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Therapy Choices

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Rituxan plus Chemotherapy Combinations

Date: December 15, 2002

by Chaya Venkat

Rituxan Combos with Purine Analogs, Alkylating Agents and Steroids

Related Article: RF Therapy
RF Risks and Benefits

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Rituxan, Fludarabine and Cyclophosphamide

Results Presented at ASH 2001

The following detailed press release describes the results presented at the 2001 American Society of Hematology Annual Meeting (abstracts no. 3212, 3210, and 1530).  Hopefully, all of you know by now how to access the ASH2001 on-line abstracts. They are free, and an excellent source of accurate information. If you do not know how to access this treasure trove, let me know and I will walk you through it.

You should also read the ASH 2001 abstracts Nos. 2650 and 3210, that deal with RFC combo therapy for previously treated and untreated patients,  respectively. These combination drug therapies, especially those including one of the monoclonal antibodies (Rituxan in this case, but I believe Campath combination trials are not far behind) are the wave of the future. Well before gene therapy of any sort becomes available to the run of the mill CLL patient, I would be willing to bet dollars for donuts that the majority of patients currently in watch and wait mode will eventually be treated with some  variation on this theme.

Announcement:

Genentech, Inc. (NYSE: DNA - news) and IDEC Pharmaceuticals Corporation (Nasdaq: IDEC - news) today announced the results of three studies presented at the annual meeting of the American Society of Hematology (ASH) that examine the role of Rituxan®  (Rituximab) alone and in combination with chemotherapy in the early treatment of newly-diagnosed patients with chronic  lymphocytic leukemia (CLL).

"The studies examining the combination of Rituxan with chemotherapy -- treatments with complementary mechanisms of action --  showed initial positive results in clinical trials as a way to attack B-cell cancer in newly diagnosed patients,'' commented Gwen Fyfe,  M.D., Genentech's senior director of Oncology, Medical Affairs. "We also are encouraged that in an investigational study, patients  who received maintenance doses of Rituxan continued to respond throughout the course of their treatment.''

I. Rituxan and Fludarabine Combination Therapy in CLL (Abstract No. 3212)

In a randomized Phase II study conducted by the Cancer and Leukemia Group B (CALGB), a total of 104 previously-untreated  patients with CLL were enrolled to compare the effect of four infusions of Rituxan given at the same time as Fludarabine (concurrent)  or two months following initial treatment with fludarabine (sequential).

Ninety percent (46/51) of patients in the concurrent arm responded, with 47 percent (24/51 patients) and 43 percent (22/51  patients) achieving complete (defined as disappearance of all detectable signs of cancer) and partial responses (defined as decrease in tumor size greater than 50 percent), respectively. In the sequential arm, the overall response rate was 77 percent (41/53), with 28 percent (15/53 patients) achieving a complete response and 49 percent (26/53 patients) a partial response.

In the concurrent arm, 29 percent of patients developed Grade 3/4 infusion toxicity during the first infusion of Rituxan, as compared  to six percent of patients in the sequential arm. Infusion reactions with the second treatment in both arms were uncommon. Adverse events specific to concurrent therapy included neutropenia (29 percent Grade 3; 48 percent Grade 4), thrombocytopenia (14 percent Grade 3; 6 percent Grade 4) and infection (18 percent Grade 3). Adverse events for fludarabine in the sequential arm were neutropenia (11 percent Grade 3; 30 percent Grade 4), thrombocytopenia (8 percent Grade 3; 4 percent Grade 4) and infection (19 percent Grade 3; 2 percent Grade 4).

II. Rituxan and Fludarabine/Cyclophosphamide Combination Therapy (Abstract No. 3210)

A Phase II study conducted at the University of Texas M.D. Anderson Cancer Center was designed to evaluate the safety and  effectiveness of Rituxan and fludarabine/cyclophosphamide as frontline combination CLL treatment. A total of 79 patients received six cycles of fludarabine (25 mg/m2), cyclophosphamide (250 mg/m2) and Rituxan (375mg/m2 for first cycle; 500 mg/m2 all  subsequent cycles). Treatment was given over three days and repeated every four weeks for the six cycles.

Sixty-six percent (52/79) of patients achieved a complete response (disappearance of all detectable signs of cancer), 15 percent (12/79 patients) achieved a partial response (decrease in tumor size greater than 50 percent) and 14 percent (11/79 patients) a nodular partial response (residual lymphoid nodules in bone marrow).

"Taken together, the preliminary data from these two investigational studies show that Rituxan used front-line in combination with chemotherapy appears to potentially increase complete responses in CLL,'' said Dr. Fyfe. ``We are most excited by the fact that in addition to CLL, all of the data presented at ASH demonstrated positive preliminary results when Rituxan was used in combination with chemotherapy for various forms of lymphoma.''

Treatment was well tolerated with 76 percent of patients completing six cycles and only 2.5 percent of patients completing less than three treatment cycles. Fever and chills were experienced by nearly half of the patients with the first Rituxan infusion. Eighteen  percent of patients experienced hypotension, 18 percent nausea and 10 percent dyspnea.

Neutropenia (Grade 4) was observed in 20 percent of all cycles administered, with patients experiencing Grade 3 or 4 thrombocytopenia in four percent of all cycles. In three percent of all cycles, patients experienced major infections (one percent sepsis; two percent pneumonia). Patients experienced minor infections in 14 percent of all cycles.

III. Single Agent Rituxan Given Every Six Months (Abstract No. 1530)

Researchers explored the effectiveness of front-line single agent and maintenance treatment with Rituxan in CLL and small lymphocytic lymphoma (SLL), a relatively rare form of B-cell non-Hodgkin's lymphoma.

Sixty-eight previously-untreated patients with CLL or SLL were treated with single-agent Rituxan for four weeks (375 mg/m2 weekly). All patients were re-evaluated for response two weeks after completing Rituxan therapy. Patients with objective responses (decrease in tumor size greater than 50 percent) or stable disease (cancer that is neither decreasing nor increasing in extent or severity) continued maintenance courses of Rituxan (using a standard four-week schedule) every six months for a maximum of four courses.

At the time of first re-evaluation, 33 of 66 evaluable patients (50 percent) achieved an objective response to Rituxan, and 32 additional patients (48 percent) had stable disease. Twenty-seven (41 percent) patients are continuing to receive maintenance courses of Rituxan, so the final response rate cannot yet be determined. However, four additional patients receiving maintenance Rituxan have already responded, for a current response rate of 56 percent. In the first group of 24 patients treated (all with SLL), median progression-free survival was 31 months.

"While preliminary, these results show that Rituxan is active as a front-line therapy for CLL and SLL,'' said John D. Hainsworth, M.D., director of clinical research, The Sarah Cannon Cancer Center, Nashville, TN.

Adverse effects seen in this trial were limited to Rituxan-related infusion reactions. These symptoms include, but are not limited to, flu-like fever, chills/rigors, nausea, urticaria, headache, bronchospasm, angioedema and hypotension. These symptoms vary in severity and generally are reversible with medical intervention. In rare instances, severe and fatal infusion-related reactions have occurred, nearly all of which have been associated with the first Rituxan infusion. Only two patients experienced reversible Grade 3 or 4 toxicity, one of which was nausea and the other fatigue.

About Rituxan

Rituxan is a monoclonal antibody that binds to a particular protein -- the CD20 antigen -- on the surface of normal and malignant B-cells. It then recruits the body's natural defenses to attack and kill the marked B-cells. Stem cells (B-cell progenitors) in bone marrow lack the CD20 antigen, allowing healthy B-cells to regenerate after treatment and return to normal levels within several months.

Rituxan received FDA approval in November 1997 for the treatment of relapsed or refractory low-grade or follicular, CD20 positive, B-cell NHL. It also was approved in the European Union (EU) under the trade name MabThera® in June 1998. Genentech and IDEC co-market Rituxan in the United States, Roche markets Rituxan in the rest of the world, except Japan where Rituxan is co-marketed with Zenyaku Kogyo Co. Ltd.

Rituxan Safety Profile

The majority of patients experience infusion-related symptoms with their first Rituxan infusion. These symptoms include, but are not limited to, flu-like fever, chills/rigors, nausea, urticaria, headache, bronchospasm, angioedema and hypotension. These symptoms vary in severity and generally are reversible with medical intervention. In rare instances, severe and fatal infusion-related reactions have occurred, nearly all of which have been associated with the first Rituxan infusion. These events appear as manifestations of an infusion-related complex and include hypoxia, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, cardiogenic shock and tumor lysis syndrome. Patients who develop clinically significant infusion-related cardiopulmonary events should have their Rituxan infusion discontinued and receive medical treatment.

In rare instances, severe mucocutaneous skin reactions have occurred that may be associated with Rituxan therapy. Many of these reactions have been described as paraneoplastic pemphigus which is known to be associated with various B-cell lymphomas particularly NHL and chronic lymphocytic leukemia (CLL). Patients who develop a severe mucocutaneous skin reaction should have Rituxan discontinued and receive appropriate medical treatment, including a skin biopsy to guide therapy.

RFC Combo

Here is the ASH abstract that should be mandatory reading for all CLL patients considering "RFC" combo treatment. 

M.D. Anderson has been doing much of the work in this area, and while there have been snippets of information coming out for a while, this is the first definitive statistics I have seen on this effort. Out of 135 patients, 67% received complete response (CR), 19% received a NPR, and 18% received a PR. (See my article on the definitions of CR, NPR and PR). 

What is particularly encouraging is the large percentage of patients who were "PCR negative": Out of 78 patients who had PCR performed on bone marrow, 41 patients were PCR negative. True, there was PCR relapse in some of these patients, but only in a small percentage. I have not seen definitive statistics on overall survival advantage, mainly because sufficient time has not passed since the start of this protocol, but the buzz is that there is likely to be statistically significant survival advantage for patients going through this combo therapy, as compared to previous "best available" therapies. 

These are important statistics, since the RFC protocol is rapidly becoming the new gold standard for treating CLL patients. Until a cure becomes available, this standardized protocol remains the best option available to a lot of people, outside of clinical trial settings.

Abstract:

A High Proportion of Molecular Remission Can Be Obtained with a Fludarabine, Cyclophosphamide, Rituximab Combination (FCR) in Chronic Lymphocytic Leukemia (CLL).

Michael Keating, Taghi Manshouri, Susan O'Brien, William Wierda,  Hagop Kantarjian, LaShonda Washington, Susan Lerner, Maher Albitar. 

Leukemia, UT M. D. Anderson Cancer Center, Houston, TX, USA; Hematopathology, UT M. D. Anderson Cancer Center, Houston, TX

Definitions of complete and partial remissions (CR+PR) in CLL have become more stringent as treatments have become more effective. The NCI Working Group (NCIWG) categorizes patients (pts) as having CR, nodular (N) PR (CR except for residual lymphoid aggregates on bone marrow (BM) biopsy) and other PRs. Many CR pts have clonal disease detectable on flow cytometry and molecular remissions (PCR negative for IgVh gene) have been infrequently reported. A combination chemoimmunotherapy protocol has been developed (FCR) which combines fludarabine 25 mg/m2 per day for three days, cyclophosphamide 250 mg/m2 per day for three days, and Rituximab 375 mg - 500 mg/m2 on day 1 (Proc ASH 98:771a, #3210, 2001). The use of FCR  as initial therapy for 135 CLL pts has resulted in 67% CR, 19% NPR, and 18% PR. Nine responders have relapsed clinically and 12/135 pts have died: 2/19 (2%) CR, 1/19 (5%) NPR, 4/18 (22%) PR and 5/7 (71%) Fail. Seventy- seven pts had PCR performed on BM at the end of therapy (usually 6 cycles) and 125 pts had flow cytometry performed. The relationship between NCIWG response, PCR and CD5 + 19 co-expression on flow, and likelihood of relapse is shown below.

NCIWG Response PCR  - CD5+19 Flow Relapse Clinical Relapse
CR            67% 91       35/61   11/35 74/88     84% 0/74    0% 2        2%
NPR          19%  19        4/11    1/4 5/17       29% 1/5    20%  2      11%     
PR            18%  18        2/6      0/2 6/16       38% 1/6    17% 5      28%

CD5+19% co-expression < 1% occurred more frequently in pts < 70 years of age, spleen size < 5 cm, below the L costal margin, beta-2-microglobulin < 3 mg/L and lower marrow cellularity. No characteristics predicted for PCR negativity. The degree of PCR positivity is semi-quantitated by comparing the level of PCR amplification of IgVh to the ras gene and developing an IgVh/ras ratio. 13/41 PCR negative pts have become low level PCR positive usually within six months of follow-up. Nine of the 36 PCR positive pts have increased the ratio by more than 100% and 13 have had a > 50% decrease. None of the PCR negative pts have had a clinical or flow relapse while three of 36 pts have had a flow relapse and two a clinical relapse. Two of 85 pts (2%) with CD5+19 co-expression < 1% have had a flow relapse vs. 15/34 (44%) with 1% (P<.001). With longer follow-up, the better quality remissions obtained with FCR will allow exploration of the characteristics of response, which are the best predictors of prolonged survival.

Rituxan plus Prednisone/Methylprednisolone

Here is an abstract from ASH 2002, authored by Tom Kipps. It talks about combining Rituxan and Prednisone. May be it has something to do with "nurse like cells", as these researchers speculate, or may be, as we have been discussing in previous articles on CLL Topics, prednisone blocks the NF-kB pathway, prevents the CLL cells from developing survival advantages and proliferating, and makes them that much easier to kill by the combined efforts of the Rituxan and the body's own immune system. 

If you go all the way to the bottom of the abstract, you will find the results: out of 5 patients who completed the therapy, one is in partial remission, while four are in complete remission. Not bad at all, considering these were previously treated patients. 

Hmmmm. I wonder if the added boost to Rituxan's efficacy can be brought about by other drugs capable of blocking the NF-kB pathway, much less toxic drugs like aspirin and salicylate. Just thinking out loud people, please do not take this as medical advice. But intriguing thought, isn't it? We are all told to take Tylenol for infusion related side effects, when good old aspirin may be better?!? Some doctor once told me that aspirin is truly a miracle drug and after several decades of using it, we still do not know all the things it does.

Abstract:

Combined Rituximab and High-Dose Methylprednisolone for the Treatment of Chronic Lymphocytic Leukemia.

Jan Bole, Yan Li, Nobuhiro Tsukada, Thomas J. Kipps. Division of Hematology/Oncology, University of California, San Diego, La Jolla, CA,

Rituximab is a humanized murine monoclonal antibody directed against human CD20 that has been approved for the treatment of patients with chemotherapy-refractory low-grade follicular lymphoma. At similar doses as used to treat follicular lymphoma, Rituximab induces partial responses in less than a quarter the of patients with chronic lymphocytic leukemia (CLL). The low response rates of patients with CLL have been attributed to lower CD20 expression-levels on CLL cells as compared to follicular lymphoma cells. However, the mechanism(s) of action of Rituximab is not known. We examined the in vitro activity of Rituximab on CLL cells alone and in the context of nurse- like cells (NLC) that can protect CLL cells from spontaneous apoptosis in vitro (Blood 96:2655-63, 2000). In these pre-clinical studies, we found that Rituximab had little effect on CLL cell survival in vitro, particularly in the presence of NLC. However, Rituximab acted synergistically with glucocorticoids to induce apoptosis of CLL cells, particularly in the presence of such cells. Because NLC may reside in the secondary lymphoid tissue of patients with CLL (Blood 99:1030, 2002), we speculated that Rituximab may have enhanced activity in CLL if co-administered with glucocorticoids. Accordingly, we developed a pilot clinical trial in which we co- administered Rituximab and methylprednisilone to patients with CLL who still required therapy after demonstrating themselves to be intolerant or resistant to fludarabine or fludarabine-based treatment regimens. Eligible patients received methylprednisilone at 1 gm/m2 daily on days 1-5 of each cycle and Rituximab (375 mg/m2) each week during the four-week cycle. A total of three cycles were given with follow-up of patients for response. Five patients have completed therapy, and an additional patient is currently being treated on protocol. The median age of treated patients was 63 with a standard deviation of 9 years. The patient cohort consisted of subjects who were refractory to fludarabine or to combination therapy with fludarabine and Rituximab. The median hemoglobin for the patient cohort was 11.5 g/dl at baseline, 14.2 g/dl at response evaluation, and 14.4 g/dl at the last follow-up visit. The median platelet counts for the patient cohort were 88,000/ml at baseline, 153,000/ml at response evaluation, and 144,000/ml at the last follow-up visit. The median absolute lymphocyte count for the patient cohort was 11,100/ml at baseline, 1,500/ml at response evaluation, and 1,900/ml at the last follow-up visit. All patients had lymphadenopathy and splenomegaly at baseline evaluation and all experienced significant reductions in lymphadenopathy and splenomegaly at the conclusion of therapy. Two months after completion of the protocol treatment, one patient satisfied the NCI-sponsored working group criteria for partial response, and four patients satisfied the criteria for complete response. The longest follow-up interval for these patients is 17 months. Given these encouraging results, additional patients with refractory disease will be evaluated in a larger multi- institutional study that will be conducted by the CLL Research Consortium. 
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Jan Bole, Dr. Kipps nurse, made a presentation of this particular trial. The URL link to her presentation is no longer active and the trial is not listed on the UCSD site as currently recruiting.

Here are a few excerpts and comments from the original publicity material on the trial. 

First, they are not kidding when they call this "HDMP" plus Rituxan. HDMP stands for "High Dosage Methyl Prednisolone". The protocol calls for 1 gram/meter square of this corticosteroid on days 1 through 5. As we discussed in my previous article, a man who is 5' 10'' and weighs 180 lbs has a BSA of 2 meter square. Such a patient would therefore get 2 grams of methylprednisolone per day for a total of 5 days. Just for comparison, one of our members is getting 10 milligrams per day. (There are 1000 milligrams per gram). In other words, our typical man in this pilot study will get a total of 10 grams over the five days, or as much methylprednisolone as our patient profiler would get over a period of one thousand days, or 2.7 years!! No kidding, this is "High Dose" indeed! And this is just the first cycle, there are a total of three.

Second, Rituxan is administered at the now standard dosage of 375 milligrams/meter square, once a week, for a total of four weeks, constituting one cycle. Therefore , the way I read this, there are a total of 12 Rituxan administrations, over a period of 12 weeks. Our standard issue patient with a BSA of 2.0 will get 750 milligrams each time. 

Third, the presentation lists pretty stringent restrictions for participation in this trial. For example, newbies just coming out of w&w would not be eligible. I understood this trial is now going to be conducted at some of the other CLL Consortium centers as well, I do not know if these new trials will also have similar eligibility criteria. 

Fourth, the patients get pretty broad-spectrum antibiotics, anti-virals and anti-fungals during the administration of the protocol. I expect this is because of the heavy dose corticosteroid, which does a real number on suppressing the immune system, and therefore your ability to fight infections of any sort. I am afraid I do not have any information, yet, on how long the immune suppression lasts, with this kind of a regimen. 

My usual advice, please do read the details of this approach, check out the toxicities of the drugs involved. And do re-read my article of a few days ago on the good, bad and down right ugly effects of Prednisone. By the way, Prednisone and methylprednisolone are closely related drugs. This protocol, if it stays the same, has some serious issues you should discuss with your medical advisors prior to making any decisions. As one would expect from such an early stage trial, the one reported in the ASH abstract is just a pilot, (sort of a pre-phase -1 trial), there is no information available on long term toxicity or side effects.

Rituxan plus Pentostatin

Here is a report on Pentostatin with Rituxan in previously treated CLL patients, part of the ASH 2002 abstracts bonanza. 

Just to refresh your memory, pentostatin is a purine analogue, just like its better known cousin fludarabine. (Cladribine is the third member of this group of drugs). Pentostatin has proved to be an effective agent against Hairy Cell Leukemia (HCL), but it was considered to be not as effective in CLL. Nevertheless, there has been discussion that pentostatin is less damaging to the bone-marrow than fludarabine (less myelosuppressive), and there should be comparisons of combo drug therapies using pentostatin rather than fludarabine. I understand Dr. Weiss of Memorial Sloan Kettering has a "RPC" (Rituxan, pentostatin and cyclophosphamide) trial underway, to compare against the better known "RFC" trials at Anderson and elsewhere. 

"RF" trials are also quite well known, that leave out the Cyclophosphamide component of RFC. We have members who have been through several rounds of "RF", and seem to be doing quite  well. The abstract below addresses the Pentostatin version of this, with a "RP" trial.

Let me know if you see something here that I do not: I am quite disappointed in these results. Even for a previously treated group of patients, the percentage of people who responded was only one out of three. Complete responses were rare, at less than 6%. The average duration of the response was less than 10 months. What was most disheartening was that more than half the patients (55%) dropped out of the study for a variety of medical reasons. I do not see the advantages of lower toxicity here, compared to better understood RF protocols. 

One trial does not a drug make (or break), I am quite aware this is just one trial. Nevertheless, I see nothing here that would make me want to substitute fludarabine with pentostatin, if the choice came down to one or the other. 

Abstract:

Phase II Multicenter Trial of Pentostatin and Rituximab in Patients with Previously Treated or Untreated Chronic Lymphocytic Leukemia.

Robert Drapkin, Nicholas J. Di Bella, Luceli C. Cuasay, Gerald Edelman, Donald Richards, Mae Mirabel, Lina Asmar. US Oncology, Inc., Houston, TX

Between June 2000 and May 2001, 62 patients (pts) with chronic lymphocytic leukemia (CLL) were enrolled in a multicenter trial to assess the efficacy and safety of the combination of pentostatin (P) + rituximab (R). On Day 1, pts received IV R (375mg/m2). On Day 8, pts received the 2nd dose of R and the 1st dose of IV P (4 mg/m2). Both drugs were administered on Day 15, 22, 36, 43, and 50. Premedication with acetaminophen, prednisone, and diphenhydramine was allowed to minimize the risk of hypersensitivity reactions to R. On Days 57-64, pts were evaluated. If in PR or SD, treatment Days 8-50 were repeated. On Days 113-119, final disease evaluations were done. The median age of pts was 61 years (range: 41-85). The majority were male (72.6%) and Caucasian (85%); 49 (79%) had ECOG performance status (PS) of 0, 11 (17.8%) had PS 1, and 2 (3.2%) had PS 2. The largest percentage of pts (31%) were stage IV; 42% were either stage II (21%) or III (21%). Thirty-eight (61.3%) pts had prior chemotherapy. Preliminary results: of 54 evaluable pts, 18 (33.3%) achieved an objective response (5.5% CR, 3.7% CRu, 16.7% PR, 7.4% PRu), with a median duration of 9.8 months (range: <1-19.1). 29 pts (53.7%) had SD and 7 (13%) had PD. Response rates were very similar  in previously treated and untreated pts, 33.4% and 33.3%, respectively, and there was no apparent difference in response rates according to clinical stage. A total of 34 pts (54.8%) discontinued treatment for the following reasons: toxicity (6), PD/relapse (13), disease-related death (2), non-small cell lung cancer (1), other non- disease related illness (4), physician's decision (4), withdrawal of consent/treatment refusal (3), and insurance problem (1). Grade 3 ties occurred in 27 pts and included neutropenia (29.0%), febrile neutropenia (1.6%), leukopenia (8.1%), thrombocytopenia (5.3%), pulmonary (3.2%), gastrointestinal (3.2%), and infection (3.2%). Other toxicities included anemia, fatigue, fever, edema, and cellulitis. Deaths were due to progression (5), sepsis (1), lung cancer (1), and treatment-related pneumonia  (1). The results indicate that the combination of P+R is well-tolerated in both previously treated and untreated CLL pts, with a very low incidence of febrile neutropenia, leukopenia, thrombocytopenia, and constitutional symptoms. The response rate and duration of response are comparable to other phase II CLL studies. The apparent activity and low toxicity of P and R will be utilized in future CLL studies. Future studies will evaluate the combination of R and P   with cyclophosphamide based on preclinical and clinical evidence of the additive effect of cyclophosphamide with P.

Supported by SuperGen, Dublin, CA, USA.

Keywords: Chronic lymphocytic leukemia\ Pentostatin\ Rituximab
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