Rituximab/Mabthera/Rituxan - a kind of immunotherapy - for  non-Hodgkin's Lymphoma
Here  some articles about Rituximab/Mabthera/Rituxan, treatments which are used for non-Hodgkin.
1. J Clin Oncol 2002 Oct 15;20(20):4261-7
Rituximab as first-line and maintenance therapy for patients with indolent non-hodgkin's lymphoma. Hainsworth JD, Litchy S, Burris HA 3rd, Scullin DC Jr, Corso SW, Yardley DA, Morrissey L, Greco FA.
Sarah Cannon Cancer Center and Tennessee Oncology, Professional Limited Liability Corporation, Nashville, TN, USA. jhainsworth@tnonc.com 
PURPOSE: To evaluate response to single-agent rituximab in patients with indolent non-Hodgkin's lymphoma (NHL) and no previous systemic therapy, and the feasibility, toxicity, and efficacy of maintenance rituximab, administered at 6-month intervals, in patients with objective response or
stable disease after first-line rituximab therapy.
PATIENTS AND METHODS:
Patients with indolent NHL (follicular or small lymphocytic subtypes) previously untreated with systemic therapy received rituximab 375 mg/m(2) intravenously weekly for 4 weeks. Patients were restaged at week 6 for response; those with objective response or stable disease received maintenance rituximab courses (identical dose and schedule) at 6-month intervals. Maintenance was continued for a maximum of four rituximab courses or until progression. Between March 1998 and May 1999, 62 patients were entered onto this trial; minimum follow-up was 24 months.
RESULTS:
Sixty patients (97%) completed the first 4-week course of rituximab and were assessable for response. All have now completed rituximab therapy; 36 (58%) received four courses at 6-month intervals. The objective response rate at 6 weeks was 47%; 45% of patients had stable disease. With continued maintenance, final response rate increased to 73%, with 37% complete responses. Response was similar in patients with follicular versus small lymphocytic subtypes (76% v 70%, respectively). Median actuarial progression-free survival was 34 months. Two patients experienced grade 3/4 toxicity with the first dose; one patient was removed from treatment. No cumulative or additional toxicities were seen with maintenance courses.
  CONCLUSION: 
Rituximab is highly active and extremely well tolerated as first-line single-agent therapy for indolent NHL. First-line treatment with scheduled maintenance at 6-month intervals produces high overall and complete response rates and a longer progression-free survival (34 months) than has been reported with a standard 4-week treatment.

2. Rituximab in Lymphoma: A Review of a Province-Wide Initiative after One Year. (18-11-2001) Matthew C. Cheung, Ralph Meyer, Jan Hux, William Evans, Marilyn Nefsky, Kevin R. Imrie Cancer Care Ontario, Toronto, Ontario, Canada; Institute for Clinical Evaluative Sciences, Toronto, Ontario, Canada; Toronto-Sunnybrook Regional Cancer Centre, Toronto, Ontario, Canada; Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
Ontario is the most populous province in Canada, with 11.8 million people.
There are 2300 new cases of non-Hodgkins lymphoma (NHL) in Ontario each year, an incidence rate among the highest in the world (18 cases/100 000 population). Patients with cancer in Ontario are treated in a range from primary to quaternary care facilities located in large urban centres and smaller communities. New cancer therapies are funded centrally by a state agency, Cancer Care Ontario (CCO), to ensure universal access throughout the province.
Rituximab has been funded for use as monotherapy in indolent lymphomas since April 2000. We conducted a retrospective review of rituximab use over the first year of drug availability to assess the nature and outcome of treatment in Ontario. Criteria for approval of funding were: patients with follicular, mantle cell, or other CD20-positive indolent B-cell lymphomas who progressed after anthracycline or purine analogue chemotherapy, or who were unable to tolerate further chemotherapy
Funding for retreatment with rituximab was available for responding patients provided retreatment was not required within 1 year of initial therapy. The CCO database captures all non-clinical trial use of rituximab in Ontario that meets these eligibility criteria. Between April 1, 2000 and March 31, 2001, 230 patients were treated with rituximab. The mean patient age was 60.7 (range 22 to 83 yrs); 58.8% were male.
The majority of patients were treated outside of a CCO Regional Cancer Centre (57.8%); 52.3% of patients were treated in an academic hospital and 47.7% were treated in a community hospital. The most common diagnosis treated was follicular lymphoma (66.4%), followed by mantle cell lymphoma (16.0%), post-transplant lymphoproliferative disorder (2.4%), and other CD 20-positive low-grade lymphomas (15.2%). Indications for rituximab treatment included failure of previous anthracycline or purine analogue treatment in 43.9% of patients and inability to tolerate further chemotherapy in 35.6%.
In preliminary data from a subgroup of the cohort, clinical outcomes of interest (progression-free survival and survival) are consistent with published results. The drug acquisition costs for this agent for use in the first year were $1.74 million (US dollars). A state administered central funding structure for rituximab results in equitable access throughout a geographically large region.

3. Europe Approves MabThera (Rituximab)/Standard Chemo Combination for Aggressive Non-Hodgkin's Lymphoma
BASEL, SWITZERLAND -- March 25, 2002 -- Revolutionary anti-cancer drug MabThera AE (rituximab), combined with standard chemotherapy, was today given approval in Europe for use in fighting an increasingly common form of blood cancer called aggressive non-Hodgkin's lymphoma (NHL).
For thousands of patients across Europe, this decision by the European Medicines Evaluation Agency (EMEA) will mean availability of a drug combination that can increase the chance of cure and prolong survival in this rapidly fatal form of cancer.
The EMEA's decision was based on results looking at MabThera plus standard chemotherapy (CHOP) versus CHOP alone in the pivotal GELA (Groupe d'Etude des Lymphomes de l'Adulte) study. CHOP chemotherapy uses the drugs cyclophosphamide, doxorubicin, vincristine, and prednisolone. The interim analysis looked at 328 out of the enrolled 399 previously untreated elderly patients (60 years or older) with aggressive NHL. Patients were randomised to receive standard CHOP chemotherapy alone (every three weeks for eight cycles) or MabThera (375 mg/m=B2) plus CHOP. MabThera was administered at the same time as CHOP for eight cycles.
In this study patients on the MabThera combination had a 13 percent greater chance of survival than those on standard therapy alone. It is estimated that after two years of follow-up, 70 percent of patients will be alive and well with the MabThera plus CHOP combination, compared to 57 percent after standard chemotherapy alone. Current medical opinion indicates that if patients survive past the two-year milestone their chances of a cure can be up to 90 percent.
Welcoming the news of the treatment's approval, Alan Bartle, Chief Executive of the United Kingdom Lymphoma Association said, "This is the first time since 1978 a new treatment combination has been able to offer patients the chance for a longer and better life, as well as the possibility of a cure. It has been a long time coming, but finally we are seeing real advances in treatment for this little known, but increasingly common, form of blood cancer. I hope NHL sufferers everywhere become aware of the new treatment options available to combat this disease."
Non-Hodgkin's lymphoma affects approximately 1.5 million around the world and is the third fastest growing form of cancer behind melanoma of the skin and lung cancer. It is a more common form of blood cancer than leukaemia and approximately 55 percent of cases of NHL are categorised as aggressive.
SOURCE: Roche Pharmaceuticals

5. Optimizing Anti-CD20 Immunotherapy of Lymphomas and Chronic Lymphocytic Leukemia. David G. Maloney, MD, PhD, and Robert S. Mocharnuk, MD
Introduction
The island of Maui, Hawaii, served as the meeting place for researchers and clinicians who shared their experience with anti-CD20 immunotherapy at a symposium preceding the Pan Pacific Lymphoma Conference. The sessions focused on maximizing the therapeutic potential of the anti-CD20 antibody rituximab for the treatment of patients with non-Hodgkin's lymphoma (NHL) as well as chronic lymphocytic leukemia (CLL).
Single-Agent Immunotherapy of NHL
A More Rational Approach to Dosing and Scheduling Dr. David G. Maloney, Associate Member at the Fred Hutchinson Cancer Research Center in Seattle, Washington, acknowledged that rituximab has already been integrated into many clinical practices for the treatment of patients with NHL. 
He pointed out that rituximab has shown activity as a single agent, but this may represent only the proverbial iceberg tip of antibody therapy. Important questions that remain to be answered include the effect of rituximab on the natural course of lymphoma, especially when combined with or following standard chemotherapy. Recent clinical trials are providing interesting clinical results.
Dr. Maloney reviewed the data that led to the US Food and Drug Administration (FDA) approval of the use of rituximab in patients with NHL. The original phase 1 trial enrolled patients with relapsed low-grade NHL, who received a single dose of rituximab ranging from 10 mg/m2 to 500 mg/m2.[1] While dose-limiting toxicity was not reached at the 500 mg/m2 level, the infusion-related symptoms of fever, chills, and, more rarely, hypotension and/or dyspnea, resulted in prolonged infusion times that were not practical for outpatient administration. The protocol had predefined limits for infusion rates and allowed for the antibody treatment to be slowed or stopped in the presence of side effects. Phase 2 trials evaluated weekly dosing x 4 with doses of 125 mg/m2 to 375 mg/m2. Again, there was no dose-limiting toxicity observed at the higher doses used. Doses higher than 375 mg/m2 were not explored in this trial due to limited availability of the antibody.
FDA approval was given for use of the 375 mg/m2 weekly x 4 schedule, for treatment of patients with relapsed low-grade or follicular lymphoma, based on the pivotal trial results showing a 48% response rate among 166 patients.[2] Approval has also been given for expanding to 8 weekly doses
based on a small phase 2 study. In this trial, a slightly higher response rate and longer time to progression were observed. However, the study was small and it was not a randomized comparison. Higher doses, including 500 mg/m2 each week x 8 have been used in patients with aggressive NHL, but they did not show higher activity and were associated with a higher rate of infusion-related toxicity compared with 375 mg/m2.[3]

The data obtained are more controversial in patients with CLL, a clinical setting where both dose and scheduling may need to be different. In fact, since there is a more rapid antibody elimination in these patients, trials have explored higher doses and more frequent antibody administrations.
Ultimately, optimal dosing may require adjustments based on antibody pharmacokinetics, biologic effects (B-cell depletion) and clinical response.

Pharmacokinetics
Several factors are involved in the pharmacokinetics of antibody therapy. One variable among patients is the antigen burden. This is reflected in both the number of tumor cells vs normal B cells, as well as the density of CD20 molecules on the cell surface. This antigen sink will "sop up" antibody, resulting in lower serum antibody levels and more rapid clearance. Patients with rapid tumor growth will have increasing CD20 antigen burden, while patients with responding tumors will have decreasing antigen load, a process that can affect antibody levels.
Although CD20 does not undergo rapid modulation, all surface molecules turn over at some rate. There is evidence to suggest that CD20 does modulate at a slow rate and that some cells may release CD20 or cell fragments more readily than others, thus contributing to a more rapid clearance of the antibody from the serum. Lastly, the clearance of antibody from the serum, in part determined by antibody levels, is a complex process that may change owing to variable receptor expression patterns. In a limited number of studies, 2 patterns of pharmacokinetic clearance have been observed. Some patients tend to accumulate antibody during the 4 weekly infusions, with increasingly higher levels observed both immediately prior to subsequent infusions and increasingly higher peak serum levels following each infusion. In other patients, the antibody is rapidly cleared from the blood and may be almost completely eliminated before the next infusion.
Patients with accumulating antibody levels have a much higher response rate compared with patients who have a rapid clearance. However, other issues such as tumor type and tumor burden complicate this analysis further. Patients with small lymphocytic NHL are more likely to fall in the latter category and have had a low response rate; patients with follicular lymphoma generally have favorable pharmacokinetics and a higher response rate.
Clinical trials based on measured serum antibody levels should be able to answer the question of whether higher doses or more frequent antibody administration would result in higher response rates for patients with unfavorable pharmacokinetics. It is unlikely that repeated administration of standard dosing will affect response rate in nonresponding patients with poor pharmacokinetics. Conversely, repeated dosing of rituximab may prolong time to progression in responding patients.

Biologic Effects of Rituximab
Normal circulating B-cells are rapidly depleted from the peripheral blood following administration of rituximab. Recovery of these B-cells begins approximately 6 months afterward with return to the normal range in about 1 year. This is similar to the time to tumor progression that has been observed in patients with relapsed disease treated with rituximab. Retreatment with rituximab is one option that may prevent recovery of circulating B-cells and extend the duration of response.
Hainsworth and associates[4] have published data on the use of "maintenance" rituximab every 6 months following initial treatment of patients with low-grade, follicular, or small lymphocytic NHL. Eligible patients had achieved stable disease, a partial response (PR) or complete response (CR) following 4 weekly courses of rituximab. Among the 62 patients enrolled, 45% achieved either a PR or CR (6% CR) after the first course of therapy.
Subsequent courses of treatment saw response rates rise to 65% with 27% CRs.
Response rates after 3 or 4 courses were approximately 70%.
At 2 years, 67% of responding patients remained in remission. These results appear superior to those observed in the original single-agent rituximab trials in relapsed patients, where the initial response rate was 48% with a time to progression in responding patients of approximately 12 months.
Retreatment of responding patients at the time of relapse demonstrated a 40% response rate and increased duration of response when compared with their earlier response to rituximab.
Subset analysis has shown that even among patients with bulky disease, a 43% response rate was observed, which is again superior to outcomes seen in prior studies. Not surprisingly, duration of response was generally shorter at 8.1 months, compared with historic controls.
Similar to the clearance of B-cells from the peripheral blood, patients can be analyzed for evidence of cells with the t(14;18) translocation, which is present in most follicular lymphomas, using a polymerase chain reaction (PCR) specific for the translocation. Rituximab treatment results in the clearing of cells from the peripheral blood in 62% of pts and from the bone marrow in 56% of pts.

It remains to be proven whether the molecular clearance of cells from these compartments correlates with the degree and duration of response, although preliminary evidence seems to support this concept. Among patients with residual nodal disease who achieved PCR clearance, time to progression seems to be longer than in patients in whom PCR was positive or equivocal. It is possible that future studies will use molecular analysis for tumor cell detection as a surrogate measure for antibody dosing and/or antibody retreatment.

Are 8 Treatments Better Than 4?
Based upon the original phase 1 data that showed a linear relationship between antibody dose and area under the curve, with an increasing maximum concentration and longer antibody half-life, 4-week and 8-week treatment schedules have been used. In the 4-treatment trials, a more rapid antibody clearance was observed in nonresponders vs responders. Even in those patients achieving late responses, antibody clearance was more rapid than in early responders. Does this mean that nonresponding patients fail because they do not accumulate antibody, or does this simply serve as a marker for nonresponders?
A trial evaluating 8 weekly doses found that the antibody levels generally reach a plateau after 6 doses. However, some patients (generally nonresponders) continued to have poor pharmacokinetics. Conversely, responding patients had higher antibody levels that were sustained longer.
The response rate was 57% among patients receiving 8 courses of rituximab, compared with the 48% response rate observed in the initial 4-treatment studies.[5] Median time to progression for responding patients was 19 months in the 8-treatment study vs 13 months in the standard treatment study. However, this was a small study and data evaluating the 4 vs 8 infusion protocol in a randomized setting have not been published yet.

Treating Earlier in the Course of the Disease
Perhaps using rituximab earlier in the course of disease will have more of an impact. The initial studies suggested that first relapse response rates were superior to the response rates seen after second or third relapses. The French Lymphoma Group addressed this issue by administering up-front rituximab to 49 treatment-naive patients as 4 weekly infusions.[6] An initial response rate of 73% was observed (26% CRs, 49% PRs), although this was later updated to 80% after additional follow-up.

Elimination of the t(14;18) translocation from the blood and bone marrow was recorded in 17 pts, 10 who had achieved CR; and at 1 year following completion of therapy, only 1 of these patients had progressed. Thirteen patients who responded to rituximab continued to express t(14;18), but none of these were complete responders. At 1 year, 8 of these 13 persistent PCR-positive patients had disease progression (62%).These data support the premise that molecular responses may correlate with clinical responses, and that molecular remissions may predict for longer time to tumor progression.

Rituximab in Combination Treatment of Lymphoma
Dr. Julie Vose, of the University of Nebraska, reviewed what is known about combining rituximab with cytotoxic chemotherapy in the treatment of NHL. In spite of many questions and controversies regarding combination therapy, it is clear that the clinical community has eagerly combined rituximab with conventional chemotherapy combinations. This has been based on the single-agent activity of rituximab, the nonoverlapping toxicities observed, the different mechanism of action, and the potential synergy with chemotherapeutic agents. A wide number of chemotherapy regimens have been combined with rituximab, with the cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) regimen leading the way.

Low-Grade NHL
Dr. Czuczman and colleagues[7] published the first data on combination therapy using CHOP combined with 6 doses of rituximab for the treatment of 38 patients with low-grade lymphoma, the majority (32) of which had received no prior treatment. A 100% response rate was observed with 55% CRs. Median time to progression had not been reached at 48 months. These results must be interpreted cautiously since the number of patients was small and since study entrants were not prospectively randomized. PCR analysis was also done on a handful of patients in this study. Eight patients who were PCR positive for Bcl-2 became negative by both blood and bone marrow assays following combination treatment.
Five of 7 patients remained PCR negative up to 38 months following completion of therapy. As observed previously, even patients who achieve only PRs with residual nodal disease were found to be PCR negative.
Rituximab has also been combined with other chemotherapy regimens besides CHOP. Czuczman and associates[8] treated an initial cohort of 10 indolent lymphoma patients with rituximab given between cycles of fludarabine. Six of 7 patients completed therapy, and all 6 patients achieved CRs. Three patients discontinued treatment secondary to myelosuppression. Among those completing therapy, a significant amount of neutropenic fevers were observed with some associated opportunistic infections, necessitating the use of growth factor support in most.
Because of this, the regimen was modified, with discontinuation of prophylactic antibiotics (secondary to concerns regarding drug-induced myelosuppression), and a 40% reduction in fludarabine from 5 consecutive doses per treatment cycle to 3. Twenty patients were treated with these modifications and 17 patients completed therapy. CRs were observed in 16, and only 1 of 3 patients discontinued therapy on account of myelosuppression.
Fewer infectious complications occurred and significantly less growth factor support was required. A handful of patients did require dose reductions starting with cycles 3 or 4.
An objective response rate of 93% was recorded, with 80% CRs (both confirmed and unconfirmed). Median duration of response was greater than 14 months with some patients in CR after more than 2 years.Nine of 9 patients screened for Bcl-2 in blood converted from positive to negative, while 6 of 7 became negative by bone marrow analysis. Investigators at the MD Anderson Cancer Center in Houston, Texas, also studied rituximab in combination with fludarabine, mitoxantrone, and dexamethasone (FND) among 134 patients with low-grade NHL.[9] Patients were randomized to receive 8 cycles of either concurrent FND with rituximab or FND followed by rituximab. Interferon was also administered for 1 year following completion of treatment. PCR analysis of blood and bone marrow specimens was done every 6 months.

Baseline Bcl-2 rearrangement was found among 70 patients (74%) in blood or one marrow at time of initial testing. At 12 months follow-up, 79% of specimens tested in the concurrent arm and 92% of the specimens tested in the sequential arms were seronegative for Bcl-2. Similarly, 73% of concurrent and 67% of sequential arm marrow specimens were negative for Bcl-2 at 12 months.

Aggressive NHL
Clinical data suggest that rituximab may be useful in the treatment of aggressive lymphomas. Most clinicians are familiar with the data published by Dr. Richard Fisher[10] showing equivalency between standard CHOP and 3 other more complicated treatment regimens, in which 5-year disease-free survival rates were 35% to 40%. Using these figures as historic benchmarks, a multicenter phase 2 trial administered CHOP plus rituximab to 33 patients with aggressive lymphoma.[11]

Patients received rituximab 375 mg/m2 on day 1 of each 3-week cycle, followed by CHOP on day 3. All patients received all 6 scheduled treatment cycles. Most of these patients had either diffuse large B-cell or follicular large-cell histology. Twenty patients (60%) had CR while 11 patients (33%) had PR. Initially, there was disappointment with these numbers, considering the equivalent historic response rates to CHOP therapy alone. Yet, it became clear after time that many of those patients deemed partial responders continued to respond and remained failure-free over a long period of time.
No differences in response were observed between patients younger or older than 60 years. Patients with higher International Prognostic Indicator (IPI) scores had a slightly lower response rate when compared with their low IPI counterparts, but this was not statistically significant, given the small number of patients studied. With a minimum of 2 years follow-up, over 90% of patients with an IPI score of 2 or less remained disease-free. For patients with an IPI score greater than 2, event-free survival at 2 years was still greater than 80%. While these results are intriguing, the small patient numbers argue for phase 3 testing before definitive conclusions can be drawn.

The most important trial to date is the randomized phase 3 trial in which elderly patients with diffuse large B-cell NHL were randomized to receive CHOP vs CHOP plus rituximab (given concurrently on day 1). This trial has been presented in preliminary form and was recently updated at the May American Society of Clinical Oncology meeting in San Francisco.[12] As reported by the Groupe d'Etude des Lymphomes de l'Adulte (GELA), 159 patients were treated with 8 cycles of CHOP while 169 patients received 8 cycles of CHOP plus rituximab. It should be noted that 60% of patients enrolled had IPI scores of 2 or more.
Consistent with previous historic data, the control CHOP arm recorded a complete response rate of 60%. There was a 75% complete response rate in the CHOP plus rituximab treatment arm. Median follow-up was only 12 months, but there was statistically superior event-free and overall survival in the combination arm.

The Eastern Cooperative Oncology Group trial E4494, which randomized patients to 8 cycles of CHOP vs 8 cycles of CHOP plus rituximab, has completed accrual of over 600 patients, and will be an important confirmatory study to the GELA data when analyzed. This study follows the original Czuczman format, in which rituximab was interspersed between CHOP treatments. Unlike the GELA trial, patients will also be randomized to 4 weekly doses of rituximab maintenance every 6 months for 2 years vs no maintenance therapy.

Clearly, combination therapy with rituximab for NHL has arrived, and, as indicated by several questions following Dr. Vose's formal presentation, its use as a radiosensitizer, as an adjunct to treatment in patients with mantle-cell lymphoma, and as a purging agent in stem cell transplant regimens continues to be explored.

Single-Agent Treatment of CLL
Dr. Susan O'Brien, of the MD Anderson Cancer Center in Houston, Texas,concluded this symposium by focusing on the role of rituximab in CLL. As a reference point, the initial phase 1 and 2 data discussed previously included a small number of CLL patients, for whom response rates were particularly low. Possible explanations for this difference in response include less CD20 expression on cell surface membranes as well as more rapid antibody clearance among nonresponders. As discussed by Dr. Maloney, perhaps dosing and scheduling need to be customized for individuals with CLL histology. Based upon hematopathology data generated at the MD Anderson Cancer Center, there seems to be circulating CD20 antigen in CLL patients, resulting in extratumoral antibody binding. This has been confirmed by Western blot analysis as well as by enzyme-linked immunosorbent assay among 106 patients with CLL compared with 20 normal controls.[13] These data also appear to link higher levels of circulating CD20 expression with more advanced stage disease. What is not known is whether higher baselines of circulating CD20 are present in nonresponders.

While these hypotheses are being tested in ongoing prospective trials, Dr. O'Brien and colleagues shied away from standard doses of rituximab in their initial single-agent CLL trials, based, in large part, on the low response rates noted by other investigators. Given the lack of dose-limiting toxicity observed in the phase 1 studies with rituximab, Dr. O'Brien initiated phase 1 testing for CLL at an initial dose of 375 mg/m2, to be escalated on weeks 2, 3, and 4.[14] The highest dose given was 2250 mg/m2.
Forty of the 50 patients included had CLL, while the remaining patients had lymphomas with high levels of circulating cells and included marginal-zone lymphomas, mantle-cell lymphomas, and prolymphocytic leukemia. All patients except 1 with marginal-zone lymphoma had been previously treated with a median number of 2 prior regimens. Half of the CLL patients were refractory to fludarabine (ie, they failed to respond to their last fludarabine treatment). Mild grade 1 and 2 fevers and chills were observed in 48 of 50 patients (94%) treated with standard-dose rituximab. Six patients (12%) experienced grade 3 and 4 toxicity, including high fevers, chills, dyspnea, and hypoxia. Five patients became hypotensive and 1 patient became hypertensive. Only 1 of the 40 CLL patients experienced severe toxicity, whereas the other 5 cases were observed in the remaining histologic types.
While circulating CD20 may be responsible in part for this, it is also known that CD20 expression in mantle-cell and marginal-zone lymphoma is much more intense than in CLL.Maybe the combination of both circulating antigen and antigen overexpression accounts for the degree of toxicity experienced.
With dose escalation at week 2, only 3 patients experienced mild toxicity, even at doses of 1500 mg/m2. At the 2250 mg/m2 dose level, 8 of 12 patients experienced moderate (grade 1 and 2) toxicity, including fevers, chills, and malaise. Response rates ranged from 23% at the lowest dose delivered, to 80% at the maximum dose delivery, although little bone marrow clearance was observed. Lymph node size did not appear to predict for response, although prior resistance to fludarabine appeared to correlate with lower responses. A trend to lower response in more advanced stage was observed, but this did not reach statistical significance.
Median time to progression was approximately 8 months, shorter than the time to progression observed in the NHL trials. This trial confirmed that there was significant activity for rituximab in the treatment of CLL, and that responses appeared to be dose-related, although it failed to establish criteria for frequency of treatment or optimal dosing. Dr. John Byrd and colleagues,[15] at the Walter Reed Army Medical Center in Washington, DC, also initiated a dose-escalation trial in CLL, the results of which were recently published. Because of concerns regarding first dose toxicity, all patients received a limited dose of 100 mg of rituximab on day 1. This was followed by thrice weekly administration of 250 mg/m2 for the first 3 patients, with all remaining patients dose-escalated to a standard dose of 375 mg/m2 given 3 times weekly for 4 wks.

Little toxicity was observed after the first dose, and this led to speculation that subsequent doses could be administered over a 1-hour time period, which they were. No increased toxicity was observed. Of the 33 patients enrolled, 31 had CLL and 2 had small lymphocytic lymphoma. Patients had received a median number of 2 prior treatments, although there were a handful of treatment-naive CLL patients.

The overall response rate observed in this study was 45%, with a trend to lower response rate in more advanced stage disease, and higher responses among the previously untreated (6 of 7 patients responded). A lower response rate was not observed among the fludarabine refractory patients, nor were there response differences based upon size of lymph nodes. An assay was developed to measure surface CD20 expression, but no correlation between response and expression was made.

The presence of first-dose reactions was also analyzed for response, and no differences were noted. Toxicity was still significant, even when a low dose of 100 mg of rituximab was given, but as observed previously in the MD Anderson data, no significant toxicity was observed during or beyond dose 3.
Toxicity profiles did not appear to be influenced by patient age, elevation of initial lymphocyte count, or cell surface expression of CD20.

Combination Therapy for CLL
In an abstract presented during the last American Society of Hematology (ASH) meeting, an in vitro t(14;18) cell line was incubated with complement, then exposed to either single-agent rituximab, fludarabine, or both drugs.[16]. Cell lysis was most dramatic when the 2 drugs were combined. Downregulation of CD55 was observed following fludarabine treatment. Since cell surface CD55 is known to protect against complement-mediated lysis, it was hypothesized that downregulation of CD55 by fludarabine potentially increased the efficacy of rituximab-induced, complement-mediated cytotoxicity. Independent of the intriguing science behind this abstract, a trial was launched at MD Anderson Cancer Center, inspired by the success of other combination therapy trials in other hematologic malignancies.

Building on a reference regimen of daily fludarabine 30 mg/m2 plus cyclophosphamide 300 mg/m2 for 3 days (FC), rituximab 375 mg/m2 was added. During the first cycle, rituximab was given on day 1, followed by 3 days of concurrent FC (FRC). In subsequent courses, all 3 drugs were started on day 1, and rituximab was increased to 500 mg/m2.
Among the first 8 patients treated, 2 experienced severe tumor lysis, and 1required temporary hemodialysis. The white blood cell count dropped precipitously but no other myelosuppression was observed. For these reasons, subsequent doses of fludarabine and cyclophosphamide were decreased to 25 mg/m2 and 250 mg/m2, respectively. Among the 59 chemotherapy-naive CLL patients thus treated, grade 3 and 4 toxicity was noted in 7% at the time of first infusion. Virtually no B-cells were detectable in the marrow after 3 cycles.

In an as yet unpublished update expanding upon a recently published ASH abstract,[17] 55 patients have completed 3 courses of treatment while 42 have completed 6. The complete remission rate stands at approximately 60%.
Historically, the fludarabine plus cyclophosphamide combination has produced CRs in the 30% to 35% range, although conclusions regarding the superiority of FRC over FC are difficult to draw since there is no comparative internal control group in this study.

Among 12 patients achieving CRs, 6 became PCR-negative by bone marrow analysis. Duration of response cannot be determined at this short follow-up interval, particularly when one considers that the historic median time to progression following FC in treatment-naive patients is approximately 4 years. If remission duration continues to parallel response rate, then one can anticipate marked prolongation in those patients responding to FRC.

The Cancer and Leukemia Group B also conducted a trial in which patients were randomized to receive fludarabine plus rituximab concurrently vs fludarabine followed by rituximab.[18] Those patients randomized to receive concurrent treatment were given rituximab on days 1 and 4 during the first cycle, then on day 1 thereafter for a total of 6 cycles. Fludarabine was given in a 25 mg/m2 day 1-5 schedule. In the sequential arm, fludarabine was given for 6 cycles, followed by 4 weekly treatments of standard-dose rituximab.

Among the 104 patients enrolled, a higher incidence of neutropenia was observed in the concurrent treatment arm, although no differences were noted in the degree of anemia or thrombocytopenia. Response rates were approximately twice as high in the concurrent drug arm, compared with the fludarabine-only arm prior to administration of rituximab, echoing the MD Anderson findings seen with FRC.

When "consolidation" rituximab is factored in, the overall response rate for the concurrent treatment arm was still significantly higher, although there was no difference in time to progression. Again, these results must be interpreted cautiously due to short follow-up and small patient numbers.

Upregulation of cellular-surface CD20 expression may play a role in future treatment strategies, and studies are currently ongoing looking at various stimulatory agents, including interferon, interleukin-4, and granulocyte-macrophage colony stimulating factor (GM-CSF). Another ongoing trial has combined monoclonal antibody against the CD52 receptor (alemtuzumab) with rituximab, and is showing an initial response rate of approximately 40% across all patient types (chemotherapy refractory, chemotherapy nonrefractory, etc.).

Conclusions
Clearly, the use of monoclonal antibody therapy will continue to escalate as more becomes known about their specific mechanisms of action as well as their interactions with chemotherapy, radiation, novel agents, and other antibodies. Clinical trials are moving antibody therapy into the forefront of treatment of many hematologic and solid malignancies, and for the first time in a long time, it seems that these agents can significantly alter survival patterns that have resisted change with other treatment strategies. The next few years of investigation promise to be exciting ones.

Non-Hodgkin (Follicular lymphoma - FL) and vaccination, shows very promising results - 90% survives 7 yearsborder without any relapse -  in phase II study
Source: Accentia-website. http://www.accentia.net/companies/biovestimmunotherapy
The Biovest cancer immunotherapy stems from work begun in 1986 on development of a patient-specific follicular lymphoma (FL) vaccine. The cancer vaccine evokes the power of each patient's immune system and primes it to recognize and eliminate cancerous lymphoma cells, while sparing normal B-cells. In the vaccine's cancer target, B-cell lymphoma, the process is made possible by the presence of a hallmark surface antigen of the cancer cells that is not present in non-cancerous tissue. By priming the immune system with this antigen in the form of an autologous vaccine, the vaccine induces a powerful immune response against the cancerous cells that in many cases results in pronounced, complete cancer clearance. Because each dose of Biovest's vaccine is derived from individual patient's cancerous cells, the vaccine is a true targeted, customized therapy. The vaccine's powerful anti-tumor effect vastly exceeds that of non-targeted traditional therapy, as it arises from the immune system's defense cells' innate ability to selectively target foreign antigens. Most importantly, the immune response triggered by the vaccine against the cancerous tissue is a natural disease-fighting mechanism and has almost none of the side-effects associated with the broad-spectrum chemotherapy and radiation used to traditionally treat this type of lymphoma. 

Biovest Immunotherapy - Levy Study Results
In Hsu, et al.'s study at Stanford University, researchers immunized patients with the autologous vaccine against the Ig (antigen) expressed by their tumor and observed their clinical outcomes. After standard chemotherapy, 41 patients with non-Hodgkins Lymphoma (NHL) received a series of injections consisting of tumor Ig protein coupled to keyhole limpet. Note that this prototype vaccine did not include the immunostimulant GM-CSF (see below). The median duration of followup for all patients was 7.3 years from the diagnosis and 5.3 years from the final chemotherapy given before the vaccination.
Twenty patients (49%) generated specific immune responses against the idiotypes of their tumor Ig. Two patients who had residual disease experienced complete tumor regression in association with the development of these immune responses. The median duration of freedom from disease progression and overall survival of all 20 patients mounting an anti-idiotype immune response were significantly prolonged compared to the patients who did not mount an immune response.
Thirty-two patients were in their first remission and nine were in subsequent remissions before beginning vaccine treatments. Analysis of the 32 first remission patients also shows an improved clinical outcome for those patients who mounted a specific immune response compared to those who did not (freedom from progression, 7.9 years v 1.3 years and a median survival from time of last chemotherapy that exceeded the time of observation v 7 years for non-responding patients).
The full study results are published at:
Hsu, JH, Caspar CB, et al. Tumor-specific idiotype vaccines in the treatment of patients with B-cell lymphoma-long term results of a clinical trial. Blood 89(9):3129-3135 May 1997
Biovest Immunotherapy - Bendandi et al. Study Results of Vaccine+GM-CSF
The Biovest cancer vaccine is an improvement over the prototype vaccine developed at Stanford and it has demonstrated extremely encouraging results in initial clinical trials. The NCI tested the use of an approved immunostimulant, GM-CSF, as an adjunct to the Id-keyhole limpet hemocyanin antigen. A 20-patient Phase II study to evaluate the vaccine was reported by the National Cancer Institute (NCI) in 1999. The study evaluated the ability of the BioVest idiotype protein vaccine formulation to eradicate residual lymphoma cells in 20 patients in a homogeneous, chemotherapy-induced first clinical complete remission. In this trial as opposed to the prototype vaccine developed at Stanford, the difference was patient eligibility and the addition of granulocyte-monocyte colony-stimulating factor (GM-CSF) to the vaccine formulation. The inclusion of GM-CSF was based on previous studies demonstrating GM-CSF's ability to generate tumor-specific CD8 T-cell immunity by enhancing the processing of introduced antigen.
11 patients in the study with detectable primary tumor markers (translocations), showed detectable cells in their blood by PCR both at diagnosis and following the first round of standard chemotherapy. The vaccine's clearance of these residual cancer cells in the blood is an important distinction between the efficacy of traditional therapy and that of a targeted cancer vaccine. Out of 11 vaccinated patients who were tested by the molecular analysis, FL tumor cells were detectable in only 3 patients. This is extremely encouraging, since the disease is detectable by this method even in those patients who go into complete clinical remission after other treatments. 
The final study results are even more striking, with 18 of 20 (90%) of the patients demonstrating continous clinical remission with a median followup of 42+ months. Tumor-specific cytotoxic CD8+ and CD4+ T cells were uniformly found (19 of 20 patients) in the patients treated. Vaccination was thus associated with prolonged clearance of lymphoma cells. 
The full study results are published at:
Bendandi M, Gocke CD, et al. Complete molecular remissions induced by patient-specific vaccination plus granulocyte-monocyte colony-stimulating factor against lymphoma. Nature Medicine. 5(10):1171-1177. October 1999. 

These results contrast with the expected course of the disease after standard chemotherapy and radiation, which shows median relapse time for FL patients of three years, with 90% of patients dying of a tumor-related mortality within 7 years of the date of diagnosis.

Long term Followup and Study Results 
Long-term follow up of these patients in the Phase II was recently completed (summer 2003) and demonstrates in the study patients. Induction of CD4+ T cell response in 100% of patients, induction of CD8+ T cell response in 86% patients (defined by lysis of autologous lymphoma targets), induction of molecular remission in 75% of patients, and most critically, the median time to relapse has now exceeded 7 years since the start of the trials.

Pivotal Phase III
As a result of the promising Phase II results, the FDA and NCI have approved a pivotal Phase III study involving 375 patients. In January 2000, the NCI opened a multi-institutional phase III randomized clinical trial that is scientifically designed to definitively evaluate the question of clinical benefit induced by patient-specific idiotype vaccines in follicular lymphoma patients. Previously untreated advanced stage follicular lymphoma patients are initially treated with a uniform chemotherapy regimen that has produced complete response in virtually all patients to date (84%). Approximately six months after the completion of chemotherapy, patients in complete remission or complete remission unconfirmed are treated with either the experimental tumor-specific vaccine (Id-KLH vaccine + GM-CSF) or the control non-specific vaccine (KLH + GM-CSF). 

Patients who attain a CR or complete response unconfirmed (CRu) with a standard uniform chemotherapy regimen of Prednisone, Doxorubicin, Cyclophosphamide, and Etoposide (PACE) chemotherapy are randomized to the experimental tumor-specific vaccination arm (Id-KLH vaccine + GM-CSF) or the control non-specific vaccination arm (KLH + GM-CSF). There is no placebo treatment arm. The randomization is done in a 2:1 ratio in favor of the specific vaccination arm. Neither the patient, treating physician or anyone directly involved with treating patients on the study is aware of the treatment a patient has been assigned. Patients who remain in CR or CRu, begin vaccination approximately 6 months (or whenever a customized vaccine is available, up to a maximum period of 12 months) after the completion of chemotherapy to allow time for immunological recovery. Each patient receives five subcutaneous vaccinations over a period of 6 months.

Study Participation
As of January 2003, 128 patients have been accrued on to the Phase III study. Of the 96 patients that completed chemotherapy, 81 patients ( ~ 85%) achieved complete remission or molecular complete remission. CR or CRu. Twenty-nine patients have either completed or started the vaccination. The toxicities due to the PACE chemotherapy are generally those related to the chemotherapy agents, including some serious toxicities such as secondary leukemias. The side effects of the vaccine have been mainly local such as erythema, induration and mild tenderness at the site of injection. The vaccine or GM-CSF may cause fever, chills and flu-like symptoms. Bone pain and occasionally hypotension have been observed with GM-CSF. No long-term toxicities or deaths have been associated with the vaccine in the completed phase II study.

Expanded Applications
In addition to forms of non-Hodgkins lymphoma other than the follicular type (FL), the vaccine technology has the potential to offer substantial benefits to other related B-cell derived neoplasms such as multiple myeloma and chronic lymphocytic leukemia. Like non-Hodgkins lymphoma, these neoplasms also express an id on the surface of their tumor cells. 

d.d. january 2001: Cancer Vaccine Pioneer At NYU To Review Personalized Cancer Vaccines,Pioneering Biotherapies Are At Advanced Trials Stage

NEW YORK--(BUSINESS WIRE)--Jan. 25, 2001--Dr. Larry W. Kwak, M.D., Ph.D.,Senior Investigator at the National Institutes of Health, will present published findings related to work on personalized cancer vaccine technologies, at 1 p.m. on Jan. 26, 2001, at The New York University Medical Center (NYU). Specifically, Dr. Kwak will discuss pioneering advances in the field of tumor-specific personalized cancer vaccines, to treat a variety of lethal cancers.

As one example, on Sept. 27, 1999, the National Cancer Institute (NCI) announced that, for the first time ever, results of a Phase II cancer vaccine study demonstrated an anti-tumor effect in a small group of patients vaccinated over a five-year period. NCI researchers reported that 18 of 20 patients vaccinated against this common blood-cell tumor remained in complete remission an average of four years after vaccine therapy began. Prior to vaccination, all of the patients in the Phase II study had minimal disease or were in a chemotherapy-induced first remission.

As a result, NCI launched a large-scale, randomized, Phase III clinical trial to test these experimental cancer vaccines, which are custom-made from patients' own tumor cells when in complete remission after chemotherapy. The side effects of the vaccine appear to be minor or non-existent. Its production requires extremely unique technologies.

NYU is considering an opportunity to participate in, and play a pivotal role in, this national Phase III trial. Currently, cancer vaccine trials are in Phase III trials at five leading medical centers: Northwestern University Medical School, University of Pennsylvania, Duke University, the Moffitt Cancer Center at University of Southern Florida, and at the National Cancer Institute in Bethesda, Maryland.

In the year 2001, an estimated 54,900 people are expected to be diagnosed with non-Hodgkin's lymphoma. Biovest International is currently producing the aforementioned cancer vaccines for the national Phase III trial.

 Nipent seems effective for different kinds of bloodcancers, , also for non-Hodgkin

-- Supergen Says Study Shows Nipent Effective --

DUBLIN, Calif. -(Dow Jones)- SuperGen Inc. (SUPG) said several studies showed
its anticancer drug, Nipent, can treat a variety of hematological malignancies.
Nipent is currently marketed by SuperGen for the treatment of hairy cell
leukemia, a potentially fatal cancer of the blood and bone marrow that is
characterized by a reduction in white blood cells, red blood cells and
platelets.
In a press release Friday, the biopharmaceutical company said a long-term
follow-up study of 180 hairy cell leukemia patients treated with Nipent between
1986 and 2000 resulted in a response rate of 98%.
In another study, 13 patients with indolent, or non-aggressive, non-Hodgkin's
lymphoma and chronic lymphocytic leukemia were given a three-pronged therapy
consisting of Nipent, cyclophosphamide and Rituximab. Ten of the 11 patients who
could be evaluated showed the tumor response sought by the study.
A Phase II multicenter clinical trial involving 62 patients with chronic
lymphocytic leukemia was conducted to assess how effective and safe it was to
use a combined treatment of Nipent and Rituximab. Of the 54 evaluable patients,
33% achieved an objective response.
In a Phase I study, 23 patients with a variety of hematological malignancies
were enrolled to assess Nipent as a treatment for steroid refractory acute
graft-versus-host disease. Twenty patients were evaluable for response and they
included 11 complete responses, three partial responses, three with mixed
responses and three with progressive disease.
Fifteen patients with myelodysplastic syndrome received a new preparative
regimen consisting of Nipent, low-dose radiation and photophoresis treatments -
where blood is exposed to ultraviolet light - prior to an allogeneic bone marrow
transplant. Thirteen patients experienced full engraftment and subsequently,
full remission.

FAQ from website from  Supergen Inc. :

WHAT IS NIPENT'S FDA APPROVED USE ?

Nipent® is indicated as a single-agent treatment for both untreated and alpha-interferon-refractory hairy cell leukemia patients with active disease as defined by clinically significant anemia, neutropenia, thrombocytopenia, or disease-related symptoms.

WHAT ARE THE COMMON SIDE EFFECTS OF NIPENT THERAPY ?

The most serious adverse reactions reported with Nipent therapy are myelosuppression, rash and exacerbation of infection. Please see full prescribing information.

IS SUPERGEN CONDUCTING ANY CLINICAL TRIALS WITH Nipent ?

Multiple clinical trials with pentostatin (the active ingredient in Nipent) are currently ongoing in various other diseases. If you have specific questions regarding Nipent please contact SuperGen’s Professional Services Department at (800) 353-1075.

HOW IS NIPENT SUPPLIED ?

Nipent is available as a sterile lyophilized powder for reconstitution in 10 mg vials (J code J9268).

HOW IS NIPENT ADMINISTERED ?

For the treatment of hairy cell leukemia, Nipent is administered as an outpatient regimen at 4 mg/m2 intravenously every 2 weeks. Nipent can be administered as a bolus infusion or as a 20 to 30 minute infusion.

Patients should be properly hydrated to avoid renal complications. Patient should receive 500mL to 1000mL of 5% dextrose in 0.5 normal saline or equivalent prior to Nipent Administration, and an additional 500mL following Nipent administration.

HOW DO I ORDER NIPENT ?

Please call our distributor, Abbott Laboratories, (800) 222-6883 to order Nipent (5am-4pm PST Monday-Friday). For faster service, please refer to Nipent’s Product number R0800-01-01 when ordering.

WHO DO I CALL IF I HAVE REIMBURSEMENT CONCERNS ?

Please call SuperGen’s reimbursement hotline at (800) 340-8667 (6am-5pm PST).

Prozac could beat non-Hodgkin?
d.d. april 2003: Source: BBC-Health
Prozac 'could beat cancer'
The drug could help tackle cancer 
The anti-depressant drug Prozac could help doctors tackle cancer, says a UK-based research team. The drug has been around for well over a decade, and is an established treatment for depression. However, in recent years, doctors have suggested it might have other benefits. Researchers from Birmingham University looked at the effects of a variety of chemicals on cancer cells of a type called Burkitt's lymphoma. This type of cancer - a type of non-Hodgkin's lymphoma - frequently develops in Aids patients, whose weakened state means that conventional chemotherapy may not be appropriate. It is an aggressive and frequently lethal form of the disease. 
Cell suicide. The scientists found that even moderate doses of Prozac appeared to trigger "cell death" - a process in which the cancer cells "commit suicide". The cell death, or apoptosis, was described by the researchers as "rapid and extensive". However, it cannot be certain that the same effect would be reproduced in a real patient as opposed to cells in a laboratory test tube. But the experts leading the research are hopeful that it might do so, and perhaps even help in the fight against some other cancers. Clinical trials. Professor John Gordon said: "This new development is very exciting. "We were intrigued as to the impact of fluoxetine (Prozac) on the cancer and found that by increasing its dosage the Burkitt's cells are killed. "We are already discussing with clinicians about using these drugs as a therapy for Burkitt's lymphoma." Ken Campbell, from the Leukaemia Research Fund, welcomed the research.  He said: "While there is still some way to go before doctors can start prescribing these drugs to patients with this cancer, these findings could be of major importance to those patients with the Aids-related form of the disease, and to those patients who are not in a position to tolerate intensive chemotherapy. "Alternative treatments such as this which are inexpensive and have low levels of toxicity would be major step forward in the treatment of this disease." Source: Reuters
Prozac Kills Burkitt's Lymphoma Cells: Scientists Tue April 15, 2003 02:47 PM ET 
By Richard Woodman
LONDON (Reuters Health) - British scientists said on Tuesday that early lab research suggests Prozac and similar antidepressants could treat at least one form of the cancer lymphoma.
The University of Birmingham team said they had discovered that, in the test tube, the drugs could make Burkitt's lymphoma tumor cells commit suicide. Burkitt's lymphoma is a fast-growing cancer that makes up only a small percentage of all lymphomas, but is common in Africa.
The drugs tested all belong to a class of anti-depressants called selective serotonin reuptake inhibitors (SSRIs).
"The drugs activate the signaling mechanism that leads to the apoptosis (suicide) program. The end results is that within 24 hours the cells are dead," John Gordon, professor of immunology told Reuters Health. Last year the same team reported that the brain chemical serotonin activates the suicide program and that SSRI drugs can block the entry of serotonin, thereby protecting cancer cells. But the latest findings, published in the American journal Blood, show that by increasing the quantity of the drug they could reverse this process, forcing the cells to commit suicide. Gordon said in a statement: "This new development is very exciting. We were intrigued as to the impact of the SSRIs on the cancer and found that by increasing the dosage of SSRIs the Burkitt's cells are killed. "The initial indicators are exceedingly positive and we are already discussing with clinicians about using these drugs as a therapy for Burkitt's lymphoma. We are now examining the effect the SSRIs have on other cancer types." Neuropharmacologist Nicholas Barnes said the SSRIs were associated with very few side effects, even when used at high dosages. "It should therefore be possible to determine whether our research has direct clinical benefit with the minimum of delay."
At present, Burkitt's lymphoma is treated with chemotherapy, which generally achieves a high cure rate. However, the scientist said response rates in the case of AIDS-related Burkitt's lymphoma are much lower. "Furthermore, the combination of chemotherapy, and the clinical support required is not always readily available in underdeveloped countries where the disease is endemic," the researcher said. Britain's Leukemia Research Fund said: "Burkitt's lymphoma is a particularly aggressive form of cancer which affects a huge number of people in Africa and a significant number of people in the UK. "While there is still some way to go before doctors can start prescribing these drugs to patients with this cancer, these findings could be of major importance to those patients with the AIDS-related form of the disease, and to those patients who are not in a position to tolerate the intensive chemotherapy. "Alternative treatments such as this which are inexpensive and have low levels of toxicity would be a major step forward in the treatment of this disease." A spokesman for Eli Lilly, which makes Prozac, said the company was not involved in the latest research. The drug -- once the company's biggest earner -- no longer has patent protection.