For non-variant type, the use fo the first two together is based on a study reported very recently in ASCO on 3/2020 byKreitmen et al as reported in ASCO 2020. This regimen is for patients who have minimal residual disease after 6 months. In the trial, 68 patients with purine analog-naive classic hairy cell leukemia were randomly assigned to receive 0.15 mg/kg of cladribine intravenously on days 1 to 5 with eight weekly doses of rituximab at 375 mg/m2 started on day 1 (concurrent group, n = 34) or 6 months later after detection of minimal residual disease in their blood (delayed group, n = 34). Minimal residual disease tests included blood and bone marrow flow cytometry and bone marrow immunohistochemistry.

Patients in either group could receive a second course of rituximab 6 months after the first. The primary endpoint was 6-month minimal residual diseasefree complete remission rates with concurrent treatment vs cladribine monotherapy in the delayed group. THe delayed group did better nad ahd less toxicity. In the trial, 68 patients with purine analognaive classic hairy cell leukemia were randomly assigned to receive 0.15 mg/kg of cladribine intravenously on days 1 to 5 with eight weekly doses of rituximab at 375 mg/m2 started on day 1 (concurrent group, n = 34) or 6 months later after detection of minimal residual disease in their blood (delayed group, n = 34). Minimal residual disease tests included blood and bone marrow flow cytometry and bone marrow immunohistochemistry.

Patients in either group could receive a second course of rituximab 6 months after the first. The primary endpoint was 6-month minimal residual disease-free complete remission rates with concurrent treatment vs cladribine monotherapy in the delayed group, which favored the concurrent group, but with more thrmbocytopenia..
The investigators concluded: “Achieving minimal residual disease-free complete remission of hairy cell leukemia after first-line cladribine is greatly enhanced by concurrent rituximab and less so by delayed rituximab. Longer follow-up will determine if minimal residual disease-free survival leads to less need for additional therapy or cure of hairy cell leukemia.”

NCCN lists single-agent cladribine or pentostatin in first line and a purine analog with rituximab for recurrent or refractory disease only. and Elitek, not in combination.

Jones G, Parry-Jones N, Wilkins B, Else M, Catovsky D, British Committee for Standards in Haematology. Revised guidelines for the diagnosis and management of hairy cell leukaemia and hairy cell leukaemia variant. Br J Haematol. 2012 Jan;156(2):186-95. [60 references]

Jones G, Parry-Jones N, Wilkins B, et al. Revised guidelines for the diagnosis and management of hairy cell leukaemia and hairy cell leukaemia variant. Br J Haematol 2012; 156:186.

Hagberg H, Lundholm L. Rituximab, a chimaeric anti-CD20 monoclonal antibody, in the treatment of hairy cell leukaemia. Br J Haematol 2001; 115:609.

Robak T. Current treatment options in hairy cell leukemia and hairy cell leukemia variant. Cancer Treat Rev 2006; 32:365.

Arons E, Suntum T, Stetler-Stevenson M, Kreitman RJ. VH4-34+ hairy cell leukemia, a new variant with poor prognosis despite standard therapy. Blood 2009; 114:4687.

Robak T. Hairy-cell leukemia variant: recent view on diagnosis, biology and treatment. Cancer Treat Rev 2011; 37:3.

Grever MR, Abdel-Wahab O, Andritsos LA, et al. Consensus guidelines for the diagnosis and management of patients with classic hairy cell leukemia. Blood 2017; 129:553.

https://www.ascopost.com/news/march-2020/first-line-cladribine-with-concurrent-or-delayed-rituximab-for-hairy-cell-leukemia/

nccn, hcl-1, A- 2020

For Lay Version see here

Freudenberg LS, Antoch G, Schutt P, et al. FDG-PET/CT in re-staging of patients with lymphoma. Eur J Nucl Med Mol Imaging. 2004;31:325–329

Yuliya S. Jhanwar and David J. Straus The Role of PET in Lymphoma Journal of Nuclear Medicine Vol. 47 No. 8 1326-1334, 2006

Bruce D. Cheson MD, Non-Hodgkin’s Lymphomas: New Insights and Therapeutic Strategies
Staging and Evaluation of the Patient with Lymphoma
Hematology/Oncology Clinics of North America
Volume 22, Issue 5, October 2008, Pages 825-837

According to an article published in The Lancet, the chemotherapy combination consisting of Fludara® (fludarabine) plus Cytoxan® (cyclophosphamide) significantly improves progression-free survival compared to Fludara alone without compromising quality of life in the treatment of chronic lymphocytic leukemia. The researchers concluded that the combination of Fludara plus Cytoxan “should now become the standard treatment for chronic lymphocytic leukaemia and the basis for new protocols that incorporate monoclonal antibodies.”

This regimen is NCCN recommended.

To date, analysis of phase II data shows that fludarabine plus Rituxan® appear to be superior to fludarabine chemotherapy alone. This was confirmed by a recent Phase III trial in previously treated patients. Furthermore, fludarabine and cyclophosphamide plus Rituxan® improves survival over historical treatments including fludarabine plus or minus prednisone and fludarabine/cyclophosphamide. NCCN has now included the FCR regimen in its recommendations for patients less than 70 years of age. Accordingly, it has become standard for this disease.

Byrd JC, Rai KR, Peterson BL, Appelbaum FR, et al. The Addition of Rituximab to Fludarabine Significantly Improves Progression-Free and Overall Survival in Previously Untreated Chronic Lymphocytic Leukemia (CLL) Patients. Proc Am Soc Hem, Blood 2003; 102(11):73a, Abstract #245. Wierda W, O Brien S, Faderl S, Ferrajoli A, et al. Improved Survival in Patients with Relapsed -Refractory Chronic Lymphocytic Leukemia (CLL) Treated with Fludarabine, Cyclophosphamide, and Rituximab (FCR) Combination. Proc Am Soc Hem, Blood 2003; 102(11):110a, Abstract #373.

Rai KR et al. Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia. N Engl J Med 2000;343:1750-7.

Tournilhac O et al. Impact of frontline fludarabine and cyclophosphamide combined treatment on peripheral blood stem cell mobilization in B-cell chronic lymphocytic leukemia. Blood 2004;103:363-5.

Catovsky D, Richards S, Matutes E, et al. Assessment of fludarabine plus cyclophosphamide for patients with chronic lymphocytic leukaemia (the LRF CLL4 Trial): a randomised controlled trial. The Lancet. 2007;379: 230-239.

http://nccn.org/professionals/physician_gls/PDF/nhl.pdf, p.16

T. Robak, A. Dmoszynska, P. Solal-Celigny, K. Warzocha, J. Loscertales, J. Catalano, B. V. Afanasiev, L. Larratt, C. H. Geisler, M. Montillo, et al.
Rituximab Plus Fludarabine and Cyclophosphamide Prolongs Progression-Free Survival Compared With Fludarabine and Cyclophosphamide Alone in Previously Treated Chronic Lymphocytic Leukemia J. Clin. Oncol., April 1, 2010; 28(10): 1756 – 1765.

Nabhan C, Rosen ST, Chronic lymphocytic leukemia: a clinical review. JAMA. 2014 Dec 3;312(21):2265-76.

The impact of maintenance treatment with rituximab on overall survival is one of the most important open questions for patients with indolent non-Hodgkin lymphoma. Recent randomized trials performed by the German Low Grade Lymphoma Study Group (GLSG) and by the EORTC demonstrated the superiority of rituximab maintenance after immunochemotherapy and after chemotherapy compared with observation alone.

Clinical trials have demonstrated prolongation of progression-free survival and, in some cases, increased survival when “maintenance” rituximab is given following rituximab induction, chemotherapy induction, or rituximab/chemotherapy (relapsed setting).

A recent guideline says this about maintenance rituximab for low grade lymphoma: “For previously treated patients with follicular or other indolent B-cell-histology lymphoma (such as mantle cell lymphoma, marginal zone lymphoma, and lymphoplasmacytoid lymphoma), excluding small lymphocytic lymphoma (SLL):
However, a Canadian guideline does recommend this approach and it is becoming the predominant approach in clinical practice.NCCN also lists it as category 1 recommendation on p. FOLL-B. First line extended therapy – If initially treated with single-agent Rituxan, consolidation with Rituximab 375mg/m2 one dose q 12 weeks is supported. FDA approved Rituxan as a maintenance therapy for patients with advanced follicular lymphoma in January of 2011. Farthermore, NCCN marginal lymphoma guideliens take one to the follicular lymphoma pages, where maintenance is recommended

On June 13, 2011, at the 16th Congress of the European Hematology Association in London, there was presented a study of maintenance rituximab after responding to initial therapy. It was restricted to elderly patients and showed that maintenance doubled the duration of remission doubled. Overall survival at 4 years also improved with rituximab maintenance, and experts suggest it should become the new standard of care. At 4 years, 57% of the patients treated with rituximab were still in in remission, compared with 26% of those treated with interferon (P = .0117). ” This study has not yet been published. The schedule is not NCCN prescribed and various schedules have been reported. NCCN recommends up to 2 years of maintenance therapy on FOll-B, 1

For large cell lymphoma, NCCN does NOT recommend maintenance Rituxan. Rituxan after CHOP, but not after R-CHOP, significantly prolongs TTF, but fails to prolong OS, possibly due to a delayed pattern of relapse and/or the efficacy of rituximab in the salvage setting(An Intergroup E4494/C9793 update). NCCN on p. BCEL specifically states that and does not recommend it.

For mantle cell lymphoma, NCCN also does not recommend maintenance. On June 13, 2011, at the 16th Congress of the European Hematology Association in London, there was presented a study of maintenance rituximab after responding to initial therapy. It was restricted to elderly patients and showed that maintenance doubled the duration of remission doubled. Overall survival at 4 years also improved with rituximab maintenance, and experts suggest it should become the new standard of care. At 4 years, 57% of the patients treated with rituximab were still in in remission, compared with 26% of those treated with interferon (P = .0117). ” This study has not yet been published.

NCCN recommends it for marginal zone lymphoma

NCCN, MZA-A, 2 2017

NCCN.ORG, NHLm follicular 2017

NCCN, MANT-4 2017

Revised 2/4/2012

Imrie K, Stevens A, Meyer R, Hematology Disease Site Group. Rituximab in lymphoma and chronic lymphocytic leukemia: a clinical practice guideline. Toronto (ON): Cancer Care Ontario (CCO); 2005 Dec 22. 46 p. (Evidence-based series; no. 6-8). [65 references]

S. J. Horning
Optimizing Rituximab in B-Cell Lymphoma
J. Clin. Oncol., February 20, 2005; 23(6): 1056 – 1058.

John D. Hainsworth, Sharlene Litchy, Don W. Shaffer, Van L. Lackey, Manuel Grimaldi, F. Anthony Greco, Maximizing Therapeutic Benefit of Rituximab: Maintenance Therapy Versus Re-Treatment at Progression in Patients With Indolent Non-Hodgkin’s Lymphoma—A Randomized Phase II Trial of the Minnie Pearl Cancer Research Network
Journal of Clinical Oncology, Vol 23, No 6 (February 20), 2005: pp. 1088-1095

Habermann TM, Weller EA, Morrison VA, et al. Rituximab-CHOP versus CHOP alone or with maintenance rituximab in older patients with diffuse large B-cell lymphoma. J Clin Oncol 2006;24:3121–3127.

Revlimid is an orally administered derivative of thalidomide, which is a very active agent for the treatment of multiple myeloma but has serious side effects, especially thromboembolism. Revlimid is reported to have less toxicity than thalidomide but retains antimyeloma effects. Revlimid has recently been approved by the FDA for review of treatment of myelodysplastic syndromes (MDS) wih a 5q- mutation and for first line treatment of multiple myeloma in conjunction with dexamethasone. Revlimid is in clinical trials for the evaluation of treatment for other hematologic cancers including CLL.

There are many studies supporting effectiveness of Revlimid, although most of them are small and presented in the abstract form.

Researchers from the Roswell Park Cancer Center and the Toronto Sunnybrook Regional Cancer Center have reported that Revlimid has significant activity in CLL. This study was also presented at the 2005 meeting of the American Society of Hematology in December 2005. Thalidomide has also demonstrated activity when combined with Fludara for initial treatment of CLL. This was a small study involving only 16 patients, but the complete response rate was over 50%.

The study presented at ASH 2005 and ASCO 2006 involved 29 patients with relapsed or refractory CLL. More than 50% has failed Rituxan combinations and more than 50% had failed fludarabine combinations. The complete response rate was 15%, the partial response rate was 53% and an additional 15% had stable disease. Two patients had complete molecular responses. The most common side effects reported were fatigue, neutropenia and thrombocytopenia. Approximately 60% had “flare reaction”—described as tender swelling of lymph nodes and rash—which was successfully treated with steroids. In-vitro studies showed an increased number of natural killer cells but no increase in apoptosis.

In 2008, Celgene reported two REVLIMID (lenalidomide) Phase II studies at the 50th American Society of Hematology Meeting. Both demonstrated high response rates and manageable side effects in patients previously untreated with symptomatic chronic lymphocytic leukemia (CLL). The studies demonstrated greater than 90 percent disease control across all evaluable patients. In 2009, at ASH, there was presented a phase II study of Rituxan. Revlimid combination conducted at MD Anderson Cancer Center demonstrated a 64 percent overall response after 12 cycles, including the observation of complete responses. In 2008, at ASH, there was presented a phase II study of Rituxan. Revlimid combination conducted at MD Anderson Cancer Center demonstrated a 64 percent overall response after 12 cyces, including the observation of complete responses.

It is also listed by the Drugdex compendium for CLL. The most recent noteworthy paper was in Blood 2011. Sixty patients with CLL age 65 years and older received treatment with lenalidomide orally 5 mg daily for 56 days, then titrated up to 25 mg per day as tolerated. Treatment was continued until disease progression. At a median follow-up of 29 months, 53 patients (88%) are alive and 32 patients (53%) remain on therapy. Estimated 2-year progression-free survival is 60%. The overall response rate to lenalidomide therapy is 65% including 10% complete response, 5% complete response with residual cytopenia, 7% nodular partial response, and 43% partial response. These are very good results for the limited reported toxicity in the ederly population.

Miller K, Czuczman MS, Dimicli L, et al. Lenalidomide (L) induces high response rates with molecular remission in patients (pts) with relapsed (rel) refractory (ref) chronic lymphocytic leukemia (CLL). Proceedings from the 42nd annual meeting of the American Society of Clinical Oncology. Atlanta, Ga. 2006. Abstract # 6605.

Chanan-Khan AA, Miller KC, DiMicheli L, et al. Results of a phase II study of lenalidomide (L) (Revlimid) in patients with relapsed or refractory chronic lymphocytic leukemia (CLL). Blood 2005;135a, abstract # 447.

Chanan-Khan A, Miller KC, Takeshita K, et al. Results of a phase 1 clinical trial of thalidomide in combination with fludarabine as initial therapy for patients with treatment-requiring chronic lymphocytic leukemia (CLL). Blood. 2005;106:3348-3352.

Chanan-Khan A, Miller KC, Musial L, et al. Clinical efficacy of lenalidomide in patients with relapsed or refractory chronic lymphocytic leukemia: results of a phase II study. Journal of Clinical Oncology. 2006;24:5343-5349.

Chen C, Paul H, Xu W, et al. A phase II study of lenalidomide in previously untreated, symptomatic chronic lymphocytic leukemia (CLL). Blood. 2008;112:23, abstract number 44.

Kornblau SM, Burger JA, Ferrajoli A.et al, Lenalidomide (REVLIMID) as initial therapy of elderly patients with chronic lymphocytic leukemia.Blood. 2011 Jul 1.

Takvorian and colleagues (1987) studied 49 patients with either high-grade (n = 29), intermediate-grade (n =14) or low-grade (n = 6) lymphoma. All patients were considered to have a poor prognosis either due to relapse (n = 41) or poor prognostic factors (n = 8). These latter 8 patients were in at least partial remission but were considered to be at high-risk for relapse due to a bulky tumor mass, or multiple sites of extranodal involvement. All patients had a good performance status. The common feature of all these patients was that they were responsive to conventional induction therapy such that at the time of HDC, all patients had a minimal disease burden. In fact, 23 patients were considered to be in complete remission. A total of 34 of the 49 patients remained in complete remission for 2 to 52 months post-HDC, which translated into a 65 % probability that patients would remain disease free for greater than 11 months. Two patients died from treatment-related toxicity and relapse occurred in 13 others. All relapses occurred before 11 months. Other earlier studies of HDC had included all patients relapsing from disease, regardless of their performance status or whether the lymphoma was chemo-resistant. In these studies the mortality rate ranged from 20 to 40 % and long-term disease survival was seen in only 20 % of patients. Considering their improved results, the authors suggested that HDC should be a treatment option for patients with relapsing disease but with a minimal tumor burden that is still responsive to chemotherapy.

Schouten et al (1994) reported their findings of 92 patients with low-grade NHL treated with HDC and ASCT. At the time of ASCT, the majority of patients had chemosensitive disease in first or subsequent remission (37 %) or disease with a good response to chemotherapy (49 %). At a median follow-up of 19 months, the progression free survival is 52 %. Patients with complete remission or responding relapse at the time of ASCT had a significantly better progression-free survival compared to patients with refractory disease. Patients with transformed low-grade NHL at ASCT had a very poor outcome. Despite the relatively short follow-up of this study, the data suggested that chemosensitive disease responded better to HDC followed by stem cell transplant than refractory disease at the time of ASCT.

Mills and colleagues (1995) reported the main prognostic factors in 107 patients with relapsed or resistant intermediate- or high-grade NHL who underwent HDC with ASCT. All patients had failed to achieve a complete remission to conventional chemotherapy or had subsequently relapsed. Additionally, there was no bone marrow involvement in any of the patients. Forty-two patients (40 %) had chemoresistant disease at the time of HDC, 55 (51 %) had chemosensitive disease, and 10 (9 %) had untested relapse. At 3 months, 44 patients (41 %) were assessed to be in complete remission, 34 (32 %) were in partial remission and 22 (21 %) showed no response or had progressive disease. There were 7 early procedure-related deaths. Overall survival rate at 5 years is 41 % and progression free survival rate is 35 %. None of the patients who were unresponsive to HDC survived beyond 18 months, whereas at a median follow-up of 34 months, 50 % of the partial responders were alive. Patients with chemosensitive disease, small masses, and ASCT after one line of chemotherapy had the best outcome.

In a randomized clinical trial (The European CUP trial), Schouten, et al. (2003) examined if high-dose therapy (HDT) followed by ASCT is more effective than standard treatment with regard to progression-free survival (PFS) and overall survival (OS) in patients with relapsed follicular NHL; and evaluated the additional value of B-cell purging of the stem-cell graft with regards to PFS and OS. Patients received three cycles of chemotherapy. Responding patients with limited bone marrow infiltration were eligible for random assignment to three further cycles of chemotherapy (C), unpurged HDT (U), or purged HDT (P). A total of 140 patients were registered from 36 centers internationally, and 89 were randomly assigned. Reasons for not randomizing included patient refusal, early progression, or death on induction therapy. With a 69-month median follow-up, the log-rank P value for PFS and OS were 0.0037 and 0.079, respectively. The authors concluded that HDT significantly improves PFS and OS in patients under age of 60 years with recurrent chemosensitive disease. Furthermore, there is no clear evidence of benefit through purging. This is in agreement with the observations of Alvarnas and Forman (2004) who stated that data to justify routine use of hematopoietic stem cell graft purging are insufficient.

In a recent review on stem cell transplantation in follicular lymphoma, Tse, et al. (2004) stated that ASCT or allogeneic stem cell transplantation in first remission remains an investigational procedure.

A 2011 review concludes: “Stem cell transplantation (SCT) including both autologous and allogeneic SCT or experimental agent therapy is considered for recurrent disease.”

Freedman A. Follicular lymphoma: 2011 update on diagnosis and management.Am J Hematol. 2011 Sep;86(9):768-75.

HC Schouten, PJ Bierman, WP Vaughan, A Kessinger, JM Vose, DD Weisenburger, and JO Armitage
Autologous bone marrow transplantation in follicular non-Hodgkin’s lymphoma before and after histologic transformation
Blood 74: 2579-2584.

Arnold S. Freedman Biology and Management of Histologic Transformation of Indolent Lymphoma Hematology 2005 © 2005 The American Society of Hematology

It would stand to reason that patients with poor prognostic features benefit more from transplantation. However, a recent retrospective analysis show that alloSCT leads to the best outcome in the subgroup of patients with good risk profile CLL, contradicting their conclusions and leaving the debate open as to why this aggressive strategy did not translate into improved outcome in the high-risk patients. Thus, this remains a controversial and debated topic. A recent guideline states: “The possibility of an allogeneic transplant procedure should be considered for younger patients with good performance status who have been previously treated and have poor risk disease. Suitable patients should be discussed with a transplant centre at an early stage in their disease before the development of drug resistant disease for inclusion into a clinical research protocol (grade B recommendation, level III evidence).”  NCCN  lists considering an allogeneic transplant as a standard option in patients without comorbidities (CSLL-5). NCCN does not recommend transplantation.

Luca Laurenti, Michela Tarnani, Patrizia Chiusolo, Federica Sor� and Simona Sica. Allogeneic Transplantation for Chronic Lymphocytic Leukemia Mediterranean Journal of hematology and infectious disease. Vol 2, No 2(2010)

C. Nabhan and J. D. Bitran Chronic Lymphocytic Leukemia: To Transplant or Not to Transplant… That Is the Question? . Clin. Oncol., November 1, 2005; 23(31): 8126 – 8127.

Oscier D, Fegan C, Hillmen P, Illidge T, Johnson S, Maguire P, Matutes E, Milligan D, Guidelines Working Group of the UK CLL Forum, British Committee for Standards in Haematology. Guidelines on the diagnosis and management of chronic lymphocytic leukaemia. Br J Haematol 2004 May;125(3):294-317. [169 references]

nccn.org, CLL 2012

Michallet M, Dreger P, Sutton L, et al. Autologous hematopoietic stem cell transplantation in chronic lymphocytic leukemia: results of European intergroup randomized trial comparing autografting versus observation. Blood. Feb 3 2011;117(5):1516-1521

Gribben JG. How I treat CLL up front. Blood. Jan 14 2010;115(2):187-97.

Oscier D, Fegan C, Hillmen P, Illidge T, Johnson S, Maguire P, Matutes E, Milligan D, Guidelines Working Group of the UK CLL Forum, British Committee for Standards in Haematology. Guidelines on the diagnosis and management of chronic lymphocytic leukaemia. Br J Haematol 2004 May;125(3):294-317. [169 references]

Johan Aschan Allogeneic haematopoietic stem cell transplantation: current status and future outlook Medical Bulletin 2006 77-78(1):23-36;

When purine analogs were first introduced in the treatment ofpatients with CLL, the issue of whether or not these agentsshowed cross-resistance was a matter of extensive debate. Thecurrent notion is that cross-resistance does exist. However,pentostatin combined with cyclophosphamide has been reportedto produce responses (77% including one CR) in a small seriesof 13 patients who did not respond to fludarabine-based therapy. A second phase II study was recentlypublished. In fludarabine-refractory patients,75% responded. Toxicity was acceptable, with grade 3/4 infections(including fever of unknown origin) in 28%. The regimen waswell tolerated, with 72% of patients receiving the planned treatmentat full dose.

Mark A. Weiss, Peter G. Maslak, Joseph G. Jurcic, David A. Scheinberg, Timothy B. Aliff, Nicole Lamanna, Stanley R. Frankel, Steven E. Kossman, Denise Horgan , Pentostatin and Cyclophosphamide: An Effective New Regimen in Previously Treated Patients With Chronic Lymphocytic Leukemia Journal of Clinical Oncology, Vol 21, Issue 7 (April), 2003: 1278-1284
N. Lamanna, M. Kalaycio, P. Maslak, J. G. Jurcic, M. Heaney, R. Brentjens, A. D. Zelenetz, D. Horgan, A. Gencarelli, K. S. Panageas, D. A. Scheinberg, and M. A. Weiss
Pentostatin, Cyclophosphamide, and Rituximab Is an Active, Well-Tolerated Regimen for Patients With Previously Treated Chronic Lymphocytic Leukemia
J. Clin. Oncol., April 1, 2006; 24(10): 1575 – 1581.

E. Montserrat, C. Moreno, J. Esteve, A. Urbano-Ispizua, E. Gine, and F. Bosch
How I treat refractory CLL
Blood, February 15, 2006; 107(4): 1276 – 1283.

AVN-944 is an inhibitor of inosine monophosphate dehydrogenase (IMPDH), an enzyme that catalyzes the rate-limiting step in guanine nucleotide synthesis, and induces apoptosis in malignant hematopoietic cell lines in vitro.

Pre-clinical studies showed that AVN944 is a highly specific inhibitor of IMPDH, suppresses pools of GTP, and in cultured cells has a selective growth inhibition effect on cancer cells vs. normal cells.

An earlier single-dose, dose-escalation, healthy volunteer clinical trial conducted in the United Kingdom showed that AVN944 was well tolerated at all tested doses with no notable side effects; had good pharmacokinetic properties; and had a significant inhibitory effect on IMPDH enzyme activity.

A recent phase I study is a repeat-dose dose escalation trial in patients with advanced hematologic malignancies. Patients are dosed for 21 days on a 28-day cycle. A minimum of three patients are treated at each dose level. The study is divided into two arms, one for treatment of leukemia patients and the other for treatment of patients with lymphoma and myeloma. For the leukemia arm of the study, patients are currently being treated at the fourth dose level, 100 mg twice daily. For the lymphoma and myeloma arm, patients are currently being treated at the fifth dose level, 125 mg twice daily. There have been no drug-related Serious Adverse Events (SAEs), indicating that AVN944 is being well tolerated thus far at all dose levels. Pharmacokinetics measurements indicate dose proportional plasma levels of AVN944 during treatment and sustained plasma concentrations at the dose levels tested thus far.

Early Activity Indicators: This Phase I study has also been designed to evaluate several pharmacodynamic and efficacy-related endpoints. Upon entering the trial, all patients have refractory, progressive disease and have failed all prior therapies. Thus far, 12 of 24 patients have had stabilized disease after one cycle of treatment with AVN944. These include patients with both leukemia and multiple myeloma. Patients who have achieved stable disease following completion of a one-month treatment cycle with AVN944, as determined by the clinical investigator, may be advanced to a subsequent cycle.

Four multiple myeloma patients in the study have maintained stabilized disease for several months of treatment with AVN944; two of these patients completed five months of treatment and two others completed eight successive cycles. These two patients continue to have stable disease and are in their ninth month of treatment. it is clearly experimental.

Author(s): R. B. Klisovic, G. Tricot, S. Coutre, T. Kovacsovics, F. Giles, T. Genna, D. K. Bol, J. W. Strovel, J. M. Hamilton, B. Mitchell A phase I trial of AVN944 in patients with advanced hematologic malignancies. Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 14026