incidence of MDS - Is the treatment worse than the disease?

[Guest guest]

A bit dated, but still relevant, I think ... the writer providing a

well-balanced discussion of risks and benefits of transplant therapy for the

lymphomas.

===

Blood, 1 March 2003, Vol. 101, No. 5, pp. 1666-1667

Is the cure worse than the disease?

No, it isn't. The worrisome observations of the delayed development of

t-MDS/AML in some lymphoma patients after HDC and AHSCT should not obscure

the overall success of this procedure in selected patients.

That said, t-MDS/AML is the serious nonrelapse problem in these patients,

and efforts to identify risk factors that would reliably identify patients

at high risk of developing t-MDS/AML would be beneficial, both in focusing

increased study of such patients and potentially, to develop therapies to

decrease the impact of this (currently) very lethal complication.

The report of Metayer and colleagues in this issue (page 2015) adds to a

growing, if inconsistent, literature regarding risk factors. Using detailed

data from 12 institutions in the Autologous Blood and Marrow Transplant

Registry, they performed a case-control study using 56 patients who

developed t-MDS/AML and 168 matched control patients from a larger group of

2739 lymphoma patients receiving transplants at these centers over 6 years.

.... The cumulative incidence of t-MDS/AML was 3.7% at 7 years. (For unclear

reasons, this is lower than reported in other published series, and it would

be unrealistic to state that the " true incidence " is known with certainty.)

In multivariate analysis, exposure to certain alkylating agents with a known

leukemogen pedigree (especially nitrogen mustard and chlorambucil, with

notation of a dose effect), as well as conditioning regimens that included

TBI, but only at doses of 1320 cGy, were associated with a statistically

significant increased risk of developing t-MDS/AML.

The use of reconstituting cells from either steady-state or

mobilized blood was associated with an increased risk as well, albeit a

non-significant one. Thus, both pre-transplantation and

transplantation-related factors were implicated.

The authors are to be commended for this effort, which clearly gives

additional direction to strategies or techniques that might decrease this

risk. That said, significant limitations of this study must be acknowledged;

to a large degree, these limitations are generic to studies evaluating " late

events " that require prolonged follow-up for delineation in a field in which

evolutionary therapy changes are routine.

.... For example, this analysis includes both Hodgkin and the non-Hodgkin

lymphomas, whereas other series focused on one or the other, in the main.

This obviously may have implications on the specific therapy given and the

contribution to the MDS/AML.

Also, the routine use of the nitrogen mustard, chlorambucil, and perhaps

other suspect drugs has been greatly curtailed in the past decade, as the

CHOP and ABVD regimens have become standards of care for many non-Hodgkin

and Hodgkin lymphoma patients, respectively.

.... In the same context, the use of local radiotherapy (a potential

contributor exonerated in this analysis) as either primary therapy or as an

adjunct to the above or similar regimens appears to be declining. Also, the

use of TBI is not considered critical and may also be declining in use.

Thus, the warning about these specific agents arrives as the danger is

receding.

In contrast, the issue of potential increased risk from the use of

reconstituting cells obtained from the blood is more complex; this technique

has almost fully supplanted marrow harvest in autotransplantation and has

been the standard of care for nearly a decade.

Since the main advantages of using mobilized blood reconstituting cells are

usually not reflected onto major outcome parameters, further delineation of

this point is critical to ensure we are not increasing t-MDS/AML by the use

of this technique.

What lessons can be learned from this experience? First, a prolonged period

of observation of patients is necessary to delineate late complications such

as t-MDS/AML.

Next, before we breathe a sigh of relief at the passing of the routine use

of agents such as the nitrogen mustard and chlorambucil, we may get another

chance to revisit this situation as long-term effects of increased use of

topoisomerase-II inhibitors and possibly radioimmunotherapies are assessed.

In addition, we will need to become more facile at being able to identify

high-risk patients on an individual rather than a population basis;

conventional cytogenetics are clearly inadequate, but other techniques

(perhaps including FISH, SKY, or selective gene array studies) may be more

suitable.

Finally, however, we should again take note of the potency of the HDC/AHSCT

technique in lymphoma patients: thousands of such patients are alive today

because of this procedure; moreover, refinements of HDC/AHSCT---as well as

other strategies (eg, the use of reduced-intensity allografts)---may be

expected to further improve results.

.... Nonetheless, we must be vigilant to the development of t-MDS/AML using

our newer techniques and develop methods to identify, prevent, and/or treat

such patients early in their course.

---Gordon L. , II

University of Rochester Medical Center

All the best,

~ Karl

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