are lacking. Strategies such as combination antifungal therapy and immunotherapy often are used as first-line treatment approaches in patients with documented invasive aspergillosis despite a paucity of clinical trial data. Recent advances in our understanding of the epidemiology, pathogenesis, and treatment of invasive aspergillosis in patients with hematologic malignancies are reviewed. The problems and controversies associated with defining optimal treatment strategies for invasive aspergillosis in this heavily immunocompromised population are highlighted.

Antifungal Agents↗

PubMed2001

[The minimal residual disease (MRD) in hematological malignancies].

Molecular genetic and cytoimmunological markers have been applied for the detection of minimal residual disease (MRD) in hematological malignancies. These markers include surface markers or rearranged T-cell receptor and immunoglobulin genes in the lymphoid malignancies and fused genes associated with chromosomal translocations such as BCR-ABL in t(9;22) or PML-RAR alpha in t(15;17) in myeloid malignancies. The expression of the WT1 gene is recognized as the universal tumor marker for a wide variety of hematological malignancies. Using these sensitive markers, a tumor cell in 10,000 to 1,000,000 normal cells can be detected. By examining a large number of patients, it has been shown that the MRD in the early phase of chemotherapy has a correlation with the prognosis of childhood ALL. Based on these observations, a new strategy of chemotherapy in which the post-remission therapy is modified based on the MRD results has begun. The amount of tumor cells contaminated in the autologous stem cell grafts in ALL patients might be related to the prognosis. The diagnosis of MRD will be used as an important routine examination in chemotherapy for leukemia/lymphoma patients.

Adult↗

PubMed2006

Retrospective analysis of cord blood transplantation on 62 adult patients with advanced hematological malignancies.

The Japan Cord Blood Network was established in 1999 and 8 institutions from the Kyushu Hematology Organization Study Group had performed cord blood transplantation (CBT) 67 times on 62 patients with advanced hematological malignancies from 1999 to 2004, which included acute and chronic leukemias in 34 patients, non-Hodgkin's lymphoma in 14, adult T-cell leukemia in 11 and others in 3 patients. The median age was 44 and disease status was no remission on 50 patients prior to CBT. Myeloablative conditioning regimens were used in 27 patients while 35 patients received non-myeloablatives. Engraftment could not be determined in 25 patients and the median survival time was 70 days. Thirteen patients were alive from 288 to 1277 days and 49 had been expired. The causes of death were the underlying disease in 19 patients, severe infection in 14 and graft-versus-host disease in 3 and miscellaneous in the remaining patients. This retrospective study shows that some patients with far-advanced hematological malignances could be successfully treated with CBT at the expense of many early deaths due to early relapse and severe infection. It is of importance that the appropriate indication for CBT should be discussed between transplant experts and patients and their families in each case.

Adolescent↗

PubMed1995

[Outcome and cost of mechanical ventilation in patients with inoperable solid tumors and hematologic malignancies].

The application of mechanical ventilation can be life-saving in patients with acute respiratory failure, but is frequently ineffective in terminally ill patients. To analyze the outcome and cost of mechanical ventilation for patients with malignancies, we retrospectively reviewed 115 patients with inoperable solid tumors or hematologic malignancies who received mechanical ventilation. Eighty eight of these 115 patients (77%) died while on mechanical ventilation; 18 patients (16%) were weaned from mechanical ventilation but still died during their hospitalization. Six patients (5%) were discharged but survived less than 3 months and only three patients (3%) survived for more than 3 months after discharge. The total time of mechanical ventilation was 772 person-days, which represented 5.5% (772/13974) of the total mechanical ventilator use in our hospital in 1993. The total hospital cost from initiation of mechanical ventilation to discharge or death of these 115 patients was NT $11,238,022 (US $432,200) and daily hospital cost per person during mechanical ventilation was approximately NT $10,845 (US $420). The "daily cost of discharge survival" (defined as total hospitalization cost from the initiation of mechanical ventilation to discharge or death divided by total discharge person-days) for patients with inoperable solid tumors was NT $73,421 (US $2,820)/per person-day. We concluded that mechanical ventilation should not be routinely used in patients with inoperable solid tumors and hematologic malignancies. Physicians should explain the poor outcome to these patients and their families in advance and inquire about their willingness to forego mechanical ventilation.

Aged↗

PubMed1987

[Clinical studies on cefoperazone and polymyxin B for the treatment of infections in patients with hematological malignancies].

Cefoperazone (CPZ) was used for the treatment of 20 febrile episodes in 18 patients with hematological malignancies and polymyxin B (PL) was applied to the antimicrobial decontamination of the digestive tract in 9 patients with acute leukemia during remission induction therapy. The clinical evaluation of effectiveness was as follows: Excellent in 9 patients (45%), good in 6 patients (30%) and poor in 5 patients (25%). In neutropenic patients the overall efficacy rate was 70%. Side effects were recognized in 3 patients. Allergic reactions such as eruption and eosinophilia were seen and transient liver dysfunction was recognized. This study indicates that CPZ is effective for the treatment of infections in patients with hematological malignancies.

Adult↗

PubMed2003

Reduced-intensity allogeneic stem cell transplantation for patients whose prior autologous stem cell transplantation for hematologic malignancy failed.

Autologous hematopoietic stem cell transplantation (autoSCT) is an effective treatment for patients with various hematologic malignancies. Despite the significant improvement in the overall outcome, disease progression after transplantation remains the major cause of treatment failure. With longer follow-up, therapy-related myelodysplasia/acute myelogenous leukemia is becoming an important cause of treatment failure. The prognosis for these 2 groups of patients is very poor. Allogeneic hematopoietic stem cell transplantation (alloSCT) is a potential curative treatment for these patients. However, the outcome with conventional myeloablative alloSCT after failed autoSCT is typically poor because of high transplant-related mortality. In an attempt to reduce the treatment-related toxicity, we studied a reduced-intensity conditioning regimen followed by alloSCT for patients with progressive disease or therapy-related myelodysplasia/acute myelogenous leukemia after autoSCT. This report describes the outcomes of 28 patients with hematologic malignancies who received a reduced-intensity alloSCT after having treatment failure with a conventional autoSCT. Fourteen patients received a hematopoietic stem cell transplant from a related donor and 14 from an unrelated donor. The conditioning regimen consisted of low-dose (2 Gy) total body irradiation with or without fludarabine in 4 patients and the combination of melphalan (140 mg/m(2)) and fludarabine in 24. Cyclosporine and mycophenolate mofetil were used for posttransplantation immunosuppressive therapy, as well as graft-versus-host disease (GVHD) prophylaxis, in all patients. All patients engrafted and had >90% donor chimerism on day 100 after SCT. Currently, 13 patients (46%) are alive and disease free, 7 patients (25%) developed disease progression after alloSCT, and 8 (32%) died of nonrelapse causes. Day 100 mortality and nonrelapse mortality were 25% and 21%, respectively. With a median follow-up of 24 months for surviving patients, the 2-year probabilities of overall survival, event-free survival, and relapse rates were 56.5%, 41%, and 41.9%, respectively. Six patients (21%) developed grade III to IV acute GVHD. Among 21 evaluable patients, 15 (67%) developed chronic GVHD. We conclude that (1) reduced-intensity alloSCT is feasible and has an acceptable toxicity profile in patients who have previously received autoSCT and that (2) although follow-up was short, a durable remission may be achieved in some patients who would otherwise be expected to have a poor outcome.

Adult↗