Aggressive Transformation

There is much confusion about aggressive transformation in chronic lymphocytic leukemia (CLL). Unlike chronic myeloid leukemia where such a transformation is the rule, in CLL it is rare. Moreover, transformation to acute lymphoblastic leukemia (ALL), although reported in the literature,1 is a myth based on a misunderstanding of the nature of CLL. We can, however, recognize different ways in which CLL can transform (Table 27.1).

RICHTER'S SYNDROME Incidence

In 1928, Maurice Richter described an aggressive lymphoma occurring in a patient with CLL.2 Richter's syndrome is now recognized as a rare but regular culmination of CLL. In the largest series of cases, Robertson et al.3 reported 39 patients with Richter's syndrome among 1374 with CLL (2.8%). The accuracy of this estimate of prevalence is not clear. Patients with CLL are often elderly when diagnosed, and elderly patients dying of disseminated cancer may never have the type of cancer elucidated. This point was emphasized by a series of 1011 patients from Rome.4 There were 12 cases of Richter's syndrome among the 207 aged under 55 years (5.9%), but only 10 among the 807 cases over 55 (1.2%). As the authors stated, "the rate of lymphomas in the old age group is possibly underestimated, because very old patients with advanced and unresponsive disease are not always submitted, for ethical reasons, to surgical biopsies." On the other hand, both the MD Anderson Cancer Center and the University "La Sapienza" in Rome are special places that attract the most difficult cases. It is probable that nonprogressive, uncomplicated cases of CLL not requiring treatment are underrepresented in both series and that Richter's syndrome is even rarer than has been reported.

Definition

It has been accepted that any type of aggressive lymphoma occurring in a patient with CLL may be called Richter's syndrome. Thus, cases of diffuse large B-cell lymphoma, Hodgkin's disease,5 and even high-grade T-cell lymphoma6 have received that appellation.

Clinical features

Richter's transformation is often characterized by sudden clinical deterioration and development of systemic symptoms of fever and weight loss.3 There is usually a rapid enlargement of lymph node masses, especially of retroperitoneal lymph nodes. Hepatomegaly and splenomegaly are common, and extranodal disease is often seen. A rise in serum lactate dehydrogenase is usual, and in nearly half the patients, a monoclonal immunoglobulin can be detected. Hypercalcemia may be seen and this may or may not be accompanied by lytic bone lesions.

Pathogenesis

It is clear that there are at least two separate phenomena involved: the first is a true transformation to a clonally related, aggressive lymphoma, and the second is the occurrence of a clonally unrelated, new tumor, perhaps because of diminished immune surveillance.

Clonally related tumors The relationship between CLL and aggressive lymphoma was originally tested by examining the light-chain type of the surface immunoglobulin,7 but this is not sufficient to either confirm or refute an origin from a single clone, and subsequent studies have used a combination of immunophenotyping,8 karyotyping,9 fluorescent in situ hybridization,10 restriction fragment length polymorphism analysis,11 reaction with anti-idio-typic antibody,12 and immunoglobulin variable

Table 27.1 Transformation of CLL

Richter's syndrome Clonally related Diffuse large cell lymphoma—B cell Hodgkin's disease Clonally unrelated EBV related Hodgkin's disease

Diffuse large-cell lymphoma—B cell Diffuse large-cell lymphoma—T cell EBV status unknown

Prolymphocytoid transformation Transient Stable Progressive

Acute lymphoblastic leukemia Blastic mantle cell lymphoma Mythologic region heavy-chain (IgVH) gene sequencing.13 The conclusion of these studies is that sometimes the two tumors are clonally related and sometimes they are not. An interesting study using IgVH gene sequencing showed that in five out of six patients whose CLL used unmutated IgVH genes, the diffuse large-cell lymphoma (DLCL) clone evolved from the CLL clone, whereas in the two CLL patients whose disease used mutated IgVH genes, the DLCL clone was unrelated to the CLL clone.13

With the recognition that Hodgkin's disease is a tumor of B cells, it is perhaps less surprising than would have been thought a decade ago that Reed-Sternberg cells should have an identical IgH CDRIII sequence to that of the CLL cells in two out of three cases of Hodgkin's disease supervening in CLL.14 A remarkable case was investigated by van den Berg et al.15 in which histology demonstrated a composite lymphoma consisting in part of small-cell lymphoma, in part Hodgkin's disease, and in part anaplastic large-cell lymphoma. All three tumors were clonally related. The CLL component was CD5 negative.

Clonally unrelated tumors If the second lymphoid tumor is not clonally related, is it any more than part of the spectrum of second cancers long been believed to occur in patients with CLL?16 Among more recent studies, Davis17 found a relative risk for second lymphoid tumors of 4.5 and for nonlymphoid tumors of 2.3 among 419 patients with CLL in Washington. Travis18 analyzed data for 9456 patients with CLL from the National Cancer Institute's Surveillance, Epidemiology, and End results (SEER) program. The observed over expected (O/E) ratio for second malignancies was 1.28 (confidence intervals [CI] 1.19-1.37). Significant excesses were found for cancers of the lung and brain, melanoma (including intraocular melanoma), and

Hodgkin's disease. A Danish study of 7391 patients again found standardized incidence ratios of 2.0 for men and 1.2 for women for second malignancies.19 Increased risks were found for carcinoma of the kidney, nonmelanomatous skin cancer and sarcoma for both sexes, and lung and prostate cancer for men. A more recent evaluation of the SEER program,20 now totaling 16,367 patients, found a standardized incidence ratio for second malignancies of 1.2 (CI 1.15-1.26), with significant excesses for Kaposi's sarcoma (O/E 5.09) and melanoma (O/E 3.18) and cancers of the larynx (O/E 1.72) and lung (O/E 1.66). In men, brain cancers were more common (O/E 1.91), and in women cancers of the stomach (O/E 1.76) and bladder (O/E 1.52) were commoner.

These figures need to be interpreted with caution. In many series, cancers diagnosed concurrently with or before the CLL are included. Since CLL is diagnosed as an incidental finding in 75% of cases and is clinically silent in a large proportion of patients, there is an inbuilt bias in favor of diagnosing CLL in cancer patients who have more blood tests than the general population. Patients with cancer are often nonspecifi-cally unwell before the diagnosis of cancer is made and will have blood tests to investigate this, with the result that the inconsequential CLL is diagnosed before the cancer reveals itself. In addition, patients with CLL are seen more frequently by doctors than members of the general population, and other cancers are more readily detected.

It is also possible that treatment of CLL, particularly with alkylating agents, predisposes the patient to the development of a second malignancy. This may account for the higher incidence of bladder cancer among women in the latest SEER analysis. Some excesses in specific tumors may be the consequence of data dredging, especially if the tumor excess is confined to one sex.

One important question is whether the immunodeficiency of CLL is what that leads to second malignancies. Kaposi's sarcoma is a disease of impaired immunity, and both melanomas and renal cell cancers are tumors known to be influenced by the immune system. It is also likely that the excess of lymphomas is mediated by the immune deficiency. However, apart from these, any increase in second cancers may be more apparent than real.

The suspicion that clonally unrelated lymphomas occurring in CLL might be virally induced was raised by Momose et al.21 Occasionally, apparent Reed-Sternberg cells can be found scattered among the small lymphocytes in the lymph node histology of CLL. Among 13 cases where these were found, Momose et al. detected Epstein-Barr virus (EBV) RNA in 12 by in situ hybridization. Three of these cases later developed disseminated Hodgkin's disease. Rubin et al.22 studied two cases of Richter's syndrome with Hodgkin's disease characteristics in which they found EBV DNA in the lymph nodes using the polymerase chain reaction (PCR) and EBV

latent membrane protein (LMP) in the Reed-Sternberg cells by immunohistochemistry.

Matolcsy et al.23 found EBV genome integration in the DLCL component but not the CLL component of a case of Richter's syndrome where the clones were unrelated. Petrella et al.24 reported two further cases where EBV could be detected in Reed-Sternberg cells by in situ hybridization. A Japanese case was reported by Otsuka et al.25 in which EBV nuclear antigen and LMP could be detected in the DLCL cells and in situ hybridization revealed the presence of EBV-encoded small RNA. Ansell et al. studied 25 patients with Richter's syndrome presenting to the Mayo Clinic.26 Four showed evidence of EBV in the DLCL cells: three with a B-cell phenotype were positive for LMP, and EBV DNA and RNA, and one with a T-cell phenotype was positive for EBV RNA. Six further cases (four from Italy and two from Belgium) of Hodgkin's disease supervening on CLL all support the hypothesis that this is often an EBV-driven event.27 28 In a delicate study using single-cell PCR, Kanzler et al.29 enunciated the principle that Hodgkin's disease may be clonally unrelated to the CLL, in which case it is driven by EBV, but in rare cases it is clonally related to the CLL and in these cases EBV cannot be detected. The same may be said for DLCL, though cases with a T-cell immunophe-notype are presumably always clonally unrelated. The evidence for EBV involvement in Richter's syndrome is very sparse except in the case of Hodgkin's disease, and for the vast majority of cases of DLCL occurring in patients with CLL, there is no information as to patho-genesis.

That lymphomas may arise from EBV-driven clones in CLL questions the wisdom of treating CLL with agents that reinforce the already-present immunodeficiency, especially in patients without poor prognostic factors. Agents such as fludarabine and alemtuzumab are potent immunosuppressants and their use may lead to EBV reactivation.30

Treatment

Richter's syndrome has a poor prognosis. A study of 25 patients from France in 19815 reported a median survival of 4 months and a complete remission rate following intensive chemotherapy of 24%. Seventeen years later a survey of the experience of the MD Anderson Cancer Center in Houston31 found a median survival of 6 months. There have been no large-scale studies of treatment of Richter's syndrome, but the MD Anderson reported two phase II studies of combination chemotherapy regimens. The first32 described the use of hyper-CVXD (fractionated cyclophosphamide, vincristine, DaunoXome, and dexamethasone) in 29 patients. Although there were 11 complete responses, they were mostly short lived. There was a treatment-related mortality of 20% during the first course of therapy, and the median survival was only 10 months. The second trial33 was of the combination of fludara-

bine, cytarabine, cyclophosphamide, cisplatin, and granulocyte-macrophage colony-stimulating factor in 15 patients with Richter's syndrome together with a small number of other patients with refractory low-grade lymphomas. Only one patient achieved a complete remission, and there was considerable toxicity.

Despite these dismal results, there have been anecdotal reports of good responses to conventional chemotherapy for both the Hodgkin's and non-Hodgkin's varieties of Richter's syndrome.34-36 Allogeneic stem cell transplantation has been reported in eight patients, three of whom were alive at 14, 47, and 67 months.37 An interesting patient was reported by Espanol et al.38 Richter's syndrome developed in a patient 4 months after an allogeneic stem cell transplant for CLL. Complete remission and full donor chimerism was obtained by withdrawal of immunosuppression and donor lymphocyte infusions.

PROLYMPHOCYTOID TRANSFORMATION Definition

Prolymphocytes are large lymphocytes, some 10-15 ^m in diameter compared to 7-10 ^m for CLL cells. They have round or indented nuclei with chromatin that is less dense than that of CLL cells, but more dense than that of lymphoblasts. They possess a single prominent nucleolus. The cytoplasm is more abundant than that of a typical CLL cell, and in Romanowsky-stained specimens it is pale blue and agranular. Although small numbers of prolymphocytes are usually found in CLL, there is a distinct B-cell prolymphocytic leukemia (PLL) that is completely unrelated to CLL. Clinically, splenomegaly without lymphadenopathy is the rule, but it is defined by the presence of >55% circulating prolymphocytes.39 It is immunophenotypi-cally distinct, with strong positivity for surface immunoglobulin, CD20, CD22, CD79b, and FMC7, while it is negative for CD23 and mouse rosettes. The reaction with CD5 is controversial. Most cases are CD5 negative, but perhaps 20% are CD5 positive. This may be explained by the discovery of a splenomegalic form of mantle cell lymphoma with t(11;14) that morphologically resembles PLL.40'41

Prolymphocytoid transformation of CLL was first reported by David Galton's group at the Royal Postgraduate Medical School in London.42 It was specifically noted that the cells retained the immunopheno-type of CLL cells. In a series of papers,43-46 the Galton Group defined typical CLL as having <10% prolymphocytes and CLL/PLL as those cases with between 10 and 55% prolymphocytes. Although as a group patients with CLL/PLL had more surface immunoglob-ulin than those with typical CLL, there was no sudden transition from a lower density at an earlier stage of the disease, and the immunophenotype of small and large cells was indistinguishable.

Contrary to the common perception, in a study of 55 cases of CLL/PLL,44 half showed a stable picture without a progressive increase in prolymphocytes. The prognosis of this group was similar to that of stable CLL without prolymphocytes. In one-third of cases, the increase in prolymphocytes was unsustained, and in only 18% was there a definite progression toward a more malignant phase of the disease. In a multivariate analysis of prognostic factors in CLL/PLL, only an absolute number of prolymphocytes and spleen size were of independent prognostic significance. The median survival for patients with prolymphocytes >15 X 109/L was 3 years.39

Karyotype

Cellular morphology seems to be closely related to karyotype. In a study of 544 patients, Matutes et al.47 found trisomy 12 in 18%. Thirty-one percent of these had CLL/PLL compared to 10% of the whole series. Subsequent studies have shown that such atypical morphology is also associated with a deletion at 6q2148 and t(14;19) translocations,49 both of which are associated with an adverse prognosis. Even more significantly, 80% of patients with p53 abnormalities have CLL/PLL morphology.50

Oscier et al. found evidence of karyotypic evolution in 16% of 112 patients with CLL studied by sequential cytogenetic studies.51 Finn et al. found a higher incidence of 43% in 51 patients.52 The most common extra abnormality was a structural abnormality of 6q21. Bea et al. found sequential increases in chromosomal abnormalities in six out of ten patients with Richter's transformation or other types of clinical progression.53

Treatment may induce evolution. It may be thought of as a selective pressure-inducing change. Just as antibiotics can select for drug-resistant bacteria, similarly chemotherapy may kill only the susceptible cells, allowing drug-resistant cells to regrow. These may be morphologically more extreme, karyotypically different, and may express greater amounts of CD38.54

Implications for management

Merely finding increased numbers of prolymphocytes in the blood is not necessarily an indication of transformation of CLL. The increase may be transient, indicative of a recent infection or other unknown event. Some karyotypic abnormalities (such as trisomy 12) are associated with >15% circulating prolymphocytes; yet these patients may remain stable for many years. Increasing numbers of prolymphocytes and karyotypic evolution usually have a poor prognosis. Most authors have been unable to attach an independent prognostic effect to deletions at 6q21, but acquisition of p53 abnormalities at 17p13 carries the worse possible prognosis.55-57 This is often associated with morphologic change (prolymphocytoid transforma-tion50 or Richter's syndrome53) and drug resistance.58

The indications for treatment in CLL/PLL are the same as those for CLL itself: systemic symptoms and bone marrow failure. The presence of prolymphocytes should raise the possibility of abnormalities of the p53 pathway, indicating potential drug resistance and a call for nonstandard therapy, such as alemtuzumab or high-dose methylprednisolone.

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