Drug-resistance in multiple myeloma and non-Hodgkin's lymphoma: detection of P-glycoprotein and potential circumvention by addition of verapamil to chemotherapy.

1989 ◽  
Vol 7 (4) ◽  
pp. 415-424 ◽  
Author(s):  
W S Dalton ◽  
T M Grogan ◽  
P S Meltzer ◽  
R J Scheper ◽  
B G Durie ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Drug Resistance ◽  
Tumor Cells ◽  
Hodgkin’S Lymphoma ◽  
Progressive Disease ◽  
Hodgkin's Lymphoma ◽  
Drug Resistant ◽  
P Glycoprotein ◽  
Non Hodgkin’S Lymphoma ◽  
Non Hodgkin's Lymphoma

The B-cell neoplasms, multiple myeloma and non-Hodgkin's lymphoma, frequently become drug resistant, despite initial responses to chemotherapeutic drugs. Tumor cells from eight patients with clinically drug-refractory disease were evaluated by immuno-histochemical staining for monoclonal immunoglobulin (Ig) expression, nuclear proliferation antigen, P-glycoprotein (P-gly) expression, and other cellular antigens. P-gly was detected on tumor cells from six of eight patients with drug-resistant disease. Of the six patients with P-gly-positive tumors, five patients had advanced multiple myeloma and one had a drug-refractory non-Hodgkin's lymphoma. Cellular RNA analysis confirmed the over-expression of P-gly. In an effort to overcome drug resistance, a pilot study evaluated possible verapamil enhancement of chemotherapy in these eight patients. All patients had developed progressive disease while receiving a regimen containing vincristine and doxorubicin, and seven of eight patients had previously received continuous infusion vincristine and doxorubicin plus oral dexamethasone (VAD). At the time of progressive disease, continuous infusion verapamil was added to the VAD regimen. Three of the eight patients who were refractory to vincristine and doxorubicin alone responded when verapamil was added to VAD. The three patients who responded had P-gly-positive tumors. Verapamil increased the intracellular accumulation of doxorubicin and vincristine in vitro for both a P-gly-positive myeloma cell line and tumor cells from two patients with end-stage myeloma which over-expressed P-gly. The dose-limiting side effect associated with the addition of verapamil to chemotherapy was temporary impairment of cardiac function, manifest as hypotension and cardiac arrhythmia. We conclude that P-gly expression occurs in drug-refractory B-cell neoplasms and may contribute to the development of clinical drug resistance. However, other factors, such as the proliferative activity of the tumor, may also play a role in determining response to chemotherapy. The administration of verapamil along with VAD chemotherapy may partially circumvent drug resistance in patients whose tumors over-express P-gly.

Childhood non-Hodgkin's lymphoma involving the testis: clinical features and treatment outcome.

1989 ◽  
Vol 7 (8) ◽  
pp. 1066-1070 ◽  
Author(s):  
S J Kellie ◽  
C H Pui ◽  
S B Murphy
Keyword(s):  
Poor Prognosis ◽  
Hodgkin’S Lymphoma ◽  
Progressive Disease ◽  
Hodgkin's Lymphoma ◽  
Advanced Stage ◽  
Drug Resistant ◽  
The Third ◽  
Resistant Disease ◽  
Non Hodgkin’S Lymphoma ◽  
Non Hodgkin's Lymphoma

Among 131 boys with advanced (stage III or IV) non-Hodgkin's lymphoma (NHL) consecutively treated at St. Jude Children's Research Hospital, testicular involvement was present at the time of diagnosis in six and as an isolated site of relapse in three. Testicular involvement was not seen in any patient with localized (stage I or II) disease. Four of the six patients with involvement at presentation are free of disease 2.9+ to 8.3+ years after diagnosis, following chemotherapy alone (three patients) or chemotherapy plus orchiectomy. Overt testicular relapse while on therapy resulted in death from progressive disease in two patients; the third relapsed after completing therapy for Burkitt's lymphoma and is in second remission after chemotherapy, orchiectomy, and scrotal irradiation. The prolonged remissions seen in children with testicular involvement at diagnosis suggest that scrotal irradiation may not be necessary in chemosensitive disease. By contrast, testicular relapse on therapy appears to indicate drug-resistant disease and a poor prognosis, despite testicular irradiation and chemotherapy.

Rapid Mobilization of CD34+ Cells Following Administration of the CXCR4 Antagonist AMD3100 to Patients With Multiple Myeloma and Non-Hodgkin's Lymphoma

2004 ◽  
Vol 22 (6) ◽  
pp. 1095-1102 ◽  
Author(s):  
Steven M. Devine ◽  
Neal Flomenberg ◽  
David H. Vesole ◽  
Jane Liesveld ◽  
Daniel Weisdorf ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Hodgkin’S Lymphoma ◽  
Hodgkin's Lymphoma ◽  
Clinical Effects ◽  
Cxcr4 Antagonist ◽  
Cell Counts ◽  
Non Hodgkin’S Lymphoma ◽  
Non Hodgkin's Lymphoma ◽  
Cd34 Cells ◽  
The Absolute

PurposeInteractions between the chemokine receptor CXCR4 and its ligand stromal derived factor-1 regulate hematopoietic stem-cell trafficking. AMD3100 is a CXCR4 antagonist that induces rapid mobilization of CD34+ cells in healthy volunteers. We performed a phase I study assessing the safety and clinical effects of AMD3100 in patients with multiple myeloma (MM) and non-Hodgkin's lymphoma (NHL).Patients and MethodsThirteen patients (MM, n = 7; NHL, n = 6) received AMD3100 at a dose of either 160 μg/kg (n = 6) or 240 μg/kg (n = 7). WBC and peripheral blood (PB) CD34+ cell counts were analyzed at 4 and 6 hours following injection.ResultsAMD3100 caused a rapid and statistically significant increase in the total WBC and PB CD34+ counts at both 4 and 6 hours following a single injection. The absolute CD34+ cell count increased from a baseline of 2.6 ± 0.7/μL (mean ± SE) to 15.6 ± 3.9/μL and 16.2 ± 4.3/μL at 4 hours (P = .002) and 6 hours after injection (P = .003), respectively. The absolute CD34+ cell counts observed at 4 and 6 hours following AMD3100 were higher in the 240 μg/kg group (19.3 ± 6.9/μL and 20.4 ± 7.6/μL, respectively) compared with the 160 μg/kg group (11.3 ± 2.7/μL and 11.3 ± 2.5/μL, respectively). The drug was well tolerated and only grade 1 toxicities were encountered.ConclusionAMD3100 appears to be a safe and effective agent for the rapid mobilization of CD34+ cells in patients who have received prior chemotherapy. Further studies in combination with granulocyte colony-stimuating factor in patients with lymphoid malignancies are warranted.

scholarly journals Recombinant human erythropoietin in transfusion-dependent anemic patients with multiple myeloma and non-Hodgkin's lymphoma--a randomized multicenter study. The European Study Group of Erythropoietin (Epoetin Beta) Treatment in Multiple Myeloma and Non-Hodgkin's Lymphoma

Blood ◽  
1996 ◽  
Vol 87 (7) ◽  
pp. 2675-2682 ◽  
Author(s):  
A Osterborg ◽  
MA Boogaerts ◽  
R Cimino ◽  
U Essers ◽  
J Holowiecki ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Regression Analysis ◽  
Recombinant Human Erythropoietin ◽  
Hodgkin’S Lymphoma ◽  
Hodgkin's Lymphoma ◽  
Fixed Dose ◽  
Control Group ◽  
Human Erythropoietin ◽  
Non Hodgkin’S Lymphoma ◽  
Non Hodgkin's Lymphoma

One hundred twenty-one anemic, transfusion-dependent patients with multiple myeloma (MM) or low-grade non-Hodgkin's lymphoma (NHL) were randomly allocated to receive (a) recombinant human erythropoietin (rhEPO) 10,000 U/d subcutaneously 7 days a week (fixed dose group) (n = 38), or (b) rhEPO 2,000 U/d subcutaneously for 8 weeks followed by step- wise escalation of the rhEPO dose (titration group) (n = 44), or (c) no rhEPO therapy (control group) (n = 39). The total treatment period was 24 weeks. There were no differences between the three groups with regard to baseline clinical, demographic, or health status measures. The cumulative response frequency, defined as elimination of the transfusion need in combination with an increase in the hemoglobin concentration by >20 g/L, was 60% in both rhEPO treatment groups and 24% in the control group (P = .01 and .02, respectively, log rank test). For patients in the titration group the response rate on the first dose level (2,000 U/d) was only 14%. Cox's univariate regression analysis revealed that an inadequately low endogenous erythropoietin concentration in relation to the degree of anemia and a baseline platelet concentration > or = 100 x 10(9)/L were significant predictors for response to rhEPO therapy (P < .01). Multivariate regression analysis showed that relative erythropoietin concentration was the most important factor and the platelet count had no additional influence on response. Treatment with rhEPO was well tolerated. We conclude that treatment with rhEPO may be indicated in anemic MM and NHL patients with a relative erythropoietin deficiency. An initial dose of 5,000 U/d subcutaneously may be recommended.

Interim Analysis of a Phase II Study of Denileukin Diftitox (Ontak) for Relapsed/Refractory T-Cell Non-Hodgkin’s Lymphoma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2641-2641 ◽  
Author(s):  
Nam H. Dang ◽  
Barbara Pro ◽  
Fredrick B. Hagemeister ◽  
Dan Jones ◽  
Barry Samuels ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Cells ◽  
Phase Ii ◽  
Hodgkin’S Lymphoma ◽  
Phase Ii Study ◽  
Single Agent ◽  
Hodgkin's Lymphoma ◽  
Denileukin Diftitox ◽  
Non Hodgkin’S Lymphoma ◽  
Non Hodgkin's Lymphoma

Abstract Denileukin diftitox (Ontak) is a fusion protein combining the enzymatically active domain of diphtheria toxin and the full-length sequence of interleukin-2 (IL-2) that targets tumor cells expressing the IL-2 receptor (IL-2R). The drug has established efficacy in cutaneous T-cell lymphoma (CTCL), and we have recently demonstrated its single-agent activity in B-cell non Hodgkin’s lymphoma (NHL) (Dang et al. Journal of Clinical Oncology. In Press). We initiated a phase II study to evaluate its efficacy in relapsed/refractory T-cell NHL, excluding CTCL. Denileukin diftitox was administered at a dose schedule of 18 μg/kg/day by IV infusion once daily for 5 days every three weeks, for up to 8 cycles. Premedications in the form of corticosteroids, antihistamines and fluids were given prior to each drug infusion to reduce the incidence and severity of acute hypersensitivity. 14 patients are currently evaluable for response. Median age was 57 (range 26–80), and mean number of previous treatments was 2.2 (range 1–4). Tumor CD25 status was determined by immunohistochemistry and/or flow cytometry, with CD25-positivity being defined as 10% or more of tumor cells expressing detectable CD25. Of the 7 patients with CD25+ T-NHL, there were 2 CR (1 case of Alk-1 negative ALCL and 1 case of PTCL), 3 PR (1 case of PTCL and 2 cases of angioimmunoblastic lymphoma), 1 SD (1 case of PTCL) and 1 PD (1 case of PTCL). Of the 7 patients with CD25− T-NHL, there were 2 PR (1 case of PTCL and 1 case of T/NK-lymphoma), 4 SD (3 cases of PTCL and 1 case of Sezary syndrome), and 1 PD (1 case of angioimmunoblastic lymphoma). Overall response rate (CR+ PR) was 50%, with 2 of 14 patients having CR (14%) and 5 of 14 patients having PR (36%). One patient with Alk-1negative ALCL still has an ongoing CR at 15+ months. Treatment was well-tolerated, with the majority of toxicity being grade 1 or 2 and transient. Denileukin diftitox appears to have activity in relapsed/refractory T-cell NHL, and is well-tolerated at the dosing schedule tested. Additional patients are being studied to further evaluate the relationship between detectable CD25 expression and tumor response to denileukin diftitox.

AMD3100 Plus G-CSF Mobilizes the Majority of Non-Hodgkin’s Lymphoma (NHL), Multiple Myeloma (MM), and Hodgkin’s Disease (HD) Patients Who Failed Prior Mobilization with Other Regimens.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5218-5218
Author(s):  
Gary Calandra ◽  
John McCarty ◽  
Joseph McGuirk ◽  
Bart Barlogie ◽  
Sue-Anne Crocker ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Hodgkin's Disease ◽  
Hodgkin’S Lymphoma ◽  
Hodgkin’S Disease ◽  
Median Number ◽  
Disease State ◽  
Hodgkin's Lymphoma ◽  
Non Hodgkin’S Lymphoma ◽  
Non Hodgkin's Lymphoma ◽  
Cd34 Cells

Abstract Background: AMD3100, an inhibitor of SDF1 binding to CXCR4, synergizes with G-CSF to allow mobilization of sufficient CD34+ cells/kg for autologous transplantation in pts unable to collect adequate CD34+ cells with G-CSF alone. Therefore, a single patient use (SPU) protocol for AMD3100 was adopted for more than one patient entry per site and termed Compassionate Use Protocol (CUP). The only difference of standard of care was the addition of AMD3100 to a G-CSF mobilization on the evening prior to each day of apheresis. Pts who could not proceed to apheresis due to low peripheral blood counts or pts who did not collect a minimum of 2 × 10^6 CD34+ cell/kg were eligible. Methods: Overall, more than 280 patients with proven poor mobilization including 137 NHL, 73 MM, and 31 HD have been included in CUP. A data audit was performed to validate data from pts with either non-Hodgkin’s lymphoma (NHL), multiple myeloma (MM), or Hodgkin’s Disease (HD). Sites were selected based on most patients entered, >3 of all diseases entered at a site, and sites conducting an AMD3100 trial. Audit included all pts, regardless of success or failure of the outcome; all information was collected on CRFs. Success of outcome was collection of ≥ 2×10^6 CD34+ cells/kg during the CUP procedure. CUP apheresis was done on day 5 after G-CSF (10mg/kg SC QD) and AMD3100 (240mg/kg SC Q10 PM) starting day 4. Results: Charts and CRFs were available for review for 115 pts; 63 (55%) were NHL patients from 29 sites, 35 (30%) were MM from 23 sites and 17 (15%) were HD from 13 sites. Of these pts, 58% were male, the median age was 59 years (range 21–77), 88% were Caucasian, and patient weight ranged from 43–128 kg. Prior treatments included a median of two regimens of chemotherapy in each of the three groups. Safety was generally favorable with no drug-related SAE’s and with an AE profile similar to that seen in research trials. The rates of successful collection of ≥ 2×10^6 CD34+ cells/kg per disease state as well as prior mobilization regimen are summarized in table 1. The median number of mobilizations for the successful patients was 3 days for NHL and HD and 4 for MM. Eighty-eight of the patients underwent transplantation with any cells. For example, of the 47 NHL patients transplanted, 24 had CUP only cells and 23 had mixed cells. The median number of days to engraftment was 11 for PMN and 18 for platelets. Long term follow up is limited, but there do not appear to be graft failures. At least 12 of the pts have died. Conclusions: AMD3100 in a poor mobilizer population is generally safe and well tolerated and is very effective in mobilizing > 2×10^6 CD34+ cells/kg. Mobilization success rate by disease state: overall and prior mobilization regimen Overall Prior Cytokine Prior Chemotherapy NHL 60% 53% 68% HD 76% 78% 75% MM 71% 73% 71%

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