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

R-MCOP for lymphoma

The aging of the population and the increased incidence of non-Hodgkin's lymphoma will result in a large number of elderly patients with this disorder. Newer therapies will be required for this group of patients. One common modification is substituting Novantroen for Doxorubicin in the standard CHOP or R-CHOP regimen. This produces less cariotoxicity which is a particular problem for the elderly.

Mitoxantrone was evaluated in combination with other agents for the treatment of NHL. A total of 28 patients were treated with different regimens. A first-line comparative trial of the combination of intermediate dose methotrexate with leucovorin rescue + bleomycin + doxorubicin + cyclophosphamide + vincristine + dexamethasone (m-BACOD) versus the same combination with 10 mg/mmitoxantrone replacing doxorubicin (m-BNCOD) has shown activity: 4 PR's in 6 evaluable patients with m-BNCOD and 3 PR's in 6 with m-BACOD. The combination of mitoxantrone at 10 mg/m daily for 3 days, + vincristine + dexamethasone (NOD) produced 3 PR's in 5 evaluable patients. A first-line comparative trial of the combination of cyclophosphamide + vincristine + prednisone + doxorubicin (CHOP) versus the same combinations with 10 mg/mmitoxantrone replacing doxorubicin (CNOP) showed equivalence.

R-CHOP is now standard of care for diffuse large cell lymphomaas and follcular lymphomas. The substituion is supported by a randomized study referenced below. These dose-reduced regimens can be given with nearly 100% dose intensity with 65% of patients completing all the treatment. Survival is comparable to that observed with the more intensive regimens given in this age group.Although Rituxan ahs not been sepcifically proven with MCOP regimen, since ti is aprt of the standrd R-CHOP and the CHOP part is equivalent to MCOP ro CNOP, addition of Rituxan should not deem R-MCOP to be experimental

Bessell EM, Burton A, Haynes AP, Glaholm J, Child JA, Cullen MH, Davies JM, Smith GM, Ellis IO, Jack A, Jones EL; Central Lymphoma Group UK.A randomised multicentre trial of modified CHOP versus MCOP in patients aged 65 years and over with aggressive non-Hodgkin's lymphoma.Ann Oncol. 2003 Feb;14(2):258-67.

nccn.org, lymphoma

How long to PET after remission of lymphoma

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.

In regard to followup, a recent study showed that a negative PET scan after completion of therapy does not exclude the presence of residual microscopic disease and does not indicate complete remission. The majority of studies evaluating FDG-PET in lymphoma include patients with diffuse large B-cell non-Hodgkin’s lymphoma (NHL) or Hodgkin’s disease. There are limited data available on the role of PET in other histologies.

A negative PET scan at the end of therapy appears to provide favorable prognostic information. Persistently positive PET scans at the end of therapy, or in follow-up, warrant close follow-up or additional diagnostic procedures, since some of those patients may remain in prolonged remission.

The Imaging Subcommittee of the International Harmonization Project (IHP) in Lymphoma developed guidelines for performing and interpreting positron emission tomography (PET) for treatment assessment in patients with lymphoma. The new recommendations, targeting both clinical practice and clinical trials, are published in the January 22 Early Release issue of the 2007 al of Clinical Oncology. They are based on experts' consensus and not randomized evidence.

Specific recommendations related to followup are:

After treatment completion, PET should be performed at least 3 weeks, and preferably 6 to 8 weeks, after chemotherapy or chemoimmunotherapy, and 8 to 12 weeks after radiation or chemoradiotherapy. Noncontrast PET/CT can be used instead of contrast-enhanced diagnostic CT to follow-up patients with lymphoma, although patients with hepatic or splenic involvement should continue to receive contrast-enhanced diagnostic CT. Attenuation-corrected PET is much preferred over nonattenuation-corrected scans.

In regard to this case, I consider the PET to be medically necessary ONCE. This is because PET after the initial post-therapy PET is not recommended by NCCN, is not recommended specifically for T-cell histology and the duration of PET followup after remission is not well defined in guidelines.

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

Lavely WC, Delbeke D, Greer JP, Morgan DS, Byrne DW, Price RR, Hallahan DE, G PET in the follow-up management of patients with newly diagnosed Hodgkin and non-Hodgkin lymphoma after first-line chemotherapy.Int J Radiat Oncol Biol Phys. 2003 Oct 1;57(2):307-15.

Jonathan W. Friedberg, Vaseem ChengaziPET Scans in the Staging of Lymphoma: Current Status The Oncologist, Vol. 8, No. 5, 438–447, October 2003

J. W. Fletcher, B. Djulbegovic, H. P. Soares, B. A. Siegel, V. J. Lowe, G. H. Lyman, R. E. Coleman, R. Wahl, J. C. Paschold, N. Avril, et al.
Recommendations on the Use of 18F-FDG PET in Oncology
J. Nucl. Med., March 1, 2008; 49(3): 480 - 508.

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.

Gemzar and Navelbine salvage for lypnoma

Gemcitabine, vinorelbine and prednisone or otehr drugs are being investigated to treat refractory or relapsed aggressive non-Hodgkin lymphomas (NHL).
Lay Summary: Gemcitabine and vinorelbine are somewhat effective but toxic when few options remain, but more investigation is needed.

The optimum therapy for patients with relapsed or refractory aggressive NHL not qualifying for platinum-based and/or high-dose chemotherapy is not known. In one  prospective phase II study evaluating a regimen consisting of gemcitabine (1 g/m2, days 1 and 8), vinorelbine (30 mg/m2, days 1 and 8) and prednisone (100 mg/day, days 1-8) (GVP) given every 21 days, there was substantial activity in poor prognosis relapsed or refractory aggressive lymphomas. It was generally well tolerated, but haematological toxicity is dose limiting. Several other studies yilded similar results.

One has to conclude that despite these results the treatment is still experimental as it is being studies in various studies with otehr agents added and a prospective phase III trial is necessary.

Efstathios S. Papageorgiou, Panagiotis Tsirigotis, Meletios Dimopoulos, Nikolaos Pavlidis, George Fountzilas, Sotirios Papageorgiou, Theofanis Economopoulos (2005)  Combination chemotherapy with gemcitabine and vinorelbine in the treatment of relapsed or refractory diffuse large B-cell lymphoma: a phase-II trial by the Hellenic Cooperative Oncology Group European Journal of Haematology 75 (2), 124–129.

A. Spencer, K. Reed and C. Arthur. (2007) Pilot study of an outpatient-based approach for advanced lymphoma using vinorelbine, gemcitabine and filgrastim. Internal Medicine Journal 37:11, 760–766

Fatih M. Uckun, Sanda Morar and Sanjive Qazi. (2006) Vinorelbine-based salvage chemotherapy for therapy-refractory aggressive leukaemias. British Journal of Haematology 135:4, 500–508

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

Umbilical cord stem cells

Lay summary: Cord stem cells have been shown to be equivalent to other allogeneic cells for transplantation in leukemia but not yet for other diagnoses.

Cord blood transplatation ifs a fairly recent but rapidly becoming established technique for transplnatation in leukemia. The first unrelated cord blood transplantations were performed in children. The first 25 unrelated cord blood transplantations were reported in 1996. Since then a number of reports appeared. This work has been followed by several studies, showing similar results in children. The New York Blood Center reported on 562 cases, 82% children, who underwent transplantation in a variety of centers with differing conditioning regimens and graft-versus-host disease prophylaxis. However, there have been retrospective matched pair analyses. Two studies in the New England Journal of Medicine reinforce the role of cord-blood transplantation in the treatment of leukemia in adults. Although this treatment is not recommended over HLA-matched donors from unrelated donor sources, it is a viable alternative that can be effective. (N Engl J Med. 2004;351:2255-2265, 2276, 2328). Although guidelines ahve not yet listed this alternative, more recent review articles and an editorial state that it is an equivalently effective approach, even in adults. Both reports reinforce the role of cord-blood transplantation in the treatment of adults with leukemia. It is realistic to anticipate that the current results for cord-blood transplantation in adults with hematologic cancers will contribute to more extended use in the coming years.

J. Aschan Allogeneic haematopoietic stem cell transplantation: current status and future outlook Br. Med. Bull., October 5, 2006; (2006)

Karen K. Ballen New trends in umbilical cord blood transplantation
Blood, 15 May 2005, Vol. 105, No. 10, pp. 3786-3792

Vikram Mathews, MD and John F. DiPersio, MD, PhD Stem Cell Transplantation in Acute Myelogenous Leukemia in First Remission: What Are the Options? Current Hematology Reports 2004,

Autologous stem cell transplantation for diffuse large cell lymphoma (NHL)

uLy Summary: NHL is currently the second most frequent indication for autologous hematopoietic stem cell transplantation. It is not a useful treatment option for all patients with NHL, but in certain circumstances, autologous stem cell transplantation does provide patients the best opportunity for cure.

Diffuse large-cell lymphoma is the most common form of NHL, and autologous stem cell transplantation has been shown to be beneficial in some subsets with this illness. For patients with diffuse large-cell lymphoma who relapse from a CR but remain chemotherapy-responsive, autologous transplantation is the treatment of choice. The most significant study supporting transplantation is the PARMA study by Philip et al. Patients were randomized to autologous stem cell transplantation versus conventional-dose chemotherapy with dexamethasone, high-dose cytarabine, and cisplatin (DHAP) if the patient responded to two initial cycles of DHAP. The event-free survival at 5 years was 46% for the transplant arm and 12% for the conventional therapy arm (p = 0.001). Overall survival was 53% for transplant and 32% for the conventional therapy group (p = 0.038). In addition to transplant being shown to be beneficial in this group of patients, additional analysis has demonstrated that an initial remission of fewer than 12 months is an adverse prognostic indicator.

There are also trials that have found contradictory results. Reyes et al. in the LNH93-3 trial randomized 370 patients to standard chemotherapy or autologous transplantation after an abbreviated standard-dose induction regimen. They found the 3-year event-free survival for the hematopoietic stem cell transplant group was 41% versus 54% for the standard therapy arm (p = 0.01). Overall survival was also in favor of standard therapy with 63% disease-free survival versus 47% in the transplanted group (p = 0.003) [62]. A trial by Verdonck et al. randomized 69 patients who had achieved a partial response to cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) to additional CHOP or autologous bone marrow transplantation. The 4-year event-free survival was 53% for the CHOP arm and 41% for the transplantation arm. Disease-free survival at 4 years was 72% for the CHOP group and 60% for transplantation. The reason for the disrepancy is not well understood but these were smaller studies than the PARMA study.

At the present time, high-risk patients who achieve a CR after a full course of standard-dose chemotherapy and have a high risk for relapse may derive the most benefit from stem cell transplantation. The second accepted group is those who evidence chemoresponsiveness after relapse and this is stated in the NCCN guidelines. No additional trials are planned and the Parma results have been accepted as standard therapy.

H. Bertz, R. Zeiser, W. Lange, S. Fetscher, C. F. Waller, and J. Finke
Long-term follow-up after high-dose chemotherapy and autologous stem-cell transplantation for high-grade B-cell lymphoma suggests an improved outcome for high-risk patients with respect to the age-adjusted International Prognostic Index
Ann. Onc., September 1, 2004; 15(9): 1419 - 1424.

M. D. Caballero, J. A. Perez-Simon, A. Iriondo, J. J. Lahuerta, J. Sierra, J. Marin, M. Gandarillas, R. Arranz, J. Zuazu, V. Rubio, A. Fernandez de Sevilla, E. Carreras, J. Garcia-Conde, J. Garcia-Larana, C. Grande, A. Sureda, M. J. Vidal, J. Rifon, C. Perez-Equiza, R. Varela, J. M. Moraleda, J. C. Garcia Ruiz, C. Albo, R. Cabrera, J. F. San Miguel, and E. Conde
High-dose therapy in diffuse large cell lymphoma: results and prognostic factors in 452 patients from the GEL-TAMO Spanish Cooperative Group
Ann. Onc., January 1, 2003; 14(1): 140 - 151.

S. A. Mink and J. O. Armitage
High-Dose Therapy in Lymphomas: A Review of the Current Status of Allogeneic and Autologous Stem Cell Transplantation in Hodgkin's Disease and Non-Hodgkin's Lymphoma
Oncologist, June 1, 2001; 6(3): 247 - 256.

Angioimmunoblastic T-cell

Angioimmunoblastic T-cell lymphoma (AILD) is considered a variety of T-cell lymphoma, which usually occurs in adults.   Patients present with profound lymphadenopathy, fever, night sweats, weight loss, skin rash, a positive Coomb's test, and polyclonal hypergammaglobulinemia. It is quite rare and no standrd approach has beend efined.   Angioimmunoblastic T-cell lymphoma was formerly called angioimmunoblastic lymphadenopathy with dysproteinemia. Characterized by clonal T-cell receptor gene rearrangement, this entity is managed like diffuse large cell lymphoma. Opportunistic infections are frequent due to an underlying immune deficiency. Doxorubicin-based combination chemotherapy is recommended as it is for other aggressive lymphomas. Myeloablative chemotherapy and radiation therapy with autologous peripheral stem cell support has been described in anecdotal reports. Occasional spontaneous remissions and protracted responses to steroids only have been reported. A few patients may progress to an EBV-positive diffuse large B-cell lymphoma. I have not found any studies reporting the use of autologous SC for this entity. A recent (2006) retrospective review of ASCT in T-cell lymhomas reported good results in 6 angioimmunoblastic lymphoma patients. All angioimmunoblastic T-cell lymphoma (AILT) and subcutaneous panniculitis-like T-cell lymphoma (SPTCL) patients achieved CR; 5 of 6 have remained disease free for more than 3 years. However, this is a very small sample.

A search of current trials reveals a variety of investigtional approaches to this disease, including stem cell transplant in second remission.

http://clinicaltrials.gov/ct/search?term=%22T-cell+lymphoma%22+%5BCONDITION%5D+AND+angioimmunoblastic+%5BALL-FIELDS%5D&submit=Search

Reimer P, Schertlin T, Rüdiger T, et al.: Myeloablative radiochemotherapy followed by autologous peripheral blood stem cell transplantation as first-line therapy in peripheral T-cell lymphomas: first results of a prospective multicenter study. Hematol J 5 (4): 304-11, 2004.

Pautier P, Devidas A, Delmer A et al. Angioimmunoblastic-like T-cell non Hodgkin's lymphoma: outcome after chemotherapy in 33 patients and review of the literature. Leuk Lymphoma 1999; 32: 545–552

Yamazaki T, Sawada U, Kura Y, et al.
Treatment of high-risk peripheral T-Cell lymphomas other than anaplastic large-cell lymphoma with a dose-intensified CHOP regimen followed by high-dose chemotherapy
ACTA HAEMATOLOGICA 116 (2): 90-95 2006