Cancer Treatment

Velcade for low grade lymphoma

Bortezomib is a drug that belongs to the class of drugs called proteasome inhibitors. The proteasome is a protein complex that breaks down rusty and modified proteins that cells are meant to dispose off. Its housekeeping job is very important for the cells to keep functioning. Research studies have shown that if the proteasome is inhibited (or stopped from functioning) some cancer cells, including some lymphoma cells may find it difficult to carry out normal functions and even die. Bortezomib (Velcade) is a type of drug that inhibits proteasomes. Theoretically it can be efective in a wide spectrum of malignancies.

It has shown great results in the treatment of relapsed multiple myeloma, another type of cancer that affects the bone marrow. Trials that have tried Velcade in relapsed lymphomas over the past few years have resulted in good responses in certain types of lymphoma, especially Mantle Cell Lymphomas. Bortezomib (Velcade) has been granted approval for the treatment of relapsed or refractory Mantle Cell Lymphoma by the FDA in December 2006. It represents an important step in the approach to second-line treatments in Mantle Cell Lymphoma, a potentially difficult to treat lymphoma.

A number of trials in low grade lymhomas are ongoing. For example, Millennium Pharmaceuticals and development partner Johnson & Johnson have initiated a phase III clinical trial of Velcade in non-Hodgkin's lymphoma. The trial will evaluate the drug in combination with rituximab in patients with relapsed or refractory follicular lymphoma, a subtype of non-Hodgkin's lymphoma (NHL). Anoterh study that Millenium is sponsoring is to determine if the combination of VELCADE and rituximab improves progression free survival relative to rituximab alone in patients with relapsed or refractory B-cell non-Hodgkin"s lymphoma (B-NHL) who never received rituximab or who have previously responded to rituximab. This is an international study being conducted in the United States and in many countries around the world.
An Italian study,NCT00509379,  A Phase II Multicenter Non-Randomized Study to Assess Safety, Toxicity and Clinical Activity of the Association of Bortezomib(VELCADE)With Rituximab in Relapsed/Refractory Indolent Non Follicular and Mantle-Cell Non-Hodgkin Lymphoma, is looking at activity in several low grade lymphoma types, including SLL.

Schenkein D. Proteasome inhibitors in the treatment of B-cell malignancies. Clin Lymphoma. 2002;3(1):49-55.

Cheson BD. Hematologic malignancies: New developments and future treatments. Semin Oncol. 2002;29(4 Suppl 13):33-45.

nccn.org, chronic lymphocytic leukemia

Single agent Rituxan for CLL

Rituximab has been shown to prolong survival when used with chemotherapy in CLL.
The findings come from a comparative analysis of two completed national phase II and phase III clinical trials. The two multicenter clinical trials compare the antibody rituximab plus fludarabine, a chemotherapeutic drug, to fludarabine alone. Rituximab is an antibody-based drug approved for lymphoma. The findings of the two studies show that after an average of 43 months, rituximab plus the drug fludarabine increases progression-free survival by 22 percent and overall survival by 12 percent compared to fludarabine alone.

There is insufficient evidence at this time to support or refute the use of single-agent rituximab or a rituximab-containing chemotherapy regimen in patients with chronic lymphocytic leukemia (CLL). Rituximab, the mAb targeting CD20, was approved by the US FDA for patients with relapsed low-grade non-Hodgkin lymphoma. Relatively low levels of CD20 are expressed on CLL B cells, compared to normal B or neoplastic B cells of other lymphomas. In addition, soluble CD20 has been demonstrated in plasma of patients with CLL; this may inhibit the capacity of rituximab to bind to CLL B cells, thereby resulting in rapid clearance and negatively affecting pharmacokinetics.31 Standard-dose rituximab (375 mg/m2 weekly for 4 weeks) has very limited activity for patients with CLL. Dose-intense33 and dose-dense34 single-agent rituximab has been shown to increase efficacy. Rituxan is not listed by NCCN as a single agent.

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]

W. G. Wierda Current and Investigational Therapies for Patients with CLL
Hematology, January 1, 2006; 2006(1): 285 - 294.

Huhn D, von Schilling C, Wilhelm M, et al. Rituximab therapy of patients with B-cell chronic lymphocytic leukemia. Blood. 2001;98:1326–1331.

Fludara and Cytoxan for Chronic Lymphocytic Leukemia

Fludarabine is highly effective in the treatment of chronic lymphocytic leukemia, producing higher response rates than alkylating agents such as chlorambucil alone. Fludarabine is used in various combinations with cyclophosphamide, mitoxantrone, dexamethasone and rituximab in the treatment of indolent non-Hodgkins lymphomas and CLL.

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.

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.12

Gleevec for acute lymphocytic leukemia

Lay Summary: There is now evidence that GLeevec is very effective in Philadelphia chromosome positive ALL.

Philadelphia-positive ALL is a very difficult disease to treat successfully. In the recent past, the standard approach was to use daunorubicin/vincristine/prednisone-based induction therapy to achieve remission and then, if the patient was a reasonable candidate and a donor could be found, to perform an allogeneic transplant. Now, the use of tyrosine kinase inhibitor therapy may be altering this strategy. Single-agent treatment with imatinib and probably with dasatinib is fairly likely to achieve hematologic responses, but the likelihood of cytogenetic response is lower.

A study reported by Dr. Kirk Schultz on behalf of the Children's Oncology Group (COG) showed that imatinib mesylate could be given safely in combination with chemotherapy in children with Philadelphia-positive ALL. Patients aged 1-21 with Philadelphia-positive ALL who achieved remission with standard COG induction therapy received an intensive multidrug combination chemotherapy regimen, with introduction of imatinib at 340 mg/m2 for 21 days into an increasing number of treatment blocks in successive cohorts of patients. Patients receiving imatinib had a higher incidence of transaminase elevation in first consolidation and maintenance. However, there were few significant additional increased toxicities compared with historical and contemporaneous controls not receiving imatinib. This appeared to be a feasible combination of a targeted therapy with chemotherapy and will be explored further in subsequent trials.

Dr. Deborah Thomas, a pioneer in the use of imatinib mesylate and chemotherapy in adults with Philadelphia-positive ALL,[11] presented her most recent data at ASH 2007. This is the  Phase II Pilot Study of Intensified Chemotherapy With or Without Allogeneic Hematopoietic Stem Cell Transplantation in Children With Very High-Risk Acute Lymphoblastic Leukemia. The chemotherapy backbone was the MD Anderson standard of hyper-CVAD, which is fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate and high-dose ara-C. Although a high rate of remission was achieved historically with the use of this regimen in patients with Philadelphia-positive ALL, disease-free survival was brief. Dr. Thomas and colleagues added imatinib at 400 mg per day on days 1 through 14 to each of 8 courses followed by 12 months of imatinib. In later iterations of her work, imatinib was increased to 600 mg per day on days 1 through 14 for courses 1 through 8, with imatinib being given indefinitely after maintenance was completed. Overall, 52 patients with imatinib-naive or minimally treated Philadelphia-positive ALL received therapy from April 2001 to July 2006. With a 3-year treatment follow-up, there were only 7 relapses (14%); however, 12 patients died. The 3-year remission and disease-free survival rates for the combination compared favorably with hyper-CVAD alone (83% vs 24%, and 55% vs 14%, respectively).

1. Schultz KR, Aledo A, Bowman WP, et al. Minimal toxicity of imatinib mesylate in combination with intensive chemotherapy for Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) in children: a report of the Children's Oncology Group (COG) AALL0031 protocol for very high risk ALL. Blood. 2006;108:87a. Abstract 283.
2. Thomas DA, Faderl S, Cortes J, et al. Treatment of Philadelphia chromosome-positive acute lymphocytic leukemia with hyper-CVAD and imatinib mesylate. Blood. 2004;103:4396-4407

3. Oliver G. Ottmann and Barbara Wassmann Treatment of Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia  ASH Hematology 2005

   © 2005 The American Society of Hematology
   

Donor Lymphocyte Infusions (DLI) for CLL

Lay Summary: DLI is well studied in chronic myelogenous leukemia but less so in other hematological conditions.

DLI induces complete remissions in the majority of patients with chronic myeloid leukemia (CML) in early-stage relapse and in less than 30% of patients with relapsed acute leukemia, myelodysplasia, and multiple myeloma. DLI-induced remissions of chronic phase CML are durable, but as many as half of patients with other diseases ultimately relapse. Complications of DLI include acute and chronic graft-vs-host disease (GVHD) and aplasia, which induce profound immunosuppression and susceptibility to opportunistic infections. There is a strong correlation of GVHD and disease response.
Other hematologic malignancies do not respond to DLI as well as early-stage CM. In general, less than 30% of patients with relapsed acute leukemia,myelodysplasia, and multiple myeloma achieve complete responses to DLI. As many close to half or more of patients who do achieve a complete response may be expected to relapse after DLI. DLI has been researched as a treatment for a variety of hematologic malignancies, including most prominently chronic myeloid leukemia, but also acute myeloid leukemia, acute lymphocytic leukemia, multiple myeloma, myelodysplastic syndromes, chronic lymphocytic leukemia, Hodgkin’s disease, and non-Hodgkin’s lymphoma. Studies are limited due to small numbers but they have provided evidence that DLI can establish a graft-versus-leukemia/lymphoma effect.

Chronic lymphocytic leukemia (CLL) also appears to be responsive to allogeneic donor T cells.However, clinical expereince is limited.  Some patient have obtained a remission following DLI as treatment of persistent disease following alloBMT. Other CLL patients have obtained complete remissions, including molecular complete remissions, following discontinuation of posttransplant immunosuppression. However, there is not much literature credibly supporting routine use of DLI for CLL.

AVN944

Lay Summary: AVN-944 is reviewed.

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

PET for lymphomas

Although CT remains the gold standard for the staging and follow-up of malignant lymphomas, 18F-FDG PET has a potential role in accurately staging disease and in predicting response to therapy. This role has the potential to affect both the initial choice of chemotherapy and the decision to alter management based on the initial response to therapy . PET performed early in a chemotherapeutic regimen has demonstrated a role in identifying patients who will experience relapse and may require further treatment, but attention to the timing of the scan in relation to chemotherapy and growth factors is crucial. Many studies have used subjective grading systems to assess response and have evaluated progression-free survival on the basis of negative or positive findings on follow-up scans. Further studies should focus on measuring response on the basis of SUV: Determining a cutoff value when assessing the percentage of change in SUV may improve the prognostic value of interim PET. Because most studies have shown variable SUVs among both aggressive and indolent lymphomas, the usefulness of a follow-up scan hinges on the existence of a pretherapy scan demonstrating 18F-FDG–avid disease. The role of 18F-FDG PET for indolent lymphomas, like CLL, remains unclear, and further studies have to be designed to investigate the role of PET for specific histologic types.

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

PET to"fish" for a diagnosis

Lay Summary: PET should not be used to "fish" for a diagnosis. On the other hand, when a pathological diagnosis is already established, PET can be useful for follow-up, staging and reassessment after therapy.

PET scanning is an excellent modality to assess tumor size and metabolic activity and it is coming into wider use as supporting data becomes avaialble for various tumor types. Unfortunately, there is no literature to support use of PEt to "fish" for diagnosis when no histologic diagnosis has been obtained. Since lymphadenopathy can be caused by a variety of conditions with different degree of gadolinium uptake and different specificites, sensitivities and accuracies, PET is potentially msileading and even harmful when used in this fashion. A NCT00068146 study is looking at a related question:  the usefulness of FDG-PET scanning in distinguishing autoimmune lymphoproliferative syndrome (ALPS) from lymphoma. Much more investigation will neeed to be done before PET can be used to disitnguish different types of lymphadenopathies.

Ref: http://clinicaltrials.gov/show/NCT00068146

Cook GJR, Fogelman I, Maisey MN. Normal physiological and benign pathological variants of 18-FDG PET scanning: potential for error in interpretation. Sem Nucl Med 1996;26:308–14

Allogeneic transplant for CLL

Lay Summary: Allogeneic transplantation is finding a place in the treatment of young patients with CLL.

Patients with low-grade non-Hodgkin's lymphoma (NHL) have a median survival of 4-8 years from diagnosis and a cause-specific survival of about 10 years. Radiotherapy can be curative in a small proportion of patients with very localized disease, but the majority of patients have advanced disease at diagnosis and it is not clear that any current therapy is curative in this situation. While in many instances patients with high-grade NHL are cured by chemotherapy, those with low-grade NHL, despite impressive response rates, almost invariably relapse. A 'watch-and-wait' strategy can therefore delay the onset of chemotherapy by 2-3 years, without affecting survival. Results with autologous stem cell transplantation have been similarly disappointing to date. Rituximab is a human-mouse chimeric monoclonal antibody that represents a novel approach to treatment of low-grade NHL, targeting malignant cells without the side effects associated with chemotherapy. A pivotal study has demonstrated a response rate of 56% in relapsed or refractory low-grade NHL. The relatively benign side-effect profile means rituximab can be used early in the disease process, and in combination with chemotherapeutic regimens and autologous transplantation.

Allogeneic transplantation has been increasingly utilized in patients with lymphoid malignancies but is associated with high toxicity. Recently, reduced-intensity conditioning regimens have shown encouraging results, attributed to graft-versus-lymphoma effects. The use of recently introduced reduced-intensity and truly nonmyeloablative conditioning regimens has shifted some or all of the burden of tumor-cell kill from the conditioning regimens to the graft-versus-tumor effects. These regimens are less toxic than conventional regimens and allow for the treatment of older patients and patients with comorbid conditions. Early experience with high-dose chemoradiotherapy and allogeneic SCT in patients with heavily pretreated disease demonstrated high non-relapse mortality rates (10% to 40%), but the suggestion of plateau on survival curves. Recent data available on 38 patients who had undergone transplantations from unrelated donors from the National Marrow Donor Program revealed a 5-year failure-free survival rate of 32%. Sorror et al32 recently reported the outcome of 64 patients with advanced CLL who were treated with nonmyeloablative conditioning consisting of 2 Gy of total body irradiation with (n = 53) or without (n = 11) fludarabine from related (n = 44) or unrelated (n = 20) donors. The median age was 56 years, and the median interval between diagnosis and transplantation was 4.4 years. There was a median of 4 prior treatment regimens, and chemotherapy resistance to pretransplantation salvage treatment was present in 53% of patients. The incidence of acute II–IV GVHD was 61%. The 2-year estimated OS and DFS rates were 60% and 52%, respectively.

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 guidelines state: "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.

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

Current treatment of follicular and low-grade non-Hodgkin's lymphoma. Anticancer Drugs. 2001 Jun;12 Suppl 2:S5-9.

Carol Moreno, Neus Villamor, Dolors Colomer, Jordi Esteve, Rodrigo Martino, Josep Nomdedéu, Francesc Bosch, Armando López-Guillermo, Elías Campo, Jorge Sierra, Emili

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;

Revlimid for Chronic lymphocytic leukemia

Lay Summary: Revlimid is promising but still experimental for CLL.

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 treatmetn of multiple myeloma in conjunction with dexamethasone. Revlimid is in clinical trials for the evaluation of treatment for other hematologic cancers including CLL.

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.

Many studies are now underway to evaluate the activity of Revlimid in combination with rituximab in patients with lymphoma. The initial analysis of the first 46 patients of a 200 patient
phase-II, multi-center open-label clinical study, NHL-003, shows
encouraging results that are consistent with those of the earlier
NHL-002 trial (Abstract #2565). Responses were seen across all
sub-types of NHL. Furthermore, prognostic factors have been identified
that may be predictive of response to REVLIMID monotherapy. The study reported that overall response to single agent lenalidomide was 28%, with 6 responses in the diffuse large B-cell lymphoma group (21%) and 5 in the mantle cell lymphoma group (38%). Ten patients had stable disease (SD). This was reported at ASH in December 2007.

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.