melphalan and Leukemia--Lymphocytic--Chronic--B-Cell

Autologous stem cell transplantation (ASCT) has been intensively investigated for treatment of patients with chronic lymphocytic leukemia (CLL) during recent years. To assess the potential therapeutic value of ASCT for CLL, the present article aims at answering the following crucial questions: (1) Does ASCT have curative potential? (2) What is the therapeutic potential of ASCT in terms of disease control in relation to toxicity? (3) What is the role of ASCT in the current arsenal of CLL treatment modalities? Evidence from clinical and minimal residual disease (MRD) studies suggests that ASCT has curative potential in only a few patients, if any. Nevertheless, ASCT might be capable of prolonged disease control even in CLL with poor-risk features. Uncontrolled prospective studies have indicated the superiority of ASCT over alkylator and fludarabine monotherapy but not necessarily over purine analogue cyclophosphamide or antibody combinations. A significant risk of secondary neoplasms, in particular myelodysplasias, has to be taken into account. Therefore, ASCT cannot be considered as standard treatment for CLL and should be performed only in the context of clinical trials.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Purging; Bone Marrow Transplantation; Carmustine; Combined Modality Therapy; Cytarabine; Dexamethasone; Etoposide; Evidence-Based Medicine; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Melphalan; Neoplasm, Residual; Neoplasms, Second Primary; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome; Whole-Body Irradiation

The importance of early therapy intensification in B-cell CLL (B-CLL) patients remains to be defined. Even though several studies have been published, no randomized trials comparing directly autologous stem cell transplant (ASCT) and the accepted conventional therapy (that is, rituximab, fludarabine and CY; R-FC) have been reported so far. To assess the benefit of a first-line aggressive therapy, we designed a multicenter, randomized, phase 3 trial comparing R-FC and high-dose chemotherapy supported by ASCT in patients under 65 years of age, with stage B(II) or C B-CLL. Primary end point was CR: 96 patients were enrolled (48 in each arm). On an intent-to-treat basis, the CR rates in the ASCT and R-FC arms were 62.5% and 58%, respectively. After 5 years of follow-up, PFS was 60.4% in the ASCT arm and 65.1% in the R-FC arm, time to progression 65.8 and 70.5%, and overall survival 88% vs 88.1%, respectively. Our trial demonstrates, for the first time in a randomized manner, that frontline ASCT does not translate into a survival advantage when compared with benchmark chemoimmunotherapy in B-CLL patients; the possibility of its clinical benefit in certain subgroups remains uncertain.

Topics: Adult; Aged; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Cytarabine; Doxorubicin; Female; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Melphalan; Middle Aged; Prednisone; Prospective Studies; Rituximab; Transplantation, Autologous; Vidarabine; Vincristine

Allogeneic stem cell transplant (SCT) after high-dose conditioning with BEAM/fludarabine/total body irradiation (TBI) in patients with relapsed or refractory lymphoma has shown promising results in a pilot study. In this trial, we treated 50 consecutive patients with refractory or relapsed lymphoma or chronic lymphocytic leukemia (CLL). The patients included were considered to have poor-prognosis disease (eg, one-third was chemo-refractory at transplantation and more than one-half had failed previous autologous or allogeneic SCT). All patients engrafted and achieved full donor chimerism. Grade II-IV acute graft-versus-host disease (aGVHD) occurred in 64% of patients (95% confidence interval [CI], 52% to 79%), and chronic GVHD (cGVHD) in 51% (95% CI, 36% to 66%). At 3 years, overall survival was 61% (95% CI, 46% to 75%). Progression-free survival was 55% (95% CI, 40% to 70%), with 30% (95% CI, 19% to 47%) transplantation-related mortality and a relapse incidence of 15% (95% CI, 7% to 32%). Disease classification and stage as well as remission status at transplantation and type of previous treatment (including previous SCT) had no significant impact on transplantation outcome. In conclusion, allogeneic SCT after BEAM/fludarabine/TBI provides excellent tumor control with complete and durable remissions in patients with poor-prognosis lymphoma and CLL. High rates of GVHD and GVHD-related mortality associated with this regimen are a major concern and warrant modification of the regimen in the future.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cytarabine; Disease-Free Survival; Female; Graft vs Host Disease; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma; Melphalan; Middle Aged; Myeloablative Agonists; Podophyllotoxin; Recurrence; Stem Cell Transplantation; Survival Rate; Transplantation Conditioning; Transplantation, Homologous; Vidarabine; Whole-Body Irradiation

Myeloablative radio-chemotherapy with subsequent autologous stem cell transplantation (ASCT) significantly prolongs progression free and probably overall survival in follicular lymphoma (FL) in first remission. The current trial explored prospectively the rate of successful stem cell mobilization in patients with advanced stage FL after initial therapy with either Mitoxantrone, Chlorambucil, Prednisone (MCP) or Cyclophosphamide, Doxorubicin, Vincristine, Prednisone (CHOP) as part of a prospective randomized comparison of both regimens. ASCT patients received Dexa-BEAM (Dexamethasone, BCNU, Melphalan, Etoposide, Cytarabine) for mobilization of stem cells. Stem cells were collected and a minimum of 2x2.0x106/kg bw CD34+ was required for ASCT. Of 79 evaluable patients, 58 (73%) had follicular lymphoma, 13 (16%) mantle cell lymphoma and 8 (10%) lymphoplasmacytic lymphoma. In the 45 patients assigned to CHOP, stem cell collection was successful in 42 cases (93%, 95% CI 82% to 99%). This high mobilization rate after CHOP could be confirmed in 61 subsequent patients (87%). In contrast, after MCP therapy stem cell collection was successful in only 15 of 34 patients (44%, 95% CI 27% to 62%; P=0.0003). In conclusion, initial therapy with MCP significantly impairs the ability to collect stem cells and should be avoided for first line therapy of younger patients potentially qualifying for high dose consolidation and ASCT in first remission.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Chlorambucil; Cyclophosphamide; Cytarabine; Dexamethasone; Doxorubicin; Etoposide; Female; Germany; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Follicular; Lymphoma, Mantle-Cell; Male; Melphalan; Middle Aged; Mitoxantrone; Prednisolone; Prednisone; Prospective Studies; Survival Rate; Treatment Outcome; Vincristine

CBV and BEAM are the two most frequently used regimens for patients with lymphoma undergoing autologous hematopoietic stem-cell transplantation (ASCT). This study compared their morbidity and transplant-related mortality (TRM) in 113 patients with non-Hodgkin's lymphoma (69) and Hodgkin's disease (44) undergoing ASCT between 1990 - 2004. CBV (cyclophosphamide, 6000 mg m(-2); VP-16, 750 mg m(-2); and high-dose BCNU, 800 mg m(-2)) was administered to 75 patients and 38 received BEAM (BCNU, 300 mg m(-2); VP-16, 800 mg m(-2); cytarabine, 800 mg m(-2); melphalan, 140 mg m(-2)). Patients in the BEAM group had a significantly higher median age (p = 0.002) and were more heavily treated before ASCT (p = 0.003). More patients showed active disease at transplant in the BEAM group (p = 0.04). Sinusoidal obstruction syndrome (SOS) was more frequent in the CBV group (11% vs 0%, p = 0.048). There were 20 (18%) transplant-related deaths, 18 in the CBV and two in the BEAM group. Infectious complications (12 patients, seven with pneumonia) and SOS (four) were the most frequent causes of death. The cumulative incidences of TRM were 25% in the CBV and 7% in the BEAM group (p = 0.02). CBV thus produced a higher incidence of SOS and TRM than BEAM in this series.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cyclophosphamide; Cytarabine; Etoposide; Female; Hematopoietic Stem Cell Transplantation; Hepatic Veno-Occlusive Disease; Humans; Infections; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Lymphoid; Male; Melphalan; Middle Aged; Morbidity; Mortality; Podophyllotoxin; Transplantation Conditioning; Transplantation, Autologous

B-cell chronic lymphocytic leukaemia (CLL) cannot be cured by conventional therapy. To improve the prognosis of patients with CLL, we have designed a sequential treatment strategy that comprises intensive chemotherapy for mobilization of peripheral blood progenitor cells (PBPCs) and induction of minimal disease, followed by high-dose radiochemotherapy with stem cell reinfusion and post-transplant molecular monitoring by polymerase chain reaction (PCR) amplification of the complementary determining region III (CDRIII) gene. In a prospective study, we have evaluated this protocol in 18 patients with CLL, also including early stages of the disease. The median age was 49 (29-61) years; Binet stages were A, six; B, nine; and C, three. Adverse prognostic factors [high lymphocyte count and/or diffuse bone marrow (BM) infiltration] were present in 16 out of 18 patients. All patients showed a clone-specific molecular marker as demonstrated by PCR amplification of CDRIII rearrangements. For stem cell mobilization and reduction of tumour load, one to two cycles of Dexa-BEAM chemotherapy were administered, resulting in minimal disease (circulating lymphoma cells <1 x 10(9) l(-1); BM infiltration <20%; lymphomas <2 cm) in 16 out of 18 patients, including four patients who already had minimal disease before Dexa-BEAM. Stem cell harvesting was successful in 14 patients. All grafts [three BM, 11 peripheral blood (PB)] were purged from leukaemic cells using immunomagnetic methods. Thirteen patients having achieved minimal disease were reinfused with purged autologous stem cells (ASC) after preparation with total body irradiation and cyclophosphamide. Engraftment was delayed in patients receiving BM (n = 3) but prompt [neutrophils >0.5 x 10(9) l(-1) after 10 (9-13) days, platelets >20 x 10(9) l(-1) after 11 (9-214) days] in patients restored with PBPCs (n = 10). Procedure-related deaths did not occur. Although the results of CDRIII PCR suggest persistence or recurrence of the leukaemic clone in at least three cases, to date only one patient has relapsed, whereas all others survive without clinical evidence of disease with a maximum follow-up of 48 months. We conclude that sequential high-dose therapy using Dexa-BEAM and autologous stem cell transplantation is a safe and highly effective treatment for patients with CLL. However, a longer follow-up is needed to assess whether definite cures can be achieved using this strategy.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Chlorambucil; Cisplatin; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Dexamethasone; Dose-Response Relationship, Drug; Doxorubicin; Etoposide; Female; Fluorouracil; Follow-Up Studies; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Humans; Hydrocortisone; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Melphalan; Methotrexate; Methylprednisolone; Middle Aged; Mitomycins; Prednisone; Prospective Studies; Treatment Outcome; Vincristine

The effect of methylprednisolone on fresh cells from patients with chronic lymphocytic leukaemia (CLL) has been studied using the differential staining cytotoxicity (DiSC) assay resulting in LC90s of < or = 0.2 to 2,000 micrograms/ml. Cells from previously treated patients were, on average, significantly more sensitive to methylprednisolone than those from untreated patients (mean LC90 = 5.7 micrograms/ml, n = 61 vs 31.0 micrograms/ml, n = 17, respectively; p < 0.05). Twelve patients with advanced disease were given high-dose methylprednisolone (1 g/m2/day i.v. x 5 days). In 7 cases, > or = 3 courses were given; 3 patients did not respond (2 achieved palliation) and 4 (57%) achieved a good partial response. These latter 4 patients were all clinically resistant to chlorambucil and anthracyclines and 2 were resistant to fludarabine. In 5 cases, 1 or 2 courses were given but no patients responded. The 8 nonresponders survived a median of 3.5 months whilst the responders have survived a median of 28.5+ months (3 of 4 still alive). This work suggests a rationale for why CLL patients resistant to standard chemotherapy may benefit from high-dose methylprednisolone therapy. Due to cost and toxicity associated with therapy, the decision to treat would be best made on the basis of a DiSC assay result. This pilot study requires confirmation with a well-designed controlled clinical trial.

Topics: Adult; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Cell Survival; Chlorambucil; Cyclophosphamide; Doxorubicin; Drug Resistance; Drug Screening Assays, Antitumor; Fatal Outcome; Female; Humans; Ifosfamide; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Melphalan; Methylprednisolone; Middle Aged; Neoplastic Stem Cells; Palliative Care; Pilot Projects; Prednisolone; Prednisone; Remission Induction; Staining and Labeling; Survival Analysis; Treatment Outcome; Tumor Cells, Cultured; Vidarabine; Vinca Alkaloids; Vincristine

Forty-five patients suffering from advanced B-CLL were randomized to receive interferon-alpha (IFN alpha) or no treatment after achieving complete remission or partial response, following a chemotherapy protocol called MiNa. The two groups were fully comparable in terms of clinical characteristics and level of response obtained by chemotherapy. IFN alpha was given at a dose of 3 megaunits three times a week intramuscularly for 1 year. The IFN-treated patient group showed a significantly longer duration of response and a less frequent incidence of infections as compared to the no treatment group. A minority of patients who had had partial response to chemotherapy obtained complete remission while on therapy with IFN alpha. Toxicity was mild and patient compliance was excellent. We conclude that IFN alpha may have a role as maintenance therapy in CLL for patients responding to chemotherapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Dose-Response Relationship, Drug; Female; Humans; Incidence; Injections, Intramuscular; Interferon alpha-2; Interferon-alpha; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Melphalan; Middle Aged; Neoplasm Staging; Peptichemio; Prednisone; Recombinant Proteins; Vincristine

Ninety-six previously untreated patients (67 males/29 females; mean age: 63 years; range: 46-84) with CLL in stage B (62 cases) or C (34 cases) were randomized to be treated with either chlorambucil (0.4 mg/kg orally days 5 and 6) plus prednisone (60 mg/m2 orally days 1 to 4) (CL + PDN) every 2 weeks or cyclophosphamide (160 mg/m2 orally days 1 to 4), melphalan (6 mg/m2 orally days 1 to 4), and prednisone (60 mg/m2 orally days 1 to 4) (CMP) every 3 weeks for 10 months. Forty-eight patients were treated with CLR + PDN, and the remaining 48 with CMP. The following types of response were considered: complete response (CR): total disappearance of symptoms and signs related to the disease. Partial response (PR): shift of the disease to a less advanced stage. Stable disease (SD) no change in the stage after treatment. Progressive disease (PD): progression of the disease to a more advanced stage. Thirty-six (75%) responses (27% CR) with CLR + PDN and 26 (54.5%, 12.5% CR) with CMP were observed (p = 0.054). Although more responses were achieved in stage B (69%, 24% CR) than in stage C (54%, 12% CR) this difference did not achieve statistical significance. Survival was statistically not different for those patients treated with LCR + PDN as compared to those receiving CMP.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Chlorambucil; Clinical Trials as Topic; Cyclophosphamide; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Melphalan; Middle Aged; Neoplasm Staging; Prednisone; Random Allocation; Spain

The optimal dose intensity for conditioning prior to allogeneic hematopoietic stem cell transplantation (alloHSCT) for chronic lymphocytic leukemia (CLL) is unknown.. We retrospectively compared outcomes of patients who received a first alloHCST after non-myeloablative (NMA) and reduced intensity conditioning (RIC). Data of 432 patients with a median age of 55 years were included, of which 86 patients underwent NMA and 346 RIC.. The median follow-up after alloHSCT was 4.3 years. Compared to the RIC group, more NMA patients had purine-analog-sensitive disease, were in complete remission and received matched related donor transplantation. After RIC, the probabilities for 5-year OS, EFS, CIR, and NRM were 46%, 38%, 28%, and 35% and after NMA the respective probabilities were 52%, 43%, 25%, and 32%. In multivariate analysis, remission status prior to conditioning but not RIC versus NMA conditioning had a significant impact on CIR, EFS, and OS.. Presumed higher anti-leukemic activity of RIC versus NMA conditioning did not translate into better outcomes after alloHSCT, but better remission status prior to conditioning did. Effective pathway inhibitor-based salvage therapies combined with NMA conditioning might thus represent the most attractive contemporary approach for alloHSCT for patients with CLL.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Combined Modality Therapy; Cyclophosphamide; Female; Follow-Up Studies; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Incidence; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Melphalan; Middle Aged; Prognosis; Remission Induction; Retrospective Studies; Survival Rate; Transplantation Conditioning; Transplantation, Homologous; Young Adult

Topics: Aged, 80 and over; Anemia, Hemolytic, Autoimmune; Antigens, CD; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Bortezomib; Clonal Evolution; Clone Cells; Cyclophosphamide; Dexamethasone; Disease Progression; Female; Humans; Immunosuppressive Agents; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Plasma Cell; Lymphocytosis; Melphalan; Prednisolone; Rituximab

Haploidentical transplantation (Haplo-SCT) with post-transplantation cyclophosphamide (PTCy) is increasingly utilized for the treatment of lymphoma and almost exclusively with the nonmyeloablative fludarabine (Flu)/cyclophosphamide/total body irradiation (TBI) conditioning regimen. We present early results of a reduced-intensity (RIC) regimen utilizing fludarabine and melphalan (FM) for the treatment of advanced lymphoma. All patients with a diagnosis of lymphoma or chronic lymphocytic leukemia (CLL) who received Haplo-SCT at the University of Texas MD Anderson Cancer Center between 2009 and 2014 were reviewed (N = 22). Patients received Flu 160 mg/m(2) and melphalan 100 mg/m(2) to 140 mg/m(2) with thiotepa 5 mg/kg or 2 Gy TBI. Because of concerns of increased treatment-related mortality (TRM) with the melphalan 140 mg/m(2) regimen (FM140), a RIC regimen with melphalan 100 mg/m(2) (FM100) was devised. Rituximab was included for CD20(+) disease. Graft-versus-host disease prophylaxis consisted of PTCy 50 mg/kg on days +3 and + 4, tacrolimus, and mycophenolate mofetil. Sixty-eight percent of all patients were not in complete remission at the time of transplantation. The 2-year progression-free survival (PFS) and overall survival (OS) for the entire cohort were 54%, 1-year TRM was 19%, and the cumulative incidence of relapse at 2 years was 27%. Two-year PFS for Hodgkin lymphoma, non-Hodgkin lymphoma, and CLL/small lymphocytic lymphoma were 57%, 51%, and 75%. Patients treated with FM100 compared to FM140 had equivalent PFS (71% versus 37%, P = .246) and OS (71% versus 58%, P = .32). These early results establish Flu and melphalan 100 mg/m(2) with 2 Gy TBI or thiotepa 5 mg/kg as a very promising conditioning regimen for the treatment of advanced lymphoma with Haplo-SCT and PTCy.

Topics: Adult; Allografts; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma; Male; Melphalan; Middle Aged; Rituximab; Transplantation Conditioning

Chronic lymphatic leukemia (CLL) is often associated with nephritic syndrome. Effective treatment of CLL by chlorambucil and bendamustine leads to the restoration of renal function. In this contribution, we sought to elucidate the impact of organic anion transporters (OATs) on the uptake of bendamustine and chlorambucil as a probable reason for the superior efficacy of bendamustine over chlorambucil in the treatment of CLL. We examined the effects of structural analogs of p-aminohippurate (PAH), melphalan, chlorambucil, and bendamustine, on OAT1-mediated [(3)H]PAH uptake and OAT3- and OAT4-mediated [(3)H]estrone sulfate (ES) uptake in stably transfected human embryonic kidney-293 cells. Melphalan had no significant inhibitory effect on any OAT, whereas chlorambucil reduced OAT1-, OAT3-, and OAT4-mediated uptake of PAH or ES down to 14.6%, 16.3%, and 66.0% of control, respectively. Bendamustine inhibited only OAT3-mediated ES uptake, which was reduced down to 14.3% of control cells, suggesting that it interacts exclusively with OAT3. The IC50 value for OAT3 was calculated to be 0.8 μM. Real-time PCR experiments demonstrated a high expression of OAT3 in lymphoma cell lines as well as primary CLL cells. OAT3-mediated accumulation of bendamustine was associated with reduced cell proliferation and an increased rate of apoptosis. We conclude that the high efficacy of bendamustine in treating CLL might be partly contributed to the expression of OAT3 in lymphoma cells and the high affinity of bendamustine for this transporter.

Topics: Antineoplastic Agents, Alkylating; Apoptosis; Bendamustine Hydrochloride; Cell Proliferation; Chlorambucil; Dose-Response Relationship, Drug; Estrone; HEK293 Cells; Humans; Jurkat Cells; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, T-Cell; Melphalan; Nitrogen Mustard Compounds; Organic Anion Transport Protein 1; Organic Anion Transporters, Sodium-Independent; p-Aminohippuric Acid; Transfection; Tumor Cells, Cultured

A captive 3-yr-old male dhole (Cuon alpinus) was presented for poor body condition. Pancytopenia concurrent with bone marrow aspiration that revealed severe medullary infiltration by a population of initially small lymphocytes was diagnostic of an aleukemic chronic lymphocytic leukemia. Chemotherapy was initiated, but euthanasia was elected after the animal's rapid deteriorating condition and sudden lymphoid organs hypertrophy several days after initial presentation. Histology revealed lymphoid organs and bone marrow infiltration by highly proliferating immature lymphocytes compatible with a blast crisis. On immunohistochemistry, neoplastic cells appeared CD3 positive, confirming a T lymphoid origin. This is the first report of a lymphocytic leukemia in a wild canid species.

Topics: Animals; Canidae; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Melphalan; Prednisolone

A 56-year-old married female presented in May 1998 with a 5-month history of xanthelasma of the eyelids, followed 4 months later by two enlarged lymph nodes of the left side of the neck and three of the left axilla. At the same time, she developed xanthomatous patches on the face, neck, and shoulders (Fig. 1). The cutaneous lesions were xanthomatous nodules and plaques, affecting the periorbital regions. Later, the whole face was affected, followed by ulcerated lesions on the scalp, chest, back, and extremities (Fig. 2). The skin lesions became painful, pruritic, ulcerated tumors (Fig. 3). In July 1998, computed tomography (CT) scans of the chest and abdomen with contrast medium showed pretracheal, bilateral axillary, right retrochural, paracaval, aortocaval, and para-aortic lymph node enlargement. These findings were suggestive of lymphoma. CT scan also showed slight heterogeneous hypodensity in the upper part of the right lobe of the liver, suggesting fatty infiltration. The spleen, pancreas, and suprarenal glands appeared normal. One cervical and two left axillary lymph nodes were excised. They revealed total replacement of the nodular architecture by a diffuse proliferation of mature lymphoid cells having small nuclei and a crumbled chromatin pattern, and very rare mitosis. It was concluded from the lymph node biopsies that these changes were typical of non-Hodgkin's lymphoma, diffuse and small cell type, of low-grade malignancy. A bone marrow aspirate showed a marrow heavily infiltrated by lymphoid cells with some immaturity. The megakaryopoiesis was adequate. Trephine biopsies showed similar changes. Iron stores appeared to be absent. The bone marrow picture was consistent with diffuse, well-differentiated non-Hodgkin's lymphoma, developing into chronic lymphocytic leukemia (CLL). Endoscopy showed antral-type gastric mucosa exhibiting mild chronic gastritis. Skin biopsy from a fresh lesion on the back showed a diffuse inflammatory cell infiltrate with collections of histiocytic cells. It also showed necrobiotic foci, surrounded by mixed inflammatory cells, dark palisaded foamy histiocytes, and a few Touton giant cells. These findings are compatible with necrobiotic xanthogranuloma (NXG) (Figs 4 and 5). Blood film showed normochromic, normocytic erythrocytes with anisopoikilocytotic leukocytes and normal platelets. The sedimentation rate was 90 mm in the first hour. The blood picture also showed monoclonal IgG paraprotein (3170 mg/dL) of the kappa li

Topics: Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Chlorambucil; Cyclophosphamide; Female; Glucocorticoids; Granuloma; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Non-Hodgkin; Melphalan; Middle Aged; Necrobiotic Disorders; Paraproteinemias; Skin Diseases; Treatment Failure; Treatment Outcome; Xanthomatosis

Topics: Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal, Murine-Derived; Antibodies, Neoplasm; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cell Transformation, Neoplastic; Cyclophosphamide; Cytarabine; Doxorubicin; Hematopoietic Stem Cell Transplantation; Humans; Immunotherapy, Adoptive; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphocyte Transfusion; Melphalan; Podophyllotoxin; Prednisone; Remission Induction; Rituximab; Time Factors; Vincristine

Three adult dogs with chronic lymphocytic leukaemia (CLL) were successfully treated with melphalan and prednisolone. Based on the immunophenotypic analysis of leukaemic cells, two dogs were diagnosed with B cell CLL and one dog was tentatively diagnosed as having T cell CLL. One dog with B cell CLL had IgM monoclonal gammopathy. The clinical signs and haematological abnormalities associated with CLL in the three dogs improved with the administration of cytoreductive melphalan (3 to 5 mg/m2/day) and prednisolone (4.3 to 30 mg/m2/day) for eight to 210 days. There were no severe adverse effects except a mild increase in plasma alkaline phosphatase activity. Melphalan and prednisolone therapy may achieve remission with few side effects in dogs with CLL.

Topics: Animals; Antineoplastic Agents, Alkylating; Blood Cell Count; Blood Chemical Analysis; Blood Platelets; Diagnosis, Differential; Dog Diseases; Dogs; Drug Therapy, Combination; Female; Glucocorticoids; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphocytes; Male; Melphalan; Prednisolone

B-cell chronic lymphocytic leukaemia (B-CLL) can be divided into two clinical entities based on the immunoglobulin variable heavy chain (VH) gene mutation status, as cases with unmutated VH genes display a more aggressive disease with shorter survival time than mutated cases. The aim of this study was to investigate whether differences in cellular drug resistance could give an explanation for these divergent clinical courses.. The VH gene mutation status was analysed in patients with previously untreated B-CLL using VH gene family-specific PCR amplification and nucleotide sequencing. In vitro sensitivity to cytarabine, fludarabine, cladribine, doxorubicin, idarubicin, vincristine, cyclophosphamide, melphalan and prednisolone was assessed using the non-clonogenic in vitro assay, fluorometric microculture cytotoxicity assay.. The VH genes and in vitro drug resistance were successfully analysed in 46 cases, revealing that 25 (54%) cases showed unmutated and 21 (46%) cases mutated VH genes. Interestingly, the unmutated group generally tended to be more chemosensitive than the mutated group with significant differences for cytarabine and prednisolone (P < or = 0.01).. The propensity of inferior drug response in mutated B-CLL may reflect a more differentiated disease than in unmutated B-CLL. We conclude that the difference in prognosis between B-CLL cases with unmutated and mutated VH genes could not be explained by difference in cellular drug resistance.

Topics: Antineoplastic Agents; Cell Differentiation; Cell Line, Tumor; Cladribine; Cyclophosphamide; Cytarabine; DNA Mutational Analysis; Doxorubicin; Drug Resistance, Neoplasm; Gene Rearrangement, B-Lymphocyte, Heavy Chain; Genes, Immunoglobulin; Humans; Idarubicin; Immunoglobulin Heavy Chains; Immunoglobulin Variable Region; Leukemia, Lymphocytic, Chronic, B-Cell; Life Tables; Melphalan; Prednisolone; Survival Analysis; Vidarabine; Vincristine

Nucleoside derivatives are currently used in the treatment of hematologic malignancies. Although intracellular events involved in the pharmacologic action of these compounds have been extensively studied, the role of plasma membrane transporters in nucleoside-derived drug bioavailability and action in leukemia cells has not been comprehensively addressed. We have monitored the amounts of mRNA for the 5 nucleoside transporter isoforms cloned so far (CNT1, CNT2, CNT3, ENT1, and ENT2) in several human cell types and in normal human leukocytes. We then examined the expression patterns of these plasma membrane proteins in patients with chronic lymphocytic leukemia (CLL) and correlated them with in vitro fludarabine cytotoxicity. Despite a huge individual variability in the mRNA amounts for every transporter gene expressed in CLL cells (CNT2, CNT3, ENT1, and ENT2), no relationship between mRNA levels and in vitro fludarabine cytotoxicity was observed. Fludarabine accumulation in CLL cells was mostly, if not exclusively, mediated by ENT-type transporters whose biologic activity was clearly correlated with fludarabine cytotoxicity, which reveals a role of ENT-mediated uptake in drug responsiveness in patients with CLL.

Topics: Adaptor Proteins, Signal Transducing; Adaptor Proteins, Vesicular Transport; Adult; Aged; Aged, 80 and over; Biological Transport; Carrier Proteins; Cell Survival; Drug Resistance, Neoplasm; Equilibrative Nucleoside Transporter 1; Female; Gene Expression; Humans; Immunoglobulin G; Leukemia, Lymphocytic, Chronic, B-Cell; Leukocytes; Male; Melphalan; Membrane Transport Proteins; Middle Aged; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Saccharomyces cerevisiae Proteins; Tumor Cells, Cultured; Vidarabine

Topics: Aged; Angioedema; Antineoplastic Combined Chemotherapy Protocols; Complement C1 Inactivator Proteins; Diagnosis, Differential; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Melphalan; Prednisone

Long-term outcome, after first line intensified high-dose sequential (i-HDS) chemotherapy, was evaluated in 46 patients, aged < or =65 years, with advanced low-grade lymphoma. Seventeen patients had small lymphocytic lymphoma (SLL), 29 had follicular lymphoma (FL), 10 of them with histologic transformation. I-HDS included: (1) tumor debulking, by 2 APO+2 DHAP courses; (2) sequential administration of high-dose (hd) etoposide, methotrexate, and cyclophosphamide, followed by peripheral blood progenitor cell (PBPC) harvest; (3) hd-mitoxantrone + melphalan with PBPC autograft. Ten FL patients had their PBPC immunologically purged ex vivo. There were two treatment-related deaths; five FL patients had short-lasting response followed by disease progression, five SLL reached a stable PR; overall, 34 patients (74%) reached CR. At a median follow-up of 4.3 years, the estimated 9-year OS and EFS were 84% and 45%, respectively. No significant differences were observed in the OS among patients at low, intermediate or high IPI score, with an estimated OS projection of 95%, 78%, and 75%, respectively. FL had longer survival without evidence of residual disease (9-year EFS: 59%) as compared to SLL patients (8.8-year EFS: 17%); however, both groups had prolonged survival and no need of salvage treatment, as shown by the time to disease progression curve, projected to 66% and 62% for SLL and FL, respectively. The results indicate that hd-approach in low-grade lymphoma: (1) is associated with longer progression-free survival as compared to conventional therapies; (2) may imply higher tumor mass reduction in FL as compared to SLL patients; (3) offers long life expectancy, with potential survival benefits at least for patients at intermediate/high IPI score.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Dexamethasone; Disease Progression; Disease-Free Survival; Doxorubicin; Drug Administration Schedule; Etoposide; Feasibility Studies; Female; Follow-Up Studies; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Follicular; Lymphoma, Non-Hodgkin; Male; Melphalan; Methotrexate; Middle Aged; Mitoxantrone; Remission Induction; Survival Analysis; Treatment Outcome; Vincristine

Autologous transplantation has an established role in the treatment of lymphoproliferative disorders, but allogeneic transplantation remains controversial. In an attempt to reduce the high procedure-related mortality reported with allografting in lymphoma, we have used BEAM (BCNU, etoposide, cytarabine and melphalan), a standard conditioning regimen for autologous transplantation. As BEAM may be insufficiently immunosuppressive to permit durable engraftment in the allogeneic setting, patients received additional pretransplant immunosuppression with the anti-CD52 antibody CAMPATH-1G from day -5 to day -1. Twelve patients (median age 46 years) underwent allogeneic transplantation for lymphoma (n = 11) or chronic lymphocytic leukaemia (n = 1) from HLA-identical (n = 9) or mismatched (n = 3) sibling donors. Cyclosporin A and methotrexate were used as graft-versus-host disease (GVHD) prophylaxis. One patient died of progressive lymphoma at day +12, the remaining 11 patients engrafted rapidly, with eight demonstrating full donor chimerism. One patient had an episode of rejection and received a further stem cell infusion with sustained recovery. Only one patient developed GVHD (grade I). The low incidence of acute GVHD may be in part related to persisting levels of in vivo CAMPATH-IG at the time of transplantation. Of 11 evaluable patients, nine achieved complete remission (CR), and a further patient achieved CR after donor lymphocyte infusion at 5 months. Our preliminary experience is that this regimen was well tolerated with a low risk of GVHD and appears no more toxic than a BEAM autograft. Further follow-up is required to see whether the low incidence of GVHD impacts upon relapse risk.

Topics: Adult; Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cyclosporine; Cytarabine; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma; Lymphoproliferative Disorders; Male; Melphalan; Methotrexate; Middle Aged; Podophyllotoxin; Transplantation Conditioning; Transplantation, Homologous

Chronic lymphocytic leukemia (CLL) cells were cultured in a medium supplemented with 0.01-1 ng/ml interleukin-4 (IL-4) for 18 h, fixed and analyzed on a flow cytometer. The percentage of apoptotic (AP) cells with hypodiploid DNA content was determined from DNA histograms. IL-4 at 0.01 ng/ml protected from spontaneous apoptosis of cells from previously treated CLL patients, but had very little effect on apoptotic death in cultures of cells from untreated patients. The number of AP cells in the absence of IL-4 was similar in cultures from treated and untreated patients. The concentration of IL-4 which inhibited spontaneous apoptosis by 50% was less than 0.01 ng/ml for pretreated patients and close to 1 ng/ml for untreated patients. Stage of the disease had no effect on the level of spontaneous apoptosis and its sensitivity to IL-4. Protection from apoptosis by IL-4 was not accompanied by the upregulation of bcl-2 protein. The number of AP cells in methylprednisolone hemisuccinate (MP) treated cultures from previously treated patients was significantly lower than in cultures from untreated patients in the presence of 0.01-1.0 ng/ml IL-4. Treatment with the combination L-phenylalanine mustard (L-PAM)+ fludarabine induced synergistic apoptotic response. Apoptosis induced by this combination was relatively resistant to IL-4 in patients treated with chlorambucil and prednisone, but not in patients previously treated with fludarabine. Protection from cytotoxicity by IL-4 may be one of the mechanisms of acquired drug resistance in CLL.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Apoptosis; Drug Resistance, Neoplasm; Drug Synergism; Female; Humans; Interleukin-4; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphocytes; Male; Melphalan; Middle Aged; Tumor Cells, Cultured; Vidarabine

The effect of IL4 on cell viability, cell growth, apoptotic fraction, melphalan-induced cytotoxicity and the degree of interstrand DNA cross-linking after alkylating agent exposure was investigated in peripheral blood B-cell chronic lymphocytic leukaemia (B-CLL) cells obtained from 10 patients suffering from chronic lymphocytic leukaemia and in B lymphocytes from five normal individuals. The addition of IL4 to culture medium maintained in-vitro viability and decreased spontaneous in-vitro apoptosis in both B-CLL cells and normal peripheral blood B lymphocytes. IL4 did not, however, stimulate proliferation of either cell type. IL4 sensitized alkylator-resistant B-CLL cells to the cytotoxic effects of melphalan (L-phenylalanine mustard) but had no influence on melphalan-induced cytotoxicity against normal B lymphocytes. The enhanced cytotoxicity against B-CLL cells was accompanied by an increase in the amount of interstrand-DNA cross-linking in these cells following short-term exposure to melphalan.

Topics: Aged; Antineoplastic Agents, Alkylating; Apoptosis; B-Lymphocytes; Cell Division; Dose-Response Relationship, Drug; Female; Humans; Interleukin-4; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Melphalan; Middle Aged

Bifunctional alkylating agents, such as melphalan, are widely used in the treatment of hematological malignancies. The effects of these drugs on particular types of hematological cells and the causes of treatment failure are poorly understood. The aim of this work was to establish an ability to measure the extent to which melphalan reacts with the DNA of individual tumor cells, thereby creating new possibilities for molecular pharmacological studies on clinical samples. A novel approach for staining drug-DNA adducts is described in which cells were embedded in agarose and then lysed. The DNA from each cell remained in an ideal state for quantitative immunofluorescent staining using a previously described monoclonal antibody. Immunofluorescence and DNA-Hoechst dye fluorescence were quantified using a cooled slow scan charge coupled device camera and image analysis procedures. Immunofluorescence of drug-treated cells from a human leukemia cell line was partially correlated with DNA content. Mean integrated immunofluorescence of 50 to 100 cells was dependent on drug concentration and was linearly related to adduct levels. In these cells and in chronic lymphocytic leukemia cells obtained from patients, there was considerable intercell heterogeneity in apparent adduct levels. This was also seen in peripheral blood mononuclear cells isolated from a patient after melphalan therapy.

Topics: Antineoplastic Agents, Alkylating; Bisbenzimidazole; DNA Adducts; DNA, Neoplasm; Feasibility Studies; Fluorescent Dyes; Hematopoietic Stem Cells; Humans; Image Processing, Computer-Assisted; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Non-Hodgkin; Melphalan; Neoplastic Stem Cells; Sepharose; Staining and Labeling; Tissue Embedding; Tumor Cells, Cultured

Nitrogen mustard resistance in B-cell chronic lymphocytic leukemia (B-CLL) has been associated with enhanced DNA repair and increased expression of DNA repair enzymes. Lymphocytes from patients with nitrogen mustard resistant B-CLL displayed a fivefold increase in resistance to melphalan in vitro as compared to those from untreated patients concordant with our definition of clinical resistance. We have performed Northern analysis using a cohort consisting of 11 untreated and 12 treated-resistant patients. Increased expression of ERCC-1 was not found to be associated with nitrogen mustard resistance, nor did we find altered expression of the DNA repair enzymes: ERCC-2, DNA polymerase beta, or topoisomerase I. There was also no difference in the levels of ERCC-1 protein between melphalan sensitive and resistant B-CLL lymphocytes. Analysis of genes involved in nitrogen mustard detoxification revealed that metallothionein was weakly expressed, while transcripts encoding glutathione-S-transferase alpha were undetectable. Thus, it is unlikely either of these proteins plays a role in the resistance. The results of the cytotoxicity assay validate the use of B-CLL as a model to study nitrogen mustard resistance. This model allows us to perform in vitro studies using a tumor which develops resistance in vivo. The results of this study suggest that nucleotide excision repair, as represented by ERCC-1 and ERCC-2, is not the limiting step in B-CLL nitrogen mustard resistance.

Topics: Aged; Aged, 80 and over; DNA Helicases; DNA Ligases; DNA Polymerase I; DNA Repair; DNA Topoisomerases, Type I; DNA-Binding Proteins; Drug Resistance; Endonucleases; Female; Humans; Inactivation, Metabolic; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Melphalan; Middle Aged; Nitrogen Mustard Compounds; Protein Biosynthesis; Proteins; RNA, Messenger; Transcription Factors; Tumor Cells, Cultured; Xeroderma Pigmentosum Group D Protein

Acquired resistance is a limiting factor in chemotherapy. We have employed nitrogen mustard resistant B-cell chronic lymphocytic leukemia (B-CLL) as a clinically relevant model to study this phenomenon. Resistance in B-CLL is associated with enhanced repair of nitrogen mustard crosslinks. In order to identify the repair pathway responsible for nitrogen mustard resistance, lymphocytes were screened for cross-resistance to a variety of DNA damaging agents. The MTT assay was used to measure the resistance of B-CLL lymphocytes to various DNA damaging agents, including nitrogen mustards, UV light, methyl methanesulfonate, and mitomycin C. We have shown that B lymphocytes from patients with nitrogen mustard resistant chronic lymphocytic leukemia reflect their clinical status. This assay allows us to classify lymphocytes as nitrogen mustard sensitive or resistant, based on in vitro observations. The resistant population was 5.6 and 4.1 fold more resistant to the nitrogen mustard analogs, chlorambucil and melphalan, respectively. Resistant lymphocytes displayed no increased resistance to either methyl methanesulfonate or UV light, indicating that neither classical base nor nucleotide excision repair is rate-limiting in resistance. Resistant lymphocytes were 6.0 and 2.2 fold more resistant to mitomycin C and cis-diamminedichloroplatinum (II), respectively, suggesting enhanced crosslink repair. Neither glutathione nor glutathione S-transferase levels correlated with resistance. The development of nitrogen mustard drug resistance in B-CLL appears to be associated with cross-resistance to other bifunctional alkylating agents which produce interstrand crosslinks. Our results indicate that resistance to nitrogen mustards in chronic lymphocytic leukemia is associated with enhanced repair of DNA crosslinks which may involve a recombination dependent system. This model should prove very useful in the elucidation of the molecular mechanisms of crosslink repair.

Topics: B-Lymphocytes; Chlorambucil; Cisplatin; Cross-Linking Reagents; DNA Adducts; DNA Damage; DNA Repair; DNA, Neoplasm; Drug Resistance; Humans; Inactivation, Metabolic; Leukemia, Lymphocytic, Chronic, B-Cell; Melphalan; Methyl Methanesulfonate; Mitomycin; Nitrogen Mustard Compounds; Tetrazolium Salts; Thiazoles; Tumor Cells, Cultured

A case of primary malignant lymphoma of the bladder is reported. A 70-year-old woman was admitted to our clinic with the chief complaint of intermittent gross hematuria on March 31, 1992. Examination of cystoscopy, IVP, ultrasonography and CT scan suggested a non-papillary invasive bladder tumor. Pathological examination of transurethral biopsy revealed malignant lymphoma, B cell type. After 5 courses of intraarterial COMPA (CDDP, VCR, MTX, PEP, ADR) chemotherapy, she have been in complete remission. Intraarterial COMPA chemotherapy might be effective and useful for primary malignant lymphoma of the urinary bladder.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Doxorubicin; Female; Humans; Infusions, Intra-Arterial; Leukemia, Lymphocytic, Chronic, B-Cell; Melphalan; Prednisone; Urinary Bladder Neoplasms; Vincristine

As a means of identifying damage recognition proteins involved in repair of nitrogen mustard lesions in chronic lymphocytic leukemia, we performed Southwestern analysis using a probe damaged with melphalan and protein extracts from chronic lymphocytic leukemia patients. We detected proteins with molecular weights of 116,000, 66,000, and 64,000 which bound the damaged probe with a higher specificity than the undamaged probe. The M(r) 66,000 and 64,000 proteins were determined to be degradation products of the M(r) 116,000 protein. The M(r) 116,000 protein was identified as poly(ADP-ribose) polymerase. The use of methoxyamine, an inhibitor of DNA strand breakage following depurination, significantly reduced binding of the melphalan damaged probe to poly(ADP-ribose) polymerase. Following depletion of poly(ADP-ribose) polymerase from the cell extracts, no other binding activity was discovered. Thus, poly(ADP-ribose) polymerase is the only demonstrable protein in chronic lymphocytic leukemia cells which can bind to a DNA probe damaged with melphalan.

Topics: Alkylation; Blotting, Southern; Blotting, Western; DNA; DNA Damage; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Melphalan; Poly(ADP-ribose) Polymerases

Resistance to the nitrogen mustards in patients with chronic lymphocytic leukemia (CLL) correlates with an enhanced removal of melphalan-induced DNA interstrand cross-links. This finding suggests that DNA repair enzymes may be involved in this process. The activity of 3-methyladenine-DNA glycosylase, which can release altered bases, including adducts at the N-7 position of guanine, was increased significantly in lymphocytes from patients with resistant CLL compared with those from untreated CLL patients. Since glycosylase activity varies with cell proliferation, the amount of [3H]thymidine incorporated into DNA was determined and found to be elevated almost threefold in lymphocytes from patients with resistant CLL. The ratio of glycosylase activity to level of thymidine incorporation did not differ between these two groups of patients. Northern blot analysis of ERCC1 gene (a putative DNA repair enzyme involved in nucleotide excision repair) expression in lymphocytes from patients with CLL revealed multiple gene transcripts (1.1, 3.4, and 3.8 kilobases). In addition, analysis of two samples revealed the presence of a 2.6-kilobase transcript. The 2.6-kilobase transcript was recognized by specific RNA probes that hybridize to antisense ERCC1 transcripts. Levels of expression of the 1.1-kilobase protein encoding transcript in lymphocytes from patients with resistant CLL were increased twofold to threefold above those of untreated patients with CLL. These results indicate that increased expression of ERCC1 and increased activity of 3-methyladenine-DNA glycosylase occur with the development of resistance to the nitrogen mustards in patients with CLL, suggesting a role for enhanced DNA repair in this process.

Topics: Aged; Aged, 80 and over; Biological Transport; Blotting, Northern; Chromatography, High Pressure Liquid; DNA Glycosylases; DNA Repair; DNA, Neoplasm; Drug Resistance; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphocytes; Male; Melphalan; Middle Aged; N-Glycosyl Hydrolases; Nitrogen Mustard Compounds; RNA, Messenger; RNA, Neoplasm

The MiNa protocol (vincristine, cyclophosphamide, melphalan, peptichemio, and prednisone) was given to 20 patients with advanced B-cell chronic lymphocytic leukemia. Complete remission (absence of all clinical and bone marrow evidence of leukemia) was obtained in 35% of cases; partial response (greater than 50% reduction in organ enlargement and decreasement of lymphocyte count to less than 15(9) X 10/l) was observed in 35% of patients. Of 12 patients (60%) previously treated with chlorambucil and corticosteroids, nine responded to treatment. Toxicity was mild and the relapse rate particularly low. It was concluded that the MiNa protocol represents an effective chemotherapy for advanced and/or progressive CLL.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Drug Administration Schedule; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Melphalan; Middle Aged; Peptichemio; Prednisone; Remission Induction; Vincristine

Topics: DNA; DNA Repair; Drug Resistance; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphocytes; Melphalan; Nitrogen Mustard Compounds

Twenty patients with stage III and IV diffuse well-differentiated lymphocytic lymphoma were treated with combination chemotherapy consisting of BCNU, cyclophosphamide, vincristine, melphalan and prednisone (M-2). Treatment was given every 5 weeks for 11 cycles in responding patients. The median age of the patients was 62 years (range 45-76). There were 12 complete remissions and 6 partial remissions for an overall response rate of 90%. The median duration of remission was 24 months (range 12-79 months) and was identical for complete responders and partial responders. All but 2 responding patients have been subsequently retreated for relapse. The median survival was 84 months (range 1-108 months). Myelosuppression was mild. Nausea/vomiting, neuropathy, alopecia and gastrointestinal symptoms from prednisone were seen in the minority of patients. One patient expired from sepsis/neutropenia during the first cycle of therapy. The M-2 protocol produces effective remissions in diffuse well-differentiated lymphocytic lymphoma. The relapse and survival pattern are similar to the results achieved with other chemotherapy regimens in low-grade lymphoma.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cyclophosphamide; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Melphalan; Middle Aged; Prednisone; Vincristine